Document K6oEV3kM503jnLqVr8Ek7ko32

/' API TOXICOLOGICAL REVIEW BENZENE SECOND EDITION, 1960 The information and recommendations cgpained in this publication have been compiled from sources b e l i e d to be to the best currefit %ginionon the s e c t . No warranty, guarantee, or representation is made by th? American Petroleum Insstitute as to the absolute correctness or su5ciency of any representation contained in this and other Toxicologicd Reviews, and the Institute assumes no responsibility in connecti.on th.erew.ith; nor can it be assumed that all -ble safety measures are -tn_thrl.th er Toxicological Reviews, or that other or a d d i w a l m e a s m m t be rewired under particular or excep f@al conditions or cirC-ces. The American Petroleum Institute, as sponsor of this review, takes no position as to whether or not any method contained herein is covered by an existingpatent, nor as to the validity of any patent alleged to cover any such method. Furthermore, nothing contained in this review grants any right, by implication or otherwise, for the manufacture, sale, or use in connection with any method, apparatus, or product covered by letters patent. This review was prepared at the Harvard School of Public Health, Boston, Mass., under the direction of Qofessor Philiu D*.'Anyone desiring to submit addi- tional information or proposed changes for consideration prior to reissuance of this review is requested to send them to the American Petroleum Institute. AMERICAN PETROLEUM INSTITUTE 1271 AVENUE OF THE AMERICAS NEW YORK20, N. Y. Price 25 Cents API TOXICOLOGICAL REVIEW OF BENZENE I. Substance Benzene Formula: c& 0Structural formula: Molecular weight: 78.11 Synonyms: benzol phene IL Properties and Characteristics ** Boiling point d O . 1 C (176.2 F) at 760 mm. Melting point ~ 5 . C4 to 5.5 C (41.7 F to 41.9 F). .Vapor pressure =74.6 mm of mercury at 20 C (68 F) Liquid density =0.899 g per milliliter at 0 C (32F). Explosive limits =1.4 to 8 per cent. Flash point = 12 F (closed cup). Refractive index= 1.5016 at 20 C (68 F). Specific gravity ~ 0 . 8 7 8 7at 15 C (59 F). 1 mg per liter =313 ppm; 1ppm=0.00319- mg per liter. Benzene is a clear, colorless liquid with a characteristic pleasant odor at low concentrations and a disagreeable odor at higher concentrations. It forms a hi-ghly flammable and explosive mixture with air at concentrations ranging from 1.4 to 8.0 per cent benzene by volume. Pure benzene bums with a yellow, luminous, smoky flame and is a fire hazard unless proper care is taken in handlins and storage. Benzene is relatively insoluble in water (0.08 g in 100 ml of water at 22 C) but is readily miscible in all proportions with alcohol, ether, acetic acid, chloroform, carbon disulfide, carbon tetrachloride, and similar organic solvents. Commercialbenzene is practically never pure and usually contains varying amounts of xylene, phenol, and toluene; commercial benzene also contains traces of carbon disulfide (0.2 to 1.0 per cent), thiophene (0.1 to 0.2 per cent), olefins, naphthalene, and similar substances. Chemically, benzene is the simplest of the aromatic hydrocarbons. It is relatively stable but is capable of a variety of substitution reactions such as chlorination, nitration, sulfonation, and alkylation. Benzene is an excellent solvent for most organic substances. a Figcres refer to BIBLIOGRAPHY on p. 6. III. Manufacture, Uses, and Possible Sources of Exposure Benzene is usually manufactured from catalytically reformed light naphthas from which it is isolated by distillation or solvent extraction. Benzene is used as a solvent in many applicatiom. It is also used as a component of some motor fuels and as the raw material for the manufacture of a host of synthetic chemicals. Examples are: styrene, phenol, aniline, DDT, chlorobenzene, cumem, nitrobenzene, diphenyl, cyclohexane, adipic acid, and detergents. Because of its volatility, benzene presents a vapor hazard. The vapor may arise from numerous handling operations, as well as from leaks and accidental spills. Skin contact is a possibility when handling or packaging. IV. Toxicology a. ACQWEffects Acute benzene poisoning generally results from the inhalation of relatively high concentrations of vapor. Exposure to air.containing benzene in concentrations of 19,000 ppm to 20,000 ppm (61 to 65 mg per liter of air) may cause death within 5 to 10 min, whereas concentrations of 7,500 ppm (25 mg per liter) are dangerous to life in one-half to one hour: Severe toxic effects may be caused by 1-hour exposure to concentrations of 1,500 ppm (4.8 mg per liter). Concentrations of 500 ppm (1.6 mg per liter) may lead to symp toms of illness when exposure continues for more than a short time.' Inhalation of 50 ppm to 150 ppm (0.10 to 0.48 mg per liter) of benzene for 5 hours caused slight headache, weariness, and lassitude. The red-blood count decreased, the white-blood count was unchanged except for mild lymphocytosis, eosinopenia, and monocytopenia. The albumin-globulin ratio increased slightly at lower concentrations but decreased with higher concentrations. The urinary coproporphyrins were increased, whereas the urinary sulfate ratio was decreased.6 Skin contact will cause dehydration and defatting which may lead to dermatitis. Systemic intoxication by cutaneous absorption is unlikely. Drinking benzene causes acute symptoms with local evidence of acute irritation of the mouth, throat, and stomach. A tablespoonful or less of benzene when swallowed has been known to cause serious collapse. Subse- 2 n C-t L BJ3 quently, it may result in bronchitis or pneumonia which isprobably caused by benzene enteringthe air passages.' Acute exposure to benzene exerts a toxic action on the central nervous system. Benzene first behaves as a stimulant-in the early stages of acute poisoning, persons show excitement, euphoria, hilarity; then quite suddenly this changes to weariness, fatigue, and sleepiness, followed by coma and death.' Acute exposure to benzene produces rapidly increasing symptoms of dizziness, excitation, and pallor, followed by ffushing, weakness, headache, breathIessness, constriction in the chest, and fear of impending death. Visual disturbances, tremors, and muscular weakness are also encountered. The victim may lose consciousness and pass into coma or may develop acute mania and delirium. Convulsions occur frequently. Death may supervene almost at once or several hours to several days following exposure.o Recovery from acute benzene poisoning requires from one to four weeks. Immediately after exposure there are temporary symptoms of chest and head pains, shortness of breath, giddiness, nausea, and loss of a p petite. Evidence of unsteady gait, nervous irritability, and breathlessness may persist for two or three weeks, whereas cardiac distress and a peculiar yellow pallor to the skin may last for as long as a month. Recovery from acute poisoning is generally complete after this period, although evidences of chronic benzene poisoning may be encountered later.s Benzene also sensitizes the heart muscle to the action of epinephrine, so that instant death may occur as a result of ventricular fibrillation.' Muscular activity increases the rate and severity of acute benzene poisoning. Persons dying of acute benzene poisoning generally show absence of clotting of the blood and widespread petechial hemorrhages in the brain, plema, pericardium, urinary tract, intestinal tract, mucous membranes, and skin. There are no specific lesions of diagnostic importance.s Local effects from acute exposure are seldom severe. Continued skin contact with benzene results in defatting of the ski0 acd leads to erythema, dry scaling, and, in some cases, the formation of vesicular papules. Prolonged exposure may produce lesions resembling firstor second-degree bums. It may cause considerable irritation of the eyes or mucous membranes of the nose and throat on contact. Benzene poisoning by skin absorption has received scant attention in the literature. The possibility of percutaneous absorption of benzene has been studied in three cases. Immersion of the hands and forearms from 25 to 35 showed no evidence of skin absorption.10 Unquestionably, small amounts of benzene can be absorbed through the skin, but it is very doubtful that enough would be absorbed by this mute to cause'systemic poisoning.' b. Chronic Effects Chronic benzene poisoning results from repeated or continuous exposure to relatively low concentratfons of benzene va-por. spry to The'le-olvnmeindn&xveaery of exmsure widely. There are at Ileast two well-Men ticated cases of r-7 -wes to 12 ~ p p ~ . l . .- - effm Symptoms may be present over Ions periods, i.e. headaches, d a e s s , fatigue, anoresin. and dyspnqa. They may be varied and vague and not ob- viously connected with benzene poisoning. During the early stages of poisoning, Heinz bodies mmay be present in the red-blood cells and a neutropenia is oftenseen. . ge the blood picture mav re- 1turn to normal after removal from contact with benzene. ing, burning ;ensations bf the eyes and throat, and hemorrhages from mucous membranes, tongue, and gums becpme manifest. Purpuric spots and ecchy- moses may follow the slightest injury, and epistaxis may occur. Menorrhagia, metrorrhagia, a n d a n t a n e o u s . ab0a 'o e may develop in othe- v wo- Blood examination at this point may show leukopenia (below 4,000 white cells), neutropenia, ckd a severe anemia. Later the platelet count falls so that thrombo- penia is marked. The blood condition, at this stage, may have become irreversible. The clinical picture of a worker with chronic benzene poisoning at this stage is characteristic-he complains of headaches, giddiness, drowsiness, lassitude, loss of appetite, and nausea with occasional vomiting. He looks pale; is short of breath; has a rapid pulse, a low blood pressure, and a mildly ele- vated temperature. He may also have epistaxis, bleeding from the gums, a purpuric rash, or subconjunctival hemorrhages. The condition progresses slowly to acute -leukopenia ending in fatal aplastic anemia.6 Repeated small doses of benzene by mouth can produce the same type of chronic poisoning.7 Repeated contact of benzene with the skin will cause dehydration and delipidization predisposing to derma- titis. Benzene is relatively insoluble in body fluids and tis- sues. Therefore, o d y small amounts are absorbed by the body. Equilibrium between blood and air is ap- proached within a few minutes after exposure is bepun, and practically complete eliminationof benzene from the .f 4 M I TOXICOLOGICAL REVIEW blood occurs within a few minutes after exposure is ter- minated. Higher concentrations of benzene are obtained in tissues with a greater fat content, and saturation and elimination are more gradual.12 Human subjects inhaled benzene in concentrations of 340micrograms per liter of air for 5 hours. Between 33 and 65 per cent of the inhaled benzene was retained (385 mg). During the &saturation period 3.8 to 27.8 per cent of retained benzene was excreted through the lungs and 0.1 to 0.2 per cent in the urine and other body excreta. Of the absorbed benzene, 9.7 to 42 per cent was excreted in the urine as phenol, 0 .to5.4per cent as pyrocatechol, and 0.1 to 3.3 per cent as hydroquinone. Excretion of phenol and pyrocatechol was highest during the k t 24 hours and complete in 48 hours, whereas hydroquinone took more than 48 hours. Excretion of organic sulfates in urine of exposed subjects was in- creased. The opinion was expressed that benzene affects the metabolism of proteins, the metaboLites of which are excreted in urine as ethereal sulfates.'* Benzene is unique in its myelotoxicity. It has been shown that the introduction of an alkyl group into the aromatic ring results in a loss of its myelotoxic property. This difference may be a result of the difference in the metabolic pathway. Benzene is metabolized to phenols and quinones which inhibit cell production. The in vivo metabolites of alkyl benzenes are alcohols and carboxylic acids resulting from side chain oxidations. These com- pounds have a lowsrder toxicity and are devoid of spe- cific cell destructive effects." A variety of reactions may be encountered as the re- sult of the chronic effect of benzene poisoning. There is little c o r r c l a t i o n f l Cnd the severity or nature of the findin- ~ n microscopic c x a m i y consist ozreduction in redcell, w h z e U ,- or d- atelet levels- -in any two of these or in all three. These changes mav . The blood usually shows elk (below 3.5 million), white cells (below 4,500), and platelets. Blood exami- nations for evidence of benzene poisoning should con- sist of a complete study of red, white, and platelet frac- tions. Progressive changes are more significant than the absolute levels. In anemia caused by benzene, it has been shown that there is a constant increase in serum iron (average in- crease, 213 micrograms) which is associated with a re- duction of transerrin (average reduction, 225 rnicro- grams). The iron saturation of transferrin is above normal and is matched by iron saturation of the tissue. The cause of the disturbance of iron metabolism in ben- zene poisoning is the failure of the marrow to utilize iron as well as increased intake of iron supplied parenterally by There is some evidence that chronic benzene poisoning produces a blood-clotting defect which is caused by functional and morphological as well as a quantitative alteration of the platelets.I7 The marrow cells exhibit a decrease in peroxidase in benzene poisoning. Because benzene inhibits granulocyte maturation, it may act on peroxidase metabolites, or the peroxidase may be used up in detoxifying benzene.'* The bone marrow may be hypoplastic, fairly n o d , or hyperplastic in appearance. Abnormal forms OK young cells may abound, and Ieukemia as a result of -chronic benz.ene e.xposure has been reported.- V zene-cases with symptoms fairly soon after exposure usually have fewer cells in the marrow,whereas cases developing later are more apt to have an increased number of cells in the marrow. It is believed that this represents an early weeding out of those who develop hypoplastic changes, rather than a gradual shift from one type of response to the other.loVm In a long-term follow-up of chronic benzene poisoning 4,538 cases were studied from 2 to 12 years after cessation of work involving exposure. There has been only one fatal case, six cases involving bone marrow changes, and one case of lowered resistance to infec- tiomZLThe otpers were practically well but show varying degrees of neutropenia. Benzene is eliminated from the body via the lungs and the kidneys. In one study C-14 -labeled benzene was given orally to rabbits. In 2 days 45 per cent of the dose was eliminated in the expired air (43per cent as unchanged benzene and 1.5 per cent as carbon dioxide), and 35 per cent was eliminated as metabolites in urine (23 per cent as phenol, 4.8 per cent as quinol, 2.2 per cent as catechol, 0.3per cent as hydroxyquinol, 0.5 per cent as L-phenylmercapturic acid, and 1.3 per cent as trans-, tmuns-muconic acid). Five per kent of the administered radioactivity was found in the tissues occurring mainly as metabolites.*' wei t individuals -ore co d,4aand a 1said to- -promote the -e. The presence of W or lu -. J/ c -. 1 . .c. BENZENE 5 -C G Recommended Limit of Atmospheric E x p ~ ~ l ~ e The generally reco@& acceptable con- centration for benzene vapor is 25 ppm by volume air (0.08 mg per liter of air) for an &hour daily ex- posure.'IIn Germany the maximum permissible concentration to which workers may be exposed is 31.3 ppm by volume in air (0.1mg per liter of air) .2s The Massachusetts laws have established 25 ppm as a m&um benzene c~ncentration.~~ 4,000,000, hemoglobin less than 12 g per 100 ml (80 per cent), blood platelets less than ~~~~~~~ per cu -3 difIenntial count less than 50 per cent poly- morphonuclear ledocY% and more than a very few n ~ a s u r ethe degree Of benzene poisoning nor the blood changes present.' V. Treatment Acute benzene poisoning should be considered an acute emergency. Remove the victim from further exposure at once and call a physician immediately. The patient should be kept warm and quiet in the recumbent position. If breathing has stopped, artificial respira- tion should be started at once. Oxygen should be administered by a qualified as longas necessary to maintain the normal Of skin and mucous mem- branes. This may prevent the development of severe pulmonary edema. Stimulants will rarely be necessary when adequate oxygenation is maintained.' Care should be taken that rescuers are not also over- VII. Precautionary Measur- The safety measures necessary for the Prevention of benzene poisoning are primarily those designed to pre- -vent the inhalation of benzene vapor. P ~ Q Wr ventilation, local exhaust, and closed systems should be used to* maintain a conce- e maximum acceptable shouldPkaionncepniptriantgionof25 rn vo r e z a L dSF-mau. P= tetatically for leakage. When excessive concentrations are unavoidably encountered in operations such as the cleaning of cars, vats, or storage -, air masks ~ c VI. Esamination If the hands are likely to have contact with benzene, impervious gloves or protective creams should be used. Proper ventilation, routine plant inspection, control of benzene air concentration, and periodic medical examinations are all of the utmost importance.*s '@e Dre-ernployment examination should include a detailed history, physical examination, chest X-ray, and complete blood count. Workers with organic disease, of the heart, lungs, liver, or kidneys should be elimi- include a brief interval history and physical examhation, together with a complete blood study. The D r e s e w worker should be withdrawn from further exposure. The following changes call for re-examination: whiteblood count less than 4,000, red-blood count less than 5 E Z 5 s i v e exposure may be encoyntered. I'%- bk done by a variety of procedures among w%ch are the butanone method,? the rndinitrobenzene reduction method: an absorptiometric method, and a photocolorimetric determination. The latter method involves the nitration of benzene with Stepanov mixture which forms rndinitrobenzene. This gives a color reaction with acetone in alkaline solutions. Under similar conditions toluene gives a faint violet color. Based on these photocolorimetric methods small quantities of benzene and toluene can be determined in air.29 More recently a silica gel adsorption method has been reported.*O Accurate quantitative study of atmospheric benzene as low as 0.003 mg per ml (0.9 ppm) may be determined by adsorption on activated silica gel and elution with absolute alcohol. The benzene content is then determined spectrophotometri- cally according to ASTM Designation D 1017: Method -.. 1 . .' ..- * I _ * 6 API TOXICOLOGICAL REVIEW of Test for Benzene arid Toluene by Ultraviolet Spec- trophotometry. The range of measurement is 0.003 mg to 1.28 mg per liter. The mean yield was approximately 98 per cent. There are a number of instruments on the market which measure hydrocarbon air contamination. The presence of more than one hydrocarbon vapor, however, produces erratic results. MII. Bibliography E. Browning, Toxicity of Industrial Organic Solvents, Industrial Health Research Board Report No. 80, London (1937). 2 M. G. Jacobs, The Analytical Chemistry of Industrial Poisons, Hazarak, and Solvents, 399, Interscience Publishers, Inc., New York (1944). aC. D. H o d p a n and H. N. Holmes, Handbook of Chemistry and Physics, 25th edn., Chemical Rubber Publishing Co.,Cleveland (1941). Y. Henderson and H. W. Haggard, Noxious Gases and rhe Principles o f Respuation Influencing Their Action. 164, Chemical Catalog Co., New York (1943). M. W. Goldblatt, "Research in Industrial Health in the Chemical Industry," Brit. J. Ind. Med. 12 1 (1955). Genichi Watanabe, Jun Yashioka, Haruo Hondo, Masao Matouchi, and Taker0 Sakaguchi, J. Sci. Labour (Japan) 29 70 (1953); from Chem. Absrr. 6051 (1954). `"Threshold Limit Values for 1959," American Conference of Governmental Industrial Hygienisfs, A N A . Arch. Znd. Health 20 266 (1959). * J. B. Lune, "Occupational Health Hazards io the Manu- facture of Insecticides," s. Afr. Jour. Clin. Sci. 3 212 (1951). J. L. Svirbely, R. C. DUM, and W. F. von Oettingen, "The Acute Toxicity of Vapors of Certain Solvents Containing Appreciable Amounts of Benzene and Toluene," J. Ind. Hyg. Toxicol. 25 366 (1943) ;and `The Chronic Toxicity of Moderate Concentrations of Benzene and Mixtures of Benzene and Its Homologues for Rats and Dogs," J . Ind. Hyg. Toxicol. 26 37 (1944). loG. L. Conca and A. Maltaglioti, "Study On Transcutaneous Absorption of Benzene," Med. lavoro 45 194 (1955) ; from Cltem. Abstr.. 16231 (1955). l1 M e H. B. Elkins, "Chrokc Exposure to &me e-I: de, - udn 21 321 (1939). H. H. Schrenk, W. P. Yant, S.J. Pearce, F. A. Patty, and R. R. Sayers. "Absorption, Distribution, and Elimina- tion of Benzene by Body Tissues and Fluids of Dogs Ex- posed to Benzene Vapor," J. Ind. Hyg. Toxicol. 23 20 (1941). --laJ. Teisinger, V. Bergerova-Fiserova, and J. Kudrna, "Metabolism of Benzene in Man," Charles Univ. .IPrame1. I. Pracovni Lekarstvi 4 175 (1952); from Chem. Abstr., 4181 (1955). H. W. Gerarde, "Toxicological Studies on Hydrocar- bons," A.M.A. Arch. Znd. Health 13 468 (1956). Is L. A. Erf and C. P. Bhcrads, `The Hematological Ef- f(ehms of B.enzene Poisoning," 3. Ind. HvaT?oxrcoi. zi 421 `-Fernis and L. Mareo, "Metabolism of Iron in HemopathiesDue to Benzene," Med. lavoro 46 325 (1955); from Chem. Absrr., I4996 (1955). '`G. Saita, E. sartarelli, and F. Calaresu, `The Blood Clotting Process in Chronic Benzene Poisoning," Med. lavoro 45 313 (1954); from Chem. Abstr., I1652 (1954). V. Prato and G. F. Rubino, "Bone Marrow Peroxidase in Benzene Poisoning," Univ. Turin (Italy) Minerva med. IT,357 (1954); from Chem. Abstr., 5662 (19%). T. B. Mallory, E. A. Gall,and W. J. Brickley, "Chronic Exposure to Benzene-111: The Pathological Results," J. Ind. Hyg. Toxicol. 21 356 (1945). - "Karel Rejsek and Maria Rejskova. "Long Term Observation of Chronic Benzene Poisoning," Acta Med. S c a d . 152 71 (1955). 2z D. V. Parke and R. T. Williams,"Studies in Detoxication 49, Metabolism o Benzene Containing C1* Ben- .zene." Biochem. J . 54 231 (195-31,. A.Feil, "Le benzolisme professionel," Presse rned. 41 6. 129 (1933). 24C. E. A. Winslow, "Summary of the National Safety CounciI Study of Benzol Poisoning," J . Ind. Hya. 9 61 (1927). *g J. L. Gutierres de Alles, "Sterility in Laborers Caused by Benzene and Other Solvents" Med y seguridad trabajo 31 4 ( 1954); from Chem. Abstr., 13556 (1955). 2sR. W. van Hoesen KorndoBer, `Toxicology of Solvents," Plastica 4 11 (1951); from Chem. Absrr., 11178 (1955). 2Mi ass. Div. of Occup. Hyg. Bull., Maximum Allowable Concentrations (1957). 2s Occupation and Health Encyclopedia of Hygiene, Pathology and Social Welfare, International Labor Office, Geneva 1,228 (1930). mF. I. Berezovskaya, B. E. Reznik, and S. S. Gitis, "Photometric Determination of Benzene and Toluene," Nauch. Zapiski, Dnepropetrovsk. Gosudarst. Univ. 43 45 (1953); from Chern. Abstr., 783 (1955). *O "Per Ovrum, Determination of Atmospheric Benzene Concentration by Displacement Following Adsorption on Silica Gel,'' Brit. J . Ind. Med. 13 210 (1956). 2M-Aug. 1560 API TOXICOLOGICAL REVIEWS SECOND EDITION Benzene (1960) ............................................... $ .25 Butadiene (1959) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 Copper Naphtheaate (1959) ...................................... 3 5 NaphthaIene (1959) ............................................ 35 Naphthenic Acids (1959) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 Toluene (1960) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 Xylene (1960) ................................................ .25