Document QgnpkVG66qGv2VxzpBbq2LVYR

TOXICITY INFORMATION: METHYL CHLOROFORM Ch3CCI3 Acute Toxicity: 1.1.1- Trichloroethane, (methyl chloroform), has been reported to produce a functional (narcotic) depression of the C.N.S., possibly resulting in fatal respiratory depression. Ventricular arrhythmia may be induced with sensitization to epinephrine. Permanent liver and kidney damage is unknown. Eye contact can result in discomfort, pain and mild conjunctivitis. While 1.1.1- Trichloroethane has been reported to be poorly absorbed through the skin, it does have skin defatting properties. Lethal doses have been calculated to be: Oral LD50 (rabbit, Guinea pig)-- 5.6 - 9.5 gm/kg LD50 (Rat)- 10-12 gm/kg Inhalation LC50 (Rat)-- 8,000 ppm/7 hr. In man, incoordination, as well as other effects, has been reported at 800 to 1,000 ppm. Concentrations around 30,000 ppm may be lethal in five to six minutes. Eye irritation has be reported at 500 ppm in man. Chronic Toxicity: Torkelson, et. al. (1959) has reported that femaleguinea pigs had slight inflamnation of lungs and fatty changes in liver at chronic exposure con centrations of 2,000 ppm. Other information on chronic toxicity is sketchy if not nonexistent. Properties: Volatile, colorless liquid with aromatic chloroform-like odor. Odor threshold reported to be between 20--100 ppm. SL 036380 2- Molecular weight is 133.42, vapor pressure 125 nm Hg at 25C. Except for inhibited methyl chloroform, no flash point has been reported. Thermal decomposition may product toxic concentrations of chlorine, HC1 and phosgene. Noninhibited methyl chloroform should not be used with aluminum due to its reactivity. This information has been prepared from informations in the following publications: Industrial Toxicology, Hamilton/Hardy, 1974 Toxicity and Metabolism of Industrial Solvents, Browning, 1965 Toxicology, the Basic Science of Poisons, Casarett/Doull, 1975 Registry of Toxic Effects of Chemical Substances, NIOSH, 1975 SL 036381 Cf3 To RULF REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES KI94500. ITHANETHIOIC ACID CAS 000507095 MW 76 12 M0LFM 0 S-C2-H4 WLN SHV1 SYN. ACETIC ACID. THIO- ETHANETHIOLIC ACID * METHANECARBOTHIOLIC ACID * THIACETIC acid THIOACETIC ACID THIOLACETIC ACID TXDS ipr-mus LDLo-750 mg/kg NTIS*' AD691-490 ETHANETMIOIC S-ACIO. 2-FLUOROETHYL ESTER see AJ 75250 ACETIC ACID. THIO-, S-(2-FLUOROETHYL) ESTER KJ21000. ETHANETHIOL, 2-(METHYLAMIN0)- CAS 010061402 MW 9119 MOLFM NSC3-H9 WLN SH2M1 SYN. N-MONOMETHYLCYSTEAMIN (German) N- MONOMETHYLCYSTEAMINE * TXDS scu-mus LD50 262 mg/kg AEPPAE 225,428.5: ETHANETHIOL, 2-(METHYLTHIO)-, 0,0-DIMETHYL PHOSPHOROTHIOAT TF94500 PHOSPHOROTHIOICACIO, O.O-DIMETHYL S-(2 (METHYLTHIO)ETHYL) ester ETHANETMIOIC S-ACID. 4-flU0R0UTYL ESTER nee AJ69000 ACETIC ACID, THIO-, S-(4-FlU0R0BUTYL) ESTER K196250. ETHANETMIOl CAS 000075081 MW 62 14 MOLFM S-C2H6 WLN SH2 SYN AETHANETHIOL (German) AETHYLMERCAPTAN (German) * ETANTIOLO (Italian) ETHAANTHIOL (Dutch) * ETHYL HYDROSULFIDE ETHYLMERCAPTAAN (Dutch) ETHYL MERCAPTAN ETHYL SULFHYDRATE * ETHYL THIOALCOHOL ETILMERCAPTANO (Italian) THIOETHANOL * THIOETHYl ALCOHOL TXDS ihl-hmn TCLo 4 ppm TFX CNS DTLVS* orl-rot LD50 682 mg/kg AIHAAP 19,171,58 ihl-rot LC50 4420 ppm/4H AIHAAP 19,171,58 ipr-rot LD50 450 mgikg AIHAAP 19,171.58 ihl-mus LC50 2770 mg/kg AIHAAP 19,171,58 U S OCCUPATIONAL STANDARD USOS- FEREAC 37,22139,72 oir CLIO ppm ETHANETHIOl. 2-IACETYLAMINO)- nee. AC46200 ACETAMIDE. N-(betaMERCAPTOETHYL)- KJ01750. ETHANETHIOL, 2-AMINO- CAS 000060231 MW: 77.16 MOLFM N-S-C2-H7 WLN: Z2SH SYN 2-AMIN0ETHANETHI0L ' 2-AMINOETHYL MERCAPTAN BECAPTAN * CYSTEAMINE CYSTEINAMINE * DECARBOXYCYSTEINE * LAMBRATEN * MERCAMINE MERCAPT AMINE * beta- MERCAPTOETHYLAMINE (2-MERCAPTOETHYDAMINE * THIOETHANOLAMINE TXDS- ipr-mus LD50 305 mg/kg BCPCA6 14,289,65 scu-mus LD50.247 mg/kg AIPTAK 109,108,57 KJ03500. ETHANETHIOL. 2-CHL0R0- CAS 004325977 MW: 96.58 WLN SH2G TXDS. ivn-cat LD50 25 mg/kg MOLFM S-CI-C2-H5 NDRC** -.118.43 KJ04300. ETHANETHIOL, 2.CTANO. MW 87 15 SYN beta-CYANOETHYLMERCAPTAN MERCAPTO TXDS ipr-mus LD50-100 mg/kg MOLFM N-S-C3-H5 * ETHANE. l-CYANO-2- NTIS" AD691-490 KJ05250 ETHANETMIOL, 2>(DIETHYLAMINO)- CAS 0001003B9 MW 133.28 MOLFM N-S-C6-H15 WIN SH2N2&2 SYN- N-OIATHYL CYSTEAMIN (German) * N-DIETHYL CYSTEAMINE ` N,N-DIETHYL-CYSTEAMINE TXDS ipr-mus LD50 96 mg/kg BCPCA6 14.289.65 scu-mus LD50 120 mg/kg AIPTAK 109,108.57 nHANETHIOl, 2-LMETHYLTHIO)-, S-ESTER with O.O-DIMETHYL PHOSPHOROTHIOATE see: TF94500PH0SPH0R0THI0IC ACIO. 0 DIMETHYL S-(2-METHYLTHI0)ETHYL) ESTER KJ26250. ETHANETHIOL, 2-(TRIMnHOXYSILYl)- CAS 007538456 MW: 182.34 MOLFM 03-S-S.-C5-HU WIN 5H2-SI-/01 3 SYN 2-MERCAPT0ETHYL TRIMETHOXY SILANE * TXDS orl-rat 1050:2460 mg/kg AIHAAP 30.470,69 ETHANE TRICHLORIDE see: KJ31500 ETHANE. 1.1,2 TRICHLORO KJ297SO. ETHANE. 1,T,1-TRICHI0R0. CAS: 000071556 MW- 133 37 MOLFM CI3 C2 H3 WIN: GXGG SYN AEROTHENE TT * CHLOROFORM. METHYL CHLOROTHENEOnhibited) * CHLORTEN METHYLCHLOROFORM I.l.l-TRICHIOOREIHAAN (Dutch) I.l.l-TRICHLORAETHAN (German) * olpho-TRICHLOROETHANE * 1.1,1-T RIC HLOROETHA r * 1,1,1 -TRICLOROETANO Utolion) ` TXDS ihl-man TCLo.350 ppm TFX:PSY WEHI** 10,82.73 ihl-hmn TCLo 920 ppm/70M TFX CNS AIH--AP 19.353.58 orl-rbt LD50:5660 mg/kg " AIHAAP 19,353 5P arl-gpg LD50-9470 mg/kg " AIHAAP 19.353 Lb AOTX. U S OCCUPATIONAL STANDARD USOS-air FER1AC 37,22139 7 TWA 350ppm KJ31S00. ETHANE, 1,1,2-TRICHLORO- CAS. 000079005 MW: 133 40 MOLFM CI3-C2-H3 WLN-. GYG1G SYN. ETHANE TRICHLORIDE * beta-TRICHLOROETHANE * 1.1,2-TRICHLORETHANE ` 1,1,2 TRICHLOROETHAN, TROJCHLOROETANd,1,2) (Polish) " VINYL TRICHU TXDS: orl-rat LD50: 580 mg/kg ihl-rot LCLO:500 ppm/8H scu-mus LD50:227 mg/kg orl-dog LDLo 750 mg/kg ivn-dog LDLo-95 mg/kg scu-rbt LDLo.500 mg/kg AQTX: U.S OCCUPATIONAL STANDARD USOS- uirJWA 10 ppm(skin) AIHAAP 30.470.6) AIHAAP 3C.470.69 JPETAB 123.224,5E QJPPAL 7,205.34 OJPPAL 7.205.34 QJPPAL 7,205 34 FEREAC 37.22139 ' RJ07000. ETHANETHIOL, 2-(DIETHYLAMINO)-. HYDROCHLORIDE CAS 001942525 MW 169 74 MOLFM N-S-C6-H15 WLN: SH2N2&2 &GH TXDS ipr mus LDLo 100 mg/kg CURL" -.9,62 Cl-H KJ0*750 ETHANETHIOl. DIISOPROPYLAMINO TXDS ipr-mus LDLo 5 mg/kg CURL" -.9.62 KJ10SOO ETHANETHIOL. 2-(DIMTHYLAMINO). CAS 000108021 MW: 105 22 MOLFM N-S-C4-H11 WLN SH2N1&1 SYN N-DIMETHYl CYSTEAMIN (German) N DIMETHYL CYSTEAMINE ` TXD5 scu mus LD50 2U mg/kg AEPPAE 225,428,55 ETHANETHIOL. 2-(ETHYLSULFINYL)-, S-ESTER milk 0.0-DICTHYL PHOSPHOROOITHIOATE see TD85750PHOSPHORODITHIOIC ACID. 0.0-DIETHYL S-(2-(ETHYLSULFINYL)ETHYL)ESTER ETHANETHIOL, 2-(ETHYLSULFINYl)-. S-ESTER with O.O.OIMCTHYI PHOSPHOROTHIOATE see TG14200PHOSPHOR0THIDIC ACID. S (2 (ETHYLSULFINYL)ETHYL) o.o-dimethyl ester ETHANETHIOL. 2-(ETHYLSULE0NYL).. S-ESTER with 0.0-DinHYl i PHOSPHOROOITHIOATE see TD89250PHOSPHORODITHIOIC ACID. 0,0-DIETHYL S (2 (ETHYLSULFONYUETHYDESTER * ETHANETHIOL, 2-(ETHYLTMIO)-. S-ESHR with 0.0-DIETHYL PHOSPHOROOITHIOATE see TF3I25QPHOSPHOROTHIOIC ACID, 0.0 DIETHVI 0-(7 (ETHYLTHIOIETHYM fster SL 036382 AM' Bit AM HYGIENIC GUIDE SERIES ASSOCIATION 1,1,1-Trichloroethane (Methyl Chloroform) (Revised 1961) I. Hygienic Standards A. Recommended maximum atmospheric concentration (S hours): 500 parts of vupor per million parts of air, by volume (ppm)1 1. Basis for Recommendation: Repented administration to animals and human experience.3' 5 B. Severity of hazards: 1. Health: Moderate for acute exposure, but chronic exposin' to concentra tions that are without acute effects are unlikely to produce injury. 1,1,1Trichloroethane is readily absorbed and excreted through the lungs.3 In acute exposure thi^jjjijs^juiyoilm^t toMcaidmnisaTmudio^ ol* the cenjruLncrvons system leading ultimately to respiratory failure. K.xpenments with dogs have indicated that this material can induce uajHiailarairhvthmia similar to that proiTuceTTiw)tT7er chlorinated solvents.* Animals exposed re|>entedly to high concentrations exhibited some rQ--i" jbJ^Hiangesj^Jivi^ljj^lUsy' but they were not the severe effects asso ciated with carbon tetrachloride. Chronic exposures to 1000 ppm re sulted in moderate fatty degeneration of the liver but no liver necrosis or kidney injury. Growth depression oc curred at (150 ppm. No effects were seen from repeated 7-houi daily ex posures to 5(H) ppm. In controlled human exposures to 500 ppm no effects other than slight, transient eye irrita tion were rioted, but at 1000 ppm and above, mild eye irritation was experienced by all subjects, and some became di/.iiv.-' 1 As with most solvents, derma titis might result from re|ieated skill contact, but 1,1,1-trichloroethane is only poorly absorbed through the skin. Eve contact may result in pain and discomfort, but no impairment of vision is likely. 2. Rite: 1.1,1-Trichloroethane has no flash point when tested by standard AST51 procedures for the TAG Closed or Cleveland Open Cup tests. Some inhibited J, 1,1-trichloroothanes have been found to have explosive limits of l0'/c to 15.5Cc in air, but a high energy source is required to cause ig nition and, if the ignition source is removed, the vapor will not continue to burn.3 When inhibited products are evaporated to a small volume the resi due may flash. Thermal decomposition products are very irritating and may be quite toxic, but voluntary oxerexposure to such materials (largely hydrogen chloride)6 is not likely, C. Shout exposure tolerance: Beginning anesthetic effects, including incoordina tion, ap|iear in some human subjects excised to concentrations of S00 to 1000 ppm. They occur quickly in humans at concentrations of 2000 ppm or higher,3 Exposures to concentrations in excess of 30,000 (3ri. by volume) max- be lethal in 5-6 minutes.7 D. Atmospheric concentration immedi ately hazardous to life: 30,000 ppm (39i by volume) based on animal experi ments.1 7 Significant Properties Methyl chloroform is a volatile, colorless liquid x\it.ii an aromatic "chloroform-like" odor. The odor threshold may range from 20-100 ppm.' Chemical formula: CUaGClj Molecular weight: 133.42 Specific gravity: 1.3300 (25"/4"C) Boiling point: 74.07'X' at 700 mm Vapor pressure at 25C: Solubility: Hr 125 mm Ug Insoluble in water, but miscible xvith alcohol, ether and most organic sol vents. SL 036383 Drrcmlu'r, Will At 25C and 7(i() mm IIk1 ppm of v;i|Hr: 1 nig/htcr (if va por: Saturated air con- eentration: Relative density of vapor: Relative density of saturated air: O.OOnln mg/litcr 183 p]>m 16.5'c 4.0 (air = 1.0) 1.6 (air = 1.0) 111. Industrial Hygiene Practice A. Recognition: Methyl chloroform is used as a solvent and as a degreasing and coldcleaning agent. In many instances it lias been substituted for the more to\ic car bon tetrachloride. B. Evaluation ok exposure: 1. Instrumentation: Instruments based on the Beilstein test such as the Davis Halide Meter' and halide leak detec tors may be calibrated for 1,1,1-triehloroethane. Instruments employing measurement of the conductivity of water which has absorbed the com bustion products of this material are available, and those using hydrogen flame ionization, while almost com pletely non-siK'cifie, can probably be used. Gas chromatographic, infrared, and mass s|X'etrographie methods can be used, esiiecially when absolute identification is necessary, 2 Chemical Analysis: Direct combustion followed by absorption in a basic, re ducing solution and determination of the halide ion has been used success fully,10 as has adsorption on silica gel followed by thermal desorption and combustion,11 The method of Fahy1J using isopropyl alcohol to desorb from silica gel, followed by alkaline hydrol ysis, is said to be applicable.14 A modi fied Fujiwara reaction may be used.13 Detector tulies by various manufac turers can probably be used, but each batch should be separately calibrated before use. C. Recommended control procedures: Concentrations to which men are rel>eatedly e\|>osod should not exceed 500 ppm. General ventilation is usually suffi cient to maintain such control at room teni|ierature unless large surfaces are wet with the solvent. Halogenated solvents should not be used where their vapors (in concentrations of a few ppm or more) will come into contact with very hot sur faces (such as near a welding operation) because toxic decomposition products such as chlorine and hydrogen chloride may be formed. In such cases local ex haust ventilation will be necessary. Xon-inhibited methyl chloroform should not be used in contact with aluminum because of its reactivity with this metal. Gross skin contact should be prevented; spectacles will usually offer adequate eye protection. IV. Specific Procedures A. First aid: Remove victim to an uncon taminated atmosphere and apply artificial respiration if breathing has stopped. Re move wet clothing and do not allow it to lie re-worn until it is thoroughly dry. If eves are contaminated they should be flushed with large amounts of water. B. Specific medical procedures: Treat symptomatically, watch the cardiac rhythm in any case of anesthesia pro duced by 1 ,1-triehloroethane Oxygen therapy may be used, but epinephrine is contraindicated. Some indication of the extent of exposure may be obtained from an analysis of exhaled air.1 Urinary uro bilinogen may be of interest as a liver function test following acute excessive exiiosures.1 Recovery from a non-fatal acute episode can be exacted to be com plete and prompt. V. References 1. American Conference of Governmental Industrial Hygienists: Threshold Limit Values for 1961. Amer. Ind. Hyg. Assoc. J. 22: 325 (1961). 2. Torkelson, T. R,, et al.: Amcr, Ind. Hyg. Assoc. J. 10: 353 (1958). 3. Hake, C. L., et al.: .4 Af.t ArcA. of Env. Health 1: 101 (1960) 4. Rennick, B. R,, et al.: Federation Proc. S: 327 (1949). 5. Stewart, R. D., et al.: Anier. Ind. Hyg. Assoc. J. 22: 252 (1961). 6. Orummctt, W. D., and V. A. Stenger: Ind. Eng Chem. 4$: 434 (1956). 7. Adams, E. M., et al.: AM A Arch, of Ind. Hyg. and Occup. Med. 1: 225 (1950). 8. The Dow Chemical Company, unpub lished data. 9. Schaffer, A. \V., and H. R. Hoyle: Amcr. Ind. Hyg. Assoc. J. 22: 93 (1961). 10. Jacobs, M. B.: Analytical Chemistry of Poisons, Hazards and Solvents, 2nd Edi tion. Interscience Publishers, Inc., New York (1949). 11. Peterson, J. E., et al.: Amer. Ind. Hyg. Assoc. Quart. 17: 429 (1956). 12. Fahy, J. P.: J. Ind. Hyg. and Toxicol. 30: 205 (1948). 13. Rogers, G. W., and K. K. Kay: J, Ind. Hyg. and Toxicol. 29: 229 (1947). 14. Elkins, H. B., Personal Communication. SL 036384 H^pvicTova h lAD^S * |oy.i(_o voo- bon tetrachloride intoxication has also been reported (Tracey and Sherlock, 1968), and this compound is a potent hepatocarcinogen in animals. It is of course possible that regeneration itself in these cases is the precancerous lesion and that carbon tetrachloride is not a specific carcinogenic material. A bleeding tendency has been observed in many cases of actue carbon tetrachloride poisoning. In some cases it may reflect visceral damage. In others bleeding may be a consequence of aplastic anemia. The evidence that carbon tetrachloride is a direct bone marrow poison is not indisputable, but cases have been presented in which the nature of the exposure and the sequence of events are reasonably convincing (Straus, 1954). ETHYL CHLORIDE Ethyl chloride is a gas at room temperature; however, it is easilv liquefied and is familiar to physicians as a local anesthetic agent which freezes the skin when the agent is applied as a spray from a glass cylinder. Ethyl chloride is found in industry almost entirely as a chemical intermediate used in the synthesis of tet raethyl lead and other ethyl compounds. The physiological proper ties of ethyl chloride are related to its anesthetic effect and perhaps to its cardiotoxic properties as a sensitizer of the myocardium to endogenous epinephrine. As far as is known, this compound is excreted via the lungs without significant metabolic degradation in the body. ETHYLENE DICHLORIDE The ethylene dichloride, or ethylene chloride, of industry is 1,2-dichloroethane. 1,1-Dichloroethane is commonly known as ethylidene'dichloride or ethylidene chloride. These are saturated compounds, chlorinated ethanes, and the "ene" endings should not lead to confusion of those compounds with dichloroethylene. Much of this terminology is quite unfortunate, but is so well established among the various industrial traditions that change is unlikely. Both chlorinated ethanes are used as solvents and as chemical intermediates. They are irritating to the eyes and the respiratory tract, producing salivation, sneezing, and coughing. In those few cases of intoxication which have been reported, the anticipated anesthetic effects have been observed with associated dizziness, nausea and vomiting. In severe and fatal cases hepatic and renal injury have been observed. METHYL CHLOROFORM Methyl chloroform (1,1,1-trichloroethane) is a chlorohvdrocarbon solvent which, because of its very low toxicity (Stewart, 1971), is being utilized at an accelerated rate. It is widely applied as a SL 036385 CHLORINATED HYDROCARBONS / 285 vapor degreaser, dry cleaning agent, aerosol vehicle, and cold cleaner. Like many chlorohydrocarbons, methyl chloroform is somewhat unstable, and small amounts of stabilizing compounds are added to the solvent material sold in commerce. Such stabiliz ers or inhibitors may be various ketones, alcohols, esters, nitrogen compounds, etc., which do not change the toxicity of the commer cial product sold under trade names such as Chlorothene or Triethane. Methyl chloroform is a narcotic and skin defatting solvent as harmful effects are the chlorohydrocarbons in general. Exposures to high air con centrations of methyl chloroform may lead to narcosis and even fatal respiratory depression under conditions of grossly negligent overexposure. There is no evidence that this solvent causes hepatic or renal injury such as is characteristic of carbon tetrachloride. Experimental work (Reinhardt et al., 1971; Aviado and Belej, 1973) and clinical experience with anti-tussive preparations containing trichloroethane identifies serious cardiotoxic properties of this compound, and deaths have been attributed to cardiac arrhyth mias, probably mediated through epinephrine sensitization. 1,1,2-Trichloroethane, vinyl trichloride, an isomer of methyl chloroform, is a more potent anesthetic agent, an irritant to mu cous membranes, and a significant hepato- and nephrotoxin. It does not have major industrial uses. Industrial references to acetylene tetrachloride or tetra- TETRACHLORO chloroethane are invariably to the symmetrical isomer of ETHANE 1,1,2,2-tetrachloroethane. Clinical evidence indicates that this compound is by far the most poisonous of the chlorohydrocarbons used as industrial solvents. Unfortunately from the health point of view, it is an excellent solvent, often the best available for many applications. Early utilization of tetrachloroethane as a vehicle for the so-called dope to cover airplane fabrics led to numerous severe and fatal cases of toxic hepatitis and atrophy of the liver. The compound is the best solvent for cellulose acetate, which for many years was the best available coating material for fabrics to be used in aviation and products requiring a thin, light, impervious sur face. The recognized toxicity of tetrachloroethane has caused it to be eliminated from most industrial uses unless its specific solvent properties are necessary. The use of this compound is rarely jus tified. Toxic manifestations resemble those associated with carbon tetrachloride; however, the hepatotoxicity of tetrachloroethane is much more prominent. SL 036386 n l;-'ti. rJ-'A* * TbfY&iC SciersiSie oF po 130^3 508 Toxic Agents microsomal enzyme system all support the hypothesis that metabolism is a prerequisite to carbon tetrachloride hepatotoxicity. Methyl Chloroform (1,1,1-Trichloroethane, CI3CCHj) Methyl chloroform has received widespread acceptance as an industrial solvent since it has many of the solvent and volatility characteristics of carbon tetrachloride. Like the other halogenated hydrocarbons solvents, methyl chloroform has a depressant action on the central nervous system. Irish (1963) reports that humans ex posed to 2000 ppm exhibited drunkenness and incoordination. Exposures at 1000 ppm showed no significant response in individuals exposed for as long as 70 minutes. Irish also reports that only two fatal cases are known and they occurred in a tank where the concentration may well have been close to saturation. Acute vapor exposures in animals, as reported by Adams and coworkers (1950), indicated that rats could survive a seven-hour exposure at 8000 ppm. At 3000 ppm, rabbits and monkeys showed no abnormal response over a two-month period. The acute LD50 in male rats is approximately 12 g/kg and in female rats approximately lOg/kg. Experi mental human exposures to 500 ppm of methyl chloroform for 6.5 to 7 hours per day for five days gave no evidence of abnormal organ function as measured by a variety of clinical laboratory tests. Ability to perceive the odor decreased during the exposure period. The subjective responses obtained during the ex posure were mild and inconsistent except for the complaint of drowsiness (Stewart et at., 1969). Studies of the comparative toxicity of a series of halogenated hydrocarbons (Klaassen and Plaa, 1969; Watrous and Plaa, 1972) have demonstrated that in experimental animals, near-lethal doses of I,I,I-trichloroethane are required to produce a measurable hepaiotoxic response to a single dose. As shown in these same reports, 1,1,2-trichloroethane is consider ably more toxic than 1,1,1-trichloroethane; thus it is apparent that one must be certain of the correct identification of chemical compounds in order to prevent confusion and error in defining their toxicity. The present TLV for methyl chloroform is 350 ppm. The metabolism of 1,1,1-trichloroethane is also somewhat different from that of 1,1,2trichloroethane in that it is partially metabolized to trichloroethanol and to a lesser extent to trichloroacetic acid (Ikeda and Ohtsuji, 1972). The overall metabolism of 1,1,1-trichloroethane was considerably less than that of trichloro ethylene. Although some metabolism of 1,1,2- trichloroethane was apparent, the low levels made identification of the products uncertain. Trichloroethylene C1*C=CHC1 Trichloroethylene is widely used as an indus trial solvent in degreasing and extraction processes as well as in the dry-cleaning industry. The toxicity of trichloroethylene has been included in a number of reviews (Browning, 1965; Smith, 1966). Overexposure to trichloroethylene produces central nervous system depression resulting in mental confusion, incoordination, and insomnia. The acute response of experimental animals to trichloroethylene vapor has been reported by Adams and coworkers (1951). At 3000 ppm, a six-month daily exposure resulted in increased liver and kidney weights. Rats and rabbits exposed for a six-month period to 200 ppm showed no effect. Baker (1958) reported severe changes in the cerebellum, particularly in the Purkinje cell layers in dogs chronically exposed to trichloroethylene. Fatal cases of trichloro ethylene exposure reported by Kleinfeld and Tabershaw (1954), showed no tissue abnormal ities at autopsy. Death was evidently due to cardiac arrhythmia resulting from the potentia tion of endogenous epinephrine by trichloro ethylene. Comparative studies on the hepatotoxicity of chlorinated hydrocarbons demonstrated that large, near-fatal acute doses were required to produce mild hepatic dys function. In this respect, the acutely toxic response was comparable to that seen with 1,1,1 -trichloroethane. Butler (1949) indicated that trichloroacetic acid, trichloroethanol, and small amounts of chloroform and monochloroacteic acid were the metabolic products of trichloroethylene. Several early reports had attempted to relate the con centration of trichloroacetate in urine to the inhalation exposure to trichloroethylene in man (Ahlmark and Forssman, 1951). Additional studies on the metabolism of trichloroethylene (Bartonicek, 1962; Stewart eta/., 1970a) confirm the major metabolites of trichloroethylene as trichloroacetic (TCA) acid and trichloroethanol (TCE). In general, considerably more TCE is excreted than TCA. For example, in animal studies (Ikeda and Ohtsuji, 1972) rats excreted five to seven times more TCE than TCA after being exposed to trichloroethylene. With respect to the toxicity of these metabolites, Mikixkova and Mikiska (1966) demonstrated that trichloro ethanol had a pronounced depressant effect upon the central nervous system and suggested that the rate of metabolism of trichloroethylene appeared sufficient for trichloroethanol to play a role in its depressant action. SL 036387 YA-e~fs\3oLf o |lfO S0Lv/ev\TS 25. Trichloroethane Trichloeroethane exists in two isomers; i,i,j - the a isomer and 1,1,2 - the /? isomer. Until recently it has been stated that the a-isomer is more toxic than the /J. The error apparently arose from a misconception of the results of experiments published by Lazarew in 1929 on its minimal anaesthetic concentration, though this was given at the time as 45 mg/1 compared with 15 mg/1 for the ^-isomer and the respective lethal doses as 65 mg/1 and 60 mg/1. Boehring (1958, personal communication) and Stewart (1963) both agree that the at-isomer is the less toxic of the two. .V) nonyms: methylchloroform, vinyl trichloride Structuralformula: 1,1,1 -trichloroethane Cl H 1,1,2-trichloroethane ah Molecularformula: C2H3C13 Molecular weight: 133.42 CjH3C13 133-42 25a. 1,1,1-Trichloroethane Properties: a volatile colourless liquid with chloroform-like odour boiling point: 74.1 C melting point: none? (Stewart, 1963) vapour pressure: 127 mm Hg at 25 C vapour density (air = 1); 4.6 specific gravity (liquid density) : 1.336 at 25 C fash point: none (Irish, 1963) conversion factors: 1 p.p.m. = 5.46 mg/m3 1 mg/l = 183 p.p.m. solubility: soluble in many organic solvents, but only slightly in water (Van Arkcl and Vies, 1936). maximum allowable concentration: 500 p.p.m. (Threshold Limit Values, 1962) [2S31 SL 036388 254 HALOGENATED HYDROCARBONS ECONOMY, SOURCES AND USES 5 Production Reacts with aluminium and aluminium alloys, but inhibited formulae are now marketed under trade names (Stewart, 1963) such as Chlorothene, a compound which contains 94-97% of 1,1,1-trichloroethane, 2.4-3% of dioxane, 0.12-0,3% of butanol and small amounts of ethylene dichloride, water and other materials (Torkclson et al., 1958). It is not flammable, nor will it support combustion, but it will decompose if sufficient heat is applied. At 500 F large amounts of HC1 and trace amounts of phosgene are formed (Crummett and Stenger, 1956). . Industrial uses The volatility and solvent power of 1,1,1-trichloroethane closely resemble those of CC14 and it has come into wider use as a substitute for CC14 in recent years: (1) as a solvent for natural and synthetic resins, oils, waxes, tar and alkaloids, (2) as a degreaser, (3) in organic synthesis. BIOCHEMISTRY Estimation (1) In the atmosphere Like many other halogenated hydrocarbons, 1,1,1-trichloroethane can be determined by hydrolysis with alkali in isopropyl alcohol. The method advised by Elkins (1959) is based on absorption of the vapour in sec.-butyl or isopropyl alcohol. The vapour is collected on a silica-gel absorber, followed by reduction with metallic sodium. The silica gel is then extracted with the alcohol and refluxed with metallic sodium; ethylalcohol (95%) is then added and the refluxing continued until all the sodium has reacted. After cooling and addi tion of water through the condenser, phenolphthalein and dilute nitric acid arc added until the solution is acid. After addition of 0.1 N AgNOj, filtration and washing of the precipitate with water, ferric sulphate solution is added and titra tion with 0.05 N KCNS solution carried out until a permanent yellow' colour is obtained. The amount of hydrolysis of 1,1,1 -trichlorocthane is 39% compared with 84% for CC14. SL 036389 l.'IW II ini li.ih lull HU '.id : ml*. 11 be ur in 1 lx-1. with filed n 1111 - 1 aie and lira, ur it Mth TRICHLOROETHANE 255 (;) In blood and tissues A rapid infra-red technique for the analysis of certain organic compounds m ihe blood has been described by Stewart et al. (1959). They state that it has hern satisfactory for 1,1,1-trichloroethane. In this method the suitable extracting uN cut is added to the oxalated blood and, after centrifuging, the solvent layer is transferred to a standard infra-red sample cell of any standard infra-red spectro meter and the spectrum scanned from 2-16 m/u. 131 In urine `1 lie aforementioned method has also been applied successfully to urine. Metabolism Williams (1959) stated that the metabolic fate of 1.1.1-tiichloroethane was unknown, but according to Hake et al. (i960) it is very stable in the body, and while a large part of an intravenous dose is excreted unchanged by the lungs, a sny small amount is metabolised to chlorocthanol and excreted in the urine as the glucuronatc. Irish (1963) remarks that the high stability and rapid excretion may well account for the low toxicity and quick recovery from anaesthetic coninitratious. TOXICOLOGY "Jhrie is no doubt that methylchloroform is much less toxic than carbon tetra chloride. Its main toxic effect is exerted on the central nervous system, in a manner tmnl.ir to that of any anaesthetic agent. In animals lethal dosage causes central urrvous depression culminating in respiratory paralysis (Adams et al., 1950) and *t anaesthetic level it has the property of sensitising the heart to epinephrine, with induction of idioventricular rhythms (Rennick et al., 1949). For this reason it n advisable that epinephrine should never be given to a person overcome by *. s.qxmr. It can also cause a mild conjunctivitis if in contact with the eyes, but is not ks;hlv irritant to the skin except for the irritation caused by its defatting action uiih repeated contact. With chronic exposure, the only animal species showing significant organic trsjmy were, in the experiments of Torkelson et al. (1959), female guinea pigs: tlxv showed slight inflammation of the lungs and fatty changes in the liver. In industry 3 deaths have been reported from high exposure, all from open ur.ki; in one case to a concentration of more than several thousand p.p.m. on ft. 163 SL 036390 256 HALOGENATED HYDROCARBONS 5 Toxicity to animals (1) Acute (a) Lethal dose. - (i) By oral administration - for rats 10.3-12.3 g/kg, for rab bits 5.6 g/kg, for guinea pigs, 9.47 g/kg (Torkelson et al., 1958). - (it) By inhale lion, - for rats,30,000p.p.m.for6min; 15,000 p.p.m. for i| h; 8000 p.p.m. for 7 h (Adams et al., 1950). (b) Narcotic dose. - 18,000 p.p.m. in 18 min, 8000 p.p.m. in 5 h (Irish, 1963). (2) Chronic The effects of repeated administration, either oral or by inhalation, do not suggest a high potential chronic toxicity. Rats, rabbits, guinea pigs and monkeys exposed to 500 p.p.m. 7 h a day, 5 days a week for 6 months showed no evidence of impairment of growth or health, and when the concentration was increased to 10,000 p.p.m. male rats showed as the only sign of organic injury a slight in crease in the weight of the liver. A separate group of guinea pigs (female) however, exposed to 2000 p.p.m. for periods of up to half an hour a day, 69 times in 98 days, did show some irritation of the lungs and fatty infiltration of the liver, and some, at the shorter periods of exposure, an increased incidence of interstitial nephritis; since this did not occur at the higher intensities of exposure, Torkelson et al. believed that it was probably not related to the exposure. Adams et al, (1950) also carried out experiments with repeated exposure over long periods. Rats which succumbed to 10,000 p.p.m. appeared to have died from either cardiac or respiatory failure, but they survived 31 exposures to 5000 p.p.m. without apparent injury, while rabbits showed slight retardation of growth. Inhalation of concentrations of 1000 p.p.m. 7 h a day for 5 days a week were lethal to guinea pigs after two exposures, to rats after 3 to 14, to rabbits, after 2 to 64. Dogs, cats and monkeys were less susceptible, surviving for 23 to 55 days (Heppel et al., 1944). Some variation in species susceptibility was noted by Spencer et al. (1951), rats and guinea pigs showing a high mortality at 400 p.p.m. SYMPTOMS OF INTOXICATION Lethal doses cause anaesthesia followed by respiratory arrest. Concentrations somewhat below the lethal level (about 10,000 p.p.m.) cause irregular respiration and a semicomatose state. Some central nervous depression; the eyes of dogs showed reversible clouding of the cornea, with repeated exposure they became resistant to this effect (Heppel et al., 1944). (1) The skin Some irritation of the shaven skin of a rabbit following application of a pad saturated with methyl chloroform, and when applied under a cuff in a dosage of 15-8 g/kg killed less than half of the rabbits treated. 03&391 TRICHLOROETHANE 257 (t) Respiratory disturbances Ktl'cct on the circulation. - Depression of the blood pressure of dogs and mutikeys anaesthetised by 1, t, 1 -trichloroethane was observed by Krantz etal. the level reaching about half its normal value at the point of respiratory artnt. Administration of epinephrine during anaesthesia produces ventricular fibrillation in animals (Rennick et ai, 1949). CHANGES IN THE ORGANISM ft) The lungs Only mild congestion even after 125 exposures to 200 p.p.m. (Heppel, 1944). (ej Liter and kidneys Only slight pathological changes, most marked in guinea pigs with repeated ri(>iKurc to 200 p.p.m., none in rats. Toxicity to human beings Human beings were exposed to concentrations ranging from 506-1900 p.p.m. l-r |>rriods of 5-45 min (Stewart et al., 1961). At 1000 p.p.m. a strong unpleasant odour \\as noted after 30 min, and at 920 p.p.m. three of the individuals exposed *Jwwrd a slight loss of co-ordination and equilibrium, and complained of lightbradrdness. These signs of intoxication became very obvious, with a positive Romberg tnt. at 1900 p.p.m. for 5 min (Stewart, 1963). No evidence of systemic injury, as judged by tests of urine and liver function, was observed. f\Ju>irial poisoning. - In industry three fatal cases due to high exposure have been rjined. In the two recorded by Torkelson et al. (1958) the exposure occurred m an open tank where the concentration was believed to be close to saturation, and in one case for a period of about 30 min. The third case, recorded by Stewart .iyij), was also due to entry into an open tank, and the concentration was stated lie "more than several thousand p.p.m.". The symptoms resembled those of 4iu<Aenncss, with disturbance of equilibrium and incoordination. Pretention ofpoisoning. -- The measures ofprevention advised by Stewart (1963) i-vlutle protection of the eyes by safety glasses, and of the skin by removing conummatrd clothing in case of spillage; keeping the workroom atmosphere to a Imrl not higher than 500 p.p.m.; if higher levels should be present owing to Ktulent or unavoidable circumstances, no workman should be allowed to remain m inntact for more than a few minutes. 1 reatmeni. - Removal to fresh air; if breathing has stopped artificial respiraii'in thould be tried, but epinephrine should never be given in case ventricular (txill.ition should supervene. Oxygen may be necessary if there is severe hypotrr.iioii. f'\r on />. zG'j SL 036392 December, 1963 i mation, loss of ! depression of distress was most nra pig. Rabbits r\ress of 10 ppm id eyanosis. Signs -liiinilation were d-iiiiro-2-butene inlogical changes rat consisted of i II count, homo 's. and moderate A significant deImcytes to polyi lined following Immature forms liter exposure to butene. s included conud, occasionally, in the nasal pas''iichi; arid conhuge, consolida- abscess formaI'he processes I abscess forma|1 animals which >. 'sure. >*1 Physiology of Los n-i`> (1952). h \iwick: Industrial 1`owt-r Plants (Gas i( Couffrt'uts on Air 1 .Nov, 1958) "ii the Practicability "i tHrfm Content of n Pollution Control M (Aptil, 1959). \ir Polliihou Come on Air Pollu- "lii/HM Stuoml Aii 1. |* -7, Coin.mnati, V Okcutt, L. A. 'inn Report .Vo, l, (.otttrol Dnt/ut, p. n ' Report Vo. 24, ii'fOhK, and G. E. upon Exnoiimcntai ; `M2 (1958). Duchmann, M. G. i"ii of Conjugated \u I'ullulion. hid. `hunt Air Pollution Cincinnati, Olno is'Air Pollution Reu innati Ohio (Dec, 1 KfcpN; The PhysioMid to a Mixture of l Hyff. & Twitol Toxicity of a Solvent Mixture of 1,1,1-Trichloroethane and Tetrachloroethylene as Determined by Experiments on Laboratory Animals and Human Subjects V. K. ROWE, T. WUJKOWSKI, M.A. WOLF, S. E. SADEK, D.V.M., Ph.D., and R. D. STEWART, M.D.* lln,chemical Research Laboratory and Medical Research Laboratory, The Dow Chemical Company, Midland, Michigan (gj Thr toxicological properties of a solvent mixture (Dowclenef EC cleaner) con sisting by weight of 75Cr inhibited 1,1,1-rrichloroethane (Chlorothene NU solvent) and 250 tetrachloroethylene were studied on rats, mice, guinea pigs, rabbits, dogs and human subjects. The material was low in oral toxicity, not appreciably irritating to the eyes or skin, not absorbed through the skin to an appreciable extent, and was low in toxicity when inhaled. The animals given seven-hour exposures five days a week for six months to a vapor concentration of 1,000 ppm of the mixture suffered slight changes of a reversible character in the liver and kidney. Rats exposed four hours a day for six months to 1,000 ppm and the animals (4 species) exposed seven hours a day for six months to 500 ppm exhibited no evidence of adverse effects. Human subjects were exposed seven hours a day for up to five days to 500 ppm and subjected to intehsive medical study. No adverse effects were detected. The rate of excretion of the solvent via the lungs was studied in both dogs and humans. Introduction A NEEO was established for a solvent S- V which would be more effective than the solvent systems presently available for the cleaning of sizeable pieces of equipment. An example of such a need is in the cleaning of large electrical generators where the flushing off of dissolved soil is necessary, but without slow drying of the cleaned equipment. It was agreed that such a solvent should possess the following characteristics: (a) good solubility for greases, oils, tars, and other common soils; (b) negligible elfects on insulating materials during a noimal cleaning cycle; (c) essential ly no electrical conductivity; (d) no flash or fire point; (e) an evaporation rate slow enough to permit efficient cleaning and yet fast enough to permit prompt reuse of the equipment; (f) low cost; and (g) favorable toxicological properties. The solvent com bination consideted in this paper was found *Dr. Stewart is with tin- Medical Research Laboratory. tTradein.ilk uf the Dow Chemical Company. to possess the desired physical and chemical attributes. Although toxicological data on the indi vidual constituents of the combination have been reported,1'2 none was available on the system as a whole. These studies were under taken to provide data upon which the hazards of handling and using the material could be evaluated and upon which an industrial hy giene standard could be based. The following report summarizes the re sults of acute oral, eye and skin irritation, and acute and repeated exposures of laboratory animals and human subjects to controlled vapor concentrations of the mixture. Material Chemical The solvent system studied was a colorless, pleasant smelling liquid having a specific gravity of 1.373 at 25/25C, a boiling range (5-95%) of 77 to 122C at 760 mm Hg, and a freezing point of -56.6C. Like many 541 SL 036393 I 542 Mmember-Deeembcr, 1963 chlorinated hydrocarbons, this material reacts readily with aluminum and aluminum al loys, therefore it must be inhibited if cor rosion is to be prevented. The mixture studied was shown by infra red analysis to contain on a molecular basis. 74% 1,1,1-trichloroethane, 22% tetrachloroethylene, 3.3% dioxane, 0.31% butylene oxide and 0.16% of unidentified impurities. Tt has no (lash point or fin- [joint using stand ard ASTM procedures for the Tag closed cup and Cleveland open cup tests. Animals The rats, rabbits, and guinea pigs were from the stock colony of this laboratory1 ex cept that the guinea pigs used in the pairedfeeding study as well as the mice, and the dogs were obtained from commercial sup pliers. The mice were Webster-Swiss whites obtained from Buckberg Laboratory Animals of Croton Falls, New York; the guinea pigs from Milton Erard of Decker, Michigan; and the dogs from Heric Fahrenbach of Essexville, Michigan. The rats, mice and dogs were maintained on Famo Laboratory Ration, the rabbits on Famo Rabbit Ration, and the guinea pigs on Famo Guinea Pig Ration. All of these rations are. products of the Harris Milling Company of Mt.`Pleasant, Michigan. In all cases, neither food nor water was available to the animals while they were in any exposure chamber but both were avail able immediately after each exposure. Human Subjects All subjects were healthy male volunteers, ranging in age from 32 to 62 years from the Medical Department, the Biochemical Re search Laboratory, and the Chemical Physics Laboratory of The Dow Chemical Company. Procedures Oral Administration, Eye Contact, and Skin Contact The animals and methods used for deter mining the toxicity from single oral doses, eye contact and skin contact have been described previously.3 Skin absorption studies were conducted by employing the "sleeve" tech nique described by Draize ct ald with slight modifications. Inhalation Single e.xposiue--rats. The animals, equip ment. and procedures used to determine the single-dose vapor toxicity of the solvent mix ture weie essentially the same as described previously.1 Repeated exposurcs--animals. Large metal chambers (3700 liter capacity) were used for the repealed exposures to 1000 and 300 ppm and for the air-exposed control animals. The desired concentrations were obtained by metering the liquid and vaporizing it into the airflow entering the chamber. Metering of the liquid was done by Dual Syringe Pumps (Modern Metalcraft, Midland, Michigan). Total air flow through all three chambers was measured by means of calibrated flow meters and maintained at 450 liters per minute. All exposures were continuously monitored by a calibrated conductivity combustion an alyzer,1 In addition, spot samples were an alyzed frequently by pyrolyzing a known volume of solvent-laden air, trapping the re sulting chloride in a 1% sodium formate-- 1% sodium carbonate solution, and then de termining the liberated chloride using a micro-Volhard technique. The mean con centrations found were 1005.9 (range 954 to 1092) and 496.1 (range 470 to 559) ppm, respectively. All of the animals used in these experi ments were carefully selected on the basis of general appearance, body weight, and growth during a preliminary period of observation. Groups, each consisting of 24 male and 24 female rats, nine male and eight female guinea pigs, three male and three female rabbits and one male and one female dog. were exposed seven hours a day to either 1000 or 500 ppm of the mixture. Actually the rats were divided into two groups of 12 males and 12 females each, one group (A) to be sacrificed at the end of the six-month exposure period and the other group (B) to Indu be s sepai pose two. mom T1 with num exp<> the coni of I loui T bon foi n rats wei sect doo m:i' Tin per SCI I at cae gr.. aft' all hoi sul tw an gf tin oh an Cl ' al tii ai C' in ei o u Si c SL 036394 'cembeTj 1963 'C "sleeve" techt ai* with slight ic animals, equiptn determine the the solvent mixmie as described mis. Large metal !>) were used for '00 and 500 ppm t rol animals. The re obtained by arizing it into the ier. Metering of 11 Syringe Pumps land, Michigan). I three chambers f calibrated flow r 450 liters per ^^>usly monitored ^Hombustion an^amples were an alyzing a known trapping the re odium formate-- on, and then dehloride using a The mean con">.9 (range 954 to '0 to 559) ppm, in these experid on the basis of right, and growth I of observation, f 24 male and 24 tnd eight female ind three female one female dog, a day to either nixture. Actually two groups of 12 . one group (A) of the six-month her group (B) to industrial Hygiene Journal 543 be sacrificed six weeks later. In addition, separate groups of 10 male rats each were ex posed to either 1000 or 500 ppm for four, two, or one hour per day for a period of six months. The control groups were well-matched with the experimental animals in respect to number, age, sex, and body weigiit. The "unexposed controls" were simply maintained in the animal quarters, while the "air-exposed controls" were exposed repeatedly to a flow of room air in a manner similar to that fol lowed with the solvent-exposed animals. The animals exposed repeatedly for seven hours a day were placed in tire chamber be fore any of the solvent was introduced. The rats exposed repeatedly for short daily periods were introduced into the chamber during the seven-hour exposures without opening the doors by dropping the rats through chutes made of 3)4 inch stainless steel tubing. These chutes were dosed with a rubber stop per except during the brief time it took to in sert the rats. The chutes, which weie sloped at a 45 angle, ended in covered, screened cages inside the chamber. The additional groups were started three, five and six hours after the seven-hour exposures started. Since all the animals were removed when the sevenhour exposure was completed, this routine re sulted in daily exposures lasting, seven, four, two or one hour. During the course of the experiment, each animal was weighed twice a week until the growth pattern was established, after which they were weighed once a week. They were observed frequently for general appearance and behavior. Hematological examinations consisting of erythrocyte, leukocyte, and differential counts and hematocrit and hemoglobin determina tions were made on all the dogs and rabbits and representative groups of rats prior to any exposure, after about eight weeks of exposure, and about a week before the exposures ended. Urinalyses consisted of routine evaluations of appearance, color, reducing sugar, albu men, pH, and specific gravity and micro scopic checks for erythrocytes, leukocytes, casts, bacteria, crystalline material, and mucous. They were done on samples of urine from representative groups of rats and on samples from each rabbit and each dog about a week before exposure ended. Alkaline phosphatase and serum-ureanitrogen (SUN) determinations were made on blood taken at autopsy from representa tive rats, each of the rabbits, and each of the dogs. At the same time serum-glutamicpyruvic-transaininase (SGPT) determina tions were made on the blood from each of the dogs. Bromsulfalein (BSP) retention was determined before exposures began and about a week before they ended. The dose of the dye was 10 mg/kg and tlu- blood sample for analysis was drawn 15 minutes later. Liver biopsies were performed on each dog prior to any exposure and about midway dur ing the study. Expired air samples were, collected from the dogs at frequent intervals during the first two weeks of exposure and were col lected occasionally during the rest'of the ex periment. Collection was accomplished by having them breath through a mask fitted with a 2-way Collins plastic "J" valve. (Warren E. Collins, Incorporated, Boston, Massachusetts). This allowed them to in hale fresh air and to exhale into a collapsed 10-litcr saran bag. The exhaled air in the bag was analyzed by infrared spectrometry using a 10-meter gas cell.15'1 The 1,1,1-trichlorocthane was determined by absorbance at 9.2n and the tetrachloroethylene at 10.9/t. The method of analysis was highly accurate and reliable, the lower limit of detection being 0.5 0.1 ppm for the 1,1,1-trichloroethane and 0.25rfc 0.2 ppm for the tetra chloroethylene. Failing animals were sacrificed for exami nation when moribund, or nearly so. At the termination of the experiment, part of the rats were starved overnight and then these and all the guinea pigs, and rabbits were de capitated and examined for evidence of or ganic injury on the day following the expos ure. The dogs were sacrificed by exsanguination after anesthesia with thiamylal sodium (Surital sodium, Parke-Davis). The weights of the principal organs (lung, heart, liver, kidney, spleen and testes) were SL 036395 } 544 November-December, 1963 obtained routinely from all animals of each species. These weights were compared to the corresponding weights of the air-exposed con trol group on both an absolute and relative basis. Portions of numerous tissues were taken and fixed for histopathological examination. Routinely, histologic examinations were made on hemaloxylin-rosin stained sections of the lung, heart, thyroid, liver, spleen, adrenal, kidney, pancreas, and testes. In addition, sections of die brain, sciatic nerve, lymph nodes, stomach, small and large intestine, urinary bladder, gall bladder, and skeletal muscle from the dogs were also examined. The rats that were not killed the day aftci exposures were stopped, were maintained without exposure for six weeks and then sacrificed and studied in the manner de scribed above. A paired-feeding study was conducted using 24 male guinea pigs. Prior to begin ning the critical portion of the study all the guinea pigs were exposed to air seven hours a day. five days a week in a control chamber. It was necessary to continue this routine for 34 days before all of the animals were gain ing weight normally. At this time, six animals were selected foi exposure to 500 ppm and six for exposure to 1000 ppm of the solvent vapor. Each of these animals was paired to one of the remaining twelve which were to continue exposure to room air in a control chamber. Each exposed guinea pig w'as of fered 60 grains of feed daily, more than their normal daily consumption. The controls which were exposed in the air-exposed cham ber were fed the. exact amount of food their paired, exposed-mate had eaten the day be fore. Records of growth and daily food con sumption were kept. At the termination of the experiment, all animals were autopsied. final organ weights were obtained, and tissues were saved for microscopic examination. Food efficiency data were calculated for the 5-week period. The t-test was used in comparing mean values of body weights and of organ weights; probability values (P) of 0.05 or less were interpreted to indicate a significant dif ference. Repeated inhalation studies--humans. Ex posures were conducted in a room measuring 32 x 13x8 feet in size and provided with a continuous, positive air supply. The vapor concentration was generated by atomizing the solvent mixture into the faces of two large circulating fans. The vapor concentration was automatically controlled and continuous ly monitored by an. infrared spectrophoto meter equipped with a recorder. Vapor con centrations were also measured continuously with a Oasis Halide ^leter0 and spot samples were taken from various portions of the room either in saran bags for measurement by an other infrared analyzer or on silica gel for analysis by combustion and chloride determi nation.10 The time-weighted concentration was 520 ppm with a range of 476 to 500; the duration of the extreme concentrations being but a few minutes. All of the persons participating in this study were given a complete history and physical examination the week preceding the exposure. The criteria employed in an effort to detect any adverse effect of the ex posure were as follows: Immediately before each exposure: oral temperature: blood pressure; pulse rate; expirogram: venous blood for complete blood count, sermn-glutamic-oxalacctic-transaminase (SCOT), serum electrophoresis, and total cosinophile count; and urine for com plete analysis. During the exposures: complete neurolog ical examination after six hours of vapor ex posure; evaluation of vestibular, cerebellar, and proprioceptive function every 75 min utes: questioning as to odor perception, eye, nose, or throat irritation, headache, dizziness, or speech difficulty every 45 minutes; Craw ford Manual Dexterity Test every three hours; Flanagan Aptitude Classification Tests; expirograms; expired air for solvent concentration after three hours of exposure; two-hour postprandial blood sugar; blood for cosinophile count after six hours of exposure; urine collection begun for 24-hour urobil- hu. ue at i th in in a.- ex se h. it tl w R t ( i i ^December, 1963 significant dif- rs--humans. Exi room measuring provided with a iply. The vapor ' by atomizing the res of two large or concentration 1 and continuous `d spectrophoto>der. Vapor con ned continuously and spot samples lions of the room "iirement by annn silica gel for i blonde determi(.1 concentration of 476 to 590; concentrations sparing in this rte history and jveek preceding ployed in an ^Wect of the ex exposure : oral pulse rate; excomplete blood 11 acetic--transami ophoresis, and urine for coin- uplete neurolog ies of vapor exdar, cerebellar, every 75 minperception, eye, lache, dizziness, minutes; Crawt every three Classification air for solvent rs of exposure; agar; blood for irs of exposure: 14-hour urobil- Industrial Hygiene Journal Table I Single-Dose Oral Toxicity of a Solvent Mixture (Dowclene EC Cleaner) Species Ruts Rata Mice Guinea Pigs Rabbits Sex Male Female Female Male Mixed No. of Animals Used '20 20 25 16 16 LDi, Value Rm/k* H.N 14.x 10.3 5.7 12.6 Range gm/kK 10.0--20.7 9.0 --22.8 8:4 -- 12,8 3.5-- 9.2 6.2--25.6 545 inogon detennination; and electrocardiogram after Master's double two-step exercise after three hours of exposure. Following the exposures: serial expired air analyses for solvent concentration; 24-hour urinary urobilinogen determinations for ten days; complete blood count 72 hours after exposure; serial SCOT determinations; and serum protein electrophoresis. The expired air samples were obtained by having the subject take a deep breath, hold it for five seconds, then forcibly expel all of the breath possihle into a saran bag. This was repeated until a sample of about 15 liters was obtained. Results Oral Administration: Rats, Mice, Guinea Pigs, and Rabbits Groups of five male and five female rats, five female mice, five male guinea pigs and four male or female rabbits were given graded doses of the undiluted solvent mixture by intubation. The LDr,,, values and their ranges are given in Table I. The typical signs in the treated animals were various stages of anesthesia, diarrhea, and sometimes death. Deaths occurred from a few hours to a few days after feeding. The cause of death appeared to be respiratory failure. Gross ex amination of rats sacrificed 24 hours after treatment with various sized doses revealed only mild liver and kidney effects. Eye Contact: Rabbit When die undiluted solvent mixture was introduced directly into the eye of a rabbit, it caused immediate pain and a slight con junctival irritation which cleared within 48 hours. Shin Contact: Rabbits Repeated applications (nine applications in 11 days) to the uncovered car of a rabbit caused only a very slight eiythcma and ex foliation. When cotton pads wet with the solvent mixture were bandaged onto shaven intact abdominal skin nine times in 11 days, slight to moderate erythema, slight edema and slight exfoliation resulted. No necrosis occurred. When the material was bandaged onto abraded skin three, times in three days, moderate erythema, edema, and exfoliation occurred. Healing was complete within a week without scar information. Studies to evaluate the capacity of the material to penetrate the skin showed that doses as large as 30 gm/kg were not lethal to rabbits. Some weight loss did occur during the first few days post exposure, but recovery was Complete within two weeks. The skin of these animals was burned superficially but healed promptly without scarring. Inhalation Single esc/insure--rats. Thirty groups of ten female rats each were exposed for either 0.5. 1.0, 2.0, 4.0. or 7.0 hours to various con centrations of the solvent vapor. The EDr,,, values weie calculated and the results are shown in Figure 1. For comparison, similar data were obtained on the' two major con stituents. l.I.l-tricliloroclhano and telrachloroeth)lene. of the solvent mixture and these results are shown also in Figure 1. The only important effect of excessive acute exposure was depression of the central nervous system (anesthetic effect). The de gree of depression varied with the intensity of the exposure and deaths generally were attributable to cardiac or respiratory failure. ! 546 November-Dccembcr, 1963 Iruln Final Figure 1. Comparison of the single-dose inhalation toxicity for rats of a solvent mixture (Dowclene EC Cleaner) with that of its major constituents, 1,1,1-trichIoroethane and tetrachlorocthylcne. The middle line (solid dots) represents the LCm values for the solvent mixture: the top line (triangles), the same for 1,1,1 -trichloroethane; and the bottom line (circles), the same for tetrachloroethylene. A lew delayed deaths occurred but when ex aminations were possible evidence of respira tory infection was alwavs found. Repeated e\paunr---rats. Rats tolerated as many as 180 seven-hour ex|x>sures in 186 days to either 1000 or 500 ppm of the solvent vapor without evidence of adverse effects as judged by mortality, general appearance, be havior, hematologic examination, urinalysis, alkaline phophatase and urea nitrogen levels in the serum, and organ and organ-to-bodyweight ratios. The most pertinent of these data are given in Tabic II. Detailed data for those animals maintained as controls for six weeks after the exposures ceased (group B) and those that received repeated ex posures over a six-month period for four, two, or one hour per day are not tabulated be cause they were all within normal limits when compared to the control groups. This would be expected in view of the data pre sented. Microscopic, examination of the sections prepared from the various organs taken at autopsy from the rats exposed seven hours a day over a period of six months to 1000 ppm of the solvent vapor revealed only the following abnormalities. Changes in the liver were characterized by moderate diffuse cloudy swelling, occasional vacuolization, scattered foci of focal necrosis in the central portion of the lobule, and some enlarged liver cells having a hyperchroinatic nucleus and a prominent nucleolus. In the kidney, the only abnormality observed was a mod erate degenerative change in the epithelial lining of the convoluted tubules. These or other deviations from normal were not observed in those rats exposed in a similar way to 500 ppm of the solvent vapor. Repeated exposure--guinea pigs. Groups each consisting of nine males and eight female guinea pigs were started on tile ex periment at both the 500 and 1000 ppm Unoxp1 Air-c^i tJnfxr Air-**xi V * Hit ** An lt*vr! that tinm level food anin as i rate epid the groi min fieir mil few pos' lull', voh S min abo bfr-)ecember, 1963 HU io.o v for 'f its ' Icne. i the 1-triletra- 'lion of the sections ` i ious organs taken at exposed seven hours I six months to 1000 ;>or revealed only the v Changes in tire 1 by moderate diffuse idonal vacuolization, necrosis in the central , and some enlarged perchromatic nucleus olus. In the kidney, i >bserved was a mod*nge in the epithelial d tubules. iations from normal l iose rats exposed in a i of the solvent vapor. guinea pigs. Groups me males and eight re started on the ex- 500 and 1000 ppm Industrial Hyginie Journal 547 Table II Final Average Body, Liver, and Kidney Weights and Biochemical Values Irom Rats that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleaner) Five Days a Week,for Six Months Vapor Cone. ppm Unexposed control Airexpoaed control 1000 600 Unexpoaed control Air-exposed control 1000 500 No. of each group surviving, Sex group A group B M 11 9 M9 MH M 10 10 H 10 F 10 11 F it Fn F 12 11 8 10 Final** Av*. Body Wt,, gm 333 340 341 343 190 193 193 207 Organ ^ /eights* gm/lOOgni Body Wt. Liver Kidney Aik, Phosphatase* Serum Urea King-Armstrong Nitrogen* Units mg/100 ml. 2.63 0.73 32.fi 2l.fi 2.70 2.07 2.67 0.79 0.77 0.7# 22.4 2H.fi 23.7 18.2 18.7 19.6 2.99 0,83 20.4 26.5 3.12 3.19 3.03 0.81 0.86 0.82 14.fi 14.fi 16.1 24.8 26,6 26.9 * Based on animal of group A, autopaied the day after the last exposure. ** Animals starved for 24 hours. levels. After a few weeks it became apparent that growth of the males in both concentra tions and of the females at the 1000 ppm level was being depressed. Measurement of food consumption revealed that the exposed animals were consuming only about one half as much food as the controls. Before the cause of this effect could he determined, an epidemic of respiratory infection occurred in the control as well as in the experimental groups and this made it necessary to ter minate this portion of the study by sacri ficing the few remaining animals. Gross and microscopic examinations of sections of the few remaining animals in the control and ex posed groups revealed severe infection in the lungs with pronounced liver and kidney in volvement in all groups. Since it was believed important to deter mine whether the growth depression noted above was due to simple anorexia or to in jury lo sonic organ, a paired-feeding study was initiated. Males were used in this study because it appeared from the previous study that they were more sensitive than the females. At the beginning of the experiment it was apparent promptly that the exposure to the solvent caused a marked reduction in food intake during the week when exposures were given. On the weekends, when no exposures were given, food consumption was essentially nonnal. Also, the magnitude of the reduc tion in food intake was markedly smaller for those animals exposed to 500 ppm than for those exposed to 1000 ppm of the solvent. The magnitude of tire reduction in both ex perimental groups decreased each succeeding week so that after four weeks, food consump tion was essentially nonnal for both experi mental groups. The growth of the animals exposed to the Table III Final Average Body, Liver, and Kidney Weights and Food Efficiency Values from Male Guinea Pigs that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleaner) Five days a Week for Seven Weeks in a Paired-feeding Study Vapor Cone. ppm Air-exposed control Sou Air-exposed control 1000 U> P -0 027 fh) [' ,0.25 No, of Animals 6 <; o 6 * Final Avg, Body Wt.f gm 740 702 700 706 Avif. Bodv Wt. gain, tem 100 129 73 74 Organ Weights gm/loOgm Body Wt. --------.------- - Liver Kidney 3.15 4.00(a) 0.67 0.71 3.37 3.75(b) 0.07 0.68 Food Efficiency ----------------------- ------ gm of food eaten / gm of wt. gained 12.3 10,fi 16.0 16.0 SL 036399 548 Novcmber-Dccernber, 1963 Table IV Final Average Body, Liver, and Kidney Weights and Biochemical Values from Rabbits that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleaner) Five Days a Week for Six Months Vapor Cone. ppm Unexposed rontrol Expound control 1000 500 Unexposed control Exposed control 1000 500 No, Surviving Sox No. Started M 3/3 M 2/3 M 3/3 M 2/3 V 3/3 K 3/3 F :i/s F .1/3 Final Avk. Rodv Wt,, kg. 3.57 3.42 3.K8 3.38 4.01 3.45 3.00 3.xi; Organ Weights gm/lOOgm Body Wt. Liver Kidney 2.29 2.00 2.63 2.G6 2.42 2.48 2.53 2.79 0.48 0.54 0.51 0-47 0.40 0.44 0.17 0.45 Aik. Phosphatase King-Armstrong Units 9.1 5.H 0.8 14.2 10.4 7.5 11,2 9.1 Serum Urea Nitrogen mg/100 ml 24.5 2S.2 21.5 24.0 2H,S 23.1 26.1 2M.2 solvent vapors was not significantly different from that of their controls eating the same amount of food. The animals exposed to 1000 ppm of vapor ate less and hence gained less than those exposed to 500 ppm. Also, the food efficiency (grams of food required per gram of weight gained ) of those exposed' to 1000 ppm of s apor was poorer than that of those exposed at 500 ppm, but it was essen tially the same as that of their controls. The pertinent data obtained from tile paired-feeding study is given in Table Ilf. Organ weight studies show that the livers of those animals that received .500 ppm of sol vent vapor were elevated slightly above those of their controls. Although the difference is statistically significant, it is not consistent with the findings for those animals exposed to 1000 ppm. Furthermore, histopathologic ex amination of sections from the livers and other organs from those animals exposed to 500 ppm revealed no changes when com pared to the controls whereas sections from the guinea pigs exposed to 1000 ppm did re veal changes in the liver and kidney. In the liver, moderate hydropic degenerative changes in the central areas of the lobule and a few loci of focal necrosis were observed. 1 he effect on the kidneys was characterized by degenerative changes in the epithelial lining of the convoluted tubules and round cell infiltration in the interstitial tissues, par ticularly around the glomeruli. Repealed expouue--labbils. Rabbits toler ated 126 seven-hour e.\|x>sures in 182 days to 1000 ppm of the solvent vapor without any evidence of adverse effects except mild changes in the liver and kidneys observed microscopically. The changes were of the same character, hut milder in intensity than those described for the rats. The rabbits exposed to 500 ppm of solvent vapor did not show these changes and were normal in all respects when compared to con trol animals. The pertinent data are given in Table IV. Repeated exposure--dot's. Dogs tolerated 131 seven-hour exposures in 189 days to 1000 ppm of the solvent vapor without any ad verse effects as judged by appearance, be havior, mortality, growth, hematologic studies, urinalyses, organ weights, and the re sults of the various biochemical studies shown in Tables V and VI. Microscopic ex amination of sections of liver taken from each dog [trior to any exposure, after about three months of exposure, and at autopsy revealed that definite changes had occurred in the lit er of the. female dog exposed to 1000 ppm of the solvent vapor. There was little dif ference between the effects noted in the sec tions trom the midterm biopsy and those pre pared horn the liver taken at autopsy. The liver cells were large and distended and their nuclei were hyperchromatic. There was a 036  a- g o' p a p s M Sr o TOX3 PCL fPt 3 < < s; * 2 cr o -< ^ 3 o c. 3 ^ sft ^ o " S o p Han ?5 = 3 gI 2 E 2 5- o ft $ a 8 5 aS O 3^-i-- - O co aaft Tv3> CL "S _ fl> f&gff*- np 23 o 5 ^ cr 2 } o o^n o cl 3 p stCoO MO Qfj -[J - " in ,_+ ^O cn-r* rTr1 3ft S ? r> 3 3< tOr CL 5r- p3 Q. nf-t >i p 3* o . , --ftt CL FS` 3 o<2. O* pCL 5 O O *D D- _ Fo Ln -. cftl pcr 3 o- a 35 p ,, a <3- s r_ O o CL P s a 3P T33 033 T"33 P a.o p o 3 3 *"* CL g ft ^3 -- Oq S3 55 ft ft i3n aft '< o sr- 3 *> S' B: i? m *5 o <* rr f3t ft % ' Xn o rfrt cr ^ ~-r.r rrcoor Ece. Llr o n 3.' 3- ET 3 ^C 't rr a c Cl cl ^ o 1' l|e*M L to *C 3C L> 3 9 IQ 2 13 ST 1 sisr" mkm to toeoro m 3 IQ CO Z% M L i. x b crt to in O O 33 S ' pa ft f<t CL a O- to Fto1 & 036401 Table V' Final Average Body and Organ Weights from Dogs that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleaner) Five Days a Week for Six Months Vapor Cone, ppm Une sposed control Air-exposed control 1000 500 Unexpoaed control Air-exposed control 10UU 500 Final No. of Avif. Sex Animals Body Wt., kg M 1 10.4 M l 12.5 M 11.7 M L 14.1 F 7.9 F l 12.3 F1 6.4 F1 9.6 Lung 0.99 0.72 0.85 0.56 0.90 0.69 1.05 0.86 Heart (l,,S5 0.57 0.78 0.66 0.66 0.72 0.94 0.84 Organs Weights gm lOOgra Body Weight Liver Kidney 3.5a 0.52 2.85 2.95 2.11 0.41 0.49 0.35 3.40 0.40 2.50 2.74 3.71 0.34 0.55 0.52 Spleen 0.24 0.21 0.27 0.1S 0.19 0.25 0.29 0.40 Testes 0.16 0.10 0.13 0.09 Table VI Summary of Biochemical Values from Dogs that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleaner) Five Days a Week for Six Months Vapor Cone. ppm No. Sex of Doga Alkaline Phosphatase Kmg-Armstrong Units Serum Urea Nitrogen mg LOO ml Brornsulfalcin Percent Retention in Serum Pre-exposure Midterm Terminal Pre-exposure Midterm Terminal Pre-exposure Terminal UnexpiKud control M 1 12.4 11.3 7.0 27.3 15.8 30.0 0.8 3.0 Air-exposed control M 1 12.2 6.3 3.8 17.0 20.0 15.1 3.4 3.9 1000 M1 20.2 11.8 5.6 20.4 16.0 21.4 4.2 5.6 500 M1 13.3 11.1 5.2 23.3 26.6 24.2 5.7 6.2 Unexposed control F 1 14.2 10.4 6.1 19.3 30.9 16.1 2.9 3.9 Air-exposed control F l 15.4 12.9 5.0 23.6 25.0 25.4 lost lost 1000 F1 5.8 4.5 3.4 20.4 16.0 11.9 lost 4.0 500 F1 13.7 13.1 3.6 31.2 13.8 18.6 7.6 5.0 sr.p-T SigmaFrankel Units Terminal lost 20 20 19 20 27 26 23 >J1 k Tahi.e VII Average Concentration of Vapors in Expired Air of Dogs! that Received Repeated Seven-hour Exposures to a Solvent Mixture (Dowclene EC Cleanerl Five Days a Week for up to Six Months Specks Dog No. Sex Exposure Cone. ppm No, of Exposures 0.2 0.05 A* ppm B* ppm Time Sample Taken from Dogs Alter Last Exposure (Hours) 1.2 0.2 3.5 0.1 17 0.5 A ppm B ppm A ppm B ppm A ppm B ppm 65 1 A ppm B ppm 272 270 274 233 276-279 F M F M M-F 500 500 1000 moo None 60 15 40 10 19 7.5 4.7 3.4 1.2 1.4 Up 50 U 27 7.1 15 4,6 7.1 3.5 2.4 1.8 to 119 24 H5 21 44 16 7.7 7.7 1.8 1.8 115 94 2l> 55 16 25 7.8 11.3 6.S 1.9 1.5 None detected *A =* 1,1,1--trichlorocthane **B = tetrachloroethylene ,. . ., , , , , w .. ..... | values include an undetermined dilution factor inherent in the sampling procedure employed and hence they arc not directly comparable with the values given m ruble V III. Novcmbcr-Dccetnbcr, 1963 ' Industrial It r* --; ZZ . 2; Z ^ * x *n* * SrH ? ^=1 ? 2,= 2 o'-< i 22 5`~T-- ''Calls 2 ? s 2 i =: g- J4- = S. O O' ' ,: 5 " = 2 ^ S 2. = 2- S 5 5 ,, S >2 = L. ~ Industrial Hygiene Journal 551 slight increase in the amount of connective tissue in the portal spaces. The. male dog re ceiving the same exposure showed minimal changes which were considered to be within normal limits. Sections from the numerous other tissues taken revealed no changes at tributable to the exposure. The dogs that received 131 seven-hour exposures to 500 ppm of the solvent vapor were normal in all respects as judged by all of the criteria employed. Single and repeated expos me--human sub jects. The human beings that received cither one, four, or live seven-hour exposures to 520 ppm of the vapor of the solvent mixture ex hibited no evidence of any adverse effect nor deviations outside normal limits in the nu merous clinical tests to which they were sub jected. The only untoward subjective symp tom observed was the assertion by one subject that his throat felt dry during exposures. Observations in regard to the odor of the vapor of the mixture arc worthy of note. The consensus of the group was as follows: initially the odor was strong but not objec tionable, after an hour it was perceptible but not strong, and after five hours it was barely perceptible. Persons exposed on consecutive days were barely able to detect the solvent odor after two or three hours of exposure, and then only upon deep inspiration. Analysis of expired air from dogs and human subjects. The results of analyses of the samples of expired air taken from the dogs and human subjects are given in Tables VII and VIII. Although it is not apparent from the summary data given in Table VII, the concentration of either 1,1,1-trichloroethane or tetrachloroethylene in the expired air of the dogs at any given time after an ex posure was not related to the number of ex posures. For example, the range of concen trations found in samples taken from dog number 272 about 1.2 hours after 1, 2, 5, 10, 29, and 113 exposures were 49, 43, 32, 35, 41, and 41 ppm of 1,1,1-trichlorocthane and 10.1, 9.7, 10.8, 9.4, 12.9, and 9.1 ppm of tetrachloroethylene. The same type of data were obtained at the other sampling times. The ranges were always narrow for any one dog but varied from one dog to another. It is interesting to note, also that 65 hours alter the last exposure, the levels of each constit uent material in the exhaled air of the dogs do not appear to be dependent upon the con centration inhaled, at least within tire range of 500 to 1000 ppm. The data in Table VIII indicate that the concentration of cither 1,1,1-lrichloroelhane or tetrachloroethylene in the expired air of humans becomes stabilized after two or three seven-hour exposures, rather than alter one exposure as in a dog. It also indicates that although the levels of solvent in the expired air one-half hour after a single exposure are similar to the levels one-half hour after sev eral exposures, the levels an hour or more postexposure are distinctly lower. The rate of excretion, after the first few hours appears to be independent of the number of ex posures. This suggests that there is some deposition of both constituent solvents with in the body as a result of a single exposure, and that the level of deposition is only slight ly greater after repeated exposures than after one. Discussion The results of the studies described in this report show that the solvent mixture does not possess toxic properties above and beyond those which would be expected from a knowl edge of the toxicity of its constituents. Ex posure to 500 ppm of the vapors of the mix ture amounts to simultaneous exposure to 400 ppm of inhibited 1.1,1-trichloroethane (Chlorothene NU Solvent) and 100 ppm of tetrachloroethylene. Under the conditions described, neither material alone in these concentrations would be expected to cause any adverse effect and in the absence of po tentiation, none would be expected from the mixture; the data obtained substantiate this expectation. Likewise, exposure to 1000 ppm of the vapors of the mixture amounts to simultaneous exposure to 800 ppm of in hibited 1.1,1-trichloroethane and 200 ppm of tetrachloroethylene. Although 800 pptn of SL 036403 N> Table VIII Concentration of Vapors in Expired Air of Male Human Subjects that Received Seven-hour Exposures to 520 ppm of a Solvent Mixture (Dowclene EC Cleaner) Individual No. of Exposures R.S. D.E. H.O. V.R. T.T. 1 2 3 4 5 2 3 4 5 1 2 3 4 5 1 2 3 4 1 0.5 A* ppm B** ppm 82 20 90 22 9_1 2_6 81 27 83 22 92 28 114 27 93 32 6863 2200 8_1 2_2 6? 21 ___ _ 75 20 83 20 *A ** 1,14--triehloroethane **B = tetrachloroethylene 1.0 A ppm B ppm 73 75 8618 2107 22 20 66 23 62 6664 19 20 21 57 21 76 28 64 14 53 15 52 16 49 17 57 19 __ 64 6664 2108 10 45 13 Tim; After Exposure Sample Was Taken (Hours) 3.0 A ppm B ppm 16 A ppm B ppm --33 40 34 43 9 11 15 17 LL 17 16 4 --8 8 46 16 -- -- 32 40 44 44 10 10 15 16 -- 21 18 18 --4 10 10 44 17 -- -- 30 38 33 40 40 8 10 12 13 12 9 1--2 12 -- 3 --5 6 -- 39 39 1120 10 16 42 13 16 43 14 14 3 65 7 20 . 6 10 3 A ppm 24 B ppm n5 ---- 12 4 11 4 ---- 64 AB ppm 10 4 74 4 ---- 6.5 2.4 } i- o " ui p j 1 O ^ & :r X 3 ~ U-33 S 2E- T ^ 2 Nr-- IO 5. Q ST -- ti.. STM T3^ = r .S c gO 'HPT* o *O 3r*v ^/I fcL rN --, 2~ c/> y 2. ^ "2. H 3Q tz 5T Sf EH pn 3 Er o* 2- -t* o OP y C-"3 2 3 y " _ 7= v ? : 3 5T; ."i-5 p 5` 5'^ 'c' f 5- /'frS--:3 5'c` 3 g J. 5 2-JoI g.J * - |r =; 3" 2. ^ * s*I 31: t tetrachloroethj k-nu i Oecember, 1963 j ii Industrial Hygiene Journal 553 the inhibited 1,1.1-trichlofoethnnc alone low for rats, the I,,C,,, concentration heing ap ! would not be expected to cause organic in- proximately 24.000. 20.000, 16.500, 14,000, l jury, some injmy would be expected from 200 and 12.000 ppm for exposures of 0.5, 1.0, 2,0, ppm of tetrachlorocthylenc. Again, if there 4.0, and 7.0 hours. i is no potentiation, some, but not substantial The repeated-dose inhalation toxicity of injury would be expected and the data ob the solvent also is low. Rats, guinea pigs, tained substantiate this expectation. Further rabbits, and one of two dogs that received support for this is found in the residts of the repealed seven-hour exposures to 1000 ppm i single-dose inhalation studies shown in Figure of the vapor exhibited mild and reversible j 1. The fact that the LCr,,, curve for the mix liver and kidney changes. Rats exposed to ture lies below, but close to the curve for 1000 ppm for four hours a day or less and 1,1,1-trichloroethane alone, is evidence of the those maintained under control conditions for j lack of potentiation. This was confirmed by six weeks after six months of daily exposure calculating an "expected LC,,, curve"' for the were normal. The growth of guinea pigs was ; mixture from the I,C.,,, data for each con depressed; a paired-feeding study showed this stituent; this resulted in a line essentially to be due to a decreased intake of food. j superimposed on the observed line. Rats, guinea pigs, rabbits, and dogs that I The data obtained from the analysis of ex received repeated seven-hour exposures to pired air samples from both dogs and human 500 ppm of the vapor suffered no adverse subjects gives valuable information, the sig effects other than a slight depression of nificance of which may not be entirely clear growth in the guinea pigs; again, this was at the present time because of the lack of due to decreased intake of food. similar data on other substances. Human subjects that received from one to The similarity in data obtained from the five seven-hour exposures to 520 ppm of the . dogs exposed for six months and that ob solvent vapor experienced no adverse effects tained from the human subjects exposed for when judged by a battery of subjective ob up to 5 days, strongly suggests that a state of servations and clinical and laboratory studies. equilibrium must be readily attained; and further, the major portion of any deposits Excretion of both major constituents of the which occur must be readily depleted in the mixture via the lungs occurs in both dogs absence of ex]>osure. Confirmation of these and human subjects at a substantial rate, interpretations will have to await further particularly during the first 18 to 24 hours study involving not only expired-air samples [x>stexposure. This fact may well be one of but also serial sampling and analysis of body the main reasons why the toxicity, both acute tissues and possibly material balance studies. and chronic, is so low. As a result of the extensive studies con Summary ducted, it is concluded that there is no ap preciable hazard from repeated seven-hour A solvent mixture (Dowclene EC Cleaner) exposures to 500 ppm of the solvent mixture consisting essentially of 75% of inhibited 1,1,- (Dowclene EC Cleaner). Therefore, it is 1-trichloroethane and 25% of tetrachlorueth- recommended for normal operation that the 1 ylene by weight has been studied extensively concentrations of vapor to which persons are ; using mice, rats, guinea pigs, rabbits, dogs, exposed repeatedly, seven to eight hours a 1 and human subjects. The solvent is low in day, be below 500 ppm. Occasional ex t single-dose oral toxicity, the Ll),0 doses rang- posure of short duration to slightly higher i ing from 5.7 to 14.8 gm/kg for the four species concentrations would not be expected to i of small animals. It is but mildly irritating to cause organic injury, but from a subjective 1 the eyes and skin of rabbits. It is not readily viewpoint, might well be objectionable to absorbed through the skin of rabbits; the LD,,,, some people. It is further recommended that for 24-hour exposures being greater than 30 any exposures to concentrations exceeding gm/kg. The single-dose inhalation toxicity is 800 ppm be avoided and that the time- j t t 554 November-December, 1963 weighted average concentration not exceed 400 ppm. Acknowledgment The authors wish to thank H, II. Gay, M.D., D. S. Erley, C. F. Licht, H, Ode, G. J. Wright, T. R. Torkelson for participating in the studies on human subjects, A. W. Schaffer and Lorna Stolpe for their help in monitoring the vapor concentrations to which persons were exposed, and the many other persons who assisted in the biochemical and analytical work. References 1. Torkrlson, T. R., F. Oyen, D. D. McColurtkr, and V- K* Rowf.: Toxicity of 1,1,1-TrichJoroethane as De termined on Laboratory Animals and Human Subjects. Amer. Ind. Hyp, Assoc. ] 19: 353 (1958), 2. Rowk, V. K., D. D. McCollister, H. C. Spencer, E. M. Adams, and D. D. Irish: Vapor Toxicity of Tetrachloroethylene for Laboratory Animals and Human Subjects. AMA Arch. Ind. Hyp. and Occup. Med. 5: 566 (1925), 3. Won', M. A., V, K. Rowe, D. D. McColustf.k, R, L. Hollingsworth, and F, Oyen: Toxicological Studies on Certain Alkylated Benzenes and Benzene. AMA Arch. Ind. Health 14: 387 (1956). 4. Draize. J. IL, G. Woodard, and H. O Camery: Methods for the Study of Irritation and Toxicity of Substances Applied Topically to the Skin and Mucous Membranes. J. Pharmacol. Exptl. Thcrap. 82 : 377 (1944). 5. Yafpt, C. IT, D. H. Byers, and A. D. IIosey, Tech nical Editors1: Encyclopedia of Instrumentation for In dustrial Hygiene. p. 95, University of Michigan Instiinle of Industrial Health, Ann Arbor, Michigan (1956). 6- Sty.wart, R, D.( H, H. Gay, 1). S, Erley, C. L, Hake, and A. W. Schaffer: Human Exposure to 1,1,1-Trirhloroethane Vapor: Relationship of Expired Air and Blood Concentrations to Exposure and Toxicity. Amer, Ind. Hyp. Assoc. /. 22: 252 (1961). 7. Stewart, R. D., H. H. Gay, D. S. Erlfy, C, L. Hake, and A. W. Schaffer: Human Exposure to Tctrachloroethylene Vapor: Relationship of Expired Air and Blood Concentrations to Exposure and Toxicity. AMA Arch. Environ. Health 2: 516 (1961), 8. Fisher, R. A,: Statistical Methods for Research Work ers, Ed. 7, London, Oliver and Boyd Lid., (1938). 9. Schaffer, A, W., and II, R, Hoyle: Nine Years' Ex perience with the Davis Halide Meter. Amer. Ind. Hyg. Assoc. J. 22: 93 (1961). 10. Peterson, J. E., H. R. Hoyle, and E. J. Schneider: The Analysis of Air for Halogenated Hydrocarbon Con taminants by Means of Adsorption on Silica Gel. Amer. Ind. Hyg. Assoc. J. 17 : 429 (1956). Obituary Dr. Charles W. LaBelle, Assistant Professor of Environmental Hygiene at Jefferson Medical College of Philadelphia, died on November 7, 1963, after an illness of only two days' duration. He received his bachelor degree from the University of Rochester in 1945. He became a Research Assistant in the De partment of Pharmacology of the. Medical School of this University and par ticipated in its Atomic Energy Project. From 1950 to 1954, he worked as toxicologist at the Army Chemical Center. Since then, he had been with the De partment of Preventive Medicine, Jefferson Medical College, and obtained the doctoral degree in pharmacology and toxicology in 1959. Dr. LaBelle is widely known for his work in the field of behavior and biological effects oi particulate air contaminants. This Journal was privileged to publish one of his most recent publications in the preceding issue. He joined the American Industrial Hygiene Association in 1948 and had been an active member of the Association since that time. We join Dr. LaBelle's friends and co-workers in expressing our deep sense of loss, both personal and professional. A Continuous!' Air-1 ALFRED L. u. s. Pubi (g A vacuum tube cl ble, shortened con ion concentrations in which produce a conislant of approximate! levels of concentration Introduction INTEREST in the biologi borne ions dates from t F. Dcssauer in 1921, and 1 jeet of many investigations An attempt to make a i| of the effects of ions on anil able instruments for gem measuring their concentrn describes an instrument l> concentrations in air. A review of the literatii struments and techniques o us to adopt many of the i ion collectors and to de\ inexpensive, continuously trometer. The advantau recording over intermitle apparent; one important any change in the ion I< the ion generators is quick effects of adjustments are li ly that it is relatively sim|il best ways to generate the r of ions desired. The ions found in tin to be formed by the actio other circumstances whir electron from an otherwi gas. The immediate prod event is an ion pair; the atom or molecule with i and an electron which q> Present address: The Uoivc School of Public Health, Chapel lt< 036406 si* THE TOXICOLOGY OF 1,1,1 -TRICHLOROETHANE Richard D. Stewart Department of Environmental Medicine, Marquette University School of Medicine, Milwaukee, Wisconsin, U.S.A. {Received 23 September 1967) Abstract--Judging from the human toxiological data reported, 1,1,1-trichloroethane appears to be one of the least toxic members of the group of chlorinated aliphatic hydrocarbon solvents. This compound is rapidly absorbed through the lungs and the gastrointestinal tract. Most of it is excreted unchanged via the lungs. The absorption of a toxic quantity results in a functional depression of the central nervous system which may result in death from respiratory arrest or peripheral vascular collapse. Acute over-exposure to anesthetic concentrations of the vapour can result in transcient kidney or liver dysfunction. Permanent organic injury has not been observed following recovery from the anesthetic effects of this solvent. The diagnosis of exposure to this compound can be made by specifically identifying 1,1,1trichloroethane in the expired breath of the exposed person. Comparison of the results of serial breath analyses with available human data affords a means with which to estimate the magnitude of the chemical exposure. Since the commercial introduction of 1,1,1 -trichloroethane (methyl chloroform) in 1954, this solvent (in its inhibited form available under the trademark Chlorothene NU) has become increasingly popular, primarily because of its low toxicity. Its use now exceeds 40 million pounds per year in the United States, where it has been used principally for cold-cleaning, dip-cleaning, and bucket-cleaning of metal for the removal of greases, oils, and waxes. It has also proved useful in dry-cleaning, in vapour degreasing, and in aerosol applications. Because of the solvent's increasing use in Europe and since it is being promoted as one of the safest of the chlorinated aliphatic hydrocarbon solvents, it is appropriate for the physician to examine the existing toxicological information. Physical and chemical properties 1.1.1- trichloroethane, CH,CCU, is a colourless liquid possessing a distinctive, chloroform-like odour. It has a specific gravity of 1 -336 at 25C, a vapour pressure of 127 mm Hg at 25C, and a boiling point of 74-lC. This compound is very soluble in organic solvents such as carbon bisulfide and carbon tetrachloride, but it is only slightly soluble in water (Van Arkel and Vles, 1936). Like many chlorinated hydrocarbons it reacts with aluminium and aluminium 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 in air at standard temperature and pressure. The limits of flammability of the vapours of the 71 mmmf ^ 036A07^B!ll^WPiPP)Wp|i>W kzC-Jh1 lO JAN 15 1975 ........... 1----- - 72 Richard D. SfF.WART inhibited compound arc 10 15-5 per cent in air with hot wire ignition only when considerable energy is used lor ignition. It has no flash point or fire point using the standard ASTM procedures for the Tag closed-cup and Cleveland open-cup tests. At temperatures below 260C, only minimal thermal decomposition occurs. At 260C, large amounts of hydrogen chloride and trace amounts of phosgene are formed (Crummet and Stenger, 1956). Sufficient hydrogen chloride is formed to provide adequate warning. Absorption, metabolism, and excretion 1,1,1-trichloroethane is rapidly absorbed through the lungs and the gastro intestinal tract. Following absorption, most of the compound is eliminated unchanged via the lungs. Nearly 9# per cent was excreted unchanged in the expired air of the rat following an intraperitoneal injection of C'Mabeled compound (Hake et at., I960). One-half per cent of the dose was metabolized to carbon dioxide while the remainder appeared in the urine as the glucuronide of 2,2,2-trichloroethanol. Man, like the rat, is able to metabolize a small percentage of this solvent to trichloroethanol (Stewart et a/.). Five male volunteers were exposed to 500 ppm of inhibited* 1,1,1-trichloroethane, 7 hours per day for five consecutive days. Nine months later the same subjects were exposed to trichloroethylene vapour, 200 ppm, 7 hours per day for live days. Twenty-four hour urine collections obtained before, during, and following these vapour exposures were analyzed for trichloroethanol and trichloroacetic acid. These data are presented in Table 1. The difference in the metabolism of these two compounds in man is striking. Table l.f Urinary excretion of trichloroacetic acid (TAC) and trichloroethanol (TCE) IN FIVE SUBJECTS DURING AND FOLLOWING VAPOR EXPOSURES TO 1,1,1-TRICHLOROETHANE AND TRICHLOROETHYLENE Control value (mean and range) 1,1,1 -Trichloroethane, 500 ppm 7 hr/day for 5 days TCA TCE (mg/24 hr) (mg/24 hr) 14,2(8-22,8) <11-1) Trichloroethylene, 200 ppm 7 hr/day for 5 days TCA TCE (mg/24 hr) (mg/24 hr) 2 (1-4) <1 l-3) 1st Exposure day 2nd Exposure day 3rd Exposure day 4th Exposure day 5th Day following last exposure 12th Day following last exposure 7,5 (2,6-10,5) 20,1 (7,9-49) 10,9 (8,2-19,3) 30,1 (14,8-66,5 175 (113-238) 12,3 (5,6-27) 29,3 (19,1-51) 229(148-416) 14,1 (7,8-19,2) 46,6 (23,4-93,6) 306 (231-439) 18 (13-26) 7(1-14,9) 50(35-61) 17,5 (8-22) <11, ) 8(2-22) jvo 339 (294-480) 399 (296-546) 538 (249-822) 15 (10-18) 14 (1-37) tStewart et at., to be published. The absorption of 1,1,1-trichloroethane through the skin of the hand has been measured in six human subjects (Stewart and Dodd, 1964). Continuous immersion of the thumb for 30 minutes demonstrated that this solvent was able to penetrate the skin, enter the blood stream, and be excreted in part through the lungs. The total Chlorothene-NU. 1 i I * i t amount topical less abs confinci through l k,. I. IT skin expov in far less Toxicity Acute is a funct tude of e> Huma prompt, Torkelso humans Y also may Below have been strated th 1,1.1 -trich test p/-ocei sensitive, The Th is a limiting centrations ' tModifie one foot. SL 036408 mmmmm The toxicology of 1,1,1-trichloroethane 73 amount absorbed through the skin, however, was very small (Fig. 1). Continuous topical application of this solvent to the entire hand for 30 minutes resulted in even less absorption. These skin absorption studies showed that unless the solvent is confined to the skin beneath an impermeable barrier, absorption of toxic amounts through the skin in the course of normal industrial operations is highly unlikely. Time in hours Fig. 1. The alveolar air concentrations for 1,1,1-trichloroethane during and following 30 minutes of skm exposure are plotted vs. time. Topical application of the solvent to the skin of the hand resulted m far less absorption than when the hand was continuously immersed for a similar period of time. Toxicity Acute vapour exposure. The principal toxic action of a single vapour exposure ts a functional depression of the central nervous system, proportional to the magni tude of exposure, and typical of an anesthetic agent. Humans exposed to 900-1000 ppm experienced transient, mild eye irritation and prompt, though minimal, impairment of coordination (Stewart et al., 1961; Torkelson et al., 1958). Above 1700 ppm obvious disturbances of equilibrium in humans have been observed (Stewart et al., 1961). Exposures of this magnitude also may induce headache and lassitude. Nausea has not been reported. Below the current Threshold Limit Value* of 350 ppm no physiological effects have been observed. The studies on man which have been conducted have demon't rated that there is a variation in human response to a given concentration of t.l.l-trichloroethane vapour (Stewart et ah, 1961 and unpublished work). Of the test procedures investigated, the modified Romberg test) has proved to be the most sensitive, objective, neurological sign of over-exposure (Stewart et ah, 1961 and `The Threshold Limit Value of the American Conference of Governmental Industrial Hygienists is a limiting concentration which should not be exceeded by the average of the time-weighted con centrations throughout the 8-hr day. tModified Romberg test: subject with eyes closed and with his arms at his sides, balances on one foot. WIRJI1 I. <*** .U[) lUiJifW SL. 036409 74 Richard D. Stewart unpublished work). In the past 15 years, two individuals have been studied who normally had difficulty in performing the modified Romberg test and who demonstrated increased difficulty in performing the test at a vapour concentration of 400 ppm. Another individual has demonstrated a normal modified Romberg test at a vapour concentration of 2650 ppm (Stewart et al, 1961). Thirty healthy volunteer subjects exposed to a vapour concentration of 500 ppm for periods from one hour to one work week, were able to repeatedly perform normal modified Romberg tests (Stewart et al, 1961 and unpublished work; Torkelson et al, 1958). General anesthesia in 51 humans, male and female, ranging in age from 9 to 70 years, has been reported (Krantz era/., 1959; Dornette and Jones, 1960). Recovery from anesthesia and regaining of reflexes was quite rapid, usually within 3 to 5 minutes after discontinuance of the anesthetic agent if the patient had been in a light plane. Recovery from deeper planes was slightly more prolonged. Twenty patients were conscious and responsive before being taken into the recovery room and the majority of the others recovered soon after arriving. These patients had a very low incidence of post-operative nausea and vomiting and the normal serum glutamic oxaloactic transaminase values measured on the second, fourth, and sixth post operative days suggested that anesthesia with this compound up to two hours duration would not produce hepatotoxicity (Dornette and Jones, 1960). Six human deaths as a result of over-exposure to 1,1,1-trichloroethane have been reported. Four deaths occurred following exposure to very high concentrations in unventilated tanks (Stewart et al., 1961; Kleinfeld and Feiner, 1966) In one of these tanks the concentration of 1,1,1-trichloroethane at the time of the accident was "well in excess of 5000 ppm" (Kleinfeld and Feiner, 1966). One death occurred in an open tank in which vapour concentrations exceeded several thousand ppm (Rowe, personal communication). Two suicide deaths by inhalation have been reported (Hall and Hine, 1966). One of these deaths was attributed to respiratory arrest while the second death was caused by aspiration pneumonitis. In 1964 the Toxicology Committee of the American Industrial Hygiene Associa tion presented a new series of guides to Emergency Exposure Limits which were intended to give guidance to industrial hygienists in the management of single, brief exposures to airborne contaminants in the working environment. Table 2 lists the recommendations for 1,1,1-trichloroethane (Toxicology Committee, Am. Ind. Hyg. Ass., 1964). Vapour 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 (Adams et al, 1950). A vapour concentration of 18,000 ppm for three hours was lethal for 50 per cent of exposed white rats; a 3-hr exposure to 10,000 ppm produced irregular respiration and a semicomatose state, but no deaths resulted. A disturbing property of this compound, as is the case with most solvents, is that at anesthetic concentrations, idioventricular rhythms may be induced in animals with epinephrine (Rennick et al, 1949). Therefore, it is possible that ventricular fibrillation leading to sudden death could occur in humans exposed to anesthetic concentrations. 1 i > ' < Ta Exposi time (min 5 15 30 60 *Toxii (H) (M) ] (R) I Studi by a clo; 60 minui blood pr arrest, thi This is it ether-indi Rats 33-3 per c observed The fail as measur by Plaa < studied, a; chloroethy form, and dosages oi renal dysfi W10 r.itcd ppm. pour \iocts ivorW v Am o 70 very -.o 5 light cnts the low mic ost- :ion een > in of vas l in ME, # ia:re ief he 'gl ut irt m :if lr it s r c> The toxicology of 1,1,1 -trichloroethane 75 Tabu 2.* Probable result of sinole exposure to the vapors of 1,1,1 -trichloroethanb Exposure time (min) Concentration in air (ppm) Expected effect in humans 5 20.000 Complete incoordination and helplessness (R) 10,000 Pronounced loss of coordination (R) 5000 Definite incoordination (R, M) 2000 Disturbance of equilibrium. Odor is unpleasant but tolerable (H) 15 10,000 Pronounced loss of coordination (R) 2000 Loss of equilibrium (H) 1000 Possible beginning loss of equilibrium (H) 30 10,000 Pronounced loss of coordination (R) 5000 Incoordination (R, M) 2000 Loss of equilibrium (H) 1000 Mild eye and nasal discomfort; possible slight loss ofequilibrium (H) 60 20,000 Surgical anesthesia, possible death (R) 10,000 Pronounced loss of coordination (R) 5000 Obvious loss of coordination (R, M) 2000 Loss of coordination (H) 1000 Very slight loss of equilibrium (H) 500 No detectable effect, but odor is obvious (R, H) 100 Apparent odor threshold (H) Toxicology Committee, Am. Ind. Hyg. Ass., 1964. (H) Expected effects are based on human data. (M) Expected effects are based on monkey data. (R) Expected effects are based on rat data. Studies conducted on dogs and monkeys anesthetized with 1,1,1'trichloroethane by a closed technique revealed no significant change in electrocardiograms during 60 minutes of deep surgical anesthesia; however, a depressor response upon the blood pressure was observed (Krantz et al., 1959). At the point of respiratory arrest, the blood pressure was reduced to approximately one-half of its normal value. This is in contrast to the minimal blood pressure depression produced by ethyl cther-indiced respiratory arrest. Rats deeply anesthetized with 1,1,1-trichloroethane for one hour showed a 33*3 per cent diminution in oxygen uptake of the myocardium, very similar to that observed with chloroform anesthesia (Krantz et al., 1959). The failure of 1,1,1-trichloroethane to significantly impair liver function in mice, as measured by the prolongation of pentobarbital sleeping time, has been reported by Plaa et al. (1958). The hepatotoxic potency of the chlorinated hydrocarbons studied, arranged in order of increasing toxicity was: 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene, tetrachloroethane, 1,1,2-trichloroethane, chloro form, and carbon tetrachloride. Following intraperitoneal injections of near-lethal dosages of 1,1,1-trichloroethane into mice, only mild hepatic dysfunction and no renal dysfunction was noted (Klaassen et al., 1966). c SL 036411 mmi 76 Richard D. Stewart To produce histological evidence of liver injury in white rats, vapour concen trations of 8000 ppm for 7 hours were required (Adams et al., 1950). A 5-hr exposure at the same concentration did not result in histological evidence of liver injury. Flo. 2. 1,1,1-Trichloroethane alveolar air concentrations following exposures to different vapor concentrations and for varying periods of time are shown. Mean and range breath concentrations are plotted. , [ , Repeated vapour exposure It is unlikely that significant organic injury resulting from repeated vapour exposure will occur in the absence of acute effects. No injury to man following repeated exposures to vapour concentrations of less than 500 ppm has been observed (Stewart et al., 1961 and unpublished work; Dow Chemical Company, Medical Records). Rats, guinea-pigs, rabbits, and monkeys were unaffected after 6 months repeated 7-hr exposures, 5 days per week to 500 ppm (Torkelson et al., 1958; Adams et al., 1950). Female guinea pigs which were found to be the most sensitive in previous experiments were able to tolerate 1000 ppm for 0-6 hr per day for three months. Male rats tolerated exposure of 0-5 hr per day to 10,000 ppm with no organic injury (Torkelson et al, 1958). Rabbits and dogs exposed to 2200 ppm for 8 hr per day for 6 weeks showed no visible signs of toxicity, although body weight loss occurred (Prendergast et al., 1967). Ingestion Absorption of a substantial amount of 1,1,1-trichloroethane from the gastrointestinal tract will produce the same functional depression of the central nervous system as described following vapour inhalation. If the amount ingested is sufficient to produce loss of consciousness, impairment of liver function may result. I I l The case ol 1,1,1-trichloroc minutes after s. tion he began hours after ing after ingestion complaint was limits. Two an l-r proieinuria 48 hours follow blood cell cou; serum glutamic performed thro The median experimental an 1949). Eye contact Several drop a mild conjunct) Medical Record Skin contact Prolonged oi slight irritation, tion is unlikely skin surface bem Diagnosis of exp> The presumpt by the history. I compound can b When excessive ; observed which followed by trans Diagnosis of unequivocally up* blood, tissue, or . practical and mos have been describe Stewart et al.. If If a significant < breath in sufficient IMF" SD 036*12 p * vapor iltons iuht The toxicology of 1,1,Mrichloroethane 77 The case of a 47 year old male, who accidentally ingested one ounce of inhibited l.l,l-trichloroethane, has been reported (Stewart and Andrews, 1966). Thirty minutes after solvent ingestion the patient became nauseated. One hour after inges tion he began vomiting and experienced the onset of diarrhea. Two and one-half hours after ingestion, the vomiting and diarrhea became incapacitating. Six hours jltcr ingestion the diarrhea and vomiting subsided at which time the patient's only complaint was fatigue. The physical examination was completely within normal limits. Two and one-half hours after ingestion, the patient had a leukocytosis and I r proteinuria. A slight elevation in the serum bilirubin concentration was noted 48 hours following admission. No deviation from normal was noted in serial complete blood cell counts, urinalyses, tests for serum glutamic oxaloacetic transaminase, scrum glutamic pyruvic transaminase, blood urea nitrogen and electrocardiograms performed throughout the hospital stay and again six months following the incident. The median lethal oral dose of inhibited 1,1,1-trichloroethane in four species of experimental animals is reported to range from 8-6 to 14*3 gm/kg (Carpenter el at., 1949). Eye contact Several drops of 1,1,1-trichloroethane splashed directly on the cornea may produce a mild conjunctivitis which will subside within a few days (Dow Chemical Company, Medical Records). Skin contact Prolonged or repeated contact with the skin results in transient erythema and slight irritation, secondary to the solvent's defatting action. Significant skin absorp tion is unlikely in industrial applications unless the compound is confined to the skin surface beneath an impermeable barrier. Diagnosis of exposure to 1,1,1 -trichloroethane The presumptive diagnosis of 1,1,1-trichloroethane exposure is usually suggested by the history. In the cases of acute intoxication, the chloroform-like odour of the compound can be detected on the patient's breath for several hours after exposure. When excessive absorption of the compound has occurred, a clinical complex is observed which features depression of the central nervous system, occasionally followed by transient hepatic and renal dysfunction. Diagnosis of excessive absorption of 1,1,1-trichloroethane can be established unequivocally upon quantitative determination of the compound in the patient's blood, tissue, or expired breath. At the present time, breath analysis is die most practical and most sensitive detection method to employ. The analytical techniques have been described in detail (Stewart and Dodd, 1964; Stewart and Erley, 1965; Sii wart et al., 1965). If a significant exposure has occurred, the compound will be present in the expired breath in sufficient concentrations to allow specific identification by simple infrared mmm n'im, 78 Richard D. Stewart spectrographic techniques for at least 24 hours into the post-exposure period (Stewart et al., 1961 and unpublished work). Gas chromatographic techniques offer exquisite sensitivity and can be used to detect compound in the breath for days following vapour exposure. Expired air (alveolar) for analysis is conveniently collected in 6 I. plastic (Saran) bags when infrared techniques arc to be employed (Stewart und Eru.y, 1965). When the gas chromatographic techniques are used, 50 ml aliquots of breath are collected in small glass pipettes (Stewart and Dodd, 1964). Breath samples can be stored for long periods of time in the pipettes, which can be conveniently mailed to analytical laboratories. The concentration of 1,1,1-trichloroethane in the post-exposure expired air is directly related to several factors: (1) the atmospheric concentration of the solvent, (2) the duration of exposure, (3) the time elapsed following exposure, (4) the respiratory characteristics of the individual during and following the exposure, and (5) the total body-lipid repository. Serial breath analyses establish the rate of excretion through the lungs. Com parison of the patient's peak breath concentration and rate of excretion with those human data available (Fig. 2) affords the physician a means with which to estimate the magnitude of the chemical exposure (Stewart et al., 1964 and unpublished work; Torkelson, 1958). ' * There is no specific treatment for 1,1,1-trichloroethane intoxication. Prompt supportive measures should be utilized to combat the effects of central nervous system depression. Because this compound is primarily excreted via the lungs, oxygen with carbon dioxide can be administered to facilitate its elimination. Breathing should be assisted if the respiratory centre has been overly depressed. Severe hypotension may be induced by a combination of central nervous system depression and myocardial anoxia, secondary to poor oxygen uptake. Epinephrinelike drugs must not be used to combat this hypotension because of the danger of inducing ventricular fibrillation. This danger is not unique to 1,1,1-trichloroethane, but is common to many solvents. Acknowledgement--This work was performed while the author was employed by The Dow Chemical Company and is published with their permission. > REFERENCES Adams, E. M., Spencer, H. C., Rowe, V. K. and Irish, D. C. (1950) Vapor toxicity of 1,1,1-trich loroethane (methyl chloroform) determined by experiments on laboratory animals. A.M.A. Arclu. ind. Hyg, I, 225. Carpenter, C. P., Smyth, H. F., Jr. and Pozzani, U. C. (1949) The assay of acute vapor toxicity and the grading and interpretation of results on 96 chemical compounds. J. ind. Hyg. Toxicol. 31,343. Crummett, W. B. and Stenger, V, A. (1956) Thermal stability of methyl chloroform and carbon tetrachloride. Ind. Engng Chem. analyt. Edn 48,434. Dornette, W. H. L. and Jones, J. P. (1960) Clinical experiences with 1,1,1-tridiloroethane (a preliminary report of 50 anesthetic administrations). Anesth. Anaig. 39,249-253. The Dow Hakf, C. I.I.I-n 11AI f , I. lH.fi ire Kl AAV,I N, llVL-r .III Kllinffiu ocrup. Kraniz, J of 1,1,1 Plaa, g. ; hydroc; PRENDERG, of Ion dichlori Rennick. 1 rhythmRowe, V. 1 Stewart, F Ass. 195 Stewart, 1 tetrachli Am. ind Stewart, R in Hum StolmaStewart, R Stewart, P exposure exposure Stewart, R mental h Torkelson, chloroeth 353. Toxicology limits. A/ Van Arkel, 55, 407. 036A1` T The toxicology of 1,1,1 -trichloroethane 79 The Dow Chemical Company, Midland, Michigan. Medical Records. Hake. C. L., Waggoner, T. B., Robertson, D. N. and Rowe, V. K. (1960) The metabolism of 1,1,1-trichloroethane by the rat. Arch. emir. Hlth. 1,101. HaluF. B. and Hine, C. H. (1966) Trichloroethane Intoxication, a report of two cases presented before the American Academy of Forensic Sciences, Chicago, Illinois. Kiaassen, C. D. and Plaa, G. L. (1966) Relative effects of various chlorinated hydrocarbons on liver and kidney function in mice. Toxic, oppl. Pharmac. 9, 139 Kuineeld, M. and Feiner, B. (1966) Health hazards associated with work in confined spaces, /. occup. Med. 8, 358-364. Krantz, J. C. Jr., Park, C. S. and Ling, J. S. L. (1959) Anesthesia LX: the anesthesic properties of 1,1,1-trichloroethane. Anesthesiology 20,635. Plaa, G. L,, Evans, E. A. and Hine, C. H. (1958) Relative hepatotoxicity of seven halogcnated hydrocarbons. /. Pharmac. exp. Ther. 123, 224. Prendergast, J. A., Jones, R. A., Jenkins, L. I. and Siegel, 1. (1967) Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodjfiuoromethane, and 1,1-dichloroethylene. Toxic, appl. Pharmac. 10, 270. rennick, B. R,, Malton, S. D., Moe, G. K. and Seevers, M. H. (1949) Induction of idioventricular rhythms by 1,1,1-trichloroethane and epinephrine. J. Pharmac. exp. Ther. 8,327. Rowe, V. K. The Dow Chemical Company, Midland, Michigan. Personal communication. Siewart, R. D. and Andrews, J. T. (1966) Acute intoxication with methylchloroform. J, Am, med. Ass. 195, No. 11. Stewart, R. D. and Dodd, H. C. (1964) Absorption of carbon tetrachloride, trichloroethane, tetrachloroethylene, methylene chloride, and 1,1,1-trichloroethane through the human skin. Am. ind. Hyg. Ass, J, 25,439-446. Siewart, R. D. and Erley, D. S. (1965) Detection of Volatile Organic Compounds and Toxic Cases in Humans by Rapid Infrared Techniques, in Progress in Chemical Toxicology (Edited by Stolman, A.) Vol. 2, Academic Press, Inc., pp. 183-220. New York. Siewart, R. D. ei al. (1965) Diagnosis of solvent poisoning. J. Am. med. Ass. 193, 1097-1100, Sri wart, R. D,, Gay, H. H,, Erley, D. S,, Hake, C. L. and Schaffer, A. W. (1961) Human exposure to 1,1,1-trichloroethane vapor: relationship of expired air and blood concentrations to exposure and toxicity. Am. ind. Hyg. Ass. J. 22, 252. Stewart, R. D., Gay, H. H., Dodd, H. C., Schaffer, A. W., Rowe, V. K. and Erley, D. S. Experi mental human exposure to 1,1,1-trichloroethane vapor. Archs. envir. Hlth. to be published. Torkelson, T. R., Oyen, F., McCoelister, D. D. and Rowe, V. K. (1958) Toxicity of 1,1,1-tri chloroethane as determined on laboratory animals and human subjects. Am. ind. Hyg, Ass. J, 19, 353. Toxicology Committee, American Industrial Hygiene Association. (1964) Emergency exposure limits. Am. ind. Hyg. Ass. J. 25, 578-586. Van Arkel, A. E. and Vles, S. E. (1936) Solubility of organic compounds in water. Revue Trav. Chim. 55, 407. SL 036415 iwmmmrn mmrnrnmm