NTP TECHNICAL REPORT
 

ON THE 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF
 

PYRIDINE
 

(CAS NO. 110-86-1) 

IN F344/N RATS, WISTAR RATS, AND B6C3F1 MICE 

(DRINKING WATER STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

March 2000 

NTP TR 470
 

NIH Publication No. 00-3960
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

National Institutes of Health
 
FOREWORD
 

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

and 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), Centers for Disease Control and Prevention. 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 Health Service agencies relating to basic and applied research and to 

biological assay development 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 and for the primary 

prevention of disease. 

The studies described in this Technical Report were performed under the direction of 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. Animal care and use were in accordance with 

the 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 subjected to 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 

quantitative risk analyses for humans require wider analyses beyond the purview of these studies. Selection 

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

Listings of all published NTP reports and ongoing studies are available from NTP Central Data Management, 

NIEHS, P.O. Box 12233, MD E1-02, Research Triangle Park, NC 27709 (919-541-3419). The Abstracts and 

other study information for 2-year studies are also available at the NTP’s World Wide Web site: http://ntpserver.niehs.nih.gov. 
NTP TECHNICAL REPORT
 

ON THE
 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF
 

PYRIDINE
 

(CAS NO. 110-86-1) 

IN F344/N RATS, WISTAR RATS, AND B6C3F1 MICE 

(DRINKING WATER STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

March 2000 

NTP TR 470
 

NIH Publication No. 00-3960
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

National Institutes of Health
 
2 Pyridine, NTP TR 470 

CONTRIBUTORS
 

National Toxicology Program 

Evaluated and interpreted results and reported findings 

J.K. Dunnick, Ph.D., Study Scientist 

D.A. Bridge, B.S. 

J.R. Bucher, Ph.D. 

R.E. Chapin, Ph.D. 

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

J.K. Haseman, Ph.D. 

R.R. Maronpot, D.V.M. 

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

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

C.S. Smith, Ph.D. 

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

D.B. Walters, Ph.D. 

K.L. Witt, M.S., Integrated Laboratory Systems 

TSI Mason Research Institute 

Conducted studies, evaluated pathology findings for 13-week and 

2-year studies in rats and mice 

A.G. Braun, Sc.D., Principal Investigator, 13-week studies 

M.R. Osheroff, Ph.D., Principal Investigator, 2-year studies 

C. Gamba-Vitalo, Ph.D. 

D. Norlin, Ph.D. 

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

PATHCO, Inc. 

Histopathologic evaluation for 2-year studies in F344/N and 

Wistar rats 

D.G. Goodman, V.M.D. 

P.K. Hildebrandt, D.V.M. 

Experimental Pathology Laboratories, Inc. 

Provided pathology quality assurance 

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

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

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

Dynamac Corporation 

Prepared quality assurance audits 

S. Brecher, Ph.D., Principal Investigator 

NTP Pathology Working Group 

Evaluated slides, prepared pathology report on F344/N and Wistar 

rats (22 July 1997) 

M.P. Jokinen, D.V.M., Chairperson 

Pathology Associates International 

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

Experimental Pathology Laboratories, Inc. 

S. Ching, D.V.M., Ph.D. 

SVC Associates, Inc. 

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

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

P.B. Little, D.V.M., Ph.D., Observer 

Pathology Associates International 

S. Platz, D.V.M., Ph.D., Observer 

Boehringer Ingelheim 

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

National Toxicology Program 

A. Yoshida, D.V.M., Ph.D., Observer 

National Toxicology Program 

Evaluated slides, prepared pathology report on kidney step sections 

of male F344/N and Wistar rats (8 August 1997) 

P.B. Little, D.V.M., Ph.D., Chairperson 

Pathology Associates International 

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

National Toxicology Program 

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

National Toxicology Program 

J. Mahler, D.V.M. 

National Toxicology Program 

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

National Toxicology Program 

Evaluated slides, prepared pathology report on mice (19 September 

1996) 

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

PATHCO, Inc. 

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

Experimental Pathology Laboratories, Inc. 

R. Cattley, V.M.D., Ph.D. 

Chemical Industry Institute of Toxicology 

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

National Toxicology Program 

A. Nyska, D.V.M. 

National Toxicology Program 

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

National Toxicology Program 
Pyridine, NTP TR 470 3 

Analytical Sciences, Inc. 

Provided statistical analyses 

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

S.R. Lloyd, M.S. 

N.G. Mintz, B.S. 

Biotechnical Services, Inc. 

Prepared Technical Report 

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

J.R. Carlton, B.A. 

G. Gordon, M.A. 

L.M. Harper, B.S. 

A.M. Macri-Hanson, M.A., M.F.A. 
4 

CONTENTS
 

ABSTRACT ............................................................................ 7 
 

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ................ 13 
 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE . . . .................................... 14 
 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS . ........... 15 
 

INTRODUCTION ....................................................................... 17 
 

MATERIALS AND METHODS ........................................................... 25 
 

RESULTS .............................................................................. 35 
 

DISCUSSION AND CONCLUSIONS ....................................................... 67 
 

REFERENCES .......................................................................... 73 
 

APPENDIX A Summary of Lesions in Male F344/N Rats in the 2-Year Drinking Water Study
 

of Pyridine ............................................................... 83 
 

APPENDIX B Summary of Lesions in Female F344/N Rats in the 2-Year Drinking Water Study
 

of Pyridine ............................................................... 115 
 

APPENDIX C Summary of Lesions in Male Wistar Rats in the 2-Year Drinking Water Study
 

of Pyridine ............................................................... 149 
 

APPENDIX D Summary of Lesions in Male Mice in the 2-Year Drinking Water Study
 

of Pyridine ............................................................... 189 
 

APPENDIX E Summary of Lesions in Female Mice in the 2-Year Drinking Water Study
 

of Pyridine ............................................................... 227 
 

APPENDIX F Genetic Toxicology ........................................................ 261 
 

APPENDIX G Hematology and Clinical Chemistry Results . . . ................................ 275 
 

APPENDIX H Organ Weights and Organ-Weight-to-Body-Weight Ratios . . . .................... 285 
 

APPENDIX I Reproductive Tissue Evaluations and Estrous Cycle Characterization . . ........... 289 
 

APPENDIX J Determinations of Pyridine in Plasma ......................................... 293 
 

APPENDIX K Chemical Characterization and Dose Formulation Studies ....................... 295 
 
Pyridine, NTP TR 470 5 

APPENDIX L Water and Compound Consumption in the 2-Year Drinking Water Studies 

of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 

APPENDIX M Ingredients, Nutrient Composition, and Contaminant Levels 

in NIH-07 Rat and Mouse Ration ............................................ 319 

APPENDIX N Sentinel Animal Program .................................................. 323 
6 Pyridine, NTP TR 470
 
 

N
 

 

 

 

 

7 

ABSTRACT
 

PYRIDINE 

CAS No. 110-86-1 

Chemical Formula: C5H5N 

Synonyms: Azabenzene, azine 

Pyridine is used as a denaturant in alcohol and antifreeze mixtures, as a solvent for paint, rubber, and 

polycarbonate resins, and as an intermediate in the 

manufacture of insecticides, herbicides, and fungicides. 

It is used in the production of piperidine, an intermediate in the manufacture of rubber and mepiquat 

chloride, and as an intermediate and solvent in the 

preparation of vitamins and drugs, dyes, textile water 

repellants, and flavoring agents in food. Pyridine was 

nominated for study because of its large production 

volume and its use in a variety of food, medical, and 

industrial products. Male and female F344/N rats, male 

Wistar rats, and male and female B6C3F1 mice were 

exposed to pyridine (approximately 99% pure) in 

drinking water for 13 weeks or 2 years. Genetic 

toxicology studies were conducted in Salmonella 

typhimurium, L5178Y mouse lymphoma cells, cultured 

Chinese hamster ovary cells, Drosophila melanogaster, 

and mouse bone marrow cells. 

13-WEEK STUDY IN F344/N RATS 

Groups of 10 male and 10 female F344/N rats were 

exposed to pyridine in drinking water at concentrations 

of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to 

average daily doses of 5, 10, 25, 55, or 90 mg pyridine/ 

kg body weight). Two females exposed to 1,000 ppm 

Molecular Weight: 79.10 

died during week 1. Final mean body weights of 

1,000 ppm males and females and 500 ppm females 

were significantly less than controls. Water consumption by female rats exposed to 1,000 ppm was less than 

that by controls. At study termination, evidence of 

anemia persisted in the 500 and 1,000 ppm males and 

all exposed groups of females. There was evidence of 

hepatocellular injury and/or altered hepatic function 

demonstrated by increased serum alanine aminotransferase and sorbitol dehydrogenase activities and bile 

acid concentrations in 500 and 1,000 ppm rats. The 

estrous cycle length of 1,000 ppm females was significantly longer than that of the controls. Liver weights of 

males and females exposed to 250 ppm or greater were 

significantly greater than controls. In the liver, the 

incidences of centrilobular degeneration, hypertrophy, 

chronic inflammation, and pigmentation were generally 

increased in 500 and 1,000 ppm males and females 

relative to controls. In the kidney, the incidences of 

granular casts and hyaline degeneration (hyaline 

droplets) were significantly increased in 1,000 ppm 

males and slightly increased in 500 ppm males; these 

lesions are consistent with α2u-globulin nephropathy. 

Additionally, there were increased incidences and/or 

severities of protein casts, chronic inflammation, 

mineralization, and regeneration primarily in 500 and 

1,000 ppm males. 
 

 

 

8 Pyridine, NTP TR 470 

13-WEEK STUDY 

IN MALE WISTAR RATS 

Groups of 10 male Wistar rats were exposed to pyridine 

in drinking water at concentrations of 0, 50, 100, 250, 

500, or 1,000 ppm (equivalent to average daily doses of 

5, 10, 30, 60, or 100 mg/kg). One male rat exposed to 

500 ppm died during week 1. Final mean body weights 

of rats exposed to 250, 500, or 1,000 ppm were significantly less than those of the controls. Water consumption by rats exposed to 1,000 ppm was lower than that 

by controls. There was evidence of hepatocellular 

injury and/or altered hepatic function in the 500 and 

1,000 ppm groups, similar to that observed in the 

13-week study in F344/N rats. Incidences of centrilobular degeneration, hypertrophy, chronic inflammation, and pigmentation in the liver of rats exposed to 

500 or 1,000 ppm were significantly increased relative 

to controls. 

13-WEEK STUDY IN MICE 

Groups of 10 male and 10 female B6C3F1 mice were 

exposed to pyridine in drinking water at concentrations 

of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to 

average daily doses of 10, 20, 50, 85, or 160 mg/kg for 

males and 10, 20, 60, 100, or 190 mg/kg for females). 

One female mouse exposed to 250 ppm died during 

week 2. Final mean body weights of female mice 

exposed to 1,000 ppm were significantly less than those 

of controls. Water consumption by exposed female 

mice was lower than that by controls at week 1 but 

generally slightly higher than controls at week 13. 

Sperm motility in exposed male mice was significantly 

decreased relative to controls. Liver weights were 

significantly increased relative to controls in males 

exposed to 100 ppm or greater and in 250 and 500 ppm 

females. No chemical-related lesions were observed in 

male or female mice. 

2-YEAR STUDY IN F344/N RATS 

Groups of 50 male and 50 female F344/N rats were 

exposed to pyridine in drinking water at concentrations 

of 0, 100, 200, or 400 ppm (equivalent to average daily 

doses of 7, 14, or 33 mg/kg) for 104 (males) or 105 

(females) weeks. 

Survival, Body Weights, 

and Water Consumption 

Survival of exposed males and females was similar to 

that of controls. Mean body weights of 400 ppm males 

and females were generally less than those of the 

controls throughout the study, and those of 200 ppm 

males and females were less during the second year of 

the study. Water consumption by males and females 

exposed to 200 or 400 ppm was generally greater than 

that by controls. 

Pathology Findings 

Incidences of renal tubule adenoma and renal tubule 

adenoma or carcinoma (combined) in male rats exposed 

to 400 ppm were significantly increased compared to 

controls and exceeded the historical control ranges. 

The findings from an extended evaluation (step section) 

of the kidneys did not reveal additional carcinomas, but 

additional adenomas were observed in each group of 

males. In the standard evaluation, an increased incidence of renal tubule hyperplasia was observed in 

400 ppm males compared to controls. Incidences of 

mononuclear cell leukemia in female rats were significantly increased in the 200 and 400 ppm groups, and 

the incidence in the 400 ppm group exceeded the 

historical control range. 

Exposure concentration-related nonneoplastic liver 

lesions were observed in males and females, and the 

incidences were generally increased in groups exposed 

to 400 ppm. These included centrilobular cytomegaly, 

cytoplasmic vacuolization, periportal fibrosis, fibrosis, 

centrilobular degeneration and necrosis, and pigmentation. Bile duct hyperplasia occurred more often in 

exposed females than in controls. 

2-YEAR STUDY IN MALE WISTAR RATS 

Groups of 50 male Wistar rats were exposed to pyridine 

in drinking water at concentrations of 0, 100, 200, or 

400 ppm (equivalent to average daily doses of 8, 17, or 

36 mg/kg) for 104 weeks. 

Survival, Body Weights, 

and Water Consumption 

Survival of rats exposed to 200 or 400 ppm was significantly less than that of the controls. Mean body 
 

 

 

Pyridine, NTP TR 470 9 

weights of rats exposed to 100, 200, or 400 ppm were 

significantly less than controls. Water consumption 

was similar by control and exposed rats. 

Pathology Findings 

The incidence of testicular interstitial cell adenoma in 

rats exposed to 400 ppm was significantly increased 

compared to controls. Incidences of interstitial cell 

hyperplasia were observed in control and exposed 

groups and were slightly, but not significantly, 

increased in rats exposed to 200 or 400 ppm. 

Severity of nephropathy was marked in all groups, and 

additional evidence of kidney disease, including 

mineralization in the glandular stomach, parathyroid 

gland hyperplasia, and fibrous osteodystrophy, was 

observed in 100 and 200 ppm rats. The incidences of 

hepatic centrilobular degeneration and necrosis, fibrosis, periportal fibrosis, and/or pigmentation were 

increased in one or more exposed groups. 

2-YEAR STUDY IN MICE 

Groups of 50 male B6C3F1 mice were exposed to 

pyridine in drinking water at concentrations of 0, 250, 

500, or 1,000 ppm (equivalent to average daily doses of 

35, 65, or 110 mg/kg) for 104 weeks, and groups of 50 

female B6C3F1 mice were exposed to pyridine in 

drinking water at concentrations of 0, 125, 250, or 

500 ppm (equivalent to average daily doses of 15, 35, 

or 70 mg/kg) for 105 weeks. 

Survival, Body Weights, 

and Water Consumption 

Survival of exposed males and females was similar to 

that of the controls. Mean body weights of 250 and 

500 ppm females were less than controls. Water consumption by males exposed to 250 or 500 ppm was 

generally greater than that by controls during the last 

year of the study; male mice exposed to 1,000 ppm 

consumed less water than controls throughout the 

study. Water consumption by exposed females was 

generally lower than that by controls during the first 

year of the study, but greater than controls during the 

second year. 

Pathology Findings 

Hepatocellular neoplasms, including hepatoblastomas, 

in exposed male and female mice were clearly related 

to pyridine exposure. Additionally, many mice had 

multiple hepatocellular neoplasms. The incidences of 

hepatocellular neoplasms in exposed males and females 

generally exceeded the historical control ranges for 

drinking water studies. Neoplasms from control mice, 

1,000 ppm males, and 500 ppm females were negative 

when stained for p53 protein. 

GENETIC TOXICOLOGY 

Pyridine was not mutagenic in Salmonella typhimurium 

strains TA98, TA100, TA1535, or TA1537 or in 

L5178Y mouse lymphoma cells, with or without S9 

metabolic activation, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. 

Pyridine was tested for induction of sex-linked recessive lethal mutations in adult male Drosophila melanogaster, and mixed results were obtained. In one experiment, administration by injection gave negative results, 

but feeding produced an equivocal response. A second 

experiment generated negative results by injection and 

feeding. A third experiment showed significant 

increases in sex-linked recessive lethal mutations in 

flies treated with pyridine by injection but not by 

feeding. Overall, results of the sex-linked recessive 

lethal mutations test in Drosophila melanogaster were 

considered negative by feeding and equivocal by 

injection. Results of a single reciprocal translocation 

test in male Drosophila melanogaster were negative. 

No induction of chromosomal aberrations or micronuclei was noted in bone marrow cells of male mice 

administered pyridine via intraperitoneal injection. 

CONCLUSIONS 

Under the conditions of these 2-year drinking water 

studies, there was some evidence of carcinogenic 

activity* of pyridine in male F344/N rats based on 

increased incidences of renal tubule neoplasms. There 

was equivocal evidence of carcinogenic activity of 

pyridine in female F344/N rats based on increased 

incidences of mononuclear cell leukemia. There was 

equivocal evidence of carcinogenic activity in male 

Wistar rats based on an increased incidence of 

interstitial cell adenoma of the testis. There was clear 

evidence of carcinogenic activity of pyridine in male 

and female B6C3F1 mice based on increased incidences 

of malignant hepatocellular neoplasms. 
 

__________ 

10 Pyridine, NTP TR 470 

In F344/N rats, exposure to pyridine resulted in Wistar rats, pyridine exposure resulted in increased 

increased incidences of centrilobular cytomegaly and incidences of centrilobular degeneration and necrosis, 

degeneration, cytoplasmic vacuolization, and pigmen- fibrosis, periportal fibrosis, and pigmentation in the 

tation in the liver of males and females; periportal liver, and, secondary to kidney disease, mineralization 

fibrosis, fibrosis, and centrilobular necrosis in the liver in the glandular stomach and parathyroid gland hyperof males; and bile duct hyperplasia in females. In male plasia. 

*	 Explanation of Levels of Evidence of Carcinogenic Activity is on page 13. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 15. 
Pyridine, NTP TR 470 11 

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Pyridine 

Male Female Male Male Female
 

F344/N Rats F344/N Rats Wistar Rats B6C3F1 Mice B6C3F1 Mice
 

Concentrations in 0, 100, 200, or 

drinking water 400 ppm 

Body weights	 200 and 400 ppm 

groups less than 

control group 

Survival rates	 25/50, 20/50, 25/50, 

16/50 

Nonneoplastic effects	 Liver: centrilobular 

cytomegaly (0/50, 

4/49, 8/50, 6/50); 

cytoplasmic 

vacuolization (4/50, 

6/49, 13/50, 17/50); 

periportal fibrosis 

(0/50, 0/49, 2/50, 

29/50); fibrosis (1/50, 

1/49, 1/50, 10/50); 

centrilobular 

degeneration (1/50, 

3/49, 2/50, 8/50); 

centrilobular necrosis 

(0/50, 3/49, 0/50, 

5/50); pigmentation 

(4/50, 11/49, 20/50, 

25/50) 

Neoplastic effects	 Kidney: renal tubule 

adenoma (standard 

evaluation - 1/50, 

0/48, 2/50, 6/49; 

standard and extended 

evaluations 

combined- 2/50, 

3/48, 6/50, 10/49); 

renal tubule adenoma 

or carcinoma 

(standard evaluation -

1/50, 1/48, 2/50, 6/49; 

standard and extended 

evaluations 

combined- 2/50, 4/48, 

6/50, 10/49) 

Uncertain findings	 None 

Level of evidence of Some evidence 

carcinogenic activity 

0, 100, 200, or 

400 ppm 

200 and 400 ppm 

groups less than 

control group 

32/50, 37/50, 29/50, 

26/50 

Liver: centrilobular 

cytomegaly (0/50, 

1/50, 4/50, 20/50); 

cytoplasmic 

vacuolization (10/50, 

7/50, 9/50, 18/50); 

centrilobular 

degeneration (1/50, 

2/50, 2/50, 7/50); 

bile duct hyperplasia 

(20/50, 29/50, 34/50, 

29/50); pigmentation 

(6/50, 2/50, 6/50, 

17/50) 

None 

Mononuclear cell 

leukemia: (12/50, 

16/50, 22/50, 23/50) 

Equivocal evidence 

0, 100, 200, or 

400 ppm 

Exposed groups less 

than control group 

22/50, 14/50, 11/50, 

7/50 

Liver: centrilobular 

degeneration (1/50, 

15/50, 25/50, 33/50); 

centrilobular necrosis 

(5/50, 6/50, 4/50, 

23/50); fibrosis (1/50, 

5/50, 26/50, 31/50); 

periportal fibrosis 

(0/50, 0/50, 5/50, 

7/50); pigmentation 

(6/50, 15/50, 34/50, 

42/50) 

Glandular Stomach: 

mineralization (8/49, 

25/50, 16/48, 6/48) 

Parathyroid Gland: 

hyperplasia (16/48, 

32/47, 29/48, 12/47) 

None 

Testis: interstitial cell 

adenoma (5/50, 6/49, 

4/49, 12/50) 

Equivocal evidence 

0, 250, 500, or 

1,000 ppm 

Exposed groups 

similar to control 

group 

35/50, 28/50, 35/49, 

35/50 

None 

Liver: hepatocellular 

adenoma (29/50, 

40/50, 34/49, 39/50); 

hepatocellular 

carcinoma (15/50, 

35/50, 41/49, 40/50); 

hepatoblastoma (2/50, 

18/50, 22/49, 15/50); 

hepatocellular 

adenoma, 

hepatocellular 

carcinoma, or 

hepatoblastoma 

(38/50, 47/50, 46/49, 

47/50) 

None 

Clear evidence 

0, 125, 250, or 

500 ppm 

Exposed groups less 

than control group 

32/50, 30/50, 22/50, 

29/50 

None 

Liver: hepatocellular 

adenoma (37/49, 

39/50, 43/50, 34/50); 

hepatocellular 

carcinoma (13/49, 

23/50, 33/50, 41/50); 

hepatoblastoma (1/49, 

2/50, 9/50, 16/50); 

hepatocellular 

adenoma, 

hepatocellular 

carcinoma, or 

hepatoblastoma 

(41/49, 42/50, 45/50, 

44/50) 

None 

Clear evidence 
12 Pyridine, NTP TR 470 

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Pyridine 

Genetic toxicology 

Salmonella typhimurium gene mutations:
 

Mouse lymphoma gene mutations:
 

Sister chromatid exchanges
 

Cultured Chinese hamster ovary cells in vitro: 

Chromosomal aberrations 

Cultured Chinese hamster ovary cells in vitro: 

Mouse bone marrow in vivo: 

Sex-linked recessive lethal mutations 

Drosophila melanogaster: 

Reciprocal translocations 

Drosophila melanogaster: 

Micronucleated erythrocytes 

Mouse bone marrow in vivo: 

Negative in strains TA98, TA100, TA1535, and TA1537, with and without S9 

Negative with and without S9 

Negative with and without S9 

Negative with and without S9 

Negative 

Equivocal by injection; negative by feeding 

Negative 

Negative 
Pyridine, NTP TR 470 13 

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY 

The National Toxicology Program describes 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 that a chemical is not a carcinogen, inasmuch as the experiments are conducted under a limited set of 

conditions. Positive results demonstrate that a chemical is carcinogenic for laboratory animals under the conditions of the study and indicate 

that exposure to the chemical has the potential for hazard to humans. Other organizations, such as the International Agency for Research on 

Cancer, assign a strength of evidence for conclusions based on an examination of all available evidence, including animal studies such as those 

conducted by the NTP, epidemiologic studies, and estimates of exposure. Thus, the actual determination of risk to humans from chemicals 

found to be carcinogenic in laboratory animals requires a wider analysis that extends beyond the purview of these studies. 

Five categories of evidence of carcinogenic activity are used in the Technical Report series to summarize the strength of the evidence observed in 

each experiment: two categories for positive results (clear evidence and some evidence); one category for uncertain findings (equivocal 

evidence); one category for no observable effects (no evidence); and one category for experiments that cannot be evaluated because of major 

flaws (inadequate study). These categories of interpretative conclusions were first adopted in June 1983 and then revised in March 1986 for 

use in the Technical Report series to 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 evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a dose-related (i) increase 

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

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

•	 Some evidence of carcinogenic activity is demonstrated by studies that are 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. 

•	 Equivocal evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a marginal increase of 

neoplasms that may be chemical related. 

•	 No evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing no chemical-related increases 

in malignant or benign neoplasms. 

•	 Inadequate study of carcinogenic activity is demonstrated by studies that, because of major qualitative or quantitative
 

limitations, cannot be interpreted as valid for showing either the presence or absence of carcinogenic activity.
 

When a conclusion statement for a particular experiment is selected, consideration must be given to 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 

understanding of long-term carcinogenesis studies in laboratory animals, especially for those evaluations that may be on the borderline between 

two adjacent levels. These considerations should include: 

• adequacy of the experimental design and conduct;
 

• occurrence of common versus uncommon neoplasia;
 

•	 progression (or lack thereof) from benign to malignant neoplasia as 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 known to be a possibility, the most prudent course is to 

assume that benign neoplasms of those types 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;
 

•	 latency in tumor induction; 

•	 multiplicity in site-specific neoplasia; 

• metastases; 

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

lesion in another sex or species);
 

•	 presence or absence of dose relationships; 

•	 statistical significance of the observed tumor increase; 

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

•	 survival-adjusted analyses and false positive or false negative concerns; 

•	 structure-activity correlations; and 

•	 in some cases, genetic toxicology. 
__________ 

14 Pyridine, NTP TR 470 

NATIONAL TOXICOLOGY PROGRAM BOARD OF SCIENTIFIC COUNSELORS
 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE
 

The members of the Technical Reports Review Subcommittee who evaluated the draft NTP Technical Report on pyridine on 10 December 1997 

are listed below. Subcommittee members serve as independent scientists, not as representatives of any institution, company, or governmental 

agency. In this capacity, subcommittee members have five major responsibilities in reviewing the NTP studies: 

• to ascertain that all relevant literature data have been adequately cited and interpreted, 

• to determine if the design and conditions of the NTP studies were appropriate, 

• to ensure that the Technical Report presents the experimental results and conclusions fully and clearly, 

• to judge the significance of the experimental results by scientific criteria, and 

• to assess the evaluation of the evidence of carcinogenic activity and other observed toxic responses. 

Gary P. Carlson, Ph.D., Chairperson John M. Cullen, Ph.D., V.M.D., Principal Reviewer 

School of Health Sciences Department of Microbiology, Parasitology, and Pathology 

Purdue University College of Veterinary Medicine 

West Lafayette, IN North Carolina State University 

Raleigh, NC 

A. John Bailer, Ph.D. 

Department of Mathematics and Statistics Susan M. Fischer, Ph.D., Principal Reviewer 

Miami University M.D. Anderson Cancer Center 

Oxford, OH University of Texas 

Smithville, TX 

Steven A. Belinsky, Ph.D.* 

Inhalation Toxicology Research Institute Thomas L. Goldsworthy, Ph.D. 

Kirkland Air Force Base Integrated Laboratory Systems 

Albuquerque, NM Research Triangle Park, NC 

James S. Bus, Ph.D., Principal Reviewer Irma Russo, M.D. 

Health and Environmental Sciences Fox Chase Cancer Center 

Dow Chemical Company Philadelphia, PA 

Midland, MI 

Linda A. Chatman, D.V.M. 

Pfizer, Inc. 

Groton, CT 

Special Reviewers 

Stephen S. Hecht, Ph.D. Jose Russo, M.D. 

University of Minnesota Cancer Centers Fox Chase Cancer Center 
 

Minneapolis, MN Philadelphia, PA
 

Michele Medinsky, Ph.D. 

Chemical Industry Institute of Toxicology 

Research Triangle Park, NC 

* Did not attend 
 

 

 

 

 

 

 

Pyridine, NTP TR 470 15 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS
 

On 10 December 1997, the draft Technical Report on 

the toxicology and carcinogenesis studies of pyridine 

received public review by the National Toxicology 

Program’s Board of Scientific Counselors’ Technical 

Reports Review Subcommittee. The meeting was held 

at the National Institute of Environmental Health 

Sciences, Research Triangle Park, NC. 

Dr. J.K. Dunnick, NIEHS, introduced the toxicology 

and carcinogenesis studies of pyridine by discussing the 

uses of the chemical and the rationale for study, 

describing the experimental design, reporting on any 

survival and body weight effects, and commenting on 

compound-related neoplastic and nonneoplastic lesions 

in rats and mice. The proposed conclusions for the 

2-year studies were some evidence of carcinogenic 

activity in male F344/N rats, equivocal evidence of 

carcinogenic activity in female F344/N rats and male 

Wistar rats, and clear evidence of carcinogenic activity 

in male and female B6C3F1 mice. 

Dr. Cullen, a principal reviewer, agreed with the 

proposed conclusions. He noted the large amount of 

inflammation in mouse livers and asked whether they 

had been screened for the possible presence of Helicobacter hepaticus infection. Dr. J.R. Hailey, NIEHS, 

said there was no frozen tissue available to perform 

PCR-based assays for identification of H. hepaticus. 

However, the liver lesions observed were not consistent 

with those typically associated with H. hepaticus 

infection. 

Dr. Fischer, the second principal reviewer, agreed with 

the conclusions. She said the discussion should include 

comments on increased incidences of metastatic neoplasms in mice compared to rats. Dr. Dunnick agreed. 

Dr. Fischer expressed concern that the Wistar rats 

exposed to 400 ppm did not live long enough to produce neoplasms, and, thus, this experiment was not 

informative. 

Dr. Bus, the third principal reviewer, did not agree with 

the proposed conclusions for female rats and mice and 

for male Wistar rats. He said the proposed conclusion 

of equivocal evidence in female rats was not warranted 

based on the lack of dose response, incidence values 

that only slightly exceeded recent NTP historical 

control values, and excessive body weight depressions 

that confound interpretation of chemical-associated 

neoplasms. Dr. Dunnick responded that by definition, 

the increases in the incidences of mononuclear cell 

leukemia were uncertain findings. With regard to male 

Wistar rats, Dr. Bus stated that the severe toxicity 

associated with markedly decreased survival and effects 

on body weight gain, especially at 200 and 400 ppm, 

compromised interpretation of the increased incidence 

of testicular adenomas in the 400 ppm group. Finally, 

he thought it difficult to understand a conclusion of 

clear evidence in female mice in view of the profound 

body weight loss over the last 25 weeks of the study, 

and though there was an exposure-related increase in 

the incidences of malignant liver neoplasms, liver 

adenomas and total neoplasms were not altered. 

Dr. Dunnick said the level of clear evidence was 

justified by the large exposure-related increased incidences of malignant neoplasms. The body weight loss 

was due in part to the development of liver neoplasms. 

Dr. J.K. Haseman, NIEHS, noted that while the incidence of liver neoplasms in control female mice may 

have been one of the highest seen in the NTP, almost 

all neoplasms were adenomas. On the other hand, 

almost every exposed animal that lived one year or 

longer developed a liver neoplasm, often multiple 

neoplasms, and often carcinomas or hepatoblastomas, 

with many neoplasms metastasizing to the lung, constituting one of the strongest carcinogenic effects ever 

seen at this site in his experience. Dr. Bus said this 

changed his perspective on the neoplasms in female 

mice. 

Further discussion of whether hepatoblastomas should 

be viewed and weighed separately from hepatocellular 

carcinomas ensued. Dr. Hailey thought they should be 

viewed as part of a natural progression and that with 

chemicals having neoplasm promoter activity there is 

almost always an associated increase in hepatoblastomas. There was discussion about the appropriateness 

in general of combining benign and malignant neoplasms. Dr. J. Russo argued that combining can be 

misleading. Dr. Hailey commented that with some 

neoplasm types combining might be controversial but 

with the liver (mice) and the kidney (rats), the sites at 

issue here, there is a spectrum of lesions from foci or 

hyperplasia to adenoma to carcinoma that represents a 
16 Pyridine, NTP TR 470 

morphological and biological continuum, and combining seems appropriate. Dr. Bailer said that, based on 

the data in the report, he would have considered clear 

evidence as the proposed conclusion for male rats. 

Dr. Bucher observed that NTP is using its combined 

experience to delineate between some evidence and 

clear evidence based on its historical perspective. 

Dr. Bus moved that the Technical Report on pyridine 

be accepted with the revisions discussed and the 

conclusions as written for male F344/N rats, some 

evidence of carcinogenic activity, and for male and 

female B6C3F1 mice, clear evidence of carcinogenic 

activity. He moved that the conclusions for female 

F344/N rats and male Wistar rats be changed from 

equivocal evidence of carcinogenic activity to inadequate study of carcinogenic activity. Dr. Cullen 

seconded the motion. Dr. Haseman said that inadequate study is a category of evidence generally used 

only when there is some major flaw that makes the 

study uninterpretable. Dr. Bailer moved to amend the 

motion to keep the level of evidence for female F344/N 

rats and male Wistar rats as originally proposed, 

equivocal evidence of carcinogenic activity. Dr. Cullen 

seconded the amendment, which was accepted by six 

yes votes to one no vote (Dr. Bus). Dr. Bus’s motion as 

amended by Dr. Bailer was accepted unanimously with 

seven votes. 
 

N
 

 

 

 

 

17 

INTRODUCTION
 

PYRIDINE 

CAS No. 110-86-1 

Chemical Formula: C5H5N 

Synonyms: Azabenzene, azine 

CHEMICAL AND PHYSICAL PROPERTIES 

Pyridine is a slightly yellow or colorless, hygroscopic 

liquid with a characteristic nauseating odor and a 

burning taste. It is miscible with water, alcohols, 

diethyl ether, benzene, ligroin, and fatty oils and is 

slightly alkaline in reaction (pKa of 5.19). Pyridine 

boils at approximately 115 C at 760 mm Hg and has 

a specific gravity of 0.982, a vapor pressure of approximately 20 torr at 25 C, and a vapor density of 2.73 

(Jori et al., 1983; Hawley’s, 1987; Merck Index, 1989; 

Lewis, 1993). The liquid has a flash point (closed cup) 

of 20 C and is flammable when exposed to heat, 

flame, or oxidizers; the vapor explodes upon contact 

with a flame or spark. When heated to decomposition, 

it emits cyanide fumes (Hawley’s, 1987; Sittig, 1991; 

Lewis, 1993). 

PRODUCTION, USE, 

AND HUMAN EXPOSURE 

Pyridine is produced by coal carbonization and recovery from coke-oven gases and coal tar middle oil. 

Since the 1950s it has also been produced synthetically 

from the vapor phase reaction of acetaldehyde and 

ammonia, with formaldehyde and methanol sometimes 

added (Jori et al., 1983; NCI, 1985). 

Molecular Weight: 79.10 

Pyridine is a solvent that is widely employed in industry and the laboratory. It is used as a denaturant in 

alcohol and antifreeze mixtures, as a solvent for paint, 

rubber, and polycarbonate resins, and as an intermediate in the manufacture of insecticides (chlorpyrifos), herbicides (paraquat and trichloropyr), and 

fungicides. It is used in the production of piperidine, 

an intermediate in the manufacture of rubber and 

mepiquat chloride. Pyridine is also used as an intermediate and solvent in the preparation of vitamins and 

drugs, dyes, textile water repellants, and flavoring 

agents in food (NCI, 1985; Hawley’s, 1987; ATSDR, 

1992). 

Manufacturers and consumers used an estimated 

300,000 kg pyridine in 1977. Approximately 4.5 to 

8.9×106

 kg pyridine was produced in the United States 

in 1975, 27×106

 kg in 1976, and 11.6×106 kg in 1978 

(Pyridine Task Force, correspondence from Chairmen 

to U.S. Environmental Protection Agency, Office of 

Toxic Substances, Washington, DC, 1978). No information on the current annual production of pyridine is 

available in the literature (ATSDR, 1992). 

The greatest potential for exposure to pyridine is in the 

workplace. Occupational exposures, usually by inhalation or dermal absorption, may occur during pyridine 
 

 

 

 

18 Pyridine, NTP TR 470 

production or its use as a chemical intermediate or 

solvent (NCI, 1985). Exposure may also occur at cokeoven and oil-shale processing facilities. The U.S. 

Environmental Protection Agency (EPA) (1978) 

estimated that 249,000 persons were occupationally 

exposed to pyridine. The National Institute for Occupational Safety and Health (NIOSH) (1990) estimated 

the extent of potential human exposure between 1981 

and 1983 at over 41,000 workers. The 8-hour, timeweighted average permissible exposure level for 

pyridine is 5 ppm (16 mg/m3

) (ACGIH, 1997). NIOSH 

(1985) determined the concentration immediately 

dangerous to life or health to be 3,600 ppm. The 

pungent odor of pyridine (odor threshold of 0.17 ppm 

in air) serves to limit voluntary exposure (NCI, 1985). 

The odor becomes objectionable to unaccustomed 

individuals at 10 ppm, and olfactory fatigue occurs at 

greater than 5 ppm (Jori et al., 1983). 

Pyridine has rarely been detected in ambient air, water, 

or soil except near industrial sources (ATSDR, 1992). 

Pyridine is released into the atmosphere as fugitive 

emissions from coal gasification and oil shale processing facilities, from ironworking and coking plants 

(Masek, 1981), and from the combustion of polyisocyanate foam products (Seader et al., 1972; Junk and 

Ford, 1980). The Agency for Toxic Substances and 

Disease Registry estimated that 298,438 pounds of 

pyridine were released in air, 4,630 pounds in surface 

water, and 303,650 pounds in groundwater in 1987; 

209,880 pounds of pyridine were disposed of in publicly owned wastewater treatment plants (ATSDR, 

1992). Pyridine has been identified in effluent from 

waste-water treatment plants (Ellis et al., 1982), natural 

waters (Shelton and Hites, 1978), and groundwater near 

an underground coal gasification site (Stuermer et al., 

1982). An estimated 28,656 pounds of pyridine were 

released from industrial sources to land in 1987 

(ATSDR, 1992). Many states have regulations concerning the acceptable ambient air concentrations of 

pyridine. For an 8-hour period, ambient air limits have 

been set at 300 μg/m3

 in Connecticut, 150 μg/m3 in 

Indiana, 0.357 μg/m3

 in Nevada, 0.3 μg/m3 in Tampa, 

Florida, and 0.15 μg/m3

 in Vermont. Eighteen- and 

24-hour limits have been set at 0.30 μg/m3

 and 

250 μg/m3 in North Dakota and Virginia, respectively, 

and annual limits have been set at 2.0 μg/m3

 in New 

York and 35.7 μg/m3

 in Kansas (NATICH, 1989). 

In the United States, the general population may be 

exposed to low concentrations of pyridine by the ingestion of foods. Pyridine was detected among the natural 

volatile components of several foods, including fried 

chicken, cheese, and fried bacon (ATSDR, 1992). The 

EPA (1978) estimated the ingestion of pyridine in the 

United States to be about 500 mg per person per year. 

The FDA has approved the use of pyridine as a flavoring agent (21 CFR, § 172.515). Pyridine is also a 

coffee aroma constituent (ATSDR, 1992). Pyridine has 

been identified as a component of tobacco and marijuana smoke (Schmeltz and Hoffmann, 1977; 

Schumacher et al., 1977; Meril et al., 1981; Curvall 

et al., 1984; Eatough et al., 1989); the concentration of 

pyridine in indoor air contaminated with cigarette 

smoke may be as high as 16 μg/m3

 (ATSDR, 1992). 

REGULATORY STATUS 

The EPA Office of Toxic Substances has included 

pyridine in its toxic chemical release reporting rule 

(40 CFR, Part 372), its health and safety data reporting 

rule (40 CFR, § 716.120), and its preliminary assessment information reporting rule (40 CFR, § 712.30). 

The annual reportable quantity of pyridine release to 

the environment has been set at 1,000 pounds by the 

EPA Office of Emergency and Remedial Response 

(40 CFR, § 302.4). The EPA Office of Solid Wastes 

lists pyridine as a constituent of hazardous waste 

(40 CFR, Part 261), monitors its levels in groundwater 

(40 CFR, Part 264), and restricts its disposal on land 

(40 CFR, Part 268). 

ENVIRONMENTAL IMPACT 

Pyridine exists in the atmosphere as a vapor. Atmospheric pyridine may be slowly photodegraded by 

hydroxyl radicals in the troposphere; the estimated 

atmospheric lifetime is 23 to 46 days. A large fraction 

of the atmospheric pyridine vapor phase would tend to 

dissolve in water vapor (clouds and rain) due to its high 

water solubility. The magnitude of the Henry’s law 

constant for aqueous solutions of pyridine indicates that 

much of the atmospheric pyridine is removed by 

precipitation and suggests that the pyridine in water 

does not volatilize readily into the atmosphere. The 

volatility and sorption of pyridine from water varies 

considerably and is pH dependent. The rate of removal 

of pyridine from unfiltered river water by biodegradation depends on the initial pyridine concentration. At 

concentrations less than 20 mg/L, pyridine degradation 

was virtually complete in 8 days or less. Pyridine in 
 

N O 

O 2-Pyridone 

N N 

CH3 CH3
 

N + N +
 

OH 

Pyridine- Pyridine N-Methyl­ Hydroxy-N-methylpyridinium N-oxide pyridinium ion 

N N 

OH 

O 

4-Pyridone 3-Hydroxypyridine 

 

 

 

 

 

Pyridine, NTP TR 470 19 

water may partition to soils and sediments to an extent 

that depends on the pH of the water and the organic 

carbon content of the soil. Due to its low carbon/water 

partition coefficient, pyridine is highly mobile in soil. 

In laboratory screening tests, however, 94% to 100% of 

the pyridine added to municipal wastewater biodegraded in 2 to 21 days (ATSDR, 1992). 

ABSORPTION, DISTRIBUTION, 

METABOLISM, AND EXCRETION 

Pyridine is absorbed by inhalation and by oral or 

dermal exposure. Pyridine is eliminated in exhaled air, 

feces, and urine as free base and/or metabolites (Jori 

et al., 1983; NCI, 1985). 

Pyridine is metabolized primarily by N-methylation 

and/or aromatic hydroxylation; urinary excretion of 

metabolites and unchanged compound is the major 

route of elimination (NCI, 1985). The metabolic 

pathway in Figure 1 incorporates all the major urinary 

metabolites of pyridine that have been identified 

(ATSDR, 1992). 

Experimental Animals 

In a series of studies on pyridine N-methylation by 

D’Souza et al. (1980), a single dose of [14C]-pyridine 

(7 mg/kg) was administered by intraperitoneal injection 

to groups of one to five female Wistar albino rats, 

female Tuck mice, male and female Dunkin-Hartley 

guinea pigs, female gerbils, female golden Syrian 

hamsters, male and female New Zealand White rabbits, 

and mongrel female cats. In the rat, mouse, guinea pig, 

gerbil, and hamster, 48% to 67% of the administered 

radiolabel was recovered in the urine within 24 hours. 

In both the cat and rabbit, 75% and 77% of the 

FIGURE 1 

Proposed Metabolic Pathway for Pyridine (ATSDR, 1992) 
 

 

 

 

20 Pyridine, NTP TR 470 

administered radiolabel were recovered at 48 and 

72 hours, respectively. Pyridine N-methylation was 

extensive (15% to 40% of the administered dose) in the 

guinea pig, gerbil, hamster, rabbit, and cat, and lower 

(approximately 5% to 12%) in the rat and mouse. To 

determine whether the N-methylpyridinium ion formed 

during the metabolism of pyridine is further metabolized, groups of three female rats and guinea pigs were 

injected intraperitoneally with 8 mg/kg N-methyl[2,6­

14C]-pyridinium as an aqueous solution of the iodide. 

Greater than 95% of the radiolabel recovered in the 

urine was unchanged compound, indicating that 

N-methylpyridinium is largely metabolically stable 

(D’Souza et al., 1980). 

The effects of route of administration, dose, and 

methionine supplementation on the N-methylation of 

pyridine were also investigated by D’Souza et al. 

(1980) in the rat (a poor pyridine methylator) and 

guinea pig (a good pyridine methylator). [14C]-Pyridine 

was administered orally at doses of 7, 68, or 357 mg/kg 

or intraperitoneally at doses of 1, 7, or 500 mg/kg to 

groups of three animals. N-Methylation of pyridine 

was found to be independent of the route of administration but dependent on the dose. In rats given 

7 mg/kg [14C]-pyridine orally, 58% of the total 14C was 

excreted within 24 hours, with 3.1% of the dose as the 

N-methylpyridinium ion; 48% of the total 14C was 

excreted within 24 hours following intraperitoneal 

injection of 7 mg/kg, with 5.0% of the dose as 

N-methylpyridinium ion. In the guinea pig, 31% of the 

administered dose was recovered in the urine as the 

N-methylpyridinium ion, regardless of the route of 

administration (recovery of orally and intraperitoneally 

administered total 14C was 76% and 66%, respectively). 

In contrast, a study by Okuda (1959) demonstrated that 

2.5 times more N-methylpyridine was produced following subcutaneous administration than following oral 

administration of pyridine to dogs. 

For both the rat and guinea pig (D’Souza et al., 1980), 

overall urinary recovery of 14C was inversely proportional to the dose. The metabolic reaction was saturable in both species. In another experiment (D’Souza 

et al., 1980), rats were pretreated with an injection of 

1 g DL-methionine/kg 24 hours prior to administration 

of 7 mg [14C]-pyridine/kg and then maintained on a diet 

enriched with DL-methionine. The excretion of total 

14C and N-methylpyridinium ion were unaffected by 

methionine supplementation, which demonstrated that 

low N-methylation in the rat is unrelated to a relative 

deficiency of source methyl groups. In these same 

cross-species studies, Damani et al. (1982) identified 

2-pyridine, 3-hydroxypyridine, and 4-pyridone in the 

urine of all species and pyridine N-oxide in all species 

except the rabbit, although the relative amounts of 

metabolites differed across species. In hamsters, 

guinea pigs, and cats, most of the urinary radioactivity 

was identified as unchanged pyridine and its C- and 

N-oxidized and N-methylated derivatives. A significant proportion of the excreted radioactivity in rats, 

gerbils, and rabbits could not be accounted for by the 

metabolites monitored in these studies, but 3-hydroxypyridine (not measured) was probably represented in 

the urine in a conjugated form. In rats, an unidentified 

cationic metabolite accounted for about 7.4% of the 

recovered radiolabel (Damani et al., 1982). 

D’Souza et al. (1980) suggested that N-methylation and 

quaternization of pyridine may result in the formation 

of a conjugation product (the N-methylpyridinium ion) 

more toxic than pyridine itself. The intraperitoneal 

LD50 for N-methylpyridinium ion in mice is 0.22 g/kg, 

compared to 1.2 g/kg for pyridine. Production of 

N-oxides, generally associated with detoxification and 

increased elimination in several animal species and 

humans, may conceivably result in an increase in 

toxicity or carcinogenicity, and the N-oxidation of 

pyridine may represent a route for bioactivation (NCI, 

1985; Kim et al., 1991a). 

Pyridine, which is metabolized by cytochromes P2E1 

and P4B (CYP2E1 and CYP4B), enhances the expression of various hepatic P450 isozymes in rats and rabbits 

(Kim and Novak, 1990; Kim et al., 1991a, 1993; 

Nikula et al., 1995). A series of studies demonstrated 

that pyridine enhances the expression of different gene 

subfamilies of rat hepatic cytochrome P450 including 

CYP2E1, CYP1A1, CYP1A2, CYP2B1, and CYP2B2 

(Kim and Novak, 1990; Kim et al., 1991a,b; Hotchkiss 

et al., 1993; Iba et al., 1993; Agarwal et al., 1994). 

Pyridine caused a dose-dependent, 4- to 22-fold elevation of hepatic CYP2B1/2B2 over the intraperitoneal 

dosing regimen of 100 to 400 mg/kg per day in 

Sprague-Dawley rats. Pyridine treatment increased 

CYP2B1 and CYP2B2 poly (A)+ RNA levels approximately 69- and 34-fold, respectively, while CYP2E 

poly (A)+ levels failed to increase (Kim et al., 1993). 

Pyridine is similar to phenobarbital (Lubet et al., 1989) 

and oxazepam (Griffin et al., 1995) in this induction of 

CYP2B enzymes. Lubet et al. (1989) have associated 
 

Pyridine, NTP TR 470 21 

the strength of this CYP2B induction response to the 

strength of liver neoplasm promotion in the rat, 

although the mechanisms are not known. Rice et al. 

(1994) have also studied the association between 

CYP2B induction and liver neoplasm-promoting 

activity in the rat, and while there is a correlation with 

an induction of CYP2B and liver neoplasm promotion 

(after initiation with N-nitrosodiethylamine), other 

factors may be involved. Chemicals such as phenobarbital, which induces cytochrome P450s in the rodent 

liver, induce a wide variety of enzyme systems (referred 

to as pleiotropic response), and it is likely that several 

effects of the chemical play a role in its liver neoplasmpromoting ability (McClain, 1990). 

Male Sprague-Dawley rats were given intraperitoneal 

doses of 2.5 mmol of pyridine or a metabolite (including pyridine-N-oxide, 2-hydroxypyridine, 3-hydroxypyridine, 4-hydroxypyridine, and pyridinium methyl 

iodide) per kg of body weight for 1 to 5 days and 

sacrificed after the final dose. Only pyridine and 

2-hydroxypyridine caused hepatotoxicity as measured 

by increases in serum sorbitol dehydrogenase. Pyridine, pyridine-N-oxide, 3-hydroxypyridine, and 

4-hydroxypyridine were all effective inducers of 

CYP2E1-mediated metabolism (Carlson, 1996). As an 

inducer of cytochrome P4502E1 in both liver and lung, 

pyridine has been shown to affect the metabolism of 

xenobiotics including 2-butanol (Page and Carlson, 

1993), ethyl carbamate (urethane) (Page and Carlson, 

1994), and carbon tetrachloride (Day et al., 1993) in 

various species including rat, mouse, and/or rabbit. 

Humans 

N-Methylpyridinium ion (5.5% and 12% of the dose) 

was present in urine collected 24 hours after two human 

volunteers received 3.4 mg [14C]-pyridine in orange 

juice (approximately 0.05 mg/kg) (D’Souza et al., 

1980). Pyridine-N-oxide was identified as a metabolite 

in the urine sample, accounting for 32% of the administered dose (Damani et al., 1982). Approximately 25% 

of the urinary metabolites were not identified. 

Pyridine and a number of its derivatives have been 

shown to cause selective inhibition of thromboxane 

synthetase in vitro in fresh citrated human blood 

(Miyamoto et al., 1980) and in a test system employing 

the microsomal fraction of human platelet microsomes 

(Tai et al., 1980); thromboxane A2 is a potent labile 

inducer of platelet aggregation and vascular constriction. The inhibitory potency of pyridine on thromboxane synthetase in these systems was 60 μM in blood 

and 270 μM in platelet microsomes. In addition, 

pyridine (1.5 mM) inhibited the aggregation of human 

platelets induced by arachidonic acid or adenosine 

triphosphate (Tai et al., 1980). 

TOXICITY 

Experimental Animals 

Reported pyridine LD50/LC50 values for rats are 891 to 

1,580 mg/kg (oral), 360 mg/kg (intravenous), 866 to 

1,150 mg/kg (subcutaneous), and approximately 8,000 

to 9,000 ppm for 1 hour (inhalation) (Vernot et al., 

1977; Jori et al., 1983; ATSDR, 1992). LD50 values for 

mice are 1,500 mg/kg (oral), 1,200 mg/kg (intraperitoneal), 420 mg/kg (intravenous), and 1,250 mg/kg 

(subcutaneous) (Jori et al., 1983). 

Pyridine has been reported to cause toxic effects in the 

liver and kidney in experimental animal model systems. 

Pyridine administration (oral gavage) to dogs has 

produced toxic effects in the liver and kidney (Jori 

et al., 1983). Decreased glutamine concentration and 

increased ammonia excretion were observed in rats 

(age and strain not specified) exposed to pyridine 

vapors at a concentration of 5 to 10 mg/L for a single 

40-minute exposure (ATSDR, 1992). 

In a study in Sprague-Dawley rats (Anderson, 1987), 

pyridine was administered by gavage at 0, 0.24, 1, 10, 

25, or 50 mg/kg per day in water for 90 consecutive 

days. No treatment-related deaths occurred during the 

study. Body weights relative to controls were significantly reduced in male rats in the 50 mg/kg per day 

group. Dose-related, mildly elevated serum cholesterol 

levels occurred in females at 25 and 50 mg/kg per day 

on days 30 and 90, and female rats that received 

10 mg/kg or greater had significantly increased liver 

weights. Mild inflammatory hepatic lesions were seen 

in 70% of males and 20% of females in the 50 mg/kg 

groups; the incidence of inflammatory hepatic lesions 

was 10% in male and female control groups. Lesions 

included mixed peribiliary infiltrate, bile ductule 

proliferation, enlarged and vacuolated hepatocytes, and 

necrosis of hepatocytes. Liver lesions also occurred in 

the 10 and 25 mg/kg groups. 

In a study in which rats were given subcutaneous 

injections of pyridine twice weekly for a year at doses 

of 3, 10, 30, or 100 mg/kg (Mason et al., 1971), 
 

 

 

22 Pyridine, NTP TR 470 

survival rates and neoplasm incidences in pyridinetreated rats were similar to those in the controls. Mean 

body weights of the dosed groups ranged from 84% to 

95% of those of the controls at the end of the study. 

Inhalation of 5 or 444 ppm pyridine 6 hours per day for 

4 days was associated with olfactory epithelial lesions 

in the nasal mucosa of male F344/N rats characterized 

by vacuolar degeneration of sustentacular cells, focal, 

marked attenuation of the epithelium, loss of sensory 

neurons, and intraepithelial luminal structures (Nikula 

and Lewis, 1994). These lesions were associated with 

induction of carboxylesterase (Nikula et al., 1995). 

Humans 

There are no adequate studies on the toxicity of pyridine in humans. Several reports indicate that pyridine 

may be moderately toxic by the oral, dermal, 

intravenous, and inhalation routes. The chemical can 

cause skin irritation and severe eye damage (Sittig, 

1991; Lewis, 1993). 

In a review of the literature on pyridine, ATSDR 

(1992) reported the death of a man receiving pyridine 

as an intermittent medication for the treatment of 

epilepsy. The patient was also taking other medications 

(including phenobarbital), and it was not possible to 

attribute this death specifically to pyridine. 

A 29-year-old man who accidentally swallowed 1⁄2 cup 

(approximately 125 mL) of pyridine experienced nausea, dizziness, abdominal pain, and lung congestion 

followed by death within 2 days (Jori et al., 1983). 

Inhalation is a primary route of exposure to pyridine, 

and mild symptoms of central nervous system injury 

may result from exposure to approximately 10 ppm 

(Jori et al., 1983; NCI, 1985). Similar symptoms 

(headache, dizziness, insomnia, nausea, and anorexia) 

were reported in workers exposed to 125 ppm pyridine, 

4 hours per day for 1 to 2 weeks (Jori et al., 1983). 

REPRODUCTIVE 

AND DEVELOPMENTAL TOXICITY 

Injection of 10 or 20 mg pyridine into eggs caused 

muscular hypoplasia in 15% or 67% of chicks, respectively. The 20 mg dose induced defective beaks in 

4.9% of the chicks and short or twisted necks in 1.1% 

(ATSDR, 1992). No information related to the reproductive or developmental toxicity of pyridine in 

humans was found in a search of the available literature. 

CARCINOGENICITY 

No information related to the carcinogenicity of pyridine in experimental animals or humans was found in 

a search of the available literature. 

GENETIC TOXICITY 

Pyridine has been tested in a variety of in vivo and 

in vitro assays, and with few exceptions, results were 

negative. No mutation induction (Pai et al., 1978) or 

growth inhibition due to DNA damage was noted in 

Escherichia coli after treatment with pyridine (Warren 

et al., 1981; Riebe et al., 1982). No increases in gene 

mutation frequencies were observed in a variety of 

Salmonella typhimurium strains exposed to pyridine in 

the presence or the absence of S9 activation enzymes 

(Florin et al., 1980; Kawachi et al., 1980; Warren et al., 

1981; Riebe et al., 1982; Haworth et al., 1983). 

Zimmermann et al. (1986) reported induction of 

aneuploidy in S. cerevisiae D61.M after treatment with 

up to 1.1% pyridine, presumably resulting from disruption of microtubule assembly processes. No significant 

increases in mutant frequencies were seen in L5178Y 

mouse lymphoma cell cultures after incubation with 

pyridine, with or without S9 activation (McGregor 

et al., 1988). There are two published data sets from 

Drosophila melanogaster sex-linked recessive lethal 

assays with pyridine, and the results are mixed. 

Valencia et al. (1985) reported negative results when 

pyridine was administered to adult male flies by injection (7,000 ppm) and equivocal results when feeding 

(700 ppm) was used as the route of administration. 

Mason et al. (1992) reported negative results in a 

sex-linked recessive lethal assay from a feeding study 

(500 ppm) but positive results after injection of 

4,300 ppm pyridine. This positive result with pyridine 

in the sex-linked recessive lethal assay was followed by 

a test for induction of reciprocal translocations in male 

Drosophila, and negative results were obtained in this 

assay (Mason et al., 1992). 

Cytogenetic investigations in mammalian test systems 

yielded negative results with pyridine for induction of 

chromosomal aberrations and sister chromatid 

exchanges in cultured Chinese hamster ovary cells, 
 

Pyridine, NTP TR 470 23 

tested in the absence of S9 activation enzymes (Abe 

and Sasaki, 1977; Ishidate and Odashima, 1977; 

Kawachi et al., 1980). In vivo, no induction of micronuclei in mouse bone marrow cells (Harper et al., 1984) 

or chromosomal aberrations in rat bone marrow cells 

was reported after treatment with pyridine. 

There are little mutagenicity data for metabolites of 

pyridine. Pyridine-1-oxide was negative in bacterial 

tests for gene mutation induction (Voogd et al., 1980) 

and growth inhibition due to DNA damage, and it did 

not produce growth inhibition secondary to DNA 

damage in S. cerevisiae (Nagao and Sugimura, 1972). 

These tests were conducted without S9. 3-Hydroxypyridine, another pyridine metabolite, did not cause 

gene reversion in S. typhimurium, with or without S9 

(Florin et al., 1980). 

In summary, there appears to be little evidence to 

indicate that pyridine is mutagenic in standard shortterm tests. 

STUDY RATIONALE 

Pyridine was tested by the National Toxicology Program because of the large amount produced and its use 

in a variety of industrial products. The oral route of 

administration was selected to evaluate the systemic 

effects of pyridine. Pyridine has been shown to 

increase the severity of leukemia in a transplant model 

for leukemia in male F344/N rats (Dieter et al., 1989), 

and male Wistar rats were added to these studies in 

order to evaluate the effects of pyridine in a rat model 

with a low spontaneous incidence of mononuclear cell 

leukemia. 
24 Pyridine, NTP TR 470
 
 

 

 

 

 

 

 

25 

MATERIALS AND METHODS
 

PROCUREMENT 

AND CHARACTERIZATION 

OF PYRIDINE 

Pyridine was obtained from Aldrich Chemical Company (Milwaukee, WI) in one lot (00103BV). Identity, 

purity, and stability analyses were conducted by the 

analytical chemistry laboratory, Midwest Research 

Institute (Kansas City, MO) (Appendix K). Reports on 

analyses performed in support of the pyridine studies 

are on file at the National Institute of Environmental 

Health Sciences. 

The chemical, a clear, colorless liquid, was identified as 

pyridine by infrared, ultraviolet/visible, and nuclear 

magnetic resonance spectroscopy. The purity of lot 

00103BV was determined by elemental analyses, Karl 

Fischer water analysis, functional group titration, and 

gas chromatography. Elemental analyses for hydrogen 

and nitrogen were in agreement with the theoretical 

values for pyridine; results for carbon were slightly 

low. Karl Fischer water analysis indicated 

0.049% ± 0.003% water. Functional group titration 

indicated a purity of 99.8% ± 0.6%. Two gas chromatography systems indicated one major peak and no 

impurities with as much as 0.1% of the major peak 

area. The overall purity was determined to be greater 

than 99%. 

Stability studies of the bulk chemical were performed 

by the analytical chemistry laboratory using gas chromatography. To ensure stability, the bulk chemical was 

stored at 1 to 8 C in amber glass bottles in the dark. 

Stability was monitored during the 13-week and 2-year 

studies using gas chromatography. No degradation of 

the bulk chemical was detected. 

PREPARATION AND ANALYSIS 

OF DOSE FORMULATIONS 

The dose formulations were prepared as needed by 

mixing pyridine with deionized water (Table K1). 

Stability studies of a 0.01 mg/mL formulation were 

performed by the analytical chemistry laboratory using 

high-performance liquid chromatography. The stability 

of the dose formulation was confirmed for at least 

3 weeks when stored in the dark at room temperature. 

Periodic analyses of the dose formulations of pyridine 

were conducted at the study laboratory and analytical 

chemistry laboratory using high-performance liquid 

chromatography. For the 13-week studies, dose formulations were analyzed after preparation at the beginning, midpoint, and end of the studies (Table K2). 

During the 2-year studies, dose formulations were 

analyzed approximately every 6 to 10 weeks 

(Table K3). All dose formulations analyzed and used 

during the 13-week studies were within 10% of the 

target concentration. Of the dose formulations analyzed during the 2-year studies, 191 of 192 were within 

10% of the target concentration. One formulation was 

47% less than the target concentration; because records 

indicated that the proper amounts of pyridine and 

deionized water were used, it is possible that the wrong 

dose formulation was sampled for analysis. This dose 

formulation was remixed, and the remix was found to 

be within 10% of the target concentration. All animal 

room samples were within 10% of the target concentration. Results of periodic referee analyses performed by 

the analytical chemistry laboratory during the 13-week 

studies agreed with the results obtained by the study 

laboratory (Table K4). 

13-WEEK STUDIES 

The 13-week studies were conducted to evaluate the 

cumulative toxic effects of repeated exposure to pyridine and to determine the appropriate exposure concentrations to be used in the 2-year studies. 

Male and female F344/N rats and B6C3F1 mice were 

obtained from Taconic Farms (Germantown, NY); male 

Wistar rats were obtained from Charles River Laboratories (Kingston, NY). On receipt, rats and mice were 

approximately 5 weeks old. Animals were quarantined 
 

 

 

 

 

 

 

 

26 Pyridine, NTP TR 470 

for 12 to 14 days and were 7 or 8 weeks old on the first 

day of the studies. Before initiation of the studies, five 

male and five female F344/N rats and mice and five 

male Wistar rats were randomly selected 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 

F344/N rats and mice and five male sentinel Wistar rats 

using the protocols of the NTP Sentinel Animal Program (Appendix N). 

Groups of 10 male and 10 female F344/N rats and 

B6C3F1 mice and 10 male Wistar rats were given 

drinking water containing 0, 50, 100, 250, 500, or 

1,000 ppm pyridine (core study). Groups of 10 male 

and 10 female F344/N rats and 10 male Wistar rats 

exposed to the same concentrations were designated as 

special study animals for hematology and clinical 

chemistry analyses. Feed and water were available 

ad libitum; fresh control or treated water was provided 

twice weekly. Rats were housed five per cage, and 

mice were housed individually. Clinical findings were 

recorded weekly for rats and mice. Water consumption 

was recorded twice weekly by cage for core study 

animals. The animals were weighed initially and 

weekly thereafter. Details of the study design and 

animal maintenance are summarized in Table 1. 

Blood from the retroorbital sinus was collected from 

special study rats on days 5 and 20 and core study rats 

at study termination for hematology and clinical chemistry analyses. Erythrocyte, leukocyte, and platelet 

counts; hemoglobin concentration; hematocrit, mean 

cell volume; mean cell hemoglobin; and mean cell 

hemoglobin concentration were measured with a 

Sysmex TOA E-2500. Blood smears were stained with 

Wright/Giemsa; differential leukocyte counts were 

based on classifying a minimum of 100 cells. Reticulocyte counts were done on a smear prepared from whole 

blood, stained with new methylene blue N, and incubated at room temperature; 1,000 erythrocytes were 

counted and the percent reticulocytes was determined. 

Clinical chemistry analyses were performed on the 

Roche Cobas FARA automated centrifugal analyzer 

(Roche Diagnostic Systems, Inc., Montclair, NJ). The 

hematology and clinical chemistry parameters measured are listed in Table 1. 

At the end of the 13-week studies, blood was collected 

from the retroorbital sinus of all rats and mice for 

plasma pyridine concentration measurements. Pilot 

studies determined that samples could be collected 

between 8 a.m. and 10 a.m. The samples were taken in 

silicon-coated tubes which contained buffered sodium 

citrate. A plasma analysis procedure was developed 

and evaluated at the study laboratory for the analysis of 

plasma pyridine concentrations ranging from 0.063 to 

100 μg/mL. Concentrations less than the experimental 

level of quantitation (0.063 μg/mL) should be considered approximations. Plasma samples were treated 

with sodium hydroxide and 3-methylpyridine, the 

internal standard. The samples were extracted with 

dichloromethane, then analyzed using gas chromatography with nitrogen-phosphorous detection. The 

gas chromatography was performed on a 20% 

Carbowax 20M-TPA on 80/100 Chromosorb column, 

with a nitrogen carrier gas at a flow rate of 

30 mL/minute, and an oven temperature of 89 C for 

7 minutes, then to 170 C at 20 C per minute, with 

a 2-minute hold. Three standard curve ranges were 

used to encompass the 1,600-fold quantitation range. 

Results from these analyses for rats are presented in 

Appendix J. Analyses of the samples for mice were not 

considered adequate and these data are not reported. 

At the end of the 13-week studies, samples were collected for sperm motility and vaginal cytology evaluations on F344/N rats and mice exposed to 0, 250, 

500, or 1,000 ppm. The parameters evaluated are listed 

in Table 1. Methods used were those described in the 

NTP’s sperm morphology and vaginal cytology 

evaluations protocol (NTP, 1987). For 12 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 count and 

motility. The left testis and left epididymis were isolated and weighed. The tail of the epididymis (cauda 

epididymis) was then removed from the epididymal 

body (corpus epididymis) and weighed. Test yolk (rats) 

or modified Tyrode’s buffer (mice) was applied to 

slides, and a small incision was made at the distal 

border of the cauda epididymis. The sperm effluxing 

from the incision were dispersed in the buffer on the 

slides, and the numbers of motile and nonmotile 

spermatozoa were counted for five fields per slide by 

two observers. Following completion of sperm motility 

estimates, each left cauda epididymis was placed in 
 

 

 

 

Pyridine, NTP TR 470 27 

buffered saline solution. Caudae were finely minced, 

and the tissue was incubated in the saline solution and 

then heat fixed at 65 C. Sperm density was then 

determined microscopically with the aid of a 

hemacytometer. To quantify spermatogenesis, the 

testicular spermatid head count was determined by 

removing the tunica albuginea and homogenizing the 

left testis in phosphate-buffered saline containing 10% 

dimethyl sulfoxide. Homogenization-resistant 

spermatid nuclei were counted with a hemacytometer. 

A necropsy was performed on all core study animals. 

The heart, right kidney, liver, lung, right testis, and 

thymus were weighed. Tissues for microscopic examination were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in 

paraffin, sectioned to a thickness of 5 to 6 μm, and 

stained with hematoxylin and eosin. A complete histopathologic examination was performed on control and 

1,000 ppm animals, and target organs were examined 

to the no-effect level. Table 1 lists the tissues and 

organs routinely examined. α2u-Globulin immunohistochemistry, using a primary antibody from Hazleton 

Laboratories, was assayed on selected animals from 

each exposure group. 

2-YEAR STUDIES 

Study Design 

Groups of 50 male and 50 female F344/N rats and 

50 male Wistar rats were given drinking water containing 0, 100, 200, or 400 ppm pyridine for 104 (males) or 

105 (females) weeks. Groups of 50 male B6C3F1 mice 

were exposed to 0, 250, 500, or 1,000 ppm pyridine in 

drinking water for 104 weeks, and groups of 50 female 

B6C3F1 mice were exposed to 0, 125, 250, or 500 ppm 

pyridine in drinking water for 105 weeks. 

Source and Specification of Animals 

Male and female F344/N rats and B6C3F1 mice were 

obtained from Taconic Farms (Germantown, NY), and 

male Wistar rats were obtained from Charles River 

Laboratories (Portage, MI) for use in the 2-year studies. 

Rats and mice were quarantined for 12 to 14 days 

before the beginning of the studies. Five male and five 

female F344/N rats and mice and five male Wistar rats 

were randomly selected for parasite evaluation and 

gross observation of disease. Rats and mice were 

approximately 7 weeks old at the beginning of the 

studies. The health of the animals was monitored 

during the studies according to the protocols of the 

NTP Sentinel Animal Program (Appendix N). 

Animal Maintenance 

F344/N rats were housed five per cage, male Wistar 

rats were housed three per cage, and mice were housed 

individually. Feed and water were available ad libitum. 

Water consumption was measured weekly by cage for 

the first 13 weeks and every 4 weeks thereafter. Cages 

and racks were rotated every two weeks. Further details 

of animal maintenance are given in Table 1. Information on feed composition and contaminants is provided 

in Appendix M. 

Clinical Examinations and Pathology 

All animals were observed twice daily. Clinical 

findings were recorded at 4-week intervals, and body 

weights were recorded at the start of the study, weekly 

for the first 13 weeks, every 4 weeks until week 92 

(F344/N rats), week 88 (male Wistar rats), or week 96 

(mice), and then once every 2 weeks until study 

termination. 

A complete necropsy and microscopic examination 

were performed on all rats and mice. At necropsy, all 

organs and tissues were examined for grossly visible 

lesions, and all major tissues were fixed and preserved 

in 10% neutral buffered formalin, processed and 

trimmed, embedded in paraffin, sectioned to a thickness 

of 5 to 6 μm, and stained with hematoxylin and eosin 

for microscopic examination. For all paired organs 

(e.g., adrenal gland, kidney, ovary), samples from each 

organ were examined. For extended evaluation of renal 

proliferative lesions in male rats, kidneys were step 

sectioned at 1-mm intervals, and four additional sections were obtained from each kidney. Tissues examined microscopically are listed in Table 1. 

Microscopic evaluations were completed by the study 

laboratory pathologist, and the pathology data were 

entered into the Toxicology Data Management System. 

The slides, paraffin blocks, and residual wet tissues 

were sent to the NTP Archives for inventory, slide/ 

block match, and wet tissue audit. The slides, individual animal data records, and pathology tables were 

evaluated by an independent quality assessment laboratory. The individual animal records and tables were 

compared for accuracy, the slide and tissue counts were 

verified, and the histotechnique was evaluated. For the 

2-year rat studies, a quality assessment pathologist 

evaluated slides from all tumors and all potential target 
 

 

28 Pyridine, NTP TR 470 

organs, which included the liver and kidney of male 

F344/N rats, the liver of female F344/N rats, and the 

liver, kidney, and testis of male Wistar rats. For the 

2-year mouse studies, a quality assessment pathologist 

evaluated slides from all tumors and all potential target 

organs, which included the liver, nose, and spleen of 

male and female mice, the adrenal cortex and lung of 

male mice, and the ovary and pituitary gland of female 

mice. 

The quality assessment report and the reviewed slides 

were submitted to the NTP Pathology Working Group 

(PWG) chairperson, who reviewed the selected tissues 

and addressed any inconsistencies in the diagnoses 

made by the laboratory and quality assessment 

pathologists. Representative histopathology slides 

containing examples of lesions related to chemical 

administration, examples of disagreements in diagnoses

 between the laboratory and quality assessment pathologists, or lesions of general interest were presented by 

the chairperson to the PWG for review. The PWG 

consisted of the quality assessment pathologist and 

other pathologists experienced in rodent toxicologic 

pathology. This group examined the tissues without 

any knowledge of dose groups or previously rendered 

diagnoses. When the PWG consensus differed from 

the opinion of the laboratory pathologist, the diagnosis 

was changed. Final diagnoses for reviewed lesions 

represent a consensus between the laboratory pathologist, reviewing pathologist(s), and the PWG. Details of 

these review procedures have been described, in part, 

by Maronpot and Boorman (1982) and Boorman et al. 

(1985). For subsequent analyses of the pathology data, 

the decision of whether to evaluate the diagnosed 

lesions for each tissue type separately or combined was 

generally based on the guidelines of McConnell et al. 

(1986). 
Pyridine, NTP TR 470 29 

TABLE 1 

Experimental Design and Materials and Methods in the Drinking Water Studies of Pyridine 

13-Week Studies 2-Year Studies 

Study Laboratory 

TSI Mason Research Institute (Worcester, MA) 

Strain and Species 

Rats: F344/N and Wistar 

Mice: B6C3F1 

Animal Source 

F344/N rats: Taconic Farms (Germantown, NY)
 

Wistar rats: Charles River Laboratories (Kingston, NY)
 

Mice: Taconic Farms (Germantown, NY)
 

Time Held Before Studies 

F344/N rats: 14 days (males) or 12 days (females) 

Wistar rats: 13 days 

Mice: 13 days (males) or 14 days (females) 

Average Age When Studies Began 

7 weeks, except special study F344/N rats at 8 weeks 

Date of First Exposure 

Core Studies: 

F344/N rats: 24 January (males) or 22 January (females) 1990 

Wistar rats: 8 February 1990 

Mice: 20 December (males) or 21 December (females) 1989 

Special Studies: 

F344/N rats: 3 February (males) or 1 February (females) 1990 

Wistar rats: 1 March 1990 

Duration of Exposure 

13 weeks (core study animals) 

19 days (special study F344/N rats) 

20 days (special study Wistar rats) 

Date of Last Exposure 

Core Studies: 

F344/N rats: 25 April (males) or 23 April (females) 1990 

Wistar rats: 30 May 1990 

Mice: 21 March (males) or 22 March (females) 1990 

Special Studies: 

F344/N rats: 22 February (males) or 20 February (females) 1990 

Wistar rats: 20 March 1990 

Necropsy Dates 

F344/N rats: 25 April (males) or 23 April (females) 1990 

Wistar rats: 30 May 1990 

Mice: 21 March (males) or 22 March (females) 1990 

Average Age at Necropsy 

19 weeks (core study) 

Size of Study Groups 

F344/N rats and mice: 10 males and 10 females 

Wistar rats: 10 males 

TSI Mason Laboratories (Worcester, MA)
 

Rats: F344/N and Wistar
 

Mice: B6C3F1
 

F344/N rats: Taconic Farms (Germantown, NY)
 

Wistar rats: Charles River Laboratories (Portage, MI)
 

Mice: Taconic Farms (Germantown, NY)
 

F344/N rats: 12 days (males) or 13 days (females)
 

Wistar rats: 13 days
 

Mice: 13 days (males) or 14 days (females)
 

7 weeks
 

F344/N rats: 23 April (males) or 24 April (females) 1991
 

Wistar rats: 14 May 1991
 

Mice: 3 April (males) or 4 April (females) 1991
 

F344/N and Wistar rats: 104 weeks (males) or 105 weeks
 

(females)
 

Mice: 104 weeks (males) or 105 weeks (females)
 

F344/N rats: 13 April (males) or 22 April (females) 1993
 

Wistar rats: 4 May 1993
 

Mice: 25 March (males) or 1 April (females) 1993
 

F344/N rats: 13 April (males) or 21-22 April (females) 1993
 

Wistar rats: 4 May 1993
 

Mice: 24-25 March (males) or 1 April (females) 1993
 

F344/N and Wistar rats: 110 weeks (males) or 111 weeks
 

(females)
 

Mice: 110 weeks (males) or 111 weeks (females)
 

F344/N rats and mice: 50 males and 50 females
 

Wistar rats: 50 males
 
30 Pyridine, NTP TR 470 

TABLE 1 

Experimental Design and Materials and Methods in the Drinking Water Studies of Pyridine 

13-Week Studies 2-Year Studies 

Method of Distribution 

Animals were distributed randomly into groups of approximately 

equal initial mean body weights. 

Animals per Cage 

F344/N and Wistar rats: 5 

Mice: 1 

Method of Animal Identification 

Tail tattoo 

Diet 

NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, 

PA), available ad libitum 

Water 

Deionized water via glass water bottles with stainless steel sipper 

tubes, available ad libitum, changed twice per week 

Cages 

See-Through Systems polycarbonate, solid bottom (Lab Products, 

Inc., Rochelle Park, NJ), changed twice per week (rats) or weekly 

(mice) 

Bedding 

F344/N and Wistar rats: Sani Chips (P.J. Murphy Products Corp., 

Montville, NJ), changed twice per week 

Mice: Beta Chips (P.J. Murphy Products Corp., Montville, NJ), 

changed weekly 

Cage Filters 

Nonwoven fiber (Snow Filtration, Cincinnati, OH), changed once 

every 2 weeks 

Racks 

Stainless steel (Lab Products, Inc., Rochelle Park, NJ), changed once 

every 2 weeks 

Animal Room Environment 

Temperature: 20.6 -23.9 C (F344/N rats); 18.9 -23.3 C 

(Wistar rats); 20.6 -24.4 C (mice) 

Relative humidity: 31%-57% (F344/N rats); 35%-56% 

(Wistar rats); 26%-49% (mice) 

Room fluorescent light: 12 hours/day 

Room air changes: 10/hour 

Exposure Concentrations 

0, 50, 100, 250, 500, or 1,000 ppm 

Same as 13-week studies 

F344/N rats: 5 

Wistar rats: 3 

Mice: 1 

Tail tattoo 

Same as 13-week studies 

Same as 13-week studies 

Same as 13-week studies, except changed three times per week for 

male rats 

Heat-treated hardwood chips (P.J. Murphy Forest Products, 

Montville, NJ), changed three times per week (male rats), twice 

per week (female rats), or weekly (mice) 

Same as 13-week studies 

Same as 13-week studies 

Temperature: 19.4 -24.4 C (F344/N rats); 18.9 -26.7 C 

(Wistar rats); 20.0 -24.4 C (mice) 

Relative humidity: 24%-71% (F344/N rats); 25%-78% 

(Wistar rats); 20%-65% (mice) 

Room fluorescent light: 12 hours/day 

Room air changes: 10/hour 

F344/N and Wistar rats: 0, 100, 200, or 400 ppm 

Mice: 0, 250, 500, or 1,000 ppm (males); 0, 125, 250, or 500 ppm 

(females) 
Pyridine, NTP TR 470 31 

TABLE 1 

Experimental Design and Materials and Methods in the Drinking Water Studies of Pyridine 

13-Week Studies 2-Year Studies 

Type and Frequency of Observation 

Observed twice daily; animals were weighed initially and weekly 

thereafter; clinical findings were recorded weekly. Water 

consumption was recorded twice per week by cage. 

Method of Sacrifice 

CO2 

Necropsy 

Necropsy performed on all core study animals. Organs weighed were 

heart, right kidney, liver, lung, right testis, and thymus. 

Clinical Pathology 

Blood was collected from the retroorbital sinus of special study rats
 

on days 5 and 20 and of core study rats at the end of the study for
 

hematology and clinical chemistry analyses. 

Hematology: hematocrit; hemoglobin concentration; erythrocyte,
 

reticulocyte, nucleated erythrocyte, and platelet counts; mean cell
 

volume; mean cell hemoglobin; mean cell hemoglobin concentration;
 

and leukocyte count and differentials
 

Clinical chemistry: urea nitrogen, creatinine, protein, albumin,
 

alanine aminotransferase, alkaline phosphatase, creatine kinase,
 

sorbital dehyrodrogenase, bile acids
 

Histopathology 

Complete histopathology was performed on 0 and 1,000 ppm animals. 

In addition to gross lesions and tissue masses, the following tissues 

were examined: adrenal gland, bone (with marrow), brain, clitoral 

gland, esophagus, gallbladder (mice), heart, large intestine (cecum, 

colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, 

liver, lung, lymph nodes (mandibular and mesenteric), mammary 

gland (with adjacent skin), nose, ovary, pancreas, parathyroid gland, 

pituitary gland, preputial gland, prostate gland, salivary gland, spleen, 

stomach, testis (with epididymis and seminal vesicle), thymus, thyroid 

gland, trachea, urinary bladder, and uterus. The kidney of male rats 

and the liver of all rats were also examined in all other exposure 

groups. 

Sperm Motility and Vaginal Cytology 

At the end of the studies, sperm samples were collected from male 

F344/N rats and mice in the 0, 250, 500, and 1,000 ppm groups for 

sperm motility evaluations. The following parameters were evaluated: 

spermatid heads per gram testis, spermatid heads per testis, sperm 

count, epididymal sperm concentration, and epididymal sperm 

motility. The left cauda, epididymis, and testis were weighed. 

Vaginal samples were collected for up to 12 consecutive days prior to 

the end of the studies from all females exposed to 0, 250, 500, or 

1,000 ppm for vaginal cytology evaluations. The following 

parameters were evaluated: estrous cycle length and relative 

frequency of estrous stages. 

Determinations of Pyridine in Plasma 

At the end of the 13-week studies, blood was collected from the 

retroorbital sinus of all rats just before sacrifice for plasma pyridine 

concentration measurements. 

Observed twice daily; animals were weighed initially, weekly for 

the first 13 weeks, every 4 weeks until week 92 (F344/N rats), 

week 88 (Wistar rats), or week 96 (mice), and then once every 

2 weeks; clinical findings were recorded at 4-week intervals. 

Water consumption was measured weekly by cage for the first 

13 weeks and every 4 weeks thereafter. 

70%:30% CO2:O2 

Necropsy performed on all animals. 

None 

Complete histopathology was performed on all rats and mice. In 

addition to gross lesions and tissue masses, the following tissues 

were examined: adrenal gland, bone (with marrow), brain, clitoral 

gland, esophagus, gallbladder (mice), heart, large intestine (cecum, 

colon, rectum), small intestine (duodenum, jejunum, ileum), 

kidney, liver, lung, lymph nodes (mandibular and mesenteric), 

mammary gland (with adjacent skin), nose, ovary, pancreas, 

parathyroid gland, pituitary gland, preputial gland, prostate gland, 

salivary gland, spleen, stomach, testis (with epididymis and 

seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, 

and uterus. 

None 

None 
 

 

 

 

 

 

 

32 Pyridine, NTP TR 470 

STATISTICAL METHODS 

Survival Analyses 

The probability of survival was estimated by the 

product-limit procedure of Kaplan and Meier (1958) 

and is presented in the form of graphs. Animals found 

dead of other than natural causes or removed from 

study for other reasons were censored from the survival 

analyses; animals dying from natural causes were not 

censored. Statistical analyses for possible dose-related 

effects on survival used Cox’s (1972) method for 

testing two groups for equality and Tarone’s (1975) life 

table test to identify dose-related trends. All reported 

P values for the survival analyses are two sided. 

Calculation of Incidence 

The incidences of neoplasms or nonneoplastic lesions 

are presented in Tables A1, A5, B1, B5, C1, C4, D1, 

D5, E1, and E5 as the numbers of animals bearing such 

lesions at a specific anatomic site and the numbers of 

animals with that site examined microscopically. For 

calculation of statistical significance, the incidences of 

most neoplasms (Tables A3, B3, C3, D3, and E3) and 

all nonneoplastic lesions are given as the numbers of 

animals affected at each site examined microscopically. 

However, when macroscopic examination was required 

to detect neoplasms in certain tissues (e.g., harderian 

gland, intestine, mammary gland, and skin) before 

microscopic evaluation, or when neoplasms had multiple potential sites of occurrence (e.g., leukemia or 

lymphoma), the denominators consist of the number of 

animals on which a necropsy was performed. 

Tables A3, B3, C3, D3, and E3 also give the survivaladjusted neoplasm rate for each group and each sitespecific neoplasm. This survival-adjusted rate (based 

on the Poly-3 method described below) accounts for 

differential mortality by assigning a reduced risk of 

neoplasm, proportional to the third power of the fraction of time on study, to animals that do not reach 

terminal sacrifice. 

Analysis of Neoplasm 

and Nonneoplastic Lesion Incidences 

The Poly-k test (Bailer and Portier, 1988; Portier and 

Bailer, 1989; Piegorsch and Bailer, 1997) was used to 

assess neoplasm and nonneoplastic lesion prevalence. 

This test is a survival-adjusted quantal-response procedure that modifies the Cochran-Armitage linear trend 

test to take survival differences into account. More 

specifically, this method modifies the denominator in 

the quantal estimate of lesion incidence to approximate 

more closely the total number of animal years at risk. 

For analysis of a given site, each animal is assigned a 

risk weight. This value is one if the animal had a lesion 

at that site or if it survived until terminal sacrifice; if the 

animal died prior to terminal sacrifice and did not have 

a lesion at that site, its risk weight is the fraction of the 

entire study time that it survived, raised to the kth 

power. 

This method yields a lesion prevalence rate that 

depends only upon the choice of a shape parameter for 

a Weibull hazard function describing cumulative lesion 

incidence over time (Bailer and Portier, 1988). Unless 

otherwise specified, a value of k=3 was used in the 

analysis of site-specific lesions. This value was recommended by Bailer and Portier (1988) following an 

evaluation of neoplasm onset time distributions for a 

variety of site-specific neoplasms in control F344 rats 

and B6C3F1 mice (Portier et al., 1986). Bailer and 

Portier (1988) showed that the Poly-3 test gave valid 

results if the true value of k was anywhere in the range 

from 1 to 5. A further advantage of the Poly-3 method 

is that it does not require lesion lethality assumptions. 

Variation introduced by the use of risk weights, which 

reflect differential mortality, was accommodated by 

adjusting the variance of the Poly-3 statistic as recommended by Bieler and Williams (1993). 

Tests of significance included pairwise comparisons of 

each exposed group with controls and a test for an 

overall exposure-related trend. Continuity-corrected 

tests were used in the analysis of lesion incidence, and 

reported P values are one sided. Values of P greater 

than 0.5 are presented as 1 P with the letter N added 

to indicate a lower incidence or negative trend in neoplasm occurrence relative to the control group 

(e.g., P=0.99 is presented as P=0.01N). 

Analysis of Continuous Variables 

Two approaches were employed to assess the significance of pairwise comparisons between exposed and 

control groups in the analysis of continuous variables. 

Organ and body weight data, which have approximately 

normal distributions, were analyzed with the parametric 

multiple comparison procedures of Dunnett (1955) and 

Williams (1971, 1972). 

Hematology, clinical chemistry, plasma concentration, 

urinalysis, spermatid, and epididymal spermatozoal 

data, which have typically skewed distributions, were 

analyzed using the nonparametric multiple comparison 
 

 

 

 

 

Pyridine, NTP TR 470 33 

methods of Shirley (1977) and Dunn (1964). 

Jonckheere’s test (Jonckheere, 1954) was used to 

assess the significance of the dose-related trends and to 

determine whether a trend-sensitive test (Williams’ or 

Shirley’s test) was more appropriate for pairwise 

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

Prior to statistical analysis, extreme values identified by 

the outlier test of Dixon and Massey (1951) were 

examined by NTP personnel, and implausible values 

were eliminated from the analysis. Average severity 

values were analyzed for significance with the MannWhitney U test (Hollander and Wolfe, 1973). Because 

vaginal cytology data are proportions (the proportion of 

the observation period that an animal was in a given 

estrous stage), an arcsine transformation was used to 

bring the data into closer conformance with a normality 

assumption. Treatment effects were investigated by 

applying a multivariate analysis of variance (Morrison, 

1976) to the transformed data to test for simultaneous 

equality of measurements across exposure 

concentrations. 

Historical Control Data 

Although the concurrent control group is always the 

first and most appropriate control group used for 

evaluation, historical control data can be helpful in the 

overall assessment of neoplasm incidence in certain 

instances. Consequently, neoplasm incidences from the 

NTP historical control database, which is updated 

yearly, are included in the NTP reports for neoplasms 

appearing to show compound-related effects. 

QUALITY ASSURANCE METHODS 

The 13-week and 2-year studies were conducted in 

compliance with Food and Drug Administration Good 

Laboratory Practice Regulations (21 CFR, Part 58). In 

addition, as records from the 2-year studies were 

submitted to the NTP Archives, these studies were 

audited retrospectively by an independent quality 

assurance contractor. Separate audits covered completeness and accuracy of the pathology data, pathology 

specimens, final pathology tables, and a draft of this 

NTP Technical Report. Audit procedures and findings 

are presented in the reports and are on file at NIEHS. 

The audit findings were reviewed and assessed by NTP 

staff, and all comments were resolved or otherwise 

addressed during the preparation of this Technical 

Report. 

GENETIC TOXICOLOGY 

The genetic toxicity of pyridine was assessed by testing 

the ability of the chemical to induce mutations in 

various strains of Salmonella typhimurium, mutations 

in L5178Y mouse lymphoma cells, sister chromatid 

exchanges and chromosomal aberrations in cultured 

Chinese hamster ovary cells, sex-linked recessive lethal 

mutations in Drosophila melanogaster, and increases 

in the frequency of micronucleated erythrocytes in bone 

marrow of mice. The protocols for these studies and 

the results are given in Appendix F. 

The genetic toxicity studies of pyridine are part of a 

larger effort by the NTP to develop a database that 

would permit the evaluation of carcinogenicity in 

experimental animals from the molecular structure and 

the effects of the chemical in short-term in vitro and 

in vivo genetic toxicity tests. These genetic toxicity 

tests were originally developed to study mechanisms of 

chemical-induced DNA damage and to predict carcinogenicity in animals, based on the electrophilicity theory 

of chemical mutagenesis and the somatic mutation 

theory of cancer (Miller and Miller, 1977; Straus, 1981; 

Crawford, 1985). 

There is a strong correlation between a chemical’s 

potential electrophilicity (structural alert to DNA 

reactivity), mutagenicity in Salmonella, and carcinogenicity in rodents. The combination of electrophilicity 

and Salmonella mutagenicity is highly correlated with 

the induction of carcinogenicity in rats and mice and/or 

at multiple tissue sites (Ashby and Tennant, 1991). 

Other in vitro genetic toxicity tests correlate less well 

with rodent carcinogenicity (Tennant et al., 1987; 

Zeiger et al., 1990), although these other tests can 

provide information on the types of DNA and chromosome effects that can be induced by the chemical being 

investigated. Data from NTP studies show that a 

positive response in Salmonella is the most predictive 

in vitro test for rodent carcinogenicity (89% of the 

Salmonella mutagens are rodent carcinogens), and that 

there is no complementarity among the in vitro genetic 

toxicity tests. That is, no battery of tests that included 

the Salmonella test improved the predictivity of the 

Salmonella test alone. 

The predictivity for carcinogenicity of a positive 

response in bone marrow chromosome aberration or 

micronucleus tests appears to be less than the Salmonella test (Shelby et al., 1993; Shelby and Witt, 1995). 

Positive responses in long-term peripheral blood 
 

34 Pyridine, NTP TR 470 

micronucleus tests have not been formally evaluated for somatic and germ cells, the determination of in vivo 

their predictivity for rodent carcinogenicity. But, genetic effects is important to the overall understanding 

because of the theoretical and observed associations of the risks associated with exposure to a particular 

between induced genetic damage and adverse effects in chemical. 
 

35 

RESULTS
 

F344/N RATS 

13-WEEK STUDY 

Two females exposed to 1,000 ppm died during 

week 1; all other F344/N rats survived until the end of 

the study (Table 2). Final mean body weights of 

1,000 ppm males and 500 and 1,000 ppm females and 

mean body weight gains of males and females exposed 

to 500 or 1,000 ppm were significantly less than those 

of the controls. Water consumption by female rats 

exposed to 1,000 ppm was less than that by the controls 

at week 1. Drinking water concentrations of 50, 100, 

TABLE 2 

250, 500, or 1,000 ppm pyridine resulted in average 

daily doses of 5, 10, 25, 55, or 90 mg pyridine/kg body 

weight. There were no exposure-related clinical 

findings. 

The hematology and clinical chemistry data for F344/N 

rats are listed in Table G1. On day 5, an erythrocytosis, 

demonstrated by increased hematocrit values, hemoglobin concentrations, and erythrocyte counts relative 

to controls, occurred in males exposed to 100 ppm or 

greater. An erythrocytosis would be consistent with 

dehydration, which can cause a relative erythrocytosis 

Survival, Body Weights, and Water Consumption of F344/N Rats in the 13-Week Drinking Water Study 

of Pyridine 

Concentration 

(ppm) Survivala 

Initial 

Mean Body Weightb (g) 

Final Change 

Final Weight 

Relative to 

Controls 

(%) 

Water 

Consumptionc 

Week 1 Week 13 

Male 

0 

50 

100 

250 

500 

1,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

149 ± 4 

145 ± 4 

149 ± 4 

148 ± 4 

150 ± 4 

150 ± 4 

346 ± 9 

345 ± 7 

348 ± 6 

346 ± 7 

328 ± 5 

296 ± 5** 

197 ± 6 

201 ± 5 

199 ± 5 

198 ± 4 

177 ± 2** 

145 ± 4** 

100 

101 

100 

95 

85 

132 

138 

145 

136 

131 

128 

78 

76 

74 

82 

90 

85 

Female 

0 

50 

100 

250 

500 

1,000 

10/10 

10/10 

10/10 

10/10 

10/10 

8/10d 

111 ± 2 

110 ± 2 

110 ± 2 

111 ± 2 

108 ± 2 

110 ± 2 

206 ± 3 

203 ± 4 

202 ± 2 

205 ± 4 

193 ± 1** 

187 ± 3** 

95 ± 2 

93 ± 3 

92 ± 2 

95 ± 4 

85 ± 2* 

78 ± 3** 

99 

98 

100 

94 

91 

126 

128 

127 

126 

123 

85 

91 

89 

93 

91 

98 

89 

* Significantly different (P 0.05) from the control group by Williams’ test 

** P 0.01 

a Number of animals surviving at 13 weeks/number initially in group b	 Weights and weight changes are given as mean ± standard error. Subsequent calculations are based on animals surviving to the end of the 

study. 

Water consumption is expressed as grams of water consumed per kg body weight per day. d Week of death: 1 

c 
 

 

 

36 Pyridine, NTP TR 470 

due to decreased blood volume and hemoconcentration 

(Jain, 1986). On day 20, the erythrocytosis was 

replaced by a developing normocytic, normochromic, 

nonresponsive anemia, demonstrated by decreased 

hematocrit values, hemoglobin concentrations, and 

erythrocyte counts relative to controls in males and 

females exposed to 250 ppm or greater. Normocytosis, 

normochromia, and lack of an erythropoietic response 

were evidenced by the absence of changes relative to 

controls in mean cell volumes, mean cell hemoglobin 

concentrations, and reticulocyte counts, respectively. 

At week 13, evidence of the anemia persisted in 

500 and 1,000 ppm males and expanded to all exposed 

females. 

Albumin and total protein concentrations were 

increased relative to controls at various time points in 

males and females exposed to 100 ppm or greater. 

Increased albumin concentration would be consistent 

with dehydration and hemoconcentration; overproduction of albumin is not known to occur in any animal 

(Kaneko, 1989). The increase of total protein is 

probably a reflection of the increase of albumin. This 

evidence of dehydration could suggest that the severity 

of the anemia was tempered by the hemoconcentration 

and that the anemia may have been more severe than 

what the data indicate. 

There was evidence of hepatocellular injury and/or 

altered hepatic function demonstrated by increased 

serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations that 

predominantly occurred in 500 and 1,000 ppm males 

and females relative to controls. Increases of bile acid 

concentrations also can indicate cholestasis. But 

activity of serum alkaline phosphatase, another biomarker of cholestasis, was decreased relative to controls in all exposed males and females at various time 

points; this suggests cholestasis was not involved. 

However, decreased alkaline phosphatase activity was 

not exposure concentration-related and, thus, could 

indicate chemical inhibition of the enzyme or interference with the assay method. Additionally, circulating alkaline phosphatase in a normal rat is primarily 

of intestinal and bone origin (Righetti and Kaplan, 

1971), and fasting or food restriction causes decreases 

in serum alkaline phosphatase activity (Jenkins and 

Robinson, 1975). If rats decreased their food intake 

due to treatment-related toxicity or poor food palatability, decreases in alkaline phosphatase activity relative 

to controls might be related to loss of the normally 

circulating intestinal fraction. Thus, increases in 

alkaline phosphatase activity due to cholestasis could 

be counterbalanced by the negative effect of decreased 

food intake. Final mean body weights of 500 and 

1,000 ppm males and females were significantly less 

than those of the controls, supporting the possibility of 

decreased food intake. Changes in other hematology 

and clinical chemistry variables were minimal, inconsistent between males and females, and within physiological values and thus were not considered toxicologically relevant. 

Epididymis and testis weights of 1,000 ppm males were 

significantly less than controls but were probably 

related to decreased body weights (Table I1). The 

estrous cycle length of 1,000 ppm females was significantly longer than that of the controls (Table I2). 

Absolute and relative liver weights of males exposed to 

250, 500, or 1,000 ppm and of females exposed to 100, 

250, 500, or 1,000 ppm were significantly greater than 

controls (Table H1). At the end of the study, plasma 

concentrations of pyridine in 50, 100, 250, and 

500 ppm females were greater than those in males; 

however, plasma concentration in 1,000 ppm females 

was less than in males (Table J1). 

Multiple hepatic alterations were observed in the livers 

of males and females exposed to 500 or 1,000 ppm 

(Table 3). Incidences of centrilobular degeneration and 

hypertrophy were increased relative to controls in males 

and females exposed to 500 or 1,000 ppm. Incidences 

of chronic inflammation were increased in 1,000 ppm 

males and females and 500 ppm males compared to 

controls. Incidences of pigmentation were significantly 

increased in 500 and 1,000 ppm males and females and 

250 ppm females relative to controls. Degeneration 

consisted of clusters of hepatocytes, primarily centrilobular, that were strikingly ballooned and whose 

rarefied cytoplasm had strands or granules of eosinophilic material. Hypertrophy was a minimal increase in 

the size of centrilobular hepatocytes. Chronic inflammation consisted of lymphocytes, macrophages, and 

fibrous connective tissue that was primarily centrilobular but bridged across lobules in more severe cases. 

The macrophages often contained a yellow-brown 

pigment that special stains showed had characteristics 
 

Pyridine, NTP TR 470 37 

of both lipofuscin and hemosiderin. The pigment was 

positive with PAS, Perl’s, and Schmorl’s staining but 

was acid-fast negative. 

In the kidney, the incidences of granular casts and 

hyaline degeneration (hyaline droplets) of minimal 

severity were significantly increased in 1,000 ppm 

males and slightly increased in 500 ppm males 

(Table 3). Lumens from one to three tubules per 

kidney were filled with a granular eosinophilic material 

(granular casts) thought to represent cellular debris 

from dead and sloughed renal tubule epithelial cells 

from a more proximal region of the tubule. 

TABLE 3 

Hyaline droplets were characterized by eosinophilic 

proteinaceous material within the cytoplasm of renal 

tubular epithelial cells. This change occurred in all 

kidneys from males in the 13-week study but was only 

diagnosed when the quantity exceeded that observed in 

control males. An immunohistochemical stain specific 

for α2u-globulin was positive in both control and 

exposed males; the intensity of staining appeared 

slightly greater in the 1,000 ppm group. These changes, 

consistent with α2u-globulin nephropathy, were minimal in 1,000 ppm males. There was marginal evidence 

of an effect in the 500 ppm group and a no-effect level 

in the 250 ppm group. 

Incidences of Selected Nonneoplastic Lesions in F344/N Rats in the 13-Week Drinking Water Study 

of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

Livera 

Centrilobular, Degenerationb 

10 

0 

10 

0 

10 

0 

10 

0 

10 

9** (1.0)

c 10 

9** (1.8) 

Hypertrophy 0 0 0 0 9** (1.0) 9** (1.0) 

Inflammation, Chronic 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 7** (1.0) 9** (1.9) 

Pigmentation 0 0 0 0 6** (1.0) 10** (1.1) 

Kidney 10 10 10 10 10 10 

Casts 0 0 3 (1.0) 3 (1.0) 9** (1.0) 9** (1.0) 

Inflammation, Chronic 0 0 0 2 (1.0) 4* (1.0) 9** (1.0) 

Mineralization 2 (1.0) 2 (1.0) 2 (1.0) 6 (1.0) 9** (1.0) 10** (1.0) 

Renal Tubule, Regeneration 10 (1.0) 10 (1.0) 10 (1.0) 10 (1.1) 10 (1.6) 10 (1.4) 

Casts Granular 0 0 0 0 3 (1.0) 8** (1.0) 

Renal Tubule, Hyaline Degeneration 1 (1.0) 0 1 (1.0) 1 (1.0) 3 (1.0) 7** (1.0) 

Female 

Liver 10 10 10 10 10 10 

Centrilobular, Degeneration 0 0 0 0 9** (1.0) 9** (1.8) 

Hypertrophy 0 0 0 0 9** (1.0) 8** (1.0) 

Inflammation, Chronic 0 0 0 0 1 (1.0) 4* (1.8) 

Pigmentation 0 0 0 7** (1.0) 7** (1.0) 8** (1.1) 

Kidney 10 10 

Casts 0 2 (1.0) 

Mineralization 10 (1.6) 10 (1.3) 

* Significantly different (P 0.05) from the control group by the Fisher exact test 

** P 0.01 

a Number examined microscopically b Number of animals with lesion 

Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked c 
 

 

38 Pyridine, NTP TR 470 

Additionally, there were increased incidences and/or 

severities of protein casts, chronic inflammation, mineralization, and regeneration primarily in 500 and 

1,000 ppm males. These lesions are qualitatively similar to those associated with spontaneous nephropathy 

observed in young control male F344/N rats and may 

have been exacerbated by administration of pyridine. 

Exacerbation of these lesions also occurs with 

α2u-globulin nephropathy and may have contributed to 

the increases observed in this study. 

Exposure Concentration Selection Rationale: The 

highest exposure concentration selected for the 2-year 

F344/N rat study was 400 ppm based on increased 

incidences and severities of liver (including increased 

alanine aminotransferase and sorbitol dehydrogenase 

activities and bile acids concentrations) and kidney 

lesions and lower final mean body weights and body 

weight gains relative to controls in rats exposed to 500 

or 1,000 ppm in the 13-week study. Lesions observed 

in the liver of female rats exposed to 250 ppm consisted of only scant pigment in macrophages in the 

vicinity of the central veins, and there was no effect on 

the kidney. Pyridine plasma levels were measured at 

the end of the 13-week studies in rats (Tables J1 

and J2). A clear inflection point in the serum levels 

cannot be determined from the pyridine data, but the 

serum levels at 500 and 1,000 ppm appear disproportionally high when compared to those at 100 and 

250 ppm. 
Pyridine, NTP TR 470 39 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male and 

female F344/N rats are shown in Table 4 and in the 

Kaplan-Meier survival curves (Figure 2). Survival of 

exposed males and females was not significantly 

different from controls. 

Body Weights, Water and Compound 

Consumption, and Clinical Findings 

Mean body weights of 400 ppm males and females 

were generally less than those of controls throughout 

TABLE 4 

the study, and those of 200 ppm males and females 

were generally less during the second year of the study 

(Figure 3; Tables 5 and 6). Water consumption by 

400 ppm males and females was greater than that by 

controls throughout the study, and water consumption 

by 200 ppm males and females was greater during the 

second year of the study (Tables L1 and L2). Drinking 

water concentrations of 100, 200, or 400 ppm pyridine 

resulted in average daily doses of 7, 14, or 33 mg/kg. 

There were no treatment-related clinical findings. 

Survival of F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Male 

Animals initially in study 50 50 50 50 

Moribund 11 13 15 10 

Natural deaths 14 17 10 24 

Animals surviving to study termination 

Percent probability of survival at end of studya 

Mean survival (days)b 

25 

50 

663 

20 

40 

666 

25 

50 

665 

16 

32 

646 

Survival analysisc P=0.124 P=0.403 P=1.000 P=0.095 

Female 

Animals initially in study 50 50 50 50 

Moribund 3 8 7 2 

Natural deaths 15 5 14 22 

Animals surviving to study termination 32 37 29 26 

Percent probability of survival at end of study 64 74 58 52 

Mean survival (days) 694 703 693 672 

Survival analysis P=0.055 P=0.392N P=0.700 P=0.204 

a Kaplan-Meier determinations b	 Mean of all deaths (uncensored, censored, and terminal sacrifice) 

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

1972) with the controls are in the exposed group columns. Lower mortality in an exposure group is indicated by N. 

c 
40 Pyridine, NTP TR 470 

FIGURE 2
 

Kaplan-Meier Survival Curves for Male and Female F344/N Rats 


Exposed to Pyridine in Drinking Water for 2 Years
 
Pyridine, NTP TR 470 41 

FIGURE 3
 

Growth Curves for Male and Female F344/N Rats
 

Exposed to Pyridine in Drinking Water for 2 Years
 
42 Pyridine, NTP TR 470 

TABLE 5 

Mean Body Weights and Survival of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

Weeks 0 ppm 100 ppm 200 ppm 400 ppm 

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 (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors 

1 136 50 135 99 50 135 99 50 136 100 50 

2 173 50 172 100 50 169 98 50 167 97 50 

3 207 50 208 101 50 206 99 50 201 97 50 

4 236 50 234 99 50 232 98 50 227 96 50 

5 255 50 253 99 50 250 98 50 245 96 50 

6 275 50 267 97 50 272 99 50 258 94 50 

7 293 50 286 98 50 289 99 50 272 93 50 

8 302 50 295 98 50 295 98 50 282 94 50 

9 314 50 309 98 50 306 97 50 291 93 50 

10 331 50 326 99 50 323 98 50 309 93 50 

11 333 50 329 99 50 328 99 50 311 94 50 

12 342 50 339 99 50 340 100 50 323 95 50 

13 351 50 349 99 50 348 99 50 328 94 50 

17 384 50 382 100 50 378 99 50 355 93 50 

21 409 50 405 99 50 404 99 50 376 92 50 

25 426 50 420 99 50 420 98 50 392 92 50 

29 437 50 431 99 50 433 99 50 403 92 49 

33 453 50 448 99 50 448 99 50 421 93 49 

37 465 50 461 99 50 460 99 50 434 93 49 

41 478 50 468 98 50 469 98 49 443 93 49 

45 483 50 480 99 50 480 100 49 452 94 49 

49 489 49 479 98 50 480 98 49 453 93 49 

53 487 49 482 99 50 482 99 49 453 93 49 

57 502 47 489 98 50 484 97 49 462 92 49 

61 503 47 491 98 50 487 97 49 459 91 49 

65 508 46 492 97 49 484 95 49 455 90 47 

69 511 45 500 98 47 485 95 49 457 89 46 

73 511 45 500 98 47 480 94 48 446 87 46 

77 510 45 497 98 47 475 93 46 446 87 43 

81 494 45 497 101 45 467 94 44 441 89 42 

85 501 42 486 97 45 462 92 41 428 86 40 

89 499 39 484 97 41 440 88 39 414 83 37 

93 501 36 478 95 35 428 85 35 406 81 33 

95 495 35 452 91 35 422 85 33 403 81 30 

97 491 33 464 95 28 414 84 30 391 80 28 

99 474 33 459 97 25 401 85 29 379 80 24 

101 468 31 458 98 23 397 85 27 388 83 19 

103 461 29 440 95 21 374 81 26 369 80 19 

Mean for weeks 

1-13 273 269 99 269 99 258 95 

14-52 447 442 99 441 99 414 93 

53-103 495 479 97 449 91 425 86 
Pyridine, NTP TR 470 43 

TABLE 6 

Mean Body Weights and Survival of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

Weeks 0 ppm 100 ppm 200 ppm 400 ppm 

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 (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors 

1 110 50 110 100 50 110 101 50 111 101 50 

2 129 50 128 99 50 127 99 50 124 96 50 

3 144 50 145 100 50 143 99 50 139 96 50 

4 152 50 152 100 50 151 99 50 148 97 50 

5 160 50 160 100 50 159 100 50 155 97 50 

6 167 50 167 100 50 164 98 50 160 96 50 

7 173 50 173 100 50 171 98 50 167 96 50 

8 180 50 179 100 50 176 98 50 170 95 50 

9 183 50 183 100 50 178 97 50 173 94 50 

10 186 50 185 100 50 181 98 50 175 94 50 

11 192 50 190 99 50 185 96 50 178 93 50 

12 196 50 194 99 50 187 96 50 182 93 50 

13 198 50 197 100 50 191 97 50 185 93 50 

17 213 50 210 99 50 204 96 50 196 92 50 

21 223 50 220 99 50 212 95 50 205 92 50 

25 228 50 225 99 50 218 95 50 208 91 50 

29 234 50 233 100 50 224 96 50 214 91 50 

33 242 50 238 98 50 228 94 50 220 91 50 

37 251 50 247 98 50 239 95 50 225 90 50 

41 261 50 257 99 50 247 95 50 234 90 50 

45 270 50 269 100 50 257 95 50 240 89 50 

49 279 50 280 101 50 266 95 50 247 89 50 

53 285 50 287 101 50 273 96 50 252 88 50 

57 288 50 290 101 50 273 95 50 255 89 49 

61 299 49 297 99 50 280 94 50 258 86 49 

65 301 49 302 100 50 284 94 50 259 86 49 

69 310 49 308 99 50 290 93 50 269 87 48 

73 314 47 313 100 49 292 93 49 275 88 47 

77 322 47 313 97 49 299 93 48 282 88 46 

81 326 47 323 99 47 299 92 47 283 87 46 

85 330 46 327 99 46 306 93 43 281 85 44 

89 331 45 328 99 45 306 92 42 286 86 39 

93 338 43 332 98 44 307 91 41 286 85 33 

95 334 42 335 100 43 305 91 41 281 84 32 

97 344 38 332 96 41 306 89 39 286 83 30 

99 340 36 333 98 40 301 89 38 286 84 29 

101 337 35 333 99 39 298 89 35 284 85 28 

103 340 35 332 98 39 303 89 31 286 84 26 

Mean for weeks 

1-13 167 166 99 163 98 159 95 

14-52 245 242 99 233 95 221 90 

53-103 321 318 99 295 92 276 86 
 

 

44 Pyridine, NTP TR 470 

Pathology and Statistical Analyses 

This section describes the statistically significant or 

biologically noteworthy changes in the incidences of 

neoplasms and nonneoplastic lesions of the kidney, 

liver, and lung and incidences of mononuclear cell 

leukemia. Summaries of the incidences of neoplasms 

and nonneoplastic lesions, individual animal tumor 

diagnoses, statistical analyses of primary neoplasms 

that occurred with an incidence of at least 5% in at least 

one animal group, and historical incidences for the 

neoplasms mentioned in this section are presented in 

Appendix A for male F344/N rats and Appendix B for 

female F344/N rats. 

Kidney: In the standard evaluation, the number of renal 

tubule adenomas in male rats exposed to 400 ppm was 

significantly greater than in the controls and exceeded 

the historical control range (Tables 7, A3, and A4). 

One renal tubule carcinoma was observed in a 100 ppm 

male. Additional step sections of kidneys were prepared from residual wet tissue so that each kidney 

yielded four additional sections spaced 1 mm apart. 

The step sections did not reveal additional carcinomas, 

but additional adenomas were observed in each group 

of exposed and control males (Table 7). The incidence 

of renal tubule hyperplasia was increased in 400 ppm 

males in single sections compared to controls (Tables 7 

and A5). 

Renal tubule hyperplasia consisted of multiple layers 

rather than the normal single layer of epithelium, 

frequently resulting in an increased tubule diameter 

(Plate 1). Severity of hyperplasia depended on the 

number of layers and the complexity of their patterns. 

Some had papillary projections, but cells retained their 

orientation to the basement membrane. The renal 

tubule adenomas in both single and step sections were 

typical of those occurring spontaneously. Adenomas 

were masses of epithelial cells five or more tubule 

diameters in size (Plate 2). Cells in the adenomas were 

disorganized and had lost their orientation to the tubule 

basement membrane. The renal tubule carcinoma 

observed in the single sections was approximately 

3 mm in diameter and had densely packed, widely 

pleomorphic epithelial cells that infiltrated the adjacent 

parenchyma. 

TABLE 7 

Incidences of Selected Neoplasms and Nonneoplastic Lesions in Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Kidney 50 48 50 49 

Single Sections (Standard Evaluation) 

Nephropathya 47 (2.3)b 47 (2.3) 49 (2.5) 49 (2.6) 

Renal Tubule, Hyperplasia 1 (1.0) 0 4 (3.0) 7* (1.7) 

Renal Tubule, Adenomac

 (includes multiple) 

Overall rated 1/50 (2%) 

Adjusted ratee 2.4% 

Terminal ratef 1/25 (4%) 

First incidence (days) 722 (T) 

Poly-3 testg P=0.003 

0/48 (0%) 

0.0% 

0/20 (0%) 

—h 

P=0.510N 

2/50 (4%) 

4.9% 

1/25 (4%) 

708 

P=0.498 

6/49 (12%) 

15.9% 

2/16 (13%) 

644 

P=0.042 

Renal Tubule, Carcinomai 0 1 0 0 

Renal Tubule, Adenoma or Carcinomac 

Overall rate 1/50 (2%) 1/48 (2%) 2/50 (4%) 6/49 (12%) 

Adjusted rate 2.4% 2.6% 4.9% 15.9% 

Terminal rate 1/25 (4%) 1/20 (5%) 1/25 (4%) 2/16 (13%) 

First incidence (days) 722 (T) 722 (T) 708 644 

Poly-3 test P=0.008 P=0.750 P=0.498 P=0.042 
Pyridine, NTP TR 470 45 

TABLE 7 

Incidences of Selected Neoplasms and Nonneoplastic Lesions in Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 9 (2.0) 7 (2.1) 11 (3.0) 15 (2.4) 

Renal Tubule, Adenoma 1 3 5 9** 

Single Sections and Step Sections (Combined) 

Renal Tubule, Hyperplasia 10 (1.9) 7 (2.1) 14 (3.1) 16 (2.4) 

Renal Tubule, Adenoma 

Overall rate 2/50 (4%) 3/48 (6%) 6/50 (12%) 10/49 (20%) 

Adjusted rate 4.9% 7.6% 14.5% 26.3% 

Terminal rate 2/25 (8%) 2/20 (10%) 3/25 (12%) 5/16 (31%) 

First incidence (days) 722 (T) 673 627 644 

Poly-3 test P=0.002 P=0.480 P=0.133 P=0.008 

Renal Tubule, Carcinoma 0 1 0 0 

Renal Tubule, Adenoma or Carcinoma 

Overall rate 2/50 (4%) 4/48 (8%) 6/50 (12%) 10/49 (20%) 

Adjusted rate 4.9% 10.2% 14.5% 26.3% 

Terminal rate 2/25 (8%) 3/20 (15%) 3/25 (12%) 5/16 (31%) 

First incidence (days) 722 (T) 673 627 644 

Poly-3 test P=0.003 P=0.316 P=0.133 P=0.008 

Stomach, Glandular 50 49 50 49 

Mineralization 0 2 (2.0) 2 (1.5) 8** (2.0) 

Parathyroid Gland 50 50 50 48 

Hyperplasia 0 1 (2.0) 3 (2.3) 3 (2.0) 

Bone 50 50 50 50 

Fibrous Osteodystrophy 2 (3.0) 1 (3.0) 4 (2.3) 6 (2.5) 

* Significantly different (P 0.05) from the control group by the Poly-3 test 

** P 0.01 

(T)Terminal sacrifice

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked c Historical incidence for 2-year drinking water studies with untreated control groups (mean ± standard deviation): 1/327 (0.3% ± 0.8%); 

range, 0%-2% d Number of animals with neoplasm per number of animals with kidney examined microscopically e Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality f Observed incidence at terminal kill 

g	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values 

corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in 

animals that do not reach terminal sacrifice. A lower incidence in an exposure group is indicated by N. h Not applicable; no neoplasms in animal group i Historical incidence: 0/327 

The severity of nephropathy was not significantly exposed males, and the incidence of stomach mineralincreased in males (Table 7). Incidences of minerali- ization in 400 ppm males was significantly increased 

zation of the stomach, parathyroid gland hyperplasia, compared to controls (Tables 7 and A5). These extraand fibrous osteodystrophy were observed in a few renal lesions are indicative of kidney disease. 
 

 

 

46 Pyridine, NTP TR 470 

Mononuclear Cell Leukemia: Incidences of mononuclear cell leukemia in female rats were significantly 

increased in the 200 and 400 ppm groups compared to 

controls, and the incidence in the 400 ppm group 

exceeded the historical control range (Tables 8, B3, and 

B4). In all animals with this neoplasm, neoplastic cells 

were found in the spleen and usually also in the 

TABLE 8 

liver. Infiltrations in the lung, bone marrow, lymph 

nodes, adrenal gland, and kidney were also common. 

Incidences of mononuclear cell leukemia in male rats 

were similar to those in controls (0 ppm, 29/50; 

100 ppm, 32/50; 200 ppm, 26/50; 400 ppm, 27/50; 

Table A3). 

Incidences of Mononuclear Cell Leukemia in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Mononuclear Cell Leukemiaa 

Overall rateb 

Adjusted ratec 

Terminal rated 

12/50 (24%) 

26.5% 

8/32 (25%) 

16/50 (32%) 

34.3% 

12/37 (32%) 

22/50 (44%) 

45.4% 

8/29 (28%) 

23/50 (46%) 

48.7% 

5/26 (19%) 

First incidence (days) 

Poly-3 teste 636 

P=0.013 

546 

P=0.279 

496 

P=0.043 

380 

P=0.020 

a Historical incidence for 2-year drinking water studies with untreated control groups (mean ± standard deviation): 102/330 (30.9% ± 10.0%); 

range, 16%-44% b Number of animals necropsied c Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality d Observed incidence at terminal kill e Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values 

corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in 

animals that do not reach terminal sacrifice. 

Liver: Incidences of hepatocellular neoplasms were not 

significantly increased in exposed rats compared to 

controls, but exposure concentration-related nonneoplastic liver lesions were observed (Tables 9, A5, and 

B5). Incidences of centrilobular cytomegaly and 

cytoplasmic vacuolization were increased in males 

exposed to 200 or 400 ppm and females exposed to 

400 ppm relative to controls. In 400 ppm males, incidences of periportal fibrosis, fibrosis, and centrilobular 

degeneration and necrosis were significantly increased 

relative to controls. The incidence of centrilobular 

degeneration was increased in 400 ppm females compared to controls. Bile duct hyperplasia was observed 

in control and exposed males and females, and the 

incidences were significantly increased in exposed 

females compared to controls. Incidences of pigmentation increased compared to controls in all exposed 

groups of males and in 400 ppm females. Incidences of 

basophilic foci were decreased relative to controls in 

200 and 400 ppm males and all exposed groups of 

females. The incidence of clear cell foci relative to 

controls was decreased in 100 ppm males; incidences 

of clear cell foci were increased relative to controls in 

200 and 400 ppm females. The incidence of eosinophilic foci was increased relative to controls in 

100 ppm males. 

Centrilobular cytomegaly consisted of an increased 

amount of cytoplasm containing varying amounts of 

homogeneous eosinophilic material that enlarged 

hepatocytes. Cytoplasmic vacuolization referred to 

vacuolized hepatocytes in noncentrilobular areas. 

Periportal fibrosis consisted of bands of fibrous 

connective tissue in portal areas. Fibrosis was defined 

as fibrous connective tissue under the capsule of the 

liver and extending downward along the vasculature. 

Bile duct hyperplasia was a cluster of six or more bile 

ducts. Pigmentation was yellowish brown material in 
 

 

Pyridine, NTP TR 470 47 

TABLE 9 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Male 

Number Examined Microscopically 

Basophilic Focusa 50 12 

49 

5 

50 

0** 

50 

1** 

Clear Cell Focus 7 1* 7 4 

Eosinophilic Focus 

Centrilobular, Cytomegaly 

14 

0 

23* 

4 (1.3)b 

23 

8** (1.3) 

13 

6* (2.0) 

Vacuolization Cytoplasmic 4 (1.5) 6 (1.8) 13* (1.7) 17** (2.4) 

Periportal Fibrosis 0 0 2 (2.5) 29** (1.8) 

Fibrosis 1 (2.0) 1 (2.0) 1 (1.0) 10** (1.6) 

Centrilobular, Degeneration 1 (2.0) 3 (2.3) 2 (2.0) 8* (2.1) 

Centrilobular, Necrosis 0 3 (1.7) 0 5* (2.2) 

Bile Duct, Hyperplasia 46 (1.4) 43 (1.5) 44 (1.6) 49 (1.6) 

Pigmentation 4 (1.0) 11* (1.3) 20** (1.3) 25** (2.0) 

Hepatocellular Adenoma 1 1 0 3 

Hepatocellular Carcinoma 0 0 1 0 

Hepatocellular Adenoma or Carcinoma 1 1 1 3 

Female 

Number Examined Microscopically 50 50 50 50 

Basophilic Focus 38 28* 11** 0** 

Clear Cell Focus 4 9 11* 16** 

Eosinophilic Focus 19 24 22 15 

Centrilobular, Cytomegaly 0 1 (1.0) 4 (1.0) 20** (1.4) 

Vacuolization Cytoplasmic 10 (1.8) 7 (1.0) 9 (1.8) 18* (1.6) 

Centrilobular, Degeneration 1 (2.0) 2 (2.5) 2 (1.5) 7* (1.1) 

Bile Duct, Hyperplasia 20 (1.0) 29* (1.1) 34** (1.0) 29* (1.0) 

Pigmentation 6 (1.5) 2 (1.5) 6 (2.3) 17** (1.6) 

Hepatocellular Adenoma 1 0 1 0 

* Significantly different (P 0.05) from the control group by the Poly-3 test 

** P 0.01 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked 

macrophages, often present in areas of fibrosis. epithelial hyperplasia was also observed in the 100 and 

Centrilobular degeneration was used to denote vacuo- 400 ppm groups (0/50, 3/50, 0/50, 3/50; Table A5). 

lated hepatocytes in the center of hepatic lobules. Although these neoplasms are relatively uncommon, 

incidences up to eight of 50 have occurred in untreated 

Lung: Incidences of alveolar/bronchiolar adenoma or control groups from other recent NTP 2-year carcinocarcinoma (combined) in males occurred with a posi- genicity studies. This marginally increased neoplasm 

tive trend (1/50, 0/50, 2/50, 4/50; Table A3). Alveolar incidence was not considered to be chemical-related. 
 

 

 

 

48 

c 

Pyridine, NTP TR 470 

WISTAR RATS 

13-WEEK STUDY 

One male rat exposed to 500 ppm died during the first 1,000 ppm was lower than that by controls. Drinking 

week of the study (Table 10). Final mean body weights water concentrations of 50, 100, 250, 500, or 

and body weight gains of rats exposed to 250, 500, or 1,000 ppm pyridine resulted in average daily doses of 

1,000 ppm were significantly less than those of the 5, 10, 30, 60, or 100 mg/kg. There were no treatmentcontrols. Water consumption by rats exposed to related clinical findings. 

TABLE 10 

Survival, Body Weights, and Water Consumption of Male Wistar Rats 

in the 13-Week Drinking Water Study of Pyridine 

Concentration 

(ppm) Survivala 

Initial 

Mean Body Weightb (g) 

Final Change 

Final Weight 

Relative to 

Controls 

(%) 

Water 

Consumptionc 

Week 1 Week 13 

0 

50 

100 

250 

500 

1,000 

10/10 

10/10 

10/10 

10/10 

9/10d 

10/10 

161 ± 3 

161 ± 3 

159 ± 3 

159 ± 3 

157 ± 4 

159 ± 3 

511 ± 9 

476 ± 13 

490 ± 7 

463 ± 17** 

443 ± 8** 

420 ± 15** 

350 ± 9 

315 ± 11 

331 ± 8 

304 ± 16** 

286 ± 6** 

260 ± 14** 

93 

96 

91 

87 

82 

169 

152 

148 

136 

141 

111 

120 

118 

116 

95 

127 

74 

** Significantly different (P 0.01) from the control group by Williams’ test

a Number of animals surviving at 13 weeks/number initially in group b	 Weights and weight changes are given as mean ± standard error. Subsequent calculations are based on animals surviving to the end of the 

study. 

Water consumption is expressed as grams of water consumed per kg body weight per day. d Week of death: 1 

The hematology and clinical chemistry data for Wistar 

rats are presented in Table G2. Similar to male F344/N 

rats, an erythrocytosis, demonstrated by increased 

hematocrit values, hemoglobin concentrations, and 

erythrocyte counts, occurred in 500 and 1,000 ppm rats 

on day 5. An erythrocytosis would be consistent with 

dehydration, which can cause a relative erythrocytosis 

due to decreased blood volume and hemoconcentration. 

Hemoconcentration would be supported by the 

increased albumin concentration in 1,000 ppm rats 

relative to controls. Additionally, urea nitrogen concentrations were increased relative to controls in 500 

and 1,000 ppm rats on days 5 and 20; creatinine concentration, another marker of renal function, was 

unaffected. Urea nitrogen concentration can be influenced by many extrarenal factors: high protein diets, 

dehydration, liver function, animal health, and nutritional status (Finco, 1989). Serum creatinine, a product 

of muscle metabolism, is not as affected by extrarenal 

factors (Ragan, 1989). A nonrenal effect, such as 

dehydration caused by decreased water intake due to 

poor palatability of dosed water, could result in a urea 

nitrogen concentration increase, while creatinine 

concentration remains unchanged. 

Also similar to F344/N rats, there was evidence of 

hepatocellular injury and/or altered hepatic function 

demonstrated by increased serum alanine aminotransferase and sorbitol dehydrogenase activities and bile 

acid concentrations at all time points in 500 and 

1,000 ppm rats relative to controls. Decreased alkaline 

phosphatase activity relative to controls was observed, 

but with less consistency, in 250 and 1,000 ppm rats. 

Organ weights of exposed rats were not significantly 

different from those of controls (Table H2). Plasma 

concentrations of pyridine increased with increasing 

dose (Table J2). 
 

 

 

Pyridine, NTP TR 470 49 

Incidences of centrilobular degeneration, hypertrophy, 

chronic inflammation, and pigmentation in the liver of 

rats exposed to 500 or 1,000 ppm were significantly 

increased relative to controls (Table 11). Two types of 

enlarged centrilobular hepatocytes were separately 

diagnosed. Degeneration consisted of mildly to moderately enlarged, palely stained hepatocytes, primarily 

centrilobular, that had lacy to vacuolated cytoplasm 

containing an eosinophilic granular to flocculent 

material. Hypertrophy was a minimal increase in size 

of centrilobular hepatocytes without vacuolated or lacy 

cytoplasm. Chronic inflammation consisted of lymphocytes, macrophages, and fibrous connective tissue that 

was primarily centrilobular and bridged across lobules 

in more severe cases. The macrophages often contained a yellow-brown pigment that special stains 

showed had characteristics of both lipofuscin and 

hemosiderin. The pigment was positive with PAS, 

Perl’s, and Schmorl’s staining but was acid-fast 

negative. 

Incidences of kidney lesions in exposed rats were not 

significantly different from those of controls 

(Table 11). Many lesions (protein casts, inflammation 

mineralization, and regeneration of renal tubule epithelium) are components of spontaneous nephropathy 

that is common in male rats. The incidences of spontaneous nephropathy in control Wistar males were high, 

and possible nephrotoxicity was not clear. Granular 

casts, which indicate more severe renal tubule damage 

than protein casts, were noted in one rat in the 1,000 

ppm group. The incidence, but not the severity, of 

hyaline degeneration was increased, although not 

significantly, in the 1,000 ppm group. Hyaline degeneration refers to eosinophilic refractile protein material 

in the cytoplasm of renal tubule epithelium. Immunohistochemistry for α2u-globulin was positive in all 

males tested. 

Exposure Concentration Selection Rationale: The 

highest exposure concentration selected for the 2-year 

Wistar rat study was 400 ppm based on increased incidences and severities of liver lesions (including 

increased alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations) in rats 

exposed to 500 or 1,000 ppm compared to controls. 

Pyridine plasma levels were measured at the end of the 

13-week studies in rats (Tables J1 and J2). A clear 

inflection point in the serum levels could not be determined from the pyridine data, but the serum levels at 

500 and 1,000 ppm appeared disproportionally high 

when compared to those at 100 and 250 ppm. 

TABLE 11 

Incidences of Selected Nonneoplastic Lesions in Male Wistar Rats in the 13-Week Drinking Water Study 

of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Livera 

Centrilobular, Degenerationb 

10 

0 

10 

0 

10 

0 

10 

0 

9 

9** (1.7)

c 10 

9** (1.4) 

Hypertrophy 0 0 0 0 9** (1.0) 10** (1.0) 

Inflammation, Chronic 0 0 0 2 (1.0) 9** (1.7) 9** (2.2) 

Pigmentation 0 0 0 0 9** (1.0) 9** (1.3) 

Kidney 10 10 10 10 9 10 

Casts 3 (1.0) 3 (1.0) 4 (1.0) 4 (1.5) 4 (1.0) 5 (1.0) 

Inflammation, Chronic 0 1 (1.0) 1 (2.0) 0 0 2 (1.0) 

Mineralization 7 (1.0) 5 (1.2) 4 (1.0) 8 (1.3) 8 (1.0) 10 (1.0) 

Renal Tubule, Regeneration 5 (1.0) 6 (1.0) 5 (1.0) 9 (1.0) 7 (1.0) 8 (1.1) 

Casts Granular 0 0 0 0 0 1 (1.0) 

Renal Tubule, Hyaline Degeneration 2 (1.0) 0 0 2 (1.0) 3 (1.0) 6 (1.0) 

** Significantly different (P 0.01) from the control group by the Fisher exact test

a Number examined microscopically b Number of animals with lesion 

Average severity grade of lesion in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked c 
50 

c 

Pyridine, NTP TR 470 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male 

Wistar rats are shown in Table 12 and in the KaplanMeier survival curves (Figure 4). Survival of rats 

exposed to 200 or 400 ppm was significantly less than 

that of the controls. 

TABLE 12 

Body Weights, Water and Compound 

Consumption, and Clinical Findings 

Mean body weights of rats exposed to 100, 200, or 

400 ppm were significantly less than controls (Figure 5 

and Table 13). Water consumption by exposed rats 

was similar to that by controls (Table L3). Drinking 

water concentrations of 100, 200, or 400 ppm pyridine 

resulted in average daily doses of 8, 17, or 36 mg/kg. 

There were no treatment-related clinical findings. 

Survival of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Animals initially in study 50 50 50 50 

Moribund 2 9 9 10 

Natural deaths 26 27 30 33 

Animals surviving to study termination 

Percent probability of survival at end of studya 

Mean survival (days)b 

22 

44 

661 

14 

28 

625 

11 

22 

618 

7 

14 

577 

Survival analysisc P<0.001 P=0.090 P=0.020 P<0.001 

a Kaplan-Meier determinations b	 Mean of all deaths (uncensored, censored, and terminal sacrifice) 

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

1972) with the controls are in the exposed group columns. 
Pyridine, NTP TR 470 51 

FIGURE 4 

Kaplan-Meier Survival Curves for Male Wistar Rats 

Exposed to Pyridine in Drinking Water for 2 Years 

FIGURE 5 

Growth Curves for Male Wistar Rats 

Exposed to Pyridine in Drinking Water for 2 Years 
52 Pyridine, NTP TR 470 

TABLE 13 

Mean Body Weights and Survival of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

Weeks 0 ppm 100 ppm 200 ppm 400 ppm 

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 (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors 

1 201 50 198 98 50 199 99 50 198 98 50 

2 255 50 250 98 50 246 97 50 240 94 50 

3 294 50 289 98 50 285 97 50 280 95 50 

4 327 50 326 100 50 321 98 50 312 95 50 

5 357 50 359 101 50 347 97 50 345 96 50 

6 382 50 380 99 50 372 97 50 358 94 50 

7 413 50 411 100 50 402 97 50 388 94 50 

8 426 50 428 101 50 412 97 50 400 94 50 

9 448 50 446 100 50 435 97 50 419 94 50 

10 464 50 463 100 50 452 97 50 431 93 50 

11 479 50 478 100 50 463 97 50 443 93 50 

12 494 50 492 100 50 479 97 50 457 93 50 

13 506 50 503 99 50 490 97 50 466 92 50 

17 546 50 542 99 50 527 97 50 502 92 49 

21 569 50 575 101 50 562 99 50 528 93 49 

25 599 50 602 101 50 583 97 50 552 92 49 

29 627 50 630 100 50 612 98 50 576 92 49 

33 658 50 657 100 50 638 97 50 599 91 49 

37 672 50 673 100 50 651 97 50 610 91 49 

41 691 50 686 99 50 664 96 50 627 91 49 

45 715 49 711 99 50 684 96 50 642 90 49 

49 736 49 719 98 49 695 94 50 654 89 49 

53 755 49 735 97 48 705 93 49 662 88 49 

57 774 49 748 97 47 714 92 49 668 86 49 

61 789 49 753 95 47 718 91 48 669 85 49 

65 795 49 757 95 46 720 91 47 661 83 48 

69 800 48 739 92 45 699 87 46 658 82 42 

73 803 48 736 92 43 706 88 39 657 82 37 

77 797 48 725 91 42 717 90 36 644 81 34 

81 799 45 698 87 38 698 88 34 624 78 27 

85 782 41 707 91 35 699 89 32 630 81 21 

89 775 37 692 89 31 676 87 31 614 79 18 

92 777 35 667 86 29 665 86 26 613 79 15 

93 779 32 678 87 27 657 84 25 612 79 15 

95 753 31 671 89 24 630 84 24 581 77 14 

97 757 30 675 89 22 618 82 22 590 78 13 

99 715 27 666 93 20 618 86 17 609 85 8 

101 725 25 675 93 17 578 80 16 604 83 8 

103 710 23 646 91 15 591 83 12 598 84 7 

Mean for weeks 

1-13 388 386 99 377 97 364 94 

14-52 646 644 100 624 97 588 91 

53-103 770 704 91 671 87 629 82 
 

 

 

 

 

53 

c 

Pyridine, NTP TR 470 

Pathology and Statistical Analyses 

This section describes the statistically significant or 

biologically noteworthy changes in the incidences of 

neoplasms and nonneoplastic lesions of the testis, 

kidney, and liver. Summaries of the incidences of 

neoplasms and nonneoplastic lesions, individual animal 

tumor diagnoses, and statistical analyses of primary 

neoplasms that occurred with an incidence of at least 

5% in at least one animal group are presented in 

Appendix C for male Wistar rats. 

Testis: The incidence of testicular interstitial cell adenoma in rats exposed to 400 ppm was significantly 

increased compared to controls (Tables 14 and C3). 

Interstitial cell hyperplasia was observed in control and 

exposed groups and the incidences were slightly, but 

not significantly, increased in rats exposed to 200 or 

400 ppm (Tables 14 and C4). The appearance of 

interstitial cells was similar in both hyperplasia and 

adenoma and the diagnoses were based on size. Some 

interstitial cell neoplasms nearly replaced normal tissue 

(Plate 3). Hyperplasia was defined as a proliferation no 

larger than the diameter of a seminiferous tubule, and 

interstitial cell adenoma was larger. 

TABLE 14 

Incidences of Neoplasms and Nonneoplastic Lesions of the Testis in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Number Examined Microscopically 

Interstitial Cell Hyperplasiaa 50 3 (2.3)b 

49 

4 (2.0) 

49 

7 (2.3) 

50 

7 (2.9) 

Adenoma (interstitial cell) 

Overall ratec 

Adjusted rated 

Terminal ratee 

5/50 (10%) 

12.3% 

3/22 (14%) 

6/49 (12%) 

16.9% 

3/14 (21%) 

4/49 (8%) 

11.9% 

1/11 (9%) 

12/50 (24%) 

36.6% 

3/7 (43%) 

First incidence (days) 

Poly-3 testf 

592 

P=0.008 

486 

P=0.404 

660 

P=0.618N 

464 

P=0.012 

a Number examined microscopically b	 Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked 

Number of animals with neoplasm per number of animals with testis examined microscopically d	 Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality e	 Observed incidence at terminal kill 

f	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values 

corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in 

animals that do not reach terminal sacrifice. A lower incidence in an exposure group is indicated by N. 

Kidney: Incidences of renal tubule neoplasms in 

exposed rats were not significantly different from control incidences in the standard evaluation (Tables 15, 

C1, and C3). Renal tubule adenomas were observed in 

control and exposed rats and were similar to those 

observed in F344/N rats. Cells in renal tubule adenomas were disorganized and had lost their orientation to 

the tubule basement membrane. One renal tubule carcinoma approximately 5 cm in diameter was observed in 

the 400 ppm group. This neoplasm had multiple large, 

solid, irregular proliferations of densely packed, 

enlarged epithelial cells interspersed with areas of 

necrosis and inflammatory cells. In an extended evaluation, kidneys were step sectioned because of the 

carcinoma in the 400 ppm group, because of increased 

incidences of renal tubule hyperplasia in 100 ppm 

males relative to controls (Tables 15 and C4), and for 

comparison with F344/N male rats. Step sections were 

prepared from residual wet tissue so that each kidney 

yielded four additional sections spaced 1 mm apart. 

Step sectioning did not detect any significant treatmentrelated increase in incidences of renal tubule hyperplasia, adenoma, or carcinoma. 
 

54 

c 

Pyridine, NTP TR 470 

TABLE 15 

Incidences of Selected Neoplasms and Nonneoplastic Lesions in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Kidneya 50 50 50 50 

Single Sections (Standard Evaluation) 

Renal Tubule, Hyperplasiab 6 (1.7)c 17** (2.1) 8 (2.4) 5 (2.6) 

Nephropathy 50 (3.3) 50 (3.6) 50 (3.4) 50 (3.2) 

Cyst 21 (2.0) 31 (2.5) 19 (2.5) 16 (2.1) 

Mineralization 8 (1.5) 17 (2.1) 8 (1.9) 5 (1.4) 

Inflammation, Acute 0 2 (3.0) 0 1 (1.0) 

Renal Tubule, Adenoma (includes multiple) 2 5 1 2 

Renal Tubule, Carcinoma 0 0 0 1 

Renal Tubule, Adenoma or Carcinoma 2 5 1 3 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 5 (2.2) 13 (2.8) 10 (2.1) 9 (2.8) 

Renal Tubule, Oncocytoma 0 1 0 0 

Renal Tubule, Adenoma 1 2 4 2 

Renal Tubule, Carcinoma 0 0 1 0 

Renal Tubule, Adenoma or Carcinoma 1 2 5 2 

Single Sections and Step Sections (Combined) 

Renal Tubule, Hyperplasia 10 (1.8) 22 (2.5) 14 (2.4) 13 (2.8) 

Renal Tubule, Adenoma 3 6 5 4 

Renal Tubule, Carcinoma 0 0 1 1 

Renal Tubule, Adenoma or Carcinoma 3 6 6 4 

Stomach, Glandular 49 50 48 48 

Mineralization 8 (2.8) 25** (2.8) 16* (2.5) 6 (2.7) 

Parathyroid Gland 48 47 48 47 

Hyperplasia 16 (3.3) 32** (3.2) 29** (3.0) 12 (2.5) 

Bone 50 50 50 50 

Fibrous Osteodystrophy 10 (2.8) 21* (2.8) 16 (2.9) 6 (1.7) 

* Significantly different (P 0.05) from the control group by the Poly-3 test 

** P 0.01 

a Number examined microscopically b Number of animals with lesion 

Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked 

Hyperplasia consisted of multiple layers rather than the 

normal single layer of cells, frequently with an 

increased diameter of the tubule. Severity of hyperplasia depended on the number of layers and the 

complexity of their patterns. Some had papillary projections, but all maintained their orientation to the 

basement membrane. Nephropathy was observed in all 

control and exposed rats (Tables 15 and C4). Nephropathy is a common spontaneous kidney disease that 

increases in severity with increasing age. Lesions 

associated with nephropathy include renal cysts, 

mineralization of basement membranes, and inflammation of the renal parenchyma (Tables 15 and C4). 

Nephropathy was moderately severe in control and 

exposed groups of Wistar males and was considered to 

be the cause of their high mortality in this study. 

Probably because the kidney lesions were so severe in 

the controls, no treatment-related increase in the 

severity of nephropathy could be detected. However, 

incidences of extrarenal lesions of kidney disease such 
 

 

 

 

Pyridine, NTP TR 470 55 

as mineralization in the glandular stomach, parathyroid 

gland hyperplasia, and fibrous osteodystrophy were 

generally increased in rats exposed to 100 or 200 ppm 

compared to controls. These extrarenal lesions suggest 

that nephropathy was generally more severe in these 

groups. Kidney disease in 400 ppm rats may have been 

less severe because of their reduced survival and lower 

body weights. 

Liver: Incidences of hepatocellular neoplasms were not 

increased in exposed Wistar rats compared to controls, 

but exposure-related nonneoplastic liver lesions were 

observed (Tables 16, C1, and C4). Incidences of 

centrilobular degeneration (cytoplasmic vacuolization) 

occurred in exposed groups and increased with increasing exposure concentration, and the severities of 

cytoplasmic vacuolization were slightly increased in the 

exposed groups. The incidence of centrilobular necrosis was increased in the 400 ppm group compared to 

controls. Incidences of fibrosis and periportal fibrosis 

were increased in the 200 and 400 ppm groups relative 

to controls. Incidences of pigmentation were increased 

in each exposed group compared to controls. The incidences of eosinophilic foci decreased compared to 

controls in rats exposed to 200 or 400 ppm. In general, 

these liver lesions were more severe in Wistar rats than 

in F344/N rats. 

The overall structure was maintained, but exposed rats 

tended to have centrilobular hepatocytes that were 

necrotic or had an altered appearance with an increase 

in fibrous connective tissue in portal areas and extending downward from the liver capsule. Fibrosis was 

defined as fibrous connective tissue under the capsule 

of the liver and extending downward along the vasculature. Periportal fibrosis consisted of bands of fibrous 

connective tissue in portal areas. Pigmentation consisted of yellow-brown material in macrophages. 

TABLE 16 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Number Examined Microscopically 

Basophilic Focusa 50 0 

50 

0 

50 

0 

50 

2 

Clear Cell Focus 15 7 8 8 

Eosinophilic Focus 

Vacuolization Cytoplasmic 

14 

18 (1.6)b 

12 

18 (1.9) 

4* 

12 (1.8) 

2** 

15 (1.9) 

Centrilobular, Degeneration 1 (1.0) 15** (1.8) 25** (2.1) 33** (2.4) 

Centrilobular, Necrosis 5 (2.8) 6 (2.0) 4 (2.8) 23** (2.5) 

Fibrosis 1 (2.0) 5 (1.4) 26** (1.6) 31** (1.8) 

Periportal Fibrosis 0 0 5* (2.0) 7** (2.4) 

Pigmentation 6 (1.5) 15* (1.3) 34** (1.8) 42** (1.8) 

Hepatocellular Adenoma 2 0 1 0 

* Significantly different (P 0.05) from the control group by the Poly-3 test 

** P 0.01 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked 
 

56 Pyridine, NTP TR 470 

MICE 

13-WEEK STUDY 

One female mouse exposed to 250 ppm died during than controls at week 13; water consumption by 

week 2 (Table 17). Final mean body weights and body exposed and control male mice was similar. Estimated 

weight gains of female mice exposed to 1,000 ppm water consumption declined over the course of the 

were significantly less than those of controls; final study. Drinking water concentrations of 50, 100, 250, 

mean body weights and body weight gains of all other 500, or 1,000 ppm pyridine resulted in average daily 

exposed groups were similar to controls. Water con- doses of 10, 20, 50, 85, or 160 mg/kg for males and 10, 

sumption by exposed female mice was lower than that 20, 60, 100, or 190 mg/kg for females. There were no 

by controls at week 1 but was generally slightly higher treatment-related clinical findings. 

TABLE 17 

Survival, Body Weights, and Water Consumption of Mice in the 13-Week Drinking Water Study 

of Pyridine 

Concentration 

(ppm) Survivala 

Initial 

Mean Body Weightb (g) 

Final Change 

Final Weight 

Relative to 

Controls 

(%) 

Water 

Consumptionc 

Week 1 Week 13 

Male 

0 

50 

100 

250 

500 

1,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

23.7 ± 0.4 

23.5 ± 0.3 

23.8 ± 0.3 

23.8 ± 0.3 

23.4 ± 0.3 

23.7 ± 0.3 

39.4 ± 0.9 

38.4 ± 1.1 

39.3 ± 0.9 

40.2 ± 1.1 

39.1 ± 0.8 

37.2 ± 0.7 

15.7 ± 0.8 

14.9 ± 1.0 

15.4 ± 0.8 

16.3 ± 1.0 

15.8 ± 0.6 

13.5 ± 0.6 

97 

100 

102 

99 

94 

395 

349 

318 

364 

336 

377 

147 

162 

186 

167 

146 

121 

Female 

0 

50 

100 

250 

500 

1,000 

10/10 

10/10 

10/10 

9/10d 

10/10 

10/10 

19.0 ± 0.3 

18.7 ± 0.3 

18.9 ± 0.1 

18.7 ± 0.3 

19.4 ± 0.3 

18.7 ± 0.2 

33.6 ± 1.1 

37.4 ± 1.1 

34.4 ± 0.9 

34.2 ± 1.1 

33.2 ± 0.9 

29.7 ± 0.9** 

14.6 ± 1.0 

18.8 ± 1.1 

15.5 ± 0.8 

15.4 ± 1.0 

13.8 ± 0.8 

11.0 ± 0.8** 

111 

102 

102 

99 

88 

441 

278 

271 

375 

292 

201 

149 

147 

192 

214 

172 

195 

** Significantly different (P 0.01) from the control group by Williams’ or Dunnett’s test

a Number of animals surviving at 13 weeks/number initially in group b	 Weights and weight changes are given as mean ± standard error. Subsequent calculations are based on animals surviving to the end of the 

studies. 

Water consumption is expressed as grams of water consumed per kg body weight per day. d Week of death: 2 

c 
 

 

 

 

Pyridine, NTP TR 470 57 

Sperm motility in exposed male mice was decreased 

relative to controls (Table I3). There were no significant differences in estrous cycle lengths between 

control and exposed females (Table I4). 

Absolute and relative liver weights were significantly 

increased relative to controls in males exposed to 

100 ppm or greater and in 250 and 500 ppm females 

(Table H3). No histopathologic lesions were observed 

in the liver despite the increased liver weights, nor were 

any chemical-related lesions observed in any other 

tissue. 

Exposure Concentration Selection Rationale: The 

highest exposure concentration for the 2-year male 

mouse study was set at 1,000 ppm based on the lack of 

target organ lesions in the 13-week study. The highest 

exposure concentration for the 2-year female mouse 

study was set at 500 ppm based on decreased mean 

body weight gains relative to controls and decreased 

water consumption. 
 

58 Pyridine, NTP TR 470 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male and 

female mice are shown in Table 18 and in the KaplanMeier survival curves (Figure 6). Survival of exposed 

males and females was similar to that of the controls. 

Body Weights, Water and Compound 

Consumption, and Clinical Findings 

Mean body weights of exposed males were similar to 

those of the controls; mean body weights of 250 and 

500 ppm females were less than controls (Tables 19 

TABLE 18 

and 20; Figure 7). Water consumption by males 

exposed to 250 or 500 ppm was generally greater than 

that by controls during the last year of the study; male 

mice exposed to 1,000 ppm consumed less water than 

controls throughout the study (Table L4). Water consumption by exposed females was generally lower than 

that by controls during the first year of the study, but 

greater than controls during the second year (Table L5). 

Drinking water concentrations of 250, 500, or 

1,000 ppm pyridine resulted in average daily doses of 

35, 65, or 110 mg/kg for male mice and concentrations 

of 125, 250, or 500 ppm pyridine resulted in average 

daily doses of 15, 35, or 70 mg/kg for female mice. 

There were no treatment-related clinical findings. 

Survival of Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

Animals initially in study 50 50 50 50 

Accidental deathsa 2 1 1 3 

Othera 0 0 1 0 

Moribund 2 3 3 1 

Natural deaths 11 18 11 11 

Animals surviving to study termination 

Percent probability of survival at end of studyb 

Mean survival (days)c 

35 

73 

685 

28 

57 

660 

34 

71 

670 

35 

75 

656 

Survival analysisd P=0.507N P=0.138 P=0.928 P=1.000N 

0 ppm 125 ppm 250 ppm 500 ppm 

Female 

Animals initially in study 50 50 50 50 

Accidental deathsa 3 6 4 5 

Moribund 3 2 3 5 

Natural deaths 12 12 21 11 

Animals surviving to study termination 32 30 22 29 

Percent probability of survival at end of study 68 68 48 65 

Mean survival (days) 671 640 638 624 

Survival analysis P=0.487 P=1.000N P=0.090 P=0.755 

a Censored from survival analyses b	 Kaplan-Meier determinations 

Mean of all deaths (uncensored, censored, and terminal sacrifice) d	 The result of the life table trend test (Tarone, 1975) is in the control column, and the results of the life table pairwise comparisons (Cox, 

1972) with the controls are in the exposed group columns. A negative trend or lower mortality in an exposure group is indicated by N. 

c 
Pyridine, NTP TR 470 59 

FIGURE 6
 

Kaplan-Meier Survival Curves for Male and Female Mice
 

Exposed to Pyridine in Drinking Water for 2 Years
 
60 Pyridine, NTP TR 470 

TABLE 19 

Mean Body Weights and Survival of Male Mice in the 2-Year Drinking Water Study of Pyridine 

Weeks 0 ppm 250 ppm 500 ppm 1,000 ppm 

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 (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors 

1 26.1 50 25.9 99 50 25.8 99 50 25.8 99 50 

2 27.6 50 27.4 99 49 27.3 99 49 26.6 96 49 

3 29.2 50 28.7 98 49 29.0 99 49 28.4 97 48 

4 30.9 50 30.5 99 49 30.7 99 49 30.1 97 48 

5 32.8 50 32.3 99 49 32.2 98 49 30.6 93 48 

6 33.9 50 34.2 101 49 33.5 99 49 32.0 94 48 

7 35.4 50 35.4 100 49 35.3 100 49 33.9 96 48 

8 37.6 50 37.1 99 49 36.7 98 49 35.6 95 48 

9 38.7 50 37.9 98 49 37.7 97 49 36.5 94 48 

10 39.6 50 40.1 101 49 39.8 101 49 37.7 95 47 

11 40.6 50 41.0 101 49 41.0 101 49 38.8 96 47 

12 41.8 50 42.3 101 49 41.7 100 49 39.8 95 47 

13 42.4 50 42.9 101 49 42.7 101 49 40.6 96 47 

17 47.0 50 46.2 98 49 45.9 98 49 43.5 93 47 

21 48.1 49 48.3 100 49 47.4 99 49 45.2 94 47 

25 50.0 49 49.6 99 49 49.9 100 49 47.5 95 47 

29 49.6 49 50.8 102 49 51.3 103 49 48.5 98 47 

33 51.6 49 51.7 100 49 51.1 99 49 50.0 97 47 

37 53.2 49 52.9 99 48 53.0 100 48 51.8 97 47 

41 54.5 49 53.8 99 48 53.7 99 48 52.5 96 47 

45 54.1 49 53.9 100 48 54.4 101 48 52.7 97 47 

49 55.3 49 54.6 99 48 55.4 100 48 53.4 97 47 

53 55.4 49 55.6 100 48 56.2 101 48 54.7 99 47 

57 55.2 49 55.4 100 48 56.0 101 48 54.0 98 47 

61 55.2 49 56.1 102 48 56.4 102 48 54.2 98 46 

65 54.4 49 56.3 104 48 56.1 103 48 54.1 99 45 

69 55.1 49 56.5 103 48 55.5 101 48 54.4 99 45 

73 54.4 49 56.6 104 48 53.9 99 48 54.1 99 45 

77 52.8 48 55.1 104 46 52.2 99 45 52.4 99 45 

81 51.4 47 53.7 105 44 50.2 98 45 49.2 96 45 

85 49.2 46 51.5 105 42 47.8 97 44 47.3 96 45 

89 46.6 45 49.7 107 39 45.8 98 44 45.6 98 44 

93 45.5 41 46.4 102 37 44.7 98 39 43.7 96 42 

97 43.8 37 43.6 100 36 42.9 98 36 41.8 95 39 

99 44.5 37 43.5 98 32 42.7 96 36 41.2 93 37 

101 44.2 37 41.9 95 30 41.6 94 36 40.6 92 36 

103 44.0 35 41.2 94 28 40.0 91 35 39.8 91 35 

Mean for weeks 

1-13 35.1 35.1 100 34.9 99 33.6 96 

14-52 51.5 51.3 100 51.3 100 49.5 96 

53-103 50.1 50.9 102 49.5 99 48.5 97 
Pyridine, NTP TR 470 61 

TABLE 20 

Mean Body Weights and Survival of Female Mice in the 2-Year Drinking Water Study of Pyridine 

Weeks 0 ppm 125 ppm 250 ppm 500 ppm 

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 (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors 

1 20.8 50 20.7 100 50 20.6 99 50 20.5 99 50 

2 21.8 50 21.4 98 49 21.6 99 49 21.5 99 50 

3 23.2 50 22.8 98 49 22.8 98 49 22.6 97 47 

4 24.1 50 24.0 100 47 23.9 99 49 23.7 98 47 

5 25.5 50 25.3 99 47 25.5 100 49 25.6 100 47 

6 26.7 50 26.5 99 47 26.3 99 48 26.9 101 47 

7 28.2 50 28.4 101 47 28.8 102 47 28.5 101 47 

8 29.6 50 29.9 101 47 29.8 101 47 30.0 101 47 

9 31.1 50 30.1 97 47 30.8 99 47 30.4 98 47 

10 31.7 49 32.0 101 47 32.7 103 47 32.9 104 47 

11 33.3 49 33.2 100 47 33.7 101 47 33.7 101 47 

12 34.1 49 34.2 100 47 35.2 103 47 35.1 103 47 

13 35.8 49 35.5 99 47 36.5 102 47 36.3 101 47 

17 40.2 49 39.4 98 47 40.5 101 47 40.4 101 47 

21 41.1 49 40.0 97 47 41.6 101 47 41.4 101 47 

25 45.9 48 44.2 96 47 45.8 100 47 45.1 98 47 

29 45.7 48 44.9 98 46 47.2 103 46 46.5 102 46 

33 49.1 48 47.7 97 46 49.5 101 46 48.7 99 46 

37 51.0 48 49.4 97 46 51.0 100 46 50.1 98 46 

41 53.1 48 51.1 96 46 53.2 100 46 52.0 98 46 

45 54.0 48 52.5 97 46 54.1 100 46 52.2 97 45 

49 56.2 48 54.5 97 46 55.6 99 46 54.4 97 45 

53 56.9 48 55.6 98 46 57.1 100 46 55.5 98 45 

57 58.2 47 56.4 97 45 58.0 100 46 56.8 98 44 

61 59.5 47 57.9 97 44 59.3 100 45 58.1 98 44 

65 59.9 47 58.5 98 44 61.0 102 45 58.6 98 43 

69 61.6 46 59.3 96 44 62.1 101 45 58.2 95 43 

73 62.8 46 60.2 96 44 62.2 99 45 58.0 92 42 

77 63.3 46 61.0 96 44 61.9 98 44 55.4 88 40 

81 62.2 45 60.3 97 43 60.4 97 43 51.6 83 40 

85 61.1 43 58.6 96 42 58.8 96 41 48.7 80 39 

89 60.0 43 58.0 97 39 54.4 91 41 45.8 76 37 

93 57.4 40 56.3 98 38 50.9 89 37 43.7 76 36 

97 55.7 38 52.7 95 37 47.1 85 35 40.2 72 36 

99 56.1 37 53.3 95 34 46.1 82 33 40.1 72 33 

101 55.5 35 52.5 95 33 42.8 77 27 39.9 72 30 

103 56.1 33 50.7 90 31 41.2 73 25 39.1 70 29 

Mean for weeks 

1-13 28.1 28.0 100 28.3 101 28.3 101 

14-52 48.5 47.1 97 48.7 100 47.9 99 

53-103 59.1 56.8 96 54.9 93 50.0 85 
62 Pyridine, NTP TR 470 

FIGURE 7
 

Growth Curves for Male and Female Mice
 

Exposed to Pyridine in Drinking Water for 2 Years
 
 

 

 

 

 

Pyridine, NTP TR 470 63 

Pathology and Statistical Analyses 

This section describes the statistically significant or 

biologically noteworthy changes in the incidences of 

neoplasms and/or nonneoplastic lesions of the liver and 

other organs. Summaries of the incidences of neoplasms and nonneoplastic lesions, individual animal 

tumor diagnoses, statistical analyses of primary neoplasms that occurred with an incidence of at least 5% in 

at least one animal group, and historical incidences for 

the neoplasms mentioned in this section are presented 

in Appendix D for male mice and Appendix E for 

female mice. 

Liver: Hepatocellular neoplasms in male and female 

mice were clearly related to pyridine exposure. Incidences of hepatocellular adenoma were significantly 

increased relative to controls in 250 ppm males and 

females and 1,000 ppm males (Tables 21, D3, and E3). 

Incidences of hepatocellular carcinoma and hepatoblastoma were significantly increased relative to 

controls in all exposed groups of males and females 

except for the incidence of hepatoblastoma in 125 ppm 

females. Incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) 

were significantly increased in all exposed male groups 

and in 250 and 500 ppm females. The incidences of 

hepatocellular neoplasms in exposed males and females 

generally exceeded the historical control ranges 

(Tables 21, D4, and E4). Incidences of hepatoblastoma in control and exposed males and females 

exceeded the historical control range. While the 

control incidence of liver neoplasms in female mice 

was among the highest historically, almost all neoplasms were adenomas. 

Almost every exposed animal that lived one year or 

more developed one or multiple liver neoplasms, often 

carcinomas or hepatoblastomas, with many metastasizing to the lung. Hepatocellular neoplasms in 

exposed mice were similar to those that occur spontaneously. A hepatocellular adenoma was typically a 

discrete proliferation of hepatocytes that compressed 

adjacent tissue and had uneven growth patterns resulting in a slightly abnormal architecture (Plate 4). 

Hepatocellular carcinomas had a distinctly altered 

structure, cells were often pleomorphic, and the boundary with the adjacent parenchyma was often unclear 

(Plate 5). Hepatoblastomas had very poorly differentiated cells (frequently basophilic, small, and spindleshaped) that had markedly altered architectures of solid 

sheets, rosettes, ribbons, or trabeculae (Plate 6). Hepatoblastomas nearly always were found in the midst of a 

hepatocellular carcinoma, but unless there was a clearly 

separate hepatocellular carcinoma, only the diagnosis 

of hepatoblastoma was made. 

Some of the hepatocellular carcinomas and many of the 

hepatoblastomas had areas of necrosis, and metastatic 

lesions were noted in the lungs or, less frequently, in 

the lymph nodes or adjacent abdominal organs 

(Tables D1 and E1). There were no treatment-related 

increased incidences of foci of cellular alteration 

relative to controls (Tables 21, D5, and E5). Foci of 

cellular alteration were contiguous hepatocytes of less 

than a lobule up to approximately four lobules; they 

varied tinctorially from the rest of the liver but tended 

to merge imperceptibly with the adjacent parenchyma. 

Liver neoplasms from control mice, 500 ppm females, 

and 1,000 ppm males were stained for p53 protein and 

compared to a control carcinoma from the mammary 

gland of a p53 positive transgenic mouse. All of the 

liver sections tested were negative for p53 protein. 

Other Organs: Incidences of hematopoietic cell proliferation in the spleen were increased relative to 

controls in exposed males (0 ppm, 13/49; 250 ppm, 

30/50; 500 ppm, 26/47; 1,000 ppm, 23/49; Table D5) 

and females (0 ppm, 29/49; 125 ppm, 27/50; 250 ppm, 

32/48; 500 ppm, 39/49; Table E5) and may have been 

compensation for destruction of blood cells in the 

altered vasculature of the hepatic neoplasms and their 

metastases. Increased incidences of follicular cell 

hyperplasia in the thyroid gland of exposed males and 

females were not accompanied by a significant 

increased incidence of thyroid gland neoplasms relative 

to controls (males: 8/49, 14/50, 20/49, 12/50; females: 

14/50, 21/50, 22/50, 23/50; Tables D1, D5, E1, and 

E5). An apparent decrease in the incidences of hyaline 

degeneration in the respiratory epithelium of exposed 

males and females (males: 20/50, 10/49, 15/49, 2/50; 

females: 26/50, 16/50, 12/47, 13/50) and increases in 

incidences of hyaline degeneration in the olfactory 

epithelium of exposed females (19/50, 27/50, 35/47, 

36/50) compared to controls were of unknown biological significance. Hyaline degeneration in the nasal epithelium is an accumulation of eosinophilic material in 

the cytoplasm and a common alteration in aging mice. 
64 Pyridine, NTP TR 470 

TABLE 21 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

Number Examined Microscopically 

Basophilic Focusa 50 3 

50 

1 

49 

0 

50 

0 

Eosinophilic Focus 19 22 18 15 

Mixed Cell Focus 4 2 1 1 

Hepatocellular Adenoma, Multiple 16 29* 29* 28* 

Hepatocellular Adenoma (includes multiple)b 

Overall ratec 

Adjusted rated 

Terminal ratee 

29/50 (58%) 

63.2% 

24/35 (69%) 

40/50 (80%) 

88.0% 

27/28 (96%) 

34/49 (69%) 

75.7% 

27/34 (79%) 

39/50 (78%) 

84.9% 

31/35 (89%) 

First incidence (days) 

Poly-3 testf 

520 

P=0.031 

522 

P=0.003 

513 

P=0.134 

406 

P=0.011 

Hepatocellular Carcinoma, Multiple 3 19** 26** 18** 

Hepatocellular Carcinoma (includes multiple)g 

Overall rate 15/50 (30%) 35/50 (70%) 41/49 (84%) 40/50 (80%) 

Adjusted rate 32.3% 78.7% 89.9% 85.1% 

Terminal rate 9/35 (26%) 23/28 (82%) 32/34 (94%) 28/35 (80%) 

First incidence (days) 574 522 513 406 

Poly-3 test P<0.001 P<0.001 P<0.001 P<0.001 

Hepatoblastoma, Multiple 1 4 6* 2 

Hepatoblastoma (includes multiple)h 

Overall rate 2/50 (4%) 18/50 (36%) 22/49 (45%) 15/50 (30%) 

Adjusted rate 4.5% 41.2% 49.8% 34.4% 

Terminal rate 2/35 (6%) 11/28 (39%) 17/34 (50%) 13/35 (37%) 

First incidence (days) 722 (T) 549 514 624 

Poly-3 test P=0.005 P<0.001 P<0.001 P<0.001 

Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastomai 

Overall rate 38/50 (76%) 47/50 (94%) 46/49 (94%) 47/50 (94%) 

Adjusted rate 80.1% 98.9% 98.5% 100.0% 

Terminal rate 29/35 (83%) 28/28 (100%) 34/34 (100%) 35/35 (100%) 

First incidence (days) 520 522 513 406 

Poly-3 test P<0.001 P=0.002 P=0.003 P<0.001 
Pyridine, NTP TR 470 65 

TABLE 21 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice 

in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Female (continued) 

Number Examined Microscopically 49 50 50 50 

Basophilic Focus 1 0 0 0 

Eosinophilic Focus 17 12 14 9 

Mixed Cell Focus 5 4 3 0 

Hepatocellular Adenoma, Multiple 24 34* 37** 30 

Hepatocellular Adenoma (includes multiple)j 

Overall rate 37/49 (76%) 39/50 (78%) 43/50 (86%) 34/50 (68%) 

Adjusted rate 82.5% 87.9% 97.3% 79.1% 

Terminal rate 27/32 (84%) 27/30 (90%) 22/22 (100%) 23/29 (79%) 

First incidence (days) 554 419 509 430 

Poly-3 test P=0.372N P=0.336 P=0.015 P=0.442N 

Hepatocellular Carcinoma, Multiple 3 11* 14** 30** 

Hepatocellular Carcinoma (includes multiple)k 

Overall rate 13/49 (27%) 23/50 (46%) 33/50 (66%) 41/50 (82%) 

Adjusted rate 29.8% 55.0% 78.1% 97.1% 

Terminal rate 8/32 (25%) 18/30 (60%) 20/22 (91%) 29/29 (100%) 

First incidence (days) 476 573 556 479 

Poly-3 test P<0.001 P=0.014 P<0.001 P<0.001 

Hepatoblastoma, Multiple 0 0 3 4 

Hepatoblastoma (includes multiple)l 

Overall rate 1/49 (2%) 2/50 (4%) 9/50 (18%) 16/50 (32%) 

Adjusted rate 2.4% 4.9% 21.6% 39.6% 

Terminal rate 1/32 (3%) 1/30 (3%) 3/22 (14%) 12/29 (41%) 

First incidence (days) 729 (T) 599 564 510 

Poly-3 test P<0.001 P=0.493 P=0.007 P<0.001 

Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastomam 

Overall rate 41/49 (84%) 42/50 (84%) 45/50 (90%) 44/50 (88%) 

Adjusted rate 89.9% 94.6% 99.6% 99.5% 

Terminal rate 29/32 (91%) 29/30 (97%) 22/22 (100%) 29/29 (100%) 

First incidence (days) 476 419 509 430 

Poly-3 test P=0.009 P=0.323 P=0.042 P=0.045 

* Significantly different (P 0.05) from the control group by the Poly-3 test 

** P 0.01 

a Number of animals with lesion 

b Historical incidence for 2-year drinking water studies with untreated control groups (mean ± standard deviation): 179/289 (61.9% ± 9.1%); 

range, 47%-70% c Number of animals with neoplasm per number of animals with liver examined microscopically d Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality e Observed incidence at terminal kill 

f Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values 

corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in 

animals that do not reach terminal sacrifice. A lower incidence in an exposure group is indicated by N. g Historical incidence: 80/289 (27.7% ± 11.7%); range, 10%-42% h Historical incidence: 9/289 (3.1% ± 5.0%); range, 0%-12% i Historical incidence: 212/289 (73.4% ± 11.7%); range, 53%-81% j Historical incidence: 150/289 (51.9% ± 20.8%); range, 26%-80% k Historical incidence: 55/289 (19.0% ± 13.7%); range, 8%-42% l Historical incidence: 0/289 m Historical incidence: 173/289 (59.9% ± 21.3%); range, 32%-82% 
 

 

 

 

 

 

66 Pyridine, NTP TR 470 

GENETIC TOXICOLOGY 

Pyridine (100-10,000 μg/plate) was not mutagenic in 

Salmonella typhimurium strain TA98, TA100, 

TA1535, or TA1537, with or without S9 metabolic 

activation enzymes (Haworth et al., 1983; Table F1). 

Further, no significant increase in mutation frequencies 

was observed in L5178Y mouse lymphoma cells tested 

with and without S9 metabolic activation (McGregor 

et al., 1988; Table F2). In cytogenetic tests with 

cultured Chinese hamster ovary cells, pyridine did not 

induce sister chromatid exchanges (Table F3) or 

chromosomal aberrations (Table F4), with or without 

S9. At the highest viable dose (1,673 μg/mL) tested for 

sister chromatid exchange induction in the absence of 

S9, pyridine induced marked cell cycle delay, and an 

extended culture time (31 hours) was used to allow 

sufficient cells to accumulate for analysis. 

Pyridine was tested on three separate occasions in two 

different laboratories for induction of sex-linked 

recessive lethal mutations in adult male Drosophila 

melanogaster (Valencia et al., 1985; Mason et al., 

1992; Foureman et al., 1994; Table F5), and mixed 

results were obtained. In the first experiment (Valencia 

et al., 1985), administration of pyridine by injection 

(7,000 ppm in aqueous 0.7% saline solution) gave 

negative (P=0.225) results, but feeding (600 or 

700 ppm pyridine in aqueous 5% sucrose) produced an 

increase in recessive lethal mutations that was considered to be equivocal (P=0.043). A second experiment 

performed in the same laboratory using both injection 

(500 ppm) and feeding (729 ppm) yielded negative 

results (Foureman et al., 1994). In the third experiment 

(Mason et al., 1992) performed in a second laboratory, 

results of a feeding (500 ppm) experiment were negative (P=0.998), but administration of pyridine by 

injection (4,300 ppm) induced a significant increase in 

the frequency of sex-linked recessive lethal mutations 

(P=0.008). Overall, pyridine was considered to be 

negative in sex-linked recessive lethal tests when 

administered by feeding and equivocal when administered by injection. This positive result in the sex-linked 

recessive lethal test led to the performance of a test for 

induction of reciprocal translocations in germ cells of 

treated male Drosophila melanogaster (Mason et al., 

1992; Table F6); results of this test were negative. 

In vivo assays for chromosomal effects were conducted 

with male mice. No induction of chromosomal aberrations (Table F7) was noted in bone marrow cells at 

either of two sampling times (400-600 mg/kg pyridine; 

single injection), and no increase in the frequency of 

micronucleated polychromatic erythrocytes (Table F8) 

was noted in bone marrow after intraperitoneal injection of pyridine (up to 500 mg/kg administered three 

times at 24-hour intervals). 

In summary, with the exception of the single positive 

result obtained in a Drosophila melanogaster sexlinked recessive lethal assay, no indication of mutagenic activity was seen with pyridine in a variety of 

in vitro and in vivo assays for gene mutation and chromosomal damage. 
PLATE 1

Kidney from a male F344/N rat exposed to 400 ppm pyridine in drinking 

water for 2 years. Hyperplasia of the renal tubular epithelium are indicated 

by asterisks. Note that multiple cross sections of the tubule are distended 

with epithelial cells. H&E; 66× 

PLATE 3

Testis from a male Wistar rat exposed to 400 ppm pyridine in drinking water 

for 2 years. A large interstitial cell adenoma compresses degenerate 

seminiferous tubules (arrows). H&E; 13× 

PLATE 2

Kidney from a male F344/N rat exposed to 400 ppm pyridine in drinking 

water for 2 years. Note the renal tubule adenoma consisting of a larger 

cluster of cells than a hyperplasia and resulting in a loss of tubular structure. 

H&E; 66× 

PLATE 4

Liver from a female B6C3F mouse exposed to 250 ppm pyridine in the 1 

drinking water for 2 years. A large hepatocellular adenoma compresses 

(arrows) the parenchyma. H&E; 8× 
PLATE 5 PLATE 6

Liver from a male B6C3F mouse exposed to 1,000 ppm pyridine for 2 years. Liver from a male B6C3F1 mouse exposed to 500 ppm pyridine for 2 years. 1 

A hepatocellular carcinoma with a trabecular pattern shows clusters of Note the small spindle-shaped cells of a hepatoblastoma rather than normal 

hepatocytes (arrows) rather than the normal lobular architecture. H&E; 33× polyhedral hepatocytes. H&E; 66× 
 

 

 

 

 

 

 

 

 

67 

DISCUSSION AND CONCLUSIONS
 

Pyridine was nominated by the National Cancer Institute for toxicity and carcinogenicity studies because of 

its large annual production and the potential for human 

exposure. No previous 2-year carcinogenesis bioassays 

for pyridine have been reported in the literature. 

Pyridine is used in a variety of industrial processes 

including the production of pesticides and herbicides, 

and it is found as a natural component in some foods. 

The target organs in the 13-week drinking water studies 

included the liver and kidney in male F344/N and 

Wistar rats and the liver in female F344/N rats. 

Decreased water consumption and/or body weight 

effects were observed in 1,000 ppm mice in the 

13-week study, but no target organ lesions were 

observed. The liver and kidney have previously been 

reported as target organs in rats administered pyridine 

in feed at 0.34% to 1.0% for up to 4 months (Baxter, 

1948). Liver toxicity was observed in Sprague-Dawley 

rats administered 50 mg pyridine/kg body weight per 

day by oral gavage for 13 weeks (Anderson, 1987). 

Kidney: In a number of NTP studies with F344/N rats 

the kidney is the site of a spectrum of lesions. Some 

lesions may be spontaneous and age-related, particularly chronic, progressive nephropathy. Others result 

from direct or indirect effects of the test chemical. In 

13-week studies small, eosinophilic hyaline droplets are 

sometimes seen within the cytoplasm of the epithelial 

cells of the P2 segment of the renal tubule. These 

protein droplets typically contain a low molecular 

weight protein (α2u-globulin), which is synthesized 

under the control of androgens and growth hormones. 

The α2u-globulin is filtered in the glomerulus; approximately half is reabsorbed by the proximal tubule 

epithelium and half is excreted in the urine (Neuhaus 

et al., 1981). Normally only small amounts of the reabsorbed protein are visible as hyaline droplets as it is 

degraded by enzymes in the tubule epithelium. Some 

chemicals (inducers) reversibly combine with reabsorbed α2u-globulin and make it more resistant to 

enzymatic degradation, resulting in protein material 

accumulation in the renal tubule epithelium (LehmanMcKeeman et al., 1989). It is theorized that phagosomal accumulation of the proteinaceous material can 

result in accelerated renal tubule epithelium cell death. 

Hyaline droplet nephropathy or α2u-globulin nephropathy are terms used to describe the renal changes 

associated with α2u-globulin inducers. In addition to 

accumulation of hyaline droplets, other microscopic 

changes consistent with hyaline droplet nephropathy 

include granular cast within tubular lumens of the outer 

medulla and exacerbated nephropathy. The casts are 

thought to consist of aggregates of sloughed necrotic 

cells from the affected P2 segment. Less specific, but 

generally considered a component of the spectrum of 

renal changes brought on by α2u-globulin, is an exacerbation of the spontaneous chronic progressive nephropathy. Other findings generally associated with 

α2u-globulin in 2-year studies include an increase in 

linear foci of mineralization within the renal medulla 

and an increase in proliferative lesions (including 

neoplasms) of the renal tubules. It is theorized that 

phagolysosomal accumulation of proteinaceous matter 

leads to an overload phenomenon, resulting in accelerated renal tubule cell death with subsequent regeneration by increased cell replication. Increased cell 

replication is thought to be lined with eventual development of renal tubule neoplasms (USEPA, 1991). 

In male F344/N rats from the 13-week study of pyridine, kidney changes consistent with α2u-globulin 

inducers were observed in the 1,000 ppm group and to 

a lesser extent in the 500 ppm group. These changes 

included a very subtle increase in the amount of hyaline 

droplets which appeared positive for α2u-globulin by 

immunohistochemistry and one to three small granular 

casts in 1,000 and 500 ppm males; at the next lowest 

exposure concentration (250 ppm) no changes were 

observed consistent with hyaline droplet nephropathy. 

In the 2-year studies there was a marginal increase in 

the incidence of renal tubule adenomas in the 400 ppm 

male F344/N rats. An extended evaluation of the entire 
 

 

 

 

 

 

 

 

68 Pyridine, NTP TR 470 

kidney by step sectioning confirmed a significant 

exposure-related increase in the incidences of renal 

tubule adenomas in this group. Slight increases in the 

incidences of renal tubule hyperplasia were also 

observed for 400 ppm male F344/N rats and 100 ppm 

Wistar rats. 

Establishing causation between neoplastic outcome and 

the α2u-globulin response in male rats requires demonstration of similar exposure-response relationships 

between renal tubule neoplasm incidence and 

α2u-globulin accumulation (as determined by histopathology and immunohistochemistry), reversible 

binding of the chemical or its metabolite to 

α2u-globulin, and sustained cell proliferation in the 

renal cortex. In studies in which the association 

between hyaline droplet nephropathy and neoplasm 

development was clearly demonstrated, the severities of 

hyaline droplets and granular casts exceeded those 

observed in the present study. Moreover, the rat renal 

tubule neoplastic response occurred mainly at an 

exposure concentration (400 ppm) lower than the concentration at which only subtle lesions characteristic of 

α2u-globulin inducers were observed (500 ppm). 

Additionally, six renal tubule neoplasms occurred in 

the 200 ppm group compared with two in the control 

group. No evidence of α2u-globulin nephropathy was 

observed at 250 ppm or below in the 13-week studies. 

In the F344/N rats in this study of pyridine, there was 

no significant exacerbation of nephropathy after 

2 years, nor were there any significant increases in the 

incidences of parathyroid gland hyperplasia or fibrous 

osteodystrophy, two common changes in NTP studies 

with chemical-exacerbated chronic progressive nephropathy. There were also no liner foci of mineralization 

within the renal medulla in this study. By contrast to 

the findings in the F344/N rat, there was evidence 

(parathyroid gland hyperplasia, fibrous osteodystrophy, 

and glandular stomach mineralization) that chronic 

progressive nephropathy was more severe after 2 years 

in Wistar rats receiving 100 and 200 ppm, although 

there was no evidence of hyaline droplet nephropathy 

in male Wistar rats in the 13-week study. All of these 

considerations combined suggest that the neoplastic 

response to pyridine in the male F344/N rat kidney was 

not attributable to α2u-globulin. 

There was no evidence for a carcinogenic effect in the 

kidney of Wistar rats. The same diagnostic criteria and 

terminology were used in evaluating lesions in the 

kidney of both strains of rats. The severity of spontaneous nephropathy in control Wistar rats was moderate, whereas that in control male F344/N rats was mild. 

The results of these studies suggest that the male Wistar 

rat is not as susceptible as the male F344/N rat to the 

formation of kidney neoplasms from pyridine exposure. 

The NTP has not compared the susceptibility of male 

F344/N rats and male Wistar rats to other kidney 

carcinogens. 

Liver: Liver lesions in F344/N rats were characterized 

by centrilobular cytomegaly, degeneration, and necrosis; cytoplasmic vacuolization; foci of cellular alteration; fibrosis; and pigmentation in Kupffer’s cells and 

macrophages. Bile duct hyperplasia was observed in 

all exposed groups of males and females and the incidences were significantly increased in exposed females 

compared to controls. Periportal fibrosis was a prominent lesion in 400 ppm males. There were no statistically significant increases in the incidences of hepatocellular neoplasms in exposed F344/N or Wistar rats. 

The same diagnostic criteria and terminology were 

applied to the liver lesions in both strains of rats. In 

general, except for the incidences of centrilobular 

cytomegaly, which was highest in 400 ppm females, 

periportal fibrosis, which was highest in 400 ppm male 

F344/N rats, and cytoplasmic vacuolization, which 

occurred in control and exposed Wistar rats, treatmentrelated nonneoplastic liver lesions occurred at higher 

incidences and with greater severities in Wistar rats 

than in male or female F344/N rats. These lesions, 

along with nephropathy, probably contributed to early 

deaths in Wistar rats. Incidences of fibrosis, extending 

from the liver capsule downwards into the parenchyma, 

were significantly increased relative to controls in 200 

and 400 ppm Wistar rats but were increased less 

significantly in 400 ppm male F344/N rats and were not 

treatment related in females. 

Exposure to pyridine was associated with progression 

of liver neoplasms from benign to malignant in male 

and female mice. Hepatocellular adenomas, hepatocellular carcinomas, and hepatoblastomas represent a 
 

 

 

 

Pyridine, NTP TR 470 69 

biological and morphological continuum in progression 

of proliferative lesions. It is probable that hepatoblastomas do not represent further progression to a more 

malignant state but rather are composed of cells that are 

more primitive. Hepatoblastomas are considered to 

represent a phenotypic, and possibly genotypic, variant 

of a malignant liver neoplasm. Because the malignant 

potential of hepatocellular carcinomas and hepatoblastomas appear similar and hepatoblastomas are generally 

observed in the hepatocellular neoplasms (mostly 

carcinomas), it is appropriate to combine the incidences 

of hepatoblastomas with those of hepatocellular adenoma and carcinoma when interpreting the carcinogenic potential of a chemical. Hepatoblastomas, which 

are rare, are observed in relatively high numbers only 

after chemical administration (primarily in mice) and 

have previously been observed in NTP studies with 

primidone (NTP, 1999), oxazepam (NTP, 1993a), 

o-nitroanisole (NTP, 1993b), benzofuran (NTP, 1989), 

ethylene thiourea (NTP, 1992), 1-amino-2,4-

dibromoanthraquinone (NTP, 1996), methylphenidate 

hydrochloride (NTP, 1995), and coumarin (NTP, 

1993c). 

Pyridine, like primidone (NTP, 1999), phenobarbital 

(McClain, 1990), and oxazepam (NTP, 1993a, 1998b), 

induces liver neoplasms in mice but not in rats, even 

though in rats these chemicals cause a spectrum of 

toxic liver lesions. The mouse, an animal with a high 

background rate of liver neoplasms, seems to be particularly sensitive to subsequent development of malignant liver neoplasms after chemical exposure 

(Drinkwater et al., 1990; Drinkwater, 1994; Bennett 

et al., 1995; Lee et al., 1995). While there are no 

studies of the relationship between pyridine exposure 

and cancer incidence, it is of interest that use of primidone and phenobarbital to treat epilepsy in human 

(Olsen et al., 1995). 

Testis: In the Wistar rat at 2 years, the incidence of 

interstitial cell adenoma of the testis was increased in 

the 400 ppm group relative to controls. There was no 

corresponding increase in interstitial cell hyperplasia. 

The NTP does not have a historical database for neoplasms in Wistar rats. In one study analyzing neoplasm 

rates in 1,370 control Wistar rats (from Charles River 

Laboratories, Kingston, NY, or Hilltop Laboratory 

Animals, Scottdale, PA, from 1980 to 1990) a control 

rate of 3.9% (range, 0%-22%) was reported for interstitial cell neoplasms of the testis in animals weighing 

between 556 and 717 g (Walsh and Poteracki, 1994). 

The rate for interstitial cell adenomas in Wistar rats 

exposed to 400 ppm pyridine was only marginally 

outside this historical range, and inci dences of this 

neoplasm were not increased relative to controls in the 

100 or 200 ppm groups. This was considered to be 

equivocal evidence for a carcinogenic effect. The mean 

body weights of the control male Wistar rats in this 

study were somewhat higher during the second year of 

the study (reaching a high of 803 g at week 73). 

Increased body weights have been associated with 

higher neoplasm rates at some sites in rodents, and this 

difference, combined with other differences in animal 

husbandry condition and time of study, may be a factor 

in the incidences of interstitial cell neoplasms observed 

in the present study. The spontaneous rate for interstitial cell neoplasms of the testis in F344/N rats is high 

(about 90%) and often precludes the conclusion of a 

carcinogenic effect at this site. 

Mononuclear Cell Leukemia: Mononuclear cell 

leukemia is a common neoplasm in F344/N rats. The 

Wistar rat was added to these studies because it has a 

low background incidence of mononuclear cell leukemia in comparison to the male F344/N rat, and there 

was a suggestion from a study by Dieter et al. (1989) 

that pyridine may cause leukemia. However, in these 

studies, pyridine did not appear to affect the rate for 

leukemia in male rats. Incidences of mononuclear cell 

leukemia were increased relative to controls in 200 and 

400 ppm F344/N female rats. These incidences were at 

or just outside the historical control range for this 

neoplasm, and because there was no supportive evidence for an increase in mononuclear cell leukemia in 

male rats compared with the incidences of mononuclear 

cell leukemia in control animals in a concurrent drinking water study at the same laboratory (19/50; NTP, 

1998a), the rate observed in the 400 ppm group in this 

study does not seem to be significant. 

Pyridine is metabolized primarily by N-methylation 

and/or aromatic hydroxylation. Metabolites identified 

include N-methylpyridinium, 3-hydroxy pyridine, and 
 

 

 

70 Pyridine, NTP TR 470 

N-methyl pyridinium hydroxide. Pyridine is metabolized by cytochromes P2E1 and P4B (CYP2E1 and 

CYP4B) (Nikula et al., 1995) and enhances the expression of several forms of P450, including CYP2E1, 

CYP1A1/1A2, and CYP2B1/2B2 in both hepatic and 

renal tissues (tissues from rat used as the model system) 

(Kim and Novak, 1990; Kim et al., 1991a; Kim et al., 

1993). 

Some studies suggest that the induction of cytochrome 

P4502B enzymes are associated with mouse liver neoplasm formation (Lubet et al., 1989; Rice et al., 1994). 

Pyridine-induced liver neoplasms from control, 

500 ppm male, and 1,000 ppm female mice showed no 

staining with p53 antibody, a marker that correlates 

with p53 gene alterations. Chemicals such as phenobarbital, which induces cytochrome P450s in the rodent 

liver, induce a wide variety of enzyme systems (referred 

to as pleiotropic response), and it is likely that several 

effects of the chemical play a role in its liver neoplasmpromoting ability (McClain, 1990). Another nonmutagenic mouse liver carcinogen, methylphenidate, also 

showed no evidence for p53 protein accumulation in 

methylphenidate-induced liver neoplasms in the 

B6C3F1 mouse and similar to pyridine was negative in 

the p53 (+/-) transgenic mouse model (Tennant et al., 

1995, 1999). Tennant et al. (1999) also reported that 

pyridine failed to induce a carcinogenic response in 

6 month studies with the TgAC mouse, but Bucher 

(1998) pointed out that neither the TgAC nor the p53 

(+/-) transgenic mouse assays appear responsive to 

chemicals that induce mouse liver neoplasms in standard 2-year assays. 

There is a developing field of study regarding specific 

genetic changes in mouse and human liver neoplasms. 

In one series of human hepatoblastomas, p53 alterations were not seen in hepatoblastomas of fetal or 

mesenchymal origin but did occur in hepatoblastomas 

classified as small cell (Ruck et al., 1994). Other 

studies also report a low frequency of p53 mutations in 

hepatoblastomas (Kar et al., 1993; Kennedy et al., 

1994). In contrast, in a study of hepatoblastomas in 

Japanese patients, p53 mutations were found in nine of 

10 cases (Oda et al., 1995). Overexpression of p53 is 

a rare event in Caucasian patients with hepatocellular 

carcinoma (Laurent-Puig et al., 1992). 

Accumulation of p53 protein has been associated with 

liver neoplasms caused by viral hepatitis (42%) 

(Ojanguren et al., 1995; Greenblatt et al., 1997) and in 

aflatoxin hepatocarcinogenesis (Shen and Ong, 1996). 

Three studies of liver neoplasms in mice suggest that 

the p53 gene plays a minimal role in the development 

of these neoplasms (Kress et al., 1992; Chen et al., 

1993; Calvert et al., 1995). Mutations of the neoplasm 

suppressor gene p53 have been found in hepatocellular 

carcinomas from patients in many countries (e.g., Japan 

and Asian countries) where there may be an association 

between neoplasms and virus infection or aflatoxin 

exposure. In the United States, p53 mutations are 

usually not found in hepato cellular carcinomas 

(Kazachkov et al., 1996), and the etiology of the liver 

cancer is not known. 

Pyridine is negative in most studies for genotoxicity. 

Pyridine was not mutagenic in Salmonella typhimurium 

strain TA98, TA100, TA1535, or TA1537, with or 

without S9 metabolic activation enzymes. Further, no 

significant increase in mutant frequencies was observed 

in L5178Y mouse lymphoma cells, tested with and 

without S9 metabolic activation. In cytogenetic tests 

with cultured Chinese hamster ovary cells, pyridine did 

not induce sister chromatid exchanges or chromosomal 

aberrations, with or without S9. Results were positive 

for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster following injection 

of pyridine but were negative by the same route of 

administration for induction of reciprocal translocations 

in germ cells of D. melanogaster. No induction of 

chromosomal aberrations and no increase in the frequency of micronucleated polychromatic erythrocytes 

was noted in mouse bone marrow cells after intraperitoneal injection of pyridine. 
__________ 

Pyridine, NTP TR 470 71 

CONCLUSIONS 

Under the conditions of these 2-year drinking water 

studies, there was some evidence of carcinogenic 

activity* of pyridine in male F344/N rats based on 

increased incidences of renal tubule neoplasms. There 

was equivocal evidence of carcinogenic activity of 

pyridine in female F344/N rats based on increased 

incidences of mononuclear cell leukemia. There was 

equivocal evidence of carcinogenic activity in male 

Wistar rats based on an increased incidence of interstitial cell adenoma of the testis. There was clear 

evidence of carcinogenic activity of pyridine in male 

and female B6C3F1 mice based on increased incidences 

of malignant hepatocellular neoplasms. 

In F344/N rats, exposure to pyridine resulted in 

increased incidences of centrilobular cytomegaly and 

degeneration, cytoplasmic vacuolization, and pigmentation in the liver of males and females; periportal 

fibrosis, fibrosis, and centrilobular necrosis in the liver 

of males; and bile duct hyperplasia in females. In male 

Wistar rats, pyridine exposure resulted in increased 

incidences of centrilobular degeneration and necrosis, 

fibrosis, periportal fibrosis, and pigmentation in the 

liver, and secondary to kidney disease, mineralization 

in the glandular stomach and parathyroid gland 

hyperplasia. 

* Explanation of Levels of Evidence of Carcinogenic Activity is on page 13. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 15. 
72 Pyridine, NTP TR 470
 
 

 

 

 

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U.S. Environmental Protection Agency (USEPA) 

(1991). Alpha2u-globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the 

Male Rat. EPA/625/3-91/019F. Risk Assessment 

Forum, U.S. Environmental Protection Agency, 

Washington, DC. 

Valencia, R., Mason, J.M., Woodruff, R.C., and 

Zimmering, S. (1985). Chemical mutagenesis testing 

in Drosophila. III. Results of 48 coded compounds 

tested for the National Toxicology Program. Environ. 

Mutagen. 7, 325-348. 

Vernot, E.H., MacEwen, J.D., Haun, C.C., and 

Kinkead, E.R. (1977). Acute toxicity and skin 

corrosion data for some organic and inorganic 

compounds and aqueous solutions. Toxicol. Appl. 

Pharmacol. 42, 417-423. 

Voogd, C.E., van der Stel, J.J., and Jacobs, J.J.J.A.A. 

(1980). The mutagenic action of quindoxin, carbadox, 

olaquindox and some other N-oxides on bacteria and 

yeast. Mutat. Res. 78, 233-242. 

Walsh, K.M., and Poteracki, J. (1994). Spontaneous 

neoplasms in control Wistar rats. Fundam. Appl. 

Toxicol. 22, 65-72. 

Warren, G., Abbott, E., Schultz, P., Bennett, K., and 

Rogers, S. (1981). Mutagenicity of a series of 

hexacoordinate rhodium(III) compounds. Mutat. Res. 

88, 165-173. 

Williams, D.A. (1971). A test for differences between 

treatment means when several dose levels are compared 

with a zero dose control. Biometrics 27, 103-117. 

Williams, D.A. (1972). The comparison of several 

dose levels with a zero dose control. Biometrics 28, 

519-531. 

Zeiger, E., Haseman, J.K., Shelby, M.D., 

Margolin, B.H., and Tennant, R.W. (1990). Evaluation 

of four in vitro genetic toxicity tests for predicting 

rodent carcinogenicity: Confirmation of earlier results 

with 41 additional chemicals. Environ. Mol. Mutagen. 

16 (Suppl. 18), 1-14. 

Zimmermann, F.K., Henning, J.H., Scheel, I., and 

Oehler, M. (1986). Genetic and anti-tubulin effects 

induced by pyridine derivatives. Mutat. Res. 163, 

23-31. 
82 Pyridine, NTP TR 470
 
83 

APPENDIX A
 

SUMMARY OF LESIONS IN MALE F344/N RATS
 

IN THE 2-YEAR DRINKING WATER STUDY
 

OF PYRIDINE
 

TABLE A1 Summary of the Incidence of Neoplasms in Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 85 
 

TABLE A2 Individual Animal Tumor Pathology of Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 88 
 

TABLE A3 Statistical Analysis of Primary Neoplasms in Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 104 
 

TABLE A4 Historical Incidence of Renal Tubule Neoplasms in Untreated Male F344/N Rats . ...... 108 
 

TABLE A5 Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 109 
 
84 Pyridine, NTP TR 470
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 85 

TABLE A1 

Summary of the Incidence of Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 11 13 15 10 

Natural deaths 14 17 10 24 

Survivors 

Terminal sacrifice 25 20 25 16 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (48) (50) (49) 

Lipoma 1 (2%) 

Intestine large, cecum (49) (47) (50) (49) 

Lipoma 1 (2%) 

Intestine small, duodenum (50) (47) (50) (48) 

Intestine small, jejunum (50) (47) (50) (47) 

Carcinoma 1 (2%) 

Intestine small, ileum (50) (47) (50) (47) 

Liver (50) (49) (50) (50) 

Cholangiocarcinoma 1 (2%) 

Hepatocellular carcinoma 1 (2%) 

Hepatocellular adenoma 1 (2%) 1 (2%) 2 (4%) 

Hepatocellular adenoma, multiple 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Mesentery (11) (14) (7) (8) 

Schwannoma benign 1 (9%) 

Oral mucosa (1) (2) 

Pharyngeal, squamous cell papilloma 1 (100%) 1 (50%) 

Pancreas (50) (48) (50) (49) 

Acinus, adenoma 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Stomach, forestomach (50) (49) (50) (49) 

Squamous cell papilloma 1 (2%) 

Stomach, glandular (50) (49) (50) (49) 

Tongue (1) 

Squamous cell papilloma 1 (100%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Carcinoma 1 (2%) 

Adrenal medulla (50) (49) (50) (49) 

Pheochromocytoma complex 1 (2%) 

Pheochromocytoma benign 11 (22%) 2 (4%) 14 (28%) 4 (8%) 

Bilateral, pheochromocytoma benign 6 (12%) 1 (2%) 

Islets, pancreatic (50) (48) (50) (49) 

Adenoma 4 (8%) 2 (4%) 1 (2%) 

Parathyroid gland (50) (50) (50) (48) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

86 Pyridine, NTP TR 470 

TABLE A1 

Summary of the Incidence of Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Endocrine System (continued) 

Pituitary gland (50) (50) (50) (50) 

Pars distalis, adenoma 16 (32%) 13 (26%) 12 (24%) 11 (22%) 

Pars intermedia, adenoma 1 (2%) 

Thyroid gland (50) (50) (50) (49) 

Bilateral, C-cell, adenoma 1 (2%) 

C-cell, adenoma 2 (4%) 3 (6%) 2 (4%) 

C-cell, carcinoma 1 (2%) 

Follicular cell, adenoma 2 (4%) 

General Body System 

None 

Genital System 

Epididymis (49) (49) (49) (48) 

Preputial gland (50) (47) (49) (48) 

Adenoma 3 (6%) 7 (14%) 2 (4%) 

Carcinoma 5 (10%) 2 (4%) 1 (2%) 

Prostate (50) (48) (50) (49) 

Seminal vesicle (50) (47) (50) (48) 

Testes (49) (49) (49) (48) 

Bilateral, interstitial cell, adenoma 33 (67%) 35 (71%) 37 (76%) 40 (83%) 

Interstitial cell, adenoma 9 (18%) 8 (16%) 6 (12%) 3 (6%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Melanoma malignant, metastatic, skin 1 (2%) 

Lymph node (20) (25) (20) (23) 

Lymph node, mandibular (50) (50) (50) (50) 

Lymph node, mesenteric (50) (47) (50) (48) 

Spleen (49) (48) (50) (49) 

Thymus (50) (49) (48) (50) 

Thymoma benign 1 (2%) 

Integumentary System 

Mammary gland (49) (48) (50) (49) 

Carcinoma 1 (2%) 

Fibroadenoma 4 (8%) 3 (6%) 6 (12%) 4 (8%) 

Skin (50) (50) (50) (50) 

Basal cell adenoma 1 (2%) 

Keratoacanthoma 6 (12%) 4 (8%) 1 (2%) 5 (10%) 

Keratoacanthoma, multiple 1 (2%) 

Squamous cell papilloma 4 (8%) 1 (2%) 1 (2%) 

Trichoepithelioma 1 (2%) 1 (2%) 

Pinna, melanoma malignant 1 (2%) 2 (4%) 

Subcutaneous tissue, fibroma 4 (8%) 2 (4%) 4 (8%) 

Subcutaneous tissue, lipoma 1 (2%) 1 (2%) 

Musculoskeletal System 

Skeletal muscle (1) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 87 

TABLE A1 

Summary of the Incidence of Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Nervous System 

Brain 

Oligodendroglioma malignant

Spinal cord

(50) 

 (1) 

(50) 

 1 (2%) 

(48) (50) 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar carcinoma

Carcinoma, metastatic, mammary gland

Carcinoma, metastatic, Zymbal’s gland

Melanoma malignant, metastatic, skin 

Osteosarcoma, metastatic, nose

Nose 

Osteosarcoma

Respiratory epithelium, squamous cell

 carcinoma

Trachea 

(50) 

 1 (2%)

 1 (2%) 

(50) 

 1 (2%) 

(50) 

(50) 

 1 (2%) 

 1 (2%) 

(50) 

 1 (2%) 

(50) 

(50) 

 2 (4%) 

1 (2%) 

(49) 

(50) 

(50) 

 4 (8%) 

(50) 

(50) 

Special Senses System 

Zymbal’s gland

Carcinoma

 (1)

 1 (100%)

 (1)

 1 (100%)

 (1)

 1 (100%)

 (1) 

 1 (100%) 

Urinary System 

Kidney 

Mesenchymal tumor malignant

Renal tubule, adenoma

Renal tubule, adenoma, multiple

Renal tubule, carcinoma

Urinary bladder 

(50) 

 1 (2%)

(50) 

(48) 

 1 (2%) 

 1 (2%) 

(47) 

(50) 

 1 (2%)

 1 (2%)

(50) 

(49) 

 4 (8%) 

 2 (4%) 

(49) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

Leukemia mononuclear

Lymphoma malignant

Mesothelioma benign

Mesothelioma malignant

(50) 

 1 (2%) 

 29 (58%)

 1 (2%)

 1 (2%)

(50) 

 32 (64%)

 1 (2%) 

(50) 

 26 (52%)

 1 (2%) 

(50) 

 27 (54%) 

 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

Total primary neoplasms 

Total animals with benign neoplasms 

Total benign neoplasms 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

49 

151 

47 

112 

34 

39 

1 

1 

49 

120 

46 

77 

40 

43 

2 

2 

49 

133 

48 

102 

29 

31 

1 

2 

49 

123 

49 

89 

29 

34 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms c 
 

 

 

 

 

 

 

 

 

 

 

 

88 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

3334455556666666666777777 

Number of Days on Study 0883777790024456699011111 

9884314952450467725158899 

0000000000000000000000000 

Carcass ID Number 2134244111030341400240101 

5245318510764839421295633 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + +M+ + + 

Intestine small, duodenum +++++++++++++++++++++++++ 

Intestine small, jejunum +++++++++++++++++++++++++ 

Carcinoma X 

Intestine small, ileum +++++++++++++++++++++++++ 

Liver +++++++++++++++++++++++++ 

Hepatocellular adenoma X 

Histiocytic sarcoma 

Mesentery +++ + + ++ 

Schwannoma benign X 

Oral mucosa + 

Pharyngeal, squamous cell papilloma X 

Pancreas +++++++++++++++++++++++++ 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Tooth 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma benign X XX X 

Bilateral, pheochromocytoma benign X X 

Islets, pancreatic +++++++++++++++++++++++++ 

Adenoma X X X 

Parathyroid gland +++++++++++++++++++++++++ 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X X X XX X 

Pars intermedia, adenoma X 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + +M+ + + + 

Penis 

Preputial gland +++++++++++++++++++++++++ 

Adenoma X 

Carcinoma X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 89 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 0001112222222333333344445 Tissues/ 

6894780146789012357902670 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 50 

Intestine large, rectum +++++++++++++++++++++++++ 50 

Intestine large, cecum +++++++++++++++++++++++++ 49 

Intestine small, duodenum +++++++++++++++++++++++++ 50 

Intestine small, jejunum +++++++++++++++++++++++++ 50 

Carcinoma 1 

Intestine small, ileum +++++++++++++++++++++++++ 50 

Liver +++++++++++++++++++++++++ 50 

Hepatocellular adenoma 1 

Histiocytic sarcoma X 1 

Mesentery + + + + 11 

Schwannoma benign 1 

Oral mucosa 1 

Pharyngeal, squamous cell papilloma 1 

Pancreas +++++++++++++++++++++++++ 50 

Acinus, adenoma X X 2 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Stomach, glandular +++++++++++++++++++++++++ 50 

Tooth + + 2 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 50 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma benign X X X X XXX 11 

Bilateral, pheochromocytoma benign X X X X 6 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Adenoma X 4 

Parathyroid gland +++++++++++++++++++++++++ 50 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma XX XXX X XX X 16 

Pars intermedia, adenoma 1 

Thyroid gland +++++++++++++++++++++++++ 50 

C-cell, adenoma X X 2 

General Body System 

None 

Genital System 

Epididymis +++++++++++++++++++++++++ 49 

Penis + 1 

Preputial gland +++++++++++++++++++++++++ 50 

Adenoma X X 3 

Carcinoma X X XX 5 
 

 

 

 

 

 

 

 

 

 

 

 

90 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

3334455556666666666777777 

Number of Days on Study 0883777790024456699011111 

9884314952450467725158899 

0000000000000000000000000 

Carcass ID Number 2134244111030341400240101 

5245318510764839421295633 

Genital System (continued) 

Prostate +++++++++++++++++++++++++ 

Seminal vesicle +++++++++++++++++++++++++ 

Testes + + + + + + + + + + + + + + + + + + + +M+ + + + 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma X X X 

X XXXX

X 

XXX

X X 

X XXXX 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Histiocytic sarcoma 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ +++ ++++ + + + ++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++A+++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+ + + + + + + + + + + + + + +M+ + + + + + + + + 

X 

Skin +++++++++++++++++++++++++ 

Keratoacanthoma X 

Squamous cell papilloma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, lipoma 

X X 

X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Nervous System 

Brain +++++++++++++++++++++++++ 

Spinal cord + 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Osteosarcoma, metastatic, nose 

Nose 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

Osteosarcoma X 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Zymbal’s gland 

Carcinoma 

+ 

X 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

X XX XXXXXX X X XXXXX 

Mesothelioma benign 

Mesothelioma malignant 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 91 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 0001112222222333333344445 

6894780146789012357902670 

Tissues/ 

Tumors 

Genital System (continued) 

Prostate +++++++++++++++++++++++++ 50 

Seminal vesicle +++++++++++++++++++++++++ 50 

Testes +++++++++++++++++++++++++ 49 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

X X 

X 

XXXX X

X 

X

X 

XXXXXXXXXX XX 33 

9 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Histiocytic sarcoma 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Spleen 

Thymus 

X 

+ + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

1 

20 

50 

50 

49 

50 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+++++++++++++++++++++++++ 

X XX 

49 

4 

Skin +++++++++++++++++++++++++ 50 

Keratoacanthoma X X X X X 6 

Squamous cell papilloma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, lipoma 

X 

XX 

X XX 4 

4 

1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Spinal cord 1 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Osteosarcoma, metastatic, nose 

Nose 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

50 

1 

1 

50 

Osteosarcoma 1 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

Zymbal’s gland 

Carcinoma 

1 

1 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

50 

1 

50 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

X 

XXX XX X XX XX X XX 

50 

1 

29 

Mesothelioma benign 

Mesothelioma malignant X 

X 1 

1 
 

 

 

 

 

 

92 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

4445556666666666666666666 

Number of Days on Study 4563590001222446666666778 

4568384478058124556667372 

0000000000100000000000000 

Carcass ID Number 9957967878087569675679996 

4967899127091321042730656 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon + + + + + + + + + + + + + + +M+ + + + + + +M+ 

Intestine large, rectum + + + + + + + + + + + + + + +M+ + + + + + +M+ 

Intestine large, cecum + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Intestine small, duodenum + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Intestine small, jejunum + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Intestine small, ileum + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Liver + + + + + + + + + + + + + + +M+ + + + + + + + + 

Hepatocellular adenoma 

Mesentery ++ + + + + 

Pancreas + + + + + + + + +M+ + + + +M+ + + + + + + + + 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach + + + + + + + + + + + + + + +M+ + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + +M+ + + + + + + + + 

Tooth 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + +M+ + + + + + + + + 

Carcinoma 

Adrenal medulla + + + + + + + + + + + + + + +M+ + + + + + + + + 

Pheochromocytoma benign X 

Bilateral, pheochromocytoma benign 

Islets, pancreatic + + + + + + + + +M+ + + + +M+ + + + + + + + + 

Adenoma 

Parathyroid gland +++++++++++++++++++++++++ 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X X XX X 

Thyroid gland +++++++++++++++++++++++++ 

Bilateral, C-cell, adenoma 

C-cell, carcinoma X 

Follicular cell, adenoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + +M+ 

Preputial gland + + + + + + + + +M+ + + + + + + + + + + + +M+ 

Carcinoma 

Prostate + + + + + + + + + + + + + + +M+ + + + + + +M+ 

Seminal vesicle + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Testes + + + + + + + + + + + + + + + + + + + + + + +M+ 

Bilateral, interstitial cell, adenoma X X X XXXX X XX X XX X 

Interstitial cell, adenoma X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 93 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

6777777777777777777777777 

Number of Days on Study 9000122222222222222222222 

8018822222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 5788755555666667788888999 Tissues/ 

9032514578134586804568237 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 48 

Intestine large, rectum +++++++++++++++++++++++++ 48 

Intestine large, cecum +++++++++++++++++++++++++ 47 

Intestine small, duodenum +++++++++++++++++++++++++ 47 

Intestine small, jejunum +++++++++++++++++++++++++ 47 

Intestine small, ileum +++++++++++++++++++++++++ 47 

Liver +++++++++++++++++++++++++ 49 

Hepatocellular adenoma X 1 

Mesentery ++ + + ++ + + 14 

Pancreas +++++++++++++++++++++++++ 48 

Acinus, adenoma X 1 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 49 

Stomach, glandular +++++++++++++++++++++++++ 49 

Tooth + 1 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 50 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 49 

Carcinoma X 1 

Adrenal medulla +++++++++++++++++++++++++ 49 

Pheochromocytoma benign X 2 

Bilateral, pheochromocytoma benign X 1 

Islets, pancreatic +++++++++++++++++++++++++ 48 

Adenoma X X 2 

Parathyroid gland +++++++++++++++++++++++++ 50 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X X XX X XX 13 

Thyroid gland +++++++++++++++++++++++++ 50 

Bilateral, C-cell, adenoma X 1 

C-cell, carcinoma 1 

Follicular cell, adenoma X X 2 

General Body System 

None 

Genital System 

Epididymis +++++++++++++++++++++++++ 49 

Preputial gland + + + + + + + + + + + + + + + + + +M+ + + + + + 47 

Carcinoma X X 2 

Prostate +++++++++++++++++++++++++ 48 

Seminal vesicle +++++++++++++++++++++++++ 47 

Testes +++++++++++++++++++++++++ 49 

Bilateral, interstitial cell, adenoma XXXXXXX X XXXXXXXXX XXX X 35 

Interstitial cell, adenoma X X 8 
 

 

 

94 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

4445556666666666666666666 

Number of Days on Study 4563590001222446666666778 

4568384478058124556667372 

0000000000100000000000000 

Carcass ID Number 9957967878087569675679996 

4967899127091321042730656 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+++++++ +++ + + +++ 

+++++++++++++++++++++++++ 

+ + + + + + + + +M+ + + + +M+ + + + + + +M+ 

+ + + + + + + + +M+ + + + +M+ + + + + + + + + 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Carcinoma 

+ + + + + + + + + + + + + + +M+ + + + + + + + + 

Fibroadenoma 

Skin +++++++++++++++++++++++++ 

Keratoacanthoma X 

Squamous cell papilloma 

Trichoepithelioma 

Subcutaneous tissue, fibroma X X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Skeletal muscle + 

Nervous System 

Brain +++++++++++++++++++++++++ 

Oligodendroglioma malignant X 

Respiratory System 

Lung 

Carcinoma, metastatic, mammary gland 

Carcinoma, metastatic, Zymbal’s gland 

Nose 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Respiratory epithelium, squamous cell carcinoma 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Eye 

Zymbal’s gland 

Carcinoma 

Urinary System 

Kidney + + + + + + + + +M+ + + + +M+ + + + + + + + + 

Mesenchymal tumor malignant 

Renal tubule, carcinoma 

Urinary bladder + + + + + + + + +M+ + + + +M+ + + + + + +M+ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear XXXXXXX XXXXX XXX XXX 

Mesothelioma malignant X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 95 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

6777777777777777777777777 

Number of Days on Study 9000122222222222222222222 

8018822222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 5788755555666667788888999 

9032514578134586804568237 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Spleen 

Thymus 

++ ++ ++ + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+ + + + + + + + + + + + + + + +M+ + + + + + + + 

25 

50 

47 

48 

49 

Integumentary System 

Mammaryg land 

Carcinoma 

M+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

48 

1 

Fibroadenoma X X X 3 

Skin +++++++++++++++++++++++++ 50 

Keratoacanthoma X X X 4 

Squamous cell papilloma 

Trichoepithelioma 

Subcutaneous tissue, fibroma 

X 

X 

1 

1 

2 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Skeletal muscle 1 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Oligodendroglioma malignant 1 

Respiratory System 

Lung 

Carcinoma, metastatic, mammary gland 

Carcinoma, metastatic, Zymbal’s gland 

Nose 

+++++++++++++++++++++++++ 

X 

X 

+++++++++++++++++++++++++ 

50 

1 

1 

50 

Respiratory epithelium, squamous cell carcinoma 

Trachea 

X 

+++++++++++++++++++++++++ 

1 

50 

Special Senses System 

Eye 

Zymbal’s gland 

Carcinoma 

+ 

X 

+ 1 

1 

1 

Urinary System 

Kidney 

Mesenchymal tumor malignant 

Renal tubule, carcinoma 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

X 

+++++++++++++++++++++++++ 

48 

1 

1 

47 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

XX XXXXXXX XX XXX 

50 

32 

Mesothelioma malignant 1 
 

 

 

 

 

 

 

 

96 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

2455555555666666666667777 

Number of Days on Study 6822338889023444466770001 

9659480596972048829390089 

1111111111111111111111111 

Carcass ID Number 1314241300454303322411213 

7859373348602490190868147 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Lipoma 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum +++++++++++++++++++++++++ 

Lipoma 

Intestine small, duodenum +++++++++++++++++++++++++ 

Intestine small, jejunum +++++++++++++++++++++++++ 

Intestine small, ileum +++++++++++++++++++++++++ 

Liver +++++++++++++++++++++++++ 

Hepatocellular carcinoma 

Mesentery + + ++ 

Oral mucosa + 

Pharyngeal, squamous cell papilloma 

Pancreas +++++++++++++++++++++++++ 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Squamous cell papilloma X 

Stomach, glandular +++++++++++++++++++++++++ 

Tooth 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma benign X X XX XX X 

Islets, pancreatic +++++++++++++++++++++++++ 

Adenoma 

Parathyroid gland +++++++++++++++++++++++++ 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X XX X X X 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + +M+ + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + +M+ + + + + + + + + + + + 

Adenoma XX X 

Prostate +++++++++++++++++++++++++ 

Seminal vesicle +++++++++++++++++++++++++ 

Testes + + + + + + + + + + + +M+ + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X XXXXXXXXXX 

Interstitial cell, adenoma X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 97 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

1111111111111111111111111 Total 

Carcass ID Number 0000001111222222333344444 Tissues/ 

1235670129245678256901345 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 50 

Lipoma X 1 

Intestine large, rectum +++++++++++++++++++++++++ 50 

Intestine large, cecum +++++++++++++++++++++++++ 50 

Lipoma X 1 

Intestine small, duodenum +++++++++++++++++++++++++ 50 

Intestine small, jejunum +++++++++++++++++++++++++ 50 

Intestine small, ileum +++++++++++++++++++++++++ 50 

Liver +++++++++++++++++++++++++ 50 

Hepatocellular carcinoma X 1 

Mesentery + + + 7 

Oral mucosa + 2 

Pharyngeal, squamous cell papilloma X 1 

Pancreas +++++++++++++++++++++++++ 50 

Acinus, adenoma X 1 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Squamous cell papilloma 1 

Stomach, glandular +++++++++++++++++++++++++ 50 

Tooth + 1 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 50 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma benign X X X X X X X 14 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Adenoma X 1 

Parathyroid gland +++++++++++++++++++++++++ 50 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X X XX X 12 

Thyroid gland +++++++++++++++++++++++++ 50 

C-cell, adenoma X X X 3 

General Body System 

None 

Genital System 

Epididymis +++++++++++++++++++++++++ 49 

Preputial gland +++++++++++++++++++++++++ 49 

Adenoma X X X X 7 

Prostate +++++++++++++++++++++++++ 50 

Seminal vesicle +++++++++++++++++++++++++ 50 

Testes +++++++++++++++++++++++++ 49 

Bilateral, interstitial cell, adenoma X X X X XXXXXXXXXXXXXXXXXXX 37 

Interstitial cell, adenoma X 6 
 

 

 

 

 

 

 

98 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

2455555555666666666667777 

Number of Days on Study 6822338889023444466770001 

9659480596972048829390089 

1111111111111111111111111 

Carcass ID Number 1314241300454303322411213 

7859373348602490190868147 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Melanoma malignant, metastatic, skin 

Lymph node

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

++ ++++++ + + ++ + ++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+++++++++++++++++++++++++ 

X X X 

Skin +++++++++++++++++++++++++ 

Keratoacanthoma 

Keratoacanthoma, multiple 

Squamous cell papilloma 

Pinna, melanoma malignant 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, lipoma X 

X X 

X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Nervous System 

Brain +++++++++++++++++++++++++ 

Respiratory System 

Lung 

Alveolar/bronchiolar carcinoma 

Melanoma malignant, metastatic, skin 

Nose 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Zymbal’s gland 

Carcinoma

+ 

X 

Urinary System 

Kidney 

Renal tubule, adenoma 

Renal tubule, adenoma, multiple 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear

+++++++++++++++++++++++++ 

X XXXX X XXXX XX X X 

Mesothelioma benign 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 99 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

1111111111111111111111111 Total 

Carcass ID Number 0000001111222222333344444 

1235670129245678256901345 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Melanoma malignant, metastatic, skin 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Spleen 

Thymus 

X 

+ ++ + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+ + +M+ + + + + + + + + + + + + + + + + + +M+ 

1 

20 

50 

50 

50 

48 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+++++++++++++++++++++++++ 

X X X 

50 

6 

Skin +++++++++++++++++++++++++ 50 

Keratoacanthoma X 1 

Keratoacanthoma, multiple 

Squamous cell papilloma 

Pinna, melanoma malignant 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, lipoma 

X X 

X 

X 

1 

1 

1 

4 

1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + +M+ + + + + 48 

Respiratory System 

Lung 

Alveolar/bronchiolar carcinoma 

Melanoma malignant, metastatic, skin 

Nose 

+++++++++++++++++++++++++ 

XX 

X 

++ ++++++++++++++++++++++ 

50 

2 

1 

49 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

Zymbal’s gland 

Carcinoma 

1 

1 

Urinary System 

Kidney 

Renal tubule, adenoma 

Renal tubule, adenoma, multiple 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

50 

1 

1 

50 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

X XX X X XXX XXXX 

50 

26 

Mesothelioma benign X 1 
 

 

 

 

 

 

100 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

1444555555566666666666666 

Number of Days on Study 9246122468901223444577778 

4845503324816274477102561 

1111111111111111111111111 

Carcass ID Number 5769796769995585658587686 

5739485022512471933601680 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum + + + + + + + + + + + + + + + + + +M+ + + + + + 

Intestine large, cecum +++++++++++++++++++++++++ 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + +M+ + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + MM + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + MM + + + + + 

Liver +++++++++++++++++++++++++ 

Cholangiocarcinoma 

Hepatocellular adenoma X 

Hepatocellular adenoma, multiple 

Mesentery + + ++ + 

Pancreas +++++++++++++++++++++++++ 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Tongue 

Squamous cell papilloma 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + +M+ 

Pheochromocytoma complex 

Pheochromocytoma benign X 

Islets, pancreatic +++++++++++++++++++++++++ 

Parathyroid gland M+ + + + + + + + + + + + + + + + + + + + +M+ + 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X X X X XX 

Thyroid gland M+ + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + +M+ + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + +M+ + + + + + + + + + + + 

Adenoma 

Carcinoma 

Prostate +++++++++++++++++++++++++ 

Seminal vesicle + + + +M+ + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + +M+ + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X X X X X X XXXXXXX 

Interstitial cell, adenoma X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 101 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

Number of Days on Study 

6666677777777777777777777 

8999901112222222222222222 

5117707992222222222222222 

Carcass ID Number 

1111111111111111111111112 

6796759785566777888889990 

8301584617947289245693670 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus 

Intestinel arge,c olon 

Intestinel arge,r ectum 

Intestinel arge,c ecum 

Intestines mall,d uodenum 

Intestine small, jejunum 

Intestines mall,i leum 

Liver 

Cholangiocarcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery 

Pancreas 

Acinus, adenoma 

Salivaryg lands 

Stomach,f orestomach 

Stomach, glandular 

Tongue 

Squamous cell papilloma 

+++++++++++++++++++++++++ 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

X 

X 

X 

+ ++ 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

X 

+++++++++++++++++++++++++ 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ 

X 

50 

49 

49 

49 

48 

47 

47 

50 

1 

2 

1 

8 

49 

1 

50 

49 

49 

1 

1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pheochromocytoma complex X 1 

Pheochromocytoma benign X XX 4 

Islets, pancreatic + + + + + M + + + + + + + + + + + + + + + + + + + 49 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X XXX 11 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X 2 

General Body System 

None 

Genital System 

Epididymis + + + + +M+ + + + + + + + + + + + + + + + + + + 48 

Preputial gland + + + + +M+ + + + + + + + + + + + + + + + + + + 48 

Adenoma X X 2 

Carcinoma X 1 

Prostate + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Seminal vesicle + + + + +M+ + + + + + + + + + + + + + + + + + + 48 

Testes + + + + +M+ + + + + + + + + + + + + + + + + + + 48 

Bilateral, interstitial cell, adenoma XXXXX XXXXXXXXXXXXXXXXXXX 40 

Interstitial cell, adenoma 3 
 

 

 

 

 

 

 

 

 

102 Pyridine, NTP TR 470 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

Number of Days on Study 

1444555555566666666666666 

9246122468901223444577778 

4845503324816274477102561 

Carcass ID Number 

1111111111111111111111111 

5769796769995585658587686 

5739485022512471933601680 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Spleen 

Thymus 

Thymoma benign 

+++++++++++++++++++++++++ 

+++ + ++++ + + ++ 

+++++++++++++++++++++++++ 

M+ + + + + + + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Fibroadenoma 

Skin 

Basal cell adenoma 

Keratoacanthoma 

Trichoepithelioma 

Pinna, melanoma malignant 

+ + + + + + + + + + + + + + + + + + + + +M+ + + 

X 

+++++++++++++++++++++++++ 

X X 

X X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Nervous System 

Brain +++++++++++++++++++++++++ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Nose 

Trachea 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Special Senses System 

Ear 

Zymbal’s gland 

Carcinoma 

+ 

+ 

X 

+ 

Urinary System 

Kidney 

Renal tubule, adenoma 

Renal tubule, adenoma, multiple 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

X 

+++++++++++++++++++++++++ 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear

Lymphoma malignant 

+++++++++++++++++++++++++ 

XXXX XXX XX XX X X XX 
 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 103 

TABLE A2 

Individual Animal Tumor Pathology of Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

Number of Days on Study 

6666677777777777777777777 

8999901112222222222222222 

5117707992222222222222222 

Carcass ID Number 

1111111111111111111111112 

6796759785566777888889990 

8301584617947289245693670 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Spleen 

Thymus 

Thymoma benign 

+++++++++++++++++++++++++ 

++++ + + + + + + + 

+++++++++++++++++++++++++ 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

X 

50 

23 

50 

48 

49 

50 

1 

Integumentary System 

Mammaryg land 

Fibroadenoma 

Skin 

Basal cell adenoma 

Keratoacanthoma 

Trichoepithelioma 

Pinna, melanoma malignant 

+++++++++++++++++++++++++ 

X X X 

+++++++++++++++++++++++++ 

X 

X X X 

X 

49 

4 

50 

1 

5 

1 

2 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X XX 4 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 

Zymbal’s gland 

Carcinoma 

2 

1 

1 

Urinary System 

Kidney 

Renal tubule, adenoma 

Renal tubule, adenoma, multiple 

Urinary bladder 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

X X X 

X 

+ + + + +M+ + + + + + + + + + + + + + + + + + + 

49 

4 

2 

49 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear

Lymphoma malignant 

+++++++++++++++++++++++++ 

XX XX X X X XXXXX 

X 

50 

27 

1 
104 Pyridine, NTP TR 470 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Adrenal Medulla: Benign Pheochromocytoma 

Overall ratea 17/50 (34%) 3/49 (6%) 14/50 (28%) 4/49 (8%)
 

Adjusted rateb 40.4% 7.5% 32.8% 10.6%
 

Terminal ratec 11/25 (44%) 1/20 (5%) 7/25 (28%) 3/16 (19%)
 

First incidence (days) 571 628 585 675
 

Poly-3 testd P=0.014N P<0.001N P=0.306N P=0.002N
 

Adrenal Medulla: Benign or Complex Pheochromocytoma 

Overall rate 17/50 (34%) 3/49 (6%) 14/50 (28%) 5/49 (10%)
 

Adjusted rate 40.4% 7.5% 32.8% 13.3%
 

Terminal rate 11/25 (44%) 1/20 (5%) 7/25 (28%) 4/16 (25%)
 

First incidence (days) 571 628 585 675
 

Poly-3 test P=0.030N P<0.001N P=0.306N P=0.005N
 

Kidney (Renal Tubule): Adenoma (Single Sections) 

Overall rate 1/50 (2%) 0/48 (0%) 2/50 (4%) 6/49 (12%) 

Adjusted rate 2.4% 0.0% 4.9% 15.9% 

Terminal rate 1/25 (4%) 0/20 (0%) 1/25 (4%) 2/16 (13%) e First incidence (days) 722 (T) — 708 644 

Poly-3 test P=0.003 P=0.510N P=0.498 P=0.042 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single Sections) 

Overall rate 1/50 (2%) 1/48 (2%) 2/50 (4%) 6/49 (12%)
 

Adjusted rate 2.4% 2.6% 4.9% 15.9%
 

Terminal rate 1/25 (4%) 1/20 (5%) 1/25 (4%) 2/16 (13%)
 

First incidence (days) 722 (T) 722 (T) 708 644
 

Poly-3 test P=0.008 P=0.750 P=0.498 P=0.042
 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 2/50 (4%) 3/48 (6%) 6/50 (12%) 10/49 (20%)
 

Adjusted rate 4.9% 7.6% 14.5% 26.3%
 

Terminal rate 2/25 (8%) 2/20 (10%) 3/25 (12%) 5/16 (31%)
 

First incidence (days) 722 (T) 673 627 644
 

Poly-3 test P=0.002 P=0.480 P=0.133 P=0.008
 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 2/50 (4%) 4/48 (8%) 6/50 (12%) 10/49 (20%)
 

Adjusted rate 4.9% 10.2% 14.5% 26.3%
 

Terminal rate 2/25 (8%) 3/20 (15%) 3/25 (12%) 5/16 (31%)
 

First incidence (days) 722 (T) 673 627 644
 

Poly-3 test P=0.003 P=0.316 P=0.133 P=0.008
 

Liver: Hepatocellular Adenoma 

Overall rate 1/50 (2%) 1/49 (2%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 2.4% 2.5% 0.0% 7.8% 

Terminal rate 0/25 (0%) 1/20 (5%) 0/25 (0%) 1/16 (6%) 

First incidence (days) 718 722 (T) — 622 

Poly-3 test P=0.153 P=0.754 P=0.501N P=0.283 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 1/50 (2%) 1/49 (2%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 2.4% 2.5% 2.4% 7.8% 

Terminal rate 0/25 (0%) 1/20 (5%) 1/25 (4%) 1/16 (6%) 

First incidence (days) 718 722 (T) 722 (T) 622 

Poly-3 test P=0.153 P=0.754 P=0.760 P=0.283 
Pyridine, NTP TR 470 105 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 1/50 (2%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 2.4% 0.0% 0.0% 10.4% 

Terminal rate 1/25 (4%) 0/20 (0%) 0/25 (0%) 3/16 (19%) 

First incidence (days) 722 (T) — — 697 

Poly-3 test P=0.024 P=0.503N P=0.501N P=0.157 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 1/50 (2%) 0/50 (0%) 2/50 (4%) 4/50 (8%) 

Adjusted rate 2.4% 0.0% 4.9% 10.4% 

Terminal rate 1/25 (4%) 0/20 (0%) 2/25 (8%) 3/16 (19%) 

First incidence (days) 722 (T) — 722 (T) 697 

Poly-3 test P=0.033 P=0.503N P=0.498 P=0.157 

Mammary Gland: Fibroadenoma 

Overall rate 4/50 (8%) 3/50 (6%) 6/50 (12%) 4/50 (8%) 

Adjusted rate 9.7% 7.4% 14.4% 10.4% 

Terminal rate 3/25 (12%) 2/20 (10%) 3/25 (12%) 1/16 (6%) 

First incidence (days) 718 708 538 681 

Poly-3 test P=0.439 P=0.507N P=0.378 P=0.609 

Mammary Gland: Fibroadenoma or Carcinoma 

Overall rate 4/50 (8%) 4/50 (8%) 6/50 (12%) 4/50 (8%) 

Adjusted rate 9.7% 9.9% 14.4% 10.4% 

Terminal rate 3/25 (12%) 3/20 (15%) 3/25 (12%) 1/16 (6%) 

First incidence (days) 718 708 538 681 

Poly-3 test P=0.487 P=0.637 P=0.378 P=0.609 

Pancreatic Islets: Adenoma 

Overall rate 4/50 (8%) 2/48 (4%) 1/50 (2%) 0/49 (0%) 

Adjusted rate 9.6% 5.1% 2.4% 0.0% 

Terminal rate 1/25 (4%) 2/20 (10%) 1/25 (4%) 0/16 (0%) 

First incidence (days) 625 722 (T) 722 (T) — 

Poly-3 test P=0.033N P=0.366N P=0.184N P=0.075N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 16/50 (32%) 13/50 (26%) 12/50 (24%) 11/50 (22%) 

Adjusted rate 36.9% 31.0% 27.0% 26.6% 

Terminal rate 9/25 (36%) 7/20 (35%) 5/25 (20%) 3/16 (19%) 

First incidence (days) 434 628 269 428 

Poly-3 test P=0.177N P=0.365N P=0.221N P=0.215N 

Preputial Gland: Adenoma 

Overall rate 3/50 (6%) 0/47 (0%) 7/49 (14%) 2/48 (4%) 

Adjusted rate 7.2% 0.0% 16.7% 5.4% 

Terminal rate 2/25 (8%) 0/19 (0%) 4/25 (16%) 2/16 (13%) 

First incidence (days) 604 — 529 722 (T) 

Poly-3 test P=0.427 P=0.134N P=0.158 P=0.556N 

Preputial Gland: Carcinoma 

Overall rate 5/50 (10%) 2/47 (4%) 0/49 (0%) 1/48 (2%) 

Adjusted rate 11.9% 5.3% 0.0% 2.7% 

Terminal rate 4/25 (16%) 2/19 (11%) 0/25 (0%) 1/16 (6%) 

First incidence (days) 388 722 (T) — 722 (T) 

Poly-3 test P=0.046N P=0.255N P=0.034N P=0.133N 
106 Pyridine, NTP TR 470 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Preputial Gland: Adenoma or Carcinoma 

Overall rate 8/50 (16%) 2/47 (4%) 7/49 (14%) 3/48 (6%) 

Adjusted rate 18.9% 5.3% 16.7% 8.2% 

Terminal rate 6/25 (24%) 2/19 (11%) 4/25 (16%) 3/16 (19%) 

First incidence (days) 388 722 (T) 529 722 (T) 

Poly-3 test P=0.212N P=0.063N P=0.511N P=0.146N 

Skin: Squamous Cell Papilloma 

Overall rate 4/50 (8%) 1/50 (2%) 1/50 (2%) 0/50 (0%)
 

Adjusted rate 9.7% 2.5% 2.4% 0.0%
 

Terminal rate 4/25 (16%) 1/20 (5%) 1/25 (4%) 0/16 (0%)
 

First incidence (days) 722 (T) 722 (T) 722 (T) —
 

Poly-3 test P=0.035N P=0.181N P=0.179N P=0.069N
 

Skin: Keratoacanthoma 

Overall rate 6/50 (12%) 4/50 (8%) 2/50 (4%) 5/50 (10%)
 

Adjusted rate 14.5% 9.8% 4.9% 12.9%
 

Terminal rate 5/25 (20%) 2/20 (10%) 1/25 (4%) 1/16 (6%)
 

First incidence (days) 656 673 708 670
 

Poly-3 test P=0.474N P=0.378N P=0.134N P=0.548N
 

Skin: Squamous Cell Papilloma or Keratoacanthoma 

Overall rate 8/50 (16%) 5/50 (10%) 3/50 (6%) 5/50 (10%)
 

Adjusted rate 19.3% 12.3% 7.3% 12.9%
 

Terminal rate 7/25 (28%) 3/20 (15%) 2/25 (8%) 1/16 (6%)
 

First incidence (days) 656 673 708 670
 

Poly-3 test P=0.250N P=0.282N P=0.099N P=0.318N
 

Skin: Squamous Cell Papilloma, Keratoacanthoma, Trichoepithelioma, or Basal Cell Adenoma 

Overall rate 8/50 (16%) 6/50 (12%) 3/50 (6%) 7/50 (14%)
 

Adjusted rate 19.3% 14.7% 7.3% 18.1%
 

Terminal rate 7/25 (28%) 4/20 (20%) 2/25 (8%) 2/16 (13%)
 

First incidence (days) 656 673 708 670
 

Poly-3 test P=0.474N P=0.396N P=0.099N P=0.556N
 

Skin (Subcutaneous Tissue): Fibroma 

Overall rate 4/50 (8%) 2/50 (4%) 4/50 (8%) 0/50 (0%)
 

Adjusted rate 9.6% 4.8% 9.6% 0.0%
 

Terminal rate 2/25 (8%) 0/20 (0%) 2/25 (8%) 0/16 (0%)
 

First incidence (days) 625 553 580 —
 

Poly-3 test P=0.092N P=0.341N P=0.642 P=0.071N
 

Testes: Adenoma 

Overall rate 42/49 (86%) 43/49 (88%) 43/49 (88%) 43/48 (90%)
 

Adjusted rate 93.0% 90.2% 93.2% 95.6%
 

Terminal rate 23/25 (92%) 18/20 (90%) 24/25 (96%) 16/16 (100%)
 

First incidence (days) 473 444 529 444
 

Poly-3 test P=0.275 P=0.450N P=0.662 P=0.464 

Thyroid Gland (C-cell): Adenoma 

Overall rate 2/50 (4%) 1/50 (2%) 3/50 (6%) 2/49 (4%) 

Adjusted rate 4.9% 2.5% 7.3% 5.2% 

Terminal rate 2/25 (8%) 1/20 (5%) 3/25 (12%) 2/16 (13%) 

First incidence (days) 722 (T) 722 (T) 722 (T) 722 (T) 

Poly-3 test P=0.466 P=0.505N P=0.497 P=0.668 
107 

c 

Pyridine, NTP TR 470 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 2/50 (4%) 2/50 (4%) 3/50 (6%) 2/49 (4%) 

Adjusted rate 4.9% 4.9% 7.3% 5.2% 

Terminal rate 2/25 (8%) 1/20 (5%) 3/25 (12%) 2/16 (13%) 

First incidence (days) 722 (T) 666 722 (T) 722 (T) 

Poly-3 test P=0.531 P=0.691 P=0.497 P=0.668 

All Organs: Mononuclear Cell Leukemia 

Overall rate 29/50 (58%) 32/50 (64%) 26/50 (52%) 27/50 (54%) 

Adjusted rate 62.7% 67.8% 57.4% 59.7% 

Terminal rate 13/25 (52%) 11/20 (55%) 12/25 (48%) 7/16 (44%) 

First incidence (days) 309 466 529 444 

Poly-3 test P=0.317N P=0.378 P=0.381N P=0.468N 

All Organs: Benign Neoplasms 

Overall rate 47/50 (94%) 46/50 (92%) 48/50 (96%) 49/50 (98%) 

Adjusted rate 99.2% 93.4% 98.0% 100.0% 

Terminal rate 25/25 (100%) 19/20 (95%) 25/25 (100%) 16/16 (100%) 

First incidence (days) 434 444 269 428 

Poly-3 test P=0.228 P=0.136N P=0.712N P=0.996 

All Organs: Malignant Neoplasms 

Overall rate 34/50 (68%) 40/50 (80%) 29/50 (58%) 29/50 (58%) 

Adjusted rate 71.8% 81.5% 63.1% 63.9% 

Terminal rate 16/25 (64%) 14/20 (70%) 14/25 (56%) 8/16 (50%) 

First incidence (days) 309 444 486 444 

Poly-3 test P=0.091N P=0.182 P=0.243N P=0.270N 

All Organs: Benign or Malignant Neoplasms 

Overall rate 49/50 (98%) 49/50 (98%) 49/50 (98%) 49/50 (98%) 

Adjusted rate 99.7% 98.3% 98.6% 100.0% 

Terminal rate 25/25 (100%) 20/20 (100%) 25/25 (100%) 16/16 (100%) 

First incidence (days) 309 444 269 428 

Poly-3 test P=0.580 P=0.656N P=0.760N P=1.000 

(T)Terminal sacrifice

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, kidney, 

liver, lung, pancreatic islets, pituitary gland, preputial gland, testis, and thyroid gland; for other tissues, denominator is number of animals necropsied. b	 Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

d	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A 

negative trend or a lower incidence in an exposure group is indicated by N. e Not applicable; no neoplasms in animal group 
108 Pyridine, NTP TR 470 

TABLE A4 

Historical Incidence of Renal Tubule Neoplasms in Untreated Male F344/N Ratsa 

Adenoma 

Incidence in Controls 

Carcinoma Adenoma or 

Carcinoma 

Overall Historical Incidence 

Total 

Standard deviation 

Range 

1/327 (0.3%) 

0.8% 

0%-2% 

0/327 1/327 (0.3%) 

0.8% 

0%-2% 

a Data as of 1 August 1997 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 109 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 11 13 15 10 

Natural deaths 14 17 10 24 

Survivors 

Terminal sacrifice 25 20 25 16 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (48) (50) (49) 

Hyperplasia, lymphoid 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 

Parasite metazoan 4 (8%) 4 (8%) 3 (6%) 2 (4%) 

Intestine large, rectum (50) (48) (50) (49) 

Edema 1 (2%) 

Parasite metazoan 4 (8%) 2 (4%) 1 (2%) 

Intestine large, cecum (49) (47) (50) (49) 

Edema 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 

Inflammation, acute 1 (2%) 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Parasite metazoan 1 (2%) 1 (2%) 

Ulcer 1 (2%) 

Intestine small, duodenum (50) (47) (50) (48) 

Ectopic pancreas 1 (2%) 

Intestine small, jejunum (50) (47) (50) (47) 

Congestion 1 (2%) 

Intestine small, ileum (50) (47) (50) (47) 

Fibrosis 1 (2%) 

Hyperplasia, lymphoid 6 (12%) 9 (19%) 3 (6%) 4 (9%) 

Liver (50) (49) (50) (50) 

Angiectasis 1 (2%) 1 (2%) 1 (2%) 

Basophilic focus 12 (24%) 5 (10%) 1 (2%) 

Clear cell focus 7 (14%) 1 (2%) 7 (14%) 4 (8%) 

Congestion 1 (2%) 

Degeneration, cystic 4 (8%) 12 (24%) 11 (22%) 3 (6%) 

Developmental malformation 1 (2%) 1 (2%) 

Eosinophilic focus 14 (28%) 23 (47%) 23 (46%) 13 (26%) 

Fibrosis 1 (2%) 1 (2%) 1 (2%) 10 (20%) 

Hematopoietic cell proliferation 2 (4%) 1 (2%) 

Hepatodiaphragmatic nodule 3 (6%) 1 (2%) 

Mitotic alteration 2 (4%) 

Mixed cell focus 2 (4%) 1 (2%) 3 (6%) 1 (2%) 

Necrosis 2 (4%) 1 (2%) 1 (2%) 2 (4%) 

Pigmentation 4 (8%) 11 (22%) 20 (40%) 25 (50%) 

Thrombosis 1 (2%) 

Vacuolization cytoplasmic 4 (8%) 6 (12%) 13 (26%) 17 (34%) 

Bile duct, hyperplasia 46 (92%) 43 (88%) 44 (88%) 49 (98%) 

Centrilobular, cytomegaly 4 (8%) 8 (16%) 6 (12%) 

Centrilobular, degeneration 1 (2%) 3 (6%) 2 (4%) 8 (16%) 

Centrilobular, necrosis 3 (6%) 5 (10%) 

Periportal, fibrosis 2 (4%) 29 (58%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

110 Pyridine, NTP TR 470 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Alimentary System (continued) 

Mesentery (11) (14) (7) (8) 

Cyst 1 (9%) 

Hemorrhage 1 (14%) 

Inflammation, acute 1 (7%) 

Fat, necrosis 10 (91%) 13 (93%) 6 (86%) 8 (100%) 

Oral mucosa (1) (2) 

Pharyngeal, hyperplasia 1 (50%) 

Pancreas (50) (48) (50) (49) 

Atrophy 18 (36%) 15 (31%) 17 (34%) 12 (24%) 

Cytoplasmic alteration 2 (4%) 

Hyperplasia 2 (4%) 4 (8%) 2 (4%) 3 (6%) 

Inflammation, chronic 1 (2%) 3 (6%) 

Acinus, hyperplasia 1 (2%) 

Artery, inflammation, acute 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Cellular alteration 1 (2%) 

Inflammation, chronic active 1 (2%) 

Stomach, forestomach (50) (49) (50) (49) 

Hyperkeratosis 2 (4%) 

Inflammation, acute 1 (2%) 1 (2%) 

Inflammation, chronic active 2 (4%) 8 (16%) 

Ulcer 2 (4%) 10 (20%) 3 (6%) 4 (8%) 

Epithelium, hyperplasia, squamous 1 (2%) 7 (14%) 7 (14%) 11 (22%) 

Stomach, glandular (50) (49) (50) (49) 

Erosion 15 (30%) 17 (35%) 12 (24%) 12 (24%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Mineralization 2 (4%) 2 (4%) 8 (16%) 

Necrosis 1 (2%) 

Ulcer 2 (4%) 5 (10%) 1 (2%) 1 (2%) 

Tooth (2) (1) (1) 

Dysplasia 1 (100%) 

Inflammation, acute 1 (50%) 

Inflammation, chronic active 1 (50%) 1 (100%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Cardiomyopathy 45 (90%) 43 (86%) 43 (86%) 46 (92%) 

Mineralization 1 (2%) 3 (6%) 2 (4%) 

Thrombosis 2 (4%) 6 (12%) 3 (6%) 4 (8%) 

Coronary artery, inflammation, chronic active 1 (2%) 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Accessory adrenal cortical nodule 1 (2%) 1 (2%) 

Congestion 1 (2%) 

Hyperplasia 8 (16%) 7 (14%) 7 (14%) 2 (4%) 

Hypertrophy 1 (2%) 2 (4%) 

Vacuolization cytoplasmic 9 (18%) 5 (10%) 9 (18%) 7 (14%) 

Adrenal medulla (50) (49) (50) (49) 

Hyperplasia 17 (34%) 22 (45%) 19 (38%) 15 (31%) 

Bilateral, hyperplasia 1 (2%) 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 111 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Endocrine System (continued) 

Islets, pancreatic (50) (48) (50) (49) 

Hyperplasia 5 (10%) 2 (4%) 1 (2%) 1 (2%) 

Parathyroid gland (50) (50) (50) (48) 

Hyperplasia 1 (2%) 3 (6%) 3 (6%) 

Pituitary gland (50) (50) (50) (50) 

Pars distalis, angiectasis 2 (4%) 2 (4%) 2 (4%) 

Pars distalis, cyst 2 (4%) 8 (16%) 3 (6%) 1 (2%) 

Pars distalis, degeneration 1 (2%) 

Pars distalis, ectasia 1 (2%) 

Pars distalis, hemorrhage 1 (2%) 

Pars distalis, hyperplasia 22 (44%) 16 (32%) 18 (36%) 12 (24%) 

Pars distalis, thrombosis 1 (2%) 

Thyroid gland (50) (50) (50) (49) 

Pigmentation 1 (2%) 

Ultimobranchial cyst 1 (2%) 1 (2%) 1 (2%) 

C-cell, hyperplasia 7 (14%) 5 (10%) 3 (6%) 3 (6%) 

Follicle, dilatation 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Follicular cell, hyperplasia 1 (2%) 5 (10%) 1 (2%) 2 (4%) 

General Body System 

None 

Genital System 

Epididymis (49) (49) (49) (48) 

Fibrosis 1 (2%) 

Inflammation, chronic 2 (4%) 

Penis (1) 

Inflammation, chronic active 1 (100%) 

Preputial gland (50) (47) (49) (48) 

Atrophy 1 (2%) 

Hyperplasia 4 (8%) 3 (6%) 5 (10%) 4 (8%) 

Inflammation, acute 2 (4%) 2 (4%) 

Inflammation, chronic 17 (34%) 25 (53%) 17 (35%) 23 (48%) 

Inflammation, chronic active 5 (10%) 14 (30%) 14 (29%) 5 (10%) 

Duct, dilatation 2 (4%) 2 (4%) 

Prostate (50) (48) (50) (49) 

Hemorrhage, chronic 1 (2%) 

Hyperplasia, focal 1 (2%) 1 (2%) 4 (8%) 2 (4%) 

Inflammation, acute 2 (4%) 2 (4%) 1 (2%) 

Inflammation, chronic 2 (4%) 1 (2%) 4 (8%) 3 (6%) 

Inflammation, chronic active 31 (62%) 29 (60%) 24 (48%) 22 (45%) 

Seminal vesicle (50) (47) (50) (48) 

Dilatation 1 (2%) 

Fibrosis 1 (2%) 

Inflammation, acute 1 (2%) 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 2 (4%) 1 (2%) 

Mineralization 1 (2%) 

Testes (49) (49) (49) (48) 

Atrophy 2 (4%) 

Necrosis 1 (2%) 

Thrombosis 1 (2%) 

Bilateral, interstitial cell, hyperplasia 3 (6%) 2 (4%) 3 (6%) 1 (2%) 

Interstitial cell, hyperplasia 9 (18%) 6 (12%) 6 (12%) 4 (8%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

112 Pyridine, NTP TR 470 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Depletion cellular 2 (4%) 4 (8%) 3 (6%) 1 (2%) 

Fibrosis 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Lymph node (20) (25) (20) (23) 

Iliac, hyperplasia, lymphoid 1 (5%) 1 (4%) 

Iliac, infiltration cellular, plasma cell 1 (5%) 

Mediastinal, congestion 5 (20%) 4 (17%) 

Mediastinal, ectasia 1 (5%) 

Mediastinal, hemorrhage 1 (5%) 1 (4%) 2 (10%) 

Mediastinal, hyperplasia, lymphoid 1 (4%) 

Mediastinal, pigmentation 1 (5%) 

Pancreatic, congestion 1 (5%) 2 (9%) 

Pancreatic, edema 1 (4%) 

Pancreatic, hyperplasia, lymphoid 1 (5%) 

Pancreatic, inflammation, chronic active 1 (4%) 

Pancreatic, necrosis 1 (5%) 

Pancreatic, pigmentation 1 (5%) 

Renal, congestion 1 (5%) 1 (5%) 3 (13%) 

Renal, edema 1 (5%) 

Renal, fibrosis 1 (4%) 

Renal, hyperplasia, lymphoid 2 (10%) 

Renal, pigmentation 1 (5%) 4 (17%) 

Lymph node, mandibular (50) (50) (50) (50) 

Congestion 1 (2%) 1 (2%) 

Ectasia 4 (8%) 3 (6%) 2 (4%) 3 (6%) 

Hyperplasia, lymphoid 1 (2%) 

Inflammation, chronic active 1 (2%) 

Lymph node, mesenteric (50) (47) (50) (48) 

Congestion 2 (4%) 1 (2%) 

Ectasia 2 (4%) 3 (6%) 2 (4%) 1 (2%) 

Fibrosis 2 (4%) 

Hemorrhage 1 (2%) 1 (2%) 

Inflammation, acute 1 (2%) 

Necrosis 3 (6%) 

Spleen (49) (48) (50) (49) 

Atrophy 1 (2%) 

Congestion 1 (2%) 1 (2%) 

Fibrosis 14 (29%) 11 (23%) 9 (18%) 12 (24%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 1 (2%) 

Hyperplasia, focal 1 (2%) 

Necrosis 4 (8%) 2 (4%) 1 (2%) 

Pigmentation 2 (4%) 

Thrombosis 1 (2%) 

Thymus (50) (49) (48) (50) 

Cyst 1 (2%) 

Ectopic parathyroid gland 1 (2%) 

Fibrosis 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 113 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Integumentary System 

Mammary gland (49) (48) (50) (49) 

Concretion 1 (2%) 

Galactocele 1 (2%) 

Hyperplasia 1 (2%) 3 (6%) 2 (4%) 3 (6%) 

Duct, dilatation 14 (29%) 16 (33%) 12 (24%) 15 (31%) 

Skin (50) (50) (50) (50) 

Cyst epithelial inclusion 2 (4%) 

Hyperkeratosis 1 (2%) 

Hyperplasia, squamous 1 (2%) 1 (2%) 

Inflammation, acute 1 (2%) 

Necrosis 1 (2%) 

Epidermis, degeneration 1 (2%) 

Subcutaneous tissue, inflammation, chronic

 active 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Fibrous osteodystrophy 2 (4%) 1 (2%) 4 (8%) 6 (12%) 

Hyperostosis 1 (2%) 

Osteomalacia 1 (2%) 

Osteopetrosis 1 (2%) 2 (4%) 

Nervous System 

Brain (50) (50) (48) (50) 

Hemorrhage 1 (2%) 

Hydrocephalus 1 (2%) 

Inflammation, acute 1 (2%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Congestion 1 (2%) 2 (4%) 

Hemorrhage 2 (4%) 2 (4%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 

Infiltration cellular, histiocyte 6 (12%) 4 (8%) 9 (18%) 9 (18%) 

Inflammation, chronic 8 (16%) 10 (20%) 12 (24%) 9 (18%) 

Metaplasia, osseous 1 (2%) 

Alveolar epithelium, hyperplasia 3 (6%) 3 (6%) 

Nose (50) (50) (49) (50) 

Cyst 1 (2%) 1 (2%) 

Cyst epithelial inclusion 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 26 (52%) 18 (36%) 21 (43%) 25 (50%) 

Polyp inflammatory 1 (2%) 

Nasolacrimal duct, cyst 1 (2%) 1 (2%) 

Nasolacrimal duct, inflammation, acute 1 (2%) 1 (2%) 

Squamous epithelium, nasolacrimal duct,

 hyperplasia 1 (2%) 

Special Senses System 

Eye (1) 

Atrophy 1 (100%) 
 

 

 

 

 

 

 

 

 

 

114 Pyridine, NTP TR 470 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Urinary System 

Kidney (50) (48) (50) (49) 

Atrophy 1 (2%) 

Cyst 3 (6%) 3 (6%) 13 (26%) 10 (20%) 

Developmental malformation 2 (4%) 

Hydronephrosis 3 (6%) 1 (2%) 2 (4%) 

Inflammation, acute 1 (2%) 

Nephropathy 47 (94%) 47 (98%) 49 (98%) 49 (100%) 

Pigmentation 1 (2%) 

Artery, inflammation, acute 1 (2%) 

Artery, inflammation, chronic active 1 (2%) 

Capsule, hemorrhage, chronic 1 (2%) 

Pelvis, inflammation, acute 1 (2%) 

Renal tubule, hyperplasia 1 (2%) 4 (8%) 7 (14%) 

Urinary bladder (50) (47) (50) (49) 

Hemorrhage 1 (2%) 1 (2%) 1 (2%) 

Inflammation, chronic 4 (8%) 1 (2%) 1 (2%) 
115 

APPENDIX B
 

SUMMARY OF LESIONS IN FEMALE F344/N RATS
 

IN THE 2-YEAR DRINKING WATER STUDY
 

OF PYRIDINE
 

TABLE B1 Summary of the Incidence of Neoplasms in Female F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 116 
 

TABLE B2 Individual Animal Tumor Pathology of Female F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 120 
 

TABLE B3 Statistical Analysis of Primary Neoplasms in Female F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 138 
 

TABLE B4 Historical Incidence of Leukemias in Untreated Female F344/N Rats ................. 141 
 

TABLE B5 Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine ................................... 142 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

116 Pyridine, NTP TR 470 

TABLE B1 

Summary of the Incidence of Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 3 8 7 2 

Natural deaths 15 5 14 22 

Survivors 

Terminal sacrifice 32 37 29 26 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Esophagus (50) (50) (50) (50) 

Schwannoma malignant, metastatic, uterus 1 (2%) 

Intestine large, colon (50) (50) (50) (50) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Intestine large, cecum (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Intestine small, duodenum (50) (50) (50) (50) 

Carcinoma, metastatic, pancreas 1 (2%) 

Carcinoma, metastatic, uterus 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Intestine small, jejunum (50) (50) (50) (50) 

Carcinoma, metastatic, pancreas 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Intestine small, ileum (50) (49) (50) (50) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Liver (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Carcinoma, metastatic, pancreas 1 (2%) 

Carcinoma, metastatic, uterus 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Hepatocellular adenoma 1 (2%) 1 (2%) 

Mesentery (9) (11) (7) (12) 

Carcinoma, metastatic, uterus 1 (9%) 

Fibrous histiocytoma 1 (11%) 

Schwannoma malignant, metastatic, uterus 1 (9%) 

Oral mucosa (2) (1) (2) 

Pharyngeal, squamous cell carcinoma 2 (100%) 

Pharyngeal, squamous cell papilloma 1 (50%) 

Pancreas (49) (50) (50) (50) 

Carcinoma 2 (4%) 

Carcinoma, metastatic, uterus 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Acinus, adenoma 1 (2%) 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Stomach, forestomach (50) (50) (50) (50) 

Stomach, glandular (50) (50) (50) (50) 

Carcinoma, metastatic, uterus 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Tongue (1) (2) 

Squamous cell papilloma 1 (50%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 117 

TABLE B1 

Summary of the Incidence of Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Cardiovascular System 

Heart (49) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Adrenal medulla (50) (50) (50) (49) 

Pheochromocytoma benign 2 (4%) 1 (2%) 

Bilateral, pheochromocytoma benign 1 (2%) 

Islets, pancreatic (49) (50) (50) (50) 

Adenoma 1 (2%) 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Parathyroid gland (48) (50) (48) (50) 

Pituitary gland (49) (50) (50) (50) 

Pars distalis, adenoma 17 (35%) 12 (24%) 18 (36%) 15 (30%) 

Pars distalis, adenoma, multiple 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Bilateral, C-cell, adenoma 1 (2%) 

C-cell, adenoma 3 (6%) 2 (4%) 2 (4%) 

General Body System 

None 

Genital System 

Clitoral gland (47) (48) (50) (49) 

Adenoma 2 (4%) 3 (6%) 1 (2%) 

Carcinoma 1 (2%) 1 (2%) 2 (4%) 

Bilateral, adenoma 1 (2%) 

Ovary (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Carcinoma, metastatic, pancreas 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Granulosa-theca tumor malignant 1 (2%) 

Uterus (50) (50) (50) (50) 

Carcinoma 1 (2%) 

Carcinoma, metastatic, pancreas 1 (2%) 

Polyp stromal 4 (8%) 7 (14%) 9 (18%) 7 (14%) 

Polyp stromal, multiple 1 (2%) 

Sarcoma stromal 1 (2%) 

Schwannoma malignant, metastatic, uterus 1 (2%) 

Vagina (1) 

Lipoma 1 (100%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Lymph node (7) (9) (15) (19) 

Mediastinal, carcinoma, metastatic, kidney 1 (11%) 

Mediastinal, carcinoma, metastatic, pancreas 1 (11%) 

Mediastinal, fibrous histiocytoma,

 metastatic, mesentery 1 (14%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

118 Pyridine, NTP TR 470 

TABLE B1 

Summary of the Incidence of Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Hematopoietic System (continued) 

Lymph node, mandibular (49) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Lymph node, mesenteric (49) (50) (50) (50) 

Carcinoma, metastatic, pancreas 1 (2%) 

Carcinoma, metastatic, uterus 1 (2%) 

Fibrous histiocytoma, metastatic, mesentery 1 (2%) 

Spleen (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Carcinoma, metastatic, pancreas 1 (2%) 

Carcinoma, metastatic, uterus 1 (2%) 

Thymus (50) (50) (50) (50) 

Carcinoma, metastatic, kidney 1 (2%) 

Carcinoma, metastatic, pancreas 1 (2%) 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Adenoma 2 (4%) 1 (2%) 1 (2%) 

Carcinoma 1 (2%) 2 (4%) 1 (2%) 1 (2%) 

Fibroadenoma 19 (38%) 15 (30%) 14 (28%) 18 (36%) 

Fibroadenoma, multiple 8 (16%) 10 (20%) 6 (12%) 2 (4%) 

Sarcoma 1 (2%) 

Skin (50) (50) (50) (50) 

Basal cell adenoma 1 (2%) 

Keratoacanthoma 1 (2%) 

Trichoepithelioma 1 (2%) 

Musculoskeletal System 

Skeletal muscle (2) (1) 

Carcinoma, metastatic, uterus 1 (100%) 

Abdominal, fibrous histiocytoma, metastatic,

 mesentery 1 (50%) 

Abdominal, lipoma 1 (50%) 

Nervous System 

Brain (50) (50) (50) (50) 

Astrocytoma malignant 2 (4%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar adenoma 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Carcinoma, metastatic, clitoral gland 1 (2%) 

Carcinoma, metastatic, kidney 1 (2%) 

Carcinoma, metastatic, mammary gland 1 (2%) 

Carcinoma, metastatic, pancreas 2 (4%) 

Carcinoma, metastatic, uterus 1 (2%) 

Nose (50) (50) (50) (50) 

Pleura (1) 

Carcinoma, metastatic, kidney 1 (100%) 

Trachea (50) (50) (50) (50) 
 

 

 

 

 

 

119 

c 

Pyridine, NTP TR 470 

TABLE B1 

Summary of the Incidence of Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Special Senses System 

Zymbal’s gland

Carcinoma

 (1)

 1 (100%)

 (1) 

 1 (100%) 

Urinary System 

Kidney 

Carcinoma, metastatic, pancreas

Transitional epithelium, carcinoma

Urinary bladder 

(50) 

(50) 

(50) 

 1 (2%) 

 1 (2%) 

(50) 

(50) 

(50) 

(50) 

(50) 

Systemic Lesions 

Multiple organsb 

Leukemia mononuclear

Lymphoma malignant

(50) 

 12 (24%)

 1 (2%)

(50) 

 16 (32%)

(50) 

 22 (44%)

(50) 

 23 (46%) 

 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

Total primary neoplasms 

Total animals with benign neoplasms 

Total benign neoplasms 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

45 

84 

39 

63 

21 

21 

1 

13 

42 

78 

34 

54 

22 

24 

5 

36 

45 

80 

35 

55 

23 

25 

1 

1 

44 

80 

35 

52 

28 

28 

1 

1 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

120 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

3455566666666667777777777 

Number of Days on Study 9908923466778891122222222 

9338626917131767729999999 

2222222222222222222222222 

Carcass ID Number 2355223266614244511122222 

3390909101290569586724678 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Intestine small, duodenum +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Intestine small, jejunum +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Intestine small, ileum +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Liver +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Hepatocellular adenoma 

Mesentery + + ++ 

Fibrous histiocytoma 

Oral mucosa + + 

Pharyngeal, squamous cell carcinoma X X 

Pancreas ++++++A++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Fibrous histiocytoma, metastatic, mesentery 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic ++++++A++++++++++++++++++ 

Adenoma 

Fibrous histiocytoma, metastatic, mesentery 

Parathyroid gland + + + + + + + + + + + + + + +M+ + +M+ + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + +M+ 

Pars distalis, adenoma XX XX X XXX X X 

Pars distalis, adenoma, multiple X 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma X X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + M + MM + + + + + + + + + + 

Adenoma X X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 121 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222223333333333333 

9999999999990000000000000 

2222222222222222222222222 Total 

Carcass ID Number 3333333355554444444555666 Tissues/ 

0124567812341234578678345 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Intestine large, rectum +++++++++++++++++++++++++ 50 

Intestine large, cecum +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Intestine small, duodenum +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Intestine small, jejunum +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Intestine small, ileum +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Liver +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Hepatocellular adenoma X 1 

Mesentery + ++ + + 9 

Fibrous histiocytoma X 1 

Oral mucosa 2 

Pharyngeal, squamous cell carcinoma 2 

Pancreas +++++++++++++++++++++++++ 49 

Fibrous histiocytoma, metastatic, mesentery X 1 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Stomach, glandular +++++++++++++++++++++++++ 50 

Fibrous histiocytoma, metastatic, mesentery X 1 

Cardiovascular System 

Heart +++++ +++++++++++++++++++ 49 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma benign X X 2 

Bilateral, pheochromocytoma benign 1 

Islets, pancreatic +++++++++++++++++++++++++ 49 

Adenoma X 1 

Fibrous histiocytoma, metastatic, mesentery X 1 

Parathyroid gland +++++++++++++++++++++++++ 48 

Pituitary gland +++++++++++++++++++++++++ 49 

Pars distalis, adenoma X X XXXX X 17 

Pars distalis, adenoma, multiple 1 

Thyroid gland +++++++++++++++++++++++++ 50 

C-cell, adenoma X 3 

General Body System 

None 

Genital System 

Clitoralg land 

Adenoma 

+++++++++++++++++++++++++ 47 

2 
 

 

 

 

 

 

 

122 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

3455566666666667777777777 

Number of Days on Study 9908923466778891122222222 

9338626917131767729999999 

2222222222222222222222222 

Carcass ID Number 2355223266614244511122222 

3390909101290569586724678 

Genital System (continued) 

Ovary 

Fibrous histiocytoma, metastatic, mesentery 

Uterus 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Polyp stromal 

Sarcoma stromal X 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node 

Mediastinal, fibrous histiocytoma,

 metastatic, mesentery 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Fibrous histiocytoma, metastatic, mesentery 

Spleen 

Thymus 

+ + ++ + 

+ + +M+ + + + + + + + + + + + + + + + + + + + + 

+ +M+ + + + + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Adenoma 

+++++++++++++++++++++++++ 

X 

Carcinoma 

Fibroadenoma X X XX X X X 

Fibroadenoma, multiple 

Sarcoma 

X XXX 

X 

XX 

Skin +++++++++++++++++++++++++ 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Skeletal muscle 

Abdominal, fibrous histiocytoma,

 metastatic, mesentery 

Abdominal, lipoma 

Nervous System 

Brain +++++++++++++++++++++++++ 

Astrocytoma malignant X 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma 

Nose +++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Harderian gland 

Urinary System 

Kidney 

Urinary bladder 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear X XX X X X X 

Lymphoma malignant 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 123 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222223333333333333 

9999999999990000000000000 

2222222222222222222222222 Total 

Carcass ID Number 3333333355554444444555666 

0124567812341234578678345 

Tissues/ 

Tumors 

Genital System (continued) 

Ovary 

Fibrous histiocytoma, metastatic, mesentery 

Uterus 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

50 

1 

50 

Polyp stromal 

Sarcoma stromal 

X X X X 4 

1 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node 

Mediastinal, fibrous histiocytoma, 

metastatic, mesentery 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Fibrous histiocytoma, metastatic, mesentery 

Spleen 

Thymus 

+ + 

X 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

7 

1 

49 

49 

1 

50 

50 

Integumentary System 

Mammaryg land 

Adenoma 

+++++++++++++++++++++++++ 

X 

50 

2 

Carcinoma X 1 

Fibroadenoma X X X X XXXX XXXX 19 

Fibroadenoma, multiple 

Sarcoma 

XX 8 

1 

Skin +++++++++++++++++++++++++ 50 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Skeletal muscle + + 2 

Abdominal, fibrous histiocytoma, 

metastatic, mesentery 

Abdominal, lipoma 

X 

X 

1 

1 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Astrocytoma malignant X 2 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Nose 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

50 

1 

50 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

Harderian gland + 1 

Urinary System 

Kidney +++++++++++++++++++++++++ 50 

Urinary bladder +++++++++++++++++++++++++ 50 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 50 

Leukemia mononuclear X X X X X 12 

Lymphoma malignant X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

124 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

4555666666677777777777777 

Number of Days on Study 8347145668912222222222222 

8360120662578999999999999 

2223232233223222222222222 

Carcass ID Number 8780817910671666777778888 

0740828951741689023691235 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Schwannoma malignant, metastatic, uterus X 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum +++++++++++++++++++++++++ 

Carcinoma, metastatic, kidney X 

Intestine small, duodenum +++++++++++++++++++++++++ 

Carcinoma, metastatic, pancreas X 

Carcinoma, metastatic, uterus X 

Intestine small, jejunum +++++++++++++++++++++++++ 

Carcinoma, metastatic, pancreas X 

Intestine small, ileum ++++ ++++++++++++++++++++ 

Liver +++++++++++++++++++++++++ 

Carcinoma, metastatic, kidney X 

Carcinoma, metastatic, pancreas X 

Carcinoma, metastatic, uterus X 

Mesentery + + + + + + + 

Carcinoma, metastatic, uterus X 

Schwannoma malignant, metastatic, uterus X 

Oral mucosa + 

Pancreas +++++++++++++++++++++++++ 

Carcinoma X X 

Carcinoma, metastatic, uterus X 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Carcinoma, metastatic, uterus X 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Carcinoma, metastatic, kidney X 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Carcinoma, metastatic, kidney X 

Adrenal medulla +++++++++++++++++++++++++ 

Islets, pancreatic +++++++++++++++++++++++++ 

Parathyroid gland +++++++++++++++++++++++++ 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X XX X X X X 

Thyroid gland +++++++++++++++++++++++++ 

Bilateral, C-cell, adenoma 

C-cell, adenoma X 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 125 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

7777777777777777777777777 

Number of Days on Study	 2222222222222222233333333 

9999999999999999900000000 

2222222333333333322222223 Total 

Carcass ID Number 9999999000000011177888990 Tissues/ 

1234678245678903415679053 Tumors 

Alimentary System 

Esophagus 	 + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma malignant, metastatic, uterus 1 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, kidney	 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, pancreas 1 

Carcinoma, metastatic, uterus 1 

Intestine small, jejunum	 + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, pancreas 1 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, kidney 1 

Carcinoma, metastatic, pancreas 1 

Carcinoma, metastatic, uterus 1 

Mesentery + + + + 11 

Carcinoma, metastatic, uterus 1 

Schwannoma malignant, metastatic, uterus 1 

Oral mucosa	 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma 2 

Carcinoma, metastatic, uterus 1 

Acinus, adenoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, uterus 1 

Cardiovascular System 

Heart 

Carcinoma, metastatic, kidney 

+++++++++++++++++++++++++ 50 

1 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Adrenal medulla +++++++++++++++++++++++++ 50 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Parathyroid gland +++++++++++++++++++++++++ 50 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X XX X X 12 

Thyroid gland +++++++++++++++++++++++++ 50 

Bilateral, C-cell, adenoma X 1 

C-cell, adenoma X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

126 Pyridine, NTP TR 470
 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

4555666666677777777777777 

Number of Days on Study	 8347145668912222222222222 

8360120662578999999999999 

2223232233223222222222222 

Carcass ID Number 8780817910671666777778888 

0740828951741689023691235 

Genital System 

Clitoral gland + + +M+ + + + + + + + + + + + + + + + + + + + + 
 

Adenoma X X
 

Ovary +++++++++++++++++++++++++ 
 

Uterus +++++++++++++++++++++++++ 
 

Polyp stromal X X XX 
 

Carcinoma X 
 

Carcinoma, metastatic, kidney X
 

Carcinoma, metastatic, pancreas X
 

Carcinoma X
 

Carcinoma, metastatic, pancreas X
 

Schwannoma malignant, metastatic, uterus X
 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 
 

Carcinoma, metastatic, kidney X
 

Lymph node + + + + + +
 

Lymph node, mandibular +++++++++++++++++++++++++ 
 

Lymph node, mesenteric +++++++++++++++++++++++++ 
 

Spleen +++++++++++++++++++++++++ 
 

Thymus +++++++++++++++++++++++++ 
 

Mediastinal, carcinoma, metastatic, kidney X
 

Mediastinal, carcinoma, metastatic, pancreas X
 

Carcinoma, metastatic, kidney X
 

Carcinoma, metastatic, pancreas X
 

Carcinoma, metastatic, uterus X
 

Carcinoma, metastatic, kidney X
 

Carcinoma, metastatic, pancreas X
 

Carcinoma, metastatic, uterus X
 

Carcinoma, metastatic, kidney X
 

Carcinoma, metastatic, pancreas X
 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 
 

Adenoma X
 

Fibroadenoma XXXXXXX X X X 
 

Fibroadenoma, multiple XXXXX 
 

Skin +++++++++++++++++++++++++ 
 

Carcinoma X
 

Basal cell adenoma X
 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Skeletal muscle + 

Carcinoma, metastatic, uterus	 X
 

Nervous System 

Brain 	 +++++++++++++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 127 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222233333333 

9999999999999999900000000 

2222222333333333322222223 Total 

Carcass ID Number 9999999000000011177888990 Tissues/ 

1234678245678903415679053 Tumors 

Genital System 

Clitoral gland + + + + + + + +M+ + + + + + + + + + + + + + + + 48 

Adenoma X 3 

Carcinoma 1 

Ovary +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Carcinoma, metastatic, pancreas 1 

Uterus +++++++++++++++++++++++++ 50 

Carcinoma 1 

Carcinoma, metastatic, pancreas 1 

Polyp stromal X X X 7 

Schwannoma malignant, metastatic, uterus 1 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Lymph node + + + 9 

Mediastinal, carcinoma, metastatic, kidney 1 

Mediastinal, carcinoma, metastatic, pancreas 1 

Lymph node, mandibular +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Lymph node, mesenteric +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, pancreas 1 

Carcinoma, metastatic, uterus 1 

Spleen +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Carcinoma, metastatic, pancreas 1 

Carcinoma, metastatic, uterus 1 

Thymus +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, kidney 1 

Carcinoma, metastatic, pancreas 1 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 50 

Adenoma 1 

Carcinoma X 2 

Fibroadenoma X X X XX 15 

Fibroadenoma, multiple XX X X X 10 

Skin +++++++++++++++++++++++++ 50 

Basal cell adenoma 1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Skeletal muscle 1 

Carcinoma, metastatic, uterus 1 

Nervous System 

Brain +++++++++++++++++++++++++ 50 
 

 

 

 

 

 

 

128 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

4555666666677777777777777 

Number of Days on Study	 8347145668912222222222222 

8360120662578999999999999 

2223232233223222222222222 

Carcass ID Number 8780817910671666777778888 

0740828951741689023691235 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma 

Carcinoma, metastatic, kidney X 

Carcinoma, metastatic, pancreas X X 

Carcinoma, metastatic, uterus X 

Nose +++++++++++++++++++++++++ 

Pleura + 

Carcinoma, metastatic, kidney X 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Zymbal’s gland + 

Carcinoma X 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Carcinoma, metastatic, pancreas X 

Transitional epithelium, carcinoma X 

Urinary bladder 	 +++++++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 129 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222233333333 

9999999999999999900000000 

2222222333333333322222223 Total 

Carcass ID Number 9999999000000011177888990 Tissues/ 

1234678245678903415679053 Tumors 

Respiratory System 

Lung +++++++++++++++++++++++++ 50 

Alveolar/bronchiolar adenoma X 1 

Carcinoma, metastatic, kidney 1 

Carcinoma, metastatic, pancreas 2 

Carcinoma, metastatic, uterus 1 

Nose +++++++++++++++++++++++++ 50 

Pleura 1 

Carcinoma, metastatic, kidney 1 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

Zymbal’s gland 1 

Carcinoma 1 

Urinary System 

Kidney +++++++++++++++++++++++++ 50 

Carcinoma, metastatic, pancreas 1 

Transitional epithelium, carcinoma 1 

Urinary bladder +++++++++++++++++++++++++ 50 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 50 

Leukemia mononuclear X X X X X X 16 
 

 

 

 

 

 

 

130 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

4555555666666677777777777 

Number of Days on Study 9246788026789900001122222 

6191306545178903771819999 

3333333333333333333333333 

Carcass ID Number 3425156553534562145411222 

9873793144676720850069123 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum +++++++++++++++++++++++++ 

Intestine small, duodenum +++++++++++++++++++++++++ 

Intestine small, jejunum +++++++++++++++++++++++++ 

Intestine small, ileum +++++++++++++++++++++++++ 

Liver +++++++++++++++++++++++++ 

Hepatocellular adenoma 

Mesentery + + + + 

Pancreas +++++++++++++++++++++++++ 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Tongue 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma benign 

Islets, pancreatic +++++++++++++++++++++++++ 

Adenoma X 

Parathyroid gland + + + + + + + + + + + +M+ + + + + + + + + + + + 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma XX X X XX XX 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma X 

General Body System 

None 

Genital System 

Clitoral gland +++++++++++++++++++++++++ 

Carcinoma X 

Bilateral, adenoma 

Ovary +++++++++++++++++++++++++ 

Granulosa-theca tumor malignant X 

Uterus +++++++++++++++++++++++++ 

Polyp stromal X X X 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node + ++++ ++ ++ ++ 

Lymph node, mandibular +++++++++++++++++++++++++ 

Lymph node, mesenteric +++++++++++++++++++++++++ 

Spleen +++++++++++++++++++++++++ 

Thymus +++++++++++++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 131 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

9999999999999999999999999 

3333333333333333333333333 Total 

Carcass ID Number 2222233333334444445556666 Tissues/ 

4568901235681234792580145 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 50 

Intestine large, rectum +++++++++++++++++++++++++ 50 

Intestine large, cecum +++++++++++++++++++++++++ 50 

Intestine small, duodenum +++++++++++++++++++++++++ 50 

Intestine small, jejunum +++++++++++++++++++++++++ 50 

Intestine small, ileum +++++++++++++++++++++++++ 50 

Liver +++++++++++++++++++++++++ 50 

Hepatocellular adenoma X 1 

Mesentery + + + 7 

Pancreas +++++++++++++++++++++++++ 50 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Stomach, glandular +++++++++++++++++++++++++ 50 

Tongue + 1 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 50 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma benign X 1 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Adenoma 1 

Parathyroid gland + + + + + + + + + + + + + +M+ + + + + + + + + + 48 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X X X X XXXXX X 18 

Thyroid gland +++++++++++++++++++++++++ 50 

C-cell, adenoma X 2 

General Body System 

None 

Genital System 

Clitoral gland +++++++++++++++++++++++++ 50 

Carcinoma 1 

Bilateral, adenoma X 1 

Ovary +++++++++++++++++++++++++ 50 

Granulosa-theca tumor malignant 1 

Uterus +++++++++++++++++++++++++ 50 

Polyp stromal X X X X XX 9 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node +++ + 15 

Lymph node, mandibular +++++++++++++++++++++++++ 50 

Lymph node, mesenteric +++++++++++++++++++++++++ 50 

Spleen +++++++++++++++++++++++++ 50 

Thymus +++++++++++++++++++++++++ 50 
 

 

 

 

 

 

132 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

4555555666666677777777777 

Number of Days on Study	 9246788026789900001122222 

6191306545178903771819999 

3333333333333333333333333 

Carcass ID Number 3425156553534562145411222 

9873793144676720850069123 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 

Adenoma X 

Carcinoma X 

Fibroadenoma X X X X X 

Fibroadenoma, multiple X X X 

Skin 	 +++++++++++++++++++++++++ 

Musculoskeletal System 

Bone 	 +++++++++++++++++++++++++ 

Nervous System 

Brain 	 +++++++++++++++++++++++++ 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma X 

Carcinoma, metastatic, mammary gland X 

Nose +++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Eye 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Urinary bladder +++++++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear XXX XXXX X XX X XXX XX 
 

 

 

 

 

 

 

Pyridine, NTP TR 470 133 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

7777777777777777777777777 

Number of Days on Study	 2222222222222222222222222 

9999999999999999999999999 

Carcass ID Number 

3333333333333333333333333 

2222233333334444445556666 

4568901235681234792580145 

Total 

Tissues/ 

Tumors 

Integumentary System 

Mammaryg land 

Adenoma 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

+++++++++++++++++++++++++ 

XX X X X XX X X 

X X X 

+++++++++++++++++++++++++ 

50 

1 

1 

14 

6 

50 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Carcinoma, metastatic, mammary gland 

Nose 

Trachea 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

50 

1 

1 

50 

50 

Special Senses System 

Eye + 1 

Urinary System 

Kidney 

Urinary bladder 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

50 

50 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

X XX X X X 

50 

22 
 

 

 

 

 

 

 

 

134 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

3455555666666666666666777 

Number of Days on Study 8501888000122333447789012 

0731349358658469192372519 

3333443343333443433344333 

Carcass ID Number 9776017908699019099600896 

4427438612889343971925106 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum +++++++++++++++++++++++++ 

Intestine large, cecum +++++++++++++++++++++++++ 

Intestine small, duodenum +++++++++++++++++++++++++ 

Intestine small, jejunum +++++++++++++++++++++++++ 

Intestine small, ileum +++++++++++++++++++++++++ 

Liver +++++++++++++++++++++++++ 

Mesentery + + + ++ ++ 

Oral mucosa 

Pharyngeal, squamous cell papilloma 

Pancreas +++++++++++++++++++++++++ 

Acinus, adenoma 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Tongue + 

Squamous cell papilloma X 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Islets, pancreatic +++++++++++++++++++++++++ 

Parathyroid gland +++++++++++++++++++++++++ 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X XXXX X 

Thyroid gland +++++++++++++++++++++++++ 

General Body System 

None 

Genital System 

Clitoral gland +++++++++++++++++++++++++ 

Adenoma 

Carcinoma 

Ovary +++++++++++++++++++++++++ 

Uterus +++++++++++++++++++++++++ 

Polyp stromal X X 

Polyp stromal, multiple X 

Vagina + 

Lipoma X 
 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 135 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

7777777777777777777777777 

Number of Days on Study	 2222222222222222222222223 

9999999999999999999999990 

3333333333333333444444443 Total 

Carcass ID Number 7777778888888899000011117 Tissues/ 

0136790345678925067801255 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +++++++++++++++++++++++++ 50 

Intestine large, rectum +++++++++++++++++++++++++ 50 

Intestine large, cecum +++++++++++++++++++++++++ 50 

Intestine small, duodenum +++++++++++++++++++++++++ 50 

Intestine small, jejunum +++++++++++++++++++++++++ 50 

Intestine small, ileum +++++++++++++++++++++++++ 50 

Liver +++++++++++++++++++++++++ 50 

Mesentery + + ++ + 12 

Oral mucosa + + 2 

Pharyngeal, squamous cell papilloma X 1 

Pancreas +++++++++++++++++++++++++ 50 

Acinus, adenoma X 1 

Salivary glands +++++++++++++++++++++++++ 50 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Stomach, glandular +++++++++++++++++++++++++ 50 

Tongue + 2 

Squamous cell papilloma 1 

Cardiovascular System 

Heart +++++++++++++++++++++++++ 50 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla ++++++++++++ ++++++++++++ 49 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Parathyroid gland +++++++++++++++++++++++++ 50 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X XXX XX X X X 15 

Thyroid gland +++++++++++++++++++++++++ 50 

General Body System 

None 

Genital System 

Clitoral gland + +M+ + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Carcinoma X X 2 

Ovary +++++++++++++++++++++++++ 50 

Uterus +++++++++++++++++++++++++ 50 

Polyp stromal XX X X X 7 

Polyp stromal, multiple 1 

Vagina 1 

Lipoma 1 
 

 

 

 

136 Pyridine, NTP TR 470 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

3455555666666666666666777 

Number of Days on Study	 8501888000122333447789012 

0731349358658469192372519 

3333443343333443433344333 

Carcass ID Number 9776017908699019099600896 

4427438612889343971925106 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node + ++ +++ ++++ +++ ++ 

Lymph node, mandibular +++++++++++++++++++++++++ 

Lymph node, mesenteric +++++++++++++++++++++++++ 

Spleen +++++++++++++++++++++++++ 

Thymus +++++++++++++++++++++++++ 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 

Carcinoma 

Fibroadenoma X X X X 

Fibroadenoma, multiple X 

Skin +++++++++++++++++++++++++ 

Keratoacanthoma 

Trichoepithelioma 

Musculoskeletal System 

Bone 	 +++++++++++++++++++++++++ 

Nervous System 

Brain 	 +++++++++++++++++++++++++ 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma X 

Carcinoma, metastatic, clitoral gland 

Nose +++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Eye 

Zymbal’s gland 

Carcinoma 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Urinary bladder +++++++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear X XX XXXX XXXXXX X XXXX 

Lymphoma malignant 
 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 137 

TABLE B2 

Individual Animal Tumor Pathology of Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222223 

9999999999999999999999990 

3333333333333333444444443 Total 

Carcass ID Number 7777778888888899000011117 Tissues/ 

0136790345678925067801255 Tumors 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node + + + + 19 

Lymph node, mandibular +++++++++++++++++++++++++ 50 

Lymph node, mesenteric +++++++++++++++++++++++++ 50 

Spleen +++++++++++++++++++++++++ 50 

Thymus +++++++++++++++++++++++++ 50 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 50 

Carcinoma X 1 

Fibroadenoma X XXX X X XX X X XXX X 18 

Fibroadenoma, multiple X 2 

Skin +++++++++++++++++++++++++ 50 

Keratoacanthoma X 1 

Trichoepithelioma X 1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Respiratory System 

Lung +++++++++++++++++++++++++ 50 

Alveolar/bronchiolar adenoma X 2 

Carcinoma, metastatic, clitoral gland X 1 

Nose +++++++++++++++++++++++++ 50 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

Eye ++ 2 

Zymbal’s gland + 1 

Carcinoma X 1 

Urinary System 

Kidney +++++++++++++++++++++++++ 50 

Urinary bladder +++++++++++++++++++++++++ 50 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 50 

Leukemia mononuclear X XX X X 23 

Lymphoma malignant X 1 
138 Pyridine, NTP TR 470 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Adrenal Medulla: Benign Pheochromocytoma 

Overall ratea 3/50 (6%) 0/50 (0%) 1/50 (2%) 0/49 (0%) 

Adjusted rateb 6.7% 0.0% 2.3% 0.0% 

Terminal ratec 2/32 (6%) 0/37 (0%) 1/29 (3%) 0/25 (0%) e First incidence (days) 667 — 729 (T) —
 

Poly-3 testd P=0.094N P=0.114N P=0.311N P=0.140N
 

Clitoral Gland: Adenoma 

Overall rate 2/47 (4%) 3/48 (6%) 1/50 (2%) 1/49 (2%) 

Adjusted rate 4.7% 6.8% 2.3% 2.5% 

Terminal rate 1/32 (3%) 3/36 (8%) 1/29 (3%) 1/25 (4%) 

First incidence (days) 622 729 (T) 729 (T) 729 (T) 

Poly-3 test P=0.295N P=0.521 P=0.487N P=0.522N 

Clitoral Gland: Adenoma or Carcinoma 

Overall rate 2/47 (4%) 4/48 (8%) 2/50 (4%) 3/49 (6%) 

Adjusted rate 4.7% 9.0% 4.6% 7.6% 

Terminal rate 1/32 (3%) 3/36 (8%) 1/29 (3%) 3/25 (12%) 

First incidence (days) 622 728 707 729 (T) 

Poly-3 test P=0.483 P=0.359 P=0.680N P=0.472 

Mammary Gland: Fibroadenoma 

Overall rate 27/50 (54%) 25/50 (50%) 20/50 (40%) 20/50 (40%)
 

Adjusted rate 58.5% 53.7% 44.6% 47.3%
 

Terminal rate 18/32 (56%) 19/37 (51%) 15/29 (52%) 15/26 (58%)
 

First incidence (days) 596 666 580 589
 

Poly-3 test P=0.139N P=0.398N P=0.126N P=0.193N
 

Mammary Gland: Fibroadenoma or Adenoma 

Overall rate 27/50 (54%) 25/50 (50%) 20/50 (40%) 20/50 (40%)
 

Adjusted rate 58.5% 53.7% 44.6% 47.3%
 

Terminal rate 18/32 (56%) 19/37 (51%) 15/29 (52%) 15/26 (58%)
 

First incidence (days) 596 666 580 589
 

Poly-3 test P=0.139N P=0.398N P=0.126N P=0.193N
 

Mammary Gland: Adenoma or Carcinoma 

Overall rate 3/50 (6%) 3/50 (6%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 6.8% 6.5% 4.5% 2.5% 

Terminal rate 2/32 (6%) 1/37 (3%) 0/29 (0%) 1/26 (4%) 

First incidence (days) 717 650 699 729 (T) 

Poly-3 test P=0.223N P=0.646N P=0.503N P=0.337N 

Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma 

Overall rate 27/50 (54%) 26/50 (52%) 21/50 (42%) 21/50 (42%)
 

Adjusted rate 58.5% 55.5% 46.7% 49.6%
 

Terminal rate 18/32 (56%) 19/37 (51%) 15/29 (52%) 16/26 (62%)
 

First incidence (days) 596 650 580 589
 

Poly-3 test P=0.191N P=0.468N P=0.174N P=0.262N
 

Pancreas: Adenoma or Carcinoma 

Overall rate 0/49 (0%) 3/50 (6%) 0/50 (0%) 1/50 (2%) 

Adjusted rate 0.0% 6.4% 0.0% 2.5% 

Terminal rate 0/32 (0%) 1/37 (3%) 0/29 (0%) 1/26 (4%) 

First incidence (days) — 546 — 729 (T) 

Poly-3 test P=0.609 P=0.131 —f P=0.486 
Pyridine, NTP TR 470 139 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 18/49 (37%) 12/50 (24%) 18/50 (36%) 15/50 (30%) 

Adjusted rate 39.9% 25.8% 40.4% 35.8% 

Terminal rate 10/31 (32%) 8/37 (22%) 13/29 (45%) 10/26 (39%) 

First incidence (days) 588 642 671 634 

Poly-3 test P=0.509 P=0.110N P=0.565 P=0.431N 

Thyroid Gland (C-cell): Adenoma 

Overall rate 3/50 (6%) 3/50 (6%) 2/50 (4%) 0/50 (0%) 

Adjusted rate 6.7% 6.5% 4.6% 0.0% 

Terminal rate 1/32 (3%) 2/37 (5%) 1/29 (3%) 0/26 (0%) 

First incidence (days) 687 695 707 — 

Poly-3 test P=0.087N P=0.649N P=0.506N P=0.135N 

Uterus: Stromal Polyp 

Overall rate 4/50 (8%) 7/50 (14%) 9/50 (18%) 8/50 (16%) 

Adjusted rate 9.0% 15.3% 20.4% 19.1% 

Terminal rate 4/32 (13%) 7/37 (19%) 6/29 (21%) 5/26 (19%) 

First incidence (days) 729 (T) 729 (T) 687 503 

Poly-3 test P=0.125 P=0.278 P=0.111 P=0.147 

Uterus: Stromal Polyp or Stromal Sarcoma 

Overall rate 5/50 (10%) 7/50 (14%) 9/50 (18%) 8/50 (16%) 

Adjusted rate 11.1% 15.3% 20.4% 19.1% 

Terminal rate 4/32 (13%) 7/37 (19%) 6/29 (21%) 5/26 (19%) 

First incidence (days) 493 729 (T) 687 503 

Poly-3 test P=0.177 P=0.390 P=0.180 P=0.227 

All Organs: Mononuclear Cell Leukemia 

Overall rate 12/50 (24%) 16/50 (32%) 22/50 (44%) 23/50 (46%) 

Adjusted rate 26.5% 34.3% 45.4% 48.7% 

Terminal rate 8/32 (25%) 12/37 (32%) 8/29 (28%) 5/26 (19%) 

First incidence (days) 636 546 496 380 

Poly-3 test P=0.013 P=0.279 P=0.043 P=0.020 

All Organs: Benign Neoplasms 

Overall rate 39/50 (78%) 34/50 (68%) 35/50 (70%) 35/50 (70%) 

Adjusted rate 81.6% 72.5% 77.1% 78.6% 

Terminal rate 24/32 (75%) 27/37 (73%) 25/29 (86%) 23/26 (89%) 

First incidence (days) 588 642 580 503 

Poly-3 test P=0.511N P=0.203N P=0.385N P=0.459N 

All Organs: Malignant Neoplasms 

Overall rate 21/50 (42%) 23/50 (46%) 23/50 (46%) 28/50 (56%) 

Adjusted rate 44.3% 46.7% 47.4% 59.3% 

Terminal rate 13/32 (41%) 13/37 (35%) 8/29 (28%) 10/26 (39%) 

First incidence (days) 399 488 496 380 

Poly-3 test P=0.077 P=0.486 P=0.459 P=0.100 
140 

c 

Pyridine, NTP TR 470 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

All Organs: Benign or Malignant Neoplasms 

Overall rate 45/50 (90%) 43/50 (86%) 45/50 (90%) 44/50 (88%) 

Adjusted rate 91.2% 86.0% 91.7% 91.0% 

Terminal rate 28/32 (88%) 30/37 (81%) 26/29 (90%) 23/26 (89%) 

First incidence (days) 399 488 496 380 

Poly-3 test P=0.452 P=0.307N P=0.613 P=0.627N 

(T)Terminal sacrifice

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, clitoral 

gland, pancreas, pituitary gland, thyroid gland, and uterus; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

d	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A 

negative trend or a lower incidence in an exposure group is indicated by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
Pyridine, NTP TR 470 141 

TABLE B4 

Historical Incidence of Leukemias in Untreated Female F344/N Ratsa 

Incidence in Controls 

Overall Historical Incidence 

Total 102/330 (30.9%) 

Standard deviation 10.0% 

Range 16%-44% 

a Data as of 1 August 1997; includes data for lymphocytic, monocytic, mononuclear cell, and undifferentiated leukemias 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

142 Pyridine, NTP TR 470 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 3 8 7 2 

Natural deaths 15 5 14 22 

Survivors 

Terminal sacrifice 32 37 29 26 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (50) (50) (50) 

Hyperplasia, lymphoid 1 (2%) 

Parasite metazoan 3 (6%) 3 (6%) 3 (6%) 1 (2%) 

Intestine large, rectum (50) (50) (50) (50) 

Parasite metazoan 1 (2%) 2 (4%) 1 (2%) 2 (4%) 

Intestine large, cecum (50) (50) (50) (50) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 

Parasite metazoan 1 (2%) 

Ulcer 1 (2%) 

Intestine small, duodenum (50) (50) (50) (50) 

Ectopic pancreas 1 (2%) 

Inflammation, chronic active 1 (2%) 

Intestine small, ileum (50) (49) (50) (50) 

Hyperplasia, lymphoid 3 (6%) 2 (4%) 2 (4%) 5 (10%) 

Inflammation, chronic active 1 (2%) 

Liver (50) (50) (50) (50) 

Angiectasis 2 (4%) 2 (4%) 3 (6%) 2 (4%) 

Basophilic focus 38 (76%) 28 (56%) 11 (22%) 

Clear cell focus 4 (8%) 9 (18%) 11 (22%) 16 (32%) 

Congestion 4 (8%) 1 (2%) 3 (6%) 2 (4%) 

Developmental malformation 1 (2%) 2 (4%) 1 (2%) 

Eosinophilic focus 19 (38%) 24 (48%) 22 (44%) 15 (30%) 

Fibrosis 1 (2%) 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 2 (4%) 

Hemorrhage 1 (2%) 1 (2%) 

Hepatodiaphragmatic nodule 9 (18%) 8 (16%) 3 (6%) 3 (6%) 

Inflammation, chronic active 9 (18%) 1 (2%) 2 (4%) 4 (8%) 

Mitotic alteration 1 (2%) 1 (2%) 

Mixed cell focus 2 (4%) 4 (8%) 1 (2%) 5 (10%) 

Necrosis 6 (12%) 1 (2%) 1 (2%) 

Pigmentation 6 (12%) 2 (4%) 6 (12%) 17 (34%) 

Tension lipidosis 3 (6%) 1 (2%) 

Vacuolization cytoplasmic 10 (20%) 7 (14%) 9 (18%) 18 (36%) 

Bile duct, hyperplasia 20 (40%) 29 (58%) 34 (68%) 29 (58%) 

Capsule, inflammation, chronic 2 (4%) 

Centrilobular, cytomegaly 1 (2%) 4 (8%) 20 (40%) 

Centrilobular, degeneration 1 (2%) 2 (4%) 2 (4%) 7 (14%) 

Centrilobular, necrosis 1 (2%) 2 (4%) 1 (2%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 143 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Alimentary System (continued) 

Mesentery (9) (11) (7) (12) 

Ectopic spleen 1 (14%) 

Inflammation 1 (8%) 

Fat, necrosis 8 (89%) 9 (82%) 6 (86%) 11 (92%) 

Oral mucosa (2) (1) (2) 

Pharyngeal, hyperplasia 1 (50%) 

Pharyngeal, inflammation, acute 1 (100%) 

Pancreas (49) (50) (50) (50) 

Atrophy 22 (45%) 14 (28%) 13 (26%) 14 (28%) 

Cytoplasmic alteration 1 (2%) 

Ectopic liver 2 (4%) 2 (4%) 3 (6%) 

Hyperplasia 3 (6%) 2 (4%) 

Inflammation, chronic 1 (2%) 2 (4%) 

Salivary glands (50) (50) (50) (50) 

Atrophy 2 (4%) 3 (6%) 1 (2%) 

Cytoplasmic alteration 1 (2%) 1 (2%) 

Inflammation, chronic 2 (4%) 

Stomach, forestomach (50) (50) (50) (50) 

Fibrosis 1 (2%) 

Hyperkeratosis 1 (2%) 

Inflammation, acute 1 (2%) 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, chronic active 2 (4%) 1 (2%) 2 (4%) 1 (2%) 

Ulcer 3 (6%) 3 (6%) 4 (8%) 4 (8%) 

Epithelium, hyperplasia, squamous 2 (4%) 2 (4%) 2 (4%) 1 (2%) 

Stomach, glandular (50) (50) (50) (50) 

Erosion 6 (12%) 9 (18%) 9 (18%) 7 (14%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 2 (4%) 

Ulcer 1 (2%) 1 (2%) 3 (6%) 

Tongue (1) (2) 

Epithelium, hyperplasia 1 (100%) 1 (50%) 

Cardiovascular System 

Heart (49) (50) (50) (50) 

Cardiomyopathy 42 (86%) 43 (86%) 43 (86%) 36 (72%) 

Inflammation, chronic active 1 (2%) 

Mineralization 1 (2%) 

Thrombosis 2 (4%) 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Accessory adrenal cortical nodule 1 (2%) 

Atrophy 1 (2%) 

Congestion 1 (2%) 1 (2%) 

Cyst 1 (2%) 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia 11 (22%) 12 (24%) 9 (18%) 6 (12%) 

Vacuolization cytoplasmic 6 (12%) 8 (16%) 6 (12%) 3 (6%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

144 Pyridine, NTP TR 470 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Endocrine System (continued) 

Adrenal medulla (50) (50) (50) (49) 

Hyperplasia 5 (10%) 7 (14%) 8 (16%) 2 (4%) 

Necrosis 1 (2%) 

Islets, pancreatic (49) (50) (50) (50) 

Hyperplasia 1 (2%) 1 (2%) 

Parathyroid gland (48) (50) (48) (50) 

Hyperplasia 1 (2%) 

Pituitary gland (49) (50) (50) (50) 

Pigmentation 1 (2%) 

Pars distalis, angiectasis 11 (22%) 9 (18%) 12 (24%) 4 (8%) 

Pars distalis, cyst 16 (33%) 18 (36%) 20 (40%) 8 (16%) 

Pars distalis, ectasia 1 (2%) 

Pars distalis, hemorrhage 1 (2%) 

Pars distalis, hyperplasia 22 (45%) 29 (58%) 21 (42%) 18 (36%) 

Pars intermedia, hyperplasia 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Ultimobranchial cyst 3 (6%) 1 (2%) 

C-cell, hyperplasia 16 (32%) 17 (34%) 13 (26%) 10 (20%) 

Follicular cell, hyperplasia 1 (2%) 

General Body System 

None 

Genital System 

Clitoral gland (47) (48) (50) (49) 

Hyperplasia 1 (2%) 2 (4%) 1 (2%) 2 (4%) 

Inflammation, acute 1 (2%) 2 (4%) 

Inflammation, chronic 3 (6%) 1 (2%) 5 (10%) 2 (4%) 

Inflammation, chronic active 1 (2%) 1 (2%) 2 (4%) 1 (2%) 

Vacuolization cytoplasmic 1 (2%) 

Bilateral, inflammation, acute 1 (2%) 

Duct, ectasia 3 (6%) 5 (10%) 4 (8%) 2 (4%) 

Ovary (50) (50) (50) (50) 

Congestion 1 (2%) 

Cyst 3 (6%) 7 (14%) 4 (8%) 2 (4%) 

Hyperplasia 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Pigmentation 1 (2%) 

Bilateral, cyst 1 (2%) 2 (4%) 

Uterus (50) (50) (50) (50) 

Angiectasis 1 (2%) 

Cyst 1 (2%) 1 (2%) 

Developmental malformation 1 (2%) 

Dilatation 1 (2%) 1 (2%) 2 (4%) 

Hemorrhage 1 (2%) 1 (2%) 

Hyperplasia 1 (2%) 

Hyperplasia, cystic 6 (12%) 5 (10%) 7 (14%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Metaplasia, squamous 1 (2%) 

Necrosis 1 (2%) 1 (2%) 

Cervix, hypertrophy 1 (2%) 

Cervix, inflammation, chronic 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 145 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Depletion cellular 1 (2%) 2 (4%) 2 (4%) 

Fibrosis 1 (2%) 1 (2%) 

Hyperplasia 3 (6%) 4 (8%) 1 (2%) 

Hyperplasia, reticulum cell 1 (2%) 

Necrosis 1 (2%) 

Erythroid cell, hyperplasia 1 (2%) 

Myeloid cell, hyperplasia 1 (2%) 

Lymph node (7) (9) (15) (19) 

Iliac, congestion 2 (29%) 

Iliac, ectasia 2 (11%) 

Mediastinal, congestion 3 (43%) 1 (11%) 4 (27%) 1 (5%) 

Mediastinal, hyperplasia, lymphoid 1 (7%) 

Mediastinal, pigmentation 1 (14%) 1 (5%) 

Pancreatic, congestion 1 (7%) 

Pancreatic, pigmentation 1 (11%) 

Renal, congestion 1 (14%) 1 (11%) 1 (7%) 

Renal, ectasia 1 (11%) 1 (5%) 

Renal, hyperplasia, lymphoid 1 (5%) 

Lymph node, mandibular (49) (50) (50) (50) 

Atrophy 1 (2%) 

Congestion 1 (2%) 1 (2%) 

Ectasia 3 (6%) 4 (8%) 9 (18%) 2 (4%) 

Edema 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 1 (2%) 

Hyperplasia, plasma cell 1 (2%) 

Infiltration cellular, plasma cell 1 (2%) 

Necrosis 1 (2%) 

Lymph node, mesenteric (49) (50) (50) (50) 

Congestion 2 (4%) 3 (6%) 

Ectasia 4 (8%) 

Hemorrhage 1 (2%) 

Hyperplasia, lymphoid 2 (4%) 2 (4%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 

Spleen (50) (50) (50) (50) 

Atrophy 1 (2%) 

Congestion 1 (2%) 2 (4%) 

Fibrosis 2 (4%) 3 (6%) 3 (6%) 4 (8%) 

Hematopoietic cell proliferation 2 (4%) 4 (8%) 2 (4%) 

Hemorrhage 2 (4%) 

Metaplasia, osseous 1 (2%) 

Necrosis 1 (2%) 2 (4%) 1 (2%) 

Pigmentation 1 (2%) 

Capsule, inflammation, chronic 1 (2%) 

Thymus (50) (50) (50) (50) 

Congestion 1 (2%) 

Cyst 1 (2%) 

Ectopic parathyroid gland 2 (4%) 1 (2%) 1 (2%) 2 (4%) 

Fibrosis 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

146 Pyridine, NTP TR 470 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Galactocele 3 (6%) 5 (10%) 1 (2%) 

Hyperplasia 5 (10%) 2 (4%) 6 (12%) 5 (10%) 

Inflammation, chronic active 1 (2%) 

Duct, dilatation 13 (26%) 9 (18%) 13 (26%) 13 (26%) 

Skin (50) (50) (50) (50) 

Hyperkeratosis 2 (4%) 

Hyperplasia, squamous 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Inflammation, acute 1 (2%) 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 2 (4%) 1 (2%) 1 (2%) 

Subcutaneous tissue, fibrosis 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Osteopetrosis 9 (18%) 12 (24%) 10 (20%) 5 (10%) 

Nervous System 

Brain (50) (50) (50) (50) 

Hemorrhage 1 (2%) 1 (2%) 2 (4%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Congestion 1 (2%) 

Hemorrhage 1 (2%) 

Infiltration cellular, histiocyte 13 (26%) 10 (20%) 9 (18%) 11 (22%) 

Inflammation, chronic 9 (18%) 8 (16%) 6 (12%) 8 (16%) 

Bronchiole, alveolus, hyperplasia 1 (2%) 

Nose (50) (50) (50) (50) 

Congestion 1 (2%) 

Cyst 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Inflammation, chronic 2 (4%) 3 (6%) 

Inflammation, chronic active 15 (30%) 15 (30%) 16 (32%) 19 (38%) 

Nasolacrimal duct, cyst 2 (4%) 

Nasolacrimal duct, inflammation, chronic

 active 1 (2%) 1 (2%) 

Respiratory epithelium, hyperplasia 1 (2%) 

Special Senses System 

Eye (1) (2) 

Hemorrhage 1 (100%) 2 (100%) 

Harderian gland (1) 

Inflammation, chronic 1 (100%) 
 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 147 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Urinary System 

Kidney (50) (50) (50) (50) 

Accumulation, hyaline droplet 1 (2%) 

Congestion 2 (4%) 1 (2%) 

Cyst 1 (2%) 

Hydronephrosis 2 (4%) 

Inflammation, acute 1 (2%) 

Mineralization 3 (6%) 4 (8%) 6 (12%) 

Nephropathy 41 (82%) 42 (84%) 35 (70%) 37 (74%) 

Pigmentation 2 (4%) 1 (2%) 

Renal tubule, hyperplasia 1 (2%) 

Urinary bladder (50) (50) (50) (50) 

Hemorrhage 1 (2%) 

Inflammation, chronic 3 (6%) 1 (2%) 2 (4%) 
148 Pyridine, NTP TR 470
 
149 

APPENDIX C 

SUMMARY OF LESIONS IN MALE WISTAR RATS 

IN THE 2-YEAR DRINKING WATER STUDY 

OF PYRIDINE 

TABLE C1 Summary of the Incidence of Neoplasms in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 

TABLE C2 Individual Animal Tumor Pathology of Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 

TABLE C3 Statistical Analysis of Primary Neoplasms in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 

TABLE C4 Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

150 Pyridine, NTP TR 470 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 2 9 9 10 

Natural deaths 26 27 30 33 

Survivors 

Terminal sacrifice 22 14 11 7 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, cecum (32) (37) (29) (27) 

Carcinoma 1 (3%) 

Intestine small, duodenum (39) (44) (42) (42) 

Carcinoma 1 (2%) 

Intestine small, jejunum (37) (36) (34) (35) 

Carcinoma 1 (3%) 2 (6%) 

Intestine small, ileum (28) (32) (28) (31) 

Liver (50) (50) (50) (50) 

Cholangiocarcinoma 1 (2%) 2 (4%) 

Hepatocellular adenoma 2 (4%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Oral mucosa (5) (1) (1) 

Squamous cell carcinoma 1 (20%) 

Pancreas (46) (50) (50) (49) 

Carcinoma 1 (2%) 

Acinus, adenoma 6 (13%) 7 (14%) 8 (16%) 7 (14%) 

Acinus, adenoma, multiple 8 (17%) 4 (8%) 4 (8%) 

Acinus, carcinoma 2 (4%) 2 (4%) 

Acinus, carcinoma, multiple 2 (4%) 1 (2%) 

Stomach, forestomach (49) (50) (50) (49) 

Fibrosarcoma 1 (2%) 

Squamous cell papilloma 1 (2%) 

Stomach, glandular (49) (50) (48) (48) 

Fibrosarcoma, metastatic, stomach,

 forestomach 1 (2%) 

Tongue (1) 

Squamous cell carcinoma 1 (100%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Endocardium, schwannoma benign 2 (4%) 2 (4%) 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Adenoma 1 (2%) 

Carcinoma 1 (2%) 

Adrenal medulla (50) (50) (50) (50) 

Pheochromocytoma malignant 1 (2%) 1 (2%) 1 (2%) 1 (2%) 

Pheochromocytoma benign 5 (10%) 4 (8%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 151 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Endocrine System (continued) 

Islets, pancreatic (47) (50) (49) (49) 

Adenoma 8 (17%) 3 (6%) 

Carcinoma 1 (2%) 1 (2%) 

Parathyroid gland (48) (47) (48) (47) 

Adenoma 1 (2%) 

Pituitary gland (49) (49) (50) (50) 

Pars distalis, adenoma 15 (31%) 16 (33%) 12 (24%) 13 (26%) 

Pars distalis, adenoma, multiple 1 (2%) 1 (2%) 

Pars intermedia, adenoma 1 (2%) 1 (2%) 

Thyroid gland (49) (50) (48) (49) 

Bilateral, follicular cell, adenoma 1 (2%) 

C-cell, adenoma 4 (8%) 2 (4%) 3 (6%) 

Follicular cell, adenoma 4 (8%) 

Follicular cell, carcinoma 3 (6%) 3 (6%) 1 (2%) 

General Body System 

Tissue NOS (1) 

Hemangiosarcoma 1 (100%) 

Genital System 

Epididymis (50) (49) (49) (50) 

Preputial gland (50) (48) (50) (50) 

Adenoma 1 (2%) 1 (2%) 1 (2%) 

Prostate (50) (49) (50) (50) 

Adenoma 3 (6%) 1 (2%) 1 (2%) 

Schwannoma malignant 1 (2%) 

Seminal vesicle (49) (49) (50) (49) 

Testes (50) (49) (49) (50) 

Bilateral, interstitial cell, adenoma 3 (6%) 1 (2%) 1 (2%) 5 (10%) 

Interstitial cell, adenoma 2 (4%) 5 (10%) 3 (6%) 7 (14%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Lymph node (31) (44) (38) (32) 

Iliac, hemangiosarcoma 1 (2%) 

Pancreatic, histiocytic sarcoma 1 (3%) 

Lymph node, mandibular (48) (49) (47) (48) 

Histiocytic sarcoma 1 (2%) 

Lymph node, mesenteric (46) (50) (50) (50) 

Hemangioma 1 (2%) 

Hemangiosarcoma 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Spleen (49) (50) (49) (49) 

Hemangiosarcoma 1 (2%) 

Thymus (48) (49) (49) (50) 

Thymoma benign 1 (2%) 2 (4%) 

Thymoma malignant 1 (2%) 
 

 

152 Pyridine, NTP TR 470 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Integumentary System 

Mammary gland (48) (46) (44) (46) 

Carcinoma 1 (2%) 

Fibroadenoma 1 (2%) 1 (2%) 1 (2%) 

Skin (50) (50) (50) (50) 

Basal cell adenoma 1 (2%) 

Basal cell carcinoma 1 (2%) 

Carcinoma, metastatic, Zymbal’s gland 1 (2%) 

Fibroma 2 (4%) 

Keratoacanthoma 7 (14%) 3 (6%) 2 (4%) 1 (2%) 

Squamous cell carcinoma 1 (2%) 

Squamous cell papilloma 2 (4%) 1 (2%) 1 (2%) 

Sebaceous gland, adenoma 1 (2%) 

Subcutaneous tissue, fibroma 5 (10%) 6 (12%) 1 (2%) 

Subcutaneous tissue, fibroma, multiple 1 (2%) 

Subcutaneous tissue, fibrosarcoma 1 (2%) 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Cranium, osteoma 1 (2%) 

Joint, sarcoma 1 (2%) 

Skeletal muscle (1) (2) 

Fibroma 1 (50%) 

Lipoma 1 (100%) 1 (50%) 

Nervous System 

Brain (50) (49) (50) (50) 

Astrocytoma malignant 1 (2%) 1 (2%) 1 (2%) 

Hemangioma 1 (2%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar carcinoma 1 (2%) 

Carcinoma, metastatic, Zymbal’s gland 1 (2%) 1 (2%) 

Fibrosarcoma, metastatic, skin 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Nose (50) (50) (50) (50) 

Chondroma 1 (2%) 

Squamous cell carcinoma, metastatic, oral

 mucosa 1 (2%) 

Special Senses System 

Zymbal’s gland (1) (2) (3) 

Carcinoma 1 (100%) 2 (100%) 3 (100%) 
 

 

153 

c 

Pyridine, NTP TR 470 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Urinary System 

Kidney (50) (50) (50) (50) 

Alveolar/bronchiolar carcinoma, metastatic,

 lung 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Lipoma 1 (2%) 

Renal tubule, adenoma 1 (2%) 4 (8%) 1 (2%) 2 (4%) 

Renal tubule, adenoma, multiple 1 (2%) 1 (2%) 

Renal tubule, carcinoma 1 (2%) 

Systemic Lesions 

Multiple organsb (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Leukemia mononuclear 1 (2%) 1 (2%) 2 (4%) 

Lymphoma malignant 2 (4%) 1 (2%) 

Mesothelioma malignant 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 43 38 32 39 

Total primary neoplasms 101 79 68 62 

Total animals with benign neoplasms 40 37 29 33 

Total benign neoplasms 84 61 51 47 

Total animals with malignant neoplasms 17 14 12 13 

Total malignant neoplasms 17 18 17 15 

Total animals with metastatic neoplasms 1 3 2 

Total metastatic neoplasms 1 4 2 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

 

154 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

2455555555566666666666667 

Number of Days on Study 8635577889901123445677890 

3867926792816849444046151 

0000000000000000000000000 

Carcass ID Number 3150443403212343240240332 

6303711318844260385747956 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon A+AAA+ +A+ + +AA+ +AAAA ++++A+ 

Intestine large, rectum A+ +A+ + +A+ + +AA+ + + + + + + + + + + + 

Intestine large, cecum A+AAAA+A+A+AA+AAAAA ++++A+ 

Carcinoma 

Intestine small, duodenum A+ +AA+ +A+ + +AA+ + +AA+ + + + +A+ 

Intestine small, jejunum A + + A A + + + + + +AAA+AAA+ + + + +A+ 

Carcinoma 

Intestine small, ileum A+ +AAA+AAAAAAA+AAAAAA+AA+ 

Liver +++++++++++++++++++++++++ 

Cholangiocarcinoma 

Hepatocellular adenoma X 

Mesentery + + ++ 

Oral mucosa + + + 

Squamous cell carcinoma X 

Pancreas +++++++++++A++++A++++++ + 

Acinus, adenoma 

Acinus, adenoma, multiple X 

Acinus, carcinoma 

Acinus, carcinoma, multiple 

Salivary glands + + + + + + + + + + + + + + + + + + + +M+ + + + 

Stomach, forestomach M+ + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular ++++++++++++++++A++++++++ 

Tooth 

Cardiovascular System 

Blood vessel + ++ + + + + 

Heart +++++++++++++++++++++++++ 

Endocardium, schwannoma benign 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma malignant X 

Pheochromocytoma benign 

Islets, pancreatic +++++++++++A++++A++++++++ 

Adenoma X X 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + +M+ + + 

Adenoma 

Pituitary gland + + + + + + + + + + + + + + +M+ + + + + + + + + 

Pars distalis, adenoma X X X X XXX 

Pars distalis, adenoma, multiple 

Pars intermedia, adenoma 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma X 

Follicular cell, carcinoma X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 155 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 0012222222222222222222222 

5772222222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 2210000011111112223334444 Tissues/ 

5192468901256780293470259 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon AAA+ + + + + + + + + + + + + + + + + + + + + + 35 

Intestine large, rectum AAA+ + + + + + + + + + + + + + + + + + + + + + 42 

Intestine large, cecum AMA + + + + + + + + + + + + + + + + + + + + + + 32 

Carcinoma X 1 

Intestine small, duodenum +AA+ + + + + + + + + + + + + + + + + + + + + + 39 

Intestine small, jejunum A A A ++++++++++++++++++++++ 37 

Carcinoma X 1 

Intestine small, ileum AAA+ + + + + + + + + + + + + + + + + + + + + + 28 

Liver +++++++++++++++++++++++++ 50 

Cholangiocarcinoma X 1 

Hepatocellular adenoma X 2 

Mesentery ++ + 7 

Oral mucosa + + 5 

Squamous cell carcinoma 1 

Pancreas +A+++++++++++++++++++++++ 46 

Acinus, adenoma X X X X X X 6 

Acinus, adenoma, multiple X X X X X X X 8 

Acinus, carcinoma X X 2 

Acinus, carcinoma, multiple X X 2 

Salivary glands +M+ + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach +++++++++++++++++++++++++ 49 

Stomach, glandular +++++++++++++++++++++++++ 49 

Tooth + + 2 

Cardiovascular System 

Blood vessel + 8 

Heart +++++++++++++++++++++++++ 50 

Endocardium, schwannoma benign X X 2 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma malignant 1 

Pheochromocytoma benign XX X X X 5 

Islets, pancreatic +A+++++++++++++++++++++++ 47 

Adenoma X XX X X X 8 

Parathyroid gland +M+ + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X 1 

Pituitary gland +++++++++++++++++++++++++ 49 

Pars distalis, adenoma XXX XX X X X 15 

Pars distalis, adenoma, multiple X 1 

Pars intermedia, adenoma X 1 

Thyroid gland +M+ + + + + + + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X X 4 

Follicular cell, carcinoma X X 3 
 

 

 

 

 

 

 

 

 

 

156 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

Number of Days on Study 

2455555555566666666666667 

8635577889901123445677890 

3867926792816849444046151 

0000000000000000000000000 

Carcass ID Number 3150443403212343240240332 

6303711318844260385747956 

General Body System 

None 

Genital System 

Coagulating gland + + + + + +M+ + + + + + + + + + + + + + + + + + 

Epididymis +++++++++++++++++++++++++ 

Preputial gland +++++++++++++++++++++++++ 

Adenoma 

Prostate +++++++++++++++++++++++++ 

Adenoma 

Seminal vesicle ++++++++++++++++A++++++++ 

Testes +++++++++++++++++++++++++ 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma X 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node +++ + + ++ +++ + ++ +++ 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + +M+ + + + 

Lymph node, mesenteric +M+AA+ + + + + +A+ + + + + + + + + + + + + 

Spleen +++++++++++++++++++++++++ 

Thymus + + + + + + + + + + + M+ + + + + + + + + + + + 

Thymoma benign 

Thymoma malignant X 

Integumentary System 

Mammary gland +++++++++++++++++++++++++ 

Fibroadenoma 

Skin +++++++++++++++++++++++++ 

Keratoacanthoma X X 

Squamous cell papilloma X 

Subcutaneous tissue, fibroma X X 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Cranium, osteoma X 

Skeletal muscle 

Lipoma 

Nervous System 

Brain +++++++++++++++++++++++++ 

Astrocytoma malignant X 

Hemangioma 

Peripheral nerve 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Nose +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

oral mucosa X 

Trachea +++++++++++++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 157 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 0012222222222222222222222 

5772222222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 2210000011111112223334444 Tissues/ 

5192468901256780293470259 Tumors 

General Body System 

None 

Genital System 

Coagulating gland + + + + + + + + + + + + + +M+ + + + + + + + + + 48 

Epididymis +++++++++++++++++++++++++ 50 

Preputial gland +++++++++++++++++++++++++ 50 

Adenoma X 1 

Prostate +++++++++++++++++++++++++ 50 

Adenoma X X X 3 

Seminal vesicle +++++++++++++++++++++++++ 49 

Testes +++++++++++++++++++++++++ 50 

Bilateral, interstitial cell, adenoma X X X 3 

Interstitial cell, adenoma X 2 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node + +++ + ++ ++++ + +++ 31 

Lymph node, mandibular +M+ + + + + + + + + + + + + + + + + + + + + + + 48 

Lymph node, mesenteric +++++++++++++++++++++++++ 46 

Spleen +A+++++++++++++++++++++++ 49 

Thymus +++++++++++++++++++++++++ 48 

Thymoma benign X 1 

Thymoma malignant 1 

Integumentary System 

Mammary gland +M+ + + + + + + + + + + + + + + + + +M+ + + + 48 

Fibroadenoma X 1 

Skin +++++++++++++++++++++++++ 50 

Keratoacanthoma X X X X X 7 

Squamous cell papilloma X 2 

Subcutaneous tissue, fibroma X X X 5 

Subcutaneous tissue, sarcoma 1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Cranium, osteoma 1 

Skeletal muscle + 1 

Lipoma X 1 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Astrocytoma malignant 1 

Hemangioma X 1 

Peripheral nerve + 1 

Respiratory System 

Lung +++++++++++++++++++++++++ 50 

Nose +++++++++++++++++++++++++ 50 

Squamous cell carcinoma, metastatic, 

oral mucosa 1 

Trachea +++++++++++++++++++++++++ 50 
 

 

 

158 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

2455555555566666666666667 

Number of Days on Study 8635577889901123445677890 

3867926792816849444046151 

0000000000000000000000000 

Carcass ID Number 3150443403212343240240332 

6303711318844260385747956 

Special Senses System 

Ear +
 

Harderian gland
 

Zymbal’s gland +
 

Carcinoma X 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Lipoma 

Renal tubule, adenoma X 

Renal tubule, adenoma, multiple X 

Urinary bladder A+++A++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear 
 

 

 

 

 

 

Pyridine, NTP TR 470 159 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7777777777777777777777777 

Number of Days on Study 0012222222222222222222222 

5772222222222222222222222 

0000000000000000000000000 Total 

Carcass ID Number 2210000011111112223334444 

5192468901256780293470259 

Tissues/ 

Tumors 

Special Senses System 

Ear 1 

Harderian gland 

Zymbal’s gland 

Carcinoma 

+ 1 

1 

1 

Urinary System 

Kidney 

Lipoma 

Renal tubule, adenoma 

Renal tubule, adenoma, multiple 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+A+++++++++++++++++++++++ 

50 

1 

1 

1 

47 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear 

+++++++++++++++++++++++++ 

X 

50 

1 
 

 

 

 

 

 

 

 

 

 

 

 

160 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

3334444555555555566666666 

Number of Days on Study 3574778034456789911333444 

6225096661921313501489279 

0000000100000000000000000 

Carcass ID Number 8867985075998676787655595 

0237618083288095052474291 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon + + + +A+ + + + + + + +A+AA+A+ + + + +A 

Intestine large, rectum + + + + + + + + + + + + +A+AA+A+ + + + +A 

Intestine large, cecum +A+AA+ + + + + + + + + +AA+A+ +A+ +A 

Intestine small, duodenum +++++A++A++++++A++A++++++ 

Carcinoma 

Intestine small, jejunum + + + A A A + + + +A+ +A+A+ +AA+ + + + + 

Carcinoma 

Intestine small, ileum +A+AAA+ + + + +A+A+AA+AA+A+AA 

Liver +++++++++++++++++++++++++ 

Mesentery + 

Oral mucosa 

Pancreas +++++++++++++++++++++++++ 

Carcinoma X 

Acinus, adenoma X X X X X 

Acinus, adenoma, multiple X X 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach +++++++++++++++++++++++++ 

Stomach, glandular +++++++++++++++++++++++++ 

Tooth 

Cardiovascular System 

Blood vessel + + ++++++ + +++ ++ 

Heart +++++++++++++++++++++++++ 

Endocardium, schwannoma benign X 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adenoma 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma malignant 

Pheochromocytoma benign X 

Islets, pancreatic +++++++++++++++++++++++++ 

Carcinoma X 

Parathyroid gland + + + + + + + + + + +M+ + + + + + + + + + + +M 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X X X X 

Pars distalis, adenoma, multiple 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma X 

Follicular cell, carcinoma X X 

General Body System 

Tissue NOS 

Hemangiosarcoma 

Genital System 

Coagulating gland + +M+ + + + + + + +M+ + + + + + + + + + +M+ 

Epididymis +++++++++++++++++++++++++ 

Penis 

Preputial gland +++++++++++++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 161 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

6666666677777777777777777 

Number of Days on Study 5667899911122222222222222 

1089207804622222222222222 

0000000000000000000000000 Total 

Carcass ID Number 5699859887656666777788999 Tissues/ 

9613455731761289345669047 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon A+ + +AAA+ +A+ + + + + + + + + + + + + + + 39 

Intestine large, rectum A+ + +AA+ + + + + + + + + + + + + + + + + + + 42 

Intestine large, cecum AA+ +AAA+ + + + + + + + + + + + + + + + + + 37 

Intestine small, duodenum A+++++++++A++++++++++++++ 44 

Carcinoma X 1 

Intestine small, jejunum A + + + A A A + + A A ++++++++++++++ 36 

Carcinoma X X 2 

Intestine small, ileum A+ + +AAA+ +A+ + + + + + + + + + + + + + + 32 

Liver +++++++++++++++++++++++++ 50 

Mesentery 1 

Oral mucosa + 1 

Pancreas +++++++++++++++++++++++++ 50 

Carcinoma 1 

Acinus, adenoma XX 7 

Acinus, adenoma, multiple X X 4 

Salivary glands + + + +M+ + + + + + + + + + + + + + + + + + + + 49 

Stomach, forestomach +++++++++++++++++++++++++ 50 

Stomach, glandular +++++++++++++++++++++++++ 50 

Tooth + + 2 

Cardiovascular System 

Blood vessel + ++ ++ ++ + + 23 

Heart +++++++++++++++++++++++++ 50 

Endocardium, schwannoma benign X 2 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Adenoma X 1 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma malignant X 1 

Pheochromocytoma benign X X X 4 

Islets, pancreatic +++++++++++++++++++++++++ 50 

Carcinoma 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + +M+ + + + + 47 

Pituitary gland + + + +M+ + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X XXXXXX X XXX 16 

Pars distalis, adenoma, multiple X 1 

Thyroid gland +++++++++++++++++++++++++ 50 

C-cell, adenoma X 2 

Follicular cell, carcinoma X 3 

General Body System 

Tissue NOS + 1 

Hemangiosarcoma X 1 

Genital System 

Coagulating gland + + + + + M + + + MM + + + + M + M + + + + + + + 42 

Epididymis + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Penis + 1 

Preputial gland + + + + +M+ + + + +M+ + + + + + + + + + + + + 48 
 

 

 

 

 

 

 

 

162 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

3334444555555555566666666 

Number of Days on Study 3574778034456789911333444 

6225096661921313501489279 

0000000100000000000000000 

Carcass ID Number 8867985075998676787655595 

0237618083288095052474291 

Genital System (continued) 

Prostate +++++++++++++++++++++++++ 

Adenoma 

Seminal vesicle +++++++++++++++++++++++++ 

Testes +++++++++++++++++++++++++ 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma X X 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node

Iliac, hemangiosarcoma 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Hemangiosarcoma 

Spleen 

Hemangiosarcoma 

Thymus 

++++++ +++++++++++ +++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Fibroadenoma 

M+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

Skin +++++++++++++++++++++++++ 

Basal cell adenoma 

Keratoacanthoma X 

Squamous cell carcinoma 

Squamous cell papilloma 

Subcutaneous tissue, fibroma X X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Nervous System 

Brain +++++++++++++++++++++++++ 

Astrocytoma malignant 

Peripheral nerve 

Spinal cord 

+ 

+ 

+ 

+ 

+ 

+ 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Nose +++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

None 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Renal tubule, adenoma X X 

Renal tubule, adenoma, multiple 

Urinary bladder +++++++++++++++++++++++++ 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear X 

Lymphoma malignant X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 163 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 100 ppm 

6666666677777777777777777 

Number of Days on Study 5667899911122222222222222 

1089207804622222222222222 

0000000000000000000000000 Total 

Carcass ID Number 5699859887656666777788999 

9613455731761289345669047 

Tissues/ 

Tumors 

Genital System (continued) 

Prostate + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Seminal vesicle + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Testes + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma X X 

X 

X 

1 

5 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node 

Iliac, hemangiosarcoma 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Hemangiosarcoma 

Spleen 

Hemangiosarcoma 

Thymus 

+++++ ++++++++++++++ +++ 

X 

+ + + +M+ + + + + + + + + + + + + + + + + + + + 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

X 

M+ + + + + + + + + + + + + + + + + + + + + + + + 

44 

1 

49 

50 

1 

50 

1 

49 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+ + +M+M+ + + +M+ + + + + + + + + + + + + + 46 

1 

Skin +++++++++++++++++++++++++ 50 

Basal cell adenoma X 1 

Keratoacanthoma X X 3 

Squamous cell carcinoma 

Squamous cell papilloma 

Subcutaneous tissue, fibroma 

X 

XXX X 

X 

1 

1 

6 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Nervous System 

Brain + + + +M+ + + + + + + + + + + + + + + + + + + + 49 

Astrocytoma malignant 

Peripheral nerve 

Spinal cord 

+ 

+ 

X 1 

4 

4 

Respiratory System 

Lung +++++++++++++++++++++++++ 50 

Nose +++++++++++++++++++++++++ 50 

Trachea +++++++++++++++++++++++++ 50 

Special Senses System 

None 

Urinary System 

Kidney +++++++++++++++++++++++++ 50 

Renal tubule, adenoma X X 4 

Renal tubule, adenoma, multiple X 1 

Urinary bladder + + + + +M+ + + + + + + + + + + + + + + + + + + 49 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 50 

Leukemia mononuclear 1 

Lymphoma malignant X 2 
 

 

 

 

 

 

 

 

 

 

164 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

3444444445555555556666666 

Number of Days on Study 5047788890011246780223334 

4473916740105081588280125 

1111111111111111111111111 

Carcass ID Number 1124440033132023331214405 

3499747320917847385325660 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon + + + + + +AA+ + +A+ +AA+ +AA+ +AA+ 

Intestine large, rectum + + + + + +AA+ + +A+ + + + + + +A+ + +A+ 

Intestine large, cecum + + + + + +AA+ + +A+ +AA+AAA+ +AAA 

Intestine small, duodenum +++++++A+++++++A+A+A++A++ 

Intestine small, jejunum + + + + + +AA+ + + + + + AAAAAAA+AA+ 

Intestine small, ileum + +A+ + +AA+ + +A+ +AAA+AAAAAAA 

Liver +++++++++++++++++++++++++ 

Hepatocellular adenoma 

Mesentery 

Oral mucosa 

Pancreas +++++++++++++++++++++++++ 

Acinus, adenoma X X X X 

Acinus, adenoma, multiple X 

Acinus, carcinoma 

Acinus, carcinoma, multiple 

Salivary glands + + + + + + + + + + +M+ + +M+M+ + + + + + + 

Stomach, forestomach +++++++++++++++++++++++++ 

Fibrosarcoma 

Stomach, glandular +++++++++++++++++++A+++++ 

Fibrosarcoma, metastatic, stomach, forestomach 

Tongue 

Squamous cell carcinoma 

Tooth + + 

Cardiovascular System 

Blood vessel + + +++ ++++ 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma malignant X 

Pheochromocytoma benign 

Islets, pancreatic +++++++++++++++++++++++A+ 

Adenoma X 

Parathyroid gland + + + + + + + + + + + + + + +M+M+ + + + + + + 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X XX 

Thyroid gland + + + + + + + + + + + + + + +M+M+ + + + + + + 

Bilateral, follicular cell, adenoma 

Follicular cell, adenoma X 

Follicular cell, carcinoma X 

General Body System 

None 

Genital System 

Coagulating gland +++++++++++++++++++++++++ 

Epididymis + + + + + + + + + + + + + + + + + + + + +M+ + + 

Preputial gland +++++++++++++++++++++++++ 

Adenoma X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 165 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

Number of Days on Study 

6666666677777777777777777 

5667788800001222222222222 

0044523804453122222222222 

Carcass ID Number 

1111111111111111111111111 

0441420412332200011122334 

1188309212568124506756490 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus 

Intestinel arge,c olon 

Intestinel arge,r ectum 

Intestinel arge,c ecum 

Intestines mall,d uodenum 

Intestine small, jejunum 

Intestines mall,i leum 

Liver 

Hepatocellular adenoma 

Mesentery 

Oral mucosa 

Pancreas 

Acinus, adenoma 

Acinus, adenoma, multiple 

Acinus, carcinoma 

Acinus, carcinoma, multiple 

Salivaryg lands 

Stomach,f orestomach 

Fibrosarcoma 

Stomach, glandular 

Fibrosarcoma, metastatic, stomach, forestomach 

Tongue 

Squamous cell carcinoma 

Tooth 

+++++++++++++++++++++++++ 

AA+AA+ + +A+ + + + + + + + + + + + + + + + 

AA+A+ + + +A+ + + + + + + + + + + + + + + + 

AAAAAA+AA+ +A + + + + + + + + + +M+ + 

++++A+++A++A+++++++++++++ 

+ + A + A + + A A + + A +++++++++++++ 

A+AAAA+AA+ +A +++++++++++++ 

+++++++++++++++++++++++++ 

X 

+ + 

+ 

+++++++++++++++++++++++++ 

X X X X 

X XX 

X X 

X 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

X 

++++++++A++++++++++++++++ 

X 

+ 

X 

+ + 

50 

36 

41 

29 

42 

34 

28 

50 

1 

2 

1 

50 

8 

4 

2 

1 

47 

50 

1 

48 

1 

1 

1 

4 

Cardiovascular System 

Blood vessel 

Heart 

Endocrine System 

Adrenalc ortex 

Adrenal medulla 

Pheochromocytoma malignan

Pheochromocytoma benign 

Islets,p ancreatic 

Adenoma 

Parathyroidg land 

Pituitaryg land 

Pars distalis, adenoma 

Thyroidg land 

Bilateral, follicular cell, aden

Follicular cell, adenoma 

Follicular cell, carcinoma 

General Body System 

None 

t 

oma 

+ + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

X X 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

XXX X X X XX 

+++++++++++++++++++++++++ 

X 

X X X 

12 

50 

50 

50 

1 

1 

49 

3 

48 

50 

12 

48 

1 

4 

1 

Genital System 

Coagulatingg land 

Epididymis 

Preputialg land 

Adenoma 

MM + + + + + + + + M + M + + M + + + + + + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

45 

49 

50 

1 
 

 

 

 

 

 

 

 

 

 

 

 

166 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

3444444445555555556666666 

Number of Days on Study 5047788890011246780223334 

4473916740105081588280125 

1111111111111111111111111 

Carcass ID Number 1124440033132023331214405 

3499747320917847385325660 

Genital System (continued) 

Prostate +++++++++++++++++++++++++ 

Adenoma 

Seminal vesicle +++++++++++++++++++++++++ 

Testes + + + + + + + + + + + + + + + + + + + + +M+ + + 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Hemangiosarcoma 

Spleen 

Thymus 

Thymoma benign 

+ + + ++++++++++++ + ++++ 

+ + + + + + + + + + +M+ + +M+M+ + + + + + + 

+++++++++++++++++++++++++ 

+++++++++++++++++++A+++++ 

+++++++++++++++++++++++++ 

X 

Integumentary System 

Mammaryg land 

Carcinoma 

+ + +M+ + + + + + + + + + + + + + + + + + + + + 

Skin +++++++++++++++++++++++++ 

Carcinoma, metastatic, Zymbal’s gland 

Fibroma 

X 

Keratoacanthoma 

Squamous cell papilloma 

Sebaceous gland, adenoma 

Subcutaneous tissue, fibrosarcoma 

X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Skeletal muscle + 

Fibroma X 

Lipoma 

Nervous System 

Brain +++++++++++++++++++++++++ 

Astrocytoma malignant 

Peripheral nerve 

Spinal cord 

+ 

+ 

Respiratory System 

Lung 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, Zymbal’s gland 

Nose 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Ear + 

Eye 

Harderian gland 

Lacrimal gland 

Zymbal’s gland 

Carcinoma 

+ 

+ 

+ 

+ 

X 

+ + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 167 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

6666666677777777777777777 

Number of Days on Study 5667788800001222222222222 

0044523804453122222222222 

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 

Carcass ID Number 0 4 4 1 4 2 0 4 1 2 3 3 2 2 0 0 0 1 1 1 2 2 3 3 4 Tissues/ 

1 1 8 8 3 0 9 2 1 2 5 6 8 1 2 4 5 0 6 7 5 6 4 9 0 Tumors 

Genital System (continued) 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Bilateral, interstitial cell, adenoma X 1 

Interstitial cell, adenoma X X X 3 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + + + + + + + + + + + + + 38 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Thymus + + + + + + + + + + + + M + + + + + + + + + + + + 49 

Thymoma benign X 2 

Integumentary System 

Mammary gland M + + M + M M + + + + + + + + + + M + + + + + + + 44 

Carcinoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, Zymbal’s gland 1 

Fibroma X X 2 

Keratoacanthoma X X 2 

Squamous cell papilloma 1 

Sebaceous gland, adenoma X 1 

Subcutaneous tissue, fibrosarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle + 2 

Fibroma 1 

Lipoma X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Astrocytoma malignant X 1 

Peripheral nerve + 2 

Spinal cord + 2 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma X 1 

Carcinoma, metastatic, Zymbal’s gland 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 1 

Eye 1 

Harderian gland + 4 

Lacrimal gland 1 

Zymbal’s gland + 2 

Carcinoma X 2 
168 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

3444444445555555556666666 

Number of Days on Study 5047788890011246780223334 

4473916740105081588280125 

1111111111111111111111111 

Carcass ID Number 1124440033132023331214405 

3499747320917847385325660 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Renal tubule, adenoma 

Urinary bladder + + + + + + + + + + + + + + + + + + +AA+ + + + 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Leukemia mononuclear 

Mesothelioma malignant 
 

 

 

 

Pyridine, NTP TR 470 169 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 200 ppm 

Number of Days on Study 

6666666677777777777777777 

5667788800001222222222222 

0044523804453122222222222 

Carcass ID Number 

1111111111111111111111111 

0441420412332200011122334 

1188309212568124506756490 

Total 

Tissues/ 

Tumors 

Urinary System 

Kidney 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Renal tubule, adenoma 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

X 

++++++++++++A++++++++++++ 

50 

1 

1 

47 

Systemic Lesions 

Multipleo rgans 

Leukemia mononuclear 

Mesothelioma malignant 

+++++++++++++++++++++++++ 

X X 

X 

50 

2 

1 
 

 

 

 

 

 

 

 

 

 

170 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

0444444444444555555555555 

Number of Days on Study 9456666688899133345555566 

4303467836939112950233628 

1111111111111111111111111 

Carcass ID Number 8568987796786776586889897 

0819931926864609415285472 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Intestine large, colon +AA+A+ + + +A+ + + +A+ +A+A+ +A+A 

Intestine large, rectum +AA+A+ + + + + + + + +A+ +A+ + + + + + + 

Intestine large, cecum +AA+A+ + + +A+ + +AA+AA+A+AA+A 

Intestine small, duodenum +AA+ + + + + + + + + + +A+ +A+ + + + + + + 

Intestine small, jejunum + A A +++++++++++A++A+A++++A 

Intestine small, ileum +AA+A+ +A+ +A+ + +A+ +A+ + +A+ +A 

Liver +++++++++++++++++++++++++ 

Cholangiocarcinoma X X 

Histiocytic sarcoma X 

Mesentery + 

Pancreas ++++++++++++++A++++++++++ 

Acinus, adenoma XX X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + +M 

Stomach, forestomach +++++++++++++++++A+++++++ 

Squamous cell papilloma X 

Stomach, glandular + + A ++++++++++++++A+++++++ 

Tooth 

Cardiovascular System 

Blood vessel + + 

Heart +++++++++++++++++++++++++ 

Endocardium, schwannoma benign 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Carcinoma 

Adrenal medulla +++++++++++++++++++++++++ 

Pheochromocytoma malignant X 

Islets, pancreatic ++++++++++++++A++++++++++ 

Carcinoma 

Parathyroid gland +M+ + + + + + + + + + +M+ + + + + + + + + + + 

Pituitary gland +++++++++++++++++++++++++ 

Pars distalis, adenoma X X X X 

Pars intermedia, adenoma 

Thyroid gland +++++++++++++++++++++++++ 

C-cell, adenoma 

General Body System 

None 

Genital System 

Coagulating gland + + + + + + +M+ + + + + + + + + + + + + + + + + 

Epididymis +++++++++++++++++++++++++ 

Preputial gland +++++++++++++++++++++++++ 

Adenoma 

Prostate +++++++++++++++++++++++++ 

Schwannoma malignant 

Seminal vesicle +++++++++++++++++++++++++ 

Testes +++++++++++++++++++++++++ 

Bilateral, interstitial cell, adenoma X 

Interstitial cell, adenoma X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 171 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

5555566666666666677777777 

Number of Days on Study 7888901223567888802222222 

4027566791804235792222222 

2111111111111111111111111 Total 

Carcass ID Number 0995557987996686755556679 Tissues/ 

0342797655012378413560738 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 50 

Intestine large, colon +A+A+ +A+ + + + +AA+AAA+ + + + + + + 33 

Intestine large, rectum + + +A+ + + + + + + +AA+A+A+ + + + + + + 40 

Intestine large, cecum +A+A+AA+A+A+AA+AAA+ + + + + + + 27 

Intestine small, duodenum + + + + + + + + + + + +A+ +AAA+ + + + + + + 42 

Intestine small, jejunum + A + A + + A + A + + + A A + A A A +++++++ 35 

Intestine small, ileum +A+A+AA+A+ + +AA+AAA+ + + + + + + 31 

Liver +++++++++++++++++++++++++ 50 

Cholangiocarcinoma 2 

Histiocytic sarcoma 1 

Mesentery + 2 

Pancreas +++++++++++++++++++++++++ 49 

Acinus, adenoma X X XX 7 

Salivary glands + + + + + +M+ + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach +++++++++++++++++++++++++ 49 

Squamous cell papilloma 1 

Stomach, glandular +++++++++++++++++++++++++ 48 

Tooth + + + 3 

Cardiovascular System 

Blood vessel + 3 

Heart +++++++++++++++++++++++++ 50 

Endocardium, schwannoma benign X 1 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 50 

Carcinoma X 1 

Adrenal medulla +++++++++++++++++++++++++ 50 

Pheochromocytoma malignant 1 

Islets, pancreatic +++++++++++++++++++++++++ 49 

Carcinoma X 1 

Parathyroid gland + + + + + +M+ + + + + + + + + + + + + + + + + + 47 

Pituitary gland +++++++++++++++++++++++++ 50 

Pars distalis, adenoma X XX XXXX X X 13 

Pars intermedia, adenoma X 1 

Thyroid gland + + + + + +M+ + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X X 3 

General Body System 

None 

Genital System 

Coagulating gland + + + + + + AM+ + + +M+ + + +M+ + + + + + + 45 

Epididymis +++++++++++++++++++++++++ 50 

Preputial gland +++++++++++++++++++++++++ 50 

Adenoma X 1 

Prostate +++++++++++++++++++++++++ 50 

Schwannoma malignant X 1 

Seminal vesicle ++++++A++++++++++++++++++ 49 

Testes +++++++++++++++++++++++++ 50 

Bilateral, interstitial cell, adenoma X X X X 5 

Interstitial cell, adenoma X X X 7 
 

 

 

 

 

 

 

 

 

172 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

0444444444444555555555555 

Number of Days on Study 9456666688899133345555566 

4303467836939112950233628 

1111111111111111111111111 

Carcass ID Number 8568987796786776586889897 

0819931926864609415285472 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Histiocytic sarcoma 

Lymph node 

Pancreatic, histiocytic sarcoma 

Lymphn ode, mandibular 

Histiocytic sarcoma 

Lymphn ode, mesenteric 

Hemangioma 

Histiocytic sarcoma 

Spleen 

Thymus 

X 

+ +++++ ++++++ ++++++ + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + +M 

X 

+++++++++++++++++++++++++ 

X 

++++++++++++++A++++++++++ 

+++++++++++++++++++++++++ 

Integumentary System 

Mammaryg land 

Fibroadenoma 

+ +M+ + +M+ + + + + + + + + + + + + + + + + + 

Skin +++++++++++++++++++++++++ 

Basal cell carcinoma 

Keratoacanthoma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, fibroma, multiple 

Subcutaneous tissue, fibrosarcoma 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Joint, sarcoma 

Nervous System 

Brain +++++++++++++++++++++++++ 

Peripheral nerve 

Spinal cord 

+ + 

+ 

Respiratory System 

Lung 

Carcinoma, metastatic, Zymbal’s gland 

Fibrosarcoma, metastatic, skin 

Histiocytic sarcoma 

Nose 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

Chondroma 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

Ear + 

Harderian gland 

Zymbal’s gland 

Carcinoma 

+ 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 173 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

5555566666666666677777777 

Number of Days on Study 7888901223567888802222222 

4027566791804235792222222 

2 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 

Carcass ID Number 0 9 9 5 5 5 7 9 8 7 9 9 6 6 8 6 7 5 5 5 5 6 6 7 9 Tissues/ 

0 3 4 2 7 9 7 6 5 5 0 1 2 3 7 8 4 1 3 5 6 0 7 3 8 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Lymph node + + + + + + + + + + + + + 32 

Pancreatic, histiocytic sarcoma 1 

Lymph node, mandibular + + + + + + M + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma X 1 

Histiocytic sarcoma 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Integumentary System 

Mammary gland + + M + + + + + + + + + + + + + + M + + + + + + + 46 

Fibroadenoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Basal cell carcinoma X 1 

Keratoacanthoma X 1 

Subcutaneous tissue, fibroma X 1 

Subcutaneous tissue, fibroma, multiple X 1 

Subcutaneous tissue, fibrosarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Joint, sarcoma X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve + + + 5 

Spinal cord + + + 4 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, Zymbal’s gland X 1 

Fibrosarcoma, metastatic, skin X 1 

Histiocytic sarcoma 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Chondroma X 1 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 1 

Harderian gland + 1 

Zymbal’s gland + + 3 

Carcinoma X X 3 
 

 

 

174 Pyridine, NTP TR 470 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

0444444444444555555555555 

Number of Days on Study 9456666688899133345555566 

4303467836939112950233628 

1111111111111111111111111 

Carcass ID Number 8568987796786776586889897 

0819931926864609415285472 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Histiocytic sarcoma X 

Renal tubule, adenoma 

Renal tubule, carcinoma 

Urinary bladder +++++++++A++++A++++++A++A 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Histiocytic sarcoma X 

Lymphoma malignant X 
 

 

 

 

Pyridine, NTP TR 470 175 

TABLE C2 

Individual Animal Tumor Pathology of Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine: 400 ppm 

5555566666666666677777777 

Number of Days on Study 7888901223567888802222222 

4027566791804235792222222 

2111111111111111111111111 Total 

Carcass ID Number 0995557987996686755556679 Tissues/ 

0342797655012378413560738 Tumors 

Urinary System 

Kidney +++++++++++++++++++++++++ 50 

Histiocytic sarcoma 1 

Renal tubule, adenoma X X 2 

Renal tubule, carcinoma X 1 

Urinary bladder ++++++A+++++++++A++++++++ 44 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 50 

Histiocytic sarcoma 1 

Lymphoma malignant 1 
176 Pyridine, NTP TR 470 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Adrenal Medulla: Benign Pheochromocytoma 

Overall ratea 5/50 (10%) 4/50 (8%) 1/50 (2%) 0/50 (0%) 

Adjusted rateb 12.5% 11.1% 3.0% 0.0% 

Terminal ratec 5/22 (23%) 2/14 (14%) 0/11 (0%) 0/7 (0%) e First incidence (days) 722 (T) 486 721 —

Poly-3 testd P=0.022N P=0.568N P=0.144N P=0.073N
 

Adrenal Medulla: Benign or Malignant Pheochromocytoma 

Overall rate 6/50 (12%) 5/50 (10%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 14.8% 13.8% 5.8% 3.5% 

Terminal rate 5/22 (23%) 2/14 (14%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 587 486 481 553 

Poly-3 test P=0.055N P=0.582N P=0.189N P=0.133N 

Small Intestine (Duodenum, Jejunum): Carcinoma 

Overall rate 1/50 (2%) 3/50 (6%) 0/50 (0%) 0/50 (0%)
 

Adjusted rate 2.5% 8.5% 0.0% 0.0%
 

Terminal rate 1/22 (5%) 2/14 (14%) 0/11 (0%) 0/7 (0%)
 

First incidence (days) 722 (T) 698 — —
 

Poly-3 test P=0.221N P=0.259 P=0.534N P=0.569N
 

Kidney (Renal Tubule): Adenoma (Single Sections) 

Overall rate 2/50 (4%) 5/50 (10%) 1/50 (2%) 2/50 (4%) 

Adjusted rate 4.9% 13.9% 3.0% 7.0% 

Terminal rate 0/22 (0%) 1/14 (7%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 576 610 721 606 

Poly-3 test P=0.531N P=0.167 P=0.564N P=0.562 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single Sections) 

Overall rate 2/50 (4%) 5/50 (10%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 4.9% 13.9% 3.0% 10.4% 

Terminal rate 0/22 (0%) 1/14 (7%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 576 610 721 606 

Poly-3 test P=0.420 P=0.167 P=0.564N P=0.348 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 3/50 (6%) 6/50 (12%) 5/50 (10%) 4/50 (8%) 

Adjusted rate 7.4% 16.5% 14.4% 13.6% 

Terminal rate 1/22 (5%) 1/14 (7%) 2/11 (18%) 0/7 (0%) 

First incidence (days) 576 610 520 550 

Poly-3 test P=0.288 P=0.187 P=0.271 P=0.328 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 3/50 (6%) 6/50 (12%) 6/50 (12%) 4/50 (8%) 

Adjusted rate 7.4% 16.5% 17.2% 13.6% 

Terminal rate 1/22 (5%) 1/14 (7%) 2/11 (18%) 0/7 (0%) 

First incidence (days) 576 610 520 550 

Poly-3 test P=0.258 P=0.187 P=0.167 P=0.328 

Pancreas: Adenoma 

Overall rate 14/46 (30%) 11/50 (22%) 12/50 (24%) 7/49 (14%)
 

Adjusted rate 37.4% 28.3% 32.9% 23.7%
 

Terminal rate 13/22 (59%) 4/14 (29%) 4/11 (36%) 3/7 (43%)
 

First incidence (days) 589 372 486 545
 

Poly-3 test P=0.176N P=0.267N P=0.433N P=0.168N
 
Pyridine, NTP TR 470 177 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Pancreas: Carcinoma 

Overall rate 4/46 (9%) 1/50 (2%) 3/50 (6%) 0/49 (0%) 

Adjusted rate 10.8% 2.8% 8.9% 0.0% 

Terminal rate 4/22 (18%) 0/14 (0%) 3/11 (27%) 0/7 (0%) 

First incidence (days) 722 (T) 638 722 (T) — 

Poly-3 test P=0.107N P=0.190N P=0.550N P=0.105N 

Pancreas: Adenoma or Carcinoma 

Overall rate 16/46 (35%) 11/50 (22%) 13/50 (26%) 7/49 (14%) 

Adjusted rate 42.7% 28.3% 35.6% 23.7% 

Terminal rate 15/22 (68%) 4/14 (29%) 5/11 (45%) 3/7 (43%) 

First incidence (days) 589 372 486 545 

Poly-3 test P=0.098N P=0.131N P=0.343N P=0.077N 

Pancreatic Islets: Adenoma 

Overall rate 8/47 (17%) 0/50 (0%) 3/49 (6%) 0/49 (0%) 

Adjusted rate 20.8% 0.0% 8.8% 0.0% 

Terminal rate 5/22 (23%) 0/14 (0%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 624 — 510 — 

Poly-3 test P=0.005N P=0.005N P=0.134N P=0.014N 

Pancreatic Islets: Adenoma or Carcinoma 

Overall rate 8/47 (17%) 1/50 (2%) 3/49 (6%) 1/49 (2%) 

Adjusted rate 20.8% 2.8% 8.8% 3.6% 

Terminal rate 5/22 (23%) 0/14 (0%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 624 638 510 631 

Poly-3 test P=0.025N P=0.020N P=0.134N P=0.048N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 16/49 (33%) 17/49 (35%) 12/50 (24%) 13/50 (26%) 

Adjusted rate 38.2% 45.7% 33.1% 39.7% 

Terminal rate 9/22 (41%) 5/14 (36%) 4/11 (36%) 2/7 (29%) 

First incidence (days) 468 506 494 483 

Poly-3 test P=0.480N P=0.324 P=0.404N P=0.545 

Prostate Gland: Adenoma 

Overall rate 3/50 (6%) 1/49 (2%) 1/50 (2%) 0/50 (0%) 

Adjusted rate 7.5% 2.9% 3.0% 0.0% 

Terminal rate 3/22 (14%) 1/14 (7%) 1/11 (9%) 0/7 (0%) 

First incidence (days) 722 (T) 722 (T) 722 (T) — 

Poly-3 test P=0.097N P=0.363N P=0.368N P=0.195N 

Skin: Keratoacanthoma 

Overall rate 7/50 (14%) 3/50 (6%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 17.2% 8.5% 5.9% 3.5% 

Terminal rate 4/22 (18%) 2/14 (14%) 1/11 (9%) 0/7 (0%) 

First incidence (days) 598 639 705 687 

Poly-3 test P=0.035N P=0.216N P=0.128N P=0.090N 

Skin: Squamous Cell Papilloma or Keratoacanthoma 

Overall rate 9/50 (18%) 4/50 (8%) 3/50 (6%) 1/50 (2%) 

Adjusted rate 21.8% 11.3% 8.7% 3.5% 

Terminal rate 5/22 (23%) 3/14 (21%) 1/11 (9%) 0/7 (0%) 

First incidence (days) 576 639 548 687 

Poly-3 test P=0.014N P=0.177N P=0.106N P=0.038N 
178 Pyridine, NTP TR 470 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Skin: Squamous Cell Papilloma, Keratoacanthoma, or Squamous Cell Carcinoma 

Overall rate 9/50 (18%) 5/50 (10%) 3/50 (6%) 1/50 (2%) 

Adjusted rate 21.8% 14.1% 8.7% 3.5% 

Terminal rate 5/22 (23%) 4/14 (29%) 1/11 (9%) 0/7 (0%) 

First incidence (days) 576 639 548 687 

Poly-3 test P=0.013N P=0.282N P=0.106N P=0.038N 

Skin: Squamous Cell Papilloma, Keratoacanthoma, Basal Cell Adenoma, Basal Cell Carcinoma, or Squamous Cell Carcinoma 

Overall rate 9/50 (18%) 6/50 (12%) 3/50 (6%) 2/50 (4%) 

Adjusted rate 21.8% 17.0% 8.7% 7.1% 

Terminal rate 5/22 (23%) 5/14 (36%) 1/11 (9%) 1/7 (14%) 

First incidence (days) 576 639 548 687 

Poly-3 test P=0.036N P=0.401N P=0.106N P=0.096N 

Skin: Fibroma 

Overall rate 5/50 (10%) 6/50 (12%) 2/50 (4%) 2/50 (4%) 

Adjusted rate 12.3% 16.7% 5.9% 7.1% 

Terminal rate 3/22 (14%) 4/14 (29%) 1/11 (9%) 2/7 (29%) 

First incidence (days) 572 552 683 722 (T) 

Poly-3 test P=0.198N P=0.412 P=0.294N P=0.388N 

Skin: Fibroma, Fibrosarcoma, or Sarcoma 

Overall rate 6/50 (12%) 6/50 (12%) 3/50 (6%) 3/50 (6%) 

Adjusted rate 14.6% 16.7% 8.8% 10.7% 

Terminal rate 3/22 (14%) 4/14 (29%) 1/11 (9%) 2/7 (29%) 

First incidence (days) 572 552 674 709 

Poly-3 test P=0.282N P=0.527 P=0.338N P=0.453N 

Testes: Adenoma 

Overall rate 5/50 (10%) 6/49 (12%) 4/49 (8%) 12/50 (24%)
 

Adjusted rate 12.3% 16.9% 11.9% 36.6%
 

Terminal rate 3/22 (14%) 3/14 (21%) 1/11 (9%) 3/7 (43%)
 

First incidence (days) 592 486 660 464
 

Poly-3 test P=0.008 P=0.404 P=0.618N P=0.012
 

Thyroid Gland (C-cell): Adenoma 

Overall rate 4/49 (8%) 2/50 (4%) 0/48 (0%) 3/49 (6%) 

Adjusted rate 10.2% 5.6% 0.0% 10.6% 

Terminal rate 3/22 (14%) 1/14 (7%) 0/11 (0%) 1/7 (14%) 

First incidence (days) 701 581 — 574 

Poly-3 test P=0.483N P=0.382N P=0.085N P=0.634 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 0/49 (0%) 0/50 (0%) 5/48 (10%) 0/49 (0%)
 

Adjusted rate 0.0% 0.0% 14.9% 0.0%
 

Terminal rate 0/22 (0%) 0/14 (0%) 1/11 (9%) 0/7 (0%)
 

First incidence (days) — — 630 —
 

Poly-3 test P=0.220 —f P=0.019 —
 

Thyroid Gland (Follicular Cell): Carcinoma 

Overall rate 3/49 (6%) 3/50 (6%) 1/48 (2%) 0/49 (0%)
 

Adjusted rate 7.6% 8.4% 3.0% 0.0%
 

Terminal rate 1/22 (5%) 1/14 (7%) 0/11 (0%) 0/7 (0%)
 

First incidence (days) 674 593 645 —
 

Poly-3 test P=0.093N P=0.618 P=0.370N P=0.196N
 
Pyridine, NTP TR 470 179 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 3/49 (6%) 3/50 (6%) 6/48 (13%) 0/49 (0%) 

Adjusted rate 7.6% 8.4% 17.7% 0.0% 

Terminal rate 1/22 (5%) 1/14 (7%) 1/11 (9%) 0/7 (0%) 

First incidence (days) 674 593 630 — 

Poly-3 test P=0.355N P=0.618 P=0.168 P=0.196N 

Zymbal’s Gland: Carcinoma 

Overall rate 1/50 (2%) 0/50 (0%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 2.5% 0.0% 5.8% 10.3% 

Terminal rate 0/22 (0%) 0/14 (0%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 660 — 494 466 

Poly-3 test P=0.063 P=0.528N P=0.447 P=0.200 

All Organs: Hemangiosarcoma 

Overall rate 0/50 (0%) 3/50 (6%) 1/50 (2%) 0/50 (0%) 

Adjusted rate 0.0% 8.5% 3.0% 0.0% 

Terminal rate 0/22 (0%) 2/14 (14%) 0/11 (0%) 0/7 (0%) 

First incidence (days) — 660 705 — 

Poly-3 test P=0.519N P=0.096 P=0.466 — 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 1/50 (2%) 3/50 (6%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 2.5% 8.5% 3.0% 3.5% 

Terminal rate 0/22 (0%) 2/14 (14%) 0/11 (0%) 0/7 (0%) 

First incidence (days) 705 660 705 631 

Poly-3 test P=0.573N P=0.259 P=0.722 P=0.678 

All Organs: Benign Neoplasms 

Overall rate 40/50 (80%) 37/50 (74%) 29/50 (58%) 33/50 (66%) 

Adjusted rate 86.7% 84.4% 72.4% 81.9% 

Terminal rate 21/22 (96%) 13/14 (93%) 8/11 (73%) 6/7 (86%) 

First incidence (days) 468 372 486 464 

Poly-3 test P=0.214N P=0.497N P=0.055N P=0.353N 

All Organs: Malignant Neoplasms 

Overall rate 17/50 (34%) 14/50 (28%) 12/50 (24%) 13/50 (26%) 

Adjusted rate 40.2% 37.5% 33.2% 40.5% 

Terminal rate 9/22 (41%) 7/14 (50%) 3/11 (27%) 2/7 (29%) 

First incidence (days) 587 552 481 466 

Poly-3 test P=0.513N P=0.496N P=0.341N P=0.584 

All Organs: Benign or Malignant Neoplasms 

Overall rate 43/50 (86%) 38/50 (76%) 32/50 (64%) 39/50 (78%) 

Adjusted rate 91.2% 86.1% 78.4% 90.9% 

Terminal rate 21/22 (96%) 13/14 (93%) 9/11 (82%) 7/7 (100%) 

First incidence (days) 468 372 481 464 

Poly-3 test P=0.534N P=0.306N P=0.050N P=0.656N 

(T)Terminal sacrifice

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, kidney, 

pancreas, pancreatic islets, pituitary gland, prostate gland, testis, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

d	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A 

negative trend or a lower incidence in an exposure group is indicated by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 

c 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

180 Pyridine, NTP TR 470 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 100 ppm 200 ppm 400 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 2 9 9 10 

Natural deaths 26 27 30 33 

Survivors 

Terminal sacrifice 22 14 11 7 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Esophagus (50) (50) (50) (50) 

Foreign body 1 (2%) 1 (2%) 

Inflammation, acute 1 (2%) 

Ulcer 1 (2%) 

Muscularis, degeneration 1 (2%) 

Intestine large, colon (35) (39) (36) (33) 

Mineralization 1 (3%) 1 (3%) 

Parasite metazoan 1 (3%) 

Intestine large, rectum (42) (42) (41) (40) 

Hemorrhage 1 (2%) 

Mineralization 1 (2%) 

Parasite metazoan 1 (3%) 

Ulcer 1 (3%) 

Intestine large, cecum (32) (37) (29) (27) 

Congestion 1 (3%) 

Edema 1 (3%) 

Hemorrhage 1 (3%) 2 (5%) 1 (3%) 

Inflammation, acute 2 (5%) 2 (7%) 1 (4%) 

Inflammation, chronic 1 (3%) 1 (4%) 

Ulcer 2 (5%) 2 (7%) 

Artery, mineralization 1 (3%) 

Intestine small, jejunum (37) (36) (34) (35) 

Inflammation, chronic 1 (3%) 

Liver (50) (50) (50) (50) 

Angiectasis 5 (10%) 9 (18%) 2 (4%) 

Basophilic focus 2 (4%) 

Cholangiofibrosis 1 (2%) 

Clear cell focus 15 (30%) 7 (14%) 8 (16%) 8 (16%) 

Congestion 19 (38%) 12 (24%) 6 (12%) 17 (34%) 

Degeneration, cystic 7 (14%) 13 (26%) 9 (18%) 5 (10%) 

Eosinophilic focus 14 (28%) 12 (24%) 4 (8%) 2 (4%) 

Fibrosis 1 (2%) 5 (10%) 26 (52%) 31 (62%) 

Hemorrhage 1 (2%) 1 (2%) 5 (10%) 3 (6%) 

Hepatodiaphragmatic nodule 2 (4%) 1 (2%) 2 (4%) 

Hypertrophy 1 (2%) 

Infarct 1 (2%) 

Infiltration cellular, histiocyte 1 (2%) 2 (4%) 

Inflammation, acute 1 (2%) 1 (2%) 3 (6%) 1 (2%) 

Mineralization 1 (2%) 3 (6%) 3 (6%) 

Mixed cell focus 1 (2%) 1 (2%) 1 (2%) 

Necrosis 6 (12%) 7 (14%) 6 (12%) 2 (4%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 181 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Alimentary System (continued) 

Liver (continued) (50) (50) (50) (50) 

Pigmentation 6 (12%) 15 (30%) 34 (68%) 42 (84%) 

Regeneration 2 (4%) 

Tension lipidosis 1 (2%) 

Thrombosis 1 (2%) 

Vacuolization cytoplasmic 18 (36%) 18 (36%) 12 (24%) 15 (30%) 

Artery, mineralization 1 (2%) 

Bile duct, cyst 2 (4%) 3 (6%) 

Bile duct, dilatation 2 (4%) 

Bile duct, hyperplasia 31 (62%) 33 (66%) 30 (60%) 27 (54%) 

Centrilobular, cytomegaly 1 (2%) 1 (2%) 1 (2%) 

Centrilobular, degeneration 1 (2%) 15 (30%) 25 (50%) 33 (66%) 

Centrilobular, hypertrophy 1 (2%) 

Centrilobular, necrosis 5 (10%) 6 (12%) 4 (8%) 23 (46%) 

Hepatocyte, atrophy 2 (4%) 1 (2%) 1 (2%) 

Oval cell, hyperplasia 1 (2%) 

Periportal, fibrosis 5 (10%) 7 (14%) 

Sinusoid, congestion 1 (2%) 

Mesentery (7) (1) (2) (2) 

Mineralization 1 (14%) 

Artery, inflammation 5 (71%) 1 (100%) 1 (50%) 

Artery, mineralization 2 (29%) 

Fat, necrosis 1 (14%) 1 (50%) 

Vein, thrombosis 2 (100%) 

Oral mucosa (5) (1) (1) 

Hyperplasia, squamous 1 (100%) 1 (100%) 

Inflammation, suppurative 3 (60%) 

Pancreas (46) (50) (50) (49) 

Atrophy 2 (4%) 3 (6%) 3 (6%) 1 (2%) 

Basophilic focus 1 (2%) 

Edema 1 (2%) 

Fibrosis 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia 18 (39%) 18 (36%) 8 (16%) 8 (16%) 

Necrosis 1 (2%) 

Acinus, hyperplasia 1 (2%) 1 (2%) 

Artery, inflammation 3 (7%) 5 (10%) 3 (6%) 

Artery, mineralization 2 (4%) 6 (12%) 1 (2%) 

Duct, hyperplasia 1 (2%) 1 (2%) 1 (2%) 

Salivary glands (48) (49) (47) (48) 

Atrophy 1 (2%) 

Inflammation, acute 1 (2%) 

Artery, mineralization 2 (4%) 3 (6%) 

Duct, cyst 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

182 Pyridine, NTP TR 470 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Alimentary System (continued) 

Stomach, forestomach (49) (50) (50) (49) 

Cyst 1 (2%) 2 (4%) 

Erosion 1 (2%) 

Fibrosis 1 (2%) 

Foreign body 1 (2%) 2 (4%) 

Hemorrhage 1 (2%) 

Hyperplasia, squamous 2 (4%) 13 (26%) 11 (22%) 10 (20%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 3 (6%) 5 (10%) 3 (6%) 1 (2%) 

Ulcer 2 (4%) 4 (8%) 3 (6%) 4 (8%) 

Ulcer, chronic 1 (2%) 

Stomach, glandular (49) (50) (48) (48) 

Erosion 3 (6%) 3 (6%) 2 (4%) 4 (8%) 

Fibrosis 1 (2%) 

Hemorrhage 2 (4%) 

Hyperplasia 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 8 (16%) 25 (50%) 16 (33%) 6 (13%) 

Ulcer 1 (2%) 

Artery, mineralization 1 (2%) 1 (2%) 

Serosa, edema 1 (2%) 

Tooth (2) (2) (4) (3) 

Peridontal tissue, inflammation, chronic 1 (33%) 

Peridontal tissue, inflammation, chronic

 active 1 (50%) 1 (33%) 

Peridontal tissue, inflammation,

 granulomatous 1 (50%) 

Peridontal tissue, inflammation, suppurative 1 (50%) 1 (50%) 4 (100%) 1 (33%) 

Cardiovascular System 

Blood vessel (8) (23) (12) (3) 

Mineralization 6 (75%) 6 (26%) 1 (8%) 

Aorta, mineralization 7 (88%) 21 (91%) 10 (83%) 3 (100%) 

Pulmonary artery, degeneration 1 (4%) 

Pulmonary artery, mineralization 3 (38%) 3 (13%) 5 (42%) 2 (67%) 

Heart (50) (50) (50) (50) 

Cardiomyopathy 49 (98%) 49 (98%) 49 (98%) 47 (94%) 

Inflammation, chronic 1 (2%) 

Mineralization 6 (12%) 17 (34%) 12 (24%) 3 (6%) 

Thrombosis 1 (2%) 1 (2%) 

Artery, inflammation 1 (2%) 

Artery, inflammation, acute 1 (2%) 

Artery, mineralization 4 (8%) 15 (30%) 9 (18%) 2 (4%) 

Artery, thrombosis 1 (2%) 

Atrium, dilatation 1 (2%) 1 (2%) 

Atrium, thrombosis 4 (8%) 2 (4%) 5 (10%) 3 (6%) 

Valve, inflammation 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 183 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Accessory adrenal cortical nodule 1 (2%) 

Angiectasis 1 (2%) 1 (2%) 

Congestion 2 (4%) 1 (2%) 

Degeneration 2 (4%) 

Hemorrhage 3 (6%) 

Hyperplasia 1 (2%) 2 (4%) 1 (2%) 1 (2%) 

Hypertrophy 2 (4%) 2 (4%) 2 (4%) 

Mineralization 1 (2%) 

Necrosis 2 (4%) 

Thrombosis 1 (2%) 1 (2%) 

Vacuolization cytoplasmic 17 (34%) 13 (26%) 12 (24%) 7 (14%) 

Adrenal medulla (50) (50) (50) (50) 

Hyperplasia 3 (6%) 4 (8%) 2 (4%) 1 (2%) 

Islets, pancreatic (47) (50) (49) (49) 

Hyperplasia 1 (2%) 1 (2%) 2 (4%) 1 (2%) 

Parathyroid gland (48) (47) (48) (47) 

Hyperplasia 16 (33%) 32 (68%) 29 (60%) 12 (26%) 

Inflammation, chronic 1 (2%) 

Pituitary gland (49) (49) (50) (50) 

Angiectasis 1 (2%) 

Congestion 2 (4%) 

Cyst 17 (35%) 13 (27%) 18 (36%) 11 (22%) 

Hemorrhage 1 (2%) 1 (2%) 

Hyperplasia 13 (27%) 10 (20%) 7 (14%) 3 (6%) 

Hypertrophy 1 (2%) 

Pars distalis, hyperplasia 2 (4%) 1 (2%) 

Thyroid gland (49) (50) (48) (49) 

Inflammation, granulomatous 1 (2%) 

C-cell, hyperplasia 1 (2%) 1 (2%) 

Follicle, cyst 2 (4%) 4 (8%) 5 (10%) 1 (2%) 

Follicular cell, hyperplasia 2 (4%) 1 (2%) 

General Body System 

None 

Genital System 

Coagulating gland (48) (42) (45) (45) 

Inflammation, acute 1 (2%) 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 

Artery, mineralization 1 (2%) 

Epididymis (50) (49) (49) (50) 

Arteriole, mineralization 1 (2%) 

Artery, inflammation 1 (2%) 

Epithelium, hyperplasia 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

184 Pyridine, NTP TR 470 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Genital System (continued) 

Preputial gland (50) (48) (50) (50) 

Atrophy 1 (2%) 

Hyperplasia, squamous 1 (2%) 

Inflammation, chronic 2 (4%) 2 (4%) 3 (6%) 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Inflammation, suppurative 12 (24%) 9 (19%) 10 (20%) 3 (6%) 

Duct, cyst 49 (98%) 43 (90%) 46 (92%) 48 (96%) 

Prostate (50) (49) (50) (50) 

Fibrosis 2 (4%) 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 

Hyperplasia 4 (8%) 4 (8%) 1 (2%) 2 (4%) 

Inflammation, acute 4 (8%) 1 (2%) 

Inflammation, chronic 3 (6%) 4 (8%) 5 (10%) 2 (4%) 

Inflammation, chronic active 5 (10%) 5 (10%) 2 (4%) 2 (4%) 

Artery, mineralization 1 (2%) 

Seminal vesicle (49) (49) (50) (49) 

Cyst 1 (2%) 

Hyperplasia 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 

Artery, mineralization 1 (2%) 

Testes (50) (49) (49) (50) 

Atrophy 20 (40%) 20 (41%) 18 (37%) 9 (18%) 

Congestion 1 (2%) 

Inflammation, granulomatous 1 (2%) 1 (2%) 

Mineralization 6 (12%) 2 (4%) 9 (18%) 4 (8%) 

Artery, inflammation 24 (48%) 24 (49%) 14 (29%) 11 (22%) 

Artery, mineralization 3 (6%) 2 (4%) 

Interstitial cell, hyperplasia 3 (6%) 4 (8%) 7 (14%) 7 (14%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Atrophy 1 (2%) 1 (2%) 

Erythroid cell, hyperplasia 1 (2%) 

Myeloid cell, hyperplasia 2 (4%) 1 (2%) 1 (2%) 

Lymph node (31) (44) (38) (32) 

Ectasia 2 (6%) 1 (2%) 

Hemorrhage 2 (6%) 1 (2%) 

Hyperplasia, plasma cell 2 (6%) 

Iliac, ectasia 5 (16%) 3 (7%) 3 (8%) 1 (3%) 

Iliac, hemorrhage 1 (3%) 2 (5%) 2 (5%) 3 (9%) 

Iliac, hyperplasia, lymphoid 1 (2%) 2 (5%) 1 (3%) 

Iliac, hyperplasia, plasma cell 4 (9%) 2 (5%) 2 (6%) 

Inguinal, atrophy 1 (3%) 

Inguinal, ectasia 1 (3%) 1 (3%) 

Inguinal, hemorrhage 1 (2%) 1 (3%) 1 (3%) 

Inguinal, hyperplasia, lymphoid 1 (3%) 

Inguinal, infiltration cellular, histiocyte 1 (3%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 185 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Hematopoietic System (continued) 

Lymph node (continued) (31) (44) (38) (32) 

Mediastinal, atrophy 1 (2%) 

Mediastinal, congestion 1 (3%) 3 (7%) 2 (5%) 1 (3%) 

Mediastinal, ectasia 6 (19%) 12 (27%) 9 (24%) 6 (19%) 

Mediastinal, hemorrhage 8 (26%) 15 (34%) 10 (26%) 9 (28%) 

Mediastinal, hyperplasia, lymphoid 1 (3%) 

Mediastinal, hyperplasia, plasma cell 2 (5%) 1 (3%) 1 (3%) 

Pancreatic, ectasia 2 (6%) 5 (11%) 1 (3%) 

Pancreatic, hemorrhage 4 (13%) 5 (11%) 4 (11%) 7 (22%) 

Pancreatic, hyperplasia, lymphoid 2 (6%) 1 (2%) 4 (13%) 

Pancreatic, hyperplasia, plasma cell 1 (3%) 2 (5%) 2 (6%) 

Pancreatic, pigmentation 1 (3%) 

Renal, ectasia 15 (48%) 20 (45%) 16 (42%) 10 (31%) 

Renal, fibrosis 2 (5%) 

Renal, hemorrhage 10 (32%) 17 (39%) 19 (50%) 12 (38%) 

Renal, hyperplasia, lymphoid 1 (3%) 2 (6%) 

Renal, hyperplasia, plasma cell 1 (2%) 6 (16%) 2 (6%) 

Renal, pigmentation 3 (8%) 

Lymph node, mandibular (48) (49) (47) (48) 

Congestion 5 (10%) 1 (2%) 4 (8%) 

Ectasia 15 (31%) 8 (16%) 10 (21%) 10 (21%) 

Hemorrhage 3 (6%) 1 (2%) 3 (6%) 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 

Hyperplasia, plasma cell 4 (8%) 8 (16%) 6 (13%) 4 (8%) 

Lymph node, mesenteric (46) (50) (50) (50) 

Atrophy 6 (12%) 1 (2%) 2 (4%) 

Ectasia 5 (11%) 6 (12%) 6 (12%) 5 (10%) 

Hemorrhage 12 (26%) 14 (28%) 12 (24%) 12 (24%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 2 (4%) 5 (10%) 

Hyperplasia, plasma cell 2 (4%) 1 (2%) 

Spleen (49) (50) (49) (49) 

Angiectasis 1 (2%) 

Atrophy 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Congestion 1 (2%) 1 (2%) 

Fibrosis 1 (2%) 1 (2%) 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 2 (4%) 2 (4%) 

Hyperplasia, lymphoid 1 (2%) 

Necrosis 1 (2%) 

Artery, mineralization 1 (2%) 1 (2%) 

Thymus (48) (49) (49) (50) 

Atrophy 15 (31%) 29 (59%) 28 (57%) 24 (48%) 

Cyst 5 (10%) 6 (12%) 4 (8%) 6 (12%) 

Ectopic parathyroid gland 3 (6%) 5 (10%) 1 (2%) 1 (2%) 

Ectopic thyroid 1 (2%) 

Fibrosis 1 (2%) 

Hemorrhage 8 (17%) 6 (12%) 8 (16%) 14 (28%) 

Hyperplasia, lymphoid 1 (2%) 

Hyperplasia, squamous 2 (4%) 

Artery, mineralization 1 (2%) 

Epithelial cell, hyperplasia 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

186 Pyridine, NTP TR 470 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Integumentary System 

Mammary gland (48) (46) (44) (46) 

Cyst 2 (4%) 1 (2%) 

Hyperplasia 4 (8%) 2 (5%) 4 (9%) 

Artery, mineralization 3 (6%) 5 (11%) 

Duct, dilatation 6 (13%) 7 (15%) 5 (11%) 4 (9%) 

Skin (50) (50) (50) (50) 

Cyst 1 (2%) 2 (4%) 1 (2%) 

Hyperkeratosis 1 (2%) 

Hyperplasia, squamous 2 (4%) 1 (2%) 2 (4%) 

Inflammation, chronic 1 (2%) 2 (4%) 1 (2%) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Ulcer 1 (2%) 1 (2%) 2 (4%) 

Hair follicle, cyst 1 (2%) 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Fibrous osteodystrophy 10 (20%) 21 (42%) 16 (32%) 6 (12%) 

Inflammation, chronic active 1 (2%) 

Osteosclerosis 1 (2%) 

Cartilage, degeneration 1 (2%) 

Cranium, fibrous osteodystrophy 10 (20%) 15 (30%) 13 (26%) 2 (4%) 

Joint, arthrosis 1 (2%) 

Joint, fibrosis 1 (2%) 

Joint, inflammation, chronic 1 (2%) 1 (2%) 

Mandible, hyperplasia 1 (2%) 

Metacarpal, inflammation, chronic active 1 (2%) 

Metatarsal, hyperplasia 1 (2%) 

Metatarsal, inflammation, chronic active 1 (2%) 

Periosteum, hyperplasia 1 (2%) 

Rib, callus 1 (2%) 

Vertebra, fibrous osteodystrophy 4 (8%) 2 (4%) 

Vertebra, inflammation, chronic 1 (2%) 

Nervous System 

Brain (50) (49) (50) (50) 

Degeneration 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 

Hydrocephalus 1 (2%) 1 (2%) 

Peripheral nerve (1) (4) (2) (5) 

Degeneration 1 (100%) 

Mineralization 2 (50%) 2 (100%) 

Radicular neuropathy 4 (100%) 1 (50%) 2 (40%) 
 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 187 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Respiratory System 

Lung (50) (50) (50) (50) 

Congestion 4 (8%) 2 (4%) 4 (8%) 

Edema 2 (4%) 

Hemorrhage 2 (4%) 1 (2%) 10 (20%) 7 (14%) 

Inflammation, acute 1 (2%) 3 (6%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Inflammation, granulomatous 4 (8%) 1 (2%) 5 (10%) 2 (4%) 

Mineralization 1 (2%) 

Necrosis 1 (2%) 1 (2%) 

Alveolar epithelium, hyperplasia 1 (2%) 2 (4%) 

Alveolar epithelium, hypertrophy 1 (2%) 

Alveolus, infiltration cellular, histiocyte 8 (16%) 5 (10%) 4 (8%) 

Alveolus, mineralization 2 (4%) 

Artery, mineralization 2 (4%) 3 (6%) 

Bronchus, inflammation, acute 1 (2%) 

Bronchus, mineralization 1 (2%) 

Interstitium, fibrosis 4 (8%) 6 (12%) 4 (8%) 1 (2%) 

Interstitium, inflammation, chronic 2 (4%) 

Nose (50) (50) (50) (50) 

Cyst 1 (2%) 

Erosion 1 (2%) 

Foreign body 11 (22%) 4 (8%) 6 (12%) 1 (2%) 

Hemorrhage 3 (6%) 1 (2%) 

Hyperplasia, squamous 1 (2%) 

Inflammation, acute 7 (14%) 7 (14%) 4 (8%) 2 (4%) 

Inflammation, chronic 7 (14%) 1 (2%) 2 (4%) 1 (2%) 

Inflammation, chronic active 4 (8%) 6 (12%) 5 (10%) 6 (12%) 

Metaplasia, squamous 1 (2%) 1 (2%) 2 (4%) 

Thrombosis 1 (2%) 

Ulcer 2 (4%) 

Artery, thrombosis 1 (2%) 

Olfactory epithelium, hyperplasia 1 (2%) 

Olfactory epithelium, metaplasia 1 (2%) 

Respiratory epithelium, hyperplasia 20 (40%) 9 (18%) 12 (24%) 15 (30%) 

Respiratory epithelium, metaplasia 1 (2%) 

Respiratory epithelium, metaplasia, squamous 1 (2%) 

Trachea (50) (50) (50) (50) 

Cyst 1 (2%) 

Foreign body 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic active 1 (2%) 

Special Senses System 

Eye (1) 

Cornea, ulcer 1 (100%) 

Harderian gland (1) (4) (1) 

Inflammation, chronic 1 (100%) 

Lacrimal gland (1) 

Atrophy 1 (100%) 
 

188 Pyridine, NTP TR 470 

TABLE C4 

Summary of the Incidence of Nonneoplastic Lesions in Male Wistar Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Urinary System 

Kidney (50) (50) (50) (50) 

Congestion 4 (8%) 2 (4%) 

Cyst 21 (42%) 31 (62%) 19 (38%) 16 (32%) 

Hydronephrosis 19 (38%) 20 (40%) 30 (60%) 15 (30%) 

Inflammation, acute 2 (4%) 1 (2%) 

Mineralization 8 (16%) 17 (34%) 8 (16%) 5 (10%) 

Nephropathy 50 (100%) 50 (100%) 50 (100%) 50 (100%) 

Artery, mineralization 5 (10%) 8 (16%) 3 (6%) 

Renal tubule, accumulation, hyaline droplet 1 (2%) 1 (2%) 

Renal tubule, hyperplasia 6 (12%) 17 (34%) 8 (16%) 5 (10%) 

Vein, thrombosis 2 (4%) 1 (2%) 3 (6%) 

Urinary bladder (47) (49) (47) (44) 

Dilatation 1 (2%) 

Edema 1 (2%) 

Hemorrhage 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 

Ulcer 1 (2%) 

Artery, mineralization 1 (2%) 

Transitional epithelium, hyperplasia 1 (2%) 3 (6%) 1 (2%) 
189 

APPENDIX D 

SUMMARY OF LESIONS IN MALE MICE 

IN THE 2-YEAR DRINKING WATER STUDY 

OF PYRIDINE 

TABLE D1 Summary of the Incidence of Neoplasms in Male Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 

TABLE D2 Individual Animal Tumor Pathology of Male Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 

TABLE D3 Statistical Analysis of Primary Neoplasms in Male Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 

TABLE D4 Historical Incidence of Liver Neoplasms in Untreated Male B6C3F1 Mice . . . . . . . . . . . . . 221 

TABLE D5 Summary of the Incidence of Nonneoplastic Lesions in Male Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 
190 Pyridine, NTP TR 470
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 191 

TABLE D1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 2 1 1 3 

Moribund 2 3 3 1 

Natural deaths 11 18 11 11 

Survivors 

Other 1 

Terminal sacrifice 35 28 34 35 

Animals examined microscopically 50 50 49 50 

Alimentary System 

Intestine small, duodenum (43) (44) (43) (44) 

Intestine small, jejunum (40) (46) (42) (44) 

Carcinoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Liver (50) (50) (49) (50) 

Hemangioma 1 (2%) 

Hemangiosarcoma 1 (2%) 

Hemangiosarcoma, multiple 2 (4%) 

Hepatoblastoma 1 (2%) 14 (28%) 16 (33%) 13 (26%) 

Hepatoblastoma, multiple 1 (2%) 4 (8%) 6 (12%) 2 (4%) 

Hepatocellular carcinoma 12 (24%) 16 (32%) 15 (31%) 22 (44%) 

Hepatocellular carcinoma, multiple 3 (6%) 19 (38%) 26 (53%) 18 (36%) 

Hepatocellular adenoma 13 (26%) 11 (22%) 5 (10%) 11 (22%) 

Hepatocellular adenoma, multiple 16 (32%) 29 (58%) 29 (59%) 28 (56%) 

Hepatocholangiocarcinoma, multiple 1 (2%) 

Histiocytic sarcoma 1 (2%) 2 (4%) 

Mast cell tumor malignant, metastatic, skin 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Mesentery (2) (7) (6) (4) 

Hepatocholangiocarcinoma, metastatic, liver 1 (14%) 

Histiocytic sarcoma 1 (14%) 

Sarcoma 1 (14%) 1 (17%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (25%) 

Pancreas (49) (50) (48) (50) 

Squamous cell carcinoma, metastatic, 

 uncertain primary site 1 (2%) 

Stomach, forestomach (49) (50) (48) (49) 

Squamous cell papilloma 1 (2%) 

Stomach, glandular (49) (50) (48) (47) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Cardiovascular System 

Heart (50) (50) (49) (50) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

192 Pyridine, NTP TR 470 

TABLE D1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Endocrine System 

Adrenal cortex (49) (49) (49) (49) 

Adenoma 1 (2%) 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Capsule, adenoma 2 (4%) 

Capsule, sarcoma, metastatic, mesentery 1 (2%) 

Capsule, squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Adrenal medulla (48) (48) (49) (49) 

Pheochromocytoma benign 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Islets, pancreatic (49) (50) (48) (50) 

Adenoma 1 (2%) 2 (4%) 1 (2%) 

Thyroid gland (49) (50) (49) (50) 

Follicular cell, adenoma 2 (4%) 2 (4%) 1 (2%) 2 (4%) 

Follicular cell, adenoma, multiple 1 (2%) 

General Body System 

Peritoneum (1) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (100%) 

Tissue NOS (1) 

Thoracic, hemangiosarcoma 1 (100%) 

Genital System 

Coagulating gland (1) 

Sarcoma, metastatic, mesentery 1 (100%) 

Epididymis (50) (50) (49) (50) 

Sarcoma 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Preputial gland (50) (50) (49) (49) 

Sarcoma, metastatic, mesentery 1 (2%) 

Prostate (50) (48) (48) (49) 

Sarcoma, metastatic, mesentery 1 (2%) 

Seminal vesicle (49) (49) (49) (50) 

Sarcoma, metastatic, mesentery 1 (2%) 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Testes (50) (50) (49) (50) 

Sarcoma, metastatic, mesentery 1 (2%) 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Hematopoietic System 

Bone marrow (49) (50) (49) (50) 

Hemangiosarcoma 1 (2%) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Mast cell tumor malignant, metastatic, skin 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 193 

TABLE D1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Hematopoietic System (continued) 

Lymph node (2) (4) (4) (2) 

Mediastinal, hepatocholangiocarcinoma,

 metastatic, liver 1 (25%) 

Mediastinal, sarcoma, metastatic, mesentery 1 (25%) 1 (25%) 

Mediastinal, squamous cell carcinoma,

 metastatic, uncertain primary site 1 (50%) 

Lymph node, mandibular (48) (47) (48) (50) 

Mast cell tumor malignant, metastatic, skin 1 (2%) 

Squamous cell carcinoma, metastatic, skin 1 (2%) 

Lymph node, mesenteric (43) (47) (44) (50) 

Hemangioma 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Spleen (49) (50) (47) (49) 

Hemangiosarcoma 1 (2%) 3 (6%) 1 (2%) 1 (2%) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Mast cell tumor malignant, metastatic, skin 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Thymus (46) (46) (39) (47) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Sarcoma, metastatic, mesentery 1 (3%) 

Integumentary System 

Skin (49) (50) (48) (50) 

Squamous cell carcinoma 1 (2%) 

Subcutaneous tissue, basal cell adenoma 1 (2%) 

Subcutaneous tissue, hemangioma 1 (2%) 1 (2%) 

Subcutaneous tissue, hemangiosarcoma 1 (2%) 

Subcutaneous tissue, histiocytic sarcoma 1 (2%) 

Subcutaneous tissue, mast cell tumor

 malignant 1 (2%) 

Musculoskeletal System 

Skeletal muscle (3) (2) (1) 

Hepatoblastoma, metastatic, liver 1 (33%) 

Sarcoma, metastatic, mesentery 1 (33%) 1 (50%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (100%) 

Nervous System 

Brain (50) (50) (49) (50) 

Histiocytic sarcoma 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

194 Pyridine, NTP TR 470 

TABLE D1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Respiratory System 

Lung (49) (50) (49) (50) 

Alveolar/bronchiolar adenoma 10 (20%) 5 (10%) 7 (14%) 6 (12%) 

Alveolar/bronchiolar adenoma, multiple 2 (4%) 1 (2%) 2 (4%) 

Alveolar/bronchiolar carcinoma 1 (2%) 2 (4%) 1 (2%) 1 (2%) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Hepatoblastoma, metastatic, liver 4 (8%) 7 (14%) 3 (6%) 

Hepatocellular carcinoma, metastatic, liver 7 (14%) 7 (14%) 11 (22%) 13 (26%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Mediastinum, hepatocellular carcinoma,

 metastatic, liver 1 (2%) 

Mediastinum, hepatocholangiocarcinoma,

 metastatic, liver 1 (2%) 

Nose (50) (49) (49) (50) 

Special Senses System 

Harderian gland (5) (1) 

Adenoma 3 (60%) 1 (100%) 

Carcinoma 2 (40%) 

Urinary System 

Kidney (49) (50) (48) (50) 

Hemangiosarcoma, metastatic, tissue NOS 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Mast cell tumor malignant, metastatic, skin 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Renal tubule, adenoma 1 (2%) 1 (2%) 

Urinary bladder (48) (49) (44) (50) 

Hemangioma 1 (2%) 

Squamous cell carcinoma, metastatic,

 uncertain primary site 1 (2%) 

Transitional epithelium, papilloma 1 (2%) 

Systemic Lesions 

Multiple organsb (50) (50) (49) (50) 

Histiocytic sarcoma 1 (2%) 2 (4%) 1 (2%) 

Lymphoma malignant 3 (6%) 3 (6%) 3 (6%) 1 (2%) 

Mesothelioma malignant 1 (2%) 1 (2%) 
195 

c 

Pyridine, NTP TR 470 

TABLE D1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Neoplasm Summary 

Total animals with primary neoplasmsc 43 49 48 47 

Total primary neoplasms 79 122 122 114 

Total animals with benign neoplasms 35 42 36 39 

Total benign neoplasms 51 53 49 54 

Total animals with malignant neoplasms 22 46 47 42 

Total malignant neoplasms 28 69 73 60 

Total animals with metastatic neoplasms 8 12 19 14 

Total metastatic neoplasms 8 30 35 30 

Total animals with malignant neoplasms

 of uncertain primary site 1 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

196 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

1 5 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 2 4 7 9 2 3 3 3 5 6 7 7 0 1 2 2 2 2 2 2 2 2 2 2 

8 0 2 4 8 1 3 7 9 3 3 0 2 6 4 2 2 2 2 2 2 2 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 1 3 4 2 3 0 1 4 0 3 2 2 2 2 3 1 1 1 1 1 1 1 2 2 2 

2 7 0 5 2 5 7 3 1 0 7 1 3 4 4 1 3 4 5 6 8 9 0 2 6 

Alimentary System 

Esophagus +++++++++++ +++A++++++++++ 

Gallbladder +M+ + + + + +AA+ AA+A+ + + + +M+ + + + 

Intestine large, colon +++++++++++A++A++++++++++ 

Intestine large, rectum +++++++++++A+A+++++++++++ 

Intestine large, cecum + + + + + +A+ + ++ + +AA+ + + + + + + + + + 

Intestine small, duodenum A + + + A + + + + A+ AMAA + + + + + + + + + + 

Intestine small, jejunum A + + + A + AAAA+ AAAA ++++++++++ 

Intestine small, ileum A+ + +A+A+AA+ A+AA+ + + + + + + + + + 

Liver +++++++++++ ++++++++++++++ 

Hemangiosarcoma X 

Hepatoblastoma 

Hepatoblastoma, multiple 

Hepatocellular carcinoma X X X X X 

Hepatocellular carcinoma, multiple X XX 

Hepatocellular adenoma X X X XX X 

Hepatocellular adenoma, multiple X X XX X 

Histiocytic sarcoma X 

Mesentery 

Oral mucosa + 

Pancreas +++++++++++ +++A++++++++++ 

Salivary glands + + + + + + + + + ++M+ +A+ + + + + + + + + + 

Stomach, forestomach +++++++++++ +++A++++++++++ 

Squamous cell papilloma 

Stomach, glandular +++++++++++ +++A++++++++++ 

Tongue 

Tooth ++++++ +++ +++ +++ + +++ 

Cardiovascular System 

Blood vessel +++++++++++ ++++++++++++++ 

Heart +++++++++++ ++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++ +++A++++++++++ 

Adenoma 

Capsule, adenoma X 

Adrenal medulla + + + + + + + +M++ + + +A+ + + + + + + + + + 

Islets, pancreatic +++++++++++ +++A++++++++++ 

Parathyroid gland + + M + M + + + M + + + + + AM + MMM + + + MM 

Pituitary gland + + + + + + + + +M+ + + I A + + + + + + +M+ + 

Thyroid gland +++++++++++ +++A++++++++++ 

Follicular cell, adenoma X X 

General Body System 

None 

Genital System 

Epididymis +++++++++++ ++++++++++++++ 

Preputial gland +++++++++++ ++++++++++++++ 

Prostate +++++++++++ ++++++++++++++ 

Seminal vesicle +++++++++++ +++A++++++++++ 

Testes +++++++++++ ++++++++++++++ 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 197 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 2 2 4 4 4 4 4 4 4 4 5 0 0 0 0 0 0 0 1 3 3 3 3 3 3 Tissues/ 

8 9 1 2 4 5 6 7 8 9 0 2 3 4 6 7 8 9 0 1 3 5 6 8 9 Tumors 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 49 

Gallbladder +++++++++++ ++++++++++++++ 43 

Intestine large, colon +++++++++++ ++++++++++++++ 48 

Intestine large, rectum +++++++++++ ++++++++++++++ 48 

Intestine large, cecum +++++++++++ ++++++++++++++ 47 

Intestine small, duodenum +++++++++++ ++++++++++++++ 43 

Intestine small, jejunum +++++++++++ ++++++++++++++ 40 

Intestine small, ileum +++++++++++ ++++++++++++++ 42 

Liver +++++++++++ ++++++++++++++ 50 

Hemangiosarcoma 1 

Hepatoblastoma X 1 

Hepatoblastoma, multiple X 1 

Hepatocellular carcinoma X XXXXX X 12 

Hepatocellular carcinoma, multiple 3 

Hepatocellular adenoma X XXXX X X 13 

Hepatocellular adenoma, multiple X X X X X X X X X X X 16 

Histiocytic sarcoma 1 

Mesentery + + 2 

Oral mucosa 1 

Pancreas +++++++++++ ++++++++++++++ 49 

Salivary glands +++++++++++ ++++++++++++++ 48 

Stomach, forestomach +++++++++++ ++++++++++++++ 49 

Squamous cell papilloma X 1 

Stomach, glandular +++++++++++ ++++++++++++++ 49 

Tongue + 1 

Tooth +++++ +++++ +++++++++++ ++ 42 

Cardiovascular System 

Blood vessel 

Heart 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

50 

50 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 49 

Adenoma X 1 

Capsule, adenoma X 2 

Adrenal medulla +++++++++++ ++++++++++++++ 48 

Islets, pancreatic +++++++++++ ++++++++++++++ 49 

Parathyroid gland + MM + + + + MM +M + M + + + + M + + + + M + M 31 

Pituitary gland +++++++++++ ++++++++++++++ 46 

Thyroid gland +++++++++++ ++++++++++++++ 49 

Follicular cell, adenoma 2 

General Body System 

None 

Genital System 

Epididymis 

Preputial gland 

Prostate 

Seminal vesicle 

Testes 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

50 

50 

50 

49 

50 
 

 

 

 

 

 

 

 

 

 

 

 

 

198 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

1 5 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 2 4 7 9 2 3 3 3 5 6 7 7 0 1 2 2 2 2 2 2 2 2 2 2 

8 0 2 4 8 1 3 7 9 3 3 0 2 6 4 2 2 2 2 2 2 2 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 1 3 4 2 3 0 1 4 0 3 2 2 2 2 3 1 1 1 1 1 1 1 2 2 2 

2 7 0 5 2 5 7 3 1 0 7 1 3 4 4 1 3 4 5 6 8 9 0 2 6 

Hematopoietic System 

Bone marrow +++++++++++ +++A++++++++++ 

Histiocytic sarcoma 

Lymph node 

Lymphn ode, mandibular 

Squamous cell carcinoma, metastatic, skin 

Lymphn ode, mesenteric 

Spleen 

Hemangiosarcoma 

Thymus 

X 

+ + 

+ + + + + + + + + ++M+ +A+ + + + + + + + + + 

X 

+ + + + + +M+M+ + A +MA + + + + + + + + + + 

+++++++++++ +++A++++++++++ 

+ + + + + + + + +M+ M+ + A + + + + + + +M+ + 

Integumentary System 

Mammary gland 

Skin 

MMMMMMMMMMM MMMMMMMMM + MM + M 

+++++++++++ +++A++++++++++ 

Squamous cell carcinoma 

Subcutaneous tissue, hemangiosarcoma 

X 

X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Nervous System 

Brain +++++++++++ ++++++++++++++ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic, liver 

Nose 

+++++++++++ +++A++++++++++ 

X X X X X X X 

X 

XX XX 

+++++++++++ ++++++++++++++ 

Trachea +++++++++++ +++A++++++++++ 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

M + 

X 

+ 

X 

Carcinoma 

Urinary System 

Kidney 

Urinaryb ladder 

Transitional epithelium, papilloma 

+++++++++++ +++A++++++++++ 

++++++++A++ +++A++++++++++ 

X 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Lymphoma malignant 

+++++++++++ ++++++++++++++ 

X 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 199 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 2 2 4 4 4 4 4 4 4 4 5 0 0 0 0 0 0 0 1 3 3 3 3 3 3 

8 9 1 2 4 5 6 7 8 9 0 2 3 4 6 7 8 9 0 1 3 5 6 8 9 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow +++++++++++ ++++++++++++++ 49 

Histiocytic sarcoma 

Lymph node 

Lymphn ode, mandibular 

Squamous cell carcinoma, metastatic, skin 

Lymphn ode, mesenteric 

Spleen 

Hemangiosarcoma 

Thymus 

+++++++++++ ++++++++++++++ 

+ + + + + + +M+ ++ + + + + + +M+ + + + + + + 

+++++++++++ ++++++++++++++ 

X 

+++++++++++ ++++++++++++++ 

1 

2 

48 

1 

43 

49 

1 

46 

Integumentary System 

Mammary gland 

Skin 

M + MMMMMMMMM + M + MMMMMMMMMMM

+++++++++++ ++++++++++++++ 

5 

49 

Squamous cell carcinoma 

Subcutaneous tissue, hemangiosarcoma 

1 

1 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 50 

Nervous System 

Brain +++++++++++ ++++++++++++++ 50 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic, liver 

Nose 

+++++++++++ ++++++++++++++ 

X X X 

X X 

X X X 

+++++++++++ ++++++++++++++ 

49 

10 

2 

1 

7 

50 

Trachea +++++++++++ ++++++++++++++ 49 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

+ + 

X 

+ 

+ 

1 

5 

3 

Carcinoma X X 2 

Urinary System 

Kidney 

Urinaryb ladder 

Transitional epithelium, papilloma 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

49 

48 

1 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Lymphoma malignant 

+++++++++++ ++++++++++++++ 

X X 

50 

1 

3 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

200 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

0 2 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 0 3 2 3 4 4 6 8 9 9 0 3 4 5 7 7 7 8 9 9 0 1 2 2 2 

8 7 2 2 6 9 1 7 1 5 8 8 5 0 4 6 7 0 2 6 2 5 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 7 7 6 6 9 8 7 7 9 8 5 5 8 7 8 5 6 6 6 7 6 8 5 5 5 

8 0 3 9 4 9 5 7 7 1 2 9 8 4 0 7 8 7 1 9 2 5 1 3 4 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 

Gallbladder + + + + MA + A + A + A A + + A A + A AMM + + + 

Intestine large, colon ++++A++++++ +++++++A++++++ 

Intestine large, rectum + + + + +A+M+A+ + + + + + + + + + + + + + + 

Intestine large, cecum + + + +AA+ + + ++ +A+ + +M+AA+ + + + + 

Intestine small, duodenum + + + +A+ + + + ++ +A+A+A+AA+ + + + + 

Intestine small, jejunum + + + +A+ + + + ++ + + + + + +AAA+ + + + + 

Intestine small, ileum + + +AAA+ + +A+ +A+ + + +AAA+A+ + + 

Liver +++++++++++ ++++++++++++++ 

Hemangioma 

Hemangiosarcoma, multiple X X 

Hepatoblastoma X X X XX X X 

Hepatoblastoma, multiple X X 

Hepatocellular carcinoma X X XX X X 

Hepatocellular carcinoma, multiple X X X X X X X X X 

Hepatocellular adenoma X X X X X 

Hepatocellular adenoma, multiple X X X X X X X X X X X 

Hepatocholangiocarcinoma, multiple X 

Histiocytic sarcoma X X 

Sarcoma, metastatic, mesentery X 

Mesentery ++ + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Histiocytic sarcoma X 

Sarcoma X 

Pancreas +++++++++++ ++++++++++++++ 

Salivary glands +++++++++++ ++++++++++++++ 

Stomach, forestomach +++++++++++ ++++++++++++++ 

Stomach, glandular +++++++++++ ++++++++++++++ 

Tooth + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + ++ + + + + +M+ + + + + + + + 

Heart +++++++++++ ++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Adrenal medulla + + + + + + + + + ++ + + + + + +M+ + + + + + + 

Pheochromocytoma benign 

Sarcoma, metastatic, mesentery X 

Islets, pancreatic +++++++++++ ++++++++++++++ 

Adenoma 

Parathyroid gland M + + + + + + M + + + + + + + + M + M + MM + + + 

Pituitary gland + + + + + + + + + ++ + +M+ + + + + + + + + + + 

Thyroid gland +++++++++++ ++++++++++++++ 

Follicular cell, adenoma X 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 201 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 Total 

Carcass ID Number 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 9 9 9 9 9 9 0 8 9 9 Tissues/ 

5 6 8 0 4 5 6 1 2 3 6 2 3 4 6 0 1 2 3 8 9 0 7 5 6 Tumors 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 50 

Gallbladder +M+ + + +M+ + ++M+ + + + +M+ + + +M+ + 33 

Intestine large, colon +++++++++++ ++++++++++++++ 48 

Intestine large, rectum +++++++++++ ++++++++++++++ 47 

Intestine large, cecum +++++++++++ ++++++++++++++ 44 

Intestine small, duodenum +++++++++++ ++++++++++++++ 44 

Intestine small, jejunum +++++++++++ ++++++++++++++ 46 

Intestine small, ileum +++++++++++ ++++++++++++++ 41 

Liver +++++++++++ ++++++++++++++ 50 

Hemangioma X 1 

Hemangiosarcoma, multiple 2 

Hepatoblastoma X X X X X X X 14 

Hepatoblastoma, multiple X X 4 

Hepatocellular carcinoma X X XXX XX XX X 16 

Hepatocellular carcinoma, multiple XXX X X X X X X X 19 

Hepatocellular adenoma X X X X X X 11 

Hepatocellular adenoma, multiple XXX XXXX X X XX XXXXXX X 29 

Hepatocholangiocarcinoma, multiple 1 

Histiocytic sarcoma 2 

Sarcoma, metastatic, mesentery 1 

Mesentery + + + 7 

Hepatocholangiocarcinoma, metastatic, liver 1 

Histiocytic sarcoma 1 

Sarcoma 1 

Pancreas +++++++++++ ++++++++++++++ 50 

Salivary glands +++++++++++ ++++++++++++++ 50 

Stomach, forestomach +++++++++++ ++++++++++++++ 50 

Stomach, glandular +++++++++++ ++++++++++++++ 50 

Tooth + ++ + + + 10 

Cardiovascular System 

Blood vessel 

Heart 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

49 

50 

Endocrine System 

Adrenal cortex + + + + + + + + + ++ +M+ + + + + + + + + + + + 49 

Sarcoma, metastatic, mesentery 1 

Adrenal medulla + + + + + + + + + ++ +M+ + + + + + + + + + + + 48 

Pheochromocytoma benign X 1 

Sarcoma, metastatic, mesentery 1 

Islets, pancreatic +++++++++++ ++++++++++++++ 50 

Adenoma X 1 

Parathyroid gland M + M + M + + + + + + + M + + + MMM + + + + MM 35 

Pituitary gland + + + + + +M+ + ++ + + + + + + + + + +M+ + + 47 

Thyroid gland +++++++++++ ++++++++++++++ 50 

Follicular cell, adenoma X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

202 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

0 2 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 0 3 2 3 4 4 6 8 9 9 0 3 4 5 7 7 7 8 9 9 0 1 2 2 2 

8 7 2 2 6 9 1 7 1 5 8 8 5 0 4 6 7 0 2 6 2 5 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 7 7 6 6 9 8 7 7 9 8 5 5 8 7 8 5 6 6 6 7 6 8 5 5 5 

8 0 3 9 4 9 5 7 7 1 2 9 8 4 0 7 8 7 1 9 2 5 1 3 4 

Genital System 

Coagulating gland + 

Sarcoma, metastatic, mesentery X 

Epididymis +++++++++++ ++++++++++++++ 

Sarcoma 

Sarcoma, metastatic, mesentery X 

Preputial gland +++++++++++ ++++++++++++++ 

Prostate + + + + + + + + + ++ + + + + + + + + + +M+ + + 

Seminal vesicle +++++++++++ ++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Testes +++++++++++ ++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Hematopoietic System 

Bone marrow +++++++++++ ++++++++++++++ 

Hemangiosarcoma X 

Hemangiosarcoma, metastatic, liver X 

Histiocytic sarcoma X 

Lymph node + + + + 

Mediastinal, hepatocholangiocarcinoma, 

metastatic, liver X 

Mediastinal, sarcoma, metastatic, mesentery X 

Lymph node, mandibular + +M+ + + + + + ++ + +M+ + + + + + + + + + + 

Lymph node, mesenteric + +M+M+ + + + ++ + + + + + + + + + + + + + + 

Hemangioma X 

Histiocytic sarcoma X 

Spleen +++++++++++ ++++++++++++++ 

Hemangiosarcoma X 

Hemangiosarcoma, metastatic, liver X 

Histiocytic sarcoma X 

Thymus + + + + + + + + + + M + + I + + + + + I + + + + + 

Hepatocellular carcinoma, metastatic, liver X 

Integumentary System 

Mammary gland MMMMMMMMM +MM + MMMMMMMMMMMM 

Skin +++++++++++ ++++++++++++++ 

Subcutaneous tissue, hemangioma X 

Subcutaneous tissue, histiocytic sarcoma X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Skeletal muscle + + + 

Hepatoblastoma, metastatic, liver X 

Sarcoma, metastatic, mesentery X 

Nervous System 

Brain +++++++++++ ++++++++++++++ 

Histiocytic sarcoma X 

Peripheral nerve + 

Spinal cord + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 203 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 Total 

Carcass ID Number 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 9 9 9 9 9 9 0 8 9 9 Tissues/ 

5 6 8 0 4 5 6 1 2 3 6 2 3 4 6 0 1 2 3 8 9 0 7 5 6 Tumors 

Genital System 

Coagulating gland 1 

Sarcoma, metastatic, mesentery 1 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma X 1 

Sarcoma, metastatic, mesentery 1 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + M + + + + + + + + + + + + + + + + + + + + + + + 48 

Seminal vesicle + M + + + + + + + + + + + + + + + + + + + + + + + 49 

Sarcoma, metastatic, mesentery 1 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, mesentery 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Hemangiosarcoma, metastatic, liver 1 

Histiocytic sarcoma 1 

Lymph node 4 

Mediastinal, hepatocholangiocarcinoma, 

metastatic, liver 1 

Mediastinal, sarcoma, metastatic, mesentery 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + M + + + + + 47 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + M + 47 

Hemangioma 1 

Histiocytic sarcoma 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X X 3 

Hemangiosarcoma, metastatic, liver 1 

Histiocytic sarcoma 1 

Thymus + + + + + + + + + + + + + + + + + + + + + + M + + 46 

Hepatocellular carcinoma, metastatic, liver 1 

Integumentary System 

Mammary gland MMMMMMMMMMM MMMMM + MMMMMMMM 3 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Subcutaneous tissue, hemangioma 1 

Subcutaneous tissue, histiocytic sarcoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle 3 

Hepatoblastoma, metastatic, liver 1 

Sarcoma, metastatic, mesentery 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Peripheral nerve 1 

Spinal cord 1 
 

 

 

 

 

 

204 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

0255555555666666666677777 

Number of Days on Study 0323446899034577789901222 

8722691715885046702625222 

0000000000000000000000000 

Carcass ID Number 7766987798558785666768555 

8039495771298407871925134 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar carcinoma 

Hemangiosarcoma, metastatic, liver

Hepatoblastoma, metastatic, liver

Hepatocellular carcinoma, metastatic, liver

Hepatocholangiocarcinoma, metastatic, liver

Histiocytic sarcoma 

Mediastinum, hepatocellular 

carcinoma, metastatic, liver 

Mediastinum, hepatocholangiocarcinoma, 

metastatic, liver

Nose 

+++++++++++++++++++++++++ 

X X 

X 

X X X 

 XX X X X 

X 

X 

X 

X 

+ + + + + + + + + + + + + + + + + + A+ + + + + + 

Trachea +++++++++++++++++++++++++ 

Special Senses System 

None 

Urinary System 

Kidney 

Histiocytic sarcoma

Renal tubule, adenoma 

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+++++++++++++++++++++++++ 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma

Lymphoma malignant

+++++++++++++++++++++++++ 

X X 

X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 205 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222333 

Carcass ID Number 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar carcinoma

Hemangiosarcoma, metastatic, liver 

Hepatoblastoma, metastatic, liver

Hepatocellular carcinoma, metastatic, liver

Hepatocholangiocarcinoma, metastatic, liver 

Histiocytic sarcoma 

Mediastinum, hepatocellular 

carcinoma, metastatic, liver 

Mediastinum, hepatocholangiocarcinoma, 

metastatic, liver 

Nose 

Trachea 

Special Senses System 

None 

0000000000000000000001000 

5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 9 9 9 9 9 9 0 8 9 9 T

5 6 8 0 4 5 6 1 2 3 6 2 3 4 6 0 1 2 3 8 9 0 7 5 6 T

+++++++++++++++++++++++++ 

X X X 

X X 

X 

X X 

1 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Total 

issues/ 

umors 

50 

5 

2 

1 

4 

7 

1 

1 

1 

49 

50 

Urinary System 

Kidney 

Histiocytic sarcoma 

Renal tubule, adenoma

Urinary bladder 

+++++++++++++++++++++++++ 

X 

+ M+ + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

1 

49 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Lymphoma malignant 

+++++++++++++++++++++++++ 50 

2 

3 
 

 

 

 

 

 

206 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

025555666666667777777777 

Number of Days on Study 021128233445660222222222 

363466307237148222222222 

111111111111111111111111 

Carcass ID Number 220122023341300000011111 

401667356185754267801234 

Alimentary System 

Esophagus ++++++++++++++++++++++++ 

Gallbladder + + A + A MA + + MA A A M + + + + + M+ + + + 

Intestine large, colon + + + + AA+ + + + A+ + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + A M+ + + + + + + + + + + + 

Intestine large, cecum + + A + + A + + + MA + AAA+ + + + + + + + + 

Intestine small, duodenum + + A+ AA+ + + + A+ AA+ + + + + + + + + + 

Intestine small, jejunum + + A + A + + + + AA+ AA+ + + + + + + + + + 

Histiocytic sarcoma 

Intestine small, ileum + + + + AA+ + + + A+ AAA+ + + + + + + + + 

Liver ++++++++++++++++++++++++ 

Hepatoblastoma X X X X X X X 

Hepatoblastoma, multiple X X X X 

Hepatocellular carcinoma X XX X X X XX 

Hepatocellular carcinoma, multiple XX XX X X X XX 

Hepatocellular adenoma X X X 

Hepatocellular adenoma, multiple X X XX X XXX XXX 

Mast cell tumor malignant,

 metastatic, skin 

Mesentery + + + + 

Sarcoma X 

Pancreas + + + + + + + + + + A+ + + + + + + + + + + + + 

Salivary glands ++++++++++++++++++++++++ 

Stomach, forestomach + + + + + + + + + + A+ + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + A+ + + + + + + + + + + + + 

Tooth 

Cardiovascular System 

Blood vessel MM+ + + + + + + + + + + + + + + + + + + + + + 

Heart ++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex ++++++++++++++++++++++++ 

Capsule, sarcoma, metastatic, mesentery X 

Adrenal medulla ++++++++++++++++++++++++ 

Islets, pancreatic + + + + + + + + + + A+ + + + + + + + + + + + + 

Adenoma X X 

Parathyroid gland + + + + + + M+ + + + + + M+ + + + + + M+ + M 

Pituitary gland + + + + + + M+ + + I + + + + + + + + + + + + + 

Thyroid gland ++++++++++++++++++++++++ 

Follicular cell, adenoma 

Follicular cell, adenoma, multiple 

General Body System 

Tissue NOS + 

Thoracic, hemangiosarcoma X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 207 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

1111111111111111111111111 Total 

Carcass ID Number 1112222233333334444444445 Tissues/ 

7891238902345890123456790 Tumors 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 49 

Gallbladder M+ MM+ MM+ + + + MA M+ + + + + + + + + + M 30 

Intestine large, colon +++++++++++++++++++++++++ 46 

Intestine large, rectum +++++++++++++++++++++++++ 47 

Intestine large, cecum +++++++++++++++++++++++++ 42 

Intestine small, duodenum +++++++++++++++++++++++++ 43 

Intestine small, jejunum + + + + + + + + + + + + A+ + + + + + + + + + + + 42 

Histiocytic sarcoma X 1 

Intestine small, ileum +++++++++++++++++++++++++ 43 

Liver +++++++++++++++++++++++++ 49 

Hepatoblastoma X X XX XX X XX 16 

Hepatoblastoma, multiple XX 6 

Hepatocellular carcinoma X X X X X X X 15 

Hepatocellular carcinoma, multiple XX XX XXXXXXXX X X X XX 26 

Hepatocellular adenoma X X 5 

Hepatocellular adenoma, multiple XX X XXXXXXXXXXXXXXX 29 

Mast cell tumor malignant, 

metastatic, skin X 1 

Mesentery + + 6 

Sarcoma 1 

Pancreas +++++++++++++++++++++++++ 48 

Salivary glands +++++++++++++++++++++++++ 49 

Stomach, forestomach +++++++++++++++++++++++++ 48 

Stomach, glandular +++++++++++++++++++++++++ 48 

Tooth + 1 

Cardiovascular System 

Blood vessel +++++++++++++++++++++++++ 47 

Heart +++++++++++++++++++++++++ 49 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 49 

Capsule, sarcoma, metastatic, mesentery 1 

Adrenal medulla +++++++++++++++++++++++++ 49 

Islets, pancreatic +++++++++++++++++++++++++ 48 

Adenoma 2 

Parathyroid gland + + + M+ M+ + + + + + + + + + + + M+ M+ + M+ 40 

Pituitary gland + + M+ + + + + + + + + M+ + + + + + + + + + + + 45 

Thyroid gland +++++++++++++++++++++++++ 49 

Follicular cell, adenoma X 1 

Follicular cell, adenoma, multiple X 1 

General Body System 

Tissue NOS 1 

Thoracic, hemangiosarcoma 1 
 

 

 

 

 

 

 

 

 

208 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

025555666666667777777777 

Number of Days on Study 021128233445660222222222 

363466307237148222222222 

111111111111111111111111 

Carcass ID Number 220122023341300000011111 

401667356185754267801234 

Genital System 

Epididymis ++++++++++++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Penis + 

Preputial gland ++++++++++++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Prostate + + + + + + + + + + + + + + + + + + + + + + I + 

Sarcoma, metastatic, mesentery X 

Seminal vesicle ++++++++++++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Testes ++++++++++++++++++++++++ 

Sarcoma, metastatic, mesentery X 

Hematopoietic System 

Bone marrow ++++++++++++++++++++++++ 

Mast cell tumor malignant,

 metastatic, skin 

Lymph node + + + 

Mediastinal, sarcoma, metastatic, mesentery X 

Lymph node, mandibular ++++++++++++++++++++++++ 

Mast cell tumor malignant,

 metastatic, skin 

Lymph node, mesenteric + + + + A+ + + + + A+ + + + + + + + + + + + + 

Hemangioma X 

Histiocytic sarcoma 

Sarcoma, metastatic, mesentery X 

Spleen + + + + A+ + + + + A+ + + + + + + + + + + + + 

Hemangiosarcoma 

Mast cell tumor malignant,

 metastatic, skin 

Thymus + + + + + + M+ + MM+ + M+ + + + + + + + + + 

Sarcoma, metastatic, mesentery X 

Integumentary System 

Mammary gland MMMMMMMMMMMMMMMMMMMMMMMM 

Skin ++++++++++++++++++++++++ 

Subcutaneous tissue, mast cell tumor malignant 

Musculoskeletal System 

Bone ++++++++++++++++++++++++ 

Skeletal muscle ++ 

Sarcoma, metastatic, mesentery X 

Nervous System 

Brain ++++++++++++++++++++++++ 

Peripheral nerve + 

Spinal cord + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 209 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

1111111111111111111111111 Total 

Carcass ID Number 1112222233333334444444445 Tissues/ 

7891238902345890123456790 Tumors 

Genital System 

Epididymis +++++++++++++++++++++++++ 49 

Sarcoma, metastatic, mesentery 1 

Penis 1 

Preputial gland +++++++++++++++++++++++++ 49 

Sarcoma, metastatic, mesentery 1 

Prostate +++++++++++++++++++++++++ 48 

Sarcoma, metastatic, mesentery 1 

Seminal vesicle +++++++++++++++++++++++++ 49 

Sarcoma, metastatic, mesentery 1 

Testes +++++++++++++++++++++++++ 49 

Sarcoma, metastatic, mesentery 1 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 49 

Mast cell tumor malignant, 

metastatic, skin X 1 

Lymph node + 4 

Mediastinal, sarcoma, metastatic, mesentery 1 

Lymph node, mandibular + + + + + + + + + M+ + + + + + + + + + + + + + + 48 

Mast cell tumor malignant, 

metastatic, skin X 1 

Lymph node, mesenteric + + + + + + + + + M+ MM+ + + + + + + + + + + + 44 

Hemangioma 1 

Histiocytic sarcoma X 1 

Sarcoma, metastatic, mesentery 1 

Spleen +++++++++++++++++++++++++ 47 

Hemangiosarcoma X 1 

Mast cell tumor malignant, 

metastatic, skin X 1 

Thymus + + + M+ + MM+ MM+ M+ + + + + + + + + + + + 39 

Sarcoma, metastatic, mesentery 1 

Integumentary System 

Mammary gland MMMMMMMMMMMMMMMMMMMMMMMMM 

Skin + + M+ + + + + + + + + + + + + + + + + + + + + + 48 

Subcutaneous tissue, mast cell tumor malignant X 1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 49 

Skeletal muscle 2 

Sarcoma, metastatic, mesentery 1 

Nervous System 

Brain +++++++++++++++++++++++++ 49 

Peripheral nerve 1 

Spinal cord 1 
 

 

 

 

210 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

025555666666667777777777 

Number of Days on Study 021128233445660222222222 

363466307237148222222222 

111111111111111111111111 

Carcass ID Number 220122023341300000011111 

401667356185754267801234 

Respiratory System 

Lung ++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma X X X 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver X XX X 

Hepatocellular carcinoma, metastatic, liver X X X 

Nose ++++++++++++++++++++++++ 

Trachea ++++++++++++++++++++++++ 

Special Senses System 

None 

Urinary System 

Kidney + + + + + + + + + + A+ + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, tissue NOS X 

Mast cell tumor malignant, metastatic, skin 

Sarcoma, metastatic, mesentery X 

Renal tubule, adenoma X 

Urinary bladder + + A + A + + + M+ A + + + + + + + + + + + + + 

Hemangioma X 

Systemic Lesions 

Multiple organs ++++++++++++++++++++++++ 

Histiocytic sarcoma 

Lymphoma malignant X X 

Mesothelioma malignant 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 211 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222222222 

Carcass ID Number 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar adenoma, mu

Alveolar/bronchiolar carcinoma

Hepatoblastoma, metastatic, liver

Hepatocellular carcinoma, metasta

Nose 

Trachea 

Special Senses System 

None 

ltiple

tic, liver

1111111111111111111111111 

1 1 1 2 2 2 2 2 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 5 T

7 8 9 1 2 3 8 9 0 2 3 4 5 8 9 0 1 2 3 4 5 6 7 9 0 T

+++++++++++++++++++++++++ 

X X X X 

X 

X 

X XX 

XX X X X X X X 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

Total 

issues/ 

umors 

49 

7 

1 

1 

7 

11 

49 

49 

Urinary System 

Kidney 

Hemangiosarcoma, metastatic, tiss

Mast cell tumor malignant, metasta

Sarcoma, metastatic, mesentery 

Renal tubule, adenoma 

Urinaryb ladder 

Hemangioma 

ue NOS 

tic, skin

+++++++++++++++++++++++++ 

X 

+ + + + + + + + + + + + A+ + + + + + + + + + + + 

48 

1 

1 

1 

1 

44 

1 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma

Lymphoma malignant

Mesothelioma malignant

+++++++++++++++++++++++++ 

X 

X 

X 

49 

1 

3 

1 
 

 

 

 

 

 

 

 

 

 

 

 

212 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

0004456666666677777777777 

Number of Days on Study 0050392346788902222222222 

3996244995206992222222222 

1111111111111111111111111 

Carcass ID Number 5767779675895585555566666 

6083514647884341258901345 

Alimentary System 

Esophagus +++++++++++++++++++++++++ 

Gallbladder + A + A M+ + A A A MA M ++++++++++++ 

Intestine large, colon +++++++++++++++++++++++++ 

Intestine large, rectum + + + + + + + + + + + A+ + + + + + + + + + + + + 

Intestine large, cecum + + + + AA+ + + AAA+ + + + + + + + + + + + + 

Intestine small, duodenum + A+ AAA+ + + AA+ + + + + + + + + + + + + + 

Intestine small, jejunum + A + A A + + + + AA+ + A+ + + + + + + + + + + 

Carcinoma X 

Intestine small, ileum + A+ AAA+ + + AA+ + + + + + + + + + + + + + 

Liver +++++++++++++++++++++++++ 

Hepatoblastoma X X X X 

Hepatoblastoma, multiple X X 

Hepatocellular carcinoma XXX XXXX X XXXX 

Hepatocellular carcinoma, multiple X XXX XX XX 

Hepatocellular adenoma X XX X X 

Hepatocellular adenoma, multiple X XXX XX XX XXXXX 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Mesentery + + + 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Pancreas +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Salivary glands +++++++++++++++++++++++++ 

Stomach, forestomach + + + + A+ + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + AA+ + + + + + A+ + + + + + + + + + + + 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Tooth + 

Cardiovascular System 

Blood vessel M+ + + + + + + + + + + + + + + + + + + + + + + + 

Heart +++++++++++++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++++++++++++++++ 

Adenoma X 

Capsule, squamous cell carcinoma, 

metastatic, uncertain primary site X 

Adrenal medulla +++++++++++++++++++++++++ 

Islets, pancreatic +++++++++++++++++++++++++ 

Adenoma 

Parathyroid gland + + + + + M+ M+ M+ M+ + M+ M+ + + + + MM+ 

Pituitary gland +++++++++++++++++++++++++ 

Thyroid gland +++++++++++++++++++++++++ 

Follicular cell, adenoma X 

General Body System 

Peritoneum + 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 213 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

Number of Days on Study 

7777777777777777777777777 

2222222222222222222222222 

2222222222222222222233333 

Carcass ID Number 

1111111111111111111211111 

7777788888888999999066699 

2678901235679012579027936 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus 

Gallbladder 

Intestinel arge,c olon 

Intestinel arge,r ectum 

Intestinel arge,c ecum 

Intestines mall,d uodenum 

Intestine small, jejunum 

Carcinoma 

Intestines mall,i leum 

Liver 

Hepatoblastoma

Hepatoblastoma, multiple 

Hepatocellular carcinoma

Hepatocellular carcinoma, multiple

Hepatocellular adenoma

Hepatocellular adenoma, multiple 

Squamous cell carcinoma, metastatic, 

uncertain primary site 

Mesentery

Squamous cell carcinoma, metastatic, 

uncertain primary site 

Pancreas 

Squamous cell carcinoma, metastatic, 

uncertain primary site 

Salivaryg lands 

Stomach,f orestomach 

Stomach, glandular 

Squamous cell carcinoma, metastatic, 

uncertain primary site 

Tooth 

+++++++++++++++++++++++++ 

+ + + + M+ MM+ M+ + + + + + + + + + + + M+ + 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

X X X XXXX X X 

XX X XXX X X XX 

X XX X X XX X XX 

X XX X X X 

XXX XX X X XXXX XX X X 

+ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

+ + 

50 

36 

50 

49 

45 

44 

44 

1 

44 

50 

13 

2 

22 

18 

11 

28 

1 

4 

1 

50 

1 

50 

49 

47 

1 

3 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + M + + + + + + + + + + 49 

Adenoma 1 

Capsule, squamous cell carcinoma, 

metastatic, uncertain primary site 1 

Adrenal medulla + + + + + + + + + + + + + + M + + + + + + + + + + 49 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Parathyroid gland M + M M + + M + + M M + M + + M M + + + + + M M + 31 

Pituitary gland + + + + + + + I + + + + + + + + + + + + + + + + + 49 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X 2 

General Body System 

Peritoneum 

Squamous cell carcinoma, metastatic, 

uncertain primary site 

1 

1 
 

 

 

 

 

 

 

 

 

 

 

 

214 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

0004456666666677777777777 

Number of Days on Study 0050392346788902222222222 

3996244995206992222222222 

1111111111111111111111111 

Carcass ID Number 5767779675895585555566666 

6083514647884341258901345 

Genital System 

Epididymis +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Preputial gland + + + + + + + + + + + + M+ + + + + + + + + + + + 

Prostate + + + + + + + + + + + + M+ + + + + + + + + + + + 

Seminal vesicle +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Testes +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 

Lymph node + 

Mediastinal, squamous cell carcinoma, 

metastatic, uncertain primary site X 

Lymph node, mandibular +++++++++++++++++++++++++ 

Lymph node, mesenteric +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Spleen + + + + + + + M+ + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Thymus + + + + + M+ + + + + + + + M+ + + + + + + + + + 

Integumentary System 

Mammary gland MMMMMMMMMMMMMMMMMMMMMMMMM 

Skin +++++++++++++++++++++++++ 

Subcutaneous tissue, basal cell adenoma 

Subcutaneous tissue, hemangioma X 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 

Skeletal muscle + 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Nervous System 

Brain +++++++++++++++++++++++++ 

Respiratory System 

Lung +++++++++++++++++++++++++ 

Alveolar/bronchiolar adenoma X X 

Alveolar/bronchiolar adenoma, multiple X 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver X X 

Hepatocellular carcinoma, metastatic, liver X X XXXX X X 

Nose +++++++++++++++++++++++++ 

Trachea +++++++++++++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 215 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222233333 

1111111111111111111211111 Total 

Carcass ID Number 7777788888888999999066699 Tissues/ 

2678901235679012579027936 Tumors 

Genital System 

Epididymis +++++++++++++++++++++++++ 50 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Preputial gland +++++++++++++++++++++++++ 49 

Prostate +++++++++++++++++++++++++ 49 

Seminal vesicle +++++++++++++++++++++++++ 50 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Testes +++++++++++++++++++++++++ 50 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Hematopoietic System 

Bone marrow +++++++++++++++++++++++++ 50 

Lymph node + 2 

Mediastinal, squamous cell carcinoma, 

metastatic, uncertain primary site 1 

Lymph node, mandibular +++++++++++++++++++++++++ 50 

Lymph node, mesenteric +++++++++++++++++++++++++ 50 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Spleen +++++++++++++++++++++++++ 49 

Hemangiosarcoma 1 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Thymus + + + + + + M+ + + + + + + + + + + + + + + + + + 47 

Integumentary System 

Mammary gland MMMMMMMMMMMMMMMMMMMMMMMMM 

Skin +++++++++++++++++++++++++ 50 

Subcutaneous tissue, basal cell adenoma X 1 

Subcutaneous tissue, hemangioma 1 

Musculoskeletal System 

Bone +++++++++++++++++++++++++ 50 

Skeletal muscle 1 

Squamous cell carcinoma, metastatic, 

uncertain primary site 1 

Nervous System 

Brain +++++++++++++++++++++++++ 50 

Respiratory System 

Lung +++++++++++++++++++++++++ 50 

Alveolar/bronchiolar adenoma X X XX 6 

Alveolar/bronchiolar adenoma, multiple X 2 

Alveolar/bronchiolar carcinoma X 1 

Hepatoblastoma, metastatic, liver X 3 

Hepatocellular carcinoma, metastatic, liver X X X X X 13 

Nose +++++++++++++++++++++++++ 50 

Trachea +++++++++++++++++++++++++ 50 
 

216 Pyridine, NTP TR 470 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

0004456666666677777777777 

Number of Days on Study 0050392346788902222222222 

3996244995206992222222222 

1111111111111111111111111 

Carcass ID Number 5767779675895585555566666 

6083514647884341258901345 

Special Senses System 

Eye + 

Harderian gland + 

Adenoma X 

Urinary System 

Kidney +++++++++++++++++++++++++ 

Urinary bladder +++++++++++++++++++++++++ 

Squamous cell carcinoma, metastatic, 

uncertain primary site X 

Systemic Lesions 

Multiple organs +++++++++++++++++++++++++ 

Lymphoma malignant X 

Mesothelioma malignant X 
 

 

Pyridine, NTP TR 470 217 

TABLE D2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Pyridine: 1,000 ppm 

7777777777777777777777777 

Number of Days on Study 2222222222222222222222222 

2222222222222222222233333 

Carcass ID Number 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

1111111111111111111211111 

7777788888888999999066699 

2678901235679012579027936 

Total 

Tissues/ 

Tumors 

1 

1 

1 

Urinary System 

Kidney 

Urinaryb ladder 

Squamous cell carcinoma, metastatic, 

uncertain primary site 

+++++++++++++++++++++++++ 

+++++++++++++++++++++++++ 

50 

50 

1 

Systemic Lesions 

Multipleo rgans 

Lymphoma malignant 

Mesothelioma malignant 

+++++++++++++++++++++++++ 50 

1 

1 
218 Pyridine, NTP TR 470 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Adrenal Cortex: Adenoma 

Overall ratea 

Adjusted rateb 

Terminal ratec 

First incidence (days) 

Poly-3 testd 

3/49 (6%) 

6.8% 

2/35 (6%) 

598 

P=0.234N 

0/49 (0%) 

0.0% 

0/27 (0%) 

—e 

P=0.134N 

0/49 (0%) 

0.0% 

0/34 (0%) 

— 

P=0.126N 

1/49 (2%) 

2.4% 

1/34 (3%) 

722 (T) 

P=0.321N 

Harderian Gland: Adenoma 

Overall rate 3/50 (6%) 0/50 (0%) 0/49 (0%) 1/50 (2%) 

Adjusted rate 6.7% 0.0% 0.0% 2.3% 

Terminal rate 1/35 (3%) 0/28 (0%) 0/34 (0%) 1/35 (3%) 

First incidence (days) 633 — — 722 (T) 

Poly-3 test P=0.235N P=0.133N P=0.130N P=0.320N 

Harderian Gland: Adenoma or Carcinoma 

Overall rate 5/50 (10%) 0/50 (0%) 0/49 (0%) 1/50 (2%) 

Adjusted rate 11.1% 0.0% 0.0% 2.3% 

Terminal rate 3/35 (9%) 0/28 (0%) 0/34 (0%) 1/35 (3%) 

First incidence (days) 633 — — 722 (T) 

Poly-3 test P=0.052N P=0.038N P=0.036N P=0.111N 

Liver: Hepatocellular Adenoma 

Overall rate 29/50 (58%) 40/50 (80%) 34/49 (69%) 39/50 (78%) 

Adjusted rate 63.2% 88.0% 75.7% 84.9% 

Terminal rate 24/35 (69%) 27/28 (96%) 27/34 (79%) 31/35 (89%) 

First incidence (days) 520 522 513 406 

Poly-3 test P=0.031 P=0.003 P=0.134 P=0.011 

Liver: Hepatocellular Carcinoma 

Overall rate 15/50 (30%) 35/50 (70%) 41/49 (84%) 40/50 (80%) 

Adjusted rate 32.3% 78.7% 89.9% 85.1% 

Terminal rate 9/35 (26%) 23/28 (82%) 32/34 (94%) 28/35 (80%) 

First incidence (days) 574 522 513 406 

Poly-3 test P<0.001 P<0.001 P<0.001 P<0.001 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 37/50 (74%) 45/50 (90%) 45/49 (92%) 47/50 (94%) 

Adjusted rate 78.0% 96.5% 96.8% 100.0% 

Terminal rate 28/35 (80%) 28/28 (100%) 34/34 (100%) 35/35 (100%) 

First incidence (days) 520 522 513 406 

Poly-3 test P<0.001 P=0.004 P=0.004 P<0.001 

Liver: Hepatoblastoma 

Overall rate 2/50 (4%) 18/50 (36%) 22/49 (45%) 15/50 (30%) 

Adjusted rate 4.5% 41.2% 49.8% 34.4% 

Terminal rate 2/35 (6%) 11/28 (39%) 17/34 (50%) 13/35 (37%) 

First incidence (days) 722 (T) 549 514 624 

Poly-3 test P=0.005 P<0.001 P<0.001 P<0.001 

Liver: Hepatocellular Carcinoma or Hepatoblastoma 

Overall rate 17/50 (34%) 42/50 (84%) 45/49 (92%) 42/50 (84%) 

Adjusted rate 36.7% 91.3% 96.8% 89.4% 

Terminal rate 11/35 (31%) 26/28 (93%) 34/34 (100%) 30/35 (86%) 

First incidence (days) 574 522 513 406 

Poly-3 test P<0.001 P<0.001 P<0.001 P<0.001 
Pyridine, NTP TR 470 219 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Liver: Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastoma 

Overall rate 38/50 (76%) 47/50 (94%) 46/49 (94%) 47/50 (94%)
 

Adjusted rate 80.1% 98.9% 98.5% 100.0%
 

Terminal rate 29/35 (83%) 28/28 (100%) 34/34 (100%) 35/35 (100%)
 

First incidence (days) 520 522 513 406
 

Poly-3 test P<0.001 P=0.002 P=0.003 P<0.001
 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 12/49 (24%) 5/50 (10%) 8/49 (16%) 8/50 (16%)
 

Adjusted rate 27.0% 11.9% 18.5% 18.3%
 

Terminal rate 9/35 (26%) 4/28 (14%) 6/34 (18%) 6/35 (17%)
 

First incidence (days) 520 546 526 639
 

Poly-3 test P=0.303N P=0.065N P=0.245N P=0.239N
 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 13/49 (27%) 7/50 (14%) 9/49 (18%) 8/50 (16%)
 

Adjusted rate 29.1% 16.6% 20.8% 18.3%
 

Terminal rate 9/35 (26%) 6/28 (21%) 7/34 (21%) 6/35 (17%)
 

First incidence (days) 520 546 526 639
 

Poly-3 test P=0.197N P=0.130N P=0.258N P=0.174N
 

Spleen: Hemangiosarcoma 

Overall rate 1/49 (2%) 3/50 (6%) 1/47 (2%) 1/49 (2%) 

Adjusted rate 2.3% 7.1% 2.4% 2.4% 

Terminal rate 1/35 (3%) 2/28 (7%) 1/34 (3%) 1/35 (3%) 

First incidence (days) 722 (T) 532 722 (T) 722 (T) 

Poly-3 test P=0.459N P=0.292 P=0.748 P=0.755 

All Organs: Hemangioma 

Overall rate 0/50 (0%) 3/50 (6%) 2/49 (4%) 1/50 (2%) 

Adjusted rate 0.0% 7.2% 4.7% 2.3% 

Terminal rate 0/35 (0%) 1/28 (4%) 2/34 (6%) 1/35 (3%) 

First incidence (days) — 680 722 (T) 722 (T) 

Poly-3 test P=0.536 P=0.107 P=0.225 P=0.493 

All Organs: Hemangiosarcoma 

Overall rate 2/50 (4%) 4/50 (8%) 2/49 (4%) 1/50 (2%) 

Adjusted rate 4.5% 9.4% 4.7% 2.3% 

Terminal rate 1/35 (3%) 2/28 (7%) 1/34 (3%) 1/35 (3%) 

First incidence (days) 706 532 630 722 (T) 

Poly-3 test P=0.276N P=0.313 P=0.678 P=0.512N 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 2/50 (4%) 7/50 (14%) 4/49 (8%) 1/50 (2%) 

Adjusted rate 4.5% 16.4% 9.4% 2.3% 

Terminal rate 1/35 (3%) 3/28 (11%) 3/34 (9%) 1/35 (3%) 

First incidence (days) 706 532 630 722 (T) 

Poly-3 test P=0.215N P=0.067 P=0.316 P=0.512N 

All Organs: Malignant Lymphoma 

Overall rate 3/50 (6%) 3/50 (6%) 3/49 (6%) 1/50 (2%) 

Adjusted rate 6.6% 7.1% 6.9% 2.3% 

Terminal rate 2/35 (6%) 0/28 (0%) 2/34 (6%) 1/35 (3%) 

First incidence (days) 542 595 226 722 (T) 

Poly-3 test P=0.233N P=0.632 P=0.643 P=0.322N 
220 

c 

Pyridine, NTP TR 470 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

All Organs: Benign Neoplasms 

Overall rate 35/50 (70%) 42/50 (84%) 36/49 (73%) 39/50 (78%) 

Adjusted rate 74.7% 91.2% 79.1% 84.9% 

Terminal rate 27/35 (77%) 27/28 (96%) 28/34 (82%) 31/35 (89%) 

First incidence (days) 520 522 513 406 

Poly-3 test P=0.275 P=0.023 P=0.398 P=0.157 

All Organs: Malignant Neoplasms 

Overall rate 22/50 (44%) 46/50 (92%) 47/49 (96%) 42/50 (84%) 

Adjusted rate 46.5% 94.8% 98.4% 89.4% 

Terminal rate 13/35 (37%) 26/28 (93%) 34/34 (100%) 30/35 (86%) 

First incidence (days) 542 237 226 406 

Poly-3 test P<0.001 P<0.001 P<0.001 P<0.001 

All Organs: Benign or Malignant Neoplasms 

Overall rate 43/50 (86%) 49/50 (98%) 48/49 (98%) 47/50 (94%) 

Adjusted rate 88.7% 100.0% 100.0% 100.0% 

Terminal rate 31/35 (89%) 28/28 (100%) 34/34 (100%) 35/35 (100%) 

First incidence (days) 520 237 226 406 

Poly-3 test P=0.009 P=0.018 P=0.019 P=0.021 

(T)Terminal sacrifice

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, liver, 

lung, and spleen; for other tissues, denominator is number of animals necropsied. b	 Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

d	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A 

negative trend or a lower incidence in an exposure group is indicated by N. e Not applicable; no neoplasms in animal group 
Pyridine, NTP TR 470 221 

TABLE D4 

Historical Incidence of Liver Neoplasms in Untreated Male B6C3F1 Micea 

Incidence in Controls 

Hepatocellular 

Adenoma 

Hepatocellular 

Carcinoma 

Hepatoblastoma Hepatocellular Adenoma, 

Hepatocellular Carcinoma, 

or Hepatoblastoma 

Overall Historical Incidence 

Total 

Standard deviation 

Range 

179/289 (61.9%) 

9.1% 

47%-70% 

80/289 (27.7%) 

11.7% 

10%-42% 

9/289 (3.1%) 

5.0% 

0%-12% 

212/289 (73.4%) 

11.7% 

53%-81% 

a Data as of 1 August 1997 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

222 Pyridine, NTP TR 470 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 2 1 1 3 

Moribund 2 3 3 1 

Natural deaths 11 18 11 11 

Survivors 

Other 1 

Terminal sacrifice 35 28 34 35 

Animals examined microscopically 50 50 49 50 

Alimentary System 

Gallbladder (43) (33) (30) (36) 

Hyperplasia 1 (3%) 

Infiltration cellular, lymphocyte 1 (2%) 

Ulcer 1 (3%) 

Intestine large, colon (48) (48) (46) (50) 

Inflammation, chronic active 1 (2%) 

Intestine large, cecum (47) (44) (42) (45) 

Lymphoid tissue, hyperplasia 2 (5%) 1 (2%) 

Lymphoid tissue, necrosis 1 (2%) 

Intestine small, jejunum (40) (46) (42) (44) 

Peyer’s patch, hyperplasia, lymphoid 1 (3%) 1 (2%) 3 (7%) 1 (2%) 

Liver (50) (50) (49) (50) 

Angiectasis 1 (2%) 1 (2%) 

Basophilic focus 3 (6%) 1 (2%) 

Clear cell focus 1 (2%) 3 (6%) 1 (2%) 2 (4%) 

Cyst 1 (2%) 

Eosinophilic focus 19 (38%) 22 (44%) 18 (37%) 15 (30%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Infiltration cellular, mixed cell 1 (2%) 1 (2%) 1 (2%) 

Mixed cell focus 4 (8%) 2 (4%) 1 (2%) 1 (2%) 

Necrosis 3 (6%) 5 (10%) 7 (14%) 6 (12%) 

Vacuolization cytoplasmic, diffuse 2 (4%) 1 (2%) 

Centrilobular, congestion 1 (2%) 

Centrilobular, hypertrophy 1 (2%) 

Centrilobular, vacuolization cytoplasmic 1 (2%) 2 (4%) 6 (12%) 

Periportal, vacuolization cytoplasmic 1 (2%) 2 (4%) 

Mesentery (2) (7) (6) (4) 

Fat, necrosis 2 (100%) 3 (43%) 1 (17%) 2 (50%) 

Oral mucosa (1) 

Ulcer 1 (100%) 

Pancreas (49) (50) (48) (50) 

Acinus, atrophy 3 (6%) 2 (4%) 1 (2%) 1 (2%) 

Acinus, cytoplasmic alteration 1 (2%) 1 (2%) 

Duct, cyst 1 (2%) 1 (2%) 

Salivary glands (48) (50) (49) (50) 

Infiltration cellular, lymphocyte 31 (65%) 33 (66%) 26 (53%) 34 (68%) 

Stomach, forestomach (49) (50) (48) (49) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 2 (4%) 2 (4%) 

Ulcer 1 (2%) 

Epithelium, hyperplasia 1 (2%) 2 (4%) 2 (4%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 223 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Alimentary System (continued) 

Stomach, glandular (49) (50) (48) (47) 

Necrosis 2 (4%) 2 (4%) 4 (8%) 1 (2%) 

Glands, dysplasia 2 (4%) 

Tooth (42) (10) (1) (3) 

Developmental malformation 42 (100%) 10 (100%) 1 (100%) 3 (100%) 

Cardiovascular System 

Blood vessel (50) (49) (47) (49) 

Aorta, thrombosis 1 (2%) 

Heart (50) (50) (49) (50) 

Cardiomyopathy 1 (2%) 

Mineralization 3 (6%) 

Thrombosis 1 (2%) 

Artery, inflammation, chronic active 2 (4%) 

Myocardium, hypertrophy 1 (2%) 

Endocrine System 

Adrenal cortex (49) (49) (49) (49) 

Cytoplasmic alteration 18 (37%) 13 (27%) 9 (18%) 11 (22%) 

Hyperplasia 2 (4%) 1 (2%) 2 (4%) 

Vacuolization cytoplasmic 2 (4%) 1 (2%) 

Capsule, hyperplasia 42 (86%) 29 (59%) 30 (61%) 29 (59%) 

Islets, pancreatic (49) (50) (48) (50) 

Hyperplasia 5 (10%) 2 (4%) 

Parathyroid gland (31) (35) (40) (31) 

Cyst 1 (3%) 1 (3%) 

Pituitary gland (46) (47) (45) (49) 

Cyst 1 (2%) 1 (2%) 

Pars distalis, hyperplasia 1 (2%) 

Thyroid gland (49) (50) (49) (50) 

Infiltration cellular, lymphocyte 1 (2%) 

Follicle, cyst 1 (2%) 

Follicular cell, hyperplasia 8 (16%) 14 (28%) 20 (41%) 12 (24%) 

General Body System 

None 

Genital System 

Epididymis (50) (50) (49) (50) 

Angiectasis 1 (2%) 

Infiltration cellular, lymphocyte 1 (2%) 4 (8%) 4 (8%) 4 (8%) 

Inflammation, granulomatous 1 (2%) 1 (2%) 3 (6%) 

Penis (1) 

Inflammation, chronic active 1 (100%) 

Preputial gland (50) (50) (49) (49) 

Atrophy 48 (96%) 45 (90%) 47 (96%) 42 (86%) 

Cyst 29 (58%) 25 (50%) 32 (65%) 28 (57%) 

Inflammation, chronic 18 (36%) 18 (36%) 13 (27%) 12 (24%) 

Inflammation, chronic active 4 (8%) 6 (12%) 3 (6%) 6 (12%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

224 Pyridine, NTP TR 470 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Genital System (continued) 

Prostate (50) (48) (48) (49) 

Cyst 1 (2%) 

Hyperplasia 1 (2%) 1 (2%) 

Inflammation, chronic 7 (14%) 3 (6%) 10 (21%) 8 (16%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Testes (50) (50) (49) (50) 

Atrophy 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Mineralization 1 (2%) 

Interstitial cell, hyperplasia 1 (2%) 

Hematopoietic System 

Bone marrow (49) (50) (49) (50) 

Atrophy 2 (4%) 

Erythroid cell, hyperplasia 1 (2%) 

Myeloid cell, hyperplasia 1 (2%) 1 (2%) 1 (2%) 

Lymph node (2) (4) (4) (2) 

Iliac, hyperplasia, lymphoid 1 (50%) 

Mediastinal, congestion 1 (50%) 

Pancreatic, hyperplasia, lymphoid 1 (25%) 

Renal, hemorrhage 2 (50%) 1 (50%) 

Renal, necrosis 1 (25%) 

Lymph node, mandibular (48) (47) (48) (50) 

Hyperplasia, lymphoid 3 (6%) 1 (2%) 1 (2%) 

Hyperplasia, plasma cell 2 (4%) 

Necrosis 1 (2%) 

Lymph node, mesenteric (43) (47) (44) (50) 

Angiectasis 2 (4%) 

Atrophy 1 (2%) 

Hematopoietic cell proliferation 2 (5%) 3 (6%) 6 (14%) 1 (2%) 

Hemorrhage 13 (30%) 10 (21%) 10 (23%) 12 (24%) 

Hyperplasia, histiocytic 2 (5%) 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 5 (11%) 3 (7%) 4 (8%) 

Hyperplasia, plasma cell 1 (2%) 1 (2%) 

Necrosis 1 (2%) 

Spleen (49) (50) (47) (49) 

Atrophy 2 (4%) 3 (6%) 

Hematopoietic cell proliferation 13 (27%) 30 (60%) 26 (55%) 23 (47%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 1 (2%) 

Necrosis 1 (2%) 

Thymus (46) (46) (39) (47) 

Atrophy 26 (57%) 21 (46%) 16 (41%) 16 (34%) 

Cyst 1 (2%) 

Necrosis 1 (3%) 1 (2%) 

Integumentary System 

Skin (49) (50) (48) (50) 

Inflammation, chronic active 1 (2%) 

Ulcer 1 (2%) 

Subcutaneous tissue, edema 1 (2%) 1 (2%) 

Subcutaneous tissue, inflammation, acute 1 (2%) 

Subcutaneous tissue, inflammation, chronic

 active 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 225 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Musculoskeletal System 

None 

Nervous System 

Brain (50) (50) (49) (50) 

Hemorrhage 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 41 (82%) 27 (54%) 30 (61%) 35 (70%) 

Peripheral nerve (1) (1) 

Sciatic, degeneration 1 (100%) 

Respiratory System 

Lung (49) (50) (49) (50) 

Congestion 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Hemorrhage 1 (2%) 

Infiltration cellular, lymphocyte 4 (8%) 2 (4%) 

Alveolar epithelium, hyperplasia 4 (8%) 8 (16%) 1 (2%) 2 (4%) 

Alveolus, infiltration cellular, histiocyte 1 (2%) 2 (4%) 4 (8%) 1 (2%) 

Nose (50) (49) (49) (50) 

Foreign body 1 (2%) 

Olfactory epithelium, degeneration, hyaline 15 (30%) 31 (63%) 35 (71%) 7 (14%) 

Olfactory epithelium, glands, hyperplasia 1 (2%) 

Respiratory epithelium, degeneration, hyaline 20 (40%) 10 (20%) 15 (31%) 2 (4%) 

Respiratory epithelium, hyperplasia 20 (40%) 22 (45%) 11 (22%) 15 (30%) 

Respiratory epithelium, inflammation,

 chronic active 2 (4%) 1 (2%) 1 (2%) 

Special Senses System 

Eye (1) (1) 

Cataract 1 (100%) 

Cornea, inflammation, chronic 1 (100%) 

Cornea, inflammation, chronic active 1 (100%) 

Urinary System 

Kidney (49) (50) (48) (50) 

Atrophy 1 (2%) 

Cyst 4 (8%) 2 (4%) 4 (8%) 

Fibrosis 1 (2%) 

Hydronephrosis 1 (2%) 

Infarct 2 (4%) 1 (2%) 2 (4%) 6 (12%) 

Infiltration cellular, lymphocyte 3 (6%) 1 (2%) 2 (4%) 6 (12%) 

Inflammation, chronic active 2 (4%) 

Mineralization 2 (4%) 3 (6%) 

Nephropathy 34 (69%) 27 (54%) 25 (52%) 32 (64%) 

Artery, inflammation, chronic 1 (2%) 

Artery, inflammation, chronic active 1 (2%) 

Renal tubule, accumulation, hyaline droplet 1 (2%) 

Renal tubule, dilatation 1 (2%) 2 (4%) 5 (10%) 

Renal tubule, hyperplasia 3 (6%) 1 (2%) 1 (2%) 

Renal tubule, pigmentation 5 (10%) 3 (6%) 2 (4%) 

Urinary bladder (48) (49) (44) (50) 

Infiltration cellular, lymphocyte 8 (17%) 7 (14%) 9 (20%) 8 (16%) 
226 Pyridine, NTP TR 470
 
227 

APPENDIX E 

SUMMARY OF LESIONS IN FEMALE MICE 

IN THE 2-YEAR DRINKING WATER STUDY 

OF PYRIDINE 

TABLE E1 Summary of the Incidence of Neoplasms in Female Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 

TABLE E2 Individual Animal Tumor Pathology of Female Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 

TABLE E3 Statistical Analysis of Primary Neoplasms in Female Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 

TABLE E4 Historical Incidence of Liver Neoplasms in Untreated Female B6C3F1 Mice . . . . . . . . . . . . 255 

TABLE E5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

228 Pyridine, NTP TR 470 

TABLE E1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 125 ppm 250 ppm 500 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 3 6 4 5 

Moribund 3 2 3 5 

Natural deaths 12 12 21 11 

Survivors 

Terminal sacrifice 32 30 22 29 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Esophagus (50) (50) (50) (50) 

Gallbladder (37) (40) (33) (34) 

Intestine large, rectum (44) (48) (47) (47) 

Intestine large, cecum (44) (49) (40) (45) 

Leiomyosarcoma 1 (2%) 

Intestine small, jejunum (42) (47) (38) (43) 

Intestine small, ileum (43) (48) (37) (41) 

Carcinoma 1 (2%) 

Liver (49) (50) (50) (50) 

Hemangioma 1 (2%) 

Hepatoblastoma 1 (2%) 2 (4%) 6 (12%) 12 (24%) 

Hepatoblastoma, multiple 3 (6%) 4 (8%) 

Hepatocellular carcinoma 10 (20%) 12 (24%) 19 (38%) 11 (22%) 

Hepatocellular carcinoma, multiple 3 (6%) 11 (22%) 14 (28%) 30 (60%) 

Hepatocellular adenoma 13 (27%) 5 (10%) 6 (12%) 4 (8%) 

Hepatocellular adenoma, multiple 24 (49%) 34 (68%) 37 (74%) 30 (60%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 

Mesentery (17) (18) (13) (13) 

Hepatoblastoma, metastatic, liver 1 (8%) 1 (8%) 

Histiocytic sarcoma 2 (11%) 

Lipoma 1 (6%) 

Sarcoma 2 (11%) 

Pancreas (49) (49) (47) (48) 

Histiocytic sarcoma 2 (4%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Salivary glands (50) (50) (49) (50) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Stomach, forestomach (49) (49) (49) (49) 

Squamous cell papilloma 1 (2%) 

Stomach, glandular (48) (49) (48) (49) 

Cardiovascular System 

Blood vessel (48) (47) (47) (47) 

Aorta, histiocytic sarcoma 1 (2%) 

Heart (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 229 

TABLE E1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Endocrine System 

Adrenal cortex (49) (50) (48) (50) 

Carcinoma, multiple 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Capsule, adenoma 1 (2%) 

Islets, pancreatic (49) (50) (47) (49) 

Adenoma 1 (2%) 2 (4%) 

Pituitary gland (47) (44) (42) (46) 

Pars distalis, adenoma 8 (17%) 9 (20%) 6 (14%) 2 (4%) 

Thyroid gland (50) (50) (50) (50) 

Follicular cell, adenoma 3 (6%) 2 (4%) 3 (6%) 3 (6%) 

General Body System 

Peritoneum (2) 

Hepatoblastoma, metastatic, liver 1 (50%) 

Tissue NOS (2) 

Alveolar/bronchiolar carcinoma, metastatic,

 lung 1 (50%) 

Hepatoblastoma, metastatic, liver 1 (50%) 

Genital System 

Clitoral gland (47) (48) (48) (45) 

Ovary (47) (49) (46) (49) 

Cystadenoma 4 (9%) 3 (6%) 1 (2%) 

Granulosa cell tumor benign 1 (2%) 1 (2%) 

Hemangioma 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Oviduct (1) 

Schwannoma malignant, metastatic, skin 1 (100%) 

Uterus (48) (50) (47) (50) 

Adenoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Polyp stromal 2 (4%) 1 (2%) 

Hematopoietic System 

Bone marrow (49) (50) (49) (50) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Lymph node (10) (10) (7) (7) 

Iliac, histiocytic sarcoma 1 (10%) 1 (10%) 

Iliac, rhabdomyosarcoma, metastatic,

 skeletal muscle 1 (10%) 

Mediastinal, sarcoma, metastatic, mesentery 1 (10%) 

Mediastinal, sarcoma, metastatic, skin 1 (10%) 

Pancreatic, hepatoblastoma, metastatic, liver 1 (14%) 

Pancreatic, sarcoma, metastatic, mesentery 1 (10%) 

Lymph node, mandibular (48) (50) (49) (47) 

Histiocytic sarcoma 2 (4%) 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 

Schwannoma malignant, metastatic, skin 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

230 Pyridine, NTP TR 470 

TABLE E1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Hematopoietic System (continued) 

Lymph node, mesenteric (48) (47) (43) (45) 

Hemangioma 1 (2%) 

Hepatoblastoma, metastatic, liver 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 2 (4%) 

Spleen (49) (50) (48) (49) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Thymus (45) (44) (46) (39) 

Alveolar/bronchiolar carcinoma, metastatic,

 lung 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Integumentary System 

Skin (49) (50) (50) (50) 

Squamous cell papilloma 1 (2%) 1 (2%) 

Subcutaneous tissue, hemangioma 1 (2%) 

Subcutaneous tissue, hemangiosarcoma 1 (2%) 

Subcutaneous tissue, sarcoma 2 (4%) 2 (4%) 3 (6%) 4 (8%) 

Subcutaneous tissue, schwannoma malignant 1 (2%) 1 (2%) 1 (2%) 1 (2%) 

Musculoskeletal System 

Skeletal muscle (1) (1) (1) 

Hepatoblastoma, metastatic, liver 1 (100%) 

Rhabdomyosarcoma 1 (100%) 

Nervous System 

Brain (50) (50) (50) (50) 

Respiratory System 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar adenoma 1 (2%) 3 (6%) 3 (6%) 

Alveolar/bronchiolar adenoma, multiple 1 (2%) 

Alveolar/bronchiolar carcinoma 2 (4%) 1 (2%) 2 (4%) 3 (6%) 

Carcinoma, metastatic, harderian gland 1 (2%) 

Hepatoblastoma, metastatic, liver 1 (2%) 3 (6%) 

Hepatocellular carcinoma, metastatic, liver 2 (4%) 6 (12%) 10 (20%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Rhabdomyosarcoma, metastatic, skeletal muscle 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Sarcoma, metastatic, skin 2 (4%) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Mediastinum, alveolar/bronchiolar carcinoma,

 metastatic, lung 1 (2%) 

Mediastinum, sarcoma, metastatic, skin 1 (2%) 

Mediastinum, schwannoma malignant,

 metastatic, skin 1 (2%) 

Nose (50) (50) (47) (50) 

Sarcoma 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 

Trachea (50) (50) (50) (50) 
 

 

 

 

 

 

 

 

 

 

231 

c 

Pyridine, NTP TR 470 

TABLE E1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Special Senses System 

Harderian gland

Adenoma

Carcinoma

 (1)

 1 (100%)

 (1)

 1 (100%) 

 (1) 

 1 (100%) 

Urinary System 

Kidney 

Histiocytic sarcoma

Schwannoma malignant, metastatic, skin

Urinary bladder 

Histiocytic sarcoma

(49) 

 1 (2%)

(45) 

(50) 

 1 (2%) 

 1 (2%) 

(49) 

 1 (2%) 

(49) 

(44) 

(49) 

(43) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

Leukemia granulocytic

Lymphoma malignant

Mesothelioma malignant

(50) 

 2 (4%)

 6 (12%)

(50) 

 2 (4%) 

 1 (2%) 

 7 (14%)

(50) 

 4 (8%)

(50) 

 6 (12%) 

 2 (4%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

Total primary neoplasms 

Total animals with benign neoplasms 

Total benign neoplasms 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

47 

90 

40 

61 

26 

29 

5 

6 

45 

105 

41 

63 

30 

42 

3 

14 

45 

108 

43 

55 

40 

53 

10 

21 

45 

122 

36 

45 

44 

77 

12 

15 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

 

 

 

232 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

0 1 3 4 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 5 7 7 5 6 6 2 4 4 6 7 8 9 9 1 1 1 2 2 2 2 2 2 2 

4 1 5 6 4 5 8 5 4 4 2 0 7 1 7 1 4 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

Carcass ID Number 6 2 5 3 3 4 4 2 5 5 1 2 4 4 5 2 5 6 1 1 1 2 2 2 2 

4 7 8 5 0 8 4 6 0 3 7 8 5 7 6 4 7 3 6 8 9 0 1 2 3 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 

Gallbladder A + + + + AA + + AA AMA + AAA + + + + + + + 

Intestine large, colon + + + + + +A+ + +A + + + + +A+ + + + + + + + 

Intestine large, rectum A + + + + + + + + +A + AA + + AM+ + + + + + + 

Intestine large, cecum A+ + + +A+ + + +A +AA+ +A+ + + + + + + + 

Intestine small, duodenum A+ +A+ + + + + +A +A+ +AA+ + + + + + + + 

Intestine small, jejunum A + + A + A A + + A A + A + + + A ++++++++ 

Intestine small, ileum A+ + + +A+ + + +AAAA+ +A+ + + + + + + + 

Liver +++++++++++ +++++A++++++++ 

Hepatoblastoma 

Hepatocellular carcinoma XX X X X 

Hepatocellular carcinoma, multiple X 

Hepatocellular adenoma XX X X X 

Hepatocellular adenoma, multiple X X X X XXX X X X 

Histiocytic sarcoma X 

Sarcoma, metastatic, skin 

Mesentery +++ + +++ + + + 

Pancreas +++++++++++ +++++A++++++++ 

Salivary glands +++++++++++ ++++++++++++++ 

Stomach, forestomach +++++++++++ +++++A++++++++ 

Stomach, glandular +++++++++++ +A+++A++++++++ 

Tooth 

Cardiovascular System 

Blood vessel M+ + + + + + + + +A + + + + + + + + + + + + + + 

Heart +++++++++++ ++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++ +++++A++++++++ 

Carcinoma, multiple X 

Histiocytic sarcoma X 

Capsule, adenoma X 

Adrenal medulla +++++++++++ +++++A++++++++ 

Islets, pancreatic +++++++++++ +++++A++++++++ 

Adenoma X 

Parathyroid gland M+ + + +M+M+ ++M+ + MMMMM + MM + + M 

Pituitary gland + + + +M+ + + + + I + + + + + + + + + + + + + + 

Pars distalis, adenoma X 

Thyroid gland +++++++++++ ++++++++++++++ 

Follicular cell, adenoma X 

General Body System 

None 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 233 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 2 2 3 3 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 Tissues/ 

5 9 1 2 3 4 6 7 8 9 0 1 2 3 6 9 1 2 4 5 9 0 1 2 5 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + M + + + + + + + + + + + + + + + + + + + + + M + 37 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 42 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 43 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hepatoblastoma X 1 

Hepatocellular carcinoma X XXX X 10 

Hepatocellular carcinoma, multiple X X 3 

Hepatocellular adenoma X X X X X X X X 13 

Hepatocellular adenoma, multiple X X X X X X X X X X X X X X 24 

Histiocytic sarcoma 1 

Sarcoma, metastatic, skin X 1 

Mesentery ++ + ++++ 17 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Tooth + + 2 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Carcinoma, multiple 1 

Histiocytic sarcoma 1 

Capsule, adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma 1 

Parathyroid gland + + M + + M M + + + + + M + + + + + + + M M + M + 31 

Pituitary gland + + + + + + + + + + + + + + M + + + + + + + + + + 47 

Pars distalis, adenoma XX X XX X X 8 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X X 3 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

234 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

0 1 3 4 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 5 7 7 5 6 6 2 4 4 6 7 8 9 9 1 1 1 2 2 2 2 2 2 2 

4 1 5 6 4 5 8 5 4 4 2 0 7 1 7 1 4 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

Carcass ID Number 6 2 5 3 3 4 4 2 5 5 1 2 4 4 5 2 5 6 1 1 1 2 2 2 2 

4 7 8 5 0 8 4 6 0 3 7 8 5 7 6 4 7 3 6 8 9 0 1 2 3 

Genital System 

Clitoralg land 

Ovary 

Cystadenoma 

Granulosa cell tumor benign 

Histiocytic sarcoma 

Uterus 

+++++++++++ +++ I ++++++++++ 

+ + + + + +M+ + +M + + + + + A + + + + + + + + 

X 

X 

+ + + + + + + + + +A + + + + +A+ + + + + + + + 

Adenoma 

Polyp stromal X X 

Hematopoietic System 

Bone marrow +++++++++++ +++++A++++++++ 

Histiocytic sarcoma 

Lymph node 

Iliac, histiocytic sarcoma 

Mediastinal, sarcoma, metastatic, skin 

Lymphn ode, mandibular 

Histiocytic sarcoma 

Lymphn ode, mesenteric 

Histiocytic sarcoma 

Spleen 

Histiocytic sarcoma 

Thymus 

X 

+ ++ + ++ + 

X 

+ + + + + + + + + +M + + + + + A + + + + + + + + 

X X 

+ + + + + + + + + +A + + + + +A+ + + + + + + + 

X 

+ + + + + + + + + +A + + + + + + + + + + + + + + 

X 

+ + + + + + + + MM+ + + + + + A + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

+ + + + + + + + + +A + +A+ + + + + + + + + + + 

+++++++++++ ++A+++++++++++ 

Squamous cell papilloma 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Nervous System 

Brain +++++++++++ ++++++++++++++ 

Peripheral nerve + 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, harderian gland 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Nose 

+++++++++++ ++++++++++++++ 

X 

X X 

X 

+++++++++++ ++++++++++++++ 

Sarcoma, metastatic, skin 

Trachea +++++++++++ ++++++++++++++ 

Special Senses System 

Harderian gland 

Carcinoma 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 235 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 2 2 3 3 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 Tissues/ 

5 9 1 2 3 4 6 7 8 9 0 1 2 3 6 9 1 2 4 5 9 0 1 2 5 Tumors 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + M + + + + I + + + 47 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Cystadenoma X X X X 4 

Granulosa cell tumor benign 1 

Histiocytic sarcoma 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X 1 

Polyp stromal 2 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Histiocytic sarcoma 1 

Lymph node + + + 10 

Iliac, histiocytic sarcoma 1 

Mediastinal, sarcoma, metastatic, skin X 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 2 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Histiocytic sarcoma 1 

Thymus + + + + + + + + + M + + + + + + + + + + + + M + + 45 

Integumentary System 

Mammary gland + + + + + + + + + + + M + + + + + + + + + + + + + 47 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Squamous cell papilloma X 1 

Subcutaneous tissue, sarcoma X X 2 

Subcutaneous tissue, schwannoma malignant 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve 1 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X 1 

Alveolar/bronchiolar adenoma, multiple X 1 

Alveolar/bronchiolar carcinoma X 2 

Carcinoma, metastatic, harderian gland X 1 

Hepatocellular carcinoma, metastatic, liver 2 

Histiocytic sarcoma 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, skin X 1 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Harderian gland + 1 

Carcinoma X 1 
 

 

 

236 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

01345556666 66667777777777 

Number of Days on Study 65775662446 78991112222222 

41564585442 07171499999999 

22222222222 22222222222222 

Carcass ID Number 62533442551 24452561112222 

47850846037 85764736890123 

Urinary System 

Kidney +++++++++++ +++++A++++++++ 

Histiocytic sarcoma X 

Urinary bladder + + + + + A + + + AA + A + + + A + + + + + + + + 

Systemic Lesions 

Multiple organs +++++++++++ ++++++++++++++ 

Histiocytic sarcoma X X 

Lymphoma malignant X XXX X 
 

 

 

Pyridine, NTP TR 470 237 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 0 ppm 

77777777777 77777777777777 

Number of Days on Study 22222222222 22222222222222 

99999999999 99999999999999 

22222222222 22222222222222 Total 

Carcass ID Number 22333333334 44444555556666 Tissues/ 

59123467890 12369124590125 Tumors 

Urinary System 

Kidney +++++++++++ ++++++++++++++ 49 

Histiocytic sarcoma 1 

Urinary bladder +++++++++++ ++++++++++++++ 45 

Systemic Lesions 

Multiple organs +++++++++++ ++++++++++++++ 50 

Histiocytic sarcoma 2 

Lymphoma malignant X 6 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

238 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

0 0 0 1 3 4 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

Number of Days on Study 0 1 2 7 7 1 5 7 9 0 0 4 4 7 7 8 9 1 1 2 2 2 2 2 2 

4 6 0 2 2 9 5 3 9 5 8 2 9 4 7 0 6 1 3 4 9 9 9 9 9 

2 2 2 3 2 3 2 2 2 2 2 3 2 2 2 2 2 3 2 3 2 2 2 2 2 

Carcass ID Number 7 8 7 0 8 1 9 8 6 7 9 0 7 9 9 8 6 0 7 0 6 6 7 7 7 

0 4 9 5 1 1 5 9 9 7 1 1 1 4 7 2 8 6 5 7 6 7 2 3 4 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 

Gallbladder A+ +A+ +A+A+A +A+ +A+AA+ + + + + + 

Intestine large, colon +++++++++++ +++++++A++++++ 

Intestine large, rectum A++++++++++ ++++++++++++++ 

Intestine large, cecum A++++++++++ ++++++++++++++ 

Intestine small, duodenum A+ + + + + + + + ++ + + + + + +AA+ + + + + + 

Intestine small, jejunum A + + + + + + + + + + + + + +MA + + + + + + + + 

Intestine small, ileum A+++++A++++ ++++++++++++++ 

Liver +++++++++++ ++++++++++++++ 

Hepatoblastoma X X 

Hepatocellular carcinoma X X X X 

Hepatocellular carcinoma, multiple X X X X 

Hepatocellular adenoma X X X X 

Hepatocellular adenoma, multiple XXX X X X XX XXXXX 

Histiocytic sarcoma 

Mesentery +++ + ++ + + + 

Histiocytic sarcoma 

Lipoma X 

Sarcoma X X 

Pancreas + + + + + + + + + +M + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Sarcoma, metastatic, mesentery X 

Salivary glands +++++++++++ ++++++++++++++ 

Schwannoma malignant, metastatic, skin X 

Stomach, forestomach A++++++++++ ++++++++++++++ 

Squamous cell papilloma 

Stomach, glandular A ++++++++++ ++++++++++++++ 

Cardiovascular System 

Blood vessel MM + + + + + + + + + + + + M + + + + + + + + + + 

Aorta, histiocytic sarcoma 

Heart +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Sarcoma, metastatic, mesentery X 

Adrenal medulla +++++++++++ +++ I ++++++++++ 

Islets, pancreatic +++++++++++ ++++++++++++++ 

Adenoma X 

Parathyroid gland + + + + + + + M + +MM + M + MM + M + + MMMM 

Pituitary gland + + + + + +M+ + ++ + + +M+ + + + + + + + + + 

Pars distalis, adenoma X X X X 

Thyroid gland +++++++++++ ++++++++++++++ 

Follicular cell, adenoma X 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 239 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 7 7 8 8 8 8 8 8 9 9 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 Tissues/ 

6 8 0 3 5 6 7 8 0 2 3 6 8 9 0 2 3 4 8 9 0 2 3 4 5 Tumors 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 50 

Gallbladder + +M+ + + + + + ++ + + + + + + + + + + + + + + 40 

Intestine large, colon +++++++++++ ++++++++++++++ 49 

Intestine large, rectum + + +M+ + + + + ++ + + + + + + + + + + + + + + 48 

Intestine large, cecum +++++++++++ ++++++++++++++ 49 

Intestine small, duodenum +++++++++++ ++++++++++++++ 47 

Intestine small, jejunum +++++++++++ ++++++++++++++ 47 

Intestine small, ileum +++++++++++ ++++++++++++++ 48 

Liver +++++++++++ ++++++++++++++ 50 

Hepatoblastoma 2 

Hepatocellular carcinoma X X X X X X XX 12 

Hepatocellular carcinoma, multiple X X X X X X X 11 

Hepatocellular adenoma X 5 

Hepatocellular adenoma, multiple XXXXXX XXXX XXXXXXXXX X X 34 

Histiocytic sarcoma X 1 

Mesentery + + + + + ++ ++ 18 

Histiocytic sarcoma X X 2 

Lipoma 1 

Sarcoma 2 

Pancreas +++++++++++ ++++++++++++++ 49 

Histiocytic sarcoma X X 2 

Sarcoma, metastatic, mesentery 1 

Salivary glands +++++++++++ ++++++++++++++ 50 

Schwannoma malignant, metastatic, skin 1 

Stomach, forestomach +++++++++++ ++++++++++++++ 49 

Squamous cell papilloma X 1 

Stomach, glandular +++++++++++ ++++++++++++++ 49 

Cardiovascular System 

Blood vessel +++++++++++ ++++++++++++++ 47 

Aorta, histiocytic sarcoma X 1 

Heart +++++++++++ ++++++++++++++ 50 

Histiocytic sarcoma X 1 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 50 

Histiocytic sarcoma X 1 

Sarcoma, metastatic, mesentery 1 

Adrenal medulla +++++++++++ ++++++++++++++ 49 

Islets, pancreatic +++++++++++ ++++++++++++++ 50 

Adenoma X 2 

Parathyroid gland M + M + M + + + M + + MMM + + + + + + + M + MM 29 

Pituitary gland MM + + + + + M + + + + + M + + + + + + + + + + + 44 

Pars distalis, adenoma X X X X X 9 

Thyroid gland +++++++++++ ++++++++++++++ 50 

Follicular cell, adenoma X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

240 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

Number of Days on Study 

0 0 0 1 3 4 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

0 1 2 7 7 1 5 7 9 0 0 4 4 7 7 8 9 1 1 2 2 2 2 2 2 

4 6 0 2 2 9 5 3 9 5 8 2 9 4 7 0 6 1 3 4 9 9 9 9 9 

Carcass ID Number 

2 2 2 3 2 3 2 2 2 2 2 3 2 2 2 2 2 3 2 3 2 2 2 2 2 

7 8 7 0 8 1 9 8 6 7 9 0 7 9 9 8 6 0 7 0 6 6 7 7 7 

0 4 9 5 1 1 5 9 9 7 1 1 1 4 7 2 8 6 5 7 6 7 2 3 4 

Genital System 

Clitoral gland + + + + + +M+ + ++ + + + + + + + + + + + + + + 
 

Ovary +++++++++++ ++++++++++++++ 
 

Cystadenoma X X 

Histiocytic sarcoma 

Sarcoma, metastatic, mesentery X 

Oviduct + 

Schwannoma malignant, metastatic, skin X 

Uterus +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Polyp stromal 

Hematopoietic System 

Bone marrow +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Lymph node + + +++ + + 

Iliac, histiocytic sarcoma 

Iliac, rhabdomyosarcoma, metastatic, 

skeletal muscle X 

Mediastinal, sarcoma, metastatic, mesentery X 

Pancreatic, sarcoma, metastatic, mesentery X 

Lymph node, mandibular +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Schwannoma malignant, metastatic, skin X 

Lymph node, mesenteric + + + + + + + + + ++ + +M+ + + + + + +M+ + + 

Histiocytic sarcoma 

Spleen +++++++++++ ++++++++++++++ 

Histiocytic sarcoma 

Thymus + + + + + + + +M++M+M+ + + + +M+ + + + + 

Histiocytic sarcoma 

Integumentary System 

Mammary gland +++++++++++ ++++++++++++++ 

Skin +++++++++++ ++++++++++++++ 

Squamous cell papilloma 

Subcutaneous tissue, sarcoma X X 

Subcutaneous tissue, schwannoma malignant X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Skeletal muscle + 

Rhabdomyosarcoma X 

Nervous System 

Brain +++++++++++ ++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 241 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 7 7 8 8 8 8 8 8 9 9 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 Tissues/ 

6 8 0 3 5 6 7 8 0 2 3 6 8 9 0 2 3 4 8 9 0 2 3 4 5 Tumors 

Genital System 

Clitoral gland + + M + + + + + + + + + + + + + + + + + + + + + + 48 

Ovary + + + + + + + + + + + + + M + + + + + + + + + + + 49 

Cystadenoma X 3 

Histiocytic sarcoma X 1 

Sarcoma, metastatic, mesentery 1 

Oviduct 1 

Schwannoma malignant, metastatic, skin 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Polyp stromal X 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Lymph node + + + 10 

Iliac, histiocytic sarcoma X 1 

Iliac, rhabdomyosarcoma, metastatic, 

skeletal muscle 1 

Mediastinal, sarcoma, metastatic, mesentery 1 

Pancreatic, sarcoma, metastatic, mesentery 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Schwannoma malignant, metastatic, skin 1 

Lymph node, mesenteric + + + + + + + + + + + + + M + + + + + + + + + + + 47 

Histiocytic sarcoma X X 2 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Thymus + + + + + + + + + M + + + I + + + + + + + + + + + 44 

Histiocytic sarcoma X 1 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X 1 

Subcutaneous tissue, sarcoma 2 

Subcutaneous tissue, schwannoma malignant 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle 1 

Rhabdomyosarcoma 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

242 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

0 0 0 1 3 4 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

Number of Days on Study 0 1 2 7 7 1 5 7 9 0 0 4 4 7 7 8 9 1 1 2 2 2 2 2 2 

4 6 0 2 2 9 5 3 9 5 8 2 9 4 7 0 6 1 3 4 9 9 9 9 9 

2 2 2 3 2 3 2 2 2 2 2 3 2 2 2 2 2 3 2 3 2 2 2 2 2 

Carcass ID Number 7 8 7 0 8 1 9 8 6 7 9 0 7 9 9 8 6 0 7 0 6 6 7 7 7 

0 4 9 5 1 1 5 9 9 7 1 1 1 4 7 2 8 6 5 7 6 7 2 3 4 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Histiocytic sarcoma 

Rhabdomyosarcoma, metastatic, 

skeletal muscle 

+++++++++++ ++++++++++++++ 

X X 

X 

Sarcoma, metastatic, mesentery 

Schwannoma malignant, metastatic, skin 

Mediastinum, schwannoma malignant, 

metastatic, skin 

Nose 

X 

X 

X 

+++++++++++ ++++++++++++++ 

Trachea +++++++++++ ++++++++++++++ 

Special Senses System 

Harderian gland 

Adenoma 

Urinary System 

Kidney 

Histiocytic sarcoma 

Schwannoma malignant, metastatic, skin 

Urinaryb ladder 

Histiocytic sarcoma 

+++++++++++ ++++++++++++++ 

X 

A++++++++++ ++++++++++++++ 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Leukemia granulocytic 

Lymphoma malignant 

+++++++++++ ++++++++++++++ 

X 

X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 243 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 125 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 7 7 8 8 8 8 8 8 9 9 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 

6 8 0 3 5 6 7 8 0 2 3 6 8 9 0 2 3 4 8 9 0 2 3 4 5 

Tissues/ 

Tumors 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Histiocytic sarcoma 

Rhabdomyosarcoma, metastatic, 

skeletal muscle 

+++++++++++ ++++++++++++++ 

X 

X 

X 

50 

3 

1 

1 

1 

Sarcoma, metastatic, mesentery 

Schwannoma malignant, metastatic, skin 

Mediastinum, schwannoma malignant, 

metastatic, skin 

Nose +++++++++++ ++++++++++++++ 

1 

1 

1 

50 

Trachea +++++++++++ ++++++++++++++ 50 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

1 

1 

Urinary System 

Kidney 

Histiocytic sarcoma 

Schwannoma malignant, metastatic, skin 

Urinaryb ladder 

Histiocytic sarcoma 

+++++++++++ ++++++++++++++ 

X 

+++++++++++ ++++++++++++++ 

X 

50 

1 

1 

49 

1 

Systemic Lesions 

Multipleo rgans 

Histiocytic sarcoma 

Leukemia granulocytic 

Lymphoma malignant 

+++++++++++ ++++++++++++++ 

X X 

X X X 

50 

2 

1 

7 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

244 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

0 0 0 1 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 

Number of Days on Study 0 3 4 7 1 0 5 6 8 2 3 3 4 4 5 7 8 9 9 9 9 0 0 0 1 

3 3 0 5 7 9 6 4 3 4 2 3 2 8 9 8 4 2 6 7 9 0 0 8 2 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

Carcass ID Number 2 3 1 1 6 5 4 6 5 5 4 2 3 5 4 6 2 4 2 2 3 2 4 4 5 

9 7 6 8 0 4 2 5 2 5 8 0 4 7 7 4 7 5 2 4 6 6 3 1 9 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 

Gallbladder AAA + AAAAAM+ + + A + + A + AAA + AA + 

Intestine large, colon +A+++++++++ ++A+++++++++++ 

Intestine large, rectum AA+ + + + + + + ++ + +A+ + + + + + + + + + + 

Intestine large, cecum AA+ + + + +A+ ++ A+A+A+ + +AA+AA+ 

Intestine small, duodenum A A A + + M + A + + A + + A A + A + + A + + A + + 

Intestine small, jejunum A A A + A + + A + + + + A A + A A + + A A + M + + 

Intestine small, ileum A A A + A + + A + + A A + A A + A + + A A + A + + 

Liver +++++++++++ ++++++++++++++ 

Hepatoblastoma X X X X X 

Hepatoblastoma, multiple X 

Hepatocellular carcinoma XX X XX XX X X 

Hepatocellular carcinoma, multiple X X 

Hepatocellular adenoma X X X 

Hepatocellular adenoma, multiple X XX X X XXXXXXXXXX 

Mesentery +++ + + 

Hepatoblastoma, metastatic, liver X 

Pancreas +A+++++++++ ++A+++++A+++++ 

Salivary glands +M+ + + + + + + ++ + + + + + + + + + + + + + + 

Stomach, forestomach +++++++++++ ++A+++++++++++ 

Stomach, glandular + A +++++++++ ++A+++++++++++ 

Cardiovascular System 

Blood vessel MM + + + + + + + + + + + A + + + + + + + + + + + 

Heart +++++++++++ ++++++++++++++ 

Sarcoma, metastatic, skin X 

Endocrine System 

Adrenal cortex + + + + + + + + + ++M+A+ + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + MMA + + + + + + + + AM + 

Islets, pancreatic +A+++++++++ ++A+++++A+++++ 

Parathyroid gland + M + M + + M + A +M + M + M + + M + MM + + MM 

Pituitary gland + I M + + + + + + I M I + + + + + + + + + + MM + 

Pars distalis, adenoma X 

Thyroid gland +++++++++++ ++++++++++++++ 

Follicular cell, adenoma 

General Body System 

Peritoneum + + 

Hepatoblastoma, metastatic, liver X 

Tissue NOS + 

Alveolar/bronchiolar carcinoma,

 metastatic, lung 

Hepatoblastoma, metastatic, liver X 

Genital System 

Clitoral gland +M+ + + + + + + ++ + + + + + + + + + + + + + + 

Ovary + + + + + +M+ + ++ + +A+ + + + +A+ + + + + 

Cystadenoma 

Granulosa cell tumor benign X 

Uterus +A+++++++++ ++A+++++A+++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 245 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 3 7 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 6 3 2 1 1 2 2 2 3 3 3 3 3 3 4 4 4 4 5 5 5 5 5 6 6 Tissues/ 

1 8 3 7 9 1 5 8 0 1 2 3 5 9 0 4 6 9 0 1 3 6 8 2 3 Tumors 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 50 

Gallbladder + + +M+ + + + + ++ + + + + + + + + + + + + + + 33 

Intestine large, colon ++A++++++++ ++++++++++++++ 47 

Intestine large, rectum +++++++++++ ++++++++++++++ 47 

Intestine large, cecum +++++++++++ ++++++++++++++ 40 

Intestine small, duodenum +++++++++++ ++++++++++++++ 39 

Intestine small, jejunum +++++++++++ ++++++++++++++ 38 

Intestine small, ileum +++++++++++ ++++++++++++++ 37 

Liver +++++++++++ ++++++++++++++ 50 

Hepatoblastoma X 6 

Hepatoblastoma, multiple X X 3 

Hepatocellular carcinoma X X X X X X X X X X 19 

Hepatocellular carcinoma, multiple XX XXXX X XX X XX 14 

Hepatocellular adenoma XX X 6 

Hepatocellular adenoma, multiple XXXXXXXXXXX XXXXXX XXXXX 37 

Mesentery + M+ + + ++ + + 13 

Hepatoblastoma, metastatic, liver 1 

Pancreas +++++++++++ ++++++++++++++ 47 

Salivary glands +++++++++++ ++++++++++++++ 49 

Stomach, forestomach +++++++++++ ++++++++++++++ 49 

Stomach, glandular +++++++++++ ++++++++++++++ 48 

Cardiovascular System 

Blood vessel +++++++++++ ++++++++++++++ 47 

Heart +++++++++++ ++++++++++++++ 50 

Sarcoma, metastatic, skin 1 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 48 

Adrenal medulla +++++++++++ ++++++++++++++ 45 

Islets, pancreatic +++++++++++ ++++++++++++++ 47 

Parathyroid gland + M + + + M + MMM+ + + + M + + M + M + + + + + 30 

Pituitary gland + + + + + + + + + ++ + + + + + + + + + + +M+ + 42 

Pars distalis, adenoma X X X X X 6 

Thyroid gland +++++++++++ ++++++++++++++ 50 

Follicular cell, adenoma X X X 3 

General Body System 

Peritoneum 2 

Hepatoblastoma, metastatic, liver 1 

Tissue NOS + 2 

Alveolar/bronchiolar carcinoma, 

metastatic, lung X 1 

Hepatoblastoma, metastatic, liver 1 

Genital System 

Clitoral gland + + + + + + + + + ++ +M+ + + + + + + + + + + + 48 

Ovary + + +M+ + + + + ++ + + + + + + + + + + + + + + 46 

Cystadenoma X 1 

Granulosa cell tumor benign 1 

Uterus +++++++++++ ++++++++++++++ 47 
 

 

 

 

 

 

 

 

 

 

 

 

 

246 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

0 0 0 1 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 

Number of Days on Study 0 3 4 7 1 0 5 6 8 2 3 3 4 4 5 7 8 9 9 9 9 0 0 0 1 

3 3 0 5 7 9 6 4 3 4 2 3 2 8 9 8 4 2 6 7 9 0 0 8 2 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

Carcass ID Number 2 3 1 1 6 5 4 6 5 5 4 2 3 5 4 6 2 4 2 2 3 2 4 4 5 

9 7 6 8 0 4 2 5 2 5 8 0 4 7 7 4 7 5 2 4 6 6 3 1 9 

Hematopoietic System 

Bone marrow ++++A++++++ ++++++++++++++ 

Lymph node 

Pancreatic, hepatoblastoma, 

metastatic, liver 

Lymphn ode, mandibular 

Sarcoma, metastatic, skin 

Lymphn ode, mesenteric 

Hepatoblastoma, metastatic, liver 

Spleen 

Thymus 

Alveolar/bronchiolar carcinoma,

 metastatic, lung 

++ ++ + 

X 

+M+ + + + + + + ++ + + + + + + + + + + + + + + 

X 

MA + + + + + + + +A + + A +M+ + + A + + + + + 

X 

+++++++++++ ++A+++++A+++++ 

+M+ + + + + + + ++ + +M+M+ + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

+++++++++++ ++A+++++++++++ 

+++++++++++ ++++++++++++++ 

Subcutaneous tissue, hemangioma 

Subcutaneous tissue, hemangiosarcoma 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant 

X 

X 

X X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Skeletal muscle + 

Hepatoblastoma, metastatic, liver X 

Nervous System 

Brain +++++++++++ ++++++++++++++ 

Respiratory System 

Lung +++++++++++ ++++++++++++++ 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver X 

Hepatocellular carcinoma, metastatic, liver X X 

Sarcoma, metastatic, skin X X 

Mediastinum, alveolar/bronchiolar

 carcinoma, metastatic, lung 

Mediastinum, sarcoma, metastatic, skin X 

Nose +A+++++A+++ ++A+++++++++++ 
 

Trachea +++++++++++ ++++++++++++++ 
 

Special Senses System 

None 

Urinary System 

Kidney +++++++++++ ++++++++++++A+ 

Urinary bladder +A+ +M+ +A+ ++ + +A+ + + +AA+ + + + + 

Systemic Lesions 

Multiple organs +++++++++++ ++++++++++++++ 

Lymphoma malignant X X XX 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 247 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 250 ppm 

Number of Days on Study 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

2 3 7 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

Carcass ID Number 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

6 3 2 1 1 2 2 2 3 3 3 3 3 3 4 4 4 4 5 5 5 5 5 6 6 

1 8 3 7 9 1 5 8 0 1 2 3 5 9 0 4 6 9 0 1 3 6 8 2 3 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Pancreatic, hepatoblastoma, 

metastatic, liver 

Lymphn ode, mandibular 

Sarcoma, metastatic, skin 

Lymphn ode, mesenteric 

Hepatoblastoma, metastatic, liver 

Spleen 

Thymus 

Alveolar/bronchiolar carcinoma, 

metastatic, lung 

+++++++++++ ++++++++++++++ 

+ + 

+++++++++++ ++++++++++++++ 

+ + + + + + + + + ++ + + + + + + +M+ + + + + + 

+++++++++++ ++++++++++++++ 

M+ + + + + + + + ++ + + + + + + + + + + + + + + 

X 

49 

7 

1 

49 

1 

43 

1 

48 

46 

1 

Integumentary System 

Mammaryg land 

Skin 

Subcutaneous tissue, hemangioma 

Subcutaneous tissue, hemangiosarcoma 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

X 

X 

49 

50 

1 

1 

3 

1 

Musculoskeletal System 

Bone 

Skeletal muscle 

Hepatoblastoma, metastatic, liver 

+++++++++++ ++++++++++++++ 50 

1 

1 

Nervous System 

Brain 

Respiratory System 

Lung 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver 

Hepatocellular carcinoma, metastati

Sarcoma, metastatic, skin 

Mediastinum, alveolar/bronchiolar 

carcinoma, metastatic, lung 

Mediastinum, sarcoma, metastatic,

Nose 

Trachea 

Special Senses System 

None 

Urinary System 

Kidney 

Urinaryb ladder 

c, liver 

skin 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

X X 

X X X X 

X 1 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

50 

50 

2 

1 

6 

2 

1 

47 

50 

49 

44 

Systemic Lesions 

Multipleo rgans 

Lymphoma malignant 

+++++++++++ ++++++++++++++ 50 

4 
 

 

 

 

 

 

 

 

 

248 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

0 0 0 1 2 3 4 4 5 5 5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 

Number of Days on Study 1 1 1 8 9 6 3 7 1 2 7 9 1 2 7 8 8 9 9 0 0 2 2 2 2 

2 4 5 8 9 6 0 9 0 6 1 5 5 6 7 0 6 0 0 0 3 9 9 9 9 

4 4 3 4 3 3 4 3 3 3 4 3 3 3 4 4 3 3 3 3 4 3 3 3 3 

Carcass ID Number 1 0 9 0 9 7 1 9 9 7 1 8 8 9 0 0 7 8 9 7 0 6 6 6 6 

3 5 5 6 1 1 4 9 4 7 5 8 4 8 2 4 2 6 3 4 9 6 7 8 9 

Alimentary System 

Esophagus +++++++++++ ++++++++++++++ 

Gallbladder +M+ + + + + +A++ + + + A A A AMMAMA + M 

Intestine large, colon A+ + + + + + + + ++ + + +AA+ + +AA+ + + + 

Intestine large, rectum + + + + + + + + + ++ + + + +AA+ +A+ + + + + 

Intestine large, cecum A+ + + + + + + + ++ + + +A+AA+A+ + + + + 

Leiomyosarcoma 

Intestine small, duodenum A+++++++A++ +++ AAAA+AA ++++ 

Intestine small, jejunum A A + + + + + + + ++ + + +A+M+AAA+ + + + 

Intestine small, ileum A++A+++++++ +++ AAAAAAA ++++ 

Carcinoma 

Liver +++++++++++ ++++++++++++++ 

Hemangioma X 

Hepatoblastoma X X X X XXX 

Hepatoblastoma, multiple 

Hepatocellular carcinoma X X X X XX 

Hepatocellular carcinoma, multiple XX XXXXX X XX 

Hepatocellular adenoma X X X X 

Hepatocellular adenoma, multiple X X X X X X X X X 

Mesentery + + ++ + 

Hepatoblastoma, metastatic, liver X 

Pancreas +++++++++++ ++++++A++A++++ 

Salivary glands +++++++++++ ++++++++++++++ 

Stomach, forestomach +++++++++++ +++++++++A++++ 

Stomach, glandular +++++++++++ +++++++++A++++ 

Cardiovascular System 

Blood vessel M+ + + + + + + ++ + + + + + + + + + + + + + + 

Heart +++++++++++ ++++++++++++++ 

Endocrine System 

Adrenal cortex +++++++++++ ++++++++++++++ 

Adrenal medulla + + + + + + + + + ++ + + + + +M+ + + + + + + + 

Islets, pancreatic +++++++++++ +++++++++A++++ 

Parathyroid gland + M + + + + + + + M+ + + + M + M + + MM + + + + 

Pituitary gland + + + + + + + + + ++ + +M+ + + + + +M+ + +M 

Pars distalis, adenoma 

Thyroid gland +++++++++++ ++++++++++++++ 

Follicular cell, adenoma X X 

General Body System 

None 

Genital System 

Clitoral gland + MM + + + + + + + + + + M + + + + + + + + + + + 

Ovary + + + + + + + + + + + + + + + + + + I + + + + + + 

Hemangioma 

Uterus +++++++++++ ++++++++++++++ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 249 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 7 7 7 7 7 7 8 8 8 8 8 8 8 9 9 9 9 0 0 0 0 0 1 1 1 Tissues/ 

0 3 5 6 8 9 0 1 2 3 5 7 9 0 2 6 7 0 1 3 7 8 0 1 2 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder M + M + + + + M + + + M + + + + + + + + + + + + + 34 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 45 

Leiomyosarcoma X 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 42 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 43 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 41 

Carcinoma X 1 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma 1 

Hepatoblastoma X X X X X 12 

Hepatoblastoma, multiple XX X X 4 

Hepatocellular carcinoma X X X X X 11 

Hepatocellular carcinoma, multiple X X X X X X X X X X X X X X X X X X X X 30 

Hepatocellular adenoma 4 

Hepatocellular adenoma, multiple X X X X X X X X X X X X X X X X X X X X X 30 

Mesentery ++ +++ ++ + 13 

Hepatoblastoma, metastatic, liver 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Cardiovascular System 

Blood vessel + + + M + + + + + + + + + + + + + + + + + + + + + 47 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Parathyroid gland + + M + + + M + + + + + M M M + M + M M + + + + + 36 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + M + 46 

Pars distalis, adenoma X X 2 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X 3 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + I + + + + + + + M + + + + + + 45 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangioma X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

250 Pyridine, NTP TR 470 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

0 0 0 1 2 3 4 4 5 5 5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 

Number of Days on Study 1 1 1 8 9 6 3 7 1 2 7 9 1 2 7 8 8 9 9 0 0 2 2 2 2 

2 4 5 8 9 6 0 9 0 6 1 5 5 6 7 0 6 0 0 0 3 9 9 9 9 

4 4 3 4 3 3 4 3 3 3 4 3 3 3 4 4 3 3 3 3 4 3 3 3 3 

Carcass ID Number 1 0 9 0 9 7 1 9 9 7 1 8 8 9 0 0 7 8 9 7 0 6 6 6 6 

3 5 5 6 1 1 4 9 4 7 5 8 4 8 2 4 2 6 3 4 9 6 7 8 9 

Hematopoietic System 

Bone marrow +++++++++++ ++++++++++++++ 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Hemangioma 

Hepatoblastoma, metastatic, liver 

Spleen 

Thymus 

+ + 

+ + + + + + + + + M+ + + + + + + + + + + + MM + 

MM + + + + + + + + + + + + A + A + + + A + + + + 

X 

M+ + + + + + + + ++ + + + + + + + + + + + + + + 

+ + + + + + + + + M + + + M M + M M A M M + I + I 

Integumentary System 

Mammary gland 

Skin 

+ + + + + + + + + ++ + + + + + + + +M+ + + + + 

+++++++++++ ++++++++++++++ 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant 

X X X 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 

Skeletal muscle + 

Nervous System 

Brain +++++++++++ ++++++++++++++ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Nose 

+++++++++++ ++++++++++++++ 

X 

X X X 

X 

X X X 

+++++++++++ ++++++++++++++ 

Sarcoma X 

Trachea +++++++++++ ++++++++++++++ 

Special Senses System 

Harderian gland 

Carcinoma 

Urinary System 

Kidney 

Urinary bladder 

A++++++++++ ++++++++++++++ 

+++++++++++ +++ AAAAAAA ++++ 

Systemic Lesions 

Multipleo rgans 

Lymphoma malignant 

Mesothelioma malignant 

+++++++++++ ++++++++++++++ 

X 

X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 251 

TABLE E2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Pyridine: 500 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 7 7 7 7 7 7 8 8 8 8 8 8 8 9 9 9 9 0 0 0 0 0 1 1 1 

0 3 5 6 8 9 0 1 2 3 5 7 9 0 2 6 7 0 1 3 7 8 0 1 2 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow +++++++++++ ++++++++++++++ 50 

Lymph node 

Lymphn ode, mandibular 

Lymphn ode, mesenteric 

Hemangioma 

Hepatoblastoma, metastatic, liver 

Spleen 

Thymus 

+ + + ++ 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

X 

+++++++++++ ++++++++++++++ 

+ + + + + + + + + ++ +M+ + + + + + + + + + + + 

7 

47 

45 

1 

1 

49 

39 

Integumentary System 

Mammary gland 

Skin 

+ + +M+ + + + + ++ + + + + + + + + + + + + + + 

+++++++++++ ++++++++++++++ 

48 

50 

Subcutaneous tissue, sarcoma 

Subcutaneous tissue, schwannoma malignant 

X 

X 

4 

1 

Musculoskeletal System 

Bone +++++++++++ ++++++++++++++ 50 

Skeletal muscle 1 

Nervous System 

Brain +++++++++++ ++++++++++++++ 50 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Hepatoblastoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Nose 

+++++++++++ ++++++++++++++ 

X X 

X X 

XX X XX X X 

+++++++++++ ++++++++++++++ 

50 

3 

3 

3 

10 

50 

Sarcoma 1 

Trachea +++++++++++ ++++++++++++++ 50 

Special Senses System 

Harderian gland 

Carcinoma 

+ 

X 

1 

1 

Urinary System 

Kidney 

Urinary bladder 

+++++++++++ ++++++++++++++ 

+++++++++++ ++++++++++++++ 

49 

43 

Systemic Lesions 

Multipleo rgans 

Lymphoma malignant 

Mesothelioma malignant 

+++++++++++ ++++++++++++++ 

X X X XX 

50 

6 

2 
252 Pyridine, NTP TR 470 

TABLE E3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Liver: Hepatocellular Adenoma 

Overall ratea 37/49 (76%) 39/50 (78%) 43/50 (86%) 34/50 (68%)
 

Adjusted rateb 82.5% 87.9% 97.3% 79.1%
 

Terminal ratec 27/32 (84%) 27/30 (90%) 22/22 (100%) 23/29 (79%)
 

First incidence (days) 554 419 509 430
 

Poly-3 testd P=0.372N P=0.336 P=0.015 P=0.442N
 

Liver: Hepatocellular Carcinoma 

Overall rate 13/49 (27%) 23/50 (46%) 33/50 (66%) 41/50 (82%)
 

Adjusted rate 29.8% 55.0% 78.1% 97.1%
 

Terminal rate 8/32 (25%) 18/30 (60%) 20/22 (91%) 29/29 (100%)
 

First incidence (days) 476 573 556 479
 

Poly-3 test P<0.001 P=0.014 P<0.001 P<0.001
 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 41/49 (84%) 42/50 (84%) 44/50 (88%) 44/50 (88%)
 

Adjusted rate 89.9% 94.6% 98.4% 99.5%
 

Terminal rate 29/32 (91%) 29/30 (97%) 22/22 (100%) 29/29 (100%)
 

First incidence (days) 476 419 509 430
 

Poly-3 test P=0.011 P=0.323 P=0.081 P=0.045
 

Liver: Hepatoblastoma 

Overall rate 1/49 (2%) 2/50 (4%) 9/50 (18%) 16/50 (32%)
 

Adjusted rate 2.4% 4.9% 21.6% 39.6%
 

Terminal rate 1/32 (3%) 1/30 (3%) 3/22 (14%) 12/29 (41%)
 

First incidence (days) 729 (T) 599 564 510
 

Poly-3 test P<0.001 P=0.493 P=0.007 P<0.001
 

Liver: Hepatocellular Carcinoma or Hepatoblastoma 

Overall rate 13/49 (27%) 23/50 (46%) 36/50 (72%) 43/50 (86%)
 

Adjusted rate 29.8% 55.0% 82.8% 99.0%
 

Terminal rate 8/32 (25%) 18/30 (60%) 20/22 (91%) 29/29 (100%)
 

First incidence (days) 476 573 556 479
 

Poly-3 test P<0.001 P=0.014 P<0.001 P<0.001
 

Liver: Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastoma 

Overall rate 41/49 (84%) 42/50 (84%) 45/50 (90%) 44/50 (88%)
 

Adjusted rate 89.9% 94.6% 99.6% 99.5%
 

Terminal rate 29/32 (91%) 29/30 (97%) 22/22 (100%) 29/29 (100%)
 

First incidence (days) 476 419 509 430
 

Poly-3 test P=0.009 P=0.323 P=0.042 P=0.045
 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 2/50 (4%) 3/50 (6%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 4.7% 7.2% 0.0% 7.8% 

Terminal rate 2/32 (6%) 1/30 (3%) 0/22 (0%) 2/29 (7%) e First incidence (days) 729 (T) 555 — 703 

Poly-3 test P=0.463 P=0.486 P=0.254N P=0.455 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 2/50 (4%) 1/50 (2%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 4.7% 2.5% 5.0% 7.6% 

Terminal rate 1/32 (3%) 1/30 (3%) 1/22 (5%) 0/29 (0%) 

First incidence (days) 662 729 (T) 727 595 

Poly-3 test P=0.287 P=0.521N P=0.665 P=0.460 
Pyridine, NTP TR 470 253 

TABLE E3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 4/50 (8%) 4/50 (8%) 2/50 (4%) 5/50 (10%) 

Adjusted rate 9.3% 9.6% 5.0% 12.7% 

Terminal rate 3/32 (9%) 2/30 (7%) 1/22 (5%) 2/29 (7%) 

First incidence (days) 662 555 727 595 

Poly-3 test P=0.399 P=0.624 P=0.374N P=0.445 

Ovary: Cystadenoma 

Overall rate 4/47 (9%) 3/49 (6%) 1/46 (2%) 0/49 (0%) 

Adjusted rate 9.9% 7.6% 2.7% 0.0% 

Terminal rate 4/32 (13%) 2/29 (7%) 1/21 (5%) 0/29 (0%) 

First incidence (days) 729 (T) 696 729 (T) — 

Poly-3 test P=0.029N P=0.513N P=0.210N P=0.069N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 8/47 (17%) 9/44 (20%) 6/42 (14%) 2/46 (4%) 

Adjusted rate 19.7% 25.0% 17.1% 5.7% 

Terminal rate 8/31 (26%) 6/26 (23%) 5/21 (24%) 2/27 (7%) 

First incidence (days) 729 (T) 608 700 729 (T) 

Poly-3 test P=0.041N P=0.391 P=0.502N P=0.071N 

Skin (Subcutaneous Tissue): Sarcoma 

Overall rate 2/50 (4%) 2/50 (4%) 3/50 (6%) 4/50 (8%) 

Adjusted rate 4.7% 4.9% 7.4% 9.9% 

Terminal rate 2/32 (6%) 1/30 (3%) 0/22 (0%) 1/29 (3%) 

First incidence (days) 729 (T) 573 556 299 

Poly-3 test P=0.197 P=0.679 P=0.477 P=0.311 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 3/50 (6%) 2/50 (4%) 3/50 (6%) 3/50 (6%) 

Adjusted rate 7.0% 4.9% 7.6% 7.8% 

Terminal rate 3/32 (9%) 1/30 (3%) 3/22 (14%) 3/29 (10%) 

First incidence (days) 729 (T) 674 729 (T) 729 (T) 

Poly-3 test P=0.472 P=0.522N P=0.628 P=0.615 

All Organs: Hemangioma 

Overall rate 0/50 (0%) 0/50 (0%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 2.5% 7.7% 

Terminal rate 0/32 (0%) 0/30 (0%) 1/22 (5%) 2/29 (7%) 

First incidence (days) 

Poly-3 test 

— 

P=0.017 

— 

—f 729 (T) 

P=0.485 

615 

P=0.103 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 0/50 (0%) 0/50 (0%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 5.0% 7.7% 

Terminal rate 0/32 (0%) 0/30 (0%) 1/22 (5%) 2/29 (7%) 

First incidence (days) — — 723 615 

Poly-3 test P=0.022 — P=0.221 P=0.103 

All Organs: Malignant Lymphoma 

Overall rate 6/50 (12%) 7/50 (14%) 4/50 (8%) 6/50 (12%) 

Adjusted rate 13.9% 17.1% 9.8% 15.3% 

Terminal rate 2/32 (6%) 5/30 (17%) 0/22 (0%) 5/29 (17%) 

First incidence (days) 687 599 624 510 

Poly-3 test P=0.546N P=0.460 P=0.407N P=0.554 
254 

c 

Pyridine, NTP TR 470 

TABLE E3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

All Organs: Benign Neoplasms 

Overall rate 40/50 (80%) 41/50 (82%) 43/50 (86%) 36/50 (72%) 

Adjusted rate 85.5% 91.5% 97.3% 83.7% 

Terminal rate 28/32 (88%) 28/30 (93%) 22/22 (100%) 25/29 (86%) 

First incidence (days) 151 419 509 430 

Poly-3 test P=0.445N P=0.275 P=0.035 P=0.527N 

All Organs: Malignant Neoplasms 

Overall rate 26/50 (52%) 30/50 (60%) 40/50 (80%) 44/50 (88%) 

Adjusted rate 56.0% 69.7% 90.1% 99.2% 

Terminal rate 14/32 (44%) 20/30 (67%) 20/22 (91%) 29/29 (100%) 

First incidence (days) 375 573 556 299 

Poly-3 test P<0.001 P=0.128 P<0.001 P<0.001 

All Organs: Benign or Malignant Neoplasms 

Overall rate 47/50 (94%) 45/50 (90%) 45/50 (90%) 45/50 (90%) 

Adjusted rate 96.5% 99.7% 99.6% 99.7% 

Terminal rate 31/32 (97%) 30/30 (100%) 22/22 (100%) 29/29 (100%) 

First incidence (days) 151 419 509 299 

Poly-3 test P=0.174 P=0.348 P=0.366 P=0.347 

(T)Terminal sacrifice

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver, lung, ovary, 

pituitary gland, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Observed incidence at terminal kill 

d	 Beneath the control incidence are the P values associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A 

negative trend or a lower incidence in an exposure group is indicated by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
Pyridine, NTP TR 470 255 

TABLE E4 

Historical Incidence of Liver Neoplasms in Untreated Female B6C3F1 Micea 

Incidence in Controls 

Hepatocellular 

Adenoma 

Hepatocellular 

Carcinoma 

Hepatoblastoma Hepatocellular Adenoma, 

Hepatocellular Carcinoma, 

or Hepatoblastoma 

Overall Historical Incidence 

Total 

Standard deviation 

Range 

150/289 (51.9%) 

20.8% 

26%-80% 

55/289 (19.0%) 

13.7% 

8%-42% 

0/289 173/289 (59.9%) 

21.3% 

32%-82% 

a Data as of 1 August 1997 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

256 Pyridine, NTP TR 470 

TABLE E5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Pyridinea 

0 ppm 125 ppm 250 ppm 500 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 3 6 4 5 

Moribund 3 2 3 5 

Natural deaths 12 12 21 11 

Survivors 

Terminal sacrifice 32 30 22 29 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Gallbladder (37) (40) (33) (34) 

Hyperplasia 1 (3%) 

Intestine large, rectum (44) (48) (47) (47) 

Artery, necrosis 1 (2%) 

Intestine large, cecum (44) (49) (40) (45) 

Edema 1 (3%) 

Intestine small, jejunum (42) (47) (38) (43) 

Peyer’s patch, hyperplasia, lymphoid 1 (2%) 

Intestine small, ileum (43) (48) (37) (41) 

Peyer’s patch, hyperplasia, lymphoid 1 (2%) 

Liver (49) (50) (50) (50) 

Basophilic focus 1 (2%) 

Clear cell focus 1 (2%) 5 (10%) 1 (2%) 2 (4%) 

Cyst 1 (2%) 

Eosinophilic focus 17 (35%) 12 (24%) 14 (28%) 9 (18%) 

Hematopoietic cell proliferation 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Infiltration cellular, lymphocyte 4 (8%) 

Mixed cell focus 5 (10%) 4 (8%) 3 (6%) 

Necrosis 5 (10%) 2 (4%) 5 (10%) 7 (14%) 

Vacuolization cytoplasmic, diffuse 1 (2%) 1 (2%) 

Centrilobular, congestion 1 (2%) 

Centrilobular, degeneration 1 (2%) 1 (2%) 

Midzonal, vacuolization cytoplasmic 1 (2%) 

Periportal, vacuolization cytoplasmic 2 (4%) 1 (2%) 

Mesentery (17) (18) (13) (13) 

Infiltration cellular, lymphocyte 1 (6%) 

Inflammation, chronic active 2 (12%) 

Fat, necrosis 12 (71%) 13 (72%) 11 (85%) 9 (69%) 

Pancreas (49) (49) (47) (48) 

Infiltration cellular, lymphocyte 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 2 (4%) 

Acinus, atrophy 2 (4%) 1 (2%) 2 (4%) 

Artery, inflammation, chronic 1 (2%) 

Duct, cyst 1 (2%) 2 (4%) 2 (4%) 

Salivary glands (50) (50) (49) (50) 

Infiltration cellular, lymphocyte 33 (66%) 35 (70%) 36 (73%) 29 (58%) 

Stomach, forestomach (49) (49) (49) (49) 

Ulcer 1 (2%) 

Epithelium, hyperplasia 1 (2%) 

Stomach, glandular (48) (49) (48) (49) 

Necrosis 3 (6%) 3 (6%) 4 (8%) 3 (6%) 

Tooth (2) 

Developmental malformation 2 (100%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 257 

TABLE E5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Cardiovascular System 

Blood vessel (48) (47) (47) (47) 

Aorta, inflammation, chronic active 1 (2%) 

Heart (50) (50) (50) (50) 

Cardiomyopathy 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 1 (2%) 

Atrium, thrombosis 1 (2%) 

Endocrine System 

Adrenal cortex (49) (50) (48) (50) 

Cytoplasmic alteration 2 (4%) 2 (4%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 2 (4%) 

Hyperplasia 1 (2%) 

Capsule, hyperplasia 41 (84%) 35 (70%) 39 (81%) 37 (74%) 

Adrenal medulla (49) (49) (45) (49) 

Hyperplasia 1 (2%) 2 (4%) 

Islets, pancreatic (49) (50) (47) (49) 

Hyperplasia 2 (4%) 3 (6%) 

Parathyroid gland (31) (29) (30) (36) 

Infiltration cellular, lymphocyte 1 (3%) 

Pituitary gland (47) (44) (42) (46) 

Hemorrhage 1 (2%) 

Pars distalis, angiectasis 1 (2%) 1 (2%) 

Pars distalis, hyperplasia 5 (11%) 4 (9%) 6 (14%) 8 (17%) 

Pars intermedia, hyperplasia 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Infiltration cellular, lymphocyte 3 (6%) 3 (6%) 

C-cell, hyperplasia 1 (2%) 

Follicle, cyst 4 (8%) 1 (2%) 

Follicular cell, hyperplasia 14 (28%) 21 (42%) 22 (44%) 23 (46%) 

General Body System 

Peritoneum (2) 

Inflammation, chronic active 1 (50%) 

Genital System 

Clitoral gland (47) (48) (48) (45) 

Atrophy 45 (96%) 43 (90%) 45 (94%) 43 (96%) 

Cyst 3 (6%) 

Inflammation, chronic 2 (4%) 2 (4%) 1 (2%) 4 (9%) 

Inflammation, chronic active 2 (4%) 3 (6%) 

Pigmentation 2 (4%) 1 (2%) 3 (7%) 

Ovary (47) (49) (46) (49) 

Angiectasis 1 (2%) 

Cyst 14 (30%) 9 (18%) 11 (24%) 11 (22%) 

Periovarian tissue, hyperplasia, lymphoid 1 (2%) 

Uterus (48) (50) (47) (50) 

Congestion 1 (2%) 

Cyst 3 (6%) 3 (6%) 5 (11%) 2 (4%) 

Hyperplasia, cystic 44 (92%) 43 (86%) 38 (81%) 39 (78%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Pigmentation 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

258 Pyridine, NTP TR 470 

TABLE E5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Hematopoietic System 

Bone marrow (49) (50) (49) (50) 

Atrophy 1 (2%) 1 (2%) 

Myeloid cell, hyperplasia 1 (2%) 2 (4%) 

Lymph node (10) (10) (7) (7) 

Iliac, hemorrhage 1 (10%) 

Iliac, hyperplasia, lymphoid 3 (30%) 2 (29%) 

Iliac, inflammation, chronic active 1 (14%) 

Iliac, pigmentation 1 (10%) 

Inguinal, hyperplasia, lymphoid 1 (14%) 

Mediastinal, hemorrhage 1 (10%) 1 (14%) 

Mediastinal, hyperplasia, plasma cell 1 (10%) 

Mediastinal, inflammation, chronic active 1 (10%) 

Mediastinal, pigmentation 1 (14%) 

Renal, hemorrhage 1 (14%) 

Renal, hyperplasia, lymphoid 1 (10%) 

Lymph node, mandibular (48) (50) (49) (47) 

Hemorrhage 3 (6%) 1 (2%) 1 (2%) 

Hyperplasia, lymphoid 2 (4%) 2 (4%) 

Lymph node, mesenteric (48) (47) (43) (45) 

Angiectasis 1 (2%) 2 (4%) 

Ectasia 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 

Hemorrhage 4 (8%) 2 (4%) 3 (7%) 2 (4%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 

Artery, necrosis 1 (2%) 

Spleen (49) (50) (48) (49) 

Atrophy 1 (2%) 1 (2%) 

Hematopoietic cell proliferation 29 (59%) 27 (54%) 32 (67%) 39 (80%) 

Hemorrhage 1 (2%) 1 (2%) 

Hyperplasia, lymphoid 2 (4%) 5 (10%) 4 (8%) 2 (4%) 

Inflammation, chronic active 1 (2%) 

Pigmentation 1 (2%) 1 (2%) 

Thymus (45) (44) (46) (39) 

Atrophy 11 (24%) 11 (25%) 13 (28%) 10 (26%) 

Ectopic parathyroid gland 1 (2%) 2 (4%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 

Inflammation, acute 1 (2%) 

Necrosis 2 (4%) 4 (9%) 3 (7%) 3 (8%) 

Integumentary System 

Mammary gland (47) (50) (49) (48) 

Hyperplasia 2 (4%) 1 (2%) 

Skin (49) (50) (50) (50) 

Inflammation, chronic active 1 (2%) 1 (2%) 1 (2%) 1 (2%) 

Subcutaneous tissue, necrosis 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Fibrous osteodystrophy 5 (10%) 2 (4%) 

Hyperostosis 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pyridine, NTP TR 470 259 

TABLE E5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Nervous System 

Brain (50) (50) (50) (50) 

Cyst epithelial inclusion 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 

Infiltration cellular, histiocyte 1 (2%) 

Mineralization 25 (50%) 27 (54%) 18 (36%) 19 (38%) 

Meninges, inflammation, chronic active 1 (2%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Congestion 2 (4%) 4 (8%) 3 (6%) 

Hemorrhage 1 (2%) 1 (2%) 

Infiltration cellular, lymphocyte 4 (8%) 2 (4%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Alveolar epithelium, hyperplasia 5 (10%) 3 (6%) 1 (2%) 

Alveolus, infiltration cellular, histiocyte 2 (4%) 2 (4%) 

Nose (50) (50) (47) (50) 

Foreign body 1 (2%) 

Olfactory epithelium, degeneration, hyaline 19 (38%) 27 (54%) 35 (74%) 36 (72%) 

Olfactory epithelium, inflammation,

 chronic active 1 (2%) 

Olfactory epithelium, necrosis 1 (2%) 

Respiratory epithelium, degeneration, hyaline 26 (52%) 16 (32%) 12 (26%) 13 (26%) 

Respiratory epithelium, hyperplasia 12 (24%) 8 (16%) 12 (26%) 4 (8%) 

Respiratory epithelium, inflammation,

 chronic active 3 (6%) 1 (2%) 

Respiratory epithelium, necrosis 1 (2%) 

Special Senses System 

None 

Urinary System 

Kidney (49) (50) (49) (49) 

Infarct 1 (2%) 2 (4%) 1 (2%) 

Infiltration cellular, plasma cell 1 (2%) 

Infiltration cellular, lymphocyte 4 (8%) 2 (4%) 5 (10%) 2 (4%) 

Nephropathy 5 (10%) 10 (20%) 7 (14%) 8 (16%) 

Glomerulus, amyloid deposition 1 (2%) 

Renal tubule, dilatation 1 (2%) 2 (4%) 2 (4%) 

Renal tubule, pigmentation 3 (6%) 2 (4%) 

Renal tubule, regeneration 1 (2%) 1 (2%) 

Urinary bladder (45) (49) (44) (43) 

Infiltration cellular, lymphocyte 16 (36%) 16 (33%) 17 (39%) 22 (51%) 
260 Pyridine, NTP TR 470
 
261 

APPENDIX F
 

GENETIC TOXICOLOGY
 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL .................................... 262 
 

MOUSE LYMPHOMA MUTAGENICITY TEST PROTOCOL .......................................... 262 
 

CHINESE HAMSTER OVARY CELL CYTOGENETICS PROTOCOLS ................................... 263 
 

DROSOPHILA MELANOGASTER TEST PROTOCOLS ................................................ 264 
 

MOUSE BONE MARROW CYTOGENETIC TEST PROTOCOLS ....................................... 265 
 

RESULTS ............................................................................... 266 
 

TABLE F1 Mutagenicity of Pyridine in Salmonella typhimurium ................................ 267 
 

TABLE F2 Induction of Trifluorothymidine Resistance in L5178Y Mouse Lymphoma Cells
 

by Pyridine .................................................................. 268 
 

TABLE F3 Induction of Sister Chromatid Exchanges in Chinese Hamster Ovary Cells
 

by Pyridine .................................................................. 270 
 

TABLE F4 Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells by Pyridine . . . . 271
 

TABLE F5 Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster
 

by Pyridine .................................................................. 272 
 

TABLE F6 Induction of Reciprocal Translocations in Drosophila melanogaster by Pyridine ......... 273 
 

TABLE F7 Induction of Chromosomal Aberrations in Mouse Bone Marrow Cells by Pyridine ...... 273 
 

TABLE F8 Induction of Micronuclei in Bone Marrow Polychromatic Erythrocytes of Mice
 

Treated with Pyridine by Intraperitoneal Injection ................................. 274 
 
262 Pyridine, NTP TR 470 

GENETIC TOXICOLOGY 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL 

Testing was performed as reported by Haworth et al. (1983). Pyridine was sent to the laboratory as a coded 

aliquot from Radian Corporation (Austin, TX). It was incubated with the Salmonella typhimurium tester 

strains TA98, TA100, TA1535, and TA1537 either in buffer or S9 mix (metabolic activation enzymes and 

cofactors from Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver) for 20 minutes at 37E

C. Top agar supplemented with L-histidine and d-biotin was added, and the contents of the tubes were mixed 

and poured onto the surfaces of minimal glucose agar plates. Histidine-independent mutant colonies arising on 

these plates were counted following incubation for 2 days at 37E C. 

Each trial consisted of triplicate plates of concurrent positive and negative controls and five doses of pyridine; 

10,000 μg/plate was selected as the high dose. All trials were repeated. 

In this assay, a positive response is defined as a reproducible, dose-related increase in histidine-independent 

(revertant) colonies in any one strain/activation combination. An equivocal response is defined as an increase 

in revertants that is not dose-related, is not reproducible, or is not of sufficient magnitude to support a 

determination of mutagenicity. A negative response is 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. 

MOUSE LYMPHOMA MUTAGENICITY TEST PROTOCOL 

The experimental protocol is presented in detail by McGregor et al. (1988). Pyridine was supplied as a coded 

aliquot by Radian Corporation. The high dose of pyridine did not exceed 5,000 μg/mL in the absence of 

toxicity. L5178Y mouse lymphoma cells were maintained at 37E C as suspension cultures in supplemented 

Fischer’s medium; normal cycling time was approximately 10 hours. To reduce the number of spontaneously 

occurring cells resistant to trifluorothymidine (TFT), subcultures were exposed to medium containing 

thymidine, hypoxanthine, methotrexate, and glycine for 1 day; to medium containing thymidine, hypoxanthine, 

and glycine for 1 day; and to normal medium for 3 to 5 days. For cloning, the horse serum content was 

increased and Noble agar was added. 

All treatment levels within an experiment, including concurrent positive and solvent controls, were replicated. 

Treated cultures contained 6 × 106

 cells in 10 mL medium. This volume included the S9 fraction in those 

experiments performed with metabolic activation. Incubation with pyridine continued for 4 hours, at which 

time the medium plus pyridine was removed, and the cells were resuspended in fresh medium and incubated 

for an additional 2 days to express the mutant phenotype. Cell density was monitored so that log phase growth 

was maintained. After the 48-hour expression period, cells were plated in medium and soft agar supplemented 

with TFT for selection of TFT-resistant cells, and cells were plated in nonselective medium and soft agar to 

determine cloning efficiency. Plates were incubated at 37E C in 5% CO2 for 10 to 12 days. The test was 

initially performed without S9. Because a clearly positive response was not obtained, the test was repeated 

using freshly prepared S9 from the livers of Aroclor 1254-induced male 344 rats. 

Minimum criteria for accepting an experiment as valid and a detailed description of the statistical analysis and 

data evaluation are presented by Caspary et al. (1988). All data were evaluated statistically for trend and peak 

responses. Both responses had to be significant (P# 0.05) for pyridine to be considered positive, i.e., capable 

of inducing TFT resistance. A single significant response led to a “questionable” conclusion, and the absence 

of both a trend and a peak response resulted in a “negative” call. 
 

Pyridine, NTP TR 470 263 

CHINESE HAMSTER OVARY CELL CYTOGENETICS PROTOCOLS 

Testing was performed as reported by Galloway et al. (1987). Pyridine was sent to the laboratory as a coded 

aliquot by Radian Corporation. It was tested in cultured Chinese 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 cofactor mix. Cultures were handled under gold 

lights to prevent photolysis of bromodeoxyuridine-substituted DNA. Each test consisted of concurrent solvent 

and positive controls and of at least three doses of pyridine; the high dose was limited by toxicity or, in the 

absence of toxicity, 5,000 μg/mL was selected as the high dose. A single flask per dose was used, and tests 

yielding equivocal or positive results were repeated. 

Sister Chromatid Exchange Test: In the SCE test without S9, CHO cells were incubated for 26 hours with 

pyridine in supplemented McCoy’s 5A medium. Bromodeoxyuridine (BrdU) was added 2 hours after culture 

initiation. After 26 hours, the medium containing pyridine was removed and replaced with fresh medium plus 

BrdU and Colcemid, and incubation was continued for 2 hours. Cells were then harvested by mitotic 

shake-off, fixed, and stained with Hoechst 33258 and Giemsa. In the SCE test with S9, cells were incubated 

with pyridine, serum-free medium, and S9 for 2 hours. The medium was then removed and replaced with 

medium containing serum and BrdU and no pyridine. Incubation proceeded for an additional 26 hours, with 

Colcemid present for the final 2 hours. Harvesting and staining were the same as for cells treated without S9. 

All slides were scored blind, and those from a single test were read by the same person. Fifty second-division 

metaphase cells were scored for frequency of SCEs/cell from each dose level. Because significant chemicalinduced cell cycle delay was seen, incubation time was lengthened to ensure a sufficient number of scorable 

(second-division metaphase) cells. 

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% above the 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 than 0.01; the probability for such a chance occurrence at two dose points is less than 

0.001. An increase of 20% or greater at any single dose was considered weak evidence of activity; increases at 

two or more doses resulted in a determination that the trial was positive. A statistically significant trend 

(P<0.005) in the absence of any responses reaching 20% above background led to a call of equivocal. 

Chromosomal Aberrations Test: In the Abs test without S9, cells were incubated in McCoy’s 5A medium 

with pyridine for 11.5 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 

with pyridine and S9 for 2 hours, after which the treatment medium was removed and the cells were incubated 

for 11.5 hours in fresh medium, with Colcemid present for the final 2 hours. Cells were harvested in the same 

manner as for the treatment without S9. The harvest time for the Abs test was based on the cell cycle 

information obtained in the SCE test. 

Cells were selected for scoring on the basis of good morphology and completeness of karyotype 

(21 ± 2 chromosomes). All slides were scored blind, and those from a single test were read by the same 

person. Two-hundred first-division metaphase cells were scored at each dose level. Classes of aberrations 

included simple (breaks and terminal deletions), complex (rearrangements and translocations), and other 

(pulverized cells, despiralized chromosomes, and cells containing 10 or more aberrations). 

Chromosomal aberration data are presented as 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 (P#0.05) difference for one dose point and a significant trend (P#0.015) 

were considered weak evidence for a positive response; significant differences for 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 
 

264 Pyridine, NTP TR 470 

resulted in an equivocal call (Galloway et al., 1987). Ultimately, the trial calls were based on a consideration 

of the statistical analyses as well as the biological information available to the reviewers. 

DROSOPHILA MELANOGASTER TEST PROTOCOLS 

The assays for induction sex-linked recessive lethal (SLRL) mutations and chromosomal reciprocal 

translocations (RTs) were performed with adult flies as described by Valencia et al. (1985) and Mason et al. 

(1992). Pyridine was supplied as a coded aliquot by Radian Corporation. 

Sex-Linked Recessive Lethal Mutation Test: Pyridine was assayed in the SLRL test by feeding for 3 days to 

adult Canton-S wild-type males no more than 24 hours old at the beginning of treatment. Because no clearly 

positive response was obtained in the feeding experiments, it was retested by injection into adult males. 

To administer pyridine by injection, a glass Pasteur pipette was drawn out in a flame to a microfine filament, 

and the tip was broken off to allow delivery of the test solution. Injection was performed either manually, by 

attaching a rubber bulb to the other end of the pipette and forcing through sufficient solution (0.2-0.3 μL) to 

slightly distend the abdomen of the fly, or by attaching the pipette to a microinjector that automatically 

delivered a calibrated volume. Flies were anesthetized with ether and immobilized on a strip of tape. Injection 

into the thorax, under the wing, was performed with the aid of a dissecting microscope. 

Toxicity tests were performed to set concentrations of pyridine at a level that would induce 30% mortality after 

72 hours of feeding or 24 hours after injection, while keeping induced sterility at an acceptable level. 

Canton-S males were allowed to feed for 72 hours on a solution of pyridine in 5% sucrose. In the injection 

experiments, 24- to 72-hour old Canton-S males were treated with a solution of pyridine dissolved in saline 

and allowed to recover for 24 hours. A concurrent saline control group was also included. In the adult 

exposures, treated males were mated to three Basc females for 3 days and were given fresh females at 2-day 

intervals to produce three matings of 3, 2, and 2 days (in each case, sample sperm from successive matings 

were treated at successively earlier postmeiotic stages). F1 heterozygous females were mated with their 

siblings and then placed in individual vials. F1 daughters from the same parental male were kept together to 

identify clusters. (A cluster occurs when a number of mutants from a given male result from a single 

spontaneous premeiotic mutation event and is identified when the number of mutants from that male exceeds 

the number predicted by a Poisson distribution.) If a cluster was identified, all data from the male in question 

were discarded. Presumptive lethal mutations were identified as vials containing fewer than 5% of the 

expected number of wild-type males after 17 days; these were retested to confirm the response. 

SLRL data were analyzed by simultaneous comparison with the concurrent and historical controls (Mason 

et al., 1992) using a normal approximation to the binomial test (Margolin et al., 1983). A test result was 

considered positive if the P value was less or equal to 0.01 and the mutation frequency in the tested group was 

greater than 0.10% or if the P value was less than or equal to 0.05 and the frequency in the treatment group 

was greater than 0.15%. A test was considered to be inconclusive if the P value was between 0.05 and 0.01 

but the frequency in the treatment group was between 0.10% and 0.15% or if the P value was between 0.10 

and 0.05 but the frequency in the treatment group was greater than 0.10%. A test was considered negative if 

the P value was greater than or equal to 0.10 or if the frequency in the treatment group was less than 0.10%. 

Reciprocal Translocation Test: Because one of the injection experiments (Mason et al., 1992) produced a 

positive result in the SLRL test, pyridine was assayed for induction of RTs using the same exposure method. 

The treatment regimen was essentially the same as that for the SLRL test, except that Canton-S males were 

mated en masse to marker (bw;st or bw;e) females. The females were transferred to fresh medium every 3 to 4 

days for a period of about 3 weeks to produce a total of six broods. The results of the SLRL test were used to 

determine the germ cell stages most likely to be affected by pyridine. F1 heterozygous males were backcrossed 
 

Pyridine, NTP TR 470 265 

individually to bw;st females, and the F2 progeny were screened for pseudolinkage, which results from the 

induction of a translocation in a germ cell of the parental male. Flies suspected of carrying RTs were retested 

to confirm the findings. The translocation data were analyzed according to the conditional binomial response 

test of Kastenbaum and Bowman (1970). 

MOUSE BONE MARROW CYTOGENETIC TEST PROTOCOLS 

Chromosomal Aberrations Test: A dose range-finding study was performed in the absence of adequate 

toxicity information from the literature, and the highest dose was limited by toxicity. Pyridine was tested for 

induction of Abs in mouse bone marrow by two different protocols. The first protocol used a standard harvest 

time of 17 hours, and the second protocol used a delayed harvest time of 36 hours. 

Male B6C3F1 mice (10 animals per dose group) were injected intraperitoneally with pyridine dissolved in 

phosphate-buffered saline (PBS) (injection volume=0.4 mL.). Solvent control mice received equivalent 

injections of PBS alone. The positive control was mitomycin C. The mice were subcutaneously implanted 

with a BrdU tablet (McFee et al., 1983) 18 hours before the scheduled harvest. (For the standard protocol, this 

required BrdU implantation to precede injection with pyridine by 1 hour). The use of BrdU allowed selection 

of the appropriate cell population for scoring. (Abs induced by chemical administration are present in 

maximum number at the first metaphase following treatment; they decline in number during subsequent 

nuclear divisions due to cell death.) Two hours before sacrifice, the mice received an intraperitoneal injection 

of colchicine in saline. The animals were killed 17 or 36 hours after pyridine injection (18 hours after BrdU 

dosing). One or both femurs were removed, and the marrow was flushed out with PBS (pH 7.0). Cells were 

treated with a hypotonic salt solution, fixed, and dropped onto chilled slides. After a 24-hour drying period, 

the slides were stained and scored. 

Fifty first-division metaphase cells were scored from each of eight animals per group. Responses were 

evaluated as the percentage of aberrant metaphase cells, excluding gaps. The data were analyzed by a trend 

test (Margolin et al., 1986). 

Micronucleus Test: Preliminary range-finding studies were performed. Factors affecting dose selection 

included chemical solubility and toxicity and the extent of cell cycle delay induced by pyridine exposure. The 

standard three-exposure protocol is described in detail by Shelby et al. (1993). Male B6C3F1 mice were 

injected intraperitoneally three times at 24-hour intervals with pyridine dissolved in PBS; the total dosing 

volume was 0.4 mL. Solvent control animals were injected with 0.4 mL of PBS only. The positive control 

animals received injections of cyclophosphamide. The animals were killed 24 hours after the third injection, 

and blood smears were prepared from bone marrow cells obtained from the femurs. Air-dried smears were 

fixed and stained; 2,000 polychromatic erythrocytes (PCEs) were scored for the frequency of micronucleated 

cells in each of five animals per dose group. In addition, the percentage of PCEs among the total erythrocyte 

population in the bone marrow was scored for each dose group as a measure of toxicity. 

The results were tabulated as the mean of the pooled results from all animals within a treatment group plus or 

minus the standard error of the mean. The frequency of micronucleated cells among PCEs was analyzed by a 

statistical software package that tested for increasing trend over dose groups using a one-tailed 

Cochran-Armitage trend test, followed by pairwise comparisons between each dosed group and the control 

group (ILS, 1990). In the presence of excess binomial variation, as detected by a binomial dispersion test, the 

binomial variance of the Cochran-Armitage test was adjusted upward in proportion to the excess variation. In 

the micronucleus test, an individual trial is considered positive if the trend test P value is less than or equal to 

0.025 or if the P value for any single dose group is less than or equal to 0.025 divided by the number of dose 

groups. A final call of positive for micronucleus induction is preferably based on reproducibly positive trials 
266 Pyridine, NTP TR 470 

(as noted above). Ultimately, the final call is determined by the scientific staff after considering the results of 

statistical analyses, the reproducibility of any effects observed, and the magnitude of those effects. 

RESULTS 

Pyridine (100-10,000 μg/plate) was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or 

TA1537, with or without S9 metabolic activation enzymes (Haworth et al., 1983; Table F1). Further, no 

significant increase in mutant frequencies was observed in L5178Y mouse lymphoma cells, tested with and 

without S9 metabolic activation (McGregor et al., 1988; Table F2). In cytogenetic tests with cultured CHO 

cells, pyridine did not induce SCEs (Table F3) or Abs (Table F4), with or without S9. At the highest viable 

dose (1,673 μg/mL) tested for SCE induction in the absence of S9, pyridine induced marked cell cycle delay, 

and an extended culture time (31 hours) was used to allow sufficient cells to accumulate for analysis. 

Pyridine was tested on three separate occasions in two different laboratories for induction of SLRL mutations 

in adult male D. melanogaster (Valencia et al., 1985; Mason et al., 1992; Foureman et al., 1994; Table F5), 

and mixed results were obtained. In the first experiment (Valencia et al., 1985), administration of pyridine by 

injection (7,000 ppm in aqueous 0.7% saline solution) gave negative (P=0.225) results, but feeding (600 and 

700 ppm pyridine in aqueous 5% sucrose) produced an increase in recessive lethal mutations that was 

considered to be equivocal (P=0.043). A second experiment performed in the same laboratory using both 

injection (500 ppm) and feeding (729 ppm) yielded negative results (Foureman et al., 1994). In the third 

experiment (Mason et al., 1992) performed in a second laboratory, results of a feeding (500 ppm) experiment 

were negative (P=0.998), but administration of pyridine by injection (4,300 ppm) induced a significant 

increase in the frequency of SLRL mutations (P=0.008). Overall, pyridine was considered to be negative in 

SLRL tests when administered by feeding and equivocal when administered by injection. This positive result 

in the SLRL test led to the performance of a test for induction of RTs in germ cells of treated male D. 

melanogaster (Mason et al., 1992; Table F6); results of this test were negative. 

In vivo assays for chromosomal effects were conducted with male mice. No induction of Abs (Table F7) was 

noted in bone marrow cells at either of two sampling times (400-600 mg/kg pyridine; single injection), and no 

increase in the frequency of micronucleated PCEs (Table F8) was noted in bone marrow after intraperitoneal 

injection of pyridine (up to 500 mg/kg administered three times at 24-hour intervals). 

In summary, with the exception of the single positive result obtained in a D. melanogaster SLRL assay, no 

indication of mutagenic activity was seen with pyridine in a variety of in vitro and in vivo assays for gene 

mutation and chromosomal damage. 
Pyridine, NTP TR 470 267 

TABLE F1 

Mutagenicity of Pyridine in Salmonella typhimuriuma 

Strain Dose 

(μg/plate) 

Trial 1 

!S9 

Trial 2 

Revertants/plateb 

+10% hamster S9 

Trial 1 Trial 2 

+10% rat S9 

Trial 1 Trial 2 

TA100 0 

100 

333.3

1,000

3,333.3

10,000 

115 ± 8.3 

106 ± 6.4 

93 ± 3.6 

96 ± 5.2

 93 ± 0.0 

96 ± 10.7 

105 ± 3.5 

113 ± 1.5 

114 ± 5.5 

114 ± 16.5

105 ± 4.6 

117 ± 8.4

116 ± 9.8

116 ± 5.4

103 ± 1.7 

94 ± 2.3 

121 ± 6.9

 94 ± 2.8 

107 ± 14.4 

131 ± 10.5 

131 ± 8.6 

115 ± 5.8 

135 ± 12.2 

148 ± 4.8 

113 ± 2.4 

119 ± 6.4

129 ± 3.1

127 ± 1.3 

122 ± 8.3 

112 ± 8.1

105 ± 8.0 

107 ± 17.0 

112 ± 15.1 

117 ± 3.0 

114 ± 3.9 

119 ± 10.7 

Trial summary 

Positive controlc Negative 

483 ± 7.2 

Negative 

416 ± 11.3 

Negative 

1,119 ± 119.8 

Equivocal 

2,115 ± 14.6 

Negative 

1,075 ± 30.0 

Negative 

549 ± 71.3 

TA1535 0 

100 

333.3 

1,000 

3,333.3 

10,000 

31 ± 0.7 

34 ± 1.3 

29 ± 5.6 

27 ± 4.0 

32 ± 3.8 

33 ± 7.1 

21 ± 5.6 

21 ± 4.8

18 ± 1.2 

18 ± 1.5 

17 ± 2.0 

17 ± 4.0 

12 ± 2.3 

9 ± 1.5 

11 ± 2.1 

10 ± 2.5 

14 ± 1.9 

14 ± 5.3 

12 ± 1.9 

13 ± 2.3 

11 ± 2.3 

12 ± 1.8 

11 ± 1.8 

14 ± 1.2 

11 ± 1.8 

14 ± 0.6 

12 ± 1.3 

14 ± 2.3 

11 ± 1.7 

13 ± 4.1 

14 ± 0.9 

15 ± 3.7 

12 ± 0.6 

11 ± 1.2 

12 ± 0.9 

15 ± 1.9 

Trial summary 

Positive control 

Negative 

412 ± 9.4 

Negative 

346 ± 14.4 

Negative 

257 ± 13.8 

Negative 

266 ± 9.5 

Negative 

314 ± 14.9 

Negative 

167 ± 4.9 

TA1537 0

100 

333.3

1,000 

3,333.3 

10,000 

9 ± 1.3 

13 ± 5.7 

9 ± 0.6 

14 ± 1.2 

10 ± 3.0 

14 ± 0.3 

5 ± 1.5 

6 ± 1.2 

6 ± 0.9 

7 ± 1.0 

5 ± 0.3 

6 ± 0.9 

18 ± 3.5 

20 ± 1.9

18 ± 4.9

18 ± 3.8 

20 ± 4.7

17 ± 4.2

10 ± 0.7 

7 ± 0.6 

8 ± 2.3 

10 ± 2.2 

9 ± 1.7 

5 ± 1.8 

23 ± 2.1 

20 ± 1.0 

17 ± 2.2 

22 ± 3.0 

17 ± 2.7 

18 ± 1.2 

6 ± 1.0 

7 ± 0.7 

4 ± 1.5 

6 ± 1.0 

5 ± 0.6 

6 ± 1.5 

Trial summary 

Positive control 

Negative 

329 ± 159.1 

Negative 

847 ± 54.3 

Negative 

459 ± 52.4 

Negative 

411 ± 10.3 

Negative 

495 ± 52.6 

Negative 

239 ± 24.6 

TA98 0 

100 

333.3 

1,000 

3,333.3 

10,000 

35 ± 4.7 

35 ± 4.9 

35 ± 2.3 

33 ± 4.9 

25 ± 0.7 

22 ± 3.5 

37 ± 3.5 

33 ± 3.5 

31 ± 5.9 

29 ± 2.3 

29 ± 3.4

27 ± 3.8 

49 ± 5.6 

45 ± 2.0 

39 ± 5.7 

46 ± 7.5 

50 ± 14.2 

43 ± 6.4 

35 ± 2.3 

39 ± 0.3 

40 ± 0.9 

37 ± 2.6 

30 ± 4.7 

43 ± 7.8 

31 ± 5.2 

41 ± 2.4 

36 ± 3.2 

34 ± 1.5 

33 ± 3.5 

30 ± 5.6 

34 ± 3.2 

40 ± 0.3 

32 ± 5.1 

38 ± 0.3 

28 ± 1.8 

26 ± 5.6 

Trial summary 

Positive control 

Negative 

691 ± 10.1 

Negative 

671 ± 57.5 

Negative 

570 ± 57.5 

Negative 

1,271 ± 7.8 

Negative 

574 ± 22.3 

Negative 

365 ± 22.9 

a Study was performed at SRI International. The detailed protocol and these data are presented by Haworth et al. (1983). 0 μg/plate was the 

solvent control. 

b	 Revertants are presented as mean ± standard error from three plates. 

The positive controls in the absence of metabolic activation were sodium azide (TA100 and TA1535), 9-aminoacridine (TA1537), and 

4-nitro-o-phenylenediamine (TA98). The positive control for metabolic activation with all strains was 2-aminoanthracene. 

c 
268 Pyridine, NTP TR 470 

TABLE F2 

Induction of Trifluorothymidine Resistance in L5178Y Mouse Lymphoma Cells by Pyridinea 

Compound Concentration 

(μg/mL) 

Cloning 

Efficiency 

(%) 

Relative 

Total Growth 

(%) 

Mutant 

Count 

Mutant 

Fractionb 

Average 

Mutant 

Fraction 

!S9 

Trial 1 

Mediumc 112 

99 

108 

101 

102 

106 

103 

89 

95 

86 

100 

92 

28 

29 

31 

31 30 

Methyl methanesulfonated 15 43 

49 

26 

26 

239 

195 

186 

133 160* 

Pyridine 625 

1,250 

2,500 

5,000 

89 

105 

73 

86 

94 

78 

82 

88 

100 

102 

88 

101 

69 

71 

70 

77 

99 

95 

47 

80 

81 

56 

60 

113 

37 

30 

21 

31 

29 

24 

24 

43 

34 

26 

26 

34 

Trial 2 

Medium 76 

99 

84 

65 

98 

102 

97 

102 

89 

136 

122 

120 

39 

46 

49 

62 49 

Methyl methanesulfonate 15 27 

24 

23 

20 

440 

473 

550 

671 610* 

Pyridine 

Trial 3 

Medium 

1,000 

2,000 

3,000 

4,000 

5,000 

82 

58 

74 

68 

78 

71 

47 

55 

48 

69 

98 

108 

71 

102 

101 

90 

77 

78 

68 

76 

68 

76 

57 

66 

100 

110 

84 

106 

160 

106 

154 

167 

182 

161 

97 

154 

138 

151 

60 

67 

70 

85 

65 

61 

69 

81 

78 

76 

68 

94 

97 

73 

20 

21 

33 

28 

63 

75 

77* 

81* 

85* 

25 

Methyl methanesulfonate 15 25 

23 

14 

13 

126 

103 

166 

151 159* 

Pyridine 2,000 

3,000 

4,000 

5,000 

90 

79 

116 

90 

72 

88 

82 

89 

87 

85 

85 

79 

75 

79 

70 

67 

68 

53 

89 

64 

86 

145 

73 

79 

25 

22 

26 

24 

40 

55 

30 

30 

24 

25 

47* 

30 
269 

c 

Pyridine, NTP TR 470 

TABLE F2 

Induction of Trifluorothymidine Resistance in L5178Y Mouse Lymphoma Cells by Pyridine 

Cloning Relative Mutant Mutant Average 

Compound Concentration Efficiency Total Growth Count Fraction Mutant 

(μg/mL) (%) (%) Fraction 

+S9 

Trial 1 

Medium	 90 90 126 47 

79 104 124 53 

83 102 137 55 

74 105 141 64 55 

Methylcholanthrened 2.5	 50 18 820 552 

43 20 726 561 556* 

Pyridine 1,000 82 88 133 54 

89 96 152 57 56 

2,000 94 77 230 82 

77 99 123 53 68 

3,000 77 86 204 89 

89 80 140 52 71 

4,000 100 70 167 55 

78 79 147 63 59 

5,000 95 81 158 55 

98 73 207 70 63 

Trial 2 

Solvent control	 85 101 111 43 

91 108 138 50 

100 93 188 62 

105 98 159 50 52 

Methylcholanthrene 2.5	 54 24 686 421 

58 28 791 451 436* 

Pyridine 2,000 86 104 95 37 

87 108 119 46 41 

3,000 78 101 87 37 

79 105 117 49 43 

4,000 80 97 94 39 

84 91 107 42 41 

5,000 109 78 101 31 

109 84 115 35 33 

* Positive response (P#0.05) versus the solvent control a Study was performed at Inveresk Research International. The detailed protocol and these data are presented by McGregor et al. (1988). b Mutant fraction=mutant cells/106

 clonable cells 

Solvent control 

d Positive control 
270 

c 

Pyridine, NTP TR 470 

TABLE F3 

Induction of Sister Chromatid Exchanges in Chinese Hamster Ovary Cells by Pyridinea 

Total No. of SCEs/ Relative 

Concentration Cells Chromo- No. of Chromo- SCEs/ Hrs Change of SCEs/ 

Compound (μg/mL) Scored somes SCEs some Cell in BrdU Chromosomeb 

(%) 

!S9 

Summary: Negative 

Distilled waterc	 50 1,049 415 0.39 8.3 26.0 

50 1,049 424 0.40 8.5 31.0e 

Mitomycin-Cd 0.001	 50 1,049 665 0.63 13.3 26.0 56.84 

0.004 10 208 201 0.96 20.1 26.0 139.08 

Pyridine 167 50 1,043 407 0.39 8.1 26.0 !3.46 

502 50 1,049 437 0.41 8.7 26.0 3.07 

1,673 50 1,050 434 0.41 8.7 31.0 2.26 

5,020 0

 P=0.273f 

+S9 

Summary: Negative 

Distilled water	 50 1,050 389 0.37 7.8 26.0 

Cyclophosphamided 0.125	 50 1,051 598 0.56 12.0 26.0 53.58 

0.5 10 207 186 0.89 18.6 26.0 142.54 

Pyridine 502 50 1,048 416 0.39 8.3 26.0 7.14 

1,673 50 1,051 421 0.40 8.4 26.0 8.12 

5,020 50 1,051 388 0.36 7.8 26.0 !0.35 

P=0.494 

a Study was performed at SITEK Research Laboratories. The detailed protocol is presented by Galloway et al. (1987). SCE=sister chromatid 

exchange; BrdU=bromodeoxyuridine b SCEs/chromosome in treated cells versus SCEs/chromosome in solvent control cells 

Solvent control 

d Positive control e Due to cell cycle delay, harvest time was extended to maximize the number of second-division metaphase cells available for analysis. f Significance of SCEs/chromosome tested by the linear regression trend test versus log of the dose 
271 

c 

Pyridine, NTP TR 470 

TABLE F4 

Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells by Pyridinea 

Compound Concentration 

(μg/mL) 

Total Cells 

Scored 

Number 

of Aberrations 

Aberrations/ 

Cell 

Cells with 

Aberrations (%) 

!S9 

Harvest time: 13.5 hours 

Summary: Negative 

Distilled waterb 200 2 0.01 1.0 

Mitomycin-Cc 0.4 25 37 1.48 76.0 

Pyridine 503 

1,081 

2,325 

200 

200 

200 

0 

0 

2 

0.00 

0.00 

0.01 

0.0 

0.0 

1.0 

P=0.450d 

+S9 

Harvest time: 13.5 hours 

Summary: Negative 

Distilled water 200 2 0.01 1.0 

Cyclophosphamidec 20 25 42 1.68 48.0 

Pyridine 1,081 

2,325 

5,000 

200 

200 

200 

1 

1 

3 

0.01 

0.01 

0.02 

0.5 

0.5 

1.5 

P=0.305 

a Study was performed at SITEK Research Laboratories. The detailed protocol is presented by Galloway et al. (1987). b Solvent control 

Positive control 

d Significance of percent cells with aberrations tested by the linear regression trend test versus log of the dose 
272 

c 

Pyridine, NTP TR 470 

TABLE F5 

Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster by Pyridinea 

Route of Dose Incidence of Incidence of No. of Lethals/No. of X Chromosomes Tested 

Exposure (ppm) Death (%) Sterility (%) Mating 1 Mating 2 Mating 3 Totalb 

Study performed at Brown Universityc 

Feed 600 5 0 0/1,116 1/1,123 1/1,136 2/3,375 (0.06%) 

0 0/1,214 1/1,128 0/1,050 1/3,392 (0.03%) 

700 20 2 4/1,027 1/1,069 0/1,082 5/3,178 (0.16%) 

0 0/1,114 1/1,142 0/1,105 1/3,361 (0.03%) 

Combined data set (600 ppm and 700 ppm trials): 4/2,143 2/2,192 1/2,218 7/6,553 (0.11%) 

0/2,328 2/2,270 0/2,155 2/6,753 (0.03%) 

P=0.043d 

Injection 7,000 5 0 1/1,770 1/2,281 3/2,039 5/6,090 (0.08%) 

0 1/2,170 2/2,750 0/1,379 3/6,299 (0.05%) 

P=0.225 

Feed 729 22 0 1/1,724 0/2,664 1/1,121 2/5,509 (0.04%) 

0 0/1,902 1/2,541 6/1,413 7/5,856 (0.12%) 

P=0.943 

Injection 500 4 0 4/1,916 1/2,006 2/1,944 7/5,866 (0.12%) 

0 2/1,908 1/1,933 0/1,921 3/5,762 (0.05%) 

P=0.108 

Study performed at University of Wisconsin, Madisone 

Feed 500 12 1 1/2,063 0/1,989 0/1,666 1/5,718 (0.02%) 

0 3/1,947 5/1,726 2/1,438 10/5,111 (0.20%) 

P=0.998 

Injection 4,300 26 9 7/1,854 1/1,731 1/1,608 9/5,193 (0.17%) 

0 3/4,163 2/3,949 1/3,285 6/11,397 (0.05%) 

P=0.008 

a The mean mutant frequency from 518 negative control experiments is 0.074% (Mason et al., 1992). b Total number of lethal mutations/total number of X chromosomes tested for three mating trials 

The detailed protocol and these data are presented by Valencia et al. (1985) (first two exposures) and Foureman (1994) (last 2 exposures). d Data from the 600 ppm and 700 ppm trials were combined to provide and adequate sample size for statistical analysis. The P value was 

generated from the combined data set. e The detailed protocol and these data are presented by Mason et al. (1992). 
Pyridine, NTP TR 470 273 

TABLE F6 

Induction of Reciprocal Translocations in Drosophila melanogaster by Pyridinea 

Route of 

Exposure 

Dose 

(ppm) 1 

Translocations/Total F1 Tested 

2 3 4 5 6 

No. of 

Tests 

Total Total 

No. of Translocations 

Translocations (%) 

Injection 4,300 0/1,483 0/1,413 0/1,243 0/819 0/254 0/11 5,223 0 0 

Historical 

control 

0/27,245 0/31,611 0/22,410 2/23,623 0/10,506 0/768 116,163 2 0.002 

a Study was performed at University of Wisconsin, Madison. The detailed protocol and these data are presented by Mason et al. (1992). 

Results were not significant at the 5% level (Kastenbaum and Bowman, 1970). 

TABLE F7 

Induction of Chromosomal Aberrations in Mouse Bone Marrow Cells by Pyridinea 

Compound Dose Total Cells Total Aberrations Cells with Aberrationsb 

(mg/kg) Scored (!gaps) (%) 

Trial 1 

Sample time: 17 hours 

Phosphate-buffered salinec 400 2 0.50 ± 0.33 

Mitomycin-Cd 1 400 11 2.25 ± 0.45 

2 400 48 9.50 ± 1.76 

Pyridine 400 400 2 0.50 ± 0.50 

500 400 8 1.75 ± 0.59 

600 400 2 0.50 ± 0.33 

P=0.222e 

Trial 2 

Sample time: 36 hours 

Phosphate-buffered saline 400 6 1.50 ± 0.63 

Mitomycin-C 1 400 14 3.00 ± 0.85 

2 400 68 6.25 ± 2.31 

Pyridine 400 400 3 0.75 ± 0.53 

500 400 6 1.50 ± 0.82 

600 400 0 0.00 ± 0.00 

P=0.948 

a Study was performed at Environmental Health Research and Testing, Inc. Fifty first-division metaphase cells were scored from each of eight 

mice per group. The detailed protocol and these data are presented by McFee (1989). b Mean ± standard error
 

Solvent control
 d Positive control e Significance tested by the one-tailed trend test; significant at P#0.05 (Margolin et al., 1986) 

c 
274 

c 

Pyridine, NTP TR 470 

TABLE F8 

Induction of Micronuclei in Bone Marrow Polychromatic Erythrocytes of Mice Treated with Pyridine 

by Intraperitoneal Injectiona 

Compound 

Dose 

(mg/kg) 

Number of Mice 

with Erythrocytes 

Scored 

Micronucleated PCEs/ 

1,000 PCEsb 

PCEsb 

(%) 

Phosphate-buffered salinec 

Cyclophosphamided 15 

5 

5 

1.60 ± 0.51 

11.50 ± 0.91 

52.52 ± 4.30 

52.46 ± 1.71 

Pyridine 31.25 

62.5 

125 

250 

500 

5 

5 

5 

5 

5 

1.40 ± 0.29 

1.60 ± 0.43 

1.10 ± 0.51 

1.10 ± 0.37 

1.20 ± 0.25 

52.22 ± 1.11 

53.04 ± 3.89 

51.40 ± 3.66 

51.22 ± 1.61 

48.02 ± 1.88 

P=0.811e 

a Study was performed at Environmental Health Research and Testing, Inc. The detailed protocol and these data are presented by Shelby et al. 

(1993). b Mean ± standard error
 

Solvent control
 d Positive control e Significance of micronucleated PCEs/1,000 PCEs tested by the one-tailed trend test; significant at P#0.025 (ILS, 1990) 
275 

APPENDIX G 

HEMATOLOGY AND CLINICAL CHEMISTRY 

RESULTS 

TABLE G1 

TABLE G2 

Hematology and Clinical Chemistry Data for F344/N Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 

Hematology and Clinical Chemistry Data for Male Wistar Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 

276 

281 
 

 

 

 

276 Pyridine, NTP TR 470 

TABLE G1 

Hematology and Clinical Chemistry Data for F344/N Rats in the 13-Week Drinking Water Study of Pyridinea 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

Hematology 

n 

Day 5 10 9 10 10 10 10 

Day 20 10 10 10 10 10 9 

Week 13 10 10 10 10 10 10 

Automated hematocrit (%) 

Day 5 46.8 ± 0.3 47.3 ± 0.5 48.1 ± 0.4* 47.9 ± 0.5* 47.9 ± 0.5 49.6 ± 0.4** 

Day 20 49.6 ± 0.4 50.4 ± 0.3 48.2 ± 0.6 47.9 ± 0.3** 47.8 ± 0.4** 45.0 ± 0.4** 

Week 13 46.9 ± 0.5 46.4 ± 0.3 46.8 ± 0.2 46.1 ± 0.3 45.9 ± 0.3 44.4 ± 0.7** 

Manual hematocrit (%) 

Day 5 44.2 ± 0.3 44.7 ± 0.6 45.2 ± 0.3* 45.4 ± 0.5 45.5 ± 0.6 46.5 ± 0.5** 

Day 20 48.0 ± 0.3 49.1 ± 0.6 46.6 ± 0.5 46.3 ± 0.5 46.5 ± 0.5* 43.3 ± 0.5** 

Week 13 45.7 ± 0.5 44.8 ± 0.4 45.6 ± 0.4 44.7 ± 0.2 44.3 ± 0.4* 42.7 ± 0.7** 

Hemoglobin (g/dL) 

Day 5 15.3 ± 0.1 15.4 ± 0.1 15.6 ± 0.1 15.7 ± 0.1 15.8 ± 0.1** 16.0 ± 0.2** 

Day 20 16.3 ± 0.2 16.6 ± 0.1 15.7 ± 0.2 15.6 ± 0.1** 15.7 ± 0.1* 14.8 ± 0.2** 

Week 13 15.4 ± 0.2 15.2 ± 0.1 15.3 ± 0.1 15.0 ± 0.2 14.9 ± 0.1* 14.3 ± 0.2** 

Erythrocytes (106

/μL) 

Day 5 8.40 ± 0.07 8.41 ± 0.13 8.54 ± 0.08 8.54 ± 0.07 8.58 ± 0.10 8.79 ± 0.08** 

Day 20 8.92 ± 0.07 9.07 ± 0.07 8.62 ± 0.11 8.62 ± 0.07* 8.66 ± 0.10 8.27 ± 0.13** 

Week 13 9.09 ± 0.11 9.00 ± 0.07 9.12 ± 0.05 8.88 ± 0.07 8.87 ± 0.09 8.52 ± 0.20* 

Reticulocytes (106

/μL) 

Day 5 0.18 ± 0.03 0.26 ± 0.05 0.20 ± 0.01 0.15 ± 0.02 0.15 ± 0.01 0.15 ± 0.01 

Day 20 0.18 ± 0.02 0.17 ± 0.02 0.18 ± 0.01 0.20 ± 0.01 0.19 ± 0.02 0.16 ± 0.01 

Week 13 0.17 ± 0.01 0.18 ± 0.02 0.19 ± 0.02 0.19 ± 0.02 0.19 ± 0.01 0.19 ± 0.02 

Nucleated erythrocytes (103

/μL) 

Day 5 0.01 ± 0.01 0.04 ± 0.02 0.00 ± 0.00 0.02 ± 0.02 0.04 ± 0.02 0.00 ± 0.00 

Day 20 0.00 ± 0.00 0.03 ± 0.02 0.01 ± 0.01 0.05 ± 0.02* 0.02 ± 0.01 0.03 ± 0.02 

Week 13 0.02 ± 0.01 0.04 ± 0.02 0.03 ± 0.02 0.01 ± 0.01 0.01 ± 0.01 0.06 ± 0.02 

Mean cell volume (fL) 

Day 5 55.8 ± 0.3 56.3 ± 0.4 56.4 ± 0.3 56.2 ± 0.3 55.9 ± 0.3 56.6 ± 0.2 

Day 20 55.5 ± 0.2 55.5 ± 0.4 55.8 ± 0.3 55.5 ± 0.3 55.3 ± 0.4 54.6 ± 0.5 

Week 13 51.6 ± 0.2 51.5 ± 0.2 51.4 ± 0.2 52.0 ± 0.3 51.8 ± 0.5 52.3 ± 0.7 

Mean cell hemoglobin (pg) 

Day 5 18.3 ± 0.1 18.3 ± 0.1 18.3 ± 0.1 18.3 ± 0.1 18.5 ± 0.1 18.2 ± 0.1 

Day 20 18.3 ± 0.1 18.3 ± 0.1 18.3 ± 0.1 18.1 ± 0.1 18.1 ± 0.1 17.9 ± 0.1* 

Week 13 17.0 ± 0.1 16.9 ± 0.1 16.8 ± 0.1 16.8 ± 0.1 16.8 ± 0.2 16.9 ± 0.2 

Mean cell hemoglobin concentration (g/dL) 

Day 5 32.8 ± 0.2 32.4 ± 0.1 32.5 ± 0.1 32.7 ± 0.1 33.1 ± 0.2 32.3 ± 0.2 

Day 20 32.8 ± 0.2 33.0 ± 0.2 32.6 ± 0.2 32.7 ± 0.2 32.8 ± 0.2 32.9 ± 0.2 

Week 13 32.8 ± 0.1 32.9 ± 0.1 32.7 ± 0.1 32.4 ± 0.2 32.5 ± 0.1* 32.3 ± 0.1** 

Platelets (103

/μL) 

Day 5 908.7 ± 26.6 973.1 ± 33.9 957.3 ± 23.1 924.4 ± 27.9 880.7 ± 21.4 937.0 ± 19.9 

Day 20 856.9 ± 12.1 902.3 ± 31.3 880.4 ± 22.8 917.8 ± 15.1* 1,065.7 ± 39.8** 949.0 ± 28.2** 

Week 13 731.0 ± 26.3 711.2 ± 12.1 732.3 ± 15.5 760.1 ± 15.5 791.8 ± 42.0* 869.5 ± 65.4* 

Leukocytes (103

/μL) 

Day 5 10.82 ± 0.44 11.72 ± 0.45 11.25 ± 0.43 10.36 ± 0.40 10.19 ± 0.45 10.82 ± 0.42 . 

Day 20 9.31 ± 0.42 11.48 ± 0.49* 8.83 ± 0.22 9.32 ± 0.34 9.62 ± 0.51 9.42 ± 0.49 

Week 13 9.46 ± 0.43 10.24 ± 0.31 9.93 ± 0.50 9.96 ± 0.37 10.24 ± 0.49 11.26 ± 0.56 

Segmented neutrophils (103

/μL) 

Day 5 1.84 ± 0.14 1.66 ± 0.13 1.47 ± 0.16 1.60 ± 0.13 1.45 ± 0.13 1.77 ± 0.23 

Day 20 1.45 ± 0.15 1.68 ± 0.17 1.08 ± 0.13 1.28 ± 0.10 1.54 ± 0.22 1.00 ± 0.09 

Week 13 2.01 ± 0.20 1.84 ± 0.14 1.64 ± 0.21 1.78 ± 0.23 1.90 ± 0.16 2.16 ± 0.29 
 

 

 

Pyridine, NTP TR 470 277 

TABLE G1 

Hematology and Clinical Chemistry Data for F344/N Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male (continued) 

Hematology (continued) 

n 

Day 5 10 9 10 10 10 10 

Day 20 10 10 10 10 10 9 

Week 13 10 10 10 10 10 10 

Lymphocytes (103

/μL) 

Day 5 8.84 ± 0.39 9.95 ± 0.44 9.73 ± 0.46 8.61 ± 0.36 8.66 ± 0.39 9.02 ± 0.34 

Day 20 7.80 ± 0.32 9.73 ± 0.49* 7.68 ± 0.27 8.00 ± 0.37 7.99 ± 0.48 8.32 ± 0.45 

Week 13 7.40 ± 0.37 8.37 ± 0.28 8.25 ± 0.48 8.15 ± 0.41 8.27 ± 0.51 9.03 ± 0.44* 

Monocytes (103

/μL) 

Day 5 0.11 ± 0.04 0.05 ± 0.02 0.05 ± 0.02 0.09 ± 0.04 0.05 ± 0.02 0.01 ± 0.01 

Day 20 0.05 ± 0.02 0.03 ± 0.02 0.04 ± 0.02 0.01 ± 0.01 0.03 ± 0.01 0.06 ± 0.02 

Week 13 0.02 ± 0.01 0.01 ± 0.01 0.02 ± 0.01 0.01 ± 0.01 0.03 ± 0.02 0.05 ± 0.04 

Basophils (103

/μL) 

Day 5 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Day 20 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Week 13 0.000 ± 0.000 0.011 ± 0.011 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Eosinophils (103

/μL) 

Day 5 0.02 ± 0.01 0.06 ± 0.03 0.01 ± 0.01 0.06 ± 0.03 0.03 ± 0.02 0.03 ± 0.02 

Day 20 0.01 ± 0.01 0.04 ± 0.02 0.04 ± 0.01 0.03 ± 0.02 0.06 ± 0.02 0.04 ± 0.02 

Week 13 0.02 ± 0.02 0.01 ± 0.01 0.02 ± 0.01 0.02 ± 0.02 0.05 ± 0.02 0.02 ± 0.01 

Clinical Chemistry 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 9 

Week 13 10 10 10 10 10 10 

Urea nitrogen (mg/dL) 

Day 5 23.1 ± 0.7 24.1 ± 0.8 25.5 ± 0.7 25.9 ± 0.9 24.1 ± 0.8 23.8 ± 0.8 

Day 20 24.3 ± 0.6 22.8 ± 0.6 23.9 ± 0.5 24.8 ± 0.4 23.2 ± 0.5 25.0 ± 0.5 

Week 13 25.1 ± 0.4 23.1 ± 0.7 23.9 ± 0.6 23.9 ± 0.7 25.0 ± 1.0 25.3 ± 1.1 

Creatinine (mg/dL) 

Day 5 0.49 ± 0.01 0.51 ± 0.02 0.53 ± 0.02 0.49 ± 0.01 0.51 ± 0.01 0.50 ± 0.01 

Day 20 0.61 ± 0.03 0.56 ± 0.03 0.59 ± 0.02 0.60 ± 0.02 0.60 ± 0.03 0.61 ± 0.02 

Week 13 0.59 ± 0.02 0.55 ± 0.03 0.60 ± 0.03 0.60 ± 0.04 0.59 ± 0.03 0.64 ± 0.03 

Total protein (g/dL) 

Day 5 6.3 ± 0.1 6.4 ± 0.1 6.6 ± 0.1 6.5 ± 0.1 6.4 ± 0.1 6.3 ± 0.1 

Day 20 6.8 ± 0.1 7.0 ± 0.1 7.1 ± 0.1 7.1 ± 0.1 7.1 ± 0.1 7.1 ± 0.1 

Week 13 6.4 ± 0.1 6.5 ± 0.1 6.8 ± 0.1* 6.9 ± 0.1** 7.1 ± 0.1** 6.8 ± 0.1** 

Albumin (g/dL) 

Day 5 3.5 ± 0.1 3.6 ± 0.1 3.8 ± 0.1* 3.7 ± 0.1* 3.6 ± 0.1 3.6 ± 0.1 

Day 20 3.8 ± 0.1 4.0 ± 0.1 4.0 ± 0.1 4.0 ± 0.1 4.1 ± 0.1** 3.9 ± 0.1 

Week 13 3.5 ± 0.1 3.6 ± 0.1 3.9 ± 0.1** 3.8 ± 0.0** 4.0 ± 0.0** 3.9 ± 0.1** 

Alanine aminotransferase (IU/L) 

Day 5 42 ± 2 46 ± 1 51 ± 1** 47 ± 1 60 ± 11 46 ± 1 

Day 20 53 ± 3 44 ± 3 40 ± 1* 39 ± 2** 49 ± 6 54 ± 6 

Week 13 60 ± 2 56 ± 4 52 ± 5 44 ± 2* 50 ± 3 583 ± 268 

Alkaline phosphatase (IU/L) 

Day 5 441 ± 15 468 ± 8 454 ± 16 423 ± 9 465 ± 10 456 ± 10 

Day 20 411 ± 11 302 ± 12** 385 ± 14** 320 ± 14** 275 ± 21** 331 ± 10** 

Week 13 236 ± 6 219 ± 4 223 ± 6 203 ± 3* 176 ± 8** 278 ± 25 
278 Pyridine, NTP TR 470 

TABLE G1 

Hematology and Clinical Chemistry Data for F344/N Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male (continued) 

Clinical Chemistry (continued) 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 9 

Week 13 10 10 10 10 10 10 

Creatine kinase (U/L) 

Day 5 

Day 20 

Week 13 

275 ± 63 

169 ± 14b 

234 ± 62 

260 ± 66 

241 ± 31b 

243 ± 63 

262 ± 43 

167 ± 14 

223 ± 58 

183 ± 17 

198 ± 20 

202 ± 56 

244 ± 33b 

180 ± 20 

339 ± 115 

193 ± 21 

171 ± 28 

161 ± 32b 

Sorbitol dehydrogenase (IU/L) 

Day 5 8 ± 0 9 ± 0 10 ± 1* 9 ± 1 27 ± 17 11 ± 0** 

Day 20 10 ± 0 8 ± 0 10 ± 1 10 ± 1 39 ± 13 23 ± 7 

Week 13 12 ± 1 11 ± 1 10 ± 1 10 ± 1 12 ± 1 395 ± 217 

Bile acids (μmol/L) 

Day 5 33.5 ± 4.0 34.7 ± 3.5 38.6 ± 7.5 26.6 ± 1.7 45.9 ± 7.3 40.6 ± 5.1 

Day 20 28.3 ± 3.2 40.3 ± 3.7* 26.6 ± 3.7 30.3 ± 2.7 61.0 ± 6.1** 59.6 ± 7.6** 

Week 13 30.5 ± 4.7 29.5 ± 4.2 26.0 ± 3.9 40.3 ± 7.7 62.1 ± 12.9* 150.0 ± 19.7** 

Female 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 10 

Week 13 10 10 10 10 10 8 

Hematology 

Automated hematocrit (%) 

Day 5 48.4 ± 0.5 48.9 ± 0.5 50.3 ± 0.6 48.6 ± 0.6 50.7 ± 0.7 50.5 ± 1.0 

Day 20 48.2 ± 0.4 47.4 ± 0.5 47.8 ± 0.3 47.0 ± 0.5 45.5 ± 0.6** 48.2 ± 1.0 

Week 13 46.5 ± 0.3 45.4 ± 0.3* 45.5 ± 0.3* 43.5 ± 0.5** 43.1 ± 0.3** 43.8 ± 0.4** 

Manual hematocrit (%) 

Day 5 44.9 ± 0.7 45.5 ± 0.4 46.9 ± 0.4 45.5 ± 0.6 46.9 ± 0.5 47.0 ± 0.9 

Day 20 46.7 ± 0.3 45.8 ± 0.6 46.3 ± 0.2 45.5 ± 0.4 44.4 ± 0.6* 47.4 ± 0.9 

Week 13 44.8 ± 0.3 44.0 ± 0.3 44.0 ± 0.4 41.3 ± 0.8** 40.9 ± 0.4** 41.5 ± 0.5** 

Hemoglobin (g/dL) 

Day 5 16.0 ± 0.1 16.0 ± 0.2 16.4 ± 0.1 15.9 ± 0.2 16.6 ± 0.2 16.5 ± 0.3 

Day 20 16.6 ± 0.2 16.3 ± 0.1 16.3 ± 0.1 15.8 ± 0.1** 15.6 ± 0.2** 16.2 ± 0.3** 

Week 13 15.8 ± 0.1 15.3 ± 0.1** 15.2 ± 0.1** 14.4 ± 0.2** 14.2 ± 0.1** 14.3 ± 0.1** 

Erythrocytes (106

/μL) 

Day 5 7.96 ± 0.07 7.97 ± 0.11 8.19 ± 0.11 7.86 ± 0.09 8.30 ± 0.11 8.18 ± 0.21 

Day 20 8.25 ± 0.09 8.06 ± 0.08 8.14 ± 0.07 7.92 ± 0.10 7.85 ± 0.09 8.43 ± 0.18 

Week 13 8.66 ± 0.06 8.43 ± 0.04** 8.40 ± 0.11* 7.94 ± 0.11** 7.93 ± 0.10** 8.17 ± 0.11** 

Reticulocytes (106

/μL) 

Day 5 0.18 ± 0.02 0.17 ± 0.01 0.18 ± 0.02 0.13 ± 0.01 0.19 ± 0.02 0.16 ± 0.01 

Day 20 0.16 ± 0.01 0.16 ± 0.02 0.16 ± 0.01 0.18 ± 0.01 0.17 ± 0.02 0.17 ± 0.01 

Week 13 0.15 ± 0.01 0.15 ± 0.01 0.15 ± 0.01 0.15 ± 0.01 0.15 ± 0.01 0.17 ± 0.01 

Nucleated erythrocytes (103

/μL) 

Day 5 0.03 ± 0.03 0.05 ± 0.02 0.04 ± 0.03 0.06 ± 0.02 0.04 ± 0.02 0.04 ± 0.03 

Day 20 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.02 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 

Week 13 0.00 ± 0.00 0.00 ± 0.00 0.03 ± 0.01 0.03 ± 0.02 0.01 ± 0.01 0.00 ± 0.00 
Pyridine, NTP TR 470 279 

TABLE G1 

Hematology and Clinical Chemistry Data for F344/N Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Female (continued) 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 10 

Week 13 10 10 10 10 10 8 

Hematology (continued) 

Mean cell volume (fL) 

Day 5 60.9 ± 0.4 61.6 ± 0.5 61.6 ± 0.3 61.7 ± 0.4 61.3 ± 0.3 61.7 ± 0.7 

Day 20 58.4 ± 0.4 58.7 ± 0.3 58.7 ± 0.3 59.4 ± 0.5 58.0 ± 0.3 57.3 ± 0.4 

Week 13 53.7 ± 0.2 54.0 ± 0.1 54.2 ± 0.6 54.2 ± 0.2 54.4 ± 0.4 53.6 ± 0.3 

Mean cell hemoglobin (pg) 

Day 5 20.1 ± 0.2 20.1 ± 0.2 20.1 ± 0.2 20.2 ± 0.2 20.0 ± 0.1 20.2 ± 0.2b 

Day 20 20.1 ± 0.1 20.2 ± 0.1 20.0 ± 0.1 19.9 ± 0.1 19.8 ± 0.1 19.3 ± 0.1** 

Week 13 18.2 ± 0.1 18.1 ± 0.1 18.2 ± 0.2 18.2 ± 0.2 18.0 ± 0.2** 17.5 ± 0.2** 

Mean cell hemoglobin concentration (g/dL) 

Day 5 33.1 ± 0.2 32.7 ± 0.1 32.7 ± 0.3 32.7 ± 0.3 32.7 ± 0.2 32.7 ± 0.2 

Day 20 34.4 ± 0.2 34.4 ± 0.2 34.0 ± 0.2 33.7 ± 0.2 34.2 ± 0.3 33.7 ± 0.2* 

Week 13 34.0 ± 0.1 33.7 ± 0.2 33.5 ± 0.1* 33.1 ± 0.2** 33.0 ± 0.1** 32.7 ± 0.2** 

Platelets (103

/μL) 

Day 5 941.7 ± 30.3 885.4 ± 26.5 971.4 ± 26.3 906.8 ± 11.8b 863.3 ± 21.2 857.5 ± 61.5 

Day 20 930.8 ± 22.3 885.0 ± 28.0 884.6 ± 44.3 982.5 ± 23.9 919.7 ± 16.9 812.6 ± 61.7 

Week 13 721.5 ± 17.2 741.0 ± 9.5 729.4 ± 32.6 738.5 ± 38.4 759.2 ± 36.4 751.3 ± 45.7 

Leukocytes (103

/μL) 

Day 5 10.19 ± 0.41 9.35 ± 0.34 8.84 ± 0.35 8.67 ± 0.26 8.97 ± 0.50 8.36 ± 0.56* 

Day 20 9.54 ± 0.29 9.60 ± 0.34 9.15 ± 0.42 9.41 ± 0.32 9.05 ± 0.35 8.95 ± 0.43 

Week 13 8.01 ± 0.32 8.38 ± 0.18 8.35 ± 0.23 7.93 ± 0.47 8.89 ± 0.28 8.70 ± 0.49 

Segmented neutrophils (103

/μL) 

Day 5 1.18 ± 0.18 1.48 ± 0.22 1.17 ± 0.13 0.98 ± 0.12 1.20 ± 0.23 1.15 ± 0.17 

Day 20 1.31 ± 0.14 1.49 ± 0.19 1.32 ± 0.13 1.44 ± 0.17 1.41 ± 0.17 1.87 ± 0.25 

Week 13 1.55 ± 0.15 1.48 ± 0.18 1.42 ± 0.09 1.39 ± 0.14 1.62 ± 0.19 1.27 ± 0.16 

Lymphocytes (103

/μL) 

Day 5 8.89 ± 0.42 7.81 ± 0.43 7.61 ± 0.41 7.64 ± 0.28 7.93 ± 0.52 7.14 ± 0.62 

Day 20 8.18 ± 0.32 8.06 ± 0.42 7.75 ± 0.46 7.82 ± 0.26 7.54 ± 0.36 6.99 ± 0.48 

Week 13 6.41 ± 0.23 6.87 ± 0.23 6.86 ± 0.24 6.42 ± 0.41 7.20 ± 0.28 7.40 ± 0.48 

Monocytes (103

/μL) 

Day 5 0.11 ± 0.04 0.03 ± 0.02 0.04 ± 0.02 0.04 ± 0.02 0.04 ± 0.01 0.03 ± 0.01 

Day 20 0.05 ± 0.02 0.04 ± 0.03 0.04 ± 0.02 0.11 ± 0.03 0.08 ± 0.04 0.07 ± 0.04 

Week 13 0.04 ± 0.01 0.02 ± 0.01 0.03 ± 0.01 0.04 ± 0.02 0.04 ± 0.02 0.01 ± 0.01 

Basophils (103

/μL) 

Day 5 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Day 20 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Week 13 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Eosinophils (103

/μL) 

Day 5 0.01 ± 0.01 0.03 ± 0.02 0.03 ± 0.01 0.01 ± 0.01 0.02 ± 0.01 0.05 ± 0.03 

Day 20 0.01 ± 0.01 0.01 ± 0.01 0.04 ± 0.03 0.04 ± 0.02 0.02 ± 0.01 0.03 ± 0.02 

Week 13 0.02 ± 0.01 0.03 ± 0.01 0.04 ± 0.02 0.05 ± 0.02 0.04 ± 0.01 0.03 ± 0.02 
280 Pyridine, NTP TR 470 

TABLE G1 

Hematology and Clinical Chemistry Data for F344/N Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Female (continued) 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 10 

Week 13 10 10 10 10 10 8 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Day 5 20.9 ± 1.0 21.2 ± 2.0 20.6 ± 0.8 20.3 ± 1.0 24.0 ± 1.0 22.9 ± 0.7 

Day 20 21.5 ± 0.7 22.0 ± 1.3 22.1 ± 1.1 22.6 ± 0.6 22.0 ± 0.6 25.9 ± 1.4 

Week 13 21.0 ± 0.8 20.4 ± 0.8 21.5 ± 1.2 18.3 ± 0.6 19.8 ± 0.7 23.4 ± 1.3 

Creatinine (mg/dL) 

Day 5 

Day 20 

0.55 ± 0.02 

0.58 ± 0.02 

0.55 ± 0.03 

0.56 ± 0.03 

0.51 ± 0.01 

0.61 ± 0.02 

0.52 ± 0.03 

0.56 ± 0.03 

0.58 ± 0.01 

0.57 ± 0.02 

0.56 ± 0.02 

0.59 ± 0.02b 

Week 13 0.62 ± 0.02 0.60 ± 0.01 0.63 ± 0.03 0.61 ± 0.02 0.60 ± 0.03 0.61 ± 0.05 

Total protein (g/dL) 

Day 5 6.0 ± 0.1 6.2 ± 0.1 6.7 ± 0.0** 6.2 ± 0.1 6.5 ± 0.1** 6.0 ± 0.1 

Day 20 6.4 ± 0.1 6.6 ± 0.1 6.5 ± 0.1 6.8 ± 0.1* 6.9 ± 0.1** 6.8 ± 0.1** 

Week 13 6.8 ± 0.1 6.6 ± 0.1 6.7 ± 0.1 6.8 ± 0.1 7.0 ± 0.1 6.7 ± 0.1 

Albumin (g/dL) 

Day 5 3.7 ± 0.0 3.7 ± 0.1 4.0 ± 0.1** 3.7 ± 0.1 3.9 ± 0.1* 3.8 ± 0.1 

Day 20 3.5 ± 0.1 3.6 ± 0.1 3.7 ± 0.1 3.8 ± 0.1** 4.1 ± 0.1** 4.0 ± 0.1** 

Week 13 3.9 ± 0.1 3.9 ± 0.0 4.0 ± 0.1 4.0 ± 0.1 4.0 ± 0.1 4.0 ± 0.1 

Alanine aminotransferase (IU/L) 

Day 5 36 ± 1 34 ± 1 33 ± 1 35 ± 2 45 ± 5 432 ± 294 

Day 20 35 ± 1 33 ± 2 30 ± 1 28 ± 1* 29 ± 2* 1,295 ± 1,133 

Week 13 40 ± 1 31 ± 2** 33 ± 2* 30 ± 1** 30 ± 1** 141 ± 72 

Alkaline phosphatase (IU/L) 

Day 5 419 ± 7 375 ± 11* 367 ± 7** 368 ± 8** 405 ± 10 410 ± 12 

Day 20 357 ± 8 328 ± 5** 315 ± 7** 287 ± 3** 283 ± 6** 314 ± 18** 

Week 13 210 ± 5 193 ± 5 176 ± 4** 162 ± 7** 168 ± 5** 209 ± 17** 

Creatine kinase (IU/L) 

Day 5 

Day 20 

195 ± 28 

266 ± 74 

230 ± 43 

222 ± 53 

257 ± 22 

208 ± 45 

207 ± 21b 

175 ± 38 

300 ± 27** 

143 ± 9 

288 ± 39* 

144 ± 15b 

Week 13 169 ± 23 119 ± 19 187 ± 42 210 ± 40 159 ± 20 240 ± 70 

Sorbitol dehydrogenase (IU/L) 

Day 5 

Day 20 

8 ± 1 

8 ± 1 

7 ± 0 

9 ± 1 

6 ± 1 

10 ± 0 

7 ± 0 

10 ± 0 

39 ± 20 

17 ± 6** 

111 ± 91 

383 ± 162**b 

Week 13 8 ± 0 9 ± 0 8 ± 1 9 ± 1 10 ± 1 289 ± 204** 

Bile acids (μmol/L) 

Day 5 32.3 ± 3.4 28.3 ± 5.1 20.9 ± 2.8 43.0 ± 5.9 39.3 ± 11.2 69.2 ± 25.7 

Day 20 34.1 ± 3.9 37.0 ± 5.9 41.1 ± 6.1 40.0 ± 8.9 55.0 ± 4.9* 202.0 ± 114.1** 

Week 13 47.3 ± 9.8 39.5 ± 4.9 38.0 ± 5.6 38.9 ± 4.6 54.5 ± 7.9 87.3 ± 21.8 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error. Statistical tests were performed on unrounded data. b n=9 
Pyridine, NTP TR 470 281 

TABLE G2 

Hematology and Clinical Chemistry Data for Male Wistar Rats in the 13-Week Drinking Water Study of Pyridinea 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Hematology 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 9 9 9 10 10 

Week 13 10 10 10 10 9 10 

Automated hematocrit (%) 

Day 5 40.7 ± 0.4 40.1 ± 0.7 41.0 ± 0.5 41.5 ± 0.6 45.6 ± 0.7** 45.0 ± 1.0** 

Day 20 43.0 ± 0.5 43.0 ± 0.7 42.6 ± 0.8 43.1 ± 0.5 42.9 ± 0.3 44.2 ± 0.9 

Week 13 45.0 ± 0.5 45.3 ± 0.7 45.4 ± 0.3 46.2 ± 0.7 46.0 ± 0.3 44.6 ± 0.7 

Manual hematocrit (%) 

Day 5 39.3 ± 0.4 38.6 ± 0.9 39.8 ± 0.5 40.1 ± 0.7 44.2 ± 0.8** 43.4 ± 1.0** 

Day 20 41.3 ± 0.6 42.7 ± 0.7 41.8 ± 0.8 42.2 ± 0.5 41.3 ± 0.4 43.5 ± 1.0 

Week 13 43.5 ± 0.6 44.0 ± 0.6 44.2 ± 0.2 44.7 ± 0.6 44.4 ± 0.4 43.4 ± 0.6 

Hemoglobin (g/dL) 

Day 5 13.3 ± 0.1 13.1 ± 0.2 13.5 ± 0.2 13.7 ± 0.2 15.1 ± 0.2** 14.8 ± 0.3** 

Day 20 14.3 ± 0.2 14.2 ± 0.2 14.0 ± 0.2 14.1 ± 0.2 14.0 ± 0.1 14.6 ± 0.3 

Week 13 15.1 ± 0.2 15.2 ± 0.2 15.2 ± 0.1 15.5 ± 0.1 15.3 ± 0.1 14.8 ± 0.2 

Erythrocytes (106

/μL) 

Day 5 6.43 ± 0.07 6.35 ± 0.10 6.43 ± 0.09 6.62 ± 0.08 7.34 ± 0.16** 7.13 ± 0.17** 

Day 20 6.99 ± 0.12 6.94 ± 0.10 6.90 ± 0.12 7.04 ± 0.10 7.07 ± 0.09 7.36 ± 0.13 

Week 13 8.52 ± 0.14 8.59 ± 0.17 8.71 ± 0.12 8.61 ± 0.14 8.64 ± 0.12 8.42 ± 0.10 

Reticulocytes (106

/μL) 

Day 5 0.27 ± 0.02 0.29 ± 0.03 0.29 ± 0.02 0.32 ± 0.02 0.27 ± 0.02 0.26 ± 0.02 

Day 20 0.21 ± 0.01 0.21 ± 0.01 0.18 ± 0.01 0.19 ± 0.01 0.22 ± 0.02 0.23 ± 0.01 

Week 13 0.13 ± 0.01 0.15 ± 0.01 0.14 ± 0.01 0.16 ± 0.01 0.18 ± 0.02 0.15 ± 0.01 

Nucleated erythrocytes (103

/μL) 

Day 5 0.06 ± 0.02 0.02 ± 0.01 0.04 ± 0.02 0.01 ± 0.01* 0.02 ± 0.01 0.02 ± 0.01 

Day 20 0.01 ± 0.01 0.01 ± 0.01 0.02 ± 0.01 0.03 ± 0.02 0.03 ± 0.02 0.01 ± 0.01 

Week 13 0.00 ± 0.00 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 0.03 ± 0.02 0.04 ± 0.02 

Mean cell volume (fL) 

Day 5 63.5 ± 0.6 63.2 ± 0.7 63.9 ± 0.7 62.6 ± 0.6 62.2 ± 0.5 63.2 ± 0.7 

Day 20 61.7 ± 0.7 62.1 ± 0.9 61.8 ± 0.7 61.4 ± 0.6 60.7 ± 0.4 60.2 ± 0.5 

Week 13 52.9 ± 0.6 52.9 ± 0.5 52.4 ± 0.5 53.8 ± 0.6 53.3 ± 0.7 53.2 ± 0.5 

Mean cell hemoglobin (pg) 

Day 5 20.8 ± 0.2 20.7 ± 0.2 21.0 ± 0.2 20.6 ± 0.2 20.6 ± 0.2 20.8 ± 0.2 

Day 20 20.4 ± 0.2 20.5 ± 0.2 20.4 ± 0.2 20.1 ± 0.2 19.8 ± 0.2 19.8 ± 0.2* 

Week 13 17.7 ± 0.3 17.7 ± 0.2 17.5 ± 0.2 18.0 ± 0.2 17.7 ± 0.2 17.6 ± 0.2 

Mean cell hemoglobin concentration (g/dL) 

Day 5 32.8 ± 0.1 32.7 ± 0.1 32.9 ± 0.2 32.9 ± 0.2 33.1 ± 0.2 32.9 ± 0.1 

Day 20 33.2 ± 0.2 33.1 ± 0.3 33.0 ± 0.2 32.8 ± 0.2 32.7 ± 0.1 33.0 ± 0.1 

Week 13 33.5 ± 0.2 33.6 ± 0.1 33.5 ± 0.2 33.5 ± 0.2 33.3 ± 0.2 33.3 ± 0.1 

Platelets (103

/μL) 

Day 5 1,356.5 ± 55.6 1,361.6 ± 46.8 1,398.8 ± 66.0 1,297.1 ± 70.9 1,364.3 ± 50.5 1,421.5 ± 75.1 

Day 20 1,227.3 ± 39.0 1,227.0 ± 49.9 1,225.9 ± 46.1 1,177.4 ± 67.6 1,207.3 ± 52.1 1,258.0 ± 78.4 

Week 13 

Leukocytes (103

/μL) 

1,055.2 ± 89.2 993.1 ± 57.2 1,012.2 ± 53.8 1,040.8 ± 55.8 1,232.1 ± 62.4 1,047.6 ± 72.7 

Day 5 9.82 ± 0.56 11.44 ± 0.45 9.11 ± 0.94 9.29 ± 0.61 8.98 ± 0.32 9.05 ± 0.84 

Day 20 10.09 ± 0.61 12.41 ± 0.53 10.14 ± 0.87 9.52 ± 0.35 10.16 ± 0.78 11.15 ± 0.92 

Week 13 9.81 ± 0.77 10.67 ± 0.88 9.89 ± 0.61 10.45 ± 0.43 11.38 ± 0.47 10.81 ± 0.87 

Segmented neutrophils (103

/μL) 

Day 5 1.34 ± 0.17 1.98 ± 0.27 1.39 ± 0.21 1.47 ± 0.20 1.52 ± 0.14 1.26 ± 0.16 

Day 20 1.46 ± 0.19 1.84 ± 0.24 1.54 ± 0.14 1.29 ± 0.17 1.55 ± 0.15 2.02 ± 0.34 

Week 13 1.66 ± 0.17 1.52 ± 0.16 1.55 ± 0.21 1.71 ± 0.14 2.08 ± 0.19 1.67 ± 0.21 
 

 

282 Pyridine, NTP TR 470 

TABLE G2 

Hematology and Clinical Chemistry Data for Male Wistar Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Hematology (continued) 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 9 9 9 10 10 

Week 13 10 10 10 10 9 10 

Lymphocytes (103

/μL) 

Day 5 8.41 ± 0.49 9.32 ± 0.35 7.64 ± 0.78 7.70 ± 0.51 7.38 ± 0.34 7.69 ± 0.86 

Day 20 8.52 ± 0.60 10.48 ± 0.62 8.51 ± 0.80 8.13 ± 0.37 8.50 ± 0.66 9.01 ± 0.74 

Week 13 8.06 ± 0.72 9.06 ± 0.79 8.24 ± 0.70 8.63 ± 0.42 9.19 ± 0.50 9.05 ± 0.81 

Monocytes (103

/μL) 

Day 5 0.04 ± 0.02 0.08 ± 0.03 0.05 ± 0.03 0.09 ± 0.03 0.03 ± 0.01 0.04 ± 0.02 

Day 20 0.08 ± 0.03 0.08 ± 0.03 0.07 ± 0.02 0.07 ± 0.02 0.05 ± 0.02 0.09 ± 0.02 

Week 13 0.03 ± 0.02 0.05 ± 0.03 0.03 ± 0.02 0.03 ± 0.02 0.06 ± 0.03 0.07 ± 0.02 

Basophils (103

/μL) 

Day 5 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Day 20 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Week 13 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 

Eosinophils (103

/μL) 

Day 5 0.03 ± 0.02 0.06 ± 0.03 0.03 ± 0.02 0.03 ± 0.03 0.05 ± 0.02 0.06 ± 0.03 

Day 20 0.03 ± 0.02 0.01 ± 0.01 0.03 ± 0.02 0.03 ± 0.02 0.06 ± 0.03 0.04 ± 0.02 

Week 13 0.06 ± 0.02 0.05 ± 0.02 0.07 ± 0.03 0.09 ± 0.04 0.05 ± 0.03 0.02 ± 0.01 

Clinical Chemistry 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 10 

Week 13 10 10 10 10 9 10 

Urea nitrogen (mg/dL) 

Day 5 19.9 ± 0.8 19.4 ± 0.6 18.4 ± 1.0 18.9 ± 1.0 23.1 ± 1.1* 25.2 ± 1.3** 

Day 20 23.3 ± 0.9 24.5 ± 0.5 22.7 ± 0.6 25.6 ± 1.0 25.8 ± 0.6* 28.0 ± 1.1** 

Week 13 28.1 ± 0.8 27.5 ± 0.9 27.0 ± 1.0 26.8 ± 1.7 31.2 ± 1.8 29.7 ± 2.3 

Creatinine (mg/dL) 

Day 5 0.50 ± 0.03 0.52 ± 0.02 0.46 ± 0.02 0.48 ± 0.02 0.53 ± 0.03 0.52 ± 0.01 

Day 20 0.54 ± 0.02 0.53 ± 0.02 0.54 ± 0.02 0.53 ± 0.05 0.57 ± 0.02 0.57 ± 0.04 

Week 13 0.62 ± 0.04 0.68 ± 0.02 0.68 ± 0.02 0.72 ± 0.03 0.74 ± 0.04 0.67 ± 0.03 

Total protein (g/dL) 

Day 5 5.9 ± 0.1 5.8 ± 0.1 5.8 ± 0.1 5.9 ± 0.1 5.8 ± 0.1 6.1 ± 0.2 

Day 20 6.5 ± 0.1 6.7 ± 0.1 6.4 ± 0.1 6.8 ± 0.1 6.7 ± 0.1 6.7 ± 0.1 

Week 13 6.6 ± 0.1 6.7 ± 0.1 6.7 ± 0.1 7.0 ± 0.1 6.9 ± 0.1 6.6 ± 0.1 

Albumin (g/dL) 

Day 5 3.0 ± 0.0 3.2 ± 0.1 3.1 ± 0.0 3.2 ± 0.1 3.2 ± 0.1 3.3 ± 0.1* 

Day 20 3.3 ± 0.1 3.4 ± 0.1 3.3 ± 0.1 3.5 ± 0.0 3.4 ± 0.1 3.4 ± 0.1 

Week 13 3.6 ± 0.1 3.8 ± 0.1 3.8 ± 0.1 3.9 ± 0.1* 3.8 ± 0.1 3.8 ± 0.1 

Alanine aminotransferase (IU/L) 

Day 5 52 ± 2 53 ± 2 52 ± 2 53 ± 4 117 ± 30** 134 ± 74 

Day 20 48 ± 2 43 ± 1 45 ± 2 45 ± 2 45 ± 2 299 ± 162 

Week 13 54 ± 2 51 ± 4 50 ± 3 47 ± 3 146 ± 51 62 ± 11 

Alkaline phosphatase (IU/L) 

Day 5 339 ± 13 343 ± 19 327 ± 20 303 ± 26 339 ± 29 378 ± 30 

Day 20 294 ± 11 281 ± 21 268 ± 16 229 ± 16* 262 ± 19 288 ± 30 

Week 13 179 ± 7 189 ± 8 160 ± 7 157 ± 6* 168 ± 18 143 ± 11* 
Pyridine, NTP TR 470 283 

TABLE G2 

Hematology and Clinical Chemistry Data for Male Wistar Rats in the 13-Week Drinking Water Study of Pyridine 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Clinical Chemistry (continued) 

n 

Day 5 10 10 10 10 10 10 

Day 20 10 10 10 10 10 10 

Week 13 10 10 10 10 9 10 

Creatine kinase (U/L) 

Day 5 242 ± 23 211 ± 22 280 ± 31 255 ± 21 306 ± 35 291 ± 51 

Day 20 223 ± 42 322 ± 69 345 ± 80 298 ± 56 333 ± 91 362 ± 99 

Week 13 274 ± 65 454 ± 136 290 ± 45 272 ± 58 331 ± 64 309 ± 56 

Sorbitol dehydrogenase (IU/L) 

Day 5 8 ± 1 8 ± 1 7 ± 1 7 ± 0 615 ± 179** 370 ± 289** 

Day 20 7 ± 0 7 ± 1 7 ± 1 8 ± 1 9 ± 1 1,075 ± 605** 

Week 13 7 ± 0 8 ± 1 7 ± 1 9 ± 1 253 ± 94** 49 ± 29** 

Bile acids (μmol/L) 

Day 5 100.0 ± 14.8 77.4 ± 8.4 118.5 ± 12.6 119.1 ± 16.9 235.0 ± 44.4** 191.3 ± 27.9** 

Day 20 70.2 ± 8.1 76.0 ± 8.4 98.0 ± 14.9 159.1 ± 41.2* 111.5 ± 23.3 172.4 ± 37.9* 

Week 13 75.5 ± 13.9 66.7 ± 6.7 67.4 ± 6.3 64.1 ± 8.1 117.8 ± 24.9 116.3 ± 20.2 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error. Statistical tests were performed on unrounded data. 
284 Pyridine, NTP TR 470
 
285 

APPENDIX H 

ORGAN WEIGHTS AND 

ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS 

TABLE H1 Organ Weights and Organ-Weight-to-Body-Weight Ratios for F344/N Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 286 

TABLE H2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Male Wistar Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 287 

TABLE H3 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice 

in the 13-Week Drinking Water Study of Pyridine . ................................ 288 
286 Pyridine, NTP TR 470 

TABLE H1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for F344/N Rats in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

n 10 10 10 10 10 10 

Necropsy body wt 335 ± 9 334 ± 7 337 ± 6 334 ± 7 316 ± 5 287 ± 5** 

Heart 

Absolute 1.145 ± 0.034 1.187 ± 0.049 1.140 ± 0.038 1.140 ± 0.029 1.129 ± 0.059 1.159 ± 0.037 

Relative 3.42 ± 0.08 3.56 ± 0.13 3.38 ± 0.08 3.42 ± 0.08 3.57 ± 0.17 4.04 ± 0.12** 

R. Kidney 

Absolute 1.352 ± 0.037 1.333 ± 0.039 1.345 ± 0.032 1.398 ± 0.040 1.381 ± 0.026 1.396 ± 0.037 

Relative 4.04 ± 0.05 3.99 ± 0.06 3.99 ± 0.05 4.18 ± 0.08 4.38 ± 0.08** 4.87 ± 0.08** 

Liver 

Absolute 14.384 ± 0.601 14.901 ± 0.579 15.415 ± 0.429 16.091 ± 0.541* 16.535 ± 0.295* 15.512 ± 0.500* 

Relative 42.81 ± 0.99 44.52 ± 0.77 45.75 ± 0.76* 48.07 ± 0.81** 52.41 ± 0.99** 54.06 ± 1.27** 

Lung 

Absolute 1.837 ± 0.061 1.782 ± 0.048 1.791 ± 0.050 1.844 ± 0.077 1.747 ± 0.051 1.558 ± 0.053** 

Relative 5.49 ± 0.16 5.36 ± 0.17 5.33 ± 0.17 5.51 ± 0.18 5.55 ± 0.20 5.43 ± 0.16 

R. Testis 

Absolute 1.502 ± 0.026 1.474 ± 0.020 1.486 ± 0.025 1.502 ± 0.019 1.516 ± 0.013 1.437 ± 0.019 

Relative 4.51 ± 0.15 4.43 ± 0.10 4.42 ± 0.08 4.50 ± 0.05 4.81 ± 0.07* 5.02 ± 0.08** 

Thymus 

Absolute 0.320 ± 0.022 0.363 ± 0.031 0.352 ± 0.020 0.350 ± 0.018 0.362 ± 0.026 0.294 ± 0.023 

Relative 0.95 ± 0.06 1.08 ± 0.07 1.04 ± 0.05 1.05 ± 0.04 1.15 ± 0.08 1.03 ± 0.08 

Female 

n 10 10 10 10 10 8 

Necropsy body wt 198 ± 3 196 ± 4 195 ± 2 197 ± 4 185 ± 2** 180 ± 3** 

Heart 

Absolute 0.807 ± 0.033 0.752 ± 0.027 0.797 ± 0.030 0.786 ± 0.033 0.806 ± 0.029 0.767 ± 0.054 

Relative 4.07 ± 0.16 3.83 ± 0.11 4.10 ± 0.17 3.99 ± 0.15 4.37 ± 0.18 4.26 ± 0.30 

R. Kidney 

Absolute 0.752 ± 0.017 0.731 ± 0.018 0.741 ± 0.008 0.795 ± 0.012 0.774 ± 0.019 0.739 ± 0.024 

Relative 3.80 ± 0.09 3.74 ± 0.10 3.81 ± 0.06 4.04 ± 0.05 4.19 ± 0.11** 4.10 ± 0.10* 

Liver 

Absolute 6.866 ± 0.135 7.305 ± 0.133 7.874 ± 0.212** 8.732 ± 0.244** 9.391 ± 0.152** 9.619 ± 0.293** 

Relative 34.68 ± 0.53 37.32 ± 0.76 40.46 ± 1.23** 44.30 ± 0.82** 50.80 ± 0.75** 53.44 ± 1.79** 

Lung 

Absolute 1.277 ± 0.049 1.230 ± 0.048 1.253 ± 0.070 1.289 ± 0.059 1.290 ± 0.034 1.173 ± 0.022 

Relative 6.46 ± 0.27 6.26 ± 0.15 6.45 ± 0.40 6.53 ± 0.22 6.98 ± 0.16 6.51 ± 0.07 

Thymus 

Absolute 0.265 ± 0.011 0.295 ± 0.013 0.280 ± 0.008 0.305 ± 0.037 0.313 ± 0.034 0.252 ± 0.011 

Relative 1.34 ± 0.06 1.50 ± 0.06 1.44 ± 0.04 1.54 ± 0.18 1.70 ± 0.19 1.39 ± 0.05 

* Significantly different (P#0.05) from the control group by Williams’ or Dunnett’s test 

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/g 

body weight (mean ± standard error). 
Pyridine, NTP TR 470 287 

TABLE H2 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Male Wistar Rats in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

n 10 10 10 10 9 10 

Necropsy body wt 490 ± 10 457 ± 12 469 ± 6 445 ± 17* 428 ± 8** 405 ± 15** 

Heart 

Absolute 1.679 ± 0.043 1.730 ± 0.088 1.780 ± 0.051 1.712 ± 0.090 1.560 ± 0.081 1.513 ± 0.071 

Relative 3.44 ± 0.09 3.78 ± 0.14 3.80 ± 0.13 3.84 ± 0.10 3.63 ± 0.13 3.74 ± 0.12 

R. Kidney 

Absolute 1.948 ± 0.069 1.924 ± 0.061 2.004 ± 0.046 2.085 ± 0.079 2.041 ± 0.115 1.998 ± 0.114 

Relative 3.98 ± 0.11 4.21 ± 0.09 4.27 ± 0.10 4.70 ± 0.13** 4.76 ± 0.21** 4.92 ± 0.19** 

Liver 

Absolute 20.949 ± 0.624 21.152 ± 0.840 21.528 ± 0.608 21.706 ± 0.945 22.662 ± 1.098 21.367 ± 1.160 

Relative 42.79 ± 0.98 46.33 ± 1.47 45.90 ± 1.25 48.78 ± 0.97** 52.77 ± 1.68** 52.60 ± 1.65** 

Lung 

Absolute 2.534 ± 0.090 2.366 ± 0.129 2.429 ± 0.098 2.217 ± 0.104 2.133 ± 0.134 2.213 ± 0.111 

Relative 5.22 ± 0.28 5.16 ± 0.20 5.20 ± 0.25 5.00 ± 0.19 4.97 ± 0.25 5.46 ± 0.19 

R. Testis 

Absolute 1.737 ± 0.046 1.632 ± 0.074 1.843 ± 0.039 1.731 ± 0.051 1.939 ± 0.181 1.823 ± 0.085 

Relative 3.56 ± 0.14 3.59 ± 0.17 3.93 ± 0.09 3.92 ± 0.12 4.50 ± 0.34** 4.52 ± 0.18** 

Thymus 

Absolute 0.479 ± 0.039 0.501 ± 0.035 0.458 ± 0.026 0.499 ± 0.036 0.423 ± 0.029 0.507 ± 0.061 

Relative 0.98 ± 0.08 1.11 ± 0.09 0.98 ± 0.06 1.12 ± 0.07 0.99 ± 0.06 1.23 ± 0.12 

* Significantly different (P#0.05) from the control group by Williams’ or Dunnett’s test 

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/g 

body weight (mean ± standard error). 
288 Pyridine, NTP TR 470 

TABLE H3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Drinking Water Study of Pyridinea 

0 ppm 50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

n 10 10 10 10 10 10 

Necropsy body wt 38.9 ± 0.8 37.6 ± 1.1 38.8 ± 0.9 39.6 ± 1.2 38.8 ± 0.8 36.9 ± 0.7 

Heart 

Absolute 0.199 ± 0.008 0.193 ± 0.010 0.211 ± 0.013 0.203 ± 0.010 0.188 ± 0.006 0.193 ± 0.008 

Relative 5.12 ± 0.17 5.15 ± 0.26 5.41 ± 0.28 5.11 ± 0.19 4.85 ± 0.14 5.25 ± 0.19 

R. Kidney 

Absolute 0.304 ± 0.007 0.291 ± 0.010 0.302 ± 0.016 0.293 ± 0.011 0.254 ± 0.009* 0.274 ± 0.008* 

Relative 7.85 ± 0.24 7.76 ± 0.16 7.80 ± 0.43 7.41 ± 0.23 6.57 ± 0.26** 7.44 ± 0.24 

Liver 

Absolute 1.855 ± 0.044 1.878 ± 0.048 2.058 ± 0.057* 2.177 ± 0.083** 2.264 ± 0.066** 2.249 ± 0.067** 

Relative 47.81 ± 1.21 50.16 ± 1.06 53.08 ± 1.19** 54.85 ± 0.76** 58.36 ± 1.23** 60.96 ± 1.01** 

Lung 

Absolute 

Relative 

0.281 ± 0.020 

7.31 ± 0.66 

0.267 ± 0.017 

7.13 ± 0.44 

0.293 ± 0.022 

7.54 ± 0.48 

0.274 ± 0.018b 

6.85 ± 0.41b 

0.288 ± 0.017 

7.46 ± 0.47 

0.269 ± 0.008 

7.36 ± 0.33 

R. Testis 

Absolute 0.125 ± 0.003 0.125 ± 0.004 0.127 ± 0.004 0.129 ± 0.004 0.123 ± 0.002 0.117 ± 0.004 

Relative 3.22 ± 0.10 3.34 ± 0.07 3.27 ± 0.12 3.27 ± 0.10 3.18 ± 0.06 3.18 ± 0.12 

Thymus 

Absolute 0.057 ± 0.007 0.059 ± 0.005 0.065 ± 0.007 0.057 ± 0.009 0.055 ± 0.005 0.047 ± 0.006 

Relative 1.46 ± 0.17 1.59 ± 0.16 1.65 ± 0.17 1.42 ± 0.18 1.42 ± 0.13 1.28 ± 0.14 

Female 

n 10 10 10 9 10 10 

Necropsy body wt 33.0 ± 1.1 37.1 ± 1.1 33.9 ± 0.9 34.0 ± 1.1 32.9 ± 0.9 29.4 ± 0.9* 

Heart 

Absolute 0.146 ± 0.007 0.157 ± 0.006 0.139 ± 0.003 0.134 ± 0.006 0.141 ± 0.006 0.129 ± 0.003* 

Relative 4.45 ± 0.24 4.27 ± 0.21 4.13 ± 0.17 3.93 ± 0.10 4.28 ± 0.14 4.40 ± 0.12 

R. Kidney 

Absolute 0.199 ± 0.006 0.219 ± 0.004 0.193 ± 0.010 0.203 ± 0.007 0.206 ± 0.004 0.204 ± 0.005 

Relative 6.07 ± 0.14 5.94 ± 0.14 5.73 ± 0.32 5.97 ± 0.12 6.28 ± 0.14 6.98 ± 0.19** 

Liver 

Absolute 1.513 ± 0.039 1.766 ± 0.039* 1.630 ± 0.044 1.743 ± 0.081* 1.836 ± 0.059** 1.609 ± 0.071 

Relative 46.04 ± 1.09 47.80 ± 0.84 48.29 ± 1.67 51.04 ± 1.20** 55.71 ± 0.81** 54.69 ± 1.58** 

Lung 

Absolute 0.263 ± 0.016 0.268 ± 0.015 0.224 ± 0.008 0.233 ± 0.009 0.252 ± 0.012 0.231 ± 0.012 

Relative 7.98 ± 0.44 7.25 ± 0.41 6.60 ± 0.24* 6.90 ± 0.35 7.66 ± 0.32 7.91 ± 0.46 

Thymus 

Absolute 0.062 ± 0.005 0.068 ± 0.004 0.060 ± 0.005 0.065 ± 0.005 0.056 ± 0.003 0.055 ± 0.003 

Relative 1.87 ± 0.12 1.85 ± 0.12 1.78 ± 0.13 1.91 ± 0.15 1.72 ± 0.12 1.89 ± 0.10 

* Significantly different (P#0.05) from the control group by Williams’ or Dunnett’s test 

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/g 

body weight (mean ± standard error). b n=9 
289 

APPENDIX I 

REPRODUCTIVE TISSUE EVALUATIONS 

AND ESTROUS CYCLE CHARACTERIZATION 

TABLE I1 Summary of Reproductive Tissue Evaluations for Male F344/N Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 290 

TABLE I2 Summary of Estrous Cycle Characterization for Female F344/N Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 290 

TABLE I3 Summary of Reproductive Tissue Evaluations for Male Mice 

in the 13-Week Drinking Water Study of Pyridine . ................................ 291 

TABLE I4 Summary of Estrous Cycle Characterization for Female Mice 

in the 13-Week Drinking Water Study of Pyridine . ................................ 291 
290 Pyridine, NTP TR 470 

TABLE I1 

Summary of Reproductive Tissue Evaluations for Male F344/N Rats in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

n 10 10 10 10 

Weights (g) 

Necropsy body wt 339 ± 9 334 ± 7 316 ± 5* 287 ± 5** 

L. cauda epididymis 0.1834 ± 0.0057 0.1866 ± 0.0040 0.1939 ± 0.0039 0.1785 ± 0.0042 

L. epididymis 0.4590 ± 0.0105 0.4529 ± 0.0037 0.4723 ± 0.0030 0.4201 ± 0.0068** 

L. testis 1.5272 ± 0.0165 1.5036 ± 0.0181 1.5726 ± 0.0150 1.4368 ± 0.0125** 

Spermatid measurements 

Spermatid heads (107

/g testis) 

Spermatid heads (107

/testis) 

11.29 ± 0.72b 

17.29 ± 1.17b 

10.86 ± 0.41b 

16.31 ± 0.60b 

10.87 ± 0.35 

17.07 ± 0.49 

11.36 ± 0.37 

16.33 ± 0.58 

Spermatid count 

 (mean/10!4

 mL suspension) 86.47 ± 5.84b 81.53 ± 3.01b 85.33 ± 2.44 81.63 ± 2.88 

Epididymal spermatozoal measurements 

Motility (%) 98.89 ± 0.19 98.96 ± 0.16 99.00 ± 0.13 98.87 ± 0.15 

Concentration 

 (106

/g cauda epididymal tissue) 748 ± 34 733 ± 24 683 ± 18 714 ± 36 

* Significantly different (P#0.05) from the control group by Williams’ test
 

** Significantly different (P#0.01) from the control group by Williams’ test (body weights) or Dunnett’s test (epididymal and testis weights)
 a Data are presented as mean ± standard error. Differences from the control group are not significant by Dunnett’s test (caudal weight) or 

Dunn’s test (spermatid and epididymal spermatozoal measurements). b n=9 

TABLE I2 

Summary of Estrous Cycle Characterization for Female F344/N Rats in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

n 10 10 10 8 

Necropsy body wt (g) 

Estrous cycle length (days) 

198 ± 3 

5.00 ± 0.00b 

197 ± 4 

5.00 ± 0.00 

185 ± 2** 

5.30 ± 0.30 

180 ± 3** 

6.08 ± 0.30**c 

Estrous stages (% of cycle) 

Diestrus 42.5 45.8 40.8 54.2 

Proestrus 13.3 16.7 16.7 12.5 

Estrus 25.0 19.2 23.3 19.8 

Metestrus 19.2 18.3 19.2 13.5 

** Significantly different (P#0.01) from the control group by Williams’ test (body weights) or Shirley’s test (estrous cycle length) a Necropsy body weight and estrous cycle length data are presented as mean ± standard error. By multivariate analysis of variance, exposed 

females do not differ significantly from the control females in the relative length of time spent in the estrous stages. b Estrous cycle was longer than 12 days or unclear in 1 of 10 animals. 

Estrous cycle was longer than 12 days or unclear in 2 of 8 animals. c 
Pyridine, NTP TR 470 291 

TABLE I3 

Summary of Reproductive Tissue Evaluations for Male Mice in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

n 10 10 10 10 

Weights (g) 

Necropsy body wt 38.9 ± 0.8 39.6 ± 1.2 38.8 ± 0.8 36.9 ± 0.7 

L. cauda epididymis 0.0170 ± 0.0011 0.0166 ± 0.0006 0.0170 ± 0.0008 0.0155 ± 0.0008 

L. epididymis 0.0453 ± 0.0018 0.0480 ± 0.0016 0.0449 ± 0.0017 0.0446 ± 0.0019 

L. testis 0.1174 ± 0.0036 0.1181 ± 0.0034 0.1169 ± 0.0033 0.1088 ± 0.0044 

Spermatid measurements 

Spermatid heads (107

/g testis) 

Spermatid heads (107

/testis) 

15.81 ± 0.62 

1.85 ± 0.09 

13.37 ± 0.56 

1.57 ± 0.05* 

15.53 ± 1.05 

1.80 ± 0.11 

14.73 ± 1.10 

1.61 ± 0.14 

Spermatid count 

 (mean/10!4 mL suspension) 57.90 ± 2.69 49.00 ± 1.69* 56.28 ± 3.37 50.45 ± 4.26 

Epididymal spermatozoal measurements 

Motility (%) 99.31 ± 0.13 98.58 ± 0.12** 98.16 ± 0.26** 97.21 ± 0.42** 

Concentration 

 (106

/g cauda epididymal tissue) 1,630 ± 126 1,432 ± 57 1,360 ± 54 1,461 ± 72 

* Significantly different (P#0.05) from the control group by Dunn’s test 

** Significantly different (P#0.01) from the control group by Shirley’s test a Data are presented as mean ± standard error. Differences from the control group are not significant by Dunnett’s test (body and tissue 

weights) or Dunn’s test (spermatid heads per gram testis and epididymal spermatozoal concentration). 

TABLE I4 

Summary of Estrous Cycle Characterization for Female Mice in the 13-Week Drinking Water Study 

of Pyridinea 

0 ppm 250 ppm 500 ppm 1,000 ppm 

n 10 9 10 10 

Necropsy body wt (g) 

Estrous cycle length (days) 

33.0 ± 1.1 

4.72 ± 0.55b 

34.0 ± 1.1 

4.50 ± 0.16c 32.9 ± 0.9 4.72 ± 0.22b 

29.4 ± 0.9* 

4.28 ± 0.15b 

Estrous stages (% of cycle) 

Diestrus 36.7 35.2 31.7 31.7 

Proestrus 20.0 13.9 17.5 20.0 

Estrus 25.0 35.2 35.8 27.5 

Metestrus 18.3 15.7 15.0 20.8 

*	 Significantly different (P#0.05) from the control group by Dunnett’s test a Necropsy body weight and estrous cycle length data are presented as mean ± standard error. Differences from the control group for estrous 

cycle length are not significant by Dunn’s test. By multivariate analysis of variance, exposed females do not differ significantly from the 

control females in the relative length of time spent in the estrous stages. b	 Estrous cycle was longer than 12 days or unclear in 1 of 10 animals. 

Estrous cycle was longer than 12 days or unclear in 1 of 9 animals. c 
292 Pyridine, NTP TR 470
 
293 

APPENDIX J
 

DETERMINATIONS OF PYRIDINE IN PLASMA
 

TABLE J1 Plasma Concentrations of Pyridine in F344/N Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 294 
 

TABLE J2 Plasma Concentrations of Pyridine in Male Wistar Rats 

in the 13-Week Drinking Water Study of Pyridine . ................................ 294 
 
294 

c 

c 

Pyridine, NTP TR 470 

TABLE J1 

Plasma Concentrations of Pyridine in F344/N Rats in the 13-Week Drinking Water Study of Pyridinea 

50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

Male 

n 10b 10c 9d 9 10 

Concentration (μg/mL) 0.045 ± 0.016 0.018 ± 0.007 0.084 ± 0.022 4.760 ± 1.334 38.140 ± 4.173 

Female 

n 10e 10e 10 10 8 

Concentration (μg/mL) 0.057 ± 0.014 0.075 ± 0.019 2.851 ± 0.602 14.810 ± 1.682 28.351 ± 5.070 

a Mean ± standard error; the minimum detection limit (MDL) was calculated to be 0.009 μg/mL. A value of 0 was used for samples with a 

concentration below the MDL. 

b	 Three samples were less than the MDL. 

Five samples were less than the MDL. d	 One sample was less than the MDL. e Two samples were less than the MDL. 

TABLE J2 

Plasma Concentrations of Pyridine in Male Wistar Rats in the 13-Week Drinking Water Study of Pyridinea 

50 ppm 100 ppm 250 ppm 500 ppm 1,000 ppm 

n 10b 9c 9d 9 9 

Concentration (μg/mL) 0.153 ± 0.096 0.043 ± 0.010 2.811 ± 1.406 8.278 ± 1.716 22.602 ± 5.798 

a Mean ± standard error; the minimum detection limit (MDL) was calculated to be 0.009 μg/mL. A value of 0 was used for samples with a 

concentration below the MDL. 

b	 Five samples were less than the MDL. 

Two samples were less than the MDL. d	 One sample was less than the MDL. 
295 

APPENDIX K
 

CHEMICAL CHARACTERIZATION
 

AND DOSE FORMULATION STUDIES
 

PROCUREMENT AND CHARACTERIZATION OF PYRIDINE .......................................... 296 
 

PREPARATION AND ANALYSIS OF DOSE FORMULATIONS .......................................... 297 
 

FIGURE K1 Infrared Absorption Spectrum of Pyridine ........................................ 298 
 

FIGURE K2 Nuclear Magnetic Resonance Spectrum of Pyridine ................................. 299 
 

TABLE K1 Preparation and Storage of Dose Formulations
 

in the Drinking Water Studies of Pyridine ......................................... 300 
 

TABLE K2 Results of Analyses of Dose Formulations Administered to F344/N Rats,
 

Wistar Rats, and Mice in the 13-Week Drinking Water Studies of Pyridine . ............ 301 
 

TABLE K3 Results of Analyses of Dose Formulations Administered to F344/N Rats,
 

Wistar Rats, and Mice in the 2-Year Drinking Water Studies of Pyridine ............... 304 
 

TABLE K4 Results of Referee Analyses of Dose Formulations Administered to F344/N Rats, 

Wistar Rats, and Mice in the 13-Week Drinking Water Studies of Pyridine . ............ 311 
 
296 Pyridine, NTP TR 470 

CHEMICAL CHARACTERIZATION 

AND DOSE FORMULATION STUDIES 

PROCUREMENT AND CHARACTERIZATION OF PYRIDINE 

Pyridine was obtained from Aldrich Chemical Company (Milwaukee, WI) in one lot (00103BV), which was 

used during the 13-week and 2-year studies. Identity, purity, and stability analyses were conducted by the 

analytical chemistry laboratory, Midwest Research Institute (Kansas City, MO). Reports on analyses 

performed in support of the pyridine studies are on file at the National Institute of Environmental Health 

Sciences. 

The chemical, a clear colorless liquid, was identified as pyridine by infrared, ultraviolet/visible, and nuclear 

magnetic resonance spectroscopy. All spectra were consistent with those expected for the structure and with 

the literature spectra (Sadtler Standard Spectra) of pyridine. The infrared and nuclear magnetic spectra are 

presented in Figures K1 and K2. 

The purity of lot 00103BV was determined by elemental analyses, Karl Fischer water analysis, functional 

group titration, and gas chromatography. For amine group titration, the sample was dissolved in glacial acetic 

acid, then titrated with 0.1 N perchloric acid in glacial acetic acid to a potentiometric endpoint. The titration 

was monitored with a combination mV/pH electrode filled with aqueous 3 M potassium chloride. Gas 

chromatography was performed using a flame ionization detector. Two systems were used: 

A)	 10% Carbowax 20M-TPA on 80/100 Chromosorb W AW glass column, with an isothermal oven 

temperature of 93E C, an oven temperature program of 60E C for 6 minutes, then 60E to 220E C at 

10E C per minute, and a nitrogen carrier gas at a flow rate of 70 mL/minute, and 

B)	 DB-5 Capillary fused silica column, with an oven temperature program of 50E C for 5 minutes, 

then 50E to 250E C at 10E C per minute, and a helium carrier gas at a flow rate of 5 mL/minute. 

Elemental analyses for hydrogen and nitrogen were in agreement with the theoretical values for pyridine; 

results for carbon were slightly low. Karl Fischer water analysis indicated 0.049% ± 0.003% water. 

Functional group titration indicated a purity of 99.8% ± 0.6%. Gas chromatography using systems A and B 

indicated one major peak and no impurities with an area greater than or equal to 0.1% relative to the major 

peak area. Concomitant analyses of lot 00103BV with lot 18400080202, a previously analyzed lot that was 

not used in the current studies, were performed with gas chromatography by system A but with an isothermal 

oven temperature of 95E C and with n-butanol as an internal standard. Results indicated a purity of 99.9% ± 

0.7% for lot 00103BV relative to lot 18400080202. The overall purity of lot 00103BV was determined to be 

greater than 99%. 

The analytical chemistry laboratory conducted bulk stability studies on lot 18400080202 with gas 

chromatography. A flame ionization detector was used with a 20% SP-2100/0.1% Carbowax 1500 on 100/120 

Supelcoport glass column, a nitrogen carrier gas at a flow rate of 70 mL/minute, an oven temperature of 50E C, 

and a 0.4% ethyl acetate internal standard. Samples stored for 2 weeks at 25E or 60E C showed some 

decomposition. To ensure stability, the bulk chemical was stored at 1E to 7E C (13-week studies) or 2E to 8E C 

(2-year studies) in amber glass bottles in the dark. Stability was monitored during the studies using gas 

chromatography. No degradation of the bulk chemical was detected. 
Pyridine, NTP TR 470 297 

PREPARATION AND ANALYSIS OF DOSE FORMULATIONS 

The dose formulations were prepared as needed by mixing pyridine with deionized water (Table K1). 

Formulations were stored in Teflon®-capped amber glass bottles (13-week studies) or glass carboys (2-year 

studies) at room temperature in the dark for up to 3 weeks. 

Stability studies of a 0.01 mg/mL formulation were performed by the analytical chemistry laboratory using 

high-performance liquid chromatography with a Waters μBondapak C18 column, ultraviolet (254 nm) 

detection, a solvent system of 0.005 M triethanolamine in water:methanol (30:70) with the pH adjusted to 7.0 

with 10% phosphoric acid, and a flow rate of 1 mL/minute. The stability of the dose formulation was 

confirmed for at least 3 weeks when stored in the dark at room temperature. Solutions stored at room 

temperature exposed to air and light were also stable for 96 hours. In an earlier study by the analytical 

chemistry laboratory, the stability of a 19.64 mg/mL formulation was tested by gas chromatography using 

flame ionization detection, a 10% Carbowax 20 M/2% KOH on 80/100 mesh Chromosorb W AW silenized 

glass column, a nitrogen carrier gas at 25 mL/minute, and an oven temperature of 80E C. Stability was 

confirmed for 7 days at room temperature. 

Periodic analyses of the dose formulations of pyridine were conducted at the study laboratory and the 

analytical chemistry laboratory using HPLC. For the 13-week studies, dose formulations were analyzed after 

preparation at the beginning, midpoint, and end of the studies (Table K2). During the 2-year studies, dose 

formulations were analyzed approximately every 6 to 10 weeks (Table K3). All 45 dose formulations analyzed 

and used during the 13-week studies were within 10% of the target concentration; 44 of 45 animal room 

samples were within 10% of the target concentration. Results of periodic referee analyses performed by the 

analytical chemistry laboratory during the 13-week studies agreed with the results obtained by the study 

laboratory (Table K4). During the 2-year studies, 191 of 192 of the dose formulations analyzed were within 

10% of the target concentration. One formulation was 47% less than the target concentration; because records 

indicated that the proper amounts of pyridine and deionized water were used, it is possible that the wrong dose 

formulation was sampled for analysis. This dose formulation was remixed, and the remix was found to be 

within 10% of the target concentration. All 69 animal room samples were within 10% of the target 

concentration. 
298 Pyridine, NTP TR 470
 

FIGURE K1 

Infrared Absorption Spectrum of Pyridine 
Pyridine, NTP TR 470
 299 

FIGURE K2 

Nuclear Magnetic Resonance Spectrum of Pyridine 
300 Pyridine, NTP TR 470 

TABLE K1 

Preparation and Storage of Dose Formulations in the Drinking Water Studies of Pyridine 

13-Week Studies 2-Year Studies 

Preparation 

Dose formulations were prepared as needed by combining weighed 

amounts of pyridine at room temperature and deionized water, then 

diluting to volume with additional water and mixing. 

Same as 13-week studies 

Chemical Lot Number 

00103BV 00103BV 

Maximum Storage Time 

3 weeks 3 weeks 

Storage Conditions 

Stored in sealed Teflon®-capped, amber glass bottles at room 

temperature in the dark 

Stored in sealed glass carboys at room temperature in the dark 

Study Laboratory 

TSI Mason Research Institute (Worcester, MA) TSI Mason Laboratories (Worcester, MA) 

Referee Laboratory 

Midwest Research Institute (Kansas City, MO) None performed 
Pyridine, NTP TR 470 301 

TABLE K2 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 13-Week Drinking Water Studies of Pyridine 

Date Prepared Date Analyzed 

Target 

Concentrationa 

(mg/mL) 

Determined 

Concentrationb 

(mg/mL) 

Difference 

from Target 

(%) 

F344/N Rats 

11 January 1990 11 January 1990 0.05 

0.10 

0.25 

0.50 

1.00 

0.048 

0.097 

0.235 

0.492 

0.989 

!4 

!3 

!6 

!2 

!1 

26 January 1990c 0.05 

0.10 

0.25 

0.50 

1.00 

0.044 

0.096 

0.246 

0.487 

0.973 

!12 

!4 

!2 

!3 

!3 

1 March 1990 1 March 1990 0.05 

0.10 

0.25 

0.50 

1.00 

0.051 

0.100 

0.249 

0.501 

0.973 

+2 

0 

0 

0 

!3 

13 March 1990c 0.05 

0.10 

0.25 

0.50 

1.00 

0.053 

0.100 

0.241 

0.504 

0.966 

+6 

0 

!4 

+1 

!3 

12 April 1990 16 April 1990 0.05 

0.10 

0.25 

0.50 

1.00 

0.050 

0.098 

0.249 

0.502 

0.996 

0 

!2 

0 

0 

0 

25 April 1990c 0.05 

0.10 

0.25 

0.50 

1.00 

0.050 

0.097 

0.249 

0.506 

0.993 

0 

!3 

0 

+1 

!1 

Wistar Rats 

15 February 1990 16 February 1990 0.05 

0.10 

0.25 

0.50 

1.00 

0.050 

0.100 

0.254 

0.507 

1.005 

0 

0 

+2 

+1 

+1 

2 March 1990c 0.05 

0.10 

0.25 

0.50 

1.00 

0.050 

0.099 

0.249 

0.493 

0.998 

0 

!1 

0 

!1 

0 
302 Pyridine, NTP TR 470 

TABLE K2 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 13-Week Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Wistar Rats (continued) 

5 April 1990 5 April 1990 0.05 0.051 +2 

0.10 0.101 +1 

0.25 0.250 0 

0.50 0.500 0 

1.00 0.999 0 

16 April 1990c 0.05 0.049 !2 

0.10 0.097 !3 

0.25 0.248 !1 

0.50 0.494 !1 

1.00 0.996 0 

17 May 1990 17 May 1990 0.05 0.048 !4 

0.10 0.099 !1 

0.25 0.248 !1 

0.50 0.494 !1 

1.00 1.006 +1 

25 May 1990c 0.05 0.050 0 

0.10 0.098 !2 

0.25 0.246 !2 

0.50 0.495 !1 

1.00 0.997 0 

Mice 

7 December 1989 7 December 1989 0.05 0.049 !2 

0.10 0.097 !3 

0.25 0.242 !3 

0.50 0.483 !3 

1.00 0.966 !3 

27 December 1989c 0.05 0.051 +2 

0.10 0.099 !1 

0.25 0.246 !2 

0.50 0.504 +1 

1.00 0.986 !1 

25 January 1990 26 January 1990 0.05 0.052 +4 

0.10 0.097 !3 

0.25 0.246 !2 

0.50 0.487 !3 

1.00 0.981 !2 

13 February 1990c 0.05 0.049 !2 

0.10 0.097 !3 

0.25 0.240 !4 

0.50 0.489 !2 

1.00 0.973 !3 
303 

c 

Pyridine, NTP TR 470 

TABLE K2 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 13-Week Drinking Water Studies of Pyridine 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentration 

(mg/mL) 

Difference 

from Target 

(%) 

Mice (continued) 

1 March 1990 1 March 1990 0.05 

0.10 

0.25 

0.50 

1.00 

0.051 

0.100 

0.249 

0.501 

0.973 

+2 

0 

0 

0 

!3 

13 March 1990c 0.05 

0.10 

0.25 

0.50 

1.00 

0.052 

0.096 

0.239 

0.494 

0.952 

+4 

!4 

!4 

!1 

!5 

a 0.05 mg/mL=50 ppm; 0.10 mg/mL=100 ppm; 0.25 mg/mL=250 ppm; 0.50 mg/mL=500 ppm; 1.00 mg/mL=1,000 ppm b	 Results of duplicate analyses 

Animal room samples 
304 Pyridine, NTP TR 470 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentrationa Concentrationb from Target 

(mg/mL) (mg/mL) (%) 

F344/N Rats 

11 April 1991 12 April 1991 0.1 0.100 0 

0.2 0.196 !2 

0.4 0.396 !1 

2 May 1991c 0.1 0.099 !1 

0.2 0.199 0 

0.4 0.398 0 

23 May 1991 24 May 1991 0.1 0.099 !1 

0.1 0.099 !1 

0.2 0.198 !1 

0.2 0.198 !1 

0.4 0.394 !1 

0.4 0.399 0 

1 July 1991 1-3 July 1991 0.1 0.100 0 

0.1 0.100 0 

0.2 0.202 +1 

0.2 0.201 +1 

0.4 0.388 !3 

0.4 0.211 !47 

3 July 1991 3 July 1991 0.4 0.398d 0 

29 August 1991 30 August 1991 0.1 0.101 +1 

0.1 0.098 !2 

0.2 0.197 !1 

0.2 0.191 !4 

0.4 0.374 !6 

0.4 0.390 !2 

20 September 1991c 0.1 0.101 +1 

0.1 0.098 !2 

0.2 0.201 +1 

0.2 0.201 +1 

0.4 0.400 0 

0.4 0.396 !1 

24 October 1991 25 October 1991 0.1 0.102 +2 

0.2 0.209 +5 

0.4 0.416 +4 

19 December 1991 20 December 1991 0.1 0.099 !1 

0.2 0.197 !1 

0.4 0.398 0 
Pyridine, NTP TR 470 305 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

F344/N Rats (continued) 

13 February 1992 14 February 1992 0.1 0.100 0 

0.2 0.198 !1 

0.4 0.392 !2 

3 March 1992c 0.1 0.098 !2 

0.2 0.195 !2 

0.4 0.397 !1 

9 April 1992 10 April 1992 0.1 0.100 0 

0.1 0.098 !2 

0.2 0.197 !1 

0.2 0.199 0 

0.4 0.392 !2 

0.4 0.402 +1 

4 June 1992 5 June 1992 0.1 0.097 !3 

0.2 0.198 !1 

0.4 0.396 !1 

30 July 1992 31 July 1992 0.1 0.098 !2 

0.2 0.193 !3 

0.4 0.393 !2 

2 September 1992c 0.1 0.097 !3 

0.2 0.195 !2 

0.4 0.383 !4 

24 September 1992 25 September 1992 0.1 0.102 +2 

0.2 0.201 +1 

0.4 0.399 0 

19 November 1992 20-24 November 1992 0.1 0.101 +1 

0.2 0.206 +3 

0.4 0.395 !1 

14 January 1993 15 January 1993 0.1 0.098 !2 

0.1 0.099 !1 

0.2 0.193 !3 

0.2 0.198 !1 

0.4 0.395 !1 

0.4 0.392 !2 

8 February 1993c 0.1 0.090 !10 

0.1 0.095 !5 

0.2 0.195 !2 

0.2 0.195 !2 

0.4 0.386 !3 

0.4 0.386 !3 

11 March 1993 12 March 1993 0.1 0.098 !2 

0.2 0.197 !1 

0.4 0.396 !1 
306 Pyridine, NTP TR 470 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Wistar Rats 

2 May 1991 2 May 1991 0.1 0.099 !1 

0.2 0.198 !1 

0.4 0.397 !1 

24 May 1991c 0.1 0.099 !1 

0.2 0.197 !1 

0.4 0.398 0 

1 July 1991 1-2 July 1991 0.1 0.100 0 

0.2 0.190 !5 

0.4 0.396 !1 

29 August 1991 30 August 1991 0.1 0.099 !1 

0.2 0.197 !1 

0.4 0.408 +2 

24 October 1991 25 October 1991 0.1 0.104 +4 

0.1 0.101 +1 

0.2 0.210 +5 

0.2 0.206 +3 

0.4 0.408 +2 

0.4 0.416 +4 

1 November 1991c 0.1 0.095 !5 

0.1 0.098 !2 

0.2 0.197 !1 

0.2 0.197 !1 

0.4 0.403 +1 

0.4 0.403 +1 

19 December 1991 20 December 1991 0.1 0.098 !2 

0.2 0.195 !2 

0.4 0.395 !1 

13 February 1992 14 February 1992 0.1 0.100 0 

0.2 0.199 0 

0.4 0.398 0 

9 April 1992 10 April 1992 0.1 0.100 0 

0.2 0.198 !1 

0.4 0.394 !1 

27 April 1992c 0.1 0.099 !1 

0.2 0.198 !1 

0.4 0.421 +5 

4 June 1992 5 June 1992 0.1 0.099 !1 

0.2 0.198 !1 

0.4 0.390 !2 

30 July 1992 31 July 1992 0.1 0.099 !1 

0.2 0.195 !2 

0.4 0.390 !2 
Pyridine, NTP TR 470 307 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Wistar Rats (continued) 

24 September 1992 25 September 1992 0.1 0.101 +1 

0.2 0.200 0 

0.4 0.385 !4 

9 October 1992c 0.1 0.100 0 

0.2 0.198 !1 

0.4 0.398 0 

19 November 1992 20-24 November 1992 0.1 0.101 +1 

0.1 0.099 !1 

0.1 0.099 !1 

0.2 0.202 +1 

0.2 0.198 !1 

0.2 0.199 0 

0.4 0.401 0 

0.4 0.399 0 

0.4 0.394 !1 

14 January 1993 15 January 1993 0.1 0.100 0 

0.2 0.193 !3 

0.4 0.389 !3 

11 March 1993 12 March 1993 0.1 0.100 0 

0.2 0.197 !1 

0.4 0.394 !1 

1 April 1993c 0.1 0.099 !1 

0.2 0.197 !1 

0.4 0.393 !2 

22 April 1993 23 April 1993 0.1 0.102 +2 

0.2 0.201 +1 

0.4 0.405 +1 

Male Mice 

21 March 1991 22 March 1991 0.25 0.249 0 

0.50 0.498 0 

1.00 0.990 !1 

12 April 1991c 0.25 0.246 !2 

0.50 0.492 !2 

1.00 0.979 !2 

9 May 1991 10 May 1991 0.25 0.244 !2 

0.50 0.494 !1 

1.00 0.981 !2 

1 July 1991 1 July 1991 0.25 0.246 !2 

0.50 0.491 !2 

1.00 0.986 !1 
308 Pyridine, NTP TR 470 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Male Mice (continued) 

29 August 1991 30 August 1991 0.25 0.236 !6 

0.50 0.479 !4 

1.00 0.944 !6 

20 September 1991c 0.25 0.251 0 

0.50 0.513 +3 

1.00 1.000 0 

24 October 1991 25 October 1991 0.25 0.258 +3 

0.50 0.520 +4 

1.00 1.025 +3 

19 December 1991 20 December 1991 0.25 0.255 +2 

0.50 0.500 0 

1.00 0.991 !1 

13 February 1992 14 February 1992 0.25 0.246 !2 

0.50 0.489 !2 

1.00 0.990 !1 

3 March 1992c 0.25 0.244 !2 

0.50 0.488 !2 

1.00 0.977 !2 

9 April 1992 10 April 1992 0.25 0.245 !2 

0.50 0.484 !3 

1.00 0.981 !2 

4 June 1992 5 June 1992 0.25 0.246 !2 

0.50 0.487 !3 

1.00 0.970 !3 

30 July 1992 31 July 1992 0.25 0.245 !2 

0.50 0.492 !2 

1.00 0.973 !3 

2 September 1992c 0.25 0.244 !2 

0.50 0.501 0 

1.00 0.988 !1 

24 September 1992 25 September 1992 0.25 0.253 +1 

0.50 0.495 !1 

1.00 0.999 0 

19 November 1992 20-24 November 1992 0.25 0.247 !1 

0.50 0.496 !1 

1.00 0.987 !1 
Pyridine, NTP TR 470 309 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Male Mice (continued) 

14 January 1993 15 January 1993 0.25 0.250 0 

0.50 0.487 !3 

1.00 0.972 !3 

8 February 1993c 0.25 0.245 !2 

0.50 0.476 !5 

1.00 0.961 !4 

11 March 1993 12 March 1993 0.25 0.252 +1 

0.50 0.497 !1 

1.00 0.981 !2 

Female Mice 

21 March 1991 22 March 1991 0.125 0.124 !1 

0.250 0.248 !1 

0.500 0.504 +1 

12 April 1991c 0.125 0.126 +1 

0.250 0.244 !2 

0.500 0.495 !1 

9 May 1991 10 May 1991 0.125 0.122 !2 

0.250 0.246 !2 

0.500 0.490 !2 

1 July 1991 1 July 1991 0.125 0.124 !1 

0.250 0.251 0 

0.500 0.494 !1 

29 August 1991 30 August 1991 0.125 0.118 !6 

0.250 0.234 !6 

0.500 0.473 !5 

20 September 1991c 0.125 0.125 0 

0.250 0.245 !2 

0.500 0.499 0 

24 October 1991 25 October 1991 0.125 0.126 +1 

0.250 0.260 +4 

0.500 0.517 +3 

19 December 1991 20 December 1991 0.125 0.127 +2 

0.250 0.248 !1 

0.500 0.495 !1 
310 Pyridine, NTP TR 470 

TABLE K3 

Results of Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, and Mice 

in the 2-Year Drinking Water Studies of Pyridine 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Female Mice (continued) 

13 February 1992 14 February 1992 0.125 0.125 0 

0.250 0.247 !1 

0.500 0.491 !2 

3 March 1992c 0.125 0.124 !1 

0.250 0.248 !1 

0.500 0.490 !2 

9 April 1992 10 April 1992 0.125 0.123 !2 

0.250 0.245 !2 

0.500 0.491 !2 

4 June 1992 5 June 1992 0.125 0.120 !4 

0.250 0.243 !3 

0.500 0.488 !2 

30 July 1992 31 July 1992 0.125 0.127 +2 

0.250 0.244 !2 

0.500 0.491 !2 

2 September 1992c 0.125 0.126 +1 

0.250 0.249 0 

0.500 0.502 0 

24 September 1992 25 September 1992 0.125 0.127 +2 

0.250 0.253 +1 

0.500 0.494 !1 

19 November 1992 20-24 November 1992 0.125 0.125 0 

0.250 0.249 0 

0.500 0.482 !4 

14 January 1993 15 January 1993 0.125 0.122 !2 

0.250 0.245 !2 

0.500 0.483 !3 

8 February 1993c 0.125 0.118 !6 

0.250 0.245 !2 

0.500 0.483 !3 

11 March 1993 12 March 1993 0.125 0.127 +2 

0.250 0.247 !1 

0.500 0.498 0 

a 0.1 mg/mL=100 ppm; 0.125 mg/mL=125 ppm; 0.2 mg/mL=200 ppm; 0.25 mg/mL=250 ppm; 0.4 mg/mL=400 ppm; 0.50 mg/mL=500 ppm; 

1.00 mg/mL=1,000 ppm b Results of duplicate analyses 

Animal room samples d Results of remix 

c 
Pyridine, NTP TR 470 311 

TABLE K4 

Results of Referee Analyses of Dose Formulations Administered to F344/N Rats, Wistar Rats, 

and Mice in the 13-Week Drinking Water Studies of Pyridine 

Date Prepared Target Concentration 

(mg/mL) 

Determined Concentration (mg/mL) 

Study Laboratorya Referee Laboratoryb 

F344/N Rats 

11 January 1990 0.50 0.492 0.512 ± 0.005 

Wistar Rats 

15 February 1990 1.00 1.005 0.994 ± 0.002 

Mice 

7 December 1989 0.10 0.097 0.106 ± 0.000 

a Results of duplicate analyses b Results of triplicate analyses (mean ± standard error) 
312 Pyridine, NTP TR 470
 
313 

APPENDIX L 

WATER AND COMPOUND CONSUMPTION 

IN THE 2-YEAR DRINKING WATER STUDIES 

OF PYRIDINE 

TABLE L1 

TABLE L2 

TABLE L3 

TABLE L4 

TABLE L5 

Water and Compound Consumption by Male F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Water and Compound Consumption by Female F344/N Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Water and Compound Consumption by Male Wistar Rats 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Water and Compound Consumption by Male Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Water and Compound Consumption by Female Mice 

in the 2-Year Drinking Water Study of Pyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

314 

315 

316 

317 

318 
314 Pyridine, NTP TR 470 

TABLE L1 

Water and Compound Consumption by Male F344/N Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Water Body Water Body Dose/ Water Body Dose/ Water Body Dose/ 

(g/day)a Weight (g/day) Weight Dayb (g/day) Weight Day (g/day) Weight Day 

Week (g) (g) (mg/kg) (g) (mg/kg) (g) (mg/kg) 

1 20.4 136 19.5 135 14 18.6 135 28 18.5 136 55 

2 21.4 173 20.7 172 12 20.9 169 25 21.5 167 51 

3 22.6 207 22.1 208 11 21.8 206 21 24.3 201 48 

4 20.5 236 21.2 234 9 19.9 232 17 24.1 227 43 

5 22.1 255 21.6 253 9 23.0 250 18 23.4 245 38 

6 20.6 275 21.1 267 8 21.7 272 16 22.6 258 35 

7 20.4 293 20.7 286 7 21.5 289 15 22.8 272 34 

8 22.4 302 22.8 295 8 22.6 295 15 24.9 282 35 

9 22.4 314 22.4 309 7 22.5 306 15 24.7 291 34 

10 23.3 331 22.9 326 7 21.8 323 14 25.8 309 33 

11 22.3 333 21.4 329 7 22.0 328 13 26.9 311 35 

12 24.9 342 23.6 339 7 22.7 340 13 26.9 323 33 

13 21.5 351 20.6 349 6 21.6 348 12 24.6 328 30 

17 21.8 384 21.4 382 6 20.3 378 11 23.8 355 27 

21 22.5 409 21.3 405 5 22.1 404 11 23.6 376 25 

25 22.4 426 22.2 420 5 22.7 420 11 25.7 392 26 

29 22.7 437 23.0 431 5 22.7 433 11 25.7 403 26 

33 22.9 453 23.3 448 5 23.5 448 11 24.8 421 24 

37 24.5 465 21.8 461 5 22.3 460 10 25.0 434 23 

41 25.3 478 22.8 468 5 25.0 469 11 25.7 443 23 

45 21.6 483 20.8 480 4 20.8 480 9 23.1 452 20 

49 22.4 489 20.9 479 4 22.3 480 9 24.1 453 21 

53 21.7 487 21.6 482 5 22.3 482 9 25.8 453 23 

57 23.8 502 23.0 489 5 26.1 484 11 29.3 462 25 

61 24.1 503 22.7 491 5 25.4 487 10 28.7 459 25 

65 26.0 508 25.4 492 5 28.8 484 12 32.3 455 28 

69 25.0 511 24.3 500 5 29.0 485 12 35.2 457 31 

73 25.6 511 25.7 500 5 30.0 480 13 37.4 446 34 

77 24.5 510 24.1 497 5 27.9 475 12 35.8 446 32 

81 26.1 494 26.5 497 5 30.1 467 13 40.3 441 37 

85 27.7 501 28.3 486 6 35.5 462 15 45.1 428 42 

89 29.3 499 29.8 484 6 34.7 440 16 43.7 414 42 

93 32.5 501 31.7 478 7 38.0 428 18 46.7 406 46 

97 30.6 491 29.2 464 6 35.0 414 17 40.3 391 41 

101 36.3 468 36.6 458 8 37.0 397 19 49.0 388 51 

Mean for weeks 

1-13 21.9 273 21.6 270 9 21.6 269 17 23.9 258 39 

14-52 22.9 447 21.9 441 5 22.4 441 10 24.6 414 24 

53-101 27.2 499 26.8 486 6 30.8 460 14 37.6 434 35 

a Grams of water consumed per animal per day b Milligrams of pyridine consumed per kilogram body weight per day 
Pyridine, NTP TR 470 315 

TABLE L2 

Water and Compound Consumption by Female F344/N Rats in the 2-Year Drinking Water Study 

of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Water 

(g/day)a Body 

Weight 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Dayb 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Week (g) (g) (mg/kg) (g) (mg/kg) (g) (mg/kg) 

1 16.2 110 16.9 110 15 16.7 110 30 17.4 111 63 

2 16.4 129 16.7 128 13 17.1 127 27 18.7 124 60 

3 16.4 144 16.9 145 12 18.0 143 25 17.7 139 51 

4 15.2 152 16.1 152 11 16.8 151 22 16.9 148 46 

5 17.2 160 15.2 160 10 15.1 159 19 17.1 155 44 

6 16.7 167 14.5 167 9 14.5 164 18 16.5 160 41 

7 15.3 173 15.5 173 9 15.3 171 18 16.6 167 40 

8 16.2 180 16.7 179 9 16.0 176 18 17.2 170 41 

9 16.3 183 17.5 183 10 17.0 178 19 18.8 173 43 

10 16.2 186 16.9 185 9 17.0 181 19 18.5 175 42 

11 16.0 192 16.5 190 9 17.6 185 19 17.1 178 38 

12 15.3 196 15.9 194 8 16.1 187 17 16.2 182 36 

13 14.3 198 14.7 197 8 15.0 191 16 15.7 185 34 

17 14.3 213 16.1 210 8 17.0 204 17 17.3 196 35 

21 14.8 223 15.4 220 7 16.6 212 16 17.4 205 34 

25 15.9 228 16.1 225 7 16.3 218 15 18.2 208 35 

29 15.1 234 16.3 233 7 17.3 224 15 18.7 214 35 

33 17.0 242 17.2 238 7 17.7 228 16 19.3 220 35 

37 14.9 251 15.6 247 6 16.4 239 14 16.8 225 30 

41 16.9 261 17.2 257 7 17.7 247 14 20.0 234 34 

45 14.6 270 15.6 269 6 16.7 257 13 17.6 240 29 

49 15.5 279 16.2 280 6 15.3 266 12 17.9 247 29 

53 15.8 285 16.4 287 6 17.3 273 13 18.6 252 30 

57 17.2 288 18.1 290 6 17.7 273 13 21.0 255 33 

61 16.5 299 17.1 297 6 18.7 280 13 20.7 258 32 

65 18.7 301 19.1 302 6 18.8 284 13 22.6 259 35 

69 18.7 310 18.7 308 6 20.4 289 14 23.1 269 34 

73 19.0 314 18.8 313 6 20.9 292 14 24.2 275 35 

77 19.3 322 19.7 313 6 19.6 299 13 23.3 282 33 

81 19.5 326 21.3 323 7 21.6 299 15 23.6 283 33 

85 21.0 330 23.0 327 7 24.0 306 16 26.5 281 38 

89 18.0 331 20.0 328 6 19.9 306 13 22.5 286 32 

93 21.2 338 24.6 332 7 24.3 307 16 27.7 286 39 

95 19.5 334 20.8 335 6 21.4 305 14 23.9 281 34 

97 20.3 344 21.9 332 7 24.0 306 16 23.9 286 34 

99 19.6 340 20.7 333 6 21.5 301 14 21.2 286 30 

101 18.9 337 21.6 333 7 24.0 298 16 23.3 284 33 

104 20.6 342 21.2 327 7 24.4 303 16 26.2 289 36 

Mean for weeks 

1-13 16.0 167 16.2 166 10 16.3 163 21 17.3 159 45 

14-52 15.4 245 16.2 242 7 16.8 233 15 18.1 221 33 

53-104 19.0 321 20.2 318 6 21.2 295 14 23.3 276 34 

a Grams of water consumed per animal per day b Milligrams of pyridine consumed per kilogram body weight per day 
316 Pyridine, NTP TR 470 

TABLE L3 

Water and Compound Consumption by Male Wistar Rats in the 2-Year Drinking Water Study of Pyridine 

0 ppm 100 ppm 200 ppm 400 ppm 

Water Body Water Body Dose/ Water Body Dose/ Water Body Dose/ 

(g/day)a Weight (g/day) Weight Dayb (g/day) Weight Day (g/day) Weight Day 

Week (g) (g) (mg/kg) (g) (mg/kg) (g) (mg/kg) 

1 37.6 201 37.5 198 19 39.3 199 40 35.9 198 72 

2 40.9 255 38.9 250 16 39.8 246 32 37.9 240 63 

3 38.9 294 40.2 289 14 41.3 285 29 41.9 280 60 

4 42.1 327 42.1 326 13 43.9 321 27 42.7 312 55 

5 46.3 357 48.6 359 14 48.5 347 28 45.7 345 53 

6 39.4 382 39.3 380 10 39.9 372 21 38.9 358 43 

7 40.8 413 44.3 411 11 44.4 402 22 46.0 388 47 

8 47.4 426 43.5 428 10 47.1 412 23 45.6 400 46 

9 53.3 448 49.2 446 11 49.5 435 23 48.7 419 47 

10 42.7 464 41.4 463 9 43.3 452 19 43.2 431 40 

11 50.3 479 46.3 478 10 47.0 463 20 47.0 443 42 

12 48.2 494 47.3 492 10 47.3 479 20 43.9 457 38 

13 46.8 506 46.7 503 9 46.6 490 19 46.3 466 40 

17 44.0 546 42.3 542 8 41.9 527 16 41.0 502 33 

21 46.5 569 42.8 575 7 41.5 562 15 44.8 528 34 

25 41.9 599 39.4 602 7 41.0 583 14 42.9 552 31 

29 40.4 627 36.7 630 6 40.0 612 13 41.6 576 29 

33 43.6 658 42.8 657 7 39.9 638 13 44.2 599 30 

37 46.8 672 46.6 673 7 48.1 651 15 48.6 610 32 

41 38.4 691 38.8 686 6 39.2 664 12 40.3 627 26 

45 43.5 715 42.9 711 6 43.0 684 13 44.0 642 27 

49 40.5 736 40.5 719 6 41.9 695 12 44.5 654 27 

53 50.9 755 48.3 735 7 52.6 705 15 53.5 662 32 

57 45.4 774 47.3 748 6 48.8 714 14 50.7 668 30 

61 54.7 789 53.9 753 7 59.4 718 17 57.4 669 34 

65 49.8 795 52.5 757 7 55.6 720 15 55.7 661 34 

69 54.3 800 55.5 739 8 56.7 699 16 58.2 658 35 

73 54.6 803 60.1 736 8 59.8 706 17 62.6 657 38 

77 56.3 797 60.5 725 8 63.2 717 18 63.7 644 40 

81 58.1 799 66.8 698 10 64.3 698 18 62.2 624 40 

85 60.1 782 65.1 707 9 64.4 699 18 57.4 630 36 

89 60.5 775 68.4 692 10 67.0 676 20 64.6 614 42 

93 69.3 779 69.2 678 10 67.7 657 21 57.7 612 38 

97 66.1 757 71.2 675 11 61.2 618 20 55.7 590 38 

101 59.6 725 59.0 675 9 54.5 578 19 57.5 604 38 

Mean for weeks 

1-13 44.2 388 43.5 386 12 44.5 377 25 43.4 364 50 

14-52 42.8 646 41.4 644 6 41.8 624 14 43.5 588 30 

53-101 56.9 779 59.8 717 8 59.6 685 17 58.2 638 37 

a Grams of water consumed per animal per day b Milligrams of pyridine consumed per kilogram body weight per day 
Pyridine, NTP TR 470 317 

TABLE L4 

Water and Compound Consumption by Male Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 250 ppm 500 ppm 1,000 ppm 

Water 

(g/day)a Body 

Weight 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Dayb 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Week (g) (g) (mg/kg) (g) (mg/kg) (g) (mg/kg) 

1 6.5 26.1 6.8 25.9 66 5.7 25.8 109 5.6 25.8 218 

2 5.7 27.6 5.6 27.4 51 5.2 27.3 95 4.5 26.6 171 

3 5.6 29.2 5.3 28.7 46 5.2 29.0 90 4.3 28.4 150 

4 5.7 30.9 5.3 30.5 44 5.0 30.7 82 4.3 30.1 142 

5 5.6 32.8 5.3 32.3 41 5.5 32.2 85 4.9 30.6 160 

6 5.3 33.9 5.0 34.2 36 4.6 33.5 69 3.9 32.0 123 

7 5.5 35.4 5.0 35.4 35 4.9 35.3 69 3.8 33.9 112 

8 5.0 37.6 4.9 37.1 33 4.6 36.7 63 3.9 35.6 110 

9 5.4 38.7 5.2 37.9 34 5.0 37.7 66 4.3 36.5 119 

10 5.4 39.6 5.7 40.1 36 5.2 39.8 65 4.4 37.7 117 

11 5.7 40.6 6.4 41.0 39 5.3 41.0 64 4.5 38.8 117 

12 5.5 41.8 5.8 42.3 34 5.0 41.7 60 5.0 39.8 126 

13 5.5 42.4 5.9 42.9 34 5.6 42.7 66 5.2 40.6 129 

17 5.2 47.0 5.3 46.2 28 5.2 45.9 57 4.3 43.5 99 

21 6.9 48.1 6.5 48.3 34 5.8 47.4 61 4.1 45.2 90 

25 5.3 50.0 5.4 49.6 27 5.1 49.9 51 4.7 47.5 98 

29 7.0 49.6 6.6 50.8 32 7.1 51.3 69 5.6 48.5 116 

33 5.2 51.6 5.1 51.7 25 4.9 51.1 48 4.5 50.0 91 

37 5.4 53.2 5.2 52.9 24 4.7 53.0 45 4.3 51.8 84 

41 6.8 54.5 6.9 53.8 32 6.4 53.7 60 6.6 52.5 126 

45 5.8 54.1 6.4 53.9 30 6.0 54.4 55 5.0 52.7 95 

49 6.6 55.3 6.0 54.6 28 7.2 55.4 65 4.9 53.4 92 

53 6.1 55.4 5.8 55.6 26 5.7 56.2 51 

57 6.5 55.2 6.6 55.4 30 6.3 56.0 56 5.7 54.0 106 

61 5.9 55.2 6.0 56.1 27 5.7 56.4 51 4.7 54.2 88 

65 5.6 54.4 6.0 56.3 27 5.6 56.1 50 4.3 54.1 80 

69 5.8 55.1 6.8 56.5 30 6.7 55.5 61 5.2 54.4 96 

73 5.8 54.4 6.5 56.6 29 6.6 53.9 61 4.7 54.1 87 

77 5.8 52.8 7.2 55.1 32 7.0 52.2 67 5.2 52.4 99 

81 5.8 51.4 7.7 53.7 36 7.4 50.2 74 5.1 49.2 105 

85 6.0 49.2 7.4 51.5 36 7.2 47.8 75 5.2 47.3 109 

89 5.5 46.6 8.4 49.7 42 7.0 45.8 76 5.4 45.6 119 

93 5.4 45.5 8.2 46.4 44 7.3 44.7 81 5.4 43.7 122 

97 6.6 43.8 8.0 43.6 46 7.7 42.9 89 6.0 41.8 144 

99 6.2 44.5 8.4 43.5 48 7.7 42.7 91 6.0 41.2 146 

101 6.3 44.2 7.7 41.9 46 8.0 41.6 96 6.1 40.6 150 

Mean for weeks 

1-13 5.6 35.1 5.6 35.1 41 5.1 34.9 75 4.5 33.6 138 

14-52 6.0 51.5 5.9 51.3 29 5.8 51.3 57 4.9 49.5 99 

53-101 6.0 50.6 7.2 51.6 36 6.9 50.1 70 5.3 48.7 112 

a Grams of water consumed per animal per day b Milligrams of pyridine consumed per kilogram body weight per day 
318 Pyridine, NTP TR 470 

TABLE L5 

Water and Compound Consumption by Female Mice in the 2-Year Drinking Water Study of Pyridine 

0 ppm 125 ppm 250 ppm 500 ppm 

Water 

(g/day)a Body 

Weight 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Dayb 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Water 

(g/day) 

Body 

Weight 

Dose/ 

Day 

Week (g) (g) (mg/kg) (g) (mg/kg) (g) (mg/kg) 

1 7.3 20.8 7.5 20.7 45 6.8 20.6 82 6.3 20.5 154 

2 6.9 21.8 6.6 21.4 39 6.6 21.6 76 5.7 21.5 132 

3 7.5 23.2 7.1 22.8 39 7.4 22.8 81 6.5 22.6 144 

4 6.5 24.1 6.8 24.0 35 6.4 23.9 67 5.6 23.7 118 

5 7.7 25.5 7.0 25.3 34 6.9 25.5 68 5.4 25.6 106 

6 6.1 26.7 5.8 26.5 28 6.3 26.3 59 4.9 26.9 90 

7 5.8 28.2 5.8 28.4 25 6.1 28.8 53 5.1 28.5 89 

8 6.0 29.6 5.4 29.9 23 5.6 29.8 47 5.0 30.0 84 

9 5.9 31.1 5.7 30.1 24 5.7 30.8 46 5.2 30.4 85 

10 5.5 31.7 6.3 32.0 24 6.4 32.7 49 5.7 32.9 86 

11 6.7 33.3 6.3 33.2 24 6.2 33.7 46 5.7 33.7 85 

12 7.1 34.1 6.4 34.2 23 6.0 35.2 43 5.4 35.1 76 

13 6.1 35.8 5.7 35.5 20 5.4 36.5 37 5.4 36.3 74 

17 5.0 40.2 4.8 39.4 15 5.1 40.5 31 5.1 40.4 64 

21 11.5 41.1 6.8 40.0 21 6.9 41.6 41 8.6 41.4 104 

25 4.5 45.9 4.6 44.2 13 4.4 45.8 24 4.3 45.1 48 

29 5.3 45.7 5.0 44.9 14 4.4 47.2 23 5.5 46.5 60 

33 4.9 49.1 4.6 47.7 12 4.4 49.5 22 4.3 48.7 44 

37 4.4 51.0 4.4 49.4 11 4.4 51.0 22 4.2 50.1 42 

41 5.9 53.1 6.3 51.1 15 5.8 53.2 27 6.2 52.0 60 

45 5.8 54.0 5.7 52.5 14 5.6 54.1 26 6.1 52.2 58 

49 5.5 56.2 5.4 54.5 12 6.3 55.6 28 6.3 54.4 58 

53 5.2 56.9 5.0 55.6 11 5.2 57.1 23 5.8 55.5 52 

57 5.4 58.2 5.1 56.4 11 5.6 58.0 24 5.2 56.8 46 

61 4.8 59.5 4.8 57.9 10 4.8 59.3 20 4.9 58.1 42 

65 4.6 59.9 5.0 58.5 11 4.6 61.0 19 5.0 58.6 42 

69 5.1 61.6 6.0 59.3 13 5.7 62.1 23 6.1 58.2 53 

73 4.9 62.8 5.4 60.2 11 5.1 62.2 20 6.4 58.0 55 

77 5.0 63.3 5.4 61.0 11 6.2 61.9 25 7.8 55.4 71 

81 4.6 62.2 4.9 60.3 10 5.8 60.4 24 7.3 51.6 70 

85 4.9 61.1 5.4 58.6 11 7.7 58.8 33 8.6 48.7 89 

89 2.6 60.0 2.7 58.0 6 3.4 54.4 16 3.2 45.8 35 

93 5.8 57.4 7.1 56.3 16 9.7 50.9 47 8.5 43.7 97 

97 6.0 55.7 7.8 52.7 18 10.4 47.1 55 8.6 40.2 106 

99 6.0 56.1 8.4 53.3 20 10.1 46.1 55 8.0 40.1 100 

101 5.4 55.5 9.2 52.5 22 10.7 42.8 62 8.0 39.9 100 

104 5.9 55.3 8.7 49.0 22 10.7 41.5 64 8.0 38.0 106 

Mean for weeks 

1-13 6.5 28.1 6.3 28.0 30 6.3 28.3 58 5.5 28.3 102 

14-52 5.8 48.5 5.3 47.1 14 5.3 48.7 27 5.6 47.9 60 

53-104 5.1 59.0 6.1 56.6 14 7.0 54.9 34 6.8 49.9 71 

a Grams of water consumed per animal per day b Milligrams of pyridine consumed per kilogram body weight per day 
319 

APPENDIX M 

INGREDIENTS, NUTRIENT COMPOSITION, 

AND CONTAMINANT LEVELS 

IN NIH-07 RAT AND MOUSE RATION 

TABLE M1 

TABLE M2 

TABLE M3 

TABLE M4 

Ingredients of NIH-07 Rat and Mouse Ration . .................................... 

Vitamins and Minerals in NIH-07 Rat and Mouse Ration . . ......................... 

Nutrient Composition of NIH-07 Rat and Mouse Ration . . . ......................... 

Contaminant Levels in NIH-07 Rat and Mouse Ration ............................. 

320 

320 

321 

322 
 

 

320 Pyridine, NTP TR 470 

TABLE M1 

Ingredients of NIH-07 Rat and Mouse Rationa 

Ingredientsb 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; NIH, 1978 b Ingredients were ground to pass through a U.S. Standard Screen No. 16 before being mixed. 

TABLE M2 

Vitamins and Minerals in NIH-07 Rat and Mouse Rationa 

Amount Source 

Vitamins

 A 5,500,000 IU Stabilized vitamin A palmitate or acetate

 D3 

K3 

d-α-Tocopheryl acetate 

4,600,000 IU 

2.8 g 

20,000 IU

D-activated animal sterol

Menadione 

 Choline 560.0 g Choline chloride

 Folic acid 2.2 g

 Niacin 30.0 g 

d-Pantothenic acid 18.0 g d-Calcium pantothenate

 Riboflavin 3.4 g

 Thiamine 10.0 g Thiamine mononitrate

 B12 

 Pyridoxine 

4,000 μg

1.7 g Pyridoxine hydrochloride

 Biotin 140.0 mg d-Biotin 

Minerals

 Iron 120.0 g Iron sulfate

 Manganese 60.0 g Manganous oxide

 Zinc 16.0 g 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 
 

Pyridine, NTP TR 470 321 

TABLE M3 

Nutrient Composition of NIH-07 Rat and Mouse Ration 

Mean ± Standard 

Nutrient Deviation Range Number of Samples

 Protein (% by weight) 23.45 ± 0.49 22.3 ) 24.3 26

 Crude fat (% by weight) 5.34 ± 0.18 5.00 ) 5.90 26

 Crude fiber (% by weight) 3.32 ± 0.32 2.60 ) 4.30 26

 Ash (% by weight) 6.42 ± 0.21 5.94 ) 6.81 26 

Amino Acids (% of total diet)

 Arginine 1.273 ± 0.083 1.100 ) 1.390 12

 Cystine 0.307 ± 0.068 0.181 ) 0.400 12

 Glycine 1.152 ± 0.051 1.060 ) 1.220 12

 Histidine 0.581 ± 0.029 0.531 ) 0.630 12

 Isoleucine 0.913 ± 0.034 0.867 ) 0.965 12

 Leucine 1.969 ± 0.053 1.850 ) 2.040 12

 Lysine 1.269 ± 0.050 1.200 ) 1.370 12

 Methionine 0.436 ± 0.104 0.306 ) 0.699 12

 Phenylalanine 0.999 ± 0.114 0.665 ) 1.110 12

 Threonine 0.899 ± 0.059 0.824 ) 0.985 12

 Tryptophan 0.216 ± 0.146 0.107 ) 0.671 12

 Tyrosine 0.690 ± 0.091 0.564 ) 0.794 12

 Valine 1.079 ± 0.057 0.962 ) 1.170 12 

Essential Fatty Acids (% of total diet)

 Linoleic 2.389 ± 0.223 1.830 ) 2.570 11

 Linolenic 0.273 ± 0.034 0.210 ) 0.320 11 

Vitamins

 Vitamin A (IU/kg) 6,681 ± 1,265 5,280 ) 11,450 26

 Vitamin D (IU/kg) 4,450 ± 1,382 3,000 ) 6,300 4 

α-Tocopherol (ppm) 35.24 ± 8.58 22.5 ) 48.9 12

 Thiamine (ppm) 17.27 ± 2.14 13.0 ) 22.0 26

 Riboflavin (ppm) 7.78 ± 0.899 6.10 ) 9.00 12

 Niacin (ppm) 98.73 ± 23.21 65.0 ) 150.0 12

 Pantothenic acid (ppm) 32.94 ± 8.92 23.0 ) 59.2 12

 Pyridoxine (ppm) 9.28 ± 2.49 5.60 ) 14.0 12

 Folic acid (ppm) 2.56 ± 0.70 1.80 ) 3.70 12

 Biotin (ppm) 0.265 ± 0.046 0.190 ) 0.354 12

 Vitamin B12 (ppb) 41.6 ± 18.6 10.6 ) 65.0 12

 Choline (ppm) 2,955 ± 382 2,300 ) 3,430 11 

Minerals

 Calcium (%) 1.16 ± 0.05 1.09 ) 1.28 26

 Phosphorus (%) 0.92 ± 0.05 0.760 ) 1.00 26

 Potassium (%) 0.886 ± 0.059 0.772 ) 0.971 10

 Chloride (%) 0.531 ± 0.082 0.380 ) 0.635 10

 Sodium (%) 0.316 ± 0.031 0.258 ) 0.370 12

 Magnesium (%) 0.165 ± 0.010 0.148 ) 0.180 12

 Sulfur (%) 0.266 ± 0.060 0.208 ) 0.420 11

 Iron (ppm) 348.0 ± 83.7 255.0 ) 523.0 12

 Manganese (ppm) 93.27 ± 5.62 81.7 ) 102.0 12

 Zinc (ppm) 59.42 ± 9.73 46.1 ) 81.6 12

 Copper (ppm) 11.63 ± 2.46 8.09 ) 15.4 12

 Iodine (ppm) 3.49 ± 1.14 1.52 ) 5.83 11

 Chromium (ppm) 1.57 ± 0.53 0.60 ) 2.09 12

 Cobalt (ppm) 0.81 ± 0.27 0.49 ) 1.23 8 
 

 

 

 

 

 

 

 

322 Pyridine, NTP TR 470 

TABLE M4 

Contaminant Levels in NIH-07 Rat and Mouse Rationa 

Mean ± Standard 

Deviationb Range Number of Samples 

Contaminants

 Arsenic (ppm) 0.49 ± 0.16 0.10 ) 0.70 26

 Cadmium (ppm) 0.13 ± 0.07 0.04 ) 0.20 26

 Lead (ppm) 0.36 ± 0.24 0.10 ) 1.00 26

 Mercury (ppm)c <0.02 0.02 ) 0.03 26

 Selenium (ppm) 0.32 ± 0.10 0.05 ) 0.40 26

 Aflatoxins (ppb) <5.0 26

 Nitrate nitrogen (ppm)d 7.78 ± 3.83 2.90 ) 17.0 26

 Nitrite nitrogen (ppm)d 0.18 ± 0.12 0.10 ) 0.50 26

 BHA (ppm)e 2.46 ± 4.04 1.0 ) 20.0 26

 BHT (ppm)e 1.35 ± 0.84 1.0 ) 5.0 26

 Aerobic plate count (CFU/g) 95,542 ± 158,814 6,500 ) 710,000 26

 Coliform (MPN/g) 3.1 ± 0.3 3 ) 4 26 

Escherichia coli (MPN/g) <3 26 

Salmonella (MPN/g) Negative 26

 Total nitrosoamines (ppb)f 7.87 ± 1.92 4.7 ) 11.4 26 

N-Nitrosodimethylamine (ppb)f 5.73 ± 1.31 2.9 ) 8.2 26 

N-Nitrosopyrrolidine (ppb)f 2.14 ± 1.26 1.0 ) 6.0 26 

Pesticides (ppm) 

α-BHC <0.01 26 

β-BHC <0.02 26 

γ-BHC <0.01 26 

δ-BHC <0.01 26

 Heptachlor <0.01 26

 Aldrin <0.01 26

 Heptachlor epoxide <0.01 26

 DDE <0.01 26

 DDD <0.01 26

 DDT <0.01 26

 HCB <0.01 26

 Mirex <0.01 26

 Methoxychlor <0.05 26

 Dieldrin <0.01 26

 Endrin <0.01 26

 Telodrin <0.01 26

 Chlordane <0.05 26

 Toxaphene <0.10 26

 Estimated PCBs <0.20 26

 Ronnel <0.01 26

 Ethion <0.02 26

 Trithion <0.05 26

 Diazinon <0.10 26

 Methyl parathion <0.02 26

 Ethyl parathion <0.02 26

 Malathion 0.24 ± 0.23 0.05 ) 0.97 26

 Endosulfan I <0.01 26

 Endosulfan II <0.01 26

 Endosulfan sulfate <0.03 26 

a CFU=colony-forming units; MPN=most probable number; BHC=hexachlorocyclohexane or benzene hexachloride b For values less than the limit of detection, the detection limit is given as the mean. 

All values except for the lots milled November and December 1991 were less than the detection limit. The detection limit is given as the 

mean. d Sources of contamination: alfalfa, grains, and fish meal e Sources of contamination: soy oil and fish meal f All values were corrected for percent recovery. 

c 
323 

APPENDIX N 

SENTINEL ANIMAL PROGRAM 

METHODS 

TABLE N1 

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

Murine Virus Antibody Determinations for Rats and Mice 

in the 13-Week and 2-Year Studies of Pyridine .................................... 

324 

327 
324 Pyridine, NTP TR 470 

SENTINEL ANIMAL PROGRAM 

METHODS 

Rodents used in the Carcinogenesis Program of the National Toxicology Program are produced in optimally 

clean facilities to eliminate potential pathogens that may affect study results. The Sentinel Animal Program is 

part of the periodic monitoring of animal health that occurs during the toxicologic evaluation 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 animals are 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. 

Serum samples were collected from randomly selected rats and mice during the 13-week and 2-year studies. 

Blood from each animal was collected and allowed to clot, and the serum was separated. The samples were 

processed appropriately and sent to Microbiological Associates, Inc. (Bethesda, MD), for determination of 

antibody titers. The laboratory serology methods and viral agents for which testing was performed are 

tabulated below; the times at which blood was collected during the studies are also listed. 

Method and Test Time of Analysis 

F344/N RATS 

13-Week Study 

ELISA 

PVM (pneumonia virus of mice) Study termination 

RCV/SDA (rat coronavirus/

 sialodacryoadenitis) Study termination
 

Sendai Study termination
 

Hemagglutination Inhibition 

H-1 (Toolan’s H-1 virus) Study termination 

KRV (Kilham rat virus) Study termination 

2-Year Study 

ELISA 

Mycoplasma arthritidis Study termination 

Mycoplasma pulmonis Study termination 

PVM 6, 12, 16, 18, and 19 months, study termination 

RCV/SDA 6, 12, 16, 18, and 19 months, study termination 

Sendai 6, 12, 16, 18, and 19 months, study termination 

Immunofluorescence Assay 

Parvovirus 6 months 

RCV/SDA Study termination 

Sendai 12 months 

Hemagglutination Inhibition 

6, 12, 16, 18, and 19 months, study termination 

KRV 6, 12, 16, 18, and 19 months, study termination 

H-1 
Pyridine, NTP TR 470 325 

WISTAR RATS 

13-Week Study 

ELISA 

PVM 

RCV/SDA 

Sendai 

Hemagglutination Inhibition 

H-1 

KRV 

2-Year Study 

ELISA 

M. arthritidis 

M. pulmonis 

PVM
 

RCV/SDA
 

Sendai
 

Immunofluorescence Assay 

Parvovirus 

RCV/SDA 

Hemagglutination Inhibition 

H-1 

KRV 

MICE 

13-Week Study 

ELISA 

Ectromelia virus 

GDVII (mouse encephalomyelitis virus) 

LCM (lymphocytic choriomeningitis virus) 

MHV (mouse hepatitis virus) 

PVM 

Reovirus 3 

Sendai 

Immunofluorescence Assay 

EDIM (epizootic diarrhea of infant mice) 

Mouse adenoma virus 

MVM (minute virus of mice) 

Hemagglutination Inhibition 

K (papovavirus) 

Polyoma virus 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

6 months, study termination 

6 months, study termination 

1 week, 3, 5, 6, 12, 14, and 18 months, study termination 

1 week, 3, 5, 6, 12, 14, and 18 months, study termination 

1 week, 3, 5, 6, 12, 14, and 18 months, study termination 

3 months, study termination 

Study termination 

1 week, 3, 5, 6, 12, 14, and 18 months, study termination 

1 week, 3, 5, 6, 12, 14, and 18 months, 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 
326 Pyridine, NTP TR 470 

MICE (continued) 

2-Year Study 

ELISA 

Ectromelia virus 

EDIM 

GDVII 

LCM 

Mouse adenoma virus-FL 

MHV 

M. arthritidis 

M. pulmonis 

PVM
 

Reovirus 3
 

Sendai
 

Immunofluorescence Assay 

GDVII 

MHV 

Hemagglutination Inhibition 

K 

MVM 

Polyoma virus 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

Study termination 

Study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

12 months 

12 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

Results of serology tests are presented in Table N1. 
Pyridine, NTP TR 470 327 

TABLE N1 

Murine Virus Antibody Determinations for Rats and Mice in the 13-Week and 2-Year Studies of Pyridine 

Interval Incidence of Antibody Positive Serologic
 

in Sentinel Animals Reaction for
 

13-Week Studies 

F344/N Rats 

Study termination 0/10 None positive 

Wistar Rats 

Study termination 0/5 None positive 

Mice 

Study termination 0/10 None positive 

2-Year Studies 

F344/N Rats 

6 Months 1/10 Parvovirus 

1/10 H-1 

12 Months 0/10 None positive 

16 Months 0/1 None positive 

18 Months 0/8 None positive 

19 Months 

Study termination

0/1 

6/16a None positive 

M. arthritidis 

Wistar Rats 

1 Week 0/8 None positive 

3 Months 1/2 Parvovirus 

1/2 H-1 

5 Months 0/1 None positive 

6 Months 0/6 None positive 

12 Months 0/5 None positive 

14 Months 0/1 None positive 

18 Months 0/5 None positive 

Study termination 0/10 None positive 

Mice 

6 Months 0/10 None positive 

12 Months 0/8 None positive 

18 Months 0/8 None positive 

Study termination 0/10 None positive 

a Further evaluation of samples positive for M. arthritidis by immunoblot and Western blot procedures indicated that the positive titers may 

have been due to cross reaction with antibodies of nonpathogenic Mycoplasma or other agents. There were no clinical findings or 

histopathologic changes of M. arthritidis infection in animals with positive titers. Accordingly, M. arthritidis-positive titers were considered 

false positives. 
328 Pyridine, NTP TR 470