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Topical Review The Toxicology of Methyl Chloroform RICHARD D. STEWART, M.D., Midland, Mich. ethyl chloroform, 1,1,1-trichloroethane, Only minimal thermal decomposition may he M has become an increasingly popular sol induced at temperatures below 500F,; at 500F. vent in recent years because of its low toxicityla. rge amounts of hydrogen chloride and trace It has been used primarily for cold-cleaning, dip . amounts of phosgene are formed. Sufficient hy cleaning, and bucket-cleaning of metal for the drogen chloride is formed to provide adequate U removal of greases, oils, and waxes. Its use as a warning. . solvent in several other applications is being investigated, e.g., agricultural chemicals, ^dry- Absorption, Metabolism, and Excretion cleaning, and vapor degreasing. Because of its increasing use and since it has been promoted as a carbon tetrachloride substitute, it is appropri ate for the physician to examine the existing toxi cological information. The 1,1,2-isomer, a more toxic compound,1- has had only limited use in the laboratory and will not be included in the discussion to follow. 1,1,1-Trichloroethane is rapidly absorbed through the lungs and the gastrointestinal tract. It may be absorbed in toxic quantities throughthe intact skin if trapped against the skin beneath an impermeable barrier. Following absorption, most of the compound is eliminated unchanged via the lungs. Nearly 98% was excreted un changed in the expired air of the rat following an Physical and Chemical Properties intraperitoneal injection of C'Mabeled com pound. One-half per cent of the dose was metab 1.1.1-Trichloroethane, CH,CCI3, is a colorless liquid possessing a distinctive, chloroform-like odor. It has a specific gravity of 1.336 at 25C., olized to carbon dioxide while the remainder ap peared in the urine as the glucuronide of 2,2,2trichloroethanol. a vapor pressure of 127 mm. Hg at 25C., and a , boiling point of 74.1 tfC. This compound is readi ly soluble in organic solvents such as carbon bi- Toxicity Acute Vapor Exposure | sulfide and carbon tetrachloride, but it is only slightly soluble in water.1 Like many chlorinated hydrocarbons it reacts with aluminum and alu minum alloys and must be inhibited if corrosion is to be prevented. Inhibited formulations are marketed under various trade names. 1.1.1-Trichloroethane is not flammable, nor will it support combustion. The limits of flamma bility of the vapors of the inhibited compound are 10-15.5% in air with hot wire ignition only when considerable energy is used for ignition. It has no flash point or fire point using the stand ard ASTM procedures for the Tag closed-cup and Cleveland open-cup tests. The principal toxic action of a single vapor ex posure is a functional depression or the central nervous system, proportional to the magnitude of exposure, and typical of an anesthetic agent. Humans exposed to 900-1000 ppm experience transient, mild eye irritation and prompt, though minimal, impairment of coordination.1,8 Below the current Threshold Limit Value of 500. ppm no physiological effects" have been observed. Above 1700 ppm obvious disturbances of equilib rium in htlfnans have been observed.7 Exposures of this magnitude also may induce headache and lassitude. Nausea has not been reported. Anesthesia in a human volunteer was main Dr. Stewart lit with the Medical Research laboratory of tbe Dow Chemical Company. Submitted for publication Nor. It, 1963. tained uneventfully for 30 min. No significant electrocardiographic changes occurred during anesthesia; the blood pressure stabilized at 70? 409 'yw-*1 Hill SL 036601 i ,r`J STEWART 261 piagnosisof Exposure lo J, 1, l-Tricblbroclhnnc The diagnosis of exposure to 1,1,1-trichlorocthanc may be confirmed by detection of the compound in the expired air, blood,1 or tissue of the individual. If the exposure has been signifi cant, the compound will be present in the expired breath in sufficient concentration to allow spe liver insult following exposure. An increase in urinary urobilinogen lias been observed on tire seventh day following vapor exposures ranging from 900 to 2650 ppm.7 Other liver function studies, including the serum transaminases, re mained normal. The significance^ such a find-ing remains obscure, but this delayed elevation of the urinary Urobilinogen followingexposure to other chlorinated hydrocarbons has been ob cific identification by simple infrared spectro- served.15,17 graphic techniques in the immediate postexpo sure period,*113 Treatment The concentration in the expired air and in the blood is directly related to several factors: (1) There is no specific treatment for 1,1,1-trichlo- the concentration of. the vapor inhaled; (2) the roethane intoxication. Prompt supportive meas duration of exposure; (3) the time elapsed fol- ures should be utilized to combat the effects of lowing exposure; (4) the breathing rate of the central nervous system depression. Oxygen with individual during the exposure; and (5) the carbon dioxide should be administered. Breath whole-blood lipid concentration. The latter two ing should be assisted if the respiratory center Q factors account for most of the individual varia fails to, respond to the carbon dioxide stimula tion noted among persons who have experienced tion. identical exposures. For example, a vapor ex Severe hypotension may be induced by a com posure of 500 ppm for 1 hr. resulted in expireiair bination of central nervous system depression concentrations of 22 5 ppm in a group of indi and myocardial anoxia secondly-to poor oxygen viduals 1 hr. following exposure.7 This decreased uptake. Unless the situatidpirfS desperate, epi to 1.5 0.5 ppm, 20 hr. following exposure. nephrine must not be used to combat this hypo When the vapor exposure was extended to 3 hr., tension because of the danger of inducing ven the expired air concentration was in the range of tricular fib* illation. 38 1 ppm 1 hr. after exposure and 3 1 ppm It is hot anticipated that permanent organic in 20 hr, after exposure. Limited expired air data jury will result following recovery from the anes , . have been published.7 thetic effects of the compound. Expired air for infrared analysis may be col lected, in 6-L.-volume Saran bags. The bagged Summary air .is introduced into a long path-length gas cell and the absorbance at 9.2 fi is measured to deter-1 1,1,1-Trichloroethane (methyl chloroform), a / j mine the concentration. The exponential elimi popular solvent and carbon tetrachloride substi nation of the compound in the expired air may be tute, is rapidly absorbed through the lung? and ' A followed for a prolonged period of time with the the gastrointestinal tract ^pst of the compound use of the electron capture detector.15 While this is eliminated unchanged via the lungs. The ab device possesses exquisite sensitivity, it does lack sorption of a toxic quantity results in a functional the specificity of the infrared spectrographic method. depression of the central "nervous system which may result in death from respiratory arrest or Following a vapor exposure, the blood con peripheral vascular collapse. centration decreases exponentially and may not The diagnosis 'of exposure to this compound be detected by infrared methods7 unless the va may be confirmed by specifically identifying it. por concentration has approached anesthetic in the expired breath of the exposed person. Us levels. ing the.expired-air data, it may be possible to make a crude estimate of the magnitude of the Clinical Laboratory Tests exposure. Very limited lmmnn data have been published regarding laboratory test findings following ex posure to this compound. From the information available, it appears that the urinary urobilino No detrimental effect upon man has been ob-1 served when vapor exposures have not exceeded 500 ppm. The Dow Chemical Company Medical Research Laboratory gen excretion may be the most sensitive index of Midland, Mich, SL 036603 ' ...l Journal of 260 METHYL CHLOROFORM OmuPi,.I Modicln. of the prcancsthetic value. Recovery was slow, but uneventful. The subject complained of be ing tired for several hours after anesthesia. Three human deaths as a result of over-expo sure to 1,1,1-trichiorocthane have been reported. One death occurred in an open tank in which vapor concentrations exceeded several thousand ppm,1" and in 2 cases, death followed exposure to very high concentrations in unventilated tanks.* Vapor exposures in experimental animals have been the basis' for most of our understanding of the effects of 1,1,1-trichloroethane on man. Acute deaths in experimental animals presumably have been due to central nervous system depression culminating in respiratory arrest.* A vapor con(' centration of 18,000 ppm for 3 hr. was lethal for 5035 of exposed white rats; a 3-fir. exposure to 10,000 ppm produced irregular respiratioiwuid a semicomatose state, but no deaths resulted. There is a modest safety factor present in that the ratio between the concentration of the vapor, causing the loss of reflexes and that producing death in mice is 20, as compared to 15 for chloro form.1 A disturbing property of this compound is that, at anesthetic concentrations, idioventricular rhythms may be induced in animals with epi nephrine.11 Therefore, it is possible that ventric ular fibrillation leading to sudden death could occur in humans exposed to anesthetic concen trations. This is not a unique property of 1,1,1trichloroethane, but one common to most of the chlorinated aliphatic hydrocarbon solvents. ( , Studies conducted on dogs and monkeys anes thetized with 1,1,1-trichloroethane by a closed technique revealed no significant change in elec trocardiograms during 60 min. of deep surgical anesthesia; however, a depressor response upon the blood pressure was observed. At the point of respiratory arrest, the blood pressure was re duced to approximately one-half of its normal value. This is in contrast to the minimal blood pressure depression produced by ethyl ether-in duced respiratory arrest. Rats deeply anesthetized with 1,1,1-trichloroethanc for one hour showed a 33.3% diminution in oxygen uptake of the myocardium, very simi lar to that observed with chloroform anesthesia." The failure of 1,1,1-trichlorocthanc to impair significantly liver function in mice, as measured by the prolongation of pentobarbital sleeping time, has been reported by Plan ct nf.ia The hepatotoxic potency of the chlorinated hyd,... studied, arranged in order of increasing toxicity was: 1,1,1-trichloroethane,- tetrachlorocthylcnc, trichloroethylene,: tetrachlorocthane, 1,1,2-trichloroethane, chloroform, and carbon tetrachlo ride. To produce histological evidence of liver in jury in white rats, vapor concentrations of 8000 ppm for 7 hr. were required. A 5-hr. exposure at the same concentration did not result in his tological evidence of liver injury. Repeated Vapor Exposure It is unlikely that significant organic injury re sulting from repeated vapor exposure will occur in the absence of acute effects. No injury to man following repeated exposures to vapor concen trations of less than 500 ppm has been observed.1 Rats, guinea pigs, rabbits, and monkeys were un affected after 6 months of repeated 7-hr. expo sures, 5 days per week to 500 ppm.8,8 Of the laboratory animals investigated, the guinea pig appears most prone to liver injury. While an -earlier study reported no organic in jury after 3 months of repeated daily exposure to 1500 ppm, 7 hr. per day, a later study reported the presence of slight lung and liver pathology in guinea pigs exposed repeatedly to 1000 ppm for 1.2 hr. per day, or 2000 ppm for 0.5 hr. per day. This inconsistency merits further investigation. Ingestion Absorption of a substantial amount of 1,1,1trichloroethane from the gastrointestinal tract will produce the same functional depression of the central nervous system as described follow ing vapor inhalation. If the amount ingested is sufficient to produce loss of consciousness, im pairment of liver function may result... Eye Contact Several drops of 1,1,1-trichloroethane placed directly-on the comea may produce a mild con junctivitis which will subside within a few days.18 r Skin Contact Prolonged or repeated contact with the skin re sults in slight irritation, secondary to the solvent's defatting action. Significant skin absorption is unlikely in industrial applications unless the compound is confined to the skin surface beneath 036602 iwr " 1. i v*' Journal of 202 MET1IYL CHLOROFORM Occupational Medicine References 1. Lazarf.w, N. W. On the narcotic action of chlorine derivatives of methane, ethane, and ethylene. Arch, cxjter. Path. U. Pharmakol. 141:19, 1929. 2.^ Carpenter, C. P., Smyth, H. F., Jb., and Pozzani, U. C. The assay of acwlc vapor toxicity and the grad ing and interpretation of results on 96 chemical com pounds^ J. Indust. Htjg. and Tax. 31:343,1949. 3> Adams, E. M., Spencer, H. C., Rowe, V. K., and Ibish, D. D. Vapor toxicity of 1,1.1-trichlorocthane (methyl chloroform) determined by experiments on lalwmtory animals. A.M.A. Arch, lndtist. Hyg, and Occup. Med. 1:225,1950. 4. Van Aiucel, A. E., and Vles, S. E. Solubility of or ganic compounds in water. Rev. Trav. Chim. 55:407, 1936. 5. Cbummett, W. B., and Stenger, V,' A. Thermal stability of methyl chloroform and carbon tetrachlo-' ride. Ind. Eng. Chem. 48:434,1956. 6. Hake, C. L., Waggoner, T. B., Robertson, D. N., and Rowe, V. K. The metabolism of 1,1,1-trichloroethane by the rat. A.M.A. Arch. Environ. Health 1: 101,1960. 7. Stewart, R. D,, Gay, H. H., Ebley, D. S^Hake, C. L., and Schaffer, A. W. Human exposure to 1,1,1-tricholoroethane vapor: Relationship of expired air and blood concentrations to exposure and toxicity. Am. Ini. Htjg. A. J. 22:252,1961. 8. Torkelson, T. R., Oyen, F., McCollistf.r, D. D., and Rowe, V, K. Toxicity of 1,1,1-trichlorocthane as determined on laboratory animals and human sub jects. Am. Ind. Htjg. A. J. 19:353,1958. 9. Krantz, J. C., Jr., Park, C. S., and Ling, J. S. L.. Anesthesia LX: The anesthcsic'properties of 1,1,1* trichlorocthane. Anesthesiology 20:635, 1959. 10, Personal communication from V, K. Rowe, The Dow Chemical Company, Midland, Mich. 11., Rennick, B.jR., Malton, S. D., Moe, C. K., and Seevers, M. H. Induction of idioventricular rhythms by 1,1,1-trichloroethane and epinephrine. J. Pharma col b Exper. Therap. 8:327,1949. 12. Plaa, G. L., Evans, E, A., and Hike, C. H. Relative hepatotoxicity of seven halogenated hydrocarbons. /. Pharmacol. 6- Exper.,Therap. 123:224,1958. 13.. Medical records, The Dow Chemical Company, Mid land, Mich. 14. Robertson, D. N., and Erley, D. S. Infrared analy sis of volatile organic materials in animal tissues. Anal. Biochem. 2.-45,1961. 15. -Unpublished data. The Dow Chemical Company, Midland, Mich. 16. Stewart, R. D., Boettner, E. A., Southworth, R. R., and Cerny, J. C. Acute carbon tetrachloride intoxication. JA.M.A., in press. 17. Stewart, R. D., Erley, D. S., Schaffer, A. W,, and Gay, H. H. Accidental vapor exposure to anes thetic concentrations of a solvent containing tetrachlorccthylene. Indud. Med. 30:327,1951. [ .A f. ... o 0''- If H, SL 036604 '**"t*r Tjpsy.