GOLD ETAL. - CORE

GOLD ETAL.

Appendix 1. Species

Code SpeciesH hamsterM mouseN prosimianP monkeyR rat

Methods for Nonhuman PrimatesThe NCI Laboratory of Chemical Pathology has ended its 36-year project(1961-1997) on lifetime carcinogenesis studies in cynomolgus and rhe-sus monkeys. Our plot includes final lifetable analyses on 25 chemicalsincluding 17 that we reported earlier with interim control data (indicatedwith a "j" notecode on the plot).'

We have relaxed some of the rules of the CPDB in order to includethese monkey experiments. The following methodology has been adopted:* An experiment with fewer than 5 animals is considered inadequate and

is not included in the CPDB. To obtain at least 5 animals per group inthese studies, results have been combined for both sexes of cyno-molgus and separately for both sexes of rhesus monkeys. For somechemicals, fewer than 5 monkeys were on test even when both sexeswere combined and those are not reported; no tumors occurred inthose cases when the chemical was evaluated as not carcinogenic inthe other species. A few chemicals were studied in African Green mon-keys, but the tests usually had fewer than 5 dosed monkeys. Becauseof a viral outbreak, African Green monkey studies were discontinued.We have excluded African Green studies from the CPDB.

* Although experiments with surgical intervention are generallyexcluded from the CPDB, in these monkey tests, laparoscopic exami-nation of the liver was performed every 3-6 months, followed bywedge or needle biopsies of observed liver lesions.

* A few positive experiments are included that are shorter than one-halfthe standard 20-year life span even though such tests are generallyexcluded from the CPDB. (For cycasin, 2-amino-3-methylimidazo[4,5-f]quinoline [10], N-nitrosodipropylamine [DPN], N-nitrosodiethylamine[DEN] in bush babies, nearly all dosed animals had tumors in this shorttime. Some experiments on adriamycin were longer than 10 years andsome were shorter; we have included them all for completeness.) Theplotted TD50 value for experiments shorter than half the life span aresurrounded by parentheses.

* Experiments on sodium arsenate and sterigmatocystin are includedeven though monkeys were put on test as adults, at 4 years of age.

* Control monkeys are from the colony at NCI, which included breed-ers, offspring, and a small number of feral monkeys. The age of con-trol animals ranged from neonate to greater than 25 years at a giventime. Control monkeys were included only if they lived to be olderthan 8 months, the age of the first tumor in any group. Concurrent,vehicle controls were used only for 10.Some colony control monkeys were not examined histologically, andthey have been excluded from the analyses because tumors may nothave been detected at necropsy: control n = 106 cynomolgus (11 un-examined excluded), 120 rhesus (36 unexamined excluded). Weinvestigated whether results would be similar if the unexamined con-trols had been included in our analyses, and we determined that they

'The 25 chemicals in monkeys are 2-acetylaminofluorene, 2,7-acetylaminofluorene,adriamycin, aflatoxin B,, sodium arsenate, azathioprine, cycasin and methyla-zoxymethanol acetate, sodium cyclamate, cyclophosphamide, DDT, N,N-dimethy-4-aminoazobenzene, IQ, melphalan, 3'-methyl-4-dimethylaminoazobenzene,Nmethyl-N'-nitro-Nnitrosoguanidine, 3-methylcholanthrene, Nnitroso-N-methyl-urea, N-nitrosodiethylamine, Nnitrosodimethylamine, Nnitrosodipropylamine, Nnitrosopiperidine, procarbazine.HCI, sodium saccharin, sterigmatocystin, andurethane. In future we will report final results of studies on MelQx and PhIP, whichwere begun at NCI and will be completed under the auspices of the JapaneseNational Cancer Center Research Institute.

would be: For target sites, all results were significant (p < 0.001)regardless of whether the unexamined were excluded or not. TD50values calculated without unexamined animals were within a factorof 2 of TD50 values calculated with them.

* The dose rate for a group is calculated as the mean of the dose-rateof individual monkeys. To obtain the daily dose rate for each mon-key, the cumulative dose in mg/kg reported by NCI, was divided bythe number of days of its life. Dosing schedules ranged acrosschemicals from once every 4 weeks to 5 times per week; for mostexperiments the chemicals were administered in a vitamin sandwich5 times per week.

* TD50 values are estimated using lifetable data and are reported forevery site at which a tumor occurred, benign or malignant, in dosedanimals.

* In experiments with multiple target sites, a composite TD50 value isreported on the plot for all animals with tumors at any of the targetsites ("MXB,MXB" on the plot, as with NCI/NTP bioassays in rodents).

See Appendix 6, Notecodes and Definitions, under "W" and `w fordetails about plotted results on monkeys.

Appendix 2. Strain Codes and DefinitionsCode Strain

aap Alpk/Apain ACI/naps Alderly Parkb6c B6C3F,bal BALB/cbbb Bush babies [Ga/ago crassicaudatus]c3h C3Hc5c C57BL/1 OScSnc5j C57BL/1 0Jcb6 C57BL/6cdl Charles River CD1cdf CDF,cdr Charles River CD (Sprague-Dawley)cen C3H/HeNchh C3H/Heclw Colworth (Wistar derived)crw Charles River Crl:COBS(Wl)BRcym Cynomolgus [Macaca fascicularis]d2b D2B6F1 micedba DBA/2f34 Fischer 344f3d F344/DuCrjf3j Fischer 344/Jclf3t Fischer 344/Toxicm ICRleb long-Evans BLU:(LE)lew Lewislwj LEW/Crj (Lewis)nmr NMRIofl OF1ofs OFA (Sprague-Dawley derived)rhe Rhesus [Macaca mulattalsda Sprague-Dawleysdj SD(Crj:CD) Sprague-Dawleysen SENCARsis SIc-Wistar

smb Syrian, MB strainswa Swiss albinoswi Swisssyg Syrian Goldenwil Wistar/LAC-P

Environmental Health Perspectives * Vol 107, Supplement 4 * August 1999590

CARCINOGENIC POTENCY DATABASE

Code Strainwis Wistarwky WKY/NCrj (Wistar)wsj Crj:Wistarwsr Wistar-random

Appendix 3. Routes of AdministrationCode Route of Administration

eat dietgav gavageinh inhalationipj intraperitoneal injectionivj intravenous injection

mix multiple routesused for two compounds in monkeys: 1) procarbazine.HCI: avariety of combinations of diet, subcutaneous, intraperitoneal,and intravenous injection; 2) aflatoxin B,: a combination of dietand intraperitoneal injection

orl for tamoxifen citrate, gavage for 3 months, followed by dietwat water

Appendix 4. Site CodesCode Site

adramdascbil

bonbrabrececchpclicoldgtduoeduepgesoforgabgamgnvhagheahedhumilmitnjejk/pkcxkidlarleglepIgilivlmrlun

mam

all target sitesadrenal glandadrenal medullaascending colonbile ductbonebrainbreastcecumcheek pouchclitoral glandcolondigestive tractduodenumear ductepiglottisesophagusforestomachgall bladder/bile ductgastric mucosagingivaHarderian glandheartheadhumerusileumintestinejejunumkidney/pelviskidney cortexkidneylarynxlegleptomeningeslarge intestineliverlymphoreticular systemlungmammary tissue (other than or including more than mammary gland)

Code SitemglMXAMXBnacnasnplnsensporcovapaepalpanpelphrpitplspndpnipnmprepropylrecsbgsclsevskiskuslgsmisplstgstnstosubTBAtbatesthmthytontyfublugiutevagzym

mammary glandmore than one site, combined by NCI/NTPmore than one site, combined by Berkeleynasal mucosanasal cavitynipplenosenasopharynxoral cavityovarypancreas, exocrinepalatepancreaspelvispharynxpituitary glandpalate, softpancreas/pancreatic ductpancreatic isletsperiniumpreputial glandprostatepylorusrectumsebaceous glandscalpseminal vesicleskinskullsalivary glandsmall intestinespleenstomach, glandularstomach, nonglandularstomachsubcutaneous tissueall tumor bearing animals, NCI/NTPall tumor bearing animals, general literaturetestisthymus glandthyroid glandtonguethyroid follicleurinary bladderupper gastrointestinal tractuterusvaginaZymbal's gland

Appendix 5. HistopathologyCode Histopathology

a/aa/cabtacbaccadcadeadpagfalaalc

alveolar/bronchiolar adenomaalveolar/bronchiolar carcinomaalveolar/bronchiolar tumoralveolar/bronchiolar adenocarcinomaacinar-cell carcinomaadenocarcinomaadenomaadenomatous polypangioma/fibroangiomaalveolar-cell adenomaalveolar-cell carcinoma

Environmental Health Perspectives * Vol 107, Supplement 4 * August 1999 591

Histopathologyacanthomaacinar-cell adenomaadenoma, bilateralacute nonlymphocytic leukemiaastrocytomabasal-cell adenomabasal-cell carcinomabronchiolar adenomabile duct adenomaintrahepatic bile duct tumor, benignintrahepatic bile duct tumorintrahepatic bile duct tumor, malignantbenign tumorhepatoma, benignbiliary cystadenomabronchogenic carcinomabasophilic nodulecarcinomacarcinosarcomac-cell adenomac-cell carcinoma, bilateralc-cell carcinomacholangioma, cysticcholangiosarcomacholangiomacarcinoma, in situcholangiocarcinomacarcinoma, bilateralcortical adenomacortical carcinomaductal papillomaeccrine cylindromaendometrial adenocarcinomaesthesioneuroepitheliomaeosinophilic noduleendometrial stromal polypendometrial stromal sarcomafollicular-cell adenoma, bilateralfibroadenomafibroleiomyomafibrosarcomafollicular-cell adenomafollicular-cell carcinomafollicular-cell tumorfollicular adenocarcinomafibromagranulosa cell adenomagranulosa-cell tumor, benigngranulocytic leukemiahepatocholangiocarcinomahistiocytic sarcomahepatocellular tumorhemangiomahemangiosarcomahemangioendothelial sarcomahamartomahyperplastic nodulehepatocellular adenomahepatoblastomahepatocellular carcinomainterstitial-cell adenoma, bilateralinterstitial-cell adenomainterstitial-cell tumor

Code Histopatologyisa islet-cell adenomaisc islet-cell carcinomaker keratoacanthomaIc lymphocytic lymphomaldc leydig-cell tumorlei leiomyosarcomaleu leukemialey leiomyomaIkm lymphoma, leukemialie lymphocytic leukemialmt lymphoma malignant, thymic originlya leydig cell adenomaIym lymphomalys lymphosarcomamal malignant tumormca microadenomamec muco-epidermoid carcinomamhp malignant hepatomamix more than one tumor type; tumor types specified in published papermly malignant lymphomammx mesenchymal hemangio-sarcoma, -pericytoma, or -endothelioma,

malignantmnl mononuclear-cell leukemiamnr meningioma, granular cellmsm mesothelioma, malignantMXA more than one tumor type, combined by NCI/NTPMXB more than one tumor type, combined by Berkeleymxp neoplasm of liver cell, bile duct, mesenchyme, Kupffer cell, or

unknownnen neoplasm, NOSngs neurogenic sarcomannd neoplastic noduleost osteosarcomapai papilloma, invertedpam papillomapbb pheochromocytoma benign, bilateralpda pars distalis adenomapdc pars distalis carcinomaphe pheochromocytomaphm pheochromocytoma, malignantpla polypoid adenomapmb pheochromocytoma malignant, bilateralpob pheochromocytoma, benignppa papillary adenomarab renal tubule adenoma, bilateralrca renal-cell adenomarcc renal-cell carcinomarhb rhabdomyosarcomarhm rhabdomyoblastomarua tubule adenomaruc tubule carcinomasar sarcomascc spindle-cell carcinomasea sebaceous adenomasqc squamous-cell carcinomasqp squamous-cell papillomasxb sex-cord stromal tumor, benign, bilateralsxs sex-cord stromal tumor, benigntcc transitional-cell carcinomatla tubular-cell adenomatic tubular-cell carcinomatit tubular-cell tumortpp transitional-cell papilloma


GOLD ET AL.

Codeamaanaanbaniastbcabccbcdbdabdbbdhbdmbenbhpbicbrobsncarcasccaccbccrccychcchocicclccnbcoacocdppeccenaeneesnespessfabfbafbifbsfcafccfctfdcfibgcagcbgrihcchcshcthemheshmshmthndhpahpbhpciabicaict

592


Code Histopathologytri trichoepitheliomatsc transitional epithelium, squamous-cell carcinomatsp transitional epithelium, squamous-cell papillomatum tumor or more than one tumor type; tumor types not specified in

paperAppendix 6. Notecodes and DefinitionsCode Definition

a The exposure time reported on the plot is an average of the dif-ferent exposure times of the individual dose groups in theexperiment. For NCI/NTP, both exposure and experiment timeshave been averaged because of differential survival among thedose groups. (In the TD50 calculation for the NCI/NTP bioassays,full lifetable data have been used.)

C Quantitative data is reported in the paper on cell division indosed and control animals (e.g., labeling index). The "C" note-code does not indicate whether there was an associationbetween cell division and tumorigenesis.

D Dietary restrictione For the general literature we have used an effective number of

animals in a group whenever possible. This effective number iseither: 1) the number of animals alive at the time of appearanceof the first tumor, or if that is not reported, then 2) the numberof animals examined.

g Some or all of the animals were used as breeders during thecourse of the experiment.Control and dosed animals received isocaloric diets.

j The data for this test have been previously published in theCPDB. The experimental results have been revised eitherbecause of a later publication by the same authors or becauseof a personal communication. In the CPDB, we give the samereference number to the experiment in all plot publications.

k For interim and serial sacrifice experiments, we have reported,as a separate experiment with a "k" notecode, each sacrificetime that otherwise met the inclusion rules of the database.Wherever possible, we have included unscheduled deaths withthe terminal sacrifice data, and when this has been done, thereis no "k" notecode for the terminal sacrifice experiment.

m The calculated dose level for a group is an average of either (1)different doses administered to individual animals, or (2) therange of doses administered.

r Restricted site analysis; the authors either examined or chose toreport data for only a few selected tissues.

s Authors noted that survival was decreased because of toxicity,disease, or accidental death.

v Variable or irregular dosing schedules have been used, e.g.,dose level changed during the experiment.

w For nonhuman primates, denominators for tumor incidence on theplot represent the number alive at the age of the first tumor of thattype; since that age varies for different tumor types, denominatorson the plot for control and dosed animals can vary widely from onesite to another within an experiment. Only a few chemicals weretested at more than one dose level; we use the symbol "-/-" toindicate that for one of the dose groups all animals were deadbefore the occurrence of tumors of that type in another group. Themaximum number of animals used in any TD50 for an experiment isindicated by the denominator of the tumor incidence for "all tumor-bearing animals" ("tba" on the plot) and represents the numberalive at the first tumor in any group.

W Tumors in control monkeys that lived longer than the last dosedanimal in the experiment are deleted from the analysis. SeeAppendix 1 for details on monkey experiments.

Appendix 7. Dose Response Curve andPlot SymbolsCode Dose-Response Curve

* consistent with linearity/ significant departure from linearity, upward curvature\ significant departure from linearity, downward curvatureZ significant departure from linearity, more than three dose

groups including controlsblank either no dose-related effect, or no curve shape could be deter-

mined because experiment had only two dose groups includingcontrols

Code Plot symbol+ TD50p<0.01+ TD500.01 <p<0.1<+ 100% of dosed animals had the tumor on this line of the plot> For all TD50s in the experiment p > 0.10

99% confidence limits for lifetable TD5099% confidence limits for summary TD50

() Length of the experiment is less than 1/2 the standard life spanor exposure is less than 1/4 the standard life span. The casesare primarily a) of borderline lengths, b) stop-exposure tests ofNTP in addition to a 2-year bioassay, c) or NCI monkey studiesfor which length criteria of the CPDB have been relaxed.

Appendix 8. Author's OpinionCode Author's Opinion for Each Site

c NTP evaluation is clear evidence of carcinogenic activity, i.e.,"studies that are interpreted as showing a dose-related (i)increase of malignant neoplasms, (ii) increase of a combinationof malignant and benign neoplasms, or (iii) marked increase ofbenign neoplasms if there is an indication from this or otherstudies of the ability of such tumors to progress to malignancy."

e NTP evaluation is equivocal evidence of carcinogenic activity,i.e. "studies that are interpreted as showing a marginal increaseof neoplasms that may be chemically related."

p NTP evaluation is some evidence of carcinogenic activity, i.e."studies that are interpreted as showing a chemically relatedincreased incidence of neoplasms (malignant, benign, or com-bined) in which the strength of the response is less than thatrequired for clear evidence."

+ Author in general literature evaluated site as positive.- NTP evaluation is no evidence of carcinogenic activity, i.e.

"studies that are interpreted as showing no chemically relatedincreases in malignant or benign neoplasms." In the general lit-erature author evaluated the site as negative.

blank For NTP and general literature: a site for which no opinion is stated.

Appendix 9. Berkeley CodesCode Definitions of Berkeley Codes for NCI/NTP

C The TD50 includes all animals with a tumor at any site with a"c" opinion. The mix was created for the CPDB, and MXBappears on the left side of the plot.

S The TD50 has been included in the plot because the sites werestatistically significant in the tables of analyses of primarytumors and the TD50 was significant at the p < 0.05 level; how-ever, the NCI/NTP report did not evaluate the site as evidenceof carcinogenicity.


GOLD ET AL.

Appendix 10. JournalsCode Reference

acot Acta Otolaryngologicaajim American Journal of Industrial Medicineanya Annals of the New York Academy of Sciencesartx Archives of Toxicologyarzn Arzneimittel-Forschungcanr Cancer Researchcarc Carcinogenesiscebp Cancer Epidemiology, Biomarkers & Preventionclet Cancer letters

cmde Carcinogenic and Mutagenic Effects of Diesel Engine Exhaust (NIshinishi, A Koizumi, RO McClellan, W Stober, eds). NewYork:Elsevier Science, 1986.

dact Drug and Chemical Toxicologyeaes Ecotoxicology and Environmental Safetyejca European Journal of Cancer and Clinical Oncology (formerly

European Journal of Cancer, until 1982)enhp Environmental Health Perspectivesextp Experimental and Toxicologic Pathologyfaat Fundamental and Applied Toxicology (journal name changed to

Toxicological Sciences in December 1997)fctx Food and Chemical Toxicology (formerly Food and Cosmetics

Toxicology, until 1982)gann Japanese Journal of Cancer Research (formerly Gann until 1984)ijcn International Journal of Cancer (formerly International Union

Against Cancer until 1964)indh Industrial Healthjact Journal of the American College of Toxicologyjapt Journal of Applied Toxicologyjnci Journal of the National Cancer Institute (U.S. National Cancer

Institute Journal)jtxe Journal of Toxicology and Environmental Healthjtxs Journal of Toxicological Sciencesonco Oncologyoncr Oncology Reportsossc Organ and Species Specificity in Chemical Carcinogenesis

(R Langenbach, S Nesnow JM Rice, eds). New York:PlenumPress, 1 982.

phrm Pharmacometricsphtx Pharmacology & Toxicologypseb Proceedings of the Society for Experimental Biology and

Medicine (New York)rtxp Regulatory Toxicology and Pharmacologystnd Safety Testing of New Drugs: Laboratory Predictions and Clinical

Performance (DR Laurence, AEM McLean, M Weatherall, eds),Orlando, FL:Academic Press, 1984.

tcam Teratogenesis, Carcinogenesis, and Mutagenesistxap Toxicology and Applied Pharmacologytxcy Toxicologytxih Toxicology and Industrial Healthtxit Toxicology Letterstxpy Toxicologic Pathology

Appendix 1 1. Chemical Names and Synonymsin this PlotCAS Number Chemical Name

p

53-96-3 2-AAF (see 2-ACETYLAMINOFLUORENE)75-05-8 ACETONITRILE53-96-3 2-ACETYLAMINOFLUORENE

304-28-9 2,7-ACETYLAMINOFLUORENE107-02-8 ACROLEIN79-10-7 ACRYLIC ACID

2321 4-92-8 ADRIAMYCIN1162-65-8 AFLATOXIN Bi

64-17-5 ALCOHOL (see ETHYL ALCOHOL)81-49-2 1 -AMINO-2,4-DIBROMOANTHRAQUINONE

77500-04-0 2-AMINO-3,8-DIMETHYLIMIDAZO[4,5-f] QUINOXALINE(see MelQx)2-AMINO-1-METHYL-6-PHENYLIMIDAZO [4,5-bl-PYRI-DINE.HCI (see PhIP.HCI)2-AM NO-3-METHYL-9H-PYRI DO-[2,3-b]-1 N DOLEACETATE (see MeA-alpha-C ACETATE)

76180-96-6 2-AMINO-3-METHYLIMIDAZO[4,5-f] QUINOLINE (see 10)60-32-2 6-AMINOCAPROIC ACID60-80-0 ANTIPYRINE (see PHENAZONE)

7631-89-2 ARSENATE, SODIUM50-81-7 L-ASCORBIC ACID50-78-2 ASPIRIN

51706-40-2 DL-ATENOLOL.HCI42583-61-7 ATEROMIXOL (see POLICOSANOL)446-86-6 AZATHIOPRINE

54896-26-0 BENZALAZINE71-43-2 BENZENE65-85-0 BENZOIC ACID98-07-7 BENZOTRICHLORIDE

622-78-6 BENZYL ISOTHIOCYANATE3012-37-1 BENZYL THIOCYANATE25013-16-5 BHA (see BUTYLATED HYDROXYANISOLE)3296-90-0 2,2-BIS(BROMOMETHYL)-1 ,3-PROPANEDIOL, TECHNI-

CAL GRADE6731-86-8 1,1 -BIS(tert-BUTYLPEROXY)-3,3,5-TRIMETHYLCYCLO-

HEXANE22260-51-1 BROMOCRIPTINE MESYLATE

98-07-7 BTC (see BENZOTRICHLORIDE)75-65-0 tert-BUTYL ALCOHOL

25013-16-5 2(3)-tert-BUTYL-4-HYDROXYANISOLE (see BUTYLATEDHYDROXYANISOLE)

25013-16-5 BUTYLATED HYDROXYANISOLE732-26-3 2,4,6-TRI-tert-BUTYLPHENOL58-08-2 CAFFEINE

33433-82-8 CALCIUM VALPROATE59721-29-8 CAMOSTAT MESYLATE2425-06-1 CAPTAFOL133-06-2 CAPTAN120-80-9 CATECHOL57-74-9 CHLORDANE, TECHNICAL GRADE

CHLORINATED WATER50892-23-4 [4-CHLORO-6-(2,3-XYLIDINO)-2-PYRIMIDINYLTHIO]-

ACETIC ACID77-92-9 CITRIC ACID76-57-3 CODEINE

51630-58-1 CYANO-(3-PHENOXYPHENYL)METHYL-4-CHLORO-alpha-(1-METHYLETHYL) BENZENE ACETATE (see FEN-VALERATE)

mixture CYCASIN AND METHYLAZOXYMETHANOL ACETATE(CAS NUMBER 592-62-1 and 14901-08-7)


2

j

r

2

r

2

r

2

c

r

r.

594


CAS Number Chemical Name139-05-9 CYCLAMATE, SODIUM50-1 8-0 CYCLOPHOSPHAMIDE50-18-0 CYTOXAN (see CYCLOPHOSPHAMIDE)60-11-7 DAB (see N,N-DIMETHYL-4-AMINOAZOBENZENE)79-43-6 DCA (see DICHLOROACETIC ACID)50-29-3 DDT117-81-7 DEHP (see DI(2-ETHYLHEXYL) PHTHALATE)53-43-0 DEHYDROEPIANDROSTERONE

141-05-9 DEM (see DIETHYLMALEATE)55-18-5 DEN (see N-NITROSODIETHYLAMINE)56-53-1 DES (see DIETHYLSTILBESTROL)50-02-2 DEXAMETHAZONE

3296-90-0 DIBROMONEOPENTYL GLYCOL (see 2,2-BIS(BRO-MOMETHYL)-1,3-PROPANEDIOL, TECHNICAL GRADE)

79-43-6 DICHLOROACETIC ACID106-46-7 1,4-DICHLOROBENZENE75-09-2 DICHLOROMETHANE (see METHYLENE CHLORIDE)56-53-1 4,4'-(1,2-DIETHYL-1,2-ETHENEDIYL)BIS-PHENOL (see

DIETHYLSTILBESTROL)41340-25-4 1,8-DIETHYL-1,3,4,9-TETRAHYDROPYRANO-[3,4-

6]1INDOLE-1-ACETIC ACID (see ETODOLAC)141-05-9 DIETHYLMALEATE55-18-5 DIETHYLNITROSAMINE (see N-NITROSODIETHYLAMINE)56-53-1 DIETHYLSTILBESTROL

70052-1 2-9 2-(DIFLUOROMETHYL)-DL-ORNITHINE120-80-9 1,2-DIHYDROXYBENZENE (see CATECHOL)60-11-7 N,N-DIMETHYL-4-AMINOAZOBENZENE68-12-2 DIMETHYLFORMAMIDE62-75-9 DIMETHYLNITROSAMINE (see N-NITROSODIMETHYL-

AMINE)29110-68-7 2,4-DINITRO-6-tert-BUTYLPHENYL METHANESUL-

FONATE606-20-2 2,6-DINITROTOLUENE121-14-2 2,4-DINITROTOLUENE (CONTAINING 1.0-1.5% 2,6-

DINITROTOLUENE)57-41-0 5,5-DIPHENYLHYDANTOIN

621-64-7 DIPROPYLNITROSAMINE (see N-NITROSODIPRO-PYLAMINE)

62-75-9 DMN (see N-NITROSODIMETHYLAMINE)3-0-DODECYLCARBOMETHYLASCORBIC ACID

562-10-7 DOXYLAMINE SUCCINATE3604-87-3 alpha-ECDYSONE476-66-4 ELLAGIC ACID50-18-0 ENDOXAN (see CYCLOPHOSPHAMIDE)

989-51-5 (-)-EPIGALLOCATECHIN GALLATE (85% (-)-EPIGALLO-CATECHIN GALLATE, 10% (-)-EPIGALLOCATECHIN, 5%(-)-EPICATECHIN GALLATE)

57-63-6 ETHINYL ESTRADIOL91-53-2 ETHOXYQUIN140-88-5 ETHYL ACRYLATE64-17-5 ETHYL ALCOHOL51-79-6 ETHYL CARBAMATE (see URETHANE)

86404-04-8 3-0-ETHYLASCORBIC ACID100-41-4 ETHYLBENZENE117-81-7 DI(2-ETHYLHEXYL)PHTHALATE

41 340-25-4 ETODOLAC77-09-8 EX-LAX (see PHENOLPHTHALEIN)

51630-58-1 FENVALERATE2338-05-8 FERRIC CITRATE TETRAHYDRATE

98319-26-7 FINASTERIDE86386-73-4 FLUCONAZOLE

53-96-3 FLUORENYLACETAMIDE (see 2-ACETYLAMINO-FLUORENE)

CAS Number Chemical Name53-96-3 N-2-FLUORENYLACETAMIDE (see 2-ACETYLAMINO-

FLUORENE)93957-54-1 FLUVASTATIN

133-07-3 FOLPET (see N-(TRICHLOROMETHYLTHIO)PHTHALIMIDE)50-00-0 FORMALDEHYDE

59721-29-8 FOY 305 (see CAMOSTAT MESYLATE)3296-90-0 FR-1 138 (see 2,2-BIS(BROMOMETHYL)-1,3-PROPANE-

DIOL, TECHNICAL GRADE)75-09-2 FREON 30 (see METHYLENE CHLORIDE)

149-91-7 GALLIC ACID118-74-1 HCB (see HEXACHLOROBENZENE)

29110-68-7 HE 166 (see 2,4-DINITRO-6-tert-BUTYLPHENYLMETHANESULFONATE)

118-74-1 HEXACHLOROBENZENE148081-72-5 1 -O-HEXYL-2,3,5-TRIMETHYLHYDROQUINONE64896-26-0 (2-HYDROXY-5-[(4-CARBOXYPHENYL) AZO]BENZOIC

ACID (see BENZALAZINE)446-86-6 IMURAN (see AZATHIOPRINE)53-86-1 INDOMETHACIN

115436-74-3 IPAZILIDE FUMARATE761 80-96-6 10

542-56-3 ISOBUTYL NITRITE78-79-5 ISOPRENE

123482-23-5 LY277359 MALEATE (see ZATOSETRON MALEATE)mixture MAM ACETATE AND CYCASIN (see CYCASIN AND

METHYLAZOXYMETHANOL ACETATE)1972-08-3 MARINOL (see 1-trans-delta9-TETRAHYDRO-

CANNABINOL)MeA-alpha-C ACETATE

77500-04-0 MelOx148-82-3 MELPHALAN

2425-06-1 MERPAFOL (see CAPTAFOL)934-00-9 3-METHOXYCATECHOL150-76-5 4-METHOXYPHENOL78-79-5 2-METHYL-1,3-BUTADIENE (see ISOPRENE)

1634-04-4 METHYL tert-BUTYL ETHER75-05-8 METHYL CYANIDE (see ACETONITRILE)55-80-1 3'-METHYL-4-DIMETHYLAMINOAZOBENZENE70-25-7 N-METHYL-N'-NITRO-N-NITROSOGUANIDINE

684-93-5 N-METHYL-N-NITROSOUREA (see N-NITROSO-N-METHYLUREA)

75-65-0 2-METHYL-2-PROPANOL (see tert-BUTYL ALCOHOL)mixture METHYLAZOXYMETHANOL ACETATE AND CYCASIN

MIXTURE (see CYCASIN AND METHYLAZOXY-METHANOL ACETATE)

452-86-8 4-METHYLCATECHOL56-49-5 METHYLCHOLANTHRENE (see 3-METHYLCHOLAN-

THRENE)56-49-5 3-METHYLCHOLANTHRENE75-09-2 METHYLENE CHLORIDE

119-47-1 2,2'-METHYLENEBIS(4-METHYL-6-tert-BUTYLPHENOL)90-12-0 1-METHYLNAPHTHALENE

64091-91-4 4-(M ETHYLN ITROSAM I NO)-1 -(3-PYR I DYL)- 1 -

(BUTANONE)298-59-9 METHYLPHENIDATE.HCI70-25-7 MNNG (see N-METHYL-N'-NITRO-N-NITROSOGUANI-

DINE)684-93-5 MNU (see N-NITROSO-N-METHYLUREA)79-11-8 MONOCHLOROACETIC ACID108-88-3 MONOMETHYL BENZENE (see TOLUENE)76-57-3 MORPHINE MONOMETHYL ETHER (see CODEINE)

1634-04-4 MTBE (see METHYL tert-BUTYL ETHER)3771-19-5 NAFENOPIN


GOLD ETAL

CAS Number Chemical Name389-08-2 NALIDIXIC ACID

77191-36-7 NEFIRACETAM10101-97-0 NICKEL (II) SULFATE HEXAHYDRATE10101-97-0 NICKELOUS SULFATE (see NICKEL (II) SULFATE HEXA-

HYDRATE)7632-00-0 NITRITE, SODIUM

98-95-3 NITROBENZENE79-24-3 NITROETHANE

10102-44-0 NITROGEN DIOXIDE5522-43-0 1 -NITROPYRENE684-93-5 N-NITROSO-N-METHYLUREA55-18-5 N-NITROSODIETHYLAMINE62-75-9 N-NITROSODIMETHYLAMINE

621-64-7 N-NITROSODIPROPYLAMINE932-83-2 N-NITROSOHEXAMETHYLENEIMINE684-93-5 NITROSOMETHYLUREA (see N-NITROSO-N-

METHYLUREA)100-75-4 N-NITROSOPIPERIDINE

64091-91-4 NNK (see 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-(BUTANONE))

29082-74-4 OCTACHLOROSTYRENE117-81-7 DI-sec-OCTYL PHTHALATE (see DI(2-ETHYlHEXYl)-

PHTHALATE)64224-21-1 OLTIPRAZ

154-85-8 OROTIC ACID, MONOSODIUM SALT11042-64-1 gamma-ORYZANOL14698-29-4 OXOLINIC ACID10028-15-6 OZONE

148-82-3 L-PAM (see MELPHALAN)22260-51-1 PARLODEL (see BROMOCRIPTINE MESYLATE)

60-80-0 PHENAZONE2257-09-2 PHENETHYL ISOTHIOCYANATE

50-06-6 PHENOBARBITAL57-30-7 PHENOBARBITAL, SODIUM50-06-6 PHENOBARBITONE (see PHENOBARBITAL)57-30-7 PHENOBARBITONE, SODIUM (see PHENOBARBITAL,

SODIUM)77-09-8 PHENOLPHTHALEIN50-06-6 PHENYLETHYLBARBITURIC ACID (see PHENOBARBITAL)

133920-06-6 6-PHENYLHEXYL ISOTHIOCYANATE57-41-0 PHENYTOIN (see 5,5-DIPHENYLHYDANTOIN)

PhIP.HCI51-03-6 PIPERONYL BUTOXIDE

142583-61-7 POLICOSANOL298-14-6 POTASSIUM BICARBONATE

7447-40-7 POTASSIUM CHLORIDE366-70-1 PROCARBAZINE.HCI318-98-9 PROPRANOLOL.HCI621-64-7 DI-N-PROPYlNITROSAMINE (see N-NITROSODI-

PROPYLAMINE)59-33-6 PYRILAMINE MALEATE

127-47-9 RETINOL ACETATE298-59-9 RITALIN (see METHYLPHENIDATE.HCI)128-44-9 SACCHARIN, SODIUM148-82-3 L-SARCOLYSIN (see MELPHALAN)

SDZ 200-11 07647-14-5 SODIUM CHLORIDE

28302-36-5 SODIUM COPPER CHLOROPHYLLIN139-05-9 SODIUM CYCLAMATE (see CYCLAMATE, SODIUM)

10588-01-9 SODIUM DICHROMATE7632-00-0 SODIUM NITRITE (see NITRITE, SODIUM)10048-13-2 STERIGMATOCYSTIN54965-24-1 TAMOXIFEN CITRATE

CAS Number Chemical Name1401-55-4 TANNIC ACIDS, PHARMACEUTICAL GRADE (85.69%

TANNIC ACIDS, 8.84% GALLIC ACIDS)76-03-9 TCA (see TRICHLOROACETIC ACID)79-01-6 TCE (see TRICHLOROETHYLENE (WITHOUT EPICHLORO-

HYDRIN))1972-08-3 1 -trans-delta9-TETRAHYDROCANNABINOL1972-08-3 THC (see 1-trans-delta9-TETRAHYDROCANNABINOL)148-79-8 THIABENDAZOLE148-79-8 2-(4-THIAZOLYL)-BENZIMAZOLE (see THIABENDAZOLE)108-88-3 TOLUENE

26471-62-5 TOLUENE DIISOCYANATE, COMMERCIAL GRADE (2,4(80%)- AND 2,6(20%)-)

89778-26-7 TOREMIFENE CITRATE76-03-9 TRICHLOROACETIC ACID79-01-6 TRICHLOROETHYLENE (WITHOUT EPICHLOROHYDRIN)

133-07-3 N-(TRICHLOROMETHYLTHIO) PHTHALIMIDE1582-09-8 TRIFLURALIN, TECHNICAL GRADE

95-63-6 1,2,4-TRIMETHYLBENZENE58-08-2 1,3,7-TRIMETHYLXANTHINE (see CAFFEINE)

6138-79-0 TRIPROLIDINE.HCI MONOHYDRATE51-79-6 URETHANE

27774-13-6 VANADYL SULFATE108-05-4 VINYL ACETATE127-47-9 VITAMIN A, ACETATE (see RETINOL ACETATE)50-81-7 VITAMIN C (see L-ASCORBIC ACID)

115436-74-3 WIN 54177-4 (see IPAZILIDE FUMARATE)50892-23-4 WY14643 (see [4-CHLORO-6-(2,3-XYLIDINO)-2-

PYRIMIDINYLTHIO] ACETIC ACID)mixture XYLENE MIXTURE (50.31% m-XYLENE, 26.9% o-

XYLENE, 22.24% p-XYLENE) (CAS NUMBER 108-38-3,95-47-6, and 106-42-3)

60-11-7 BUTTER YELLOW (see N,N-DIMETHYL-4-AMINOAZO-BENZENE)

123482-23-5 ZATOSETRON MALEATECAS NUMBER = Chemical Abstracts Service registry number

Appendix 12. Chemical Names in this PlotListed by CAS NumberCAS Number Chemical Name

mixture XYLENE MIXTURE (50.31% m-XYLENE, 26.9% o-XYLENE,22.24% p-XYLENE) (CAS NUMBER 108-38-3, 95-47-6,and 106-42-3)

mixture CYCASIN AND METHYLAZOXYMETHANOL ACETATE(CAS NUMBER 592-62-1 and 14901-08-7)

50-00-0 FORMALDEHYDE50-02-2 DEXAMETHAZONE50-06-6 PHENOBARBITAL (phenobarbitone)50-18-0 CYCLOPHOSPHAMIDE (endoxan)50-29-3 DDT50-78-2 ASPIRIN50-81-7 L-ASCORBIC ACID (vitamin C)51-03-6 PIPERONYL BUTOXIDE51-79-6 URETHANE (ethyl carbamate)53-43-0 DEHYDROEPIANDROSTERONE53-86-1 INDOMETHACIN53-96-3 2-ACETYLAMINOFLUORENE (N-2-fluorenylacetamide,

2-AAF)55-18-5 N-NITROSODIETHYLAMINE (DEN)55-80-1 3'-METHYL-4-DIMETHYLAMINOAZOBENZENE56-49-5 3-METHYLCHOLANTHRENE56-53-1 DIETHYLSTILBESTROL (DES)57-30-7 PHENOBARBITAL, SODIUM (phenobarbitone, sodium)



5,5-DIPHENYLHYDANTOIN (phenytoin)ETHINYL ESTRADIOLCHLORDANE, TECHNICAL GRADECAFFEINEPYRILAMINE MALEATEN,N-DIMETHYL-4-AMINOAZOBENZENE (butter yellow)6-AMINOCAPROIC ACIDPHENAZONEN-NITROSODIMETHYLAMINE (DMN)ETHYL ALCOHOLBENZOIC ACIDDIMETHYLFORMAMIDEN-METHYL-N'-NITRO-N-NITROSOGUANIDINE (MNNG)BENZENEACETONITRILE (methyl cyanide)METHYLENE CHLORIDE (dichloromethane, Freon 30)tert-BUTYL ALCOHOLTRICHLOROACETIC ACIDCODEINEPHENOLPHTHALEIN (Ex-Lax)CITRIC ACIDISOPRENE (2-methyl-1,3-butadiene)TRICHLOROETHYLENE (WITHOUT EPICHLOROHYDRIN)(TCE)ACRYLIC ACIDMONOCHLOROACETIC ACIDNITROETHANEDICHLOROACETIC ACID1 -AMINO-2,4-DIBROMOANTHRAQUINONE1 -METHYLNAPHTHALENEETHOXYQUIN1 ,2,4-TRIMETHYLBENZENEBENZOTRICHLORIDE (BTC)NITROBENZENEETHYLBENZENEN-NITROSOPIPERIDINE1 ,4-DICHLOROBENZENEACROLEINVINYL ACETATETOLUENE (monomethyl benzene)DI(2-ETHYLHEXYL)PHTHALATE (di-sec-octyl phthalate,DEHP)HEXACHLOROBENZENE2,2'-METHYLENEBIS(4-METHYL-6-tert-BUTYLPHENOL)CATECHOL (1,2-dihydroxybenzene)2,4-DINITROTOLUENE (CONTAINING 1.0-1.5% 2,6-DINITROTOLUENE)RETINOL ACETATE (vitamin A, acetate)SACCHARIN, SODIUMCAPTANN-(TRICHLOROMETHYLTHIO) PHTHALIMIDE (folpet)CYCLAMATE, SODIUMETHYL ACRYLATEDIETHYLMALEATETHIABENDAZOLE (2-(4-thiazolyl)-benzimazole)MELPHALAN (L-sarcolysin)GALLIC ACID4-METHOXYPHENOLOROTIC ACID, MONOSODIUM SALTPOTASSIUM BICARBONATEMETHYLPHENIDATE.HCI (ritalin)2,7-ACETYLAMINOFLUORENEPROPRANOLOL.HCI

CAS Number Chemical Name366-70-1 PROCARBAZINE.HCI389-08-2 NALIDIXIC ACID446-86-6 AZATHIOPRINE (imuran)452-86-8 4-METHYLCATECHOL476-66-4 ELLAGIC ACID542-56-3 ISOBUTYL NITRITE562-10-7 DOXYLAMINE SUCCINATE606-20-2 2,6-DINITROTOLUENE621-64-7 N-NITROSODIPROPYLAMINE622-78-6 BENZYL ISOTHIOCYANATE684-93-5 N-NITROSO-N-METHYLUREA732-26-3 2,4,6-TRI-tert-BUTYLPHENOL932-83-2 N-NITROSOHEXAMETHYLENEIMINE934-00-9 3-METHOXYCATECHOL989-51-5 (-)-EPIGALLOCATECHIN GALLATE (85% (-)-EPIGALLO-

CATECHIN GALLATE, 10% (-)-EPIGALLOCATECHIN, 5%(-)-EPICATECHIN GALLATE)

1162-65-8 AFLATOXIN Bi1401-55-4 TANNIC ACIDS, PHARMACEUTICAL GRADE (85.69%

TANNIC ACIDS, 8.84% GALLIC ACIDS)1582-09-8 TRIFLURALIN, TECHNICAL GRADE1634-04-4 METHYL tert-BUTYL ETHER (MTBE)1972-08-3 1 -trans-delta9-TETRAHYDROCANNABINOL2257-09-2 PHENETHYL ISOTHIOCYANATE2338-05-8 FERRIC CITRATE TETRAHYDRATE2425-06-1 CAPTAFOL3012-37-1 BENZYL THIOCYANATE3296-90-0 2,2-BIS(BROMOMETHYL)-1 ,3-PROPANEDIOL, TECHNI-

CAL GRADE (DIBROMONEOPENTYL GLYCOL)3604-87-3 alpha-ECDYSONE3771-19-5 NAFENOPIN5522-43-0 1 -NITROPYRENE6138-79-0 TRIPROLIDINE.HCI MONOHYDRATE6731-86-8 1,1 -BIS(tert-BUTYLPEROXY)-3,3,5-TRIMETHYLCYCLO-

HEXANE7447-40-7 POTASSIUM CHLORIDE7631-89-2 ARSENATE, SODIUM7632-00-0 NITRITE, SODIUM7647-14-5 SODIUM CHLORIDE10028-15-6 OZONE10048-13-2 STERIGMATOCYSTIN10101-97-0 NICKEL (II) SULFATE HEXAHYDRATE10102-44-0 NITROGEN DIOXIDE10588-01-9 SODIUM DICHROMATE11042-64-1 gamma-ORYZANOL14698-29-4 OXOLINIC ACID22260-51-1 BROMOCRIPTINE MESYLATE (Parlodel)23214-92-8 ADRIAMYCIN25013-16-5 BUTYLATED HYDROXYANISOLE (BHA, 2(3)-tert-butyl-4-

hydroxyanisole)26471-62-5 TOLUENE DIISOCYANATE, COMMERCIAL GRADE (2,4

(80%)- AND 2,6(20%)-)27774-13-6 VANADYL SULFATE28302-36-5 SODIUM COPPER CHLOROPHYLLIN29082-74-4 OCTACHLOROSTYRENE29110-68-7 2,4-DINITRO-6-tert-BUTYLPHENYL METHANESULFONATE

(HE 166)33433-82-8 CALCIUM VALPROATE41340-25-4 ETODOLAC (1,8-diethyI-1,3,4,9-tetrahydropyrano-[3,4-

6Jindole-1 -acetic acid)50892-23-4 [4-CHLORO-6-(2,3-XYLIDINO)-2-PYRIMIDINYLTHIO]-

ACETIC ACID (WY14643)


CAS Number Chemical Name57-41-057-63-657-74-958-08-259-33-660-11-760-32-260-80-062-75-964-17-565-85-068-12-270-25-771-43-275-05-875-09-275-65-076-03-976-57-377-09-877-92-978-79-579-01-6

79-10-779-11-879-24-379-43-681-49-290-12-091-53-295-63-698-07-798-95-3

100-41 -4100-75-4106-46-7107-02-8108-05-4108-88-3117-81 -7

118-74-1119-47-1120-80-9121 -14-2

127-47-9128-44-9133-06-2133-07-3139-05-9140-88-5141-05-9148-79-8148-82-3149-91 -7150-76-5154-85-8298-14-6298-59-9304-28-9318-98-9

597

GOLD ET AL.

CAS Number Chemical Name51630-58-1 FENVALERATE (cyano-(3-phenoxyphenyl) methyl-4-

chloro-alpha-(1-methylethyl) benzene acetate)51706-40-2 DL-ATENOLOL.HCI54965-24-1 TAMOXIFEN CITRATE59721-29-8 CAMOSTAT MESYLATE (FOY 305)64091-91-4 4-(METHYLNITROSAMINO)-1 -(3-PYRIDYL)-1 -(BUTANONE)

(NNK)64224-21-1 OLTIPRAZ64896-26-0 BENZALAZINE (2-hydroxy-5-[(4-carboxyphenyl)azolben-

zoic acid)70052-12-9 2-(DIFLUOROMETHYL)-DL-ORNITHINE76180-96-6 IQ (2-amino-3-methylimidazo[4,5-f]quinoline)77191-36-7 NEFIRACETAM77500-04-0 MelQx (2-amino-3,8-dimethylimidazo[4,5-fjquinoxaline)86386-73-4 FLUCONAZOLE86404-04-8 3-0-ETHYLASCORBIC ACID89778-26-7 TOREMIFENE CITRATE93957-54-1 FLUVASTATIN98319-26-7 FINASTERIDE

115436-74-3 IPAZILIDE FUMARATE (WIN 54177-4)123482-23-5 ZATOSETRON MALEATE (LY277359 maleate)133920-06-6 6-PHENYLHEXYL ISOTHIOCYANATE142583-61-7 POLICOSANOL (ateromixol)148081-72-5 1 -O-HEXYL-2,3,5-TRIMETHYLHYDROQUINONE

CHLORINATED WATERMeA-alpha-C ACETATE (2-amino-3-methyl-9H-pyrido-[2,3-b]-indole acetate)PhlP.HCI (2-amino-1-methyl-6-phenylimidazo[4,5-bl-pyri-dine.HCI)3-0-DODECYLCARBOMETHYLASCORBIC ACIDSDZ 200-11 0

CAS NUMBER = Chemical Abstracts Service registry number.

Appendix 13. Bibliography: NationalToxicology Program Technical Reports

Technical PublicationChemical name Report number dateAcetonitrile TR447 19961 -Amino-2,4-dibromoanthraquinone TR383 19962,2-Bis(bromomethyl)-1,3-propanediol TR452 1996tert-Butyl alcohol TR436 1995Codeine TR455 1996Isobutyl nitrite TR448 1996Isoprenea TX31 1995Methylphenidate.HCI TR439 1995Nickel sulfate hexahydrate TR454 1996Phenolphthalein TR465 19961 -trans-69-Tetrahydrocannabinol TR446 1996aThe isoprene test in mice was reported in the NTP Toxicity Reportseries (indicated by "TX"), rather than the Techincal Report series (indi-cated by "TR"). Additional information for our analyses was reported inMelnick et al. (91) which is referenced in Appendix 14.

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