PROCTOR AND HUGHES’

CHEMICAL HAZARDSof the

WORKPLACEFifth Edition

Gloria J. Hathaway, Ph.D.Nick H. Proctor, Ph.D.

A JOHN WILEY & SONS, INC., PUBLICATION

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Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

I Introduction: Toxicological Concepts 1

Toxicological Concepts—Setting Exposure Limits 3

II The Chemical Hazards 11

CONTENTS

Barium (and compounds) 65Bauxite 66Benomyl 67Benz[a]anthracene 68Benzene 69Benzidine 732,3-Benzofuran 75Benzoic acid 75Benzo[a]pyrene 76Benzotrichloride 78Benzoyl peroxide 79Benzyl chloride 80Beryllium (and compounds) 81Biphenyl 83Bismuth telluride 84Bisphenol A 85Borates, tetra, sodium salts 87Boron oxide 88Boron tribromide 88Boron trifluoride 89Bromine 90Bromine pentafluoride 91Bromodichloromethane 91Bromoform 931,3-Butadiene 94n-Butane 96n-Butyl acetate 98sec-Butyl acetate 99tert-Butyl acetate 99n-Butyl acrylate 100n-Butyl alcohol 101sec-Butyl alcohol 102tert-Butyl alcohol 102Butylamine 103tert-Butyl chromate 104n-Butyl glycidyl ether 105n-Butyl mercaptan 105o-sec-Butylphenol 106p-tert-Butyl toluene 107

Acetaldehyde 13Acetamide 14Acetic acid 15Acetic anhydride 16Acetone 17Acetonitrile 192-Acetylaminofluorene 20Acetylene tetrabromide 22Acrolein 22Acrylamide 24Acrylic acid 27Acrylonitrile 28Aldrin 30Allyl alcohol 32Allyl chloride 32Allyl glycidyl ether 34Allyl propyl disulfide 35Aluminum 36Aluminum oxides 384-Aminodiphenyl 40p-Aminophenol 412-Aminopyridine 42Amitrole 43Ammonia 45Ammonium chloride fume 46Ammonium perfluorooctanoate 46Ammonium sulfamate 48n-Amyl acetate 48sec-Amyl acetate 49Aniline 50Anisidine 52Antimony (and compounds) 52ANTU 54Arsenic (and compounds) 55Arsine 58Asbestos 59Asphalt fumes 61Atrazine 63Azinphos-methyl 64

v

Cadmium (and compounds) 108Calcium carbonate 110Calcium cyanamide 111Calcium hydroxide 111Calcium oxide 112Calcium silicate 113Calcium sulfate 114Camphor 114Caprolactam 115Carbaryl 116Carbon black 118Carbon dioxide 120Carbon disulfide 121Carbon monoxide 123Carbon tetrabromide 126Carbon tetrachloride 126Catechol 129Cellulose (and compounds) 130Cesium hydroxide 131Chlordane 131Chlordecone 133Chlorinated dibenzo-p-dioxins 134Chlorinated diphenyl oxide 137Chlorine 138Chlorine dioxide 140Chlorine trifluoride 142Chloroacetaldehyde 142Chloroacetone 143a-Chloroacetophenone 144Chloroacetyl chloride 145Chlorobenzene 146o-Chlorobenzylidene malononitrile 147Chlorobromomethane 149p-Chloro-m-cresol 150Chlorodibromomethane 150Chlorodifluoromethane 152Chlorodiphenyl, 42% chlorine 153Chlorodiphenyl, 54% chlorine 156Chloroform 158bis(Chloromethyl)ether 160Chloromethyl methyl ether 1621-Chloro-1-nitropropane 163Chloropentafluoroethane 164Chloropicrin 165b-Chloroprene 166o-Chlorostyrene 168Chlorothalonil 168o-Chlorotoluene 169Chlorpyrifos 170

Chromium (metal and inorganic compounds, as Cr) 172

Chromyl chloride 175Chrysene 176Coal dust 177Coal tar pitch volatiles 178Cobalt 180Cobalt hydrocarbonyl 182Copper (dust and fume) 183Cotton dust, raw 184Cresol (all isomers) 186Crotonaldehyde 187Cumene 188Cyanamide 189Cyanides 190Cyanogen 191Cyanogen chloride 193Cyclohexane 193Cyclohexanol 195Cyclohexanone 195Cyclohexene 197Cycloheximide 197Cyclohexylamine 198Cyclopentadiene 199Cyclopentane 200Cymene 201DDT 202Decaborane 203Decalin 204Demeton 206Diacetone alcohol 2072,4-Diaminotoluene 208Diazomethane 209Dibenz[a,h]anthracene 210Diborane 2111,2-Dibromo-3-chloropropane 2122-N-Dibutylaminoethanol 2142,6-Di-tert-butyl-p-cresol 215Dibutyl phenyl phosphate 216Dibutyl phosphate 217Dibutyl phthalate 217Dichloroacetylene 219o-Dichlorobenzene 220p-Dichlorobenzene 2213,3¢-Dichlorobenzidine 223Dichlorodifluoromethane 2251,3-Dichloro-5,5-dimethylhydantoin 2261,1-Dichloroethane 2271,2-Dichloroethylene 228

vi CONTENTS

Dichloroethyl ether 229Dichlorofluoromethane 2301,1-Dichloro-1-nitroethane 2312,4-Dichlorophenol 2312,4-Dichlorophenoxyacetic acid 2331,3-Dichloropropene 2352,2-Dichloropropionic acid 237Dichlorotetrafluoroethane 238Dichlorvos 239Dicyclopentadiene 241Dicyclopentadienyl iron 242Dieldrin 243Diepoxybutane 244Diethanolamine 245Diethylamine 2472-Diethylaminoethanol 248Diethylene triamine 249Diethylhexyl adipate 250Di(2-ethylhexyl) phthalate 251Diethyl ketone 253Diethyl phthalate 253Diethyl sulfate 254Difluorodibromomethane 255Diglycidyl ether 256Diisobutyl ketone 257Diisopropylamine 258Dimethoxyethyl phthalate 258Dimethylacetamide 259Dimethylamine 2614-Dimethylaminoazobenzene 262N,N-Dimethylaniline 263Dimethyl carbamoyl chloride 264Dimethylformamide 2651,1-Dimethylhydrazine 267Dimethyl hydrogen phosphite 268Dimethyl methylphosphonate 2702,4-Dimethylphenol 271Dimethyl phthalate 272Dimethyl sulfate 273Dinitrobenzene (all isomers) 275Dinitro-o-cresol 2772,4-Dinitrophenol 278Dinitrotoluene (all isomers) 279Dioxane 281Diphenylamine 2831,2-Diphenylhydrazine 284Dipropylene glycol methyl ether 285Dipropyl ketone 285Diquat 286

Disulfiram 287Disulfoton 288Divinyl benzene 289Endosulfan 290Endrin 291Enflurane 293Epichlorohydrin 294EPN 2961,2-Epoxybutane 297Epoxy resins 298Ethane 301Ethanolamine 3022-Ethoxyethanol 3032-Ethoxyethyl acetate 304Ethyl acetate 306Ethyl acrylate 307Ethyl alcohol 308Ethylamine 310Ethyl amyl ketone 310Ethyl benzene 311Ethyl bromide 312Ethyl butyl ketone 314Ethyl chloride 314Ethylene 316Ethylene chlorohydrin 317Ethylenediamine 318Ethylene dibromide 319Ethylene dichloride 321Ethylene glycol 323Ethylene glycol dinitrate 325Ethylene glycol monobutyl ether 326Ethylene oxide 328Ethylene thiourea 330Ethylenimine 332Ethyl ether 333Ethyl formate 3342-Ethylhexyl acrylate 334Ethylidene norbornene 335Ethyl mercaptan 336N-Ethylmorpholine 337Ethyl silicate 338Fenthion 338Ferbam 340Ferrovanadium dust 341Fibrous glass/glasswool 342Fluoranthene 344Fluorides 345Fluorine 347Formaldehyde 347

CONTENTS vii

Formic acid 351Fuel oils 352Furfural 353Furfuryl alcohol 354Gasoline 356Germanium tetrahydride 358Glutaraldehyde 358Glycidol 360Graphite (natural) 361Graphite (synthetic) 362Hafnium (and compounds) 363Halothane 364Helium 366Heptachlor 366Heptachlor epoxide 367n-Heptane 368Hexachlorobenzene 369Hexachlorobutadiene 371Hexachlorocyclopentadiene 373Hexachloroethane 374Hexachloronaphthalene 375Hexafluoroacetone 376Hexamethylene diisocyanate 378Hexamethyl phosphoramide 379n-Hexane 380sec-Hexyl acetate 382Hexylene glycol 382HMX 383Hydrazine 384Hydrogenated terphenyls 386Hydrogen bromide 386Hydrogen chloride 387Hydrogen cyanide 389Hydrogen fluoride 390Hydrogen peroxide (90%) 392Hydrogen selenide 393Hydrogen sulfide 394Hydroquinone 395Hydroxylamine (and salts) 3972-Hydroxypropyl acrylate 399Indene 399Indenol(1,2,3-cd )pyrene 400Indium (and compounds) 400Iodine 402Iodoform 403Iron oxide fume 404Iron pentacarbonyl 405Isoamyl acetate 405Isoamyl alcohol 406Isobutane 407

Isobutyl acetate 408Isobutyl alcohol 408Isooctyl alcohol 409Isophorone 410Isophorone diisocyanate 4112-Isopropoxyethanol 412Isopropyl acetate 412Isopropyl alcohol 413Isopropylamine 415N-isopropylaniline 415Isopropyl ether 417Isopropyl glycidyl ether 417Jet fuels 418Ketene 420Lead (inorganic compounds) 420Lead arsenate 423Lead chromate 424Lindane 426Liquefied petroleum gas 427Lithium hydride 428Magnesite 429Magnesium oxide fume 429Malathion 430Maleic anhydride 432Manganese (and compounds) 433Manganese cyclopentadienyl tricarbonyl 435Manganese tetroxide 436Mercury 436Mercury (alkyl compounds) 438Mesityl oxide 440Methacrylic acid 441Methane 442Methomyl 443Methoxychlor 4442-Methoxyethanol 4452-Methoxyethyl acetate 4474-Methoxyphenol 448Methyl acetate 449Methyl acetylene 450Methyl acrylate 450Methylacrylonitrile 451Methylal 453Methyl alcohol 453Methylamine 455Methyl n-amyl ketone 455N-methyl aniline 456Methyl bromide 457Methyl butyl ketone 460Methyl chloride 462Methyl 2-cyanoacrylate 463

viii CONTENTS

Methylcyclohexane 464Methylcyclohexanol 465o-Methylcyclohexanone 4662-Methylcyclopentadienyl

manganese tricarbonyl 4664,4¢-Methylene bis(2-chloroaniline) 467Methylene bis-(4-hexylisocyanate) 469Methylene bisphenyl isocyanate 470Methylene chloride 4714,4¢-Methylene dianiline 474Methyl ethyl ketone 476Methyl ethyl ketone peroxide 478Methyl formate 479Methyl hydrazine 480Methyl iodide 481Methyl isoamyl ketone 483Methyl isobutyl carbinol 483Methyl isobutyl ketone 484Methyl isocyanate 485Methyl isopropyl ketone 486Methyl mercaptan 487Methyl methacrylate 488Methyl parathion 490Methyl propyl ketone 492N-methyl-2-pyrrolidone 493Methyl silicate 494a-Methyl styrene 495Mevinphos 496Mica 497Molybdenum (and compounds) 498Morpholine 500Mustard gas 501Naled 503Naphtha, coal tar 505Naphthalene 506b-Naphthylamine 507Nickel (and inorganic compounds) 508Nickel carbonyl 511Nicotine 512Nitric acid 513Nitric oxide 514p-Nitroaniline 515Nitrobenzene 516p-Nitrobiphenyl 518o-Nitrochlorobenzene 519p-Nitrochlorobenzene 520Nitroethane 522Nitrogen dioxide 523Nitrogen mustards (blister agents) 525Nitrogen trifluoride 526

Nitroglycerin 527Nitromethane 5291-Nitropropane 5302-Nitropropane 531N-nitrosodimethylamine 532N-nitrosodiphenylamine 534N-nitrosodi-n-propylamine 535N-nitrosomorpholine 536Nitrotoluene 537Nitrous oxide 538Nonane 540Nonylphenol 541Nuisance particulates 542Octachloronaphthalene 543Octane 544Oil mist (mineral) 544Osmium tetroxide 546Oxalic acid 546Oxygen difluoride 547Ozone 548Paraquat 550Parathion 552Particulate matter 554Pentaborane 555Pentachloroethane 556Pentachloronaphthalene 558Pentachlorophenol 559Pentaerythritol 561Pentane 5622,4-Pentanedione 563Perchloroethylene 564Perchloromethyl mercaptan 567Perchloryl fluoride 567Phenol 568p-Phenylenediamine 5702-Phenylethanol 571Phenyl ether 572Phenyl glycidyl ether 573Phenylhydrazine 574Phenyl mercaptan 575N-Phenyl-b-naphthylamine 576Phenylphosphine 578Phosgene 579Phosphine 580Phosphoric acid 581Phosphorus (yellow) 582Phosphorus oxychloride 584Phosphorus pentachloride 584Phosphorus pentasulfide 585Phosphorus trichloride 585

CONTENTS ix

Phthalic anhydride 586m-Phthalodinitrile 587Picric acid 588Pindone 589Piperazine dihydrochloride 589Platinum (and soluble salts) 590Polybrominated biphenyls 591Polytetrafluoroethylene decomposition

products 593Portland cement 594Potassium hydroxide 596Propane 596Propane sultone 597Propargyl alcohol 598Propene 599b-Propiolactone 600Propionic acid 601n-Propyl acetate 602n-Propyl alcohol 603Propylene dichloride 604Propylene glycol dinitrate 605Propylene glycol monomethyl ether 607Propyleneimine 608Propylene oxide 609n-Propyl nitrate 611Pyrethrum 612Pyridine 613Quinone 614Radon 615RDX 616Resorcinol 617Rhodium (and compounds) 618Ronnel 620Rotenone 620Rubber, natural latex 622Selenium (and compounds) 623Selenium hexafluoride 625Silica, amorphous—diatomaceous earth 625Silica, amorphous—fume 626Silica, crystalline—quartz 628Silicon 630Silicon carbide 631Silicon tetrahydride 632Silver (and compounds) 632Soapstone 634Sodium fluoroacetate 634Sodium hydroxide 636Sodium metabisulfite 637Stibine 638Stoddard solvent 638

Strychnine 639Styrene, monomer 640Styrene oxide 642Sulfolane 643Sulfur dioxide 644Sulfur hexafluoride 645Sulfur monochloride 646Sulfur pentafluoride 647Sulfur tetrafluoride 647Sulfuric acid 648Sulfuryl fluoride 650Talc (nonasbestos form) 651Tantalum 654Tellurium 654Tellurium hexafluoride 655Terphenyls 6561,1,2,2-Tetrachloro-1,2-difluoroethane 6571,1,2,2-Tetrachloroethane 657Tetrachloronaphthalene 659Tetraethyl lead 659Tetraethyl pyrophosphate 661Tetrahydrofuran 662Tetralin 664Tetramethyl lead 665Tetramethyl succinonitrile 666Tetranitromethane 666Tetrasodium pyrophosphate 667Tetryl 668Thallium 669Thiazoles—rubber components 671Thioacetamide 6724,4¢-Thiobis(6-tert-butyl-m-cresol) 672Thioglycolic acid 673Thionyl chloride 674Thiram 675Tin (inorganic compounds) 677Tin (organic compounds) 678Titanium dioxide 679Toluene 681Toluene-2,4-diisocyanate 683Toluidine 686Toxaphene 687Tributyl phosphate 689Trichloroacetic acid 6901,2,4-Trichlorobenzene 6921,1,1-Trichloroethane 6921,1,2-Trichloroethane 694Trichloroethylene 696Trichlorofluoromethane 698Trichloronaphthalene 699

x CONTENTS

2,4,6-Trichlorophenol 7002,4,5-Trichlorophenoxyacetic acid 7011,2,3-Trichloropropane 7031,1,2-Trichloro-1,2,2-trifluoroethane 704Triethanolamine 706Triethylamine 707Triethylene tetramine 708Trifluorobromomethane 709Trimellitic anhydride 710Trimethylamine 712Trimethyl benzene 712Trimethyl phosphite 7132,4,6-Trinitrotoluene 714Triorthocresyl phosphate 716Triphenyl amine 717Triphenyl phosphate 718Triphenyl phosphite 719Tungsten (and compounds) 720Turpentine 721Uranium 722Used mineral-based crankcase oil 724

n-Valeraldehyde 726Vanadium pentoxide 726Vinyl acetate 728Vinyl bromide 730Vinyl chloride 7314-Vinylcyclohexene 733Vinyl cyclohexene dioxide 734Vinylidene chloride 736Vinyltoluene 738VM&P naphtha 739Warfarin 740Wood dust 741Xylene 744Xylidine (mixed isomers) 746Yttrium 747Zinc chloride fume 748Zinc dithiocarbamates—rubber

components 749Zinc oxide 750Zirconium compounds 751

CONTENTS xi

III CAS Number Index 753

IV Index of Compounds and Synonyms 761

Part

I❏

INTRODUCTION:

TOXICOLOGICAL CONCEPTS❏

TOXICOLOGICAL CONCEPTS—SETTINGEXPOSURE LIMITS

Nick H. Proctor, Ph.D.

DEFINITIONS

In occupational health practice, the followingterms describe the states of matter in whichchemical atmospheres may occur:

Gas: A formless fluid that completely occu-pies the space of an enclosure at 25°C and 760torr (1 atmosphere) pressure.

Vapor: The gaseous phase of a material thatis liquid or solid at 25°C and 760 torr (1 atmos-phere) pressure.

Aerosol: A dispersion of particles of micro-scopic size in a gaseous medium; may be solidparticles (dust, fume, smoke) or liquid particles(mist, fog).

Dust: Airborne solid particles (an aerosol)that range in size from 0.1 to 50mm and largerin diameter. A person with normal eyesight cansee dust particles as small as 50mm in diameter.Smaller airborne particles cannot be seenunless strong light is reflected from the parti-cles. Dust of respirable size (below 10mm)cannot be seen without the aid of a microscope.

Fume: An aerosol of solid particles gener-ated by condensation from the gaseous state,

generally after volatilization from moltenmetals. The solid particles that make up a fume are extremely fine, usually less than 1.0mm in diameter. In most cases, the volatilizedsolid reacts with oxygen in the air to form anoxide. A common example is cadmium oxidefume.

Smoke: An aerosol of carbon or soot par-ticles less than 0.1mm in diameter that results from the incomplete combustion of carbonaceous materials such as coal or oil.Smoke generally contains droplets as well asdry particles.

Mist: An aerosol of suspended liquiddroplets generated by condensation from thegaseous to the liquid state or by the breakingup of a liquid into a dispersed state, such as by splashing, foaming, or atomizing. Examplesare the oil mist produced during cutting andgrinding operations, acid mists from electro-plating, acid or alkali mists from pickling oper-ations, and paint spray mist from sprayingprocedures.

Fog: A visible liquid aerosol formed by con-densation.

3

The following terms of measurement arecommonly used in toxicological testing and inindustrial hygiene practice:

ppm: Parts of vapor or gas per million partsof air by volume

mg/m3: Milligrams of a substance per cubicmeter of air

mg/l: Milligrams of a substance per liter of air

TOXICOLOGICAL CONCEPTS

Routes of Entry of Chemicals into the Body

In the occupational setting, inhalation is themost important route of entry of chemicalagents into the body, followed by contact withskin and subsequent cutaneous absorption.Although the gastrointestinal tract is a poten-tial site of absorption, the ingestion of signifi-cant amounts of chemicals is rare in theoccupational setting.

Inhalation

The respiratory tract is exposed to chemi-cals in the inspired air. The two main factorsthat determine the tissue responses to chemi-cals are the functional anatomy of the respira-tory tract and the physicochemical nature ofthe material.1–3

The respiratory tract may be divided intothree major regions: the nasopharyngeal (upperairways), the tracheobronchial tree (lowerairways), and the pulmonary (alveoli).

The nasopharynx begins with the anteriornares and extends down to the larynx. Thenasal passages are lined with vascular mucousepithelium composed of ciliated epitheliumand scattered mucous glands. The nasopharynxfilters out large inhaled particles and is wherethe relative humidity is increased and the tem-perature of the air is moderated.

The airways (trachea, bronchi, and bron-chioles or tracheobronchial tree) serve as con-

ducting airways between the nasopharynx andalveoli. They are lined with ciliated epitheliumand coated with a thin layer of mucus secretedprimarily by goblet cells in the upper airwaysand primarily by Clara cells at the bronchiolarlevel. This mucous covering terminates at thefilm covering the alveolar membrane. Thesurface of the airways serves as a mucociliaryescalator, moving particles up to the oral cavity,where they are swallowed and excreted orexpectorated.

The ciliated cells are most vulnerable todamage. The most frequent degenerativechanges in these cells are loss of cilia, necrosis,and sloughing of cells into the airway lumen.Necrosis and desquamation of nonciliated andsecretory cells are less frequently observed.

After acute mild insult the nonciliated cellsproliferate and the epithelium regenerates tonormal. In the airways, nonciliated basal cellsare the main proliferating population. In thebronchioles, the Clara cell is the main precur-sor cell for regeneration. Because of the deli-cate nature of the respiratory tract epitheliumand the close proximity of subepithelial bloodvessels, an inflammatory response occurs to allbut the mildest form of injury. Many lesions aretherefore diagnosed as rhinitis, tracheitis, andbronchiolitis and qualified as acute, subacute,and chronic depending on the stage of theresponse.

If the insult persists, hyperplasia (cell pro-liferation) proceeds and leads to an abnormalepithelium. Injury produced by chronic expo-sure to irritants such as SO2, NO2, O3,formaldehyde, and tobacco smoke includesundifferentiated basal cells (hyperplasia), squa-mous metaplasia, and goblet cell metaplasia. Inpractice, many irritants produce responsesbetween mild and severe, and various combi-nations of degeneration, inflammation, andproliferation may be observed.

The lower respiratory tract (pulmonaryregion or alveolar ducts and sacs) is the areawhere gas exchange occurs. Alveolar sacs, clus-ters of two or more alveoli, branch from alve-olar ducts. It is generally considered that thereis a total of approximately 300 million alveoliin the lungs of adult humans.4 The total alveo-lar surface area in the lungs of adult humans is

4 TOXICOLOGICAL CONCEPTS

about 35m2 during expiration, 70–80m2 atthree-fourths total lung capacity, and 100m2

during deep inspiration.5

The alveoli are lined by two main types ofepithelial cells. Type I cells (squamous pneu-monocytes) have flattened nuclei and thin butvery extensive cytoplasm covering most of thealveolar wall. Because this cell has a very largesurface area it is very susceptible to injury.

Type II cells (granular pneumonocytes) are distributed throughout the alveoli betweenType I cells. Although they are more numerousthan Type I cells, they are cuboidal in shape andoccupy far less of the alveolar surface area. Theprime function of this cell is the production ofpulmonary surfactant, and it is generally lesssusceptible to injury than the Type I cell.

The other main cell type in the alveoli isthe alveolar macrophage, which plays animportant role by phagocytizing particulatesand removing them from the alveoli. Phagocytosis of toxic particulates may injuremacrophages, and the discharge of their contents may cause alveolar damage. Stromalcells such as fibroblasts are infrequent but may increase sufficiently in number duringchronic inflammatory reactions to interferewith gaseous exchange and compromise lungfunction.

Most direct toxins entering the alveoli pri-marily affect Type I cells and their associatedcapillary endothelial cells. After acute injury,the epithelium and/or underlying capillaryendothelial cells may swell and disrupt, distort,or lose their connections with others, leavinglarge areas of basement membrane uncovered.This allows fluid to move into the alveolarlumen from capillaries, with subsequent pul-monary edema.

The sequel to acute injury depends on thepotency and concentration of the toxic agentand the duration of exposure. Potent gasesproduce a severe vascular reaction and alveolarflooding. The fluid prevents gaseous exchange,and death of the human or animal ensues. Afteracute mild nonlethal damage, excess fluid isremoved and the resistant Type II cells prolif-erate and reline the alveoli. The cells subse-quently differentiate into Type I cells.

If the chemical is a moderate irritant and

causes significant damage to the basementmembrane and stroma as well to the epithelialcells, fibroblastic repair and fibrous scarringresult in the alveoli. These fibrotic alveoli aregenerally lined by atypical Type II cells. Thelining of alveoli by Type II cells, either in theearly phases of repair of mild damage or as anend stage of more severe damage, is oftenreferred to as alveolar epithelialization. Occa-sionally, the alveoli may be relined by a prolif-eration of bronchiolar epithelium. This istermed alveolar bronchiolization. Intra-alveolaraccumulation of macrophages is also a promi-nent feature.

Gases

The rate of removal of gases from theairstream during inhalation depends mostly onthe water solubility of the gas. Highly water-soluble gases such as ammonia, hydrogen chlo-ride, and hydrogen fluoride dissolve readily inthe moisture associated with the mucouscoating of the nasopharyngeal region, causingirritation at those sites. At high atmosphericconcentrations, some of the gas will not beabsorbed at the upper respiratory sites, andamounts sufficient to reach the alveoli cancause severe irritation and pulmonary edema.

Comparatively insoluble gases such asnitrogen dioxide and phosgene are notremoved by the moisture in the upper respira-tory tract and can easily reach the alveoli. Sub-stances of intermediate solubility such aschlorine can cause irritation at points all alongthe respiratory tract.

Bronchoconstriction is one of the mostcommon immediate responses observed oninhalation of a number of reactive gases. Theconstriction may be caused by a direct actionon the airway smooth muscles or indirectlythrough the release of histamine and othermediators.

Particulates

The chief factor that determines the site ofdeposition of particulate matter in the respira-tory tract is its size.3,6 Particles having an aero-dynamic diameter of 5–30mm are primarily

Toxicological Concepts—Setting Exposure Limits 5

deposited in the nasopharyngeal region byimpaction with nose hairs and the angular wallsof the nasopharyngeal passages.

Particles with an aerodynamic diameter of1–5m are deposited in the airways (tracheo-bronchial regions) by sedimentation undergravitational forces. As the alveolar regions areapproached, the velocity of the airflowdecreases significantly, allowing more time forsedimentation. The very small particles, gener-ally less than 1m, that penetrate to the alveoliare deposited there mainly by diffusion.

In extrapolating results from rodents tohumans, it is important to understand the dif-ferences in deposition that occur.7,8 Smallrodents usually have lower fractional deposi-tion of inhaled particles in the lung thanhumans, but rodents inhale more air per unitof lung mass or lung surface than humans. Themost important interspecies differences in dep-osition are associated with particles larger thanabout 5m in aerodynamic diameter becausethese larger particles cannot readily reach thepulmonary region in small nose-breathingrodents.

In contrast, a decreasing proportion of par-ticles from 1m (100%) up to 10m (1%) reachesthe pulmonary region in the human lungduring normal breathing via the nose.9 Oncethere, maximum pulmonary deposition occursfor particle sizes of 1–4m: about 25% of 1m,35% of 2m, 30% of 3m, and 25% of 4m.10

Mouth breathing by humans during exer-tion may result in deposition that is distinctlydifferent from that associated with nasalbreathing, with increased deposition of thelarger particles up to about 15m in both the tra-cheobronchial and pulmonary regions.8

Particle Clearance

Particles deposited in the nasopharyngealregion are moved to the pharynx by the ciliatedcells and mucus and expectorated or swal-lowed.10 The clearance rate is relatively rapidwith a half-life of 12–24 hours.

Particles deposited on or in the lungparenchyma are cleared primarily by alveolarmacrophages. These phagocytized particlesmigrate to the ciliated epithelium or to the

lymphatic system at times ranging from 2 to 6weeks. However, for some materials, this timeis longer, such that half-lives of many monthsoccur.

Certain chemicals such as silicon dioxidehave a cytotoxic effect on the alveolarmacrophage, which results in the accumulationof particles in a given area. As the macrophageslose their activity, these particles become lesssubject to removal, leading to the developmentof masses containing dead cells and particles.

Fibers

When using animal inhalation studies forassessment of the risk to human health of airborne fibers, it is critical to demonstrate that the characteristics and concentrations of the experimental fiber aerosols are comparableto those in human exposure situations.11

NIOSH has two criteria for defining fibers: “A”rules (total fibers) and “B” rules (respirablefibers).12

NIOSH “A” rules count fibers with alength-to-diameter ratio ≥3 :1, length ≥5m.

NIOSH “B” rules count fibers with alength-to-diameter ratio >5 :1, length ≥5m,and diameter

The epidermis consists of several types ofcells. The epidermal cell type apposed to thedermis is the stratum germinativum (basal celllayer), over which are the stratum spinosum,stratum granulosum, stratum ludicum, and theoutermost layer or stratum corneum. The basalcell layer consists of one layer of columnarepithelial cells. On division, the basal cells are pushed up and become the stratum spin-osum, which consists of several layers of cells.As these cells approach the surface of the skin they become larger and form the stratumgranulosum.

At this point the nuclei are broken up,resulting in the death of the cell. The nextlayer, stratum ludicum, is ill defined except inareas of thick skin, and is said to containeleidin, a transformation product of the kera-tohyalin present in the stratum granulosum.

In the outermost layer, the stratumcorneum, the eleidin has been converted intokeratin, which represents the ultimate fate ofthe epidermal cell. Keratin, continuouslysloughed off or worn away, is replaced by thecells beneath it. The time required for a basalcell to migrate from the stratum germinativumto the outer part of the stratum corneum is esti-mated at 26–28 days.

The dermis is a thick fibrous network ofcollagen and elastin and is composed of twolayers. The outer, thinner layer is the papillarylayer, which has prominent papillae that mergewith the thick reticular layer. The papillae arewell supplied with blood by the capillaries thatare prominent in them, which serves the basalcell layer in the dermis with nutrients.

The dermis contains several types of cells,including fibroblasts, fat cells, macrophages,histiocytes, mast cells, and cells associated withthe blood vessels and nerves of the skin. Thepredominant cell is the fibroblast, which isassociated with biosynthesis of the fibrous pro-teins and ground substances such as hyaluronicacid, chondroitin sulfates, and mucopolysac-charides.

The appendages of skin are hair follicles,sebaceous glands, eccrine and apocrine sweatglands, hair, nails, and arrector pili muscles.

When a substance contacts the skin,various actions are possible:

The skin and its associated film of lipid andsweat may act as an effective barrier thatthe substance cannot penetrate

The substance may react with the skinsurface and cause primary irritation (acids,alkalies, many organic solvents)

The substance may penetrate the skin andcause allergic contact dermatitis(formaldehyde, nickel, phthalic anhydride)

The agent may penetrate the skin, enterthe blood, and act systemically (aniline,parathion)

To pass into the skin, the substance mustenter through one or more of the followingroutes: the epidermal cells, the sweat glands,the sebaceous glands, or the hair follicles. Thepathway through the stratum corneum and theepidermal cells is the main avenue of penetra-tion, as this tissue constitutes the majority ofthe surface area of the skin.

The stratum corneum plays a critical rolein determining cutaneous permeability.Absorption is faster through skin that isabraded or inflamed. Chemicals that are notnormally considered hazardous may be dan-gerous to individuals suffering from activeinflammatory dermatoses.

The skin not only is a barrier to restrictdiffusion of chemicals into the body, it is alsoan organ that can metabolize a variety of topi-cally applied substances before they becomesystemically available.14 The skin has many ofthe same enzymes as the liver. The activities ofseveral cutaneous enzymes in whole skinhomogenates have been measured and com-pared to hepatic activity in the mouse.15 Theactivities of the enzymes in the whole skinhomogenates were typically 2–6% of thehepatic values. However, there is evidence thatthe enzymes are present primarily in the epi-dermis. Because the epidermis makes up only2–3% of the total skin, the real activities mayrange from 80% to 240% of those in the liver.Enzyme systems present include a cytochromeP-450 system and a mixed-function oxidasesystem.

Toxicological Concepts—Setting Exposure Limits 7

Dose and Response

Toxicology is the study of the noxious effects ofchemical and physical agents. The most funda-mental concept in toxicology states that thereis a relationship between the dose of an agentand the response that is produced in a biolog-ical system. The concept was first formalizedby Paracelsus (1493–1541 A.D.).

Initial toxicity data on an uncharacterizedagent usually are obtained by oral, intraperi-toneal, or dermal administration to laboratoryanimals. This provides an estimate of the lethalpotency of the material. Observation of theanimals after administration of the materialoften provides valuable information concern-ing the effects that may occur in humans.Autopsy of the animals will show the likelytarget organs in humans.

Toxicity and Hazard

Toxicity is the ability of a substance tocause injury to biological tissue. The hazard orrisk of a substance is the probability that it willcause injury in a given environment or situa-tion. The hazard of a substance depends onseveral factors, including its toxicity; how it isabsorbed, metabolized, and excreted; howrapidly it acts; its warning properties; and itspotential for fire and explosion.

Exposure

Exposure to chemicals in toxicologicaltests of animals is classified according to fre-quency and duration, as follows:

• Acute exposure is exposure for up to 24hours.

• Subacute exposure is repeated exposurefor 1 month or less.

• Subchronic exposure is repeated exposurefor 1–3 months.

• Chronic exposure is repeated exposurethat lasts for more than 3 months, andoften for 24 months or the lifetime ofrodent species.

In the occupational setting, acute humanexposure generally refers to exposure that

causes an effect within 24 hours, whereas theterm chronic exposure is applied to repeatedexposures over time.

THE STANDARDS SETTINGPROCESS

Threshold Limit Value (TLV)

The American Conference of GovernmentalIndustrial Hygienists (ACGIH) has prepared a list of the threshold limit values (TLVs) for approximately 800 substances. The following three categories of TLVs are specified.16

Threshold Limit Value-Time-WeightedAverage (TLV-TWA): The time-weightedaverage concentration for a normal 8-hourworkday and a 40-hour workweek, to whichnearly all workers may be repeatedly exposed,day after day, without adverse effect.

Threshold Limit Value-Short Term ExposureLimit (TLV-STEL): The concentration towhich workers can be exposed continuously fora short period of time without suffering from1) irritation, 2) chronic or irreversible tissuedamage, or 3) narcosis of sufficient degree toincrease the likelihood of accidental injury,impair self-rescue, or materially reduce workefficiency, and provided that the daily TLV-TWA is not exceeded. It is not a separate inde-pendent exposure limit; rather, it supplementsthe time-weighted average (TWA) limit wherethere are recognized acute effects from a sub-stance whose toxic effects are primarily of achronic nature. STELs are recommended onlywhere toxic effects have been reported fromhigh short-term exposures in either humans oranimals.

A STEL is defined as a 15-minute TWAexposure that should not be exceeded at anytime during a workday even if the 8-hour TWAis within the TLV-TWA. Exposures above theTLV-TWA up to the STEL should not belonger than 15 minutes and should not occurmore than four times per day. There should beat least 60 minutes between successive expo-

8 THE STANDARDS SETTING PROCESS

sures in this range. An averaging period other than 15 minutes may be recommendedwhen this is warranted by observed biologicaleffects.

Threshold Limit Value-Ceiling (TLV-C): Theconcentration that should not be exceededduring any part of the working exposure.

In the absence of a STEL, excursions inworker exposure levels may exceed three timesthe TLV-TWA for no more than a total of 30minutes during a workday, and under no cir-cumstances should they exceed five times theTLV-TWA, provided that the TLV-TWA isnot exceeded.

“Skin” Notation. Substances on the list fol-lowed by the designation “Skin” refer to thepotential significant contribution to the overallexposure by the skin route, including mucousmembranes and the eyes, either by contact withvapors or, of probable greater significance, bydirect skin contact with the substance.

TLVs are revised by the ACGIH annuallyas new information becomes available. Eachyear, additional substances of interest are addedto the TLV list. Certain compounds that areproven or suspected carcinogens in humanssuch as benzidine, 4-aminodiphenyl, and 4-nitrodiphenyl have no TLV value, and humanexposure to these agents should be avoided.Note: For a detailed discussion of carcinogenicrisks to humans, the publications of the IARCshould be consulted.17

OSHA Standards

The first occupational safety and health stan-dards were set when, with only minor changes,the 1968 ACGIH list of nearly 400 TLVs, aswell as certain standards of the AmericanNational Standards Institute (ANSI), wereincorporated into the Walsh–Healey PublicContracts Act. They thereby became limits ofexposure for employees of federal governmentcontractors.

Subsequently, under the authority of theOccupational Safety and Health Act of 1970,these same 1968 TLVs and ANSI standardswere promulgated by the Occupational Safetyand Health Administration (OSHA) as the

start-up Permissible Exposure Limits (PEL)for all workers covered by the Act.

REFERENCES

1. Glaister JR: Principles of Toxicological Pathology,pp 62–74. Philadelphia, PA, Taylor &Francis, 1986

2. West JB: Respiratory Physiology—The Essen-tials. Baltimore, MD, Williams & Wilkins,1985

3. Gordon T, Amdur MO: Responses of the res-piratory system to toxic agents. In AmdurMO, Doull J, Klaasen CD (eds): Casarett andDoull’s Toxicology, 4th ed, pp 383–406. NewYork, Pergamon Press, 1991

4. Charnock EL, Doershuk CF: Developmentaspects of the human lung. Pediatr Clin NorthAm 20:275–292, 1973

5. Weibel ER: Morphometry of the Human Lung.New York, Academic Press, 1963

6. Salem H: Principles of inhalation toxicology.In Salem H (ed): Inhalation Toxicology, pp1–34. New York, Marcel Dekker, 1987.

7. Raabe OG: Deposition and clearance ofinhaled particles. In Gee JBL, MorganWKC, Brooks SM (eds): Occupational LungDisease, pp 1–38. New York, Raven Press,1984

8. Raabe OG et al: Regional deposition ofinhaled monodisperse coarse and fine parti-cles in small laboratory animals. Ann OccupHyg 32, Suppl 1:53–63, 1988

9. American Conference of GovernmentalIndustrial Hygienists (ACGIH): 1994–1995Threshold Limit Values and Biological ExposureIndices, p 45. Cincinnati, OH, ACGIH, 1994

10. Kennedy GK Jr :Inhalation toxicology. InHayes AW: Principles and Methods of Toxicol-ogy, 2d ed, pp 361–382. New York, RavenPress, 1989

11. Hesterberg TW, Hart GA: Comparison of human exposures to fiberglass with those used in a recent rat chronic inhalationstudy. Regul Toxicol Pharmacol 20:S35–S47,1994

12. NIOSH (National Institute for OccupationalSafety and Health): NIOSH Manual of Ana-lytical Methods, Method 7400, Revision 3.Washington, DC, US Government PrintingOffice, 1989

13. Rongue EL: Skin structure, function, andbiochemistry. In: Marzulli FN, Maibach HI

Toxicological Concepts—Setting Exposure Limits 9

(eds) Dermatotoxicology, 3rd ed, pp 1–70. NewYork, Hemisphere 1987

14. Noonan PK, Wester RC: Cutaneous bio-transformations. In: Marzulli FN, MaibachHI (eds) Dermatotoxicology, 3rd ed, pp 71–94.New York, Hemisphere, 1987

15. Pohl R, Philpot R, Fouts J: Cytochrome P-450 content and mixed-function oxidaseactivity in microsomes isolated from mouseskin. Drug Metab Dispos 4:442–450, 1976

16. American Conference of GovernmentalIndustrial Hygienists (ACGIH): 1994–1995 Threshold Limit Values for Chemical Sub-stances and Physical Agents and Biological Exposure Limits. Cincinnati, OH, ACGIH,1994

17. IARC Monographs on the Evaluation of Car-cinogenic Risks to Humans, Vols 1–83. Lyon,France, International Agency for Research onCancer, 1972–2002.

10 REFERENCES

Part

II❏

THE CHEMICAL HAZARDS❏

ACETALDEHYDECAS: 75-07-0

CH3CHO

Synonyms: Ethanal; acetic aldehyde; ethyl-aldehyde; methyl formaldehyde

Physical Form. Colorless liquid

Uses. As a chemical intermediate in synthe-sis of acetic acid, pentaerythritol, and pyridine;in the production of perfumes, polyester resins,and dyes and as a food preservative and flavor-ing agent

Exposure. Inhalation

Toxicology. Acetaldehyde is an irritant of theeyes, skin, and respiratory tract; at high con-centrations it causes narcosis; it is carcinogenicin experimental animals.

Nausea, loss of consciousness, and pul-monary edema have been reported with heavyexposure.1 At 134ppm for 30 minutes there wasmild upper respiratory irritation, whereas 15minutes at 50ppm produced mild eye irrita-tion.2 Sensitive subjects have noted eye irrita-tion after 15-minute exposures at 25ppm.3

Splashed in the eyes, the liquid causes aburning sensation, lacrimation, blurred vision,and corneal injury.1 On the skin for a prolongedperiod of time, the liquid causes erythema andburns.

In animal studies the 4-hour inhalationLC50 was 17,000ppm for hamsters and 13,300ppm for rats.4 Exposure to 5000ppm for 10 minutes produced a 50% decrease inrespiration rate in mice; in anesthetized ratssignificant increases in blood pressure wereobserved at 1700ppm and concentrationsabove 6000ppm significantly increased heartrate.5,6

Hamsters repeatedly exposed to 4500ppmfor 3 months had growth retardation, ocularand nasal irritation, increased erythrocytecounts, and severe histopathological changes inthe respiratory tract.7

Chronic inhalation of acetaldehyde pro-duced tumors of the respiratory tract in ratsand hamsters.8 The incidence of laryngeal car-cinomas was increased in hamsters exposed for

1 year to 1500ppm.9 In a lifetime inhalationstudy (52 weeks, with recovery for 26 or 52weeks), rats exposed at 750, 1500, or 3000ppmhad exposure-related increases in adenocarci-nomas and squamous cell carcinomas of thenasal mucosa.10 Associated changes includedgrowth retardation, degenerative changes ofthe olfactory epithelium, and metaplasia of therespiratory epithelium, frequently accompa-nied by keratinization.10,11

The IARC has determined that there issufficient evidence for carcinogenicity ofacetaldehyde to experimental animals. Onelimited epidemiological study that found anincreased relative frequency of bronchial andoral cavity tumors among nine cancer cases in aldehyde-exposed workers provided inade-quate evidence for human carcinogenicity.4,8

Acetaldehyde is considered to be possiblycarcinogenic to humans.8

Acetaldehyde has demonstrated genotoxi-city in a variety of cell culture systems.12 Thereis indirect evidence from in vitro and in vivostudies to suggest that acetaldehyde can induceprotein-DNA and DNA-DNA cross-links.13

In several studies, parenteral exposure ofpregnant rats and mice has produced embry-otoxic, fetotoxic, and teratogenic effects;however, maternal toxicity was not adequatelyevaluated, and the selective developmentaleffects of acetaldehyde cannot be evaluated.13

The 2003 ACGIH ceiling threshold limitvalue (C-TLV) for acetaldehyde is 25ppm (45mg/m3) with an A3-animal carcinogendesignation.

REFERENCES

1. Von Burg R, Stout T: Toxicology update.Acetaldehyde. J Appl Toxicol 11:373–376,1991

2. Silverman L, Schulte HF, and First MW:Further studies on sensory response tocertain industrial solvent vapors. J Ind HygToxicol 28:262–266, 1946

3. Chemical Hazard Information Profile: Acetalde-hyde. Washington, DC, US EnvironmentalProtection Agency, 1983

4. IARC Monographs on the Evaluation of theCarcinogenic Risk of Chemicals to Humans. Vol36, Allyl compounds, aldehydes, epoxidesand peroxides, pp 101–136. Lyon, Interna-tional Agency for Research on Cancer, 1985

13

5. Kane LE, Dombroske R, Alaire Y: Evaluationof sensory irritation from some commonindustrial solvents. Am Ind Hyg Assoc J41:451–455, 1980

6. Egle JL Jr: Effects of inhaled acetaldehydeand propionaldehyde on blood pressure andheart rate. Toxicol Appl Pharmacol 23:131–135,1972

7. Kruysse A, Feron VJ, Til HP: Repeated expo-sure to acetaldehyde vapor. Studies in Syriangolden hamsters. Arch Environ Health30:449–452, 1975

8. IARC Monographs on the Evaluation of the Car-cinogenic Risk of Chemicals to Humans, Vol 71,Re-evaluation of some organic chemicals,hydrazine and hydrogen peroxide, pp319–335. Lyon, International Agency forResearch on Cancer, 1999

9. Feron VJ, Kruysse A, Woutersen RA:Respiratory tract tumors in hamsters exposedto acetaldehyde vapor alone or simultane-ously to benzo(a)pyrene or diethylni-trosamine. Eur J Cancer Clin Oncol 18:13–31,1982

10. Woutersen RA, Appleman LM, et al: Inhala-tion toxicity of acetaldehyde in rats. III. Car-cinogenicity study. Toxicology 41(2):213–231,1986

11. Woutersen RA, Feron VJ: Inhalation toxicityof acetaldehyde in rats. IV. Progression andregression of nasal lesions after discontinua-tion of exposure. Toxicology 47:295–305, 1987

12. Heck H: Mechanisms of aldehyde toxicity:Structure activity studies. CIIT Activities5(10):106, 1985

13. World Health Organization: EnvironmentalHealth Criteria 167 Acetaldehyde, 129pp.International Programme on ChemicalSafety (IPCS), Geneva, 1995

ACETAMIDECAS: 60-35-5

CH3CONH2

Synonyms: Acetic acid amide; ethanamide

Physical Form. Deliquescent crystals

Uses. Cryoscopy; organic synthesis; generalsolvent; lacquers; explosives, soldering flux;wetting agent; plasticizer

Exposure. Ingestion; inhalation; skin absorp-tion

Toxicology. Acetamide is a mucous mem-brane irritant, a liver toxin, and a carcinogen inanimals.

There are no data regarding the toxicity ofacetamide to humans.

In animals, acetamide was stated to be amild irritant to skin and eyes, although exper-imental details were not available. Oral admin-istration of acetamide to rodents producedlethality with doses of 1–7g/kg.1 In anotherreport, single oral dose LD50 values for malerats and male mice were 10.3 and 10.1g/kg,respectively.2 Minor changes in liver histologyoccur after acute exposures in rats.1

Oral doses of 0.3g/kg acetamide adminis-tered on days 6 through 18 of gestation pro-duced no toxicity or terata in rabbits. Nomaternal toxicity was seen at 1g/kg, althoughone rabbit aborted; fetal numbers and bodyweights were lowered, with no terata. At 3g/kg,maternal toxicity was encountered, fetalnumbers and weights were reduced, thenumber of dead implants was elevated, andcleft palate was seen.1 No reproductive, embry-otoxic, or teratogenic effects were observed inrats.1

Acetamide produced benign and malignantliver tumors in rats after oral administration. Inmale mice, an increased incidence of malignantlymphomas also was observed.2

Acetamide was mutagenic in Escherichia coliand Salmonella typhimurium; this effect wasindependent of dose. Acetamide producedmorphological transformation in Syrianhamster embryo cells in the absence of meta-bolic activation. However, acetamide did notinduce reversions in several Salmonellatyphimurium strains.1

The IARC has determined that there issufficient evidence of carcinogenicity foracetamide in experimental animals and that itis possibly carcinogenic to humans.3

14 ACETAMIDE

ACGIH has not established a thresholdlimit value for acetamide.

REFERENCES

1. Kennedy GL, Jr: Biological effects onacetamide, formamide, and their monomethyland dimethyl derivatives. CRC Crit Rev Toxicol17:129–182, 1986

2. IARC Monographs on the Evaluation of the Car-cinogenic Risk of Chemicals to Man, Vol 7, Someanti-thyroid and related substances, nitrofu-rans and industrial chemicals, pp 197–200.Lyon, International Agency for Research onCancer, 1974

3. IARC Monographs on the Evaluation of theCarcinogenic Risk of Chemicals to Humans, Vol71, Re-evaluation of some organic chemicals,hydrazine and hydrogen peroxide. pp1211–1221. Lyon, International Agency forResearch on Cancer, 1999

ACETIC ACIDCAS: 64-19-7

CH3COOH

Synonyms: Ethanoic acid; ethylic acid;methane carboxylic acid; vinegar (4–6% solu-tion in water)

Physical Form. Liquid

Uses. Production of cellulose and vinylacetate; dyeing; pharmaceuticals and foodprocessing

Exposure. Inhalation

Toxicology. Acetic acid vapor is a severe irri-tant of the eyes, mucous membranes, and skin;chronic exposure may cause bronchitis andcracking and darkening of exposed skin.

Exposure to 50ppm or more is intolerableto most persons and results in intensivelacrimation and irritation of the eyes, nose, and

throat, with pharyngeal edema and chronicbronchitis.1 Unacclimatized humans experi-ence extreme eye and nasal irritation at con-centrations in excess of 25ppm; conjunctivitisfrom concentrations below 10ppm has beenreported.1

In one case report a 37-year-old malemaintenance fitter was accidentally exposed toa large cloud of hot acetic acid while discon-necting a pressurized pump.2 The patient suf-fered first-degree burns on the hands and faceand developed progressive dyspnea. At 3months there were persistent extensive crack-les in the basal area of the lungs, widespreadbronchial inflammatory changes, and diffusemoderate interstitial pneumonitis thatpromptly improved after treatment with corti-costeroids and bronchodilators.

In a study of five workers exposed for 7–12years to concentrations of 80–200ppm atpeaks, the principal findings were blackeningand hyperkeratosis of the skin of the hands,conjunctivitis (but no corneal damage), bron-chitis and pharyngitis, and erosion of theexposed teeth (incisors and canines).3 Digestivedisorders with pyrosis and constipation havealso been reported at unspecified prolongedexposures.4

Chronic exposure to fumes of heatedglacial acetic acid in a canning factory has beenassociated with a late airway response resultingin chronic inflammation and severe bronchialasthma. Inhalation challenge induced a lateasthmatic response, confirming sensitization.5

A study of cancer mortality among 1359workers involved in the production of aceticacid and acetic anhydride found that mortalityfrom all causes decreased but mortality fromprostate cancer was significantly increased,based on six deaths. Measurements of aceticacid levels were not made for most of the studyperiod, but recent monitoring found exposuresranging between 0.1 and 1.2ppm.6

Glacial (100%) acetic acid caused severeinjury when applied to the eyes of rabbits; inhumans it has caused permanent corneal opaci-fication.7 A splash of vinegar (4–10% acetic acidsolution) in the human eye causes immediatepain and conjunctival hyperemia, sometimeswith injury of the corneal epithelium.7

ACETIC ACID 15

On the guinea pig skin, the liquid in con-centrations in excess of 80% produced severeburns; concentrations of 50–80% producedmoderate to severe burns; solutions below 50%caused relatively mild injury; no injury was pro-duced by 5–10% solutions.3

Although ingestion is unlikely to occur inindustrial use, as little as 1.0ml of glacial acetic acid has resulted in perforation of theesophagus.1

Acetic acid was not clastogenic in Chinesehamster ovary (CHO) cells in vitro when thepH of the culture medium was neutralized.8

The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) for aceticacid is 10ppm (25mg/m3) with a short-termexposure limit of 15ppm (37mg/m3).

REFERENCES

1. AIHA Hygienic Guide Series: Acetic Acid. Akron,OH, American Industrial Hygiene Associa-tion, 1978

2. Rajan KG, Davies BH: Reversible airwaysobstruction and interstitial pneumonitis due toacetic acid. Br J Ind Med 46:67–68, 1989

3. Guest D et al: Aliphatic carboxylic acids. InClayton GD, Clayton FE (eds): Patty’s Indus-trial Hygiene and Toxicology, 3rd ed, rev, Vol 2C,Toxicology, pp 4909–4911. New York, Wiley-Interscience, 1982

4. Hazard Data Bank: Sheet No 64, Acetic Acid.The Safety Practioner, pp 11–12, April 1985

5. Kivity S, Fireman E, Lerman Y: Late asthmaticresponse to inhaled glacial acetic acid. Thorax49(7):727–8, 1994

6. Whorton MD, Amsel J, Mandel J: Cohortmortality study of prostrate cancer amongchemical workers. Am J Ind Med 33(3):293–296, 1998

7. Grant WM: Toxicology of the Eye, 2nd ed, pp80–82, Springfield, IL, Charles C. Thomas,1974

8. Morita T, Takeda K, Okumura K: Evaluationof clastogenicity of formic acid, acetic acid andlactic acid on cultured mammalian cells. MutatRes 240(3):195–202, 1990

ACETIC ANHYDRIDECAS: 108-24-7

(CH3CO)2O

Synonyms: Acetic oxide; acetyl oxide; ethanoicanhydrate; acetic acid anhydride

Physical Form. Colorless liquid

Uses. Manufacture of cellulose esters, plas-tics, pharmaceuticals, photographic films,cigarette filters, and magnetic tape; inorganicsynthesis as an acetylating agent, bleachingagent, and dehydrating agent

Exposure. Inhalation

Toxicology. Acetic anhydride vapor is asevere irritant of the eyes, mucous membranes,and skin.

Humans exposed to undetermined buthigh vapor concentrations complained imme-diately of severe conjunctival and nasopharyn-geal irritation, harsh cough, and dyspnea.1

Workers exposed to vapors from a boilingmixture complained of severe eye irritation andlacrimation.1 The immediate effect of exposureto vapor concentrations above 5ppm is acuteirritation of the eyes and upper respiratorytract; inhalation of high vapor concentrationsmay produce ulceration of the nasal mucosaand, in some instances, bronchospasm.2

Delayed deaths due to acetic anhydride expo-sure have been reported. In one case, a workersustained burns to 35% of his body after theexplosion of a drum of acetic anhydride; deathoccurred after 67 days from progressive lungdamage that included pneumothoraces andbronchopulmonary fistulae.3 Autopsy revealedextensive fibrous adhesions within the pleuralcavity.

Both the liquid and the vapor can causesevere damage to the human eye; this is char-acterized by immediate burning, followed somehours later by an increasing severity of reactionwith corneal and conjunctival edema.1 Intersti-tial corneal opacity may develop over a period

16 ACETIC ANHYDRIDE

of several days because of progression of tissueinfiltration; in mild cases, this condition isreversible, but permanent opacification withloss of vision may also occur. Workers exposedto acetic anhydride vapor may show evidenceof conjunctivitis with associated photophobia.1

Prolonged dermal contact with the liquidmay cause the skin to redden and subsequentlyturn white and wrinkled but may not be imme-diately painful.4 Skin burns may appear later.Repeated skin exposure to the liquid or vapormay cause irritation.

Generalized skin reactions in guinea pigssensitized to acetic anhydride have beendemonstrated, and skin sensitization in humansoccasionally occurs.2

Although ingestion of the liquid is unlikelyin ordinary industrial use, the highly corrosivenature of the substance may be expected toproduce serious burns of the mouth and esoph-agus.

Acetic anhydride has good warning prop-erties.

The 2003 ACGIH threshold limit value-time-weighted value (TLV-TWA) is 5ppm (21mg/m3).

REFERENCES

1. AIHA Hygienic Guide Series: Acetic Anhydride.Akron, OH, American Industrial HygieneAssociation, 1978

2. Fassett DW: Organic Acids and related com-pounds. In Fassett DW and Irish DD (eds.):Patty’s Industrial Hygiene and Toxicology, 2nd ed,Vol 2, Toxicology, pp 1817–1818, New York,Interscience, 1963

3. Sinclair JS, McManus DT, O’Hara MD, et al:Fatal inhalation injury following an industrialaccident involving acetic anhydride. Burns20(5):469–470, 1994

4. Hazard Data Bank: Sheet No. 70, AceticAnhydride. Safety Practioner 3:12–13, Oct.1985

ACETONECAS: 67-64-1

(CH3)2CO

Synonyms: Dimethyl ketone; 2-propanone; b-ketopropane

Physical Form. Colorless liquid

Uses. Solvent for fats, oils, waxes, rubber,plastics; in the production of lubricating oils; inthe dyeing and celluloid industries; as a chem-ical intermediate; paint and varnish remover;major component of nail polish remover

Exposure. Inhalation; skin absorption

Toxicology. Acetone is an irritant of the eyes and mucous membranes; at very highconcentrations it is a central nervous systemdepressant.

Acetone is considered to be of low risk tohealth because few adverse effects have beenreported despite widespread use for manyyears.1 One early study, often quoted, reportseye, nose, and throat irritation in volunteersexposed to 500ppm.2

In more recent studies, subjects exposed to500ppm were aware of odor but exhibited noeffects.3 Mild eye irritation occurred around1000ppm.4 Higher concentrations producedheadache, light-headedness, and nose andthroat irritation.4 Concentrations above 12,000ppm depressed the central nervous system(CNS), causing dizziness, weakness, and loss ofconsciousness.5

Neurobehavioral tests have found slight,but statistically significant, performance decre-ments after 4-hour exposure to 250ppm, sug-gesting mild CNS depression at this level.6

In a retrospective mortality study of over 900 workers exposed from 3 months to 23 years to median time-weighted acetoneconcentrations up to 1070ppm there was nosignificant risk of death from any cause (allcauses, malignant neoplasm, circulatory systemdisease, ischemic heart disease) compared withrates for the general population.7

ACETONE 17

Topical application of 1ml of acetone for90 minutes produced reversible skin damage tohumans.8

Acetone is metabolized mainly in the liverby three separate pathways, leading to theproduction of glucose with the subsequentliberation of carbon dioxide.7 None of theintermediate metabolites appears to be toxic,with the possible exception of formate. Acetoneand acetone-derived carbon dioxide areexcreted in expired air and have little tendencyto accumulate in the body.

High concentrations of acetone wererequired to produce death in animals; the 4-hour inhalation LC50 value is 32,000ppm forrats.9 Administered in the drinking water for 13 weeks, the minimal toxic doses were20,000ppm for male rats and mice and 50,000ppm for female mice.10 The kidney,hematopoietic system, and testis were targetorgans in male rats, and the liver was the targetorgan for mice.

In animal studies acetone has been foundto potentiate the toxicity of other solvents byaltering their metabolism through induction ofmicrosomal enzymes, particularly cytochromeP-450. Reported effects include: enhancementof the ethanol-induced loss of righting reflex inmice by reduction of the elimination rate ofethanol; increased hepatotoxicity of com-pounds such as carbon tetrachloride andtrichloroethylene in the rat; potentiation ofacrylonitrile toxicity by altering the rate atwhich it is metabolized to cyanide; and poten-tiation of the neurotoxicity of n-hexane byaltering the toxicokinetics of its 2,4-hexane-dione metabolite.11–14 Because occupationallyexposed workers are most often exposed to amixture of solvents, use of the rule of additiv-ity may underestimate the effect of combinedexposures.15

Significant developmental toxicity asdetermined by increased incidences of resorp-tions occurred in mice at levels of 6600ppm,which also caused maternal toxicity.16

Depressed sperm motility and epididymalweight and elevated evidence of abnormalsperm were observed in male rats receiving50,000ppm acetone in their drinking water for13 weeks.10

Acetone may be weakly genotoxic, but themajority of assays were negative.7 It was nottumorigenic in skin painting studies in mice.

The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) foracetone is 750ppm (1780mg/m3) with a short-term excursion level of 1000ppm (2380mg/m3).

REFERENCES

1. National Institute for Occupational Safetyand Health, US Department of Health, Edu-cation and Welfare: Criteria for a Recom-mended Standard . . . Occupational Exposure toKetones. DHEW (NIOSH) 78–173. Wash-ington, DC, US Government PrintingOffice, 1978

2. Nelson KW, Ege JF Jr, Ross M, et al: Sensoryresponse to certain industrial solvent vapors.Am Ind Hyg Assoc J 25:282–285, 1943

3. DiVincenzo GO, Yanno FJ, Astill BD: Expo-sure of man and dog to low concentrations of acetone vapor. Am Ind Hyg Assoc J34:329–336, 1973

4. Raleigh RL, McGee WA: Effects of short,high-concentration exposures to acetone asdetermined by observation in the work area.J Occup Med 14:607–610, 1972

5. Ross DS: Short communications—acuteacetone intoxication involving eight maleworkers. Ann Occup Hyg. 16:73–75, 1973

6. Dick RB, Setzer JV, Taylor BT, et al:Neurobehavioral effects of short durationexposures to acetone and methyl ethylketone. Br J Ind Med 46:111–121, 1989

7. Agency for Toxic Substances and DiseaseRegistry (ATSDR): Toxicological Profile forAcetone. pp 1–243. Atlanta, GA, US Depart-ment of Health and Human Services, PublicHealth Service, 1994

8. Lupulescu AP, Birmingham DJ: Effect ofprotective agent against lipid-solvent-induced damages—ultrastructural and scan-ning electron microscopical study of humanepidermis. Arch Environ Health 31:33–36,1976

9. World Health Organization: EnvironmentalHealth Criteria, 207, Acetone. 159 pp. Inter-national Programme on Chemical Safety(IPCS), Geneva, 1998

10. National Toxicology Program: Toxicity Studiesof Acetone in F344/N Rats and B6C3F1 Mice

18 ACETONE

(Drinking Water Studies). Toxicity reportseries 3, pp 1–38, 1991

11. Cunningham J, Sharkawi M, Plaa G: Phar-macological and metabolic interactionsbetween ethanol and methyl n-butyl ketone,methyl isobutyl ketone, methyl ethyl ketone,or acetone in mice. Fundam Appl Toxicol13:102–109, 1989

12. Charbonneau M, Perreault F, Greselin E, etal: Assessment of the minimal effective doseof acetone for potentiation of the hepatoxic-ity induced by trichloroethylene-carbontetrachloride mixtures. Fundam Appl Toxicol10:431–438, 1988

13. Freeman JJ, Hayes EP: Microsomal metabo-lism of acetonitrile to cyanide: Effects ofacetone and other compounds. Biochem Phar-macol 37:1153–1160, 1988

14. Ladefofoged O, Perbellini L: Acetoneinduced changes in the toxicokinetics of 2,5-hexanedione in rabbits. Scand J Work EnvironHealth 12:627–629, 1987

15. Noraberg J, Arlien-Soborg P: Neurotoxicinteractions of industrially used ketones.Neurotoxicology 21(3):409–418, 2000

16. Mast TJ, Rommereim RL, Weigel RJ, et al:Developmental toxicity study of acetone in mice and rats. Teratology 39(5): 468A, 1989

ACETONITRILECAS: 75-05-8

CH3CN

Synonyms: Methyl cyanide; cyanomethane;ethanenitrile

Physical Form. Colorless volatile liquid withsweetish odor

Uses. Chemical intermediate; solvent;extractant for animal and vegetable oils

Exposure. Inhalation; skin absorption

Toxicology. Acetonitrile causes headache,dizziness, and nausea; at extremely high con-

centrations it can cause convulsions, coma, anddeath.

Of 15 painters exposed to the vapor of amixture containing 30–40% acetonitrile for 2consecutive workdays, 10 developed symptomsranging in severity from nausea, headache, andlassitude among the lesser exposed to vomiting,respiratory depression, extreme weakness, andstupor in the more heavily exposed. Five casesrequired hospitalization and one died; thisworker experienced the onset of chest pain 4hours after leaving the job on the second dayof exposure, followed shortly by massivehematemesis, convulsions, shock. and coma,with death occurring 14 hours after cessationof exposure.1 At autopsy, cyanide ion concen-trations (in mg%) were: blood 796, urine 215,kidney 204, spleen 318, and lung 128; cyanideion was not detected in the liver.1

Two human subjects inhaled 160ppm for 4 hours; one of them experienced a slightflushing of the face 2 hours later and a slightfeeling of bronchial tightness 5 hours later. A week before this, the same two subjects had inhaled 80ppm with no effects.2 Bloodcyanide and urine thiocyanate levels did notcorrelate with exposure and, therefore, are notreliable indicators of brief exposure to lowconcentrations.

In male rats the LC50 was 7500ppm for asingle 8-hour exposure; there was prostrationfollowed by convulsive seizures; at autopsythere was pulmonary hemorrhage.2 Ratsexposed 6 hours/day, 5 days/week for 4 weeksto concentrations greater than 600ppm hadrespiratory and ocular irritation and anemia.3

In another study rats repeatedly exposed to 665ppm for 7 hours daily developed pul-monary inflammation, and there were minorchanges in the liver and kidneys in someanimals.2

All mice and some rats receiving 1600ppmby inhalation 6 hours/day for up to 13 weeksdied.4 Clinical findings included hypoactivity,abnormal posture, and, in rats, clonic convul-sions. Male mice administered 400ppm andfemales given 200ppm, also for 13 weeks, hadfocal epithelial hyperplasia and ulceration ofthe forestomach.

In chronic studies, mice exposed 6

ACETONITRILE 19

hours/day, 5 days/week for 2 years to concen-trations of up to 200ppm had no increases in the incidences of neoplasms.4 High-dosefemales had a significantly increased incidenceof squamous hyperplasia of the epithelium of theforestomach. In male rats receiving up to 400ppm for the same duration there was a slightincrease in the combined incidence of hepato-cellular adenoma and carcinoma. There were noexposure-related liver lesions in female rats.

Acetonitrile was not mutagenic in Salmo-nella typhimurium assays, with or without meta-bolic activation.4 Positive results were obtainedin a micronucleus assay, and weakly positiveresponses for sister chromatid exchanges andchromosomal aberrations occurred in Chinesehamster ovary cells.4

No malformations related to acetonitrileexposure were observed in the offspring of rats orally exposed at maternally toxic levels.5,6

Inhalation of 5000 or 8000ppm for 60 minutesby pregnant hamsters on day 8 of gestation wasassociated with production of severe axialskeletal disorders; maternal toxicity includingirritation, respiratory difficulty, lethargy, ataxia,hypothermia, and increased mortality wasnoted.7 At lower doses there were no signs ofmaternal toxicity and offspring were normal.7

In the rabbit eye, a drop of the liquidcaused superficial injury.8 The liquid on thebelly of a rabbit caused a faint erythema ofshort duration.9 The toxic effects of acetonitrileare attributed to the metabolic release ofcyanide via hepatic metabolism; cyanide in turnacts by inhibiting cytochrome oxidase and thusimpairs cellular respiration.10 Evidence of thecyanide effect is supported by the reportedeffectiveness of specific cyanide antidotes inacetonitrile poisonings.10

The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) for acetonitrile is 40ppm (67mg/m3) with a short-term excursion level of 60ppm(101mg/m3).

REFERENCES

1. Amdur ML: Accidental group exposure toacetonitrile. J Occup Med 1:627–633, 1959

2. Pozzani UC, Carpenter CP, Palm PE, et al:An investigation of the mammalian toxicity ofacetonitrile. J Occup Med 1:634–642, 1959

3. Roloff V, Short R, Ribelin W, et al: Com-parison of subchronic inhalation toxicity offive aliphatic nitriles in rats. Toxicologist 5:30,1985

4. National Toxicology Program: NTP Techni-cal Report on the Toxicology and CarcinogenesisStudies of Acetonitrile (CAS No. 75-05-8) inF344/N Rats and B6C3F1 Mice (InhalationStudies). NTP TR 447, NIH Pub No. 96-3363, US Department of Health and HumanServices, Public Health Service, NationalInstitutes of Health, 1996

5. Saillenfait AM, Bonnet P, Guenier JP, et al:Relative developmental toxicities of inhaledaliphatic mononitriles in rats. Fundam ApplToxicol 20:365–375, 1993

6. Berteau PE, Levinskas GJ, Rodwell DE:Teratogenic evaluation of aliphatic nitriles inrats. Toxicologist 2:118, 1982

7. Willhite CC: Developmental toxicology ofacetonitrile in the syrian golden hamster.Teratology 27:313–325, 1983

8. Grant WM: Toxicology of the Eye, 3rd ed, p 52.Springfield, IL, Charles C. Thomas, 1986

9. Union Carbide Corporation: ToxicologyStudies, Acetonitrile. New York, UnionCarbide Corporation, 1965

10. National Institute for Occupational Safetyand Health, US Department of Health,Education, and Welfare: Criteria for a Recom-mended Standard . . . Occupational Exposure toNitriles. DHEW (NIOSH) Pub 78–212, pp155. Washington, DC, US GovernmentPrinting Office, 1978

2-ACETYLAMINOFLUORENECAS: 53-96-3

C15H13NO

Synonyms: N-2-fluorenylacetamide; 2-acetaminofluorene; N-acetylaminophenanthrene; AAF

Physical Form. Light tan crystals

Uses. As a laboratory reagent for research

20 2-ACETYLAMINOFLUORENE

purposes (specifically, a positive control for car-cinogenicity and mutagenicity studies)

Exposure. Inhalation

Toxicology. 2-Acetylaminofluorene (AAF) isa potent carcinogen in dogs, hamsters, and rats.

There is no toxicity information onhumans.1

Four of five dogs developed tumors of theliver and urinary bladder after ingestion of0.6–1.2g AAF/kg diet for up to 91 months.2

Animals developing tumors received a total of90–198g AAF, whereas the animal with notumor formation ingested 45g; another groupof four dogs receiving 32–37g over 2.25 yearsdid not develop tumors.2 The extent of tumorformation was directly related to the amount ofAAF consumed, being most marked in thoseanimals that received nearly 200g during thefeeding period.2 Liver tumors of varied typeswere observed. Multiple papillomas were pro-duced in the urinary bladder, and in one dogthere was invasion of the submucosa andmuscle by the tumor cells.

Intratracheal administration of 5–15mgAAF one to two times per week for 17 monthsin hamsters (total dose 1100mg) causedbladder tumors in 10 of 23 animals; all tumorswere transitional cell carcinomas with orwithout focal squamous cell carcinomas.3

In rats, AAF had no demonstrable acutetoxicity in quantities up to 50mg/kg subcuta-neously and 1g/kg gastrically; however, AAFwas very toxic when administered in the diet.4

Incorporation of 0.031% AAF or higher for atleast 95 days led to epithelial hyperplasia of thebladder, renal pelvis, liver, pancreas, and lung;19 of 39 rats developed malignant tumors, 16of which were carcinomas.4

Animal studies have indicated that N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) is a proximate carcinogenic metabolite ofAAF.5 AAF is not carcinogenic in the guineapig, and no N-hydroxylation of AAF has beendetected in vivo or in vitro in this species;however, administration of N-hydroxy-AAFcauses tumors in guinea pigs.5 In addition, N-hydroxy-AAF has proved to be a carcinogen ofmuch greater potency than AAF in rats, mice,

hamsters, and rabbits at sites of local applica-tion.5 Recent toxicological studies suggest thatboth initiating (genotoxic) as well as promot-ing properties (nongenotoxic interference withmitochondrial respiration and oxidative phos-phorylation) of AAF contribute to the forma-tion of tumors in animals.6

AAF is classified as a cytotoxic teratogen.1

Because of demonstrated carcinogenicity inanimals, contact by all routes should beavoided. In recent years this compound hasbeen used only in laboratories as a model oftumorigenic activity in animals.7 It is of littleoccupational health importance.

The ACGIH has not established a thresh-old limit value for AAF.

REFERENCES

1. Doull J, Klaasen CD, Amdur MO (eds): Toxi-cology. The Basic Science of Poisons, 2nd ed, p 163.New York, Macmillan 1980

2. Morris HP and Eyestone WH: Tumors of theliver and urinary bladder of the dog afteringestion of 2-acetylaminofluorene. J NatlCancer Inst 13:1139–1165, 1953

3. Oyasu R, Kitajima T, Hoop ML, et al: Induc-tion of bladder cancer in hamsters by repeated intratracheal administrations of 2-acetylaminofluorene. J Natl Cancer Inst 50:503–506, 1973

4. Wilson RH, Deeds F, Cox AJ Jr: The toxicity and carcinogenic activity of 2-acetaminofluorene. Cancer Res 1:595–608,1941

5. Miller EC, Miller JA, Enomoto M: The com-parative carcinogenicities of 1-acetylaminoflu-orene and its N-hydroxy metabolite in mice,hamsters, and guinea pigs. Cancer Res24:2018–2031, 1964

6. Neumann HG, Bitsch A, Kloon PC: The dualrole of 2-acetylaminofluorene in hepatocar-cinogenesis: specific targets for initiation andpromotion. Mutat Res 376:169–176, 1997

7. Benya TJ, Cornish HH: Aromatic nitro and amino compounds. In Clayton GD andClayton FE (eds): Patty’s Industrial Hygiene andToxicology 4th ed, Vol II, part B Toxicology, pp968–970. New York, John Wiley and Sons,1994

2-ACETYLAMINOFLUORENE 21

ACETYLENE TETRABROMIDECAS: 79-27-6

CHBr2CHBr2

Synonyms: Tetrabromoethane; Muthmann’sliquid; 1,1,2,2-tetrabromoethane

Physical Form. Colorless to yellow liquid

Uses. Gauge fluid; solvent; refractive indexliquid in microscopy

Exposure. Inhalation

Toxicology. Acetylene tetrabromide is aneye and nasal irritant, central nervous systemdepressant, and hepatotoxin.

A chemist working with the substance for7.5 hours with no local exhaust ventilationdeveloped severe, nearly fatal, liver damage andwas hospitalized for 9 weeks; his estimatedexposure during most of the work shift beforethe onset of symptoms was 1–2ppm, althoughhe had a single 10-minute exposure to approx-imately 16ppm.1 He complained first ofheadache, anorexia, and nausea within hours ofthe exposure, and within 5 days he developedabdominal pain with bilirubinuria and a mono-cytosis of 17%. In this case, exposure to higherconcentrations or significant skin absorptionmight have occurred. The similarity of thesymptoms to viral hepatitis is also noted. Otherworkers in the same laboratory complainedonly of slight eye and nose irritation, withheadache and lassitude.

Rats exposed to a saturated atmosphere for7 hours exhibited slight eye and nose irrita-tion.2 Guinea pigs exposed for 90 minutes to asaturated vapor became comatose, seemed torecover, but died after several days; the sameexposure for up to 3 hours was not lethal to ratsand rabbits.3 No mortality was observed in rats,guinea pigs, rabbits, mice, and a monkeyexposed 7 hours/day to 14ppm for 100 days;findings at 14ppm did include edema of thelungs and slight fatty degeneration of the liverin all species except guinea pigs, which onlyshowed growth depression.2 Repeated exposure

to 4ppm for 180 days caused slight histopatho-logic changes in the liver and lungs of someanimals, but no effects were observed at 1ppm.

Repeated application of 15mg to the skinof mice caused a statistically significant increasein the incidence of forestomach papillomas.4

The liquid instilled in the rabbit eye causedslight to moderate pain, conjunctival irritation,and corneal injury that disappeared after 24hours.1 When bandaged onto the shavedabdomen of the rabbit for 72 hours, moderateredness, edema, and blistering were observed.1

Acetylene tetrabromide has a sweetish,unpleasant odor that is readily apparent andobjectionable to most persons at concentra-tions greater than 1–2ppm.1,2

The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) for acety-lene tetrabromide is 1ppm.

REFERENCES

1. Van Haaften AB: Acute tetrabromoethane(acetylene tetrabromide) intoxication in man.Am Ind Hyg Assoc J 30:251–256, 1969

2. Hollingsworth RL, Rowe VK, Oyen F: Toxic-ity of acetylene tetrabromide determined onexperimental animals. Am Ind Hyg Assoc J24:28–35, 1963

3. Gray MG: Effect of exposure to the vapors oftetrabromoethane (acetylene tetrabromide).Arch Ind Hyg Occup Med 2:407–419, 1950

4. Van Duuren BL, Goldschmidt BM, Lowen-gart G, et al: Carcinogenicity of halogenatedolefinic and aliphatic hydrocarbons in mice. JNatl Cancer Inst 63:1433–1439, 1979

ACROLEINCAS: 107-02-8

C3H4O

Synonyms: Acrylaldehyde; 2-propenal; allylaldehyde; propylene aldehyde; Aqualin

Physical Form. Colorless or yellowish liquid

22 ACETYLENE TETRABROMIDE

Uses. Intermediate in the manufacture ofacrylic acid; herbicide; algicide; in pharmaceu-ticals, perfumes, food supplements, and resins;as a warning agent in methyl chloride refriger-ating systems

Exposure. Inhalation

Toxicology. Acrolein is an intense irritant ofthe upper respiratory tract, eyes, and skin.

Exposure to high concentrations maycause tracheobronchitis and pulmonaryedema.1 The irritation threshold in humans is0.25–0.5ppm, and concentrations above 1ppmare extremely irritating to all mucous mem-branes within 5 minutes.1 Fatalities have beenreported at levels as low as 10ppm, and 150ppm was lethal after 10 minutes.2,3 The violentirritant effect usually prevents chronic toxicityin humans.1 Skin contact causes irritation,burns, and epidermal necrosis.4 Eye splashescause corneal damage, palpebral edema, ble-pharoconjunctivitis, and fibrinous or purulentdischarge.5

In experimental animals the respiratorysystem is a primary target of acrolein exposureafter inhalation, and there is an inverse rela-tionship between the exposure concentrationand the time it takes for death to occur.4 Inhala-tion LC50 values of 327ppm for 10 minutes and130ppm for 30 minutes have been reported inrats.4 Of 57 male rats, 32 died after exposure to4ppm for 6 hours/day for up to 62 days.6

Desquamation of the respiratory epitheliumfollowed by airway occlusion and asphyxiationis the primary mechanism for acrolein-inducedmortality in animals.4 Sublethal acrolein expo-sure in mice at 3 and 6ppm suppressed pul-monary antibacterial defense mechanisms.7 Acombination of epithelial cell injury and inhi-bition of macrophage function may be respon-sible for acrolein-induced suppression ofpulmonary host defense.8

Intra-amniotic administration of acroleinin rats induced a significant number of fetalmalformations, whereas intravenous adminis-tration was embryo lethal.9 Pregnant rabbitsgiven 4.0 and 6.0mg/kg/day on days 7 through19 of gestation had high incidences of mater-

nal mortality, spontaneous abortion, resorp-tions, clinical signs, gastric ulceration, andsloughing of the gastric mucosa.10 Acrolein didnot cause statistically significant embryo-fetaleffects at lower doses and was not consideredto be a developmental toxicant at doses that didnot cause severe maternal toxicity. Similarresults were reported in two generations of ratsadministered up to 6mg/kg; reduced pupweight occurred at levels that also producedsignificant maternal deaths.11

The carcinogenic potential of acrolein has been examined in a number of studies.Hamsters exposed to 4.0ppm, 7 hours/day, for52 weeks showed no evidence of respiratorytract tumors or tumors in other tissues andorgans.12 Rats exposed for 10–18 months to 8ppm 1 hour/day also showed no evidence of atumorigenic response.4

Extensive histopathologic examination didnot reveal any carcinogenic effects in rats,mice, or dogs after oral exposure to 2.5, 4.5, or2mg/kg/day acrolein, respectively, for 12–24 months.4 In the one study that reported pos-itive findings, 20 female rats given acrolein inthe drinking water (625mg/liter water, equiva-lent to daily doses approaching 40mg/kg bodyweight) for 104–124 weeks had an increasedincidence of adrenal cortex neoplasms com-pared with controls.13 The small numbers ofanimals used in this study make it unsuitablefor evaluating the carcinogenic potential ofacrolein. Furthermore, reevaluation of thisstudy by an independent pathology groupfailed to confirm the original findings.14 (Theworking group determined that the slightlyelevated incidence of pheochromocytomas inthe treated females was within limits forhistorical controls and was of no biologicalsignificance.)

A 2-year study of rats treated by dailygavage with 0, 0.05, 0.5, or 2.5mg/kg for 102weeks found no evidence of a neoplasticresponse.14 Chronic gavage studies in mice for18 months and capsular administration to dogsfor 1 year also revealed no indication of a car-cinogenic response.15 The IARC has deter-mined that there is inadequate evidence in bothanimals and humans for the carcinogenicity ofacrolein.16 Acrolein has been found to be muta-

ACROLEIN 23

genic to bacteria and to induce sister chromatidexchanges in vitro.16

The 2003 threshold limit value-time-weighted average (TLV-TWA) is 0.1ppm (0.23mg/m3) with a short-term excursion levelof 0.3ppm (0.69mg/m3).

REFERENCES

1. Beauchamp RO Jr, Andjelkovich DA,Kligerman AD, et al: A critical review of theliterature on acrolein toxicity. Crit Rev Toxicol14:309–380, 1985

2. Henderson Y, Haggard HW: Noxious Gases, p 138. New York, Reinhold Publishing, 1943

3. Prentiss AM: Chemicals in War. A Treatise ofChemical Warfare, pp 139–140. New York,McGraw-Hill, 1937

4. Agency for Toxic Substances and DiseaseRegistry (ASTDR): Toxicological Profile forAcrolein, US Department of Health andHuman Services, Public Health Service, TP-90–01, pp 145, 1990

5. Grant WM: Toxicology of the Eye, 3rd ed, pp49–50. Springfield, IL, Charles C. Thomas,1986

6. Kutzman RS et al: Changes in rat lungstructure and composition as a result ofsubchronic exposure to acrolein. Toxicology34:139–151, 1985

7. Astry CL, Jakab GJ: The effects of acroleinexposure on pulmonary antibacterialdefenses. Toxicol Appl Pharmacol 67:49–54,1983

8. Li L, Holian A: Acrolein: a respiratory toxinthat suppresses pulmonary host defense. RevEnviron Health 13(1-2):99–108, 1998

9. Slott VL, Hales BF: Teratogenicity andembryolethality of acrolein and structurallyrelated compounds in rats. Teratology32:65–72, 1985

10. Parent RA, Caravello HE, Christian MS, et al: Developmental toxicity of acrolein inNew Zealand White rabbits. Fundam ApplToxicol 20:248–256, 1993

11. Parent RA, Caravello HE, Hoberman AM:Reproductive study of acrolein on two gen-erations of rats. Fundam Appl Toxicol19:228–237, 1992

12. Feron VJ, Kruysse A: Effects of exposure toacrolein vapor in hamsters simultaneouslytreated with benzo(a)pyrene or diethylni-

trosamine. J Toxicol Environ Health 3:379–394, 1977

13. Lijinsky W, Reuber MD: Chronic carcino-genesis studies of acrolein and relatedcompounds. Toxicol Ind Health 3:337–345,1987

14. Parent RA, Caravello HE, Long JE: Two-year toxicity and carcinogenicity study ofacrolein in rats. J Appl Toxicol 12:131–139,1992

15. Parent RA, Caravello HE, Balmer MF, et al:One-year toxicity of orally administeredacrolein to the Beagle dog. J Appl Toxicol 12:311–316, 1992

16. IARC Monographs on the Evaluation of theCarcinogenic Risks to Humans, Vol 63, Drycleaning, some chlorinated solvents and otherindustrial chemicals, pp 337–72. Lyon, Inter-national Agency for Research on Cancer,1995

ACRYLAMIDECAS: 79-06-1

C3H5NO

Synonyms: Acrylic amide; propenamide;ethylenecarboxamide; vinyl amide

Physical Form. White crystalline powder

Uses. In the production of polyacrylamides,which are used in water and waste treat-ment, paper and pulp processing, cosmeticadditives, and textile processing; in adhesivesand grouts; as cross-linking agents in vinylpolymers

Exposure. Inhalation; skin absorption;ingestion

Toxicology. Acrylamide causes central-peripheral axonopathy; in laboratory animals itis carcinogenic and causes male reproductivetoxicity.

A variety of signs and symptoms have beendescribed in cases of acrylamide poisoning sug-

24 ACRYLAMIDE

gesting involvement of the central, peripheral,and autonomic nervous systems.1 Effects on thecentral nervous system are characterized byabnormal fatigue, memory difficulties, anddizziness. With severe poisoning, confusion,disorientation, and hallucinations occur.Truncal ataxia, nystagmus, and slurred speechhave also been observed. Peripheral neuropa-thy symptoms can include muscular weakness,paresthesia, numbness in hands, feet, lowerlegs, and lower arms, unsteadiness, and diffi-culties in walking and standing. Clinical signsare loss of peripheral tendon reflexes, impair-ment of vibration sense, and muscular wastingin the extremities. Nerve biopsy shows loss oflarge-diameter nerve fibers as well as regener-ating fibers. Autonomic nervous systeminvolvement is indicated by excessive sweating,peripheral vasodilation, and difficulties in mic-turation and defecation.

Central nervous system effects predomi-nate in acute exposures at massive doses,whereas peripheral neuropathy is morecommon with lower doses.1,2 After cessation ofexposure to acrylamide, most cases recover,although the course of improvement canextend over months to years and depends onthe severity of exposure.1,2 Because peripheralneurons can regenerate and central axonscannot, severely affected individuals may stillexperience residual ataxia, distal weakness,reflex loss, or sensory disturbance.

Because most cases of human poisoninghave included skin absorption, the dose-response relationship has not been determined.On the skin acrylamide causes local irritationcharacterized by blistering and desquamationof the palms and soles combined with bluenessof the hands and feet.1

For a number of species the oral LD50 wasapproximately 150–180mg/kg body weight. Incats a total cumulative dose of 70–130mg/kgwas characterized by delayed onset of ataxia.3

Cats fed 10mg/kg diet/day developed definitehind limb weakness after 26 days; at 3mg/kg/day there was twitching in the hindquartersafter 26 days and signs of hind limb weaknessafter 68 days.4 The underlying lesion involvesdistal retrograde degeneration of long andlarge-diameter axons.5

Teratogenic effects were not observed inthe offspring of rats given up to 50mg/kg dietfor 2 weeks before mating and for 19 daysduring gestation.1 In mice, high doses pro-duced decreased sperm count and an increasein abnormal sperm morphology.6

Acrylamide produced dominant lethalreproductive effects in males as evidenced byreduced numbers of live pups and increasedresorptions at exposure levels (30ppm in drink-ing water) below those that caused neurotoxic-ity.7 In another report, acrylamide caused adose-dependent increase in the frequency ofmorphologic abnormalities in preimplantationembryos (single-cell eggs, growth retardation,and blastomere lysis) after paternal treatment(10–50mg/kg, for 5 days).8 These more recentfindings indicate a potential risk to the off-spring of men exposed to acrylamide.

A statistically significant increase inmesothelioma of the scrotal cavity wasobserved in rats given drinking water formu-lated to provide 0.5mg/kg body weight/day for2 years; in females there were significantincreases in the number of neoplasms of thecentral nervous system, thyroid, mammarygland, oral cavity, clitoral gland, and uterus.9

Acrylamide has also been reported to act asa skin tumor initiator in mice by three expo-sure routes and to increase the yield of lungadenomas in another strain of mice.10

In a human mortality study of 371 workersno increase in total malignant neoplasms or anyspecific cancers attributable to acrylamideexposure were found.11 Exposure levels reached1.0mg/m3 before 1957 and were between 0.1and 0.6mg/m3 after 1970. However, this studywas of such a limited sample size that only largeexcesses could have been detected.

A much larger cohort of 8854 men, 2293of whom were exposed to acrylamide, from1925 to 1983 was examined for mortality.12

This cohort consisted of four chemical plantpopulations. No statistically significant excessof all-cause or cause-specific mortality wasfound among acrylamide workers. Analysis byacrylamide exposure levels showed no trend ofincreased risk of mortality from several cancersites. Although th