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APPENDIX A SAMPLE OF 675 SUBSTANCES AND SUBSAMPLE OF 100 SUBSTANCES FROM THE " SELECT UNIVERSE " me 675 substances in the sample and their CAS Registry numbers (where available) are listed below in randomly ordered sequence within the following seven categories: pesticides and inert ingredients of pesticide formulations, cosmetic ingredients, drugs ana excipients in drug formulations, food additives, and the three production categories of chemicals in commerce as listed in the Inventory of the Toxic Substances Control Act. The chemical names are formatted as they appeared in the lists from which they were selected, with a few minor changes for clarity. Substances that were selected for the subsamole of 100 are ~ 1 _ ~ ~ ~ ~1_ _ _ _ ~ ~ nocea when an asterisk (a). Tne selection process to form the subsample in each category ceased where a solid line appears; it indicates that the required number for the subsample in the given category had been found. An equal sign (=) is used to indicate a word broken for spacing purposes where no hyphen normally occurs. PESTICIDES AND INERT INGREDIENTS OF PESTICIDE FORMULATIONS Chemical CAS number * * * * * * * * Ammonium ligninsulfonate Diethylaminoethanolamine [2,2,2-Trichloro-l-hydroxyethyl) dimethylphosphonate] Alkyldimethylbenzylammonium chloride Carbamic acid, dipropylthio-, _-tert-butyl ester Soap bark 1,2,4-Thiadiazole, 5-ethoxy-3-(trichloromethyl) 1-Butanesulfonothioic acid, S-(chloromethyl) ester Phenol, 4-(di-2-propenylamino)-3,5-dimethyl-, methyl= carbamate (ester) Sulfonated oleic acid, potassium salt 2H-1,3,5-Thiadiazine-2-thione, tetrahydro-3,5-dimethyl Ethanol, 2-butoxy-, phosphate (3:1) Sodium decyldiphenyletherdisulfonate Trichlorobenzyl chloride Benzenecarbothioamide, 2,5-dichloro Citric acid, trisodium salt Benzenamine, compound with 1,3,5-trinitro benzene (1:1) Ethylene thiourea Acetic acid, (2,4-dichlorophenoxy)-, compound with 1,1',1"-nitrilotrisE2-propanol] 4,4'-Bipyridinium, 1,1'-dimethyl-, dichloride Oxirane, methyl-, polymer with oxirane, monobutyl ether Potassium iodate . . 129 . 8061-53 -8 Unava liable 52-68-6 8001-54-4 2212 -63 -7 Unava liable 2593-15-9 16008-31-4 6392-46-7 Unava liable 533-74-4 78-51-3 36445-71-3 1344-32-7 69622-81-7 68-04-2 3101-79 -9 96-45-7 32341-80-3 1910-42-5 9038-95-3 7758-05-6
PESTICIDES AND INERT INGREDIENTS OF PESTICIDE FORMULATIONS, continued Pyridine Phosphorodithioic acid, S-(chloromethyl) O,O-, diethyl ester 2,3,5-Trichloro-4-(propylsulfonyl~pyridine * p-Benzoquinone Glycine, N-~2-[bistcarboxymethyl~aminoJethyl) N-~2-hydroxyethyl)-, trisodium salt 2-Propanamine, sulfate * p-Nitrophenyldimethylthionophosphate 2,4-Dichlorophenoxyacetic acid, alkylamine salt * Sodium acetate Agrobacterium radiobacter , Carbamic acid, dimethyl-, 3-methyl-1-phenyl lH-pyrazol-5-yl ester Carbonic acid, methyl 2-~1-methylheptyl)-, 4,6-dinitrophenyl ester * Phosphorodithioic acid, O,O-dimethyl ester, S-ester with N-(mercaptomethyl~phthalimide * C.I. Pigment green 21 (Copper acetoarsenite, solid) . . . . 2,5-Cyclohexediene-1,4-dione, 2,3,5,6-tetrachloro- 118-75-2 Mercury, (acetato-O) (methylphenyl)- 1300-78-3 Copper hydroxide [Cu(OH)2] 20427-59-2 Acetic acid, (2,4-dichlorophenoxy)-, methyl-2-(methyl- 53535-28-7 2-Emethyl-2-~2-methylpropoxy~ethoxy]-ethoxy~ethyl ester Phenarsezine, 10,10'-oxybis[5,10-dihydro Alkyldimethylbenzylammonium chloride Benzoic acid, 2-hydroxy-, compound with 4-chloro= benzenamine (1:1) N-~2-~2-Hydroxyethoxypoly~ethyleneoxy~polypropylene= oxy)]propyl~hexanamide Heptadecenylimidazoline Benzenamine, ar,ar-dichloro Sulfuric acid, zinc salt (1:1), monohydrate Sodium pentaborate 1~-Imidazot4,5-b~pyridine, 6-chloro-2-(trifluoromethyl) [l,l'-Biphenyl]-2-ol, a~mnonium salt 110-86-1 24934-91-6 38827-35-9 106-51-4 139-89-9 60828-92-4 297-97-2 Unavailable 127-09-3 Unavailable 87-47-8 5386-68-5 732-11-6 1~'002-03-8 COSMETIC INGREDIENTS Poloxamine 1301 Sucrose benzoate/sucrose acetate isobutyrate Acetylated lanolin ricinoleate PEG-70 hydrogenated lanolin 130 4095-45-8 8001-54-5 53404-66-3 Unavailable Unavailable 27134-27-6 7446-19-7 Unavailable 13577-71-4 52704-98-0 11111-34-5 Unavailable 977055-85-8 68648-27-1
COSMETIC INGREDIENTS Chemical CAS Number - * Maleic acid Pareth-91-8 Methylpropylcellulose Safflower glyceride PEG-30 glyceryl oleate Octadecene/maleic anhydride copolymer * FD & C Red No. 40 Ammonium phosphate PPG-8-ceteth-10 * 4,4'-Isopropylidenediphenol * Ethyl linolenate Allantoin calcium pantothenate Nonoxynol-8 * * * * * * * * Calcium acetate Sucrose benzoate Laureth-3 Potassium oleate PEG-100 stearate Cocamine oxide Sodium myristyl sulfate Tetrasodium EDTA Cetearyl alcohol Dimethyl cocamine p-Cresol DM Hydantoin Isosteareth-6 carboxylic acid Dehydroacetic acid Spinach extract Benzophenone-11 PEG-200 Guanidine carbonate PPG-2 methyl ether D & C Orange No. 5 zirconium lake Hydrogenated tallow amine oxide * Sodium bromate Barium sulfide Oleth-15 Phloroglucinol Zinc myristate Acetylated glycol stearate Vinylpyrrolidone/vinyl acetate/itaconic Sorbitan triisostearate PEG-14 oleate 131 110-16-7 68439-46-3 977057-25-~ 977058-10-8 68889-49-6 25266-02-8 25956-17-6 7722-76-1 9087-53-0 80-05-7 1191-41-9 4207-41-4 26027-38-3 37205-87-1 62-54-4 12738-64-6 3055-94-5 143-18-0 9004-99-3 61788-90-7 1191-50-0 64-02-8 8005-44-5 61788-93-0 106-44-5 77-71-4 Unavailable 520-45-6 Unavailable 1341-54-4 25322-68-3 593-85-1 13429-07-7 37 ~ 86-64-9 977054-31-1 61788-94-1 7789-38-0 21109-95-5 9004-98-2 25190-05-0 108-73-6 16260-28-8 Unavailable 68928-72-3 54392-27-7 9004-96-0
COSMETIC INGREDIENTS, continued Chemical , CAS Number Honey extract Quaternium-8 * Trisodium EDTA PEG-45 stearate Acetylated hydrogenated tallow glycerides Trioleth-8 phosphate * Zinc carbonate , Glyceryl tri-C10_lg acids Potassium iodide Benzophenone-7 Ethylene brassylate Sodium monodiethylaminopropyl cocoaspartate Nonoxyno1-4 Ceteareth-17 Ammonium myreth sulfate Poloxamine 908 Isostearamidopropyl dimethylamine lactate Ditridecyl sodium sulfosuccinate Styrene/maleic anhydride copolymer ~ e Grape Julce FD & C Green No. 3 Corn poppy extract PEG-8 oleate Unavailable 977066-07-1 150-38-9 9004-99-3 977063-59-4 977058-53-9 3486-35-9 Unavailable 7681-11-0 85-19-8 105-95-3 977068-51-1 7311-27-5 977063-70-9 27731-61-9 11111-34-5 55852-15-8 2673-22-5 9011-13-6 977064-74-6 2353-45-9 Unavailable 9004-96-0 977055-26-7 101-54-2 39464-69-2 8014-29-7 977064-18-8 104-98-3 68439-53-2 75-31-0 68989-01-5 61788-85-0 8016-70-4 977068-15-7 557-04-0 31692-79-2 9087-53-0 633-96-5 75-57-0 144-55-8 977067-59-6 ~5322-68-3 28474-90-0 1643-20-5 Unavailable N-Phenyl-~-phenylenediamine Oleth-4-phosphate Rue oil Decyl mercaptomethylimidazole Urocanic acid PPG-20 lanolin ether Isopropylamine Quaternium-3 PEG-7 hydrogenated castor oil Hydrogenated soybean oil Cll_l3 isoparaffin Magnesium stearate Dimethiconol PPG-4-ceteth-5 D & C Orange No. 4 Tetramethylammonium chloride Sodium bicarbonate Sorbitan sesquiisostearat PEG-32 Ascorbyl dipalmitate Lauramine oxide Hydrogenated animal glyceride 132
COSMETIC INGREDIENTS, continued Chemical . ~: r . ~: CAS Number d PEG-7 glyceryl cocoate Cocamidopropylamine oxide TEA-oleamido PEG-2 sulfosuccinate Pareth-45-11 Nonyl nonoxynol-10 phosphate Stearoxytrimethylsilane Solvent yellow 44 Alginic acid DRUGS AND EXCIPIENTS IN DRUG FORMULATIONS 977064-68-8 68155-09-9 Unavailable Unavailable Unavailable Unavailable 0478-20-8 9005-3~-7 * Acetylcysteine616-91-1 Linear tridecyl benzene sulfonateUnavailable * Dichlorophen97-23-4 * Diphenidol hydrochloride3254-89-5 * Lactose63-42-3 Benzalkonium chloride8001-54-5 * Methylergonovine maleate57432-61-8 Flavor aniseUnavailable Chlorphenoxamine hydrochloride562-09-4 * Spironolactone52-01-7 * Norethindrone acetate51-98-9 * Methamphetamine hydrochloride300-42-5 Amylopectin9037-22-3 Flavor mintUnavailable * Phytonadione84-80-0 * Cottonseed oil 8001-29-4 Potassium formate 590-29-4 Polyoxyethylene propylene Unavailable Ethyl vanillin 121-32-4 Triethanolamine polypeptide oleate condensate Unavailable * Amantadine hydrochloride 665-66-7 Sulfoxone sodium 144-75-2 * Carboxypolymethylene 9007-20-9 * Peanut oil 8002-03-7 Insulin suspension, isophane, purified pork Unavailable Bromodiphenhydramine hydrochloride 1808-12-4 * Pyridoxine hydrochloride 58-56-0 Calcium phosphate, tribasic 12167-74-7 * Gelatin 9000-70-8 Promalgen type G Unavailable Mullein leaf Unavailable Sodium chromate, CR-51 10039-53-9 Phenacemide 63-98-9 133
DRUGS AND EXCIPIENTS IN DRUG FORMULATIONS, continued Chemical CAS Number , . . . . . . Guanidine hydrochloride Orphenadrine hydrochloride Deferoxamine mesylate Cetyl alcohol Clonazepam Testosterone Epinephrine Sennoside A Thyrotropin Opalux AS 8010-A (Black) Ipodate sodium Undecoylium chloride-iodine Flavor sherry, imitation Wax, white Hydrolose Mebutamate Sodium phosphate, monobasic FOOD ADDITIVES Mannose 3,5-Dimethyltetrahydro-1,3,5-thiadiazine 2-thione * * p-Acetamidobenzoic acid Vanadium tetrachloride Ethyl 3-hydroxybutyrate 2,7-Dinitroso-l-naphthol Fennel * Norharman Ionone, gamma Triethylamine hydrochloride Cupric sulfate, anhydrous Ammonium thiocyanate Yeast extract, Baker's Dimethylphenylpiperazinium iodide Sulfide ion Allyl nonanoate Geranium oil Benzyl thiocyanate Polyvinyl ethyl ether Elemene, alpha- Methyl isobutyrate Jasmine absolute 134 50-01-1 341-69-5 70-51-9 124-29-8 1622-61-3 58-22-0 51-43-4 Unavailable 9002-7-5 Unavailable 1221-56-3 1338-54-1 Unavailable 8006-40-4 8012-89-3 9004-64-2 64-55-1 7558-80-7 31103-86-3 533-74-4 556-08-1 7632-51-1 5405-41-4 977014-63-3 977001-13-0 244-63-3 79-76-5 554-68-7 7758-98-7 1762-95-4 8013-01-2 54-77-3 18496-25-8 7493-72-3 8000-46-2 3012-37-1 25104-37-4 5951-67-7 547-63-7 8031-01-4
FOOD ADDITIVES, continued Chemical , . . . . . CAS Number * Calcium stearate1592-23-0 Pentserythritol tetrakis(3-mercaptopropionate)7575-23-7 Propyl 2-furanacrylate623-22-3 Butter fat977018-87-3 CI Fluorescent Brightener #109 61951-68-6 Soybean mill feed 977030-55-9 Cobalt(2+) caprylate 1588-79-0 Tetramethyl tin 594-27-4 Chromous oxide 12018-00-7 * 1-Monostearin 123-94-4 Asafetida oil 977017-80-3 * Hydrazine hydrate 7803-57-8 DI-Dodecyl tin oxide 22 73-48-5 Molybdic acid 11099-00-6 Celery seed extract Unavailable Diethylene glycol dibenzoate 120-55-8 ~-Menth- 1-en-9-o 1 184 7 9-68-0 * Sodium lauryl sulfate 151-21-3 Guanidoethyl cellulose 9069-21-0 Lipase, animal 977033-78-5 S i 1 icon 7440-21-3 2-Ethylhexyl 9,10-epoxystearate 141-38-8 1,4-Dihydroxy-9,10-anthraquinone 81-64-1 Phytoene 540-04-5 Isoamyl isobutyrate 2050-01-3 2-Tridecanone 593-08-8 _-tert-Butylacrylamide 107-58-4 * Riboflavin supplement 977030-53-7 * Acenaphthylene 208-96-8 Mannide monoleate 25339-93-9 * Di-~2-methoxyethyl) phthalate 117-82-8 * Diethylene glycol 111-46-6 * Linseed oil 8001-26-1 Artichoke leaf Unavailable N-Stearoylsarcosine 142-48-3 - Ethyl 2-methylbutyrate 7452-79-1 Chromium hydroxide 12626-43-6 Xylyl sulfone 27043-27-2 E:-Cymen-8-ol 1197-01-9 Molybdate Orange 12656-85-8 Ammonium isovalerate 7563-33-9 Feculose starch acetate 977033-03-6 Rhynchosia pyramidalis 977030-08-2 Cobalt tallate 61789-52-4 135
FOOD ADDITIVES, continued Ghemical CAS Number 1 . - 1 1 * Sodium laureth-3 sulfate * Silica Elaidic acid 2-tert-Butyl-4-ethylphenol Allyl isovalerate 1-Methylpiperazine * Calcium saccharin Polyvinyl chloride Isoamyl cinnamate Benzyl phenylacetate Sulfasomidine Butirosin sulfate Guaiaretic acid Soybean hull, ground Norbixin Triethyl lead Propyl phenol Humulus Phthalocyanine Cupric hydroxide Cedarwood oil terpene C.I. Disperse Orange #3 1,4-Dianilinoanthraquinone Dimethylol melamine Tetrakisthydroxymethyl~phosphonium chloride 2-Ethylhexyl mercaptoacetate Pentaerythritol monostearate Itaconic acid-methyl methacrylate copolymer 2,6,6-Trimethyl-2-cyclohexen-1-one Geranial 3,4,5,6-Dibenzacridine Ion-exchange membrane Methyl hydrogen siloxane Valproic acid 13150-00-0 7631-86-9 112-79-8 96-70-8 2835-39-4 109-01-3 6381-91-5 9002-86-2 7779-65-9 102-16-9 [515-64-0] 51022-98-1 500-40-3 977032-85-1 54~-40-5 5224-23-7 31019-46-2 977001-58-3 574-93-6 20427-59-2 68608-32-2 730-40-5 2944-12-9 5001-80-9 124-64-1 7659-86-1 78-23-9 27155-24-4 20013-73-4 141-27-5 ~24-53-3 Unavailable 63148-57-2 99-66-1 CHEMICALS IN COMMERCE Product~on at Least 1 Million Pounds/Year Chemical CAS Number ~ 1 . 7-Oxabicyclo[4~1~0]heptan-2-one' 6-methyl-3 (l-methylethyl) 2-Pyrazolin-5-one, 1-~-aminophenyl)-3-ethoxy Bismuth, compound with gadolinium (1:1) 136 5286-38-4 4105-91-3 12010-44-5
Production CHEMICALS IN COMMERCE Least 1 Million Pounds/Year, continued Chemical _ C:AS Number Benzene, (2-iodoethyl) Molybdenum phosphide (MoP) D-Glucose, enzyme-hydrolyzed Thiazole, 2-~2-methylpropyl) 1,2-Benzenedicarboxylic acid, bis{2-ethylhexyl) ester, polymer with 1,3 - iisocyanatomethyl benzene, methyloxirane, and 1,2,3-propanetriol Amines, N,N,N'-trimethyl-N'-tallow alkyl= trimethylenedi 2-Propenoic acid, butyl ester, polymer with ethenyl acetate and 2-hydroxyethyl-2-propenoate Poly foxy-1 , 2-ethanediyl), alpha, alPha ' * [(ethyloctadecyliminio)di-2,1-ethanediyl]= bistomega-hydroxy-, ethyl sulfate 1,7-Naphthalenedisulfonic acid, 4-~2,4~ichloro= benzoyl~aminol-5-hydroxy-6-~2-methoxyphenyl) = azo]-, disodium salt Benzenesulfinic acid, 4-chlor~ 1,2-Benzenediamine, _-methyl-, dihydrochloricte Bismuth hydroxide * . . * * * 17376-04-4 12163-69-8 68921-30-2 18640-74-9 68492-79-5 68783-25-5 65776-73-0 42845-62-5 6416-33-7 Ethanol, 2-l(Z-1~2-aminoethyl~aminolethyl)= aminol Phenol, 4,4'- (3H-2,1-benzoxathiol-3-ylidene)= bis(2,5 - imethyl-, S,S -lioxide Benzenethiol, 4 ~odecy1-, hydrogen phosphoro= dithioate, zinc salt Isoguinoline, 1,2,3,4-tetrahydr~ Pentanamicie, N,N~ imethyl 2-Propenamide, N- (hydroxymethyl)-, polymer with 1,3-butadiene and 2-propenenitrile 9H-Fluorene, 2-nitr~ Tannins, salts with 2-~3- (1,3-dihydr~ 1,3,3-trimethyl-2H-indol-2-ylidene)-1-propenyll- 1,3,3-trimethyl-3H-indolium Benzenepropanoic acid, 4-(bist2-(benzoyloxy)= ethYllamino)-alpha~beta~ icYano-, ethY1 ester Silane, (3-isocyanatopropyl) trimethoxy) Benzenesulfonic acid, 3-~(ethoxycarbonyl~aminol-, monosodium salt Hexanedioic acid, polymer with methyloxirane polymer with oxirane ether with oxybis= [propanol ] ~ 2: 1) Octanoic acid, mixed esters with triethylene glycol hexanoate Benzene, 1-iod~ 3 -n itr~ 137 100-03-0 25148-68-9 10361-43-0 1965-29-3 125-31-5 65045-85-4 91-21 - 4 6225-06-5 26603-98-5 607-57-8 68957-25-5 65151-61-3 15396-00-6 71215 -93 -5 63549-52-0 68130-48-3 645-00-1
CHEMICALS IN COMMERCE Production at Least 1 Million Pounds/Year, continued Chemical CAS Number Calcium hydroxide, reaction products with iron oxide (Fe2O3) and magnesium hydroxide 1-Propanaminium, N-ethyl-N,N-dimethyl-3-~1-oxo= eicosyl~amino]-, ethyl sulfate 8-Oxa-3,5-dithia-4-stannaundecan-1-ol, 4,4-dimethyl-9-oxo-,propanoate PDlytoxy-1,2-ethanediyl), alpha-~2,4-bis= (2-phenyl-1-propenyl~phenyll-omega-hydroxy 2-Naphthalenesulfonic acid, 7-amino-5-~4-~2- bromo-l-oxo-2-propenyl~amino]-2-~4-methyl- 3-sulfophenyl~sulfonyliphenylazo)~-, disodium salt Acetamide, N,N'-1,3-propanediylbis-, N-~3-C20_30-(alkyloxy~propyl] derivatives Benzene, 1,1'-~1,2-ethanediylbis~thio)]bis 2-Naphthalenesulfonic acid, 6-~2,6-dimethylphenyl)= aminol-4-hydroxy 1-Propanamine, 2-chloro-N,N-dimethyl-, hydrochloride Ethanone, 1-~2,4,5-triethoxyphenyl) Acetonitrile, 2,2',2 " ,2 " '_ O_~-h=~^Ai`~= dinitrilo~tetrakis ~, ~ - ~__~ _ * Carbamic acid, (4-chlorophenyl)-, 1-methylethyl ester 2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-phenyl 1-(phenylmethyl) Yttrium oxide sulfate, ytterbiumrdoped Didymium (rare earth mixture) Ethanol, 2,2'-oxybis-, polymer with alPha-hyOr omega-hydroxypolytoxy-1,4-butanediyl) and 1,1'-methylenebisE4-isocyanatobenzene] * Benzene, 1,2,3,5-tetramethyl Phenol, isooctyldinitro 1,3,-Naphthalenedisulfonic acid, 7-~4-~4-~4-aminobenzoyl~aminol-2-methyl= phenyl~azo]-2-methylphenyl~azol-, disodium salt Hexanedioic acid, dimethyl ester, polymer with N,N'-bis(2-aminoethyl)-1,2-ethanediamine and dimethyl pentanedioate Bicycloi3.1.0]hex-2-ene, 2-methyl-5-~1-methylethyl)- 2867-05-2 Benzolalphenoxazin-7-ium, 9-(dimethylamino)-, 966-62-1 chloride Acetic acid, chloro-, 2-phenylethyl ester Antimony phosphiae (SbP) Polyfoxy-1,2-ethanediyl), alPha-hydro-omega-hydroxy-, ether with 2- ~ (2-hydroxyethyl) amino] -2- (hydroxy= methyl) -1 , 3-propanediol ~4: 1) * 68411-13-2 67846-22-4 67905-21-9 72088-88-1 70210-02-5 70528-81-3 622-20-8 23973-67-3 4584-49-0 63213-29-6 5766-67-6 2239-92-1 72846-00-5 68585-88-6 8006-73-3 64078-69-9 527-53-7 37224-61-6 6949-09-3 72175-31-6 138 7476-91-7 25889-81-0 72269-66-0
CHEMICALS I N COMMERCE Production at Least 1 Million Pounds/Year, continued Chemical CAS Number Iron, complexes with diazotized 2-amino-4, 6-dinitro= phenol monosodium salt coupled with diazotized 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid, diazotized 4-amino-3-methylbenzenesulfonic acid, diazotized 4-nitrobenzenamine, and resorcinol Glycerides, tallow di 1,3-Isobenzofurandione, polymer with 1,2-ethane= dial, 2,5-furandione, and 2,2'-oxybisiethanol] 2-Naphthalenesulfonic acid, 5-[bistmethylaulfonyl)= aminol-l-~(methylsulfonyl~oxy]-, sodium salt 2-Butenedioic acid, (E)-, polymer with 1,3-butadiene, ethenylbenzene, (l-methylethenyl~benzene, methyl 2-methyl-2-propenoate, and 2-propenenitrile Phosphonic acid, (1,6-hexanediylbis~nitrilobis= (methylene)~)tetrakis-, hexammonium disodium salt Vanadic acid (H4V2O7), tetracesium salt Cyclohexanone, 2,6-dimethyl-4-~3-methylbutyl) Oxirane, methyl-, polymer with oxirane, mono= (hydrogen sulfate), tridecyl ether Oils, menhaden, polymers with benzoic acid, glycerol, and isophthalic acid Benzenesulfonic acid, 2,5-dichloro 4-~4-~3-~3-~1-~2,5-dichloro-4-sulfophenyl) 4,5-dihydro-5-oxo-1H-pyrazol-4-yliazo~benzoyll= [phenylmethyl~amino)-4-methylphenyl~azo) 4,5-dihydro-5-oxo-1H-pyrazol-l-yll-, disodium salt lH-Purine-2,6,8~3H)-trione, 7,9-dihydro-, calcium salt Vanadium silicide {V3Si) Formaldehyde, polymer with methylphenol and 1,3,5,7-tetraazatricyclo[3.3.1.13~7ldecane Coal, sulfonated 2,5-Hexanediol, 2,5-dimethyl 1~3H)-Isobenzofuranone, 3,3-bist4-(sulfooxy)= phenyll-, dipotassium salt Benzene, 1,2,4-trichloro-3-(chloromethyl) Ethanone, 2-(acetyloxy)-1,2-diphenyl lH-Isoinaol-l-one, 3-amino Poly~difluoromethylene), alpha-hydro-= omega-~(phosphonooxy~methyll PolyLoxy~methyl-1,2-ethanediyl)], alpha-hydro- omega-~3~2-~1-aziridinyl~ethoxy~carbonyl)= amino~methylphenyl~aminolcarbonyl~oxy]-, ether with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol (3:1) 139 71662-50-5 68553-08-2 28679-80-3 58596-06-8 69898-51-7 68298-90-8 55343-67-4 71820-43-4 70850-89-4 68458-39-9 71050-54-9 827-37-2 12039-76-8 68845-06-7 69013-20-3 110-03-2 52322-16-4 1424-79-9 574-06-1 14352-51-3 72987-44-1 68015-74-7
CHEMICALS IN COMMERCE Production at Least 1 Million Pounds/Year, continued Ch_ ___ CAS Number . [1,1'-Binaphthalene]-,8,8'-dicarboxylic acid lH-Isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo Ternenes and terPenoids, Litsea cubela-oil, * _, ~ ~ _ hydrogenated (1,1'-Bicyclohexyl)-2-carboxylic acid, 4',5-di= hydroxy-2',3-dimethyl-5',6-bisttl-oxo-2-pro= penyl~oxy]-, methyl ester Ethene, (2,2,2-trifluoroethoxy) Acetamide, N-~2-(acetyloxy~ethyll Chromate(3-), (3-hydroxy-4-~2-hydroxy-1-naphthalenyl)= azo]-7-nitro-1-naphthalenesulfonatoi3-~= (4-hydroxy-3-~2-hydroxy-5-~4-(phenylazo)= phenyl~azo~phenyl~methyleneJamino~benzene= sulfonato[3-~-, trisodium * Stannane, difluorodimethYl 29878-91-9 20262-55-9 68608-36-6 67952-52-7 406-90-6 16180-96-4 72479-29-9 3582-17-0 , Butanedioic acid, bist2-mercaptoethyl) ester Starch, 2,3-dialaehydo 2-Propenoic acid, 2-methyl-, 2-ethyl-2~2-methyl 1-oxo-2-propenyl~oxy~methyl)-1,3-propanediyl ester, polymer with ethenylbenzene, chloromethylated, trimethylamine-quaternized Benzene, 1,2-dichloro-4-(trichloromethyl) Cyclopentanone, 2-~3-methyl-2-butenyl) 1,3-Benzenedicarbonyl dichloride, 5-hydroxy Acetic acid, (4-formylphenoxy) Ethanaminium, N,N,N-trimethyl-2-~2-methyl-1-oxo 2-propenyl~oxy]-, chloride, polymer with 2-propenamide and N,N,N-trimethyl-~-[ (2-methyl 1-oxo-2-propenyl~oxy] ethanaminium methyl sulf ate 4~1H)-Pyrimidinone, 6-hydroxy Phenol, 4,4'-~1-methylethylidene~bis-, polymer with N,N'-bis(2-aminoethyl)-1,2-ethanediamine and (chloromethyl)oxtrane, nonylphenol-modified Naphthalenesulfonic acid, dibutyl-, ammonium salt 1,4-Benzenedicarboxylic acid, dimethyl ester, polymer with dimethyl pentanedioate, I,6-hexanediol, and 2,2'-oxybisiethanol] Resin acids and rosin acids, hydrogenated, esters with diethylene glycol Benzenesulfonic acid, 5-chloro-2,4-dinitro Cyclohexane, isocyanato Triethylenetetramine, polymer with ethylene oxide Pyrazineethanethiol 1,4-Benzenedicarboxylic acid, polymer with 1,3-dihydro-1,3-dioxo-5-isobenzofurancarboxylic acid, hexanedioic acid and 1,2-propanediol 140 60642-67-3 9047-50-1 68908-37-2 130i4-24-9 2520-60-7 61842-44-2 22042-71-3 68227-15-6 1193-24-4 68951-48-4 68379-06-6 71519-81-8 68648-51-1 56961-56-9 3173-53-3 31510-83-5 35250-53-4 70729-94-1
CHEMICALS IN COMMERCE Production at Least 1 Million Pounds/Year, continued Chemical CAS Number . Fatty acids, castor-oil, polymers with cottonseed-oil fatty acids, dehydrated castor-oil fatty acids, glycerol, phthalic anhydride and soya fatty acids 2-Propenoic acid, 2-methyl-, 3-(trimethoxysilyl)= propyl ester, polymer with N-(l,l-dimethyl-3-oxo= butyl)-2-propenamide, ethenyl acetate and 2-ethylhexyl 2-propenoate Iron, complexes with 2-ethylhexanoic acid and tall- oil fatty acids Uranium bromide (UBr4) Hexanoyl chloride Benzeneethanol, alpha-butyl-, acetate Cyclotrisiloxane, hexamethyl-, polymer with (l,l-dimethylethyl~ethenylbenzene and (l-methyl= ethenyl~benzene 1,2-Benzenedicarboxylic acid, compound with benzenamine (1:1) Imidodisulfuric acid, ammonium salt Benzenamine, _,N-dimethyl-4-~4-(methylamino)= phenyl]methyl) Zinc, chloro(~2,2',2 "-nitrilotris= (ethanolato)~(l-~-N,O,O',O " ) Uranium fluoride (UF5) Safflower oil, polymer with glycerol and TDI Polytoxy-1,2-ethanediyl), alpha,alpha'-~(docosyl= imino~di-2,1-ethanediyllbistomega-hydroxy Cyclopentanecarboxylic acid, 1-amino Benzenediazonium, 5-~(butylamino~sulfonyl]-2-methoxy-, (T-41-tetrachlorozincate(2-) {2:1) 3-Butenal, 2,3-dimethyl-4-~2,6,6-trimethyl-2-cyclo= hexen-l-yl) Fatty acids, C5_10, esters with polypentaerythritol 2-Propenoic acid, 2-methyl-, C7_1g-alkyl esters, polymer with 2-(methyl[(gamma-omega-perfluoro- Cg_l4-alkyl~sulfonyliaminoJethyl 2-methyl- 2-propenoate Alcohols, C6_12, ethoxylated 2-Propenoic acid, 2-chloro-, methyl ester Benzene, 1-methyl-4-phenoxy 1-Propanaminium, N-ethyl-N,N-dimethyl- 3-~2-methyl-1-oxo-2-propenyl~amino]-, ethyl sulfate 141 68525-89-3 67785-57-3 68187-36-0 13470-20-7 142-61-0 40628-77-1 66836-92-8 50930-79-5 27441-86-7 53477-27-3 33520-38-6 13775-07-0 68072-09-3 38796-84-8 52-52-8 62778-15-8 68140-49-8 68915-66-2 68988-55-6 68439-45-2 80-63-7 1706-12-3 70942-19-7
CHEMICALS IN COMMERCE Production Less-than 1 Million PoundstYear 1-Hexene, 6-chloro Formaldehyde, polymer with phenol and 3a,4,7,7a-tetrahydro-4,7-methano-lH-indene 4,7-Methano-lH-indenecarboxaldehyde, octahydro Hexedecanoic acid, octadecyl ester Poly~oxy-1,2-ethanedlyl), alpha-~1-oxo-2-propenyl) gmeRa-methoxy 2-Propenoic acid, 2-methyl-, 2-hydroxypropyl ~ster, homopolymer lH-Benzimidazole, 5-chloro-2-methyl S~lane, bicyclo[2.2.1]hept-2-yltrichloro Pyridinium, 1-~2-~-~2-cyano-4-nitrophenyl)= azo]-N-ethylanilinojethyl]-, chloride 2-Furanmethanol, tetrahydro-, phosphate (3:1) m-Dioxane, 2,5,5-trimethyl-2-propyl Silicic acid (H4SiO4), tetraphenyl ester Benzemide, 4-methoxy-3-nitro-N-phenyl Indol-3-ol, dihydrogen phosphate (ester), disodium salt * 1-Propanaminium, N,N,N-tripropyl-, bromide Heptanoic acid, anhydride Nitrous acid, 3-methylbutyl ester Dextran, hydrogen sulfate Azulene, 1,2,3,4,5,6,7,8-octahydro-1,4-dimethyl 7-~1-methylethylidene)-, (lS-cis) Silane, 1,4-phenylenebistchlorodimethyl Formic acid, rubidium salt * Butanedioic acid, tetrafluoro Glycols, polyethylene, hydrogen sulfate, eicosyl ether, sodium salt * Silane, dichloroethenylethyl * 2,8,9-Trioxa-5-aza-1-silabicyclot3.3.3Jundecane, 1-me thy l Methanediamine, dihydrochloride * Ichthammol Benzenediazonium, 4,4'-~1,2-ethenediyl~bis= [3-sulfo-, dichloride D-Arabinitol488-82-4 Phosphatetl-), h~xafluoro-, ammonium16941-11-0 Platinum, dichlorotl,2,5,6-eta)-12080-32-9 1,5-cyclooctadiene] * Terbium oxide lH-Benzotriazolecarboxylic acid Hexanoic acid, decyl ester Docosanoic acid, 3-hydroxy-2,2-bisthydroxymethyl)= propyl ester Ethanol, 2, 2,2-trifluoro-, 4-methylbenzenesulfonate Ethanol, 2-methoxy-, sodium salt 928-89-2 29862-25-7 30772-79-3 2598-99-4 32171-39-4 142 25703-79-1 2818-69-1 18245-29-9 23258-43-7 10427-00-6 5421-99-8 1174-72-7 97-32-5 3318-43-2 1941-30-6 626-27-7 110-46-3 9042-14-2 38-84-6 1078-97-3 3495-35-0 377-38-8 26636-38-4 10138-21-3 2288-13-3 57166-92-4 8029-68-3 13954-62-6 1~738-76-0 60932-58-3 52363-43-6 53161-46-9 433-06-7 3139-99-9
CHEMICALS IN COMMERCE Production Less than 1 Million Pounds/Year, continued I ~ . , ~ . ~ r Chemical CAS Number ~1 Benzene, 1-(chloromethyl)-2,4-dimethyl 2-Butenoic acid, 2-methyl-, butyl ester, (Z) 1,6-Hexanediamine, N,N'-dibutylidene Benzenesulfonamide, N. 4-d imethyl 2-Naphthalenecarboxylic acid, 5-(acetylamino) 1-hydroxy 9,10-Anthracenedione, 1,4-bis[~2,6-diethyl= phenyl~amino] * Ethanesulfonyl chloride, 2-chloro lH-1,2,4-Triazol-3-amine, 5-(methylthio) Benzemide, N-hydroxy-N-phenyl Phosphonic acid, dodecyl-, diethyl ester Iridium oxide 9-Octadecenoic acid (Z.)-, methyl ester, sulfurized, copper-treated 2-Propenoic acid, ethyl ester, polymer with ethenylbenzene, formaldehyde, and 2-propenamide lH-3a,7-Methanoazulene, octahydro-3,8,8-trimethyl 6-methylene-, [3R-~3alpha,3abeta,7beta,= 8aalpha)~- 1,2-Propanediol, 3-~2-hydroxyethyl~thio] Lead ruthenium oxide 2-Butenedioic acid (Z)-, mono(2-ethylhexyl) ester, polymer with ethenyl acetate and 2-ethylhexyl 2-propenoate 2,3b-Methano-3bH-cyclopenta[1,3]cyclopropa= 59056-64-3 [1,2Jbenzene-4-methanol, octahydro 7,7,8,8-tetramethyl Benzenemethanesulfonic acid, alpha,4-dihydroxy 3-methoxy-, monosodium salt 1,2-Ethanediamine, N,N'-bis~l,l-dimethylethyl) 2-Propenal, 2-methyl-3-~2-~1-methylethyl~phenyl] 9,12-Tetradecadien-l-ol, (Z,E) Hexanoic acid, 2,2,3,3,4,4,5,6,6,6-decafluoro 5-(trifluoromethyl) 1,3-Benzenedicarboxylic acid, polymer with 2,5-furandione, 1,6-hexanediol, and 1,2-propanediol Butanamide, N-~3-aminophenyl)-3-oxo-, mono= hydrochloride Acetic acid, sec-octyl ester Trisiloxane, 1,1,1,3,5,5,5-heptamethyl 3-~(trimethylsilyl~oxy] Benzenepropanol, 4-~1,1-dimethylethyl)-beta-methyl- 56107-04-1 Benzoic acid, 2-hydroxy-, strontium salt (2:1) 526-26-1 824-55-5 7785-64-0 1002-91-1 640-61-9 63133-78-8 20241-74-1 1622-32-8 45534-08-5 304-88-1 4844-38-6 1312-46-5 61788-34-9 28650-65-9 546-28-1 1468-40-2 37194-88-0 61909-78-2 19473-05-3 4062-60-6 6502-23-4 51937-00-9 15899-29-3 42133-48-2 59994-21-7 54515-77-4 17928-28-8 143
CHEMTCALS IN COMMERCE Production Less than 1 Million Pounds/Year, continued , ChemicalCAS Number _ - ~ 1 ~ ~. 2-Propenoic acid, dies ter with butanediol Acetamide, 2-chloro-2,2-difluoro Docosanoic acid, octadecyl ester 3-Cyclohexene-l-carboxaldehyde, dimethyl 2-Propenoic acid, 3-(lH-imidazol-4-yl) Propanedinitrile, (~3-chloro-4-(octadecyl= oxy~phenyl~hydrazono)-, Phenol, 4,4'-~2-pyridinylmethylene~bis-, diacetate 603-50-9 (ester) 1-Butanesulfonic acid, 4-~4-aminophenyl~butyl= 35079-64-2 amino] 31442-13-4 354-28-9 24271-12-3 27939-60-2 104-98-3 41319-88-4 Benzoic acid, 4-[1-([(5-[(4-[2,4-bis(l,l-dimethyl=63217-24-3 propyl)phenoxy]-l-oxobutyl)amino]-2-chloro= phenyl)amino]carbonyl)-3,3-dime thyl-2-oxo= butoxy]-, methyl ester Oils, cascarilla8007-06-5 * 1,3-Cyclopentadiene, 1,2,3,4,5, 5-hexachloro-77-47-4 1,2-Benzenediamine, 4-nitro-, dihydrochloride6219-77-8 1-Nonanamine1 12-2 0-9 * Hexanoic acid, 2-propenyl ester123-68-2 Furan, 2, 2, 3, 3,4,4,5-heptafluorotetrahydro 5-(nonafluorobutyl) 9-Octadecenoic acid, (Z.)-, potassium salt Thiocyanic acid, armnonium salt Styrax balsam 4(lH)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo Bicyclo[3.1.1]heptane, 2,6,6-trimethyl Benzenesulfonic acid, 2,5-dichloro-4-~4,5-dihydro 3-methyl-5-oxo-4-(phenylazo)-lH-pyrazol-l-yl]-, sodium salt Benzoic acid, 2-hydroxy-, methyl ester 1-Octen-3-ol 2-Naphthalenesulfonic acid, 8-hydroxy-5,7-dinitro 1,8-Naphthalenedicarboxylic acid, dipotassium salt Barium peroxide 2-Propenoic acid, octadecyl ester 9,10-Anthracenedione, 1,4-diamino 2-Propenoic acid, homopolymer, sodium salt Chromate(3-), bist5-~5-chloro-2-hydroxyphenyl]= azo)-6-hydroxy-2-naphthalenesulfonato(3-~-, disodium hydrogen 9-Octadecenamide, N-~2-aminoethyl)-N-~2-hydroxy= ethyl)-, (Z) Benzenesulfonamide, 4-amino Orange flower water 144 335-36-4 143-18-0 1762-95-4 8046-19-3 5 1-5 2-5 473-55-2 6359-97-3 1 19-36-8 339 1-86-4 483-84-1 1209-84-3 13 04-29-6 48 13-5 7-4 12 8-95-0 9003-04-7 6408-02-2 93-81-2 63-74-1 8030-28-2
CHEMICALS IN COMMERCE Production Less than 1 Million Pounds/Year, continued Chemical _ CAS Number 9,10-Anthracenedione Benzene, fluoro 1~3H)-Isobenzofuranone, 6-(dimethylamino) 3,3-bis[4-(dimethylamino~phenyl] Benzaldehyde Butanamide, N-~2-methoxyphenyl)-3-oxo Oils, citronella 9_-Carbazole, 9-ethyl-3-nitro C.I. Pigment Yellow 35 Phosphoric acid, monosodium salt 2-Propen-l-ol, 2-methyl 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy 3-~4-nitrophenyl~azo]-6-(phenylazo)-, disodium salt Benzeneacetic acid, alpha-amino-, (+~- Lead Poly~oxy-1,2-ethanedlyl), alpha-(isooctylphenyl) omega-hydroxy Benzenamine, N,N-diethyl-4-nitro Benzeneacetic acid, 1-methylethyl ester 2,4-Pentanediol, 2-methyl Dammar 2-Imidazoline-l-ethanol, 2-~8-heptadecynyl)-, monoacetate (salt) 3,4-Pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride L-Serine vi Gamin B12 2-Propenoic acid, 2-methyl-, dodecyl ester Benzenesulfonic acid, 2,2'-~1,2-ethenedlyl~bis= (5-~4-[bis(2-hydroxyethyl~amino]-6-(phenyl= amino)-1,3,5-triazin-2-yl~amino]-, disodium salt 1,3-Propanediol, 2-~(benzoyloxy~methyl] 2-methyl-, dibenzoate Octadecanoic acid, 12-hydroxy-, methyl ester CHEMICALS IN COMMERCE Production Unknown or Inaccessible , - , , , 2-Propanone, 1-(2-furanyl) 1-Hexadecen-3-ol, 3,7,11,15-tetramethyl Phenol,dodecyl-, lead(2+) salt Poly~oxy-1,2-ethanediyl), alpha-~2,4-bis= (l-methylpropyl~phenyl]-omega-hydroxy 145 84-65-1 462-06-6 1552-42-7 100-52-7 92- 15-9 8000-29-1 86-20-4 8048-07-5 7558-80-7 5 13-42-8 1064-48-8 283 5-06-5 7439-92-1 9004-87-9 22 16-15-1 4861-85-2 107-41-5 9000- 16-2 3388-72-5 58-56-0 56-45-1 68-19-9 142-90-5 4193-55-9 4 196-8 7-6 141-23-1 697 5-60-6 505-32-8 68586-21-0 67970-22-3
CHEMICALS IN COMMERCE Production Unknown or Inaccessible, continued Chemical , 2,7-Naphthalenedisulfonic acid, 4-amino- 6-~4-~4-~2,4-diaminophenyl~azo~phenyl)= aminoisulfonyl~phenyl~azo)-5-hydroxy- 3-~4-nitrophenyl~azo] Fatty acids, tall-oil, polymers with glycerol, maleic anhydride, phthalic anhydride, and soybean oil Benzoic acid, 2-hydroxy-5-~4-nitrophenyl~azo]-, monosodium salt Safflower oil, polymer with conjugated safflower oil, glycerol, methyl methacrylate, pen ta= erythritol, phthalic anhydride, and styrene Propanoic acid, 3,3'-thiobis-, diethyl ester Distillates (petroleum), solvent-dewaxed light paraffinic Poly~oxy-1,2-ethanedlyl), alpha-(carboxymethyl)- ome~a-hydroxy-, C12-13-alkyl ethers Trisiloxane, 1,1,1,5,5,5-hexamethyl-3-phenyl- 3-~(trimethylsilyl~oxy] 2-Propenoic acid, 2-methyl-, methyl ester, polymer with ethenylbenzene, 2-propenenitrile, and 2-propenoic acid Quaternary ammonium compounds, bis~hydrogenated tallow alkyl~dimethyl, methyl sulfates Manganese alloy, base, Mn 65-68' FelO-23' Sil2-21, C0.5-3, Po_0.2 (ASTM A483) 2-Naphthalenesulfonic acid, 6-hydroxy- 5-~2-methoxy-5-methyl-4-sulfophenyl~azo]-, disodium salt Germanium 2-Propenenitrile, polymer with 1,3-butadiene and ethenylbenzene, ammonium salt Phenol, 4-~2,4-dichlorophenoxy) Lithium, (l-methylpropyl) Oils, menhaden, polymers with p-tert-butylphellol, formaldehyde, glycerol, penteerythritol, phthalic anhydride, and rosin 6-Octenoic acid, 3,7-dimethyl-, methyl ester Propanal, 2-methyl Ethanaminium, N-~4-~4-(diethylamino~phenyl]= [4-(ethylamino)-1-naphthalenylimethylene)- 2,5-cyclohexedien-1-ylidene]-N-ethyl-, trihydroxypentatriacontaoxotphosphato(3-~ dodecamolybdate(4-) (4:1) 146 ,J= CAS Number . 72089-20-4 68015-41-8 1718-34-9 68083-08-9 673-79-0 64742-56-9 70750-17-3 2116-84-9 38684-13-8 61789-81-9 12743-28-1 25956-17-6 7440-56-4 67952-85-6 40843-73-0 598-30-1 68553-68-4 2270-60-2 78-84-2 69070-64-0
CHEMICALS IN COMMERCE Production Unknown or Inaccessible, continued . Chemical ~. . . . CAS Number - 1,3-Propanediol, 2-methyl-2-[(nitrooxy)methyl]-,3032-55-1 dinitrate (ester) 2,6,10,14,18,22-Tetracosahexsene, 2,6,10, 15,19,23-hexamethyl-, (all-E) Benzene, 1,1'-oxybis[2,3,4,5,6-pentabromo 2-Propenoic acid, polymer with ethenylbenzene, ethyl 2-propencate, formaldehyde, and 2-propenamide 2,7-Naphthalenedisulfonic acid, 4-hydroxy 3-(~4-~2-(sulfooxy~ethyl~sulfonyl~phenyl]= azo)-, tripotassium salt 1-Penten-3-one, 1-~2,6,6-trimethyl-2-cyclo= hexen-l-yl) Fatty acids, C12_18, polymers with adipic acid' C14-18 fatty acids, 1,6-hexanediol, isodecanol, and propylene glycol * Bicyclo[7.2.0Jundec-4-ene, 4,11,11-trimethyl 8-methylene-, [lR-(lR*,4E,9S*~- Vanadic acid, ammonium salt 2-Propanethiol 1-Octacosanol * Carbonic acid, nickel(2+) salt * Ferrocene Soybean oil, polymer with isophthalic acid and trimethylolethane Tin hydroxide * C.I. Pigment Green 7 Zeolites, calcium-iron-magnesium-vanadium containing Glycine, N-phenyl-, monosodium salt * tert-Dodecanethiol - 2-Anthracenesulfonic acid, 1-amino-9,10-dihydro 4-~4-~(methylamino~methyl~phenyl~amino] 9,10-dioxo-, monosodium salt Benzenemethanol, alpha-ethynyl-alpha-methyl Fatty acids, tall-oil, polymers with dipropylene glycol, maleic anhydride, and pitch * Acetaldehyde, chloro- 107-20-0 Fatty acids, tall-oil, compounds with N-cyclohexyl- 68188-05-6 N-methylcyclohexanamine Benzenesulfinic acid, methyl-, bis[4-(dimethyl= 29061-52-7 amino~phenylimethyl ester , , = 111-02-4 1163-19-5 67846-51-9 72187-37-2 127-42-4 71060-65-6 87-44-5 11115-67-6 75-33-2 557-61-9 3333-67-3 102-54-S 66070-63-1 12054-72-7 1328-53-6 68918-02-5 10265-69-7 25103-58-6 67905-55-9 127-66-2 68459-12-1 * Zinc, bis(2,4-pentanedionato-0,0')-, (T-4)- 14024-63-6 lH-Benzotriazole, sodium salt 15217-42-2 147
CHEMICALS IN COMMERCE Production Unknown or Inaccessible, continued . . . Chemical Poly(oxy-1,2-ethanediyl), alpha,alpha',alpha ",= alpha -~1,4-phenylenebistmethylenetoctadecyl= nitrilio~di-2,1-ethanediyl])tetrakis= [omega-hydroxy-, dichloride Leach solutions, copper, spent Oils, walnut, polymers with glycerol and phthalic anhydride Amides, C16_18 and Clg-unsaturated, N,N-bis= (hydroxyethyl) 2-Propenoic acid, 3,3'-~1,4-phenylene~bis Lanthanum iodide (LaI3) * 2,5-Cyclohexediene-1,4-dione, dioxime Cyclohexene, 1-ethenyl Ethane, 1,1-dichloro-1,2,2,2-tetrafluoro * Hydroxylamine, sulfate (2:1) 2-Naphthalenecarboxanilide, 3-hydroxy- 4-~4-methoxy-2-nitrophenyl~azo] Benzene, trichloro-, polymer with 1,4-dichloro= benzene and sodium sulfide (Na2S) 1,4-Benzenedimethanamine lH-Pyrazole-3-carboxylic acid, 1-~3-aminophenyl)- 4-~2-methoxy-4-~3-sulfophenyl~azo~phenyl)= azo]-, disodium salt Hexanoic acid, 2-ethyl-, cobalt(2+) salt Urea, polymer with formaldehyde and 1,3,5,7-tetre= azatricyclo-~3.3.1.13~7]decane, butylated ethylated 2-Propenoic acid, 4-(1-methyl-1-phenylethyl)phenyl ester * 2-Butene, 1,4-dibromo-, (E) Benzene, 1-chloro-4-(methylthio)-2-nitro 8-Quinolinol, 7-C12_l6-alkyl derivatives Phenol, 2,2'-methylenebis[4-chloro Ethanesulfonic acid, 2-[cyclohexyl~l-oxo= tetradecyl~amino]-, sodium salt Silicon+, tris(2,4-pentanedionato-O,O')-, (OC-6-11~-, hexafluoroantimonatetl-) 3H-Pyrazol-3-imine, 2,4-dihydro-5-methyl-2-phenyl Poly~oxy-1,2-ethanediyl), alpha-sulfo- omega-~9,12-octadecadienyloxy)-, sodium salt, (Z,Z) Benzenediazonium, 5-methoxy-4-methyl- 2-~2-(methylsulfonyl)-4-nitrophenyl~azo)-, sulfate (1:1) 148 CAS Number . . . . 68 140-77-2 690 12-76-6 68553-87-7 68603-38-3 16323-43-6 13 8 13 -2 2-4 105-1 1-3 2622-21-1 374-07-~ 1003 9-54-0 4 154-63-6 72276-00-7 539-48-0 68227-66-7 136-52-7 69898-36-8 54449-74-0 82 1-06-7 1199-36-6 68511-63-7 97-23-4 63`217-16-3 67251-37-0 6401-97-4 65086-42-2 72 15 2-44-4
CHEMICALS IN COMMERCE, Production Unknown or Inaccessible, continued Chemical CAS Number . 51838-10-9 2-Naphthalenesulfonic acid, 4-hydroxy 3-~4-methoxy-2-sulfophenyl~azo] 7-(methylamino) Gallium oxide 12024-21-4 Hexanedioic acid, polymer with 5-amino- 68212-31-7 1,3,3-trimethylcyclohexanemethanamine, 1,3-diiso=cyanatomethylbenzene, and 1,2-propanediol Acetic acid, mercapto-, 2,2-bis(~(mercapLo= acetyl~oxy~methyl)-1,3-propanediyl ester Benzenesulfonic acid, dodecyl-, sodium salt Soybean oil, polymer with benzoic acid, isophthalic acid, and phthalic anhydride Safflower oil, polymer with E~tert-butylbenzoic acid, glycerol, lauric acid, and phthalic anhydride Acetic acid, (3-methylbutoxy)-, 2-propenyl ester Fatty acids, coca, polymers with isophthalic acid neopentyl glycol, and trimellitic anhydride 1,4-Diisocyanatobenzene * Tunesten carbide Benzene, 2-methoxy-1-~1-methoxyethoxy)-4 (2-propenyl) Amides, coca Oxirane, methyl-, polymer with oxirane, mono= (hydrogen, sulfate), sodium salt Benzeneacetic acid, 5-methyl-2-~1-methylethyl)= cyclohexyl ester, [lR-(lalpha,2beta,5alpha) 3,6,9,12,15,18,21,24-Octaoxaheptacosanoyl fluoride, 2,4,4,5,7,7,8,10,10,11,13,13,14,= 16,16,17,19,19,20,22,22,23,25,25,26,26,= 27,27,27,-nonacosafluoro-2,5,8,11,14,17,20,= 23-octakis~trifluoromethyl) 3-Thiazolidineethanol, 2-imino-alpha-phenyl-, 4-methylbenzenesulfonate (salt) (1:1) Aluminum hydroxide Amines, di-C14_lg-alkyl Zinc, diawninebis~nitrato-O,O') Polytoxy~methyl-1,2-ethanediyl)], alpha~alphat,= alpha " ,alpha " '-~1,2-ethanedlylbistnitrilo= bis~methyl-2,1-ethanedlyl)~)tetrakis= [omega-hydroxy-, sodium salt Phosphoramidic acid, dibutyl-, diethyl es ter Amines, bis (hydrogenated tallow alkyl) 149 10193-99-4 25155-30-0 68554-84-7 68474-53-3 67634-00-8 68525-97-3 104-49-4 12070-12-1 68213-85-4 61789-19-3 67426-60-2 26171-78-8 13140-26-6 18126-02-8 21645-51-2 68037-98-9 33363-00-7 68567-72-6 67828-17-5 61789-79-5
CHEMICALS IN COMMERCE Production Unknown or Inaccessible, continued ~, . . .. Chemical , , , . , _ CAS Number - Starch, polymer with 2-propenenitrile, hydrolyzed, sodium salt Coconut oil, polymer with ethylene glycol, penteerythritol, and phthalic anhydride Manganese nitride 12033-07-7 Thiols, C4-20, ~ iE!~Perfluoro 68140-19-2 1,3-Benzenedicarboxylic acid, 5-sulfo-, 24019-46-3 1,3-bis(2-hydroxyethyl) ester, monosodium salt Fatty acids, tallow, lithium salts 64755-02-8 Amines, C10_16-alkyldimethyl 6 7700-98-5 1,3,5-Triazine-2,4,6-triamine, polymer with 62412-64-0 formaldehyde, hydrochloride Octanoic acid, 2-butyl Cyclopentanone, 2-hexylidene Fatty acids, tall-oil, reaction products with 2-~2-aminoethyl~aminoJethanol, quaternized with sulfate diethyl Benzenediazonium, 4-(diethylamino)-, chloride, compound with zinc chloride Titanium nitride Quaternary ammonium compounds, bisthydrogenated tallow alkyl~dimethyl, chlorides 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, isobutylated Hexanedioic acid, polymer with 1,6-hexanediol Naphtho[1,2-d~thiazol-2-amine Formaldehyde, polymer with oxybistpropanol] and phenol, methylated Oils, cod, polymerized, oxidized Fatty acids, C6-12 2-Propenoic acid, 2-methyl-, methyl ester, polymer with butyl 2-propenoate Polytoxy~methyl-1,2-ethanedlyl)], alpha-hydro-= omega-hydroxy-, polymer with 1,1'-methylene= bis[4-isocyanatobenzene] Hexanedioic acid, polymer with 2-ethyl-2-(hydroxy= 28183-09-7 methyl)-1,3-propanediol and 2,2'-oxybistethanol] Bacillus megaterium 68038-67-5 Ethanedio ~ is(3~4,6-trichloro-2-[(pentyl= 30431-54-0 oxy)carbonyl]phenyl) ester 68442-56-8 66070-89-1 27610-92-0 17373-89-6 70955-34-9 17409-47-1 25583-20-4 61789-80-8 68002-21-1 25212-06-0 40172-65-4 68441-82-7 68082-76-8 67762-36-1 25852-37-3 9048-57-1 150
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~4 :' A o a: ~5 - ·~. c 8 - v x a P. o ·r. o ..-, Q. o ye ~ ~4 Ll 0 In ha Cal . - TIC ~ ~1 X 1 1 1 TIC 1 1 1 1 X X ·It X X 1 X 1 1 . 1 X 1 1 1 1 X X X X X 1 X 1 1 1 1 1 1 1 1 ~1 0 ~In 1 ~0) :~. ~ c: · - ~ ~JJ ~ ~ ~ ~ c: ~·- ~ `: e ~ ~ u ~ ~ ~ ~ ~ x P4 ~·- ~ ~ ~ o. - :e O ~X O ~ ~ Ll ~ a: ~ ~ an 0 0 in ·- ~ 0 ~ ~ O 0 1 ~JJ 1 X ~ ~ ~ ~ ~ ~ ~ O 1 ~1 1 _ O ~ L. . - ~ ~ aC ~ ' - :>, 1 ~ ~ ~ ~ ~ ~ ·- ~ ~ O ^.~ ·rl ~ ~ ~ o4 do ~ C: 1 ~ ~ O U] J~ r. ~ ·- ~ X ~ ~ ~ ~ I ~ N · - C U · - ~ O ~ ~ · - CO ~ ~ · - ~ ~ Ll · - ~ ~ ~ ~ ~ ·. ~ ~ C C ~ ~ ~ ~ JJ · - X aC ~ X C ~ ~ >1' - 0 ' - 14 :>. ~ O ~ C O ~ ~ O ~ ~ ·e ~ ~ ~ ~ ~ · - ~ ~ ~ 41) Ll C ~ ~ V~ dJ a, r~ ~ O ·- ~ _I C J~ c ~v O C I ·~4 ~ ~ O Q. C ~ J~ (IJ-- ~ ~ C _d (V 1 Y O ~ ~ C ~ <- O ~ -U O ~ ~ O C- - C ~ ~ ~ C O C C Q. C J~ ' - ~ O ~ C -1 ~ ~ ~ ~ ~ 4 `° ~ ~ ~ ~ o~ ~ ~ ~ ~ e ~e ~ ~ c~ ~ c X ~ ~ -H ~ C ~o ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ 0 ~ ~ o ~ ~ - :3 ~ ~ ~ ~ U Y ~ ~ Y x: E~ ~ ~ C) ~cn u ~u ~#¢ cn ~ ~ u~ · e · · e e e e e e e ~ O ~ ~ ~ ~ U~ _~ C ~ ~ C~ ~ C~ 162 e e e e O ~ ~ ~
Symbols and reference notations for Appendixes B-G X = b = e = = g = h i = j k = 1 = - - m n = P = Appropriate test; list of checked tests will be considered as minimal necessary for evaluation of adequate data base. If indicated by available data or information; it will be responsibility of reviewing toxicologist to examine data from listed necessary tests and then judge whether these additional tests also will be necessary. Use rodent other than rat. Use only rat. If carcinogenicity is suspected. Lifetime--rat if carcinogenicity is suspected; short-term for absorbable sutures; ocular for ophthalmic sutures. Do repeat patch test with photosensitization test. Acute toxicity should be determined in three or four species by appropriate routers) of intended use. By appropriate route of intended use. Will also require up to 6-mo study by appropriate route. 18- or 24-mo study. 12-mo study. May require up to 6 mo on intact skin. Four species; 3 h/d (5 d/wk) under conditions to be used clinically. One species; duration commensurate with clinical use. Duration and number of applications determined by intended use. Additional studies appropriate to duration and route of intended use; some studies required in target species; if target species is food-producing animal, see direct food additives in Appendix B. Or perform test 24. Or perform tests 22 and 23. 163
APPENDIX H REFERENCE PROTOCOLS FOR TOXICITY TESTING Test Reference Sourcea 1. Acute oral toxicity--rodent IRLG, 1981c 2. Acute oral toxicity--nonrodent 3. Acute dermal toxicity 4. Acute parenteral toxicity 5. Acute inhalation toxicity 6. Acute dermal irritation--corrosivity Acute eye irritation--corrosivity 8. Skin sensitization--guinea pig 9. Subahronic oral toxicity--rodent: 14- or 28-d study 10. Subahronic toxicity--nonrodent 14- or 28-d study 11. Subahronic oral toxicity--rodent: 90-d study 12. Subchronic oral toxicity--nonrodent: 90-d study 165 OECD, 1981, 401:1-7;b when rabbit is used as nonrodent, fewer than 10 (5 per sex) at each dosage will be acceptable; for dogs or other large nonrodents, ascending-dose study will be acceptable IRLG, 1981a OECD, 1981, 401:1-7; guidelines for acute oral toxicity should be followed, but administration will be by intravenous, intramuscular, subcutaneous, or intraperitoneal routes NRC, 1977a OECD, 1981, 404:1-6 IRLG, 1981b OECD, 198], 406:1-9; OECD, 1981, 407:1-9 OECD, 1981, 407:1-9 OECD, 1981, 408:1-10 OECD, 1981, 409:1-9
Test 13. Subchronic oral toxicity--nonrodent: 6- to 12-mo study 14. Subchronic dermal toxicity: 21- or 28-d study 15. Subchronic dermal toxicity: 90-d study 16. Subchronic inhalation toxicity: 28- or 14-d study 17. Subchronic inhalation toxicity: 90-d study 18. Subchronic neurotoxicity: 90-d study 19. Teratology study--rodent, rabbit 20. Multigeneration reproduction study-- rodent 21. Toxicokinetics 22. Carcinogenicity--rodent 23. Chronic toxicity 24. Combined chronic toxicity- carcinogenicity--rodent 25. Genetic toxicity 26. Subchronic eye toxicity 27. Segment 1: fertility and reproductive performance 28. Segment III: perinatal and postnatal performance 166 Reference sources OECD, 1981, 409:1-9 OECD, 1981, 410:1-8 OECD, 1981, 411:1 - 10 NRC, 1977a NRC, 1977a OECD, 1979, pp. 106 - 109 IRLG, 1981d U.S. Environmental Protection Agency, 1978 OECD, 1981, 415:1 - 5 OECD, 1981, 451:1-19 OECD, 1981, 452:1 - 15 OECD, 1981, 453:1-16 OECD, 1979, pp. 114 - 116 U.S. Department of Health, Education, and Welfare, 1973c U.S. Department of Health, Education, and Welfare, 1973 U.S. Department of Health, Education, and Welfare, 1973c
29. Acute delayed neurotoxicity 30. Skin painting--chronic 31. Implantation studies 32. Human sensitization studies 33. Skin penetration studies _ a U.S. Environmental Protection Agency, 1978 OECD, 1981, 451:1-15 Guidelines for chronic toxicity (test 23) should be followed with test material implanted, rather than administered in Diet or pa rente rally Marzulli and Maibach, 1980 Marzulli et al., 1969 IRLG = Interagency Regulatory Liaison Group; 0ECD = 0rganisation for Economic Co-operation and Development; NRC = National Research Council. Penultimate version of OECD guidelines. Further descriptions of segments I and III, the Food and Drug Administration Bureau of Drugs requirements for reproduction studies, may be found in Collins (1978~. REFERENCES Collins, T. F. X. 1978. Reproduction and teratology guidelines. J. Environ. Path. and Taxicol. 2:141-147. Interagency Regulatory Liaison Group, Testing Standards and Guidelines Work Group. 1981a. Recommended Guidelines for Acute Dermal Toxicity Test. Washington, D.C.: Interagency Regulatory Liaison Group. 12 pp. Interagency Regulatory Liaison Group, Testing Standards and Guidelines Work Group. 1981b. Recommended Guideline for Acute Eye Irritation Testing. Washington, D.C.: Interagency Regulatory Liaison Group. 12 pp. Interagency Regulatory Liaison Group, Testing Standards and Guidelines Work Group. 1981c. Recommended Guideline for Acute Oral Toxicity Testing in Rodents. Washington, D.C.: Interagency Regulatory Liaison Group. 11 PP. Interagency Regulatory Liaison Group, Testing Standards and Guidelines Work Group. 1981d. Recommended Guidelines for Teratogenicity Studies in the Rat, Mouse, Hamster, or Rabbit. Washington, D.C.: Interagency Regulatory Liaison Group. 12 pp. Marzulli, F. N., W. C. Brown, and H. I. Maibach. 1969. Techniques for studying skin penetration. Toxicol. Appl. Pharmacol. (Suppl.) 3:76-83. 167
Marzulli, F. N., and H. I. Maibach. 1980. Contact allergy: Predictive testing of fragrance ingredients in humans by Draize and Maximization methods. J. Environ. Pathol. and Toxicol. 3:235-245. National Research Council, Committee for the Revision of NAS Publication 1138. 1977. Principles and Procedures for Evaluating the Toxicity of Household Substances. Washington, D.C.: National Academy of Sciences. 130 pp. Organisation for Economic Co-operation and Development. 1979. Short-Term and Long-Term Toxicology Groups. Final Report. 185 pp. (unpublished) Organisation for Economic Co-operation and Development. 1981. Guidelines for the Testing of Chemicals. Paris: Organisation for Economic Co-operation and Development. c. 700 pp. U.S. Department of Health, Education, and Welfare, Food and Drug Administration. 1973. Introduction to Total Drug Quality. DREW Publication No. (FDA) 74-3006. Washington, D.C.: U.S. Department of Health, Education, and Welfare. 101 pp. U.S. Environmental Protection Agency. 1978. Proposed guidelines for registering pesticides in the United States; Hazard evaluation: Humans and domestic animals. Fed. Reg. 43~163~:37336-37403. 168
APPENDIX I REFERENCE PROTOCOL GUIDELINES FOR NEUROBE~VTORAL-TOX ICITY TESTS Neurobehavioral-toxicity testing requires both morphologic and behavioral assessment. With current methods, the effects of some chemicals are most reliably detected by measuring morphologic changes, whereas other chemicals produce behavioral changes without, as yet, the identification of any morphologic basis. Because methods for neurobehavioral-toxicity testing are still being developed and validated, a high degree of standardization in such testing is inappropriate at this time. Nevertheless, a scheme proposed by a committee of the National Research Council (1977) gave specific and detailed suggestions of protocols for neurobehavioral-toxicity testing. The scheme, presented here, is a reasonable starting point for neurobehavioral-toxicity testing, and the suggested protocols were used as the reference protocol guideline in this study. The 1977 committee recommended that both conditioned and unconditioned behaviors be studied. For unconditioned behavior, it suggested that circadian patterns of spontaneous motor activity (SMOG) be measured. SMA in rodents has been widely studied to document behavioral changes produced by chemicals. This procedure does not require any special training of personnel. For conditioned behavior, it suggested that performance maintained by schedules of food presentation be used as a measure. Some types of schedule-controlled responding require little training of the animal, but provide an estimate of the effects of a substance on fairly complex behavioral Processes. Reiter et al. (1981) have found that measurements x Spontaneous motor activity (SMA) is a measurement of an animal's body movement under a given set of environmental conditions. SMA may be detected by a variety of techniques, including photocell-beam interruption and changes in a capacitance field. It is important that measurements be objective and unbiased. Use of automatic instrumentation is recommended for the measurement of SMOG. Schedule-controlled responding is maintained by reinforcement. For example, animals are trained to make specific responses to specific stimuli to obtain food or water or to avoid shock. The relationship of ~ is called the schedule of _ reinforcement, and the behavior may be referred to as schedule-controlled responding (Ferster and Skinner, 19571. the response to delivery of such reinforcers 169
of SMA and schedule-controlled behavior are two of the most sensitive tests for determining the behavioral effects of pesticides. A battery of sophisticated techniques for more detailed evaluation of substances for neurobehavioral effects is gradually being developed (Geller et al., 1979~. Measurement of morphologic changes in the nervous system requires in situ perfusion of the animal and the use of contemporary methods of nervous system preparation for examination by light microscopy and perhaps electron microscopy. Spencer et al. (1980) have developed procedures for tissue preparation based on glutaraldehyde fixation that permit classification of neurotoxins according to their target sites (e.g., some and myelin). Their system permits assessment of the location, type, and degree of neurotoxic damage. For the neurotoxins studied thus far, there is a good correlation between the type of neurotoxic damage observed in animal models and the type of neurotoxic damage produced by the same substances in humans. In addition to the behavioral and morphologic testing recommended for the screening of neurotoxins, a host of other approaches to neurotoxicity testing are under development. Among these are tests involving tissue cultures, electrophysiology, and neurochemistry. The current stage of development of some of these approaches has been outlined briefly by Spencer et al. (1980~. PRINCIPLES AND DESCRIPTION OF TESTIS FOR NEUROBEHAVIORAL EFFECTS Many substances damage the nervous system (Spencer and Schaumburg, 1980) and thereby produce a variety of behavioral changes. Although no substance or series of substances can now be recommended as a reference for neurotoxicity testing, positive controls are always desirable. Agents with established neurobehavioral toxicity should be tested repeatedly to establish the sensitivity of the measurement system when new substances with potential neurobehavioral toxicity are under investigation. A range of doses of a substance should be administered for acute-toxicity testing of neurobehavioral effects, including doses large enough to produce obvious effects. Fractions of the LD50 should be used, and the substances should be administered by the route of likely human exposure. Effects of the substances on SMA and schedule-controlled behavior should then be determined. Later, the animals should be sacrificed for histologic examination by light microscopy and possibly electron microscopy. For subchronic studies, three doses, including the highest dose that did not affect behavior or produce morphologic changes on acute administration, should be administered repeatedly. Healthy adult animals should be randomly assigned to treatment and control groups. In some instances, behavior is exceedingly stable, and pre-exposure behavior provides control observations for the exposure period. Rats are the preferred animal, although mice are also appropriate. Standard breeds and strains should be used, and at least six animals should be studied at each dose. 170
SMA must be measured under carefully controlled conditions (National Research Council, 1977~. For example, strain of animal, feeding and watering schedules, time of day of testing, and conditions of temperature, humidity, and lighting must be specified. The device used to measure SMA must also be described in detail, although no particular method has yet been recommended. For measurement of schedule-controlled responding, conditions must also be specified in detail. Again, the species, body weight, feeding and watering schedules, etc., must be specified. The reinforcement schedule should be described in sufficient detail to allow others to repeat the experiment under nearly identical conditions. A reasonable time should be allowed to elapse, after the substance is administered, for absorption and distribution before behavior is measured. Animals should be tested daily for at least 1 wk after acute administration to determine the consequences of delayed neurotoxicity, such as that observed with alkyl tin compounds. Similar principles should be followed for subohronic testing. Where possible, it is desirable to have histologic examinations and behavioral testing of the same animals. Additional animals exposed to the substance, but not tested for behavioral effects, can be added to the design as necessary to increase group size for time-response effects. Methods similar to those described by Spencer et al. (1980) are appropriate. Tests of statistical significance should be applied to the data. Reproductions of histologic slides can often be used to illustrate types of neurotoxicity, although tables are generally necessary to document the frequency with which the illustrated events occurred. Specificity of neurobehavioral toxicity may be expressed as the ratio of the LDso to the neurobehaviorally toxic dose. Neurobehavioral-toxicity evaluation and its relative importance should include a comparison with other toxicity data on the substance. For example, neurotoxic effects manifested only by a dose 10 times higher than that required for carcinogenicity would be of little regulatory interest. The test report should include dose-ettect data for behavior and morphology, a description of the location and type of neural lesions, the time course of the development of behavioral and morphologic changes, statistical treatment of the results, and an indication of the degree to which the toxicity is reversible. Detection of either morphologic changes or behavioral changes caused by effects on the central nervous system can be considered as evidence of neurobehavioral toxicity that may be extrapolated to humans. The degree to which such extrapolation is valid is under investigation. More sophisticated understanding of specific types of behavioral toxicity would require a series of tests that is beyond the present protocol. When morphologic changes have been observed, the selection of later behavioral tests should be strongly influenced by the type, degree, and location of the morphologic changes. 171
DETERMINATION OF ADEQUACY OF NEUROBE~VIO=L-TOXIC I TY TESTI Because no reference protocol guidelines for neurobehavioral-toxicity testing have been established and because much evidence of neurobehavioral toxicity exists in qualitative descriptions of the adverse effects of substances, the Committee on Toxicity Data Elements has established a series of criteria for judging the adequacy of neurobehavioral-toxicity testing, including observations of effects. The neurobehavioral-toxicity data base (see Figure I-1) should contain studies on function (both conditioned and unconditioned behavior) and morphology (neuropathology). The committee regarded neurobehavioral-toxicity testing to be (1) adequate, according to reference protocol guidelines, only if all three study types followed the procedures described here; (~) adequate, but not according to reference protocol guidelines, if all three study types were conducted adequately, but not according to the procedures described here; and (3) inadequate if at least one of the three study types was missing or was conducted inadequately. The need to repeat studies conducted inadequately depends on the amount and quality of existing neurobehavioral-toxicity information on a substance. For example, documentation of extensive neural lesions (a morphologic response) might make behavioral testing (a functional response) unnecessary for regulatory purposes, because the neuropathologic effects already constitute a hazard. These criteria allowed the committee to determine whether neurobehavioral effects were observed with adequate or inadequate procedures. 172
/ Review of the Toxicity Data Bases of Chemicals in the Sample Neurobehavioral toxicity / \ Functional Morphologic (behavioral) (neuropathologic) \ Conditioned Unconditioned behavior behavior FIGURE I-l Studies necessary for judging adequacy of neurobehavioral toxicity testing. 173 ~ -
REFERENCES Ferster, C. B., and B. F. Skinner. 1957. New York: Appleton-Century-Crofts. Schedules of Reinforcement. Geller, I., W. C. Stebbins, and M. J. Wayner. 1979. Test methods for definition of effects of toxic substances on behavior and neuromotor function. Neurobehav. Toxicol. l:Suppl. 1. National Research Council. 1977. Behavioral toxicity tests, pp. 111-118. In Principles and Procedures for Evaluating the Toxicity of Household Subtances. Washington, D.C.: National Academy of Sciences. Reiter, L. W., R. C. MacPhail, P. H. Ruppert, and D. A. Eckerman. 1981. Animal models of toxicity: Some comparative data on the sensitivity of behavioral tests, pp. 11-23. In Proceedings of the Eleventh Conference on Environmental Toxicology. AFAMRL-TR-80-125. Patterson, Ohio: Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base. Spencer, P. S., and H. H. Schaumburg. 1980. Classification of neurotoxic disease. A morphological approach, pp. 92-99. In P. S. Spencer and H. H. Schaumburg, Eds. Experimental and Clinical Neurotoxicology. Baltimore: Williams and Wilkins. Spencer, P. S., M. C. Bischoff, and H. H. Schaumburg. 1980. Neuro- pathological methods for the detection of neurotoxic disease, pp. 743-757. In P. S. Spencer and H. H. Schaumburg, Eds. Experimental and Clinical Neurotoxicology. Baltimore: Williams and Wilkins. 174
APPENDIX J REFERENCE PROTOCOL GUIDELINES FOR GENETIC-TOXICITY TESTS The OECD (Organisation for Economic Co-operation and Development, 1981) has recommended a set of guidelines for the assessment of genetic toxicity. Government agencies in the United States are attempting to make their approaches compatible with those guidelines, and the Committee on Toxicity Data Elements accepted the guidelines as the standard against which genetic-toxicity studies were to be measured. The OECD testing strategy has two stages. The first stage is the generation of a minimal set of data on previously untested substances: one test for gene mutation (Ames Salmonella/liver microsome reverse-mutation assay or Escherichia cold reverse-mutation assay) and one test for chromosomal damage (rodent micronucleus assay or in vitro ch~omosomal-aberration assay). OECD-approved protocols have been published for the conduct of these four assays. For a substance to be considered in compliance with the OECD guidelines, it must have been tested under at least one approved protocol for each of the two end points. The second stage of the OECD strategy is additional testing of substances that produced positive results in the first step, as indicated in Figure J-1. Protocols have been drafted for several additional in vitro and in viva assays. Some of these assays focus on both gene mutations and chromosomal damage. The protocols for the additional tests are in draft form and have not been approved by the OECD working groups. Once the protocols have been approved, a substance identified as positive in one or both of the Stage 1 tests will require additional testing in a Stage 2 assay or assays measuring the end pointed found positive in Stage 1. Such a substance will not be viewed as having been adequately tested without assessment in at least one Stage 2 test. Using this framework for assessing the adequacy of genetic-toxicity testing protocols, the Committee on Toxicity Data Elements established the following criteria for its use in determining adequacy of genetic-toxicity testing within the subsample of 100 substances: · A substance studied for each Stage ~ end point in tests conducted according to the OECD protocol guidelines was considered as having met the committee's standard for the genetic-toxicity reference protocol guidelines (G). ~ A substance studied for each Stage 1 end point in one test conducted according to the OECD protocol guidelines and in the other not according to the OECD protocol guidelines, but nevertheless regarded by the committee as adequate, was considered to have met the committee's standard for an adequate (A) study of genetic toxicity. 175
· A substance studied for each Stage 1 end point in tests not conducted according to the OECD protocol guidelines, but nevertheless regarded by the committee as adequate, was considered to have met the committee's standard for an adequate (A) study of genetic toxicity. · A substance studied for only one Stage 1 end point in tests conducted according to the OECD protocol guidelines, or nevertheless regarded by the committee as adequate, was considered to be inadequately tested (I). Tests must be conducted for both Stage 1 end points for a substance to be regarded as adequately tested. · A substance studied for only one Stage 1 end point in tests conducted according to an acceptable standard (not necessarily in accordance with the OECD protocol guidelines) and also studied in other adequately conducted mutagenicity tests not prescribed in Stage 1 was considered to be inadequately tested (I). Nevertheless, further genetic-toxicity testing might not be required by the committee. Reference protocol guidelines for genetic toxicity Besting Stage 1 Assays for gene muteeion end point Ames Salnonelle/liver microsome reverse mutation assay or Escherichis cold reverse mutation assay - Assays fo r chromo some demage end po in Rodent micronuc lee 8 as say or In vitro chromosome aberreeion assay Bo th tests SO ah Bests One test Sufficient negative positive positive, Besting ~I | one negative i f pro to co 1 s to 1 lowed Stage 2 Conduct stage 2 test( 8) Assays for gene mutation end point Drosophila melanogester sex-linked recessive lethal essay Mouse lymphoma L5178Y (TK+/-) forward gene mutation assay CHO (HGPRT) forward gene mutation assay V79 (HGPRT) forward gene mutation assay Assays for chromosome damage endpo int _ viva chromosome aberration analysis in rodent bone marrow Rodent dominant lethal assay FIGURE J-1 End points and tests defining them in the two-stage assessment of genetic toxicity. REFERENCE Organisation for Economic Co-operation and Development. ~ 981. Guidel ines for the Testing of Chemical s. Paris: Organisation for Economic Co-operation and Development. 700 pp. 176
APPENDIX K CONCEPTUAL ISSUES CONCERNING THE INTERPRETATION OF RESULTS OF STUDIES OF REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Interpretation of studies of reproductive and developmental toxicity required an awareness of potential confounding factors, such as interspecies differences in toxicokinetics and developmental biology. These factors notwithstanding, tests for adverse effects on reproduction are not the same as tests for adverse effects on development (e.g., in utero growth retardation, functional decrements evident after birth, death of the conceptus, and production of live or dead terata). Some overlap of effects can be expected in studies designed to evaluate reproductive or developmental effects. A multigeneration study may be designed primarily to assess effects on reproduction, but litter size, for instance, may be reduced, not only by diminished fertility, but also through death or resorption of malformed concept), thereby indicating a substance's ability to disrupt development. Similarly, a Segment II study,* designed primarily to reveal developmental effects, may show that a substance induces abortion by affecting uterine function. This is not evidence that it directly disrupts the development of the embryo. Thus, in evaluation of the adequacy of results of a Segment II study, data from other studies may be used. If groups in the Segment II study are too small to provide useful results, a multigeneration study can sometimes be used as an aid to determine whether the developmental effects of a substance have been adequately tested. If results with a restricted number of animals in a Segment II study are consistent with those of a multigeneration study, the Segment II report may be judged as an adequate assessment of developmental effects. A substance's developmental toxicity might range from the apparent absence of effect to a clearly defined and obvious dose-response relationship. Even if such dose-related findings do not prove to be statistically significant (because of the use of small samples), they may be biologically important in light of data from related studies. In a Segment II study, two species of pregnant animals are exposed only during organogenesis, and fetuses are examined 1 day before parturition to determine developmental toxicity. 177
APPENDIX L MAJOR COMPONENTS OF A DOSSIER A dossier consisted of (1) a synopsis containing a substance's physicochemical characteristics, manufacturing processes, production, intended and other uses, chemical fates, exposure potentials, and all retrieved information deemed by the NRC staff to be relevant; (2) a list or lists of the adequacy ratings of required toxicity tests that were performed; (3) summary ratings for the quality of all information in the dossier; and (4) a data sheet detailing physicochemical, use, and exposure information. mese four components are given below. SYNOPSIS Chemical name, CAS Registry number, and intended-use category Physicochemical properties, manufacturing processes, production, uses, chemical fate, and exposure potential Physicochemical properties State(s) Solubility (fat, water) Chemical uniqueness Manufacturing process Production level Consumption level Uses Intended From other than originating lists Other than those indicated from sampling lists Statement of chemical fate Exposure potential In intended-use setting (dose, duration, frequency, route) In occupational setting (dose, duration, frequency, route) In environmental setting (dose, duration, frequency, route) Roadblocks to getting above information ~^nr~rn hound on all the above information Level of ~ Synopsis of the health-effects data base Human Animal Summary of the toxicity data base Toxicologic uniqueness (e.g., reversibility of effect) For required tests For tests not required Roadblocks to getting toxicity information Adequacy of the data base Analysis of individual toxicity studies Analysis of the complete toxicity data base Analysis of the complete data base 179
Adequacy Ratings of Required Toxicity Tests That Were_Performed for a Pesticide or Inert Ingredient of Pesticide Formulationa Necessary Toxicit Testsb ~. . . 1. Acute oral toxicity--rodent 3. Acute dermal toxicity 5. Acute inhalation toxicity 7. Acute eye irritation-corrosivity 8. Skin sensitization--guinea pig 11. Subchronic oral toxicity--rodent: 90-d 12. Subohronic oral toxicity--nonrodent: 90-d 14. Subahronic dermal toxicity: 21- or 28-d 16. Subahronic inhalation toxicity: 28- or 14-d 18. Neurobehavioral toxicity a. Functional: conditioned behavior b. Functional: unconditioned behavior c. Morphological 19. Teratology--rodent, rabbit 20. Multigeneration reproduction--rodent 21. Toxicokinetics 22. Carcinogenicity--rodent 23. Chronic toxicity 24. Combined chronic toxicity-carcinogenicity--rodent 25. Genetic toxicity a. Ames reverse mutation (his-) b. E. cold reverse mutation (top-) c. Rodent micronucleus d. In vitro chromosomal aberration e. Drosophila SLRL f. Mouse lymphoma (TK) forward mutation g. CHO (HGPRT) forward mutation h. V79 (HGPRT) forward mutation i. In viva chromosomal analysis in bone marrow j. Rodent dominant-lethal assay 29. Acute delayed neurotoxicity Other tests not required but performed: Ref. Intended-Use NotationC Exposure q q r * a This is a sample summary for a pesticide or inert ingredient of a pesticide formulation in intended-use setting. Similar summaries were prepared for occupational and environmental settings and for all other intended-use categories for the substance being evaluated. Toxicity tests necessary for these settings are described in Appendix F. Measures of adequacy are according to the criteria described in Chapter 4e b Test numbers are those used in the list of 33 test types in Appendix F. c These and other reference notations are described in the legend of symbols and reference notations following Appendix G. 180
Summary Ratings for the Quality of All Information in a Dossier 1. Breadth of known exposure a. Widespread b. Limited, but intensive to specific groups c. Limited d. Rare e. Unknown 2. Trend in per capita exposure a. Increasing b. Decreasing c. Stable d. Unknown 3A. Level of concern resulting from physicochemical properties and chemical fatea a. High b. Moderate c. Low d. Unknown 3B. Level of concern resulting from physicochemical properties and exposure potentials a. High b. Moderate c. Low d. Unknown a Ranking substances according to level of concern is based on chemical and physical data for only two exposure groups--adult males and adult females--not the conceptus. Chemical and physical data are generally not applicable to fetal development, nor is molecular structure indicative of a potential for reproductive/developmental toxicity. For instance, alkylating agents have been shown to injure embryos, yet they are of low priority for reproductive/ developmental toxicity testing, because they are no more hazardous to embryos than to adults. Even without testing, reproductive/developmental toxicity will be evident only at or very near the toxic dose for adults. 181
4. Strength of evidence of toxicity in humans a. High b. Medium Low or absent 5. Severity of chronic human toxicity a. Serious b. Moderate c. Minor d. Unknown (no evidence of toxicity or evidence of no toxicity) 6. Evidence of inaccessible toxicity data a. Yes b. No 7. Availability of appropr late test battery Intended Use a. Complete b. Incomplete c. Essentially no results available 8. Quality of available tests a. Most high b. Mixed c. Most low d. None available Occupational Environmental 9. Is all available information sufficient to allow an assessment of the hazard? Yes Limited assessment is possible No assessment is possible Intended Use Occupational 182 Environmental
Physicochemical, Use, and Exposure Information I. Chemical Identification A. Nomenclature B. Structure C. Chemical Abstracts Service (CAS) Registry number D. Defined purity E. Impurities/contaminants IT. Production, Use, and Waste Disposal A. Origin 1. Starting materials 2. Manufacturing processes B. Products 1 - - . 2. C. Wastes 1. (identity and quantity) Major products (percent yield) Magnitude of byproducts (number and volume) Identity 2. Quantity 3. Disposal methods 4. Estimated unintentional losses (quantity) 5. Physical state (gas, liquid, solid) D. Production 1. Yearly volume (lb/yr) 2. Intended/registered uses 3. Estimated unintentional losses (quantity) 4. Physical state (gas, liquid, solid) III. Physical Characteristics A. Boiling point B. Density or specific gravity C. Vapor pressure D. Particle size E. Water solubility F. Organic (fat) Volubility G. Complexity (single compound, family, mixture of families) H. I. pH Dissociation constant IV. Chemical Reactivity in Nonbiolog~c Systems Shelf life/chemical stability B. Potential for oxidation/reduction C. Potential for hydrolysis D. Potential for photochemical changes E. Potential adsorption/desorption 183
V. Availability of Analytic Methods for Detection A. Evaluation of neat compound in nonbiologic systems B. Evaluation of chemical reactions in biologic systems C. Evaluation of environmental media only (air, water, food), not to include human exposure D. Evaluation of direct human substrates (urine, blood, other fluids, tissues, etc.) VI. Chemical Bioavailability A. Environmental stability, turnover rates B. Biodegradation, excretion, elimination C. Occurrence in air, water, tissues, and/or food chain D. Bioaccumulation VII. Exposure A. Production processes 1. Open 2. Closed B. Occupational exposure 1. Number of people exposed: a. Production and direct use b. Other 2. Monitoring 3. Route of exposure 4. Commentsa Environmental exposure 1. Numbe r of people exposed 2. Monitoring 3. Commentsa D. Intentional exposure 1. Route Number of people exposed a. Conditions of recommended use b. Abuse 3. Monitoring 4. Commentsa a Information regarding special groups (age, sex, and ethnic groups, both demographic and geographic). 184
APPENDIX M PROCEDURES, RATIONALE, AND RESULTS OF DATA IDENTIFICATION AND ACQUISITION TYPES OF DATA COLLECTED To estimate the potential for human exposure, the Committee on Toxicity Data Elements sought information on manufacturing processes, intended uses, production and consumption, ana chemical and physical properties of each substance. In addition, potential exposure routes were identified, where possible, and durations and frequencies of exposures were estimated. The committee recognized that the potential for exposure may vary for each manufacturing process, intended use, or grade (purity) of the substance. For each substance, therefore, searches were made for information on the following subjects: · The chemistry of the substance, including its chemical and generic nomenclature and Chemical Abstracts Service (CAS) Registry number, purity, identification of contaminants, and physical and chemical properties that influence its potential toxicity {fat and water Volubility, molecular weight, and volatility). ~ Manufacturing processes, including pathways of chemical synthesis, and production volumes. Uses, both industrial and consumer, including information on transportation, storage, and disposal. · Chemical fate (including environmental pathways that lead to secondary human exposure), persistence, and bioavailability. · Exposure of humans, including route, duration, dose, and frequency of human exposure and rate of absorption. · Toxicity, particularly data with the potential to predict hazards to human health, including results of studies in mammalian and nonmammalian animal models. · Epidemiologic and clinical studies. 185
SOUPBONES OF DATA Resources were not sufficient to search every possible source of remotely relevant information. Data banks were selected after consideration of the likelihood of redundancy with other data sources, the time required to retrieve citations and collect cited materials and review them for relevance, and the accessibility of the identified data. Five general sources of data were used in the initial search: · On-line data bases, in which chemical information and citations of toxicologic and related biomedical publications are mechanically stored. · Secondary sources, such as textbooks and technical review documents, which generally contain citations to primary sources that could be reviewed if necessary. · The collection of toxicologic documents maintained since 1957 by the Toxicology Information Center (TIC) of the NRC Board on Toxicology and Environmental Health Hazards. · Government agency files (both confidential and open to public access) on sample substances that are regulated. · Manufacturers, trade associations, and large industrial consumers of the substances in the sample. ACCESS TO DATA The Committee on Toxicity Data Elements encountered several roadblocks when searching for data. These difficulties affected the completeness of the data bases compiled for each substance and, as a consequence, assessment of their adequacy. The following discussion is important, because these impediments to data access not only have affected this study, but also can be expected to influence future data evaluation and analysis. Some information (especially that important for exposure estimation) has been classified as confidential and is stored in the files of government agencies or manufacturing companies. The committee questions whether the secrecy of data pertinent to human exposure is in the public interest or even in the narrower interests of industry. Data compiled in technical reports or bulletins that have not been published in the open literature are also inaccessible. Some primary data sources no longer exist or cannot be found, because they have been filed in large, poorly indexed record repositories. 186
Some kinds of data that are important to the determination of the adequacy of toxicity testing protocols often are not reported. Included in this category are detailed identification of chemical contaminants or substances used in mixtures; the species, strain, age, sex, breeding source, breeding techniques, diet, and water supply of the animal tested; and the length of time between exposure and observed effect or between exposure and a conclusion that no effect occurred. Negative results (findings of no toxic effects) often are not reported art all. Such data may be important to the assessment of data-base adequacy, but may be unavailable or even unknown to the organization that holds them. AUTOMATED STORAGE AND RETRIEVAL DATA BASES me committee anticipated that on-line data bases would provide most of the needed toxicity references, as well as the information on uses of chemicals. However, there is only limited coverage of data published before the mid-1960s, when the first large-scale automated data bases were developed. The primary set of data bases chosen for this study collectively covers a broad spectrum of chemical and toxicologic information. Table M-1 lists these data bases and briefly describes their scope. The numbers of records listed are those at the time the search was initiated. As indicated in the table, some of the data bases grew during the year that the searches were conducted. The committee also used a secondary set of data bases that are more specialized data bases created for comprehensive coverage of specific topics. Specialized collections with relevance to the committee's task are described in Table M-2. The amount and type of data retrieved by on-line searching of bibliographic files depend in great measure on the search strategy used. In the retrieval of computerized information, the selection process is a stepwise removal of unwanted data. At each step, the operator judges whether the information is relevant or not. Information designated as not useful is "discarded" from the process. For this project, the operators were conservative in their selection process, because it seemed better to retrieve irrelevant information and remove it manually than to overlook important citations. The NRC personnel in charge of the on-line retrieval consistently tended to keep more information than committee members believed to be relevant. The committee recognized the need for uniformity in the search for data on each substance. For some compounds, very little information was found, even through a search of all the data bases. For others, thousands of indexed documents were identified by the computer as having 187
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some potentially relevant information. In the latter situation, time constraints precluded review of every document. For this reason, review articles were provided to committee members, who were asked to identify citations that applied to each of the toxicity tests required for a substance's category of intended use. Those primary documents were then collected. When some required toxicity data elements were not uncovered in this way, the data bases were searched again with a focus on the missing elements. EOr this purpose, a list of search terms was developed for each of the major toxicity subjects: carcinogenicity, mutagenicity, reproductive/developmental toxicity, organ and system toxicity, and metabolic effects (toxicokinetics). This procedure eliminated many citations that were not relevant or were already identified. This strategy of data compilation included feedback from committee members after they examined data on a substance. On the basis of their experience, they identified what data might be missing. If the result of a search seemed inappropriate in any way, a followup search was conducted. The greatest difficulty encountered in the use of the powerful searching capabilities of automated files was specific identification of substances that were not clearly defined. Some chemical terms on the list constituting the "select universe" signify materials with uniform compositions, but others describe generic sets of compounds or single compounds that may occur in a variety of physical forms. Still others are chemical mixtures or biologic products that vary in composition from source to source or sample to sample. A few of the chemical names were vague or ambiguous. OTHER SOURCES Textbooks, technical reports, reviews, abstracts, and patent applications provided only limited toxicologic information, but were excellent sources of information on chemical and physical properties, intended uses, and manufacturing processes. To obtain a consistent base of data, a standard search pattern was instituted. One source of information was the computerized toxicity data bases. In addition to abstracts of research papers, abstracts of patent applications were found by computer searches. These often contained information on potential uses. Helpful information was also obtained from the files of the Registry of Toxic Effects of Chemical Substances and from the Toxicology Data Bank. Six reference books were consulted for information on each chemical (Doull et al., 1980; Hawley, 1977; Physicians Desk Reference, 1981; Sollmann, 1957; Weast and Astle, 1979; Windholz et al., 1976~. In addition, other sources were searched for particular types of chemicals (U.S. Environmental Protection Agency, 1980; Estrin et al., 1982; Hayes, 1975; National Research Council, 19811. The nature and extent of the information in these references depend on the uses of a given substance and, hence, are correlated with the listed on which the substance appears. 191
NRC TOXICOL~Y INFORMATION CENTER ( TIC) Because of the need to gain access both to pre-1965 data and to very recently published data, both of which were not present on computer data bases, the card catalogs of the TIC were searched manually. The 26-yr-old collection of toxicologic information in the TIC includes data produced before the collection began and acquired through retrospective literature searches, in addition to data generated from the establishment of the collection to the present. The TIC is also a repository of reprints gathered for reports of NaC committees, as well as of some private reprint collections donated by toxicologists. Although comprehensive in its collection of information on chemicals encountered environmentally and occupationally, the TIC generally excludes some types of substances, notably drugs and nutrients. GOVERNMENT AGENCY FILES - Some research or regulatory agencies--e.g., the National Institute for Occupational Safety and Health (NIOSH), FDA, EPA, and the Department of Defense (DOD)--have repositories of data on toxicity, manufacturing processes, production volumes, and intended use (including the amounts of substances associated with each type of intended use). Because the committee's intent was not to report the production process and volume data, but rather to use the Data as components of an exposure profile, it asked each agency for permission to gain access to confidential information pertaining to substances in the sample. All the regulatory agencies expressed concern about granting the committee access to trade-secret information provided by industries. In some cases, the agency responses were severely constrained by law, regulation, agency policies, and restrictions imposed by organizations that provided the data. These constraints varied markedly from agency to agency. No criticism of agency responses should be inferred from discussions in the following paragraphs. EPA provided the toxicology portions of pesticide registration applications to NRC staff ano to some committee members not involved in occupations associated with organizations that could benefit from company trade secrets. The information augmented the data in the published literature. Little specific information on extent of environmental contamination was obtained from EPA data files. Because those files are not centralized, it was difficult to gain the required information from them. FDA was reluctant to open files; however, its Bureau of Foods provided access to the SCOGS (Select Committee on GRAS Substances) 192
reports on substances in the sample. Most of the data in these reports were also identified by other means. The FDA Bureau of Drugs readily provided information on clinical use, route of administration, duration of use, and types of formulations for active drugs, as well as estimates of population exposure to those drugs and adverse reactions to them. Access to information contained in the Bureau of Drugs division reviews, new drug applications (NDAs), investigative new drug (IND) files, and abbreviated new drug applications (ANDAs) was more complex. Regardless of degree of confidentiality, these data were either inaccessible or were made accessible only with great difficulty, because of the excessive costs of manpower required to locate relevant information. There were long delays before the bureau responded to requests from the committee--not because of unwillingness to be responsive, but rather because of acute deficiencies in the bureau's data management. These deficiencies were most apparent after two major requests were made by the committee: · The committee asked for a list of currently marketed prescription drugs, over-the-counter drugs, and excipients used in formulations of these drugs. The product was provided 6 months after the request was made, because manpower in the Bureau of Drugs was insufficient and the automated data management systems were incapable of generating the required list readily. · The committee asked for toxicity information on chemicals that were sampled from the list eventually provided by the bureau. Within several weeks of the request, some NDAs, ANDAs, INDs, and division reviews were made accessible to cleared NRC staff members, who then had to locate the files and identify pertinent information in them. Most files consisted of many volumes that lacked indexing or content organization, except for chronologic entry of documents. Thus, the search for relevant information required manual scanning of every page in every volume. In many cases, the desired volumes were not available, because they were stored in a warehouse in a manner that made their retrieval extremely difficult or they were lost and could not be traced. Much of the information identified as lost had been submitted to FDA by industries that did not later publish the material. Information collected by NIOSH on some of the substances was organized and readily accessible through that agency's health-hazard evaluations, criteria documents, and Current Intelligence Bulletins. However, these documents contained only a few of the substances of interest to the committee. Toxicity data on several chemicals were found in unclassified documents maintained by NIOSH (National Institute for Occupational Safety and Health, 1982~. 193
MANUFACTURERS, CO-ED IAL USED, AND T. - DE O~ANI ZATIONS Manufacturers and trade associations are repositories of otherwise unobtainable information on potential occupational exposures, manufacturing processes, waste disposal practices, and production. Their assistance in obtaining information on the 100-substance subsample was requested through the Federal Register on March 16, 1982 (Public Health Service, 1982), and through correspondence with manufacturers of the 40 representative chemicals in commerce selected for the subsample from the TSCA Inventory. Approximately 600 companies were identified in the TSCA Inventory as being manufacturers of at least one of the 40 chemicals in commerce in the subsample. Each company was contacted by telephone, a brief explanation of the project was given, and the information to be sent to them was described. A followup letter--which included a complete description of the project, an alphabetized list of the 100 substances, a request for unpublished toxicity data, and a questionnaire--was sent to each company. The questionnaire contained the following questions: · Is the material that is produced in your work environment regulated by FDA, OSHA [the Occupational Safety and Health Administration], EPA, or DOT [Department of Transportation] (and are there guidelines for limiting exposure)? · If so, how do you control the chance of exposure? A. By engineering control? B. By personal protective clothing (e.g., the use of respirators)? C. By ventilation (e.g., roof fan, open exhaust)? D. Other (please specify)? Is the material measured in the air? Do you store the material? If so, for how long? · Do you run a continuous or batch operation to produce the material? . Mow old is the equipment used to manufacture the material? · How frequently is maintenance required on the equipment? · Can you indicate how much of this material you produce per year and at what site it is produced? · What are the potential uses of this chemical in manufacturing, in commerce, and by consumers? 194
Some trade associations were contacted directly; others were forwarded the questionnaire by the manufacturers. The Research Institute for Fragrance Materials, the Cosmetic Ingredient Review, the Cosmetic, Toiletry, and Fragrance Association, the American Petroleum Institute, the Soap and Detergent Association, and the Flavor and Extract Manufacturers' Association were some that responded to inquiries. The committee also contacted persons whose professional expertise equipped them to provide additional information on potential human exposure. When information was particularly limited, authors of research papers were contacted in an attempt to obtain more information. Responses to the inquiries were mixed, both in quantity and in usefulness. The few respondents to the Federal Register notice provided much information that was not in the open literature. Approximately 30% of the 600 manufacturers who were contacted responded. Approximately 15% of the 600 stated that they did not manufacture any of the substances. Responses from approximately 3% of the companies indicated that a general willingness to cooperate was frustrated or delayed by resource constraints, lack of expertise, etc. Approximately 5% of the companies supplied answers to the questionnaire, and an additional 5% provided documents and other information on the chemicals of interest. Only 1% of the companies that were contacted responded by indicating that they would not cooperate. Reluctance or inability of industry to cooperate in studies like this was found to be only one factor inhibiting the collection of information on industrial practices and occupational exposure. It is very difficult--often impossible--to locate and contact all the current manufacturers of a given substance. AVAILABILITY AND ROLE OF INFORMATION OTHER THAN TOXICITY DATA Information on intended uses was readily available from the reference textbooks for most cosmetic ingredients, drugs and excipients in drug formulations, and food additives. Similar information on pesticides and inert ingredients of pesticide formulations was more often obtained from computer searches (including patent abstracts), government files, or other special sources. Information on the intended uses of chemicals in commerce (as listed in the TSCA Inventory) was obtained less often from either of these sources than from patent applications and primary literature. Chemical and physical properties were most readily available, although that information was not located for approximately 20% of the substances selected from the TSCA Inventory. Availability of information on manufacturing processes was variable. Even when information on synthesis could be located, several processes were often presented with no indication of which ones were used for bulk production. Limitations of resources did not allow for the case-by-case collection of these data from manufacturers or other sources beyond the collection already described. 195
Data on the 100 substances in the subsample (chemistry, production and consumption, intended uses, methods of waste and product disposal, and environmental persistence) were considered to be essential for evaluating the adequacy of the toxicity data base. Such data can be used to estimate the number of people potentially exposed, the magnitude and duration of exposure, and the routes of direct and indirect exposure. Without such data, only the most crude and untestable subjective estimates can be made. From the outset, the committee recognized that the desired data on manufacturing processes and environmental persistence would be difficult to obtain, even for high-volume substances. A major limitation was the absence of known data bases in which such information was systematically stored. Furthermore, the data kept in industry files were largely inaccessible or were organized in ways that made it difficult to retrieve pertinent information. If such information were made available, the effort needed to assemble and process it would have added substantially to the workload, and that would have reduced the capacity to acquire and process the toxicity data. Although the task was, at the least, formidable or, more likely, infeasible, an earnest effort was made to address it. Letters sent to known producers requested information on production, occupational exposure, and waste disposal. The responses received contained little usable information. Likewise, requests to government agencies for data on occupational exposure and environmental contamination in general yielded very little specific information on the chemicals of interest. Nominal data had been accumulated by these agencies and not in accessible files. Even the simplest of the relevant data (e.g., reliable annual production rates) could not be obtained in most cases. There were strong indications that three of the 10 subsample substances listed in the TSCA Inventory as having 1977 production of at least 1 million pounds (454 metric tons) were no longer in production or were produced in markedly smaller quantities. As a result, the committee's assessment of the adequacy of the toxicity data on many substances had to be based on sketchy data and subjective estimates of the numbers of persons exposed and the routes, durations, and intensities of their exposure. In most cases, the committee relied solely on information about the products' intended uses, their chemical and physical properties, and the general background knowledge of committee members. The serious weakness of the exposure data base limits the committee's confidence in the adequacy of the toxicity-testing protocols for conducting health-hazard assessments. The lack of suitable exposure data places an even more severe limitation on the application of inferences drawn from analyses of the chemicals in the final sample to the larger "select universe" and on the development of quantitative dose-response models for chemicals in the environment. The assembled toxicity data on the 100 substances provide a good base for examining the predictive nature of toxicity-testing models; however, the absence of exposure data prevents a similar examination of exposure models. 196
The unavailability of reliable exposure data will be a continuing limitation for NTP in its planning of toxicity testing. NTP would benefit greatly if data of this kind were obtained in cooperation with other federal agencies--such as NIOSH, FDA, EPA, and the Consumer Product Safety Commission--that have an interest in and a need to collect similar information on exposure. REFERENCES , Doull, J., C. D. Klasssen, and M. O. Amdur, Eds. 1980. Casarett and Doull's Toxicology: The Basic Science of Poisons. New York: Macmillan. 778 pp. Estrin, N. F., P. A. Crosley, and C. R. Haynes. 1982. CTFA Cosmetic Ingredient Dictionary, 3rd ed. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association, Inc. 610 pp. Hawley, G. G., Ed. 1977. The Condensed Chemical Dictionary, 9th ed. New York: Van Nostrand-Reinhold. 957 pp. Hayes, W. J. 1975. Toxicology of Pesticides. Baltimore, Md.: Williams & Wilkins. 580 pp. National Institute for Occupational Safety and Health, Chemical Systems Laboratory. 1982. Subfile excerpted from the NIOSH Registry of Toxic Effects of Chemical Substances. Rockville, Md.: National Institute for Occupational Safety and Health. National Research Council. 1981. Food Chemicals Codex, 3rd ed. Washington, D.C.: National Accademy Press. 735 pp. Physicians Desk Reference. 1981. 35th ed. Oradell, N.J.: Medical Economics Co. 2,047 pp. Public Health Service. 1982. National Toxicology Program. Fed. Reg. 47:11321. Sollmann, T. 1957. A Manual of Pharmacology and Its Applications to Therapeutics and Toxicology, 8th ed. Philadelphia, Pa: W. B. Saunders. 1,535 pp. U.S. Environmental Protection Agency. 1980. Code of Federal Regulations 40. 1980. Subpart D. Exemptions from tolerances, pp. 277-297. In Tolerances and exemptions from tolerances for pesticide chemicals in or on raw agricultural commodities. Section 180.1001. Weast, R. C., and M. J. Astle, eds. 1979. CRC Handbook of Chemistry and Physics, 59th ed. (1978-1979~. West Palm Beach, Fla.: CRC Press. Windholz, J., S. Budavari, L. Y. Stroumtsos, and M. N. Fertig, Eds. 1976. me Merck Index. An Encyclopedia of Chemicals. 9th ed. Rahway, N.J.: Merck & Co. 1,313+ pp. 197
