NTP TECHNICAL REPORT 

ON THE 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF TETRAFLUOROETHYLENE
 

(CAS NO. 116-14-3) 

IN F344/N RATS AND B6C3F1 MICE

(INHALATION STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

April 1997
 

NTP TR 450 

NIH Publication No. 97-3366 

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. 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. 

These NTP Technical Reports are available for sale from the National Technical Information Service, 

U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161 (703-487-4650). Single copies of 

this Technical Report are available without charge while supplies last from NTP Central Data Management, 

NIEHS, P.O. Box 12233, MD E1-02, Research Triangle Park, NC 27709 (919-541-3419). Listings of all 

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

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

http//ntp-server.niehs.nih.gov. 
NTP TECHNICAL REPORT 

ON THE 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF TETRAFLUOROETHYLENE
 

(CAS NO. 116-14-3) 

IN F344/N RATS AND B6C3F1 MICE

(INHALATION STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

April 1997
 

NTP TR 450 

NIH Publication No. 97-3366 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

National Institutes of Health
 
2 Tetrafluoroethylene, NTP TR 450 

CONTRIBUTORS
 

National Toxicology Program 

Evaluated and interpreted results and reported findings 

J.H. Roycroft, Ph.D., Study Scientist 

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

D.A. Bridge, B.S. 

J.R. Bucher, Ph.D. 

L.T. Burka, Ph.D. 

R.E. Chapin, Ph.D. 

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

J.K. Haseman, Ph.D. 

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

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

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

D.B. Walters, Ph.D. 

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

Battelle Pacific Northwest Laboratories 

Conducted 16-day, 13-week, and 2-year studies,

 evaluated pathology findings 

B.J. Chou, D.V.M., Ph.D., Principal Investigator 

J.R. Decker, B.S. 

S.L. Grumbein, D.V.M., Ph.D. 

P.W. Mellick, D.V.M., Ph.D. 

H.A. Ragan, D.V.M. 

S.E. Rowe, D.V.M., M.S. 

R.B. Westerberg, Ph.D. 

Experimental Pathology Laboratories, Inc. 

Provided pathology quality assurance 

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

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

Dynamac Corporation 

Prepared quality assurance audits 

S. Brecher, Ph.D., Principal Investigator 

Analytical Sciences, Inc. 

Provided statistical analyses 

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

N.G. Mintz, B.S. 

S. Rosenblum, M.S. 

NTP Pathology Working Group 

Evaluated slides, prepared pathology report on rats 

(2 February 1993) 

M.A. Stedham, D.V.M., M.S., Chairperson 

Pathology Associates, Inc. 

J.M. Cullen, V.M.D., Ph.D. 

North Carolina State University 

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

National Toxicology Program 

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

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

C.C. Shackelford, D.V.M., M.S., Ph.D. 

National Toxicology Program 

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

National Toxicology Program 

Evaluated slides, prepared pathology report on mice 

(3 June 1993) 

M.A. Stedham, D.V.M., M.S., Chairperson 

Pathology Associates, Inc. 

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

National Toxicology Program 

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

Chemical Industry Institute of Toxicology 

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

National Toxicology Program 

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

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

D.D. Sharpnack, D.V.M., M.S. 

National Institute for Occupational Safety and Health 

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

National Toxicology Program 

W.M. Witt, D.V.M., Ph.D. 

National Center for Toxicological Research 

Biotechnical Services, Inc. 

Prepared Technical Report 

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

L.M. Harper, B.S. 

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

D.C. Serbus, Ph.D. 

S.M. Swift, B.S. 
3 

CONTENTS
 

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

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ................... 12
 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE .......................................... 13
 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS ............... 14
 

INTRODUCTION ............................................................................ 15
 

MATERIALS AND METHODS ............................................................... 21
 

RESULTS ................................................................................... 33
 

DISCUSSION AND CONCLUSIONS ........................................................... 69
 

REFERENCES .............................................................................. 75
 

APPENDIX A Summary of Lesions in Male Rats in the 2-Year Inhalation Study
 

of Tetrafluoroethylene ......................................................... 79
 

APPENDIX B Summary of Lesions in Female Rats in the 2-Year Inhalation Study
 

of Tetrafluoroethylene ......................................................... 125
 

APPENDIX C Summary of Lesions in Male Mice in the 2-Year Inhalation Study
 

of Tetrafluoroethylene ......................................................... 165
 

APPENDIX D Summary of Lesions in Female Mice in the 2-Year Inhalation Study
 

of Tetrafluoroethylene ......................................................... 209
 

APPENDIX E Genetic Toxicology ............................................................ 253
 

APPENDIX F Organ Weights and Organ-Weight-to-Body-Weight Ratios ......................... 255
 

APPENDIX G Hematology, Clinical Chemistry, and Urinalysis Results ............................ 263
 

APPENDIX H Reproductive Tissue Evaluations and Estrous Cycle Characterization ................ 273
 

APPENDIX I Chemical Characterization and Generation of Chamber Concentrations .............. 277
 

APPENDIX J Ingredients, Nutrient Composition, and Contaminant Levels 

in NIH-07 Rat and Mouse Ration ............................................... 299
 
4 Tetrafluoroethylene, NTP TR 450 

APPENDIX K Sentinel Animal Program ...................................................... 303 

APPENDIX L H-ras Codon 61 Mutation Spectra in Hepatocellular Neoplasms From B6C3F 1 Mice 

Exposed to Tetrafluoroethylene for 2 Years ....................................... 307 
 

5 

ABSTRACT 

F F 

C C 

F F 

TETRAFLUOROETHYLENE 

CAS No. 116-14-3 

Chemical Formula: C 2 4 F Molecular Weight: 100.02

Synonyms: Perfluoroethylene; tetrafluoroethene; 1,1,2,2-tetrafluoroethylene; TFE 

Tetrafluoroethylene is used in the production o f 

polytetrafluoroethylene (Teflon®) and other polymers. 

Tetrafluoroethylene was nominated by the Nationa l 

Cancer Institute for toxicity and ca rcinogenicity studies 

based on the potential for human exposure to th e 

chemical due to the large production volume and on the 

lack of adequate data for tetrafluoroethylene in th e 

literature. Male and female F344/N rats and B6C3F 1 

mice were exposed to tetrafluoro ethylene (98% to 99% 

pure) by whole body inhalation exposure for 16 days, 

13 weeks, or 2 years. Genetic toxicity studies wer e 

conducted in mouse peripheral blood erythrocytes. 

16-DAY STUDY IN RATS 

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

exposed to 0, 312, 625, 1,250, 2,500, or 5,000 pp m 

tetrafluoroethylene by inhalation for 6 hours per day , 

5 days per week for a total of 12 exposures during a 

16-day period. All rats survived to the end of th e 

study. The final mean body weights and body weight 

gains of males and females exposed to 5,000 pp m 

were significantly less than those of the controls. The 

mean body weight gain of females exposed t o 

2,500 ppm was also significantly less than that of the 

controls. There were no exposure-related clinica l 

findings in male or female rats. There were no significant differences in hematology parameters that wer e 

considered to be related to tetrafluoroethylene expo ­

sure. Absolute and relative kidney weights of al l 

exposed groups of males were significantly greate r 

than those of the controls, as were those of females in 

the 2,500 and 5,000 ppm gro ups. The absolute kidney 

weight of females exposed to 1,250 ppm was als o 

significantly greater than that of the controls. Th e 

relative liver weights of all exposed groups of male s 

and the absolute liver weights of males in the 625 and 

2,500 ppm groups were significantly greater than those 

of the controls. Increased incidences of renal tubul e 

degeneration occurred in males and females exposed to 

625 ppm or greater; this lesion was located predominantly at the corticomedullary junction. The severit y 

of degeneration increased with increasing exposur e 

concentration and was slightly greater in males tha n 

females. 

16-DAY STUDY IN MICE 

Groups of five male and five female B6C3F 1 mice 

were exposed to 0, 312, 625, 1,250, 2,500, o r 

5,000 ppm tetrafluoroethylene by inhalation fo r 

6 hours per day, 5 days per week for a total o f 

12 exposures during a 16-day period. All mic e 

survived to the end of the study. Final mean bod y 

weights and body weight gains of all exposed groups 

of mice were similar to those of the controls. Ther e 

were no exposure-related clinical findings in male o r 

female mice. There were no significant differences in 
6 Tetrafluoroethylene, NTP TR 450 

hematology parameters that were considered to b e 

related to tetrafluoroethylene exposure. The absolute 

and relative liver weights of females exposed t o 

5,000 ppm were significantly greater than those of the 

controls, as was the absolute kidney weight of females 

in that group and the absolute liver weight of females 

in the 2,500 ppm group. Renal tubule karyomegal y 

was observed in male and female mice in the 1,250 , 

2,500, and 5,000 ppm groups, and the severity of this 

lesion increased with increasing exposure concentra ­

tion. Karyomegaly was located predominantly in th e 

inner renal cortex. 

13-WEEK STUDY IN RATS 

Groups of 10 male and 9 or 10 female F344/N rat s 

were exposed to 0, 312, 625, 1,250, 2,500, o r 

5,000 ppm tetrafluoroethylene by inhalation fo r 

6 hours per day, 5 days per week, for 13 weeks. Al l 

rats survived to the end of the study. The final mea n 

body weight and body weight g ain of males exposed to 

5,000 ppm were significantly less than those of th e 

controls, as was the mean body weight gain of females 

in this exposure group. There we re no clinical findings 

attributed to exposure to tetrafluoroethylene . 

Exposure of rats to tetrafluoroethylene resulted in a 

concentration-dependent normocytic, normochromic , 

nonresponsive anemia consistent with a secondar y 

hypoproliferative anemia. An exposure concentrationdependent proteinuria also occurred, consistent wit h 

renal tubule degeneration observed histopathologically. 

The absolute and relative liver weights of all exposed 

groups of males and of females in the 5,000 pp m 

group were significantly greater than those of th e 

controls. The absolute and relative right kidne y 

weights of males and females expo sed to 1,250 ppm or 

greater and of females in the 625 ppm group were also 

significantly greater than those of the controls. There 

were no differences in sperm morphology or vagina l 

cytology parameters between control and expose d 

groups of rats. Incidences of renal tubule degeneration 

in males exposed to 625 ppm or greater and in females 

exposed to 2,500 or 5,000 ppm were significantl y 

greater than those in the controls. Renal lesions were 

similar to those observed in the 16-day study and were 

located predominantly at the cortic omedullary junction. 

13-WEEK STUDY IN MICE 

Groups of 10 male and 10 female B6C3F 1 mice were 

exposed to 0, 312, 625, 1,250, 2,500, or 5,000 pp m 

tetrafluoroethylene by inhalation for 6 hours per day , 

5 days per week, for 13 weeks. All mice survived t o 

the end of the study. Final mean body weights an d 

body weight gains of all exposed groups of male an d 

female mice were generally similar to those of th e 

controls. There were no clinical findings that wer e 

considered to be related to tetrafluoroethylene expo ­

sure. Exposure of mice to tetrafluoroethylene resulted 

in a concentration-dependent normocytic, normochromic, nonresponsive anemia, consistent with a secondary hypoproliferative anemia, and in polyuria . 

Differences in sperm morphology parameters an d 

estrous cycle lengths were not considered to b e 

exposure related. Incidences of karyomegaly of th e 

renal tubule epithelial cells in male and female mic e 

exposed to 1,250 ppm or greater were significantl y 

greater than those in the controls. Karyomegaly wa s 

similar to that observed in the 16-day study and wa s 

observed primarily in the inner renal cortex. 

2-YEAR STUDY IN RATS 

Groups of 60 male rats were exposed to 156, 312, or 

625 ppm and groups of 60 female r ats were exposed to 

312, 625, or 1,250 ppm tetrafluoroethylene b y 

inhalation for 6 hours per day, 5 days per week, fo r 

104 weeks, with an observation period of 11 day s 

following the final ex posure. Ten male and ten female 

rats from each exposure group were evaluated a t 

15 months for organ weights and clinical pathology. 

Survival, Body Weights, 

and Clinical Findings 

Survival rates of males in the 625 ppm group and o f 

all exposed groups of females were significantly les s 

than those of the controls. Mean body weights o f 

males exposed to 625 ppm were lower than those o f 

the controls from week 81 until the end of the study , 

and the mean body weight of 1,250 ppm females was 

slightly lower than that of the controls at the end of the 

study. The only clinical finding associated wit h 

exposure to tetrafluoroethylen e was opacity of the eyes 

in exposed groups of female rats; this change wa s 

observed microscopically as cataracts. 
Tetrafluoroethylene, NTP TR 450 7 

Hematology, Clinical Chemistry, 

and Urinalysis 

At the 15-month interim evaluation, there were n o 

differences in hematology, clinical chemistry, o r 

urinalysis parameters that were considered to b e 

related to tetrafluoroethylene exposure. 

Pathology Findings 

The absolute and relative kidney weights of male s 

exposed to 625 ppm and females exposed t o 

1,250 ppm and the absolute kidney weight of females 

exposed to 625 ppm were significantly greater tha n 

those of the controls at the 15-month interim evalua ­

tion. At 15 months, renal tubule hyperplasia wa s 

observed in one male exposed to 312 ppm and on e 

male and one female exposed to 625 ppm; oncocyti c 

hyperplasia was observed in one female exposed t o 

1,250 ppm. At the end of the study, incidences o f 

renal tubule adenoma were greater in males an d 

females exposed to 312 ppm or greater than those i n 

the controls. This exposure-related increase was confirmed by examination of step sections (extende d 

evaluations). At the end of the study, the incidences of 

renal tubule hyperplasia in males exposed to 625 ppm 

and females exposed to 1,250 ppm were significantly 

greater than those in the controls. The incidences o f 

renal tubule adenoma and renal tubule adenoma o r 

carcinoma (combined) in the extended evaluations and 

in the standard and extended evalu ations (combined) in 

the 1,250 ppm female group and the 625 ppm mal e 

group were significantly greater than those in th e 

controls, and the incidences occurred with significant 

positive trends. Oncocytic hyperplasia was observed 

at the end of the study in one male exposed to 312 ppm 

and in three females exposed to 1,250 ppm. A t 

15 months and at the end of the study, the incidences 

of renal tubule degeneration in all exposed groups o f 

males and in females in the 6 25 and 1,250 ppm groups 

were greater than those in the controls. Renal tubul e 

degeneration was similar to that observed in th e 

13-week study and was located predominantly at th e 

corticomedullary junction. The severity of nephrop ­

athy generally increased with increasing exposur e 

concentration in male rats at 15 months and 2 years. 

The absolute and relative liver weights of females i n 

the 1,250 ppm group and the absolute liver weight of 

females exposed to 625 ppm were significantly greater 

than those of the controls at the 15-month interi m 

evaluation. At 2 years, the incide nces of hepatocellular 

carcinoma and hepatocellular adenoma or carcinom a 

(combined) in males exposed to 312 ppm, the inci ­

dences of hepatocellular adenoma and adenoma o r 

carcinoma (combined) in females in all expose d 

groups, and the incidences of hepatocellular carcinoma 

in females exposed to 312 or 625 ppm were signifi ­

cantly greater than those in the controls. Also a t 

2 years, the incidence of hemangiosarcoma in females 

exposed to 625 ppm was signifi cantly greater than that 

in the controls. In all exposed groups of males, th e 

incidences of clear cell foci at 15 months were greater 

than those in the controls; at 2 years, the incidences of 

eosinophilic foci in all exposed groups of males an d 

the incidences of basophilic and mixed cell foci i n 

males in the 312 and 625 ppm groups were greate r 

than those in the controls. The incidences of mixe d 

cell foci at 15 months in females exposed to 625 o r 

1,250 ppm and at 2 years in females exposed t o 

1,250 ppm were also significan tly greater than those in 

the controls. At the end of the 2-year study, increased 

incidences of cystic degeneration occurred in the liver 

of all exposed groups of males, and increased inci ­

dences of hepatic angiectasis were observed in exposed 

groups of females. 

Incidences of mononuclear cell leukemia in male s 

exposed to 156 ppm and in all exposed groups o f 

females were significantly greater than those in th e 

controls. 

Incidences of cataracts in females exposed t o 

1,250 ppm were greater than those in the controls a t 

the end of the 2-year study. 

At the end of the study, there were slight increases in 

the incidences of testicular interstitial cell adenoma in 

rats exposed to 312 or 625 ppm. 

2-YEAR STUDY IN MICE 

Groups of 58 male and 58 female B6C3F 1 mice were 

exposed to 0, 312, 625, or 1,250 ppm tetrafluoro ­

ethylene by inhalation for 6 hours per day, 5 days per 

week, for 95 to 96 weeks. Ten male and ten femal e 

mice from each exposure group were evaluated a t 

15 months for organ weights. 
8 Tetrafluoroethylene, NTP TR 450 

Survival, Body Weights, 

and Clinical Findings 

The survival rates of all exposed groups of males and 

females were significantly less than those of th e 

controls. Because of the reduced survival due t o 

exposure-related liver neoplasms, the study wa s 

terminated during week 96. Mean body weights o f 

exposed groups of males and females were generall y 

similar to those of the contro ls, except at the end of the 

study, when they were somewhat less than those of the 

controls. There were no clinical findings related t o 

tetrafluoroethylene exposure. 

Pathology Findings 

At the 15-month interim evaluation, there were n o 

differences in absolute o r relative kidney, liver, or lung 

weights between exposed and control groups of mice. 

At the end of the study, the incidences of multifoca l 

coagulative necrosis of the liver were increased i n 

males in the 625 and 1,250 ppm groups. Also at th e 

end of the study, females in all exposed groups ha d 

greater incidences of hematopoiet ic cell proliferation in 

the liver than the controls. Angiectasis occurred in all 

exposed groups of males and females at 15 month s 

and at the end of the study. At the 15-month interi m 

evaluation, hemangiosarcomas were observed in three 

males exposed to 1,250 ppm and in one female ex ­

posed to 312 ppm. The incidences of hemangiosar ­

coma in all exposed groups of male s and females at the 

end of the study were significantly greater than thos e 

in the controls and exceeded the historical chambe r 

control ranges. Also at the end of the study, th e 

incidences of hemangioma in males and female s 

exposed to 312 ppm and in males exposed to 625 ppm 

were also significantly greater than those in the con ­

trols and exceeded the range in historical chambe r 

controls. At 15 months, hepatocellular adenomas and 

carcinomas occurred in control males and all exposed 

groups of males and femal es. Females exposed to 625 

or 1,250 ppm had significantly greater incidences o f 

eosinophilic foci than the controls at the 15-mont h 

interim evaluation. At the end of the study, the inci ­

dences of eosinophilic foci in males exposed to 625 or 

1,250 ppm and in females exposed to 312 or 625 ppm 

were significantly greater tha n those in the controls. In 

male and female mice, increased inc idences of a variety 

of hepatocellular neoplasms, including adenomas , 

multiple adenomas, carcinomas, and multiple carci ­

nomas, were considered related to tetrafluoroethylene 

exposure. 

At the end of the study, the incidences of histiocyti c 

sarcoma (all organs) in all exposed groups of male s 

and females were significantly greater than those in the 

controls and exceeded the historical control ranges for 

all organs. The greatest incidences of histiocyti c 

sarcomas were observed in the live r and lung, but these 

neoplasms were also observed in the spleen, lymp h 

nodes, bone marrow, and kidney. 

Significantly increased incidences of renal tubul e 

dilatation (males) and karyomegaly (males and fe ­

males), located predominantly in the inner cortex, were 

observed in mice exposed to 625 or 1,250 ppm a t 

15 months. At the end of the study, the increase d 

incidences of dilatation and karyomegaly in all ex ­

posed groups of males and of karyomegaly i n 

1,250 ppm females were generally significant. 

Incidences of hematopoietic cell proliferation in th e 

spleen of all exposed groups of males and female s 

were significantly greater than those in the controls at 

the end of the study. Additionally, the severity of this 

lesion increased with increasing exposure concentra ­

tion. 

GENETIC TOXICOLOGY 

No increases in the frequency of micronucleate d 

erythrocytes were observed in peripheral blood sam ­

ples obtained from male and female mice at the end of 

the 13-week inhalation study of tetrafluoroethylene. 

CONCLUSIONS 

Under the conditions of these 2-y ear inhalation studies, 

there was clear evidence of carcinogenic activity* of 

tetrafluoroethylene in male F344/N rats based o n 

increased incidences of renal t ubule neoplasms (mainly 

adenomas) and hepatocellular neoplasms. There was 

clear evidence of carcinogenic activity of tetrafluoroethylene in female F344/N rats based on increase d 

incidences of renal tubule neoplasms, liver hemangiosarcomas, hepatocellular neoplasms, and mononuclear 

cell leukemia. There was clear evidence of carcinogenic activity of tetrafluoroethylene in male an d 

female B6C3F mice based on increased incidences of 1 

liver hemangiomas and hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas. 
___________ 

Tetrafluoroethylene, NTP TR 450 9 

Slight increases in the incidences of mononuclear cell of kidney nephropathy in males, and increased inci ­

leukemia and testicular interstitial cell adenomas i n dences of liver angiectasis and cataracts in females . 

male rats may have been related to exposure to tetra- Exposure of mice to tetrafluoroethylene resulted i n 

fluoroethylene. increased incidences of hematopoietic cell proliferation 

of the liver in females, liver angiectasis in males an d 

Exposure of rats to tetrafluoroethylene resulted i n females, renal tubule dilatation in males, renal tubule 

increased incidences of renal tubule hyperplasia an d karyomegaly in males and females, and splenic hemadegeneration in males and females, increased severity topoietic cell proliferation in males and females. 

*	 Explanation of Levels of Evidence of Carcinogenic Activity is on page 12. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 14. 
10 Tetrafluoroethylene, NTP TR 450 

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

Male 

F344/N Rats 

Female 

F344/N Rats 

Male 

B6C3F Mice 1 

Female 

B6C3F Mice 1 

Exposure 

Concentrations 

0, 156, 312, or 625 ppm 0, 312, 625, or 

1,250 ppm 

0, 312, 625, or 

1,250 ppm 

0, 312, 625, or 

1,250 ppm 

Body Weights 625 ppm group lower 

than controls 

1,250 ppm group 

slightly lower than 

controls at end of study 

Exposed groups lower 

than controls at end of 

study 

Exposed groups lower 

than controls at end of 

study 

Survival Rates 17/50, 12/50, 17/50, 

1/50 (2 years) 

28/50, 16/50, 15/50, 

18/50 (2 years) 

38/48, 11/48, 2/48, 

1/48 (22 months) 

36/48, 4/48, 6/48, 4/48 

(22 months) 

Nonneoplastic 

Effects 

Kidney (renal tubule): 

hyperplasia (single

sections - 1/50, 1/50, 

1/50, 6/50; single and 

step sections - 7/50, 

11/50, 7/50, 24/50); 

degeneration (2/50,

20/50, 50/50, 49/50); 

severity of nephropathy 

(2.3, 1.9, 2.7, 3.5) 

Kidney (renal tubule): 

hyperplasia (single 

sections - 1/50, 3/50, 

6/50, 12/50; single and 

step sections - 3/50, 

6/50, 11/50, 25/50); 

degeneration (0/50,

0/50, 35/50, 46/50) 

Liver: angiectasis 

(0/50, 9/50, 9/50, 

14/50) 

Eye: cataracts (15/50, 

4/50, 10/50, 45/50) 

Liver: angiectasis 

(0/48, 6/48, 10/48, 

13/48) 

Kidney (renal tubule): 

dilatation (0/48, 4/48, 

16/48, 36/48); 

karyomegaly (1/48, 

2/48, 10/48, 28/48) 

Spleen: hematopoietic 

cell proliferation 

(14/48, 32/48, 41/46, 

42/46) 

Liver: hematopoietic 

cell proliferation (3/48, 

19/48, 13/47, 15/47); 

angiectasis (1/48, 9/48, 

6/47, 4/47) 

Kidney (renal tubule): 

karyomegaly (0/48, 

0/48, 0/47, 38/48) 

Spleen: hematopoietic 

cell proliferation 

(18/48, 39/48, 41/46, 

41/47) 
Tetrafluoroethylene, NTP TR 450 11 

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Tetrafluoroethylene (continued) 

Male Female Male Female 

F344/N Rats F344/N Rats B6C3F Mice 1 B6C3F Mice 1 

Neoplastic Effects Kidney (renal tubule): 

adenoma (single 

Kidney (renal tubule): 

adenoma (single 

Liver: hemangioma 

(0/48, 10/48, 5/48, 

Liver: hemangioma 

(0/48, 5/48, 2/47, 

sections - 0/50, 0/50, sections - 0/50, 3/50, 2/48); 1/47); 

6/50, 3/50; single and 1/50, 3/50; single and hemangiosarcoma hemangiosarcoma 

step sections - 2/50, step sections - 0/50, (0/48, 21/48, 27/48, (0/48, 27/48, 27/47, 

4/50, 9/50, 13/50); 3/50, 3/50, 8/50); 37/48); hemangioma 34/47); hemangioma 

carcinoma (single carcinoma (single or hemangiosarcoma or hemangiosarcoma 

sections - 1/50, 0/50, sections - 0/50, 0/50, (0/48, 26/48, 30/48, (0/48, 31/48, 28/47, 

2/50, 0/50; single and 0/50, 2/50; single and 38/48); hepatocellular 35/47); hepatocellular 

step sections - 1/50, step sections - 0/50, carcinoma (11/48, carcinoma (4/48, 

1/50, 2/50, 0/50); 0/50, 0/50, 3/50); 20/48, 33/48, 26/48); 28/48, 22/47, 20/47); 

adenoma or carcinoma adenoma or carcinoma hepatocellular hepatocellular 

(single sections - 1/50, (single sections - 0/50, adenoma or carcinoma adenoma or carcinoma 

0/50, 6/50, 3/50; 3/50, 1/50, 5/50; (26/48, 34/48, 39/48, (17/48, 33/48, 29/47, 

single and step sections single and step sections 35/48) 28/47) 

- 3/50, 5/50, 9/50, - 0/50, 3/50, 3/50, Hematopoietic system Hematopoietic system 

13/50) 10/50) (all organs): (all organs): 

Liver: hepatocellular Liver: histiocytic sarcoma histiocytic sarcoma 

carcinoma (1/50, 1/50, hemangiosarcoma (0/48, 12/48, 7/48, (1/48, 21/48, 19/47, 

10/50, 3/50); (0/50, 0/50, 5/50, 7/48) 18/48) 

hepatocellular 1/50); hepatocellular 

adenoma or carcinoma adenoma (0/50, 4/50, 

(4/50, 7/50, 15/50, 5/50, 6/50); 

8/50) hepatocellular 

carcinoma (0/50, 4/50, 

9/50, 2/50); 

hepatocellular 

adenoma or carcinoma 

(0/50, 7/50, 12/50, 

8/50) 

Mononuclear cell 

leukemia: (16/50, 

31/50, 23/50, 36/50) 

Uncertain Mononuclear cell None None None 

Findings leukemia: (34/50, 

43/50, 38/50, 31/50) 

Testis: interstitial cell 

adenoma (39/50, 

40/50, 48/50, 47/50) 

Level of Evidence Clear evidence Clear evidence Clear evidence Clear evidence 

of Carcinogenic 

Activity 

Genetic Toxicology 

Micronucleated erythrocytes 

Mouse peripheral blood in vivo: Negative 
12 Tetrafluoroethylene, NTP TR 450 

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 longterm 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. 
___________ 

Tetrafluoroethylene, NTP TR 450 13 

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 tetrafluoroethylene on December 5, 

1995, 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 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. 

Arnold L. Brown, M.D., Chairperson Irma Russo, M.D. 

University of Wisconsin Medical School Fox Chase Cancer Center 

Madison, WI Philadelphia, PA 

Gary P. Carlson, Ph.D., Principal Reviewer Louise Ryan, Ph.D., Principal Reviewer 

School of Health Sciences Division of Biostatistics 

Purdue University Dana-Farber Cancer Institute 

West Lafayette, IN Boston, MA 

Thomas L. Goldsworthy, Ph.D. Robert E. Taylor, M.D., Ph.D. 

Department of Experimental Pathology and Toxicology Department of Pharmacology 

Chemical Industry Institute of Toxicology Howard University College of Medicine 

Research Triangle Park, NC Washington, DC 

Robert LeBoeuf, Ph.D. Frederick L. Tyson, Ph.D. 

Corporate Professional and Regulatory Services St. Mary's Hospital and Medical Center 

Human Safety Department Cancer Research Institute 

The Procter & Gamble Company Grand Junction, CO 

Cincinnati, OH 

Jerrold M. Ward, D.V.M., Ph.D. * 

Janardan K. Reddy, M.D., Principal Reviewer* National Cancer Institute 

Department of Pathology Frederick, MD 

Northwestern University Medical School 

Chicago, IL 

* Did not attend 
14 Tetrafluoroethylene, NTP TR 450 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS
 

On 5 December 1995, the draft Technical Report on the 

toxicology and carcinogenesis studies of tetrafluoroethylene received public review by the National Toxicology 

Program's Board of Scientific Counselors' Technical 

Reports Review Subcommittee. The review meeting was 

held at the National Institute of Environmental Health 

Sciences, Research Triangle Park, NC. 

Dr. J.H. Roycroft, NIEHS, introduced the toxicology and 

carcinogenesis studies of tetrafluoroethylene by describing the uses of the chemical, describing the experimental 

design, reporting on survival and body weight effects, 

and commenting on compound-related neoplasms and 

nonneoplastic lesions in male and female rats and mice. 

Dr. R.C. Sills, NIEHS, presented data from ongoing 

molecular biology studies characterizing the H-ras 

codon 61 mutation spectra in hepatocellular neoplasms 

from control B6C3F1 mice and mice exposed to tetrafluoroethylene for 2 years. Data were also presented 

comparing the mutation profiles of hepatocellular neoplasms from the current study with those from the NTP 

study of tetrachloroethylene. The proposed conclusions 

for the 2-year studies were clear evidence of carcinogenic activity in male and female F344/N rats and male 

and female B6C3F mice. 1 

Dr. Ryan, a principal reviewer, agreed with the proposed 

conclusions. She inquired as to whether short-burst, high 

exposures had been considered in the study design as 

being more similar to a typical occupational exposure. 

Dr. Roycroft replied that this regimen had not been 

considered; the 6-hour-per-day, 5-day-per-week design 

used was similar to continuous exposure in a workplace 

situation. Dr. Ryan asked whether there was information 

on the degree of human exposure encountered through 

spills or leaks. Dr. Roycroft noted that tetrafluoroethylene is produced and maintained in closed-capture 

systems, no occupational exposure limits have been 

established, and no information on spills or leaks has 

been found. 

Dr. Carlson, the second principal reviewer, agreed with 

the proposed conclusions. He observed that the 

numbers of clinical pathology measurements appeared to 

be decreased from past reports and, in view of the types 

of lesions seen, wondered why. Dr. Roycroft responded 

that, in actuality, there were more mea-surements; in 

addition to standard time points and collections at 

13 weeks, clinical pathology analyses were performed on 

animals killed at 15 months. Dr. Carlson said a sentence 

needed to be added to the Abstract regarding the reason 

for terminating the mouse study early. Dr. Roycroft 

agreed. 

Dr. Reddy, the third principal reviewer, was unable to 

attend the meeting but had submitted his review, which 

Dr. L.G. Hart, NIEHS, read into the record. Dr. Reddy 

agreed with the proposed conclusions and found the 

report acceptable. 

There was some discussion about the mixing of rats and 

mice in exposure chambers. Dr. Goldsworthy asked if 

hormonal alterations were seen. Dr. Roycroft said that 

hormone measurements were not made, but if a chemical 

to be studied was known to affect hormone levels, then 

separate housing might have to be considered. 

Dr. G.N. Rao, NIEHS, noted that rats and mice are 

produced in the same rooms so each species is 

accustomed to the other's presence; he pointed out that 

each inhalation chamber is by itself a room, and within 

the chamber, rats and mice are not side by side in cages, 

but rather in racks. This provides more efficient and 

economical use of available space. Dr. LeBoeuf 

commended the NTP for the molecular biology studies 

evaluating the H-ras activation profiles and noted the 

usefulness of such studies for risk assessment purposes. 

Dr. Ryan moved that the Technical Report on tetrafluoroethylene be accepted with the revisions discussed 

and with the conclusions as written for male and female 

rats and male and female mice, clear evidence of 

carcinogenic activity. Dr. Carlson seconded the motion, 

which was accepted unanimously with seven votes. 
 

 

15 

INTRODUCTION
 

F F
 

C C
 

F F 

TETRAFLUOROETHYLENE 

CAS No. 116-14-3 

Chemical Formula: C 2 4 F Molecular Weight: 100.02

Synonyms: Perfluoroethylene; tetrafluoroethene; 1,1,2,2-tetrafluoroethylene; TFE 

CHEMICAL AND PHYSICAL 

PROPERTIES 

Tetrafluoroethylene is a colorless, odorless gas with 

a melting point of 142.5 C, a boiling point of 

76.3 C, a specific gravity of 1.52 at 76 C, a 

vapor density of 3.87, and a vapor pressure of 

428.4 mm Hg. It is insoluble in water. Tetrafluoroethylene is a highly flammable gas that reacts with 

oxidants and has a flash point of less than 0 C and 

an autoignition temperature of 188 C. The lower 

explosion limit of the chemical is 10% v/v and the 

upper explosion limit is 50% v/v. Tetrafluoroethylene can dimerize under appropriate temperature 

and pressure conditions to a stable perfluorocyclobutene and polymerizes easily in the absence of 

inhibitors or in the presence of heat or oxygen 

(IARC, 1979; Bretherick, 1985; Weast, 1985; 

NFPA, 1986; Material Safety Data Sheet 

Collection, 1993; HSDB, 1995). 

PRODUCTION , USE, 

AND HUMAN EXPOSURE 

Tetrafluoroethylene is generally produced by the 

pyrolysis of chlorodifluoromethane or trifluoromethane (IARC, 1979; Hawley, 1981; Material 

Safety Data Sheet Collection, 1993). Although 

tetrafluoroethylene was reported to the United States 

International Trade Commission for the year 1992, 

there was no estimate of the annual production 

(USITC, 1994). The most recent estimated United 

States annual production figure of 28 million pounds 

was reported in 1978. Virtually all of the tetrafluoroethylene produced in the United States is used 

in the synthesis of Teflon®, one of several polytetrafluoroethylene polymers (Kennedy, 1990). Because 

of its chemical properties, tetrafluoroethylene is 

produced and maintained in closed-capture systems. 

For this reason, human exposure would be primarily 

through leakage from these systems or through 

contact with one of several decomposition products 

of high-temperature processing or pyrolysis of 

Teflon® and other polymers (Kennedy, 1990). 

According to the National Occupational Exposure 

Survey, 14,963 male and 325 female workers were 

potentially exposed to tetrafluoroethylene from the 

years 1981 to 1983 (NIOSH, 1990). Currently, no 

occupational exposure limits have been established. 

There were no reports in the literature of the 

detection of tetrafluoroethylene in ambient air, 

drinking water, or wastewater, and the chemical is 

not known to occur naturally. 
16 Tetrafluoroethylene, NTP TR 450 

ABSORPTION, DISTRIBUTION, 

METABOLISM , AND EXCRETION 

Experimental Animals 

Dilley et al. (1974) reported the urinary excretion of 

fluoride ion following a 30-minute exposure of 

Sprague-Dawley rats to 3,500 ppm tetrafluoroethylene by inhalation. A significant increase in 

fluoride excretion occurred on days 6, 13, and 14 

following exposure. Urinary creatinine, potassium, 

and volume were significantly increased following 

exposure to tetrafluoroethylene. Increased urinary 

fluoride was observed in male rats and hamsters 

exposed to 100 to 2,500 ppm tetrafluoroethylene by 

inhalation for 2 weeks; however, urinary fluoride 

concentrations returned to normal upon cessation of 

exposure (Kennedy, 1990). Male and female rats 

and hamsters exposed to 200 to 2,000 ppm tetrafluoroethylene by inhalation for 18 weeks displayed 

an exposure-related increase in urinary fluoride 

(Kennedy, 1990). Ding et al. (1980) exposed 

rabbits to 1,000 ppm tetrafluoroethylene for 60 

minutes via a face mask and determined alveolar 

absorption to be 6.76%. Animals were evaluated 

during exposure and for a period of up to 75 minutes 

after exposure ended. The lung, bone, and kidney 

had the highest fluoride content of the sites 

examined. 

As a part of an investigation of tetrafluoroethyleneinduced nephrotoxicity, Odum and Green (1984) 

demonstrated that liver slices from Wistar rats 

metabolized tetrafluoroethylene to S-(1,1,2,2-tetrafluoroethyl)glutathione. The reaction was catalyzed 

by both microsomal and cytosolic glutathione 

S-transferases, with the rate of formation with microsomal fractions occurring at four times the rate with 

cytosol fractions. These same authors also identified 

the cysteinylglycine and cysteine conjugates of 

tetrafluoroethylene in bile from rats exposed to 

6,000 ppm tetrafluoroethylene for 6 hours. Oral 

administration of the cysteine conjugate [ S-(1,1,2,2-­

tetrafluoroethyl)- L-cysteine] to rats caused renal 

damage identical to that caused by tetrafluoroethylene. Cytochrome P 450 oxidation did not appear 

to be involved in tetrafluoroethylene metabolism. 

Cysteine conjugates of the nephrotoxins hexachlorobutadiene, tetrafluoroethylene, and hexafluoropropane, together with those of trichloroethylene and perchloroethylene, have been chemically 

synthesized, and a relationship between their structures, nephrotoxicity, and mutagenicity in vitro has 

been determined (Green and Odum, 1985). All of 

the conjugates had a marked effect on the uptake of 

both the organic anion p-aminohippuric acid and the 

cation tetraethylammonium bromide into rat kidney 

slices, suggesting activation of the conjugates in the 

slices to a toxic species which interferes with ion 

transport. This observation is consistent with the 

known nephrotoxicity of hexachlorobutadiene, 

tetrafluoroethylene, and hexafluoropropene in vivo. 

Each of the conjugates was found to be metabolized 

by rat kidney slices and by semi-purified rat kidney 

-lyase to pyruvate, ammonia, and an unidentified 

reactive metabolite (postulated at that time to be a 

thiol). When semi-purified -lyase was used, 

stoichiometric amounts of pyruvate and ammonia 

were produced. Although all of the conjugates were 

activated by -lyase and had a similar effect on ion 

transport, their mutagenicity differed markedly. The 

conjugates of hexachlorobutadiene, 

trichloroethylene, and tetrachloroethylene were 

mutagenic in the Ames bacterial mutation assay 

when activated by rat kidney S9. Metabolic 

cofactors were not required, suggesting that 

activation was due to the enzyme -lyase. In the 

same assay, conjugates of tetrafluoroethylene and 

hexafluoropropene were not mutagenic either in the 

presence or absence of rat kidney S9 and cofactors. 

With a limited number of cysteine conjugates, a clear 

distinction was identified between the conjugates of 

fluoroalkenes that were similarly nephrotoxic but not 

mutagenic. The mutagenicity of the cysteine 

conjugate of hexachlorobutadiene is consistent with 

the known renal carcinogenicity of this chemical. 

Since the initial observations by Odum and Green 

(1984), a number of laboratories have investigated 

the in vitro and in vivo metabolism of nephrotoxic 

haloalkenes (including tetrafluoroethylene) and their 

cysteine conjugates in order to determine the mechanism of haloalkene-induced nephrotoxicity. The 

bioactivation of the haloalkenes likely begins with 

glutathione conjugation in the liver. These conjugates are primarily excreted via the bile in the small 

intestine, where biliary and intestinal peptidases 

degrade them to cysteine- S-conjugates which may be 
Tetrafluoroethylene, NTP TR 450 17 

reabsorbed from the small intestine. Glutathione 

conjugates released into the general circulation from 

the liver are hydrolyzed to the cysteine- S-conjugates 

by renal peptidases and are bioactivated by renal 

-lyase to unstable, reactive thiols. Commandeur 

et al. (1988) administered tetrafluoroethylenemercapturic acid intraperitoneally to Wistar rats at 

doses of 50 μmol/kg body weight or greater. After 

48 hours, nephrotoxicity, but not liver toxicity, 

ensued, as evidenced by increased blood urea nitrogen, urinary protein and glucose, and relative kidney 

weights. Excretion of difluoroacetic acid was dose 

related, represented 10% of the dose of 50 μmol/kg 

body weight, and occurred primarily during the first 

24 hours. Difluoroacetic acid, pyruvate, hydrogen 

sulfide, and thiosulfate were formed during in vitro 

metabolism of the tetrafluoroethylene-cysteine 

conjugate by rat renal cytosol. Difluoroacetic acid 

formation was inhibited by aminooxyacetic acid, a 

-lyase inhibitor, which points to a -lyase 

dependency for its formation. This suggests that the 

tetrafluoroethylene-cysteine conjugate is bioactivated 

to a significant extent to difluorothionacyl fluoride 

and is subsequently metabolized to difluoroacetic 

acid (Commandeur et al., 1988). Male Wistar rats 

were also injected with 50 μmol tetrafluoroethylenecysteine conjugate/kg body weight. After 48 hours, 

4% of the dose was excreted as the corresponding 

mercapturic acid. In order to evaluate the enzymatic 

activation or deactivation of various halogenated 

cysteine conjugates and mercapturic acids, rat liver 

and kidney cytosol (activation) and microsomes 

(deactivation) were incubated with the 

tetrafluoroethylene-cysteine conjugates and 

mercapturic acid or various chloro- and bromofluoro 

cysteine conjugates and mercapturic acids. 

Tetrafluoroethylene-cysteine conjugate incubated 

with -lyase or tetrafluoroethylene-mercapturic acid 

with N-deacetylase demonstrated a greater activation 

activity with kidney cytosol than with liver. In 

addition, tetrafluoroethylene-cysteine conjugates and 

mercapturic acids demonstrated greater activity than 

chloro- or bromofluoro compounds. Deactivation as 

evidenced by N-acetyltransferase activity (microsomes) was greater with the chloro- and bromofluoro 

compounds than with tetrafluoroethylene conjugates 

or mercapturic acid. Deactivation activity was 

greatest with renal microsomes for both tetrafluoroethylene compounds (Commandeur et al., 1991). 

The same laboratory also demonstrated that when 

isolated proximal tubule cells from Wistar rat 

kidneys were incubated with 100 μmol of 

tetrafluoroethylene-cysteine conjugates or 

mercapturic acid and other chloro- and bromofluoro 

compounds, tetrafluoroethylene compounds were 

more toxic, as evidenced by their ability to inhibit 

-methylglucose uptake by the cells (Boogaard 

et al., 1989). The cytotoxicity induced by both 

tetrafluoroethylene compounds was inhibited by 

aminooxyacetic acid; however, only the toxicity 

induced by tetrafluoroethylene-mercapturic acid 

could be inhibited by probenecid, suggesting that the 

two tetrafluoroethylene compounds are transported 

by a different carrier system. Tetrafluoroethylene 

cysteine accumulated in the proximal tubule cells on 

exposure to either tetrafluoroethylene-cysteine conjugate or tetrafluoroethylene-mercapturic acid 

(Boogaard et al., 1989). Commandeur et al. (1989) 

demonstrated that the tetrafluoroethylene-cysteine 

conjugate may be bioactivated in the rat kidney and, 

to a lesser extent, in the rat liver to electrophilic 

thioacylating reactive intermediates, probably thionacetyl fluorides, which are the putative reactive 

intermediates for tetrafluoroethylene-induced 

nephrotoxicity. 

A number of studies have demonstrated that the 

tetrafluoroethylene-cysteine conjugate and tetrafluoroethylene-derived thionacetyl fluorides affect 

rat and rabbit kidney macromolecules. Using 

isolated rat kidney mitochondria, Hayden and 

Stevens (1990) demonstrated that 

tetrafluoroethylene-cysteine conjugate was a good 

substrate for the mitochondrial -lyase, inhibited 

ADP-stimulated respiration (primarily stage III), was 

covalently bound to macromolecules (blocked by 

aminooxyacetic acid), and was metabolized by 

mitochondria. Rabbit renal proximal tubules 

incubated with 25 μmol tetrafluoroethylene-cysteine 

conjugate produced similar results, including a 

sevenfold increase in lipid peroxidation (Groves 

et al., 1993). Although the majority of binding in rat 

mitochondria is associated with the protein fraction, 

Hayden et al. (1992) have shown that significant 

binding occurs in the lipid fraction, and the major 

phospholipid adduct is the thioamide adduct of 

phosphatidylethanolamine. 

Harris et al. (1992) administered 110 mmol 

tetrafluoroethylene-cysteine conjugate intraperito­
18 Tetrafluoroethylene, NTP TR 450 

neally to male Fischer rats. After 1 hour, kidneys 

were removed, and cytosolic, microsomal, and mitochondrial fractions were obtained. The single, stable 

amino acid adduct formed with renal protein was 

N-(difluorothioacetyl)lysine. Urine taken from 

bladders at necropsy was analyzed for metabolites. 

Mercapturic acids, dihaloacetic acids, and inorganic 

fluoride were present, as in previously reported 

studies. In a similar experiment, Hayden et al. 

(1991a) intraperitoneally administered 30 mg 

tetrafluoroethylene-cysteine conjugate/kg body 

weight to male Sprague-Dawley rats. The resulting 

kidney toxicity showed a good correlation with 

metabolite binding in that difluorothioamide adducts 

and toxicity were localized to the medullary ray, 

which contains the S3C and S3M segments of the 

proximal tubule. Cell death occurred only in cells 

containing adducts. 

Protein adducts such as N-acetyl-N-(difluorothionacetyl)lysine (Hayden et al., 1991b) from rat renal 

subcellular fractions and N-(difluorothionoacetyl)-S-(1,1,2,2-tetrafluoroethyl)- L-cysteine 

(Commandeur et al., 1989) from rat renal and liver 

subcellular fractions have been isolated. Bruschi 

et al. (1993) have demonstrated that as many as five 

mitochondrial proteins are modified following intraperitoneal injection of male F344/N rats with 30 mg 

tetrafluoroethylene-cysteine conjugate/kg body 

weight; modification also occurs at the time of 

formation of the N-acetyl-N-(difluorothionacetyl) 

lysine adduct. Two of the proteins have been identified as the heat shock proteins HSP60 (P1 protein) 

and HSP70-like protein (mortalin). HSP70 and 

HSP70 mRNA are increased in porcine renal epithelial cell cultures when tetrafluoroethylene-cysteine 

conjugate is added (Chen et al., 1992). Lock and 

Schnellmann (1990), using in vitro studies with rat 

renal mitochondrial or cytosolic preparations, have 

demonstrated that the addition of 

tetrafluoroethylene-cysteine conjugate inhibits lipoyl 

dehydrogenase and glutathione reductase activity, 

respectively. 

Humans 

No studies on the absorption, distribution, metabolism, or excretion of tetrafluoroethylene by humans 

were found in the available literature (National 

Library of Medicine, 1995). 

TOXICITY 

Experimental Animals 

Sakharova and Tolgskaya (1977) reported LC 50 

values of 31,000 to 32,000 ppm for rats; 

35,000 ppm for mice; and 28,000 ppm for guinea 

pigs following 4-hour inhalation exposures to 

tetrafluoroethylene. Kennedy (1990) reported a 

similar 4-hour LC 50 of 28,500 ppm for hamsters. 

Zhemerdei (1958) reported that the lowest 

concentration of tetrafluoroethylene that caused 

mortality in rabbits was 40,000 ppm. 

Odum and Green (1984) exposed male Wistar rats to 

tetrafluoroethylene for 6 hours at concentrations of 

1,000, 2,000, 3,000, 4,000, and 6,000 ppm to evaluate the potential renal toxicity of the compound. 

Blood urea nitrogen values, urine volume and urinary 

excretion of glucose, and alkaline phosphatase and 

-glutamyltranspeptidase activities were 

significantly increased in rats exposed to 4,000 or 

6,000 ppm. These changes are indicative of renal 

tubule damage. Histopathologic evaluations of the 

kidneys were conducted on rats in the control and 

6,000 ppm groups. All exposed rats exhibited 

marked renal necrosis involving the pars recta of the 

proximal tubules. In addition, there were intertubule 

calcified deposits in the medulla. The noobservable-effect level for kidney toxicity was 

2,000 ppm. As in previously discussed studies, oral 

exposure to tetrafluoroethylene-cysteine conjugate 

caused renal damage identical to that observed 

following exposure to tetrafluoroethylene via 

inhalation. 

A number of industry-sponsored studies with tetrafluoroethylene have been conducted but not 

published. Kennedy (1990) has provided a brief 

review of some of these studies. Because few 

repeated-exposure studies with tetrafluoroethylene 

are presented in the available published literature, 

several of the studies are summarized here. Syrian 

hamsters and male Crl:CD rats were exposed to 

tetrafluoroethylene for 6 hours per day, 5 days per 

week, for 2 weeks at exposure concentrations of 0, 

100, 500, 1,000, and 2,500 ppm. Some of the 

animals were evaluated at the end of the exposure 

period, and the remaining animals were evaluated 

following a 14-day recovery period. No clinical 

signs of toxicity were observed in either species. 

There were no significant differences in hamster 
Tetrafluoroethylene, NTP TR 450 19 

absolute or relative organ weights (liver or kidney) at 

either evaluation period. After the tenth exposure, 

absolute and relative kidney and liver weights were 

significantly increased in rats exposed to 2,500 ppm 

tetrafluoroethylene; however, following the recovery 

period, kidney and liver weights were similar to 

those of the control group. Exposure-related kidney 

lesions in rats exposed to 2,500 ppm were 

characterized by swelling of the tubular epithelial 

cells and dilation of the tubular lumen. Sparse 

cellular degeneration was observed and localized to 

the juxtamedullary cortex. No significant lesions 

were apparent following the 14-day recovery period. 

No significant histopathologic changes were 

observed in tetrafluoroethylene-exposed hamsters 

after the tenth exposure; however, following the 

14-day recovery period, testicular atrophy was 

observed in the 2,500 ppm group. This effect 

consisted of degeneration and sloughing of germinal 

epithelial cells, resulting in an absence or reduction 

in the number of mature sperm in both the testes and 

epididymides, and the presence of degenerative germ 

cells sloughed into the lumen of the epididymal 

ducts. These effects were noted less frequently in 

animals exposed to lower concentrations. 

Kennedy (1990) summarized the results of a study in 

which male and female rats and hamsters were exposed to 200, 600, or 2,000 ppm tetrafluoroethylene 

for 6 hours per day, 5 days per week, for 18 weeks. 

Hamsters appeared to be less affected than rats in 

that there was no reduction in the rate of weight gain 

in any exposed group of hamsters, while rats 

exposed to 2,000 ppm exhibited a reduction in the 

rate of weight gain. Additionally, toxic nephrosis 

associated with the straight portions of the proximal 

convoluted tubules was observed in rats exposed to 

600 or 2,000 ppm tetrafluoroethylene. This was 

accompanied by increased urine volume and urine 

fluoride concentrations and decreased urine 

creatinine concentrations. The effects were more 

pronounced in female rats than in male rats. No 

effects on the kidneys of exposed groups of hamsters 

were observed; however, testicular atrophy similar to 

that reported in the 14-day study in male Syrian 

hamsters and Crl:CD rats was observed. 

Although a number of animal studies have been 

performed with pyrolysis products of tetrafluoroethylene polymers, they are not reported here 

because these products are mixtures of a number of 

chemical vapors and particulates, and any observable 

effects cannot be solely attributed to the inhalation of 

tetra-fluoroethylene monomer. 

Humans 

Epidemiological studies relative to exposure to tetrafluoroethylene alone were not found in the literature 

(National Library of Medicine, 1995). Although 

monomeric tetrafluoroethylene is generally 

considered an irritant to the eyes and respiratory 

tract, there is a paucity of firm toxicologic data. 

There are considerable data in the literature on 

human exposure to pyrolysis products of 

tetrafluoroethylene polymers. However, those 

studies are not considered here because toxic effects 

from exposure to the polymer fumes cannot be 

attributed solely to inhalation of tetrafluoroethylene 

monomer. Following exposure to pyrolysis products 

of tetrafluoroethylene, influenza-like symptoms 

commonly referred to as “polymer-fume fever” do 

occur. The symptoms include fever, chills, 

headaches, dizziness, nausea, weakness, cough, and 

rigor-like shaking of the limbs (IARC, 1979; 

Gosselin et al., 1984; Material Safety Data Sheet 

Collection, 1993; Patty's Industrial Hygiene and 

Toxicology, 1994). The symptoms are transient if 

the oxygen supply to the subject is increased and the 

subject is removed from the contaminated environment. 

S-(1,1,2,2-tetrafluoroethyl)- L-cysteine and other 

cysteine and glutathione conjugates such as 

S-(1,2-di-chlorovinyl)glutathione, S-(1,2-dichlorovinyl)-L-cysteine, S-(1,2,3,4,4-pentachlorobutadienyl)-Lcysteine, and S-(2-chloro1,1,2-trifluoroethyl)-L-cysteine were found to be toxic to 

human proximal tubule cells in culture, as indicated 

by the release of lactate dehydrogenase (Chen et al., 

1990). Aminooxyacetic acid protected the cells from 

the toxicity of all the conjugates and inhibited the 

covalent binding of the sulfur-containing metabolites 

to cellular macromolecules and thus prevented cell 

death. 

REPRODUCTIVE 

AND DEVELOPMENTAL TOXICITY 

No information on the reproductive or 

developmental toxicity of tetrafluoroethylene in 
20 Tetrafluoroethylene, NTP TR 450 

experimental animals or in humans was found in a 

search of the available literature (National Library of 

Medicine, 1995). 

CARCINOGENICITY 

No information on the carcinogenicity of tetrafluoroethylene in experimental animals or in humans was 

found in a search of the available literature (National 

Library of Medicine, 1995). Tetrachloroethylene, 

which is structurally similar to tetrafluoroethylene, 

produced hepatocellular carcinomas in male and 

female B6C3F1 mice (NCI, 1977). Male mice were 

administered 450 or 900 mg tetrachloroethylene/kg 

body weight in corn oil by gavage for 11 weeks, then 

550 or 1,100 mg/kg for 67 weeks. Female mice 

were administered 300 or 600 mg/kg tetrachloroethylene in corn oil by gavage for 11 weeks, then 

400 or 800 mg/kg for 67 weeks. Exposure of male 

and female F344/N rats to 200 or 400 ppm 

tetrachloroeth-ylene by inhalation for 2 years 

resulted in increased incidences of renal tubule 

adenoma or adenocarcinoma in males and increased 

incidences of mononuclear cell leukemia in males 

all these tests were conducted with and without 

Aroclor-induced liver S9 enzymes. 

STUDY RATIONALE 

Tetrafluoroethylene was nominated to the NTP by 

the National Cancer Institute for testing following a 

review of related monomers and polymers. The 

and females. (NTP, 1986). In the same inhalation 

study, mice exposed to 100 or 200 ppm for 2 years 

developed increased incidences of hepatocellular 

adenoma (males) and carcinoma (males and 

females). 

GENETIC TOXICOLOGY 

Kennedy (1990) reported that tetrafluoroethylene 

was not mutagenic in Salmonella typhimurium with 

or without metabolic activation. 

Cysteine conjugates of tetrafluoroethylene were not 

mutagenic in the Salmonella assay, with or without 

rat kidney S9 (Green and Odum, 1985). 

The structurally similar tetrachloroethylene was not 

mutagenic in Salmonella (Haworth et al., 1983), 

gave equivocal results in the mouse lymphoma 

mutagenicity assay with L5178Y mouse lymphoma 

cells (Myhr et al., 1990), and did not induce sister 

chromatid exchanges or chromosomal aberrations in 

cultured Chinese hamster ovary cells (Galloway 

et al., 1987); 

nomination was based on the potential for human 

exposure to the chemical due to the large production 

volume and on the lack of adequate test data for 

tetrafluoroethylene. Inhalation was chosen as the 

route of exposure because human exposure occurs 

primarily via this route. Sixteen-day, 13-week, and 

2-year whole body inhalation studies were performed 

in male and female F344/N rats and B6C3F 1 mice. 
21 

MATERIALS AND METHODS
 

PROCUREMENT 

AND CHARACTERIZATION 

OF TETRAFLUOROETHYLENE 

Tetrafluoroethylene was obt ained from SCM Specialty 

Chemicals (Gainesville, FL) in one lot (10271), which 

was used for the identity and pur ity analyses conducted 

by the analytical chemistry laboratory, Midwes t 

Research Institute (Kansas City, MO) (Appendix I) . 

Tetrafluoroethylene was also obtained from IC I 

Americas, Inc. (Bayonne, NJ), in five lots. The study 

laboratory assigned a lot number to each shipment of 

as many as 12 cylinders. Lot 12017 -8 was used during 

the 16-day studies and during most of the 13-wee k 

studies; lot 12017-77 was used during the remainde r 

of the 13-week studies; and lots 12438-6, 12438-79 , 

and 12438-92 were used during the 2-year studies . 

Identity and purity analyses were also conducted by the 

study laboratory on each lot used during the studies . 

Reports on analyses performed in support of th e 

tetrafluoroethylene studies are on file at the Nationa l 

Institute of Environmental Health Sciences (NIEHS). 

Each lot of the chemical, a color less gas, was identified 

as tetrafluoroethylene by the analytical chemistry o r 

study laboratory using infrared spectroscopy and th e 

purity of each lot was determined by gas chromatography. Gas chromatography of lot 10271 indicated one 

major peak and one impurity with an area of 0.1 % 

relative to the major peak. In addition, analysis fo r 

d-limonene, which is added to tetrafluoroethylene as a 

stabilizer, was conducted by the analytical chemistr y 

laboratory using gas chromatography and indicate d 

0.03% ± 0.00% d-limonene. Gas chromatograph y 

conducted by the study laboratory for each cylinder of 

each lot used during the studies indicated tha t 

perfluorocyclobutane was present at concentration s 

less than or equal to 462 ppm (0.05%) for the 16-day 

studies and 2,604 ppm (0.26%) for the 13-wee k 

studies. During the 2-year studies, gas chromatogra ­

phy indicated peaks for perfluorocyclobutane wit h 

areas less than or equal to 1.21% relative to the major 

peak. Gas chromatography conducted by the stud y 

laboratory for each cylin der of each lot used during the 

13-week studies indicate d that d-limonene was present 

at concentrations less than or equal to 2,837 pp m 

(0.28%). During the 2-year studies, gas chromatography of lots 12438-6, 12438-79, and 12438-92 indi ­

cated peaks for d-limonene with areas less than o r 

equal to 0.56% relative to the major peak. The manufacturer indicated that the following impurities wer e 

also present at concentrations less than or equal t o 

1.7 ppm: trifluoroethylene, methylene fluoride, vinyl 

fluoride, and vinylidene fluoride. The overall purity of 

lots 12017-8, 12017-77, and 12438-92 was deter ­

mined to be greater than 99%. The overall purity o f 

lots 12438-6 and 12438-79 was determined to b e 

greater than 98%. 

The manufacturer indicated that tetrafluoroethylen e 

would be stable for up to 1 year when stored in th e 

original containers at room temperature. To ensur e 

stability, the bulk chemical was stored in the origina l 

metal cylinders at 10 to 22 C. Stability was monitored during the 13-week and 2-year studies using gas 

chromatography. The relative concentrations o f 

perfluorocyclobutane were expected to increase due to 

the slow dimerization of tetrafluoroethylene; therefore, 

the gas cylinders were m onitored for this dimer as well 

as for d-limonene during the 2-year studies. Tw o 

cylinders from lot 12438-6 contained higher concentrations of these compounds t han canisters from the same 

lot that were analyzed earlier in the studies. One o f 

these two cylinders, which contained 1.21 % 

perfluorocyclobutane and 0.56% d-limonene, was 

replaced immediately after gas chromatographi c 

analysis was performed; it is not known if the dime r 

formed in the canister due to degradation o f 

tetrafluoroethylene or was present as an impurity a t 

receipt. Stability was generally considered acceptable 

throughout the studies. 

VAPOR GENERATION 

AND EXPOSURE SYSTEM 

Because tetrafluoroethylene is a gas at room temperature, the generation and delivery system incorporate d 

gas distribution under regulated pressure with indi ­

vidual adjustment and monitoring of the chemical flow 
22 Tetrafluoroethylene, NTP TR 450 

rate to each chamber. Tetrafluoroethylene was take n 

directly from the cylinder in which it was shipped and 

was metered to each exposu re chamber. A sample line 

was included downstream from each gas cylinder . 

Stainless-steel chambers designed at Battelle Pacifi c 

Northwest Laboratories were used for all studie s 

(Figure I3). 

VAPOR CONCENTRATION MONITORING 

The concentrations of tetrafluoroethylene wer e 

monitored using an on-line gas chromatograph, an d 

samples were drawn and analyzed from each exposure 

chamber, the control chamber, the exposure suite, and 

an on-line standard. Summaries of the chambe r 

concentrations during the studies are presented i n 

Tables I1 through I3. The monthly mean exposur e 

concentrations for the 2-year studies are presented i n 

Figures I7 through I15; all were within 10% of th e 

acceptable concentration range. 

CHAMBER ATMOSPHERE 

CHARACTERIZATION 

The time for the exposure concentration to build up to 

90% of the final exposure concentration (T 90) used for 

all studies was 12 minutes . During the 16-day studies, 

T was approximately 12 minutes and T (the time 90 10 

for the exposure concentration to decay to 10% of the 

exposure concentration) was approximately 9 minutes 

with and without animals in the chambers. During the 

13-week studies, T90 was 11 minutes with animals i n 

the chambers and ranged from 11 to 14 minute s 

without animals; T10 ranged from 9 to 11 minutes with 

and without animals in the chambers. During th e 

2-year studies, T90 ranged from 8 to 10 minute s 

without animals in the chambers and from 10 t o 

16 minutes with animals present; T10 ranged from 7 to 

9 minutes without animals and from 9 to 12 minute s 

with animals. The T90 value was not affected by th e 

presence of animals. 

Uniformity of tetrafluoroethylene concentration in the 

exposure chambers was measured using on-line ga s 

chromatography before each of the studies, onc e 

during the 16-day and 13-week studies, and approxi ­

mately every 3 months during the 2-year studies . 

Uniformity of exposure concentrations within eac h 

chamber was acceptable, and relative standar d 

deviations were less than 5%. 

The persistence of tetrafluoroethylene in th e 

1,250 ppm exposure chamber after shutting off th e 

system was monitored without animals before th e 

2-year studies began and with animals present during 

the 2-year studies. The concentration of tetrafluoro ­

ethylene in the exposure chamber fell rapidly to les s 

than 1% of the beginning concentration withi n 

20 minutes. Tetrafluoroethylene concentrations in the 

building exhaust and room air were also monitore d 

during all studies. 

Information supplied by the manufacturer indicate d 

that all cylinders contained d-limonene as a stabilizer. 

d-Limonene and perfluorocyclobutane are less volatile 

than tetrafluoroethylene and c oncentrate in the cylinder 

as the tetrafluoroethylene is removed. Cylinder usage 

was regulated to minimize concentrations of thes e 

chemicals in the exposure chambers; a maximum o f 

80% of the tetrafluoroethylene in each cylinder wa s 

used. Gas chromatography of chamber samples an d 

cylinder headspace in used and unused cylinders wa s 

conducted for d-limonene and perfluorocyclobutane . 

The results indicated that tetrafluoroethylene wa s 

stable during generation and in the exposure chambers 

and that perfluorocyclobutane was not formed i n 

significant quantities by the generation system. 

16-DAY STUDIES 

Male and female F344/N rats and B6C3F 1 mice were 

obtained from Frederick Cancer Research Facilit y 

(Frederick, MD). On receipt, the rats and mice wer e 

approximately 4 weeks old. Anim als were quarantined 

for 11 days (rats) or 12 days (mice) and wer e 

approximately 6 weeks old on the first day of th e 

studies. Groups of five male and five female rats and 

mice were exposed to tetrafluoroethylene at concen ­

trations of 0, 312, 625, 1,250, 2,500, and 5,000 ppm. 

The animals were exposed for 6 hours plus T 90 

(12 minutes) per day, 5 days per week for 12 exposure 

days during a 16-day period. Feed was availabl e 

ad libitum except during exposure periods, and water 

was available ad libitum. Rats and mice were housed 

individually. Clinical findings were recorded tw o 

times during each exposure day for rats and mice. The 

animals were weighed on days 1, 8, and 15 and a t 
Tetrafluoroethylene, NTP TR 450 23 

necropsy. Details of the study design and anima l 

maintenance are summarized in Table 1. 

At the end of the 16-day studies, blood was collected 

from the retroorbital (rats ) or supraorbital (mice) sinus 

for hematology analyses. Rats and mice wer e 

anesthetized with CO . 2 Blood for hematology deter ­

minations was placed in tubes containing potassiu m 

EDTA as the anticoagula nt. Analyses were performed 

with an Ortho ELT-8/ds hematology analyzer (Ortho 

Instruments; Westwood, MA). Leukocyte differential 

counts were determined by light microscopi c 

examination of blood films stained with Wright -

Giemsa. Reticulocyte counts were determined by light 

microscopy using smears stained supravitally wit h 

New Methylene Blue and a Miller disc for reticulocyte 

quantitation. Hematology parameters measured ar e 

listed in Table 1. 

A necropsy was performed on all rats and mice. The 

brain, heart, left and right kidneys, liver, lung, righ t 

testis, and thymus were weighed. Histopathologi c 

examinations were performed on all control an d 

5,000 ppm rats and mice. Selected organs wer e 

examined to a no-effect level in groups of animal s 

exposed to lower concentrations of tetrafluoroethylene. 

Table 1 lists the tissues and organs examined. 

13-WEEK STUDIES 

The 13-week studies were conducted to evaluate th e 

cumulative toxic effects of repeated exposure t o 

tetrafluoroethylene and to determine the appropriat e 

exposure levels to be used in the 2-year studies. 

Male and female F344/N rats and B6C3F 1 mice were 

obtained from Taconic Farms, Inc. (Germantown , 

NY). On receipt, rats and mice were approximatel y 

4 weeks old. Animals were quarantined for 12 day s 

(rats) or 14 days (mice) and were approximatel y 

6 weeks old on the first day of the studies. Before the 

studies began, five male and five female rats and mice 

were randomly selected for parasite evaluation an d 

gross observation for evidence of disease. At the end 

of the studies, serologic analyses were performed o n 

five male and five female sentinel rats and mice using 

the protocols of the NTP Sentinel Animal Progra m 

(Appendix K). 

Groups of 10 male and 10 female rats and mice were 

exposed to tetrafluoroethylene at concentrations of 0, 

312, 625, 1,250, 2,500, or 5,000 ppm. (One femal e 

rat assigned to the 2,500 ppm group was missexed and 

discarded at week 6.) The animals were exposed fo r 

6 hours plus T90 (12 minutes) per day, 5 days pe r 

week, for 13 weeks (excluding holidays). Feed wa s 

available ad libitum except during exposure periods , 

and water was available ad libitum. Rats and mice 

were housed individually. Clinical findings wer e 

recorded once weekly for rats and mice. The animals 

were weighed prior to the start of the studies an d 

weekly thereafter. Details of the study design an d 

animal maintenance are summarized in Table 1. 

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

from the retroorbital (rats ) or supraorbital (mice) sinus 

for hematology analyses. Rats and mice wer e 

anesthetized with CO . 2 Hematology determination s 

were analyzed as described for the 16-day study . 

Fourteen days (rats) or 10 days (mice) before the end 

of the studies, rats and mice were placed in metabolism 

cages (with access to water but not food) for a 16-hour 

urine collection. Four days before the end of th e 

studies, rats were again placed in metabolism cage s 

and were deprived of water for 16 hours to determine 

urine concentrating ability; urine was expressed from 

the bladders of all rats, and urine was collected for the 

following 4 hours while water deprivation continued . 

Specific gravity was determined on an A/ O 

refractometer; urine glucose was determined using an 

Abbott VP glucose oxidase methodology (Abbot t 

Laboratories, Abbott Park, IL); urine protein wa s 

determined by a Coomas sie blue reaction; and fluoride 

was measured using an ion-specific electrode . 

Hematology and urinalysis parameters measured ar e 

listed in Table 1. 

At the end of the 13-week studies, samples wer e 

collected for sperm morphology and vaginal cytology 

evaluations on rats and mice exposed to 0, 312, 1,250, 

and 5,000 ppm. The parameters evaluated are listed in 

Table 1. Methods used were those described in th e 

NTP's sperm morphology and vaginal cytolog y 

evaluations protocol (NTP, 1984). For 7 consecutive 

days prior to scheduled terminal sacrifice, the vaginal 

vaults of the females were moistened with saline, i f 

necessary, and samples of vaginal fluid and cells were 

stained. Relative numbers of leukocytes, nucleate d 

epithelial cells, and large squamous epithelial cell s 
24 Tetrafluoroethylene, NTP TR 450 

were determined and used to ascertain estrous cycl e 

stage (i.e., diestrus, proestrus, estrus, and metestrus). 

Male animals were evaluated for sperm morphology , 

count, and motility. The right testis and righ t 

epididymis were isolated and weighed. The tail of the 

epididymis (cauda epididymis ) was then removed from 

the epididymal body (corpu s epididymis) and weighed. 

Test yolk (rats) or modified Tyrod e's buffer (mice) was 

applied to slides and a small incision was made at the 

distal border of the cauda epididymis. The sper m 

effluxing from the incision were dispersed in the buffer 

on the slides, and the num bers of motile and nonmotile 

spermatozoa were counted for five fields per slide by 

two observers. Following completion of sper m 

motility estimates, each right cauda epididymis wa s 

placed in buffered saline solution. Caudae were finely 

minced, and the tissue was incubated in the salin e 

solution and then heat fixed at 65 C. Sperm density 

was then determined microscopically with the aid of a 

hemacytometer. To quantify spermatogenesis , 

testicular spermatid head count was determined b y 

removing the tunica albuginea and homogenizing th e 

left testis in phosphate-b uffered saline containing 10% 

dimethyl sulfoxide. Homogenization-resistan t 

spermatid nuclei were counted with a hemacytometer. 

A necropsy was performed on all animals. The brain, 

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

were weighed. Tissues for microscopic examinatio n 

were fixed and preserved in 10% neutral buffere d 

formalin, processed and trimmed, embedded i n 

paraffin, sectioned to a thickness of 5 to 6 μm, an d 

stained with hematoxylin and eosin. A complet e 

histopathologic examination was performed on al l 

control and 5,000 ppm rats and mice and on selecte d 

organs from rats and mice exposed to lower concen ­

trations. Table 1 lists the tissues and organ s 

examined. 

2-YEAR STUDIES 

Study Design 

Groups of 60 male rats were exposed to tetrafluoro ­

ethylene at concentrations of 0, 156 , 312, and 625 ppm 

for 6 hours plus T90 (12 minutes) per day, 5 days pe r 

week, for 104 weeks. Groups of 60 female rats an d 

58 male and female mice were exposed t o 

tetrafluoroethylene at concentrations of 0, 312, 625 , 

and 1,250 ppm for 6 hours plus T 90 (12 minutes) per 

day, 5 days per week, for 104 weeks (female rats) o r 

95 to 96 weeks (mice). Following the last day o f 

exposure, rats were observed for approximatel y 

11 days before necropsy. Ten ma le and ten female rats 

and mice from each group were evalu ated at 15 months 

for alterations in hematology, clinical chemistry, an d 

urinalysis parameters (rats only) and organ weight s 

(rats and mice). 

Source and Specification of Animals 

Male and female F344/N rats and B6C3F 1 mice were 

obtained from Simonsen Laborat ories (Gilroy, CA) for 

use in the 2-year studies. Rats and mice were quarantined for 15 days before the beginning of the studies . 

Five male and five female rats and mice 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 th e 

animals was monitored during the studies according to 

the protocols of the NTP Sentinel Animal Progra m 

(Appendix K). 

Animal Maintenance 

Rats and mice were housed individually. Feed wa s 

available ad libitum except during exposure periods , 

and water was available ad libitum. Chambers and 

cages were rotated weekly. Further details of anima l 

maintenance are provided in Table 1. Information on 

feed composition and contaminants is provided i n 

Appendix J. 

Clinical Examinations and Pathology 

All animals were observed twice daily. Clinica l 

findings were recorded m onthly until the last 13 weeks 

(rats) or 5 weeks (mice), when they were recorde d 

twice monthly. Animals were weighed prior to th e 

start of the studies, weekly for the first 13 weeks, and 

monthly thereafter, until the last 13 weeks (rats) o r 

5 weeks (mice), when they were weighed ever y 

2 weeks. 

Ten male and ten female rats and mice per exposur e 

group were designated for interim evaluation a t 

15 months. Two weeks before the scheduled evaluation, designated rats were placed in metabolism cages 

for a 16-hour urine collection. One week later, mal e 

and female rats were again placed in metabolism cages 

for a urine concentrating study. Rats were deprived of 

water for 16 hours, and urine was expressed from the 

bladders of the animals; urine was then collecte d 

during the next 6 hours for a u rine concentrating study. 
Tetrafluoroethylene, NTP TR 450 25 

At the 15-month interim evaluation, blood was take n 

from the retroorbital plexu s of rats for hematology and 

clinical chemistry analyses. The methods used wer e 

those described for the 13-week studies, and parameters measured are listed in Table 1. 

A complete necropsy and microscopic examinatio n 

were performed on all rats and mice. At the 15-month 

interim evaluation, the right kidney, liver, and lun g 

were weighed. At necropsy, all organs and tissue s 

were examined for grossly visible lesions, and al l 

major tissues were fixed and preserved in 10% neutral 

buffered formalin, processed and trimmed, imbedde d 

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

stained with hematoxylin and eosin for microscopi c 

examination. For all paire d organs (i.e., adrenal gland, 

kidney, ovary), samples from each organ were exam ­

ined. For extended evaluation of renal proliferativ e 

lesions, kidneys were st ep sectioned at 1 mm intervals, 

and six to ten additional sections were obtained fro m 

each kidney. Tissues examined microscopically ar e 

listed in Table 1. 

Microscopic evaluations were completed by the study 

laboratory pathologist, and the pathology data wer e 

entered into the Toxicology Data Management System. 

The slides, paraffin blocks, and residual wet tissue s 

were sent to the NTP Archives for inventory , 

slide/block match, and wet tissue audit. The slides , 

individual animal data records, and pathology table s 

were evaluated by an independent quality assessment 

laboratory. The individual animal records and table s 

were compared for accuracy, the slide and tissu e 

counts were verified, and the histotechnique wa s 

evaluated. For the 2-year rat and mouse studies, a 

quality assessment pathologist reviewed the following 

organs: adrenal medulla, kidney, liver, and splee n 

(male rats); eye, kidney, liver, and spleen (female rats); 

kidney, liver, and spleen (male mice); and harderia n 

gland, liver, and spleen (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 diagnose s 

made by the laboratory and quality assessmen t 

pathologists. Representative histopathology slide s 

containing examples of lesions related to chemica l 

administration, examples of disagr eements indiagnoses 

between the laboratory and quality assessmen t 

pathologists, or lesions of general interest wer e 

presented by the chairperson to the PWG for review . 

The PWG consisted of the quality assessmen t 

pathologist and other pathologists experienced i n 

rodent toxicologic pathology. This group examine d 

the tissues without any knowledge of dose groups o r 

previously rendered diagnoses. When the PW G 

consensus differed from the opinion of the laboratory 

pathologist, the diagnosis was changed. Thus, th e 

final diagnoses represent a consensus of contracto r 

pathologists, the PWG chairperson, and the PWG . 

Details of these review procedures have bee n 

described, in part, by Maronpot and Boorman (1982) 

and Boorman et al. (1985). For subsequent analyses 

of the pathology data, the diagnosed lesions for eac h 

tissue type were evaluated separately or combine d 

according to the guidelines of Mc Connell et al. (1986). 

STATISTICAL METHODS 

Survival Analyses 

The probability of survival was estimated by th e 

product-limit procedure of Kaplan and Meier (1958 ) 

and is presented in the form of graphs. Animals found 

dead of other than natural causes were censored from 

the survival analyses; animals dying from natura l 

causes were not censored. Statistical analyses fo r 

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 

as presented in Tables A1, A5, B1, B5, C1, C5, D1 , 

and D5 are given as the number of animals bearin g 

such lesions at a specifi c anatomic site and the number 

of animals with that site examined microscopically . 

For calculation of statistical significance, th e 

incidences of most neoplasms (Ta bles A3, B3, C3, and 

D3) and all nonneoplastic lesions are given as th e 

numbers of animals affected at each site examine d 

microscopically. However, when macroscopi c 

examination was required to detect neoplasms i n 

certain tissues (e.g., harderian gland, intestine , 

mammary gland, and skin) before microscopi c 

evaluation, or when neoplasms had multiple potential 

sites of occurrence (e.g., leukemia or lymphoma), the 
26 Tetrafluoroethylene, NTP TR 450 

denominators consist of the number of animals o n 

which a necropsy was performed. Tables A3, B3, C3, 

and D3 also give the survival-adjusted neoplasm rate 

for each group and each site-specifi c neoplasm, i.e., the 

Kaplan-Meier estimate of the neoplasm incidence that 

would have been observed at the end of the study in the 

absence of mortality from all other competing risk s 

(Kaplan and Meier, 1958). 

Analysis of Neoplasm Incidences 

For those neoplasms considered incidental in thes e 

studies, the primary statistical method used wa s 

logistic regression analysis, which assumed that th e 

diagnosed neoplasms were discovered as the result of 

death from an unrelated cause and thus did not affect 

the risk of death. In this approach, neoplasm preva ­

lence was modeled as a logistic function of chemica l 

exposure and time. Both linear and quadratic terms in 

time were incorporated initial ly, and the quadratic term 

was eliminated if the fit of the model was not significantly enhanced. The neoplasm incidences of exposed 

and control groups were compared on the basis of the 

likelihood score test for the regression coefficient o f 

dose. This method of adjusting for intercurrent mortality is the prevalence analysis of Dinse and Lagako s 

(1983), further described and illustrated by Dinse and 

Haseman (1986). When neop lasms are incidental, this 

comparison of the time-specific neoplasm prevalences 

also provides a comparison of the time-specific neo ­

plasm incidences (McKnight and Crowley, 1984). 

In addition to logistic regression, other methods o f 

statistical analysis were used, and the results of these 

tests are summarized in the appendixes. These methods include the life table test (Cox, 1972; Tarone , 

1975), appropriate for rapidly lethal neoplasms, an d 

the Fisher exact test and the Cochran-Armitage trend 

test (Armitage, 1971; Gart et al., 1979), procedure s 

based on the overall proportion of neoplasm-bearin g 

animals. 

Tests of significance includ ed pairwise comparisons of 

each exposed group with controls and a test for a n 

overall dose-related trend. Continuity-corrected tests 

were used in the analysis of neoplasm incidence, an d 

reported P values are one sided. The procedure s 

described in the preceding paragraphs were also used 

to evaluate selected nonneoplastic lesions. For further 

discussion of these statistical methods, refer t o 

Haseman (1984). 

Analysis of Nonneoplastic Lesion Incidences 

Because all nonneoplastic lesions in this study wer e 

considered to be incidental to the cause of death or not 

rapidly lethal, the primary statistical analysis used was 

a logistic regression analysis in which nonneoplasti c 

lesion prevalence was modeled as a logistic function of 

chemical exposure and time. For lesions detected a t 

the interim evaluation, the Fisher exact test, a proce ­

dure based on the overall proportion of affecte d 

animals, was used. 

Analysis of Continuous Variables 

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

control groups in the analysis of continuous variables. 

Organ and body weight data, which have approxi ­

mately normal distributions, were analyzed using th e 

parametric multiple comparis on procedures of Dunnett 

(1955) and Williams (1971, 1972). Hematology , 

clinical chemistry, spermatid, and epididymal spermatozoa data, which have typically skewed distributions, 

were analyzed using the nonparametric multipl e 

comparison methods of Shirley (1977) and Dun n 

(1964). Jonckheere's test (Jon ckheere, 1954) was used 

to assess the significance of the d ose-related trends and 

to determine whether a trend-sensitive test (Williams' 

or Shirley's test) was more appropriate for pairwis e 

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 identifie d 

by the outlier test of Dixon and Massey (1951) wer e 

examined by NTP personnel, and implausible value s 

were eliminated from the analysis. Average severit y 

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

the vaginal cytology data are proportions (the proportion of the observation period that an animal was in a 

given estrous stage), an arcsine transformation wa s 

used to bring the data into closer conformance with a 

normality assumption. Tr eatment effects were investigated by applying a multivariate analysis of varianc e 

(Morrison, 1976) to the transformed data to test fo r 

simultaneous equality of measurements across expo ­

sure levels. 

Historical Control Data 

Although the concurrent control group is always th e 

first and most appropriate control group used fo r 

evaluation, historical control data can be helpful in the 

overall assessment of neoplasm incidence in certai n 
Tetrafluoroethylene, NTP TR 450 27 

instances. Consequently, neoplasm incidences fro m

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 i n 

compliance with Food and Drug Administration Good 

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

addition, as records from the 2-year studies wer e 

submitted to the NTP Archives, these studies wer e 

audited retrospectively by an independent qualit y 

assurance contractor. Separate audits covering com ­

pleteness and accuracy of the pathology data, pathology specimens, final pathology tables, and a draft of 

 this NTP Technical Report were conducted. Audi t 

procedures and findings are presented in the report s 

and are on file at NIEHS. The audit findings wer e 

reviewed and assessed by NTP staff, so all comments 

had been resolved or were otherwise addressed during 

the preparation of this Technical Report. 

GENETIC TOXICOLOGY 

The genetic toxicity of tetrafluoroethylene was as ­

sessed by testing the ability of the chemical to induce 

increases in the frequency of micronucleated erythrocytes in peripheral blood samples obtained from male 

and female mice at the end of the 13-week study. The 

protocol for this study and the results are given i n 

Appendix E. 
28 Tetrafluoroethylene, NTP TR 450 

TABLE 1 

Experimental Design and Materials and Methods in the Inhalation Studies of Tetrafluoroethylene 

16-Day Studies 13-Week Studies 2-Year Studies 

Study Laboratory 

Battelle Pacific Northwest Laboratories 

(Richland, WA) 

Strain and Species 

Rats: F344/N 

Mice: B6C3F1 

Animal Source 

Frederick Cancer Research Facility (Frederick, 

MD) 

Time Held Before Studies 

Rats: 11 days 

Mice: 12 days 

Average Age When Studies Began 

6 weeks 

Date of First Exposure 

Rats: 30 September 1985 

Mice: 1 October 1985 

Duration of Exposure 

6 hours plus T (12 minutes) per day, 5 days 90 

per week, for 16 days 

Date of Last Exposure 

Rats: 15 October 1985 

Mice: 16 October 1985 

Necropsy Dates 

Rats: 16 October 1985 

Mice: 17 October 1985 

Battelle Pacific Northwest Laboratories 

(Richland, WA) 

Rats: F344/N 

Mice: B6C3F1 

Taconic Farms, Inc. 

(Germantown, NY) 

Rats: 12 days 

Mice: 14 days 

6 weeks 

Rats: 25 March 1986 

Mice: 27 March 1986 

6 hours plus T (12 minutes) per day, 5 days 90 

per week, for 13 weeks 

Rats: 

24 June 1986 (males) 

25 June 1986 (females) 

Mice: 

26 June 1986 (males) 

25 June 1985 (females) 

Rats: 

24 June 1986 (males) 

25 June 1986 (females) 

Mice: 

27 June 1986 (males) 

26 June 1986 (females) 

Battelle Pacific Northwest Laboratories 

(Richland, WA) 

Rats: F344/N 

Mice: B6C3F1 

Simonsen Laboratories 

(Gilroy, CA) 

15 days 

7 weeks 

Rats: 23 June 1988 

Mice: 9 June 1988 

6 hours plus T (12 minutes) per day, 5 days 90 

per week, for 104 weeks (rats) (followed by an 

observation period of approximately 11 days), 

or 95 to 96 weeks (mice) 

Rats: 

15-month interim evaluation 

17-18 September 1989 

terminal sacrifice 

14 June 1990 

Mice: 

15-month interim evaluation 

6-7 September 1989 

terminal sacrifice 

4-5 April 1990 

Rats: 

15-month interim sacrifice 

18-19 September 1989 

terminal sacrifice 

25 June 1990 (males) 

or 26-27 June 1990 (females) 

Mice: 

15-month interim sacrifice 

7-8 September 1989 

terminal sacrifice 

5 April 1990 (males) 

or 6 April 1990 (females) 
Tetrafluoroethylene, NTP TR 450 29 

TABLE 1
 

Experimental Design and Materials and Methods in the Inhalation Studies of Tetrafluoroethylene (continued)
 

16-Day Studies 13-Week Studies	 2-Year Studies 

Average Age at Necropsy 

8 weeks 19 weeks Rats: 

15-month interim evaluation - 71 weeks 

terminal sacrifice - 111-112 weeks 

Mice: 

15-month interim evaluation - 72 weeks 

terminal sacrifice - 102 weeks 

Size of Study Groups 

5 males and 5 females	 10 males and 10 females 15-Month interim evaluation: 

(one rat assigned to the 2,500 ppm female 10 males and 10 females 

group was determined to be missexed and was Terminal sacrifice: 

discarded during week 6) 50 males and 50 females (rats) 

or 48 males and 48 females (mice) 

Method of Distribution 

Animals were distributed randomly into Same as 16-day studies Same as 16-day studies 

groups of approximately equal initial mean 

body weight. 

Animals per Cage 

1 1 1 

Method of Animal Identification 

Toe clips and placement within cage unit Same as 16-day studies Rats: Tail tattoos and placement within 

cage unit 

Mice: Toe clips and placement within cage 

unit 

Diet 

NIH-07 pelleted feed (Zeigler Brothers, Inc., Same as 16-day studies Same as 16-day studies 

Gardners, PA); available ad libitum, except 

during exposure periods 

Maximum Storage Time for Feed 

120 days post-milling	 Same as 16-day studies Same as 16-day studies 

Water 

Tap water (Richland municipal supply) via Same as 16-day studies Same as 16-day studies 

automatic watering system (Edstrom 

Industries; Waterford, WI); available 

ad libitum 

Cages 

Stainless steel (Hazleton Systems, Inc., Same as 16-day studies Stainless steel (Lab Products, Inc., Harford 

Aberdeen, MD), changed weekly Division, Aberdeen, Md), changed weekly 

Bedding/Cage Board 

Techsorb®, Shepherd Specialty Papers, Inc. Same as 16-day studies Same as 16-day studies 

(Kalamazoo, MI), used during non-exposure 

periods, 7 days per week 
30 Tetrafluoroethylene, NTP TR 450 

TABLE 1
 

Experimental Design and Materials and Methods in the Inhalation Studies of Tetrafluoroethylene (continued)
 

16-Day Studies 13-Week Studies 2-Year Studies 

Chamber Air Supply Filters 

Duct pre-filter, dual and single HEPA 

(American Air Filter, Louisville, KY); checked 

biannually 

Chambers 

Stainless steel (Hazleton Systems, Inc., 

Aberdeen, MD); changed weekly 

Chamber Environment 

Temperature: 22.3 23.2 C 

Relative humidity: 52.7% 55.4% 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

Exposure Concentrations 

0, 312, 625, 1,250, 2,500, or 5,000 ppm 

Type and Frequency of Observation 

All animals were observed twice daily. 

Clinical findings were recorded two times each 

exposure day. All animals were weighed on 

days 1, 8, 15, and at necropsy. 

Method of Sacrifice 

Anesthetization with sodium pentobarbital 

followed by exsanguination 

Necropsy 

Necropsy performed on all animals. Organs 

weighed were brain, heart, left and right 

kidneys, liver, lung, right testis, and thymus. 

Same as 16-day studies 

Stainless steel (Hazleton Systems, Inc., 

Aberdeen, MD); changed weekly 

Temperature: 23.1 23.7 C 

Relative humidity: 56.1% 60.5% 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

0, 312, 625, 1,250, 2,500, or 5,000 ppm 

All animals were observed twice daily. 

Clinical findings were recorded once weekly 

for rats and mice. The animals were weighed 

before the studies began and weekly thereafter. 

Anesthetization with CO followed by 2 

exsanguination 

Necropsy performed on all animals. Organs 

weighed were brain, heart, right kidney, liver, 

lung, right testis, and thymus. 

Single HEPA (Flanders Filters, Inc., San 

Rafael, CA) and charcoal (RSE, Inc., New 

Baltimore, MI); changed before the studies 

began and once yearly thereafter 

Stainless steel (Lab Products, Inc., Harford 

Division, Aberdeen, MD); changed weekly 

Temperature: 24.1 24.5 C 

Relative humidity: 53% 58% 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

Rats: 

males - 0, 156, 312, or 625 ppm 

females - 0, 312, 625, or 1,250 ppm 

Mice: 

0, 312, 625, or 1,250 ppm 

All animals were observed twice daily. 

Clinical findings were recorded monthly until 

the last 13 weeks (rats) or 5 weeks (mice), 

when they were recorded twice monthly. 

Animals were weighed before the studies 

began, weekly for the first 13 weeks, and 

monthly thereafter, until the last 13 weeks 

(rats) or 5 weeks (mice) when they were 

weighed every 2 weeks. 

Anesthetization with CO followed by 2 

exsanguination 

Necropsy performed on all animals. Organs 

weighed at the 15-month interim evaluation 

were the right kidney, liver, and lung. 
Tetrafluoroethylene, NTP TR 450 31 

TABLE 1
 

Experimental Design and Materials and Methods in the Inhalation Studies of Tetrafluoroethylene (continued)
 

16-Day Studies 13-Week Studies 2-Year Studies 

Clinical Pathology 

Blood was collected from all animals from the Blood was collected from all animals from the At the 15-month interim evaluation, blood was 

retroorbital (rats) or supraorbital (mice) sinus retroorbital (rats) or supraorbital (mice) sinus taken from the retroorbital plexus of rats for 

for hematology analyses. for hematology analyses. Fourteen days (rats) hematology and clinical chemistry analyses. 

Hematology: hematocrit; hemoglobin or 10 days (mice) before the end of the studies, Two weeks prior to the scheduled evaluation, 

concentration; erythrocyte, reticulocyte, animals were placed in metabolism cages (with designated rats were placed in metabolism 

nucleated erythrocyte, and platelet counts; access to water but not food) for a 16-hour cages for a 16-hour urine collection. One 

mean cell volume; mean cell hemoglobin; urine collection. Four days before the end of week prior to the evaluation, rats were again 

mean cell hemoglobin concentration; and the studies, rats were again placed in placed in metabolism cages and were deprived 

leukocyte count and differentials metabolism cages and were deprived of water of water for 16 hours; urine was expressed 

for 16 hours; urine was expressed from the from the bladders of all rats, and urine was 

bladders of all rats, and urine was collected for collected for the following 6 hours while water 

the following 4 hours while water deprivation deprivation continued. 

continued. Hematology: hematocrit; hemoglobin 

Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, 

concentration; erythrocyte and platelet counts; nucleated erythrocyte, and platelet counts; 

mean cell volume; mean cell hemoglobin; mean cell volume; mean cell hemoglobin; 

mean cell hemoglobin concentration; and mean cell hemoglobin concentration; and 

leukocyte count and differentials leukocyte count and differentials 

Urinalysis: fluoride, glucose, and protein Clinical chemistry: urea nitrogen, creatinine, 

concentrations; volume; and specific gravity sodium, potassium, chloride, calcium, and 

phosphorus concentrations 

Urinalysis: glucose and protein 

concentrations; volume; and specific gravity 

Histopathology 

Complete histopathology was performed on Complete histopathology was performed on Complete histopathology was performed on all 

rats and mice exposed to 0 or 5,000 ppm. In rats and mice exposed to 0 or 5,000 ppm. In control and exposed rats and mice. In addition 

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

tissues examined included: adrenal gland, tissues examined included: adrenal gland, examined included: adrenal gland, brain, 

brain, clitoral gland, esophagus, eye (if grossly brain, clitoral gland, esophagus, gallbladder clitoral gland, esophagus, femur, gallbladder 

abnormal), gallbladder (mice only), heart, (mice only), heart, large intestine (cecum, (mice only), heart, large intestine (cecum, 

large intestine (cecum, colon, rectum), small colon, rectum), small intestine (duodenum, colon, rectum), small intestine (duodenum, 

intestine (duodenum, jejunum, ileum), kidney, jejunum, ileum), kidney, larynx, liver, lungs, jejunum, ileum), kidney, liver, lungs, lymph 

larynx, liver, lungs, lymph nodes (bronchial, lymph nodes (bronchial, mandibular, nodes (bronchial, mandibular, mediastinal, 

mandibular, mediastinal, mesenteric), mediastinal, mesenteric), mammary gland, mesenteric), mammary gland, muscle (thigh), 

mammary gland, nose, ovaries, pancreas, nose, ovaries, pancreas, parathyroid gland, nose, oral cavity (larynx and pharynx), 

parathyroid gland, pituitary gland, preputial pituitary gland, preputial gland, prostate gland, ovaries, pancreas, parathyroid gland, pituitary 

gland, prostate gland, salivary gland, skin, salivary gland, skin, spleen, sternebrae gland, preputial gland, prostate gland, salivary 

spleen, sternebrae (including marrow), (including marrow), stomach (forestomach and gland, skin, spleen, sternebrae (including 

stomach (forestomach and glandular), testis, glandular), testis, thymus, thyroid gland, marrow), stomach (forestomach and 

thymus, thyroid gland, trachea, urinary trachea, urinary bladder, and uterus. glandular), testis, thymus, thyroid gland, 

bladder, and uterus. Additionally, the kidney Additionally, the following organs were trachea, urinary bladder, and uterus. 

of all other exposed groups of male and female examined in lower exposure groups: the 

rats and mice was examined, as was the kidney of all exposed groups of male and 

pancreas of male and female rats exposed to female rats and mice (except female rats 

2,500 ppm. exposed to 312 ppm); the cecum of 625 ppm 

male rats; the eye and mandibular lymph node 

of 2,500 ppm female rats; and the thymus and 

lung of 625 ppm male mice. 
32 Tetrafluoroethylene, NTP TR 450 

TABLE 1
 

Experimental Design and Materials and Methods in the Inhalation Studies of Tetrafluoroethylene (continued)
 

16-Day Studies 13-Week Studies 2-Year Studies 

Sperm Morphology and Vaginal Cytology 

None At terminal sacrifice, sperm samples were None 

collected from all male animals in the 0, 312, 

1,250, and 5,000 ppm groups for sperm 

morphology evaluations. The parameters 

evaluated included sperm morphology, 

concentration, and motility. The right cauda, 

right epididymis, and right testis were weighed. 

Vaginal samples were collected for up to 

7 consecutive days prior to the end of the 

studies from all females exposed to 0, 312, 

1,250, or 5,000 ppm for vaginal cytology 

evaluations. The parameters evaluated 

included the relative frequency of estrous 

stages and estrous cycle length. 
 

33 

RESULTS
 

RATS 

16-DAY STUDY 

All rats survived to the end of the study (Table 2). 

The final mean body weights and body weight gains 

of males and females exposed to 5,000 ppm were 

significantly less than those of the controls. The 

mean body weight gain of females exposed to 

2,500 ppm was also significantly less than that of 

the control group. There were no exposure-related 

clinical findings in male or female rats. 

There were no significant differences in hematology 

parameters that were considered to be related to 

TABLE 2 

tetrafluoroethylene exposure (Table G1). Absolute 

and relative left and right kidney weights of all 

exposed groups of males were significantly greater 

than those of the controls (Table F1), as were those 

of females in the 2,500 and 5,000 ppm groups. The 

absolute left and right kidney weight of females 

exposed to 1,250 ppm was also significantly greater 

than that of the controls. All exposed groups of 

males had significantly greater relative liver weights 

than the controls; males in the 625 and 2,500 ppm 

groups also had greater absolute liver weights than 

the controls. Other organ weight differences were 

not considered to be related to chemical exposure. 

Survival and Body Weights of Rats in the 16-Day Inhalation Study of Tetrafluoroethylene 

Exposure 

Concentration 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

312 

625 

1,250 

2,500 

5,000 

5/5 

5/5 

5/5 

5/5 

5/5 

5/5 

120 ± 3 

121 ± 2 

122 ± 1 

119 ± 1 

119 ± 1 

116 ± 2 

167 ± 4 

176 ± 4 

172 ± 3 

165 ± 1 

162 ± 2 

143 ± 3** 

48 ± 1 

55 ± 3 

50 ± 3 

46 ± 1 

43 ± 2 

27 ± 2** 

105 

103 

99 

96 

86 

Female 

0 

312 

625 

1,250 

2,500 

5,000 

5/5 

5/5 

5/5 

5/5 

5/5 

5/5 

98 ± 1 

104 ± 2* 

97 ± 2 

103 ± 1 

100 ± 2 

99 ± 1 

126 ± 3 

131 ± 2 

125 ± 3 

131 ± 3 

119 ± 4 

113 ± 2* 

28 ± 2 

27 ± 2 

28 ± 2 

28 ± 3 

19 ± 3* 

14 ± 1** 

104 

99 

104 

94 

89 

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

** P 0.01 a Number of animals surviving at 16 days/number initially in group b Weights and weight changes are given as mean ± standard error. 
34 Tetrafluoroethylene, NTP TR 450 

Increased incidences of renal tubule degeneration 

occurred in males and females exposed to 625 ppm 

or greater (Table 3). The severity of these lesions 

increased with increasing exposure concentration and 

was slightly greater in males than in females. Renal 

lesions occurred predominantly in the inner cortical 

tubular epithelial cells at the junction of the cortex 

and medulla. Degeneration was characterized by 

inner cortical tubules that contained lumenal debris 

and were lined by cells with vacuolated or eosinophilic cytoplasm. Other tubule epithelial cells had 

occasional dark pyknotic nuclei and shrunken, 

eosinophilic cytoplasm. Associated with renal 

tubule degeneration was regeneration of renal 

cortical tubule 

epithelium, characterized by epithelial cells with 

basophilic cytoplasm, enlarged vesicular nuclei, and 

slightly increased numbers of mitotic figures. The 

increased kidney weights were associated with the 

renal lesions. Histopathologic examination revealed 

no chemical-related lesions in the livers of exposed 

male or female rats. 

Exposure Concentration Selection Rationale: Based 

on the lack of overt toxicity following exposure of 

male and female rats to 5,000 ppm for 16 days, the 

13-week exposure concentrations selected were 0, 

312, 625, 1,250, 2,500, and 5,000 ppm. 

TABLE 3 

Incidences of Nonneoplastic Lesions of the Kidney in Rats in the 16-Day Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Number Examined Microscopically 5 5 5 5 5 5 a b Renal Tubule, Degeneration 0 0 5** (1.0) 5** (1.4) 5** (2.0) 5** (3.0) 

Female 

Number Examined Microscopically 5 5 5 5 5 5 

Renal Tubule, Degeneration 0 0 3 (1.0) 5** (1.2) 5** (1.8) 5** (3.2) 

** Significantly different (P 0.01) from the control group by the Fisher exact test a Number of animals with lesion 

b Average severity grade of lesions in affected rats: 1=minimal; 2=mild; 3=moderate; 4=marked 
Tetrafluoroethylene, NTP TR 450 35 

13-WEEK STUDY 

All rats survived to the end of the study (Table 4); one 

rat in the 2,500 ppm female group was missexed and 

was removed from the study. The final mean bod y 

weight and body weight gain of males and the mea n 

body weight gain of females exposed to 5,000 pp m 

were significantly less than those of the controls . 

There were no clinical findings attributed to exposure 

to tetrafluoroethylene. 

The hematology and clinical chemistry data for rats in 

the 13-week study are presented in Table G2. Exposure to tetrafluoroethylene caused a concentration ­

dependent anemia, evidenced by decreased hematocrit 

values, hemoglobin concentrations, and erythrocyt e 

counts in all exposed groups of males and in female s 

exposed to 5,000 ppm. There were no changes in the 

mean cell volume values of exposed groups of rats , 

indicating the erythrocytes were normocytic. There 

were minimal decreases of the mean cell hemoglobi n 

concentration in males exposed to 1,250 ppm o r 

greater; this did not occur in exposed female rats . 

Decreases in mean cell hemoglobin concentration s 

without alterations in mean cell volumes have bee n 

related to the early stages of iron deficiency. Because 

the mean cell hemoglobin concentration values o f 

exposed groups of male ra ts were well within a normal 

physiological range and no changes occurred in ex ­

posed groups of females, the significance of the mean 

cell hemoglobin concentration alterations was con ­

sidered questionable a nd the erythrocytes were characterized as normochromic. There were no increases in 

reticulocyte counts to indi cate a bone marrow response 

to the anemia. Therefore, the anemia would b e 

characterized as normocytic, normochromic, an d 

nonresponsive. Normocytic, normochromic , 

nonresponsive anemias have been related to selective 

suppression of erythropoiesis in a variety of disorders 

and may be due to decreased erythropoietin 

TABLE 4 

Survival and Body Weights of Rats in the 13-Week Inhalation Study of Tetrafluoroethylene 

Exposure 

Concentration 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

312 

625 

1,250 

2,500 

5,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

116 ± 3 

117 ± 2 

115 ± 2 

114 ± 2 

113 ± 2 

115 ± 3 

328 ± 5 

337 ± 5 

339 ± 4 

330 ± 4 

327 ± 4 

299 ± 6** 

212 ± 3 

220 ± 4 

225 ± 3 

216 ± 4 

214 ± 4 

184 ± 4** 

103 

103 

101 

100 

91 

Female 

0 

312 

625 

1,250 

2,500 

5,000 

10/10 

10/10 

10/10 

10/10 

9/9 

10/10 

91 ± 2 

97 ± 3 

93 ± 2 

95 ± 2 

89 ± 4 

94 ± 2 

185 ± 6 

196 ± 3 

195 ± 5 

192 ± 4 

177 ± 7 

174 ± 4 

94 ± 4 

99 ± 3 

102 ± 5 

97 ± 3 

88 ± 4 

80 ± 3* 

106 

105 

104 

95 

94 

* Significantly different (P 0.05) from the control group by Williams' or Dunnett's 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. 
36 Tetrafluoroethylene, NTP TR 450 

elaboration, bone marrow suppression, or defectiv e 

iron metabolism. 

A concentration-dependent proteinuria occurred in all 

exposed groups of male rat s and in females exposed to 

2,500 or 5,000 ppm. Proteinuria could be related t o 

glomerular or renal tubule injury and is consistent with 

the renal tubule degeneration observed histo ­

pathologically. However, the renal injury did no t 

appear to affect the abi lity of the kidney to concentrate 

the urine, as evidenced by appropriate increases i n 

urine specific gravity in response to a wate r 

concentration test. There was a concentration ­

dependent increase of urinary fluoride excretion in all 

exposed groups of male and female rats, consisten t 

with metabolism and excretion of tetrafluoroethylene. 

A possible polyuria, evidenced by increased 16-hou r 

urine volumes, occurred in males in the 5,000 pp m 

group and in all exposed groups of females. 

The absolute and relative liver weights of all exposed 

groups of males and of females in the 5,000 pp m 

group were significantly greater than those of th e 

controls (Table F2). The absolute and relative righ t 

kidney weights of males and females exposed t o 

1,250 ppm or greater and of females in the 625 ppm 

group were also significantly greater than those of the 

controls. The absolute and relative heart weights o f 

males exposed to 1,250, 2,500, or 5,000 ppm wer e 

generally significantly greater than those of th e 

controls. Other organ weight differences were no t 

considered to be related to chemical exposure. 

There were no differences in sperm morpholog y 

parameters or in the length of estrous cycles betwee n 

control and exposed groups of rats (Tables H1 an d 

H2). 

Incidences of renal tubule degeneration in male s 

exposed to 625 ppm or gre ater and in females exposed 

to 2,500 or 5,000 ppm were significantly greater than 

those in the controls (Table 5). The renal lesions , 

which were similar to those observed in the 16-da y 

study, increased in severity with exposur e 

concentration and were slightly more severe in male s 

than females. Renal lesions were observed at th e 

junction of the cortex and medulla and involved inner 

cortical tubules. Degeneration was characterized b y 

inner cortical tubules that were dilated, containe d 

lumenal debris, and had occasional pyknotic nuclei . 

Associated with degeneration was regeneration , 

characterized by renal tubule epithelial cells that were 

lined by cells with basophilic cytoplasm havin g 

pleomorphic 

TABLE 5 

Incidences of Nonneoplastic Lesions of the Kidney in Rats in the 13-Week Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Number Examined Microscopically 10 10 10 10 10 10 a b Renal Tubule, Degeneration 0 0 10** (1.0) 10** (1.0) 10** (2.0) 10** (2.0) 

Female 

c Number Examined Microscopically 10 — 10 10 9 10 

Renal Tubule, Degeneration 0 0 0 9** (1.0) 10** (2.0) 

** Significantly different (P 0.01) from the control group by the Fisher exact test a Number of animals with lesion 

b Average severity grade of lesions in affected rats: 1=minimal; 2=mild; 3=moderate; 4=marked 

Kidney not examined at this exposure concentration c 
Tetrafluoroethylene, NTP TR 450 37 

nuclei with large, prominent nucleoli, a slightl y 

increased number of mitotic figures, and varyin g 

degrees of karyomegaly. The inc reased kidney weights 

were associated with the renal lesions . 

Histopathologically, there were no chemical-relate d 

lesions in the livers of male or female rats exposed to 

tetrafluoroethylene. 

Exposure Concentration Selection Rationale: Exposure concentrations for the 2-year rat study in male s 

were based on kidney effects. Although the severit y 

and incidence of kidney lesions were identical for male 

rats exposed to 625 or 1,250 ppm, the absolute an d 

relative kidney weights of males e xposed to 1,250 ppm 

were significantly greater than those of the controls . 

Therefore, the highest exposure concentration selected 

was 625 ppm, which was expected to cause minima l 

toxicity in the kidney following 2 years of exposure. 

Although kidney effects were the main toxicologi c 

consideration for exposure concentration selection i n 

the 2-year study in female rats, the highest exposure 

concentration was selected, in part, based on th e 

number of chambers to be used in this inhalatio n 

study. When possible in inhalation studies, males and 

females of a species for each concentration are housed 

in the same chamber. When it is obvious that the same 

exposure concentration will cause more severe effects 

in one sex of the same species, space is sought i n 

chambers housing the other species. In the presen t 

study, concentrations selected for the 2-year mous e 

study were 312, 625, and 1,250 ppm. At the time o f 

selection of concentrations for the mouse study, it was 

believed that female rats could tolerate exposure t o 

2,500 ppm with minimal toxic effects. However, i t 

was decided that an additional chamber solely fo r 

female rats could not be justified economically ; 

therefore, female rats were housed in the sam e 

chambers as mice. In addition, because of th e 

increased absolute and relative kidney weights o f 

females exposed to 625 ppm or greater (even in th e 

absence of histopathologic effects), it was believe d 

that toxicity might occur at 625 or 1,250 ppm . 

Therefore, because there was additional space in th e 

mouse chambers, 1,250 ppm was selected as th e 

highest exposure concentration for the 2-year study in 

female rats. 
38 Tetrafluoroethylene, NTP TR 450 

2-YEAR STUDY 

Survival 

Estimates of 2-year surv ival probabilities for male and 

female rats are shown in Table 6 and in the Kaplan -

Meier survival curves (Figure 1). The survival rates of 

males in the 625 ppm g roup and of all exposed groups 

of females were significantly less than those of th e 

controls. 

Body Weights and Clinical Findings 

Mean body weights of males exposed to 625 ppm were 

lower than those of the con trols from week 81 until the 

end of the study; the mean body weights of male s 

exposed to 156 or 312 ppm and of females exposed to 

312 or 625 ppm were similar to those of 

the controls throughout the study (Figure 2 an d 

Tables 7 and 8). Mean body weights of female s 

exposed to 1,250 ppm were slightly lower than those 

of the controls at the end of the study; the final mean 

body weight of this group was 91% that of th e 

controls. The only clinical finding associated wit h 

exposure to tetrafluoroethylene was opacity of one or 

both eyes in exposed groups of female rats; thi s 

change was observed microscopically as cataracts. 

Hematology, Clinical Chemistry, 

and Urinalysis 

At the 15-month interim evaluation, no differences in 

hematology, clinical chemistry, or urinalysis param ­

eters were considered to be related to tetrafluoro ­

ethylene exposure (Table G3). 
39 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE 6 

Survival of Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Male 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Moribund 27 34 32 48 

Natural deaths 6 4 1 1 

Animals surviving to study termination 

Percent probability of survival at end of studyb 

Mean survival (days)c 

17 

34 

665 

12 

24 

644 

17 

34 

665 

1 

2 

609 

Survival analysesd P<0.001 P=0.216 P=0.829 P<0.001 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Accidental deatha 0 0 0 1 

Moribund 21 33 31 25 

Natural deaths 1 1 4 6 

Animals surviving to study termination 28 16e 15 18 

Percent probability of survival at end of study 56 32 30 37 

Mean survival (days) 694 642 651 620 

Survival analyses P=0.034 P=0.008 P=0.007 P=0.014 

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. e Includes one animal that died during the last week of the study 
40 Tetrafluoroethylene, NTP TR 450 

FIGURE 1
 

Kaplan-Meier Survival Curves for Male and Female Rats Administered Tetrafluoroethylene
 

by Inhalation for 2 Years
 
Tetrafluoroethylene, NTP TR 450 41 

FIGURE 2
 

Growth Curves for Male and Female Rats Administered Tetrafluoroethylene
 

by Inhalation for 2 Years
 
42 Tetrafluoroethylene, NTP TR 450 

TABLE 7 

Mean Body Weights and Survival of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

Weeks 0 ppm 156 ppm 312 ppm 625 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 

1 126 60 126 100 60 126 100 60 125 99 60 

2 176 60 177 101 60 179 102 60 176 100 60 

3 203 60 204 101 60 207 102 60 202 100 60 

4 230 60 231 100 60 234 102 60 229 100 60 

5 250 60 251 100 60 255 102 60 250 100 60 

6 267 60 267 100 60 271 102 60 266 100 60 

7 284 60 285 100 60 289 102 60 283 100 60 

8 298 60 299 100 60 303 102 60 297 100 60 

9 310 60 312 101 60 317 102 60 310 100 60 

10 324 60 327 101 60 329 102 60 323 100 60 

11 329 60 334 102 60 336 102 60 331 101 60 

12 339 60 343 101 60 347 102 60 340 100 60 

13 346 60 350 101 60 353 102 60 346 100 60 

17 375 60 381 102 60 384 103 60 377 101 60 

21 398 60 406 102 60 408 103 60 402 101 60 

25 415 60 422 102 60 424 102 60 420 101 60 

29 430 60 436 101 60 439 102 60 436 101 60 

33 443 60 451 102 60 454 102 60 448 101 60 

37 451 60 462 102 60 465 103 60 456 101 60 

41 455 60 464 102 60 469 103 60 461 101 60 

45 461 60 473 103 60 477 104 60 465 101 60 

49 464 59 478 103 60 484 104 60 475 102 60 

53 465 59 478 103 59 485 104 60 472 101 59 

57 476 58 485 102 59 492 103 60 479 101 59 

61 483 58 489 101 59 497 103 59 480 99 59 

65a 482 48 489 102 48 499 104 49 477 99 49 

69 486 48 492 101 47 504 104 49 484 100 47 

73 481 47 490 102 45 501 104 49 472 98 47 

77 484 45 488 101 43 496 102 49 468 97 42 

81 482 43 485 101 41 493 102 45 447 93 39 

85 483 41 490 101 38 495 103 42 433 90 33 

89 477 39 485 102 30 479 100 36 423 89 22 

91 479 36 485 101 29 481 101 31 419 88 17 

93 476 35 477 100 29 478 101 30 409 86 14 

95 471 34 479 102 26 475 101 28 399 85 11 

97 463 31 473 102 24 469 101 23 390 84 9 

99 456 27 462 102 21 464 102 21 389 85 6 

101 448 24 449 100 17 462 103 20 372 83 4 

103 454 19 452 99 13 450 99 20 359 79 3 

Mean for weeks 

1-13 268 270 101 273 102 268 100 

14-52 432 441 102 445 103 438 101 

53-103 473 479 101 484 102 434 92 

a Interim evaluation occurred during week 65. 
Tetrafluoroethylene, NTP TR 450 43 

TABLE 8 

Mean Body Weights and Survival of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

Weeks 0 ppm 312 ppm 625 ppm 1,250 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 

1 102 60 102 100 60 102 100 60 101 99 60 

2 121 60 121 100 60 121 101 60 119 99 59 

3 132 60 132 100 60 133 101 60 130 99 59 

4 143 60 144 100 60 143 100 60 140 98 59 

5 151 60 151 101 60 152 101 60 149 99 59 

6 159 60 161 101 60 161 101 60 158 99 59 

7 163 60 165 101 60 166 102 60 163 100 59 

8 171 60 173 101 60 174 101 60 170 100 59 

9 174 60 175 101 60 178 102 60 176 101 59 

10 178 60 179 101 60 183 103 60 179 101 59 

11 183 60 184 101 60 188 103 60 185 101 59 

12 186 60 189 102 60 192 103 60 190 102 59 

13 189 60 192 102 60 195 103 60 193 102 59 

17 201 60 203 101 60 207 103 60 203 101 59 

21 209 60 214 102 60 218 104 60 213 102 59 

25 220 60 222 101 60 229 104 60 223 101 59 

29 229 60 232 101 60 238 104 60 232 101 59 

33 236 60 239 101 60 248 105 60 238 101 59 

37 245 60 245 100 59 253 104 60 243 99 59 

41 252 60 255 101 59 265 105 60 251 100 59 

45 262 60 266 102 59 279 106 60 262 100 59 

49 263 60 270 103 59 282 107 60 262 100 59 

53 281 60 287 102 59 300 107 59 279 100 59 

57 290 60 298 103 59 307 106 58 291 100 57 

61 302 60 305 101 58 315 104 58 297 98 57 

65a 301 59 309 103 58 318 106 58 300 100 55 

69 307 48 315 103 46 318 104 45 303 99 43 

73 302 47 310 103 46 316 105 44 296 98 42 

77 314 47 320 102 44 329 105 42 305 97 39 

81 319 46 322 101 40 328 103 41 306 96 38 

85 331 45 330 100 35 335 101 37 313 95 34 

89 330 44 333 101 29 333 101 34 309 94 28 

91 333 43 333 100 28 333 100 33 313 94 25 

93 330 41 333 101 26 326 99 33 310 94 24 

95 333 40 336 101 25 330 99 31 308 93 23 

97 332 39 337 101 24 339 102 25 312 94 21 

99 325 38 339 104 23 339 104 24 312 96 20 

101 336 33 334 100 21 344 102 20 311 93 19 

103 333 30 323 97 20 340 102 19 304 91 19 

Mean for weeks 

1-13 158 159 101 161 102 158 100 

14-52 235 238 101 247 105 236 100 

53-103 318 321 101 326 103 304 96 

a Interim evaluation occurred during week 65. 
 

44 Tetrafluoroethylene, NTP TR 450 

Pathology and Statistical Analyses 

This section describes the statistically significant o r 

biologically noteworthy changes in the incidences o f 

mononuclear cell leukemia and of neoplasms and/o r 

nonneoplastic lesions of the kidney, liver, eye, testis , 

and mammary gland. Summaries of the incidences of 

neoplasms and nonneoplastic lesions, individua l 

animal tumor diagnoses, statis tical analyses of primary 

neoplasms that occurred with an incidence of at leas t 

5% in at least one animal group, and historica l 

incidences for the neoplasms mentioned in this section 

are presented in Appendix A for male rats an d 

Appendix B for female rats. 

Absolute and relative lung weights of exposed groups 

of rats were similar to those of the controls at th e 

15-month interim evaluation (Table F3), and no lung 

lesions related to tetrafluoroethylene exposur e 

occurred. 

Kidney: At the 15-month interim evaluation, th e 

absolute and relative right kidney weights of male s 

exposed to 625 ppm and females exposed t o 

1,250 ppm were significantly greater than those of the 

controls (Table F3). Additionally, the absolute kidney 

weight of females exposed t o 625 ppm and the relative 

kidney weight of males exposed to 312 ppm wer e 

significantly greater than those of the controls. 

At 15 months, renal tubule hyperplasia was observed 

in one male exposed to 312 ppm and in one mal e 

exposed to 625 ppm. At the end of the study, th e 

incidences of renal tubule hyperplasia in male s 

exposed to 625 ppm and of renal tubule adenoma i n 

males exposed to 312 ppm were significantly greate r 

than those in the controls (Tables 9, A3, and A5). The 

combined incidence of renal tubule adenoma o r 

carcinoma in males exposed to 312 or 625 pp m 

exceeded the range in historical controls from 2-yea r 

NTP inhalation studies (Tables 9 and A4a). 

At 15 months, renal tubule hyperplasia was observed 

in one female exposed to 625 ppm. At the end of the 

study, the incidence of renal tubule hyperplasia in 

females in the 1,250 ppm group was significantl y 

greater than that in the controls (Tables 9 and B5); the 

incidences of renal tubule adenoma and renal tubul e 

adenoma or carcinoma (combined) in females exposed 

to 1,250 ppm were also greater than those in th e 

controls (Tables 9 and B3), and the incidence s 

occurred with significant trends. The incidences o f 

renal tubule adenoma or carcinoma (combined) i n 

females exposed to 312 or 1,250 ppm exceeded th e 

range in historical controls (Tables 9 and A4a). 

Initially, a single hematoxylin- and eosin-staine d 

section of each kidney was prepared. Primaril y 

because of the increased incidences of renal tubul e 

hyperplasia, adenomas, and carcinomas that wer e 

observed in some groups in the standard evaluation of 

the 2-year studies, additional step sections of kidne y 

were prepared from the remaining formalin-fixe d 

tissues of interim evaluation an d 2-year study rats. Six 

to ten additional kidney sections taken at 1-m m 

intervals were prepared for each male and female . 

Additional males and females with focal hyperplasia or 

adenomas and one 156 ppm male with a carcinom a 

were identified among rats exposed for 2 years. Th e 

incidences of these proliferative le sions in standard and 

extended evaluations are presented in Table 9. 

At the 2-year extended evaluations and combine d 

standard and extended evaluations, males in th e 

625 ppm group and females in the 1,250 ppm grou p 

had significantly greater incidences of renal tubul e 

hyperplasia, renal tubule adenoma, and renal tubul e 

adenoma or carcinoma (combined) than the control s 

(Tables 9 and A3). In the combined standard an d 

extended evaluations, the incidences of renal tubul e 

hyperplasia in females exposed to 625 ppm and renal 

tubule adenoma in males exposed to 312 ppm wer e 

also significantly greater than those in the controls . 

The incidences renal tubul e adenoma in females and of 

renal tubule adenoma or carcinoma (combined) i n 

males and females occurred with significant positiv e 

trends in the extended and combined standard an d 

extended evaluations. 
Tetrafluoroethylene, NTP TR 450 45 

TABLE 9 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Single Sections (Standard Evaluation) 

Nephropathya 

Renal Tubule, Degeneration 

Renal Tubule, Hyperplasia 

Renal Tubule, Carcinoma 

10 

1 

0 

0 

(1.8)b 

(1.0) 

10 (1.8) 

8** (1.0) 

0 

0 

10 (1.6) 

10** (2.0) 

1 (1.0) 

0 

10 (2.4) 

10** (3.0) 

1 (1.0) 

1 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 0 0 1 (1.0) 0 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Single Sections (Standard Evaluation) 

Nephropathy 

Renal Tubule, Degeneration 

Renal Tubule, Hyperplasia 

Renal Tubule, Hyperplasia, Oncocytic 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinomac 

49 

2 

1 

0 

0 

1 

1 

(2.3) 

(1.0) 

(1.0) 

50 (1.9) 

20** (1.1) 

1 (1.0) 

0 

0 

0 

0 

50 (2.7) 

50** (2.3) 

1 (4.0) 

1 (1.0) 

6* 

2 

6 

50 (3.5) 

49** (3.6) 

6* (1.3) 

0 

3 

0 

3 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinoma 

7 

2 

0 

2 

10 

4 

1 

5 

7 

3 

0 

3 

18** 

11** 

0 

11** 

Single and Step Sections (Combined) 

Renal Tubule, Hyperplasia 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinoma 

7 

2 

1 

3 

11 

4 

1 

5 

7 

9* 

2 

9 

24** 

13** 

0 

13** 

(continued) 
46 Tetrafluoroethylene, NTP TR 450 

TABLE 9 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Single Sections (Standard Evaluation) 

Nephropathy 

Renal Tubule, Degeneration 

Renal Tubule, Hyperplasia 

Renal Tubule, Hyperplasia, Oncocytic 

8 

0 

0 

0 

(1.0) 9 

0 

0 

0 

(1.0) 9 (1.2) 

10** (2.0) 

1 (1.0) 

0 

10 (1.0) 

10** (2.6) 

0 

1 (1.0) 

Renal Tubule, Adenoma 

Mixed Tumor, Malignant 

0 

0 

0 

0 

0 

0 

1 

1 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 0 1 0 4* 

Renal Tubule, Adenoma 0 0 0 2 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Single Sections (Standard Evaluation) 

Nephropathy 

Renal Tubule, Degeneration 

Renal Tubule, Hyperplasia 

Renal Tubule, Hyperplasia, Oncocytic 

48 

0 

1 

0 

(1.7) 

(2.0) 

46 

0 

3 

0 

(1.5) 

(1.7) 

48 (1.7) 

35** (1.3) 

6 (1.2) 

0 

47 (2.0) 

46** (2.0) 

12** (1.8) 

3 (1.0) 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinomad 

0 

0 

0 

3 

0 

3 

1 

0 

1 

3 

2 

5** 

Step Sections (Extended Evaluation) 

Renal Tubule, Hyperplasia 2 3 7 17** 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinoma 

0 

0 

0 

0 

0 

0 

2 

0 

2 

5* 

1 

5* 

Single Sections and Step Sections (Combined) 

Renal Tubule, Hyperplasia 3 6 11* 25** 

Renal Tubule, Adenoma 

Renal Tubule, Carcinoma 

Renal Tubule, Adenoma or Carcinoma 

0 

0 

0 

3 

0 

3 

3 

0 

3 

8** 

3 

10** 

* Significantly different (P 0.05) from the control group by the Fisher exact test (15-month interim evaluation) or the logistic regression test (2-year 

study) 

** P 0.01 a Number of animals with lesion 

b Average severity grade of lesion in affected animals: 1=minimal; 2=mild; 3=moderate; 4=marked
 

Historical incidence for 2-year NTP inhalation studies with chamber control groups at all labs (mean ± standard deviation): 6/652 (0.9% ± 1.3%);
 

range, 0%-4%. Historical incidence for 2-year NTP inhalation studies with chamber control groups at Battelle Pacific Northwest Laboratories: 

5/347 (1.4% ± 1.5%); range, 0%-4% d Historical incidence at all labs: 2/650 (0.3% ± 0.8%); range, 0%-2%. Historical incidence at Battelle Pacific Northwest Laboratories: 2/346 

(0.6% ± 1.0%); range, 0%-2% 

c 
 

Tetrafluoroethylene, NTP TR 450 47 

Renal tubule hyperplasia, as defined in the presen t 

study, was distinguished from regenerative epithelia l 

changes commonly seen as a part of nephropathy and 

was considered a preneoplastic lesion. Renal tubul e 

hyperplasia, adenoma, and carcinoma constitute a 

morphologic continuum. Hyperplasia was generally a 

focal, minimal to mild lesion consisting of tubules that 

were dilated to 1.5 to 2 times the normal diameter and 

were lined by increased numbers of tubule epithelia l 

cells, which partially or totally filled the tubule lumen 

(Plate 1). Cells within hyperplastic lesions varie d 

slightly in size and sometimes stained more basophilic 

than normal cells, but otherwise appeared similar t o 

normal tubule epithelial cells. Renal tubule adenomas 

were larger, discrete lesions, ranging from greater than 

five tubule diameters to 1 mm or mor e in size (Plate 2). 

Cells within adenomas were mildly to moderatel y 

pleomorphic, sometimes had vacuolated cytoplasm , 

and tended to form complex patterns, particularl y 

microtubular structures. Renal tu bule carcinomas were 

differentiated from adenomas in that they usually were 

larger and less discrete and had a more prominen t 

vascular supply and more anaplasia and cellular atypia 

(Plate 3). Renal tubule cell carcinoma was characterized by vesiculate nuclei with prominent nucleoli and 

increased numbers of mitotic figures (Plate 4). 

Oncocytic hyperplasia was observed at the end of the 

study in one male exposed to 312 ppm and in thre e 

females exposed to 1,250 ppm (Tab les 9, A5, and B5). 

This lesion was characterized by individual tubules or 

small clusters of tubules that were somewhat dilate d 

and totally filled by large polygonal cells wit h 

abundant brightly eosin ophilic granular cytoplasm and 

small, centrally located, basophilic nuclei (oncocytes). 

These lesions are thought to arise from the dista l 

tubule epithelium. 

At 15 months and at the end of the study, the inci ­

dences of renal tubule degeneration in all expose d 

groups of males and in females in the 625 an d 

1,250 ppm groups were greater than those in th e 

controls (Tables 9, A5, and B5). Renal tubul e 

degeneration was similar to that observed in th e 

13-week study. Degeneration was characterized b y 

dilatation of renal tubule epithelial cells and wa s 

located predominantly at the corticomedullary junction 

(Plates 5 and 6). Dilated tubules sometimes contained 

eosinophilic debris and/or proteinaceous fluid in their 

lumens. The tubules were lined by flattened t o 

cuboidal epithelium (Plate 6) and often had bot h 

basophilic and eosinophilic cells lining adjacent areas 

of the same tubule. At 15 months, renal tubul e 

degeneration was easily detected; however, in th e 

2-year study, it was sometimes obscured by th e 

presence of concurrent nephropathy. The location o f 

the renal tubule degeneration at the corticomedullar y 

junction was the primary feature which distinguishe d 

this lesion from chronic progressive nephropathy . 

Also lacking in tetrafluoroethylene-induced rena l 

tubule degeneration, but present in chronic progressive 

nephropathy, were thickened basement membranes , 

interstitial fibrosis, inflammatory infiltrates, an d 

prominent protein casts in dilated tubules throughout 

the cortex and medulla. 

The severity of nephropathy generally increased wit h 

increasing exposure concentration in male and female 

rats at 15 months and 2 years, although the increase in 

exposed female rats was not as pronounced. Thes e 

increases were observed at the end of the 2-year study 

in males exposed to 312 or 625 ppm and in female s 

exposed to 1,250 ppm. 

Liver: The absolute and relative liver weights o f 

females in the 1,250 ppm group and the absolute liver 

weight of females exposed to 625 ppm wer e 

significantly greater than those of the controls at th e 

15-month interim evaluation (Table F3). A t 

15 months, all exposed groups of males had signifi ­

cantly greater incidences of clear cell foci than th e 

controls; females exposed to 625 or 1,250 ppm ha d 

significantly greater incidences of mixed cell foci than 

the controls (Tables 10, A5, and B5). At the end o f 

the study, the incidences of eosinophilic foci in al l 

exposed groups of males and of mixed cell foci an d 

basophilic foci in males exposed to 312 or 625 pp m 

were significantly greater than those in the controls, as 

was the incidence of mixed cell foci in female s 

exposed to 1,250 ppm. The incidences of hepatocel ­

lular carcinoma and hepatocellular adenoma o r 

carcinoma (combined) in males exposed to 312 pp m 

were significantly greater than those in the controls at 

the end of the study (Tables 10 and A3). At 2 years, 

the incidences of hepatocell ular adenoma and adenoma 

or carcinoma (combined) in all exposed groups o f 

females were significantly greater than those in th e 

controls, and the incidences occurred with significant 

positive trends (Tables 10 and B3). Additionally , 

females exposed to 312 or 625 ppm had significantly 
48 Tetrafluoroethylene, NTP TR 450 

greater incidences of hepatoc ellular carcinoma than the discrete aggregates of often enlarged hepatocytes, and 

controls at 2 years. The combined incidence o f the lobular pattern of the liver was generally retained. 

hepatocellular neoplasms in each exposed group o f Hepatocellular adenomas consisted of nodules o f 

males and females exceeded the historical contro l hepatocytes which compressed adjacent hepati c 

ranges in chamber controls from 2-year NT P parenchyma and lacked the normal lobular an d 

inhalation studies (Tables 10, A4b, and B4b). Also at sinusoidal pattern (Plate 7). Hepatocellula r 

2 years, the incidence of hemangiosarcoma in females carcinomas consisted of solid sheets of hepatocytes or 

exposed to 625 ppm was significantly greater than in trabeculae, three or more cells thick (Plate 8) . 

the controls. The incidence of liver hemangiosarcoma Neoplastic hepatocytes were anaplastic, with promi ­

in 625 ppm females exceeded the historical range for nent nuclei containing one or more nucleoli an d 

hemangiosarcomas in all organs in control female rats variable amounts of cytoplasm. Hemangiosarcoma s 

from NTP 2-year inhalation studies (Table 10), an d were malignant vascular neoplasms characterized b y 

liver hemangiosarcomas have not been observed i n irregular, vascular spaces filled with erythrocyte s 

historical control females. (Plate 9) and lined by variable numb ers of pleomorphic 

endothelial 

Hepatocellular foci are considered potential preneo ­

plastic lesions. Hepatocellular foci were relatively 

TABLE 10 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 

Basophilic Focusa 10 6 

10 

4 

10 

7 

10 

4 

Clear Cell Focus 4 10** 9* 10** 

Cystic Degeneration 0 1 3 0 

Eosinophilic Focus 1 0 0 1 

Mixed Cell Focus 0 2 2 2 

Hepatocellular Adenoma 0 0 1 0 

Hepatocellular Carcinoma 0 0 0 1 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Basophilic Focus 22 19 33* 29** 

Clear Cell Focus 7 8 11 3 

Eosinophilic Focus 3 18** 22** 19** 

Cystic Degeneration 17 39** 35** 32** 

Mixed Cell Focus 5 5 16** 13** 

Hepatocellular Adenoma 3 6 8 5 

Hepatocellular Carcinoma 

Hepatocellular Adenoma or Carcinomab 

Overall ratec 

Adjusted rated 

Terminal ratee 

1 

4/50 (8%) 

16.3% 

2/17 (12%) 

1 

7/50 (14%) 

34.4% 

3/12 (25%) 

10** 

15/50 (30%) 

62.1% 

9/17 (53%) 

3 

8/50 (16%) 

100.0% 

1/1 (100%) 

First incidence (days) 

Logistic regression testf 

624 

P=0.025 

600 

P=0.223 

617 

P=0.003 

572 

P=0.112 

(continued) 
Tetrafluoroethylene, NTP TR 450 49 

TABLE 10 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Angiectasis 0 1 0 0 

Basophilic Focus 9 9 10 10 

Clear Cell Focus 0 2 3 3 

Eosinophilic Focus 0 5* 2 0 

Mixed Cell Focus 0 1 6** 4* 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Angiectasis 0 9** 9** 14** 

Basophilic Focus 41 38 41 37 

Clear Cell Focus 10 3 12 9 

Eosinophilic Focus 1 4 5* 4 

Mixed Cell Focus 12 14 16 18* 

Hepatocellular Adenoma 0 4* 5** 6** 

Hepatocellular Carcinoma 

Hepatocellular Adenoma or Carcinomag 

0 4* 9** 2 

Overall rate 0/50 (0%) 7/50 (14%) 12/50 (24%) 8/50 (16%) 

Adjusted rate 0.0% 36.3% 65.4% 37.8% 

Terminal rate 

First incidence (days) 

0/28 (0%) 

—h 5/16 (31%) 

583 

9/15 (60%) 

668 

5/18 (28%) 

677 

Logistic regression test P=0.001 P=0.002 P<0.001 P<0.001 

Hemangiosarcomai 

Overall rate 0/50 (0%) 0/50 (0%) 5/50 (10%) 1/50 (2%) 

Adjusted rate 0.0% 0.0% 19.5% 5.0% 

Terminal rate 0/28 (0%) 0/16 (0%) 0/15 (0%) 0/18 (0%) 

First incidence (days) — — 589 703 

Logistic regression test P=0.182 — P=0.025 P=0.435 

* Significantly different (P 0.05) from the control group by the Fisher exact test (15-month interim evaluation) or the logistic regression test (2-year 

study) 

** P 0.01 a Number of animals with lesion 

b Historical incidence for 2-year NTP inhalation studies with chamber control groups at all labs (mean ± standard deviation): 28/653 

(4.3% ± 2.9%); range, 2%-9%. Historical incidence for 2-year NTP inhalation studies with chamber control groups at Battelle Pacific Northwest 

Laboratories: 11/347 (3.2% ± 2.3%); range, 2%-8% c Number of animals with neoplasm per number of animals with liver examined microscopically d Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality e Observed incidence in animals surviving until the end of the study f In the control column are the P values associated with the trend test. In the exposed group columns are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The logistic regression test regards neoplasms in animals dying prior to terminal kill as 

nonfatal. 

g	 Historical incidence at all labs: 10/650 (1.5% ± 2.0%); range, 0%-6%. Historical incidence at Battelle Pacific Northwest Laboratories: 7/346 

(2.0% ± 2.3%); range, 0%-6% h Not applicable; no neoplasms in animal group i Historical incidence for all organs at all labs: 2/653 (0.3% ± 0.8%); range, 0%-2% (incidence in liver: 0/650) 
 

50 Tetrafluoroethylene, NTP TR 450 

cells. Occasionally, hemangiosarcomas metastasized to 

the lung. 

At the end of the 2-year study, increased incidences of 

hepatic cystic degeneration occurred in all exposed 

groups of males, and increased incidences of hepatic 

angiectasis were observed in exposed groups of females 

(Tables 10, A5, and B5). Cystic degeneration was 

characterized by multifocal dilated areas with cysts 

containing fluid, fibrin, and/or erythrocytes; these lesions 

occur spontaneously in aging rats at low incidences but 

are common following chemical exposure to a 

hepatocarcinogen. Hepatic angiectasis was characterized 

by multifocal, dilated, blood-filled sinusoids with 

prominent lining endothelial cells; these lesions are 

sometimes associated with hepatocellular neoplasms. 

Mononuclear Cell Leukemia: Incidences of mononuclear cell leukemia in males exposed to 156 ppm and 

in all exposed groups of females were significantly 

greater than those in the controls (Tables 11, A3, and 

B3), and the incidences occurred with significant positive 

trends in males and females. The incidence of this 

neoplasm in male controls exceeded the historical range 

for all types of leukemia in 2-year NTP inhalation studies 

(Tables 11 and A4c), as did the incidences in males 

exposed to 156 or 312 ppm. However, the incidence in 

females exposed to 0 ppm was within the historical 

control range (Tables 11 and B4c), and the incidences in 

females exposed to 312 or 1,250 ppm exceeded that 

range. 

Eye: The incidence of cataracts in females exposed to 

1,250 ppm was greater than that in the controls at the 

end of the 2-year study (0 ppm, 15/50; 312 ppm, 4/50; 

625 ppm, 10/50; 1,250 ppm, 45/50; Table B5). 

Cataracts were characterized by a disruption of the 

normal organization of lens filters, with swelling, 

vacuolization, and mineralization. 

Testis: At the end of the study, there was a slight 

increase in the incidences of interstitial cell adenoma in 

rats exposed to 312 or 625 ppm (39/50, 40/50, 48/50, 

47/50; Table A3). At 15 months, there were no increases 

in the incidences of interstitial cell hyperplasia or 

adenoma. Interstitial cell hyperplasia and adenomas are 

very common in F344/N rats, and nearly all rats will 

develop such proliferative lesions if allowed to complete 

their natural life span. It is uncertain whether the slightly 

increased incidences of interstitial cell adenoma were 

related to tetrafluoroethylene exposure, although the 

control incidence is within the historical control range for 

2-year NTP inhalation studies with chamber controls 

(450/655; mean ± standard deviation, 68.7% ± 8.7%; 

range, 54%-83%). 

Mammary Gland: At 2 years, the incidences of 

fibroadenoma in the mammary gland of exposed female 

rats were decreased (22/50, 11/50, 9/50, 7/50; 

Table B3). Fibroadenomas are the most common benign 

neoplasm of the mammary gland in the female F344/N 

rat. In other studies, decreases in the incidence of this 

neoplasm have been associated with decreases in body 

weights; however, in the present study, the decreases are 

not related to body weight changes. The biological 

significance of these decreased incidences is uncertain. 
51 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE 11 

Incidences of Mononuclear Cell Leukemia in Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Male 

Mononuclear Cell Leukemia (All Organs)a 

b Overall rate 34/50 (68%) 43/50 (86%) 38/50 (76%) 31/50 (62%) c Adjusted rate 81.5% 95.3% 91.9% 100.0% 

d Terminal rate 10/17 (59%) 10/12 (83%) 14/17 (82%) 1/1 (100%) 

First incidence (days) 509 351 413 509 

Life table teste P<0.001 P=0.016 P=0.231 P<0.001 e Logistic regression test P=0.064N P=0.020 P=0.254 P=0.079N 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

Mononuclear Cell Leukemia (All Organs)f 

Overall rate 16/50 (32%) 31/50 (62%) 23/50 (46%) 36/50 (72%) 

Adjusted rate 43.7% 76.5% 65.1% 82.6% 

Terminal rate 8/28 (29%) 7/16 (44%) 6/15 (40%) 11/18 (61%) 

First incidence (days) 621 468 469 372 

Life table test P<0.001 P<0.001 P=0.008 P<0.001 

Logistic regression test P<0.001 P<0.001 P=0.105 P<0.001 

a Historical incidence for 2-year NTP inhalation studies with chamber control groups at all labs (mean ± standard deviation): 356/655
 

(54.4% ± 8.8%); range, 34%-66%. Historical incidence for 2-year NTP inhalation studies with chamber control groups at Battelle Pacific
 

Northwest Laboratories: 195/348 (56.0% ± 8.7%); range, 38%-66% b Number of animals with neoplasm per number of animals necropsied
 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality d Observed incidence in animals surviving until the end of the study e In the control column are the P values associated with the trend test. In the exposed group columns are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The life table test regards neoplasms in animals dying prior to terminal kill as being 

(directly or indirectly) the cause of death. The logistic regression test regards these neoplasms as nonfatal. A negative trend or a lower incidence in 

an exposure group is indicated byN. f Historical incidence at all labs: 262/653 (40.1% ± 7.2%); range, 30%-54%. Historical incidence at Battelle Pacific Northwest Laboratories: 

146/348 (42.0% ± 7.2%); range, 30%-54% 
52 Tetrafluoroethylene, NTP TR 450 

MICE 

16-DAY STUDY 

All mice survived to the end of the study (Table 12) . 

Final mean body weights and body weight gains of all 

exposed groups of mice were similar to those of th e 

controls. There were no exposure-related clinica l 

findings in male or female mice. 

There were no significant differences in hematolog y 

parameters that were considered to be related t o 

tetrafluoroethylene exposure (Tabl e G4). The absolute 

and relative liver weights of females exposed t o 

5,000 ppm were significantly greater than those of the 

controls, as were the absolute ki dney weight of females 

in that group and the absolute liver weight of females 

in the 2,500 ppm group (Table F4). Other differences 

in organ weights were not considered to be related t o 

chemical exposure. 

Renal tubule karyomegaly was observed in male mice 

exposed to 1,250 or greater, in females in the 2,50 0 

and 5,000 ppm groups, and in one female exposed to 

1,250 ppm; the severity of this lesion increased wit h 

increasing exposure concentration (Table 13). Karyomegaly of renal tubule cells was observed primarily in 

the inner renal cortex and was characterized by nuclei 

that were enlarged, pleomorphic, an d vesicular and that 

had prominent nucleoli. In the areas with karyo ­

megaly, individual tubule epithelial cells had pyknotic 

nuclei consistent with minimal to mild scattere d 

necrosis. 

Exposure Concentration Selection Rationale: Based on 

the lack of overt toxicity foll owing exposure of mice to 

5,000 ppm for 16 days, exposure concentration s 

selected for the 13-week study were 0, 312, 625 , 

1,250, 2,500, and 5,000 ppm. 

TABLE 12 

Survival and Body Weights of Mice in the 16-Day Inhalation Study of Tetrafluoroethylene 

b Exposure Mean Body Weight (g) Final Weight a Concentration Survival Initial Final Change Relative to Controls 

(ppm) (%) 

Male 

0 5/5 22.4 ± 0.3 25.3 ± 0.2 3.0 ± 0.3 

312 5/5 22.6 ± 0.7 25.5 ± 0.7 2.9 ± 0.3 101 

625 5/5 22.2 ± 0.5 24.8 ± 0.6 2.6 ± 0.4 98 

1,250 5/5 21.5 ± 0.7 24.8 ± 1.2 3.4 ± 0.6 98 

2,500 5/5 21.8 ± 0.7 25.7 ± 0.5 3.9 ± 0.2 102 

5,000 5/5 21.8 ± 1.0 25.2 ± 1.0 3.4 ± 0.3 100 

Female 

0 5/5 18.8 ± 0.7 20.8 ± 0.6 2.0 ± 0.6 

312 5/5 18.8 ± 1.2 20.8 ± 1.1 2.0 ± 0.3 100 

625 5/5 18.8 ± 0.3 20.9 ± 0.3 2.1 ± 0.1 101 

1,250 5/5 18.2 ± 1.0 21.0 ± 0.8 2.7 ± 0.5 101 

2,500 5/5 18.9 ± 0.6 21.5 ± 0.7 2.6 ± 0.5 104 

5,000 5/5 18.2 ± 0.4 21.3 ± 0.6 3.1 ± 0.5 103 

a Number of animals surviving at 16 days/number initially in group b Weights and weight changes are given as mean ± standard error. Differences from the control group were not significant by Williams' or Dunnett's 

test. 
Tetrafluoroethylene, NTP TR 450 53 

TABLE 13 

Incidences of Kidney Lesions in Mice in the 16-Day Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Number Examined Microscopically 

Renal Tubule, Karyomegalya 5 0 

5 

0 

5 

0 

5 

5** (1.0)b 

5 

5** (1.2) 

5 

5** (2.4) 

Female 

Number Examined Microscopically 

Renal Tubule, Karyomegaly 

5 

0 

5 

0 

5 

0 

5 

1 (1.0) 

5 

5** (2.0) 

5 

5** (3.0) 

** Significantly different (P 0.01) from the control group by the Fisher exact test a Number of animals with lesion 

b Average severity grade of lesions in affected mice: 1=minimal; 2=mild; 3=moderate; 4=marked 
54 Tetrafluoroethylene, NTP TR 450 

13-WEEK STUDY 

All mice survived to the end of the study (Table 14) . 

Males in the 1,250, 2,500, and 5,000 ppm groups had 

significantly lower initial mean body weights than the 

controls; however, final mean body weights and body 

weight gains of all exposed groups of male and female 

mice were generally similar to those of the controls . 

There were no clinical findings that were considere d 

related to tetrafluoroethylene exposure. 

The hematology and urinalysis data for mice in th e 

13-week inhalation study of tetrafluoroethylene ar e 

presented in Table G5. A normocytic, normochromic, 

nonresponsive anemia, similar to that observed in the 

13-week rat study, occurred in males exposed t o 

2,500 ppm and in male s and females in the 5,000 ppm 

groups. The anemia was evidenced by minima l 

decreases of hematocrit values, hemoglobi n 

concentrations, and erythrocyte counts. There were 

no alterations of mean cell volume or mean cel l 

hemoglobin concentration; thus, the erythrocytes were 

normocytic and normochromic. The lack of a bon e 

marrow response was evidenced by the absence of an 

increase in reticulocyte counts. 

A concentration-dependent polyuria, evidenced b y 

increased 16-hour urine vo lumes, occurred in male and 

female mice exposed to 2,500 or 5,000 ppm. Th e 

increased urine volumes were accompanied b y 

decreased urine specific gravity values; these findings 

are consistent with increased water consumption o r 

lack of urine concentrating ab ility of the kidney. There 

was a concentration-dependent increase of urinar y 

fluoride excretion in all exposed groups of male an d 

female mice, consistent wi th metabolism and excretion 

of tetrafluoroethylene. No biologically significan t 

differences in organ weights were observed. 

TABLE 14 

Survival and Body Weights of Mice in the 13-Week Inhalation Study of Tetrafluoroethylene 

Exposure 

Concentration 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

312 

625 

1,250 

2,500 

5,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

25.5 ± 0.3 

24.9 ± 0.3 

25.0 ± 0.4 

24.0 ± 0.2** 

24.8 ± 0.2** 

24.0 ± 0.2** 

33.6 ± 0.6 

32.4 ± 0.3 

33.6 ± 0.7 

33.3 ± 0.6 

32.6 ± 0.3 

31.6 ± 0.5* 

8.2 ± 0.5 

7.4 ± 0.3 

8.6 ± 0.5 

9.3 ± 0.4 

7.9 ± 0.4 

7.6 ± 0.4 

96 

100 

99 

97 

94 

Female 

0 

312 

625 

1,250 

2,500 

5,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

20.2 ± 0.3 

20.0 ± 0.2 

20.1 ± 0.4 

19.7 ± 0.1 

19.9 ± 0.2 

19.9 ± 0.1 

28.8 ± 0.8 

28.5 ± 0.7 

27.8 ± 0.9 

27.5 ± 0.6 

27.8 ± 0.7 

26.3 ± 0.4 

8.7 ± 0.7 

8.4 ± 0.6 

7.7 ± 0.8 

7.8 ± 0.6 

7.9 ± 0.6 

6.4 ± 0.4 

99 

96 

95 

96 

91 

* Significantly different (P 0.05) from the control group by Williams’ or Dunnett’s 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. 
Tetrafluoroethylene, NTP TR 450 55 

Differences in sperm morphology parameters an d tubule epithelial cells. The severity of the kidne y 

estrous cycle length were not considered to be related lesions was slightly more pronounced in males than in 

to chemical administration (Tables H3 and H4). females. 

Incidences of karyomegaly of the renal tubule epithe- ExposureConcentration Selection Rationale: Based on 

lial cells in male and female mice exposed t o the incidence and severity of kidney lesions in mal e 

1,250 ppm or greater were significantly greater tha n and female mice exposed to 2,500 or 5,000 pp m 

those in the controls (Table 15). As in the 16-da y tetrafluoroethylene, the absence of kidney lesions i n 

study, the renal changes were observed primarily in the mice exposed to 625 ppm, and the absence of kidney 

inner renal cortex. Karyomegaly was characterized by weight effects in exposed groups of mice, exposur e 

nuclei that were enlarged, pleomorphic, and vesicular concentrations selected for the 2-year mouse stud y 

and had large, hyperchromatic, prominent nucleoli. In were 312, 625, and 1,250 ppm. The highes t 

areas of karyomegaly, there was minimal cytomegaly concentration (1,250 ppm) was expected to caus e 

and scattered necrosis of individual minimal toxicity in the 2-year study. 

TABLE 15 

Incidences of Nonneoplastic Lesions of the Kidney in Mice in the 13-Week Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Number Examined Microscopically 

Karyomegalya 10 0 

10 

0 

10 

0 

10 

10** (2.8)b 

10 

10** (2.8) 

10 

10** (3.0) 

Female 

Number Examined Microscopically 

Karyomegaly 

10 

0 

10 

0 

10 

0 

10 

10** (1.8) 

10 

10** (2.8) 

10 

10** (2.2) 

** Significantly different (P 0.01) from the control group by the Fisher exact test a Number of animals with lesion 

b Average severity grade of lesions in affected mice: 1=minimal; 2=mild; 3=moderate; 4=marked 
56 Tetrafluoroethylene, NTP TR 450 

2-YEAR STUDY 

Survival 

Estimates of 2-year surv ival probabilities for male and 

female mice are shown in Table 16 and in the KaplanMeier survival curves (Figure 3). The survival rates of 

all exposed groups of males and females wer e 

significantly less than those of the controls. Because 

of the reduced survival, the study was terminate d 

during week 96. 

TABLE 16 

Body Weights and Clinical Findings 

Mean body weights of exposed groups were generally 

similar to those of the controls except at the end of the 

study, when they were somewhat lower; however, the 

number of exposed mice surviving at the end of th e 

study was considerably less than the number o f 

controls surviving (Tables 17 and 18 and Figure 4) . 

There were no clinical findings related t o 

tetrafluoroethylene exposure. 

Survival of Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Male 

Animals initially in study 58 58 58 58 

15-Month interim evaluationa 10 10 10 10 

Moribund 6 24 26 27 

Natural deaths 4 13 20 20 

Animals surviving to study termination 38 11 2 1 

b Percent probability of survival at end of study 79 23 4 2 

Mean survival (days) c 647 561 554 548 

d Survival analyses P<0.001 P<0.001 P<0.001 P<0.001 

Female 

Animals initially in study 58 58 58 58 

15-Month interim evaluationa 10 10 10 10 

Accidental deatha 0 0 1 0 

Moribund 8 28 26 27 

Natural deaths 4 16 15 17 

Animals surviving to study termination 36 4 6 4 

Percent probability of survival at end of study 75 8 13 8 

Mean survival (days) 643 597 587 560 

Survival analyses P<0.001 P<0.001 P<0.001 P<0.001 

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. 

c 
Tetrafluoroethylene, NTP TR 450 57 

FIGURE 2
 

Growth Curves for Male and Female Rats Administered Tetrafluoroethylene
 

by Inhalation for 2 Years
 
58 Tetrafluoroethylene, NTP TR 450 

TABLE 17 

Mean Body Weights and Survival of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

Weeks 0 ppm 312 ppm 625 ppm 1,250 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 24.1 58 24.0 100 58 24.0 100 58 23.8 99 58 

2 26.6 58 26.7 100 58 26.9 101 58 26.9 101 57 

3 27.4 58 27.7 101 58 27.7 101 58 27.8 102 57 

4 27.7 58 28.2 102 58 28.5 103 58 28.3 102 57 

5 29.0 58 29.8 103 58 29.8 103 58 29.9 103 57 

6 29.7 58 30.5 103 58 30.7 103 58 30.7 103 57 

7 30.2 58 30.8 102 58 31.3 104 58 31.6 105 57 

8 30.9 58 31.9 103 57 31.9 103 58 32.2 104 57 

9 31.8 58 32.6 103 57 33.0 104 58 32.9 104 57 

10 32.3 58 33.1 103 57 33.6 104 58 33.4 103 57 

11 32.9 58 33.7 102 57 34.3 104 58 34.2 104 57 

12 33.6 58 34.5 103 55 34.6 103 58 34.6 103 57 

13 33.4 58 34.2 102 55 34.1 102 58 34.7 104 57 

14 35.2 58 35.9 102 55 35.8 102 58 36.2 103 57 

18 37.0 58 37.9 102 55 38.4 104 58 38.1 103 57 

22 39.1 58 39.3 101 55 39.7 102 58 39.7 102 57 

26 41.3 58 41.9 102 55 42.3 102 58 41.5 101 57 

30 43.6 58 44.0 101 55 44.5 102 58 43.4 100 57 

34 45.3 58 45.9 101 55 45.8 101 58 44.7 99 57 

38 46.3 58 46.9 101 55 46.8 101 58 45.5 98 56 

42 46.2 58 46.6 101 55 46.6 101 58 45.7 99 56 

46 48.1 58 48.1 100 55 47.3 98 58 47.1 98 55 

50 48.5 58 49.0 101 55 48.2 99 58 48.2 99 55 

54 48.7 58 48.5 100 55 47.9 98 56 48.2 99 54 

58 48.4 58 48.9 101 55 48.3 100 56 49.1 101 53 

62 49.5 58 49.3 100 55 48.5 98 54 49.4 100 53 

66a 49.0 47 48.1 98 45 47.6 97 41 49.3 101 43 

70 50.2 46 49.1 98 43 47.8 95 40 49.5 99 41 

74 50.5 46 49.3 98 40 47.9 95 37 49.0 97 41 

78 50.1 45 49.7 99 33 48.8 97 28 48.8 97 34 

82 50.8 44 49.5 97 29 49.6 98 22 46.8 92 26 

86 49.8 42 48.0 96 23 48.3 97 16 46.1 93 18 

90 49.9 41 45.9 92 17 47.9 96 9 44.6 89 7 

92 49.6 40 44.9 91 15 46.5 94 6 

94 49.2 38 44.7 91 12 

Mean for weeks 

1-13 30.0 30.6 102 30.8 103 30.8 103 

14-52 43.1 43.6 101 43.5 101 43.0 100 

53-94 49.6 48.0 97 48.1 97 48.1 97 

a Interim evaluation occurred during week 66. 
Tetrafluoroethylene, NTP TR 450 59 

TABLE 18 

Mean Body Weights and Survival of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

Weeks 0 ppm 312 ppm 625 ppm 1,250 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 19.3 58 19.2 100 58 19.1 99 58 19.2 100 58 

2 21.6 58 21.7 101 58 21.6 100 58 21.6 100 58 

3 22.2 58 22.3 101 58 22.2 100 58 21.8 98 58 

4 22.6 58 22.4 99 58 22.5 100 58 22.6 100 58 

5 23.9 58 24.0 100 58 23.9 100 58 24.1 101 58 

6 24.4 58 24.8 102 58 24.6 101 58 24.8 102 58 

7 25.1 58 25.0 100 58 25.3 101 58 25.1 100 58 

8 25.3 58 25.7 102 58 25.6 101 58 25.4 100 58 

9 26.2 58 26.2 100 58 26.4 101 58 26.3 100 58 

10 26.8 58 26.9 100 58 26.9 100 58 26.8 100 58 

11 27.1 58 27.3 101 58 27.5 102 58 27.3 101 58 

12 27.3 58 28.1 103 58 27.5 101 58 27.6 101 58 

13 27.8 58 27.9 100 58 27.5 99 58 27.7 100 58 

14 29.2 58 29.4 101 58 29.6 101 58 29.1 100 58 

18 30.7 58 30.9 101 58 32.2 105 58 30.5 99 58 

22 34.3 58 34.0 99 58 34.6 101 58 33.3 97 56 

26 36.2 58 36.6 101 58 37.1 103 58 34.4 95 56 

30 38.0 58 39.0 103 58 39.7 105 58 37.0 97 56 

34 40.2 58 40.5 101 58 41.9 104 58 38.3 95 56 

38 41.7 58 42.6 102 58 43.7 105 58 39.8 95 56 

42 43.1 58 43.4 101 58 44.1 102 58 41.8 97 56 

46 45.0 58 45.2 100 58 46.0 102 58 44.0 98 56 

50 45.7 58 46.0 101 58 47.2 103 58 44.2 97 56 

54 47.1 58 47.7 101 58 48.7 103 58 45.8 97 55 

58 48.0 57 49.6 103 58 49.8 104 58 47.3 99 55 

62 51.0 57 51.3 101 58 52.1 102 58 49.5 97 55 

66a 50.9 47 50.6 99 44 51.1 100 48 48.8 96 45 

70 51.8 47 50.7 98 44 50.9 98 43 49.1 95 42 

74 51.6 46 50.4 98 43 49.8 97 40 48.7 94 39 

78 51.9 45 51.8 100 38 51.6 99 35 49.5 95 35 

82 52.0 44 50.7 98 35 49.4 95 31 48.3 93 28 

86 50.7 41 48.8 96 32 50.0 99 22 47.1 93 17 

90 49.6 38 45.7 92 20 48.2 97 18 41.4 84 10 

92 50.9 37 43.8 86 14 49.2 97 13 41.3 81 7 

94 50.5 37 50.8 101 7 40.1 79 4 

Mean for weeks 

1-13 24.6 24.7 100 24.7 100 24.6 100 

14-52 38.4 38.8 101 39.6 103 37.2 97 

53-94 50.5 49.2 97 50.1 99 46.4 92 

a Interim evaluation occurred during week 66. 
60 Tetrafluoroethylene, NTP TR 450 

FIGURE 4
 

Growth Curves for Male and Female Mice Administered Tetrafluoroethylene
 

by Inhalation for 2 Years
 
 

Tetrafluoroethylene, NTP TR 450 61 

Pathology and Statistical Analyses 

This section describes the statistically significant o r 

biologically noteworthy changes in the incidences o f 

histiocytic sarcoma and of neoplasms and/or nonneoplastic lesions of the liver, kidney, and spleen. Sum ­

maries of the incidences of neo plasms 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 anima l 

group, and historical incidences for the neoplasm s 

mentioned in this section are presented in Appendix C 

for male mice and Appendix D for female mice. 

At the 15-month interim evaluation, absolute an d 

relative lung weights of exposed groups of mice were 

similar to those of the cont rols (Table F6), and no lung 

lesions related to tetrafluoroethylene exposure oc ­

curred. 

Liver: At the 15-month interim evaluation, absolut e 

and relative liver weights of exposed groups of mic e 

were similar to those of the controls (Table F6). A t 

15 months and at the end of the study, vascular neo ­

plasms and nonneoplastic lesi ons occurred in the livers 

of exposed male and female mice. At the 15-mont h 

interim evaluation, hemangiosarcomas occurred i n 

three males exposed to 1,250 ppm and in one femal e 

exposed to 312 ppm (Tables 19, C1, and D1). At the 

end of the study, the incidences of hemangioma i n 

males and females exposed to 312 ppm and in male s 

exposed to 625 ppm were significantly greater tha n 

those in the controls (Tables 19, C3, and D3); th e 

incidences of hemangioma in all exposed groups o f 

males and in females exposed to 312 or 625 pp m 

exceeded the range in hist orical chamber controls from 

2-year NTP inhalation studies (Tables 19, C4a, an d 

D4a). The incidences of hemangiosarcoma in al l 

exposed groups of males and females were signifi ­

cantly greater than those in the controls and exceeded 

the historical control ranges. The incidences occurred 

with a significant positive trend in males and females. 

Multiple hemangiomas occurred in all exposed groups 

of males and females except females in the 1,250 ppm 

group, and multiple hemangiosarcomas occurred in all 

exposed groups of males and females. 

Hemangiomas are benign, vascular neoplasms characterized by dilated vascular spaces (Plate 10), with a n 

increase in the number of neoplastic endothelial cell s 

(Plate 11). Hemangiosarc omas are malignant vascular 

neoplasms characterized by large, irregular, cavernous 

spaces filled with erythrocytes and masses of fibri n 

(Plate 12) and lined by variable numbers of pleomorphic endothelial cells which form fronds, solid sheets 

(Plate 13), or vascular channels around and withi n 

extensive areas of thrombosis and necrosis. Although 

there were high incidences of hepatic hemangiosarcomas in all groups of exposed mice, incidences of thi s 

neoplasm in other organs were low. Hemangiosarcomas were observed in the lung, mesentery, pancreas , 

ovary, bone marrow, and subcutaneo us tissues of a few 

mice exposed to tetrafluoroethylene, and all of thes e 

mice had hepatic hemangiosarcomas. It was not clear 

whether the few extra-hepa tic hemangiosarcomas were 

metastases or whether they arose concomitantly i n 

extra-hepatic sites. There were no hemangiosarcomas 

in the liver or in other organs of control mice. 

At 15 months and at the end of the studies, increased 

incidences of angiectasis occurred in all expose d 

groups of males and females (Tables 19, C5, and D5). 

Angiectasis is charact erized by dilated vascular spaces 

of sinusoids in which the endothelial cells are normal 

in morphology and number, and the lesion is com ­

monly observed following exposure to a hepato ­

carcinogen. 

At 15 months, hepatocellular adenomas and carci ­

nomas occurred in all control and exposed groups o f 

males, but only in exposed groups of female s 

(Tables 19, C1, and D1). Additionally, the incidences 

of eosinophilic foci were significantly greater i n 

females exposed to 625 or 1,250 ppm than in th e 

controls (Tables 19 and D5). At the end of the study, 

the incidence of hepatocellular adenoma in female s 

exposed to 625 ppm was signifi cantly greater than that 

in the controls and exceeded the historical contro l 

range from 2-year NTP inhalation studies. Multipl e 

hepatocellular adenomas occurred in all control an d 

exposed groups of males and females, and the inci ­

dences in exposed females were significantly 
62 Tetrafluoroethylene, NTP TR 450 

TABLE 19 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 

Angiectasisa 10 0 

10 

1 

10 

5* 

10 

2 

Eosinophilic Focus 0 0 3 0 

Necrosis, Coagulative, Multifocal 1 1 0 1 

Hemangiosarcoma 0 0 0 3 

Hepatocellular Adenoma 6 2 4 1 

Hepatocellular Adenoma, Multiple 1 0 2 0 

Hepatocellular Carcinoma 2 4 2 2 

2-Year Study 

Number Examined Microscopically 48 48 48 48 

Angiectasis 0 6** 10** 13** 

Eosinophilic Focus 1 6 7* 7* 

Necrosis, Coagulative, Multifocal 4 3 13* 11* 

Hemangiomab 0 10** 5* 2 

Hemangioma, Multiple 

Hemangiosarcomac 0 

0 

7** 

21** 

2 

27** 

1 

37** 

Hemangiosarcoma, Multiple 0 16** 17** 18** 

Hemangioma or Hemangiosarcoma 0 26** 30** 38** 

Hepatocellular Adenoma 17 17 12 20 

Hepatocellular Adenoma, Multiple 6 6 7 7 

Hepatocellular Carcinoma 11 20** 33** 26** 

Hepatocellular Carcinoma, Multiple 

Hepatocellular Adenoma or Carcinomad 

4 

26 

9** 

34** 

9** 

39** 

6* 

35** 

(continued) 
63 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE 19 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Angiectasis 0 4* 2 1 

Eosinophilic Focus 0 1 4* 5* 

Hemangiosarcoma 0 1 0 0 

Hepatocellular Adenoma 0 2 3 2 

Hepatocellular Adenoma, Multiple 0 0 0 1 

Hepatocellular Carcinoma 0 3 1 3 

2-Year Study 

Number Examined Microscopically 48 48 47 47 

Angiectasis 1 9* 6 4 

Eosinophilic Focus 5 13* 12** 7 

Hematopoietic Cell Proliferation 3 19** 13 15** 

Hemangiomae 0 5* 2 1 

Hemangioma, Multiple 

Hemangiosarcomaf 

0 

0 

1 

27** 

1 

27** 

0 

34** 

Hemangiosarcoma, Multiple 0 8** 12** 15** 

Hemangioma or Hemangiosarcoma 0 31** 28** 35** 

Hepatocellular Adenoma 15 17 20* 15 

Hepatocellular Adenoma, Multiple 1 7** 9** 7** 

Hepatocellular Carcinoma 4 28** 22** 20** 

Hepatocellular Carcinoma, Multiple 

Hepatocellular Adenoma or Carcinomag 

0 

17 

5** 

33** 

7** 

29** 

7** 

28** 

*	 Significantly different (P 0.05) from the control group by the Fisher exact test (15-month interim evaluation), the logistic regression test (2-year 

study, nonneoplastic lesions and benign neoplasms), or the life table test (2-year study malignant neoplasms and combined incidences, benign and 

malignant) 

** P 0.01 a Number of animals with lesion 

b Historical incidence for 2-year NTP inhalation studies with chamber control groups at all labs (mean ± standard deviation): 2/947 (0.2% ± 0.7%);
 

range, 0%-2%. Historical incidence for 2-year NTP inhalation studies with chamber control groups at Battelle Pacific Northwest Laboratories: 

1/448 (0.2% ± 0.7%); range, 0%-2%
 

Historical incidence at all labs: 12/947 (1.3% ± 1.7%); range, 0%-6%. Historical incidence at Battelle Pacific Northwest Laboratories: 2/448
 

(0.5% ± 0.9%); range, 0%-2% d Historical incidence at all labs: 358/947 (37.8% ± 12.5%); range, 11%-60%. Historical incidence at Battelle Pacific Northwest Laboratories: 

186/448 (41.5% ± 9.2%); range, 30%-60% e Historical incidence at all labs: 1/937 (0.1% ± 0.5%); range, 0%-2%. Historical incidence at Battelle Pacific Northwest Laboratories: 0/446 f Historical incidence at all labs: 5/937 (0.5% ± 1.0%); range, 0%-3%. Historical incidence at Battelle Pacific Northwest Laboratories: 2/446 

(0.5% ± 0.9%); range, 0%-2% 

g	 Historical incidence at all labs: 200/937 (21.3% ± 11.9%); range, 3%-54%. Historical incidence at Battelle Pacific Northwest Laboratories: 

95/446 (21.3% ± 14.8%); range, 6%-54% 
64 Tetrafluoroethylene, NTP TR 450 

increased compared to the controls. The incidences of 

hepatocellular carcinoma in all exposed groups o f 

males and females were significant ly greater than those 

in the controls and exceeded the historical contro l 

ranges (Tables 19, C4a, and D4a). 

Multiple hepatocellular carcinomas occurred in al l 

groups of males, including controls. However, i n 

female mice, multiple hepatocellular carcinomas were 

observed only in the exposed groups. The combine d 

incidences of hepatocel lular adenomas and carcinomas 

in exposed males and females were significantl y 

greater than those in the controls and exceeded th e 

historical control ranges. The incidences in males and 

females occurred with significant positive trends . 

Hepatocellular adenomas consisted of nodules o f 

hepatocytes that compressed adjacent liver paren ­

chyma and lacked the normal lobular and sinusoida l 

pattern (Plate 14). Hepatocellular carcinomas con ­

sisted of solid sheets of hepatocytes or trabeculae , 

three or more cells thick (Plate 15). Neoplasti c 

hepatocytes were anaplastic, with prominent nucle i 

containing one or more nucleoli and variable amounts 

of cytoplasm. Frequently, carcinomas had multipl e 

foci of necrosis, hemor rhage, and thrombi. Also at the 

end of the study, females exposed to 312 or 625 ppm 

had significantly greater incide nces of eosinophilic foci 

than the controls (Tables 19 and D5). 

At 15 months, coagulative multifocal necrosis of th e 

liver occurred in one control male , one male exposed to 

312 ppm, and one male exposed to 1,250 pp m 

(Tables 19 and C5). At the end of the study, inci ­

dences of coagulative multifocal necrosis wer e 

significantly greater in males exposed to 625 o r 

1,250 ppm than in the controls. Also at the end of the 

study, all exposed groups of females had greate r 

incidences of 

hematopoietic cell proliferation of the liver than th e 

controls, and the increases in females exposed to 312 

or 1,250 ppm were significant (Tables 19 and D5) . 

Both coagulative multifocal necrosis an d 

hematopoietic cell proliferation are often associate d 

with malignant neoplasms in the liver of mice. 

Hematopoietic System: At the end of the study, th e 

incidences of histiocytic sarcoma (all organs) in al l 

exposed groups of males and females were signifi ­

cantly greater than those in the controls (Tables 20 , 

C3, and D3). The incidences of histiocytic sarcoma in 

all exposed groups of male and female mice exceeded 

the historical control ranges for all organs (Tables 20, 

C4b, and D4b). Although the incidences of thi s 

neoplasm were increased in exposed groups of males 

and females, females had higher incidences than males. 

The highest incidences of histiocytic sarcoma wer e 

observed in the liver and lung, and lower incidence s 

were observed in the spleen, lymph nodes, bon e 

marrow, and kidney. The neoplastic histiocytic cell s 

infiltrated the liver diffusely, but sometimes forme d 

nodular patterns (Plate 16). Marked variations in the 

size and shape of the neoplastic cells and nuclei an d 

the high cytoplasmic-to-nuclear ratio wer e 

distinguishing characteristics. Neoplastic cells ha d 

abundant eosinophilic cytoplasm, and nuclei wer e 

hyperchromatic and sometimes bean shaped (Plate 17). 

Occasional giant cells were present. In the lung , 

marked perivascular infiltrate s of neoplastic histiocytic 

cells were observed, and neoplastic cells were als o 

present in vascular spaces. M any mice with histiocytic 

sarcomas had cytoplasmic eosinophilic droplets i n 

renal tubule epithelial cells; this is consistent wit h 

other studies in which an association between rena l 

tubule hyaline droplet and lysozyme accumulation i n 

mice with histiocytic sarcomas has been demonstrated. 
65 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE 20 

Incidences of Histiocytic Sarcoma in Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Male 

Livera 0/48 (0%) 12/48 (25%) 7/48 (15%) 7/48 (15%)

Lung 0/48 (0%) 7/48 (15%) 4/48 (8%) 3/48 (6%)
 

Spleen 0/48 (0%) 2/48 (4%) 1/46 (2%) 2/46 (4%)
 

Mesenteric Lymph Node 0/47 (0%) 4/42 (10%) 1/41 (2%) 2/40 (5%)
 

Bone Marrow 0/48 (0%) 1/48 (2%) 1/47 (2%) 2/47 (4%)
 

Kidney 0/48 (0%) 3/48 (6%) 3/48 (6%) 2/48 (4%)
 

All Organsb 

a Overall rate	 0/48 (0%) 12/48 (25%) 7/48 (15%) 7/48 (15%) c Adjusted rate	 0.0% 47.8% 35.1% 65.8% 

d Terminal rate	 0/38 (0%) 1/11 (9%) 0/2 (0%) 0/1 (0%) f First incidence (days) — 513 415 527 

Life table teste P<0.001 P<0.001 P<0.001 P<0.001 e Logistic regression test	 P=0.100 P<0.001 P=0.039 P=0.004 

Female 

Liver 1/48 (2%) 21/48 (44%) 19/47 (40%) 18/47 (38%) 

Lung 1/48 (2%) 16/48 (33%) 13/47 (28%) 13/47 (28%) 

Uterus 1/48 (2%) 0/48 (0%) 0/45 (0%) 0/47 (0%) 

Spleen 1/48 (2%) 7/48 (15%) 8/46 (17%) 9/47 (19%) 

Mesenteric Lymph Node 1/43 (2%) 6/40 (15%) 7/41 (17%) 6/43 (14%) 

Bone Marrow 0/48 (0%) 6/48 (13%) 5/46 (11%) 4/47 (9%) 

Kidney 1/48 (2%) 7/48 (15%) 4/47 (9%) 3/47 (6%) 

All Organsg 

Overall rate 1/48 (2%) 21/48 (44%) 19/47 (40%) 18/48 (38%) 

Adjusted rate 2.1% 77.6% 51.3% 78.2% 

Terminal rate 0/36 (0%) 1/4 (25%) 0/6 (0%) 1/4 (25%) 

First incidence (days) 400 429 457 484 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.015 P<0.001 P<0.001 P<0.001 

a Number of animals with neoplasm per number of animals examined microscopically b Historical incidence for 2-year NTP inhalation studies with chamber control groups at all labs (mean ± standard deviation): 6/950 (0.6% ± 1.2%);
 

range, 0%-4%. Historical incidence for 2-year NTP inhalation studies with chamber controls at Battelle Pacific Northwest Laboratories: 2/450
 

(0.4% ± 0.9%); range, 0%-2%.
 

Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality d Observed incidence in animals surviving until the end of the study e In the control column are the P values associated with the trend test. In the exposed group columns are the P values corresponding to pairwise 

comparisons between the controls and that exposed group. The life table test regards neoplasms in animals dying prior to terminal kill as being 

(directly or indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. f Not applicable; no neoplasms in animal group 

g	 Historical incidence at all labs: 26/941 (2.8% ± 3.1%); range, 0%-10%. Historical incidence at Battelle Pacific Northwest Laboratories: 14/447 

(3.1% ± 3.0%); range, 0%-8% 
 

66 Tetrafluoroethylene, NTP TR 450 

Kidney: At the 15-month interim evaluation, absolute 

and relative kidney weights of exposed groups of male 

and female mice were similar to those of the controls 

(Table F6). Significantly increased incidences of renal 

tubule dilatation and karyomegaly were observed in male 

mice exposed to 625 or 1,250 ppm at 15 months 

(Tables 21 and C5). At the end of the study, the 

increased incidences of these lesions in exposed groups 

of males were generally significant. These increased 

incidences were considered to be related to exposure to 

tetrafluoroethylene. The severity of renal tubule 

dilatation was slightly increased at the end of the study in 

males exposed to 1,250 ppm. Karyomegaly was similar 

to that observed in the 13-week study and was most 

TABLE 21 

prominent in the inner renal cortex (Plates 18 and 19). 

Dilated renal tubules were filled with eosinophilic 

amorphous material and were lined by flattened epithelium (Plates 20 and 21). Karyomegaly in renal tubule 

cells was characterized by nuclei that were enlarged, 

pleomorphic, and vesicular and had large, prominent, 

hyperchromatic nucleoli (Plate 20). At 15 months, 

karyomegaly was present in females exposed to 625 or 

1,250 ppm, but at the end of the study, this lesion was 

observed only in females in the 1,250 ppm group. 

Tubule dilatation was not present in female mice at 

15 months or at the end of the study. At the interim 

evaluation, tubule changes were more clearly 

Incidences of Nonneoplastic Lesions of the Kidney in Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 

Renal Tubule, Dilatationa 

Renal Tubule, Karyomegaly 

10 

0 

0 

10 

0 

0 

10 

6** (1.0) b 

4* (1.0) 

10 

10** (1.2) 

10** (1.0) 

2-Year Study 

Number Examined Microscopically 

Renal Tubule, Dilatation 

Renal Tubule, Karyomegaly 

48 

0 

1 (1.0) 

48 

4** (1.0) 

2 (1.0) 

48 

16** (1.0) 

10** (1.0) 

48 

36** (1.4) 

28** (1.0) 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 

Renal Tubule, Karyomegalyc 10 0 

10 

0 

10 

10** (1.0) 

10 

10** (2.0) 

2-Year Study 

Number Examined Microscopically 

Renal Tubule, Karyomegalyc 48 0 

48 

0 

47 

0 

48 

38** (1.8) 

* Significantly different (P 0.05) from the control group by the Fisher exact test (15-month interim evaluation) or the logistic regression test (2-year 

study) 

** P 0.01 a Number of animals with lesion 

b Average severity grade of lesion in affected mice: 1=minimal; 2=mild; 3=moderate; 4=severe
 

Results of a special review
 c 
Tetrafluoroethylene, NTP TR 450 67 

defined; however, by the end of the study, the changes associated with the presence of malignant neoplasms in
 

were sometimes obscured by concurrent age-related the livers of affected mice.
 

background lesions (i.e., inflammation). Karyomegaly
 

was located in the tubules in the inner renal cortex.
 

Spleen: Incidences of hematopoietic cell proliferation in GENETIC TOXICOLOGY
 

all exposed groups of males and females were signifi- No increases in the frequency of micronucleated
 

cantly greater than those in the controls at the end of the normochromatic erythrocytes were observed in peripheral
 

study (Tables 22, C5, and D5). Additionally, the severity blood samples obtained from male and female mice at the
 

of this lesion increased with increasing exposure concen- end of the 13-week inhalation study of tetrafluoroethylene
 

tration. Hematopoietic cell proliferation was frequently (Table E1).
 

TABLE 22 

Incidences of Nonneoplastic Lesions of the Spleen in Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 

Hematopoietic Cell Proliferationa 10 2 (2.0)b 

10 

4 (2.0) 

10 

5 (1.6) 

10 

3 (1.7) 

2-Year Study 

Number Examined Microscopically 

Hematopoietic Cell Proliferation 

48 

14 (2.1) 

48 

32* (2.7) 

46 

41** (2.9) 

46 

42** (3.0) 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 

Hematopoietic Cell Proliferation 

10 

2 (1.5) 

10 

4 (1.8) 

10 

4 (1.5) 

10 

3 (2.0) 

2-Year Study 

Number Examined Microscopically 

Hematopoietic Cell Proliferation 

48 

18 (2.1) 

48 

39** (2.8) 

46 

41** (2.9) 

47 

41** (2.9) 

* Significantly different (P 0.05) from the control group by the logistic regression test 

** P 0.01 a Number of animals with lesion 

b Average severity grade of lesion in affected mice: 1=minimal; 2=mild; 3=moderate; 4=severe 
 

 

 

 

 

 

 

PLATE 1 

Kidney of a male F344/N rat exposed to 312 ppm tetrafluoroethylene by inhalation 

for 2 years. Hyperplasia is focal. Note that the renal tubule is lined by increased 

numbers of tubule epithelial cells, which totally fill the tubule lumen. H&E; 33× 

PLATE 3 

Renal tubule carcinoma in the kidney of a female F344/N rat exposed to 

1,250 ppm tetrafluoroethylene by inhalation for 2 years. Note the carcinoma is 

much larger, less discrete, and has a more prominent vascular supply than the 

adenoma in Plate 2. H&E; 6.6× 

PLATE 2 

Renal tubule adenoma in the kidney of a male F344/N rat exposed to 625 ppm 

tetrafluoroethylene by inhalation for 2 years. Note the adenoma is greater than five 

renal tubules in diameter and neoplastic cells are mildly pleomorphic and tend to form 

irregular clusters. H&E; 33× 

PLATE 4 

Higher magnification of Plate 3. Note neoplastic cells are arranged in irregular 

clusters and are characterized by vesiculate nuclei with prominent nucleoli and 

increased mitotic figures (arrow). H&E; 100× 
 

 

 

 

PLATE 5 PLATE 6 

Renal tubule degeneration (arrows) in a male F344/N rat exposed to 625 ppm Higher magnification of Plate 5 at the corticomedullary junction. Degeneration is 

tetrafluoroethylene by inhalation for 2 years. Degeneration is characterized by characterized by dilatation of renal tubules with or without eosinophilic debris and/or 

dilatation of renal tubules in the cortex near the corticomedullary junction, with or proteinaceous fluid in their lumens. The renal tubules are lined by cuboidal 

without eosinophilic debris and/or proteinaceous fluid in their lumens. H&E; 5× epithelium. H&E; 66× 
 

 

 

 

 

PLATE 7 

Hepatocellular adenoma in the liver of a female F344/N rat exposed to 312 ppm 

tetrafluoroethylene by inhalation for 2 years. Note the hepatocellular adenoma 

caused compression of the adjacent liver parenchyma (arrows), and the adenoma 

lacks normal lobular architecture. H&E; 16× 

PLATE 9 

Hemangiosarcoma in the liver of a female F344/N rat exposed to 625 ppm 

tetrafluoroethylene by inhalation for 2 years. Note the irregular, vascular spaces 

(arrow) containing variable numbers of erythrocytes. This hemangiosarcoma 

metastasized to the lung. H&E; 33× 

PLATE 8 

Hepatocellular carcinoma from a male F344/N rat exposed to 312 ppm 

tetrafluoroethylene by inhalation for 2 years. The high magnification shows the 

trabecular pattern, three or more cells thick. Note the prominent mitotic figures 

(arrow). H&E; 66× 
 

 

 

PLATE 10 PLATE 11 

Hemangioma (arrows) in the liver (L) of a male B6C3F1 mouse exposed to Higher magnification of Plate 10 showing the dilated sinusoids with an increased 

312 ppm tetrafluoroethylene by inhalation for 2 years. H&E; 6.6× number of neoplastic endothelial cells (arrows). H&E; 66× 

PLATE 12
 

Hemangiosarcoma in the liver of a male B6C3F1 mouse exposed to 1,250 ppm 

tetrafluoroethylene by inhalation for 2 years. Note the large, irregular, cavernous 

spaces filled with erythrocytes (arrows). H&E; 5× 

PLATE 13
 

Higher magnification of Plate 12, showing sheets of anaplastic, pleomorphic, 

endothelial cells that efface the liver parenchyma with only a few hepatocytes 

remaining (arrows). H&E; 80× 
 

 

 

 

 

PLATE 14 

Hepatocellular adenoma in the liver of a male B6C3F1 mouse exposed to 

1,250 ppm tetrafluoroethylene by inhalation for 2 years. Note the hepatocellular 

adenoma caused compression of the adjacent liver parenchyma (arrows), and the 

adenoma lacks normal lobular architecture. H&E; 10× 

PLATE 16 

Histiocytic sarcoma in the liver of a male B6C3F1 mouse exposed to 1,250 ppm 

tetrafluoroethylene by inhalation for 2 years. Note the nodular (arrows) and 

infiltrative (arrowheads) nature of the neoplastic cells between hepatic plates. H&E; 

25× 

PLATE 15 

Hepatocellular carcinoma from a male B6C3F1 mouse exposed to 1,250 ppm 

tetrafluoroethylene by inhalation for 2 years. The high magnification shows the 

trabecular pattern, three or more cells thick. Note the prominent mitotic figures 

(arrows). H&E; 80× 

PLATE 17 

Higher magnification of Plate 16. Note the neoplastic cells have abundant 

eosinophilic cytoplasm and nuclei are hyperchromatic and sometimes bean-shaped. 

H&E; 100× 
 

 

 

 

 

 

 

PLATE 18 

Kidney of a male B6C3F1 mouse exposed to 1,250 ppm tetrafluoroethylene for 

2 years. Compare to kidney from a control mouse in Plate 19. Renal tubule 

dilatation (arrows) and karyomegaly were most prominent at the junction between 

the cortex (C) and medulla (M). H&E; 5× 

PLATE 20 

Higher magnification of Plate 18 at the corticomedullary junction. Note the dilated 

renal tubules are filled with eosinophilic amorphous material and lined by flattened 

epithelium (arrows). Karyomegaly in renal tubule cells was characterized by nuclei 

that were enlarged and had prominent nucleoli (arrowhead). Compare with kidney 

from a control mouse in Plate 21. H&E; 66× 

PLATE 19 

Kidney from a male B6C3F1 mouse exposed to filtered air for 2 years. Note the 

lack of tubular dilatation at the junction between the cortex (C) and medulla (M). 

H&E; 5× 

PLATE 21 

Higher magnification of Plate 19. Note the lack of tubular dilatation and 

karyomegaly. H&E; 66× 
68 Tetrafluoroethylene, NTP TR 450 
69 

DISCUSSION AND CONCLUSIONS
 

Tetrafluoroethylene was evaluated for toxicity an d 

carcinogenicity in 16-day, 13-week, and 2-year studies 

in male and female F344/N rats and B6C3F 1 mice, 

with whole body inhalation as the route of exposure. 

In the 16-day studies, there were no exposure-relate d 

deaths, clinical findings, or effects on hematologi c 

parameters. Mean body weights of male and femal e 

rats exposed to 5,000 ppm were lower than those o f 

the controls. Absolute kidney weights of all exposed 

groups of male rats, female rats ex posed to 1,250 ppm, 

and female mice exposed to 5,000 ppm were greate r 

than those of controls. Relative liver weights of al l 

exposed groups of male rats and of female mic e 

exposed to 5,000 ppm were also greater than those of 

the controls; however, there were no histopathologi c 

effects in the liver. There were exposure concentra ­

tion-related effects on the kidneys of exposed rats and 

mice, although the effects were different between th e 

species. In rats, the kidney lesion (renal tubule degeneration) was located predominantl y in the inner cortical 

tubule epithelial cells at the junction of the cortex and 

medulla and was observed in male and female rat s 

exposed to 625 ppm or greater. This lesion has been 

observed previously in rats exposed to tetrafluoro ­

ethylene and other halogenated compounds and is well 

documented in the literature. In mice, the lesion wa s 

characterized as renal tubule karyomegaly; however, it 

was also located primarily in the inner renal cortex. 

In the 13-week studie s, there were no exposure-related 

deaths or clinical findings. Mean body weight gains of 

male and female rats exposed to 5,000 ppm wer e 

marginally reduced. Although there were no treat ­

ment-related lesions in the livers of exposed rats o r 

mice, absolute and rel ative liver weights of female rats 

exposed to 5,000 ppm and all exposed groups of male 

rats were significantly increased. Absolute and relative 

kidney weights of male rats exposed to 1,250 ppm or 

greater and females exposed to 625 ppm or greate r 

were significantly increased. Absolute and relativ e 

kidney weights of exposed mice were not significantly 

different from those of the controls. 

Exposure concentration-related renal lesions similar to 

those observed in the 16-day study were observed i n 

male rats exposed to 625 ppm or greater and in female 

rats in the 2,500 and 5,000 ppm groups. These lesions 

were considered mild at most. As with exposed rats , 

mice exposed to 1,250 ppm or greater in the 13-week 

study also developed kidney lesions similar to thos e 

observed in mice at 16 days, and these lesions wer e 

slightly more severe in males than in females. A 

concentration-related proteinuria occurred in al l 

exposed groups of rats with kidney lesions. Protein ­

uria could be related to either glomerular or proximal 

tubule renal injury and, in the present study, would be 

consistent with the renal tubule degeneration observed 

morphologically. Polyuria occurred in exposed mic e 

and probably in rats and could be re lated to a variety of 

conditions, including overdrinking, osmotic diuresis , 

damage to the proximal and/or distal portions of th e 

renal tubule, and alterations of metabolism or kidne y 

response to antidiuretic hormone (Finco, 1989). Based 

on an appropriate response to a water concentratio n 

test (rats only), the ability of the kidney to concentrate 

the urine was not compromised, indicating that th e 

pituitarykidney ADH axis was intact and that ther e 

was no medullary washout (which could occur wit h 

conditions such as long-term overhydration o r 

hyperadrenocorticism). Therefore, the renal damag e 

observed morphologically, although different for rats 

and mice, would appear to involve primarily th e 

proximal convoluted tubules. 

An exposure concentration-dependent normocytic , 

normochromic, nonresponsive anemia occurred i n 

exposed rats and mice in the 13-week studies . 

Normocytic, normochromic, nonresponsive anemia s 

have been related to selective suppression of erythropoiesis in a variety of chronic disorders and may b e 

related to decreased erythropoietin elaboration, bon e 

marrow suppression, or defective iron metabolis m 

(Jain, 1986). Because there was histopathologi c 

evidence of exposure concentration-dependent rena l 

lesions in male and female rats and mice, the anemi a 

would be consistent with a second ary hypoproliferative 
70 Tetrafluoroethylene, NTP TR 450 

anemia, possibly related to altered erythropoieti n 

production/metabolism in the kidney. 

In the 2-year study, survival was reduced in male rats 

exposed to 625 ppm and in all exposed female rats . 

Mean body weights of exposed rats were generall y 

similar to those of the controls until the end of th e 

study, at which time mean body weights were lower in 

males in the 625 ppm group and females in th e 

1,250 ppm group than in the controls. These reduc ­

tions reflected the mean body weights of a very small 

number of surviving rats. The only exposure-relate d 

clinical finding was eye opacity in female rats, whic h 

upon histological examination was determined to b e 

cataracts. At the 15-month interim evaluation, relative 

kidney weights of male rats exposed to 312 o r 

625 ppm and absolute kidney and liver weights o f 

females exposed to 625 or 1,250 ppm were signifi ­

cantly greater than those of the controls. 

The renal toxicity noted in male and female rats in the 

13-week study was exacerbated in the 2-year study in 

that exposure to tetrafluoroethylene caused increase d 

incidences of neoplasms and nonneoplastic lesions of 

the kidney in rats. As in the 13-week studies, rena l 

tubule degeneration was associated with the proximal 

tubules at the corticomedullary junction, and th e 

incidence was significantly increased at 15 months and 

2 years. The only difference between the two tim e 

points was that the renal lesions were generally mor e 

severe and more numerous after 2 years. 

Additional sections of the kidney were taken to further 

evaluate the renal proliferative effects. These sections 

did detect additional proli ferative lesions and generally 

confirmed the findings of the single sections . 

Exposure to tetrafluoroethylene caused significantl y 

increased incidences of hyperplasia at 15 months and 

2 years in male and female rats. In the combine d 

extended and standard evaluations, the incidences o f 

renal tubule adenoma or carcinoma (combined) wer e 

significantly increased, w ith positive trends in exposed 

males and females. Because these neoplasms, whic h 

are considered uncommon, occurred consistently an d 

because the incidences increased with increasin g 

exposure concentration, the neoplasms are considered 

to have been caused by tetrafluoroethylene exposure . 

Similarly, increased incidences of renal tubul e 

hyperplasia, adenoma, and carcino ma in male rats have 

been reported following inhalation exposure to 20 0 

and 400 ppm tetrachloroeth ylene, a structurally related 

compound (NTP, 1986). In addition, incidences o f 

karyomegaly were significantly increased in male and 

female rats exposed to tetrachloroethylene. 

Considerable effort has been expended in the pas t 

10 years investigating the mechanism o f 

tetrafluoroethylene-induced renal proximal tubul e 

toxicity, primarily in rats (Odum and Green, 1984 ; 

Boogaard et al., 1989; Commandeur et al., 1989; 

Hayden et al., 1991a,b), and that induced by othe r 

halogenated compounds. Tetrafluoroethylene i s 

conjugated in the liver with glutathione and sub ­

sequently excreted via the bile to the small intestine , 

where biliary and intestinal peptidases degrade them to 

cysteine-S-conjugates which may be reabsorbed from 

the small intestine. Glutathione conjugates release d 

into the general circulation from the liver are als o 

hydrolyzed to cysteine-S-conjugates by renal pepti ­

dases, where they are bioactivated by renal -lyase to 

unstable reactive thiols. The tetrafluoroethylen e 

cysteine conjugate, S-(1,1,2,2-tetrafluoroethyl) ­

L-cysteine, and tetrafluoroethylene mercapturic aci d 

have been shown to cause renal damage in vivo 

identical to that caused by tetrafluoroethylene and t o 

have greater enzyme activation activity than severa l 

chlorinated or brominated compounds; additionally , 

exposure to these compounds causes thei r 

accumulation in the proximal tubule cell s 

(Commandeur et al., 1989). Like tetrafluoroethylene, 

they are not mutagenic. The tetrafluoroethylen e 

cysteine conjugate has also been shown to cause death 

to cultured human proximal tubule cells, as indicate d 

by the release of lactate dehydrogenase. Toxicity and 

binding to macromolecules in human renal cells can be 

prevented with aminooxyacetic acid, a known -lyase 

inhibitor; this process has also been demonstrated for 

rat renal cells (Chen et al., 1990). In rats, the cysteine 

conjugate is further bioactivated in the kidney and, to 

a lesser extent, in the liver to a difluorothionacety l 

fluoride, the putative reactive metabolite fo r 

tetrafluoroethylene-induced nephrotoxicity. Th e 

thionacetyl fluorides cause mitochondrial dysfunction 

by inhibiting adenosine diphosphate-stimulate d 

respiration, increasing lipid peroxidation, modifyin g 

mitochondrial proteins (HSP60 and HSP70), an d 

inhibiting lipoyl dehydrogenase; by binding t o 

macromolecules; and by forming protein an d 

phospholipid adducts. The difluorothioamide adduc t 

has been shown to cause nephrotoxicity in th e 
 

Tetrafluoroethylene, NTP TR 450 71 

proximal tubule. Considering the similarity in effects oral route of exposure. Hepatic angiectasis, characterand location of renal lesions in the present 2-yea r ized by multifocal, dilated, blood-filled sinusoids with 

inhalation studies and the metabolism and toxicit y prominent lining endothelial cells, was observed i n 

studies reported in the literature, similar metabolite s exposed groups of female rats. This lesion is some ­

and common mechanisms may be involved in th e times associated with hepatocellular neoplasms . 

carcinogenic response in the kidney of tetrafluoro - Cystic degeneration of the liver occurs at a low inci ­

ethylene-exposed animals. dence in aging rats; however, following exposure o f 

rats to hepatocarcinogens, the incidence has bee n 

Although no liver lesions were observed in th e shown to be increased. In fact, the incidences of cystic 

13-week studies, exposure to tetrafluoroethylene fo r degeneration in exposed groups of male rats wer e 

2 years caused increased incidences of nonneoplasti c significantly greater than the control group incidence. 

lesions and uncommon neoplasms of the liver in rats; 

these neoplasmsinclude hemangiosarcomas, which have The incidence of mononuclear cell leukemia in mal e 

not been observed previously in chamber control rats rats exposed to 156 ppm was significantly greater than 

from 2-year NTP inhalation studies. Hepatocellula r in controls. In males, interpretation of the increase d 

foci (including clear cell, eosinophilic, and mixed cell) incidence of mononuclear cell leukemia is complicated 

were observed in rats at the 15-month interim evalua- by reduced survival in rats exposed to 625 ppm an d 

tion. At 2 years, the incidences of eosinophilic an d the fact that the control incidence exceeded the previmixed cell foci were significantly increased in exposed ous historical chamber contr ol range. The incidence of 

male rats and slightly increased in exposed female rats. mononuclear cell leukemia in male rats exposed t o 

At 15 months, one male exposed to 312 ppm had a 312 ppm, although not significantly greater than tha t 

hepatocellular adenoma and one male exposed t o in the control group, also exceeded the previou s 

625 ppm had a hepatocellular carcinoma. At the end historical range. Whether this response in male rat s 

of the 2-year study, male rats in the 312 ppm grou p was caused by tetrafluoroethylene exposure is uncer ­

had significantly increased inc idences of hepatocellular tain. However, there was a significant increase in the 

carcinoma and hepatocellular adenoma or carcinom a incidence of mononuclear cell leukemia in all exposed 

(combined); in females, the incidences of hepatocel - groups of female rats. The incidence of mononuclear 

lular adenoma and hepatocellular adenoma or carci - cell leukemia in female controls from the present study 

noma (combined) in all exposed groups and th e was within the historical control range. The increased 

incidences of hepatocellular carcinoma in the 312 and incidence of mononuclear cell leukemia in female rats 

625 ppm groups were significantly greater than those is considered to have been caused by exposure t o 

in the controls. There were no adenomas or carci - tetrafluoroethylene. Exposure to tetrachloroethylen e 

nomas in control females. The incidences of hepato - for 2 years (NTP, 1986) also caused an increase in the 

cellular adenoma or carcinoma (combined) occurre d incidence of mononuclear cell leukemia in male an d 

with positive trends in exposed males and females , female F344/N rats exposed to 200 or 400 ppm. 

even though the 8% incidence in the control male rats 

in the present study exceeds the previous highes t At 15 months, there were no increases in the incidence 

incidence of 4% for inhalation chamber controls. The of interstitial adenoma or interstitial cell hyperplasia . 

fact that fewer hepatocellular neoplasms occurred i n At the end of the 2-year study, there was a slight bu t 

male and female rats expos ed to the highest concentra- statistically significant increase in the incidence o f 

tions (625 ppm for males, 1,250 ppm for females) than interstitial cell adenoma in the testes of rats exposed to 

in rats exposed to lower con centrations may be a result 312 or 625 ppm. It is uncertain whether these in ­

of reduced survival. Also, the highest exposur e creased incidences of adenomas were due to tetra ­

concentration for males was half that for females. fluoroethylene exposure; however, there was a similar 

slight but significant increase in the incidence o f 

Exposure to tetrafluoroethylene also caused heman - interstitial cell adenomas in F344/N rats exposed t o 

giosarcomas of the liver in female rats. These uncom- 200 or 400 ppm tetrachloroethylene for 2 years (NTP, 

mon liver neoplasms have not been observed previ - 1986). 

ously in male or female chamber controls from 2-year 

NTP inhalation studies or in untreated controls by any 
72 Tetrafluoroethylene, NTP TR 450 

Exposure to tetrafluoroethylene for 2 years caused a 

significant increase in the incidence of cataracts i n 

female rats exposed to 1,250 ppm. The lesion wa s 

characterized by a disruption of the normal organization of lens fibers, with swelling, vacuolization, an d 

mineralization. 

In the 2-year mouse study, survival was reduced in all 

exposed male and female mice to the extent that th e 

study was terminated at week 96. The reduction i n 

survival was considered to be the result of exposure ­

related neoplasms of the liver. Mean body weights of 

exposed mice were generally similar to those o f 

controls except at the end of the study, where survival 

was significantly decreased. 

As observed in the 2-year rat study, exposure of mice 

to tetrafluoroethylene caused significant increases i n 

the incidences of nonneopl astic lesions and uncommon 

neoplasms of the liver in mice at 15 months an d 

2 years. Exposure to tetrafluoroethylene cause d 

hemangiomas in the liver of mal e and female mice, and 

multiple hemangiomas were observed in males an d 

females. These uncommon neoplasms were no t 

observed in control mice. Hemangiosarcomas caused 

by exposure to tetrafluoroethylene were observed a s 

early as 15 months in males in the 1,250 ppm grou p 

and females in the 312 ppm group. Hemangiosarco ­

mas occurred with statistically significant incidence s 

and with a positive trend in all groups of expose d 

males and females. The inc idences of multiple hemangiosarcomas were significant in all exposed groups of 

males and females. In a few males and females, th e 

hemangiosarcomas metastasized to the lung. Hemangiosarcomas were not observed in male or femal e 

control mice. The incidences of hemangioma o r 

hemangiosarcoma (combined) we re also highly significant and occurred with a positive trend for expose d 

groups of males and females. Hemangiomas an d 

hemangiosarcomas are uncommon neo-plasms in mice 

in studies using such routes as fee d or dosed water, and 

the historical incidences of these neoplasms in un ­

treated mice from 2-year NTP feed and dosed wate r 

studies are similar to those for inhalation chambe r 

control mice. The rarity of these neoplasms furthe r 

accentuates the striking results of the present study . 

These uncommon neoplasms probably had a signifi ­

cant effect on the surviv al of mice in the present study. 

Although exposure to 100 or 200 ppm tetrachloro ­

ethylene for 2 years caused increased incidences o f 

hepatocellular adenoma and carcinoma in male an d 

female mice, there were no exposure-related increases 

in hemangioma or hemangi osarcoma incidences (NTP, 

1986). However, chronic inhalation exposure to vinyl 

chloride (chloroethylene) has caused heman ­

giosarcomas and hepatocellular adenomas and carci ­

nomas in several strains of rats, mice, and hamster s 

(IARC, 1979, 1987). More importantly, a number of 

epidemiologic studies have shown that worker s 

exposed to vinyl chloride have higher mortality rate s 

and a high incidence of neoplasms in the liver, brain , 

lung, and lymphatic and hematopoietic systems, al l 

attributed to vinyl chloride exposure. Neoplasm s 

observed in the liver of these workers include hemangiosarcomas and hepatocellular adenomas and carci ­

nomas. Liver neoplasms caused by vinyl chlorid e 

exposure in laboratory anim als and humans are similar 

to those observed in rats and mice exposed t o 

tetrafluoroethylene. 

Angiectasis, eosinophilic foci, and coagulative multifocal necrosis of the liver were observed at 15 months 

and were significantly increased in incidence an d 

severity at 2 years. The incidences of hepatocellula r 

adenoma or carcinoma (combined) were increased i n 

all exposed groups of male mice and were signifi ­

cantly greater in all exposed groups of female mic e 

than in the control group. Many animals had multiple 

adenomas or carcinomas. In all exposed groups, th e 

incidences of multiple adenomas and multiple carci ­

nomas in female mice and mu ltiple carcinomas in male 

mice were significantly increased. A number of th e 

carcinomas in exposed males and females, but onl y 

one carcinoma in each of the male and female control 

groups, metastasized to the lung. Incidences o f 

hepatocellular adenoma, carcinoma, and adenoma o r 

carcinoma (combined) in contr ol male and female mice 

were within the historical ranges in chamber contro l 

mice from 2-year NTP inhalation studies. Th e 

increased incidences of these neoplasms in expose d 

male and female mice were considered to be exposure 

related. A low frequency (15%) of H- ras codon 61 

mutations was observed in tetrafluoroethylene-induced 

hepatocellular neoplasms when compared to th e 

frequency in neoplasms in controls (59%) or i n 

spontaneous liver neoplasms of B6C3F 1 mice (56%) 

(Appendix L). This frequency is similar to tha t 

detected in liver neoplasms in B6C3 F1 mice exposed to
___________ 

Tetrafluoroethylene, NTP TR 450 73 

tetrachloroethylene (24%) (Anna et al., 1994). 

Although a few neoplasms in the tetrachloroethylen e 

study were found to have a K-ras mutation, none were 

found in neoplasms in the tetrafluoroethylene study . 

These data indicate that these two hepatocellula r 

carcinogens induce liver neoplasms via a rasindependent pathway. 

The incidence of histiocytic sarcoma was markedl y 

increased in exposed male mice and significantl y 

increased in all female mice, although not in a n 

exposure concentration-related manner. Among mice 

with any histiocytic sarcomas, histiocytic sarcoma s 

were present in the liver of all animals and in the lung 

of many animals. The spleen, lymph nodes, bon e 

marrow, and kidney were also affected. Combine d 

with the hepatocellular adenomas and carcinomas , 

hemangiomas, and hemangio sarcomas, the presence of 

histiocytic sarcomas in exposed mice compromise d 

liver function, ultimately leading to the death of th e 

mice. 

In the 13-week mouse study, renal tubule karyomegaly, 

accompanied by a polyuria, occurred in male an d 

female mice exposed to 1,250 ppm or greater and was 

the only consideration for exposure concentratio n 

selection for the 2-year study. Although there were no 

kidney neoplasms in exposed groups of mice as were 

observed in the 2-year rat study, there wer e 

significantly increased incidences of renal tubul e 

dilatation in exposed males and renal tubule karyo ­

megaly, located in the tubules in the inner cortex, i n 

males and females. These lesions were observed a t 

15 months as well as at the end of the study. I n 

general, only the incidences of these lesions increased 

over the course of the study, while the severitie s 

remained essentially uncha nged; in fact, the severity of 

karyomegaly was similar to that observed in th e 

13-week study at the same exposure concentration . 

Although these lesions were observed in all expose d 

groups of males at the end of the study, incidences of 

karyomegaly were observed only in 1,250 pp m 

females; however, this group had a high incidence. As 

in the 13-week study, males were affected more tha n 

females, and the increased incidences of bot h 

nonneoplastic lesions were considered to be related to 

exposure to tetrafluoroethylene. The effect o f 

tetrafluoroethylene exposure on the kidney of mice is 

very similar to the effects of exposure to 100 o r 

200 ppm tetrachloroethylene for 2 years (NTP, 1986), 

in that tetrachloroethylene caused increased incidences 

of karyomegaly in male and female mice withou t 

causing increased incidences of kidney neoplasms. 

CONCLUSIONS 

Under the conditions of these 2-y ear inhalation studies, 

there was clear evidence of carcinogenic activity* of 

tetrafluoroethylene in male F344/N rats based o n 

increased incidences of renal t ubule neoplasms (mainly 

adenomas) and hepatocellular neo-plasms. There was 

clear evidence of carcinogenic activity of 

tetrafluoroethylene in female F344/N rats based o n 

increased incidences of renal tubule neoplasms, live r 

hemangiosarcomas, hepatocellular neoplasms, an d 

mononuclear cell leukemia. There was clear evidence 

of carcinogenic activity of tetrafluoroethylene in male 

and female B6C3F1 mice based on increase d 

incidences of liver hemangiomas an d 

hemangiosarcomas, hepatocellular neoplasms, an d 

histiocytic sarcomas. 

Slight increases in the incidences of mononuclear cell 

leukemia and testicular interstitial cell adenomas i n 

male rats may have been related to exposure t o 

tetrafluoroethylene. 

Exposure of rats to tetrafluoroethylene resulted i n 

increased incidences of renal tubule hyperplasia an d 

degeneration in males and females, increased severity 

of kidney nephropathy in males, and increase d 

incidences of liver angiectasis and cataracts in females. 

Exposure of mice to tetrafluoroethylene resulted i n 

increased incidences of hematop oietic cell proliferation 

of the liver in females, liver angiectasis in males an d 

females, renal tubule dilatation in males, renal tubule 

karyomegaly in males and females, and spleni c 

hematopoietic cell proliferation in males and females. 

* Explanation of Levels of Evidence of Carcinogenic Activity is on page 12. A summary of the Technical Reports Review Subcommittee comments 

and the public discussion on this Technical Report appears on page 14. 
74 Tetrafluoroethylene, NTP TR 450 
75 

REFERENCES
 

Anna, C.H., Maronpot, R.R., Pereira, M.A.,
 

Foley, J.F., Malarkey, D.E., and Anderson, M.W.
 

(1994). ras Proto-oncogene activation in
 

dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice. 

Carcinogenesis 15, 2255-2261.
 

Armitage, P. (1971). Statistical Methods in Medical
 

Research, pp. 362-365. John Wiley and Sons,
 

New York.
 

Boogaard, P.J., Commandeur, J.N.M., Mulder, G.J.,
 

Vermeulen, N.P.E., and Nagelkerke, J.F. (1989). 

Toxicity of the cysteine S-conjugates and mercapturic
 

acids of four structurally related difluoroethylenes in
 

isolated proximal tubular cells from rat kidney. Uptake
 

of the conjugates and activation to toxic metabolites. 

Biochem. Pharmacol. 38, 3731-3741.
 

Boorman, G.A., Montgomery, C.A., Jr., Eustis, S.L.,
 

Wolfe, M.J., McConnell, E.E., and Hardisty, J.F.
 

(1985). Quality assurance in pathology for rodent
 

carcinogenicity studies. In Handbook of Carcinogen
 

Testing (H.A. Milman and E.K. Weisburger, Eds.),
 

pp. 345-357. Noyes Publications, Park Ridge, NJ.
 

Bretherick, L. (1985). Handbook of Reactive Chemical Hazards, 3rd ed., p. 1348. Butterworths, Boston,
 

MA.
 

Bruschi, S.A., West, K.A., Crabb, J.W., Gupta, R.S.,
 

and Stevens, J.L. (1993). Mitochondrial HSP60 (P1
 

protein) and a HSP70-like protein (Mortalin) are major
 

targets for modification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteine-induced nephrotoxicity. J. Biol.
 

Chem. 268, 23,157-23,161.
 

Chen, J.C., Stevens, J.L., Trifillis, A.L., and 

Jones, T.W. (1990). Renal cysteine conjugate -lyasemediated toxicity studied with primary cultures of 

human proximal tubular cells. Toxicol. Appl. 

Pharmacol. 103, 463-473. 

Chen, Q., Yu, K., and Stevens, J.L. (1992). Regulation of the cellular stress response by reactive 

electrophiles. The role of covalent binding and cellular 

thiols in transcriptional activation of the 70-kilodalton 

heat shock protein gene by nephrotoxic cysteine 

conjugates. J. Biol. Chem. 267, 24,322-24,327. 

Code of Federal Regulations (CFR) 21, Part 58. 

Commandeur, J.N.M., Brakenhoff, J.P.G., de Kanter, 

F.J.J., and Verneulen, N.P.E. (1988). Nephrotoxicity 

of mercapturic acids of three structurally related 

2,2-difluoroethylenes in the rat. Biochem. Pharmacol. 

37, 4495-4504. 

Commandeur, J.N.M., de Kanter, F.J.J., and 

Vermeulen, N.P.E. (1989). Bioactivation of the 

cysteine-S-conjugate and mercapturic acid of tetrafluoroethylene to acylating reactive intermediates in the 

rat: Dependence of activation and deactivation 

activities on acetyl coenzyme A availability. Mol. 

Pharmacol. 36, 654-663. 

Commandeur, J.N.M., Stijntjes, G.J., Wijngaard, J., 

and Vermeulen, N.P.E. (1991). Metabolism of 

L-cysteine S-conjugates and N-(trideuteroacetyl)­

L-cysteine S-conjugates of four fluoroethylenes in the 

rat. Role of balance of deacetylation and acetylation in 

relation to the nephrotoxicity of mercapturic acids. 

Biochem. Pharmacol. 42, 31-38. 
76 Tetrafluoroethylene, NTP TR 450 

Cox, D.R. (1972). Regression models and life-tables. 

J. R. Stat. Soc. B34, 187-220. 

Dilley, J.V., Carter, V.L., Jr., and Harris, E.S. (1974). 

Fluoride ion excretion by male rats after inhalation of 

one of several fluoroethylenes or hexafluoropropene. 

Toxicol. Appl. Pharmacol.27, 582-590. 

Ding, X.Z., Yu, H.T., Hu, M., Liu, C.F., and Ko, F.Z. 

(1980). Studies on the absorption, distribution, and 

elimination of four organofluorine compounds in 

rabbits. Chung Hua Yu Fang I Hsueh Tsa Chih14, 

39-42. 

Dinse, G.E., and Haseman, J.K. (1986). Logistic 

regression analysis of incidental-tumor data from 

animal carcinogenicity experiments. Fundam. Appl. 

Toxicol. 6, 44-52. 

Dinse, G.E., and Lagakos, S.W. (1983). Regression 

analysis of tumour prevalence data. Appl. Statist. 32, 

236-248. 

Dixon, W.J., and Massey, F.J., Jr. (1951). Introduction to Statistical Analysis, 1st ed., pp. 145-147. 

McGraw-Hill Book Company, New York. 

Dunn, O.J. (1964). Multiple comparisons using rank 

sums. Technometrics 6, 241-252. 

Dunnett, C.W. (1955). A multiple comparison 

procedure for comparing several treatments with a 

control. J. Am. Stat. Assoc. 50, 1096-1121. 

Finco, D.R. (1989). Kidney function. In Clinical 

Biochemistry of Domestic Animals(J.J. Kaneko, Ed.), 

4th ed., pp. 496-542. Academic Press, Inc., San 

Diego, CA. 

Galloway, S.M., Armstrong, M.J., Reuben, C., 

Colman, S., Brown, B., Cannon, C., Bloom, A.D., 

Nakamura, F., Ahmed, M., Duk, S., Rimpo, J., 

Margolin, B.H., Resnick, M.A., Anderson, B., and 

Zeiger, E. (1987). Chromosome aberrations and sister 

chromatid exchanges in Chinese hamster ovary cells: 

Evaluations of 108 chemicals. Environ. Mol. 

Mutagen. 10 (Suppl. 10), 1-175. 

Gart, J.J., Chu, K.C., and Tarone, R.E. (1979). Statistical issues in interpretation of chronic bioassay tests 

for carcinogenicity. J. Natl. Cancer Inst. 62, 957-974. 

Gosselin, R.E., Hodge, H.C., Smith, R.P., and 

Gleason, M.N. (1984). Clinical Toxicology of Commercial Products: Acute Poisoning, Vol. II, p. 412. 

Williams and Wilkins, Baltimore, MD. 

Green, T., and Odum, J. (1985). Structure/activity 

studies of the nephrotoxic and mutagenic action of 

cysteine conjugates of chloro- and fluoro-alkenes. 

Chem.-Biol. Interact. 54, 15-31. 

Groves, C.E., Hayden, P.J., Lock, E.A., and 

Schnellmann, R.G. (1993). Differential cellular effects 

in the toxicity of haloalkene and haloalkane cysteine 

conjugates to rabbit renal proximal tubules. J. 

Biochem. Toxicol. 8, 49-56. 

Harris, J.W., Dekant, W., and Anders, M.W. (1992). 

In vivo detection and characterization of protein 

adducts resulting from bioactivation of haloethene 

cysteine S-conjugates by 19F NMR: Chlorotrifluoroethene and tetrafluoroethene. Chem. Res. 

Toxicol. 5, 34-41. 

Haseman, J.K. (1984). Statistical issues in the design, 

analysis and interpretation of animal carcinogenicity 

studies. Environ. Health Perspect.58, 385-392. 

Hawley, G.G., Ed. (1981). The Condensed Chemical 

Dictionary, 10th ed. Van Nostrand Reinhold, New 

York. 

Haworth, S., Lawlor, T., Mortelmans, K., Speck, W., 

and Zeiger, E. (1983). Salmonella mutagenicity test 

results for 250 chemicals. Environ. Mutagen. 5 

(Suppl. 1), 3-142. 

Hayden, P.J., and Stevens, J.L. (1990). Cysteine 

conjugate toxicity, metabolism, and binding to macromolecules in isolated rat kidney mitochondria. Mol. 

Pharmacol. 37, 468-476. 
Tetrafluoroethylene, NTP TR 450 77 

Hayden, P.J., Ichimura, T., McCann, D.J., Pohl, L.R., 

and Stevens, J.L. (1991a). Detection of cysteine 

conjugate metabolite adduct formation with specific 

mitochondrial proteins using antibodies raised against 

halothane metabolite adducts. J. Biol. Chem. 266, 

18,415-18,418. 

Hayden, P.J., Yang, Y., Ward, A.J.I., Dulik, D.M., 

McCann, D.J., and Stevens, J.L. (1991b). Formation 

of difluorothionacetyl-protein adducts by 

S-(1,1,2,2-tetrafluoroethyl)-L-cysteine metabolites: 

Nucleophilic catalysis of stable lysyl adduct formation 

by histidine and tyrosine. Biochemistry 30, 

5935-5943. 

Hayden, P.J., Welsh, C.J., Yang, Y., Schaefer, W.H., 

Ward, A.J.L., and Stevens, J.L. (1992). Formation of 

mitochondrial phospholipid adducts by nephrotoxic 

cysteine conjugate metabolites. Chem. Res. Toxicol. 5, 

231-237. 

Hazardous Substances Data Base (HSDB) (1995). 

Maintained, reviewed, and updated on the National 

Library of Medicine's Toxicology Data Network 

(TOXNET). Available through the Medlars System. 

Hollander, M., and Wolfe, D.A. (1973). Nonparametric Statistical Methods, pp. 120-123. John Wiley 

and Sons, New York. 

International Agency for Research on Cancer (IARC) 

(1979). Some Monomers, Plastics and Synthetic 

Elastomers, and Acrolein. In IARC Monographs on 

the Evaluation of the Carcinogenic Risk of Chemicals 

to Humans. Vol. 19, pp. 285-301. Lyon, France. 

International Agency for Research on Cancer (IARC) 

(1987). Overall Evaluations of Carcinogenicity: An 

Updating of IARC Monographs. In IARC Monographs on the Evaluation of the Carcinogenic Risk of 

Chemicals to Humans. Vols. 1-42, Suppl. 7. Lyon, 

France. 

Jain, N.C., Ed. (1986). Depression or hypoproliferative anemias. In Schalm's Veterinary Hematology, 

4th ed., pp. 655-675. Lea and Febiger, Philadelphia, 

PA. 

Jonckheere, A.R. (1954). A distribution-free k-sample 

test against ordered alternatives. Biometrika 41, 133­

145. 

Kaplan, E.L., and Meier, P. (1958). Nonparametric 

estimation from incomplete observations. J. Am. Stat. 

Assoc. 53, 457-481. 

Kennedy, G.L. (1990). Toxicology of fluorinecontaining monomers. In Critical Reviews in Toxicology, Vol. 21, pp. 149-170. CRC Press, Boca 

Raton, FL. 

Lock, E.A., and Schnellmann, R.G. (1990). The effect 

of haloalkene cysteine conjugates on rat renal 

glutathione reductase and lipoyl dehydrogenase 

activities. Toxicol. Appl. Pharmacol.104, 180-190. 

McConnell, E.E., Solleveld, H.A., Swenberg, J.A., and 

Boorman, G.A. (1986). Guidelines for combining 

neoplasms for evaluation of rodent carcinogenesis 

studies. JNCI 76, 283-289. 

MacGregor, J.T., Wehr, C.M., Henika, P.R., and 

Shelby, M.D (1990). The in vivo erythrocyte micronucleus test: Measurement at steady increases assay 

efficiency and permits integration with toxicity studies. 

Fundam. Appl. Toxicol. 14, 513-522. 

McKnight, B., and Crowley, J. (1984). Tests for 

differences in tumor incidence based on animal 

carcinogenesis experiments. J. Am. Stat. Assoc. 79, 

639-648. 

Maronpot, R.R., and Boorman, G.A. (1982). 

Interpretation of rodent hepatocellular proliferative 

alterations and hepatocellular tumors in chemical safety 

assessment. Toxicol. Pathol. 10, 71-80. 

Material Safety Data Sheet Collection(1993). 

Tetrafluoroethylene. Sheet No. 851. Genium 

Publishing Corp., Schenectady, NY. 

Morrison, D.F. (1976). Multivariate Statistical 

Methods, 2nd ed., pp. 170-179. McGraw-Hill Book 

Company, New York. 

Myhr, B., McGregor, D., Bowers, L., Riach, C., 

Brown, A.G., Edwards, I., McBride, D., Martin, R., 

and Caspary, W.J. (1990). L5178Y mouse lymphoma 

cell mutation assay results with 41 compounds. 

Environ. Mol. Mutagen. 16 (Suppl. 18), 138-167. 
78 Tetrafluoroethylene, NTP TR 450 

National Cancer Institute (NCI) (1976). Guidelines for 

Carcinogen Bioassay in Small Rodents. Technical 

Report Series No. 1. NIH Publication No. 76-801. 

U.S. Department of Health, Education, and Welfare, 

Public Health Service, National Institutes of Health, 

Bethesda, MD. 

National Cancer Institute (NCI) (1977). Bioassay of 

Tetrachloroethylene for Possible Carcinogenicity. 

(CAS No. 127-18-4). Technical Report Series No. 13. 

NIH Publication No. 77-813. U.S. Department of 

Health and Human Services, Public Health Service, 

National Institutes of Health, Bethesda, MD. 

National Fire Protection Association (NFPA) (1986). 

Fire Protection Guide on Hazardous Materials. 9th ed., 

Sect. 49, pp. 86-87. National Fire Protection 

Association, Quincy, MA. 

National Institute for Occupational Safety and Health 

(NIOSH) (1990). National Occupational Exposure 

Survey (1981-1983), unpublished provisional data as 

of July 1, 1990. NIOSH, Cincinnati, OH. 

National Institutes of Health (NIH) (1978). Open 

Formula Rat and Mouse Ration (NIH-07). Specification NIH-11-1335. U.S. Department of Health, 

Education, and Welfare, Public Health Service, 

National Institutes of Health, Bethesda, MD. 

National Library of Medicine (1995). MEDLINE, 

CANCERLIT, TOXLINE. Toxicology Data Bank 

databases maintained by the National Library of 

Medicine. U.S. Department of Health and Human 

Services, Public Health Service, National Institutes of 

Health, Bethesda, MD. 

National Toxicology Program (NTP) (1984). Technical Protocol for Sperm Morphology and Vaginal 

Cytology Evaluations in Toxicity Testing for Rats and 

Mice, 10/31/82 version (updated October 1984). 

Research Triangle Park, NC. 

National Toxicology Program (NTP) (1986). NTP 

Technical Report on the Toxicology and Carcinogenesis of Tetrachloroethylene (Perchloroethylene) 

(CAS No. 127-18-4) in F344/N Rats and B6C3F1 

Mice (Inhalation Studies). Technical Report Series 

No. 311. NIH Publication No. 86-2567. U.S. 

Department of Health and Human Services, Public 

Health Service, National Institutes of Health, Research 

Triangle Park. 

Odum, J., and Green, T. (1984). The metabolism and 

nephrotoxicity of tetrafluoroethylene in the rat. 

Toxicol. Appl. Pharmacol.76, 306-318. 

Patty's Industrial Hygiene and Toxicology(1994). 

4th ed., Vol. II (G.D. Clayton and F.E. Clayton, Eds.), 

p. 1149. Wiley-Interscience, New York. 

Sakharova, L.N., and Tolgskaya, M.S. (1977). 

Toxicity and the nature of action of some halogen 

derivatives of ethylene, such as difluorodichloroethylene, trifluorochloroethylene and tetrafluoroethylene. Gig. Tr. Prof. Zabol. 21, Vol. 5, 36-42. 

Schmid, W. (1976). The micronucleus test for 

cytogenetic analysis. In Chemical Mutagens, Principles and Methods for Their Detection(A. Hollaender, 

Ed.), Vol. 4, pp. 31-53. Plenum Press, New York. 

Shirley, E. (1977). A non-parametric equivalent of 

Williams' test for contrasting increasing dose levels of 

a treatment. Biometrics 33, 386-389. 

Tarone, R.E. (1975). Tests for trend in life table 

analysis. Biometrika 62, 679-682. 

U.S. International Trade Commission (USITC) (1994). 

Synthetic Organic Chemicals, United States Production 

and Sales, 1992. USITC Publication No. 2720. 

USITC, Washington, DC. 

Weast, R.C., Ed. (1985). CRC Handbook of Chemistry and Physics, 66th ed., p. C272. CRC Press, 

Boca Raton, FL. 

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. 

Zhemerdei, A.I. (1958). Toxicology of tetrafluoroethylene. Tr. Leningr. Sanit. Gig. Med. Inst.44, 164. 
79 

APPENDIX A 

SUMMARY OF LESIONS IN MALE RATS 

IN THE 2-YEAR INHALATION STUDY 

OF TETRAFLUOROETHYLENE 

TABLE A1 

TABLE A2 

TABLE A3 

TABLE A4a 

TABLE A4b 

TABLE A4c 

TABLE A5 

Summary of the Incidence of Neoplasms in Male Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Individual Animal Tumor Pathology of Male Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Statistical Analysis of Primary Neoplasms in Male Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Historical Incidence of Renal Tubule Neoplasms 

in Chamber Control Male F344/N Rats .............................................. 

Historical Incidence of Hepatocellular Neoplasms 

in Chamber Control Male F344/N Rats .............................................. 

Historical Incidence of Mononuclear Cell Leukemia 

in Chamber Control Male F344/N Rats .............................................. 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

81 

86 

108 

115 

115 

116 

117 
80 Tetrafluoroethylene, NTP TR 450 
 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 81 

TABLE A1 a Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Moribund 

Natural deaths 

Survivors 

Terminal sacrifice 

60 

10 

27 

6 

17 

60 

10 

34 

4 

12 

60 

10 

32 

1 

17 

60 

10 

48 

1 

1 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, colon 

Polyp adenomatous

Intestine small, duodenum 

Liver 

Hepatocellular carcinoma

Hepatocellular adenoma

Mesentery

(10) 

(10) 

(10) 

(2)

(10) 

 1 (10%) 

(10) 

(10) 

(10) 

(10) 

(10) 

 1 (10%) 

(2)

(10) 

(10) 

(10) 

 1 (10%) 

(4) 

Endocrine System 

Pituitary gland 

Pars distalis, adenoma

Pars distalis, adenoma, multiple

Pars intermedia, adenoma

Thyroid gland 

Follicular cell, adenoma

(10)

 2 (20%) 

 1 (10%) 

 1 (10%) 

(10) 

 1 (10%) 

(9) 

 3 (33%) 

(10) 

(10) 

 1 (10%) 

(10) 

(10) 

 4 (40%) 

(10) 

Genital System 

Epididymis 

Preputial gland 

Carcinoma

Testes 

Bilateral, interstitial cell, adenoma

Interstitial cell, adenoma

(10) 

(10) 

 1 (10%) 

(10) 

 7 (70%) 

 2 (20%) 

(10) 

(10) 

(10) 

 5 (50%) 

 2 (20%) 

(10) 

(10) 

(10) 

 10 (100%)

(10) 

(10) 

(10) 

 9 (90%) 

 1 (10%) 

Integumentary System 

Skin 

Subcutaneous tissue, sarcoma

(10) (10) (10) 

 1 (10%) 

(10) 

Respiratory System 

Lung 

Alveolar/bronchiolar carcinoma

(10) 

 1 (10%) 

(10) (10) (10) 
 

 

 

 

 

 

 

 

 

 

 

 

82 Tetrafluoroethylene, NTP TR 450 

TABLE A1
 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

15-Month Interim Evaluation (continued) 

Urinary System 

Kidney (10) (10) (10) (10) 

Renal tubule, carcinoma 1 (10%) 

Urinary bladder (10) (10) (10) (10) 

Transitional epithelium, papilloma 1 (10%) 

Systemic Lesions

Multiple organs b (10) (10) (10) (10) 

Leukemia mononuclear 1 (10%) 

Mesothelioma malignant 1 (10%) 

Systems Examined With No Neoplasms Observed 

Cardiovascular System 

General Body System 

Hematopoietic System 

Musculoskeletal System 

Nervous System 

Special Senses System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (50) (50) 

Intestine large, cecum (50) (50) (50) (50) 

Intestine small, duodenum (50) (50) (50) (50) 

Intestine small, jejunum (48) (47) (49) (50) 

Intestine small, ileum (49) (49) (50) (50) 

Liver (50) (50) (50) (50) 

Hepatocellular carcinoma 1 (2%) 1 (2%) 10 (20%) 3 (6%) 

Hepatocellular adenoma 2 (4%) 3 (6%) 5 (10%) 4 (8%) 

Hepatocellular adenoma, multiple 1 (2%) 3 (6%) 3 (6%) 1 (2%) 

Hepatocholangioma 1 (2%) 

Mesentery (15) (11) (18) (14) 

Hepatocellular carcinoma, metastatic, liver 1 (7%) 

Pancreas (50) (50) (50) (50) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Acinus, adenoma 2 (4%) 1 (2%) 1 (2%) 

Pharynx (1) 

Palate, squamous cell carcinoma 1 (100%) 

Salivary glands (50) (50) (50) (50) 

Stomach, forestomach (50) (50) (50) (50) 

Stomach, glandular (50) (50) (50) (50) 

Tongue (1) (1) (1) 

Squamous cell papilloma 1 (100%) 1 (100%) 
 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 83 

TABLE A1
 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Schwannoma NOS 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Adenoma 2 (4%) 

Adrenal medulla (50) (50) (50) (50) 

Ganglioneuroma 1 (2%) 

Pheochromocytoma malignant 2 (4%) 1 (2%) 

Pheochromocytoma complex 1 (2%) 

Pheochromocytoma benign 15 (30%) 8 (16%) 8 (16%) 6 (12%) 

Bilateral, pheochromocytoma benign 4 (8%) 3 (6%) 1 (2%) 4 (8%) 

Islets, pancreatic (50) (50) (50) (50) 

Adenoma 3 (6%) 1 (2%) 1 (2%) 2 (4%) 

Carcinoma 1 (2%) 5 (10%) 1 (2%) 1 (2%) 

Parathyroid gland (50) (50) (50) (49) 

Pituitary gland (50) (49) (49) (49) 

Pars distalis, adenoma 39 (78%) 37 (76%) 35 (71%) 23 (47%) 

Pars intermedia, adenoma 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

C-cell, adenoma 7 (14%) 8 (16%) 5 (10%) 4 (8%) 

C-cell, carcinoma 2 (4%) 1 (2%) 4 (8%) 1 (2%) 

Follicular cell, adenoma 1 (2%) 1 (2%) 

General Body System 

None 

Genital System 

Epididymis (50) (50) (50) (50) 

Preputial gland (50) (50) (50) (49) 

Adenoma 1 (2%) 3 (6%) 5 (10%) 2 (4%) 

Carcinoma 3 (6%) 3 (6%) 1 (2%) 4 (8%) 

Bilateral, carcinoma 1 (2%) 

Prostate (50) (50) (50) (50) 

Seminal vesicle (50) (50) (50) (50) 

Testes (50) (50) (50) (50) 

Bilateral, interstitial cell, adenoma 35 (70%) 37 (74%) 40 (80%) 42 (84%) 

Interstitial cell, adenoma 4 (8%) 3 (6%) 8 (16%) 5 (10%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Lymph node (11) (17) (16) (17) 

Lymph node, bronchial (45) (50) (46) (47) 

Lymph node, mandibular (50) (49) (49) (46) 

Lymph node, mesenteric (50) (50) (50) (50) 

Lymph node, mediastinal (49) (47) (48) (46) 

Spleen (50) (50) (50) (50) 

Thymus (49) (47) (47) (45) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

84 Tetrafluoroethylene, NTP TR 450 

TABLE A1
 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Integumentary System 

Mammary gland (33) (36) (41) (34) 

Adenoma 1 (3%) 

Carcinoma 1 (3%) 1 (2%) 

Fibroadenoma 2 (6%) 2 (6%) 2 (5%) 1 (3%) 

Skin (49) (50) (50) (50) 

Basosquamous tumor benign 2 (4%) 1 (2%) 

Keratoacanthoma 3 (6%) 1 (2%) 1 (2%) 

Squamous cell carcinoma 1 (2%) 1 (2%) 

Squamous cell papilloma 1 (2%) 1 (2%) 

Subcutaneous tissue, fibroma 3 (6%) 1 (2%) 1 (2%) 

Subcutaneous tissue, fibrosarcoma 1 (2%) 1 (2%) 

Subcutaneous tissue, hemangiosarcoma 1 (2%) 

Subcutaneous tissue, neurofibroma 1 (2%) 1 (2%) 

Subcutaneous tissue, neurofibrosarcoma 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Osteosarcoma 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Meningioma NOS 1 (2%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar adenoma 1 (2%) 2 (4%) 1 (2%) 

Carcinoma, metastatic, kidney 1 (2%) 

Chordoma, metastatic, uncertain primary site 1 (2%) 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Nose (50) (50) (50) (50) 

Trachea (50) (50) (50) (50) 

Special Senses System 

Zymbal's gland (1) 

Carcinoma 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Bilateral, renal tubule, adenoma 1 (2%) 

Renal tubule, adenoma 5 (10%) 3 (6%) 

Renal tubule, carcinoma 1 (2%) 2 (4%) 

Transitional epithelium, papilloma 1 (2%) 

Urinary bladder (49) (50) (50) (50) 

Transitional epithelium, papilloma 3 (6%) 
85 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE A1
 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Systemic Lesions 

Multiple organs (50) (50) (50) (50) 

Leukemia mononuclear 34 (68%) 43 (86%) 38 (76%) 31 (62%) 

Mesothelioma malignant 5 (10%) 1 (2%) 2 (4%) 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 10 9 10 10 

2-Year study 49 49 50 49 

Total primary neoplasms 

15-Month interim evaluation 16 12 13 18 

2-Year study 177 175 194 149 

Total animals with benign neoplasms 

15-Month interim evaluation 10 9 10 10 

2-Year study 49 48 50 49 

Total benign neoplasms 

15-Month interim evaluation 14 12 12 14 

2-Year study 126 117 127 106 

Total animals with malignant neoplasms 

15-Month interim evaluation 2 1 4 

2-Year study 39 46 48 35 

Total malignant neoplasms 

15-Month interim evaluation 2 1 4 

2-Year study 51 57 66 43 

Total animals with metastatic neoplasms 

2-Year study 1 1 1 2 

Total metastatic neoplasms 

2-Year study 1 1 1 3 

Total animals with malignant neoplasms

 of uncertain primary site 

2-Year study 1 1 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 1 1 

Total uncertain neoplasms 

2-Year study 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
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

86 Tetrafluoroethylene, NTP TR 450 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm 

3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 3 7 8 0 2 5 5 8 9 9 9 2 3 3 4 5 6 7 7 7 8 9 9 0 0 

6 1 9 9 5 5 9 8 1 3 4 4 2 5 9 9 4 4 7 9 6 0 1 1 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 2 5 5 1 5 3 5 2 4 5 4 4 0 2 5 0 4 1 2 4 3 0 2 3 3 

0 2 6 3 0 0 3 8 3 9 8 4 7 3 4 6 7 6 6 1 6 4 7 3 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + A + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + A + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + A + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X 

Hepatocellular adenoma X 

Hepatocellular adenoma, multiple 

Mesentery + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Pharynx + 

Palate, squamous cell carcinoma X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tongue 

Squamous cell papilloma 

Tooth + + 

Cardiovascular System 

Blood vessel 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant 

Pheochromocytoma benign X X X X X X X X 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X 

Pars intermedia, adenoma X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma 

C-cell, carcinoma 

Follicular cell, adenoma 

General Body System 

None 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 87 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

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 0 0 0 0 1 1 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 7 8 9 5 6 1 7 3 3 3 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 4 1 3 1 2 2 0 2 0 0 0 1 1 1 1 1 2 3 3 3 4 4 4 5 5 Tissues/ 

6 2 7 1 5 4 9 1 1 3 8 4 5 7 8 9 9 1 2 9 0 2 5 1 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma 1 

Hepatocellular adenoma X 2 

Hepatocellular adenoma, multiple X 1 

Mesentery + + + + + + + + + + + + 15 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pharynx 1 

Palate, squamous cell carcinoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + 1 

Squamous cell papilloma X 1 

Tooth 2 

Cardiovascular System 

Blood vessel + 1 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma malignant X X 2 

Pheochromocytoma benign X X X X X X X 15 

Bilateral, pheochromocytoma benign X X X 4 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X X 3 

Carcinoma 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X X X 39 

Pars intermedia, adenoma 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X X X X 7 

C-cell, carcinoma X X 2 

Follicular cell, adenoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

88 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 3 7 8 0 2 5 5 8 9 9 9 2 3 3 4 5 6 7 7 7 8 9 9 0 0 

6 1 9 9 5 5 9 8 1 3 4 4 2 5 9 9 4 4 7 9 6 0 1 1 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 2 5 5 1 5 3 5 2 4 5 4 4 0 2 5 0 4 1 2 4 3 0 2 3 3 

0 2 6 3 0 0 3 8 3 9 8 4 7 3 4 6 7 6 6 1 6 4 7 3 4 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X 

Interstitial cell, adenoma X 

Hematopoietic System 

Blood
 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node + + + + + +
 

Lymph node, bronchial + + + + + M + + + + + + M + + M + + + + + + + + +
 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mediastinal + + + + + + + + + + + + + + M + + + + + + + + + +
 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + +
 

Thymus + + + + + + + + + + + + + + + + M + + + + + + + +
 

Integumentary System 

Mammary gland M + + M M + M + + + + + + + M + + + M + + M + + + 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + M + + + + + 

Basosquamous tumor benign 

Keratoacanthoma X 

Squamous cell carcinoma 

Squamous cell papilloma 

Subcutaneous tissue, fibroma X X 

Subcutaneous tissue, neurofibroma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, kidney X 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 89 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

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 0 0 0 0 1 1 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 7 8 9 5 6 1 7 3 3 3 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 4 1 3 1 2 2 0 2 0 0 0 1 1 1 1 1 2 3 3 3 4 4 4 5 5 Tissues/ 

6 2 7 1 5 4 9 1 1 3 8 4 5 7 8 9 9 1 2 9 0 2 5 1 7 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Carcinoma X X X 3 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X X 35 

Interstitial cell, adenoma X X X 4 

Hematopoietic System 

Blood + 1 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + 11 

Lymph node, bronchial + + + + + M M + + + + + + + + + + + + + + + + + + 45 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Integumentary System 

Mammary gland M + + + + + + M + + M + M + M M + M M + + + + M M 33 

Fibroadenoma X X 2 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Basosquamous tumor benign X X 2 

Keratoacanthoma X X 3 

Squamous cell carcinoma X 1 

Squamous cell papilloma X 1 

Subcutaneous tissue, fibroma X 3 

Subcutaneous tissue, neurofibroma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, kidney 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 45 
 

 

 

90 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 3 7 8 0 2 5 5 8 9 9 9 2 3 3 4 5 6 7 7 7 8 9 9 0 0 

6 1 9 9 5 5 9 8 1 3 4 4 2 5 9 9 4 4 7 9 6 0 1 1 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 2 5 5 1 5 3 5 2 4 5 4 4 0 2 5 0 4 1 2 4 3 0 2 3 3 

0 2 6 3 0 0 3 8 3 9 8 4 7 3 4 6 7 6 6 1 6 4 7 3 4 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, carcinoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + I + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X X 

Mesothelioma malignant X X X X 
 

 

 

Tetrafluoroethylene, NTP TR 450 91 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

Number of Days on Study 

7 

0 

5 

7 

0 

7 

7 

0 

8 

7 

0 

9 

7 

1 

5 

7 

1 

6 

7 

2 

1 

7 

2 

7 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

Carcass ID Number 

0 

4 

6 

0 

1 

2 

0 

3 

7 

0 

1 

1 

0 

2 

5 

0 

2 

4 

0 

0 

9 

0 

2 

1 

0 

0 

1 

0 

0 

3 

0 

0 

8 

0 

1 

4 

0 

1 

5 

0 

1 

7 

0 

1 

8 

0 

1 

9 

0 

2 

9 

0 

3 

1 

0 

3 

2 

0 

3 

9 

0 

4 

0 

0 

4 

2 

0 

4 

5 

0 

5 

1 

0 

5 

7 

Total 

Tissues/ 

Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, carcinoma 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X 34 

Mesothelioma malignant X 5 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

92 Tetrafluoroethylene, NTP TR 450 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 156 ppm 

3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 5 7 9 0 2 3 5 5 8 8 9 9 9 9 0 0 1 1 2 2 5 5 5 6 

1 0 0 4 9 9 3 5 5 1 9 2 4 4 4 0 4 2 6 1 7 2 3 9 4 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 7 5 5 4 4 3 5 2 4 3 6 7 2 3 4 6 4 6 6 3 2 6 2 3 3 

3 0 3 6 1 7 2 8 4 9 0 8 9 0 8 1 3 7 4 1 7 2 2 6 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + A A + + + + + + + + + + + A + + + + + + + 

Intestine small, ileum + + + + A + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X 

Hepatocellular adenoma X X 

Hepatocellular adenoma, multiple 

Hepatocholangioma 

Mesentery + + + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Acinus, adenoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tongue 

Squamous cell papilloma 

Tooth + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Schwannoma NOS X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma complex 

Pheochromocytoma benign X X X X 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + I + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X X X 

C-cell, carcinoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 93 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 156 ppm (continued)
 

6 6 6 6 6 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 6 8 8 9 9 0 0 0 1 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 1 6 1 8 0 2 5 1 5 6 6 0 3 3 3 3 3 3 3 3 3 3 3 3 

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 5 3 4 6 3 7 7 6 6 7 3 3 7 2 2 2 4 5 5 5 6 6 7 7 8 Tissues/ 

5 2 7 5 5 6 2 9 3 9 3 8 0 1 5 6 9 1 7 9 6 8 4 7 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma 1 

Hepatocellular adenoma X 3 

Hepatocellular adenoma, multiple X X X 3 

Hepatocholangioma X 1 

Mesentery + + + + + + 11 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Acinus, adenoma X X 2 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + 1 

Squamous cell papilloma X 1 

Tooth + 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma NOS 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma complex X 1 

Pheochromocytoma benign X X X X 8 

Bilateral, pheochromocytoma benign X X 3 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Carcinoma X X X X 5 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X 37 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X 8 

C-cell, carcinoma X 1 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X X 3 

Carcinoma X 3 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

94 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 156 ppm (continued)
 

3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 5 7 9 0 2 3 5 5 8 8 9 9 9 9 0 0 1 1 2 2 5 5 5 6 

1 0 0 4 9 9 3 5 5 1 9 2 4 4 4 0 4 2 6 1 7 2 3 9 4 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 7 5 5 4 4 3 5 2 4 3 6 7 2 3 4 6 4 6 6 3 2 6 2 3 3 

3 0 3 6 1 7 2 8 4 9 0 8 9 0 8 1 3 7 4 1 7 2 2 6 4 

Genital System (continued)
 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + +
 

Testes + + + + + + + + + + + + + + + + + + + + + + + + +
 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X 

Interstitial cell, adenoma X 

Hematopoietic System 

Blood + 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + + + + + + + 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + M + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + + + + + + + + + + + + + M + + M + + + + + + 

Integumentary System 

Mammary gland + + M + + + M + + + + M + M M + M + M + + + + + + 

Carcinoma 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, fibroma 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma 

Chordoma, metastatic, uncertain

 primary site 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + 

Harderian gland 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Transitional epithelium, papilloma X 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X X X X 

Mesothelioma malignant 
 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 95 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 156 ppm (continued)
 

6 6 6 6 6 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 6 8 8 9 9 0 0 0 1 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 1 6 1 8 0 2 5 1 5 6 6 0 3 3 3 3 3 3 3 3 3 3 3 3 

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 5 3 4 6 3 7 7 6 6 7 3 3 7 2 2 2 4 5 5 5 6 6 7 7 8 Tissues/ 

5 2 7 5 5 6 2 9 3 9 3 8 0 1 5 6 9 1 7 9 6 8 4 7 0 Tumors 

Genital System (continued) 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X X X X 37 

Interstitial cell, adenoma X X 3 

Hematopoietic System 

Blood 1 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + + 17 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mandibular + + + + + + + + + + + + + + M + + + + + + + + + + 49 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + + + M + + M + + + + + + + + + + + + + + + + 47 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + M + + + + + + + + + + + + + + + + + + + + + + 47 

Integumentary System 

Mammary gland + M M + + M M + + + + M + + + + + + + M + + M + + 36 

Carcinoma X 1 

Fibroadenoma X X 2 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Subcutaneous tissue, fibroma X 1 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + 

X

+ + + + + + + + + + + + + + + + + + + + 50 

1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X 1 

Chordoma, metastatic, uncertain

 primary site X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + M + + + + + + + + + + + + 42 

Harderian gland + 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Transitional epithelium, papilloma X X 3 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X X X X X 43 

Mesothelioma malignant X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

96 Tetrafluoroethylene, NTP TR 450 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 3 4 5 6 7 7 8 1 1 1 1 1 2 2 3 3 3 3 3 5 6 6 6 7 

3 8 7 9 4 5 6 1 4 4 6 7 7 1 7 1 2 2 5 8 8 3 4 4 4 

1 2 2 2 2 1 1 1 2 2 1 1 1 2 2 2 1 2 2 2 2 2 2 2 1 

Carcass ID Number 9 1 2 2 1 9 8 9 2 3 9 8 8 0 2 0 9 2 2 3 1 0 0 3 9 

6 9 2 9 3 5 9 8 0 8 2 1 7 7 5 6 4 4 7 5 8 3 4 4 3 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + A + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X X X X 

Hepatocellular adenoma X 

Hepatocellular adenoma, multiple 

Mesentery + + + + + + + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Acinus, adenoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tooth 

Cardiovascular System 

Blood vessel + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant X 

Pheochromocytoma benign X X X X 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X 

C-cell, carcinoma X 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X X X X 

Carcinoma X 

Bilateral, carcinoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 97 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

6 6 6 6 6 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 7 7 8 9 9 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 7 8 1 3 3 6 9 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

2 1 1 2 2 2 1 2 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 2 8 9 1 1 3 8 0 8 8 9 9 0 0 0 0 1 1 1 1 2 2 3 3 3 Tissues/ 

8 6 1 7 2 7 8 5 2 5 0 7 0 1 2 8 1 4 5 6 3 6 0 1 3 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma X X X X X X 10 

Hepatocellular adenoma X X X X 5 

Hepatocellular adenoma, multiple X X X 3 

Mesentery + + + + + + + + + 18 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Acinus, adenoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tooth + 1 

Cardiovascular System 

Blood vessel + + 3 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma malignant 1 

Pheochromocytoma benign X X X X 8 

Bilateral, pheochromocytoma benign 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Carcinoma X 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pituitary gland + + + + + + + + + + M + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X 35 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X 5 

C-cell, carcinoma X X X 4 

Follicular cell, adenoma 1 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 5 

Carcinoma 1 

Bilateral, carcinoma 1 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

98 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 3 4 5 6 7 7 8 1 1 1 1 1 2 2 3 3 3 3 3 5 6 6 6 7 

3 8 7 9 4 5 6 1 4 4 6 7 7 1 7 1 2 2 5 8 8 3 4 4 4 

1 2 2 2 2 1 1 1 2 2 1 1 1 2 2 2 1 2 2 2 2 2 2 2 1 

Carcass ID Number 9 1 2 2 1 9 8 9 2 3 9 8 8 0 2 0 9 2 2 3 1 0 0 3 9 

6 9 2 9 3 5 9 8 0 8 2 1 7 7 5 6 4 4 7 5 8 3 4 4 3 

Genital System (continued)
 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + +
 

Testes + + + + + + + + + + + + + + + + + + + + + + + + +
 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X 

Interstitial cell, adenoma X X X X X X X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node + + + + + + + +
 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + M + M + + +
 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mediastinal + + + + + + M + + + + + + + + + + + + + + M + + +
 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + +
 

Thymus + + M + + + + + + + + + + + + + + + + + M + + + +
 

Integumentary System 

Mammary gland M + + + + + M + + + + + + + + M + + + M + M + + + 

Carcinoma X 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Keratoacanthoma X 

Squamous cell carcinoma 

Subcutaneous tissue, fibrosarcoma X 

Subcutaneous tissue, hemangiosarcoma X 

Subcutaneous tissue, neurofibroma 

Subcutaneous tissue,

 neurofibrosarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Skeletal muscle 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Meningioma NOS 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X 

Hepatocellular carcinoma, metastatic,

 liver 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + 

Zymbal's gland 

Carcinoma 
 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 99 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

6 6 6 6 6 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 7 7 8 9 9 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 7 8 1 3 3 6 9 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

2 1 1 2 2 2 1 2 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 2 8 9 1 1 3 8 0 8 8 9 9 0 0 0 0 1 1 1 1 2 2 3 3 3 Tissues/ 

8 6 1 7 2 7 8 5 2 5 0 7 0 1 2 8 1 4 5 6 3 6 0 1 3 Tumors 

Genital System (continued) 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X X X X X X X X 40 

Interstitial cell, adenoma X 8 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + + + 16 

Lymph node, bronchial M + + + + + + M + + + + + + + + + + + + + + + + + 46 

Lymph node, mandibular + + + + + + + + + + + + + + + + + M + + + + + + + 49 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + M + + + + + + + + + + + + + + + + + + + + 47 

Integumentary System 

Mammary gland M + M + M + + + + + + + + + + + M + + + + + + + + 41 

Carcinoma 1 

Fibroadenoma X X 2 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Keratoacanthoma 1 

Squamous cell carcinoma X 1 

Subcutaneous tissue, fibrosarcoma 1 

Subcutaneous tissue, hemangiosarcoma 1 

Subcutaneous tissue, neurofibroma X 1 

Subcutaneous tissue,

 neurofibrosarcoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle + 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Meningioma NOS X 1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X 2 

Hepatocellular carcinoma, metastatic,

 liver X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Zymbal's gland + 1 

Carcinoma X 1 
 

 

 

 

100 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 3 4 5 6 7 7 8 1 1 1 1 1 2 2 3 3 3 3 3 5 6 6 6 7 

3 8 7 9 4 5 6 1 4 4 6 7 7 1 7 1 2 2 5 8 8 3 4 4 4 

1 2 2 2 2 1 1 1 2 2 1 1 1 2 2 2 1 2 2 2 2 2 2 2 1 

Carcass ID Number 9 1 2 2 1 9 8 9 2 3 9 8 8 0 2 0 9 2 2 3 1 0 0 3 9 

6 9 2 9 3 5 9 8 0 8 2 1 7 7 5 6 4 4 7 5 8 3 4 4 3 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, renal tubule, adenoma X 

Renal tubule, adenoma X X 

Renal tubule, carcinoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X 

Mesothelioma malignant 
 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 101 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

6 6 6 6 6 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 7 7 8 9 9 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 7 8 1 3 3 6 9 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

2 1 1 2 2 2 1 2 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 2 8 9 1 1 3 8 0 8 8 9 9 0 0 0 0 1 1 1 1 2 2 3 3 3 Tissues/ 

8 6 1 7 2 7 8 5 2 5 0 7 0 1 2 8 1 4 5 6 3 6 0 1 3 Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, renal tubule, adenoma 1 

Renal tubule, adenoma X X X 5 

Renal tubule, carcinoma X 2 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X X X 38 

Mesothelioma malignant X X 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

102 Tetrafluoroethylene, NTP TR 450 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 

Number of Days on Study 6 5 8 0 1 2 2 3 4 5 5 7 7 7 8 8 9 9 9 0 0 0 1 1 1 

1 5 1 9 0 3 5 1 4 5 9 1 2 2 3 6 0 3 4 3 4 8 1 6 7 

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 4 1 4 1 3 1 0 2 0 5 0 0 3 4 6 0 3 3 0 5 4 3 4 2 0 

3 3 9 8 9 0 7 9 2 9 5 6 0 8 0 3 3 8 1 5 6 7 0 8 8 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X 

Hepatocellular adenoma X X 

Hepatocellular adenoma, multiple X 

Mesentery + + + + + 

Hepatocellular carcinoma, metastatic,

 liver 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma, metastatic,

 liver 

Acinus, adenoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tongue 

Tooth + + 

Cardiovascular System 

Blood vessel + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Ganglioneuroma X 

Pheochromocytoma benign X X 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X 

Parathyroid gland M + + + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X 

C-cell, carcinoma 

General Body System 

Tissue NOS + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 103 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 3 3 3 3 3 3 5 6 6 6 7 8 8 9 9 0 1 2 3 3 

7 7 1 6 6 0 2 2 9 9 9 2 3 3 8 4 8 8 1 5 2 2 1 0 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 3 Total 

Carcass ID Number 1 5 1 5 5 2 2 3 0 1 2 4 0 5 4 3 2 2 3 1 5 3 1 2 2 Tissues/ 

2 0 4 4 8 0 3 4 9 5 7 5 4 6 2 2 5 6 6 9 7 5 1 1 4 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 carcinoma X X 3 

Hepatocellular adenoma X X 4 

Hepatocellular adenoma, multiple 1 

Mesentery + + + + + + + + + 14 

Hepatocellular carcinoma, metastatic,

 liver X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma, metastatic,

 liver X 1 

Acinus, adenoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + 1 

Tooth 2 

Cardiovascular System 

Blood vessel + + + + + + + + + 12 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Ganglioneuroma 1 

Pheochromocytoma benign X X X X 6 

Bilateral, pheochromocytoma benign X X X 4 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Carcinoma 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + M 49 

Pars distalis, adenoma X X X X X X X X X X X X X X 23 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X 4 

C-cell, carcinoma X 1 

General Body System 

Tissue NOS 1 
 

 

 

 

 

 

 

 

 

 

 

 

104 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 

Number of Days on Study 6 5 8 0 1 2 2 3 4 5 5 7 7 7 8 8 9 9 9 0 0 0 1 1 1 

1 5 1 9 0 3 5 1 4 5 9 1 2 2 3 6 0 3 4 3 4 8 1 6 7 

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 4 1 4 1 3 1 0 2 0 5 0 0 3 4 6 0 3 3 0 5 4 3 4 2 0 

3 3 9 8 9 0 7 9 2 9 5 6 0 8 0 3 3 8 1 5 6 7 0 8 8 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma X X X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X X 

Interstitial cell, adenoma X X X X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + + + 

Lymph node, bronchial + M + + + + + + + + + + + + + + + + + + + + + M + 

Lymph node, mandibular + + + + + M + + + + + + + + + + M + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + M 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + M + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Adenoma 

+ M M M M + 

X 

M M M + + + + M + + + M M + M + + + + 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Basosquamous tumor benign 

Keratoacanthoma 

Squamous cell papilloma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, sarcoma 

X 

X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X 

Chordoma, metastatic, uncertain

 primary site 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 105 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 3 3 3 3 3 3 5 6 6 6 7 8 8 9 9 0 1 2 3 3 

7 7 1 6 6 0 2 2 9 9 9 2 3 3 8 4 8 8 1 5 2 2 1 0 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 3 Total 

Carcass ID Number 1 5 1 5 5 2 2 3 0 1 2 4 0 5 4 3 2 2 3 1 5 3 1 2 2 Tissues/ 

2 0 4 4 8 0 3 4 9 5 7 5 4 6 2 2 5 6 6 9 7 5 1 1 4 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + M + + + + + + + + + + + + + + + + 49 

Adenoma X 2 

Carcinoma X 4 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X X X X X X X X X X X X X 42 

Interstitial cell, adenoma X 5 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + + + + + + 17 

Lymph node, bronchial + + + + + + + + + + + + M + + + + + + + + + + + + 47 

Lymph node, mandibular + + + + + + M + + M + + + + + + + + + + + + + + + 46 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + M + + + + M + + + + + + + + + + + + M + + + 46 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + M + + + + + + + + + + + + + + M + M M + + + 45 

Integumentary System 

Mammary gland 

Adenoma

+ + + + + M + + + + M M + M + + + M + + + + + + + 34 

1 

Fibroadenoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Basosquamous tumor benign 

Keratoacanthoma 

X

X

 1 

1 

Squamous cell papilloma 

Subcutaneous tissue, fibroma

Subcutaneous tissue, fibrosarcoma

Subcutaneous tissue, sarcoma 

X

X

 1 

1 

1 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma 1 

Chordoma, metastatic, uncertain

 primary site X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 42 
 

 

 

106 Tetrafluoroethylene, NTP TR 450 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 

Number of Days on Study 6 5 8 0 1 2 2 3 4 5 5 7 7 7 8 8 9 9 9 0 0 0 1 1 1 

1 5 1 9 0 3 5 1 4 5 9 1 2 2 3 6 0 3 4 3 4 8 1 6 7 

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 4 1 4 1 3 1 0 2 0 5 0 0 3 4 6 0 3 3 0 5 4 3 4 2 0 

3 3 9 8 9 0 7 9 2 9 5 6 0 8 0 3 3 8 1 5 6 7 0 8 8 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma 

Transitional epithelium, papilloma 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X X 

Mesothelioma malignant X 
 

 

 

 

Tetrafluoroethylene, NTP TR 450 107 

TABLE A2
 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 3 3 3 3 3 3 5 6 6 6 7 8 8 9 9 0 1 2 3 3 

7 7 1 6 6 0 2 2 9 9 9 2 3 3 8 4 8 8 1 5 2 2 1 0 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 3 Total 

Carcass ID Number 1 5 1 5 5 2 2 3 0 1 2 4 0 5 4 3 2 2 3 1 5 3 1 2 2 Tissues/ 

2 0 4 4 8 0 3 4 9 5 7 5 4 6 2 2 5 6 6 9 7 5 1 1 4 Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X X X 3 

Transitional epithelium, papilloma X 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X 31 

Mesothelioma malignant 1 
 

 

 

108 Tetrafluoroethylene, NTP TR 450 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 156 ppm 312 ppm 625 ppm 

Adrenal Medulla: Benign Pheochromocytoma a Overall rate 19/50 (38%) 11/50 (22%) 9/50 (18%) 10/50 (20%) b Adjusted rate 60.0% 44.2% 33.4% 52.8% c Terminal rate 6/17 (35%) 2/12 (17%) 4/17 (24%) 0/1 (0%) 

First incidence (days) 588 594 576 481 

d Life table test P=0.282 P=0.280N P=0.058N P=0.083 

d Logistic regression test P=0.108N P=0.090N P=0.024N P=0.180N 

d Cochran-Armitage test P=0.040N 

d Fisher exact test P=0.063N P=0.022N P=0.038N 

Adrenal Medulla: Benign, Complex, or Malignant Pheochromocytoma 

Overall rate 20/50 (40%) 12/50 (24%) 9/50 (18%) 10/50 (20%) 

Adjusted rate 63.6% 49.8% 33.4% 52.8% 

Terminal rate 7/17 (41%) 3/12 (25%) 4/17 (24%) 0/1 (0%) 

First incidence (days) 588 594 576 481 

Life table test P=0.331 P=0.305N P=0.039N P=0.087 

Logistic regression test P=0.078N P=0.123N P=0.015N P=0.151N 

Cochran-Armitage test P=0.023N 

Fisher exact test P=0.066N P=0.013N P=0.024N 

Kidney (Renal Tubule): Adenoma (Single Sections) 

Overall rate 0/50 (0%) 0/50 (0%) 6/50 (12%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 25.7% 18.4% 

Terminal rate 0/17 (0%) 0/12 (0%) 3/17 (18%) 0/1 (0%) e First incidence (days) — — 627 617 

Life table test P<0.001 — P=0.015 P=0.032 

Logistic regression test P=0.015 — P=0.015 P=0.097 

Cochran-Armitage test P=0.047 

Fisher exact test — P=0.013 P=0.121 

Kidney (Renal Tubule): Adenoma (Step Sections) 

Overall rate 2/50 (4%) 4/50 (8%) 3/50 (6%) 11/50 (22%) 

Adjusted rate 10.8% 24.9% 10.2% 85.3% 

Terminal rate 1/17 (6%) 2/12 (17%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 721 555 614 572 

Life table test P<0.001 P=0.217 P=0.506 P<0.001 

Logistic regression test P<0.001 P=0.259 P=0.492 P<0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.339 P=0.500 P=0.007 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 2/50 (4%) 4/50 (8%) 9/50 (18%) 13/50 (26%) 

Adjusted rate 10.8% 24.9% 33.3% 87.7% 

Terminal rate 1/17 (6%) 2/12 (17%) 3/17 (18%) 0/1 (0%) 

First incidence (days) 721 555 614 572 

Life table test P<0.001 P=0.217 P=0.029 P<0.001 

Logistic regression test P<0.001 P=0.259 P=0.024 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.339 P=0.026 P=0.002 
Tetrafluoroethylene, NTP TR 450 109 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single Sections) 

Overall rate 1/50 (2%) 0/50 (0%) 6/50 (12%) 3/50 (6%) 

Adjusted rate 2.8% 0.0% 25.7% 18.4% 

Terminal rate 0/17 (0%) 0/12 (0%) 3/17 (18%) 0/1 (0%) 

First incidence (days) 649 — 627 617 

Life table test P=0.004 P=0.543N P=0.049 P=0.094 

Logistic regression test P=0.052 P=0.497N P=0.055 P=0.270 

Cochran-Armitage test P=0.114 

Fisher exact test P=0.500N P=0.056 P=0.309 

Kidney (Renal Tubule): Adenoma or Carcinoma (Step Sections) 

Overall rate 2/50 (4%) 5/50 (10%) 3/50 (6%) 11/50 (22%) 

Adjusted rate 10.8% 28.4% 10.2% 85.3% 

Terminal rate 1/17 (6%) 2/12 (17%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 721 555 614 572 

Life table test P<0.001 P=0.123 P=0.506 P<0.001 

Logistic regression test P<0.001 P=0.151 P=0.492 P<0.001 

Cochran-Armitage test P=0.004 

Fisher exact test P=0.218 P=0.500 P=0.007 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 3/50 (6%) 5/50 (10%) 9/50 (18%) 13/50 (26%) 

Adjusted rate 13.3% 28.4% 33.3% 87.7% 

Terminal rate 1/17 (6%) 2/12 (17%) 3/17 (18%) 0/1 (0%) 

First incidence (days) 649 555 614 572 

Life table test P<0.001 P=0.224 P=0.060 P<0.001 

Logistic regression test P<0.001 P=0.281 P=0.057 P<0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.357 P=0.061 P=0.006 

Liver: Hepatocellular Adenoma 

Overall rate 3/50 (6%) 6/50 (12%) 8/50 (16%) 5/50 (10%) 

Adjusted rate 14.1% 32.0% 43.1% 100.0% 

Terminal rate 2/17 (12%) 3/12 (25%) 7/17 (41%) 1/1 (100%) 

First incidence (days) 632 600 638 572 

Life table test P=0.004 P=0.127 P=0.082 P=0.018 

Logistic regression test P=0.103 P=0.193 P=0.065 P=0.240 

Cochran-Armitage test P=0.352 

Fisher exact test P=0.243 P=0.100 P=0.357 

Liver: Hepatocellular Carcinoma 

Overall rate 1/50 (2%) 1/50 (2%) 10/50 (20%) 3/50 (6%) 

Adjusted rate 2.6% 3.4% 41.3% 18.8% 

Terminal rate 0/17 (0%) 0/12 (0%) 5/17 (29%) 0/1 (0%) 

First incidence (days) 624 652 617 590 

Life table test P=0.003 P=0.710 P=0.005 P=0.113 

Logistic regression test P=0.053 P=0.756N P=0.004 P=0.301 

Cochran-Armitage test P=0.149 

Fisher exact test P=0.753N P=0.004 P=0.309 
110 Tetrafluoroethylene, NTP TR 450 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 4/50 (8%) 7/50 (14%) 15/50 (30%) 8/50 (16%) 

Adjusted rate 16.3% 34.4% 62.1% 100.0% 

Terminal rate 2/17 (12%) 3/12 (25%) 9/17 (53%) 1/1 (100%) 

First incidence (days) 624 600 617 572 

Life table test P<0.001 P=0.137 P=0.004 P=0.003 

Logistic regression test P=0.025 P=0.223 P=0.003 P=0.112 

Cochran-Armitage test P=0.140 

Fisher exact test P=0.262 P=0.005 P=0.178 

Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma 

Overall rate 2/50 (4%) 2/50 (4%) 3/50 (6%) 2/50 (4%) 

Adjusted rate 10.4% 12.7% 14.2% 11.1% 

Terminal rate 1/17 (6%) 1/12 (8%) 2/17 (12%) 0/1 (0%) 

First incidence (days) 715 698 627 523 

Life table test P=0.117 P=0.580 P=0.491 P=0.229 

Logistic regression test P=0.386 P=0.598 P=0.463 P=0.631 

Cochran-Armitage test P=0.569 

Fisher exact test P=0.691N P=0.500 P=0.691N 

Pancreatic Islets: Adenoma 

Overall rate 3/50 (6%) 1/50 (2%) 1/50 (2%) 2/50 (4%) 

Adjusted rate 15.3% 5.6% 5.9% 20.5% 

Terminal rate 2/17 (12%) 0/12 (0%) 1/17 (6%) 0/1 (0%) 

First incidence (days) 705 705 733 (T) 626 

Life table test P=0.248 P=0.433N P=0.324N P=0.182 

Logistic regression test P=0.463 P=0.400N P=0.339N P=0.521 

Cochran-Armitage test P=0.475N 

Fisher exact test P=0.309N P=0.309N P=0.500N 

Pancreatic Islets: Carcinoma 

Overall rate 1/50 (2%) 5/50 (10%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 3.4% 31.5% 5.9% 3.0% 

Terminal rate 0/17 (0%) 3/12 (25%) 1/17 (6%) 0/1 (0%) 

First incidence (days) 690 664 733 (T) 593 

Life table test P=0.432 P=0.049 P=0.730 P=0.587 

Logistic regression test P=0.550N P=0.059 P=0.744 P=0.768 

Cochran-Armitage test P=0.313N 

Fisher exact test P=0.102 P=0.753N P=0.753N 

Pancreatic Islets: Adenoma or Carcinoma 

Overall rate 4/50 (8%) 6/50 (12%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 18.2% 35.3% 11.8% 22.9% 

Terminal rate 2/17 (12%) 3/12 (25%) 2/17 (12%) 0/1 (0%) 

First incidence (days) 690 664 733 (T) 593 

Life table test P=0.202 P=0.192 P=0.375N P=0.144 

Logistic regression test P=0.525 P=0.228 P=0.387N P=0.553 

Cochran-Armitage test P=0.278N 

Fisher exact test P=0.370 P=0.339N P=0.500N 
Tetrafluoroethylene, NTP TR 450 111 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 39/50 (78%) 37/49 (76%) 35/49 (71%) 23/49 (47%) 

Adjusted rate 94.9% 91.1% 84.5% 86.1% 

Terminal rate 15/17 (88%) 9/12 (75%) 10/16 (63%) 0/0 

First incidence (days) 336 351 559 361 

Life table test P=0.042 P=0.213 P=0.514N P=0.003 

Logistic regression test P=0.002N P=0.500N P=0.290N P=0.014N 

Cochran-Armitage test P<0.001N 

Fisher exact test P=0.478N P=0.301N P=0.001N 

Preputial Gland: Adenoma 

Overall rate 1/50 (2%) 3/50 (6%) 5/50 (10%) 2/49 (4%) 

Adjusted rate 5.9% 25.0% 15.6% 6.0% 

Terminal rate 1/17 (6%) 3/12 (25%) 1/17 (6%) 0/1 (0%) 

First incidence (days) 733 (T) 733 (T) 538 523 

Life table test P=0.099 P=0.182 P=0.104 P=0.228 

Logistic regression test P=0.393 P=0.182 P=0.099 P=0.523 

Cochran-Armitage test P=0.428 

Fisher exact test P=0.309 P=0.102 P=0.492 

Preputial Gland: Carcinoma 

Overall rate 3/50 (6%) 3/50 (6%) 2/50 (4%) 4/49 (8%) 

Adjusted rate 15.6% 10.0% 4.9% 13.9% 

Terminal rate 2/17 (12%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 708 494 538 481 

Life table test P=0.152 P=0.552 P=0.515N P=0.077 

Logistic regression test P=0.481 P=0.656 P=0.500N P=0.471 

Cochran-Armitage test P=0.409 

Fisher exact test P=0.661N P=0.500N P=0.489 

Preputial Gland: Adenoma or Carcinoma 

Overall rate 4/50 (8%) 6/50 (12%) 6/50 (12%) 6/49 (12%) 

Adjusted rate 21.2% 32.5% 18.1% 19.0% 

Terminal rate 3/17 (18%) 3/12 (25%) 1/17 (6%) 0/1 (0%) 

First incidence (days) 708 494 538 481 

Life table test P=0.035 P=0.211 P=0.350 P=0.023 

Logistic regression test P=0.355 P=0.295 P=0.369 P=0.354 

Cochran-Armitage test P=0.337 

Fisher exact test P=0.370 P=0.370 P=0.357 

Skin: Keratoacanthoma 

Overall rate 3/50 (6%) 0/50 (0%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 14.7% 0.0% 2.2% 5.3% 

Terminal rate 2/17 (12%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 686 — 575 632 

Life table test P=0.579N P=0.184N P=0.326N P=0.598 

Logistic regression test P=0.356N P=0.165N P=0.309N P=0.609N 

Cochran-Armitage test P=0.296N 

Fisher exact test P=0.121N P=0.309N P=0.309N 
112 Tetrafluoroethylene, NTP TR 450 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

Skin: Squamous Cell Papilloma or Keratoacanthoma 

Overall rate 4/50 (8%) 0/50 (0%) 1/50 (2%) 2/50 (4%) 

Adjusted rate 19.0% 0.0% 2.2% 8.9% 

Terminal rate 2/17 (12%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 686 — 575 617 

Life table test P=0.525 P=0.112N P=0.197N P=0.375 

Logistic regression test P=0.452N P=0.095N P=0.186N P=0.629N 

Cochran-Armitage test P=0.373N 

Fisher exact test P=0.059N P=0.181N P=0.339N 

Skin: Squamous Cell Papilloma, Keratoacanthoma, or Squamous Cell Carcinoma 

Overall rate 5/50 (10%) 0/50 (0%) 2/50 (4%) 2/50 (4%) 

Adjusted rate 23.5% 0.0% 7.7% 8.9% 

Terminal rate 2/17 (12%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 686 — 575 617 

Life table test P=0.552 P=0.071N P=0.233N P=0.421 

Logistic regression test P=0.401N P=0.056N P=0.236N P=0.550N 

Cochran-Armitage test P=0.263N 

Fisher exact test P=0.028N P=0.218N P=0.218N 

Skin: Squamous Cell Papilloma, Keratoacanthoma, Benign Basosquamous Tumor, or Squamous Cell Carcinoma 

Overall rate 7/50 (14%) 0/50 (0%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 32.3% 0.0% 7.7% 12.6% 

Terminal rate 3/17 (18%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 686 — 575 617 

Life table test P=0.527 P=0.029N P=0.092N P=0.301 

Logistic regression test P=0.369N P=0.019N P=0.095N P=0.529N 

Cochran-Armitage test P=0.211N 

Fisher exact test P=0.006N P=0.080N P=0.159N 

Skin (Subcutaneous Tissue): Fibroma 

Overall rate 3/50 (6%) 1/50 (2%) 0/50 (0%) 1/50 (2%) 

Adjusted rate 11.3% 5.6% 0.0% 2.6% 

Terminal rate 1/17 (6%) 0/12 (0%) 0/17 (0%) 0/1 (0%) 

First incidence (days) 635 705 — 571 

Life table test P=0.430N P=0.420N P=0.150N P=0.700N 

Logistic regression test P=0.224N P=0.343N P=0.122N P=0.346N 

Cochran-Armitage test P=0.200N 

Fisher exact test P=0.309N P=0.121N P=0.309N 

Testes: Adenoma 

Overall rate 39/50 (78%) 40/50 (80%) 48/50 (96%) 47/50 (94%) 

Adjusted rate 92.5% 97.3% 100.0% 100.0% 

Terminal rate 14/17 (82%) 11/12 (92%) 17/17 (100%) 1/1 (100%) 

First incidence (days) 489 470 413 418 

Life table test P<0.001 P=0.101 P=0.081 P<0.001 

Logistic regression test P<0.001 P=0.361 P=0.009 P=0.003 

Cochran-Armitage test P=0.004 

Fisher exact test P=0.500 P=0.007 P=0.020 
Tetrafluoroethylene, NTP TR 450 113 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

Thyroid Gland (C-cell): Adenoma 

Overall rate 7/50 (14%) 8/50 (16%) 5/50 (10%) 4/50 (8%) 

Adjusted rate 31.8% 37.3% 21.6% 20.6% 

Terminal rate 3/17 (18%) 3/12 (25%) 2/17 (12%) 0/1 (0%) 

First incidence (days) 707 533 631 571 

Life table test P=0.283 P=0.286 P=0.437N P=0.128 

Logistic regression test P=0.348N P=0.386 P=0.438N P=0.636 

Cochran-Armitage test P=0.152N 

Fisher exact test P=0.500 P=0.380N P=0.262N 

Thyroid Gland (C-cell): Carcinoma 

Overall rate 2/50 (4%) 1/50 (2%) 4/50 (8%) 1/50 (2%) 

Adjusted rate 11.8% 8.3% 18.4% 3.8% 

Terminal rate 2/17 (12%) 1/12 (8%) 2/17 (12%) 0/1 (0%) 

First incidence (days) 733 (T) 733 (T) 658 617 

Life table test P=0.204 P=0.623N P=0.307 P=0.508 

Logistic regression test P=0.403 P=0.623N P=0.291 P=0.754 

Cochran-Armitage test P=0.500N 

Fisher exact test P=0.500N P=0.339 P=0.500N 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 8/50 (16%) 9/50 (18%) 9/50 (18%) 5/50 (10%) 

Adjusted rate 36.7% 44.3% 37.2% 23.7% 

Terminal rate 4/17 (24%) 4/12 (33%) 4/17 (24%) 0/1 (0%) 

First incidence (days) 707 533 631 571 

Life table test P=0.105 P=0.263 P=0.433 P=0.073 

Logistic regression test P=0.530N P=0.357 P=0.420 P=0.577 

Cochran-Armitage test P=0.204N 

Fisher exact test P=0.500 P=0.500 P=0.277N 

Urinary Bladder: Papilloma 

Overall rate 0/49 (0%) 3/50 (6%) 0/50 (0%) 0/50 (0%)
 

Adjusted rate 0.0% 14.8% 0.0% 0.0%
 

Terminal rate 0/17 (0%) 1/12 (8%) 0/17 (0%) 0/1 (0%)
 

First incidence (days) — 600 — —
 

Life table test P=0.509N P=0.085 — —
 

Logistic regression test P=0.354N P=0.113 — —
 

Cochran-Armitage test P=0.308N
 

Fisher exact test P=0.125 — —
 

All Organs: Mononuclear Cell Leukemia 

Overall rate 34/50 (68%) 43/50 (86%) 38/50 (76%) 31/50 (62%) 

Adjusted rate 81.5% 95.3% 91.9% 100.0% 

Terminal rate 10/17 (59%) 10/12 (83%) 14/17 (82%) 1/1 (100%) 

First incidence (days) 509 351 413 509 

Life table test P<0.001 P=0.016 P=0.231 P<0.001 

Logistic regression test P=0.064N P=0.020 P=0.254 P=0.079N 

Cochran-Armitage test P=0.108N 

Fisher exact test P=0.028 P=0.252 P=0.338N 
114 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE A3
 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 156 ppm 312 ppm 625 ppm 

All Organs: Malignant Mesothelioma 

Overall rate 5/50 (10%) 1/50 (2%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 15.0% 3.8% 9.5% 2.3% 

Terminal rate 1/17 (6%) 0/12 (0%) 1/17 (6%) 0/1 (0%) 

First incidence (days) 489 664 674 525 

Life table test P=0.248N P=0.154N P=0.253N P=0.278N 

Logistic regression test P=0.076N P=0.089N P=0.222N P=0.062N 

Cochran-Armitage test P=0.093N 

Fisher exact test P=0.102N P=0.218N P=0.102N 

All Organs: Benign Neoplasms 

Overall rate 49/50 (98%) 48/50 (96%) 50/50 (100%) 49/50 (98%) 

Adjusted rate 100.0% 100.0% 100.0% 100.0% 

Terminal rate 17/17 (100%) 12/12 (100%) 17/17 (100%) 1/1 (100%) 

First incidence (days) 336 351 413 361 

Life table test P<0.001 P=0.130 P=0.365 P<0.001 

Logistic regression test P=0.460 P=0.529N P=0.894 P=0.759N 

Cochran-Armitage test P=0.500 

Fisher exact test P=0.500N P=0.500 P=0.753N 

All Organs: Malignant Neoplasms 

Overall rate 39/50 (78%) 46/50 (92%) 48/50 (96%) 35/50 (70%) 

Adjusted rate 87.9% 97.8% 98.0% 100.0% 

Terminal rate 12/17 (71%) 11/12 (92%) 16/17 (94%) 1/1 (100%) 

First incidence (days) 489 351 413 481 

Life table test P<0.001 P=0.025 P=0.087 P<0.001 

Logistic regression test P=0.035N P=0.030 P=0.009 P=0.042N 

Cochran-Armitage test P=0.075N 

Fisher exact test P=0.045 P=0.007 P=0.247N 

All Organs: Benign or Malignant Neoplasms 

Overall rate 49/50 (98%) 49/50 (98%) 50/50 (100%) 49/50 (98%) 

Adjusted rate 100.0% 100.0% 100.0% 100.0% 

Terminal rate 17/17 (100%) 12/12 (100%) 17/17 (100%) 1/1 (100%) 

First incidence (days) 336 351 413 361 

Life table test P<0.001 P=0.105 P=0.365 P<0.001 

Logistic regression test P=0.655N P=0.769N P=0.894 P=0.759N 

Cochran-Armitage test P=0.617 

Fisher exact test P=0.753N P=0.500 P=0.753N 

(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, 

pancreatic islets, pituitary gland, preputial gland, testes, thyroid gland, and urinary bladder; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study 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 life table test regards neoplasms in animals dying prior to terminal kill as being (directly or indirectly) 

the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the overall incidence 

rates. For all tests, a negative trend or a lower incidence in an exposure group is indicated byN. e Not applicable; no neoplasms in animal group 
Tetrafluoroethylene, NTP TR 450 115 

TABLE A4a 

Historical Incidence of Renal Tubule Neoplasms in Chamber Control Male F344/N Rats a

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 1/50 0/50 1/50 

Acetonitrile 1/48 0/48 1/48 

-Chloroacetophenone 1/49 0/49 1/49 

Epinephrine Hydrochloride 0/50 0/50 0/50 

Ethyl Chloride 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 0/50 0/50 

Ozone 2/50 0/50 2/50 

Total 5/347 (1.4%) 0/347 (0%) 5/347 (1.4%) 

Standard deviation 1.5% 1.5% 

Range 0%-4% 0%-4% 

Overall Historical Incidence 

Total 6/652 (0.9%) 0/652 (0%) 6/652 (0.9%) 

Standard deviation 1.3% 1.3% 

Range 0%-4% 0%-4% 

a Data as of 12 May 1995 

TABLE A4b 

Historical Incidence of Hepatocellular Neoplasms in Chamber Control Male F344/N Rats a

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 2/50 2/50 4/50 

Acetonitrile 0/48 1/48 1/48 

-Chloroacetophenone 1/49 0/49 1/49 

Epinephrine Hydrochloride 1/50 0/50 1/50 

Ethyl Chloride 0/50 1/50 1/50 

Hexachlorocyclopentadiene 1/50 0/50 1/50 

Ozone 2/50 0/50 2/50 

Total 7/347 (2.0%) 4/347 (1.2%) 11/347 (3.2%) 

Standard deviation 1.6% 1.6% 2.3% 

Range 0%-4% 0%-4% 2%-8% 

Overall Historical Incidence 

Total 20/653 (3.1%) 8/653 (1.2%) 28/653 (4.3%) 

Standard deviation 2.8% 1.5% 2.9% 

Range 0%-8% 0%-4% 2%-9% 

a Data as of 12 May 1995 
116 Tetrafluoroethylene, NTP TR 450 

TABLE A4c 

Historical Incidence of Mononuclear Cell Leukemia in Chamber Control Male F344/N Rats a

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 29/50 

Acetonitrile 29/48 

-Chloroacetophenone 29/50 

Epinephrine Hydrochloride 19/50 

Ethyl Chloride 33/50 

Hexachlorocyclopentadiene 29/50 

Ozone 27/50 

Total 195/348 (56.0%) 

Standard deviation 8.7% 

Range 38%-66% 

Overall Historical Incidence 

Total 356/655 (54.4%) 

Standard deviation 8.8% 

Range 34%-66% 

a Data as of 12 May 1995; includes data for lymphocytic, monocytic, and undifferentiated cell type leukemias 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 117 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 156 ppm 312 ppm 625 ppm 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 27 34 32 48 

Natural deaths 6 4 1 1 

Survivors 

Terminal sacrifice 17 12 17 1 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, cecum (10) (10) (10) (10) 

Fibrosis 1 (10%) 

Liver (10) (10) (10) (10) 

Basophilic focus 6 (60%) 4 (40%) 7 (70%) 4 (40%) 

Clear cell focus 4 (40%) 10 (100%) 9 (90%) 10 (100%) 

Degeneration, cystic 1 (10%) 3 (30%) 

Eosinophilic focus 1 (10%) 1 (10%) 

Hepatodiaphragmatic nodule 1 (10%) 1 (10%) 1 (10%) 

Mixed cell focus 2 (20%) 2 (20%) 2 (20%) 

Regeneration 1 (10%) 

Bile duct, hyperplasia 7 (70%) 9 (90%) 6 (60%) 3 (30%) 

Serosa, fibrosis 1 (10%) 

Mesentery (2) (2) (4) 

Fat, hemorrhage 1 (50%) 

Fat, necrosis 1 (50%) 2 (100%) 3 (75%) 

Pancreas (10) (10) (10) (10) 

Basophilic focus 2 (20%) 

Hyperplasia 1 (10%) 

Acinus, atrophy 4 (40%) 7 (70%) 2 (20%) 4 (40%) 

Stomach, glandular (10) (10) (10) (10) 

Mineralization 1 (10%) 

Cardiovascular System 

Heart (10) (10) (10) (10) 

Cardiomyopathy 10 (100%) 10 (100%) 10 (100%) 10 (100%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Hyperplasia 1 (10%) 2 (20%) 1 (10%) 2 (20%) 

Adrenal medulla (10) (10) (10) (10) 

Hyperplasia 3 (30%) 1 (10%) 

Pituitary gland (10) (9) (10) (10) 

Pars distalis, hyperplasia 6 (60%) 3 (33%) 4 (40%) 7 (70%) 

Thyroid gland (10) (10) (10) (10) 

C-cell, hyperplasia 4 (40%) 6 (60%) 5 (50%) 6 (60%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

118 Tetrafluoroethylene, NTP TR 450 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

15-Month Interim Evaluation (continued) 

Genital System 

Preputial gland (10) (10) (10) (10) 

Inflammation, chronic active 3 (30%) 8 (80%) 7 (70%) 6 (60%) 

Testes (10) (10) (10) (10) 

Atrophy 1 (10%) 

Interstitial cell, hyperplasia 2 (20%) 4 (40%) 1 (10%) 

Hematopoietic System 

Bone marrow (10) (10) (10) (10) 

Hyperplasia, reticulum cell 1 (10%) 1 (10%) 

Lymph node, mandibular (10) (8) (10) (10) 

Hemorrhage 1 (10%) 

Lymph node, mesenteric (10) (10) (10) (10) 

Inflammation, chronic active 1 (10%) 

Lymph node, mediastinal (10) (10) (10) (10) 

Hemorrhage 2 (20%) 1 (10%) 2 (20%) 1 (10%) 

Spleen (10) (10) (10) (10) 

Developmental malformation 2 (20%) 1 (10%) 

Capsule, fibrosis 1 (10%) 

Integumentary System 

Mammary gland (5) (7) (4) (5) 

Galactocele 1 (20%) 

Skin (10) (10) (10) (10) 

Inflammation, chronic active 1 (10%) 1 (10%) 

Respiratory System 

Larynx (10) (10) (10) (10) 

Inflammation, chronic active 4 (40%) 5 (50%) 5 (50%) 7 (70%) 

Metaplasia, squamous 1 (10%) 

Mineralization 6 (60%) 8 (80%) 8 (80%) 9 (90%) 

Lung (10) (10) (10) (10) 

Hemorrhage 10 (100%) 10 (100%) 10 (100%) 10 (100%) 

Metaplasia, osseous 1 (10%) 

Alveolar epithelium, hyperplasia 1 (10%) 2 (20%) 3 (30%) 

Urinary System 

Kidney (10) (10) (10) (10) 

Cyst 1 (10%) 

Nephropathy 10 (100%) 10 (100%) 10 (100%) 10 (100%) 

Renal tubule, degeneration 1 (10%) 8 (80%) 10 (100%) 10 (100%) 

Renal tubule, hyperplasia 1 (10%) 1 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 119 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

15-Month Interim Evaluation (continued) 

Systems Examined With No Lesions Observed 

General Body System 

Musculoskeletal System 

Nervous System 

Special Senses System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (50) (50) 

Mineralization 1 (2%) 2 (4%) 1 (2%) 

Parasite metazoan 2 (4%) 1 (2%) 3 (6%) 

Intestine large, rectum (49) (50) (50) (50) 

Parasite metazoan 3 (6%) 1 (2%) 2 (4%) 

Intestine large, cecum (50) (50) (50) (50) 

Inflammation, suppurative 1 (2%) 

Parasite metazoan 2 (4%) 1 (2%) 

Intestine small, duodenum (50) (50) (50) (50) 

Necrosis 1 (2%) 

Intestine small, ileum (49) (49) (50) (50) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Mineralization 1 (2%) 

Peyer's patch, inflammation, granulomatous 1 (2%) 

Liver (50) (50) (50) (50) 

Angiectasis 3 (6%) 2 (4%) 3 (6%) 

Basophilic focus 22 (44%) 19 (38%) 33 (66%) 29 (58%) 

Clear cell focus 7 (14%) 8 (16%) 11 (22%) 3 (6%) 

Congestion 1 (2%) 

Cyst 1 (2%) 

Degeneration, cystic 17 (34%) 39 (78%) 35 (70%) 32 (64%) 

Eosinophilic focus 3 (6%) 18 (36%) 22 (44%) 19 (38%) 

Fatty change 5 (10%) 3 (6%) 4 (8%) 5 (10%) 

Fibrosis 1 (2%) 

Hepatodiaphragmatic nodule 2 (4%) 2 (4%) 3 (6%) 4 (8%) 

Hyperplasia 1 (2%) 

Mineralization 1 (2%) 

Mixed cell focus 5 (10%) 5 (10%) 16 (32%) 13 (26%) 

Necrosis, focal 1 (2%) 

Regeneration 3 (6%) 4 (8%) 1 (2%) 

Thrombosis 1 (2%) 

Bile duct, hyperplasia 44 (88%) 43 (86%) 44 (88%) 42 (84%) 

Centrilobular, necrosis 3 (6%) 1 (2%) 1 (2%) 

Mesentery (15) (11) (18) (14) 

Inflammation, suppurative 2 (13%) 

Fat, hemorrhage 1 (7%) 3 (17%) 1 (7%) 

Fat, necrosis 11 (73%) 11 (100%) 16 (89%) 12 (86%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

120 Tetrafluoroethylene, NTP TR 450 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Alimentary System (continued) 

Pancreas (50) (50) (50) (50) 

Basophilic focus 4 (8%) 1 (2%) 4 (8%) 

Hyperplasia 3 (6%) 1 (2%) 3 (6%) 

Acinus, atrophy 32 (64%) 25 (50%) 31 (62%) 20 (40%) 

Duct, concretion 1 (2%) 

Stomach, forestomach (50) (50) (50) (50) 

Acanthosis 2 (4%) 1 (2%) 2 (4%) 5 (10%) 

Diverticulum 2 (4%) 1 (2%) 2 (4%) 

Infiltration cellular, mast cell 1 (2%) 1 (2%) 

Mineralization 1 (2%) 2 (4%) 3 (6%) 

Necrosis 6 (12%) 4 (8%) 1 (2%) 6 (12%) 

Stomach, glandular (50) (50) (50) (50) 

Mineralization 1 (2%) 3 (6%) 4 (8%) 13 (26%) 

Necrosis 5 (10%) 3 (6%) 3 (6%) 

Tongue (1) (1) (1) 

Epithelium, hyperplasia 1 (100%) 

Tooth (2) (2) (1) (2) 

Dysplasia 2 (100%) 2 (100%) 1 (100%) 2 (100%) 

Cardiovascular System 

Blood vessel (1) (3) (12) 

Mineralization 1 (100%) 2 (67%) 3 (25%) 

Aorta, mineralization 1 (100%) 3 (100%) 12 (100%) 

Heart (50) (50) (50) (50) 

Cardiomyopathy 46 (92%) 44 (88%) 43 (86%) 48 (96%) 

Mineralization 1 (2%) 2 (4%) 4 (8%) 

Atrium, thrombosis 2 (4%) 3 (6%) 1 (2%) 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Hyperplasia 16 (32%) 13 (26%) 21 (42%) 17 (34%) 

Hypertrophy 4 (8%) 4 (8%) 5 (10%) 4 (8%) 

Vacuolization cytoplasmic 2 (4%) 

Adrenal medulla (50) (50) (50) (50) 

Hyperplasia 21 (42%) 21 (42%) 23 (46%) 26 (52%) 

Islets, pancreatic (50) (50) (50) (50) 

Hyperplasia 1 (2%) 1 (2%) 

Parathyroid gland (50) (50) (50) (49) 

Hyperplasia 1 (2%) 3 (6%) 7 (14%) 25 (51%) 

Pituitary gland (50) (49) (49) (49) 

Thrombosis 1 (2%) 

Pars distalis, angiectasis 1 (2%) 

Pars distalis, hyperplasia 4 (8%) 3 (6%) 4 (8%) 8 (16%) 

Thyroid gland (50) (50) (50) (50) 

C-cell, hyperplasia 22 (44%) 24 (48%) 35 (70%) 20 (40%) 

Follicular cell, hyperplasia 2 (4%) 2 (4%) 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 121 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Genital System 

Epididymis (50) (50) (50) (50) 

Granuloma sperm 1 (2%) 

Thrombosis 1 (2%) 

Preputial gland (50) (50) (50) (49) 

Hyperplasia 1 (2%) 1 (2%) 

Inflammation, chronic active 10 (20%) 8 (16%) 10 (20%) 14 (29%) 

Inflammation, granulomatous 1 (2%) 

Duct, ectasia 1 (2%) 1 (2%) 

Prostate (50) (50) (50) (50) 

Inflammation, chronic active 2 (4%) 1 (2%) 

Inflammation, suppurative 1 (2%) 

Seminal vesicle (50) (50) (50) (50) 

Inflammation, suppurative 1 (2%) 

Mineralization 2 (4%) 1 (2%) 

Testes (50) (50) (50) (50) 

Atrophy 2 (4%) 2 (4%) 2 (4%) 

Interstitial cell, hyperplasia 8 (16%) 10 (20%) 6 (12%) 8 (16%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Thrombosis 1 (2%) 

Lymph node (11) (17) (16) (17) 

Iliac, pigmentation 1 (6%) 

Lumbar, hemorrhage 2 (12%) 

Pancreatic, edema 1 (6%) 

Renal, edema 2 (12%) 

Renal, hemorrhage 1 (6%) 

Renal, pigmentation 1 (6%) 

Lymph node, bronchial (45) (50) (46) (47) 

Hemorrhage 1 (2%) 

Lymph node, mandibular (50) (49) (49) (46) 

Hemorrhage 2 (4%) 

Infiltration cellular, plasma cell 2 (4%) 5 (10%) 2 (4%) 

Lymph node, mesenteric (50) (50) (50) (50) 

Edema 1 (2%) 

Hemorrhage 1 (2%) 2 (4%) 

Lymph node, mediastinal (49) (47) (48) (46) 

Hemorrhage 3 (6%) 1 (2%) 3 (7%) 

Inflammation, granulomatous 1 (2%) 1 (2%) 

Spleen (50) (50) (50) (50) 

Congestion 1 (2%) 

Developmental malformation 2 (4%) 3 (6%) 1 (2%) 4 (8%) 

Fibrosis 9 (18%) 14 (28%) 11 (22%) 6 (12%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 2 (4%) 

Infiltration cellular, lipocyte 1 (2%) 

Capsule, fibrosis 1 (2%) 1 (2%) 

Thymus (49) (47) (47) (45) 

Hemorrhage 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

122 Tetrafluoroethylene, NTP TR 450 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Integumentary System 

Mammary gland (33) (36) (41) (34) 

Galactocele 1 (3%) 1 (2%) 

Inflammation, chronic active 1 (3%) 1 (3%) 

Skin (49) (50) (50) (50) 

Acanthosis 1 (2%) 

Fibrosis 1 (2%) 

Hemorrhage 1 (2%) 

Hyperkeratosis 1 (2%) 1 (2%) 1 (2%) 

Inflammation, chronic active 9 (18%) 4 (8%) 4 (8%) 4 (8%) 

Necrosis 1 (2%) 

Prepuce, edema 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Hyperostosis 1 (2%) 1 (2%) 1 (2%) 

Cranium, fibrous osteodystrophy 1 (2%) 1 (2%) 3 (6%) 17 (34%) 

Femur, fibrous osteodystrophy 1 (2%) 1 (2%) 3 (6%) 19 (38%) 

Sternum, developmental malformation 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Compression 12 (24%) 11 (22%) 9 (18%) 6 (12%) 

Hemorrhage 1 (2%) 1 (2%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Inflammation, chronic active 10 (20%) 9 (18%) 8 (16%) 12 (24%) 

Metaplasia, squamous 1 (2%) 1 (2%) 1 (2%) 

Mineralization 36 (72%) 38 (76%) 36 (72%) 33 (66%) 

Lung (50) (50) (50) (50) 

Congestion 1 (2%) 

Hemorrhage 9 (18%) 5 (10%) 3 (6%) 8 (16%) 

Inflammation, chronic active 1 (2%) 

Mineralization 1 (2%) 1 (2%) 3 (6%) 12 (24%) 

Thrombosis 1 (2%) 1 (2%) 

Alveolar epithelium, hyperplasia 5 (10%) 4 (8%) 3 (6%) 3 (6%) 

Nose (50) (50) (50) (50) 

Inflammation, suppurative 5 (10%) 3 (6%) 4 (8%) 7 (14%) 

Thrombosis 2 (4%) 1 (2%) 

Nasolacrimal duct, inflammation, chronic

 active 1 (2%) 

Olfactory epithelium, degeneration 1 (2%) 

Respiratory epithelium, hyperplasia 1 (2%) 

Respiratory epithelium, metaplasia, squamous 2 (4%) 

Trachea (50) (50) (50) (50) 

Metaplasia, squamous 1 (2%) 1 (2%) 

Mineralization 1 (2%) 2 (4%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 123 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 156 ppm 312 ppm 625 ppm 

2-Year Study (continued) 

Special Senses System 

Eye (45) (42) (48) (42) 

Cataract 3 (7%) 4 (8%) 

Degeneration 1 (2%) 4 (8%) 

Cornea, inflammation, chronic active 1 (2%) 4 (10%) 

Cornea, mineralization 1 (2%) 2 (4%) 7 (17%) 

Retina, atrophy 3 (7%) 2 (5%) 5 (10%) 2 (5%) 

Harderian gland (1) 

Hypertrophy 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Developmental malformation 1 (2%) 

Infarct 3 (6%) 

Mineralization 1 (2%) 3 (6%) 4 (8%) 

Nephropathy 49 (98%) 50 (100%) 50 (100%) 50 (100%) 

Pelvis, dilatation 1 (2%) 

Renal tubule, degeneration 2 (4%) 20 (40%) 50 (100%) 49 (98%) 

Renal tubule, hyperplasia 1 (2%) 1 (2%) 1 (2%) 6 (12%) 

Renal tubule, hyperplasia, oncocytic 1 (2%) 

Urinary bladder (49) (50) (50) (50) 

Hemorrhage 1 (2%) 

Inflammation, suppurative 1 (2%) 

Transitional epithelium, hyperplasia 1 (2%) 
124 Tetrafluoroethylene, NTP TR 450 
125 

APPENDIX B 

SUMMARY OF LESIONS IN FEMALE RATS 

IN THE 2-YEAR INHALATION STUDY 

OF TETRAFLUOROETHYLENE 

TABLE B1 

TABLE B2 

TABLE B3 

TABLE B4a 

TABLE B4b 

TABLE B4c 

TABLE B5 

Summary of the Incidence of Neoplasms in Female Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Individual Animal Tumor Pathology of Female Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Statistical Analysis of Primary Neoplasms in Female Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

Historical Incidence of Renal Tubule Neoplasms 

in Chamber Control Female F344/N Rats ............................................. 

Historical Incidence of Liver Neoplasms 

in Chamber Control Female F344/N Rats ............................................. 

Historical Incidence of Mononuclear Cell Leukemia 

in Chamber Control Female F344/N Rats ............................................. 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats 

in the 2-Year Inhalation Study of Tetrafluoroethylene .................................. 

127 

132 

150 

157 

157 

158 

159 
126 Tetrafluoroethylene, NTP TR 450 
 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 127 

TABLE B1 a Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Accidental death 

Moribund 

Natural deaths 

Survivors 

Died last week of study 

Terminal sacrifice 

60 

10 

21 

1 

28 

60 

10 

33 

1 

1 

15 

60 

10 

31 

4 

15 

60 

10 

1 

25 

6 

18 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Endocrine System 

Pituitary gland 

Pars distalis, adenoma

(10) 

 1 (10%) 

(10) 

 2 (20%) 

(10) 

 1 (10%) 

(10) 

Genital System 

Clitoral gland 

Adenoma

Carcinoma

Uterus 

Polyp stromal

(10) 

(10) 

(10) 

 1 (10%) 

 1 (10%) 

(10) 

(10) 

(10) 

 2 (20%) 

(10) 

(10) 

 1 (10%) 

Hematopoietic System 

Bone marrow 

Histiocytic sarcoma

(10) 

 1 (10%) 

(10) (10) (10) 

Integumentary System 

Mammary gland 

Fibroadenoma

(10) (10) (10) (10) 

 1 (10%) 

Respiratory System 

Lung 

Histiocytic sarcoma, metastatic, bone marrow

(10) 

 1 (10%) 

(10) (10) (10) 

Urinary System 

Kidney 

Mixed tumor malignant

Renal tubule, adenoma

(10) (10) (10) (10) 

 1 (10%) 

 1 (10%) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

(10) 

 1 (10%) 

(10) (10) (10) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

128 Tetrafluoroethylene, NTP TR 450 

TABLE B1
 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Systems Examined With No Neoplasms Observed 

Alimentary System 

Cardiovascular System 

General Body System 

Musculoskeletal System 

Nervous System 

Special Senses System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (49) (50) 

Intestine large, rectum (50) (50) (49) (50) 

Sarcoma stromal, metastatic, uterus 1 (2%) 

Intestine large, cecum (50) (50) (49) (50) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Intestine small, duodenum (49) (50) (49) (50) 

Intestine small, jejunum (50) (50) (47) (49) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Intestine small, ileum (50) (49) (48) (49) 

Liver (50) (50) (50) (50) 

Hemangiosarcoma 5 (10%) 1 (2%) 

Hepatocellular carcinoma 4 (8%) 6 (12%) 2 (4%) 

Hepatocellular carcinoma, multiple 3 (6%) 

Hepatocellular adenoma 3 (6%) 4 (8%) 5 (10%) 

Hepatocellular adenoma, multiple 1 (2%) 1 (2%) 1 (2%) 

Sarcoma 1 (2%) 

Mesentery (6) (4) (4) (6) 

Leiomyosarcoma, metastatic, uterus 1 (17%) 

Pancreas (50) (50) (49) (50) 

Salivary glands (50) (50) (50) (50) 

Adenoma 1 (2%) 

Stomach, forestomach (50) (50) (48) (50) 

Squamous cell carcinoma 1 (2%) 

Stomach, glandular (50) (50) (49) (50) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Tongue (2) (2) (1) 

Squamous cell papilloma 2 (100%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Schwannoma NOS 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Adrenal medulla (50) (50) (50) (50) 

Pheochromocytoma benign 4 (8%) 1 (2%) 2 (4%) 5 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 129 

TABLE B1
 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Endocrine System (continued) 

Islets, pancreatic (50) (50) (49) (50) 

Adenoma 1 (2%) 

Carcinoma 1 (2%) 

Parathyroid gland (48) (49) (49) (47) 

Adenoma 1 (2%) 

Pituitary gland (50) (50) (49) (50) 

Pars distalis, adenoma 43 (86%) 34 (68%) 36 (73%) 34 (68%) 

Pars distalis, carcinoma 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

C-cell, adenoma 5 (10%) 9 (18%) 5 (10%) 2 (4%) 

C-cell, carcinoma 2 (4%) 2 (4%) 3 (6%) 2 (4%) 

Follicular cell, carcinoma 1 (2%) 

General Body System 

Tissue NOS

Abdominal, fat, hemangiosarcoma, metastatic, 

tissue NOS

 (1) 

 1 (100%) 

Genital System 

Clitoral gland (49) (49) (50) (48) 

Adenoma 6 (12%) 6 (12%) 2 (4%) 

Carcinoma 1 (2%) 1 (2%) 2 (4%) 2 (4%) 

Ovary (50) (50) (50) (50) 

Granulosa-theca tumor benign 1 (2%) 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Uterus (50) (50) (50) (50) 

Leiomyosarcoma 1 (2%) 1 (2%) 

Polyp stromal 5 (10%) 4 (8%) 4 (8%) 5 (10%) 

Polyp stromal, multiple 1 (2%) 1 (2%) 

Sarcoma stromal 1 (2%) 1 (2%) 

Vagina (1) (1) (1) 

Polyp 1 (100%) 1 (100%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Lymph node (3) (7) (7) (13) 

Iliac, osteosarcoma, metastatic, bone 1 (8%) 

Lymph node, bronchial (50) (50) (50) (48) 

Lymph node, mandibular (48) (49) (50) (50) 

Lymph node, mesenteric (50) (50) (50) (50) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Lymph node, mediastinal (49) (49) (49) (45) 

Spleen (50) (50) (49) (50) 

Thymus (47) (48) (49) (48) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

130 Tetrafluoroethylene, NTP TR 450 

TABLE B1
 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Adenoma 1 (2%) 1 (2%) 1 (2%) 

Carcinoma 3 (6%) 1 (2%) 3 (6%) 1 (2%) 

Carcinoma, multiple 1 (2%) 

Fibroadenoma 17 (34%) 10 (20%) 8 (16%) 5 (10%) 

Fibroadenoma, multiple 5 (10%) 1 (2%) 1 (2%) 2 (4%) 

Skin (50) (50) (50) (50) 

Basosquamous tumor malignant 1 (2%) 1 (2%) 

Keratoacanthoma 2 (4%) 1 (2%) 

Squamous cell papilloma 1 (2%) 1 (2%) 

Subcutaneous tissue, fibroma 1 (2%) 

Subcutaneous tissue, neurofibroma 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 1 (2%) 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Vertebra, osteosarcoma 1 (2%) 

Vertebra, sarcoma 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Astrocytoma NOS 1 (2%) 1 (2%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar adenoma 1 (2%) 

Alveolar/bronchiolar carcinoma 1 (2%) 

Carcinoma, metastatic, mammary gland 1 (2%) 

Carcinoma, metastatic, pituitary gland 1 (2%) 

Carcinoma, metastatic, thyroid gland 1 (2%) 1 (2%) 

Hemangiosarcoma, metastatic, liver 3 (6%) 

Hepatocellular carcinoma, metastatic, liver 2 (4%) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Osteosarcoma, metastatic, bone 1 (2%) 

Sarcoma, metastatic, bone 1 (2%) 

Sarcoma, metastatic, liver 1 (2%) 

Nose (50) (50) (50) (50) 

Trachea (50) (50) (50) (50) 

Special Senses System 

Eye (50) (50) (50) (50) 

Zymbal's gland (1) (1) 

Adenoma 1 (100%) 
 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 131 

TABLE B1
 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Urinary System 

Kidney (50) (50) (50) (50) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Renal tubule, adenoma 3 (6%) 1 (2%) 3 (6%) 

Renal tubule, carcinoma 2 (4%) 

Urinary bladder (49) (50) (50) (49) 

Sarcoma stromal, metastatic, uterus 1 (2%) 

Transitional epithelium, papilloma 2 (4%) 

Systemic Lesions 

Multiple organs (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Leukemia mononuclear 16 (32%) 31 (62%) 23 (46%) 36 (72%) 

Mesothelioma malignant 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 1 4 3 3 

2-Year study 49 50 49 48 

Total primary neoplasms 

15-Month interim evaluation 2 4 3 4 

2-Year study 121 123 121 118 

Total animals with benign neoplasms 

15-Month interim evaluation 1 3 3 3 

2-Year study 46 43 43 40 

Total benign neoplasms 

15-Month interim evaluation 1 3 3 3 

2-Year study 93 75 72 68 

Total animals with malignant neoplasms 

15-Month interim evaluation 1 1 1 

2-Year study 21 41 35 42 

Total malignant neoplasms 

15-Month interim evaluation 1 1 1 

2-Year study 27 47 49 49 

Total animals with metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 2 3 8 3 

Total metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 6 4 9 7 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 1 1 1 

Total uncertain neoplasms 

2-Year study 1 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
 c 
 

 

 

 

 

 

 

 

 

 

 

132 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm 

4 4 4 5 5 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 8 8 5 8 2 2 4 4 6 7 8 9 9 9 9 0 0 0 1 2 2 3 3 3 

3 1 1 4 1 1 6 8 9 3 7 5 2 3 8 9 2 7 7 4 1 6 4 4 4 

1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 

Carcass ID Number 0 7 1 0 1 2 9 9 9 7 1 8 8 6 9 7 9 6 1 6 1 9 6 6 6 

2 3 5 7 2 0 9 3 2 1 7 0 3 3 4 0 5 7 8 6 3 8 1 2 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Mesentery + + + + 

Leiomyosarcoma, metastatic, uterus X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell carcinoma 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tongue + 

Squamous cell papilloma X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Schwannoma NOS 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + + + + + M + + + + M + + + + + + + + + + 

Adenoma X 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X 

C-cell, carcinoma 

General Body System 

None 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 133 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

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 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 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 6 6 7 7 7 8 8 8 8 8 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 Tissues/ 

5 8 2 6 9 2 4 5 8 9 0 1 6 7 0 1 4 5 8 9 0 1 4 6 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + M + + + + + + + + + + + 49 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + 6 

Leiomyosarcoma, metastatic, uterus 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell carcinoma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + 2 

Squamous cell papilloma X 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma NOS X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic, uterus 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X 4 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma 1 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X X X 43 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X 5 

C-cell, carcinoma X X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

134 Tetrafluoroethylene, NTP TR 450 

TABLE B2
 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

4 4 4 5 5 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 8 8 5 8 2 2 4 4 6 7 8 9 9 9 9 0 0 0 1 2 2 3 3 3 

3 1 1 4 1 1 6 8 9 3 7 5 2 3 8 9 2 7 7 4 1 6 4 4 4 

1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 

Carcass ID Number 0 7 1 0 1 2 9 9 9 7 1 8 8 6 9 7 9 6 1 6 1 9 6 6 6 

2 3 5 7 2 0 9 3 2 1 7 0 3 3 4 0 5 7 8 6 3 8 1 2 4 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + M + + + + + + + 

Adenoma X X 

Carcinoma 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Polyp stromal X X X 

Polyp stromal, multiple 

Vagina + 

Polyp X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Lymph node + + + 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mandibular + + + + + + + + M + + + + + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + M + + + + + + + + + + + + + + + + + + M + + M + 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X X 

Fibroadenoma X X X X X X X X X 

Fibroadenoma, multiple X X X X X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Keratoacanthoma X 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone 

Vertebra, sarcoma 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma, metastatic, bone X 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 135 

TABLE B2
 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

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 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 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 6 6 7 7 7 8 8 8 8 8 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 Tissues/ 

5 8 2 6 9 2 4 5 8 9 0 1 6 7 0 1 4 5 8 9 0 1 4 6 9 Tumors 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X X X X 6 

Carcinoma X 1 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma 1 

Polyp stromal X X 5 

Polyp stromal, multiple X 1 

Vagina 1 

Polyp 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Lymph node 3 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mandibular + + + + + + + + + + + + + + + + M + + + + + + + + 48 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic, uterus 1 

Lymph node, mediastinal + + + + + + + + + + + + + + + + M + + + + + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Carcinoma X 3 

Fibroadenoma X X X X X X X X 17 

Fibroadenoma, multiple 5 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Keratoacanthoma X 2 

Subcutaneous tissue, sarcoma 1 

Musculoskeletal System 

Bone 

Vertebra, sarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma, metastatic, bone 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 1 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

136 Tetrafluoroethylene, NTP TR 450 

TABLE B2
 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

4 4 4 5 5 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 8 8 5 8 2 2 4 4 6 7 8 9 9 9 9 0 0 0 1 2 2 3 3 3 

3 1 1 4 1 1 6 8 9 3 7 5 2 3 8 9 2 7 7 4 1 6 4 4 4 

1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 

Carcass ID Number 0 7 1 0 1 2 9 9 9 7 1 8 8 6 9 7 9 6 1 6 1 9 6 6 6 

2 3 5 7 2 0 9 3 2 1 7 0 3 3 4 0 5 7 8 6 3 8 1 2 4 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Urinary bladder + + + + + + + + M + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Leukemia mononuclear X X X X X X X X 
 

 

 

Tetrafluoroethylene, NTP TR 450 137 

TABLE B2
 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

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 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 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 6 6 7 7 7 8 8 8 8 8 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 Tissues/ 

5 8 2 6 9 2 4 5 8 9 0 1 6 7 0 1 4 5 8 9 0 1 4 6 9 Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic, uterus 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Leukemia mononuclear X X X X X X X X 16 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

138 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

2 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 

Number of Days on Study 4 1 6 6 1 2 3 5 6 6 7 7 8 8 8 9 9 0 1 1 1 2 3 4 5 

7 3 8 8 7 3 7 7 5 5 4 4 1 3 8 4 7 0 7 8 8 5 8 9 3 

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 

Carcass ID Number 9 7 5 8 4 7 5 7 5 7 4 6 9 9 8 5 7 6 8 6 6 7 5 9 0 

2 2 2 8 8 9 5 6 0 1 4 5 0 1 1 4 4 9 7 1 7 0 8 7 0 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Sarcoma stromal, metastatic, uterus X 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Pharynx + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tooth + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X 

Parathyroid gland + + M + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X 

Pars distalis, carcinoma 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X 

C-cell, carcinoma X 

Follicular cell, carcinoma 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + M + 

Adenoma X 

Carcinoma 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Polyp stromal 

Polyp stromal, multiple X 

Sarcoma stromal X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 139 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

6 6 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 7 9 0 0 0 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 1 1 4 7 2 3 0 0 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

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 5 6 9 4 9 4 5 5 8 9 4 5 6 6 7 7 7 8 8 8 8 8 9 9 9 Tissues/ 

3 0 3 5 5 2 9 6 5 4 3 7 3 8 3 5 7 0 2 3 4 6 6 8 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma stromal, metastatic, uterus 1 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum A + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma X X X 4 

Hepatocellular adenoma X X X 3 

Hepatocellular adenoma, multiple X 1 

Mesentery + 4 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pharynx 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tooth 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X 34 

Pars distalis, carcinoma X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X X X X 9 

C-cell, carcinoma X 2 

Follicular cell, carcinoma X 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X X X X X 6 

Carcinoma X 1 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma 1 

Polyp stromal X X X X 4 

Polyp stromal, multiple 1 

Sarcoma stromal 1 
 

 

 

 

 

 

 

 

 

 

 

 

140 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

2 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 

Number of Days on Study 4 1 6 6 1 2 3 5 6 6 7 7 8 8 8 9 9 0 1 1 1 2 3 4 5 

7 3 8 8 7 3 7 7 5 5 4 4 1 3 8 4 7 0 7 8 8 5 8 9 3 

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 

Carcass ID Number 9 7 5 8 4 7 5 7 5 7 4 6 9 9 8 5 7 6 8 6 6 7 5 9 0 

2 2 2 8 8 9 5 6 0 1 4 5 0 1 1 4 4 9 7 1 7 0 8 7 0 

Hematopoietic System 

Blood 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mandibular + + + + + + + + + + + + + M + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal + + M + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + M M + + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X 

Fibroadenoma X X X X X 

Fibroadenoma, multiple X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain 

Astrocytoma NOS 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, pituitary

 gland 

Carcinoma, metastatic, thyroid gland 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 

Harderian gland 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Sarcoma stromal, metastatic, uterus X 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X 

Mesothelioma malignant X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 141 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

6 6 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 7 9 0 0 0 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 1 1 4 7 2 3 0 0 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

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 5 6 9 4 9 4 5 5 8 9 4 5 6 6 7 7 7 8 8 8 8 8 9 9 9 Tissues/ 

3 0 3 5 5 2 9 6 5 4 3 7 3 8 3 5 7 0 2 3 4 6 6 8 9 Tumors 

Hematopoietic System 

Blood + 1 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + 7 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma 1 

Fibroadenoma X X X X X 10 

Fibroadenoma, multiple 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Subcutaneous tissue, fibroma X 1 

Subcutaneous tissue, sarcoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain 

Astrocytoma NOS

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma X 1 

Carcinoma, metastatic, pituitary

 gland X 1 

Carcinoma, metastatic, thyroid gland X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Harderian gland + 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X X 3 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma stromal, metastatic, uterus 1 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X 31 

Mesothelioma malignant 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

142 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

3 3 4 4 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 8 6 7 7 0 3 3 4 8 8 8 8 0 0 1 2 5 5 6 6 6 7 7 7 

3 7 9 7 8 4 4 6 4 1 7 7 9 7 8 1 5 2 3 4 8 8 2 4 7 

4 3 3 4 3 3 3 3 4 4 3 4 4 3 3 4 3 4 3 4 3 3 3 4 3 

Carcass ID Number 0 6 7 1 8 7 6 7 1 1 9 0 1 6 7 0 9 1 6 0 6 8 9 1 9 

3 9 9 0 5 3 5 7 1 9 2 0 2 2 4 4 6 5 1 1 4 4 4 4 8 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + I + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + A + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + A + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X X 

Hepatocellular carcinoma X 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Sarcoma 

Mesentery + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + M + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + M + + + + + + + + + + + + + + + + + + + + + + + 

Tongue 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, liver 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X 

C-cell, carcinoma 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Carcinoma X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Granulosa-theca tumor benign X 

Hepatocellular carcinoma, metastatic,

 liver 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal 

Vagina + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 143 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

6 6 6 6 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 8 9 9 9 0 1 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 8 8 9 2 6 9 3 3 3 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

3 3 3 3 3 4 4 3 3 4 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 Total 

Carcass ID Number 8 7 8 7 8 0 1 6 9 1 6 6 7 7 8 8 8 8 9 9 9 9 0 0 2 Tissues/ 

8 5 1 0 2 8 8 6 3 7 3 8 1 6 0 3 6 7 0 1 7 9 5 6 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, cecum + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Intestine small, jejunum + + A + + A + + + + + + + + + + + + + + + + + + + 47 

Intestine small, ileum + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X X X 5 

Hepatocellular carcinoma X X X X X 6 

Hepatocellular carcinoma, multiple X X X 3 

Hepatocellular adenoma X X X X 4 

Hepatocellular adenoma, multiple X 1 

Sarcoma X 1 

Mesentery + + 4 

Pancreas + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Tongue + + 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma, metastatic, liver X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 2 

Islets, pancreatic + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Parathyroid gland + M + + + + + + + + + + + + + + + + + + + + + + + 49 

Pituitary gland + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X 36 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X 5 

C-cell, carcinoma X X X 3 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Carcinoma X 2 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Granulosa-theca tumor benign 1 

Hepatocellular carcinoma, metastatic,

 liver X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X X X 4 

Vagina 1 
 

 

 

 

 

 

 

 

 

 

 

 

144 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

Number of Days on Study 

3 

6 

3 

3 

8 

7 

4 

6 

9 

4 

7 

7 

4 

7 

8 

5 

0 

4 

5 

3 

4 

5 

3 

6 

5 

4 

4 

5 

8 

1 

5 

8 

7 

5 

8 

7 

5 

8 

9 

6 

0 

7 

6 

0 

8 

6 

1 

1 

6 

2 

5 

6 

5 

2 

6 

5 

3 

6 

6 

4 

6 

6 

8 

6 

6 

8 

6 

7 

2 

6 

7 

4 

6 

7 

7 

Carcass ID Number 

4 

0 

3 

3 

6 

9 

3 

7 

9 

4 

1 

0 

3 

8 

5 

3 

7 

3 

3 

6 

5 

3 

7 

7 

4 

1 

1 

4 

1 

9 

3 

9 

2 

4 

0 

0 

4 

1 

2 

3 

6 

2 

3 

7 

4 

4 

0 

4 

3 

9 

6 

4 

1 

5 

3 

6 

1 

4 

0 

1 

3 

6 

4 

3 

8 

4 

3 

9 

4 

4 

1 

4 

3 

9 

8 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node + + + +
 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + M + + +
 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + +
 

Thymus + + + + + + + + + + + + + + + + + + + + + M + + +
 

Integumentary System 

Mammary gland 

Adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X X 

Carcinoma, multiple 

Fibroadenoma X X X X 

Fibroadenoma, multiple 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Basosquamous tumor malignant 

Squamous cell papilloma 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Carcinoma, metastatic, mammary gland 

Hemangiosarcoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Sarcoma, metastatic, liver 

Nose 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Zymbal's gland 

Adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Transitional epithelium, papilloma X 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 145 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

Number of Days on Study 

6 

8 

5 

6 

9 

8 

6 

9 

8 

6 

9 

9 

7 

0 

2 

7 

1 

6 

7 

2 

9 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

7 

3 

5 

Carcass ID Number 

3 

8 

8 

3 

7 

5 

3 

8 

1 

3 

7 

0 

3 

8 

2 

4 

0 

8 

4 

1 

8 

3 

6 

6 

3 

9 

3 

4 

1 

7 

3 

6 

3 

3 

6 

8 

3 

7 

1 

3 

7 

6 

3 

8 

0 

3 

8 

3 

3 

8 

6 

3 

8 

7 

3 

9 

0 

3 

9 

1 

3 

9 

7 

3 

9 

9 

4 

0 

5 

4 

0 

6 

4 

2 

0 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + 7 

Lymph node, bronchial + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spleen + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Integumentary System 

Mammary gland 

Adenoma 

+ + + + + 

X

+ + + + + + + + + + + + + + + + + + + + 50 

1 

Carcinoma X 3 

Carcinoma, multiple 

Fibroadenoma X X 

X

X X

 1 

8 

Fibroadenoma, multiple 

Skin + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + 

1 

50 

Basosquamous tumor malignant 

Squamous cell papilloma 

Subcutaneous tissue, sarcoma

X

X

 1 

1 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Carcinoma, metastatic, mammary gland

Hemangiosarcoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Sarcoma, metastatic, liver 

Nose 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

50 

50 

1 

1 

3 

2 

1 

50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye 

Zymbal's gland 

Adenoma 

+ + + + + + + + + + + 

+

X

+ + + + + + + + + + + + + + 50 

1 

1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Transitional epithelium, papilloma X 2 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X 23 
 

 

 

 

 

 

 

 

 

146 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

0 3 3 4 4 4 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 

Number of Days on Study 0 7 7 3 3 6 8 0 0 1 3 3 7 7 7 8 9 0 0 1 2 2 2 2 3 

6 2 8 3 9 1 1 4 9 8 1 8 2 6 9 3 4 3 8 0 1 1 4 8 5 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 6 7 5 4 6 3 3 7 5 5 5 7 3 2 2 6 6 3 6 6 6 6 4 8 5 

4 7 2 6 5 5 2 6 1 3 6 1 6 8 4 0 8 9 6 2 1 3 7 0 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, liver 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + A + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, liver 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery + + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, liver 

Tongue 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + M M + + + + + + + M + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X 

C-cell, carcinoma 

General Body System 

Tissue NOS 

Abdominal, fat, hemangiosarcoma,

 metastatic, tissue NOS 

Genital System 

Clitoral gland + + + + + + + + + + M + + + + + + + + + + + + + M 

Carcinoma X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Granulosa-theca tumor benign X 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X X X 

Sarcoma stromal X 

Vagina + 

Polyp X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 147 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

6 6 6 6 6 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 3 5 6 7 7 0 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 3 8 7 8 3 7 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 2 2 7 4 4 3 4 2 2 2 3 3 3 4 4 4 4 5 5 6 6 7 7 7 7 Tissues/ 

2 1 3 3 4 1 5 3 5 7 0 7 8 1 2 8 9 0 5 7 9 0 2 4 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma, metastatic, liver X 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma, metastatic, liver X 1 

Intestine small, ileum + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 1 

Hepatocellular carcinoma X X 2 

Hepatocellular adenoma X X X X X 5 

Hepatocellular adenoma, multiple X 1 

Mesentery + + 6 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma, metastatic, liver X 1 

Tongue + 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X 5 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X 34 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X 2 

C-cell, carcinoma X X 2 

General Body System 

Tissue NOS + 1 

Abdominal, fat, hemangiosarcoma,

 metastatic, tissue NOS X 1 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma X 2 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Granulosa-theca tumor benign 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X 5 

Sarcoma stromal 1 

Vagina 1 

Polyp 1 
 

 

 

 

 

 

 

 

 

 

 

 

148 Tetrafluoroethylene, NTP TR 450 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

0 3 3 4 4 4 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 

Number of Days on Study 0 

6 

7 

2 

7 

8 

3 

3 

3 

9 

6 

1 

8 

1 

0 

4 

0 

9 

1 

8 

3 

1 

3 

8 

7 

2 

7 

6 

7 

9 

8 

3 

9 

4 

0 

3 

0 

8 

1 

0 

2 

1 

2 

1 

2 

4 

2 

8 

3 

5 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 6 

4 

7 

7 

5 

2 

4 

6 

6 

5 

3 

5 

3 

2 

7 

6 

5 

1 

5 

3 

5 

6 

7 

1 

3 

6 

2 

8 

2 

4 

6 

0 

6 

8 

3 

9 

6 

6 

6 

2 

6 

1 

6 

3 

4 

7 

8 

0 

5 

4 

Hematopoietic System 

Bone marrow 

Lymph node 

Iliac, osteosarcoma, metastatic, bone 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Thymus 

+ + 

+ 

M + 

+ + 

+ + 

+ + 

+ + 

+ + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ + 

+ + 

+ + 

+ + 

M + 

+ + 

+ + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ + 

+ 

X 

+ + 

+ + 

+ + 

M + 

+ + 

M + 

+ + 

+ 

+ + 

+ + 

+ + 

M + 

+ + 

+ + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ + 

+ 

+ + 

+ + 

+ + 

+ + 

+ + 

M + 

Integumentary System 

Mammary gland 

Adenoma 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Basosquamous tumor malignant 

Keratoacanthoma 

Squamous cell papilloma 

Subcutaneous tissue, neurofibroma 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Musculoskeletal System 

Bone 

Vertebra, osteosarcoma 

+ + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + 

Nervous System 

Brain 

Astrocytoma NOS 

+ + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, thyroid gland 

Osteosarcoma, metastatic, bone X 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 

Zymbal's gland 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma 

Renal tubule, carcinoma 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 149 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

6 6 6 6 6 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 3 

9 

5 

3 

6 

8 

7 

7 

7 

8 

0 

3 

2 

7 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 2 

2 

2 

1 

7 

3 

4 

3 

4 

4 

3 

1 

4 

5 

2 

3 

2 

5 

2 

7 

3 

0 

3 

7 

3 

8 

4 

1 

4 

2 

4 

8 

4 

9 

5 

0 

5 

5 

6 

7 

6 

9 

7 

0 

7 

2 

7 

4 

7 

9 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Iliac, osteosarcoma, metastatic, bone

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Thymus 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ + 

+ 

M + 

+ + 

+ + 

M + 

+ + 

+ + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ + 

+ + 

+ + 

+ + 

M + 

+ + 

+ + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

50 

13 

1 

48 

50 

50 

45 

50 

48 

Integumentary System 

Mammary gland 

Adenoma 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Basosquamous tumor malignant 

Keratoacanthoma 

Squamous cell papilloma 

Subcutaneous tissue, neurofibroma 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

X

X 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

X

50 

1 

1 

5 

2 

50 

1 

1 

1 

1 

Musculoskeletal System 

Bone 

Vertebra, osteosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Nervous System 

Brain 

Astrocytoma NOS

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, thyroid gland X 1 

Osteosarcoma, metastatic, bone 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Zymbal's gland + 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X X X 3 

Renal tubule, carcinoma X X 2 

Urinary bladder + + M + + + + + + + + + + + + + + + + + + + + + + 49 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X X 36 
150 Tetrafluoroethylene, NTP TR 450 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Adrenal Medulla: Benign Pheochromocytoma 

Overall ratea 

Adjusted rateb 

Terminal ratec 

4/50 (8%) 

12.7% 

2/28 (7%) 

1/50 (2%) 

3.2% 

0/16 (0%) 

2/50 (4%) 

9.6% 

1/15 (7%) 

5/50 (10%) 

20.4% 

2/18 (11%) 

First incidence (days) 

Life table testd 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

698 

P=0.136 

P=0.188 

P=0.273 

618 

P=0.347N 

P=0.247N 

P=0.181N 

653 

P=0.577N 

P=0.461N 

P=0.339N 

610 

P=0.239 

P=0.354 

P=0.500 

Clitoral Gland: Adenoma 

Overall rate 6/49 (12%) 6/49 (12%) 2/50 (4%) 0/48 (0%) 

Adjusted rate 18.7% 31.4% 11.9% 0.0% 

Terminal rate 

First incidence (days) 

4/28 (14%) 

648 

4/16 (25%) 

617 

1/15 (7%) 

733 

0/18 (0%) 

—e 

Life table test P=0.029N P=0.263 P=0.365N P=0.062N 

Logistic regression test P=0.020N P=0.382 P=0.242N P=0.046N 

Cochran-Armitage test P=0.006N 

Fisher exact test P=0.620N P=0.128N P=0.014N 

Clitoral Gland: Adenoma or Carcinoma 

Overall rate 7/49 (14%) 7/49 (14%) 4/50 (8%) 2/48 (4%) 

Adjusted rate 22.1% 37.1% 19.5% 8.6% 

Terminal rate 5/28 (18%) 5/16 (31%) 1/15 (7%) 1/18 (6%) 

First incidence (days) 648 617 625 610 

Life table test P=0.152N P=0.223 P=0.594N P=0.243N 

Logistic regression test P=0.114N P=0.333 P=0.412N P=0.180N 

Cochran-Armitage test P=0.042N 

Fisher exact test P=0.613N P=0.251N P=0.084N 

Kidney (Renal Tubule): Adenoma (Single Sections) 

Overall rate 0/50 (0%) 3/50 (6%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 0.0% 13.7% 3.3% 16.7% 

Terminal rate 0/28 (0%) 1/16 (6%) 0/15 (0%) 3/18 (17%) 

First incidence (days) — 574 668 734(T) 

Life table test P=0.095 P=0.066 P=0.443 P=0.054 

Logistic regression test P=0.099 P=0.100 P=0.505 P=0.054 

Cochran-Armitage test P=0.165 

Fisher exact test P=0.121 P=0.500 P=0.121 

Kidney (Renal Tubule): Adenoma (Step Sections) 

Overall rate 0/50 (0%) 0/50 (0%) 2/50 (4%) 5/50 (10%) 

Adjusted rate 0.0% 0.0% 11.9% 23.0% 

Terminal rate 0/28 (0%) 0/16 (0%) 1/15 (7%) 3/18 (17%) 

First incidence (days) — — 733 628 

Life table test P<0.001 — P=0.133 P=0.008 

Logistic regression test P<0.001 — P=0.143 P=0.013 

Cochran-Armitage test P=0.003 

Fisher exact test — P=0.247 P=0.028 
 

Tetrafluoroethylene, NTP TR 450 151 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 0/50 (0%) 3/50 (6%) 3/50 (6%) 8/50 (16%) 

Adjusted rate 0.0% 13.7% 14.8% 38.4% 

Terminal rate 0/28 (0%) 1/16 (6%) 1/15 (7%) 6/18 (33%) 

First incidence (days) — 574 668 628 

Life table test P<0.001 P=0.066 P=0.057 P<0.001 

Logistic regression test P<0.001 P=0.100 P=0.076 P<0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.121 P=0.121 P=0.003 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single Sections) 

Overall rate 0/50 (0%) 3/50 (6%) 1/50 (2%) 5/50 (10%)
 

Adjusted rate 0.0% 13.7% 3.3% 27.8%
 

Terminal rate 0/28 (0%) 1/16 (6%) 0/15 (0%) 5/18 (28%)
 

First incidence (days) — 574 668 734 (T) 

Life table test P=0.012 P=0.066 P=0.443 P=0.007
 

Logistic regression test P=0.010 P=0.100 P=0.505 P=0.007
 

Cochran-Armitage test P=0.029
 

Fisher exact test P=0.121 P=0.500 P=0.028
 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 0/50 (0%) 3/50 (6%) 3/50 (6%) 10/50 (20%) 

Adjusted rate 0.0% 13.7% 14.8% 48.8% 

Terminal rate 0/28 (0%) 1/16 (6%) 1/15 (7%) 8/18 (44%) 

First incidence (days) — 574 668 628 

Life table test P<0.001 P=0.066 P=0.057 P<0.001 

Logistic regression test P<0.001 P=0.100 P=0.076 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.121 P=0.121 P<0.001 

Liver: Hemangiosarcoma 

Overall rate 0/50 (0%) 0/50 (0%) 5/50 (10%) 1/50 (2%) 

Adjusted rate 0.0% 0.0% 19.5% 5.0% 

Terminal rate 0/28 (0%) 0/16 (0%) 0/15 (0%) 0/18 (0%) 

First incidence (days) — — 589 703 

Life table test P=0.143 — P=0.013 P=0.400 

Logistic regression test P=0.182 — P=0.025 P=0.435 

Cochran-Armitage test P=0.242 

Fisher exact test — P=0.028 P=0.500 

Liver: Hepatocellular Adenoma 

Overall rate 0/50 (0%) 4/50 (8%) 5/50 (10%) 6/50 (12%) 

Adjusted rate 0.0% 22.6% 33.3% 28.2% 

Terminal rate 0/28 (0%) 3/16 (19%) 5/15 (33%) 3/18 (17%) 

First incidence (days) — 707 734 (T) 677 

Life table test P=0.006 P=0.017 P=0.003 P=0.003 

Logistic regression test P=0.004 P=0.020 P=0.003 P=0.003 

Cochran-Armitage test P=0.026 

Fisher exact test P=0.059 P=0.028 P=0.013 
152 Tetrafluoroethylene, NTP TR 450 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Liver: Hepatocellular Carcinoma 

Overall rate 0/50 (0%) 4/50 (8%) 9/50 (18%) 2/50 (4%)
 

Adjusted rate 0.0% 20.9% 48.1% 11.1%
 

Terminal rate 0/28 (0%) 3/16 (19%) 6/15 (40%) 2/18 (11%)
 

First incidence (days) — 583 668 734 (T)
 

Life table test P=0.146 P=0.020 P<0.001 P=0.147 

Logistic regression test P=0.128 P=0.037 P<0.001 P=0.147 

Cochran-Armitage test P=0.309 

Fisher exact test P=0.059 P=0.001 P=0.247 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 0/50 (0%) 7/50 (14%) 12/50 (24%) 8/50 (16%) 

Adjusted rate 0.0% 36.3% 65.4% 37.8% 

Terminal rate 0/28 (0%) 5/16 (31%) 9/15 (60%) 5/18 (28%) 

First incidence (days) — 583 668 677 

Life table test P=0.002 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.001 P=0.002 P<0.001 P<0.001 

Cochran-Armitage test P=0.020 

Fisher exact test P=0.006 P<0.001 P=0.003 

Mammary Gland: Fibroadenoma 

Overall rate 22/50 (44%) 11/50 (22%) 9/50 (18%) 7/50 (14%) 

Adjusted rate 55.2% 41.8% 38.1% 28.0% 

Terminal rate 11/28 (39%) 5/16 (31%) 4/15 (27%) 3/18 (17%) 

First incidence (days) 481 468 534 504 

Life table test P=0.033N P=0.277N P=0.162N P=0.055N 

Logistic regression test P=0.003N P=0.024N P=0.009N P=0.004N 

Cochran-Armitage test P=0.001N 

Fisher exact test P=0.016N P=0.004N P<0.001N 

Mammary Gland: Fibroadenoma or Adenoma 

Overall rate 23/50 (46%) 11/50 (22%) 10/50 (20%) 8/50 (16%) 

Adjusted rate 57.8% 41.8% 41.1% 32.8% 

Terminal rate 12/28 (43%) 5/16 (31%) 4/15 (27%) 4/18 (22%) 

First incidence (days) 481 468 534 504 

Life table test P=0.050N P=0.232N P=0.196N P=0.068N 

Logistic regression test P=0.005N P=0.016N P=0.011N P=0.006N 

Cochran-Armitage test P=0.002N 

Fisher exact test P=0.010N P=0.005N P=0.001N 

Mammary Gland: Carcinoma 

Overall rate 3/50 (6%) 1/50 (2%) 4/50 (8%) 1/50 (2%)
 

Adjusted rate 8.9% 2.6% 18.6% 5.6%
 

Terminal rate 1/28 (4%) 0/16 (0%) 2/15 (13%) 1/18 (6%)
 

First incidence (days) 693 581 611 734 (T)
 

Life table test P=0.523N P=0.461N P=0.262 P=0.501N 

Logistic regression test P=0.431N P=0.318N P=0.421 P=0.461N 

Cochran-Armitage test P=0.343N
 

Fisher exact test P=0.309N P=0.500 P=0.309N 
Tetrafluoroethylene, NTP TR 450 153 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Mammary Gland: Adenoma or Carcinoma 

Overall rate 4/50 (8%) 1/50 (2%) 5/50 (10%) 2/50 (4%)
 

Adjusted rate 12.2% 2.6% 22.5% 11.1%
 

Terminal rate 2/28 (7%) 0/16 (0%) 2/15 (13%) 2/18 (11%)
 

First incidence (days) 693 581 611 734 (T)
 

Life table test P=0.522 P=0.336N P=0.226 P=0.575N 

Logistic regression test P=0.558N P=0.213N P=0.389 P=0.565N 

Cochran-Armitage test P=0.420N
 

Fisher exact test P=0.181N P=0.500 P=0.339N 

Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma 

Overall rate 24/50 (48%) 12/50 (24%) 13/50 (26%) 8/50 (16%) 

Adjusted rate 59.0% 43.3% 49.8% 32.8% 

Terminal rate 12/28 (43%) 5/16 (31%) 5/15 (33%) 4/18 (22%) 

First incidence (days) 481 468 534 504 

Life table test P=0.050N P=0.260N P=0.386N P=0.054N 

Logistic regression test P=0.004N P=0.016N P=0.037N P=0.004N 

Cochran-Armitage test P=0.001N 

Fisher exact test P=0.011N P=0.019N P<0.001N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 43/50 (86%) 34/50 (68%) 36/49 (73%) 34/50 (68%) 

Adjusted rate 93.4% 88.4% 94.0% 88.9% 

Terminal rate 25/28 (89%) 12/16 (75%) 13/15 (87%) 14/18 (78%) 

First incidence (days) 481 413 387 433 

Life table test P=0.177 P=0.156 P=0.074 P=0.164 

Logistic regression test P=0.270N P=0.112N P=0.253N P=0.251N 

Cochran-Armitage test P=0.063N 

Fisher exact test P=0.028N P=0.096N P=0.028N 

Pituitary Gland (Pars Distalis): Adenoma or Carcinoma 

Overall rate 43/50 (86%) 35/50 (70%) 36/49 (73%) 34/50 (68%) 

Adjusted rate 93.4% 91.3% 94.0% 88.9% 

Terminal rate 25/28 (89%) 13/16 (81%) 13/15 (87%) 14/18 (78%) 

First incidence (days) 481 413 387 433 

Life table test P=0.186 P=0.112 P=0.074 P=0.164 

Logistic regression test P=0.248N P=0.176N P=0.253N P=0.251N 

Cochran-Armitage test P=0.052N 

Fisher exact test P=0.045N P=0.096N P=0.028N 

Skin: Squamous Cell Papilloma, Keratoacanthoma, or Malignant Basosquamous Tumor 

Overall rate 2/50 (4%) 0/50 (0%) 2/50 (4%) 3/50 (6%)
 

Adjusted rate 7.1% 0.0% 11.1% 16.7%
 

Terminal rate 2/28 (7%) 0/16 (0%) 1/15 (7%) 3/18 (17%)
 

First incidence (days) 734 (T) — 702 734 (T)
 

Life table test P=0.136 P=0.368N P=0.470 P=0.301
 

Logistic regression test P=0.120 P=0.368N P=0.550 P=0.301
 

Cochran-Armitage test P=0.237
 

Fisher exact test P=0.247N P=0.691N P=0.500
 
154 Tetrafluoroethylene, NTP TR 450 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Thyroid Gland (C-cell): Adenoma 

Overall rate 5/50 (10%) 9/50 (18%) 5/50 (10%) 2/50 (4%) 

Adjusted rate 16.7% 35.0% 22.7% 8.2% 

Terminal rate 4/28 (14%) 1/16 (6%) 2/15 (13%) 1/18 (6%) 

First incidence (days) 698 523 587 579 

Life table test P=0.265N P=0.044 P=0.316 P=0.420N 

Logistic regression test P=0.169N P=0.084 P=0.487 P=0.370N 

Cochran-Armitage test P=0.086N 

Fisher exact test P=0.194 P=0.630N P=0.218N 

Thyroid Gland (C-cell): Carcinoma 

Overall rate 2/50 (4%) 2/50 (4%) 3/50 (6%) 2/50 (4%)
 

Adjusted rate 7.1% 8.2% 20.0% 11.1%
 

Terminal rate 2/28 (7%) 1/16 (6%) 3/15 (20%) 2/18 (11%)
 

First incidence (days) 734 (T) 468 734 (T) 734 (T)
 

Life table test P=0.406 P=0.536 P=0.228 P=0.528 

Logistic regression test P=0.427 P=0.701N P=0.228 P=0.528 

Cochran-Armitage test P=0.569 

Fisher exact test P=0.691N P=0.500 P=0.691N 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 7/50 (14%) 11/50 (22%) 7/50 (14%) 4/50 (8%) 

Adjusted rate 23.6% 40.6% 34.6% 19.0% 

Terminal rate 6/28 (21%) 2/16 (13%) 4/15 (27%) 3/18 (17%) 

First incidence (days) 698 468 587 579 

Life table test P=0.365N P=0.041 P=0.215 P=0.548N 

Logistic regression test P=0.253N P=0.110 P=0.386 P=0.543N 

Cochran-Armitage test P=0.117N 

Fisher exact test P=0.218 P=0.613N P=0.262N 

Uterus: Stromal Polyp 

Overall rate 6/50 (12%) 5/50 (10%) 4/50 (8%) 5/50 (10%) 

Adjusted rate 19.7% 24.2% 21.2% 18.2% 

Terminal rate 5/28 (18%) 3/16 (19%) 2/15 (13%) 2/18 (11%) 

First incidence (days) 626 583 699 439 

Life table test P=0.432 P=0.405 P=0.538 P=0.489 

Logistic regression test P=0.552 P=0.569 P=0.564N P=0.568N 

Cochran-Armitage test P=0.437N 

Fisher exact test P=0.500N P=0.370N P=0.500N 

Uterus: Stromal Polyp or Stromal Sarcoma 

Overall rate 6/50 (12%) 6/50 (12%) 4/50 (8%) 6/50 (12%) 

Adjusted rate 19.7% 26.9% 21.2% 20.8% 

Terminal rate 5/28 (18%) 3/16 (19%) 2/15 (13%) 2/18 (11%) 

First incidence (days) 626 583 699 439 

Life table test P=0.328 P=0.270 P=0.538 P=0.348 

Logistic regression test P=0.468 P=0.456 P=0.564N P=0.582 

Cochran-Armitage test P=0.530N 

Fisher exact test P=0.620N P=0.370N P=0.620N 
 

Tetrafluoroethylene, NTP TR 450 155 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Hemangiosarcoma 

Overall rate 0/50 (0%) 0/50 (0%) 5/50 (10%) 1/50 (2%) 

Adjusted rate 0.0% 0.0% 19.5% 5.0% 

Terminal rate 0/28 (0%) 0/16 (0%) 0/15 (0%) 0/18 (0%) 

First incidence (days) — — 589 703 

Life table test P=0.143 — P=0.013 P=0.400 

Logistic regression test P=0.182 — P=0.025 P=0.435 

Cochran-Armitage test P=0.242 

Fisher exact test — P=0.028 P=0.500 

All Organs: Mononuclear Cell Leukemia 

Overall rate 16/50 (32%) 31/50 (62%) 23/50 (46%) 36/50 (72%) 

Adjusted rate 43.7% 76.5% 65.1% 82.6% 

Terminal rate 8/28 (29%) 7/16 (44%) 6/15 (40%) 11/18 (61%) 

First incidence (days) 621 468 469 372 

Life table test P<0.001 P<0.001 P=0.008 P<0.001 

Logistic regression test P<0.001 P<0.001 P=0.105 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.002 P=0.109 P<0.001 

All Organs: Benign Neoplasms 

Overall rate 46/50 (92%) 43/50 (86%) 43/50 (86%) 40/50 (80%) 

Adjusted rate 95.8% 97.6% 100.0% 95.1% 

Terminal rate 26/28 (93%) 15/16 (94%) 15/15 (100%) 16/18 (89%) 

First incidence (days) 481 413 387 433 

Life table test P=0.080 P=0.016 P=0.013 P=0.057 

Logistic regression test P=0.305N P=0.546N P=0.499N P=0.360N 

Cochran-Armitage test P=0.065N 

Fisher exact test P=0.262N P=0.262N P=0.074N 

All Organs: Malignant Neoplasms 

Overall rate 21/50 (42%) 41/50 (82%) 35/50 (70%) 42/50 (84%) 

Adjusted rate 52.7% 93.0% 84.0% 91.1% 

Terminal rate 10/28 (36%) 13/16 (81%) 9/15 (60%) 14/18 (78%) 

First incidence (days) 433 413 387 372 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P=0.005 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P=0.004 P<0.001 
156 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE B3
 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Benign or Malignant Neoplasms 

Overall rate 49/50 (98%) 50/50 (100%) 49/50 (98%) 48/50 (96%) 

Adjusted rate 98.0% 100.0% 100.0% 98.0% 

Terminal rate 27/28 (96%) 16/16 (100%) 15/15 (100%) 17/18 (94%) 

First incidence (days) 433 247 387 372 

Life table test P=0.021 P=0.003 P=0.004 P=0.009 

Logistic regression test P=0.526N P=0.612 P=0.629 P=0.748 

Cochran-Armitage test P=0.247N 

Fisher exact test P=0.500 P=0.753N P=0.500N 

(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, 

kidney, liver, pituitary gland, thyroid gland, and uterus; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study 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 life table test regards neoplasms in animals dying prior to terminal kill as being (directly or indirectly) 

the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the overall incidence 

rates. For all tests, a negative trend or a lower incidence in an exposure group is indicated byN. e Not applicable; no neoplasms in animal group 
Tetrafluoroethylene, NTP TR 450 157 

TABLE B4a 

Historical Incidence of Renal Tubule Neoplasms in Chamber Control Female F344/N Rats a

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 0/49 0/49 0/49 

Acetonitrile 0/48 0/48 0/48 

-Chloroacetophenone 0/49 0/49 0/49 

Epinephrine Hydrochloride 0/50 0/50 0/50 

Ethyl Chloride 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 1/50 1/50 

Ozone 1/50 0/50 1/50 

Total 1/346 (0.3%) 1/346 (0.3%) 2/346 (0.6%) 

Standard deviation 0.8% 0.8% 1.0% 

Range 0%-2% 0%-2% 0%-2% 

Overall Historical Incidence 

Total 1/650 (0.2%) 1/650 (0.2%) 2/650 (0.3%) 

Standard deviation 0.6% 0.6% 0.8% 

Range 0%-2% 0%-2% 0%-2% 

a Data as of 12 May 1995 

TABLE B4b 

Historical Incidence of Liver Neoplasms in Chamber Control Female F344/N Rats a

Incidence in Controls 

Study Hemangiosarcoma Adenoma Carcinoma Adenoma 

or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 0/49 3/49 0/49 3/49 

Acetonitrile 0/48 0/48 0/48 0/48 

-Chloroacetophenone 0/49 0/49 0/49 0/49 

Epinephrine Hydrochloride 0/50 2/50 0/50 2/50 

Ethyl Chloride 0/50 0/50 1/50 1/50 

Hexachlorocyclopentadiene 0/50 1/50 0/50 1/50 

Ozone 0/50 0/50 0/50 0/50 

Total 0/346 6/346 (1.7%) 1/346 (0.3%) 7/346 (2.0%) 

Standard deviation 2.4% 0.8% 2.3% 

Range 0%-6% 0%-2% 0%-6% 

Overall Historical Incidence 

Total 0/650 9/650 (1.4%) 1/650 (0.2%) 10/650 (1.5%) 

Standard deviation 2.1% 0.6% 2.0% 

Range 0%-6% 0%-2% 0%-6% 

a Data as of 12 May 1995 
158 Tetrafluoroethylene, NTP TR 450 

TABLE B4c 

Historical Incidence of Mononuclear Cell Leukemia in Chamber Control Female F344/N Rats a

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile (CS-2) 24/50 

Acetonitrile 18/48 

-Chloroacetophenone 27/50 

Epinephrine Hydrochloride 24/50 

Ethyl Chloride 20/50 

Hexachlorocyclopentadiene 16/50 

Ozone 17/50 

Total 146/348 (42.0%) 

Standard deviation 8.2% 

Range 32%-54% 

Overall Historical Incidence 

Total 262/653 (40.1%) 

Standard deviation 7.2% 

Range 30%-54% 

a Data as of 12 May 1995; includes data for lymphocytic, monocytic, and undifferentiated cell type leukemias 
 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 159 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Accidental death 1 

Moribund 21 33 31 25 

Natural deaths 1 1 4 6 

Survivors 

Died last week of study 1 

Terminal sacrifice 28 15 15 18 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver (10) (10) (10) (10) 

Angiectasis 1 (10%) 

Basophilic focus 9 (90%) 9 (90%) 10 (100%) 10 (100%) 

Clear cell focus 2 (20%) 3 (30%) 3 (30%) 

Eosinophilic focus 5 (50%) 2 (20%) 

Hepatodiaphragmatic nodule 2 (20%) 1 (10%) 

Mixed cell focus 1 (10%) 6 (60%) 4 (40%) 

Bile duct, hyperplasia 1 (10%) 

Mesentery (2) (2) (3) (1) 

Fat, necrosis 2 (100%) 2 (100%) 3 (100%) 1 (100%) 

Pancreas (10) (10) (10) (10) 

Metaplasia, hepatocyte 2 (20%) 

Acinus, atrophy 3 (30%) 1 (10%) 2 (20%) 3 (30%) 

Stomach, forestomach (10) (10) (10) (10) 

Acanthosis 1 (10%) 

Ulcer 1 (10%) 

Cardiovascular System 

Heart (10) (10) (10) (10) 

Cardiomyopathy 8 (80%) 10 (100%) 9 (90%) 10 (100%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Hyperplasia 1 (10%) 1 (10%) 1 (10%) 2 (20%) 

Hypertrophy 2 (20%) 

Parathyroid gland (10) (10) (10) (10) 

Hyperplasia 1 (10%) 

Pituitary gland (10) (10) (10) (10) 

Pars distalis, hyperplasia 6 (60%) 5 (50%) 8 (80%) 7 (70%) 

Thyroid gland (10) (10) (10) (10) 

C-cell, hyperplasia 9 (90%) 7 (70%) 9 (90%) 9 (90%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

160 Tetrafluoroethylene, NTP TR 450 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Genital System 

Clitoral gland (10) (10) (10) (10) 

Inflammation, chronic active 1 (10%) 1 (10%) 

Ovary (10) (10) (10) (10) 

Cyst 1 (10%) 1 (10%) 

Hematopoietic System 

Bone marrow (10) (10) (10) (10) 

Hyperplasia, reticulum cell 2 (20%) 2 (20%) 3 (30%) 2 (20%) 

Lymph node (1) 

Renal, hemorrhage 1 (100%) 

Lymph node, mediastinal (8) (10) (10) (9) 

Hemorrhage 3 (38%) 2 (20%) 1 (10%) 

Spleen (10) (10) (10) (10) 

Developmental malformation 1 (10%) 

Respiratory System 

Larynx (10) (10) (10) (10) 

Inflammation, chronic active 2 (20%) 3 (30%) 5 (50%) 3 (30%) 

Metaplasia, squamous 2 (20%) 1 (10%) 1 (10%) 

Mineralization 7 (70%) 6 (60%) 10 (100%) 10 (100%) 

Lung (10) (10) (10) (10) 

Hemorrhage 10 (100%) 10 (100%) 10 (100%) 10 (100%) 

Infiltration cellular, histiocyte 1 (10%) 1 (10%) 3 (30%) 1 (10%) 

Inflammation, chronic active 1 (10%) 

Alveolar epithelium, hyperplasia 1 (10%) 1 (10%) 2 (20%) 

Nose (10) (10) (10) (10) 

Inflammation, chronic active 1 (10%) 

Special Senses System 

Eye (1) 

Cataract 1 (100%) 

Retina, atrophy 1 (100%) 

Urinary System 

Kidney (10) (10) (10) (10) 

Nephropathy 8 (80%) 9 (90%) 9 (90%) 10 (100%) 

Renal tubule, degeneration 10 (100%) 10 (100%) 

Renal tubule, hyperplasia 1 (10%) 

Renal tubule, hyperplasia, oncocytic 1 (10%) 

Urinary bladder (10) (10) (10) (10) 

Transitional epithelium, hyperplasia 1 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 161 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Systems Examined With No Lesions Observed 

General Body System 

Integumentary System 

Musculoskeletal System 

Nervous System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (49) (50) 

Cyst 1 (2%) 

Parasite metazoan 4 (8%) 5 (10%) 3 (6%) 3 (6%) 

Intestine large, rectum (50) (50) (49) (50) 

Diverticulum 1 (2%) 

Parasite metazoan 5 (10%) 2 (4%) 2 (4%) 6 (12%) 

Intestine large, cecum (50) (50) (49) (50) 

Diverticulum 1 (2%) 

Fibrosis 1 (2%) 

Infiltration cellular, eosinophil 1 (2%) 

Parasite metazoan 1 (2%) 1 (2%) 4 (8%) 

Intestine small, duodenum (49) (50) (49) (50) 

Necrosis 1 (2%) 

Liver (50) (50) (50) (50) 

Angiectasis 9 (18%) 9 (18%) 14 (28%) 

Basophilic focus 41 (82%) 38 (76%) 41 (82%) 37 (74%) 

Clear cell focus 10 (20%) 3 (6%) 12 (24%) 9 (18%) 

Degeneration, cystic 1 (2%) 4 (8%) 1 (2%) 3 (6%) 

Embolus bacterial 1 (2%) 

Eosinophilic focus 1 (2%) 4 (8%) 5 (10%) 4 (8%) 

Fatty change 15 (30%) 20 (40%) 17 (34%) 10 (20%) 

Hepatodiaphragmatic nodule 3 (6%) 5 (10%) 10 (20%) 5 (10%) 

Mitotic alteration 1 (2%) 

Mixed cell focus 12 (24%) 14 (28%) 16 (32%) 18 (36%) 

Necrosis, focal 1 (2%) 2 (4%) 

Regeneration 1 (2%) 2 (4%) 3 (6%) 8 (16%) 

Bile duct, hyperplasia 9 (18%) 18 (36%) 12 (24%) 18 (36%) 

Centrilobular, necrosis 2 (4%) 2 (4%) 

Mesentery (6) (4) (4) (6) 

Polyarteritis 1 (17%) 1 (25%) 

Fat, necrosis 4 (67%) 4 (100%) 4 (100%) 4 (67%) 

Pancreas (50) (50) (49) (50) 

Basophilic focus 3 (6%) 1 (2%) 2 (4%) 1 (2%) 

Hyperplasia 1 (2%) 

Metaplasia 1 (2%) 

Acinus, atrophy 15 (30%) 14 (28%) 9 (18%) 9 (18%) 

Pharynx (1) 

Palate, hyperplasia 1 (100%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

162 Tetrafluoroethylene, NTP TR 450 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Alimentary System (continued) 

Stomach, forestomach (50) (50) (48) (50) 

Acanthosis 4 (8%) 4 (8%) 1 (2%) 1 (2%) 

Diverticulum 1 (2%) 

Inflammation, suppurative 1 (2%) 

Mineralization 1 (2%) 

Necrosis 5 (10%) 4 (8%) 

Stomach, glandular (50) (50) (49) (50) 

Mineralization 1 (2%) 1 (2%) 2 (4%) 

Necrosis 2 (4%) 1 (2%) 2 (4%) 1 (2%) 

Tongue (2) (2) (1) 

Hyperplasia, squamous 1 (50%) 

Epithelium, hyperplasia 1 (50%) 1 (100%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Cardiomyopathy 41 (82%) 40 (80%) 40 (80%) 33 (66%) 

Embolus bacterial 1 (2%) 

Polyarteritis 1 (2%) 

Atrium, thrombosis 1 (2%) 2 (4%) 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Embolus bacterial 1 (2%) 

Fibrosis 1 (2%) 

Hyperplasia 18 (36%) 11 (22%) 16 (32%) 22 (44%) 

Hypertrophy 4 (8%) 4 (8%) 3 (6%) 5 (10%) 

Metaplasia, osseous 1 (2%) 

Necrosis 1 (2%) 

Vacuolization cytoplasmic 5 (10%) 3 (6%) 4 (8%) 3 (6%) 

Adrenal medulla (50) (50) (50) (50) 

Embolus bacterial 1 (2%) 

Hyperplasia 6 (12%) 9 (18%) 3 (6%) 8 (16%) 

Islets, pancreatic (50) (50) (49) (50) 

Hyperplasia 1 (2%) 

Pituitary gland (50) (50) (49) (50) 

Pars distalis, angiectasis 1 (2%) 

Pars distalis, hemorrhage 1 (2%) 

Pars distalis, hyperplasia 4 (8%) 8 (16%) 8 (16%) 13 (26%) 

Thyroid gland (50) (50) (50) (50) 

C-cell, hyperplasia 48 (96%) 40 (80%) 41 (82%) 38 (76%) 

Follicular cell, hyperplasia 2 (4%) 1 (2%) 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 163 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Genital System 

Clitoral gland (49) (49) (50) (48) 

Dilatation 1 (2%) 

Hyperplasia 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Inflammation, chronic active 2 (4%) 4 (8%) 7 (14%) 2 (4%) 

Duct, ectasia 1 (2%) 

Ovary (50) (50) (50) (50) 

Cyst 4 (8%) 3 (6%) 2 (4%) 2 (4%) 

Uterus (50) (50) (50) (50) 

Cyst 1 (2%) 1 (2%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Hyperplasia, reticulum cell 1 (2%) 

Myelofibrosis 3 (6%) 1 (2%) 

Lymph node (3) (7) (7) (13) 

Lumbar, pigmentation 1 (14%) 

Renal, hemorrhage 1 (33%) 1 (14%) 2 (15%) 

Lymph node, bronchial (50) (50) (50) (48) 

Hemorrhage 2 (4%) 

Lymph node, mandibular (48) (49) (50) (50) 

Hemorrhage 1 (2%) 2 (4%) 

Infiltration cellular, plasma cell 3 (6%) 2 (4%) 

Lymph node, mesenteric (50) (50) (50) (50) 

Embolus bacterial 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 

Lymph node, mediastinal (49) (49) (49) (45) 

Hemorrhage 1 (2%) 3 (6%) 2 (4%) 2 (4%) 

Spleen (50) (50) (49) (50) 

Angiectasis 1 (2%) 1 (2%) 

Fibrosis 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Hematopoietic cell proliferation 1 (2%) 

Infiltration cellular, lipocyte 2 (4%) 

Thymus (47) (48) (49) (48) 

Cyst 1 (2%) 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Cyst 1 (2%) 

Hyperplasia, focal 1 (2%) 

Skin (50) (50) (50) (50) 

Inflammation, chronic active 2 (4%) 4 (8%) 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Hyperostosis 6 (12%) 14 (28%) 8 (16%) 3 (6%) 

Tibia, fracture 1 (2%) 

Turbinate, fracture 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

164 Tetrafluoroethylene, NTP TR 450 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Nervous System 

Brain (50) (50) (50) (50) 

Compression 30 (60%) 23 (46%) 20 (40%) 19 (38%) 

Embolus bacterial 1 (2%) 

Hemorrhage 2 (4%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Inflammation, chronic active 13 (26%) 14 (28%) 14 (28%) 21 (42%) 

Metaplasia, squamous 2 (4%) 1 (2%) 2 (4%) 4 (8%) 

Mineralization 31 (62%) 29 (58%) 31 (62%) 30 (60%) 

Lung (50) (50) (50) (50) 

Hemorrhage 17 (34%) 8 (16%) 12 (24%) 5 (10%) 

Infiltration cellular, lymphocyte 1 (2%) 

Infiltration cellular, histiocyte 2 (4%) 2 (4%) 

Inflammation, chronic active 2 (4%) 3 (6%) 1 (2%) 

Metaplasia, osseous 1 (2%) 

Alveolar epithelium, hyperplasia 8 (16%) 4 (8%) 9 (18%) 6 (12%) 

Mediastinum, polyarteritis 1 (2%) 

Nose (50) (50) (50) (50) 

Inflammation, chronic active 1 (2%) 

Inflammation, suppurative 1 (2%) 2 (4%) 3 (6%) 5 (10%) 

Thrombosis 1 (2%) 

Nares, inflammation, chronic active 1 (2%) 

Nasolacrimal duct, inflammation, suppurative 1 (2%) 

Special Senses System 

Eye (50) (50) (50) (50) 

Cataract 15 (30%) 4 (8%) 10 (20%) 45 (90%) 

Degeneration 2 (4%) 1 (2%) 3 (6%) 2 (4%) 

Hemorrhage 3 (6%) 3 (6%) 2 (4%) 3 (6%) 

Cornea, inflammation, chronic active 1 (2%) 2 (4%) 

Cornea, mineralization 1 (2%) 2 (4%) 2 (4%) 3 (6%) 

Retina, atrophy 21 (42%) 11 (22%) 15 (30%) 21 (42%) 

Retina, degeneration 33 (66%) 23 (46%) 14 (28%) 13 (26%) 

Harderian gland (1) 

Inflammation, chronic active 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Embolus bacterial 1 (2%) 

Hyperplasia, atypical 1 (2%) 

Nephropathy 48 (96%) 46 (92%) 48 (96%) 47 (94%) 

Papilla, necrosis 1 (2%) 

Pelvis, dilatation 1 (2%) 1 (2%) 

Renal tubule, degeneration 35 (70%) 46 (92%) 

Renal tubule, hyperplasia 1 (2%) 3 (6%) 6 (12%) 12 (24%) 

Renal tubule, hyperplasia, oncocytic 3 (6%) 

Urinary bladder (49) (50) (50) (49) 

Transitional epithelium, hyperplasia 1 (2%) 1 (2%) 
165 

APPENDIX C
 

SUMMARY OF LESIONS IN MALE MICE
 

IN THE 2-YEAR INHALATION STUDY
 

OF TETRAFLUOROETHYLENE
 

TABLE C1 Summary of the Incidence of Neoplasms in Male Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 167
 

TABLE C2 Individual Animal Tumor Pathology of Male Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 172
 

TABLE C3 Statistical Analysis of Primary Neoplasms in Male Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 194
 

TABLE C4a Historical Incidence of Liver Neoplasms in Chamber Control Male B6C3F 1 Mice .......... 199
 

TABLE C4b Historical Incidence of Histiocytic Sarcoma in Chamber Control Male B6C3F 1 Mice ....... 200
 

TABLE C5 Summary of the Incidence of Nonneoplastic Lesions in Male Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 201
 
166 Tetrafluoroethylene, NTP TR 450 
 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 167 

TABLE C1 a Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Moribund 

Natural deaths 

Survivors 

Terminal sacrifice 

58 

10 

6 

4 

38 

58 

10 

24 

13 

11 

58 

10 

26 

20 

2 

58 

10 

27 

20 

1 

Animals examined microscopically 58 58 58 58 

15-Month Interim Evaluation 

Alimentary System 

Liver 

Hemangiosarcoma

Hepatocellular carcinoma

Hepatocellular adenoma

Hepatocellular adenoma, multiple

Histiocytic sarcoma

Stomach, forestomach 

Squamous cell papilloma

(10) 

 2 (20%) 

 5 (50%) 

 1 (10%) 

(10) 

(10) 

 4 (40%) 

 2 (20%) 

(10) 

(10) 

 2 (20%) 

 2 (20%) 

 2 (20%) 

(10) 

 1 (10%) 

(10) 

 3 (30%) 

 2 (20%) 

 1 (10%) 

 1 (10%) 

(10) 

Hematopoietic System 

Thymus

Thymoma NOS

 (8) (9) 

 1 (11%) 

(10) (9) 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Hepatocellular carcinoma, metastatic, liver

Histiocytic sarcoma

(10) 

 1 (10%) 

 1 (10%) 

(10) (10) 

 1 (10%) 

(10) 

 1 (10%) 

 1 (10%) 

Special Senses System 

Harderian gland

Adenoma

 (1)

 1 (100%)

 (2)

 2 (100%)

 (1) 

 1 (100%) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

(10) (10) (10) (10) 

 1 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

168 Tetrafluoroethylene, NTP TR 450 

TABLE C1
 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Systems Examined With No Neoplasms Observed 

Cardiovascular System 

Endocrine System 

General Body System 

Genital System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Urinary System 

2-Year Study 

Alimentary System 

Liver (48) (48) (48) (48) 

Carcinoma, metastatic, harderian gland 1 (2%) 

Carcinoma, metastatic, lung 1 (2%) 

Hemangioma 3 (6%) 3 (6%) 1 (2%) 

Hemangioma, multiple 7 (15%) 2 (4%) 1 (2%) 

Hemangiosarcoma 5 (10%) 10 (21%) 19 (40%) 

Hemangiosarcoma, multiple 16 (33%) 17 (35%) 18 (38%) 

Hepatocellular carcinoma 7 (15%) 11 (23%) 24 (50%) 20 (42%) 

Hepatocellular carcinoma, multiple 4 (8%) 9 (19%) 9 (19%) 6 (13%) 

Hepatocellular adenoma 11 (23%) 11 (23%) 5 (10%) 13 (27%) 

Hepatocellular adenoma, multiple 6 (13%) 6 (13%) 7 (15%) 7 (15%) 

Histiocytic sarcoma 12 (25%) 7 (15%) 7 (15%) 

Mesentery (2) (3) (2) (7) 

Carcinoma, metastatic, lung 1 (33%) 

Hemangioma 1 (14%) 

Hemangiosarcoma 1 (14%) 

Hepatocellular carcinoma, metastatic, liver 1 (14%) 

Histiocytic sarcoma 1 (50%) 

Pancreas (48) (48) (46) (45) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Stomach, forestomach (48) (48) (46) (46) 

Squamous cell carcinoma 1 (2%) 

Squamous cell papilloma 2 (4%) 1 (2%) 1 (2%) 

Cardiovascular System 

Heart (48) (48) (48) (48) 

Carcinoma, metastatic, lung 1 (2%) 1 (2%) 

Endocrine System 

Adrenal cortex (48) (48) (47) (48) 

Adenoma 1 (2%) 1 (2%) 

Islets, pancreatic (48) (48) (46) (45) 

Adenoma 1 (2%) 

Thyroid gland (48) (48) (47) (47) 

Follicular cell, adenoma 3 (6%) 

Follicular cell, carcinoma 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 169 

TABLE C1
 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

General Body System 

Tissue NOS (1) (2) (2) 

Carcinoma, metastatic, lung 1 (50%) 

Hemangioma 1 (50%) 

Genital System 

Epididymis (48) (48) (48) (48) 

Leiomyoma 1 (2%) 

Leiomyosarcoma 1 (2%) 

Hematopoietic System 

Bone marrow (48) (48) (47) (47) 

Hemangioma 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 2 (4%) 

Lymph node (3) (1) (2) 

Renal, histiocytic sarcoma 1 (100%) 1 (50%) 

Lymph node, bronchial (36) (36) (35) (26) 

Histiocytic sarcoma 3 (8%) 1 (4%) 

Lymph node, mandibular (36) (34) (32) (34) 

Histiocytic sarcoma 2 (6%) 1 (3%) 

Lymph node, mesenteric (47) (42) (41) (40) 

Histiocytic sarcoma 4 (10%) 1 (2%) 2 (5%) 

Lymph node, mediastinal (30) (34) (32) (29) 

Carcinoma, metastatic, lung 1 (3%) 1 (3%) 

Histiocytic sarcoma 2 (6%) 1 (3%) 

Spleen (48) (48) (46) (46) 

Hemangiosarcoma 2 (4%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 2 (4%) 

Thymus (43) (40) (34) (37) 

Histiocytic sarcoma 1 (3%) 

Integumentary System 

Skin (48) (48) (48) (48) 

Subcutaneous tissue, hemangioma 1 (2%) 

Subcutaneous tissue, hemangiosarcoma 1 (2%) 1 (2%) 

Musculoskeletal System 

Bone (48) (48) (48) (48) 

Carcinoma, metastatic, harderian gland 1 (2%) 

Skeletal muscle (1) 

Carcinoma, metastatic, lung 1 (100%) 

Nervous System 

Brain (48) (48) (48) (48) 

Carcinoma, metastatic, harderian gland 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

170 Tetrafluoroethylene, NTP TR 450 

TABLE C1
 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Respiratory System 

Lung (48) (48) (48) (48) 

Alveolar/bronchiolar adenoma 9 (19%) 7 (15%) 12 (25%) 3 (6%) 

Alveolar/bronchiolar adenoma, multiple 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Alveolar/bronchiolar carcinoma 2 (4%) 4 (8%) 3 (6%) 1 (2%) 

Carcinoma 1 (2%) 1 (2%) 

Carcinoma, metastatic, harderian gland 1 (2%) 1 (2%) 

Hemangiosarcoma, metastatic, liver 2 (4%) 2 (4%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 7 (15%) 14 (29%) 8 (17%) 

Histiocytic sarcoma 7 (15%) 4 (8%) 3 (6%) 

Nose (48) (47) (46) (47) 

Carcinoma, metastatic, harderian gland 1 (2%) 

Special Senses System 

Harderian gland (6) (8) (5) (6) 

Adenoma 5 (83%) 7 (88%) 4 (80%) 4 (67%) 

Carcinoma 1 (17%) 1 (13%) 1 (17%) 

Urinary System 

Kidney (48) (48) (48) (48) 

Carcinoma, metastatic, lung 1 (2%) 

Hemangiosarcoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 3 (6%) 3 (6%) 2 (4%) 

Urinary bladder (48) (43) (43) (42) 

Systemic Lesions 

Multiple organs (48) (48) (48) (48) 

Histiocytic sarcoma 12 (25%) 7 (15%) 7 (15%) 

Lymphoma malignant mixed 2 (4%) 1 (2%) 1 (2%) 
171 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE C1
 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 6 7 6 6 

2-Year study 37 44 48 46 

Total primary neoplasms 

15-Month interim evaluation 10 9 7 9 

2-Year study 53 110 107 112 

Total animals with benign neoplasms 

15-Month interim evaluation 6 4 4 3 

2-Year study 26 30 27 27 

Total benign neoplasms 

15-Month interim evaluation 8 4 5 3 

2-Year study 35 48 36 35 

Total animals with malignant neoplasms 

15-Month interim evaluation 2 4 2 4 

2-Year study 16 39 47 46 

Total malignant neoplasms 

15-Month interim evaluation 2 4 2 6 

2-Year study 18 62 71 77 

Total animals with metastatic neoplasms 

15-Month interim evaluation 1 1 

2-Year study 2 8 14 11 

Total metastatic neoplasms 

15-Month interim evaluation 1 1 

2-Year study 3 12 17 20 

Total animals with uncertain neoplasmsbenign or malignant 

15-Month interim evaluation 1 

Total uncertain neoplasms 

15-Month interim evaluation 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
 
 

 

 

 

 

 

 

 

 

172 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm 

4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 7 3 4 9 9 1 3 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

2 5 8 1 7 7 1 9 0 0 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

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 3 4 4 3 2 4 1 1 1 2 0 0 0 0 0 0 1 1 1 1 1 2 2 2 2 

2 2 3 7 8 8 5 8 7 5 2 4 5 6 7 9 0 2 4 6 9 1 2 3 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + M M + + + A + A + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + A + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + A I + + + + + + + + + + + + + + + 

Intestine large, cecum + + M + + + A + A + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + A + + + + + A + + M + + + + + + + + + + + + + 

Intestine small, jejunum + + A + + + + + A + + + + + + + + + + + + + + + + 

Intestine small, ileum + + A + + + + + A + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X X X X X X X 

Hepatocellular carcinoma, multiple X 

Hepatocellular adenoma X X X X 

Hepatocellular adenoma, multiple X X X X 

Mesentery + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma X 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tooth + + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + M + + M M + M + + + + + + + M + + M M M + + + M 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

General Body System 

Tissue NOS A 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + + + + + + + + M + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + 

Lymph node, bronchial M M M + M + + + M + + M + M + + + + + + + + + + + 

Lymph node, mandibular M + M M + + + I + M + + + + + M + + + + + + + + + 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 173 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

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 2 3 3 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 5 5 5 Tissues/ 

6 7 9 0 1 4 5 6 8 9 0 4 5 7 9 0 1 2 3 5 6 7 8 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder M + + + A + + + + + + + + + + + + + + + + + + 42 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Hepatocellular carcinoma 7 

Hepatocellular carcinoma, multiple X X X 4 

Hepatocellular adenoma X X X X X X X 11 

Hepatocellular adenoma, multiple X X 6 

Mesentery + 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 48 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 48 

Squamous cell papilloma X 2 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 48 

Tooth 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 48 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 48 

Parathyroid gland + M M M + + + M + + M + + M M M + + + + M + + 30 

Pituitary gland + + + + + + + + + + + + + + + I + + + + + + + 47 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 48 

General Body System 

Tissue NOS +

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + 48 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Prostate + + + + + + I + + + + + + + + + + + + + + + + 46 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + 48 

Testes + + + + + + + + + + + + + + + + + + + + + + + 48 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 48 

Lymph node + 3 

Lymph node, bronchial + M + M M + M + + + + + + + + M + + + + + + + 36 

Lymph node, mandibular M M + + + M + + + M + + + + + + + M + M + + + 36 

 1 
 

 

 

 

 

 

 

 

 

 

 

174 Tetrafluoroethylene, NTP TR 450 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 7 3 4 9 9 1 3 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

2 5 8 1 7 7 1 9 0 0 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

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 3 4 4 3 2 4 1 1 1 2 0 0 0 0 0 0 1 1 1 1 1 2 2 2 2 

2 2 3 7 8 8 5 8 7 5 2 4 5 6 7 9 0 2 4 6 9 1 2 3 4 

Hematopoietic System (continued)
 

Lymph node, mesenteric + + M + + + + + + + + + + + + + + + + + + + + + +
 

Lymph node, mediastinal M + + + + M + + + + + I + + M + + + M + + + M + +
 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + +
 

Hemangiosarcoma 

Thymus + + + + + + + + + + + + + M + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

M M M M M M M M M M M M M M M M M M M M + 

+ + + + + + + + + + + + + + + + + + + + + 

M M M M 

+ + + + 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma,

 multiple 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, harderian

 gland 

Hepatocellular carcinoma, metastatic,

 liver 

+ 

+ 

+ 

+ 

X 

A 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, harderian

 gland 

Trachea + + A + 

X 

+ + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear M + 

Harderian gland 

Adenoma 

+ + 

X 

+ 

X 

+ 

X 

Carcinoma X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymphoma malignant mixed X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 175 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued) 

Number of Days on Study 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

6 

Carcass ID Number 

0 

2 

6 

0 

2 

7 

0 

2 

9 

0 

3 

0 

0 

3 

1 

0 

3 

4 

0 

3 

5 

0 

3 

6 

0 

3 

8 

0 

3 

9 

0 

4 

0 

0 

4 

4 

0 

4 

5 

0 

4 

7 

0 

4 

9 

0 

5 

0 

0 

5 

1 

0 

5 

2 

0 

5 

3 

0 

5 

5 

0 

5 

6 

0 

5 

7 

0 

5 

8 

Total 

Tissues/ 

Tumors 

Hematopoietic System (continued) 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + 47 

Lymph node, mediastinal M + M M + M M M M + + M M M + + + M + + + + M 30 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangiosarcoma X X 2 

Thymus + + + M + + M + M + + + + + + + + + + + M + + 43 

Integumentary System 

Mammary gland 

Skin 

M M M M M M M M M M M M M M M M M M M M M M M

+ + + + + + + + + + + + + + + + + + + + + + + 

1 

48 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + 48 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma,

 multiple 

Alveolar/bronchiolar carcinoma

Carcinoma, metastatic, harderian

 gland 

Hepatocellular carcinoma, metastatic,

 liver 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

47 

48 

9 

1 

2 

1 

1 

Nose + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, harderian

 gland 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 

1 

47 

Special Senses System 

Ear 1 

Harderian gland 

Adenoma 

+ 

X 

+

X

 6 

5 

Carcinoma 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + 48 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Lymphoma malignant mixed 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

176 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

0 0 0 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 4 7 7 6 6 9 0 0 1 2 3 3 3 4 4 4 5 5 6 6 7 8 9 9 9 

4 5 7 2 3 5 8 9 3 2 7 7 7 1 1 1 1 2 6 9 3 6 0 3 3 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 3 3 5 5 6 7 5 2 5 3 5 6 6 2 2 2 2 5 6 3 3 5 7 4 5 

5 1 8 1 9 2 5 0 9 8 0 3 6 4 5 7 3 6 2 6 2 4 3 9 2 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + A A M + + M M A A + A + + + + + + + + A + + A + 

Intestine large, colon + A A + + + + + + A + + + + + + + + + + A + + + + 

Intestine large, rectum + A + + + + + + + + + + + + + + A + + + + + + + + 

Intestine large, cecum + A A A + + + + + A + + + + + + A + + + A + + A + 

Intestine small, duodenum + A A A + + A + A A + + + + + + A + + + A + + A + 

Intestine small, jejunum + A A A + + + + + A + + + + + + A + + + A + + A + 

Intestine small, ileum + A A A + + + + A A + + + + + + A + + + A + + A + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, lung X 

Hemangioma X X 

Hemangioma, multiple 

Hemangiosarcoma X 

Hemangiosarcoma, multiple X X X X X 

Hepatocellular carcinoma X X X X X X X X 

Hepatocellular carcinoma, multiple X X X X 

Hepatocellular adenoma X X X 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma X X X X 

Mesentery + 

Carcinoma, metastatic, lung X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma X 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tooth + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, lung X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + M + + I + + + + + + + + + + I + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + M M + + + + + + M M M + + M + M + + + M + M 

Pituitary gland + M + + + + + + + + + + M + + + + + + + + M M + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

Follicular cell, carcinoma 

General Body System 

Tissue NOS 

Carcinoma, metastatic, lung 

Hemangioma 

+ 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 177 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 0 1 1 1 2 3 3 4 4 4 6 6 6 6 6 6 6 6 6 6 6 6 

9 0 4 4 6 5 1 7 6 6 9 0 6 6 6 6 6 6 6 6 6 6 6 

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 6 3 1 4 3 4 4 4 1 5 2 3 2 2 2 4 4 4 5 6 6 6 6 Tissues/ 

5 0 8 3 7 2 0 7 7 3 9 3 1 6 8 4 5 6 7 0 1 4 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder A A + + A + + + + + + + + + + + + + + + + + + 35 

Intestine large, colon + A + + + + + + + + + + + + + + + + + + + + + 43 

Intestine large, rectum + A + + + + + + + + + + + + + + + + + + + + + 45 

Intestine large, cecum + A + + + + + + + + + + + + + + + + + + + + + 40 

Intestine small, duodenum + A + + + + + + + + + + + + + + + + + + + + + 38 

Intestine small, jejunum + A + + + + + + + + + + + + + + + + + + + + + 40 

Intestine small, ileum + A + + + + + + + + + + + + + + + + + + + + + 39 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, lung 1 

Hemangioma X 3 

Hemangioma, multiple X X X X X X X 7 

Hemangiosarcoma X X X X 5 

Hemangiosarcoma, multiple X X X X X X X X X X X 16 

Hepatocellular carcinoma X X X 11 

Hepatocellular carcinoma, multiple X X X X X 9 

Hepatocellular adenoma X X X X X X X X 11 

Hepatocellular adenoma, multiple X X X X X X 6 

Histiocytic sarcoma X X X X X X X X 12 

Mesentery + + 3 

Carcinoma, metastatic, lung 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 48 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 48 

Squamous cell papilloma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 48 

Tooth + 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, lung 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 48 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 45 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 48 

Parathyroid gland + M M M M + + + + + M M M M M + M + + + + M + 28 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + 44 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Follicular cell, adenoma X X X 3 

Follicular cell, carcinoma X 1 

General Body System 

Tissue NOS + 2 

Carcinoma, metastatic, lung 1 

Hemangioma X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

178 Tetrafluoroethylene, NTP TR 450 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

0 0 0 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 4 7 7 6 6 9 0 0 1 2 3 3 3 4 4 4 5 5 6 6 7 8 9 9 9 

4 5 7 2 3 5 8 9 3 2 7 7 7 1 1 1 1 2 6 9 3 6 0 3 3 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 3 3 5 5 6 7 5 2 5 3 5 6 6 2 2 2 2 5 6 3 3 5 7 4 5 

5 1 8 1 9 2 5 0 9 8 0 3 6 4 5 7 3 6 2 6 2 4 3 9 2 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + A + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + A + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Lymph node 

Renal, histiocytic sarcoma 

Lymph node, bronchial M M + + + + + M + + M M + + + + + M + + + + + M + 

Histiocytic sarcoma X 

Lymph node, mandibular + M + M + M M + + + M + + + + M M M + + + + + M I 

Histiocytic sarcoma 

Lymph node, mesenteric + + + + + + + + + + + M + + + + + + + + + + M I M 

Histiocytic sarcoma X 

Lymph node, mediastinal + + + M + + M M + + M + + + + + M M + + + + + + M 

Carcinoma, metastatic, lung X 

Histiocytic sarcoma 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Thymus M + + + + + + M + + M I M + + + M + + + + + + + + 

Integumentary System 

Mammary gland M M M M M + M M M M M M M M M M M M M M M M M M + 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangioma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X 

Alveolar/bronchiolar adenoma,

 multiple 

Alveolar/bronchiolar carcinoma X 

Carcinoma X 

Hepatocellular carcinoma, metastatic,

 liver X X X X X X X 

Histiocytic sarcoma X X X 

Nose + A + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + A + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 179 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 0 1 1 1 2 3 3 4 4 4 6 6 6 6 6 6 6 6 6 6 6 6 

9 0 4 4 6 5 1 7 6 6 9 0 6 6 6 6 6 6 6 6 6 6 6 

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 6 3 1 4 3 4 4 4 1 5 2 3 2 2 2 4 4 4 5 6 6 6 6 Tissues/ 

5 0 8 3 7 2 0 7 7 3 9 3 1 6 8 4 5 6 7 0 1 4 7 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + 48 

Leiomyosarcoma 1 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Prostate + + + + + + + + M + + + + + + + + + + + + + + 46 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + 47 

Testes + + + + + + + + + + + + + + + + + + + + + + + 48 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X 1 

Lymph node + 1 

Renal, histiocytic sarcoma X 1 

Lymph node, bronchial + + I + + + + + + + + + + M + + + + M M + + M 36 

Histiocytic sarcoma X X 3 

Lymph node, mandibular + + + + + M + + + + + + + + + M M + + + M + + 34 

Histiocytic sarcoma X X 2 

Lymph node, mesenteric + + + + + + + I + + + + + + + I + + + + + + + 42 

Histiocytic sarcoma X X X 4 

Lymph node, mediastinal M + + + M + + + + + M + M + + M + M + M + + + 34 

Carcinoma, metastatic, lung 1 

Histiocytic sarcoma X X 2 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X 2 

Thymus + + + + + M + + + + + + + + + + + + M + + + + 40 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M 2 

Skin + + + + + + + + + + + + + + + + + + + + + + + 48 

Subcutaneous tissue, hemangioma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + 48 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + 48 

Lung + + + + + + + + + + + + + + + + + + + + + + + 48 

Alveolar/bronchiolar adenoma X X X X X 7 

Alveolar/bronchiolar adenoma,

 multiple X 1 

Alveolar/bronchiolar carcinoma X X X 4 

Carcinoma 1 

Hepatocellular carcinoma, metastatic,

 liver 7 

Histiocytic sarcoma X X X X 7 

Nose + + + + + + + + + + + + + + + + + + + + + + + 47 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 47 
 

 

 

 

 

180 Tetrafluoroethylene, NTP TR 450 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

0 0 0 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 4 7 7 6 6 9 0 0 1 2 3 3 3 4 4 4 5 5 6 6 7 8 9 9 9 

4 5 7 2 3 5 8 9 3 2 7 7 7 1 1 1 1 2 6 9 3 6 0 3 3 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 3 3 5 5 6 7 5 2 5 3 5 6 6 2 2 2 2 5 6 3 3 5 7 4 5 

5 1 8 1 9 2 5 0 9 8 0 3 6 4 5 7 3 6 2 6 2 4 3 9 2 

Special Senses System 

Eye 

Harderian gland + 

Adenoma X 

Carcinoma 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Urinary bladder + A + A + + + + + + + + + + + + A + A + + + + + M 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X 

Lymphoma malignant mixed 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 181 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm (continued)
 

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 0 1 1 1 2 3 3 4 4 4 6 6 6 6 6 6 6 6 6 6 6 6 

9 0 4 4 6 5 1 7 6 6 9 0 6 6 6 6 6 6 6 6 6 6 6 

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 6 3 1 4 3 4 4 4 1 5 2 3 2 2 2 4 4 4 5 6 6 6 6 Tissues/ 

5 0 8 3 7 2 0 7 7 3 9 3 1 6 8 4 5 6 7 0 1 4 7 Tumors 

Special Senses System 

Eye + 1 

Harderian gland + + + + + + + 8 

Adenoma X X X X X X 7 

Carcinoma X 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X 3 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + 43 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X X X X X 12 

Lymphoma malignant mixed X 1 
 

 

 

 

 

 

 

 

 

 

182 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

3 3 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 6 6 1 2 3 4 4 8 8 9 0 1 1 1 1 3 3 4 4 4 4 4 4 5 5 

3 8 5 0 3 6 7 4 5 7 9 6 7 8 8 1 9 1 1 1 7 8 8 1 4 

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 7 8 5 6 5 8 5 6 3 4 7 6 4 8 8 5 3 4 5 8 7 5 7 4 5 

8 2 5 2 8 7 9 1 4 1 9 4 4 1 6 6 3 0 0 4 6 1 0 2 2 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + A + + + + 

Gallbladder A + + A A A + + M M A + A A + + M + + + A + + A A 

Intestine large, colon A + + + A + + + + + A + + + + + + + + + A + + A A 

Intestine large, rectum A + + + + + I + + + A + + + + + + + + + A + + A A 

Intestine large, cecum A + + + A + + + + + A + + A + + A + + + A + + A A 

Intestine small, duodenum A + + + A A + + + + A A A A + + A + + + A + + A A 

Intestine small, jejunum A + + A A + + + + + A A A A + + A + + + A + + A A 

Intestine small, ileum A + + + A + + + + + A A A A + + A + + + A + + A A 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma X X 

Hemangioma, multiple 

Hemangiosarcoma X X 

Hemangiosarcoma, multiple X X X X X X 

Hepatocellular carcinoma X X X X X X X X X X X X X X X X X 

Hepatocellular carcinoma, multiple X X X X 

Hepatocellular adenoma X 

Hepatocellular adenoma, multiple X X X X 

Histiocytic sarcoma X X X 

Mesentery + 

Histiocytic sarcoma X 

Pancreas A + + + + + + + + + + + + + + + + + + + A + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach A + + + + + + + + + + + + + + + + + + + A + + + + 

Stomach, glandular A + + + + + + + + + + + + + + + + + + + A + + + + 

Tooth + + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + A + + + + 

Adenoma 

Adrenal medulla + + + + + + + M + + + + + + + + + + + + A + + + + 

Islets, pancreatic A + + + + + + + + + + + + + + + + + + + A + + + + 

Parathyroid gland + M M + M I + + M M + + M + + I M M + + + M + + M 

Pituitary gland A + + + + + + + + + + + + + + + I + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + A + + + + 

General Body System 

Tissue NOS + + 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate A + + + + + + + + + + M + + + + + + + + A + + + + 

Seminal vesicle A + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 183 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 7 8 8 8 9 9 0 0 0 0 1 1 1 3 3 3 4 4 5 5 6 6 

9 3 6 9 9 3 7 0 7 8 8 5 6 8 1 2 9 6 9 3 7 6 6 

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 4 5 8 3 6 6 4 8 7 6 7 7 6 5 3 8 5 9 7 4 6 4 4 Tissues/ 

9 3 8 6 5 6 8 0 4 7 1 7 3 4 8 9 7 0 3 3 0 6 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 47 

Gallbladder + + + + + + + + + + + M M + A A + + + + + + + 31 

Intestine large, colon + + + + + + + + + + + A + + + + + + + + + + + 41 

Intestine large, rectum + + + + + + + + + + + + + + + I + + + + + + + 41 

Intestine large, cecum + + + + + + + + + + + A A + M A + + + + + + + 36 

Intestine small, duodenum + + + + + + + + + + + + A + A A + + + + + + + 34 

Intestine small, jejunum + + + + + + + + + + + A A + + A + + + + + + + 34 

Intestine small, ileum + + + + + + + + + + + A A + + A + + + + + + + 35 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangioma X 3 

Hemangioma, multiple X X 2 

Hemangiosarcoma X X X X X X X X 10 

Hemangiosarcoma, multiple X X X X X X X X X X X 17 

Hepatocellular carcinoma X X X X X X X 24 

Hepatocellular carcinoma, multiple X X X X X 9 

Hepatocellular adenoma X X X X 5 

Hepatocellular adenoma, multiple X X X 7 

Histiocytic sarcoma X X X X 7 

Mesentery + 2 

Histiocytic sarcoma 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 46 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 46 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 46 

Tooth + + 4 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 47 

Adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 46 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 46 

Parathyroid gland + + + M M + + + M + M + + M + M + + + + + M + 29 

Pituitary gland + + + + + + + + + + + + + + + M + + + M + + + 44 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 47 

General Body System 

Tissue NOS

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + 48 

Preputial gland + + + + + + + + + + + + M + + + + + + + + + M 46 

Prostate + + + + + + + + + + + M + + + + + + + + + + + 44 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + 47 

Testes + + + + + + + + + + + + + + + + + + + + + + + 48 

 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

184 Tetrafluoroethylene, NTP TR 450 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

3 3 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 6 6 1 2 3 4 4 8 8 9 0 1 1 1 1 3 3 4 4 4 4 4 4 5 5 

3 8 5 0 3 6 7 4 5 7 9 6 7 8 8 1 9 1 1 1 7 8 8 1 4 

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 7 8 5 6 5 8 5 6 3 4 7 6 4 8 8 5 3 4 5 8 7 5 7 4 5 

8 2 5 2 8 7 9 1 4 1 9 4 4 1 6 6 3 0 0 4 6 1 0 2 2 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + A + + + + 

Hemangioma X 

Histiocytic sarcoma X 

Lymph node 

Renal, histiocytic sarcoma 

Lymph node, bronchial A M M + + + M + + + + + + + I + + M M + + M + + + 

Lymph node, mandibular M + + + + + + + + + + + + M + M M + M M + M + + + 

Histiocytic sarcoma X 

Lymph node, mesenteric A + + + + + M + + + A + + + M M + + + + A + + + + 

Histiocytic sarcoma 

Lymph node, mediastinal A + + + + + M I + + M I M M M + M + + + + M + M + 

Spleen A + + + + + + + + + + + + + + + + + + + A + + + + 

Histiocytic sarcoma X 

Thymus A M + + + M M M M + M + M M + + + + + + + M M M + 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx A + + + + + + + + + + + + + + + + + + + A + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X X X X X 

Alveolar/bronchiolar adenoma,

 multiple
 

Alveolar/bronchiolar carcinoma X
 

Hemangiosarcoma, metastatic, liver X
 

Hepatocellular carcinoma, metastatic,

 liver X X X X X X X X X 

Histiocytic sarcoma X X 

Nose A + + + + + + + + + + + + + + + + + + + A + + + + 

Trachea A + + + + + + + + + + + + + + + + + + + A + + + + 

Special Senses System 

Eye + + 

Harderian gland + + + + 

Adenoma X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 185 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 7 8 8 8 9 9 0 0 0 0 1 1 1 3 3 3 4 4 5 5 6 6 

9 3 6 9 9 3 7 0 7 8 8 5 6 8 1 2 9 6 9 3 7 6 6 

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 4 5 8 3 6 6 4 8 7 6 7 7 6 5 3 8 5 9 7 4 6 4 4 Tissues/ 

9 3 8 6 5 6 8 0 4 7 1 7 3 4 8 9 7 0 3 3 0 6 7 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangioma 1 

Histiocytic sarcoma 1 

Lymph node + + 2 

Renal, histiocytic sarcoma X 1 

Lymph node, bronchial + + + M M + + + + M + + + M + M + + + + + + + 35 

Lymph node, mandibular M I I + M + + + M M + + + M + + + I M + + + + 32 

Histiocytic sarcoma 1 

Lymph node, mesenteric + + + + + + + + + + + + + + M + + + + + + + + 41 

Histiocytic sarcoma X 1 

Lymph node, mediastinal + M + + + + + + + + + + + + M + + M + + + M M 32 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 46 

Histiocytic sarcoma 1 

Thymus + + + + + + M + + + M + + + + + + + + + + + + 34 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + 48 

Subcutaneous tissue, hemangiosarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + 48 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + 46 

Lung + + + + + + + + + + + + + + + + + + + + + + + 48 

Alveolar/bronchiolar adenoma X X X X X X 12 

Alveolar/bronchiolar adenoma,

 multiple X 1 

Alveolar/bronchiolar carcinoma X X 3 

Hemangiosarcoma, metastatic, liver X 2 

Hepatocellular carcinoma, metastatic,

 liver X X X X X 14 

Histiocytic sarcoma X X 4 

Nose + + + + + + + + + + + + + + + + + + + + + + + 46 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 46 

Special Senses System 

Eye 2 

Harderian gland + 5 

Adenoma X 4 
 

 

186 Tetrafluoroethylene, NTP TR 450 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

3 3 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 6 6 1 2 3 4 4 8 8 9 0 1 1 1 1 3 3 4 4 4 4 4 4 5 5 

3 8 5 0 3 6 7 4 5 7 9 6 7 8 8 1 9 1 1 1 7 8 8 1 4 

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 7 8 5 6 5 8 5 6 3 4 7 6 4 8 8 5 3 4 5 8 7 5 7 4 5 

8 2 5 2 8 7 9 1 4 1 9 4 4 1 6 6 3 0 0 4 6 1 0 2 2 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, liver X 

Histiocytic sarcoma X 

Urinary bladder A + + + + + + + + + + A + + + + + + + + A + + A + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 
 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 187 

TABLE C2
 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm (continued)
 

5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 7 8 8 8 9 9 0 0 0 0 1 1 1 3 3 3 4 4 5 5 6 6 

9 3 6 9 9 3 7 0 7 8 8 5 6 8 1 2 9 6 9 3 7 6 6 

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 4 5 8 3 6 6 4 8 7 6 7 7 6 5 3 8 5 9 7 4 6 4 4 Tissues/ 

9 3 8 6 5 6 8 0 4 7 1 7 3 4 8 9 7 0 3 3 0 6 7 Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangiosarcoma, metastatic, liver 1 

Histiocytic sarcoma X X 3 

Urinary bladder + + + + + + + + + + + + + + + A + + + + + + + 43 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X 7 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

188 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

0 2 3 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 0 5 1 5 0 6 8 1 2 2 3 4 4 4 4 4 4 4 5 5 6 6 7 7 7 

5 9 5 6 1 5 3 8 7 7 6 1 1 1 3 4 8 8 1 9 3 5 4 5 8 

4 3 3 3 3 3 3 3 3 3 4 3 3 4 3 3 3 3 3 3 3 4 3 3 3 

Carcass ID Number 0 7 9 5 9 9 5 7 8 9 0 6 8 0 5 7 7 8 7 7 7 0 9 9 9 

3 1 1 2 0 3 4 3 7 5 2 0 3 1 5 9 0 4 6 7 2 4 8 7 4 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + M + + + + 

Gallbladder A + M A M M + M + + + + + + + A A M M M A M + + + 

Intestine large, colon + + A A + A + + + + + + + + + M A + + A A A + + + 

Intestine large, rectum + + A A + A + + + + + + + + + A A + + A A A + + + 

Intestine large, cecum + + A A + A + + + + + + + + + A A + + A A A + + + 

Intestine small, duodenum A + A A + A + + + + + + + + + A A + A A A A + + + 

Intestine small, jejunum A + A A + A + + + + + + + + + A A + A A A A + + + 

Intestine small, ileum A + A A + A + + + + + + + + + A A + A A A A + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, harderian

 gland X 

Hemangioma 

Hemangioma, multiple 

Hemangiosarcoma X X X X X X X X X X X X X 

Hemangiosarcoma, multiple X X X 

Hepatocellular carcinoma X X X X X X X X X 

Hepatocellular carcinoma, multiple X X X X 

Hepatocellular adenoma X X X X X 

Hepatocellular adenoma, multiple X X X X 

Histiocytic sarcoma X X X 

Mesentery + + 

Hemangioma 

Hemangiosarcoma X 

Hepatocellular carcinoma, metastatic,

 liver X 

Pancreas + + + A + M + + + + + + + + + + + + + + A + + + + 

Hepatocellular carcinoma, metastatic,

 liver 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + A + + + + + + + + + + + + + + + + A + + + + 

Squamous cell carcinoma 

Squamous cell papilloma 

Stomach, glandular + + A A + + + + + + + + + + + + + + + + A + + + + 

Tooth + + + + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, lung 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + A + A + + + + + + + + + + + + + + A + + + + 

Adenoma X 

Parathyroid gland + M + + + M + M M M + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + M + M + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 189 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

Number of Days on Study 

5 

8 

3 

5 

8 

5 

5 

8 

6 

5 

8 

6 

5 

8 

9 

5 

9 

9 

6 

0 

0 

6 

0 

0 

6 

0 

6 

6 

0 

8 

6 

0 

8 

6 

0 

8 

6 

1 

0 

6 

1 

3 

6 

1 

3 

6 

2 

3 

6 

2 

9 

6 

3 

0 

6 

3 

1 

6 

4 

3 

6 

4 

6 

6 

5 

4 

6 

6 

6 

Carcass ID Number 

3 

5 

9 

3 

8 

9 

3 

8 

0 

3 

9 

9 

3 

6 

5 

3 

6 

7 

3 

6 

3 

3 

7 

5 

4 

0 

5 

3 

5 

7 

3 

6 

4 

3 

8 

1 

3 

8 

6 

3 

6 

6 

3 

7 

4 

3 

7 

8 

3 

6 

9 

3 

8 

2 

4 

0 

6 

3 

4 

9 

3 

9 

2 

4 

0 

0 

3 

6 

1 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 47 

Gallbladder + + + + + A + A + M + + + M M + M + + A + A + 27 

Intestine large, colon + + + + + + + A + + + + + + + + + + + + + + + 39 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + 40 

Intestine large, cecum + + + + + + + A + + + + + + + + + + + + + + + 39 

Intestine small, duodenum + + + + + + + A + + + A + + + + + + + + + + + 36 

Intestine small, jejunum + + + + + + + A + + + A + A + + + + + + + A + 34 

Intestine small, ileum + + + + + + + A + + + A + + + + + + + + + + + 36 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, harderian

 gland 1 

Hemangioma X 1 

Hemangioma, multiple X 1 

Hemangiosarcoma X X X X X X 19 

Hemangiosarcoma, multiple X X X X X X X X X X X X X X X 18 

Hepatocellular carcinoma X X X X X X X X X X X 20 

Hepatocellular carcinoma, multiple X X 6 

Hepatocellular adenoma X X X X X X X X 13 

Hepatocellular adenoma, multiple X X X 7 

Histiocytic sarcoma X X X X 7 

Mesentery + + + + + 7 

Hemangioma X 1 

Hemangiosarcoma 1 

Hepatocellular carcinoma, metastatic,

 liver 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 45 

Hepatocellular carcinoma, metastatic,

 liver X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 46 

Squamous cell carcinoma X 1 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 45 

Tooth + + + 7 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, lung X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 48 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 48 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 45 

Adenoma 1 

Parathyroid gland + + M + + + + + + I + + + + + + + + + + M M + 39 

Pituitary gland + + + + + M M + + + + + + + + + + + + + + + + 44 

Thyroid gland + + M + + + + + + + + + + + + + + + + + + + + 47 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

190 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

Number of Days on Study 

0 

0 

5 

2 

5 

9 

3 

1 

5 

3 

5 

6 

4 

0 

1 

4 

6 

5 

4 

8 

3 

5 

1 

8 

5 

2 

7 

5 

2 

7 

5 

3 

6 

5 

4 

1 

5 

4 

1 

5 

4 

1 

5 

4 

3 

5 

4 

4 

5 

4 

8 

5 

4 

8 

5 

5 

1 

5 

5 

9 

5 

6 

3 

5 

6 

5 

5 

7 

4 

5 

7 

5 

5 

7 

8 

Carcass ID Number 

4 

0 

3 

3 

7 

1 

3 

9 

1 

3 

5 

2 

3 

9 

0 

3 

9 

3 

3 

5 

4 

3 

7 

3 

3 

8 

7 

3 

9 

5 

4 

0 

2 

3 

6 

0 

3 

8 

3 

4 

0 

1 

3 

5 

5 

3 

7 

9 

3 

7 

0 

3 

8 

4 

3 

7 

6 

3 

7 

7 

3 

7 

2 

4 

0 

4 

3 

9 

8 

3 

9 

7 

3 

9 

4 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + +
 

Leiomyoma X
 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + +
 

Prostate + + A A + A + + + + + + + + + + + + + + A + + + +
 

Seminal vesicle + + A A + A + + + + + + + + + + + + + + A + + + +
 

Testes + + + + + + + + + + + + + + + + + + + + + + + + +
 

Hematopoietic System 

Bone marrow + + + + + A + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Lymph node, bronchial M M + M M A M + M + + M + M M M + M M + I + + + + 

Histiocytic sarcoma 

Lymph node, mandibular + M + + + M + + M + + + + + + + M + + + M + + + + 

Lymph node, mesenteric + + + A + A + + + + + + + + + + M + M M A + + + M 

Histiocytic sarcoma 

Lymph node, mediastinal M + + + + M + + M + I + + M + M M M M + M + + + + 

Carcinoma, metastatic, lung 

Histiocytic sarcoma 

Spleen + + + A + + + + + + + + + + + + + + + + A + + + + 

Histiocytic sarcoma X X 

Thymus + + + M + A M + + + + + M + + M + + M M + + + + + 

Histiocytic sarcoma X 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, harderian

 gland X 

Skeletal muscle 

Carcinoma, metastatic, lung 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, harderian

 gland X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 191 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

Number of Days on Study 

5 

8 

3 

5 

8 

5 

5 

8 

6 

5 

8 

6 

5 

8 

9 

5 

9 

9 

6 

0 

0 

6 

0 

0 

6 

0 

6 

6 

0 

8 

6 

0 

8 

6 

0 

8 

6 

1 

0 

6 

1 

3 

6 

1 

3 

6 

2 

3 

6 

2 

9 

6 

3 

0 

6 

3 

1 

6 

4 

3 

6 

4 

6 

6 

5 

4 

6 

6 

6 

Carcass ID Number 

3 

5 

9 

3 

8 

9 

3 

8 

0 

3 

9 

9 

3 

6 

5 

3 

6 

7 

3 

6 

3 

3 

7 

5 

4 

0 

5 

3 

5 

7 

3 

6 

4 

3 

8 

1 

3 

8 

6 

3 

6 

6 

3 

7 

4 

3 

7 

8 

3 

6 

9 

3 

8 

2 

4 

0 

6 

3 

4 

9 

3 

9 

2 

4 

0 

0 

3 

6 

1 

Total 

Tissues/ 

Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + 48 

Leiomyoma 1 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Prostate + + + + + + + + + + + + + + + + + + + + + + + 44 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + 44 

Testes + + + + + + + + + + + + + + + + + + + + + + + 48 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 2 

Lymph node, bronchial M I + M + + + M + M M + + + + I + + M + + + + 26 

Histiocytic sarcoma X 1 

Lymph node, mandibular M M M + M + + + + + M M + + + M + + + M + M + 34 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + M + + 40 

Histiocytic sarcoma X X 2 

Lymph node, mediastinal + + + + + + M M + + M M + M + + I M M + + M + 29 

Carcinoma, metastatic, lung X 1 

Histiocytic sarcoma X 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 46 

Histiocytic sarcoma 2 

Thymus + M M M + + + + + + + M + + + + + + + + + + + 37 

Histiocytic sarcoma 1 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + 48 

Subcutaneous tissue, hemangiosarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, harderian

 gland 1 

Skeletal muscle + 1 

Carcinoma, metastatic, lung X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, harderian

 gland 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

192 Tetrafluoroethylene, NTP TR 450 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

0 2 3 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 0 5 1 5 0 6 8 1 2 2 3 4 4 4 4 4 4 4 5 5 6 6 7 7 7 

5 9 5 6 1 5 3 8 7 7 6 1 1 1 3 4 8 8 1 9 3 5 4 5 8 

4 3 3 3 3 3 3 3 3 3 4 3 3 4 3 3 3 3 3 3 3 4 3 3 3 

Carcass ID Number 0 7 9 5 9 9 5 7 8 9 0 6 8 0 5 7 7 8 7 7 7 0 9 9 9 

3 1 1 2 0 3 4 3 7 5 2 0 3 1 5 9 0 4 6 7 2 4 8 7 4 

Respiratory System 

Larynx + + + A + A + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X 

Alveolar/bronchiolar adenoma,

 multiple X 

Alveolar/bronchiolar carcinoma 

Carcinoma 

Carcinoma, metastatic, harderian

 gland X 

Hemangiosarcoma, metastatic, liver X 

Hepatocellular carcinoma, metastatic,

 liver X X X X X 

Histiocytic sarcoma X 

Nose + + + + + A + + + + + + + + + + + + + + + + + + + 

Trachea + + A A + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Harderian gland + + + 

Adenoma X X 

Carcinoma X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, lung 

Histiocytic sarcoma X X 

Urinary bladder + + A A + A + + + + + + + + + + A + + A A + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 

Lymphoma malignant mixed 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 193 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 8 8 8 8 9 0 0 0 0 0 0 1 1 1 2 2 3 3 4 4 5 6 

3 5 6 6 9 9 0 0 6 8 8 8 0 3 3 3 9 0 1 3 6 4 6 

3 3 3 3 3 3 3 3 4 3 3 3 3 3 3 3 3 3 4 3 3 4 3 Total 

Carcass ID Number 5 8 8 9 6 6 6 7 0 5 6 8 8 6 7 7 6 8 0 4 9 0 6 Tissues/ 

9 9 0 9 5 7 3 5 5 7 4 1 6 6 4 8 9 2 6 9 2 0 1 Tumors 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + 46 

Lung + + + + + + + + + + + + + + + + + + + + + + + 48 

Alveolar/bronchiolar adenoma X X 3 

Alveolar/bronchiolar adenoma,

 multiple X 2 

Alveolar/bronchiolar carcinoma X 1 

Carcinoma X 1 

Carcinoma, metastatic, harderian

 gland 1 

Hemangiosarcoma, metastatic, liver X 2 

Hepatocellular carcinoma, metastatic,

 liver X X X 8 

Histiocytic sarcoma X X 3 

Nose + + + + + + + + + + + + + + + + + + + + + + + 47 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 46 

Special Senses System 

Ear + 1 

Harderian gland + + + 6 

Adenoma X X 4 

Carcinoma 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma, metastatic, lung X 1 

Histiocytic sarcoma 2 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + 42 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X 7 

Lymphoma malignant mixed X 1 
194 Tetrafluoroethylene, NTP TR 450 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Harderian Gland: Adenoma 

Overall ratea 

Adjusted rateb 

Terminal ratec 

5/48 (10%) 

12.6% 

4/38 (11%) 

7/48 (15%) 

35.3% 

2/11 (18%) 

4/48 (8%) 

13.8% 

0/2 (0%) 

4/48 (8%) 

24.7% 

0/1 (0%) 

First incidence (days) 

Life table testd 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

597 

P=0.047 

P=0.381N 

P=0.316N 

463 

P=0.022 

P=0.239 

P=0.379 

447 

P=0.100 

P=0.481N 

P=0.500N 

465 

P=0.052 

P=0.545N 

P=0.500N 

Harderian Gland: Adenoma or Carcinoma 

Overall rate 6/48 (13%) 8/48 (17%) 4/48 (8%) 5/48 (10%) 

Adjusted rate 14.6% 42.5% 13.8% 26.6% 

Terminal rate 4/38 (11%) 3/11 (27%) 0/2 (0%) 0/1 (0%) 

First incidence (days) 597 463 447 465 

Life table test P=0.033 P=0.016 P=0.166 P=0.058 

Logistic regression test P=0.389N P=0.230 P=0.319N P=0.487N 

Cochran-Armitage test P=0.312N 

Fisher exact test P=0.387 P=0.370N P=0.500N 

Liver: Hemangioma 

Overall rate 0/48 (0%) 10/48 (21%) 5/48 (10%) 2/48 (4%) 

Adjusted rate 0.0% 53.2% 60.1% 12.3% 

Terminal rate 

First incidence (days) 

0/38 (0%) 

—e 4/11 (36%) 

590 

1/2 (50%) 

548 

0/1 (0%) 

599 

Life table test P=0.012 P<0.001 P<0.001 P=0.066 

Logistic regression test P=0.289N P<0.001 P=0.015 P=0.188 

Cochran-Armitage test P=0.448N 

Fisher exact test P<0.001 P=0.028 P=0.247 

Liver: Hemangiosarcoma 

Overall rate 0/48 (0%) 21/48 (44%) 27/48 (56%) 37/48 (77%) 

Adjusted rate 0.0% 89.3% 95.6% 100.0% 

Terminal rate 0/38 (0%) 9/11 (82%) 1/2 (50%) 1/1 (100%) 

First incidence (days) — 522 497 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

Liver: Hemangioma or Hemangiosarcoma 

Overall rate 0/48 (0%) 26/48 (54%) 30/48 (63%) 38/48 (79%) 

Adjusted rate 0.0% 95.7% 100.0% 100.0% 

Terminal rate 0/38 (0%) 10/11 (91%) 2/2 (100%) 1/1 (100%) 

First incidence (days) — 522 497 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 
Tetrafluoroethylene, NTP TR 450 195 

TABLE C3
 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Liver: Hepatocellular Adenoma 

Overall rate 17/48 (35%) 17/48 (35%) 12/48 (25%) 20/48 (42%) 

Adjusted rate 42.1% 83.5% 70.3% 71.3% 

Terminal rate 15/38 (39%) 8/11 (73%) 1/2 (50%) 0/1 (0%) 

First incidence (days) 452 566 485 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.043 P=0.059 P=0.444N P=0.181 

Cochran-Armitage test P=0.322 

Fisher exact test P=0.584N P=0.187N P=0.338 

Liver: Hepatocellular Carcinoma 

Overall rate 11/48 (23%) 20/48 (42%) 33/48 (69%) 26/48 (54%) 

Adjusted rate 24.4% 63.4% 94.3% 100.0% 

Terminal rate 5/38 (13%) 3/11 (27%) 1/2 (50%) 1/1 (100%) 

First incidence (days) 475 462 363 315 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.150 P=0.056 P=0.055 P=0.245 

Cochran-Armitage test P=0.001 

Fisher exact test P=0.040 P<0.001 P=0.002 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 26/48 (54%) 34/48 (71%) 39/48 (81%) 35/48 (73%) 

Adjusted rate 57.4% 96.8% 100.0% 100.0% 

Terminal rate 19/38 (50%) 10/11 (91%) 2/2 (100%) 1/1 (100%) 

First incidence (days) 452 462 363 315 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.236 P=0.015 P=0.289 P=0.550N 

Cochran-Armitage test P=0.040 

Fisher exact test P=0.070 P=0.004 P=0.045 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 10/48 (21%) 8/48 (17%) 13/48 (27%) 5/48 (10%) 

Adjusted rate 24.7% 41.7% 76.8% 23.1% 

Terminal rate 8/38 (21%) 3/11 (27%) 1/2 (50%) 0/1 (0%) 

First incidence (days) 475 522 433 548 

Life table test P=0.007 P=0.079 P<0.001 P=0.042 

Logistic regression test P=0.297N P=0.597 P=0.324 P=0.344N 

Cochran-Armitage test P=0.159N 

Fisher exact test P=0.397N P=0.317 P=0.130N 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 2/48 (4%) 5/48 (10%) 3/48 (6%) 2/48 (4%) 

Adjusted rate 5.3% 28.4% 51.9% 20.0% 

Terminal rate 2/38 (5%) 2/11 (18%) 0/2 (0%) 0/1 (0%) 

First incidence (days) 666 (T) 537 548 606 

Life table test P=0.014 P=0.015 P=0.004 P=0.043 

Logistic regression test P=0.355 P=0.103 P=0.150 P=0.330 

Cochran-Armitage test P=0.420N 

Fisher exact test P=0.218 P=0.500 P=0.692N 
196 Tetrafluoroethylene, NTP TR 450 

TABLE C3
 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 12/48 (25%) 13/48 (27%) 16/48 (33%) 7/48 (15%) 

Adjusted rate 29.7% 61.8% 88.8% 38.5% 

Terminal rate 10/38 (26%) 5/11 (45%) 1/2 (50%) 0/1 (0%) 

First incidence (days) 475 522 433 548 

Life table test P<0.001 P=0.003 P<0.001 P=0.004 

Logistic regression test P=0.383N P=0.218 P=0.136 P=0.537N 

Cochran-Armitage test P=0.130N 

Fisher exact test P=0.500 P=0.250 P=0.153N 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 0/48 (0%) 3/48 (6%) 0/47 (0%) 0/47 (0%)
 

Adjusted rate 0.0% 23.3% 0.0% 0.0%
 

Terminal rate 0/38 (0%) 2/11 (18%) 0/2 (0%) 0/1 (0%)
 

First incidence (days) — 637 — —
 

Life table test P=0.345 P=0.008 — —
 

Logistic regression test P=0.590 P=0.020 — —
 

Cochran-Armitage test P=0.316N
 

Fisher exact test P=0.121 — —
 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 0/48 (0%) 4/48 (8%) 0/47 (0%) 0/47 (0%)
 

Adjusted rate 0.0% 31.8% 0.0% 0.0%
 

Terminal rate 0/38 (0%) 3/11 (27%) 0/2 (0%) 0/1 (0%)
 

First incidence (days) — 637 — —
 

Life table test P=0.228 P=0.001 — —
 

Logistic regression test P=0.478 P=0.004 — —
 

Cochran-Armitage test P=0.252N
 

Fisher exact test P=0.059 — —
 

All Organs: Hemangioma 

Overall rate 0/48 (0%) 11/48 (23%) 6/48 (13%) 3/48 (6%) 

Adjusted rate 0.0% 54.7% 61.3% 26.9% 

Terminal rate 0/38 (0%) 4/11 (36%) 1/2 (50%) 0/1 (0%) 

First incidence (days) — 566 541 599 

Life table test P=0.005 P<0.001 P<0.001 P=0.005 

Logistic regression test P=0.311N P<0.001 P=0.011 P=0.057 

Cochran-Armitage test P=0.563N 

Fisher exact test P<0.001 P=0.013 P=0.121 

All Organs: Hemangiosarcoma 

Overall rate 2/48 (4%) 21/48 (44%) 27/48 (56%) 37/48 (77%) 

Adjusted rate 5.3% 89.3% 95.6% 100.0% 

Terminal rate 2/38 (5%) 9/11 (82%) 1/2 (50%) 1/1 (100%) 

First incidence (days) 666 (T) 522 497 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 
Tetrafluoroethylene, NTP TR 450 197 

TABLE C3
 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 2/48 (4%) 27/48 (56%) 30/48 (63%) 38/48 (79%) 

Adjusted rate 5.3% 95.8% 100.0% 100.0% 

Terminal rate 2/38 (5%) 10/11 (91%) 2/2 (100%) 1/1 (100%) 

First incidence (days) 666 (T) 522 497 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

All Organs: Histiocytic Sarcoma 

Overall rate 0/48 (0%) 12/48 (25%) 7/48 (15%) 7/48 (15%) 

Adjusted rate 0.0% 47.8% 35.1% 65.8% 

Terminal rate 0/38 (0%) 1/11 (9%) 0/2 (0%) 0/1 (0%) 

First incidence (days) — 513 415 527 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.100 P<0.001 P=0.039 P=0.004 

Cochran-Armitage test P=0.143 

Fisher exact test P<0.001 P=0.006 P=0.006 

All Organs: Benign Neoplasms 

Overall rate 26/48 (54%) 30/48 (63%) 27/48 (56%) 27/48 (56%) 

Adjusted rate 61.6% 100.0% 100.0% 100.0% 

Terminal rate 22/38 (58%) 11/11 (100%) 2/2 (100%) 1/1 (100%) 

First incidence (days) 452 463 433 401 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.135 P=0.015 P=0.329 P=0.179 

Cochran-Armitage test P=0.520N 

Fisher exact test P=0.267 P=0.500 P=0.500 

All Organs: Malignant Neoplasms 

Overall rate 16/48 (33%) 39/48 (81%) 47/48 (98%) 46/48 (96%) 

Adjusted rate 34.6% 94.9% 100.0% 100.0% 

Terminal rate 8/38 (21%) 9/11 (82%) 2/2 (100%) 1/1 (100%) 

First incidence (days) 475 462 363 315 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 
198 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE C3
 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Benign or Malignant Neoplasms 

Overall rate 37/48 (77%) 44/48 (92%) 48/48 (100%) 46/48 (96%) 

Adjusted rate 78.6% 100.0% 100.0% 100.0% 

Terminal rate 28/38 (74%) 11/11 (100%) 2/2 (100%) 1/1 (100%) 

First incidence (days) 452 462 363 315 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.012 P=0.002 P=0.171 P=0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.045 P<0.001 P=0.007 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver, lung, and thyroid gland; 

for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study 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 life table test regards neoplasms in animals dying prior to terminal kill as being (directly or indirectly) 

the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the overall incidence 

rates. For all tests, a negative trend or a lower incidence in an exposure group is indicated byN. e Not applicable; no neoplasms in animal group 
Tetrafluoroethylene, NTP TR 450 199 

TABLE C4a 

Historical Incidence of Liver Neoplasms in Chamber Control Male B6C3F a 1 Mice

Incidence in Controls 

Study Hemangioma Hemangiosarcoma Hepatocellular Hepatocellular Hepatocellular 

Adenoma Carcinoma Adenoma 

or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 0/50 13/50 11/50 21/50 

Acetonitrile 0/50 1/50 13/50 7/50 19/50 

Allyl Glycidyl Ether 0/49 0/49 15/49 10/49 23/49 

-Chloroacetophenone 0/50 0/50 5/50 11/50 16/50 

Epinephrine Hydrochloride 0/50 1/50 10/50 12/50 20/50 

Ethyl Chloride 0/50 0/50 6/50 9/50 15/50 

Hexachlorocyclopentadiene 0/50 0/50 19/50 7/50 24/50 

o-Chlorobenzalmalononitrile (CS-2) 1/49 0/49 4/49 14/49 18/49 

Ozone 0/50 0/50 23/50 12/50 30/50 

Total 1/448 (0.2%) 2/448 (0.5%) 108/448 (24.1%) 93/448 (20.8%) 186/448 (41.5%) 

Standard deviation 0.7% 0.9% 13.0% 4.9% 9.2% 

Range 0%-2% 0%-2% 8%-46% 14%-29% 30%-60% 

Overall Historical Incidence 

Total 2/947 (0.2%) 12/947 (1.3%) 200/947 (21.1%) 184/947 (19.4%) 358/947 (37.8%) 

Standard deviation 0.7% 1.7% 11.6% 5.8% 12.5% 

Range 0%-2% 0%-6% 4%-46% 9%-29% 11%-60% 

a Data as of 12 May 1995 
200 Tetrafluoroethylene, NTP TR 450 

TABLE C4b 

Historical Incidence of Histiocytic Sarcoma in Chamber Control Male B6C3F a 1 Mice

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 

Acetonitrile 0/50 

Allyl Glycidyl Ether 0/50 

-Chloroacetophenone 0/50 

Epinephrine Hydrochloride 1/50 

Ethyl Chloride 0/50 

Hexachlorocyclopentadiene 0/50 

o-Chlorobenzalmalononitrile (CS-2) 1/50 

Ozone 0/50 

Total 2/450 (0.4%) 

Standard deviation 0.9% 

Range 0%-2% 

Overall Historical Incidence 

Total 6/950 (0.6%) 

Standard deviation 1.2% 

Range 0%-4% 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 201 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 58 58 58 58 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 6 24 26 27 

Natural deaths 4 13 20 20 

Survivors 

Terminal sacrifice 38 11 2 1 

Animals examined microscopically 58 58 58 58 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, colon (10) (9) (10) (10) 

Diverticulum 1 (10%) 

Inflammation, chronic 1 (10%) 

Liver (10) (10) (10) (10) 

Angiectasis 1 (10%) 5 (50%) 2 (20%) 

Basophilic focus 1 (10%) 1 (10%) 

Clear cell focus 2 (20%) 1 (10%) 

Eosinophilic focus 3 (30%) 

Fatty change 4 (40%) 1 (10%) 1 (10%) 1 (10%) 

Granuloma 1 (10%) 

Hematopoietic cell proliferation 1 (10%) 

Infarct 1 (10%) 

Infiltration cellular, mixed cell 1 (10%) 2 (20%) 

Mixed cell focus 1 (10%) 1 (10%) 3 (30%) 3 (30%) 

Necrosis, coagulative, multifocal 1 (10%) 1 (10%) 1 (10%) 

Salivary glands (10) (10) (10) (10) 

Infiltration cellular, mononuclear cell 4 (40%) 2 (20%) 1 (10%) 3 (30%) 

Stomach, forestomach (10) (10) (10) (10) 

Epithelium, hyperplasia 1 (10%) 

Tooth (1) 

Inflammation, suppurative 1 (100%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Capsule, hyperplasia 6 (60%) 4 (40%) 7 (70%) 2 (20%) 

Islets, pancreatic (10) (10) (10) (10) 

Hyperplasia 1 (10%) 1 (10%) 

Thyroid gland (10) (10) (10) (10) 

Ultimobranchial cyst 1 (10%) 

Genital System 

Preputial gland (10) (10) (10) (10) 

Ectasia 4 (40%) 1 (10%) 1 (10%) 

Infiltration cellular, mononuclear cell 1 (10%) 2 (20%) 1 (10%) 

Inflammation, suppurative 3 (30%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

202 Tetrafluoroethylene, NTP TR 450 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Hematopoietic System 

Bone marrow (10) 

Hyperplasia, neutrophil

Lymph node, mandibular (8)

Hyperplasia, plasma cell

Spleen (10) 

Hematopoietic cell proliferation 2 (20%) 

Infiltration cellular, polymorphonuclear

(10) 

 1 (10%) 

(3)

(10) 

 4 (40%) 

(10) 

 2 (20%) 

(6)

(10) 

 5 (50%) 

 1 (10%) 

(10) 

 1 (10%) 

(8) 

 1 (13%) 

(10) 

 3 (30%) 

Integumentary System 

Skin 

Inflammation, chronic

(10) (9) 

 1 (11%) 

(10) (10) 

Musculoskeletal System 

Bone 

Sternum, fracture healed

(10) (10) (10) 

 1 (10%) 

(10) 

Nervous System 

Brain 

Mineralization

(10) 

 5 (50%) 

(10) (10) 

 2 (20%) 

(10) 

 6 (60%) 

Respiratory System 

Larynx 

Exudate, mucopurulent

Lung 

Alveolus, hemorrhage, multifocal

(10) 

(10) 

 1 (10%) 

(10) 

(10) 

(10) 

(10) 

(10) 

 1 (10%) 

(10) 

Urinary System 

Kidney 

Infiltration cellular, mononuclear cell

Inflammation, chronic active

Nephropathy

Bilateral, pelvis, dilatation

Renal tubule, dilatation

Renal tubule, karyomegaly

Urinary bladder 

Inflammation, chronic active

(10) 

 1 (10%) 

 3 (30%) 

(10) 

(10) 

 3 (30%) 

 1 (10%) 

(10) 

(10) 

 1 (10%) 

 1 (10%) 

 6 (60%) 

 4 (40%) 

(10) 

 1 (10%) 

(10) 

 3 (30%) 

 10 (100%) 

 10 (100%) 

(10) 

Systems Examined With No Lesions Observed 

Cardiovascular System 

General Body System 

Special Senses System 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 203 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study 

Alimentary System 

Gallbladder (42) (35) (31) (27) 

Inflammation, chronic active 1 (4%) 

Intestine small, jejunum (46) (40) (34) (34) 

Peyer's patch, hyperplasia, lymphoid 1 (2%) 1 (3%) 

Intestine small, ileum (46) (39) (35) (36) 

Peyer's patch, inflammation, chronic active 1 (2%) 

Liver (48) (48) (48) (48) 

Angiectasis 6 (13%) 10 (21%) 13 (27%) 

Basophilic focus 1 (2%) 1 (2%) 4 (8%) 3 (6%) 

Clear cell focus 1 (2%) 

Eosinophilic focus 1 (2%) 6 (13%) 7 (15%) 7 (15%) 

Fatty change 2 (4%) 

Hematopoietic cell proliferation 1 (2%) 2 (4%) 4 (8%) 

Hemorrhage 1 (2%) 1 (2%) 

Infarct 1 (2%) 6 (13%) 2 (4%) 4 (8%) 

Infiltration cellular, mixed cell 1 (2%) 5 (10%) 3 (6%) 3 (6%) 

Mixed cell focus 2 (4%) 2 (4%) 3 (6%) 

Necrosis, coagulative, multifocal 4 (8%) 3 (6%) 13 (27%) 11 (23%) 

Thrombosis 1 (2%) 3 (6%) 

Bile duct, hyperplasia 1 (2%) 

Centrilobular, necrosis 1 (2%) 1 (2%) 

Hepatocyte, regeneration 1 (2%) 

Mesentery (2) (3) (2) (7) 

Angiectasis 1 (14%) 

Fat, hemorrhage 2 (29%) 

Fat, necrosis 1 (50%) 2 (67%) 1 (50%) 3 (43%) 

Pancreas (48) (48) (46) (45) 

Granuloma 1 (2%) 

Duct, ectasia 1 (2%) 

Salivary glands (48) (48) (48) (48) 

Infiltration cellular, mononuclear cell 7 (15%) 7 (15%) 3 (6%) 

Stomach, forestomach (48) (48) (46) (46) 

Foreign body 1 (2%) 

Granuloma 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia, squamous 1 (2%) 

Inflammation, focal 1 (2%) 

Ulcer 1 (2%) 1 (2%) 

Epithelium, hyperplasia 2 (4%) 3 (6%) 2 (4%) 3 (7%) 

Serosa, inflammation 1 (2%) 

Stomach, glandular (48) (48) (46) (45) 

Foreign body 1 (2%) 

Necrosis 2 (4%) 

Tooth (2) (2) (4) (7) 

Dysplasia 1 (50%) 1 (50%) 3 (43%) 

Inflammation, suppurative 1 (50%) 4 (100%) 4 (57%) 

Peridontal tissue, proliferation connective

 tissue 1 (50%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

204 Tetrafluoroethylene, NTP TR 450 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Cardiovascular System 

Heart (48) (48) (48) (48) 

Cardiomyopathy 2 (4%) 2 (4%) 

Fibrosis 1 (2%) 

Infiltration cellular, mixed cell 1 (2%) 

Atrium, thrombosis 1 (2%) 

Endocrine System 

Adrenal cortex (48) (48) (47) (48) 

Accessory adrenal cortical nodule 1 (2%) 

Cyst 1 (2%) 

Hyperplasia 1 (2%) 3 (6%) 

Capsule, hyperplasia 29 (60%) 26 (54%) 24 (51%) 20 (42%) 

Islets, pancreatic (48) (48) (46) (45) 

Hyperplasia 2 (4%) 1 (2%) 7 (15%) 2 (4%) 

Pituitary gland (47) (44) (44) (44) 

Pars distalis, cyst 1 (2%) 1 (2%) 1 (2%) 

Pars distalis, hyperplasia 1 (2%) 

Pars intermedia, hemorrhage 1 (2%) 

Thyroid gland (48) (48) (47) (47) 

Ultimobranchial cyst 1 (2%) 1 (2%) 

Follicle, cyst 1 (2%) 1 (2%) 1 (2%) 

Follicular cell, hyperplasia 1 (2%) 1 (2%) 

General Body System 

Tissue NOS (1) (2) (2) 

Infiltration cellular, mononuclear cell 1 (50%) 

Necrosis 1 (50%) 

Genital System 

Epididymis (48) (48) (48) (48) 

Granuloma sperm 1 (2%) 

Hemorrhage 1 (2%) 

Preputial gland (48) (48) (46) (48) 

Atrophy 1 (2%) 

Ectasia 2 (4%) 2 (4%) 1 (2%) 

Infiltration cellular, mononuclear cell 6 (13%) 5 (10%) 7 (15%) 3 (6%) 

Inflammation, chronic 5 (10%) 5 (10%) 4 (9%) 1 (2%) 

Inflammation, suppurative 1 (2%) 4 (8%) 7 (15%) 3 (6%) 

Prostate (46) (46) (44) (44) 

Hyperplasia 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Seminal vesicle (48) (47) (47) (44) 

Dilatation 4 (8%) 1 (2%) 2 (4%) 

Hyperplasia 1 (2%) 

Inflammation, chronic 2 (4%) 2 (4%) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Testes (48) (48) (48) (48) 

Atrophy, focal 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 205 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Hematopoietic System 

Bone marrow (48) (48) (47) (47) 

Hyperplasia, neutrophil 2 (4%) 1 (2%) 1 (2%) 

Lymph node (3) (1) (2) 

Iliac, hemorrhage 1 (50%) 

Iliac, hyperplasia, lymphoid 1 (33%) 

Iliac, hyperplasia, plasma cell 2 (100%) 

Iliac, pigmentation, hemosiderin 1 (50%) 

Renal, hyperplasia, lymphoid 1 (33%) 

Lymph node, bronchial (36) (36) (35) (26) 

Hemorrhage 2 (6%) 

Hyperplasia, lymphoid 2 (6%) 1 (3%) 

Pigmentation, hemosiderin 1 (3%) 

Lymph node, mandibular (36) (34) (32) (34) 

Congestion 1 (3%) 

Hemorrhage 1 (3%) 

Hyperplasia, histiocytic 1 (3%) 2 (6%) 

Hyperplasia, lymphoid 1 (3%) 1 (3%) 

Pigmentation, hemosiderin 2 (6%) 1 (3%) 

Lymph node, mesenteric (47) (42) (41) (40) 

Hematopoietic cell proliferation 1 (2%) 1 (3%) 

Hemorrhage 1 (2%) 2 (5%) 2 (5%) 

Hyperplasia, histiocytic 2 (4%) 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 2 (5%) 

Inflammation, chronic active 1 (2%) 1 (2%) 1 (3%) 

Lymph node, mediastinal (30) (34) (32) (29) 

Congestion 1 (3%) 

Hematopoietic cell proliferation 1 (3%) 

Hemorrhage 3 (9%) 2 (7%) 

Hyperplasia, histiocytic 1 (3%) 2 (7%) 

Hyperplasia, lymphoid 1 (3%) 1 (3%) 

Spleen (48) (48) (46) (46) 

Atrophy 1 (2%) 

Hematopoietic cell proliferation 14 (29%) 32 (67%) 41 (89%) 42 (91%) 

Hyperplasia, lymphoid 1 (2%) 

Pigmentation, melanin 2 (4%) 

Thymus (43) (40) (34) (37) 

Mineralization 1 (3%) 

Integumentary System 

Skin (48) (48) (48) (48) 

Acanthosis 1 (2%) 

Atrophy 1 (2%) 

Inflammation, chronic 2 (4%) 4 (8%) 2 (4%) 3 (6%) 

Inflammation, suppurative 1 (2%) 

Ulcer 2 (4%) 4 (8%) 5 (10%) 

Prepuce, acanthosis 1 (2%) 2 (4%) 

Prepuce, inflammation, chronic 2 (4%) 

Prepuce, inflammation, suppurative 1 (2%) 

Prepuce, pigmentation, melanin 1 (2%) 

Prepuce, ulcer 1 (2%) 1 (2%) 

Subcutaneous tissue, congestion 1 (2%) 

Subcutaneous tissue, hemorrhage 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

206 Tetrafluoroethylene, NTP TR 450 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Musculoskeletal System 

Bone (48) (48) (48) (48) 

Fracture 1 (2%) 

Sternum, developmental malformation 2 (4%) 

Nervous System 

Brain (48) (48) (48) (48) 

Hemorrhage 1 (2%) 1 (2%) 

Mineralization 23 (48%) 19 (40%) 13 (27%) 24 (50%) 

Necrosis, liquifactive 2 (4%) 

Respiratory System 

Larynx (47) (48) (46) (46) 

Cytoplasmic alteration 1 (2%) 

Exudate, mucopurulent 2 (4%) 1 (2%) 

Hemorrhage 1 (2%) 

Metaplasia, squamous 2 (4%) 

Lung (48) (48) (48) (48) 

Congestion 2 (4%) 5 (10%) 1 (2%) 

Crystals 1 (2%) 

Hemorrhage 6 (13%) 4 (8%) 2 (4%) 1 (2%) 

Infarct 1 (2%) 

Pigmentation, hemosiderin 1 (2%) 

Alveolar epithelium, hyperplasia 1 (2%) 1 (2%) 1 (2%) 

Alveolus, infiltration cellular, histiocyte 4 (8%) 5 (10%) 1 (2%) 1 (2%) 

Interstitium, infiltration cellular, mixed

 cell 1 (2%) 

Nose (48) (47) (46) (47) 

Inflammation, suppurative 1 (2%) 3 (7%) 1 (2%) 

Proliferation connective tissue, multifocal 1 (2%) 

Nasolacrimal duct, inflammation, suppurative 1 (2%) 

Respiratory epithelium, cytoplasmic

 alteration 1 (2%) 

Respiratory epithelium, degeneration 1 (2%) 

Vomeronasal organ, hypertrophy 1 (2%) 

Trachea (47) (47) (46) (46) 

Cytoplasmic alteration 1 (2%) 

Special Senses System 

Eye (1) (2) 

Degeneration, diffuse 1 (50%) 

Phthisis bulbi 1 (50%) 

Retinal detachment 1 (50%) 

Cornea, inflammation, chronic 1 (50%) 

Harderian gland (6) (8) (5) (6) 

Hyperplasia 1 (20%) 1 (17%) 
 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 207 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Urinary System 

Kidney (48) (48) (48) (48) 

Cyst 2 (4%) 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Infiltration cellular, mononuclear cell 2 (4%) 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Inflammation, suppurative 2 (4%) 

Nephropathy 32 (67%) 12 (25%) 10 (21%) 16 (33%) 

Renal tubule, dilatation 4 (8%) 16 (33%) 36 (75%) 

Renal tubule, karyomegaly 1 (2%) 2 (4%) 10 (21%) 28 (58%) 

Urinary bladder (48) (43) (43) (42) 

Infiltration cellular, mononuclear cell 1 (2%) 

Inflammation, chronic active 2 (4%) 1 (2%) 1 (2%) 

Inflammation, suppurative 1 (2%) 1 (2%) 
208 Tetrafluoroethylene, NTP TR 450 
209 

APPENDIX D
 

SUMMARY OF LESIONS IN FEMALE MICE
 

IN THE 2-YEAR INHALATION STUDY
 

OF TETRAFLUOROETHYLENE
 

TABLE D1 Summary of the Incidence of Neoplasms in Female Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 211
 

TABLE D2 Individual Animal Tumor Pathology of Female Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 216
 

TABLE D3 Statistical Analysis of Primary Neoplasms in Female Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 240
 

TABLE D4a Historical Incidence of Liver Neoplasms 

in Chamber Control Female B6C3F 1 Mice ........................................... 244
 

TABLE D4b Historical Incidence of Histiocytic Sarcoma
 

in Chamber Control Female B6C3F 1 Mice ........................................... 245
 

TABLE D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 246
 
210 Tetrafluoroethylene, NTP TR 450 
 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 211 

TABLE D1 a Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Accidental death 

Moribund 

Natural deaths 

Survivors 

Terminal sacrifice 

58 

10 

8 

4 

36 

58 

10 

28 

16 

4 

58 

10 

1 

26 

15 

6 

58 

10 

27 

17 

4 

Animals examined microscopically 58 58 57 58 

15-Month Interim Evaluation 

Alimentary System 

Intestine small, jejunum 

Liver 

Hemangiosarcoma

Hepatocellular carcinoma

Hepatocellular adenoma

Hepatocellular adenoma, multiple

(10) 

(10) 

(10) 

(10) 

 1 (10%) 

 3 (30%) 

 2 (20%) 

(10) 

(10) 

 1 (10%) 

 3 (30%) 

(10) 

(10) 

 3 (30%) 

 1 (10%) 

 1 (10%) 

Endocrine System 

Adrenal medulla 

Pheochromocytoma benign

Thyroid gland 

Follicular cell, adenoma

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar adenoma, multiple

Hepatocellular carcinoma, metastatic, liver

(10) (10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

Special Senses System 

Harderian gland

Adenoma

Bilateral, adenoma

 (1)

 1 (100%)

 (2) 

 1 (50%) 

 1 (50%) 

Systemic Lesions 

Multiple organsb 

Lymphoma malignant mixed

(10) (10) (10) (10) 

 1 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

212 Tetrafluoroethylene, NTP TR 450 

TABLE D1
 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Systems Examined With No Neoplasms Observed 

Cardiovascular System 

General Body System 

Genital System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Urinary System 

2-Year Study 

Alimentary System 

Intestine large, colon (47) (45) (42) (40) 

Sarcoma 1 (2%) 

Intestine large, cecum (47) (42) (40) (36) 

Leiomyosarcoma 1 (2%) 

Sarcoma 1 (2%) 

Intestine small, duodenum (45) (39) (39) (35) 

Sarcoma 1 (3%) 

Intestine small, jejunum (46) (37) (39) (35) 

Intestine small, ileum (46) (39) (40) (35) 

Leiomyosarcoma, metastatic, uterus 1 (3%) 

Sarcoma 1 (3%) 

Liver (48) (48) (47) (47) 

Hemangioma 4 (8%) 1 (2%) 1 (2%) 

Hemangioma, multiple 1 (2%) 1 (2%) 

Hemangiosarcoma 19 (40%) 15 (32%) 19 (40%) 

Hemangiosarcoma, multiple 8 (17%) 12 (26%) 15 (32%) 

Hepatocellular carcinoma 4 (8%) 23 (48%) 15 (32%) 13 (28%) 

Hepatocellular carcinoma, multiple 5 (10%) 7 (15%) 7 (15%) 

Hepatocellular adenoma 14 (29%) 10 (21%) 11 (23%) 8 (17%) 

Hepatocellular adenoma, multiple 1 (2%) 7 (15%) 9 (19%) 7 (15%) 

Histiocytic sarcoma 1 (2%) 21 (44%) 19 (40%) 18 (38%) 

Sarcoma 1 (2%) 

Mesentery (9) (13) (7) (6) 

Hemangiosarcoma 2 (15%) 

Histiocytic sarcoma 1 (11%) 1 (8%) 

Leiomyosarcoma, metastatic, uterus 1 (8%) 

Sarcoma 1 (8%) 1 (17%) 

Pancreas (48) (47) (44) (47) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 1 (2%) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Sarcoma 1 (2%) 

Stomach, forestomach (48) (48) (47) (47) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Squamous cell papilloma 1 (2%) 1 (2%) 

Stomach, glandular (48) (48) (45) (45) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Sarcoma 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 213 

TABLE D1
 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Cardiovascular System 

Heart (48) (48) (47) (48) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Endocrine System 

Adrenal cortex (48) (47) (47) (47) 

Adenoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 3 (6%) 1 (2%) 

Capsule, adenoma 1 (2%) 

Capsule, carcinoma 1 (2%) 

Islets, pancreatic (48) (45) (44) (47) 

Adenoma 1 (2%) 1 (2%) 

Pituitary gland (46) (45) (44) (46) 

Histiocytic sarcoma 1 (2%) 

Pars distalis, adenoma 4 (9%) 5 (11%) 2 (5%) 6 (13%) 

Pars intermedia, adenoma 1 (2%) 

Thyroid gland (48) (48) (46) (46) 

Follicular cell, adenoma 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

General Body System 

Tissue NOS (1) 

Sarcoma 1 (100%) 

Genital System 

Ovary (47) (47) (45) (46) 

Cystadenoma 2 (4%) 2 (4%) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 5 (11%) 4 (9%) 3 (7%) 

Luteoma 2 (4%) 

Sarcoma 1 (2%) 

Periovarian tissue, histiocytic sarcoma 1 (2%) 

Uterus (48) (48) (45) (47) 

Histiocytic sarcoma 1 (2%) 

Leiomyosarcoma 1 (2%) 

Polyp stromal 1 (2%) 1 (2%) 

Cervix, granular cell tumor NOS 1 (2%) 

Hematopoietic System 

Bone marrow (48) (48) (46) (47) 

Histiocytic sarcoma 6 (13%) 5 (11%) 4 (9%) 

Lymph node (5) (6) (4) (6) 

Axillary, histiocytic sarcoma 1 (20%) 

Iliac, histiocytic sarcoma 1 (20%) 1 (17%) 1 (25%) 1 (17%) 

Pancreatic, histiocytic sarcoma 1 (25%) 1 (17%) 

Renal, histiocytic sarcoma 1 (17%) 2 (50%) 2 (33%) 

Lymph node, bronchial (40) (36) (40) (38) 

Histiocytic sarcoma 4 (11%) 6 (15%) 4 (11%) 

Sarcoma 1 (3%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

214 Tetrafluoroethylene, NTP TR 450 

TABLE D1
 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Hematopoietic System (continued) 

Lymph node, mandibular (39) (35) (34) (32) 

Histiocytic sarcoma 1 (3%) 3 (9%) 2 (6%) 2 (6%) 

Lymph node, mesenteric (43) (40) (41) (43) 

Hemangioma 1 (2%) 

Histiocytic sarcoma 1 (2%) 6 (15%) 7 (17%) 6 (14%) 

Lymph node, mediastinal (28) (35) (35) (33) 

Histiocytic sarcoma 1 (4%) 9 (26%) 9 (26%) 4 (12%) 

Spleen (48) (48) (46) (47) 

Histiocytic sarcoma 1 (2%) 7 (15%) 8 (17%) 9 (19%) 

Sarcoma 1 (2%) 

Thymus (46) (42) (39) (38) 

Histiocytic sarcoma 2 (5%) 2 (5%) 2 (5%) 

Integumentary System 

Mammary gland (48) (46) (45) (46) 

Carcinoma 1 (2%) 

Skin (47) (48) (47) (48) 

Hemangioma 1 (2%) 

Squamous cell papilloma 1 (2%) 

Subcutaneous tissue, sarcoma 2 (4%) 

Musculoskeletal System 

Bone (48) (48) (47) (48) 

Osteosarcoma 1 (2%) 

Rib, leiomyosarcoma, metastatic, uterus 1 (2%) 

Skeletal muscle (1) 

Leiomyosarcoma, metastatic, uterus 1 (100%) 

Nervous System 

Brain (48) (48) (47) (48) 

Astrocytoma NOS 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Respiratory System 

Lung (48) (48) (47) (47) 

Alveolar/bronchiolar adenoma 5 (10%) 5 (11%) 3 (6%) 

Alveolar/bronchiolar adenoma, multiple 1 (2%) 1 (2%) 

Alveolar/bronchiolar carcinoma 2 (4%) 1 (2%) 

Carcinoma 1 (2%) 

Carcinoma, metastatic, mammary gland 1 (2%) 

Hemangiosarcoma, metastatic, liver 3 (6%) 

Hemangiosarcoma, metastatic, pancreas 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 8 (17%) 6 (13%) 4 (9%) 

Histiocytic sarcoma 1 (2%) 16 (33%) 13 (28%) 13 (28%) 

Osteosarcoma, metastatic, bone 1 (2%) 

Sarcoma 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 
 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 215 

TABLE D1
 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Special Senses System 

Harderian gland (3) (6) (4) (6) 

Adenoma 2 (67%) 3 (50%) 6 (100%) 

Urinary System 

Kidney (48) (48) (47) (47) 

Histiocytic sarcoma 1 (2%) 7 (15%) 4 (9%) 3 (6%) 

Osteosarcoma, metastatic, bone 1 (2%) 

Urinary bladder (46) (43) (43) (37) 

Leiomyosarcoma, metastatic, uterus 1 (2%) 

Sarcoma 1 (2%) 

Systemic Lesions 

Multiple organs (48) (48) (47) (48) 

Histiocytic sarcoma 1 (2%) 21 (44%) 19 (40%) 18 (38%) 

Lymphoma malignant lymphocytic 1 (2%) 

Lymphoma malignant mixed 5 (10%) 2 (4%) 2 (4%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 2 6 5 6 

2-Year study 34 47 45 46 

Total Primary Neoplasms 

15-Month interim evaluation 3 7 5 8 

2-Year study 53 132 104 115 

Total animals with benign neoplasms 

15-Month interim evaluation 2 3 4 4 

2-Year study 27 24 26 29 

Total benign neoplasms 

15-Month interim evaluation 3 3 4 4 

2-Year study 37 34 34 36 

Total animals with malignant neoplasms 

15-Month interim evaluation 3 1 4 

2-Year study 14 46 45 46 

Total malignant neoplasms 

15-Month interim evaluation 4 1 4 

2-Year study 14 98 70 79 

Total animals with metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 3 9 6 9 

Total metastatic neoplasms 

15-Month interim evaluation 1 

2-Year study 4 16 6 9 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 2 

Total uncertain neoplasms 

2-Year study 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
 c 
 

 

 

 

 

 

 

 

 

 

 

 

 

216 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm 

4 4 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 0 8 3 4 7 9 9 0 1 2 2 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

0 8 1 1 3 5 7 3 7 1 6 0 7 7 7 7 7 7 7 7 7 7 7 7 7 

1 0 1 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 1 8 0 8 7 1 0 9 7 0 6 6 5 6 6 6 6 6 6 6 7 7 7 7 7 

0 9 3 2 4 4 5 4 7 0 0 4 9 1 2 3 5 6 7 9 0 1 2 3 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + + + + A + + + + + + A + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + A + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + A + + + + + + + + + + + + + 

Leiomyosarcoma X 

Intestine small, duodenum + + + M A + + + + + + A + + + + + + + + + + + + + 

Intestine small, jejunum + + + + A + + + + + + A + + + + + + + + + + + + + 

Intestine small, ileum + + + + M + + + + + + A + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X X 

Hepatocellular adenoma X X X X X X X X X X 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma X 

Mesentery + + + + + + + + 

Histiocytic sarcoma X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Tooth + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Capsule, adenoma X 

Capsule, carcinoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + + M + + M + + + M M + M + + M + + + M + + + + + 

Pituitary gland + M + + + + + + + + I + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Pars distalis, adenoma X 

Pars intermedia, adenoma 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 217 

TABLE D2
 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 8 8 8 8 8 9 9 9 9 9 9 9 0 0 0 0 0 1 1 1 1 1 Tissues/ 

8 1 4 5 6 7 1 3 5 6 7 8 9 1 2 6 7 9 1 2 3 5 6 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder + I + M + + + + + + + + + + + + + M + + A + + 42 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + 47 

Leiomyosarcoma 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Hepatocellular carcinoma X X 4 

Hepatocellular adenoma X X X X 14 

Hepatocellular adenoma, multiple X 1 

Histiocytic sarcoma 1 

Mesentery + 9 

Histiocytic sarcoma 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 48 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 48 

Tooth + 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Capsule, adenoma 1 

Capsule, carcinoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 48 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X 1 

Parathyroid gland + + M M M + M M + M M M + M M M M + + + M + + 28 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + 46 

Histiocytic sarcoma 1 

Pars distalis, adenoma X X X 4 

Pars intermedia, adenoma X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Follicular cell, adenoma X X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

218 Tetrafluoroethylene, NTP TR 450 

TABLE D2
 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

4 4 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 0 8 3 4 7 9 9 0 1 2 2 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

0 8 1 1 3 5 7 3 7 1 6 0 7 7 7 7 7 7 7 7 7 7 7 7 7 

1 0 1 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 1 8 0 8 7 1 0 9 7 0 6 6 5 6 6 6 6 6 6 6 7 7 7 7 7 

0 9 3 2 4 4 5 4 7 0 0 4 9 1 2 3 5 6 7 9 0 1 2 3 5 

Genital System 

Clitoral gland M M + + + + + + + + + + M + + + + + + M + M + + + 

Ovary + M + + + + + + + + + + + + + + + + + + + + + + + 

Cystadenoma X X 

Histiocytic sarcoma X 

Luteoma X 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Polyp stromal 

Cervix, granular cell tumor NOS 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + 

Axillary, histiocytic sarcoma X 

Iliac, histiocytic sarcoma X 

Lymph node, bronchial + + + + + + + + + + + + + + M + + + M + + + + + + 

Lymph node, mandibular + + + + + M + + + M + + + M + + + + + + + + M + + 

Histiocytic sarcoma X 

Lymph node, mesenteric + + I + + + + + M + + + + + I + + + + + + + + + + 

Histiocytic sarcoma X 

Lymph node, mediastinal + + + + + + + M + + + M + + + + + M M M + M M M + 

Histiocytic sarcoma X 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Thymus M I + + + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + 

Nervous System 

Brain 

Astrocytoma NOS 

+ + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 219 

TABLE D2
 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 8 8 8 8 8 9 9 9 9 9 9 9 0 0 0 0 0 1 1 1 1 1 Tissues/ 

8 1 4 5 6 7 1 3 5 6 7 8 9 1 2 6 7 9 1 2 3 5 6 Tumors 

Genital System 

Clitoral gland + + + + + + + + + + + + + M + + + + + + + + + 42 

Ovary + + + + + + + + + + + + + + + + + + + + + + + 47 

Cystadenoma 2 

Histiocytic sarcoma 1 

Luteoma X 2 

Uterus + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Polyp stromal X 1 

Cervix, granular cell tumor NOS X 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 48 

Lymph node + + 5 

Axillary, histiocytic sarcoma 1 

Iliac, histiocytic sarcoma 1 

Lymph node, bronchial M + + + M + + + M + M + + + + + + + I + M + + 40 

Lymph node, mandibular M + + M + M + + + + + + + + + + M + + + M + + 39 

Histiocytic sarcoma 1 

Lymph node, mesenteric + + + + + + + M + + + I + + + + + + + + + + + 43 

Histiocytic sarcoma 1 

Lymph node, mediastinal + + + M + + M + + M + M M M M I M M M + M + + 28 

Histiocytic sarcoma 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Thymus + + + + + + + + + + + + + + + + + + + + + + + 46 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Carcinoma 1 

Skin M + + + + + + + + + + + + + + + + + + + + + + 47 

Musculoskeletal System 

Bone 

Osteosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + 48 

1 

Nervous System 

Brain 

Astrocytoma NOS

+ + + + + + + + + + + + + + + + + + + + + + + 48 

1 
 

 

 

 

 

 

 

 

 

 

 

220 Tetrafluoroethylene, NTP TR 450 

TABLE D2
 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

4 4 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 0 8 3 4 7 9 9 0 1 2 2 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

0 8 1 1 3 5 7 3 7 1 6 0 7 7 7 7 7 7 7 7 7 7 7 7 7 

1 0 1 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 1 8 0 8 7 1 0 9 7 0 6 6 5 6 6 6 6 6 6 6 7 7 7 7 7 

0 9 3 2 4 4 5 4 7 0 0 4 9 1 2 3 5 6 7 9 0 1 2 3 5 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X 

Alveolar/bronchiolar adenoma,

 multiple
 

Carcinoma, metastatic, mammary gland X
 

Hepatocellular carcinoma, metastatic,

 liver X
 

Histiocytic sarcoma X
 

Osteosarcoma, metastatic, bone X
 

Nose + + + + + + + + + + + A + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Harderian gland + + 

Adenoma X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Osteosarcoma, metastatic, bone X 

Urinary bladder + + + + + + + + + + + A + + + + + + + + + M + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Lymphoma malignant mixed X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 221 

TABLE D2
 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 0 ppm (continued)
 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 8 8 8 8 8 9 9 9 9 9 9 9 0 0 0 0 0 1 1 1 1 1 Tissues/ 

8 1 4 5 6 7 1 3 5 6 7 8 9 1 2 6 7 9 1 2 3 5 6 Tumors 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + 48 

Lung + + + + + + + + + + + + + + + + + + + + + + + 48 

Alveolar/bronchiolar adenoma X X X 5 

Alveolar/bronchiolar adenoma,

 multiple X 1 

Carcinoma, metastatic, mammary gland 1 

Hepatocellular carcinoma, metastatic,

 liver 1 

Histiocytic sarcoma 1 

Osteosarcoma, metastatic, bone 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + 47 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 48 

Special Senses System 

Ear 1 

Harderian gland + 3 

Adenoma X 2 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Osteosarcoma, metastatic, bone 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + 46 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Lymphoma malignant mixed X X X 5 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

222 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 

Number of Days on Study 2 2 5 5 9 3 3 3 4 4 4 4 6 8 8 9 0 0 0 0 0 1 1 1 1 

9 9 4 5 3 0 0 9 1 1 1 1 6 5 8 6 0 0 3 7 9 4 4 4 4 

1 2 1 2 1 1 2 1 1 1 2 2 2 2 2 2 1 1 1 2 2 1 1 2 2 

Carcass ID Number 9 1 8 0 9 7 1 8 7 9 1 2 0 3 0 1 7 8 8 0 2 7 9 1 2 

2 2 0 5 6 6 6 7 7 4 9 3 3 1 7 3 9 2 8 6 0 5 7 1 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + + A A A + + A + + + + + A + M A + + + A A + + + 

Intestine large, colon + + A + + + + + + + + + + + + A + + + + + A + + + 

Sarcoma 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + A A + + A + + + + + + + + + + + + + A + + + 

Sarcoma 

Intestine small, duodenum + + A A A + + A + + + + I + + A A + + + + M + + + 

Sarcoma 

Intestine small, jejunum + + A A A A + A + + + + + + + A A + + + + A + + + 

Intestine small, ileum + + + A A + + A + + + + + + A A A + + + + A + + + 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma X 

Hemangioma, multiple X 

Hemangiosarcoma X X X X X X X 

Hemangiosarcoma, multiple X X X 

Hepatocellular carcinoma X X X X X X X X X X 

Hepatocellular carcinoma, multiple X X 

Hepatocellular adenoma X X X X X X 

Hepatocellular adenoma, multiple X X 

Histiocytic sarcoma X X X X X X X X 

Sarcoma 

Mesentery + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Squamous cell papilloma 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + M + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Histiocytic sarcoma X 

Adrenal medulla + + M + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + I I + + + + + + + + + + + + + + + + + + + + + 

Adenoma 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 223 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

Number of Days on Study 

6 

1 

4 

6 

1 

5 

6 

1 

8 

6 

3 

1 

6 

3 

6 

6 

3 

6 

6 

3 

8 

6 

3 

9 

6 

3 

9 

6 

4 

3 

6 

4 

4 

6 

4 

5 

6 

4 

6 

6 

4 

6 

6 

4 

6 

6 

4 

9 

6 

5 

1 

6 

5 

7 

6 

5 

9 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

Carcass ID Number 

2 

2 

9 

1 

9 

8 

2 

3 

0 

2 

0 

0 

1 

7 

8 

2 

3 

2 

2 

2 

4 

1 

8 

3 

2 

0 

4 

1 

8 

6 

2 

1 

4 

2 

2 

7 

2 

1 

0 

2 

1 

8 

2 

2 

6 

2 

1 

5 

2 

2 

2 

1 

8 

5 

1 

9 

3 

1 

8 

1 

1 

8 

9 

2 

0 

1 

2 

1 

7 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder + + + + + + + + + M A + + + A + + + + + + + + 36 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + 45 

Sarcoma X 1 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine large, cecum + + + + + + + + + + A + + + A + + + + + + + + 42 

Sarcoma X 1 

Intestine small, duodenum + + + + + + + + + + + + + + A + + + + + + + + 39 

Sarcoma X 1 

Intestine small, jejunum + + + + + + + + + + A + + + A + A + + + + + + 37 

Intestine small, ileum + + + + + + + + + + A + + + A + + + + + + + + 39 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma X 1 

Liver + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangioma X X X 4 

Hemangioma, multiple 1 

Hemangiosarcoma X X X X X X X X X X X X 19 

Hemangiosarcoma, multiple X X X X X 8 

Hepatocellular carcinoma X X X X X X X X X X X X X 23 

Hepatocellular carcinoma, multiple X X X 5 

Hepatocellular adenoma X X X X 10 

Hepatocellular adenoma, multiple X X X X X 7 

Histiocytic sarcoma X X X X X X X X X X X X X 21 

Sarcoma X 1 

Mesentery + + + + + + + + 13 

Hemangiosarcoma X 2 

Histiocytic sarcoma X 1 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma X 1 

Pancreas + + + + + + + + + + + I + + + + + + + + + + + 47 

Histiocytic sarcoma 2 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 48 

Leiomyosarcoma, metastatic, uterus 1 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 48 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma X 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 47 

Adenoma 1 

Histiocytic sarcoma X X 3 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 47 

Islets, pancreatic + + + + + + + + + + + M + + + + + + + + + + + 45 

Adenoma X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

224 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

Number of Days on Study 

4 

2 

9 

4 

2 

9 

4 

5 

4 

4 

5 

5 

4 

9 

3 

5 

3 

0 

5 

3 

0 

5 

3 

9 

5 

4 

1 

5 

4 

1 

5 

4 

1 

5 

4 

1 

5 

6 

6 

5 

8 

5 

5 

8 

8 

5 

9 

6 

6 

0 

0 

6 

0 

0 

6 

0 

3 

6 

0 

7 

6 

0 

9 

6 

1 

4 

6 

1 

4 

6 

1 

4 

6 

1 

4 

Carcass ID Number 

1 

9 

2 

2 

1 

2 

1 

8 

0 

2 

0 

5 

1 

9 

6 

1 

7 

6 

2 

1 

6 

1 

8 

7 

1 

7 

7 

1 

9 

4 

2 

1 

9 

2 

2 

3 

2 

0 

3 

2 

3 

1 

2 

0 

7 

2 

1 

3 

1 

7 

9 

1 

8 

2 

1 

8 

8 

2 

0 

6 

2 

2 

0 

1 

7 

5 

1 

9 

7 

2 

1 

1 

2 

2 

5 

Endocrine System (continued) 

Parathyroid gland M + + M + M + + + M M + M + + M M M + M M M + M + 

Pituitary gland + + + + + + + I + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

Tissue NOS 

Sarcoma 

Genital System 

Clitoral gland + + M + + + + M + + + M + M + + + + + M + + + + M 

Ovary + + M + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X X X X 

Sarcoma 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X 

Lymph node + + 

Iliac, histiocytic sarcoma 

Renal, histiocytic sarcoma X 

Lymph node, bronchial + + M M + + + M I + + + M + + + + M + + + + + + M 

Histiocytic sarcoma X X X 

Sarcoma 

Lymph node, mandibular + + M + M + + + + + + + M + + + + M M M + + + + + 

Histiocytic sarcoma X X X 

Lymph node, mesenteric + + + + + I M + + + + + + + + + M + + + + + + + + 

Histiocytic sarcoma X X X X 

Lymph node, mediastinal + + M + + M M + + + + + + + + I M + + I M M + + + 

Histiocytic sarcoma X X X X X 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X 

Sarcoma 

Thymus + + M + + + + + + + + + + + I M M + + + + + + + + 

Histiocytic sarcoma X X 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + M + + + + + + + + I 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Rib, leiomyosarcoma, metastatic,

 uterus X 

Skeletal muscle + 

Leiomyosarcoma, metastatic, uterus X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 225 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

Number of Days on Study 

6 

1 

4 

6 

1 

5 

6 

1 

8 

6 

3 

1 

6 

3 

6 

6 

3 

6 

6 

3 

8 

6 

3 

9 

6 

3 

9 

6 

4 

3 

6 

4 

4 

6 

4 

5 

6 

4 

6 

6 

4 

6 

6 

4 

6 

6 

4 

9 

6 

5 

1 

6 

5 

7 

6 

5 

9 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

Carcass ID Number 

2 

2 

9 

1 

9 

8 

2 

3 

0 

2 

0 

0 

1 

7 

8 

2 

3 

2 

2 

2 

4 

1 

8 

3 

2 

0 

4 

1 

8 

6 

2 

1 

4 

2 

2 

7 

2 

1 

0 

2 

1 

8 

2 

2 

6 

2 

1 

5 

2 

2 

2 

1 

8 

5 

1 

9 

3 

1 

8 

1 

1 

8 

9 

2 

0 

1 

2 

1 

7 

Total 

Tissues/ 

Tumors 

Endocrine System (continued) 

Parathyroid gland + M + + + + + M M M + M + M M + + M + + + M M 25 

Pituitary gland + + + + + + + + + + + M + + + + + + M + + + + 45 

Pars distalis, adenoma X X X 5 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 48 

Follicular cell, adenoma X 1 

General Body System 

Tissue NOS + 1 

Sarcoma X 1 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + 42 

Ovary + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangiosarcoma 1 

Histiocytic sarcoma X 5 

Sarcoma X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + 48 

Leiomyosarcoma 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X 6 

Lymph node + + + + 6 

Iliac, histiocytic sarcoma X 1 

Renal, histiocytic sarcoma 1 

Lymph node, bronchial + + + M + + + + + M M M + M + + + + + + + + + 36 

Histiocytic sarcoma X 4 

Sarcoma X 1 

Lymph node, mandibular + + + M I + + + + + + + + M M I + + M + + M + 35 

Histiocytic sarcoma 3 

Lymph node, mesenteric + M + + + + + M M + M + + + M + + + + + + + + 40 

Histiocytic sarcoma X X 6 

Lymph node, mediastinal + + + + + + + + + M + + + + M I + M + + M + + 35 

Histiocytic sarcoma X X X X 9 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X 7 

Sarcoma X 1 

Thymus + + M + + + + + + + + + + + + + + M + + + + + 42 

Histiocytic sarcoma 2 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + 46 

Skin + + + + + + + + + + + + + + + + + + + + + + + 48 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Rib, leiomyosarcoma, metastatic,

 uterus 1 

Skeletal muscle 1 

Leiomyosarcoma, metastatic, uterus 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

226 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 

Number of Days on Study 2 

9 

2 

9 

5 

4 

5 

5 

9 

3 

3 

0 

3 

0 

3 

9 

4 

1 

4 

1 

4 

1 

4 

1 

6 

6 

8 

5 

8 

8 

9 

6 

0 

0 

0 

0 

0 

3 

0 

7 

0 

9 

1 

4 

1 

4 

1 

4 

1 

4 

1 2 1 2 1 1 2 1 1 1 2 2 2 2 2 2 1 1 1 2 2 1 1 2 2 

Carcass ID Number 9 

2 

1 

2 

8 

0 

0 

5 

9 

6 

7 

6 

1 

6 

8 

7 

7 

7 

9 

4 

1 

9 

2 

3 

0 

3 

3 

1 

0 

7 

1 

3 

7 

9 

8 

2 

8 

8 

0 

6 

2 

0 

7 

5 

9 

7 

1 

1 

2 

5 

Nervous System 

Brain 

Histiocytic sarcoma 

+ + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + 

Respiratory System 

Larynx 

Lung 

Carcinoma 

Hepatocellular carcinoma, metastatic,

 liver 

Histiocytic sarcoma 

Sarcoma 

Nose 

Trachea 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

A 

+ 

X 

+ 

+ 

+ 

+ 

X 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

Special Senses System 

Ear 

Harderian gland 

Adenoma 

+ 

+ 

+ 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 

Urinary bladder + + + A + + + A + + + + + + + A + + + + + A + + + 

Leiomyosarcoma, metastatic, uterus X 

Sarcoma 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X X X 

Lymphoma malignant lymphocytic X 

Lymphoma malignant mixed 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 227 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 312 ppm 

(continued) 

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 

4 

1 

5 

1 

8 

3 

1 

3 

6 

3 

6 

3 

8 

3 

9 

3 

9 

4 

3 

4 

4 

4 

5 

4 

6 

4 

6 

4 

6 

4 

9 

5 

1 

5 

7 

5 

9 

6 

7 

6 

7 

6 

7 

6 

7 

2 1 2 2 1 2 2 1 2 1 2 2 2 2 2 2 2 1 1 1 1 2 2 Total 

Carcass ID Number 2 

9 

9 

8 

3 

0 

0 

0 

7 

8 

3 

2 

2 

4 

8 

3 

0 

4 

8 

6 

1 

4 

2 

7 

1 

0 

1 

8 

2 

6 

1 

5 

2 

2 

8 

5 

9 

3 

8 

1 

8 

9 

0 

1 

1 

7 

Tissues/ 

Tumors 

Nervous System 

Brain 

Histiocytic sarcoma

+ + + + + + + + + + + + + + + + + + + + + + + 48 

1 

Respiratory System 

Larynx 

Lung 

Carcinoma

Hepatocellular carcinoma, metastatic,

 liver 

Histiocytic sarcoma 

Sarcoma 

Nose 

Trachea 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

X 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

47 

48 

1 

8 

16 

1 

48 

48 

Special Senses System 

Ear

Harderian gland 

Adenoma 

+ + 

X 

+ 

X 

+

X

 1 

6 

3 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X 7 

Urinary bladder + + + + + + + + + A + + + + + + + + + + + + + 43 

Leiomyosarcoma, metastatic, uterus 1 

Sarcoma X 1 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X X X X X X X X X X 21 

Lymphoma malignant lymphocytic 1 

Lymphoma malignant mixed X X 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

228 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 5 7 7 8 8 8 9 1 3 4 4 4 4 5 5 5 6 6 6 6 6 8 8 9 

7 6 8 1 4 9 2 0 5 1 1 1 1 2 5 6 6 9 9 9 9 0 9 5 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3 2 2 3 3 2 3 3 

Carcass ID Number 1 3 0 0 3 2 0 1 1 0 0 2 4 3 9 4 0 9 9 2 4 9 2 1 

8 4 4 0 7 3 2 7 6 1 8 6 3 9 5 8 7 2 8 4 5 1 5 1 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + + M + + A + A A + + A + A + A M + A M + + + + 

Intestine large, colon + + + + + + + A A + + + + A + A + + + + + + + + 

Intestine large, rectum + + + + + A + A A + + + + A + A + + + + + + + + 

Intestine large, cecum + + + + + A + A A + + + + A + A + + M + + + + + 

Intestine small, duodenum + + A + + A + A A + + + + A + A + + + + + + + + 

Intestine small, jejunum + + A + + A + A A + + + + A + A + + + + + + + + 

Intestine small, ileum + + + + + A + A A + + + + A + A + + A + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma 

Hemangioma, multiple X 

Hemangiosarcoma X X X X 

Hemangiosarcoma, multiple X X X X 

Hepatocellular carcinoma X X X X X X X 

Hepatocellular carcinoma, multiple X X 

Hepatocellular adenoma X X X X X 

Hepatocellular adenoma, multiple X X 

Histiocytic sarcoma X X X X X X X X X X X X X X X 

Mesentery + + + + + 

Pancreas + + + + + + + A A + + + + A + + + + + + + + + + 

Histiocytic sarcoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma 

Stomach, glandular + + + + + + + A A + + + + + + + + + + + + + + + 

Tooth 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + A A + + + + + + + + + + + + + + + 

Parathyroid gland + + M M + + M + + + + M + + M M + M M + M + + + 

Pituitary gland + + + + + + + + M + + + + + + + + + + + + + + + 

Pars distalis, adenoma 

Thyroid gland + + + + + + + + A + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 

Genital System 

Clitoral gland + + + + + M M + + M + + + M + + M M + + + + + + 

Ovary + + + + + + + + + + + M + + + + + + + + + + + + 

Histiocytic sarcoma X X X X 

Periovarian tissue, histiocytic

 sarcoma X 

Uterus + + + + + + + A A + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 229 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 0 1 1 1 2 3 3 3 3 4 5 5 5 5 5 6 6 6 6 6 6 6 

7 8 4 5 9 9 0 0 1 6 2 0 2 3 3 3 1 7 7 7 7 7 7 

3 3 3 2 2 3 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 1 1 2 9 9 1 0 1 9 3 4 3 3 3 3 4 4 0 1 2 2 3 4 Tissues/ 

9 4 7 6 3 5 6 3 9 3 2 2 0 5 6 7 0 3 0 1 8 1 6 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 47 

Gallbladder + + + + A + + + + + A A + + + + + + + + + + + 34 

Intestine large, colon + + + + + + + + + + A + + + + + + + + + + + + 42 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + 42 

Intestine large, cecum + + + + + + + + + + A + + + + + + + + + + + + 40 

Intestine small, duodenum + + + + + + + + + + A A + + + + + + + + + + + 39 

Intestine small, jejunum + + + + A + + + + + A + + + + + + + + + + + + 39 

Intestine small, ileum + + + + + + + + + + A + + + + + + + + + + + + 40 

Liver + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangioma X 1 

Hemangioma, multiple 1 

Hemangiosarcoma X X X X X X X X X X X 15 

Hemangiosarcoma, multiple X X X X X X X X 12 

Hepatocellular carcinoma X X X X X X X X 15 

Hepatocellular carcinoma, multiple X X X X X 7 

Hepatocellular adenoma X X X X X X 11 

Hepatocellular adenoma, multiple X X X X X X X 9 

Histiocytic sarcoma X X X X 19 

Mesentery + + 7 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 44 

Histiocytic sarcoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 47 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 47 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 45 

Tooth 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 47 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 47 

Islets, pancreatic + + A + + + + + + + + + + + + + + + + + + + + 44 

Parathyroid gland M M + M M + M + M + + + + M + M M M + + + M + 27 

Pituitary gland + + + + M + + M + + + + + + + + + + + + + + + 44 

Pars distalis, adenoma X X 2 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 46 

Follicular cell, adenoma X 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + M + + + + + + + + + + + + + M + + + M 38 

Ovary + + M + + + + + + + + + + + + + + + + + + + + 45 

Histiocytic sarcoma 4 

Periovarian tissue, histiocytic

 sarcoma 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + 45 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

230 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 5 7 7 8 8 8 9 1 3 4 4 4 4 5 5 5 6 6 6 6 6 8 8 9 

7 6 8 1 4 9 2 0 5 1 1 1 1 2 5 6 6 9 9 9 9 0 9 5 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3 2 2 3 3 2 3 3 

Carcass ID Number 1 3 0 0 3 2 0 1 1 0 0 2 4 3 9 4 0 9 9 2 4 9 2 1 

8 4 4 0 7 3 2 7 6 1 8 6 3 9 5 8 7 2 8 4 5 1 5 1 

Hematopoietic System 

Blood + 

Bone marrow + + + + + + + + A + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X 

Lymph node + + + + 

Iliac, histiocytic sarcoma X 

Pancreatic, histiocytic sarcoma X 

Renal, histiocytic sarcoma X X 

Lymph node, bronchial + + + + + + + + + + + + + + + M + + M + + + M + 

Histiocytic sarcoma X X X X X 

Lymph node, mandibular + + + + + M + M + + + + + M + + + + + M M M + 

Histiocytic sarcoma X X 

Lymph node, mesenteric + + + + + + + A M + + + + A + + + + + + + + + + 

Hemangioma 

Histiocytic sarcoma X X X X X X 

Lymph node, mediastinal + + + + + + + + + M + + M M M + M + M + + M + + 

Histiocytic sarcoma X X X X X X X 

Spleen + + + + + + + A + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X 

Thymus M + + + M + + + M I + + + I + + + M + + + + + + 

Histiocytic sarcoma X 

Integumentary System 

Mammary gland + + M + + + + + M + + + + + + + + + + + + + + + 

Skin + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + A + A A + + + + A + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X X 

Alveolar/bronchiolar adenoma,

 multiple X 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic,

 liver X X X X X 

Histiocytic sarcoma X X X X X X X X X X X 

Nose + + + + + A + + A + + + + + + + + + + + + + + + 

Trachea + + + + + + + + A + + + + A + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 231 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 0 1 1 1 2 3 3 3 3 4 5 5 5 5 5 6 6 6 6 6 6 6 

7 8 4 5 9 9 0 0 1 6 2 0 2 3 3 3 1 7 7 7 7 7 7 

3 3 3 2 2 3 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 1 1 2 9 9 1 0 1 9 3 4 3 3 3 3 4 4 0 1 2 2 3 4 Tissues/ 

9 4 7 6 3 5 6 3 9 3 2 2 0 5 6 7 0 3 0 1 8 1 6 Tumors 

Hematopoietic System 

Blood 1 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 46 

Histiocytic sarcoma 5 

Lymph node 4 

Iliac, histiocytic sarcoma 1 

Pancreatic, histiocytic sarcoma 1 

Renal, histiocytic sarcoma 2 

Lymph node, bronchial M + + + + + + + + + A + M + + + + + + + + M + 40 

Histiocytic sarcoma X 6 

Lymph node, mandibular + + + I M + + + + + M + + I M + + + + M + + + 34 

Histiocytic sarcoma 2 

Lymph node, mesenteric + M + + M + + + + + + + + + I + + + + + + + + 41 

Hemangioma X 1 

Histiocytic sarcoma X 7 

Lymph node, mediastinal M M M + + + + + + + + + + + + M + + + + M + + 35 

Histiocytic sarcoma X X 9 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 46 

Histiocytic sarcoma X X 8 

Thymus + + + + + + + + + + + + M + M + + + + + + + + 39 

Histiocytic sarcoma X 2 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + 45 

Skin + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangioma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 47 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + 47 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + 43 

Lung + + + + + + + + + + + + + + + + + + + + + + + 47 

Alveolar/bronchiolar adenoma X X 5 

Alveolar/bronchiolar adenoma,

 multiple 1 

Alveolar/bronchiolar carcinoma X X 2 

Hepatocellular carcinoma, metastatic,

 liver X 6 

Histiocytic sarcoma X X 13 

Nose + + + + + + + + + + + + + + + + + + + + + + + 45 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 45 
 

 

 

232 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

Number of Days on Study 

4 

5 

7 

4 

7 

6 

4 

7 

8 

4 

8 

1 

4 

8 

4 

4 

8 

9 

4 

9 

2 

5 

1 

0 

5 

3 

5 

5 

4 

1 

5 

4 

1 

5 

4 

1 

5 

4 

1 

5 

5 

2 

5 

5 

5 

5 

5 

6 

5 

6 

6 

5 

6 

9 

5 

6 

9 

5 

6 

9 

5 

6 

9 

5 

8 

0 

5 

8 

9 

5 

9 

5 

Carcass ID Number 

3 

1 

8 

3 

3 

4 

3 

0 

4 

3 

0 

0 

3 

3 

7 

3 

2 

3 

3 

0 

2 

3 

1 

7 

3 

1 

6 

3 

0 

1 

3 

0 

8 

3 

2 

6 

3 

4 

3 

3 

3 

9 

2 

9 

5 

3 

4 

8 

3 

0 

7 

2 

9 

2 

2 

9 

8 

3 

2 

4 

3 

4 

5 

2 

9 

1 

3 

2 

5 

3 

1 

1 

Special Senses System 

Harderian gland + + 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X 

Urinary bladder + + + + + + + A A + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 233 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 625 ppm 

(continued) 

Number of Days on Study 

5 

9 

7 

6 

0 

8 

6 

1 

4 

6 

1 

5 

6 

1 

9 

6 

2 

9 

6 

3 

0 

6 

3 

0 

6 

3 

1 

6 

3 

6 

6 

4 

2 

6 

5 

0 

6 

5 

2 

6 

5 

3 

6 

5 

3 

6 

5 

3 

6 

6 

1 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

Carcass ID Number 

3 

1 

9 

3 

1 

4 

3 

2 

7 

2 

9 

6 

2 

9 

3 

3 

1 

5 

3 

0 

6 

3 

1 

3 

2 

9 

9 

3 

3 

3 

3 

4 

2 

3 

3 

2 

3 

3 

0 

3 

3 

5 

3 

3 

6 

3 

4 

7 

3 

4 

0 

3 

0 

3 

3 

1 

0 

3 

2 

1 

3 

2 

8 

3 

3 

1 

3 

4 

6 

Total 

Tissues/ 

Tumors 

Special Senses System 

Harderian gland + + 4 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 4 

Urinary bladder + + + + I + + + + + + + + + + + + + M + + + + 43 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma X X X X 19 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

234 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

1 1 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 3 4 6 6 8 8 0 0 1 1 3 4 4 4 5 5 5 6 6 6 8 8 8 8 8 

5 4 6 8 4 4 7 9 3 8 6 1 1 8 2 2 5 3 5 9 0 5 6 6 6 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 2 0 5 2 5 6 1 6 5 1 2 0 4 1 1 2 1 2 1 4 3 3 1 1 2 

1 7 3 6 4 3 5 1 1 4 2 8 5 6 9 5 2 7 1 2 1 9 3 7 9 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder A + + + + + + A A + + + + + + + M A + + A A + + + 

Intestine large, colon A + + + + + + A + + + + + + + + + + + + A A + + + 

Intestine large, rectum A + + + + + + + + + + + + + + I + + + + A + + + + 

Intestine large, cecum A + + + + + A A A + A + + + + + + + + + A A + + + 

Intestine small, duodenum A + + + + + A A + + + M + + + + + A + + A A + + + 

Intestine small, jejunum A + + + + + + A A + A + + + + + + A + + A A + + + 

Intestine small, ileum A + + + + + A A A + A + + + + + + A + + A A + + + 

Liver A + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma 

Hemangiosarcoma X X X X X X X 

Hemangiosarcoma, multiple X X X X X X X X X 

Hepatocellular carcinoma X X X X X X X X 

Hepatocellular carcinoma, multiple X X 

Hepatocellular adenoma X X X 

Hepatocellular adenoma, multiple X X X 

Histiocytic sarcoma X X X X X X X X 

Mesentery + + + 

Sarcoma 

Pancreas A + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach A + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular A + + + + + + + + + + + + + + + + + + + A A + + + 

Tooth + + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Endocrine System 

Adrenal cortex A + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Adrenal medulla A + + + + + + + + + + + + + + + + + + + M + + + + 

Islets, pancreatic A + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland A + + + + + + + + + + + + M M + + M + M + M + + + 

Pituitary gland A + M + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X 

Thyroid gland A + + + + + + + + + + + + + I + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 235 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 8 8 8 9 9 0 0 0 0 0 1 2 2 2 3 4 4 4 6 6 6 6 

7 8 8 9 7 7 0 6 8 8 8 9 3 6 9 9 2 6 6 7 7 7 7 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 5 1 5 3 5 5 5 4 2 3 4 6 6 4 2 3 2 3 4 3 3 4 4 Tissues/ 

7 8 9 2 2 6 8 9 0 7 4 4 0 8 3 8 4 0 3 4 6 0 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder M + + + + A M A + + + + A A + + A + + + + + + 34 

Intestine large, colon + + + + + A + + + + + + A A + + A + + + + + + 40 

Intestine large, rectum + + + + + A + + M + + + A A + + + + + + + + + 41 

Intestine large, cecum + + + + + A A + + + + + A A + + A + + + + + + 36 

Intestine small, duodenum A + + + + A + A + + + + A A + + A + + + + + + 35 

Intestine small, jejunum A + + + + A + A + + + + A A + + A + + + + + + 35 

Intestine small, ileum A + + + + A + + + + + + A A + + A + + + + + + 35 

Liver + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangioma X 1 

Hemangiosarcoma X X X X X X X X X X X X 19 

Hemangiosarcoma, multiple X X X X X X 15 

Hepatocellular carcinoma X X X X X 13 

Hepatocellular carcinoma, multiple X X X X X 7 

Hepatocellular adenoma X X X X X 8 

Hepatocellular adenoma, multiple X X X X 7 

Histiocytic sarcoma X X X X X X X X X X 18 

Mesentery + + + 6 

Sarcoma X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + 47 

Hemangiosarcoma 1 

Histiocytic sarcoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + 47 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + 45 

Tooth + 3 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + 46 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + 47 

Parathyroid gland M + M + M M M M + + M M M + + M + + M + + + + 31 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + 46 

Pars distalis, adenoma X X X X X 6 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + 46 

Follicular cell, adenoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

236 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

Number of Days on Study 

1 

3 

5 

1 

4 

4 

3 

6 

6 

4 

6 

8 

4 

8 

4 

4 

8 

4 

5 

0 

7 

5 

0 

9 

5 

1 

3 

5 

1 

8 

5 

3 

6 

5 

4 

1 

5 

4 

1 

5 

4 

8 

5 

5 

2 

5 

5 

2 

5 

5 

5 

5 

6 

3 

5 

6 

5 

5 

6 

9 

5 

8 

0 

5 

8 

5 

5 

8 

6 

5 

8 

6 

5 

8 

6 

Carcass ID Number 

4 

2 

1 

4 

0 

7 

4 

5 

3 

4 

2 

6 

4 

5 

4 

4 

6 

3 

4 

1 

5 

4 

6 

1 

4 

5 

1 

4 

1 

4 

4 

2 

2 

4 

0 

8 

4 

4 

5 

4 

1 

6 

4 

1 

9 

4 

2 

5 

4 

1 

2 

4 

2 

7 

4 

1 

1 

4 

4 

2 

4 

3 

1 

4 

3 

9 

4 

1 

3 

4 

1 

7 

4 

2 

9 

Genital System 

Clitoral gland M M + M + + + + + + + + + + + + + + + + M + + + + 

Ovary A + + + + + + A + + + + + + + + + + + + + + + + + 

Cystadenoma 

Histiocytic sarcoma X X X 

Uterus A + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X 

Hematopoietic System 

Blood 

Bone marrow A + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 

Lymph node + + 

Iliac, histiocytic sarcoma 

Pancreatic, histiocytic sarcoma 

Renal, histiocytic sarcoma X X 

Lymph node, bronchial + + + + M + + + + + M + M M + + + M + + + + + + + 

Histiocytic sarcoma X X X 

Lymph node, mandibular A + + + + M + M M + M + + + + + + M + M + M + + 

Histiocytic sarcoma X X 

Lymph node, mesenteric A + + + M + + + + + + + + + + + M + + + + A + + + 

Histiocytic sarcoma X X X 

Lymph node, mediastinal M M + + + + M M M M + M M + + M M + + + + + + + + 

Histiocytic sarcoma X X X 

Spleen A + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X 

Thymus + I + + M + + + + I + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain 

Histiocytic sarcoma 

+ + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 237 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

Number of Days on Study 

5 

8 

7 

5 

8 

8 

5 

8 

8 

5 

8 

9 

5 

9 

7 

5 

9 

7 

6 

0 

0 

6 

0 

6 

6 

0 

8 

6 

0 

8 

6 

0 

8 

6 

1 

9 

6 

2 

3 

6 

2 

6 

6 

2 

9 

6 

3 

9 

6 

4 

2 

6 

4 

6 

6 

4 

6 

6 

6 

7 

6 

6 

7 

6 

6 

7 

6 

6 

7 

Carcass ID Number 

4 

5 

7 

4 

1 

8 

4 

5 

9 

4 

3 

2 

4 

5 

2 

4 

5 

6 

4 

5 

8 

4 

4 

9 

4 

2 

0 

4 

3 

7 

4 

4 

4 

4 

6 

4 

4 

6 

0 

4 

4 

8 

4 

2 

3 

4 

3 

8 

4 

2 

4 

4 

3 

0 

4 

4 

3 

4 

3 

4 

4 

3 

6 

4 

4 

0 

4 

4 

7 

Total 

Tissues/ 

Tumors 

Genital System 

Clitoral gland + + + + + + M M + M M + + + + + + + M + + + + 39 

Ovary + + + + + + + + + + + + + + + + + + + + + + + 46 

Cystadenoma X X 2 

Histiocytic sarcoma 3 

Uterus + + + + + + + + + + + + + + + + + + + + + + + 47 

Polyp stromal 1 

Hematopoietic System 

Blood + 1 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma X 4 

Lymph node + + + + 6 

Iliac, histiocytic sarcoma X 1 

Pancreatic, histiocytic sarcoma X 1 

Renal, histiocytic sarcoma 2 

Lymph node, bronchial + + + + + M M + + M + + + + + + M + + + M + + 38 

Histiocytic sarcoma X 4 

Lymph node, mandibular M + + + + + + M M M + M + M M + + + + + + + + 32 

Histiocytic sarcoma 2 

Lymph node, mesenteric + + + + + + + M + + + + + + + + + + + + + + + 43 

Histiocytic sarcoma X X X 6 

Lymph node, mediastinal + + + M + + M + M + + + + + + + + + M M + + + 33 

Histiocytic sarcoma X 4 

Spleen + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma X X X 9 

Thymus M + + + + + + + + M + M + + M M + + M + M + + 38 

Histiocytic sarcoma 2 

Integumentary System 

Mammary gland M + + + + + + + + M + + + + + + + + + + + + + 46 

Skin + + + + + + + + + + + + + + + + + + + + + + + 48 

Squamous cell papilloma X 1 

Subcutaneous tissue, sarcoma X 2 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + 48 

Nervous System 

Brain 

Histiocytic sarcoma

+ + + + + + + + + + + + + + + + + + + + + + + 48 

1 
 

 

 

 

 

 

 

 

 

238 Tetrafluoroethylene, NTP TR 450 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

1 1 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 3 

5 

4 

4 

6 

6 

6 

8 

8 

4 

8 

4 

0 

7 

0 

9 

1 

3 

1 

8 

3 

6 

4 

1 

4 

1 

4 

8 

5 

2 

5 

2 

5 

5 

6 

3 

6 

5 

6 

9 

8 

0 

8 

5 

8 

6 

8 

6 

8 

6 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 2 0 5 2 5 6 1 6 5 1 2 0 4 1 1 2 1 2 1 4 3 3 1 1 2 

1 7 3 6 4 3 5 1 1 4 2 8 5 6 9 5 2 7 1 2 1 9 3 7 9 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Hemangiosarcoma, metastatic, liver 

Hemangiosarcoma, metastatic, pancreas 

Hepatocellular carcinoma, metastatic,

 liver 

+ 

A 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

A 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

Nose A + 

X 

M + 

X 

+ 

X 

+ + A + + + + + + 

X 

+ 

X 

+ 

X 

+ + + + 

X 

+ + + + 

X 

+ 

Trachea A + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

+ 

X 

Urinary System 

Kidney A + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 

Urinary bladder A + + + + M + + A + + + + + + + + + + + A A + + I 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X X X X X X 

Lymphoma malignant mixed 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 239 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene: 1,250 ppm 

(continued) 

5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 

7 

8 

8 

8 

8 

8 

9 

9 

7 

9 

7 

0 

0 

0 

6 

0 

8 

0 

8 

0 

8 

1 

9 

2 

3 

2 

6 

2 

9 

3 

9 

4 

2 

4 

6 

4 

6 

6 

7 

6 

7 

6 

7 

6 

7 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 5 

7 

1 

8 

5 

9 

3 

2 

5 

2 

5 

6 

5 

8 

4 

9 

2 

0 

3 

7 

4 

4 

6 

4 

6 

0 

4 

8 

2 

3 

3 

8 

2 

4 

3 

0 

4 

3 

3 

4 

3 

6 

4 

0 

4 

7 

Tissues/ 

Tumors 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Hemangiosarcoma, metastatic, liver 

Hemangiosarcoma, metastatic, pancreas

Hepatocellular carcinoma, metastatic,

 liver 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

47 

47 

3 

1 

3 

1 

4 

Histiocytic sarcoma 

Sarcoma, metastatic, skin

Nose 

X 

+ 

X 

+ + + + + + + + + 

X 

+ + + + 

X 

+ + 

X 

+ 

X 

+ + + + + + 

13 

1 

45 

Trachea + + + + + + + + + + + + + + + + + + + + + + + 47 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

+ 

X 

+ 

X 

+

X

 6 

6 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 3 

Urinary bladder + + + + + A + + + + + I M A + + + + + I + + + 37 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + 48 

Histiocytic sarcoma X X X X X X X X X X 18 

Lymphoma malignant mixed X X 2 
240 Tetrafluoroethylene, NTP TR 450 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Harderian Gland: Adenoma 

Overall ratea 

Adjusted rateb 

Terminal ratec 

First incidence (days) 

Life table testd 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

2/48 (4%) 

5.6% 

2/36 (6%) 

667 (T) 

P<0.001 

P=0.009 

P=0.078 

3/48 (6%) 

39.7% 

1/4 (25%) 

639 

P=0.012 

P=0.109 

P=0.500 

0/47 (0%) 

0.0% 

0/6 (0%) 

—e 

P=0.669N 

P=0.669N 

P=0.253N 

6/48 (13%) 

61.6% 

2/4 (50%) 

484 

P<0.001 

P=0.040 

P=0.134 

Liver: Hemangioma 

Overall rate 0/48 (0%) 5/48 (10%) 2/47 (4%) 1/47 (2%) 

Adjusted rate 0.0% 37.1% 13.0% 25.0% 

Terminal rate 0/36 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 

First incidence (days) — 541 569 667 (T) 

Life table test P=0.145 P<0.001 P=0.084 P=0.091 

Logistic regression test P=0.523 P=0.024 P=0.224 P=0.091 

Cochran-Armitage test P=0.510N 

Fisher exact test P=0.028 P=0.242 P=0.495 

Liver: Hemangiosarcoma 

Overall rate 0/48 (0%) 27/48 (56%) 27/47 (57%) 34/47 (72%) 

Adjusted rate 0.0% 100.0% 95.5% 93.5% 

Terminal rate 0/36 (0%) 4/4 (100%) 5/6 (83%) 2/4 (50%) 

First incidence (days) — 530 481 468 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

Liver: Hemangioma or Hemangiosarcoma 

Overall rate 0/48 (0%) 31/48 (65%) 28/47 (60%) 35/48 (73%) 

Adjusted rate 0.0% 100.0% 96.0% 96.7% 

Terminal rate 0/36 (0%) 4/4 (100%) 5/6 (83%) 3/4 (75%) 

First incidence (days) — 530 481 468 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

Liver: Hepatocellular Adenoma 

Overall rate 15/48 (31%) 17/48 (35%) 20/47 (43%) 15/47 (32%) 

Adjusted rate 37.2% 89.1% 93.2% 76.8% 

Terminal rate 11/36 (31%) 3/4 (75%) 5/6 (83%) 2/4 (50%) 

First incidence (days) 595 530 541 536 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.090 P=0.138 P=0.016 P=0.198 

Cochran-Armitage test P=0.515 

Fisher exact test P=0.414 P=0.176 P=0.560 
Tetrafluoroethylene, NTP TR 450 241 

TABLE D3
 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Liver: Hepatocellular Carcinoma 

Overall rate 4/48 (8%) 28/48 (58%) 22/47 (47%) 20/47 (43%) 

Adjusted rate 10.8% 95.0% 87.7% 72.5% 

Terminal rate 3/36 (8%) 3/4 (75%) 4/6 (67%) 1/4 (25%) 

First incidence (days) 660 530 478 484 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.042 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P=0.012 

Fisher exact test P<0.001 P<0.001 P<0.001 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 17/48 (35%) 33/48 (69%) 29/47 (62%) 28/47 (60%) 

Adjusted rate 42.2% 100.0% 95.6% 88.6% 

Terminal rate 13/36 (36%) 4/4 (100%) 5/6 (83%) 2/4 (50%) 

First incidence (days) 595 530 478 484 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.045 P<0.001 P<0.001 P=0.005 

Cochran-Armitage test P=0.055 

Fisher exact test P=0.001 P=0.009 P=0.015 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 6/48 (13%) 0/48 (0%) 6/47 (13%) 3/47 (6%) 

Adjusted rate 16.7% 0.0% 40.6% 30.2% 

Terminal rate 6/36 (17%) 0/4 (0%) 2/6 (33%) 1/4 (25%) 

First incidence (days) 667 (T) — 510 509 

Life table test P=0.056 P=0.442N P=0.026 P=0.162 

Logistic regression test P=0.563 P=0.442N P=0.505 P=0.636N 

Cochran-Armitage test P=0.424N 

Fisher exact test P=0.013N P=0.605 P=0.254N 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 6/48 (13%) 1/48 (2%) 8/47 (17%) 4/47 (9%) 

Adjusted rate 16.7% 2.5% 49.2% 33.8% 

Terminal rate 6/36 (17%) 0/4 (0%) 2/6 (33%) 1/4 (25%) 

First incidence (days) 667 (T) 541 510 509 

Life table test P=0.017 P=0.694N P=0.003 P=0.064 

Logistic regression test P=0.413 P=0.148N P=0.232 P=0.575 

Cochran-Armitage test P=0.565 

Fisher exact test P=0.056N P=0.370 P=0.384N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 4/46 (9%) 5/45 (11%) 2/44 (5%) 6/46 (13%) 

Adjusted rate 10.6% 55.3% 18.2% 53.0% 

Terminal rate 3/36 (8%) 2/4 (50%) 0/6 (0%) 1/4 (25%) 

First incidence (days) 617 585 652 565 

Life table test P=0.002 P=0.018 P=0.374 P=0.002 

Logistic regression test P=0.071 P=0.282 P=0.665 P=0.123 

Cochran-Armitage test P=0.352 

Fisher exact test P=0.486 P=0.360N P=0.370 
242 Tetrafluoroethylene, NTP TR 450 

TABLE D3
 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Hemangioma 

Overall rate 0/48 (0%) 5/48 (10%) 4/47 (9%) 1/48 (2%)
 

Adjusted rate 0.0% 37.1% 33.5% 25.0%
 

Terminal rate 0/36 (0%) 0/4 (0%) 1/6 (17%) 1/4 (25%)
 

First incidence (days) — 541 569 667 (T)
 

Life table test P=0.054 P<0.001 P=0.002 P=0.091 

Logistic regression test P=0.353 P=0.024 P=0.018 P=0.091 

Cochran-Armitage test P=0.544N
 

Fisher exact test P=0.028 P=0.056 P=0.500 

All Organs: Hemangiosarcoma 

Overall rate 0/48 (0%) 27/48 (56%) 27/47 (57%) 34/48 (71%) 

Adjusted rate 0.0% 100.0% 95.5% 93.5% 

Terminal rate 0/36 (0%) 4/4 (100%) 5/6 (83%) 2/4 (50%) 

First incidence (days) — 530 481 468 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 0/48 (0%) 31/48 (65%) 28/47 (60%) 35/48 (73%) 

Adjusted rate 0.0% 100.0% 96.0% 96.7% 

Terminal rate 0/36 (0%) 4/4 (100%) 5/6 (83%) 3/4 (75%) 

First incidence (days) — 530 481 468 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

All Organs: Histiocytic Sarcoma 

Overall rate 1/48 (2%) 21/48 (44%) 19/47 (40%) 18/48 (38%) 

Adjusted rate 2.1% 77.6% 51.3% 78.2% 

Terminal rate 0/36 (0%) 1/4 (25%) 0/6 (0%) 1/4 (25%) 

First incidence (days) 400 429 457 484 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.015 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P<0.001 P<0.001 P<0.001 

All Organs: Lymphocytic or Mixed Malignant Lymphoma 

Overall rate 5/48 (10%) 3/48 (6%) 0/47 (0%) 2/48 (4%) 

Adjusted rate 12.8% 18.0% 0.0% 30.0% 

Terminal rate 3/36 (8%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 

First incidence (days) 595 530 — 608 

Life table test P=0.471 P=0.348 P=0.250N P=0.377 

Logistic regression test P=0.276N P=0.419N P=0.068N P=0.551N 

Cochran-Armitage test P=0.115N 

Fisher exact test P=0.357N P=0.030N P=0.218N 
243 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE D3
 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 

All Organs: Benign Neoplasms 

Overall rate 27/48 (56%) 24/48 (50%) 26/47 (55%) 29/48 (60%) 

Adjusted rate 64.2% 100.0% 95.0% 100.0% 

Terminal rate 21/36 (58%) 4/4 (100%) 5/6 (83%) 4/4 (100%) 

First incidence (days) 595 530 510 484 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P=0.005 P=0.319 P=0.133 P=0.016 

Cochran-Armitage test P=0.290 

Fisher exact test P=0.341N P=0.546N P=0.418 

All Organs: Malignant Neoplasms 

Overall rate 14/48 (29%) 46/48 (96%) 45/47 (96%) 46/48 (96%) 

Adjusted rate 32.3% 100.0% 100.0% 100.0% 

Terminal rate 7/36 (19%) 4/4 (100%) 6/6 (100%) 4/4 (100%) 

First incidence (days) 400 429 457 366 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P<0.001 P<0.001 

All Organs: Benign or Malignant Neoplasms 

Overall rate 34/48 (71%) 47/48 (98%) 45/47 (96%) 46/48 (96%) 

Adjusted rate 77.2% 100.0% 100.0% 100.0% 

Terminal rate 26/36 (72%) 4/4 (100%) 6/6 (100%) 4/4 (100%) 

First incidence (days) 400 429 457 366 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P<0.001 P=0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P<0.001 P=0.001 P<0.001 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver, lung, and pituitary 

gland; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study 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 life table test regards neoplasms in animals dying prior to terminal kill as being (directly or indirectly) 

the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the overall incidence 

rates. For all tests, a negative trend or a lower incidence in an exposure group is indicated byN. e Not applicable; no neoplasms in animal group 
244 Tetrafluoroethylene, NTP TR 450 

TABLE D4a 

Historical Incidence of Liver Neoplasms in Chamber Control Female B6C3F a 1 Mice

Incidence in Controls 

Study Hemangioma Hemangiosarcoma Hepatocellular Hepatocellular Hepatocellular 

Adenoma Carcinoma Adenoma 

or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/49 1/49 11/49 4/49 15/49 

Acetonitrile 0/49 0/49 4/49 7/49 9/49 

Allyl Glycidyl Ether 0/50 0/50 1/50 5/50 6/50 

-Chloroacetophenone 0/50 0/50 4/50 8/50 12/50 

Epinephrine Hydrochloride 0/50 1/50 2/50 1/50 3/50 

Ethyl Chloride 0/49 0/49 0/49 3/49 3/49 

Hexachlorocyclopentadiene 0/49 0/49 5/49 4/49 9/49 

o-Chlorobenzalmalononitrile (CS-2) 0/50 0/50 4/50 7/50 11/50 

Ozone 0/50 0/50 20/50 15/50 27/50 

Total 0/446 2/446 (0.5%) 51/446 (11.4%) 54/446 (12.1%) 95/446 (21.3%) 

Standard deviation 0.9% 12.5% 8.1% 14.8% 

Range 0%-2% 0%-40% 2%-30% 6%-54% 

Overall Historical Incidence 

Total 1/937 (0.1%) 5/937 (0.5%) 114/937 (12.2%) 103/937 (11.0%) 200/937 (21.3%) 

Standard deviation 0.5% 1.0% 9.7% 6.7% 11.9% 

Range 0%-2% 0%-3% 0%-40% 0%-30% 3%-54% 

a Data as of 12 May 1995 
Tetrafluoroethylene, NTP TR 450 245 

TABLE D4b 

Historical Incidence of Histiocytic Sarcoma in Chamber Control Female B6C3F a 1 Mice

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 3/50 

Acetonitrile 2/49 

Allyl Glycidyl Ether 3/50 

-Chloroacetophenone 1/50 

Epinephrine Hydrochloride 1/50 

Ethyl Chloride 0/49 

Hexachlorocyclopentadiene 4/49 

o-Chlorobenzalmalononitrile (CS-2) 0/50 

Ozone 0/50 

Total 14/447 (3.1%) 

Standard deviation 3.0% 

Range 0%-8% 

Overall Historical Incidence 

Total 26/941 (2.8%) 

Standard deviation 3.1% 

Range 0%-10% 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

246 Tetrafluoroethylene, NTP TR 450 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Disposition Summary 

Animals initially in study 58 58 58 58 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Accidental death 1 

Moribund 8 28 26 27 

Natural deaths 4 16 15 17 

Survivors 

Terminal sacrifice 36 4 6 4 

Animals examined microscopically 58 58 57 58 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, cecum (10) (10) (10) (10) 

Developmental malformation 1 (10%) 

Liver (10) (10) (10) (10) 

Angiectasis 4 (40%) 2 (20%) 1 (10%) 

Basophilic focus 1 (10%) 

Clear cell focus 1 (10%) 

Eosinophilic focus 1 (10%) 4 (40%) 5 (50%) 

Fatty change 1 (10%) 1 (10%) 

Hematopoietic cell proliferation 1 (10%) 

Infarct, chronic 1 (10%) 

Infiltration cellular, mixed cell 1 (10%) 4 (40%) 3 (30%) 1 (10%) 

Mixed cell focus 1 (10%) 1 (10%) 

Necrosis, coagulative, multifocal 1 (10%) 

Thrombosis 1 (10%) 

Hepatocyte, karyomegaly 1 (10%) 

Mesentery (1) (1) (1) 

Fat, necrosis 1 (100%) 1 (100%) 1 (100%) 

Salivary glands (10) (10) (10) (10) 

Infiltration cellular, mononuclear cell 4 (40%) 3 (30%) 4 (40%) 1 (10%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Capsule, hyperplasia 5 (50%) 10 (100%) 5 (50%) 9 (90%) 

X-zone, vacuolization cytoplasmic 1 (10%) 2 (20%) 3 (30%) 1 (10%) 

Thyroid gland (10) (10) (10) (10) 

Ultimobranchial cyst 1 (10%) 

Genital System 

Clitoral gland (9) (9) (9) (9) 

Ectasia 1 (11%) 

Infiltration cellular, mononuclear cell 1 (11%) 1 (11%) 

Ovary (10) (10) (10) (10) 

Abscess 1 (10%) 

Cyst 1 (10%) 1 (10%) 2 (20%) 

Uterus (10) (10) (10) (10) 

Endometrium, hyperplasia, cystic 4 (40%) 6 (60%) 4 (40%) 7 (70%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 247 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

15-Month Interim Evaluation (continued) 

Hematopoietic System 

Bone marrow (10) (10) (10) (10) 

Hyperplasia, neutrophil 1 (10%) 1 (10%) 1 (10%) 

Lymph node (1) 

Pancreatic, hyperplasia, lymphoid 1 (100%) 

Lymph node, mandibular (7) (4) (9) (6) 

Hyperplasia, lymphoid 1 (25%) 

Lymph node, mediastinal (7) (7) (8) (3) 

Hemorrhage 1 (13%) 

Hyperplasia, lymphoid 1 (13%) 

Spleen (10) (10) (10) (10) 

Hematopoietic cell proliferation 2 (20%) 4 (40%) 4 (40%) 3 (30%) 

Hyperplasia, lymphoid 1 (10%) 

Infiltration cellular, polymorphonuclear 1 (10%) 

Nervous System 

Brain (10) (10) (9) (10) 

Mineralization 4 (40%) 1 (10%) 1 (11%) 4 (40%) 

Respiratory System 

Lung (10) (10) (10) (10) 

Embolus, focal 1 (10%) 

Hemorrhage 1 (10%) 1 (10%) 

Urinary System 

Kidney (10) (10) (10) (10) 

Infiltration cellular, mononuclear cell 2 (20%) 2 (20%) 1 (10%) 

Pelvis, infiltration cellular, mononuclear

 cell 1 (10%) 

Renal tubule, dilatation 1 (10%) 

Renal tubule, karyomegaly 10 (100%) 10 (100%) 

Urinary bladder (9) (10) (10) (9) 

Hyperplasia, lymphoid 2 (22%) 1 (10%) 1 (11%) 

Systems Examined With No Lesions Observed 

Cardiovascular System 

General Body System 

Integumentary System 

Musculoskeletal System 

Special Senses System 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

248 Tetrafluoroethylene, NTP TR 450 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study 

Alimentary System 

Gallbladder (42) (36) (34) (34) 

Inflammation, chronic active 1 (2%) 

Intestine large, colon (47) (45) (42) (40) 

Infarct 1 (2%) 

Mesothelium, inflammation, chronic active 2 (4%) 

Intestine large, rectum (48) (48) (42) (41) 

Mesothelium, inflammation, chronic active 1 (2%) 

Intestine large, cecum (47) (42) (40) (36) 

Lymphoid tissue, hyperplasia, lymphoid 1 (2%) 

Mesothelium, inflammation, chronic active 1 (2%) 

Intestine small, duodenum (45) (39) (39) (35) 

Mesothelium, inflammation, chronic active 1 (2%) 

Peyer's patch, hyperplasia, lymphoid 1 (2%) 1 (3%) 

Intestine small, jejunum (46) (37) (39) (35) 

Hemorrhage 1 (3%) 

Perforation 1 (2%) 

Mesothelium, inflammation, chronic active 1 (2%) 

Peyer's patch, hyperplasia, lymphoid 1 (3%) 

Intestine small, ileum (46) (39) (40) (35) 

Mesothelium, inflammation, chronic active 2 (4%) 

Peyer's patch, hyperplasia, lymphoid 1 (3%) 1 (3%) 

Liver (48) (48) (47) (47) 

Angiectasis 1 (2%) 9 (19%) 6 (13%) 4 (9%) 

Basophilic focus 1 (2%) 2 (4%) 

Clear cell focus 1 (2%) 

Eosinophilic focus 5 (10%) 13 (27%) 12 (26%) 7 (15%) 

Fatty change 3 (6%) 

Hematopoietic cell proliferation 3 (6%) 19 (40%) 13 (28%) 15 (32%) 

Hyperplasia, lymphoid 1 (2%) 

Infarct 2 (4%) 1 (2%) 

Infiltration cellular, mixed cell 8 (17%) 8 (17%) 9 (19%) 3 (6%) 

Inflammation, suppurative 1 (2%) 

Mixed cell focus 3 (6%) 1 (2%) 

Necrosis, coagulative, multifocal 4 (8%) 11 (23%) 8 (17%) 8 (17%) 

Thrombosis 1 (2%) 

Centrilobular, necrosis 3 (6%) 1 (2%) 

Serosa, fibrosis 1 (2%) 1 (2%) 

Mesentery (9) (13) (7) (6) 

Angiectasis 1 (11%) 

Cyst 1 (8%) 

Hyperplasia, lymphoid 1 (14%) 

Mineralization 1 (14%) 

Fat, hemorrhage 1 (8%) 

Fat, necrosis 7 (78%) 8 (62%) 6 (86%) 5 (83%) 

Mesothelium, inflammation, chronic active 1 (11%) 

Pancreas (48) (47) (44) (47) 

Fibrosis 1 (2%) 1 (2%) 

Infiltration cellular, lymphocyte 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic active 3 (6%) 

Acinus, atrophy 1 (2%) 1 (2%) 3 (7%) 

Acinus, vacuolization cytoplasmic 1 (2%) 

Duct, ectasia 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 249 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Alimentary System (continued) 

Salivary glands (48) (48) (47) (48) 

Infiltration cellular, mononuclear cell 19 (40%) 6 (13%) 9 (19%) 2 (4%) 

Inflammation, focal, suppurative 1 (2%) 

Stomach, forestomach (48) (48) (47) (47) 

Hyperplasia, squamous 1 (2%) 

Ulcer 1 (2%) 

Epithelium, hyperplasia 4 (8%) 4 (9%) 

Serosa, inflammation, chronic active 1 (2%) 

Stomach, glandular (48) (48) (45) (45) 

Mineralization 1 (2%) 

Serosa, inflammation, chronic active 1 (2%) 

Tooth (2) (3) 

Dysplasia 1 (50%) 2 (67%) 

Peridontal tissue, inflammation, suppurative 1 (33%) 

Cardiovascular System 

Heart (48) (48) (47) (48) 

Cardiomyopathy 2 (4%) 

Polyarteritis 1 (2%) 

Endocrine System 

Adrenal cortex (48) (47) (47) (47) 

Cyst 1 (2%) 1 (2%) 

Degeneration, fatty 1 (2%) 

Hyperplasia 1 (2%) 1 (2%) 

Capsule, hyperplasia 45 (94%) 45 (96%) 47 (100%) 41 (87%) 

Capsule, mineralization 1 (2%) 

X-zone, vacuolization cytoplasmic 1 (2%) 1 (2%) 2 (4%) 

Adrenal medulla (48) (47) (47) (46) 

Angiectasis 1 (2%) 

Islets, pancreatic (48) (45) (44) (47) 

Hyperplasia 1 (2%) 

Pituitary gland (46) (45) (44) (46) 

Pars distalis, angiectasis 2 (4%) 

Pars distalis, congestion 2 (4%) 2 (4%) 

Pars distalis, cyst 3 (7%) 1 (2%) 

Pars distalis, hyperplasia 6 (13%) 3 (7%) 2 (5%) 5 (11%) 

Thyroid gland (48) (48) (46) (46) 

Inflammation, focal 1 (2%) 1 (2%) 

Polyarteritis 1 (2%) 

Ultimobranchial cyst 2 (4%) 2 (4%) 2 (4%) 2 (4%) 

Follicle, cyst 2 (4%) 2 (4%) 

Follicular cell, hyperplasia 2 (4%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

250 Tetrafluoroethylene, NTP TR 450 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

General Body System 

None 

Genital System 

Clitoral gland (42) (42) (38) (39) 

Infiltration cellular, mononuclear cell 1 (2%) 1 (2%) 

Ovary (47) (47) (45) (46) 

Atrophy 2 (4%) 4 (9%) 5 (11%) 2 (4%) 

Congestion 1 (2%) 2 (4%) 1 (2%) 

Cyst 13 (28%) 27 (57%) 16 (36%) 18 (39%) 

Hemorrhage 1 (2%) 

Inflammation, chronic 1 (2%) 

Metaplasia, osseous 1 (2%) 

Pigmentation, hemosiderin 1 (2%) 

Pigmentation, hemosiderin, cholesterol 1 (2%) 

Pigmentation, lipofuscin 1 (2%) 

Polyarteritis 1 (2%) 

Uterus (48) (48) (45) (47) 

Dilatation 3 (6%) 1 (2%) 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Necrosis 1 (2%) 

Endometrium, hyperplasia, cystic 23 (48%) 21 (44%) 24 (53%) 24 (51%) 

Hematopoietic System 

Bone marrow (48) (48) (46) (47) 

Hyperplasia, erythrocyte 2 (4%) 2 (4%) 

Hyperplasia, neutrophil 2 (4%) 1 (2%) 

Lymph node (5) (6) (4) (6) 

Axillary, hyperplasia, lymphoid 1 (25%) 

Iliac, angiectasis 1 (17%) 

Iliac, hyperplasia, lymphoid 1 (17%) 1 (25%) 

Iliac, inflammation, chronic active 1 (17%) 

Lumbar, hyperplasia, lymphoid 1 (25%) 

Pancreatic, hyperplasia, histiocytic 1 (20%) 

Pancreatic, hyperplasia, lymphoid 1 (17%) 1 (17%) 

Renal, hemorrhage 1 (17%) 2 (33%) 

Renal, hyperplasia, lymphoid 1 (17%) 

Lymph node, bronchial (40) (36) (40) (38) 

Congestion 1 (3%) 

Hemorrhage 1 (3%) 2 (5%) 3 (8%) 

Hyperplasia, histiocytic 1 (3%) 1 (3%) 

Hyperplasia, lymphoid 1 (3%) 5 (14%) 3 (8%) 

Hyperplasia, plasma cell 1 (3%) 1 (3%) 

Inflammation 1 (3%) 

Pigmentation, hemosiderin 1 (3%) 1 (3%) 1 (3%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tetrafluoroethylene, NTP TR 450 251 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Hematopoietic System (continued) 

Lymph node, mandibular (39) (35) (34) (32) 

Hemorrhage 1 (3%) 1 (3%) 

Hyperplasia, histiocytic 1 (3%) 1 (3%) 

Hyperplasia, lymphoid 2 (5%) 1 (3%) 2 (6%) 1 (3%) 

Hyperplasia, plasma cell 1 (3%) 1 (3%) 

Inflammation 1 (3%) 

Lymph node, mesenteric (43) (40) (41) (43) 

Angiectasis 1 (2%) 

Hemorrhage 2 (5%) 1 (3%) 3 (7%) 2 (5%) 

Hyperplasia, histiocytic 1 (2%) 1 (3%) 3 (7%) 

Hyperplasia, lymphoid 5 (13%) 4 (10%) 2 (5%) 

Hyperplasia, plasma cell 1 (2%) 

Inflammation, chronic active 2 (5%) 

Lymph node, mediastinal (28) (35) (35) (33) 

Congestion 1 (3%) 2 (6%) 

Hematopoietic cell proliferation 1 (3%) 

Hemorrhage 3 (9%) 

Hyperplasia, histiocytic 2 (6%) 

Hyperplasia, lymphoid 2 (7%) 2 (6%) 4 (11%) 

Hyperplasia, plasma cell 1 (4%) 

Inflammation 1 (4%) 

Pigmentation, hemosiderin 1 (3%) 1 (3%) 

Spleen (48) (48) (46) (47) 

Hematopoietic cell proliferation 18 (38%) 39 (81%) 41 (89%) 41 (87%) 

Hyperplasia, lymphoid 2 (4%) 2 (4%) 1 (2%) 

Pigmentation, melanin 1 (2%) 

Capsule, hematocyst 1 (2%) 

Thymus (46) (42) (39) (38) 

Atrophy 1 (3%) 

Hyperplasia, lymphoid 1 (2%) 

Necrosis 4 (10%) 

Integumentary System 

Mammary gland (48) (46) (45) (46) 

Hyperplasia 1 (2%) 2 (4%) 2 (4%) 

Skin (47) (48) (47) (48) 

Congestion 1 (2%) 

Musculoskeletal System 

Bone (48) (48) (47) (48) 

Fracture healed 1 (2%) 

Nervous System 

Brain (48) (48) (47) (48) 

Compression 1 (2%) 1 (2%) 1 (2%) 

Hemorrhage 1 (2%) 

Mineralization 20 (42%) 9 (19%) 14 (30%) 21 (44%) 

Ventricle, dilatation 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

252 Tetrafluoroethylene, NTP TR 450 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study 

of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

2-Year Study (continued) 

Respiratory System 

Lung (48) (48) (47) (47) 

Congestion 2 (4%) 1 (2%) 

Hemorrhage 2 (4%) 5 (10%) 5 (11%) 3 (6%) 

Inflammation, chronic 2 (4%) 

Pigmentation, hemosiderin 2 (4%) 3 (6%) 

Pigmentation, hemoglobin 1 (2%) 

Alveolar epithelium, hyperplasia 1 (2%) 2 (4%) 

Alveolus, infiltration cellular, histiocyte 1 (2%) 1 (2%) 2 (4%) 3 (6%) 

Interstitium, infiltration cellular, mixed

 cell 3 (6%) 1 (2%) 

Nose (47) (48) (45) (45) 

Inflammation, suppurative 1 (2%) 

Nasolacrimal duct, inflammation, suppurative 1 (2%) 

Respiratory epithelium, cytoplasmic

 alteration 1 (2%) 

Special Senses System 

Harderian gland (3) (6) (4) (6) 

Hyperplasia 2 (33%) 3 (75%) 

Urinary System 

Kidney (48) (48) (47) (47) 

Hemorrhage 1 (2%) 

Infarct, chronic 2 (4%) 1 (2%) 

Infiltration cellular, mononuclear cell 3 (6%) 1 (2%) 4 (9%) 

Inflammation, chronic active 1 (2%) 

Metaplasia, osseous 1 (2%) 1 (2%) 

Nephropathy 1 (2%) 1 (2%) 

Pigmentation, hemosiderin 1 (2%) 1 (2%) 

Polyarteritis 1 (2%) 

Renal tubule, karyomegaly 38 (81%) 

Glomerulus, amyloid deposition 1 (2%) 

Urinary bladder (46) (43) (43) (37) 

Hyperplasia, lymphoid 2 (4%) 1 (2%) 2 (5%) 

Infiltration cellular, mononuclear cell 1 (2%) 

Inflammation, chronic active 1 (2%) 

Metaplasia, squamous 1 (2%) 
253 

APPENDIX E
 

GENETIC TOXICOLOGY
 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOL ....................................... 254
 

RESULTS ................................................................................ 254
 

TABLE E1 Frequency of Micronuclei in Mouse Peripheral Blood Erythrocytes
 

Following Treatment with Tetrafluoroethylene by Inhalation for 13 Weeks ............... 254
 
254 Tetrafluoroethylene, NTP TR 450 

GENETIC TOXICOLOGY 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOL 

A detailed discussion of this assay is presented in MacGregor et al. (1990). Peripheral blood samples were obtained from male 

and female B6C3F mice at the end of the 13-week study. Smears were immediately prepared and fixed in absolute methanol 1 

and stained with Giemsa. Slides were scanned at 630× or 1,000× magnification using a semi-automated image analysis system 

to determine the frequency of micronuclei in 10,000 normochromatic erythrocytes (NCEs) in each of 10 animals per exposure 

group. The criteria of Schmid (1976) were used to define micronuclei; the minimum size limit was approximately 1/20 the 

diameter of the NCE. 

Log transformation of the NCE data, testing for normality by the Shapiro-Wilk test, and testing for heterogeneity of variance by 

Cochran's test were performed before statistical analyses. The frequency of micronucleated cells among NCEs was analyzed by 

analysis of variance using the SAS GLM procedure. The NCE data for each exposure group were compared with the concurrent 

solvent control by Student's t-test. 

RESULTS 

No increases in the frequency of micronucleated NCEs were observed in peripheral blood samples obtained from male and 

female mice at the end of the 13-week inhalation study of tetrafluoroethylene (Table E1). 

TABLE E1 

Frequency of Micronuclei in Mouse Peripheral Blood Erythrocytes Following Treatment 

with Tetrafluoroethylene by Inhalation for 13 Weeks a 

Dose Micronucleated Normochromatic Cells/ 

(ppm) 1,000 Normochromatic Cells 

Male 

0 1.15 ± 0.10 

1,250 1.31 ± 0.07 

2,500 1.29 ± 0.07 

5,000 1.29 ± 0.06 

P=0.1276b 

Female 

0 1.05 ± 0.08 

1,250 1.04 ± 0.07 

2,500 1.07 ± 0.07 

5,000 1.14 ± 0.04 

P=0.7150 

a Study was performed at USDA Western Regional Center. Data are presented as mean ± standard error. 10,000 normochromatic erythrocytes were scored for each of 

10 animals per exposure group. b Trend test, linear contrasts from analysis of variance 
255 

APPENDIX F
 

ORGAN WEIGHTS
 

AND ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS
 

TABLE F1 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats 

in the 16-Day Inhalation Study of Tetrafluoroethylene ................................. 256
 

TABLE F2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats
 

in the 13-Week Inhalation Study of Tetrafluoroethylene ............................... 257
 

TABLE F3 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats
 

at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 258
 

TABLE F4 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice
 

in the 16-Day Inhalation Study of Tetrafluoroethylene ................................. 259
 

TABLE F5 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice
 

in the 13-Week Inhalation Study of Tetrafluoroethylene ............................... 260
 

TABLE F6 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice
 

at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 261
 
256 Tetrafluoroethylene, NTP TR 450 

TABLE F1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 16-Day Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

n 5 5 5 5 5 5 

Male 

Necropsy body wt 153 ± 4 161 ± 4 160 ± 3 153 ± 1 148 ± 2 130 ± 3** 

Brain 

Absolute 1.702 ± 0.013 1.752 ± 0.026 1.738 ± 0.025 1.724 ± 0.012 1.686 ± 0.021 1.648 ± 0.023 

Relative 11.12 ± 0.21 10.93 ± 0.18 10.87 ± 0.31 11.27 ± 0.08 11.40 ± 0.24 12.72 ± 0.31** 

Heart 

Absolute 0.522 ± 0.010 0.610 ± 0.015* 0.602 ± 0.024* 0.604 ± 0.023* 0.594 ± 0.025 0.524 ± 0.014 

Relative 3.41 ± 0.08 3.80 ± 0.07 3.77 ± 0.18 3.95 ± 0.17** 4.01 ± 0.14** 4.04 ± 0.10** 

L. and R. Kidneys 

Absolute 1.200 ± 0.042 1.396 ± 0.037** 1.402 ± 0.031** 1.418 ± 0.017** 1.512 ± 0.038** 1.624 ± 0.049** 

Relative 7.82 ± 0.15 8.70 ± 0.08** 8.75 ± 0.15** 9.27 ± 0.15** 10.21 ± 0.17** 12.51 ± 0.27** 

Liver 

Absolute 4.952 ± 0.289 6.094 ± 0.339 6.198 ± 0.411* 5.888 ± 0.274 6.622 ± 0.257** 5.282 ± 0.219 

Relative 32.20 ± 1.24 38.02 ± 2.08* 38.57 ± 1.92* 38.50 ± 1.87* 44.72 ± 1.60** 40.71 ± 1.49** 

Lung 

Absolute 0.886 ± 0.025 1.150 ± 0.103* 1.288 ± 0.086** 1.114 ± 0.033 0.978 ± 0.051 0.926 ± 0.016 

Relative 5.79 ± 0.17 7.13 ± 0.51* 8.03 ± 0.45** 7.29 ± 0.24* 6.60 ± 0.32 7.15 ± 0.20* 

R. Testis 

Absolute 1.940 ± 0.039 2.070 ± 0.027 2.055 ± 0.054 2.018 ± 0.027 2.006 ± 0.023 1.728 ± 0.063** 

Relative 12.68 ± 0.43 12.93 ± 0.35 12.85 ± 0.44 13.19 ± 0.16 13.57 ± 0.32 13.33 ± 0.48 

Thymus 

Absolute 0.312 ± 0.017 0.355 ± 0.013 0.342 ± 0.019 0.313 ± 0.022 0.341 ± 0.012 0.258 ± 0.019 

Relative 2.04 ± 0.12 2.21 ± 0.06 2.13 ± 0.08 2.05 ± 0.15 2.30 ± 0.06 1.98 ± 0.12 

Female 

Necropsy body wt 116 ± 2 121 ± 2 115 ± 3 120 ± 2 110 ± 3 101 ± 2** 

Brain 

Absolute 1.656 ± 0.018 1.686 ± 0.036 1.648 ± 0.021 1.620 ± 0.030 1.620 ± 0.007 1.620 ± 0.039 

Relative 14.34 ± 0.31 13.95 ± 0.21 14.32 ± 0.23 13.57 ± 0.41 14.84 ± 0.49 16.16 ± 0.59* 

Heart 

Absolute 0.458 ± 0.008 0.498 ± 0.010* 0.458 ± 0.013 0.470 ± 0.014 0.464 ± 0.005 0.438 ± 0.006 

Relative 3.97 ± 0.11 4.12 ± 0.07 3.98 ± 0.11 3.93 ± 0.09 4.25 ± 0.13 4.36 ± 0.08* 

L. and R. Kidneys 

Absolute 1.008 ± 0.020 1.130 ± 0.021 1.082 ± 0.020 1.142 ± 0.040* 1.202 ± 0.045** 1.456 ± 0.061** 

Relative 8.73 ± 0.25 9.35 ± 0.04 9.41 ± 0.27 9.54 ± 0.23 10.97 ± 0.26** 14.49 ± 0.51** 

Liver 

Absolute 4.016 ± 0.204 4.438 ± 0.177 4.006 ± 0.093 4.200 ± 0.245 3.986 ± 0.189 4.064 ± 0.110 

Relative 34.74 ± 1.75 36.67 ± 1.06 34.82 ± 1.05 35.08 ± 1.71 36.34 ± 1.04 40.51 ± 1.34* 

Lung 

Absolute 0.876 ± 0.028 0.918 ± 0.038 0.898 ± 0.038 0.984 ± 0.048 0.886 ± 0.029 0.714 ± 0.012* 

Relative 7.59 ± 0.29 7.59 ± 0.28 7.83 ± 0.51 8.23 ± 0.37 8.09 ± 0.19 7.11 ± 0.11 

Thymus 

Absolute 0.275 ± 0.018 0.308 ± 0.019 0.271 ± 0.012 0.274 ± 0.026 0.249 ± 0.011 0.233 ± 0.027 

Relative 2.38 ± 0.14 2.54 ± 0.11 2.36 ± 0.11 2.29 ± 0.20 2.27 ± 0.05 2.32 ± 0.26 

* 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). 
Tetrafluoroethylene, NTP TR 450 257 

TABLE F2 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

n 10 10 10 10 10 10 

Male 

Necropsy body wt 329 ± 5 343 ± 5 345 ± 4 333 ± 4 331 ± 4 301 ± 5** 

Brain 

Absolute 1.889 ± 0.011 1.913 ± 0.018 1.895 ± 0.018 1.884 ± 0.014 1.886 ± 0.016 1.866 ± 0.017 

Relative 5.75 ± 0.07 5.59 ± 0.06 5.50 ± 0.06 5.66 ± 0.05 5.71 ± 0.07 6.21 ± 0.08** 

Heart 

Absolute 0.875 ± 0.021 0.913 ± 0.010 0.913 ± 0.017 0.964 ± 0.027* 0.981 ± 0.035** 0.904 ± 0.019 

Relative 2.66 ± 0.05 2.67 ± 0.02 2.65 ± 0.04 2.90 ± 0.08** 2.97 ± 0.10** 3.00 ± 0.03** 

R. Kidney 

Absolute 2.218 ± 0.055 2.369 ± 0.044 2.372 ± 0.051 2.512 ± 0.055** 3.527 ± 0.087** 2.915 ± 0.048** 

Relative 6.74 ± 0.14 6.91 ± 0.08 6.88 ± 0.11 7.54 ± 0.12** 10.66 ± 0.20** 9.68 ± 0.06** 

Liver 

Absolute 11.587 ± 0.337 13.125 ± 0.407** 13.494 ± 0.296** 13.829 ± 0.354** 14.825 ± 0.265** 14.398 ± 0.402** 

Relative 35.19 ± 0.74 38.29 ± 0.98* 39.16 ± 0.82** 41.48 ± 0.72** 44.92 ± 1.10** 47.81 ± 1.01** 

Lung 

Absolute 2.008 ± 0.064 2.033 ± 0.040 2.039 ± 0.041 2.175 ± 0.106 1.895 ± 0.072 1.890 ± 0.100 

Relative 6.10 ± 0.17 5.94 ± 0.14 5.92 ± 0.12 6.56 ± 0.37 5.74 ± 0.24 6.28 ± 0.32 

R. Testis 

Absolute 1.384 ± 0.023 1.412 ± 0.029 1.343 ± 0.043 1.375 ± 0.031 1.472 ± 0.019 1.417 ± 0.020 

Relative 4.21 ± 0.05 4.12 ± 0.08 3.90 ± 0.12 4.13 ± 0.10 4.45 ± 0.05* 4.71 ± 0.05** 

Thymus 

Absolute 0.236 ± 0.007 0.247 ± 0.014 0.256 ± 0.006 0.248 ± 0.007 0.244 ± 0.007 0.222 ± 0.006 

Relative 0.72 ± 0.02 0.72 ± 0.04 0.74 ± 0.02 0.75 ± 0.02 0.74 ± 0.02 0.74 ± 0.02 

Female 

Necropsy body wt 189 ± 5 198 ± 3 197 ± 5 194 ± 4 177 ± 8 173 ± 4* 

Brain 

Absolute 1.755 ± 0.017 1.795 ± 0.013 1.784 ± 0.021 1.763 ± 0.018 1.716 ± 0.035 1.704 ± 0.017 

Relative 9.32 ± 0.16 9.07 ± 0.12 9.13 ± 0.25 9.08 ± 0.12 9.89 ± 0.57 9.87 ± 0.20 

Heart 

Absolute 0.596 ± 0.021 0.636 ± 0.012 0.644 ± 0.011 0.633 ± 0.014 0.597 ± 0.025 0.620 ± 0.010 

Relative 3.15 ± 0.05 3.21 ± 0.04 3.28 ± 0.05 3.26 ± 0.05 3.38 ± 0.05** 3.59 ± 0.06** 

R. Kidney 

Absolute 1.326 ± 0.039 1.432 ± 0.028 1.485 ± 0.027* 1.583 ± 0.038** 1.710 ± 0.083** 1.877 ± 0.043** 

Relative 7.01 ± 0.08 7.23 ± 0.13 7.57 ± 0.12** 8.14 ± 0.12** 9.66 ± 0.10** 10.83 ± 0.13** 

Liver 

Absolute 6.618 ± 0.260 6.687 ± 0.122 6.812 ± 0.114 7.044 ± 0.294 6.816 ± 0.331 7.567 ± 0.249* 

Relative 34.95 ± 0.84 33.75 ± 0.43 34.79 ± 0.80 36.17 ± 1.17 38.55 ± 0.78** 43.58 ± 0.63** 

Lung 

Absolute 1.411 ± 0.061 1.472 ± 0.023 1.501 ± 0.046 1.399 ± 0.037 1.307 ± 0.034 1.231 ± 0.030** 

Relative 7.47 ± 0.27 7.44 ± 0.12 7.64 ± 0.14 7.20 ± 0.15 7.49 ± 0.31 7.11 ± 0.11 

Thymus 

Absolute 0.204 ± 0.007 0.227 ± 0.004 0.227 ± 0.005 0.217 ± 0.007 0.188 ± 0.017 0.181 ± 0.006 

Relative 1.08 ± 0.03 1.15 ± 0.02 1.16 ± 0.02 1.11 ± 0.03 1.05 ± 0.07 1.05 ± 0.04 

* 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). 
258 Tetrafluoroethylene, NTP TR 450 

TABLE F3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene a 

0 ppm 156 ppm 312 ppm 625 ppm 

n 10 10 10 10 

Male 

Necropsy body wt 490 ± 9 490 ± 10 485 ± 11 484 ± 11 

R. Kidney 

Absolute 1.487 ± 0.025 1.527 ± 0.045 1.592 ± 0.042 2.076 ± 0.077** 

Relative 3.04 ± 0.03 3.12 ± 0.07 3.28 ± 0.05* 4.28 ± 0.11** 

Liver 

Absolute 15.921 ± 0.258 16.155 ± 0.558 16.323 ± 0.507 16.912 ± 0.616 

Relative 32.56 ± 0.40 32.92 ± 0.70 33.61 ± 0.50 34.96 ± 1.13 

Lung 

Absolute 2.283 ± 0.160 2.354 ± 0.074 2.178 ± 0.106 2.378 ± 0.154 

Relative 4.63 ± 0.25 4.81 ± 0.14 4.49 ± 0.20 4.92 ± 0.31 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

Necropsy body wt 301 ± 8 299 ± 8 327 ± 4* 304 ± 8 

R. Kidney 

Absolute 0.915 ± 0.020 0.933 ± 0.019 1.051 ± 0.026** 1.178 ± 0.058** 

Relative 3.04 ± 0.05 3.13 ± 0.07 3.21 ± 0.07 3.88 ± 0.16** 

Liver 

Absolute 8.759 ± 0.225 8.818 ± 0.239 9.922 ± 0.224** 9.785 ± 0.226** 

Relative 29.08 ± 0.24 29.53 ± 0.43 30.32 ± 0.52 32.26 ± 0.52** 

Lung 

Absolute 1.578 ± 0.058 1.468 ± 0.060 1.560 ± 0.064 1.487 ± 0.052 

Relative 5.25 ± 0.17 4.91 ± 0.15 4.76 ± 0.17 4.90 ± 0.15 

* 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). 
Tetrafluoroethylene, NTP TR 450 259 

TABLE F4 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 16-Day Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

n 5 5 5 5 5 5 

Male 

Necropsy body wt 21.2 ± 0.4 21.2 ± 0.6 20.5 ± 0.5 20.4 ± 1.1 22.0 ± 0.7 21.2 ± 0.9 

Brain 

Absolute 0.440 ± 0.005 0.456 ± 0.007 0.466 ± 0.009 0.452 ± 0.005 0.454 ± 0.009 0.494 ± 0.042 

Relative 20.78 ± 0.37 21.59 ± 0.79 22.73 ± 0.39 22.28 ± 0.82 20.64 ± 0.41 23.23 ± 1.55 

Heart 

Absolute 0.140 ± 0.015 0.128 ± 0.014 0.138 ± 0.007 0.124 ± 0.011 0.128 ± 0.009 0.146 ± 0.008 

Relative 6.60 ± 0.67 6.07 ± 0.72 6.74 ± 0.38 6.11 ± 0.61 5.82 ± 0.39 6.90 ± 0.38 

L. and R. Kidneys 

Absolute 0.408 ± 0.007 0.420 ± 0.013 0.404 ± 0.009 0.400 ± 0.017 0.428 ± 0.026 0.446 ± 0.019 

Relative 19.26 ± 0.34 19.83 ± 0.56 19.71 ± 0.50 19.63 ± 0.52 19.43 ± 1.06 21.02 ± 0.53 

Liver 

Absolute 0.988 ± 0.031 1.002 ± 0.032 0.970 ± 0.044 0.986 ± 0.031 1.078 ± 0.052 1.032 ± 0.054 

Relative 46.66 ± 1.65 47.34 ± 1.60 47.19 ± 1.25 48.48 ± 1.46 49.04 ± 2.51 48.53 ± 0.65 

Lung 

Absolute 0.190 ± 0.006 0.192 ± 0.008 0.208 ± 0.004 0.184 ± 0.005 0.204 ± 0.007 0.192 ± 0.008 

Relative 8.97 ± 0.26 9.10 ± 0.53 10.16 ± 0.31 9.07 ± 0.39 9.26 ± 0.21 9.07 ± 0.34 

R. Testis 

Absolute 0.197 ± 0.012 0.202 ± 0.006 0.204 ± 0.009 0.202 ± 0.013 0.202 ± 0.007 0.199 ± 0.007 

Relative 9.31 ± 0.54 9.52 ± 0.13 9.94 ± 0.37 9.85 ± 0.27 9.18 ± 0.17 9.38 ± 0.18 

Thymus 

Absolute 0.044 ± 0.009 0.042 ± 0.006 0.044 ± 0.007 0.047 ± 0.009 0.045 ± 0.006 0.045 ± 0.003 

Relative 2.07 ± 0.41 1.99 ± 0.26 2.12 ± 0.33 2.27 ± 0.36 2.06 ± 0.26 2.13 ± 0.13 

Female 

Necropsy body wt 16.2 ± 0.4 16.7 ± 0.8 16.1 ± 0.2 16.8 ± 0.8 17.5 ± 0.6 17.5 ± 0.5 

Brain 

Absolute 0.458 ± 0.007 0.458 ± 0.020 0.458 ± 0.007 0.450 ± 0.018 0.464 ± 0.010 0.456 ± 0.002 

Relative 28.33 ± 0.84 27.46 ± 0.86 28.49 ± 0.47 27.06 ± 1.79 26.55 ± 0.72 26.18 ± 0.79 

Heart 

Absolute 0.104 ± 0.004 0.120 ± 0.012 0.122 ± 0.006 0.104 ± 0.002 0.122 ± 0.007 0.128 ± 0.006 

Relative 6.44 ± 0.31 7.13 ± 0.54 7.58 ± 0.34 6.24 ± 0.28 6.96 ± 0.33 7.33 ± 0.31 

L. and R. Kidneys 

Absolute 0.270 ± 0.009 0.284 ± 0.015 0.276 ± 0.010 0.278 ± 0.011 0.306 ± 0.015 0.316 ± 0.009* 

Relative 16.65 ± 0.24 16.97 ± 0.15 17.15 ± 0.53 16.59 ± 0.27 17.48 ± 0.72 18.10 ± 0.38 

Liver 

Absolute 0.722 ± 0.025 0.786 ± 0.031 0.736 ± 0.030 0.800 ± 0.058 0.858 ± 0.045* 0.900 ± 0.047** 

Relative 44.66 ± 1.87 47.12 ± 1.04 45.72 ± 1.47 47.53 ± 1.89 48.88 ± 1.28 51.36 ± 1.35** 

Lung 

Absolute 0.176 ± 0.009 0.178 ± 0.015 0.190 ± 0.004 0.182 ± 0.012 0.198 ± 0.011 0.184 ± 0.010 

Relative 10.90 ± 0.67 10.59 ± 0.59 11.82 ± 0.32 10.83 ± 0.48 11.34 ± 0.70 10.52 ± 0.45 

Thymus 

Absolute 0.046 ± 0.003 0.054 ± 0.003 0.046 ± 0.002 0.056 ± 0.006 0.055 ± 0.004 0.063 ± 0.005* 

Relative 2.83 ± 0.19 3.23 ± 0.15 2.86 ± 0.15 3.31 ± 0.21 3.15 ± 0.23 3.63 ± 0.25* 

* 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). 
260 Tetrafluoroethylene, NTP TR 450 

TABLE F5 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 pm 5,000 ppm 

n 10 10 10 10 10 10 

Male 

Necropsy body wt 36.2 ± 0.7 35.3 ± 0.5 35.9 ± 0.8 34.6 ± 0.5* 34.0 ± 0.3** 32.1 ± 0.5** 

Brain 

Absolute 0.464 ± 0.004 0.464 ± 0.006 0.465 ± 0.005 0.469 ± 0.002 0.464 ± 0.004 0.469 ± 0.006 

Relative 12.84 ± 0.25 13.18 ± 0.21 12.99 ± 0.27 13.58 ± 0.22* 13.64 ± 0.13* 14.64 ± 0.24** 

Heart 

Absolute 0.159 ± 0.004 0.157 ± 0.004 0.156 ± 0.004 0.158 ± 0.006 0.151 ± 0.005 0.145 ± 0.004 

Relative 4.39 ± 0.12 4.45 ± 0.10 4.35 ± 0.10 4.57 ± 0.15 4.43 ± 0.13 4.52 ± 0.09 

R. Kidney 

Absolute 0.588 ± 0.009 0.606 ± 0.019 0.571 ± 0.017 0.573 ± 0.013 0.557 ± 0.012 0.550 ± 0.011 

Relative 16.26 ± 0.30 17.18 ± 0.44 15.89 ± 0.31 16.56 ± 0.28 16.35 ± 0.27 17.15 ± 0.24 

Liver 

Absolute 1.672 ± 0.040 1.705 ± 0.047 1.687 ± 0.051 1.721 ± 0.045 1.622 ± 0.056 1.600 ± 0.049 

Relative 46.13 ± 0.61 48.31 ± 0.91 46.93 ± 0.87 49.70 ± 0.86 47.58 ± 1.32 49.86 ± 1.28* 

Lung 

Absolute 0.247 ± 0.004 0.242 ± 0.004 0.239 ± 0.007 0.232 ± 0.004* 0.230 ± 0.003** 0.216 ± 0.003** 

Relative 6.82 ± 0.08 6.87 ± 0.07 6.65 ± 0.13 6.71 ± 0.13 6.76 ± 0.09 6.75 ± 0.17 

R. Testis 

Absolute 0.117 ± 0.003 0.117 ± 0.002 0.116 ± 0.001 0.118 ± 0.001 0.114 ± 0.002 0.112 ± 0.003 

Relative 3.24 ± 0.07 3.31 ± 0.04 3.25 ± 0.06 3.41 ± 0.07 3.36 ± 0.06 3.50 ± 0.10* 

Thymus 

Absolute 0.032 ± 0.001 0.033 ± 0.002 0.033 ± 0.002 0.031 ± 0.001 0.031 ± 0.002 0.029 ± 0.001 

Relative 0.89 ± 0.03 0.94 ± 0.04 0.93 ± 0.06 0.90 ± 0.04 0.90 ± 0.05 0.90 ± 0.05 

Female 

Necropsy body wt 31.5 ± 0.7 30.8 ± 0.8 30.9 ± 0.8 29.8 ± 0.6 30.7 ± 0.8 29.2 ± 0.5 

Brain 

Absolute 0.473 ± 0.004 0.468 ± 0.003 0.471 ± 0.006 0.479 ± 0.004 0.469 ± 0.005 0.474 ± 0.003 

Relative 15.07 ± 0.32 15.28 ± 0.41 15.34 ± 0.39 16.11 ± 0.25 15.36 ± 0.35 16.26 ± 0.28 

Heart 

Absolute 0.131 ± 0.003 0.127 ± 0.002 0.126 ± 0.002 0.127 ± 0.002 0.127 ± 0.004 0.126 ± 0.002 

Relative 4.17 ± 0.09 4.14 ± 0.09 4.10 ± 0.11 4.27 ± 0.06 4.15 ± 0.11 4.32 ± 0.11 

R. Kidney 

Absolute 0.384 ± 0.005 0.382 ± 0.014 0.372 ± 0.006 0.382 ± 0.009 0.382 ± 0.011 0.379 ± 0.010 

Relative 12.22 ± 0.24 12.41 ± 0.38 12.11 ± 0.28 12.82 ± 0.19 12.46 ± 0.27 12.98 ± 0.33 

Liver 

Absolute 1.475 ± 0.043 1.460 ± 0.069 1.508 ± 0.026 1.506 ± 0.052 1.503 ± 0.063 1.498 ± 0.036 

Relative 46.81 ± 0.97 47.30 ± 1.63 49.09 ± 1.28 50.44 ± 1.08 48.92 ± 1.44 51.32 ± 1.25* 

Lung 

Absolute 0.238 ± 0.010 0.229 ± 0.006 0.249 ± 0.005 0.226 ± 0.004 0.236 ± 0.009 0.237 ± 0.011 

Relative 7.53 ± 0.20 7.45 ± 0.17 8.10 ± 0.21 7.59 ± 0.13 7.69 ± 0.18 8.15 ± 0.44 

Thymus 

Absolute 

Relative 

0.041 ± 0.001 

1.29 ± 0.03 

0.039 ± 0.002 

1.26 ± 0.05 

0.039 ± 0.002 

1.26 ± 0.05 

0.039 ± 0.002b 

1.30 ± 0.06b 

0.040 ± 0.002c 

1.30 ± 0.06c 0.035 ± 0.003 

1.18 ± 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 c n=9 n=8 
Tetrafluoroethylene, NTP TR 450 261 

TABLE F6 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene a 

0 ppm 312 ppm 625 ppm 1,250 ppm 

n 10 10 10 10 

Male 

Necropsy body wt 50.2 ± 1.6 50.8 ± 0.9 50.5 ± 1.6 48.5 ± 1.1 

R. Kidney 

Absolute 0.413 ± 0.010 0.406 ± 0.012 0.420 ± 0.013 0.413 ± 0.011 

Relative 8.26 ± 0.13 8.00 ± 0.22 8.41 ± 0.40 8.52 ± 0.15 

Liver 

Absolute 2.845 ± 0.356 2.683 ± 0.231 2.455 ± 0.147 2.493 ± 0.175 

Relative 59.58 ± 10.80 53.33 ± 5.04 49.30 ± 3.64 51.70 ± 3.96 

Lung 

Absolute 0.297 ± 0.013 0.316 ± 0.019 0.291 ± 0.013 0.308 ± 0.010 

Relative 5.95 ± 0.24 6.22 ± 0.36 5.77 ± 0.15 6.36 ± 0.17 

Female 

Necropsy body wt 48.5 ± 1.5 50.8 ± 1.5 53.3 ± 3.0 48.3 ± 2.5 

R. Kidney 

Absolute 0.286 ± 0.011 0.270 ± 0.006 0.287 ± 0.009 0.278 ± 0.010 

Relative 5.96 ± 0.31 5.33 ± 0.13 5.49 ± 0.26 5.83 ± 0.21 

Liver 

Absolute 1.886 ± 0.094 2.135 ± 0.173 2.210 ± 0.174 2.423 ± 0.321 

Relative 39.02 ± 1.94 42.75 ± 4.42 41.34 ± 1.80 50.96 ± 7.10 

Lung 

Absolute 0.258 ± 0.006 0.283 ± 0.016 0.275 ± 0.008 0.278 ± 0.012 

Relative 5.38 ± 0.24 5.59 ± 0.30 5.31 ± 0.34 5.90 ± 0.42 

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). Differences from the control group were not significant by Williams' or Dunnett's test. 
262 Tetrafluoroethylene, NTP TR 450 
263 

APPENDIX G 

HEMATOLOGY, CLINICAL CHEMISTRY, 

AND URINALYSIS RESULTS 

TABLE G1 

TABLE G2 

TABLE G3 

TABLE G4 

TABLE G5 

Hematology Data for Rats in the 16-Day Inhalation Study 

of Tetrafluoroethylene ............................................................ 

Hematology and Urinalysis Data for Rats in the 13-Week Inhalation Study 

of Tetrafluoroethylene ............................................................ 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats 

at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene ................................. 

Hematology Data for Mice in the 16-Day Inhalation Study 

of Tetrafluoroethylene ............................................................ 

Hematology and Urinalysis Data for Mice in the 13-Week Inhalation Study 

of Tetrafluoroethylene ............................................................ 

264 

265 

267 

269 

270 
264 Tetrafluoroethylene, NTP TR 450 

TABLE G1 

Hematology Data for Rats in the 16-Day Inhalation Study of Tetrafluoroethylene a

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

n 5 5 5 5 4 5 

Hematocrit (%) 43.0 ± 0.3 42.4 ± 0.6 41.7 ± 0.2 42.1 ± 0.4 41.9 ± 0.3 42.6 ± 0.5 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 16.2 ± 0.2 

7.93 ± 0.05 

16.0 ± 0.3 

7.70 ± 0.14 

15.7 ± 0.1 

7.67 ± 0.12 

15.9 ± 0.2 

7.68 ± 0.10 

15.8 ± 0.2 

7.72 ± 0.05 

16.0 ± 0.2 

7.77 ± 0.10 

Reticulocytes (per 5 oil

 immersion fields) 53.00 ± 8.56 54.40 ± 4.07 66.80 ± 8.29 70.00 ± 5.52 68.75 ± 7.22 69.20 ± 5.44 

Nucleated erythrocytes

 (10 /μL) 3 0.01 ± 0.01 0.00 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 

Mean cell volume (fL) 54.2 ± 0.2 55.0 ± 0.3 54.6 ± 0.7 55.0 ± 0.6 54.3 ± 0.3 55.0 ± 0.6 

Mean cell hemoglobin (pg) 20.5 ± 0.1 20.8 ± 0.2 20.5 ± 0.3 20.8 ± 0.2 20.4 ± 0.2 20.6 ± 0.2 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

37.8 ± 0.1 

641.4 ± 10.3 

3.66 ± 0.17 

37.7 ± 0.2 

699.4 ± 22.4 

4.12 ± 0.09 

37.7 ± 0.1 

603.0 ± 74.8 

4.26 ± 0.49 

37.8 ± 0.1 

677.6 ± 15.2 

3.68 ± 0.35 

37.6 ± 0.1 

745.3 ± 20.3* 

4.20 ± 0.67 

37.5 ± 0.1 

641.8 ± 31.4 

4.18 ± 0.32 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.70 ± 0.09 

2.92 ± 0.16 

0.02 ± 0.02 

0.01 ± 0.01 

0.71 ± 0.09 

3.35 ± 0.03 

0.03 ± 0.02 

0.04 ± 0.01 

0.82 ± 0.16 

3.38 ± 0.41 

0.06 ± 0.04 

0.00 ± 0.00 

0.70 ± 0.14 

2.91 ± 0.20 

0.07 ± 0.03 

0.01 ± 0.01 

0.60 ± 0.04 

3.54 ± 0.67 

0.03 ± 0.01 

0.04 ± 0.02 

0.65 ± 0.06 

3.52 ± 0.34 

0.01 ± 0.01 

0.00 ± 0.00 

Female 

n 5 5 5 5 5 5 

Hematocrit (%) 45.6 ± 0.3 45.7 ± 0.5 45.8 ± 0.1 46.9 ± 0.4 46.6 ± 0.3 46.2 ± 0.6 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 16.8 ± 0.1 

8.11 ± 0.18 

16.8 ± 0.2 

8.16 ± 0.11 

16.9 ± 0.1 

8.12 ± 0.12 

17.3 ± 0.1 

8.28 ± 0.09 

17.2 ± 0.2 

8.49 ± 0.14 

17.1 ± 0.3 

8.34 ± 0.11 

Reticulocytes (per 5 oil

 immersion fields) 46.00 ± 7.77 42.00 ± 5.65 32.20 ± 1.59 37.20 ± 3.09 35.00 ± 3.48 31.40 ± 1.33 

Nucleated erythrocytes

 (10 /μL) 3 0.00 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 0.00 ± 0.00 

Mean cell volume (fL) 56.4 ± 1.3 56.0 ± 0.6 56.6 ± 1.0 56.8 ± 0.4 55.0 ± 0.6 55.6 ± 0.4 

Mean cell hemoglobin (pg) 20.8 ± 0.5 20.6 ± 0.1 20.8 ± 0.4 20.9 ± 0.1 20.3 ± 0.2 20.5 ± 0.2 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

36.9 ± 0.1 

626.8 ± 22.5 

4.80 ± 0.10 

36.7 ± 0.2 

705.6 ± 17.5 

4.16 ± 0.46 

36.9 ± 0.2 

626.2 ± 12.7 

3.96 ± 0.27 

37.0 ± 0.1 

650.2 ± 49.6 

4.72 ± 0.48 

36.9 ± 0.1 

552.2 ± 20.8 

4.82 ± 0.77 

36.9 ± 0.2 

599.8 ± 14.1 

4.18 ± 0.44 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.81 ± 0.10 

3.86 ± 0.16 

0.11 ± 0.02 

0.02 ± 0.01 

0.70 ± 0.14 

3.37 ± 0.42 

0.08 ± 0.03 

0.02 ± 0.02 

0.55 ± 0.15 

3.29 ± 0.30 

0.10 ± 0.04 

0.02 ± 0.01 

0.70 ± 0.03 

3.86 ± 0.41 

0.11 ± 0.04 

0.05 ± 0.02 

1.07 ± 0.22 

3.68 ± 0.60 

0.07 ± 0.02 

0.01 ± 0.01 

1.08 ± 0.23 

2.88 ± 0.31 

0.18 ± 0.04 

0.04 ± 0.01 

* Significantly different (P 0.05) from the control group by Dunn's test a Mean ± standard error. Statistical tests were performed on unrounded data. 
Tetrafluoroethylene, NTP TR 450 265 

TABLE G2 

Hematology and Urinalysis Data for Rats in the 13-Week Inhalation Study of Tetrafluoroethylene a

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Hematology 

n 10 9 9 10 9 10 

Hematocrit (%) 47.3 ± 0.3 45.5 ± 0.3** 45.9 ± 0.4** 44.9 ± 0.6** 44.3 ± 0.3** 44.3 ± 0.3** 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 3 

15.8 ± 0.1 

9.45 ± 0.06 

91.2 ± 47.5 

15.2 ± 0.1** 

9.11 ± 0.07** 

118.8 ± 60.3 

15.3 ± 0.1** 

9.22 ± 0.09* 

109.9 ± 41.7 

14.8 ± 0.2** 

9.02 ± 0.12** 

84.2 ± 44.1 

14.6 ± 0.1** 

8.91 ± 0.08** 

116.9 ± 82.7 

14.5 ± 0.1** 

8.80 ± 0.07** 

87.0 ± 61.2 

Mean cell volume (fL) 50.2 ± 0.3 49.9 ± 0.2 49.7 ± 0.2 49.9 ± 0.2 49.8 ± 0.2 50.3 ± 0.2 

Mean cell hemoglobin (pg) 16.7 ± 0.1 16.7 ± 0.1 16.6 ± 0.1 16.5 ± 0.2* 16.4 ± 0.1** 16.5 ± 0.1* 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

33.4 ± 0.1 

515.4 ± 8.6 

6.38 ± 0.20 

33.3 ± 0.1 

530.1 ± 15.8 

6.27 ± 0.20 

33.3 ± 0.1 

540.6 ± 23.8* 

6.43 ± 0.27 

33.0 ± 0.3* 

599.4 ± 21.8** 

6.59 ± 0.31 

33.0 ± 0.1* 

581.1 ± 10.6** 

6.02 ± 0.45 

32.8 ± 0.1** 

637.4 ± 12.4** 

6.59 ± 0.27 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

1.06 ± 0.10 

5.07 ± 0.18 

0.22 ± 0.05 

0.04 ± 0.02 

1.16 ± 0.11 

4.82 ± 0.26 

0.18 ± 0.04 

0.10 ± 0.01* 

0.89 ± 0.07 

5.33 ± 0.19 

0.16 ± 0.06 

0.05 ± 0.02 

0.91 ± 0.10 

5.51 ± 0.29 

0.09 ± 0.03 

0.07 ± 0.02 

0.86 ± 0.11 

4.95 ± 0.38 

0.17 ± 0.04 

0.04 ± 0.02 

0.97 ± 0.08 

5.39 ± 0.21 

0.19 ± 0.05 

0.04 ± 0.01 

Urinalysis 

n 10 10 10 10 10 10 

Fluoride (μg/16 hr) 

Glucose (mg/16 hr) 

7.98 ± 0.37 

0.09 ± 0.01b 

35.68 ± 1.82** 

0.02 ± 0.00**b 

45.87 ± 2.42** 

0.08 ± 0.02 

69.91 ± 5.63** 

0.04 ± 0.01 

122.41 ± 12.02** 

0.05 ± 0.02 

205.45 ± 16.71** 

2.81 ± 1.27b 

Protein (mg/16 hr) 14 ± 1 17 ± 1** 19 ± 1** 23 ± 2** 23 ± 1** 35 ± 2** 

Volume (mL/16 hr) 24.8 ± 2.4 21.5 ± 3.1 27.0 ± 2.1 24.0 ± 2.8 28.7 ± 2.0 38.6 ± 4.5 

Volume (mL)

 (concentrated) 0.9 ± 0.2b 0.8 ± 0.1b 0.9 ± 0.2b 1.1 ± 0.2 1.2 ± 0.1 1.1 ± 0.2 

Specific gravity 1.010 ± 0.001 1.014 ± 0.002 1.009 ± 0.001 1.012 ± 0.002 1.009 ± 0.001 1.009 ± 0.001 

Specific gravity

 (concentrated) 1.037 ± 0.006b 1.064 ± 0.001**b 1.060 ± 0.002b 1.058 ± 0.003* 1.055 ± 0.002 1.060 ± 0.002* 
266 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE G2
 

Hematology and Urinalysis Data for Rats in the 13-Week Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Female 

Hematology 

n 10 10 10 10 9 10 

Hematocrit (%) 47.5 ± 0.4 47.3 ± 0.3 46.8 ± 0.5 47.2 ± 0.3 48.0 ± 0.7 45.3 ± 0.3**
 

Hemoglobin (g/dL) 15.7 ± 0.2 15.7 ± 0.2 15.6 ± 0.2 15.6 ± 0.1 15.9 ± 0.2 14.9 ± 0.1**
 6 Erythrocytes (10 /μL) 8.67 ± 0.08 8.67 ± 0.08 8.67 ± 0.09 8.66 ± 0.05 8.79 ± 0.08 8.34 ± 0.09* 3 Reticulocytes (10 /μL) 82.8 ± 36.4 88.6 ± 22.1 71.5 ± 30.5 86.6 ± 33.0 67.2 ± 41.2 96.4 ± 33.3 

Mean cell volume (fL) 54.9 ± 0.2 54.4 ± 0.2 54.1 ± 0.2* 54.5 ± 0.2 54.7 ± 0.3 54.5 ± 0.4 

Mean cell hemoglobin (pg) 18.1 ± 0.1 18.1 ± 0.1 17.9 ± 0.1 18.0 ± 0.1 18.0 ± 0.1 17.9 ± 0.2** 

Mean cell hemoglobin

 concentration (g/dL) 33.2 ± 0.1 33.1 ± 0.2 33.3 ± 0.2 33.1 ± 0.1 33.1 ± 0.1 32.8 ± 0.1 3 Platelets (10 /μL) 589.0 ± 31.3 584.7 ± 11.8 571.1 ± 17.2 585.5 ± 14.3 614.4 ± 25.8 665.5 ± 19.1 3 Leukocytes (10 /μL) 6.19 ± 0.43 5.07 ± 0.15 5.55 ± 0.28 5.35 ± 0.23 5.74 ± 0.33 4.84 ± 0.26* 

Segmented neutrophils 3 (10 /μL) 0.66 ± 0.05 0.65 ± 0.09 0.86 ± 0.07 0.67 ± 0.09 0.82 ± 0.12 0.76 ± 0.06 3 Lymphocytes (10 /μL) 5.39 ± 0.43 4.26 ± 0.20 4.58 ± 0.29 4.51 ± 0.22 4.81 ± 0.33 3.95 ± 0.22* 

Monocytes (10 3/μL) 0.11 ± 0.03 0.10 ± 0.03 0.08 ± 0.02 0.13 ± 0.04 0.10 ± 0.03 0.11 ± 0.03 3 Eosinophils (10 /μL) 0.03 ± 0.02 0.05 ± 0.01 0.03 ± 0.02 0.04 ± 0.02 0.02 ± 0.01 0.02 ± 0.01 

Urinalysis 

n 10 10 10 10 8 10 

b c Fluoride (μg/16 hr) 4.33 ± 0.17 20.71 ± 1.12** 32.30 ± 1.22** 49.86 ± 4.38** 73.80 ± 4.68** 118.76 ± 5.00** 

Glucose (mg/16 hr) 0.12 ± 0.06 0.10 ± 0.03 0.18 ± 0.07 0.09 ± 0.02 0.21 ± 0.04** 0.06 ± 0.01 

Protein (mg/16 hr) 1 ± 0 1 ± 0 1 ± 0 1 ± 0 2 ± 0** 2 ± 0** 

Volume (mL/16 hr) 11.9 ± 1.5 18.1 ± 2.1* 20.0 ± 3.1* 23.3 ± 1.9** 34.3 ± 3.7** 38.5 ± 3.1** 

Volume (mL) b c b d e (concentrated) 0.5 ± 0.2 0.8 ± 0.2 0.6 ± 0.2 0.6 ± 0.2 0.4 ± 0.2 0.4 ± 0.1 

Specific gravity 1.015 ± 0.002 1.009 ± 0.001* 1.010 ± 0.001 1.008 ± 0.001** 1.005 ± 0.001** 1.006 ± 0.000** 

Specific gravity b c b d e (concentrated) 1.049 ± 0.007 1.053 ± 0.013 1.064 ± 0.005 1.062 ± 0.012 1.079 ± 0.011 1.057 ± 0.007 

* 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
 

n=8
 d n=7 e n=6 
Tetrafluoroethylene, NTP TR 450 267 

TABLE G3 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene a 

0 ppm 156 ppm 312 ppm 625 ppm 

Male 

n 10 10 10 10 

Hematology 

Hematocrit (automated) (%) 44.0 ± 0.9 45.0 ± 0.7 45.0 ± 1.0 42.1 ± 0.9 

Hematocrit (manual) (%) 43.0 ± 0.8 43.5 ± 0.8 43.7 ± 0.9 41.1 ± 0.8 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

14.1 ± 0.3 

8.37 ± 0.13 

0.30 ± 0.03 

0.12 ± 0.03 

14.2 ± 0.2 

8.40 ± 0.15 

0.30 ± 0.02 

0.13 ± 0.02 

14.5 ± 0.3 

8.54 ± 0.20 

0.30 ± 0.02 

0.09 ± 0.02 

13.4 ± 0.3 

7.79 ± 0.26 

0.36 ± 0.08 

0.27 ± 0.14 

Mean cell volume (fL) 52.7 ± 0.8 53.6 ± 0.3 52.8 ± 0.4 54.2 ± 0.9 

Mean cell hemoglobin (pg) 16.9 ± 0.3 16.9 ± 0.1 17.0 ± 0.1 17.3 ± 0.3 

Mean cell hemoglobin concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

Segmented neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

32.2 ± 0.1 

535.7 ± 21.9 

3.45 ± 0.83 

1.76 ± 0.49 

1.66 ± 0.35 

0.01 ± 0.00 

0.02 ± 0.01 

31.6 ± 0.1* 

531.8 ± 8.2 

2.89 ± 0.56 

1.11 ± 0.21 

1.74 ± 0.36 

0.01 ± 0.01 

0.03 ± 0.02 

32.2 ± 0.1 

562.0 ± 16.4 

2.19 ± 0.13 

0.96 ± 0.08 

1.21 ± 0.12 

0.00 ± 0.00 

0.01 ± 0.01 

31.9 ± 0.1 

520.8 ± 32.4 

3.06 ± 0.41 

1.11 ± 0.12 

1.89 ± 0.36 

0.01 ± 0.01 

0.05 ± 0.01 

Clinical Chemistry 

Blood urea nitrogen (mg/dL) 18.4 ± 0.3 19.7 ± 0.7 19.3 ± 0.5 20.6 ± 0.7* 

Creatinine (mg/dL) 0.63 ± 0.02 0.67 ± 0.03 0.59 ± 0.02 0.67 ± 0.02 

Sodium (mEq/L) 152 ± 1 152 ± 1 151 ± 1 151 ± 1 

Potassium (mEq/L) 5.2 ± 0.1 5.1 ± 0.1 5.1 ± 0.1 5.3 ± 0.1 

Chloride (mEq/L) 107 ± 1 106 ± 1 107 ± 0 106 ± 1 

Calcium (mg/dL) 11.42 ± 0.15 11.48 ± 0.15 11.78 ± 0.12 11.48 ± 0.15 

Phosphorus (mg/dL) 5.9 ± 0.3 6.0 ± 0.3 6.4 ± 0.2 6.4 ± 0.2 

Urinalysis 

Glucose (mg/16 hr) 1.5 ± 0.1 1.4 ± 0.1 1.0 ± 0.1** 1.0 ± 0.0** 

Protein (mg/16 hr) 19 ± 2 17 ± 2 14 ± 1 27 ± 4 

Volume (mL/16 hr)

 Week 63 14.7 ± 2.8 9.0 ± 0.8 8.3 ± 0.6* 12.9 ± 0.8 

Week 64 0.7 ± 0.2 0.8 ± 0.2 1.0 ± 0.3 1.4 ± 0.3 

Specific gravity

 Week 63 

Week 64 

1.022 ± 0.002 

1.048 ± 0.006b 

1.029 ± 0.001 

1.045 ± 0.007b 

1.026 ± 0.001 

1.039 ± 0.008c 1.023 ± 0.001 1.045 ± 0.006d 
268 Tetrafluoroethylene, NTP TR 450 

TABLE G3 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats at the 15-Month Interim Evaluation 

in the 2-Year Inhalation Study of Tetrafluoroethylene (continued) 

0 ppm 312 ppm 625 ppm 1,250 ppm 

Female 

n 10 10 10 10 

Hematology 

Hematocrit (automated) (%) 44.4 ± 0.4 44.9 ± 0.5 44.0 ± 0.4 43.9 ± 0.5 

Hematocrit (manual) (%) 42.9 ± 0.4 43.4 ± 0.4 42.6 ± 0.4 42.9 ± 0.5 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

14.3 ± 0.2 

7.82 ± 0.07 

0.23 ± 0.02 

0.09 ± 0.02 

14.4 ± 0.2 

7.95 ± 0.07 

0.25 ± 0.01 

0.07 ± 0.01 

14.1 ± 0.1 

7.81 ± 0.09 

0.25 ± 0.01 

0.08 ± 0.01 

14.0 ± 0.2 

7.87 ± 0.08 

0.27 ± 0.01* 

0.06 ± 0.01 

Mean cell volume (fL) 56.9 ± 0.2 56.4 ± 0.2 56.3 ± 0.3 55.8 ± 0.2** 

Mean cell hemoglobin (pg) 18.3 ± 0.1 18.1 ± 0.1 18.1 ± 0.1 17.8 ± 0.1** 

Mean cell hemoglobin concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

Segmented neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

32.1 ± 0.2 

463.3 ± 16.9 

1.45 ± 0.18 

0.43 ± 0.06 

1.00 ± 0.14 

0.01 ± 0.01 

0.02 ± 0.01 

32.0 ± 0.1 

492.4 ± 11.8 

1.51 ± 0.15 

0.47 ± 0.05 

1.01 ± 0.11 

0.01 ± 0.01 

0.02 ± 0.01 

32.0 ± 0.1 

479.8 ± 12.6 

1.86 ± 0.28 

0.65 ± 0.10* 

1.19 ± 0.19 

0.01 ± 0.01 

0.01 ± 0.01 

32.0 ± 0.1 

491.0 ± 9.8 

1.89 ± 0.16* 

0.70 ± 0.09** 

1.16 ± 0.12 

0.01 ± 0.01 

0.02 ± 0.01 

Clinical Chemistry 

Blood urea nitrogen (mg/dL) 17.6 ± 0.8 17.4 ± 0.6 17.6 ± 0.7 17.7 ± 0.5 

Creatinine (mg/dL) 0.67 ± 0.03 0.64 ± 0.02 0.61 ± 0.02 0.62 ± 0.03 

Sodium (mEq/L) 148 ± 0 148 ± 1 148 ± 1 147 ± 1 

Potassium (mEq/L) 5.2 ± 0.1 5.1 ± 0.1 5.0 ± 0.1 5.2 ± 0.1 

Chloride (mEq/L) 100 ± 1 102 ± 1 99 ± 0 100 ± 1 

Calcium (mg/dL) 11.55 ± 0.09 11.44 ± 0.17 11.26 ± 0.12 11.18 ± 0.17 

Phosphorus (mg/dL) 6.2 ± 0.3 5.9 ± 0.4 6.0 ± 0.3 6.5 ± 0.2 

Urinalysis 

Glucose (mg/16 hr) 0.8 ± 0.1 0.8 ± 0.0 0.7 ± 0.1 0.8 ± 0.4 

Protein (mg/16 hr) 4 ± 1 4 ± 1 5 ± 1 5 ± 1 

Volume (mL/16 hr) 

Week 63 9.6 ± 2.2 6.1 ± 0.5 7.4 ± 0.8 10.1 ± 0.7 

Week 64 0.2 ± 0.1 0.2 ± 0.1 0.2 ± 0.1 0.2 ± 0.1 

Specific gravity

 Week 63 1.019 ± 0.002 1.027 ± 0.002* 1.021 ± 0.002 1.019 ± 0.001 

Week 64 1.038 ± 0.012e 1.046 ± 0.006c 1.060 ± 0.002e 1.061 ± 0.007e 

* 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=6
 

n=5
 d n=9 e n=3 

c 
Tetrafluoroethylene, NTP TR 450 269 

TABLE G4 

Hematology Data for Mice in the 16-Day Inhalation Study of Tetrafluoroethylene a

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

n 5 5 5 5 5 5 

Hematocrit (%) 44.3 ± 0.4 45.2 ± 0.9 44.4 ± 0.4 43.6 ± 0.5 43.5 ± 0.5 43.8 ± 0.3 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 17.7 ± 0.2 

8.24 ± 0.09 

18.0 ± 0.4 

8.46 ± 0.17 

17.6 ± 0.1 

8.38 ± 0.06 

17.0 ± 0.3 

8.14 ± 0.09 

17.2 ± 0.3 

7.94 ± 0.07 

17.3 ± 0.2 

8.18 ± 0.03 

Reticulocytes (per 5 oil

 immersion fields) 29.80 ± 2.99 15.20 ± 4.53* 21.80 ± 5.03 21.40 ± 5.77 23.20 ± 4.31 24.00 ± 1.55 

Nucleated erythrocytes

 (10 /μL) 3 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 

Mean cell volume (fL) 53.8 ± 0.4 53.6 ± 0.6 53.0 ± 0.3 53.6 ± 0.2 55.0 ± 0.0 53.6 ± 0.2 

Mean cell hemoglobin (pg) 21.4 ± 0.2 21.3 ± 0.2 21.0 ± 0.1 20.9 ± 0.2 21.7 ± 0.2 21.2 ± 0.1 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

39.8 ± 0.3 

805.0 ± 39.9 

1.62 ± 0.26 

39.9 ± 0.2 

782.2 ± 16.7 

1.54 ± 0.41 

39.6 ± 0.1 

759.8 ± 4.1 

1.92 ± 0.59 

39.1 ± 0.5 

778.0 ± 24.1 

1.24 ± 0.38 

39.6 ± 0.4 

815.6 ± 70.7 

1.10 ± 0.30 

39.6 ± 0.3 

799.4 ± 34.8 

1.90 ± 0.23 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.48 ± 0.09 

1.10 ± 0.30 

0.04 ± 0.02 

0.00 ± 0.00 

0.22 ± 0.04 

1.29 ± 0.35 

0.03 ± 0.02 

0.00 ± 0.00 

0.72 ± 0.35 

1.16 ± 0.26 

0.05 ± 0.02 

0.00 ± 0.00 

0.26 ± 0.08 

0.92 ± 0.33 

0.05 ± 0.03 

0.01 ± 0.01 

0.17 ± 0.08 

0.90 ± 0.23 

0.03 ± 0.01 

0.00 ± 0.00 

0.52 ± 0.08 

1.33 ± 0.20 

0.05 ± 0.03 

0.00 ± 0.00 

Female 

n 4 5 5 5 5 5 

Hematocrit (%) 44.6 ± 0.7 43.8 ± 0.8 43.5 ± 0.6 43.3 ± 0.6 44.3 ± 0.3 43.3 ± 0.4 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 17.5 ± 0.3 

8.24 ± 0.12 

17.2 ± 0.3 

8.16 ± 0.15 

17.0 ± 0.3 

7.95 ± 0.11 

17.1 ± 0.2 

8.08 ± 0.14 

17.4 ± 0.1 

8.22 ± 0.06 

17.0 ± 0.1 

8.07 ± 0.07 

Reticulocytes (per 5 oil

 immersion fields) 25.00 ± 1.91 29.00 ± 3.39 21.40 ± 3.16 15.00 ± 2.02 29.40 ± 3.72 20.20 ± 4.18 

Nucleated erythrocytes

 (10 /μL) 3 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 

Mean cell volume (fL) 54.3 ± 0.3 53.6 ± 0.4 54.6 ± 0.2 53.6 ± 0.2 53.8 ± 0.2 53.8 ± 0.2 

Mean cell hemoglobin (pg) 21.2 ± 0.1 21.1 ± 0.2 21.4 ± 0.2 21.2 ± 0.3 21.1 ± 0.1 21.1 ± 0.1 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

39.1 ± 0.1 

797.3 ± 26.7 

0.85 ± 0.22 

39.3 ± 0.1 

764.4 ± 32.2 

0.76 ± 0.08 

39.2 ± 0.2 

734.2 ± 25.6 

0.64 ± 0.13 

39.6 ± 0.4 

775.0 ± 27.0 

0.94 ± 0.18 

39.2 ± 0.3 

785.6 ± 30.2 

0.98 ± 0.22 

39.3 ± 0.1 

797.6 ± 24.9 

0.86 ± 0.16 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.30 ± 0.04 

0.55 ± 0.21 

0.00 ± 0.00 

0.00 ± 0.00 

0.14 ± 0.03 

0.62 ± 0.07 

0.00 ± 0.00 

0.00 ± 0.00 

0.24 ± 0.04 

0.39 ± 0.12 

0.01 ± 0.01 

0.00 ± 0.00 

0.29 ± 0.13 

0.64 ± 0.12 

0.01 ± 0.01 

0.00 ± 0.00 

0.38 ± 0.18 

0.59 ± 0.07 

0.01 ± 0.01 

0.00 ± 0.00 

0.13 ± 0.02 

0.72 ± 0.15 

0.01 ± 0.01 

0.00 ± 0.00 

* Significantly different (P 0.05) from the control group by Dunn's test a Mean ± standard error. Statistical tests were performed on unrounded data. 
270 Tetrafluoroethylene, NTP TR 450 

TABLE G5 

Hematology and Urinalysis Data for Mice in the 13-Week Inhalation Study of Tetrafluoroethylene a

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Male 

Hematology 

n 10 10 10 10 10 10 

Hematocrit (%) 50.6 ± 0.4 50.0 ± 0.5 50.2 ± 0.4 50.4 ± 0.7 47.9 ± 0.4** 46.3 ± 0.5** 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 3 

17.0 ± 0.2 

10.51 ± 0.10 

70 ± 43 

16.7 ± 0.1 

10.35 ± 0.09 

93 ± 45 

16.7 ± 0.1 

10.42 ± 0.11 

108 ± 135 

16.7 ± 0.1 

10.44 ± 0.13 

80 ± 24 

16.0 ± 0.1** 

10.03 ± 0.08** 

75 ± 27 

15.4 ± 0.2** 

9.65 ± 0.14** 

102 ± 115 

Howell-Jolly bodies

 (% erythrocytes) 0.1 ± 0.0 0.0 ± 0.0 0.2 ± 0.0 0.1 ± 0. 0.1 ± 0.0 0.2 ± 0.0 

Mean cell volume (fL) 48.0 ± 0.3 48.4 ± 0.2 48.1 ± 0.2 48.2 ± 0.4 47.9 ± 0.3 48.0 ± 0.4 

Mean cell hemoglobin (pg) 16.1 ± 0.1 16.2 ± 0.1 16.0 ± 0.1 16.0 ± 0.1 15.9 ± 0.1 16.0 ± 0.1 

Mean cell hemoglobin

 concentration (g/dL) 

Platelets (10 /μL) 3 

Leukocytes (10 /μL) 3 

33.5 ± 0.1 

961.6 ± 16.8 

4.15 ± 0.44 

33.4 ± 0.2 

932.9 ± 20.3 

3.36 ± 0.29 

33.3 ± 0.2 

969.7 ± 25.4 

3.16 ± 0.28 

33.1 ± 0.2 

993.5 ± 18.9 

3.71 ± 0.31 

33.4 ± 0.2 

996.2 ± 18.3 

2.89 ± 0.34 

33.3 ± 0.1 

1,017.3 ± 27.7 

3.16 ± 0.39 

Segmented neutrophils

 (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.54 ± 0.08 

3.52 ± 0.38 

0.07 ± 0.02 

0.02 ± 0.01 

0.49 ± 0.08 

2.77 ± 0.25 

0.07 ± 0.02 

0.04 ± 0.02 

0.51 ± 0.12 

2.57 ± 0.27 

0.04 ± 0.01 

0.04 ± 0.01 

0.67 ± 0.12 

2.93 ± 0.26 

0.08 ± 0.01 

0.04 ± 0.01 

0.65 ± 0.12 

2.14 ± 0.28** 

0.07 ± 0.01 

0.03 ± 0.01 

0.82 ± 0.13 

2.25 ± 0.31** 

0.05 ± 0.01 

0.04 ± 0.02 

Urinalysis 

n 10 10 9 10 10 10 

Fluoride (μg/16 hr) 1.35 ± 0.10b 19.68 ± 3.15**c 18.06 ± 4.66**d 25.94 ± 3.62** 56.48 ± 11.66** 66.20 ± 6.15** 

Glucose (mg/16 hr) 0.16 ± 0.01 0.13 ± 0.02 0.09 ± 0.02 0.13 ± 0.01 0.12 ± 0.03 0.16 ± 0.02 

Protein (mg/16 hr) 1 ± 0 1 ± 0 1 ± 0 1 ± 0 2 ± 0 2 ± 0 

Volume (mL/16 hr) 

Specific gravity 

2.4 ± 0.5 

1.027 ± 0.002 

1.2 ± 0.3 

1.038 ± 0.004b 

0.8 ± 0.2 

1.039 ± 0.004 

2.0 ± 0.4 

1.025 ± 0.002 

5.9 ± 1.2 

1.013 ± 0.002** 

5.6 ± 0.8 

1.015 ± 0.003** 
271 

10 

c 

Tetrafluoroethylene, NTP TR 450 

TABLE G5
 

Hematology and Urinalysis Data for Mice in the 13-Week Inhalation Study of Tetrafluoroethylene (continued)
 

0 ppm 312 ppm 625 ppm 1,250 ppm 2,500 ppm 5,000 ppm 

Female 

n 10 10 10 10 10 

Hematology 

Hematocrit (%) 49.1 ± 0.5 48.8 ± 0.3 48.4 ± 0.3 49.5 ± 0.3 48.3 ± 0.5 47.1 ± 0.5**
 

Hemoglobin (g/dL) 16.4 ± 0.2 16.4 ± 0.1 16.3 ± 0.1 16.3 ± 0.1 16.2 ± 0.2 15.8 ± 0.1**
 6 Erythrocytes (10 /μL) 10.20 ± 0.09 10.27 ± 0.07 10.16 ± 0.07 10.29 ± 0.06 10.17 ± 0.10 9.93 ± 0.11 3 Reticulocytes (10 /μL) 111 ± 40 113 ± 39 90 ± 42 108 ± 61 132 ± 51 117 ± 52 

Howell-Jolly bodies

 (% erythrocytes) 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 

Mean cell volume (fL) 48.1 ± 0.2 47.6 ± 0.3 47.7 ± 0.3 48.1 ± 0.3 47.6 ± 0.2 47.4 ± 0.3 

Mean cell hemoglobin (pg) 16.1 ± 0.1 16.0 ± 0.1 16.0 ± 0.1 15.9 ± 0.1 15.9 ± 0.1 15.9 ± 0.1 

Mean cell hemoglobin

 concentration (g/dL) 33.4 ± 0.2 33.7 ± 0.1 33.6 ± 0.1 33.0 ± 0.2 33.5 ± 0.2 33.6 ± 0.1 3 Platelets (10 /μL) 899.1 ± 24.7 893.5 ± 14.5 901.0 ± 17.2 868.1 ± 17.4 911.2 ± 20.2 945.1 ± 21.2 3 Leukocytes (10 /μL) 3.80 ± 0.25 3.18 ± 0.14* 3.17 ± 0.23* 3.36 ± 0.26 2.62 ± 0.30** 2.97 ± 0.21** 

Segmented neutrophils 3 (10 /μL) 0.59 ± 0.08 0.50 ± 0.06 0.30 ± 0.03* 0.44 ± 0.05 0.39 ± 0.09 0.42 ± 0.07 3 Lymphocytes (10 /μL) 3.11 ± 0.22 2.62 ± 0.11 2.78 ± 0.24 2.76 ± 0.21 2.15 ± 0.21** 2.41 ± 0.19** 

Monocytes (10 3/μL) 0.03 ± 0.02 0.03 ± 0.01 0.02 ± 0.01 0.07 ± 0.02 0.06 ± 0.02 0.10 ± 0.03 3 Eosinophils (10 /μL) 0.07 ± 0.02 0.03 ± 0.01 0.05 ± 0.02 0.08 ± 0.02 0.02 ± 0.01 0.04 ± 0.01 

Urinalysis 

b b Fluoride (μg/16 hr) 1.01 ± 0.07 7.79 ± 2.20** 12.05 ± 2.73** 8.74 ± 1.38** 19.34 ± 3.65** 23.94 ± 1.72** 

Glucose (mg/16 hr) 0.12 ± 0.02 0.13 ± 0.02 0.12 ± 0.02 0.13 ± 0.02 0.18 ± 0.03 0.22 ± 0.02* 

Protein (mg/16 hr) 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 1 ± 0 

Volume (mL/16 hr) 1.1 ± 0.2 1.2 ± 0.3 1.0 ± 0.1 1.1 ± 0.2 3.9 ± 0.8* 6.4 ± 1.0** 

Specific gravity 1.025 ± 0.003 1.025 ± 0.003 1.027 ± 0.003 1.022 ± 0.002 1.012 ± 0.002** 1.008 ± 0.001** 

* Statistically 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
 

n=7
 d n=5 
272 Tetrafluoroethylene, NTP TR 450 
273 

APPENDIX H 

REPRODUCTIVE TISSUE EVALUATIONS 

AND ESTROUS CYCLE CHARACTERIZATION 

TABLE H1 Summary of Reproductive Tissue Evaluations 

for Male Rats in the 13-Week Inhalation Study of Tetrafluoroethylene ................... 274 

TABLE H2 Summary of Estrous Cycle Characterization 

for Female Rats in the 13-Week Inhalation Study of Tetrafluoroethylene ................. 274 

TABLE H3 Summary of Reproductive Tissue Evaluations 

for Male Mice in the 13-Week Inhalation Study of Tetrafluoroethylene .................. 275 

TABLE H4 Summary of Estrous Cycle Characterization 

for Female Mice in the 13-Week Inhalation Study of Tetrafluoroethylene ................. 275 
274 Tetrafluoroethylene, NTP TR 450 

TABLE H1 

Summary of Reproductive Tissue Evaluations for Male Rats in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 1,250 ppm 5,000 ppm 

n 10 10 10 10 

Weights (g) 

Necropsy body wt 329 ± 5 343 ± 5 333 ± 4 301 ± 5** 

R. cauda 0.170 ± 0.004 0.175 ± 0.004 0.161 ± 0.004 0.161 ± 0.005 

R. epididymis 0.472 ± 0.008 0.479 ± 0.010 0.469 ± 0.010 0.477 ± 0.009 

R. testis 1.384 ± 0.023 1.412 ± 0.029 1.375 ± 0.031 1.417 ± 0.020 

Epididymal spermatozoal parameters 

Abnormal sperm (%) 0.680 ± 0.085 0.480 ± 0.080 0.640 ± 0.088 0.600 ± 0.107 

Motility (%) 82.22 ± 1.29 80.60 ± 1.63 79.42 ± 1.96 80.21 ± 0.76 

Concentration

 (10 /g cauda epididymal tissue) 6 452 ± 25 445 ± 21 408 ± 34 426 ± 20 

** Significantly different (P 0.01) from the control group by Williams' test a Data are presented as mean ± standard error. Differences from the control group were not significant by Dunnett's test (organ weights) or Dunn's test (epididymal 

spermatozoal parameters). 

TABLE H2 

Summary of Estrous Cycle Characterization for Female Rats in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 1,250 ppm 5,000 ppm 

n 10 10 10 10 

Necropsy body wt (g) 189 ± 5 198 ± 3 194 ± 4 173 ± 4* 

Estrous cycle length (days) 4.70 ± 0.21 5.10 ± 0.18 5.00 ± 0.27b 5.43 ± 0.43c 

Estrous stage (% of cycle) 

Diestrus 38.6 42.9 35.7 51.4 

Proestrus 14.3 12.9 11.4 21.4 

Estrus 21.4 27.1 27.1 14.3 

Metestrus 24.3 17.1 25.7 12.9 

Unclear diagnosis 1.4 0.0 0.0 0.0 

* Significantly different (P 0.05) from the control group by Williams' 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 groups do not differ significantly from the control group in the relative length of time spend 

in the estrous stages. b Estrous cycle was longer than 12 days or unclear in 2 of 10 animals.
 

Estrous cycle was longer than 12 days or unclear in 3 of 10 animals.
 c 
Tetrafluoroethylene, NTP TR 450 275 

TABLE H3 

Summary of Reproductive Tissue Evaluations for Male Mice in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 1,250 ppm 5,000 ppm 

n 10 10 10 10 

Weights (g) 

Necropsy body wt 36.2 ± 0.7 35.3 ± 0.5 34.6 ± 0.5* 32.1 ± 0.5** 

R. cauda 0.016 ± 0.001 0.017 ± 0.001 0.016 ± 0.000 0.014 ± 0.000* 

R. epididymis 0.049 ± 0.002 0.048 ± 0.001 0.047 ± 0.001 0.045 ± 0.002 

R. testis 0.117 ± 0.003 0.117 ± 0.002 0.118 ± 0.001 0.112 ± 0.003 

Epididymal spermatozoal parameters 

Abnormal sperm (%) 1.100 ± 0.141b 0.920 ± 0.108 1.360 ± 0.168 0.860 ± 0.116 

Motility (%) 75.36 ± 4.15 73.56 ± 2.02 70.08 ± 1.26* 69.89 ± 2.60 

Concentration

 (10 /g cauda epididymal tissue) 6 976 ± 134b 1,010 ± 62 921 ± 72 947 ± 101 

* Significantly different (P 0.05) from the control group by Williams' test (body weights), Dunnett's test (organ weights), or Dunn's test (epididymal spermatozoal 

parameters) 

** Significantly different (P 0.01) from the control group by Williams' test a Data are presented as mean ± standard error. b n=8 

TABLE H4 

Summary of Estrous Cycle Characterization for Female Mice in the 13-Week Inhalation Study 

of Tetrafluoroethylene a 

0 ppm 312 ppm 1,250 ppm 5,000 ppm 

n 10 10 10 10 

Necropsy body wt (g) 31.5 ± 0.7 30.8 ± 0.8 29.8 ± 0.6 29.2 ± 0.5 

Estrous cycle length (days) 4.33 ± 0.24b 4.88 ± 0.23c 4.56 ± 0.18b 5.22 ± 0.28b 

Estrous stage (% of cycle) 

Diestrus 34.3 42.9 34.3 31.4 

Proestrus 18.6 11.4 22.9 20.0 

Estrus 28.6 30.0 22.9 27.1 

Metestrus 18.6 15.7 20.0 21.4 

a Necropsy body weight and estrous cycle length data are presented as mean ± standard error. Differences from the control group for body weights were not significant 

by Dunnett's test. Differences from the control group for estrous cycle length are not significant by Dunn's test. By multivariate analysis of variance, exposed groups 

do not differ significantly from the control group in the relative length of time spend 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 10 animals.
 c 
276 Tetrafluoroethylene, NTP TR 450 
277 

APPENDIX I 

CHEMICAL CHARACTERIZATION AND 

GENERATION OF CHAMBER CONCENTRATIONS 

PROCUREMENT AND CHARACTERIZATION OF TETRAFLUOROETHYLENE ................................. 278 

VAPOR GENERATION AND EXPOSURE SYSTEM ...................................................... 279 

VAPOR CONCENTRATION MONITORING ........................................................... 279 

CHAMBER ATMOSPHERE CHARACTERIZATION ..................................................... 279 

FIGURE I1 Infrared Absorption Spectrum of Tetrafluoroethylene ................................. 281 

FIGURE I2 Schematic of the Generation and Delivery System .................................... 282 

FIGURE I3 Schematic of the Exposure Chambers ............................................... 283 

FIGURE I4 16-Day and 13-Week Inhalation Suite ............................................... 284 

FIGURE I5 2-Year Inhalation Suite ........................................................... 285 

FIGURE I6 Schematic of the Concentration Monitoring System ................................... 286 

TABLE I1 Summary of Chamber Concentrations in the 16-Day Inhalation Studies 

of Tetrafluoroethylene ............................................................ 287 

TABLE I2 Summary of Chamber Concentrations in the 13-Week Inhalation Studies 

of Tetrafluoroethylene ............................................................ 287 

TABLE I3 Summary of Chamber Concentrations in the 2-Year Inhalation Studies 

of Tetrafluoroethylene ............................................................ 288 

FIGURE I7 Monthly Mean Concentrations and Standard Deviations 

in the 156 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study .............................................................. 289 

FIGURE I8 Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study .............................................................. 290 

FIGURE I9 Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study .............................................................. 291 

FIGURE I10 Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study .............................................................. 292 

FIGURE I11 Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study .............................................................. 293 

FIGURE I12 Monthly Mean Concentrations and Standard Deviations 

in the 1,250 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study .............................................................. 294 

FIGURE I13 Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study .............................................................. 295 

FIGURE I14 Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study .............................................................. 296 

FIGURE I15 Monthly Mean Concentrations and Standard Deviations 

in the 1,250 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study .............................................................. 297 
278 Tetrafluoroethylene, NTP TR 450 

CHEMICAL CHARACTERIZATION AND 

GENERATION OF CHAMBER CONCENTRATIONS 

PROCUREMENT AND CHARACTERIZATION OF TETRAFLUOROETHYLENE 

Tetrafluoroethylene was obtained from SCM Specialty Chemicals (Gainesville, FL) in one lot (10271), which was used for the 

identity and purity analyses conducted by the analytical chemistry laboratory, Midwest Research Institute (Kansas City, MO). 

Tetrafluoroethylene was also obtained from ICI Americas, Inc. (Bayonne, NJ), in five lots. The study laboratory assigned a lot 

number to each shipment of as many as 12 cylinders. Lot 12017-8 was used during the 16-day studies and during most of the 

13-week studies; lot 12017-77 was used during the remainder of the 13-week studies; and lots 12438-6, 12438-79, and 

12438-92 were used during the 2-year studies. Identity and purity analyses were also conducted by the study laboratory on each 

lot used during the studies. Reports on analyses performed in support of the tetrafluoroethylene studies are on file at the 

National Institute of Environmental Health Sciences. 

Each lot of the chemical, a colorless gas, was identified as tetrafluoroethylene by the analytical chemistry or study laboratory 

using infrared spectroscopy. The infrared spectrum for each lot was consistent with that expected for the structure of 

tetrafluoroethylene (Figure I1). 

The purity of lot 10271 was determined by the analytical chemistry laboratory using gas chromatography. The purity of lots 

12017-8, 12017-77, 12438-6, 12438-79, and 12438-92 was determined by the study laboratory using gas chromatography. Gas 

chromatography of each lot was conducted using a flame ionization detector with a nitrogen carrier gas at a flow rate of 

70 mL/minute, a 60/80 Carbopack B/1% glass column, and an oven temperature program of 35 C for 5 minutes, then 35 to 

200 C at 10 C per minute. 

Gas chromatography of lot 10271 indicated one major peak and one impurity with an area greater than or equal to 0.1% relative 

to the major peak. In addition, analysis for d-limonene, which is added to tetrafluoroethylene as a stabilizer, was conducted by 

the analytical chemistry laboratory using gas chromatography with the same system as that used for the purity analyses but with a 

10% SP-2100 on 100/120 Supelcoport glass column and an oven temperature program of 50 C for 5 minutes, then 50 to 

250 C at 10 C per minute. The sample contained 0.03% ± 0.00% d-limonene. Gas chromatography conducted by the study 

laboratory for each cylinder of lots 12017-8 and 12017-77 indicated that perfluorocyclobutane, the most abundant dimer 

produced during tetrafluoroethylene decomposition, was present at concentrations less than or equal to 462 ppm and 2,604 ppm 

for the 16-day and 13-week studies, respectively. For lots 12438-6, 12438-79, and 12438-92, gas chromatography indicated 

peaks for perfluorocyclobutane with areas less than or equal to 1.21% relative to the major peak. Gas chromatography 

conducted by the study laboratory for each cylinder of lots 12017-8 and 12017-77 indicated that d-limonene was present at 

concentrations less than or equal to 2,837 ppm for the 13-week studies. During the 2-year studies, gas chromatography of 

lots 12438-6, 12438-79, and 12438-92 indicated peaks for d-limonene with areas less than or equal to 0.56% relative to the 

major peak. The manufacturer indicated that trifluoroethylene, methylene fluoride, vinyl fluoride, and vinylidene fluoride were 

also present as impurities at concentrations less than or equal to 1.7 ppm. The overall purities of lots 12017-8, 12017-77, and 

12438-92 were determined to be greater than 99%. The overall purities of lots 12438-6 and 12438-79 were determined to be 

greater than 98%. 

The manufacturer indicated that tetrafluoroethylene would be stable for up to 1 year when stored in the original containers at 

room temperature. To ensure stability, the bulk chemical was stored in the original metal cylinders at 10 to 22 C. Stability 

was monitored during the 13-week and 2-year studies using the same gas chromatography system used for the purity analyses. 

The relative concentrations of perfluorocyclobutane were expected to increase due to the slow dimerization of tetrafluoroethylene, 

and therefore the gas cylinders were monitored for this dimer as well as for d-limonene during the 2-year studies. Two cylinders 

from lot 12438-6 contained higher concentrations of these compounds than canisters from the same lot that were analyzed earlier 

in the studies. One of these two cylinders, which contained 1.21% perfluorocyclobutane and 0.56% d-limonene, was replaced 

immediately after gas chromatographic analysis was performed; it is not known if the dimer formed in the canister due to 

degradation of tetrafluoroethylene or was present as an impurity at receipt. Stability was generally considered acceptable 

throughout the studies. 
Tetrafluoroethylene, NTP TR 450 279 

VAPOR GENERATION AND EXPOSURE SYSTEM 

A diagram of the tetrafluoroethylene generation and delivery system is shown in Figure I2. Because tetrafluoroethylene is a gas 

at room temperature, the system incorporated gas distribution under regulated pressure with individual adjustment and 

monitoring of the chemical flow rate to each chamber. Tetrafluoroethylene was taken directly from the cylinder in which it was 

shipped. The output pressure from the cylinder was regulated to 20 psi with a two-stage regulator. The gas was passed through 

a main exposure pneumatic valve, a check valve, and a filter to a manifold of five (16-day and 13-week studies) or six (2-year 

studies) flow meters with integral metering valves. The gas was metered to each exposure chamber through these flow meters, 

which were monitored by a pressure gauge at the manifold. A three-way solenoid valve was located in the gas delivery line to 

each exposure chamber. This valve and a nitrogen inlet valve just downstream from the main exposure valve allowed the system 

to be purged with nitrogen at the end of each exposure period. A sample line was included downstream from each gas cylinder. 

All equipment that came in contact with the tetrafluoroethylene gas was stainless steel, polytetrafluoroethylene, Viton® (E.I. 

DuPont de Nemours, Wilmington, DE), or glass. 

Stainless-steel chambers designed at Battelle Pacific Northwest Laboratories were used for all studies (Figure I3). The total 3 3 volume of each chamber was 2.3 m ; the active mixing volume of each chamber was 1.7 m . The chamber was designed so that 

uniform aerosol or vapor concentrations could be maintained throughout the chamber when the catch pans were in position, 

provided the aerosol or vapor was uniformly mixed with dilution air before entering the chamber. A diagram of the 16-day and 

13-week exposure suite is shown in Figure I4, and a diagram of the 2-year exposure suite is shown in Figure I5. 

VAPOR CONCENTRATION MONITORING 

A diagram of the tetrafluoroethylene concentration monitoring system used in all studies is shown in Figure I6. The 

concentrations of tetrafluoroethylene were monitored using an on-line gas chromatograph with a flame ionization detector, an 

80/100 Porapack Q nickel column, and a nitrogen carrier gas at a flow rate of 22 mL/minute. Samples were drawn and analyzed 

from each exposure chamber, the control chamber, the exposure suite, and an on-line standard using an automatic 8-port (16-day 

and 13-week studies) or 12-port (2-year studies) sample valve. Certified standards of tetrafluoroethylene in nitrogen (Byrne 

Specialty Gases, Inc., Seattle, WA; MG Industries Scientific Gases, Los Angeles, CA; Phoenix Distributors, Inc., Los Angeles, 

CA) were used to perform the absolute calibration of the on-line gas chromatograph and to check instrument drift throughout the 

exposure periods. Summaries of the chamber concentrations during the studies are presented in Tables I1 through I3. The 

monthly mean exposure concentrations for the 2-year studies are presented in Figures I7 through I15. 

CHAMBER ATMOSPHERE CHARACTERIZATION 

The times for the exposure concentration to build up to 90% of the final exposure concentration (T 90 ) and to decay to 10% of the

exposure concentration (T ) were measured in all studies with and without animals present. During the 16-day studies, T was 10 90 

approximately 12 minutes and T10 was approximately 9 minutes with and without animals in the chambers. During the 13-week 

studies, T90 was 11 minutes with animals in the chambers and ranged from 11 to 14 minutes without animals; T10 ranged from 9

to 11 minutes with and without animals in the chambers. During the 2-year studies, T 90 ranged from 8 to 10 minutes without 

animals in the chambers and from 10 to 16 minutes with animals present; T 10 ranged from 7 to 9 minutes without animals and 

from 9 to 12 minutes with animals. The T90 value used for all studies was 12 minutes. 

Uniformity of tetrafluoroethylene concentration in the exposure chambers was measured prior to the start of all studies, once 

during the 16-day and 13-week studies, and approximately every 3 months during the 2-year studies. The concentration was 

measured with and without animals present using the on-line gas chromatograph with the automatic 8-port (16-day and 13-week 

studies) or 12-port (2-year studies) sample valve disabled to allow continuous monitoring from a single input line. Uniformity of 

exposure concentrations in all chambers was acceptable. 

The persistence of tetrafluoroethylene in the 1,250 ppm exposure chamber after shutting off the system was monitored without 

animals before the 2-year studies began and with animals present during the 2-year studies. The concentration of 
280 Tetrafluoroethylene, NTP TR 450 

tetrafluoroethylene in the exposure chamber fell rapidly to less than 1% of the beginning concentration within 20 minutes. 

Tetrafluoroethylene concentrations in the building exhaust and room air were also monitored during all studies. 

Information supplied by the manufacturer indicated that all cylinders contained d-limonene as a stabilizer. d-Limonene and 

perfluorocyclobutane are less volatile than tetrafluoroethylene and concentrate in the cylinder as the tetrafluoroethylene is 

removed. Cylinder usage was regulated to minimize concentrations of these chemicals in the exposure chambers; a maximum of 

80% of the tetrafluoroethylene in each cylinder was used. Gas chromatography of chamber samples did not indicate any 

impurities other than perfluorocyclobutane and d-limonene. Concurrent analysis of cylinder headspace and chamber samples for 

perfluorocyclobutane demonstrated that chamber concentrations of perfluorocyclobutane matched those in the cylinder 

headspace. The contents of selected used cylinders were analyzed for d-limonene and perfluorocyclobutane. The results 

indicated that tetrafluoroethylene was stable during generation and in the exposure chambers and that perfluorocyclobutane was 

not formed in significant quantities by the generation system. As expected, the headspace concentrations of d-limonene and 

perfluorocyclobutane in the cylinders increased as tetrafluoroethylene was removed. 
281 Tetrafluoroethylene, NTP TR 450
 

FIGURE I1 

Infrared Absorption Spectrum of Tetrafluoroethylene 
282 Tetrafluoroethylene, NTP TR 450
 

FIGURE I2 

Schematic of the Generation and Delivery System 
283 Tetrafluoroethylene, NTP TR 450
 

FIGURE I3 

Schematic of the Exposure Chambers 
284 Tetrafluoroethylene, NTP TR 450
 

FIGURE I4 

16-Day and 13-Week Inhalation Suite 
285 Tetrafluoroethylene, NTP TR 450
 

FIGURE I5 

2-Year Inhalation Suite 
286 Tetrafluoroethylene, NTP TR 450
 

FIGURE I6 

Schematic of the Concentration Monitoring System 
Tetrafluoroethylene, NTP TR 450 287 

TABLE I1 

Summary of Chamber Concentrations in the 16-Day Inhalation Studies of Tetrafluoroethylene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Rat Chambers 

312 

625 

1,250 

2,500 

5,000 

250 

250 

252 

253 

255 

312 ± 6.21 

621 ± 9.66 

1,250 ± 19.2 

2,500 ± 33.9 

4,990 ± 6.19 

Mouse Chambers 

312 

625 

1,250 

2,500 

5,000 

250 

249 

252 

253 

255 

312 ± 5.60 

622 ± 9.40 

1,260 ± 19.2 

2,500 ± 34.1 

4,990 ± 59.4 

a Mean ± standard deviation 

TABLE I2 

Summary of Chamber Concentrations in the 13-Week Inhalation Studies of Tetrafluoroethylene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Rat Chambers 

312 

625 

1,250 

2,500 

5,000 

1,107 

1,106 

1,146 

1,154 

1,149 

314 ± 9.3 

628 ± 16 

1,260 ± 40 

2,520 ± 77 

5,050 ± 136 

Mouse Chambers 

312 

625 

1,250 

2,500 

5,000 

1,104 

1,103 

1,145 

1,153 

1,147 

314 ± 9.4 

627 ± 16 

1,260 ± 35 

2,520 ± 67 

5,050 ± 128 

Mean ± standard deviation a 
288 Tetrafluoroethylene, NTP TR 450 

TABLE I3 

Summary of Chamber Concentrations in the 2-Year Inhalation Studies of Tetrafluoroethylene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Male Rat Chambers 

156 

312 

625 

6,470 

6,523 

6,533 

155 ± 7 

312 ± 12 

623 ± 24 

Female Rat Chambers 

312 

625 

1,250 

6,106 

6,146 

6,154 

312 ± 10 

625 ± 20 

1,250 ± 43 

Mouse Chambers 

312 

625 

1,250 

5,577 

5,619 

5,633 

311 ± 10 

625 ± 19 

1,250 ± 42 

Mean ± standard deviation a 
1 Tetrafluoroethylene, NTP TR 450 

FIGURE I7 

Monthly Mean Concentrations and Standard Deviations 

in the 156 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study 
Tetrafluoroethylene, NTP TR 450 2 

FIGURE I8 

Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study 
3 Tetrafluoroethylene, NTP TR 450 

FIGURE I9 

Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Male Rat Exposure Chamber 

for the 2-Year Study 
Tetrafluoroethylene, NTP TR 450 4 

FIGURE I10 

Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study 
5 Tetrafluoroethylene, NTP TR 450 

FIGURE I11 

Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study 
Tetrafluoroethylene, NTP TR 450 6 

FIGURE I12 

Monthly Mean Concentrations and Standard Deviations 

in the 1,250 ppm Tetrafluoroethylene Female Rat Exposure Chamber 

for the 2-Year Study 
7 Tetrafluoroethylene, NTP TR 450 

FIGURE I13 

Monthly Mean Concentrations and Standard Deviations 

in the 312 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study 
Tetrafluoroethylene, NTP TR 450 8 

FIGURE I14 

Monthly Mean Concentrations and Standard Deviations 

in the 625 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study 
9 Tetrafluoroethylene, NTP TR 450 

FIGURE I15 

Monthly Mean Concentrations and Standard Deviations 

in the 1,250 ppm Tetrafluoroethylene Mouse Exposure Chamber 

for the 2-Year Study 
298 Tetrafluoroethylene, NTP TR 450 
299 

APPENDIX J 

INGREDIENTS, NUTRIENT COMPOSITION, 

AND CONTAMINANT LEVELS 

IN NIH-07 RAT AND MOUSE RATION 

TABLE J1 

TABLE J2 

TABLE J3 

TABLE J4 

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

300 

300 

301 

302 
300 Tetrafluoroethylene, NTP TR 450 

TABLE J1 

Ingredients of NIH-07 Rat and Mouse Ration a 

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 J2 

Vitamins and Minerals in NIH-07 Rat and Mouse Ration a 

Amount Source 

Vitamins 

A 5,500,000 IU Stabilized vitamin A palmitate or acetate 

D3 4,600,000 IU D-activated animal sterol 

K3 2.8 g Menadione 

d­ -Tocopheryl acetate 20,000 IU 

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 4,000 μg 

Pyridoxine 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 
Tetrafluoroethylene, NTP TR 450 301 

TABLE J3 

Nutrient Composition of NIH-07 Rat and Mouse Ration 

Mean ± Standard 

Nutrient Deviation Range Number of Samples 

Protein (% by weight) 22.97 ± 0.81 21.7 )24.2 24 

Crude fat (% by weight) 5.37 ± 0.32 4.60 )5.90 24 

Crude fiber (% by weight) 3.66 ± 0.39 2.80 )4.20 24 

Ash (% by weight) 6.62 ± 0.31 6.11 )7.30 24 

Amino Acids (% of total diet) 

Arginine 1.280 ± 0.083 1.110 )1.390 11 

Cystine 0.308 ± 0.071 0.181 )0.400 11 

Glycine 1.158 ± 0.048 1.060 )1.220 11 

Histidine 0.584 ± 0.027 0.531 )0.630 11 

Isoleucine 0.917 ± 0.033 0.867 )0.965 11 

Leucine 1.975 ± 0.051 1.850 )2.040 11 

Lysine 1.274 ± 0.049 1.200 )1.370 11 

Methionine 0.437 ± 0.109 0.306 )0.699 11 

Phenylalanine 0.999 ± 0.120 0.665 )1.110 11 

Threonine 0.904 ± 0.058 0.824 )0.985 11 

Tryptophan 0.218 ± 0.153 0.107 )0.671 11 

Tyrosine 0.685 ± 0.094 0.564 )0.794 11 

Valine 1.086 ± 0.055 0.962 )1.170 11 

Essential Fatty Acids (% of total diet) 

Linoleic 2.407 ± 0.227 1.830 )2.570 10 

Linolenic 0.259 ± 0.065 0.100 )0.320 10 

Vitamins 

Vitamin A (IU/kg) 6,771 ± 1,915 4,180 )12,140 24 

Vitamin D (IU/kg) 4,450 ± 1,382 3,000 )6,300 4 

-Tocopherol (ppm) 36.12 ± 9.15 22.5 )48.9 10 

Thiamine (ppm) 19.00 ± 2.36 16.0 )28.0 24 

Riboflavin (ppm) 7.83 ± 0.92 6.10 )9.00 11 

Niacin (ppm) 98.64 ± 25.51 65.0 )150.0 10 

Pantothenic acid (ppm) 30.55 ± 3.52 23.0 )34.6 11 

Pyridoxine (ppm) 9.11 ± 2.53 5.60 )14.0 11 

Folic acid (ppm) 2.46 ± 0.63 1.80 )3.70 11 

Biotin (ppm) 0.268 ± 0.047 0.190 )0.354 11 

Vitamin B12 (ppb) 40.5 ± 19.1 10.6 )65.0 11 

Choline (ppm) 2,991 ± 382 2,400 )3,430 10 

Minerals 

Calcium (%) 1.25 ± 0.11 1.10 )1.54 24 

Phosphorus (%) 0.95 ± 0.032 0.890 )1.00 24 

Potassium (%) 0.886 ± 0.063 0.772 )0.971 9 

Chloride (%) 0.529 ± 0.087 0.380 )0.635 9 

Sodium (%) 0.316 ± 0.033 0.258 )0.371 11 

Magnesium (%) 0.166 ± 0.010 0.148 )0.181 11 

Sulfur (%) 0.272 ± 0.059 0.208 )0.420 10 

Iron (ppm) 350.5 ± 87.3 255.0 )523.0 11 

Manganese (ppm) 92.48 ± 5.14 81.7 )99.4 11 

Zinc (ppm) 59.33 ± 10.2 46.1 )81.6 11 

Copper (ppm) 11.81 ± 2.50 8.09 )15.4 11 

Iodine (ppm) 3.54 ± 1.19 1.52 )5.83 10 

Chromium (ppm) 1.66 ± 0.46 0.85 )2.09 11 

Cobalt (ppm) 0.76 ± 0.23 0.49 )1.15 7 
302 Tetrafluoroethylene, NTP TR 450 

TABLE J4 

Contaminant Levels in NIH-07 Rat and Mouse Ration a 

Mean ± Standard 

Deviationb Range Number of Samples 

Contaminants 

Arsenic (ppm) 0.23 ± 0.17 0.05 )0.60 24 

Cadmium (ppm) 0.09 ± 0.02 0.05 )0.10 24 

Lead (ppm) 0.24 ± 0.18 0.10 )1.00 24 

Mercury (ppm) 0.05 ± 0.02 0.02 )0.11 24 

Selenium (ppm) 0.40 ± 0.20 0.16 )1.21 24 c Aflatoxins (ppb) <5.0 23 

d Nitrate nitrogen (ppm) 16.60 ± 4.13 8.60 )24.0 24 

d Nitrite nitrogen (ppm) 0.20 ± 0.17 0.10 )0.60 24 e BHA (ppm) 1.54 ± 0.65 0.10 )3.00 24 e BHT (ppm) 1.30 ± 0.62 0.10 )3.00 24 

Aerobic plate count (CFU/g) 46,404 ± 24,682 6,700 )120,000 24 

Coliform (MPN/g) 50 ± 224 3 )1,100 24 

Escherichia coli (MPN/g) 3 ± 0.2 3 )4 24 

Salmonella (MPN/g) Negative 24 

f Total nitrosoamines (ppb) 8.05 ± 3.23 3.60 )16.50 24 

f N-Nitrosodimethylamine (ppb) 5.85 ± 2.71 2.60 )13.00 24 

f N-Nitrosopyrrolidine (ppb) 2.20 ± 1.25 0.90 )5.20 24 

Pesticides (ppm) 

-BHC <0.01 24 

-BHC <0.02 24 

-BHC <0.01 24 

-BHC <0.01 24 

Heptachlor <0.01 24 

Aldrin <0.01 24 

Heptachlor epoxide <0.01 24 

DDE <0.01 24 

DDD <0.01 24 

DDT <0.01 24 

HCB <0.01 24 

Mirex <0.01 24 

Methoxychlor <0.05 24 

Dieldrin <0.01 24 

Endrin <0.01 24 

Telodrin <0.01 24 

Chlordane <0.05 24 

Toxaphene <0.10 24 

Estimated PCBs <0.20 24 

Ronnel <0.01 24 

Ethion <0.02 24 

Trithion <0.05 24 

Diazinon <0.10 24 

Methyl parathion <0.02 24 

Ethyl parathion <0.02 24 

Malathion 0.24 ± 0.23 0.05 )1.00 24 

Endosulfan I <0.01 24 

Endosulfan II <0.01 24 

Endosulfan sulfate <0.03 24 

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.
 

No aflatoxin measurement was recorded for the lot milled on 2 October 1989.
 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 
APPENDIX K 

SENTINEL ANIMAL PROGRAM 

METHODS ......................................................................................... 

TABLE K1 Murine Virus Antibody Determinations for Rats and Mice 

in the 13-Week and 2-Year Studies of Tetrafluoroethylene .................................. 

304 

306 
304 Tetrafluoroethylene, NTP TR 450 

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 

RATS 

13-Week Study 

ELISA 

Mycoplasma arthritidis Study termination 

Mycoplasma pulmonis Study termination 

PVM (pneumonia virus of mice) Study termination 

RCV/SDA

 (rat coronavirus/sialodacryoadenitis virus) 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 

M. arthritidis 22 and 24 months 

M. pulmonis 22 and 24 months 

PVM 6, 12, 18, 22, and 24 months 

RCV/SDA 6, 12, 18, 22, and 24 months 

Sendai 6, 12, 18, 22, and 24 months 

Hemagglutination Inhibition 

H-1 6, 12, 18, 22, and 24 months 

KRV 6, 12, 18, 22, and 24 months 
Tetrafluoroethylene, NTP TR 450 305 

MICE 

13-Week Study 

Complement Fixation 

LCM (lymphocytic choriomeningitis virus) 

ELISA 

Ectromelia virus 

GDVII (mouse encephalomyelitis virus) 

Mouse adenoma virus 

MHV (mouse hepatitis virus) 

M. arthritidis 

M. pulmonis 

PVM
 

Reovirus 3
 

Sendai
 

Immunofluorescence Assay 

EDIM (epizootic diarrhea of infant mice) 

Hemagglutination Inhibition 

K (papovavirus) 

MVM (minute virus of mice) 

Polyoma virus 

2-Year Study 

ELISA 

Ectromelia virus 

EDIM 

GDVII 

LCM 

MVM 

Mouse adenoma virus 

MHV 

M. arthritidis 

M. pulmonis 

PVM
 

Reovirus 3
 

Sendai
 

Immunofluorescence Assay 

EDIM 

LCM 

Reovirus 3 

MVM 

Mouse adenoma virus 

Hemagglutination Inhibition 

K 

MVM 

Polyoma virus 

Results of serology tests are presented in Table K1. 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

Study termination 

6, 12, 18, and 22 months 

22 months 

6, 12, 18, and 22 months 

18 and 22 months 

6 and 12 months 

6, 12, 18, and 22 months 

6, 12, 18, and 22 months 

22 months 

22 months 

6, 12, 18, and 22 months 

6, 12, 18, and 22 months 

6, 12, 18, and 22 months 

6, 12, 18, and 22 months 

6 and 12 months 

12 months 

18 and 22 months 

22 months 

6, 12, 18, and 22 months 

18 months 

6, 12, 18, and 22 months 
306 Tetrafluoroethylene, NTP TR 450 

TABLE K1 

Murine Virus Antibody Determinations for Rats and Mice in the 13-Week and 2-Year Studies 

of Tetrafluoroethylene 

Interval Incidence of Antibody Positive Serologic 

in Sentinel Animals Reaction for 

13-Week Studies 

Rats 

Study termination 0/10 None positive 

Mice 

Study termination 0/10 None positive 

2-Year Studies 

Rats 

6 Months 0/10 None positive 

12 Months 0/10 None positive 

18 Months 0/11 None positive 

22 Months 0/2 None positive 

24 Months 2/10 M. arthritidisa 

Mice 

6 Months 0/16 None positive 

12 Months 1/16 Reovirus 3b 

18 Months 0/13 None positive 

22 Months 0/10 None positive 

a Further evaluation of samples positive forM. arthritidis by immunoblot and Western blot procedures indicated that the positive titers may be due to cross reaction 

with antibodies of nonpathogenicMycoplasma or other agents. Only sporadic samples were positive and there were no clinical findings or histopathologic changes of 

M. arthritidis infection in mice with positive titers. Accordingly,M. arthritidis-positive titers were considered to be false positives. b Negative for Reovirus 3 by Western blot; false positive 
307 

APPENDIX L
 

H-RAS CODON 61 MUTATION SPECTRA
 

IN HEPATOCELLULAR NEOPLASMS
 

FROM B6C3F1 MICE EXPOSED

TO TETRAFLUOROETHYLENE FOR 2 YEARS 

Robert C. Sills, H. Lily Hong, Joe Roycroft,
 

Theodora R. Devereux, and Gary A. Boorman
 

National Institute of Environmental Health Sciences
 

Research Triangle Park, North Carolina
 

INTRODUCTION ..................................................................................... 308
 

MATERIALS AND METHODS ........................................................................... 308
 

RESULTS .......................................................................................... 309
 

DISCUSSION ........................................................................................ 309
 

REFERENCES ....................................................................................... 310
 

TABLE L1 H-ras Mutations at Codon 61 in Spontaneously Occurring
 

and Tetrafluoroethylene-Induced Liver Neoplasms from B6C3F 1 Mice ....................... 312 

TABLE L2 Frequency of K- ras Proto-oncogene Activation in Spontaneously Occurring 

and Tetrafluoroethylene-Induced Liver Neoplasms from B6C3F 1 Mice ....................... 312 

TABLE L3 H-ras Mutations at Codon 61 Detected in Hepatocellular Adenomas 

and Carcinomas from B6C3F 1 Mice ..................................................... 313
 
308 Tetrafluoroethylene, NTP TR 450 

H-RAS CODON 61 MUTATION SPECTRA 

IN HEPATOCELLULAR NEOPLASMS 

FROM B6C3F1 MICE EXPOSED

TO TETRAFLUOROETHYLENE FOR 2 YEARS 

INTRODUCTION 

Liver neoplasms are commonly seen in B6C3F1 mice in 2-year inhalation studies, occurring with a typical incidence of 40% in

control males and 20% in control females. Chemical-induced neoplasms in mice have a high frequency of proto-oncogene 

activation, particularly by point mutations in codon 61 of H-ras genes (Maronpot et al., 1995). The frequency of ras activation 

in these neoplasms is often greater than detected in neoplasms occurring in control animals (Reynolds et al., 1987), and there is 

evidence for chemical specificity in the pattern of oncogene activation (Wiseman et al., 1986; Maronpot et al., 1995). The 

specific types of oncogene-activating mutations induced by a chemical carcinogen often agree with what is expected based on the 

DNA adducts formed by the agent (Wiseman et al., 1986). Even for “nongenotoxic carcinogens,” the patterns of ras gene 

mutations in neoplasms can give clues about the mechanism of tumorigenesis (Devereux et al., 1993; Maronpot et al., 1995). 

MATERIALS AND METHODS 

Liver neoplasms: Male and female B6C3F1 mice were exposed to 0, 312, 625, or 1,250 ppm tetrafluoroethylene by inhalation

for 6 hours per day, 5 days per week for 2 years. At necropsy, liver neoplasms were fixed in 10% neutral buffered formalin, 

routinely processed, embedded in paraffin, sectioned to a thickness of 5 μm, and stained with hematoxylin and eosin (H&E). 

Subsequently, six unstained serial sections (10 μm thick) were prepared from paraffin blocks containing hepatocellular 

adenomas or carcinomas for isolation of DNA for polymerase chain reaction (PCR)-based assays. In order to isolate adequate 

amounts of DNA, liver neoplasms greater than 1 mm in diameter were identified for analysis. Based on the size criterion, a total 

of 66 paraffin-embedded neoplasms were examined for genetic alterations in the H- ras gene. These included 53 neoplasms from 

tetrafluoroethylene-exposed mice and 13 neoplasms from control mice. Also, 13 frozen liver neoplasms were evaluated for 

H-ras and K-ras mutations. For the liver neoplasms from which frozen and paraffin-embedded tissue were available, both were 

examined to confirm the results. 

DNA isolation: The DNA isolation procedure is described in Marmur (1961) and in Sills et al. (1995). The paraffin-embedded 

tissue was deparaffinized and rehydrated before digesting with proteinase K (Wright and Manos, 1990). The frozen tumor tissue 

was digested with 10 mg/mL pronase in 1% sodium dodecyl sulfate in TNE buffer (10 mM TRIS; 150 mM NaCl; and 2 mM 

EDTA disodium salt, pH 7.5). DNA was extracted with phenol and chloroform and precipitated with ethanol. DNA was 

quantified by optical density at 260 nm and 200 ng/μL was used for amplification. 

DNA amplification: DNA was amplified by the polymerase chain reaction (Saiki et al., 1988; Sills et al., 1995); details of the 

use of nested primers are described in Devereux et al. (1991, 1993). 

Restriction fragment length polymorphic identification: A “cold” method was employed to identify mutation in the H-ras gene 

at codon 61 from liver neoplasms. This was based on restriction fragment length polymorphism in the DNA containing a CAA 

to AAA, CTA, or CGA mutation in codon 61 of exon 2 (Sukumuar and Barbacid, 1990). The sense primer used for 

amplification of exon 2 was 5 -GACATCTTAGACACAGCAGTT-3 . A restriction site for MSEI, XbaI, or TaqI enzyme (New 

England Biolaboratory, Beverly, MA) is created by the presence of a C to A, A to T, or A to G mutation in the first or second 

base of codon 61, respectively. By using this technique, we detected codon 61 AAA, CTA, and CGA mutations by MSEI, XbaI, 

and TaqI digestion, respectively; the normal sequence (CAA) of codon 61 is not cut by these enzymes. The reaction was 

incubated at 37 C (for MSEI or XbaI) or 60 C (for TaqI) for 2 hours. Fifteen μL of the mixture with bromophenol blue dye 

was loaded onto the 6% acrylamide TBE gel (8 × 8 cm × 1 mm; 15 wells) (Novex, San Diego, CA). The gel was run at 

100 volts for 1 hour on the Novex gel electrophoresis unit. Gels were stained with a 5 μg/mL solution of ethidium bromide for 
Tetrafluoroethylene, NTP TR 450 309 

20 minutes and then destained in distilled water. Ethidium bromide-stained bands were visualized using a 312 nm ultraviolet 

viewing box and were photographed. 

Single-strand conformational analysis: Single-strand conformation analysis (Orita et al., 1989) was performed with PCR 

products into which [ -

33P]dATP was incorporated during the inner amplification. For the first exon of K- ras, 10% acrylamide 

gel containing 10% glycerol and 1X TRIS-borate-EDTA buffer was electrophoresed at room temperature with constant power at 

8 watts for 16 hours on a Model S2 sequencing gel electrophoresis apparatus (Bethesda Research Labs, Gaithersburg, MD). For 

the second exon of H-ras, 12% acrylamide gel with 5% glycerol in 1X TRIS-borate-EDTA buffer was used at 35 watts in a 4 C 

cold room for 5 hours. 

RESULTS 

In order to determine if the tetrafluoroethylene-induced neoplasms contained an H- ras mutation profile similar to that observed 

with ``spontaneous'' neoplasms, sample groups of 29 neoplasms consisting of adenomas and carcinomas from the two highest 

exposure groups, four neoplasms from the low exposure group, and 17 neoplasms from the chamber controls were evaluated by 

polymerase chain reaction amplification of H-ras exon 2 followed by restriction fragment length polymorphism analysis for the 

three common codon 61 mutations in the B6C3F mouse (Table L1). Single-stranded conformation polymorphism was used as 1 

an alternative screening method for detection of H- and K-ras mutations in DNA from 19 neoplasms following 

tetrafluoroethylene exposure and from four chamber controls (Table L2). A low frequency (9/62, 15%) of H- ras mutations was 

detected in hepatocellular neoplasms when compared to the high frequency (10/17 or 59% in controls from the present study and 

183/333 or 56% in historical controls) detected in spontaneous liver neoplasms from B6C3F 1 mice (Table L1). In addition, the

proportion of H-ras mutations in hepatocellular neoplasms was 1:1:1 for codon 61 AAA, CGA, and CTA mutations, 

respectively, when compared to 3:6:1 for controls from the present study or 5:2:1 for spontaneous hepatocellular neoplasms in 

historical controls. There were generally no differences in the mutation frequency and spectrum between exposure groups and 

between benign and malignant hepatocellular neoplasms (Tables L1 and L3). K- ras mutations were not detected in 

hepatocellular neoplasms following tetrafluoroethylene exposure. 

DISCUSSION 

The low frequency (9/62, 15%) of H-ras mutations detected in hepatocellular neoplasms following tetrafluoroethylene exposure 

is similar to that reported with other nongenotoxic agents such as phenobarbital (7%), chloroform (21%), and ciprofibrate (31%) 

when compared to the generally higher frequency (183/333, 56%) observed in spontaneous liver neoplasms from B6C3F 1 mice 

(Fox et al., 1990; Maronpot et al., 1995). Other nongenotoxic hepatocellular carcinogens associated with low frequencies of 

H-ras include hexachlorobenzene (Rumsby et al., 1992), dieldrin, (Bauer-Hofmann et al., 1992), methylclofenapate (Stanley 

et al., 1994), and oxazepam (NTP, 1993). Nongenotoxic agents, by definition, are not positive in in vitro mutation assays, and 

therefore the parent chemical or metabolites do not react with the DNA directly to cause mutations. Our findings of a decreased 

frequency of ras mutations at codon 61 are consistent with the lack of mutagenicity in the Salmonella typhimurium assay and 

suggest that tetrafluoroethylene may be acting in the liver as a nongenotoxic carcinogen. In addition, the finding of no increases 

in the frequency of micronucleated erythrocytes in peripheral blood samples supports this theory. 

The decreased frequency of H-ras mutations in tetrafluoroethylene-induced hepatocellular neoplasms is similar to that detected in 

B6C3F mice exposed to the structurally similar tetrachloroethylene (24%) (Anna et al., 1994). Unlike the lack of K-ras 1 

mutations in the tetrafluoroethylene study, a few K-ras mutations were detected in the tetrachloroethylene study. Data from the 

present study support the hypothesis that the liver tumors induced by these two structurally similar hepatocellular carcinogens 

may be acting via a ras-independent pathway. Recently, chlordane-induced hepatocarcinogenesis in B6C3F 1 mice was shown to 

be independent of ras activation (Malarkey et al., 1995). Alternate pathways such as cytotoxicity followed by enhanced cell 

proliferation may also not be playing a major role in the development of hepatocellular neoplasms with tetrafluoroethylene since 

at 16 days or 13 weeks, there was no evidence of hepatocellular toxicity. Furthermore, since the mutation spectrum at H- ras 

codon 61 was not similar to that of spontaneous hepatocellular neoplasms, the data also argue against the theory that 

tetrafluoroethylene-induced tumors may be acting by a simple promotional mechanism involving ras-mutated cells. If this was 
310 Tetrafluoroethylene, NTP TR 450 

the case, one would expect that a number of the hepatocellular neoplasms would have had similar mutation profiles to those of 

the controls, due to the clonal expansion of spontaneously initiated cells with ras mutations. 

The low frequency of H-ras mutations in the liver is consistent with the findings with various nongenotoxic carcinogens; 

however, the variety of different types of neoplasms in the liver of B6C3F1 mice supports the hypothesis that a potential in vivo

genotoxic event(s) may be associated with the carcinogenesis process. The multiplicity of hepatocellular neoplasms and the 

development of liver hemangiosarcomas, and the significant increase in histiocytic sarcomas in the liver suggest that 

metabolizing enzymes in the liver may have produced unique tetrafluoroethylene metabolites which may have played a role, 

perhaps through as yet undetected genotoxic events, in the development of the marked increase in tumors in the liver. Similar to 

tetrafluoroethylene, 1,3-butadiene (Melnick et al., 1990) and vinyl chloride (Froment et al., 1994) induced hepatic 

hemangiosarcomas and hepatocellular neoplasms and were both genotoxic carcinogens. 

REFERENCES 

Anna, C.H., Maronpot, R.R., Pereira, M.A., Foley, J.F., Malarkey, D.E., and Anderson, M.W. (1994). ras Proto-oncogene 

activation in dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice. 

Carcinogenesis 15, 2255-2261. 

Bauer-Hofmann, R., Buchmann, A., Mahr, J., Kress, S., and Schwarz, M. (1992). The tumour promoters dieldrin and 

phenobarbital increase the frequency of c-Ha-ras wild-type, but not of c-Ha-ras mutated focal liver lesions in male C3H/He 

mice. Carcinogenesis 13, 477-481. 

Devereux, T.R., Anderson, M.W., and Belinsky, S.A. (1991). Role of ras protooncogene activation in the formation of 

spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. Carcinogenesis 12, 299-303. 

Devereux, T.R., Foley, J.F., Maronpot, R.R., Kari, F., and Anderson, M.W. (1993). ras Proto-oncogene activation in liver and 

lung tumors from B6C3F1 mice exposed chronically to methylene chloride. Carcinogenesis 14, 795-801. 

Fox, T.R., Schumann, A.M., Wantanabe, P.G., Yano, B.L., Maher, V.M., and McCormick, J.J. (1990). Mutational analysis of 

the H-ras oncogene in spontaneous C57BL/6 × C3H/He mouse liver tumors and tumors induced with genotoxic and 

nongenotoxic hepatocarcinogens. Cancer Res. 50, 4014-4019. 

Froment, O., Boivin, S., Barbin, A., Bancel, B., Trepo, C., and Marion, M.-J. (1994). Mutagenesis of ras proto-oncogenes in 

rat liver tumors induced by vinyl chloride. Cancer Res. 54, 5340-5345. 

Malarkey, D.E., Devereux, T.R., Dinse, G.E., Mann, P.C., and Maronpot, R.R. (1995). Hepatocarcinogenicity of chlordane in 

B6C3F1 and B6D2F1 male mice: Evidence for regression in B6C3F1 mice and carcinogenesis independent of ras protooncogene activation. Carcinogenesis 16, 2617-2625. 

Marmur, J. (1961). A procedure for the isolation of deoxyribonucleic acid micro-organisms. J. Mol. Biol. 3, 208-218. 

Maronpot, R.R., Fox, T., Malarkey, D.E., and Goldsworthy, T.L. (1995). Mutations in the ras proto-oncogene: Clues to 

etiology and molecular pathogenesis of mouse liver tumors. Toxicology 101, 125-156. 

Melnick, R.L., Huff, J., Chou, B.J., and Miller, R.A. (1990). Carcinogenicity of 1,3-butadiene in C57BL/6 × C3H F 1 mice at 

low exposure concentrations. Cancer Res. 50, 6592-6599. 

National Toxicology Program (NTP) (1993). Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in 

Swiss-Webster and B6C3F Mice (Feed Studies). Technical Report Series No. 443. NIH Publication No. 93-3359. U.S. 1 

Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park. 
Tetrafluoroethylene, NTP TR 450 311 

Orita, M., Suzuki, Y., Sekiya, T., and Hayashi, K. (1989). Rapid and sensitive detection of point mutations and DNA 

polymorphisms using the polymerase chain reaction. Genomics 5, 874-879. 

Reynolds, S.H., Stowers, S.J., Patterson, R.M., Maronpot, R.R., Aaronson, S.A., and Anderson, M.W. (1987). Activated 

oncogenes in B6C3F1 mouse liver tumors: Implications for risk assessment. Science 237, 1309-1316. 

Rumsby, P.C., Evans, J.G., Phillimore, H.E., Carthew, P., and Smith, A.G. (1992). Search for Ha- ras codon 61 mutations in 

liver tumours caused by hexachlorobenzene and Aroclor 1254 in C57BL/10ScSn mice with iron overload. Carcinogenesis 13, 

1917-1920. 

Saiki, R.K., Gelfand, D.H., Stoffel, S., Scharf, S.J., Higuchi, R., Horn, G.T., Mullis, K.B., and Erlich, H.A. (1988). Primerdirected enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239, 487-491. 

Sills, R.C., Hong, H.L., Greenwell, A., Herbert, R.A., Boorman, G.A., and Devereux, T.R. (1995). Increased frequency of Kras mutations in lung neoplasms from female B6C3F1 mice exposed to ozone for 24 or 30 months. Carcinogenesis 16, 

1623-1628. 

Stanley, L.A., Blackburn, D.R., Devereux, S., Foley, J., Lord, P.G., Maronpot, R.R., Orton, T.C., and Anderson, M.W. (1994). 

Ras mutations in methylclofenapate-induced B6C3F1 and C57BL/10J mouse liver tumours. Carcinogenesis 15, 1125-1131. 

Sukumar, S., and Barbacid, M. (1990). Specific patterns of oncogene activation in transplacentally induced tumors. Proc. Natl. 

Acad. Sci. USA 87, 718-722. 

Wiseman, R.W., Stowers, S.J., Miller, E.C., Anderson, M.W., and Miller, J.A. (1986). Activating mutations of the c-Ha- ras 

protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse. Proc. Natl. Acad. Sci. USA83, 5825-5829. 

Wright, D.K., and Manos, M.M. (1990). Sample preparation from paraffin-embedded tissues. In PCR Protocols. A Guide to 

Methods and Applications(M.A. Innis, D.H. Gelfand, J.J. Sninsky, and T.J. White, Eds.), pp. 153-158. Academic Press, San 

Diego, CA. 
312 Tetrafluoroethylene, NTP TR 450 

TABLE L1 

H-ras Mutations at Codon 61 in Spontaneously Occurring and Tetrafluoroethylene-Induced 

Liver Neoplasms from B6C3F 1 Mice 

Treatment Activated H-ras Codon 61 

H-ras (%) AAA CGA CTA 

Control, Historicala 183/333 (56%) 106/177 (60%) 50/177 (28%) 21/177 (12%) 

Control 10/17 (59%) 3/10 (30%) 6/10 (60%) 1/10 (10%) 

Tetrafluoroethylene (312 ppm) 0/3 (0%) — — — 

Tetrafluoroethylene (625 ppm) 6/29 (21%) 2/6 (33%) 2/6 (33%) 2/6 (33%) 

Tetrafluoroethylene (1,250 ppm) 3/27 (10%) 1/3 (33%) 1/3 (33%) 1/3 (33%) 

Tetrafluoroethylene (Total) 9/59 (15%) 3/9 (33%) 3/9 (33%) 3/9 (33%) 

a Data are presented in Maronpotet al. (1995). 

TABLE L2 

Frequency of K- ras Proto-oncogene Activation in Spontaneously Occurring 

and Tetrafluoroethylene-Induced Liver Neoplasms from B6C3F 1 Mice 

Treatment K-ras Mutations (%) 

Control, Historicala 

Controlb 

Tetrafluoroethyleneb 

3/167 (1.8%) 

0/4 (0%) 

0/19 (0%) 

a 

b Data are presented in Maronpotet al. (1995). 

Determined only for first exon of K-ras at codons 12 and 13. 
Tetrafluoroethylene, NTP TR 450 313 

TABLE L3 

H-ras Mutations at Codon 61 Detected in Hepatocellular Adenomas and Carcinomas from B6C3F 1 Mice 

Treatment Activated H-ras Codon 61 

H-ras (%) AAA CGA CTA 

Controls 

Hepatocellular Adenoma 5/11 (46%) 1 3 1 

Hepatocellular Carcinoma 5/6 (83%) 2 3 0 

Tetrafluoroethylene 

Hepatocellular Adenoma 4/20 (20%) 1 2 1 

Hepatocellular Carcinoma 5/39 (13%) 2 1 2