NTP TECHNICAL REPORT
 

ON THE
 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF CHLOROPRENE
 

(CAS NO. 126-99-8)
 

IN F344/N RATS AND B6C3F1 MICE

(INHALATION STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

September 1998
 

NTP TR 467
 

NIH Publication No. 98-3957
 

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. 

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

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

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

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

ON THE
 

TOXICOLOGY AND CARCINOGENESIS
 

STUDIES OF CHLOROPRENE
 

(CAS NO. 126-99-8)
 

IN F344/N RATS AND B6C3F1 MICE

(INHALATION STUDIES) 

NATIONAL TOXICOLOGY PROGRAM
 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

September 1998
 

NTP TR 467
 

NIH Publication No. 98-3957
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

National Institutes of Health
 
2 Chloroprene, NTP TR 467 

CONTRIBUTORS
 

National Toxicology Program 

Evaluated and interpreted results and reported findings 

R.L. Melnick, Ph.D., Study Scientist 

D.A. Bridge, B.S. 

J.R. Bucher, Ph.D. 

R.E. Chapin, Ph.D. 

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

J.K. Haseman, Ph.D. 

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

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

J.H. Roycroft, Ph.D. 

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

C.S. Smith, Ph.D. 

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

D.B. Walters, Ph.D. 

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

Battelle Pacific Northwest Laboratories 

Conducted studies, evaluated pathology findings for 16-day, 

13-week, and 2-year studies in rats and mice 

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

A.W. Gieschen, B.S. 

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

T.J. Mast, Ph.D. 

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

R.A. Renne, D.V.M. 

R.B. Westerberg, Ph.D. 

Experimental Pathology Laboratories, Inc. 

Provided pathology quality assurance 

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

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

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 

S.R. Lloyd, M.S. 

N.G. Mintz, B.S. 

NTP Pathology Working Group 

Evaluated slides, prepared pathology report on rats 

(6 June 1996) 

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

PATHCO, Inc. 

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

National Toxicology Program 

E.E. McConnell, D.V.M., M.S. 

A. Nyska, D.V.M. 

National Toxicology Program 

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

National Toxicology Program 

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

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

Evaluated slides, prepared pathology report on mice 

(27 June 1996) 

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

Pathology Associates International 

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

Chemical Industry Institute of Toxicology 

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

National Toxicology Program 

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

Pathology Associates International 

E.E. McConnell, D.V.M., M.S. 

K. McDorman, D.V.M., Observer 

A. Nyska, D.V.M. 

National Toxicology Program 

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

National Toxicology Program 

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

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

Biotechnical Services, Inc. 

Prepared Technical Report 

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

L.M. Harper, B.S. 

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

E.S. Rathman, M.S. 
3 

CONTENTS
 

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

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ............. 14
 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE ................................ 15
 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS .......... 16
 

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

MATERIALS AND METHODS ................................................ 23
 

RESULTS ............................................................... 37
 

DISCUSSION AND CONCLUSIONS ............................................ 87
 

REFERENCES ........................................................... 99
 

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

of Chloroprene ................................................ 109
 

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

of Chloroprene ................................................ 153
 

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

of Chloroprene ................................................ 187
 

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

of Chloroprene ................................................ 229
 

APPENDIX E Genetic Toxicology ............................................. 273
 

APPENDIX F Organ Weights and Organ-Weight-to-Body-Weight Ratios .................. 281
 

APPENDIX G Hematology, Clinical Chemistry, and Urinalysis Results .................... 291
 

APPENDIX H Tissue Nonprotein Sulfhydryl Concentration Results ....................... 305
 

APPENDIX I Reproductive Tissue Evaluations and Estrous Cycle Characterization ........... 311
 

APPENDIX J Neurobehavioral Studies .......................................... 315
 

APPENDIX K Chemical Characterization and Generation of Chamber Concentrations ......... 317
 
4 Chloroprene, NTP TR 467
 

APPENDIX L	 Ingredients, Nutrient Composition, and Contaminant Levels 

in NIH-07 Rat and Mouse Ration ................................... 333
 

APPENDIX M	 Sentinel Animal Program ......................................... 337
 

APPENDIX N	 K-ras Mutation Frequency and Spectra in Lung and Harderian Gland
 

Neoplasms from B6C3F Mice Exposed to Chloroprene for 2 Years 1 ............. 341
 

APPENDIX O	 Impact of Helicobacter hepaticus Infection in B6C3F1
 Mice

From 12 NTP 2-Year Carcinogenesis Studies ............................ 351
 
H Cl
 H H 

C C C C 

H H 

 

5 

ABSTRACT
 

CHLOROPRENE 

CAS No. 126-99-8 

Chemical Formula: C 4H 5 Cl Molecular Weight: 88.54

Synonyms: Chlorobutadiene; 2-chlorobuta-1,3-diene; 2-chloro-1,3-butadiene; $-chloroprene 

Chloroprene is used almost exclusively in the 

manufacture of neoprene (polychloroprene). Chloroprene was chosen for study because it is a high-volume 

production chemical with limited information on its 

carcinogenic potential and because it is the 2-chloro 

analogue of 1,3-butadiene, a potent, multi-species, 

multi-organ carcinogen. Male and female F344/N rats 

and B6C3F1 mice were exposed to chloroprene 

(greater than 96% pure) by inhalation for 16 days, 

13 weeks, or 2 years. Genetic toxicology studies were 

conducted in Salmonella typhimurium, Drosophila 

melanogaster, and B6C3F1 mice (bone marrow cells 

and peripheral blood erythrocytes). 

16-DAY STUDY IN RATS 

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

exposed to 0, 32, 80, 200, or 500 ppm chloroprene by 

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

16 days. Three 500 ppm males died on day 2 or 3 of 

the study. Mean body weight gains of 200 ppm males 

and females and 500 ppm females were significantly 

less than those of the chamber control groups. On the 

first day of exposure, rats exposed to 500 ppm were 

hypoactive and unsteady and had rapid shallow 

breathing. These effects were also observed to some 

degree in animals exposed to 200 ppm. After the 

second day of exposure, the effects in these groups 

worsened, and hemorrhage from the nose was 

observed. 

A normocytic, normochromic, responsive anemia; 

thrombocytopenia; and increases in serum activities of 

alanine aminotransferase, glutamate dehydrogenase, 

and sorbitol dehydrogenase occurred on day 4 in 

200 ppm females and 500 ppm males. Kidney weights 

of 80 and 500 ppm females were significantly greater 

than those of the chamber control group, as were the 

liver weights of 200 and 500 ppm females. 

The incidences of minimal to mild olfactory epithelial 

degeneration of the nose in all exposed groups of 

males and females were significantly greater than those 

in the chamber control groups. The incidence of 

squamous metaplasia of the respiratory epithelium was 

significantly increased in 500 ppm males. The 

incidences of centrilobular to random hepatocellular 

necrosis in 500 ppm males and 200 ppm females were 

significantly greater than those in the chamber control 

groups. 
6 Chloroprene, NTP TR 467 

16-DAY STUDY IN MICE 

Groups of 10 male and 10 female B6C3F1 mice were

exposed to 0, 12, 32, 80, or 200 ppm chloroprene by 

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

16 days. All males and females exposed to 200 ppm 

died on day 2 or day 3 of the study. Mean body 

weight gains of males exposed to 32 or 80 ppm were 

significantly less than that of the chamber control 

group. Mice exposed to 200 ppm exhibited narcosis 

during exposure and were hypoactive with reduced 

body tone after the first day of exposure. In general, 

hematology and clinical chemistry parameters measured for exposed males and females were similar to 

those of the chamber control groups. Thymus weights 

of 80 ppm males and females were significantly less 

than those of the chamber control groups. Liver 

weights of 80 ppm females were significantly greater 

than those of the chamber control groups. 

Increased incidences of multifocal random hepatocellular necrosis occurred in males and females 

exposed to 200 ppm. Hypertrophy of the myocardium, foci of hemorrhage, and mucosal erosion 

were observed in three males and three females exposed to 200 ppm. Squamous epithelial hyperplasia of 

the forestomach was observed in two males and two 

females exposed to 80 ppm. Thymic necrosis, 

characterized by karyorrhexis of thymic lymphocytes, 

was observed in all males and females in the 200 ppm 

groups. 

13-WEEK STUDY IN RATS 

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

exposed to chloroprene at concentrations of 0, 5, 12, 

32, 80, or 200 ppm by inhalation, 6 hours per day, 

5 days per week, for 13 weeks. One male exposed to 

200 ppm died during the study. The final mean body 

weights and body weight gains of all exposed groups 

of males and females were similar to those of the 

chamber control groups. Clinical findings in 200 ppm 

males included red or clear discharge around the nose 

and eye region. 

At week 13, a normocytic, normochromic, and nonresponsive anemia occurred in 200 ppm males and 

females. A thrombocytopenia occurred in 200 ppm 

males and females on day 2 and in 80 and 200 ppm 

females on day 22. However, at week 13, platelet 

counts rebounded and were minimally increased in 

200 ppm males and females. On day 2, a minimal to 

mild increase in activated partial thromboplastin time 

and prothrombin time occurred in 200 ppm males and 

females. The 200 ppm males and females also had increased activities of serum alanine aminotransferase, 

glutamate dehydrogenase, and sorbitol dehydrogenase 

on day 22; these increases were transient, and by week 

13 the serum activities of these enzymes were similar 

to those of the chamber controls. An alkaline 

phosphatase enzymeuria occurred in 200 ppm females 

on day 22; at week 13, an alkaline phosphatase 

enzymeuria occurred in 32, 80, and 200 ppm males 

and 200 ppm females. At week 13, a proteinuria 

occurred in 200 ppm males. Liver nonprotein sulfhydryl concentrations in male rats immediately 

following 1 day or 12 weeks of exposure to 200 ppm 

and in females exposed to 200 ppm for 12 weeks were 

significantly less than those of the chamber control 

groups. 

Kidney weights of 200 ppm males and females and 

80 ppm females were significantly greater than those 

of the chamber control groups. Sperm motility of 

200 ppm males was significantly less than that of the 

controls. In neurobehavioral assessments, horizontal 

activity was increased in male rats exposed to 32 ppm 

or greater and total activity was increased in 32 and 

200 ppm males. 

Increased incidences of minimal to mild olfactory 

epithelial degeneration and respiratory metaplasia 

occurred in males and females exposed to 80 or 

200 ppm. The incidence of olfactory epithelial degeneration in 32 ppm females was also significantly 

greater than that in the chamber control group. The 

incidence of hepatocellular necrosis in 200 ppm 

females was significantly greater than that in the 

chamber control group. Scattered chronic inflammation also occurred in the liver of male and female 

rats in the 200 ppm groups; the incidence in 200 ppm 

females was significantly greater than that in the 

chamber control group. The incidences of hemosiderin pigmentation were significantly increased in males 

and females exposed to 200 ppm. 

13-WEEK STUDY IN MICE 

Groups of 10 male and 10 female B6C3F1 mice were

exposed to chloroprene at concentrations of 0, 5, 12, 

32, or 80 ppm by inhalation, 6 hours per day, 5 days 

per week, for 13 weeks. All male and female mice 
Chloroprene, NTP TR 467 7 

survived to the end of the study. The final mean body 

weight and body weight gain of males exposed to 

80 ppm were significantly less than those of the 

chamber control group. 

Hematocrit concentrations of females exposed to 32 or 

80 ppm and erythrocyte counts of 80 ppm females 

were significantly less than those of the chamber control group. Platelet counts of 32 and 80 ppm females 

were also greater than that of the chamber control 

group. Increased incidences of squamous epithelial 

hyperplasia of the forestomach occurred in males and 

females exposed to 80 ppm. 

2-YEAR STUDY IN RATS 

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

exposed to chloroprene at concentrations of 0, 12.8, 

32, or 80 ppm by inhalation, 6 hours per day, 5 days 

per week, for 2 years. 

Survival, Body Weights, and Clinical Findings 

Survival of males exposed to 32 or 80 ppm was 

significantly less than that of the chamber control 

group. Mean body weights of males exposed to 

80 ppm were less than those of the chamber controls 

after week 93. Masses of the torso were observed 

during the study in exposed female groups, and these 

clinical findings correlated with mammary gland 

fibroadenomas observed at necropsy. 

Pathology Findings 

The incidences of squamous cell papilloma and squamous cell papilloma or squamous cell carcinoma 

(combined) of the oral cavity in male rats exposed to 

32 ppm and male and female rats exposed to 80 ppm 

were significantly greater than those in the chamber 

controls and exceeded the historical control ranges. 

The incidences of thyroid gland follicular cell adenoma or carcinoma (combined) in males exposed to 32 

or 80 ppm were significantly greater than that in the 

chamber control group and exceeded the historical 

control range. Although the incidences of follicular 

cell adenoma and follicular cell adenoma or carcinoma 

(combined) in 80 ppm females were not significantly 

greater than those in the chamber controls, they did 

exceed the historical control range for these 

neoplasms. 

The incidences of alveolar epithelial hyperplasia of the 

lung were significantly greater in all exposed groups 

of males and females than in the chamber control 

groups. The incidences of alveolar/bronchiolar 

carcinoma and alveolar/bronchiolar adenoma or 

carcinoma (combined) in 80 ppm males were slightly 

greater than those in the chamber control group. 

Although these neoplasm incidences were not significant, they exceeded the historical control range. 

The incidence of alveolar/bronchiolar adenoma, 

although not significant, was greater in 80 ppm 

females than in the chamber control group. 

The incidences of multiple fibroadenoma of the 

mammary gland in all exposed groups of females were 

greater than that in the chamber control group. The 

incidences of fibroadenoma (including multiple 

fibroadenoma) in 32 and 80 ppm females were significantly greater than that in the chamber controls. 

The incidences of fibroadenoma in the chamber control group and in all exposed groups of females 

exceeded the historical control range. 

The severity of nephropathy in exposed groups of 

male and female rats was slightly greater than in the 

chamber controls. Renal tubule adenoma and 

hyperplasia were observed in males and females. 

Additional kidney sections from male and female 

control and exposed rats were examined to provide a 

clearer indication of the potential effects of 

chloroprene on the kidney. The combined single- and 

step-section incidences of renal tubule hyperplasia in 

32 and 80 ppm males and 80 ppm females and the incidences of adenoma and adenoma or carcinoma 

(combined) in all exposed males were significantly 

greater than those in the chamber controls. 

A slight increase in the incidence of transitional 

epithelium carcinoma of the urinary bladder was 

observed in 80 ppm females. In addition, one 32 ppm 

male had a transitional epithelium carcinoma and one 

80 ppm male had a transitional cell papilloma. These 

findings are noteworthy because no urinary bladder 

neoplasms have been observed in chamber control 

male or female F344/N rats. 

In the nose, the incidences of atrophy, basal cell 

hyperplasia, metaplasia, and necrosis of the olfactory 

epithelium in 32 and 80 ppm males and females and of 
8 Chloroprene, NTP TR 467 

atrophy and necrosis in 12.8 ppm males were 

significantly greater than those in the chamber control 

groups. The incidences of chronic inflammation were 

significantly increased in males exposed to 12.8 or 

32 ppm and in males and females exposed to 80 ppm. 

The incidences of fibrosis and adenomatous 

hyperplasia in 80 ppm males and females were 

significantly greater than those in the chamber controls. Generally, lesions in the nasal cavity were mild 

to moderate in severity. 

2-YEAR STUDY IN MICE 

Groups of 50 male and 50 female B6C3F1 mice were

exposed to chloroprene at concentrations of 0, 12.8, 

32, or 80 ppm by inhalation, 6 hours per day, 5 days 

per week, for 2 years. 

Survival, Body Weights, and Clinical Findings 

Survival of males exposed to 32 or 80 ppm and of all 

exposed female groups was significantly less than that 

of the chamber controls. The mean body weights of 

80 ppm females were significantly less than those of 

the chamber control group after week 75. Clinical 

findings included masses of the head, which correlated 

with harderian gland adenoma and/or carcinoma in 

32 ppm males and 80 ppm males and females. Dorsal 

and lateral torso masses of female mice correlated with 

mammary gland neoplasms in 32 and 80 ppm females 

and subcutaneous sarcomas in 12.8, 32, and 80 ppm 

females. 

Pathology Findings 

The incidences of alveolar/bronchiolar neoplasms in 

the lungs of all groups of exposed males and females 

were significantly greater than those in the chamber 

control groups and generally exceeded the historical 

control ranges. The incidences of multiple alveolar/ 

bronchiolar adenoma and alveolar/bronchiolar carcinoma were increased in all exposed groups of males 

and females. The incidences of bronchiolar hyperplasia in all exposed groups of males and females were 

significantly greater than those in the chamber control 

groups. 

Male mice had a pattern of nonneoplastic liver lesions 

along with silver-staining helical organisms within the 

liver consistent with infection with Helicobacter 

hepaticus. An organism compatible with H. hepaticus 

was confirmed with a polymerase chain reactionrestriction fragment length polymorphism (PCRRFLP)-based assay. In NTP studies with 

H. hepaticus-associated hepatitis, increased incidences 

of hemangiosarcoma have been seen in the livers of 

male mice. Therefore, hemangiosarcomas of the liver 

were excluded from the analyses of circulatory (endothelial) neoplasms in males in this study. Even with 

this exclusion, the combined occurrence of hemangioma or hemangiosarcoma at other sites was 

significantly increased at all chloroprene exposure 

concentrations in males and in 32 ppm females. 

Incidences of neoplasms at other sites in this study of 

chloroprene were not considered to have been significantly impacted by the infection with H. hepaticus 

or its associated hepatitis. 

The incidences of harderian gland adenoma and 

harderian gland adenoma or carcinoma (combined) in 

males exposed to 32 or 80 ppm and females exposed 

to 80 ppm were significantly greater than those in the 

chamber controls. The incidences of harderian gland 

adenoma or carcinoma (combined) in 32 ppm males 

and 80 ppm males and females exceeded the historical 

control ranges. 

The incidences of mammary gland carcinoma and 

adenoacanthoma or carcinoma (combined) in 80 ppm 

females were significantly greater than those in the 

chamber control group. The incidences of mammary 

gland carcinoma and of adenoacanthoma in 32 and 

80 ppm females exceeded the historical control ranges. 

Multiple mammary gland carcinomas occurred in 

exposed females. 

The incidences of hepatocellular carcinoma in all 

exposed female groups and hepatocellular adenoma or 

carcinoma (combined) in 32 and 80 ppm females were 

significantly greater than those in the chamber controls; in the 80 ppm group, the incidence exceeded the 

historical control ranges for carcinoma and adenoma 

or carcinoma (combined). The incidence of eosinophilic foci in 80 ppm females was also significantly 

greater than that in the chamber controls. 

The incidences of sarcoma of the skin were significantly greater in all exposed groups of females than 

in the chamber controls. The incidences of sarcoma of 

the mesentery were also increased in all exposed 

groups of females. 
Chloroprene, NTP TR 467 9 

The incidence of squamous cell papilloma in 80 ppm 

females was greater than that in the chamber controls; 

the difference was not significant, but the incidence 

exceeded the historical control range. Males also 

showed a positive trend in the incidence of squamous 

cell papilloma of the forestomach. In males and 

females exposed to 80 ppm, the incidences of 

hyperplasia of the forestomach epithelium were 

significantly greater than those in the chamber 

controls. 

Carcinomas of the Zymbal’s gland were seen in three 

80 ppm females, and two carcinomas metastasized to 

the lung. Zymbal’s gland carcinomas have not been 

reported in control female mice in the NTP historical 

database. 

The incidence of renal tubule adenoma in 80 ppm 

males was greater than that in the chamber controls. 

Though this difference was not significant, the incidence of this rare neoplasm exceeded the historical 

control range. The incidences of renal tubule hyperplasia in males exposed to 32 or 80 ppm were significantly greater than that in the chamber controls. 

Additional sections of kidney were examined from 

control and exposed males to verify these findings. 

The combined single- and step-section incidence of 

renal tubule adenoma in 80 ppm males and the combined incidences of renal tubule hyperplasia in all 

groups of exposed male mice were greater than those 

in the chamber controls. 

The incidences of olfactory epithelial atrophy, adenomatous hyperplasia, and metaplasia in 80 ppm males 

and females were significantly greater than those in the 

chamber controls. The incidences of hematopoietic 

proliferation of the spleen in 32 and 80 ppm males and 

in all groups of exposed females were significantly 

greater than those in the chamber controls. 

GENETIC TOXICOLOGY 

Chloroprene was not mutagenic in any of the tests 

performed by the NTP. No induction of mutations 

was noted in any of four strains of S. typhimurium in 

the presence or the absence of S9 metabolic activation 

enzymes, and no induction of sex-linked recessive 

lethal mutations was observed in germ cells of male 

D. melanogaster treated with chloroprene via feeding 

or injection. In male mice exposed to chloroprene by 

inhalation for 12 days over a 16-day period, no 

induction of chromosomal aberrations, sister chromatid exchanges, or micronucleated erythrocytes in bone 

marrow or peripheral blood occurred. Results of a 

second micronucleus assay in male and female mice 

after 13 weeks of exposure to chloroprene via inhalation were also negative. 

CONCLUSIONS 

Under the conditions of these 2-year inhalation 

studies, there was clear evidence of carcinogenic 

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

increased incidences of neoplasms of the oral cavity; 

increased incidences of neoplasms of the thyroid 

gland, lung, and kidney were also attributed to chloroprene exposure. There was clear evidence of carcinogenic activity of chloroprene in female F344/N rats 

based on increased incidences of neoplasms of the oral 

cavity; increased incidences of neoplasms of the 

thyroid gland, mammary gland, and kidney were also 

attributed to exposure to chloroprene. Low incidences 

of urinary bladder neoplasms in male and female rats 

and lung neoplasms in female rats may also have been 

related to exposure to chloroprene. 

There was clear evidence of carcinogenic activity of 

chloroprene in male B6C3F 1 mice based on increased

incidences of neoplasms of the lung, circulatory 

system (hemangiomas and hemangiosarcomas), and 

harderian gland; increased incidences of neoplasms of 

the forestomach and kidney were also attributed to 

exposure to chloroprene. There was clear evidence of 

carcinogenic activity of chloroprene in female B6C3F1 

mice based on increased incidences of neoplasms of 

the lung, circulatory system (hemangiomas and hemangiosarcomas), harderian gland, mammary gland, liver, 

skin, and mesentery; increased incidences of 

neoplasms of the forestomach and Zymbal’s gland 

were also attributed to exposure to chloroprene. 

Exposure of male and female rats to chloroprene was 

associated with increased incidences of alveolar 

epithelial hyperplasia in the lung; nephropathy; and 

several nonneoplastic effects in the nose including 

olfactory epithelial atrophy, fibrosis, adenomatous 

hyperplasia, basal cell hyperplasia, chronic inflammation, respiratory metaplasia, and necrosis. Exposure of male and female mice to chloroprene was 

associated with increased incidences of bronchiolar 

hyperplasia and histiocytic cell infiltration in the 

lung; epithelial hyperplasia in the forestomach; renal 
10 Chloroprene, NTP TR 467 

tubule hyperplasia (males only); several effects in the metaplasia, and adenomatous hyperplasia; and hemanose including olfactory epithelial atrophy, respiratory topoietic cell proliferation in the spleen. 

*	 Explanation of Levels of Evidence of Carcinogenic Activity is on page 14. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 16. 
Chloroprene, NTP TR 467 11 

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

Male Female Male 

F344/N Rats F344/N Rats B6C3F Mice 1 

Female 

B6C3F Mice 1 

0, 12.8, 32, or 80 ppm 0, 12.8, 32, or 80 ppm 0, 12.8, 32, or 80 ppm 0, 12.8, 32, or 80 ppm 

by inhalation by inhalation by inhalation by inhalation 

80 ppm group less than Exposed groups similar to Exposed groups similar to 80 ppm group less than 

chamber control group chamber control group chamber control group chamber control group 

13/50, 9/50, 5/50, 4/50 29/49, 28/50, 26/50, 27/50, 27/50, 14/50, 35/50, 16/50, 1/50, 3/50 

21/50 13/50 

Lung: alveolar epthelial Lung: alveolar epithelial Lung: bronchiolar Lung: bronchiolar 

hyperplasia (5/50, 16/50, hyperplasia (6/49, 22/50, hyperplasia (0/50, 10/50, hyperplasia (0/50, 15/49, 

14/49, 25/50) 22/50, 34/50) 18/50, 23/50); histiocytic 12/50, 30/50); histiocytic 

cell infiltration (7/50, cell infiltration (1/50, 

Kidney: severity of Kidney: severity of 8/50, 11/50, 22/50)

nephropathy (2.8, 3.0, 

14/49, 18/50, 23/50) 

3.1, 3.5) nephropathy (1.9, 2.0, 

2.0, 2.2) Forestomach: epithelial Forestomach: epithelial 

hyperplasia (4/50, 6/48, hyperplasia (4/50, 3/49, 

Nose (olfactory ose (olfactory 7/49, 29/50) 

ithelium): atrophy 

N 8/49, 27/50) 

ep epithelium): atrophy (3/50, 12/50, 46/49, (0/49, 1/50, 40/50, Kidney: renal tubule Nose (olfactory 

50/50); fibrosis (0/49, 48/49); fibrosis (0/50, hyperplasia (0/50, 4/49, epithelium): atrophy 

0/50, 0/50, 49/50); 0/50, 0/49, 47/49); 5/50, 5/50) (6/50, 5/49, 4/49, 47/50); 

adenomatous hyperplasia adenomatous hyperplasia metaplasia (2/50, 3/49, 

(2/50, 0/50, 1/49, 42/49); (0/49, 0/50, 0/50, 27/50); Nose (olfactory 1/49, 44/50); 

basal cell hyperplasia basal cell hyperplasia epithelium): atrophy adenomatous hyperplasia 

(0/49, 0/50, 17/50, (0/50, 0/50, 38/49, (7/50, 8/48, 7/50, 49/50); (2/50, 3/49, 0/49, 44/50) 

46/49); chronic 49/50); chronic metaplasia (6/50, 5/48,

inflammation (0/49, 0/50, inflammation (0/50, 5/50, 5/50, 49/50); Spleen: hematopoietic 

2/50, 33/50); metaplasia 9/49, 49/49); metaplasia adenomatous hyperplasia cell proliferation (13/50, 

(0/49, 1/50, 35/50, /50, 5/50, 45/49, (3/50, 2/48, 2/50, 48/50)

48/49); necrosis (0/50, 

(6 25/49, 42/49, 39/50) 

50/50); necrosis (0/49, 

0/50, 8/50, 12/50) 11/50, 26/49, 19/49) Spleen: hematopoietic

cell proliferation (26/50, 

22/49, 35/50, 31/50) 

Exposure 

concentrations 

Body weights 

Survival rates 

Nonneoplastic effects 
12 Chloroprene, NTP TR 467 

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

Male Female Male Female
 

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

Neoplastic effects Oral cavity: squamous 

cell papilloma (0/50, 

Oral cavity: squamous 

cell papilloma (1/49, 

Lung: alveolar/ 

bronchiolar adenoma 

Lung: alveolar/ 

bronchiolar adenoma 

2/50, 4/50, 10/50); 2/50, 2/50, 7/50); (8/50, 18/50, 22/50, (2/50, 16/49, 29/50, 

squamous cell papilloma squamous cell papilloma 28/50); alveolar/ 26/50) alveolar/ 

or squamous cell or squamous cell bronchiolar carcinoma bronchiolar carcinoma 

carcinoma (0/50, 2/50, carcinoma (1/49, 3/50, (6/50, 12/50, 23/50, (2/50, 14/49, 16/50, 

5/50, 12/50) 5/50, 11/50) 28/50); alveolar/ 28/50); alveolar/ 

bronchiolar adenoma or bronchiolar adenoma or 

Thyroid gland: follicular Thyroid gland: follicular carcinoma (13/50, 28/50, carcinoma (4/50, 28/49, 

cell adenoma or cell adenoma or 36/50, 43/50) 34/50, 42/50) 

carcinoma (0/50, 2/50, carcinoma (1/49, 1/50, 

4/49, 5/50) 1/50, 5/50) Circulatory system: Circulatory system: 

hemangiosarcoma (3/50, hemangioma (0/50, 0/50, 

Lung: alveolar/ Mammary gland: 13/50, 22/50, 19/50); 2/50, 3/50); 

bronchiolar carcinoma fibroadenoma (24/49, hemangiosarcoma hemangiosarcoma (4/50, 

(0/50, 2/50, 1/49, 4/50); 32/50, 36/50, 36/50) (excludes liver) (1/50, 6/50, 17/50, 5/50); 

alveolar/bronchiolar 11/50, 16/50, 15/50); hemangioma or 

adenoma or carcinoma Kidney: renal tubule hemangioma or hemangiosarcoma (4/50, 

(2/50, 2/50, 4/49, 6/50) adenoma or carcinoma hemangiosarcoma (3/50, 6/50, 18/50, 8/50) 

(standard and extended 14/50, 23/50, 21/50); 

Kidney: renal tubule evaluations combined ­ hemangioma or Harderian gland: 

adenoma (extended 0/49, 0/50, 0/50, 4/50) hemangiosarcoma adenoma (1/50, 3/50, 

evaluation - 1/50, 6/50, (excludes liver) (1/50, 3/50, 8/50); adenoma or 

6/50, 7/50; standard and 12/50, 18/50, 17/50) carcinoma (2/50, 5/50, 

extended evaluations 3/50, 9/50) 

combined - 1/50, 7/50, Harderian gland: 

6/50, 8/50); renal tubule adenoma (2/50, 5/50, Mammary gland: 

adenoma or carcinoma 8/50, 10/50); adenoma or carcinoma (3/50, 4/50, 

(extended evaluation ­ carcinoma (2/50, 5/50, 7/50, 12/50) 

1/50, 7/50, 6/50, 7/50; 10/50, 12/50) 

standard and extended Liver: hepatocellular 

evaluations combined - Forestomach: squamous carcinoma (4/50, 11/49, 

1/50, 8/50, 6/50, 8/50) cell papilloma (1/50, 14/50, 19/50); 

0/50, 2/50, 4/50) hepatocellular adenoma or 

carcinoma (20/50, 26/49, 

Kidney: renal tubule 20/50, 30/50) 

adenoma (extended 

evaluation 0/50, 1/49, Skin: sarcoma (0/50, 

2/50, 6/50); standard and 11/50, 11/50, 18/50) 

extended evaluations 

combined - 0/50, 2/49, Mesentery: sarcoma 

3/50, 9/50) (0/50, 4/50, 8/50, 3/50) 

Forestomach: squamous 

cell papilloma or 

squamous cell carcinoma 

(1/50, 0/50, 0/50, 4/50) 

Zymbal’s gland: 

carcinoma (0/50, 0/50, 

0/50, 3/50) 
Chloroprene, NTP TR 467 13 

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

Male Female Male Female
 

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

Uncertain findings	 Urinary bladder: Urinary bladder: None None 

transitional epithelium transitional epithelium 

carcinoma (0/50, 0/50, carcinoma (0/49, 0/50, 

1/50, 0/49); transitional 0/50, 2/50) 

epithelium papilloma 

(0/50, 0/50, 0/50, 1/49) Lung: alveolar/ 

bronchiolar adenoma 

(1/49, 0/50, 0/50, 3/50) 

Levels of evidence Clear evidence Clear evidence Clear evidence Clear evidence 

of carcinogenic 

activity 

Genetic toxicology 

Salmonella typhimurium gene mutation: Negative with and without S9 in strains TA98, 

TA100, TA1535, and TA1537 

Sex-linked recessive lethal mutations 

Drosophila melanogaster: Negative 

Sister chromatid exchanges 

Mouse bone marrow cells in vivo: Negative in male mice 

Chromosomal aberrations 

Mouse bone marrow cells in vivo: Negative in male mice 

Micronucleated erythrocytes
 

Mouse peripheral blood in vivo (12 exposures): Negative in male mice
 

Mouse peripheral blood in vivo (13-week exposure): Negative in male and female mice
 
14 Chloroprene, NTP TR 467 

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY 

The National Toxicology Program describes the results of individual experiments on a chemical agent and notes the strength of the evidence 

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

animals, do not necessarily mean that a chemical is not a carcinogen, inasmuch as the experiments are conducted under a limited set of 

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

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

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

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

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

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

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

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

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

in March 1986 for use in the Technical Report series to incorporate more specifically the concept of actual weight of evidence of 

carcinogenic activity. For each separate experiment (male rats, female rats, male mice, female mice), one of the following five categories is 

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

•	 Clear evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a dose-related 

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

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

•	 Some evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a chemical-related increased 

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

evidence. 

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

neoplasms that may be chemical related. 

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

malignant or benign neoplasms. 

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

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

When a conclusion statement for a particular experiment is selected, consideration must be given to key factors that would extend the actual 

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

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

between two adjacent levels. These considerations should include: 

• adequacy of the experimental design and conduct;
 

• occurrence of common versus uncommon neoplasia;
 

•	 progression (or lack thereof) from benign to malignant neoplasia as well as from preneoplastic to neoplastic lesions; 

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

impossible to identify the difference. Therefore, where progression is known to be a possibility, the most prudent course is to 

assume that benign neoplasms of those types have the potential to become malignant; 

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

tissue; 

•	 latency in tumor induction; 

•	 multiplicity in site-specific neoplasia; 

•	 metastases; 

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

in another sex or species); 

•	 presence or absence of dose relationships; 

•	 statistical significance of the observed tumor increase; 

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

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

•	 structure-activity correlations; and 

•	 in some cases, genetic toxicology. 
Chloroprene, NTP TR 467 15 

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 chloroprene on 

11 December 1996 are listed below. Subcommittee members serve as independent scientists, not as representatives of any institution, 

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

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

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

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

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

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

Gary P. Carlson, Ph.D., Chairperson Irma Russo, M.D., Principal Reviewer 

School of Health Sciences Fox Chase Cancer Center 

Purdue University Philadelphia, PA 

West Lafayette, IN 

Louise Ryan, Ph.D. Arnold L. Brown, M.D. Division of Biostatistics 

University of Wisconsin Medical School Dana-Farber Cancer Institute 

Madison, WI Boston, MA 

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

Integrated Laboratory Systems Department of Pharmacology 

Research Triangle Park, NC Howard University College of Medicine 

Washington, DC 

Robert LeBoeuf, Ph.D. 

Corporate Professional and Regulatory Services Frederick L. Tyson 

Human Safety Department St. Mary’s Hospital and Medical Center 

The Procter & Gamble Company Cancer Research Institute 

Cincinnati, OH Grand Junction, CO 

Janardan K. Reddy, M.D. Jerrold M. Ward, D.V.M., Ph.D., Principal Reviewer 

Department of Pathology National Cancer Institute 

Northwestern University Medical School Frederick, MD 

Chicago, IL 
 

16 Chloroprene, NTP TR 467 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS
 

On 11 December 1996, the draft Technical Report on 

the toxicity and carcinogenesis studies of chloroprene 

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. R.L. Melnick, NIEHS, introduced the toxicology 

and carcinogenesis studies of chloroprene by discussing the uses of the chemical and rationale for 

study, describing the experimental design, reporting 

on survival and body weight effects, and reporting on 

compound-related neoplastic and nonneoplastic lesions 

in rats and mice. The proposed conclusions for the 

2-year studies were clear evidence of carcinogenic 

activity in male and female F344/N rats and B6C3F1 

mice. 

Dr. Ward, a principal reviewer, agreed with the 

proposed conclusions. He commented that there were 

many nonneoplastic lesions in the nasal cavity of rats 

and mice but no nasal neoplasms. He stated that the 

Discussion section should indicate that many toxic and 

reparative nasal lesions did not lead to neoplasms, in 

regard to a current theory/hypothesis that chronic 

lesions may lead to cancer. Dr. Ward said it was important to know whether the hyperplasias in many 

organs were focal or diffuse. Dr. Melnick said most 

of the hyperplasias were focal and this would be 

emphasized in the text. Because so many tissues were 

involved, Dr. Ward suggested an additional summary 

table for comparison to 1,3-butadiene, which might list 

target organs of toxicity and carcinogenesis. 

Dr. Melnick agreed. 

Dr. Goldsworthy, the second principal reviewer, 

agreed with the proposed conclusions. He noted the 

significant changes in survival and body weights that 

occurred during the study. Dr. Goldsworthy thought 

the differing decreases in body weights between 

exposure concentrations might call into question the 

numbers derived from the dose-response curves. 

Additionally, he asked for clarification of the impact 

of Helicobacter infection on the interpretation of 

hepatocellular neoplasms and liver hemangiomas in 

male mice (see Appendix O). 

Dr. Russo, the third principal reviewer, agreed with 

the proposed conclusions. 

Dr. Goldsworthy moved that the Technical Report on 

chloroprene be accepted with the revisions discussed 

and with the conclusions as written for male and 

female rats and mice, clear evidence of carcinogenic 

activity. Dr. Russo seconded the motion, which was 

accepted unanimously with nine votes. 
 

H Cl
 H H 

C C C C 

H H 

 

17 

INTRODUCTION
 

CHLOROPRENE 

CAS No. 126-99-8 

Chemical Formula: C H Cl Molecular Weight: 88.54 4 5 

Synonyms: Chlorobutadiene; 2-chlorobuta-1,3-diene; 2-chloro-1,3-butadiene; $-chloroprene 

CHEMICAL AND PHYSICAL PROPERTIES 

Chloroprene is a pungent-smelling, ether-like, colorless, flammable liquid with a boiling point of 59.4E C, 

a specific gravity of 0.9583 at 20E C, and a vapor 

pressure of 188 mm Hg at 20E C. It is soluble in 

ether, acetone, benzene, and most organic solvents and 

is slightly soluble in water. Chloroprene has a flash 

point of –20E C and an explosive limit of 4% to 20% 

in air and is therefore highly flammable (IARC, 1979; 

Patty’s, 1981; Hawley’s, 1987). Chloroprene is 

highly reactive, forming peroxides and spontaneously 

polymerizing at room temperature and in the presence 

of oxygen (Stewart, 1971). 

PRODUCTION, USE, 

AND HUMAN EXPOSURE 

Chloroprene is produced by the addition of hydrochloric acid to dimerized acetylene or by the chlorination of 1,3-butadiene (IARC, 1979; Hawley’s, 

1987). Large volumes of chloroprene are produced 

for industrial use; cumulative annual production in 

Japan, Western Europe, and the United States in 1989 

was approximately 880 million pounds (Weissermel 

and Arpe, 1990). 

Chloroprene is used almost exclusively as an intermediate in the production of polychloroprene elastomer (neoprene). Polychloroprene is used in automotive rubber goods, wire and cable coatings, 

construction applications, fabric coatings, cements, 

sealants, and adhesives (IARC, 1979; ACGIH, 1985; 

Hawley’s, 1987). The United States Food and Drug 

Administration permits the use of polychloroprene as 

a component of coatings and in rubber articles intended for use in contact with food (CFR 21 §§ 175.105, 

175.300, 177.2600). Polychloroprene may contain up 

to 0.5% free chloroprene (ACGIH, 1986). 

The main sources of environmental releases of chloroprene are probably the effluent and emmissions from 

facilities that produce chloroprene or polychloroprene 

elastomers. Volatilization is the predominant mechanism of removal of chloroprene from water. Chloroprene’s fate in the atmosphere may follow one of two 

paths: reaction with photochemically generated 

hydroxyl radicals or reaction with ozone (ACGIH, 

1985). Reaction of chloroprene with hydroxyl radicals 

or ozone may form formaldehyde, 1-chloroacrolein, 

glyoxal, chloroglyoxal, and chlorohydroxy acids or 

other aldehydes. 
18 Chloroprene, NTP TR 467 

The most probable route of human exposure to 

chloroprene is inhalation by workers employed in the 

manufacture of chloroprene or polychloroprene. 

Human exposure may also occur through ingestion or 

by contact with the skin or eye (IARC, 1979). In 

1977 an estimated 2,500 to 3,000 workers were exposed to chloroprene during its manufacture and 

polymerization; potential concentrations were as high 

as 6,760 ppm in some polymerization areas (Infante 

et al., 1977). The National Occupational Exposure 

Survey estimated that from 1981 through 1983, 

approximately 17,700 workers were occupationally 

exposed to chloroprene (NIOSH, 1990a). Chloroprene is an irritant to the eyes, skin, and mucous 

membranes of the respiratory tract and may also cause 

temporary hair loss. Chloroprene may also affect the 

central nervous system, liver, kidneys, myocardium, 

and digestive system (Patty’s, 1981; Sittig, 1985; 

ACGIH, 1986). In 1980, based on results from rodent 

studies, the American Conference of Governmental 

Industrial Hygienists lowered the recommended 

threshold limit value for chloroprene in the work 

3 environment from 25 ppm to 10 ppm (36 mg/m )

(ACGIH, 1996). The Occupational Safety and Health 

Administration has set the occupational exposure 

standard for chloroprene at 25 ppm, based largely on 

results of 4-week inhalation toxicity studies in rats and 

hamsters (Clary et al., 1978). NIOSH recommends a 

3 15-minute ceiling value of 1 ppm (3.6 mg/m )

(NIOSH, 1990b). 

ABSORPTION, DISTRIBUTION, 

METABOLISM, AND EXCRETION 

Chloroprene may be absorbed from the skin, lungs, 

and gastrointestinal tract (ACGIH, 1985). The wide 

distribution of chloroprene or its metabolites in the 

body is evidenced by the numerous target sites of 

acute or subchronic exposure: liver, lungs, spleen, 

central nervous system, kidneys, epicardium, testes, 

and bone marrow (ACGIH, 1985). 

There have been no conclusive studies on the metabolic fate of chloroprene. It has been suggested that 

chloroprene metabolism may follow a pathway similar 

to that of vinyl chloride, with 2-chloro-1,2-epoxybutene-3 and 2-chloro-3,4-epoxybutene-1 formed as 

intermediates. These epoxide intermediates may then 

be detoxified by glutathione conjugation (Haley, 

1978). This hypothesis is supported by the work of 

Summer and Greim (1980), who observed rapid 

depletion of hepatic glutathione and elevated excretion 

of urinary thioethers in rats administered 200 mg/kg 

chloroprene in olive oil by gavage. The epoxide 

intermediate may also be detoxified by epoxide hydrolase (Plugge and Jaeger, 1979). 

TOXICITY 

Experimental Animals 

The oral LD for chloroprene is 251 mg/kg body 50 

weight in rats and 260 mg/kg in mice (Asmagulian and 

Badalian, 1971). In rats, the approximate LC50 of 

chloroprene for a 4-hour inhalation exposure is 

2,280 ppm (Clary et al., 1978). A study by 

von Oettingen et al. (1936) reported a minimum lethal 

dose of 2.5 mg/L (700 ppm) in cats administered 

chloroprene by inhalation for 8 hours; death occurred 

1 to 3 hours after exposure ended. The International 

Technical Information Institute (1981) lists 8-hour 

inhalation LC100 values of 165 ppm for rats, 825 ppm 

for mice, 355 ppm for cats, and 1,064 ppm for rabbits 

and a subcutaneous injection LCLO value of 1,450 mg 

chloroprene/kg body weight for mice. 

The brain, kidney, liver, lung, heart, and testis have 

been identified as target organs of chloroprene toxicity. Plugge and Jaeger (1979) observed liver injury, 

evidenced by increased serum sorbitol dehydrogenase 

activity, in male Sprague-Dawley rats exposed to 225 

or 300 ppm chloroprene by inhalation for 4 hours and 

necropsied 24 hours after exposure ended. Liver nonprotein sulfhydryl concentrations were increased in 

fasted rats exposed to 100, 150, 225, or 300 ppm, and 

serum lactate dehydrogenase activity was increased in 

rats exposed to 300 ppm. Lung nonprotein sulfhydryl 

concentrations were decreased in the 100 and 300 ppm 

groups; no other evidence of lung injury was 

observed. 

In 4-week inhalation studies (6 hours per day, 5 days 

per week) conducted by Clary et al. (1978), signs of 

toxicity were observed in male and female Wistar rats 

and Syrian golden hamsters exposed to 40, 160, or 

625 ppm chloroprene, and chemical-related deaths 

occurred in both species in the 160 and 625 ppm 

groups. In the 625 ppm groups of each species, signs 

of toxicity included eye irritation, restlessness, 

lethargy, nasal discharge, orange urine, hair loss, and 

reduced body weight gains. Body weights of rats were 
Chloroprene, NTP TR 467 19 

less in all exposed groups than in the controls. 

Hematology and urinalysis parameters were not 

affected significantly by exposure to chloroprene. 

Chloroprene exposure produced significant changes in 

kidney, liver, and lung weights of male and female 

rats and hamsters. Gross examination of animals that 

died during exposure revealed that livers were dark 

and swollen and lungs were grayish with hemorrhagic 

areas; livers of several rats and hamsters in the 

625 ppm groups that survived until the end of the 

studies were also dark and swollen. Microscopic 

examination revealed slight to severe centrilobular 

degeneration and necrosis in the livers in 10 of 

10 male rats and 8 of 10 female rats exposed to 

625 ppm and in two of the three male rats exposed to 

160 ppm that died before the end of the study. The 

mucous membrane of the nasal cavity of exposed 

hamsters was irritated, and the lungs of rats that died 

early exhibited small hemorrhages and perivascular 

edema. Renal tubule epithelial degeneration was also 

observed in exposed rats. 

Nyström (1948) tested the effect of inhalation of 

1,400 ppm chloroprene (5 mg/L air) for 6 hours on 

renal function in a group of five milk-fed rats. By the 

fourth day after exposure, urea nitrogen clearance was 

reduced, with values returning to normal by the fourteenth day of exposure. Jaeger et al. (1975a,b) found 

that fasted adult male Holtzman rats were markedly 

more sensitive to chloroprene hepatotoxicity than were 

exposed rats fed ad libitum. Additionally, rats were 

more sensitive to chloroprene exposure at night, when 

glutathione concentrations were low (Jaeger et al., 

1975a). 

3 Inhalation of 0.56 or 3 mg chloroprene/m (0.16 or

0.8 ppm chloroprene) by rats for 6 months was 

reported to result in damage to the cerebral cortex, 

Ammon’s horn, corpora quadrigemina, optic thalamus, 

and pons and to produce hyperemia of the brain, cell 

shriveling, pyknotic nuclei, karyolysis, and 

decomposition of cytoplasm (Mnatsakanyan, 1965). 

In toxicity studies reviewed by Haley (1978), dogs 3 exposed to 8 to 20 mL/L (7.7 to 19.2 mg/m ) chloroprene by inhalation developed jaundice. Chronic inhalation of chloroprene by dogs produced decreased 

blood glucose concentration, increased blood pyruvate 

concentration, excitation, mydriasis, convulsions, 

muscle atonia, hemoptysis, and narcosis and death 

from pulmonary edema. Changes in higher nervous 

activity, the cells of the cerebral cortex, and brain 

vasculature, as well as decreases in serum 

cholinesterase activity, have been observed following 

chronic inhalation exposure of dogs to chloroprene. 

Thirteen-week inhalation toxicology studies were 

conducted in male and female F344/N rats and 

B6C3F mice at exposure concentrations of 0, 5, 12, 1 

32, and 80 ppm (6 hours per day, 5 days per week; 

Melnick et al., 1996a). A 200 ppm exposure group 

was also included for rats only. In rats, exposure to 

80 or 200 ppm chloroprene caused degeneration and 

metaplasia of the olfactory epithelium, while anemia, 

hepatocellular necrosis, and reduced sperm motility 

were seen only in the 200 ppm group. In mice, 

exposure to 80 ppm chloroprene caused a marginal 

decrease in body weight gain in males and epithelial 

hyperplasia of the forestomach in males and females. 

The complete results of these studies are presented in 

this Technical Report. 

Humans 

Symptoms of acute exposure to high concentrations of 

chloroprene in air include central nervous system 

depression; injury to the lung, liver, and kidney; skin 

and mucous membrane irritation; and respiratory 

difficulties (Nyström, 1948; Irish, 1963). Contact 

with chloroprene and its polymers may also produce 

hair loss and dermatitis (Schwartz, 1945; Nyström, 

1948; Ritter and Carter, 1948; Volkova, 1971). 

Chloroprene exposure (0.3 to 0.48 mg/L; 83 to 

133 ppm) was reported to induce diuresis and increased 17-ketosteroid concentrations in Soviet 

children (Mnatsakanyan, 1966). Arevshatyan (1972) 

also reported periodontal changes in workers exposed 

to chloroprene. 

Reports of chronic exposure to chloroprene cite effects 

on blood morphology and the cardiovascular system 

and on liver, lung, kidney, and nervous function, as 

well as corneal conjunctivitis and focal necrosis, 

nausea, indigestion, and loss of appetite (ITII, 1981). 

Studies by Volkova (1976) and Bagdinov (1973) cited 

in Sanotskii (1976) reported decreased erythrocyte, 

leukocyte, and thrombocyte counts in workers at a 

chloroprene production facility. There was a 

particularly sharp decrease in thrombocyte counts of 

women who had worked at the facility from 1 to 

5 years. In addition, hemoglobin concentrations were 

often reduced below the normal range. Cardiovascular 

effects included tachycardia, reduced arterial pressure, 
20 Chloroprene, NTP TR 467 

and muffled heart sounds. Liver effects include 

hepatomegaly, toxic hepatitis, and decreased liver 

function (Orlova and Solovyova, 1962; Bagdinov, 

1973; Volkova, 1976; NIOSH, unpublished). Gooch 

and Hawn (1981) found no clinically significant 

hematologic or biochemical alterations in workers 

exposed to chloroprene at a DuPont chemical facility. 

REPRODUCTIVE 

AND DEVELOPMENTAL TOXICITY 

Experimental Animals 

Soviet researchers have reported that chloroprene is 

embryotoxic and teratogenic at concentrations below 

1 ppm (IARC, 1979). Sal’nikova (1968) and 

Sal’nikova and Fomenko (1973) exposed pregnant rats 

and mice to chloroprene concentrations between 

15 ppb and 4.1 ppm by inhalation; concentrations of 

36 ppb and greater were reported to be embryotoxic. 

Maternal exposure to chloroprene was also linked to 

decreased pup survival prior to weaning and low pup 

body weights at weaning. In a review of the Soviet 

literature, Sanotskii (1976) reported that male white 

3 rats exposed to 1.7 mg/m (0.5 ppm) chloroprene for

4.5 months had decreased numbers of normal sperm, 

decreased sperm motility, and increased numbers of 

dead sperm. Sanotskii (1976) also reported an increase in the number of seminiferous tubules with desquamating epithelium in male C57BL/6 mice exposed 3 to 0.32 mg/m (0.09 ppm) for 2 months and increased 

dominant lethal mutations in germ cells of male and 

3 female C57BL/6 mice exposed to 3.5 mg/m (1 ppm) 

for 2 months. Exposure of pregnant white rats to 

4 mg/m3 (1.1 ppm) produced decreased fetal body 

weights and increased fetal death. 

Other reports do not support or agree with the Soviet 

findings. Culik et al. (1978) observed slight increases 

in resorptions and fetal body lengths in litters of 

ChR-CD rats exposed to 10 ppm and in fetal body 

weights and lengths in litters of dams exposed to 

25 ppm chloroprene by inhalation, 4 hours per day, 

from gestation days 3 to 20; however, these authors 

observed no other reproductive or developmental 

effects in a series of teratology, embryotoxicity, and 

reproductive toxicity studies at exposures up to 

25 ppm chloroprene. Exposure of pregnant New 

Zealand white rabbits to 10, 40, or 175 ppm chloroprene vapor, 6 hours per day, 7 days per week, on 

gestation days 6 through 28 produced no observable 

toxic effects to the dam or the offspring (Mast et al., 

1994). 

Humans 

Chloroprene exposure has been reported to affect male 

reproductive function; however, many of these reports 

cite the same Russian study, Fomenko (1974). 

Sanotskii’s (1976) review of this study stated that 

examination of chloroprene workers revealed 

functional disturbances in spermatogenesis after 6 to 

10 years of work in chloroprene production and morphological abnormalities of sperm after 11 or more 

years. Cases of spontaneous abortion in the wives of 

chloroprene workers occurred more than three times 

as often as in the control group. Sanotskii (1976) also 

cited reports of congenital abnormalities in the children of women working in a chloroprene factory and 

cases of pregnancies “taking an unfavorable course” in 

women working with chloroprene latex. However, the 

methods used to gather data in these studies have been 

questioned (ACGIH, 1985). 

CARCINOGENICITY 

Experimental Animals 

Chloroprene is the 2-chloro analogue of 1,3-butadiene, 

a chemical which was shown by NTP to be a potent 

multi-organ carcinogen in mice exposed by inhalation 

(Huff et al., 1985; Melnick et al., 1990a; NTP, 1993). 

Qinan et al. (1989) exposed Kunming albino mice to 

3 0, 2.9, 19, or 189 mg chloroprene/m by inhalation 

(0, 0.8, 5.3, or 53 ppm, respectively), 4 hours per 

day, 6 days per week, for 7 months. All surviving 

mice were killed at the end of the eighth month of the 

study. Compared to controls, exposed mice developed 

a significantly greater number of lung tumors (1.3%, 

8.1%, 9.4%, and 19.7% in the respective groups). 

Tumor multiplicity was significantly increased in the 

189 mg/m3 group. Most of these tumors were 

papilloadenomas, although a few were adenomas. 

The USEPA summarized a study by Zil’fian and 

Fichidzhyan (1972), who investigated the effect of 

chloroprene administration in 60 mixed-breed white 

mice. Groups of 30 mice received either 0.1 mg/g 

peach oil subcutaneously or transplanted Crocker murine sarcoma cells in suspension in 0.1 mg/g peach oil. 

In the latter group, chloroprene administration was 
Chloroprene, NTP TR 467 21 

found to increase neoplasm growth. This effect was chloroprene) or with finished polychloroprene. Conattributed to an immunosuppressive activity of centrations between 0.14 and 0.2 ppm were measured 

chloroprene. in the air at the man’s place of work. The individual 

had no prior exposure to any chemicals linked to this 

Menezes et al. (1979) transplanted chloroprene-treated 

(1, 10, or 100 mg/mL for 42 days) and untreated 

cultured hamster lung cells subcutaneously into newly 

born hamsters and intraocularly into adult hamsters. 

Untreated cells did not produce neoplasms; however, 

cells treated with 1 mg chloroprene/mL produced 

fibrosarcomas within 14 weeks. Sills et al. (1993) 

found that several types of neoplasms from 

chloroprene-treated B6C3F mice were positive for the 1 

protein product of the mutated p53 tumor suppressor 

gene. 

Zil’fian et al. (1975) found no induction of neoplasms 

in mice receiving skin applications of chloroprene or 

in rats dosed subcutaneously or by intragastric gavage. Ponomarkov and Tomatis (1980) dosed female 

DB IV rats with 100 mg chloroprene/kg in olive oil by 

gavage on gestation day 17 and dosed their offspring 

with 50 mg/kg by stomach tube for their life span after 

weaning. Although exposed rats had higher 

incidences of subcutaneous fibroma, chloroprene 

administration did not affect overall neoplasm 

incidences. 

Humans 

In a study of the relationship between industrial 

chemical exposure and lung cancer risk, Khachatrian 

(1972a) found that workers were 2.67 times less likely 

to develop lung cancer if they had not worked with 

chloroprene-related chemicals. Khachatrian (1972b) 

also found a correlation between the incidence of skin 

cancer and degree of exposure to chloroprene; an 

inverse relationship was found between degree of 

exposure and age at diagnosis of skin cancer. 

Khachatrian’s (1972a,b) methodology has been criticized (IARC, 1979). Pell (1978) reported increased 

incidences of digestive, lymphatic, and hematopoietic 

cancer in chloroprene workers at two DuPont plants. 

Pell (1978) did not distinguish between chloroprene 

manufacturing and polychloroprene manufacturing or 

attempt to control for confounding variables such as 

prior occupational exposure to other chemicals. 

Herbert (1976) reported a case of liver angiosarcoma 

in a man who had worked for 15 years with liquid 

polychloroprene (which may contain up to 5,000 ppm 

particular neoplasm (e.g., vinyl chloride). Although 

information on the carcinogenicity of chloroprene is 

limited, this singular occurrence was considered a 

potential health concern due to the rarity of liver 

angiosarcoma in the general population and the 

structural similarity between chloroprene and vinyl 

chloride (Infante et al., 1977). In both case control 

and cohort studies in China of workers exposed to 

chloroprene, Shouqi et al. (1989) found a significant 

correlation between cancer deaths and exposure to 

chloroprene. Maintenance mechanics had the highest 

risk of cancer. Standardized mortality ratios for liver, 

lung, and lymphatic cancers were significantly elevated in this group. 

GENETIC TOXICITY 

Results of mutagenicity tests with chloroprene appear 

to indicate little mutagenic activity, but the inconsistency among laboratories in the weakly positive responses noted in some tests complicate an assessment 

of the overall genetic toxicity profile of chloroprene. 

Chloroprene was reported to be mutagenic, with and 

without metabolic activation with induced liver S9 

enzymes, to Salmonella typhimurium strains TA100 

(Bartsch et al., 1975) and TA1530 (Bartsch et al., 

1979); in these investigations, the level of mutagenic 

activity was enhanced by the addition of S9. In contrast, Zeiger et al. (1987) found no evidence of mutagenic activity for chloroprene in four strains of 

S. typhimurium, including strain TA100. More recently, Westphal et al. (1994), using a modified preincubation protocol to control for the volatility of 

chloroprene, reported no mutagenic activity for freshly distilled chloroprene (highly pure) in strain TA100; 

however, an S9-independent mutagenic response that 

correlated directly with the age of older aliquots of 

chloroprene was observed with and without volatility 

control. Westphal et al. (1994) attributed the increasing mutagenicity of aged chloroprene samples to the 

accumulation of several decomposition products in the 

chloroprene distillate, notably cyclic chloroprene 

dimers, which were identified by gas chromatography/ 

mass spectrometry. Like Bartsch et al. (1975, 1979), 

Westphal et al. (1994) found that S9 enhanced the 

mutagenic response of S. typhimurium strain TA100 to 

aged chloroprene. In eukaryotic test systems, 
22 Chloroprene, NTP TR 467 

chloroprene was not mutagenic in cultured V79 

Chinese hamster cells (Drevon and Kuroki, 1979). It 

gave conflicting responses in Drosophila sex-linked 

recessive lethal assays; Vogel (1979) reported weakly 

positive results in a feeding study conducted within a 

sealed desiccator, and, more recently, Foureman et al. 

(1994) reported no significant increase in sex-linked 

recessive lethal mutations in germ cells of male flies 

exposed to chloroprene through feeding or injection. 

Foureman et al. (1994) also provided a thorough discussion of the possible reasons for the discordant 

results obtained between the two laboratories in this 

assay, including differences in chloroprene purity, 

Drosophila strain tested, statistical methods of data 

analysis, and sample size. 

In mammalian systems in vivo, chloroprene, administered by inhalation at concentrations from 0.036 to 

0.97 ppm for 2 months, was reported to induce dominant lethal mutations in germ cells of male rats and 

mice and chromosomal aberrations in bone marrow 

cells of C57BL/6 mice (Sanotskii, 1976). A more 

recent study of the in vivo mutagenic activity of 

chloroprene showed no effects on the frequencies of 

sister chromatid exchanges, chromosomal aberrations, 

or micronucleated erythrocytes in bone marrow or 

peripheral blood of B6C3F mice exposed for 12 days 1 

to chloroprene at concentrations of 12, 32, or 80 ppm 

(Tice et al., 1988). Results of a second micronucleus 

assay in male and female mice after 90 days of exposure to chloroprene (5 to 80 ppm) by inhalation 

were also negative. The differences in bone marrow 

chromosomal effects between these studies and those 

of Sanotskii (1976) may have been the result of strainrelated differences in chloroprene tissue distribution 

and detoxification processes or of variations in 

experimental protocols, including the age of the 

chloroprene. 

STUDY RATIONALE 

Chloroprene was chosen for study by the National 

Toxicology Program because it is a high-volume 

production chemical and because information on its 

carcinogenic potential in experimental animals and 

humans was limited. In addition, chloroprene is the 

2-chloro analogue of 1,3-butadiene, a potent multiorgan carcinogen in rats and mice, which has consistently been associated with increased risk of lymphatic 

and hematopoietic cancers in occupationally exposed 

workers. Thus, the results of the current studies allow 

assessment of the effects of the chlorine substitution on 

the carcinogenicity of 1,3-butadiene. Inhalation was 

chosen as the route of exposure because it is the most 

likely route of human exposure. 
23 

MATERIALS AND METHODS
 

PROCUREMENT AND 

CHARACTERIZATION OF CHLOROPRENE 

Chloroprene was obtained for the 16-day and 13-week 

studies from Denka Chemical Company (Houston, TX) 

in five lots. Chloroprene for the 2-year studies was 

supplied by Mobay Synthetic Corporation (Houston, 

TX) in 12 lots. Identity, purity, and stability studies 

of lot 12103-4-1, from the first shipment of 

chloroprene to the study laboratory, were performed 

by the analytical chemistry laboratory, Midwest 

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

Reports on the analyses conducted by the analytical 

chemistry laboratory and performed in support of the 

chloroprene studies are on file at the National Institute 

of Environmental Health Sciences. Subsequent purity 

and identity analyses of chloroprene lots were performed by the study laboratory. 

The chemical, a clear colorless liquid, was identified 

as chloroprene by infrared, ultraviolet/visible, and nuclear magnetic resonance spectroscopy and by boiling 

point and density. The purity of lot 12103-4-1 was 

determined by elemental analysis, Karl Fischer water 

analysis, approximation of t-butylcatechol, thin-layer 

chromatography, and gas chromatography. Peroxide 

concentration was analyzed for lot 12103-4-1. Elemental analyses for carbon, hydrogen, and chlorine 

agreed with the theoretical values for chloroprene. 

Karl Fischer water analysis indicated less than 0.01% 

water. Approximation of t-butylcatechol inhibitor indicated 40 to 50 ppm. Thin-layer chromatography 

indicated one major spot. Thin-layer chromatography 

of a second sample left at room temperature overnight 

revealed another spot in addition to the major spot. 

Gas chromatography by one system indicated four 

impurities with a cumulative peak area of 0.96% 

relative to the major peak; gas chromatography by a 

second system indicated six impurities with a total area 

of 3.30% relative to the major peak area. Gas 

chromatography/mass spectrometry identified six impurities: chlorobutene, chlorobutadiene, toluene, and 

three chloroprene dimers. Five additional impurity 

peaks with areas less than 0.1% were also observed. 

Titration for peroxide indicated 1.96 ± 0.06 mEq 

peroxide per kilogram of sample. The overall purity 

was determined to be approximately 96%. 

The remaining lots were identified by the study laboratory as chloroprene by infrared spectroscopy. 

Purity of the remaining lots was determined by the 

laboratory using gas chromatography; all lots exceeded the 96% purity minimum required by the study 

design. 

Chloroprene received for the 16-day and 13-week 

studies was fortified at the study laboratory with 0.1% 

each of the stabilizers phenothiazine and t-butylcatechol. Chloroprene received for the 2-year studies 

was procured with 0.1% of each stabilizer added by 

the producer. 

Stability was monitored by the study laboratory 

throughout the studies by gas chromatography using 

flame ionization detection and titration for peroxides. 

The concentrations of the stabilizers phenothiazine and 

t-butylcatechol were also determined with gas 

chromatography. No degradation of the bulk chemical 

was detected; all lots used during the studies had less 

than 1 mEq peroxide per kilogram. The stabilizer 

concentrations were acceptable. To ensure stability, 

the bulk chemical was stored under a nitrogen headspace in the original containers at approximately 

20E C. 

VAPOR GENERATION 

AND EXPOSURE SYSTEM 

The vapor generation system consisted of an evaporation flask in a hot-water bath (72° C, 16-day 

studies; 66° C, 13-week and 2-year studies) and a 

temperature-controlled, cooled condenser column. 

The chloroprene vapor was pumped at a steady rate 

from a dry-ice-chilled reservoir into the rotating flask 

(16-day studies) or held covered under a positive 

nitrogen headspace (13-week and 2-year studies). A 

calibrated flow of nitrogen was metered into the base 

of the cooled condenser column, which was attached 

to the flask, and carried vapor rising from the flask 
 

24 Chloroprene, NTP TR 467 

through the condenser. The vapor temperature was 

controlled by a thermostat set to 1E C to return to the 

flask any components boiling at a higher temperature 

than chloroprene. The temperature of the remaining 

chloroprene-saturated nitrogen vapor was monitored 

by a sensor at the top of the column; the vapor pressure was calculated and used to determine the vapor 

output. Detailed descriptions of the inhalation suites 

and vapor generation system are provided in 

Appendix K. 

Vapor entering the distribution manifold was diluted 

with HEPA- and charcoal-filtered air (16-day and 

13-week studies) or with additional nitrogen (2-year 

studies). Flow to each chamber was controlled by 

compressed-air-driven vacuum pumps; vapor flowed 

through separate metering valves for each exposure 

chamber and was diluted with air before entering the 

chamber. 

The study laboratory designed the stainless steel inhalation exposure chambers (Hazleton H-2000®, 

Harford Systems Division of Lab Products, Inc., 

Aberdeen, MD) so that uniform vapor concentrations 

could be maintained throughout the chamber when 

catch pans were in place. A small particle detector 

(Type CN, Gardner Associates, Schenectady, NY) was 

used with and without animals in the exposure 

chambers to ensure that chloroprene vapor, and not 

aerosol, was produced. No particle counts above the 

minimum resolvable level (approximately 200 par­ 3 ticles/cm ) were detected.

VAPOR CONCENTRATION MONITORING 

Chamber concentrations of chloroprene were monitored by an on-line gas chromatograph. Samples 

were drawn from the exposure chambers at least once 

every hour by a 12-port stream selection valve. 

During the 16-day and 2-year studies, samples from 

the distribution line were monitored for purity with a 

second gas chromatograph; during the 13-week 

studies, distribution line samples were monitored by 

the same gas chromatograph that was used to monitor 

the exposure chambers. The on-line chromatograph 

was calibrated based on qualitative analysis of grab 

samples collected in dimethylformaldehyde-filled 

bubblers. Results were compared to those of an offline gas chromatograph calibrated with gravimetrically 

prepared chloroprene standards in dimethylformaldehyde. Chamber concentration uniformity was 

maintained throughout the studies. Summaries of the 

chamber concentrations for the 16-day, 13-week, and 

2-year studies are listed in Tables K1 through K3. 

CHAMBER ATMOSPHERE 

CHARACTERIZATION 

The times for the exposure concentration to build up 

to 90% of the final exposure concentration (T ) and 90 

to decay to 10% of the exposure concentration (T ) 10 

were measured in all studies with and without animals 

present. For the various studies, these values ranged 

from 7 to 15 minutes. The T90 used during all the 

studies was 12 minutes. 

Studies of chloroprene degradation and monitoring for 

impurities, inhibitors, and stabilizers were conducted 

throughout the 13-week and 2-year studies by analyzing bubbler samples with gas chromatography or with 

a fluorescence detector. No significant degradation of 

chloroprene was observed during the studies. 

16-DAY STUDIES 

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

obtained from Taconic Farms (Germantown, NY). On 

receipt, the rats and mice were 4 to 5 weeks old. 

Animals were quarantined for 10 to 13 days and were 

6 to 7 weeks old at the beginning of the studies. 

Groups of 10 male and 10 female rats and mice were 

exposed to chloroprene by inhalation at concentrations 

of 0, 32, 80, 200, or 500 ppm (rats) or 0, 12, 32, 80, 

or 200 ppm (mice). Additional groups of 10 male and 

10 female mice designated for day 5 hematology and 

clinical chemistry analyses were exposed to 0, 12, 32, 

80, or 200 ppm chloroprene. Rats and mice were exposed for 6 hours plus T (12 minutes) per day, 90 

5 days per week, for 16 days. Feed was available 

ad libitum except during exposure periods and urine 

collection periods, and water was available ad libitum. 

Rats and mice were housed individually. Clinical 

findings were recorded twice daily. Animals were 

weighed initially, after one week, and at the end of the 

studies. Details of the study design and animal maintenance are summarized in Table 1. 

On day 4 of exposure, rats were placed in metabolism 

cages for 16-hour urine collection. Specific gravity 

was determined with an A/O refractometer, urine 
Chloroprene, NTP TR 467 25 

protein concentration was determined using the ses were performed on five male and five female 

Coomassie blue reaction, and thioethers were mea­ sentinel rats and mice using the protocols of the NTP 

sured as described by Summer et al. (1979). All other Sentinel Animal Program (Appendix M). 

urine parameters were measured using Abbott VP 

(Abbott Laboratories, Abbott Park, IL) methodologies. 

At the end of the urine collection period, rats were 

anesthetized with 70% CO2 and blood was collected 

from the retroorbital sinus for hematology and clinical 

chemistry analyses. On exposure day 8, mice 

designated for hematology and clinical chemistry 

analyses were anesthetized with 70% CO2 and blood 

was collected from the retroorbital sinus. Blood for 

hematology determinations was placed in tubes containing potassium EDTA as an anticoagulant and the 

analyses were performed with an Ortho ELT-8/ds 

hematology analyzer (Ortho Instruments, Westwood, 

MA). Blood smears were stained with Wright/Giemsa 

stain. The Miller disc method was used to determine 

the reticulocyte count. Blood for clinical chemistry 

analyses was placed in tubes with no anticoagulant; 

Abbott VP methodologies were used to perform the 

serum chemistry analyses. The hematology and clinical chemistry parameters measured are listed in 

Table 1. 

A necropsy was performed on all core animals. The 

brain, heart, right kidney, liver, lungs, spleen, thymus, and right testis were weighed. Histopathologic 

examinations were performed on chamber controls, 

80 ppm female rats, 200 and 500 ppm male and female 

rats, and 80 and 200 ppm male and female mice. 

Histopathologic examination was also performed on all 

target organs in other exposure groups to a no-effect 

level. Table 1 lists the tissues and organs examined. 

13-WEEK STUDIES 

The 13-week studies were conducted to evaluate the 

cumulative toxic effects of repeated exposure to 

chloroprene and to determine the appropriate exposure 

concentrations to be used in the 2-year studies. 

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

obtained from Taconic Farms (Germantown, NY). On 

receipt, the rats and mice were 4 to 5 weeks old. 

Animals were quarantined for 12 to 15 days and were 

6 to 7 weeks old on the first day of the studies. 

Before initiation of the studies, five male and five 

female rats and mice were randomly selected for 

parasite evaluation and gross observation for evidence 

of disease. At the end of the studies, serologic analyGroups of 10 male and 10 female rats were exposed to 

chloroprene by inhalation at concentrations of 0, 5, 

12, 32, 80, or 200 ppm (core study). Groups of 

10 male and 10 female mice were exposed to chloroprene at concentrations of 0, 5, 12, 32, or 80 ppm 

(core study). Additional study groups of 10 male and 

10 female rats designated for clinical pathology 

analyses were exposed to 0, 5, 12, 32, 80, or 

200 ppm. Additional study groups of five male and 

five female rats exposed to 0, 5, 32, or 200 ppm and 

groups of five male and five female mice exposed to 0, 

12, 32, or 80 ppm were designated for tissue 

glutathione studies. Additional study groups of 

10 male and 10 female rats were exposed to 0, 32, 80, 

or 200 ppm for a coagulation study and for day 2 

hematology analyses. Rats and mice were exposed for 

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

week, for 13 weeks. Feed was available ad libitum 

except during exposure and urine collection periods, 

and water was available ad libitum. Rats and mice 

were housed individually. Clinical findings were 

recorded weekly for rats and mice. The animals were 

weighed initially, weekly, and at the end of the 

studies. Blood for hematology and clinical chemistry 

analyses was collected from the supraorbital sinus of 

all mice surviving to the end of the study. On day 22 

and prior to the end of the study, male and female rats 

designated for clinical pathology analyses were placed 

in metabolism cages for 16-hour urine collection. 

Urinalysis methodologies were similar to those 

described for the 16-day studies. After urine collection, animals were anesthetized and blood was 

collected from the retroorbital sinus for hematology 

and clinical chemistry analyses. Rats were discarded 

after the final blood collection. For hematology analyses, samples were collected in containers containing 

EDTA as an anticoagulant. For clinical chemistry, 

samples were collected in tubes with no anticoagulant. 

Erythrocyte, leukocyte, and platelet counts; hemoglobin concentrations; volume of packed red cells; 

mean cell volume; mean cell hemoglobin; and mean 

cell hemoglobin concentration were measured with an 

Ortho ELT-8/ds hematology analyzer. Blood smears 

were stained with Wright/Giemsa; differential leukocyte counts were based on classifying a minimum of 

100 white cells. Reticulocytes were enumerated as a 

reticulocyte/erythrocyte ratio using the Miller disc 
26 Chloroprene, NTP TR 467 

method. Clinical chemistry parameters were measured pulling. Gauge needle deflections (grams) were 

using Abbott VP methodologies. The hematology and recorded for each trial. The mean of three trials (both 

clinical chemistry parameters measured are listed in forelimb and hindlimb grip strength) for each rat was 

Table 1. recorded as the score. 

Rats and mice designated for tissue glutathione studies A Socrel Tail Flick Analgesiometer (Socrel, Varese, 

were killed after the first day of exposure or at Italy) was used to conduct the thermal sensitivity 

week 13. The kidney, liver, lung, and thymus were measurements. The apparatus consisted of an infrared 

removed from rats and mice designated for tissue heat source (100-W bulb) focused by a parabolic 

glutathione assays for determination of tissue non- mirror on a photocell. Each rat was placed with its 

protein sulfhydryl (glutathione) concentrations and tail on the photocell window, occluding the beam. A 

total sulfhydryl concentrations. The assay methods for foot peddle was depressed to activate the heat source 

nonprotein sulfhydryl and total sulfhydryl con- and a timer. When the rat flicked its tail out of the 

centrations were similar to those described by Ellman path of the beam, the photocell was energized, turning 

(1959) as modified by Sedlak and Lindsay (1968). off the timer and the heat source. The time to remove 

(flick) the tail was recorded in seconds. The startle 

After two days of exposure, blood was collected from response to acoustic stimulation was measured using 

supplemental groups designated for coagulation an SR-Lab Startle Response System (SRI, Scientific 

studies. Blood samples were also collected for day 2 and Professional Support Group, La Jolla, CA). 

hematology analyses. Rats were anesthetized with in- During test sessions, individual rats were placed in the 

traperitoneal pentobarbital sodium, and samples were system, which was then placed in a soundproof 

collected from the lumbar aorta using plastic syringes cabinet. Following a 3-minute habituation period, the 

and placed in tubes containing potassium EDTA as an animal was exposed to six 40-millisecond bursts of 

anticoagulant for hematology and tubes containing 120-decibel white noise spaced 15 seconds apart. In 

3.8% sodium citrate for the coagulation tests. Pro- each trial, both the maximum response amplitude 

thrombin times and activated partial thromboplastin (startle response, measured as volts) and the time to 

times were quantitated using a BBL Fibrinometer and maximum response (response latency, recorded as 

Dade methodologies. Commercial kits (Dade) were milliseconds) were recorded automatically. 

used for the measurement of euglobulin lysis times and 

fibrinogen concentrations. At the end of the 13-week studies, samples were 

collected for sperm morphology and vaginal cytology 

At week 11, all surviving male and female core study evaluations on core study rats exposed to 0, 5, 32, or 

rats were administered neurobehavioral tests. Motor 200 ppm and core study mice exposed to 0, 12, 32, or 

activity and exploration/habituation were assessed 80 ppm. The parameters evaluated are listed in 

using New Standard Systems residential mazes. Table 1. Methods used were those described in the 

Residential mazes allow the automated measure of NTP’s sperm morphology and vaginal cytology evalhorizontal and vertical activity by infrared sensors uations protocol (NTP, 1985). For 7 consecutive days 

located throughout the maze. To preclude disturbance prior to scheduled terminal sacrifice, the vaginal vaults 

of rats during testing, mazes were housed in sound- of the females were moistened with saline, if 

proof cabinets. Motor activity was measured for each necessary, and samples of vaginal fluid and cells were 

rat during a 1-hour session. Forelimb and hindlimb stained. Relative numbers of leukocytes, nucleated 

grip strengths were measured on a horizontal platform epithelial cells, and large squamous epithelial cells 

with calibrated push-pull strain gauges mounted at were determined and used to ascertain estrous cycle 

each end. A rectangular forelimb grip bar was stage (i.e., diestrus, proestrus, estrus, and metestrus). 

attached to one gauge, and a hindlimb T-bar was Male animals were evaluated for sperm morphology, 

attached to the other gauge. Rats were allowed to grip count, and motility. The right testis and right epididthe forelimb grip bar with their front paws and were ymis were isolated and weighed. The tail of the 

pulled along the platform until their grip was broken. epididymis (cauda epididymis) was then removed from 

As the backward motion continued, the rat’s hindpaws the epididymal body (corpus epididymis) and weighed. 

reached the T-shaped hindlimb grip bar, which it was Test yolk (rats) or modified Tyrode’s buffer (mice) 

allowed to grip and then forced to release by further was applied to slides and a small incision was made at 
Chloroprene, NTP TR 467 27 

the distal border of the cauda epididymis. The sperm 

effluxing from the incision were dispersed in the 

buffer on the slides, and the numbers of motile and 

nonmotile spermatozoa were counted for five fields 

per slide by two observers. Following completion of 

sperm motility estimates, each right cauda epididymis 

was placed in buffered saline solution. Caudae were 

finely minced, and the tissue was incubated in the 

saline solution and then heat fixed at 65E C. Sperm 

density was then determined microscopically with the 

aid of a hemacytometer. Four sperm morphology 

slides were prepared for each animal evaluated. An 

aliquot of killed sperm suspension was stained in a test 

tube, spread on a microscope slide, coverslipped, and 

examined. 

A necropsy was performed on all core study animals 

that survived to the end of the 13-week studies. The 

brain, heart, right kidney, liver, lung, spleen, right 

testis, and thymus were weighed. Histopathologic examinations were performed on chamber control rats 

and mice and on 200 ppm rats and 80 ppm mice. The 

liver of 80 ppm rats and the nose of 12, 32, and 

80 ppm rats were examined microscopically. Target 

organs were examined in 5, 12, and 32 ppm mice to a 

no-effect level. Lungs of 5, 12, and 32 ppm male 

mice and forestomachs of 32 ppm male and female 

mice were examined microscopically. All lesions observed grossly in rats and mice were examined 

microscopically. Tissues for microscopic examination 

were fixed and preserved in 10% neutral buffered 

formalin, processed and trimmed, embedded in 

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

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

control groups of rats and mice, on 200 ppm rats, and 

on 80 ppm mice. Table 1 lists the tissues and organs 

routinely examined. 

2-YEAR STUDIES 

Study Design 

Groups of 50 male and 50 female rats and mice were 

exposed by inhalation to chloroprene at concentrations 

of 0, 12.8, 32, or 80 ppm for 6 hours plus T90 

(12 minutes) per day, 5 days per week, for 105 weeks. 

Source and Specification of Animals 

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

obtained from Simonsen Laboratories, Inc. (Gilroy, 

CA) for use in the 2-year studies. Rats and mice were 

quarantined for 14 days before the beginning of the 

studies. Five and five female rats and mice were randomly selected for parasite evaluation and gross observation of disease. Rats and mice were approximately 6 weeks old at the beginning of the studies. 

The health of the animals was monitored during the 

studies according to the protocols of the NTP Sentinel 

Animal Program (Appendix M). 

Animal Maintenance 

Rats and mice were housed individually. Feed was 

available ad libitum except during exposure periods, 

and water was available ad libitum. Cages and chambers were changed weekly. Further details of animal 

maintenance are given in Table 1. Information on feed 

composition and contaminants is provided in 

Appendix L. 

Clinical Examinations and Pathology 

All animals were observed twice daily. Body weights 

were recorded initially, weekly through week 12, 

approximately every 4 weeks from week 15 through 

week 91, and every 2 weeks until the end of the study. 

Clinical findings were recorded initially, at weeks 4, 

5 (mice), 8, 12, and 15 (rats), every 4 weeks through 

week 91, and every 2 weeks until the end of the study. 

A complete necropsy and microscopic examination 

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

organs and tissues were examined for grossly visible 

lesions, and all major tissues were fixed and preserved 

in 10% neutral buffered formalin, processed and 

trimmed, embedded in paraffin, sectioned to a thickness of 5 to 6 μm, and stained with hematoxylin and 

eosin for microscopic examination. For all paired 

organs (i.e., adrenal gland, kidney, ovary), samples 

from each organ were examined. Tissues examined 

microscopically are listed in Table 1. 

Microscopic evaluations were completed by the study 

laboratory pathologist, and the pathology data were 

entered into the Toxicology Data Management System. 

The slides, paraffin blocks, and residual wet tissues 
28 Chloroprene, NTP TR 467 

were sent to the NTP Archives for inventory, 

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

individual animal data records, and pathology tables 

were evaluated by an independent quality assessment 

laboratory. The individual animal records and tables 

were compared for accuracy, the slide and tissue 

counts were verified, and the histotechnique was 

evaluated. For the 2-year rat study, a quality 

assessment pathologist evaluated slides from all tumors 

and all potential target organs, which included the 

esophagus, kidney, larynx, lung, nose, oral mucosa, 

stomach, tongue, and trachea of male and female rats 

and the mammary gland of female rats. For the 2-year 

mouse study, a quality assessment pathologist 

evaluated slides from all tumors and all potential target 

organs, which included the esophagus, harderian 

gland, larynx, liver, lung, mesentery, nose, skin, 

spleen, stomach and forestomach, and trachea of male 

and female mice, the kidney of male mice, and the 

mammary gland and Zymbal’s gland of female mice. 

Step sections were made from the residual kidney wet 

tissue of male and female rats and male mice because 

of a slightly increased trend of proliferative lesions in 

the standard evaluation. Eight additional kidney 

sections taken at 1-mm intervals were prepared for 

each male and female. 

The quality assessment report and the reviewed slides 

were submitted to the NTP Pathology Working Group 

(PWG) chairperson, who reviewed the selected tissues 

and addressed any inconsistencies in the diagnoses 

made by the laboratory and quality assessment 

pathologists. Representative histopathology slides 

containing examples of lesions related to chemical 

administration, examples of disagreements in diagnoses between the laboratory and quality assessment 

pathologists, or lesions of general interest were 

presented by the chairperson to the PWG for review. 

The PWG consisted of the quality assessment 

pathologist and other pathologists experienced in 

rodent toxicologic pathology. This group examined 

the tissues without any knowledge of dose groups or 

previously rendered diagnoses. When the PWG 

consensus differed from the opinion of the laboratory 

pathologist, the diagnosis was changed. Final 

diagnoses for reviewed lesions represent a consensus 

between the laboratory pathologist, reviewing 

pathologist(s), and the PWG. Details of these review 

procedures have been described, in part, by Maronpot 

and Boorman (1982) and Boorman et al. (1985). For 

subsequent analyses of the pathology data, the decision 

of whether to evaluate the diagnosed lesions for each 

tissue type separately or combined was generally based 

on the guidelines of McConnell et al. (1986). 
Chloroprene, NTP TR 467 29 

TABLE 1 

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

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 

Taconic Farms 

(Germantown, NY) 

Time Held Before Studies 

Rats: 10 days (males) or 11 days (females) 

Mice: 12 days (males) or 13 days (females) 

Average Age When Studies Began 

6 to 7 weeks 

Date of First Exposure 

Rats: 28 September 1986 (males) 

29 September 1986 (females) 

Mice: 30 September 1986 (males) 

1 October 1986 (females) 

Duration of Exposure 

6 hours plus T90 (12 minutes) per day, 

5 days per week, for 16 days 

Date of Last Exposure 

Rats: 13 October 1986 (males) 

14 October 1986 (females) 

Mice: 15 October 1986 (males) 

16 October 1986 (females) 

Necropsy Dates 

Rats: 14 October 1986 (males) 

15 October 1986 (females) 

Mice: 16 October 1986 (males) 

17 October 1986 (females) 

Average Age at Necropsy 

8 to 9 weeks 

Size of Study Groups 

10 males and 10 females 

Method of Distribution 

Animals were distributed randomly into 

groups of approximately equal initial mean 

body weight. 

Battelle Pacific Northwest Laboratories 

(Richland, WA) 

Rats: F344/N 

Mice: B6C3F1 

Taconic Farms 

(Germantown, NY) 

Rats: 12 days (males) or 13 days (females) 

Mice: 14 days (males) or 15 days (females) 

Rats: 6 to 7 weeks 

Mice: 6 weeks 

Rats: 10 March 1987 (males) 

11 March 1987 (females) 

Mice: 12 March 1987 (males) 

13 March 1987 (females) 

6 hours plus T90 (12 minutes) per day, 

5 days per week, for 13 weeks 

Rats: 8 June 1987 (males) 

9 June 1987 (females) 

Mice: 10 June 1987 (males) 

11 June 1987 (females) 

Rats: 9 June 1987 (males) 

10 June 1987 (females) 

Mice: 11 June 1987 (males) 

12 June 1987 (females) 

Rats: 19 to 20 weeks 

Mice: 20 weeks 

10 males and 10 females 

Same as 16-day studies 

Battelle Pacific Northwest Laboratories 

(Richland, WA) 

Rats: F344/N 

Mice: B6C3F1 

Simonsen Laboratories, Inc. 

(Gilroy, CA) 

14 days 

6 weeks 

Rats: 20 September 1990 

Mice: 13 September 1990 

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

per week, for 105 weeks 

Rats: 18 September 1992 

Mice: 11 September 1992 

Rats: 21-23 September 1992 

Mice: 14-16 September 1992 

111-112 weeks 

50 males and 50 females 

Same as 16-day studies 
30 

1 

Chloroprene, NTP TR 467 

TABLE 1 

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

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

Animals per Cage 

Method of Animal Identification 

Toe clip 

Diet 

NIH-07 open formula pelleted diet (Zeigler 

Brothers, Inc., Gardners, PA), available 

ad libitum, except during exposure and 

urine collection periods; changed daily 

Water 

Tap water (Richland, WA, municipal 

supply) via automatic watering system 

(Edstrom Industries, Waterford, WI), 

available ad libitum 

Cages 

Stainless steel wire bottom (Hazleton 

Systems, Inc., Aberdeen, MD), changed 

weekly 

Cageboard 

Untreated Techsorb® (Shepherd Specialty 

Papers, Inc., Kalamazoo, MI), changed 

daily 

Chamber Air Supply Filters 

Charcoal filter 

HEPA filters (Flanders Filters, Inc., San 

Rafael, CA), checked twice per year 

Chambers 

Stainless steel, (Hazleton Lab Products, 

Inc., Aberdeen, MD), changed weekly 

Chamber Environment 

Temperature: 21.6E-25.2E C (rats) 

21.9E-25.1E C (mice) 

Relative humidity: 35%-82% (rats)

 35%-87% (mice) 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

Exposure Concentrations 

Rats: 0, 32, 80, 200, or 500 ppm 

Mice: 0, 12, 32, 80, or 200 ppm 

1
 

Ear tag (core study rats)
 

Toe clip (special study rats and all mice)
 

Same as 16-day studies
 

Same as 16-day studies
 

Same as 16-day studies
 

Same as 16-day studies
 

Same as 16-day studies
 

Same as 16-day studies 

Temperature: 21.9E-25.6E C (rats)
 

21.6E-25.1E C (mice) 

Relative humidity: 29%-79% 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

Rats: 0, 5, 12, 32, 80, or 200 ppm 

Mice: 0, 5, 12, 32, or 80 ppm 

1 

Tail tattoo 

Same as 16-day studies 

Tap water (Richland, WA, municipal supply) 

via automatic watering system (System 

Engineering, Napa, CA), available ad libitum 

Stainless steel wire bottom (Lab Products, 

Inc., Maywood, NJ), changed weekly 

Untreated Techsorb® (Shepherd Specialty 

Papers, Inc., Kalamazoo, MI) or untreated 

cageboard (Bunzl Cincinnati Paper Co., 

Cincinnati, OH), changed daily 

Same as 16-day studies 

Same as 16-day studies 

Temperature: 20.2E-26.9E C (rats) 

20.5E-28.5E C (mice) 

Relative humidity: 28%-89% (rats) 

26%-88% (mice) 

Room fluorescent light: 12 hours/day 

Chamber air changes: 15/hour 

0, 12.8, 32, or 80 ppm 
Chloroprene, NTP TR 467 31 

TABLE 1 

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

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

Type and Frequency of Observation 

Observed twice daily; animals were weighed 

initially, after one week, and at the end of 

the studies; clinical findings were recorded 

twice daily. 

Method of Sacrifice 

70% CO2 asphyxiation 

Necropsy 

Necropsy was performed on all animals. 

Organs weighed were the brain, heart, right 

kidney, liver, lungs, spleen, thymus, and 

right testis. 

Clinical Pathology 

On day 4 of exposure, rats were placed in 

metabolism cages for 16-hour urine 

collection. After urine collection, rats were 

anesthetized with CO2 and blood was 

collected from the retroorbital sinus. 

Additional groups of 10 male and 10 female 

mice designated for day 5 hematology 

analyses were exposed to 0, 12, 32, 80, or 

200 ppm. On exposure day 8, mice were 

anesthetized with CO2 and blood was 

collected. 

Hematology: hematocrit; hemoglobin 

concentration; erythrocyte, nucleated 

erythrocyte, reticulocyte, and platelet 

counts; Howell-Jolly bodies (mice); mean 

cell volume; mean cell hemoglobin; mean 

cell hemoglobin concentration; leukocyte 

count and differentials 

Clinical chemistry: urea nitrogen, 

creatinine, alanine aminotransferase, 

glutamate dehydrogenase, and sorbitol 

dehydrogenase 

Urinalysis: volume, specific gravity, 

creatinine, glucose, protein, alkaline 

phosphatase, aspartate aminotransferase, 

urea, and thioethers 

Observed twice daily; animals were weighed 

initially, after one week, and at the end of 

the studies; clinical finding were recorded 

weekly. 

Same as 16-day studies 

Necropsy was performed on all core 

animals. Organs weighed were brain, heart, 

right kidney, liver, lungs, spleen, thymus, 

and right testis. 

Rats bled for hematology and clinical 

chemistry were first placed in metabolism 

cages for 16-hour urine collection. Separate 

groups of 10 male and 10 female rats were 

exposed to 0, 5, 12, 32, 80, or 200 ppm for 

22 days or 13 weeks for hematology, 

clinical chemistry, and urinalysis 

evaluations. Blood was collected from the 

retroorbital sinus of rats designated for 

clinical pathology on day 23 and at week 

14 from the supraorbital sinus of all core 

study mice surviving to the end of the study 

for hematology and clinical chemistry. 

Blood for hematology analyses was also 

collected from the lumbar aorta of groups of 

10 male and 10 female rats (designated for 

coagulation studies) exposed to 0, 32, 80, or 

200 ppm for 2 days. 

Hematology: hematocrit; hemoglobin 

concentration; erythrocyte, nucleated 

erythrocyte, reticulocyte, and platelet 

counts; Howell-Jolly bodies (mice); mean 

cell volume; mean cell hemoglobin; mean 

cell hemoglobin concentrations; leukocytes 

and differentials (reticulocytes and nucleated 

erythrocytes were not counted on day 2) 

Clinical chemistry: urea nitrogen, 

creatinine, alanine aminotransferase, 

glutamate dehydrogenase, and sorbitol 

dehydrogenase 

Urinalysis: creatinine, glucose, protein, 

alkaline phosphatase, aspartate 

aminotransferase, volume, specific gravity, 

urea, and alanine aminotransferase 

Observed twice daily; animals were weighed 

initially, weekly through week 12, 

approximately every 4 weeks from week 15 

through week 91, and every 2 weeks until the 

end of the study; clinical findings were 

recorded initially, at weeks 4, 5 (mice), 8, 12, 

and 15 (rats), every 4 weeks through week 91, 

and every 2 weeks until the end of the study. 

Same as 16-day studies 

Necropsy was performed on all animals. 

None 
32 Chloroprene, NTP TR 467 

TABLE 1 

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

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

Histopathology 

Histopathology was performed on 0, 200, 

and 500 ppm male rats, 0, 80, 200, and 

500 ppm female rats, and 0, 80, and 

200 ppm mice, as well as on target organs 

in other exposure groups to a no-effect 

level. In addition to gross lesions and tissue 

masses, the following tissues were 

examined: bone marrow, brain, heart, 

Complete histopathology was performed on 

0 and 200 ppm rats and 0 and 80 ppm mice. 

The liver of 80 ppm rats and the nose of 

12, 32, and 80 ppm rats were examined 

microscopically. Target organs were 

examined in 5, 12, and 32 ppm mice to a 

no-effect level. Lungs of 5, 12, and 32 ppm 

male mice and forestomachs of 32 ppm male 

Complete histopathology was performed on all 

rats and mice. In addition to gross lesions and

tissue masses, the following tissues were 

examined: adrenal gland, bone and marrow, 

brain, clitoral gland, esophagus, gallbladder 

(mice), heart, large intestine (cecum, colon, 

and rectum), small intestine (duodenum, 

jejunum, and ileum), kidney, liver, lung, 

kidney, larynx, liver, lung, lymph nodes 

(tracheobronchial), nose, spleen, stomach 

(forestomach and glandular stomach), testis 

and epididymis, thymus, and trachea. 

mice were examined microscopically. The 

forestomachs of 32 ppm female mice were 

also examined microscopically. In addition 

to gross lesions and tissue masses, the 

following tissues were examined: adrenal 

lymph nodes (bronchial, mandibular, 

mediastinal, and mesenteric), mammary gland, 

nose, ovary, pancreas, parathyroid gland, 

pituitary gland, preputial gland, prostate gland, 

salivary gland, spleen, stomach (forestomach 

gland, bone and marrow, brain, clitoral and glandular stomach), testis with epididymis 

gland (rats), esophagus, gallbladder (mice), and seminal vesicle, thymus, thyroid gland, 

heart, large intestine (cecum, colon, and trachea, urinary bladder, and uterus. 

rectum), small intestine (duodenum, 

jejunum, and ileum), kidney, liver, lung, 

lymph nodes (bronchial, mandibular, 

mediastinal, and mesenteric), mammary 

gland, nose, ovary, pancreas, parathyroid 

gland, pituitary gland, preputial gland (rats), 

prostate gland, salivary gland, spleen, 

stomach (forestomach and glandular 

stomach), testis with epididymis and seminal 

vesicle, thymus, thyroid gland, trachea, 

urinary bladder, and uterus. 

Sperm Morphology 

and Vaginal Cytology 

None Groups of 10 male and 10 female rats were None 

exposed to 0, 5, 32, or 200 ppm and groups 

of 10 male and 10 female mice were 

exposed to 0, 12, 32, or 80 ppm. At the 

end of the studies, sperm samples were 

collected from male rats and mice for sperm 

morphology evaluations. The following 

parameters were evaluated: sperm 

morphology, count, and motility. The right 

cauda and right epididymis were weighed. 

Vaginal samples were collected for up to 

7 consecutive days prior to the end of the 

studies for vaginal cytology evaluations. 

The following parameters were evaluated: 

relative frequency of estrous stages and 

estrous cycle length. 
Chloroprene, NTP TR 467 33 

TABLE 1 

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

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

Glutathione Evaluation 

None Five male and five female rats were exposed None 

to 0, 5, 32, or 200 ppm and five male and 

five female mice were exposed to 0, 12, 32, 

or 80 ppm for 1 day. Additional groups of 

five male and five female rats and mice 

were exposed to the same concentrations for 

12 weeks. After exposure, animals were 

killed and the kidney, liver, lung, and 

thymus were collected and homogenized for 

determination of total and nonprotein 

sulfhydryl concentrations. 

Coagulation Study 

None Ten male and 10 female rats were exposed None 

to 0, 32, 80, or 200 ppm for two days. 

Blood samples were collected from the 

lumbar aorta and animals were discarded. 

The following parameters were evaluated: 

prothrombin time, activated partial 

thromboplastin time, euglobulin lysis time, 

and platelet and fibrinogen concentration. 

Neurobehavioral Evaluation 

None At week 11, all male and female core study None 

rats were administered neurobehavioral 

tests. The following parameters were 

measured: forelimb/hindlimb grip strength, 

horizontal activity, rearing activity, total 

activity, tailflick latency, startle response 

latency, and startle response amplitude. 
34 Chloroprene, NTP TR 467 

STATISTICAL METHODS 

Survival Analyses 

The probability of survival was estimated by the 

product-limit procedure of Kaplan and Meier (1958) 

and is presented in the form of graphs. Animals found 

dead of other than natural causes or pregnant were 

censored from the survival analyses; animals dying 

from natural causes were not censored. Statistical 

analyses for possible dose-related effects on survival 

used Cox’s (1972) method for testing two groups for 

equality and Tarone’s (1975) life table test to identify 

dose-related trends. All reported P values for the survival analyses are two sided. 

Calculation of Incidence 

The incidences of neoplasms or nonneoplastic lesions 

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

and D5 are given as the number of animals bearing 

such lesions at a specific anatomic site and the number 

of animals with that site examined microscopically. 

For calculation of statistical significance, the incidences of most neoplasms (Tables A3, B3, C3, and 

D3) and all nonneoplastic lesions are given as the 

numbers of animals affected at each site examined 

microscopically. However, when macroscopic examination was required to detect neoplasms in certain 

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

gland, and skin) before microscopic evaluation, or 

when neoplasms had multiple potential sites of occurrence (e.g., leukemia or lymphoma), the denominators consist of the number of animals on which a 

necropsy was performed. Tables A3, B3, C3, and D3 

also give the survival-adjusted neoplasm rate for each 

group and each site-specific 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 risks 

(Kaplan and Meier, 1958). 

Analysis of Neoplasm Incidences 

The majority of neoplasms in these studies were 

considered to be incidental to the cause of death or not 

rapidly lethal. Thus, the primary statistical method 

used was logistic regression analysis, which assumed 

that the 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 prevalence was modeled as a logistic function of 

chemical exposure and time. Both linear and quadratic 

terms in time were incorporated initially, 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 of dose. This method of adjusting for intercurrent mortality is the prevalence 

analysis of Dinse and Lagakos (1983), further described and illustrated by Dinse and Haseman (1986). 

When neoplasms are incidental, this comparison of the 

time-specific neoplasm prevalences also provides a 

comparison of the time-specific neoplasm incidences 

(McKnight and Crowley, 1984). 

In addition to logistic regression, other methods of 

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, and 

the Fisher exact test and the Cochran-Armitage trend 

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

based on the overall proportion of neoplasm-bearing 

animals. 

Tests of significance included pairwise comparisons of 

each exposed group with controls and a test for an 

overall dose-related trend. Continuity-corrected tests 

were used in the analysis of neoplasm incidence, and 

reported P values are one sided. The procedures described in the preceding paragraphs were also used to 

evaluate selected nonneoplastic lesions. For further 

discussion of these statistical methods, refer to 

Haseman (1984). 

Because of the increased mortality in the chloropreneexposed groups of mice, supplemental analyses were 

performed by the survival-adjusted Poly-3 quantal 

response test (Bailer and Portier, 1988; Portier and 

Bailer, 1989). This procedure, which is currently 

being evaluated by the NTP, modifies the CochranArmitage/Fisher exact test by adjusting the denominators of the neoplasm rates to take into account 

survival differences. This adjustment was derived by 

Portier and Bailer (1989), based on their fitting a 

Weibull model to historical control neoplasm data for 

a variety of site-specific neoplasms. The use of the 

power of k=3 in the poly-k adjustment for intercurrent mortality in the chloroprene study is justified by 

the following: (1) For liver and lung neoplasms in 

historical control animals, the observed survivaladjusted value of k that best fits the data is approximately 3 in both male and female mice (Portier et al., 
Chloroprene, NTP TR 467 35 

1986). In male mice, the value of k for all neoplasms 

combined was approximately 3, and for females it was 

approximately 4.5. (2) Simulations have shown that it 

is better (in terms of preserving false positive error 

rate) to underestimate the value of k than to overestimate it. Thus, for example, it is better to use k=3 

when in truth k=6 than it is to use k=6 when in truth 

k=3. Because none of the values for k estimated by 

Portier et al. (1986) were significantly less than 3, and 

few were significantly greater than 3, the choice of 3 

seems reasonable. 

Determining Dose-Response Shape 

and ED10 Values for Chloroprene 

For those neoplasms showing chemical-related effects 

in mice, the shape of the dose-response curve was 

estimated by fitting the following modified Weibull 

model (Portier et al., 1986) to the data: 

shape) P(dose) = 1 - e -(intercept + scale · dose

where P(dose) is the probability of a neoplasm for 

animals administered dose dose of chloroprene. The 

parameters intercept, scale, and shape are estimated 

via maximum likelihood estimation using the 

likelihood

 3 

L = Gx log[P(d )i ] + (n - xi)log[1-P(d )] i=0 i i i 

where xi is the number of animals with neoplasm in 

dose group di, and ni is the Poly-3 adjusted number of 

animals at risk in dose group di. A likelihood ratio 

test is used to test the hypothesis that the shape 

parameter equals 1. The test statistic is given as 

–2 times the differences in the log-likelihoods. A onesided test was used so that the critical values are 2.706 

for P=0.05 and 5.410 for P=0.01 (these are the 

squares of the critical regions from standard normal 

distribution). The shape parameter was restricted to 

be less than or equal to 10. 

If the estimated shape parameter is greater than 1, the 

resulting dose response has more curvature than a 

linear model and exhibits “threshold-like” behavior. 

If the estimated shape parameter is less than 1, then 

the dose-response curve is very steep in the low-dose 

region. The ED10 values obtained from these doseresponse curves represent the exposure concentrations 

associated with an excess cancer risk of 10%. 

Analysis of Nonneoplastic Lesion Incidences 

Because all nonneoplastic lesions in this study were 

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 nonneoplastic 

lesion prevalence was modeled as a logistic function of 

chemical exposure and time. 

Analysis of Continuous Variables 

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

and control groups in the analysis of continuous variables. Organ and body weight data, which have approximately normal distributions, were analyzed with 

the parametric multiple comparison procedures of 

Dunnett (1955) and Williams (1971, 1972). Hematology, clinical chemistry, spermatid, epididymal 

spermatozoal, and neurobehavioral data, which have 

typically skewed distributions, were analyzed using the 

nonparametric multiple comparison methods of Shirley 

(1977) and Dunn (1964). Jonckheere’s test 

(Jonckheere, 1954) was used to assess the significance 

of the dose-related trends and to determine whether a 

trend-sensitive test (Williams’ or Shirley’s test) was 

more appropriate for pairwise comparisons than a test 

that does not assume a monotonic dose-related trend 

(Dunnett’s or Dunn’s test). Prior to statistical analysis, extreme values identified by the outlier test of 

Dixon and Massey (1951) were examined by NTP 

personnel, and implausible values were eliminated 

from the analysis. Average severity values were 

analyzed for significance with the Mann-Whitney U 

test (Hollander and Wolfe, 1973). Because vaginal 

cytology data are proportions (the proportion of the 

observation period that an animal was in a given 

estrous stage), an arcsine transformation was used to 

bring the data into closer conformance with a normality assumption. Treatment effects were investigated by applying a multivariate analysis of 

variance (Morrison, 1976) to the transformed data to 

test for simultaneous equality of measurements across 

exposure concentrations. 

Historical Control Data 

Although the concurrent control group is always the 

first and most appropriate control group used for 

evaluation, historical control data can be helpful in the 

overall assessment of neoplasm incidence in certain 

instances. Consequently, neoplasm incidences from 

the NTP historical control database, which is updated 
36 Chloroprene, NTP TR 467 

yearly, are included in the NTP reports for neoplasms 

appearing to show compound-related effects. 

QUALITY ASSURANCE METHODS 

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

compliance with Food and Drug Administration Good 

Laboratory Practice Regulations (21 CFR, Part 58). 

In addition, as records from the 2-year studies were 

submitted to the NTP Archives, these studies were 

audited retrospectively by an independent quality 

assurance contractor. Separate audits covering completeness and accuracy of the pathology data, pathology specimens, final pathology tables, and a draft of 

this NTP Technical Report were conducted. Audit 

procedures and findings are presented in the reports 

and are on file at NIEHS. The audit findings were reviewed and assessed by NTP staff, so all comments 

had been resolved or were otherwise addressed during 

the preparation of this Technical Report. 

GENETIC TOXICOLOGY 

The genetic toxicity of chloroprene was assessed by 

testing the ability of the chemical to induce mutations 

in various strains of Salmonella typhimurium, sexlinked recessive lethal mutations in Drosophila 

melanogaster, sister chromatid exchanges and chromosomal aberrations in cultured mouse bone marrow 

cells, and increases in the frequency of micronucleated 

erythrocytes in peripheral blood cells of mice. The 

protocols for these studies and the results are given in 

Appendix E. 

The genetic toxicity studies of chloroprene are part of 

a larger effort by the NTP to develop a database that 

would permit the evaluation of carcinogenicity in experimental animals from the molecular structure and 

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

in vivo genetic toxicity tests. These genetic toxicity 

tests were originally developed to study mechanisms of 

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

theory of chemical mutagenesis and the somatic mutation theory of cancer (Miller and Miller, 1977; 

Straus, 1981; Crawford, 1985). 

There is a strong correlation between a chemical’s 

potential electrophilicity (structural alert to DNA 

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

correlated with the induction of carcinogenicity in rats 

and mice and/or at multiple tissue sites (Ashby and 

Tennant, 1991). Other in vitro genetic toxicity tests 

correlate less well with rodent carcinogenicity 

(Tennant et al., 1987; Zeiger et al., 1990), although 

these other tests can provide information on the types 

of DNA and chromosome effects that can be induced 

by the chemical being investigated. Data from NTP 

studies show that a positive response in Salmonella is 

the most predictive in vitro test for rodent carcinogenicity (89% of the Salmonella mutagens are 

rodent carcinogens), and that there is no complementarity among the in vitro genetic toxicity tests. 

That is, no battery of tests that included the 

Salmonella test improved the predictivity of the 

Salmonella test alone. 

The predictivity for carcinogenicity of a positive 

response in bone marrow chromosome aberration or 

micronucleus tests appears to be less than the 

Salmonella test (Shelby et al., 1993; Shelby and Witt, 

1995). Positive responses in long-term peripheral 

blood micronucleus tests have not been formally evaluated for their predictivity for rodent carcinogenicity. 

But, because of the theoretical and observed associations between induced genetic damage and 

adverse effects in somatic and germ cells, the determination of in vivo genetic effects is important to the 

overall understanding of the risks associated with exposure to a particular chemical. 
37 

RESULTS
 

RATS 

16-DAY STUDY 

Three male rats exposed to 500 ppm died on day 2 or 

3 of the study. Twenty-three deaths on day 5 

(10 males and 13 females) occurred when blood was 

withdrawn for clinical pathology evaluations; hence, 

the mortality pattern in this study did not reflect the 

effect of chloroprene exposure. Mean body weight 

gains of 200 ppm males and females and 500 ppm 

females were significantly less than those of the 

TABLE 2 

chamber control groups (Table 2). On the first day of 

exposure, rats exposed to 500 ppm were hypoactive 

and unsteady and had rapid shallow breathing. These 

effects were also observed to some degree in animals 

exposed to 200 ppm. After the second day of 

exposure, the effects in these groups became more 

severe, and blood was observed on the noses of many 

animals. 

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

Dose 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

32 

80 

200 

500 

7/10c 

10/10 

10/10 

9/10c 

1/10d 

115 ± 4 

113 ± 4 

118 ± 5 

114 ± 4 

114 ± 4 

139 ± 5 

134 ± 6 

136 ± 5 

127 ± 5 

104e 

20 ± 2 

20 ± 2 

18 ± 1 

11 ± 2** 

4e 

96 

98 

91 

75 

Female 

0 

32 

80 

200 

500 

9/10c 

9/10c 

9/10c 

3/10c 

7/10c 

100 ± 2 

100 ± 2 

103 ± 2 

101 ± 2 

102 ± 2 

110 ± 3 

109 ± 3 

112 ± 2 

101 ± 4 

103 ± 3 

9 ± 1 

8 ± 1 

9 ± 1 

4 ± 1** 

!1 ± 1** 

99 

102 

92 

94 

** Significantly different (P#0.01) from the chamber control group by Williams’ or Dunnett’s test a Number of animals surviving at 16 days/number initially in group b	 Weights and weight changes are given as mean ± standard error. Subsequent calculations are based on animals surviving to the end of 

the study. 

Day of death: 5 d	 Day of death: 2, 2, 3, 5, 5, 5, 5, 5, 5 e No standard error calculated due to high mortality 

c 
38 Chloroprene, NTP TR 467 

The day 4 hematology, clinical chemistry, and urinal- The incidences of minimal to mild olfactory epithelial 

ysis data for rats are listed in Table G1. A mild to degeneration in all exposed groups of males and 

marked anemia, evidenced by decreases in hematocrit females were significantly greater than those in the 

values, hemoglobin concentrations, and erythrocyte chamber control groups (Table 3). These effects were 

counts occurred in the 200 ppm female and 500 ppm most prominent in the posterior portion of the nasal 

male and female rats. The anemia was characterized cavity, which consists primarily of the ethmoid turbias normocytic and normochromic, as evidenced by the nates covered by olfactory epithelium. The olfactory 

lack of alterations in mean cell volume and mean cell epithelium lining the dorsal meatus, median septum, 

hemoglobin concentration values. Also, there was evi- and tips of the ethmoturbinates was most often afdence of an hematopoietic response to the anemia, fected. Olfactory degeneration consisted of focal thincharacterized by increased reticulocyte and nucleated ning or disorganization of normally stratified olfactory 

erythrocyte counts. A thrombocytopenia, evidenced neurons and sustentacular cells. In some areas of 

by a reduction in circulating platelet numbers, degeneration, there were focal erosions of the 

occurred in the 200 ppm female and 500 ppm male olfactory epithelium and mineralizations within the 

and female rats. mucosa. Frequently, the olfactory epithelium along 

the median septum, dorsal meatus, or tips of the 

The 200 ppm female and 500 ppm male and female ethmoturbinates was replaced by a simple columnar 

rats had increased serum activities of alanine amino- respiratory-like epithelium (metaplasia) in males and 

transferase, glutamate dehydrogenase, and sorbitol females exposed to chloroprene. Other lesions in the 

dehydrogenase relative to the chamber controls; these nasal cavity included squamous metaplasia of the 

findings would be consistent with increased hepato- respiratory epithelium in males and females exposed 

cellular permeability and leakage. Changes in other 500 ppm. Mild to moderate, centrilobular to random 

clinical pathology variables were sporadic and did not hepatocellular necrosis was observed in rats exposed 

demonstrate a treatment relationship; they were not to 200 or 500 ppm. The incidences of centrilobular 

considered toxicologically relevant. necrosis in 500 ppm males and 200 ppm females were 

significantly greater than those in the chamber control 

Absolute and relative right kidney weights of 80 and groups. Scattered chronic centrilobular inflammation 

500 ppm females were significantly greater than those characterized by focal aggregates of lymphocytes and 

of the chamber control group (Table F1). The ab- macrophages was also present in the liver of females 

solute and relative liver weights of 200 and 500 ppm exposed to 200 or 500 ppm and in one male exposed 

females and the absolute liver weight of 80 ppm to 500 ppm. 

females were significantly greater than those of the 

chamber control group. 
39 

c 

Chloroprene, NTP TR 467 

TABLE 3 

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

Chamber 

Control 32 ppm 80 ppm 200 ppm 500 ppm 

Male 

Nosea 

Degeneration, 

Olfactory Epitheliumb 

Metaplasia, Squamous, 

Olfactory Epithelium

Metaplasia, Respiratory, 

Olfactory Epithelium

Metaplasia, Squamous, 

Respiratory Epithelium

10 

1 

0

 0

 1 

(1.0)c 

(1.0)

10 

10** (1.0) 

0

 2 (1.0)

 1 (1.0)

10 

10** (1.1) 

0

 5* (1.0)

 0

10 

10** (1.9) 

1 (2.0)

 6** (1.0)

 0

10 

10** (3.8) 

4* (1.8) 

1 (2.0) 

 7** (1.7) 

Liver 

Necrosis, Centrilobular

Inflammation, Chronic

10

 0

 0

 1 

0

 0

10 

0

 0

10 

1 

0

(2.0)

10 

 9** (3.4) 

1 (2.0) 

Female 

Nose 

Degeneration, 

Olfactory Epithelium

Metaplasia, Squamous, 

Olfactory Epithelium

Metaplasia, Respiratory, 

Olfactory Epithelium

Metaplasia, Squamous, 

Respiratory Epithelium

10 

0

 0

 0

 1 (2.0)

10 

 9** (1.2) 

1 (1.0)

 7** (1.0)

 1 (1.0)

10 

10** (1.6) 

1 (1.0)

 8** (1.2)

 0

10 

10** (3.4) 

4* (1.0)

 3 (1.0)

 0

10 

10** (3.3) 

0 

 7** (1.4) 

4 (1.3) 

Liver 

Necrosis, Centrilobular

Inflammation, Chronic

10

 0

 0

 3 

0

 0

10 

0

 0

10 

 7** (2.6)

 2 (1.0)

10 

3 

5* 

(2.0) 

(1.0) 

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

** P#0.01 a Number of animals with tissue examined microscopically b Number of animals with lesion 

Average severity grade of lesions in affected rats: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked 
40 

c 

Chloroprene, NTP TR 467 

13-WEEK STUDY
 

One male exposed to 200 ppm died during the study groups. In the 200 ppm male group, clinical findings 

(Table 4). The final mean body weights and body related to chloroprene exposure included red or clear 

weight gains of all exposed groups of males and discharge around the nose and eye region and blood 

females were similar to those of the chamber control on the feet. 

TABLE 4 

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

Dose 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

5 

12 

32 

80 

200 

10/10 

10/10 

10/10 

10/10 

10/10 

9/10c 

109 ± 4 

119 ± 2* 

116 ± 1 

117 ± 2 

116 ± 1 

116 ± 3 

311 ± 9 

323 ± 11 

306 ± 9 

327 ± 11 

301 ± 8 

304 ± 8 

202 ± 8 

204 ± 10 

190 ± 8 

209 ± 10 

184 ± 7 

185 ± 7 

104 

98 

105 

97 

98 

Female 

0 

5 

12 

32 

80 

200 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

102 ± 2 

101 ± 1 

102 ± 2 

101 ± 2 

103 ± 1 

102 ± 1 

191 ± 4 

193 ± 4 

199 ± 5 

195 ± 4 

192 ± 3 

183 ± 3 

89 ± 3 

92 ± 3 

97 ± 4 

94 ± 4 

90 ± 3 

81 ± 3 

101 

104 

102 

101 

96 

* Significantly different (P#0.05) from the chamber control group by Williams’ or Dunnett’s test a Number of animals surviving at 13 weeks/number initially in group b Weights and weight changes are given as mean ± standard error. Subsequent calculations are based on animals surviving to the end of the 

study. 

Day of death: 2 

The hematology, clinical chemistry, and urinalysis mean cell volume, mean cell hemoglobin 

data for rats are listed in Table G2. On day 2, min- concentration, and reticulocyte values, respectively. A 

imal increases in hematocrit values, hemoglobin con- thrombocytopenia, evidenced by a reduction in 

centrations, and erythrocyte counts occurred in males circulating platelet numbers, occurred in the 200 ppm 

exposed to 32 ppm or greater and in females exposed male and female rats on days 2 and 80 and 200 ppm 

to 200 ppm; these findings are consistent with a min- females on day 22. At study termination, platelet 

imal relative erythrocytosis related to hemocon- counts rebounded and were minimally increased in 

centration. At week 13, however, a minimal anemia, 200 ppm male and female rats, suggesting an increase 

evidenced by decreased hematocrit values, hemo- in platelet production. On day 2, minimal to mild 

globin concentrations, and erythrocyte counts occurred increases in activated partial thromboplastin time and 

in 200 ppm male and female rats. The anemia was prothrombin time occurred in 200 ppm male and 

characterized as normocytic, normochromic, and non- female rats. 

responsive, as evidenced by the lack of alterations in 
Chloroprene, NTP TR 467 41 

The 200 ppm male and female rats also had increased The absolute and relative kidney weights of 200 ppm 

serum activities of alanine aminotransferase, glutamate males and females and 80 ppm females were sigdehydrogenase, and sorbitol dehydrogenase on day 22; nificantly greater than those of the chamber control 

these increases were transient, and by week 13, the groups (Table F2). The sperm motility of males exserum activities of these enzymes were similar to those posed to 200 ppm was significantly less than that of 

of the chamber controls. There were increases in the chamber control group (Table I1). 

urine volume on day 22 and at week 13 in the 

200 ppm male and female rats; the significance of Neurobehavioral parameters are listed in Table J1. 

these increases was tempered by the inappropriately Compared to chamber controls, horizontal activity was 

high urine volumes for the chamber control animals increased in male rats exposed to 32 ppm or greater. 

which suggested that the urine may have been Total activity was increased in 32 and 200 ppm males. 

contaminated with water. The urine volume increase Other neurobehavioral parameters measured in male 

for the 200 ppm animals, however, was substantial and rats as well as all parameters measured in female rats 

extreme; this suggested that the marked increase in were not affected by chloroprene exposure. 

urine volume in the 200 ppm animals was not of renal 

origin but was probably related to excessive Increased incidences of minimal to mild olfactory 

manipulation of water bottles (for example, due to epithelial degeneration and respiratory metaplasia 

nasal or pharyngeal irritation) exacerbating water occurred in males and females exposed to 80 or 

contamination of the urine collected. Additionally, 200 ppm (Table 5). The incidence of olfactory epithere was no indication of severe renal injury, as thelial degeneration in 32 ppm females was also 

evidenced by the lack of increases in the serum significantly greater than that in the chamber control 

concentration of urea nitrogen or creatinine. Regard- group. These effects were most prominent in the posless of the apparent water contamination, the data for terior portion of the nasal cavity (Level III), which 

the urine constituents could be evaluated based on a consists primarily of the ethmoid turbinates covered by 

urine constituent/urine creatinine ratio, thus amelio- olfactory epithelium. The olfactory epithelium lining 

rating the effects of variable urine volumes. An the dorsal meatus, median septum, and tips of the 

alkaline phosphatase enzymeuria, evidenced by in- ethmoturbinates was most often affected. Olfactory 

creased urine alkaline phosphatase activity, occurred degeneration consisted of focal thinning or disin the 200 ppm female rats on day 22. At week 13, an organization of the normally stratified olfactory neualkaline phosphatase enzymeuria occurred in the males rons and sustentacular cells. In some areas of deexposed to 32 ppm or greater and females exposed to generation, there were focal erosions of the olfactory 

200 ppm. At week 13, a proteinuria, evidenced by epithelium and mineralization within the mucosa. A 

increased urine protein concentration, also occurred in minimal, suppurative inflammatory cell exudate was 

the 200 ppm male rats. Changes in other clinical sometimes present in the nasal cavity adjacent to these 

pathology variables were sporadic, did not erosions. Frequently, the olfactory epithelium along 

demonstrate a treatment relationship, and were not the median septum, dorsal meatus, or tips of the 

considered toxicologically relevant. ethmoturbinates was replaced by a simple columnar 

respiratory-like epithelium (metaplasia). Minimal to 

Tissue nonprotein sulfhydryl (glutathione) deter- mild, centrilobular to random hepatocellular necrosis 

minations are listed in Table H1. Significant reduc- was observed only in rats exposed to 200 ppm. 

tions in nonprotein sulfhydryl concentrations were 

observed in the liver of male rats immediately follow- In 200 ppm females, the incidence of hepatocellular 

ing 1 day or 12 weeks of exposure to 200 ppm and in necrosis was significantly greater than that in the 

the liver of females exposed to 200 ppm for 12 weeks. chamber control group. Scattered chronic inflamNonprotein sulfhydryl concntrations were also reduced mation characterized by focal aggregates of lymphoin the lung of 200 ppm female rats after 1 day but not cytes and macrophages was also present in the liver of 

after 12 weeks of exposure to 200 ppm. Nonprotein male and female rats in the 200 ppm groups; the 

sulfhydryl concentrations in the kidney and thymus incidence in 200 ppm females was significantly greater 

were not reduced by exposure to chloroprene. than that in the chamber control group. Minimal to 
42 Chloroprene, NTP TR 467 

mild, variably sized aggregates of yellow or brown Exposure Concentration Selection Rationale: Based 

material consistent with hemosiderin appeared in small on anemia and hepatocellular necrosis caused by 

vessels or lymphatics in or near portal triads or in exposure to 200 ppm chloroprene, the highest exKupffer cells of rats exposed to 200 ppm. The in- posure concentration selected for the 2-year study was 

cidences of hemosiderin pigmentation were signifi- 80 ppm. The range of exposure concentrations 

cantly increased in males and females exposed to selected for the 2-year study included a no-observable200 ppm. effect level for degenerative lesions of the olfactory 

epithelium. 

TABLE 5 

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

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

Nosea 

Degeneration, 

Olfactory Epitheliumb 

Metaplasia, 

Respiratory, 

Olfactory Epithelium

10

 0

 0

 0 

—

 —

10 

0

 0

10 

3 

0

(1.0)c 

10 

10** (1.6) 

4* (1.3)

10 

10** (2.0) 

4* (1.3) 

Liver 

Necrosis, Centrilobular

Inflammation, Chronic

Hemosiderin Pigmentation

10

 0

 0

 0

 2

 0

 1 

0

(1.0)

 1

 0

 0

 0

 1 

0

 0

 0

10 

0

 1 

0

(1.0)

10 

3 

2 

5* 

(2.0) 

(1.0) 

(1.6) 

Female 

Nose 

Degeneration, 

Olfactory Epithelium 

Metaplasia, 

Respiratory, 

Olfactory Epithelium

10

 0

 0

 0 

—

 —

10 

0

 0

10 

4* 

0

(1.0)

10 

 9** (1.9) 

 8** (2.0)

10 

10** (1.9) 

9** (2.0) 

Liver 

Necrosis, Centrilobular

Inflammation, Chronic

Hemosiderin Pigmentation

10

 0

 2 

3 

(2.0)

(1.0)

 2

 0

 0

 0

 5

 0

 1 

1 

(2.0)

(3.0)

 3 

0

 0

 0

10 

0

 1 

0

(2.0)

10 

5* 

8* 

9** 

(1.0) 

(1.3) 

(1.7) 

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

** P#0.01 a Number of animals with tissue examined microscopically b Number of animals with lesion 

Average severity grade of lesions in affected rats: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c 
43 

c 

Chloroprene, NTP TR 467 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male and 

female rats are shown in Table 6 and in the KaplanMeier survival curves (Figure 1). Survival of males 

exposed to 32 or 80 ppm was significantly less than 

that of the chamber control group. 

TABLE 6 

Body Weights and Clinical Findings 

Mean body weights of males exposed to 80 ppm were 

less than those of the chamber controls after week 93 

(Figure 2 and Tables 7 and 8). Masses of the torso in 

exposed female groups were observed during the 

study, and these findings correlated with mammary 

gland fibroadenomas observed at necropsy. 

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

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Animals initially in study	 50 50 50 50 

Moribund 34 40 41 41 

Natural deaths 3 1 4 5 

Animals surviving to study termination 13 9 5 4 a Percent probability of survival at end of study 26 18 10 8 

Mean survival (days)b 646 638 609 609 

c Survival analysis	 P=0.013 P=0.615 P=0.025 P=0.025 

Female 

Animals initially in study	 50 50 50 50 

Moribund 19 21 23 27 

Natural deaths 1 1 1 2 

Pregnantd 1 0 0 0 

Animals surviving to study termination 29 28 26 21 

Percent probability of survival at end of study 59 56 52 42 

Mean survival (days) 686 685 672 673 

Survival analysis	 P=0.085 P=1.000 P=0.473 P=0.151 

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

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

(Cox, 1972) with the chamber controls are in the exposed group columns. d	 Censored from survival analyses 
 

44 Chloroprene, NTP TR 467 

FIGURE 1
 

Kaplan-Meier Survival Curves for Male and Female Rats
 

Exposed to Chloroprene by Inhalation for 2 Years
 
 

Chloroprene, NTP TR 467 45 

FIGURE 2
 

Growth Curves for Male and Female Rats Exposed
 

to Chloroprene by Inhalation for 2 Years
 
46 Chloroprene, NTP TR 467 

TABLE 7 

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

Weeks Chamber Control 12.8 ppm 32 ppm 80 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 

1 133 50 132 99 50 129 97 50 127 95 50 

2 179 50 179 100 50 175 98 50 170 95 50 

3 209 50 210 100 50 210 101 50 203 97 50 

4 232 50 232 100 50 234 101 50 226 97 50 

5 254 50 253 100 50 256 101 50 246 97 50 

6 274 50 273 99 50 275 100 50 267 97 50 

7 289 50 288 100 50 292 101 50 283 98 50 

8 303 50 301 99 50 307 101 50 299 99 50 

9 317 50 316 100 50 321 102 50 312 99 50 

10 330 50 328 100 50 335 102 50 321 98 50 

11 339 50 339 100 50 346 102 50 334 99 50 

12 351 50 351 100 50 356 102 50 344 98 50 

15 380 50 379 100 50 386 102 50 371 98 50 

19 407 50 406 100 50 413 101 50 401 98 50 

23 428 50 427 100 50 434 101 50 419 98 50 

27 446 50 446 100 50 451 101 50 438 98 50 

31 460 50 461 100 50 468 102 50 454 99 50 

35 471 50 471 100 50 480 102 50 466 99 50 

39 478 50 478 100 50 485 102 50 472 99 50 

43 487 50 487 100 50 495 102 50 481 99 50 

47 494 50 494 100 50 504 102 50 491 99 48 

51 504 50 499 99 50 512 102 50 498 99 48 

55 506 50 506 100 49 517 102 50 500 99 48 

59 516 50 513 99 49 525 102 50 508 98 48 

63 515 50 517 100 48 526 102 50 506 98 48 

68 516 49 520 101 48 536 104 48 510 99 47 

71 516 48 517 100 48 531 103 48 508 98 46 

75 518 48 523 101 47 544 105 41 517 100 44 

79 529 43 532 101 41 548 104 36 516 98 38 

83 527 37 514 98 39 535 102 29 510 97 34 

87 524 34 521 100 33 532 102 25 499 95 29 

91 514 28 511 99 30 510 99 19 499 97 21 

93 525 23 504 96 26 504 96 17 479 91 19 

95 520 21 495 95 24 488 94 16 485 93 13 

97 511 21 502 98 19 487 95 14 481 94 10 

99 494 21 497 101 17 489 99 11 464 94 9 

101 481 16 484 101 11 462 96 9 428 89 6 

103 472 14 478 101 10 466 99 7 387 82 5 

Mean for weeks 

1-13 268 267 100 270 101 261 97 

14-52 456 455 100 463 102 449 99 

53-103 512 508 99 513 100 487 95 
Chloroprene, NTP TR 467 47 

TABLE 8 

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

Weeks Chamber Control 12.8 ppm 32 ppm 80 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 

1 107 50 106 99 50 105 98 50 103 96 50 

2 129 50 129 101 50 125 97 50 121 94 50 

3 140 50 140 101 50 137 98 50 133 95 50 

4 151 50 151 100 50 147 98 50 142 94 50 

5 159 50 161 101 50 156 98 50 150 95 50 

6 166 50 168 101 50 163 98 50 159 96 50 

7 171 50 174 102 50 171 100 50 165 97 50 

8 175 50 177 101 50 175 100 50 170 97 50 

9 181 50 183 101 50 181 100 50 176 97 50 

10 187 50 189 101 50 188 101 50 181 97 50 

11 191 50 193 102 50 193 101 50 187 98 50 

12 195 50 198 102 50 197 101 50 192 98 50 

15 208 50 209 101 50 211 102 50 203 98 50 

19 219 50 219 100 50 222 102 50 220 101 50 

23 230 50 231 101 50 233 101 50 226 99 50 

27 238 50 237 100 50 241 101 50 236 99 50 

31 249 50 248 100 50 252 101 50 248 100 50 

35 257 49 260 101 50 263 103 50 258 101 50 

39 267 49 269 101 50 274 103 50 269 101 50 

43 280 49 280 100 50 284 102 50 280 100 50 

47 290 49 293 101 49 297 102 50 293 101 50 

51 297 49 304 102 48 306 103 50 302 102 50 

55 304 48 308 101 48 310 102 50 308 101 50 

59 318 48 320 101 48 324 102 50 320 101 50 

63 323 47 326 101 48 332 103 50 328 101 49 

68 330 47 333 101 48 340 103 49 336 102 48 

71 336 47 338 101 47 344 103 48 336 100 48 

75 344 47 342 99 47 351 102 48 345 100 48 

79 348 47 346 99 46 353 102 45 350 101 47 

83 353 45 351 100 44 362 103 44 358 102 44 

87 359 41 360 100 43 370 103 36 361 100 42 

91 360 40 360 100 42 367 102 34 365 101 36 

93 355 39 358 101 42 366 103 33 369 104 33 

95 356 36 360 101 41 368 103 31 366 103 32 

97 365 33 360 99 38 366 100 31 367 101 28 

99 365 32 361 99 34 366 100 29 369 101 27 

101 366 30 361 99 33 367 100 27 370 101 25 

103 364 30 366 101 31 367 101 27 363 100 23 

Mean for weeks 

1-13 163 164 101 162 99 157 96 

14-52 254 255 101 258 102 254 100 

53-103 347 347 100 353 102 351 101 
 

48 Chloroprene, NTP TR 467 

Pathology and Statistical Analysis 

This section describes the statistically significant or 

biologically noteworthy changes in the incidences of 

neoplasms and/or nonneoplastic lesions of the oral 

cavity, thyroid gland, lung, mammary gland, kidney, 

urinary bladder, and nose. Summaries of the incidences of neoplasms and nonneoplastic lesions, 

individual animal tumor diagnoses, statistical analysis 

of primary neoplasms that occurred with an incidence 

of at least 5% in at least one group, and historical 

incidences for the neoplasms mentioned in this section 

are presented in Appendix A for male rats and 

Appendix B for female rats. 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, and 

Gingiva): The incidences of squamous cell papilloma and squamous cell papilloma or squamous cell 

carcinoma (combined) in male rats exposed to 32 ppm 

and male and female rats exposed to 80 ppm were significantly greater than those in the chamber controls 

and exceeded the historical control ranges (Tables 9, 

A3, A4a, B3, and B4a ). Squamous cell carcinoma, 

squamous cell papilloma, and squamous hyperplasia 

involved the palate, pharynx, gingiva, cheek, and 

tongue. One squamous cell papilloma was located in 

the upper esophagus of an 80 ppm female. Squamous 

cell carcinomas were characterized by multiple 

papillary projections covered by several layers of welldifferentiated to anaplastic squamous epithelium 

overlying a fibrovascular core (Plates 1 and 2). 

Islands of anaplastic epithelium invaded the stalk 

and/or underlying connective tissue; keratin “pearls” 

were often present. Mitotic activity was sometimes 

increased in the neoplastic cells. Squamous cell 

papillomas were well differentiated and did not invade 

adjacent tissues (Plates 3 and 4). In most cases 

papillomas had a narrow base or stalk connecting to 

adjacent unaffected mucosa. Squamous hyperplasia 

observed in three males in the 80 ppm group was 

characterized by focal thickening and folding of the 

squamous epithelium with a few blunt papillary 

projections. 
 

Chloroprene, NTP TR 467 49 

TABLE 9 

Incidences of Neoplasms and Nonneoplastic Lesions of the Oral Cavity in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Necropsied 50 50 50 50 

Squamous Cell Hyperplasiaa 0 0 0 3 (2.7)b 

Squamous Cell Papillomac 

Overall rated 0/50 (0%) 2/50 (4%) 4/50 (8%) 10/50 (20%) e Adjusted rate 0.0% 13.8% 25.4% 71.7% 

Terminal ratef 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) —h 701 620 539 

Logistic regression testg P<0.001 P=0.217 P=0.040 P<0.001 

Squamous Cell Carcinoma 

Overall rate 0/50 0/50 1/50 (2%) 2/50 (4%) 

Squamous Cell Papilloma or Squamous Cell Carcinomai 

Overall rate 0/50 (0%) 2/50 (4%) 5/50 (10%) 12/50 (24%) 

Adjusted rate 0.0% 13.8% 28.4% 74.9% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) — 701 609 539 

Logistic regression test P<0.001 P=0.217 P=0.022 P<0.001 

Female 

Squamous Cell Papillomaj 

Overall rate 1/49 (2%) 2/50 (4%) 2/50 (4%) 7/50 (14%) 

Adjusted rate 3.0% 6.2% 7.7% 29.5% 

Terminal rate 0/29 (0%) 1/28 (4%) 2/26 (8%) 5/21 (24%) 

First incidence (days) 687 681 733 (T) 660 

Logistic regression test P=0.003 P=0.508 P=0.469 P=0.020 

Squamous Cell Carcinoma 

Overall rate 0/49 (0%) 1/50 (2%) 3/50 (6%) 4/50 (8%) 

Squamous Cell Papilloma or Squamous Cell Carcinomak 

Overall rate 1/49 (2%) 3/50 (6%) 5/50 (10%) 11/50 (22%) 

Adjusted rate 3.0% 9.2% 17.4% 40.8% 

Terminal rate 0/29 (0%) 1/28 (4%) 4/26 (15%) 6/21 (29%) 

First incidence (days) 687 681 588 660 

Logistic regression test P<0.001 P=0.315 P=0.093 P=0.001 

(T)Terminal sacrifice 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 8/655 (1.2% ± 1.9%); 

range 0%-6% d	 Number of animals with neoplasm per number of animals necropsied e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Not applicable; no neoplasms in animal group i	 Historical incidence: 9/655 (1.4% ± 1.9%); range 0%-6% j Historical incidence: 3/653 (0.5% ± 0.9%); range 0%-2% k Historical incidence: 8/653 (1.2% ± 1.7%); range 0%-6% 
50 Chloroprene, NTP TR 467 

Thyroid Gland: The incidences of follicular cell adenoma or carcinoma (combined) in males exposed to 

32 or 80 ppm were significantly greater than that in 

the chamber control group and exceeded the historical 

control range (Tables 10, A3, and A4b). Although the 

incidences of follicular cell adenoma and follicular cell 

adenoma or carcinoma (combined) in 80 ppm females 

were not significantly greater than those in the 

chamber controls, they did exceed the historical 

control range for these neoplasms (Tables 10, B3, and 

B4b). Follicular cell carcinomas obliterated the 

thyroid gland and sometimes invaded the capsule or 

adjacent structures. Patterns varied from solid to 

papillary to follicular, with a mixture of these patterns 

present in most neoplasms. Cells were pleomorphic 

and cuboidal to high columnar, with a high 

nucleus:cytoplasm ratio and varying degrees of 

atypia. Mitoses were common in carcinomas, as were 

areas of necrosis, mineralization, and cholesterol 

clefts. 

Follicular cell adenomas were characterized by 

branching papillary or follicular patterns of relatively 

uniform cuboidal to columnar cells on a delicate 

fibrovascular stroma. Adenomas were well demarcated and cells were hyperchromatic, while mitotic 

figures were rare. The incidence of follicular cell hyperplasia was significantly increased in 32 ppm males. 

Follicular cell hyperplasia was focal and characterized 

by one or a few enlarged follicles with several much 

smaller follicles inside and to one side. The increased 

number of cells resulted in a few simple papillary 

projections into the lumen. 
Chloroprene, NTP TR 467 51 

TABLE 10 

Incidences of Neoplasms and Nonneoplastic Lesions of the Thyroid Gland in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Follicular Cell Hyperplasiaa 50 0

50 

2 (2.0)b 

49 

4* (1.8)

50 

1 (1.0) 

Follicular Cell Adenomac 

Overall rated 0/50 (0%) 2/50 (4%) 2/49 (4%) 4/50 (8%) 

Follicular Cell Carcinoma 

Overall rate 0/50 (0%) 0/50 (0%) 2/49 (4%) 1/50 (2%) 

Follicular Cell Adenoma or Carcinomae 

Overall rate 

Adjusted ratef 

Terminal rateg 

First incidence (days) 

Logistic regression testh 

0/50 (0%) 

0.0% 

0/13 (0%) 

—i 

P=0.029 

2/50 (4%) 

13.5% 

1/9 (11%) 

597 

P=0.232 

4/49 (8%) 

29.5% 

1/5 (20%) 

569 

P=0.050 

5/50 (10%) 

36.3% 

1/4 (25%) 

307 

P=0.044 

Female 

Number Examined Microscopically 49 50 50 50 

Follicular Cell, Hyperplasia 0 0 0 2 (2.5) 

Follicular Cell Adenomaj 

Overall rate 1/49 (2%) 1/50 (2%) 0/50 (0%) 3/50 (6%) 

Follicular Cell Carcinoma 

Overall rate 0/49 (0%) 0/50 (0%) 1/50 (2%) 2/50 (4%) 

Follicular Cell Adenoma or Carcinomak 

Overall rate 1/49 (2%) 1/50 (2%) 1/50 (2%) 5/50 (10%) 

Adjusted rate 3.4% 3.2% 3.8% 16.8% 

Terminal rate 1/29 (3%) 0/28 (0%) 1/26 (4%) 1/21 (5%) 

First incidence (days) 733 (T) 721 733 (T) 617 

Logistic regression test P=0.017 P=0.753N P=0.738 P=0.098 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

(T)Terminal sacrifice 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 3/641 (0.5% ± 0.9%);
 

range 0%-2% d	 Number of animals with neoplasm per number of animals with thyroid gland examined microscopically e Historical incidence: 11/641 (1.7% ± 1.6%); range 0%-4% f	 Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality g	 Observed incidence in animals surviving until the end of the study h	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. A lower incidence in an exposure group is indicated by N. i	 Not applicable; no neoplasms in animal group j Historical incidence: 2/642 (0.3% ± 0.8%); range 0%-2% k Historical incidence: 8/642 (1.3% ± 1.9%); range 0%-6% 
52 Chloroprene, NTP TR 467 

Lung: The incidences of alveolar epithelial hyperplasia were significantly greater in all exposed groups 

of males and females than in the chamber control 

groups (Table 11). Most hyperplasia was graded minimal; however, exposed rats had more foci of hyperplasia per lung section than did chamber controls. The 

incidences of alveolar/bronchiolar carcinoma and 

alveolar/bronchiolar adenoma or carcinoma (combined) in 80 ppm males were slightly greater than 

those in the chamber control group (Tables 11 and 

A1). Although these incidences were not significant, 

they exceeded the historical control range for these 

neoplasms (Table A4c). Furthermore, one male exposed to 80 ppm had multiple alveolar/bronchiolar 

carcinomas, and one male exposed to 80 ppm and one 

exposed to 32 ppm had carcinomas which metastasized to mediastinum or bronchial lymph nodes 

(Table A1). Although not significant, the incidence of 

alveolar/bronchiolar adenoma was greater in 80 ppm 

females than in the chamber controls. Alveolar/ 

bronchiolar carcinomas were solid or papillary, 

obliterated normal pulmonary architecture, and 

sometimes invaded the pleura or other adjacent structures. A scirrhous response was seen in some carcinomas. Cells were cuboidal to columnar but often 

pleomorphic, with a high nucleus:cytoplasm ratio and 

numerous mitoses. Alveolar adenomas were usually 

papillary and distorted the alveolar architecture. Cells 

were cuboidal to columnar and well differentiated. 
Chloroprene, NTP TR 467 53 

TABLE 11 

Incidences of Neoplasms and Nonneoplastic Lesions of the Lung in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Alveolar Epithelium, Hyperplasiaa 50 5 (1.4)b 

50 

16** (1.4) 

49 

14* (1.9) 

50 

25** (1.4) 

Alveolar/bronchiolar Adenoma 

Overall ratec 2/50 (4%) 0/50 (0%) 3/49 (6%) 3/50 (6%) 

Alveolar/bronchiolar Carcinomad 

Overall rate 

Adjusted ratee 

Terminal ratef 

First incidence (days) 

Logistic regression testg 

0/50 (0%) 

0.0% 

0/13 (0%) 

—h 

P=0.023 

2/50 (4%) 

17.9% 

1/9 (11%) 

702 

P=0.200 

1/49 (2%) 

6.7% 

0/5 (0%) 

667 

P=0.452 

4/50 (8%) 

35.1% 

1/4 (25%) 

540 

P=0.052 

Alveolar/bronchiolar Adenoma or Carcinomai 

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

Adjusted rate 6.9% 17.9% 19.9% 59.3% 

Terminal rate 0/13 (0%) 1/9 (11%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 616 702 505 540 

Logistic regression test P=0.039 P=0.684 P=0.366 P=0.094 

Female 

Number Examined Microscopically 49 50 50 50 

Alveolar Epithelium, Hyperplasia 6 (1.8) 22** (1.4) 22** (1.5) 34** (1.3) 

Alveolar/bronchiolar Adenomaj 

Overall rate 1/49 (2%) 0/50 (0%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 3.4% 0.0% 0.0% 9.6% 

Terminal rate 1/29 (3%) 0/28 (0%) 0/26 (0%) 1/21 (5%) 

First incidence (days) 733 (T) — — 613 

Logistic regression test P=0.066 P=0.507N P=0.522N P=0.314 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Number of animals with neoplasm per number of animals with lung examined microscopically d	 Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 6/654 (0.9% ± 1.0%); 

range 0%-2% e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. A lower incidence in an exposure group is indicated by N 

h	 Not applicable; no neoplasms in animal group i	 Historical incidence: 23/654 (3.5% ± 3.7%); range 0%-10% j Historical incidence: 7/650 (1.1% ± 1.6%); range 0%-4% 
 

54 

c 

Chloroprene, NTP TR 467 

Mammary Gland: The incidences of multiple fi- historical control range (Tables 12 and B4d). 

broadenoma in all exposed groups of female rats were Fibroadenomas were characterized by collections of 

greater than that in the chamber control group glandular epithelium arranged in acini and ducts and 

(Tables 12 and B1). The incidences of fibroadenoma surrounded by fibrous connective tissue. The relative 

(including multiple fibroadenoma) in 32 and 80 ppm amounts of glandular and fibrous elements varied 

females were significantly greater than that in the greatly among neoplasms. Epithelial cells were usuchamber controls (Tables 12, B1, and B3). The inci- ally uniform and arranged in a single layer; a few 

dences of fibroadenoma in the chamber control group fibroadenomas had small areas of cellular atypia. 

and in all exposed groups of females exceeded the 

TABLE 12 

Incidences of Neoplasms of the Mammary Gland in Female Rats in the 2-Year Inhalation Study 

of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Fibroadenoma (multiple) 

Overall ratea 5/49 (10%) 12/50 (24%) 15/50 (30%)** 19/50 (38%)* 

Fibroadenoma (includes multiple)b 

Overall rate 

Adjusted ratec 

Terminal rated 

24/49 (49%) 

65.4% 

17/29 (59%) 

32/50 (64%) 

86.0% 

23/28 (82%) 

36/50 (72%) 

85.3% 

20/26 (77%) 

36/50 (72%) 

89.7% 

17/21 (81%) 

First incidence (days) 

Logistic regression teste 366 

P=0.005 

302 

P=0.130 

470 

P=0.011 

433 

P=0.009 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 a Number of animals with neoplasm per number of animals necropsied b	 Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 180/653 (27.6% ± 7.7%); 

range 16%-42% 

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 chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. 

Kidney: The severity of nephropathy in exposed intervals were prepared for each male and female. 

groups of male and female rats was slightly greater Additional males and females with focal hyperplasia or 

than in the chamber controls (Table 13). The inci- adenomas and one 12.8 ppm male with a carcinoma 

dences of renal tubule nephropathy in 32 and 80 ppm were identified. The incidences of these proliferative 

females were significantly increased relative to that in lesions in standard and extended evaluations are 

the chamber control group (Tables 13 and B5). presented in Table 13. 

Initially, a single hematoxylin- and eosin-stained 

section of each kidney was prepared. Primarily 

because of the slightly increased trends and incidences The step-section and combined single- and step-section 

of renal tubule hyperplasia and renal tubule adenoma incidences of renal tubule hyperplasia in 32 ppm males 

identified in male and female rats by the standard and 80 ppm males and females were significantly 

evaluation, additional step sections of kidney were greater than those in the chamber controls. In all 

prepared from the remaining formalin-fixed tissues. exposed groups of males, the step-section and 

Eight additional kidney sections taken at 1-mm combined single- and step-section incidences of 
Chloroprene, NTP TR 467 55 

TABLE 13 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 50 50 50 50 

Single Sections (Standard Evaluation) 

Nephropathya 50 (2.8)b 50 (3.0) 50 (3.1) 50 (3.5)** 

Renal Tubule Hyperplasia 2 (2.5) 3 (2.3) 6 (2.5) 6 (1.8) 

Oncocytic Hyperplasia 0 0 0 2 (2.5) 

Mesenchymal Tumor, NOS 

Overall ratec 0/50 (0%) 0/50 (0%) 0/50 (0%) 2/50 (4%) 

Renal Tubule Adenomad 

Overall rate 0/50 (0%) 1/50 (0%) 1/50 (2%) 2/50 (4%) 

Step Sections (Extended Evaluation) 

Renal Tubule Hyperplasia 12 (1.9) 19 (2.6) 27** (2.0) 34** (2.8) 

Renal Tubule Adenoma 

Overall rate 

Adjusted ratee 

Terminal ratef 

1/50 (2%) 

7.7% 

1/13 (8%) 

6/50 (12%) 

37.0% 

2/9 (22%) 

6/50 (12%) 

52.5% 

0/5 (0%) 

7/50 (14%) 

65.9% 

2/4 (50%) 

First incidence (days) 

Logistic regression testg 

733 (T) 

P=0.010 

600 

P=0.047 

679 

P=0.007 

625 

P=0.005 

Renal Tubule Adenoma or Carcinoma 

Overall rate 1/50 (2%) 7/50 (14%) 6/50 (12%) 7/50 (14%) 

Adjusted rate 7.7% 39.8% 52.5% 65.9% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Logistic regression test P=0.016 P=0.025 P=0.007 P=0.005 

Single Sections and Step Sections (Combined) 

Renal Tubule Hyperplasia 14 (2.0) 20 (2.6) 28** (2.1) 34** (2.9) 

Renal Tubule Adenoma 

Overall rate 1/50 (2%) 7/50 (14%) 6/50 (12%) 8/50 (16%) 

Adjusted rate 7.7% 40.7% 52.5% 70.7% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Logistic regression test P=0.005 P=0.024 P=0.007 P=0.002 

Renal Tubule Adenoma or Carcinoma 

Overall rate 1/50 (2%) 8/50 (16%) 6/50 (12%) 8/50 (16%) 

Adjusted rate 7.7% 43.4% 52.5% 70.7% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Logistic regression test P=0.008 P=0.013 P=0.007 P=0.002 
56 

c 

Chloroprene, NTP TR 467 

TABLE 13 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Female 

Number Examined Microscopically 49 50 50 50 

Single Sections (Standard Evaluation) 

Nephropathy 

Renal Tubule Hyperplasia 

Oncocytic Hyperplasia 

43 

0 

0 

(1.9) 48 

0 

0 

(2.0) 49* (2.0) 

1 (2.0) 

0 

49* (2.2)* 

4 (1.5) 

1 (2.0) 

Mesenchymal Tumor, NOS 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 1/50 (2%) 

Renal Tubule Adenomah 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 2/50 (4%) 

Step Sections (Extended Evaluation) 

Renal Tubule Hyperplasia 6 (1.3) 6 (1.8) 11 (2.1) 19** (1.9) 

Renal Tubule Adenoma 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 2/50 (4%) 

Single Sections and Step Sections (Combined) 

Renal Tubule Hyperplasia 6 (1.3) 6 (1.8) 11 (2.1) 21** (2.0) 

Renal Tubule Adenoma or Carcinoma 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

*	 Significantly different (P#0.05) from the chamber control group by the logistic regression test (incidences) or by the Mann-Whitney U test 

(severity) 

** P#0.01 

(T)Terminal sacrifice 

a	 Number of animals with lesion 

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

Number of animals with lesion per number of animals microscopically examined d Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 6/652 (0.9% ±1.3%); 

range 0%-4% e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Historical incidence: 1/650 (0.2% ± 0.6%); range 0%!2% 

renal tubule adenoma and renal tubule adenoma or dilated to l.5 to 2 times the normal diameter and were 

carcinoma (combined) were significantly greater than lined by increased numbers of tubule epithelial cells 

those in the chamber control group. Renal tubule that partially or totally filled the tubule lumen. Cells 

hyperplasia, as defined in the present study, was within hyperplastic lesions varied slightly in size and 

distinguished from regenerative epithelial changes sometimes stained more basophilic then normal cells 

commonly seen as a part of nephropathy and was con- but otherwise appeared similar to normal tubule 

sidered a preneoplastic lesion. Renal tubule hyper- epithelial cells. Renal tubule adenomas were larger, 

plasia, adenoma, and carcinoma constitute a morpho- discrete lesions ranging from greater than five tubule 

logic continuum. Hyperplasia was generally a focal, diameters to 1 mm or more in size. Cells within ademinimal to mild lesion consisting of tubules that were nomas were mildly to moderately pleomorphic, 
Chloroprene, NTP TR 467 57 

sometimes had vacuolated cytoplasm, and tended to were generally minimal to mild in severity. Necrosis 

form complex patterns, particularly microtubular of the olfactory epithelium was characterized by areas 

structures. Renal tubule carcinoma was well of karyorrhexis and sloughing of olfactory epithelium 

differentiated from adenoma in that it was larger and with cell debris in the lumen in the dorsal meatus. 

less discrete and had a prominent vascular supply, Chronic inflammation was characterized by 

more anaplasia, and more cellular atypia. Renal serofibrinous exudate (neutrophils, fibrin, 

tubule carcinoma was characterized by vesiculate proteinaceous fluid, cell debris) in the lumen of Levels 

nuclei with prominent nucleoli and increased numbers II and III with necrosis and fusion of turbinates. Most 

of mitotic figures. Oncocytic hyperplasia was often involved were the dorsal meatus, dorsal septum, 

observed at the end of the study in two males and one and adjacent portions of ethmoid turbinates. Atrophy 

female exposed to 80 ppm. This lesion was of the olfactory epithelium was characterized by 

characterized by individual tubules or small clusters of decreased numbers of layers of olfactory epithelium 

tubules that were somewhat dilated and totally filled and included loss of Bowman’s glands and olfactory 

by large polygonal cells with abundant, brightly axons in more severe cases. Atrophy was usually 

eosinophilic, granular cytoplasm and small, centrally accompanied by respiratory metaplasia. Metaplasia of 

located, basophilic nuclei (oncocytes). These lesions the olfactory epithelium was characterized by 

are thought to arise from the distal tubule epithelium. replacement of olfactory epithelium with ciliated, 

Transitional cell neoplasms were also observed in one columnar, respiratory-like epithelium. Adenomatous 

male and one female in the 12.8 ppm groups. In hyperplasia of the olfactory epithelium was 

addition, mesenchymal tumors of the kidney were characterized by proliferation of respiratory-like 

observed in one male and one female exposed to epithelium in areas of inflammation, usually involving 

80 ppm (Tables A1 and B1). the dorsal septum and adjacent portions of turbinates 

(Plates 5 and 6). The epithelium was taller than 

Urinary Bladder: Two 80 ppm females had transi- normal and had increased numbers of cells, including 

tional epithelium carcinomas (Table B1). One tran- goblet cells; underlying glands were often lined by 

sitional epithelium carcinoma was observed in a goblet cells and dilated by mucus. The hyperplasia 

32 ppm male, and one transitional cell papilloma was varied in severity from forming a few folds in the 

observed in an 80 ppm male (Table A1). These find- epithelium, to folds with accompanying hyperplastic 

ings are noteworthy because no urinary bladder glands, to extensive papillary formations. It was 

neoplasms have been seen in chamber control male or primarily observed in the 80 ppm groups. Basal cell 

female F344/N rats (Tables A4e and B4f). hyperplasia of the olfactory epithelium was 

characterized by proliferation or increased thickness of 

Nose (Olfactory Epithelium): The incidences of atro- the basal cell layer in turbinates and septum of Level 

phy, basal cell hyperplasia, metaplasia, and necrosis of III and dorsally in Level II (Plates 7 and 8). Fibrosis 

the olfactory epithelium in 32 and 80 ppm males and of the olfactory epithelium was characterized by 

females and atrophy and necrosis in 12.8 ppm males replacement of normal lamina propria in turbinates and 

were significantly greater than those in the chamber septum of Level III with collagenous connective tissue. 

control groups (Tables 14, A5, and B5). The It was usually associated with basal cell hyperplasia. 

incidences of chronic inflammation were significantly Focal fibrosis of the turbinate was characterized by 

increased in males exposed to 12.8 or 32 ppm and in turbinates that were abnormally fused with the septum 

males and females exposed to 80 ppm. The incidences or each other, and there was no active inflammation in 

of fibrosis and adenomatous hyperplasia in 80 ppm the section. Such fusion was found in a few rats 

males and females were significantly greater than those exposed to 12.8 or 32 ppm and may have represented 

in the chamber controls. Lesions in the nasal cavity a healed site of previous necrosis. 
 

 

 

 

 

 

 

 

 

58 Chloroprene, NTP TR 467 

TABLE 14 

Incidences of Nonneoplastic Lesions of the Olfactory Epithelium in Rats 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Atrophya 

Fibrosis

Hyperplasia, Adenomatous

Hyperplasia, Basal Cell

Inflammation, Chronic Active

Metaplasia

Necrosis

50 

3 

0

 2 

0

 0

 6 

0 

(1.7)b 

(2.0) 

(1.7) 

50 

12* 

0

 0

 0 

5* 

5 

11** 

(1.8) 

(1.0) 

(1.0) 

(2.0) 

49 

46** (2.2) 

0 

1 (2.0) 

38** (1.6) 

9** (1.6) 

45** (1.8) 

26** (2.0) 

49 

48** 

47** 

42** 

46** 

49** 

48** 

19** 

(3.6) 

(2.7) 

(2.0) 

(2.2) 

(2.7) 

(3.1) 

(2.2) 

Female 

Number Examined Microscopically 

Atrophy

Fibrosis

Hyperplasia, Adenomatous

Hyperplasia, Basal Cell

Inflammation, Chronic Active

Metaplasia

Necrosis

49 

0

 0

 0

 0

 0

 0 

0

50 

1 

0

 0

 0 

0

 1 

0

(1.0) 

(1.0) 

50 

40** (1.3) 

0 

0 

17** (1.1) 

2 (1.0) 

35** (1.0) 

8** (2.0) 

50 

50** 

49** 

27** 

49** 

33** 

50** 

12** 

(2.9) 

(2.2) 

(2.0) 

(2.3) 

(2.0) 

(2.7) 

(1.3) 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal, 2 = mild, 3 = moderate, 4 = marked 
59 

c 

Chloroprene, NTP TR 467 

MICE
 

16-DAY STUDY group. Mice exposed to 200 ppm exhibited narcosis 

All males and females exposed to 200 ppm died on during exposure and were hypoactive with reduced 

day 2 or day 3 of the study (Table 15). Mean body body tone after the first day of exposure. There were 

weight gains of males exposed to 32 or 80 ppm were no other clinical findings related to chloroprene 

significantly less than that of the chamber control exposure. 

TABLE 15 

Survival and Body Weights of Mice in the 16-Day Inhalation Study of Chloroprene 

Dose 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

12 

32 

80 

200 

10/10 

10/10 

10/10 

10/10 

0/10c 

24.7 ± 0.5 

24.8 ± 0.5 

25.3 ± 0.3 

24.8 ± 0.5 

24.2 ± 0.4 

27.0 ± 0.5 

27.1 ± 0.6 

26.5 ± 0.3 

26.1 ± 0.6 

— 

2.3 ± 0.1 

2.3 ± 0.3 

1.2 ± 0.3** 

1.3 ± 0.2** 

— 

100 

98 

97 

— 

Female 

0 

12 

32 

80 

200 

10/10 

10/10 

10/10 

10/10 

0/10d 

19.5 ± 0.7 

20.4 ± 0.8 

19.9 ± 1.0 

20.1 ± 0.8 

20.0 ± 0.6 

22.6 ± 0.5 

23.1 ± 0.4 

22.1 ± 0.2 

22.5 ± 0.3 

— 

2.3 ± 0.3 

2.6 ± 0.3 

1.8 ± 0.3 

2.7 ± 0.3 

— 

102 

98 

100 

— 

** Significantly different (P#0.01) from the chamber control group by Williams’ or Dunnett’s test a Number of animals surviving at 16 days/number initially in group b Weights and weight changes are given as mean ± standard error. No data were calculated for groups with 100% mortality. 

Day of death: 2, 2, 2, 2, 2, 3, 3, 3, 3, 3 d Day of death: 2, 2, 2, 2, 2, 2, 3, 3, 3, 3 

In general, hematology and clinical chemistry para- Increased incidences of multifocal random hepatometers measured for exposed males and females were cellular necrosis occurred in males and females 

similar to those of the chamber control group exposed to 200 ppm. Hypertrophy of the myocar­

(Table G3). dium, foci of hemorrhage, and mucosal erosion were 

observed in three males and three females exposed to 

The absolute and relative thymus weights of 80 ppm 200 ppm. Squamous epithelial hyperplasia of the 

rats were significantly less than those of the chamber forestomach was observed in two males and two 

control groups (Table F3). The absolute and relative females exposed to 80 ppm. Thymic necrosis, characliver weights of 80 ppm females and relative liver terized by karyorrhexis of thymic lymphocytes, was 

weights of 80 ppm males were significantly greater observed in all males and females in the 200 ppm 

than those of the chamber control groups. groups. 
 

60 Chloroprene, NTP TR 467 

13-WEEK STUDY 

All male and female mice survived to the end of the significantly less than those of the chamber control 

study (Table 16). The final mean body weight and group. There were no clinical findings attributed to 

body weight gain of males exposed to 80 ppm were chloroprene exposure. 

TABLE 16 

Survival and Body Weights of Mice in the 13-Week Inhalation Study of Chloroprene 

Dose 

(ppm) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

5 

12 

32 

80 

10/10 

10/10 

10/10 

10/10 

10/10 

25.5 ± 0.4 

25.2 ± 0.3 

25.2 ± 0.2 

25.4 ± 0.2 

24.7 ± 0.3 

35.9 ± 0.9 

35.1 ± 0.9 

34.9 ± 0.6 

36.0 ± 0.9 

32.7 ± 0.6* 

10.5 ± 0.7 

10.0 ± 0.7 

9.7 ± 0.6 

10.6 ± 0.9 

7.9 ± 0.5* 

98 

97 

100 

91 

Female 

0 

5 

12 

32 

80 

10/10 

10/10 

10/10 

10/10 

10/10 

20.4 ± 0.2 

20.9 ± 0.3 

20.4 ± 0.3 

20.8 ± 0.2 

20.5 ± 0.2 

30.3 ± 1.0 

32.2 ± 0.9 

30.1 ± 0.6 

32.6 ± 0.8 

30.2 ± 1.3 

9.9 ± 0.9 

11.3 ± 0.9 

9.7 ± 0.6 

11.8 ± 0.7 

9.7 ± 1.2 

106 

99 

108 

100 

* Significantly different (P#0.05) from the chamber control group by Williams’ or Dunnett’s test a Number of animals surviving at 13 weeks/number initially in group b Weights and weight changes are given as mean ± standard error. 

The hematology and clinical chemistry data are listed ulocyte values. Additionally, platelet counts were 

in Table G4. In general, changes in the hematology minimally increased in 32 and 80 ppm females, sugvariables were similar to, albeit milder than, what oc- gesting an increase in platelet production. 

curred in the 13-week rat study. At week 13, a minimal anemia evidenced by decreases of hematocrit 

values and erythrocyte counts occurred in 32 and No biologically significant organ weight effects were 

80 ppm female mice. The anemia was characterized as observed (Table F4). Sperm morphology and vaginal 

normocytic, normochromic, and nonresponsive, as cytology parameters of exposed male and female mice 

evidenced by the lack of alterations in mean cell vol- were similar to those of the chamber controls 

ume, mean cell hemoglobin concentration, and retic- (Table I2). 
Chloroprene, NTP TR 467 61 

Significantly increased incidences of squamous epi- thickened, and the submucosa occasionally had a
 

thelial hyperplasia of the forestomach occurred in minimal to mild mixed inflammatory cell infiltrate.
 

males and females exposed to 80 ppm (Table 17).
 

Hyperplasia was characterized by minimal to mild Exposure Concentration Selection Rationale: Based
 

thickening and folding of the forestomach epithelium. on mortality in mice exposed to 200 ppm chloroprene
 

Most of the lesions were somewhat multifocal to in the 16-day study, the highest exposure condiffuse and were located at the pole of the fore- centration selected for the 2-year study was 80 ppm.
 

stomach. Hyperplasia was usually limited to acan- Squamous epithelial hyperplasia of the forestomach,
 

thosis and minimal hyperkeratosis. The underlying observed at 80 ppm in the 13-week study, was not
 

muscular layers of the forestomach tended to be considered to be life threatening.
 

TABLE 17 

Incidences of Forestomach Lesions in Mice in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Squamous Epithelial Hyperplasiaa 10 0

 3

 0

 0 

0 

10 

0

10 

4* (1.5)b 

Female 

Number Examined Microscopically 

Squamous Epithelial Hyperplasia

10

 0

 0

 0

 0 

0 

10 

0

10 

9** (1.9) 

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

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected rats: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked 
62 Chloroprene, NTP TR 467 

2-YEAR STUDY
 

Survival 

Estimates of 2-year survival probabilities for male and 

female mice are shown in Table 18 and in the KaplanMeier survival curves (Figure 3). Survival of males 

exposed to 32 or 80 ppm and all groups of exposed 

females was significantly less than that of the chamber 

controls. 

Body Weights and Clinical Findings 

The mean body weights of 80 ppm females were less 

than those of the chamber control group after week 75 

TABLE 18 

(Tables 19 and 20 and Figure 4). The mean body 

weights of 32 ppm females were greater than those of 

the chamber control group after week 97, but the body 

weights were based on, at the most, three animals. 

Clinical findings included masses of the head, which 

correlated with harderian gland adenoma and/or 

carcinoma in 32 ppm males and 80 ppm males and 

females. Dorsal and lateral torso masses of female 

mice correlated with mammary gland neoplasms in 32 

and 80 ppm females and subcutaneous sarcoma in 

12.8, 32, and 80 ppm females. 

Survival of Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Animals initially in study 50 50 50 50 

Moribund 15 16 26 34 

Natural deaths 8 7 10 3 

Animals surviving to study termination 

Percent probability of survival at end of studya 

Mean survival (days)b 

27 

54 

689 

27 

54 

683 

14 

28 

646 

13 

26 

646 

Survival analysisc P<0.001 P=1.000 P=0.007 P=0.003 

Female 

Animals initially in study 50 50 50 50 

Accidental deathd 0 1 0 1 

Moribund 13 27 38 41 

Natural deaths 2 6 11 5 

Animals surviving to study termination 35 16 1 3e 

Percent probability of survival at end of study 70 33 2 6 

Mean survival (days) 686 641 558 562 

Survival analysis P<0.001 P<0.001 P<0.001 P<0.001 

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

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

(Cox, 1972) with the chamber controls are in the exposed group columns. d	 Censored from survival analyses e Includes one animal that died during the last week of the study 

c 
 

Chloroprene, NTP TR 467 63 

FIGURE 3
 

Kaplan-Meier Survival Curves for Male and Female Mice
 

Exposed to Chloroprene by Inhalation for 2 Years
 
64 Chloroprene, NTP TR 467 

TABLE 19 

Mean Body Weights and Survival of Male Mice in the 2-Year Inhalation Study of Chloroprene 

Weeks Chamber Control 12.8 ppm 32 ppm 80 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 24.9 50 25.0 100 50 24.5 98 50 24.4 98 50 

2 26.6 50 27.0 102 50 26.0 98 50 25.9 97 50 

3 27.4 50 27.6 101 50 27.2 99 50 26.8 98 50 

4 27.9 50 28.4 102 50 28.1 101 50 27.9 100 50 

5 28.8 50 29.0 101 50 28.9 100 50 28.6 99 50 

6 29.7 50 29.9 101 50 29.7 100 50 29.5 99 50 

7 30.2 50 30.3 100 50 30.4 101 50 29.5 98 50 

8 30.7 50 30.9 101 50 30.5 99 50 30.1 98 50 

9 31.5 50 31.3 99 50 31.0 98 50 30.5 97 50 

10 32.1 50 32.2 100 50 31.8 99 50 31.2 97 50 

11 32.6 50 32.8 101 50 32.3 99 50 31.9 98 50 

12 32.4 50 33.7 104 50 33.3 103 50 32.4 100 50 

15 34.3 50 35.6 104 50 35.0 102 50 34.0 99 50 

19 36.9 50 38.8 105 50 37.8 102 50 37.1 101 50 

23 38.7 50 40.1 104 50 39.6 102 50 38.6 100 50 

27 40.4 50 42.1 104 50 41.6 103 50 40.9 101 50 

31 42.2 50 44.0 104 50 43.2 102 50 42.8 101 50 

35 43.9 50 45.6 104 50 44.6 102 50 44.5 101 50 

39 45.3 50 46.6 103 50 45.8 101 50 45.3 100 50 

43 46.4 50 47.0 101 50 46.8 101 50 45.5 98 50 

47 46.1 50 47.1 102 50 47.4 103 50 46.3 100 50 

51 47.0 50 47.5 101 50 47.7 102 50 46.8 100 50 

55 47.2 50 48.4 103 50 48.3 102 49 47.4 100 50 

59 48.3 50 49.1 102 50 49.2 102 49 48.5 100 49 

63 48.8 50 48.7 100 50 49.4 101 49 48.6 100 48 

67 49.3 49 49.6 101 49 49.9 101 48 49.1 100 47 

71 48.8 49 49.2 101 49 49.5 101 46 48.1 99 47 

75 49.3 49 50.1 102 48 50.4 102 44 48.7 99 46 

79 49.4 48 50.4 102 46 50.3 102 43 48.8 99 45 

83 49.0 46 49.5 101 46 49.6 101 40 47.9 98 44 

87 48.5 43 49.5 102 42 50.2 104 35 47.1 97 38 

91 47.5 40 49.8 105 39 51.2 108 30 45.8 96 33 

93 47.6 37 50.0 105 36 51.1 107 29 45.3 95 28 

95 47.2 37 49.6 105 35 49.8 106 28 45.3 96 21 

97 47.0 34 48.6 103 34 49.1 105 25 44.3 94 19 

99 46.4 31 47.5 102 32 48.4 104 20 44.9 97 15 

101 46.4 31 46.6 100 29 47.0 101 18 43.7 94 13 

103 44.8 31 45.1 101 28 46.1 103 14 42.4 95 13 

Mean for weeks 

1-13 29.6 29.9 101 29.5 100 29.1 98 

14-52 42.1 43.4 103 43.0 102 42.2 100 

53-103 47.8 48.9 102 49.3 103 46.6 97 
Chloroprene, NTP TR 467 65 

TABLE 20 

Mean Body Weights and Survival of Female Mice in the 2-Year Inhalation Study of Chloroprene 

Weeks Chamber Control 12.8 ppm 32 ppm 80 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 19.8 50 20.1 102 50 20.0 101 50 19.7 100 50 

2 21.8 50 21.8 100 50 21.9 101 50 21.5 99 49 

3 22.9 50 22.7 99 50 23.1 101 50 22.2 97 49 

4 23.4 50 23.8 102 50 23.8 102 50 23.1 99 49 

5 24.2 50 24.5 101 50 24.6 102 50 23.9 99 49 

6 25.1 49 25.2 100 50 25.8 103 50 25.0 100 49 

7 26.0 49 25.8 99 50 26.4 102 50 25.2 97 49 

8 26.1 49 26.2 100 50 26.3 101 50 25.8 99 49 

9 26.0 49 26.6 102 50 26.4 102 50 26.1 100 49 

10 27.0 49 27.1 100 50 27.4 102 50 26.9 100 49 

11 27.7 49 28.1 101 50 28.1 101 50 27.1 98 49 

12 27.8 49 28.8 104 50 28.4 102 50 27.6 99 49 

15 29.8 49 31.0 104 50 29.8 100 50 28.4 95 49 

19 31.6 49 33.3 105 50 32.2 102 50 30.6 97 49 

23 34.1 49 35.5 104 50 34.5 101 50 32.3 95 49 

27 36.9 49 38.3 104 50 37.1 101 50 35.5 96 49 

31 38.0 49 40.3 106 50 38.4 101 50 37.2 98 49 

35 40.2 49 42.8 107 50 41.2 103 49 39.9 99 49 

39 42.1 49 44.8 106 50 42.9 102 49 41.7 99 48 

43 44.6 49 45.7 103 49 45.2 101 49 42.6 96 48 

47 44.8 49 46.9 105 47 47.0 105 49 45.2 101 47 

51 46.5 49 48.3 104 47 47.6 102 48 46.1 99 46 

55 47.3 49 50.3 106 47 49.8 105 47 47.6 101 46 

59 49.4 49 52.3 106 47 51.6 105 45 49.4 100 45 

63 50.7 49 53.7 106 47 53.1 105 44 50.1 99 45 

67 51.8 49 54.3 105 45 54.6 105 41 51.7 100 41 

71 52.4 46 55.1 105 44 55.6 106 39 52.0 99 39 

75 54.6 46 56.4 103 43 56.5 104 34 52.1 95 38 

79 56.2 44 57.2 102 40 57.7 103 28 53.1 95 31 

83 56.1 44 57.0 102 38 57.4 102 25 51.7 92 29 

87 56.0 44 57.0 102 38 54.5 97 21 51.6 92 25 

91 54.7 43 57.7 106 32 55.0 101 11 48.7 89 15 

93 54.9 41 57.9 106 31 53.3 97 10 47.7 87 12 

95 54.2 41 56.2 104 31 56.5 104 6 47.6 88 8 

97 53.6 40 54.9 102 29 57.3 107 3 47.4 88 4 

99 52.8 38 52.2 99 24 54.0 102 3 46.0 87 3 

101 51.8 38 52.5 101 19 55.3 107 2 46.6 90 3 

103 51.1 36 51.7 101 18 60.0 117 1 46.7 91 3 

Mean for weeks 

1-13 24.8 25.1 101 25.2 102 24.5 99 

14-52 38.9 40.7 105 39.6 102 38.0 98 

53-103 53.0 54.8 104 55.1 104 49.4 93 
 

66 Chloroprene, NTP TR 467 

FIGURE 4
 

Growth Curves for Male and Female Mice
 

Exposed to Chloroprene by Inhalation for 2 Years
 
Chloroprene, NTP TR 467 67 

Pathology and Statistical Analysis 

This section describes the statistically significant or 

biologically noteworthy changes in the incidences of 

neoplasms and/or nonneoplastic lesions of the lung, 

circulatory system, harderian gland, mammary gland, 

liver, skin and mesentery, forestomach, Zymbal’s 

gland, kidney, nose, trachea, and spleen. Summaries 

of the incidences of neoplasms and nonneoplastic 

lesions, individual animal tumor diagnoses, statistical 

analysis of primary neoplasms that occurred with an 

incidence of at least 5% in at least one group, and 

historical incidences for the neoplasms mentioned in 

this section are presented in Appendix C for male rats 

and Appendix D for female rats. 

Lung: The incidences of alveolar/bronchiolar neoplasms in all exposed male and female groups were 

significantly greater than those in the chamber control 

groups (Tables 21, C3, and D3). The incidences of 

alveolar/bronchiolar neoplasms generally exceeded the 

historical control ranges (Tables 21, C4a, and D4a). 

The incidences of multiple alveolar/bronchiolar 

adenoma and carcinoma were increased in all exposed 

groups of males and females (Plates 9 and 10). The 

morphology of lung neoplasms was similar in control 

and exposed groups. Alveolar/bronchiolar adenoma 

was a discrete neoplasm that replaced and compressed 

adjacent lung parenchyma and consisted of solid and 

papillary patterns composed of single layers of welldifferentiated cuboidal to columnar epithelial cells. 

Alveolar/bronchiolar carcinoma was usually larger 

than an adenoma and consisted of solid and papillary 

patterns and clusters of moderately pleomorphic 

cuboidal to columnar epithelial cells that generally 

formed multiple layers and/or solid masses. Carcinomas had increased cellular pleomorphism, increased 

numbers of mitoses, and evidence of local invasion. 

The incidences of bronchiolar hyperplasia in all 

groups of exposed males and females were significantly greater than those in the chamber control 

groups (Tables 21, C5, and D5). Bronchiolar hyperplasia was characterized by diffuse thickening of the 

cuboidal cells lining the terminal bronchioles and in 

some cases caused papillary projections into the 

lumen. Accompanying this change was extension of 

cuboidal cells into alveolar ducts or alveolar sacs 

immediately adjacent to the bronchiolar epithelium. 

The incidences of histiocytic cell infiltration in 80 ppm 

males and in all exposed groups of females were 

significantly greater than those in the chamber control 

groups. This change consisted of histiocytes within 

alveolar lumens, usually adjacent to alveolar/ 

bronchiolar neoplasms. The histiocyte infiltrate was 

very commonly seen in lungs with alveolar/ 

bronchiolar neoplasms and was considered to be 

secondary to the presence of the neoplasm. 

Lung neoplasms from chamber control and exposed 

mice were analyzed for genetic alterations in K-ras 

and H-ras proto-oncogenes. DNA was isolated from 

paraffin embedded tissues and analyzed by several 

assays based on polymerase chain reaction (PCR), 

including restriction fragment length polymorphism 

(RFLP) analysis, single-strand conformation 

polymorphism analysis, and direct sequencing 

(Appendix N). In comparison to spontaneous lung 

neoplasms, a higher frequency of K-ras mutations, 

with a predominance of unique A to T transversions at 

codon 61, was detected in the chloroprene-induced 

lung neoplasms. 
68 Chloroprene, NTP TR 467 

TABLE 21 

Incidences of Neoplasms and Nonneoplastic Lesions of the Lung in Mice in the 2-Year Inhalation Study 

of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Bronchiole Hyperplasiaa 50 0 

50 

10** (2.0)b 

50 

18** (1.7) 

50 

23** (2.2) 

Histiocytic Cell Infiltration 7 (1.6) 8 (3.3) 11 (2.5) 22** (2.9) 

Alveolar/bronchiolar Adenoma, Multiple 

Overall ratec 0/50 (0%) 6/50 (12%)* 7/50 (14%)** 13/50 (26%)** 

Alveolar/bronchiolar Adenoma (includes multiple)d 

Overall rate 

Adjusted ratee 

Terminal ratef 

8/50 (16%) 

23.8% 

4/27 (15%) 

18/50 (36%) 

54.8% 

13/27 (48%) 

22/50 (44%) 

68.3% 

6/14 (43%) 

28/50 (56%) 

84.7% 

9/13 (69%) 

First incidence (days) 

Logistic regression testg 

635 

P<0.001 

530 

P=0.016 

382 

P=0.002 

523 

P<0.001 

Alveolar/bronchiolar Carcinoma, Multiple 

Overall rate 2/50 (4%) 4/50 (8%) 10/50 (20%)** 15/50 (30%)** 

Alveolar/bronchiolar Carcinoma (includes multiple)h 

Overall rate 6/50 (12%) 12/50 (24%) 23/50 (46%) 28/50 (56%) 

Adjusted rate 21.3% 37.9% 76.7% 85.1% 

Terminal rate 5/27 (19%) 8/27 (30%) 8/14 (57%) 9/13 (69%) 

First incidence (days) 729 638 567 524 

Logistic regression test P<0.001 P=0.075 P<0.001 P<0.001 

Alveolar/bronchiolar Adenoma or Carcinomai 

Overall rate 13/50 (26%) 28/50 (56%) 36/50 (72%) 43/50 (86%) 

Adjusted rate 39.2% 79.4% 89.0% 100.0% 

Terminal rate 8/27 (30%) 20/27 (74%) 10/14 (71%) 13/13 (100%) 

First incidence (days) 635 530 382 523 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Female 

Number Examined Microscopically 50 49 50 50 

Bronchiole Hyperplasia 0 15** (2.0) 12** (2.2) 30** (2.2) 

Histiocytic Cell Infiltration 1 (3.0) 14** (2.0) 18** (2.3) 23** (2.4) 

Alveolar/bronchiolar Adenoma, Multiple 

Overall rate 0/50 (0%) 6/49 (12%)* 12/50 (24%)** 16/50 (32%)** 

Alveolar/bronchiolar Adenoma (includes multiple)j 

Overall rate 2/50 (4%) 16/49 (33%) 29/50 (58%) 26/50 (52%) 

Adjusted rate 5.7% 57.9% 100.0% 100.0% 

Terminal rate 2/35 (6%) 6/16 (38%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 734 (T) 447 346 453 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Alveolar/bronchiolar Carcinoma, Multiple 

Overall rate 0/50 (0%) 6/49 (12%)* 8/50 (16%)** 17/50 (34%)** 
Chloroprene, NTP TR 467 69 

TABLE 21 

Incidences of Neoplasms and Nonneoplastic Lesions of the Lung in Mice in the 2-Year Inhalation Study 

of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Female (continued) 

Alveolar/bronchiolar Carcinoma (includes multiple)k 

Overall rate 2/50 (4%) 14/49 (29%) 16/50 (32%) 28/50 (56%) 

Adjusted rate 5.5% 51.9% 100.0% 95.4% 

Terminal rate 1/35 (3%) 6/16 (38%) 1/1 (100%) 2/3 (67%) 

First incidence (days) 706 447 524 324 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

Alveolar/bronchiolar Adenoma or Carcinomal 

Overall rate 4/50 (8%) 28/49 (57%) 34/50 (68%) 42/50 (84%) 

Adjusted rate 11.0% 83.5% 100.0% 100.0% 

Terminal rate 3/35 (9%) 11/16 (69%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 706 447 346 324 

Logistic regression test P<0.001 P<0.001 P<0.001 P<0.001 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 

(T)Terminal sacrifice a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Number of animals with neoplasm per number of animals with lung examined microscopically d	 Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 141/947 (14.9% ± 7.0%); 

range 6%-36% e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Historical incidence: 75/947 (7.9% ± 5.7%); range 0%-16% i	 Historical incidence: 205/947 (21.7% ± 8.0%); range 10%-42% j Historical incidence: 61/939 (6.5% ± 3.2%); range 0%-14% k	 Historical incidence: 38/939 (4.1% ± 3.2%); range 0%-12% l	 Historical incidence: 97/939 (10.3% ± 3.7%); range 0%-16% 

Circulatory System: The incidences of hemangio- occasionally. In some cases, hemangiosarcomas ocsarcoma and hemangioma or hemangiosarcoma (com- curred in more than one organ in the same animal. 

bined) in all groups of exposed males and in 32 ppm Hemangiosarcomas consisted of multiple, variably 

females were significantly greater than those in the sized, blood-filled spaces that were lined by abundant, 

chamber control groups. These incidences were sig- plump, mildly to moderately pleomorphic endothelial 

nificant even when hemangioma and hemangiosarcoma cells. A number of hemangiosarcomas of the mesenof the liver in male mice were excluded because of the tery invaded adjacent tissues such as the pancreas, 

possible complication from Helicobacter hepaticus prostate gland, mesenteric lymph node, and kidney. 

infection (see liver pathology section). The incidences In the liver, these blood-filled spaces were sometimes 

of hemangiosarcoma and hemangioma or heman- separated by cords of hepatocytes. Hemangiomas 

giosarcoma (combined) exceeded the historical control were found only in the mesentery. Hemangiomas 

ranges (Tables 22, C3, C4b, D3, and D4b). consisted of discrete clusters of blood-filled spaces 

Hemangiosarcomas in males and females occurred lined by small numbers of relatively normal-appearing 

primarily in the mesentery, subcutis of the skin, and endothelial cells. 

liver; the bone and spleen were also affected 

TABLE 22 
 

 

70 Chloroprene, NTP TR 467 

Incidences of Hemangioma and Hemangiosarcoma in Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Hemangioma, All Organs (excludes liver) a Overall rate 0/50 1/50 2/50 2/50 

Hemangioma, All Organsb 

Overall rate 0/50 1/50 2/50 2/50 

Hemangiosarcoma, Bone Marrowc 

Overall rate 0/50 1/49 2/50 1/50 

Hemangiosarcoma, Liver 

Overall rate 2/50 5/50 6/50 8/49* 

Hemangiosarcoma, Mesentery 

Overall rate 0/50 3/50 13/50** 7/50** 

Hemangiosarcoma, Skin 

Overall rate 1/50 4/50 1/50 7/50* 

Hemangiosarcoma, All Organs (excludes liver) 

Overall test 1/50 11/50* 16/50** 15/50** 

Hemangiosarcoma, All Organsd 

Overall rate 3/50 (6%) 13/50 (26%) 22/50 (44%) 19/50 (38%) e Adjusted rate 11.1% 38.6% 69.8% 68.0% 

Terminal ratef 3/27 (11%) 7/27 (26%) 6/14 (43%) 6/13 (46%) 

First incidence (days) 733 (T) 659 495 454 

Logistic regression testg P<0.001 P=0.006 P<0.001 P<0.001 

Hemangioma or Hemangiosarcoma, All Organs (excludes liver) 

Overall rate 1/50 12/50** 18/50** 17/50** 

Hemangioma or Hemangiosarcoma, All Organsh 

Overall rate 3/50 (6%) 14/50 (28%) 23/50 (46%) 21/50 (42%) 

Adjusted rate 11.1% 41.7% 70.7% 74.1% 

Terminal rate 3/27 (11%) 8/27 (30%) 6/14 (43%) 7/13 (54%) 

First incidence (days) 733 (T) 659 495 454 

Logistic regression test P<0.001 P=0.003 P<0.001 P<0.001 
 

Chloroprene, NTP TR 467 71 

TABLE 22 

Incidences of Hemangioma and Hemangiosarcoma in Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Female 

Hemangioma, All Organsi 

Overall rate 0/50 (0%) 0/50 (0%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 100.0% 39.5% 

Terminal rate 

First incidence (days) 

Logistic regression test 

0/35 (0%) 

—j 

P=0.004 

0/16 (0%) 

— 

—k 

1/1 (100%) 

607 

P=0.072 

1/3 (33%) 

624 

P=0.037 

Hemangiosarcoma, Bone Marrow 

Overall rate 0/50 1/49 1/49 0/50 

Hemangiosarcoma, Liver 

Overall rate 1/50 0/49 1/50 0/50 

Hemangiosarcoma, Mesentery 

Overall rate 0/50 4/50* 13/50** 4/50 

Hemangiosarcoma, Skin 

Overall rate 2/50 1/50 2/50 1/50 

Hemangiosarcoma, All Organsl 

Overall rate 4/50 (8%) 6/50 (12%) 17/50 (34%) 5/50 (10%) 

Adjusted rate 10.6% 25.7% 100.0% 18.3% 

Terminal rate 3/35 (9%) 2/16 (13%) 1/1 (100%) 0/3 (0%) 

First incidence (days) 541 482 216 523 

Logistic regression test P=0.493N P=0.330 P=0.009 P=0.486 

Hemangioma or Hemangiosarcoma, All Organsm 

Overall rate 4/50 (8%) 6/50 (12%) 18/50 (36%) 8/50 (16%) 

Adjusted rate 10.6% 25.7% 100.0% 50.8% 

Terminal rate 3/35 (9%) 2/16 (13%) 1/1 (100%) 1/3 (33%) 

First incidence (days) 541 482 216 523 

Logistic regression test P=0.248 P=0.330 P=0.005 P=0.110 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 

(T) Terminal sacrifice a Number of animals with neoplasm per number of animals examined. Denominator is number examined microscopically for bone marrow 

and liver; for other tissues, denominator is number of animals necropsied. b	 Historical incidence for 2-year inhalation studies with chamber control groups: 8/950 (0.8% ± 1.0%); range 0%-2% c Historical incidence: 0/938

d Historical incidence: 26/950 (2.7% ± 2.9%); range 0%-9% e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. A negative trend is indicated by N. h	 Historical incidence: 34/950 (3.6% ± 3.4%); range 0%-10% i	 Historical incidence: 15/941 (1.6% ± 1.9%); range 0%-4% j Not applicable; no neoplasms in animal group k	 Value of statistic cannot be computed. l	 Historical incidence: 28/941 (3.0% ± 2.3%); range 0%-6% m Historical incidence: 43/941 (4.6% ± 3.2%); range 0%-10% 
 

72 Chloroprene, NTP TR 467 

Harderian Gland: The incidences of harderian gland 

adenoma and harderian gland adenoma or carcinoma 

(combined) in males exposed to 32 or 80 ppm and 

females exposed to 80 ppm were significantly greater 

than those in the chamber controls (Tables 23, C3, and 

D3). The incidences of harderian gland adenoma or 

carcinoma (combined) in 32 ppm males and 80 ppm 

males and females exceeded the historical control 

ranges (Tables 23, C4c, and D4c). Adenomas were 

composed of large, irregular glandular struc-tures, 

which often formed papillary structures con-sisting of 

one to three layers of cuboidal to tall columnar 

epithelial cells with eosinophilic to finely vacuolated 

cytoplasm. Carcinomas were composed of solid to 

papillary, irregular clusters of pleomorphic cells with 

moderately to markedly vacuolated cytoplasm; 

neoplastic cells often invaded the adjacent stroma and 

occasionally metastasized to the lung. 
73 

c 

Chloroprene, NTP TR 467 

TABLE 23 

Incidences of Neoplasms of the Harderian Gland in Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Adenomaa 

Overall rateb 

Adjusted ratec 

Terminal rated 

2/50 (4%) 

5.8% 

1/27 (4%) 

5/50 (10%) 

17.7% 

4/27 (15%) 

8/50 (16%) 

36.8% 

4/14 (29%) 

10/50 (20%) 

46.4% 

4/13 (31%) 

First incidence (days) 

Logistic regression teste 596 

P=0.004 

701 

P=0.205 

596 

P=0.035 

589 

P=0.007 

Carcinoma 

Overall rate 0/50 (0%) 0/50 (0%) 2/50 (4%) 2/50 (4%) 

Adenoma or Carcinomaf 

Overall rate 2/50 (4%) 5/50 (10%) 10/50 (20%) 12/50 (24%) 

Adjusted rate 5.8% 17.7% 42.3% 58.3% 

Terminal rate 1/27 (4%) 4/27 (15%) 4/14 (29%) 6/13 (46%) 

First incidence (days) 596 701 596 589 

Logistic regression test P<0.001 P=0.205 P=0.010 P=0.001 

Female 

Adenomag 

Overall rate 1/50 (2%) 3/50 (6%) 3/50 (6%) 8/50 (16%) 

Adjusted rate 2.9% 14.9% 12.0% 74.4% 

Terminal rate 1/35 (3%) 2/16 (13%) 0/1 (0%) 2/3 (67%) 

First incidence (days) 734 (T) 621 524 467 

Logistic regression test P=0.001 P=0.225 P=0.293 P=0.007 

Carcinoma 

Overall rate 1/50 (2%) 2/50 (4%) 0/50 (0%) 1/50 (2%) 

Adenoma or Carcinomah 

Overall rate 2/50 (4%) 5/50 (10%) 3/50 (6%) 9/50 (18%) 

Adjusted rate 5.0% 23.8% 12.0% 77.0% 

Terminal rate 1/35 (3%) 3/16 (19%) 0/1 (0%) 2/3 (67%) 

First incidence (days) 527 621 524 467 

Logistic regression test P=0.004 P=0.186 P=0.577 P=0.016 

(T)Terminal sacrifice 

a Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 47/950 (5.0% ± 4.5%); 

range 0%-14% 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 chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. f Historical incidence: 49/950 (5.2% ± 4.5%); range 0%-14% g Historical incidence: 26/941 (2.8% ± 4.1%); range 0%-16% h Historical incidence: 32/941 (3.4% ± 4.4%); range 0%-16% 
74 Chloroprene, NTP TR 467 

Mammary Gland: The incidence of mammary gland relatively well-differentiated appearing epithelial cells 

carcinoma in 80 ppm females was significantly greater separated by a small to moderate amount of fibrous 

than in the chamber control group (Tables 24 and D3). stroma (Plate 11). Some mammary gland neoplasms 

The incidences of mammary gland carcinoma in 32 consisted of solid clusters of basophilic epithelial cells 

and 80 ppm females exceeded the historical control admixed with large areas of keratinizing stratified 

range (Table D4d). Multiple mammary gland carci- squamous epithelium and were classified as adenonomas occurred in exposed females. The incidence of acanthoma (Plate 12). Adenoacanthomas are uncomadenoacanthoma was not significantly increased in mon neoplasms usually seen as a result of chemical 

any exposed group, but in the 32 and 80 ppm groups, exposure. Mammary gland hyperplasia was present in 

the incidences exceeded the historical control range. a few females exposed to chloroprene but not in the 

Carcinomas consisted of highly irregular acinar and chamber controls (Tables 24 and D5). 

ductlike structures composed of densely packed, 

TABLE 24 

Incidences of Neoplasms and Nonneoplastic Lesions of the Mammary Gland in Female Mice 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Number Examined Microscopically 49 49 50 50 

Hyperplasiaa 0 1 (1.0)b 1 (1.0) 3 (2.0) 

Adenoacanthomac 

Overall rated 0/50 (0%) 1/50 (2%) 3/50 (6%) 2/50 (4%) e Adjusted rate 0.0% 2.1% 7.7% 7.9% 

Terminal ratef 0/35 (0%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) —h 440 425 582 

Logistic regression testg P=0.355 P=0.496 P=0.205 P=0.252 

Carcinoma, Multiple 

Overall rate 3/50 (6%) 4/50 (8%) 6/50 (12%) 11/50 (22%) 

Carcinoma (includes multiple)i 

Overall rate 3/50 (6%) 4/50 (8%) 7/50 (14%) 12/50 (24%) 

Adjusted rate 7.4% 13.6% 35.1% 56.4% 

Terminal rate 1/35 (3%) 1/16 (6%) 0/1 (0%) 1/3 (33%) 

First incidence (days) 527 447 394 336 

Logistic regression test P=0.008 P=0.553 P=0.207 P=0.036 

Adenoacanthoma or Carcinoma 

Overall rate 3/50 (6%) 5/50 (10%) 10/50 (20%) 14/50 (28%) 

Adjusted rate 7.4% 15.4% 40.1% 59.8% 

Terminal rate 1/35 (3%) 1/16 (6%) 0/1 (0%) 1/3 (33%) 

First incidence (days) 527 440 394 336 

Logistic regression test P=0.006 P=0.427 P=0.093 P=0.012 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 1/941 (0.1% ± 0.5%); 

range 0%-2% d	 Number of animals with neoplasm per number of animals necropsied e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Not applicable; no neoplasms in animal group i	 Historical incidence: 29/941 (3.1% ± 2.6%); range 0%-8% 
 

Chloroprene, NTP TR 467 75 

Liver: The incidences of hepatocellular carcinoma in was mild to moderate and consisted of multifocal 

all exposed groups of females and hepatocellular ade- proliferation of small to moderate numbers of oval 

noma or carcinoma (combined) in 32 and 80 ppm cells and bile ducts, which extended outwardly from 

females were significantly greater than those in the portal areas and sometimes extended between adjacent 

chamber controls; in the 80 ppm group, the incidences portal areas. 

exceeded the historical control ranges for carcinoma 

and adenoma or carcinoma (combined) (Tables 25, Slight chronic inflammation consisting of aggregates of 

D3, and D4e). The incidence of eosinophilic foci in small numbers of lymphocytes and macrophages 

80 ppm females was also significantly greater than that around proliferating bile ducts and oval cells was also 

in the chamber controls. Eosinophilic foci were seen. Karyomegaly was usually minimal to mild and 

discrete spherical lesions composed of normal-sized to diffuse, was characterized by enlargement of the 

enlarged cells with eosinophilic cytoplasm which nucleus from approximately 1.5 to 2 times the normal 

produced no compression of the surrounding paren- size and was sometimes accompanied by enlargement 

chyma. Hepatocellular adenomas had discrete bor- of the entire hepatocyte due to an increase in the 

ders, compressed the surrounding parenchyma, and amount of cytoplasm. Regeneration was generally 

were composed of disorganized cords which mild to marked and characterized by the presence of 

intersected at sharp angles with the hepatic cords of one or more nodules, ranging in size from less than 

the surrounding parenchyma. Hepatocellular car- 1 mm up to 1 cm in diameter, which were composed 

cinomas differed from adenomas in that the neoplastic of a mixture of varying numbers of small, normalhepatocytes within carcinomas often were more sized, and enlarged hepatocytes containing oval cells 

atypical than in adenomas and formed solid sheets and bile ducts and sometimes chronic inflammatory 

and/or trabeculae that were three or more cells thick; cell infiltrates. 

a number of carcinomas metastasized to the lung. The 

increased incidences of hematopoietic cell proliferation The incidences of hepatoceulluar adenoma or 

of the liver in 32 and 80 ppm females were most likely carcinoma (combined) in chamber control and exposed 

secondary to the presence of the sarcomas and groups of male mice and 80 ppm female mice 

mammary gland neoplasms in exposed females. exceeded the historical control ranges [males: 

358/947 (37.8% ± 12.5%), range 11%-60%; females: 

The livers of most control and exposed males con- Table D4e]. The incidences of hemangiosarcoma of 

tained a spectrum of lesions consistent with the liver were increased in exposed groups of male 

Helicobacter infection; these changes, which generally mice (Tables 22 and C3) and exceeded the historical 

occurred together in the same liver, included bile duct control range [12/947 (1.3% ±1.7%), range 0%-6%]. 

hyperplasia, karyomegaly, and regeneration of hepato- Hemangiosarcomas were morphologically similar to 

cytes (Plates 13 and 14). Liver sections from five of those observed spontaneously and in other tissues in 

five males with liver lesions were positive for bac- this study. Based upon a retrospective analysis of the 

terial organisms consistent with H. hepaticus when recent 2-year studies showing evidence of an active 

examined using Steiner’s modification of the Warthin- hepatitis resulting from H. hepaticus infection, it has 

Starry stain. Using a PCR-RFLP-based assay, frozen been determined that the incidences of hepatocellular 

liver sections from 5 of 10 mice (chamber control and adenomas, hepatocellular carcinomas, and hemangioexposed males and females) were found to be positive sarcomas are increased under these conditions. 

for the presence of a Helicobacter organism Interpretation of the increased incidence of 

compatible with H. hepaticus. Also, the spectrum of hemangiosarcoma in the liver of male mice in this 

nonneoplastic liver lesions was consistent with that study was confounded by the H. hepaticus-associated 

observed with H. hepaticus infection. In contrast to liver disease. Neoplastic responses (including hemanmales, liver lesions typical of H. hepaticus infection giosarcomas) at other sites were not considered to be 

were not present in females. Bile duct hyperplasia affected by this infection. 
76 Chloroprene, NTP TR 467 

TABLE 25 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Karyomegalya 50 19 (1.5)b 

50 

13 (1.5) 

50 

20 (1.7) 

49 

29* (1.9) 

Regeneration 22 (2.8) 25 (3.1) 25 (3.0) 27* (3.0) 

Bile Duct, Hyperplasia 34 (2.1) 31 (2.3) 34 (2.4) 36 (2.9) 

Hepatocellular Adenoma or Carcinoma 

Overall ratec 43/50 (86%) 37/50 (74%) 42/50 (84%) 41/49 (84%) 

Female 

Number Examined Microscopically 50 49 50 50 

Eosinophilc Focus 13 12 15 28** 

Hematopoietic Cell Proliferation 1 (1.0) 5 (1.6) 9* (1.6) 12** (1.5) 

Hepatocellular Adenoma, Multiple 

Overall rate 5/50 (10%) 7/49 (14%) 2/50 (4%) 9/50 (18%) 

Hepatocellular Adenoma (includes multiple)d 

Overall rate 

Adjusted ratee 

Terminal ratef 

17/50 (34%) 

47.0% 

16/35 (46%) 

19/49 (39%) 

69.1% 

9/16 (56%) 

11/50 (22%) 

100.0% 

1/1 (100%) 

16/50 (32%) 

85.1% 

1/3 (33%) 

First incidence (days) 

Logistic regression testg 

637 

P=0.070 

523 

P=0.157 

505 

P=0.064 

383 

P=0.141 

Hepatocellular Carcinoma, Multiple 

Overall rate 0/50 (0%) 1/49 (2%) 7/50 (14%)* 4/50 (8%) 

Hepatocellular Carcinoma (includes multiple)h 

Overall rate 4/50 (8%) 11/49 (22%) 14/50 (28%) 19/50 (38%) 

Adjusted rate 10.3% 41.8% 100.0% 91.5% 

Terminal rate 2/35 (6%) 4/16 (25%) 1/1 (100%) 2/3 (67%) 

First incidence (days) 493 440 503 524 

Logistic regression test P<0.001 P=0.040 P=0.002 P<0.001 

Hepatocellular Adenoma or Carcinomai 

Overall rate 20/50 (40%) 26/49 (53%) 20/50 (40%) 30/50 (60%) 

Adjusted rate 52.2% 81.8% 100.0% 100.0% 

Terminal rate 17/35 (49%) 11/16 (69%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 493 440 503 383 

Logistic regression test P<0.001 P=0.051 P=0.011 P<0.001 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Number of animals with neoplasm per number of animals with liver examined microscopically d	 Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 114/937 (12.2% ± 9.7%); 

range 0%-40% e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Historical incidence: 103/937 (11.0% ± 6.7%); range 0%-30% i	 Historical incidence: 200/937 (21.3% ± 11.9%); range 3%-54% 
 

77 

c 

Chloroprene, NTP TR 467 

Skin and Mesentery: The incidences of sarcoma of the control group. These sarcomas were pleomorphic and 

skin in all exposed groups of females were highly invasive. Increased incidences of mesentery 

significantly greater than in the chamber controls sarcoma were present in exposed groups of female 

(Tables 26 and D3). The sarcomas occurred pri- mice (Tables 26 and D3). These neoplasms generally 

marily in the subcutis and consisted of sheets and occurred in females that did not have either mesentery 

interlacing bundles of undifferentiated and highly hemangiosarcoma or skin (subcutaneous) sarcoma. 

pleomorphic mesenchymal cells. In exposed females, Incidences of sarcomas of the skin and mesentery exmorphologically similar sarcomas were also present in ceeded the historical control ranges (Tables 26, D4f, 

the mesentery, and the incidence in 32 ppm females and D4g). 

was significantly greater than that in the chamber 

TABLE 26 

Incidences of Sarcoma of the Skin and Mesentery in Female Mice in the 2-Year Inhalation Study 

of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Skina 

Overall rateb 0/50 (0%) 11/50 (22%) 11/50 (22%) 18/50 (36%) c Adjusted rate 0.0% 35.3% 100.0% 69.6% 

Terminal rated 0/35 (0%) 2/16 (13%) 1/1 (100%) 0/3 (0%) 

First incidence (days) —f 285 524 462 e Logistic regression test P<0.001 P=0.001 P<0.001 P<0.001 

Mesenteryg 

Overall rate 0/50 (0%) 4/50 (8%) 8/50 (16%) 3/50 (6%) 

Adjusted rate 0.0% 16.3% 46.5% 12.6% 

Terminal rate 0/35 (0%) 1/16 (6%) 0/1 (0%) 0/3 (0%) 

First incidence (days) — 523 463 443 

Logistic regression test P=0.308 P=0.060 P=0.004 P=0.157 

a Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 5/941 (0.5% ± 0.9%); 

range 0%-2% 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 chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. f Not applicable; no neoplasms in animal group g Historical incidence: 0/941 
 

78 Chloroprene, NTP TR 467 

Forestomach: The incidence of squamous cell papilloma in 80 ppm females was greater than that in the 

chamber controls; the difference was not significant 

but exceeded the historical control range (Tables 27, 

D3, and D4h). Male mice exhibited a positive trend 

in squamous cell papilloma of the forestomach 

(Tables 27 and C3). Squamous cell papilloma was 

characterized as an arboriform structure consisting of 

a branching core of fibrous tissue, which was 

connected to the submucosa of the forestomach by a 

thin stalk and was covered by multiple layers of 

hyperplastic epithelial cells (Plate 15). In males and 

females exposed to 80 ppm, the incidences of 

hyperplasia of the forestomach epithelium were 

significantly greater than those in chamber controls, 

and the lesions were similar to those seen in the 

13-week study. Hyperplasia was a focal to multifocal 

change characterized by an increase in the number of 

cell layers in the epithelium (Plate 16). 
Chloroprene, NTP TR 467 79 

TABLE 27 

Incidences of Neoplasms and Nonneoplastic Lesions of the Forestomach in Mice 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Epithelial Hyperplasiaa 50 4 (3.0)b 

48 

6 (1.8)

49 

7 (2.3) 

50 

29** (2.2) 

Squamous Cell Papillomac 

Overall rated 

Adjusted ratee 

Terminal ratef 

First incidence (days) 

Logistic regression testg 

1/50 (2%) 

3.7% 

1/27 (4%) 

733 (T) 

P=0.030 

0/50 (0%) 

0.0% 

0/27 (0%) 

—h 

P=0.500N 

2/50 (4%) 

14.3% 

2/14 (14%) 

733 (T) 

P=0.276 

4/50 (8%) 

12.7% 

0/13 (0%) 

587 

P=0.216 

Female 

Number Examined Microscopically 50 49 49 50 

Epithelial Hyperplasia 4 (2.0) 3 (3.7) 8 (1.6) 27** (2.7) 

Squamous Cell Papillomai 

Overall rate 0/50 (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 0.0% 0.0% 0.0% 18.8% 

Terminal rate 0/35 (0%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 

Logistic regression test 

— 

P=0.001 

— 

—j — 

— 

576 

P=0.053 

Squamous Cell Papilloma or Carcinomak 

Overall rate 1/50 (2%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 2.9% 0.0% 0.0% 18.8% 

Terminal rate 1/35 (3%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 734 (T) — — 576 

Logistic regression test P=0.007 P=0.656N P=0.998N P=0.120 

** Significantly different (P#0.01) from the chamber control group by the logistic regression test 

(T)Terminal sacrifice 

a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked c Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 6/950 (0.6% ± 1.2%); 

range 0%-4% d	 Number of animals with neoplasm per number of animals necropsied e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. A lower incidence in an exposure group is indicated by N. h	 Not applicable; no neoplasms in animal group i	 Historical incidence: 11/941 (1.2% ± 1.8%); range 0%-6% j Value of statistic cannot be computed. k Historical incidence: 13/941 (1.4% ± 1.8%); range 0%-6% 
80 Chloroprene, NTP TR 467 

Zymbal’s Gland: Carcinomas of the Zymbal’s gland proliferative lesions in standard and extended evaluwere seen in three 80 ppm females (Table D1); two of ations are presented in Tables 28 and C3. The stepthese carcinomas metastasized to the lung. These section and step- and single-section (combined) 

neoplasms were characterized by multiple variably incidences of renal tubule adenoma in 80 ppm males 

sized cellular clusters admixed with multiple large and the step- and single-section (combined) incidences 

duct-like structures that were lined with stratified in 32 ppm males were significantly greater than those 

squamous epithelium and contained eosinophilic in the chamber control group (Tables 28 and C3). The 

material, separated by small to moderate amounts of step-section and step- and single-section (combined) 

fibrous stroma. The cellular clusters consisted of incidences of renal tubule hyperplasia in all exposed 

densely packed, deeply basophilic, basal-like cells groups of males were significantly greater than those 

surrounding a centrally located cluster of large in the chamber controls (Tables 28 and C5). 

sebaceous-like cells with abundant foamy cytoplasm. 

Zymbal’s gland carcinomas have not been reported in Renal tubule hyperplasia, adenoma, and carcinoma 

the NTP historical database for control female mice constitute a morphologic continuum. Hyperplasia was 

(Table D4i). generally a focal, minimal to mild lesion consisting of 

tubules that were dilated two to five times the normal 

Kidney: Although not significantly increased, the diameter and were lined by increased numbers of 

incidence of renal tubule adenoma in 80 ppm males tubule epithelial cells that partially or totally filled the 

was greater than that in the chamber control group and tubule lumen. Cells within hyperplastic lesions varied 

exceeded the historical control range (Tables 28, C3, slightly in size and sometimes stained more basophilic 

and C4e). In addition, incidences of renal tubule then normal cells but otherwise appeared similar to 

hyperplasia were significantly increased in 32 and normal tubule epithelial cells. Renal tubule adenomas 

80 ppm males relative to the chamber control group. were larger, discrete lesions, ranging from greater 

Initially, a single hematoxylin- and eosin-stained than five tubule diameters to 1 mm or more in size. 

section of each kidney was prepared. Primarily Cells within adenomas consisted of relatively normalbecause of the slightly positive trend and increased appearing tubule epithelial cells that sometimes formed 

incidences of renal tubule hyperplasia and renal tubule solid masses of multiple clusters of cells. Oncocytic 

adenoma in the standard evaluation and the rarity of hyperplasia was observed at the end of the study in 

renal proliferative lesions in mice, additional step one male exposed to 12.8 ppm. Oncocytic hyperplasia 

sections of kidney were prepared from the remaining was characterized by multiple, confluent, discrete foci, 

formalin-fixed tissues. Eight additional kidney sec- which were a few tubule diameters in size, and was 

tions taken at 0.5-mm intervals were prepared for each composed of oncocytes that were large cells with 

male. Additional males with focal hyperplasia or abundant, brightly eosinophilic, granular cytoplasm 

adenomas were identified. The incidences of these and a moderately basophilic, centrally placed nucleus. 
81 

c 

Chloroprene, NTP TR 467 

TABLE 28 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Male Mice 

in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Number Examined Microscopically 50 49 50 50 

Single Sections (Standard Evaluation) 

Renal Tubule Hyperplasiaa 0 4 (1.3)b 5* (1.2) 5* (1.4) 

Renal Tubule Adenomac 

Overall rated 

Adjusted ratee 

Terminal ratef 

First incidence (days) 

Logistic regression testg 

0/50 (0%) 

0.0% 

0/27 (0%) 

—h 

P=0.039 

1/49 (2%) 

3.6% 

0/27 (0%) 

722 

P=0.492 

1/50 (2%) 

7.1% 

1/14 (7%) 

733 (T) 

P=0.369 

3/50 (6%) 

13.8% 

1/13 (8%) 

587 

P=0.121 

Step Sections (Extended Evaluation) 

Renal Tubule Hyperplasia 2 (2.0) 12** (1.4) 16** (1.6) 17** (1.5) 

Renal Tubule Adenoma 

Overall rate 0/50 (0%) 1/49 (2%) 2/50 (4%) 6/50 (12%) 

Adjusted rate 0.0% 3.7% 12.9% 30.2% 

Terminal rate 0/27 (0%) 1/27 (4%) 1/14 (7%) 2/13 (15%) 

First incidence (days) — 733 (T) 715 567 

Logistic regression test P<0.001 P=0.500 P=0.135 P=0.011 

Single Sections and Step Sections (Combined) 

Renal Tubule Hyperplasia 2 (2.0) 16** (1.4) 17** (1.6) 18** (1.6) 

Renal Tubule Adenoma 

Overall rate 0/50 (0%) 2/49 (4%) 3/50 (6%) 9/50 (18%) 

Adjusted rate 0.0% 7.1% 19.6% 40.7% 

Terminal rate 0/27 (0%) 1/27 (4%) 2/14 (14%) 3/13 (23%) 

First incidence (days) — 722 715 567 

Logistic regression test P<0.001 P=0.227 P=0.042 P=0.002 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 

(T)Terminal sacrifice 

a Number of animals with lesion 

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

Historical incidence for 2-year inhalation studies with chamber controls (mean ± standard deviation): 2/946 (0.2% ± 0.5%); 

range 0%-2% d Number of animals with neoplasm per number of animals with kidney examined microscopically e Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality f	 Observed incidence in animals surviving until the end of the study g	 In the chamber control column are the P values associated with the trend test. In the exposed group columns are the P values 

corresponding to the pairwise comparisons between the chamber controls and that exposed group. The logistic regression test regards 

lesions in animals dying prior to terminal kill as nonfatal. h	 Not applicable; no neoplasms in animal group 
82 Chloroprene, NTP TR 467 

Nose: The incidences of olfactory epithelium atrophy, 

adenomatous hyperplasia, and metaplasia in 80 ppm 

males and females were significantly greater than in 

the chamber control groups (Table 29). The incidences of suppurative inflammation in 32 and 80 ppm 

females were significantly greater than that in the 

chamber control group. These nasal lesions involved 

the olfactory regions of Levels II and III. Atrophy of 

the olfactory epithelium was characterized by decreased numbers of layers of olfactory epithelium and 

included loss of Bowman’s glands and olfactory axons 

in more severe cases. Metaplasia of the olfactory epithelium was characterized by replacement of olfactory 

epithelium with ciliated columnar respiratory-like epithelium. Adenomatous hyperplasia of the olfactory 

epithelium was characterized by respiratory-like epithelium which was taller than normal and had 

increased numbers of cells with multiple folds, 

including goblet cells; underlying glands were often 

lined by goblet cells and dilated by mucus (Plates 17 

and 18). Adenomas of the respiratory epithelium were 

present in one 32 ppm female and one 80 ppm male. 

Both adenomas were very small (0.5 mm in diameter) 

arboriform masses and consisted of multiple papillary 

structures covered by multiple layers of cuboidal, 

nonciliated epithelial cells. These adenomas have not 

been documented in the NTP historical control 

database. 

Trachea: Single papillary adenomas were detected in 

one 12.8 ppm male and in one 32 ppm male 

(Table C1). These lesions consisted of a thin, branching core of fibrous tissue covered by two to three 

layers of epithelial cells. These adenomas have not 

been documented in the NTP historical database. 

Spleen: The incidences of hematopoietic proliferation 

in 32 and 80 ppm males and in all exposed groups of 

females were significantly greater than those in the 

chamber controls (males: chamber control, 26/50; 

12.8 ppm, 22/49; 32 ppm, 35/50; 80 ppm, 31/50; 

females: 13/50, 25/49, 42/49, 39/50; Tables C5 and 

D5). The increased incidences of hematopoietic 

proliferation may have been chemical related. 
Chloroprene, NTP TR 467 83 

TABLE 29 

Incidences of Nonneoplastic Lesions of the Nose in Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Male 

Number Examined Microscopically 

Suppurative Inflammationa 

Olfactory Epithelium, Atrophy

Olfactory Epithelium, Adenomatous Hyperplasia

Olfactory Epithelium, Metaplasia

Respiratory Epithelium, Hyaline Degeneration

50 

2 

7 

3 

6 

3 

(2.0)b 

(1.1)

(1.0)

(1.0)

(1.3)

48 

1 

8 

2 

5 

4 

(1.0)

(1.4)

(1.0)

(1.4)

(1.3)

50 

4 

7 

2 

5 

2 

(1.0)

(1.1) 

(1.0) 

(1.0) 

(1.0) 

50 

6 

49** 

48** 

49** 

10* 

(1.5) 

(2.5) 

(2.0) 

(2.5) 

(1.2) 

Adenoma, Respiratory Epithelium 0 0 0 1 

Female 

Number Examined Microscopically 

Suppurative Inflammation

Olfactory Epithelium, Atrophy

Olfactory Epithelium, Adenomatous Hyperplasia

Olfactory Epithelium, Metaplasia

Respiratory Epithelium, Hyaline Degeneration 

50 

0

 6 

2 

2 

17 

(1.2)

(1.0)

(1.0)

(1.0)

49 

1 

5 

3 

3 

9 

(1.0)

(1.2)

(1.0)

(1.0)

(1.2) 

49 

3* 

4 

0 

1 

10 

(1.7)

(1.3) 

(2.0) 

(1.3) 

50 

4** 

47** 

44** 

44** 

25** 

(1.5) 

(2.0) 

(1.9) 

(2.0) 

(1.2) 

Adenoma, Respiratory Epithelium 0 0 1 0 

* Significantly different (P#0.05) from the chamber control group by the logistic regression test 

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1 = minimal; 2 = mild; 3 = moderate; 4 = marked 
84 Chloroprene, NTP TR 467 

Supplemental Analyses in Mice 

Because of the large number of early deaths of mice 

exposed to chloroprene, survival-adjusted neoplasm 

rates were estimated using the Poly-3 survival-adjusted 

quantal response method of Portier and Bailer (1989) 

to provide a clearer indication of exposure-response 

relationships for neoplasms induced by chloroprene. 

This adjustment accounts for the impact of early 

mortality on the expression of late-developing 

neoplasms. The Poly-3 survival-adjusted neoplasm 

rates for mice in the 2-year inhalation study of chloroprene are presented in Table 30. The neoplasm incidence values in this table represent the ratio of the 

number of animals in an exposure group bearing the 

specific neoplasm relative to the adjusted number of 

animals at risk. These risk-adjusted values were 

determined by combining the proportion of lifetime 

neoplasm risk for each animal in a particular group as 

follows: animals that survived to the end of the study 

and animals that had the particular neoplasm (including animals that died early and had the neoplasm and 

animals that lived until the end of the study, at which 

time the neoplasm was detected) were given a risk 

weight of one unit; the risk weight for an animal that 

died before study termination but was free of the particular neoplasm being analyzed was estimated by calculating the fractional survival time on study for that 

animal raised to the third power. For example, if an 

animal died after one-half of the study (approximately 

52 weeks) and did not have the particular neoplasm 

being analyzed, it was considered to contribute 0.125 3 risk for that neoplasm (1⁄2) . The use of the third 

power was selected because cumulative neoplasm rates 

have been found to occur generally as a third- to 

fourth-order function of age in animals. Simulation 

experiments have shown that this method is valid even 

when the actual values for the power are as low as 1 

or as high as 5 (Bailer and Portier, 1988). This type 

of analysis had also been performed on neoplasms induced by 1,3-butadiene in B6C3F mice (NTP, 1993). 1 
Chloroprene, NTP TR 467 85 

TABLE 30 

Survival-Adjusted Neoplasm Rates for Mice in the 2-Year Inhalation Study of Chloroprenea 

Males (%) Females (%) 

Chamber Chamber 

Control 12.8 ppm 32 ppm 80 ppm Control 12.8 ppm 32 ppm 80 ppm 

Lung 

Alveolar/bronchiolar 

Carcinoma 

Alveolar/bronchiolar 

Adenoma or 

Carcinoma 

14.1** 

29.8** 

28.3 

63.7** 

56.9** 

79.2** 

66.4**

92.9**

 4.6** 

9.1** 

35.6** 

68.3** 

53.8** 

85.8** 

76.0** 

96.1** 

All Organs 

Hemangioma or 

Hemangiosarcomab 2.4** 28.2** 45.2** 43.6** 9.0* 16.0 53.1** 27.7* 

Harderian Gland 

Adenoma or Carcinoma 4.7** 12.0 26.3** 32.0** 4.5** 13.5 11.7 31.2** 

Mammary Gland 

Adenoacanthoma or 

Carcinoma 6.7** 12.9 33.7** 42.5** 

Liver 

Hepatocellular Carcinoma

Hepatocellular Adenoma 

or Carcinoma 

9.0** 

44.8 

28.4* 

62.9 

47.5** 

63.3 

58.2** 

79.7** 

Forestomach 

Squamous Cell Papilloma 

or Carcinoma 2.4** 0 5.6 13.3 2.3** 0 0 14.6 

Kidney 

Renal Tubule Adenoma 

(single section)

(single+step section)

 0*

 0**

 2.4

 4.8

 2.8

 8.3 

8.2 

23.9** 

Skin 

Sarcoma 0* 27.5** 39.0** 52.6** 

Mesentery 

Sarcoma 0 10.7* 28.9** 11.0 

* In the chamber control column, indicates a significant trend (P<0.05) across all dose groups by the Poly-3 quantal response test; in the 

exposed group columns, indicates a significant difference from the chamber control group by pairwise comparison 

** P<0.01 a Survival-adjusted neoplasm rates were estimated using the Poly-3 survival-adjusted quantal response method of Portier and Bailer (1989). b Liver hemangiomas and hemangiosarcomas were excluded for male mice. 
86 Chloroprene, NTP TR 467 

GENETIC TOXICOLOGY 

Chloroprene showed no evidence of mutagenicity in 

tests performed in vitro or in vivo. Chloroprene was 

not mutagenic in any of four strains of Salmonella 

typhimurium (TA98, TA100, TA1535, or TA1537) 

when tested with a preincubation protocol at concentrations up to 3,333 μg/plate, with and without 

Aroclor-induced rat or hamster liver S9 (Zeiger et al., 

1987; Table E1). No induction of sex-linked recessive 

lethal mutations was noted in germ cells of male 

Drosophila melanogaster administered chloroprene via 

feeding or injection (Foureman et al., 1994; 

Table E2). In vivo assays in male mice for induction 

of chromosomal aberrations, sister chromatid exchanges, and increases in the frequency of 

micronucleated erythrocytes after 12 inhalation 

exposures to chloroprene (12, 32, or 80 ppm) all gave 

negative results (Tice et al., 1988; Tables E3, E4, and 

E5). In addition, no increase was observed in the 

frequency of micronucleated erythrocytes in peripheral 

blood of male and female mice exposed for 13 weeks 

to chloroprene (5 to 80 ppm) via inhalation 

(Table E6). 
PLATE 1 

Squamous cell carcinoma in the tongue of a female F344/N rat 

exposed to 80 ppm chloroprene by inhalation for 2 years. Note the 

islands of neoplastic cells that have infiltrated the muscular layers 

(arrow). H&E; 2.5× 

PLATE 3 

Squamous cell papilloma in the tongue of a male F344/N rat exposed 

to 80 ppm chloroprene by inhalation for 2 years. Note the absence of 

inflammation or hyperplasia in the adjacent tongue mucosa. H&E; 4× 

PLATE 2 

Higher magnification of the squamous cell carcinoma in Plate 1. 

Note the islands of neoplastic epithelial cells that have extended 

through the basal lamina and the associated inflammatory infiltrate. 

H&E; 13.2× 

PLATE 4 

Higher magnification of Plate 3. Note that the neoplastic cells have 

not extended beyond the basal lamina of the submucosa. H&E; 80× 
PLATE 5 

Adenomatous hyperplasia of the areas of respiratory metaplasia of the 

septum and turbinates in nasal Level II in the nasal cavity of a female 

F344/N rat exposed to 80 ppm chloroprene by inhalation for 2 years. 

Note the numerous folds in the hyperplastic epithelium. H&E; 8× 

PLATE 7 

Basal cell hyperplasia (arrows) and fibrosis in the turbinate of nasal 

Level III in the nasal cavity of a female F344/N rat exposed to 80 ppm 

chloroprene by inhalation for 2 years. H&E; 25× 

PLATE 6 

Higher magnification of Plate 5. Note that the olfactory epithelium is 

replaced with thickened respiratory epithelium and the underlying 

glands are dilated in areas of inflammation. H&E; 80× 

PLATE 8 

Higher magnification of Plate 7 showing several layers of basal cells 

(arrows) and fibrosis. H&E; 66× 
PLATE 9 PLATE 10 

Higher magnification of Plate 9. Note the mixed pattern of the multiple alveolar/bronchiolar carcinomas consisting of solid and papillary 

patterns and the vacuolated cytoplasm of malignant cells consistent 

with type II cells. Note that the neoplastic cells are in filtrating the 

adjacent normal lung parenchyma. H&E; 50× 

Lung of a male B6C3F1 mouse exposed to 80 ppm chloroprene by 

inhalation for 2 years. Note the multiple alveolar/bronchiolar carcinomas. H&E; 2.5× 

PLATE 11 

Mammary gland carcinoma of a female B6C3F1 mouse exposed to 80 

ppm chloroprene by inhalation for 2 years. Note that the normal 

architecture of the mammary gland is replaced by malignant epithelia 

that are forming glandular patterns. H&E; 5× 

PLATE 12 

Mammary gland adenoacanthoma of a female B6C3F1 mouse 

exposed to 80 ppm chloroprene by inhalation for 2 years. Note that 

the normal architecture of the mammary gland is replaced by dense 

cellular solid foci of pleomorphic cells with a high nucleus:cytoplasm 

ratio. Also note the abundant squamous cell differentiation (arrows), 

a prominent feature of this neoplasm. H&E; 50× 
PLATE 13	 

Normal liver of a male B6C3F mouse exposed to filtered air by	 1 

inhalation for 2 years. H&E; 50×	 

PLATE 14 

Liver of a male B6C3F mouse exposed to filtered air by inhalation 1 

for 2 years with inflammatory lesions consistent with Helicobacter 

infection. Compare to Plate 13 and note the prominent bile duct 

hyperplasia (arrows), karyomegaly (arrowheads), and regeneration of 

hepatocytes. H&E; 50× 

PLATE 15	 

Squamous cell papilloma in the forestomach of a male B6C3F1 

mouse exposed to 80 ppm chloroprene by inhalation for 2 years. The 

squamous cell papilloma has multiple fronds of thickened epithelium 

radiating from a central narrow stalk. H&E; 16× 

PLATE 16 

Squamous cell hyperplasia in the forestomach of a female B6C3F1 

mouse exposed to 80 ppm chloroprene by inhalation for 2 years. The 

epithelium is thickened and is associated with marked hyperkeratosis. 

H&E; 25× 
PLATE 17 

Nasal cavity of a male B6C3F1 mouse exposed to filtered air by 

inhalation for 2 years. Note the normal olfactory epithelium lining 

the septum and dorsal meatus in nasal Level III. H&E; 20× 

PLATE 18 

Nasal cavity of a male B6C3F1 mouse exposed to 80 ppm 

chloroprene by inhalation for 2 years. Compare to Plate 17 and note 

the respiratory metaplasia and atrophy of the olfactory epithelium of 

dorsal meatus in nasal Level III. Note the adenomatous hyperplasia 

of the septum characterized by numerous folds in the hyperplastic 

epithelium. H&E; 20× 
87 

DISCUSSION AND CONCLUSIONS
 

Chloroprene was selected for study by the National forestomach, harderian gland, ovary, mammary gland, 

Toxicology Program (NTP) because it is an important and preputial gland. A 2-year inhalation study of 

high-volume production chemical with a potential for 1,3-butadiene in Sprague-Dawley rats, sponsored by 

human exposure, there is limited information available the International Institute of Synthetic Rubber Proon its carcinogenic potential in experimental animals ducers, used exposure concentrations of 1,000 and 

and humans, and it is the 2-chloro analogue of 8,000 ppm. In rats, 1,3-butadiene was carcinogenic to 

1,3-butadiene. Chloroprene is also structurally similar the mammary gland, brain, Zymbal’s gland, uterus, 

to vinyl chloride, a human carcinogen known to pancreas, testis, and thyroid gland (Owen et al., 

induce hemangiosarcomas in the liver of laboratory 1987). These studies established 1,3-butadiene as a 

animals and exposed workers. Based on results of a multiple-species, multiple-organ carcinogen, with mice 

previous NTP study of 1,3-butadiene in mice in which eliciting the more striking response. Because of 

neoplasms were induced at multiple organ sites (NTP, differences in sites of tumor induction and in the 

1984; Huff et al., 1985), NTP examined chloroprene effective exposure-related responses between rats and 

and isoprene (2-methyl-1,3-butadiene) to see if either mice, recent research has focused on trying to underof these structural analogues of 1,3-butadiene produces stand the basis for this species difference, especially as 

effects similar to those of 1,3-butadiene. A second it may relate to assessment of human risk. Based on 

study of 1,3-butadiene was also conducted over an available epidemiological and mechanistic data on 

expanded exposure range to provide a bet- 1,3-butadiene as well as the similarities in response 

ter characterization of dose-response effects. between 1,3-butadiene and ethylene oxide, Melnick 

and Kohn (1995) concluded that butadiene should be 

1,3-Butadiene has been studied intensely over the past considered a human carcinogen and that the mouse is 

12 years, and results from those studies have raised an appropriate model for assessing human cancer risk. 

the level of concern for humans exposed to this 

chemical and heightened the importance of understanding the toxicologic and carcinogenic potential Epidemiologic studies have consistently associated 

of chloroprene and isoprene. This report presents the excess mortality from lymphatic and hematopoietic 

findings of 16-day, 13-week, and 2-year chloroprene cancers with occupational exposure to 1,3-butadiene. 

inhalation studies in F344/N rats and B6C3F1 mice and Significant increases in incidences of lymphosarcoma

makes comparisons to the toxicologic effects of have been observed in individuals who work in the 

1,3-butadiene. 1,3-butadiene production industry (Divine, 1990; 

Ward et al., 1995), whereas increases in the incidence 

In the two NTP long-term inhalation toxicology/ of leukemia have been found in individuals who work 

carcinogenicity studies of 1,3-butadiene in B6C3F 1 in the styrene-butadiene rubber manufacturing industry 

mice, exposure concentrations ranged from 6.25 to (Matanoski et al., 1990; Santos-Burgoa et al., 1992). 

1,250 ppm (Huff et al., 1985; Melnick et al., 1990a; Recent follow-up studies of synthetic-rubber producers 

NTP, 1984, 1993). Particularly noteworthy in these have confirmed the association between exposure to 

studies were the induction of malignant lymphomas as 1,3-butadiene and chronic leukemia (Delzell et al., 

early as 20 weeks after the start of exposure and 1996). The finding that the risk of chronic leukemia 

uncommon hemangiosarcomas of the heart. Further- in humans exposed to 1,3-butadiene was similar to risk 

more, malignant lung neoplasms were induced in estimates that were based on the induction of 

female mice at all exposure concentrations. Other lymphocytic lymphoma in exposed mice supports the 

sites of neoplasm induction in mice included the liver, use of mice in studies for human risk assessment. 
88 Chloroprene, NTP TR 467 

Based on data available on 1,3-butadiene, the Occupational Safety and Health Administration (OSHA) has 

recently lowered the occupational exposure standard 

for 1,3-butadiene from 1,000 to 1 ppm, expressed as 

an 8-hour, time-weighted, average work-place 

exposure limit, and set a 15-minute short-term 

exposure limit of 5 ppm (29 CFR, Parts 1910, 1915, 

and 1926). The current OSHA standard for chloroprene is 25 ppm, based largely on results of 4-week 

inhalation toxicity studies in rats and hamsters (Clary 

et al., 1978). 

16-Day and 13-Week Studies 

in Rats and Mice 

Exposure of F344/N rats to chloroprene for 16 days at 

chamber concentrations ranging from 32 to 500 ppm 

produced several toxic effects: 1) mortality at 

500 ppm and reductions in body weight gain in males 

exposed to 200 or 500 ppm; 2) regenerative, 

normocytic, normochromic anemia in males exposed 

to 500 ppm and in females exposed to 200 or 

500 ppm; 3) centrilobular hepatocellular necrosis in 

the 200 and 500 ppm groups and increases in alanine 

aminotransferase (ALT), glutamate dehydrogenase 

(GDH), and sorbitol dehydrogenase (SDH) activities 

in 200 ppm females and 500 ppm males and females; 

4) olfactory epithelial degeneration in all exposed 

groups and respiratory metaplasia in the 500 ppm 

groups; and 5) thymic atrophy. Similar effects in the 

liver were reported in a 4-week inhalation study of 

chloroprene in Wistar rats (Clary et al., 1978). 

The hemorrhage observed clinically (epistaxis) in this 

study suggests that the rapidly developing normocytic, 

normochromic, responsive anemia that occurred on 

day 4 in the 500 ppm groups may have been related to 

acute blood loss. The thrombocytopenia seen in this 

study is also consistent with the clinically observed 

hemorrhage. 1,3-Butadiene has also been shown to 

cause an anemia in mice (Irons et al., 1986; Melnick 

et al., 1990b); however, in this species the anemia was 

macrocytic, normochromic, and nonresponsive and 

was suggested to involve altered bone marrow 

production of erythrocytes. No hematologic effects 

were observed in rats exposed to 1,3-butadiene or 

isoprene at concentrations as high as 8,000 ppm and 

7,000 ppm, respectively (Crouch et al., 1979; Melnick 

et al., 1994). 

Findings from the 13-week inhalation toxicity studies 

of chloroprene in F344/N rats and B6C3F mice have 1 

been reported by Melnick et al. (1996a). Exposure of 

rats to 32 ppm chloroprene or greater concentrations 

caused olfactory epithelial degeneration, and 80 ppm 

or greater caused respiratory metaplasia; exposure to 

200 ppm caused anemia (characterized as normocytic, 

normochromic, and nonresponsive), minimal to mild 

hepatocellular necrosis, and reduced sperm motility. 

These lesions had not been observed in rats exposed to 

1,3-butadiene or isoprene even at exposure concentrations as high as 8,000 and 7,000 ppm, respectively (Crouch et al., 1979; Melnick et al., 1994). 

Neurobehavioral assessments showed an increase in 

motor activity in exposed males but not females with 

no effects on grip strength or startle response in either 

male or female rats (Tilson, 1990). 

As in the 16-day rat study, rats in the 200 ppm groups 

demonstrated evidence of hemorrhage, which may, in 

part, explain the minimal normocytic, normochromic, 

and nonresponsive anemia that was observed at 

week 13. The increase in activated partial thromboplastin time and prothrombin time on day 2 of the 

13-week study suggests that coagulopathy may have 

contributed to the hemorrhage and subsequent anemia. 

The lack of a bone marrow response at the end of the 

13-week study may be because the changes in erythroid parameters were not severe enough to stimulate 

a demonstrable erythropoietic response. 

Increases in serum ALT, GDH, and SDH activities 

indicative of hepatocellular pathology resulting in a 

loss of cell membrane integrity, or cellular necrosis 

with subsequent enzyme release, were observed in 

both the 16-day and 13-week studies. These changes 

were transient, however, and by week 13 the activities 

of these serum enzymes had returned to chamber 

control levels. Centrilobular necrosis was also observed in the liver of rats exposed to 200 ppm or 

greater concentrations of chloroprene, and this would 

account for the increases in the serum activities of 

these enzymes. However, while the biochemical 

effects appeared to be transient, liver injury (hepatocellular necrosis) was still evident at study termination. 

In the 13-week study, proteinuria and alkaline phosphatase enzymeuria occurred in the 200 ppm animals 

as early as day 22; these findings suggest a renal 

tubule effect. There were no microscopic lesions to 
Chloroprene, NTP TR 467 89 

support these biochemical alterations, suggesting that 

the renal injury was too mild to result in structural 

damage or that the biochemical effects may precede 

the eventual development of microscopic lesions. 

Exposure-related increases in kidney weights also 

suggest a renal effect and support the biochemical 

findings. These findings suggest that the kidney is a 

target tissue for the inhalation toxicity of chloroprene 

and that the renal effects would not have been identified by microscopic evaluation alone. 

In the 16-day inhalation study of chloroprene in 

B6C3F1 mice, exposure concentrations were slightly 

less than those in the rat study (from 12 to 200 ppm in 

mice versus 32 to 500 ppm in rats). In spite of the 

lower exposure concentration, all mice exposed to 

200 ppm died during the first 3 days of the study. 

Chloroprene at exposure concentrations up to 80 ppm 

had no effect on survival, body weight gain, hematology, or clinical chemistry parameters. Histopathologic findings in the 200 ppm group included 

multifocal hepatic necrosis, thymic necrosis, and focal 

hemorrhage, erosions, or necrosis of the glandular 

stomach mucosa. Squamous epithelial hyperplasia of 

the forestomach was observed in a small number of 

mice exposed to 80 ppm. 

In the 13-week inhalation study in B6C3F1 mice, 

exposure to 80 ppm caused a marginal decrease in 

body weight gain in males and epithelial hyperplasia of 

the forestomach in males and females. This lesion had 

also been observed in mice exposed to isoprene or 

1,3-butadiene. A mild, normocytic, normochromic, 

nonresponsive anemia was also detected in exposed 

female mice. Decreases in hepatic nonprotein sulfhydryl concentrations in mice exposed to 80 ppm were 

not associated with any histopathologic changes in the 

liver. 

In conjunction with these toxicity studies on chloroprene, additional groups of mice were included for 

evaluations of cytogenetic effects after 12 exposures 

over a 16-day period. Unlike the effects seen in mice 

exposed to 1,3-butadiene or isoprene, chloroprene did 

not induce cytogenetic damage in bone marrow cells of 

mice exposed to concentrations up to 80 ppm (Tice 

et al., 1988). For 1,3-butadiene, this exposure concentration produced increases in sister chromatid 

exchanges and in the frequency of micronuclei in 

peripheral blood. Isoprene also produced cytogenetic 

effects in mice but at exposure concentrations greater 

than those that could be achieved with chloroprene. 

The 16-day and 13-week studies indicate that chloroprene is substantially more toxic to rats and mice than 

either 1,3-butadiene or isoprene. This difference is 

reflected in the maximum tolerated exposures that 

were selected for long-term studies of these chemicals: 

1,3-butadiene, 8,000 ppm for rats (Owen et al., 1987) 

and 1,250 ppm for mice (NTP, 1993; Huff et al., 

1985); isoprene, 7,000 ppm for rats and mice 

(Melnick et al., 1994); and chloroprene, 200 ppm for 

rats and 80 ppm for mice. Table 31 shows that the 

profile of toxicologic effects of chloroprene, in terms 

of target sites and effective exposures, differs considerably from that of isoprene or 1,3-butadiene; this 

may be due in part to differences in exposure 

concentrations that were used in the toxicology studies 

of these compounds but is also likely due to the 

influence of the chlorine substitution on the toxicokinetics and biotransformation of this chemical and the 

reactivity of metabolic intermediates with tissue 

macromolecules. 
90 Chloroprene, NTP TR 467 

TABLE 31 

Toxicologic Effects (Lowest-Observable-Adverse-Effect Level in ppm) of Chloroprene, 1,3-Butadiene, 

and Isoprene in Rats and Micea 

Rats Mice 

Toxic Effect Chloroprene Butadiene Isoprene Chloroprene Butadiene Isoprene 

b c d b e d Anemia 200 neg(8,000) neg(7,000) neg(80) 62.5 220 

b c d b f d Liver, necrosis 200 neg(8,000) neg(7,000) neg(80) 625 neg(7,000) 

Nose, olfactory b c d b g d epithelium degeneration 32 neg(8,000) neg(7,000) neg(80) 625 220 

Forestomach, squamous b c d b e h epithelial hyperplasia neg(200) neg(8,000) neg(7,000) 80 200 438
 

b c d b e h Testes, atrophy neg(200) neg(8,000) neg(7,000) neg(80) 625 7,000 

Cytogenetic damage i j i Chromosomal aberrations NS NS NS neg(80) 625 neg (7,000) k i j l Sister chromatid exchange NS neg(10,000) NS neg(80) 6.25 220 

k i l i Micronuclei NS neg(10,000) NS neg(80) 6.25 438 

a Taken from Melnick et al., 1996a. Neg = no effect. NS = not studied. The highest concentration studied is given in parentheses. b The current study c Crouch et al., 1979 

d Melnick et al., 1994 e Melnick et al., 1990b 

f NTP, 1984 

g NTP, 1993 h Melnick et al., 1990c 

i Tice et al., 1988 

j Tice et al., 1987 

k Cunningham et al., 1986 

l Shelby, 1990 
Chloroprene, NTP TR 467 91 

2-Year Study in Rats 

In the 2-year study of chloroprene in rats, survival 

rates were less in all exposed groups of males and 

significantly reduced in 32 and 80 ppm males relative 

to the chamber controls. Males exposed to 80 ppm 

had decreased body weights compared to the chamber 

controls; a large part of this difference occurred 

during the last month of the study. There were no 

differences in survival or body weights among the 

female exposed and chamber control rats. 

TABLE 32 

Exposure of rats to chloroprene produced a multipleorgan carcinogenic response. Some sites affected by 

chloroprene were not affected by 1,3-butadiene, 

whereas other sites were affected similarly even 

though the exposure concentrations used in the studies 

of these two chemicals differed substantially 

(Table 32). Exposure-related carcinogenic effects of 

chloroprene were seen in the lung, oral cavity, thyroid 

gland, mammary gland, and kidney. In addition, low 

incidences of rare neoplasms in the urinary bladder in 

males and females may have been exposure related. 

Sites of Increased Incidences of Neoplasms in the 2-Year Inhalation Studies 

of Chloroprene and 1,3-Butadiene in Rats and Mice 

Chloroprenea 1,3-Butadieneb 

Male Female Male Female 

Rats 

Pancreas 

Uterus 

Oral Cavity Oral Cavity 

Thyroid gland Thyroid gland Thyroid gland 

Lung 

Mammary gland Mammary gland 

Kidney Kidney 

Testis 

Zymbal’s gland 

Brain 

Mice 

Hematopoietic system Hematopoietic system 

Lung Lung Lung Lung 

Circulatory system Circulatory system 

Heart (hemangiosarcoma) Heart (hemangiosarcoma) 

Harderian gland Harderian gland Harderian gland Harderian gland 

Forestomach Forestomach Forestomach Forestomach 

Kidney Kidney 

Mammary gland Mammary gland 

Liver Liver Liver 

Skin 

Mesentery 

Zymbal’s gland 

Preputial gland 

Ovary 

a Current study in F344/N rats and B6C3F mice 

b 1 

Studies in Sprague-Dawley rats at exposure concentrations of 1,000 or 8,000 ppm (Owen et al., 1987) and B6C3F mice at exposure 1 

concentrations of 6.25, 20, 62.5, 200, or 625 ppm (Melnick et al., 1990a; NTP, 1993) 
92 Chloroprene, NTP TR 467 

In rats exposed to chloroprene, increased incidences of morphologic continuum of proliferative kidney lesions 

proliferative lesions of the oral cavity included squa- leading to renal tubule adenoma and carcinoma. Even 

mous cell hyperplasia, squamous cell papilloma, and though the severity of nephropathy was increased 

squamous cell carcinoma and involved the palate, slightly in exposed rats compared to the chamber 

pharynx, gingiva, cheek, and tongue. In addition to controls, the renal tubule hyperplasias observed in this 

the positive exposure-related trends, the incidences of study were distinguishable from regenerative epithelial 

squamous cell papilloma and squamous cell carcinoma changes associated with renal nephropathy in this 

(combined) increased significantly in males and strain of rat. Because renal tubule neoplasms are 

females and far exceeded the NTP historical control uncommon in chamber control F344/N rats, additional 

incidence. Oral cavity neoplasms have not been kidney sections were examined from chamber control 

reported in rats or mice exposed to 1,3-butadiene or and exposed male and female rats to provide a clearer 

isoprene (NTP, 1993, 1995). indication of the potential effects of chloroprene in this 

organ. Analyses of the step-section data indicated that 

Exposure-related positive trends and increased inci- the incidences of renal tubule hyperplasia were 

dences of follicular cell adenoma or carcinoma increased significantly in 32 and 80 ppm males and 

(combined) in rats were indicative of a carcinogenic 80 ppm females. The incidences of renal tubule 

effect of chloroprene in the thyroid gland. Thyroid adenoma or carcinoma (combined) were increased in 

gland follicular cell neoplasms have been reported to all exposed groups of males compared to the chamber 

be induced in female Sprague-Dawley rats exposed to controls. Particularly unusual was the finding of renal 

1,000 or 8,000 ppm 1,3-butadiene (Owen et al., tubule adenomas in four 80 ppm females and a renal 

1987). tubule carcinoma in one 12.8 ppm male. Thus, the 

results from the additional kidney step sections support 

The incidences of alveolar epithelial hyperplasia were the evidence from the original pathology review, 

increased in all exposed groups of male and female which indicated that chloroprene induces proliferative 

rats relative to their respective chamber control renal tubule lesions, including neoplasms, in male and 

groups, and there was also a slight increase in the female rats. 

incidence of alveolar/bronchiolar carcinomas (4 of 50) 

in 80 ppm males. The NTP historical control database A variety of exposure-related nasal lesions were 

recorded only 6 of 654 (0.9%) chamber control male induced in male and female rats including necrosis, 

rats with alveolar/bronchiolar carcinoma. Although chronic active inflammation, atrophy, respiratory 

exposure to 1,3-butadiene or isoprene induced lung metaplasia, adenomatous hyperplasia, basal cell 

neoplasms in mice, neither of these chemicals has been hyperplasia, and fibrosis of the olfactory epithelium. 

reported to cause lung neoplasms in rats (NTP, 1993, Although the incidences of many of these lesions 

1995). approached or reached 100% in the 80 ppm groups, 

there was no evidence of progression of these lesions 

The incidences of mammary gland fibroadenoma were to neoplasms. Similar nasal lesions without neoplastic 

increased in female rats exposed to 32 or 80 ppm; effects were seen in several other NTP 2-year studies, 

however, the incidence of mammary gland carcinoma including 2-chloroacetophenone, o-chlorobenzalwas not increased. Increases in the incidences of malononitrile, l-epinephrine hydrochloride, vinyl 

multiple fibroadenoma of the mammary gland in toluene, and tetranitromethane (NTP, 1990a,b,c,d,e). 

female rats support the conclusion that this effect is Although increased cell turnover may contribute to 

exposure related. Exposure of female rats to multistage carcinogenesis, a review of 19 NTP in1,3-butadiene also caused increases in the incidence halation bioassays found that chronic toxicity and cell 

and multiplicity of mammary gland fibroadenoma proliferation frequently were not associated with nasal 

(Owen et al., 1987; Melnick and Huff, 1992). carcinogenesis (Ward et al., 1993). Olfactory epithelial degeneration and respiratory metaplasia in rats 

Slight increases in the incidences of renal tubule ade- had been identified as a toxic effect of chloroprene in 

noma and renal tubule hyperplasia were observed in the 13-week studies; however, nasal lesions were not 

male and female rats exposed to chloroprene com- observed in rats exposed to 8,000 ppm 1,3-butadiene 

pared to the chamber controls. Renal tubule hyper- for 2 years (Owen et al., 1987) or to 7,000 ppm 

plasias are thought to represent an early stage in the isoprene for 26 weeks (Melnick et al., 1994). 
Chloroprene, NTP TR 467 93 

2-Year Study in Mice 

In the 2-year study of chloroprene in mice, survival 

rates were less in 32 and 80 ppm males and in all exposed groups of females than in the chamber controls. 

Many early deaths and moribund kills were associated 

with chloroprene-induced neoplasms. Mean body 

weights of 80 ppm female mice were less than those of 

chamber controls after week 75. 

Exposure of mice to chloroprene produced a potent 

multisite carcinogenic response. Several organs that 

were targets of 1,3-butadiene carcinogenicity in mice 

were similarly affected by chloroprene, including the 

lung, harderian gland, liver, forestomach, and mammary gland; however, some carcinogenic effects of 

1,3-butadiene in mice were not seen in the chloroprene study (Table 32). Most notable was the lack of 

lymphomas in mice exposed to chloroprene compared 

to the early occurrence and extensive development of 

lymphocytic lymphomas in mice exposed to 625 ppm 

1,3-butadiene. This may be related to differences in 

exposure to the parent compound and differences in 

target organ dosimetry and/or reactivity of metabolic 

intermediates. Exposure of mice to 1,3-butadiene was 

also associated with the development of rarely occurring hemangiosarcomas of the heart. Although 

exposure to chloroprene in the present study did not 

induce hemangiosarcomas of the heart, there were 

exposure-related increases in the incidences of 

hemangioma and hemangiosarcoma at multiple organ 

sites. In addition, 1,3-butadiene, but not chloroprene, 

induced granulosa cell tumors of the ovary; and 

chloroprene, but not 1,3-butadiene, induced skin and 

mesentery sarcomas in female mice. Small numbers of 

renal tubule adenomas were observed in male mice 

exposed to either 1,3-butadiene or chloroprene. The 

present studies included a step-section evaluation of 

the kidneys from chamber control and exposed male 

mice to more clearly ascertain the potential relationship between exposure to chloroprene and kidney 

neoplasms. The occurrence of Zymbal’s gland 

carcinomas in three female mice exposed to 80 ppm 

chloroprene is also indicative of an exposure-related 

effect. The four organ sites where isoprene was 

reported to induce neoplasms in mice (lung, liver, 

harderian gland, and forestomach; Melnick et al., 

1994) were also affected by chloroprene. 

The lung was a major target organ of chloropreneinduced neoplasms in male and female mice. In addition to producing increases in the incidences of 

bronchiolar epithelial hyperplasia and alveolar/ 

bronchiolar adenoma or carcinoma (combined), 

chloroprene exposure caused significant increases in 

the incidences of alveolar/bronchiolar carcinoma, 

multiple adenoma, and multiple carcinoma. Qinan 

et al. (1989) also observed an increase in lung 

neoplasm incidence and multiplicity in mice exposed 

to chloroprene for 7 months. Lung neoplasms including alveolar/bronchiolar carcinoma were induced 

in female mice exposed to 1,3-butadiene at concentrations as low as 6.25 ppm (Melnick et al., 1990a; 

NTP, 1993). Lung neoplasms were also induced by 

vinyl chloride in male and female mice (Maltoni et al., 

1981). 

The livers of most chamber control and exposed male 

mice contained a spectrum of lesions consistent with 

Helicobacter infection; these included karyomegaly, 

regeneration, and bile duct hyperplasia. The liver 

lesions associated with Helicobacter infection were not 

present in female mice, and an exposure-related 

increase in the incidences of hepatocellular carcinoma 

was evident. Neoplasm responses in female mice or at 

other sites in male mice (including hemangiosarcoma) 

were not considered to be affected by the Helicobacter 

infection. 

Based on retrospective analyses, Helicobacter 

hepaticus was determined to have infected mice in 

12 recent NTP 2-year studies (Appendix O). Of the 

12 studies, mice (primarily males) from nine studies 

(including this chloroprene study) had H. hepaticusassociated hepatitis. Qualitatively, the hepatitis and 

silver-staining organisms within the liver were similar 

among the nine studies. An organism compatible with 

H. hepaticus was identified by an assay based on 

polymerase chain reaction-restriction fragment length 

polymorphism (PCR-RFLP) in studies from which 

adequately preserved (frozen) liver tissue was available, including livers from 5 animals in this chloroprene study. Generally, efforts to identify H. hepaticus from tissue fixed in formalin for over a week 

were not successful (Malarkey et al., 1997). Because 

of the presence of the typical liver lesions, silverpositive helical organisms, and confirmation with 

PCR-RFLP-based assays, mice from the current study 

were determined to be infected with H. hepaticus. 

Increased incidences of hepatocellular neoplasms in 

male mice have been shown to be associated with 

H. hepaticus infection when hepatitis is also present 
94 Chloroprene, NTP TR 467 

(Ward et al., 1994; Fox et al., 1996; Appendix O). 

Additionally, in NTP studies with H. hepaticusassociated hepatitis, increased incidences of 

hemangiosarcoma were seen in the livers of male mice 

(Appendix O). In this study of chloroprene, 

hemangiosarcomas and hemangiomas, which are 

endothelial cell neoplasms derived from blood vessels, 

occurred primarily in the mesentery, subcutis of the 

skin, and liver; the bone and spleen were sometimes 

affected. Because of the association noted above, 

hemangiosarcomas of the liver were excluded from the 

analyses of circulatory (endothelial) neoplasms in 

males in this study. Hemangiomas did not occur in 

the liver of male mice in this study. Even with this 

exclusion, the incidences of the combined occurrence 

of hemangiosarcoma or hemangioma at other sites 

were significantly increased at all chloroprene exposure concentrations in males and in 32 ppm females. 

Incidences of neoplasms at other sites in this study of 

chloroprene were not considered to have been 

significantly impacted by the infection with 

H. hepaticus or its associated hepatitis (Appendix O). 

As with 1,3-butadiene, mammary gland neoplasms 

induced by chloroprene included both carcinomas and 

adenoacanthomas. The detection of mammary gland 

adenoacanthomas provides an additional indicator of 

an exposure-related effect because the historical incidence of these neoplasms is much less than that of 

mammary gland carcinoma in control female mice 

(0.1% versus 3.1%). 

The slight increases in incidences of squamous cell 

papilloma of the forestomach were considered to be 

exposure related because there were similar increases 

in the incidences of this uncommon neoplasm in 

exposed groups of male and female mice, and these 

responses were accompanied by increased incidences 

of hyperplasia of the forestomach epithelium. The 

latter lesion probably represents a proliferative preneoplastic change caused by chloroprene. 

As in the study of chloroprene in rats, exposurerelated increases in the incidences of renal tubule 

hyperplasia and renal tubule adenoma were observed 

in male mice. Because renal tubule adenomas are 

uncommon in historical control B6C3F mice (0.2%), 1 

additional sections of kidney from chamber control 

and chloroprene-exposed male mice were examined to 

verify the proliferative effects of chloroprene in this 

organ. The step-section data confirmed the original 

findings that exposure to chloroprene increased the 

incidences of renal tubule hyperplasia and produced an 

exposure-related increase in the incidences of renal 

tubule hyperplasia and renal tubule adenoma in males. 

The incidence of renal tubule adenoma in the 80 ppm 

group was significantly greater than that in the 

chamber controls, and the incidences of renal tubule 

hyperplasia were increased in all exposed groups of 

males. No renal tubule neoplasms were seen in 

chamber control males even after step sectioning. 

Several sites of neoplasm induction by chloroprene in 

mice have been mentioned as sites of increased risk of 

human cancer associated with occupational exposure 

to chloroprene, including the lung, skin, and liver 

(Infante et al., 1977; Shouqi et al., 1989). 

Exposure of male and female mice to 80 ppm chloroprene produced high incidences of olfactory epithelial 

atrophy, metaplasia, and adenomatous hyperplasia in 

the nose of males and females. These changes were 

not associated with neoplastic effects, although an 

adenoma of the respiratory epithelium was detected in 

one 80 ppm male and one 32 ppm female. Olfactory 

epithelial degeneration has been observed in mice 

exposed to 1,3-butadiene or isoprene (Melnick et al., 

1988; NTP, 1993). 

For neoplasms in mice showing exposure-related 

effects, the shapes of the dose-response curves and 

ED10 values were estimated by fitting a modified 

Weibull model (Portier et al., 1986) to the Poly-3 

survival-adjusted neoplasm rates. These values for 

chloroprene are shown along with those for 

1,3-butadiene in Table 33. If the estimated shape 

parameter is greater than 1, the resulting dose 

response has more curvature than a linear model 

(shape parameter equal to 1) and exhibits “thresholdlike behavior.” If the estimated shape parameter is 

less than 1, then the dose-response curve is very steep 

(supralinear) in the low-dose region. The ED10 values 

represent the estimated exposure concentration 

associated with an excess cancer risk of 10% at each 

site. Small differences in mean body weights between 

the chamber control group and groups of mice 

exposed to chloroprene or 1,3-butadiene were not 
Chloroprene, NTP TR 467 95 

TABLE 33 

Comparison of Dose-Response Shape Parameter and ED10 Values (ppm) for Chloroprene (Chl) 

and 1,3-Butadiene (BD) in Micea 

Males Females 

Shape Parameter ED -Chl 10 ED 10 -BD Shape Parameter ED -Chl 10 ED 10 -BD

Chl BD (LCL, UCL) (LCL, UCL) Chl BD (LCL, UCL) (LCL, UCL) 

Lung 

Alveolar/bronchiolar 

Carcinoma 0.743 0.576* 3.7 8.1 0.686 0.456** 1.9 2.8 

(0.1, 13.7) (1.1, 30.7) (0.05, 6.7) (0.3, 7.8) 

Alveolar/bronchiolar

 Adenoma

 or Carcinoma 0.682 0.459** 0.9 2.1 0.597* 0.374** 0.3 0.3 

(<0.01, 4.8) (0.01, 21.2) (<0.01, 1.6) (<0.01, 1.8) 

All organsb 

Hemangioma or

 Hemangiosarcoma 0.292** 0.737 0.2 14.0 0.329* 0.982 1.4 24.4 

(<0.01, 4.8) (14.0, 28.4) (<0.01, 17.4) (11.4, 46.6) 

Harderian Gland 

Adenoma

 or Carcinoma 0.661 0.649** 12.1 5.8 0.814 0.574* 22.5 9.4 

(<0.01, 39.6) (1.4, 16.2) (<0.01, 79.2) (1.0, 40.9) 

Mammary Gland 

Adenoacanthoma 

or Carcinoma 0.844 0.706** 11.8 13.1 

(0.5, 34.5) (5.4, 24.1) 

Liver 

Hepatocellular 

Carcinoma 0.414 0.399* 0.6 2.33 0.605 0.279* 2.7 9.1 

(<0.01, 20.2) (<0.01, 29.0) (<0.01, 13.3) (<0.01, 112.8) 

Hepatocellular Adenoma

 or Carcinoma 1.330 0.362* 36.9 0.7 0.584 0.315 1.9 7.2 

(11.7, 79.5) (<0.01, 22.8) (<0.01, 78.4) (<0.01, 625) 

Forestomach 

Squamous Cell Papilloma

 or Carcinoma 1.83 1.412 70.0 120.4 >10.0* 1.182 79.1 63.9 

(51.3, 79.9) (87.5, 172.1) (76.9, 80 ) c (37.5, 185.4) 

Kidney 

Renal Tubule Adenoma

 Single Section 0.773 0.247 80c 625c 

(51, 80) (241, 625)

 Single +

 Step Section 1.01 32.2 

(14.2, 60.8) 
96 

c 

Chloroprene, NTP TR 467 

TABLE 33 

Comparison of Dose-Response Shape Parameter and ED10 Values (ppm) for Chloroprene (Chl) 

and 1,3-Butadiene (BD) in Mice 

Males 

Shape Parameter ED -Chl 10 

Chl BD (LCL, UCL) 

ED 10 -BD

(LCL, UCL) 

Shape Parameter 

Chl BD 

Females 

ED -Chl 10 

(LCL, UCL) 

ED 10 -BD

(LCL, UCL) 

Skin 

Sarcoma 0.459** 0.555 1.1 

(<0.01, 6.3) 

70.4 

(65.1, 237.9) 

Mesentery 

Sarcoma 0.074**>10.0 0.02 

(<0.01, 17.5) 

602 

(577.6, 618.4) 

* Shape is significantly different (P<0.05) from 1 by a likelihood ratio test 

** P<0.01 a Shape parameter and ED10 values were estimated by fitting a modified Weibull model (Portier et al., 1986) to the Poly-3 survival-adjusted 

neoplasm rates for chloroprene and for 1,3-butadiene. The 95% lower confidence limit (LCL) and 95% upper confidence limit (UCL) are 

given in parentheses. b	 Liver hemangioma and hemangiosarcoma were excluded for chloroprene-exposed male mice. 

Estimates and upper limits of ED10 values were not allowed to exceed the maximum exposure concentration. 

considered to have a substantial impact on the 

neoplasm dose-response evaluations. 

For many of the chloroprene-induced neoplastic effects 

that were evaluated, the dose responses were 

consistent with a linear model. In most instances in 

which a departure from linearity was evident, the 

shape parameter indicated a dose-response curve that 

was supralinear (concave downward) in the low-dose 

region (hemangioma and hemangiosarcoma in male 

and female mice, alveolar/bronchiolar adenoma or 

carcinoma, skin and mesentery sarcomas in female 

mice). Only squamous cell papilloma or carcinoma of 

the forestomach in female mice had evidence of a 

sublinear (concave upward) dose response. For 

1,3-butadiene, the shape parameter values indicated 

supralinear dose responses for lung, harderian gland, 

and liver neoplasms in male and female mice and for 

mammary gland neoplasms in female mice. 

ED10 values, which are central tendency estimates 

within the region of experimental observation, have 

been used to compare cancer potency between carcinogens. The data in Table 33 indicate that chloroprene is more potent than 1,3-butadiene at inducing 

hemangiomas or hemangiosarcomas in male and female mice and skin and mesentery sarcomas in female 

mice. The two chemicals were nearly equivalent in 

their potency to induce lung and harderian gland neoplasms in male and female mice and mammary gland, 

liver, and forestomach neoplasms in female mice. 

ED10 values for neoplasms induced by 1,3-butadiene 

but not by chloroprene (e.g., malignant lymphoma and 

granulosa cell tumors of the ovary) were higher than 

those estimated for 1,3-butadiene-induced lung 

neoplasms, harderian gland neoplasms, or hemangioma and hemangiosarcoma. Hence, the carcinogenic 

potency of chloroprene in mice appears to be 

equivalent to or greater than that of 1,3-butadiene. 

A similar type of analysis on the dose response and 

potency of vinyl chloride-induced neoplasms was not 

possible because of differences in study design (including different strains of rats and mice and different 

durations of exposure) and because individual animal 

data were not available. However, vinyl chloride 

(Maltoni et al., 1981) and chloroprene have several 

common sites of induction of neoplasms, in particular 

hemangiosarcomas as well as mammary gland neoplasms in rats and neoplasms of the liver, lung, mammary gland, and forestomach in mice. 

Bartsch et al. (1975, 1979) reported that chloroprene 

was mutagenic to Salmonella typhimurium with and 

without metabolic activation; however, others have 

found no evidence of mutagenicity for chloroprene in 
Chloroprene, NTP TR 467 97 

S. typhimurium (Zeiger et al., 1987; Westphal et al., 

1994). Westphal et al. (1994) observed mutagenic 

effects in S. typhimurium with aged samples of chloroprene but not with freshly distilled samples. These 

results indicate either that chloroprene is not mutagenic to S. typhimurium or that in the systems used to 

determine its mutagenicity, the reactive alkylating 

intermediate did not reach the target DNA. In addition, chloroprene did not induce sex-linked recessive 

lethal mutations in germ cells of male Drosophila 

melanogaster, nor did it induce chromosomal aberrations, sister chromatid exchanges, or micronucleated 

erythrocytes in bone marrow or peripheral blood of 

mice exposed to concentrations as high as 80 ppm. 

Using similar protocols, both 1,3-butadiene and 

isoprene induced cytogenetic changes in mice. 

Clearly, in vivo and in vitro genotoxicity data were not 

predictive of the potent multisite carcinogenic effects 

of chloroprene. These results reveal the in-adequacy 

of relying on oversimplified operational classification 

systems, such as genotoxic versus non-genotoxic, in 

regard to cancer risk rather than focusing on 

increasing the understanding of causal relationships 

between exposure and cancer outcome (Melnick et al., 

1996b). The finding of a higher frequency of unique 

K-ras mutations, predominantly A to T transversions 

at codon 61 in chloroprene-induced lung and harderian 

gland neoplasms (Appendix N), suggests the 

involvement of a mutagenic event in chloropreneinduced neoplasia. A similar high frequency of A to 

T transversions at codon 61 of K-ras were detected in 

lung and harderian gland neoplasms induced by 

isoprene. 

The carcinogenic effects of 1,3-butadiene have been 

attributed to its mutagenic epoxide intermediates 

(Melnick and Kohn, 1995). Similarly, the mutagenic 

and carcinogenic effects of vinyl chloride have been 

attributed to its epoxide metabolite, chlorothyleneoxide, and the rearrangement product, chloroacetaldehyde, both of which can react with DNA to 

form a variety of adducts (Guengerich, 1992; Singer, 

1996). Neither the metabolic fate of chloroprene nor 

the biological properties of its metabolic intermediates 

have been well studied. Oxidation of chloroprene to 

epoxide intermediates (2-chloro-1,2-epoxybutene-3 

and 2-chloro-3,4-epoxybutene-1) was suggested to 

occur based on the detection of alkylated 

4-(4-itrobenzyl)pyridine in incubations of chloroprene 

and mouse liver microsomes (Haley, 1978; Bartsch 

et al., 1979). Analogous to the formation of chloroacetaldehyde subsequent to the oxidation of vinyl 

chloride to chloroethylene oxide, 2-chloro-1,2­

epoxybutene-3 could undergo rearrangement to form 

an unsaturated chloroketone. These postulated oxidative intermediates of chloroprene metabolism may be 

protein and/or DNA reactive and may account for the 

cytotoxicity and carcinogenic effects of this compound. Differences in stability, distribution, and 

reactivity of these various intermediates may account 

for differences in dose-related carcinogenic effects of 

chloroprene and 1,3-butadiene. Further studies are 

needed to understand the processes involved in 

chloroprene carcinogenesis. 

CONCLUSIONS 

Under the conditions of these 2-year inhalation 

studies, there was clear evidence of carcinogenic 

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

increased incidences of neoplasms of the oral cavity; 

increased incidences of neoplasms of the thyroid 

gland, lung, and kidney were also attributed to chloroprene exposure. There was clear evidence of carcinogenic activity of chloroprene in female F344/N rats 

based on increased incidences of neoplasms of the oral 

cavity; increased incidences of neoplasms of the 

thyroid gland, mammary gland, and kidney were also 

attributed to exposure to chloroprene. Low incidences 

of urinary bladder neoplasms in male and female rats 

and lung neoplasms in female rats may also have been 

related to exposure to chloroprene. 

There was clear evidence of carcinogenic activity of 

chloroprene in male B6C3F 1 mice based on increased

incidences of neoplasms of the lung, circulatory 

system (hemangiomas and hemangiosarcomas), and 

harderian gland; increased incidences of neoplasms of 

the forestomach and kidney were also attributed to 

exposure to chloroprene. There was clear evidence of 

carcinogenic activity of chloroprene in female B6C3F1 

mice based on increased incidences of neoplasms of 

the lung, circulatory system (hemangiomas and 

hemangiosarcomas), harderian gland, mammary gland, 

liver, skin, and mesentery; increased incidences of 

neoplasms of the forestomach and Zymbal’s gland 

were also attributed to exposure to chloroprene. 
98 Chloroprene, NTP TR 467 

Exposure of male and female rats to chloroprene was 

associated with increased incidences of alveolar 

epithelial hyperplasia in the lung; nephropathy; and 

several nonneoplastic effects in the nose including 

olfactory epithelial atrophy, fibrosis, adenomatous 

hyperplasia, basal cell hyperplasia, chronic inflammation, respiratory metaplasia, and necrosis. Exposure of male and female mice to chloroprene was 

associated with increased incidences of bronchiolar 

hyperplasia and histiocytic cell infiltration in the lung; 

epithelial hyperplasia in the forestomach; renal tubule 

hyperplasia (males only); several effects in the nose 

including olfactory epithelial atrophy, respiratory 

metaplasia, and adenomatous hyperplasia; and hematopoietic cell proliferation in the spleen. 

* Explanation of Levels of Evidence of Carcinogenic Activity is on page 14. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 16. 
99 

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109 

APPENDIX A 

SUMMARY OF LESIONS IN MALE RATS 

IN THE 2-YEAR INHALATION STUDY 

OF CHLOROPRENE 

TABLE A1 

TABLE A2 

TABLE A3 

TABLE A4a 

TABLE A4b 

TABLE A4c 

TABLE A4d 

TABLE A4e 

TABLE A5 

Summary of the Incidence of Neoplasms in Male Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Individual Animal Tumor Pathology of Male Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Statistical Analysis of Primary Neoplasms in Male Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Historical Incidence of Oral Cavity Neoplasms 

in Chamber Control Male F344/N Rats .................................. 

Historical Incidence of Thyroid Gland Follicular Cell Neoplasms 

in Chamber Control Male F344/N Rats .................................. 

Historical Incidence of Alveolar/bronchiolar Neoplasms 

in Chamber Control Male F344/N Rats .................................. 

Historical Incidence of Renal Tubule Neoplasms 

in Chamber Control Male F344/N Rats .................................. 

Historical Incidence of Urinary Bladder Neoplasms 

in Chamber Control Male F344/N Rats .................................. 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

110 

114 

136 

144 

144 

145 

145 

146 

147 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

110 Chloroprene, NTP TR 467 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 34 40 41 41 

Natural deaths 3 1 4 5 

Survivors 

Terminal sacrifice 13 9 5 4 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (49) (48) (49) 

Intestine large, cecum (48) (49) (46) (48) 

Polyp adenomatous 1 (2%) 

Intestine small, duodenum (50) (49) (49) (50) 

Polyp adenomatous 1 (2%) 1 (2%) 

Intestine small, jejunum (48) (49) (46) (47) 

Carcinoma 1 (2%) 

Intestine small, ileum (49) (49) (46) (46) 

Liver (50) (50) (49) (50) 

Histiocytic sarcoma 2 (4%) 

Schwannoma malignant, metastatic, heart 1 (2%) 

Mesentery (16) (13) (18) (13) 

Hemangioma 1 (8%) 

Sarcoma 1 (6%) 

Schwannoma malignant 1 (6%) 

Fat, lipoma 1 (8%) 

Oral mucosa (2) (1) (7) 

Buccal, squamous cell papilloma 1 (14%) 

Gingival, squamous cell papilloma 1 (14%) 

Pharyngeal, squamous cell papilloma 2 (100%) 1 (100%) 2 (29%) 

Pancreas (50) (50) (49) (50) 

Adenoma 1 (2%) 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Stomach, forestomach (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Stomach, glandular (49) (50) (49) (50) 

Histiocytic sarcoma 1 (2%) 

Tongue (4) (8) 

Squamous cell carcinoma 1 (25%) 2 (25%) 

Squamous cell papilloma 3 (75%) 6 (75%) 

Cardiovascular System 

Blood vessel (3) (1) 

Aorta, schwannoma malignant, metastatic,

 heart 1 (33%) 

Heart (50) (50) (50) (50) 

Schwannoma malignant 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 111 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Endocrine System 

Adrenal cortex (50) (50) (49) (50) 

Adenoma 2 (4%) 1 (2%) 

Adrenal medulla (50) (50) (49) (50) 

Pheochromocytoma malignant 1 (2%) 1 (2%) 

Pheochromocytoma benign 14 (28%) 13 (26%) 11 (22%) 9 (18%) 

Bilateral, pheochromocytoma benign 5 (10%) 7 (14%) 10 (20%) 9 (18%) 

Islets, pancreatic (50) (50) (49) (50) 

Adenoma 3 (6%) 3 (6%) 2 (4%) 2 (4%) 

Carcinoma 3 (6%) 5 (10%) 3 (6%) 1 (2%) 

Parathyroid gland (48) (49) (50) (50) 

Adenoma 1 (2%) 

Pituitary gland (50) (49) (50) (49) 

Pars distalis, adenoma 40 (80%) 40 (82%) 43 (86%) 39 (80%) 

Pars intermedia, adenoma 1 (2%) 

Thyroid gland (50) (50) (49) (50) 

C-cell, adenoma 3 (6%) 6 (12%) 4 (8%) 7 (14%) 

C-cell, carcinoma 2 (4%) 2 (4%) 2 (4%) 

Follicular cell, adenoma 2 (4%) 2 (4%) 4 (8%) 

Follicular cell, carcinoma 2 (4%) 1 (2%) 

General Body System 

Peritoneum (3) 

Genital System 

Epididymis (50) (50) (50) (50) 

Preputial gland (50) (50) (48) (50) 

Adenoma 3 (6%) 3 (6%) 4 (8%) 1 (2%) 

Carcinoma 3 (6%) 3 (6%) 4 (8%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Prostate (50) (50) (50) (50) 

Adenoma 1 (2%) 3 (6%) 1 (2%) 

Seminal vesicle (50) (50) (50) (49) 

Histiocytic sarcoma 1 (2%) 

Testes (50) (50) (50) (50) 

Bilateral, interstitial cell, adenoma 23 (46%) 21 (42%) 15 (30%) 17 (34%) 

Interstitial cell, adenoma 11 (22%) 13 (26%) 13 (26%) 12 (24%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Lymph node (12) (18) (11) (15) 

Iliac, histiocytic sarcoma 1 (7%) 

Lymph node, bronchial (45) (31) (44) (43) 

Alveolar/bronchiolar carcinoma, metastatic,

 lung 1 (2%) 

Histiocytic sarcoma 2 (5%) 

Lymph node, mandibular (47) (45) (44) (49) 

Lymph node, mesenteric (50) (50) (48) (50) 

Histiocytic sarcoma 1 (2%) 

Lymph node, mediastinal (46) (47) (48) (47) 

Alveolar/bronchiolar carcinoma, metastatic,

 lung 1 (2%) 

Histiocytic sarcoma 2 (4%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

112 Chloroprene, NTP TR 467 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Hematopoietic System (continued) 

Spleen (50) (50) (49) (50) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Sarcoma 1 (2%) 1 (2%) 

Thymus (42) (42) (46) (48) 

Histiocytic sarcoma 1 (2%) 

Thymoma benign 1 (2%) 2 (4%) 

Integumentary System 

Mammary gland (30) (23) (30) (28) 

Adenoma 1 (3%) 

Carcinoma 1 (4%) 1 (3%) 

Fibroadenoma 2 (7%) 1 (4%) 1 (4%) 

Skin (50) (50) (50) (50) 

Basal cell adenoma 1 (2%) 

Basal cell carcinoma 2 (4%) 

Histiocytic sarcoma 1 (2%) 

Keratoacanthoma 2 (4%) 4 (8%) 2 (4%) 4 (8%) 

Squamous cell papilloma 1 (2%) 1 (2%) 

Sebaceous gland, adenoma 1 (2%) 2 (4%) 

Subcutaneous tissue, fibroma 2 (4%) 1 (2%) 

Subcutaneous tissue, fibrosarcoma 1 (2%) 

Subcutaneous tissue, lipoma 2 (4%) 

Subcutaneous tissue, melanoma malignant 1 (2%) 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 1 (2%) 1 (2%) 

Subcutaneous tissue, schwannoma malignant 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Osteosarcoma 1 (2%) 1 (2%) 

Skeletal muscle (1) 

Sarcoma 1 (100%) 

Nervous System 

Brain (50) (50) (50) (50) 

Glioma malignant, mixed cell 1 (2%) 

Glioma malignant, mixed 1 (2%) 

Meninges, granular cell tumor benign 1 (2%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Lung (50) (50) (49) (50) 

Alveolar/bronchiolar adenoma 2 (4%) 3 (6%) 3 (6%) 

Alveolar/bronchiolar carcinoma 2 (4%) 1 (2%) 3 (6%) 

Alveolar/bronchiolar carcinoma, multiple 1 (2%) 

Histiocytic sarcoma 2 (4%) 

Melanoma malignant, metastatic, skin 1 (2%) 

Osteosarcoma, metastatic, bone 1 (2%) 

Mediastinum, alveolar/bronchiolar carcinoma,

 metastatic, lung 1 (2%) 

Mediastinum, schwannoma malignant,

 metastatic, heart 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 113 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Respiratory System (continued) 

Nose 

Respiratory epithelium, adenoma

Trachea 

(50) 

(50) 

(50) 

(50) 

(49) 

(50) 

(49) 

 1 (2%) 

(50) 

Special Senses System 

Zymbal’s gland

Adenoma

Carcinoma

 (1)

 1 (100%)

 (1)

 1 (100%)

 (2) 

 1 (50%) 

 1 (50%) 

Urinary System 

Kidney 

Histiocytic sarcoma

Mesenchymal tumor NOS

Bilateral, renal tubule, adenoma

Renal tubule, adenoma

Transitional epithelium, carcinoma

Urinary bladder 

Histiocytic sarcoma

Transitional epithelium, carcinoma

Transitional epithelium, papilloma

(50) 

(50) 

(50) 

 1 (2%) 

 1 (2%) 

(50) 

(50) 

 1 (2%) 

(50) 

 1 (2%) 

(50) 

 1 (2%) 

 1 (2%) 

 2 (4%) 

(49) 

 1 (2%) 

 1 (2%) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

Leukemia mononuclear

Mesothelioma malignant

(50) 

 33 (66%) 

(50) 

 34 (68%) 

 1 (2%) 

(50) 

 29 (58%) 

 5 (10%) 

(50) 

 2 (4%) 

 27 (54%) 

 3 (6%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

Total primary neoplasms 

Total animals with benign neoplasms 

Total benign neoplasms 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

Total animals with uncertain neoplasms— 

benign or malignant 

Total uncertain neoplasms 

50 

166 

50 

118 

40 

47 

1 

1 

50 

181 

50 

123 

37 

58 

1 

1 

50 

176 

50 

121 

37 

55 

2 

5 

50 

180 

48 

133 

36 

46 

2 

2 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

114 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

Number of Days on Study 

4 4 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

6 8 2 3 3 3 4 6 6 7 7 7 8 8 0 0 1 1 1 1 3 3 3 3 4 

9 9 5 3 4 6 1 9 9 1 5 6 0 9 0 4 3 3 6 6 4 4 7 7 2 

Carcass ID Number 

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 

3 2 4 2 0 2 3 4 4 3 0 1 3 1 0 0 1 2 0 2 1 3 0 1 4 

9 3 4 7 2 0 8 5 6 4 1 1 1 6 9 3 5 4 6 9 9 3 7 2 9 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Polyp adenomatous 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Pancreas 

Adenoma 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

A + + + + + + + + + + + + + + + + + + + + + + + A 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

A + + + + + + + + + + + + + + + + + + + + + + + A 

A + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + A 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant 

Pheochromocytoma benign X X 

Bilateral, pheochromocytoma benign X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma X 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

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 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X 

C-cell, carcinoma X 

General Body System 

None 

Genital System 

Coagulating gland + 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Penis + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X X 

Carcinoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 115 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 

Number of Days on Study 4 4 5 5 9 9 9 9 0 1 1 2 3 3 3 3 3 3 3 3 3 3 3 3 3 

6 9 7 8 3 5 5 5 2 6 6 2 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 5 0 4 1 1 3 4 2 0 4 0 1 1 1 2 2 2 2 3 3 3 3 4 4 Tissues/ 

7 0 5 2 3 4 6 0 2 8 8 4 0 7 8 1 5 6 8 0 2 5 7 1 3 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp adenomatous 1 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + + + + 16 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 2 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma malignant X 1 

Pheochromocytoma benign X X X X X X X X X X X X 14 

Bilateral, pheochromocytoma benign X X X 5 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 3 

Carcinoma X X 3 

Parathyroid gland + + M + M + + + + + + + + + + + + + + + + + + + + 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 40 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X 3 

C-cell, carcinoma X 2 

General Body System 

None 

Genital System 

Coagulating gland 1 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Penis 1 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 3 

Carcinoma X X 3 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

116 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

4 4 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 6 

9 

8 

9 

2 

5 

3 

3 

3 

4 

3 

6 

4 

1 

6 

9 

6 

9 

7 

1 

7 

5 

7 

6 

8 

0 

8 

9 

0 

0 

0 

4 

1 

3 

1 

3 

1 

6 

1 

6 

3 

4 

3 

4 

3 

7 

3 

7 

4 

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 3 2 4 2 0 2 3 4 4 3 0 1 3 1 0 0 1 2 0 2 1 3 0 1 4 

9 3 4 7 2 0 8 5 6 4 1 1 1 6 9 3 5 4 6 9 9 3 7 2 9 

Genital System (continued) 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

+ 

+ 

X 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Sarcoma 

Thymus 

Thymoma benign 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

M 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Integumentary System 

Mammary gland 

Fibroadenoma 

Skin 

Basal cell adenoma 

Keratoacanthoma 

Sebaceous gland, adenoma 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, sarcoma 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

M 

+ 

M 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

M 

+ 

+ 

+ 

M 

+ 

M 

+ 

+ 

+ 

+ 

+ 

X 

M 

+ 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + 

Glioma malignant, mixed 

Respiratory System 

Larynx + 

Lung + 

Alveolar/bronchiolar adenoma 

Nose + 

Trachea + 

Special Senses System 

Zymbal’s gland 

Carcinoma 

Urinary System 

Kidney + 

Urinary bladder + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 117 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 

Number of Days on Study 4 

6 

4 

9 

5 

7 

5 

8 

9 

3 

9 

5 

9 

5 

9 

5 

0 

2 

1 

6 

1 

6 

2 

2 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

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 

7 

5 

0 

0 

5 

4 

2 

1 

3 

1 

4 

3 

6 

4 

0 

2 

2 

0 

8 

4 

8 

0 

4 

1 

0 

1 

7 

1 

8 

2 

1 

2 

5 

2 

6 

2 

8 

3 

0 

3 

2 

3 

5 

3 

7 

4 

1 

4 

3 

Tissues/ 

Tumors 

Genital System (continued) 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X X X X X 

X X 

50 

50 

23 

11 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Sarcoma

Thymus 

Thymoma benign 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + 

+ + + + + + + + M + + + + + + + + + M + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + M + + + + M + + M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + M + + + M + M + + + + M + + + + + 

X

50 

12 

45 

47 

50 

46 

50 

1 

42 

1 

Integumentary System 

Mammary gland 

Fibroadenoma 

Skin 

Basal cell adenoma

Keratoacanthoma 

Sebaceous gland, adenoma 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, lipoma 

Subcutaneous tissue, sarcoma

M + + + + M + + + M + M M M M + + M + + + M M M + 

X X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

X

X

X

30 

2 

50 

1 

2 

1 

1 

2 

1 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

1 

Nervous System 

Brain 

Glioma malignant, mixed

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

2 

50 

50 

Special Senses System 

Zymbal’s gland

Carcinoma

 1 

1 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

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 

50 

33 
 

 

 

 

 

 

 

 

 

 

 

 

118 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

Number of Days on Study 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

5 3 9 2 3 3 4 4 4 5 7 8 8 9 0 0 0 0 1 1 3 3 4 5 5 

7 7 7 5 0 4 1 1 4 6 5 1 1 7 0 3 8 9 3 8 7 8 5 0 1 

Carcass ID Number 

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 

4 3 2 2 1 0 2 3 1 3 4 2 4 4 3 4 4 3 0 1 2 0 2 2 5 

0 1 3 0 2 4 8 2 5 4 7 9 5 8 5 9 3 8 8 1 7 1 1 6 0 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Polyp adenomatous 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Hemangioma 

Oral mucosa 

Pharyngeal, squamous cell papilloma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tooth 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + I + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Schwannoma malignant 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant 

Pheochromocytoma benign X X X X X X 

Bilateral, pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma X 

Parathyroid gland + + + + + + + + + + M + + + + + + + + + + + + + + 

Pituitary gland + + + M + + + + + + + + + + + + + + + + + + + + + 

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 

C-cell, carcinoma 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + +
 

Penis +
 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + +
 

Adenoma X 

Carcinoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 119 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 

Number of Days on Study 6 6 6 6 7 7 7 8 0 0 0 0 0 0 0 3 3 3 3 3 3 3 3 3 3 

3 5 5 5 0 7 9 9 0 0 1 1 2 6 7 0 3 3 3 3 3 3 3 3 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 2 Total 

Carcass ID Number 1 0 2 3 1 1 3 0 0 4 1 1 1 3 3 4 0 0 0 1 2 2 3 4 4 Tissues/ 

3 9 4 6 7 9 7 6 3 1 4 6 0 3 9 4 2 5 7 8 2 5 0 2 6 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + A + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + A I + + + + + + + + + + + + + + + + 47 

Intestine large, cecum + + + + + + + A + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + + + A + + + + + + + + + + + + + + + + + 49 

Polyp adenomatous 1 

Intestine small, jejunum + + + + + + + A + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + A + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + + + + + + + 13 

Hemangioma X 1 

Oral mucosa + + 2 

Pharyngeal, squamous cell papilloma X X 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tooth 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma malignant X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma malignant X 1 

Pheochromocytoma benign X X X X X X X 13 

Bilateral, pheochromocytoma benign X X X X X X X 7 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 3 

Carcinoma X X X X 5 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X X 40 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X X 6 

C-cell, carcinoma X X 2 

Follicular cell, adenoma X 2 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Penis + + 3 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 3 

Carcinoma X X 3 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 
 

 

 

 

 

 

 

120 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 3 9 2 3 3 4 4 4 5 7 8 8 9 0 0 0 0 1 1 3 3 4 5 5 

7 7 7 5 0 4 1 1 4 6 5 1 1 7 0 3 8 9 3 8 7 8 5 0 1 

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 4 3 2 2 1 0 2 3 1 3 4 2 4 4 3 4 4 3 0 1 2 0 2 2 5 

0 1 3 0 2 4 8 2 5 4 7 9 5 8 5 9 3 8 8 1 7 1 1 6 0 

Genital System (continued) 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma 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 M + M + M + M M M + + + M + M + + + M M M 

Lymph node, mandibular + + + + + + M + + + + + + + + + + + M + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal + + + + + + + M + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Sarcoma 

Thymus + + + + + + + M + + + + + + + + M M + + + + + + + 

Integumentary System 

Mammary gland M M + M + M M M + + M + + M M M + + M M + M M + + 

Carcinoma 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Basal cell carcinoma X 

Keratoacanthoma X X 

Sebaceous gland, adenoma X 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, melanoma malignant 

Subcutaneous tissue, schwannoma malignant X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Skeletal muscle 

Sarcoma 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma 

Melanoma malignant, metastatic, skin 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Zymbal’s gland 

Carcinoma 
 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 121 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 

Number of Days on Study 6 

3 

6 

5 

6 

5 

6 

5 

7 

0 

7 

7 

7 

9 

8 

9 

0 

0 

0 

0 

0 

1 

0 

1 

0 

2 

0 

6 

0 

7 

3 

0 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

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 2 Total 

Carcass ID Number 1 

3 

0 

9 

2 

4 

3 

6 

1 

7 

1 

9 

3 

7 

0 

6 

0 

3 

4 

1 

1 

4 

1 

6 

1 

0 

3 

3 

3 

9 

4 

4 

0 

2 

0 

5 

0 

7 

1 

8 

2 

2 

2 

5 

3 

0 

4 

2 

4 

6 

Tissues/ 

Tumors 

Genital System (continued) 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

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 

50 

50 

21 

13 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Sarcoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + 

+ + + + + M M + + + + + + + M + + + M + M M + + + 

+ + + + + + + + + + + + + + M + + + + + + + M + M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + M + + + + + + + + + + + + + + + + M + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ M + + + + + + + + + + M + + M + + + M + + M + + 

50 

18 

31 

45 

50 

47 

50 

1 

42 

Integumentary System 

Mammary gland 

Carcinoma 

Fibroadenoma 

Skin 

Basal cell carcinoma 

Keratoacanthoma 

Sebaceous gland, adenoma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, melanoma malignant 

Subcutaneous tissue, schwannoma malignant 

M M + + M + M + M M M M + + + M M + M + M + M + + 

X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X

X

X X

X 

23 

1 

1 

50 

2 

4 

2 

2 

1 

1 

Musculoskeletal System 

Bone 

Skeletal muscle 

Sarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

X

50 

1 

1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar carcinoma 

Melanoma malignant, metastatic, skin 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

2 

1 

50 

50 

Special Senses System 

Eye 

Zymbal’s gland 

Carcinoma 

+

+

X

 1 

1 

1 
 

122 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

3 4 4 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 5 3 9 2 3 3 4 4 4 5 7 8 8 9 0 0 0 0 1 1 3 3 4 5 5 

7 7 7 5 0 4 1 1 4 6 5 1 1 7 0 3 8 9 3 8 7 8 5 0 1 

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 4 3 2 2 1 0 2 3 1 3 4 2 4 4 3 4 4 3 0 1 2 0 2 2 5 

0 1 3 0 2 4 8 2 5 4 7 9 5 8 5 9 3 8 8 1 7 1 1 6 0 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, renal tubule, adenoma 

Transitional epithelium, carcinoma 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X X X 

Mesothelioma malignant 
 

 

 

Chloroprene, NTP TR 467 123 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 

Number of Days on Study 6 6 6 6 7 7 7 8 0 0 0 0 0 0 0 3 3 3 3 3 3 3 3 3 3 

3 5 5 5 0 7 9 9 0 0 1 1 2 6 7 0 3 3 3 3 3 3 3 3 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 2 Total 

Carcass ID Number 1 0 2 3 1 1 3 0 0 4 1 1 1 3 3 4 0 0 0 1 2 2 3 4 4 Tissues/ 

3 9 4 6 7 9 7 6 3 1 4 6 0 3 9 4 2 5 7 8 2 5 0 2 6 Tumors 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, renal tubule, adenoma X 1 

Transitional epithelium, carcinoma 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 X X X X X 34 

Mesothelioma malignant X 1 
 

 

 

 

 

 

 

124 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 6 6 9 9 0 0 1 2 2 2 3 3 4 4 6 6 6 6 6 6 6 8 8 9 9 

0 0 7 7 5 6 2 3 4 8 4 4 0 9 1 5 7 8 9 9 9 4 5 0 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 2 5 3 4 3 2 3 0 4 1 0 1 1 2 3 1 1 0 0 1 2 4 4 0 3 

5 0 0 8 1 7 9 4 4 7 8 2 9 3 8 1 6 3 5 3 1 2 7 7 7 

Alimentary System 

Esophagus + + + + + + I + + + + + + + + + + + + + + + + + + 

Intestine large, colon + A + + + + + + + + + + + + + + + A + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + A + + + A + + + + + + + + + + + A + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + A + + + + + + + 

Intestine small, jejunum + A + + + A + + + + + + + + + + + A + + + + + + + 

Intestine small, ileum + A + + + A + + + + + + + + + + + A + + + + + + + 

Liver + + + + + + + + + + + + + + + + + A + + + + + + + 

Schwannoma malignant, metastatic, heart 

Mesentery + + + + + + + + 

Sarcoma 

Schwannoma malignant X 

Oral mucosa 

Pharyngeal, squamous cell papilloma 

Pancreas + + + + + + + + + + + + + + + + + A + + + + + + + 

Adenoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + A + + + + + + + 

Tongue 

Squamous cell carcinoma 

Squamous cell papilloma 

Cardiovascular System 

Blood vessel 

Aorta, schwannoma malignant,

 metastatic, heart 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Schwannoma malignant 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + A + + + + + + + 

Adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + A + + + + + + + 

Pheochromocytoma benign X X X X 

Bilateral, pheochromocytoma benign X X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + A + + + + + + + 

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 X X X 

Thyroid gland + + + + + + + + + + + + + + + + + A + + + + + + + 

C-cell, adenoma 

C-cell, carcinoma 

Follicular cell, adenoma X 

Follicular cell, carcinoma 

General Body System 

Peritoneum + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 125 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

6 

0 

9 

6 

0 

9 

6 

2 

0 

6 

2 

2 

6 

2 

2 

6 

2 

2 

6 

3 

7 

6 

4 

2 

6 

5 

2 

6 

6 

5 

6 

6 

7 

6 

7 

9 

6 

8 

1 

6 

8 

1 

7 

0 

2 

7 

0 

5 

7 

0 

7 

7 

2 

1 

7 

2 

1 

7 

2 

5 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

Carcass ID Number 

4 

2 

4 

4 

4 

5 

4 

0 

1 

4 

1 

4 

4 

3 

5 

4 

4 

6 

4 

0 

2 

4 

0 

6 

4 

3 

6 

4 

2 

0 

4 

4 

9 

4 

2 

6 

4 

3 

4 

4 

4 

3 

4 

2 

2 

4 

1 

0 

4 

3 

2 

4 

1 

8 

4 

2 

9 

4 

2 

8 

4 

0 

9 

4 

1 

5 

4 

3 

3 

4 

4 

0 

4 

4 

1 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + A + + + + + + 46 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + A + + + + + + 46 

Intestine small, ileum + + + + + + + + + + + + + + + + + + A + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Schwannoma malignant, metastatic, heart X 1 

Mesentery + + + + + + + + + + 18 

Sarcoma X 1 

Schwannoma malignant 1 

Oral mucosa + 1 

Pharyngeal, squamous cell papilloma X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Tongue + + + + 4 

Squamous cell carcinoma X 1 

Squamous cell papilloma X X X 3 

Cardiovascular System 

Blood vessel + + + 3 

Aorta, schwannoma malignant,

 metastatic, heart X 1 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma malignant X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pheochromocytoma benign X X X X X X X 11 

Bilateral, pheochromocytoma benign X X X X X X X 10 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X X 2 

Carcinoma X X X 3 

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 X 43 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X X X 4 

C-cell, carcinoma X X 2 

Follicular cell, adenoma X 2 

Follicular cell, carcinoma X X 2 

General Body System 

Peritoneum + 3 
 

 

 

 

 

 

 

 

 

 

126 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 6 6 9 9 0 0 1 2 2 2 3 3 4 4 6 6 6 6 6 6 6 8 8 9 9 

0 0 7 7 5 6 2 3 4 8 4 4 0 9 1 5 7 8 9 9 9 4 5 0 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 2 5 3 4 3 2 3 0 4 1 0 1 1 2 3 1 1 0 0 1 2 4 4 0 3 

5 0 0 8 1 7 9 4 4 7 8 2 9 3 8 1 6 3 5 3 1 2 7 7 7 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + M + + + + + + + A + + + + + + + 

Adenoma X X 

Carcinoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X X X X X 

Interstitial cell, adenoma X X X X X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + + 

Lymph node, bronchial + M + + + + + + + + + + + + + M + + + + + + M + + 

Alveolar/bronchiolar carcinoma,

 metastatic, lung 

Lymph node, mandibular + + + M + + M M + + + + M + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + A + + + + + + + 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + M 

Alveolar/bronchiolar carcinoma,

 metastatic, lung 

Spleen + + + + + + + + + + + + + + + + + A + + + + + + + 

Hemangiosarcoma X 

Thymus + + + + + + + + M + + + + + + + + + + M + + + + M 

Integumentary System 

Mammary gland + M + + + M + + M + M M M + + + + M + + + + + M M 

Adenoma 

Carcinoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Keratoacanthoma X 

Squamous cell papilloma X 

Subcutaneous tissue, melanoma malignant X 

Subcutaneous tissue, sarcoma 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + A + + + + + + + 

Alveolar/bronchiolar adenoma X X 

Alveolar/bronchiolar carcinoma 

Mediastinum, schwannoma malignant,

 metastatic, heart 

Nose + + + + + + + + + + + + + + + + + A + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 127 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

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 

Number of Days on Study 0 0 2 2 2 2 3 4 5 6 6 7 8 8 0 0 0 2 2 2 3 3 3 3 3 

9 9 0 2 2 2 7 2 2 5 7 9 1 1 2 5 7 1 1 5 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 Total 

Carcass ID Number 2 4 0 1 3 4 0 0 3 2 4 2 3 4 2 1 3 1 2 2 0 1 3 4 4 Tissues/ 

4 5 1 4 5 6 2 6 6 0 9 6 4 3 2 0 2 8 9 8 9 5 3 0 1 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X X 4 

Carcinoma X X X 4 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X X 3 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X 15 

Interstitial cell, adenoma X X X X X X X X 13 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + 11 

Lymph node, bronchial M + M + + + + + + + + M + + + + + + + + + + + + + 44 

Alveolar/bronchiolar carcinoma,

 metastatic, lung X 1 

Lymph node, mandibular + M + + M + + + + + + + + + + + + + + + + + + + + 44 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + M + + + + + + + 48 

Lymph node, mediastinal + + M + + + + + + + + + + + + + + + + + + + + + + 48 

Alveolar/bronchiolar carcinoma,

 metastatic, lung X 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Thymus + + + + + M + + + + + + + + + + + + + + + + + + + 46 

Integumentary System 

Mammary gland + + + M + M + M + M M M M M M + + + + + + + + M M 30 

Adenoma X 1 

Carcinoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Keratoacanthoma X 2 

Squamous cell papilloma 1 

Subcutaneous tissue, melanoma malignant 1 

Subcutaneous tissue, sarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Alveolar/bronchiolar adenoma X 3 

Alveolar/bronchiolar carcinoma X 1 

Mediastinum, schwannoma malignant,

 metastatic, heart X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

128 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

4 

6 

0 

4 

6 

0 

4 

9 

7 

4 

9 

7 

5 

0 

5 

5 

0 

6 

5 

1 

2 

5 

2 

3 

5 

2 

4 

5 

2 

8 

5 

3 

4 

5 

3 

4 

5 

4 

0 

5 

4 

9 

5 

6 

1 

5 

6 

5 

5 

6 

7 

5 

6 

8 

5 

6 

9 

5 

6 

9 

5 

6 

9 

5 

8 

4 

5 

8 

5 

5 

9 

0 

5 

9 

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 2 5 3 4 3 2 3 0 4 1 0 1 1 2 3 1 1 0 0 1 2 4 4 0 3 

5 0 0 8 1 7 9 4 4 7 8 2 9 3 8 1 6 3 5 3 1 2 7 7 7 

Special Senses System 

Eye 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Transitional epithelium, carcinoma 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X 

Mesothelioma malignant X X 
 

 

 

 

Chloroprene, NTP TR 467 129 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

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 

Number of Days on Study 0 0 2 2 2 2 3 4 5 6 6 7 8 8 0 0 0 2 2 2 3 3 3 3 3 

9 9 0 2 2 2 7 2 2 5 7 9 1 1 2 5 7 1 1 5 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 Total 

Carcass ID Number 2 4 0 1 3 4 0 0 3 2 4 2 3 4 2 1 3 1 2 2 0 1 3 4 4 Tissues/ 

4 5 1 4 5 6 2 6 6 0 9 6 4 3 2 0 2 8 9 8 9 5 3 0 1 Tumors 

Special Senses System 

Eye + 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Transitional epithelium, carcinoma X 1 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X X 29 

Mesothelioma malignant X X X 5 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

130 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

3 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 

0 0 6 7 9 2 3 3 3 3 4 4 5 6 7 7 8 9 0 0 0 0 1 1 1 

5 7 3 0 7 2 0 2 3 9 0 9 8 7 6 8 3 7 1 3 8 9 1 3 7 

Carcass ID Number 

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 

3 1 2 4 4 0 2 4 4 2 4 1 0 1 4 3 2 0 1 1 3 0 2 3 2 

1 7 3 3 8 1 2 4 0 9 2 0 2 1 1 4 5 9 9 8 2 4 4 3 6 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Polyp adenomatous 

Intestine small, duodenum 

Intestine small, jejunum 

Carcinoma 

Intestine small, ileum 

Liver 

Histiocytic sarcoma 

Mesentery 

Fat, lipoma 

Oral mucosa 

Buccal, squamous cell papilloma 

Gingival, squamous cell papilloma 

Pharyngeal, squamous cell papilloma 

Pancreas 

Adenoma 

Histiocytic sarcoma 

Salivary glands 

Stomach, forestomach 

Histiocytic sarcoma 

Stomach, glandular 

Histiocytic sarcoma 

Tongue 

Squamous cell carcinoma 

Squamous cell papilloma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + A + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + A + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

A + + + + + + + + A + + + + + + + + + + + + + + + 

X 

A + + + + + + A + A + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

+ + + + + 

+ + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ 

X 

Cardiovascular System 

Blood vessel 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

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 

Pars intermedia, adenoma X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X 

Follicular cell, adenoma X X 

Follicular cell, carcinoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 131 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 2 2 2 2 4 4 5 5 6 6 6 6 6 7 7 9 9 0 0 1 2 3 3 3 3 

5 5 5 8 6 9 1 1 0 0 3 3 7 2 3 1 3 2 2 5 8 3 3 3 3 

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 Total 

Carcass ID Number 1 1 3 2 0 0 3 4 3 4 0 2 2 3 0 4 1 3 3 5 4 0 1 1 2 Tissues/ 

2 6 8 7 8 7 0 5 5 9 5 8 0 7 6 6 4 6 9 0 7 3 3 5 1 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + I + + + + + + + + + + 49 

Intestine large, cecum + + + + + + + + + + + + + + A + + + + + + + + + + 48 

Polyp adenomatous 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + A + + + + + + + + + + 47 

Carcinoma 1 

Intestine small, ileum + + + + + + + + + + + + + + A + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 2 

Mesentery + + + + + + + + 13 

Fat, lipoma X 1 

Oral mucosa + + + + 7 

Buccal, squamous cell papilloma X 1 

Gingival, squamous cell papilloma X 1 

Pharyngeal, squamous cell papilloma X 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Histiocytic sarcoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Tongue + + + + + + + 8 

Squamous cell carcinoma X X 2 

Squamous cell papilloma X X X X X 6 

Cardiovascular System 

Blood vessel + 1 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X X X X 9 

Bilateral, pheochromocytoma benign X X X X X X X X 9 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Carcinoma X 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pituitary gland + + + + + + + + + + + + + + + + + + + + I + + + + 49 

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 7 

Follicular cell, adenoma X X 4 

Follicular cell, carcinoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

132 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

3 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 

Number of Days on Study 0 0 6 7 9 2 3 3 3 3 4 4 5 6 7 7 8 9 0 0 0 0 1 1 1 

5 7 3 0 7 2 0 2 3 9 0 9 8 7 6 8 3 7 1 3 8 9 1 3 7 

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 3 1 2 4 4 0 2 4 4 2 4 1 0 1 4 3 2 0 1 1 3 0 2 3 2 

1 7 3 3 8 1 2 4 0 9 2 0 2 1 1 4 5 9 9 8 2 4 4 3 6 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma 

Histiocytic sarcoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Seminal vesicle + + + + + + + A + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X X 

Interstitial cell, adenoma X X X X X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Lymph node + + + + + + + + + 

Iliac, histiocytic sarcoma X 

Lymph node, bronchial + + M + + + + + + + + M + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Lymph node, mediastinal M + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Thymoma benign 

Integumentary System 

Mammary gland + M + + + + + M M + M + M M + M + M M M + M M M + 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Keratoacanthoma 

Squamous cell papilloma 

Subcutaneous tissue, fibroma X 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Osteosarcoma X 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Glioma malignant, mixed cell 

Meninges, granular cell tumor benign X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 133 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 2 2 2 2 4 4 5 5 6 6 6 6 6 7 7 9 9 0 0 1 2 3 3 3 3 

5 5 5 8 6 9 1 1 0 0 3 3 7 2 3 1 3 2 2 5 8 3 3 3 3 

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 Total 

Carcass ID Number 1 1 3 2 0 0 3 4 3 4 0 2 2 3 0 4 1 3 3 5 4 0 1 1 2 Tissues/ 

2 6 8 7 8 7 0 5 5 9 5 8 0 7 6 6 4 6 9 0 7 3 3 5 1 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Carcinoma X 1 

Histiocytic sarcoma 1 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Histiocytic sarcoma 1 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X X 17 

Interstitial cell, adenoma X X X X X X X 12 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Lymph node + + + + + + 15 

Iliac, histiocytic sarcoma 1 

Lymph node, bronchial + + M + M + + + + + + + + + + + + + M + M + + + M 43 

Histiocytic sarcoma 2 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + M + + + + + + 49 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Lymph node, mediastinal + + + M + + + M + + + + + + + + + + + + + + + + + 47 

Histiocytic sarcoma 2 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Thymus + + + + + + + + + M + + + + + + M + + + + + + + + 48 

Histiocytic sarcoma 1 

Thymoma benign X X 2 

Integumentary System 

Mammary gland M + M + M + + + + + M M + + M + M M M + + + + + + 28 

Fibroadenoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Keratoacanthoma X X X X 4 

Squamous cell papilloma X 1 

Subcutaneous tissue, fibroma 1 

Subcutaneous tissue, sarcoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Osteosarcoma 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Glioma malignant, mixed cell X 1 

Meninges, granular cell tumor benign 1 
 

 

 

 

 

 

 

 

 

 

 

134 Chloroprene, NTP TR 467 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

3 3 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 

Number of Days on Study 0 0 6 7 9 2 3 3 3 3 4 4 5 6 7 7 8 9 0 0 0 0 1 1 1 

5 7 3 0 7 2 0 2 3 9 0 9 8 7 6 8 3 7 1 3 8 9 1 3 7 

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 3 1 2 4 4 0 2 4 4 2 4 1 0 1 4 3 2 0 1 1 3 0 2 3 2 

1 7 3 3 8 1 2 4 0 9 2 0 2 1 1 4 5 9 9 8 2 4 4 3 6 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma X X 

Alveolar/bronchiolar carcinoma, multiple 

Histiocytic sarcoma X X 

Osteosarcoma, metastatic, bone X 

Mediastinum, alveolar/bronchiolar

 carcinoma, metastatic, lung 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory epithelium, adenoma 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Zymbal’s gland + + 

Adenoma X 

Carcinoma X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Mesenchymal tumor NOS X 

Renal tubule, adenoma 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Transitional epithelium, papilloma X 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X 

Leukemia mononuclear X X X X X X X X X 

Mesothelioma malignant X 
 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 135 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

6 

2 

5 

6 

2 

5 

6 

2 

5 

6 

2 

8 

6 

4 

6 

6 

4 

9 

6 

5 

1 

6 

5 

1 

6 

6 

0 

6 

6 

0 

6 

6 

3 

6 

6 

3 

6 

6 

7 

6 

7 

2 

6 

7 

3 

6 

9 

1 

6 

9 

3 

7 

0 

2 

7 

0 

2 

7 

1 

5 

7 

2 

8 

7 

3 

3 

7 

3 

3 

7 

3 

3 

7 

3 

3 

Carcass ID Number 

6 

1 

2 

6 

1 

6 

6 

3 

8 

6 

2 

7 

6 

0 

8 

6 

0 

7 

6 

3 

0 

6 

4 

5 

6 

3 

5 

6 

4 

9 

6 

0 

5 

6 

2 

8 

6 

2 

0 

6 

3 

7 

6 

0 

6 

6 

4 

6 

6 

1 

4 

6 

3 

6 

6 

3 

9 

6 

5 

0 

6 

4 

7 

6 

0 

3 

6 

1 

3 

6 

1 

5 

6 

2 

1 

Total 

Tissues/ 

Tumors 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Histiocytic sarcoma

Osteosarcoma, metastatic, bone

Mediastinum, alveolar/bronchiolar

 carcinoma, metastatic, lung 

Nose 

Respiratory epithelium, adenoma 

Trachea 

Special Senses System 

Ear

Zymbal’s gland

Adenoma

Carcinoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X

X

X 

X 

+ + + + + + + + + + + + + + A + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

3 

3 

1 

2 

1 

1 

49 

1 

50 

1 

2 

1 

1 

Urinary System 

Kidney 

Histiocytic sarcoma

Mesenchymal tumor NOS

Renal tubule, adenoma 

Urinary bladder 

Histiocytic sarcoma

Transitional epithelium, papilloma

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

+ + + + + I + + + + + + + + + + + + + + + + + + + 

50 

1 

1 

2 

49 

1 

1 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma

Leukemia mononuclear 

Mesothelioma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X X X X X X X X 

X X

50 

2 

27 

3 
136 Chloroprene, NTP TR 467 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Adrenal Medulla: Benign Pheochromocytoma a Overall rate 19/50 (38%) 20/50 (40%) 21/49 (43%) 18/50 (36%) 

Adjusted rateb 76.2% 78.0% 82.2% 100.0% c Terminal rate 8/13 (62%) 4/9 (44%) 2/5 (40%) 4/4 (100%) 

First incidence (days) 576 534 497 540 

d Life table test P=0.029 P=0.280 P=0.027 P=0.022 

Logistic regression testd P=0.312 P=0.444 P=0.150 P=0.237 

Cochran-Armitage testd P=0.422N 

d Fisher exact test P=0.500 P=0.387 P=0.500N 

Adrenal Medulla: Benign or Malignant Pheochromocytoma 

Overall rate 19/50 (38%) 21/50 (42%) 21/49 (43%) 18/50 (36%) 

Adjusted rate 76.2% 82.4% 82.2% 100.0% 

Terminal rate 8/13 (62%) 5/9 (56%) 2/5 (40%) 4/4 (100%) 

First incidence (days) 576 534 497 540 

Life table test P=0.031 P=0.214 P=0.027 P=0.022 

Logistic regression test P=0.336 P=0.356 P=0.150 P=0.237 

Cochran-Armitage test P=0.388N 

Fisher exact test P=0.419 P=0.387 P=0.500N 

Kidney (Renal Tubule): Adenoma (Step Section) 

Overall rate 1/50 (2%) 6/50 (12%) 6/50 (12%) 7/50 (14%) 

Adjusted rate 7.7% 37.0% 52.5% 65.9% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Life table test P=0.002 P=0.036 P=0.008 P=0.002 

Logistic regression test P=0.010 P=0.047 P=0.007 P=0.005 

Cochran-Armitage test P=0.080 

Fisher exact test P=0.056 P=0.056 P=0.030 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 1/50 (2%) 7/50 (14%) 6/50 (12%) 8/50 (16%) 

Adjusted rate 7.7% 40.7% 52.5% 70.7% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Life table test P<0.001 P=0.021 P=0.008 P<0.001 

Logistic regression test P=0.005 P=0.024 P=0.007 P=0.002 

Cochran-Armitage test P=0.058 

Fisher exact test P=0.030 P=0.056 P=0.015 

Kidney (Renal Tubule): Adenoma or Carcinoma (Step Section) 

Overall rate 1/50 (2%) 7/50 (14%) 6/50 (12%) 7/50 (14%) 

Adjusted rate 7.7% 39.8% 52.5% 65.9% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Life table test P=0.004 P=0.021 P=0.008 P=0.002 

Logistic regression test P=0.016 P=0.025 P=0.007 P=0.005 

Cochran-Armitage test P=0.109 

Fisher exact test P=0.030 P=0.056 P=0.030 
Chloroprene, NTP TR 467 137 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 1/50 (2%) 8/50 (16%) 6/50 (12%) 8/50 (16%) 

Adjusted rate 7.7% 43.4% 52.5% 70.7% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 733 (T) 600 679 625 

Life table test P=0.002 P=0.012 P=0.008 P<0.001 

Logistic regression test P=0.008 P=0.013 P=0.007 P=0.002 

Cochran-Armitage test P=0.080 

Fisher exact test P=0.015 P=0.056 P=0.015 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 2/50 (4%) 0/50 (0%) 3/49 (6%) 3/50 (6%) 

Adjusted rate 6.9% 0.0% 14.2% 52.9% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) e First incidence (days) 616 — 505 660 

Life table test P=0.092 P=0.235N P=0.381 P=0.254 

Logistic regression test P=0.200 P=0.233N P=0.563 P=0.370 

Cochran-Armitage test P=0.230 

Fisher exact test P=0.247N P=0.490 P=0.500 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 0/50 (0%) 2/50 (4%) 1/49 (2%) 4/50 (8%) 

Adjusted rate 0.0% 17.9% 6.7% 35.1% 

Terminal rate 0/13 (0%) 1/9 (11%) 0/5 (0%) 1/4 (25%) 

First incidence (days) — 702 667 540 

Life table test P=0.007 P=0.173 P=0.433 P=0.021 

Logistic regression test P=0.023 P=0.200 P=0.452 P=0.052 

Cochran-Armitage test P=0.044 

Fisher exact test P=0.247 P=0.495 P=0.059 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

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

Adjusted rate 6.9% 17.9% 19.9% 59.3% 

Terminal rate 0/13 (0%) 1/9 (11%) 0/5 (0%) 2/4 (50%) 

First incidence (days) 616 702 505 540 

Life table test P=0.009 P=0.639 P=0.224 P=0.040 

Logistic regression test P=0.039 P=0.684 P=0.366 P=0.094 

Cochran-Armitage test P=0.058 

Fisher exact test P=0.691N P=0.329 P=0.134 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, Gingiva): Squamous Cell Papilloma 

Overall rate 0/50 (0%) 2/50 (4%) 4/50 (8%) 10/50 (20%) 

Adjusted rate 0.0% 13.8% 25.4% 71.7% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) — 701 620 539 

Life table test P<0.001 P=0.198 P=0.029 P<0.001 

Logistic regression test P<0.001 P=0.217 P=0.040 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.247 P=0.059 P<0.001 
138 Chloroprene, NTP TR 467 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, Gingiva): Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 0/50 (0%) 2/50 (4%) 5/50 (10%) 12/50 (24%) 

Adjusted rate 0.0% 13.8% 28.4% 74.9% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) — 701 609 539 

Life table test P<0.001 P=0.198 P=0.013 P<0.001 

Logistic regression test P<0.001 P=0.217 P=0.022 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.247 P=0.028 P<0.001 

Oral Mucosa: Squamous Cell Papilloma 

Overall rate 0/50 (0%) 2/50 (4%) 1/50 (2%) 4/50 (8%) 

Adjusted rate 0.0% 13.8% 4.3% 15.5% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 0/4 (0%) 

First incidence (days) — 701 620 540 

Life table test P=0.019 P=0.198 P=0.447 P=0.048 

Logistic regression test P=0.034 P=0.217 P=0.508 P=0.065 

Cochran-Armitage test P=0.043 

Fisher exact test P=0.247 P=0.500 P=0.059 

Pancreatic Islets: Adenoma 

Overall rate 3/50 (6%) 3/50 (6%) 2/49 (4%) 2/50 (4%) 

Adjusted rate 17.6% 18.1% 16.0% 20.0% 

Terminal rate 2/13 (15%) 1/9 (11%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 576 525 609 691 

Life table test P=0.492 P=0.574 P=0.601 P=0.529 

Logistic regression test P=0.515N P=0.651 P=0.627N P=0.659N 

Cochran-Armitage test P=0.393N 

Fisher exact test P=0.661N P=0.510N P=0.500N 

Pancreatic Islets: Carcinoma 

Overall rate 3/50 (6%) 5/50 (10%) 3/49 (6%) 1/50 (2%) 

Adjusted rate 13.2% 29.1% 14.9% 5.3% 

Terminal rate 0/13 (0%) 1/9 (11%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 489 603 609 651 

Life table test P=0.337N P=0.315 P=0.488 P=0.444N 

Logistic regression test P=0.181N P=0.346 P=0.652 P=0.306N 

Cochran-Armitage test P=0.140N 

Fisher exact test P=0.357 P=0.651 P=0.309N 

Pancreatic Islets: Adenoma or Carcinoma 

Overall rate 6/50 (12%) 8/50 (16%) 5/49 (10%) 3/50 (6%) 

Adjusted rate 28.4% 42.8% 28.6% 24.2% 

Terminal rate 2/13 (15%) 2/9 (22%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 489 525 609 651 

Life table test P=0.452N P=0.300 P=0.433 P=0.583N 

Logistic regression test P=0.194N P=0.369 P=0.601N P=0.331N 

Cochran-Armitage test P=0.118N 

Fisher exact test P=0.387 P=0.514N P=0.243N 
Chloroprene, NTP TR 467 139 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 40/50 (80%) 40/49 (82%) 43/50 (86%) 39/49 (80%) 

Adjusted rate 92.2% 97.0% 100.0% 96.3% 

Terminal rate 10/13 (77%) 8/9 (89%) 5/5 (100%) 3/4 (75%) 

First incidence (days) 469 357 460 470 

Life table test P=0.018 P=0.340 P=0.009 P=0.036 

Logistic regression test P=0.508 P=0.526 P=0.263 P=0.466 

Cochran-Armitage test P=0.506N 

Fisher exact test P=0.520 P=0.298 P=0.579N 

Preputial Gland: Adenoma 

Overall rate 3/50 (6%) 3/50 (6%) 4/48 (8%) 1/50 (2%) 

Adjusted rate 12.3% 24.7% 21.6% 3.1% 

Terminal rate 1/13 (8%) 2/9 (22%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 534 613 497 601 

Life table test P=0.451N P=0.567 P=0.331 P=0.440N 

Logistic regression test P=0.239N P=0.655 P=0.533 P=0.285N 

Cochran-Armitage test P=0.230N 

Fisher exact test P=0.661N P=0.477 P=0.309N 

Preputial Gland: Carcinoma 

Overall rate 3/50 (6%) 3/50 (6%) 4/48 (8%) 1/50 (2%) 

Adjusted rate 17.3% 24.8% 29.2% 25.0% 

Terminal rate 2/13 (15%) 2/9 (22%) 1/5 (20%) 1/4 (25%) 

First incidence (days) 541 637 497 733 (T) 

Life table test P=0.551N P=0.553 P=0.237 P=0.649N 

Logistic regression test P=0.318N P=0.642 P=0.438 P=0.431N 

Cochran-Armitage test P=0.230N 

Fisher exact test P=0.661N P=0.477 P=0.309N 

Preputial Gland: Adenoma or Carcinoma 

Overall rate 6/50 (12%) 6/50 (12%) 7/48 (15%) 2/50 (4%) 

Adjusted rate 28.6% 48.0% 43.3% 27.3% 

Terminal rate 3/13 (23%) 4/9 (44%) 1/5 (20%) 1/4 (25%) 

First incidence (days) 534 613 497 601 

Life table test P=0.418N P=0.463 P=0.196 P=0.399N 

Logistic regression test P=0.153N P=0.600 P=0.437 P=0.172N 

Cochran-Armitage test P=0.099N 

Fisher exact test P=0.620N P=0.468 P=0.134N 

Prostate Gland: Adenoma 

Overall rate 0/50 (0%) 1/50 (2%) 3/50 (6%) 1/50 (2%) 

Adjusted rate 0.0% 11.1% 35.0% 5.9% 

Terminal rate 0/13 (0%) 1/9 (11%) 1/5 (20%) 0/4 (0%) 

First incidence (days) — 733 (T) 679 660 

Life table test P=0.182 P=0.427 P=0.038 P=0.458 

Logistic regression test P=0.263 P=0.427 P=0.045 P=0.465 

Cochran-Armitage test P=0.448 

Fisher exact test P=0.500 P=0.121 P=0.500 
140 Chloroprene, NTP TR 467 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Skin: Keratoacanthoma 

Overall rate 2/50 (4%) 4/50 (8%) 2/50 (4%) 4/50 (8%) 

Adjusted rate 11.7% 15.6% 10.1% 34.1% 

Terminal rate 1/13 (8%) 0/9 (0%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 657 609 540 625 

Life table test P=0.145 P=0.336 P=0.514 P=0.122 

Logistic regression test P=0.265 P=0.324 P=0.646 P=0.195 

Cochran-Armitage test P=0.359 

Fisher exact test P=0.339 P=0.691N P=0.339 

Skin: Squamous Cell Papilloma or Keratoacanthoma 

Overall rate 2/50 (4%) 4/50 (8%) 3/50 (6%) 5/50 (10%) 

Adjusted rate 11.7% 15.6% 12.8% 43.5% 

Terminal rate 1/13 (8%) 0/9 (0%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 657 609 540 625 

Life table test P=0.063 P=0.336 P=0.312 P=0.051 

Logistic regression test P=0.145 P=0.324 P=0.477 P=0.094 

Cochran-Armitage test P=0.215 

Fisher exact test P=0.339 P=0.500 P=0.218 

Skin: Squamous Cell Papilloma, Keratoacanthoma, Basal Cell Adenoma, or Basal Cell Carcinoma 

Overall rate 3/50 (6%) 5/50 (10%) 3/50 (6%) 5/50 (10%) 

Adjusted rate 14.9% 20.8% 12.8% 43.5% 

Terminal rate 1/13 (8%) 0/9 (0%) 0/5 (0%) 0/4 (0%) 

First incidence (days) 637 609 540 625 

Life table test P=0.134 P=0.361 P=0.457 P=0.116 

Logistic regression test P=0.273 P=0.341 P=0.644 P=0.201 

Cochran-Armitage test P=0.376 

Fisher exact test P=0.357 P=0.661N P=0.357 

Testes: Adenoma 

Overall rate 34/50 (68%) 34/50 (68%) 28/50 (56%) 29/50 (58%) 

Adjusted rate 90.7% 100.0% 93.7% 100.0% 

Terminal rate 10/13 (77%) 9/9 (100%) 4/5 (80%) 4/4 (100%) 

First incidence (days) 469 525 460 463 

Life table test P=0.061 P=0.289 P=0.154 P=0.077 

Logistic regression test P=0.348N P=0.529 P=0.238N P=0.448N 

Cochran-Armitage test P=0.140N 

Fisher exact test P=0.585N P=0.151N P=0.204N 

Thyroid Gland (C-cell): Adenoma 

Overall rate 3/50 (6%) 6/50 (12%) 4/49 (8%) 7/50 (14%) 

Adjusted rate 18.0% 21.6% 44.0% 55.3% 

Terminal rate 2/13 (15%) 0/9 (0%) 1/5 (20%) 1/4 (25%) 

First incidence (days) 616 541 609 549 

Life table test P=0.024 P=0.227 P=0.172 P=0.019 

Logistic regression test P=0.092 P=0.233 P=0.287 P=0.078 

Cochran-Armitage test P=0.183 

Fisher exact test P=0.243 P=0.489 P=0.159 
 

 

Chloroprene, NTP TR 467 141 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 5/50 (10%) 7/50 (14%) 6/49 (12%) 7/50 (14%) 

Adjusted rate 27.3% 25.8% 50.6% 55.3% 

Terminal rate 3/13 (23%) 0/9 (0%) 1/5 (20%) 1/4 (25%) 

First incidence (days) 571 541 609 549 

Life table test P=0.076 P=0.333 P=0.148 P=0.070 

Logistic regression test P=0.240 P=0.366 P=0.285 P=0.240 

Cochran-Armitage test P=0.396 

Fisher exact test P=0.380 P=0.486 P=0.380 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 0/50 (0%) 2/50 (4%) 2/49 (4%) 4/50 (8%) 

Adjusted rate 0.0% 13.5% 22.5% 33.1% 

Terminal rate 0/13 (0%) 1/9 (11%) 1/5 (20%) 1/4 (25%) 

First incidence (days) — 597 569 307 

Life table test P=0.013 P=0.202 P=0.117 P=0.027 

Logistic regression test P=0.063 P=0.232 P=0.201 P=0.089 

Cochran-Armitage test P=0.054 

Fisher exact test P=0.247 P=0.242 P=0.059 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 0/50 (0%) 2/50 (4%) 4/49 (8%) 5/50 (10%) 

Adjusted rate 0.0% 13.5% 29.5% 36.3% 

Terminal rate 0/13 (0%) 1/9 (11%) 1/5 (20%) 1/4 (25%) 

First incidence (days) — 597 569 307 

Life table test P=0.007 P=0.202 P=0.021 P=0.014 

Logistic regression test P=0.029 P=0.232 P=0.050 P=0.044 

Cochran-Armitage test P=0.029 

Fisher exact test P=0.247 P=0.056 P=0.028 

Tongue: Squamous Cell Papilloma 

Overall rate 0/50 (0%) 0/50 (0%) 3/50 (6%) 6/50 (12%) 

Adjusted rate 0.0% 0.0% 22.0% 66.4% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) — — 622 539 

f Life table test P<0.001 — P=0.063 P<0.001 

Logistic regression test P<0.001 — P=0.077 P=0.005 

Cochran-Armitage test P=0.001 

Fisher exact test — P=0.121 P=0.013 

Tongue: Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 0/50 (0%) 0/50 (0%) 4/50 (8%) 8/50 (16%) 

Adjusted rate 0.0% 0.0% 25.2% 70.2% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 2/4 (50%) 

First incidence (days) — — 609 539 

Life table test P<0.001 — P=0.028 P<0.001 

Logistic regression test P<0.001 — P=0.041 P=0.001 

Cochran-Armitage test P<0.001 

Fisher exact test — P=0.059 P=0.003 
142 Chloroprene, NTP TR 467 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Mononuclear Cell Leukemia 

Overall rate 33/50 (66%) 34/50 (68%) 29/50 (58%) 27/50 (54%) 

Adjusted rate 86.3% 90.8% 94.1% 95.6% 

Terminal rate 8/13 (62%) 6/9 (67%) 4/5 (80%) 3/4 (75%) 

First incidence (days) 489 525 506 540 

Life table test P=0.121 P=0.296 P=0.099 P=0.116 

Logistic regression test P=0.169N P=0.461 P=0.470N P=0.408N 

Cochran-Armitage test P=0.082N 

Fisher exact test P=0.500 P=0.268N P=0.154N 

All Organs: Malignant Mesothelioma 

Overall rate 0/50 (0%) 1/50 (2%) 5/50 (10%) 3/50 (6%) 

Adjusted rate 0.0% 4.8% 27.1% 21.1% 

Terminal rate 0/13 (0%) 0/9 (0%) 0/5 (0%) 0/4 (0%) 

First incidence (days) — 670 497 609 

Life table test P=0.039 P=0.500 P=0.014 P=0.061 

Logistic regression test P=0.092 P=0.494 P=0.031 P=0.089 

Cochran-Armitage test P=0.113 

Fisher exact test P=0.500 P=0.028 P=0.121 

All Organs: Benign Neoplasms 

Overall rate 50/50 (100%) 50/50 (100%) 50/50 (100%) 48/50 (96%) 

Adjusted rate 100.0% 100.0% 100.0% 100.0% 

Terminal rate 13/13 (100%) 9/9 (100%) 5/5 (100%) 4/4 (100%) 

First incidence (days) 469 357 460 307 

Life table test P=0.013 P=0.308 P=0.013 P=0.021 

Logistic regression test P=0.170N — — P=0.576N 

Cochran-Armitage test P=0.043N 

Fisher exact test P=1.000N P=1.000N P=0.247N 

All Organs: Malignant Neoplasms 

Overall rate 40/50 (80%) 37/50 (74%) 37/50 (74%) 36/50 (72%) 

Adjusted rate 95.0% 94.4% 96.5% 96.9% 

Terminal rate 11/13 (85%) 7/9 (78%) 4/5 (80%) 3/4 (75%) 

First incidence (days) 489 525 497 305 

Life table test P=0.026 P=0.465 P=0.047 P=0.048 

Logistic regression test P=0.496N P=0.370N P=0.547N P=0.434N 

Cochran-Armitage test P=0.262N 

Fisher exact test P=0.318N P=0.318N P=0.241N 
143 

c 

Chloroprene, NTP TR 467 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Benign or Malignant Neoplasms 

Overall rate 50/50 (100%) 50/50 (100%) 50/50 (100%) 50/50 (100%)
 

Adjusted rate 100.0% 100.0% 100.0% 100.0%
 

Terminal rate 13/13 (100%) 9/9 (100%) 5/5 (100%) 4/4 (100%)
 

First incidence (days) 469 357 460 305
 

Life table test P=0.007 P=0.308 P=0.013 P=0.013
 

Logistic regression test — — — —
 

Cochran-Armitage test —
 

Fisher exact test P=1.000N P=1.000N P=1.000N
 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, 

kidney, lung, pancreatic islets, pituitary gland, preputial gland, prostate gland, testes, 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 chamber 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 chamber 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 by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
144 Chloroprene, NTP TR 467 

TABLE A4a 

Historical Incidence of Oral Cavity Neoplasms in Chamber Control Male F344/N Ratsa 

Incidence in Controls 

Study Squamous Cell Squamous Cell Squamous Cell 

Papilloma Carcinoma Papilloma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/50 0/50 0/50 

Acetonitrile 0/48 0/48 0/48 

2-Chloroacetophenone 3/50 0/50 3/50 

l-Epinephrine Hydrochloride 1/50 0/50 1/50 

Chloroethane 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 0/50 0/50 

Ozone 1/50 0/50 1/50 

Overall Historical Incidence 

Total 8/655 (1.2%) 1/655 (0.2%) 9/655 (1.4%) 

Standard deviation 1.9% 0.6% 1.9% 

Range 0%-6% 0%-2% 0%-6% 

a Data as of 12 May 1995. Includes oral mucosa, tongue, pharynx, tooth, and gingiva 

TABLE A4b 

Historical Incidence of Thyroid Gland Follicular Cell Neoplasms in Chamber Control Male F344/N Ratsa 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/48 0/48 0/48 

Acetonitrile 0/48 0/48 0/48 

2-Chloroacetophenone 1/45 0/45 1/45 

l-Epinephrine Hydrochloride 0/50 2/50 2/50 

Chloroethane 0/49 2/49 2/49 

Hexachlorocyclopentadiene 0/49 0/49 0/49 

Ozone 0/49 1/49 1/49 

Overall Historical Incidence 

Total 3/641 (0.5%) 8/641 (1.3%) 11/641 (1.7%) 

Standard deviation 0.9% 1.5% 1.6% 

Range 0%-2% 0%-4% 0%-4% 

a Data as of 12 May 1995 
Chloroprene, NTP TR 467 145 

TABLE A4c 

Historical Incidence of Alveolar/bronchiolar Neoplasms in Chamber Control Male F344/N Ratsa 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 4/50 0/50 4/50 

Acetonitrile 1/48 1/48 2/48 

2-Chloroacetophenone 1/49 1/49 2/49 

l-Epinephrine Hydrochloride 4/50 1/50 5/50 

Chloroethane 0/50 0/50 0/50 

Hexachlorocyclopentadiene 5/50 0/50 5/50 

Ozone 1/50 1/50 2/50 

Overall Historical Incidence 

Total 17/654 (2.6%) 6/654 (0.9%) 23/654 (3.5%) 

Standard deviation 3.6% 1.0% 3.7% 

Range 0%-10% 0%-2% 0%-10% 

a Data as of 12 May 1995 

TABLE A4d 

Historical Incidence of Renal Tubule Neoplasms in Chamber Control Male F344/N Ratsa 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 1/50 0/50 1/50 

Acetonitrile 1/48 0/48 1/48 

2-Chloroacetophenone 1/49 0/49 1/49 

l-Epinephrine Hydrochloride 0/50 0/50 0/50 

Chloroethane 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 0/50 0/50 

Ozone 2/50 0/50 2/50 

Overall Historical Incidence 

Total 6/652 (0.9%) 0/652 6/652 (0.9%) 

Standard deviation 1.3% 1.3% 

Range 0%-4% 0%-4% 

a Data as of 12 May 1995 
146 Chloroprene, NTP TR 467 

TABLE A4e 

Historical Incidence of Urinary Bladder Neoplasms in Chamber Control Male F344/N Ratsa 

Study Incidence in Controls 

Carcinoma Papilloma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 

Acetonitrile 

2-Chloroacetophenone 

l-Epinephrine Hydrochloride 

Chloroethane 

Hexachlorocyclopentadiene 

Ozone 

0/49 

0/48 

0/49 

0/50 

0/50 

0/50 

0/50 

0/49 

0/48 

0/49 

0/50 

0/50 

0/50 

0/50 

Overall Historical Incidence 

Total 

Standard deviation 

Range 

1/652 (0.2%) 

0.6% 

0%-2% 

0/652 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 147 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 34 40 41 41 

Natural deaths 3 1 4 5 

Survivors 

Terminal sacrifice 13 9 5 4 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (49) (48) (49) 

Mineralization 1 (2%) 

Parasite metazoan 4 (8%) 7 (14%) 3 (6%) 

Intestine large, rectum (50) (47) (50) (49) 

Mineralization 1 (2%) 1 (2%) 

Parasite metazoan 2 (4%) 1 (2%) 2 (4%) 

Intestine large, cecum (48) (49) (46) (48) 

Necrosis 1 (2%) 

Parasite metazoan 10 (21%) 7 (14%) 7 (15%) 6 (13%) 

Intestine small, duodenum (50) (49) (49) (50) 

Necrosis 1 (2%) 

Liver (50) (50) (49) (50) 

Angiectasis 2 (4%) 5 (10%) 6 (12%) 5 (10%) 

Basophilic focus 16 (32%) 17 (34%) 21 (43%) 13 (26%) 

Clear cell focus 8 (16%) 6 (12%) 3 (6%) 2 (4%) 

Degeneration, cystic 13 (26%) 18 (36%) 20 (41%) 21 (42%) 

Degeneration, fatty 3 (6%) 4 (8%) 4 (8%) 3 (6%) 

Eosinophilic focus 3 (6%) 4 (8%) 

Hepatodiaphragmatic nodule 2 (4%) 1 (2%) 4 (8%) 3 (6%) 

Inflammation, chronic 1 (2%) 

Mixed cell focus 1 (2%) 2 (4%) 1 (2%) 

Necrosis 2 (4%) 1 (2%) 1 (2%) 

Regeneration 2 (4%) 3 (6%) 3 (6%) 

Thrombosis 1 (2%) 

Bile duct, hyperplasia 36 (72%) 40 (80%) 35 (71%) 34 (68%) 

Centrilobular, necrosis 13 (26%) 13 (26%) 13 (27%) 8 (16%) 

Mesentery (16) (13) (18) (13) 

Inflammation, chronic active 1 (6%) 1 (8%) 1 (8%) 

Artery, mineralization 1 (6%) 

Fat, hemorrhage 1 (6%) 

Fat, necrosis 15 (94%) 13 (100%) 14 (78%) 11 (85%) 

Oral mucosa (2) (1) (7) 

Pharyngeal, hyperplasia, squamous 3 (43%) 

Pancreas (50) (50) (49) (50) 

Atrophy 27 (54%) 27 (54%) 30 (61%) 23 (46%) 

Basophilic focus 2 (4%) 2 (4%) 2 (4%) 1 (2%) 

Hyperplasia 7 (14%) 3 (6%) 5 (10%) 1 (2%) 

Artery, inflammation 2 (4%) 

Salivary glands (50) (50) (50) (50) 

Atrophy 1 (2%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

148 Chloroprene, NTP TR 467 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Alimentary System (continued) 

Stomach, forestomach (50) (50) (50) (50) 

Hyperplasia, squamous 2 (4%) 1 (2%) 2 (4%) 1 (2%) 

Inflammation, chronic active 5 (10%) 

Mineralization 1 (2%) 1 (2%) 1 (2%) 

Necrosis 2 (4%) 5 (10%) 2 (4%) 3 (6%) 

Ulcer 1 (2%) 1 (2%) 6 (12%) 11 (22%) 

Stomach, glandular (49) (50) (49) (50) 

Mineralization 5 (10%) 5 (10%) 3 (6%) 5 (10%) 

Necrosis 2 (4%) 2 (4%) 6 (12%) 2 (4%) 

Tooth (2) 

Developmental malformation 1 (50%) 

Inflammation, chronic active 2 (100%) 

Cardiovascular System 

Blood vessel (3) (1) 

Aorta, mineralization 2 (67%) 1 (100% 

Heart (50) (50) (50) (50) 

Cardiomyopathy 43 (86%) 46 (92%) 39 (78%) 45 (90%) 

Artery, mineralization 2 (4%) 

Atrium, thrombosis 1 (2%) 1 (2%) 4 (8%) 2 (4%) 

Endocrine System 

Adrenal cortex (50) (50) (49) (50) 

Atrophy 1 (2%) 

Hyperplasia 23 (46%) 25 (50%) 26 (53%) 23 (46%) 

Hypertrophy 1 (2%) 1 (2%) 1 (2%) 1 (2%) 

Necrosis 2 (4%) 1 (2%) 2 (4%) 

Vacuolization cytoplasmic 1 (2%) 4 (8%) 3 (6%) 2 (4%) 

Adrenal medulla (50) (50) (49) (50) 

Hyperplasia 23 (46%) 19 (38%) 19 (39%) 17 (34%) 

Necrosis 1 (2%) 

Islets, pancreatic (50) (50) (49) (50) 

Hyperplasia 3 (6%) 2 (4%) 3 (6%) 3 (6%) 

Parathyroid gland (48) (49) (50) (50) 

Hyperplasia 5 (10%) 10 (20%) 19 (38%) 24 (48%) 

Pituitary gland (50) (49) (50) (49) 

Pars distalis, cyst 1 (2%) 

Pars distalis, hyperplasia 7 (14%) 4 (8%) 5 (10%) 2 (4%) 

Pars intermedia, hyperplasia 1 (2%) 

Thyroid gland (50) (50) (49) (50) 

C-cell, hyperplasia 34 (68%) 24 (48%) 23 (47%) 28 (56%) 

Follicular cell, hyperplasia 2 (4%) 4 (8%) 1 (2%) 

General Body System 

None 

Genital System 

Coagulating gland (1) 

Hyperplasia 1 (100%) 

Epididymis (50) (50) (50) (50) 

Granuloma sperm 2 (4%) 3 (6%) 1 (2%) 

Hyperplasia 2 (4%) 6 (12%) 1 (2%) 

Necrosis, fatty 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 149 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Genital System (continued) 

Penis (1) (3) 

Vein, fibrosis 1 (33%) 

Preputial gland (50) (50) (48) (50) 

Hyperplasia 4 (8%) 3 (6%) 1 (2%) 1 (2%) 

Inflammation, chronic active 9 (18%) 6 (12%) 3 (6%) 4 (8%) 

Prostate (50) (50) (50) (50) 

Hyperplasia 7 (14%) 7 (14%) 5 (10%) 4 (8%) 

Inflammation, chronic active 2 (4%) 4 (8%) 4 (8%) 5 (10%) 

Mineralization 1 (2%) 

Seminal vesicle (50) (50) (50) (49) 

Amyloid deposition 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 1 (2%) 

Testes (50) (50) (50) (50) 

Atrophy 1 (2%) 4 (8%) 4 (8%) 1 (2%) 

Hyperplasia 1 (2%) 

Artery, inflammation, chronic active 2 (4%) 2 (4%) 4 (8%) 3 (6%) 

Interstitial cell, hyperplasia 10 (20%) 4 (8%) 9 (18%) 7 (14%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Necrosis 1 (2%) 

Lymph node (12) (18) (11) (15) 

Iliac, ectasia 1 (6%) 

Pancreatic, hemorrhage 1 (9%) 

Renal, ectasia 1 (7%) 

Renal, hemorrhage 1 (8%) 2 (11%) 3 (27%) 5 (33%) 

Renal, infiltration cellular, plasma cell 1 (9%) 

Renal, pigmentation 1 (7%) 

Lymph node, mandibular (47) (45) (44) (49) 

Ectasia 1 (2%) 

Hemorrhage 1 (2%) 

Infiltration cellular, plasma cell 2 (4%) 1 (2%) 

Lymph node, mesenteric (50) (50) (48) (50) 

Hemorrhage 1 (2%) 

Infiltration cellular, plasma cell 1 (2%) 

Lymph node, mediastinal (46) (47) (48) (47) 

Hemorrhage 1 (2%) 

Spleen (50) (50) (49) (50) 

Accessory spleen 2 (4%) 1 (2%) 1 (2%) 

Fibrosis 17 (34%) 19 (38%) 17 (35%) 20 (40%) 

Hematopoietic cell proliferation 2 (4%) 2 (4%) 3 (6%) 6 (12%) 

Hemorrhage 1 (2%) 1 (2%) 

Metaplasia, lipocyte 1 (2%) 

Necrosis 1 (2%) 2 (4%) 3 (6%) 

Thrombosis 1 (2%) 

Integumentary System 

Mammary gland (30) (23) (30) (28) 

Galactocele 4 (13%) 3 (13%) 3 (10%) 1 (4%) 

Inflammation, chronic 1 (3%) 

Skin (50) (50) (50) (50) 

Cyst epithelial inclusion 1 (2%) 

Hyperkeratosis 2 (4%) 1 (2%) 

Inflammation, chronic active 3 (6%) 4 (8%) 8 (16%) 5 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

150 Chloroprene, NTP TR 467 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Fibrous osteodystrophy 4 (8%) 7 (14%) 11 (22%) 

Hyperplasia 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Hemorrhage 1 (2%) 

Hydrocephalus 1 (2%) 

Mineralization 1 (2%) 

Necrosis 1 (2%) 2 (4%) 

Respiratory System 

Larynx (50) (50) (50) (50) 

Inflammation, acute 1 (2%) 1 (2%) 

Lung (50) (50) (49) (50) 

Foreign body 1 (2%) 

Hemorrhage 1 (2%) 2 (4%) 1 (2%) 1 (2%) 

Infiltration cellular 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Metaplasia, cartilagenous 1 (2%) 

Metaplasia, osseous 1 (2%) 

Mineralization 1 (2%) 1 (2%) 1 (2%) 

Thrombosis 1 (2%) 

Alveolar epithelium, hyperplasia 5 (10%) 16 (32%) 14 (29%) 25 (50%) 

Artery, mediastinum, mineralization 1 (2%) 2 (4%) 

Nose (50) (50) (49) (49) 

Cyst 1 (2%) 

Inflammation, suppurative 1 (2%) 1 (2%) 4 (8%) 

Thrombosis 10 (20%) 9 (18%) 3 (6%) 2 (4%) 

Olfactory epithelium, atrophy 3 (6%) 12 (24%) 46 (94%) 48 (98%) 

Olfactory epithelium, fibrosis 47 (96%) 

Olfactory epithelium, hyperplasia, basal cell 38 (78%) 46 (94%) 

Olfactory epithelium, hyperplasia,

 adenomatous 2 (4%) 1 (2%) 42 (86%) 

Olfactory epithelium, inflammation, chronic

 active 5 (10%) 9 (18%) 49 (100%) 

Olfactory epithelium, metaplasia 6 (12%) 5 (10%) 45 (92%) 48 (98%) 

Olfactory epithelium, necrosis 11 (22%) 26 (53%) 19 (39%) 

Respiratory epithelium, hyperplasia 1 (2%) 

Turbinate, fibrosis, focal 5 (10%) 

Trachea (50) (50) (50) (50) 

Mineralization 1 (2%) 

Special Senses System 

Ear (1) 

External ear, inflammation, chronic active 1 (100%) 

Eye (1) (1) 

Cataract 1 (100%) 

Retina, atrophy 1 (100%) 1 (100%) 
 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 151 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Urinary System 

Kidney (50) (50) (50) (50) 

Cyst 3 (6%) 3 (6%) 3 (6%) 5 (10%) 

Hyperplasia, oncocytic 2 (4%) 

Infarct 2 (4%) 2 (4%) 

Mineralization 1 (2%) 2 (4%) 1 (2%) 

Nephropathy 50 (100%) 50 (100%) 50 (100%) 50 (100%) 

Pelvis, inflammation, acute 1 (2%) 

Renal tubule, hyperplasia 2 (4%) 3 (6%) 6 (12%) 6 (12%) 

Transitional epithelium, hyperplasia 1 (2%) 

Urinary bladder (50) (50) (50) (49) 

Hemorrhage 1 (2%) 1 (2%) 

Infiltration cellular 1 (2%) 

Inflammation, chronic active 2 (4%) 1 (2%) 1 (2%) 

Transitional epithelium, hyperplasia 1 (2%) 
152 Chloroprene, NTP TR 467
 
 

 

153 

APPENDIX B 

SUMMARY OF LESIONS IN FEMALE RATS 

IN THE 2-YEAR INHALATION STUDY 

OF CHLOROPRENE 

TABLE B1 

TABLE B2 

TABLE B3 

TABLE B4a 

TABLE B4b 

TABLE B4c 

TABLE B4d 

TABLE B4e 

TABLE B4f 

TABLE B5 

Summary of the Incidence of Neoplasms in Female Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Individual Animal Tumor Pathology of Female Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Statistical Analysis of Primary Neoplasms in Female Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

Historical Incidence of Oral Cavity Neoplasms 

in Chamber Control Female F344/N Rats ................................ 

Historical Incidence of Thyroid Gland Follicular Cell Neoplasms 

in Chamber Control Female F344/N Rats ................................ 

Historical Incidence of Alveolar/bronchiolar Adenoma 

in Chamber Control Female F344/N Rats ................................ 

Historical Incidence of Mammary Gland Fibroadenoma 

in Chamber Control Female F344/N Rats ................................ 

Historical Incidence of Renal Tubule Neoplasms 

in Chamber Control Female F344/N Rats ................................ 

Historical Incidence of Urinary Bladder Carcinoma 

in Chamber Control Female F344/N Rats ................................ 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats 

in the 2-Year Inhalation Study of Chloroprene ............................. 

154 

158 

174 

180 

180 

181 

181 

182 

182 

183 
 

 

 

 

 

 

 

 

 

 

 

 

154 Chloroprene, NTP TR 467 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 19 21 23 27 

Natural deaths 1 1 1 2 

Survivors 

Terminal sacrifice 29 28 26 21 

Pregnant 1 

Animals examined microscopically 49 50 50 50 

Alimentary System 

Esophagus (49) (50) (50) (50) 

Squamous cell papilloma 1 (2%) 

Intestine large, colon (49) (49) (50) (49) 

Intestine large, cecum (48) (49) (50) (49) 

Intestine small, duodenum (49) (49) (50) (50) 

Intestine small, jejunum (49) (49) (49) (48) 

Intestine small, ileum (48) (49) (49) (48) 

Liver (49) (50) (50) (50) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Mesentery (5) (6) (8) (11) 

Lipoma 1 (13%) 

Oral mucosa (1) (1) (2) (1) 

Buccal, squamous cell papilloma 1 (100%) 

Gingival, squamous cell papilloma 1 (50%) 

Pharyngeal, squamous cell carcinoma 1 (50%) 

Pharyngeal, squamous cell papilloma 1 (100%) 1 (100%) 

Pancreas (49) (50) (50) (50) 

Salivary glands (49) (50) (50) (50) 

Stomach, forestomach (49) (50) (50) (50) 

Stomach, glandular (49) (50) (50) (50) 

Tongue (1) (4) (5) (12) 

Squamous cell carcinoma 1 (25%) 2 (40%) 4 (33%) 

Squamous cell papilloma 2 (50%) 1 (20%) 6 (50%) 

Squamous cell papilloma, multiple 1 (8%) 

Cardiovascular System 

Heart (49) (50) (50) (50) 

Endocrine System 

Adrenal cortex (49) (50) (50) (50) 

Adenoma 2 (4%) 4 (8%) 2 (4%) 1 (2%) 

Adrenal medulla (49) (50) (50) (50) 

Pheochromocytoma complex 1 (2%) 

Pheochromocytoma benign 3 (6%) 3 (6%) 3 (6%) 2 (4%) 

Bilateral, pheochromocytoma benign 1 (2%) 
 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 155 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Endocrine System (continued) 

Islets, pancreatic (49) (50) (50) (50) 

Adenoma 2 (4%) 1 (2%) 1 (2%) 

Carcinoma 1 (2%) 1 (2%) 1 (2%) 

Pituitary gland (48) (50) (50) (50) 

Pars distalis, adenoma 36 (75%) 44 (88%) 44 (88%) 36 (72%) 

Thyroid gland (49) (50) (50) (50) 

Bilateral, C-cell, adenoma 1 (2%) 

C-cell, adenoma 7 (14%) 2 (4%) 5 (10%) 5 (10%) 

C-cell, carcinoma 1 (2%) 2 (4%) 1 (2%) 

Follicular cell, adenoma 1 (2%) 1 (2%) 3 (6%) 

Follicular cell, carcinoma 1 (2%) 2 (4%) 

General Body System 

None 

Genital System 

Clitoral gland (46) (48) (46) (46) 

Adenoma 2 (4%) 5 (10%) 2 (4%) 2 (4%) 

Carcinoma 5 (10%) 4 (9%) 2 (4%) 

Bilateral, adenoma 1 (2%) 

Bilateral, carcinoma 1 (2%) 

Ovary (49) (50) (50) (50) 

Uterus (49) (50) (50) (50) 

Deciduoma malignant 1 (2%) 

Granular cell tumor malignant 1 (2%) 

Leiomyosarcoma 1 (2%) 

Polyp stromal 6 (12%) 4 (8%) 5 (10%) 8 (16%) 

Polyp stromal, multiple 1 (2%) 2 (4%) 

Schwannoma malignant 1 (2%) 

Vagina (1) 

Schwannoma malignant, metastatic, uterus 1 (100%) 

Hematopoietic System 

Bone marrow (49) (50) (50) (50) 

Lymph node (1) (4) (4) (5) 

Lymph node, bronchial (35) (34) (30) (36) 

Lymph node, mandibular (44) (48) (37) (50) 

Lymph node, mesenteric (49) (50) (49) (49) 

Lymph node, mediastinal (44) (43) (43) (45) 

Spleen (48) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Thymus (43) (41) (48) (46) 

Thymoma malignant 1 (2%) 

Integumentary System 

Mammary gland (49) (50) (50) (50) 

Carcinoma 4 (8%) 5 (10%) 4 (8%) 4 (8%) 

Fibroadenoma 19 (39%) 20 (40%) 21 (42%) 17 (34%) 

Fibroadenoma, multiple 5 (10%) 12 (24%) 15 (30%) 19 (38%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

156 Chloroprene, NTP TR 467 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Integumentary System (continued) 

Skin 

Basal cell carcinoma

Keratoacanthoma

Subcutaneous tissue, fibroma

Subcutaneous tissue, fibrosarcoma

Subcutaneous tissue, lipoma

Subcutaneous tissue, melanoma malignant

(49) 

 2 (4%) 

 1 (2%) 

(50) (50) 

 1 (2%) 

 1 (2%) 

 1 (2%) 

 1 (2%) 

(50) 

 1 (2%) 

 1 (2%) 

Musculoskeletal System 

Bone 

Chordoma

Hemangiosarcoma

Osteosarcoma

(49) 

 1 (2%) 

(50) (50) 

 1 (2%) 

(50) 

 1 (2%) 

Nervous System 

Brain 

Astrocytoma benign

Glioma benign

(49) 

 1 (2%) 

(50) 

 1 (2%) 

(50) (50) 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar adenoma, multiple

Carcinoma, metastatic, thyroid gland

Chordoma, metastatic, bone

Hemangiosarcoma, metastatic, liver

Nose 

Trachea 

(49) 

(49) 

 1 (2%) 

(49) 

(49) 

(50) 

(50) 

(50) 

(50) 

(50) 

(50) 

 1 (2%) 

 1 (2%) 

(50) 

(50) 

(50) 

(50) 

 2 (4%) 

 1 (2%) 

 1 (2%) 

(50) 

(50) 

Special Senses System 

None 

Urinary System 

Kidney (49) (50) (50) (50) 

Mesenchymal tumor NOS 1 (2%) 

Renal tubule, adenoma 2 (4%) 

Transitional epithelium, carcinoma 1 (2%) 

Urinary bladder (49) (50) (50) (50) 

Leiomyosarcoma 1 (2%) 

Schwannoma malignant, metastatic, uterus 1 (2%) 

Transitional epithelium, carcinoma 2 (4%) 
 

157 

c 

Chloroprene, NTP TR 467 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Systemic Lesions 

Multiple organsb (49) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Leukemia mononuclear 18 (37%) 18 (36%) 20 (40%) 26 (52%) 

Mesothelioma benign 1 (2%) 

Mesothelioma NOS 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 47 50 50 49 

Total primary neoplasms 119 137 144 156 

Total animals with benign neoplasms 44 48 49 46 

Total benign neoplasms 87 102 103 112 

Total animals with malignant neoplasms 26 26 31 37 

Total malignant neoplasms 31 35 41 43 

Total animals with metastatic neoplasms 1 2 1 

Total metastatic neoplasms 2 2 1 

Total animals with uncertain neoplasms—

 benign or malignant 1 1 

Total uncertain neoplasms 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 
 

 

 

 

 

 

 

 

 

 

 

158 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

3 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 

Number of Days on Study 6 3 5 7 8 8 0 0 2 4 5 5 6 6 6 7 8 9 0 2 3 3 3 3 

6 2 3 3 1 9 0 1 2 4 1 1 1 5 5 0 7 7 2 1 3 3 3 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 

Carcass ID Number 0 3 3 2 3 3 2 1 0 0 1 5 4 3 4 4 4 0 2 0 2 3 4 0 

3 8 0 2 7 1 5 0 8 2 2 0 0 6 4 6 1 6 8 1 1 9 2 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + A + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + A + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + 

Mesentery + + + + 

Oral mucosa + 

Pharyngeal, squamous cell papilloma X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + 

Tongue 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + M 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X X X X 

C-cell, carcinoma 

Follicular cell, adenoma 

General Body System 

None 

Genital System 

Clitoral gland M + + + + + + + + M + + + + + + + + + + + + + + 

Adenoma X X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + 

Granular cell tumor malignant 

Leiomyosarcoma 

Polyp stromal X 

Schwannoma malignant X 

Vagina + 

Schwannoma malignant, metastatic, uterus X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 159 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 5 5 5 5 5 5 5 5 5 5 5 5 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 0 1 1 1 1 1 2 2 3 3 3 4 4 0 0 1 1 1 2 2 2 2 4 4 4 Tissues/ 

9 1 5 6 7 8 0 6 2 3 4 3 9 4 7 3 4 9 3 4 7 9 5 7 8 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Mesentery + 5 

Oral mucosa 1 

Pharyngeal, squamous cell papilloma 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Tongue + 1 

Cardiovascular System 

Heart + 

Endocrine System 

Adrenal cortex + 

Adenoma 

Adrenal medulla + 

Pheochromocytoma benign 

Islets, pancreatic + 

Adenoma 

Carcinoma 

Parathyroid gland + 

Pituitary gland + 

Pars distalis, adenoma X 

Thyroid gland + 

C-cell, adenoma 

C-cell, carcinoma 

Follicular cell, adenoma 

General Body System 

None 

+ 

+ 

+ 

+ 

+ 

M 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

X

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

X

+ 

+ 

X

+ 

+ 

X

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

X 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

49 

49 

2 

49 

3 

49 

2 

1 

48 

48 

36 

49 

7 

1 

1 

Genital System 

Clitoral gland + 

Adenoma

Ovary + 

Uterus + 

Granular cell tumor malignant 

Leiomyosarcoma 

Polyp stromal 

Schwannoma malignant

Vagina

Schwannoma malignant, metastatic, uterus

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

X

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

X

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

46 

2 

49 

49 

1 

1 

6 

1 

1 

1 
 

 

 

 

 

 

 

 

 

 

 

 

160 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

3 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 

Number of Days on Study	 6 3 5 7 8 8 0 0 2 4 5 5 6 6 6 7 8 9 0 2 3 3 3 3 

6 2 3 3 1 9 0 1 2 4 1 1 1 5 5 0 7 7 2 1 3 3 3 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 

Carcass ID Number 0 3 3 2 3 3 2 1 0 0 1 5 4 3 4 4 4 0 2 0 2 3 4 0 

3 8 0 2 7 1 5 0 8 2 2 0 0 6 4 6 1 6 8 1 1 9 2 5 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ 

M + + M + + + + + + + + + + + + + + + + M M + + 

M + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + M + + + + + + + + + M + + 

+ + + + + + + + + + + + + + + + + A + + + + + + 

M + + + + + + M + + + + + + + M + + + + M + + + 

Integumentary System 

Mammary gland 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, melanoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X X X X X X X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

Musculoskeletal System 

Bone 

Osteosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

Nervous System 

Brain 

Astrocytoma benign 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + 

Urinary System 

Kidney 

Urinary bladder 

Schwannoma malignant, metastatic, uterus 

+ + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

Mesothelioma benign 

Mesothelioma NOS 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X X 

X 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 161 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 5 5 5 5 5 5 5 5 5 5 5 5 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 0 

9 

1 

1 

1 

5 

1 

6 

1 

7 

1 

8 

2 

0 

2 

6 

3 

2 

3 

3 

3 

4 

4 

3 

4 

9 

0 

4 

0 

7 

1 

3 

1 

4 

1 

9 

2 

3 

2 

4 

2 

7 

2 

9 

4 

5 

4 

7 

4 

8 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ M M + M + + + + + M M M M M M + + + + M + + + + 

M + + + + + + + + + + + + + + + + + + + + M M M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + M M + + + + + + + + + + + + M + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + M + + + + + + + + + + + M + + + + 

49 

1 

35 

44 

49 

44 

48 

43 

Integumentary System 

Mammary gland 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, melanoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X X X X X X X X X X X 

X X X X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

49 

4 

19 

5 

49 

2 

1 

Musculoskeletal System 

Bone 

Osteosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 49 

1 

Nervous System 

Brain 

Astrocytoma benign

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

49 

1 

1 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

49 

49 

1 

49 

49 

Special Senses System 

Eye 1 

Urinary System 

Kidney 

Urinary bladder 

Schwannoma malignant, metastatic, uterus

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

49 

49 

1 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

Mesothelioma benign

Mesothelioma NOS

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

49 

18 

1 

1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

162 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

Number of Days on Study 

3 3 4 5 5 5 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

0 5 8 2 6 7 0 3 5 6 6 7 7 8 8 9 9 0 0 2 2 2 3 3 3 

2 2 5 5 5 6 8 0 7 5 7 1 9 1 1 1 4 7 7 1 1 6 3 3 3 

Carcass ID Number 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

1 3 4 0 1 2 4 1 3 0 0 0 3 0 3 3 0 2 4 1 4 4 0 2 3 

8 1 7 1 3 4 8 0 9 5 9 2 2 8 8 7 7 2 2 2 0 6 6 3 6 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Oral mucosa 

Pharyngeal, squamous cell papilloma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tongue 

Squamous cell carcinoma 

Squamous cell papilloma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + 

X 

X X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma complex X 

Pheochromocytoma benign X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

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 X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, C-cell, adenoma 

C-cell, adenoma 

C-cell, carcinoma 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + M + + + + + + + M 

Adenoma X X X 

Carcinoma X X X X 

Bilateral, adenoma 

Bilateral, carcinoma 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 163 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 

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 4 4 4 5 0 1 1 1 1 2 2 2 3 3 3 4 0 1 1 2 2 2 2 3 4 Tissues/ 

1 3 4 0 3 1 5 7 9 0 6 8 3 4 5 9 4 4 6 1 5 7 9 0 5 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + + 6 

Oral mucosa 1 

Pharyngeal, squamous cell papilloma 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + 4 

Squamous cell carcinoma 1 

Squamous cell papilloma 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 4 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma complex 1 

Pheochromocytoma benign X 3 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

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 X X 44 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, C-cell, adenoma X 1 

C-cell, adenoma X X 2 

C-cell, carcinoma X X 2 

Follicular cell, adenoma 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X X 5 

Carcinoma X 5 

Bilateral, adenoma X 1 

Bilateral, carcinoma X 1 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X 4 

50 
 

 

 

 

 

 

 

164 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

3 3 4 5 5 5 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

Number of Days on Study 0 5 8 2 6 7 0 3 5 6 6 7 7 8 8 9 9 0 0 2 2 2 3 3 3 

2 2 5 5 5 6 8 0 7 5 7 1 9 1 1 1 4 7 7 1 1 6 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 3 3 

Carcass ID Number 1 3 4 0 1 2 4 1 3 0 0 0 3 0 3 3 0 2 4 1 4 4 0 2 3 

8 1 7 1 3 4 8 0 9 5 9 2 2 8 8 7 7 2 2 2 0 6 6 3 6 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + 

Lymph node, bronchial + M + + M M + + + M M M + M + + + M M + + M + + + 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal M + + + + + + + M + + M + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + + M + + + + + + M + + + + + M + + + + + + M 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X X X 

Fibroadenoma X X X X X X X X X 

Fibroadenoma, multiple X X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Glioma benign 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Transitional epithelium, carcinoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 165 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 

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 4 4 4 5 0 1 1 1 1 2 2 2 3 3 3 4 0 1 1 2 2 2 2 3 4 Tissues/ 

1 3 4 0 3 1 5 7 9 0 6 8 3 4 5 9 4 4 6 1 5 7 9 0 5 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + 4 

Lymph node, bronchial M M + + + + + + + + + M + M + M + M + + + + + + + 34 

Lymph node, mandibular + M + + M + + + + + + + + + + + + + + + + + + + + 48 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mediastinal + M + + + + + M + + + M + + + + + + M + + + + + + 43 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + M + + + + + + + M + + M + + + + + + + M + + + M 41 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma X X 5 

Fibroadenoma X X X X X X X X X X X 20 

Fibroadenoma, multiple X X X X X X X X X X 12 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Glioma benign X 1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Transitional epithelium, carcinoma 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X 18 

50 
 

 

 

 

 

 

 

 

 

 

 

 

 

166 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

4 4 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

5 7 3 4 4 6 8 8 9 9 9 0 0 0 1 3 4 5 5 7 9 9 9 2 3 

0 0 4 0 4 7 5 8 0 7 7 1 4 8 8 4 6 1 1 9 1 3 3 1 3 

Carcass ID Number 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

2 1 3 2 2 0 0 1 4 0 1 2 4 4 1 3 0 2 3 3 1 0 2 1 0 

5 2 0 7 6 7 5 4 4 3 7 3 7 6 6 9 8 2 1 8 0 9 4 5 1 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Lipoma 

Oral mucosa 

Gingival, squamous cell papilloma 

Pharyngeal, squamous cell carcinoma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tongue 

Squamous cell carcinoma 

Squamous cell papilloma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + A + + + + 

+ + + + + + + + + + + + + + + + + + + + A + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

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 X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X 

C-cell, carcinoma X 

Follicular cell, carcinoma 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Carcinoma X X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Deciduoma malignant X 

Polyp stromal X X
 

Polyp stromal, multiple
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 167 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Total 

Carcass ID Number 1 3 3 0 1 1 2 2 3 4 4 4 4 5 0 0 1 2 2 3 3 3 4 4 4 Tissues/ 

8 4 6 2 1 9 0 8 3 0 2 3 8 0 4 6 3 1 9 2 5 7 1 5 9 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 + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + + 8 

Lipoma 1 

Oral mucosa + + 2 

Gingival, squamous cell papilloma X 1 

Pharyngeal, squamous cell carcinoma X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + + + 5 

Squamous cell carcinoma X 2 

Squamous cell papilloma X 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X 3 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

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 X 44 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X X 5 

C-cell, carcinoma 1 

Follicular cell, carcinoma X 1 

General Body System 

None 

Genital System 

Clitoral gland M M + + + + + M + + + + + + + + + + M + + + + + + 46 

Adenoma X 2 

Carcinoma X X 4 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Deciduoma malignant 1 

Polyp stromal X X X 5 

Polyp stromal, multiple X 1 
 

 

 

 

 

 

 

 

 

168 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

4 4 5 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 5 7 3 4 4 6 8 8 9 9 9 0 0 0 1 3 4 5 5 7 9 9 9 2 3 

0 0 4 0 4 7 5 8 0 7 7 1 4 8 8 4 6 1 1 9 1 3 3 1 3 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Carcass ID Number 2 1 3 2 2 0 0 1 4 0 1 2 4 4 1 3 0 2 3 3 1 0 2 1 0 

5 2 0 7 6 7 5 4 4 3 7 3 7 6 6 9 8 2 1 8 0 9 4 5 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + 

Lymph node, bronchial M + + M M + M + M M + + M + + M + M M + + M + M + 

Lymph node, mandibular + M + + M M + + + + + + + + + + + + M + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal + + + + + M + + + + + + + + + + M + M + + M + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + + + + + + + + + + M + + + + + + + + + + + + 

Thymoma malignant X 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X X 

Fibroadenoma X X X X X X X X X X X X 

Fibroadenoma, multiple X X X X X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Basal cell carcinoma 

Subcutaneous tissue, fibroma X 

Subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, melanoma malignant X 

Musculoskeletal System 

Bone 

Chordoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx 

Lung 

Carcinoma, metastatic, thyroid gland 

Chordoma, metastatic, bone 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + + + 

Urinary System 

Kidney 

Urinary bladder 

Leiomyosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 169 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Total 

Carcass ID Number 1 3 3 0 1 1 2 2 3 4 4 4 4 5 0 0 1 2 2 3 3 3 4 4 4 Tissues/ 

8 4 6 2 1 9 0 8 3 0 2 3 8 0 4 6 3 1 9 2 5 7 1 5 9 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + 4 

Lymph node, bronchial + + + + M + + + + M + + M + M + + + M + + M + M M 30 

Lymph node, mandibular M + + M M + M + M M + + M M + + + + + M + + + + + 37 

Lymph node, mesenteric + + + + + + + + + M + + + + + + + + + + + + + + + 49 

Lymph node, mediastinal + + + + + M M + + + + + + + + + + + + + + + M + + 43 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + M 48 

Thymoma malignant 1 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma X X 4 

Fibroadenoma X X X X X X X X X 21 

Fibroadenoma, multiple X X X X X X X X X X 15 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Basal cell carcinoma X 1 

Subcutaneous tissue, fibroma 1 

Subcutaneous tissue, fibrosarcoma X 1 

Subcutaneous tissue, melanoma malignant 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Chordoma X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, thyroid gland X 1 

Chordoma, metastatic, bone X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye 3 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma 1 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X 20 

50 
 

 

 

 

 

 

 

 

 

 

 

 

 

170 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

3 6 2 5 7 7 8 9 0 1 1 1 2 2 3 4 4 6 6 6 7 7 7 0 0 

3 3 5 3 2 6 9 1 9 1 3 7 4 4 7 8 9 0 6 7 1 3 9 5 5 

Carcass ID Number 

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 

3 1 2 1 0 3 0 3 2 2 4 3 0 1 0 2 1 4 4 3 3 1 5 2 4 

5 8 6 6 5 7 7 1 1 4 4 4 8 1 1 5 4 6 3 9 0 5 0 8 7 

Alimentary System 

Esophagus 

Squamous cell papilloma 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Histiocytic sarcoma 

Mesentery 

Oral mucosa 

Buccal, squamous cell papilloma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

Tongue 

Squamous cell carcinoma 

Squamous cell papilloma 

Squamous cell papilloma, multiple 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + A + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + A + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + A + + + + + + 

+ + + + + + + + + + + + + + + + + + A + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

+ + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + 

X X X 

X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Bilateral, pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + M + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma 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 

Follicular cell, adenoma X 

Follicular cell, carcinoma X X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + M + + + + 

Adenoma X X 

Carcinoma X X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X X X 

Polyp stromal, multiple X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 171 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

6 0 1 9 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 

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 Total 

Carcass ID Number 4 1 1 2 2 3 4 0 0 0 1 1 2 2 2 3 4 4 4 0 0 1 3 3 4 Tissues/ 

5 0 9 7 0 2 0 2 4 9 3 7 2 3 9 3 1 8 9 3 6 2 6 8 2 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X 1 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + A + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine small, ileum + A + + + + + + + + + + + + + + + + + + + + + + + 48 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Histiocytic sarcoma 1 

Mesentery + + + + 11 

Oral mucosa + 1 

Buccal, squamous cell papilloma X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tongue + + + + + + + + 12 

Squamous cell carcinoma X 4 

Squamous cell papilloma X X X X X 6 

Squamous cell papilloma, multiple X 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X 2 

Bilateral, pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + + + + + + + + + M + + + + + + 48 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma 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 

Follicular cell, adenoma X X 3 

Follicular cell, carcinoma 2 

General Body System 

None 

Genital System 

Clitoral gland M + + + + + + + + + + M + + + + + + + + + M + + + 46 

Adenoma 2 

Carcinoma 2 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X X X X 8 

Polyp stromal, multiple 2 
 

 

 

 

 

 

 

 

 

 

 

 

172 Chloroprene, NTP TR 467 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 3 

3 

6 

3 

2 

5 

5 

3 

7 

2 

7 

6 

8 

9 

9 

1 

0 

9 

1 

1 

1 

3 

1 

7 

2 

4 

2 

4 

3 

7 

4 

8 

4 

9 

6 

0 

6 

6 

6 

7 

7 

1 

7 

3 

7 

9 

0 

5 

0 

5 

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 

Carcass ID Number 3 1 2 1 0 3 0 3 2 2 4 3 0 1 0 2 1 4 4 3 3 1 5 2 4 

5 8 6 6 5 7 7 1 1 4 4 4 8 1 1 5 4 6 3 9 0 5 0 8 7 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Histiocytic sarcoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

+ + + + + + + + + + + + M M M M + M + + M M + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + M 

+ + + + + + + + + + + + + + + + + + + + + + + M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + M + + + 

Integumentary System 

Mammary gland 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Keratoacanthoma 

Subcutaneous tissue, lipoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X X X X X X X X X X 

X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone 

Hemangiosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Hemangiosarcoma, metastatic, liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye + 

Urinary System 

Kidney 

Mesenchymal tumor NOS 

Renal tubule, adenoma 

Urinary bladder 

Transitional epithelium, carcinoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 173 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 

6 

2 

0 

2 

1 

2 

9 

3 

3 

3 

3 

3 

3 

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 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

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 Total 

Carcass ID Number 4 

5 

1 

0 

1 

9 

2 

7 

2 

0 

3 

2 

4 

0 

0 

2 

0 

4 

0 

9 

1 

3 

1 

7 

2 

2 

2 

3 

2 

9 

3 

3 

4 

1 

4 

8 

4 

9 

0 

3 

0 

6 

1 

2 

3 

6 

3 

8 

4 

2 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Spleen 

Histiocytic sarcoma

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + +

M + + + + M + + + + + + M + + + + M M + M + + M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

M + M + + + M + M + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + M + + M + + + + + + + + + + + + + M + + + + + 

50 

5 

36 

50 

49 

45 

50 

1 

46 

Integumentary System 

Mammary gland 

Carcinoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Keratoacanthoma 

Subcutaneous tissue, lipoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

X X X X X X X 

X X X X X X X X X X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

50 

4 

17 

19 

50 

1 

1 

Musculoskeletal System 

Bone 

Hemangiosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar adenoma, multiple 

Hemangiosarcoma, metastatic, liver

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

2 

1 

1 

50 

50 

Special Senses System 

Eye + 2 

Urinary System 

Kidney 

Mesenchymal tumor NOS 

Renal tubule, adenoma

Urinary bladder 

Transitional epithelium, carcinoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

2 

50 

2 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X X X X X X X X X 

50 

1 

26 
174 Chloroprene, NTP TR 467 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Adrenal Cortex: Adenoma a Overall rate 2/49 (4%) 4/50 (8%) 2/50 (4%) 1/50 (2%) 

Adjusted rateb 6.5% 12.1% 7.7% 4.8% c Terminal rate 1/29 (3%) 2/28 (7%) 2/26 (8%) 1/21 (5%) 

First incidence (days) 697 630 733 (T) 733 (T) d Life table test P=0.348N P=0.347 P=0.649 P=0.594N 

Logistic regression testd P=0.287N P=0.349 P=0.659 P=0.549N 

Cochran-Armitage testd P=0.240N 

d Fisher exact test P=0.349 P=0.684N P=0.492N 

Adrenal Medulla: Benign Pheochromocytoma 

Overall rate 3/49 (6%) 3/50 (6%) 3/50 (6%) 3/50 (6%) 

Adjusted rate 10.3% 9.4% 10.9% 13.6% 

Terminal rate 3/29 (10%) 1/28 (4%) 2/26 (8%) 2/21 (10%) 

First incidence (days) 733 (T) 681 693 729 

Life table test P=0.434 P=0.659 P=0.613 P=0.511 

Logistic regression test P=0.494 P=0.641N P=0.614 P=0.543 

Cochran-Armitage test P=0.586N 

Fisher exact test P=0.651N P=0.651N P=0.651N 

Adrenal Medulla: Benign or Complex Pheochromocytoma 

Overall rate 3/49 (6%) 4/50 (8%) 3/50 (6%) 3/50 (6%) 

Adjusted rate 10.3% 12.8% 10.9% 13.6% 

Terminal rate 3/29 (10%) 2/28 (7%) 2/26 (8%) 2/21 (10%) 

First incidence (days) 733 (T) 681 693 729 

Life table test P=0.494 P=0.495 P=0.613 P=0.511 

Logistic regression test P=0.555 P=0.528 P=0.614 P=0.543 

Cochran-Armitage test P=0.513N 

Fisher exact test P=0.511 P=0.651N P=0.651N 

Clitoral Gland: Adenoma 

Overall rate 2/46 (4%) 6/48 (13%) 2/46 (4%) 2/46 (4%) 

Adjusted rate 6.8% 18.1% 7.0% 5.3% 

Terminal rate 1/28 (4%) 3/27 (11%) 1/22 (5%) 0/19 (0%) 

First incidence (days) 721 525 601 609 

Life table test P=0.433N P=0.143 P=0.632 P=0.623 

Logistic regression test P=0.324N P=0.145 P=0.667 P=0.693N 

Cochran-Armitage test P=0.321N 

Fisher exact test P=0.148 P=0.692N P=0.692N 

Clitoral Gland: Carcinoma 

Overall rate 0/46 (0%) 6/48 (13%) 4/46 (9%) 2/46 (4%) 

Adjusted rate 0.0% 18.1% 13.3% 5.1% 

Terminal rate 0/28 (0%) 3/27 (11%) 2/22 (9%) 0/19 (0%) e First incidence (days) — 630 544 572 

Life table test P=0.508 P=0.021 P=0.049 P=0.225 

Logistic regression test P=0.555N P=0.019 P=0.074 P=0.290 

Cochran-Armitage test P=0.566N 

Fisher exact test P=0.015 P=0.058 P=0.247 
 

 

Chloroprene, NTP TR 467 175 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Clitoral Gland: Adenoma or Carcinoma 

Overall rate 2/46 (4%) 12/48 (25%) 5/46 (11%) 3/46 (7%) 

Adjusted rate 6.8% 34.0% 17.7% 7.3% 

Terminal rate 1/28 (4%) 6/27 (22%) 3/22 (14%) 0/19 (0%) 

First incidence (days) 721 525 544 572 

Life table test P=0.364N P=0.007 P=0.159 P=0.432 

Logistic regression test P=0.220N P=0.005 P=0.202 P=0.545 

Cochran-Armitage test P=0.217N 

Fisher exact test P=0.005 P=0.217 P=0.500 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 0.0% 0.0% 0.0% 9.7% 

Terminal rate 0/29 (0%) 0/28 (0%) 0/26 (0%) 1/21 (5%) 

First incidence (days) — — — 609 

f Life table test P=0.002 — — P=0.053 

Logistic regression test P=0.002 — — P=0.070 

Cochran-Armitage test P=0.002 

Fisher exact test — — P=0.061 

Kidney (Renal Tubule): Adenoma or Carcinoma (Single and Step Sections) 

Overall rate 0/49 (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 0.0% 0.0% 0.0% 9.7% 

Terminal rate 0/29 (0%) 0/28 (0%) 0/26 (0%) 1/21 (5%) 

First incidence (days) — — — 609 

Life table test P=0.002 — — P=0.053 

Logistic regression test P=0.002 — — P=0.070 

Cochran-Armitage test P=0.002 

Fisher exact test — — P=0.061 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 1/49 (2%) 0/50 (0%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 3.4% 0.0% 0.0% 9.6% 

Terminal rate 1/29 (3%) 0/28 (0%) 0/26 (0%) 1/21 (5%) 

First incidence (days) 733 (T) — — 613 

Life table test P=0.046 P=0.507N P=0.522N P=0.246 

Logistic regression test P=0.066 P=0.507N P=0.522N P=0.314 

Cochran-Armitage test P=0.066 

Fisher exact test P=0.495N P=0.495N P=0.316 

Mammary Gland: Fibroadenoma 

Overall rate 24/49 (49%) 32/50 (64%) 36/50 (72%) 36/50 (72%) 

Adjusted rate 65.4% 86.0% 85.3% 89.7% 

Terminal rate 17/29 (59%) 23/28 (82%) 20/26 (77%) 17/21 (81%) 

First incidence (days) 366 302 470 433 

Life table test P<0.001 P=0.087 P=0.009 P=0.002 

Logistic regression test P=0.005 P=0.130 P=0.011 P=0.009 

Cochran-Armitage test P=0.025 

Fisher exact test P=0.096 P=0.016 P=0.016 
176 Chloroprene, NTP TR 467 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Mammary Gland: Carcinoma 

Overall rate 4/49 (8%) 5/50 (10%) 4/50 (8%) 4/50 (8%) 

Adjusted rate 12.1% 15.1% 13.4% 14.1% 

Terminal rate 2/29 (7%) 2/28 (7%) 2/26 (8%) 2/21 (10%) 

First incidence (days) 661 671 634 609 

Life table test P=0.486 P=0.527 P=0.576 P=0.527 

Logistic regression test P=0.546N P=0.518 P=0.628 P=0.643 

Cochran-Armitage test P=0.510N 

Fisher exact test P=0.513 P=0.631N P=0.631N 

Mammary Gland: Fibroadenoma or Carcinoma 

Overall rate 28/49 (57%) 34/50 (68%) 36/50 (72%) 36/50 (72%) 

Adjusted rate 72.7% 89.1% 85.3% 89.7% 

Terminal rate 19/29 (66%) 24/28 (86%) 20/26 (77%) 17/21 (81%) 

First incidence (days) 366 302 470 433 

Life table test P=0.006 P=0.177 P=0.045 P=0.011 

Logistic regression test P=0.039 P=0.235 P=0.068 P=0.059 

Cochran-Armitage test P=0.115 

Fisher exact test P=0.182 P=0.091 P=0.091 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, Gingiva): Squamous Cell Papilloma 

Overall rate 1/49 (2%) 2/50 (4%) 2/50 (4%) 7/50 (14%) 

Adjusted rate 3.0% 6.2% 7.7% 29.5% 

Terminal rate 0/29 (0%) 1/28 (4%) 2/26 (8%) 5/21 (24%) 

First incidence (days) 687 681 733 (T) 660 

Life table test P=0.002 P=0.516 P=0.464 P=0.013 

Logistic regression test P=0.003 P=0.508 P=0.469 P=0.020 

Cochran-Armitage test P=0.007 

Fisher exact test P=0.508 P=0.508 P=0.032 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, Gingiva): Squamous Cell Carcinoma 

Overall rate 0/49 (0%) 1/50 (2%) 3/50 (6%) 4/50 (8%) 

Adjusted rate 0.0% 3.2% 9.8% 14.8% 

Terminal rate 0/29 (0%) 0/28 (0%) 2/26 (8%) 1/21 (5%) 

First incidence (days) — 721 588 671 

Life table test P=0.017 P=0.507 P=0.109 P=0.047 

Logistic regression test P=0.028 P=0.510 P=0.121 P=0.055 

Cochran-Armitage test P=0.034 

Fisher exact test P=0.505 P=0.125 P=0.061 

Oral Cavity (Oral Mucosa, Tongue, Pharynx, Gingiva): Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 1/49 (2%) 3/50 (6%) 5/50 (10%) 11/50 (22%) 

Adjusted rate 3.0% 9.2% 17.4% 40.8% 

Terminal rate 0/29 (0%) 1/28 (4%) 4/26 (15%) 6/21 (29%) 

First incidence (days) 687 681 588 660 

Life table test P<0.001 P=0.324 P=0.086 P<0.001 

Logistic regression test P<0.001 P=0.315 P=0.093 P=0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.316 P=0.107 P=0.002 
Chloroprene, NTP TR 467 177 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Pancreatic Islets: Adenoma or Carcinoma 

Overall rate 3/49 (6%) 2/50 (4%) 2/50 (4%) 0/50 (0%) 

Adjusted rate 9.9% 6.1% 6.3% 0.0% 

Terminal rate 2/29 (7%) 1/28 (4%) 1/26 (4%) 0/21 (0%) 

First incidence (days) 702 679 601 — 

Life table test P=0.133N P=0.491N P=0.549N P=0.172N 

Logistic regression test P=0.100N P=0.481N P=0.516N P=0.146N 

Cochran-Armitage test P=0.090N 

Fisher exact test P=0.490N P=0.490N P=0.117N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 36/48 (75%) 44/50 (88%) 44/50 (88%) 36/50 (72%) 

Adjusted rate 89.8% 97.7% 93.6% 83.3% 

Terminal rate 24/28 (86%) 27/28 (96%) 23/26 (88%) 14/21 (67%) 

First incidence (days) 553 352 450 463 

Life table test P=0.198 P=0.150 P=0.051 P=0.171 

Logistic regression test P=0.193N P=0.061 P=0.043 P=0.549N 

Cochran-Armitage test P=0.160N 

Fisher exact test P=0.080 P=0.080 P=0.458N 

Thyroid Gland (C-cell): Adenoma 

Overall rate 7/49 (14%) 3/50 (6%) 5/50 (10%) 5/50 (10%) 

Adjusted rate 20.3% 10.7% 16.2% 19.1% 

Terminal rate 3/29 (10%) 3/28 (11%) 3/26 (12%) 3/21 (14%) 

First incidence (days) 622 733 (T) 590 463 

Life table test P=0.481 P=0.162N P=0.460N P=0.538N 

Logistic regression test P=0.516N P=0.145N P=0.391N P=0.380N 

Cochran-Armitage test P=0.485N 

Fisher exact test P=0.151N P=0.365N P=0.365N 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 8/49 (16%) 5/50 (10%) 6/50 (12%) 5/50 (10%) 

Adjusted rate 23.4% 17.9% 18.4% 19.1% 

Terminal rate 4/29 (14%) 5/28 (18%) 3/26 (12%) 3/21 (14%) 

First incidence (days) 622 733 (T) 590 463 

Life table test P=0.493N P=0.282N P=0.474N P=0.440N 

Logistic regression test P=0.333N P=0.249N P=0.392N P=0.282N 

Cochran-Armitage test P=0.302N 

Fisher exact test P=0.264N P=0.371N P=0.264N 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 1/49 (2%) 1/50 (2%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 3.4% 3.2% 0.0% 12.0% 

Terminal rate 1/29 (3%) 0/28 (0%) 0/26 (0%) 1/21 (5%) 

First incidence (days) 733 (T) 721 — 705 

Life table test P=0.090 P=0.760 P=0.522N P=0.229 

Logistic regression test P=0.104 P=0.753N P=0.522N P=0.252 

Cochran-Armitage test P=0.142 

Fisher exact test P=0.747N P=0.495N P=0.316 
178 Chloroprene, NTP TR 467 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 1/49 (2%) 1/50 (2%) 1/50 (2%) 5/50 (10%) 

Adjusted rate 3.4% 3.2% 3.8% 16.8% 

Terminal rate 1/29 (3%) 0/28 (0%) 1/26 (4%) 1/21 (5%) 

First incidence (days) 733 (T) 721 733 (T) 617 

Life table test P=0.010 P=0.760 P=0.738 P=0.072 

Logistic regression test P=0.017 P=0.753N P=0.738 P=0.098 

Cochran-Armitage test P=0.022 

Fisher exact test P=0.747N P=0.747N P=0.107 

Tongue: Squamous Cell Papilloma 

Overall rate 0/49 (0%) 2/50 (4%) 1/50 (2%) 7/50 (14%) 

Adjusted rate 0.0% 6.2% 3.8% 29.5% 

Terminal rate 0/29 (0%) 1/28 (4%) 1/26 (4%) 5/21 (24%) 

First incidence (days) — 681 733 (T) 660 

Life table test P<0.001 P=0.248 P=0.478 P=0.003 

Logistic regression test P<0.001 P=0.244 P=0.478 P=0.005 

Cochran-Armitage test P=0.001 

Fisher exact test P=0.253 P=0.505 P=0.007 

Tongue: Squamous Cell Carcinoma 

Overall rate 0/49 (0%) 1/50 (2%) 2/50 (4%) 4/50 (8%) 

Adjusted rate 0.0% 3.2% 6.1% 14.8% 

Terminal rate 0/29 (0%) 0/28 (0%) 1/26 (4%) 1/21 (5%) 

First incidence (days) — 721 588 671 

Life table test P=0.014 P=0.507 P=0.225 P=0.047 

Logistic regression test P=0.023 P=0.510 P=0.248 P=0.055 

Cochran-Armitage test P=0.026 

Fisher exact test P=0.505 P=0.253 P=0.061 

Tongue: Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 0/49 (0%) 3/50 (6%) 3/50 (6%) 11/50 (22%) 

Adjusted rate 0.0% 9.2% 9.8% 40.8% 

Terminal rate 0/29 (0%) 1/28 (4%) 2/26 (8%) 6/21 (29%) 

First incidence (days) — 681 588 660 

Life table test P<0.001 P=0.131 P=0.109 P<0.001 

Logistic regression test P<0.001 P=0.126 P=0.121 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.125 P=0.125 P<0.001 

Uterus: Stromal Polyp 

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

Adjusted rate 19.3% 11.9% 20.5% 31.2% 

Terminal rate 5/29 (17%) 2/28 (7%) 4/26 (15%) 3/21 (14%) 

First incidence (days) 644 565 608 572 

Life table test P=0.029 P=0.377N P=0.540 P=0.112 

Logistic regression test P=0.067 P=0.352N P=0.571 P=0.199 

Cochran-Armitage test P=0.079 

Fisher exact test P=0.357N P=0.606N P=0.220 
179 

c 

Chloroprene, NTP TR 467 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Mononuclear Cell Leukemia 

Overall rate 18/49 (37%) 18/50 (36%) 20/50 (40%) 26/50 (52%) 

Adjusted rate 43.4% 43.4% 51.4% 83.0% 

Terminal rate 8/29 (28%) 6/28 (21%) 8/26 (31%) 16/21 (76%) 

First incidence (days) 366 485 540 525 

Life table test P=0.010 P=0.541N P=0.321 P=0.020 

Logistic regression test P=0.044 P=0.536 P=0.504 P=0.088 

Cochran-Armitage test P=0.046 

Fisher exact test P=0.553N P=0.449 P=0.092 

All Organs: Benign Neoplasms 

Overall rate 44/49 (90%) 48/50 (96%) 49/50 (98%) 46/50 (92%) 

Adjusted rate 95.6% 100.0% 100.0% 95.8% 

Terminal rate 27/29 (93%) 28/28 (100%) 26/26 (100%) 19/21 (90%) 

First incidence (days) 366 302 450 433 

Life table test P=0.046 P=0.326 P=0.092 P=0.067 

Logistic regression test P=0.584 P=0.184 P=0.081 P=0.454 

Cochran-Armitage test P=0.588N 

Fisher exact test P=0.210 P=0.098 P=0.487 

All Organs: Malignant Neoplasms 

Overall rate 26/49 (53%) 26/50 (52%) 31/50 (62%) 37/50 (74%) 

Adjusted rate 60.2% 61.5% 68.2% 89.7% 

Terminal rate 13/29 (45%) 12/28 (43%) 12/26 (46%) 17/21 (81%) 

First incidence (days) 366 485 470 525 

Life table test P=0.002 P=0.539N P=0.168 P=0.008 

Logistic regression test P=0.020 P=0.538N P=0.322 P=0.027 

Cochran-Armitage test P=0.009 

Fisher exact test P=0.538N P=0.243 P=0.025 

All Organs: Benign or Malignant Neoplasms 

Overall rate 47/49 (96%) 50/50 (100%) 50/50 (100%) 49/50 (98%) 

Adjusted rate 95.9% 100.0% 100.0% 98.0% 

Terminal rate 27/29 (93%) 28/28 (100%) 26/26 (100%) 20/21 (95%) 

First incidence (days) 366 302 450 433 

Life table test P=0.044 P=0.396 P=0.163 P=0.071 

Logistic regression test P=0.666 P=0.246 P=0.262 P=0.613 

Cochran-Armitage test P=0.575 

Fisher exact test P=0.242 P=0.242 P=0.492 

(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, lung, pancreatic islets, 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 chamber 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 chamber 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 by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
180 Chloroprene, NTP TR 467 

TABLE B4a 

Historical Incidence of Oral Cavity Neoplasms in Chamber Control Female F344/N Ratsa 

Incidence in Controls 

Study Squamous Cell Squamous Cell Squamous Cell 

Papilloma Carcinoma Papilloma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/50 0/50 0/50 

Acetonitrile 1/48 0/48 1/48 

2-Chloroacetophenone 0/50 0/50 0/50 

l-Epinephrine Hydrochloride 0/50 0/50 0/50 

Chloroethane 1/50 0/50 1/50 

Hexachlorocyclopentadiene 0/50 1/50 1/50 

Ozone 1/50 0/50 1/50 

Overall Historical Incidence 

Total 3/653 (0.5%) 5/653 (0.8%) 8/653 (1.2%) 

Standard deviation 0.9% 1.7% 1.7% 

Range 0%-2% 0%-6% 0%-6% 

a Data as of 12 May 1995 

TABLE B4b 

Historical Incidence of Thyroid Gland Follicular Cell Neoplasms in Chamber Control Female F344/N Ratsa 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/48 0/48 0/48 

Acetonitrile 0/48 1/48 1/48 

2-Chloroacetophenone 0/47 2/47 2/47 

l-Epinephrine Hydrochloride 0/50 0/50 0/50 

Chloroethane 1/49 2/49 3/49 

Hexachlorocyclopentadiene 1/50 0/50 1/50 

Ozone 0/50 1/50 1/50 

Overall Historical Incidence 

Total 2/642 (0.3%) 6/642 (0.9%) 8/642 (1.3%) 

Standard deviation 0.8% 1.6% 1.9% 

Range 0%-2% 0%-4% 0%-6% 

a Data as of 12 May 1995 
Chloroprene, NTP TR 467 181 

TABLE B4c 

Historical Incidence of Alveolar/bronchiolar Adenoma in Chamber Control Female F344/N Ratsa 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 2/49 

Acetonitrile 0/48 

2-Chloroacetophenone 1/49 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 0/50 

Hexachlorocyclopentadiene 1/50 

Ozone 0/50 

Overall Historical Incidence 

Total 7/650 (1.1%) 

Standard deviation 1.6% 

Range 0%-4% 

a Data as of 12 May 1995 

TABLE B4d 

Historical Incidence of Mammary Gland Fibroadenoma in Chamber Control Female F344/N Ratsa 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 16/50 

Acetonitrile 16/48 

2-Chloroacetophenone 12/50 

l-Epinephrine Hydrochloride 10/50 

Chloroethane 11/50 

Hexachlorocyclopentadiene 12/50 

Ozone 20/50 

Overall Historical Incidence 

Total 180/653 (27.6%) 

Standard deviation 7.7% 

Range 16%-42% 

a Data as of 12 May 1995 
182 Chloroprene, NTP TR 467 

TABLE B4e 

Historical Incidence of Renal Tubule Neoplasms in Chamber Control Female F344/N Ratsa 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/49 0/49 0/49 

Acetonitrile 0/48 0/48 0/48 

2-Chloroacetophenone 0/49 0/49 0/49 

l-Epinephrine Hydrochloride 0/50 0/50 0/50 

Chloroethane 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 1/50 1/50 

Ozone 1/50 0/50 1/50 

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 B4f 

Historical Incidence of Urinary Bladder Carcinoma in Chamber Control Female F344/N Ratsa 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

o-Chlorobenzalmalononitrile 0/47 

Acetonitrile 0/48 

2-Chloroacetophenone 0/48 

l-Epinephrine Hydrochloride 0/49 

Chloroethane 0/49 

Hexachlorocyclopentadiene 0/50 

Ozone 0/50 

Overall Historical Incidence 

Total 0/644 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 183 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 19 21 23 27 

Natural deaths 1 1 1 2 

Survivors 

Terminal sacrifice 29 28 26 21 

Pregnant 1 

Animals examined microscopically 49 50 50 50 

Alimentary System 

Intestine large, colon (49) (49) (50) (49) 

Parasite metazoan 4 (8%) 6 (12%) 2 (4%) 

Intestine large, rectum (49) (49) (50) (50) 

Inflammation, acute 1 (2%) 

Mineralization 2 (4%) 1 (2%) 

Parasite metazoan 2 (4%) 5 (10%) 7 (14%) 2 (4%) 

Intestine large, cecum (48) (49) (50) (49) 

Inflammation, acute 1 (2%) 1 (2%) 

Parasite metazoan 5 (10%) 4 (8%) 8 (16%) 5 (10%) 

Intestine small, jejunum (49) (49) (49) (48) 

Inflammation, chronic active 1 (2%) 

Intestine small, ileum (48) (49) (49) (48) 

Parasite metazoan 1 (2%) 1 (2%) 

Liver (49) (50) (50) (50) 

Angiectasis 3 (6%) 7 (14%) 5 (10%) 8 (16%) 

Basophilic focus 39 (80%) 43 (86%) 45 (90%) 44 (88%) 

Clear cell focus 15 (31%) 16 (32%) 14 (28%) 6 (12%) 

Degeneration, cystic 2 (4%) 

Degeneration, fatty 5 (10%) 5 (10%) 3 (6%) 3 (6%) 

Eosinophilic focus 2 (4%) 1 (2%) 2 (4%) 

Hepatodiaphragmatic nodule 4 (8%) 7 (14%) 9 (18%) 9 (18%) 

Mixed cell focus 7 (14%) 6 (12%) 6 (12%) 9 (18%) 

Necrosis 1 (2%) 1 (2%) 2 (4%) 

Bile duct, hyperplasia 9 (18%) 10 (20%) 11 (22%) 16 (32%) 

Centrilobular, necrosis 1 (2%) 3 (6%) 5 (10%) 8 (16%) 

Mesentery (5) (6) (8) (11) 

Inflammation, chronic active 1 (20%) 1 (9%) 

Fat, necrosis 4 (80%) 6 (100%) 7 (88%) 9 (82%) 

Pancreas (49) (50) (50) (50) 

Atrophy 18 (37%) 14 (28%) 17 (34%) 9 (18%) 

Basophilic focus 1 (2%) 1 (2%) 1 (2%) 3 (6%) 

Hyperplasia 2 (4%) 1 (2%) 2 (4%) 

Lipomatosis 1 (2%) 2 (4%) 

Metaplasia, hepatocyte 1 (2%) 

Artery, inflammation 1 (2%) 

Salivary glands (49) (50) (50) (50) 

Atrophy 1 (2%) 3 (6%) 

Basophilic focus 1 (2%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

184 Chloroprene, NTP TR 467 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Alimentary System (continued) 

Stomach, forestomach (49) (50) (50) (50) 

Hyperplasia, squamous 1 (2%) 1 (2%) 3 (6%) 

Mineralization 1 (2%) 1 (2%) 

Necrosis 2 (4%) 3 (6%) 1 (2%) 

Ulcer 1 (2%) 1 (2%) 

Stomach, glandular (49) (50) (50) (50) 

Mineralization 1 (2%) 1 (2%) 4 (8%) 3 (6%) 

Necrosis 1 (2%) 

Tongue (1) (4) (5) (12) 

Hyperplasia, squamous 1 (100%) 1 (25%) 1 (20%) 1 (8%) 

Cardiovascular System 

Heart (49) (50) (50) (50) 

Cardiomyopathy 38 (78%) 38 (76%) 31 (62%) 41 (82%) 

Artery, inflammation, chronic 1 (2%) 1 (2%) 

Atrium, thrombosis 1 (2%) 

Schwann cell, hyperplasia 1 (2%) 

Endocrine System 

Adrenal cortex (49) (50) (50) (50) 

Atrophy 1 (2%) 

Hyperplasia 23 (47%) 22 (44%) 22 (44%) 20 (40%) 

Hypertrophy 8 (16%) 10 (20%) 7 (14%) 10 (20%) 

Necrosis 2 (4%) 1 (2%) 

Vacuolization cytoplasmic 9 (18%) 5 (10%) 10 (20%) 8 (16%) 

Adrenal medulla (49) (50) (50) (50) 

Hyperplasia 7 (14%) 11 (22%) 7 (14%) 10 (20%) 

Islets, pancreatic (49) (50) (50) (50) 

Hyperplasia 1 (2%) 1 (2%) 3 (6%) 

Parathyroid gland (48) (50) (50) (48) 

Fibrosis 1 (2%) 

Hyperplasia 2 (4%) 1 (2%) 

Pituitary gland (48) (50) (50) (50) 

Pars distalis, hyperplasia 9 (19%) 5 (10%) 3 (6%) 10 (20%) 

Thyroid gland (49) (50) (50) (50) 

Fibrosis 1 (2%) 

C-cell, hyperplasia 38 (78%) 38 (76%) 35 (70%) 28 (56%) 

Follicular cell, hyperplasia 2 (4%) 

General Body System 

None 

Genital System 

Clitoral gland (46) (48) (46) (46) 

Hyperplasia 2 (4%) 1 (2%) 4 (9%) 4 (9%) 

Inflammation, chronic active 4 (9%) 4 (8%) 6 (13%) 4 (9%) 

Ovary (49) (50) (50) (50) 

Cyst 7 (14%) 6 (12%) 1 (2%) 3 (6%) 

Inflammation, granulomatous 2 (4%) 1 (2%) 1 (2%) 

Uterus (49) (50) (50) (50) 

Hydrometra 1 (2%) 

Cervix, hypertrophy 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 185 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Hematopoietic System 

Bone marrow (49) (50) (50) (50) 

Atrophy 3 (6%) 1 (2%) 

Hyperplasia, histiocytic 2 (4%) 

Lymph node (1) (4) (4) (5) 

Iliac, ectasia 1 (25%) 1 (20%) 

Renal, infiltration cellular, plasma cell 1 (25%) 

Lymph node, mandibular (44) (48) (37) (50) 

Hemorrhage 1 (2%) 

Spleen (48) (50) (50) (50) 

Accessory spleen 1 (2%) 1 (2%) 

Angiectasis 1 (2%) 

Fibrosis 3 (6%) 1 (2%) 3 (6%) 5 (10%) 

Hematopoietic cell proliferation 1 (2%) 4 (8%) 4 (8%) 6 (12%) 

Hemorrhage 4 (8%) 

Integumentary System 

Mammary gland (49) (50) (50) (50) 

Galactocele 1 (2%) 1 (2%) 2 (4%) 

Skin (49) (50) (50) (50) 

Cyst epithelial inclusion 1 (2%) 

Hyperkeratosis 1 (2%) 

Inflammation, acute 1 (2%) 

Inflammation, chronic active 3 (6%) 5 (10%) 2 (4%) 3 (6%) 

Musculoskeletal System 

Bone (49) (50) (50) (50) 

Fracture 1 (2%) 

Hyperostosis 4 (8%) 5 (10%) 4 (8%) 3 (6%) 

Hyperplasia 1 (2%) 

Nervous System 

Brain (49) (50) (50) (50) 

Hemorrhage 1 (2%) 1 (2%) 

Respiratory System 

Larynx (49) (50) (50) (50) 

Lung (49) (50) (50) (50) 

Congestion, chronic 1 (2%) 

Hemorrhage 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Alveolar epithelium, hyperplasia 6 (12%) 22 (44%) 22 (44%) 34 (68%) 

Artery, mediastinum, inflammation 1 (2%) 

Trachea (49) (50) (50) (50) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

186 Chloroprene, NTP TR 467 

TABLE B5 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Respiratory System (continued) 

Nose (49) (50) (50) (50) 

Inflammation, suppurative 1 (2%) 2 (4%) 

Thrombosis 1 (2%) 1 (2%) 3 (6%) 

Nasolacrimal duct, hyperplasia, squamous 1 (2%) 

Olfactory epithelium, atrophy 1 (2%) 40 (80%) 50 (100%) 

Olfactory epithelium, fibrosis 49 (98%) 

Olfactory epithelium, hyperplasia, basal cell 17 (34%) 49 (98%) 

Olfactory epithelium, hyperplasia,

 adenomatous 27 (54%) 

Olfactory epithelium, inflammation, chronic

 active 2 (4%) 33 (66%) 

Olfactory epithelium, metaplasia 1 (2%) 35 (70%) 50 (100%) 

Olfactory epithelium, necrosis 8 (16%) 12 (24%) 

Olfactory epithelium, glands, atypia cellular 2 (4%) 

Turbinate, fibrosis, focal 1 (2%) 3 (6%) 

Special Senses System 

Eye (1) (1) (3) (2) 

Cataract 1 (100%) 2 (67%) 2 (100%) 

Degeneration 1 (100%) 

Retina, atrophy 2 (67%) 2 (100%) 

Urinary System 

Kidney (49) (50) (50) (50) 

Hydronephrosis 1 (2%) 

Hyperplasia, oncocytic 1 (2%) 

Infarct 1 (2%) 1 (2%) 

Mineralization 1 (2%) 

Nephropathy 43 (88%) 48 (96%) 49 (98%) 49 (98%) 

Artery, inflammation 1 (2%) 

Pelvis, inflammation, acute 1 (2%) 

Renal tubule, hyperplasia 1 (2%) 4 (8%) 

Urinary bladder (49) (50) (50) (50) 

Hemorrhage 1 (2%) 

Transitional epithelium, hyperplasia 1 (2%) 1 (2%) 
 

 

187 

APPENDIX C
 

SUMMARY OF LESIONS IN MALE MICE
 

IN THE 2-YEAR INHALATION STUDY
 

OF CHLOROPRENE
 

TABLE C1 Summary of the Incidence of Neoplasms in Male Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 188
 

TABLE C2 Individual Animal Tumor Pathology of Male Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 192
 

TABLE C3 Statistical Analysis of Primary Neoplasms in Male Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 214
 

TABLE C4a Historical Incidence of Alveolar/bronchiolar Neoplasms
 

in Chamber Control Male B6C3F Mice 1 ................................. 221
 

TABLE C4b	 Historical Incidence of Hemangioma and Hemangiosarcoma (All Sites)
 

in Chamber Control Male B6C3F Mice 1 ................................. 221
 

TABLE C4c	 Historical Incidence of Harderian Gland Neoplasms
 

in Chamber Control Male B6C3F Mice 1 ................................. 222
 

TABLE C4d	 Historical Incidence of Squamous Cell Papilloma of the Forestomach
 

in Chamber Control Male B6C3F Mice 1 ................................. 222
 

TABLE C4e	 Historical Incidence of Renal Tubule Adenoma
 

in Chamber Control Male B6C3F Mice 1 ................................. 223
 

TABLE C5	 Summary of the Incidence of Nonneoplastic Lesions in Male Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 224
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

188 Chloroprene, NTP TR 467 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 15 16 26 34 

Natural deaths 8 7 10 3 

Survivors 

Terminal sacrifice 27 27 14 13 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Gallbladder (41) (40) (37) (40) 

Intestine large, cecum (48) (44) (45) (48) 

Hemangioma 1 (2%) 

Muscularis, leiomyoma 1 (2%) 

Intestine small, jejunum (46) (43) (47) (49) 

Intestine small, ileum (46) (45) (46) (48) 

Liver (50) (50) (50) (49) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (2%) 

Cholangiocarcinoma 1 (2%) 

Hemangiosarcoma 2 (4%) 5 (10%) 6 (12%) 8 (16%) 

Hepatoblastoma 2 (4%) 3 (6%) 1 (2%) 

Hepatocellular carcinoma 10 (20%) 18 (36%) 18 (36%) 16 (33%) 

Hepatocellular carcinoma, multiple 14 (28%) 10 (20%) 19 (38%) 17 (35%) 

Hepatocellular adenoma 8 (16%) 11 (22%) 12 (24%) 11 (22%) 

Hepatocellular adenoma, multiple 14 (28%) 5 (10%) 7 (14%) 10 (20%) 

Hepatocholangiocarcinoma 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Sarcoma 1 (2%) 

Mesentery (2) (8) (16) (11) 

Hemangioma 1 (6%) 2 (18%) 

Hemangiosarcoma 3 (38%) 13 (81%) 7 (64%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (13%) 

Sarcoma, metastatic, liver 1 (13%) 

Oral mucosa (1) 

Gingival, squamous cell carcinoma 1 (100%) 

Pancreas (50) (48) (49) (50) 

Hemangiosarcoma 1 (2%) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 1 (2%) 

Sarcoma, metastatic, liver 1 (2%) 

Stomach, forestomach (50) (48) (49) (50) 

Squamous cell carcinoma 1 (2%) 

Squamous cell papilloma 1 (2%) 2 (4%) 4 (8%) 

Cardiovascular System 

Heart (50) (49) (50) (50) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 2 (4%) 

Hemangioma 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 189 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 2 (4%) 

Capsule, adenoma 1 (2%) 

Adrenal medulla (50) (49) (50) (49) 

Pheochromocytoma malignant 1 (2%) 

Pheochromocytoma benign 1 (2%) 1 (2%) 

Pituitary gland (49) (47) (47) (48) 

Pars distalis, adenoma 1 (2%) 

Thyroid gland (50) (49) (50) (50) 

Follicular cell, adenoma 1 (2%) 1 (2%) 1 (2%) 1 (2%) 

General Body System 

None 

Genital System 

Epididymis (50) (49) (50) (50) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Leiomyoma 1 (2%) 

Leiomyosarcoma 1 (2%) 

Preputial gland (50) (47) (47) (50) 

Hemangiosarcoma 2 (4%) 

Prostate (49) (48) (48) (49) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Seminal vesicle (49) (48) (49) (48) 

Sarcoma, metastatic, liver 1 (2%) 

Testes (50) (49) (50) (50) 

Hemangiosarcoma 1 (2%) 

Interstitial cell, adenoma 1 (2%) 

Hematopoietic System 

Bone marrow (50) (49) (50) (50) 

Hemangiosarcoma 1 (2%) 2 (4%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Lymph node (1) (2) (3) 

Renal, hemangiosarcoma 1 (33%) 

Lymph node, bronchial (32) (23) (33) (28) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 4 (14%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (4%) 

Histiocytic sarcoma 1 (3%) 

Lymph node, mandibular (32) (28) (27) (34) 

Histiocytic sarcoma 1 (4%) 

Lymph node, mesenteric (47) (48) (46) (48) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 

Lymph node, mediastinal (34) (38) (37) (37) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (3%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (3%) 

Sarcoma, metastatic, liver 1 (3%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

190 Chloroprene, NTP TR 467 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Hematopoietic System (continued) 

Spleen (50) (49) (50) (50) 

Hemangiosarcoma 2 (4%) 2 (4%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Thymus (34) (28) (25) (34) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (3%) 

Integumentary System 

Skin (49) (48) (50) (50) 

Subcutaneous tissue, hemangiosarcoma 1 (2%) 3 (6%) 1 (2%) 7 (14%) 

Subcutaneous tissue, hemangiosarcoma, 

multiple 1 (2%) 

Subcutaneous tissue, histiocytic sarcoma 1 (2%) 1 (2%) 

Subcutaneous tissue, sarcoma, multiple 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (2%) 

Hemangiosarcoma 1 (2%) 

Skeletal muscle (1) 

Hepatocholangiocarcinoma, metastatic, liver 1 (100%) 

Nervous System 

None 

Respiratory System 

Larynx (50) (47) (50) (50) 

Lung (50) (50) (50) (50) 

Alveolar/bronchiolar adenoma 8 (16%) 12 (24%) 15 (30%) 15 (30%) 

Alveolar/bronchiolar adenoma, multiple 6 (12%) 7 (14%) 13 (26%) 

Alveolar/bronchiolar carcinoma 4 (8%) 8 (16%) 13 (26%) 13 (26%) 

Alveolar/bronchiolar carcinoma, multiple 2 (4%) 4 (8%) 10 (20%) 15 (30%) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hemangiosarcoma, metastatic, skin 1 (2%) 

Hepatoblastoma, metastatic, liver 1 (2%) 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 8 (16%) 10 (20%) 5 (10%) 4 (8%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Sarcoma, metastatic, liver 1 (2%) 

Bronchiole, adenoma 1 (2%) 

Mediastinum, alveolar/bronchiolar carcinoma, 

metastatic, lung 4 (8%) 

Mediastinum, hepatocholangiocarcinoma, 

metastatic, liver 1 (2%) 1 (2%) 

Nose (50) (48) (50) (50) 

Adenoma 1 (2%) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (2%) 

Carcinoma, metastatic, harderian gland 1 (2%) 

Respiratory epithelium, adenoma 1 (2%) 

Trachea (50) (48) (50) (50) 

Adenoma 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

191 

c 

Chloroprene, NTP TR 467 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Special Senses System 

Harderian gland

Adenoma

Carcinoma

Bilateral, adenoma

 (2)

 2 (100%)

 (5) 

 5 (100%)

(11) 

 8 (73%) 

 2 (18%) 

(12) 

 9 (75%) 

 2 (17%) 

 1 (8%) 

Urinary System 

Kidney 

Alveolar/bronchiolar carcinoma, metastatic, 

lung

Hemangiosarcoma

Hemangiosarcoma, metastatic, mesentery

Hepatocholangiocarcinoma, metastatic, liver

Histiocytic sarcoma

Renal tubule, adenoma

(50) 

 1 (2%) 

(49) 

 1 (2%) 

(50) 

 4 (8%) 

 1 (2%) 

 1 (2%) 

(50) 

 1 (2%) 

 1 (2%) 

 1 (2%) 

 3 (6%) 

Systemic Lesions 

Multiple organsb 

Histiocytic sarcoma

Lymphoma malignant

(50) 

 3 (6%) 

 2 (4%) 

(50) 

 2 (4%) 

(50) 

 2 (4%) 

 2 (4%) 

(50) 

 1 (2%) 

 4 (8%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

Total primary neoplasms 

Total animals with benign neoplasms 

Total benign neoplasms 

Total animals with malignant neoplasms 

Total malignant neoplasms 

Total animals with metastatic neoplasms 

Total metastatic neoplasms 

48 

78 

31 

38 

34 

40 

8 

8 

48 

106 

31 

43 

40 

63 

13 

22 

50 

156 

38 

59 

50 

97 

12 

14 

50 

172 

43 

72 

47 

100 

12 

31 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

192 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

Number of Days on Study 

4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 

5 3 5 7 9 0 0 0 2 2 3 3 3 6 6 7 8 8 8 1 2 2 2 3 3 

2 5 3 0 6 3 6 7 7 8 5 5 8 4 6 4 0 4 4 9 2 9 9 3 3 

Carcass ID Number 

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 

4 1 4 4 3 0 0 3 1 1 1 4 3 1 2 2 3 4 4 3 2 0 4 0 0 

9 3 2 7 5 8 1 3 9 2 1 3 7 5 0 8 0 5 6 4 7 4 1 2 3 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Muscularis, leiomyoma 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

Tooth 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

A M A A + + + M A M + + M + + + + + + + + + + + + 

+ + A + + + + + A + + + + + + + + + + + + + + + + 

+ + + A + + + + A A + + + + + + + + + + + + + + + 

+ + A + + + + + A + + + + + + + + + + + + + + + + 

M + A A + + + + A M + + + + + + + + + + + + + + + 

+ + A A + + + + A A + + + + + + + + + + + + + + + 

+ + A A + + + + A A + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X 

X X X X X X X X X 

X X X X 

X X X X X 

X 

+ 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + M + + + + + + + + M M M + + + + M + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + A + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Interstitial cell, adenoma X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 193 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 

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 

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 0 0 0 0 1 2 2 2 2 3 3 3 3 3 4 1 1 1 1 2 2 2 4 4 5 Tissues/ 

5 6 7 9 7 2 3 5 9 1 2 6 8 9 8 0 4 6 8 1 4 6 0 4 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + I + + + + + + 41 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Muscularis, leiomyoma X 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X X 2 

Hepatocellular carcinoma X 10 

Hepatocellular carcinoma, multiple X X X X X 14 

Hepatocellular adenoma X X X X 8 

Hepatocellular adenoma, multiple X X X X X X X X X 14 

Histiocytic sarcoma 1 

Mesentery + 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Tooth 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma malignant X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + M + + M + M I + M M + M I M + + M + + 35 

Pituitary gland + + M + + + + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma 1 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + M + + + + + + + + + + + + + + + + + + + + + + + 49 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Interstitial cell, adenoma 1 

50 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

194 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 

Number of Days on Study 5 

2 

3 

5 

5 

3 

7 

0 

9 

6 

0 

3 

0 

6 

0 

7 

2 

7 

2 

8 

3 

5 

3 

5 

3 

8 

6 

4 

6 

6 

7 

4 

8 

0 

8 

4 

8 

4 

1 

9 

2 

2 

2 

9 

2 

9 

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 

Carcass ID Number 4 1 4 4 3 0 0 3 1 1 1 4 3 1 2 2 3 4 4 3 2 0 4 0 0 

9 3 2 7 5 8 1 3 9 2 1 3 7 5 0 8 0 5 6 4 7 4 1 2 3 

Hematopoietic System 

Bone marrow 

Histiocytic sarcoma 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Histiocytic sarcoma 

Lymph node, mediastinal 

Spleen 

Histiocytic sarcoma 

Thymus 

+ 

M 

+ 

+ 

M 

+ 

+ 

+ 

M 

M 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

M 

+ 

+ 

M 

M 

M 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

M 

+ 

X 

M 

M 

+ 

X 

M 

+ 

X 

M 

+ 

M 

M 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

M 

M 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

I 

+ 

+ 

M 

+ 

X 

+ 

+ 

I 

+ 

+ 

+ 

M 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

M 

+ 

M 

M 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

M 

M 

+ 

+ 

+ 

M 

Integumentary System 

Mammary gland 

Skin 

Subcutaneous tissue, hemangiosarcoma 

Subcutaneous tissue, histiocytic sarcoma 

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 

+ 

M 

+ 

Musculoskeletal System 

Bone 

Hemangiosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + 

Respiratory System 

Larynx + 

Lung + 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Nose + 

Trachea + 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

X 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Urinary System 

Kidney + 

Histiocytic sarcoma 

Ureter 

Urinary bladder + 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Systemic Lesions 

Multiple organs + 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + 

X 

+ + + + + + + + + 

X 

+ + 

X 

+ + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 195 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 

3 

3 

3 

3 

3 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

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 0 

5 

0 

6 

0 

7 

0 

9 

1 

7 

2 

2 

2 

3 

2 

5 

2 

9 

3 

1 

3 

2 

3 

6 

3 

8 

3 

9 

4 

8 

1 

0 

1 

4 

1 

6 

1 

8 

2 

1 

2 

4 

2 

6 

4 

0 

4 

4 

5 

0 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Histiocytic sarcoma

Lymph node, mediastinal 

Spleen 

Histiocytic sarcoma

Thymus 

M + + + + + + + M M + + + + M + + + + + M + + + M 

M M + M + + I M + + + + + M + + + M + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + M + + M M + M + + M + M + + M + + + M M + + M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

M + + M M M + + M + M + + + + + M + + + + + + + + 

1 

32 

32 

47 

2 

34 

50 

1 

34 

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

+ + + + + + + + + + + + + + + + + + + + + + + + + 

1 

49 

Subcutaneous tissue, hemangiosarcoma 

Subcutaneous tissue, histiocytic sarcoma X 

X 1 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X

X X X

X 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

8 

4 

2 

8 

1 

50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

+

+

X

 1 

2 

2 

Urinary System 

Kidney 

Histiocytic sarcoma

Ureter 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

50 

1 

1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

50 

3 

2 
 

 

 

 

 

 

 

 

 

 

 

196 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 3 2 3 4 7 8 8 9 0 1 2 3 3 3 5 6 8 8 9 9 0 0 2 3 3 

9 3 0 6 9 2 3 6 7 4 6 5 5 8 9 7 0 8 1 1 1 8 2 3 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 2 

Carcass ID Number 3 1 4 0 1 0 1 1 4 3 4 1 2 2 4 5 3 2 1 3 4 4 2 0 0 

7 4 5 9 7 1 2 8 4 8 2 9 4 9 7 0 3 1 1 9 8 6 3 2 4 

Alimentary System 

Esophagus + + A + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + A A A + M + + + + A + + M + + A + + A + + + + + 

Intestine large, colon + A A A + + + + + + A + + + + + + + + + + + + + + 

Intestine large, rectum + A A + + + + + M + A + + + + + + + + + + + + + + 

Intestine large, cecum + A A A + + + + + + A + + + + + A + + A + + + + + 

Hemangioma 

Intestine small, duodenum + A A A + + + + + + A + + + + + A + + A + + + + + 

Intestine small, jejunum + A A A + + A + + + A + + + + + A + + A + + + + + 

Intestine small, ileum + A A A + + + + + + A + + + + + + + + A + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X X X 

Hepatoblastoma X 

Hepatocellular carcinoma X X X X X X X X X X X X 

Hepatocellular carcinoma, multiple X X X X X 

Hepatocellular adenoma X X X X X 

Hepatocellular adenoma, multiple X 

Hepatocholangiocarcinoma X 

Sarcoma X 

Mesentery + + + + + 

Hemangiosarcoma X 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma, metastatic, liver X 

Pancreas + A A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma, metastatic, liver X 

Salivary glands + + A + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + A A + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + A A + + + + + + + + + + + + + + + + + + + + + + 

Tooth 

Cardiovascular System 

Blood vessel 

Heart + + A 

+ 

+ + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + A + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + A + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + A A + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + A + + + + + + + + + + M + M M + + M M M + M M 

Pituitary gland + + A I + + + + + + + + + + + + + + + + + + + + + 

Thyroid gland + + A + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 197 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 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 Total 

Carcass ID Number 0 0 1 1 1 2 2 2 2 3 3 3 3 3 4 4 4 0 0 0 1 2 2 3 4 Tissues/ 

5 6 0 3 5 0 2 7 8 0 1 2 5 6 0 3 9 3 7 8 6 5 6 4 1 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Gallbladder + + + + + + + + + + + + + M + + + + + M + + + + + 40 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Hemangioma X 1 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 43 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 45 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X X 5 

Hepatoblastoma X 2 

Hepatocellular carcinoma X X X X X X 18 

Hepatocellular carcinoma, multiple X X X X X 10 

Hepatocellular adenoma X X X X X X 11 

Hepatocellular adenoma, multiple X X X X 5 

Hepatocholangiocarcinoma 1 

Sarcoma 1 

Mesentery + + + 8 

Hemangiosarcoma X X 3 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma, metastatic, liver 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangiosarcoma 1 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma, metastatic, liver 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Tooth + + 2 

Cardiovascular System 

Blood vessel + 2 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Parathyroid gland + + + M I + M + M + I + + M M + M + M + + + + + + 32 

Pituitary gland + + + + + + + + + + M + + + + + + + + + + + + + + 47 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Follicular cell, adenoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

198 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 3 2 3 4 7 8 8 9 0 1 2 3 3 3 5 6 8 8 9 9 0 0 2 3 3 

9 3 0 6 9 2 3 6 7 4 6 5 5 8 9 7 0 8 1 1 1 8 2 3 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 2 

Carcass ID Number 3 1 4 0 1 0 1 1 4 3 4 1 2 2 4 5 3 2 1 3 4 4 2 0 0 

7 4 5 9 7 1 2 8 4 8 2 9 4 9 7 0 3 1 1 9 8 6 3 2 4 

Genital System 

Epididymis + + A + + + + + + + + + + + + + + + + + + + + + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Preputial gland + + M + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + A + + + + + + + + + + M + + + + + + + + + + + 

Seminal vesicle + A A + + + + + + + + + + + + + + + + + + + + + + 

Sarcoma, metastatic, liver X 

Testes + + A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Hematopoietic System 

Bone marrow + + A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Lymph node 

Lymph node, bronchial M + M M + + M M M M M + + M M M M + M M + M + + M 

Lymph node, mandibular + + A + + + M + M + + + + M M + + M M + M M + M + 

Lymph node, mesenteric + A A + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mediastinal M + A M + + + + + + + + + + + M + M + M + + + + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma, metastatic, liver X 

Spleen + + A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Thymus M + 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 + + A + + + + + + + + + + + + + + + + + + + + + M 

Subcutaneous tissue, hemangiosarcoma X X 

Subcutaneous tissue, hemangiosarcoma, multiple X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + A + + + + + + + + + + + + + + + + + + + + + + 

Spinal cord 

Respiratory System 

Larynx + A A + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X X X X X 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma X X 

Alveolar/bronchiolar carcinoma, multiple X X 

Hemangiosarcoma, metastatic, skin X 

Hepatocellular carcinoma, metastatic, liver X X X X X X 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma, metastatic, liver X 

Mediastinum, hepatocholangiocarcinoma,

 metastatic, liver X 

Nose + A A + + + + + + + + + + + + + + + + + + + + + + 

Trachea + A A + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 199 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 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 Total 

Carcass ID Number 0 0 1 1 1 2 2 2 2 3 3 3 3 3 4 4 4 0 0 0 1 2 2 3 4 Tissues/ 

5 6 0 3 5 0 2 7 8 0 1 2 5 6 0 3 9 3 7 8 6 5 6 4 1 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hepatocholangiocarcinoma, metastatic, liver 1 

Preputial gland + + + + + M + + + + + + + + + + + + M + + + + + + 47 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Sarcoma, metastatic, liver 1 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma X 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma X 1 

Lymph node + 1 

Lymph node, bronchial M + M + + M + M M M M M + M + + + + + M + + + + M 23 

Lymph node, mandibular + M + M + + M + + M M M + M + M M + + M + + I M + 28 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Lymph node, mediastinal + M + + + + I + + + + + + + + + + M M + + M + + M 38 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma, metastatic, liver 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma X X 2 

Thymus + M + + + M I + M + M M + + + M M + + + M I + + + 28 

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 + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Subcutaneous tissue, hemangiosarcoma X 3 

Subcutaneous tissue, hemangiosarcoma, multiple 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spinal cord + 1 

Respiratory System 

Larynx M + + + + + + + + + + + + + + + + + + + + + + + + 47 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X X X X X 12 

Alveolar/bronchiolar adenoma, multiple X X X X X X 6 

Alveolar/bronchiolar carcinoma X X X X X X 8 

Alveolar/bronchiolar carcinoma, multiple X X 4 

Hemangiosarcoma, metastatic, skin 1 

Hepatocellular carcinoma, metastatic, liver X X X X 10 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma, metastatic, liver 1 

Mediastinum, hepatocholangiocarcinoma,

 metastatic, liver 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma 1 
 

 

 

200 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 

Number of Days on Study 3 2 3 4 7 8 8 9 0 1 2 3 3 3 5 6 8 8 9 9 0 0 2 3 3 

9 3 0 6 9 2 3 6 7 4 6 5 5 8 9 7 0 8 1 1 1 8 2 3 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 2 

Carcass ID Number 3 1 4 0 1 0 1 1 4 3 4 1 2 2 4 5 3 2 1 3 4 4 2 0 0 

7 4 5 9 7 1 2 8 4 8 2 9 4 9 7 0 3 1 1 9 8 6 3 2 4 

Special Senses System 

Eye + 

Harderian gland + 

Adenoma X 

Urinary System 

Kidney + + A + + + + + + + + + + + + + + + + + + + + + + 

Renal tubule, adenoma X 

Urinary bladder + A A + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymphoma malignant 
 

 

 

 

Chloroprene, NTP TR 467 201 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 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 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 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 Total 

Carcass ID Number 0 0 1 1 1 2 2 2 2 3 3 3 3 3 4 4 4 0 0 0 1 2 2 3 4 Tissues/ 

5 6 0 3 5 0 2 7 8 0 1 2 5 6 0 3 9 3 7 8 6 5 6 4 1 Tumors 

Special Senses System 

Eye 1 

Harderian gland + + + + 5 

Adenoma X X X X 5 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Renal tubule, adenoma 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymphoma malignant X X 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

202 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

3 4 4 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 

8 3 7 9 9 0 4 5 6 6 7 9 0 0 0 0 0 2 2 2 3 4 6 6 6 

2 9 0 1 5 2 5 1 5 7 9 6 2 6 7 7 7 0 3 9 5 9 3 6 6 

Carcass ID Number 

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 1 2 1 0 4 4 3 4 2 5 3 2 3 0 0 3 1 4 0 0 0 2 2 3 

3 9 4 0 8 4 1 3 0 1 0 4 0 8 3 6 6 5 5 7 4 2 8 5 1 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Cholangiocarcinoma 

Hemangiosarcoma 

Hepatoblastoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Hemangioma 

Hemangiosarcoma 

Pancreas 

Hemangiosarcoma, metastatic, mesentery 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ M A + M + M + + + + M + A + A + + + + + + A + + 

+ + A + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + A + + + M + + + + + 

+ + A + + + + + + + + + + A + M + + + + + + A + + 

+ + A + + + + + + + + + + A + A + + + + + + A + + 

+ + A + + + + + + + + + + A + A + + + + + + + + + 

+ + A + + + + + + + + + + + + A + + + + + + A + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X X 

X X X X X X X X X X 

X X X X X X X X X 

X X X X 

X X 

X 

+ + + + + 

X 

X X X 

+ + A + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + A + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel 

Heart 

Hemangioma 

+ 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + A + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + M + M M + M M + M + M + + + M M + + M M + + + M 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma X 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 203 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

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 

Number of Days on Study 7 7 8 8 8 9 0 0 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 9 0 8 8 3 1 5 3 5 7 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 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 3 3 4 1 2 2 4 1 0 1 2 0 0 2 4 1 1 1 1 2 3 3 3 4 4 Tissues/ 

0 2 9 8 6 7 8 1 5 6 2 1 9 3 2 2 3 4 7 9 5 7 9 6 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + M + + + + + + + A M M + + + + + + M + + + + + + 37 

Intestine large, colon + + + + + + + + + A + + + + + + + + + + + + + + + 48 

Intestine large, rectum + + + + A M + + + + + + + + + + + + + + + + + + + 46 

Intestine large, cecum + + + + + + + + + A + + + + + + + + + + + + + + + 45 

Intestine small, duodenum + + + + A + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine small, ileum + + + + A + + + + + + + + + + + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cholangiocarcinoma X 1 

Hemangiosarcoma X X X 6 

Hepatoblastoma X 3 

Hepatocellular carcinoma X X X X X X X X 18 

Hepatocellular carcinoma, multiple X X X X X X X X X X 19 

Hepatocellular adenoma X X X X X X X X 12 

Hepatocellular adenoma, multiple X X X X X 7 

Histiocytic sarcoma 1 

Mesentery + + + + + + + + + + + 16 

Hemangioma 1 

Hemangiosarcoma X X X X X X X X X X 13 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma, metastatic, mesentery X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Squamous cell papilloma X X 2 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel 1 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Parathyroid gland M + + + M + + M + + + M + + + + M + M + + M + + + 31 

Pituitary gland + + + + M + + + + + + M + + + + + + + + + M + + + 47 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

204 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

3 

8 

2 

4 

3 

9 

4 

7 

0 

4 

9 

1 

4 

9 

5 

5 

0 

2 

5 

4 

5 

5 

5 

1 

5 

6 

5 

5 

6 

7 

5 

7 

9 

5 

9 

6 

6 

0 

2 

6 

0 

6 

6 

0 

7 

6 

0 

7 

6 

0 

7 

6 

2 

0 

6 

2 

3 

6 

2 

9 

6 

3 

5 

6 

4 

9 

6 

6 

3 

6 

6 

6 

6 

6 

6 

Carcass ID Number 

4 

4 

3 

4 

1 

9 

4 

2 

4 

4 

1 

0 

4 

0 

8 

4 

4 

4 

4 

4 

1 

4 

3 

3 

4 

4 

0 

4 

2 

1 

4 

5 

0 

4 

3 

4 

4 

2 

0 

4 

3 

8 

4 

0 

3 

4 

0 

6 

4 

3 

6 

4 

1 

5 

4 

4 

5 

4 

0 

7 

4 

0 

4 

4 

0 

2 

4 

2 

8 

4 

2 

5 

4 

3 

1 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, mesentery X 

Leiomyoma X 

Leiomyosarcoma 

Penis + 

Preputial gland + + + + + + + + I + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + M + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, mesentery X 

Seminal vesicle + + A + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Lymph node + + 

Lymph node, bronchial + + + M M + + M + M + M + + M + M + + + M + + I + 

Histiocytic sarcoma X 

Lymph node, mandibular + M M + + M + + M M M + M M M M + M + + M + M M + 

Histiocytic sarcoma X 

Lymph node, mesenteric + + M + + I + + + + + + + + + + + + + + + + + M + 

Hemangiosarcoma 

Histiocytic sarcoma X 

Lymph node, mediastinal + M M + + + + + M + + + + M + M + M + M + + + + M 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X 

Thymus M + + + M + M M + M + + + + + M M M M M M + M I + 

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 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma X 

Subcutaneous tissue, histiocytic sarcoma X 

Subcutaneous tissue, sarcoma, multiple X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 205 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

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 

Number of Days on Study 7 7 8 8 8 9 0 0 1 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 9 0 8 8 3 1 5 3 5 7 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 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 3 3 4 1 2 2 4 1 0 1 2 0 0 2 4 1 1 1 1 2 3 3 3 4 4 Tissues/ 

0 2 9 8 6 7 8 1 5 6 2 1 9 3 2 2 3 4 7 9 5 7 9 6 7 Tumors 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma, metastatic, mesentery 1 

Leiomyoma 1 

Leiomyosarcoma X 1 

Penis 1 

Preputial gland + + + M + + + + + + + + + + + + + + + + + + M + + 47 

Prostate + + + + + + + + + + + + + + + + + + + M + + + + + 48 

Hemangiosarcoma, metastatic, mesentery 1 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 2 

Lymph node 2 

Lymph node, bronchial + + + + + M + + M + + + + M + + M + + M M + M + M 33 

Histiocytic sarcoma 1 

Lymph node, mandibular M + M M M + + + + M M + M + + + + + M + M + + + + 27 

Histiocytic sarcoma 1 

Lymph node, mesenteric + + + + + + + + + M + + + + + + + + + + + + + + + 46 

Hemangiosarcoma X 1 

Histiocytic sarcoma 1 

Lymph node, mediastinal M + + + M + + M + M + + + + + M + + + + + + + + + 37 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 2 

Histiocytic sarcoma 1 

Thymus + M M + M M + M M I M + + + + + + + + + + M M M M 25 

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 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Subcutaneous tissue, hemangiosarcoma 1 

Subcutaneous tissue, histiocytic sarcoma 1 

Subcutaneous tissue, sarcoma, multiple 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

206 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

3 4 4 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 

2 

3 

9 

7 

0 

9 

1 

9 

5 

0 

2 

4 

5 

5 

1 

6 

5 

6 

7 

7 

9 

9 

6 

0 

2 

0 

6 

0 

7 

0 

7 

0 

7 

2 

0 

2 

3 

2 

9 

3 

5 

4 

9 

6 

3 

6 

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 4 1 2 1 0 4 4 3 4 2 5 3 2 3 0 0 3 1 4 0 0 0 2 2 3 

3 9 4 0 8 4 1 3 0 1 0 4 0 8 3 6 6 5 5 7 4 2 8 5 1 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Hepatoblastoma, metastatic, liver 

Hepatocellular carcinoma, metastatic, liver 

Bronchiole, adenoma 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X 

X 

X X X X X 

X X X 

X 

X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, harderian gland 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

+ 

X 

+ 

X 

+ + 

Carcinoma X 

Urinary System 

Kidney 

Hemangiosarcoma, metastatic, mesentery 

Histiocytic sarcoma 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

I + + + + + + M + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 207 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

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 

Number of Days on Study 7 

9 

7 

9 

8 

0 

8 

8 

8 

8 

9 

3 

0 

1 

0 

5 

1 

3 

1 

5 

1 

7 

3 

3 

3 

3 

3 

3 

3 

3 

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 3 

0 

3 

2 

4 

9 

1 

8 

2 

6 

2 

7 

4 

8 

1 

1 

0 

5 

1 

6 

2 

2 

0 

1 

0 

9 

2 

3 

4 

2 

1 

2 

1 

3 

1 

4 

1 

7 

2 

9 

3 

5 

3 

7 

3 

9 

4 

6 

4 

7 

Tissues/ 

Tumors 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Hepatoblastoma, metastatic, liver

Hepatocellular carcinoma, metastatic, liver 

Bronchiole, adenoma 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X 

X X X X X X 

X X X X X X X X 

X X X X X X X 

X X X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

15 

7 

13 

10 

1 

5 

1 

50 

Carcinoma, metastatic, harderian gland 

Trachea 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

1 

50 

Adenoma X 1 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

+ + + 

X X 

+ + 

X X

11 

8 

Carcinoma X 2 

Urinary System 

Kidney 

Hemangiosarcoma, metastatic, mesentery 

Histiocytic sarcoma

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

4 

1 

1 

48 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

50 

2 

2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

208 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

3 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

9 2 5 2 2 6 7 8 8 9 0 0 0 2 2 2 2 3 3 3 4 4 4 4 4 

2 2 4 3 4 7 9 7 9 5 0 3 8 0 4 4 8 5 5 7 4 4 9 9 9 

Carcass ID Number 

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 1 4 1 4 1 2 4 2 3 0 1 3 0 4 3 1 2 3 1 3 2 3 4 

4 2 6 2 1 8 8 8 9 6 4 8 2 8 6 4 5 4 9 6 3 3 3 1 1 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Hemangiosarcoma 

Hepatoblastoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Hepatocholangiocarcinoma 

Mesentery 

Hemangioma 

Hemangiosarcoma 

Oral mucosa 

Gingival, squamous cell carcinoma 

Pancreas 

Hepatocholangiocarcinoma, metastatic, liver 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Squamous cell papilloma 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

M + + + + + + + + + + + + M + + + I + M M + + + + 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X 

X X X X X 

X X X X X X X X X X 

X X X X X X X 

X X X X 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X 

+ + + + + + + + + + + + + A + + + + + + + + + + + 

Cardiovascular System 

Blood vessel 

Heart 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Hepatocholangiocarcinoma, metastatic, liver 

+ 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma, metastatic, lung X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland M M + + M M + + + M + M M M I + + + + + + + M + + 

Pituitary gland + + + + + + + + + + + + + + M + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 209 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

6 

5 

6 

6 

5 

7 

6 

5 

9 

6 

5 

9 

6 

6 

3 

6 

7 

2 

6 

7 

7 

6 

7 

7 

6 

8 

0 

6 

8 

7 

7 

0 

1 

7 

0 

1 

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 

4 

7 

3 

4 

Carcass ID Number 

6 

5 

0 

6 

2 

4 

6 

2 

2 

6 

2 

5 

6 

4 

7 

6 

3 

9 

6 

3 

7 

6 

4 

5 

6 

0 

7 

6 

2 

1 

6 

1 

7 

6 

1 

9 

6 

0 

3 

6 

0 

5 

6 

0 

9 

6 

1 

5 

6 

2 

0 

6 

2 

7 

6 

3 

0 

6 

3 

2 

6 

4 

0 

6 

4 

3 

6 

4 

6 

6 

0 

1 

6 

1 

0 

Total 

Tissues/ 

Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + M + + A + + M + + + + + M + + + + + + + + + M 40 

Intestine large, colon + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Intestine large, rectum + + + M + A + + + + + M + + + M + + + + + + + + + 45 

Intestine large, cecum + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Intestine small, duodenum + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Intestine small, jejunum + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Liver + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Hemangiosarcoma X X X X X 8 

Hepatoblastoma 1 

Hepatocellular carcinoma X X X X X X X X X X X 16 

Hepatocellular carcinoma, multiple X X X X X X X 17 

Hepatocellular adenoma X X X X 11 

Hepatocellular adenoma, multiple X X X X X X 10 

Hepatocholangiocarcinoma X 1 

Mesentery + + + + + + + + + + 11 

Hemangioma X X 2 

Hemangiosarcoma X X X X X X 7 

Oral mucosa + 1 

Gingival, squamous cell carcinoma X 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocholangiocarcinoma, metastatic, liver X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell carcinoma 1 

Squamous cell papilloma X 4 

Stomach, glandular + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Cardiovascular System 

Blood vessel 1 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma, metastatic, lung X 2 

Hepatocholangiocarcinoma, metastatic, liver X 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma, metastatic, lung X 2 

Adrenal medulla + + + + + A + + + + + + + + + + + + + + + + + + + 49 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland M M + + + + + + M + M + M M + M + + M + M + M + + 30 

Pituitary gland + + + + + + + + + M + + + + + + + + + + + + + + + 48 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

210 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

3 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 

2 

2 

2 

5 

4 

2 

3 

2 

4 

6 

7 

7 

9 

8 

7 

8 

9 

9 

5 

0 

0 

0 

3 

0 

8 

2 

0 

2 

4 

2 

4 

2 

8 

3 

5 

3 

5 

3 

7 

4 

4 

4 

4 

4 

9 

4 

9 

4 

9 

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 0 1 4 1 4 1 2 4 2 3 0 1 3 0 4 3 1 2 3 1 3 2 3 4 

4 2 6 2 1 8 8 8 9 6 4 8 2 8 6 4 5 4 9 6 3 3 3 1 1 

Genital System 

Epididymis 

Histiocytic sarcoma 

Preputial gland 

Hemangiosarcoma 

Prostate 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + M + + + + + 

Seminal vesicle + + + + + + + + + + + + + A + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Lymph node 

Renal, hemangiosarcoma 

Lymph node, bronchial 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Hepatocholangiocarcinoma, metastatic, liver 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Spleen 

Hemangiosarcoma 

Thymus 

Alveolar/bronchiolar carcinoma, metastatic, lung 

X 

+ 

+ + + + M M + M + + + M M + M M + M + + + + M + + 

X X 

+ + + M M + + + M M + M + + + + + + + + + + M + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + M M + M + + + M I + + + + + + + + + + + + M 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

I M + + M M M + M + + + + + M M M + + + + + + I + 

X 

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 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma X X X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Skeletal muscle 

Hepatocholangiocarcinoma, metastatic, liver 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 211 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 5 

6 

5 

7 

5 

9 

5 

9 

6 

3 

7 

2 

7 

7 

7 

7 

8 

0 

8 

7 

0 

1 

0 

1 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

4 

3 

4 

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 Total 

Carcass ID Number 5 

0 

2 

4 

2 

2 

2 

5 

4 

7 

3 

9 

3 

7 

4 

5 

0 

7 

2 

1 

1 

7 

1 

9 

0 

3 

0 

5 

0 

9 

1 

5 

2 

0 

2 

7 

3 

0 

3 

2 

4 

0 

4 

3 

4 

6 

0 

1 

1 

0 

Tissues/ 

Tumors 

Genital System 

Epididymis 

Histiocytic sarcoma 

Preputial gland 

Hemangiosarcoma 

Prostate 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

50 

2 

49 

Seminal vesicle + + + + + A + + + + + + + + + + + + + + + + + + + 48 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma

Lymph node 

Renal, hemangiosarcoma 

Lymph node, bronchial 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Hepatocholangiocarcinoma, metastatic, liver 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Spleen 

Hemangiosarcoma

Thymus 

Alveolar/bronchiolar carcinoma, metastatic, lung

+ +

X

M + M M + M M + M + + M M + + + M M M + + M + + M 

X X 

X

+ + + + M + + M M M M M + + + M M + M M + + + + + 

+ + + + + + + + M M + + + + + + + + + + + + + + + 

M + M + + + + M M + + + + M + + + I + M + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ M + + + + + + M + M M + + + M + + I + + + + + + 

1 

3 

1 

28 

4 

1 

34 

48 

37 

1 

50 

1 

34 

1 

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 M

+ + + + + + + + + + + + + + + + + + + + + + + + + 

1 

50 

Subcutaneous tissue, hemangiosarcoma X X X X 7 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Skeletal muscle 

X 

+

1 

1 

Hepatocholangiocarcinoma, metastatic, liver X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

212 Chloroprene, NTP TR 467 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

3 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 9 2 5 2 2 6 7 8 8 9 0 0 0 2 2 2 2 3 3 3 4 4 4 4 4 

2 2 4 3 4 7 9 7 9 5 0 3 8 0 4 4 8 5 5 7 4 4 9 9 9 

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 0 1 4 1 4 1 2 4 2 3 0 1 3 0 4 3 1 2 3 1 3 2 3 4 

4 2 6 2 1 8 8 8 9 6 4 8 2 8 6 4 5 4 9 6 3 3 3 1 1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X X X X X X X X X 

Alveolar/bronchiolar adenoma, multiple X X X 

Alveolar/bronchiolar carcinoma X X X X X 

Alveolar/bronchiolar carcinoma, multiple X X X X X X 

Hemangiosarcoma, metastatic, mesentery 

Hepatoblastoma, metastatic, liver X 

Hepatocellular carcinoma, metastatic, liver X X X 

Hepatocholangiocarcinoma, metastatic, liver 

Mediastinum, alveolar/bronchiolar

 carcinoma, metastatic, lung X X X 

Mediastinum, hepatocholangiocarcinoma,

 metastatic, liver 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Respiratory epithelium, adenoma 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Harderian gland M + + + 

Adenoma X X X 

Carcinoma 

Bilateral, adenoma 

Zymbal's gland M 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Hemangiosarcoma X 

Hepatocholangiocarcinoma, metastatic, liver 

Renal tubule, adenoma X 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Lymphoma malignant X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 213 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 5 5 5 5 6 7 7 7 8 8 0 0 3 3 3 3 3 3 3 3 3 3 3 3 3 

6 7 9 9 3 2 7 7 0 7 1 1 3 3 3 3 3 3 3 3 3 3 3 4 4 

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 Total 

Carcass ID Number 5 2 2 2 4 3 3 4 0 2 1 1 0 0 0 1 2 2 3 3 4 4 4 0 1 Tissues/ 

0 4 2 5 7 9 7 5 7 1 7 9 3 5 9 5 0 7 0 2 0 3 6 1 0 Tumors 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X X X X 15 

Alveolar/bronchiolar adenoma, multiple X X X X X X X X X X 13 

Alveolar/bronchiolar carcinoma X X X X X X X X 13 

Alveolar/bronchiolar carcinoma, multiple X X X X X X X X X 15 

Hemangiosarcoma, metastatic, mesentery X 1 

Hepatoblastoma, metastatic, liver 1 

Hepatocellular carcinoma, metastatic, liver X 4 

Hepatocholangiocarcinoma, metastatic, liver X 1 

Mediastinum, alveolar/bronchiolar

 carcinoma, metastatic, lung X 4 

Mediastinum, hepatocholangiocarcinoma,

 metastatic, liver X 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Respiratory epithelium, adenoma X 1 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + 1 

Harderian gland + + + M + + + + + + 12 

Adenoma X X X X X X 9 

Carcinoma X X 2 

Bilateral, adenoma X 1 

Zymbal's gland M M 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Hemangiosarcoma 1 

Hepatocholangiocarcinoma, metastatic, liver X 1 

Renal tubule, adenoma X X 3 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 

Lymphoma malignant X 4 
214 Chloroprene, NTP TR 467 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Harderian Gland: Adenoma a Overall rate 2/50 (4%) 5/50 (10%) 8/50 (16%) 10/50 (20%) 

Adjusted rateb 5.8% 17.7% 36.8% 46.4% c Terminal rate 1/27 (4%) 4/27 (15%) 4/14 (29%) 4/13 (31%) 

First incidence (days) 596 701 596 589 

d Life table test P<0.001 P=0.213 P=0.009 P=0.001 

Logistic regression testd P=0.004 P=0.205 P=0.035 P=0.007 

Cochran-Armitage testd P=0.013 

d Fisher exact test P=0.218 P=0.046 P=0.014 

Harderian Gland: Adenoma or Carcinoma 

Overall rate 2/50 (4%) 5/50 (10%) 10/50 (20%) 12/50 (24%) 

Adjusted rate 5.8% 17.7% 42.3% 58.3% 

Terminal rate 1/27 (4%) 4/27 (15%) 4/14 (29%) 6/13 (46%) 

First incidence (days) 596 701 596 589 

Life table test P<0.001 P=0.213 P=0.002 P<0.001 

Logistic regression test P<0.001 P=0.205 P=0.010 P=0.001 

Cochran-Armitage test P=0.003 

Fisher exact test P=0.218 P=0.014 P=0.004 

Kidney (Renal Tubule): Adenoma (Single Section) 

Overall rate 0/50 (0%) 1/49 (2%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 0.0% 3.6% 7.1% 13.8% 

Terminal rate 0/27 (0%) 0/27 (0%) 1/14 (7%) 1/13 (8%) e First incidence (days) — 722 733 (T) 587 

Life table test P=0.014 P=0.486 P=0.369 P=0.060 

Logistic regression test P=0.039 P=0.492 P=0.369 P=0.121 

Cochran-Armitage test P=0.060 

Fisher exact test P=0.495 P=0.500 P=0.121 

Kidney (Renal Tubule): Adenoma (Step Section) 

Overall rate 0/50 (0%) 1/49 (2%) 2/50 (4%) 6/50 (12%) 

Adjusted rate 0.0% 3.7% 12.9% 30.2% 

Terminal rate 0/27 (0%) 1/27 (4%) 1/14 (7%) 2/13 (15%) 

First incidence (days) — 733 (T) 715 567 

Life table test P<0.001 P=0.500 P=0.111 P=0.003 

Logistic regression test P<0.001 P=0.500 P=0.135 P=0.011 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.495 P=0.247 P=0.013 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 0/50 (0%) 2/49 (4%) 3/50 (6%) 9/50 (18%) 

Adjusted rate 0.0% 7.1% 19.6% 40.7% 

Terminal rate 0/27 (0%) 1/27 (4%) 2/14 (14%) 3/13 (23%) 

First incidence (days) — 722 715 567 

Life table test P<0.001 P=0.232 P=0.035 P<0.001 

Logistic regression test P<0.001 P=0.227 P=0.042 P=0.002 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.242 P=0.121 P=0.001 
 

Chloroprene, NTP TR 467 215 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Liver: Hemangiosarcoma 

Overall rate 2/50 (4%) 5/50 (10%) 6/50 (12%) 8/49 (16%) 

Adjusted rate 7.4% 16.3% 25.4% 30.3% 

Terminal rate 2/27 (7%) 3/27 (11%) 2/14 (14%) 1/13 (8%) 

First incidence (days) 733 (T) 659 495 579 

Life table test P=0.003 P=0.219 P=0.039 P=0.008 

Logistic regression test P=0.031 P=0.201 P=0.108 P=0.036 

Cochran-Armitage test P=0.045 

Fisher exact test P=0.218 P=0.134 P=0.043 

Liver: Hepatocellular Adenoma 

Overall rate 22/50 (44%) 16/50 (32%) 19/50 (38%) 21/49 (43%) 

Adjusted rate 64.4% 47.9% 72.3% 67.7% 

Terminal rate 15/27 (56%) 11/27 (41%) 8/14 (57%) 6/13 (46%) 

First incidence (days) 635 439 439 392 

Life table test P=0.006 P=0.175N P=0.090 P=0.044 

Logistic regression test P=0.183 P=0.156N P=0.419 P=0.381 

Cochran-Armitage test P=0.397 

Fisher exact test P=0.151N P=0.342N P=0.535N 

Liver: Hepatocellular Carcinoma 

Overall rate 24/50 (48%) 28/50 (56%) 37/50 (74%) 33/49 (67%) 

Adjusted rate 50.8% 63.2% 91.5% 87.2% 

Terminal rate 6/27 (22%) 12/27 (44%) 11/14 (79%) 9/13 (69%) 

First incidence (days) 452 523 382 392 

Life table test P<0.001 P=0.301 P<0.001 P=0.003 

Logistic regression test P=0.131 P=0.295 P=0.047 P=0.189 

Cochran-Armitage test P=0.033 

Fisher exact test P=0.274 P=0.007 P=0.040 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 43/50 (86%) 37/50 (74%) 42/50 (84%) 41/49 (84%) 

Adjusted rate 87.7% 81.5% 97.5% 94.6% 

Terminal rate 21/27 (78%) 19/27 (70%) 13/14 (93%) 11/13 (85%) 

First incidence (days) 452 439 382 392 

Life table test P=0.002 P=0.272N P=0.014 P=0.015 

Logistic regression test P=0.530 P=0.087N P=0.463N P=0.402N 

Cochran-Armitage test P=0.432 

Fisher exact test P=0.105N P=0.500N P=0.483N 

Liver: Hepatoblastoma 

Overall rate 0/50 (0%) 2/50 (4%) 3/50 (6%) 1/49 (2%) 

Adjusted rate 0.0% 5.7% 12.6% 3.0% 

Terminal rate 0/27 (0%) 1/27 (4%) 0/14 (0%) 0/13 (0%) 

First incidence (days) — 523 607 635 

Life table test P=0.392 P=0.240 P=0.063 P=0.462 

Logistic regression test P=0.591 P=0.254 P=0.116 P=0.540 

Cochran-Armitage test P=0.544 

Fisher exact test P=0.247 P=0.121 P=0.495 
216 Chloroprene, NTP TR 467 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Liver: Hepatocellular Carcinoma or Hepatoblastoma 

Overall rate 24/50 (48%) 29/50 (58%) 39/50 (78%) 34/49 (69%) 

Adjusted rate 50.8% 65.7% 92.1% 87.6% 

Terminal rate 6/27 (22%) 13/27 (48%) 11/14 (79%) 9/13 (69%) 

First incidence (days) 452 523 382 392 

Life table test P<0.001 P=0.253 P<0.001 P=0.002 

Logistic regression test P=0.099 P=0.221 P=0.018 P=0.141 

Cochran-Armitage test P=0.022 

Fisher exact test P=0.212 P=0.002 P=0.025 

Liver: Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastoma 

Overall rate 43/50 (86%) 38/50 (76%) 43/50 (86%) 42/49 (86%) 

Adjusted rate 87.7% 83.8% 97.6% 94.8% 

Terminal rate 21/27 (78%) 20/27 (74%) 13/14 (93%) 11/13 (85%) 

First incidence (days) 452 439 382 392 

Life table test P=0.001 P=0.320N P=0.010 P=0.011 

Logistic regression test P=0.441 P=0.132N P=0.580N P=0.503N 

Cochran-Armitage test P=0.353 

Fisher exact test P=0.154N P=0.613N P=0.597N 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 8/50 (16%) 18/50 (36%) 22/50 (44%) 28/50 (56%) 

Adjusted rate 23.8% 54.8% 68.3% 84.7% 

Terminal rate 4/27 (15%) 13/27 (48%) 6/14 (43%) 9/13 (69%) 

First incidence (days) 635 530 382 523 

Life table test P<0.001 P=0.023 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.016 P=0.002 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.020 P=0.002 P<0.001 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 6/50 (12%) 12/50 (24%) 23/50 (46%) 28/50 (56%) 

Adjusted rate 21.3% 37.9% 76.7% 85.1% 

Terminal rate 5/27 (19%) 8/27 (30%) 8/14 (57%) 9/13 (69%) 

First incidence (days) 729 638 567 524 

Life table test P<0.001 P=0.096 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.075 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.096 P<0.001 P<0.001 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 13/50 (26%) 28/50 (56%) 36/50 (72%) 43/50 (86%) 

Adjusted rate 39.2% 79.4% 89.0% 100.0% 

Terminal rate 8/27 (30%) 20/27 (74%) 10/14 (71%) 13/13 (100%) 

First incidence (days) 635 530 382 523 

Life table test P<0.001 P=0.003 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=0.002 P<0.001 P<0.001 
Chloroprene, NTP TR 467 217 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Mesentery: Hemangiosarcoma 

Overall rate 0/50 (0%) 3/50 (6%) 13/50 (26%) 7/50 (14%) 

Adjusted rate 0.0% 10.1% 51.1% 40.3% 

Terminal rate 0/27 (0%) 2/27 (7%) 4/14 (29%) 4/13 (31%) 

First incidence (days) — 680 502 628 

Life table test P<0.001 P=0.123 P<0.001 P<0.001 

Logistic regression test P=0.006 P=0.114 P<0.001 P=0.001 

Cochran-Armitage test P=0.023 

Fisher exact test P=0.121 P<0.001 P=0.006 

Mesentery: Hemangioma or Hemangiosarcoma 

Overall rate 0/50 (0%) 3/50 (6%) 14/50 (28%) 9/50 (18%) 

Adjusted rate 0.0% 10.1% 52.5% 49.9% 

Terminal rate 0/27 (0%) 2/27 (7%) 4/14 (29%) 5/13 (38%) 

First incidence (days) — 680 502 628 

Life table test P<0.001 P=0.123 P<0.001 P<0.001 

Logistic regression test P=0.001 P=0.114 P<0.001 P<0.001 

Cochran-Armitage test P=0.005 

Fisher exact test P=0.121 P<0.001 P=0.001 

Skin (Subcutaneous Tissue): Hemangiosarcoma 

Overall rate 1/50 (2%) 4/50 (8%) 1/50 (2%) 7/50 (14%) 

Adjusted rate 3.7% 12.3% 3.4% 31.5% 

Terminal rate 1/27 (4%) 1/27 (4%) 0/14 (0%) 2/13 (15%) 

First incidence (days) 733 (T) 659 649 454 

Life table test P=0.002 P=0.183 P=0.659 P=0.005 

Logistic regression test P=0.017 P=0.172 P=0.731 P=0.033 

Cochran-Armitage test P=0.022 

Fisher exact test P=0.181 P=0.753N P=0.030 

Stomach (Forestomach): Squamous Cell Papilloma 

Overall rate 1/50 (2%) 0/50 (0%) 2/50 (4%) 4/50 (8%) 

Adjusted rate 3.7% 0.0% 14.3% 12.7% 

Terminal rate 1/27 (4%) 0/27 (0%) 2/14 (14%) 0/13 (0%) 

First incidence (days) 733 (T) — 733 (T) 587 

Life table test P=0.009 P=0.500N P=0.276 P=0.099 

Logistic regression test P=0.030 P=0.500N P=0.276 P=0.216 

Cochran-Armitage test P=0.037 

Fisher exact test P=0.500N P=0.500 P=0.181 

Stomach (Forestomach): Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 1/50 (2%) 0/50 (0%) 2/50 (4%) 5/50 (10%) 

Adjusted rate 3.7% 0.0% 14.3% 15.3% 

Terminal rate 1/27 (4%) 0/27 (0%) 2/14 (14%) 0/13 (0%) 

First incidence (days) 733 (T) — 733 (T) 587 

Life table test P=0.002 P=0.500N P=0.276 P=0.052 

Logistic regression test P=0.010 P=0.500N P=0.276 P=0.132 

Cochran-Armitage test P=0.012 

Fisher exact test P=0.500N P=0.500 P=0.102 
 

218 Chloroprene, NTP TR 467 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Hemangiosarcoma (excludes liver) 

Overall test 1/50 (2%) 11/50 (22%) 16/50 (32%) 15/50 (30%) 

Adjusted test 3.7% 33.4% 56.5% 62.6% 

Terminal rate 1/27 (4%) 6/27 (22%) 4/14 (29%) 6/13 (46%) 

First incidence (days) 733 (T) 659 502 454 

Life table test P<0.001 P=0.004 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=0.003 

Fisher exact test P=0.002 P<0.001 P<0.001 

All Organs: Hemangiosarcoma 

Overall rate 3/50 (6%) 13/50 (26%) 22/50 (44%) 19/50 (38%) 

Adjusted rate 11.1% 38.6% 69.8% 68.0% 

Terminal rate 3/27 (11%) 7/27 (26%) 6/14 (43%) 6/13 (46%) 

First incidence (days) 733 (T) 659 495 454 

Life table test P<0.001 P=0.009 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.006 P<0.001 P<0.001 

Cochran-Armitage test P=0.001 

Fisher exact test P=0.006 P<0.001 P<0.001 

All Organs: Hemangioma or Hemangiosarcoma (excludes liver) 

Overall rate 1/50 (2%) 12/50 (24%) 18/50 (36%) 17/50 (34%) 

Adjusted rate 3.7% 36.6% 59.8% 69.7% 

Terminal rate 1/27 (4%) 7/27 (26%) 4/14 (29%) 7/13 (54%) 

First incidence (days) 733 (T) 659 502 454 

Life table test P<0.001 P=0.002 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 3/50 (6%) 14/50 (28%) 23/50 (46%) 21/50 (42%) 

Adjusted rate 11.1% 41.7% 70.7% 74.1% 

Terminal rate 3/27 (11%) 8/27 (30%) 6/14 (43%) 7/13 (54%) 

First incidence (days) 733 (T) 659 495 454 

Life table test P<0.001 P=0.005 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.003 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.003 P<0.001 P<0.001 

All Organs: Histiocytic Sarcoma (excludes liver) 

Overall rate 3/50 (6%) 0/50 (0%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 8.5% 0.0% 6.4% 4.0% 

Terminal rate 1/27 (4%) 0/27 (0%) 0/14 (0%) 0/13 (0%) 

First incidence (days) 603 — 607 656 

Life table test P=0.556N P=0.130N P=0.640N P=0.480N 

Logistic regression test P=0.370N P=0.116N P=0.463N P=0.290N 

Cochran-Armitage test P=0.397N 

Fisher exact test P=0.121N P=0.500N P=0.309N 
 

Chloroprene, NTP TR 467 219 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Histiocytic Sarcoma 

Overall rate 3/50 (6%) 0/50 (0%) 2/50 (4%) 1/50 (2%) 

Adjusted rate 8.5% 0.0% 6.4% 4.0% 

Terminal rate 1/27 (4%) 0/27 (0%) 0/14 (0%) 0/13 (0%) 

First incidence (days) 603 — 607 656 

Life table test P=0.556N P=0.130N P=0.640N P=0.480N 

Logistic regression test P=0.370N P=0.116N P=0.463N P=0.290N 

Cochran-armitage test P=0.397N 

Fisher exact test P=0.121N P=0.500N P=0.309N 

All Organs: Malignant Lymphoma 

Overall rate 2/50 (4%) 2/50 (4%) 2/50 (4%) 4/50 (8%) 

Adjusted rate 6.5% 7.4% 14.3% 15.6% 

Terminal rate 1/27 (4%) 2/27 (7%) 2/14 (14%) 1/13 (8%) 

First incidence (days) 680 733 (T) 733 (T) 603 

Life table test P=0.057 P=0.694 P=0.469 P=0.166 

Logistic regression test P=0.133 P=0.683 P=0.538 P=0.329 

Cochran-Armitage test P=0.216 

Fisher exact test P=0.691N P=0.691N P=0.339 

All Organs: Benign Neoplasms 

Overall rate 31/50 (62%) 31/50 (62%) 38/50 (76%) 43/50 (86%) 

Adjusted rate 79.3% 78.8% 91.9% 97.5% 

Terminal rate 19/27 (70%) 19/27 (70%) 11/14 (79%) 12/13 (92%) 

First incidence (days) 596 439 382 392 

Life table test P<0.001 P=0.540 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.532 P=0.026 P<0.001 

Cochran-Armitage test P=0.002 

Fisher exact test P=0.582N P=0.097 P=0.006 

All Organs: Malignant Neoplasms 

Overall rate 34/50 (68%) 40/50 (80%) 50/50 (100%) 47/50 (94%) 

Adjusted rate 71.4% 83.2% 100.0% 97.9% 

Terminal rate 14/27 (52%) 19/27 (70%) 14/14 (100%) 12/13 (92%) 

First incidence (days) 452 523 382 392 

Life table test P<0.001 P=0.223 P<0.001 P<0.001 

Logistic regression test P=0.004 P=0.126 P<0.001 P=0.014 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.127 P<0.001 P<0.001 
220 

c 

Chloroprene, NTP TR 467 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Benign or Malignant Neoplasms 

Overall rate 48/50 (96%) 48/50 (96%) 50/50 (100%) 50/50 (100%) 

Adjusted rate 96.0% 97.9% 100.0% 100.0% 

Terminal rate 25/27 (93%) 26/27 (96%) 14/14 (100%) 13/13 (100%) 

First incidence (days) 452 439 382 392 

Life table test P<0.001 P=0.518 P=0.002 P<0.001 

Logistic regression test P=0.171 P=0.684N P=0.391 P=0.409 

Cochran-Armitage test P=0.106 

Fisher exact test P=0.691N P=0.247 P=0.247 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for kidney, liver, and 

lung; 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 chamber 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 chamber 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 by N. e Not applicable; no neoplasms in animal group 
Chloroprene, NTP TR 467 221 

TABLE C4a 

Historical Incidence of Alveolar/bronchiolar Neoplasms in Chamber Control Male B6C3F a Mice 1 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 18/50 5/50 21/50 

Acetonitrile 6/50 4/50 10/50 

Allyl Glycidyl Ether 7/50 0/50 7/50 

2-Chloroacetophenone 7/50 6/50 11/50 

l-Epinephrine Hydrochloride 11/50 5/50 15/50 

Chloroethane 3/50 2/50 5/50 

Hexachlorocyclopentadiene 11/49 0/49 11/49 

o-Chlorobenzalmalononitrile 7/49 7/49 14/49 

Ozone 6/50 8/50 14/50 

Overall Historical Incidence 

Total 141/947 (14.9%) 75/947 (7.9%) 205/947 (21.7%) 

Standard deviation 7.0% 5.7% 8.0% 

Range 6%-36% 0%-16% 10%-42% 

a Data as of 12 May 1995 

TABLE C4b 

Historical Incidence of Hemangioma and Hemangiosarcoma (All Sites) in Chamber Control Male B6C3F a Mice 1 

Incidence in Controls 

Study Hemangioma Hemangiosarcoma Hemangioma or 

Hemangiosarcoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 1/50 1/50 2/50 

Acetonitrile 1/50 2/50 3/50 

Allyl Glycidyl Ether 0/50 1/50 1/50 

2-Chloroacetophenone 1/50 1/50 2/50 

l-Epinephrine Hydrochloride 1/50 4/50 5/50 

Chloroethane 0/50 0/50 0/50 

Hexachlorocyclopentadiene 0/50 0/50 0/50 

o-Chlorobenzalmalononitrile 1/50 0/50 1/50 

Ozone 0/50 0/50 0/50 

Overall Historical Incidence 

Total 8/950 (0.8%) 26/950 (2.7%) 34/950 (3.6%) 

Standard deviation 1.0% 2.9% 3.4% 

Range 0%-2% 0%-9% 0%-10% 

a Data as of 12 May 1995 
222 Chloroprene, NTP TR 467 

TABLE C4c 

Historical Incidence of Harderian Gland Neoplasms in Chamber Control Male B6C3F a Mice 1 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 6/50 0/50 6/50 

Acetonitrile 5/50 0/50 5/50 

Allyl Glycidyl Ether 4/50 0/50 4/50 

2-Chloroacetophenone 3/50 0/50 3/50 

l-Epinephrine Hydrochloride 2/50 0/50 2/50 

Chloroethane 2/50 2/50 4/50 

Hexachlorocyclopentadiene 7/50 0/50 7/50 

o-Chlorobenzalmalononitrile 6/50 0/50 6/50 

Ozone 1/50 0/50 1/50 

Overall Historical Incidence 

Total 47/950 (5.0%) 2/950 (0.2%) 49/950 (5.2%) 

Standard deviation 4.5% 0.9% 4.5% 

Range 0%-14% 0%-4% 0%-14% 

a Data as of 12 May 1995 

TABLE C4d 

Historical Incidence of Squamous Cell Papilloma of the Forestomach in Chamber Control Male B6C3F a Mice 1 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 1/50 

Acetonitrile 0/50 

Allyl Glycidyl Ether 1/50 

2-Chloroacetophenone 2/50 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 0/50 

Hexachlorocyclopentadiene 0/50 

o-Chlorobenzalmalononitrile 0/50 

Ozone 0/50 

Overall Historical Incidence 

Total 6/950 (0.6%) 

Standard deviation 1.2% 

Range 0%-4% 

a Data as of 12 May 1995 
Chloroprene, NTP TR 467 223 

TABLE C4e 

Historical Incidence of Renal Tubule Adenoma in Chamber Control Male B6C3F a Mice 1 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 

Acetonitrile 0/49 

Allyl Glycidyl Ether 0/49 

2-Chloroacetophenone 0/50 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 0/50 

Hexachlorocyclopentadiene 0/50 

o-Chlorobenzalmalononitrile 0/49 

Ozone 1/50 

Overall Historical Incidence 

Total 2/946 (0.2%) 

Standard deviation 0.5% 

Range 0%-2% 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

224 Chloroprene, NTP TR 467 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Moribund 15 16 26 34 

Natural deaths 8 7 10 3 

Survivors 

Terminal sacrifice 27 27 14 13 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Esophagus (50) (49) (50) (50) 

Dysplasia 1 (2%) 

Inflammation, suppurative 1 (2%) 

Epithelium, hyperplasia 1 (2%) 

Gallbladder (41) (40) (37) (40) 

Degeneration, hyaline 5 (12%) 1 (3%) 2 (5%) 3 (8%) 

Inflammation, suppurative 1 (2%) 1 (3%) 

Necrosis 1 (2%) 

Epithelium, hyperplasia 1 (2%) 

Intestine small, duodenum (45) (44) (45) (48) 

Inflammation, suppurative 1 (2%) 

Necrosis 1 (2%) 

Intestine small, jejunum (46) (43) (47) (49) 

Peyer’s patch, hyperplasia 1 (2%) 

Intestine small, ileum (46) (45) (46) (48) 

Peyer’s patch, hyperplasia 1 (2%) 

Liver (50) (50) (50) (49) 

Angiectasis 2 (4%) 3 (6%) 1 (2%) 

Basophilic focus 4 (8%) 2 (4%) 1 (2%) 

Clear cell focus 1 (2%) 1 (2%) 

Congestion 1 (2%) 

Degeneration, cystic 1 (2%) 1 (2%) 

Eosinophilic focus 7 (14%) 7 (14%) 3 (6%) 8 (16%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 1 (2%) 4 (8%) 

Karyomegaly 19 (38%) 13 (26%) 20 (40%) 29 (59%) 

Mitotic alteration 1 (2%) 

Necrosis 9 (18%) 7 (14%) 7 (14%) 6 (12%) 

Regeneration 22 (44%) 25 (50%) 25 (50%) 27 (55%) 

Vacuolization cytoplasmic 1 (2%) 

Bile duct, hyperplasia 34 (68%) 31 (62%) 34 (68%) 36 (73%) 

Centrilobular, necrosis 1 (2%) 

Mesentery (2) (8) (16) (11) 

Angiectasis 2 (13%) 

Inflammation, focal, granulomatous 1 (9%) 

Thrombosis 1 (9%) 

Fat, inflammation, chronic 1 (50%) 1 (13%) 

Fat, necrosis 1 (50%) 2 (25%) 1 (6%) 1 (9%) 

Pancreas (50) (48) (49) (50) 

Atrophy 4 (8%) 4 (8%) 2 (4%) 2 (4%) 

Basophilic focus 1 (2%) 

Cytoplasmic alteration 1 (2%) 1 (2%) 

Hyperplasia 1 (2%) 

Hypertrophy 1 (2%) 1 (2%) 1 (2%) 2 (4%) 

Duct, cyst 1 (2%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 225 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Alimentary System (continued) 

Salivary glands (50) (49) (50) (50) 

Inflammation 1 (2%) 

Stomach, forestomach (50) (48) (49) (50) 

Infiltration cellular, mast cell 1 (2%) 

Inflammation, suppurative 1 (2%) 3 (6%) 5 (10%) 

Ulcer 2 (4%) 3 (6%) 1 (2%) 12 (24%) 

Epithelium, hyperplasia 4 (8%) 6 (13%) 7 (14%) 29 (58%) 

Stomach, glandular (50) (48) (50) (48) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Mineralization 1 (2%) 1 (2%) 1 (2%) 

Necrosis 2 (4%) 1 (2%) 1 (2%) 

Pigmentation 1 (2%) 

Tooth (2) (2) 

Developmental malformation 2 (100%) 2 (100%) 

Cardiovascular System 

Blood vessel (2) (1) (1) 

Inflammation 1 (100%) 

Mineralization 1 (50%) 

Heart (50) (49) (50) (50) 

Cardiomyopathy 43 (86%) 43 (88%) 40 (80%) 45 (90%) 

Hyperplasia, atypical 1 (2%) 

Inflammation 1 (2%) 

Mineralization 1 (2%) 

Artery, inflammation 1 (2%) 

Atrium, thrombosis 1 (2%) 1 (2%) 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Hyperplasia 2 (4%) 4 (8%) 3 (6%) 

Hypertrophy 13 (26%) 15 (31%) 12 (24%) 9 (18%) 

Capsule, hyperplasia 2 (4%) 1 (2%) 

Adrenal medulla (50) (49) (50) (49) 

Hyperplasia 3 (6%) 3 (6%) 5 (10%) 2 (4%) 

Islets, pancreatic (50) (48) (49) (50) 

Hyperplasia 1 (2%) 2 (4%) 2 (4%) 4 (8%) 

Parathyroid gland (35) (32) (31) (30) 

Hyperplasia 1 (3%) 

Pituitary gland (49) (47) (47) (48) 

Pars distalis, hyperplasia 1 (2%) 2 (4%) 1 (2%) 

Pars intermedia, hyperplasia 1 (2%) 

Pars nervosa, inflammation 1 (2%) 

Thyroid gland (50) (49) (50) (50) 

Follicular cell, hyperplasia 5 (10%) 5 (10%) 6 (12%) 7 (14%) 

General Body System 

None 

Genital System 

Epididymis (50) (49) (50) (50) 

Granuloma sperm 3 (6%) 1 (2%) 1 (2%) 

Hyperplasia 1 (2%) 

Inflammation 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

226 Chloroprene, NTP TR 467 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Genital System (continued) 

Preputial gland (50) (47) (47) (50) 

Angiectasis 1 (2%) 

Cyst 2 (4%) 7 (15%) 2 (4%) 3 (6%) 

Fibrosis 1 (2%) 

Inflammation 2 (4%) 4 (9%) 3 (6%) 1 (2%) 

Prostate (49) (48) (48) (49) 

Hyperplasia 1 (2%) 

Inflammation, suppurative 2 (4%) 1 (2%) 2 (4%) 

Seminal vesicle (49) (48) (49) (48) 

Inflammation 2 (4%) 2 (4%) 1 (2%) 

Testes (50) (49) (50) (50) 

Angiectasis 1 (2%) 

Atrophy 2 (4%) 3 (6%) 2 (4%) 4 (8%) 

Inflammation, focal, granulomatous 1 (2%) 

Hematopoietic System 

Bone marrow (50) (49) (50) (50) 

Hyperplasia 3 (6%) 1 (2%) 3 (6%) 5 (10%) 

Infiltration cellular, mast cell 1 (2%) 

Lymph node (1) (2) (3) 

Iliac, hyperplasia 2 (100%) 

Lymph node, bronchial (32) (23) (33) (28) 

Hyperplasia 4 (13%) 1 (4%) 2 (6%) 1 (4%) 

Lymph node, mandibular (32) (28) (27) (34) 

Hyperplasia 2 (6%) 2 (7%) 1 (4%) 

Infiltration cellular, mast cell 1 (4%) 

Lymph node, mesenteric (47) (48) (46) (48) 

Angiectasis 3 (6%) 3 (7%) 2 (4%) 

Hyperplasia 2 (4%) 2 (4%) 2 (4%) 

Lymph node, mediastinal (34) (38) (37) (37) 

Hematopoietic cell proliferation 1 (3%) 

Hyperplasia 1 (3%) 4 (11%) 2 (5%) 4 (11%) 

Spleen (50) (49) (50) (50) 

Accessory spleen 1 (2%) 

Angiectasis 1 (2%) 

Hematopoietic cell proliferation 26 (52%) 22 (45%) 35 (70%) 31 (62%) 

Hyperplasia, lymphoid 5 (10%) 3 (6%) 

Infiltration cellular, histiocyte 1 (2%) 

Thymus (34) (28) (25) (34) 

Hyperplasia, lymphoid 1 (3%) 

Integumentary System 

Skin (49) (48) (50) (50) 

Edema 2 (4%) 

Inflammation, chronic active 1 (2%) 1 (2%) 1 (2%) 4 (8%) 

Epidermis, hyperplasia 1 (2%) 

Prepuce, inflammation, chronic active 4 (8%) 6 (13%) 5 (10%) 1 (2%) 

Subcutaneous tissue, cyst 2 (4%) 

Subcutaneous tissue, inflammation, focal,

 granulomatous 2 (4%) 

Subcutaneous tissue, inflammation,

 suppurative 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 227 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Fibrous osteodystrophy 1 (2%) 1 (2%) 1 (2%) 

Nervous System 

Brain (50) (49) (50) (50) 

Meninges, inflammation, chronic 1 (2%) 1 (2%) 

Respiratory System 

Larynx (50) (47) (50) (50) 

Hyperplasia 3 (6%) 2 (4%) 1 (2%) 4 (8%) 

Inflammation, suppurative 2 (4%) 

Epiglottis, metaplasia, squamous 1 (2%) 1 (2%) 

Lung (50) (50) (50) (50) 

Hemorrhage 1 (2%) 

Infiltration cellular, histiocyte 7 (14%) 8 (16%) 11 (22%) 22 (44%) 

Inflammation, chronic, focal 2 (4%) 1 (2%) 

Thrombosis 1 (2%) 

Alveolar epithelium, hyperplasia 3 (6%) 5 (10%) 2 (4%) 2 (4%) 

Bronchiole, hyperplasia 10 (20%) 18 (36%) 23 (46%) 

Mediastinum, inflammation, chronic 1 (2%) 

Perivascular, infiltration cellular 1 (2%) 

Nose (50) (48) (50) (50) 

Inflammation, suppurative 2 (4%) 1 (2%) 4 (8%) 6 (12%) 

Lateral wall, necrosis 1 (2%) 

Nasolacrimal duct, inflammation, suppurative 1 (2%) 

Olfactory epithelium, atrophy 7 (14%) 8 (17%) 7 (14%) 49 (98%) 

Olfactory epithelium, degeneration, hyaline 1 (2%) 2 (4%) 

Olfactory epithelium, hyperplasia,

 adenomatous 3 (6%) 2 (4%) 2 (4%) 48 (96%) 

Olfactory epithelium, metaplasia 6 (12%) 5 (10%) 5 (10%) 49 (98%) 

Respiratory epithelium, degeneration, hyaline 3 (6%) 4 (8%) 2 (4%) 10 (20%) 

Respiratory epithelium, necrosis 1 (2%) 

Respiratory epithelium, polyp, inflammatory 1 (2%) 

Trachea (50) (48) (50) (50) 

Metaplasia, squamous 1 (2%) 

Special Senses System 

Eye (1) (1) (1) 

Inflammation 1 (100%) 1 (100%) 1 (100%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

228 Chloroprene, NTP TR 467 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Urinary System 

Kidney (50) (49) (50) (50) 

Cyst 1 (2%) 2 (4%) 1 (2%) 

Glomerulosclerosis 2 (4%) 

Hydronephrosis 1 (2%) 1 (2%) 1 (2%) 

Inflammation, chronic active 4 (8%) 2 (4%) 3 (6%) 

Metaplasia, osseous 3 (6%) 1 (2%) 1 (2%) 

Mineralization 1 (2%) 

Nephropathy 47 (94%) 44 (90%) 43 (86%) 42 (84%) 

Pigmentation, hemosiderin 1 (2%) 1 (2%) 

Papilla, necrosis 1 (2%) 

Renal tubule, hyperplasia 4 (8%) 5 (10%) 5 (10%) 

Renal tubule, necrosis 1 (2%) 1 (2%) 

Ureter (1) 

Transitional epithelium, hyperplasia 1 (100%) 

Urinary bladder (50) (48) (48) (50) 

Inflammation, suppurative 3 (6%) 1 (2%) 3 (6%) 

Transitional epithelium, hyperplasia 1 (2%) 1 (2%) 
 

 

229 

APPENDIX D
 

SUMMARY OF LESIONS IN FEMALE MICE
 

IN THE 2-YEAR INHALATION STUDY
 

OF CHLOROPRENE
 

TABLE D1 Summary of the Incidence of Neoplasms in Female Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 230
 

TABLE D2 Individual Animal Tumor Pathology of Female Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 234
 

TABLE D3 Statistical Analysis of Primary Neoplasms in Female Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 256
 

TABLE D4a Historical Incidence of Alveolar/bronchiolar Neoplasms
 

in Chamber Control Female B6C3F Mice 1 ................................ 262
 

TABLE D4b	 Historical Incidence of Hemangioma and Hemangiosarcoma (All Sites)
 

in Chamber Control Female B6C3F Mice 1 ................................ 262
 

TABLE D4c	 Historical Incidence of Harderian Gland Neoplasms
 

in Chamber Control Female B6C3F Mice 1 ................................ 263
 

TABLE D4d	 Historical Incidence of Mammary Gland Neoplasms
 

in Chamber Control Female B6C3F Mice 1 ................................ 263
 

TABLE D4e	 Historical Incidence of Hepatocellular Neoplasms 

in Chamber Control Female B6C3F Mice
 1 ................................ 264
 

TABLE D4f	 Historical Incidence of Skin Sarcoma
 

in Chamber Control Female B6C3F1 Mice
 ................................ 264

TABLE D4g	 Historical Incidence of Mesentery Sarcoma
 

in Chamber Control Female B6C3F1 Mice
 ................................ 265

TABLE D4h	 Historical Incidence of Forestomach Neoplasms
 

in Chamber Control Female B6C3F Mice 1 ................................ 265
 

TABLE D4i	 Historical Incidence of Zymbal’s Gland Carcinoma
 

in Chamber Control Female B6C3F Mice 1 ................................ 266
 

TABLE D5	 Summary of the Incidence of Nonneoplastic Lesions in Female Mice 

in the 2-Year Inhalation Study of Chloroprene ............................. 267
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

230 Chloroprene, NTP TR 467 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 1 1 

Moribund 13 27 38 41 

Natural deaths 2 6 11 5 

Survivors 

Died last week of study 1 

Terminal sacrifice 35 16 1 2

 Animals examined microscopically 50 50 50 50 

Alimentary System 

Intestine large, colon (50) (47) (48) (49) 

Sarcoma 1 (2%) 

Intestine small, duodenum (49) (45) (42) (48) 

Intestine small, ileum (50) (45) (46) (49) 

Liver (50) (49) (50) (50) 

Hemangiosarcoma 1 (2%) 1 (2%) 

Hepatocellular carcinoma 4 (8%) 10 (20%) 7 (14%) 15 (30%) 

Hepatocellular carcinoma, multiple 1 (2%) 7 (14%) 4 (8%) 

Hepatocellular adenoma 12 (24%) 12 (24%) 9 (18%) 7 (14%) 

Hepatocellular adenoma, multiple 5 (10%) 7 (14%) 2 (4%) 9 (18%) 

Hepatocholangiocarcinoma 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 2 (4%) 3 (6%) 

Sarcoma, metastatic, mesentery 1 (2%) 1 (2%) 2 (4%) 

Mesentery (10) (14) (27) (21) 

Hemangioma 2 (7%) 1 (5%) 

Hemangiosarcoma 4 (29%) 13 (48%) 4 (19%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (7%) 

Histiocytic sarcoma 1 (4%) 

Sarcoma 4 (29%) 8 (30%) 3 (14%) 

Pancreas (49) (49) (48) (50) 

Hemangiosarcoma 1 (2%) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Sarcoma, metastatic, mesentery 2 (4%) 2 (4%) 

Salivary glands (50) (49) (50) (50) 

Sarcoma, metastatic, skin 1 (2%) 

Stomach, forestomach (50) (49) (49) (50) 

Squamous cell carcinoma 1 (2%) 

Squamous cell papilloma 4 (8%) 

Stomach, glandular (50) (48) (49) (50) 

Sarcoma, metastatic, mesentery 1 (2%) 2 (4%) 1 (2%) 

Cardiovascular System 

Heart (50) (49) (50) (50) 

Endocrine System 

Adrenal cortex (50) (48) (49) (50) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Adrenal medulla (50) (48) (48) (50) 

Pheochromocytoma malignant 1 (2%) 

Pheochromocytoma benign 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 231 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Endocrine System (continued) 

Islets, pancreatic (49) (49) (48) (50) 

Adenoma 1 (2%) 2 (4%) 

Pituitary gland (49) (48) (48) (50) 

Pars distalis, adenoma 4 (8%) 6 (13%) 4 (8%) 4 (8%) 

Pars intermedia, adenoma 1 (2%) 1 (2%) 

Thyroid gland (50) (49) (49) (50) 

Follicular cell, adenoma 1 (2%) 1 (2%) 1 (2%) 

Follicular cell, carcinoma 2 (4%) 

Thyroglossal duct, adenoma 1 (2%) 

General Body System 

None 

Genital System 

Ovary (48) (47) (47) (49) 

Cystadenoma 1 (2%) 1 (2%) 1 (2%) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 

Luteoma 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Teratoma malignant 1 (2%) 

Uterus (50) (49) (50) (50) 

Hemangioma 2 (4%) 

Hemangiosarcoma 2 (4%) 

Histiocytic sarcoma 1 (2%) 2 (4%) 2 (4%) 

Leiomyosarcoma 1 (2%) 

Polyp stromal 2 (4%) 4 (8%) 2 (4%) 3 (6%) 

Sarcoma, metastatic, mesentery 1 (2%) 

Vagina (1) 

Sarcoma 1 (100%) 

Hematopoietic System 

Bone marrow (50) (49) (49) (50) 

Hemangiosarcoma 1 (2%) 1 (2%) 

Lymph node (4) (3) (5) (2) 

Iliac, hemangiosarcoma, metastatic, mesentery 1 (20%) 

Iliac, sarcoma, metastatic, mesentery 1 (50%) 

Lymph node, bronchial (32) (31) (34) (38) 

Histiocytic sarcoma 1 (3%) 

Sarcoma, metastatic, mesentery 1 (3%) 

Lymph node, mandibular (32) (40) (33) (40) 

Lymph node, mesenteric (48) (45) (48) (46) 

Hemangiosarcoma 2 (4%) 1 (2%) 1 (2%) 

Hemangiosarcoma, metastatic, mesentery 3 (6%) 

Histiocytic sarcoma 2 (4%) 

Sarcoma 1 (2%) 

Sarcoma, metastatic, mesentery 1 (2%) 4 (8%) 

Sarcoma, metastatic, skin 1 (2%) 

Sarcoma, metastatic, intestine large, colon 1 (2%) 

Lymph node, mediastinal (38) (44) (45) (40) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (3%) 1 (3%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Sarcoma, metastatic, mesentery 1 (3%) 

Sarcoma, metastatic, skin 1 (3%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

232 Chloroprene, NTP TR 467 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Hematopoietic System (continued) 

Spleen (50) (49) (49) (50) 

Hemangiosarcoma 1 (2%) 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Thymus (44) (35) (39) (39) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (3%) 

Integumentary System 

Mammary gland (49) (49) (50) (50) 

Adenoacanthoma 1 (2%) 3 (6%) 2 (4%) 

Adenoma 1 (2%) 1 (2%) 

Carcinoma 3 (6%) 4 (8%) 6 (12%) 11 (22%) 

Carcinoma, multiple 1 (2%) 1 (2%) 

Skin (49) (49) (50) (50) 

Basal cell adenoma 1 (2%) 

Squamous cell papilloma 1 (2%) 

Subcutaneous tissue, hemangiosarcoma 2 (4%) 1 (2%) 2 (4%) 1 (2%) 

Subcutaneous tissue, histiocytic sarcoma 1 (2%) 

Subcutaneous tissue, sarcoma 10 (20%) 10 (20%) 16 (32%) 

Subcutaneous tissue, sarcoma, multiple 1 (2%) 1 (2%) 2 (4%) 

Subcutaneous tissue, sarcoma, metastatic, 

mesentery 1 (2%) 

Musculoskeletal System 

Bone (50) (49) (50) (50) 

Alveolar/bronchiolar carcinoma, metastatic, 

lung 1 (2%) 

Skeletal muscle (2) (1) 

Sarcoma, metastatic, mesentery 1 (50%) 

Sarcoma, metastatic, skin 1 (50%) 1 (100%) 

Nervous System 

None 

Respiratory System 

Larynx (50) (49) (50) (50) 

Lung (50) (49) (50) (50) 

Adenoacanthoma, metastatic, mammary gland 3 (6%) 

Alveolar/bronchiolar adenoma 2 (4%) 10 (20%) 17 (34%) 10 (20%) 

Alveolar/bronchiolar adenoma, multiple 6 (12%) 12 (24%) 16 (32%) 

Alveolar/bronchiolar carcinoma 2 (4%) 8 (16%) 8 (16%) 11 (22%) 

Alveolar/bronchiolar carcinoma, multiple 6 (12%) 8 (16%) 17 (34%) 

Carcinoma, metastatic, harderian gland 1 (2%) 1 (2%) 

Carcinoma, metastatic, mammary gland 2 (4%) 2 (4%) 

Carcinoma, metastatic, Zymbal's gland 2 (4%) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 2 (4%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 1 (2%) 1 (2%) 4 (8%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 1 (2%) 

Histiocytic sarcoma 1 (2%) 2 (4%) 

Sarcoma, metastatic, mesentery 2 (4%) 1 (2%) 

Sarcoma, metastatic, skin 2 (4%) 1 (2%) 2 (4%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 233 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Respiratory System (continued) 

Lung (continued) (50) (49) (50) (50) 

Mediastinum, alveolar/bronchiolar carcinoma, 

metastatic, lung 1 (2%) 2 (4%) 

Mediastinum, hemangiosarcoma 1 (2%) 

Mediastinum, sarcoma, metastatic, mesentery 1 (2%) 1 (2%) 

Mediastinum, sarcoma, metastatic, skin 1 (2%) 1 (2%) 

Nose (50) (49) (49) (50) 

Respiratory epithelium, adenoma 1 (2%) 

Special Senses System 

Harderian gland (2) (6) (4) (9) 

Adenoma 1 (50%) 3 (50%) 3 (75%) 8 (89%) 

Carcinoma 1 (50%) 2 (33%) 1 (11%) 

Zymbal’s gland (3) 

Carcinoma 3 (100%) 

Urinary System 

Kidney (50) (49) (49) (50) 

Hemangiosarcoma, metastatic, mesentery 1 (2%) 

Hepatocholangiocarcinoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Sarcoma, metastatic, mesentery 2 (4%) 

Urinary bladder (50) (47) (46) (47) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 

Sarcoma, metastatic, mesentery 2 (4%) 

Systemic Lesions 

Multiple organsb (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 2 (4%) 3 (6%) 

Lymphoma malignant 7 (14%) 7 (14%) 3 (6%) 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 34 47 50 48 

Total primary neoplasms 55 124 151 160 

Total animals with benign neoplasms 22 32 38 42 

Total benign neoplasms 31 53 59 66 

Total animals with malignant neoplasms 20 42 49 48 

Total malignant neoplasms 24 71 92 94 

Total animals with metastatic neoplasms 3 8 23 15 

Total metastatic neoplasms 3 18 40 27 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

234 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

0 4 4 4 5 5 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study	 3 7 8 9 2 4 1 3 3 6 7 8 0 0 2 3 3 3 3 3 3 3 3 3 3 

5 7 6 3 7 1 0 5 7 3 7 1 5 6 9 4 4 4 4 4 4 4 4 4 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 4 1 3 0 3 3 2 0 4 2 3 0 2 3 1 0 1 1 1 2 2 2 3 3 4 

1 0 8 7 0 5 6 5 6 4 3 3 7 2 2 2 4 7 9 2 3 9 1 6 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + M + + 

Gallbladder + + + + + + + + + + + + + + + M M + + + M + + M + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + M 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Hepatocellular carcinoma X X X 

Hepatocellular adenoma X X X 

Hepatocellular adenoma, multiple X X 

Histiocytic sarcoma X 

Mesentery + + + + 

Oral mucosa 

Pancreas + + + + + + + + + M + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell carcinoma X 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + M + + + + + + + + + + + + + + + 

Parathyroid gland + M + + M + + + + + + + M M + M + + M + + + + + + 

Pituitary gland M + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X 

Pars intermedia, adenoma X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

Tissue NOS + 

Genital System 

Clitoral gland M M + M + I + + + + + M + M M + + + M + + + + + + 

Ovary + + + + + + + + + + + + + + + M + + + + + + + + + 

Cystadenoma 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Polyp stromal 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 235 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

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 4 4 5 0 0 0 0 0 1 1 1 1 1 2 2 2 2 3 3 3 4 4 4 4 4 Tissues/ 

7 8 0 1 4 6 8 9 1 3 5 6 8 0 1 5 8 4 7 9 0 2 3 4 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Gallbladder + + + + + M + + + + + + + + + + + + + + + + + + + 45 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + M + + + + + + + + + + + + + + + + + + 48 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + M + + + + + + + + + + + + 49 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Hepatocellular carcinoma X 4 

Hepatocellular adenoma X X X X X X X X X 12 

Hepatocellular adenoma, multiple X X X 5 

Histiocytic sarcoma 1 

Mesentery + + + + + + 10 

Oral mucosa + 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma X 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell carcinoma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel 2 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Parathyroid gland + M M M + + + + + + + M M M + + + + + M + M M + + 35 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X 4 

Pars intermedia, adenoma 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X 1 

General Body System 

Tissue NOS 1 

Genital System 

Clitoral gland + + + + + + + M + + + + + + + + + + + + + + + + + 41 

Ovary + + + + + + + + + + + + + + + + + + + + + M + + + 48 

Cystadenoma X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Polyp stromal X X 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

236 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

0 4 4 4 5 5 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study	 3 7 8 9 2 4 1 3 3 6 7 8 0 0 2 3 3 3 3 3 3 3 3 3 3 

5 7 6 3 7 1 0 5 7 3 7 1 5 6 9 4 4 4 4 4 4 4 4 4 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 4 1 3 0 3 3 2 0 4 2 3 0 2 3 1 0 1 1 1 2 2 2 3 3 4 

1 0 8 7 0 5 6 5 6 4 3 3 7 2 2 2 4 7 9 2 3 9 1 6 5 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node 

Lymph node, bronchial 

Lymph node, mandibular 

Lymph node, mesenteric 

Lymph node, mediastinal 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

+ + 

+ M M + + I + + + + + + M + + + + + + M M + M + + 

M M + + + M + M + + M + + + + + + M M + M + + + + 

+ + + + + + + + M + + + + + + + + + + + + + + + + 

+ + + M + M + + + + + + + + + + + M M + + + + M + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

+ + M + + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Carcinoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

Skin + + A + + + + + + + + + + + + + + + + + + + + + + 

Basal cell adenoma X 

Subcutaneous tissue, hemangiosarcoma X X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Peripheral nerve 

Spinal cord 

+ 

+ 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, harderian gland 

Hepatocellular carcinoma, metastatic, liver 

Histiocytic sarcoma 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

+ + 

X 

Carcinoma X 

Urinary System 

Kidney 

Ureter 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Urethra 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 237 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: Chamber Control 

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 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

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 4 4 5 0 0 0 0 0 1 1 1 1 1 2 2 2 2 3 3 3 4 4 4 4 4 Tissues/ 

7 8 0 1 4 6 8 9 1 3 5 6 8 0 1 5 8 4 7 9 0 2 3 4 9 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + 4 

Lymph node, bronchial M M + M + M + + M + + + M M M + M + + + M + + + M 32 

Lymph node, mandibular + M + + M + + M M + M + M + M + I + + + + + + M M 32 

Lymph node, mesenteric + + + + + + M + + + + + + + + + + + + + + + + + + 48 

Lymph node, mediastinal + + + + + M + + M + + + + + + M + + M M + M + + M 38 

Alveolar/bronchiolar carcinoma, metastatic, lung 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Histiocytic sarcoma 1 

Thymus + M + M + + + + + + + + + M M + M + + + + + + + + 44 

Integumentary System 

Mammary gland + + + + + + + + + + + + M + + + + + + + + + + + + 49 

Carcinoma X 3 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Basal cell adenoma 1 

Subcutaneous tissue, hemangiosarcoma 2 

Musculoskeletal System 

Bone	 + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve 1 

Spinal cord 1 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma 2 

Alveolar/bronchiolar carcinoma X 2 

Carcinoma, metastatic, harderian gland 1 

Hepatocellular carcinoma, metastatic, liver X 1 

Histiocytic sarcoma 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Eye + 1 

Harderian gland 2 

Adenoma 1 

Carcinoma 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Ureter + 1 

Urethra + 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs	 + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Lymphoma malignant	 X X X X 7 

50 
 

 

 

 

 

 

 

 

 

 

 

 

238 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

2 3 3 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 1 2 4 4 8 2 3 4 4 5 5 0 2 2 2 3 3 3 7 7 7 8 9 9 

5 8 1 0 7 2 3 1 0 8 1 1 7 1 3 4 1 1 6 3 4 7 0 0 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 

Carcass ID Number 1 3 5 1 2 4 0 2 4 1 1 2 0 2 4 0 2 4 4 1 2 1 1 2 4 

8 0 0 1 1 2 3 7 4 6 5 8 1 4 7 4 5 9 3 3 9 4 0 3 0 

Alimentary System 

Esophagus + + A + + + + M + + + + + + + + + + + + + + + + + 

Gallbladder + + A + + + A + + + + + + A + M + + + A + + + + + 

Intestine large, colon + + A + + + A + + + + + + A + + + + + + + + + + + 

Intestine large, rectum + + A + + + A + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + A + + + A + + + + + + A + + + + + A + + + + + 

Intestine small, duodenum + + A + + + A + + + + + + A + + + + + A + + + + + 

Intestine small, jejunum + + A + + + A + + + + + + + + + + + + A + + + + + 

Intestine small, ileum + + A + + + A + + + + + + A + + + + + A + + + + + 

Liver + + A + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma X X X X X 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma X X X X X X X 

Hepatocellular adenoma, multiple 

Hepatocholangiocarcinoma X 

Histiocytic sarcoma X 

Sarcoma, metastatic, mesentery X 

Mesentery + + + + + + + 

Hemangiosarcoma 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma X X 

Pancreas + + A + + + + + + + + + + + + + + + + + + + + + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Sarcoma, metastatic, mesentery X X 

Salivary glands + + A + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + A + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + A + + + + + + + + + + + + + + + + A + + + + + 

Sarcoma, metastatic, mesentery X 

Cardiovascular System 

Heart + + A + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + M + + + M + + + + + + + + + + + + + + + + + + 

Hepatocholangiocarcinoma, metastatic, liver X 

Adrenal medulla + + M + + + M + + + + + + + + + + + + + + + + + + 

Pheochromocytoma malignant 

Islets, pancreatic + + A + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Parathyroid gland M + M M + M + + + + + M + + + + + + + + M + M + + 

Pituitary gland + + A + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X 

Thyroid gland + + A + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma X 

Follicular cell, carcinoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 239 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 9 9 9 9 0 0 0 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

1 1 1 8 2 8 8 9 9 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 

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 0 1 3 4 0 3 4 3 4 0 0 3 3 4 0 0 1 1 2 2 2 3 3 3 3 Tissues/ 

8 9 2 5 6 4 6 1 1 5 9 3 5 8 2 7 2 7 0 2 6 6 7 8 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Gallbladder + + A + + + + + + + + + + + + + + + + + + + + + + 44 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, rectum + + + M + + + + + + + + + + + + + + + + + + + + + 47 

Intestine large, cecum + + A + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, duodenum + + A + + + + + + + + + + + + + + + + + + + + + + 45 

Intestine small, jejunum + + A + + + + + + + + + + + + + + + + + + + + + + 46 

Intestine small, ileum + + A + + + + + + + + + + + + + + + + + + + + + + 45 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hepatocellular carcinoma X X X X X 10 

Hepatocellular carcinoma, multiple X 1 

Hepatocellular adenoma X X X X X 12 

Hepatocellular adenoma, multiple X X X X X X X 7 

Hepatocholangiocarcinoma 1 

Histiocytic sarcoma X 2 

Sarcoma, metastatic, mesentery 1 

Mesentery + + + + + + + 14 

Hemangiosarcoma X X X X 4 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma X X 4 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hepatocholangiocarcinoma, metastatic, liver 1 

Sarcoma, metastatic, mesentery 2 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Sarcoma, metastatic, mesentery 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Hepatocholangiocarcinoma, metastatic, liver 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Pheochromocytoma malignant X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma 1 

Parathyroid gland + + M + + + + M M + + + + M + + M + M M + + M + + 35 

Pituitary gland + + + + + + + + + + + + + + + + + + + M + + + + + 48 

Pars distalis, adenoma X X X X X 6 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Follicular cell, adenoma 1 

Follicular cell, carcinoma X X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

240 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

2 3 3 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 1 2 4 4 8 2 3 4 4 5 5 0 2 2 2 3 3 3 7 7 7 8 9 9 

5 8 1 0 7 2 3 1 0 8 1 1 7 1 3 4 1 1 6 3 4 7 0 0 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 

Carcass ID Number 1 3 5 1 2 4 0 2 4 1 1 2 0 2 4 0 2 4 4 1 2 1 1 2 4 

8 0 0 1 1 2 3 7 4 6 5 8 1 4 7 4 5 9 3 3 9 4 0 3 0 

Genital System 

Clitoral gland M + A + M + M + + + + + + + + + + + + M + + + M + 

Ovary + + A + + + + + + I + + + + + + + + + + + + I + + 

Cystadenoma 

Histiocytic sarcoma X 

Luteoma X 

Teratoma malignant X 

Uterus + + A + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Leiomyosarcoma X 

Polyp stromal X X 

Hematopoietic System 

Bone marrow + + A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Lymph node + 

Lymph node, bronchial M + A + + + M M + M + M M + M M + + + + + + + + + 

Lymph node, mandibular + + A + + M M + + + + + + M + + + M + M + M + M + 

Lymph node, mesenteric + M A + + + + + + + + + + + M + + + M + + + + + + 

Hemangiosarcoma 

Sarcoma, metastatic, mesentery X 

Sarcoma, metastatic, skin X 

Lymph node, mediastinal M + M + M M + + + + + + + + + + + + + + + M M + + 

Hepatocholangiocarcinoma, metastatic liver X 

Spleen + + A + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Thymus M + M + + M + M M M + M + + + + + M + + M M + + + 

Integumentary System 

Mammary gland + + A + + + + + + + + + + + + + + + + + + + + + + 

Adenoacanthoma X 

Adenoma 

Carcinoma X X X 

Skin + + A + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma X 

Subcutaneous tissue, histiocytic, sarcoma X 

Subcutaneous tissue, sarcoma X X X X X X 

Subcutaneous tissue, sarcoma, multiple 

Musculoskeletal System 

Bone + + A + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + A + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 241 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 9 9 9 9 0 0 0 1 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

1 1 1 8 2 8 8 9 9 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 

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 0 1 3 4 0 3 4 3 4 0 0 3 3 4 0 0 1 1 2 2 2 3 3 3 3 Tissues/ 

8 9 2 5 6 4 6 1 1 5 9 3 5 8 2 7 2 7 0 2 6 6 7 8 9 Tumors 

Genital System 

Clitoral gland M + + M + + + + + + + + + + + M + + + + + + M + + 40 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Cystadenoma X 1 

Histiocytic sarcoma X 2 

Luteoma 1 

Teratoma malignant 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Histiocytic sarcoma X 2 

Leiomyosarcoma 1 

Polyp stromal X X 4 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Lymph node + + 3 

Lymph node, bronchial + + + M + + M M M + + + M + M M + M + M + + M + + 31 

Lymph node, mandibular + + + + + + + + + + + M + + + + + + + + + + + + M 40 

Lymph node, mesenteric + + + + M + + + + + + + + + + + + + + + + + + + + 45 

Hemangiosarcoma X X 2 

Sarcoma, metastatic, mesentery 1 

Sarcoma, metastatic, skin 1 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + + + + + + + + 44 

Hepatocholangiocarcinoma, metastatic, liver 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Thymus + + + M + + + + M + + + + + + + + M + + M + M + + 35 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoacanthoma 1 

Adenoma X 1 

Carcinoma X 4 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Subcutaneous tissue, hemangiosarcoma 1 

Subcutaneous tissue, histiocytic sarcoma 1 

Subcutaneous tissue, sarcoma X X X X 10 

Subcutaneous tissue, sarcoma,multiple X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

49 

49 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

242 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

2 3 3 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 8 

5 

1 

8 

2 

1 

4 

0 

4 

7 

8 

2 

2 

3 

3 

1 

4 

0 

4 

8 

5 

1 

5 

1 

0 

7 

2 

1 

2 

3 

2 

4 

3 

1 

3 

1 

3 

6 

7 

3 

7 

4 

7 

7 

8 

0 

9 

0 

9 

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 

Carcass ID Number 1 3 5 1 2 4 0 2 4 1 1 2 0 2 4 0 2 4 4 1 2 1 1 2 4 

8 0 0 1 1 2 3 7 4 6 5 8 1 4 7 4 5 9 3 3 9 4 0 3 0 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Carcinoma, metastatic, harderian gland 

Hemangiosarcoma, metastatic, mesentery 

Hepatocellular carcinoma, metastatic, liver 

Hepatocholangiocarcinoma, metastatic, liver 

Sarcoma, metastatic, skin 

Mediastinum, sarcoma, metastatic, skin 

Nose 

+ + A 

+ + A 

X 

+ + A 

+ + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + 

X X X X 

X 

X X X X X X X 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + 

Trachea + + A + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Harderian gland 

Adenoma 

+ 

X 

+ 

+ 

Carcinoma X 

Urinary System 

Kidney 

Hepatocholangiocarcinoma, metastatic, liver 

Urinary bladder 

+ + A 

+ + A 

+ + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + M + + + + + + A + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 243 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 12.8 ppm 

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 9 

1 

9 

1 

9 

1 

9 

8 

0 

2 

0 

8 

0 

8 

1 

9 

1 

9 

3 

4 

3 

4 

3 

4 

3 

4 

3 

4 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

3 

5 

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 0 

8 

1 

9 

3 

2 

4 

5 

0 

6 

3 

4 

4 

6 

3 

1 

4 

1 

0 

5 

0 

9 

3 

3 

3 

5 

4 

8 

0 

2 

0 

7 

1 

2 

1 

7 

2 

0 

2 

2 

2 

6 

3 

6 

3 

7 

3 

8 

3 

9 

Tissues/ 

Tumors 

Respiratory System 

Larynx 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Alveolar/bronchiolar carcinoma, multiple 

Carcinoma, metastatic, harderian gland 

Hemangiosarcoma, metastatic, mesentery 

Hepatocellular carcinoma, metastatic, liver 

Hepatocholangiocarcinoma, metastatic, liver

Sarcoma, metastatic, skin 

Mediastinum, sarcoma, metastatic, skin 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

X X X X X 

X

X X X X X X

X 

X

X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

49 

49 

10 

6 

8 

6 

1 

1 

1 

1 

2 

1 

49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Special Senses System 

Eye

Harderian gland 

Adenoma 

+ + 

X 

+ +

X

 1 

6 

3 

Carcinoma X 2 

Urinary System 

Kidney 

Hepatocholangiocarcinoma, metastatic, liver

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

49 

1 

47 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X X

49 

2 

7 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

244 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

Number of Days on Study 

2 3 3 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 

1 4 7 8 9 2 4 5 6 7 8 9 0 0 1 2 2 2 3 3 3 4 5 5 7 

6 6 8 9 4 5 0 4 3 2 7 9 3 5 5 3 4 7 1 7 9 3 1 1 2 

Carcass ID Number 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

0 3 4 3 4 3 0 4 1 2 2 1 0 2 2 4 3 1 1 0 0 1 2 4 3 

5 2 5 5 0 0 2 8 0 9 1 2 6 4 3 7 1 8 9 3 4 1 8 6 3 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Sarcoma 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Hepatocholangiocarcinoma 

Histiocytic sarcoma 

Sarcoma, metastatic, mesentery 

Mesentery 

Hemangioma 

Hemangiosarcoma 

Histiocytic sarcoma 

Sarcoma 

Pancreas 

Hemangiosarcoma, metastatic, mesentery 

Sarcoma, metastatic, mesentery 

Salivary glands 

Sarcoma, metastatic, skin 

Stomach, forestomach 

Stomach, glandular 

Sarcoma, metastatic, mesentery 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + M + + + + A + A A + M + + + + + + + + + + + + 

+ + + + + + + A + + + + + + + + + + + + + + + + + 

X 

+ + + + + + M A + + + + + + + + + + + + + + + + + 

+ + + + + + + A + + A + + + + + + + + + + + + + + 

+ + + + + + + A + A A + A + + + + + + + + A + + + 

+ + + + + + + A + A A + A + + + + + + + + + + + + 

+ + + + + + + A + + + + A + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X 

X X 

X 

X 

X X X 

X 

+ + + + + + + + + + + 

X X X X X X X 

X 

X X 

+ + + + + + + A + + + + + + + M + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + A + + + + + + + + + + + + + + + + + 

+ + + + + + + A + + + + + + + + + + + + + + + + + 

X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, mesentery 

Adrenal medulla + + + + + + + A + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + A + + + + + + + M + + + + + + + + + 

Adenoma X 

Parathyroid gland + + M + + M + M M I + M + M + + I + + + M + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + M + + + + + + 

Pars distalis, adenoma 

Thyroid gland + + + + + + + A + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

Thyroglossal duct, adenoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 245 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 8 8 9 0 0 0 2 2 2 2 2 3 3 3 4 4 5 5 5 6 7 7 9 1 3 

2 8 6 4 7 8 0 3 4 9 9 1 4 5 4 9 2 6 6 7 1 4 1 7 5 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Total 

Carcass ID Number 2 2 3 2 2 0 3 2 4 4 4 0 1 0 3 0 5 1 3 4 3 1 1 4 1 Tissues/ 

2 0 6 5 6 7 9 7 4 1 2 1 6 9 7 8 0 7 8 9 4 3 5 3 4 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + M + + + + + A + + + + + + + + M + + 42 

Intestine large, colon + + + + + + + A + + + + + + + + + + + + + + + + + 48 

Sarcoma 1 

Intestine large, rectum + + + M + + + A + + + + + + + + + + + + + + + + + 46 

Intestine large, cecum + + + + + + + A + + + + A I + + + + + + + + + + + 45 

Intestine small, duodenum + + + + + + + A + + + + A A + + + + + + + + + + + 42 

Intestine small, jejunum + + + + + + + A + + + + A + + + + + + + + + + + + 44 

Intestine small, ileum + + + + + + + A + + + + A + + + + + + + + + + + + 46 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Hepatocellular carcinoma X X X X X 7 

Hepatocellular carcinoma, multiple X X X X X 7 

Hepatocellular adenoma X X X X X X X X 9 

Hepatocellular adenoma, multiple X X 2 

Hepatocholangiocarcinoma 1 

Histiocytic sarcoma 3 

Sarcoma, metastatic, mesentery 1 

Mesentery + + + + + + + + + + + + + + + + 27 

Hemangioma X X 2 

Hemangiosarcoma X X X X X X 13 

Histiocytic sarcoma 1 

Sarcoma X X X X X X 8 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangiosarcoma, metastatic, mesentery X 1 

Sarcoma, metastatic, mesentery X X 2 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, skin 1 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Sarcoma, metastatic, mesentery X 2 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma, metastatic, mesentery X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + I + + + + 48 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X 2 

Parathyroid gland M M M + + + + + + M M M M + + + M + M + + + + + M 31 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + M + + 48 

Pars distalis, adenoma X X X X 4 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Follicular cell, adenoma X 1 

Thyroglossal duct, adenoma X 1 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

246 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

2 3 3 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 1 4 7 8 9 2 4 5 6 7 8 9 0 0 1 2 2 2 3 3 3 4 5 5 7 

6 6 8 9 4 5 0 4 3 2 7 9 3 5 5 3 4 7 1 7 9 3 1 1 2 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Carcass ID Number 0 3 4 3 4 3 0 4 1 2 2 1 0 2 2 4 3 1 1 0 0 1 2 4 3 

5 2 5 5 0 0 2 8 0 9 1 2 6 4 3 7 1 8 9 3 4 1 8 6 3 

Genital System 

Clitoral gland + M M + M M + + + + + + M M + + + + I + M + + + M 

Ovary + + + + + + + A + + + + + M + + + + + + + + + + + 

Cystadenoma 

Histiocytic sarcoma X 

Sarcoma, metastatic, mesentery X 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X X 

Polyp stromal X X 

Vagina 

Sarcoma 

Hematopoietic System 

Bone marrow + + + + + + + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Lymph node + 

Iliac, hemangiosarcoma, metastatic, mesentery 

Lymph node, bronchial + + M M M M + M M + + + + + + + + M + + + + M + + 

Histiocytic sarcoma X 

Lymph node, mandibular + + + + + + + + M + + M + M + + + M + + I + + M + 

Lymph node, mesenteric + + + + + M + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Hemangiosarcoma, metastatic, mesentery X 

Histiocytic sarcoma X X 

Sarcoma 

Sarcoma, metastatic, mesentery X X 

Sarcoma, metastatic, intestine large colon X 

Lymph node, mediastinal + + + + + + + + + + + + + + + + + + M + + + + M + 

Spleen + + + + + + + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X 

Thymus + + + + + M + A + + + + + + M + + + + + + + + + + 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoacanthoma X X X 

Adenoma X 

Carcinoma X X X 

Carcinoma, multiple 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, hemangiosarcoma X X 

Subcutaneous tissue, sarcoma X X 

Subcutaneous tissue, sarcoma, multiple 

Subcutaneous tissue, sarcoma, metastatic,

 mesentery 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Skeletal muscle + 

Sarcoma, metastatic, mesentery X 

Sarcoma, metastatic, skin 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 247 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 8 8 9 0 0 0 2 2 2 2 2 3 3 3 4 4 5 5 5 6 7 7 9 1 3 

2 8 6 4 7 8 0 3 4 9 9 1 4 5 4 9 2 6 6 7 1 4 1 7 5 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Total 

Carcass ID Number 2 2 3 2 2 0 3 2 4 4 4 0 1 0 3 0 5 1 3 4 3 1 1 4 1 Tissues/ 

2 0 6 5 6 7 9 7 4 1 2 1 6 9 7 8 0 7 8 9 4 3 5 3 4 Tumors 

Genital System 

Clitoral gland + + M M M + + M M + + M + + + M M + + + + M + + + 32 

Ovary + + + M + + + + + + + + + + + + + + + + + + + + + 47 

Cystadenoma X 1 

Histiocytic sarcoma 1 

Sarcoma, metastatic, mesentery 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 2 

Histiocytic sarcoma 2 

Polyp stromal 2 

Vagina + 1 

Sarcoma X 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Lymph node + + + + 5 

Iliac, hemangiosarcoma, metastatic, mesentery X 1 

Lymph node, bronchial + M + + + M M + + + + + M M + + + + + + + M M M + 34 

Histiocytic sarcoma 1 

Lymph node, mandibular + + + M + + M M M + + + M + M M + + M + + M I + M 33 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Hemangiosarcoma 1 

Hemangiosarcoma, metastatic, mesentery X X 3 

Histiocytic sarcoma 2 

Sarcoma X 1 

Sarcoma, metastatic, mesentery X X 4 

Sarcoma, metastatic, intestine large colon 1 

Lymph node, mediastinal + + + + + + + + + + + + + + M M + + + + + + + M + 45 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Histiocytic sarcoma 1 

Thymus + M M + + + M + + + M + + + M + + M M + M + + + + 39 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoacanthoma 3 

Adenoma 1 

Carcinoma X X X 6 

Carcinoma, multiple X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Subcutaneous tissue, hemangiosarcoma 2 

Subcutaneous tissue, sarcoma X X X X X X X X 10 

Subcutaneous tissue, sarcoma, multiple X 1 

Subcutaneous tissue, sarcoma, metastatic, 

mesentery X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle + 2 

Sarcoma, metastatic, mesentery 1 

Sarcoma, metastatic, skin X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

248 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

2 3 3 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 1 4 7 8 9 2 4 5 6 7 8 9 0 0 1 2 2 2 3 3 3 4 5 5 7 

6 6 8 9 4 5 0 4 3 2 7 9 3 5 5 3 4 7 1 7 9 3 1 1 2 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Carcass ID Number 0 3 4 3 4 3 0 4 1 2 2 1 0 2 2 4 3 1 1 0 0 1 2 4 3 

5 2 5 5 0 0 2 8 0 9 1 2 6 4 3 7 1 8 9 3 4 1 8 6 3 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoacanthoma, metastatic, mammary gland X X X 

Alveolar/bronchiolar adenoma X X X X X X X X 

Alveolar/bronchiolar adenoma, multiple X X X 

Alveolar/bronchiolar carcinoma X X X 

Alveolar/bronchiolar carcinoma, multiple 

Carcinoma, metastatic, mammary gland X X 

Hemangiosarcoma, metastatic, mesentery X 

Hepatocellular carcinoma, metastatic, liver X 

Hepatocholangiocarcinoma, metastatic, liver X 

Histiocytic sarcoma X X 

Sarcoma, metastatic, mesentery X 

Sarcoma, metastatic, skin 

Mediastinum, alveolar/bronchiolar carcinoma, 

metastatic, lung 

Mediastinum, hemangiosarcoma 

Mediastinum, sarcoma, metastatic, mesentery X 

Nose + + + + + + + A + + + + + + + + + + + + + + + + + 

Respiratory epithelium, adenoma 

Trachea + + + + + + + A + + + + + + + + + + + + + + + + + 

Special Senses System 

Harderian gland + 

Adenoma X 

Urinary System 

Kidney + + + + + + + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma, metastatic, mesentery 

Histiocytic sarcoma X 

Sarcoma, metastatic, mesentery 

Urinary bladder + + + + + + + A + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Histiocytic sarcoma X 

Sarcoma, metastatic, mesentery 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X X X 

Lymphoma malignant X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 249 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 32 ppm 

5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 8 8 9 0 0 0 2 2 2 2 2 3 3 3 4 4 5 5 5 6 7 7 9 1 3 

2 8 6 4 7 8 0 3 4 9 9 1 4 5 4 9 2 6 6 7 1 4 1 7 5 

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Total 

Carcass ID Number 2 2 3 2 2 0 3 2 4 4 4 0 1 0 3 0 5 1 3 4 3 1 1 4 1 Tissues/ 

2 0 6 5 6 7 9 7 4 1 2 1 6 9 7 8 0 7 8 9 4 3 5 3 4 Tumors 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoacanthoma, metastatic, mammary gland 3 

Alveolar/bronchiolar adenoma X X X X X X X X X 17 

Alveolar/bronchiolar adenoma, multiple X X X X X X X X X 12 

Alveolar/bronchiolar carcinoma X X X X X 8 

Alveolar/bronchiolar carcinoma, multiple X X X X X X X X 8 

Carcinoma, metastatic, mammary gland 2 

Hemangiosarcoma, metastatic, mesentery X 2 

Hepatocellular carcinoma, metastatic, liver 1 

Hepatocholangiocarcinoma, metastatic, liver 1 

Histiocytic sarcoma 2 

Sarcoma, metastatic, mesentery X 2 

Sarcoma, metastatic, skin X 1 

Mediastinum, alveolar/bronchiolar carcinoma, 

metastatic, lung X 1 

Mediastinum, hemangiosarcoma X 1 

Mediastinum, sarcoma, metastatic, mesentery 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Respiratory epithelium, adenoma X 1 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Special Senses System 

Harderian gland + + + 4 

Adenoma X X 3 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma, metastatic, mesentery X 1 

Histiocytic sarcoma 1 

Sarcoma, metastatic, mesentery X X 2 

Urinary bladder + + + + + + + + + M + + A + + + + M + + + + + + + 46 

Hemangiosarcoma X 1 

Histiocytic sarcoma 1 

Sarcoma, metastatic, mesentery X X 2 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 3 

Lymphoma malignant X 3 
 

 

 

 

 

 

 

 

 

 

 

 

 

250 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

Number of Days on Study 

0 2 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

0 5 2 3 8 4 5 6 6 6 8 2 2 2 2 3 3 3 4 6 7 7 7 8 9 

3 2 4 6 3 3 3 2 3 7 4 3 4 4 4 1 1 8 8 5 6 9 9 2 6 

Carcass ID Number 

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 

3 1 2 3 2 2 0 4 1 0 3 0 1 2 4 1 2 4 4 1 0 0 4 1 3 

8 1 5 4 9 1 5 1 6 1 5 9 7 2 9 5 6 5 0 0 4 2 6 4 0 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Sarcoma, metastatic, mesentery 

Mesentery 

Hemangioma 

Hemangiosarcoma 

Sarcoma 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

Sarcoma, metastatic, mesentery 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + A + M A A + + + + + + + + + + A + + + + + + + 

+ + + + + + A + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + M + + + + + + 

+ + + + + + A + + + + + + + + + + + + + + + + + + 

+ + + + + + A + + + + + + + + + + A + + + + + + + 

+ + + + + + A + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + A + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

X 

X X 

X X 

X 

+ + + + + + + + 

X X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + M + M M M + + M M + + + + + + M + + M + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X 

Pars intermedia, adenoma 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

General Body System 

None 

Genital System 

Clitoral gland + M + + + + + + + + M + + + + + M + + M + + + + M 

Ovary + + + + + + + + M + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma 

Polyp stromal X 

Sarcoma, metastatic, mesentery 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 251 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 0 1 1 2 2 3 3 3 3 3 3 3 3 4 4 5 5 6 6 7 7 8 3 3 3 

7 0 5 4 9 1 1 1 2 2 5 5 8 9 9 2 9 3 6 3 4 0 4 5 5 

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 Total 

Carcass ID Number 0 1 2 1 3 1 3 5 2 3 3 4 2 4 4 0 0 3 4 3 2 4 0 1 2 Tissues/ 

3 3 8 2 7 8 2 0 7 6 3 7 4 2 8 7 8 9 4 1 3 3 6 9 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + M + + + M + + + + M + + + + + + + + + + 42 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + M + + + + + + + + + + + + + + + + + + M + M + + 46 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma X X X X X X X X X 15 

Hepatocellular carcinoma, multiple X X X 4 

Hepatocellular adenoma X X X X X 7 

Hepatocellular adenoma, multiple X X X X X X X 9 

Sarcoma, metastatic, mesentery X 2 

Mesentery + + + + + + + + + + + + + 21 

Hemangioma X 1 

Hemangiosarcoma X X 4 

Sarcoma X X 3 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X X X 4 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, mesentery 1 

Cardiovascular System 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + M + + + M + + + + M + M + + + + M + 37 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X 4 

Pars intermedia, adenoma X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

General Body System 

None 

Genital System 

Clitoral gland M + M + M + M M + M + + + + M M + + M + + M + + + 35 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma X X 2 

Polyp stromal X X 3 

Sarcoma, metastatic, mesentery X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

252 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

0 2 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 0 5 2 3 8 4 5 6 6 6 8 2 2 2 2 3 3 3 4 6 7 7 7 8 9 

3 2 4 6 3 3 3 2 3 7 4 3 4 4 4 1 1 8 8 5 6 9 9 2 6 

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 

Carcass ID Number 3 1 2 3 2 2 0 4 1 0 3 0 1 2 4 1 2 4 4 1 0 0 4 1 3 

8 1 5 4 9 1 5 1 6 1 5 9 7 2 9 5 6 5 0 0 4 2 6 4 0 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + 

Iliac, sarcoma, metastatic, mesentery 

Lymph node, bronchial M + + + + + + + + + M + M M + + M + M + M + + M + 

Sarcoma, metastatic, mesentery 

Lymph node, mandibular + + + + + + + + + + M + + + + + + + M + + M M M + 

Lymph node, mesenteric + M + + + + + + + M + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Lymph node, mediastinal M + + + + + I + + + M + + M + + + + M + + + M + + 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Sarcoma, metastatic, mesentery 

Sarcoma, metastatic, skin X 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + M + + + + + + + M + + + + + + + M + + M + + M 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoacanthoma X 

Carcinoma X X X X X X X 

Carcinoma, multiple 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma 

Subcutaneous tissue, hemangiosarcoma X 

Subcutaneous tissue, sarcoma X X X X X X X 

Subcutaneous tissue, sarcoma, multiple X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar carcinoma, metastatic, lung 

Skeletal muscle + 

Sarcoma, metastatic, skin X 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X X X X X X 

Alveolar/bronchiolar adenoma, multiple X X X X X X X 

Alveolar/bronchiolar carcinoma X X X X X X X 

Alveolar/bronchiolar carcinoma, multiple X X 

Carcinoma, metastatic, mammary gland X X 

Carcinoma, metastatic, Zymbal's gland X 

Hepatocellular carcinoma, metastatic, liver X X 

Sarcoma, metastatic, mesentery 

Sarcoma, metastatic, skin X 

Mediastinum, alveolar/bronchiolar carcinoma,

 metastatic, lung 

Mediastinum, sarcoma, metastatic, mesentery 

Mediastinum, sarcoma, metastatic, skin X 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 253 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 0 1 1 2 2 3 3 3 3 3 3 3 3 4 4 5 5 6 6 7 7 8 3 3 3 

7 0 5 4 9 1 1 1 2 2 5 5 8 9 9 2 9 3 6 3 4 0 4 5 5 

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 Total 

Carcass ID Number 0 1 2 1 3 1 3 5 2 3 3 4 2 4 4 0 0 3 4 3 2 4 0 1 2 Tissues/ 

3 3 8 2 7 8 2 0 7 6 3 7 4 2 8 7 8 9 4 1 3 3 6 9 0 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + 2 

Iliac, sarcoma, metastatic, mesentery X 1 

Lymph node, bronchial + + + + + + + + + + + + + + + + M M + M + + + + M 38 

Sarcoma, metastatic, mesentery X 1 

Lymph node, mandibular + M + + + M + + + + + + + + + + + + M + + M + + M 40 

Lymph node, mesenteric + + + + + + + + M + + + + + + + + + M + + + + + + 46 

Hemangiosarcoma 1 

Lymph node, mediastinal M + + + + M + + + + + + + + + + + + M + + M + + + 40 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Sarcoma, metastatic, mesentery X 1 

Sarcoma, metastatic, skin 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus M + M + + + + M + + + M + + + I M + + + + + + + + 39 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoacanthoma X 2 

Carcinoma X X X X 11 

Carcinoma, multiple X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X 1 

Subcutaneous tissue, hemangiosarcoma 1 

Subcutaneous tissue, sarcoma X X X X X X X X X 16 

Subcutaneous tissue, sarcoma, multiple X 2 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar carcinoma, metastatic, lung X 1 

Skeletal muscle 1 

Sarcoma, metastatic, skin 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Larynx + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X X 10 

Alveolar/bronchiolar adenoma, multiple X X X X X X X X X 16 

Alveolar/bronchiolar carcinoma X X X X 11 

Alveolar/bronchiolar carcinoma, multiple X X X X X X X X X X X X X X X 17 

Carcinoma, metastatic, mammary gland 2 

Carcinoma, metastatic, Zymbal's gland X 2 

Hepatocellular carcinoma, metastatic, liver X X 4 

Sarcoma, metastatic, mesentery X 1 

Sarcoma, metastatic, skin X 2 

Mediastinum, alveolar/bronchiolar carcinoma, 

metastatic, lung X X 2 

Mediastinum, sarcoma, metastatic, mesentery X 1 

Mediastinum, sarcoma, metastatic, skin 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

254 Chloroprene, NTP TR 467 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

0 2 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

Number of Days on Study 0 5 2 3 8 4 5 6 6 6 8 2 2 2 2 3 3 3 4 6 7 7 7 8 9 

3 2 4 6 3 3 3 2 3 7 4 3 4 4 4 1 1 8 8 5 6 9 9 2 6 

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 

Carcass ID Number 3 1 2 3 2 2 0 4 1 0 3 0 1 2 4 1 2 4 4 1 0 0 4 1 3 

8 1 5 4 9 1 5 1 6 1 5 9 7 2 9 5 6 5 0 0 4 2 6 4 0 

Special Senses System 

Ear + 

Harderian gland + + 

Adenoma X X 

Carcinoma 

Zymbal’s gland + + 

Carcinoma X X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary bladder + + + + + + A + + I + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymphoma malignant 
 

 

 

 

 

Chloroprene, NTP TR 467 255 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Inhalation Study of Chloroprene: 80 ppm 

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 

Number of Days on Study 0 1 1 2 2 3 3 3 3 3 3 3 3 4 4 5 5 6 6 7 7 8 3 3 3 

7 0 5 4 9 1 1 1 2 2 5 5 8 9 9 2 9 3 6 3 4 0 4 5 5 

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 Total 

Carcass ID Number 0 1 2 1 3 1 3 5 2 3 3 4 2 4 4 0 0 3 4 3 2 4 0 1 2 Tissues/ 

3 3 8 2 7 8 2 0 7 6 3 7 4 2 8 7 8 9 4 1 3 3 6 9 0 Tumors 

Special Senses System 

Ear 1 

Harderian gland + + + + + + + 9 

Adenoma X X X X X X 8 

Carcinoma X 1 

Zymbal’s gland + 3 

Carcinoma X 3 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Urinary bladder + + + + + M + + + + + + + + + + + + + + + + + + + 47 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymphoma malignant X 1 
256 Chloroprene, NTP TR 467 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Harderian Gland: Adenoma 

Overall ratea 

Adjusted rateb 

Terminal ratec 

1/50 (2%) 

2.9% 

1/35 (3%) 

3/50 (6%) 

14.9% 

2/16 (13%) 

3/50 (6%) 

12.0% 

0/1 (0%) 

8/50 (16%) 

74.4% 

2/3 (67%) 

First incidence (days) 

Life table testd 734 (T) 

P<0.001 

621 

P=0.120 

524 

P=0.048 

467 

P<0.001 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

P=0.001 

P=0.006 

P=0.225 

P=0.309 

P=0.293 

P=0.309 

P=0.007 

P=0.015 

Harderian Gland: Adenoma or Carcinoma 

Overall rate 2/50 (4%) 5/50 (10%) 3/50 (6%) 9/50 (18%) 

Adjusted rate 5.0% 23.8% 12.0% 77.0% 

Terminal rate 1/35 (3%) 3/16 (19%) 0/1 (0%) 2/3 (67%) 

First incidence (days) 527 621 524 467 

Life table test P<0.001 P=0.065 P=0.157 P<0.001 

Logistic regression test P=0.004 P=0.186 P=0.577 P=0.016 

Cochran-Armitage test P=0.018 

Fisher exact test P=0.218 P=0.500 P=0.026 

Liver: Hepatocellular Adenoma 

Overall rate 17/50 (34%) 19/49 (39%) 11/50 (22%) 16/50 (32%) 

Adjusted rate 47.0% 69.1% 100.0% 85.1% 

Terminal rate 16/35 (46%) 9/16 (56%) 1/1 (100%) 1/3 (33%) 

First incidence (days) 637 523 505 383 

Life table test P<0.001 P=0.005 P<0.001 P<0.001 

Logistic regression test P=0.070 P=0.157 P=0.064 P=0.141 

Cochran-Armitage test P=0.359N 

Fisher exact test P=0.388 P=0.133N P=0.500N 

Liver: Hepatocellular Carcinoma 

Overall rate 4/50 (8%) 11/49 (22%) 14/50 (28%) 19/50 (38%) 

Adjusted rate 10.3% 41.8% 100.0% 91.5% 

Terminal rate 2/35 (6%) 4/16 (25%) 1/1 (100%) 2/3 (67%) 

First incidence (days) 493 440 503 524 

Life table test P<0.001 P=0.004 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.040 P=0.002 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.041 P=0.009 P<0.001 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 20/50 (40%) 26/49 (53%) 20/50 (40%) 30/50 (60%) 

Adjusted rate 52.2% 81.8% 100.0% 100.0% 

Terminal rate 17/35 (49%) 11/16 (69%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 493 440 503 383 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.051 P=0.011 P<0.001 

Cochran-Armitage test P=0.054 

Fisher exact test P=0.135 P=0.581N P=0.036 
Chloroprene, NTP TR 467 257 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 2/50 (4%) 16/49 (33%) 29/50 (58%) 26/50 (52%) 

Adjusted rate 5.7% 57.9% 100.0% 100.0% 

Terminal rate 2/35 (6%) 6/16 (38%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 734 (T) 447 346 453 

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 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 2/50 (4%) 14/49 (29%) 16/50 (32%) 28/50 (56%) 

Adjusted rate 5.5% 51.9% 100.0% 95.4% 

Terminal rate 1/35 (3%) 6/16 (38%) 1/1 (100%) 2/3 (67%) 

First incidence (days) 706 447 524 324 

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 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 4/50 (8%) 28/49 (57%) 34/50 (68%) 42/50 (84%) 

Adjusted rate 11.0% 83.5% 100.0% 100.0% 

Terminal rate 3/35 (9%) 11/16 (69%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 706 447 346 324 

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 

Mammary Gland: Adenoacanthoma 

Overall rate 0/50 (0%) 1/50 (2%) 3/50 (6%) 2/50 (4%) 

Adjusted rate 0.0% 2.1% 7.7% 7.9% 

Terminal rate 

First incidence (days) 

0/35 (0%) 

—e 0/16 (0%) 

440 

0/1 (0%) 

425 

0/3 (0%) 

582 

Life table test P=0.147 P=0.492 P=0.091 P=0.128 

Logistic regression test P=0.355 P=0.496 P=0.205 P=0.252 

Cochran-Armitage test P=0.216 

Fisher exact test P=0.500 P=0.121 P=0.247 

Mammary Gland: Carcinoma 

Overall rate 3/50 (6%) 4/50 (8%) 7/50 (14%) 12/50 (24%) 

Adjusted rate 7.4% 13.6% 35.1% 56.4% 

Terminal rate 1/35 (3%) 1/16 (6%) 0/1 (0%) 1/3 (33%) 

First incidence (days) 527 447 394 336 

Life table test P<0.001 P=0.322 P=0.003 P<0.001 

Logistic regression test P=0.008 P=0.553 P=0.207 P=0.036 

Cochran-Armitage test P=0.003 

Fisher exact test P=0.500 P=0.159 P=0.011 
 

258 Chloroprene, NTP TR 467 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Mammary Gland: Adenoma or Carcinoma 

Overall rate 3/50 (6%) 5/50 (10%) 8/50 (16%) 12/50 (24%) 

Adjusted rate 7.4% 18.4% 37.0% 56.4% 

Terminal rate 1/35 (3%) 1/16 (6%) 0/1 (0%) 1/3 (33%) 

First incidence (days) 527 447 394 336 

Life table test P<0.001 P=0.179 P=0.001 P<0.001 

Logistic regression test P=0.013 P=0.397 P=0.152 P=0.036 

Cochran-Armitage test P=0.005 

Fisher exact test P=0.357 P=0.100 P=0.011 

Mesentery: Hemangiosarcoma 

Overall rate 0/50 (0%) 4/50 (8%) 13/50 (26%) 4/50 (8%) 

Adjusted rate 0.0% 18.6% 59.3% 15.8% 

Terminal rate 0/35 (0%) 1/16 (6%) 0/1 (0%) 0/3 (0%) 

First incidence (days) — 691 389 523 

Life table test P=0.008 P=0.015 P<0.001 P=0.016 

Logistic regression test P=0.525N P=0.032 P<0.001 P=0.072 

Cochran-Armitage test P=0.206 

Fisher exact test P=0.059 P<0.001 P=0.059 

Mesentery: Hemangioma or Hemangiosarcoma 

Overall rate 0/50 (0%) 4/50 (8%) 15/50 (30%) 5/50 (10%) 

Adjusted rate 0.0% 18.6% 100.0% 43.9% 

Terminal rate 0/35 (0%) 1/16 (6%) 1/1 (100%) 1/3 (33%) 

First incidence (days) — 691 389 523 

Life table test P<0.001 P=0.015 P<0.001 P=0.001 

Logistic regression test P=0.132 P=0.032 P<0.001 P=0.023 

Cochran-Armitage test P=0.128 

Fisher exact test P=0.059 P<0.001 P=0.028 

Mesentery: Sarcoma 

Overall rate 0/50 (0%) 4/50 (8%) 8/50 (16%) 3/50 (6%) 

Adjusted rate 0.0% 16.3% 46.5% 12.6% 

Terminal rate 0/35 (0%) 1/16 (6%) 0/1 (0%) 0/3 (0%) 

First incidence (days) — 523 463 443 

Life table test P=0.018 P=0.023 P<0.001 P=0.041 

Logistic regression test P=0.308 P=0.060 P=0.004 P=0.157 

Cochran-Armitage test P=0.313 

Fisher exact test P=0.059 P=0.003 P=0.121 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 4/49 (8%) 6/48 (13%) 4/48 (8%) 4/50 (8%) 

Adjusted rate 11.1% 30.5% 31.6% 34.7% 

Terminal rate 3/35 (9%) 3/15 (20%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 729 636 620 443 

Life table test P=0.006 P=0.056 P=0.002 P=0.027 

Logistic regression test P=0.299 P=0.146 P=0.124 P=0.525 

Cochran-Armitage test P=0.439N 

Fisher exact test P=0.357 P=0.631 P=0.631N 
 

Chloroprene, NTP TR 467 259 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Skin (Subcutaneous Tissue): Sarcoma 

Overall rate 0/50 (0%) 11/50 (22%) 11/50 (22%) 18/50 (36%) 

Adjusted rate 0.0% 35.3% 100.0% 69.6% 

Terminal rate 0/35 (0%) 2/16 (13%) 1/1 (100%) 0/3 (0%) 

First incidence (days) — 285 524 462 

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 

Stomach (Forestomach): Squamous Cell Papilloma 

Overall rate 0/50 (0%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 0.0% 0.0% 0.0% 18.8% 

Terminal rate 0/35 (0%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) — — — 576 

f Life table test P<0.001 — — P=0.010 

Logistic regression test P=0.001 — — P=0.053 

Cochran-Armitage test P=0.002 

Fisher exact test — — P=0.059 

Stomach (Forestomach): Squamous Cell Papilloma or Squamous Cell Carcinoma 

Overall rate 1/50 (2%) 0/50 (0%) 0/50 (0%) 4/50 (8%) 

Adjusted rate 2.9% 0.0% 0.0% 18.8% 

Terminal rate 1/35 (3%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 734 (T) — — 576 

Life table test P<0.001 P=0.656N P=0.998N P=0.015 

Logistic regression test P=0.007 P=0.656N P=0.998N P=0.120 

Cochran-Armitage test P=0.018 

Fisher exact test P=0.500N P=0.500N P=0.181 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 1/50 (2%) 3/49 (6%) 1/49 (2%) 0/50 (0%)
 

Adjusted rate 2.9% 14.3% 12.5% 0.0%
 

Terminal rate 1/35 (3%) 1/16 (6%) 0/1 (0%) 0/3 (0%)
 

First incidence (days) 734 (T) 673 656 —
 

Life table test P=0.566 P=0.121 P=0.222 P=0.941N 

Logistic regression test P=0.535N P=0.197 P=0.543 P=0.941N 

Cochran-Armitage test P=0.179N
 

Fisher exact test P=0.301 P=0.747 P=0.500N 

Uterus: Stromal Polyp 

Overall rate 2/50 (4%) 4/50 (8%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 5.7% 17.7% 6.7% 23.2% 

Terminal rate 2/35 (6%) 2/16 (13%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 734 (T) 551 537 443 

Life table test P=0.037 P=0.118 P=0.187 P=0.037 

Logistic regression test P=0.438 P=0.270 P=0.668 P=0.417 

Cochran-Armitage test P=0.549 

Fisher exact test P=0.339 P=0.691N P=0.500 
 

 

260 Chloroprene, NTP TR 467 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Zymbal’s Gland: Carcinoma 

Overall rate 0/50 (0%) 0/50 (0%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 0.0% 10.8% 

Terminal rate 0/35 (0%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) — — — 565 

Life table test P=0.004 — — P=0.054 

Logistic regression test P=0.009 — — P=0.137 

Cochran-Armitage test P=0.010 

Fisher exact test — — P=0.121 

All Organs: Hemangioma 

Overall rate 0/50 (0%) 0/50 (0%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 100.0% 39.5% 

Terminal rate 0/35 (0%) 0/16 (0%) 1/1 (100%) 1/3 (33%) 

First incidence (days) — — 607 624 

Life table test P<0.001 — P=0.010 P=0.007 

Logistic regression test P=0.004 — P=0.072 P=0.037 

Cochran-Armitage test P=0.032 

Fisher exact test — P=0.247 P=0.121 

All Organs: Hemangiosarcoma 

Overall rate 4/50 (8%) 6/50 (12%) 17/50 (34%) 5/50 (10%) 

Adjusted rate 10.6% 25.7% 100.0% 18.3% 

Terminal rate 3/35 (9%) 2/16 (13%) 1/1 (100%) 0/3 (0%) 

First incidence (days) 541 482 216 523 

Life table test P=0.017 P=0.104 P<0.001 P=0.061 

Logistic regression test P=0.493N P=0.330 P=0.009 P=0.486 

Cochran-Armitage test P=0.504 

Fisher exact test P=0.370 P=0.001 P=0.500 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 4/50 (8%) 6/50 (12%) 18/50 (36%) 8/50 (16%) 

Adjusted rate 10.6% 25.7% 100.0% 50.8% 

Terminal rate 3/35 (9%) 2/16 (13%) 1/1 (100%) 1/3 (33%) 

First incidence (days) 541 482 216 523 

Life table test P<0.001 P=0.104 P<0.001 P=0.002 

Logistic regression test P=0.248 P=0.330 P=0.005 P=0.110 

Cochran-Armitage test P=0.189 

Fisher exact test P=0.370 P<0.001 P=0.178 

All Organs: Histiocytic Sarcoma 

Overall rate 1/50 (2%) 2/50 (4%) 3/50 (6%) 0/50 (0%) 

Adjusted rate 2.4% 6.9% 6.7% 0.0% 

Terminal rate 0/35 (0%) 0/16 (0%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 637 551 378 — 

Life table test P=0.508N P=0.392 P=0.180 P=0.733N 

Logistic regression test P=0.169N P=0.528 P=0.492 P=0.521N 

Cochran-Armitage test P=0.285N 

Fisher exact test P=0.500 P=0.309 P=0.500N 
261 

c 

Chloroprene, NTP TR 467 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

All Organs: Malignant Lymphoma 

Overall rate 7/50 (14%) 7/50 (14%) 3/50 (6%) 1/50 (2%) 

Adjusted rate 18.0% 26.9% 22.3% 10.0% 

Terminal rate 5/35 (14%) 2/16 (13%) 0/1 (0%) 0/3 (0%) 

First incidence (days) 35 548 539 652 

Life table test P=0.539N P=0.234 P=0.216 P=0.606N 

Logistic regression test P=0.020N P=0.579N P=0.103N P=0.021N 

Cochran-Armitage test P=0.014N 

Fisher exact test P=0.613N P=0.159N P=0.030N 

All Organs: Benign Neoplasms 

Overall rate 22/50 (44%) 32/50 (64%) 38/50 (76%) 42/50 (84%) 

Adjusted rate 57.8% 87.7% 100.0% 100.0% 

Terminal rate 19/35 (54%) 12/16 (75%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 637 447 346 383 

Life table test P<0.001 P<0.001 P<0.001 P<0.001 

Logistic regression test P<0.001 P=0.003 P<0.001 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.035 P=0.001 P<0.001 

All Organs: Malignant Neoplasms 

Overall rate 20/50 (40%) 42/50 (84%) 49/50 (98%) 48/50 (96%) 

Adjusted rate 44.8% 89.3% 100.0% 100.0% 

Terminal rate 11/35 (31%) 11/16 (69%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 35 285 216 324 

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 34/50 (68%) 47/50 (94%) 50/50 (100%) 48/50 (96%) 

Adjusted rate 77.0% 97.9% 100.0% 100.0% 

Terminal rate 25/35 (71%) 15/16 (94%) 1/1 (100%) 3/3 (100%) 

First incidence (days) 35 285 216 324 

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, pituitary 

gland, 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 chamber 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 chamber 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 by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
262 Chloroprene, NTP TR 467 

TABLE D4a 

Historical Incidence of Alveolar/bronchiolar Neoplasms in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 4/50 0/50 4/50 

Acetonitrile 7/49 1/49 8/49 

Allyl Glycidyl Ether 0/50 0/50 0/50 

2-Chloroacetophenone 4/50 3/50 6/50 

l-Epinephrine Hydrochloride 3/50 2/50 5/50 

Chloroethane 2/49 3/49 5/49 

Hexachlorocyclopentadiene 4/48 3/48 7/48 

o-Chlorobenzalmalononitrile 4/50 1/50 5/50 

Ozone 4/50 2/50 6/50 

Overall Historical Incidence 

Total 61/939 (6.5%) 38/939 (4.1%) 97/939 (10.3%) 

Standard deviation 3.2% 3.2% 3.7% 

Range 0%-14% 0%-12% 0%-16% 

a Data as of 12 May 1995 

TABLE D4b 

Historical Incidence of Hemangioma and Hemangiosarcoma (All Sites) in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Hemangioma Hemangiosarcoma Hemangioma or 

Hemangiosarcoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 2/50 3/50 5/50 

Acetonitrile 2/49 3/49 5/49 

Allyl Glycidyl Ether 0/50 2/50 2/50 

2-Chloroacetophenone 0/50 0/50 0/50 

l-Epinephrine Hydrochloride 2/50 2/50 4/50 

Chloroethane 0/49 1/49 1/49 

Hexachlorocyclopentadiene 1/49 0/49 1/49 

o-Chlorobenzalmalononitrile 1/50 2/50 3/50 

Ozone 0/50 2/50 2/50 

Overall Historical Incidence 

Total 15/941 (1.6%) 28/941 (3.0%) 43/941 (4.6%) 

Standard deviation 1.9% 2.3% 3.2% 

Range 0%-4% 0%-6% 0%-10% 

a Data as of 12 May 1995 
Chloroprene, NTP TR 467 263 

TABLE D4c 

Historical Incidence of Harderian Gland Neoplasms in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 8/50 0/50 8/50 

Acetonitrile 3/49 0/49 3/49 

Allyl Glycidyl Ether 0/50 0/50 0/50 

2-Chloroacetophenone 0/50 0/50 0/50 

l-Epinephrine Hydrochloride 1/50 1/50 2/50 

Chloroethane 2/49 0/49 2/49 

Hexachlorocyclopentadiene 4/49 1/49 5/49 

o-Chlorobenzalmalononitrile 2/50 2/50 4/50 

Ozone 1/50 2/50 3/50 

Overall Historical Incidence 

Total 26/941 (2.8%) 6/941 (0.6%) 32/941 (3.4%) 

Standard deviation 4.1% 1.4% 4.4% 

Range 0%-16% 0%-4% 0%-16% 

a Data as of 12 May 1995 

TABLE D4d 

Historical Incidence of Mammary Gland Neoplasms in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Adenoacanthoma Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 0/50 

Acetonitrile 0/49 3/49 

Allyl Glycidyl Ether 0/50 4/50 

2-Chloroacetophenone 0/50 4/50 

l-Epinephrine Hydrochloride 0/50 1/50 

Chloroethane 1/49 2/49 

Hexachlorocyclopentadiene 0/49 1/49 

o-Chlorobenzalmalononitrile 0/50 3/50 

Ozone 0/50 1/50 

Overall Historical Incidence 

Total 1/941 (0.1%) 29/941 (3.1%) 

Standard deviation 0.5% 2.6% 

Range 0%-2% 0%-8% 

a Data as of 12 May 1995 
264 Chloroprene, NTP TR 467 

TABLE D4e 

Historical Incidence of Hepatocellular Neoplasms in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 11/49 4/49 15/49 

Acetonitrile 4/49 7/49 9/49 

Allyl Glycidyl Ether 1/50 5/50 6/50 

2-Chloroacetophenone 4/50 8/50 12/50 

l-Epinephrine Hydrochloride 2/50 1/50 3/50 

Chloroethane 0/49 3/49 3/49 

Hexachlorocyclopentadiene 5/49 4/49 9/49 

o-Chlorobenzalmalononitrile 4/50 7/50 11/50 

Ozone 20/50 15/50 27/50 

Overall Historical Incidence 

Total 114/937 (12.2%) 103/937 (11%) 200/937 (21.3%) 

Standard deviation 9.7% 6.7% 11.9% 

Range 0%-40% 0%-30% 3%-54% 

a Data as of 12 May 1995 

TABLE D4f 

Historical Incidence of Skin Sarcoma in Chamber Control Female B6C3F a Mice 1 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 1/50 

Acetonitrile 0/49 

Allyl Glycidyl Ether 0/50 

2-Chloroacetophenone 0/50 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 1/49 

Hexachlorocyclopentadiene 0/49 

o-Chlorobenzalmalononitrile 1/50 

Ozone 1/50 

Overall Historical Incidence 

Total 5/941 (0.5%) 

Standard deviation 0.9% 

Range 0%-2% 

a Data as of 12 May 1995 
Chloroprene, NTP TR 467 265 

TABLE D4g 

Historical Incidence of Mesentery Sarcoma in Chamber Control Female B6C3F a Mice 1 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 

Acetonitrile 0/49 

Allyl Glycidyl Ether 0/50 

2-Chloroacetophenone 0/50 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 0/49 

Hexachlorocyclopentadiene 0/49 

o-Chlorobenzalmalononitrile 0/50 

Ozone 0/50 

Overall Historical Incidence 

Total 0/941 

a Data as of 12 May 1995 

TABLE D4h 

Historical Incidence of Forestomach Neoplasms in Chamber Control Female B6C3F a Mice 1 

Incidence in Controls 

Study Squamous Cell Papilloma Squamous Cell Papilloma 

or Carcinoma 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 0/50 

Acetonitrile 1/49 1/49 

Allyl Glycidyl Ether 1/50 1/50 

2-Chloroacetophenone 0/50 1/50 

l-Epinephrine Hydrochloride 0/50 0/50 

Chloroethane 0/49 0/49 

Hexachlorocyclopentadiene 0/49 0/49 

o-Chlorobenzalmalononitrile 2/50 2/50 

Ozone 0/50 0/50 

Overall Historical Incidence 

Total 11/941 (1.2%) 13/941 (1.4%) 

Standard deviation 1.8% 1.8% 

Range 0%-6% 0%-6% 

a Data as of 12 May 1995 
266 Chloroprene, NTP TR 467 

TABLE D4i 

Historical Incidence of Zymbal’s Gland Carcinoma in Chamber Control Female B6C3F a Mice 1 

Study Incidence in Controls 

Historical Incidence at Battelle Pacific Northwest Laboratories 

1,3-Butadiene 0/50 

Acetonitrile 0/49 

Allyl Glycidyl Ether 0/50 

2-Chloroacetophenone 0/50 

l-Epinephrine Hydrochloride 0/50 

Chloroethane 0/49 

Hexachlorocyclopentadiene 0/49 

o-Chlorobenzalmalononitrile 0/50 

Ozone 0/50 

Overall Historical Incidence 

Total 0/941 

a Data as of 12 May 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 267 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study of Chloroprenea 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Disposition Summary 

Animals initially in study 50 50 50 50 

Early deaths 

Accidental deaths 1 1 

Moribund 13 27 38 41 

Natural deaths 2 6 11 5 

Survivors 

Died last week of study 1 

Terminal sacrifice 35 16 1 2 

Animals examined microscopically 50 50 50 50 

Alimentary System 

Esophagus (49) (48) (50) (50) 

Epithelium, hyperplasia 1 (2%) 

Gallbladder (45) (44) (42) (42) 

Angiectasis 1 (2%) 

Cyst 1 (2%) 

Degeneration, hyaline 2 (5%) 

Inflammation, suppurative 3 (7%) 1 (2%) 2 (5%) 2 (5%) 

Necrosis 1 (2%) 

Intestine large, colon (50) (47) (48) (49) 

Inflammation, suppurative 1 (2%) 

Intestine large, cecum (50) (45) (45) (49) 

Hemorrhage 1 (2%) 

Lymphoid tissue, hyperplasia 1 (2%) 1 (2%) 

Intestine small, duodenum (49) (45) (42) (48) 

Necrosis 1 (2%) 

Epithelium, hyperplasia 1 (2%) 

Intestine small, jejunum (50) (46) (44) (49) 

Epithelium, hyperplasia 1 (2%) 

Peyer's patch, hyperplasia 1 (2%) 1 (2%) 

Liver (50) (49) (50) (50) 

Angiectasis 2 (4%) 3 (6%) 4 (8%) 1 (2%) 

Basophilic focus 4 (8%) 2 (4%) 

Clear cell focus 1 (2%) 

Degeneration, fatty 1 (2%) 2 (4%) 

Eosinophilic focus 13 (26%) 12 (24%) 15 (30%) 28 (56%) 

Fibrosis 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 5 (10%) 9 (18%) 12 (24%) 

Hyperplasia, lymphoid 1 (2%) 

Inflammation, chronic 1 (2%) 

Mineralization 1 (2%) 1 (2%) 

Necrosis 4 (8%) 5 (10%) 13 (26%) 7 (14%) 

Regeneration 1 (2%) 

Vacuolization cytoplasmic 2 (4%) 1 (2%) 

Bile duct, cyst 1 (2%) 1 (2%) 

Bile duct, hyperplasia 2 (4%) 1 (2%) 1 (2%) 3 (6%) 

Centrilobular, degeneration 2 (4%) 3 (6%) 

Centrilobular, necrosis 2 (4%) 2 (4%) 3 (6%) 

Mesentery (10) (14) (27) (21) 

Angiectasis 1 (10%) 1 (5%) 

Hemorrhage 1 (4%) 

Fat, inflammation, chronic 1 (7%) 

Fat, necrosis 7 (70%) 3 (21%) 2 (7%) 18 (86%) 

a Number of animals examined microscopically at the site and the number of animals with lesion 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

268 Chloroprene, NTP TR 467 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Alimentary System (continued) 

Oral mucosa (1) 

Pharyngeal, hyperplasia 1 (100%) 

Pancreas (49) (49) (48) (50) 

Angiectasis 1 (2%) 

Atrophy 3 (6%) 6 (12%) 5 (10%) 3 (6%) 

Hyperplasia 1 (2%) 

Hypertrophy 2 (4%) 3 (6%) 3 (6%) 4 (8%) 

Duct, cyst 1 (2%) 

Salivary glands (50) (49) (50) (50) 

Inflammation 1 (2%) 

Stomach, forestomach (50) (49) (49) (50) 

Diverticulum 2 (4%) 

Hyperplasia 3 (6%) 

Inflammation, suppurative 2 (4%) 8 (16%) 

Mineralization 1 (2%) 

Ulcer 2 (4%) 3 (6%) 5 (10%) 

Epithelium, hyperplasia 4 (8%) 3 (6%) 8 (16%) 27 (54%) 

Stomach, glandular (50) (48) (49) (50) 

Degeneration, hyaline 1 (2%) 

Inflammation, suppurative 4 (8%) 

Necrosis 3 (6%) 

Epithelium, hyperplasia 1 (2%) 

Cardiovascular System 

Blood vessel (2) 

Hyperplasia 1 (50%) 

Inflammation 1 (50%) 

Heart (50) (49) (50) (50) 

Cardiomyopathy 35 (70%) 35 (71%) 34 (68%) 33 (66%) 

Mineralization 1 (2%) 

Artery, inflammation 1 (2%) 

Atrium, thrombosis 1 (2%) 

Endocrine System 

Adrenal cortex (50) (48) (49) (50) 

Hematopoietic cell proliferation 1 (2%) 2 (4%) 1 (2%) 

Hyperplasia 1 (2%) 

Hypertrophy 2 (4%) 2 (4%) 3 (6%) 2 (4%) 

Inflammation, focal, granulomatous 1 (2%) 

Necrosis 1 (2%) 

Capsule, hyperplasia 1 (2%) 

Adrenal medulla (50) (48) (48) (50) 

Hyperplasia 3 (6%) 2 (4%) 1 (2%) 

Necrosis 1 (2%) 

Islets, pancreatic (49) (49) (48) (50) 

Hyperplasia 1 (2%) 1 (2%) 

Pituitary gland (49) (48) (48) (50) 

Pars distalis, angiectasis 1 (2%) 1 (2%) 

Pars distalis, hyperplasia 18 (37%) 8 (17%) 7 (15%) 9 (18%) 

Pars intermedia, hyperplasia 1 (2%) 1 (2%) 

Thyroid gland (50) (49) (49) (50) 

Follicular cell, hyperplasia 12 (24%) 15 (31%) 8 (16%) 4 (8%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 269 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

General Body System 

None 

Genital System 

Ovary (48) (47) (47) (49) 

Angiectasis 1 (2%) 

Atrophy 7 (15%) 8 (17%) 7 (15%) 6 (12%) 

Cyst 20 (42%) 18 (38%) 5 (11%) 6 (12%) 

Fibrosis 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 

Corpus luteum, hyperplasia 1 (2%) 

Granulosa cell, hyperplasia 2 (4%) 1 (2%) 

Uterus (50) (49) (50) (50) 

Angiectasis 3 (6%) 2 (4%) 2 (4%) 

Hemorrhage 1 (2%) 2 (4%) 

Hydrometra 3 (6%) 6 (12%) 2 (4%) 8 (16%) 

Hyperplasia, cystic 5 (10%) 3 (6%) 2 (4%) 3 (6%) 

Inflammation, suppurative 1 (2%) 2 (4%) 

Endometrium, hyperplasia 1 (2%) 

Hematopoietic System 

Bone marrow (50) (49) (49) (50) 

Angiectasis 1 (2%) 

Atrophy 1 (2%) 

Hyperplasia 2 (4%) 2 (4%) 3 (6%) 4 (8%) 

Necrosis 1 (2%) 

Lymph node (4) (3) (5) (2) 

Hyperplasia 1 (20%) 

Iliac, hyperplasia 1 (25%) 1 (20%) 1 (50%) 

Pancreatic, hyperplasia 1 (25%) 

Renal, hyperplasia 1 (33%) 

Lymph node, bronchial (32) (31) (34) (38) 

Congestion 1 (3%) 

Hematopoietic cell proliferation 1 (3%) 1 (3%) 

Hyperplasia 2 (6%) 3 (10%) 4 (12%) 3 (8%) 

Lymph node, mandibular (32) (40) (33) (40) 

Angiectasis 1 (3%) 

Hematopoietic cell proliferation 1 (3%) 

Hyperplasia 2 (6%) 2 (5%) 4 (10%) 

Infiltration cellular, mast cell 1 (3%) 

Lymph node, mesenteric (48) (45) (48) (46) 

Angiectasis 1 (2%) 1 (2%) 1 (2%) 

Congestion 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 2 (4%) 1 (2%) 

Hemorrhage 1 (2%) 

Hyperplasia 6 (13%) 1 (2%) 2 (4%) 2 (4%) 

Inflammation, chronic 1 (2%) 

Lymph node, mediastinal (38) (44) (45) (40) 

Hematopoietic cell proliferation 1 (2%) 

Hyperplasia 1 (2%) 7 (16%) 7 (18%) 

Spleen (50) (49) (49) (50) 

Angiectasis 1 (2%) 

Hematopoietic cell proliferation 13 (26%) 25 (51%) 42 (86%) 39 (78%) 

Hyperplasia, lymphoid 9 (18%) 5 (10%) 1 (2%) 3 (6%) 

Infiltration cellular, mononuclear cell 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

270 Chloroprene, NTP TR 467 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Hematopoietic System (continued) 

Thymus (44) (35) (39) (39) 

Angiectasis 1 (2%) 1 (3%) 

Atrophy 1 (2%) 3 (8%) 1 (3%) 

Hyperplasia, lymphoid 2 (5%) 

Integumentary System 

Mammary gland (49) (49) (50) (50) 

Galactocele 1 (2%) 

Hyperplasia 1 (2%) 1 (2%) 3 (6%) 

Skin (49) (49) (50) (50) 

Inflammation, chronic active 1 (2%) 3 (6%) 1 (2%) 

Sebaceous gland, hyperplasia 2 (4%) 

Subcutaneous tissue, inflammation,

 suppurative 2 (4%) 

Musculoskeletal System 

Bone (50) (49) (50) (50) 

Fibrous osteodystrophy 15 (30%) 11 (22%) 6 (12%) 9 (18%) 

Fracture 1 (2%) 

Nervous System 

Brain (50) (49) (50) (50) 

Gliosis 1 (2%) 

Hemorrhage 1 (2%) 

Meninges, inflammation, chronic 3 (6%) 1 (2%) 

Spinal cord (1) 

Degeneration 1 (100%) 

Respiratory System 

Larynx (50) (49) (50) (50) 

Hyperplasia 1 (2%) 1 (2%) 1 (2%) 5 (10%) 

Inflammation, suppurative 1 (2%) 1 (2%) 

Epiglottis, hyperplasia 1 (2%) 

Lung (50) (49) (50) (50) 

Angiectasis 1 (2%) 

Hemorrhage 1 (2%) 1 (2%) 1 (2%) 

Infiltration cellular, histiocyte 1 (2%) 14 (29%) 18 (36%) 23 (46%) 

Inflammation, chronic, focal 1 (2%) 

Thrombosis 1 (2%) 

Alveolar epithelium, hyperplasia 1 (2%) 1 (2%) 1 (2%) 4 (8%) 

Bronchiole, hyperplasia 15 (31%) 12 (24%) 30 (60%) 

Perivascular, infiltration cellular 1 (2%) 1 (2%) 

Nose (50) (49) (49) (50) 

Infiltration cellular, mast cell 1 (2%) 

Inflammation, chronic 1 (2%) 

Inflammation, suppurative 1 (2%) 3 (6%) 4 (8%) 

Metaplasia 1 (2%) 

Nasolacrimal duct, inflammation, suppurative 1 (2%) 

Olfactory epithelium, atrophy 6 (12%) 5 (10%) 4 (8%) 47 (94%) 

Olfactory epithelium, degeneration, hyaline 3 (6%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chloroprene, NTP TR 467 271 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Inhalation Study of Chloroprene 

Chamber Control 12.8 ppm 32 ppm 80 ppm 

Respiratory System (continued) 

Nose (continued) (50) (49) (49) (50) 

Olfactory epithelium, hyperplasia,

 adenomatous 2 (4%) 3 (6%) 44 (88%) 

Olfactory epithelium, metaplasia 2 (4%) 3 (6%) 1 (2%) 44 (88%) 

Olfactory epithelium, glands, inflammation,

 acute 1 (2%) 

Respiratory epithelium, degeneration, hyaline 17 (34%) 9 (18%) 10 (20%) 25 (50%) 

Respiratory epithelium, necrosis 1 (2%) 

Special Senses System 

Eye (1) (1) 

Inflammation 1 (100%) 

Urinary System 

Kidney (50) (49) (49) (50) 

Hydronephrosis 1 (2%) 1 (2%) 4 (8%) 

Inflammation, chronic active 1 (2%) 

Metaplasia, osseous 1 (2%) 1 (2%) 

Nephropathy 41 (82%) 35 (71%) 25 (51%) 20 (40%) 

Pigmentation, hemosiderin 1 (2%) 3 (6%) 

Artery, inflammation, chronic 1 (2%) 

Papilla, necrosis 1 (2%) 

Renal tubule, mineralization 1 (2%) 

Renal tubule, necrosis 4 (8%) 

Urinary bladder (50) (47) (46) (47) 

Hemorrhage 1 (2%) 
272 Chloroprene, NTP TR 467
 
273 

APPENDIX E
 

GENETIC TOXICOLOGY
 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL .............................. 274
 

MOUSE BONE MARROW CHROMOSOMAL ABERRATIONS
 

TABLE E2 Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster
 

DROSOPHILA MELANOGASTER TEST PROTOCOL ........................................ 274
 

AND SISTER CHROMATID EXCHANGE TEST PROTOCOLS .................................. 275
 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOLS ............................. 275
 

RESULTS ............................................................... 276
 

TABLE E1 Mutagenicity of Chloroprene in Salmonella typhimurium ....................... 277
 

by Chloroprene ................................................... 278
 

TABLE E3 Induction of Chromosomal Aberrations in Mouse Bone Marrow Cells 

by Chloroprene ................................................... 278
 

TABLE E4 Induction of Sister Chromatid Exchanges in Mouse Bone Marrow Cells 

by Chloroprene ................................................... 279
 

TABLE E5 Frequency of Micronuclei in Peripheral Blood Erythrocytes of Male Mice 

Following Treatment with Chloroprene by Inhalation for 16 Days ................. 279
 

TABLE E6 Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice 

Following Treatment with Chloroprene by Inhalation for 13 Weeks ................ 280
 
274 Chloroprene, NTP TR 467 

GENETIC TOXICOLOGY
 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL 

Testing was performed as reported by Zeiger et al. (1987). Chloroprene was sent to the laboratory as a 

coded aliquot from Radian Corporation (Austin, TX). It was incubated with the Salmonella typhimurium 

tester strains (TA98, TA100, TA1535, and TA1537) either in buffer or S9 mix (metabolic activation 

enzymes and cofactors from Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver) for 

20 minutes at 37E C. Top agar supplemented with L-histidine and d-biotin was added, and the contents of 

the tubes were mixed and poured onto the surfaces of minimal glucose agar plates. Histidine-independent 

mutant colonies arising on these plates were counted following incubation for 2 days at 37E C. 

Each trial consisted of triplicate plates of concurrent positive and negative controls and five doses of 

chloroprene. The high dose was limited by toxicity. All trials were repeated. 

In this assay, a positive response is defined as a reproducible, dose-related increase in histidine-independent 

(revertant) colonies in any one strain/activation combination. An equivocal response is defined as an 

increase in revertants that is not dose related, not reproducible, or not of sufficient magnitude to support a 

determination of mutagenicity. A negative response is obtained when no increase in revertant colonies is 

observed following chemical treatment. There is no minimum percentage or fold increase required for a 

chemical to be judged positive or weakly positive. 

DROSOPHILA MELANOGASTER TEST PROTOCOL 

The assay for induction of sex-linked recessive lethal (SLRL) mutations was performed with adult flies as 

described by Foureman et al. (1994). Chloroprene was supplied as a coded aliquot by Radian Corporation. 

It was assayed in the SLRL test by feeding for 3 days to adult Canton-S wild-type males no more than 

24 hours old at the beginning of treatment. Because no response was obtained, chloroprene was retested by 

injection into adult males. 

To administer chloroprene by injection, a glass Pasteur pipette was drawn out in a flame to a microfine 

filament and the tip was broken off to allow delivery of the test solution. Injection was performed either 

manually, by attaching a rubber bulb to the other end of the pipette and forcing through sufficient solution 

(0.2 to 0.3 FL) to slightly distend the abdomen of the fly or by attaching the pipette to a microinjector that 

automatically delivers a calibrated volume. Flies were anesthetized with ether and immobilized on a strip of 

tape. Injection into the thorax, under the wing, was performed with the aid of a dissecting microscope. 

Toxicity tests were performed to set concentrations of chloroprene at a level that would induce approximately 

30% mortality after 72 hours of feeding or 24 hours after injection, while keeping induced sterility at an 

acceptable level. Canton-S males were allowed to feed for 72 hours on a 5% sucrose solution of chloroprene 

dissolved in ethanol. In the injection experiments, 24- to 72-hour-old Canton-S males were administered a 

0.7% sodium chloride solution of chloroprene and allowed to recover for 24 hours. Treated males were 

mated to three Basc females for 3 days and given fresh females at 2-day intervals to produce three matings of 

3, 2, and 2 days (in each case, sample sperm from successive matings were treated at successively earlier 

postmeiotic stages). F heterozygous females were mated with their siblings and then placed in individual 1 

vials. F daughters from the same parental male were kept together to identify clusters. (A cluster occurs 1 

when a number of mutants from a given male result from a single spontaneous premeiotic mutation event and 

is identified when the number of mutants from that male exceeds the number predicted by a Poisson 

distribution). If a cluster was identified, all data from the male in question were discarded. Presumptive 

lethal mutations were identified as vials containing fewer than 5% of the expected number of wild-type males 

after 17 days; these were retested to confirm the response. 
Chloroprene, NTP TR 467 275 

SLRL data were analyzed by simultaneous comparison with the concurrent and historical controls with a 

normal approximation to the binomial test (Margolin et al., 1983). A test result was considered positive if 

the P value was less than or equal to 0.01 and the mutation frequency in the tested group was greater that 

0.10%, or if the P value was less than or equal to 0.05 and the frequency in the treatment group was greater 

than 0.15%. A test was considered to be inconclusive if the P value was between 0.05 and 0.01 but the 

frequency in the treatment group was between 0.10% and 0.15% or the P value was between 0.10 and 0.05 

but the frequency in the treatment group was greater than 0.10%. A test was considered negative if the 

P value was greater than or equal to 0.10 or if the frequency in the treatment group was less than 0.10%. 

MOUSE BONE MARROW CHROMOSOMAL ABERRATIONS 

AND SISTER CHROMATID EXCHANGE TEST PROTOCOLS 

The complete experimental protocols are described in detail by Tice et al. (1988). A dose range-finding 

study was performed. The highest experimental dose administered (80 ppm) was limited by toxicity. Male 

B6C3F mice (15 animals per group) were exposed 6 hours per day for 12 days to ambient air or to 1 

chloroprene (12, 32, or 80 ppm). Approximately 1 hour before the twelfth exposure began, a 50-mg 

bromodeoxyuridine (BrdU) tablet coated partially (~70%) with paraffin (McFee et al., 1983) was implanted 

subcutaneously into the abdominal area of each lightly anesthetized mouse. The use of BrdU allowed 

selection of the appropriate cell population for scoring. Chromosomal aberrations (Abs) induced by chemical 

administration are present in maximum number at the first metaphase following treatment; they decline in 

number during subsequent nuclear divisions due to cell death. Sister chromatid exchanges (SCEs) are 

properly scored in cells that are in the second division after treatment. Two hours before sacrifice, the mice 

received an intraperitoneal injection of colchicine in saline. Ten animals to be scored in each dose group for 

frequency of Abs were killed 17 to 20 hours after BrdU tablet implantation. For SCE analysis, five mice 

per dose group were killed 24 hours after BrdU implantation. One or both femurs were removed and the 

marrow was flushed out with phosphate-buffered saline (pH 7.0). Cells were treated with a hypotonic salt 

solution, fixed, and dropped onto chilled slides. After a 24-hour drying period, the slides were stained and 

scored. Fifty first-division metaphase cells were scored from each of eight animals per treatment for Abs. 

Responses were evaluated as the percentage of aberrant metaphase cells, excluding gaps. For SCE analysis, 

25 second-division metaphase cells were scored from each of four animals per treatment. Responses were 

evaluated as SCEs/cell. For both the Abs and SCE tests, the data were analyzed by trend test (Margolin et 

al., 1986). 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOLS 

16-Day Study 

The mice used for micronucleus analysis were the same ones used in the bone marrow Abs and SCE 

analyses. Preliminary range-finding studies were performed and the exposure protocol is described in detail 

by Tice et al. (1988). Male B6C3F mice were exposed 6 hours per day, 5 days per week for a total of 1 

12 exposure days over a 16-day period to ambient air or to chloroprene (12, 32, or 80 ppm). For the 

micronucleus analysis, air-dried peripheral blood samples, obtained by tail-snip and immediately fixed in 

absolute methanol, were prepared at the end of the twelfth exposure day, at the time of colchicine injection 

(necessary for Abs and SCE analyses). Slides were coded and stained with acridine orange. Each slide was 

scanned at 800× magnification using epi-illuminated fluorescence microscopy (450 to 490 nm excitation, 

520 nm emission). The frequency of micronucleated cells among 1,000 polychromatic erythrocytes (PCEs) 

and 1,000 normochromatic erythrocytes (NCEs) were scored. The results were tabulated as the mean of the 

pooled results from all animals within a treatment group, plus or minus the standard error of the mean. The 

frequency of micronucleated cells among PCEs and NCEs was analyzed over exposure groups using a 

one-tailed Cochran-Armitage trend test (Margolin and Risko, 1987), followed by pairwise comparisons 

between each exposure group and the control group. 
276 Chloroprene, NTP TR 467 

13-Week Study 

A detailed discussion of this assay is presented in MacGregor et al. (1990). At the end of the 13-week 

inhalation study, peripheral blood samples were obtained from male and female mice, and smears were 

immediately prepared and fixed in absolute methanol. The methanol-fixed slides were stained with a 

chromatin-specific fluorescent dye mixture of Hoechst 33258/pyronin Y (MacGregor et al., 1983) and 

coded. Slides were scanned at 630× or 1,000× magnification using a semi-automated image analysis system 

to determine the frequency of micronuclei in 2,000 PCEs and 10,000 NCEs in each of 10 animals per 

exposure group. The criteria of Schmid (1976) were used in defining micronuclei, with the additional 

requirement that the micronuclei exhibit the characteristic fluorescent emissions of DNA (blue with 360 nm 

and orange with 540 nm UV illumination); the minimum size limit was approximately one-twentieth the 

diameter of the NCE cell. Log transformation of the NCE data, testing for normality by the Shapiro-Wilk 

test, and testing for heterogeneity of variance by Cochran’s test were performed before statistical analyses. 

The frequency of micronucleated cells among NCEs was determined by analysis of variance with the SAS 

GLM procedure. The NCE data for each exposure group were compared with the concurrent control using 

Student’s t-test. The frequency of micronucleated cells among PCEs was analyzed by the Cochran-Armitage 

trend test, and individual dose groups were compared to the concurrent control by Kastenbaum-Bowman’s 

binomial test. 

RESULTS 

Chloroprene showed no evidence of mutagenicity in tests performed in vitro or in vivo. Chloroprene was not 

mutagenic in any of four strains of S. typhimurium (TA98, TA100, TA1535, or TA1537) when tested with a 

preincubation protocol at concentrations up to 3,333 μg/plate, with and without Aroclor-induced rat or 

hamster liver S9 (Zeiger et al., 1987; Table E1). No induction of SLRL mutations was noted in germ cells 

of male D. melanogaster administered chloroprene via feeding or injection (Foureman et al., 1994; Table 

E2). In vivo assays in male mice for induction of Abs, SCEs, and increases in the frequency of 

micronucleated erythrocytes after 12 inhalation exposures to chloroprene (12, 32, or 80 ppm) all gave 

negative results (Tice et al., 1988; Tables E3, E4, and E5). In addition, no increase was observed in the 

frequency of micronucleated erythrocytes in peripheral blood of male and female mice exposed for 13 weeks 

to chloroprene (5 to 80 ppm) via inhalation (Table E6). 
 

 

 

Chloroprene, NTP TR 467 277 

TABLE E1 

Mutagenicity of Chloroprene in Salmonella typhimuriuma 

Revertants/plateb 

Strain Dose -S9 +10% hamster S9 +10% rat S9 

(μg/plate) Trial 1 Trial 2 Trial 1 Trial 2 Trial 1 Trial 2 

TA100 

0 145 ± 1.5 120 ± 4.7 160 ± 11.8 126 ± 9.1 154 ± 16.5 117 ± 7.8 

3 146 ± 7.6 139 ± 4.1 

10 167 ± 7.9 124 ± 0.3 143 ± 1.3 146 ± 14.3 

33 164 ± 8.0 124 ± 6.6 140 ± 7.3 144 ± 2.8 149 ± 20.3 128 ± 3.5 

100 147 ± 6.1 98 ± 9.8 136 ± 10.3 141 ± 3.4 152 ± 5.1 149 ± 10.5 

333 92 ± 17.9 51 ± 16.6c 136 ± 11.4 130 ± 12.8 133 ± 6.2 158 ± 7.5 c 1,000	 94 ± 4.2 145 ± 23.2 Toxic 126 ± 7.5 c 3,333 0 ± 0.0 Toxic 

Trial summary Negative Negative Negative Negative Negative Negative d Positive control 321 ± 11.7 424 ± 16.2 2,113 ± 4.8 1,895 ± 83.7 1,055 ± 61.4 900 ± 15.3 

TA1535 

0 21 ± 3.7 15 ± 1.7 10 ± 1.7 12 ± 2.1 7 ± 2.5 10 ± 1.9 

3 24 ± 2.9 16 ± 5.0 

10 22 ± 3.5 15 ± 1.5 7 ± 0.0 8 ± 2.2 

33 20 ± 3.2 19 ± 2.2 9 ± 1.5 9 ± 4.3 11 ± 4.9 6 ± 0.6 

100 18 ± 0.3 10 ± 2.2 12 ± 1.8 14 ± 1.5 7 ± 0.3 11 ± 2.3 

333 Toxic 6 ± 2.1c 20 ± 0.3 15 ± 3.1 7 ± 2.3 10 ± 2.5 c 1,000 Toxic 11 ± 3.3 Toxic 8 ± 1.5 

3,333 Toxic Toxic 

Trial summary Negative Negative Negative Negative Negative Negative 

Positive control 384 ± 17.9 396 ± 2.3 429 ± 31.8 507 ± 35.4 255 ± 18.4 313 ± 77.0 

TA1537 

0 8 ± 0.6 5 ± 2.6 7 ± 3.0 8 ± 2.6 13 ± 2.9 6 ± 0.9 

3 7 ± 0.7 5 ± 1.2 

10 13 ± 2.1 8 ± 3.2 10 ± 2.3 5 ± 2.3 

33 9 ± 2.3 5 ± 0.9 7 ± 1.0 5 ± 0.3 12 ± 4.2 7 ± 0.6 

100 11 ± 3.0c 7 ± 3.0 8 ± 1.5 7 ± 0.9 13 ± 1.9 9 ± 3.2 

333 Toxic 4 ± 0.9c 6 ± 0.9 5 ± 0.7 11 ± 4.3 8 ± 0.7 c 1,000 Toxic 6 ± 0.9 Toxic 6 ± 1.7 

3,333 Toxic Toxic 

Trial summary Negative Negative Negative Negative Negative Negative 

Positive control 99 ± 3.5 100 ± 18.2 479 ± 6.1 353 ± 32.0 238 ± 4.4 283 ± 14.2 

TA98 

0 25 ± 0.9 22 ± 2.7 24 ± 3.7 28 ± 4.6 38 ± 6.7 24 ± 2.6 

3 23 ± 4.6 18 ± 2.8 

10 25 ± 3.5 14 ± 3.3 26 ± 1.3 26 ± 3.8 

33 26 ± 0.9 20 ± 2.1 25 ± 3.5 34 ± 4.6 31 ± 3.6 26 ± 3.3 

100 17 ± 1.5 16 ± 1.9 29 ± 1.2 28 ± 2.1 33 ± 3.8 31 ± 3.5 

333 Toxic 12 ± 2.0 24 ± 2.9 33 ± 3.8 27 ± 4.1 28 ± 2.2 

1,000 30 ± 2.5 25 ± 0.9 Toxic 33 ± 4.5 

3,333 Toxic Toxic 

Trial summary Negative Negative Negative Negative Negative Negative 

Positive control 830 ± 33.4 760 ± 8.0 1,779 ± 45.1 1,761 ± 147.7 613 ± 12.5 640 ± 8.7 

a Study was performed at SRI International. The detailed protocol and these data are presented in Zeiger et al. (1987). b	 Revertants are presented as mean ± standard error from three plates. 

Slight toxicity d	 The positive controls in the absence of metabolic activation were sodium azide (TA100 and TA1535), 9-aminoacridine (TA1537), and 

4-nitro-o-phenylenediamine (TA98). The positive control for metabolic activation with all strains was 2-aminoanthracene. 

c 
278 

c 

Chloroprene, NTP TR 467 

TABLE E2 

Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster by Chloroprenea 

Route of 

Exposure 

Dose 

(ppm) 

Incidence of 

Death (%) 

Incidence of 

Sterility (%) 

No. of Lethals/No. of X Chromosomes Tested 

Mating 1 Mating 2 Mating 3 Totalb 

Feed 1,820 

0 

24 0 5/2,021 

4/1,934 

6/1,996 

2/2,128 

9/1,903 

10/2,046 

20/5,920 (0.34%) 

16/6,108 (0.26%) 

Injection 1,820 

0 

16 2 5/2,471 

1/2,115 

1/1,587 

0/1,720 

0/1,374 

8/1,895 

6/5,432 (0.11%) 

9/5,730 (0.16%) 

a Study was performed at the University of Wisconsin, Madison. A detailed description of the protocol and these data are presented in 

Foureman et al. (1994); results were not significant at the 5% level (Margolin et al., 1983). b Total number of lethal mutations/total number of X chromosomes tested for three mating trials 

TABLE E3 

Induction of Chromosomal Aberrations in Mouse Bone Marrow Cells by Chloroprenea 

Compound Dose (ppm) Number of Total Abs Abs/Cell Cells with Abs (%) 

Mice 

b Air 0 8 0.8 0.01 1.09 

Chloroprene 

12 8 1.1 0.01 1.25 

32 8 1.8 0.02 2.00 

80 8 1.0 0.01 0.75 

P=0.683c 

a Study was performed at Brookhaven National Laboratories. The detailed protocol and these data are presented in Tice et al. (1988). 

Abs=aberrations 

b Inhalation chamber control
 

Significance tested by the one-tailed trend test (Margolin et al., 1986); significant at P<0.05
 
 

 

 

279 

c 

c 

Chloroprene, NTP TR 467 

TABLE E4 

Induction of Sister Chromatid Exchanges in Mouse Bone Marrow Cells by Chloroprenea 

Compound Dose (ppm) Number of 

Mice 

Mean SCEs/Cell 

Airb 0 4 5.06 ± 0.213 

Chloroprene 12 

32 

80 

4 

4 

4 

6.37 ± 0.827 

4.61 ± 0.426 

3.94 ± 0.329 

P=0.500c 

a Study was performed at Brookhaven National Laboratories. The detailed protocol and these data are presented in Tice et al. (1988). 

Data for mean SCEs/cell are given as mean ± standard error. SCE=sister chromatid exchange b Inhalation chamber control
 

Significance tested by the one-tailed trend test (Margolin et al., 1986); significant at P<0.05
 

TABLE E5 

Frequency of Micronuclei in Peripheral Blood Erythrocytes of Male Mice Following Treatment 

with Chloroprene by Inhalation for 16 Daysa 

Compound Dose Number of Micronucleated Cells/1,000 Cellsb 

(ppm) Mice PCEs	 NCEs 

Airc 0 15 2.07 ± 0.316 3.00 ± 0.414 

Chloroprene	 12 14 3.14 ± 0.501 2.57 ± 0.453 

32 15 2.20 ± 0.536 1.72 ± 0.284 

80 15 2.60 ± 0.456 2.80 ± 0.368 

d P = 0.394 P = 0.454 

a Study was performed at Brookhaven National Laboratories. The detailed protocol and these data are presented in Tice et al. (1988). 

PCE=polychromatic erythrocyte; NCE=normochromatic erythrocyte b Mean ± standard error 

Inhalation chamber control 

d Significance of micronucleated cells/1,000 cells tested by the one-tailed trend test (Margolin et al., 1986); significant at P<0.05 
 

 

 

 

 

280 

c 

Chloroprene, NTP TR 467 

TABLE E6 

Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice Following Treatment 

with Chloroprene by Inhalation for 13 Weeksa 

Compound Dose Number of Micronucleated Cells/1,000 Cellsb 

(ppm) Mice PCEs NCEs 

Males 

Airc 0 10 2.32 ± 0.36 1.36 ± 0.14 

Chloroprene 5 10 2.36 ± 0.45 1.28 ± 0.08 

12 10 2.43 ± 0.63 1.32 ± 0.09 

32 10 1.40 ± 0.59 1.32 ± 0.12 

80 10 1.97 ± 0.39 1.39 ± 0.12 

Females 

Air 0 10 2.09 ± 0.42 1.04 ± 0.07 

Chloroprene 5 10 1.88 ± 0.53 0.98 ± 0.20 

12 10 1.99 ± 0.33 1.15 ± 0.07 

32 10 1.06 ± 0.42 0.94 ± 0.09 

80 10 1.32 ± 0.29 1.32 ± 0.09 

a Study was performed at the USDA Western Regional Center. The detailed protocol are presented in MacGregor et al. (1990). 

PCE=polychromatic erythrocyte; NCE=normochromatic erythrocyte b Mean ± standard error
 

Inhalation chamber control
 
281 

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 Chloroprene ............................. 282 

TABLE F2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats 

in the 13-Week Inhalation Study of Chloroprene ............................ 284 

TABLE F3 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice 

in the 16-Day Inhalation Study of Chloroprene ............................. 286 

TABLE F4 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice 

in the 13-Week Study of Chloroprene ................................... 288 
282 Chloroprene, NTP TR 467 

TABLE F1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 16-Day Inhalation Study of Chloroprenea 

Chamber

 Control 32 ppm 80 ppm 200 ppm 500 ppm 

Male 

n 7 10 10 9 1b 

Necropsy body wt 186 ± 7 183 ± 7 185 ± 6 173 ± 9 150 

Brain 

Absolute 1.721 ± 0.028 1.700 ± 0.022 1.715 ± 0.020 1.703 ± 0.017 1.600 

Relative 9.31 ± 0.20 9.41 ± 0.32 9.35 ± 0.23 10.04 ± 0.46 10.67 

Heart 

Absolute 0.650 ± 0.022 0.647 ± 0.024 0.661 ± 0.023 0.609 ± 0.023 0.520 

Relative 3.50 ± 0.07 3.55 ± 0.05 3.58 ± 0.04 3.55 ± 0.08 3.47 

R. Kidney 

Absolute 0.834 ± 0.036 0.865 ± 0.025 0.867 ± 0.024 0.941 ± 0.041 0.890 

Relative 4.49 ± 0.09 4.75 ± 0.07* 4.71 ± 0.08 5.47 ± 0.08** 5.93 

Liver 

Absolute 8.800 ± 0.369 9.103 ± 0.327 9.342 ± 0.310 9.811 ± 0.534 9.750 

Relative 47.36 ± 0.96 49.90 ± 0.64 50.64 ± 0.81* 56.75 ± 0.99** 65.00 

Lung 

Absolute 1.143 ± 0.039 1.177 ± 0.069 1.234 ± 0.053 1.166 ± 0.068 1.180 

Relative 6.16 ± 0.15 6.46 ± 0.33 6.75 ± 0.36 6.77 ± 0.26 7.87 

Spleen 

Absolute 0.496 ± 0.014 0.489 ± 0.014 0.483 ± 0.014 0.478 ± 0.023 0.480 

Relative 2.68 ± 0.10 2.69 ± 0.05 2.62 ± 0.05 2.81 ± 0.17 3.20 

R. Testis 

Absolute 1.106 ± 0.036 1.064 ± 0.034 1.103 ± 0.034 1.094 ± 0.035 0.871 

Relative 5.97 ± 0.17 5.85 ± 0.10 5.98 ± 0.04 6.39 ± 0.18 5.81 

Thymus 

Absolute 0.475 ± 0.033 0.435 ± 0.016 0.475 ± 0.011 0.452 ± 0.022 0.362 

Relative 2.56 ± 0.16 2.40 ± 0.10 2.60 ± 0.11 2.63 ± 0.10 2.41 
Chloroprene, NTP TR 467 283 

TABLE F1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 16-Day Inhalation Study of Chloroprene 

Chamber 

Control 32 ppm 80 ppm 200 ppm 500 ppm 

Female 

n 9 9 9 3 7 

Necropsy body wt 130 ± 3 134 ± 4 137 ± 2 130 ± 3 130 ± 4 

Brain 

Absolute 1.619 ± 0.024 1.633 ± 0.022 1.627 ± 0.018 1.543 ± 0.009 1.571 ± 0.025 

Relative 12.49 ± 0.18 12.21 ± 0.24 11.91 ± 0.14 11.85 ± 0.23 12.17 ± 0.21 

Heart 

Absolute 0.480 ± 0.012 0.492 ± 0.015 0.508 ± 0.010 0.463 ± 0.023 0.497 ± 0.014 

Relative 3.70 ± 0.05 3.67 ± 0.05 3.72 ± 0.07 3.55 ± 0.16 3.84 ± 0.05 

R. Kidney 

Absolute 0.638 ± 0.019 0.642 ± 0.019 0.709 ± 0.013* 0.697 ± 0.012 0.839 ± 0.028** 

Relative 4.91 ± 0.09 4.79 ± 0.08 5.19 ± 0.07* 5.35 ± 0.04* 6.48 ± 0.13** 

Liver 

Absolute 5.713 ± 0.206 6.047 ± 0.260 6.329 ± 0.125* 6.817 ± 0.098* 7.474 ± 0.273** 

Relative 43.92 ± 0.94 44.96 ± 1.30 46.31 ± 0.68 52.40 ± 2.05** 57.65 ± 0.62** 

Lung 

Absolute 0.901 ± 0.029 1.013 ± 0.059 0.934 ± 0.027 0.913 ± 0.088 0.883 ± 0.048 

Relative 6.93 ± 0.12 7.49 ± 0.25 6.85 ± 0.24 7.02 ± 0.71 6.80 ± 0.23 

Spleen 

Absolute 0.413 ± 0.046 0.386 ± 0.017 0.394 ± 0.007 0.353 ± 0.023 0.404 ± 0.025 

Relative 3.19 ± 0.36 2.87 ± 0.10 2.89 ± 0.07 2.72 ± 0.23 3.13 ± 0.20 

Thymus 

Absolute 0.334 ± 0.014 0.364 ± 0.022 0.360 ± 0.011 0.358 ± 0.007 0.361 ± 0.016 

Relative 2.58 ± 0.10 2.71 ± 0.13 2.63 ± 0.07 2.75 ± 0.12 2.79 ± 0.11 

* 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 No standard error was calculated for the 500 ppm males due to high mortality in this exposure group. 
284 Chloroprene, NTP TR 467 

TABLE F2 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Inhalation Study of Chloroprenea 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

n 10 10 10 10 10 9 

Necropsy body wt 292 ± 9 306 ± 11 289 ± 8 309 ± 10 284 ± 8 284 ± 8 

Brain 

Absolute 1.869 ± 0.014 1.866 ± 0.028 1.836 ± 0.021 1.876 ± 0.015 1.863 ± 0.014 1.846 ± 0.017 

Relative 6.45 ± 0.17 6.14 ± 0.15 6.39 ± 0.17 6.13 ± 0.19 6.60 ± 0.15 6.52 ± 0.15 

Heart 

Absolute 0.835 ± 0.029 0.875 ± 0.032 0.830 ± 0.037 0.905 ± 0.030 0.827 ± 0.021 0.871 ± 0.029 

Relative 2.86 ± 0.04 2.86 ± 0.06 2.86 ± 0.07 2.93 ± 0.03 2.92 ± 0.05 3.07 ± 0.08* 

R. Kidney 

Absolute 0.967 ± 0.037 1.064 ± 0.048 0.958 ± 0.041 1.077 ± 0.037 1.045 ± 0.026 1.247 ± 0.042** 

Relative 3.31 ± 0.06 3.47 ± 0.07 3.30 ± 0.07 3.49 ± 0.05* 3.69 ± 0.04** 4.38 ± 0.07** 

Liver 

Absolute 7.974 ± 0.341 8.423 ± 0.399 7.532 ± 0.281 8.408 ± 0.278 7.857 ± 0.381 8.926 ± 0.309 

Relative 27.32 ± 0.88 27.43 ± 0.55 26.03 ± 0.47 27.25 ± 0.44 27.64 ± 0.93 31.42 ± 0.86** 

Lung 

Absolute 1.548 ± 0.040 1.591 ± 0.070 1.429 ± 0.049 1.560 ± 0.085 1.461 ± 0.064 1.521 ± 0.043 

Relative 5.33 ± 0.16 5.21 ± 0.18 4.97 ± 0.20 5.09 ± 0.32 5.15 ± 0.19 5.37 ± 0.19 

Spleen 

Absolute 0.567 ± 0.019 0.610 ± 0.015 0.553 ± 0.016 0.593 ± 0.016 0.559 ± 0.018 0.546 ± 0.017 

Relative 1.94 ± 0.04 2.00 ± 0.04 1.92 ± 0.04 1.93 ± 0.04 1.97 ± 0.05 1.92 ± 0.03 

R. Testis 

Absolute 1.324 ± 0.034 1.344 ± 0.025 1.317 ± 0.035 1.375 ± 0.038 1.282 ± 0.027 1.351 ± 0.024 

Relative 4.55 ± 0.12 4.42 ± 0.12 4.57 ± 0.12 4.46 ± 0.08 4.53 ± 0.09 4.77 ± 0.10 

Thymus 

Absolute 0.283 ± 0.014 0.309 ± 0.012 0.307 ± 0.016 0.309 ± 0.016 0.282 ± 0.010 0.293 ± 0.014 

Relative 0.97 ± 0.03 1.01 ± 0.02 1.06 ± 0.03 1.00 ± 0.04 0.99 ± 0.03 1.03 ± 0.04 
Chloroprene, NTP TR 467 285 

TABLE F2 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Female 

n 10 10 10 10 10 10 

Necropsy body wt 176 ± 3 180 ± 3 187 ± 5 181 ± 4 180 ± 3 171 ± 3 

Brain 

Absolute 1.746 ± 0.015 1.755 ± 0.021 1.731 ± 0.016 1.754 ± 0.030 1.718 ± 0.011 1.732 ± 0.007 

Relative 9.94 ± 0.17 9.75 ± 0.14 9.31 ± 0.20* 9.68 ± 0.14 9.54 ± 0.13 10.17 ± 0.13 

Heart 

Absolute 0.558 ± 0.014 0.574 ± 0.015 0.576 ± 0.009 0.566 ± 0.021 0.564 ± 0.012 0.556 ± 0.012 

Relative 3.17 ± 0.05 3.18 ± 0.05 3.09 ± 0.05 3.11 ± 0.06 3.13 ± 0.04 3.26 ± 0.04 

R. Kidney 

Absolute 0.626 ± 0.016 0.647 ± 0.017 0.648 ± 0.019 0.663 ± 0.023 0.701 ± 0.012** 0.810 ± 0.020** 

Relative 3.56 ± 0.06 3.59 ± 0.05 3.47 ± 0.06 3.65 ± 0.07 3.89 ± 0.04** 4.75 ± 0.08** 

Liver 

Absolute 4.508 ± 0.131 4.587 ± 0.193 4.743 ± 0.119 4.763 ± 0.222 4.638 ± 0.130 4.844 ± 0.133 

Relative 25.62 ± 0.64 25.37 ± 0.71 25.42 ± 0.38 26.18 ± 0.91 25.70 ± 0.54 28.39 ± 0.55* 

Lung 

Absolute 0.989 ± 0.030 1.014 ± 0.031 1.033 ± 0.028 1.028 ± 0.019 1.006 ± 0.023 0.973 ± 0.023 

Relative 5.62 ± 0.15 5.62 ± 0.11 5.54 ± 0.11 5.68 ± 0.15 5.58 ± 0.11 5.70 ± 0.07 

Spleen 

Absolute 0.374 ± 0.015 0.389 ± 0.014 0.367 ± 0.009 0.390 ± 0.015 0.355 ± 0.007 0.372 ± 0.013 

Relative 2.13 ± 0.09 2.16 ± 0.07 1.97 ± 0.03 2.15 ± 0.07 1.97 ± 0.02 2.18 ± 0.06 

Thymus 

Absolute 0.225 ± 0.005 0.233 ± 0.008 0.237 ± 0.007 0.246 ± 0.008 0.234 ± 0.007 0.211 ± 0.012 

Relative 1.28 ± 0.03 1.30 ± 0.04 1.27 ± 0.03 1.36 ± 0.04 1.30 ± 0.03 1.23 ± 0.06 

* 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). 
286 Chloroprene, NTP TR 467 

TABLE F3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 16-Day Inhalation Study of Chloroprenea 

Chamber

 Control 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

n 10 10 10 10 0 

Necropsy body wt 28.9 ± 0.7 28.9 ± 0.6 28.4 ± 0.4 28.2 ± 0.6 —b 

Brain 

Absolute 0.487 ± 0.022 0.465 ± 0.006 0.473 ± 0.003 0.467 ± 0.003 — 

Relative 16.87 ± 0.58 16.11 ± 0.22 16.67 ± 0.22 16.59 ± 0.26 — 

Heart 

Absolute 0.132 ± 0.004 0.135 ± 0.005 0.138 ± 0.006 0.134 ± 0.007 — 

Relative 4.58 ± 0.08 4.66 ± 0.10 4.84 ± 0.15 4.74 ± 0.20 — 

R. Kidney 

Absolute 0.272 ± 0.009 0.279 ± 0.007 0.280 ± 0.007 0.280 ± 0.010 — 

Relative 9.43 ± 0.22 9.65 ± 0.21 9.85 ± 0.19 9.90 ± 0.19 — 

Liver 

Absolute 1.586 ± 0.056 1.621 ± 0.043 1.663 ± 0.043 1.699 ± 0.065 — 

Relative 54.85 ± 0.80 56.03 ± 0.88 58.46 ± 0.97* 60.07 ± 1.44** — 

Lung 

Absolute 0.185 ± 0.004 0.194 ± 0.006 0.181 ± 0.005 0.188 ± 0.012 — 

Relative 6.43 ± 0.14 6.71 ± 0.20 6.37 ± 0.15 6.68 ± 0.45 — 

Spleen 

Absolute 0.079 ± 0.002 0.074 ± 0.006 0.074 ± 0.004 0.068 ± 0.003 — 

Relative 2.74 ± 0.06 2.54 ± 0.19 2.59 ± 0.11 2.40 ± 0.08 — 

R. Testis 

Absolute 0.105 ± 0.002 0.103 ± 0.002 0.106 ± 0.002 0.104 ± 0.002 — 

Relative 3.64 ± 0.10 3.58 ± 0.09 3.72 ± 0.09 3.70 ± 0.06 — 

Thymus 

Absolute 0.053 ± 0.002 0.051 ± 0.003 0.048 ± 0.003 0.041 ± 0.003** — 

Relative 1.85 ± 0.05 1.75 ± 0.09 1.67 ± 0.09 1.43 ± 0.09** — 
Chloroprene, NTP TR 467 287 

TABLE F3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 16-Day Inhalation Study of Chloroprene 

Chamber

 Control 12 ppm 32 ppm 80 ppm 200 ppm 

Female 

n 10 10 10 10 0 

Necropsy body wt 23.6 ± 0.4 23.8 ± 0.5 23.2 ± 0.3 22.9 ± 0.3 — 

Brain 

Absolute 0.468 ± 0.006 0.470 ± 0.004 0.470 ± 0.005 0.462 ± 0.004 — 

Relative 19.83 ± 0.28 19.78 ± 0.40 20.28 ± 0.28 20.24 ± 0.28 — 

Heart 

Absolute 0.116 ± 0.003 0.117 ± 0.003 0.111 ± 0.001 0.107 ± 0.002* — 

Relative 4.93 ± 0.19 4.91 ± 0.06 4.79 ± 0.07 4.68 ± 0.09 — 

R. Kidney 

Absolute 0.182 ± 0.005 0.192 ± 0.004 0.189 ± 0.003 0.188 ± 0.004 — 

Relative 7.69 ± 0.15 8.06 ± 0.08* 8.15 ± 0.12* 8.22 ± 0.13** — 

Liver 

Absolute 1.204 ± 0.027 1.307 ± 0.047 1.279 ± 0.021 1.390 ± 0.029** — 

Relative 50.92 ± 0.66 54.70 ± 1.03** 55.12 ± 0.53** 60.78 ± 0.65** — 

Lung 

Absolute 0.182 ± 0.006 0.186 ± 0.003 0.175 ± 0.003 0.190 ± 0.009 — 

Relative 7.69 ± 0.19 7.82 ± 0.15 7.56 ± 0.20 8.32 ± 0.40 — 

Spleen 

Absolute 0.090 ± 0.004 0.092 ± 0.003 0.090 ± 0.003 0.082 ± 0.003 — 

Relative 3.81 ± 0.14 3.86 ± 0.09 3.88 ± 0.12 3.58 ± 0.10 — 

Thymus 

Absolute 0.064 ± 0.003 0.064 ± 0.003 0.062 ± 0.002 0.052 ± 0.003** — 

Relative 2.72 ± 0.14 2.70 ± 0.12 2.66 ± 0.07 2.27 ± 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 No data were calculated for the 200 ppm males or females due to 100% mortality in these exposure groups. 
288 Chloroprene, NTP TR 467 

TABLE F4 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Inhalation Study of Chloroprenea 

Chamber

 Control 5 ppm 12 ppm 32 ppm 80 ppm 

Male 

n 10 10 10 10 10 

Necropsy body wt 36.0 ± 0.9 35.8 ± 1.0 35.1 ± 0.6 36.8 ± 0.9 33.4 ± 0.6 

Brain 

Absolute 0.453 ± 0.006 0.452 ± 0.004 0.451 ± 0.004 0.452 ± 0.005 0.447 ± 0.004 

Relative 12.66 ± 0.38 12.69 ± 0.30 12.87 ± 0.17 12.34 ± 0.32 13.42 ± 0.23 

Heart 

Absolute 0.150 ± 0.004 0.155 ± 0.006 0.152 ± 0.004 0.158 ± 0.005 0.142 ± 0.002 

Relative 4.18 ± 0.13 4.32 ± 0.11 4.33 ± 0.08 4.30 ± 0.13 4.26 ± 0.07 

R. Kidney 

Absolute 0.286 ± 0.010 0.291 ± 0.009 0.289 ± 0.008 0.301 ± 0.009 0.279 ± 0.007 

Relative 7.95 ± 0.21 8.17 ± 0.33 8.23 ± 0.18 8.21 ± 0.30 8.36 ± 0.13 

Liver 

Absolute 1.589 ± 0.042 1.700 ± 0.056 1.638 ± 0.047 1.642 ± 0.042 1.522 ± 0.037 

Relative 44.21 ± 1.04 47.47 ± 0.92* 46.60 ± 0.78 44.64 ± 0.55 45.58 ± 0.64 

Lung 

Absolute 0.204 ± 0.006 0.211 ± 0.008 0.203 ± 0.005 0.214 ± 0.005 0.202 ± 0.009 

Relative 5.68 ± 0.18 5.90 ± 0.20 5.79 ± 0.14 5.83 ± 0.13 6.04 ± 0.18 

Spleen 

Absolute 0.070 ± 0.002 0.072 ± 0.003 0.074 ± 0.002 0.071 ± 0.002 0.067 ± 0.002 

Relative 1.95 ± 0.06 2.01 ± 0.07 2.11 ± 0.04 1.94 ± 0.05 2.01 ± 0.06 

R. Testis 

Absolute 0.114 ± 0.004 0.120 ± 0.002 0.116 ± 0.002 0.122 ± 0.004 0.123 ± 0.004 

Relative 3.20 ± 0.17 3.37 ± 0.10 3.32 ± 0.05 3.33 ± 0.10 3.68 ± 0.09* 

Thymus 

Absolute 0.046 ± 0.004 0.043 ± 0.004 0.041 ± 0.002 0.047 ± 0.003 0.042 ± 0.004 

Relative 1.27 ± 0.09 1.21 ± 0.11 1.16 ± 0.06 1.27 ± 0.08 1.25 ± 0.11 
Chloroprene, NTP TR 467 289 

TABLE F4 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Inhalation Study of Chloroprene 

Chamber

 Control 5 ppm 12 ppm 32 ppm 80 ppm 

Female 

n 10 10 10 10 10 

Necropsy body wt 31.5 ± 1.1 33.5 ± 0.8 31.2 ± 0.7 33.5 ± 0.7 30.2 ± 1.5 

Brain 

Absolute 0.465 ± 0.005 0.470 ± 0.003 0.463 ± 0.006 0.469 ± 0.004 0.458 ± 0.006 

Relative 14.92 ± 0.55 14.10 ± 0.37 14.94 ± 0.43 14.05 ± 0.27 15.42 ± 0.60 

Heart 

Absolute 0.127 ± 0.002 0.136 ± 0.002 0.131 ± 0.004 0.134 ± 0.003 0.121 ± 0.002 

Relative 4.06 ± 0.12 4.07 ± 0.10 4.22 ± 0.14 4.01 ± 0.09 4.05 ± 0.11 

R. Kidney 

Absolute 0.194 ± 0.005 0.210 ± 0.004* 0.195 ± 0.004 0.202 ± 0.006 0.200 ± 0.004 

Relative 6.20 ± 0.19 6.29 ± 0.14 6.28 ± 0.17 6.04 ± 0.13 6.71 ± 0.24 

Liver 

Absolute 1.471 ± 0.037 1.583 ± 0.038 1.469 ± 0.023 1.622 ± 0.041* 1.499 ± 0.050 

Relative 46.87 ± 0.81 47.31 ± 1.00 47.30 ± 0.95 48.48 ± 0.93 49.90 ± 0.75 

Lung 

Absolute 0.192 ± 0.005 0.203 ± 0.004 0.187 ± 0.005 0.215 ± 0.007** 0.203 ± 0.004 

Relative 6.14 ± 0.20 6.10 ± 0.22 6.05 ± 0.27 6.42 ± 0.17 6.85 ± 0.31 

Spleen 

Absolute 0.098 ± 0.004 0.101 ± 0.003 0.094 ± 0.003 0.108 ± 0.002 0.092 ± 0.003 

Relative 3.13 ± 0.14 3.03 ± 0.13 3.04 ± 0.14 3.23 ± 0.09 3.10 ± 0.17 

Thymus 

Absolute 0.057 ± 0.005 0.058 ± 0.004 0.047 ± 0.004 0.056 ± 0.003 0.054 ± 0.005 

Relative 1.78 ± 0.09 1.71 ± 0.10 1.51 ± 0.12 1.66 ± 0.08 1.76 ± 0.12 

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

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ 

weight/g body weight (mean ± standard error). 
290 Chloroprene, NTP TR 467
 
291 

APPENDIX G 

HEMATOLOGY, CLINICAL CHEMISTRY, 

AND URINALYSIS RESULTS 

TABLE G1 

TABLE G2 

TABLE G3 

TABLE G4 

Day 4 Hematology, Clinical Chemistry, and Urinalysis Data for Rats 

in the 16-Day Inhalation Study of Chloroprene ............................. 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats 

in the 13-Week Inhalation Study of Chloroprene ............................ 

Day 5 Hematology and Clinical Chemistry Data for Mice 

in the 16-Day Inhalation Study of Chloroprene ............................. 

Hematology and Clinical Chemistry Data for Mice 

in the 13-Week Inhalation Study of Chloroprene ............................ 

292 

294 

300 

302 
292 Chloroprene, NTP TR 467 

TABLE G1 

Day 4 Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 16-Day Inhalation Study of Chloroprenea 

Chamber 

Control 32 ppm 80 ppm 200 ppm 500 ppm 

Male 

n 10 10 10 10 7 

Hematology 

Hematocrit (%) 46.2 ± 0.6 46.5 ± 0.4 46.5 ± 0.4 46.6 ± 0.8 29.8 ± 4.3* 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

15.0 ± 0.2 

8.00 ± 0.09 

0.30 ± 0.02 

0.10 ± 0.03 

15.0 ± 0.1 

7.90 ± 0.12 

0.27 ± 0.03 

0.06 ± 0.03 

15.0 ± 0.1 

8.08 ± 0.10 

0.20 ± 0.03 

0.05 ± 0.03 

15.0 ± 0.2 

8.21 ± 0.14 

0.21 ± 0.03 

0.04 ± 0.02 

9.3 ± 1.4* 

5.06 ± 0.78* 

0.92 ± 0.07* 

3.81 ± 1.31* 

Mean cell volume (fL) 57.8 ± 0.4 58.9 ± 0.9 57.6 ± 0.4 56.8 ± 0.4 59.7 ± 0.9 

Mean cell hemoglobin (pg) 18.7 ± 0.1 19.0 ± 0.3 18.6 ± 0.1 18.3 ± 0.1 18.5 ± 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 

32.4 ± 0.1 

865.5 ± 38.3 

7.21 ± 0.31 

0.53 ± 0.09 

6.43 ± 0.29 

0.25 ± 0.05 

0.02 ± 0.02 

32.2 ± 0.1 

852.4 ± 30.2 

8.17 ± 0.54 

0.73 ± 0.17 

7.07 ± 0.38 

0.36 ± 0.08 

0.02 ± 0.01 

32.3 ± 0.2 

878.3 ± 34.4 

8.14 ± 0.20 

0.81 ± 0.08* 

6.99 ± 0.18 

0.30 ± 0.07 

0.04 ± 0.02 

32.3 ± 0.1 

782.6 ± 59.8 

8.29 ± 0.38 

0.74 ± 0.09 

7.19 ± 0.36 

0.31 ± 0.06 

0.05 ± 0.02 

31.0 ± 0.4** 

516.6 ± 126.8* 

15.60 ± 3.06** 

3.29 ± 0.71** 

11.61 ± 2.58 

0.74 ± 0.21* 

0.00 ± 0.00 

Clinical Chemistry 

Urea nitrogen (mg/dL) 19.9 ± 0.7 19.4 ± 0.8 19.3 ± 0.5 18.3 ± 1.0 24.6 ± 4.9 

Creatinine (mg/dL) 1.00 ± 0.04 1.02 ± 0.04 0.95 ± 0.03 1.04 ± 0.04 0.74 ± 0.07* 

Alanine aminotransferase (IU/L) 33 ± 3 33 ± 2 31 ± 1 55 ± 15 113 ± 19** 

Glutamate dehydrogenase (IU/L) 4.3 ± 0.5 4.6 ± 0.4 3.9 ± 0.5 10.1 ± 4.0 62.5 ± 10.1** 

Sorbitol dehydrogenase (IU/L) 8 ± 1 9 ± 0 8 ± 0 10 ± 1 11 ± 1 

n 9 10 10 10 7 

Urinalysis 

Creatinine (mg/dL) 23.3 ± 2.6 14.5 ± 2.0 16.5 ± 1.7 16.1 ± 2.4 11.1 ± 2.1* 

Glucose (μg/mg creatinine) 150 ± 8 131 ± 14 123 ± 18 133 ± 17 178 ± 39 

Protein (μg/mg creatinine) 665 ± 85 644 ± 45 565 ± 41 472 ± 20* 730 ± 202 

Alkaline phosphatase (mU/mg creatinine) 210 ± 26 282 ± 55 618 ± 426 214 ± 18 336 ± 42 

Aspartate aminotransferase

 (mU/mg creatinine) 14 ± 2 14 ± 3 25 ± 11 19 ± 3 26 ± 4 

Volume (mL/16 hr) 13.0 ± 2.0 21.1 ± 3.2 18.2 ± 2.3 16.5 ± 2.9 17.0 ± 3.7 

Specific gravity 1.011 ± 0.001 1.007 ± 0.001 1.008 ± 0.001 1.008 ± 0.001 1.009 ± 0.003 

Urea (mg/mg creatinine) 26 ± 1 28 ± 2 29 ± 1 31 ± 2 45 ± 8** 

Thioethers (mM/mg creatinine) 0.044 ± 0.011 0.074 ± 0.015 0.062 ± 0.016 0.062 ± 0.024 0.113 ± 0.024 
Chloroprene, NTP TR 467 293 

TABLE G1 

Day 4 Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 16-Day Inhalation Study of Chloroprene 

Chamber 

Control 32 ppm 80 ppm 200 ppm 500 ppm 

Female 

n 10 10 10 10 10 

Hematology 

Hematocrit (%) 49.0 ± 0.7 48.0 ± 0.5 49.0 ± 0.5 42.7 ± 3.6 44.1 ± 2.6 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

15.7 ± 0.2 

8.56 ± 0.10 

0.18 ± 0.02 

0.06 ± 0.02 

15.9 ± 0.2 

8.40 ± 0.16 

0.15 ± 0.02 

0.04 ± 0.02 

15.8 ± 0.2 

8.45 ± 0.08 

0.15 ± 0.01 

0.09 ± 0.03 

13.6 ± 1.2 

7.35 ± 0.63 

0.44 ± 0.05** 

0.78 ± 0.38* 

14.3 ± 0.9 

7.67 ± 0.49 

0.38 ± 0.11* 

0.06 ± 0.03b 

Mean cell volume (fL) 57.4 ± 0.3 57.4 ± 0.8 58.1 ± 0.4 58.4 ± 0.5 58.0 ± 0.8 

Mean cell hemoglobin (pg) 18.3 ± 0.1 18.9 ± 0.2 18.6 ± 0.1 18.5 ± 0.3 18.7 ± 0.2 

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 

32.0 ± 0.2 

835.8 ± 61.6 

8.95 ± 0.33 

1.02 ± 0.11 

7.77 ± 0.38 

0.15 ± 0.04 

0.02 ± 0.01 

33.0 ± 0.1** 

851.0 ± 37.9 

9.12 ± 0.38 

0.68 ± 0.12 

8.05 ± 0.40 

0.38 ± 0.09 

0.01 ± 0.01 

32.2 ± 0.1 

890.6 ± 24.7 

8.83 ± 0.31 

0.62 ± 0.09 

7.91 ± 0.27 

0.28 ± 0.05 

0.04 ± 0.01 

31.7 ± 0.3 

395.4 ± 61.3** 

10.03 ± 1.27 

1.18 ± 0.44 

8.51 ± 0.92 

0.32 ± 0.06 

0.03 ± 0.02 

32.3 ± 0.3 

684.9 ± 72.1* 

9.17 ± 0.46b 

0.84 ± 0.13b 

7.91 ± 0.38b 

0.39 ± 0.03*b 

0.02 ± 0.02b 

Clinical Chemistry 

Urea nitrogen (mg/dL) 21.4 ± 0.4 20.5 ± 0.6 20.9 ± 0.6 17.9 ± 1.1** 19.3 ± 0.7* 

Creatinine (mg/dL) 0.99 ± 0.03 1.03 ± 0.03 0.98 ± 0.07 1.13 ± 0.07 1.32 ± 0.08** 

Alanine aminotransferase (IU/L) 32 ± 2 28 ± 1 27 ± 2 165 ± 44** 59 ± 11* 

Glutamate dehydrogenase (IU/L) 5.6 ± 0.6 4.3 ± 0.3 3.8 ± 0.5 31.3 ± 10.2** 17.1 ± 4.3* 

Sorbitol dehydrogenase (IU/L) 9 ± 1 9 ± 0 9 ± 1 15 ± 2** 11 ± 1* 

n 10 10 10 10 10 

Urinalysis 

Creatinine (mg/dL) 20.5 ± 1.7 11.4 ± 1.4** 14.0 ± 1.5** 12.6 ± 2.6** 11.2 ± 1.4** 

Glucose (μg/mg creatinine) 181 ± 7 158 ± 11 178 ± 9 180 ± 12 200 ± 23 

Protein (μg/mg creatinine) 452 ± 53 512 ± 76 476 ± 57 848 ± 108** 694 ± 58** 

Alkaline phosphatase (mU/mg creatinine) 3,084 ± 1599 2,649 ± 861 1,340 ± 587 788 ± 66 2,137 ± 890 

Aspartate aminotransferase 

(mU/mg creatinine) 50 ± 17 128.3 ± 48 43 ± 12 69 ± 80** 77 ± 39** 

Volume (mL/16 hr) 9.3 ± 1.1 17.8 ± 2.4* 13.3 ± 2.1 14.7 ± 2.0 15.2 ± 2.1 

Specific gravity 1.012 ± 0.001 1.006 ± 0.001** 1.008 ± 0.001** 1.007 ± 0.001** 1.006 ± 0.001** 

Urea (mg/mg creatinine) 37.3 ± 1.3 36.5 ± 1.0 37.8 ± 1.4 31.9 ± 1.7 34.6 ± 1.7 

Thioethers (mM/mg creatinine) 0.025 ± 0.009 0.062 ± 0.020 0.057 ± 0.015 0.048 ± 0.016 0.051 ± 0.016 

* 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 
294 Chloroprene, NTP TR 467 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprenea 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

n 

Day 2 9 0 0 9 9 10 

Day 22 10 10 10 10 10 10 

Week 13 10 10 10 10 10 9 

Hematology 

Hematocrit (%) 

Day 2 39.4 ± 0.8 —b — 40.7 ± 0.5 41.6 ± 0.4** 40.6 ± 2.5** 

Day 22 48.7 ± 0.4 48.4 ± 0.5 48.9 ± 0.3 48.6 ± 0.4 49.2 ± 0.5 47.2 ± 0.4 

Week 13 47.7 ± 0.6 46.3 ± 0.7 47.0 ± 0.5 46.9 ± 0.5 46.9 ± 0.5 44.8 ± 1.8 

Hemoglobin (g/dL) 

Day 2 12.6 ± 0.2 — — 13.2 ± 0.2 13.2 ± 0.1* 13.2 ± 0.8** 

Day 22 16.0 ± 0.1 15.9 ± 0.2 16.2 ± 0.1 16.0 ± 0.1 16.2 ± 0.1 15.6 ± 0.1 

Week 13 16.1 ± 0.2 15.6 ± 0.3 15.9 ± 0.1 15.8 ± 0.2 15.7 ± 0.2 15.1 ± 0.6 

Erythrocytes (10 /μL) 6 

Day 2 7.36 ± 0.15 — — 7.68 ± 0.14 7.76 ± 0.15 7.67 ± 0.47** 

Day 22 9.58 ± 0.11 9.64 ± 0.12 9.66 ± 0.08 9.70 ± 0.07 9.81 ± 0.08 9.64 ± 0.09 

Week 13 10.31 ± 0.11 9.97 ± 0.18 10.12 ± 0.11 10.13 ± 0.13 10.06 ± 0.10 9.85 ± 0.37 

Reticulocytes (10 /μL) 6 

Day 22 0.14 ± 0.01 0.13 ± 0.01 0.10 ± 0.01 0.15 ± 0.02 0.17 ± 0.03 0.14 ± 0.02 

Week 13 0.14 ± 0.01 0.19 ± 0.02 0.16 ± 0.01 0.15 ± 0.02 0.19 ± 0.01 0.20 ± 0.05 

Nucleated erythrocytes (10 /μL) 3 

Day 22 

Week 13 

0.01 ± 0.01 

0.00 ± 0.00 

0.00 ± 0.00 

0.00 ± 0.00 

0.00 ± 0.00 

0.01 ± 0.01 

0.00 ± 0.00 

0.00 ± 0.00 

0.00 ± 0.00 

0.01 ± 0.01 

0.00 ± 0.00 

0.00 ± 0.00c 

Mean cell volume (fL) 

Day 2 53.4 ± 0.4 — — 53.2 ± 0.5 53.9 ± 0.8 53.0 ± 0.3 

Day 22 51.0 ± 0.3 50.3 ± 0.3 50.6 ± 0.4 50.1 ± 0.3 50.2 ± 0.4 48.9 ± 0.3** 

Week 13 46.3 ± 0.3 46.5 ± 0.3 46.6 ± 0.3 46.3 ± 0.2 46.4 ± 0.2 45.7 ± 0.2 

Mean cell hemoglobin (pg) 

Day 2 17.1 ± 0.1 — — 17.2 ± 0.2 17.1 ± 0.3 17.1 ± 0.1 

Day 22 16.7 ± 0.1 16.5 ± 0.1 16.8 ± 0.1 16.4 ± 0.1* 16.5 ± 0.1* 16.2 ± 0.1** 

Week 13 15.6 ± 0.1 15.6 ± 0.1 15.7 ± 0.1 15.6 ± 0.0 15.6 ± 0.1 15.4 ± 0.1* 

Mean cell hemoglobin concentration (g/dL) 

Day 2 31.9 ± 0.2 — — 32.3 ± 0.2 31.8 ± 0.2 32.3 ± 0.2 

Day 22 32.9 ± 0.2 32.9 ± 0.2 33.1 ± 0.2 32.8 ± 0.2 32.9 ± 0.2 33.0 ± 0.2 

Week 13 33.8 ± 0.1 33.7 ± 0.1 33.7 ± 0.1 33.7 ± 0.1 33.4 ± 0.2 33.8 ± 0.2 

Platelets (10 /μL) 3 

Day 2 662.3 ± 25.0 — — 704.7 ± 20.7 682.4 ± 22.3 479.7 ± 73.2 

Day 22 631.3 ± 12.8 596.4 ± 11.8 585.7 ± 13.1 619.0 ± 11.5 629.1 ± 17.7 509.0 ± 46.6 

Week 13 510.8 ± 13.1 486.7 ± 19.6 533.4 ± 7.8 531.7 ± 13.5 565.0 ± 10.8** 617.6 ± 42.7** 

Leukocytes (10 /μL) 3 

Day 2 2.11 ± 0.19 — — 2.30 ± 0.12 1.83 ± 0.18 1.65 ± 0.15 

Day 22 6.12 ± 0.23 6.18 ± 0.37 6.21 ± 0.29 6.59 ± 0.32 6.60 ± 0.33 6.36 ± 0.32 

Week 13 6.79 ± 0.44 6.74 ± 0.37 6.70 ± 0.29 7.27 ± 0.41 6.77 ± 0.43 6.72 ± 0.47 

Segmented neutrophils (10 /μL) 3 

Day 2 0.22 ± 0.04 — — 0.24 ± 0.02 0.25 ± 0.03 0.31 ± 0.05 

Day 22 0.68 ± 0.07 0.67 ± 0.07 0.54 ± 0.07 0.63 ± 0.07 0.51 ± 0.04 0.83 ± 0.13 

Week 13 1.11 ± 0.08 0.96 ± 0.08 1.06 ± 0.06 0.91 ± 0.14 0.80 ± 0.07* 0.73 ± 0.09** 
Chloroprene, NTP TR 467 295 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male (continued) 

n 

Day 2

Day 22 

Week 13 

9

10 

10 

0 

10 

10 

0

10 

10 

9

10 

10 

9 

10 

10

10 

10 

9 

Hematology (continued) 

Lymphocytes (10 /μL) 3 

Day 2 1.85 ± 0.16

Day 22 5.15 ± 0.21 

Week 13 5.42 ± 0.44 

Monocytes (10 /μL) 3 

Day 2 0.03 ± 0.01

Day 22 0.24 ± 0.04 

Week 13 0.21 ± 0.04 

Eosinophils (10 /μL) 3 

Day 2 0.00 ± 0.00

Day 22 0.05 ± 0.02 

Week 13 0.05 ± 0.02 

Euglobulin lysis time (minutes) 

Day 2 65.9 ± 4.6d 

Fibrinogen (mg/dL) 

Day 2 228.6 ± 5.3d 

Activated partial thromboplastin time (seconds) 

Day 2 16.6 ± 0.6d 

Prothrombin time (seconds) 

Day 2 14.0 ± 0.1f 

—

5.30 ± 0.36 

5.55 ± 0.40 

—

0.19 ± 0.03 

0.22 ± 0.06 

—

0.03 ± 0.01 

0.01 ± 0.01 

—

 —

 —

 —

 — 

5.46 ± 0.25 

5.39 ± 0.27 

— 

0.17 ± 0.05 

0.21 ± 0.05 

— 

0.04 ± 0.02 

0.03 ± 0.02 

— 

— 

— 

— 

2.03 ± 0.12 

5.64 ± 0.31 

6.11 ± 0.39 

0.02 ± 0.01 

0.28 ± 0.05 

0.21 ± 0.03 

0.01 ± 0.00 

0.04 ± 0.02 

0.05 ± 0.02 

90.7 ± 21.4 

223.6 ± 14.2 

18.6 ± 0.7f 

14.2 ± 0.2 

1.56 ± 0.15 

5.78 ± 0.33 

5.81 ± 0.44 

0.02 ± 0.00 

0.27 ± 0.05 

0.14 ± 0.05 

0.00 ± 0.00 

0.04 ± 0.02 

0.01 ± 0.01 

119.0 ± 28.7d 

252.2 ± 30.1e 

17.6 ± 0.7g 

14.1 ± 0.1f 

1.32 ± 0.15* 

5.22 ± 0.31 

5.80 ± 0.50 

0.02 ± 0.01 

0.28 ± 0.04 

0.14 ± 0.04 

0.00 ± 0.00 

0.03 ± 0.02 

0.06 ± 0.03 

147.5 ± 21.3 

209.1 ± 15.2 

24.1 ± 3.2** 

17.3 ± 2.3* 

n 

Day 22 

Week 13 

9 

10 

9 

10 

10 

10 

10 

10 

10 

10 

9 

9 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Day 22 

Week 13 

Creatinine 

Day 22 

Week 13 

Alanine aminotransferase (IU/L) 

Day 22 

Week 13 

Glutamate dehydrogenase (IU/L) 

Day 22 

Week 13 

Sorbitol dehydrogenase (IU/L) 

Day 22 

Week 13 

14.5 ± 0.3 

17.5 ± 0.5 

0.94 ± 0.03 

1.23 ± 0.05 

33 ± 3 

41 ± 1 

3.7 ± 0.5 

1.9 ± 0.3 

13 ± 1 

14 ± 0 

14.1 ± 0.3 

16.7 ± 0.6 

0.91 ± 0.03 

1.16 ± 0.03 

30 ± 2 

43 ± 3 

3.8 ± 0.8 

1.9 ± 0.2 

13 ± 1 

17 ± 2 

13.9 ± 0.4 

16.3 ± 0.4 

0.94 ± 0.04 

1.19 ± 0.05 

28± 1 

40 ± 2 

2.9 ± 0.4 

1.9 ± 0.3 

13 ± 1 

15 ± 1 

14.5 ± 0.2 

16.4 ± 0.6 

0.95 ± 0.03 

1.19 ± 0.04 

29 ± 1 

43 ± 1 

3.0 ± 0.3 

2.0 ± 0.2 

14 ± 1 

17 ± 1 

13.7 ± 0.4 

15.8 ± 0.6 

1.00 ± 0.04 

1.10 ± 0.04 

33 ± 2 

38 ± 1

2.9 ± 0.6 

1.8 ± 0.2 

13 ± 1 

14 ± 1 

14.5 ± 2.1 

16.3 ± 0.6 

1.09 ± 0.05* 

1.08 ± 0.07 

279 ± 67** 

36 ± 1* 

19.0 ± 4.4* 

2.3 ± 0.5 

56 ± 12** 

13 ± 1 
296 Chloroprene, NTP TR 467 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male (continued) 

n 

Day 22 9 9 10 10 10 9 

Week 13 10 10 10 10 10 9 

Urinalysis 

Creatinine (mg/dL) 

Day 22 29.52 ± 3.68 35.41 ± 4.22 33.87 ± 3.71 31.87 ± 3.19 20.62 ± 1.23 13.77 ± 1.17** 

Week 13 87.9 ± 11.7 80.2 ± 9.6 74.0 ± 11.3 62.0 ± 8.1 55.7 ± 4.9 40.1 ± 4.2** 

Glucose (μg/mg creatinine) 

Day 22 125 ± 4 141 ± 5 137 ± 4 131 ± 4 127 ± 5 126 ± 6 

Week 13 110 ± 3 103 ± 3 108 ± 2 105 ± 4 108 ± 4 110 ± 4 

Protein (μg/mg creatinine) 

Day 22 1,574 ± 231 1,472 ± 123 1,313 ± 147 1,750 ± 148 1,565 ± 177 1,511 ± 119 

Week 13 864 ± 31 736 ± 82 818± 39 822 ± 39 886 ± 50 1,134 ± 71* 

Alkaline phosphatase (mU/mg creatinine) 

Day 22 371 ± 32 351 ± 21 339 ± 15 448 ± 36 421 ± 37 423 ± 90 

Week 13 195 ± 16 209 ± 16 237 ± 15* 259 ± 14** 266 ± 17** 353 ± 23** 

Aspartate aminotransferase (mU/mg creatinine) 

Day 22 6 ± 2 5 ± 2 8 ± 2 10 ± 3 10 ± 3 28 ± 19 

Week 13 13 ± 1 10 ± 1 13 ± 1 13 ± 1 16 ± 2 14 ± 2 

Volume (mL/16 hr) 

Day 22 19.1 ± 3.4 14.8 ± 2.1 14.0 ± 1.7 15.3 ± 2.0 19.4 ± 2.0 36.2 ± 3.1** 

Week 13 10.0 ± 1.6 10.8 ± 1.8 11.8 ± 2.1 13.9 ± 1.5 14.3 ± 1.5 22.0 ± 3.2** 

Specific gravity 

Day 22 1.010 ± 0.001 1.012 ± 0.001 1.012 ± 0.001 1.011 ± 0.001 1.007 ± 0.000 1.005 ± 0.001** 

Week 13 1.022 ± 0.003 1.019 ± 0.002 1.018 ± 0.003 1.015 ± 0.002 1.013 ± 0.001* 1.011 ± 0.001** 

Urea (mg/mg creatinine) 

Day 22 20.8 ± 0.7 20.9 ± 0.9 21.3 ± 0.6 20.8 ± 0.3 21.5 ± 0.7 24.3 ± 0.8* 

Week 13 16.1 ± 0.4 14.6 ± 0.3 15.2 ± 0.6 15.3 ± 0.5 15.3 ± 0.4 17.2 ± 0.3 
Chloroprene, NTP TR 467 297 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Female 

n 

Day 2 10 0 0 10 10 9 

Day 22 10 10 10 10 10 10 

Week 13 10 10 10 10 10 10 

Hematology 

Hematocrit (%) 

Day 2 42.8 ± 0.8 — — 41.7 ± 1.4 43.5 ± 0.6 46.7 ± 0.5** 

Day 22 50.4 ± 0.8 52.0 ± 0.5 52.0 ± 0.4 51.6 ± 0.7 51.8 ± 0.6 50.5 ± 0.4 

Week 13 48.1 ± 0.4 47.2 ± 0.4 48.2 ± 0.4 47.0 ± 0.4 48.1 ± 0.2 44.6 ± 0.8** 

Hemoglobin (g/dL) 

Day 2 14.2 ± 0.3 — — 13.9 ± 0.4 14.2 ± 0.2 15.4 ± 0.2** 

Day 22 15.9 ± 0.2 16.5 ± 0.2 16.5 ± 0.1 16.3 ± 0.2 16.4 ± 0.2 16.0 ± 0.1 

Week 13 15.9 ± 0.1 15.7 ± 0.2 16.1 ± 0.1 15.6 ± 0.1 16.0 ± 0.1 14.7 ± 0.2** 

Erythrocytes (10 /μL) 6 

Day 2 8.24 ± 0.20 — — 8.05 ± 0.26 8.19 ± 0.17 9.06 ± 0.15* 

Day 22 9.35 ± 0.16 9.66 ± 0.09 9.65 ± 0.07 9.56 ± 0.13 9.58 ± 0.14 9.60 ± 0.11 

Week 13 9.60 ± 0.07 9.46 ± 0.10 9.64 ± 0.07 9.39 ± 0.09 9.69 ± 0.04 9.01 ± 0.19* 

Reticulocytes (10 /μL) 6 

Day 22 0.09 ± 0.01 0.06 ± 0.01 0.10 ± 0.01 0.09 ± 0.01 0.07 ± 0.01 0.13 ± 0.01 

Week 13 0.16 ± 0.01 0.16 ± 0.01 0.13 ± 0.02 0.13 ± 0.01 0.14 ± 0.01 0.20 ± 0.03 

Nucleated erythrocytes (10 /μL) 3 

Day 22 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 

Week 13 0.00 ± 0.00 0.00 ± 0.00 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 

Mean cell volume (fL) 

Day 2 52.0 ± 0.5 — — 51.9 ± 0.7 53.2 ± 0.5 51.7 ± 0.4 

Day 22 53.7 ± 0.3 53.9 ± 0.2 53.9 ± 0.2 54.0 ± 0.3 54.0 ± 0.4 52.6 ± 0.3 

Week 13 50.2 ± 0.1 49.9 ± 0.2 50.1 ± 0.1 50.1 ± 0.2 49.7 ± 0.2* 49.5 ± 0.3** 

Mean cell hemoglobin (pg) 

Day 2 17.3 ± 0.1 — — 17.3 ± 0.1 17.4 ± 0.2 17.0 ± 0.1 

Day 22 17.0 ± 0.1 17.0 ± 0.1 17.1 ± 0.0 17.1 ± 0.1 17.2 ± 0.1 16.6 ± 0.1 

Week 13 16.6 ± 0.0 16.6 ± 0.1 16.7 ± 0.1 16.7 ± 0.1 16.5 ± 0.0 16.4 ± 0.1 

Mean cell hemoglobin concentration (g/dL) 

Day 2 33.3 ± 0.3 — — 33.4 ± 0.3 32.7 ± 0.1 33.1 ± 0.1 

Day 22 31.6 ± 0.1 31.7 ± 0.1 31.7 ± 0.1 31.6 ± 0.1 31.7 ± 0.1 31.6 ± 0.1 

Week 13 33.1 ± 0.2 33.2 ± 0.1 33.4 ± 0.2 33.2 ± 0.2 33.3 ± 0.1 33.1 ± 0.1 

Platelets (10 /μL) 3 

Day 2 633.9 ± 24.9 — — 669.8 ± 22.5 668.9 ± 22.5 336.3 ± 52.5** 

Day 22 640.8 ± 19.9 586.3 ± 9.2 581.9 ± 15.7 585.6 ± 22.0 577.0 ± 15.4* 491.2 ± 18.5** 

Week 13 570.5 ± 13.6 607.3 ± 12.9* 547.3 ± 7.5 604.8 ± 35.5 582.7 ± 10.8 787.7 ± 73.6** 

Leukocytes (10 /μL) 3 

Day 2 3.15 ± 0.24 — — 2.06 ± 0.21** 2.22 ± 0.10* 2.35 ± 0.18 

Day 22 5.55 ± 0.27 5.66 ± 0.34 5.50 ± 0.27 5.63 ± 0.20 5.27 ± 0.24 6.13 ± 0.42 

Week 13 6.19 ± 0.26 5.48 ± 0.33 5.06 ± 0.19* 6.24 ± 0.35 5.40 ± 0.43 6.36 ± 0.31 

Segmented neutrophils (10 /μL) 3 

Day 2 0.34 ± 0.06 — — 0.18 ± 0.02 0.20 ± 0.02 0.51 ± 0.16 

Day 22 0.71 ± 0.07 0.58 ± 0.06 0.46 ± 0.05 0.57 ± 0.09 0.48 ± 0.08* 0.68 ± 0.10 

Week 13 0.75 ± 0.07 0.94 ± 0.10 0.82 ± 0.09 1.14 ± 0.10* 0.80 ± 0.10 0.75 ± 0.08 

Lymphocytes (10 /μL) 3 

Day 2 2.74 ± 0.20 — — 1.82 ± 0.21** 1.97 ± 0.11* 1.74 ± 0.26* 

Day 22 4.63 ± 0.22 4.83 ± 0.30 4.83 ± 0.26 4.81 ± 0.18 4.59 ± 0.25 5.23 ± 0.34 

Week 13 5.21 ± 0.28 4.36 ± 0.29 4.02 ± 0.16* 4.85 ± 0.30 4.44 ± 0.41 5.37 ± 0.33 
298 Chloroprene, NTP TR 467 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Female (continued) 

n 

Day 2 

Day 22 

Week 13 

10

10 

10 

0

10 

10 

0 

10 

10 

10 

10 

10 

10 

10 

10 

9 

10 

10 

Hematology (continued) 

Monocytes (10 /μL) 3 

Day 2 0.04 ± 0.01

Day 22 0.18 ± 0.04 

Week 13 0.18 ± 0.02 

Eosinophils (10 /μL) 3 

Day 2 0.03 ± 0.01

Day 22 0.03 ± 0.02 

Week 13 0.06 ± 0.02 

Euglobulin lysis time (minutes) 

Day 2 89.8 ± 10.2e 

Fibrinogen (mg/dL) 

Day 2 197.8 ± 4.8e 

Activated partial thromboplastin time (seconds) 

Day 2 16.5 ± 0.5i 

Prothrombin time (seconds) 

Day 2 14.1 ± 0.1i 

—

0.19 ± 0.05 

0.15 ± 0.03 

—

0.06 ± 0.02 

0.03 ± 0.01 

—

 —

 —

 —

 — 

0.18 ± 0.04 

0.20 ± 0.03 

— 

0.03 ± 0.01 

0.02 ± 0.01 

— 

— 

— 

— 

0.03 ± 0.01 

0.21 ± 0.03 

0.22 ± 0.05 

0.02 ± 0.01 

0.04 ± 0.02 

0.03 ± 0.01 

139.7 ± 21.9d 

200.3 ± 6.2i 

18.7 ± 0.8 

14.0 ± 0.2 

0.03 ± 0.01 

0.15 ± 0.03 

0.15 ± 0.04 

0.02 ± 0.00 

0.05 ± 0.03 

0.02 ± 0.01 

93.4 ± 14.4f 

206.0 ± 7.5g 

18.5 ± 0.5i 

14.1 ± 0.1 

0.05 ± 0.01 

0.20 ± 0.06 

0.19 ± 0.04 

0.01 ± 0.01 

0.03 ± 0.01 

0.05 ± 0.02 

220.7 ± 24.5**h 

154.0 ± 10.7*h 

21.2 ± 1.2**f 

16.3 ± 0.8i 

n 

Day 22 

Week 13 

10 

10 

10 

10 

10 

10 

10 

10 

10 

10 

10 

10 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Day 22 

Week 13 

Creatinine (mg/dL) 

Day 22 

Week 13 

Alanine aminotransferase (IU/L) 

Day 22 

Week 13 

Glutamate dehydrogenase (IU/L) 

Day 22 

Week 13 

Sorbitol dehydrogenase (IU/L) 

Day 22 

Week 13 

16.3 ± 0.4 

20.1 ± 0.5 

1.00 ± 0.03 

1.12 ± 0.04 

30 ± 1 

37 ± 1 

3.3 ± 0.7 

1.9 ± 0.3 

15 ± 1 

11 ± 1 

15.6 ± 0.3 

19.7 ± 1.1 

0.98 ± 0.03 

1.09 ± 0.02 

30 ± 1 

35 ± 2 

4.5 ± 0.9 

2.2 ± 0.3 

14 ± 1 

11 ± 1 

15.7 ± 0.4 

19.5 ± 0.5 

1.03 ± 0.04 

1.07 ± 0.02 

32 ± 1 

35 ± 1 

4.3 ± 0.5 

2.0 ± 0.3 

16 ± 1 

10 ± 1 

16.2 ± 0.3 

19.7 ± 0.8 

0.95 ± 0.03 

1.19 ± 0.13 

31 ± 1 

34 ± 1 

4.4 ± 0.9 

1.7 ± 0.2 

14 ± 1 

11 ± 1 

14.7 ± 0.4** 

19.8 ± 0.7 

1.01 ± 0.02 

1.04 ± 0.03 

30 ± 1 

35 ± 1 

4.2 ± 0.7 

1.8 ± 0.1 

13 ± 1 

10 ± 1 

13.2 ± 0.2** 

19.7 ± 0.8 

1.17 ± 0.05 

1.02 ± 0.03 

95 ± 15** 

33 ± 1 

6.4 ± 1.1* 

1.4 ± 0.3 

17 ± 1 

11 ± 1 
Chloroprene, NTP TR 467 299 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Female (continued) 

n 

Day 22 10 10 10 10 10 10 

Week 13 10 10 10 10 10 10 

Urinalysis 

Creatinine (mg/dL) 

Day 22 18.7 ± 3.1 19.2 ± 4.0 16.9 ± 2.1 18.0 ± 2.8 19.1 ± 3.5 8.4 ± 0.9** 

Week 13 45.1 ± 4.9 31.4 ± 2.2* 45.7 ± 3.2 26.8 ± 4.0** 28.5 ± 2.9** 29.0 ± 3.2** 

Glucose (μg/mg creatinine) 

Day 22 142 ± 8 199 ± 24 146 ± 7 149 ± 10 167 ± 6 151 ± 21 

Week 13 97 ± 4 100 ± 3 105 ± 2 98 ± 4 102 ± 4 99 ± 3 

Protein (μg/mg creatinine) 

Day 22 431 ± 51 390 ± 41 416 ± 34 343 ± 31 383 ± 21 694 ± 73* 

Week 13 173 ± 13 200 ± 13 217 ± 40 203 ± 18 188 ± 14 201 ± 15 

Alkaline phosphatase (mU/mg creatinine) 

Day 22 296 ± 35 397 ± 66 337 ± 64 285 ± 30 357 ± 19 524 ± 79** 

Week 13 144 ± 7 147 ± 8 146 ± 5 141 ± 14 163 ± 10 267 ± 19** 

Aspartate aminotransferase (mU/mg creatinine) 

Day 22 

Week 13 

11 ± 1 

4 ± 1 

21 ± 12 

8 ± 2 

36 ± 28 

6 ± 1i 

13 ± 3 

5 ± 1 

27 ± 13 

7 ± 1 

26 ± 9 

9 ± 2* 

Volume (mL/16 hr) 

Day 22 19.5 ± 2.4 16.5 ± 1.9 17.4 ± 1.9 19.1 ± 2.9 18.0 ± 2.8 30.6 ± 3.0 

Week 13 10.9 ± 1.6 15.4 ± 1.6 10.7 ± 1.2 18.6 ± 2.7 18.4 ± 2.9 15.8 ± 1.5 

Specific gravity 

Day 22 1.008 ± 0.001 1.010 ± 0.002 1.008 ± 0.001 1.008 ± 0.001 1.009 ± 0.002 1.004 ± 0.000** 

Week 13 1.013 ± 0.001 1.010 ± 0.001* 1.014 ± 0.001 1.008 ± 0.001** 1.009 ± 0.001** 1.009 ± 0.001** 

Urea (mg/mg creatinine) 

Day 22 25.4 ± 0.7 27.5 ± 0.5 28.0 ± 0.7 28.4 ± 0.9 25.8 ± 0.5 27.4 ± 1.2 

Week 13 20.3 ± 0.5 20.9 ± 0.5 20.6 ± 0.4 21.8 ± 0.8 21.5 ± 0.5 21.5 ± 0.6 

* 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 Not measured at this exposure concentration c n=10 

d n=7 e n=6 

f n=8 

g n=5 

h n=3 

i n=9 
300 Chloroprene, NTP TR 467 

TABLE G3 

Day 5 Hematology and Clinical Chemistry Data for Mice in the 16-Day Inhalation Study of Chloroprenea 

Chamber 

Control 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

n 10 10 10 10 0b 

Hematology 

Hematocrit (%) 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

49.4 ± 0.5 

16.3 ± 0.2 

9.95 ± 0.13 

0.14 ± 0.02 

0.00 ± 0.00 

48.3 ± 0.5 

16.0 ± 0.1 

9.64 ± 0.12 

0.15 ± 0.02 

0.01 ± 0.01 

47.2 ± 0.8 

15.6 ± 0.3c 

9.40 ± 0.20 

0.13 ± 0.03 

0.01 ± 0.01 

48.4 ± 0.6 

15.9 ± 0.2 

9.65 ± 0.13 

0.19 ± 0.02 

0.00 ± 0.00 

— 

— 

— 

— 

— 

Howell-Jolly bodies (% erythrocytes) 0.2 ± 0.1 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.0 — 

Mean cell volume (fL) 

Mean cell hemoglobin (pg) 

49.7 ± 0.4 

16.4 ± 0.1 

50.2 ± 0.4 

16.6 ± 0.1 

50.4 ± 0.3 

16.5 ± 0.1c 50.1 ± 0.4 

16.4 ± 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 

33.0 ± 0.1 

930.2 ± 22.7 

3.40 ± 0.24 

0.37 ± 0.05 

2.99 ± 0.20 

0.04 ± 0.01 

0.00 ± 0.00 

33.1 ± 0.1 

893.2 ± 26.7 

4.33 ± 0.53 

0.39 ± 0.06 

3.87 ± 0.52 

0.06 ± 0.02 

0.00 ± 0.00 

32.7 ± 0.2c 

959.1 ± 41.2 

4.51 ± 0.66 

0.51 ± 0.10 

3.93 ± 0.56 

0.05 ± 0.02 

0.00 ± 0.00 

32.8 ± 0.2 

985.1 ± 62.7 

3.40 ± 0.34 

0.38 ± 0.07 

2.99 ± 0.30 

0.03 ± 0.01 

0.01 ± 0.01 

— 

— 

— 

— 

— 

— 

— 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Creatinine (mg/dL) 

Alanine aminotransferase (IU/L) 

41.2 ± 3.8c 

0.64 ± 0.08c 

306 ± 73 

35.4 ± 2.5c 

0.59 ± 0.07c 

333 ± 70 

40.3 ± 4.9c 

0.68 ± 0.06d 

193 ± 50c 

45.5 ± 4.6d 

0.79 ± 0.06d 

325 ± 52c 

— 

— 

— 

Glutamate dehydrogenase (IU/L) 12.0 ± 0.9 11.9 ± 1.1 11.1 ± 1.0 14.4 ± 0.9 — 

Sorbitol dehydrogenase (IU/L) 38 ± 3 37 ± 2 36 ± 2 35 ± 2 — 
301 

c 

Chloroprene, NTP TR 467 

TABLE G3 

Day 5 Hematology and Clinical Chemistry Data for Mice in the 16-Day Inhalation Study of Chloroprene 

Chamber 

Control 12 ppm 32 ppm 80 ppm 200 ppm 

Female 

n 9 10 10 10 0b 

Hematology 

Hematocrit (%) 48.5 ± 0.7 49.4 ± 0.2 48.6 ± 0.4 47.9 ± 0.4 — 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Nucleated erythrocytes (10 /μL) 3 

15.6 ± 0.3 

9.40 ± 0.18 

0.09 ± 0.03 

0.00 ± 0.00 

16.1 ± 0.1 

9.74 ± 0.09 

0.10 ± 0.01 

0.01 ± 0.00 

15.8 ± 0.1 

9.47 ± 0.11 

0.10 ± 0.03 

0.00 ± 0.00 

15.5 ± 0.1

9.37 ± 0.09

0.06 ± 0.01

0.00 ± 0.00

 — 

— 

— 

— 

Howell-Jolly bodies (% erythrocytes) 0.1 ± 0.0 0.1 ± 0.0 0.1 ± 0.1 0.1 ± 0.0 — 

Mean cell volume (fL) 51.8 ± 0.4 50.8 ± 0.2 51.4 ± 0.4 51.1 ± 0.3 — 

Mean cell hemoglobin (pg) 16.7 ± 0.1 16.5 ± 0.1 16.7 ± 0.1 16.6 ± 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 

32.3 ± 0.1 

804.2 ± 20.3 

3.30 ± 0.20 

0.42 ± 0.05 

2.79 ± 0.19 

0.09 ± 0.02 

0.00 ± 0.00 

32.6 ± 0.1 

792.5 ± 22.7 

3.29 ± 0.25 

0.41 ± 0.07 

2.80 ± 0.23 

0.07 ± 0.03 

0.00 ± 0.00 

32.4 ± 0.1 

847.1 ± 12.5 

3.20 ± 0.20 

0.40 ± 0.05 

2.72 ± 0.16 

0.09 ± 0.02 

0.00 ± 0.00 

32.4 ± 0.1

945.4 ± 24.9**

3.02 ± 0.23

0.39 ± 0.05

2.54 ± 0.18

0.09 ± 0.02

0.00 ± 0.00

 — 

— 

— 

— 

— 

— 

— 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Creatinine (mg/dL) 

34.5 ± 2.5 

0.79 ± 0.05 

29.4 ± 2.3 

0.69 ± 0.05 

29.3 ± 1.8 

0.65 ± 0.03 

32.9 ± 2.6c 

0.73 ± 0.06c — 

— 

Alanine aminotransferase (IU/L) 87 ± 13 167 ± 51 142 ± 43 238 ± 68 — 

Glutamate dehydrogenase (IU/L) 10.0 ± 0.5 10.5 ± 0.8 9.4 ± 1.0 14.3 ± 1.8 — 

Sorbitol dehydrogenase (IU/L) 30 ± 3 24 ± 1 26 ± 1 28 ± 1 — 

** Significantly different (P#0.01) from the control group by Dunn’s or Shirley’s test a Mean ± standard error. Statistical tests were performed on unrounded data. b Not measured at this exposure concentration due to high mortality 

n=9 

d n=8 
302 Chloroprene, NTP TR 467 

TABLE G4 

Hematology and Clinical Chemistry Data for Mice in the 13-Week Inhalation Study of Chloroprenea 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 

Male 

n 10 10 9 10 10 

Hematology 

Hematocrit (%) 45.3 ± 0.8 45.5 ± 0.6 44.3 ± 2.0 46.1 ± 0.4 44.9 ± 0.2 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

Howell-Jolly bodies (% erythrocytes) 

16.2 ± 0.2 

10.19 ± 0.15 

0.23 ± 0.01 

0.1 ± 0.0 

16.3 ± 0.2 

10.23 ± 0.11 

0.21 ± 0.01 

0.1 ± 0.1 

16.1 ± 0.7 

10.06 ± 0.46 

0.24 ± 0.02 

0.2 ± 0.0b 

16.7 ± 0.1 

10.41 ± 0.08 

0.23 ± 0.02 

0.2 ± 0.0 

16.3 ± 0.1 

10.21 ± 0.06 

0.20 ± 0.01 

0.1 ± 0.0 

Mean cell volume (fL) 44.5 ± 0.2 44.5 ± 0.2 43.9 ± 0.4 44.3 ± 0.3 43.9 ± 0.2 

Mean cell hemoglobin (pg) 15.9 ± 0.1 16.0 ± 0.1 16.0 ± 0.1 16.0 ± 0.1 16.0 ± 0.0 

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 

35.9 ± 0.2 

913.6 ± 18.5 

3.96 ± 0.47 

0.45 ± 0.04 

3.37 ± 0.45 

0.11 ± 0.02 

0.04 ± 0.01 

35.8 ± 0.2 

881.4 ± 17.5 

3.46 ± 0.27 

0.48 ± 0.06 

2.83 ± 0.22 

0.12 ± 0.03 

0.035 ± 0.01 

36.3 ± 0.2 

847.9 ± 44.1 

4.20 ± 0.58 

0.51 ± 0.06 

3.56 ± 0.53 

0.07 ± 0.02 

0.06 ± 0.02 

36.2 ± 0.2 

929.8 ± 17.4 

4.35 ± 0.46 

0.53 ± 0.06 

3.70 ± 0.40 

0.08 ± 0.02 

0.04 ± 0.02 

36.4 ± 0.2 

914.4 ± 30.6 

4.63 ± 0.54 

0.77 ± 0.14 

3.71 ± 0.46 

0.12 ± 0.03 

0.04 ± 0.02 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Creatinine (mg/dL) 

31.0 ± 2.3 

0.51 ± 0.03c 32.4 ± 2.1 

0.44 ± 0.05 

32.0 ± 2.0 

0.47 ± 0.04 

32.5 ± 3.6 

0.47 ± 0.09 

25.0 ± 1.8 

0.36 ± 0.04*c 

Alanine aminotransferase (IU /L) 71 ± 19 91 ± 17 108 ± 26 176 ± 56 122 ± 29 

Glutamate dehydrogenase (IU/L) 

Sorbitol dehydrogenase (IU/L) 

4.5 ± 0.6 

35 ± 3 

6.0 ± 0.9 

32 ± 1 

5.9 ± 1.1 

32 ± 3b 

7.3 ± 1.1 

31 ± 1 

6.6 ± 1.3 

33 ± 2 
303 

c 

Chloroprene, NTP TR 467 

TABLE G4 

Hematology and Clinical Chemistry Data for Mice in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 12 ppm 32 ppm 80 ppm 

Female 

n 10 10 10 10 10 

Hematology 

Hematocrit (%) 45.9 ± 0.4 45.6 ± 0.4 45.3 ± 0.3 44.7 ± 0.3* 44.3 ± 0.3** 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 

Reticulocytes (10 /μL) 6 

16.4 ± 0.1 

10.16 ± 0.05 

0.22 ± 0.03 

16.4 ± 0.1 

10.08 ± 0.07 

0.24 ± 0.03 

16.4 ± 0.1 

10.20 ± 0.05 

0.23 ± 0.01 

16.3 ± 0.1 

10.09 ± 0.05 

0.22 ± 0.02 

16.2 ± 0.1 

9.93 ± 0.06* 

0.23 ± 0.03 

Howell-Jolly bodies (% erythrocytes) 0.12 ± 0.04 0.13 ± 0.04 0.09 ± 0.03 0.09 ± 0.03 0.11 ± 0.03 

Mean cell volume (fL) 45.1 ± 0.3 45.3 ± 0.4 44.5 ± 0.2 44.2 ± 0.2 44.5 ± 0.2 

Mean cell hemoglobin (pg) 16.1 ± 0.1 16.2 ± 0.0 16.1 ± 0.1 16.2 ± 0.1 16.3 ± 0.0* 

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 

35.8 ± 0.3 

866.2 ± 18.0 

3.24 ± 0.25 

0.35 ± 0.05 

2.77 ± 0.21 

0.08 ± 0.02 

0.04 ± 0.01 

36.0 ± 0.3 

861.4 ± 15.0 

3.27 ± 0.43 

0.45 ± 0.08 

2.67 ± 0.33 

0.12 ± 0.05 

0.04 ± 0.02 

36.1 ± 0.1 

890.0 ± 11.4 

3.10 ± 0.33 

0.34 ± 0.03 

2.68 ± 0.32 

0.06 ± 0.01 

0.02 ± 0.01 

36.5 ± 0.1 

924.9 ± 18.0* 

3.81 ± 0.41 

0.68 ± 0.27 

2.97 ± 0.20 

0.12 ± 0.03 

0.04 ± 0.02 

36.6 ± 0.2* 

964.9 ± 24.5** 

3.21 ± 0.25 

0.36 ± 0.04 

2.72 ± 0.21 

0.09 ± 0.03 

0.04 ± 0.01 

Clinical Chemistry 

Urea nitrogen (mg/dL) 

Creatinine (mg/dL) 

24.8 ± 1.4 

0.63 ± 0.09 

21.7 ± 1.3* 

0.57 ± 0.03 

20.0 ± 0.8** 

0.57 ± 0.03c 19.5 ± 0.9** 

0.54 ± 0.04 

18.1 ± 0.6** 

0.51 ± 0.04c 

Alanine aminotransferase (IU/L) 46 ± 12 32 ± 3 31 ± 3 41 ± 4 48 ± 13 

Glutamate dehydrogenase (IU/L) 5.2 ± 0.8 4.0 ± 0.4 3.8 ± 0.3 4.3 ± 0.3 4.6 ± 0.5 

Sorbitol dehydrogenase (IU/L) 23 ± 3 27 ± 1 26 ± 3 30 ± 2 26 ± 1 

* 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=10
 

n=9 
304 Chloroprene, NTP TR 467
 
305 

APPENDIX H 

TISSUE NONPROTEIN SULFHYDRYL 

CONCENTRATION RESULTS 

TABLE H1 

TABLE H2 

Tissue Nonprotein Sulfhydryl Concentrations in Rats 

in the 13-Week Inhalation Study of Chloroprene ............................ 

Tissue Nonprotein Sulfhydryl Concentrations in Mice 

in the 13-Week Inhalation Study of Chloroprene ............................ 

306 

308 
306 Chloroprene, NTP TR 467 

TABLE H1 

Tissue Nonprotein Sulfhydryl Concentrations in Rats in the 13-Week Inhalation Study of Chloroprenea 

Chamber 

Control 5 ppm 32 ppm 200 ppm 

Male 

n 5 5 5 5 

Kidney nonprotein sulfhydryl 

Day 1 1.10 ± 0.12 1.22 ± 0.23 1.38 ± 0.25b 1.30 ± 0.16 

Week 12 0.72 ± 0.22 1.46 ± 0.44 1.62 ± 0.14 1.48 ± 0.40 

Liver nonprotein sulfhydryl 

Day 1 1.70 ± 0.28 1.56 ± 0.25 1.88 ± 0.18 0.50 ± 0.17* 

Week 12 5.04 ± 0.39 4.58 ± 0.34 3.90 ± 0.86 2.90 ± 0.22* 

Lung nonprotein sulfhydryl 

Day 1 0.180 ± 0.058 0.100 ± 0.000 0.080 ± 0.020 0.075 ± 0.025b 

Week 12 0.24 ± 0.07 0.14 ± 0.05 0.10 ± 0.03 0.34 ± 0.12 

Thymus nonprotein sulfhydryl 

Day 1 

Week 12 

1.52 ± 0.06 

1.80 ± 0.26b 

1.34 ± 0.17 

1.84 ± 0.15 

1.42 ± 0.20 

1.70 ± 0.18 

1.60 ± 0.12b 

1.78 ± 0.13 

Kidney total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 12.58 ± 1.33 12.32 ± 1.62 10.68 ± 1.42b 11.94 ± 1.26 

Week 12 26.44 ± 6.36 14.28 ± 4.92 9.20 ± 0.96 13.56 ± 4.05 

Liver total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 11.00 ± 2.05 11.46 ± 1.77 8.38 ± 0.96 50.42 ± 20.57 

Week 12 2.68 ± 0.25 2.70 ± 0.21 4.40 ± 1.32 4.66 ± 0.24 

Lung total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 42.8 ± 14.5 60.3 ± 5.1 69.4 ± 7.1 82.6 ± 18.4b 

Week 12 48.9 ± 16.8 69.0 ± 20.8 108.1 ± 42.8 27.5 ± 5.1 

Thymus total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 

Week 12 

5.70 ± 0.31 

5.28 ± 0.72b 

6.44 ± 0.99 

5.42 ± 0.42 

6.84 ± 1.12 

5.84 ± 0.91 

5.48 ± 0.61b 

4.98 ± 0.18 
Chloroprene, NTP TR 467 307 

TABLE H1 

Tissue Nonprotein Sulfhydryl Concentrations in Rats in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 5 ppm 32 ppm 200 ppm 

Female 

n 5 5 5 5 

Kidney nonprotein sulfhydryl 

Day 1 1.38 ± 0.16 1.50 ± 0.27 1.42 ± 0.26 1.10 ± 0.19 

Week 12 1.32 ± 0.27 1.76 ± 0.29 1.88 ± 0.14 2.70 ± 0.31** 

Liver nonprotein sulfhydryl 

Day 1 1.58 ± 0.24 1.90 ± 0.40 1.62 ± 0.30 0.96 ± 0.37 

Week 12 4.76 ± 0.30 4.48 ± 0.23 4.02 ± 0.19 1.46 ± 0.07** 

Lung nonprotein sulfhydryl 

Day 1 0.160 ± 0.060 0.160 ± 0.087 0.060 ± 0.024 0.020 ± 0.020* 

Week 12 0.16 ± 0.06 0.20 ± 0.08 0.46 ± 0.14 0.34 ± 0.10 

Thymus nonprotein sulfhydryl 

Day 1 1.98 ± 0.10 1.70 ± 0.15 2.02 ± 0.11 1.74 ± 0.09 

Week 12 1.88 ± 0.16 1.96 ± 0.12 1.90 ± 0.20 1.76 ± 0.09 

Kidney total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 8.96 ± 0.88 8.82 ± 1.23 10.08 ± 1.30 12.82 ± 2.88 

Week 12 12.50 ± 2.68 9.08 ± 1.92 7.46 ± 0.40 6.10 ± 0.65* 

Liver total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 9.98 ± 1.63 8.90 ± 1.43 10.60 ± 2.11 54.94 ± 28.14 

Week 12 3.80 ± 0.25 4.28 ± 0.22 3.86 ± 0.66 11.32 ± 0.64** 

Lung total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 53.0 ± 10.7 59.5 ± 16.6 92.0 ± 11.3 119.7 ± 29.7* 

Week 12 47.4 ± 7.4 49.3 ± 14.2 28.7 ± 14.6 34.3 ± 14.7 

Thymus total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 4.54 ± 0.14 5.02 ± 0.32 4.58 ± 0.11 4.60 ± 0.25 

Week 12 4.64 ± 0.12 4.28 ± 0.11 4.30 ± 0.15 4.70 ± 0.17 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error in units of μmole/g tissue. Statistical tests were performed on unrounded data. b n=4 
308 Chloroprene, NTP TR 467 

TABLE H2 

Tissue Nonprotein Sulfhydryl Concentrations in Mice in the 13-Week Inhalation Study of Chloroprenea 

Chamber 

Control 12 ppm 32 ppm 80 ppm 

Male 

n 5 5 5 5 

Kidney nonprotein sulfhydryl 

Day 1 1.74 ± 0.36 1.62 ± 0.26 1.66 ± 0.27 1.64 ± 0.34 

Week 12 1.98 ± 0.07 2.28 ± 0.25 2.10 ± 0.27 2.36 ± 0.20 

Liver nonprotein sulfhydryl 

Day 1 2.46 ± 0.17 2.36 ± 0.25 2.30 ± 0.18 2.54 ± 0.30 

Week 12 4.38 ± 0.35 4.90 ± 0.25 4.58 ± 0.25 3.00 ± 0.13 

Lung nonprotein sulfhydryl 

Day 1 0.68 ± 0.14 0.72 ± 0.20 0.72 ± 0.15 0.58 ± 0.09 

Week 12 1.04 ± 0.13 1.06 ± 0.12 0.86 ± 0.07 0.64 ± 0.15 

Thymus nonprotein sulfhydryl 

Day 1 1.58 ± 0.26 1.92 ± 0.12 1.56 ± 0.17 1.68 ± 0.21 

Week 12 2.06 ± 0.23 1.50 ± 0.30 1.84 ± 0.41 1.60 ± 0.15 

Kidney total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 9.28 ± 1.83 9.02 ± 1.67 8.60 ± 1.19 9.98 ± 2.19 

Week 12 6.72 ± 0.34 6.98 ± 1.20 6.94 ± 1.09 5.26 ± 0.80 

Liver total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 5.06 ± 0.32 5.44 ± 0.34 5.76 ± 0.63 5.08 ± 0.64 

Week 12 2.32 ± 0.14 2.22 ± 0.11 2.38 ± 0.17 3.32 ± 0.18** 

Lung total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 12.16 ± 2.46 11.46 ± 2.69 11.62 ± 2.34 12.92 ± 1.53 

Week 12 7.90 ± 1.50 7.14 ± 0.74 7.98 ± 0.47 14.68 ± 6.31 

Thymus total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 4.96 ± 0.36 3.92 ± 0.16 4.52 ± 0.34 5.04 ± 0.96 

Week 12 2.58 ± 0.42 2.96 ± 0.43 4.22 ± 2.01 3.12 ± 0.43 
Chloroprene, NTP TR 467 309 

TABLE H2 

Tissue Nonprotein Sulfhydryl Concentrations in Mice in the 13-Week Inhalation Study of Chloroprene 

Chamber 

Control 12 ppm 32 ppm 80 ppm 

Female 

n 5 5 5 5 

Kidney nonprotein sulfhydryl 

Day 1 1.38 ± 0.10 1.86 ± 0.10* 1.76 ± 0.17 1.74 ± 0.10 

Week 12 1.58 ± 0.22 2.08 ± 0.27 1.54 ± 0.11 1.58 ± 0.19 

Liver nonprotein sulfhydryl 

Day 1 2.12 ± 0.33 2.56 ± 0.19 2.82 ± 0.16 2.96 ± 0.19 

Week 12 4.00 ± 0.21 4.24 ± 0.34 4.04 ± 0.32 2.62 ± 0.20 

Lung nonprotein sulfhydryl 

Day 1 0.56 ± 0.09 0.82 ± 0.05 0.62 ± 0.19 0.52 ± 0.06 

Week 12 0.74 ± 0.06 0.60 ± 0.22 0.64 ± 0.16 0.50 ± 0.06 

Thymus nonprotein sulfhydryl 

Day 1 1.70 ± 0.17 1.90 ± 0.22 2.36 ± 0.34 1.94 ± 0.10 

Week 12 1.64 ± 0.08 2.16 ± 0.21 1.82 ± 0.13 1.62 ± 0.16 

Kidney total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 9.34 ± 0.46 7.38 ± 0.40 7.26 ± 0.62 8.20 ± 0.57 

Week 12 8.74 ± 1.01 7.02 ± 0.70 8.86 ± 0.70 9.22 ± 0.97 

Liver total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 6.50 ± 0.76 5.26 ± 0.47 4.66 ± 0.28 4.48 ± 0.39 

Week 12 2.78 ± 0.05 2.70 ± 0.27 2.74 ± 0.14 4.08 ± 0.29 

Lung total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 13.80 ± 2.49 9.06 ± 0.47 10.25 ± 1.39b 14.68 ± 1.15 

Week 12 9.70 ± 0.51 17.36 ± 6.01 13.28 ± 4.64 12.72 ± 1.43 

Thymus total sulfhydryl/

 nonprotein sulfhydryl 

Day 1 4.74 ± 0.39 4.14 ± 0.46 3.30 ± 0.54 4.50 ± 0.33 

Week 12 4.20 ± 0.31 3.68 ± 0.43 3.94 ± 0.34 3.50 ± 0.18 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error in units of μmole/g tissue. Statistical tests were performed on unrounded data. b n=4 
310 Chloroprene, NTP TR 467
 
311 

APPENDIX I 

REPRODUCTIVE TISSUE EVALUATIONS 

AND CYCLE CHARACTERIZATION 

TABLE I1 

TABLE I2 

Summary of Reproductive Tissue Evaluations and Estrous Cycle Characterization 

for Rats in the 13-Week Study of Chloroprene ............................. 

Summary of Reproductive Tissue Evaluations and Estrous Cycle Characterization 

for Mice in the 13-Week Study of Chloroprene ............................. 

312 

313 
312 

c 

Chloroprene, NTP TR 467 

TABLE I1 

Summary of Reproductive Tissue Evaluations and Estrous Cycle Characterization for Rats 

in the 13-Week Study of Chloroprenea 

Chamber 

Control 5 ppm 32 ppm 200 ppm 

Male 

n 10 10 9 9 

Weights (g) 

Necropsy body wt 292 ± 9 306 ± 11 309 ± 10b 284 ± 8 

R. cauda 0.1578 ± 0.0057 0.1620 ± 0.0077 0.1568 ± 0.0073 0.1547 ± 0.0048 

R. epididymis 0.4524 ± 0.0166 0.4298 ± 0.0159 0.4467 ± 0.0106 0.4328 ± 0.0117 

R. testis 1.324 ± 0.034 1.344 ± 0.025 1.375 ± 0.038 1.351 ± 0.024 

Epididymal spermatozoal parameters 

Motility (%) 86.73 ± 1.04 83.62 ± 1.93 82.16 ± 1.84 80.04 ± 1.99** 

Abnormal sperm (%) 0.70 ± 0.05 0.78 ± 0.11 0.73 ± 0.11 1.02 ± 0.14 

Concentration 

(10 /g cauda epididymal tissue) 6 698 ± 40 722 ± 62 689 ± 46 683 ± 25 

Female 

n 10 10 10 10 

Necropsy body wt (g) 

Estrous cycle length (days) 

176 ± 3 

5.00 ± 0.15 

180 ± 3 

4.67 ± 0.17c 181 ± 4 

5.00 ± 0.27d 

171 ± 3 

5.33 ± 0.17c 

Estrous stages (% of cycle) 

Diestrus 42.9 35.7 44.3 45.7 

Proestrus 15.7 18.6 11.4 17.1 

Estrus 18.6 22.9 20.0 15.7 

Metestrus 22.9 22.9 24.3 20.0 

Uncertain diagnoses 0.0 0.0 0.0 1.4 

** Significantly different (P#0.01) from the control group by Shirley's test a Weights, epididymal spermatozoal parameters, and estrous cycle lengths are presented as mean ± standard error. Differences from the 

control group are not significant by Dunn's test (epididymal spermatozoal abnormality and concentration, estrous cycle length) or 

Dunnett's test (organ and body weights). By multivariate analysis of variance, exposed females do not differ significantly from the 

chamber control females in relative length of time spent in the estrous stages. b n=10 

Estrous cycle was longer than 12 days or unclear in 1 of 10 animals. d Estrous cycle was longer than 12 days or unclear in 2 of 10 animals. 
313 

c 

Chloroprene, NTP TR 467 

TABLE I2 

Summary of Reproductive Tissue Evaluations and Estrous Cycle Characterization for Mice 

in the 13-Week Study of Chloroprenea 

Chamber 

Control 12 ppm 32 ppm 80 ppm 

Male 

n 7 8 10 10 

Weights (g) 

Necropsy body wt 36.0 ± 0.9b 35.1 ± 0.6b 36.8 ± 0.9 33.4 ± 0.6 

R. cauda 0.0172 ± 0.0006 0.0164 ± 0.0011 0.0164 ± 0.0014 0.0158 ± 0.0005 

R. epididymis 0.0492 ± 0.0021 0.0488 ± 0.0019 0.0510 ± 0.0043 0.0470 ± 0.0011 

R. testis 0.114 ± 0.004 0.116 ± 0.002 0.122 ± 0.004 0.123 ± 0.004 

Epididymal spermatozoal parameters 

Motility (%) 79.09 ± 1.20 81.07 ± 1.13 80.08 ± 1.19 80.04 ± 1.47 

Abnormal sperm (%) 1.49 ± 0.42 1.30 ± 0.22 0.98 ± 0.10 1.36 ± 0.22 

Concentration 6 (10 /g cauda epididymal tissue) 1,632 ± 138 1,447 ± 122 1,575 ± 104 1,672 ± 134 

Female 

n 10 10 10 10 

Necropsy body wt (g) 31.5 ± 1.1 31.2 ± 0.7 33.5 ± 0.7 30.2 ± 1.5 

Estrous cycle length (days) 4.00 ± 0.00 4.30 ± 0.21 4.22 ± 0.15c 4.13 ± 0.13d 

Estrous stages (% of cycle) 

Diestrus 31.4 31.4 30.0 35.7
 

Proestrus 20.0 20.0 22.9 25.7
 

Estrus 24.3 24.3 25.7 20.0
 

Metestrus 24.3 24.3 21.4 18.6
 

a Weights, epididymal spermatozoal parameters, and estrous cycle lengths are presented as mean ± standard error. Differences from the 

control group are not significant by Dunn's test (epididymal spermatozoal parameters, estrous cycle length) or Dunnett's test (organ and 

body weights). By multivariate analysis of variance, exposed females do not differ significantly from the chamber control females in 

relative length of time spent in the estrous stages. b n=10 

Estrous cycle was longer than 12 days or unclear in 1 of 10 animals. d Estrous cycle was longer than 12 days or unclear in 2 of 10 animals. 
314 Chloroprene, NTP TR 467
 
315 

APPENDIX J
 

NEUROBEHAVIORAL STUDIES
 

TABLE J1	 Neurobehavioral Data for Rats at 11 Weeks in the 13-Week Inhalation Study 

of Chloroprene ................................................... 316 
316 

c 

Chloroprene, NTP TR 467 

TABLE J1 

Neurobehavioral Data for Rats at 11 Weeks in the 13-Week Inhalation Study of Chloroprenea 

0 ppm 5 ppm 12 ppm 32 ppm 80 ppm 200 ppm 

Male 

n 10 10 10 10 10 9 

Forelimb grip strength (g) b 

Hindlimb grip strength (g) b 

515.8 ± 24.9 

409.6 ± 29.0 

526.5 ± 29.0 

397.5 ± 28.0 

506.7 ± 18.2 

396.5 ± 16.4 

558.8 ± 27.4 

440.6 ± 15.9 

525.9 ± 28.1 

410.1 ± 19.2 

467.4 ± 23.7 

393.2 ± 24.5 

Horizontal activity count (1 hour) 163.5 ± 13.9 196.4 ± 20.5 182.2 ± 7.9 201.2 ± 15.5* 207.7 ± 14.4* 218.9 ± 9.6** 

Rearing activity count (1 hour) 31.5 ± 4.4 38.7 ± 4.5 36.0 ± 5.3 42.2 ± 6.4 33.9 ± 3.9 41.1 ± 4.3 

Total activity count (1 hour) 195.0 ± 15.1 235.1 ± 23.6 218.2 ± 12.5 243.4 ± 19.4* 241.6 ± 16.6 260.0 ± 10.3** 

Tailflick latency test (seconds) 4.18 ± 0.31 4.81 ± 0.44 4.47 ± 0.57 5.70 ± 1.02 4.37 ± 0.50 4.66 ± 0.76 

Startle response 

latency (milliseconds) c 47.6 ± 2.1 43.3 ± 1.2 42.5 ± 2.3 47.5 ± 3.3 44.0 ± 2.7 40.7 ± 1.8 

Startle response 

amplitude (volts) c 93.4 ± 9.4 89.4 ± 9.3 96.1 ± 10.2 118.0 ± 18.7 104.4 ± 14.3 60.3 ± 8.6 

Female 

n 10 10 10 10 10 10 

Forelimb grip strength test (g) 460.5 ± 15.0 475.2 ± 15.5 509.2 ± 15.1 482.1 ± 18.9 490.1 ± 21.2 463.2 ± 28.2 

Hindlimb grip strength test (g) 369.8 ± 17.8 395.8 ± 15.0 394.2 ± 17.2 370.4 ± 17.0 395.4 ± 14.2 358.2 ± 15.5 

Horizontal activity count (1 hour) 244.6 ± 28.2 260.1 ± 31.4 234.4 ± 18.6 258.8 ± 19.2 270.4 ± 20.5 257.7 ± 16.8 

Rearing activity count (1 hour) 41.8 ± 3.8 37.8 ± 5.6 38.6 ± 5.9 47.0 ± 6.4 55.5 ± 7.3 50.0 ± 4.6 

Total activity count (1 hour) 286.4 ± 30.0 297.9 ± 35.9 273.0 ± 23.3 305.8 ± 22.7 325.9 ± 23.4 307.7 ± 20.0 

Tailflick latency test (seconds) 4.40 ± 0.29 6.42 ± 0.87 4.07 ± 0.34 4.43 ± 0.41 5.10 ± 0.69 4.31 ± 0.23 

Startle response 

latency (milliseconds) 43.0 ± 2.9 38.0 ± 1.9 39.6 ± 1.8 40.9 ± 2.4 40.9 ± 2.0 42.8 ± 1.9 

Startle response 

amplitude (volts) 40.4 ± 9.7 42.5 ± 4.9 45.1 ± 8.2 34.4 ± 3.9 48.2 ± 8.0 36.6 ± 3.7 

* 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 Three trials per rat 

Six trials per rat 
317 

APPENDIX K
 

CHEMICAL CHARACTERIZATION AND
 

GENERATION OF CHAMBER CONCENTRATIONS
 

PROCUREMENT AND CHARACTERIZATION OF CHLOROPRENE .............................. 318
 

VAPOR GENERATION AND EXPOSURE SYSTEM ........................................ 319
 

VAPOR CONCENTRATION MONITORING ............................................ 320
 

CHAMBER ATMOSPHERE CHARACTERIZATION ....................................... 320
 

FIGURE K1 Infrared Absorption Spectrum of Chloroprene ............................ 322
 

FIGURE K2 Nuclear Magnetic Resonance Spectrum of Chloroprene ...................... 323
 

FIGURE K3 Schematic of the Generation and Delivery System for the 16-Day Studies .......... 324
 

FIGURE K4 Schematic of the Generation and Delivery System for the 13-Week Studies ......... 325
 

FIGURE K5 Schematic of the Generation and Delivery System for the 2-Year Studies .......... 326
 

FIGURE K6 Inhalation Suite for the 16-Day Studies ................................. 327
 

FIGURE K7 Inhalation Suite for the 13-Week Studies ................................ 328
 

FIGURE K8 Inhalation Suite for the 2-Year Studies ................................. 329
 

TABLE K1 Summary of Chamber Concentrations in the 16-Day Inhalation Studies 

of Chloroprene ................................................. 330
 

TABLE K2 Summary of Chamber Concentrations in the 13-Week Inhalation Studies 

of Chloroprene ................................................. 330
 

TABLE K3 Summary of Chamber Concentrations in the 2-Year Inhalation Studies 

of Chloroprene ................................................. 331
 
 

318 Chloroprene, NTP TR 467 

CHEMICAL CHARACTERIZATION AND 

GENERATION OF CHAMBER CONCENTRATIONS 

PROCUREMENT AND CHARACTERIZATION OF CHLOROPRENE 

Chloroprene was obtained for the 16-day and 13-week studies from Denka Chemical Company (Houston, 

TX) in 5 lots. Chloroprene for the 2-year study was supplied by Mobay Synthetic Corporation (Houston, 

TX) in 12 lots. Identity, purity, and stability studies of lot 12103-4-1, from the first lot of material procured 

for these studies, were performed by the analytical chemistry laboratory, Midwest Research Institute (Kansas 

City, MO). Reports on the analyses performed by the analytical chemistry laboratory in support of the 

chloroprene studies are on file at the National Institute of Environmental Health Sciences. Subsequent purity 

and identity analyses of chloroprene lots were performed by the study laboratory. 

The chemical, a clear colorless liquid, was identified as chloroprene by infrared, ultraviolet/visible, and 

nuclear magnetic resonance spectroscopy. The infrared and nuclear magnetic resonance spectra were 

consistent with the literature spectra (Bothner-By and Harris, 1953; Szasz and Sheppard, 1953) of 

chloroprene; all spectra were consistent with the structure of chloroprene. The infrared and nuclear magnetic 

resonance spectra are presented in Figures K1 and K2. The boiling point and density of the chemical were 

also consistent with literature references (CRC Handbook of Chemistry and Physics, 1982). 

The purity of lot 12103-4-1 was determined by elemental analysis, Karl Fischer water analysis, 

approximation of t-butylcatechol, thin layer chromatography (TLC), and gas chromatography. To 

approximate the concentration of t-butylcatechol inhibitor, 1.0 N sodium hydroxide was added to a 

chloroprene sample and the resultant color was compared to t-butylcatechol standards. TLC was performed 

on Silica Gel 60, F-254 plates with a methanol solvent system. Plates were examined under iodine vapor. 

Gas chromatography was performed using a flame ionization detector. Two systems were used: 

A) 0.1% SP-1000 on 80/100 Carbopack glass column, with a nitrogen carrier gas at a flow rate 

of 70 mL per minute, and an oven temperature program of 50E C for 5 minutes, then 50E C 

to 225E C at 10E C per minute. 

3 B) DB-5 fused silica column, with a helium carrier gas at a flow rate of 50 cm per second, a

nitrogen make-up gas at a flow rate of 30 mL per minute, and an oven temperature program 

of 30E C for 5 minutes, and then 30E C to 250E C at 10E C per minute. 

Peroxide concentrations were analyzed for lot 12103-4-1. To determine peroxide concentrations a sample of 

chloroprene was dissolved in glacial acetic acid:chloroform (3:2). Saturated potassium iodide solution was 

added and the sample was allowed to stand for 1 minute. Distilled water was then added; liberated iodine 

was titrated with 0.01 sodium thiosulfate to a colorimetric endpoint using a starch indicator. 

Chloroprene procured for the 16-day and 13-week studies was fortified with 0.1% phenothiazine and 

t-butylcatechol. Chloroprene procured for the 2-year study had 0.1% phenothiazine and t-butylcatechol 

added by the producer before shipment to the study laboratory. 

Elemental analyses for carbon, hydrogen, and chlorine agreed with the theoretical values for chloroprene. 

Karl Fisher water analysis indicated less than 0.01% water. Approximation of t-butylcatechol inhibitor 

indicated 40 to 50 ppm with flame ionization detection, a DB-5 megabore capillary column, and an oven 

program from an initial temperature of 35E C for 5 minutes then ramped at 10E C/minute to a final 

temperature of 175E C using helium as the carrier gas. TLC indicated one major spot. TLC of a second 

sample left at room temperature overnight revealed another spot in addition to the major spot. Gas 
Chloroprene, NTP TR 467 319 

chromatography by system A indicated four impurities with a cumulative peak area of 0.96% relative to the 

major peak; gas chromatography by system B indicated six impurities with a total area of 3.30% relative to 

the major peak area. Gas chromatography/mass spectrometry identified six impurities: chlorobutene, 

chlorobutadiene, toluene, and three chloroprene dimers. Five additional impurity peaks with areas less than 

0.1% were also observed. Titration for peroxide indicated 1.96 ± 0.06 mEq peroxide per kilogram of 

sample. The cumulative analytical data from the analysis of lot 12103-4-1 indicated a purity of 

approximately 96%. 

During the studies, the bulk chemical was stored under a nitrogen headspace in the original containers at 

approximately S20° C. Stability was monitored by the study laboratory throughout the studies with gas 

chromatography with flame ionization detection and titration for peroxides. The concentrations of the 

stabilizers phenothiazine and t-butylcatechol were also determined with gas chromatography. No degradation 

of the bulk chemical was detected; all lots used during the studies had less than 1 mEq peroxide per 

kilogram. The stabilizer concentrations were acceptable. 

VAPOR GENERATION AND EXPOSURE SYSTEM 

Diagrams of the chloroprene vapor generation and delivery systems used in the 16-day, 13-week, and 2-year 

studies are shown in Figures K3 through K5. The vapor generation system consisted of an evaporation flask 

in a hot-water bath (72° C, 16-day studies; 66° C, 13-week and 2-year studies) and a temperature-controlled, 

cooled condenser column. For the 16-day studies and the first 6 weeks of the 13-week studies, a rotating 

evaporation flask (Buchi Rotavapor Model EL-1315) was used; thereafter, a nonrotating flask was used to 

prevent deterioration of the flask seals. The chloroprene vapor was pumped at a steady rate from a dry-icechilled reservoir into the rotating flask (16-day studies) or was held in the flask, under pressure, with a 

nitrogen headspace (13-week and 2-year studies). A calibrated flow of nitrogen was metered into the base of 

the condenser column, which was attached to the flask, and carried vapor rising from the flask through the 

condenser. Test article containing any materials boiling at a higher temperature than chloropene, which was 

controlled at 1E C by a thermostat, was condensed and returned to the flask. The temperature of the 

remaining chloroprene-saturated nitrogen vapor was monitored by a sensor at the top of the column; the 

vapor pressure was calculated and used to determine the vapor output. 

Vapor entering the distribution manifold was diluted with HEPA- and charcoal-filtered air (16-day and 

13-week studies) or with additional nitrogen (2-year studies). Flow to each chamber was controlled by 

compressed-air-driven vacuum pumps; vapor flowed through separate metering valves for each exposure 

chamber and was diluted with air before entering the chamber. The vapor concentrations were regulated by 

adjusting the amount of air entering the distribution lines from the compressor and by adjusting the amount 

of vapor entering the chambers through the metering valves. 

Diagrams of the inhalation chamber suites for all studies are shown in Figure K6 through K8. The study 

laboratory designed the stainless-steel inhalation exposure chambers (Hazleton H-2000®; Harford Systems 

Division of Lab Products, Inc., Aberdeen, MD) so that uniform vapor concentrations could be maintained 3 throughout the chamber when catch pans were in place. The total volume of each chamber was 2.3 m ; the

3 active mixing volume of each chamber was 1.7 m . A small particle detector (Type CN, Gardner Associates, 

Schenectady, NY) was used with and without animals in the exposure chambers to ensure that chloroprene 

vapor, and not aerosol, was produced. No particle counts above the minimum resolvable level 3 (approximately 200 particles/cm ) were detected.
 

 

 

 

 

320 Chloroprene, NTP TR 467 

VAPOR CONCENTRATION MONITORING 

Chamber concentrations of chloroprene were monitored by a Hewlett Packard Model 5840 (16-day and 

13-week studies) or Model 5890 (2-year) on-line gas chromatograph (Hewlett Packard, Palo Alto, CA). 

Samples were drawn from the exposure chambers at least once every hour by a 12-port stream selection 

valve. During the 16-day and 2-year studies, samples from the distribution line were monitored for purity 

with a second gas chromatograph; during the 13-week studies, distribution line samples were monitored by 

the same gas chromatograph that was used to monitor the exposure chambers. 

The on-line exposure chamber monitoring system was calibrated based on quantitative analysis of grab 

samples collected in dimethylformaldehyde-filled bubblers. Chamber monitor results were compared to those 

of an off-line gas chromatograph (Model HP 5830 or HP 5840), calibrated with a gravimetrically prepared 

chloroprene standard in dimethylformaldehyde. An on-line standard of chloroprene in nitrogen (MG 

Industries Scientific Gases, Los Angeles, CA) was used to monitor instrument drift throughout the day. 

Summaries of the chamber concentrations for the 16-day, 13-week, and 2-year studies are in Tables K1 

through K5. 

CHAMBER ATMOSPHERE CHARACTERIZATION 

The times for the exposure concentration to build up to 90% of the final exposure concentration (T ) and to 90 

decay to 10% of the exposure concentration (T ) were measured. In all studies, the T and T were 10 90 10 

measured in all exposure chambers with and without animals present. At a chamber airflow rate of 15 air 

changes per hour, the theoretical value for the T90 was calculated to be 11 minutes (16-day and 13-week 

studies) or 12.5 minutes (2-year studies). The T90 used throughout all studies was 12 minutes. 

Without animals present, T values range from 9 to 14 minutes and the T values ranged from 9 to 90 10 

12 minutes during the 16-day studies; with animals present, T90 values ranged from 9 to 11 minutes and T10 

values ranged from 9 to 13 minutes. In the 13-week study, without animals present, T90 values ranged from 

7.5 to 12 minutes for rats and from 7 to 12 minutes for mice; T10 values ranged from 8.5 to 11 minutes for 

rats and 8 to 11 minutes for mice. With animals present T90 values ranged from 10 to 13 minutes for rats 

and for mice; T values ranged from 10 to 15 minutes for rats and 10 to 13 minutes for mice. In the 2-year 10 

studies, without animals present, T values ranged from 10 to 11 minutes for rats and mice; T values 90 10 

ranged from 10 to 11 minutes for rats, and the mouse study had a T value of 11 minutes. With animals 10 

present, T values ranged from 9 to 12 minutes for rats and 11 to 13 minutes for mice; T values ranged 90 10 

from 10 to 12 minutes for rats and 10 to 11 minutes for mice. 

Vapor concentration uniformity in the exposure chambers without animals in the chambers was measured 

before each of the studies began. Concentration uniformity with animals present was measured once during 

the 16-day and 13-week studies and at 90-day intervals during the 2-year studies. Vapor concentration was 

measured using the on-line gas chromatograph with the automatic 12-port sample valve disabled to allow 

continuous monitoring from a single input line. Samples taken from several positions within each exposure 

chamber were analyzed. Chamber concentration uniformity was maintained throughout the studies. 

During the 2-year studies, the persistence of chloroprene after exposure ceased was monitored by gas 

chromatography in the 80 ppm chambers, with and without animals present, at the beginning of the 

exposures and at 90 day intervals afterward. The concentration decreased to less than 1% of the target 

concentration within 22 to 29 minutes. No chloroprene was detectable after 2 hours. 

Chloroprene from the generator flask was tested for stability during the 2-year studies with gas 

chromatography and with potentiometric titration with standardized sodium thiosulfate to determine peroxide 

content. Samples were collected at the beginning and the end of an exposure period. The sample taken at 

the beginning of exposure was determined to be 99% pure; at the end of the exposure period, the sample was 
Chloroprene, NTP TR 467 321 

95% pure. The total dimer content was approximately 3%, with the most concentrated dimer isomer present 

at approximately 2%. The peroxide concentration increased from 0.15 mEq/kg at the beginning of the 

exposure period to 0.25 mEq/kg at the end of the exposure period. The stabilizers in the bulk chloroprene, 

most of the expected impurities, and most of the degradation products caused by thermal decomposition of 

chloroprene are less volatile or have lower boiling points than chloroprene; therefore, the evaporation flask 

method of exposure removed most of these materials. The more volatile impurities, which could not be 

removed from the chloroprene vapor by the generation system, included the chlorobutenes and 

1-chlorobutadienes. Stability was monitored during the 2-year studies by analyzing chloroprene vapor 

samples collected in dimethylformamide-filled bubblers from the distribution line for t-butylcatechol and 

phenothiazine inhibitors with gas chromatography; additional distribution line samples and exposure chamber 

samples were collected in standard charcoal gas sampling tubes at the beginning and end of an exposure 

period, desorbed with methylene chloride, and analyzed for monomer impurities by gas chromatography. 

Distribution line samples contained approximately 0.5% chlorobutene and 0.1% 1-chlorobutadiene at the 

beginning of the exposure period and 0.6% chlorobutene and 0.2% 1-chlorobutadiene by area at the end of 

the exposure period. Samples from the 12.8 ppm chamber contained 0.4% chlorobutene; samples from the 

80 ppm chamber contained 0.5% chlorobutene at the beginning of the exposure period. All other impurities 

present in the distribution line and exposure chambers had concentrations at or below 0.1%. 

Peroxide formation in the distribution line and exposure chambers was analyzed with a Hewlett-Packard 

1046A fluorescence detector. Samples were collected with bubblers filled with peroxide reagents obtained 

from Sigma Chemical Company (St. Louis, MO). Fluorescence from excitation at 320 nm was measured at a 

400 nm emission wavelength. The detector was calibrated with standard chloroprene peroxide solutions. No 

peroxides were detected in the distribution line or exposure chamber samples. 

Chloroprene vapor concentrations were monitored before and during each exposure in the 13-week and 

2-year studies using a separate on-line gas chromatograph (Model HP-5890) which sampled from the 

distribution line. No decomposition or degradation products exceeding 1% of the chloroprene concentration 

were detected during the 13-week studies. At the point of sampling, the chloroprene concentration in the 

2-year studies was approximately 25,000 ppm, which allowed the detection of even small amounts of 

impurities. The system permitted the detection of volatile and non-volatile (e.g., dimers) impurities. The 

gas chromatograph allowed the detection of at least seven impurities more volatile than chloroprene that had 

total peak areas 0.13% of the chloroprene peak at the start of exposure and 0.04% at the end of exposure. 

The major volatile impurity was believed to be chloromethylpropene. Less volatile impurities that were 

detected were isomers of chlorobutene and 1-chlorobutadiene. The chlorobutene impurity had a peak area 

approximately 0.46% that of chloroprene at the start of exposure and approximately 0.52% at the end of 

exposure. The 1-chlorobutadiene impurity peak area was approximately 0.11% that of chloroprene at the 

start of exposure and approximately 0.15% at the end of exposure. No chloroprene dimer peaks were 

observed. These results were in excellent agreement with the results of analyses of charcoal tube samples. 
322
 Chloroprene, NTP TR 467
 

FIGURE K1 

Infrared Absorption Spectrum of Chloroprene 
Chloroprene, NTP TR 467
 323 

FIGURE K2 

Nuclear Magnetic Resonance Spectrum of Chloroprene 
324 Chloroprene, NTP TR 467 

FIGURE K3 

Schematic of Generation and Delivery 

System for the 16-Day Studies 
Chloroprene, NTP TR 467 325 

FIGURE K4 

Schematic of Generation and Delivery System 

for the 13-Week Studies 
326 Chloroprene, NTP TR 467 

FIGURE K5 

Schematic of Generation and Delivery 

System for the 2-Year Studies 
Chloroprene, NTP TR 467
 327 

FIGURE K6 

Inhalation Suite for the 16-Day Studies 
328 Chloroprene, NTP TR 467
 

FIGURE K7 

Inhalation Suite for the 13-Week Studies 
Chloroprene, NTP TR 467
 329 

FIGURE K8 

Inhalation Suite for the 2-Year Studies 
330 Chloroprene, NTP TR 467 

TABLE K1 

Summary of Chamber Concentrations in the 16-Day Inhalation Studies of Chloroprene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Rat Chambers 

32 

80 

200 

500 

145 

149 

140 

143 

31.1 ± 1.9 

80.7 ± 5.0 

198 ± 10 

503 ± 24 

Mouse Chambers 

12 

32 

80 

200 

142 

146 

153 

32b 

11.9 ± 0.8 

31.1 ± 2.0 

80.8 ± 5.2 

201 ± 12 

a	 Mean ± standard deviation 

b	 All mice exposed to 200 ppm died by the third day of exposure; therefore, no readings from the 200 ppm chamber were made after this 

time. 

TABLE K2 

Summary of Chamber Concentrations in the 13-Week Inhalation Studies of Chloroprene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Rat Chambers 

5 

12 

32 

80 

200 

Mouse Chambers 

5 

12 

32 

80 

761 

761 

787 

787 

785 

761 

761 

788 

788 

5.03 ± 0.18 

12.1 ± 0.4 

31.9 ± 1.0 

80.2 ± 1.7 

200 ± 5.0 

5.02 ± 0.2 

12.1 ± 0.3 

31.9 ± 0.9 

80.2 ± 1.6 

a Mean ± standard deviation 
Chloroprene, NTP TR 467 331 

TABLE K3 

Summary of Chamber Concentrations in the 2-Year Inhalation Studies of Chloroprene 

Target Concentration 

(ppm) 

Total Number of Readings Average Concentrationa 

(ppm) 

Rat Chambers 

12.8 

32 

80 

Mouse Chambers 

12.8 

32 

80 

6,220 

6,084 

5,777 

6,049 

5,775 

5,755

12.8 ± 0.4 

31.7 ± 1.1 

79.6 ± 1.6 

12.7 ± 0.4 

31.9 ± 0.9 

79.7 ± 1.7 

a Mean ± standard deviation 
332 Chloroprene, NTP TR 467
 
333 

APPENDIX L 

INGREDIENTS, NUTRIENT COMPOSITION, 

AND CONTAMINANT LEVELS 

IN NIH-07 RAT AND MOUSE RATION 

TABLE L1 

TABLE L2 

TABLE L3 

TABLE L4 

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

334 

334 

335 

336 
334 Chloroprene, NTP TR 467 

TABLE L1 

Ingredients of NIH-07 Rat and Mouse Rationa 

Ingredientsb Percent by Weight 

Ground #2 yellow shelled corn 24.50 

Ground hard winter wheat 23.00 

Soybean meal (49% protein) 12.00 

Fish meal (60% protein) 10.00 

Wheat middlings 10.00 

Dried skim milk 5.00 

Alfalfa meal (dehydrated, 17% protein) 4.00 

Corn gluten meal (60% protein) 3.00 

Soy oil 2.50 

Dried brewer’s yeast 2.00 

Dry molasses 1.50 

Dicalcium phosphate 1.25 

Ground limestone 0.50 

Salt 0.50 

Premixes (vitamin and mineral) 0.25 

a NCI, 1976; NIH, 1978 b Ingredients were ground to pass through a U.S. Standard Screen No. 16 before being mixed. 

TABLE L2 

Vitamins and Minerals in NIH-07 Rat and Mouse Rationa 

Amount Source 

Vitamins 

A 5,500,000 IU Stabilized vitamin A palmitate or acetate 

D3 4,600,000 IU D-activated animal sterol 

K3 

d-"-Tocopheryl acetate 

2.8 g 

20,000 IU 

Menadione 

Choline 560.0 g Choline chloride 

Folic acid 2.2 g 

Niacin 30.0 g 

d-Pantothenic acid 18.0 g d-Calcium pantothenate 

Riboflavin 3.4 g 

Thiamine 10.0 g Thiamine mononitrate 

B12 Pyridoxine 

4,000 μg 

1.7 g Pyridoxine hydrochloride 

Biotin 140.0 mg d-Biotin 

Minerals 

Iron 120.0 g Iron sulfate 

Manganese 60.0 g Manganous oxide 

Zinc 16.0 g Zinc oxide 

Copper 4.0 g Copper sulfate 

Iodine 1.4 g Calcium iodate 

Cobalt 0.4 g Cobalt carbonate 

a Per ton (2,000 lb) of finished product 
Chloroprene, NTP TR 467 335 

TABLE L3 

Nutrient Composition of NIH-07 Rat and Mouse Ration 

Mean ± Standard 

Nutrient Deviation Range Number of Samples 

Protein (% by weight) 23.39 ± 0.57 22.2 — 24.3 24 

Crude fat (% by weight) 5.32 ± 0.19 5.00 — 5.90 24 

Crude fiber (% by weight) 3.36 ± 0.34 2.60 — 4.30 24 

Ash (% by weight) 6.44 ± 0.19 6.12 — 6.81 24 

Amino Acids (% 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) 6,768 ± 1,337 5,730 — 11,450 24 

Vitamin D (IU/kg) 4,450 ± 1,382 3,000 — 6,300 4 

"-Tocopherol (ppm) 35.43 ± 8.98 22.5 — 48.9 11 

Thiamine (ppm) 17.50 ± 2.15 14.0 — 22.0 24 

Riboflavin (ppm) 7.83 ± 0.923 6.10 — 9.00 11 

Niacin (ppm) 99.22 ± 24.27 65.0 — 150.0 11 

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 2,300 — 3,430 10 

Minerals 

Calcium (%) 1.17 ± 0.10 1.00 — 1.49 24 

Phosphorus (%) 0.92 ± 0.05 0.760 — 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 
336 Chloroprene, NTP TR 467 

TABLE L4 

Contaminant Levels in NIH-07 Rat and Mouse Rationa 

Mean ± Standard 

Deviationb Range Number of Samples 

Contaminants 

Arsenic (ppm) 0.43 ± 0.19 0.10 — 0.70 24 

Cadmium (ppm) 0.13 ± 0.07 0.04 — 0.20 24 

Lead (ppm) 0.35 ± 0.25 0.10 — 1.00 24 c Mercury (ppm) 0.02 0.02 — 0.03 24 

Selenium (ppm) 0.32 ± 0.11 0.05 — 0.40 24 

Aflatoxins (ppm) <5.0 24 

Nitrate nitrogen (ppm)d 8.65 ± 4.26 2.90 — 17.0 24 

Nitrite nitrogen (ppm)d 0.14 ± 0.06 0.10 — 0.30 24 e BHA (ppm) 1.83 ± 1.97 1.00 — 10.0 24 e BHT (ppm) 1.58 ± 1.61 1.0 — 8.00 24 

Aerobic plate count (CFU/g) 99,500 ± 165,049 4,100 — 710,000 24 

Coliform (MPN/g) 3 ± 0.3 3 — 4 24 

Escherichia coli (MPN/g) < 3 24 

Salmonella (MPN/g) Negative 24 

Total nitrosoamines (ppb)f 7.38 ± 1.78 4.70 — 11.40 24 

N-Nitrosodimethylamine (ppb)f 5.40 ± 1.20 2.09 — 8.20 24 

N-Nitrosopyrrolidine (ppb)f 1.98 ± 1.07 1.00 — 4.30 24 

Pesticides (ppb) 

"-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 — 0.97 24 

Endosulfan I <0.01 24 

Endosulfan II <0.01 24 

Endosulfane 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. 

All but three values were less than the detection limit; the detection limit was used for the low end of the range. 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 
337 

APPENDIX M
 

SENTINEL ANIMAL PROGRAM
 

METHODS ............................................................... 338
 

RESULTS ................................................................ 339
 
338 Chloroprene, NTP TR 467 

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 

of chloroprene. 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 

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 

Mycoplasma arthritidis Study termination 

Mycoplasma pulmonis Study termination 

PVM 6, 12, and 18 months, study termination 

RCV/SDA 6, 12, and 18 months, study termination 

Sendai 6, 12, and 18 months, study termination 

Immunofluorescence Assay 

RCV/SDA 12 months 

Sendai 18 months 

Hemagglutination Inhibition 

H-1 6, 12, and 18 months, study termination 

KRV 6, 12, and 18 months, study termination 
Chloroprene, NTP TR 467 339 

MICE 

13-Week Study 

ELISA 

Ectromelia virus 

GDVII (Mouse encephalomyelitis virus) 

LCM (Lymphocytic choriomeningitis virus) 

MVM (Minute virus of mice) 

Mouse adenomavirus 

MHV (Mouse hepatitis virus) 

PVM 

Reovirus 3 

Sendai 

Immunofluorescence Assay 

EDIM (epizootic diarrhea of infant mice) 

Hemagglutination Inhibition 

Papovavirus (K) 

Polyoma virus 

2-Year Study 

ELISA 

Ectromelia virus 

EDIM 

GDVII 

LCM 

Mouse adenoma virus-FL 

MHV 

M. arthritidis 

M. pulmonis 

PVM
 

Reovirus 3
 

Sendai
 

Immunofluorescence Assay 

EDIM 

LCM 

Mouse adenoma virus-FL 

PVM 

Hemagglutination Inhibition 

K 

MVM 

Polyoma virus 

RESULTS 

All test results were negative. 

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, and 18 months, study termination 

12 and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

Study termination 

Study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6 and 18 months, study termination 

6 months 

6 and 18 months 

12 months 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 

6, 12, and 18 months, study termination 
340 Chloroprene, NTP TR 467
 
341 

APPENDIX N
 

K-RAS MUTATION FREQUENCY AND SPECTRA
 

IN LUNG AND HARDERIAN GLAND NEOPLASMS
 

FROM B6C3F1 MICE

EXPOSED TO CHLOROPRENE
 

FOR 2 YEARS
 

Robert C. Sills, H. Lily Hong, Ronald L. Melnick,
 

Theodora R. Devereux, and Gary A. Boorman
 

National Institute of Environmental Health Sciences
 

Research Triangle Park, North Carolina
 

INTRODUCTION ............................................................ 342
 

MATERIALS AND METHODS .................................................... 342
 

RESULTS ................................................................ 343
 

DISCUSSION .............................................................. 344
 

REFERENCES 345
 

TABLE N1 Pattern of K-ras Mutations in Lung Neoplasms from B6C3F Mice 1 ............... 347
 

TABLE N2 K-ras Mutation Profile in Lung Neoplasms from B6C3F Mice 1 

Exposed to Chloroprene ............................................ 347
 

TABLE N3 K-ras Mutations Detected in Alveolar/bronchiolar Adenomas and Carcinomas
 

from B6C3F1 Mice Exposed to Chloroprene ............................... 348

TABLE N4 Pattern of ras Mutations in Harderian Gland Neoplasms from B6C3F Mice 1 ......... 349
 

TABLE N5 K-ras Codon 61 Mutations in Harderian Gland Neoplasms from B6C3F Mice 1 

Exposed to Chloroprene ............................................ 349
 

TABLE N6 K-ras Codon 61 Mutations Detected in Harderian Gland Adenomas 

and Carcinomas in B6C3F 1 Mice Exposed to Chloroprene ..................... 350
342 Chloroprene, NTP TR 467 

K-RAS MUTATION FREQUENCY AND SPECTRA 

IN LUNG AND HARDERIAN GLAND NEOPLASMS 

FROM B6C3F1 MICE EXPOSED TO CHLOROPRENE

FOR 2 YEARS 

INTRODUCTION 

Lung neoplasms occur in B6C3F mice with a typical incidence of 20% in control males and 10% in control 1 

females by 2 years of age, whereas harderian gland neoplasms occur with a typical incidence of 6% in 

control males and 4% in control females by 2 years of age. Molecular analysis of lung or harderian gland 

neoplasms for genetic alterations in cancer genes such as the ras proto-oncogene provides mechanistic 

information to help distinguish spontaneous neoplasms from chemical-induced neoplasms. For example, 

chemical-induced lung (Sills et al., 1995) or harderian gland (Goodrow et al., 1994) neoplasms in mice may 

have a higher frequency of proto-oncogene activation, particularly by point mutations in codon 12, 13, or 61 

of K- or H-ras genes. The frequency of ras activation in these neoplasms is often greater than that detected 

in neoplasms occurring in control animals (Devereux et al., 1991), and there is evidence for chemical 

specificity in the pattern of mutations. 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 

(Devereux et al., 1993a). Even for “nongenotoxic carcinogens,” patterns of ras gene mutations in 

neoplasms can give clues about the mechanism of tumorigenesis (Devereux et al., 1993b). 

MATERIALS AND METHODS 

Lung and Harderian Gland Neoplasms: Male and female B6C3F mice were exposed to 0, 12.8, 32, or 1 

80 ppm chloroprene by inhalation for 6 hours per day, 5 days per week for 2 years. At necropsy, 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. Subsequently, five unstained serial sections 

(10 μm thick) were prepared from paraffin blocks containing alveolar/bronchiolar adenomas or carcinomas 

or harderian gland adenomas or carcinomas for isolation of DNA for polymerase chain reaction (PCR)-based 

assays. In order to isolate adequate amounts of DNA, neoplasms greater than 1 mm in diameter were 

identified for analysis. This included 46 paraffin-embedded lung neoplasms or 27 harderian gland neoplasms 

from chloroprene-exposed mice and six lung neoplasms or two harderian gland neoplasms from control mice. 

DNA Isolation: The DNA isolation procedure is described in Marmur (1961) and Sills et al. (1995). The 

paraffin-embedded tissue was deparaffinized and rehydrated before digesting with proteinase K (Wright and 

Manos, 1990). DNA was extracted with phenol and chloroform and precipitated with ethanol. 

DNA Amplification: DNA was amplified by PCR (Saiki et al., 1988; Sills et al., 1995); details of the use of 

nested primers are described in Devereux et al. (1991, 1993b). 

Restriction Fragment Length Polymorphism Identification: For identification of H-ras mutations at codon 61, 

restriction fragment length polymorphism (RFLP) was used, and most of exon 2 surrounding codon 61 was 

amplified (Sukumuar and Barbacid, 1990). The sense primer used for amplification of exon 2 was 

5N-GACATCTTAGACACAGCAGTT-3N. 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. By using this technique, codon 61 AAA, CTA, and CGA mutations were 

detected by MSEI, XbaI, and TaqI digestion, respectively; the normal sequence (CAA) of codon 61 is not cut 

by these enzymes. The mixture containing the H-ras exon 2 PCR products and the restriction enzyme was 
Chloroprene, NTP TR 467 343 

incubated at 37E C (MSEI and XbaI) or 60E C (TaqI) for 2 hours. Fifteen μL of the mixture with 

bromophenol blue dye was loaded onto a 6% acrylamide tris-borate-EDTA (TBE) gel (8 cm × 8 cm × 1 

mm; 15 wells) (Novex, San Diego, CA). The gel was run at 100 volts for 1 hour on a Novex gel 

electrophoresis unit. Gels were stained with a 5 μg/mL solution of ethidium bromide for 20 minutes and 

then destained in distilled water. Ethidium bromide-stained bands were visualized using a 312 nm ultraviolet 

(UV) viewing box and photographed. 

“Cold” Single-Strand Conformation Polymorphism Analysis (SSCP): A mixture consisting of 5 μL of PCR 

products (double-stranded DNA), 0.6 μL of 1M methylmercury hydroxide, 1 μL of 15% W/V Ficoll 

(molecular weight 400,000) loading buffer containing 0.25% bromophenol blue and 0.25% xylene cyanol, 

and 13.4 μL of 1X TBE buffer (Novex, San Diego, CA) was prepared to yield a total volume of 20 μL 

(Hongyo et al., 1993). This nonradioactive mixture was heated to 85E C for 5 minutes and then plunged 

into ice prior to loading the entire 20 μL onto the gel. A 20% polyacrylamide TBE gel was used for K-ras 

mutation analysis in the gel electrophoresis unit (Novex, San Diego, CA). The buffer chamber was filled 

with 1.5X TBE buffer. The gel was run at 300 volts in a 5E C cold room until a light blue marker reached 

the bottom of the gel. A positive control for K-ras mutations and one undenatured DNA control (without 

methylmercury hydroxide and no heat) were run with the unknown samples. Gels were stained with a 

0.5 μg/mL solution of ethidium bromide for 20 minutes and destained in distilled water for 5 minutes. The 

stained bands were visualized under UV viewing box and photographed. For identification of K-ras 

mutations at codon 61, RFLP was used with XbaI enzyme digestion and “cold” SSCP analysis was 

performed on the same 20% polyacrylamide TBE gel. 

Direct Sequencing: Direct sequencing of the amplified first and second exon of the K-ras gene was 

performed as described by Tindall and Stankowski (1989) using previously described sequencing primers 

(Devereux et al., 1991). 

RESULTS 

Lung Neoplasms: A higher frequency (80%) of K-ras mutations was detected in chloroprene-induced lung 

neoplasms than in spontaneous lung neoplasms of control B6C3F mice (30%) (Table N1). The predominant 1 

mutation in chloroprene-induced neoplasms consisted of an A to T transversion (CAA to CTA) in K-ras 

codon 61 (22/46). This pattern was similar to that in isoprene-induced lung neoplasms in which lung 

neoplasms (10/11) had this same K-ras mutation. In contrast, A to T transversions (CAA to CTA) in K-ras 

codon 61 were not apparent in butadiene-induced lung neoplasms nor in spontaneous lung neoplasms 

(Table N1). The majority (8/10, 12.8 ppm; 10/13, 32 ppm) of the K-ras CTA codon 61 mutations were 

from the 12.8 and 32 ppm groups, whereas 4/14 were from the 80 ppm exposure group (Table N2). We 

also investigated whether specific mutations were associated with a specific morphologic pattern of lung 

neoplasms or type of neoplasm, but no correlation was observed (Table N3). 

Harderian Gland Neoplasms: A higher frequency (100%) of ras mutations was detected in chloropreneinduced harderian gland neoplasms than in harderian gland neoplasms from control B6C3F1 mice (56%) or in

butadiene-induced harderian gland neoplasms (69%) (Table N4; Goodrow et al., 1994). The pattern of 

K-ras and H-ras mutations was generally similar to that of isoprene in which 100% of ras mutations were 

detected in the harderian gland (Table N4). The predominant mutation in chloroprene-induced neoplasms 

consisted of A to T transversions (CAA to CTA) at K-ras codon 61 (25/27). A similar response was 

detected in isoprene-induced harderian gland neoplasms in which the predominant mutation consisted of A to 

T transversions (CAA to CTA) at K-ras codon 61 (15/30). One difference between the mutation spectra of 

chloroprene and isoprene was the higher number of C to A (CAA to AAA) transversions at H-ras codon 61 

(8/30) in isoprene-induced harderian gland neoplasms. This specific pattern of K-ras mutation was not 

apparent in butadiene-induced harderian gland neoplasms nor in spontaneous harderian gland neoplasms 

(Table N4). Only 3 (10%) of harderian gland neoplasms induced by butadiene had an A to T transversion in 
344 Chloroprene, NTP TR 467 

the second base of K-ras codon 61, which is similar to the 7% frequency of K-ras mutations in spontaneous 

harderian gland neoplasms at this locus (Table N4). In harderian gland neoplasms, similar incidences for 

K-ras codon 61 CTA mutations of 100%, 80%, and 100% were detected in the 12.8, 32, or 80 ppm 

exposure groups, respectively (Table N5). The frequency and pattern of mutations in the K-ras genes were 

also examined to determine if a specific mutation was associated with the morphologic pattern of harderian 

gland neoplasms or type of neoplasms. No consistent morphologic pattern or type of harderian gland 

neoplasm was associated with specific K-ras mutations (Table N6). 

DISCUSSION 

The high frequency and unique pattern of ras mutations detected in lung and harderian gland neoplasms from 

chloroprene-, isoprene-, and butadiene-exposed B6C3F1 mice compared to ras mutations in spontaneous lung

and harderian gland neoplasms reflect the importance of ras activation in the carcinogenesis process of these 

structurally similar chemicals. Sixty percent of the chloroprene-induced lung neoplasms and 93% of 

chloroprene-induced harderian gland neoplasms exhibited K-ras codon 61 CTA mutations, an uncommon 

mutation in spontaneous lung or harderian gland neoplasms. The high frequency of specific ras mutations is 

consistent with the genotoxicity of the chemically related chemicals chloroprene, isoprene, and butadiene. 

Similar to the high frequency of A to T transversions in chloroprene- and isoprene-induced lung and 

harderian gland neoplasms, an increased frequency of A to T transversions was detected in lacI mutant bone 

marrow cells of male B6C3F1 lacI transgenic mice following 1,3-butadiene exposure (Sisk et al., 1994). 

Increased A to T transversions were also detected in hprt mutant T-lymphocytes isolated from B6C3F1 mice

exposed to 1,3-butadiene (Cochrane and Skopek, 1994). Interestingly, in harderian gland neoplasms where 

chloroprene, isoprene, and butadiene targeted adenine bases, chloroprene and isoprene had selectivity for 

K-ras codon 61, whereas butadiene targeted H-ras codon 61, as indicated by the higher frequency of A to G 

transitions. Both guanine (Citti et al., 1984) and adenine (Leuratti et al., 1994) DNA adducts have been 

associated with epoxide intermediates of butadiene. In the lung, butadiene, unlike chloroprene and isoprene, 

targeted the first guanine base at codon 13, as indicated by the higher frequency of G to C base changes. 

6 Leuratti et al. (1994) identified an adenine adduct(s) at the N position and proposed that the adduct is

involved in the mutagenesis of the diepoxide metabolite of butadiene. The mutagenic and alkylating activity 

of butadiene and isoprene are similar (Gervasi et al., 1985; Gervasi and Longo, 1990). We hypothesize that 

interactions of chloroprene, isoprene, and butadiene epoxides with DNA to form guanine or adenine adducts 

leads to point mutations in K-ras or H-ras proto-oncogenes that may represent a critical step in the 

carcinogenesis process of these structurally related chemicals. 
Chloroprene, NTP TR 467 345 

REFERENCES 

Citti, L., Gervasi, P.G., Turchi, G., Bellucci, F., and Bianchini, R. (1984). The reaction of 3,4-expoxy-1­

butene with deoxyguanosine and DNA in vitro: Synthesis and characterization of the main adducts. 

Carcinogenesis 5, 47-52. 

Cochrane, J.E., and Skopek, T.R. (1994). Mutagenicity of butadiene and its epoxide metabolites: 

II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells 

from exposed B6C3F1 mice. Carcinogenesis 15, 719-723. 

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., Belinsky, S.A., Maronpot, R.R., White, C., Hegi, M., Patel, A.C., Foley, J.F., 

Greenwell, A., and Anderson, M.W. (1993a). Comparison of pulmonary O6-methylguanine DNA adduct 

levels and K-ras activation in lung tumors from resistant and susceptible mouse strains. Mol. Carcinog. 8, 

177-185. 

Devereux, T.R., Foley, J.F., Maronpot, R.R., Kari, F., and Anderson, M.W. (1993b). Ras proto-oncogene 

activation in liver and lung tumors from B6C3F mice exposed chronically to methylene chloride. 1 

Carcinogenesis 14, 795-801. 

Gervasi, P.G., and Longo, V. (1990). Metabolism and mutagenicity of isoprene. Environ. Health Perspect. 

86, 85-87. 

Gervasi, P.G., Citti, L., Del Monte, M., Longo, V., and Benetti, D. (1985). Mutagenicity and chemical 

reactivity of epoxidic intermediates of the isoprene metabolism and other structurally related compounds. 

Mutat. Res. 156, 77-82. 

Goodrow, T.L., Nichols, W.W., Storer, R.D., Anderson, M.W., and Maronpot, R.R. (1994). Activation of 

H-ras is prevalent in 1,3-butadiene-induced and spontaneously occurring murine harderian gland tumors. 

Carcinogenesis 15, 2665-2667. 

Hongyo, T., Buzard, G.S., Calvert, R.J., and Weghorst, C.M. (1993). “Cold SSCP”: A simple, rapid and 

non-radioactive method for optimized single-strand conformation polymorphism analyses. Nucleic Acids 

Res. 21, 3637-3642. 

Leuratti, C., Jones, N.J., Marafante, E., Kostiainen, R., Peltonen, K., and Waters, R. (1994). DNA 

damage induced by environmental carcinogen butadiene: Identification of a diepoxybutane-adenine adduct 

and its detection by 32P-postlabelling. Carcinogenesis 15, 1903-1910. 

Marmur, J. (1961). A procedure for the isolation of deoxyribonucleic acid from micro-organisms. J. Mol. 

Biol. 3, 208-218. 

Saiki, R.K., Gelfand, D.H., Stoffel, S., Scharf, S.J., Higuchi, R., Horn, G.T., Mullis, K.B., and 

Erlich, H.A. (1988). Primer-directed 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 K-ras mutations in lung neoplasms from female B6C3F1 mice exposed to ozone for 

24 or 30 months. Carcinogenesis 16, 1623-1628. 
346 Chloroprene, NTP TR 467 

Sisk, S.S., Pluta, L.J., Bond, J.A., and Recio, L. (1994). Molecular analysis of lacI mutants from bone 

marrow of B6C3F1 transgenic mice following inhalation exposure to 1,3-butadiene. Carcinogenesis 15, 

471-477. 

Sukumuar, S., and Barbacid, M. (1990). Specific patterns of oncogene activation in transplacentally induced 

tumors. Proc. Natl. Acad. Sci. USA 87, 718-722. 

Tindall, K.R., and Stankowski, L.F., Jr. (1989). Molecular analysis of spontaneous mutations at the gpt 

locus in Chinese hamster ovary (AS52) cells. Mutat. Res. 220, 241-253. 

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, Inc., San Diego. 
347 

c 

Chloroprene, NTP TR 467 

TABLE N1 

Pattern of K-ras Mutations in Lung Neoplasms from B6C3F Mice Exposed to Chloroprene 1 

Treatment 

Activated 

K-ras (%) GTT 

Codon 12 

Normal=GGT 

GAT TGT CGT CTT ATT 

Codon 13 

Normal=GGC 

CGC 

Codon 61 

Normal=CAA 

CTA CAT CAC CGA 

Historical 

Controla 

Chloropreneb 

25/81 (31%) 

37/46 (80%) 

1 

2 

9 

5 

5 

1 1 1 

3 

2 22 

4 1 2 

3 

Isoprenec 

1,3-Butadiened 

11/11 (100%) 

6/9 (67%) 

1 

6 

10 

a Spontaneous lung neoplasms of control B6C3F1 mice 

b Female B6C3F1 mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 

Male B6C3F1 mice were exposed to 2,200 or 7,000 ppm isoprene by inhalation 6 hours/day, 5 days/week for a 26-week period followed 

by a 26-week recovery period. d Male and female B6C3F1 mice were exposed to 6.25 to 625 ppm 1,3-butadiene by inhalation 6 hours/day, 5 days/week, for 1 to 2 years 

(Goodrow et al., 1994). 

TABLE N2 

K-ras Mutation Profile in Lung Neoplasms from B6C3F Mice Exposed to Chloroprene 1 

Treatment 

Concentration 

(ppm) 

Activated 

K-ras (%) GTT 

Codon 12 

Normal=GGT 

GAT TGT CGT CTT ATT 

Codon 13 

Normal=GGC 

CGC 

Codon 61 

Normal=CAA 

CTA CAT CAC CGA 

Chamber Controla 

Chloropreneb

25/81 (31%) 1 

(1%) 

9 

(11%) 

5 

(6%) 

3 

(4%) 

4 

(5%) 

1 

(1%) 

2 

(2%) 

12.8 

32 

80 

10/10 (100%) 

13/14 (93%) 

14/22 (64%) 

1 1 

(10%) (10%) 

2 

(14%) 

1 2 

(5%) (9%) 

1 

(7%) 

1 

(5%) 

1 

(5%) 

2 

(9%) 

8 

(80%)

10 

(71%)

4 

(18%) 

3 

(14%) 

a Study controls combined with historical spontaneous lung neoplasms of control B6C3F1 mice 

b Female B6C3F1 mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 
348 Chloroprene, NTP TR 467 

TABLE N3 

K-ras Mutations Detected in Alveolar/bronchiolar Adenomas and Carcinomas from B6C3F Mice 1 

Treatment 

Activated 

K-ras (%) GTT 

Codon 12 

Normal=GGT 

GAT TGT CGT CTT ATT 

Codon 13 

Normal=GGC 

CGC 

Codon 61 

Normal=CAA 

CTA CAT CAC CGA 

Chamber Controla

 Adenoma 

Carcinoma 

3/18 (17%) 

22/63 (35%) 1 

1 

8 

2

3 3 4 1 2 

Chloropreneb

 Adenoma 

Papillary 

Solid 

Mixed 

Carcinoma 

Papillary 

Solid 

Mixed 

23/29 (79%) 

5/8 (63%) 

8/11 (73%) 

10/10 (100%) 

14/17 (82%) 

9/10 (90%) 

4/4 (100%) 

1/3 (33%) 

1 

1 

1 

1 

3 

1 

1 

1 

2 

1 

1 

1 

1 

1 

1 

1 

1 

2 

2 

14 

3 

6

5 

8

4

3

1 

3

1

2

a Study controls combined with historical spontaneous lung neoplasms of control B6C3F1 mice 

b Female B6C3F1 mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 
349 

c 

Chloroprene, NTP TR 467 

TABLE N4 

Pattern of ras Mutations in Harderian Gland Neoplasms from B6C3F1 Mice 

Treatment 

Activated

ras (%) 

K-ras 

 Codon 12 Codon 13 

GAT TGT CGC 

Codon 61 

CTA 

Codons 12 and 13

H-ras 

AAA 

Codon 61 

CTA TAA CGA 

Historical 

Controla 

Chloropreneb 

15/27 (56%) 

27/27 (100%) 

2 

(7%) 

25e 

(93%) 

ND 

4 

(15%) 

1 

(4%) 

4 

(15%) 

2e 

(7%) 

5 

(19%) 

2e 

(7%) 

Isoprenec 

1,3-Butadiened 

30/30 (100%) 

20/29 (69%) 

2 

(7%) 

1 

(3%) 

1 

(3%) 

15 

(50%) 

3 

(10%)f 

8 

(27%) 

2 

(7%) 

3 

(10%) 

2 

(7%) 

1 

(3%) 

12 

(41%) 

a Study controls combined with historical spontaneous lung neoplasms of control B6C3F1 mice 

b Male B6C3F mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 1 

Male B6C3F1 mice were exposed to 2,200 or 7,000 ppm isoprene by inhalation 6 hours/day, 5 days/week for a 26-week period followed 

by a 26-week recovery period. d Male and female B6C3F1 mice were exposed to 6.25 to 625 ppm 1,3-butadiene by inhalation for 1 to 2 years (Goodrow et al., 1994). e Same neoplasm had CTA mutation in both K- and H-ras at codon 61 from two mice; another one neoplasm had CTA mutation at codon 

61 of K-ras and CGA mutation of H-ras. f K-ras codon 61 mutations were evaluated in 12 harderian gland neoplasms without other mutations tested from butadiene study. 

TABLE N5 

K-ras Codon 61 Mutations in Harderian Gland Neoplasms from B6C3F Mice Exposed to Chloroprene 1 

Treatment Codon 61 

Concentration Activated Normal=CAA 

(ppm) K-ras (%) CTA 

Chamber Controla 

2/27 (7%) 2 

Chloropreneb

 12.8 5/5 (100%) 5

 32 8/10 (80%) 8

 80 12/12 (100%) 12 

a Spontaneous lung neoplasms of control B6C3F1 mice 

b Male B6C3F1 mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 
350 Chloroprene, NTP TR 467 

TABLE N6 

K-ras Codon 61 Mutations Detected in Harderian Gland Adenomas and Carcinomas in B6C3F Mice 1 

Exposed to Chloroprenea

Tumor Type/ 

Morphology Pattern 

Activated 

K-ras (%) 

Codon 61 

Normal=CAA 

CTA

 Adenoma 

Papillary 

Acinar 

Solid 

Mixed 

22/23 (96%)

15/16 (94%) 

5/5 (100%) 

1/1 (100%) 

1/1 (100%) 

15

5

1

1

 Carcinoma 

Papillary 

Solid 

Mixed 

3/4 (75%)

1/1 (100%) 

1/1 (100%) 

1/1 (100%) 

1

1

1 

a Male B6C3F1 mice were exposed to 12.8, 32, or 80 ppm chloroprene by inhalation 6 hours/day, 5 days/week, for 2 years. 
 

 

351 

APPENDIX O
 

IMPACT OF HELICOBACTER HEPATICUS
 

INFECTION IN B6C3F1
  MICE

FROM 12 NTP 2-YEAR CARCINOGENESIS STUDIES
 

1	 1 1 1 James R. Hailey , Joseph K. Haseman , John R. Bucher , Ann E. Radovsky , 2 2 1	 1 David E. Malarkey , Richard T. Miller , Abraham Nyska , and Robert R. Maronpot

1

National Institute of Environmental Health Sciences
 

Research Triangle Park, North Carolina
 

2

Department of Microbiology, Pathology, and Parasitology
 

College of Veterinary Medicine
 

North Carolina State University
 

Raleigh, North Carolina
 

ABSTRACT ............................................................... 352
 

INTRODUCTION ............................................................ 352
 

MATERIALS AND METHODS .................................................... 353
 

RESULTS AND DISCUSSION ..................................................... 355
 

REFERENCES .............................................................. 362
 

TABLE O1 Incidence of Helicobacter hepaticus-Associated Hepatitis in Control B6C3F1 Mice 
 

from Nine NTP 2-Year Studies ....................................... 366
 

TABLE O2 Identification of Helicobacter hepaticus with PCR-RFLP-Based Assays
 

in Control B6C3F Mice from 32 NTP 2-Year Studies 1
 

and Three NTP 13-Week Studies ...................................... 366
 

TABLE O3 Comparison of Neoplasm Incidences in Control B6C3F1 Mice 
 

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies .......... 367
 

TABLE O4 Liver Neoplasm Incidences and Body Weights of Control B6C3F1 Mice 
 

in Relation to Study Start Dates of Helicobacter hepaticus-Affected 

and Unaffected NTP 2-Year Studies .................................... 368
 

TABLE O5 Association of Liver Neoplasm Incidence
 

and Severity of Helicobacter hepaticus-Associated Hepatitis 

in Control B6C3F1
  Mice from Nine Affected NTP 2-Year Studies ................ 369

TABLE O6	 H-ras Codon 61 AAA Mutations in Spontaneous Liver Neoplasms 

in Control B6C3F1
  Mice from Helicobacter hepaticus-Affected

and Unaffected NTP 2-Year Studies .................................... 369
 

TABLE O7 Proliferating Cell Nuclear Antigen Labeling Indices in the Liver 

of Control B6C3F1 Mice 
 ............................................ 370

TABLE O8	 Summary of Target Sites of Carcinogenicity in B6C3F Mice 1
 

from NTP 2-Year Studies with Helicobacter hepaticus-Associated Hepatitis ......... 371
 
352 Chloroprene, NTP TR 467 

IMPACT OF HELICOBACTER HEPATICUS 

INFECTION IN B6C3F MICE 1 

FROM 12 NTP 2-YEAR CARCINOGENESIS STUDIES 

ABSTRACT 

Male and female B6C3F1 mice from 12 NTP 2-year carcinogenesis studies were found to be infected with

Helicobacter hepaticus. Many of the male mice from nine of these studies (“affected” studies) had an 

associated hepatitis. The current evaluations were performed in an attempt to determine if the data from the 

H. hepaticus-affected NTP B6C3F1 mouse studies were compromised and unsuitable for cancer hazard

identification. The incidences of neoplasms of the liver (both hepatocellular neoplasms and 

hemangiosarcoma), but not of other organs in control male B6C3F1 mice, were found to be increased in

affected studies compared to control males from unaffected studies. The increased incidence of 

hepatocellular neoplasms was observed in those males exhibiting H. hepaticus-associated hepatitis. Other 

observations further differentiated control male mice from affected and unaffected studies. H-ras codon 61 

CAA-to-AAA mutations were less common in liver neoplasms in males from affected studies compared to 

historical and unaffected study controls. In addition, increases in cell proliferation rates and apoptosis were 

observed in the livers of male mice with H. hepaticus-associated hepatitis. These data support the hypothesis 

that the increased incidence of liver neoplasms is associated with H. hepaticus and that hepatitis may be 

important in the pathogenesis. Therefore, interpretation of carcinogenic effects in the liver of B6C3F1 mice

may be confounded if there is H. hepaticus-associated hepatitis. 

INTRODUCTION 

Helicobacter-Induced Diseases 

Since the bacterium H. pylori was isolated from humans in 1983, numerous Helicobacter species have been 

identified in several laboratory and domestic animal species. Their pathogenicity varies, with some species 

inducing significant disease while others appear merely to colonize the gastrointestinal tract. H. pylori is 

known to cause chronic gastritis and peptic ulcers in humans (Marshall and Warren, 1984; Graham, 1989; 

Lee et al., 1993) and, more recently, has been linked to adenocarcinoma and mucosa-associated lymphoma 

of the stomach (Fox et al., 1989; Nomura et al., 1991; Parsonnet et al., 1991; Wotherspoon et al., 1993). 

Based on epidemiological and pathology findings, the International Agency for Research on Cancer (1994) 

has classified H. pylori as a group 1 carcinogen in humans. H. hepaticus is associated with an increase in 

liver neoplasm incidences in A/JCr mice (Ward et al., 1994a; Fox et al., 1996). 

H. hepaticus commonly colonizes the gastrointestinal tract of many strains of mice from many sources (Fox 

et al., 1994; Ward et al., 1994b; Shames et al., 1995). It has been shown to be pathogenic, with hepatitis 

highly prevalent in some strains of mice (A/JCr, BALB/cAnNCr, C3H/HeNCr, SJL/NCr, and SCID/NCr) 

(Ward et al., 1994b). Intestinal colonization does not necessarily result in subsequent hepatitis, and the 

conditions that lead to migration of the organism from the intestine to the liver have not been determined. 

H. hepaticus appears to reside primarily within the bile canaliculi. Male mice were reported to have a 

greater incidence and severity of hepatitis than female mice, and this finding occurred in NTP studies as 

well. The recently identified H. bilis, like H. hepaticus, colonizes the biliary tract, liver, and intestine of 

mice. While H. bilis has been identified in animals with chronic hepatitis, whether it caused the hepatitis is 

not known (Fox et al., 1995). 

The pathogenesis of H. hepaticus-induced disease has not been fully characterized. In susceptible strains of 

mice, H. hepaticus can cause acute, focal, nonsuppurative, necrotizing hepatitis, which progresses to 

chronic, active hepatitis characterized by minimal necrosis, hepatocytomegaly, oval cell hyperplasia, and 
Chloroprene, NTP TR 467 353 

cholangitis. H. hepaticus has been found to possess high levels of urease (Fox et al., 1994). H. hepaticus is 

often isolated from the cecum and colon but is not necessarily isolated from the liver of A/JCr mice, even 

though these animals develop severe hepatitis. Culture supernatants from several strains of H. hepaticus and 

several other Helicobacter species were shown to cause cytopathic effects in a rodent hepatocyte cell line 

(Taylor et al., 1995). Ward et al. (1996) suggested that autoimmunity may play a role in the progressive 

hepatitis and carcinogenesis in livers infected with H. hepaticus. 

NTP Infectious Disease Surveillance 

In 1993, during the histological evaluation of an NTP 2-year study, pathologists identified a constellation of 

liver lesions (hepatitis) in control and treated male mice that was consistent with what would later be 

described in mice infected with H. hepaticus (Ward et al., 1993, 1994a; Fox et al., 1994). Subsequently, 

pathology results from all mouse studies begun since 1984 (67 two-year studies) were reviewed for diagnoses 

of the characteristic hepatitis; the lesions were identified in nine studies (NTP, 1998a,b,c,d,e,f). Silver stains 

revealed helical bacteria consistent with Helicobacter present in the liver of male mice in the nine studies. 

Every reasonable measure is taken to prevent the occurrence of infectious diseases during NTP 2-year 

carcinogenicity studies. When infections occasionally occur, care is taken to identify the causal agent and its 

source, measures are taken to ensure that animals in later studies will not be infected, and the potential 

impact on biological parameters (primarily neoplastic endpoints) important in interpretation of the study is 

determined. To date, animals (control and treated) from a few studies have had a mild pulmonary 

inflammatory response presumed to be caused by an infectious agent. In other studies, there have been 

utero-ovarian infections with Klebsiella sp. (Rao et al., 1987) and fungal infections of the nasal cavity. For 

scientifically valid reasons, interpretation of chemical-related effects was not considered significantly 

compromised in any of these studies. Unlike the previous infections, H. hepaticus involves the liver, the 

major metabolic organ, and has been associated with an increase in incidences of liver neoplasms in the 

A/JCr mouse (Ward et al., 1994a). Therefore, when the contemporary epizootic of H. hepaticus infection in 

the United States affected several NTP studies, use of the data for hazard identification was questioned. The 

first step was to determine the extent of the infection within NTP studies and then evaluate the impact the 

infection had on biological parameters important in interpretation of the carcinogenic potential of test 

chemicals. 

MATERIALS AND METHODS 

Histologic Examination 

Studies in which mice were potentially infected with H. hepaticus were identified by reviewing the summary 

pathology tables for characteristic diagnoses: oval and/or biliary epithelial hyperplasia, hepatocyte 

enlargement (often diagnosed as karyomegaly), chronic inflammation, and regenerative hyperplasia. All 

13-week and 2-year studies begun by the NTP since 1984 and for which complete pathology data were 

available (67 two-year studies) were examined. Eight contemporary studies in which the characteristic 

lesions were not identified from pathology tables were randomly selected for histologic reevaluation. Slides 

containing sections of hematoxylin- and eosin-stained livers from 20 to 25 control and 20 to 25 high-dose 

male mice from each of seven 2-year studies and one 13-week study (10 animals from each group) were 

reexamined microscopically for the presence of hepatitis potentially related to H. hepaticus infection. 

Hepatitis consistent with that observed with H. hepaticus infection was not observed in any of these studies. 

Liver sections from five or more animals from each of nine 2-year studies in which hepatitis was observed 

were prepared using the Warthin-Starry silver stain or Steiner’s modification to identify silver-positive helical 

bacteria. 
354 Chloroprene, NTP TR 467 

PCR-RFLP Detection of Helicobacter DNA 

Assays based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were 

conducted at the NIEHS (Malarkey et al., 1997) and the University of Missouri Research Animal Diagnostic 

and Investigative Laboratory (MU-RADIL) (Riley et al., 1996) on liver tissue from approximately 

20 animals from each of 32 NTP 2-year studies (including the nine affected studies) and three NTP 13-week 

studies. The majority of these studies were selected because they were begun at approximately the same time 

(1988-1990) as the nine affected studies. Also, two earlier studies (1984-1985; mouse life-span and 

p-nitroaniline studies) and one later study (1993; methyleugenol) were selected. The mouse life-span study 

was designed to evaluate the incidences of spontaneous changes associated with age; therefore, there is no 

NTP Technical Report. Pathology peer review is not complete for the methyleugenol study, and the NTP 

Technical Report (NTP, 1998g) has not been completed. Frozen tissue was available from 22 of these 

studies, while only formalin-fixed tissue was available for the remaining ten 2-year studies and the three 

13-week studies. Most of the assays were conducted by MU-RADIL, which used Helicobacter genusspecific primers; MU-RADIL used restriction endonucleases on a subset of positives to determine if the 

species was H. hepaticus. DNA was isolated from frozen liver samples with a QIAamp Tissue Kit (Qiagen 

Inc., Chatsworth, CA) according to the manufacturer’s recommendations or routine phenol/chloroform 

extraction (Malarkey et al., 1997). DNA content and purity were determined spectrophotometrically by 

measuring the A260/A280 optical density ratio. To isolate DNA from paraffin-embedded samples, five 10-μm 

sections were washed twice with 1 mL xylene and twice with 500 μL ethanol. Tissues were then dried 

within a vacuum centrifuge prior to DNA isolation as described above. Routine measures were taken to 

avoid contamination at every step from tissue collection to PCR amplification, and concurrently run controls 

without DNA were consistently negative. 

Statistical Analyses 

Multiple regression procedures were used to compare control neoplasm rates in the nine affected studies with 

the 26 unaffected contemporary studies which had no histologic evidence of H. hepaticus-associated liver 

disease. While frozen liver tissue was unavailable from 13 of these 26 studies, none showed the hepatitis 

indicative of H. hepaticus and thus were assumed to be unaffected. Potential confounding factors such as 

body weight, date study was begun, route of administration, and animal supplier were included as 

covariables in the statistical analysis. 

Analysis for H-ras Codon 61 CAA-to-AAA Mutations 

For analyses of formalin-fixed tissue, three to five unstained serial sections (10 μm thick) were cut from 

paraffin blocks containing hepatocellular adenomas or carcinomas. Paraffin-embedded tissues were 

deparaffinized and rehydrated prior to being digested with proteinase k overnight at 55E C to isolate DNA. 

Frozen tissues were digested with 10 mg/mL pronase in 1% sodium dodecyl sulfate in TNE buffer (10 mM 

TRIS, 150 mM NaCl, and 2 mM EDTA; pH 7.5) overnight at 37E C; DNA was isolated by phenol 

chloroform extraction and precipitated with ethanol (Marmur, 1961; Sills et al., 1995). 

Nested primers were used for amplification of exon 2 of H-ras by PCR. The outer primers were 5'-CCA 

CTA AGC CTG TTG TGT TTT GCA G-3' (forward primer) and 5'-CTG TAC TGA TGG ATG TCC TCG 

AAG GA-3' (reverse primer). The inner primers (second round of amplification) were 5'-GAC ATC TTA 

GAC ACA GCA GTT-3' (forward primer) and 5'-GGT GTT GTT GAT GGC AAA TAC-3' (reverse 

primer). Although the normal sequence of codon 60 is GCT, the forward PCR primer is made with a T at 

the penultimate 3' base to create the restriction site for Mse1. 

A nonradioactive RFLP method was employed to identify CAA-to-AAA mutations in the H-ras gene at 

codon 61 in liver neoplasms (Lee and Drinkwater, 1995). This was based on Mse1 enzyme restriction 

cutting only the sequence 5'-TTAA-3'. Thus, Mse1 will detect CÿA conversion mutation at the first 

position of codon 61. 
Chloroprene, NTP TR 467 355 

Analysis of PCNA and Apoptosis 

Detailed methods are included in a report by Nyska et al. (1997). Cell proliferation was assessed in 

nonneoplastic areas of the liver, kidney, and lung by determining a PCNA S-phase labeling index (the 

percentage of cells in S phase). The identification of apoptotic cells was based on morphologic criteria 

(Garewal et al., 1996; Goldsworthy et al., 1996) and confirmed immunohistochemically by the terminal 

deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure (Gavrieli et al., 

1992). 

RESULTS AND DISCUSSION 

Identification of H. hepaticus Infection in NTP Studies 

Determining the extent of H. hepaticus infection involved a three-pronged approach of histologic evaluation, 

silver stains, and PCR-RFLP based assays; all were necessary because of the limitations identified for each. 

In NTP studies, and as reported in other studies (Ward et al., 1994b), there were no obvious clinical signs of 

infection, and the only significant histologic lesion (hepatitis) was observed in the liver, primarily in males. 

Therefore, summary pathology tables were reviewed to identify studies that may have been affected by 

H. hepaticus-associated hepatitis. Male mice from nine studies were identified (Table O1) as having the 

hepatitis. Eight of the nine studies were begun during a time span of about 6 months (July 1990 to 

January 1991), while the other study was begun much earlier (October 1988). The hepatitis was not 

observed in any 13-week studies. Use of histologic evaluation for identification of infected animals has 

limitations, however. It is somewhat insensitive, as H. hepaticus has been cultured and identified by PCRRFLP methods within livers of animals with no histological evidence of infection (Fox et al., 1998). This 

may be explained in part by the limited sampling (two liver sections) and the sometimes focal nature of 

H. hepaticus-associated hepatitis. Also, while in the more severely affected animals the hepatitis appears 

somewhat characteristic, component lesions of the hepatitis are not pathognomonic, and, when the hepatitis is 

subtle in 2-year old animals, it is more difficult to recognize or attribute to H. hepaticus. 

Within affected studies, the incidences of the hepatitis in male mice varied from 16% to 78% (Table O1). 

While generally mild to moderate, the hepatitis varied in severity from barely detectable in some animals to 

extensive liver involvement and regeneration in others. Only a few females were identified as having the 

characteristic hepatitis (Table O1). In general, the incidences and severities of H. hepaticus-associated 

hepatitis were similar between control and treated groups. This constellation of nonneoplastic liver lesions, 

while not pathognomonic, was certainly suggestive of an H. hepaticus infection, particularly when observed 

in control animals. Characteristic lesions included proliferation of oval and/or biliary epithelial cells, 

hepatocyte enlargement (diagnosed as karyomegaly), and chronic inflammation. In many instances, areas of 

regenerative hyperplasia were identified within diseased liver. 

Helicobacter spp. are not usually observed on routine histologic examination of hematoxylin and eosinstained sections of liver. The methods for confirmation of infection with Helicobacter include WarthinStarry silver stain or Steiner’s modification (Garvey et al., 1985) of this stain for direct microscopic 

observation of the organisms in tissue; however, this can be a relatively insensitive technique when few 

organisms are present. In most instances, histologic differentiation between Helicobacter species is not 

possible. Speciation can usually be accomplished with electron microscopy, but this technique is both time 

consuming and labor intensive. Microbiologic culture of feces, cecal smears, and fresh or frozen liver is 

also possible. Currently, assays involving amplification of the DNA of the organism using PCR are the most 

rapid and perhaps the most sensitive methods of detection, and the use of restriction endonucleases has 

allowed a determination of the species present. PCR-based methods also can be used on feces, cecal 

contents, or liver homogenates and are most sensitive when using fresh or frozen tissue (Riley et al., 1996; 

Malarkey et al., 1997). 
356 Chloroprene, NTP TR 467 

Using Warthin-Starry silver stains or Steiner’s modification on the livers of five or more animals per study, 

helical bacteria (Helicobacter) were identified in animals from the nine affected studies. In some animals, 

helical bacteria were numerous, suggesting a heavy bacterial burden in these infected animals. However, 

even in these animals with abundant organisms, few to none were observed in proliferative hepatic lesions 

such as foci and neoplasms. Helical bacteria were not identified in approximately 25% of males with 

moderate hepatitis and were rarely identified in males without hepatitis or in females. The absence of 

identification of helical organisms by silver stains does not preclude infection, nor does the presence of 

organisms confirm H. hepaticus. Based upon current knowledge, however, the characteristic liver lesions in 

B6C3F mice, coupled with the presence of silver-positive helical organisms, are highly suggestive of 1 

H. hepaticus infection. 

As the NTP evaluation evolved, PCR-based assays were developed that appeared more sensitive than 

histologic evaluation and silver stains for identification and speciation of Helicobacter. Therefore, 

PCR-RFLP-based assays were used to confirm the presence of pathogenic Helicobacter (primarily 

H. hepaticus) within the nine affected studies and to determine whether there was H. hepaticus infection in 

other NTP studies. Unfortunately, none of the PCR-based assays had been specifically developed for, or 

proven reliable for use with, formalin-fixed tissue. Frozen tissue was available from a limited number of 

animals from a limited number of NTP studies, including only three of the nine affected studies. 

Furthermore, available frozen liver was almost always limited to tissue from a neoplasm, and, based upon 

results obtained with silver stains, organisms are generally not readily observed within proliferative hepatic 

lesions, even when organisms are abundant in adjacent liver tissue. Because the availability of frozen tissue 

was limited, a PCR-RFLP-based assay was developed and evaluated (Malarkey et al., 1997) for use with 

frozen or formalin-fixed tissue. 

The NIEHS and MU-RADIL laboratories conducted PCR-RFLP-based assays on 32 NTP 2-year studies and 

three NTP 13-week studies (data not shown); frozen tissues from 22 of the 2-year studies were available. All 

three bioassays in which hepatitis was identified and for which frozen tissue was available were positive for 

H. hepaticus by the PCR-RFLP-based assays (Table O2). At a third laboratory, H. hepaticus was also 

cultured from the liver tissue of animals in one of these studies (Fox et al., 1998). Formalin-fixed tissues 

from two of the three studies were evaluated and were also positive; these tissues had been fixed in formalin 

for less than 48 hours. In the other six affected studies, for which only formalin-fixed tissue was available, 

H. hepaticus was identified in only 1 of 120 animals (Table O2). This decreased sensitivity was considered 

to be related to the prolonged formalin fixation (Malarkey et al., 1997) rather than proof of an absence of 

H. hepaticus. The presence or absence of H. hepaticus apparently cannot be confirmed with current 

PCR-RFLP-based assays in liver that has been fixed in formalin for long periods (weeks or months). In the 

three 13-week studies with formalin-fixed tissue, only 1 of 30 animals was positive for H. hepaticus. 

Within the three affected, PCR-RFLP-positive 2-year studies, H. hepaticus was often identified by PCR in 

frozen livers of mice that had no overt hepatitis. In fact, based upon the combined data from two studies 

(including PCR results from three laboratories), of 57 animals without characteristic liver lesions, 13 of 

24 male mice (54%) and 17 of 33 female mice (52%) were positive for H. hepaticus. Furthermore, 

H. hepaticus was identified by PCR in frozen liver of several animals from three “unaffected” studies in 

which hepatitis typical of that associated with H. hepaticus was not observed (Table O2). Apparent 

variability occurs between various strains of mice and between individual mice from affected studies in 

developing hepatitis in response to H. hepaticus infection. One would assume that, within affected studies, 

most or all animals have been exposed to the organism, and even animals resistant to developing hepatitis 

may have organisms within the liver. This assumption is supported by the fact that animals without hepatitis 

are often positive with PCR-RFLP-based assays. Therefore, although alternative explanations are possible, 

the three PCR-RFLP-positive studies in which liver lesions are absent are assumed to be true positives. In 

fact, helical organisms were identified with a silver stain in one animal from one of these studies (Malarkey 

et al., 1997). Therefore, in addition to assessing the affect of H. hepaticus in the nine affected 2-year 
Chloroprene, NTP TR 467 357 

studies, the significance of a positive PCR-RFLP assay for H. hepaticus in the absence of liver lesions is also 

an important question. 

Inconsistent Results with PCR-Based Methods 

As with any technique, the PCR-RFLP-based assays have limitations even when used to assay fresh and 

frozen tissue. One assessment of the variability in results of PCR and serologic analyses for Helicobacter 

among three commercial laboratories revealed significant inconsistencies (Dew et al., 1997). Others 

(J.M. Ward and J. Thigpen, personal communications) have obtained similarly inconsistent results when 

sending replicate samples to different laboratories. Though the number of samples evaluated by both the 

NIEHS and MU-RADIL laboratories was limited, there was good, but not complete, correlation of 

PCR-RFLP results. Also, within the affected studies, the PCR assays were not positive in some animals with 

liver disease. This result may be explained, in part, by the fact that the only frozen tissues available were 

neoplasms; as described above, neoplasms are expected to have fewer organisms. 

Analysis of H. hepaticus-Affected and Unaffected Studies 

for Incidence of Common Neoplasms 

To determine whether the incidences of various neoplasms were different between control groups from 

affected and unaffected studies, the nine affected studies were compared to 26 unaffected studies begun at 

relatively similar times (Table O3). There were no statistically significant differences in body weight or 

survival among the affected and unaffected studies. The neoplasms evaluated represent those that occurred at 

high enough incidences in various organs for statistically significant differences to be detected. Using 

multiple regression procedures, male mice in the nine affected studies were demonstrated to have a 

significantly (P<0.05) increased incidence of only two neoplasm types, both of which were in the liver 

(hepatocellular neoplasms and hemangiosarcoma), when compared to the unaffected studies. Because of 

these differences, there was also a corresponding significant difference in the overall incidence of malignant 

neoplasms (all sites) as well as in the overall proportion of neoplasm-bearing animals. No other tissue site 

showed a significant difference in the incidence of neoplasms. For female mice, the slightly increased 

incidence of hepatocellular neoplasms observed in the affected studies was not statistically significant. 

This seemingly simple analysis is complicated by several potential confounding variables. There have been 

coordinate, time-related increases in body weight and in the incidence of liver neoplasms in mice in NTP 

studies (Haseman, 1992). Table O4 presents the liver neoplasm incidences in relation to the dates the studies 

began and clearly shows the increases in liver neoplasm incidences and body weights (Seilkop, 1995). In 

assessing differences in neoplasm incidences between H. hepaticus-affected and unaffected studies, the most 

relevant comparison would be between studies begun at approximately the same time. The starts of 20 of the 

26 unaffected studies were clustered near the early part of the time frame (April 1988 to June 1990), while 

the starts of the affected studies were clustered toward the later end, with eight of the nine studies begun 

between July 1990 and January 1991; incidences of liver neoplasms in these later studies are expected to be 

higher based on trends in body weight alone. While the slightly increased incidences of liver neoplasms 

observed in female control mice in the nine affected studies is likely due to clustering in time, clearly, this 

alone cannot account for the increased liver neoplasm incidences observed in control male mice in the 

affected studies (Table O3). 

Ideally, unaffected studies used in the above comparison should not only be free of histologic evidence of 

infection with H. hepaticus but should be confirmed as negative by PCR assays. Thirteen of these 26 studies 

could not be confirmed as negative by PCR because frozen tissue was not available; however, 

H. hepaticus-associated hepatitis was not present in any of the 26 studies. Because these and other data 

reported to date suggest that hepatitis is associated with neoplasm development in the liver, it seems 

reasonable to include those 13 studies, unconfirmed by PCR, in this analysis. The majority of the 13 studies 

confirmed as negative by PCR were begun much earlier than the clearly affected studies, and, therefore, 

comparing them alone to the nine affected studies is not reasonable. Although not presented here, a number 
358 Chloroprene, NTP TR 467 

of comparisons were made with various groupings of studies based on the degree of confidence in their 

infection status. Although the outcomes of the various comparisons varied somewhat, incidences of 

hepatocellular neoplasms and hemangiosarcomas of the liver were consistently increased in control male mice 

from affected studies compared to control males from unaffected studies. Significantly increased liver 

neoplasm incidences generally were not observed in females. Importantly, the following data corroborate the 

findings and association with H. hepaticus identified in these analyses. 

Analysis of Hepatitis-Positive and Hepatitis-Negative Mice 

for Liver Neoplasm Incidence 

Several infectious agents known to be associated with increased incidences of neoplasms cause chronic 

inflammation in the target tissue or organ. It is commonly hypothesized that this inflammatory process may 

cause or contribute to the development of neoplasms. One approach to address this was to stratify the mice 

from the affected studies according to the severity of hepatitis and examine liver neoplasm incidences in 

relation to these groupings. Thus, animals within the nine affected studies were placed into three groups: 

1) animals with mild to moderate hepatitis considered related to H. hepaticus infection (+), 2) animals with 

minimal to mild hepatitis that may have been associated with H. hepaticus (±), and 3) animals with no 

hepatitis that was considered to be associated with H. hepaticus (S). Within these groupings, the incidence 

of liver neoplasms was significantly increased (P<0.05) in males with mild to moderate H. hepaticusassociated hepatitis (+) when compared to animals without such hepatitis (Table O5). The neoplasm 

incidence in animals with minimal lesions (±) was also increased. The liver neoplasm incidence in males 

without hepatitis (58%) was similar to the incidence (54.8%) in males from the 26 unaffected studies 

(Table O3). This analysis clearly suggests an association of H. hepaticus-associated hepatitis with increased 

liver neoplasm incidences. Females showed a similar trend, albeit not significant; however, these 

comparisons are weak because of the low numbers of females with hepatitis. 

Analysis of H-ras Oncogene Mutations in Liver Neoplasms in Mice 

from Affected and Unaffected Studies 

Liver neoplasms commonly occur in control B6C3F mice in 2-year studies. In the historical database of 1 

333 male and female mice with liver neoplasms, 106 (32%) had H-ras codon 61 CAA-to-AAA mutations 

(Maronpot et al., 1995). This historical control database is composed primarily of male data; however, 

adequate numbers of females have been assayed, and there was no significant difference in the incidences of 

CAA-to-AAA mutations between males and females. 

In an attempt to examine further whether H. hepaticus infection had an effect on the development of 

hepatocellular neoplasms, neoplasms from control male mice from selected affected (NTP, 1998a,b,c) and 

unaffected (NTP, 1993, 1998h) studies were evaluated for H-ras codon 61 CAA-to-AAA mutations 

(Table O6). Only 6% (2/33) of the hepatocellular neoplasms from control males with hepatitis from three 

affected studies had this mutation. This percentage is significantly (P<0.01) less than the 32% (11/34) 

observed in males from the two unaffected studies and less than the 32% (106/333) that occurred in 

historical control animals. In addition, neoplasms from males without hepatitis from the affected, PCRpositive triethanolamine study (NTP, 1998a) and the unaffected, PCR-positive methyleugenol study (NTP, 

1998g) were evaluated; the incidences of mutations in those groups were 3/14 (21%) and 2/17 (12%), 

respectively. 

Neoplasms from control female mice (none had hepatitis) from affected and unaffected studies were evaluated 

for the CAA-to-AAA mutation (Table O6). The mutation rate was low in both the affected studies (1/25; 

4%) and the unaffected study (1/11; 9%) when compared to the 32% observed in the historical control 

groups. 

The finding of a different H-ras mutation profile in neoplasms of male mice from affected studies tends to 

support the association of increased neoplasm incidences with H. hepaticus, although there is no mechanistic 
Chloroprene, NTP TR 467 359 

understanding behind this observation. In a study of H. hepaticus-infected A/JCr mice, ras mutations were 

not detected in the 25 hepatocellular neoplasms analyzed using a PCR/single-strand conformation 

polymorphism assay (Sipowicz et al., 1997). Because of the low spontaneous rate of liver neoplasms in the 

A/JCr mouse, there are few or no conclusive data on ras mutations in uninfected animals, however. Point 

mutations at codons 12, 13, and 61 of the Ki-, Ha- and N-ras genes were not identified in 45 early gastric 

carcinomas in humans, whether or not H. pylori was present (Craanen et al., 1995). If the increased 

incidence of hepatocellular neoplasms is associated with hepatitis, as many suspect, then one would expect 

the neoplasms from animals without hepatitis to have a similar mutational profile as that of the historical 

controls. The data do not provide a clear answer, because the hepatitis-free males from the affected 

triethanolamine study (NTP, 1998a) and the males from the methyleugenol study (NTP, 1998g), which were 

positive by PCR but lacked hepatitis, had mutation frequencies between those of the unaffected controls and 

the hepatitis-positive mice. Furthermore, mutations in neoplasms from females, none of which had hepatitis, 

from two affected and one unaffected study were very low compared to the historical controls. These 

findings were unexpected, and their significance is not understood. 

H. hepaticus-Associated Alterations in Cell Kinetics 

Studies evaluating cell kinetics were completed to explore further the link between hepatitis and the increased 

incidence of liver neoplasms (Table O7; Nyska et al., 1997). One of the major objectives was to determine 

whether there were differences between PCNA labeling indices in the livers of animals with hepatitis from 

three affected studies, cobalt sulfate heptahydrate, chloroprene, and triethanolamine (NTP, 1998a,b,c), 

compared to animals without hepatitis, whether from the same three affected studies or from an unaffected 9 study, 1-trans-delta -tetrahydrocannabinol (NTP, 1996). Male mice with hepatitis from the three affected 

studies had a significantly increased (P<0.001) labeling index, with a 24-fold increase over males from the 

unaffected study and a sixfold increase over males without hepatitis from the same three affected studies 

(Table O7). The labeling index increase in these mice was substantial and was considered biologically 

significant. Male mice without hepatitis from the three affected studies had a significantly greater labeling 

index (increased fourfold) than male mice from the unaffected study (Table O7). The significance of this 

finding is uncertain, as differences of a similar magnitude were observed in other comparisons. For 9 example, the labeling index of females from the unaffected 1-trans-delta -tetrahydrocannabinol study

(Table O7; NTP, 1996) was increased fivefold over females from the PCR-positive, hepatitis-negative 

scopolamine hydrobromide trihydrate study (NTP, 1997). Such differences may be within the limits of 

normal variability for 2-year-old animals. 

A second objective of the cell proliferation studies of the liver was to determine if labeling indices were 

increased in animals from the PCR-positive, hepatitis-negative methyleugenol (NTP, 1998g), scopolamine 

hydrobromide trihydrate (NTP, 1997), and mouse life-span studies compared to an unaffected PCR-negative 9 and hepatitis-negative 1-trans-delta -tetrahydrocannabinol study (NTP, 1996). The scopolamine 

hydrobromide trihydrate study was evaluated and included in the study by Nyska et al. (1997), while the 

methyleugenol and mouse life-span studies were completed later and are included in Table O7. The labeling 

indices of males from two of these three studies were almost identical to those of males from the unaffected 

study. However, the labeling index of males from the mouse life-span study is increased approximately 

fivefold over that of males from the unaffected study as well as fivefold over the labeling indices of males 

from the two like studies of scopolamine hydrobromide trihydrate and methyleugenol. This finding suggests 

that the increase observed in the mouse life-span study is not attributable to the presence of H. hepaticus, as 

two other studies also positive for H. hepaticus did not show a similar increase. 

The cell proliferation data for the liver from NTP studies are consistent with data from a study by Fox et al. 

(1996) in which cell proliferation indices were evaluated at 8, 10, and 13 months in the A/JCr mouse, which 

is generally believed to be more susceptible to H. hepaticus-associated hepatitis than the B6C3F1 mouse. In 

the study by Fox et al. (1996), cell proliferation rates were significantly increased at all time points in males. 

Some increases were observed in females in that study but did not reach statistical significance. An increased 
360 Chloroprene, NTP TR 467 

incidence of hepatocellular neoplasms was observed only in the males. Though liver lesions were observed 

in females in that study, they were less severe than those in males. 

In addition to the liver, cell proliferation indices (PCNA) were evaluated in the kidneys and lungs of male 

and female mice in affected studies versus those in unaffected studies (Nyska et al., 1997). No apparent 

effect of H. hepaticus infection or the presence of hepatitis on PCNA indices was observed for the kidneys or 

lungs. 

Apoptosis (programmed cell death) is another important parameter in evaluations of cell kinetics. The 

apoptotic index in the liver of male mice with hepatitis from an affected study, cobalt sulfate heptahydrate 

(NTP, 1998b), was significantly (P<0.01) greater than that observed in males from the unaffected 1-trans­ 9 delta -tetrahydrocannabinol study and the PCR-positive, hepatitis-negative scopolamine hydrobromide

trihydrate study (Nyska et al., 1997). For females, there were no significant differences among the three 

studies. 

Two 13-week studies which were begun during the same time as the nine affected studies were randomly 

selected for evaluation of PCNA indices. H. hepaticus was not identified in either of the studies by 

PCR-RFLP; however, as with all NTP 13-week studies, only tissue fixed in formalin for an unspecified 

period was available. Because of this, no true negative control group was available; therefore, the labeling 

index of these 19- to 20-week-old animals was compared to values cited in the literature (Eldridge and 

Goldsworthy, 1996) for 20-week-old B6C3F mice. The labeling index in the NTP studies clearly was not 1 

increased (data not shown). 

The Impact of H. hepaticus on the Interpretation of 2-Year Carcinogenesis Studies 

Increases in the incidences of neoplasms are associated with a number of infectious agents. The chronic 

inflammation caused by these agents has been hypothesized to be important in the pathogenesis of the 

increased neoplasm incidences (e.g., gastric cancer associated with H. pylori). The increased incidences of 

liver neoplasms in male mice from the nine affected NTP studies were observed in the animals with 

H. hepaticus-associated hepatitis. Neoplasms from males with hepatitis tended to have an H-ras mutation 

profile different from that of animals from unaffected studies. Further, cell replication rates at 2 years were 

significantly higher in males with hepatitis compared to those in males without hepatitis. The data suggest 

that H. hepaticus-associated hepatitis is associated with the increased incidences of liver neoplasms in the 

male B6C3F1 mouse. Therefore, the most important consideration in evaluating the impact of H. hepaticus 

infection on the interpretation of study results appears to be the presence or absence of significant hepatitis. 

For any carcinogenicity study, data within and specific to the individual study provide the greatest basis for 

an accurate interpretation. However, it is prudent to consider and evaluate all data or information which may 

affect the interpretation. Based upon the data presented in this and other reports, general guidelines emerge 

that may be useful in interpreting potential chemical-associated carcinogenic effects in H. hepaticus-infected 

B6C3F mice. In a study with sufficient evidence of H. hepaticus-associated hepatitis (>10% of the animals 1 

having the characteristic hepatitis may be a reasonable guideline), interpretation of increased incidences of 

liver neoplasms (hepatocellular neoplasms and hemangiosarcoma) of male mice is considered to be 

potentially confounded. 

Altered chemical uptake and metabolism, due to the intestinal load of H. hepaticus and to H. hepaticusassociated liver disease, respectively, are possible reasons for considering that the male mouse response to 

chemical administration at sites other than the liver should also be considered confounded. Data do not 

currently exist that definitively answer this question. In this group of nine studies, however, there is no 

evidence to suggest that affected mice responded to chemical treatment in organs other than the liver in a 

manner different from mice in nonaffected studies. Within each study, there was excellent concordance in 

chemical-associated neoplasms between the male mice and the females, which had little or no hepatitis 
Chloroprene, NTP TR 467 361 

(Table O8). Furthermore, analyses indicate that H. hepaticus is not associated with neoplastic responses 

outside the liver; incidences of neoplasms at sites other than the liver were not different between control 

groups from affected and unaffected studies (Table O3). Cell replication rates in two major organs (lung and 

kidney) also were not increased in control groups from affected studies compared to those from unaffected 

studies. 

One of the more difficult issues to address is whether interpretation of a treatment-related increase in liver 

neoplasm incidences in the female mouse is confounded when H. hepaticus-associated hepatitis is present 

within the male mice in the study. Most evidence to date links hepatitis with the increased liver neoplasm 

incidences observed in males, and female B6C3F mice in affected studies do not have significant hepatitis at 1 

2 years. The lack of hepatitis in females, however, is based on an analysis in which only late time points 

were evaluated histologically. Therefore, it is conceivable that hepatitis along with increased cell 

proliferation could have occurred earlier and resolved by 18 months to 2 years. Data collected to date, 

however, suggest that H. hepaticus-associated hepatitis is a late-developing and persistent disease in the 

B6C3F1 mouse. H. hepaticus-associated hepatitis has never been observed in any NTP 13-week studies, 

including five begun during the same 6-month time span as eight of the nine affected 2-year studies. Also, 

within affected 2-year studies, more males (51%) that were 18 to 24 months of age had hepatitis than those 

(34%) that were 12 to 18 months of age. This is consistent with a report by Ward et al. (1994b) that 

H. hepaticus-associated liver lesions are not observed at early time points in the B6C3F1 mouse. 

Nonetheless, within affected studies, female control mice did have a slightly elevated incidence of liver 

neoplasms when compared to control mice from unaffected studies, and the data derived from the H-ras 

mutation frequency analysis were inconclusive. The possibility that H. hepaticus-infected female mice from 

affected studies may respond differently to a liver carcinogen than mice from unaffected studies cannot be 

eliminated at this time. However, because within an affected study hepatitis is observed only rarely in 

females, until definitive data suggest otherwise, it is concluded that the interpretation of an apparent 

chemical-induced neoplastic effect in the liver of female mice is not confounded. To censor the few females 

with H. hepaticus-associated hepatitis from any statistical analyses of hepatocellular neoplasms would be 

prudent. Studies in the ostensibly more sensitive A/JCr mouse (Fox et al., 1996) also showed significant 

increases in neoplasm incidences and cell proliferation rates in the liver of H. hepaticus-infected males, but 

not females. 

Another concern is how to interpret possible chemical-related effects in a study in which the status of 

H. hepaticus infection cannot be determined by PCR-RFLP because only tissues fixed in formalin for more 

than 48 hours are available. While histologic evaluation is inadequate to identify infection, it appears 

adequate for identifying hepatitis severe enough to alter the outcome of the study. Therefore, in the absence 

of significant histologic evidence of H. hepaticus-associated hepatitis, the outcome of a 2-year study should 

not be considered potentially compromised. 

The causality between H. hepaticus infection and neoplasia has not been proven in the B6C3F1 mouse in

these studies, nor has the mechanism of this association been determined; further studies are needed. 

However, sufficient information exists to make reasonable scientific judgments relative to the interpretation 

of data from the nine 2-year carcinogenicity studies in the B6C3F1 mouse. Refinements to the above 

interpretive positions may occur if warranted by future information. 

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366 Chloroprene, NTP TR 467 

TABLE O1 

Incidence of Helicobacter hepaticus-Associated Hepatitis in Control B6C3F Mice 1 

from Nine NTP 2-Year Studiesa 

Incidence of Hepatitis (%) 

Study Males Females 

Sodium xylenesulfonate 78 4 

AZT/5,000 U "-interferon A/D 76 4 

Cobalt sulfate heptahydrate 72 8 

AZT/500 U "-interferon A/D 66 0 

Chloroprene 54 0 

Theophylline 32 0 

"-Interferon A/D 22 4 

Triethanolamine 20 0 

AZT 16 2 

Average 48 2 

a Includes regeneration and mild to marked (excludes minimal) chronic inflammation, karyomegaly, oval cell hyperplasia, and bile duct 

hyperplasia. AZT=3N-azido-3N-deoxythymidine 

TABLE O2 

Identification of Helicobacter hepaticus with PCR-RFLP-Based Assays in Control B6C3F Mice 1 

from 32 NTP 2-Year Studies and Three NTP 13-Week Studiesa 

H. hepaticus-Positive Studiesb 

Type of Sample Total Affected Unaffected 

Studies Studies Studies 

13-Week Studies 

Formalin-fixed liver 3 — 1/3c 

2-Year Studies 

Frozen liver 

Formalin-fixed liver 

22 

10 

3/3 

1/6c 3/19 0/4 

a PCR-RFLP=polymerase chain reaction-restriction fragment length polymorphism b	 Number of H. hepaticus-positive studies/number of affected or unaffected studies. Affected studies are those in which hepatitis typical of 

that associated with H. hepaticus infection occurred in many male mice. 

Only one animal in the positive study was positive for H. hepaticus. c 
Chloroprene, NTP TR 467 367 

TABLE O3 

Comparison of Neoplasm Incidences in Control B6C3F1 Mice

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies 

Males Females 

Affected Unaffected Affected Unaffected 

Studiesa Studies Studies Studies 

Number of studies 9 26 9 26 

Survival (%) 64 71 68 68 

12-Month body wt (g) 48.0 48.3 48.1 47.0 

Neoplasm incidence (%) 

Liver 71.3* 54.8 50.3 40.5 

Lung 26.6 23.2 7.6 10.3 

Pituitary gland 0.4 0.8 14.7 14.3 

Harderian gland 5.6 6.1 6.0 4.9 

Lymphoma 6.9 6.3 16.2 15.5 

Circulatory system 9.8 6.0 5.3 4.7

 liver only 7.1* 2.5 — — 

All benign 61.8 57.2 59.1 54.6 

All malignant 61.3* 40.9 50.0 44.2 

All neoplasms 88.0* 77.4 82.7 75.4 

* Significantly different (P#0.05) from the unaffected studies a Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice. 
368 Chloroprene, NTP TR 467 

TABLE O4 

Liver Neoplasm Incidences and Body Weights of Control B6C3F Mice 1 

in Relation to Study Start Dates of Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studiesa 

Liver Neoplasm Incidence (%) Mean Body Weight (g) 

Study Start Date Affected Unaffected Affected Unaffected a Studies Studies Studies Studies 

Male 

April to September 1988 — 43.8 (8)b — 46.2 (8) 

October 1988 62.0 (1) — 48.3 (1) — 

November 1988 to September 1989 — 52.6 (7) — 48.7 (7) 

October 1989 to June 1990 — 61.2 (5) — 48.9 (5) 

July 1990 to January 1991 72.5 (8) 66.2 (4) 48.0 (8) 49.0 (4) 

February 1991 to April 1992 — 68.0 (2) — 52.8 (2) 

Average 71.3 54.8 48.0 48.3 

Female 

April to September 1988 — 31.1 (8) — 44.8 (8) 

October 1988 46.0 (1) — 46.4 (1) — 

November 1988 to September 1989 — 39.9 (7) — 47.2 (7) 

October 1989 to June 1990 — 38.6 (5) — 45.9 (5) 

July 1990 to January 1991 50.9 (8) 54.2 (4) 48.3 (8) 48.0 (4) 

February 1991 to April 1992 — 58.0 (2) — 55.6 (2) 

Average 50.3 40.5 48.1 47.0 

a Includes nine affected studies (those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice) 

and 26 unaffected studies 

b Number of studies is given in parentheses. 
Chloroprene, NTP TR 467 369 

TABLE O5 

Association of Liver Neoplasm Incidence and Severity of Helicobacter hepaticus-Associated Hepatitis a in Control B6C3F Mice from Nine Affected NTP 2-Year Studies 1 

Liver Neoplasm Incidence 

Severity of Hepatitis Males Females 

Absent 

Minimal 

Mild/moderate 

Significance of association 

101/175 (58%) 

44/57 (77%) 

176/218 (81%) 

P<0.05 

196/396 (49%) 

23/42 (55%) 

7/11 (64%) 

NSb 

a Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice. b NS=not significant 

TABLE O6 

H-ras Codon 61 AAA Mutations in Spontaneous Liver Neoplasms in Control B6C3F Mice 1 

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies 

a Study Affected H-ras AAA Mutations 

Male 

Cobalt sulfate heptahydrate + 0/10 (0%) 

Chloroprene + 1/13 (8%) 

Triethanolamine + 1/10 (10%) 

Oxazepam — 7/18 (39%) 

Diethanolamine — 4/16 (25%) 

Historical control database 106/333 (32%) 

Female 

Chloroprene + 0/10 (0%) 

Triethanolamine + 1/15 (7%) 

Diethanolamine — 1/11 (9%) 

Historical control database 106/333 (32%) 

a +=affected; — =not affected. Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection 

occurred in many male mice. 
370 

c 

Chloroprene, NTP TR 467 

TABLE O7 a Proliferating Cell Nuclear Antigen Labeling Indices in the Liver of Control B6C3F1 Mice

Hepatitis No. of PCNA Labeling Average PCNA 

Animals Indexb Labeling Indexc 

Male 

Cobalt sulfate heptahydrated + 15 0.535 ± 0.129 

Chloroprened + 12 1.452 ± 0.386 

d Triethanolamine	 + 9 1.215 ± 0.374 1.011 

Cobalt sulfate heptahydrate — 7 0.175 ± 0.117 

Chloroprene — 10 0.296 ± 0.124 

Triethanolamine — 12 0.100 ± 0.042 0.186 

9 e 1-Trans-delta -tetrahydrocannabinol — 15 0.042 ± 0.011 

Scopolamine hydrobromide trihydratef — 14 0.043 ± 0.012 

Methyleugenolf — 14 0.077 ± 0.020 

Mouse life-span studyf — 15 0.217 ± 0.880 

Female 

Cobalt sulfate heptahydrate + 5 0.161 ± 0.062 

Cobalt sulfate heptahydrate — 17 0.055 ± 0.015 

Chloroprene — 12 0.154 ± 0.050 

Triethanolamine — 12 0.138 ± 0.053 0.108 

9 1-Trans-delta -tetrahydrocannabinol — 13 0.156 ± 0.047 

Scopolamine hydrobromide trihydrate — 15 0.032 ± 0.009 

a A portion of these data are presented in Nyska et al. (1997). +=hepatitis present; — =no hepatitis present b	 Mean ± standard error; PCNA=proliferating cell nuclear antigen 

Average of the mean labeling indices for animals from all three studies d	 Affected study (one in which hepatitis typical of that associated with H. hepaticus occurred in many male mice) e Unaffected study (one in which the typical hepatitis did not occur in mice) f	 Unaffected study with no typical hepatitis, but positive for H. hepaticus by polymerase chain reaction-restriction fragment length 

polymorphism-based assay 
371 

c 

Chloroprene, NTP TR 467 

TABLE O8 

Summary of Target Sites of Carcinogenicity in B6C3F Mice from NTP 2-Year Studies 1 

with Helicobacter hepaticus-Associated Hepatitis 

Males	 Females 

Chloroprene Lung 

Circulatory systema Lung Circulatory system 

Harderian gland Harderian gland 

Forestomach Forestomach 

Kidney Liver 

Skin 

Mesentery 

Zymbal’s gland 

Mammary gland 

Cobalt sulfate heptahydrateb Lung Lung 

Triethanolamine Liver Liver 

AZTc None Vagina 

Sodium xylenesulfonate None None 

Theophylline None None 

a Hemangioma and hemangiosarcoma of the liver were excluded from the analysis in males. b	 An apparent treatment-related increase in the incidence of hemangiosarcoma of the liver was discounted in male mice because of the 

presence of H. hepaticus. 

AZT=3N-azido-3N-deoxythymidine. Includes four studies: AZT; "-interferon A/D; AZT/500 U "-interferon A/D; and 

AZT/5,000 U "-interferon A/D 
372 Chloroprene, NTP TR 467