FOREWORD 

The National Toxicology Program (NTP)is made up of four charter agencies of the U.S. Department of Health 

a:nd Human Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the National 

Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for 

Toxicological Research (NCTR), Food and Drug Administration; and the National Institute for Occupational 

Safety and Health (NIOSH), Centersfor Disease Control. In July 1981, the Carcinogenesis Bioassay Testing 

Program, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs,staff, and resources 

from these Public HealthService agencies relating to basic and applied research andto biological assay 

dlevelopment and validation. 

The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardous 

chemicals. This knowledge is used for protecting the health of the American people andfor the primary 

pirevention of disease. 

The studies described in thisTechnical Report were performed under the directionf the NIEHS and were 

conducted in compliance with NTP laboratory health and safety requirements and must meet or exceed all 

applicable federal, state, and local health and safety regulations. Animalcare and use were in accordance with 

thle Public Health Service Policy on Humane Care and Use of Animals. The prechronic and chronic studies 

were conducted in compliance with Food and Drug Administration(FDA) Good Laboratory Practice 

Regulations, and all aspects of the chronic studies were subjectedto retrospective quality assurance audits 

before being presented for public review. 

These studies are designed and conducted to characterize and evaluate the toxicologic potential, including 

carcinogenic activity, of selected chemicals in laboratory animals (usually two species, rats and mice). 

Chemicals selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of human 

exposure, level of production, and chemical structure. The interpretive conclusions presented in this Technical 

Report are based only on the results of these NTP studies. Extrapolation of these results to other species and 

quantitativerisk analyses for humans require wider analyses beyond the purviewof these studies. Selection 

per se is not an indicator of a chemical’s carcinogenic potential. 

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of this Technical Report are available without charge while supplieslast from NTP Central Data Management, 

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published NTP reports and ongoing studies arealso available from NTP Central Data Management. The 

. Abstracts and other study information for 2-year studies are also available at the NTP’s World Wide Web site: 

http://ntp-server.niehs.nih.gov. 

1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

CONTRIBUTORS 

National Toxicology Program 

Evaluated and interpreted results andreportedfindings 

R.D.&in,Ph.D., StudyScientist ' 

G.A. Boorman, D.V.M., Ph.D. 

D.A. Bridge, B.S. . .I. 

J.R. Bucher, Ph.D. 

L.T. Burka, Ph.D. .. , 

R.E. Chapin, Ph.D. 

M.R. Elwell;D.V.M., Ph.D. 

J.R., Hailey, D.V.M. 

J.K. Haseman, Ph.D. 

A. Radovsky, D.V.M., Ph.D. 

G.N. Rao, D..V.M., Ph.D. 

'J.H. Roycroft, Ph.D. 

G.S. Travlos, D.V.M. 

D.B. Walters, Ph.D. 

K;L. Witt, M.S., Oak Ridge Associated Universities 

Southern Research Institute 

Conducted 13-week studies, evaluated pathologyPndings 

J.D. Prejean, Ph.D., Principal Investigator 

J.E. Heath, D.V.M. 

A.G. Manus, D.V.M. . ,

R.B. Thompson, D.V.M., Ph.D. ,. ! 

TSIMasonLaboratories . "* .. 

Conducted 1- and 2-year studies, evaluated pathology ,findings 

A.G. Braun, Sc.D., Principal Investigator 

M.R. Osheroff, Ph. D., PrincipalInvestigator ' 

C. Gamba-Vitalo, Ph.D. 

M.E.P. Goad, D.V.M., Ph.D. .. 

J.L. Levin, D.V.M. . -

S.M. Niemi, D.V.M. 

R..Norlin, M.S. 

L.E. Sendelbach, Ph.D. 

F;A. Voelker, M.S., D.V.M. 

Experimental Pathology Laboratories, Inc. 

Provided pathology quality assurance 

J.F. Hardisty, D.V:M., Principal Investigator 

S:Botts, D.V.M., Ph.D. 

E.T. Gaillard, D.V.M., M.S. 

Dynamac Corporation 

Prepared quality assurance audits 

S. Brecher, PbD:, Principal Investigator 

NTP Pathology WorkingGroup 

Evaluated slides, prepared pathology report on rats 

(8September 1994) 

J.C. Seely, D.V.M., Chairperson 

PATHCO, Inc. 

.~ . E.T. Gaillard, D.V.M., MS. 

Experimental Pathology Laboratories, Inc. 

J.R. Hailey, D.V.M. 

National Toxicology Program 

R.A. Herbert, D.V.M., Ph.D. 

National Toxicology Program 

K. Jamison, D.V.M., Ph. D. 

ChemicalIndustry Institute of Toxicology 

J.R. Leininger, D.V.M., Ph.D. 

ChemicalIndustry Institute of Toxicology 

D.S. Marsman, D.V.M., Ph.D. 

National Toxicology Program 

A. Radovsky, D.V.M., Ph.D. 

National Toxicology Program 

Evaluated slides, prepared pathology report on mice(5 May 1994) 

J.C. Seely, D.V.M., Chairperson 

PATHCO, Inc. 

S. Botts, D.V.M., Ph.D. 

Experimental Pathology Laboratories, Inc. 

A. Enomoto, D.V.M. 

National Toxicology Program 

J.R. Hailey, D.V.M. . NationalToxicologyProgram 

R.A. Herbert, D.V.M:, Ph.D. ' 

National Toxicology Program 

J.R. Leininger, D.V.M., Ph.D. 

Chemical Industry Institute of Toxicology 

R.C. Sills, D.V.M., Ph.D. 

National Toxicology Program 

M. Wells, D.V.M. (observer) 

Experimental Pathology Laboratories, Inc.. 

Analytical Sciences, Inc. 

Provided statistical analyses 

R.W. Morris, M.S., Principal Investigator 

N.G. Mintz, B.S. 

S. Rosenblum, MS. 

Biotechnical Services, Inc. 

Prepared Technical Report 

S.R. Gunnels, M.A., Principal Investigator 

J.R. Carlton, B.A. 

T.A. King-Hunter, B.S. 

L.M. Harper, B.S. 

D.C. Serbus, Ph.D. 
3 

CONTIENTS 

ABSTRACT ............................................................................ 5 

EXPLANATIONOF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY.................. 18 

TECHNICAL REPORTS WIEVIEWSUBCOMMITTEE ......................................... . nn 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOM~TTEECO~NTS............. n2 

INTRODUCTION ....................................................................... n3 

MATEIRI[ALSAND METHODS .............................................................. ns 

RESULTS .............................................................................. 31 

DISCUSSIONANDCONCLUSIONS ....................................................... 55 

IWIEFERENCES .......................................................................... 59 

APPENDIXA Summary of Lesions in MaleRats in the %YearDermd Study 

of n.2.Dihydro.2.2. 4.trimet.ylquinolinae ....................................... 63 

APPENDIXB Summary of Lesions in Female Rats in the %YearDermal Study 

of n.2.DiPlydro.2.2. 0.trimet.ylquinoPine ....................................... 107 . . . 

.. 

APPENDIXC Summary of Lesions in Male Mice in the %YearDermal Study .. . . 

of 1.2.DihyBro.2.2. 0-trimetPlylquino.ine ............................... ., ...... ., .. 807 

APPENDIXD Summary of Lesions in Female Mice in the %YearDemal Shdy 

of 1.2.DiPlydro.2.2. 0.trimetPly..uinoline ....................................... 189 

APPENDIXE Summary of Lesions in Female SENCAR Mice in the I-Year Demd 

Initiatioflromotion Study of n.2.DiPlydro.2.2. 0.tr..et.yn.ui.o.inne ................ 229 

APPENDIXF Genetic Toxicology ......................................................... 247

APPENDIXG Organ Weights and Organ-WeigPlt-to-Body-~ei~t Ratios ........................ 257

APPENDIXW Hematology and Clinical Chemistry Results .................................... 265 . . . 

APPENDIXI Reproductive Tissue Evaluations and Estrous Cycle Characteriza~ionn.............. 271 

APPENDIX9 Chemical Characterization and Dose Formulation Studies ........................ 275 

APPENDIXB Ingredients. Nutrient Composition. and Connhminnant Levels 

in NIW-07 Rat and Mouse Ration ............................................ ' 299

APPENDIXL Sentinel Animal Program .................................................... 383 

. . . 
41 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 
5 

H 

CAS NO.147-47-7 

ChemicalFormula: C,,H,,N Molecular Weight: 173.28 

Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline;acetone anil; methylquinoline 

Trade names: Agerite Resin D; Flectol A; Flectol H; Flectol Pastilles; VulkanoxHSLG, Vulkanox HSPowder 

1,2-Dihydro-2,2,4-trimethylquinoline(monomer) is nxwxEK STUDY IN RATS 

used as an antioxidant in styrene-butadiene and nitrile-Groups of 10 male and 10 female F344/N rats were 

butadiene rubbers and latexes. It was nominated by thetopically administered 0, 5 , '20, 50, 100, or 200 mg NationalCancer Institute as part of a review of 

chemicals used in the manufacture and processing of 

rubber, during which potential occupational and consumer exposure to this compound can occur. It was 

selected for evaluation because it is a derivative of 

quinoline, a knownrodentcarcinogen,andwas 

regarded as having potentialcarcinogenicactivity. 

Because of the pattern of use and exposure, dermal 

administration was considered most appropriate. 

MaleandfemaleF344/NratsandB6C3F,mice 

receivedtopicalapplications of 1,2-dihydro-2,2,4-

trimethylquinoline in acetone (greater than90% pure) 

for 13 weeks or 2 years. Groups of female SENCAR 

1,2-dihydro-2,2,4-trimethylquinolinekgbody weight in 

acetone, 5 days per week for 13 weeks. In addition, 

there were 10 male and 10 female untreated controls. 

All rats survived to the end of the study. Final mean 

body weights and mean body weight gains of treated 

maleandfemaleratsweresimilartothose of the 

vehicle controls exceptthose of 200 mgkg males, 

which were significantly lower than those of the vehicle 

controls. The only notableclinicalobservationwas 

skin discoloration of treated rats. In the 200 mgkg 

groups, absolute and relative liver weights of males and 

absolute liver weights of females were significantly 

greater than those of the vehicle controls. There were 

no significant differencesinhematology or clinical 

micereceived 1,2-dihydro-2,2,4-trimethylquinoline chemistry parameters, reproductive tissue parameters, 

(greaterthan 90% pure)during a 1-yeardermal or estrous cycle characterization between treated and 

initiatiodpromotion study to determine the tumor initi-control groups. Histopathologic lesions of the skin at 

ation or promotion potential of the chemical. Genetic the site of applicationincludedacanthosisand 

toxicologystudieswereconductedin Salmonella hyperkeratosis in 100 and 200 mgkg males and 200 

typhimurium,cultured Chinese hamster ovary cells, andmgkg females. vacuolization Cytoplasmic of

mouse peripheral blood cells. hepatocytesof mild tomoderate severity was observed 
i 

f 

I 

4 

6 

in the liversof all 200 mgkg males and was considered 

treatment related. Based on the .incidence and severity 

of'skin and liver lesions observed in200 mgkg rats in 

the 13-week study, 100 mgkg was selected as the high 

dose for the 2-year rat study. 

ISWEEK STUDY IN MICE. ' 

Groups of 10 male and 10 female B6C3Fl mice were 

topicallyadministered 0, 2.5, 5, 10, 20, or 50 mg 

1,:2-dihydro-2,2,4-trimethylquinolinekg body weight in 

acetone, 5 days per week for 13-weeks., In addition, 

there were 10 male and 10 female untreated controls. 

All mice except one 2.5 mgkg female survived to.the 

end of the study. Final mean body weights and mean 

bodyweightgains of male andfemale 'mice were 

similar to thoseof the vehicle controls. There wereno 

treatment-related clinical observations. There. were no 

significant differences between treatedandcontrol 

groups in organ weights,. hematology, and clinical 

ch.emistry parameters, reproductive tissue parameters, 

or estrous cycle characterization. Histopathologic 

lesions of the skin at the site of application included 

acanthosis (epidermal hyperplasia), hyperkeratosis, and 

parakeratosis,all ranging from. ,minimal to mildin 

severity.Minimaltomildfibrosis.andsubchronic 

inflammation were observed in,the dems. Based on 

the incidences and severitiesof skin lesions observed in 

20 and50 mgkg mice in the 13-week study,10mgkg 

was selected as the high ..dose .for. the 2-year mouse ,. . 

. , . study. 

%YEAR STUDY IN RATS :' 

Groups of 60 male and 60 female F344/N rats were 

topicallyadministered 0, 36, 60, or I 100 mg 

1,:2-dihydro-2,2,4-trimethylquinolinekgbody weight in 

acetone, 5 daysperweek for 103 (males) or 104 

(females) weeks. Ten rats per group were evaluated 

after 15months of treatment. 

Survival and Body Weights 

Survival of treated rats was similarto that of controls. 

Mean body weights of 60 mgkg males and100mgkg 

1;2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

females were generally similar to those of the controls 

throughout the study. 

Pathology Findings 

No skin neoplasms were attributed to treatment'with 

1,2-dihydro-2,2,4-trimethylquinoline. Several nonneoplastic skin lesions were determined to be treatment 

related. Incidences I of acanthosis at the site 'of 

application., in alltreated groups of .males and in 

100 mgkg females at the 15-month interim evaluation 

were significantly greater than those in the controls. At 

the end of the 2-year study,.incidences of acanthosis. at 

the, site of application in60 and 100,mgkg males and 

females and hyperkeratosis at the site of application in 

60 mg&g .females were significantly greater than those 

in the controls. Absolute and relative right kidney 

weightsof 60 and 100 mgkg malerats .were 

significantly greater than those of .the controls at the 

15-month interim evaluation. Incidences of renal 

tubule adenoma and adenomaor carcinoma (combined) 

in all tre,ated groups of males were significantlygreater 

than those in the controls. These incidences exceeded 

the range from the historical controls in 2-year NTP 

feed studies. An extended (step section) evaluation of 

the kidneys of male rats did not reveal an additional 

increase in neoplastic response because additional 

adenomasandhyperplasiaswereobservedinthe 

controls as well as in treated groups. 

2-YEAARSTUDYIN MICE.:' ' ' 

Groups of 60 male and 60 female B6C3Fl mice were 

topically administered 0,3.6,6, or 10mg 1,2-dihydro2,2,4-trimethylquinolinekgbody weight in acetone, 5 

days per week for 103 (males) or 104 (females) weeks. 

Nine or ten mice per group were evaluated after 

15 months of treatment. 

. . Survival and Body Weights .' 

Survival of treated mice.was similar to thatof,controls. 

Mean body weights of treated' male and female pice 

were similar .to those. of .the controls throughout the 

study; 

males and females were slightly lower than those of thePathology Findings 

controls after week21.Meanbody weights,. of No.neoplasmsor nonneoplastic lesions were attributed 

36 mgkg males and females and60 mgkg to treatment with1,2-dihydro-2,2,4-trimethylquinoline. 
7 

C 

P,2-Dihydro-2;2,4-tri~et~ylquinoline, NTP TR45i 

Groups of 30 femaleSENCARmiceweretopically 

administeredvaryinginitiation/promotiontreatmentsas 

outlined in the table below. 

. . 

Suwival, Body Weights9and ClinicalFindings 

Survival in all treated groups was similar toofthat the 

respective controls, except in theyg2.57,lZdimethylbenz(a)anthracene (DMBA)/O.S yg 12-0-tetradecanoylphorbol-13-acetate(TPA) group in which 

survivalwassignificantlylowerthanthat of the 

controls. Mean body weightsof all treated groups were 

similar to those of the respective controls throughout 

thestudy. No clinical observations wereassociated 

with 1,2-dihydro-2,2,4-trimethylquinolinetreatment; 

however, mice pro'moted with TPA showed 

Design ofthe I-Year IhitiationdlPromotionDermal Shdy ~ 

. in Female SIENCAR Micea 

Treatmentb 

Initiatorc Promoterd 

Acetone Acetonee 

2.5 pg DMBA Acetone 

Acetone 0.5 pg TPA~-

2.5 pg DMBA 0.5 pg TPA 

50 mgkg TMQ 0.5 pg TPA 

2.5 pg DMBA 5 mgkg TMQg 

2.5 pg DMBA 10 mgkg TMQ 

2.5 pg DMBA 25 mgkg TMQ 

Acetone 5 mdk TMQ 

Acetone 10 mgkg TMQ 

Acetone 25 mgkg TMQ 

a Thirty mice per treatment group b 

pathaplogyFindings 

Initiation and promotion with acetone alone was not 

associated ,with any skinlesionsatthesite of 

application. The incidences of acanthosis and chronic 

inflammation were increased in all groups promoted 

with TPA regardlessof the initiator treatment; however, 

the incidences of nonneoplastic lesions were low in all 

other groups. Incidencesof squamous cell papillomas 

and squamous cell carcinomas were markedly increased 

in theDMBA/"A positive control group; however, no 

response was observed in groups initiated with DMBA 

and promoted with 5 , .lo, or- 25 mgkg 1,Zdihydro2,2,4-trimethylquinoline or in the group initiated with 

1,2-dihydro-2,2,4-trimethylquinolineandpromoted 

with TPA. 

f f I,2-DiBnyd~o-2,2,CtrimethyPq(ninoline 

I ( 

.. .. . Treatment Group 

. . 

, , 

'a, 

DMBA = 7,12-dimethylbenz(a)anthracene; TPA = 12-0-tetradecanoylphorbol-13-acetate;TMQ 

Initiators were applied once during week1 of the study in a volume of 0.1 mL. 

d Promoters were applied ina volume of 0.1 mL 

e Acetone promotion: three times per week 

TPA promotion: one time per week 

1,2-Dihydro-2,2,4-tmethylquinolinepromotion: three times per week 

Vehicle Control 

DMBA Initiation Control 

TPA Promotion Control 

InitiationPromotion Control 

TMQ Initiation 

TMQ Promotion 

TMQ Promotion 

TMQ Promotion 

TMQ Promotion Control 

TMQ Piomotion Control 

TMQ Promotion Control 

= 1,2-dihydro-2,2,4-trimethylquinoline 
8 

'GENETIC TOXICOLOGY 

1.,2-Dihydro-2,2,4-trimethylquinolinenotwas 

mutagenicinany of severalstrains of Salmonella 

typhimurium, with or without S9 metabolic activation. 

1,2-Dihydro-2,2,4-trimethylq~iinolineinducedsister 

clvomatid exchanges in cultured Chinese hamster ovary 

cells in the absence of S9, but not in the presence of S9.

However, no increase in the frequency of chromosomal 

aberrations was observed in culturedChinese hamster 

ovary cells treated with 1,2-dihydro-2,2,4-

trimethylquinoline, with or without S9. No increase in 

1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

CONCLUSIONS 

Under the conditions of these 2-year dermal studies, 

there was some evidence of carcinogenic activity* of 

1,2-dihydro-2,2,4-trimethylquinolinein male F344/N 

rats, based onincreasedincidences of renal tubule 

adenomaandadenoma or carcinoma(combined). 

There was no evidence of carcinogenic activity of 

1,2-dihydro-2,2,4-trimethylquinolinein female F344/N 

rats. receiving 36, 60, or 100 mg/kg, or in male or 

female B6C3Fl mice receiving 3.6,6, or 10mag. 

the frequency of inicronucleated erythrocytes was notedExposure of rats to 1,2-dihydro-2,2,4-trimethylin peripheral blood of male or female mice exposed 

topically to 1,2-dihydro-2,2,4-trimethylquinoline for 

13 weeks. .. 

quinoline by dermal application inacetone for 2 years 

resulted in acanthosisinmalesandfemalesand 

hyperkeratosis in femalesat the site of application. No 

nonneoplastic lesions in male or female mice were 

attributed to treatment with 1,2-dihydro-2,2,4-

trimethylquinoline. 

* Explanation of Levelsof Evidence of Carcinogenic Activity is on page 10. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appearson page 12. 

, 

1 

J 
9 

F344rn Rats 

Male Female 

F344lN Rats 

Male 

B6C3F] Mice 

Female 

B6C3Fl Mice 

Doses 0,36,60, or 100mglkg 

applied topicallyin 

acetone 

0,36,60, or 100mgkg 

applied topically in 

acetone 

0,3.6,6, or 10mglkg 

applied topically in 

acetone 

0,3.6,6, or 10 mgkg 

applied topically in 

acetone 

controlscontrols than

to thancontrols lowerlower slightlyslightlyroups

Bodyweights 10010 and60mglkg rnglkg groupTreatedgroupssimilarTretedgroupssimilar 

to controls 

2-Year survival 5/50, 2/50,4/50,1/5019/50,21/50,2/50,39/50,37/50,41/50, 34/50,40/50,40/51, 

37/50 rates

Nonneoplastic (siteSkin of (siteSkin of None None 

effects auulication): auulication):

acanthosis acanthosis (1/50,4/50, (0/50, 1/50, 

22/50 

22/50): 9/50. 14/49,21/50) 

hyperkeratosis(0/50, 

1/50,7/50, 1/50) 

Neoplastic effects m:

adenoma (standard 

renaltubuleNone None None 

evaluation-1/50, 

7/50, 10/50,7/50; 

extended evaluation6/50,5/50,6/50,8/50: 

standard and extended 

evaluations-7/50, 

11/50, 14/50, 14/50); 

renal tubule adenoma 

or carcinoma (standard 

evaluation-1/50, 

8/50, 10/50, 7/50; 

extended evaluation6/50,6/50,6/50,8/50; 

standard and extended 

evaluations-7/50, 

12/50, 14/50, 14/50) 

Level of evidence of Somevidence No evidence No evidence No evidence 

carcinogenic 

activity 

Genetic toxicology 

Salmonella typhimurium gene mutations: Negative in strains TA98, TA100, TA1535, and TA1537 with and without S9 

Sister chromatid exchanges 

Cultured Chinese hamster ovary cellsin vitro: Negative withS9; positive without S9 

Chromosomal aberrations 

Cultured Chinese hamster ovarycells in vitro: Negative with and without S9 

Micronucleated erythrocytes 

Mouse peripheral bloodin vivo: Negative 
l 

l 

l 

l 

l 

l 

l 

l 

l 

l 

l 

10 1,2-Dihydro-2,2,4-trimethylq~obe,NTP TR 456 

EXPLANATION Ol?LEYELS OF EVIDENCE OF CARCINOGENIC ACTIVITY 

The National ToxicologyProgramdescribes the results of individual experiments on a chemical agent and notes the strength of the evidence for 

conclusions regarding each study. Negative results, in which the study animals do not have a greater incidence of neoplasia than control animals,

do not necessarily mean thata chemical is nota carcinogen, inasmuchas the experimentsare conducted under a limited set of conditions. 

Positive results demonstrate 'that a chemical is Carcinogenicfor laboratory animals &der the conditions of the study and indicate that exposure to 

the chemicalhas the potential forhazardto humans. Other organizations, suchas the International Agency for Research on Cancer, assign a 

smmgth of evidence for conclwions based on an examinationallofavailable evidence, includinganimal studies suchas those conducted by the 

N'I'P, epidemiologic studies, and estimates-of exposure. Thus, the actual determination of risk to humans from chemicals found to be

wcinogenic in laboratory animals requiresa wider analysisthat extends beyond the purview of these studies. -

. . 

Five categories of evidence of carcinogenic activity are used in the Tecbnicil Report series tosummarize the strength of the evidenceobkrved in 

m:hexperiment: two categories for positive results (clear evidenceand some evidence); one category for uncerhin findings(eqbivoeal

evidence);one category for no observable effects (noevidence);ind one category for experiments that cannot be evaluated because ofhjor 

flaws (inadequatestudy). These categoriesof interpktative conclusions werefirst adopted in June 1983 and then revised in March 1986 for use 

in the Technical Report seriesto incorporate more specifically the concept of actual weight of evidence of carcinogenic activity. For each 

separate experiment (male rats, female rats, male mice, female mice), one of the following five categories is selected to describe the findings. 

These categories refer to the strength of the experimental evidence and not to potency or mechanism. 

Clear evidenceof carcinogenicactivityisdemonstrated by studiesthat are interpretedas showing a dose-related . . 

(I) increase of malignant neoplasms,(ii)increase of a combination of malignant and benign neoplasms, or (i)marked increase of I 

benign neoplasms if there is an indication from this or other studies of the ability of such tumors to progress to malignancy.

Some evidenceof qrcinogenic activity is demonstrated by studies thatare interpreted as showing a chemical-related increased 

incidence of neoplasms (malignant, benign, or combined) in which the strength of the response is less than that required for clear

evidence. . 1 

Equivocal evidenceof carcinogenic activity is demonstrated by studies that are interpreted as showigg a marginal increaseof 

neoplasms that may be chemical related. 

N o evidenceof carcinogenic activity is demonstrated by studies that are interpreted as showing no chemical-related increases in 

malignantor benign neoplasms. 

Inadequate studyof carcinogenic activity is demonstrated by studies that, because of major qualitative or quantitative limitations, 

cannot be interpretedas valid for showing either the presence or absence of carcinogenic activity. 

Wen a conclusion statement fora particular experiment is selected, consideration must he givento key factors that would extend the actual 

boundary of an individual category of evidence. Such consideration should allow for incorporation of scientific experience and current 

unkrstandingof long-term carcinogenesis studies in laboratory animals, especially for those evaluations that may be on the hrderline between 

two adjacent levels. These considerations should include: 

l adequacy of the experimental design and cpnduct: l occurrence of common versus uncommon neoplasia; l progression (or lack thereof)from benign,to malighant neoplasiaas well as from preneoplastic to neoplastic lesions;' 

some benign neoplasms have the capacity to regress but others (of the same morphologic type)progress. At present, it is impossible 

to identify the difference. Therefore, where progression is knownbetoa possibility, the most prudent courseis to assume that . . benign neoplasms of thosetypes have the potential to become malignant; 

combining benign and malignant tumor incidence known or thought to represent stages of progression in the same organ or tissue;

latencyintumorinduction; 

multiplicityinsite-specificneoplasia; 

metastases; 

supporting information from proliferative lesions (hyperplasia) in the same site of neoplasia or in other experiments (same lesion in 

another sexor species); 

presence or absenceof dose relationships; 

statistical significance of the observed tumor increase; 

concurrent control tumor incidenceas well as the historical control rate and variability for a specific neoplasm; 

survival-adjusted analyses and false positiveor false negative concerns; 

sq~cture-activity correlations; and l in somecases, genetic toxicology. 
nn 

The members of the Technical Reports Review Subcommittee who evaluated the draftNTF' Technical Report on 1,2-dihydro-2,2,4-

trimethylquinolineon June 20.1995, arelisted below.Subcommitteemembers serve as independentscientists,not as representativesofany . 

institution, company, or governmental agency.In this capacity, subcommittee members have five major responsibilities in reviewingNTF' . . , 

studies: 

0 to ascertain that all relevant literature data have been adequately cited and interpreted, 0 to determine if the design and conditions of the NTP studies were appropriate, 0 to ensure that the Technical Report presents the experimental results and conclusions fully and clearly, 0 to judge the significanceof the experimental results by scientific criteria, and 0 to assess the evaluationof.the evidence of carcinogenic activity and other observed toxic responses. 

Arnold L. Brown, M.D.,Chairperson 

University of Wisconsin Medical School 

Madison,WI 

Thomas L. Goldsworthy, Ph.D. 

Department of Experimental Pathology and Toxicology 

Chemical Industry Instituteof Toxicology 

Research Triangle Park, NC 

Meryl H. Karol, Ph.D., Principal Reviewer 

Departmentof Environmental Occupational Health 

University of Pittsburgh 

Pittsburgh, PA 

Curtis D. Klaassen, Ph.D. 

Departmentof Pharmacology and Toxicology 

University of Kansas Medical Center 

Kansas City, KS 

Claudia S . Miller, M.D., MS. 

University of Texas Health Sciences Center 

San Antonio, TX 

Janardan K. Reddy, M.D.* 

Department of Pathology 

Northwestern University Medical School 

Chicago,IL 

* Didnotattend 

Irma Russo, M.D.* 

Fox Chase Cancer Center 

Philadelphia, PA 

Louise Ryan, Ph.D.,Principal Reviewer 

Division of Biostatistics 

Harvard School of Public Health and 

Dana-Farber Cancer Institute 

Boston,MA 

Robert E. Taylor, M.D., Ph.D. 

Departmentof Pharmacology 

Howard University College of Medicine 

Washington,DC 

Mary Jo Vodicnik, Ph.D. 

Lilly MSG Development Center 

Belgium 

Jerrold M. Ward, D.V.M., Ph.D., Principal Reviewer 

National Cancer Institute 

Frederick, MD 
12 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS 

On .June 20, 1995, the draft Technical Report on the 

toxicology and carcinogenesis studies of 1,2-dihydro2,2,4-trimethylquinolinereceived public review by the 

NationalToxicologyProgram’sBoard of Scientific 

model was relatively new,it had provided an excellent 

fit to individual neoplasm and body weight datafrom 

over 3,500 animals in the NTP historical control 

database. Dr. Ryan asked whether it would be possible 

Counselors’ Technical Reports Review Subcommittee.to use a dose response model to decide on dose levels 

The review meeting was held at the National Institute of for the chronic study, based on the short-term studies, 

EnvironmentalHealthSciences,Research Triangle 

Park. NC. 

Dr. R.D. Irwin, NIEHS, introduced the toxicology and 

carcinogenesis studies of 1,2-dihydro-2,2,4-

trimethylquinoline by discussing theuses of the 

chemical and the rationale for study, describing the 

experimental design, reporting on siivival and body 

weight effects, and commenting on compound-related 

focusing her concern on why an intermediate dose 

between 50 and 100 mg/kg was not chosenas the high 

dose for female rats in the2-yearstudy. Dr. Irwin 

respondedthatdosesintermediate to those inthe 

prechronic study are frequently picked. However, the 

consensus for this stpdy was that the100mgkg dose 

for rats did not producea severe enough reactionof the 

skin to worry about in terms of the 2-year study. 

neoplastic lesions in male rats and nonneoplastic lesions Dr. Ward, the third principal reviewer, agreed with the in male andfemalerats. The proposed conclusions proposed conclusions. He noted that the incidence rate were some evidence of carcinogenic activity of 1,2- for combined liver neoplasms in 10mgkg male mice dihydro-2,2,4-trimethylquinolinein male F344/N rats exceeded the historical control range for both feed and and no evidence of carcinogenic activity infemale 

F:344/N rats or in male or female B6C3F, mice. 

Dr. :Irwin. summarized theresults of the1-year 

iriitiatioq/promotion study in female SENCAR mice. 

He said that 1,2-dihydro-2,2,4-tmethylquinoline.did 

nijt promote7,12-dimethylbenz(a)anthracene-initiated 

skin, while 12-0-tetradecihoylphorbol-13-acetate did 

nbt .,promote 1,2-dihydro-2,2,4-trimethylquinolineinitiatkd skin in SENCAR mice. nus; in this system, 

1,2-dihydro-2,2,4-trimethylquinolinedid not behaveas 

either an initiator or a promoter. 

Dr.Karol, a principalreviewer,agreedwith the. 

proposed conclusions. She noted that survival of both 

control and treated male rats was reduced from that of 

femalesbyweek90. ’ 

I ..,. . . ‘I. , . 

Dr. Ryan, the second principal reviewer, did not fully 

agree’withtheproposedconclusionsinmalemice 

where she would have’supported “equivocal” or even 

“‘some evidence of carcinogenic activity.” She asked if 

it were not premature to use the Seilkop method to 

discount the dose effect on liver neoplasms in male 

mice: % since the procedure used to’ adjust for weight 

effects. on neoplasm incidence maynot be broadly 

enough accepted at this point. . Dr. J.K. Haseman,

dermal studies, but agreed it was probably reasonable 

to discount them after adjusting for weight effects on 

neoplasm incidence. Dr. Irwin said body weight was 

not the only factor, but also lack of nonneoplasticiver 

lesions in males and the lack of supporting neoplastic lesions in female mice entered into the interpretation. 

Dr. Ward said another discussion point was that the 

incidences of liver neoplasms were similar in high and 

low dose groups, and therewereno increases in 

neoplasmmultiplicity or incidences of foci. 

Dr.Goldsworthysaid he wasunconvinced that 

increases in liverfoci had been ruled out in male mice. 

Dr. M. Stevens, Monsanto, commentedthatin his 

experience with short-term and long-termstudies with 

other quinolines, the liver was the target organ. 

Dr. Ward movedthat the Technical Report on: 1,2- 

dihydro~2,2,4-trimethylquinolinebe accepted with the 

revisions discussed and with the conclusions as written 

for male rats, some evidence of carcinogenic activity; 

and for female rats and maleandfemaleinice, no 

evidence of carcinogenic activity. Dr. Miller seconded 

the motion, which was accepted with seven yes votes 

andoneabstention(Dr. Goldsworthy, who said he 

lacked enough information onthe liver response in 

male mice to dismiss a higher level of evidence). 

NEHS, said that although Seilkop’s logistic regression .,I 

.I 

. ’ . , . - . . ..-. 

., , I : .I; ’ ’ 
H 

n,~-DrrwuDROa,~,0-T~T~lL~~OL~E , .. 

(MONOrnR) .. 

CAS NO. 147-47-7 .. 

Chemical Formula: C12H,*N MolecularWeight: 173.28 

Trade names: Agerite Resin D; Flectol A; Flectol H;Flectol Pastilles;Vulkanox HSLG Vulkanox HSlPowder 

Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline; acetone anil; methylquinoline .. 

tradename products. containing 1,2-dihydro-2,2,4- CrnrnCArr,AND rnSrrCAlL PROPIERTIUES 

trimethylquinolineduring the years 1981 to 1983 1,2-Dihydro-2,2,4-trimethylquinoline(monomer) is a 

(NIOSH, 1990). United States production of 1,2- copper-colored liquid witha density of 1.00775g/mL. dihydro-2,2,4-trimethylquinoline. (monomer) . was It is insoluble in water but soluble in acetone and boils 

withdecompositionat 90"to 95" C at atmospheric 

pressure (Merck Index, 1989). 

PRODUCTION, USE, 

AND HUMAN IEXPOSUIRIE 

Monomeric 1,2-dihydro-2,2,4-trimethylquinoline is 

usedalmostexclusively for the preparation of the 

1,2-dihydro-2,2,4-trimethylquinolinepolymer. The 

monomer and polymer of 1,2-dihydro-2,2,4-trimethylestimated to be 1.65x 10'' g in 1972and greater than 

2,000 pounds in1975;current production data are not 

available (HSDB,1995). 

ABSOWTIION, DIISTmUTIIONJ, 

METABOLISM, ANID EXCWTION 

Exp~rim~ntal Anima& 

Followingoraldministration of 11.5, 115, or 

1,150ymolekg, 1,2-dihydro-2,2,4-trimethylquinoline 

is well absorbedfromthegastrointestinaltract and. 

quinoline are used as antioxidants in styrene-butadieneexcreted primarily in urine (65% to 75%) and.feces. 

and nitrile-butadiene rubbers and latexes. These two 

antioxidants are generally mixed or milled into crude 

rubberatconcentrations of 1% to 3% by weight. 

Occupational exposure to 1,2-dihydro-2,2,4-trimethylquinoline monomer occursduringmanufacture of 

1,2-dihydro-2,2,4-trimethylquinoline polymer and 

potentially during rubber manufacture. The National 

OccupationalExposureSurveyestimates a total of 

8,109workers in the United States were potentially 

exposed to 1,2-dihydro-2,2,4-trimethylquinolineor to 

(25% to 35%) (Ioannou et al., 1987). Peak, 

concentrationsoccurredwithin 15 minutes .after 

administration in all tissues examined with the highest 

concentrationsobservedin the kidney, although no 

tendency towards concentration in any one particular 

tissue wasnoted. The cumulative urinary excretion of 

1,2-dihydro-2,2,4-trimethylquinoline-derived~ 

radioactivityamounted to 62% to 73% of the, 

administered dose with 26% excreted in feces; less than 

0.2%waseliminated as carbon dioxide. Clearance 

1 
I4 1,2-Dihydro-2,2,4-trimethylquinolioe,NTP TR 456 

from the blood was best described by a three-compo-' 

nent exponential decay curve, with a relatively rapid 

initial rate accounting for most oftheadministered 

dose, and a slow terminal rate. Following daily oral 

rived radioactivity were higher than those observed 

after a single oral administration, indicating a potential 

for bioaccumulation. However,aftercessation of 

dosing,tissuelevelsdecayed withkineticssimilarto 

those observed aftera single dose. 

closingwith1,150 ctmolekg for 6 days, tissueconcen-1,450 msflrg for mice (Kel'man, 1966); no other 

trations of 1,2-dihydro-2,2,4-trimethylquinoline-de- toxicity data were found in the published literature. 

' TOXICITY 

ExperimentalAnimals The oral LD,, for 1,2-dihydro-2,2,4-tthylquinoline 

(monomer)was reported tobe 2,000 mag for rats and 

Greater than 99% of the l.,27dihydro-2,2,4-trimethylquinoline excreted in urine and feces was in the form of 

metabolites.Thetwomostabundantmetabolitesinthe CARCINOGENICITY ' 

urinewerethe 0-sulfate of 1,2-dihydro-6-hydroxy- No informationoncarcinogenicityof1,2-&ydro2,2,4-trimethylquinolineandthe mono-0- sulfate of 2,2,4-hmethylquinolineinexperimentalanimalsor 

1,2-dihydro-3,6-dihydroxy-2,2,4-trimethylquinoline. humanswasfoundin a searchoftheavailable 

Based on these results and the apparent similarity to the literature. 

metabolism of quinoline, the partial metabolic pathway 

shown in Figure 1 was proposed. 

1,2-Dihydro-2,2,4-trimethylquinolineis alsowell 

absorbedthroughtheskin.Topicalapplication of 

14C-1,2-dihydro-2,2,4-tmethylquinoline(20pgin 

20 mgkg) to shaved male F344 rats resulted in accumulation of 14C in urine, feces,skin (site of application 

and nonapplication site), liver, fat, and kidney. After 

24 hours, approximately 80% ofthedosehadbeen 

absorbed (Frenchet al., 1987). Shah et al. (1987) also 

observedrapidabsorption of 1,2-dihydro-2,2,4-

trimethylquinoline.Within 6 hoursaftertopical 

. . . . 

Humans 

No informationon thetoxicity Of 1,2-dihydro-2,2,4- 

trimethylquinoline in humans was found in a search of 

the available literature. 

GENETICTOXICITY 

1,2-Dihydro-2,2,4-hmethylquinoline . was not 

mutagenicin Salmonella typhimurium strainTA98, 

TA100,TA1535,orTA1537,withorwithout S9 

metabolic activation (Zeigeret al., 1987). 

STUDY RATIONALE 

1,2-Dihydro-2,2,4-trimethylquinolinewas' nominated 

by the National Cancer Institute as part of a review of 

administration,50% of the material had been absorbed.chemicals used in the manufacture and processing of 

rubber, during which potential occupational and conHumans sumer exposure to this compound can occur. It was 

No information on absorption, distribution, metabolism,selected for evaluation because it is a derivative of 

0.r excretion of 1,2-dihydro-2,2,4-trimethylquinolinein quinoline, a knownrodentcarcinogen,andwas 

humanswasfoundin a searchoftheavailable regardedashavingpotentialcarcinogenicactivity. 

literature. . . Sincehumansareexposedprimarily .through skin 

i .. . , contact, dermal application was chosen as the routef

.. 

%. 

exposure. . ,l 
I I 

\ 

§U 
16 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 
trimethylquinoline)and a C-nitroso-substituted PRoeuJREMlENT AND 

trimethylquinoline. The overall purity was determined CmMCTlERIIZATIIoN to be greater than 90%. 

n,2-Di~~.aIt.an-~92~~-u~rmn~u~~n~~~~ni~e 

1,2-Dihydro-2,2,4-trimethylquinoline(monomer) was 

obtained from B.F. Goodrich Company (Akron, OH) in 

one lot (B062884), whichwasused for all studies. 

Identity, purity, and stability analyses were conducted 

by the analytical chemistry laboratory, Midwest Research Institute (Kansas City, MO; Appendix J). 

Reports on analysesperformedinsupport of the 

1,2-dihydro-2,2,4-trimethylquinolinestudies are onfile 

at the National Institute of Environmental Health 

Sciences (NIEHS). 

The chemical, a dark copper-colored viscous liquid, 

was identified as 1,2-dihydro-2,2,4-trimethylquinoline 

by infrared, ultraviolethisible, and nuclear magnetic 

resonancespectroscopy. The purity of lot BO62884 

was determined by elemental analyses, Karl Fischer 

wateranalysis, functional group titration,thin-layer 

chromatography, liquid high-performance and

chromatography.Elementalnalyses for carbon, 

hydrogen, and nitrogen were in agreement with the 

theoreticalvalues for 1,2-dihydro-2,2,4-trimethylquinoline.KarlFischerwateranalysisindicated 

0.048 f0.002% water. Functional group titration indicated a purity of 97.2 & 0.3%; however, impurities that 

also contain amine groups may have contributed to this 

value.Thin-layerchromatographyby one system 

Stability studies of the bulk chemical were previously 

performed on lot 1601 HK by the analytical chemistry 

laboratory using gas chromatography. These studies 

indicated that1,2-dihydro-2,2,4-trimethylquinolinewas 

stable as a bulk chemical for 2 weeks whenstored 

protected from light at temperatures up to 60" C. To 

ensure stability during the 13-week studies, the bulk 

chemical was stored in amberglassbottles at 5" C 

under a nitrogen headspace or at room temperature 

under a nitrogen atmosphere when the chemical was 

being used. During the 1-year and 2-year studies, the 

bulkchemicalwasstoredprotectedfrom light at 

4" & 3 O C under an argon headspace in amber glass 

bottles. Stability was monitored during the 13-week, 

1-year, and 2-year studies using infrared spectroscopy 

and gas chromatography. No degradation of the bulk 

chemical was detected. 

S9n2-Dirmneu~ymbe~~(~)~~u~It.~~e~~ 

7,12-Dimethylbenz(a)anthracene(DMBA) was obtained 

from Eastman Kodak Company (Rochester, NY)in one 

lot (K-4), which was purified by the analytical chemistry laboratory, assigned lot number M111384, and used 

for the 1-year studyIdentity, purity, and stability analyseswere conducted by the analytical chemistry laboratory,and reportsareon file at the NIEHS. 

indicated a major spot, one trace impurity, and one very 

slight trace impurity. Thin-layer chromatography by 

another system indicated a major spot and two trace 

impurities. High-performance liquid chromatography 

revealed a major peak and 11 impurities with a combined area of 8.9% relative to the major peak area. 

These impurities were further quantitated and identifed 

by gas chromatography and gas chromatography/mass 

spectrometry.Twenty-fiveimpuritiesweredetected, 

and 17 of these impurities were identified. Onlytwo of 

the impurities were present at greater than 1.O% of the 

major peak area; they were identifiedas isomers of 1,2-

dihydro-2,2,4-trimethylquinoline (3,4-dihydro-2,4,4-

The chemical, a light yellow powder, was identifiedas 

DMBA by infrared, ultraviolethisible, and nuclear 

magneticresonancespectroscopy. The purity of lot 

M111384 was determined by elemental analyses, Karl 

Fischer water analysis, thin-layer chromatography, and 

gas chromatography. Elementalanalyses for carbon 

and hydrogen were in agreement with the theoretical 

values for DMBA. Karl Fischer water analysis indicated less than0.4%water. Thin-layer chromatography 

indicated a major spot and one trace impurity. Gas 

chromatographyindicated one major peakwithno 

impurities with a peak area greater than 0.1% of the 
:is 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

lnajor peak area. The overall purity was determined toPREPARATIONAND ANALYS~ 

be greater than99%. 

r .. OF DOSEFORMULATIONS 

Stability studies of the bulk chemical were performedl~-Dihydro-2,2,4-trimethylquinolineby the analytical chemistry laboratory using gas chro-The dose formulations were prepared every 2 weeks by 

matography. These studies indicated thatDMBA was 

stable as a bulk chemical for at least 2 weeks when 

stored protected from light at temperaturestoup60" C. 

To ensurestability,thebulkchemicalwasstored 

protected from light at4" f3" C in sealed glass bottles. 

Stability was monitored by the study laboratory during.thedoseformulationswasconfirmedforatleast 

the 1-year study using infrared spectroscopy and gas 3 weeks at room temperature when stored protected 

chromatography. No degradation of the bulk chemical from light and for at least 3 hours when exposed to air

was detected. 

12-O-Tetradecanoylphorbol-13-acetate 

12-0-Tetradecanoylphorbol-13-acetate(lTA) was obtained from L.C. Services Corporation (Woburn, MA) 

in usingultravioletspectroscopy.Forthe13-week two lots (F-'121 and F-126), which were used for the studies,theformulationswereanalyzedevery4to 1-year study. Identity, purity, and stability' analyses 

we? conducted by the analytical chemistry laboratory, 5 weeks(Table J2). Duringthe1-yearand .Zyear

and reports are onfile at theNIEHS. 

Lot E12 1 of the chemical was identified as TPA by 

nuclear magnetic resonance spectroscopy, and both lots 

wereidentified as TPA bymassspectrometry.The 

purity of both lots was determined by thin-layer chr& 

matography and high-performance liquid chromatogra-toryagreedwiththeresultsobtainedbythestudy

laboratory with the exception of ,the 15 mg/mL dose phy. ,%-layer chromatography for both lots revealed formulationusedforinitiationinthe1-year-study one major spot by each system. For lot F-121, highpchformance liquid chromatography revealed a major 

peak and two impurities \;lith a combined area of 0.8% 

relative to the major peak area. For lot F-126, highp:rforqnnce liquid. chromatography revealed a major 

peak and three impurities with areas greater than or 

equal to 0.1% of the major peak area anda combined 

area of 1.0%relativetothemajor peak area.The 

overall purity of .both lots was detewed to be great& 

than 99%. 

Stability studiesof the bulk chemical were performed 

bytheanalyticalchemistrylaboratoryusinghighperforminceliquidchromatography.Therewasno 

decomposition of samples exposed toair and light at 

dbient temperatures forupto 6 days. To ensure 

mixing 1,2-dihydro-2,2,4-trimethylquinoline with 

acetone (Table Jl). Stability studies of the0.5 and 250 

mg/d dose formulationswere-performed bythe 

analytical . chemistry using laboratoryhighperformance liquid chromatography, and the stability of 

and light. . , 

Periodicanalysesofthedoseformulationsof1,2-

dihydro-2,2,4-t1imethylqujnolinewere conducted at the 

study laboratory and analytical chemistry laboratory 

studies,theformulationswere analyzed every '6 to 

8 weeks (Tables 53 and 54). Of the dose formulations 

analyzed, 92% (247/269) were within 10% of the .target 

concentration with no value greater than 18% different 

fromthetargetconcentration..Resultsofreferee 

analyses performed by the analytical chemistry labora-

(Table JS). No reason could be found for the discrepancy: 

7,12-Dimethylbenz(a)anthracene 

The dose formulation was prepared once at the beginningofthestudybymixing DMBA withacetone 

(Table Jl). , Stabilitystudiesofthe0.0025and . . 0.1 mg/mL dose. formulations were performed by the 

&dytical chemistry using laboratory ' highperformance liquid chro&tography,hd the stability of 

thedoseformulationswasconfirmedforatleast 

3 weeks at. room temperature when stored protected 

from light and for less than . . 

3 hours when expos&. to air

&d light. 

stability, the bulk chemical was stored in sealed glassPeriodic analyses of the dose formulations ofDMBA 

bottles at 4" 2 3" C. were conducted at the study laboratory and apalytical 
Mateh& annd MeUhQd.9 

chemistrylaboratoryusingultravioletspectroscopy. 

During the 1-year study, the dose formulation was 

within10% of the targetconcentration (Table 54). 

Results of referee analyses performed bythe analytical 

chemistry laboratory agreed with the results obtained 

by the study laboratory (Table 55). 

n9 

Groups of 10 male and 10 female rats were topically 

administered0,5,20,50, 100, or 200 mg 1,2-dihydro2,2,4-trimethylquinoline/kg bodyweightinacetone. 

Groups of 10male and 10female mice were topically 

administered 0,2.5,5,10,20, or 50 mag 1,Zdihydro2,2,4-trimethylquinoline in acetone.Dosks.were 

applied to clipped, interscapular skin five times per 

week. Animals were clipped24 to 48hours priorto the 

The dose formulation wasprepared as needed by first administration andthenweekly or as needed. 

mixing TPA with acetone (Table51). Stability studies Additional groups of 10 male and 10 female rats qd 

of the dose formulations were performed by the analytin2-0-?rdII.~~Q~~~~n~~~~~~n-n~~~~~~u~ 

mice were clipped but not treated. Feed and water were 

cal chemistry laboratory using high- performance liquidavailable ad libitum. Ratsandmicewerehoused 

chromatography, and the stability of the dose formula- individually. Clinical findings were recorded weekly

tions was confirmed for at least 3 weeks atroom for rats and mice. The animals were weighed initially, 

temperature when stored protected from light in sealedweekly, and at the end of the studies. Details of the 

bottles. study design and animal maintenanceare summarized 

in Table 2. . . 

Periodic analyses of the dose formulations of TPA were

At the end of the 13-week studies, blood for hematol- conducted at the study laboratory and analytical chemistry laboratory using high-performance liquid chroma- ogy and clinical chemistry analyses was collected from

tography. During the 1-year study, the formulations 

were analyzed every6 to 8 weeks, and the dose formulations were within 10% of the target concentrations 

(Table 54). Results of referee analyses performed by 

the analytical chemistrylaboratoryagreedwith the 

results obtained by the study laboratory (Table 55). 

nwmIEK STUD~S 

The 13-week studies were conducted to evaluate the 

cumulative toxic effects of repeated exposure to 1,2- 

dihydro-2,2,4-trimethylquinolineand to determine the 

appropriate dose levelsto be used in the 2-year studies. 

Male and female F344m rats and B6C3F, mice were 

obtained from Simonsen Laboratories, Inc. ,(Gilroy, 

CA). Upon receipt, rats and mice were approximately 

4weeks old. The animalswere quarantined for 11days 

and were 6 weeks old on the first day of the studies. 

Before initiation ofthe studies, five male and five 

female rats and micewererandomlyselected for 

parasite evaluation and gross observation for evidence 

of disease. At the end of the studies, serologic analyses 

were performed on five male and five female sentinel 

rats and four male and four female sentinel mice using 

the protocols of the NlT Sentinel Animal Program 

(Appendix L). 

the retroorbital sinus of all animals. Automated hematology determinations were performed using the .Ortho

ELT-8 analyzer(Ortho Instruments, Westwood,MA). 

Differential leukocyte counts and morphologic evaluation of blood cells were determined by light microscopic examination of blood films stained with a 

modified Romanowskystain. Reticulocyte counts were 

determined by light microscopy with smearsof whole 

bloodstainedwithnewmethyleneblue. Clinical 

chemistry parameters were evaluated on blood serum 

using a CentrifiChem System 500 analyzer. The 

hematology and clinical chemistry parameters measured 

are listed in Table 2. 

At the end of the 13-week studies, samples were 

collected for sperm morphology and vaginal cytology 

evaluations on untreated and vehicle control rats and 

mice, 5, 50, and 200 mag rats, and 2.5, 10, and 

50 mgkg mice. The parameters evaluated are listed in 

Table 2. Methods used were those described in the 

p$Tp's sperm morphology and vaginal cytology evaluations protocol (NTP, 1983). For 7 consecutive days 

prior to scheduled terminal sacrifice, the vaginal vaults 

of the females were moistened with saline, if necessary, 

and samples of vaginal fluid and cells were stained. 

Relative numbers of leukocytes, nucleated epithelial 

cells, and large squamous epithelial cells were determined and used to ascertain estrous cycle'stage (i.e'., 

diestrus, proestrus, estrus, and metestrus). Male animals were evaluated for sperm morphology, count, and 
280 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

motility. The right testis and right epididymiswere and mice) weeks. Skin was clipped prior to the first 

isolated and weighed. The tail of the epididymis (caudatreatment and then weekly'or as needed. Ten male aild 

e,pididymis) was then removed from the epididymal ten female rats and ten .male and nine or ten female 

body (corpus epididymis) and weighed. Test yolk (rats) mice from each group were evaluated at 15months for 

0.r.modifiedTyrode'sbuffer(mice)wasapplied to histopathology and organ weights. 

slides.and a small incision was madeat the distal border Source and Specificationof Animals

of the cauda epididymis. The sperm effluxing from the Male and female F344/N rats and B6C3F, mice were incision were dispersedin the buffer on the slides, and obtained from TaconicFgms (Geimantown, NY) for -

.themmibersof motile and nonmotile spermatozoa wereuse in the 2-year studies. Animals were quarantined for

counted for five fields per slide by two observers. 19 to 21 days (rats) or 12 to 14 days (mice) before the 

Following completion of sperm motility estimates, eachbeginning of the studies. 'Five male and'iive female rats

right .cauda epididymis was placed in buffered saline andmicewereselected for parasite evaluationand . . solution. (Caudae were:finely minced,andthetissue gross observation of disease. Serology samples were w& incubated in the saline solution and then heat fixed collected for viral screening: Rats were approximately at 65" C. Sperm density was then determined-microscopically with the aidof a hemacytometer. Four sperm 

morphology '.slides were prepired for each .animal ,.", . . 

evaluated. An aliquot of killed sperm suspension was 

stained. in a test tube, spread on a hicroscope slide 

under a coverslip, abd examined. - <I. ' .. . .. 

A nekropsy was performed on all animals. The brain, 

. he&, right kidney, liver, lungs, right ovary, right testis, 

thymus, &d uterus were weighed. Tissues for microsc6pic examinaiiori w,ere fixed and preserved in 10% 

,neutral', buffered formalin, processed andtrimmed, 

enibedded in.paraffin, sectioned to a thickness of 4 to 

6 $m,.&id stainedwithhematoxylinand eosin. A. 

complete histopathologic examination was performed 

on all untreated and vehicle control rats apd mice and 

on 200 mgkg rats and 50 mgkg mice. Additionally, 

the following orgins were examined microscopically 

fiom all ,treated groups:mediastinalandpancreatic 

lyiriph nodes of male rats, uterus of female rats, adrenal 

glkd of female mice, and skin of male and female rats 

and-&ce. Table 2 lists the tissues and organs routinely .. .

examined. ~ 

._/ I - ,

! .' , . .. . . .. . 

%YEAR STUDIES. 

Study Design 

Groups of 60 male and 60 female rats were topically 

administered 0, ' 36, 60, or 100 mg1,2-dihydro2;2,4-trime&ylquinolinekg 'body weight in acetone. 

Grpups of 60 male and60 female mice were topically 

administered ,O,3.6, 6, or 10 mg1,2-dihydro-2,2,4-

trirnethylquinoiinekg body weight in acetone.' Doses 

7 weeks old and mice were approximately6 weeks old 

at the beginning of thestudies. The health, of the 

animals was monitored during the studies according to 

the protocols of the NTP Sentinel Animal Program 

(Appendix L). 

Animal Maintenance 

Ratsand mice were housed individually. 

water were availablead libitum. Cages and racks were 

rotatedevery 2 weeks. .Further details of animal 

maintenance are given in Table2. Information on feed 

compositionand cont.aminants is provided, in 

Appendix K. 

, 

.. 

Clinical Examinations and Pathology 

All animals were observed twice daily. Clinical findings were recorded monthly. Animals were weighed at 

study initiation, weekly for the first 13 weeks, monthly 

thereafter, and at thend of the studies. 

A necropsy was perfokned on all rats and mice. The 

right kidney, liver, and spleen of all animals were ,-. weighedathe15-month 4 interim evaluations. At 

necropsy, all orgahs and tissueswereexamined for 

A -

2 

4 

grossly visible lesions, and, all major tissues were fixed 

andpreservedin 10% neutralbuffered formalin, 

processedandtrimmed, embedded' in paraffin, 

sectioned to a thickness of 4 to 6 pm, and stained with 

hematoxylin and eosin for microscopic examination. 

Complete histopathologic examinations were performed 

on all animals. For all paired organs (i.e., adrenal 

gland, kidney, ovary), samples from each'organ were 

. . 

.Feed and 

were applied to clipped interscapular skin five times per examined.Tissues examined are listed in Table 2.

week for 103 (male rats-and mice) or 104 (female rats . . , !: .. I . . 
Materials md Methods 21 

The standard evaluation of the kidneys in this study the diagnosis was changed. Thus, the final diagnoses 

included a longitudinal section through the middle of represent a consensus of quality assessment . . . the left kidney and a transverse section through the pathologists, the PWG chairperson, 1. . 

middle of the rightkidney.Because of increased and the PWG. Detailsof these review procedures have 

incidences of kidney neoplasms detected in dosedrats, been described, in part, by Maronpot. and -Boorman 

step sections were prepared from the residual kidney in (1982) and Boorman et al. (1985).Forsubsequent

the formalin-fixed wet tissues from all male rats. The analyses of the pathology data, the diagnosed lesions 

remaininghalves of the rightand left kidney were for each tissuetypewereevaluatedseparately or 

removed from the wet tissues, embedded and sectioned combined according to the guidelines of McConnell

at 1mm intervals to produce an additional six to eight et al. (1986). 

hematoxylin- and eosin-stained sectionsof kidney from 

each rat in the control and dosed groups. Step sections . .. 

were evaluated by microscopic examination and subject Il-YEAR mmarroNmoMoarroN SrnY to the quality assessmentandPathologyWorking 

Group reviews described below. . SUU" Desigm

The 1-year studywasconducted to evaluate tjie 

Microscopic evaluations were completed by the study initiating and promoting activity of topically applied

laboratory pathologist, and the pathology data were 1,2-dihydro-2,2,4-trimethylquinoline.Formaximum

sensitivity, femaleSENCAR mice Were selected'for use entered into the Toxicology Data Management System. in this study. In one set of treatment groups, a single The microscopic slides, paraffin blocks, and residual dose of DMBA was used as initiator an and oneof threk wettissuesweresent to theNTPArchives for 

doses of 1,2-dihydro-2,2,4-trimethylquinoline(5,10, or inventory, slidehlock match, and wet tissue audit. The 

25 mgkg) was appliedthreetimesperweek as a slides, individual animal data records, and pathology promoter. In another treatment group, a single dose of tableswereevaluated by anindependentquality 1,2-dihydro-2,2,4-trimethylquinoline(50 mgikg) was assessment laboratory. The individual animal records 

used as the test initiator and TPA was applied one, timi and tables were compared for accuracy, the slide and 

per week as' the promoter. Several positive. and tissue counts were verified, and the histotechnique was negative initiator/promoter control groups were 4so evaluated. For the 2-year studies, a quality assessment , examined. ' 

pathologist reviewed the kidney, mammary gland, and . .. , 

skin of male and female rats; the glandular stomachof 

male rats; and the liver, thyroid gland, and skin of male Female SENCAR mice were obtained from Frederick

and female mice. Cancer, Research Facility(Frederick,MD).Upon 

receipt, the animals were approximately5 weeks old. 

The quality assessment report and the reviewed slidesThe animals werequarantined for 27- days before 

were submitted to the NTP Pathology Working Group dosing began and' were approximately 9 weeks old ,at 

(PWG) chairperson, who reviewed the selected tissuesthe beginning of the study. At the end of quarantine, 

and addressed anyinconsistenciesin the diagnoses five mice wereselectedforparasite evaluation. and 

madebythelaboratoryandqualityassessment gross observationof disease. The health of the animals 

pathologists.Representative slides histopathology was monitored during the study according tothe NTP

containingexamples of lesions related to chemical SentinelAnimalProgram(Appendix L); . . 5 " . 

administration, examples of disagreements in diagnoses .. 

betweenthe laboratoryandqualityassessment ' Groups of 30 female SENCAR mice were' topically 

pathologist, or lesions of generalinterestwere administered varyinginitiatiodpromotion treatments .to 

presented by the chairperson to the PWG for review. the clipped, interscapularskin (Table 1). Animals were 

The PWGconsisted of the qualityassessment clipped prior to the first treatment and then weekly,oras 

pathologist and other pathologists experienced in rodent needed. All chemicals used as initiators were applied 

toxicologic pathology.This group examined the tissues once during the first weekof treatment. Following a 1, 

without any knowledge of dose groups or previously or 2-week recovery period, promoters were appfied on 

rendereddiagnoses,WhenthePWGconsensus or three times per week for the remainder of the s@dy. 

differed from the opinionf the laboratory pathologist, All doses were applied atvolume of 0.1 mL. 
3 2 2 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE1 

Design.ofthe 1-Year InitiatiodPromotion DermalStudy of 1,2-Dihydro-2,2,4-trimethylquinoline 

:in.FemaleSENCAR Micea 

. I . . 

Treatmentb 

. . Initiator' Promoterd Treatment Group .. 

- .. . _. . . . . . 

. ' Acetone Vehicle Control . 1 

., . 2.5pg DMBA DMBA Initiation Control 

Acetone TPA Promotion Contrbl 

2.5 pg DMBA. InitiationPromotion Control 

1 . I' . , 2.5 pg DMBA 

50m&g TMQ 

TMQ Promotion 

.TMQInitiation 

2.5 pg DMBA TMQPromotion ' . 

2.5 pg DMBA TMQPromotion , 

Acetone ' ' . TMQ Promotion Control 

Acetone TMQ Promotion Control 

', :I . Acetone TMQ Promotion Control.' 

.a: TI&Q ice per treatment'group b. I DMBA = 7,12-dimethylbenz(a)antne; TPA = 12-0-tetradecanoylphorbol-13-acetate;TMQ = 1,2-dihydro-2,2,4-trimethylquinoline C ,Initiatom.were applied once during week 1 of the study in a volume of 0.1 mL. 

,d Promoters were applied in a volume of 0.1 mL, . 

e Aketonepromotion: threetimesperweek 

.f ;' "PA promotion: one timeper week 

,g. 1,2-Dihydro-2,2,4-trimethylquinolinepromotion: three times per week 

,. t:. ,. 

-VehicleControl: Thirty female SENCAR mice were were administered0.5 pg TPA one time per week for 

administered a single acetone-initiator dose. Following52 weeks. 

a :2~week recovery period,micewereadministered 

acetone Bs a promotion treatment three times per week1,2-Dihydro-2,2,4-trimethylquinolineInitiation: Thirty 

.for52 weeks.,. female SENCAR mice were administered a single 50 .. , .(,. . .. 

mgkg 1,2-dihydro-2,2,4-tmethylquinolineinitiator 

7,Y2'-Dimethylbenz(a)anthracene-Initiation Control: dose. Following a 2-week recovery, period, mice were 

Thirty female SENCAR micewereadministered a administered0.5 pg TPA onetimeperweekfor 

,single 2.5 pg DMBA initiatordose.Following a 52 weeks. 

'Ziveek ' recoveryperiod,micewereadministered

'acetoneas a promotion treatment three times per weekI,2-Dihydro-2,2,4-trimethylquinoline Promotion: 

'for 52weeks. Groups of30 female SENCAR mice were administered . . 

a single 2.5 pg DMBA initiator dose. Following a 1-

12-0-Tetradecanoylphorbol-13-acetate .Promotion. week recovery period, mice were administered 5,10, or 

Control: . Thuty female SENCAR micewere 25mg 1,2-dihydro-2,2,4-trimethylquinoline/kgbody 

adrniiistered a' single acetone initiator dose. Following weight dissolved in acetone as apromotion treatment . . a', %-week 'recovery period,mice were administered three times per weekfor 52 weeks. . . 0.5 pg TPA as a promotion treatment one time per 

week for . . . . I,2-Dihydro-2,2,4-trimethylquinoline Promotion 

52'weeks. . , ' .. Control: Groups of .30 female SENCAR mice were . administered a single acetone initiator dose. Following , . :. . 1 

InitiatiodPromotion Control: Thirty female SENCAR a 1-week recovery period, mice were administered 5, 

mice were administereda single 2.5 yg DMBA initiator .lo, or 25 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg 

-dose. -Following a 2 - week recovery.. period, mice bodyweightdissolvedin ' acetoneas a .promotion 

treatment three' times per week for 52 weeks. 
,23 

todetectneoplasmsincertaintissues(e.g.,skin, 

mammary gland) .before 

available ad libitum. Cagesandrackswererotated microscopicevaluation,orwhen .neoplasms; had 

every 2 weeks. Animals were observed twice daily. multiple potential sites of occurrence (e.g., le&emia or 

Clinical findings and body weights were lymphoma), the denominators 

Mice were housed individually with feed and water intestine, harderian gland, and 

recorded at the 

beginning of the study, weekly for the first 13 weeks, was performed. Tables A3, B3, C3, D3, and E2a,b,c 

monthly thereafter, and at the end of the study. Further consist of the number of animals on which a necropsy

details of animal maintenance are given in Table 2. also give the survival-adjusted neoplasm rate for each 

group and each site-specific neoplasm, i.e., the KaplanAnecropsywasperformedonallanimals.Atne- Meier estimate of the neoplasm incidence that would 

cropsy,allorgansandtissueswereexaminedfor havebeenobservedattheendofthestudyinthe 

grosslyvisiblelesions.Tissuesformicroscopic absence of mortalityfrom all other competing risks 

examination were fmed and preserved in 10% neutral(Kaplan and Meier, 1958). 

buffered formalin, processed and trimmed, embedded 

in paraffin, sectioned to a thicknessof 4 to 6pm, and ~mdysisoff m!opnmm beidernem 

stained with hematoxylin and eosin. Histopathologic Themajority ofneoplasmsinthesestudieswere examinationswereperformedontheskin(site of considered to be incidental to the cause of death or not 

applicationanduntreated)andliver of all animals; rapidly lethal. Thus, the primary statistical method used additionally,completehistopathologicexaminations was logistic regression analysis, .which assumed that the were performed on mice that died before the end of the diagnosed neoplasms were discoveredas the result of 

study. Tissues examined are listed in Table 2. death from an unrelated cause and thus did not affect 

the risk of death. In this approach,,neoplasm 

prevalencewasmodeled as alogisticfunction of 

%l”Il’Trr(sTI@&~TlHNDIlDS chemical exposure and time. Both linear and quadratic 

Sundvd Amdyses termsintimewereincorporatedinitially,andthe 

The probability of survivalwasestimatedbythe quadratic term was eliminatedif the fit of the model 

product-limit procedure of Kaplan and Meier (1958) wasnotignificantly The enhanced.neoplasm 

and is presented in the form of graphs. Animals found incidences of exposedandcontrolgroupswere 

dead of other than natural causes were censored fromcompared on the basis of the likelihood score, test for 

thesurvivalanalyses;animalsdyingfromnatural theregressioncoefficient of dose. This methodof 

causeswerenotcensored.Statisticalanalyses for adjusting for intercurrent mortality is. the prevalence 

possible dose-related effects on survival used Cox’s analysis of Dipse and Lagakos (1983), further de@M 

(1972) method for testingtwo groups for qualify and and illustrated by Dinse and Haseman (1986). .When 

Tarone’s (1975) life table test neoplasms are incidental, this.comparison of the time- to iden@ dose-related 

trends. All reported P values for the survival analyses specificneoplasmprevalencesalsoprovides ‘.a 

are two sided. comparison of the time-specific neoplasm incidences 

(Mcbight and Crowley, 1984). 

ccdeda~ormoff IImcidermee 

The incidences of neoplasms or nonneoplastic lesions In addition to logistic regression,othermethods of 

as presented in TablesAl, A5, B1, B5, C1, C5, Dl, statistical analysis were used, and the results D4, of these 

Ela,b,c, and E3a,b,c are given as tests are spmmyizedin the appendixes..Thesemethods the number ofanimals 

bearing such lesions at a specific anatomic site and the include the life table test (Cox, 1972; Tarone, 1975),

numberanimalswith of that site examined appropriate for rapidly lethal neoplasms, and the Fisher

microscopically.For calculation of exacttestandtheCochran-Armitagetrendtest statistical 

significance,theincidences ofmostneoplasms (Armitage, 1971;Gart ef al., 1979), procedures based 

animals. (Tables A3, B3,C3,D3,andE2a,b,c)and all on the overall proportion of neoplasm-bearing 

nonneoplasticlesionsaregiven :as thenumbersof 

animalsaffected at each site examined microscopically. Tests of significance included pairwise comp~sons of

However, when macroscopic examination was required each exposedgroup with controls and a test for an
23 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

described in the preceding paragraphs were also used toHistorical Control Data 

evaluateselectednonneoplasticlesions.Forfurther Although the concurrent control group is always the 

discussionof these statistical methods, refer to Haseman firstandmostappropriatecontrolgroupusedfor 

(il984). evaluation, historical control data canbe helpful in the 

Analysis of Nonneoplastic Lesion Incidences overall assessment of neoplasm incidence in certain 

Because all nonneoplastic lesions in this study were instances. Consequently, neoplasm incidences from the

considered to be incidental to the cause of death or not NTPhistoricalcontroldatabase,whichisupdated

yearly, are included in the NTP reports for neoplasms rapidly lethal, the primary statistical analysis used was appearing to show compound-related effects. Because a logistic regression analysis in which nonneoplastic the NTP historical control database contains only two lesion prevalence was modeled asa logistic function of 

(rats) or three (mice) dermal studies using acetone as chemical exposure and time. For lesions detected at the the vehicle control, historical data from control rats and interim evaluation, the Fisher exact test was used, a 

mice in feed studies werealso used for comparison. procedure based on the overall proportion of affected 

animals. 

Analysis QUALITY ASSURANCE METHODS’ off Continuous Variables 

The13-week,1-year,and2-yearstudieswerecon- Two approaches were employed to assess the signifi- ducted in compliance with Food and Drug Administra- cance of pairwise comparisons between exposed and 

control groups in the analysisof continuous variables. tion Good Laboratory Practice Regulations (21 CFR,

Oigan and body weight data, which have approximately Part 58). In addition, as records from the 2-year studies

were submitted to theNTP Archives, these studies were nclrmal distributions, were analyzed using the paramet- auditedretrospectively byan independentquality ric: multiple comparison proceduresof Dunnett (1955) assurance contractor. Separate audits covering com- andWilliams(1971,1972).Hematology,clinical pleteness and accuracyof the pathology data, pathology chemistry, spermatid, and epididymal spermatozoa data,

which have typically skewed distributions, were ana- specimens, final pathology tables, and a draft of this 

NTP Technical Report were conducted. Audit proce- lyzedusingthenonparametricmultiplecomparison 

methods dures and findings are presented in the reports and are of Shirley and (1964). (1977)Dunn on file at NIEHS. The audit findings were reviewed Jonckheere’s test (Jonckheere, 1954) was used to assess and assessedby NTP staff, so all comments had been the significance of thedose-relatedtrendsandto 

resolvedorwereotherwiseaddressedduringthe determine whether a trend-sensitive test (Williams’ or preparation of this Technical Report. Shirley’stest) wasmoreappropriateforpairwise 

comparisons than a test that does not assumea monotonic .dose-related trend (Dunnett’s or Dunn’s test). 

Prior toanalysis,extremevaluesidentified by the GENETIC TOXICOLOGY 

outlier test of Dixon and Massey 1) were (195 examined Thegenetictoxicity of 1,2-dihydro-2,2,4-trimethylby NTPpersonnel, and implausible values were elimi-quinoline was assessedbytestingtheabilityofthe 

nated from the analysis. Average severity values were chemicaltoinducemutationsinvariousstrains of 

analyzed for significance using the Mann-WhitneyU Salmonella typhimurium, sister chromatid exchanges 

test (Hollander and Wolfe, 1973). Because the vaginal andchromosomalaberrationsinculturedChinese 

cytology data are proportions (the proportion ofthe hamster ovary cells, and the increases in frequency of

observation period thatan animal was in a given estrous micronucleated erythrocytes in’peripheral blood. The 

, stage), an arcsine transformation was used to bring the protocols for these studies and the results are given in 

data into closer conformance with a normality assump- Appendix F.

tion; Treatment effects were investigated by applying 

a multivariate analysisof variance (Morrison, 1976) to Thegenetictoxicitystudies of 1,2-dihydro-2,2,4-

the transformed data to test for simultaneous equality of trimethylquinoline are part of a larger effort by the 

measurements across exposure levels. NTPtodevelop a database thatwouldpermitthe 
evaluation of carcinogenicity in experimental animals multiple tissue sites (Ashby andTennant, 1991). Other 

from the structure and responses of the chemical in in vitro genetic toxicity tests do not correlate well with 

short-term in vitro and in vivo genetic toxicity tests. rodent carcinogenicity (Tennantet al., 1987; Zeiger et 

These genetic toxicity tests were originally developed a1.,1990),although these other tests can provide inforto study mechanisms of chemicallyinducedDNA mation on the types of DNA and chromosome effects 

damage and to predict carcinogenicity in animals, based that can be induced by the chemical being investigated.

on the electrophilic theoryof chemical carcinogenesis Data fromN"studies show thata positive response in 

and the somatic mutation theory (Miller and Miller, Salmonellais currently the most predictivein vitro test 

1977;Straw, 19sl;Crawford, 1985). for rodent carcinogenicity (89% of the Salmonella 

mutagens were rodent carcinogens), and that there is no 

There isa strong correlationbetween a chemical's complementarity among the in vitro genetic toxicity 

potentialelectrophilicity (structural alert to DNA reac- tests.That is, no battery of tests thatincludedthe 

tivity), mutagenicity inSalmonella,and carcinogenicity Salmonellatest improved the predictivityof the Salmoinrodents. The combination of electrophilicity and nella test aloneThe predictivity for carcinogenicityof a 

Salmonella mutagenicity is highly correlated with the positive response in bone marrow chromosome aberrainduction of carcinogenicity in rats and mice and/orat tion or micronucleus testsis not yet defined. 
26 1,2-Dibydro-2,2,4-trimethylquinoline, NTP TR 456 

'rABLE 2 

IExperime~ntal Design and Materialsand Methods inthe DermalStudies 

of 1,2-Dihydro-2,2,4-trimethylq~ohe 

13-Week Studies 

Study Laboratory 

Southern Research InstiNte 

(Birmingham, AL) 

Strainand Species 

Ern: F344/N 

Milice: B6C3F1 

Animal Source 

SimonsenLaboratories, Inc. 

(G~Y, CAI 

Time Held Before Studies 

11 days 

Average Age When Studies Began 

6 weeks 

Date of First Dose 

Rats: 5 May1986 

Mice:28April1986 

Duration of Dosing 

13 weeks (5 days per week excluding 

h"idays) 

Date of Last Dose 

Rats: 5-8 August1986 

Mice: 29 July - 1 August 1986 

Necropsy Dates 

Rats: 6-9August1986 

Mice: 30 July-2 August 1986 

2-Yearstudies 

TSI Mason Laboratories 

(Worcester,MA) 

Rats: F344m 

Mice: B6C3F1 

Taconic Farms 

(Germantown,NY) 

Rats: 19-21days 

Mice:12-14days 

Rats: 7weeks 

Mice: 6weeks 

Rats: 12 1989 Single September (males); 

14 September 1989 (females) 

1-Year InitiatiodPromotionStudy 

TSI Mason Laboratories 

(Worcester,MA) 

Mice:Female SENCAR 

Frederick Cancer Research' Facility 

(Frederick, MD) 

27 days 

9 weeks 

initiator treatment on 20 November

1989, followed by 1,2-dihyd~+2,2,4- 

Mice: 6June1989(males); 8 June1989trimethylquinolinepromoter on 

(females) ' 

103(males) or 104(females)weeks (5 days 

per week excluding holidays) 

Rats: 30August1991(males); 

11 September 1991 (females) 

Mice: 24 May 1991 (males); 5 June 1991 

(females) 

Rats:15-Monthinterim evyuation17December1990(males); ' ' 

18 December 1990 (females) 

Terminal-10 September 1991 

(males); 19-20 September 1991 

(females) 

Mice:15-Month inted evaluation -

4 September 1990 (males); 

5 September 1990 (females) 

Terminal-4-6June 1991(males); 

13-18 June 1991 (females) 

27 November 1989or TPA or acetone 

promoteron 4 December 1989 

54 weeks 

21-30 November'l990 

26 and 28 November 1990or 3 and 

4 %mber 1990 . 
Average Agead Necropsy 

20 weeks 

Size of Study Groups 

10 males and 10 females 

Method of Distribution 

Animals were distributed randomly into 

groups of approximately equal initial mean 

body weight. 

Anianals percage 

1 

Method of Animal IIdendEcation 

Toe clip 

Diet 

NIH-07 open formula pellet rodent feed 

(Zeigler Brothers, Inc., Gardners, PA) 

available ad libitum 

wat@rDBtrilbUtiOll 

Tap water (Birmingham,AL municipal 

supply) availablead libitum via automatic 

watering system (Edstrom Industries, Inc., 

Waterford, WI) 

cages 

Polycarbonate (Lab Products, Inc., 

Maywood, NJ), rotated once each week 

BeuBahg 

Heat-treated hardwood chips (Beta Chips) 

(Northeastern Products, Corp., Warrensburg, 

NY), changed once each week 

cage !Fatem 

ReemayB spun-bonded polyester (Andico, 

Birmingham,AL), changed once every 

2 weeks 

Racks 

Stainless steel (Lab Products, Inc., 

Maywood, NJ), changed once every 

2 weeks 

Rats: 112 (males)or 113 (females) weeks 

Mice: 109 (males) or 110 (females) weeks 

60 males and 60 females 

Randomized by weight class to randomly 

placed paired dose columns 

1 

Tail tattoo 

Same as 13-week studies 

Tap water (Worcester,MA municipal 

supply) availablead libitum via automatic 

watering system (Edstrom Industries, Inc., 

Waterford, WI) 

Polycarbonate (Lab Products, Inc., Rochelle 

Park, NJ), rotated once every2 weeks 

Heat treated hardwood chips (Sani Chips) 

(P.J. Murphy Forest Products, Montville, 

NJ), changed once each week 

Non-woven fiber (Snow Filtration, 

Cincinnati, OH), changed once every 

2 weeks 

Stainless steel (Lab Products, Inc., Rochelle 

Park, NJ), changed once every2 weeks 

62 weeks 

30 females 

Same as 2-year studies 

1 

Tail tattoo 

NIH-07 open formula mash rodent feed 

(Zeigler Brothers, Inc., Gardners, PA) 

available ad libitum 

Same as 2-year studies 

Same as 2-year studies, except cages were 

rotated every 2 weeks 

Same as 2-year studies 

Same as 2-year studies 

Same as 2-year studies 
215 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR,456 . . .. 

TABLE2 

Experimental Design and Malterials,andMetho&in the DermalStudies 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) -

13-Week Studies 

Animal Room Environment 

Temperature: 22.2' C 

Relative humidity: 56.4%(rats) or 55.2%. 

(mice) 

Fluorescent light: 12 hodday 

Room air changes: lohour 

Doses 

Rats: 0,5,20,50,100,or 200 mgkg 

administered in acetone 

Mice: 0,2.5,5, 10.20, and 50 mgkg 

administeredinacetone . 

Type and Frequencyof Observation 

Observed twice daily; animals were 

weighed initially, weekly, and at the end of 

the studies; clinical observations were 

recorded weekly 

Method of Sacrifice 

Carbon dioxide asphyxiation 

Necropsy 

Necropsy performed on all animals. Organs 

weighed were brain, heart, right kidney, 

liver, lungs, right ovary, right testis, thymus, 

and uterus. 

Clinical Pathology 

Blood was collected from all animalsfrom 

the retroorbital sinus for hematology and 

clinical chemistry analyses. 

Hematology: hematocrit, hemoglobin, 

erythrocytes, reticulocytes, platelets, mean 

cell volume, mean cell hemoglobin, mean 

cell hemoglobin concentration, leukocytes, 

and differentials 

Clin'kal Chemistry: total bilirubin, k t 

bilirubin (rats only), alanine 

aminotransferase, alkaline phosphatase, 

aspartate aminotransferase, sorbitol 

dehydrogenase, and y-glutamyltransferase 

2-Year Studies 

Temperature: 1 8"-28"C 

Relativehumidity: 30%-70% 

Fluoresient light: 12 hodday 

Room air changes: lohour 

Rats: . 0,36,60, or 100mgkg administd. 

in acetone 

Mice: 0,3.6,6, or 10 mgkg administered 

in acetone 

Observed twice daily; animals were 

weighed injtially, weekly for13 weeks, 

monthly thereafter, and at the end of the 

studies; clinical observations were recorded 

monthly 

Carbon dioxide asphyxiation 

Necropsy performed on all animals. Organs . . 

weighed at the 15-month interim evaluation 

were right kidney, liver, and spleen. 

None 

. . . , b ' . .., !\. _. ' . I / 1 

3

.' . . 

. . 

1-YearInitiatiodPromotion Study 

. : ." 0:. 

,. .. . .

Temperam: 20"-26"C 

Relative humidity: 30%-70% 

Fluorescentlight: 12.hodday . . ' 

Room air changes: lohour . I !' . 

.,.... 

, .. 

SeeTable 1 ' 

/' . 

' .. 

. . 

Observed twice daily; clinical observations , 

wererecorded and animals were weighed ., 

initially,weekly for 13 weeks,monthly ,. . 

thereafter, and at the end of the study 

. ,. 

i . . 

. .. 

Carbon asphyxiation dioxide ' , - . .

.., 

. . . .. 

~e~r~psy perform&m all animals. , ' .

.. 

.. . ., , /, 

. . .. ., 1 

None . . , . . . 

. . 

. . 
29 

n3-wek S~UCKW 

IHEsUQ~UI~RQRQ~JJ 

Complete histopathology was performed on 

untreated and vehicle controlrats and mice 

qd on200mgkg rats and50 mgkg mice. 

In additionto gross lesions and tissue 

masses, the tissues examined included 

adrenal gland, bone, brain, clitoral gland 

(rat), esophagus, eye (rat), gallbladder 

(mouse), heart, large intestine (cecum, 

colon, rectum), small intestine (duodenum, 

jejunum, ileum), kidney, liver, lung and 

mainstem bronchi, lymph nodes 

(mandibular and mesenteric), mammary 

gland, nasal cavity and turbinates, ovary, 

pancreas, parathyroid gland, pituitary gland, 

preputial gland (rat), prostate gland, salivary 

gland, seminal vesicle, skin (site of 

application and untreated), spleen, stomach 

(forestomach and glandular), testes with 

epididymis, thymus, thyroid gland, trachea, 

.urinary bladder, and uterus. Additionally, 

the following organs were examined in all 

dose groups: mediastinal and pancreatic 

lymph nodes of male rats, uterus of female 

rats, adrenal gland of female mice, and skin 

of male and female rats and mice. 

2-Hear Studies 1-Hear hitiatioflromotion Study 

CompletehistopathologywasperformedonInadditionto gross lesionsandtissue 

allratsandmice. In additionto gross masses,histopathologywasperformedon 

lesionsandtissuemasses,thetissueskinfromthesiteofapplication,skinfrom 

examined included adrenal gland,brain,untreatedsites,andliverofallmice. 

clitoral gland, esophagus, eye, femur, 

gallbladder (mouse), heart andaorta, large 

intestine (cecum, colon, rectum), small 

intestine (duodenum, jejunum, ileum), 

kidney, liver, lung and mainstem bronchi, 

lymph nodes (mandibular and mesenteric), 

mammary gland, muscle, nasal cavity and 

turbinates, ovary, pancreas, parathyroid 

gland, pituitary gland, preputial gland, 

prostate gland, salivary gland, seminal 

vesicle, skin (site of application and 

untreated), spinal cord and sciatic nerve, 

spleen, stomach (forestomach and 

glandular), testes with epididymis, thymus, 

thyroid gland, trachea, urinary bladder, and 

uterus. 

Spm MQII~~Q~Q~JJ md Vaginal Cfld~g~~ Evraluations

Atterminalsacrifice,spermsampleswereNone None 

collected from untreated and vehicle control 

rats and mice,5,50, and 200 mgkg rats, 

and 2.5,10, and 50 mag mice for sperm 

morphology evaluations. The parameters 

evaluated included: sperm count, 

morphology, and motility. The right cauda, 

right epididymis, and right testis were 

weighed. Vaginal samples were collected 

for up to7consecutive daysprior to the end 

of studies from females in thegroups listed 

above for vaginal cytology evaluations. The 

parameten evaluated included relative 

frequency of estrous stages and estrous 

cycle length. 
1,2-Dihydro-2,2,4-trimethylquinoli~NTP TR 4% 

/ . 
UTS 

nwmK STUDY 

All rats survived to the end of the study (Table 3). 200m@g females were significantly greater than those 

Final mean body weights and mean body weight gainsof the vehicle controls. Absolute thymus weights of 20, 

of male and female rats were similar to those of the 

vehiclecontrolsexceptthose of 200 mgkg males, 

which were significantly lower than those of th vehicle

controls.Theonlynotableclinicalobservationwas 

skin discolorationof treated rats. 

Absolute and relative liver weights200ofmgkg males 

and absolute liver weightsof 100 and 

Vehicle Control 10/10 117f2 

Untreated Control 10/10 116f2 

5 10/10 117f 3 

20 10/10 116f 3 

50 10/10 115f2 

100 10/10 116rt2 

200 10/10 114f2 

Vehicle Control 10110 94f2 

Untreated Control 10/10 9024 

5 10/10 98f 1 

20 10/10 9522 

50 10/10 93f2 

100 10/10 95 f 1 

2w 10/10 95f2 

50,100, and 200 mag males were significantly lower 

thanthat of the vehicle controls(Table Gl). There 

werenosignificantdifferences in hematologyor 

clinicalchemistryparametersbetweentreatedand 

control groups (Table Hl). There were no sig" 

differencesin reproductive tissue parameters or estrous 

cyclecharacterizationbetweentreatedandcontrol 

groups (Table11). 

339 f5 222 f4 

332 f 5 216 f 5 98 

345 f 4 228 f4 102 

334 f 8 217 f 6 99 

336f 5 220 f 3 99 

326f 4 210 f 3 96 

320f 6* 206 f5* 95 

191 22 97f2 

194f 3 104f7 102 

196f 2 98f2 103 

198f 3 103f 2 104 

193f 3 101f 2 101 

1972 1 102f 2 103 

193f 2 97f 1 101 

* Significantly different(PsO.05) from the vehicle control group by Williams' or Dunnett's test 

a Number of animals surviving at 13weekslnumber initially in group 

Weights and weight changesare given as mean f standarderror. 
- - 

3:2 

Hhtopathologic lesions of the skin at the site of application included acanthosis and hyperkeratosis in males 

and females (Table 4). Incidences of acanthosis in 

100 mgkg males and 200 mgkg males and females 

weresignificantly greater than thoseinthevehicle 

controls, and the severity increased with dose. Incidences of, hyperkeratosis in 100 mgkg males and 

1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

epithelial cells. Hyperkeratosis(an increase in the 

keratin layer) often accompanied acanthosis. 

Cytoplasmic vacuolization of hepatocytes of mild to 

moderateseveritywasobservedinthe livers of all 

200 mg/kg males and was considered treatment related 

(Table 4). The cytoplasm of hepatocytes in the peripor200 mgkg males and females were significantly greatertal to midzonal portionof the hepatic lobules contained 

*an thoseinthevehiclecontrols.Acanthosiswas multiple clear vacuoles. Vacuolization of hepatocytes 

characterized by thickeningof the squamous epithelium in one control male rat hada centrilobular distribution. 

due to hyperplasia and hypertrophy of 

TABLE4 

Incidencesof Selected Nonneoplastic Lesions in Rats in the 13-Week Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline 

Untreated Vehicle 

Control Cntrol 5 mgkg 20 mgkg 50 mgkg 100 mgkg 200 mgkg

Male 

(Site Skin of A plication)= 10 10 10 10 10 10 10

Acanthosis % 1 4 (1.0) 1 (1.0) 3 (1.0) 1 (1.0) lo** (1.6) lo** (2.0) 

Hyperkeratosis 0 0 0 0 0 5* (1.6) 7** (1.6) 

d Liver 10 10 1 10 10 

Hepatocytes, Vacuolization (1 1 .O) 1 (2.0) 0 1 (1.0) lo** (2.2)

Female 

(Site Skin of Application) 10 1 0 10 1 0 1 0 10 10 

Acanthosis 2 (1.0) 2 (1.0) 2 (1.0) 3 (1.0) 2 (1.0) 4 (1.0) lo** (1.8) 

Hyperkeratosis 0 0 0 0 0 2 (1.0) 6** (1.5) 

-

* Significantly different(PsO.05)from the vehicle control group by the Fisher exacttest 

** PsO.01 

a Number of animals with organ examined microscopically 

Number of animals with lesion 

Average severity gradeof lesions in affectedanimals (l=minimal;2=mild;3=moderate; 4=marked) 

Not examined atthis dose level 

Dose Selection Rationale: Because of the increased hyperkeratosis were also increased in males at 

incidences and severities of acanthosis and hyper- 100 mg/kg; however, theresponse at 50 mgkg in both 

keratosis in groups that received 200 mgkg and cyto- males and females was the same as observed in conplasmicvacuolization of hepatocytes in males that trols. Therefore, 100mgkg was selected as the high 

received 200 mg/kg, this dose was considered too high dose for the 2-year study. 

for a 2-year study. Incidences of acanthosis and 
33 

%YEAR STUDY 

Groups of 60 male and 60 female F344/N rats were 

topicallyadministered 1,2-dihydro-2,2,4-trimethylquinoline in acetoneat doses of 0, 36,60, or 

100 mgkg, 5 days per week for 103 (males) or 104 

(females) weeks. Ten rats per group were evaluated 

after 15 months of treatment. 

Suwival 

Estimates of 2-year survival probabilitiesfor male and 

female rats are shown in Table 5 and in the KaplanMeier survival curves (Figure 2). Survival of treated 

rats was similar to that of controls, although survival 

was low in control and treated groups of males. 

“e 

Animals initially in study 

15-Month interim evaluationa 

otherb 

Moribund 

Natural deaths 

Animals surviving to study termination 

Percent probability of survivalat end of study‘ 

Mean survival (days)d 

Survival analysise 

Femde 

Animals initially in study 

15-Month interim evaluationa 

Moribund 

Natural deaths 

Animals surviving to study termination 

Percent probability of survival at endof study 

Mean survival (days) 

Survival analysis 

a Censoredfromsurvivalanalyses 

60 

10 

0 

24 

21 

5 

10 

593 

P=O.O46 

60 

10 

19 

12 

19 

38 

633 

P=O.69ON 

~ ~~~ 

Body Weigh@ organ Weights9 

and Clinical Findings 

Mean body weights of 60 mgkg males and 100 mgkg 

males and females were generally 4% to 15% lower 

thanthose of the controls after week 21 (Figure 3; 

Tables 6 and 7). Meanbodyweights of 36 mgkg 

males and females and60 mgkg females were generallysimilar to those of the controls throughout the 

study.Clinicalobservationswerenotconsidered 

treatment related. 

Absolute and relative liver weights of 100 mgkg males 

were significantly greater than those of the controls at 

the 15-month interim evaluation (Table G2). 

60 60 

4 

2 

26 

22 

0 

10 

605 

8 

4 

25 

20 

1 

10 

593 

P=O.598 W.694 

60 60 

42 

21 

19 

10 

10 

633 

44 

22 

19 

9 

10 

640 

P=O.911N P=0.711N 

~~~ ~ ~ ~ 

60 

10 

0 

26 

23 

1 

2 

578 

P=O.O68 

60 

10 

9 

19 

22 

45 

636 

P=0.765N 

At necropsy, it was discovered that one of60themglkg malerats was actually a hermaphrodite; this animal was censored from survival 

analyses. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent modi& 

Mean of all deaths (uncensored, censored, and terminal sacrifice) 

e The result of the life table trend test (Tarone, 1975) is in the vehicle control column, and the results of the life table pairwise comparisons

(Cox, 1972) with the vehicle controls are in the dosed columns. A negative trendor lower mortality ina dose group is indicated by N.
34 l,Z-Dihydro-2,2,4-trimethylquinoline, NTP TR,,456:: 

I .o 

0.9 

0.8 

> 

2 0.7 

-1 

0 

LL 

2 0.6 

a 

a 

E 0.1 

0 

m 

5 0.4 

-1

g OS 

0.2 

0.I 

0.0 

15 30 45 60 75 

WEEKS ON STUDY 

90 to5 

1.o 

0.9 ... . . . . 

0.8 

2 0.7 

-I 

2 0.6 

> 

a. 

-

a 

LL 

0 

E OS 

E 0.3 

0 

m 

5 0.4 

2 

... 

......... .. 

.. 

.... 

...... 

. . 

...... 

....... 

......... 

0.2 W 0 W/KG 

0.I 60 YO/KO 

0 looYG/KC 

O.( I 

15 

I 

30. 

I 1 I 

WEEKS ON STUDY 

45 60 75 

I 

90 

1 

' 105 

, 

. 3 

FIGURE 2 

Kaplan-Meier Suryival Curves for Male and FemaleRats Administered 

1,2-Dihydro-2,2,4-trimethylquinoline Topically for2 Years 
35 

... 

.. 

../. ..;... ...... I . . .: .. 

..i .... .... 

. ................. 

I I I I I I I 

0 1s IO 45 60 75 90 105 1 

WEEKS ON STUDY 

WEEKS ON STUDY 
56 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

TABLE6 

Mean Body Weights and Survival of Male Rats in the 2-Year Dermal Study ,. , . 

of 1,2-Dihydro-2,2,4-trimethylquinoline 

weeks 

on 

Vehicle Control 

Av. Wt. No.of Av.Wt. Wt.(% of 

36mgnte 

No.of . Av.Wt. Wt.(%of 

60mdkg 

No.of Av.Wt. Wt.(% of' No.of 

100mde 

Study (9) Survivors . (8) controls)Survivors (9) controls) Survivoq (9) controls) Survivors 

2 

1 

204 

174 

60 

,GO 175 

202 

101 

99 60 

60 

203 

174 

100 

100 

60 

60 

203 

175 

100 

101 

60 

60 

3 231 60 229 99 60 230 100 60 231 ,100 60 

4 25 1 60 248 99 60 249 99 60 248 99 60. , . 

5 270 60 267 99 60 267 99 60 267 99 -60 

6 281 60 278 99 60 276 98 60 276 99 60 

7 295 60 293 99. 60 29 1 99 60 292 9 9 . 6 0 ' 

'8 302 60 302 100 60 301 100 60 301 100 60 

9 316 60 314 . 99 60 313 99 60 315 100 60 

10 327 60 324 99 60 323 99 60 326 100 - 6 0 . 

11 336 60 334 99 60 332 99 60 333 99 -60 

12 343 60 340 99 60 339 99 60 340 99 60 

13 352 ,60 349 99 60 344 98 60 ,344 '98 60 

17 372 60 37 1 100 60 364 98 60 366 98 ' 60 

21 394 60 390 99 60 382 97 60 380 96 60 

25 412 60 404 98 60 393 95 60 394 96 60-

< 29 428 60 419 98 60 405 95 60 402 94 60 . 

33 

. 

435 60 425 98 60 412 95 60 409 94 60 

41 

37 

455 

448 

60 

60 435 

441 

97 

97 60 

60 

430 

426 

95 

95 

59 

59 

423 

418 

93 

93 

60 

'60 

49 

45 

470 

466 

60 

60 

. 

446 

448 

96 

95 60 

60 

436 

436 

93 

94 

59 

59 

429 

430 

91 

92 

60 

6 0 . 

53 478 60 455 95 60 443 93 59 434 91 59 ' 

61 

57 

473 

472 

59 

60 455 

450 

96 

95 60 

60 

441 

446 

93 

95 

58 

58 

430 

435 

91 

92 

58 

58 

65 484 57 459 95 60 447 92 58 437 90 57 

68a 482 47 460 . 96 49 447 93 46 439 .91 47 . 

73 471 45 450. 95 48 444 94 46 435 92 .. 46 

77 470 40 438 93 48 43 1 92 44 '419 89. 44 

81 455 38 428 94 47 411 90 42 409 90 31 

85 432 . 36 402 , 93 43 410 95 35 384 89 35 .. 

89 422 32 388 92. 31 386 92 29 358 .85 24 

93 405 25 353 87 22 372 92 20 363 .90 14 

97 385 13 395 103 10 357 93 10 387 101 6 

101 418 .7 373 89 8 364 87 5 386 92 3 

Mean for weeks 

1-13 283 281 , 99 280 99 28 1 99 . 

14-52 43 1 420 97 409 95 406 94 

53-101 , 450 424 94 415 92 409 91 

.. 

a Interim evaluation occurred during week 66. . . 
101-ES LIE SOE 96 IOE S6 98Z 06 

ZS-PI OSZ SPZ 86 ZPZ L6 EEZ E6 

€3-1 I SL 9LI IO1 9LI IO1 ZLI 86 

mw q%3M 

101 EEE 62 EZE L6 LZ SZ€ 86 LZ LOE 26 82 

L6 SEE ZE SZE 96 ZE 91€ €6 E€ OOE 68 EE 

E6 6€E SE EZE S6 LE 91E E6 LE L6Z 88 SE 

68 ZEE LE IZE L6 op PIE 6E S6 862 06 OP 

S8 8ZE op LIE L6 IP EIE 96 ZP P6Z 06 ZP 

I8 SZE PP SIE L6 IP WE P6 €P 062 68 SP 

LL 61E SP WE S6 EP L6Z E6 9P 282 88 9P 

EL KE 9p OIE 96 W LO€ S6 9P I62 06 9P 

e69 ZIE 8P 862 S6 8P OOE 96 8P 982 26 LP 

S9 ZOE 8s 982 S6 6s 982 $6 6s SLZ 16 LS 

19 262 6s LLZ S6 65 9LZ S6 s9z 09 I6 8s 

LS 062 6S LZ 8 96 6s ELZ P6 09 z9z 06 6s 

ES E6Z 65 282 96 6s 8LZ S6 09 S9Z 16 65 

6P L8Z SLZ 6S 96 6S LZ I P6 09 09Z 16 6s 

SP 082 6S 692 96 6s 99Z S6 09 6PZ 68 09 

IP LZ I 19Z 65 09 96 LSZ S6 09 LPZ 16 09 

LE 8SZ 09 ESZ 86 09 6PZ L6 09 6EZ E6 09 

EE 6K 09 9PZ 66 09 Zpz L6 09 PEZ P6 09 

62 8EZ 09 9EZ 66 09 SEZ 66 622 09 09 96 

sz E2 I 622 09 66 09 822 66 09 zz I 09 96 

IZ EZZ 09 zzz 001 09 zzz 66 09 PIZ 09 96 

LI OIZ 09 IZ I 001 01z 09 001 09 so2 L6 09 

El EOZ 09 zoz 001 09 oz I 66 09 161 L6 09 

ZI OOZ 09 OOZ 001 09 00Z 001 09 961 86 09 

11 I L6 09 861 IO1 09 861 001 09 I P6 09 86 

01 261 09 E61 101 09 I €6 IO1 09 881 86 09 

6 681 09 161 101 09 I61 101 09 I L8 66 09 

8 I E8 09 981 I zo 09 I S8 101 09 I Z8 66 09 

L 6LI 09 081 IO1 09 I 28 IO1 09 LLI 09 66 

9 SLI 09 PLI 001 09 9LI IO1 09 ILI 86 09 

S I 69 09 I 69 001 09 I 69 001 09 I S9 L6 09 

P I E9 09 I E9 001 09 I €9 001 09 I 09 86 09 

E PSI 09 ESI 001 09 ESI 001 09 IS1 09 86 

.z PPI 09 PPI 001 09 WI 001 09 ZPI 66 09 

I IEl 09 IEl 001 09 I OE 001 09 821 86 09 

LC 
318 

Pathology Findings : 

Thissectiondescribesthe statisticallysignificant or 

biologically noteworthy changes in' the incidences of 

rlonneoplastic lesions of theskin and kidney, neoplasms 

of the kidney and mammary gland, and incidences of 

rnononuclearcellleukemia.Summaries of the inci1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

acanthosis at the site of application in all treated groups 

of males and in '100 mgkg females at the 15-month 

interim evaluation were sig&ficantly greater than those 

in the controls (Tables.8, A5, and B5). At the end.of 

the 2-year study, incidences of acanthosis in 60 and 

100 mg/kg males and females were significantly greater 

dences of neoplasmi and nonneoplastic lesions, individ-than those'in the controls. The incidence of hyperkera-

~ral animal tumordiagnoses,statisticalanalyses of tosis at the site of application in60 mgkg females at 

primary neoplasms that occurred with an incidenceof the end of the study was significantly greater than that 

alt least 5% in at least one animal group, and historicalin the controls. The incidence of hyperkeratosis in skin 

incidences for the neoplasms mentioned in this section away from the site of application in 100 mgkg males 

are presented in Appendix A for male rats and Appen-was significantly greater than that in the controls at the

dix B for female rats. end of the study.Acanthosiswascharacterized by 

, . thickening of the squiunous epithelium due to hyperplaSkin: No skin neoplasms were attributed to treatment sia and hypertrophy of epithelial cells (Plates 1and 2). 

with 1,2-dihydro-2,2,4-trimethylquinoline(Tables A3 Hyperkeratosis (an increase in the keratin layer) often 

and B3). Severalnonneoplastic.skinlesionswere accompanied acanthosis. 

determined to be treatment related. Incidencesof . . 'FABLE 8 

Ihcidencesof Nonneoplastic Lesionsof the Skin at the Siteof Applicationin Rats 

i.n the 2-Year Dermal Study of 1,2-Dihydro-2,2,4-trimethylquinoline 

Vehicle Control 36mgkg 60 mgkg 100 mgkg

Male .. 

:LJ-MonthInterim Evaluation 

Number Examined Microscopically 10 10 .lo 10 

Acanthosisa 1 (l.o)b IO** (1.0) 9** (1.0) 9** (1.0) 

%YearStudy ' I

Number Examined Microscopically 50 50 49 50 

Acanthosis 1 (1.0) 4 (1.3) 14** (1.1) 21** (1.0) 

Hyperkeratosis 2 (1.0) 2 (1.0) 2 (1.0) 3 (1.0) . 

Chronic Inflammation 0 3 (1.0) 0 0 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Acanthosis 1 (1.0) 4 (1.0) . 4 (1.0) 8** (1.0) 

Number Examined Microscopically 

2-Year Study 

50 50 50 50 

Chronic Inflammation 

Hyperkeratosis 

Acanthosis 

0 

0 

0 1 

1 

1 

(1.0) 

(1.0) 

(1.0) 

9** (1.0) 

7**(1.0) 

2 (1.0) 2 (1.0) 

1 (1.0) 

22**(1.0) 

** Significantly different(PsO.01)from the vehicle controlgroup by the Fisher exact test (interim evaluation) or the logistic regression test (2-

year study) 

a Number ofanimals with lesion 

Average severity grade of lesions in affected animals: l=minimal, 2=nkd, 3=moderate, &marked 
Kidney: Absolute and relative right kidney weights ofthe kidneyswasconducted to determine the presence of 

60 and 100 mgkg male rats were significantly greater additional proliferative lesions in control and treated 

than .those of thecontrolsatthe15-monthinterim males.Duringstandardevaluation,oneoncocytoma 

evaluation(Table G2). Incidencesofrenaltubule wasdiagnosedin a 1W mgkg male; anadditional 

adenomaandrenaltubuleadenomaorCarcinoma oncocytoma was found in a 36 mgkg male during the 

(combined) inall treated groups of males were signifi- extended evaluation. Results of the extended evaluacantly greater than those in the controls (Tables 9 and tion did not revealan additional increase in neoplastic 

A3) and exceeded the range of historical controls for 2- response in the kidney because additional adenomas

in the control group 

Because of these findings, an extended evaluation ofwell as in treated groups. 

year ITIT feed studies (0%-6%; Tables 9 and A4a). and hyperplasias were observed as 

Number Examined Microscopically 

ll§-MQm&IInnkbIEvdm~onn 

cysta 

Nephropathy, Chronic 10 

1 

10 

(2.l)b 10(2.3) 

0 

10 

10(2:3) 

1 

10 

10(2.4) 

0 

10 

%Year Suuudy 

SingleSections (S~dardEvaluation) 

Number Examined Microscopically 

Renal Tubule Hyperplasia 

Nephropathy, Chronic 

Acute Inflammation 

cyst 

50 

2 

50 

0 

13 

(4.0) 

(3.6) 

50 

0 

50 

0 

10 

(3.7) 

50 

6 

49(3.7) 

0 

17 

(3.0) 

50 

3 

50 

2 

20* 

(2.0) 

(3.7) 

(2.5) 

Renal Oncocytic Adenoma 

Renal Tubule Adenoma or Carcinomad 

Renal Tubule Carcinoma 

Renal Tubule Adenoma' 

0 

1 

0 

1 

0 

8* 

1 

7* 

0 

lo** 

0 

lo** 

1 

7* 

0 

7* 

Step seetiom(Extended Evaluation) 

Renal Tubule Hyperplasia 11(2.0) 11(1.9) 13(2.5) 13(2.1) 

Renal Oncocytic Adenoma 

Renal Tubule Adenomaor Carcinoma 

Renal Tubule Carcinoma 

Renal Tubule Adenoma 

0 

6 

0 

6 

1 

6 

1 

5 

0 

6 

0 

6 

0 

8 

0 

8 

Sie §@ctionsand Step Sections (Cornbind) 

Renal Tubule Hyperplasia 12(2.2) (1.9) 11 (2.0) 14 (2.8) ' 17 

Renal Tubule Adenoma 7 11 14* 14* 

Renal Tubule Carcinoma 0 1 0 0 

Renal Tubule Adenomaor Carcinoma 7 12 14* 14* 

Renal Oncocytic Adenoma 0 1 0 1 

* Significantly different(PsO.05) from the vehicle controlgroup by the logistic regression test 

** PsO.01 

a Number of animals with lesion 

Average severitygrade of lesions inaffected animals: l=minimal, L=d,3=moderate,4=marlced 

Historical incidencefor 2-year study with untleated control groups (meanf standard deviation): Feed -9l1.200 (0.8%i 1.5%), range0%-

6%;Dermal (Acetone) -0/1W

Historical incidence: Feed -12l1.200 range 0%-6%; Dennal (Acetone) -0/100
40 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

R.enal tubule adenomas were identified at necropsy ashyper- plastic tubule diameter varied in size up2 to to

2 to 4 mm diameter masses in the kidneys of four male 3 timesthediameterof a normaltubule(Plate4).

ratsfromthe100 mgkg group.Oneadenomawas Hyperplasticepithelialcellstypicallyformedsolid 

observed in a rat from the 60 mgkg group, and one clusters within tubules. These cells were often slightly 

aldenoma and one carcinoma were identified grossly inenlarged witha variable nuclear pleomorphism. 

two 36mgkg rats. All other adenomas were identified 

only by microscopicexamination.Adenomaswere 

composed of cells morphologically similar to those inMammary Gland Incidences of mammary gland neohyperplasia but these proliferative lesions were largerplasms in treated groups of female rats were signifi-

(generally greater than 400 microns in greatest dimen- cantly lower than those in the controls: fibroadenoma 

s:ion)andhad a morecomplexstructure(Plate3). (vehicle control, 25/48; 36 mgkg, 16/49; 60 mgkg, 

Adenomas often consisted of variably sized tubular-like15/49; 100 mgkg, 16/50); fibroadenoma or adenoma 

structures or solid nests of epithelial cells separatedby (combined) (26/48, 16/49,15/49,16/50);and fibroadea thinconnectivetissuestroma.Disruption of the noma,adenoma,orcarcinoma(combined) (29148, 

bmasement membrane by epithelial cells was present in 20/49,15/49,19/50)(TableB3).Theincidences of 

some adenomas, and some of the larger adenomas hadfibroadenoma, adenoma, or carcinoma (combined) in 

a central cystic area containing cell debris. Oncocytic the control group and treated groupsthisinstudy were 

adenomas were.characterizedby a slightly eosinophilic within the range of the historical controls from 2-year 

foamy appearance with round, centralized nuclei. The NTF’ feed studies (8%-64%; Table B4a). Because of the 

one carcinoma in a 36 mgkg male was much larger association between the incidenceof mammary gland 

than the adenomas and contained more anaplasia and neoplasms and body weight in female F344/N rats, the 

cellular atypia. Renal tubule hyperplasia was a focal decreased incidences were considered to be due to the 

lesion in the renal cortex or outer medulla in which the lower mean body weights of treated female rats. 
minimal, diffuse increased thickness of the epidermis (arrows). H&E 180~ 

dermal application. Compared to vehicle control in Plate 2, there is a 

administered 100 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline for 2 years by epidermis with skin from treated rat shown in Plate 1. H&E 180~ 

Acanthosis (hyperplasia) of epidermis in the skin of a male F344/N rat Skin from a vehicle control (acetone) male F344/N rat for comparison of 

PLATE 1 PLATE 2 

PLATE 3 PLATE 4 

application. H&E 75 x 

100 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline for 2 years by dermal 36 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline for 2 years by dermal 

Renal tubule adenoma in the kidney of a male F344/N rat administered Focal hyperplasia (arrows) in renal tubule of a male F344/N rat administered 

application. H&E 120 X 
All Organs: The incidence of mononuclear cell leuke- within the range of the historical controls (Tables .IO, 

mia in 100 mgkg female rats was significantly lower A4b, and B4b). Therefore, the decreased incicienceof 

than that in the controls at the end of the study (Tables mononuclear cell leukemia in100 mgkg females was 

10 and B3). However,theincidencesincontrolandnotconsideredtobetreatmentrelated. ' ' 

. . treated groups of males and females were 

Malea 

Overall rateb 25/50 (50%) 25/50 (50%) 17/50 (34%) 14/50 (28%) 

Adjusted rate' 93.5% 100.0% 74.4% 63.9% 

Terminal rated 4/5 (80%) 2/2 (100%) 114 (25%) 0/1 (0%)

First incidence (days) 428 47 1 455 487 . 

Life table teste E0.253N P=O.363 M.258N P=O:389N 

Femalef 

Overall rate 22/50 (44%) 16/50 (32%) 23/50 (46%) . 10/50 (20%) 

Adjusted rate 64.3% 52.7% 72.4% 32.8% . 

Terminal rate 9/19 (47%) 8/21 (38%) 14/22 (64%) 4/22 (18%) 

First incidence (days) 272 557 492 540 

Life table test P=O.O 18N EO.15ON M.503N P=O.O12N 

a Historical incidence for 2-year study with untreated control groups (mean f standard deviation): Feed -5621,203 (46.7% f 10.7%), range 

18%-62%; Dermal (Acetone) -40/100 (40.0% f 11.3%). range 32%-48% 

Number of animals with neoplasm per number of animals necropsied

' Observed incidence in animals surviving until the end of the study . I 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

e In the vehicle control column are the P values associated with the trend test. In the.dosed group columns are the P values corresponding to 

painvise comparisons between the vehicle controls and the dosed group. The life table test regards neoplasms inanimals dying prior to 

terminal kill as being (directly or indirectly) the cause of death. A negative trend or a lower incidence in a dose group is indicated by IV. 

Historical incidence: Feed -322/1,202 (26.8% * 9.0%), range 14%-52%; Dermal (Acetone)-25/100 (25.0%f 1.4%), range 24%-26% 
42 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

MICE I , ~. '. 

ISWEEK STUDY I . 

Allmiceexceptone 2.5 mgkg female survivedtotheOrganweights,hematologyandclinicalchemistry 

end ofthe study (Table 11). Final mean body weights parameters, reproductive tissue parameters, and estrous 

and mean body weight gains of male and female mice cycle characterization of treated mice were not signifiweresimilar to those of the vehiclecontrols.There canGy different fromthoseofthevehiclecontrols 

were 1x0 treatment-relatedclinicalobservations.(Tables G3,H2, and 12). 

TABLE11 

Survival and Body Weights of Mice in the 13-Week Dermal Study of 1,2-Dihydro-2,2,4-trimethylquinoline 

Mean Body Weightb (g) Final Weight

DM Initial Survivala Final Change Relative to 

(mgflrg) .( .

Male 

8:. Vehicle Controls (%) 

Vehicle Control 10/10 21.7 i0.3 32.2 i0.6 10.5 i 0.8 

Untreated Control. loll0 21.704 33.1 2 0.6. 11.4 2 0.5 103 

2.5 10/10 21.6 2 0.3 31.8 i0.6 10.2f 0.4 99 

5 10/10 21.2 f 0.3 32.2 f 0.6 11.OiO.6 100 

10 loll0 21.703 33.2 2 0.5 11.5 20.4 103 

20 loll0 21.8 i0.3 32.7 rt 0.6 10.8 f 0.7 101 

50 10/10 21.6 2 0.4 32.1 f 0.4 10.5 f 0.4 100 

Fde 

Vehicle Control 10/10 17.7 2 0.3 28.0 f 0.6 .10.32 0.4 

Unhreated Control 10/10 17.8i0.3 26.7 f 0.5 8.9 2 0.7 95 

2.5 ,9/lOC 18.1 20.2 28.5 i0.4 10.4 i0.2 102 

5 10/10 17.5i0.3 27.1 i 0.7 9.6 i0.5 97 

10 10/10 17.7 i0.3 27.5 i0.6 9.8 i0.7 98 

' 20 10/10 17.7i0.3 28.6 f 0.6 10.9 2 0.5 102 

50 10/10 17.7 2 0.3 28.4 2 0.4 10.62 0.4 101 

a Number of animals surviving at 13weekdnumber initially in group 

Weights and weight changes are given as mean 2 standard error. Subsequent calculations are based on animals surviving to the end of the 

study. Differences from the vehicle control group were not significant by Dunnett's test. 

Weekof death: 6 
Histopathologic lesionsof the skin at the siteof applica- and parakeratosis, all ranging from minimalto mild in 

tion were considered to be directlyor indirectly related severity. Fibrosis and subchronic inflammation were 

to chemical treatment. These lesions included acantho- observed in the dermis and also ranged from minimal to 

sis (epidermal hyperplasia), hyperkeratosis, mild in severity (Table 12). 

Untreated Vehicle 

ControlControl 2.5 mgkg 5 mgkg PQ mgkg 20 mgkg 5Qmgkg 

Male 

NumberExaminedMicroscopically 10 

Acanthosisa 0 

Hyperkeratosis 0 

Parakeratosis 0 

Inflammation, Dennis 0 

Fibrosis, Dermis 0 

Female 

NumberExaminedMicroscopically 10 

Acanthosis 0 

Hyperkeratosis 0 

Parakeratosis 0 

Inflammation, Dermis 0 

Fibrosis, Dermis 0 

Ulcer 0 

* Significantly different (PiO.05) from the vehicle control group by the Fisher exact test 

** PiO.01 

a Number of animals with lesion 

Average severity grade of lesions in affected animals: l=minimal,2=mild, 3=moderate,4=marked 

Dose Selection Rationale: Because of the increased dermis of 20 and 50 mgkg mice in the 13-week study, 

incidences and severitiesof lesions of the skin, particu- 10 mgkg was selected as thehigh dose for the 2-year 

larly inflammation andfibrosis within the study. 
44 

C 

d 

1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

%YEARSTUDY 

Groups of 60 male and 60 female B6C3F, mice were Meier survival curves (Figure 4). Survival rates of 

topically administered 1,2-dihydro-2,2,4-trimethyl- treated mice were similar to those of the controls.

quinoline in acetone at doses of 0, 3.6,6, or 10mgkg 

body weight, 5 days per week for 103 (males) or.104 

(females) weeks. Nine or ten miceper group were- Body Weights and Clinical Findings: 

waluateddter 15 months of treatment. The mean body weights of male and female mice administered 1,2-dihydro-2,2,4-trimethylquinolinewere 

Survival siniilar to the controls throughouthe study (Tables 14 

Estimates of 2-year survival probabilities for male and and 15; Figure 5). Clinical observations were not 

female mice are shown inTable 13 and in the Kaplan- considered treatment related. 

TABLE13 

Sudval of Mice in the 2-Year DermalStudy of 1,2-Dihydro-2,2,4-trimethylquinoline 

Vehicle Control 3.6 m'@g 6mg/kg 10mg/kg 

Male , 

Animals initially in study 60 60 60 60 

/

15-Month interim evaluationa 10 10 10 10 

Accidental deatha 1 0 0 . 0 : 

Moribund 5 4 7 3 

Natural deaths ) .6 8 2 10 - Animals surviving to study termination 39 37 - 41 37 

Percent probability of survival at end of studyb 78 76 " 82 74 

Mean survival (days)' 658 637 663 658 

.. EO.800 P=O.894 P=0.852N P3.763 

(-

Female 

Animalsinitiallyinstudy I 60 60 ' 60 ' 60

:lS-Morith interim evaluationa 10 10 9 10 \ 

Accidental deatha 0 . 0 .I '1 -0 

lb4oribund 6 7: .7 6 

IVahud deaths 10 3. 3' 4 

' Animals skiving to studytermination 34 40 40 . 40 

Percent probabilityof survival at end of study 68 80 81 ' 80 

Mean survival (days) 668 . 669 660 673 

.. 

Survival analysis v.215N P=0.302N P3.265N P3.281N 

\ a Censoredfromsurvivalanalyses 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality ' Mean of alldeaths(uncensored,censored,andterminalsacrifice) c, 

The result of the life table trend test (Tyone, 1975)is in the vehicle control column, and the results of the life table painvise comparisons 

(Cox, 1972) with the vehicle controlsare in the dosed columns. A negative trend or lower mortality ina dose gioup is indicated by N. ., .I , I .

\ . . .. ' 1 . . . 
05 

I .o 

-t 0.9 a

I 

2 

3 

v)

k 

c o.8 -3

m 

a 

m 

4 

a 0.7 

0.6 

1.01 

L 

0 

c 0.8 

=! 

m 

a 

m 

z 

a 0.7 

0.6 

!O 

WEEKS ON STUDY 
46 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

IrABLE 14 

Mean Body Weights andSurvival of Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline 

Weeks Vehicle Control 3.6 m&g 6 mdke 10 m&g 

on Av. Wt. No.of Av.Wt. Wt.(% of No.of Av.Wt. Wt.(% of No.of Av.Wt. Wt.(% of No.of

:Study (g) Survivors (8) controls) Survivors (8) . controls) Survivors (g) controls) Survivors

60 96

2 27.2 59 26.7 98 60 26.8 99 

1 26.1 60 25.4 97 25.0 60 25.8 99 60 

60 100

60 105

60 28.8 99 

27.2 60 

60 

60 

3 27.5 59 100 27.6 60 102

59 98

59 

59 

28.1 

28.5 

28.8 

4 29.1 59 97 28.3 

~5 29.2 59 100 29.3 101 

59 100

59 31.4 99 

60 103

60 100

60 100

60 100

60 101

60 100

60 100

60 100

6099 

98 60

96 44.9 

29.6 30.1 60 

60 

60 

60 

60 

60 

6 29.9 59 99 29.5 29.5 99 29.9 

7 31.2 59 100 31.1 31.3 31.3 

8 31.8 59 100 31.9 31.7 

9 32.7 59 101 33.0 59 32.5 99 33.1 

10 33.4 59 101 33.6 59 100

59 100

59 35.5 100 

33.5 33.4 

11 34.8 59 100 34.9 34.8 34.8 ,60 

12 35.5 59 101 35.7 35.4 60 

13 36.1 59 35.9 99 59 35.760 99 

17 

21 

40.5 

42.3 

59 

59 

99 

100 

40.1 

42.1 598 

59 39.960 

41.6 

99 

25 44.6 59 44.2 99 59 43.9 98 

29 

33 

37 

41 

46.8 

47.1 

48.2 

49.6 

59 

59 

59 

59 

97 

98 

98 

45.5 

45.5 

47.4 

48.6 

60 

97 

60 

60 

58 

58 

58 

59 

99 

97 

97 45.2 

45.7 

47.5 

48.7 98 

35.7 - 99 60 

39.4 97 60 

41.9 60 

43.5 60 

60 

97 45.7 60 

98 47.4 60 

98 60

99 50.2 

48.6 60 

45 50.8 59 97 49.5 60 5899 50.1 60

49 51.5 59 51.2 9960 5899 50.8 

53 51.5 59 50.9 99 57 50.7 98 

61 

57 

51.6 

51.5 

59 

59 98 

50.9 

50.7 

99 

59 

56 

5799 

99 

50.9 

50.9 

50.9 99 60 

98 60

' 59 50.9 99 60 

50.5 60 

98 50.6 60 

65 52.0 59 51.8 100 59 56 99

46 

102 

100 

51.2 98 51.1 60 

69a 53.9 49 54.1 100 49 54.0 100 98 52.8 49 

73 53.1 49 53.3 100 49 46 

46 

44 

43 

42 

54.1 100 52.9 48 

77 53.6 49 53.8 100 53.8 49 53.0 99 47 

81 52.2 49 52.8 101 48 100 46

101 

40 

40 102

40 103

52.1 51.4 99 

85 52.1 49 52.6 47 101

101 52.4 

102 53.0 52.5 44 

89 53.5 46 53.4 100 45 100 53.3 52.9 99 44

93 52.1 43 99 51.7 44 100 52.0 43

97 51.2 43 50.7 99 41 52.0 99 50.8 42

101 49.7 41 47.9 96 41 51.4 102 50.8 39 

Mean for weeks 

31.0 100 30.9 99 31.2 100 

46.0 98 45.9 . 98 45.8 98 

51.9 99 52.2 100 51.7 99 

14-52 46.8 

a Interim evaluation occurred during week 66. 

1-13 31.1 

53-101 52.2 
101-E5 9PS Z'PS 66 OSS I01 LES 86 

ZS-VI 6ZP LIP L6 p'ZP 66 S'ZP 66 

El-I 1'9Z 1'92 001 z9z 001 SZ 6 66 

ueqq JOJ S~M

IO1 8'ES ZP 1'95 POI IP OLS 901 pb 'PS 1 I01 ZP 

L6 8'PS pb 095 I zo p b , p'9S I EO S'PS SP I 00 pb 

E6 9'PS 9P I'SS IO1 SP 09s I EO SP L6 6'2s SP 

68 09s LP 69s I zo SP 695 I zo 9P E'SS 66 LP 

58 695 ' LP 66 p'9S 9P SLS I01 9P 13s L6 8P 

I8 Z'9S 8P LSS 66 LP 8'SS 66 9P 8'PS 86 8P 

LL O'LS ' 8P 1'95 86 8P 695 001 9P I'SS L6 6P 

EL 09s 8P ZPS L6 8P 1'9s 001 9P p'PS L6 6P 

69 9SS 6P OPS L6 6P Z3S 66 8P 9x7s 86 OS 

BS9 p'ES 6S 67.5 66 6S 6ES IO1 LS 9ES 001 09 

19 9ZS 65 L'OS 96 09 VIS 86 85 S E.1 86 09 

LS E'ZS 6S S'OS L6 09 1.1s 86 6S S'IS 66 09 

ES 21s 09 9'6P L6 09 S'OS 66 6s COS 86 09 

6P SOS 09 '6P I L6 09 86 9'6P 6S Z'OS 66 09 

SP Z'6P p'9P 09 P6 09 LLP L6 6S 08P 86 09 

It p'9P 09 8% L6 09 SP L 66 65 SP p' 86 09 

LE OSP 09 6EP 86 09 E'pb 86 6S p'pb 66 09 

EE Z'ZP 09 LIP 66 09 OZP I 00 6S L'ZP IO1 09 

62 6'OP 09 OW 86 09 60P 001 6S 9'OP 66 09 

SZ 8'8E 09 1'8E 86 09 06E I01 6S 1'6E IO1 09 

IZ 8'LE 09 OLE 86 09 p'LE 66 65 E'LE 66 09 

LI E'SE 09 SPE 86 09 ZSE 001 6S 6PE 66 09 

El 8'IE 09 LIE 001 09 8'IE I 00 6S E'IE 86 09 

ZI LOE 09 90E 001 09 I'IE IO1 65 SOE 66 09 

11 OOE 09 L6Z 66 09 Z'OE I01 6s I'OE 001 09 

01 L8Z 09 8'82 001 09 Z'6Z ZOI 65 L8Z 001 09 

6 LZ 9 09 LZ L 001 09 LLZ 001 65 SLZ 001 09 

8 LZ O 09 9'9Z 66 09 LZ O 001 6S L'9Z 66 09 

L 09Z 09 6'SZ 001 09 E'9Z 101 6S 091 001 09 

9 E'SZ 09 Z'SZ 001 09 'SZ 

I 66 6S 6PZ 86 09 

S 'pz I 09 p'PZ IO1 09 p'PZ 101 6S E'PZ 101 09 

P EZ S' 09 9'EZ 001 09 p'EZ 001 09 E'EZ 66 09 

E E'ZZ 09 S'ZZ I01 09 9zz IO1 09 9'ZZ 101 09 

Z E'IZ 8'12 09 I zo 09 9IZ IO1 6'02 09 86 09 

I p'oz 09 p'oz 001 09 p'oz I 00 09 'OZ 

I 66 09 
1,2-Dihydro-2,2,4-trirnethylquinoline,NTP TR 456 

" .. 

60 

55 

f 50 

fK 

4 

0 

45 

..#.:. ................. ;.................. i.................. i................. .i ................. :.................. i............... 

0 YG/KG 

Z! 

21 I 1 1 1 I I I 

15 30 45 60 75 90 105 

WEEKS ON STUDY 

55 .................. '8 ........... it; j. ......... ..... ................... . ,.............. 

...... - FEMALEMICE . . 

...... 

20 

0 15 

I 

' 30 

I 

45 

I 

60 

I 

75 

I 

90 

I 

105 

I 

, WEEKS ON STUDY 

FIGURE 5 

Growth Curves for Male and Female Mice Administered 

1,2-Dihydro-2,2,4-trimethylquinolineTopically for 2 Years 
RessoQb 09 

Pathology FiRndimgs controlsfor2-year NTP feedstudies(10%-68%, 

Thissectiondescribes thestatisticallysignificantor Table C4a). The incidences of liver neoplasms were 

biologically noteworthy changes in the incidences of not increased in exposed groups at 15 months, and after 

neoplasms and nonneoplastic lesions of the skin, liver,2 years therewasnoincreaseintheincidences of 

and kidney. Summaries of the incidences of neoplasmsmultipleadenomaorcarcinoma inexposedgroups. 

andnonneoplasticlesions,individualanimaltumor The incidences of hepatocellular adenoma and of the 

diagnoses, statistical analyses of primary neoplasms combinedincidence of hepatocellular neoplasmsin 

that occurred with an incidence of at least 5% in at least treated females were lower than thoseof the controls 

oneanimalgroup,andhistoricalincidencesforthe (Table D3). There were no treatment-related increased 

neoplasms mentioned in this section are presented in incidences in foci of hepatocellular alterationor other 

Appendix C for male mice and AppendixD for female nonneoplasticlesions of the liverinexposedmice 

mice. (Tables C5 andD4). 

Skin: Noneoplasmsornonneoplasticlesionsofthe Hepatocellularadenomaswerediscretelesionsthat 

skinwereattributedtotreatmentwith1,2-dihydro- compressed adjacent parenchyma and were composed 

2,2,4-trimethylquinoline(Tables C3,C5, D3, and D4).of well-differentiatedeosinophilic,basophilic,.or 

vacuolated cells. Normal hepatic lobular architecture 

Liver: Incidences of hepatocellular adenoma or carci- was absent, and uneven growth patterns were apparent. 

noma (combined) in 10mgkg males were significantly Hepatocellular.carcinomawascharacterized by a 

greater than those in controls at 2 years (Tables 16 and trabecular or adenoid pattern and poorly differentiated

C3). The combined incidence in the 10 mgkg group or anaplastic cells with evidenceof local invasiveness 

exceeded the rangeof historical or metastasis. 

Hepatocellular Adenoma 

Overall ratea 24/50 (48%) 30150 (60%) ~ 25/50 (50%) 26/50 (52%)

Hepatocellular Carcinoma 

Overall rate 8/50 (16%) (14%) 7/50 5/50 (10%) 13/50 (26%)

Hepatoblastoma 

Overall rate 0/50(0%) 1/50(2%) 2/50 (4%) 0/50(0%) 

Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastornab 

Overall rate 27/50 (54%) 33/50 (66%) 30/50 (60%) 37/50 (74%) 

Adjusted rate' 62.6% 78.4% 63.7% 80.2% 

Terminal rated 23/39 (59%) 28/37 (76%) 24/41 (59%) 28/37 (76%) 

First incidence (days) 612 357 385 490 

Logistic regression teste P=O.O36 P=O.O83 P4.351 P=O.O29 

a Number of animals with neoplasm per number of animals with liver examined microscopically 

Historical incidence for 2-year study with untreated control groups (mean f standard deviation): Feed -509/1,316 (38.7%2 13.9%),range

10%-68%;Dermal (Acetone)-63/150 (42.0% *'22.3%),range 18%-62% 

Observed incidence inanimals surviving until the end of the study 

Kaplan-Meier estimated neoplasm incidence at the ofendthe study after adjustment for intercurrent mortality 

e In the vehicle control columnare the P values associated with the trend test.In the dosed group columns are theP values corresponding to 

pairwise comparisons between the vehicle controls and the dosed group, The logistic regression test regards neoplasms in animals dying prior 

to terminal kill as nonfatal. 
1 

50 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

-. 

. .. ~. 

of 10 mgkg , . 

malemicewassignificantlylowerthanthatofthe (Table Dl). Although these are uncommon neoplasms 

controls at the 15-month interim evaluation (Table G4). a carcinoni in the control 

Kidney: The absolute right kidney weight There wasa renal tubule carcinoma in a control female 

inmale mice, the presence.of 

One adenoma and one carcinok were observedin both group,thelowincidence,theabsenceofanydose .

the: 3.6 and 6 mgkg groups (Table17). No neoplasms response, and the absenceof other treatment-or dosewere observed in the 10 mgkg group, and a carcinoma related effects such as hyperplasia make it unlikely that

was observed in one control male. By,contrast, only theseneoplasmswererelatedto1,2-dihydro-2,2,4-

three neoplasms were observed in over 1,300 control trimethylquinoline treatment. 

males from feed studies (Table C4b). ! 

. . 

of :L,2-Dihydro-2,2,4-trimethylquinoline 

Incidences-of Kidney .Neoplasms in Male Mice in the 2-Year Dermal Study 

TABLE17 . , 

/ 

. 

' 

, 

.. 

.. 

, . 

I 

., Vehicle Control , 3.6 mgkg 6mgkg i 

' . 10mgkg ' '' 

Renal Tubule Adenoma 

Overall ratea ' 0/50 (0%) 1/50 (2%) 1/50(2%) 0/50 (0%) 

.. ). ,

Renal Carcinoma Tubule I 

Overall rate 1 1/50(2%) 1/50(2%) 1/50(2%) 0/50 (0%) 

~ RenalTubuleAdenomaorCarcinomab 

rate Overall 1/50 (2%) ' 2/50 (4%) 2/50 (4%) 0/50 (0%) . . 

rate' Adjusted 2.6% 5.4% 4.9% 0.0% 

rated,. Terminal 1/39 (3%) 2/37 (5%) 2/41 (5%) 0/37 (0%) . . . .

e First incideye (days) . 729 (T) 729 (T) 729 (T) - , / 

~0gistic testf regression P=0.359N M.482 EO.5 18 P=0.511N .

- \ .. 

(T)'Terminal sacrifice 

Number of animals with neoplasmper number of animals with kidney examined microscopically 

Historical incidence for 2-year study with untreated control groups (mean f standard deviation): Feed -3/1,317 (0.2% f 0.6%),range 0%-'

2%;Dermal (Acetone)-11150 (0.7%f 1.2%),range 0%-2% 

Observed incidence in animals surviving until the ofendthe study 

Kaplan-Meier estimated neoplasm incidence at the endof the study after adjustment forinkrcurrent mortality . 

Not applicable; no neoplasms in animal group 

kthe vehicle control column are theP values associated with the trend test.In the dosed group columns aretheP values corresponbng to 

pairwise comparisons between the vehicle controls and the dosed group. The logistic regression test regards neoplasms in animals dying prior 

to terminal killas nonfatal. A negative trend or a lower incidencein a dose group is indicated byN. 

\ 
I-y~AR STlLJlLDy that of the controls because of moribund animals with 

SUUWiVd, &ldy w@igh&S, (QmdChbiCud FiPEdiRRgS skin neoplasms. Final mean body weights of all treated 

Survival rates and final mean body weights for female groups were similarto those of the respective controls.

SENCAR mice are shown in Table 18. Survival in all No clinical observations associated were with

treatedgroupswassimilartothat of the respective 1,2-dihydro-2,2,4-trimethylquinolinetreatment; howcontrols, except for the 2.5 pg DMBNO.5 pgTPA ever, mice promoted with TPA showed signs of irritagroup in which survival was significantly lower than tion and papilloma atthe site of application. 

BUFviWl Final Mean Body Weight (g) 

Vehicle Control 

Acetone/Acetone 28/30 47.4 

Initiator Test 

50 mgkg TMQlrpA 25/30 47.7 

Initiation Control 

AcetoneRPA 25/30 48.3 

Promoter Test 

DMBNAcetone 27/30 45.4 

DMBNS mgikg TMQ 28/30 48.3 

DMBNlO mgikg TMQ 28/30 46.5 

DMBN25 mgikg TMQ 27/30 45.6 

Promotion Control 

Acetone/S mgkg TMQ 29/30 45.7 

Acetone/lO mgkg TMQ 29/30 47.8 

Acetone/25 mgkg TMQ 27/30 47.3 

Initiation/Promotion Control 

DMBAiTPA 9/30** 45.7 

** Significantly different (P<O.Ol) from the acetondacetone control group 
52 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

Pathology Findings and promotion with acetone alone was not associated 

Thissection describesthestatisticallysignificantor with any lesionsof the skin at the siteof application. 

biologically noteworthy changes in the incidencesof Squamous cell papillomas and squamous cell carcinoneoplasmsandnonneoplasticlesions of theskin. masweremarkedlyincreasedintheDMBAfTPA 

Summariesof the incidencesof neoplasms and nonneo- positivecontrolgroup;however,noresponsewas 

plastic lesions, individual animal tumor diagnoses, and observed in groups initiated with DMBA and promoted

statistical analysesof primary neoplasms that occurred with 5, 25, 10or mgkg 1,2-dihydro-2,2,4-

with an incidenceof at least5% in at least one animal trimethylquinoline or in the group initiated with 1,2-

group are presented in Appendix E. dihydro-2,2,4-trimethylquinolineandpromotedwith

TPA.Acanthosisandchronicinflammationwere 

Skin: Theincidences of skinlesionsatthesite of increased in all groups promoted with TPA regardless 

applicationinmicetreatedwith1,2-dihydro-2,2,4- of the initiator treatment; however, the incidences of 

trimethylquinoline are shown in Table 19: Initiation nonneoplastic lesions were low in all other groups. 

TABLE19 

Ilncidences of Neoplasms and Nonneoplastic Lesionsof the Skin at the Siteof Application 

in Female SENCAR Micein the 1-Year Dermal Initiatiodl'romotionStudy 

of 1,2-Dihydro-2,2,4-trimethylquin~line~ 

SquamousCell SquamousCell Acanthosis Chronic ChronicActive Ulcer 

Carcinoma Papilloma InflammationInflammation

n 30 30 30 30 30 30 

Vehicle Control 

Acetone/Acetone Ob 0 0 0 0 0 

Initiator Test 

50 mgkg TMQrrPA 4 (1.1)1 30 (2.5)' 15 4 (3.5) 4 (3.5) 

Initiation Control 

AcetonemPA 3 1 30 (2.3) 19 (1.4) 5 (3.0) 4 (3.0) 

Promoter Test 

DMBNAcetone 0 0 l(l.0) 0 0 0 

DMBN5 mgkg TMQ 0 0 0 0 0 0 

DMBN10 mgkg TMQ 0 1 1(3.0) 0 0 0 

DMBN25 mgkg TMQ 0 0 3 (2.0) 2 (2.0) 0 1 (3.0) 

Promotion Control 

Acetone/S mgkg TMQ 0 0 l(l.0) 0 0 0 

Acetondl0 mgkg TMQ 

Acetond25 mgkg TMQ 

0 

0 0 

0 

l(l.0) 

3 (1.0) 

l(l.0) 

3 (1.0) 

0 

l(l.0) 

0 

0 

InitiatiodPromotion Control 

DMBAflTA 17 20 29 (2.9) lO(1.7) 15 (2.8) 7 (2.9) 

n = Number of animils with skin examined microscopically; TMQ= 1,2-dihydro-2,2,4-trimethylquinoline;TPA doses= 0.5 pg; DMBA 

doses = 2.5 pg 

Number of animals with lesion 

Average seventy gradeof lesions in affected animals: l=minimal, 2=mild, 3=moderate,4=marked 
53 

GIENIETIIC TOXIICOLOGY 

1,2-Dihydro-2,2,4-trimethylquinoline (1 to induced a moderate increase in sister chromatid 

333 pg/plate) wasnotmutagenicin Salmonella exchanges at a single dose level inthe first trial 

typhimurium strainsTA98,TA100,.TA1535, or conducted with S9; this increase was not reproduced in 

TA1537, with or without induced rat or hamster liver either of two subsequent trials and the overall response 

S9 (Zeiger et al., 1987; Table El). 1,2-Dihydro-2,2,4- in the presence of S9 was considered to be negative. 

trimethylquinolinewasshown to induce sister 1,2-Dihydro-2,2,4-trimethylquinolinedidnot induce 

chromatid exchanges in cultured Chinese hamster ovary chromosomal aberrations in cultured Chinese hamster 

cells in theabsence of S9 only (TableE2).All ovary cells, with or without S9 (Table E3). Cell cycle 

concentrations of 1,2-dihydro-2,2,4-trimethylquinoline delay again noted in the absence of was S9, and culture 

tested for inductionof sister chromatid exchangesin the times were extended. 

absence of S9 produced marked cell. cycle delay, 

necessitating lengthening of culture times in order to No increasesinthe frequencies of micronucleated 

ensure sufficient metaphase cells for analysis. In the erythrocytes were noted in peripheral blood samples 

presence of S9, occasional cell cycle delay was noted atobtained from male and female mice treated topically 

higher doses, and culture timeswereadjusted with 1,2-dihydro-2,2,4-trimethylquinolinefor 13 weeks 

accordingly. 1,2-Dihydro-2,2,4-trimethylquinoline (Table E4). . . 

I 
1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

. 
§§ 

of all groups of rats 

used for the synthesis of 1,2-dihydro-2,2,4-trimethyl- andmicexposed to 1,2-dihydro-2,2,4-trimethylquinoline polymer, and both the monomer quinoline was similar to that 

1,2-Dihydro-2,2,4-trimethylquinoline(monomer) is During the 2-year studies, survival 

and polymer of the controls. However, 

are usedasantioxidantsinstyrene-butadieneand 

nitrile-butadienerubbersandlatexes. 1,ZDihydro2,2,4-trimethylquinoline and other' antioxidants are 

generally mixed or milledinto crude rubber during the 

manufacturing process, and occupational exposure to 

such processing chemicals occurs primarilyas a result 

of skin contact (IARC, 1982). Quinoline and several 

substituted quinolines have been evaluated for carcinogenic potential and produced neoplasm responses in 

both rats and mice.Therefore,1,2-dihydro-2,2,4-

trimethylquinoline was considereda potential carcinogen and was selected for evaluation as a representative 

dihydroquinoline. Because of the pattern of use and 

exposure, dermal administration was considered the 

most appropriate route for. evaluationof carcinogenic 

potential. 1,2-Dihydro-2,2,4-trimethylquinolineis well 

absorbed through skin, and dermal administration also 

results in systemic exposure. 

Only mild indicationsof toxicity were associated with 

.1,2-dihydro-2,2,4-trimethylquinoline administration 

during the 13-weekstudies,andtherewereno 

treatment-related deaths. Lowermeanbodyweight 

gainwasobservedonlyin200 mgkg male rats in 

which the final mean body weight was 5% lower than 

that of the control group. The incidences of acanthosis 

and hyperkeratosis were increased at the site of application in 100 and 200 mgkg rats and 5, -10, 20, and 50 

mg/kgmice,andincidences of parakeratosiswere 

increased in 20 and 50 mgkg mice. Most of 'these 

lesions were considered within the range of minimal to 

mildinseverity,althoughtheaverageseveritywas 

somewhat greater in mice than in rats. Absolute liver 

weights were increased in100and 200 mgkg female 

rats and in 200 mgkg males but histologic changes 

(cytoplasmicvacuolization of hepatocytes)were 

observed only in the livers of 200 mgkg males. The 

starting at approximately week 20, mean body weights 

of 100mgkg rats were generally 4% lower than those 

of the controls andremainedup to 15%lower 

throughoutthestudy. The mean bodyweights of 

treated mice were similarto those of the controls. 

The incidences of renal tubule adenomas were significandy increased in all treated groups of male rats and a 

renal tubule carcinoma was found in one 36 mgkg 

male.However,theincidences of renal tubule cell 

hyperplasia in all treated groups were similarto those 

in the control group. The incidences of adenomas in 

treated groups were outside the rangesobservedin 

historical controls for 2-year NTPdermal or feed 

studies, as weretheincidences of adenoma or 

carcinoma(combined).Althoughobservedonlyin 

malerats, these proliferative lesions were not associated 

with the presence of hyaline droplets or with increased 

severity of nephropathy. Nephropathy was present in 

all groups of male and female rats, but the character and 

severity of nephropathy in treated groups was similar to 

thatin controls and wastypical of nephropathy 

normally observed in aging rats. 

Anextendedevaluation (step section) inmalerats 

revealed additional adenomas in both the control and 

treated groups. During standard evaluation,one oncocytomawasdiagnosedin a 100 mgkg male; an 

additional oncocytoma was found in a 36 mgkg male 

during step sectioning. Oncocytichyperplasiaand 

oncocytoma are proliferative lesions that occasionally 

occur spontaneously in older rats but more commonly 

areobservedinassociationwithchemical exposure 

(Bannasch et al., 1986). These lesions appear to arise 

in the epitheliumof the distal renal tubuleor collecting 

duct and by light and electronmicroscopy are 

morphologicallydistinctfromother proliferative 

rationales for dose selection for the 2-year studies were lsions of the renal tubule epithelium (Eble and Hull, 

based primarily on the severity of skin lesions in 200 1984). Oncocytomas do not progress to malignancy, 

mgkg rats and in 20 and50 mgkg mice. andthereforeanargumentmay be made thatthey 

should be given less weight than proliferative lesions 

whenclassifyingcarcinogenicresponse.However, 
56 1,2-Dihydro-2,2,4-trimethylquinoline,NTPTR 456 

even when the animals with oncocytomas are excluded,The incidences of hepatocellular adenoma or of hepatothe observed increase in adenomas is still significant cellular carcinoma were not significantly increased in 

and exceeds the historical control range. Therefore, thetreated male or female mice; however, the incidence of 

inicreased incidence of renal tubule adenomas in treatedcombinedhepatocellularneoplasmsinmalemice 

groups of male rats is considered related to 1,2-dihydro2,:2,4-trimethylquinolineadministration. 

Renal tubule adenomas were present inoe 3.6 mgkg 

and one 6 ,mgkg male mouse and renal tubule carcinomas were present in one control, one 3.6 m@g, 

and one 6 mgkg male and one control female. Al-

-- thoughrenal tubule neoplasms areuncommonin 

B6C3F, mice, the low incidence of these neoplasms, the 

lack of dose response, the absence ofother treatmentor dose-related effects such as hyperplasia, and their 

' presencein control animals suggestthattheyarenot 

associatedwith 1,2-dihydro-2,2,4-trimethylquinoline 

treatment. / 

The lower incidence of mammary gland neoplasms in 

groups of treated female rats appears to be associated 

with the lower mean body weights of these groups. The 

combined incidence of mammary glind neoplasms in 

treated groups was ,withinthe range of- historical 

controls from 2-yearNTP feed studies and there were 

no histopathologic changesor lesions present to suggest 

a direct effect of 1,2-dihydro-2,2,4-trimethylquinoline 

on the mammary gland. In an evaluation of the trends 

for growth, body weight,survival,.andneoplasm 

prevalence in diet contro1,groups of male and female 

F344/N rats from theNTP historical control database, 

Rao et al. (1990) found that 'the prevalence of mammary gland neoplasmsirfemale F344/N rats exhibitsa 

. strong positive correlation to body weight. Seilkop 

followed a positive dose-related trend and was significantly increasedthein 10 mg/kg group. 

Hepatoblastomas, uncommon phenotypic variants of 

hepatocellularcarcinomas,werepresentin one 

3.6 mgkg and two '6 mgkg males. However,+e 

incidence of hepatocellular adenoma and the incidence 

ofcombinedhepatocellularneoplasmsdecreased in 

treated female mice, and 1,2-dihydro-2,2,4-trimethylquinoline exposure wasnotassociatedwithany 

increased incidences of nonneoplastic liver lesions in 

male or female mice. ~ 

Haseman et al:, (1994)examined the correlation 

between &er dmor incidence 'and body weight in 

control groups of B6C3F,mice. Their analysis 

revealed that individually housed mice attain higher 

mean body weights and have correspondingly higher 

incidencesof liver neoplasms thangrouphoused 

animals. Because of this strong correlation between 

liver neoplasm incidence and body weight, the use of 

historical control neoplasm incidence data from studies 

in which animals differ greatly in body weight may be 

misleading.When the present study is compared to 

other recent studiesin which male mice had comparable 

mean body weights, the incidence of liver neoplasms is 

similar. 

- For example, Table 20 lists the maximum mean body 

weights for groups of untreated control male B6C3F, 

mice from'dosed feed and drinking .water studies in the (1 995) also founda strong positive correlation betweenNTP historical control database. These data show that body weight and mammary gland neoplasm incidence 

in female F344/N rats and developed a logistic regression model relating 1-year body weightsto mamniary 

gland neoplasm incidence. Using the 53-week.body 

weigdts for female rats in the present study (vehicle 

control, 293 g;-100 mgkg, 265 g) Seilkop's model 

predicts migmary gland neoplasm,rates of approximately 45% for controls and 35% for the 100 mgkg 

the incidence of hepatocellular neoplasms in untreated 

controls is strongly associated with maximum 'mean 

bodyweight and increases markedly whenbody 

weights exceed50 g. Table 21 lists the maximum mean 

body weights forall groups of male mice inthe current 

1,2-dihydro-2,2,4-trimethylquinoline,study. .. The 

incidences of hepatocellulz+r neoplasms in control, and 

dosed groups of male mice in the current study are group, which correspond closely with the actual rates of similar to those expected for groups of untreated male 58% for controls-and 38% for the 100 mgkg group. mice of equivalent maximum body weights. : . Therefore the incidencesof mammary gland neoplasms 

in female rats administered1,2-dihydro-2,2,4-trimethylqu:inoline are within the rage expected for untreated 

fernale rats with comparable body weights. 
'PS 1

6ES 
58 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

behave as either an initiator or. promoter of skin 

carcinogenesis in this model. 

Studies of quinoline and" numerous quinoline 

dexivativeshavedemonstratedthat the carcinogenic 

response to these compounds is strongly dependent on 

the presence of substituents and thelocation ofthe ' 

substituents in the quinoline ring. Quinoline, the unsubstituted parent, and 4-nitroquinoline-1-oxideare 

he:patocarcinogens in rats and mice (Hiraoet al., 1976; ' 

Shinohara et al., 1977; LaVoie et al., 1987).When 

administered in feed to F344/N rats, 8-nitroquinoline 

.induces high incidencesofforestomachneoplasms, 

whereas no carcinogenic response was observed with 

6-nitroquinoline, 6-methylquinoline, or

8-:methylquinoline (Fukushimaet al., 1981). Quinoline 

is also an initiator of skin neoplasms when applied to 

the skin of SENCAR mice and promoted by 12-0-

tetsadecanoylphorbol-13-acetate(LaVoie et al., 1984). 

However, evaluation of all seven positional isomersof 

methylquinoline for initiating activity in this same 

system revealed that 4-and 8-methylquinoline were 

also initiators while 2-, 3-, 5-, and 7-methylquinoline 

werenot(LaVoie et al., 1984). The presence of, 

substituents also influences the mutagenicityof 

quinolines. Quinoline itself is mutagenic in 

Salmonella, as are quinolines substituted at the 4 or 8 

position with hydroxyl or methyl groups or fluorine. 

However,substitutionatthe 2 position withany of 

thesesubstituents abolishes bacterial mutagenicity 

(LaVoie et al., 1991; Willems et aL, 1992). 

I 

Quinoline, 4- or 8-methylquinoline, and 5, 6-, 7-, or 

8-fluoroquinoline all induce DNA unscheduled

synthesis in freshly isolated rat hepatocytes, whereas 

2-methylquinoline or 2-fluoroquinoline donot (LaVoie

et al., 1991). 

1,2-Dihydro-2,2,4-trimethylquinolinecarries a double 

methyl substitution at the 2 position of the quinoline 

ring, and therefore the lack of mutagenicity and the 

inability to initiate mouse skin is consistent with the 

pattern of responses observed with other 2-substituted 

quinolines. 

CONCLUSIONS 

Under the conditions of these 2-year dermal studies, 

there was some evidence of carcinogenic activity* of 

1,2-dihydro-2,2,4-tri'methylquinolinein male F344/N 

rats, based on increased incidencesofrenaltubule 

adenoma and adenoma or carcinoma(combined). 

There was no evidence of carcinogenic activity of 

1,2-dihydro-2,2,4-trimethylquinolinein female F344/N 

rats receiving 36, 60, or 100 mgkg, or in male or 

female B6C3F, mice receiving 3.6, 6, or 10mgkg. 

Exposure of rats to 1,2-dihydro-2,2,4-trimethylquinoline by dermal application in acetone for 2 years 

resulted in acanthosisinmalesandfemalesand 

hyperkeratosis in femalesat the site of application. 'No 

nonneoplastic lesions in male or female mice were 

attributed to treatment with 1,2-dihydro-2,2,4-

trimethylquinoline. 

* Explanationof Levels of Evidenceof Carcinogenic Activity ison page 10. A summary of the Technical Reports ReviewSubcommitteecomments 

and the public discussion on this Technical Report appears on page 12. 
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TABLEAI 

TABLEA2 

TABLEA3 

TABLEAOa 

TABLEA& 

TABLEA5 
.;; 

64 

I. ! 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA1 

Summary of theIncidence of NeoplasmsinM,ale.Ratsinthe2-YearDermal Study. . 

of 1,2-Dihydro-2,2,4-t1jmethylquinoline'l . 

, , 

... 

. -. 

.................. ~ ........ 1. I . . . .I.' 

'.A , .r .iVehicle Control ~ , . 36 mgkg , I 6 0 mgkg 100 mgkg

Disposition Summary , .

Animals initiallyin study 60 60 60 60 

Z5-Month interim evalq&on 10 10 10 10 

Early deaths '. . 

Moribund 24 22 20 26 

' 

.. . . Naturaldeaths ' ' 21 26 25 23 

otherb 1 

Survivors 

Terminalsacrifice ' ' ' .. 5 2 4 1

Animals examined microscopically 60 60 - 60 ' 60 

15-Month Intenm Evaluation 

Alimentary System 

Liver I / /

-_ 

Pancreas 8 . -. Acinus, adenoma 

Endocrine System 

Adrenal medulla. *: . 

Pheochromocytomabenign 

Islets, pancreatic 

Carcinoma ' ' ' . 

Pituitary gland 

Pars distalis, adenoma' , . 

. 

Genital System .. - 1

.. I

Epididymis I " (10) (10) (10) (10)

Testes 2 ,_. ,. ., . . .. .. (10) ' . , (10) (10) (10) . 

Bilateral, interstitial cell, adenoma 5 (50%) 4 (40%) 2 (20%) 

Interstitial cell, adenoma 5(50%) 3(30%) 3(30%) '5 (50%) 

Systemic lmions 

Multiple organsc (10) (10) (10) * (10) 

Leukemia. mononuclear 1 (10%) 2(20%) 

..Mesotheliomamalignant . . - ..... 1 (10%) ... 

Systems Examined With No Neoplasms Observed 

Cardiovaqcular System 

General Body System 

Hematopoietic System i', 

.. . . Integume!ntary System 

Musculoskeletal System 

Nervous System 

Respiratolry System ,. 

1 , 

Special SensesSystem 

Urinary System 

~ ...... .,.I,, ............. <_ . . . . - . ..> . ,. ..... 
2-Year swy 

AIhmn~UarySystem 

Intestine large, colon 

Fibroma 

Intestine large, rectum 

Fibrous histiocytoma, metastatic, skeletal 

muscle 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Fibrosarcoma 

Liver 

Fibrosarcoma, metastatic, bone 

Fibrous histiocytoma, metastatic, skeletal 

muscle 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Osteosarcoma, metastatic, bone 

Mesentery 

Oral mucosa 

Squamous cell carcinoma 

Pancreas 

Fibrous histiocytoma, metastatic, skeletal 

muscle 

Mixed tumor benign 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tongue 

Squamous cell papilloma 

@taT~ovmscMnaPsystem 

Blood vessel 

Aorta, osteosarcoma, metastatic, bone 

Heart 

Fibrous histiocytoma, metastatic, skeletal 

muscle 

EnndnanocdmeSyshm 

Adrenal cortex 

Fibrosarcoma, metastatic, bone 

Adrenal medulla 

Fibrosarcoma, metastatic, bone 

Pheochromocytoma malignant 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Carcinoma 

Parathyroid gland 

Adenoma 

(47) 

(49) 

2 .(4%) 

. . .. 

(1) (1) . . .. 

' ' 1 (10%) 

(50) (50) (50) ' . (50)

. t 

1 (2%) . 
h\ 66 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEAJ 

Summary of the Incidenceof Neoplasms in MaleRats in the %Year Dermal Study 

of 1,2-D~ydro-2,2,4-trimethylquinoline(continued) 

I' .;'.. : Vehicle ' * ,i . Control . ' 36mgkg 60mgflrg 100 mgkg 

2-Year Study (continued) 

Endocrine System (continued) 

Pituitarygland . (49) (50) (50) (49)

Pars distalis, adenoma . ' 25 (51%) 23(46%) 18 (36%) 18 (37%) 

.Pars distalis,'adenoma, multiple 1(2%) 

Pars distalis, carcinoma 1 (2%) 

Thyroid gland (50) (50) (50) (50)

C-cell, adenoma 1 (2%) 

Follicular cell; adenoma 1 (2%) 

i 8 . 

&nerd ~ody System 

None 

Genital System 

Epididymis' (SO) . . 

Fibrous histiocytoma, metastatic, skeletal .. 

muscle 1 (2%) 

Preputial gland. (49)

Adenoma ' ' 1(2%)

Garcino~na-.. . . 2(4%) 

prostate (49)

Fibrous histiocytoma, metastatic, skeletal 

muscle 1 (2%) 

Seminal vesicle ' , (50)

Fibrous histiocytoma, metastatic, skeletal 

muscle 1 (2%) 

Testes (50) (50) (50)

Bilateral, interstitial cell, adenoma 18 (36%) 32 (64%) 27(54%) ' 

Interstitial cell, adenoma 18 (36%) 9 (18%) 14 (28%) . 

Hematopoietic System 

1 Bonemanrow . . 

Lymph node 

Lymph node, mandibular 

Carcinoma, metasktic, Zymbal's gland . . 

Fibrous histiocytoma, metastatic, skeletal 

muscle 

..Lymphmesenteric ncde, , - . . , . .

Spleen 

Fibrous histiocytoma, metastatic, skeletal 

muscle *L 

Lipoma. 

Thymus . ' 

Fibrous histiocytoma, metastatic, skeletal .. . muscle .;' ' ' 

Thymoma benign i (2%) 
Mammary gland 

Integumentary System 

2-y&2P &dy (continued) 

Fibroadenoma 

Adenoma 

Sebaceous gland, skin, site of application, 

Pinna, squamous cell papilloma 

Pinna, melanoma malignant 

Squamous cell papilloma 

Keratoacanthoma 

Basal cell adenoma 

Subcutaneous tissue,skin, site of 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, fibroma, multiple 

Subcutaneoustissue,fibroma 1 (2%) 

Skin,site of application,keratoacanthoma 1 (2%) 

Subcutaneous tissue, skin, siteof 

(42) 

Skin (50) 

1(2%) 

'. 1(2%) ' 

adenoma 

. . 

application, fibrosarcoma 

application, fibroma 

2 (4%) 

1 (2%) , . 

. ... . , 

I 

Bone 

Musculoskeletal System 

Vertebra, fibrosarcoma 

Turbinate, chondroma 

Osteosarcoma 

Carcinoma, metastatic, Zymbal's gland 

Carcinoma, metastatic, pituitary gland 

Osteosarcoma 

Fibrous histiocytoma 

Fibrosarcoma, metastatic, bone 

Skeletal muscle 

Brain 

Nervous System 

(50) 

Carcinoma, metastatic, Zymbal's gland 

Astrocytoma malignant 1(2%) 

(50) 

. .. , 

. ? .$ 

Lung 

Respiratory System 

(50) 

Fibrous histiocytoma, metastatic, skeletal 

Carcinoma, metastatic, Zymbal's gland 

Alveolarlbroncbiolar adenoma 

Osteosarcoma, metastatic, uncertain primary 

Osteosarcoma, metastatic, bone 

Melanoma malignant, metastatic, skin 

Osteosarcoma, metastatic, skeletal muscle 

muscle 

site 

1 (2%) .. . .. 
1,2-Dihydro-2,2,4-trimethylquinoIine, NTP TR 456 

TABLEA:L 

Summar!l aIf the IncidenceaIf Neoplasm in Male Rats in the 2-YearDermal Study . 

. . of 1,2-DiIrydro-2,2,4-trimethylquinoliie(continued) * . _ . . . . . . . .. 

. . ,.. ' ' ' Vehicle Control . ' 36m@g . ' aomglkg 100 m@g

. ... . . .. 

Carcinoma, metastatic, Zymbal's gland 

Ear 

Special Senses System 

(3) (1) 

1(100%) 

(2) (2) 

Carcinoma 

Zymbal's gland (1)

1(100%) 

(1) 

1(100%) 

(1)

1(100%) 

Kidney 

Urinary System 

SarcOma 

(50) (50) (50) (50)

1 (2%) 

Renal tubule, adenoma, oncocytic 

Renal tubule, adenoma, multiple 

Renal tubule, adenoma 1 (2%) 7(16%) . 8 (16%) 

2 (4%) 

7(14%) 

1 (2%) 

Renal tubule, carcinoma 

Urinary bladder (49) 

1 (2%) 

(50) (50) (48) 

Systemic IRsions 

Multiple organs 

. . Leukemiamononuclear 

(50) 

25 (50%) 

' (50) 

25 (50%) 

(50) 

17 (34%) 

(50) 

14 (28%) 

Mesothelioma malignant . . . . , , . 1 (2%)- ' - 4 (8%) :2 (4%) 2 (4%). 

. . . :? - _. ,-
~otalanimals with primary neoplasmsd 

Neoplasm Summary 

15-Month interim evaluation 7 9 9 8 '' 

2-Year study 48 50 46 49 

Total primary neoplasms 

15-hrlonth interim evaluation 12 10 14 8 

2-Year study 109 134 114 105 . . 

Total animals with benign neoplasms 

15-Month interim evaluation I 8 9 8 " 

2-Year study 48 50 45 47 

Total benign neoplasms 

15-Month interim evaluation 11 8 12 8 

2-Year study 80 96 87 80 

Total animals with malignant neoplasms 

15-Month interim evaluation 1. 2 2 . .I ., 

2-Year study 

Total malignant neoplasms 

21 33 23 21.. 

15-Month interim evaluation 1 2 2 

2-Year study 29 38 27 .25. 

Total animals with metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 1 7 6 2 

Total metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 1 30 ' '' 16 14 - -

Total animals with malignant neoplasms 

of uncertain primary site 

2-Year study 1 

a Number of animals examined microscopically at the site and the numberof animals with neoplasm 

At necropsy, it was discovered that oneof the 60mgkg male rats was actuallya hermaphrodite. However, the animal was microscopically examined and 

pathology data were included as if it were a male. 

Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
~ 70 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA.2 

Individual Animal Tumor Pathology of Male Rats in the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:Vehicle Control 

Number of Days on Study 

Carcass IID Number 

Alimentary System 

Esophagus 

Intestine large, colon 

Fibroma 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatoa:llular carcinoma 

Mesentery 

Mesothelioma malignant, metastatic, epididymis 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Heart 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Adenoma 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

General Body System 

Tissue NOS 

Genital System 

Epididymis 

Penis 

Preputial gland 

Adenoma 

Prostate 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+: Tissue examined microscopically 

A: Autolysis precludes examination 

3444455555555566666666666 

9239901222456601111222333 

3852873127273430368045017 

0000000000000000000000000 

3323325140511220103253301 

3778638814304697761050259 

......................... 

+++++++++++++A+++++++++A+ 

.......................... 

++++A++++++++-A+++AA++++A+ 

......................... 

++++A++++++++++++A+++++++ 

++++A++++++++A+++A+++++AA 

......................... 

+ +++ + + + 

X 

......................... 

. . . . . . . . . . . . . . . . . . . . . . . . . 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... X 

++++++++++M++++++++++++++ A 

......................... xxxxx x x xxxx xxxx ......................... ~~ 

........................... ++ + ......................... 

.......................... 

.......................... 

......................... X X X X 

x xxxx xx x x x 

M:Missingtissue - X: Lesionpresent 

I: Insufficient tissue Blank: Not examined 
Number of Days on Study 

Carcass IDNumber 

I 

Alimentary System 

Esophagus 

Intestine large, colon 

Fibroma 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular carcinoma 

Mesentery 

Mesothelioma malignant, metastatic, epididymis 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

I Cardiovascular System 

Heart 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Adenoma 

Pituitary gland 

Pars distalis, adenoma xxx

Thyroid gland 

General Body System 

Tissue NOS 

Genital System 

Epididymis 

Penis 

Preputial gland 

Adenoma 

Prostate 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

6666666666666666661711177 

4555555566661188890222222 

9002223627885937919299999 

0000000000000000000000000 Total 

3150354115232144550002446 Tissues/ 

9148468230558665121231230 Tumors 

......................... 50 

......................... 47 

X 1 

......................... 41 

+AA+++++++++A++++++++++++ 42 

......................... 50 

......................... 46 

AAA+A+++++++A++++++++++++ 40 

......................... 50 

X 1 

+ + + 10 

1 

......................... 50 

......................... 49 

......................... 50 

......................... 50 

.......................... 50 

........................... 50 

......................... 50 

X X 2 

X xx 3 

......................... 50 

x x xx X 6 

++M++++++++++++++++++++++ 48 

1 

+++++++++++++++++++M+++++ 49 

xx X xxx x 25 

......................... 50 

+ 1 

......................... 50 

+ + + 6 

......................... 50 

X 1 

.......................... 50 

......................... 50 

......................... 50 

x x x x xxxxx x xx x 18 

X X x x xx x X 18 
72 1,2-Dihydro-2,2,4-trimethylquinoline;NTP TR 456 

TABLEA;! . . Individuall Animal TumorPathology of Male Rats in the.2-Year Dermd Study . I ' . .,. ' r . . < of 1,2-Dih1ydro-2,2,4-trimethylquinoline:.Vehicle Control (continued)' . . 1. . . . -. ' ' .. 

.. 

34'444-55555555566666666666 

Number of'Days on Study 9 2 3 9 9 0 1'2 2 2 4 5 6 6'0 1 1 11 2 2 2.'3"3 3 

3.8 5 2 8'7 3 1. 2 I 2 I3 -4 3 0 3 6 8 0 4 5.0.1 I , .. . .- . . 

. .,. ... 000'000000,0000000000000000 

CarcassID, Nuniber 33~233,2514051122010325330'1~ I. 11 

. 3 I, 7 8 6. 3'8 8 ,1'4-3 9 4 6 9 7 ,I 6 1 , O 0 2 5 9 ~ - . . . ,+" . -, .. .. 5. 

. . Hematopoiletic System 

Bone m%ow ........................... Lymph: node + + ++ + + + +. 

' 

Lymph node, mandibular ........................... 

Lympd-node, mesenteric ......................... Spleen' ' .......................... 

+ + + + f + M,,+ + +,+ + +,+ + + + + + + + MM,+ ThYmuS'. . . .. . .. ,. +* 

Integumentary System . . 

Mammary gland + + + + M+ + M+ + MM+ +'+ + + M+ + M+ + + + 

skin ', .......................... Keratoacanthoma X 

pinna, squamous cell papilloma ' .. 

Skin, site of application, keratoacanthoma 

Sqbcuty:ous tissue, fibroma . .. .. . , . 

Musculoskeletal System 

' 

+ + + +.+,.+,+ ,+ -+ + .+ + ,+ + + + + + + + + + B??e.. . . , .. ' .. 

Nervous System . , 

Brain ' ........................... Aseytov malignant . .. I ., . . ? . I.. . i 

Respiratory System .. 

. , .... Lung ' .......................... 

.......................... i) Nose .. + +,+ .+ +'+ + + + + + + + + + +,+,? + +,+ + + + + Trachea.. . . .. , .. .. .. -

Special Senses System 

Ear + + 

Eye

Zymbai's gland + 

Carcinoma , , X . ., .. 

. ., . - .-

Urinaq System 

Kidney ............................ Re@ tubule, adenoma 

Uriniry bladder . 1- ~ '' , . + +,+ + +.+ + + + + + + + + + i + +,+ + +,+ + + A . ..- . . . . I . , 

Systemic Lesions 

Multiple organs ........................... Le$emia mononuclear X .xx x x X 'xx' xx 

Mesotheliomamalignant *_ . . .. X I -
73 

TABLEA2 

of n~-D~ydl11.o3~~~-U~eU~yU~~50~5e~ VeUni.deConnUmU (continued) 

hdi~ddAhd k~~lr P~UIOUO~ off "I@ &.US hU k 2-Ym bmd ScrOndy , , . 

. . . . .( 7 

', ' 

I . 

..". 

6666666666666666667'777777 ' 

hI4llbeU' Of &J'S QUU sbdy 4555555566667788890222222 .. ".., 

9002223627885937919299999 

. .. 

0000000000000000000000000 Total-' 

@ m m Mmber 31503541.15232144.550002446 Tissues/,

9148468230558665721231230 Tumors 

,. 

&DI&Q@C?& SySblll 

Bone marrow .......................... 50 

Lymph node + +++++++ + ++ 19,. . : 

Lymph node, mandibular .......................... 49 

Lymph node, mesenteric ......................... 50 

' 

Spleen ......................... 50 

Thymus +M+++++M+++++++.++++++++++ 45. 

hUegumemtalry sysuem .. 

Mammary gland M+M++++++++++++++++++++++ 42 

Skin ......................... 50 '. 

Keratoacanthoma 1 

Pinna, squamous cell papilloma x 1 

Skin, site of application, keratoacanthoma x '1 

Subcutanmus tissue, fibroma x . 1 

MlnscuFirloskeUe~sysuem ,. 

Bone ......................... I 

50 

Mewolns sysuem I' 

Brain ......................... 50 

Astrocytoma malignant x ,_" . 1 

RapimuQrysysuem 

Lung ........................... 50 

Nose ......................... 50 

Trachea .......................... 50 

Eye + 1 

Zymbal's gland 

Carcinoma 

1 .:. . i r 

uirhwysysuem 

Urinary bladder 

Kidney 

Renal tubule, adenoma 

......................... x ......................... 

. 

1 

50,.. 

49 . 

. ~. 

?..* 

sySIkllllk hkD!lW 

Multiple organs 

Mesothelioma malignant 

Leukemia mononuclear x x x x xx x x x x xx x x x .......................... 50' 

.25' 

1 

; 
1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR '456 

TABLEA2 %: ~. Individual AnimalTumor Pathology of Male Rats in the 2-YearDermal Study .. 

.. - . :

of 1,2-Dihydro-2,2,4-trimethylquinoline:36 mgkg , .. . 

4555555555566666666666666 

Number of Days on Study 7'0566789999000001111222~33 * . . 

1443810224801339033956709 

.a , 1100110010011001101000010 

CarcassID Number . 01971099078~10891091687818' ,.-, - .,. . 6058936243738111137187269 

AlimentarySystem 

Esophagus .......................... Intestine lirge, colon ++++t+++++++++++A++A+++++ 

Mesothelioma malignant, metastatic, testes X 

Intestinelarge, rectum' . ........................... . . Intestine large,cecum , 

+++++++++++A+++-++A+A+.++++ 

Mesothelioma malignant, metastatic, testes X 

Intestine small, duodenum ......................... Mesothelioma malignant, metastatic, testes X 

Intestine sma, jejunum +++++++A++++'++++A++A+++++ 

Mesothelioma malignant, metastatic, testes . . X 

Intestinesnkll, ileum +~++++AA+++A++A+AA+A+++~A 

Fibrosarcoma 

Mesothelioma malignant, metastatic, testes 

.Liver . :. 

Fibrosarcoma, me&@tic, bone 

Hepatokellular adenoma 

Osteosarcoma, metastatic, bone 

MesenterylMesothelioma malignant, metastatic, testes . . Pancreas 

. . Mesothelioma malignant, metastatic, testes 

Mixed tumor benign 

salivary glands 

Stomach, foiestomach .

. . Stomach. elindular 

CdovasdarSystem 

Blood vessel 

Aorta, osteosarcoma, metastatic,. bone 

Heari ,: ............................ , . 

EndocrineSystem 

Adrenal coitex .......................... . . Fibrosarcoma, metasyic, bone 

Mesothelioma malignant, metastatic, testes X. ., .

Adrenalmedullia ......................... Fibrosaicoma, metastatic, bone . . Phe6chiomacytoma malignant 

Pheochromocytoma benign X X X 'x 

Islets, pancreatic ......................... . . . .

Adenoma -X 

Carcinoma X . . Pqthyroidgland + + + + + + + +'+ + + + +'+ + + +..+ + + + + + Mi 

F'ituitary gland .......................... Pars distalis, adenoma xx x ' 'XXXX xxxxx X 

Pars distalis,carcinoma 

Thyroid glarid .......................... Ccel1,'adenoma 

Follicular cell. adenoma 
I 

Nurnber of Days on Study 

CarcassIo[D Number 

MmenhPy System 

Esophagus 

Intestine large, colon 

Mesothelioma malignant, metastatic, testes 

Intestine large, rectum 

Intestine large, cecum 

Mesothelioma malignant, metastatic, testes 

Intestine small, duodenum 

Mesothelioma malignant, metastatic, testes 

Intestine small, jejunum 

Mesothelioma malignant, metastatic, testes 

Intestine small, ileum 

Fibrosarcoma 

Mesothelioma malignant, metastatic, testes 

Liver 

Fibrosarcoma, metastatic, bone 

Hepatocellular adenoma 

Osteosarcoma, metastatic, bone 

Mesentery 

Mesothelioma malignant, metastatic, testes 

Pancreas 

Mesothelioma malignant, metastatic, testes 

Mixed tumor benign 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Crapdiov~cdarSystem 

Blood vessel 

Aorta, osteosarcoma, metastatic, bone 

Heart 

Endoche System 

Adrenal cortex 

Fibrosarcoma, metastatic, bone 

Mesothelioma malignant, metastatic, testes 

Adrenal medulla 

Fibrosarcoma, metastatic, bone 

Pheochromocytoma malignant 

Pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Carcinoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Pars distalis, carcinoma 

Thyroid gland 

C-cell, adenoma 

Follicular cell, adenoma 

.. 

6666666666666666611111111 

4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 I 9 0 0 1 1 2 2 '2 2-.,'.*.:; 

0115199001330035324685899 .. . 

000000100000.0001101110000 Total 

9 8 8 6 I I O I9 I8 9 6 I6 2 0 8 0 11 8 I9 9.TisSue~l..~.:-* 

9064299104311580250254648 Tumors . . .. 

- I 

........................... 50 I. 

++++++.++A++++++++++++++++.~ 41 r.. 

. . 1 '. " 

++++++++ A++++++++++++++++,... 49, ' 

++++++A+A++++++++++A+++++, ...44.-. 

.' , 1. ,f ,' 

......................... . 50..;., 

.. .,. . ./ 1 . +++++A++++++++A++++++++++ ,,.,45:,: -! 

' c . 1 , 

++A++A+AA++++++++A+++++++ .31. .: 

X ;1 , 

.+.l .,.> 

........................... 50 

X . + ..1 , 

X ., . .2 "* , 

X 1 . 

3 '. 

.. ;f . . 4 '8. , t 

......................... 50 ,. .. 

.,l , , :v

x ' .: I. 1 : '. 

......................... 50 ' 

............................ .~ 5Oi-- ' 

......................... 50 . .I I

~ .. 

. < . * I.' .., ,' I'

+ I.<,' . 

X , , '_ 1 .". .' 

~ 

.......................... 50 . . .L. 

.? . , . ; ,. .. . e/. 

.......................... 50 ,: . 

X 1 I. !

1 .;I . * 

......................... ,50,: ~. 

X .1 .., . 

X X 4 . ,2 ,. 

X X ,x .I ......................... 50. c .

X ..2 ' . 

1.. . . .' ......................... ,49. ..;. 

......................... 50 , ..-' I 

. xx x-x xx x X xx %23 ,t 

,-

X . .I,: ......................... .50 ! . 

X '1 i" . 

X T.1 I A 

j 

. . : 

I 
76 

. . 

. . 

1,2-Dihydro-2,2,4-trimethylquinoline,. NTP TR 456 

. , TABLEA2 

Individual1 Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study . . 

of 1,2-Dih;ydro-2,2,4-trimethylquinoliie: 36mag (continued) 

, ' 

. . ! . ' 

-. .............. 

'' . 4 5, 5 5 5 5 5 5 5 5 5 6 6'6 6 6 6'6 6 6 6 ' - 66 ,6 . 6 

Number of Days on Study 7 0.5. 6.6 7 8 9 9 9 9 . 0- 0 0 0 0 1 1 111 2'2..2 3 '3 I . " 

1 4 4.3 8 1 0 2 2 4 8-0 1 3 3.9'0 3'3 9 5 6. 7 0 9 . . - .. I.. 

', ;I 1 o o 1 1 o o 1 o O 1'1.0 0, 1 1 ' 01 ' 0 o o o 1 o .. 

Cam& ID Number , ,O 19 7. 10 9 9 0 7 8: 10 8 9.1 0.9 16.8 7 8'1 8' 

:. .' . . : -6 0 5 8 9 3 6 2 4 3 7.3'8.1 7 1. 7 3 7 1 8 7'2 6.9 

.. 

General B,dySystem . . 

None . . 

.... ...... 

Genital Sysltem 

Epididymis . . + + + + + + + + + + + + +.+.+;+ + + + + +.+ + + + 

Mesothelioma malignant, metastatic, testes x x . . 

Penis . , .. + + ++ . . 

preputial gland + +'+ + + M+ + + + + + +'+ + +'+ + + + + + +.+ + 

Adenoma ' x X 

carcinoma 

, 

Rostate, . . ........................... Mesothelialmamalignant,metastatic,testes ' . X

Seminal vesicle '+++++++++++++'i++++i++.t++.+ 

.Mesothelioma malignant, metastatic, testes x x 

Testes ........................... Bilateral; interstitial cell, adenoma x xxxxx x x X x,x x x x 

Interstitial cell, adenoma X x ' X x ...... 

Hematopoietic System 

. . 

Bone marrow . .......................... Lymph node +++ + ++ 

Lymph node, rnandibular ......................... Lymph, node, mesenteric .++++++++++++++++++++4++.++ 

Spleen : .......................... Mesothelioma malignant, metastatic, testes X 

Thymus , ' . + + +'+ + M+ + + + + + + M+ M+ + + + M,+ + +,+. 

-. .... 

Integumentary System. 

Mammy gland + + + + + + + + MM+ + + M+.MM+.+ + M'+ + + +. . 

.. Fibydenama . , . . 

Skin ... . , ......................... Ker&acanlthoma .x 

Squamous cellpapilla+ 

Pinna,squamouscell papilloma X. . . Sebaceous gland,skin, site of application, . . . . adenoma 

Subcutaneous tissue, fibroma . . 

Subcutaneous tissue, skin, siteof application, 

'fibroma ......... - -...... 

Musculoskeletal System , .

. . 

Bone, " + + + + + + +, .+ + + + + +. + ,+ + + + + +:t +.'+. .+ + 

Carcinoma, me&tatic, pituitary gland . . ,Carcinoma, metastatic, Zymbal's gland 

osteosarcom . .

Vertebm,fibrosarcomi . .: , . . . . . Skeletal muscle . 

Fibrosarcoma, metastatic, bone 

....... 
.,. . . . , , i s , TABLE A2 .. .. >. I _ .:r . (. , - b . j

IInndividnaUAnnimd Tumor P~URUQUQ~JJ of "le RaUs inn Uhe %Year Demd Sdundy 1,. r, . . 3 , , . ' 9 ' . . ,.. , . of n,2-DiRUg.d~~-2,2,~-U~meURUyn~~nn~U~nn~: I > 

36mgkg (continued) . ._.,.._. . . ..,_ .. 

6666666666666666677777777 

Number . . of Days on Study 4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 7 9 0 0 1 1 2'2"2 2' . * '.'.' '"'" 

0115'799001330035324685899 . . . ... 

0000001000000001101110000 Total 

carcass IIIIP Number 9 8 8 6 7 7 0 7 9 7 8 9 6 7 6 2 0 8 0 11 8 7 9.'9 .Tissues/.';-

90642991'043.1.7580250254648 Tumors 

. . . .,,<. . . . ._ ,. . . Boay syst@m 

None ... . ..-., 

* . . . - .*. . . Genlitralsyst@m 

Epididymis ......................... .50 , .: * 

. 3' X ., Mesothelioma malignant, metastatic, testes * . , " . 

+ + ++ + + 10 i Penis ' 

Preputial gland ......................... Adenoma ::* 2

Carcinoma 

Prostate 

Mesothelioma malignant, metastatic, testes 

Seminal vesicle 

Mesothelioma malignant, metastatic, testes 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

Hematopoietic system 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Mesothelioma malignant, metastatic, testes 

Thymus 

Integumentary System 

Mammary gland 

Fibroadenoma 

Skin 

Keratoacanthoma 

Squamous cell papilloma 

Pinna, squamous cell papilloma 

Sebaceous gland, skin, siteof application, 

adenoma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue,skin, site of application, 

fibroma 

X ,. '1 . 50' 21: 

........................... )..e 

X . .; 2 ).

......................... ,.'.50. 

X . ,. 3. : 

50 e .. 4 ......................... 

X xxxx xx X X X X X X X.X' X X X' :' 

, 

' .32 - x , ' . , , . , , -q. ', X X x x . . _. . . 

,, ;', ' k.; :, . 1. 

......................... "550 

++++ + ' 45' I . i + + ++ ~, 

+ + + + + + + + + + + +'+ + + + + + + + + + + +'+'- '*''50.'..: 

........................... .50-. 

.......................... 50 .. X .2 .. 

M+++++++++++++++++++++++M 44' " " 

, '.( : . :;. . -.,!a,. 'I -. ., . 

+++M+++M+++++++++++++++++ 42'' .-, 

X . '. 1,'

50 ' ':' .......................... 1 .

; ! 1 ": ... . ,

X 1. , . .. 

.I 

X 1 

X ' . 9: 1. .. . . . . I. 

.. 

- X -

.. .-.-. I .... 

..; . . MlasculoskdetalSystem . :> .. ,' :..

Bone ......................... 

,, 

50 .." 

Carcinoma, metastatic, pituitary gland X . , 

": 1 .. . . . . , ..x 1 ._'

. . Carcinoma, metastatic, Zymbal's gland 

Osteosarcoma . . i l X '1 ', . . Vertebra, fibrosarcoma X I ' 1 -i. 

I 

Skeletal muscle + '.1 '. 

Fibrosarcoma, metastatic, bone X 
78 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA2 

Individual .Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study 

of 1,2-Dihy1dro-2,2,4-trimethylquinoline:36 mgkg (continued) 

4555555555566666666666666 

Number ofDays on Study 7056678999900000111122233 

14438.10224801339033956709 

1100110010011001101000010 

CarcassID Number 0197109907810891091687818 

6058936243738171137187269 

Nervous System 

Brain ......................... 

Respiratory System 

Lung ......................... Osteosarcoma, metastatic, bone 

Nose ......................... Glands, adenoma 

Trachea .......................... 

Special Senses System 

EX 

Carcinoma, metastatic, Zymbal’s gland 

Eye

Zymbal’s gland 

Carcinoma 

Urinary System 

Kidney .......................... Renal tubule, adenoma x 

Renal tubule, carcinoma 

Urinary bladder ......................... Mesothelioma malignant, metastatic, testes X 

Systemic Lesions 

Multiple organs ......................... 

Leukemia mononuclear x xxxxx x x x x xx . x xxx 

Mesothelioma malienant X x x 

._ 

.. 
 

Carcass IDNumber 

Nervous System 

Brain 

Respiratory System 

Lung 

Osteosarcoma, metastatic, bone 

Nose 

Glands, adenoma 

Trachea 

Special Senses System 

Ear 

Carcinoma, metastatic, Zymbal’s gland 

Eye

Zymbal’s gland 

Carcinoma 

Urinary System 

Kidney 

Renal tubule, adenoma 

Renal tubule, carcinoma 

Urinary bladder 

Mesothelioma malignant, metastatic, testes 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

Mesothelioma malignant 

0000001000000001101110000 Total 

9886770797896762080118799 Tissues/ 

9064299104317580250254648 Tumors 

......................... 50 

......................... 50 

X 1 

++++++++++ ++++++++++++++ 49 

X 1 

.......................... 50 

+ 1 

X 1 

+++ 3 

+ 1 

X 1 

......................... 50 

x x x x X X 7 

X 1 

........................... 50 

X 2 

......................... 50 

X X X xx x x xx 25 

X 4 
80 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR'456 

TABLEA:2 

Individual Animal Tumor Pathology of Male Ratsin the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:60 mgkg 

2344555555555555666666666 

Number of Days on Study ~ 5 8 5 5 2 2 5 5 6 1 1 1 1 1 8 9 0 1 1 1 1 1 2 2 2 

0159260380005550323679012 

lalllllllllll.lllllllllllll 

3263112413615834152551223 

6967911130267083056491322 

Alimentary System 

Esophagus ......................... Intestine large, colon +++++++++++++++++++A++A++ 

Mesotheliomamalignant,metastatic,testes , X 

Intestine largg:, rectum ......................... Intestine large, cecum AA+++++++++++A+++++.A++A++ 

Intestinesmall, duodenum ......................... 

Mesothelioma malignant, metastatic, testes X 

Intestine small, jejunum .......................... . 

Intestine small, ileum +++++A+++++++A++A++A++A+A 

Liver ......................... Hepatocellular carcinoma X X 

Mesentery + + 

Mesothelioma malignant, metastatic, testes X 

Pancreas ......................... Mesothelioma malignant, metastatic, testes X 

salivary glands ......................... Stomach, forestomach . ..........................

Stomach, glandular .......................... Tongue + 

Squamous cell papilloma X 

Cardiovascular System 

Heart ........................... 

Endocrine System 

Adrenal cortex . . .......................... Adrenal'medulla ......................... Pheochron~ocytoma benign X X 

Bilateral, pheochromocytoma benign 

Islets, pancreatic ......................... Carcinoma. 

Parathyroid gland M++++++++++M+++++++++++++ 

Pituitary gland ......................... Pars distalis, 

' 

adenoma xx xx x x X X x x 

Pars distalis, adenoma, multiple 

Thyroid gland .......................... 

GeneralBody System 

None 

Genital System 

Epididymis ......................... Mesothelioma malignant, metastatic, testes X ~. 

Penis ++ 

Fkputid gland ......................... 

Adenoma X 

Carcinoma , .

Prostate ........................... Mesothelioma malignant! metastatic, testes X 

a At necropsy, it was discovered thatthis rat was actually a hermaphrodite. However, the animal was microscopically examined and the pathology data were 

included as if it were a male. 
cmms lr!4D Number 

hbmenhany System 

Esophagus 

Intestine large, colon 

Mesothelioma malignant, metastatic, testes 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Mesothelioma malignant, metastatic, testes 

Intestine small,jejunum 

Intestine small, ileum 

Liver 

Hepatocellular carcinoma 

Mesentery 

Mesothelioma malignant, metastatic, testes 

Pancreas 

Mesothelioma malignant, metastatic, testes 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tongue 

Squamous cell papilloma 

cm~ovascmlarSystem 

Heart 

~~dQc&le§ySkBll 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Carcinoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Parsdistalis,adenoma,multiple ' 

Thyroid gland 

@nerd Bdy SySt@m 

None 

@miMsysuem 

Epididymis 

Mesothelioma malignant, metastatic, testes 

Penis 

Preputial gland 

Adenoma 

Carcinoma 

Prostate 

Mesothelioma malignant, metastatic, testes 

1111111111111111111111111 

2553656467652243434324467 

5309317494121851149346802 

.......................... 

+++A+++++++A+A+++AA+A++++ 

......................... 

+A+AA++++++A+A++AAA+A++++ 

++++A+++++++A++++A+++++++ 

+A+A+++++++AA+++'+AA++++++ 

AA+A+++++++AAA++AAA+A++++ 

.......................... 

+ 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... X X X 

X .......................... 

X 

++++++++++++++M++++++M+++ 

.......................... x x x x x x X 

X ......................... 

~~~ 

......................... X 

......................... x x 

X ......................... 

Total 

Tissues/ 

Tumors 

'. 2 

50 , 

42 . I 

, 

1. 

49 .. 

36 

46 .: 

1 

42 ' 

34 

50 

2 

3 

1 

50 .. 

1. 

50 

50 

50 . 

1 : 

1 

50 . 

50 . 

50 

5 

1 

49 . 

1 

46 

50 

18 

1, 

50 . 

~~ ~ 

_I. 

50 ' 

2 

2 

49 

3. 

1-

50 . 

1 _ -

.: 
82. 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA2 

- Individual Animal Tumor Pathology of Male Rats in the 2-Year DermalStudy >I . , . . ..

of 1,2-Dihydro-2,2,4-trimethylquinoIine:60mgkg (continued) . ' I. : ,t -

, . .. .,

2344555555555555666666,666 

Number of Days on Study 58552255677777890111112,22, . , .

0159260380005550323679012 

1111111111111111111111111 

Carcass LD Number 3263772473675834752557223 , I

6967911730267083056497322 .. 

* .. .. ." 

Genital System(continued) , ..

Seminal vesicle ., ............................. ,' 

, Mesothelioma malignant, metastatic, testes X 

Testes ......................... Bilateral, interstitial cell, adenoma xxx xx x -

Interstitial cell, adenoma xx X xx x xx 

. .. . 

Hematopoietic System 

Bone mew .......................... Lymph node + + 

Lymph node, mandibular ......................... Lymph node, mesenteric .......................... Spleen ......................... Lipoma 

Mesothelioma malignant, metastatic, testes X 

Thymus +++++++M+++++++++++++++,++ 

Thymoma benign 

htkgumentary System ." 

,. . 

Mammary gland ++M+++M+++++++++++MM+++++ 

X '. 

Adenoma . , -

Skin .......................... Basal cell adenoma 

Keratoacanthoma X 

Squamous cdl papilloma 

Pinna,melanoma malignant 

Skin, site of application, keratoacanthoma ,x 

Subcutaneous tissue, fibroma, multiple x 

Musculoskeletal System 

Bone . .......................... Osteosarcoma X. 

Skeletal muscle + + 

Mesothelioma malignant, metastatic, testes X 

Osteosarcoma X 

Nervous System 

.. 

Brain ......................... 

. . .Astrocytoma malignant 

Respiratory System 

Lung ......................... Alveolar/browhiolar adenoma X 

Melanoma malignant, metastatic,skin .. . 

Osteosarcoma, metastatic, 

uncertain primary site 

Osteosarcoma, metastatic, skeletal muscle X 

Nose .......................... Osteosarcoma, metastatic, bone x 

Trachea .......................... 

_. 
~~ ~ ~~ 

@armsrnNumber 

GenitalSystem(continued) 

Seminal vesicle 

Mesothelioma malignant, metastatic, testes 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

~~~enanaa~pie~c sysaem 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Lipoma 

Mesothelioma malignant, metastatic, testes 

Thymus 

Thymoma benign 

haegmnenm-y spaem

Mammary gland 

. Adenoma 

Skin 

Basal cell adenoma 

Keratoacanthoma 

Squamouscell papilloma 

Pinna, melanoma malignant 

Skin, siteof application, keratoacanthoma 

Subcutaneous tissue, fibroma, multiple 

bbSCUnOSk&bd SyShm 

Bone 

Osteosarcoma 

Skeletal muscle 

Mesothelioma malignant, metastatic, testes 

Osteosarcoma 

N~E-VOUS sgrsaem 

Brain 

Astrocytoma malignant 

~~pimt0p.9. sysaem 

LugAlveolaribronchiolar adenoma 

Melanoma malignant, metastatic, skin 

Osteosarcoma, metastatic, 

uncertain primary site 

Osteosarcoma, metastatic, skeletal muscle 

Nose 

Osteosarcoma, metastatic, bone 

Trachea 

1111111111111111111111111 

2553656467652243434324467 

5309317494121851149346802 

.......................... X 

......................... x xxxxx x x x x x x x x x x x 

X x x X X 

......................... + + + + ......................... 

......................... 

......................... X 

......................... X . . 

++++++++++++++++++++M++++ 

X 

......................... X 

X X 

X 

~~ ~~~ 

......................... 

......................... X 

......................... 

X 

X 

.......................... 

.......................... 

Total. 

Tissues/ 

Tumors . 

50 

2 

50 

24 

13 

50 . . 

6 

50 

50 

50 

1 

1 

49 . 1 

45 

2 

49 

1 

1 

2 

1 

1 

1 

50 

1 

2 

1 

1 

50 

1 .. 

50 

1 ., 

1 

1 

1 

50 

1 

50 
84 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

TABLEA2: 

Individual Animal Tumor Pathologyof Male Ratsin the 2-Year Dermal Study 

of 1;2-Dihydro-2,2,4-trimethylquinoline:60 mgkg (continued) ~~~ ~ ~~ ~ ~ 

2344555555555555666666666 . 

Number of Days on Study 5855225567777789011111222 

0159260380005550323679012 

1111'111111111111111111111 

Carcass IDNumber 3263772473675834752557223 

6967917730267083056497322 

Special Senses System

Ear + 

Eye + 

Urinary System 

Kidney ........................... Renal tubule, adenoma X -X X 

Renal tubule, adenoma, multiple 

Urinary bladder ......................... Mesothelioma malignant, metastatic, testes X ~~ 

SystemicLesions 

Multiple organs ......................... Leukemia mononuclear X X x xx x x 

Mesothelioma malignant A 
85 

I 

TABLEA2 

1n6nific1anr~n~nimra~ TWQ~ P~WUQ~~ Mane ab in the 2-year ~emd study

dn,2-IIDI~ycIrQ-2,2,41-&rinneePngmqan:60 EDgkg (continued) 

6666666666666666666677717 

Number of Days on Study 2234444555566667899902222 

8903467133515785023739999 

1 1 1 1 , 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass Number 2553656467652243434324467 

5309317494121851149346802 

Special Senses System 

EX + 

Eye + + 

Urinary System 

Kidney ......................... Renal tubule, adenoma X X X X X 

Renal tubule, adenoma, multiple X X 

Urinary bladder .......................... Mesothelioma malignant, metastatic, testes 

Systemic Lesions 

Multiple organs ......................... Leukemia mononuclear X X x xx X X xx X 

Mesothelioma malignant X 

.. 

Total 

Tissues/ 

Tumors 

2 ; 

3 

50 

8 

2 

50 

1 

50 

17 

2 
86 1,2-Dihydro-2,2,4-trimethylquinoline,NW TR 456 

TABLEA2 

Individual Animal TumorPathology of Male Rats in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:100mgkg 

Number of Days on Study 

Carcass ID Number 

Alimentary !system 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Hepatocellular carcinoma 

Mesentery 

Oral mucosa 

Squamous cell carcinoma 

Pancreas 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Blood vessel 

Heart 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

General Body System 

None 

Genital System 

Epididymis 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Penis 

3'344555555555555555666666 .. 

3748133444556669999000001 

9857906236050456699112392 

2222221112221121112122211 

3110119982229828982903088 

9257613170836122585064464 

......................... 

,+++++++++A++++++A+++A++++ 

+++++++++++++M++++++AM+++ 

+++++++++A+++A+AA++++++++ 

......................... 

+++++++++A+++++AA+++AA++'+ 

+++++++++A+++++AA++AAA+++ 

......................... 

X 

+ 

......................... 

......................... 

. . . . . . . . . . . . . . . . . . . . . . . . . 

+++++++++++ +++++++++++++ 

+ ......................... 

......................... 

.......................... X 

........................... X 

++++++++++++++++++M++++++ 

......................... x x X x x x x ......................... 

......................... 
TABLEA2 

mnSBaduan ~mimannTUW hthddpgy ~f Mane EMS inn the 2-year Derman ~uun~dy 

dn,2-Di~yMdko-2,2,0-uki~e~~ynqani: 100 mgkg (continued)

Number of Days on Study 

@arCSS NUdleP 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Hepatocellular carcinoma 

Mesentery 

Oral mucosa 

Squamous cell carcinoma 

Pancreas 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Blood vessel 

Heart 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

General Body System 

None 

Ge~tdSystem 

Epididymis 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Penis 

6666666666666666666666777 

1111222333345555667999122 

4889248003581344283137939 

2222221221221212222211222 

0014218129039283303399102 

0230495097924131713089756 

......................... 

++++++++A+A+++++A++++++++ 

+++++++++++M++++A++++++++ 

71

A 

+++++AAAA+AA+++A+++++++++ 

++++++++++AA+++++++++++++ 

+++++A++AAAA++++A++++++++ 

+++++A++AAAA+++AA++++++++ 

........................... 

+ + + 

+ 

X 

......................... 

X 

......................... 

......................... 

......................... 

......................... 

X 

......................... 

......................... X 

......................... X X 

......................... 

++++++++M++++++++++++++++ 

xx X X xx x xxx ......................... 

......................... 

X 

+ + 

Total 

Tissues/ 

Tumors 

50 

44 

45 

1 

39 ’ 

48 

39 

~ 

37 

50 

1 

1 

4 

1 

1 

50 

1 

50 

49 

49 

1 

50 

1 

50 

50 

2 

50 

3 

49 

49 

18’ : 

50 

50 

1 

2 

I 
88 1,2-Dihydro-2,2,4-trimethylquinoline,,NTPTR 456 

TABLEAi! 

Individual Animal Tumor Pathology of Male Rats in the %-Year Dermal Study . 

of 1,2-Dih.ydro-2,2,4-trimethylquinoline:100 mgkg (continued) 

3344555555555555555666666 

Number of Days on Study 3748133444556669999000001 

9857906236050456699112392 ,. . . 

222222111222112111'2122211 

Carcass Ill1 Number 3110119982229828982903088 

9257613170836122585064464 

Genital System(continued) 

Preputial gland +++++++++++++++++++++M+++ 

Adenoma X 

Carcinoma X 

Prostate +++++++++++++++++++M+++++ 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Seminal vesicle ......................... Fibrous histiocytoma, metastatic, 

skeletal muscle 

Testes ........................... Bilateral, interstitial cell, adenoma X x x xxxxx x 

Interstitial cell, adenoma x .x x xx x xx X 

.. . 

Hematopoietic System 

Bone marrow ......................... Lymph node + + 

Lymph node, mandibular .......................... Carcinoma, metastatic, Zymbal's gland X 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Lymph node, mesenteric ......................... 

Spleen ......................... Fibrous histiocytoma, metastatic, 

skeletal muscle 

Thymus ++++++M+++++++++++++M++M+ 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Integumentary System 

Mammary gland +M+M+++++++M+M+++++M++++M 

Fibroadenoma 

Skin ......................... squamous cell papilloma 

Pinna, squamous cell papilloma 

Subcutaneous tissue, fibroma X 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, skin, 

site of a,pplication, fibrosarcoma 

Muscu1osk.eletal System 

Bone ......................... Turbinate, chondroma 

Skeletal muscle 

Fibrous histiocvtoma 
TABLEA2 

~[~“ulan Adman TWTWPathQnQa at^ in the mear ~~mlan study

Qf n~-DihydrQ-2,2,~-t~methyn~~~Q~~e: 100 mgkg (continued)

NladXT Qf Qll shdy 

@arc- IDNumber 

Gdtml Syst@m(continued) 

Preputial gland 

Adenoma 

Carcinoma 

Prostate 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Seminal vesicle 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

H@matQ@~CsySt@lll 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Carcinoma, metastatic, Zymbal’s gland 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Lymph node, mesenteric 

Spleen 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Thymus 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

hkglMn@nhpysystem 

Mammary gland 

Fibroadenoma 

Skin 

Squamous cell papilloma 

Pinna, squamous cell papilloma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, skin, 

site of application, fibrosarcoma 

hhSCdQSk@l&d sJ’St@Ill 

Bone 

Turbinate, chondroma 

Skeletal muscle 

Fibrous histiocytoma 

6666666666666666666666777 

1111222333345555667999122 

4889248003581344283137939 

2222221221221212222211222 Total 

0014218129039283303399102 Tissues/ 

0230495097924131713089756 Tumors 

......................... 49 

1 

X 2 

......................... 49 

X 1 

........................... 50 

X : 1 

......................... 50 

xxxxx x x x xx x xx x x x x x 27 

xx x x X 14 

.......................... 50 

+ ++ + + + + 9 

......................... 50 

1 

X 1 

......................... 49 

......................... 50 

X 1 

+++++++++++++M+++++++++++46 

X 1 

+M++++MM+++M+++++++++++++ 40 

X 1 

......................... 50 

x 1 

X X 2 

1 

X 1 

x 1 

......................... 50 

X 1 

+ 1 

X 1 

I 
90 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA2 

Individual Animal Tumor Pathology ofMale Rats in the.2-Year Dermal Study . .. 

of 1,2-Dihydro-2,2,4-trimethylquinoline:100 mgkg (continued) 

,. 

.. 

334455555555555555566'666.6 

Number 'ofDays on Study 374.8133444556669999000001 

9857906236050456699112392 

...~ 

2222221112221121'112122211 

Carcass ID Number 31101'199822'29828982903088 

92576131708,36122585064464 

Nervous :System 

Brain ......................... Astrocytoma malignant 

Carcinoma, metastatic, Zymbal's gland X 

Respiratory System 

Lung .......................... Carcinoma, metastatic,Zymbal's gland X 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Nose ......................... Trachea .......................... . . 

Ear 

Special Senses System 

++ 

Zymbal's gland 

Carcinoma 

+ 

X 

. .. . . . 

Urinary System 

Kidney .......................... Sarcoma 

Renal hlbule, adenoma X 

Renal hlbule, adenoma, oncocytic X 

Urinary bladder +++++++++++++++++++M+++++ 

Systemic Lesions 

Multiple organs .......................... Leukemia mononuclear xxx xx xx X 

Mesothldioma malignant X 
9n 

N~PVOUS System 

Brain 

Astrocytoma malignant 

Carcinoma, metastatic, Zymbg's gland 

%SghtQoPy 8J'Stem 

Lung 

Carcinoma, metastatic, Zymbal's gland 

Fibrous histiocytoma, metastatic, 

skeletal muscle 

Nose 

Trachea 

Special Senses System 

Ear 

Zymbal's gland 

Carcinoma 

urinary System 

Kidney 

Sarcoma 

Renal tubule, adenoma 

Renal tubule, adenoma, oncocytic 

Urinary bladder 

SystemicLesions 

Multiple organs 

Leukemia mononuclear 

Mesothelioma malignant 

6666666666666666666666777 

1111222333345555667999122 

4889248003581344283137939 

2222221221221212222211222 Total 

0014218129039283303399102 Tissues/ 

0230495097924131713089756 Tumors 

........................... 50 

X 1 

1 

......................... 50 

1 

X 1 

......................... 50 

........................... 50 

2 

1 

1 

......................... 50 

X 1 

xx x X x x 7 

1 

......................... 48 

......................... 50 

X X x xx X 14 

X 2 
92 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

I .

TABLEA3 

Statistical Analysis of Primary Neoplasm' in MaleRats in the 2-Year Dermal Study 

of l,2-Dilhydro-2,2,4-trimethylquinoline 

,Vehicle Control 

Adrenal fidedulla: Benign Pheochromocytoma 

Overall rateb 5/50 (10%) 

Adjusted rate' 34.5% 

Terminal rated 015 (0%) 

First incidence(days) 649 

Life table teste M.455N 

~ogistic regression teste Pd.232N 

Cochran-Armitage teste Pd. 169N 

Fisher exact teste 

Adrenal Medulla: Benign or Malignant Pheochromocytoma 

Overall rate 5/50 (10%) 

Adjusted rate 34.5% 

Terminal rate 0/5 (0%) 

First incidence(days) 649 

Lifetest . . table ' ' M.432N

logistic regression test ' M.208N 

Cochran-Armitage test M.14ON 

Fisher exact. test 

Kidney (Renal Tubule): Adenoma (SingleSections) 

Overall rate .1/50 (2%) 

Adjusted rate , 20.0% 

Terminal rate 115 (20%) 

First incidence(days) 729 (T) 

Life table test Pd.001 

Lo&stic regression test M.006 

Cochran-Annitage test M.019 

Fisher exact test 

Kidney (Renal Tubule): Adenoma or Carcinoma (SingleSections) 

Overall rate 1/50 (2%) 

Adjusted ralte 20.0% 

. Terminal rate lis (20%)

First incidence(days) 729 (T) 

Life table test M.003 

Logistic regression test Pd.015 

Cochran-Amitage test Pd.044 

Fisher exact test 

Kidney (Renal Tubule): Adenoma or Carcinoma(Step Sections) 

Overall rate 6/50 (12%) 

Adjusted rate 43.3% 

Terminal rate 0/5 (0%) 

First incidence(days) 613 

Life table test M.102 

Logistic regression test M.253 

Cochran-kmitage test M.318 

Fisher exact test 

. ' 36 mgkg 

7/50 (14%)

62.5% 

1/2 (50%)

568 

M.289 

Pd.403 

M.380 

9/50 (1 8%) 

69.4% 

1/2 (50%)

568 

EO. 142 

M.208 

M.194 

7/50 (14%) 

71.6% 

1/2 (50%) 

563 

Pd.009 

EO.030 

M.030 Pa.030 

8/50 (16%) 

73.3% 

1/2 (50%) 

-563 

M.004 

Pd.016 

M.015 

6/50 (12%) 

27.5% 

0/2 (0%) 

57 1 

E0.518 

M.597N 

M.62ON 

. 

60 mega 100 mgkg 

6/50 (12%) U50 (4%) 

53.5% 34.7% 

1/4 (25%) 0/1 (0%) 

568 445 

Pd.346 Pd.494N 

Pd.442 Pd.279N 

M.500 M.218N 

6/50 (12%) u50 (4%) 

53.5% 34.7% 

1/4 (25%) 0/1 (0%)

568 445 

EO.346 M.494N 

P=O.442 M.279N 

.EO.500 M.218N 

10/50 (20%) 8/50 (14%) . 

70.8% 36.3% 

U4 (50%) .O/l (0%) 

575 ' 

602 

, 

EO.003 EO.005 

E0.003 ' Pd.019 '

M.004 

. . ., 

lobo (20%) 8/50 (14%)

70.8% 36.3% 

u4 (5o%j 0/1 (0%)

575 602 

M.003 M.005 

Pd.003 Pd.019 

M.004,.' M.030

6/50 (12%) 8/50 (1 6%) 

25.7% 100.0% 

0/4 (0%) 111 (100%) , 

585 487 

EO.507 Pd.115 

M.596 Pd.288 

M.62ON M.387 

, , 

. 

.. 

, L 

. ' , 

. . 

. 
~~ ~~ 

NI I IWd 

NLOIWd 

OPS'O" 

SW 

(%OOI) I/I 

80001 

(%LE) 6W81 

NI I IWd 

NLOI'O" 

oPSO=d 

SPP 

(%OOI) III 

8OOOI 

(%LE) 6P/81 

NEPZO=d 

NSOE'O" 

N8ISO" 

96s 

(80) I/O 

8P'SI 

(89) OS/E 

NEPZO" 

NSOE'O" 

N8 I S'O" 

96s 

t%O) I/O 

%P'S1 

(89) OW 

OLOO=d 

EEOO=d 

900" 

L8P 

(soor) I/I 

BO001 

(%SZ) OS/PI 

OQU 

NSEI'O" 

NLZI'O=d 

NLZE'O" 

SSP 

t%O) PI0 

IE'6S 

(%8E) OS/61 

NSEI'O" 

NLZI '0" 

NLZE'O" 

SSP 

t%O) P/O 

IE'6S 

(%8E) OS/61 

N6SOWd 

NILOO=d 

N61I'O=d 

(.I.) 6ZL 

t%SZ) P/I 

IOSZ 

(%Z) 6PlI 

NPIOO=d 

NIZOO" 

NIPO'O=d-

(80) ho 

%OO 

(so) 6PlO 

OLOO=d 

9PO'O=d 

9PO'Fd 

SLS 

(%OS) PK 

%I'SL 

(%8Z) OS/PI 

Q9 

NO9P'O" 

N6PSO" 

PLP'O" 

ILP 

(%001) z/z 

IO001 

(%8P) OWZ 

NEPE'O=d 

NZLP'O=d 

WSWd 

I LP 

(soor) z/z 

IO001 

(%9P) OSIEZ 

NEPZO" 

NSZZO" 

NI EE'O" 

€95 

(%O) z/o

%8'1 I 

(%9) OS/C 

NPEI'O=d 

NPZI'O" 

NOOZ'O" 

E9S 

(80) z/o

%L'8 

(%PI OSK 

PSI'O" 

V9I'O=d 

9LOO=d 

E9S 

(%OS) Z/I 

8O8L 

(%PZ) osnr 
94 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

TABLEA3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Dermal Study 

of 1,2-D:ihydro-2,2,4-trimethylquinoline(continued) 

VehicleControl 36 mgkg 60 mgflrg 100 mgkg 

Preputial Gland: Adenoma 

Overall rat(: 1/50 (2%) 2/49(4%) 3/49 (6%) 1/49 (2%) 

Adjusted rate 5.3% 5.0% 18.3% 2.2% 

Terminal rate 0/5 (0%) 0/2 (0%) 0/4 (0%) 0/1 (0%) 

First incidence (days) 568 653 575 519 

Life table test P=O.442 EO.501 P=O.259 P=O.719 

Logistic regression test Pd.551 P=O.468 P=O.291 P=0.756N 

Cochran-Armitage test Pd.539 

Fisher exact test EO.492 P=O.301 P=O.747 

Adjusted rate 

Overall rate 

Preputial Gland: Adenoma'or Carcinoma 

5.3% 

1/50 (2%) 

11.3% 

3/49 (6%) 

23.1% 

4/49 (8%) 

23.3% 

3/49 (6%) 

Terminal rate 015 (0%) 0/2 (0%) 0/4 (0%) 011 (0%) 

Life table test 

First incidence (days) 

EO.135 

653 

Pd.286 

568 

Pd.145 

575 

Pd.245 

378 

Logistic re,gression test P=O.235 Pd.288 Pd. 166 EO.331 

Fisher exact test 

Cochran-Armitage test Pd.217 

P=O.301 P=O.175 EO.301 

Life table test 

First incidence (days) 

Terminal rate 

Adjusted rate 

Overall rate 

Skin: Squamous Cell Papilloma 

EO.100 

656 

0/5 (0%) 

5.6% 

1/50 (2%) 

Pd.429 

610 

0/2 (0%) 

12.6% 

2/50 (4%) 

P=O.424 

65 1 

0/4 (0%) 

12.8% 

2/50 (4%) 

P=O.173 

619 

0/1 (0%) 

24.6% 

3/50 (6%) 

Logistic regression test P=O.161 Pd.512 EO.480 P=O.244 

Fisher exact test 

Cochran-Armitage test P=O.214 

P=O.500 P=O.500 P=O.309 

Life table lest 

First incidence (days) 

Terminal rate 

Adjusted mte 

Overall rate 

Skin: Squamous Cell Papilloma or Keratoacanthoma 

Pd.321 

630 

0/5 (0%) 

14.3% 

3/50 (6%) 

EO.584 

598 

0/2 (0%) 

14.8% 

3/50 (6%) 

P=O.408 

585 

0/4 (0%) 

18.3% 

4/50 (8%) 

P=O.439 

619 

0/1 (0%) 

24.6% 

3/50 (6%) 

Fisher exact test 

Cochran-Annitage test 

Logistic regression test 

P=O.528 

Pd.478 P=O.65 1N 

Pd.661N 

Pd.488 

P=O.500 

P=O.591 

P=0.661N 

Life table test 

First incidence (days) 

Terminal rate 

Adjusted rate 

Overall rate 

Skin: Squamous Cell Papilloma, Keratoacanthoma,or Basal Cell Adenoma 

P=O.280 

630 

0/5 (0%) 

14.3% 

3/50 (6%) 

Pd.584 

598 

0/2 (0%) 

14.8% 

3/50 (6%) 

P=O.270 

585 

0/4 (0%) 

22.4% 

5/50 (10%) 

Pd.439 

619 

0/1 (0%) 

24.6% 

3/50 (6%) 

Fisher exact test 

Cochran-hitage test 

Logistic regression test 

Pd.494 

Pd.440 E0.651N 

P=0.661N 

P=O.343 

P=O.357 

P=O.591 

E0.661N 
Testes:Adenoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Annitage test 

Fisher exact test 

All Organs: Mononuclear Cell Leukemia 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Malignant Mesothelioma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Benign Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Annitage test 

Fisher exact test 

All Organs: Malignant Neoplasms

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

'VehicleControl 36 

36/50 (72%) 

100.0% 

5/5 (100%) 

513 

P=O.O06 

P=O.O70 

Pd.199 

25/50 (50%) 

93.5% 

415 (80%) 

428 

Pd.253N 

P=0.008N 

Pd.006N 

1/50 (2%) 

2.5% 

0/5 (0%) 

542 

P=O.369 

P=O.519 

P=O.488 

48/50 (96%) 

100.0% 

5/5 (100%) 

428 

P=O.O39 

P=0.324N 

P=0.212N 

27/50 (54%) 

94.2% 

415 (80%) 

428 

P=O.347 

P=0.080N 

M.061N 

mgkg 

41/50 (82%) 

100.0% 

2/2 (100%) 

471 

Pd.113 

P=O.403 

P=O.171 

25/50 (50%) 

100.0% 

2/2 (100%) 

471 

Pd.363 

P=O.55ON 

P=0.579N 

4/50 (8%) 

12.7% 

0/2 (0%) 

554 

Pd.219 

EO.109 

Pd.181 

50150 (100%) 

100.0% 

2/2 (100%) 

47 1 

P=O.229 

Pd.453 

Pd.247 

33/50 (66%) 

100.0% 

2/2 (100%) 

47 1 

P=O.106 

P=O.190 

Pd.154 

60 mg/ag 

37/50 (74%) 

97.2% 

3/4 (75%) 

522 

P=O.254 

Pd.523 

P=O.500 

17/50 (34%) 

74.4% 

1/4 (25%) 

455 

P=0.258N 

P=0.083N 

P=0.078N 

2/50 (4%) 

6.6% 

0/4 (0%) 

459 

P=O.496 

P=O.532 

P=O.500 

45/50 (90%) 

97.8% 

3/4 (75%) 

455 

P=O.438 

P=0.248N 

P=O.2 18N 

24/50 (48%) 

93.4% 

314 (75%) 

381 

Pd.535 

P=O.362N 

E0.345N 

BOO mgkg 

41/50 (82%) 

100.0% 

1/1 (100%) 

487 

Pd.006 

P=O.O77 

P=O. 171 

14/50 (28%) 

63.9% 

011 (0%) 

487 

P=0.389N 

P=0.025N 

P=0.020N 

2/50 (4%) 

100.0% 

111 (100%) 

612 

P=O.316 

P=O.479 

Pd.500 

47/50 (94%) 

100.0% 

111 (100%) 

445 

Pd.040 

Pd.593N 

P=0.500N 

21/50 (42%) 

100.0% 

1/1 (100%) 

378 

P=O.306 

Pd. 190N 

P=0.158N 
96 l,Z-Dihydro-2,Z,4-trimethylquinoline,NTP TR 456 

TABLEA3 

Statistical Analysisof Primary Neoplasmsin Male Rats in the 2-Year Dermal Study 

-of1,2-Dihydro-2,2,4-trimethylquinoline~(continued) 

. . .. ~. . VehicleControl 36 mgkg . . 60 mgkg 100 mgkg 

All Orgzim: ' Benign or Malignant Neoplasms

Overall ratc: 48/50 (96%) 50/50 (100%)(92%)(98%) 46/50 49/50 

Adjusted rate 100.0% 100.0% 97.8% . 100.0% 

Terminal rate 515 (100%) (100%) 3/42J2 (75%) l/l (100%) 

First incidence (days) 

Life table test 

47 378 428 1 381

M.023 EO.229 EO.395 P=O.O26 

Logistic reLTession test Pd.453 Pd.391 P=0.375N Pd.392 

Cochran-Armitage test EO.571 

Fisher exact test E0.339N Pd.247 P=O.500 i ,. 

(T)Terminal sacrifice ~~ 

* a- At necropsy, it was discovered that one of the60 mgkg male rats was actually a hermaphrodite. However, the animal was microscopically examined and 

pathology data were includedas if it were a male. 

b Number of neoplasm-bearing animaldnumberof animals examined. Denominator is number of animals examined microscopically for adrenal gland, kidney, 

pancreatic islets, pituitary gland, preputial gland, and testis; for other tissues, denominator isofnumberanimals necropsied. C Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality d Observed incidence at terminal kill e Beneath the vehicle control incidence are Pthevalues associated with the trend test. Beneath the dosed group incidence are the P values corresponding to 

pairwise comparisons between the vehicle controls and that dosed group. The life table test regards neoplasms in animals dying prior to terminal kill as being

(directly or indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare

directly the overall incidence rates. For all tests, a negative trend or a lower incidencein a dose groupis indicated by N.-.. .. f Not applicable; no neoplasms in animal group 

,.- . 

. ,. 
Total 0/1m 01100 0/1m 

Total 9/1,200 (0.8%) 3/1,200 (0.3%) 1211,200(1.0%) 

Standard deviation 1.5% 0.7% 1.6% 

Range O%d% 0%-2% 0%-6% . . , 

a Data as of 17June1994 

40/lW (40.0%) 

11.3% 

32%-48% 

Total 56211.203 (46.7%) 

Standard deviation 10.7% 

Range 18%-62% 

a Data as of 17 June 1994; includes data for lymphocytic, monocytic, mononuclear cell,or undifferentiated celltype leukemias 
' 98 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA5 

Summalryof the Incidence of Nonneoplastic Lesionsin Male Rats in the 2-Year'DermalStudy . . 

, % o f l,2-D.ihydro-2,2,4-trimethylquinolinea . ,' ,

j ~ ., .;. ' , I .. . Vehicle Control .. 36 mgkg '. ; 60mgkg 100 m@g 

Disposition Summary . - -

Animals initially in study 60 60 60 60

IS-Month interim evaluation 10 10 10 10 

Earlydeaths : . , 

Moribund 

Naturaldeaths . 

otherb 

Survivors . > 

Terminal sacrifice 

'Animals examined microscopically 

15-Month'lnterim Evaluation 

Alimentary System 

In@stinesma!l, ileum . .~ 

Erosion 

Inflammation, chronic active 

Ulcer 

Liver . ,. . I . 

Basophilic focus 

Clear cell focus, 

Eosinophilic focus 

Fatty change, focal 

Hepatodiaphragmatic nodule 

Necrosis Mes-en.tej .* - . .. . .. . . . 

24 22 20 . 26 . 

21 26 25 23 

1 

5 2 4 

' '60 " .. 

.' 60 60 .. - 60. 

(10) 

4 (40%) 

(10) 

3 (30%) 2 (20%) 

1 (10%) 

10(100%) 9 (90%) 8 (80%) 10(100%) 

2(20%) 1 (10%) 

'1 (10%) . . . 

Fat, inflammation, chronic active 

Fat, necrosis 

Pancreas 

Pigmentation 

Acinus, atrophy 

Salivary glands 

Duct, metaplasia,squamous ... . - .._. . . 

CardiovascularSystem 

Heart (10)

Cardiomy!>pa$y 10(100%) 

Endocrine System 

Adrenal cort~:~'. 

Hyperplasia 

Islets, pancreatic 

Hyperplasia ' 

a Number ?f @m@s examined microscopically at the site and the number of animals with lesion 

At necropsy, it was discovered that oneof the 60 mag male rats was actuallya hermaphrodite. However, the animal was microscopically examined and 

pathology data were includedas if it were a male. .. .". , I .. . . . .. . .. . ,. . .. . -
i 

I

I1 

I 

I (601) 

I I

I III1I

I II

I 1

i iII

I 

I 1

I I

I 
'I 100 1,2-Dihydro-2,2,4-trimethyiquinoiine,NTP TR 456 

TABLEA5 

Summary of,the Incidence of NonneoplasticLesions in MaleRats in the 2-Year Dermal Study' . . . 

of 1,2-Diiydro-2,2,4-trimethylquinoli1ne(continued) . . , 

. . ,,.. .L 

. Vehicle Control : 36mg/kg ': :' 6Omg/kg 100 mg/kg

15-Month Interim Evaluation (continued) 

Systems Examined WithNo Lesions Observed 

General Body System 

Musculoskeletal System 

Nervous System 

SpecialSensesSystem 

2-YearStudy 

Alimentary System 

Intestine large, colon (47) (47)

Inflammahon, Bcute. 

Ulcer 

Intestine large, rectum (47) (49)

Angiectasis 1(2%) 

mammalion, acute 2 (4%) 

Mammation, chronic active 1 (2%) 

- Necrosis 1(2%) 

Intestine large, cecum (44) (39)

Dilatation . ' ' 

Erosion 1(2%) 

Inflammation, acute 7(16%) 4 (10%) 

Necrosis 1 (2%) 1 (3%) 

Ulcer 3 (7%) 2 (5%) 

Intestinesmd, duodenum (50) (46) (48)

Diverticulum , 1 (2%) 

Erosion 2(4%) 1 (2%) 

Inflammation, chronic active 2 (4%) 

Ulcer ,I ' 1 (2%) 

Intestinesmall,jejunum (46) (45) (39)"

Inflammation, acute 1 (2%) 

Intestinesmall, ileum (40) (37) (37)

Diverticulum 1 (3%) 

Fibrosis 1 (3%) 

Inflammation, chronic 1 (3%) 1(3%) 

Metaplasia, osseous 1 (3%) 

Necrosis , 1 (3%) 

Ulcer 1 (3%) 

Liver (50) (50) (50) (50) 

Angiectasir; 6 (12%) 5 (10%) 1 (2%) 1 (2%) 

Basophilic focus 8 (16%) 4 (8%) 3 (6%) '4 (8%) 

Clear cellfocus 5 (10%) 3 (6%) 3(6%) 3 (6%) 

Congestion 1 (2%) 1 (2%) 

I Degeneration, cystic . . -3 (6%) , 6 (.12%) 7 .(14%) 2(4%)

Eosinophilic focus 1 (2%) 1 (2%) 

Hepatodiaphragmatic nodule 8 (16%) 7 (14%) 8 (16%) 4 (8%) 

Hyperplasia 1 (2%) 

Infiltration cellular, histiocyte 1 (2%) 

Mammatim, chronic 3 (6%) 

Leukocytosis 1 (2%) 

Mineralization 1 (2%) 

Mixed cell focus 1 (2%) 4 (8%) 

Necrosis 4 (8%) 2(4%) 3 (6%) 

Regeneration 1 (2%) 1 (2%) 
2-Iy&dk~ St”’ (continued)

Mientary System(continued) 

Liver (continued) 

Centrilobular, necrosis 

Centrilobular, vacuolization cytoplasmic 

Periportal, vacuolization cytoplasmic 

Serosa, fibrosis 

Serosa, necrosis 

Mesentery 

Hemorrhage 

Inflammation, chronic 

Inflammation, granulomatous 

Artery, angiectasis 

Fat, necrosis 

Pancreas 

Cytoplasmic alteration 

Inflammation, acute 

Inflammation, chronic 

Inflammation, granulomatous 

Mineralization 

Acinus, atrophy 

Acinus, hyperplasia 

Artery, angiectasis 

Artery, inflammation, chronic 

Artery, mineralization 

Salivary glands 

Fibrosis 

Stomach, forestomach 

Erosion 

Foreign body 

Hyperplasia, squamous 

Inflammation, acute 

Inflammation, chronic 

Inflammation, chronic active 

Mineralization 

Perforation 

Ulcer 

Stomach, glandular 

Erosion 

Infiltration cellular, lymphocyte. 

Inflammation, chronic 

Metaplasia, squamous 

Mineralization 

Ulcer 

(50) 

3 (6%) 

12 (24%) 

4(8%) 

(10)

2(20%) 

1(10%) 

6(60%) 

(50) 

1(2%) 

1 (2%) 

25 (50%) 

2 (4%) 

1(2%) 

(49) 

(50) 

29(58%) 

17 (34%) 

1(2%) 

1(2%) 

4(8%)

20 (40%) 

(50) 

13(26%) 

1(2%) 

3(6%)

1(2%) 

15(30%) 

2 (4%) 

2(67%) 

(50) 

1 (2%) 

1(2%) 

1 (2%) 

34(68%) 

14(28%) 

1(2%) 

5 (10%) 

25 (50%) 

(50) 

22 (44%) 

1 (2%) 

19 (38%) 

2(4%) 

(50)

2 (4%) 

8(16%) 

2 (4%) 

1(2%) 

1(2%) 

(3) 

1(33%) 

1 (33%) 

(50) 

1(2%) 

20(40%) 

4 (8%) 

1 (2%) 

(50)

1(2%) 

(50)

1(2%) 

1(2%)

31 (62%) 

2(4%)

20 (40%) 

5 (10%) 

7(14%) 

16 (32%) 

(50)

22 (44%) 

1 (2%) 

20 (40%) 

3(6%) 

(50)

4 (8%) 

7(14%) 

4 (8%) 

(4)

2 (50%) 

1 (25%) 

1(25%) 

(50) 

23 (46%) 

6(12%) 

2(4%) 

28 (57%) 

14(29%) 

2 (4%) 

4 (8%) 

15 (31%) 

(49)

17 (35%) 

1 (2%) 

16(33%) 

3 (6%) 
\ 

102 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA5 

Summaryof the Incidenceof Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoIine(continued) 

Vehicle Control 36 mag 60 mag 100mag 

2-Year Shfy (continued) 

Cardiovascular System 

Blood vessel (1)

Aorta, mineralization 1 (100%) 

Heart (50)

Cardiomyopathy 44 (88%) 

Inflammation, acute 2(4%) 

Mineralization 10 (20%) 15 (30%) 13 (26%) 9(18%) 

Thrombosis 1(2%) 

Atrium, inflammation, acute 2(4%) 

Atrium, thrombosis 4(8%) 5 (10%) 9(18%) 3(6%) 

Endocrine System 

Adrenal cortex (50) 

Angiectasis 2 (4%) 

Cytoplasmic alteration 2(4%) 

Hemorrhage - 2(4%) 2(4%) 3(6%) 1(2%) 

Hyperplasia 2(4%) 2(4%) 2(4%) 5 (10%) 

HYpe~OPhY 1 (2%) 

Inflammation, acute 1(2%) 

Necrosis 2(4%) 

Vacuolization cytoplasmic 9(18%) 11(22%) 11 (22%) 9(18%) 

Adrenal medulla (50) (50) (50) (50) 

Hyperplasia 28(56%) 33(66%) 30 (60%) 23 (46%) 

Mineralizalion 1(2%) 

Islets, pancreatic (50) (49) (50) 

Hyperplasia 1(2%) 1(2%) 

Parathyroid gland (49) (46) (49) 

Hyperplasia 21 (43%) 23 (50%) 23 (47%) 

Mineralization 1(2%) 1(2%) 

Pituitary gland (50) (50) 

Angiectasis 1(2%) 

(49)

1 (2%) . 

Mineralization 

Craniopharyngeal duct, hyperplasia 

Craniopharyngeal duct, pars nervosa, 

hyperplasia 

Parsdistalis,angiectasis ._ 

Parsdistalis, cyst 

Pars distalis,hemorrhage 

Pars distalis, hyperplasia 

Pars distalis, pigmentation 

Pars intermedia, angiectasis 

Pars intermedia, cyst 

Pars nervosa, cyst 

Rathke’s cleft, cyst 

Thyroid gland 

cyst 

Mineralization 

C-cell, hyperplasia 

4(8%) 

3(6%) 

11(22%) 

I (2%) 

2 (4%) 

1(2%) 

4(8%) 

1 (2%) 

1(2%) 

1(2%) 

2(4%) 

4(8%) 

14 (28%) 

4(8%) 

6(12%) 

12 (24%) 

2(4%) 

1(2%) 

(50)

1(2%) 

2(4%) 

1(2%) 

8(16%) 

1(2%) 

14 (29%) 

1 (2%) 

1 (2%) 

2(4%) 

(50) 

2(4%) 

104 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

TABLEA5 

Summary of the Incidence of Nonneoplastic Lesions inMale Ratsin the 2-Year DermalStudy 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

&Year Shudy (continued) 

Hematopoietic system(continued) 

Lymph node 

Mediastinall, angiectasis 

Mediastinal., congestion 

Mediastinal, ectasia 

Mediastinal, erythrophagocytosis 

Mediastinal, hemorrhage 

Mediastinal, infiltration cellular, plasma 

cell 

Mediastinal, infiltration cellular, 

histiocyte 

Mediastinal, pigmentation 

Pancreatic, angiectasis 

Pancreatic, congestion 

Pancreatic, ectasia 

Pancreatic, l~emonhage 

Pancreatic, hyperplasia, lymphoid 

Pancreatic, infiltration cellular, plasma 

cell 

Pancreatic, necrosis 

Renal, ectasia 

Renal, hemorrhage 

Lymph node, mandibular 

Ectasia 

Erythrophagocytosis 

Hemorrhage 

Hyperplasia., lymphoid 

Infiltration cellular, plasma cell 

Infiltration cellular, histiocyte 

Necrosis 

Lymph node, mesenteric 

Angiectasis 

Congestion 

Depletion lymphoid 

Ectasia 

Erythrophagocytosis 

Hemorrhage 

Hyperplasia, lymphoid 

Infiltration cellular, polymorphonuclear 

Infiltration cellular, histiocyte 

Inflammation, acute. . . Spleen 

Fibrosis 

Hematopoietic cell proliferation 

Necrosis 

Pigmentation 

Capsule, necrosis 

Lymphoid follicle, depletion cellular 

Red pulp, thrombosis 

Thymus 

Angiectasis 

Ectopic parathyroid gland 

2 (13%) 

2 (13%) 

3 (20%) 

1 (5%) 

1 (5%) 

1 (5%) 1 (7%) 

1 (5%) 

1 (7%) 

2(11%) 2 (13%) 

1 (7%) 

1 (5%) 

. 1 (5%) 

(49) (50) 

1 (2%) 

1 (2%) 

2 (4%)

5 (10%) 

1 (2%) 

1 (2%) 

(50)

12 (24%) 

' 7 (14%) 

(6) 

1 (17%) 

(50)

1 (2%) 

1 (2%) 

6(12%) 

2 (4%) 

1 (2%) 

(50)

12 (24%) 

6(12%) 

4 (8%) 

(9) 

1(11%) 

1(11%) 

1(11%) 

1(11%) 

1(11%) 

(50) 

1 (2%) 

2(4%) 

(49)

2 (4%) 

1 (2%) 

3 (6%) 

2 (4%) 

2 (4%) 
i 2-y&lkrshdy (continued) 

h(egumentary System 

Mammary gland 

Galactocele 

Skin 

Acanthosis 

Hyperkeratosis 

Inflammation, acute 

Inflammation, chronic 

Ulcer 

Skin, site of application, acanthosis 

Skin, siteof application, cyst epithelial 

inclusion I Skin, siteof application, hyperkeratosis 

Skin, siteof application, inflammation, 

i 

chronic 

Subcutaneous tissue, hemorrhage 

Subcutaneous tissue, inflammation, acute 

Subcutaneous tissue, inflammation, chronic 

Subcutaneous tissue, inflammation, chronic 

active 

Subcutaneous tissue, skin, siteof 

application, fibrosis 

I Musculoskeletal System 

Fibrous osteodystrophy 

Bone (50) (50) 

(42) 

12(29%) 

(50) 

9 (18%) 

2 (4%) 

1 (2%) 

1 (2%) 

2 (4%) 

1 (2%) 

1 (2%) 

1 (2%) 

(42) 

5 (12%) 

(50)

5 (10%) 

1 (2%) 

2 (4%) 

2 (4%) 

1 (2%) 

4 (8%) 

1 (2%) 

2 (4%) 

3 (6%) 

1 (2%) 

(45) 

3 (7%) 

(49) 

6 (12%) 

1 (2%) 

1 (2%) 

1 (2%) 

14(29%) 

2 (4%) 

2 (4%) 

27(54%) 

(40) 

2 (5%) 

(50)

I (14%) 

5 (10%) 

1 (2%) 

1 (2%) 

1 (2%) 

21(42%) 

3 (6%) 

1 (2%) 

1 (2%) 

1 (2%) 

. . . . 

' 

." 

(50) (50) 

25 (50%)

Inflammation, chronic 1 (2%) 

Osteomalacia 1 (2%) 

Mandible, cyst 1 (2%) 

1 .I Nervous System 

Brain I Hemorrhage I Inflammation, acute i Cerebrum, necrosis

1 I Respiratory System

I Lung (50) (50) (50)

Congestion 1 (2%) 1 (2%) 

Emphysema 2 (4%) 

Hemorrhage I (14%) 9 (18%) 5 (10%) 4 (8%) 

Infiltration cellular,histiocyte 10 (20%) 13(26%) 15(30%) 15 (30%) , 

Inflammation, acute 2 (4%) 1 (2%) 1 (2%) 

Inflammation, chronic 3 (6%) 3 (6%)

Inflammation, chronic active 1 (2%)

Mineralization 2 (4%) 7 (14%) 6 (12%) 6 (12%) 

Thrombosis 1 (2%) 

Alveolar epithelium, hyperplasia 3 (6%) 1 (2%) 1 (2%) 

Alveolus, edema 4 (8%) 3 (6%) 9 (18%) 5 (10%) 

Capillary, thrombosis 4 (8%) 

21(42%) 24(48%) 
106 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEA5 

Summary of the Incidenceof NonneoplasticLesions in Male Rats in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

Nose 

Respiratory System.(continued) . . 

Foreign body 

,(50) 

15 (30%) 

Hemorrhage 

Fungus . 19 (38%) 

Inflammation, chronic 

Vein, thrombosis 

Ulcer 

Thrombosir; 

Inflatiunatiiin,'chronicactive 

1 (2%) 

2 (4%) 

2 (4%) 

.26 (52%) 

Special Senses System 

Eye . I * 1 . 

Anterior chamber, inflammation, acute 

Choroid, mineralization 

Cornea, inflapnation, acute 

Iris, synecliia' -

-Lens, cataract 1 (100%) 

Retina, degeneration 

Urinary System 

Kidney 

Hydronephrosis 

cyst 

Infarct 

Inflammation,acute 

Mineralization 3 (6%) . 

Nephropathy, chronic .50 (100%) 

Pigmentation 

Cortex, mintxalization 

Renal tubule:, degeneration, hyaline 

Renal tubule, hyperplasia 

Vein, thrombosis 

Urinary bladder 

Calculus, gross observation 

Calculus, microscopic observation only 

Hemorrhage 

Mammatiom, acute 

Inflammation, chronic 1 (2%) 

Mineralization . ' 

Transitional epithelium, hyperplasia 

(49) 

11 (22%) 

21 (43%) 

1 (2%) 

1 (2%) 

24 (49%) 

4' (8%) 

(3) 

1 (33%) 

1 (33%) 

1 (33%) 

3 (100%) 

' ' . 2 (67%) 

2 (4%) 

50 (100%) 

2 (4%) 

. . 

(50) 

9 (18%) 

13 (26%) 

22 (44%) 

1 (2%) 

1 (2%) 

(3) 

1 (33%) 

3 (100%) 

1 (33%) 

(50) 

17 (34%) 

5 (10%) 

49 (98%) 

1 (2%) 

1 (2%) 

6 (12%) 

1 (2%) 

(50) 

, I . 

. 

.. .. 

..' 

' >, . 

.. 

. 

. 

(50) -' ~' 

9 (18%) 

10 (20%) 

16 (32%) 

2 (4%) 

(50) . ' 

20 (40%) 

1 (2%) 

2 (4%) 

4 (8%) 

50 (100%) 

1 (2%) 

3 (6%) 

(48) 

1 (2%) 

1 (2%) 

1 (2%). 

1 (2%) 

1 (2%) 

1 (2%) . 

,, . 

. . 
SUMMARY 
10s 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

.. . 

,. .

i 

~. .. . 

..... _. . . . . ~ 

. . 

.I 

. . 

.. . 

,... 
Early deaths 

IS-Month interim evaluation 

Animals initially in study 

Disposition Summary 

Terminal sacrifice 

Natural deaths 

Moribund 

Survivors 

19 

10 

60 

19 

12 

10 

10 

60 

21 

19 

9 

10 

60 

22 

19 

9 

10 

60 

22 

19 

Animals examined microscopically 60 60 60 60 

Stomach, forestomach 

Alimentary System 

l§-Month hnteQpippzBV~UQ~~~PP 

(10)

Squamouscell papilloma 

Pituitary gland 

Endocrine System 

Pars distalis, adenoma, multiple 

Pars distalis, adenoma 

(10) 

1 (10%) 

4 (40%) 

(10) 

3 (30%) 

(10) 

4 (40%) 

(10) 

5 (50%) 

Genital System 

Polyp stromal 

UteNs 

Adenoma 

Clitoral gland 

Fibroadenoma 

Mammary gland 

Integumentary System 

SystemicLesions 

Multiple organsb 

Lymphoma malignant 

h"QSk@k!bl SySteEn 

WematopieticSystem 

General Body System 

CardiovascularSystem 

Systems Examined WithNo N~oplasmsObserved 

uninlpry Syst42m 

Special Senses System 

Respiratory system 

Nervous System 
110 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB1 

Summary of the Incidenceof Neoplasms in Female Rats in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

2-Year.Study 

Alimentary System 

Intestine large, colon 

Intestine large, rectum 

Sarcoma stromal, metastatic, uterus 

Intestine small, jejunum 

Carcinoma 

Intestine small, ileum 

Liver 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 

Hepatocel1u;lar adenoma 

Sarcoma, mekpgic, spleen 

Mesentery .. 

Carcinoma, metastatic, uncertain primary site 

Schwayoma malignant, metastatic, uterus 

Oral mucosa 

Squamous cell carcinoma 

Pharyngeal, squ&ous cell papilloma 

Pancreas 

Sarcoma, metastatic, spleen 

Salivary glands 

Schwannoma malignant, metastatic, harderian 

gland 

Stomach, foreslomach 

Stomach, glandular 

Cardiovascular System 

Heart 

Alveolar/brorchiolar carcinoma, metastatic, 

lung 

. . 

Endocrine System 

Adrenal cortex 

Adenoma 

Adrenal medulla 

Pheochromoc,ytoma malignant 

Pheochromoc:ytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Pituitary gland 

Carcinoma 

Pars distalis, adenoma 

P&s distalis, carcinoma 

Thyroid, gland 

C-cell;adenonla . 

C-cell, carcinoma 

Follicular cell, adenoma 

(49) 

(49) 

2 (4%) 

(50) (50) 

(49) 

30 (61%) 28 (56%) 

2 (4%) 

(49) (50)

.7(14%) 5 (10%) 

1 (2%) 2 (4%) 

1 (25%) 

(50) 

1 (2%) 

31(62%) 

2 (4%) 

(48)

2 (4%) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50)

I (2%) 

33 (66%) 

1 (2%) 

(49)

2 (4%) 

1 (2%) 
%y6?OP $teddy (continued) 

General Body System 

None 

Genital System 

Clitoral gland 

Adenoma 

Carcinoma 

Carcinoma, metastatic, mammary gland 

ovary 

uterus 

Polyp stromal 

Sarcoma stromal 

Schwannoma malignant 

Vagina 

Sarcoma stromal, metastatic, uterus 

Schwannoma malignant, metastatic, uterus 

Hematopoietic System 

Bone marrow 

Lymph node 

Mediastinal, alveolarhronchiolar carcinoma, 

metastatic, lung 

Mediastinal, sarcoma, metastatic, spleen 

Lymph node, m,andibular 

Scbwannoma malignant, metastatic, harderian 

gland 

Lymph node, mesenteric 

Spleen 

Hemangiosarcoma 

Sarcoma 

Thymus 

Integumentary System 

Mammary gland 

Adenoma 

Adenoma, multiple 

Carcinoma 

carcinoma, multiple 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Fibroma 

Melanoma benign 

Squamous cell papilloma 

Pinna, melanoma malignant 

Skin, site of application, keratoacanthoma 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, sarcoma 

(49) 

4 (8%) 

1 (2%) 

1 (2%) 

(50) 

(50) 

4 (8%) 

1 (2%) 

(50) 

(13) 

(50) 

1 (2%) 

(50) 

(50) 

(47) 

(48) 

1 (2%) 

3 (6%) 

18 (38%) 

7 (15%) 

(50) 

1 (2%) 

1(2%) 

1 (2%) 

(46) 

2(4%) 

(50) 

(50) 

3 (6%) 

1 (2%) 

1 (2%) 

(1) 

1 (100%) 

(49) 

5(10%) 

10 (20%) 

6(12%) 

(50) 

1 (2%) 

1 (2%) 

(45) 

5(11%) 

1 (14%) 

1 (14%) 

(50) 

(49) 

1 (2%) 

12(24%) 

3 (6%) 

(50) 

(49) 

2 (4%) 

(50) 

(50) 

1 (2%) 

2(4%) 

1 (2%) 

15 (30%) 

1 (2%) 

(50) 

1(2%) 

1(2%) 
112 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Dermal Study 

of 1,2-Dih;ydro-2,2,4-trimethylquinoline(continued) 

Bone 

Musculoskdetal System 

2-Year ShUdy (continued) 

Skeletal muscle 

Hemangiosarcoma 

(50) 

1 (2%) 

Brain 

Nervous System 

Carcinoma, metastatic, pituitary gland 

Astrocytoma malignant 

(50) 

2 (4%) 

(50) (50) 

1 (2%) 

1 (2%) 

1 (2%) 

Lung 

Respiratory System 

Sarcoma, mtetastatic, spleen 

Carcinoma, metastatic, thyroid gland 

Carcinoma, metastatic, pituitary gland 

Carcinoma, metastatic, mammary gland 

Alveolar/bronchiolar carcinoma 

Squamous cell carcinoma, metastatic, oral 

Squamous cell carcinoma 

Nose 

mucosa 

(50)

2 (4%) 

(50) 

1 (2%) 

Carcinoma 

Zymbal's gland 

Nerve, schwannoma malignant 

Harderian gland 

Special Senses System ." 

(1) 

1 (100%) 

(1) 

1 (100%) 

Kidney 

Urinary Sysltem 

Transitional epithelium, papilloma, multiple1. 

Transitionalepithelium,carcinoma . 

Transitional epithelium, carcinoma 

Renal tubule, carcinoma 

Alveolar/brmchiolar carcinoma, metastatic, 

lung 

Urinary b1adde:r 

1 (2%) 

(48) 

1 (2%) 

1 (2%) 

(49) 

.. . 

1 (2%) 

(50) 

. . . . 

Multiple organs 

Systemic Lesions 

Leukemia mononuclear 

Leukemia granulocytic 

(50) 

22 (44%) 

1 (2%) 

(50) 

16 (32%) 

(50) 

23 (46%) 

(50) 

10 (20%) 
. . .I 

i . 

,I : 

.. .* 

.. 

. . 

. 1 

.. 

I 

I 

IZ 

81 

6s 

9 

8E 

9 

08 

9 

Et 

9 

El 

9 

ZE 

I 

8Z 

I 

z9 

P 

LE 

P 

P6 

S 

LP 

S 

P 

E 

82 

9z 

z9 

s 

LE 

P 

06 

s 

EP 

P 

I 

9 

s 

9E 

18 

9 

EP 

9 

1 LI 

9 

6P 

9 

i I

I I

I IIi

! I

I 

I 

ILf!iiom hFede Iwsncts 

TABLIE Bz 

h&~dmd hhdl Tmor h&dloa off FQidehctsin &e I[DQmd$hdg 

off lI~-IIDi~~dro-z~~~-U~Q&~U~~n~~ne~ V~hideConUroU(continued) 

MunrumkIr offDays OIm suu" . . 

Q;lmJInD Nunrumkr 

44ninnneImhlfysysuem 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Carcinoma, metastatic, uncertain primary site 

Oralmucosa 

:Pharyngeal, squamous cell papilloma 

pancreas 

salivary glands 

: Schwannoma malignant, metastatic,, 

harderian gland 

Stomach, forestomach ' 

Stomach, glandular 

wOV@SC"' SySbDUl 

Heart 

lErmdwheSysueDUl 

Adrenal cortex 

Adenoma 

Adrenal medulla 

Pheochromocytoma malignant 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic 

Parathyroid gland 

pituitary gland 

Pars distalis, adenoma 

Pars distalis. carcinoma 

Thyroid gland 

C-cell, adenoma 

Follicular cell, adenoma 

GeImenranBdy Sysuem 

None 

GeAW sysuem 

Clitoral gland 

Adenoma 

Carcinoma 

Carcinoma, metastatic,mammary gland 

. . . .. 

1111111111111111111111111 

2222333333333333333333333 

123945611~1111111111111111 

2322232222222222222222333 Total 

8016608566661111888999001 Tissues1 

1169225915613519028468053 Tumors 

......................... 50 

........................... 49 

......................... 49 

......................... 48 

......................... 49 

........................... 49 

A++A+++++++++++++++++++++ 45 

......................... 50 

+ ++ 8 

X 1 

1 

1 

......................... 50 

......................... 50 

X 1 

......................... 50 

......................... 50 

.......................... 50 

......................... 50 

1 

......................... 50 

1 

X 3 

X 1 

......................... 50 

+.+++++M+++++++M++++++++++ 44 

+++++M+++++++++++++++++++49 

xx X xxx xxxxxxx x xx x 30

X X 2 

......................... 49 

X X x x X X I 

1 

.......................... 49 

X X 4 

1 

X 1 

.' 

, . 
116 9% 1,2-Dihydro-2,2,4-trimethylquinoline,NTP.TR 456 

TABLEB2 .. 

Individual Animal Tumor Pathologyof Female Rats in the 2-Year Dermal Study .

.. \ 

, 

of 1,2-D&,ydro-2,2,4-trimethylquinoIine: Vehicle Control (continued) 

, 

. ,. . . . 

2445555555566666666667777 

Number of Days on Study 7.290256-67890022456799001..1 . ,. . . .

2780743861146156439682469 .. . . -, , .. , ~~ ~~ ~~ ~ 

Carcass IDNumber . .. . 9118689877105169900065076 

2332222222332322233322322 

3123340104036585961847920 . . ., 

Genital System(continued) 

ovary

UkNS .......................... 

......................... 

Schwannoma malignant 

Polyp stromal 

X 

X X 

.. . ,I - . . .. 

Hematopoietic System 

Bone marrow ............................ 'Lymph node + + ++ + + + 

Lymph node, mandibular ......................... Schwannoma malignant, metastatic, . . 

harderian gland 

Lymph node, mesenteric ......................... Spleen ......................... Thymus , +++++++++++++++M++M++++++ .. , . ... .. . 

Integumentary System 

Carcinoma 

Adenoma, multiple 

Mammary gland +++++++++++M+++I+++++++++ 

X 

X X 

Fibroadenoma xxxx x xx X 

Fibroadenoma, multiple X X x 

Skin ........................... Fibroma X 

Subcutaneous tissue, lipoma 

Melanoma benign 

. . . .: 

Bone 

Musculoskeletal System ......................... .. -

Brain .. 

Nervous System .......................... Carcinoma, metastatic, pituitary gland 

. _ . . , . . . 

Respiratory System 

Lung 

Alveolar/bmnchiolar carcinoma 

......................... X 

Nose ......................... Trachea .......................... ,. . . . -. 

Ear 

Special Senses System. 

+ 

Harderian gland 

Nerve, schwannoma malignant 

Zymbal's gland 

Carcinoma 

... . ,. . .. , .. .. . . 
Number of Days on Study 

Ge&d System (continued) 

ovary 

uterus 

Polyp stromal 

Schwannoma malignant 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Schwannoma malignant, metastatic, 

harderian gland 

Lymph node, mesenteric 

Spleen 

Thymus 

htewenbry Systm 

Mammary gland 

Adenoma, multiple 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Fibroma 

Melanoma benign 

Subcutaneous tissue, lipoma 

Mwcu~oskel@~ Syst@m 

Bone 

NWVOpaS SyShlXl 

Brain 

Carcinoma, metastatic, pituitary gland 

Rwpimtory System 

Lung 

Alveolarhronchiolar carcinoma 

Nose 

Trachea 

Special Senses System 

Ear 

Harderian gland 

Nerve, schwannoma malignant 

Zymbal's gland 

Carcinoma 

1111111111111111111111111 

2222333333333333333333333 

1239456111111111111111111 

2322232222222222222222333 Total 

8016608566661117888999001 Tissues/ 

1169225915613519028468053 Tumors 

......................... 50 

......................... 50 

xx 4 

1 

......................... 50 

+++ + + + 13 

........................... 50 

X 1 

......................... 50 

......................... 50 

+++++++++++++++++M+++++++41 

......................... 48 

1 

X 3 

xx xxxxxx X X 18 

X X xx I ......................... 50 

1 

'X 1 

X 1 ~~ ~~ ~~ ~~ ~~~ ~ ~~~~ ~~ 

. 

.......................... 50 

......................... 50 

X X 2 -

' 

~ ~~ ~~~ ~ ~~ ~~ ~ 

.. 

......................... 50 

X 2 

........................... 50 

.......................... 50 . 

1 

+ 1 

X 1' 

+ 1 

X 1 

. 

' 

' 

' 

-

'. . 

.' 

' 

'. 

1 
118 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB2, 

Individual AnimalTumor Pathology of Female Rats in the2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline: Vehicle Control(continued) 

Number of Days on Study 

Carcass IDNumber 

. . 

Urinary System 

Kidney 

Urinary bladder 

Transitional epithelium, carcinoma 

Systemic Lesions 

Multiple organs 

Leukemia granulocytic 

Leukemia mononuclear 

2445555555566666666667777 

7290256678900224567990011 

2780743861146156439682469 

2332222222332322233322322 

9118689877105169900065076' 

3123340104036585961847920 

.......................... 

......................... 

......................... X 

X x ' xx x xx x x x x
x x x xx x xxxx X ZZ 

I 

.......................... os 

ES089t8Z06LSEL9S16SZZ69LL u0mn.L 

100666888LLLL9999S8099LO8 Pnss!.L 

EEEZZZZZZZZZZZZZZZZEZZZEZ 14o.L 
-- 

.-

i120 1,2-Dihydro-2,2,4-trimethylquinoline,NTP' TR456 

TABLEE12 

Individual AnimalTumorPathology of Female Rats in the 2-Year Dermal Study 

of 1,2-Diihydro-2,2,4-trimethylquinoline:36mgkg 

2444455556666666666666677 

Numberof Days on Study 95889025502334456778'88911 

2451254478258795723788234 

33333333333333'33333333333 

Cam& ID Number 75226663341246142771.56262 

46583.64017819771003942402, 

AlimentarySystem 

Esophagus .......................... Intestinelarge,colon , . A+ + A,+,+ + + + +++,+++A+ + + + + + + +.+ . Intestine large, rectum ,. . 

A++A+M+++++++++++++++++++ 

Sarcoma stromal, metastatic, uterus X 

Intestine large, cecum A+ + A+ + A+ + A.+ + + + +A+ ++A+ + +A+ . 

Intestinesmall,duodenum A++A++A++A+++++A+++++++++ 

Intestine small, jejunum A++A+AA++A+++A+A+++A++++A 

Intestinesmall, i1,eum A+ + A.+ + A+ + A+ + +,A+ A+ ++A+ + + AA 

Liver 

, 

............................ Hepatocellular adenoma X 

Mesentery +++ + + + 

Oral mucosa . , .. . , . , + . , . . 

Squamous cell carcinoma X 

Pancreas ......................... Salivary glands ......................... Stomach, forestomach , ,, ,:.. ,.,+ ,+,+ + + +,+ + + + +,+ +,+ + + + +,+ + + + + + + 

Stomach, glandular ............................. ; 

Cardiovascular System 

Heart .......................... 

Endocrine System 

Adrenal cortex ......................... Adenoma 

Adrenal medulla .......................... Pheochromocytoma benign 

Islets, pancreatic .......................... Parathyroid gland ......................... Pituitary gland .......................... Pars distalis, adenoma X x x. x x xxxxx. 

Thyroid gland ......................... C-cell, adenoma X X 

Follicular cell, adenoma x X 

GeneralIM~system 

None . 

.- t 

GenitalSystem 

Clitoral gland +++++++++++MMM+++++++++++ 

Adenoma 

......................... uterus ......................... Polyp stromal X X sarcoma stromal X 

Schwannoma malignant X 

ovary 

. . Vagina + 

Sarcoma 

' 

stromal, metastatic,U@NS X 
3333333333333333333333333 Total 

Carcassm Number 557666677122.3333333444555 Tissues/. 

5758159126792345689235289 Tumors 

Alimentary System 

Esophagus ......................... 50 

Intestine large, colon ......................... 47 '1 

Intestine large, rectum ........................... 47 

Sarcoma stromal, metastatic,ute~s 1 

Intestine large, cecum ......................... 43 ' I 

Intestine small, duodenum .......................... 45 

Intestine small, jejunum ............................ 41 "-. 

Intestine small, ileum ......................... 40 

Liver ......................... 50 

Hepatocellular adenoma X 2 

Mesentery + + 8 

Oral mucosa 1 

Squamous cell carcinoma '1 

Pancreas ......................... 50 1 

Salivary glands ......................... 50 

Stomach, forestomach ......................... 50 

Stomach, glandular ......................... 50 

Cardiovascular System 

Heart ......................... 50 ~~ ~~~ I Endocrine System 

cortexAdrenal ........................... 50 

Adenoma X 1 

Adrenal medulla ......................... 50 

Pheochromocytoma benign X 1 

Islets, pancreatic .......................... 50 ' . Ii 

Parathyroid gland ......................... 50 

Pituitary gland ......................... 50 :

I adenomaPars distalis, x x X xx x x x x x x x x x x x x 28 

Thyroid gland ......................... .50 

C-cell, adenoma X X X 5 

Follicular cell, adenoma 2 

j General ~oaysyskm 

None ~~~~ ~ 

Genital Syskm 

Clitoral gland +++++++++M+++++++++++++++46 

Adenoma X X 2 

ovary ......................... 50 

uterus .......................... 50 

Polyp stromal X 3 

Sarcoma stromal ..1 

Schwannoma malignant 1 

Vagina I.,

Sarcoma stromal, metastatic, uterus 1 
. . .. . 

122 1,2-Dihydro-2,2,4-trimethylquino~ne,N"TR 456 

TABLEB12 

Individual Animal Tumor Pathology of Female Rats in the 2-YearDermal Study 

of 1,2-Diihydro-2,2,4-trimethylquinoline:36 mgkg (continued) ~~ ~~ ~ ~~~ 

2444455556666666666666677 

Number of Days on Study 9588902550233445677888911 

245125447,8258795723788234 

333333333333333333333333'3 .' ,

Carcass ID Number 75226663341246142771.56262-.:. 

4658364017819771003942402 

Hematopoietic System 

Bone marrow ........................... 

Lymph node + + . + + '+ +++ 

Lymph node, mandibular .......................... Lymph node, mesenteric ++++++++M++++++++++++++++., 

Spleen .......................... Hemangiosarcoma 

Thymus ............................. -,: 

Integumentary System . , 

Mammary gland 

Carcinoma . 

+I ............................. X X , , 

Fibroadenoma X . xx- , 

Fibroadenoma, multiple X 

Skin ................................. Pinna, melanoma malignant X 

, 

Skin, site of application, keratoacanthoma x, 

Musculoskeletal System , . 

Bone .............................. Hemangiosarcoma 

.. 

Nervous System . . 

Brain ............................. . . , 

- : 

Respiratory System 

. , 

. . 

Lung ......................... Carcinoma, metastatic, mammary gland X 

Nose .......................... Squamous cell carcinoma, metastatic, . .. 

oral mucosa .X 

Trachea . ........................... 

Special Senses System 

.. 

. . 

None .. .. 

Urinary System 

Kidney .......................... Transitional epithelium, carcinoma '. : 

Urinary bladder ,A+ + + + + + + + + + +,+ + + + + + + + + +'+ A.+ .' .:

Transitional epithelium, papilloma, multiple .. 

Systemic Lesions .. 

Multiple organs ............................ Leukemia mononuclear x .' x x .x x x x. 
Number of Days on Study 

Carcass lu[D Number 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Hemangiosarcoma 

Thymus 

Integumentary System 

Mammary .. gland 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Pinna, melanoma malignant 

Skin, siteof application, keratoacanthoma 

Musculoskeletal System 

Bone 

Hemangiosarcoma 

Nervous System 

Brain 

Respiratory System 

Lung 

Carcinoma, metastatic, mammary gland 

Nose 

Squamous cell carcinoma, metastatic, 

oral mucosa 

Trachea .. 

Special Senses System 

None 

UPinary System 

Kidney 

Transitional epithelium, carcinoma 

Urinary bladder 

Transitional papilloma, epithelium, multiple 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear ,. . 

1111111111111111111111111 

1123333333333333333333333 

4954666661111111111111111 

3333333333333333333333333 Total 

55166661712233.33333444555 Tissues/ 

515815912679.2345689235289 Tumors 

......................... 49 

+ + 10 

.......................... 50 

.......................... 49 

........................... 50 

X 1 

......................... 50 

......................... 49 

X X X 5 

x x x xx x x 10 

x x X X X 6 

......................... 50 

1 

1 

......................... 50 

X 1 

.......................... 50 

.......................... 50 

1 

......................... 50 

1 

......................... 50 

.. 

......................... 50 

X 1 

......................... 48 

X 1 

......................... 50 

X X x x x xx x x 16 
1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB12 

IndividualAnimal Tumor Pathologyof FemaleRats in the 2-YearDermal Study .. 

of 1,2-Diihydro-2,2,4-trimethylquinoline: 60 mgkg 

444455556666666666666661.7 

Number of Days on Study 459945680001256668.99999.01 .' 

7722010827996934890147892 

3344344434434433444343434 

CareassID Number 8922710193190398030928290 

9368945704370252918136742 

Alimentary System 

Esophagus ......................... Intestine large,colon +A+++++++++++++++A.+++++++ . I 

Intestine large, rectum + A+ + + + + +..+ + + + + + + + +.A+ + + + A+ + 

Intestine large, cecum +A++++++AA+++++AAA+++A+A.+ 

Intestine small, duodenum . ++++++++A++++++A+++++++A+ 

Intestine small,jejunum. ++++++++A++++++,+AA+++AAA+ 

Intestine small, ileum +A++++++A+++++A+AA+++AAA+, 

Liver ......................... -

Alveolarlbronchiolar carcinoma, 

Schwannomamalignant,meastatic,uerus 

Sarcoma, metastatic, spleen 

metastatic, lung 

Mesentery 

X 

+ + + 

X 

Pancreas ......................... S.arcomg metastatic, spleen X 

salivary glands ........................... Stomach, forestomach ++++++M++++++++++++++++++ 

Stomach, glandular ......................... 

Cardiovascular System 

Heart .......................... Alveolarlbronchiolar carcinoma, 

metastatic, lung 

Endocrine System 

Adrenal cortex ......................... Adenoma 

Adrenal medulla . . ......................... Pheochromocytomabenign X 

Islets, pancreatic .......................... Adenoma 

Parathyroid1 gland ........................... Pituitary gland ......................... Pars distalis,adenoma .xx . xx xx xxx x xxxxxx 

Pars distalis,carcinoma 

Thyroid gland +++++++++++M++++++,+++++++ 

C-cell, adenoma 

C-cell, carcinoma 

General Body System 

.None 

Genital System 

Clitoral gland MM+ + + + + + + + + + +,+ + + + + + M+'M+ + + 

Adenoma 

: ovary ........................... Uterus .......................... Polyp smmal 

Schwannoma malignant X .. 

Vagina 

Schwannoma malignant, metastatic, uterus X

+ +. 
Number of Days on Study 

carcrass lnrp NPlnnbelr 

Ahenbry System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Alveolarhronchiolar carcinoma, 

metastatic, lung 

Sarcoma, metastatic, spleen 

Mesentery 

Schwannoma malignant, metastatic, uterus 

Pancreas 

Sarcoma, metastatic, spleen 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

@ar&ovmoscmlarsystem 

Heart 

Alveolarhronchiolar carcinoma, 

metastatic, lung 

Endoche System 

Adrenal cortex 

Adenoma 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma ' 

Pars distalis, carcinoma 

Thyroid gland 

C-cell, adenoma 

C-cell, carcinoma 

General Body System 

None 

Gennitd System 

Clitoral gland 

Adenoma 

ovary 

UkNS 

Polyp stromal 

Schwannoma malignant 

Vagina 

Schwannoma malignant, metastatic, uterus 

1111111111111111111111111 

233333333333333333333,3333 

IO46666666666666666666666 

4443333333333344444444444 Total 

2001188888999900011122233 Tissues/ 

1436101418268916112802505 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

........................... 

........................... 

X 

+ 

......................... 

.......................... 

......................... 

......................... 

......................... 

X 

......................... X X 

......................... 

......................... X 

......................... 

......................... x xxxx xxx x xxxxxx 

X X 

+M+++++++++++++++++++++++ 

X X 

X 

Tumors 

50 

48 

41 . 

42 

41 

44 

42 

50 

1 

1 

4 

1 

50 

1 

50 . 

49 

50 

50 

1 

50 

2 

50 

1 

50 

1 

49 

50 

31 

2 

48 

2 

1 

++++++++++++++++M++++++++ 45 

X X xx X 5 

......................... 50 

......................... 50 

X X x x. .4 

1 

2 

1 
126 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEE12 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study 

of 1,2-Diihydro-2,2,4-trimethylquinoline:60 mgkg (continued) 

Number of Days on Study 

Carcass ID Number 

Hematopoietic System 

Bone marrow 

Lymph node 

Mediastinal, alveolarhronchiolar carcinoma, 

metastatic, lung 

Mediastinal, sarcoma, metastatic, spleen 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Sarcoma 

Thymus 

Integumentary System

Mammary gland 

Adenoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Musculoskeletal System 

Bone 

Skeletal muscle 

Nervous System 

Brain 

Astrocytoma malignant 

Carcinoma, metastatic, pituitary gland 

Peripheral nerve 

Spinal cord 

Respiratory System 

Lung 

Alveolarhronchiolar carcinoma 

Carcinoma, metastatic, pituitary gland 

Carcinoma, metastatic, thyroid gland 

Sarcoma, metastatic, spleen 

Nose 

Squamous cell carcinoma 

Trachea 

Special Senses System 

Eye

Zymbal’s gland 

Carcinoma 

4444555566666666666666677 

4599456800012566689999901 

7722010827996934890147892 

3344344434434433444343434 

8922710193190398030928290 

9368945704370252918136742 

......................... 

+ + + 

X ......................... 

......................... 

......................... X 

......................... 

. . . . . . . . . . . . . . . . . . . . . . . . . 

X 

xxx 

......................... 

......................... 

......................... X 

+ 

+ 

......................... 

X ......................... X 

.......................... 

+ 

X 
Number of Days on Study 

Carcass IDNumber 

Wematopoietic System 

Bone marrow 

. Lymphnode 

Mediastinal, alveolarbronchiolar carcinoma, 

metastatic, lung 

Mediastinal, sarcoma, metastatic, spleen 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Sarcoma 

Thymus 

Integumentary System 

Mammary gland 

Adenoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Musculoskeletal System 

Bone 

Skeletal muscle 

Nervous System 

Brain 

Astrocytoma malignant 

Carcinoma, metastatic, pituitary gland 

Peripheral nerve 

Spinal cord 

Respiratory System 

Lung 

Alveolarbronchiolar carcinoma 

Carcinoma, metastatic, pituitary gland 

Carcinoma, metastatic, thyroid gland 

Sarcoma, metastatic, spleen 

Nose 

Squamous cell carcinoma 

Trachea 

Special Senses System 

Eye

Zymbal’s gland 

Carcinoma 

7777717777711777777177777 

2333333333333333333333333 

7’046666666666666666666666 

4443333333333344444444444 

2007788888999900011122233 

1436701478268916112802505 

......................... 

+ + + + 

X 

......................... 

......................... 

......................... 

......................... ~ ~~ ~~ ~~ ~ 

......................... 

X X xxx x xx X 

X X X ......................... 

......................... + 

......................... 

X 

......................... 

X 

X 

X 

......................... 

......................... 

+ + 

Total 

Tissues/ 

Tumors 

50 

7 

1 

1 

50 

50 

50 

1 

49 ~~ ~ 

49 

1 

12 

3 

50 

50 

1 

50 

1 

1 

1 

1 

50 

1 

1 

1 

1 

50 

1 

50 

2 

1 

1 
128 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 > . 't. ' 

TABLEE12 .. 

Individual Animal Tumor Pathologyof Female Rats in the 2-Year Depal Study I . ,

,' i- . ', .. I. ., : ./',,.I r , . :', . . 1 . of 1,2-Dihydro-2,2,4-trimethylquinoline:60 nagkg (continued) 

, . 

.. 

i ., . . . . % ., ,. . -, 

444455556666666'6666666671''''' 

Numberof Days on Study 

7 I2 2 0 10 8 2 7 9 9 6 9 3 4 8 9 0 14 7 " 8 . . 92 ' . 

4599456800012566689999901 

"""~ 

. . , . 3 3 3 4 3 4 4 4 3 4 4'3 4 4 3.'3 4 4 4 <3'4 '3 .4 3 -4.-

Car%s ID Number '8922710193190398030928290 

'93689457043702529181367'4'2 :-, 

""'. 

Kidney 

Urinary System . . , , .,.. . . ' i .... . ., , . . . >.,' 

................................ , I. .. 

Alveoladbronchiolar carcinoma, 

metastatic, lung .. 

Urinary bladder ......................... '' 

Systemic Lesions . 1 . . , ; . .. 

Multiple organs 

Leukemia mononuclear X X xx x x x x ......................... , . 

, .' ' 

.. . . a . , ? ..:. . ' . 
I29 

1111111111111111111111111 

Number of Days on Study 

lo46666666666666666666666 

2333333333333333333333333 

444333333333334444444444,4 

2001788888999900011122233 

1436101478268916112802505 

Total 

Tissues/ 

Tumors 

UninaPyr System 

Kidney 

Alveolarhronchiolar carcinoma, 

metastatic, lung 

Urinary bladder 

......................... 

X 

.......................... 

50 

1 

49 

Sys~~c Lesions 

Multiple organs 

Leukemia mononuclear 

.......................... xxxxx x xxxxxxx x X 

50 

23 , 
' 130 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE;B2 .. 

<, IndividualAnimal TumorPathology of FemaleRatsinthe2-YearDermalStudy I . . ,: . ' ' 

. ., . . . ., . . of 1,2-D6hydro-2,2,4-trimethylquinoline: 100 mgkg <. ' , . 

Number of Days on Study 

., 

Carcass I D Number 

~~~~~~~~ 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large,cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Carcinoma 

Intestine small, ileum 

Liver 

Mesentery 

Pancreas 

Salivary glands. 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Heart' 

Endocrine System 

Adrenal cortex 

Adenoma 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitaiy gland 

Carcinoma 

Pars distalis,adenoma 

Pars distalis, carcinoma 

Thyroid gland 

C-cell, aJenoma 

Follicular cell, adenoma 

General Body System 

None 

Genital System 

Clitoral gland 

Adenoma 

ovary 

uterus 

Sarcoma stromal 

Schwannoma malignant 

3444555556666666666667777 

3 14 8 4 7 8 8 9 0 2.2 3 4 4 4 5 7 7 8 8'0',0'00 

6084.09'1382672146556581488 

4444"44.444444~4444444444444 

7995837.6718'84686645669744' ' 

720.8868203737843011494538 

........................... 

.AA+++++++++A.++++t++++++++ .. 

AA++++.+++++A+++++A+++++++ 

AA+++A+++++A+++++A+++++++ 

AA+++A++++AAA++++++++++++' 

AA +'+ +-A A + +:+ A +.A + + + + + + + + + +,'+ +' 

AA+++AA+++:AAA+++AA++A++++ 

............................. + ' ......................... 

.......................... 

............................ 

A+++++++++++.+++++++++++++ 

.......................... 

.......................... X ............................ 

.......................... 

........................... 

........................... x 

xxx,xxx x xxxxxxx x, xx 

X 

......................... 

+++++.++++++M+++++++++++++, . ' 

X ........................... 

.......................... 

X 

x 
s -- 

--= 

n31 

I ~ ~~ ~~~ - ~~ ~ 

1711117117111771111111171 

Number of Days on Study 

4626666666666666666666666 

1123.33333333333333333*.3333 

4.444444444444'444444444444 Total 

Carcass IDNumber, 9 9 6 3 3.4 4 4 4 4 5 5 5 5 5 6 6 7 7 I 8 8 8 8 9 .Tissues/. 

3511924569024195626915691 Tumors I ~~ ~~~ ~~~ ~ ~~ ~~ ~~ ~~ ~~ 

Intestine large, rectum 

Intestine large, colon 

Esophagus 

Alimentary System 

.......................... 

........................... 

......................... 

46 

47 

.50 

Intestine large, cecum ........................... 45 

Intestine small, duodenum ........................... -. 4 4 

Intestine small, jejunum ............................ . . 4 4 ' 

Carcinoma X .I. 

Intestine small, ileum ......................... 40 

Liver .......................... 50 

Mesentery + + 3 

Pancreas .......................... 50 

Stomach, forestomach 

Salivary glands 

......................... 

......................... 50 

50 

Stomach, glandular ......................... 49 

Heart 

Cardiovascular System ......................... 50 

Endocrine System 

Adrenal cortex ......................... ., .% , 

50 

Adenoma 1 

Adrenal medulla ......................... 50 . 

Pheochromocytoma benign X 1 

Islets, pancreatic .......................... 50 

Adenoma X 1 

Parathyroid gland .......................... 48 

Pituitary gland ......................... 50 

Carcinoma 1 

Pars distalis, adenoma xxx x x x x xx x x x x x xx 33 

Pars distalis, carcinoma 1 

C-cell, adenoma 

Thyroid gland ......................... X X 2 

49 

Follicular cell, adenoma X 1 

Clitoral gland 

Genital System ......................... 49 

Adenoma X , .2 

ovary 

uterus ......................... 

......................... 50 

50 

Sarcoma stromal 1 

Schwannoma malignant 1 
132 

I 

1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE132 

Individual Animal Tumor Pathology of Female Rats in the 2-Year DermalStudy , , I 

. I , . . of 1,2-Dihydro-2,2,4-trimethylquinoline: 100 mgkg (continued) . .. 

3444555556666666666667777 

Number of Days on Study 314847,8890223444577880.000 

.. . , - . . _. 6 0 8.4.0 9 13 8 2 6 7-2 L.4 6 5 5 6 5 8 14 8 8 .. ~~~~~~~~~~~~~~~~~~~~~~ 

.. 444444444p44444444444444.4 

CarcassIO, Number 79958376778846866456697.44 

. .. 72.0.88682037378430114.94538 .. 

Hematopoietic System 

Bone marrow ......................... Lymph node 

Lymph node, mandibular ........................... Lymph,node, mesenteric ......................... 

Thymus 

spleen^ 

. .. . . , , . . - + + 4- + + + h + + + + +.+.,+ .+ + +.+ + + +.+ + + + ......................... 

1. . . 

Integumentary System 

Mammary gland ......................... Adenoma 

Carcino.ma X 

Carcinoia, multiple 

Fibroadenoma X X x x xx x. 

Fibroadenoma, multiple 

Skin ......................... Squamous cell papilloma 

Subcutaneous tissue, sarcoma . . x , 

Musculoskeletal System 

Bone . ,-. . . .I . ............................ 

Nervous System 

Brain ......................... Carcinoma,metastatic,pituitary gland . ~ ,. . .x I

Respiratory Sstem ,

Lung ......................... Nose ......................... Trachea -... . .. ............................. 

Special Senses System 

Eye : Zymbal’s gland + 

Carcinoma. ., X 

Urinary System 

Kidney ......................... :, 

Renal tubule, carcinoma 

. Urinary bladder .. .. ............................ 

Systemic Lesions 

Multiple organs .......................... . Leukemiamononuclear x... X ~. . x x x .. ., 
X X x x X 01 

......................... OS 

......................... OS 

..................... +++ 6P 

......................... OS 

I 

......................... os 

........................... os 

I 

X I ......................... OS 

X 1 

xxx x xx xx SI 

X I 

X Z 

X I ......................... OS 

......................... OS ......................... OS 

os ......................... os ......................... + I 

.......................... OS .. 

9999999999999999999999Z9P 

EEEEEEEEEEEEEEEEEEEEEEZII 

LLLLLLLLLLLLLLLLLLLLLLLLL 
134 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB3 

Statisticad Analysis of Primary Neoplasms in Female Rats in the2-Year Dermal Study 

of 1,2-Dilhydro-2,2,4-trimethylquinoline 

Adrenal Medulla: Benign Pheochromocytoma 

Overall rate" 

Adjusted rateb 

Terminal rate' 

First (days) incidence 

Life table testd 

~ 

Logistic regression testd 

cochran-~m~tae testd d Fisher exact test 

Adrenal Medulla: Benign or Malignant Pheochromocytoma 

60 mg/kg 

1/50 (2%) 

2.5% 

0122 (0%) 

609 

Pd. 172N 

P=O. 179N 

P=0.181N 

1/50 (2%) 

2.5% 

0122 (0%) 

609 

Pd.104N 

P=O.102N 

M.102N 

5/45 (1 1%) 

22.4% 

4/21 (19%) 

730 

EO.542 

PzO.482 

Pd.445 

5/45 (1 %)1 

22.4% 

4/21 (19%) 

730 

P=0.593N 

P=O.616 

P=O.574 

15/49 (30%) 

56.7% 

11/22(50%) 

69 1 

P=0.022N 

P=O.O24N 

P4.033N 

100 mgkg 

1/50 (2%) 

4.5% 

1/22(5%) 

736 (T) 

P=O. 172N 

P=O. 176N 

E0.181N 

1/50 (2%) 

4.5% 

1/22(5%) 

736 (T) 

M.103N 

P=0.100N 

P=O. 102N 

2/49 (4%) 

7.8% 

1/22(5%) 

70 1 

P=0.318N 

P=0.332N 

P=0.339N 

2/49 (4%) 

7.8% 

1/22(5%) 

701 

P=0.209N 

P4.21ON 

P=O.2 18N 

16/50 (32%) 

49.1% 

7/22 (32%) 

484 

P=0.053N 

P=O.049N 

P=O.O52N 

Vehicle Control 36 mgkg

4/50 (8%) 1\50 (2%) 

14.7% 4.5% 

1/19(5%) 0121 (0%) 

581 734 

P=0.084N P=O. 186N 

Pd.087N P=O. 178N 

P=0.089N 

P=O. 18IN 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran:Armitage test 

Fisher exact tlest 

ClitoralGland: Adenoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

Clitoral Gland: Adenoma or Carcinoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Amitage test 

Fisher exact tefst 

MammaryGland:Fibroadenoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

5/50 (10%) 1/50 (2%) 

17.5% 4.5% 

1/19(5%) 0/21 (0%) 

581 734 

P=0.039N P=O.115N 

P=0.039N P=0.102N 

Pd.04ON 

P=O. 102N 

4/49 (8%) 2/46 (4%) 

16.0% 10.0% 

1/19(5%) 2/20 (10%) 

702 736 (T) 

P=O.314N E0.333N 

P=0.358N P=0.358N 

P=0.364N 

P4.369N 

5/49 (10%) 2/46 (4%) 

18.8% 10.0% 

1/19(5%) 2/20 (10%) 

698 736 (T) 

EO.202N P=0.223N 

P=0.231N P=0.234N 

M.241N 

P=0.245N 

25/48 (50%) 16/49 (32%) 

72.7% 55.7% 

11/19 (58%) 9/21 (43%) 

427 638 

P4.03ON P4.054N 

P=0.031N E0.048N 

P4.04ON 

P4.052N 
VehicleControl 36 mgkg 60 mgkg 1QQ mgkg 

Overall rate 

Mammary Gland: Fibroadenoma or Adenoma 

26/48 (52%) 16/49 (32%) 15/49 (30%) 16/50 (32%) 

Adjusted rate 73.3% 55.7% 56.7% 49.1% 

Terminal rate 11/19 (58%) 9/21 (43%) 11/22 (50%) 7/22 (32%) 

First incidence (days) 427 638 69 1 484 

Life table test Pd.020N P=0.040N P=0.015N P=0.039N 

Logistic regression test P=O.O2ON P=0.032N P=0.016N P=0.033N 

Cochran-Armitage test P=0.026N 

Fisher exact test Pd.034N P=0.021N P=O.O34N 

MammaryGland:Carcinoma 

Overall rate 3/48 (6%) 5/49 (10%) 0/49 (0%) 3/50 (6%) 

Adjusted rate 10.2% 19.5% 0.0% 12.5% 

First incidence (days) 

Terminal rate 

500 

1/19 (5%) 

655 

3/21 (14%) 0/22 (0%) -

e 708 

2/22 (9%) 

Life table test P=0.335N EO.383 P=0.115N P=O.63 1N 

Logistic regression test P=0.364N P=O.356 P=0.128N Pd.661N 

Fisher exact test 

Cochran-Armitage test Pd.370N 

P=O.357 P=0.121N P=0.661N 

Overall rate 

Mammary Gland: Adenoma or Carcinoma 

4/48 (8%) 5/49 (10%) 1/49 (2%) 4/50 (8%) 

Adjusted rate 12.0% 19.5% 3.4% 16.8% 

First incidence (days) 

Terminal rate 

498 

1/19 (5%) 

655 

3/21 (14%) 

697 

0/22 (0%) 

708 

3/22 (14%) 

Life table test P=0.386N Pa.519 P=0.181N P=0.607N 

Logistic regression test Pd.417N P=O.500 P=O.200N P=O.643 

Cochran-Armitage test Pd.422N 

Fisher exact test P=O.500 Pd.181N P=0.643N 

Adjusted rate 

Overall rate 

Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma 

77.8% 

29/48 (58%) 

65.4% 

20149 (40%) 

56.7% 

15/49 (30%) 

57.6% 

19/50 (38%) 

First incidence (days) 

Terminal rate 

427 

12/19 (63%) 

638 

11/21 (52%) 

69 1 

11/22 (50%) 

484 

9/22 (41%) 

Life table test P=0.016N Pd.066N P=O.WN P=0.043N 

Logistic regression test P=O.O14N P=0.051N Pd.003N P=0.034N 

Cochran-Armitage test M.019N 

Fisher exact test P=0.055N P=0.004N P=0.036N 

Adjusted rate 

Overall rate 

Pituitary Gland (ParsDistalis): Adenoma 

83.9% 

30/49 (61%) 

83.7% 

28/50 (56%) 

78.2% 

31/50 (62%) 

79.3% 

33/50 (66%) 

Terminal rate 14/19 (74%) 16/21 (76%) 14/22 (64%) 14/22 (64%) 

Life table test 

First incidence (days) 

Pd.440 

427 

P=0.339N 

492 

Pd.470N 

457 

P=O.517 

484 

Logistic regression test P=O.310 P=0.359N P=0.581N P=O.402 

Cochran-Armitage test P=O.288 

Fisher exact test P=0.373N M.55 1 P=O.388 
136 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB;3 

StatisticalAnalysis of Primary Neoplasms in Female Rats in the2-Year Dermal Study 

of 1,2-Dil1ydro-2,2,4-trimethylquinoline(continued) . . 

Vehicle Control 36 mgkg

Pituitary Gland (Pars Distalis): Adenomaor Carcinoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

Thyroid Gland (C-cell): Adenoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Amnitage test 

Fisher exact test 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 

Adjusted rate: 

Terminal rate 

First (days) incidence , 

Life table test 

Logistic repmion test 

Cochran-Amutage test 

Fisher exact test 

Uterus:St:romalPolyp 

Overall rate 

Adjusted rate ,

Terminal rate 

First incidence (days) 

Life table test .. . 

Logistic iegrcssion test 

Cocbran-Amutage test 

Fisher exact test 

Uterus: Stromal Polyp or Stromal Sarcoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table, test 

Logisticregressiontest ' 

Cochran-Armitage test 

Fisher exact test 

32/49 (65%) 28/50 (56%) 

87.7% 83.7% 

15/19 (79%) 16/21 (76%) 

427 492 . 

m.478 m.225~ 

M.351 M.209N 

Pd.323 

M.229N 

7/49 (14%) 5/50 (10%) 

3 1.2% 19.5% 

5/19 (26%) 3/2 1 (14%) 

568 655 

M.018N P=0.334N 

M.027N M.373N 

M.03ON 

M.365N 

7/49 (14%) 5/50 (10%) 

31.2% 19.5% 

5/19 (26%) 3/21 (14%) 

568 655 

M.023N Pd.334N 

Pd.036N Pd.373N 

M.04ON 

P=0.365N 

4/50 (8%) 3/50 (6%) 

15.2% 9.2% 

2/19 (11%) 1/21(5%) 

576 524 

-P=0.058N P=0.47ON 

M.071N M.500N 

P=O.O72N 

MSOON 

4/5/50(s%j 4/50 (8%) , 

15.2% 11.7% 

2/19 (11%) 1/21 (5%) 

576 524 

P=0. 125N Pd.607N 

Pd.151N Pd.644 ' 

M.147N 

M.643N 

60 mgkg 

33/50 (66%) 

83.6% 

16/22 (73%) 

457 

M.454N 

M.567N 

Pd.555 

2/48 (4%) 

9.1% 

2/22 (9%) 

736 (T) 

M.053N 

M.078N 

M.084N 

3/48 (6%) 

13.6% 

3/22 (14%) 

736 (T) 

Pd. 108N 

Pd. 154N 

Pa. 167N 

4/50 (8%) 

17.2% 

3/22 (14%) 

730 

Pd.577N 

Pd.629N 

Pd.643N 

4/50 (8%) 

17.2% 

3/22 (14%) 

730 

M.577N 

Pa.629N 

M.643N 

100 mgkg 

34/50 (68%) 

80.0% . 

14/22 (64%) 

484 

M.538N 

M.492 

M.472 . 

2/49 (4%) 

9.1% 

2/22 (9%) 

736 (T) 

Pd.054N 

M.075N 

P=0.080N 

2/49 (4%) 

9.1% 

2/22 (9%) 

736 (T) 

M.054N 

Pd.075N 

F'=O.OSON 

0/50 (0%) 

0.0%'. 

,0/22(0%) -

P=0.054N 

P=0.063N 

E0.059N 

'1/50 (2%) 

2.0% 

0/22 (0%) 

336 

M.162N 

Pd. 186N 

Pd.181N 

. 

. . 

.. 
n34 

. . . 

All Organs: Mononuclear Cell Leukemia 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Benign Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Malignant Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Benign or Malignant Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

(T)Terminal sacrifice 

. . .. . 

VehicleControl 36 mglkg 60 mim 1QQ mgkg 

22/50 (44%) 16/50 (32%) 23/50 (46%) 10/50 (20%) 

64.3% 52.7% 72.4% 32.8% 

9/19 (47%) 8/21 (38%) 14/22 (64%) 4/22 (18%) 

272 557 492 540 

P=0.018N P=0.150N E0.503N P=0.012N 

P=0.018N P=O. 15ON P=O.521 P=0.009N 

P=O.O20N 

P=0.151N P=OSOO P=0.009N. ' 

43/50 (86%) 37/50 (74%) 37/50 (74%) 38/50(76%) ' ' . ' 

,. 

95.3% 94.6% 94.5% 86.0% 

17/19 (89%) 19/21 (90%) 20/22 (9 1%) 16/22 (73%) 

427 492 457 484 

P=O.l43N P=0.163N P=O. 115N P=O. 1 80N 

P=O.115N P=0.091N P=0.077N P=O.l52N 

P=0.149N 

P=0.105N P=0.105N P=O. 154N 

30150 (60%) 26/50 (52%) 28/50 (56%) 18/50(36%) ' ' ' ' 

' 76.5% 72.6% 81.2% 51.2% 

11/19 (58%) 12/21 (57%) 16/22 (73%) 7/22 (32%) 

272 485 447 336 

P=O.O2ON P=O.265N P=0.292N P=0.025N ' 

P=0.013N P=0.272N P=0.405N P=O.O14N 

P=O.O14N 

P=O.273N P=0.420N P=O.O14N ' 

49/50 (98%) 43/50 (86%) 47/50 (94%) 43/50 (86%) I. 

98.0% 97.7% 97.9% 89.5% 

18/19 (95%) 20/21 (95%) 21/22 (95%) 17/22 (77%) 

272 485 447 336 

P=0.157N P=O. 184N P=0.272N E0.161N ' 

P=0.048N P=O.O24N P=O.296N P=0.033N 

P=0.059N 

P=0.030N P=0.309N P=0.03ON 

a Number of neoplasm-bearing animalhumber of animals examined. Denominator is number of animals examined microscopically for adrenal gland, clitoral 

gland, pituitary gland, thyroid gland, and uterus; for other tissues, denominator is number of animals necropsied. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

Beneath the vehicle control incidence are theP values associated with the trend test. Beneath the dosed group incidence areP values the corresponding to 

painvise comparisons between the vehicle controls and that dosed group. The life table test regards neoplasms in animals dying prior to terminal kill as being 

(directly or indirectly) the causeof death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare 

directly the overall incidence rates. For all tests, a negative trendor a lower incidence in a dose group is indicated by N. 

e Not applicable; no neoplasms in animal group 
138 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB4a ., 

, , Historical Incidence of Mammary Gland Neoplasms in Control Female F344/N Ratsa . 

. ,. . -. . ... , . I. _I . 

Incidence in Controls .' ,. i, '_" 

AdenomaFibroadenoma carcinoma Fibroadenoma, 

. .. Adenoma, or Carcinoma 

Overall Historical Incidence: Dermal (Acetone) Studies 

. . 

Total 33/100 (33.0%) 0/100 2/100 (2.0%) 34/100 (34.0%) 

Standard deviation - 9.9% 2.8% 11.3% 

Range 26%-40% 0%-4% 26%-42% 

Overall Historical Incidence: Feed Studies 

'Total _. - ' 465/1,202 . 32/1,202 ' . 507/1,202 (42.2%) ' 

.. 

I (38.7%) ' 2311,202 (1.9%) (2.7%) 

Standard deviation 12.7% 2.3% 2.9% 13.5% . - .. . 

Range 8%-58% 0%-8% 0%-10% ' .8%-64% '' . . 

a Data as of 17 June 1994 

, . 

TABLEB4b 

Historical Incidenceof Leukemia in Control Female F344/N Ratsa . . I . ' .. 

,. .

Incidence in Controls ,. 

Overall.Historica1 Incidence: Dermal (Acetone) Studies . *. 

Total 25/100 (25.0%) 

Standard deviation 1.4% 

Range . .. . 24%-26% 

Overall Historical Incidence: Feed Studies 

322/1,202 (26.8%) ., ~, . .. .Total.- . .,. 

Standard de;iation 9.0% 

Range 14%-52% ,. ... 

~~~~~~~~~~ 

a Data as of 17 June 1994; includes data for lymphocytic, monocytic, mononuclear cell, or undifferentiated cell type leukemias , , ~ ,,

._ - .--. . , . . .. . . 

. L I 

.. ., 
139 

. . VehicleControl . 36 mglag QQ m@g 100 mgikg 

~ ~ ~ 

Early deaths 

ISMonth interim evaluarion 

Animals initially in study 

Disposition Summary 

Terminal sacrifice 

Natural deaths 

Moribund 

Survivors 

19 

12 

19 

10 

60 

21 

19 

10 

10 

60 

22 

19 

9 

10 

60 

10 

60 

19 

9 

22 

Animals examined microscopically 60 60 60 60 

Intestinesmall,jejunum ' 

Alimentary System 

l§-Month Interim Ev~uQ~~Q~ 

Intestine small, ileum 

Erosion 

Dilatation 

Inflammation, chronic active 

Mixed cellfocus 

Hepatodiaphragmatic nodule 

Fattychange,focal : 

Eosinophilic focus 

cyst 

Clear cell focus 

Basophilic focus 

Acinus, atrophy 

Fat, necrosis 

Hyperkeratosis 

Duct, metaplasia, squamous 

Artery, inflammation, chronic active 

Inflammation, acute 

Hyperplasia, basal cell 

Liver 

Pancreas 

Mesentery 

Stomach, forestomach 

Salivary glands 

(10) 

(10) ' 

1 (10%) 

(10) 

1 (10%) 

9 (90%) 

1 (10%) 

3 (30%) 

1 (100%) 

2 (20%) 

(10) 

. (1) 

(10) 

(10) 

1 (10%) 

.. 

(10) 

(10) 

9(90%) 

1 (10%) 

1 (10%) 

(10) 

1 (10%) 

4 (40%) 

1 (10%) 

1 (100%) 

(10) 

(1) 

6 (60%) 

(10) 

(10) 

3 (30%) 

(10) 

9 (90%) 

1 (10%) 

1 (10%) 

2 (20%) 

2 (20%) 

1 (10%) 

3 (30%) 

(1)

1 (100%) 

(10) ' 

4 (40%) 

(10) 

(10)

3 (30%) 

1(10%) 

1 (10%) 

1 (10%) 

.. 

Heart 

Cardiovascular System 

Cardiomyopathy 

Endocrine System 

Hyperplasia 

Adrenal medulla 

Hyperplasia 

Adrenal cortex 

~ ~~~~~ 

a Number of animals examined microscopically at thesite and the number of animals with lesion 
140 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEB:5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study. , 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

Pituitary gland 

Endocrine System(continued) 

15-Month Interim Evaluation (continued) 

(10) 

Pars distalus, hyperplasia 

Pars distalis, cyst 

Pars distalis, angiectasis 

Follicular cell, hyperplasia 

C-cell, hyperplasia 

3 (30%) 

6 (60%) 

3 (30%) 

2 (20%) 

1(10%) 

Thyroid gland (10) 

'Follicle,cyst ~ 

(10) 

6 (60%) 

8 (80%) 

4 (40%) 

(10) 

1 (10%) 

(10) 

6 (60%) 

8 (80%) 

6 (60%) 

(10) 

' 

'5 (50%) 

7 (70%) 

6 (60%) 

(10) . . 

(10) 

Genital System 

Uterus 

cyst 

ovary 

cyst 

Integumentaj System 

Skin, site of application, inflammation, 

Skin, siteof application, hyperkeratosis 

Skin, siteof application, acanthosis 

Inflammation, chronic 

Skin 

Subcutaneous tissue, inflammation, chronic 

active 

chronic 

(10) 

3 (30%) 

1(10%) 

1(10%) 

1(10%) 

(10) 

4 (40%) 

1 (10%) 

1(10%) 

(10) 

1 (10%) 

4 (40%) 

1(10%) 

(10) 

1(10%) 

8 (80%) 

1(10%) 

. . 

Lung 

Respiratory System' 

Alveolar epithelium, hyperplasia 

Inflammation, chronic active 

Infiltration cellular, histiocyte 

Foreignbody . . 

Inflammation, acute 

Fungus ~ 

Nose 

(10) 

(10) 

1(10%) 

1(10%) 

(10) 

2 (20%) 

(10) 

Eye 

Special Senses System 

Lens, cataract 

(1) 

1 (100%) 

.. 

.. 

Kidney 

Urinary System 

Nephropathy, chronic 
101 

i

I 

khicle Control . , .

I

I ki-&hEh h&?l'hEVckbaEhl (continued) 

Systems Examined With No Lesions Observed 

General Body System 

Hematopoietic System 

Musculoskeletal System 

Nervous System 

;

2-Yeckr Sttddy 

Alimentary System 

Intestine large, colon (49)

Erosion 

I

I Intestine large, rectum (49)

Erosion 

Intestine large, cecum (48)

Edema . . Hemorrhage 

Inflammation, acute 

Ulcer 

Intestine small, jejunum (49)

Inflammation, chronic 1(2%) I 

Ulcer 1(2%) I Intestine small, ileum (45) I Inflammation, chronic

I Metaplasia, osseous 

Ulcer I Liver (50) I Angiectasis 3(6%) i

I 

Basophilic focus 35(70%) 

36 mg/ag .. 

(47) 

1(2%) 

(47)

1 (2%) 

(43) 

1 (2%) 

1(2%) 

(41) 

(40) 

1(3%) 

1 (3%) 

1 (3%) 

(50) .. 1 (2%) 

36 (72%) 

QO mgkg 

(48) 

(47) 

(42) 

1(2%) 

1(2%) 

(44) 

(42) 

(50) 

2(4%) 

32 (64%) 

100mgkg 

(47) 

(46) 

(45) 1 (2%). 

(44) 

(40) . 

(50) 

2 .(4%) 

30 (60%) i Congestion 1(2%)

1 . . ' ' . '' Eosinophilic focus ' 12 (4%) 16 (32%) 17(34%) 14(28%)

Hematopoietic cell proliferation 3 (6%) 1. (2%) 

Hepatodiaphragmatic nodule . 11 (22%) 5(10%) 6(12%) 16 (32%) ' ' 

Inflammation, chronic 3 (6%) i Inflammation, granulomatous 1(2%) 

Mixed cell focus 10 (20%) 6(12%) 9 (18%) 11 (22%) 

i ... Regeneration 1 (2%) 2(4%) 

Centrilobular,atrophy . . 

- 1 (2%) . . 

Centrilobular, necrosis 1 (2%) I Centrilobular, vacuolization cytoplasmic 11(22%) 5 (10%) 6 (12%) 9(18%) I Midzonal, vacuolization cytoplasmic 1(2%) I Periportal, vacuolization cytoplasmic 1(2%) 1(2%) I Serosa, inflammation, acute 1(2%) 

Serosa, necrosis 

1 (2%) 

Mesentery (8) (4) (3)

Inflammation, chronic 1(13%) 1(25%) , , 

. . 

Metaplasia, osseous 1(25%) I. . I 

Fat, necrosis 6 (75%) 7 (88%) 2(50%) 2(67%) I . . .. ," . . 

_. 

.. 

* . 

Clear cell focus 7(14%) 7(14%) 9 (18%) (24%) 12 ' 
142 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 . . 

TABLE115 

Summary of the Incidenceof Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

Vehicle Control 36 mgfltg 60 mgfltg 100 mgkg 

, . .. 

2-Year Study (continued) 

Al&eniai.Ji System(continued) 

Pancreas (50) (50)

Inflammation, chronic 1 (2%) 1 (2%) 

Metaplasia, hepatocyte 1 (2%) 

Acinus, atrophy 19 (38%) 15 (30%) 14 (28%) 14 (28%) 

Acinus, hyperplasia 1 (2%) 

Artery, thrombosis 1 (2%) 

Duct, cyst 1 (2%) 1 (2%) 

Salivary glands (50) (50) (50)

Atrophy 1 (2%) 1 (2%) 1 (2%) 

Duct, cyst ' 1 (2%) 

Stomach, forestomach (50) (50) (49) (50)

Diverticulum 1 (2%) 

Hyperplasia,'squamous 13 (26%) 10 (20%) 6 (12%) 7 (14%) 

Inflammation, chronic 9 (18%) 6 (12%) 5 (10%) 5 (10%) 

Perforation . . 1' (2%) 

Ulcer 10 (20%) 8 (16%) 5 (10%) 5 (10%) 

Stomach, glandular (50) (50) (50) (49)

Erosion 13 (26%) 6 (12%) 6 (12%) 7 (14%) 

Hyperplasia 1 (2%) 

Mineralization 1 (2%) 

Ulcer 1 (2%) 1 (2%) 

CardiovascularSystem 

Heart (50)

Cardiomyopathy 41 (82%) 

Mineralization . . 1 (2%) 

Atrium, thrombosis 3 (6%) 2 (4%) 2 (4%) 

Valve, thrombosis 1 (2%) 

Endocrine System 

Adrend'cortex (50) (50) 

hgiectasia, 1 (2%) 1 (2%) 

Atrophy 1 (2%) 

Degeneration 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia 7 (14%) 4 (8%) 2 (4%) 5 (10%) 

Necrosis 1 (2%) 1 (2%) 1 (2%) 

Vacuolization cytoplasmic 13 (26%) 12 (24%) 8 (16%). 

Adrenal medulla (50) (50) (50) 

Hypefplasia 8 (16%) 3 (6%) 3 (6%) 

Islets, pancreatic (50) (50) (50) 

Hyperplasia 1 (2%) 

Metaplasia; hepatocyte 1 (2%) 

Parathyroidgland. (44) (48) 

Hyperplasia 1 (2%) 1 (2%) 
Lesions in Female Rats 

,!hdy (continued) 

Endocrine System(continued) 

Pituitary gland 

Craniopharyngeal duct, pars intermedia, 

hyperplasia 

Pars distalis, angiectasis 

Pars distalis, cyst 

Pars distalis, hyperplasia 

Rathke’s cleft, cyst 

Rathke’s cleft, hemorrhage 

Thyroid gland 

Hyperplasia 

C-cell, hyperplasia 

Follicular cell, hyperplasia 

General Body System 

None 

Genital System 

Clitoral gland 

cyst 

Hyperplasia 

Inflammation, acute 

Inflammation, chronic 

Metaplasia, squamous 

ovary 

cyst 

Bilateral, cyst 

Uterus 

cyst 

Hyperplasia, cystic 

Inflammation, chronic 

Vagina 

Inflammation, chronic 

Hematopoietic System 

Bone marrow 

Hyperplasia, reticulum cell 

Myelofibrosis 

Lymph node 

Bronchial, depletion lymphoid 

Lumbar, depletion lymphoid 

Mediastinal, congestion 

Mediastinal, ectasia 

Mediastinal, hemorrhage 

Mediastinal, infiltration cellular, plasma 

cell 

Pancreatic, ectasia 

Pancreatic, erythrophagocytosis 

Pancreatic, pigmentation 

Renal, hemorrhage 

(49) 

9(18%) 

6 (12%) 

11 (22%) 

9(18%) 

(49) 

3(6%) 

3 (6%) 

1(2%) 

(50) 

8 (16%) 

1(2%) 

(50) 

1(2%) 

(50) 

(13) 

1 (8%) 

1 (8%) 

1 (8%) 

(50) 

1(2%) 

13 (26%) 

2(4%) 

13 (26%) 

12(24%) 

1(2%) 

(46) 

2(4%) 

1(2%) 

2(4%) 

(50) 

2(4%) 

(50) 

1(2%) 

(1) 

(49) 

1(2%) 

(10) 

1 (10%) 

1(10%) 

1 (10%) 

3(30%) 

1 (10%) 

1 (10%) 

1(10%) 

7 (14%) 

16 (32%) 

(48) 

11 (23%) 

(45) 

1(2%) 

2(4%) 

2 (4%) 

1(2%) 

(50) 

5(10%) 

(50) 

(2) 

1 (50%) 

(50) 

1(2%) 

(7) 

1(14%) 

1(14%) 

11(22%) 

1(2%) 

11(22%) 

1(2%) 

1(2%) 

(49)

1(2%) 

4 (8%) 

(49)

2(4%) 

1 (2%) 

(50) 

7 (14%) 

2(4%) 

(50)

1(2%) 

1(2%) 

(50) 

1(2%) 

(1) 
144 . . 

1,2-Dihydro-2,2,4-trimethylqiiinoline,NTP TR $5'6 

TABLEB:5 .;I. ,.;, 1,..s. 

, i . . Summary of the Incidenceof Nonneopiastic Lesions inFemale Rats in the 2-Year De&alStudy ' . 

. . 

, ,. I. , , , *.. ,.,, ,. ,. ,

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 'I 

. . .,.. . . . . .1 , , 

, .. 

36Vehicle Control mgkg ' 6Omgkg 100 mgkg 

2-Yew study (continued) 

Hematopoietic System(continued) 

Lymph node:, mandibular (50) (50)

Hemorrhage 3 (6%) 1(2%) 

Hyperplasia, lymphoid 1(2%) 

Infiltration cellular, plasma cell 2 (4%) 1 (2%) 

Lymph node, mesenteric (50) . . (49) (50) ' ' ' ' 

. Ectasia 1 (2%) 1 (2%) 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia, lymphoid 1(2%) 

Infiltration cellular, polymorphonuclear 1 (2%) 

Inflammation, acute 1 (2%) 

Congestion 

Spleen (50) 

1 (2%) 

(50) ' (50) , . 

I. 

Hematopoietic cell proliferation 

Fibrosis 

3 (6%) 

6 (12%) 

5 (10%) 

4 (8%) 

6 (12%) 

3 (6%) , 

. . 4 (8%) . . . ' 

Pigmentation 1 (2%) 1 (2%) 

Capsule, necrosis ' i 1 (2%) , . ' 

Thymus 

cyst 

Ectopic parathyroid gland 

(47) 

2 (4%) 

(50) 

1 (2%) 

(49) 

1 (2%). 

1 (2%)

(50) 

' 

Metaplasia,osseous ' . 1 (2%) 

Integumentary System ..i 

Mammary gland (48) (49) (49) ' (5oj. 

Galactocele 2 (4%) 10 (20%) . , 3 (6%) 5 (10%) ': ' 

.. . .. Inflammation, chronic active 1 (2%) 

Skin .. . (50, .. I: (50) I . -, ,-.. (50) (50)

Acanthosis 2 (4%) 1 (2%) 5 (10%) 3 (6%) . . 

Inflammation, acute 1(2%) ,. , .. . 

Inflammation, chronic 6 (12%) 10 (20%) 8 (16%) 8 (16%)

.( . .. Necrosis . . 1 '(2%) . . 

Necrosis, (chronic 1 (2%) 

Ulcer 1(2%) ., :* 

Skin, site of application, acanthosis 1 (2%) 9 (18%) 22 (44%) .' ' . 

Skin, siteId application, hyperkeratosis 1 (2%) 7 (14%) 1 (2%) ' 

, 

' '

.Skin, site of application, inflammation, . . ;. . 

chronic 1 (2%) 2 (4%) 2 (4%) . , Subcutaneoustissue, foreign body 1 (2%) ' ,!' '.) , ." , 

. ... Subcutaneous tissue, inflammation, chronic 2 (4%) 3 (6%) .3 (6%) ,. :1 (2%) '. . 

Subcutaneous tissue, inflammation, chronic 

active 1(2%) 

Subcutaneous tissue, skin, siteof 

application, inflammation, chronic 2 (4%) 1 (2%) 

Musculoskeletal System 

Bone 

Fibrous osteodystrophy 

Hyperostosis 

Cranium, -fracture 
n45 

2-yC?(kP .%&tdy (continued) 

Nervous System 

Brain 

Hemorrhage 

Peripheral nerve 

Axon, degeneration 

Respiratory System 

Lung 

Congestion 

Edema 

Hemorrhage 

Infiltration cellular, histiocyte 

Inflammation, acute 

Inflammation, chronic 

Inflammation, chronic active 

Inflammation, granulomatous 

Alveolar epithelium, hyperplasia 

Alveolus, edema 

Capillary, thrombosis 

Serosa, fibrosis 

Nose 

Foreign body 

Fungus 

Inflammation, chronic 

Inflammation, chronic active 

Thrombosis 

Nasolacrimal duct, inflammation, acute 

Special Senses System 

EY e 

Iris, synechia 

Lens, cataract 

Posterior chamber, hemorrhage 

Retina, atrophy 

Retina, degeneration 

Urinary System 

Kidney 

Accumulation, hyaline droplet 

Hydronephrosis 

Infarct 

Inflammation, acute 

Nephropathy, chronic 

Pigmentation 

Papilla, necrosis 

Renal tubule, hyperplasia 

Urinary bladder 

Hemorrhage 

Transitional epithelium, hyperplasia 

Vehicle Control 

(50) 

1 (2%) 

(50) 

1 (2%) 

5 (10%) 

1 (2%) 

3 (6%) 

1 (2%) 

(50) 

2 (4%) 

2 (4%) 

4 (8%) 

1 (2%) 

(50) 

4 (8%) 

1 (2%) 

49 (98%) 

(50) 

1 (2%) 

36 mgkg 

(50)

1 (2%) 

(50) 

1 (2%) 

5 (10%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

(50)

2 (4%) 

3 (6%) 

6 (12%) 

3 (6%) 

(50) 

1 (2%) 

45 (90%) 

2 (4%) 

1 (2%) 

(48) 

1 (2%) 

6Qmglkg 

(50) 

2 (4%) 

(1) 

1 (100%) 

(50) 

1 (2%) 

1 (2%) 

2 (4%) 

1 (2%) 

3 (6%) 

(50) 

2 (4%) 

2 (4%) 

3 (6%) 

3 (6%) 

(2) 

1 (50%) 

2 (100%) 

1 (50%) 

1 (50%) 

(50) 

1 (2%) 

48(96%) 

1 (2%) 

1 (2%) 

(49) 

100mgkg 

(50) 

1 (2%) 

(50) 

3 (6%) 

3 (6%) 

1 (2%) 

2 (4%) 

(49) 

4 (8%) 

2 (4%) 

1 (2%) 

I (14%) 

1 (2%) 

(3) 

3 (100%) 

1 (33%) 

2 (67%) 

(50) 

49 (98%) 

1 (2%) 

(50) 
146 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

.. 
147 
148 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

!. . 

(. . 

. .. 

. . 1 . 

. . 

. . . 

,. . . 
I 

3.6 mgkg 

60 

10 

1 

4 

8 

31 

60 

(10)

2 (20%) 

2 (20%) 

1 (10%) 

60 

10 

7 

2 

41 

60 

(10) 

1 (10%) 

(10) 

1 (10%) 

60 

10 

3 

10 

37 

60 

(10) 

1 (10%) 

2 (20%) 

(10)

2 (20%) 

1 (10%) 

Vehicle Control 

Disposition Summary 

Animals initially in study 60 

IS-Month interim evaluation 10 

Early deaths 

Accidental death 

Moribund 5 

Natural deaths 6 

Survivors 

Terminal sacrifice 39 

Animals examined microscopically 60 

%§-MOnEh InEpippa Ev~u~~oP~ 

Alimentary System 

Liver 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

It0 cell tumor malignant 

Endoche System 

Thyroid gland 

Follicular cell, adenoma 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhonchiolar adenoma, multiple 

(10) 

2 (20%) 

3 (30%) 

1 (10%) 

(10) 
150 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC:l 

Summary of the Incidence of Neoplasmsin Male Mice inthe 2-Year DermalStudy 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

Vehicle Control 3.6 mgkg 

2-Year Shdy 

Alimentary System 

Esophagus (50)

Gallbladder (47)

Carcinoma, metastatic, pancreas 1(2%) 

Intestine large, colon (50)

Carcinoma, metastatic, uncertain primary site 

Intestine large, cecum (50) 

Carcinoma 1 (2%) 

Intestine small, duodenum (49) 

Intestine small, jejunum (49)

Intestine small, ileum (47) 

Liver (50) 

Carcinoma, metastatic, uncertain primary site 

Hemangiosarcoma 2 (4%) 

Hemangiosarcoma, multiple 

Hepatoblastoma 2(4%) 

Hepatocellular carcinoma 5 (10%) 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 12 (24%) 

Hepatocellular adenoma, multiple 13 (26%) 

Hepatocholangiocarcinoma 1 (2%) 

Histiocytic sarcoma 

Squamous;cell carcinoma, metastatic, stomach, 

forestomach 1(2%) 

Mesentery (2) (3) 

Carcinoma, metastatic, uncertain primary site 1 (33%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (50%) 

Squamous cell Carcinoma, metastatic, stomach, 

forestomach 1 (33%) 

Pancreas (50) (49) 

Carcinoma 1 (2%) 

Carcinoma, metastatic, uncertain primary site 1 (2%) 

Hemangioma 

Histiocytic sarcoma 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Squamous cell papilloma 

Stomach, glandular 

Carcinoid tumor benign 

Carcinoma, metastatic, uncertain primary site 

CardiovascularSystem 

Heart (50) (50) (50) 

Hemangioma 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1(2%) 
.%y&W shdy (continued) 

hdWhe System 

Adrenal cortex 

Carcinoma, metastatic, uncertain primary site 

(49) 

Capsule, adenoma 

Pheochromocytoma benign 

Adrenal medulla (48) 

1 (2%) 

Pars intermedia, adenoma 

Pituitary gland (45) 

Follicular cell, adenoma 

Thyroid gland (49) 

Follicular cell, carcinoma 1 (2%) 

Tissue NOS 

General Body System 

Epididymis 

GenitalSystem 

Carcinoma, metastatic, pancreas 

(49) (50) 

1 (2%) 

Carcinoma, metastatic, uncertain primary site 

Squamous cell carcinoma, metastatic, stomach, 

forestomach 

Preputial gland 

Hemangiosarcoma 

Prostate 

Carcinoma, metastatic, uncertain primary site 

Seminal vesicle 

Carcinoma, metastatic, pancreas 

Carcinoma, metastatic, uncertain primary site 

Carcinoma, metastatic, pancreas 

Testes (49) 

Carcinoma, metastatic, uncertain primary site 

Squamous cell carcinoma, metastatic, stomach, 

forestomach 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Histiocytic sarcoma 

Hemangiosarcoma 

(49) 

1 (2%) 

Pancreatic, histiocytic sarcoma 

Lymph node, mesenteric 

Lymph node, mandibular 

Lymph node 

carcinoma, metastatic, pancreas 

(47) 

(48) 

(2) 

1 (50%) 

Carcinoma, metastatic, uncertain primary site 1 (2%) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Squamous cell carcinoma, metastatic. stomach, 

forestomach 1 (2%) 
152 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLECI1 

Summary of the IncidenceaIf Neoplasms in MaleMice in the 2-Year DermalStudy 

of 1,2-Di,hydro-2,2,4-trimethylquinoline(continued) 

Vehicle Control , 3.6 mgkg 6 mgkg 10 mgkg . .. . ,i 

2-Year shdy (continued) 

Hematopoietic System(continued) 

Spleen . 

Carcinoma, metastatic, uncertain primary site 

Hemangiosarcoma 

Histiocytic saicoma 

Squamous cell carcinoma, metastatic, stomach, 

forestomach 

Thymus 

Thymoma NOS 

Mediastinum, hemangioma 

Integumentary System 

Skin 

Sarcoma 

Subcutaneous tissue, sarcoma 

Musculoskeletal System 

Bone 

Osteosarcoma 

Skeletal muscle 

Carcinoma, metastatic, uncertain primary site 

Hemangioma 

Hemangiosarcoma 

Squamous cell carcinoma, metastatic, stomach, 

.forestomach 

Nervous System 

Brain 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar multiple adenoma, ' 

Alveoladbronchiolar carcinoma 

Alveolarhronchiolar carcinoma, multiple 

Carcinoma, metastatic, pancreas 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Squamous cell carcinoma, metastatic, stomach, 

forestomach 

Nose 

Hemangiosarcoma 

Trachea 

. . 

Special SensesSystem 

Harderian gland 

Adenoma, 

Carcinoma 

Bilateral, carcinoma 

(48) 

. . 

1 (2%) 

2 (4%) 

(39)

1 (3%) 

(49) 

2 (4%) 

(50) 

. (1) . , 

(49). 

1 (100%) 

(50) 

1 (2%) 

6 (12%) 

4 (8%) 

8 (16%) 

1 (2%) 

2 (4%) 

(50) 

(50) 

(4)

3 (75%) . . ' 

(5)

5.(100%) 

(49) 

1 (2%) 

' (50) 

(50)

11(22%) 

7 (14%) 

1 (2%) 

1 (2%) 

2 (4%) 

(5) 

j 3 (60%) 

1 (20%) 

' 

., 

. , , 

' 

(50)

1 (2%) 

1 (2%) 

1 '(2%) 

1 (2%) ' 

(40) 

' (49) 

1 (2%) 

(3)

1 (33%) ' , 

' ' 1 (33%) 

: 1 (33%) 

(50)

8 (16%) 

2 (4%) 

6 (12%) 

2 (4%) 

6 (12%) 

(3)' 

1 (33%) 

1 '(33%) 

1 (33%) 
lLesi~nsin Male Mice n53 

2-yQap%Udy (continued) 

Urinary System 

Kidney 

Carcinoma, metastatic, uncertain primary site 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Renal tubule, adenoma 

Renal tubule, carcinoma 

Urinary bladder 

Hemangioma 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma 

Lymphoma malignant 

Neoplasm Summary 

Total animals with primary neoplasms' 

15-Month interim evaluation 

2-Year study 

Total primary neoplasms 

15-Month interim evaluation 

2-Year study 

Total animals with benign neoplasms 

15-Month interim evaluation 

2-Year study 

Total benign neoplasms 

15-Month interim evaluation 

2-Year study 

Total animals with malignant neoplasms 

15-Month interim evaluation 

2-Year study 

Total malignant neoplasms 

15-Month interim evaluation 

2-Year study 

Total animals with metastatic neoplasms 

2-Year study 

Total metastatic neoplasms 

2-Year study 

Total animals with malignant neoplasms 

of uncertain primary site 

2-Year study 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 

Total uncertain neoplasms 

2-Year study 

(50) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

6 

42 

7 

I4 

5 

35 

5 

43 

2 

22 

2 

30 

2 

2 

1 

1 

(50) 

1 (2%) 

1 (2%) 

(50) 

5 

41 

5 

I6 

2 

33 

2 

46 

3 

24 

3 

30 

1 

1 

(50) 

1 (2%) 

1 (2%) 

(50) 

2 5 

43 46 

2 6 

75 79 

2 5 

35 34 

2 5 

51 43 

1 

20 28 

1 

24 36 

3 8 

9 31 

1 

a Number of animals examined microscopically at thesite and the numberof animals with neoplasm 

Number o f animals with any tissue examined microscopically 

Primary neopIasms: all neoplasms except metastatic neoplasms 
 

154 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE(12 

Individual Animal Tumor Pathologyof Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:Vehicle Control 

0566666661111111111111111 

Number of Days on Study 0901233190033333333333333 . 

6232689951911111111111111 

.... . 0000000000000000000000000 

Carcass IDNumber 341035501.550000111112222.2 

309416-46558158901-26801356 

Aliientary System 

Esophagus ......................... Gallbladder M++A+++A+.++++++++++++M+++ 

Intestine large, colon .......................... 

Intestine large, rectum +++A+++A+++++++++++++++++ 

Intestine large, cecum +++A+++A+++++++++++++++++ 

Intestine small, duodenum A++A+++A++,+++++++++++++++ 

Intestine small, jejunum A++A+++.A++++++++++++++-+++ 

Intestine small, ileum A++A+++A++A++++++++++++++ 

Liver ............................. Hemangiosarcoma X X 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma xx 

Hepatocellularcarcinoma,multiple , X 

Hepatocellular adenoma x x X 

Hepatocellular adenoma, multiple x x x x X 

Histiocytic sarcoma X 

Mesentery 

Pancreas ......................... 

Histiocytic sarcoma X 

Salivary glands ......................... Stomach, forestomach +++++++A+++++++++++++++++ 

Squamous cell carcinoma X 

Stomach, glandular ......................... 

Tooth + ++ + ++ + + +++ 

Cardiovkcular System 

Heart ......................... Hemangioma 

Histiocytic sarcoma X 

* Endocrine System 

Adrenal cortex .......................... 

Adrenal medulla . . . . . . . . . . . . . . . . . . . . . . . . . 

Pheochromocytoma benign 

Islets, pancreatic ......................... 

Parathyroid gland + + M,M+ + + M+ M+ + + M+ + + + + + + M+ + + 

Pituitary gland +++M+++++M++++++++M++++++ 

Thyroid ;gland .......................... Follicular cell, carcinoma 

+: Tissue examined microscopically M: Missing tissue X Lesion present 

A Autolysis precludes examination I: Insufficient tissue Blank. Not examined 
155 ...

'Lesions in Male Mice 

Number of Days on Study 

Carcass ID Number 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Pancreas 

Histiocytic sarcoma 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Stomach, glandular 

Tooth 

Cardiovascular System 

Heart 

Hemangioma 

Histiocytic sarcoma 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Parathyroid gland 

Pituitary gland 

Thyroid gland 

Follicular cell, carcinoma 

General Body System 

Tissue NOS 

7111111111111717111711117 

3333333333333333333333333 

1111111111111111111111111 

0000000000000000000000000 

2223333333444444445555556 

1890256789234561890123190 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... 

XXX' 

X 

xx 

xx 

X 

X 

x xx x 

X 

X 

x 

x x 

X 

X 

X 

+ ......................... 

......................... 

......................... X 

......................... + +++ + + ++ ++ 

......................... X 

.......................... 

......................... X 

......................... 

+ + + + + + M+ M+ MMM+ M + + + M+ + + + + + ......................... 

++++++M++++++++++++++++++ 

X 

.. 

Total 

Tissues/ 

Tumors 

50 

46 

48 

48 

48 

47 

47 

45 

50 

2 

1 

5 

3 

14 

10 

1 

1 

49 

1 

50 

49 

2 

48 

21 

50 

1 

1 

49 

48 ' 

1 

49 

31 

45 

49 

1 

1 
156 1,2-Dihydro-2,2,4-triimethylquinoline,NTP TR 456 

TABLE(22 

Individual Animal Tumor Pathology of Male Mice in'the 2-Year Dermal Study , 1 

of 1,2-Dihydro-2,2,4-trimethylquinoline:Vehicle Control (continued) 

Number of Days on Study 

Carcass I D Number 

Genital System 

Epididymis 

Penis 

Preputial gland 

Prostate 

Seminal vesicle 

Testes 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Histiocytic sarcoma 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Histiocytic sarcoma 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

Thymoma NOS 

Integumentary System , 

Mammary gland 

Skin 

Musculoskeletal System 

Bone 

Nervous System 

Brain ~~ ~~ ~~ ~ ~ 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar adenoma, multiple 

Alveolarlbronchiolar carcinoma. 

Alveolarbronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Nose 

Trachea 

Special Senses System 

Harderian gland 

Adenoma . 

~~~ ~~ ~ 

0566666667777777777777777 

0'901233790033333333333333' 

623268995191111111111.1111 

0000000000000000000000000' 

3410355015500001111122222 

309416465581589012,6801356 

......................... 

+ ......................... 

......................... 

......................... 

......................... 

......................... 

X X 

X 

+ .......................... 

M++M+++++++++++++++++++++ 

X . . . . . . . . . . . . . . . . . . . . . . . . . 

X X 

X 

M+ + + + +.MMM+ + + + + M+ + + + + + + + + +, 

MMMMMMMMMMM+ MMMMMMM.MMMMMM 

......................... ,. . , 

........................... 

........................... 

......................... x X X 

X X 

x x X 

x :. 

X 

X. ......................... 

............................ 

+ 

X 

. , 

. 
157 

I

I 

I 

. . 

~~ber of ID& 09 shay 

carcass m Number 

Genital System ' 

Epididymis 

Penis 

Preputial gland 

prostate 

Seminal vesicle 

Testes 

Interstitial cell, adenoma 

HematogoietitSystem 

Bone marrow 

Hemangiosarcoma ' ' 

Histiocytic sarcoma 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric'. 

Histiocytic sarcoma 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

Thymoma NOS 

hteegumentrarySystem 

Mammary gland 

Skin 

MusculoskeletalSystem . I 

Bone 

Nervous System 

Brain 

. > Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar adenoma, multiple 

Alveolarhronchiolar carcinoma 

Alveolarhronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Nose 

Trachea 

Specid S~QS& system . 

Harderian gland 

Adenoma 

777771777717777777~7777777 

3333333333333333333333333 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 l l l l l 

0000000000000000000000000 Total 

2223333333444444445555556 Tissues/ 

789025678923456789012379'0 Tumors 

......................... 49 

1 

++++++++++++++++++M++++++ 48 

......................... 49 

......................... 49 

......................... 49 

X 1 

......................... 49 

2 

1 

+ 2 

+++M+++++++++++++++++++++ 49 

......................... 48 

1 

+++++++++M+++++++++++++++48 

2 

1 

+ M + + M + + M + + MM+ M+ + + + + + + + + + + 39

X 1 

MM++MMMMMMMMMMMMMMMMMMMMM 3 

......................... 50 

......................... 50 

......................... 50 

......................... 50 ' 

X X X xx 8 

X X 4 

X X X 6 

1 

X 2 

1 

......................... 50 

......................... 50 

+ ++ 4 

xx 3 
158 l,2-Dihydro-2,2,4-triethylquinoline,NTP TR 456 

TABLEC2 

Individual Animal Tumor Pathologyof Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:Vehicle Control (continued) 

0566666667117117111111177 

Number of Days on Study 0901233190033333333333333 

6232689951911111111111111 

0000000000000000000000000 

Carcass ID Number 3410355015500001111122222 

3094164655815890126801356 

Urinary System 

Kidney ......................... Histiocyticsarcoma X 

Renal tubule, carcinoma 

Urinary bladder ......................... 

Hemangioma 

Systemic Lesions 

Multipleorgans ......................... Histiocyticsarcoma X 

Lymphoma malignant X 
Number of Days on Study 

CarcassIDNumber 

Urinary System 

Kidney 

Histiocytic sarcoma 

Renal tubule, carcinoma 

Urinary bladder 

Hemangioma 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

1111711717777171117111111 

3333333333333333333333333 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

0000000000000000000000000 Total 

2223333333444444445555556 Tissues/ 

7890256789234561890123190 Tumors 

......................... 50 

1 

X 1 

......................... 49 

X 1 

......................... 50 

1 

X X 3 
160 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC2 

Individual Animal Tumor Pathologyof Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:3.6 mgkg 

0234555666111111177171111 

Number (ofDays on Study 2050468124012333333333333 

2110008660804000000000000 

1000110100010000000000000 

CarcassID Number 1696116068126888888999999 

3918563820506456189023561 

Alimentary System 

Esophagus ......................... Gallbladder ++M++AMA+++++++++++++++++ 

Intestine large, colon ......................... 

Intestine large, rectum .......................... 

Intestine large, cecum ......................... Intestine small, duodenum ++A++AAA+++A+++++++++++++ 

Intestine small,jejunum ++A++AA++++A++++++++++'+++ 

Intestine small, ileum ++A+ + AA+ + + +,A+.++ + + + + + + + + + + 

Liver ......................... Hemangiosarcoma X 

Hemangiosarcoma, multiple X 

Hepatoblastoma 

Hepatocellular carcinoma X X X 

Hepatocellular'adenoma X xx X x x X 

Hepatocellular adenoma, multiple X X X 

Pancreas ......................... 

Salivary glands . . . . . . . . . . . . . . . . . . . . . . . . . 

Stomach, forestomach ......................... Squamous cell carcinoma 

Stomach, glandular ......................... Tooth + + + + ++ + 

Cardiovascular System 

Heart ! ......................... 

Endocrine System 

Adrenal cortex .......................... 

Adrenal medulla . . . . . . . . . . . . . . . . . . . . . . . . . 

Islets, pancreatic ......................... 

Parathyroid gland +M+MM+++++.+++++++++M+++++ 

Pituitary gland +++++M+M++++++MM+++++++++ 

Pars inlermedia, adenoma .. 

Thyroid gland ........................... 

General :Body System 

None 

Genital System 

Epididymis ......................... Preputial gland ......................... Hemangiosarcoma 

Prostate ......................... Seminal vesicle ......................... Testes ......................... Interstitial cell, adenoma X 
I 

Lesions in Male Mice n6n 

Number of Days on Study 

~ Carcass IDNumber 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hemangiosarcoma, multiple 

Hepatoblastoma 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Stomach, glandular 

Tooth 

Cardiovascular System 

Heart 

Endocrine System 

Adrenal cortex 

Adrenal medulla 

Islets,pancreatic 

Parathyroid gland 

Pituitary gland 

Pars intermedia, adenoma 

Thyroid gland 

General Body System 

None 

Genital System 

Epididymis 

Preputial gland 

Hemangiosarcoma 

Prostate 

Seminal vesicle 

Testes 

Interstitial cell, adenoma 

7177711717111171177171711 

3333333333333333333333333 

0000000000000011111111111 

0111111111111100000000000 Total 

9000000111111166117777888 Tissues/ 

901~2357012418941012489123 Tumors 

......................... 

......................... 

++++++++++++++++++++Mi+++ 

......................... 

......................... 

......................... 

......................... 

......................... 

......................... X X 

X 

X X X X 

x x X xx xx X xx 

x x x x X xxxx .......................... 

......................... 

......................... X 

......................... 

++ + + ++ + + + 

......................... 

......................... 

......................... 

......................... 

++++++++++++++++++++M+++i 

++M+++++++M++M+++++++++++ 

X 

......................... ~ ~ ~ ~~~ 

......................... 

......................... X 

......................... 

.......................... 

......................... 

50 

46 

48 . . 

49 

50 

45 

46 

46 

50 

3 

1 

1 

I 

11 

13 

49 

49 

50 

1 

50 

16 

50 

49 

49 

49 

45 

43 

1 

50 

50 

50 ' 

1 

50 

50 

50 

1 
162 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC12 %. , ,I . Individual Animal Tumor Pathology of Male Mice.in the 2-Year Dermal Study . . , .. . , ',, ' of 1,2-Dihydro-2,2,4-trimethylquinoline:3.6 mgkg . . (continued) . , 

Number of Days on Study 

Carcass ID Number 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Hemangiosarcoma 

Thymus 

Integumentary System 

Mammary gland 

Skin 

Musculoskeletal System 

Bone 

Skeletal muscle 

Hemangiosarcoma 

Nervous System 

Brain 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolarhronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

Special Smenses System 

Eye

Harderiangland ' 

Adenoma 

Urinary System 

Kidney 

Rend tubule, adenoma 

Renal tubule, carcinoma 

Urinary bladder 

Systemic Lesions 

Multiple organs 

Lymphoma malignant 

0234555666~111777111117111 

2050468124012333333333333 '. 

2110008660804000000000000 

10001101000100.00000000000 

1696116068726888888999999 

3918563820506456189023561 

......................... 

A 

+ + 

++++++A++++M+++++++++++++ 

........................ 

+ 

++++++M++++++++++++++++++ 

X X 

+ + + M+ + A+ M+ M+ +.+ + + + + +'+ + + M+ + 

MMMMMMMMM"MMMMMMMMM+MMMMM 

......................... 

++++M++++++++++++++++++++ 

+ 

X 

.......................... 

......................... X X 

x x X X X 

X 

........................... 

........................... 

+ 

+ + + 

X X X 

.......................... X 

X 

.......................... 

......................... x x X 
, . k!ShllS ill &"e h'fke 163 

TABLE@2 . I

I . . ~[rmdivi~~nal A*rnan TU~Q~ FJ~UMQ~JJ QIT"e MIC~in he 2-~earDeman study 

of n,2-DihydrQ-2,2,0-e~~eu~ynqanianoni: 3.6 lllT@kg (continued) 

1111117771117711777777177 

Number of Days on Study 33333333333333333333333.-33 

0000000000000011111111111 

0111111111111100000000000 Total 

Carcass IDNumber 9000000111111166111777888~Tissues/. 

9012357012478941012489123 Tumors 

Hematopoietic System 

Bone marrow ......................... ' 49 

Hemangiosarcoma 1. 

Lymph node + 3 

Lymph node, mandibular ......................... 48 . . 

Lymph node, mesenteric .......................... 47 

Lymph node, mediastinal ' 1 

Spleen ......................... 49 . Hemangiosarcoma 2 

Thymus +++++++++++I++++++"+++++ 42 ' 

. , Integumentary System 

Mammary gland +-M'MMMMMMMMMM'MMMMMMMMMMMMM . : 2 

Skin ......................... 50 

Musculoskeletal System ' . 1 ,. . . 

Bone .......................... 49 

Skeletal muscle 1: 

Hemangiosarcoma ''1 

Nervous System 

Brain ......................... 50 

Respiratory System 

Lung ......................... 50 . 

Alveolarhronchiolar adenoma X X X xx 

Alveolarhronchiolar adenoma, multiple X. '1 

Alveolarhronchiolar carcinoma 5 

Alveolar/bronchiolar carcinoma, multiple 1 

Hepatocellular carcinoma, metastatic, liver X 1 

Nose ......................... 50 

Trachea ......................... 50 ., . 

. . Special Senses System 

Eye 1 

Harderian gland + + 5 . 

Adenoma X X 5' 

Urinary System 

Kidney ......................... 50 . . 

Renal tubule, adenoma : .1 

Renal tubule, carcinoma 1 

Urinary bladder ......................... 150 

Systemic Lesions 

Multiple organs ......................... 50 

Lymphoma malignant X X 5 
,164 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC2 ,; . . Individual Animal Tumor Pathologyof Male Mice in the 2-Year DermalStudy .' 

of 1,2-Dihydro-2,2,4-trimethylquinoline: 6 mgkg ,,. ., .. .

3555666661171111117111111 

Number of Days on Study 8579016662222222222222223 

.'5312381199999999999999990 

1111111111111111111111111 

Carcass ID Number 4334523146666661111711182 

.. 2615883393456790125678902 

Alimentary System 

Esophagu!; .......................... Gallbladder M++A+++++++++++++++++++++ 

.Carcinoma,,metastatic, pancreas X 

Intestine large, colon ......................... Intestine large, rectum ........................... Intestine large, cecum .......................... Carcinoma X 

Intestine small, duodenum ......................... 

Intestine small, jejunum ......................... 

Intestine small, ileum ......................... 

Liver - ......................... Hemangiosarcoma X 

Hepatoblastoma X X 

Hepatocellular carcinoma xx X X X 

Hepatocellular adenoma xx X X xx 

Hepatocellular adenoma, multiple X X x X 

Hepatocholangiocarcinoma X 

Mesentery + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Pancreas ......................... Carcinoma- X 

Hemangioma ' 

Salivary glands ......................... Stomach, forestomach ......................... Squamous cell papilloma 

Stomach, glandular .......................... Carcinoidtumorbenign . 

Tooth +++++ +++ ++ + + 

Cardiovascular System 

Heart' ......................... 

Endocrine System 

Adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . 

Capsule, adenoma 

Adrenal medulla ++++M++++++++++++++++++++ 

Pheochromocytoma benign 

Islets, pancreatic ......................... Parathyroid gland +++M+++.M++M+++++++M++++++ 

Pituitary gland ++++++++++++M++++M+++++++ 

Thyroidglan . ......................... Follicular cell, adenoma xx 

General BodySystem 

None 
TABLE@2 

Individual A~nimdTumor P~tthd~g~~ off Mde Mice inn the %Pear Demd Study 

Of n,2-DihgrdrQ-2,2,0I-&rirmneollnyn~~inOni~e: 6 mag (continued) 

Number of Days on Study 

carcass I D Number 

Alimentary System 

Esophagus 

Gallbladder 

Carcinoma, metastatic, pancreas 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Carcinoma 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatoblastoma 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Hepatocholangiocarcinoma 

Mesentery 

Hepatocholangiocarcinoma, metastatic, liver 

Pancreas 

Carcinoma 

Hemangioma 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

Carcinoid tumor benign 

Tooth 

cardiovascular System 

Heart 

Endocrine Syst@em 

Adrenal cortex 

Capsule, adenoma 

Adrenal medulla 

Pheochromocytoma benign 

Islets, pancreatic 

Parathyroid gland 

Pituitary gland 

Thyroid gland 

Follicular cell, adenoma 

General Body System 

None 

1111111111111111111111111 

3333333333333333333333.333, 

0000000000000000000000000 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

2222233333444444555555666 Tissues/ 

3451914589134618024561012 Tumors 

......................... 50 

......................... .47 

1 

......................... 50 

......................... 50 

......................... 50 

'1 

......................... 49 

.......................... 49 

.......................... 41 

........................... 50 

X 2 

2 

5 

X X X X X X' 12 

x x X xx XXX X 13 '

1 

2 

1 

......................... 50 

:1 

X 1 

......................... 50 

......................... .50 . 

X 1 

......................... 50 

X 1 

+ +++++ ++ ++++++ 26 

......................... 50 

.......................... 49 

X X x , '.3 

......................... 49 

X '. 1 

......................... 50 

++++M+M+++++++++++++M+++M 42 

+ + + + + + + + + + + + + + MMMMM+ MMM+ + 40 

......................... 50 

*2 
166 lJ-Dihydro-2J,4-trimethylquinoline,NTP TR 456 

TABLEC2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:6 mg/kg (continued) ' . 

Number of Days on Study 

Carcass IDNumber 

Genital System 

Epididymis 

Carcinoma, metastatic, pancreas 

Preputial gland 

Prostate 

Seminal vesicle 

Carcinoma, metastatic, pancreas 

Testes 

Carcinoma, metastatic, pancreas 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Carcinoma, metastatic, pancreas 

Spleen 

Thymus 

Mediastinum, hemangioma 

Integumentary System 

Mammary gland 

Skin 

Musculoskeletal System 

Bone 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar carcinoma 

Alveolarhronchiolar carcinoma, multiple 

Carcinoma, metastatic, pancreas 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

Special Senses System 

Harderian gland 

Adenoma 

Carcinoma , 

3555666667777111717711117 

8579016662222222222222223 

531238119999999999999.9990 

1111111111111111111111111 

4334523146666661111171782~ 

2675883393456190125678902 

......................... X ......................... 

......................... 

......................... X 

......................... X 

......................... + 

++++++++++++++++++M++++++' 

......................... X 

++++++++M++++++++++++++++ 

++++++++M++M+++++++++++++ 

MMMMMMMMMMMMMMMMMMMMMMMMM 

......................... 

.......................... 

........................... + 

+ 

......................... X x xx x x xx 

X x x X 

X 

X X ......................... 

......................... 

+ + 

X X 
Number of Days on Study 

Carcass IUID Number 

Genital System 

Epididymis 

Carcinoma, metastatic, pancreas 

Preputial gland 

Prostate 

Seminal vesicle 

Carcinoma, metastatic, pancreas 

Testes 

Carcinoma, metastatic, pancreas' 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Carcinoma, metastatic, pancreas 

Spleen 

Thymus 

Mediastinum, hemangioma 

Integumentary System 

Mammary gland 

Skin 

Musculoskeletal System 

Bone 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

Respiratory System 

Lung 

Alveolarhronchioiar adenoma 

Alveolarhmnchiolar carcinoma 

Alveolarhmnchiolar carcinoma, multiple 

Carcinoma, metastatic, pancreas 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

Special Senses System 

Harderian gland 

Adenoma 

Carcinoma 

1777111171111111111111111 

3333333333333333333333333 

0000000000000000000000000 

Total 

2222233333444444555555666 Tissues/ 

3451914589134618024561012 Tumors 

1111111,111111111111111111 

......................... 50 

1 

......................... 50 

.......................... 50 

......................... 50 

1 

........................... 50 

1 

X 1 

......................... 50 

1 

......................... 49 

......................... 50 

1 

......................... 49 

........................ 46 

X 1 

MMMMMM+MMMMMMMMMMMMMMMMMM 1 

......................... 50 

......................... 50 

......................... 50 

1 

1 

......................... 50 

X xx 11 

xx X 1 

X 1 

1 

2 

......................... 50 

.......................... 50 

'+ + + 5 

X 3 

X 1 
\ 

168..’ 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC:2 

Individual AnimalTumor Pathologyof Male Mice in the 2-Year DermalStudy 

of 1,2-Dihydro-2,2,4-trimethylquinoline:6 mgkg (continued) 

3555666667177177771777711 

Number o f Days on Study 85790166622222222222222.23 

5312381199999999999999990 

1111111111111111111111111 

Carcass IDNumber 4334523146666661771177782 . .. . 2615883393456790125678902 

Urinary System 

Kidney . ........................... Renal tubule, adenoma 

Renal tubule,carcinoma 

Urinary bladder ......................... 

Systemic Lesions 

Multipleorgans . ......................... Lymphoma malignant X X 
......................... os 
1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC2 , . , . , . , IndividualAnimalTumorPathology of MaleMiceinthe 2-Year DermalStudy .. . 

. 

... , . of 1,2-Dihydro-2,2,4-trimethylquinoli1~e:10 mgkg 

, , . 

! 3 4455556666677777777777777 

Number of Days on Study 6913882678922222222222',222 

4056.123066128999999999999 

I. 2122121222222111111111111 

Carcass 1:D.Number 3801819311421888888999999 

, * ',I. 145964448501'1125789023567 

Alimentary System 

Esophagus ......................... Gallbladder .. +++AAMMAA+++A++++++++++++

Intestine large, colon ......................... 

Carcinoma, metastatic, 

uncertain primary site X 

Intestine large, rectum ......................... 

Intestine large, cecum +++AA+A+++++A++++++++++++ 

Intestine small, duodenum +++AA+A+++++A+++++++.+++++ 

Intestine small, jejunum 9 +++AA+AA++++A++++++++++++

Intestine small, ileum +++AA+AAA+++A++++++++++++ 

Liver ' ......................... Carcinoma, metastatic, 7 7 uncertain primary site A 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma '. X X x x 

Hepatoc:ellular carcinoma, multiple X xx x 

Hepatocellular adenoma xx X x xx X 

Hepatocellular adenoma, multiple x x 'X x 

Squamouscell carcinoma, metastatic, 

stomach, forestomach X 

Mesentery + + + 

Carcinoma, metastatic, 

uncertain primary site X 

Squamouscell carcinoma, metastatic, 

stomach, forestomach X 

Pancreas ......................... 

Carcinoma, metastatic, . 

uncertain primary site X 

Salivary glands ......................... Stomach; forestomach . +++A++++M++++++++++++++++ 

Squamouscell carcinoma X 

Stomach, glandular ......................... 

Carcinoma, metastatic, 

uncertain primary site X 

Tooth i + + + ++ -+ 

Cardiovascular System 

Heart - .......................... Hepatocellular carcinoma, metastatic, liver X 

Endocrine System 

Adrenal'coltex .. ......................... Carcinoma, metastatic, 

uncertain primary site X 

Capsule, adenoma 

Adrenal'medulla .. ......................... Islets, pancreatic ......................... 

Parathyroidgland - I +++MM+++++++M+++M++++M++M 

Pituitafy gland +,+++M+++M++++++++++++++++ 

Thyroid gland ......................... Follicular cell, adenoma 
Lesionsin Male Mice n71 

CarcassID Number 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Carcinoma, metastatic, 

uncertain primary site 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Carcinoma, metastatic, 

uncertain primary site 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Mesentery 

Carcinoma, metastatic, 

uncertain primary site 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Pancreas 

Carcinoma, metastatic, 

uncertain primary site 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Stomach, glandular 

Carcinoma, metastatic, 

uncertain primary site 

Tooth 

Cardiovascular System 

Heart 

Hepatocellular carcinoma, metastatic, liver 

Endocrine System 

Adrenal cortex 

Carcinoma, metastatic, 

uncertain primary site 

Capsule, adenoma 

Adrenal medulla 

Islets, pancreatic 

Parathyroid gland 

Pituitary gland 

Thyroid gland 

Follicular cell, adenoma 

1122222222222222222222222 Total 

9900000011122222222233333 Tissues/ 

890121~8903602345618902358 Tumors 

......................... 50 

+++++++++++M+M+++++++++++ 41 

......................... 49 

1 

......................... 49 

......................... 46 

......................... 46 

......................... 45 

......................... 44 

......................... 50 

1 

X 1 

X X X xx 9 

4 

xxxx X X x xx 16 

X X xx X X 10 

1 

3 

1 

1 

......................... 49 

1 

......................... 50 

......................... 48 

1 

......................... 48 

1 

++ + + + + + 13 

......................... 50 

1 

......................... 50 

1 

X 1 

......................... 50 

......................... 49 

......................... 43 

........................ 46 

......................... 50 

X 1 
1.72 1,2-Dihydro-2,2,4-triimethylquinoline, NTP TR 456

TABLEC:t 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study .. .' 

of 1,2-Dihydro-2,2,4-trimethylquinoline: 10 mgkg (continued) . . . . 

< , 

Number of Days on Study 

Carcass II)Number. .. 

General Body System 

None 

Genital System 

Epididymis 

Carcinoma, metastatic, 

uncertain primary site 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Preputial gland 

Prostate 

Carcinoma, metastatic, 

uncertain primary site 

Seminal vesicle 

Carcinoma, metastatic, 

uncertain primary site 

Testes ,' 

Carcinoma, metastatic, 

uncertain primary site 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Lymph node 

Pancreatic, histiocytic sarcoma 

Lymph node, mandibular 

Lymph node, mesenteric 

Carcinoma, metastatic, 

uncertain primary site 

Hemangiosarcoma 

Histiocytic sarcoma 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Spleen 

Carcinoma, metastatic, 

uncertain primary site 

Hemangiosarcoma 

Histiocytic sarcoma 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Thymus 

Integumentary System 

Mammary gland 

Skin 

Sarcoma 

Subcutancous tissue, sarcoma 

4455556666671117111111177 

6913882678922222222222222 

4056123066128999999999999 

2122121222222111111111111 

3801819311421888888999999 

1459644485011125189023561 

......................... 

X 

X 

.......................... 

X 

X 

X 

+++M++++++++++++++++.+++++ 

X 

+ + 

X 

++++++.+++++M+++++++++++M+ 

+++M++++++++++++M++++++++ 

X 

X 

X 

......................... 

X 

X 

X 

X 

M+M++M+++M++.+++++++M+++++ 

MMMMMMMMMMMMMMMMMMMMMMMMM 

......................... X 
General Body System 

None 

Genital System 

Epididymis 

Carcinoma, metastatic, 

uncertain primary site 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Preputial gland 

Prostate 

Carcinoma, metastatic, 

uncertain primary site 

Seminal vesicle 

Carcinoma, metastatic, 

uncertain primary site 

Testes 

Carcinoma, metastatic, 

uncertain primary site 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Lymph node 

Pancreatic, histiocytic sarcoma 

Lymph node, mandibular 

Lymph node, mesenteric 

Carcinoma, metastatic, 

uncertain primary site 

Hemangiosarcoma 

Histiocytic sarcoma 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Spleen 

Carcinoma, metastatic, 

uncertain primary site 

Hemangiosarcoma 

Histiocytic sarcoma 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Thymus 

!Integumentary System 

Mammary gland 

Skin 

Sarcoma 

Subcutaneous tissue, sarcoma 

1122222222222222222222222 Total 

9900000011122222222233333 Tissues/ 

8901278903602345618902358 Tumors 

, , 8 . ,. 

......................... 50 

. 1 

. 1 

......................... ' 50 

......................... 50 , I 

1 

........................... . 50 

1 

......................... 50 

.1 

, . 1 

X X 3 

......................... 49 ' 

dl. 

2 

1' ' 

.......................... 48. 

++++.+++M+++++++++++++++++ 47 I 

1 

X l ! 

.1 . 

. .1 

......................... 50 : 

, . 

... 1 

1 

- 1 

* : 

' 1 

++M+M+++++++M++++++++++MM 40 

MMMMMMMMMMMMMMMMMMMMMMMMM' 

.. 

'. > 

. 

......................... 50 

,1 ' 

X 1 
174 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC2 

Individwal Animal Tumor Pathology off Male Micein the 2-YearDermal Study 

of 1,2-Dilhydro-2,2,4-trimethylquinoline: 10 mgkg (continued) 

Number of Days on Study 

.. 

Carcass I D Number .. 

Musculoskeletal System 

Bone 

Osteosarcoma . 

Skeletal muscle 

Carcinoma, metastatic, 

uncertain primary site 

Hemangioma 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

.. 

Nervous System 

Brain 

Respiratory System 

Lung , 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Squamouscell carcinoma, metastatic, 

stomach, forestomach 

Nose 

Hemangiosarcoma 

Trachea . 

Special Serlses System 

Ear 

Eye

Harderian gland 

Adenoma 

Carcinoma 

Bilateral, catcindia 

Urinary System. 

Kidney 

Carcinoma, metastatic, 

uncertain primary site 

Hepatoce~lular carcinoma, metastatic, liver 

Urinq bladder 

SyGte&c Leiions 

Multip!e organs 

Histiocytic sarcoma 

Lymphoma,@ignant . . 

4455556666677777777777777 

6913882678922'222222222222 

4056123066128999999999999 

2 ~ 1 2 2 1 2 1 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 

3801819311421-888888999999 

14596444-85011125789023567 

+++M+++++++++++++++++++++ 

X 

+ + 

X 

X 

......................... 

......................... X X X X 

x x 

X X 

X 

x x X 

X 

......................... 

.......................... 

. + 

+ 

+ 

X 

......................... 

x 

X 

+++AA+A+++++A++++++++++++ 

........................... X 

X X 

.. . 
I 

Carcass ID Number 

Musculoskeletal System 

Bone 

Osteosarcoma 

Skeletal muscle 

Carcinoma, metastatic, 

uncertain primary site 

Hemangioma 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

I

I Nervous System 

Brain 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma 

Alveolarhronchiolar adenom& multiple 

Alveolarhronchiolar carcinoma 

Alveolarhronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Squamous cell carcinoma, metastatic, 

stomach, forestomach 

Nose 

Hemangiosarcoma 

Trachea 

Special Senses System 

Ear 

Eye

Harderian gland 

Adenoma 

Carcinoma 

Bilateral, carcinoma 

Urinary System 

Kidney 

Carcinoma, metastatic, 

uncertain primary site 

Hepatocellular carcinoma, metastatic, liver 

Urinary bladder 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

1122.222222222222222222222 

9900000011122222222233333 

8901218903602345618902358 

......................... 

+ 

X 

........................... 

........................... X x xx 

X x x X 

X 

X X X 

......................... X 

......................... 

+ + 

X 

X 

......................... 

X ......................... 

......................... 

X 

Total 

Tissues/ 

Tumors 

49 

1 

3 

1 

1 

1 

50 

50 

8 

2 

6 

2 

6 

1 

50 

1 

50 . 

50 

1 

2 

46 

50 

1 

3 
176.: 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC3 

Statistical Analysis of Primary Neoplasms in Male Micein the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline 

Vehicle 3.6 Control mgkg 

AdrenalCortex:Adenoma 

Overall rate" 0/49 (0%) 0/49 (0%) 

Adjusted rateb 0.0% 0.0% 

Terminal rate' 0/39 (0%) 0/37 (0%) 

First incidence (days) -

e -

Life table testd Pd. 180 -

Logistic regression testd Pd.180 -

Cochran-Armita e testd Pd.191

Fisher exact test % -

HarderianGland:Adenoma 

Overall rate 3/50 (6%) 5/50 (10%) 

Adjusted rate 7.1% 12.4% 

Terminal rate 2/39 (5%) 3/37 (8%) 

First incidence (days) 592 540 

Life table test Pd.215N Pd.329 

Logisticregressiontest , I P=0.203N P=O.356

Cochran-Amitage test P=0.199N 

Fisher exact test Pd.357 

Harderian Gland: Adenomaor Carcinoma 

Overall rate 3/50 (6%) 5/50 (10%) 

Adjusted rate 7.1% 12.4% 

Terminal rate 2/39 (5%) 3/37 (8%) 

First incidence (days) 592 540 

Life table test .. Pd.540N Pd.329 

Logistic regression test Pd.529N P4.356 

Cochran-Armitage test Pd.525N 

Fisher exact test P=O.357 

Liver:Hemangiosarcoma 

Overall rate 3/50 (6%) 4/50 (8%) 

Adjusted rate 6.8% 10.5% 

Terminal rate 1/39 (3%) 3/37 (8%) 

First (days) incidence I 592 710

Life table test P=0.191N Pd.470 

Logistic regression test . I P=O. 1 80N P4.485

Cochran-Armitage test E0.179N 

Fisher exact test P=O.500 

Liver: Hepatocellular Adenoma 

Overall rate 24/50 (48%) 30/50 (60%) 

Adjusted rate 56.9% 73.0% 

Terminal rate 21/39 (54%) 26/37 (70%) 

First (days) incidence . . 612 357

Life table test P=O.409 P=O.loo 

Logistic regression test P=O.464 P=O.O87 

Cochran-Armitagetest P=O.461 

Fisher exact test P=O.158 

6 mgkg 

3/49 (6%) 

7.3% 

3/41 (7%) 

729 (T) 

P=O.130 

EO.130 

Pd.121 

3/50 (6%). 

6.6% 

1/41 (2%) 

553 

Pd.649N 

P4.643 

Pd.661N 

4/50 (8%) 

8.9% 

2/41 (5%) 

553 

Pd.514 

Pd.482 

P=O.500 

2/50 (4%) 

4.9% 

Y41(5%) 

729 (T) 

Pd.492N 

Pd.503N 

P=0.500N 

25/50 (50%) 

54.0% 

20/41 (49%) 

385 

P=O.574 

P=O.507 

Pd.500 

10 mgkg 

1/50 (2%) 

2.7% 

1/37 (3%) 

729 (T) 

EO.489 

EO.489 

M.505 

1/50 (2%) 

2.7% 

1/37 (3%) 

729 (T) ' 

Pd.331N 

Pd.305N 

P=0.309N 

3/50 (6%) 

7.6% 

2/37 (5%) 

660. 

Pd.636 

Pd.663 

Pd.661N 

,. . 

1/50 (2%) 

2.7% 

1/37 (3%) 

729 (T) 

Pd.334N 

Pd.307N 

P=0.309N 

26/50(52%) ; 

63.1%' 

22/37 (59%) 

515 

E0.329 

EO.375 

Pd.421 
Lesions in Male Mice 177. 

Liver: HepatocellularCarcinoma 

Overall rate 8/50 (16%) 7/50 (14%) 5/50 (10%) 13/50(26%) 

Adjusted rate 18.1% 19.0% 11.4% 29.4% .'. 

Terminal rate 6/39 (15%) (16%) 6/37 3/41 (7%) 7/37 (1 9%)

First incidence (days) 588 612 618 490 

Fisher exact test 

Cochran-Armitage test 

Logistic regression test 

Life table test 

P=0.529N136 

P=0.550N 

P=O. 137 

P=O. 

P=O.132 

P=0.500N 

P=0.277N 

P=0.265N 

P=0.277N 

P=O. 160 

P=O.149 

P=O.163 

1 

.~ 

. 

Liver: HepatocellularAdenoma or Wepatocellular Carcinoma 

Overall 

Adjusted 

27/50 (54%) 33/50 (66%) 

78.4% 62.6% 

28/50 (56%) 37/50 (74%) 

60.6% 80.2% 

Terminal 23/39 (59%) 28/37 

357 612 

(76%) 23/41 (56%) 28/37 (76%) 

First 

n 

385 ,490 

Life P=O.O96 P=O.O44 P=0.567N P=O.O26 

Logistic P=O.O83 P=O.O45 P=O.508 P=O.O29 

Cochran-Armitage P=O.O43 

Fisher exact test P=O.154 P=O.500 P=O.O30 

Liver: HepatocellularCarcinoma or Wepatoblastoma 

Overall rate (16%)(1 8/508/50 6%) 7/50 (14%) 13/50 (26%)

Adjusted rate 19.0% 20.8% 15.8% 29.4% 

Terminal rate 6/39 (15%) (19%) 7/37 4/41 (10%) 7/37 (1 9%)

First incidence (days) 588 612 618 490 

Life table test P=O.555 128 P=O. P=0.479N P=O. 149 

Logistic regression test P=O.576 P=O.132 P=0.502N P=O.160 

Cochran-Armitage test P=O.132 

Fisher exact test P=0.607N P=O.5OON P=O.163 

Liver: HepatocellularAdenoma, Wepatocellular Carcinoma,or Wepatoblastoma 

Overall rate (54%) 33/5027/50 (66%) 30/50 (60%) 37/50 (74%) 

Adjusted rate 78.4% 62.6% 63.7% 80.2% 

Terminal rate 23/39 (59%) 28/37 (76%) 24/41 (59%) 28/37 (76%) 

First incidence (days) 357 612 385 490 

Fisher exact test 

Cocbran-Armitage test 

Logistic regression test 

Life table test 

P=O.O83 

P=O.O96 

P=O.O35 

P=O.O36 

P=O.O37 

P=O.154 

P=O.351 

P=O.435 

P=O.343 

P=O.O29 

P=O.O26 

P=O.O30 

I . 

Overall rate 

Lung: Alveolarhonchiolar Adenoma 

12/50(24%) 8/50 (16%) 11/50(22%) 10/50(20%) 

Adjusted rate 20.8% 28.8% 26.0% 24.5% 

Terminal rate 10/39(26%) 7/37 (19%) 10/41 (24%) 7/37 (19%) 

First incidence (days) 626 592 571 536 

Life table test P=0.276N P=0.439N P=O.456N P=0.458N 

Logistic regression test P=0.265N P=0.411N P=0.498N P=0.409N 

Cochran-Armitage test P=0.410N 

Fisher exact test P=0.227N P=0.500N P=0.405N 
178 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC!3 

Statistical Analysisof Primary Neoplasms in Male Mice in the 2-Year Dermal Study ,

of 1,2-Dihydro-2,2,4-trimethylqoinoline(continued) 

Lung: Alveolarhronchiolar Carcinoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exacl test 

Lung: Alveolarhonchiolar Adenoma or Carcinoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incideuce (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

Testes:Adenoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs:Hemangiosarcoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

., .. 

VehicleControl3.6 mgkg 6 mgkg 10 mgkg 

7/50 (14%) , 6/50(12%) 8/50 (16%) 8/50 (16%) 

17.5% 14.6% 18.8% 21.6% 

6/39 (15%) 3/37 (8%) 7/41 (17%) 8/37 (22%) 

709 588 571 729 (T) 

P=O.362 P=0.542N P=O.536 P=O.457 

.P=O.380 P=0.532N P=O.499 P=O.479 

P=O.385 

P=0.500N P4.500 P=O.500 

, .. 

18/50 (36%) 13/50 (26%) 16/50 (32%) 17/50 (34%) 

42.6% 32.2% 37.9% 42.1% 

15/39 (38%) 10/37 (27%) 15/41 (37%) 14/37 (38%) 

592 588 571 536 

P4.520 P=0.258N P=0.359N P4.571N 

P4.515N P=0.242N P=0.419N P4.529N 

P4.505N 

P=0.194N P=0.417N P=0.500N 

1/49 (2%) 1\50 (2%) 1/50 (2%) 3/50 (6%) 

2.6% 2.4% 2.4% 7.8% 

1/39 (3%) 0137 (0%) 1/41 (2%) 2/31(5%) 

I29 (T) 640 729 (T) 722 

P=O. 176 P=O.749 P=0.751N P=O.293 

P=O.181 P=0.759N P=0.751N P=O.297 

P=O. 182 

P=0.747N P=0.747N P=O.316 

. I . .. 

4/50 (8%) 7/50 (14%) 2/50 (4%) 3/50 (6%) 

8.8% 17.6% 4.9% 7.8% 

1/39 (3%) 5/37 (14%) 2/41 (5%) 2/37 (5%) 

592 560 729 (T) 69 1 

P=0.289N P=O.237 P=0.337N P=0.534N 

P=0.267N P=O.261 P=0.347N P=0.505N 

P4.268N 

P=O.262 P=0.339N P=O.5OON 

., 

6/50 (12%) 7/50 (14%) 4/50 (8%) 4/50 (8%) 

13.6% 17.6% 9.8% 10.4% 

3/39 (8%) ,5/37 (14%) 4/41 (10%) 3/31 (8%) 

592 560 . 729 (T) 691 

P=0.256N P=O.456 P=0.358N P=O.411N 

P=0.233N P=O.492 P=O.37ON P=0.370N 

P=O.234N . . 

P=O.500 P=0.370N P=O.37ON 
Lesions in Male Mice 

All Organs: Malignant Lymphoma (Not Specified) 

Overall rate 3/50 (6%) 5/50 (10%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 7.3% 12.4% 4.7% 1.1% 

Terminal rate 2/39 (5%) 3/37 (8%) 1/41 (2%) 2/37 (5%) 

First incidence (days) 679 616 66 1 686 

Life table test P=0.469N Pd.330 Pd.489N P=O.639 

Logistic regression test Pd.496N M.345 M.499N P=O.656 

Cochran-Armitage test P=0.456N 

Fisher exact test M.357 Pd.500N P=0.661N 

All Organs: Benign Neoplasms 

Overall rate 37/50 (74%) 33/50 (66%) 35/50 (70%) 36/50 (72%) 

Adjusted rate 82.1% 76.6% 74.3% 81.7% 

Terminal rate. 31/39 (79%) 27/37 (73%) 29/4 1 (7%)1 29/37 (78%)

First incidence (days) 592 357 385 515 

Life table test E0.496 P=0.413N Pd.321N P=O.5 12 

Logistic regression test E0.474N P=O.384N Pd.395N P=0.584N 

Cochran-Armitage test M.486N 

Fisher exact test Pd.257N M.412N P=0.500N 

All Organs: Malignant Neoplasms 

Overall rate 22/50 (44%) 25/50 (50%) 20/50 (40%) 28/50 (56%) 

Adjusted rate 46.7% 56.7% 42.5% 59.3% 

Terminal rate 14/39 (36%) 18/37 (49%) 14/41 (34%) 18/37 (49%) 

First incidence (days) 592 560 57 1 464 

Life table test EO.193 M.283 M.391N P=O.152 

Logistic regression test M.187 M.139 M.576N P=O. 159 

Cochran-Armitage test M.190 

Fisher exact test M.344 Pd.42ON P=O. 159 

All Organs: Benign or Malignant Neoplasms 

Overall rate 43/50 (86%) 41/50 (82%) 43/50 (86%) 46/50 (92%) 

Adjusted rate 89.6% 87.2% 86.0% 92.0% 

Terminal rate 34/39 (87%) 31/37 (84%) 34/41 (83%) 33/37 (89%) 

First incidence (days) 592 357 385 464 

Life table test Pd.222 M.553 M.458N Pd.222 

Logistic regression test Pd.219 P=0.562N M.587N Pd.271 

Cochran-Armitage test Pd.191 

Fisher exact test P=0.393N Pd.613N P=O.262 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animaldnumber of animals examined. Denominator is number of animals examined microscopically for adrenal gland, liver, 

lung, and testis; for othertissues, denominator is number of animals necropsied. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

Beneath the vehicle control incidenceare the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to 

pairwise comparisons between the vehicle controls and that dosed group. The life table test regards neoplasms in animals dying prior to terminal kill as being 

(directly or indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare 

directly the overall incidence rates. For all tests, a negative trend or a lower incidence in adose group is indicated by PI.

e Not applicable; no neoplasms in animal group 
180 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 45.6 

TABLEC4a 

Historical Incidenceof Liver Neoplasms in Control Male B6C3Fl Micea 

Incidence in Controls 

HepatocellularHepatoblastomaAdenoma, Hepatocellular Hepatocellular 

Adenoma Carcinoma Hepatocellular Carcinoma, 

or Hepatoblastoma 

Overall Historical Incidence: Dermal (Acetone) Studies 

Total 51/150 (34.0%) 25/150 (16.7%) 0/150 63/150 (42.0%) 

Standard deviation 21.1% 11.7% 22.3% 

Range 12%-54% 8%-30% 18%-62% 

Overall Historical Incidence: .Feed Studies 

Total 0/1,316220/,316344/1,316 (16.7%) (26.1%) 509/1,316 (38.7%)

Standard deviation 7.2% 13.2% 13.9% . . 

Range 4%-60% 3%-29% 10%-68% 

a Data as of 17June 1994 

Historicall Incidence of Renal Tubule Neoplasmsin Control Male B6C3Fl Micea 

TABLEC4b 

Adenoma 

Incidence in Controls 

Carcinoma Adenoma or Carcinoma 

Overall Historical Incidence: Dermal (Acetone) Studies 

Range 

Standard deviation 

Total 

0%-2% 

1.2% 

1/150 (0.7%) 0/150 

0%-2% 

1.2% 

11150 (0.7%) 

Overall Historical Incidence: Feed Studies 

Range 

Standard deviation 

Total 

0%-2% 

0.5% 

U1,317 (0.2%) 

0%-2% 

0.4% 

,111,317 (0.1%) 

0%-2% 

3/1,317 (0.2%) 

0.6% ' . 

a Data as of 17June 1994 
Animals initially in study 

DispositionSummary 

60 60 

IS-Month interim evaluation 10 10 

Early deaths 

Accidental death 1 

Moribund 5 4 

Natural deaths 

Survivors 

6 8 

Terminal sacrifice 39 31 

Animals examined microscopically 60 60 

BS-MOdl IlltWh &VdtdQdOi% 

Alimentary System 

Liver 

Basophilic focus 

Clear cell focus 

Congestion 

Eosinophilic focus 

Fatty change 5 (50%) 

Hematopoietic cell proliferation 

Hyperplasia 

Infarct 

Mixed cell focus 1(10%) 

Mesentery 

Fat, necrosis 

Pancreas 

Inflammation, chronic 

Inflammation, chronic active 

Acinus, atrophy 

Acinus, necrosis 

Salivary glands 

Infiltration cellular, lymphocyte 

Mineralization 

Stomach, forestomach 

cyst 

Stomach, glandular 

cyst 

Infiltration cellular, polymorphonuclear 

Mineralization 

Cardiovascular System 

Heart 

Cardiomyopathy 

a Number of animals examined microscopically at the site and the number of animals with lesion 

10 

60 

10 

60 

41 

2 

7 

60 

37 

10 

3 

60 

(10) 

1(10%) 

5 (50%) 

1 (10%) 

(10) 

2 (20%) 

(10) 

(10) 

(10) 

1(10%) 

1(10%) 

1(10%) 
182 1,2-Dihydro-2,2,4-trimethylquinoline,NTP,TR 456 

: I . 

TABLEC!; 

Summary of the Incidenceof Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study 

of l,2-Dihydro-2,2,4-trimethylquinoline(continued) , 

, 

. 

. 

Vehicle3.6 Control mgkg 6mgkg 10mgntg

15-Month Interim Evaluation (continued) 

Endocrine System 

Adrenal cortex (10) (9)

Cytoplasmic alteration 1 (10%) 3 (33%) 

Hy@rplasia 1 (10%) 

Capsule, hyperplasia 8(80%) 8(89%) 

Islets, pancreatic j (10) (10)

Hyperplasia 5 (50%) 2 (20%) 

pituitary gland (10) (10) 

Pars distalis, cyst 2 (20%) 

Thyroid gland (10) (10)

Ultimobranchial cyst 1 (10%) 

Follicle, hypertrophy 2 (20%) 1 (10%) 1 (10%) 

Genital System 

Preputial gland 

Dilatation 

Inflammation, chronic 

Prostate 

Concretion 

Testes 

Mineralization 

Seminiferous tubule, atrophy 

Hematopoietic System 

Thymus (9) (10) (9) 

cyst 3' (33%) 1 (10%) 

Ectopic parathyroid gland 1 (11%) 

Integumentary System 

Skin (10) 

Hyperplasia, mast cell 1 (10%) 

Skin, site of application, acanthosis 

Nervous System 

Brain 

Mineralization 

Respiratory System 

Lung 

Hemorrhage 

Metaplasia,.osseous 

Nose 

Glands, inflammation, acute 

'.184 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEC:5 

Summary of the Incidenceof Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

2-Year study (continued) 

Alimentary System(continued) 

Stomach, forestomach 

Hyperplasia, squamous 

Ulcer 

Stomach, glandular 

Erosion 

Hemorrhage 

Infiltration cellular, eosinophil 

Inflammation, chronic 

Mineralization 

Tooth 

Dysplasia 

Inflammation, chronic active 

Cardiovascular System 

Heart 

Cardiomyopathy 

Hemorrhage 

Inflammation, chronic 

Mineralization 

Valve, inflammation, acute 

Endocrine System 

Adrenalcortex , 

Angiectasis 

Cytoplasmic alteration 

Hyperplasia 

HYPeeoPhY 

Vacuolization cytoplasmic 

Capsule, hyperplasia 

Adrenal medulla 

Hyperplasia 

Islets, pancreatic 

Hyperplasia 

Pituitary gland 

Pars distalis, cyst 

Pars distalis, hyperplasia 

Thyroid gland 

Inflammation, chronic 

. ' Follicle, dilatation 

Follicular cell, hyperplasia 

~ 

General Body System 

None 

Vehicle Control 

(49) 

4 (8%) 

2(4%) 

(48) 

1 (2%) 

(21) 

21(100%) 

(50) 

2 (4%) 

1 (2%) 

1 (2%) 

1 (2%) , 

' " 1 (2%) 

(49) 

1 (2%) 

1 (2%) 

6(12%) 

23(47%) 

43 (88%) 

(48) 

2 (4%) 

(49) 

47(96%) 

(45) 

2 (4%) 

(49) 

1 (2%) 

8(16%) 

3.6 mgkg 

(50) 

1(2%) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

(16) 

15(94%) 

1 (6%) 

'. (50) 

7(14%) 

1 (2%) 

(49) 

8 (16%) 

19 (39%) 

43 (88%) 

(49) 

(49) 

45(92%) 

(43) 

2 (5%) 

1 (2%) 

(50) 

i 2 (4%) 

3 (6%) 

. . 

6 mgkg 

1 (2%) 

1 (2%) 

(26) 

26(100%) 

(50) 

. 7 (14%) 

(49) 

6(12%) 

16(33%) 

1(2%) 

42(86%) 

(49) 

1 (2%) 

(50) 

48(96%) 

(40) 

2 (5%) 

1 (3%) 

(50) 

9(18%) 

10 mgkg 

(13) 

13 (100%) 

(50) 

4(8%) 

2, (4%) 

4 (8%) 

17 (34%) . 

38 (76%) 

(50) 

1 (2%) 

(49) 

47 (96%) 

(46) 

3 (7%) 

(50) 

1 (2%) 

1 (2%) 

6(12%) 
2-Year S&dy (continued) 

Genital System 

Epididymis 

Granuloma sperm 

Hemorrhage 

Inflammation, chronic 

Inflammation, granulomatous 

Spermatocele 

Penis 

Concretion 

Inflammation, chronic active 

Preputial gland 

Dilatation 

Inflammation, acute 

Inflammation, chronic 

Inflammation, ch;o&c active 

Metaplasia, squamous 

Prostate 

Concretion 

cyst 

Inflammation, acute 

Inflammation, chronic 

Inflammation, chronic active 

Seminal vesicle 

Fibrosis 

Hyperplasia 

HYPe~oPhY 

Inflammation, chronic 

Testes 

Giant cell 

Granuloma sperm 

Seminiferous tubule, degeneration 

Hematopoietic System 

Bone marrow 

Granuloma 

Hyperplasia, mast cell 

Myelofibrosis 

Lymph node, mandibular 

Angiectasis 

Hemorrhage 

Hyperplasia, lymphoid 

Lymph node, mesenteric 

Angiectasis 

Hemorrhage 

Hyperplasia, lymphoid 

Spleen 

Angiectasis 

Hematopoietic cell proliferation 

Hyperplasia, lymphoid 

Lymphoid follicle, atrophy 

Red pulp, atrophy 

3.6Control Vehicle

(49) 

1(2%) 

1 (2%) 

2(4%) 

(1)

1 (100%) 

1 (100%) 

(48) 

14 (29%) 

1(2%) 

14 (29%) 

5 (10%) 

1(2%) 

(49) 

1 (2%) 

1 (2%) 

(49) 

2(4%) 

8 (16%) 

(49) 

2(4%) 

(49) 

1 (2%) 

(49) 

1 (2%) 

1 (2%) 

(48) 

8(17%) 

(48)

1(2%) 

7 (15%) 

1(2%) 

1 (2%) 

mgkg 

(50)

2(4%) 

1(2%) 

1 (2%) 

(50) 

11 (22%) 

18 (36%) 

2(4%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1(2%) 

1(2%) 

(49) 

1(2%) 

(48) 

3 (6%) 

(47)

2 (4%) 

1 (2%) 

(49) 

5 (10%) 

1(2%) 

6 mgkg 

(50) 

(50) 

17(34%) 

17(34%) 

2(4%) 

(50) 

1(2%) 

1 (2%) 

(50)

1 (2%) 

1 (2%) 

(50) 

(50) 

1 (2%) 

(49) 

1(2%) 

(50) 

1(2%) 

1(2%) 

(49) 

1 (2%) 

5 (10%) 

10 mg/kg 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

2(4%) 

(50) 

16 (32%) 

14 (28%) 

4 (8%) 

(50) 

1 (2%) 

1 (2%) 

2(4%) 

(50) 

2(4%) 

(50) 

2 (4%) 

(49)

1 (2%) 

1 (2%) 

(48) 

1 (2%) 

1 (2%) 

(47) 

8(17%) 

2(4%) 

(50) 

8 (16%) 

4(8%) 

1 (2%) 
186- 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE(3 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

2-YeUr shdy (continued) 

Hematopoietic System(continued) 

Thymus 

Atrophy 

cyst 

Ectopic parathyroid gland 

Hyperplasia 

Integumentary System 

Skin 

Acanthosis 

Hyperkeratosis 

Skin, siteof application,,acanthosis 

Skin, siteof application, hyperkeratosis 

Skin, siteof application, ulcer 

Subcutaneous tissue, abscess 

Subcutaneous tissue, edema 

'. .Subcutaneous granuloma tissue, ' ' '.

Subcutaneous tissue, hemorrhage 

Subcutaneoustissue,inflammation,chronic 

Subcutaneous tissue, inflammation, chronic 

active 

Subcutaneoustissue, skin, siteof 

application, inflammation, chronic 

Musculoskeletal System

Bone 

Vertebra, inflammation, chronic active 

Nervous System 

Brain 

Hemorrhage 

Thalamus, mineralization 

Spinal cord 

Demyelination 

Gray matter, necrosis 

Respiratory System 

Lung 

Congestion 

Hemorrhage 

Infiltration cellular,histiocyte 

Inflammation, chronic 

Metaplasia, osseous 

Pigmentation 

Alveolar epithelium, hyperplasia 

VehicleControl 3.6 mg/kg 6 mg/kg 10 mg/kg 

(39) 

1 (3%) 

3 (8%) 

1(3%) 

(42) 

1(2%) 

(46) 

1 (2%) 

1 (2%) 

(40) 

1(3%) 

(50) (50) 

' 

1 (2%) 

1 (2%) 

1(2%) 

1(2%) 

1(2%) 

2 (4%) 

1(2%) 

1 (2%) 

1 (2%). 

1(2%) 

1 (2%) .. 

(50)

1 (2%) 

(49) 

(50) 

24 (48%) 

(50) 

24(48%) 

1(2%) 

(50) 

(1) 

23(46%) 

1(100%) 

1(100%) 

(50) 

18(36%) 

(50) 

8 (16%) 

4 (8%) 

3(6%) 

112%) 

(50) 

3 (6%) 

5 (10%) 

4 (8%) 

(50) 

4 (8%) 

3 (6%) 

1 (2%) 

7 (14%) 

(50) 

1 (2%) 

2(4%) 

6(12%) 

4 (8%) 

1 (2%) 

6 (12%) 
OP (808) 

SP (106) EP (898) 

I (%Z) 
188 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

190 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEDl 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinolinea 

Vehicle Control 3.6 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 

IS-Month interim evaluation 10 10 9 

Early deaths 

Accidental death 1 

Moribund 6 I 7 

Natural deaths 10 3 3 

Survivors 

Terminal sacrifice 34 40 40 

Animals examined microscopically 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver (10) (9) (9) 

Hepatocellular adenoma 1 (10%) 2 (22%) 1 (11%) 

Hepatocellular adenoma, multiple 1 (10%) 

Endocrine System 

Adrenal medulla 

Pheochromocytoma benign 

Genital System 

ovary

Cystadenoma 

Uterus 

Polyp stromal 

Systems Examined With No Neoplasms Observed 

Cardiovascular System 

General Body System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Special Senses System 

Urinary System 

2-Year Study 

Alimentary System 

Gallbladder (43) (47) (48) 

Cholangiocarcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Intestine large, colon (49) (50) (51) 

, Hepatocellular carcinoma, metastatic, liver 1 (2%) 

60 

10 

6 

4 

40 

60 

(10) 

1 (10%) 

(45) 

1 (2%) 

(49) 
n9n 

Alimentary System(continued) 

Intestine large, rectum 

Carcinoma, metastatic, kidney 

Intestine large, cecum 

Carcinoma, metastatic, kidney 

Cholangiocarcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Intestine small, duodenum 

Polyp adenomatous 

Intestine small, jejunum 

Carcinoma, metastatic, kidney 

Hepatocellular carcinoma, metastatic, liver 

Intestine small, ileum 

Carcinoma, metastatic, kidney 

Hepatocellular carcinoma, metastatic, liver 

Liver 

Cholangiocarcinoma 

Hemangiosarcoma 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

Mesentery 

Cholangiocarcinoma, metastatic, liver 

Hemangioma 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Pancreas 

Cholangiocarcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

Cardiovascular System 

Heart 

Carcinoma, metastatic, kidney 

Cholangiocarcinoma, metastatic, liver 

Hemangiosarcoma 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

(49) 

1 (2%) 

(49) 

1 (2%) 

(45) 

(44)

1 (2%) 

(45) 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

12 (24%) 

1 (2%) 

21 (42%) 

9 (18%) 

1 (2%) 

1 (2%) 

(9) 

1 (11%) 

(50) 

2 (4%) 

1 (2%) 

(50) 

(50)

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

(49) 

(49) 

1 (2%) 

(49) 

(49) 

(48) 

(50) 

1 (2%) 

1 (2%) 

11 (22%) 

2 (4%) 

11 (22%) 

7 (14%) 

1 (2%) 

(8) 

1 (13%) 

(50) 

1 (2%) 

1 (2%) 

(50) 

(50)

1 (2%) 

(50) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 
I192 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

.-" .. ,.. . ,. 1 

2-Year ,%74dy (continued) 

Endocrine SystemAdrenal cortex 

Adenoma -, 

(48) 

1 (2%) 

(49) . , (51) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Capsule, hepatocellular carcinoma, 

Capsule, adenoma 

~istiocytic~sarcoma 

Cholangiocarcinoma, metastatic, liver 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

metastatic, liver 

Adrenal medulla 

Carcinoma, metastatic, kidney 

(48) 

1 (2%) 

(49) 

1 (2%) 

(49) (50) 

Pheochromocytoma malignant 

Histiocytic sarcoma 

1 (2%) 

1 (2%) 

Pheochromocytoma benign 1 (2%) 

. Pituitary gland . Adenoma . 

Islets, pancreatic 

Pars distalis, adenoma I ' 

5(11%) 

1 (2%) 

(44) 

(49) 

(48) 

(50) 

4 (8%) 

(51) 

6 (13%) 

1 (2%) 

(47) 

(50) 

4 (9%) 

1 (2%) 

(45) 

Pars distalis, carcinoma 1 (2%) 

Pars intermedia, adenoma 1 (2%) 

C-cell, adenoma 

Thyroid gland 

. 

(49) 

1 (2%) 

(50) (50) (50) 

C-cell, carcinoma 1 (2%) 

Follicular cell, adenoma 1 (2%) 2 (4%) 3 (6%) 

Genital System , 

ovary

Carcinoma ! 

(50) 

1 (2%) 

(49) 

Carcinoma,etastatic,kdney ' 1 (2%) 

Cholangiocarcinoma,metastatic, liver , . 1 (2%) 

Cystadenoma 1 (2%) 2 (4%) 

Granulosa cell tumor benign 1 (2%) 

Hemangioma 1 (2%) 

Histiocytic sarcoma 2 (4%) . . 1 (2%) 

Thecoma malignant 

Histiocytic sarcoma 

' uterlis '. .' 

1 1. . (50) '' 

1 (2%) 

' ' (50) ' '. ' 

1 (2%) 

(51) 'I- '. (50) 

1 (2%) 

Polyp stromal 2 (4%) 1 (2%) 1 (2%) 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

(50)

1 (2%) 

, .. (51) 

1 (2%) 

(50) 

Histiocytic sarcoma 1 (2%) 1 (2%) 
$tZdy (continued) 

Hematopoietic System(continued) 

Lymph node 

Sarcoma, metastatic, skin 

Mediastinal, alveolarhronchiolar carcinoma, 

metastatic, lung 

Pancreatic, hemangioma 

Pancreatic, sarcoma, metastatic, skin 

Lymph node, mandibular 

Carcinoma, metastatic, harderian gland 

Histiocytic sarcoma 

Lymph node, mesenteric 

Cholangiocarcinoma, metastatic, liver 

Hemangioma 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

Cholangiocarcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Thymoma malignant 

Mediastinum, carcinoma, metastatic, kidney 

Integumentary System 

Mammary gland 

Carcinoma 

Skin 

Sarcoma 

Skin, site of application, keratoacanthoma 

Subcutaneous tissue, hemangioma 

Subcutaneous tissue, hemangiosarcoma 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant 

Subcutaneous tissue, skin, site of 

application, sarcoma 

Musculoskeletal System 

Bone 

Vertebra, hemangiosarcoma 

Skeletal muscle 

Cholangiocarcinoma, metastatic, liver 

Hemangiosarcoma 

Hepatocellular carcinoma, metastatic, liver 

Sarcoma, metastatic, skin 

n93 

3.6 m@g 

(8) (3) 

1(33%) 

1 (13%) 1(33%) 

1 (13%) 

(50) (50) 

1 (2%) 

1 (2%) 1 (2%) 

(47) (50) 

1 (2%) 

2 (4%) 1 (2%) 

1 (2%) 

(50) (50)

1 (2%) 

2 (4%) 1 (2%) 

(45) (49) 

1 (2%) 

1 (2%) 1 (2%) 

1 (2%) 

(50) 

(50) 

2 (4%) 

(50) (50) (51) (50) 

1 (2%) 

(3) (1) (1) (1) 

1(100%) 

1 (100%) 

1 (100%) 

1 (33%) 
194 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEDl 

Summaryof the Incidenceof Neoplasms in Female Mice in the 2-Year Dermal Study, 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) / ( , . . 

&Year Study (continued) 

Nervous System 

Brain 

Carcinoma, metastitic, pituitary gland 

Spinal cord 

Hemangiosarcoma 

Respiratory System 

Lung 

Alveolaribronchiolar adenoma 

Alveolaribronchiolar adenoma, multiple 

Alveolaribronchiolar carcinoma 

Alveolaribronchiolar carcinoma, multiple 

Carcinoma, metastatic, harderian gland 

Carcinoma, metastatic, kidney 

Cholangiocarcinoma, metastatic, liver 

Hemangiosarcoma, metastatic, heart 

Hepatocellular carcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, lung 

Histiocytic sarcoma 

Mediastinum, hemangiosarcoma 

Nose 

Histiocytic sarcoma 

Special Senses System 

Harderian gland 

Adenoma 

Carcinoma 

Urinary System 

Kidney 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 

Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Renal tubule, carcinoma 

Urinary bladder 

Cholangiocarcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma 

Lymphoma malignant 

mgkg Vehicle Control 3.6

(50) 

(1) 

1 (100%) 

1 (2%) 

3 (6%) 

1 (2%) 

1 (2%) 

3 (6%) 

1 (2%) 

2 (4%) 

(50) 

2 (4%) 

1 (2%) 

(50) 

(50) 

1 (2%) 

(50) 

3 (6%) 

2 (4%) 

2 (4%) 

6 (12%) 

(1)

1 (100%) 

6 mgkg 

(51) 

(2) 

(51) 

6 (12%) 

2 (4%) 

1 (2%) 

2 (4%) 

(3)

2 (67%) 

1 (33%) 

1 (2%) 

(51) 

1 (2%) 

10 mag 

2 (4%) . , 

1 (2%) 

1 (2%) 

1 (2%) 

9 (18%) 

1 (2%) 

(50) 

1 (2%) 

(1) 

1 (100%) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 
9z 

ZE 

PZ 

I 

t79 

I 

6E 

I 

S6U 

91 

P 

IE 

9z 

EP 

I 

62 

I 

PL 

I 

IP 

I 

6 

L 

82 

ZZ 

IP 

5 

OE 

P 

69 

s 

op 

P 

IZ 

ZP 

IE 

EP 

z 

PE 

Z 

S8 

Z 

9P 

Z 

L 
196 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE112 

Individual Animal Tumor Pathology ofFemale Mice in the 2-Year Dermal Study

of 1,2-Dihydro-2,2,4-trimethylquinoline:Vehicle C,ontrol 

. 3556666677771771777777777 

Number of Days on Study 8063677800111122444444444 

.- . . .827052,548.913...441.9.1 11 1.1 11 1.1 

323223222222223222222222.2 

Carcass ID Number 1706819877997805555666667' 

066.07.12170633239678123581 

Alimentary System 

Esophagus +++++M+++++++++++++++++++ 

Gallbladder A+++AA+AA+A++A+++++++++++ 

Intestine large, colon ......................... 

Intestine large, rectum ......................... . 

Carcinoma, metastatic, kidney x 

Intestine large, cecum ......................... 

Carcinoma, metastatic, kidney X 

Intestine small, duodenum A+++AA+++MA++++++++++++++: 

Intestine small, jejunum +A++AA+AA+A+++++++++++.+++ 

Carcinoma, metastatic, kidney X 

Intestine small, ileum A+++AA++A+A++'++++++++++++ 

Carcinoma, metastatic, kidney X 

Liver ......................... Hemangiosarcoma x 

Histiocytic sarcoma 

Hepatocellular adenoma, multiple 

Hepatocellular adenoma 

Hepatocellularcarcinoma.multiple 

Hepatocellular carcinoma 

Hemangiosarcoma, multiple 

, 

X 

X 

x xx 

X 

x 

xx x xx 

X 

x 

x 

X 

x 

x xx 

X 

X 

.X 

Sarcoma, metastatic, skin 

Mesentery + + + + 

Histiocytic sarcoma 

Pancreas ......................... Histiocytic sarcoma x 

Sarcoma, metastatic, skin I ., .

Salivary glands ......................... Stomach, forestomach ........................... Squamous cell papilloma 

Stomach,glandular . , .. .............................

Cardiovascular System 

Heart. ......................... Carcinoma, metastatic, kidney X 

Hemangiosarcoma X 

Endocrine System 

Adrenal cortex .......................... 

Adenoma X 

Carcinoma, metastatic, kidney X 

Histiocytic sarcoma 

Capsule, adenoma X 

Adrenal medulla +++++++M+++++++++++++++++ 

Carcinoma, metastatic, kidney X 

Pheochromocytoma malignant X 

Pheochromocytoma benign 'X 

Islets, pancreatic ......................... 

Adenoma , I. , . 

+: Tissue examined microscopically M: Missing tissue X: Lesionpresent 

A: Autolysis precludes examination I Insufficient tissue Blank:Notexamined 
TABLED2 

JhdividuaU Animd Tumor PaUh~U~ggr~ff FemaUe Mice inn Uhe %Year Demd Shndy 

Qfn,2-IID~ydr(P-2,2,0-u~~euhyu~~nnQui~e: Vehide @QnntId (continued) ,, 

IIIIIIIIIIIIIIII-IIIIIII~I 

Number of Days on Study 4444444444444444444444444 .. 

1111111111111111111111111 

22222.2.2222222222333-333333 Total . 

Carcass ID Number 1177188888899999000000111 Tissues/,.,

2458903458901418012418235 Tumors -'. 

Alimentary System .. 

Esophagus 49 

Gallbladder 43 

Intestine large, colon 49 

Intestine large, rectum 49 

Carcinoma, metastatic, kidney 1 

Intestine large, cecum 49 

Carcinoma, metastatic, kidney 1 

Intestine small, duodenum 45 

Intestine small, jejunum 44 

Carcinoma,metastatic,kidney ' ' 1 

Intestine small, ileum 45 

Carcinoma, metastatic, kidney 1 

Liver 50 

Hemangiosarcoma 1 

Hemangiosarcoma, multiple i 

Hepatocellular carcinoma 12 

Hepatocellular carcinoma, multiple 1 

Hepatocellular adenoma 21 

Hepatocellular adenoma, multiple 9 

Histiocytic sarcoma 1 

Sarcoma, metastatic, skin 1 

Mesentery '. 9 :

Histiocytic sarcoma 1 

Pancreas 50 

Histiocytic sarcoma 2 

Sarcoma, metastatic, skin 1 

Salivary glands 50 

Stomach, forestomach 50 

Squamous cell papilloma '1 

Stomach, glandular ., 50 

Cardiovascular System 

Heart ......................... c 50.

Carcinoma, metastatic, kidney 1' 

Hemangiosarcoma 1 

Endocrine System . . 

Adrenal cortex ++++++++++++M++++++++++++' '48 

Adenoma 1 

Carcinoma, metastatic, kidney 1 

Histiocytic sarcoma X 1 

Capsule, adenoma '1 

Adrenal medulla ......................... 48 

Carcinoma, metastatic, kidney 1 

Pheochromocytoma malignant 1 

Pheochromocytoma benign 1 

Islets, pancreatic ......................... -, 

49 

' 

Adenoma X 1 
1 198 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline: Vehicle Control (continued) . . 

Number of Days on Study 

Carcass ID Number 

Endocrine System(continued) 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

C-cell, adenoma 

C-cell, carcinomaGeneral Body System 

None 

Genital System 

Clitoral gland 

ovary Carcinoma 

Carcinoma, metastatic, kidney 

Cystadenoma 

Histiocytic sarcoma 

Uterus 

Histiocytic sarcoma 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Histiocytic sarcoma 

Lymph node 

Mediastinal, alveolarbronchiolar 

carcinoma, metastatic, lung 

Pancreatic, sarcoma, metastatic, skin 

Lymph node, mandibular 

Histiocytic sarcoma 

Lymph node, mesenteric 

Histiocyric sarcoma 

Sarcoma, metastatic, skin 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

Histiocytic sarcoma 

Mediastinum, carcinoma, metastatic, kidney 

Integumentary System 

Mammary gland 

Skin 

Subcutaneous tissue, sarcoma 

Musculoskeletal System 

Bone 

Skeletal muscle 

Sarcoma, metastatic, skin 

3556666677777777777777777 

8063677800111122444444444 

8270525489134419111111111 

3232232222222232222222222 

1706819877997805555666667 

0660712170633239678123581 

+ + + + MM+ + M+ + M+ + + + + + + M+ + + M+ 

+++++M+++++++++M+++++++++ 

X ......................... 

......................... 

......................... 

X 

X 

......................... X 

......................... X 

X 

+ + + 

X 

.......................... 

......................... 

x 

......................... X 

X 

+++++++M+++M++M+M++++++++ 

X 

......................... 

......................... X 

......................... + + 
TABLED2 

hdh" hhd TPnllmQffhhDnOgy dFC!llmde Mk!e ill dhe 2-Yealr Delrllmd $tUdJ' 

of n92-Dihydlr~-2,2,0-Ulr~~eUhyn~~ill~n~~e: Vehicle ConnUlrol (continued) 

Number of Days on Study 

CarcassIUD Number 

Endocrine System(continued) 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

C-cell, adenoma 

C-cell. carcinoma ~ ~~~ 

General Body System 

None 

Genital System 

Clitoral gland 

ovary

Carcinoma 

Carcinoma, metastatic, kidney 

Cystadenoma 

Histiocytic sarcoma 

Uterus 

Histiocytic sarcoma 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma 

Histiocytic sarcoma 

Lymph node 

Mediastinal, alveolarhronchiolar 

carcinoma, metastatic, lung 

Pancreatic, sarcoma, metastatic, skin 

Lymph node, mandibular 

Histiocytic sarcoma 

Lymph node, mesenteric 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

Histiocytic sarcoma 

Mediastinum, carcinoma, metastatic, kidney I 

Integumentary System 

Mammary gland 

Subcutaneous tissue, sarcoma I 

Musculoskele(al System 

Bone 

Skeletalmuscle 

Sarcoma, metastatic, skin 

7777111177717171117777777 

4444444444444444444444444 

1111111111111111111111111 

2222222222222222333333333 Total 

7177788888899999000000111 Tissues/ 

2458903458901418012478235 Tumors 

++M+++++++,M+++++M++M+++++ 40 

M+M+++++++M++++++++++++M+ 44 

x xx x 5 

......................... 49 

X 1 

X 1 

......................... 48 

......................... 50 

X 1 

1 

X 1 

X 2 

......................... 50 

1 

......................... 50 

1 

1 

+ + ++ + 8 

1 

X 1 

......................... 50 

X 1 

+++++++++++++++M+++++++++ 47 

X 2 

A 1 

......................... 50 

1 

X 2 

+++++++++++++M+++++++++++ 45 

X 1 

1 

......................... 50 

......................... 50 

X 2 

......................... 50 

+ 3 

X 1 
200 1,2-Dihydro-2,2,4-trimethylqriinoline,NTP TR 456 

TABLED2 . I

Individual AnimalTumor Pathology of Female Mice in the'2-YearDe&d.Stuily . . 

of 1,2-Dihyd.ro-2,2,4-trimethylquinoline:Vehicle Control(continued) . . 

3556666611111111111111111 

Number of DaysonStudy , ' 806361~180011.112244444444~

._. . .- ,8270525489134,419111111111 

.. 

32322322222'22232222222222 

Carcass I , D
 Number 1106'8'19811991805555666661 .. 

.. . . . . ,0'660112110.633239618.123581 

Nervous System 

Brain ......................... Peripheral nerve + 

Spinal cord + 

Hemangiosarcoma X 

Respiratory System 

Lung ........................... Alveolarhronchiolar adenoma, multiple 

Alveolarhronchiolar carcinoma X X x 

Carcinoma, metastatic, kidney X 

Hemangiosarcoma, metastatic, heart X . .

Hepatocellular carcinoma, metastatic, liver X X 

Hepatocellular carcinoma, metastatic, lung X 

Histiocytic sarcoma X 

Nose ......................... Trachea. . , . . .. +,+ + + + M.+ +,+ + + + +*+ t.+ + + + + + + + -k + I ~ . I 

Special Senses System 

None, ._ . . _. - . , . .%..- , .. . 

Urinary System 

Kidney . ........................... Histiocytic sarcoma X 

Renal-tubule, carcinoma x. 

Urinarybladder _ _ .. .. ............................... . , . I 

Systemic Lesions 

Multiple organs ......................... Histiocytic sarcoma X xx 

Lymphoma malignant .. x x xx x .x 
~~ ~ 

Number of Days on Study 

Carcass IUD Number 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

Hemangiosarcoma 

Respiratory System 

Lung 

Alveolarhronchiolar adenoma, multiple 

Alveolarhronchiolar carcinoma 

Carcinoma, metastatic, kidney 

Hemangiosarcoma, metastatic, heart 

Hepatocellular carcinoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, lung 

Histiocytic sarcoma 

Nose 

Trachea 

Special Senses System 

None 

Urinary System 

Kidney 

Histiocytic sarcoma 

Renal tubule, carcinoma 

Urinary bladder 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

11111111111111111111~1111 

4444444444444444444444444 

1111111111111111111111111 

2222222222222222333333333 Total 

1111188888899999000000111 Tissues/ 

2458903458901418012418235 Tumors 

......................... 50 

1 

1 

1 

......................... 50 

X 1 

3 

1 

1 

X 3 

1 

X 2 

......................... 50 

......................... 49 

......................... 50 

X 2 

1 

......................... 50 

........................... 50 

X 4 

X X x x 10 
202 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED2 

Individual Animal Tumor Pathologyoff FemaleMice in-the2-Year Dermal Study 

of 1,2-Dilhydro-2,2,4-trimethylquinoline:3.6 mgkg 

4455566667777777777777777 

Number of Days on'Study 4968958992444444444444444 

8001394894000000000000000 

3333333333333333333333333 

42762.33655111122222233333 

6333474553678901257901356 

Alimentary System 

Esophagus ......................... Gallbladder +A+.+A+u+A++++++'++++++++++ 

Intestine large, colon .......................... Intestine large, rectum ......................... Intestine large, cecum .......................... 

Intestine small, duodenum ......................... 

Polyp adenomatous X 

Intestine'small, jejunum +A++A+++A++++++++++++++++ 

Intestine small, ileum ......................... 

Liver : ......................... Hemangiosarcoma 

Hepatocellular carcinoma xx x X 

Hepatocellular adenoma X x xx 

Hepatocellular adenoma, multiple xxxxx -xx x 

Mesentery + + + + 

Hemangioma X 

Pancreris ......................... Salivary glands ......................... 

Stomach,:forestomach ........................... Stomach,'glandular' ......................... 

Cardiovascular System 

Heart ......................... Hepatocellular carcinoma, metastatic, liver X 

Endocrine System 

Adrenal 'cortex . ........................... Adrenal medulla .. .......................... Islets, pancreatic ......................... Parathyroid gland + + + MM+ +'+ MM+ + M+ + + + + + M + + +++ 

Pituitary gland ......................... 

Pars'distalis, adenoma X x 

Pars distalis, carcinoma X 

Thyroidtgland .......................... Follicular. cell, adenoma 

General Body System 

None . ._ 

Genital System 

Clitoral.gland .......................... ovary " ........................... Granulosa cell tumor benign 

Thecoma malignant 

Uterus ' .......................... Polyp stromal 

.I 
Lesions in Female Mice 

CarcassIDNumber 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Polyp adenomatous 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery 

Hemangioma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Heart 

Hepatocellular carcinoma, metastatic, liver 

Endocrine System 

Adrenal cortex . . 

Adrenal medulla 

Islets, pancreatic 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Pars distalis, carcinoma 

Thyroid gland 

Follicular cell, adenoma 

General Body System 

None 

Genital System 

Clitoral gland 

ovary

Granulosa cell tumor benign 

Thecoma malignant 

uterus 

Polyp stromal 

3333333333333333333333333 

3355555664444445566661111 

8924618010134580141890125 

......................... 

........................... 

X 

X X xx 

X X xx 

X xxx x x

+ + + + 

......................... 

......................... 

......................... 

......................... 

......................... 

++++++++++++++M++++++++++ 

++++++++++++++M++++++++++ 

......................... 

......................... 

+-M+++++++++++++++++++++++ 

X X 

......................... 

X 

......................... 

......................... 

X 

X 

......................... X X 

Total 

Tissues/, 

Tumors 

50 

41 

50 

50 

49 

49 

1 

41 

49 

50 

1 

8 ,

8 

14 

8 . 

1 J 

50 

-49 

50 . 

50 

1 

50 

1 

. 49%:: 

49 

50 

4 4 	 .' 

'.48 

.4, -, 

1 

50 

1 

I . 

50 "I 

49 

1. 

1 

50

2 ,i 
204 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED2 

IndividualAnimal TumorPathology of Female Mice in the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:3.6 mgkg (continued) 

. I ,I 

'445556666111111~111171111 

Numberoff Days on Study ,4968958992'444444444444444 

8~001394894000000000000000 

33333333'3.3333'333333333333 

Carq Number 4216233655111122222233333 

6333414553618901251901~356 

Hematopoietic System 

Bone marrow ......................... Lymph node + + 

Pancreatic, hemangioma X 

Lymph node, mandibular ........................... 

Lymph node, mesenteric ........................... 

Hemangioma X 

Spleen ........................... . Hemangiosarcoma . 

Thymus + M+ + + +,MM+ + + +'+ + + + + + + + + + + + t 

Heoatoceilular carcinoma, metastatic, liver X ~ ~~ 

IntegumiAwy system 

Mammary gland ++'++M++M+++++++++++++++++ 

Carcinoma 

Skin ......................... Sarcoma 

Subcutaneous tissue, hemangioma 

Subcutaneous tissue, schwannoma malignant X 

Subcutaneous tissue,skin, 

site of armlication. sarcoma X ~~~~ ~ 

Musculoskeletal System 

Bone .......................... Skeletal muscle + 

Hemangiosarcoma X 

. I .. . .. .. ..,. . 

Nervous System 

Brain .......................... Carcinoma, metastatic, pituitary gland X 

' 3 

Respiratory System 

Lung . .......................... Alveolarhronchiolar adenoma X X 

Alveolarilxonchiolar adenoma, multiple 

Alveolarhronchiolar carcinoma 

Hepatocellularcarcinoma,liver metastatic, X X 

Nose ......................... 

Trachea,-, .. ......................... 

SpeCialsemisSistem .. . 

.. Harderian gland 

Adenoma ~~~ ~~ 

urinary syitem 

Kidney .......................... Urinary bladder ......................... 

systemic.Lesiom 

Multiple organs + +.+ + + + + + + +,+ +,+ + + + + + + +. + + + .+ + 

. Lymphoma malignyt X X 

._ . .- . . . 
Lesions in Female Mice 205 

Carcass E D Number 

Hematopoietic System 

Bone marrow 

Lymph node 

Pancreatic, hemangioma 

Lymph node, mandibular 

Lymph node, mesenteric 

Hemangioma 

Spleen 

Hemangiosarcoma 

Thymus 

Hepatocellular carcinoma, metastatic, liver 

Integumentary System 

Mammary gland 

Carcinoma 

Skin 

Sarcoma 

Subcutaneous tissue, hemangioma 

Subcutaneous tissue, schwannoma malignant 

Subcutaneous tissue, skin, 

site of application, sarcoma 

Musculoskeletal System 

Bone 

3333333333333333333333333 Total . 

3 3 5 5 5 5 5 6 6 4 4.4 4 4 4 5 5 6 6 6 6 I I 7 I .fissued' , 

89246180'10134580141890125 .Tumors ,. 

... I : 

......................... ,50 -.,! 

+ + 4 ' 

., 1 , 

.......................... 49 "" 

.......................... 48'.,' ' . 1', 

.......................... 50 

X 1 

+++++++++++++++++++++M+++ , 46 " 

. ' . _. i. .. , . . 

.. . I , . ._> . 

.......................... ' 48 

X '1 

.......................... 50 .. 

X 1 

X " 

.. 1 

' ' ''1 ' '. 

' .. 8 : ,. 

... . . . . . . 

........... 1 ,: 

. 

, . .* i, (_' 

......................... 50 ' '

Skeletal muscle 

>+, '1 .: ,:

Hemangiosarcoma r ...... .__., . . . .. - .... .I,. .. 

. . Nervous System ' . 4.-' . 

Brain .......................... 50 .. Carcinoma, metastatic, pituitary gland . . I ~ .. . .: .. I . 

, L .

Respiratory System 

Lung ......................... ,,i- 50 '.

Alveolarhronchiolar adenoma X 3 " 

Alveolarhronchiolar adenoma, multiple xx s . ,.. , 2 " 

Alveolarhronchiolar carcinoma X X , . ' ' I . 2:,"

Hepatocellular carcinoma, metastatic, liver X X xx '6' 

Nose ............................ 49 . ' 

Trachea -. ................................ 50,' :.., 

b'' :..*- 9 ' . ) , . . I. Special Senses System , . 

Harderian gland + " 1 ":'

:. 1' Adenoma x . . ..... ..... 

.. ..... Urinary System ,I 

Kidney ......................... .,5Q,. 

,.< 

. 

Urinary bladder '+ +-+,'.+ + + + + + + + +,,+.+,+ + + + + + + +,+ + + '50 , 

... .;;:. ...... I

Systemic Lesions 

Multiple organs .......................... 1 50.,' . 

, ,-. Lymphoma malignant . . x. .x ,x- xx x.x ...... 9'" 
206 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED2 

Individual Animal Tumor Pathology of Female Mice in the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:6 mgkg ~~~ ~ ~ ~ ~ 

. . .. 

Number ofDays on Study 

.. 

Cards ID Number 

Alimentary System 

Esophagus 

Gallbladder 

Hepatocellular carcinoma, metastatic, liver 

Intestine large, colon 

Hepatocellular carcinoma, metastatic, liver 

Intestine large, rectum 

Intestine large, cecum 

Hepatocellular carcinoma, metastatic, liver 

Intestine small, duodenum 

Intestine small, jejunum 

Hepatocellular,carcinoma,metastatic, liver 

Intestine small, ileum 

Hepatocellular carcinoma, metastatic, liver 

Liver 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery 

Hepatocellular carcinoma, metastatic, liver 

Pancreas 

Hepatocellular carcinoma, metastatic, liver 

SaQvary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Heit 

Endocrine System 

Adrenal cortex, 

Capsule, hepatocellular carcinoma, 

metastatic, liver 

Adrenal medulla. 

Islets; paiicreatic 

Adenoma 

Parahyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Pars intemledia, adenoma 

Thyroidgland . . 

Follicular cell; adenoma 

General-Body System 

None. ' 

~~~~~ ~ ~ ~~ ~ 

0344566111111111111111111 

2949029012333333333333333 

8460484916566666666666666 

4343434433444444444444444 

0839~183298211111122222233 

8311563981212341803561804 

X 

......................... X 

......................... 

......................... 

x ........................... 

......................... X 

A++++++++++M+++++++++++++ 

X 

.......................... X X 

X 

x xx .x X 

X x x x X 

+ + + + 

X 

.......................... X 

......................... 

......................... 

......................... 

......................... 

......................... 

X 

++++++++++++++++++++M++++ 

......................... 

M++++++M+++++++++M+++++++ 

M+++++M++++++++++++++++++ 

X X X ' 

X . . . . . . . . . . . . . . . . . . . . . . . . . 

X 

.. 
I 

I Number of DaysonStudy I

I 

1 Carcass ID Number i

I 

Alimentary System 

Esophagus 

Gallbladder 

Hepatocellular carcinoma, metastatic, liver 

Intestine large, colon 

Hepatocellular carcinoma, metastatic, liver 

Intestine large, rectum 

Intestine large, cecum 

Hepatocellular carcinoma, metastatic, liver 

Intestine small, duodenum 

Intestine small, jejunum 

Hepatocellular carcinoma, metastatic, liver 

Intestine small, ileum 

Hepatocellular carcinoma, metastatic, liver 

Liver 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery 

Hepatocellular carcinoma, metastatic, liver 

Pancreas 

Hepatocellular carcinoma, metastatic, liver 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Cardiovascular System 

Heart 

Endocrine System 

Adrenal cortex 

Capsule, hepatocellular carcinoma, 

metastatic, liver 

Adrenal medulla 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Pars intermedia, adenoma 

Thyroid gland 

Follicular cell, adenoma 

General Body System 

None 

11111711117111711111~11117 

33333444444444444444444444 

71111000000000000000000000 

44444333333333333333333444 Total 

00000111888888899999999001 Tissues/ 

01234189012458902345679670 Tumors 

............................ 51 

.......................... 48 

1 

.......................... 51 

1 

.......................... 51 

.......................... 50 

1 

.......................... 50 

.......................... 51 

1 

.......................... 49 

1 

.......................... 51 

xx X 5 

1 

X xx X x xxx 13 

x x x 8 

+ ++ ' + + + + 11

1 

.......................... 51 

1 

.......................... 51 

.......................... 51 

.......................... 51 

.......................... 51 

.......................... 51 

1 

++++M+++++++++++++++++++++ 49 . 

.......................... 51 

X 1 

M++++++++++++++++++++++M+M 45 

.......................... 41 

xx X 6 

1 

.......................... 50 

X 2 
208 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR.456 

TABLED:2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study :. ., 

of 1,2-DPydro-2,2,4-trimethylquinoline: 6 mgkg I. I (continued) .. . , I . 

0344566117771777711711177 

Number of Days on Study 294,9029012333333333333333 

' 84604'8497'6566666666666666 .. 

4343434433444444444444444 

Carcass ID Number 0839183298211111122222233 

8311563987212347803567804 .... . , , .. .. . -

Genita1,System .. -

Clitoral gland ++++++++++M++++++++++++++ 

ovary . . 

........................... 

Cystadenoma 

~ 

Hemangioma X 

UkNS ........................... Polyp stromal X . . , .. .. 

Hematopoietic System 

Bone marrow ......................... Hemangiosarcoma . . .x 

Lymph node + + + + 

Lymph node, mandibular ......................... Lymph node, mesenteric .......................... ' 

. . . . Hepatocellular carcinoma, metastatic,liver X 

Spleen ........................... Hemangiosarcoma X X 

Thymus + +'+ +'+ + + + MM+ + + + + + + + +.+ + + + + + 

Hepatocellular carcinoma, metastatic,liver X 

Thymoma malignant .. .. . ,. ..~ . -, .- ,.. . . 

Integumentary System . , Mammary gland . . . . . . . . . . . . . . . . . . . . . . . . . . .. Skin .......................... . . Subcutaneoustissue, hemangiosarcoma X 8 . Subcutaneoustissue, sarcoma X . - ).. .. .~ . .. _, . . .. . , 

Musculoskeletal System , .

Bone ............................ Vertebra, hemangiosarcoma x . .. 

Skeletal muscle + 

Hepatocellular carcinoma, metastatic, liver X ~~ 

Nervous System 

Brain ......................... Peripheral nt:rve + + 

Spinal cord + + .. .. . . .. . I 

. . .. Respiratory System 

Lung ........................... Alveolar/bronchiolar adenoma x X x x 

Alveolar/bronchiolar carcinoma 3

. . Carcinoma, metastatic, harderian gland X 

Hepatocellular carcinoma, metastatic, . . liver X X 

Mediastinum, hemangiosarcoma .x : 

Nose , ......................... Trachea .......................... 
Lesionns in Female Mice 2Q9 

Number of Days on Study 33333444444444444444444444 

11717000000000000000000000 ~~ ~~~~ ~~ 

. -

44444333333333333333333444 Total 

Carcass ID Number 00000777888888899999999001 Tissues/ 

01234789012458902345679670 Tumors 

I

i

i

I

I 

Genital System 

Clitoral gland 

ovary 

Polyp stromal 

Hemangioma 

Cystadenoma 

Uterus 

.......................... 

.......................... 

. x X 

............................ 

50 

1 

2 

50 

1 

51 

i . 

I 

Hematopoietic System 

Bone marrow .......................... 51 

Hemangiosarcoma 1 

Lymph node + 5 

Lymph node, mandibular .......................... 51 

Lymph node, mesenteric .......................... 51 

Hepatocellular carcinoma, metastatic, liver 1 

Spleen .......................... 51 

Hemangiosarcoma 2 

Thymus ++M+++++++++++++++++++++++ 48 

Hepatocellular carcinoma, metastatic, liver 1 

Thymoma malignant X 1 

Integumentary System 

Mammary gland .......................... 50 ., 

Skin .......................... 51 

Subcutaneous tissue, hemangiosarcoma 1 

Subcutaneous tissue, sarcoma X 2 

Musculoskeletal System 

Bone .......................... 51 

Vertebra, hemangiosarcoma 1 

Skeletal muscle 1 

Hepatocellular carcinoma, metastatic, liver 1 

Nervous System 

Brain .......................... 51 . 

Peripheral nerve 2 ' < 

Spinal cord 2 . 

Respiratory System 

Lung .......................... 51 

Alveolarhronchiolar adenoma X X 6 

Alveolarhronchiolar carcinoma x x 2 

Carcinoma, metastatic, harderian gland 1 

Hepatocellular carcinoma, metastatic, liver 2 

Mediastinum, hemangiosarcoma 1 

Trachea 

Nose 

.......................... 

.......................... 50 

51 I 
210 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED2 

Individual Animal Tumor Pathology of Female Mice in the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:6 mgkg (continued) .. 

0344566111111111711171111 

Number of Days on Study 2949029012333333333333333 

8460484916566666666666666 

4343434433444444444444444 

Carcass IID Number 0839183298211111122222233 

8311563981212341803561804 

EX 

Special Senses System 

+ 

Harderian gland + + + 

Adenoma X X 

Carcinoma X 

. . 

Urinary System 

Kidney ......................... Alveolarhonchiolar carcinoma, 

metastatic, lung 

Urinary bladder ......................... Hepatocellular carcinoma, metastatic, liver X 

Systemic Lesions 

Multiple organs ......................... Lymphoma malignant X x 'X X X X X 

/ 
Lesions inFemale Mice 

Number of Days on Study 

Carcass ID Number 

Special Senses System 

Ear 

Harderian gland 

Adenoma 

Carcinoma 

Urinary System 

Kidney 

Alveolarhronchiolar carcinoma, 

metastatic, lung 

Urinary bladder 

Hepatocellular carcinoma, metastatic, liver 

Systemic Lesions 

Multiple organs 

Lymphoma malignant 

77117771177111171171777777 

33333444444444444444444444 

77777000000000000000000000 

44444333333333333333333444 Total 

00000777888888899999999001 Tissues/ 

01234789012458902345679610 Tumors 

.......................... 51 

X 1 

............................ 51 

1 

.......................... 51 

X xx x x X 13 
212 1,2-Dihydro-2,2,4-trimethylquiqoline,NTP TR 456 

TABLED2 

Individual Animal Tumor PathologyoffFemale Mice in the 2-Year Dermal ,Study , e

of 1,2-Dilhydro-2,2,4-trimethylquinoline: 10 mg/kg .. '. :, . . ,

45666666111111'111111'111'11 

Number of Days on Study 9303478811333333333333333 

3138204189666666666666666, 

4'444444444444444444444444 

Carcass IDNumber 88'94198167334444444555555 . 

81264532111812,35189013561 

... . ,.,. ,

Alhentary System .. 

I.. .. Esophagus ......................... Gallbladder +AA,++++"++A+++++++++++++++ 

Cholangiocarcinoma, metastatic, liver .X 

Intestine large, colon .......................... 

Intestine large, rectum .......................... 

Intestine large, cecum ........................... 

Cholaigiocarcinoma, metastatic, liver X 

Intestine small, duodenum ......................... 

Intestine.smal1, jejunum ........................... 

Intestine small, ileum ++A++++++A+++++++++++++++ 

Liver .......................... Cholangiocarcinoma X 

Histiocytic sarcoma 

Hepatocellular adenoma, multiple 

Hepatocellular adenoma 

Hepatocellular carcinoma, multiple 

Hepatocellular carcinoma 

Hemangiosarcoma 

Cholangiocarcinoma,metastatic, liver 

Mesentery 

X 

+ 

X 

X X 

+ 

X 

X 

X 

X 

X 

xx 

X X 

X 

Pancreas ........................... Cholangiocarcinoma, metastatic, liver ' X . . Histiocytic sarcoma X 

Salivary glands ......................... Stomach, forestomach ......................... Squamous cell papilloma X 

Stomach, glandular ......................... 

. , .. ..... Cardiovascular System 

Heart ......................... Cholangiocarcinoma, metastatic, liver X 

Hemangiosarcoma X 

.Histiocytic sarcoma X 

, , . . . Endocrine System ' 

Adrenal cortex ......................... . . 

Cholangiocarcinoma, metastatic, liver X 

Histiocytic sarcoma X 

Capsule, adenoma 

Adrenal medulla .......................... Histiocytic sarcoma X 

Islets, pancreatic ......................... Adenoma 'X 

Parathyroid gland + + M+ + + + + + M+ + + + M+ + + + + + MMM+ 

Pituitary gland +++++.+++++++M+-+++++++++++',, 

Pars distalis, adenoma x 

Thyroid gland ........................... Follicular cell, adenoma 

.,, . .. .. 
~~~~~~~~ ~~~~~ 

csrcmsm Number 

, I 

Alianenhary System 

Esophagus 

Gallbladder 

Cholangiocarcinoma, metastatic, liver 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Cholangiocarcinoma, metastatic, liver 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Cholangiocarcinoma 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Cholangiocarcinoma, metastatic, liver 

Pancreas 

Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Salivary glands 

Stomach, forestomach 

Squamouscell papilloma 

Stomach, glandular 

@i3E.dbVSCdmP 8ySkm 

Heart 

Cholangiocarcinoma, metastatic, liver 

Hemangiosarcoma 

Histiocytic sarcoma 

Endocnine System 

Adrenal cortex 

Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Capsule, adenoma 

Adrenal medulla 

Histiocytic sarcoma 

Islets, pancreatic 

Adenoma 

Parathyroid gland 

Pituitary gland 

Pars distalis, adenoma 

Thyroid gland 

Follicular cell, adenoma 

~ ~ ~~ ~ ~ ~ 

44444444,44444444444444444 Total 

5666666611111118888889999 Tissues/ 

90256.18901356892456190134 Tumors 

......................... 50 

+++++++++++M+++++M+++++++ 45 

1 

......................... 49 

.......................... 49 

......................... 49 

1 

......................... 49 

......................... 49 ......................... 48 

......................... 50 

1 

X 1 

X X xx X 11 

X 2. 

X X xx x xx 11 

X x xx X X I 

1

+ + + + + + 8 

1 

......................... 50 

1 

1 

......................... 50 

......................... 50 

1
 .......................... 50 

......................... 50 

1 

1 

1 

......................... 50 

1 

1 

.x 1 

......................... 50 

, 1 

......................... 50 

1 

++++++++++M+++++++++M++++ 42 . 

++++M++M+M+++++++++++M++.+ 45 

X X X ,4 

......................... 50 

xx X '3 . . 

. 

, 

, 

" 

., 
214 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEDl2 

Individual Animal Tumor Pathologyof Female Micein the 2-YearDermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline:10 mgkg (continued) 

4566666677777777777777777, 

Number of Days on Study 9303478811333333333333333 

3738204789666666666666666 

4444444444444444444444444 

CarcassIID Number 8894798767334444444555555 

8126453217781235789013567 

General Body System 

None 

Genital System 

Clitoral gland ......................... ovary +++++++M+++++++++++++++++ 

Cholangiocarcinoma, metastatic, liver X 

Histiocytic sarcoma X 

Uterus ......................... Histiocytic sarcoma X 

Polyp stromal 

Hematopoietic System 

Bone marrow ......................... Histiocytic sarcoma X 

Lymph node + 

Sarcoma, metastatic, skin 

Mediastinal, alveolarlbronchiolar 

carcinoma, metastatic, lung X 

Lymph node, mandibular ......................... Carcinoma, metastatic, harderian gland X 

Histiocytic sarcoma X 

Lymph node, mesenteric ......................... Cholangiocarcinoma, metastatic, liver X 

Histiocytic sarcoma X 

Spleen ........................... Histiocytic sarcoma X 

Thymus - ......................... Cholangiocarcinoma, metastatic, liver .. x 

Histiocytic sarcoma X 

Integumentary System 

Mammary gland . . . . . . . . . . . . . . . . . . . . . . . . . 

Carcinoma X 

Skin ......................... Skin, site: of application, keratoacanthoma X 

Subcutaneous tissue, sarcoma 

Musculoskeletal System 

Bone ......................... Skeletal muscle + 

Cholangiocarcinoma, metastatic, liver X 

Nervous System 

Brain .......................... Peripheral nerve + 

Spinal cord + 
Number of Days on Study 

~~ 

CarcassI D Number 

General Body System 

None 

Genital System 

Clitoral gland 

ovaryCholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Uterus 

Histiocytic sarcoma 

Polyp stromal I 

Hematopoietic System 

Bone marrow 

Histiocytic sarcoma 

Lymph node 

Sarcoma, metastatic, skin 

Mediastinal, alveolaribronchiolar 

carcinoma, metastatic, lung 

Lymph node, mandibular 

Carcinoma, metastatic, harderian gland 

Histiocytic sarcoma 

Lymph node, mesenteric 

Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Spleen 

Histiocytic sarcoma 

Thymus 

Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

i Integumentary System ' Mammarygland i Carcinoma

I Skin i Skin, siteof application, keratoacanthoma

i Subcutaneous tissue, sarcoma 

Musculoskeletal System 

Bone 

Skeletal muscle 

Cholangiocarcinoma, metastatic, liver 

Nervous system 

Brain 

Peripheral nerve 

Spinal cord 

3333333333333333333333333 

6666666666666666666666666 ~ ~~~ ~~ 

4444444444444444444444444 Total 

5666666677177118888889999 Tissues/ 

9025678901356892456790134 Tumors 

......................... 50 

......................... 49 

1 

1 

......................... 50 

1 

X 1 

......................... 50 

1 

+ + 3 

X 1 

1 

......................... 50 

1 

1 

......................... 50 

1 

1 

......................... 50 

1 

++++++++++++++++++++++++M 49 

1 

1 

......................... 49 

1 

......................... 50 

1 

X 1 

.......................... 50 

1 

1 

......................... 50 

1 

1 
216 lJ-Dihydro-2J,4-trimethylquinoline, NTP TR 456 

TABLEID2 

Individual AnimalTumor Pathology of Female Mice in the 2-Year DermalStudy . . s . .

of 1,2-IDihydro-2,2,4-trimethylquinoIine: 10 mgkg (continued) ' ' . . ".. ... 45666666111,1'11~~177~1111711 

Number of Days on Study 930347881.1333333333333333.' 

313820478966666666666.6666 

. . 4,4444'44444444'444444444444 

Cartxis ID Number 8.8 9 4 1,9,8 7 6 73.3 4'4 4 4 4 4 4 5 5 5 5 5 5 , 

.. 

. , 

8.1264532.11781235189013567 . . 

. . . t i - ..* " .: 

.Reipiratory System .. Lung .......................... Alveolar/bronchiolar adenoma X .. Alveolar/bronchiolar carcinoma X 

Alveolar/l~ronchiolar carcinoma, multiple x '. 

Carcinoma, metastatic, harderian gland X 

Cholangiocarcinoma, liver metastatic, ' , X

Hepatocellular carcinoma, metastatic, liver X x x X . , X 

Histiocytic sarcoma . . , . X

Nose . . ......................... Histiocytic sarcoma x 

Trachea .......................... 

.. ... . _I I ... . . / ,

SpeCid SensesSystem , 

Harderian gland 

, . 

+ . , 

Carcinoma x . . . ........... ....

Urinary System ,. 

. ( Kidney ............................. 

X . % 

. . Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma X 

Urinary bladder .......................... 

Cholangiocarcinoma, metastatic, liver X . . 

. . .... ... . . Systemic Lesions 

Multiple organs ........................... Histiocytic sarcoma. X ...... Lymphoma malignant X X X 

.- . . ... 
r

I 

! 

i

I 

I

I Carcass IDNumber 

i

I Respiratory System 1 Lung 

Alveolarhronchiolar 

Alveolarhronchiolar

!

I Alveolarhronchiolar i Carcinoma, 

Cholangiocarcinoma, 

I

i 

, Hepatocellular I Histiocytic

1 Nose 

Histiocytic sarcoma I Trachea

! 

i Special Senses System I Harderian gland I Carcinoma I 

Urinary System i

i Kidney

I Cholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma I Urinary bladder I 

Cholangiocarcinoma, metastatic, liver i

I Systemic Lesions i Multiple organs 

Histiocytic sarcoma 

i Lymphomamalignant , 

I 

i 

j

i

I

i

i

i

I

i 

4444444444444444444444444 

5666666611111~118888889999 

902561,8901356892456190134 

.......................... adenoma X 

carcinoma X 

X X X X sarcoma 

.......................... 

............................ 

......................... 

........................... , . 

......................... 

x x X x xx 

.Total 

Tissues1 

Tumors 

50 -

2 

2 

1 

1 

1. 

9 

1 

50 

1 

50 

1 

1 

50 

1 

1 

49 

1 

50 

1 

9 

I 
218 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE113 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinolir~e 

Vehicle Control 3.6 mgkg

Harderian Gland: Adenoma or Carcinoma 

Overall ratea 0/50 (0%) 1/50 (2%) 

Adjusted rateb 0.0% 2.5% 

Terminal rate' 0/34 (0%) , 1/40 (3%) -e First incidence (days) 736 (T) 

Life table testd P=O.286 EO.532 

Logistic regression testd P~O.256 P=O,532 

Cochran-hta e testd P=O.255 8 Fisher exact test P=O.500 

Liver: Hepatocellular Adenoma 

Overall rate 30/50 (60%) 22/50 (44%) 

Adjusted rate 69.6% 53.7% 

Terminal rate 21/34 (62%) 21/40 (53%) 

First incidence (days) 567 724 

Life table test Pd.002N P=0.022N 

Logistic regression test P=O.O06N Pd.067N 

Cochran-Annitage test Pd.01ON 

Fisher exact test P=0.080N 

Liver:Hepatocellular-Carcinoma 

Overall rate 13/50 (26%) 8/50 (16%) 

Adjusted rate ,31.3% 17.8% 

Terminal rate 7/34 (21%) 5/40 (13%) 

First incidence (days) 567 448 

Life table test E0.391N Pd. 124N 

Logistic regression test Pd.494N P=0.159N 

Cochran-Armitage test P=649ON 

Fisher exact test P=O.163N 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 33/50 (66%) 27/50 (54%) 

Adjusted rate 74.8% 61.1% 

Terminal rate 23/34 (68%) 23/40 (58%) 

First incidence (days) 567 448 

Life table test P=O.O2ON Pd.055N 

Logistic regression test Pd.058N EO.151N 

Cochran-Armitage test P=O.O64N 

Fisher exact test P=O.l54N 

Lung: Alveolarhronchiolar Adenoma 

Overall rate 1/50 (2%) 5/50 (10%) 

Adjusted rate 2.9% 12.5% 

Terminal rate 1/34 (3%) . 5/40 (13%) 

First incidence (days) 736 (T) 736 (T) 

Life table test pa441 P=O.143 

Logistic regression test . Pd.378 P=O.143 

Cochran-Armitage test M.377 

Fisher exact test Pd. 102 

6 mgflrg 

3/5 1 (6%) 

7.3% 

2/40 (5%) 

726 

P=O.155 

P=O.130 

P=O.125 

21/51 (41%) 

48.8% 

18/40 (45%) 

628 

P=O.O17N 

P=0.047N 

P=0.045N 

6/51 (12%) 

13.9% 

4/40 (10%) 

446 

P=O.O44N 

P=0.055N 

P=0.057N 

27/51 (53%) 

59.9% 

22/40 (55%) 

446 

Pd.053N 

E0.150N 

P=0.128N 

6/5 1 (12%) 

13.9% 

4/40 (10%) 

504 

P=O.O84 

Pd.062 

P=O.O59 

10 mg/kg 

1/50 (2%) 

2.1% 

0/40 (0%) 

638 

P=o.504 

P=O.456 

Pd.500 

18/50 (36%) 

43.7% 

17/40 (43%) 

603 

P=0.004N 

P=O.OlON 

Pd.014N 

13/50 (26%) 

29.3% 

9/40 (23%) 

603 

P=0.459N 

Pd.585 

P=0.590N 

25/50 (50%) 

56.7% 

21/40 (53%) 

603 

P=0.027N 

P=0.062N 

P=0.078N 

2/50 (4%) 

4.7% 

1/40 (3%) 

684 

Pd.540 

P=O.503 

P=O.500 
i 

'O=d I SZ 

'O=d I I S

'O=d SI I

9EL (L)

OPIE (88) 

%S'L 

OSIE (%9) 

N98P'O'd 

NZSP'O'd 

IP'O=d NI

9EL (1)

SEIP 11) (% 

%VI1 

SPIV (86) 

N98P'O'd 

NZSP'O=d 

NIIP'O=d 

9EL (LL)

SEIP (%II) 

I %VI

SPIP (86) 

OOS'O=d 

06P'O'd 

9LS'O'd 

LES 

OPIE (88) 

%VI1 

OSIS (801) 

N199'0=d 

0S9'0'd 

NI09'0=d 

LES 

OPIZ (85)

%6'9 

OSIE (%9) 

ESZ'O=d 

ZLZ'O=d 

6LZ'O'd 

SEL 

OVII (%E) 

86P 

OSK (%P) 

LPSO=d 

9'O=d 1

6

NZ09'0'd 

SEL 

8EIS (%EI) 

%E'S1 

LPl9 (%El) 

LPS'O=d 

6190" 

NZ090" 

SEL 

8ElS (%EI) 

%E'S1 

LP/9 (%El)

881'0=d 

Z8I'o" 

SSZ'O'd 

WS 

OPl9 (%SI) 

%L81 

(%91) IS18 

N16P'Wd 

N9LP'O"d 

NOEP'O'd 

9EL (L)

OPE (%SI 

%OS 

rsn (%P) 

SOs'O=d 

ZES'O=d 

ZES'O=d 

9EL (1)

0911 (%E) 

8S'Z 

os11 (%Z) 

NELS'O=d 

NSPS'O=d 

N96VO=d 

PZL 

8ElP 11) (8

%L'Z1 

8P/S (%Or) 

NWO=d 

NOIVO=d 

N69E'O=d 

9EL (L)

8ElP (811) 

%SO1 

8PlP (%SI 

Z9Z'O=d 

OOE'O=d 

9SE'O=d 

9EL (1)

OPIL (%81) 

%S'L1 

OSIL (%PI) 

NOOS'O'd 

NP8P'O=d 

NPEP'O=d 

9EL (1)

OPIZ (8s)

%OS 

osn (%PI 

NL9P'O=d 

NPIP'O=d 

N88E'O'd 

IIL 

OEIP (%EO 

IF'S1 

WS I) (%I 

POP'O=d 

9OP'O=d 

S6P'O=d 

L PI

PEIE (16) 

I %Z'I 

OSIP (%P) 

NL9S'O'd 

N99S'O'd 

N60S'O'd 

L P I

VEn (%9) 

%P'8 

OSIE (89) 

IIiI

! iiiIiI

i I1iIiIiIIIiIIiIII!11

I III

i IIiIIIiiiII

I 
220 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEID3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

All Organs:Hemangioma 

Overall rate 0/50 (0%) 3/50 (6%) 1/51 (2%) 0/50 (0%) 

Adjusted rate 0.0% 7.2% 2.5% 0.0% 

Terminal rate 0/34 (0%) 2/40 (5%) 1/40 (3%) 0/40 (0%) 

First incidence (days) - 684 736 (T)

Life table test P=0.450N P=O.144 P=O.532 

Logistic regression test P=0.480N Pd.121 Pd.532 

Cochran-Armitage test P=0.483N 

Fisher exact test P=O.121 EO.505 

All Organs:Hemangiosarcoma 

Overall rate 4/50 (8%) 3/50 (6%) 3/51 (6%) 2/50 (4%) 

Adjusted rate 10.4% 7.2% 7.2% 4.7% 

Terminal rate 2/34 (6%) 2/40 (5%) 2/40 (5%) 1/40 (3%) 

First incidence (days) 388 684 709 684 

Life table test E0.214N P=0.439N P=0.433N Pd.293N 

Logistic regression test P=0.252N P=0.505N P=0.467N P=O.382N 

Cochran-Armitage test P=0.252N 

Fisher exact test P=0.500N P=0.489N Pd.339N 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 4/50 (8%) 5/50 (10%) 4/51 (8%) 2/50 (4%) 

Adjusted rate 10.4% 12.0% 9.6% 4.7% 

Terminal rate 2/34 (6%) 4/40 (10%) 3/40 (8%) 1/40 (3%) 

First incidence (days) 388 684 709 684 

Life table test P=0.200N P=o.577 P=0.569N P=0.293N 

Logistic regression test P=0.246N P=O.497 P=0.619N Pd.382N 

Cochran-Amitage test E0.246N 

Fisher exact test P=O.500 P=0.631N Pd.339N 

All Organs: Histiocytic Sarcoma 

Overall rate 4/50 (8%) 0/50 (0%) 015 1 (0%) 1/50 (2%) 

Adjusted rate 10.7% 0.0% 0.0% 2.4% 

Terminal rate 3/34 (9%) 0/40 (0%) 0140 (0%) 0/40 (0%) - -

First incidence (days) 502 718 

Life table test P=0.041N P=0.051N P=0.147N P=0.051N

Logistic regression test P=0.049N E0.063N P=0.195N P=0.052N

Cochran-Armitage test P=O.O5 1N 

Fisher exact test P=0.059N E0.056N P=0.181N 

All Organs: Malignant Lymphoma (Not Specified) 

Overall rate 

First incidence (days) 

(25%) (18%) 9/50(18%) 10/50(2%)13/519/50

29.9% 22.5% 24.3% 

7/40(18%) 

Adjusted rate 21.2% 

Terminal rate (23%)9/405/34 (15%) 10140 (25%) 

665 736 642 (T) 490 

Life table test Pd.405N P=O.450 P=0.391N Pd.402N 

Logistic regression test 14N P=OS E0.493N P=O.324 E0.493N 

Cochran-Armitage test P=0.522N 

Fisher exact test P=0.500N P=O.337 P=0.500N 
All Organs: Benign Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Malignant Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

All Organs: Benign or Malignant Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Cochran-Armitage test 

Fisher exact test 

(T)Terminal sacrifice 

81.3% 

35/50 (70%) 

74.9% 

33/50 (66%) 

62.9% 

29/51 (57%) 

55.5% 

24/50 (48%) 

567 

26/34 (76%) 

560 

29/40 (73%) 

394 

23/40 (58%) 

603 

21/40 (53%) 

P=0.002N P=O. 135N P=0.045N P=0.005N 

P=0.008N P=0.412N P=O. 146N P=0.014N 

P=O.OlON 

P=0.415N P=0.122N P=0.021N 

63.2% 

31/50 (62%) 

47.5% 

22/50 (44%) 

55.1% 

26/51 (5 1%) 

56.0% 

28/50 (56%) 

16/34 (47%) 16/40 (40%) 19/40 (48%) 18/40 (45%) 

388 448 446 493 

P=0.220N P=0.041N P=O. 120N P=0.213N 

P=0.416N P=0.052N P=0.173N P=0.433N 

P=0.359N 

E0.054N P=O. 180N P=0.342N 

46/50 (92%) 43/50 (86%) 41/51 (80%) 39/50 (78%) 

93.9% 89.5% 82.0% 78.0% 

31/34 (91%) 35/40 (88%) 31/40 (78%) 29/40 (73%) 

388 448 394 493 

P=0.017N P=0.082N P=0.050N P=0.030N 

P=0.027N P=0.263N P=0.093N P=0.052N 

P=0.027N 

P=0.262N P=0.080N P=0.045N 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver, lung, pituitary 

gland, and thyroid gland; for other tissues, denominator is number of animals necropsied. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

Beneath the vehicle control incidence are the P values associated withthe trend test. Beneath the dosed group incidence are the P values corresponding to

pairwise comparisons between the vehicle controls and that dosed group. The life table test regards neoplasms in animals dying prior to terminal kill as being 1

(directly or indirectly) the causeof death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare 

directly the overall incidence rates. For all tests, a negative trend or a lower incidencein a dose group is indicated by N. 

e Not applicable; no neoplasms in animal group 
222 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEID4 

Summary of the Incidenceof Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquin~line~ 

VehicleControl 

60 

10 

6 

10 

34 

60 

(10) 

1(10%) 

1(10%) 

(10) 

3 (30%) 

1(10%) 

(1) 

(10)

1 (10%) 

1(10%) 

(10) 

3.6 mg/kg 

60 

10 

I 

3 

40 

60 

(9) 

2 (22%) 

1(11%) 

1(11%) 

(10)

2 (20%) 

10 mg/ks 

60 

10 

6 

4 

40 

60 

1(100%) 

(10)

1 (10%) 

(10) 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Accidental death 

Moribund 

Natural deaths 

Survivors 

Terminal sacrifice 

Animals examined microscopically 

15-Month Interim Evaluation 

Alimentary System 

Gallbladder 

Crystals 

Inflammation 

Liver 

Clear cell focus 

Eosinophilic focus 

Hyperplasia 

Infiltration cellular, lymphocyte 

Mesentery 

Inflammation, chronic active 

Fat, necrosis 

Pancreas 

Inflammation, chronic 

Acinus, atrophy 

Salivary glands 

Infiltration cellular, lymphocyte 

Stomach, forestomach 

cyst 

Stomach, glandular 

cyst 

Inflammation, subacute 

Mineralization 

Cardiovascular System 

Heart 

Cardiomyopathy 

Endocrine System 

Adrenal cortex 

Capsule, accessory adrenal cortical nodule 

6 mg/kg 

60 

9 

1 

7 

3 

40 

60 

(9)

1(11%) 

1(11%) 

(2)

1 (50%) 

2 (100%) 

(9) 

1 (11%) 

(9) 

Capsule, hyperplasia 10(100%)10(100%) 8 (89%) 10 (100%) 

Hyperplasia 

Islets, pancreatic (10) 

2 (20%) 

(10) (9)

2 (22%) 

(10) 

Pars distalis, hyperplasia 

Pituitary gland (8) 

1(11%)

(9) (9)

1(11%) 

(9)

1(11%)

1 

a Number of animals examined microscopically at @e site and the number of animals with lesion 
BS-MQnthhZtQh8&VdtkcktkWl 

Endocrine System(continued) 

Thyroid gland 

Inflammation, chronic 

Follicle, hypertrophy 

Follicular cell, hyperplasia 

Genital System 

ovw 

cyst 

Hemorrhage 

Periovarian tissue, necrosis 

Uterus 

Dilatation 

Hyperplasia, cystic, glandular 

Hematopoietic System 

Bone marrow 

Myelofibrosis 

Lymph node, mandibular 

Hyperplasia, lymphoid 

Lymph node, mesenteric 

Hyperplasia, lymphoid 

Spleen 

Hematopoietic cell proliferation 

Hyperplasia, lymphoid 

Thymus 

cyst 

Nervous System 

Brain 

Mineralization 

Respiratory System 

Lung 

Hemorrhage 

Hyperplasia, lymphoid 

Nose 

Glands, inflammation, acute 

Urinary System 

Kidney 

Infarct 

Infiltration cellular, lymphocyte 

Inflammation, chronic 

Metaplasia, osseous 

Nephropathy 

Cortex, mineralization 

(continued) 

(10) 

2 (20%) 

1 (10%) 

(10) 

4 (40%) 

1 (10%) 

1 (10%) 

(10) 

9 (90%) 

(10) 

2 (20%) 

(10)

6 (60%) 

(10) 

4 (40%) 

3(30%) 

(10)

1(10%) 

1 (10%) 

(10)

2 (20%) 

(10) 

1 (10%) 

10 (100%) 

(10) 

1(10%) 

(10)

5(50%) 

(10) 

3(30%) 

2 (20%) 

(9) 

2 (22%) 

(9)

2 (22%) 

(9) 

9 (100%) 

(9)

2 (22%) 

(9)

3(33%) 

(9)

2 (22%) 

(9) 

1(11%) 

1 (11%) 

2 (22%) 

4 (44%) 

3(33%) 

(10) 

1 (10%) 

(10)

2 (20%) 

(10) 

9 (90%) 

(10) 

3(30%) 

(10)

3(30%) 

(10) 

1 (10%) 

4 (40%) 

1 (10%) 
224 .. 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED'4 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued)' ' 

Summary of the Incidence of Nonneoplastic. Lesions in Female Mice in the 2-Year Dermal Study , ,,. . . . ,. ' . , ,. ., 

... ., 

,. . . 

. .. . . .. . . . . . , , , . , ,. . 

,, ~ 

VehicleControl , ,3.6mgkg _I, 

, I 

, 6 mgkg 10 mgfltg 

. . .. . . . L. . .I . . . .. . 1. ~ ." 

15-Month Interim Evaluation(continued) 

Systems Examined With No Lesions Observed .. .

General Body System ~, 

Integumentary System 

Musculoskeletal System ,, , . .. 

Special Senses System . .. ~ .. 

I., 

2-Year Study . . . 

Alimentary System 

Gallbladder (43) (47) (48) (45) . . 

Hyperplasia, lymphoid 1 (2%) 

Inflammation, chronic I 1 (2%)

Intestine large, colon (49) (50) (51) (49)

Congestion 1 (2%) 

Intestine large, cecum .,Congestion . . . , . . . ., . ., . . . (49) (49) (50) (49) ;... . , . , . 1' (2%) 

Inflammation, granulomatous 1 (2%) 

Perforation 1 (2%) 

Intestine small, jejunum . . I (44) (47) (51) (49) 

Amyloid deposition 1 (2%) 

Congestion .. . ' 1 (2%) 

Hyperplasia, lymphoid 1 (2%) .,. - Intestine ileum small, ' '. -' " ' (45) ' ' ' (49) ' ' ' j. (49) ' . (48)

Congestion 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 

Liver (50) - (50) (51) . . ' (50) 

Angiectasis 1 (2%) 

' 

' . 3 (6%) 1 (2%) , . 7 (14%) 5(10%) 

Congestion 1 (2%) ... . 

17(34%) . .$ 

. ., . 20 (40%) 19(37%) 22 (44%)

Clear cell focus 9 (18%) 5 (10%) 

Eosinophilic focus ' ' " '. " 

. . Hematopoietic cell proliferation ' 1 (2%) 2 (4%)

Hyperplasia, lymphoid 1 (2%) 2 (4%) 1 (2%) 

Inflammation, chronic ' 1 (2%) 1 (2%) 1 (2%) 

Mineralization ' , ' 1 (2%)

Mixed cell focus .: 3 (6%) 2 (4%) 2 (4%) 6 (12%) 

Necrosis . , 3 (6%) 

Thrombosis 

Vacuolization cytoplirhc 2 (4%) 

Centrilobular, necrosis 

Mesentery (9) 

Hyperplasia, lymphoid 

Fat, inflammation, chronic active , I Fat, necrosis 6 (67%) 

Pancreas '. ' (50) 

Hyperplasia, lymphoid 

Inflammation, chronic 3 (6%) 

Necrosis . .~ 1 (2%) . . Acinus,atrophy ' 2 (4%) 

2 (4%) 1 (2%) 

1 (2%) .. . 4 (8%) 2 (4%) 

2 (4%) 1 (2%) . . (8) (11) (8) 

1 (9%) . . 1 (13%) 

7 (88%) 9 (82%) 7 (88%) 

(50) (5 1) (50) 

1 (2%) i. 

I . 

i . .?.. 2 (4%) 3 (6%) ,' 1 (2%) 

I Acinus,hyperplasia ..,. . . ,. . I S . .. ... , . . ' .,: , ') 1 (2%) ; . 1 (2%) . ' 

Duct, cyst 1 (2%) 2 (4%) 

226, 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED4 

Summary of the Incidenceof Nonneoplastic Lesions in Female Mice in the 2-Year Dermal. Study . 

. , . . of 1,2-Di.hydro-2,2,4-trimethylquinoline(continued) , . . 

&Year Study (continued) 

Genital System 

Clitoral gland 

Inflammation, acute 

Inflammation, chronic active 

Pigmentation 

Arteriole, inflammation, chronic 

ovary

Angiectasis 

Atrophy 

cyst 

Hemorrhage 

Infiltration cellulir, lymphocyte 

Inflammation, granulomatous 

Periovarian tissue, inflammation, chronic 

active . 

"Periovarian tissue, necrosis 

uterus 

Amyloid deposition 

Angiectasis 

Dilatation 

.Hemomtiage 

Hyperplasia,cystic - . 

Inflammation, acute 

Hematopoietic System , Bone marrow 

Myelofibrosis 

Lymph node ' 

Iliac, angiectasis 

Iliac, hemorrhage 

Pancreatic, hyperplasia, lymphoid 

Lymph'node, mandibular' 

Ectasia 

Hyperplasia, lymphoid 

Infiltration cellular, plasma cell 

Lymph node, mesenteric 

Angiectasis 

Ectasia 

Hyperplasia, lymphoid 

Infiltration cellular, plasma cell 

Spleen 

Angiectasis 

Hematopoietic cell proliferation 

Hyperplasia, lymphoid 

Lymphoid follicle, atrophy 

Thymus I* '

hgiectasis , . ' 

cyst 

-Hyperplasia, lymphoid '. .

(48) 

1 (2%) 

1 (2%) 

-1 (2%) 

(50) (49) 

1 (2%) 2 (4%) 

1 (2%) 

14 (28%) 11 (22%) 

3 (6%) 1 (2%) 

1 (2%) 

1 (2%) .. . 

3 (6%) 1 (2%) 

(50) (50) 

1 (2%) 

3 (6%) 

6 (12%) - . 3(6%) 

' 1 (2%) 

42 (84%) 45. (90%) 

1 (2%) 1 (2%) 

(50) (50)

11 (22%) 16(32%) 

(8) (4)

1 (13%) 

1(25%) 

(50) ,. (49) 

1 (2%) 

1 (2%) 2 (4%) 

(47) (48)

2 (4%) 

1 (2%) 

1 (2%) 2 (4%) 

1 (2%) 

(50) (50) 

15 (30%) 11 (22%) 

4 (8%) 9 (18%) 

1 (2%) 

(45) (46) 

1 (2%) 1 (2%) ' 

2 (4%) 

(50) .: 

1 (2%) 

10(20%) 

2 (4%) 

2 (4%) 

1 (2%) .. . .' 1 (2%) 

44 (86%) 

'(51) 

1 (2%) 

1 (2%) 

(51) 

1 (2%) 

(5 1) 

1 (2%) 

13(25%) 

3 (6%) 

" 1 (2%) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

(49) 

2 (4%) 

14 (29%) 

2 (4%) 

. ., 1(2%) ' 

.. 

1 (2%) 

(50) 

8 (16%) 

1 (2%) 

47 (94%) 

(50) 

15(30%) 

8 (16%) 

(49) 

1 (2%) 

3 (6%) 

228 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLED4 

Summary of the Incidenceof Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

.. Vehicle Control 3.6 mgkg ~ 6mgkg 10 mgkg

&Year Study (continued) - .. 

. . 

Urinary System 

Kidney 

Casts protein 

Hydronephrosis 

cyst 

(50) 

, ' .'1 (2%) 

1 (2%) 

(50) (5 1) 

1 (2%) 

(50) 

1 (2%? 

1 (2%) 

Hyperplasia, lymphoid 2 (4%) 

Infiltration cellular, lymphocyte 2 (4%) 

Inflammation, acute 1 (2%) .. 

Nephropathy, chronic 

Metaplasia, osseous 

33(66%) 

1 (2%) 

32 (64%) 37 (73%)" 

1 (2%) 

36 (72%) 

Renal tubule, necrosis 

Renal tubule, degeneration, hyaline 

Renal tubule, atrophy 

Pigmentation 

Serosa, inflammation, acute 

Arteriole, inflammation, chronic 

Hyperplasia, lymphoid 

Urinary bladder 

2 (4%) 

2 (4%) 

(50) 

1 (2%) 

8 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

(5 1) 

. .. 

2 (4%) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

1 (2%) 
229 

TABLE ma 

TABLE 

TABLE 

TABLElE2a 

TABLE E2b 

TABLE 

TABLElESa 

TABLElESb 

TABLE lE36. 
230 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEE:la 

Summary of the Incidence of Neoplasms in Female SENCAR Mice in the 1-Year Dermal InitiatiodPromotion Study: 

1,2-Dihydro-2,2,4-trimethyiquinolineas an Initiatora 

Acetond 

Acetone 

Disposition Summary 

Animals initially in study 30 

Early deaths . 

Moribund 2 

Natural deaths 

Survivors 

Died last weekof study 1 

Terminal sacrifice 27 

Animals examined microscopically 30 

Alimentary System 

Liver (30)

Hepatocellular adenoma 1 (3%) 

Sarcoma stromal, metastatic, uterus 

Genital System 

Clitoral gland 

ovary

Uterus 

Sarcoma stromal 

Integumentary System 

Mammary gland 

Adenoma 

Skin (30)

Back, squamous cell carcinoma 

Back, squamous cell carcinoma, multiple 

Back, squamous cell papilloma 

Back, squamous cell papilloma, multiple 

Musculoslreletal System 

Skeletal mude 

Alveolarhronchiolar carcinoma, metastatic, 

lung 

Respiratory System 

Lung 

Alveolarhronchiolar carcinoma 

Systemic Lesions 

Multiple organsb (30)

Leukemia granulocytic 

Lymphoma malignant lymphocytic 

Acetond 

0.5 pg TPA 

30 

4 

1 

25 

30 

(30) 

1. (3%) 

(30)

1 (3%) 

2 (7%) 

1 (3%) 

1 (100%) 

(1)

1 (100%) 

50 mgkg TMQ/ 

0.5 pg TPA 

30 

5 

25 

30 

(30)

2 (7%) 

(30)

1 (3%) 

3 (10%) 

1 (3%) 

(2)

1 (50%) 

(30)

1 (3%) 

1 (3%) 

2.5 pg DMBN 

0.5 pg TPA 

30 

18 

3 

9 

30 

. (30) 

1 (3%) 

(7) 

(5) 

1 (20%) 

(1) 

1 (100%) 

(30) 

12 (40%) 

' ' 8 (27%) 

5 (17%) 

12 (40%) 
Lesionsin Female SENCAW Mice 231 

Acetone 

Acetond Acetond 

0.5 pg TIPA 

50 m@g TMQI 

0.5 pg TPA 

2.5 pg DMBN 

0.5 pg TPA 

Urinary System 

Special SensesSystem 

Nervous System 

Hematopoietic System 

General Body System 

Endocrine System 

Cardiovascular System 

§ystems Examined With No Neoplasms Observed 

Neoplasm Smary 

Total animals with metastatic neoplasms 

Total animals with malignant neoplasms 

Total animals with benign neoplasms 

Total animals with primary neoplasms' 

Total metastatic neoplasms 

Total malignant neoplasms 

Total benign neoplasms 

Total primary neoplasms 

4 

4 

6 

6 

10 

10 

21 

21 

18 

17 

39 

24 

1 

1 

' 

a 

Primary neoplasms: all neoplasms except metastaticneoplasms 

Number of animals with any tissue examined microscopically 

Number of animals examinedmicros'opically at the site and the number of animals with neoplasm 
232 1,2-Dihydro-2,2,4-trimethylq&noline,NTP TR 456 

TABLEE:lb. 

Summary of the Incidenceof Neopla&s in Female SENCAR Mice in the 1-Year Dermal InitiatiodPromotion Study: 

1,2-Dihydro-2,2,4-trimethylquinolineas a Promotera . . , 

.. .. . .. I 

2.5 pg DMBN 2.5 pg DMBN . 2.5pg DMBN 2.5 pg DMBN 2.5pg DMBN 

Acetone 5mgkg.TMQ 

, 

' " 10mgkgTMQ . 25mgkgTMQ 0.5pgTPA . . .. -. - .. .. . 

Animals initially in study 

Disposition Summary 

30 30 30 30 30 

Early deaths 

Moribund 2 1 2 ,. 1 18 

Natural deaths 1 1 2 ' . 3 

Survivors 

Terminal sacrifice 

Died last week of study 

26 

1 

28 28 

1 

26 , , .9 

Animalsexaminedmicroscopically ' 30 30 30 30 30 

.. * I . .- ., . .. ~ . _ 

Alimentary System 

Liver (30) (30) (30) (30) (30) 

Hemangiosarcoma ' . 1 (3%) . , Sarcoma, metastatic, uncertain primary site 1 (3%) 

Sarcoma stromal, metastatic, uterus 1 (3%) 

Salivary glands , (1) 

Genital System 

ovary (2) (1) (1) (7) 

Sarcoma, metastatic, uncertain primary site I (100%)

.uterus. ./_" . ~ . (1.1 (5) 

Sarcoma stromal 1 (20%) 

Integumentary System 

Mammary gland (1) (1) 

Adenoacanthoma 1 (100%) 

Adenocarcinoma 1(100%) 

Adenoma 1 (100%) 

Skin (30) (30) (30) (30) (30) 

Squamous cell carcinoma 1 (3%) 

Back, squamous cell carcinoma 1 (3%) 12 (40%) 

Back, squamous cell carcinoma, multiple 8 (27%) 

Back, squamous cell papilloma 5 (17%) 

Back, squamous cell papilloma, multiple 12 (40%) 

Respiratory System 

Lung (1)

Alveolar/bronchiolar carcinoma . 1(100%) 

Systemic Lesions 

Multiple organsb (30) (30) (30) (30) (30)

Lymphoma malignant lymphocytic 2 (7%) 

Lymphoma malignant mixed 1 (3%) 

Lymphoma malignant undifferentiated cell 1 (3%) 
I 

I 

IZ 

IZ 

81 

LI 

6E 

pz 

c 

E 

E 

E 
234 1,2-Dihydro-2,2,4-tðylquinoline, NTP TR 456 

TABLEElc 

Summary,of the Incidenceof Neoplasms in Female SENCAR Mice in the 1-Year Dermd'InitiatiodPromotionStudy: " 

. . . . 1,2-Dihydro-2,2,4-trimethylquinolinePromotion Controla .. , 

. ..: . Acetone/ Acetone/ ;. . .Acetone/ Acetone ,. ;r; ,. , , . . ' 

' . , Acetone 5mgikgTMQ . 10mgikgTMQ 25 mgikg TMQ 

,. t l Disposition Summary 

Animals initially in . . study 30 30 30 30 

Early deaths I 

Moribund 

Natural deaths 

Survivors 

Died last week of study 

Terminal sacrifice 

An@ls epmined @croscopically .." 

. . . . 

: , I

Alimentary System 

Liver (30) (30) (30) (30) 

Hepatocellul& adenoma 1 (3%) 1 (3%) 

Sarcoma stromal, metastatic, uterus ' 1 (3%)

Stomach,forestomach . (1) 

Squamous cell papilloma 1 (100%) 

Genital System 

ovary (1) 

Sarcoma stromal, metastatic, uterus 1 (100%) 

Uterus (1) 

Sarcoma stromal 1 (100%) 

Urinary .System 

Kidney (1)

Sarcoma stromal, metastatic, uterus 

Systems Examined With No Neoplasms Observed 

Cardiovascular System 

Endocrine System 

General Body System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Special Senses System 
-235 

Acetone/ Acetone/ Acetone/ Acetone 

Acetone 5 mgkg mQ 1Q mgkg TMQ 25 mgkg TMQ 

Neoplasm . _ . Summary . -.. ~otalanimals with primary neoplasmsb 1 1 

Total primary neoplasms 1 1 

Total animals with benign neoplasms 1 

Total benign neoplasms 1 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

. . 

a Number of animals examined microscopically at the site and the numberof animals with neoplasm 

Primary neoplasms: all neoplasms except metastatic neoplasms . 

.. . 
236 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEE:2a 

Statistical Analysis of Primary Neoplasms in Female SENCAR Mice in the 1-Year Dermal InitiatiodPromotion Study: 

1,2-Dihydro-2,2,4-trimethylquinolineas an Initiator 

. . 

Liver: Hepatocellular Adenoma 

Overall rate" 

Adjusted rateb 

Terminal rate' 

First incidence (days) 

Life table testd 

Logistic regression testd 

Fisher exact testd 

Skin: Squamous Cell Papilloma . .. 

Overall rate 

Adjustedrate. I .. .

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Fisher exacttest 

Skin: Squamous Cell Papillomaor Squamous Cell Carcinoma 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Fisher exact test 

All Organs: Benign Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Fisher exact test 

All Organs Malignant Neoplasms 

Overall rate 

Adjusted rate 

Terminal rate 

First incidence (days) 

Life table test 

Logistic regression test 

Fisher exact test 

.. 

.. 

Acetonel 

0.5 pgTPA 

1/30 (3%) 

3.6% 

on5 (0%) 

313 

3/30 (10%) 

11.3% 

2/25 (8%) 

313 

3/30 (10%) 

11.3% 

2/25 (8%) 

313 

3/30 (10%) 

11.3% 

2/25 (8%) 

313 

2/30 (7%) 

7.3% 

On5 (0%) 

313 

50 mgkg TMQI 

0.5 pg TPA 

. . 

2/30 (7%) 

8.0% 

2/25 (8%) 

372 (T) 

M.496 

M.501 

Pd.500 

4/30 (13%) 

16.0% 

4/25 (1 6%) 

372 (T) 

M.497 

M.489 

pa.500 

5/30 (17%) 

20.0% 

5/25 (20%) 

372 (T) 

M.352 

M.339 

Pd.353 

6/30 (20%) 

24.0% 

6/25 (24%) 

372 (T) 

Pd.236 

Pd.221 

Pd.236 

4/30 (13%) 

14.1% 

1/25 (4%) 

213 

M.330 

M.332 

M.335 
.. . . 

. ,' 

, , 

.. ... . . ' , >.! . ... 

€90'0-

S90'O=d 

9LOO=d 

€12 

SUL (%SZ) 

IS'S€ 

OUOI (%€E) 

.. . , ., 
238 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

TABLEE2b 

Statisticd Analysisof Primary Neoplasms inFemale SENCAR Micein the 1-Year Dermal InitiatiodPromotion Study: 

1,2-Dihydlro-2,2,4-trimethylquinolineas a Promoter 

2.5 pg DMBN 2.5 pg DMBN 2.5 pg DMBN 2.5 pg DMBN 

Acetone 5 mgkg TMQ 10 mgkg TMQ 25 mgkg TMQ 

All Organs: Malignant Lymphoma (Lymphocytic, Mixed, or Undifferentiated Cell Type) 

Overall rate' 2/30 (7%) 0/30 (0%) 1/30 (3%) 1/30 (3%) 

Adjusted rateb 7.1% 0.0% 3.3% 3.7% 

Terminal rate' 1/27 (4%) 0/28 (0%) 0128 (0%) 1/27 (4%) -

e First incidence (days) 339 240 372 (T)

Life table testd P=0.303N P=0.228N P=0.492N P=0.500N 

Logistic regression testd P=0.335N P=0.261N P=0.572N P=0.501N 

cochran-~rmita e testd Pd.410N 8 Fisher exact test E0.246N P=0.500N P=0.500N 

All Organ$: Malignant NeoplaSms 

Overall rate 5/30 (ii%) 2/30 (7%) 3/30 (10%) 2/30 (7%) 

Adjusted rate 16.7% 6.7% 10.2% 7.0% 

Terminal rate 2/27 (7%) 0/28 (0%) 2/28 (7%) 1/27 (4%) 

First incidence (days) 212 346 240 242 

Life table tesl. Pd.137N P=0.205N P=0.348N E0.227N 

Logistic regression test P=0.098N P=0.230N P=0.409N P=0.143N 

Cochran-Armitage test P=O. 170N 

Fisher exact test P=0.212N P=0.353N P=0.212N 

All Organs: Benign or Malignant Neoplasms 

Overall rate 5/30 (17%) 2/30 (7%) 3/30 (10%) 2/30 (7%) 

Adjusted rate 16.7% 6.7% 10.2% 7.0% 

Terminal rate 2/27 (7%) 0/28 (0%) 2/28 (7%) 1127 (4%) 

First incidence (days) 212 346 240 242 

Life table test P=0.137N P=0.205N P=0.348N P=0.227N 

Logistic regression test P=0.098N P=0.230N P=0.409N P=0.143N 

Cochran-Armitage test P=O. 170N 

Fisher exact test P=0.212N P=0.353N P=O.212N 

(T)Terminal sacrifice

' Number of neoplasm-bearing animaldnumber of animals examined. Denominator is number of animals necropsied. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

' Beneath the2:5 pg DMBA/Acetone group incidence are theP values associated with the trend test. Beneath the promoter test groups incidences are the 

P values corresponding to painvise comparisons between the 2.5 pg DMBA/Acetone group and those groups. The life table test regards neoplasms in animals

dying prior to terminalkill as being (directly or indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The CochranArmitage and Fisher exact tests compare directly the overall incidence rates. For all tests, a negative trend or a lower incidence ina dose group is indicated by

N: e Not applicable;no neoplasms in animal group 
I 

Acetone/ Acetone/ Acetone/ Acetone/ 

Acetone 5 mgkg TMQ 1Q mgkg TMQ 25 mgkg TMQ 

I All Organs: Benign Neoplasms 

Overall ratea 2/30 (7%) 1/30 (3%) 1/30 (3%) 0/30 (0%) 1 Adjusted rateb 7.1% 3.3% 3.4% 0.0%

i Terminal rate' 2/28 (7%) 0/29 (0%) 1/29 (3%) 0/27 (0%) -

e First incidence (days) 372 (T) 327 372 (T) 

Life table testd P=0.12ON P=0.492N F'=0.488N P=0.246N 

Logistic regression testd P=0.115N P=0.469N P=0.488N P=0.246N 

Cochran-Annita e testd P=0.128N

Fisher exact test % P=O.5OON P=0.500N P=0.246N 

AM Organs: Benign or Malignant Neoplasms 

Overall rate 2/30 (7%) 2/30 (7%) 1/30 (3%) 1/30 (3%) 

Adjusted rate 7.1% 6.7% 3.4% 3.6% 

Terminal rate 2/28 (7%) 1/29 (3%) 1/29(3%) 0/27 (0%) 

First incidence (days) 372 (T) 327 372 (T) 369 

Life table test P=0.295N P=0.684N P=0.488N P=0.508N 

Logistic regression test P=0.276N P=0.691N P=0.488N P=0.515N 

Cochran-Annitage test P=0.287N 

Fisher exact test P4.694N P=0.500N P=OSOON 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/numberof animals examined. Denominatoris number of animals necropsied. 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality ' Observed incidence at terminal kill 

Beneath the Acetone/Acetone incidence are theP values associated with the trend test. Beneath the promotion control groups incidences areP values the 

corresponding to pairwise comparisons between the Acetone/Acetone group and those groups. The life table test regards neoplasms in animals dying prior to 

terminal kill as being (directlyor indirectly) the causeof death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and 

Fisher exact tests compare directly the overall incidence rates. For allatests, negative trend or a lower incidence ina dose group is indicatedby N. e Not applicable;no neoplasms in animal group 
'240 1,2-Dihydro-2,2,4-trimethylq1&oline, NTP TR456 

TABLE133a " ,, . - . ., , . * ./ 1 . ... Summany of theIncidence of NonneoplasticLesionsinFemaleSENCAR Mice. ' . ' . , 

' 

inthe 1-Year Dermal Initiatioflromotion Study: 1,2-Dihydro-2,2;~-trimetliylq1iinolineas"anInitiatora . ' I' 

....... ' 

... 

., 

'' 

'Acetone 

.Acetone/ ~ 

. ' . ' Acetone/

'. '' 0.5 pg TPA 

'+ ' .SOmgkg TMQ/ . . 

' I . 0.5 pg TPA . . 0.5 pg TPA 

2.5 pg DMBN 

._ . . . . . I . ., . .i..-~ . ~ ..., ............. ,I ... , I . 

Early deaths 

Animals initially.in study 

Disposition Summary 

Terminal sacrifice ', 

Died lastweek of study 

Natural death ' 

Moribund 

Survivors ' , 

2 

30 

27 

1 .. 

.. 

1 

4 

30 

25 

" 

5 

30 

25 , 

... 

' 

. 

30 

18 

3 

.( 9 . . 

' ' 

. . 

Animals examined microscopically ..... 30 

.... ". 

30 

................ 

30 

., ., 

30 , .. 

Dilatation 

Gallbladder , 

Alimentary System . 

Periportal, fibrosis 

Pigmentation 

Necrosis 

Inflammation, chronic 

Hematopoietic cell proliferation 

Eosinophilic focus 

Developmental malformation 

Congestion 

Angiectasis 

Liver ...... 

.. . . . . . 

Mesentery 

cyst 

. (30) ... 

7 (23%) 

1 (3%) 

1 (3%) 

-. .. 

1 (3%) 

2 (7%) 

.... 

, .. , . 

(30). .........

1 (3%) 

12 (40%) 

-. . 

- . ' 

... 

1 (3%) ". '. 

. 2 (7%) 

(30)-

(1) 

2(7%) 

1 (3%) 

1 (100%) 

.... 

12 (40%) 

I 3 ..(lo%) 

2 (7%) 

.? (7%). I. 

. .(30) 

1 (3%) . ' : 

.. .. . 

4(13%) 

4 (13%) 

17 (57%) 

-. I . 

... .': . .1 .(3%) 

,. 

(1) 

1 (loo%):, :_ * 

. 

, 

..Cyst

ovary 

Genital System 

. 

Hyperplasia, cystic 

Hematocyst 

Cyst, multiple 

Uterus 

.... . 

(1) 

. . 

1 (100%) 

.. 

(2)

1 ,(50%)................... 

1 (100%) 

1 (50%) 

(1) 

j. 1 .(loo%) 

(1) 

...... 

(1) 

. : _,-. c 

6 (86%) 

(7) ' ? 

... 

1(14%) 

(5) 

4 (80%) 

Lymph node 

HematopoieticSystem 

Hematopoietic cell proliferation 

Axillary, infiltration cellular, plasma cell 

Axillary, hyperplasia, lymphoid 

Spleen (1) 

1 (100%) 

(1). 

1 (100%) 

1 (100%) 

(2) 

(1) 

(1) 

7(100%) 

1 (100%) 

1 (100%) 

(7) 

a Number of animals examined microscopically at the site and the number of animalswith lesion 
AC~UQRR~ Acetone/ 50 mgkg TMQ/ 2.5 pg DMBM 

AceU~me 0.5 pg TPA 0.5 pg TPA 0.5 pg TBA 

Skin 

Integumentary System 

Back, inflammation, chronic 

Back, acanthosis 

(30) (30) 

19 (63%) 

30 (100%) 

(30) 

15 (50%) 

30 (100%) 

(30) 

10 (33%) 

29 (97%) .. . 

Back, ulcer 

Back, inflammation, chronic active 

4 (13%) 

5 (17%) 

4 (13%) 

4 (13%) 

7 (23%) 

15 (50%) 

Back, ulcer, multiple 1 (3%) 

Inguinal, acanthosis 1 (3%) 1 (3%) 

Subcutaneous tissue, edema 

Inguinal, inflammation, chronic 2 (7%) 1 (3%) 2 (7%) 

1 (3%) 

2 (7%) 

Respiratory System 

Lung 

Infiltration cellular, lymphocyte 

~~~~ ~~ _____~ _____~ _____~ ~~ 

Kidney 

Urinary System 

Papilla, necrosis 

Inflammation, chronic active 

(1) 

1 (100%) 

1 (100%) 

(1) .. 

Systems Examined With No iksions Obsemed 

Cardiovascular System 

Endocrine System . ..I

... 

General Body System 

Musculoskeletal System . -. 

Nervous System ,. .. 

Special Senses System :' 

. ,._ . 

. . 
242 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

. , TABLEE3b 

Summary of the Incidenceof Nonneoplastic Lesions in Female SENCAR Mice 

in the 1-Year Dermal InitiatiodPromotion Study: 1,2-Dihydro-2,2,4-trimethylquinolineas a Promotera . . 

.. 

Early deaths 

Animals initially in study 

Disposition Summary 

,: 30 .' . 30 30 30 30 

Moribund . 2 1 18 

Natural deaths 2 3 

Survivors 

Died last week ofstudy 1 

Terminal sacrifice 28 26 9 

Animals examined microscopically 30 30 30 

Alimentary System 

Gallbladder 

Dilatation 

Liver (30) (30) ' Congestion 1 (3%) 1 (3%) 

Fatty change 

Hematopoietic cell proliferation 5 (17%) 17 (57%) 

Hepatodiaphragmatic nodule 

Hyperplasia 1 (3%) 

- Inflammation 1 (3%) 

Inflammation, acute ' 1 (3%) 1 (3%)

Inflammation, chronic 3 (10%) ' 3 (10%) 4 (13%) .' 

Necrosis 3 (10%) 3 (10%) 4 (13%) 

Pigmentation 4 (13%) 2 (7%) 1 (3%) 

Centrilobular, atrophy . 1 (3%) 

Kupffer cell, hyperplasia 

Portal, fibrosis 

Mesentery (1) 

cyst 1 (100%)' ' ' 

Genital System 

ovary (2) (1) (7)

Abscess 1 (50%) 1 

cyst ' 1 (50%) 1 (100%) 4 .(86%) 

Cyst, multiple 1 (14%) 

Uterus (1) (5)

Hemorrhage 1 (100%) 

Hyperplasia, cystic 4 (80%) 

Hematopoietic System 

Lymph node (2) (1)

Axillary, hyperplasia, lymphoid . 1 (100%) 

Axillary, infiltration cellular, plasma cell , 1 (100%) 

Pancreatic, cyst 

Pancreatic, hyperplasia 

Spleen (2) (2) (7)

Hematopoietic cell proliferation 1 (50%) 1 (50%) 7 (100%) 

i 

a Number of animals examined microscopicdly at the site and the number of animals with lesion 
Lesions inFemale SENCAR Mice '243 

Integumentary System 

Skin (30) (30) (30)

3 (10%) 29(97%) . , Back, acanthosis 1 (3%) 

Back, inflammation, chronic 2 (7%) 10 (33%) " 

Back, inflammation, chronic active 15 (50%) 

Back, ulcer 1 (3%) 7 (23%) ' ' 

Back, ulcer, multiple 1 (3%) .. 

Inguinal, acanthosis 1 (3%) 1 (3%) 

Inguinal, inflammation, chronic 1 (3%) 2(7%) 

Subcutaneous tissue, edema 1 (3%) 

. ,. 

Lung 

Respiratory System 

(1) 

Infiltration cellular, lymphocyte 

(1) 

1 (100%) 

,. 

Kidney 

Urinary System 

(1) 

Renal tubule, degeneration, hyaline 1 (100%) 

, 

Special Senses System 

Nervous System 

Musculoskeletal System 

General Body System 

Endocrine System 

Cardiovascular System 

Systems Examined With No Lesions Observed 

.. ,. 

. . 

8. ' 
244 1,2-Dihydro-2,2,4-trimgthylquinoline,NTP TR 456 ,. .. . 1 

TABLEE3c 

Summary of the Incidenceof Nonneoplastic Lesions in Female SENCAR Mice * . 

in the 1-Year Dermal InitiatiodPromotion Study: 1,2-Dihydro-2,2,4-trimethylquinoline'PromotionControla ,. 

_I 

Acetone/ Acetone/ Acetone/ 

, 

Acetone 5 mgkg TMQ 25 mgkg TMQ 

Disposition Summary 

Animals initially in study 30 30 30 30 

Early deaths 

Moribund 2 1 

Natural deaths 1 1 2 

Survivors 

Died last week of study 1 

Terminal sacrifice 27 29 29 27 

Animals examined microscopically 30 30 , .30 30 ., 

Alimentary System 

Liver (30) (30) (30) 

Angiectasis 1 (3%) 

Congestion 1 (3%) 2 (7%) 1 (3%) ,I , 

Eosinophilic focus 1 (3%) 

Hematopoietic cell proliferation 7 (23%) 4 (13%) 6 (20%) 6 (20%) 

. 

Inflammation, chronic 2 ' ' (7%) 2 (7%) 1 (3%) . . . Necrosis 2 (7%) 1 (3%) 

-Pigmentation 2 (7%) 

Periportal, fibrosis 1 (3%) 

Salivary glands (1) 

Interlobular, edema 1 (100%) 

Genital System 

ovary 

cyst 

Hematocyst 

HematopoieticSystem 

Spleen (1) (1) 

Hematopoietic cell proliferation 1 (100%) 1 (100%) 

Integumentary System 

(30) 

Back, acanthosis 

Back, inflammation, chronic 3 (10%) 1 (3%) 

Back, inflammation, chronic active 1 (3%) 

Inguinal, inflammation, chronic 2 (7) 1 (3%) 3 (10%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 

Skin (30) (30) (30) 

1 (3%) 3 (10%) 1 (3%) 
Acetone 

Acetone/ . Acetone/ 

5 mglag TMQ 

Acetone/ 

10mgkg TMQ 

Acetone/ 

25 mgkg TMQ 

UUninmy system 

Kidney 

Renal tubule, degeneration, hyaline 

Papilla, necrosis 

Cortex, mineralization 

Nephropathy 

Inflammation, chronic active 

cyst 

(1) 

1(100%) 

1(100%) 

1 (100%) 

(1) 

1(100%) 

1(100%) 

(1) 

1 (100%) 

1 (100%) 
246 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 
207 

§ALMONELLA MUTAGEMCITY TESTPROTOCOL ................................................. 208 

C~SE HAMSTER OVARYCELLCYTOGENETICS PROTOCOLS .................................... 208 

MQUSEPE~EIERAL BLQOD WI[ICROWUCLEUSTESTPROTOCOL .................................... 209 

~SULTS................................................................................ 258 

TABLEFl Mnntagenicltydn,2-Dihydro-2,2,0-tri~eUItnynq~i~0nine in Salmonella typhimurium ........ 251

TABLE IF^ II~~-UUC~O~ OP sister CB~KO~~M Exchangesin ~hinnese ~anmsuerovary @ems

by n,2-DiItnypnrO-2,2,0-t~~et~ynqUi~O~ine .......................................... 252

TABLEF3 IInnd~cUi~nn off Ch~~nrm~sc~~m~al AOPe~~ations inChinese Wamster Ovary Cells

by n,2-D~ypnlrO-2,2,0-u~~euhy~~~i~O~i~e .......................................... 250

TABLE F0 Frequencyoff MicrOnucnei inn Mouse Peripheral Blood Eryth~~cytes 

FO~~OW'hg TUVahM!lUt ~th n,2-DihyPPrO-2,2,0-t~~~~Itny~~~~nOni~e

byDermananIExposureff0rn3~ee&rs............................................... 255 
,248 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

GENETIC TOXICOLOGY 

SALMONELLAMUTAGENICITY TESTPROTOCOL ' .. 

Testing was performed as reported by Zeiger'et al. (1987). 1,2-Dihydro-2,2,4-trimethylquinolinewas sent to 

the laboratory as a coded aliquot from Radian Corporation (Austin, TX). It was incubated with the Salmonellu . . ' 

typhimurium tester strains'(TA98, TA100, TA1535, and TA1537) either in buffer or S9 riix (metabolic, . ' , 

activation enzymes and cofactors from Aroclor 1254-induced male Sprague-Dawley rat Or'Syrian hamster 

liver) for 20 minutes at 37" C. Top agar supplemented with l-histidineand d-biotin was added, and the . ' ' ' 

contents of the tubes were mixed and pouredonto the surfaces of minimal glucose agar plates. Histidine-. ' 

. . independent mutant colonies &sing.on these'plates were.'counted following incubation for 2 days at 37" C. .' 

All tests were repeated using'either the same or different S9 concentrations. . . 

Each trial'consisted of triplicate plates of concurrenfpositive'and negative'controls.hd at least five doses of 

1,2-dihydro-2,2,4-trimethylquinoline.The high dose was.limited by toxicity. The precipitation of 1,2-dihydro2,2,4-trimethylquinoline noted at higher Concenkations was not a doserlimiting factor. 'Alltrials were repeated. I , . , .. 

In this assay, a positive response is defined as a reproducible, dosekelated increase in histidine-independent 

(revertant) colonies in any one straidactivation combination. An equivocal response is defined as an increase 

in revertants that is not dose related, not reproducible,or is of insufficient magnitude to support a' determination 

of mutagenicity. A negative responseis obtained when no increase in revertant colonies is observed following 

chemical treatment. There is no minimum percentage or fold increase required for a chemical to be judged 

positive or weakly positive. . , .. . I 

. .. 

. . 

CHINESE HAMSTER OVARY CELL CYTOGENETICS PROTOCOLS. . ' . . 

.. 

Testing was performedas reported.by .Galloway et al. (1987). 1,2-Dihydro-2,2,4.-trimethylquinoline was sent 

to the.laboratory as a coded aliquot by Radian Corporation,It was tested in culturedChinese hamster ovary 

(CHO) cells for induction of sister,chromatid.exchanges(SCEs) and chromosomal,aberrations (Abs), both in . , 

the presence and absence,of Aroclor 1254-induced male Sprague-Dawley rat liver S9 and ,cofactormix. . :, 

Cultures were handled under gold lights to,prevent photolysis of.bromodeoxyuridine-substitutedDNA. Each 

test consisted of concurrent solvent and positivecontrols and of at least three doses of 1,2-dihydro-2,2,4-

trimethylquinoline; the high dose was limited by toxicity. A single flask per dose was used, and tests yielding 

equivocal or positive results, were repeated.~ 9 . . . 

. . 

Sister Chromatid Eichange Test: In the'SCE test without S9, CHO cells were incubated for *at least 26 hours 

with 1,2-dihydro-2,2,4-trimethylquinolinein'McCoy's 5A medium. Bromodeoxyundine '(BrdU) was added 2 

hours after culture iriitiation. After'26 hours, the medium containing1,2-dihydro-2,2,4-trimethylquinolinewas 

removed and replaced withfresh medium plus BrdU and Colcemid, and incubation was continued.for 2 hours. 

Cells were'then h&ested by mitotic shake-off, fixed, and stined with Hoechst 33258 and Giemsa. Inthe SCE 

test withS9, cells'were incubated with1,2-dihydro-2,2,4-trimethylquinoline,serum-free medium, andS9 for. 

2 hours. The medium was then removed and replaced with medium containing serum &d.BrdU and no ' : 

1,2-dihydro-2,2,4-trimeihylquinolineand incubation proceeded for 9additional'26 hours, with Colcemid 

present'for the final 2 hours. Harvesting and staining were the she as for cells treated without S9. All slides 

were scored blind and thosefrom a single test were read by the same person. Fifty second-division metaphase 

cells were scored for frequency of SCEskell from each dose level. Because significant chemical-induced cell 

cycle delay was'seen, incubation'time was.lengthened to'ensure a'sufficient number of scorable (second-' ' .

division metaphase . . .. . j cells. . . 

. . 

. .. , . ,_ . . .I ,, . , 

. . , .. . ,. . . , -. . ~, _. 

. . . . > ,, . I . . ., .. 

.. 
Statistical analyses were conducted on the slopes of the dose-response curves and the individual dose points 

(Galloway et al., 1987). An SCE frequency 20% abovethe concurrent solvent control value was chosen as a 

statistically conservative positive response. The probability of this level of difference occurring by chance at 

one dose point is less than0.01; the probability for such a chance occurrence at twodose points is less than 

0.001. An increase of 20% or greater at any single dose was considered weak evidence ofactivity; increases at 

two or more doses resulted ina determination that the trial was positive. A statistically significant trend 

(P<O.O5) inthe absence of any responses reaching 20%above background led to a call of equivocal. 

Chromosomai Aberrations Test: In the Abs test withoutS9, cells were incubated in McCoy’s 5A medium 

with 1,2-dihydro-2,2,4-trimethylquinolinefor approximately 21 hours; Colcemid was added and incubation 

continued for 2 hours. The cells were then harvested by mitotic shake-off, fixed, and stained with Giemsa. For 

the Abs test with S9, cells were treated with1,2-dihydro-2,2,4-trimethylquinolineand S9 for 2 hours, after 

which the treatment medium was removed and the cells were incubated for 8.5 hours in fresh medium, with 

Colcemid present for the final 2 hours. Cells were harvested in thesame manner as for the treatment without 

S9. The harvest time for the Abs test was basedon the cell cycle information obtained in the SCE test; if cell 

cycle delay was anticipated, the incubation period was extended. 

Cells were selected for scoring on the basis of good morphology and completenessof karyotype 

(21 f 2 chromosomes). All slides were scored blind and those froma single test were read by the same person. 

One hundred first-division metaphasecells were scored at each dose level. Classes of aberrations included 

simple (breaks and terminaldeletions), complex (rearrangements and translocations), and other (pulverized 

cells, despiralized chromosomes, and cells containing 10 or more’aberrations). 

Chromosomal aberration data are presentedas percentage of cells with aberrations. To arrive at a statistical 

call for a trial, analyses were conducted on both the dose response curve and individual dose points. For a

single trial, a statistically significant (PsO.05) difference for one dose point anda significant trend (PsO.015) 

were considered weak evidencefor a positive response; significant differencesfor two or more doses indicated 

the trial was positive. A positive trend test in the absence of a statistically significant increase at any one dose 

resulted in an equivocal call (Galloway et al., 1987). Ultimately, the trial calls were based on a consideration 

of the statistical analysesas well as the biological information available to the reviewers. 

MOUSE PEElwnPHEML BLOOD MnccRONuclLEUrs TEST PROTOccOlL 

A detailed discussion of this assayis presented in MacGregoret al. (1990). Peripheral blood samples were 

obtained from male and female B6C3F, mice at the end of the 13-week toxicity study. Smears were 

immediately prepared and fixed in absolute methanol, stained with a chromatin-specific fluorescent dye 

mixture of Hoechst 33258/pyroninY (MacGregor et al., 1983), and coded. Slides were scanned at 63Ox or 

1,000~magnification using a semi-automated image analysis systemto determine the frequency of micronuclei 

in 2,000 polychromatic erythrocytes (PCEs) and10,000normochromatic erythrocytes (NCEs)per animal per 

dose group. The criteria of Schmid (1976) were used to define micronuclei, with the additional requirement 

that the micronuclei exhibit the characteristic fluorescent emissionsof DNA (blue with 360 nm and orange 

with 540 nm UV illumination); the minimum size limit was approximately one-twentieth the diameter of the 

NCE cell. 

Log transformation of the NCE data, testing for normality by the Shapiro-Wilk test, and testing for 

heterogeneity of variance byCochran’s test were performed before statistical analyses.The frequency of 

micronucleated cells among NCEs was analyzed by analysis of variance using the SAS GLM procedure.The 

NCE data for each dose group were compared with the concurrent solvent control using a Student’s t-test. The 

frequency of micronucleated cells among PCEs was analyzed by the Cochran-Armitage trend test, and 
250 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

individual dose groups were compared to the concurrent solvent control by Kastenbaum-Bowman's binomial 

, test. The percentage of PCEs among t0tal.erythrocyte.s was analyzedby an analysis of variance on ranks 

(classed by sex), and individual dose groups were compared with the concurrent solvent control using a t-test 

on ranks. .. .... ..... . . 

.. .. , . 

,. 

., .. .. 

RESULTS ,, . ., . ,. . 

1,2-Dihydro-2,2,4-trime~ylquinoline (1 to 333 @plate) was not mutagenic in Sulmonellu typhimurium strain 

'TA98, TAl00,' TA1535, or TA1537, with or without induced rat or hamster liver S9 (Zeiger et al., 1987; Table 

Fl). 1,2-Dihydro-2,2,4-trimethylquinolinewas shown to induce SCEs (Table F2) in cultured CHO cells in the 

absence of S9 only. All concentrations of 1,2-dihydro-2,2,4-trimethylquinolinetested for induction of SCEs in 

the absence of S9 produced marked celltycle delay; culture times were lengthened in orderto ensure sufficient 

metaphase cells for analysis. In the presence of S9, occasional cell cycle delay was noted at higher doses, and 

culture times were adjusted accordingly.1,2-Dihydro-2,2,4-trimethylquinolineinduced a moderate increase in 

SCEs at a single dose level in the first trial conducted withS9; this increase was not reproduced ineither of two 

subsequent trials and the overall responsein the presence of S9 was considered to be negative. 1,2-Dihydro2,2,4-trimethylquinolinedid not induce Abs in cultured CHO cells, with or without S9 (Table F3). Cell cycle , . delay was again noted inthe absence of S9, and culture times were extended. 

:Noincreases in the frequencies of micronucleated erythrocytes were notedin peripheral blood samples 

obtained from male and female mice treated topically with1,2-dihydro-2,2,4-trimethylquinolinefor 13 weeks 

(Table F4). 

. .

I 

. . 

...... , ._ .. .. .... . . , 

....... .. 
WevehnWplakb 

Strain Dose -$9 +lQ% hamster S9 +no./, rat $9 

(&plate) Trial1 Trial2 n Trial 2 ~~dn Trial 2 

TA1QO 0 180f 8.5 146 f 5.8 137f 6.9 90 f 3.1 155f 9.7 117f 6.5 

33 

10 

3.3 

1 

165 2 6.1 

147* 4.6 

156 * 6.7 

165 2 5.8 

158* 3.2 

161f 0.6 

133f 5.5 

144A 2.6 

147f 5.3 

I52 f 8.1 

145f 10.8 

86f2.1 

92 f 2.6 

90 6.6 

' 

144+: 5.8 

152t 5.2 

131f 1.7 

1096.3 

96 f 5.8 

108* 5.5 

100 '164 f 11.2' Toxic 149f 10.5 116f 6.2 145 f 3.4 98 f 5.0 

220 Toxic Toxic 

333 Toxic Toxic 

Positive controld 

Trial summary 

1,619f 82.0 

Negative 

1,389* 67.7 

Negative 

1,070f 32.9 

Negative 

1,711f 29.1 

Negative Negative 

1,466f 39.8 1,657 f 33.1 

Negative 

TA1535 0 142 2.3 43 * 5.3 8 f 1.2 12f 0.7 10f 1.2 10f 0.7 

3.3 

1 

15 * 3.1 

172 1.7 

39 f 5.5 

36 f 2.6 

11f 1.5 9 f 0.7 10f 0.7 11f 2.3 

10 162 1.0 46 ~t1.2 12f 1.5 '9 f2.2 10f 2.2 102 2.3 

33 16f 1.0 60 f 11.5 11f 2.0 10f 2.6 12f0.6 9 f 1.7 

100 15 f 0.7' Toxic 9 f 1.0 10i2.2 9 f 1.8 10 f 1.3 

220 Toxic Toxic 

333 Toxic Toxic 

Trial summary Negative Negative Negative Negative Negative Negative 

Positive control 1,432 f 50.4 1,551f 20.7 78 f 8.2 140f 14.3 83 f 5.0 159f 12.6 

TA1537 0 5 * 1.2 10f 2.7 7 f 0.3 9 f0.9 9 f 1.9 8 f 0.0 

33 

10 

3.3 

1 

100 2 * 1.0' 

6 * 1.0 

8 * 0.6 

5 * 0.3 

6 f 1.5 

Toxic 

9 f 1.7 

12f 0.9 

11f 2.2 

13f 2.4 

6 f 2.6 

8 * 2.0 

6 * 1.2 

10f 2.6 

8 f 0.9 

12f 2.6 

15f 1.9 

14f 2.0 

7 f 3.3 

7 f 1.5 

7 f 1.9 

5 f 2.2 

10* 1.2 

8 rt 1.2 

10f 3.4 

11f 3.2 

220 Toxic 6 k 0.5' 

333 Toxic Toxic 

Positive control 

Trial summary 

145 i:20.0 

Negative 

512 f 96.3 

Negative Negative 

88 f 9.7 

Negative 

137f 1.5 

Negative 

119f 14.1 

Negative 

176f 7.8 

TA98 

3.3 

1 

0 

21 * 0.7 

20 f 3.1 

16 i: 1.3 

17* 1.2 

17 * 1.8 

16f 2.6 

35 f 4.4 

33 f 2.6 

27 f 1.5 

30 f 2.2 

. 26 f 1.8 

27 f 2.3 

35 f4.1 

26 f 1.7 

33 

10 

18 * 2.8 

16 f 3.3 

18f 2.6 

21 f 3.2 

34 f.0.9 

25 f 2.2 

34 f 6.0 

28 f 5.3 

31 f 1.5 

32 f 2.7 

30 f 3.5 

34 f 2.4 

100 16f 3.2' 16f 2.0' 23 f 2.9 24 i2.1 27 f 4.9 32 f 3.5 

220 Toxic Toxic 

333 Toxic Toxic 

Positive control 

Trial summary 

1,595f 44.7 

Negative 

1,568f49.8 

Negative 

703 f 15.1 

Negative 

1,002f 11.3 

Negative 

898 f 82.2 

Negative 

1.064 +. 35.2 

Negative 

a Study performed atEG&G Mason Research Institute; the detailed protocol and thesedata are presented in Zeigerer al. (1987). 

Revertants are presented as mean* standard error from three plates. ' Slightoxicity 

The positive controls in the absence of metabolic activation were sodium azide (TA1535and TAlOO), 9-aminoacridine (TA1537), and 

4-nitro-o-phenylenediamine(TA98). The positive control for metabolic activation with all strainswas 2-aminoanthracene. 
252 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456

TABLEF2 

Induction of Sister Chromatid Exchanges in Chinese .. Hamster Ovary Cells 

by 1,2-Dihydro-2,2,4-trimethylq~inoline~ 

No. of scw Relative Change 

DoseTotalChromo- No. of Chromo- SCEd Hrs of SCEd 

Compound (pg/d) ' CellssomesSC&some . . 

. ' Cell 

(%I 

in BrdUChromosomeb 

-s9 

Trial 1 

Summary: Positive 

Dimethylsulfoxide 26.3 10.6 

Mitomycin-C 0.0015 50 1,047 800 0.76 16.0 26.3 51.52' 

0.0100 5 105 237 2.25 47.4 26.3 347.60 

1,2-Dihydro-2,2,4-trimethylquinoline 

50 1,049 529 0.50 

4.3' 

Dimethylsulfoxide 26.0 10.9 

1,2-Dihydro-2,2,4-dmethylquinoline

50 1.05 9.61 

26.0 0.48* 1,044 . 

18.31 33.2' 12.9 0.61 646 1,047 50 96.10e 

320.00 0 

Pd.001 

40 50 1,050 765 , 15.3 

0.60 34.2'19.55 , 12.7 

70 0 34.2' 

~4.003~ 

Trial 2 

Summary: Positive 

50 50 1.050633 ' 

60 50 1,048 680 34.2'28.67* 13.6 , 0.64 

Dimethylsulfoxide 50 1,048 403 0.38 8.1 ' 26.0 

Mitomycin-C 0.0015 50 1,050 702 0.66 14.0 26.0 73.86

0.0100 5 105 

1,2-Dihydro-2,2,4-trimethylquinoline 

233 2.21 46.6 26.0 477.06 

40 50 1,050 507 0.48 10.1 , 34.3'25.57*

34.3' 20.44* 9.7 50 0.46 50 1,045 484 

70 0 34.3' 

P4.001 I -. 

. . +s9 

Trial 1 

Summary: Weakpositive 

50 1,045 545 0.52 

Cyclophosphamide 0.8 25 526 502 0.95 20.1 ' , 26.0 82.99 

2.0 5 104 265 2.54 53.0 26.0 388.58 

1 494 0.47 . 26.0-9.88 9.9 

50, 32.00 

60 50 1,050 576 0.54 11.5 

656 0.62 13.1 

0.72 
253 

No. of §@Ed Relative Change 

.Dose ,Total !-.chromo-.. No. of Chromo- SCEd Wrs of §@Ed 

Compound &g/m~) 

, 

, Cells' ,,, somes SClEs Cell BrdU Chromosome 

4 

, 

! insome 

(%I 

. ... .. 

+s9 (continued)

Trial2 

Summary: Negative 

Dimethylsulfoxide 26.0 16.7 0.79 834 LO48 50

6013.8 0.65 50 

837 0.65 32.8'. 0.8016.7 

3.60 . 17.332.8'

Cyclophosphamide 26.0 0.94 19.9 , 0.1,047 993 

2.0 55.4 26.0228.37 I 2.61 5 .. 

1,2-Dihydro-2,2,4-tmethylquinoline 

. 

-17.23

: . 

100 , 501,0488640.82 

, 12oe 0 ' ' 

P=O.O28 

Trial3 

Summary: Negative 

Dimethylsulfoxide 

Cyclophosphamide 0.4 50 1,050868 0.82 

2.0 ' 5 105 

17.4 26.3 5 1.36 

328.98 2462.3 2.3449.2

1,2-Dihydro-2,2,4-tmethylquinoline 

, 60 5o > 1.050 , 571 0.54 11.4 ' 26.3 -0.43 

>:.. 80 , , 50 . < !1,047 . 593 , 

0.56 11.9 26.3 3.70 

' 100 . 50 1,049 ' " 588 0.56 11.8 26.3 2.63

12oe 0 

Pd.255 

* Positive response(220% increase over solvent control) a The study was performed at Litton Bionetics, Inc.A detailed descriptionof the protocol is presented in Gallowayet al. (1987). SCE=sister 

chromatid exchange; BrdU=bromodeoxyuridine. 

SCEdchromosome in treated cells versus SCEs/chromosome in solvent control cells 

Because 1,2-dihydro-2,2,4-tmethylquinolineinduced a delay in ihe cell division cycle, harvest time was extended to maximize the 

proportion of second-division cells available for analysis. 

Significance of SCEs/chromosome testedby the linear redemion Fend test versus log of the dose 

e Precipitate formed atthis and higher doses 

. 

19.18 50 

106 277 

26.0 1,046 689 

80 501,045 

568 0.54 11.4 26.3 

. . 
254 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEF3 

Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells 

by 1,2-Dihydro-2,2,4-trimethylquinolinea 

-s9 +s9 

Dose Total No. of Abd Cells with Dose Total No. of Abd Cells with

(yg/mL) Cells Abs Cell Abs (%) (pg/mL) Cells Abs Cell Abs (%) 

Harvest time: 23.3 hoursb Harvest time: 10.5 hours 

Summary: Negative Summary: Negative 

Dimethylsulfoxide Dimethylsulfoxide 

100 . 5 0.05 3.0 100 2 0.02 2.0 

Mitomycin-C Cyclophosphamide 

0.0350 100 19 0.19 17.0 5 100 19 0.19 10.0 

0.0625 25 12 0.48 36.0 20 25 13 0.52 40.0 

1,2-Dihydro-2,2,4-trimethylquinoline 1,2-Dihydro-2,2,4-trimethylquinoline 

5 5.0

1 0.01 1.o 

70 100 3.0 3 0.03 70 100 0.05 

80 100 3.0 3 0.03 80 100 

5 0.05 4.0 100" 100 5 0.05 5.0 

120 0 

100 100 

120 0 

Pd.3" P=O.215 

* Positive (P<O.O5) a The study was performed at Litton Bionetics, Inc.A detailed protocol is presented in Gallowayet al. (1987). Abs=aberrations. 

Because of significant chemical-induced cell cycle delay, incubation time prior to addition of Clcemid was lengthened to provide sufficient 

metaphase cells at harvest. " Precipitate formed atthis and higher doses 

Significance of percent cells with aberrations tested by the linear regression trend test versus of the logdose 
i 

OSOO=d 

9P'I T SI'O 

51'1 T SI'O 

82'7 T 91'0 

SO1 T SI'O 

8L'O T 01'0

11.1 11'OT 

EZP'O=d 

z91 T PZO 

IL'I T PZO 

OL'I T IZ'O 

061 T LI'O 

OS1 T SZ'O 

zs1 T PI'O 

1190" 

ZZ'I T OE'O 

56'0 T IO0 

SI'Z 7 ZE'O 

6E'I T 8S0 

8L'O T 9E'O 

OS'I T EE'O 

,909O=d 

9SI T SP'O 

WI T EE'O 

60'2 T LSO 

ZL'I T 9Z'O 

891 T 9SO 

08'1 T IE'O 

S 

S 

E 

P 

S 

01 

S 

S 

S 

S 

S 

01 

OS 

oz 

01 

S 

S'Z 

0 

OS 

oz 

01 

S 

SZ 

0 

SEZ 
256 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

258 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

of 1,2-Dihydro-2,2,4-trimethylquinolinea 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Dermal Study 

TABLEG1 

Vehicle 

Control 

Untreated 

Control - 5mgikg 20 mgikg 50 mag 100 mgikgmgikg 200

Male 

n 10 10 10 10 10 10 10 

Necropsy bodywt 345 f 6 341 f 5 353 f 5 343 f 8 343 f 5 335 f 4 328 f 7* 

Brain 

Relative 

Absolute' 

Relative . 

Absolute 

Relative 

'Absolute 

Relative 

Absolute . 

Relative 

Absolute 

Relative 

'Absolute 

Relative. 

Absolute 

Heart 

R. Kidney 

Liver 

Lung 

R. Testis 

Thymus 

1.10 f 0.04 

0.382 f 0.018 

4.31 f 0.07 

1.486 f 0.018 

4.27 f 0.14 

1.473f 0.045 

41.34f4.12 

14.261f 1.455 

4.59 f 0.12 

1.582 f 0.030 

3.09 f 0.05 

1.065f 0.021 

5.77 f 0.10 

1.989 f 0.011 

1.13 f 0.05 

0.384 f 0.018 

4.08 f0.28 

1.394f 0.101 

4.65 f 0.19 

1.584 f 0.072 

41.80 f 4.30 

14.203 f 1.471 

4.51 fO.11 

1.535 f 0.038 

3.04 f 0.07 

1.037f 0.026 

5.81 f 0.06 

1.978f 0.015 

5.66 f 0.05 

2.000 f 0.019 

4.26 f 0.04 

1.504f 0.019 

4.10 f 0.14 

1.449f 0.056 

42.97 f 0.57 

15.194f 0.329 

4.19 f0.09* 

1.482f 0.040 

3.00 f 0.04 

1.061 f 0.024 

0:342 f 0.011 

0.97 f 0.02 

2.041 f 0.0651.986 f 0.016 

5.96 f 0.135.80 f0.08 

1.045f 0.0321.069 f 0,031 

3.05 f 0.05 3.12 f 0.08 

' 1.504f 0.048 1.489 f 0.035 

4.39 f0.074.35 f 0.10 

15.169 f 0.525 15.736 f 0.515 

44.21 f0.81 45.85 f 1.29 

. 1.434f 0.0691.436 f 0.054 

4.18 fO.18 4.19 fO.15 

1.457 f 0.0331.362 f 0.106 

4.26 f 0.09 ,3.97 f 0.31 

0.324 f 0.015*0.331 f 0.01 1* 

0.95 f 0.04* 0.96 f 0.03 1.01f'O.04 

-0.336f 0.013* 

4.32 f 0.03 

1.444 ~t0.013 

4.23 f 0.16 

1.415 f0.052 

47.91 f 1.17* 

16.038 i0.435 

4.64 f 0.12 

1.550f 0.034 

3.15 f 0.06 

1.0550.026 

5.85 f0.06 

1.958* 0.012 

4.78 f 0.08 

1.567 f 0.041 

3.26 f 0.07 

1.070f 0.029 

6.00 f 0.07 

1.964 f 0.024 

17.217 rto.311** 

1.364f 0.044 

52.59 f 1.12** 

4.16 f Oil0 

4.48 f 0.06 

1.469 f 0.033 

0.94 f 0.05* 

0.308 f0.019** 

... . .. ., . 
Orgnn weight Ananysw 258 

Female 

n 10 10 10 10 10 10 10 

Necropsy body wt 190f 2 194f 3 197 f 2 200 f 2** 195f 3 198 f I* 194f 2 

Brain 

Absolute ~ 1.818 f 0.016 1.825 f0.012 1.848 f 0.021 1.843 f 0.025 1.816 f 0.023 1.849f 0.0101.814 f 0.010 

Relative 9.57 f 0.12 9.41 ~t0.11 9.39 f 0.09 9.22 f 0.1 1* 9.32 f 0.08 9.36 f 0.079.37 f 0.08 

Heart 

Absolute 0.716 f 0.012 0.728 f 0.026 0,723 f 0.023 0.723 f0.026 0.736 f 0.017 0.779 f 0.020 0.714 f 0.020 

Relative 3.77 f 0.05 3.75 f 0.12 3.67 f 0.09 3.61 f0.1 1 3.77 f 0.05 3.94 f 0.1 1 3.68 f 0.09 

R. Kidney 

Absolute 0.864 f 0.017 0.878 f 0.021 0.875 f 0.019 0.877 f 0.023 0.928 f0.032 0.974 f 0.016**0.886 f 0.014 

Relative 4.550.08 4.52 f 0.10 4.44 f0.06 4.38 f 0.09 4.76 f 0.14 4.93 f 0.07*4.57 f 0.06 

Liver 

Absolute 7.574 f 0.258 7.832 f 0,166 7.612 f 0.131 7.679 f 0.096 7.995 f 0.231 8.249 f 0.163* 8.032 f 0.143* 

Relative 39.83 f 1.21 40.32 f 0.55 38.64 f 0.45 38.420.62 40.97 f 0.81 41.73 f 0.83 41.44 f 0.57 

Lung 

Absolute 1.104 f 0.060 1.036f 0.030 1.058 f 0.032 1.018 f 0.028 1.054f 0.037 1.081f 0.0291.012 f 0.029 

Relative 5.82 f0.34 5.33 f 0.10 5.37 f 0.13 5.09 f 0.13* 5.42 f 0.21 5.47 f 0.145.22 f 0.15 

Absolute

ovary 

0.060f 0.004 0.057 f 0.004 0.064 f 0.005 0.057 f 0.003 0.064f 0.002 0.072 f 0.004 0.063 f 0.004 

Relative 0.32 f 0.02 0.30 f 0.02 0.33 f 0.02 0.29 f 0.02 0.33 f 0.01 0.36 f 0.020.32 f 0.02 

Thymus 

Absolute 0.268 f 0.012 0.269 f 0.01 1 0.262 f 0.013 0.265 f 0.010 0.486 f 0.215 0.292 f 0.0130.257 f0.009 

Relative 1.41 f 0.06 1.38 f0.06 1.33 f 0.06 1.33f 0.05 2.60f 1.22 1.48f 0.071.33 f 0.05 

Uterus 

Absolute 0.803 f 0.094 0.644f 0.068 0.662 f 0.092 0.778 f 0.079 0.562 f 0.040 0.699 f 0.061 0.719 f 0.073 

Relative 4.20 f 0.47 3.32 f 0.34 3.34 f 0.43 3.90 f 0.41 2.88 f0.20 3.53 f 0.30 3.70 f 0.36 

* Significantly different(PsO.05)from the vehicle control group by Williams’ or Dunnett’s test 

** PiO.01 

a Organ weights and body weights are given in grams; organ-weight-to-body-weight ratios are givenas mg organ weight/g body weight (mean f standard error). 
260 1,2-Dihydro-2,2,4-trimethylquinoline,Nl" TR 456 

TABLEG2 

Organ Weights andOrgan-Weight-to-Body-WeightRatios for Rats at the 15-Month Interim Evaluation 

in the 2-Year DermalStudy of 1,2-Dihydro-2,2,4-trimethylq~inoline~ ,I 

Vehicle Control 36 mgntg 60 mgntg 100 mgntg

Male 

n 10 10 10 10 

Necropsy body wt 495 f 11 463 f9* 457 f 10* 434 f lo** 

R. Kidney 

Absolute 1.944f 0.042 2.1 10f 0.056 2.167 f 0.039* 2.275 f 0.106** 

Relative 3.93 f 0.09 4.55 f 0.08** 4.75 f 0.07** 5.23 f 0.19** 

Liver 

Absolute 22.001 f 0.552 22.534 f 0.391 21.965 f 0.641 25.808 f 0.886** 

Relative 44.58 f 1.34 48.70 f0.68* 48.17 f 1.40 59.54 f 1.72** 

Spleen 

Absolute 1.160 f 0.059b 1.221f 0.140 2.108 f 0.582 1.283 f0.084 

Relative 2.29 f0.09b 2.63 f 0.28 4.66 f 1.31 2.94 f 0.16 

Female 

n 10 10 10 10 

Necropsy body wt 305 f 4 287 f 7 3oof4 278 f 11* 

R. Kidney 

Absolute 1.233 f 0.018 1.247f 0.043 1.266 f 0.030 1.252& 0.035 

Relative 4.05 f 0.07 4.35 f 0.15 4.23 f 0.09 4.54 f 0.13** 

Liver , Absolute 12.1 12f 0.294 12.525 f 0.392 12.913f 0.288 11.430 f 0.486 

Relative 39.79 f 1.05 43.73 f 1.40* 43.14 f 0.89 41.24 & 0.94 

Spleen 

Absolute 0.670 f 0.048 0.570 f 0.033 0.653 f 0.046 0.562f 0.021 

Relative 2.20 f0.17 1.99 f 0.13 2.20 f 0.18 2.06 f 0.13 

* Significantly different(PsO.05) from the vehicle control group by Williams' or Dunnett's test 

** PsO.01 

a Organ weights and body weights are given in grams; organ-weight-to-body-weight ratios are given as mg organ weight/g body weight (mean fstandard error).

n=9 
“e 

n 10 10 10 10 10 10 10 

Necropsy body wt 33.7 f 0.7 33.3 f 0.8 32.5 f 0.3 33.7 f 0.5 34.5 f 0.6 33.2 f 0.6 33.1 f 0.5 

Brain 

Absolute 0.465 t 0.007 0.469 f 0.005 0.461 f 0.005 0.464 f 0.004 0.458 f 0.003 0.463 f 0.003 0.461 f 0.005 

Relative 13.85 f 0.39 14.14f 0.30 14.19 fO.14 13.79 f 0.25 13.31 f 0.28 13.98f 0.22 13.96f 0.26 

Heart 

Absolute 0.171 f 0.005 0.165 f 0.005 0.167 f 0.006 0.166 f 0.008 0.170 f 0.007 0.162 f 0.002 0.160 f 0.005 

Relative 5.09 f 0.19 4.96 f 0.15 5.14 f 0.16 4.93 f 0.23 4.93 f 0.17 4.89 f 0.08 4.84 f 0.16 

Relative 

Absolute 

R. Kidney 

10.58 t 0.36 

0.355 t 0.008 

10.15 f 0.27 

0.337 * 0.008 

10.68f 0.17 

0.347 f 0.007 

10.16f 0.29 

0.342 f 0.008 

10.28 * 0.18 

0.354 f 0.003 

10.56 f 0.19 

0.350 f 0.006 

10.86 f 0.19 

0.359 f 0.007 

Absolute 

Liver 

1.631f 0.040 1.627 f 0.053 1.611 f 0.058 1.741f 0.083 1.769 * 0.058 1.617 f 0.045 1.649f 0.047 

Relative 48.57 f 1.56 48.89 f 1.27 49.53 f 1.52 5 1.58 f 2.22 51.30 f 1.51 48.73 f 1.15 49.89 f 1.44 

Absolute 

Lung 

0.182 2 0.006 0.175 f 0.007 0.178 f 0.007 0.179 f O.OOSb 0.184 f 0.003 0.173 f 0.005 0.183 f 0.008 

Relative 5.42 f 0.22 5.26 f 0.17 5.47 f 0.19 5.29 f 0.19b 5.34 f 0.12 5.23 f 0.17 5.53 f 0.24 

R. Testis 

Relative 

Absolute 

3.43 * 0.08 

0.115 t 0.003 

3.5 1 f0.07 

0.117 f 0.003 

3.55 f 0.03 

0.115 f 0.002 

3.49 f0.07 

0.118 *0.003 

3.38 f 0.12 

0.116 f 0.003 

3.28 f 0.31 

0.108 f 0.010 

3.57 f 0.09 

0.118 f 0.002 

Thymus 

Absolute 0.039 f 0.002 0.038 f 0.003 0.036 f 0.002 0.044f 0.003 0.041 f 0.002 0.033 f 0.001 0.040 f 0.003 

Relative 1.14 t 0.06 1.12f 0.07 1.11 f 0.05 1.32f 0.09 1.19 f 0.05 1.00 f 0.04 1.20 f 0.10 
262 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEG3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) 

Vehicle Untreated 

Control Control 2.5 mgkg 5 mgkg 

Female 

n 10 10 9 10 10 ' 10 10 

Necropsy body wt 29.1 f 0.7 27.8 f 0.5 30.2 f0.5 28.4 f 0.6 28.7 f0.5 30.1 f 0.8 30.0 f 0.5 

Brain 

Absolute 0.477 f 0.006 0.482 f0.004 0.486 f 0.008 0.474 f 0.003 0.477 f0.005 0.476 f 0.008 0.487 f 0.004 

Relative 16.47f 0.32 17.36 f 0.30 16.07f0.23 16.76 f 0.35 16.64 f 0.28 15.90f 0.48 16.26 f 0.25 

Heart 

Absolute 0.143 f 0.005b 0.144 f 0.005 0.151 f 0.006 ' 0.137 2 0.003 0.145 f 0.005 0.152 f0.006 0,149f 0.005 

Relative 4.94 f 0.20b 5.19 f 0.20 5.00 f 0.19 4.83 f0.07 5.05 f0.19 5.07 f0.23 4.97 f0.16

R. Kidney 

Absolute 0.216 f 0.022 0.23 1 f 0.005 0.248 f 0.0070.228 f 0.007 0.240 f 0.005 0.236 f 0.007 0.242 f0.005 

Relative 7.38 f 0.75 8.32 f 0.24 8.20 f0.24 8.02 f 0.12 8.36 f 0.16 7.86 f 0.21 8.07 f 0.15

Liver 

Absolute 1.473 f0.056 1.449f 0.067 1.618fO.053 1.37220.051 1.484f 0.051 1.555 f 0.064 1.544 20.038 

Relative 50.81 f 1.94 51.97 f 1.93 53.46 f 1.39 48.23 f 1.09 51.58 f 1.29 51.56 f 1.20 5 1.45 f 0.99 

Lung 

Absolute 0.183 f 0.008 0.179 f 0.006 0.197 f0.0080.176 * 0.007 0.176 f0.007 0.179 f0.007 0.182 f0.004 

Relative 6.31 f0.28 6.47 f 0.30 6.5 1 f 0.246.21 f 0.26 6.14 f 0.25 5.96 f0.21 6.08 f 0.17 

ovaryAbsolute 0.015 f 0.001 0.014 rt 0.001 0.013 f 0.001 0.014 f 0.001 0.014 f 0.001 0.013 f 0.001 0.014 f 0.001 ' 

Relative 0.50 f 0.04 0.49 f 0.03 0.42 f 0.03 . 0.49 * 0.02 0.47 f0.03 0.42 f 0.03 0.48 f0.05 

Thymus 

Absolute 0.052 f0.003 0.05 1f 0.002 0.055 f 0.003 0.051 f 0.002 0.052 f 0.001 0.053 f 0.002 0,055 f0.002 

Relative 1.78 f 0.07 1.84 f 0.05 1.82f0.10.81 f 0.07 1.80f 0.07 1.76 f 0.04 1.82f 0.07

UteNs 

Absolute 0.150 f 0.013 0.150 f0.013 0.180 f 0.015 0.129 f 0.008 0.141 f0.01 1 0.161 f0.011 0.159 f0.014 . 

Relative 5.19 f 0.47 5.39 f0.44 5.93 f 0.46 4.55 ~t0.25 4.91 f0.37 5.33 f0.28 5.32 f 0.48 

.. , ,_ ,. .. - . ~ ., 

a Organ weights and body weightsare given ingrams; organ-weightho-body-weightratios are given as mg organ weightlg body weight (meanf standard enor). . . , . n=9 . .. I

- , , . . .I 
263 

n 10 10 10 10 

Necropsy body wt 50.8 f0.9 50.7 i1.1 50.3 f 0.6 50.5 A 0.7 

R. Kidney 

Absolute 0.555 f 0.014 0.533 f 0.016 0.525 i0.009 0.500 * 0.017* 

Relative 10.96f 0.35 10.52i0.28 10.47 * 0.27 9.91 f 0.32 

Liver 

Absolute 3.809 f 0.387 4.050 f 0.430 2.932 f 0.074 3.310 f 0.385 

Relative 76.20 A 9.13 80.41 i9.24 58.41 A 1.62 65.70 f 8.04 

Spleen 

Absolute 0.104 i0.008 0.112 f 0.007 0.097 i0.005 0.105 A 0.013 

Relative 2.07 20.20 2.21 i0.14 1.94 f 0.11 2.10 f 0.28 

Female 

n 10 10 9 10 

Necropsy body wt 52.5 f 1.6 52.7 f 1.5 54.3 f 2.3 52.7 A 1.9 

R. Kidney 

Absolute 0.321 f0.008 0.332 f0.006 0.338 A 0.013 0.319 f 0.014 

Relative 6.15 2 0.17 6.33 i0.13 6.27 f 0.24 6.07 i0.19 

Liver 

Absolute 2.250 f 0.089 2.216 A 0.085 2.403 f 0.156 2.121 A 0.090 

Relative 42.98 f 1.46 42.05 f 1.21 44.26 f 1.89 40.30~ 1.11 .. 

Spleen 

Relative 

Absolute 

2.03 i0.22 

0.105 f 0.008 

2.12 f 0.10 

0.111 fO.004 

2.13 ~0.24 

0.115 A 0.014 

2.02 * 0.10 

0.106 f 0.006 

. .. 

* Significantly different(PiO.05) from the vehicle control group by Williams’ or Dunnett’s test a Organ weights and body weightsare given ingrams; organ-weight-to-body-weight ratiosare given as mg organ weightlg body weight (meanA standard error). 
264 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 
265 
266 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEH1 

Hematology and Clinical ChemistryData for Rats in the 13-Week Dermal Study 

of 1,2-Dihydro-2,2,4-trimethylquinolinea 

Vehicle Untreated 

Control Control 5 mgkg 20 mg/kg 50 mgkg 100 mgkg 200 mgkg 

Male 

Hematology 

n 9 9 8 8 10 9 8 

Hematocrit (%) 

_. 45.2 f 0.7 45.7 f 0.6 44.7 f 0.5 45.0 f 0.5 44.7 f 0.9 43.7 f 1.6 45.8 f 0.8 

Hemoglobin(g/dL) 

16.9 f 0.5 17.6 f0.7 18.0f 0.6 17.0 f 0.6 16.3f 0.6 17.0 f 1.0 17.2 f 0.7 

Erythrocytes (lo6/&) 

9.48 f 0.18 9.62 f 0.14 9.29 f 0.10 9.36 f 0.1 1 9.35 f 0.19 9.15 f 0.32 9.43 f 0.1 1 

Reticuloiytes (lo6/&) 

0.17 f 0.01 0.15 f 0.02 0.18 f 0.02 0.13 fO.02 0.13 f 0.01 0.15 f 0.03 0.14 f 0.01 

Mean cell volume(a) . . 47.8 f 0.4 47.6 f 0.2 48.3 f 0.4 48.1 f 0.3 47.9 f0.2 47.9 f 0.4 48.6 f 0.4 

Mean cell hemoglobin @g) 

17.8 f 0.6 18.2 rt 0.5 19.3f 0.5 18.2f 0.5 17.4f 0.4 18.4 f 0.5 18.2 f 0.6 

Mean cell hemoglobin concentration(g/dL) 

37.4 f 1.4 38.4 rt 1.2 40.1 f 0.9 37.9 f 1.0 36.4 f 1.0 38.6 f 1.1 37.5 f 1.0 

Platelets (lo3/&) 

693.8 f48.7 747.2 f 33.5 791.1 f29.1 750.5 f 34.8 716.3 f 15.9 680.0 f 53.2 722.8 f 14.6 

Leukocytes (lo3/&) 

8.31f 0.46 7.97 f0.69 7.63 f 0.42 8.46 f 0.55 7.66 f 0.20 6.84 ~t0.62 7.34 f 0.41 

Segmented neutrophils (lo3/&) . 1.08 & 0.20 1.28 f 0.21 1.07 0.13 1.38f0.27 1.01 f 0.21 0.92 f0.12 1.27f 0.14

Lymphocytes (Id/&) 

6.94 f 0.36 6.42 ~t0.60 6.25 f 0.37 6.82 f 0.38 6.48 f 0.28 5.80 f 0.58* 5.81 f 0.36 

Atypical lymphocytes(lo3/&) 

. 0.06 f 0.03 0.04 f 0.02 0.01 f 0.oi 0.02 f 0.02 0.01 f 0.01 0.02 f 0.01 0.02 f0.01 

Monocytes(lo3/&) 

I . 

0.17 f0.03 0.19 f 0.03 0.29 f 0.07 0.21 f 0.04 0.12 f 0.02 0.06 f 0.02 0.15 f 0.05 

Eosinoplfils(lo3/&) 

0.07 f 0.02 0.04 f 0.01 0.01 f 0.01 0.02 f 0.02 0.05 f 0.02 0.04 f 0.02 0.08 f 0.03 

Clinical Chemistry 

n 9 9 10 10 10 10 10 

Total bilirubin (mg/dL) 

11.7 f 3.3b 11.6 f 1.9 7.0 f 2.2' 13.9 f 2.9 14.9f 2.9d 9.7 f 2.5e 11.4f 2.3b 

Direct bilirubin (mg/dL) 

8.86 f 3.05b 6.22 f 1.01 7.80 f 1.85' 10.00 f 3.47 4.67 f 0.99 10.50f 3.43e 6.86 f 1.79b 

Alanine aminotransferase(IUL) 

60f 3 76f.8 66f5 59f3 59f3 57f2 57f3 

Alkaline phosphatase(IU) 

225 f 6€ 235 f 9 221 f 6 238 f 5 226 f 8 232 f 6 233 f 8 

Asp$tr: aminotransferase (NIL) 

169f 16 192f 20 162f 22 140f 13d 194f 12d 185f 19 150f 22* 

Sorbitol dehydrogenase(IUL) 

3fl 6f2 5f le 8f 1' 2f le 5f lb 4+ lb 

y-Glutanlyltransferase(IUL) 

3.9 f0.9f 3.0 f 0.0 3.7 f 0.7 3.4 f 0.4 3.0 f 0.0 3.0 f 0.0 3.7 f 0.7 
Hematology 

n 8 9 9 10 10 9 9 

Hematocrit (%) 

46.0 f 0.6 45.5 f 0.9 44.9 f 0.4 46.1 f 0.5 45.7 f 0.6 44.8 f 0.8 46.4 f 0.6 

Hemoglobin (g/dL) 

17.10.5 17.9f 0.7 16.5 f 0.3 17.4 f 0.5 17.4f 0.5 17.1 f 0.6 18.4f0.4 

Erythrocytes ( lo6/&) 

8.78 f 0.09 8.87 f 0.15 8.64 f 0.04 8.76 f 0.06 8.61 fO.16 8.66 f 0.14 8.83f 0.08 

Reticulocytes (lo6/&) 

0.11 fO.01 0.12 f 0.01 0.11 f 0.02 0.10 f 0.01 0.13 f 0.02 0.14 f 0.02 0.14 f 0.02 

Mean cell volume(&) 

52.3 f 0.4 51.2f 0.2* 51.8 f 0.3 52.6 f 0.2 53.1 f 0.4 51.7 f 0.3 52.4 f 0.4 

Mean cell hemoglobin (pg) 

19.5 f 0.5 20.1 f 0.6 19.1f 0.3 19.8 f 0.4 20.2 f 0.5 19.8f 0.4 20.8 f 0.5 

Mean cell hemoglobin concentration(“I.,) - . 

37.2 f 0.8 39.2 f 1.0 36.8 f 0.5 37.7 f 0.8 38.1 f 1.1 38.2 f 0.8 39.7 f 1.1 

Platelets (lo3/&) 

759.0 f 21.7 

Leukocytes (103/~) 

732.1 f 37.8 776.3 f 37.6 714.3 f 13.3 699.9 f 30.0* 711.825.lg 737.9 f 11.8 

5.84 f 0.30 5.08 f0.48* 5.53 f 0.41 5.32 f 0.38 5.67 f 0.45 5.76 f 0.58 5.70 f 0.45 

Segmented neutrophils (lo3/&) 

0.95 f 0.16 0.80 f 0.13 0.97 f0.14 0.89 f 0.09 0.83 f 0.12 0.87 f0.20 0.99 f 0.17 

Lymphocytes (lo3/&) 

4.68 f 0.20 4.17 A 0.43 4.36 f 0.34 4.33 f 0.36 4.64 f 0.41 4.74 f0.47 4.58 f 0.45 

Atypical lymphocytes (lo3/&) 

0.05 f 0.02 0.01 f 0.01 0.02 f0.01 0.01 f0.01 0.03 f 0.02 0.01 f 0.01 0.01 f 0.01 

Monocytes ( lo3/&) 

0.1 1 f 0.02 0.08 f 0.03 0.15 f0.05 0.06 f0.01 0.13 f 0.04 0.11 fO.03 0.1 1 f 0.04 

Eosinophils (103/~) 

0.06 f 0.02 0.03 f 0.01 0.03 f 0.03 0.04 f 0.01 0.02 f 0.01 0.02 f0.02 0.01 f0.01 

Clinical Chemistry 

n 10 10 10 10 10 10 10 

Total bilirubin (mg/dL) 

21.9 f 8.lg 

Direct bilirubin (mg/dL) 

12.9f 1.8b 8.6 f4.0‘ 16.5 f 4.Og 21.2 f 5.0d 11.2 f 3.8e 13.4f 2.3 

5.75 f 1.418 8.43 f 1.59b 8.40 f 1.81‘ 6.001.6@ 7.78 f 1.39d 10.67 f 1.82e 7.70 f 1.45 

Alanine aminotransferase(IUL) 

52 f 2d 

Alkaline phosphatase(IUL) 

54f3 62 f gd 50 f qd 54f2 53f5 47 f 2 

224 f 11 238 f 7 202 f 5 224 f 7 242 +. 10 221 f6 234 f 8 

Aspartate aminotransferase(IUL) 

162f. 16d 159f 18d 175 f 158 143rt 16d 165f 16 166 24d 143f 13 

Sorbitol dehydrogenase(IUL) 

1 foe 6f2d 3f lb 4f2h 5 f2d 7f3C 5fl 

y-Glutamyltransferase (IUL) 

3.5 f 0.5 3.4 f0.4 3.0 f 0.0 3.0 f 0.0 3.7 f 0.7 3.0 f 0.0 5.0 f 1.2 

* Significantly different (PxO.05) from the vehicle control group by Dum’s or Shirley’s test a Mean f standard error. Statistical tests were performed on unrounded data. 

n=7 ‘ n=5 n=9 e n=6 n=10 n=8 n=4 
268 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEH2 

Hematology and Clinical Chemistry Datafor Mice in the 13-Week Dermal Study 

of 1,2-Dilhydro-2,2,4-trimethylquinolinea 

Vehicle Untreated 

Control Control 2.5 mgkg 5 mgkg 10 mgkg 20 mgkg 50 mgkg 

Male 

n 5 5 5 5 5 - 5 5 

Hematology 

Hematocrit (%) 

43.6 f 0.9 42.9 f 0.3 43.5 f 0.3 44.7 f 0.6 43.5 f 0.2 43.8 f 0.3 43.1 f 0.8 

Hemoglobin(g/dL) 

16.7 f 0.4 16.4 f 0.2 16.9f 0.2 17.0f 0.3 16.4 f 0.2 16.9 f 0.1 16.7 f 0.6 

Erythrocytes (lo6/&) 

9.76 f 0.18 9.53 f 0.08 9.83 f 0.05 9.90 f 0.17 9.87 f 0.10 9.85 f 0.07 9.74 f0.21 

Reticulocytes (lo6/&) 

Mean cell volume(a) 

0.24 f 0.04 

44.8 f 0.2 

0.14 f 0.02* 

45.0 f 0.3 44.2 f 0.5 

0.15 f 0.02 

45.2 f 0.2 

0.18 f 0.01 

44.0 f 0.6 

0.13 f 0.02 

44.4 f 0.2 

0.14 f 0.02 

44.2 f 0.4 

0.21 f 0.02 

Mean cell hemoglobin (pg) 

17.1 f 0.1 17.2 f 0.2 17.2f 0.2 17.2f 0.2 16.6f 0.3 17.1f 0.1 17.1 f 0.2 

Mean cell hemoglobin concentration(ddL) 

38.3 f 0.1 38.1 f 0.5 38.8 ~t0.3 38.0 ~t0.4 37.6 20.4 38.5 rt 0.3 38.7 f 0.7 

Platelets (lo3/&) 

981.0 f 51.7 993.8 f 20.7 970.6 f 38.1 944.4 f 12.8 945.2 f 34.0 988.6f 33.7 936.8 f 59.8 

Leukocytes (lo3/$) 

5.12f 0.91 4.32 f 0.85 4.54 f 1.10 4.32 f 0.35 3.94 f 0.61 3.56 f 0.90 5.74 f 0.76 

Segmented neutrophils(lo3/&) 

0.87 f 0.15 0.86 f 0.15 0.59 f 0.20b 0.72 f 0.10 0.77 f 0.19 0.58 f 0.16 0.70 f 0.13 

Lymphocytes (lo3/$) 

4.20 f 0.85 3.40 f 0.73 3.33 f l.07b 3.56 f 0.33 3.14 f 0.49 2.97 f 0.75 4.94 f 0.64 

0.06 f 0.03 

0.00 f 0.00 

Monocytes (lo3/&) ’ 

Atypical lymphocytes(lo3/&) 

0.05 f 0.02 

0.01 f 0.01 

0.01 f 0.01 

0.00 f 0.00 

0.04 f 0.03 

0.00 f 0.00 

0.02 f 0.01 

0.01 f 0.01 

0.01 f 0.01 

0.00 f 0.00 

o.io f 0.04 

0.00 f 0.00 

Eosinophils (lo3/&) 

0.00 f 0.00 0.00 f 0.00 0.01 f0.01 0.00 f 0.00 0.00 It 0.00 0.00f0.00 0.00f 0.00 

Clinical Chemistry 

Total bilirubin (mg/dL) 

0.3 f 0.0 0.3 f 0.0 0.3 f 0.0 0.3 f 0.0 0.3 f 0.0 0.3 f 0.0 0.4 f 0.0 

32f3. 

Alanine aminotransferase (IUL) 

27 f 2 4Of3 42f5 33 f 3 27 f 2 46f8 

61 f7 

Alkaline phosphatase(IUL) 

59 f 2 61 f3 

.. 

6Of2 56f2 59f2 58% 1 

Aspartate aminotransferase(IU) 

60f 3. 58f3 69f4 74f7 66f4 6225 69f2 

40f 3 

Sorbitol dehydrogenase (IUL) 

41 f2 42+8 4of9 32f3 36f3 26 f gb 

y-Glutamyltransferase (IUL) 

4.2 f0.8 4.0 f 1.0 3.2 f0.2 3.0 f 0.0 3.0 20.0 4.6 f 1.0 3.0 f 0.0 
Vehicle Untreated 

Control Control 2.5 mglag 5 mp/ag 10mglag .20m@g 50 mglag 

Female 

n 5 5 5 5 5 5 5 

Hematology 

Hematocrit (%) 

43.3 f 0.644.4 f 0.5 43.4 f 0.1 44.1 f 0.8 43.4 f 0.5 43.4 f 0.5 42.9 f 0.6 

Hemoglobin (g/dL) 

16.8f 0.317.0 f 0.3 16.5 f 0.2 16.7 * 0.5 16.4f 0.4 16.7f 0.2 16.3f 0.4 

Erythrocytes (lo6/&) 

9.55 f 0.159.69 f 0.13 9.54 f 0.09 9.76 2 0.13 9.63 f 0.1 1 9.60 & 0.09 9.52 f 0.11 

Mean cell volume (a) 

Reticulocytes (106/pL) 

45.4 f 0.2 

0.18 f 0.03 

45.8 f 0.4 

0.18 f 0.02 

45.4 f0.4 

0.17 f 0.02 

45.0 * 0.5 

0.19 f 0.04 

45.0 f 0.0 

0.14 f 0.03 

45.2 f 0.2 

0.16 f 0.03 

45.0 f 0.0 

0.15 f 0.02 

Mean cell hemoglobin (pg) 

17.6f 0.2 17.5 f 0.2 17.3f 0.2 17.1 f 0.3 17.0f 0.2 17.4 f 0.1 17.1rt 0.3 

Mean cell hemoglobin concentration (g/dL) 

38.8 f 0.5 38.20.3 38.0 f 0.3 37.8 f 0.5 37.8 f 0.5 38.6 f 0.1 37.9 f 0.5 

Platelets (10~1~~) 

819.2 f 96.5 913.2 f 21.5 880.6 f 24.0 940.8 f 33.9 996.2 f 81.1 905.0 f 10.6 980.6 f 45.1 

Leukocytes (lo3/&) 

4.90 f 0.56 5.04 f 0.46 4.78 f 0.81 4.42 2 0.46 4.44 f 0.81 4.72 f 0.72 4.12fO.51 

1.07f 0.20 

Segmented neutrophils (lo3/@) 

1.09f 0.22 0.66 f 0.26 0.72 f 0.16 0.73 f 0.22 0.50 f 0.07 0.83 f 0.16 

Lymphocytes(103/pL) 

3.75 f 0.55 3.84 f 0.46 4.09 f 0.58 3.68 f 0.37 3.69-f 0.61 4.15 20.63 3.24 f 0.52 

Atypical lymphocytes (103/pL) 

0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 0.00 f0.00 0.00 f 0.00 0.01 f 0.01 0.00 f 0.00 

Monocytes (103/pL) 

0.08 f 0.03 0.1 1 f 0.05 0.03 f 0.02 0.02 f 0.01 0.03 f 0.02 0.03 f 0.02 0.05 f 0.02 

Eosinophils (lo3/&) 

0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 0.00 f 0.00 

Clinical Chemistry 

Total bilirubin (mg/dL) 

0.3 f 0.0 0.3 f 0.1 0.3 f O.Ob 0.4 f O.Ob 0.3 f 0.0 0.3 f O.Ob 0.3 f0.0 

Alanine aminotransferase (IUL) 

33 f 6 26f3 32 f gb 3Of3 30f 1 28 f 1 26f2 

Alkaline phosphatase (IUL) 

95 f 3 83 f 2* 93 f 4b 92f3 8Of8 84f4 83 f 5 

Aspartate aminotransferase(IUL) 

7Of7 65f7 68 f gb 7726 65 f 2 66 f gb 65 f 5 

Sorbitol dehydrogenase (IUL) 

34f5 32 f qb 39 f 3b 33 f gb 33f3 32f 1 33 f4 

y-Glutamyltransferase (IUL) 

3.0 f 0.0 5.0 f 0.7* 4.0 f 0.7b 3.4 f 0.4 3.0 f 0.0 3.0 f O.Ob 3.0 f 0.0 

* Significantly different (PiO.05) from the vehicle control group byDum’s or Shirley’s test a Mean f standard error. Statistical tests were performed on unrounded data. 

n=4 
270 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

272 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEI1 

!iummary of Reproductive Tissue Evaluations and Estrous Cycle Characterization for Rats 

in the 13-Week Dermal Study, of 1,2-Dihydro-2,2,4-trimethylquin~line~ 

Vehicle .Untreated 

Control Control 5 mgncs 50 mg/kg 200mgkg 

Male 

n 10 9 10 9 10 

Weights (g) 

Necropsy body wt. 345 f 6 341 f 5 353 f 5 343 f 5 328 f I* 

R.cauda 0.230 f 0.004 0.217 fO.O1lb 0.226 f 0.004 0.224 f 0.005 0.229 f 0.006 

R.epididymis 0.451 f 0.005 0.451 f 0.004 0.447 f 0.006 0.444 f0.007 0.446 f 0.009 

R.testis 1.486 f 0.018 1.394f 0.101 1.504f 0.019 1.362f0.106 1.469f 0.033 

Epididymal spermatozoal parameters 

Motility (%) 83.60 f 0.57 85.70 f 0.91 83.12 f 0.64 83.91 f 0.71 83.05 f0.52 

Concentration 

(106/gcaudaepididymaltissue) , 411.0 f 22.6 382.7 f 26.0 426.2 f 19.8 442.6 f 15.7 444.1 f 13.8 

Normal (per500 sperm) 496.2 f 0.5 496.1 f 0.5 494.2 f 1.2 496.6 f 0.4 496.3 f 0.7 

Abnormal (%) 0.760 f 0.093 0.778 f 0.097 1.160 f0.244 0.689 f0.075 0.740 f 0.133 

Amorphous (per500 sperm) 0.400 f 0.163 0.778 f 0.324 0.400 f 0.221 o.oO0 f o.oO0 0.300 f 0.153 

Excessive hook (per500 sperm) 0.800 f 0.291 1.oO0 f0.236 2.000 f 0.667 0.556 f 0.242 1.000f 0.333 

No hook (per500 sperm) 2.30 f 0.52 1.78f0.28 2.30 f 0.78 2.56 f 0.53 2.20 f068 

Pin-head (per500 sperm) o.oO0 f o.oO0 o.oO0 fo.oO0b o.oO0 f o.oO0 o.oO0 fo.oO0b o.oO0 fo.Oo0 

Short-headed (per500 sperm) 0.300 f 0.153 0.222 f 0.147 1.100f 0.314 0.333 f 0.167- 0.200 f0.133 

Two tails or heads (per500 sperm) o.oO0 fo.Oo0 0.000 f o.oO0b 0.000 fo.oO0 o.oO0 f o.oO0b o.oO0 f o.oO0 

Female 

n 10 10 10 10 10 

Necropsy body wt. (g) 190f 2 194 f 3 197 f 2 195f 3 194f 2 

Estrous cycle length (days) 4.60 f 0.22 4.80 f 0.13 5.00 f 0.19' 4.89 f 0.1 Id 4.90 f 0.10 

13strousstage (% of cycle) 

Diestrus 40.0 40.0 34.3 35.7 32.9 

Proestrus 11.4 18.6 14.3 15.7 22.9 

Estrus 27.1 22.9 27.1 25.7 22.9 

Metestrus 21.4 18.6 24.3 22.9 21.4 

rk Significantly different(PiO:O5) from the vehicle control group by Williams' test '' Data are presented as meanf standard error. 

" ' n=10 

Estrous cycle was longer than7 days or was unclear 2inof 10 animals. 

Estrous cycle was longer than7 days or was unclear in1 of 10 animals. 
4 273 

I

!

i

I

i 

“e 

n 10 10 10 10 10 

Weights (8) 

Necropsy body wt. 33.7 f 0.7 33.3 f 0.8 32.5 f 0.3 34.5 f 0.6 33.1 f 0.5 

R.cauda 0.022 * 0.001 0.020 f 0.000* 0.021 f 0.001 0.020 f 0.001 0.022 f 0.001 

R. epididymis 0.047 f 0.001 0.046 f 0.001 0.047 f 0.001 0.046 f 0.001 0.047 f 0.001 

R.testis 0.1 1520.003 0.117 f 0.003 0.1 15 f0.002 0.116 f 0.003 0.118 fO.002 

Epididymal spermatozoal parameters 

Motility (%) 80.27 f0.44 81.39 f 0.85 81.18 fO.50 80.70 f 0.81 81.14 f 0.95 i Concentration ~T 

! (106/gcauda epididymal tissue) 747.6 f 54.3 824.1 -c 38.3 799.8 f 57.9 787.9 f 34.5 764.3 f 39.3 

Normal (per500 sperm) 494.9 f 1.0 494.3 f 0.6 495.6 f0.5 494.5 f0.8 495.4 f 0.6 

Abnormal (%) 1.020f 0.201 1.140 f 0.127 0.880 f 0.104 l.lOO* 0.158 0.920 f 0.120 

Amorphous (per500 sperm) 2.40 f 0.65 3.30 f 0.52 2.20 f 0.36 3.50 f 0.75 2.80 f 0.53 - 1

i Banana (per500 sperm) 2.200 * 0.61 1 1.700f 0.260 1.300 f 0.213 1.400 f 0.400 0.900 f 0.277 ! Blunt hook (per500 sperm) o.Oo0 f0.000 0.300 f 0.213 0.400 f 0.221 0.100 It 0.100 0.300 f 0.213 I Pin-head (per500 sperm) 0.000 f o.Oo0 0.000 * 0.000 0.000 f 0.000 o.oO0 f0.000 0.000 f 0.000 

Short-headed (per500 sperm) 0.400 f 0.163 0.400 -c 0.163 0.200 f 0.133 0.500 f 0.307 0.500 * 0.224 

Two tails or heads (per500 sperm) 0.000 fo.Oo0 o.Oo0 * 0.000 0.200 f0.133 0.000 f 0.000 0.000 f 0.000 

Felnale 

n 10 IO 9 10 10 

Necropsy body wt. (9) 29.1 rt 0.7 27.8 f 0.5 30.2 f0.5 28.7 f0.5 30.0 f 0.5 

Estrous cycle length (days) 4.20 f 0.13 4.33 f 0.24b 4.22 f0.22 4.00 f 0.17b 4.20 f 0.20 

Estrous stages (% of cycle) 

Diestrus 24.3 27.1 30.2 21.4 17.1 

Proestrus 14.3 21.4 15.9 17.1 15.7 

Estrus 32.9 32.9 36.5 40.0 42.9 

Metestrus 28.6 18.6 17.5 21.4 24.3 

* Significantly different(PsO.05) from the control group by Dunnett’s test 

a Data are presentedas mean f standard error. 

Estrous cycle was longer than7 days or was unclear in1of 10animals. 

-1i 
1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 
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276 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

CHEMICALCHARACTERIZATIONAND ' . 

DOSE FORMULATION STUDIES 

PROCUREMENT AND CHARACTERIZATION 

1,2-Dihydro-2,2,4-trimet.hylquinoline 

1,2-Dihydro-2,2,4-trimethylquinolinewas obtained from B.F. Goodrich Company (Akron, OH) in one lot 

(B062884), which was used duringthe 13-week and 2-year studies and the 1-year initiation/promotion study. 

Identity, purity, and stability analyses were conducted bythe analytical chemistry laboratory, Midwest 

Research Institute (Kansas City, MO). Reports on analyses performed in support of the 1,Zdihydro2,2,4-trimethylquinoline studies are on file at the National Institute of Environmental Health Sciences 

(NEHS). 

The chemical, a dark copper-colored viscous liquid, was identified as 1,2-dihydro-2,2,4-trimethylquinolineby 

infrared, ultraviolethisible, and nuclear magnetic resonance spectroscopy.The infrared and nuclear magnetic 

resonance spectra were consistent with the literature spectra (Sadtler Standard Spectra; Elliot and Dunathg, 

1963) of 1,2-dihydro-2,2,4-trimethylquinoline(Figures J1 and 52). 

The purity of lot BO62884 was determined by elemental analyses, Karl Fischer water analysis, functional group 

titration, thin-layer'chromatography(TLC), and high-performance liquid chromatography (HPLC). For 

functional group titration, samples were dissolved in glacial acetic acid and titrated with 0.1 N perchloric acid 

in glacial acetic acid. Titrations were monitored potentiometrically usinga combination pWmV electrode 

filled with 4 M aqueous potassium chloride. TLC was performed on Silica Gel 60 F-254 plates with two 

solvent systems: 1) ethyl acetate and 2) toluene. Diphenylamine was used as a reference standard. Plates were 

examined under visible ind ultraviolet (254 and 366 nm) light and with a spray of ferric chloride and iodine. 

HPLC was performed witha Whatman Partisil5 ODs-3 column, a solvent program of water:acetonitrile 

(55% acetonitrile for 25 minutes; then increased linearlyto 100%acetonitrile in 30 minutes, followed bya 

10-minute hold at 100%acetonitrile), a flow rate of 1.0 mL/minute, and ultravioletdetection at 254 nm. 

Elemental analyses for carbon, hydrogen, and nitrogen werein agreement, with the theoretical values for 

1,2-dihydro-2,2,4-trimethylquinoline.Karl Fischer water analysis indicated 0.048 f 0.002% water. Functional 

group titration indicated a purity of 97.2 f 0.3%; however, impurities thatalso contain amine groups may have 

contributed to this value. TLC by system1 indicated a major spot, one trace impurity, and one very siight trace 

impurity. TLC by system2 indicated a major spot and two trace impurities. HPLC revealed a major peak and 

11impurities with a combined area of 8.9% relative to the major peak area. These impurities were further 

quantitated and identified by gas chromatography and gas chromatography/mass spectrometry. Twenty-five 

impurities were detected, and 17 of these impurities were identified. Only two of these impurities were present 

at greater than 1.0% of the major peak area. The most concentrated of the two impurities had an area of 2.2% 

relative to the major peak area and was identifiedas an isomer of 1,2-dihydro-2,2,4-trimethylquinoline.The 

other impurity had an areaof 1.5% relative to the major peak area and wasidentified as C-nitroso-substituted 

trimethylquinoline. The overall purity was determined to be greater than 90%. 

Stability studies of lot 1601 HK ofthe bulk chemical were previously performedby the analytical chemistry 

laboratory. Gas chromatography was performed usinga flame ionization detector witha nitrogen carrier gas at 

a flow rate of 70 mL/minute and a 3% SP-2401 DB on 100/120 Supelcort column with anisothermal oven 

temperature of 130" C. Octadecane was used as an internal standard. These studies indicated that 1,Zdihydro2,2,4-trimethylquinone was stableas a bulk chemical for 2 weeks when stored protectedfrom light at 

temperatures up to 60" C. To ensure stability during the 13-week studies, the bulk chemical,was stored in 

amber glass bottles at 5 O C under a nitrogen headspace or at room temperature under a nitrogen atmosphere 
@hedd@hara~ll~?dzra&i~~~ and hSC?FQlTllPnh&n 244

when the chemical was being used. During the 2-year studies and the 1-yearinitiatiodpromotion study, the 

bulk chemical was stored protected from light at 4" f 3" C under an argon headspace in amber glass bottles. 

Stability was monitored by the study laboratories and the analytical chemistry laboratory during the 13-week 

and 2-year studies and the 1-year initiatiodpromotion study using infrared spectroscopy and gas 

chromatography. No degradation of the bulk chemical was detected. 

S,n2-~irmnQu~nyn~Q~~(a~a~u~PacQ~Q 

7,12-Dimethylbenz(a)anthracene was obtained from Eastman Kodak Company (Rochester, NY) in one lot 

(K-4). The lot was purified by the analytical chemistry laboratory. The chemical was dissolved in benzene, 

passed through a neutral alumina column, and crystallized from isopropanol. The purified material was 

assigned lot number M111384 and was used throughout the 1-year initiatiodpromotion study. Reports on the 

identity, purity, and stability analyses performedby the analytical laboratory in support of the 1-year 

initiatiodpromotion study are on file at the NIEHS. 

The chemical, a light yellow powder, was identifiedas 7,12-dimethylbenz(a)anthracene by infrared, ultraviolet/ 

visible, and nuclear magnetic resonance spectroscopy. The infrared and nuclear magnetic resonance spectra 

were consistent with the literature spectra (Ozubkoet al., 1974;Aldrich Library, 1981;Sadder Standard 

Spectra) of 7,12-dimethylbenz(a)anthracene (Figures 53 and 54). 

The purity was determined by elemental analyses, Karl Fischer water analysis, TLC, and gas chromatography. 

TLC was performed onSilica Gel 60 F-254 plates using two solvent systems: 1) to1uene:hexane (64:40) and 

2) hexane:chloroform (78:22). Pyrene was usedas a reference standard. Plates were examined under 254nm 

and 366nm ultraviolet light and witha spray of 5% potassium dichromate in 40%sulfuric acid. Gas 

chromatography was performed usinga flame ionization detector witha nitrogen carrier gas ata flow rate of 

70 mWminute. Two systems were used: 

A) 3% Dexsil400 on 80/100 Chromosorb W(AW) glass column, with an oven temperature 

program of 50" C for 5 minutes, then50" to 300" C at 10" C per minute, and 

B) 3% SP-2100 on 100/120 Supelcort column, withan oven temperature program of 75" C for 

1 minute, then 75" to 275O C at 10" C per minute. 

Elemental analyses for carbon and hydrogen werein agreement with the theoretical valuesfor 

7,12"iethylbenz(a)anthracene. Karl Fischer water analysis indicated less than 0.4% water. TLCby system 1 

indicated one major spot and one trace impurity, and system2 indicated only a major spot. Gas 

chromatography using both systems indicatedone major peak andno impurities with peaks greater than 0.1% 

relative to the major peak area. The overall purity was determinedto be greater than 99%. 

Stability studies were performed with gas chromatography systemA described above except withan isothermal 

oven temperature of300" C and 2.3 mg/mL octacosane addedas an internal standard. These studies indicated 

that 7,12-dimethylbenz(a)anthracene was stable as a bulk chemical for at least 2 weeks when stored protected 

from light at temperatures upto 60" C. To ensure stability, the bulk chemical was stored protected fromlight 

at 4" k 3" C in sealed glass bottles. The stability of the bulk chemical was monitored periodically by the study 

laboratory using infrared spectroscopy andgas chromatography. No degradation of the bulk chemical was 

observed. 

n2-O-'ITQuPadQcarmaP~n~~aPP~~n-n~-a~Q~uQ 

12-0-Tetradecanoylphorbol-13-acetatewas obtained from L.C. Services, Corporation (Woburn, MA) in two 

lots (F-121 and F-126). Both lots were used during the 1-yearinitiatiodpromotion study. Identity, punty, and 
278 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

stability analyses were conducted bythe analytical chemistry laboratory. Reports on analyses performed in 

support of the study are on file at the NIEHS. 

Lot F-121 was identified as 12-0-tetradecanoylphorbol-13-acetate by nuclear magnetic resonance spectroscopy 

and both lots were identified as 12-0-tetradecanoylphorbol-13-acetateby mass spectrometry. The spectra of 

both lots were consistent with that expected for 12-0-tetradecanoylphorbol-13-acetate(Figure J5). 

The purity of both lots was determined by TLC and HPLC. TLC was performed on Silica Gel 60 F-254 plates 

using two solvent systems: 1) anhydrous diethyl ether (100%) and 2) ethyl acetate:chloroform (60:40). 

Visualization was at 254 nm and witha spray of 1% vanillin in concentrated sulfuric acid, followed by heating 

at 120" C for 10to 20 minutes. For lot F-121, HPLC was performed witha DuPont Zorbax ODS column with 

a flow rate of 1nWminute, detection at 229 nm, and a solvent system of water:acetonitrile (10:90). For 

lot F-126, HPLC was performed withe same system as that described for lot F-121 except with a Beckman 

Ultrasphere ODS column. 

TLC for both lots revealed one major spot with each system. For lot F-121, HPLC indicated one major peak 

and two impurities with areas greater thanor equal- to 0.1% of the major peak area and a combined area of

0.8% relative to the major peak area. For lot F-126, HPLC indicated one major peak and three impurities with 

areas greater than or equal to 0.1% of the major peak area and a combined area of 1.O%.relative to the major . 

peak area. The overall purity of both lots was determined to be 99%. 

The stability of the chemical was determined usingthe HPLC system described in the purity analysis of 

lot F-121. The study indicated that no decomposition had occurred in samples exposedto air and light at 

ambient temperature for up to 6 days. To ensure stability, the bulk chemical was stored protected fromlight at 

4" ? 3" C in sealed glass bottles. 

PREPARATION AND ANALYSISOF DOSEFORMULATIONS 

1,2-Dihydro-2,2,4-trimethylquinoline 

The dose formulations were prepared by mixing1,2-dihydro-2,2,4-trimethylquinolineand acetone to give the 

required concentrations (Table 51). The dose formulations were prepared every 2 weeks during the 13-week 

studies and were stored at room temperature in amber glass bottles. Doseformulations were prepared as 

needed during the 2-yearstudies and the 1-year initiatiodpromotion study and were stored protected from light. 

at 20" & 5" C in amber glass vials. All dose formulations were stored for a maximum of 3 weeks. 

Stability studies of the 250 and0.5 mg/mL dose formulations were also performed using HPLC. For the 

250 mg/mL dose formulation, aliquots were diluted with acetonitrile, butyrophenone was added' as an internal 

standard solution, and the samples werefurther diluted with acetonitri1e:water (50:50). HPLC was performed 

using a Whatman Partisil5 ODs-3 column with a flow rate of 1mL/minute, a mobile phase of 

acetonitri1e':water (initially 55:45, then linearly increasedto 99:1), and a Waters 440 detector. For the 

0.5 mg/mL dose formulation, aliquots were diluted with water:acetonitrile (38:62), and 2-bromo4,6-&nitroaniline was added as an internal standard solution. HPLC was performed usinga Burdick and 

Jackson C-18 column witha flow rate of 1mL/minute, a mobile phase of water:acetonitrile (38:62), and a 

Waters 440 detector. The stability of the dose formulations was confirmed for at least 3 weeks at room 

temperature when stored protectedfrom light and for at least 3 hours when stored at room temperature an.d 

exposed to air and light. 

Periodic analyses of the dose formulations of 1,2-dihydro-2,2,4-trimethylquinolinewere conducted at the study 

laboratory and analytical chemistry laboratory using ultraviolet spectroscopy (363 nm). During the 13-week 
studies, the formulations were analyzed every4 to 5 weeks (Table 52). For 2-year studies and the l-year 

initiatiordpromotion study, the formulations were analyzed every6 to 8 weeks (Tables 53 and 54). Of the dose 

formulations analyzed, 92% (247/269) were within10%of the target concentration with no value greater than 

18% of the target concentration. Results of referee analyses performed by the analytical chemistry laboratory 

agreed with the results obtained by the study laboratory with the exception of the 15 mg/mL dose formulation 

used for initiation in the l-year initiation/promotion study (Table J5). No explanation was provided for the 

discrepancy. 

S,n2-DirmnQuhgmbQrmz~a)a~u~rab3Q~Q 

The dose formulation was prepared by dissolving 7,12-dimethylbenz(a)anthracene in acetone to give the 

required concentration (Table Jl). The dose formulation was preparedonce at the beginningof the study. The 

dose formulation was stored at 20" 2 5" C protected from light in an amber glass bottle witha Teflon@ cap and 

was discarded 3 weeks after preparation. 

Stability analyses of the 0.0025 and0.1 mg/mL dose formulations were performed by the analytical chemistry 

laboratory. Aliquots were diluted with acetone, anthracene was addedas an internal standard solution, and the 

samples were further diluted with acetonitri1e:water (85:15). HPLC was performed using a Brownlee Rp-18 

column with a flow rate of 1mL/minute, a mobile phase of acetonitri1e:water (85:15), and detection at 365 nm. 

The stability of the dose formulations was confirmedfor at least 3 weeks at room temperature when stored in 

'the dark and for less than 3 hours when exposed to light and air. 

Analysis of the dose formulation of 7,12-dimethylbenz(a)anthracene was conducted by the study laboratory 

and analytical chemistry laboratory using ultraviolet spectroscopy(363 nm). During the l-year 

initiatiordpromotion study, the dose formulation was within 10% of the target concentration (Table 54). 

Results of the referee analyses performed by the analytical chemistry laboratory were in agreement with the 

results obtained by the study laboratory (Table J5). 

' n2-~-1I'QuradQb3armo~n~~~rb~n-lL3-aQ 

The dose formulations were preparedby mixing 12-O-tetradecanoylphorbol-13-acetateand acetone to give the 

required concentrations (Table Jl). Dose formulations were preparedas needed. The dose formulations were 

stored at 20" 2 5 O C protected from light in amber glass bottles with Teflon@ caps and were discarded 3weeks 

after the date of preparation. 

Stability analyses of the dose formulations were conductedby the analytical chemistry laboratory using the 

HPLC system used in the bulk chemical stability analyses of 12-O-tetradecanoylphorbol-13-acetate except with

a solvent ratio of 7:93. Stability of the formulations was establishedfor at least 3 weeks when stored protected 

from light at room temperature in sealed bottles. 

Periodic analyses of the dose formulations of 12-O-tetradecanoylphorbol-13-acetatewere conducted by the 

study laboratory and by the analytical chemistry laboratory with the same HPLC method as that used in the 

stability study. The formulations were analyzed every 6 to 8 weeks (Table 54). During the l-year initiation/ 

promotion study, all of the formulations were within 10%of the target concentration. Results of referee 

analyses analyzed performed by the analytical chemistry laboratory were in agreement with the results obtained 

by the study laboratory (Table J5). 
280 1,2-Dihydro;2,2,4+rimethylquinoline,.NTP TR 456 

0 0 

m 0 - cu

7 

,. .! 

. . 
f 

-Q 

..... ....._....... ........_.. ... ...... .... ... ................ ....... .. . _.............. . . ... . . .. . .
282 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

0 

v) 

v)

cu 

0 

cu 

(0 

7 .. . .. 

0 

7 

. . 

-2 

f

0 

, . 

. , . , 

.. . .. 

.. 

"! 

cu 3 0 0

3 aD (u r_ 

FIGURE 53 . . 

Infrared Absorption Spectrum-of7~,12-Dimethylbenz(a)anthracene,~I 
283 

E 

1 1 1 1 

I'd I -

0

nl 

R 
284 1,2-Dihydro-2,2,4-trimethylquinoline, NTP TR 456 

4i' 

co.caC ***"TO: .... 

0--0-0 

a 

x 

e 4 

, . 

L

.( 

I 

n 

mm 
BmpaPation 

1,2-Dihydro-2,2,4-trimethylquinoline 

was weighed and then transferred ato 

graduated cylinder. Acetone was added 

to obtain a solution with the required 

1,2-dihydro-2,2,4-trimethylquinoline 

concentration. 

Chemical Lot Number 

BO62884 

Maximum Storage Time 

3 weeks 

Storage Conditions 

Stored in amber glass bottles at room 

temperature during the 13-week studies; 

stored in amber glass bottles protected 

from light at 20"f 5" C during the 

2-year studies and the1 -year 

initiatiodpromotion study 

shay ~~aboratoq 

Southern Research Institute 

(Birmingham,AL) for the 13-week 

studies; TSI Mason Research Institute 

(Worcester, MA) for the 2-year studies 

and the 1-year initiatiodpromotion 

study 

Referee Laboratory 

Midwest Research Institute 

(Kansas City, MO) 

7,12-Dimethylbenz(a)anthracene was 

weighed and then transferred toa 

graduated cylinder. Acetone was added 

to obtain a solution with the required 

7,12-dimethylbenz(a)anthracene

concentration. 

M111384 

3 weeks 

Stored in amber glass bottles protected 

from light at 20"f 5" C 

TSI Mason Laboratories (Worcester, 

MA) for the 1-year initiatiodpromotion 

study 

Midwest Research Institute 

(Kansas City, MO) 

12-0-Tetradecanoylphorbol-13-acetate 

weighed and then transferred toa 

graduated cylinder. .Acetone was added 

to obtain a solution with the required 

12-0-tetradecanoylphorbol-13-acetate

concentration. 

F-121 and F-126 

3 weeks 

Stored in amber glass bottles protected 

from light at 20".+ 5" C 

TSI Mason Laboratories (Worcester, 

MA) for the I-year initiatiodpromotion 

study 

Midwest Research Institute 

(Kansas City, MO) 
286 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEJ:2 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week Dermal Studies of 1,2-Dihydro-2,2,4-trimethylquinoline .. 

Target Determined % Difference 

centrationDate Date 

alyzed from Target

(mglmL) (m") 

Prepared Concentrationa 

Rats 

17 April 1!)86 17-18 April 1986 1.67 1.43 -14 

3.33 2.88 -14 

6.67 5.76 -14 

6.67 5.80 -13 

13.3 11.5 -14 

26.7 23.4 -12 

33.3 28.6 -14 

66.7 58.5 -12 

133 117 -12 

267 235 - 12 

22 April 1986b 22-23 April 1986 1.67 1.74 +4 

3.33 3.41 +2 

6.67 6.96 +4 

6.67 6.86 +3 

13.3 13.8 +4 

26.7 27.9 +4 

33.3 35.4 +6 

66.7 68.8 +3 

133 136 +2 

267 276 +3 

7 May 1986' 1.67 1.74 +4 

3.33 3.34 0 

6.67 6.85 +3 

6.67 6.82 +2 

13.3 13.4 +1 

26.7 27.6 +3 

33.3 34.6 +4 

66.7 68.4 +3 

133 138 +4 

267 278 +4 
ConcentrationConcentration DatePreparedDateAnalyzed

Rats (continued) 

29 May 1986 29 May 1986 

18 June 1986' 

24 July 1986 24-25 July 1986 

11August 1986' 

Mice 

17April 1986 17-18April 1986 

Determined Target

(mglmlL) 

1.67 

3.33 

6.67 

6.67 

13.3 

26.1 

33.3 

66.7 

133 

267 

1.67 

3.33 

6.67 

6.67 

13.3 

26.7 

33.3 

66.7 

133 

267 

1.67 

3.33 

6.67 

6.67 

13.3 

26.7 

33.3 

66.7 

133 

267 

6.67 

26.7 

66.1 

133 

267 

1.67 

3.33 

6.67 

6.67 . 

13.3 

26.7 

33.3 

66.7 

133 

267 

(mg/mU 

1.57 

3.41 

6.55 

6.76 

13.1 

27.2 

33.8 

68.0 

137 

212 

1.60 

3.50 

6.62 

6.90 

13.3 

27.0 

34.2 

69.8 

140 

274 

1.71 

3.36 

6.86 

6.80 

13.8 

21.4 

33.4 

68.8 

138 

274 

6.78 

27.5 

69.2 

138 

275 

1.43 

2.88 

5.76 

5.80 

11.5 

23.4 

28.6 

58.5 

117 

235 

% Difference 

from Target 

-6 

+2 

-2 

+1 

-2 

+2 

+2 

+2 

+3 

+2 

-4 

+5 

-1 

+3 

0 

+1 

+3 

+5 

+5 

+3 

+2 

+1 

+3 

+2 

+4 

+3 

0 

+3 

+4 

+3 

+2 

+3 

+4 

+4 

+3 

-14 

-14 

-14 

-13 

-14 

-12 

-14 

-12 

-12 

-12 
288 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE52 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week Dermal Studies of 1,2-Dihydro-2,2,4-trimethylquinoline(continued) ,.. .. , 

, ? ) 

Target Determined % Difference 

ConcentrationDate Date Analyzed Prepared Concentration from Target , I (mg/mL) (mg/mL) 

Mice (continued) 

22 April 1986b 22-23 April 1986 1.67 1.74 +4 

3.33 3.41 +2 

6.67 6.96 +4 

6.67 6.86 +3 

. 13.3 13.8 +4 

26.7 27.9 +4 

33.3 35.4 +6 

66.7 68.8 +3 

133 136 +2 

267 276 +3 

7 May 1986' 1.67 1.74 +4 

3.33 3.34 0 

6.67 6.85 +3 

6.67 6.82 +2 

13.3 13.4 +1 

26.7 27.6 +3 

33.3 34.6 +4 

66.7 68.4 +3 

133 138 +4 

267 278 +4 

29 May 1986 29 May 1986 1.67 1.57 -6 

3.33 3.41 +2 

6.67 6.55 -2 

6.67 6.76 +I 

13.3 13.1 -2 

26.7 27.2 +2 

33.3 33.8 +2 

66.7 68.0 +2 

133 137 +3 

267 272 +2 

18June 1986' 1.67 1.60 -4 

3.33 3.50 +5 

6.67 6.62 -1 

6.67 6.90 +3 

13.3 13.3 0 

26.7 27.0 +1 

33.3 34.2 +3 

66.7 69.8 +5 

133 140 +5 

267 274 +3 
Date Prepared ConcentratjonDate Analyzed 

Mice (continued) 

24 July 1986 24-25 July 1986 

4 August 1986' 

a Results of duplicate analyses 

Results of remix 

Animal roomsample 

TargeE 

(mg/mlL) 

1.67 

3.33 

6.67 

6.67 

13.3 

26.7 

33.3 

66.7 

133 

267 

1.67 

3.33 

6.67 

13.3 

33.3 

Determined 

Concentration 

(m") 

1.71 

3.36 

6.86 

6.80 

13.8 

27.4 

33.4 

68.8 

138 

274 

1.71 

3.40 

6.89 

13.9 

34.0 

% Diemnce 

from Target 

+2 

+1 

+3 

+2 

+4 

+3 

0 

+3 

+4 

+3 

+2 

+2 

+3 

+5 

+2 
290 

I 

~ 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLE53 . . Results of Analysis of Dose Formulations Administered to Rats and Mice , 6.. . in the 2-Year Dermal Studies of 1,2-Dihydro-2,2,4-trimethylquinoline 

~. . , , I - ,!. ,. 

Prepared Dte ' Analyzed Concntrationa Date .. 

Rats 

29 August 1989 29 August 1989 

18 September 1989' 

30 August 1989d 31 August 1989 

18 September 1989' 

17 October 1989 17 October 1989 

.I9 December 1989 19 December 1989 

. . 

20 February 1990 20 February 1990 

8 March 1990' 

Target 

(m") 

13.2 

15.6 

22.0 

26.0 

36.6 

43.3 

13.2 

15.6 

22.0 

36.6 

43.3 

26.0 

26.0 

20.30 

32.00 

33.80 

53.50 

54.90 

89110 

24.3 

40.2 

41.9 

65.6 

68.9 

114.8 

26.7 

44.3 

46.8 

71.3 

76.3 

126.5 

26.7 

44.3 

46.8 

71.3 

76.3 

126.5 

Determined 

Concentrationb: 

(m") 

13:5 

16.1 

21.8 

28.6 

37.1 

44.3 

13.6 

16.3 

22.4 

37.5 

44.8 

26.7 

26.7 

20.30 

32.74 

34.18 

52.68 

55.54 

89.88 

25.7 

42.7 

44.1 

69.2 

73.8 

122.3 

26.9 

45.7 

47.3 

71.8 

77.8 

127.8 

28.9 

48.6 

51.2 

77.2 

84.9 

137.5 

% Difference 

from.Target 

+2 

+3 

-1 

+10 

+I 

+2 

+3 

+5 

+2 

+2 

+3 

+3 

+3 

0 

+2 

+1 

-2 

+1 

+1 

+6 

+6 

+5 

'5 

+7' 

+7 

+1 

+3 

+I 

+1 

+2 

+1 

+8 

+IO 

+9 

+8 

+I1 

+9 
ConcentrationConcentration DatePreparedDateAnalyzed.

Rats (continued) 

17April 1990 17April 1990 

12June 1990 12June 1990 

7 August 1990 7-8 August 1990 

22 August 1990' 

2 October 1990 4 October 1990 

4 December 1990 4 December 1990 

Determined Target

(m") 

28.3 

47.0 

50.2 

76.2 

80.9 

134.1 

30.4 

49.8 

52.2 

79.5 

85.1 

139.3 

32.3 

53.1 

53.5 

83.2 

87.2 

143.4 

32.3 

53.1 

53.5 

83.2 

87.2 

143.4 

33.8 

54.6 

55.6 

88.4 

88.6 

144.8 

33.2 

53.9 

55.3 

88.1 

88.3 

143.5 

(m") 

28.7 

47.8 

50.8 

77.4 

82.9 

137.2 

32.1 

50.4 

53.2 

81.4 

87.7 

141.4 

32.5 

53.9 

54.3 

85.2 

88.1 

143.8 

33.0 

55.3 

55.7 

86.7 

89.9 

150.5 

34.1 

55.6 

55.7 

. 88.8 

90.3 

146.6 

34.0 

54.3 

56.1 

90.3 

90.7 

146.3 

% DWerence 

from Target 

+1 

+2 

+1 

+2 

+2 

+2 

+6 

+1 

+2 

+2 

+3 

+2 

+1 

+2 

+1 

+2 

+1 

0 

+2 

+4 

+4 

+4 

+3 

+5 

+1 

+2 

0 

0 

+2 

+1 

+2 

+1 

+1 

+2 

+3 

+2 

., 

I . 
392 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

IFABLE 53 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of 1,2-Dihydro-2,2,4-trimethylquinoline(continued). I'

Target Determined % Difference 

ConcentrationDatePrparedDate Analyzed Concentration Target from

(mglmL) (m") 

Rsts (continued) 

22 January 1991 22 January 1991 35.7 36.6 +3 

55.2 55.9 +1 

60.0 61.5 +3 

89.3 92.7 4 

95.4 98.8 +4 

146.2 149.0 +2 

5 February 1991' 35.7 37.2 +4 

-55.2 58.9 +7 

.60.0 63.9 +7 

89.3 93.6 +5 

95.4 100.2 +5 

146.2 153.5 +5 

19 March 1991 19 March 1991 36.4 37.0 I +2 

52.6 53.5 +2 

59.4 59.9 +1 

86.1 87.0 +1 

94.0 95.3 +1 

139.5 142.6 +2 

14May1991 14 May 1991 38.0 38.5 +1 

48.2 48.8 +1 

62.0 64.3 +4 

82.1 84.2 . +3 

97.9 99.5 +2 

128.0 130.8 +2 

9 July 1991 10 July 1991 38.7 38.9 +1 

42.4 43.3 +2 

63.3 64.2 +1 

74.4 76.5 +3 

99.1 100.6 +2 

120.8 125.6 +4 

19 July 1991' 38.7 39.8 +3 

42.4 43.5 +3 

63.3 66.5 +5 

74.4 77.3 +4 

99.1 101.0 +2 

120.8 124.8 +3 

26 August 1991 27 August 1991 38.7 39.1 +1 

44.7 45.1 +1 

64.9 65.3 +I 

72.7 73.6 +1 

101.9 104.9 +3 

131.4 134.1 +2 
293 

,. 

Date Prepared 

Mice 

5 July 1989 

5 September 1989 

24 October 1989 

12 December 1989 

13 February 1990 

Analyzed ConcentrationConcentration Date

6 July 1989 

6 September 1989 

24 October 1989 

10 November 1989' 

13 December 1989 

~" 

14 February 1990 

Target 

(w") 

0.85 

1.02 

1.40 

1.71 

2.33 

2.88 

1.14 

1.29 

1191 

2.14 

3.13 

3.57 

1.24 

1.45 

2.11 

2.40 

3.49 

3.88 

1.24 

1.45 

2.11 

2.40 

3.49 

3.88 

1.37 

1.59 

2.34 

2.64 

3.91 

4.35 

1.50 

1.64 

2.52 

2.74 

.4.27 

4.57 

Determined 

(mg/d) 

0.86 

1.03 

1.41 

1.73 

2.36 

2.84 

1.15 

1.30 

1.91 

2.16 

3.16 

3.66 

1.25 

1.52 

2.12 

2.42 

3.44 

3.92 

1.27 

1.53 

2.11 

2.42 

3.60 

4.01 

1.40 

1.59 

2.35 

2.68 

3.95 

4.41 

1.51 

1.63 

2.57 

2.79 

4.31 

4.59 

% Dflerence 

from Target . 

+1 

+1 

+1 

+1 

+1 

-1 

+1 

+1 

0 

+1 

+1 

+3 

+1 

+5 

0 

+1 

-1 

+1 

+2 

+6 

0 

+1 

+3 

+3 

+2 

0 

0 

+2 

+1 

+1 

+1 

-1 

+2 

+2 

+1 

0 

+ 

.. 
294 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

.,. 

TABLE53 

Results of Analysis of Dose Formulations Administered to Rats andMice 

in the2-Year Dermal Studies of 1,2-Dihydro-2,2,4-trimethylquinoline(contin~ed) 

ConcentrationConcentration DatePreparedDateAnalyzed

(mg/mL) 

Mice (continued) 

10 April 1990 12 April 1990 

30 April 1990' 

5 June 1990 8 June 1990 

31 July 1990 1August 1990 

25 September 1990 25 September 1990 

15 October 1990' 

27November199027November1990 

Determined Target % Difference

from Target 

(mg/mL) 

1.61 1.62 +1 

1.75 1.75 0 

2.74 2.84 +4 

2.92 2.97 +2 

4.54 4.59 +1 

4.86 4.95 +2 

1.61 1.65 +2 

1.75 1.77 +1 

2.74 2.84 +4 

2.92 3.02 +3 

4.54 4.62 +2 

4.86 5.02 +3 

1.77 1.84 +4 

1.84 1.91 +4 

2.98 3.08 +3 

3.05 3.07 +1 

5.02 5.15 +3 

5.09 5.24 +3 

1.82 1.82 0 

1.83 1.84 +1 

3.05 3.17 +4 

3.07 3.18 +4 

5.06 5.13 +1 

5.15 5.21 +1 

1.86 1.91 +3 

1.91 1.93 +1 

3.07 3.15 +3 

3.24 3.28 +1 

5.11 5.27 +3 

5.36 5.47 +2 

1.86 1.90 +2 

1.91 1.94 +2 

3.07 3.11 +1 

3.24 3.33 +3 

5.11 5.20 +2 

5.36 5.51 +3 

1.94 1.94 0 

2.02 2.03 0 

3.23 3.30 +2 

3.41 3.45 +1 

5.30 5.39 +2 

5.51 5.61 +2 
Z -

0 

I+ 

I+ 

0 

I+ 

I+ 

E+ 

E+ 

Z+ 

0 

I+ 

I+ 

z+ 

0 

E+ 

0 

z+ 

Z+ 

E+ 

PE+ 

z+ 

z+ 

SQZ 

EE'S 

60's 

ZP'E 

91'E 

ZOZ 

I P8'

LS'S 

9p's 

OSE 

9ZE 

SOZ 

€6'1 

LSS 

6E'S 

9P'E 

6ZE 

"Z 

I 5 6

85'6 

OE'S 

OZ'E 

ZZ'E 

VOZ 

I E 6

SP'S 

80's 

8E'E 

ZI'E 

ZOZ 

E8'1 

ES'S 

6Z'S 

IP'E 

OZE 

SOZ 

I 2 6

ES'S 

6Z'S 

IVE 

OZ'E 

SOZ 

I 2 6

8P'S 

PI'S 

SEX 

EI'E 

OO'Z 

1 06
296 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

'FABLE 54 

Results of Analysis of Dose Formulations Administered to Mice ._ . .,. 

in the 1-Year Dermal 1nitiatioI"romotion Study of 1,2-Dihydro-2,2,4-trimet~ylquinoline 

Target Determined % Difference 

Concentrationa DatePreparedDate Concentrationb

(mglmL) (m") 

Analyzed from Target 

. . . . 1,2-Dihydro-2,2,4-trimethylquinoline 

8 November 1989 21 November 1989' 15.0 17.64 ' +18

14 November 1989 14 November 1989 1.50 1.50 0 

3.00 3.06 +2 

7.50 7.57 +1 

.. 

29 November 1989' 1.50 1.52 +I 

3.00 3.08 . +3 

7.50 7.77 +4 

9 January 1990 10 January 1990 1.54 1.56 +1 

3.09 3.15 +2 

7.71 8.03 +4 

27 February 1990 27 February 1990 1.54 1.54 0 

3.09 3.20 +4 

7.71 7.75 +1 

!7 April 1990 17 April 1990 1.54 1.55 +1 

3.09 3.17 ' +3

7.71 7.93 +3 / 

30 April 1990' 1.54 1.59 +3 

3.09 3.26 +6 

7.71 7.92 +3 

12June1990 , 12 June 1990 . . 1.54 1.59. +3 

3.09 3.19 +3 

7.71 7.85 +2. 

7 August 1990 1.54 1.56 +1 

3.09 3.06 -1 

7.71 7.78 +1 

2 October 1990 4 October 1990 1.54 1.58 +3 

3.09 3.15 +2 

7.71 7.83 +2 

15 October 1990' 1.54 1.58 +3 

3.09 3.18 +3 

7.71 7.97 +3 

13 November 1990 13November1990 . 1.54 1.55 +1 

3.09 3.14 +2 

7.71 7.86 +2 
PE8-

0 

S+ 

0 

E+ 

8 -

I+ 

PZ+ 

0 

,0661 JaWaAoN 9-5 00500'0 08WO'O 

005000 E8W00 

005000 Z9PO00 

005000 66pOOO 

005000 LZSO00 

0661 I I "+I 0661 005000 86W00 

91500'0 

19WO'O 

LOSOO'O 

6LW00 

55z00 

OSZ00 

11 
298 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

TABLEJS 

Results of Referee Analysisof Dose Formulations Administered to Rats and Mice 

in the 13-Week and 2-Year Dermal Studies and to Mice in the 1-Year Dermal InitiatiodPromotion Study 

of 1,2-Dihydro-2,2,4-trimethyPquinoline 

Target Concentration 

Date Prepared (mg/mL) ' 

13-Week Studies (Southern Research Institute) 

22April 1986 3.33 

24July 1986 26.7 

... 

2-Year Studies(TSI Mason Laboratories) 

Rats 

29 August 1989 15.6 

Mice 

12December 1989 2.64 

1-Year Study(TSI Mason Laboratories) 

8November 1989 15.0 

14November 1989 3.00 

7,12-Dirnethylbenz(a)anthracene 

8November 1989 0.0250 

12-0-Tetradecanoylphorbol-13-acetate 

22November 1989 0.00500 

a Results of duplicateanalyses 

Results of triplicate analyses (meanf standard error) 

Determined Concentration(mp/mL) 

Study Referee 

Laboratorya Laboratoryb 

3.41 3.41 f 0.01 

21.4 26.9f 0.01 

16.1 15.8 0.0 

2.68 2.64f 0.005 

15.4 12.6f 0.1 

3.06 3.12f 0.01 

0.0250 0.0246* 0.0001 

0.00479 0.00507f 0.00007 
1 

299 

.. 
300 l,2-Dihydro-2,2,4-trimethylquinoline,NTPTR 456 

?rABLE K1 . i

Ingredients of NIH-07Rat and Mouse Rationa ;'. .

.. . 

. . I 

Ingredients? Percent by Weight 

Ground #2 yellow shelled corn 24.50 

Ground hard winter wheat 23.00 

Soybean meal(49% protein) 12.00 

Fish meal(60% protein) 10.00 

Wheat middlings 10.00 

Dried skim milk 5.00 

Alfalfa meal (dehydrated,17% protein) 4.00 

Corn gluten meal(60% protein) 3.00 

Soy oil 2.50 

Dried brewer's yeast 2.00 

Dry molasses 1.50 

Dicalcium phosphate 1.25 

Ground limestone 0.50 

salt 0.50 

Premixes (vitamin and mineral) 0.25 

~~~ 

a NCI, 1976;NM, 1978 

Ingredients were ground to pass througha U.S. Standard ScreenNo. 16 before'being mixed. 

'I . * 

TABLEK2 

Vitamins and Minerals inNIH-07Rat and Mouse Rationa 

Amount Source 

Vitamins 

A 5,500,000 IU . I 

Stabilized vitaminA palmitate or acetate 

D3 4,600,OOO IU D-activated animal sterol 

K3 $, 2.8 g Menadione 

d-a-Tocopheryl acetate 20,OooIU 

Choline 560.0 g Choline chloride 

Folic acid 2.2 g 

Niacin 30.0g 

d-Pantothenic acid 18.0 g &Calcium pantothenate 

Riboflavin 3.4 g 

Thiamine 10.0 g Thiamine mononitrate 

B,, 4,000 pg 

Pyridoxine 1.7 g Pyridoxine hydrochloride 

Biotin 140.0 mg d-Biotin 

Minerals 

Iron 120.0g Iron sulfate 

Manganese 60.0 g Manganous oxide 

Zinc 16.Og . Zinc oxide 

Copper 4.0 g Copper sulfate 

Iodine 1.4 g Calcium iodate . . - . Cobalt 0.4 g Cobalt carbonate 

a Per ton (2,000 lb) of finished product .. 

. . . . 
3QPB 

Protein (Wby weight) 

Crude fat(% by weight) 

Crude fiber(% by weight) 

Ash (% by weight) 

A~~IJ Acids (% off t~~td diet)

Arginine 

Cystine 

Glycine 

Histidine 

Isoleucine 

Leucine 

Lysine 

Methionine 

Phenylalanine 

Threonine 

Tryptophan 

Tyrosine 

Valine 

&sen~fniFatty Aci& (% off UQM&et) 

Linoleic 

Linolenic 

VihUllhS 

Vitamin A (IUCg) 

Vitamin D (IUCg) 

a-Tocopherol (ppm) 

Thiamine (ppm) 

Riboflavin (ppm) 

Niacin (ppm) 

Pantothenic acid (ppm) 

Pyridoxine (ppm) 

Folic acid (ppm) 

Biotin (ppm) 

Vitamin B,, (ppb) 

Choline (ppm) 

Mmerds 

Calcium (%) 

Phosphorus(%) 

Potassium (%) 

Chloride (%) 

Sodium(a) 

Magnesium (%) 

Sulfur (%) 

(ppm)

Manganese (ppm) 

Zinc (ppm) 

Copper (ppm)

Iodine (ppm) 

chromium (PPm) 

Cobalt (ppm) 

Mean f Standard 

Deviation 

23.30 f 0.78 

5.25 f 0.16 

3.57 f 0.41 

6.40 f 0.16 

1.287 f 0.084 

0.306 f 0.075 

1.160 f 0.050 

0.58O.f 0.024 

0.917 f 0.034 

1.972 f 0.052 

1.273f 0.051 

0.437 f 0.115 

0.994 f 0.125 

0.896 f 0.055 

0.223 f 0.160 

0.677 f 0.105 

1.089 f 0.057 

2.389 f 0.233 

0.217 f 0.036 

7.058 f 2,035 

4,450 f 1,382 

36.92 f 9.32 

18.63 f 2.39 

7.92 f 0.93 

' 100.95f 25.92 

30.30 f 3.60 

9.25 f 2.62 

2.51 f 0.64 

0.267 

*0.049 

40.14 f 20.04 

3.068 f314 

1.18 fO.09 

0.94 f 0.03 

0.887 f 0.067 

0.526 f 0.092 

0.315 f 0.034 

0.168 f 0.008 

0.274 f 0.063 

356.2 f 90.0 

92.24f.5.35 

58.14 f 9.91 

11.50 f 2.40 

3.70 f 1.14 

1.71 f 0.45 

0,797f 0.23 

Range 

22.20 -24.20

4.90 -5.60

2.60 -4.30 

6.11 -6.55

1.100- 1.390 

0.181 -0.400 

1.060 -1.220

0.53 1-0.608 

0.867 -0.965 

1.850 -2.040 

1.200-1.370 

0.306 -0.699 

0.665 -1.110 . 

0.824 -0.985

0.107 -0.671 

0.564 -0.794 

0.962 -1.170

1.830-2.570 

0.210 -0.320 

._ 

4,180 12,140 -

3,000 -6,300 

22.5 -48.9 

15.0 -28.0

6.10-9.00 

65.0 -150.0

23.0 -34.6

5.60 -14.0

1.80 -3.70

0.19 -0.35 

10.6 -65.0

2,400 -3,430

1.00- 1.50 

0.85 -1.00 

0.772 -0.971 

0.380 -0.635 

0.258 -0.370 

0.151 -0.180 

0.208 -0.420 

255.0 -523.0 

8 1.70 -99.40 

46.10- 81.60 

8.090 -15.39

1.52 -5.83

0.85 -2.09 

0.490- 1.150 

Number of Samples 

27 

27 

27 

27 

10 

10 

10 

10 

10 

10 

10 

10 

10 

10 1 

10 

10 

10 

9 

9 1 . 

27 

4 

9 

27 

10 

9 

10 

10 

10 

10 

10 

9 

27 

27 

8 

8 

10 

10 

10 

10 

10 

10 

10 

10 

9 

6 
302 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

TABLEK4 

Contaminant Levels in NIH-07 Rat and Mouse Rationa 

Mean f Standard 

Deviationb -ge Number of Samples 

Contaminants 

Arsenic (ppm) 

Cadmium (ppm) 

Lead (ppm) 

Mercury (PPm) 

Selenium (ppm) 

Aflatoxins (ppb)' 

Nitrate nitrogen (ppm)d 

Nitrite nitrogen (ppm)d 

BHA (PPmle 

BHT (ppmle 

Aerobic plate count (CFU/g) 

Coliform (MPN/g) 

Escherichia coli (MPN/g) 

Salmonella (MPN/g) 

Total nitrosoamines (ppbp 

N-Nitrosodimethylamine (p b)f

N-Nitrosopyrrolidine (ppb) P

Pesticides (ppm) 

a-BHCg 

P-BHC 

y-BHC 

&BHC 

Heptachlor 

Aldrin 

Heptachlor epoxide 

DDE 

DDD 

DDT 

HCB 

Mirex 

Methoxychlor 

Dieldrin 

Endrin 

Telodrin 

Chlordane 

Toxaphene 

Estimated PCBs 

Ronnel 

Ethion 

Trithion 

Diazinon 

Methyl parathion 

Ethyl parathion 

Malathion 

Endosulfan I 

Endosulfan II 

Endosulfan sulfate 

0.34 f 0.19 

0.08 f 0.04 

0.27 f 0.23 

0.03 f 0.01 

0.42 f 0.24 

<5.0 

14.84 f 4.37 

0.22 f 0.17 

1.81 f 1.88 

1.63 f 1.52 

41,000 f 25,598 

3.00 

3.00 

Negative 

7.74 f 2.33 

5.77 f 1.81 

1.97 f 1.05 

<0.01 

<0.02 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.01 

<0.05 

<0.01 

<0.01 

<0.01 

<0.05 

<o.1 

<0.2 

<0.01 

<0.02 

<0.05 

<o.1 

co.02 

<0.02 

0.27 f 0.25 

<0.01 

<0.01 

<0.03 

a CFU = colony forming units; MPN= most probable number; BHC= 

0.07 -0.70 27 

0.05 -0.2 27, 

0.10- 1.00 27

0.02 -0.05 27 

0.10- 1.21 27 

26 

5.70 -21.0 21 

0.10 -0.70 27 

1.00 -10.0 27 

1.00 -8.00 27 

4,100 -

<3.00 

<3.00 

4.80 -

3.80 -

110,000 27 

27 

27 

27 

16.50 27 

13.00 27 

1.00 -4.30 27

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

31 

0.05 -1.00 27 

31 

31 

31 

hexachlorocyclohexaneor benzene hexachloride 

For values less than the limit of detection, the detection limit is given as the mean. ' No aflatoxin measurement was recorded for the lot milled2 October 1989. 

Sources of contamination: alfalfa, grains, and fish meal 

e Sources of contamination: soy oil and fish meal ' AII values were corrected for percent recovery. 

304 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

SENTINEL ANIMAL PROGRAM 

METHODS' 

Rodents used in the Carcinogenesis Program of the National Toxicology Programare produced in optimally 

clean facilities to eliminate potential pathogens that mayaffect study results. The Sentinel Animal Program is 

part of the periodic monitoring of animal health that occurs during the toxicologicevaluation of chemical 

compounds. Under this program, the disease state of the rodents is monitored via serology on sera from extra 

(sentinel) animals in the study rooms.These animals and the study animalsare subject to identical 

environmental conditions. The sentinel animals come from the same production source and weanling groups as 

the animals used for the studies of chemical compounds. 

RATS e .. . . 

For the 13-week study, samples were obtained fromfive male and five female sentinel animals at terminal ' . 

sacrifice: Blood from each animal was collected and allowedto clot, and the serum was separated. The 

samples were processed appropriately and sent for 

~ 

to Microbiological Associates, Inc. (Bethesda, MD), 

determination of antibody titers. The following tests were performed: 

Method and Test Time of Analvsis 

ELISA .~ .. 

CARB (cilia-associated respiratory bacillus). Study tenhination , , . - . '/ 

Mycoplasma arthritidis Study termination. 

Mycoplasma pulmonis Study termination 

PVM (pneumonia virusof mice) Study termination 

RCV/SDA (rat coronavirus/ .. . 

sialodacryoadenitis virus) Study termination 

Sendai . .. . .Studytermination . 

Hemagglutination Inhibition 

H-1 (Toolan's H- 1 virus) Study termination 

KRV (Kilham rat virus) . Study termination 

Prior to the beginning of the 2-year study, samples were obtainedfrom five male and five female F344/N rats. 

For the 2-year study, samples for viral screening .were collected from five male sentinel rats at 3 months, from 

five female sentinel rats at 4months, and.from five male agd five female sentinel rats at 12, 17, and 18 months. 

In addition, a sample was collected from one moribund male sentinel rat at 16months. Samples were obtained 

from five male rats in the60 or 100mgkg dose groups and from five female rats in the 100mgkg dose group 

at terminal sacrifice. Blood from eachanimal was collected and allowedto clot, and the serum was separated. 

Blood from each collection was processed appropriately, shipped to Microbiological.Associates,Inc., and . 

screened for the following: . .. 

_. . 

c. ,. . ,, .. . . . . 
Sh~nnPidAmimd !hTJglRilm' ' ' 309 

MeUhod and TesU 

ELISA 

PVM 

RCV/SDA 

Sendai 

. , 

. 

. ., 

Immunofluorescence Assay 

RCVISDA 

Hemagglutination Inhibition 

H-1 

KRV 

MICE 

Time off Anaahsis L ' 

Quarantine, 3,4, 12, 16, 17, and 18 months, and study 

termination 

Quarantine, 3,4,12, 16,17,and 18 months, and study 

termination 

Quarantine, 3,4,12,16,17, and 18 months, and study 

termination 

Study termination 

Quarantine, 3,4, 12,16, 17, and 18 months, and study 

termination 

Quarantine, 3,4,12, 16,17,and 18 months, and study 

termination 

For the 13-week study, samples were obtained fromfive male and five female sentinel animals at terminal 

sacrifice. Blood from each animal was collected and allowedto clot, and the serum was separated., The 

samples were processed appropriately andsent to Microbiological Associates, Inc., for determination of 

antibody titers. The following tests were performed: 

Method and Test 

Complement Fixation 

LCM (lymphocytic choriomeningitis virus) 

ELISA 

CARB 

Ectromelia virus 

GDVII (mouse encephalomyelitis virus) 

Mouse adenoma virus 

MHV (mouse hepatitis virus)

M.arthritidis 

M.pulmonis 

PVM 

Reovirus 3 

Sendai 

Immunofluorescence Assay 

EDIM (epizootic diarrhea of infant mice) 

Hemagglutination Inhibition 

K (papovavirus) 

MVM (minute virus of mice) 

Polyoma virus 

Time off Anahsis 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 
306 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR 456 

Prior to the beginning of the 2.-year study, samples were obtained fromfive male and five female B6C3Fl mice. 

For the 2-year study, samplesfor viral screening were collectedfrom as many as five male and five female 

sentinel mice at 6, 12, and 18 months. Samples were obtained from five male and five female mice in the 

4 mgkg dose group at terminal sacrifice. Blood from each animal was collected and allowed to clot, and the 

serum was separated. The samples were processed appropriately, shippedto Microbiological Associates, Inc., 

and screened for the following: . ' 

:Method and Test Time of Analvsis 

ELISA 

Ectromelia virus Quarantine, 6, 12, and 18 months, and study termination 

EDIM 12 and 18 months 

GDVII Quarantine, 6,12, and 18 months, and study termination 

LCM 6, 12, and 18 months, and study termination 

MVM Quarantine, . . 

Mouse adenoma virus Quarantine, 6,12, and 18 months, and study termination 

MHV Quarantine, 6,12, and 18 months, and study termination 

PVM Quarantine, 6,12, and 18 months, and study termination 

Reovirus 3 Quarantine, 6,12, and 18 months, and study termination 

Sendai Quarantine, 6,12, and 18 months, and study termination 

Immunofluorescence Assay 

EDIM Quarantine, 6 and 18 months, and study termination 

GDVII Study termination (females only) 

LCM Quarantine 

MVM 6 and 12 months 

MHV 6 months 

Reovirus 3 18 months 

Hemagglutination Inhibition 

K Quarantine, 6,12, and 18 months, and study termination 

MVM 18months and study termination 

Polyoma virus Quarantine, 6,12, and 18 months, and study termination 

(males only) 

Prior to the beginning of the 1-year study, samples were obtained fromfive female SENCAR mice. For the 1-

year study, samples for viral screening were collectedfrom five female sentinel mice at7 months and terminal 

sacrifice. Blood from each animal was collected and allowedto clot, and the serum was separated. The 

samples were processed appropriately, shippedto Microbiological Associates, Inc., and screened for the 

following: 

Method and Test Time of Analvsis 

ELISA 

Ectromelia virus Quarantine, 7 months, and study termination 

EDIM 7 months and study termination 

GDVII Quarantine, 7 months, and study termination 

LCM Quarantine, 7 months, and study termination 

Mouse adenoma virus Quarantine, 7 months, and study termination 

MHV Quarantine, 7 months, and study termination 

PVM Quarantine, 7 months, and study termination 

Reovirus 3 Quarantine, 7 months, and study termination 

Sendai Quarantine, 7 months, and study termination 
n--

Sentinel Animal Program 

“Id t3Jlld Test 

Immunofluorescence Assay \

EDIM Quarantine and study termination 

GDVII Study termination 

MVM Quarantine and7 months 

Mouse adenoma virus Study termination 

Hemagglutination Inhibition 

K Quarantine, 7 months, and study termination 

MVM Study termination 

Polyoma virus Quarantine, 7 months, and study termination 

Results of serology tests are presented in TableL1. 
308 1,2-Dihydro-2,2,4-trimethylquinoline,NTP TR456 

TABLEL1 

Murine Virus Antibody Determinationsfor F344N Rats and B6C3Fl Mice in the 13-Week 

and 2-Year Studies andfor SENCAR Mice in the 1-Year Studyof 1,2-Dihydro-2,2,4-trimethylquinoline 

Interval Incidence of Antibody Positive Serologic 

in Sentinel Animals Reaction for 

13-Week Studies 

Rats 

Study termination 8/10 PVM 

Mice 

. Study termination 218 Mycoplasma arfhritidisa 

2-Year Studies 

Rats 

Quarantine 0110 None positii-e 

3 Months 015 None positive 

4 Months 015 None positive 

12 Months 0110 None positive 

16 Months 011 None positive 

17 Months 0110 None positive 

18 Months 0110 None positive 

Study termination 0110 None positive 

Mice 

Quarantine 0110 None positive 

6 Months 2/10 Mouse hepatitis virus 

12 Months 0110 None positive 

18 Months 018 None positive 

Study termination 0110 None positive 

1-Year Study 

Mice 

Quarantine 015 ' Nonepositive 

7 Months 015 None positive 

Study termination 015 None positive 

a Further evaluation of samples positive forM.arthrifidis by immunoblot and Western blot procedures indicated that the positive titers may be 

due to cross reaction with antibodies of nonpathogenic Mycoplasma or other agents. Only sporadic samples were positive and there were no

clinical findings or histopathologic changesof M.arthrifidis infectionin mice with positive titers. Accordingly,M.arthrifidis-positive titers 

were considered to be false positives. 
DEPARTMENT OF 

HEALTH & HUMAN SIERVICES 

Pubiic Health Service POSTAGE AND FEES PAID 

Central Data Management 

National Toxicology Program 

P.O. BOX 12233, MD E142 

Permit No. G-811 

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ResearchTriangle Park, NC27709 

Official Business 

Penalty for Private Use - $300 

NIH Publication No. 97-3372 

February1997