## NTP TECHNICAL REPORT

ON THE


# TOXICOLOGY AND CARCINOGENESIS

STUDIES OF SODIUM CHLORATE

(CAS NO. 7775-09-9)



# IN F344/N RATS AND B6C3F 1 

# MICE

(DRINKING WATER STUDIES)

NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709

December 2005

NTP TR 517

NIH Publication No. 06-4457



## National Institutes of Health Public Health Service U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

## FOREWORD

The National Toxicology Program (NTP) is made up of four charter agencies of the U.S. Department of Health and Human Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for Toxicological Research (NCTR), Food and Drug Administration; and the National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. In July 1981, the Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs, staff, and resources from these Public Health Service agencies relating to basic and applied research and to biological assay development and validation.

The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardous chemicals. This knowledge is used for protecting the health of the American people and for the primary prevention of disease.

The studies described in this Technical Report were performed under the direction of the NIEHS and were conducted in compliance with NTP laboratory health and safety requirements and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use were in accordance with the Public Health Service Policy on Humane Care and Use of Animals. The prechronic and chronic studies were conducted in compliance with Food and Drug Administration (FDA) Good Laboratory Practice Regulations, and all aspects of the chronic studies were subjected to retrospective quality assurance audits before being presented for public review.

These studies are designed and conducted to characterize and evaluate the toxicologic potential, including carcinogenic activity, of selected chemicals in laboratory animals (usually two species, rats and mice). Chemicals selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of human exposure, level of production, and chemical structure. The interpretive conclusions presented in this Technical Report are based only on the results of these NTP studies. Extrapolation of these results to other species and quantitative risk analyses for humans require wider analyses beyond the purview of these studies. Selection per se is not an indicator of a chemical’s carcinogenic potential.

Details about ongoing and completed NTP studies, abstracts of all NTP Technical Reports, and full versions of the completed reports are available at the NTP’s World Wide Web site: http://ntp.niehs.nih.gov. In addition, printed copies of these reports are available from NTP as supplies last by contacting (919) 541-3419.

## NTP TECHNICAL REPORT

ON THE


# TOXICOLOGY AND CARCINOGENESIS

STUDIES OF SODIUM CHLORATE

(CAS NO. 7775-09-9)



# IN F344/N RATS AND B6C3F 1 

# MICE

(DRINKING WATER STUDIES)

NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709

December 2005

NTP TR 517

NIH Publication No. 06-4457



## National Institutes of Health Public Health Service U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

### 2



## National Toxicology Program Evaluated and interpreted results and reported findings



### M.J. Hooth, Ph.D., Study Scientist 

### J.R. Hailey, D.V.M., Study Pathologist 

### G.D. Hill, D.V.M., Ph.D., Study Pathologist 

### D.W. Bristol, Ph.D. J.R. Bucher, Ph.D. R.A. Herbert, D.V.M., Ph.D. G.E. Kissling, Ph.D. R.R. Maronpot, D.V.M. J.C. Peckham, D.V.M., M.S., Ph.D. S.D. Peddada, Ph.D. J.H. Roycroft, Ph.D. C.S. Smith, Ph.D. G.S. Travlos, D.V.M. K.L. Witt, M.S.



## Southern Research Institute Conducted studies and evaluated pathology findings 

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

3-week and 2-year studies 

### W.R. Richter, D.V.M., M.S., Principal Investigator,

2-year studies 

### C.D. Hébert, Ph.D. , Principal Investigator,

2-year studies 

### D.R. Farnell, D.V.M., M.S., Ph.D. J.E. Heath, D.V.M. R.B. Thompson, D.V.M., Ph.D. 

## Experimental Pathology Laboratories, Inc. Provided pathology review


### M.H. Hamlin, II, D.V.M., Principal Investigator 

### J.C. Peckham, D.V.M., M.S., Ph.D. C.C. Shackelford, D.V.M., M.S., Ph.D. G.A. Willson, B.V.M. & S. 

## Dynamac Corporation Prepared quality assurance audits


### S. Brecher, Ph.D., Principal Investigator 

# CONTRIBUTORS

NTP Pathology Working Group Evaluated slides and prepared pathology report (October 3 and November 19, 2002)


### W.G. Lieuallen, B.S., D.V.M., Ph.D., Chairperson

Pathology Associates International 

### B.J. Davis, V.M.D., Ph.D.

National Toxicology Program 

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

National Toxicology Program 

### G.D. Hill, D.V.M., Ph.D.

National Toxicology Program 

### M.P. Jokinen, D.V.M.

Pathology Associates International 

### J.C. Peckham, D.V.M., M.S., Ph.D.

Experimental Pathology Laboratories, Inc. 

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

Experimental Pathology Laboratories, Inc. 

### Y. Tani, D.V.M., Ph.D., Observer

National Toxicology Program 

### G.A. Willson, B.V.M. & S.

Experimental Pathology Laboratories, Inc. 

## Constella Group, Inc. Provided statistical analyses


### P.W. Crockett, Ph.D., Principal Investigator 

### L.J. Betz, M.S. K.P. McGowan, M.B.A.


## Biotechnical Services, Inc. Prepared Technical Report


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

### P.H. Carver, B.A. L.M. Harper, B.S. D.C. Serbus, Ph.D.

### 3



### ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY . . . . . . . . . . . . . . . . 8

TECHNICAL REPORTS REVIEW SUBCOMMITTEE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS . . . . . . . . . . . . 10

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

MATERIALS AND METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . 19

RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 29

DISCUSSION AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

APPENDIX 

### A Summary of Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

APPENDIX 

### B Summary of Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

APPENDIX 

### C Summary of Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

APPENDIX 

### D Summary of Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

APPENDIX 

### E Genetic Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 217

APPENDIX 

### F Clinical Pathology Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 223

APPENDIX 

### G Organ Weights and Organ-Weight-to-Body-Weight Ratios . . . . . . . . . . . . . . . . . . . . . . . 229

APPENDIX 

### H Chemical Characterization and Dose Formulation Studies . . . . . . . . . . . . . . . . . . . . . . . . 233

APPENDIX 

### I Water and Compound Consumption in the 2-Year Drinking Water Studies of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

APPENDIX 

### J Ingredients, Nutrient Composition, and Contaminant Levels in NTP-2000 Rat and Mouse Ration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

APPENDIX 

### K Sentinel Animal Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 53 

# CONTENTS

### 4 Sodium Chlorate, NTP TR 517



## SUMMARY

Background Sodium chlorate occurs when drinking water is disinfected by chlorine dioxide. We studied the effects of sodium chlorate in rats and mice to identify potential toxic or carcinogenic hazards to humans.

Methods We gave groups of male and female rats drinking water containing 125, 1,000, or 2,000 milligrams (mg) of sodium chlorate per liter (L) of water for two years. Male and female mice received 500, 1,000, or 2,000 mg/L. Other groups of animals received plain tap water and served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal.

Results Male and female rats receiving sodium chlorate had higher rates of follicular cell hypertrophy of the thyroid gland, and the groups receiving 2,000 mg/L had higher rates of thyroid gland cancer, compared with the control groups. Female mice exposed to sodium chlorate had a few pancreatic islet cell tumors.

Conclusions We conclude that sodium chlorate caused some thyroid gland neoplasms in male and female rats. The pancreatic islet cell tumors in female mice may have been related to sodium chlorate exposure.

# ABSTRACT

SODIUM CHLORATE

CAS No. 7775-09-9

Chemical Formula: NaClO 3 

### Molecular Weight: 106.44

Synonyms: Chlorate of soda; chloric acid, sodium salt; soda chlorate Trade names: Atlacide, Chlorax, Defol, De-Fol-Ate, Dervan, Drop-Leaf, Fall, Harvest-Aid, Kusatol, Leafex, Shed-A-Leaf ‘L’, Tumbleaf 

### 5



### Sodium chlorate is used as an oxidizing agent and bleach for paper pulp; to make chlorine dioxide used in water disinfection; in ore processing; in the manufacture of matches and explosives; in dye making and the printing and dyeing of fabrics; in leather finishing and tanning; to make perchlorates; in toothpaste and mouthwash; and as a nonselective herbicide, defoliant, and harvest aid. Chlorate is found as a stable by-product in drinking water that has been disinfected with chlorine dioxide. Sodium chlorate was nominated for study by the United States Environmental Protection Agency because of widespread consumer exposure to treated drinking water and lack of carcinogenicity data. Male and female F344/N rats and B6C3F 1 

### mice were exposed to sodium chlorate (at least 99% pure) in drinking water for 3 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes.



# 3-WEEK 

# S TUDY IN 

# R ATS Groups of 10 male and 10 female rats were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 3 weeks (equivalent to average daily doses of approximately 20, 35, 75, 170, and 300 mg sodium chlorate/kg body weight per day for males and 20, 40, 75, 150, and 340 mg/kg per day for females). All rats survived to the end of the study. Mean body weights of exposed groups were similar to those of control groups. Water consumption by exposed rats was generally similar to that by control groups throughout the study. An exposure concentration-related decrease in segmented neutrophil counts occurred in male and female rats on days 4 and 22. Heart weights were significantly decreased in 2,000 mg/L males. The incidences of minimal to mild thyroid gland follicular cell hypertrophy were significantly increased in males and females exposed to 500 mg/L or greater.



# 3-WEEK 

# S TUDY IN 

# MICE Groups of 10 male and 10 female mice were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 3 weeks (equivalent to average daily doses of approximately 20, 45, 90, 175, and 350 mg/kg per day for male mice and 20, 45, 95, 

## O

Na + 

## O Cl

O

### 6 Sodium Chlorate, NTP TR 517



### 190, and 365 mg/kg per day for female mice). All mice survived to the end of the study. Mean body weights ofexposed groups were generally similar to those of control groups. Water consumption by exposed mice was generally similar to that by control groups throughout the study. No exposure-related lesions occurred in male or female mice.



# 2-YEAR 

# S TUDY IN 

# R ATS Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 125, 1,000, or 2,000 mg/L sodium chlorate for 2 years (equivalent to average daily doses of approximately 5, 35, and 75 mg/kg per day for male rats and 5, 45, and 95 mg/kg per day for female rats). Survival of exposed rats was similar to that of the control groups. Mean body weights of all exposed groups were similar to those of the control groups throughout the study. Water consumption by exposed rats was generally similar to that by controls throughout the study.

Serum concentrations of thyroxine and triiodothyronine were significantly reduced in 1,000 and 2,000 mg/L males and females on day 4 and in 2,000 mg/L males and females at week 3. Serum concentrations of thyroid stimulating hormone were significantly increased in 1,000 and 2,000 mg/L males on day 4 and at week 3, in 1,000 and 2,000 mg/L females on day 4, in 2,000 mg/L females at week 3, and in 2,000 mg/L males and females at week 14.

All special study rats in the 1,000 and 2,000 mg/L groups had thyroid gland follicular cell hypertrophy at 3and 14 weeks. There were positive trends in the incidences of thyroid gland follicular cell carcinoma in malerats and of thyroid gland follicular cell adenoma or carcinoma (combined) in males and females. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in all exposed groups of males and in 1,000 and 2,000 mg/L females. Thyroid gland focal follicle mineralization occurred in most 1,000 and2,000 mg/L female rats. The incidences of hematopoietic cell proliferation in the spleen of 2,000 mg/L males and bone marrow hyperplasia in 1,000 and 2,000 mg/L males were significantly greater than those in the controls. 

# 2-YEAR 

# S TUDY IN 

# MICE Groups of 50 male and 50 female mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L sodium chlorate for 2 years (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg per day for male mice and 30, 60, and 120 mg/kg per day for female mice). Survival of exposed mice was similar to that of the control groups. Mean body weights of exposed females were generally less than those of thecontrol groups after week 84 of the study. Water consumption by exposed mice was generally similar to that by controls throughout the study.

There was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined) in female mice. Thyroid gland follicular cell hypertrophy was significantly increased in 2,000 mg/L females. Theincidences of bone marrow hyperplasia were significantly increased in all exposed groups of females.



# GENETIC 

# T OXICOLOGY Sodium chlorate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA102, TA104, or TA1535; all tests were conducted with and without exogenous metabolic activation (induced rat or hamster liver S9 enzymes). In vivo , no increases in thefrequencies of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male and female B6C3F 1 

### mice exposed to sodium chlorate in drinking water for 3 weeks.



# C ONCLUSIONS Under the conditions of this 2-year drinking water study, there was some evidence of carcinogenic activity * of sodium chlorate in male and female F344/N rats based on increased incidences of thyroid gland neoplasms. There was no evidence of carcinogenic activity of sodium chlorate in male B6C3F 1 

### mice exposed to 500, 1,000, or 2,000 mg/L. There was equivocal evidence of carcinogenic activity of sodium chlorate in female B6C3F 1 

### mice based on marginally increased incidences of pancreatic islet neoplasms.

Exposure to sodium chlorate resulted in nonneoplastic lesions in the thyroid gland of male and female rats and female mice, bone marrow of male rats and female mice, and spleen of male rats.

__________ * Explanation of Levels of Evidence of Carcinogenic Activity is on page 9. A summary of the Technical Reports Review Subcommittee comments and public discussion on this Technical Report appears on page 11.

### Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Sodium Chlorate

Male Female Male Female F344/N Rats F344/N Rats B6C3F 1 

### Mice B6C3F 1 

### Mice

Concentrations in drinking water

Body weights

Survival rates

Nonneoplastic effects

Neoplastic effects

Equivocal findings

Level of evidence of carcinogenic activity 0, 125, 1,000 or 2,000 mg/L

Exposed groups similar to the control group

36/50, 27/50, 31/50, 28/50

Thyroid gland : follicular cell hypertrophy (4/47, 13/44, 33/43, 40/47)

Spleen : hematopoietic cell proliferation (2/48, 6/49, 4/49, 11/50)

Bone marrow : hyperplasia (28/48, 35/48, 41/50, 40/49)

Thyroid gland : follicular cell carcinoma (0/47, 0/44, 0/43, 4/47); follicular cell adenoma or carcinoma (1/47, 0/44, 0/43, 6/47)

None

Some evidence 0, 125, 1,000 or 2,000 mg/L

Exposed groups similar to the control group

37/50, 36/50, 33/50, 41/50

Thyroid gland : follicular cell hypertrophy (3/47, 7/47, 27/43, 42/46); follicular cell mineralization (25/47, 26/47, 40/43, 44/46)

Thyroid gland : follicular cell adenoma or carcinoma (1/47, 0/47, 1/43, 4/46)

None

Some evidence 0, 500, 1,000, or 2,000 mg/L

Exposed groups similar to the control group

38/50, 41/50, 41/50, 33/50

None

None

None

No evidence 0, 500, 1,000, or 2,000 mg/L

Exposed groups less than the control group

36/49, 35/50, 31/49, 35/50

Thyroid gland : follicular cell hypertrophy (3/48, 2/50, 5/49, 14/50)

Bone marrow : hyperplasia (14/50, 28/50, 29/50, 31/50)

None

Pancreatic islets : adenoma or carcinoma (0/46, 2/47, 2/49, 4/49)

Equivocal evidence

Genetic toxicology Salmonella typhimurium gene mutations:

Micronucleated erythrocytes

Mouse peripheral blood in vivo : Negative in strains TA97, TA98, TA100, TA102, TA104, and TA1535 with and without S9

Negative in male and female mice 

### Sodium Chlorate, NTP TR 517 7

### 8 Sodium Chlorate, NTP TR 517



## 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 limitedset 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 studi es 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 increaseof 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 cl ear 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.

For studies showing multiple chemical-related neoplastic effects that if considered individually would be assigned to differentlevels of evidence categories, the following convention has been adopted to convey completely the study results. In a study with clear evidence o f carcinogenic activity at some tissue sites, other responses that alone might be deemed some evidence are indicated as “were also related” tochemical exposure. In studies with clear or some evidence of carcinogenic activity, other responses that alone might be termed equivocal evidence are indicated as “may have been” related to chemical exposure.

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 impo ssible 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 le sion 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.

### Sodium Chlorate, NTP TR 517 9



## 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 sodium chlorate on December 9, 2004, 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.



### Mary Anna Thrall, D.V.M., M.S., Chairperson

Department of Microbiology, Immunology and Pathology Colorado State University Fort Collins, CO


### Diane F. Birt, Ph.D., Principal Reviewer

Department of Food Science & Human Nutrition Iowa State University Ames, IA


### Kim Boekelheide, M.D., Ph.D.

Division of Biology and Medicine Department of Pathology and Laboratory Medicine Brown University Providence, RI


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

Pathology, Drug Safety Evaluation Pfizer Global Research and Development Groton, CT


### Thomas A. Gasiewicz, Ph.D, Principal Reviewer

Department of Environmental Medicine Environmental Health Sciences Center University of Rochester School of Medicine Rochester, NY 

### James E. Klaunig, Ph.D. Division of Toxicology Indiana University School of Medicine Indianapolis, IN


### Stephen M. Roberts, Ph.D.

Center for Environmental & Human Toxicology University of Florida Gainesville, FL


### Richard D. Storer, M.P.H., Ph.D.

Department of Genetic and Cellular Toxicology Merck Research Laboratories West Point, PA 

### Mary Vore, Ph.D., Principal Reviewer

Graduate Center for Toxicology University of Kentucky Lexington, KY 

### Cheryl Lyn Walker, Ph.D.

Department of Carcinogenesis M.D. Anderson Cancer Center The University of Texas Smithville, TX

### 10 Sodium Chlorate, NTP TR 517



### On December 9, 2004, the draft Technical Report on thetoxicology and carcinogenesis studies of sodium chlorate 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. M.J. Hooth, NIEHS, introduced the toxicology and carcinogenesis studies of sodium chlorate by describingits use as a bleach and occurrence after water disinfection, the design of the drinking water studies, and the toxic and neoplastic responses in the study animals. The proposed conclusions were some evidence of carcinogenic activity of sodium chlorate in male and female F344/N rats, no evidence of carcinogenic activity of sodium chlorate in male B6C3F 1 

### mice, and equivocal evidence of carcinogenic activity of sodium chlorate in female B6C3F 1 

### mice.

Dr. Birt, the first principal reviewer, thought the study was designed and reported well, and she agreed with the proposed conclusions.

Dr. Gasiewicz, the second principal reviewer, agreed with most of the proposed conclusions but thought the pancreatic islet neoplasms merited a conclusion of some evidence rather than equivocal evidence

. Dr. Vore, the third principal reviewer, agreed with the proposed conclusions and inquired about the presence of chlorate in the tap water.

Dr. Hooth replied that no chlorate was found above the level of detection (0.11 parts per million) in any of thewater samples assayed. She explained that the pancreatic islet neoplasms were considered equivocal evidence because they were seen only in one sex of one species, and the decreased incidences of hyperplasia were not supportive of an effect. She noted that the NTP had never made a call of carcinogenicity in mice based on pancreatic islet neoplasms.
Dr. C. Capen, representing EKA Chemical Company,spoke about the perturbation of thyroid hormone economy by sodium chlorate above a certain threshold as a possible link to the genesis of the observed thyroid gland neoplasms. Dr. Birt moved and Dr. Vore seconded that the proposedconclusions be accepted as written. The motion was carried unanimously with nine votes. Dr. W.T. Allaben, NCTR, asked if the concept of a threshold effect in the thyroid gland would be added to the discussion. Drs. Birt and Gasiewicz replied that this was a hypothesis that required more testing, and they did not feel the data yet supported their inclusion in the discussion. 

## SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS

### 11



# INTRODUCTION

SODIUM CHLORATE

CAS No. 7775-09-9

Chemical Formula: NaClO 3 

### Molecular Weight: 106.44

Synonyms: Chlorate of soda; chloric acid, sodium salt; soda chlorate Trade names: Atlacide, Chlorax, Defol, De-Fol-Ate, Dervan, Drop-Leaf, Fall, Harvest-Aid, Kusatol, Leafex, Shed-A-Leaf ‘L’, Tumbleaf



# C HEMICAL AND 

# P HYSICAL 

# P ROPERTIES Sodium chlorate occurs as colorless, odorless crystals or white granules with a salty taste ( Merck Index , 1996;HSDB, 2003). It has a melting point of 248° C, a boiling point of 300° C, and a density of 2.49 g/mL. It is soluble in water, liquid ammonia, glycerin, and alcohol ( Merck Index , 1996; HSDB, 2003). Sodium chlorate decomposes on heating above 300° C, producing oxygenand chlorine. It is a strong oxidant and reacts with combustible, reducing, and organic materials, causing fire and explosion hazards.



# P RODUCTION

# , U SE 

# , AND 

# HUMAN 

# E XPOSURE Sodium chlorate is manufactured from sodium chlorideby electrolysis (HSDB, 2003). The production capacities of the United States and Canada in 1999 were 946,000 and 1,193,000 short tons per year, respectively (Chemical Market Reporter, 1999). The demand for sodium chlorate from the United States and Canada was 1.75 million tons in 1997 and 1.85 million tons in 1998 and was estimated to be 2.35 million tons in 2002(Chemical Market Reporter, 1999). United States production for 1991 was 639,000 metric tons; imports and exports in 1984 equaled 124,000 and 1,720 metric tons, respectively (HSDB, 2003). Between the years 1983 and 1990, the commercial use of sodium chlorate in North America was estimated to be 565,000 to 967,000 tons per year (Mendiratta and Duncan, 1993),and 28,583 workers were estimated to have been occupationally exposed in 1983 (Perry et al. , 1994).

Sodium chlorate is used as an oxidizing agent and bleach for paper pulp, to make chlorine dioxide used in water disinfection, in ore processing (especially uranium ore), in the manufacture of matches and explosives, in dye making and the printing and dyeing of fabrics, in leather finishing and tanning, to make perchlorates, and in toothpaste and mouthwash ( Merck Index , 1996; HSDB, 2003). The consumption pattern for sodium chlorate in the United States in the 1990s indicated 95% was used for wood pulp bleaching in the paper industry; 3% for 

## O

Na + 

## O Cl

O

### 12 Sodium Chlorate, NTP TR 517



### the production of other chlorates, perchlorates, and chlorites; and 2% for other uses, including herbicides, water treatment, and uranium mining (HSDB, 2003).

Sodium chlorate has been widely used as a nonselective herbicide, defoliant, and harvest aid (Sheahan et al.
, 1971; Perry et al. , 1994; HSDB, 2003). It is considered phytotoxic to all green plant parts and can kill through root absorption. Sodium chlorate may be used to control morning glory, Canada thistle, Johnson grass, and St. John’s wort (EXTOXNET, 1995). It is used as a total weed control on noncrop land where it is applied at up to 600 kg/hectare (HSDB, 2003). Sodium chlorate is also used as a defoliant and desiccant for cotton, safflower, corn, flax, peppers, soybeans, grain sorghum, southern peas, dry beans, rice, and sunflowers. Sodium chlorate may be used in combination with other herbicides, including atrazine, 2,4-D, bromacil, diuron, and sodium metaborate (EXTOXNET, 1995; HSDB, 2003). Thetotal estimated annual agricultural use of sodium chlorate in the United States in 1992 for eight crops was over 5,200,000 pounds applied. Use of sodium chlorate on crops of cotton and dry beans accounted for greater than 98% of the national agricultural use (USGS, 1992).

Chlorate is also found as a stable by-product in drinking water that has been disinfected with chlorine dioxide (Condie, 1986; Pfaff and Brockhoff, 1990; Singer, 1993). Chlorine dioxide is more effective than chlorinefor killing most microorganisms, produces fewer chlorinated by-products, and does not produce significant levels of trihalomethanes (Richardson, 1998). Chloratemay be formed by inefficient chlorine dioxide generation, if the pH of the reaction mixture has not been adjusted properly, or as a result of the reaction between residual chlorite in finished water and free chlorine in the distribution system (Singer, 1993; Gallagher et al.
, 1994). In addition, chlorine dioxide disproportionates to form chlorite and chlorate in alkaline solutions and decomposes to form chlorate in acidic solutions with exposure to sunlight (Condie, 1986).

In the United States, between 500 and 900 drinking water treatment facilities used chlorine dioxide eitherseasonally or year-round, and as many as 25 million people may be drinking water treated with chlorine dioxide (Gallagher et al. , 1994). Laboratory studies estimate that 10% to 30% of the chlorine dioxide added to water is converted to chlorate (Moore et al. , 1978; Michael et al. , 1981). For water treatment plants using chlorine dioxide, chlorate concentrations in four treated water samples ranged from 21 to 330 μg/L, with a mean of 200 μg/L (USEPA, 1994). Evaluation of a United States public water supply, which was disinfected solely by chlorine dioxide, indicated average weekly chlorate levels in treated water of 0.34 to 1.13 mg/L (Michael et al., 1981). For water treatment systems thatused hypochlorite for disinfection, chlorate concentrations ranged from 11 to 660 μg/L (USEPA, 1994). Chlorate has been detected in source waters and may result from commercial wastewater from paper and pulp mills, from the use of chlorate salts as herbicides, and from the use of free chlorine to disinfect wastewater prior to its release to receiving waters (Bolyard et al.
, 1993). High levels of chlorate (0.2 to 42 g/L) have also been found in hypochlorite solutions used for drinking water disinfection (Bolyard and Fair, 1992). In addition,swimming pool water has been found to contain an average concentration of 16 mg/L chlorate, with a maximum of 124 mg/L (Beech et al. , 1980).



# ABSORPTION

# , D ISTRIBUTION

# , METABOLISM

# , AND 

# E XCRETION 

## Experimental AnimalsMost of the data on the absorption, distribution, metabolism, and excretion of chlorine dioxide, chlorite, and chlorate have been published by Abdel-Rahman et al. (1980a, 1982, 1984). These investigators utilized 36 

### Cl as a tracer for the chlorine and utilized a fractionation method to separate the 36 

### Cl compounds in various body fluids. In the rat, chlorine dioxide is metabolized to chloride, chlorite, and chlorate. Abdel-Rahman et al. (1984) administered 0.065 mg/kg 36 

### ClO 3 

### (0.85 μCi) in3 mL of a 5 mg/L solution orally to male SpragueDawley rats. The radiolabeled chlorate was rapidly absorbed from the gastrointestinal tract. A peak 36 

### Cl plasma level of 185 ng/mL was reached at 30 minutes.Distribution of radioactivity at 72 hours after administration indicated that the highest concentrations were in the plasma, followed by whole blood, stomach, testes, lung, kidney, skin, duodenum, spleen, brain, packed cells, ileum, carcass, liver, and bone marrow. Elimination from the plasma occurred in two phases; the half-life for the rapid elimination phase was about 6 hours, followed by a slower phase that had a half-life of 36.7 hours. Radioactivity first appeared in the urine, and urinary excretion accounted for up to 42% of the total initial dose in 72 hours. Approximately 2% to 4% of the initial dose was excreted in the feces at 72 hours postdosing. Chlorate was metabolized, and 20%, 4%,

### Sodium Chlorate, NTP TR 517 13



### and 13% of the initial dose was excreted as chloride, chlorite, and chlorate, respectively. Daily administration of 100 mg/L chlorate to male rats in drinking water for 1 year resulted in an increase in the chloroform concentration in the liver but not in the blood (Abdel-Rahman et al. , 1982).

Steffen and Wetzel (1993) administered 1 g/kg sodium chlorate to rabbits by gavage and determined serum andurine concentrations of chlorate. The highest serum concentrations were observed 90 minutes after dosing and remained high (10 to 20 mM) for at least 12 hours. Peak concentrations of chlorate (246 ± 99 mM) were observed in the urine at 6 hours; the elimination half-life was approximately 20 hours.



## Humans No reports were found in the literature on the absorption, distribution, metabolism, or excretion of sodium chlorate by humans.



# T OXICITY 

## Experimental Animals The oral LD 50 

### for sodium chlorate is reported to be 8,350 mg/kg in mice, 1,200 mg/kg in rats, 1,350 mg/kg in cats, 7,200 mg/kg in rabbits, and 700 mg/kg in dogs (Lewis, 1996; HSDB, 2003). In laboratory studies, the LD 50 

### for intravenous administration of sodium chlorate to male and female Sprague-Dawley rats was 2,229 mg chlorate/kg (1,743 to 2,638 mg/kg) (Jeng and Woodworth, 1990).

Chlorate toxicosis has been reported in horses, pigs, cows, sheep, chickens, and dogs and is caused primarily by accidental ingestion through the inadequate handling or disposal of herbicides or through accidental inclusion in animal feed (Gregory et al. , 1993). Ingestion of chlorates causes local irritation of the gastrointestinal tract. Hemolysis and methemoglobin formation, followed by intravascular coagulation, are also frequently observed. The kidney is a target organ, with the renal tubules being most susceptible. Clinical signs in animals have included vomiting, ataxia, dyspnea, cyanosis, hematuria, hemoglobinuria, and hemoglobinemia. Anuria, coma,and death can follow. Animals that survive chlorate poisoning may die from chronic renal failure.

Male Sprague-Dawley rats were given 10 or 100 mg/L chlorate per day in drinking water for 4 months (Abdel-Rahman et al. , 1980b). At 2 months, blood glutathione levels were decreased significantly in both exposed groups. At 4 months, blood osmotic fragility was decreased significantly in the 100 mg/L group, andabnormal erythrocyte morphology, including the presence of codocytes and echinocytes, was observed in both exposed groups.

Couri and Abdel-Rahman (1980) studied theglutathione-dependent enzyme system in the erythrocytes of male Sprague-Dawley rats after exposure to chlorate in drinking water at 0, 10, or 100 mg/L for up to 12 months. At 6 months, rats exhibited no change in glutathione reductase activity, an increase in glutathione peroxidase at 100 mg/L, a decrease in catalase activity at 100 mg/L, and a decrease in glutathione concentration at both 10 and 100 mg/L. After 12 months of treatment, there were no significant differences in the activity ofglutathione reductase, glutathione peroxidase, or catalase in either exposed group, and the glutathione concentration was significantly higher in both exposed
groups.
Male Sprague-Dawley rats were exposed to drinking water containing 0, 10, or 100 mg chlorate/L for up to 1 year (Couri et al. , 1982; Abdel-Rahman et al. , 1985). Mean body weights were significantly decreased (10%to 20%) in both treatment groups throughout the experiment. Blood osmotic fragility was significantly decreased in both exposed groups after 7 or 9 months of treatment. Reduced fragility of red blood cells was attributed to cross-linking of membrane componentswith hemoglobin and subsequent precipitation of hemoglobin. Reductions in blood glutathione levels were observed in the 100 mg/L group after 7 and 9 months of treatment and in the 10 mg/L group after 9 months of treatment. After 9 months of treatment, red blood cellcount, hematocrit, and hemoglobin content were all significantly decreased at both 10 and 100 mg/L. Evaluation of 3 

### H-thymidine incorporation into the organs of rats exposed to 10 mg/L chlorate for 3 months indicated a decrease in incorporation in the testes but not in the liver, kidney, or intestinal mucosa.

McCauley et al. (1995) conducted a subchronic (90-day)study on sodium chlorate in male and female SpragueDawley rats. Animals were exposed to 3, 12, or 48 mM(250, 1,001, or 4,005 mg/L, respectively) sodium chlorate in the drinking water, resulting in doses of 30 to 512 mg/kg per day for males and 42 to 801 mg/kg per day for females. There were no compound-related

### 14 Sodium Chlorate, NTP TR 517



### deaths, but males and females in the highest exposure group had significantly lower weights (76% and 84% of that of control values, respectively). Significant decreases in heart, kidney, and liver relative weights were observed in 4,005 mg/L males, whereas significant decreases in adrenal, thymus, and spleen relative weights were observed in 4,005 mg/L females. Red blood cell counts and percent hematocrit were decreased in 4,005 mg/L males and females. Microscopic evaluationof tissues revealed treatment-related changes in the pituitary and thyroid glands. The severity, but not the incidence, of pituitary gland vacuolization was increased in 4,005 mg/L males, whereas both the incidence and severity were increased in 4,005 mg/L females. Thyroid gland colloid depletion was present in both sexes; malesand females in the 1,001 and 4,005 mg/L groups exhibited 100% incidence with moderate to marked severity. No-observed-adverse-effect-levels of 0.36 mM/kg per day (30 mg/kg per day) and 0.50 mM/kg per day (42 mg/kg per day) were established in male and female Sprague-Dawley rats, respectively.

Bercz et al. (1982) exposed 12 African green monkeys to drinking water containing 25, 50, 100, 200, or 400 mg chlorine dioxide equivalent/L (about 4, 8, 16, 31, or 62 mg chlorate/kg per day, respectively, based on water intake of 125 mL/kg per day) in a rising doseprotocol using 30 to 60 day exposures for each concentration. Chlorate did not induce significant changes in hematological parameters or thyroid hormone levels.

Bio/dynamics, Inc. (cited in USEPA, 1994), gave Sprague-Dawley rats (14/sex per dose) sodium chlorate at doses of 0, 7.8, 78, or 784 mg/kg per day by gavage for up to 3 months. No treatment-related effects were observed in mortality, physical appearance or behavior, body weight, food consumption, clinical chemistry, gross necropsy, or organ histopathology. In the 784 mg/kg group, hematological changes indicative ofanemia included decreases in erythrocyte count, hemoglobin concentration, and percent hematocrit.

Steffen and Wetzel (1993) administered 1 g/kg sodium chlorate to New Zealand white rabbits by gavage. No methemoglobin was detected in the blood. No changes in serum values of urea, creatinine, aspartate, or alanineaminotransferase were observed. No adverse histopathological effects were observed in the kidneys 7 days after dosing.

Heywood et al. (1972) repeatedly administered 200 to 326 mg sodium chlorate/kg per day to four male and four female beagle dogs by gavage over a 5-day period. Two animals receiving more than 300 mg/kg displayed loss of appetite and body weight and had blood in their urine orfeces, and one died after 4 days of exposure. The surviving animal was allowed a 7-day recovery period.Postmortem examination of both animals revealed classic signs of chlorate poisoning, including cyanotic kidney surface and evidence of hemolysis in the liver. Dogs receiving less than 300 mg/kg sodium chlorate survivedthe exposure period and were allowed a week of recovery before necropsy. Some of these dogs exhibited extramedullary hematopoiesis in the spleen and evidenceof hemolysis in the liver. Packed cell volume, hemoglobin content, and red blood cell count were all reduced in animals treated with greater than 200 mg/kg compared to pretreatment values for each animal.

Bio/dynamics, Inc. (cited in USEPA, 1994), exposed beagle dogs (four/sex per dose) by gavage to sodium chlorate at doses of 0, 10, 60, or 360 mg/kg per day for 3 months. There was no significant effect at any doseconcentration on body weight, food consumption, clinical chemistry, organ weights, gross necropsy, or tissue histopathology.

Most of the potential adverse health effects of sodium chlorate exposure are associated with blood oxidation, including increased methemoglobin formation, decreased hematocrit, red blood cell membrane damage, and reduction in red blood cell glutathione levels. Incubation of human and rabbit erythrocytes withsodium chlorate induces a concentration-dependent oxidation of hemoglobin (Steffen and Wetzel, 1993). In vitro , rabbit erythrocytes are less sensitive to methemoglobin formation than human erythrocytes; approximately twice as much sodium chlorate is required to mimic the time course of methemoglobin formation observed for human erythrocytes. At 30 mM sodium chlorate, significant concentrations of methemoglobin were formed in rabbit erythrocytes 1 hour later thanhuman erythrocytes incubated with the same concentration of sodium chlorate.

Sodium chlorate is known to be an inhibitor of sulfation (Baeuerle and Huttner, 1986; Humphries and Silbert, 1988; Roy et al. , 1988) and has been used as a researchtool to elucidate molecular mechanisms in which sulfation, specifically proteoglycan sulfation, appears to play an important role. Davies et al. (1995) usedsodium chlorate, an inhibitor of glycosaminoglycan sulfation, to study the morphological development of the urinary-collecting ducts and nephrons in mouse

### Sodium Chlorate, NTP TR 517 15



### embryonic kidneys. Sodium chlorate has been shown to inhibit fibroblast-growth-factor-mediated cardiogenesis in chick heart precardiac mesoderm (Zhu et al. , 1996) and to inhibit extracellular matrix deposition during skeletal muscle differentiation (Melo et al. , 1996). Sodium chlorate also inhibits tyrosine sulfation (Beinfeld, 1994; Mintz et al. , 1994).



## Humans The oral LD 50 

### in adult women is reported to be 800 mg/kg (Lewis, 1996). Concern about the acute toxicity of sodium chlorate to humans stemmed from reports of death or illness resulting from accidental or intentional ingestion of large amounts of herbicides containing sodium chlorate (Timperman and Maes, 1966; Stoodley and Rowe, 1970; Jansen and Zeldenrust, 1972; Oliver et al. , 1972; Vakili, 1977; Stavrou et al.
, 1978; Bloxham et al. , 1979; Helliwell and Nunn, 1979; Proudfoot et al. , 1979; Steffen and Seitz, 1981; Cunningham, 1982; Casey and Vale, 1994). Sodium chlorate ingestion has been associated with more than 100 cases of fatal poisoning in humans (Singelmann et al. , 1984). Chlorate toxicity after ingestion can be characterized primarily by gastrointestinal irritation, massive intravascular hemolysis, disseminated intravascular coagulation, cyanosis, and renal failure. Gastrointestinal irritation appears to be the result of a direct effect of the chlorate ion on the gastrointestinal mucosa. The intravascular hemolysis occurs subsequent to the formation of methemoglobin in exposederythrocytes, eventually resulting in cyanosis. In addition, chlorate exerts a direct toxic effect on the proximal tubule of the kidney, causing necrosis and preventing theformation of urine and subsequent elimination of chlorate from the blood stream, thus prolonging exposure of the erythrocytes. Supportive management aimed atremoving or deactivating the chlorate ion includes gastric lavage, administration of activated charcoal, and oral or intravascular administration of sodium thiosulfate. Reversal of hemoglobinemia may be accomplished with methylene blue during the very early stages of poisoning (Proudfoot et al. , 1979; Steffen and Seitz, 1981). Transfusions, bicarbonate infusion containing sodiumthiosulfate, anticoagulation with heparin, and substitution of clotting factors may be called for to counteract the oxidizing effects of the chlorate on the erythrocytes (Steffen and Seitz, 1981). Peritoneal dialysis or hemodialysis is effective in treating renal failure. Death has been most frequently associated with doses of 20 g or greater, although recovery has been noted in patients who ingested as much as 200 g.

Human epidemiology studies investigating doses of chlorate more relevant to those found in drinking water have not identified any significant exposure-related effects (Michael et al. , 1981; Lubbers et al. , 1982, 1984a,b; Lubbers and Bianchine, 1984). A prospective epidemiology study was conducted on 197 volunteersduring a 12-week period when the primary water disinfectant in the community was changed from chlorine tochlorine dioxide. Chlorate levels obtained from 42 samples ranged from 0.17 to 1.79 ppm, with a mean of 0.73 ppm (Michael et al. , 1981), and chlorate exposure was estimated to be 0.010 to 0.032 mg/kg per day (USEPA, 1994). Thyroid function, as measured by serum thyroxine levels, did not appear to be altered in the human population (Bercz et al. , 1982).

Chlorine dioxide and its by-products were also administered to normal, healthy, adult-male volunteers in controlled clinical studies to determine the physiological effects of chronic ingestion of these compounds. A three-phase study was conducted to characterize the effects of chronically ingested chlorate in drinking water (Lubbers et al. , 1982, 1984a,b; Lubbers and Bianchine, 1984). In Phase I, tolerance of a rising dose of chloratein drinking water was evaluated through serum chemistry, blood counts, urinalysis, clinical chemistry, and aphysical examination. Ten normal, healthy, male volunteers drank two 500-mL aliquots of chlorate-treated water 4 hours apart. A control group received the same volume of untreated water. A physical examination wasconducted on each of the 2 days following water consumption. The 3-day study was repeated using successively higher doses of chlorate. Concentrations of 0.01, 0.1, 0.5, 1.0, 1.8, and 2.4 mg chlorate/L yielded total intakes equivalent to 0.143, 1.43, 7.14, 14.3, 25.7, and 34.3 μg/kg for a 70 kg man. No adverse health effects were noted.

In Phase II, 10 healthy male volunteers ingested a daily aliquot of 500 mL of drinking water containing 5 mg chlorate/L (35.7 μg/kg) for 12 weeks. Physical examinations and laboratory measurements were made on a weekly basis during the treatment period and for 8 weeks following cessation of treatment. There was no effect of chlorate treatment on any parameter measured. Phase III used the treatment protocol of Phase II to

### 16 Sodium Chlorate, NTP TR 517



### evaluate the effect of chlorate ingestion on three glucose-6-phosphate dehydrogenase-deficient subjects. No adverse effects were noted.

Incubation of human erythrocytes with 30 mM sodium chlorate resulted in methemoglobin formation and a dramatic increase in filtration time, beginning after 2 hours of exposure (Steffen and Singelmann, 1983). The increase in filtration time, indicating increased rigidity of the cells, suggests an explanation for the hemolysis, disseminated intravascular coagulation, andrenal failure observed in humans after chlorate poisoning, since erythrocyte rigidity may lead to impairment of the microcirculation and to the destruction of the red cells by the spleen. Further study of the effect of sodium chlorate on human erythrocytes revealed that sodium chlorate indirectly induces methemoglobinemia by inactivating glucose-6-phosphate dehydrogenase (Singelmann et al. , 1984; Steffen and Wetzel, 1993).



# REPRODUCTIVE
AND 

# D EVELOPMENTAL 

# T OXICOLOGY 

## Experimental Animals Female Sprague-Dawley rats were given 0, 1, or 10 mg chlorate/L daily in the drinking water for 2.5 months prior to mating with untreated males (Suh et al. , 1983). Administration of the treated water to pregnant females (six to nine per group) continued until gestation day 20, when they were killed and evaluated for status of uterine implants. Live fetuses were weighed, measured (crown-rump length), and evaluated for external malformations. Fetuses were then examinedfor visceral and skeletal malformations. All animals survived to scheduled necropsy. Maternal body weight wasnot affected by treatment. There was no statistically significant effect on pregnancy rate, total number of implantations per dam, or the number of live, resorbed, or dead fetuses. Fetal body weight was not adverselyaffected by treatment. Crown-rump length was significantly increased in male fetuses exposed to 10 mg/L.There was no statistically significant increase in the incidence of external, visceral, or skeletal anomalies.

Pregnant Sprague-Dawley (CD) rats were given 0, 10, 100, or 1,000 mg sodium chlorate/kg per day in distilled water by gavage on gestation days 6 through 15 (Bio/dynamics, Inc., 1987). Females were killed and evaluated on gestation day 20. There were no maternal deaths in treated animals. No treatment-related effects were evident in maternal body weight or weight gain, food consumption, physical observations, number of uterine implantations, or gross necropsy. Examination of fetuses on day 20 revealed no effects on fetal body weight or sex ratio, and no treatment-related effects on external, visceral, or skeletal abnormalities were detected.

Due to the absence of nonrodent toxicity data in the literature, the National Toxicology Program conducteddevelopmental toxicity studies of sodium chlorate in rabbits. Female New Zealand white (NZW) rabbits(24/group) were given 100, 250, or 475 mg sodium chlorate/kg per day by gavage or vehicle (deionized/distilled water) on gestation days 6 through 29 (NTP, 2002).Dams were necropsied on gestation day 30. One maternal death occurred in each dose group, but these were not considered to be treatment related. Transient changes in maternal food intake, urine color, and/or output were noted at doses of 100 mg/kg per day and greater, but clear evidence of maternal toxicity was observed only at doses greater than 475 mg/kg per day in the screening study (NTP, 1998). Sodium chlorate exposure did not affect resorptions, fetal viability, fetal body weight, or fetal external, visceral, or skeletal alterations. Sodium chlorate did not cause any significant treatment-related developmental toxicity under the conditions of this study.

Sodium chlorate was negative in the mouse sperm head abnormality assay (Meier et al. , 1985). Sodium chlorate was administered by gavage at doses of 8, 20, or 40 mg/kg per day for 5 days to male B6C3F 1 

### mice (10/group). The animals were sacrificed at 1, 3, and5 weeks after the last dose, and the sperm were examined for abnormal shapes in the head region. No evidence of an increased incidence of abnormal sperm heads was found at any dose or time of sacrifice.



## Humans No reproductive or developmental toxicity studies of sodium chlorate in humans were found in the literature.



# C ARCINOGENICITY 

## Experimental Animals Sodium chlorate was tested in male F344 rats (15/group)for potential promoting effects in two-stage rat renal carcinogenesis studies (Kurokawa et al. , 1985). Renalcarcinogenesis was initiated with 0.05% N-ethyl-Nhydroxyethylnitrosamine in the drinking water three

### Sodium Chlorate, NTP TR 517 17



### times per week for 2 weeks. Control animals received distilled water. Rats were then treated with 1% sodium chlorate (1 g/100 mL; mean consumption; 686 mg/kg per day) in the drinking water for 25 weeks. No animals died during the course of the experiment. Animals were necropsied at 27 weeks. Sodium chlorate showed no promoting effect on the incidences of renal neoplastic lesions, including dysplastic foci and renal cell tumors.



## Humans No epidemiology studies of sodium chlorate in humans were found in the literature.



# GENETIC 

# T OXICITYThe published data from investigations of sodium chlorate genetic toxicity are limited. Gocke et al. (1981), reporting results from a large screening study, listed sodium chlorate (12 μmoles per plate) as positive in a Salmonella mutagenicity assay (strain TA1535 with S9), weakly positive in a Drosophila sex-linked recessive lethal assay (0.25 M solution administered by feeding), and negative in an acute bone marrow micronucleus test in NMRI mice (2,100 mg/kg intraperitoneal or 4,200 mg/kg gavage). The report did not include data tables, and the methods and results presentations lacked detail. However, the authors pointed out that the S. typhimurium TA1535 strain that demonstrated the mutagenic response was obtained several years prior to the experiment, and that replicate trials in a more recently acquired sample of TA1535 did not demonstratethe same strength of response. In addition, the mutagenic response observed in TA1535 occurred in cultures grown on “ZLM” medium, a modified Escherichia colimedium with different salt concentrations than the standard Vogel Bonner medium typically used in Ames testing. Salmonella cultured on the standard Vogel Bonner medium did not demonstrate a pronounced reversion. Moriya et al. (1983) observed no mutagenicity with sodium chlorate in several strains of Salmonella , including TA1535, or in E. coli strain WP2 hcr; Vogel Bonner medium was used in these Salmonella assays. A publication of results from in vivo cytogenetics tests with several drinking water disinfectants reported a lack of activity with sodium chlorate (up to 40 mg/kg by gavage for 5 days) in tests for induction of micronuclei or chromosomal aberrations in bone marrow cells of male and female CD-1 Swiss mice (Meier et al. , 1985). Theconcentrations of test chemicals used in these experiments were below the maximum tolerated dose. Therefore, the tests may be considered inadequate indicators of the absence of genetic toxicity.

Further evidence in support of a lack of mutagenic activity for sodium chlorate in vivo and in vitro is provided by several industry reports from Life Science Research, Suffolk, England, cited in an Environmental Protection Agency criteria document (USEPA, 1994). Negative results were reported for gene reversion in S. typhimurium tester strains, with and without S9 activation enzymes, at sodium chlorate doses up to5,000 μg/plate. No induction of unscheduled DNA synthesis (an indicator of DNA damage repair) was observed in cultured HeLa cells in the presence orabsence of S9 liver enzymes. No consistent, reproducible induction of gene mutations at the HGPRT locus of cultured Chinese hamster V79 lung cells exposed to sodium chlorate (up to 5,000 μg/mL) was reported. However, lethality, an indicator of induced primary DNA damage, was seen in repair deficient E. coli strains WP67 and CM871, but not in the repair proficient strain WP2, with and without S9, at sodium chlorate doses of 1,000 μg/mL and higher. Results of in vivo studiesdemonstrated no induction of micronuclei in bone marrow erythrocytes of male and female CD-1 mice treated with up to 5,000 mg/kg sodium chlorate.



# S TUDY 

# R ATIONALESodium chlorate was nominated for toxicity and carcinogenicity studies by the United States Environmental Protection Agency and by the American Water Works Association and Research Council based on the presence of sodium chlorate in drinking water disinfected with chlorine dioxide. A large segment of the United States population is potentially exposed to sodium chlorate in the drinking water and from its use as a herbicide. The 3-week and 2-year studies were performed in male and female F344/N rats and B6C3F 1 

### mice to evaluate the toxicity and carcinogenicity of sodium chlorate. Drinking water was chosen as the route of exposure because it is the most likely route of human exposure.

### 18 Sodium Chlorate, NTP TR 517

### 19



# P ROCUREMENT
AND 

# C HARACTERIZATION
OF 

# S ODIUM 

# C HLORATE A single lot of sodium chlorate (14019PQ) was obtained from Aldrich Chemical Company, Inc. (Milwaukee, WI), by the analytical chemistry laboratory, Battelle Columbus (Columbus, OH), and provided to the study laboratory, Southern Research Institute (Birmingham, AL). Lot 14019PQ was used in the 3-week and 2-yearstudies. Identity, purity, and stability analyses were conducted by the analytical chemistry laboratory and thestudy laboratory. Reports on analyses performed in support of the sodium chlorate studies are on file at the National Institute of Environmental Health Sciences.

Lot 14019PQ, a white crystalline solid, was identified as sodium chlorate by infrared spectroscopy and melting point determination. The purity of lot 14019PQ was determined by argentimetric titration, anion exchange ion chromatography (IC), and elemental analysis. Karl Fischer titration indicated a moisture content of less than 0.05%. Elemental analysis for chlorine was inagreement with the theoretical value for sodium chlorate. However, elemental analysis for sodium was higher (108%) than the theoretical value. Argentimetric titration indicated a purity of 99.7%. IC indicated one major peak with no reportable impurities by one systemand a relative purity of 101% based on major peak comparison with a frozen reference standard of the same lotby a second system. Major peak area percent by the second system indicated a purity of 100%. The overall purity of lot 14019PQ was determined to be greater than 99%.

Stability studies of the bulk chemical were performed by the analytical chemistry laboratory using IC. These studies indicated that sodium chlorate was stable as a bulk chemical for 15 days when stored under a minimal headspace protected from light at temperatures up to 60° C. To ensure stability, the bulk chemical was stored at room temperature in amber glass containers with Teflon® 

### -lined lids and protected from light. Stability was monitored by the study laboratory during the 2-year studies with IC. No degradation of the bulk chemical was detected.



# P REPARATION AND 

# ANALYSIS
OF 

# D OSE 

# F ORMULATIONS The dose formulations were prepared once during the 3-week studies and every 4 weeks during the 2-year studies by mixing sodium chlorate with tap water (Table H1). Homogeneity studies of 125 and 2,000 mg/L dose formulations were performed by the study laboratory using IC. Stability studies of a 2 mg/L dose formulation were performed by the analyticalchemistry laboratory using IC. Homogeneity was confirmed. Stability was confirmed for at least 44 days for dose formulations stored in sealed NALGENE ® 

### containers at temperatures up to 25° C and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.

Periodic analyses of the dose formulations of sodium chlorate were conducted by the study laboratory using IC. During the 3-week studies, the dose formulations were analyzed once; all five of the dose formulations forrats and mice were within 10% of the target concentrations (Table H2). During the 2-year studies, the dose formulations were analyzed approximately every 10 weeks (Table H3). Of the dose formulations used for rats and mice, 40 of 42 were within 10% of the target concentrations; one dose formulation for rats and one dose formulation for mice were inadvertently used at 14% and 11% of target, respectively.



# 3-WEEK 

# S TUDIES Male and female F344/N rats and B6C3F 1 

### mice were obtained from Taconic Laboratory Animals and Services (Germantown, NY). On receipt, the rats and mice were 3 to 4 weeks old. Rats were quarantined for 11 (males) 

# MATERIALS AND METHODS

### 20 Sodium Chlorate, NTP TR 517



### or 12 (females) days, and mice were quarantined for 13 (males) or 14 (females) days; animals were 5 to 6 weeks old on the first day of the studies. Groups of 10 male and 10 female core study rats and mice and groups of 10 male and 10 female clinical pathology study rats were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 22 days. Feed and water were available ad libitum . Rats and female mice were housed five per cage; male mice were housed individually. Clinical findings were recorded weekly for core study rats and mice. Water consumption by core and special study animals was recorded weekly by cage until day 22. The animals were weighed initially, weekly, and at the end of the studies. Details of the study design and animal maintenance are summarized in Table 1.

Blood was collected from the retroorbital sinus of clinical pathology study rats on day 4 and from core studyrats and mice at the end of the 3-week studies for hematology (rats and mice) and clinical chemistry (rats) analyses. Animals were anesthetized with a CO 2

### /O 2 

### mixture. The parameters measured are listed in Table 1. Blood samples for hematology analyses were placed in tubes containing EDTA. Erythrocyte, platelet, andleukocyte counts; hematocrit values; hemoglobin concentrations; and mean cell volume, hemoglobin, and hemoglobin concentration were determined using a Technicon H-1 TM 

### (Bayer HealthCare LLC, Tarrytown, NY) with reagents from R&D Systems, Inc. (Minneapolis, MN), Bayer, Inc. (Tustin, CA), and Fisher Scientific (Norcross, GA). Reticulocytes were counted using a Coulter Model Elite Flow Cytometer (CoulterCorp., Miami, FL) with reagents supplied by the manufacturer and Molecular Probes (Eugene, OR). Methemoglobin concentration was determined using a spectrophotometric method and reagents from J.T. Baker, Inc. (Phillipsburg, NJ) and Fisher Scientific. Samples for clinical chemistry analyses were placed in tubes with no anticoagulant. Samples were analyzed using a Hitachi 911 clinical chemistry analyzer (Roche Diagnostics Corporation, Indianapolis, IN) with reagents from Boehringer Mannheim Biochemicals (Indianapolis, IN) and Sigma Chemical Co. (St. Louis, MO), except sorbitol dehydrogenase was measured using a Cobas Fara chemistry analyzer (Roche) with reagents from Sigma Chemical Co. after serum was frozen at –20° C.

Necropsies were performed on all core study rats and mice. The heart, right kidney, liver, lungs, right testis, and thymus were weighed. Histopathologic examinations were performed on core study vehicle control and 2,000 mg/L rats and mice. Table 1 lists the tissues and organs examined to the no-effect level.



# 2-YEAR 

# S TUDIES 

## Study Design Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 125, 1,000, or 2,000 mg/L sodium chlorate for 105 to 106 weeks. Additional groups of 20 male and 20 female special study rats were exposed to the same concentrations for up to 14 weeks for thyroid hormone evaluations and histopathology. Groups of 50 male and 50 female mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L sodium chlorate for 105 to 106 weeks.



## Source and Specification of Animals Male and female F344/N rats and B6C3F 1 

### mice were obtained from Taconic Laboratory Animals and Servicesfor use in the 2-year studies. Rats and mice were quarantined for 13 days before the beginning of the studies. Five male and five female core study rats and mice andfive male and five female special study rats 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 healthof the animals was monitored during the studies according to the protocols of the NTP Sentinel Animal Program (Appendix K).



## Animal Maintenance Male rats were housed three per cage. Female rats and mice were housed five per cage. Male mice were housed individually. Feed and water were available ad libitum

. Water consumption was recorded every 4 weeks by cage. Cages and racks were rotated every two weeks. Further details of animal maintenance are given in Table 1. Information on feed composition and contaminants is provided in Appendix J.



## Clinical Examinations and Pathology All animals were observed twice daily. Clinical findings were recorded every 4 weeks. Body weights were recorded initially, every 4 weeks, and at the end of the studies. Ten male and 10 female special study rats per exposure group were designated for thyroid hormone evaluations at day 4 and week 3. Additional groups of 10 male and

### Sodium Chlorate, NTP TR 517 21



### 10 female special study rats were designated for thyroid hormone evaluation at week 14. Rats were anesthetized with CO 2

### /O 2 

### for each blood collection. Blood was takenfrom the retroorbital sinus and collected into tubes containing no anticoagulant. The blood samples were processed for serum, and the serum was aliquoted into clean tubes and stored frozen (approximately –70° C or below) until analyzed for thyroid hormones. Rats bled at week 3 or week 14 were sacrificed and necropsied, and the thyroid gland was examined histopathologically. See Table 1 for a list of the parameters measured.

Complete necropsies and microscopic examinations were performed on all core study 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 (except eyes), processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined. See Table 1 for a list of the tissues examined microscopically.

Microscopic evaluations were completed by the study laboratory pathologist, and the pathology data were entered into the Toxicology Data Management System. The slides, paraffin blocks, and residual wet tissues were sent to the NTP Archives for inventory, slide/blockmatch, 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 studies, a quality assessment pathologist evaluated slides from all tumors and all potential target organs, which included the thyroid gland of male and female rats and female mice; the forestomach of male and female mice; the bone marrow, liver, preputial gland, and spleen of male rats; the liver and pancreas of female rats; and the bone marrow, mammary gland, ovary, and pancreatic islets of female mice.

The quality assessment report and the reviewed slides were submitted to the NTP Pathology Working Group (PWG) chairperson, who reviewed the selected tissues and addressed any inconsistencies in the diagnosesmade 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, orlesions 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 thePWG consensus differed from the opinion of the laboratory pathologist, the diagnosis was changed. Final diagnoses for reviewed lesions represent a consensusbetween 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 decisionof whether to evaluate the diagnosed lesions for each tissue type separately or combined was generally based on the guidelines of McConnell et al. (1986).

### 22 Sodium Chlorate, NTP TR 517



### TABLE 

### 1 Experimental Design and Materials and Methods in the Drinking Water Studies of Sodium Chlorate

3-Week Studies 2-Year Studies

Study Laboratory Southern Research Institute (Birmingham, AL)


### Strain and Species F344/N rats B6C3F 1 mice



### Animal Source Taconic Laboratory Animals and Services (Germantown, NY)



### Time Held Before Studies Rats: 11 days (males) or 12 days (females) Mice: 13 days (males) or 14 days (females)


### Average Age When Studies Began 6 weeks


### Date of First Exposure Rats: May 18 (males) or 19 (females), 1998 Mice: May 20 (males) or 21 (females), 1998


### Duration of Exposure 22 (core study) or 27 (special study) days


### Date of Last Exposure Rats: June 8 (males) or 9 (females), 1998 Mice: June 10 (males) or 11 (females), 1998


### Necropsy Dates Rats: June 8 (males) or 9 (females), 1998 Mice: June 10 (males) or 11 (females), 1998


### Average Age at Necropsy 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 weights.


### Animals per Cage Rats: 5 Mice: 1 (males) or 5 (females)



### Method of Animal Identification Tail tattoo Southern Research Institute (Birmingham, AL)

F344/N rats B6C3F 1 mice

Taconic Laboratory Animals and Services (Germantown, NY)

13 days

6 weeks

Rats: September 16, 1998 Mice: September 30, 1998

105 to 106 weeks

Rats: September 21, 2000 Mice: October 5, 2000

Rats: September 13-21, 2000 Mice: September 27 to October 5, 2000

110-111 weeks

50 males and 50 females

Animals were distributed randomly into groups of approximately equal initial mean body weights.

Rats: 3 (males) or 5 (females) Mice: 1 (males) or 5 (females)

Tail tattoo

### Sodium Chlorate, NTP TR 517 23



### TABLE 

### 1 Experimental Design and Materials and Methods in the Drinking Water Studies of Sodium Chlorate

3-Week Studies 2-Year Studies

Diet NTP-2000 irradiated pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum , changed weekly



### Water Tap water (Birmingham municipal supply) via amber glass water bottles with stainless steel screw caps (Kerr Glass Manufacturing Corp., Plainfield, IL), available ad libitum , changed twice weekly


### Cages Solid-bottom polycarbonate (Lab Products, Maywood, NJ), changed twice weekly (rats and female mice) or weekly (male mice)


### Bedding Irradiated hardwood chips (mice) or heat-treated irradiated hardwood chips (rats) (P.J. Murphy Forest Products Corp., Montville, NJ), changed once (male mice) or twice (rats and female mice) weekly



### Rack Filters Reemay® spun bonded polyester (Andico, Birmingham, AL), changed every 2 weeks



### Racks Stainless steel (Lab Products, Inc., Maywood, NJ), changed every 2 weeks



### Animal Room Environment Temperature: 72° ± 3° F Relative humidity: 50% ± 15% Room fluorescent light: 12 hours/day Room air changes: 10/hour


### Exposure Concentrations 0, 125, 250, 500, 1,000, or 2,000 mg/L in water, available ad libitum



### Type and Frequency of Observation Observed twice daily and clinical findings recorded weekly. Water consumption was recorded weekly by cage for core and special study animals until day 22. Animals were weighed initially, weekly, and at the end of the studies. NTP-2000 irradiated wafer rodent feed (Zeigler Brothers, Inc., Gardners, PA), available ad libitum , changed weekly

Tap water (Birmingham municipal supply) via amber glass water bottles with Teflon® -lined plastic screw caps (Wheaton Scientific Products, Millville, NJ), available ad libitum , changed twice weekly

Same as 3-week studies

Heat-treated irradiated hardwood chips (P.J. Murphy Forest Products Corp., Montville, NJ), changed once (male mice) or twice (rats and female mice) weekly

Same as 3-week studies

Same as 3-week studies

Temperature: 72° ± 3° F Relative humidity: 50% ± 15% Room fluorescent light: 12 hours/day Room air changes: 10/hour

Rats: 0, 125, 1,000, or 2,000 mg/L in drinking water, available ad libitum Mice: 0, 500, 1,000, or 2,000 mg/L in drinking water, available ad libitum

Observed twice daily; clinical findings and water consumption by cage were recorded every 4 weeks; core study animals were weighed initially, every 4 weeks, and at the end of the studies.

### 24 Sodium Chlorate, NTP TR 517



### TABLE 

### 1 Experimental Design and Materials and Methods in the Drinking Water Studies of Sodium Chlorate

3-Week Studies 2-Year Studies

Method of Sacrifice Carbon dioxide asphyxiation


### Necropsy Necropsies were performed on all core study animals. Organs weighed were heart, right kidney, liver, lungs, right testis, and thymus of core study animals and liver of special study animals.


### Clinical Pathology Blood was collected from the retroorbital sinus of special study rats on day 4 and from all core study animals at the end of the studies for hematology (rats and mice) and clinical chemistry (rats). Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials Clinical chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids


### Histopathology Complete histopathology was performed on all core study control and 2,000 mg/L rats and mice. In addition to gross lesions and tissue masses, the following tissues were examined to the no-effect level: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, seminal vesicle, skin, spleen, stomach (forestomach and glandular), testis (with epididymis), thymus, thyroid gland, trachea, urinary bladder, and uterus.



### Thyroid Hormone Analysis None Same as 3-week studies

Necropsies were performed on all animals.

None

Complete histopathology was performed on all core study rats and mice. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), harderian gland, heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, seminal vesicle, skin, spleen, stomach (forestomach and glandular), testis (with epididymis), thymus, thyroid gland, trachea, urinary bladder, and uterus. In addition, the thyroid gland of special study rats was examined at 3 and 14 weeks.

At 4 days, 3 weeks, and 14 weeks, blood was collected from the retroorbital sinus of up to 10 special study male and female rats per group for determinations of thyroid stimulating hormone (TSH), triiodothyronine (T 3 ), and thyroxine (T4).

### Sodium Chlorate, NTP TR 517 25



# S TATISTICAL 

# 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 missing were censored from the survival analyses; animals dying from naturalcauses were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.



## Calculation of Incidence The incidences of neoplasms or nonneoplastic lesions are presented in Tables A1, A5, B1, B5, C1, C4, D1, and D5 as the numbers of animals bearing such lesions at a specific anatomic site and the numbers of animals with that site examined microscopically. For calculation of statistical significance, the incidences of most neoplasms (Tables A3, B3, C3, and D3) and all nonneoplastic lesions are given as the numbers of animals affected at each site examined microscopically. However, whenmacroscopic examination was required to detect neoplasms in certain tissues (i.e., harderian gland, intestine,mammary gland, and skin) before microscopic evaluation, or when neoplasms had multiple potential sites ofoccurrence (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. This survival-adjusted rate (based on the Poly-3 method described below) accounts for differential mortality by assigning a reduced risk of neoplasm, proportional to the third power of the fraction of time on study, only to site-specific, lesion-free animals that do not reach terminal sacrifice.



## Analysis of Neoplasm and Nonneoplastic Lesion Incidences The Poly-k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence.This test is a survival-adjusted quantal-response procedure that modifies the Cochran-Armitage linear trend test to take survival differences into account. More specifically, this method modifies the denominator in the quantal estimate of lesion incidence to approximate more closely the total number of animal years at risk. For analysis of a given site, each animal is assigned a risk weight. This value is one if the animal had a lesion at that site or if it survived until terminal sacrifice; if the animal died prior to terminal sacrifice and did not have a lesion at that site, its risk weight is the fraction of the entire study time that it survived, raised to the kth power.

This method yields a lesion prevalence rate that depends only upon the choice of a shape parameter for a Weibull hazard function describing cumulative lesion incidence over time (Bailer and Portier, 1988). Unless otherwisespecified, a value of k=3 was used in the analysis of sitespecific lesions. This value was recommended by Bailer and Portier (1988) following an evaluation of neoplasmonset time distributions for a variety of site-specific neoplasms in control F344 rats and B6C3F 1 

### mice (Portier et al., 1986). Bailer and Portier (1988) showed that the Poly-3 test gave valid results if the true value of k was anywhere in the range from 1 to 5. A further advantage of the Poly-3 method is that it does not require lesion lethality assumptions. Variation introduced by the use of risk weights, which reflect differential mortality, was accommodated by adjusting the variance of the Poly-3 statistic as recommended by Bieler and Williams (1993).

Tests of significance included pairwise comparisons ofeach exposed group with controls and a test for an overall exposure-related trend. Continuity-corrected Poly-3 tests were used in the analysis of lesion incidence, and reported P values are one sided. The significance oflower incidences or decreasing trends in lesions is represented as 1–P with the letter N added (e.g., P=0.99 is presented as P=0.01N).



## Analysis of Continuous VariablesTwo 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 historically have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). Hematology, clinical chemistry, and thyroid hormone data, which have typically skewed distributions,

### 26 Sodium Chlorate, NTP TR 517



### were analyzed using the nonparametric multiple comparison methods of Shirley (1977) (as modified by Williams, 1986) 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 (1957) 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).



## Historical Control Data The concurrent control group represents the most valid comparison to the treated groups and is the only control group analyzed statistically in NTP bioassays. However, historical control data are often helpful in interpreting potential treatment-related effects, particularly for uncommon or rare neoplasm types. For meaningful comparisons, the conditions for studies in the historicaldatabase must be generally similar. One significant factor affecting the background incidence of neoplasms at a variety of sites is diet. In 1995, the NTP incorporated a new diet (NTP-2000) that contains less protein and morefiber and fat than the NIH-07 diet previously used in toxicity and carcinogenicity studies (Rao, 1996, 1997). The current NTP historical database contains all 23 studies that use the NTP-2000 diet with histopathology findings completed up to the present. A second potential source of variability is route of administration. In general, the historical database for a given study will include studies using the same route of administration, and the overall incidences of neoplasms for all routes of administration are included for comparison.



# Q UALITY 

# A SSURANCE 

# METHODSThe 3-week and 2-year studies were conducted in compliance with Food and Drug Administration Good Laboratory Practice Regulations (21 CFR, Part 58). Inaddition, as records from the 2-year studies were submitted to the NTP Archives, these studies were auditedretrospectively by an independent quality assurance contractor. Separate audits covered completeness and accuracy of the pathology data, pathology specimens, final pathology tables, and a draft of this NTP Technical Report. Audit procedures and findings are presented in the reports and are on file at NIEHS. The audit findings were reviewed and assessed by NTP staff, and all comments were resolved or otherwise addressed during the preparation of this Technical Report.



# GENETIC 

# T OXICOLOGY The genetic toxicity of sodium chlorate was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and increases in the frequency of micronucleated erythrocytes in mouse peripheral blood. The protocols for these studies and the results are given in Appendix E.

The genetic toxicity studies have evolved from an earlier effort by the NTP to develop a comprehensive databasepermitting a critical anticipation of a chemical’s carcinogenicity in experimental animals based on numerous considerations, including the molecular structure of the chemical and its observed effects in short-term in vitro and in vivo genetic toxicity tests (structure-activity relationships). The short-term tests were originallydeveloped to clarify proposed mechanisms of chemicalinduced DNA damage based on the relationship between electrophilicity and mutagenicity (Miller and Miller, 1977) and the somatic mutation theory of cancer (Straus, 1981; Crawford, 1985). However, it should be noted that not all cancers arise through genotoxic mechanisms.

DNA reactivity combined with Salmonella mutagenicity is highly correlated with induction of carcinogenicity in multiple species/sexes of rodents and at multiple tissue sites (Ashby and Tennant, 1991). A positive response in the Salmonella test was shown to be the most predictive in vitro indicator for rodent carcinogenicity (89% of the Salmonella mutagens are rodent carcinogens) (Tennant et al., 1987; Zeiger et al., 1990). Additionally, no battery of tests that included the Salmonella test improved the predictivity of the Salmonella test alone.However, these other tests can provide useful information on the types of DNA and chromosomal damage induced by the chemical under investigation.

The predictivity for carcinogenicity of a positive response in acute in vivo bone marrow chromosome aberration or micronucleus tests appears to be less than that in the Salmonella test (Shelby et al., 1993; Shelby and Witt, 1995). However, clearly positive results in long-term peripheral blood micronucleus tests have high

### Sodium Chlorate, NTP TR 517 27



### predictivity for rodent carcinogenicity (Witt et al., 2000); negative results in this assay do not correlate well with either negative or positive results in rodent carcinogenicity studies. 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. Most organic chemicals that are identified by the International Agency for Research on Cancer as human carcinogens, other than hormones, are genotoxic. The vast majority of these are detected by both the Salmonella assay and rodent bone marrow cytogenetics tests (Shelby, 1988; Shelby and Zeiger, 1990).

### 28 Sodium Chlorate, NTP TR 517

### 29



# R

ATS 

# 3-WEEK 

# S TUDY All rats survived to the end of the study (Table 2). Final mean body weights and body weight gains of all exposed groups were similar to those of the control groups.Water consumption by exposed rats was generally similar to that by control groups throughout the study. Drinking water concentrations of 125, 250, 500, 1,000, and 2,000 mg/L resulted in average daily doses ofapproximately 20, 35, 75, 170, and 300 mg sodium chlorate/kg body weight per day for male rats and 20, 40, 75, 150, and 340 mg/kg per day for female rats. No clinical findings attributed to sodium chlorate exposure were observed.

The hematology and clinical chemistry data are shown in Table F1. An exposure concentration-related decrease in segmented neutrophil counts occurred in male andfemale rats on days 4 and 22. In 2,000 mg/L rats, segmented neutrophil counts were decreased by approximately 64% in males and 51% in females on day 22. The cause of the decrease is unknown, but the decrease 

# RESULTS

TABLE 

### 2 Survival, Body Weights, and Water Consumption of Rats in the 3-Week Drinking Water Study of Sodium Chlorate

Final Weight Mean Body Weightb 

### (g) Relative Water Concentration Survivala 

### Initial Final Change to Controls Consumption c 

### (mg/L) (%) Week 1 Week 3

Male 0 10/10 87 ± 1 149 ± 3 61 ± 2 14 19 125 10/10 87 ± 1 148 ± 3 60 ± 2 99 14 21 250 10/10 88 ± 2 153 ± 4 65 ± 3 103 15 20 500 10/10 85 ± 1 149 ± 3 64 ± 2 100 15 20 1,000 10/10 85 ± 1 146 ± 2 61 ± 2 98 17 20 2,000 10/10 86 ± 1 144 ± 2 57 ± 2 97 16 19



### Female

0 10/10 81 ± 1 118 ± 1 36 ± 1 12 15 125 10/10 82 ± 1 118 ± 1 36 ± 2 100 13 20 250 10/10 81 ± 1 118 ± 1 37 ± 1 100 13 18 500 10/10 80 ± 1 117 ± 2 38 ± 2 100 12 16 1,000 10/10 82 ± 2 118 ± 2 35 ± 2 100 13 16 2,000 10/10 81 ± 2 117 ± 2 36 ± 1 99 14 20

a Number of animals surviving at 22 days/number initially in group b Weights and weight changes are given as mean ± standard error. Differences from the control group are not significant by Dunnett’s test. c Water consumption is expressed as grams per animal per day.

### 30 Sodium Chlorate, NTP TR 517



### may represent a redistribution of the neutrophils from the circulating pool to the marginal neutrophil pool. At day 22, there were minimal decreases (approximately 6%) in the hematocrit value, hemoglobin concentration, anderythrocyte count in the 2,000 mg/L males. No chemical-related changes in clinical chemistry parameters occurred.

Absolute and relative heart weights of 2,000 mg/L males were significantly less than those of the control group (Table G1).

Significantly increased incidences of minimal to mild thyroid gland follicular cell hypertrophy occurred in males and females receiving 500 mg/L or greater (males: 0 mg/L, 0/10; 125 mg/L, 0/10; 250 mg/L, 1/10; 500 mg/L, 5/10; 1,000 mg/L, 10/10; 2,000 mg/L, 10/10; females: 0/10, 0/10, 1/10, 8/10, 6/10, 10/10).

Exposure Concentration Selection Rationale: Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats, the highest exposure concentration selected for the 2-year study was 2,000 mg/L. Although follicular cell hypertrophy was observed at 1,000 and 2,000 mg/L, it was not considered a potential threat to the health of the rats during a 2-year study. A low dose of 125 mg/L was selected because it was anticipated to be a no-observed-adverse-effect level for thyroid gland effects.

### Sodium Chlorate, NTP TR 517 31



# 2-YEAR 

# S TUDY 

## Survival Estimates of 2-year survival probabilities for male andfemale rats are shown in Table 3 and in the KaplanMeier survival curves (Figure 1). Survival of exposed rats was similar to that of the control groups. 

## Body Weights, Water and Compound Consumption, and Clinical Findings The mean body weights of all exposed groups were similar to those of the control groups throughout the study (Figure 2; Tables 4 and 5). Water consumption by exposed rats was generally similar to that by controls throughout the study (Tables I1 and I2). Drinking water concentrations of 125, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 5, 35, and 75 mg/kg per day for male rats and 5, 45, and 95 mg/kgper day for female rats. No clinical findings were attributed to sodium chlorate exposure.

TABLE 

### 3 Survival of Rats in the 2-Year Drinking Water Study of Sodium Chlorate
0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Male

Animals initially in study 50 50 50 50

Accidental deatha 100 0 Moribund 10 13 11 14 Natural deaths 3 10 8 8 Animals surviving to study termination 36 27 31 28 Percent probability of survival at end of studyb 74 54 62 56 Mean survival (days) c 687 693 688 689
Survival analysis d P=0.412 P=0.108 P=0.353 P=0.146



### Female

Animals initially in study 50 50 50 50

Moribund 10 11 11 4 Natural deaths 3 3 6 5 Animals surviving to study termination 37 36 e 33 f 41 f Percent probability of survival at end of study 74 72 66 82 Mean survival (days) 695 687 687 711
Survival analysis P=0.368N P=0.945 P=0.498 P=0.426N

a Censored from survival analyses b Kaplan-Meier determinations c Mean of all deaths (uncensored, censored, and terminal sacrifice) d The result of the life table trend test (Tarone, 1975) is in the control column, and the results of the life table pairwise comparisons (Cox, 1972) with the controls are in the exposed group columns. A negative trend or lower mortality in an exposed group is indi cated by N

. e Includes two moribund sacrifice animals from the last week of the study f Includes one animal that died during the last week of the study

### 32 Sodium Chlorate, NTP TR 517



### F IGURE 

### 1 Kaplan-Meier Survival Curves for Male and Female Rats Exposed to Sodium Chlorate in Drinking Water for 2 Years

### Sodium Chlorate, NTP TR 517 33



### F IGURE 

### 2 Growth Curves for Male and Female Rats Exposed to Sodium Chlorate in Drinking Water for 2 Years

### 34 Sodium Chlorate, NTP TR 517



### TABLE 

### 4 Mean Body Weights and Survival of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

Weeks 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

on Av. Wt. No. of Av. Wt. Wt. (% of No. of Av. Wt. Wt. (% of No. of Av. Wt. Wt. (% of No. of Study (g) Survivors (g) controls) Survivors (g) controls) Survivors (g) controls) Survivors

1 102 50 103 101 50 103 101 50 103 101 50 4 187 50 187 100 50 185 99 50 186 99 50 8 261 50 263 101 50 266 102 50 270 104 50 12 312 50 315 101 50 319 102 50 322 103 50 16 348 50 351 101 50 357 103 50 358 103 50 20 373 50 374 100 50 379 102 50 382 102 50 24 393 50 396 101 50 402 102 50 403 103 50 28 420 50 423 101 50 429 102 50 428 102 50 32 437 50 439 101 50 445 102 49 446 102 50 36 442 50 445 101 50 452 102 49 451 102 50 40 459 50 461 100 50 466 102 49 468 102 50 44 467 50 474 101 50 477 102 49 478 102 50 48 475 50 479 101 50 482 102 49 486 102 50 52 487 50 491 101 50 493 101 49 494 101 50 56 489 49 493 101 50 497 102 49 498 102 50 60 495 49 499 101 50 501 101 49 501 101 50 64 499 48 503 101 50 505 101 49 505 101 50 68 500 47 503 101 50 504 101 49 505 101 48 72 497 47 502 101 50 506 102 48 504 102 47 76 508 45 506 100 50 508 100 48 509 100 47 80 508 44 506 100 49 507 100 48 508 100 46 84 512 43 508 99 45 513 100 45 510 100 45 88 509 43 501 99 44 516 101 43 510 100 44 92 514 40 a 501 98 41 514 100 42 508 99 43 96 507 40 500 99 38 505 100 40 498 98 40 100 497 40 486 98 35 504 101 37 488 98 36 104 490 36 497 101 28 500 102 31 496 101 28

Mean for weeks 1-13 216 217 101 218 101 220 102 14-52 430 433 101 438 102 439 102 53-104 502 500 100 506 101 503 100

a Number of animals weighed is less than the number of animals surviving.

### Sodium Chlorate, NTP TR 517 35



### TABLE 

### 5 Mean Body Weights and Survival of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

Weeks 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

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 91 50 91 99 50 91 100 50 89 98 50 4 140 50 141 101 50 140 100 50 138 99 50 8 169 50 171 101 50 170 101 50 169 100 50 12 186 50 187 101 50 188 101 50 186 100 50 16 197 50 200 101 50 199 101 50 196 100 50 20 205 50 208 101 50 208 101 50 204 100 50 24 213 50 215 101 50 216 101 50 212 100 50 28 228 50 230 101 50 232 102 50 226 99 50 32 232 50 236 102 50 237 102 50 231 100 50 36 235 50 239 101 50 240 102 50 236 100 50 40 246 50 250 102 50 248 101 50 244 99 50 44 259 50 268 103 50 265 102 50 259 100 50 48 260 50 266 102 50 263 101 50 259 100 50 52 271 50 277 102 50 276 102 50 267 98 50 56 278 50 283 102 49 284 102 50 276 99 50 60 285 50 287 101 49 293 103 49 283 99 50 64 294 49 301 102 47 304 103 49 291 99 50 68 304 48 310 102 47 309 102 49 298 98 50 72 308 48 313 102 47 316 102 49 305 99 49 76 322 47 325 101 46 328 102 47 317 98 49 80 327 46 331 101 45 332 102 46 323 99 48 84 331 45 337 102 44 337 102 45 330 100 48 88 337 43 338 101 44 341 101 43 331 98 48 92 340 42 342 101 40 345 102 38 339 100 46 96 340 40 343 101 38 352 104 37 332 98 45 100 342 40 350 103 38 351 103 37 337 99 42 104 339 38 351 104 37 359 106 33 341 101 41

Mean for weeks 1-13 147 148 101 147 101 146 99 14-52 235 239 102 238 102 233 100 53-104 319 324 102 327 103 316 99

### 36 Sodium Chlorate, NTP TR 517



## Thyroid Hormone Concentrations Assays for thyroxine (T 4

### ), triiodothyronine (T 3 

### ), and thyroid stimulating hormone (TSH) were conducted using special study rats on day 4, at week 3, and at week 14 (Table 6). Serum concentrations of T 4 

### and T 3 

### were significantly reduced in 1,000 and 2,000 mg/L males and females on day 4 and in 2,000 mg/L males and females at week 3. Serum concentrations of TSH generallyincreased with exposure concentration and were significantly increased in 1,000 and 2,000 mg/L males on day 4 and at week 3, in 1,000 and 2,000 mg/L females on day 4, in 2,000 mg/L females at week 3, and in 2,000 mg/L males and females at week 14.

TABLE 

### 6 Serum Concentrations of Thyroid Hormones in Rats in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

n 10 10 10 10



### Male

Day 4 T4 (μg/dL) 4.67 ± 0.17 5.13 ± 0.20 3.60 ± 0.12** 2.62 ± 0.17** T 3 (ng/dL) 124.60 ± 3.70 136.40 ± 4.67 95.800 ± 2.33** 80.50 ± 4.26** TSH (ng/mL) 3.33 ± 0.14 2.75 ± 0.15 7.47 ± 0.81** 12.09 ± 0.63**

Week 3 T4 (μg/dL) 4.63 ± 0.17 4.54 ± 0.21 4.08 ± 0.18 2.71 ± 0.12** T 3 (ng/dL) 88.10 ± 4.47 84.20 ± 4.15 77.80 ± 3.63 55.60 ± 3.16** TSH (ng/mL) 3.34 ± 0.29b 2.58 ± 0.24 7.77 ± 1.21** 31.03 ± 4.72**

Week 14 T4 (μg/dL) 4.81 ± 0.23 4.63 ± 0.20 4.81 ± 0.15 4.89 ± 0.18 T 3 (ng/dL) 103.60 ± 5.82 99.70 ± 6.13 99.80 ± 5.33 96.80 ± 3.16 TSH (ng/mL) 2.75 ± 0.29 3.41 ± 0.36 3.64 ± 0.49 5.22 ± 0.60**



### Female

Day 4 T4 (μg/dL) 4.12 ± 0.19 4.41 ± 0.13 3.41 ± 0.11** 2.13 ± 0.21** T 3 (ng/dL) 113.10 ± 2.97 120.20 ± 2.95 95.90 ± 2.82** 76.30 ± 4.26** TSH (ng/mL) 2.46 ± 0.22 2.67 ± 0.19 4.57 ± 0.40** 10.96 ± 1.14**

Week 3 T4 (μg/dL) 3.87 ± 0.27 3.63 ± 0.15 3.79 ± 0.17 2.35 ± 0.14** T 3 (ng/dL) 88.00 ± 6.27 c 84.20 ± 2.90 80.22 ± 3.60b 60.00 ± 2.95** TSH (ng/mL) 1.99 ± 0.20 1.75 ± 0.13 2.85 ± 0.37 13.77 ± 1.79**

Week 14 T4 (μg/dL) 3.63 ± 0.20 3.87 ± 0.15 3.60 ± 0.28 3.19 ± 0.22 T 3 (ng/dL) 100.90 ± 2.70 106.80 ± 4.43 102.70 ± 7.18 94.60 ± 3.32 TSH (ng/mL) 2.10 ± 0.32 2.71 ± 0.26 2.38 ± 0.32 3.74 ± 0.61*

* Significantly different (P # 0.05) from the control group by Shirley’s test ** P # 0.01 a Data are presented as mean ± standard error. Statistical tests were performed on unrounded data. T4=thyroxine; T 3 =triiodothyronine; TSH=thyroid stimulating hormone b n=9 c n=7

### Sodium Chlorate, NTP TR 517 37



## Pathology and Statistical AnalysesThis section describes the statistically significant or biologically noteworthy changes in the incidences ofmononuclear cell leukemia and neoplasms and/or nonneoplastic lesions of the thyroid gland, spleen, and bone marrow. Summaries of the incidences of neoplasms andnonneoplastic lesions, individual animal tumor diagnoses, statistical analyses of primary neoplasms that occurred with an incidence of at least 5% in at least oneanimal group, and the historical incidences for the neoplasms mentioned in this section are presented in Appendix A for male rats and Appendix B for female
rats.

Thyroid Gland: Slightly enlarged thyroid glands were observed in 1,000 and 2,000 mg/L special study male rats and 2,000 mg/L special study female rats at 14 weeks. All special study rats in the 1,000 and 2,000 mg/L groups had follicular cell hypertrophy at 3 and 14 weeks; this lesion did not occur in control rats (Table 7).

There were positive trends in the incidences of follicularcell carcinoma in male rats and in follicular cell adenoma or carcinoma (combined) in males and females (Tables 8, A3, and B3). The incidences of follicular cell adenoma, follicular cell carcinoma, and follicular cell adenoma or carcinoma (combined) in 2,000 mg/L males and females exceeded the historical ranges for drinking water controls (Tables 8, A4, and B4). Microscopically, adenomas were well demarcated, focal, expansilemasses consisting of well-differentiated thyroid follicular epithelial cells forming follicular structures with central colloid. Increased cell density occasionally led to the formation of papillary projections into the lumens of the follicle (Plate 1). Histologically, carcinomas were less well demarcated and less well differentiated and consisted of glandular to solid hypercellular masses of pleomorphic thyroid epithelial cells (Plate 2). Occasionally, invasion into the peripheral thyroid was noted.

The incidences of follicular cell hypertrophy in all exposed groups of males and in 1,000 and 2,000 mg/L females at 2 years were significantly greater than those in the control groups and the severity was increased in 2,000 mg/L males and females (Tables 8, A5, and B5). Histologically, the normal thyroid gland is composed of variably-sized follicles containing eosinophilic material (colloid) within the lumens (Plate 3). These follicles range in size from very small (approximately

TABLE 

### 7 Incidences of Thyroid Gland Follicular Cell Hypertrophy in Special Study Rats at Week 3 and Week 14 in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Male

Number Examined Microscopically 10 10 10 10 Week 3 a,b 0 0 10** (2.0) c 10** (2.0) Week 14 0 0 10** (2.0) 10** (2.0)



### Female

Number Examined Microscopically 10 10 10 10 Week 3 b 0 0 10** (2.0) 10** (2.0) Week 14 0 0 10** (1.0) 10** (2.0)

** Significantly different (P # 0.01) from the control group by the Fisher exact test a Number of animals with lesion b In Hooth et al. (2001), thyroid gland follicular cell hyperplasia was diagnosed. c Average severity grade of lesions of affected animals: 1=minimal, 2=mild

### 38 Sodium Chlorate, NTP TR 517



### TABLE 

### 8 Incidences of Neoplasms and Nonneoplastic Lesions of the Thyroid Gland in Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Male
Number Examined Microscopically 47 44 43 47

Follicular Cell, Hypertrophya 4 (1.3)b 13* (1.2) 33** (1.5) 40** (2.0)
Follicular Cell, Adenomac 1002
Follicular Cell, Carcinomad

Overall rate e 0/47 (0%) 0/44 (0%) 0/43 (0%) 4/47 (9%) Adjusted rate f 0.0% 0.0% 0.0% 9.6% Terminal rate g 0/36 (0%) 0/27 (0%) 0/31 (0%) 4/28 (14%) First incidence (days) — h — — 729 (T) Poly-3 testi P=0.003 — j — P=0.058
Follicular Cell, Adenoma or Carcinomak

Overall rate 1/47 (2%) 0/44 (0%) 0/43 (0%) 6/47 (13%) Adjusted rate 2.4% 0.0% 0.0% 14.4% Terminal rate 0/36 (0%) 0/27 (0%) 0/31 (0%) 6/28 (21%) First incidence (days) 705 — — 729 (T) Poly-3 test P=0.002 P=0.512N P=0.513N P=0.052



### Female
Number Examined Microscopically 47 47 43 46

Follicular Cell, Hypertrophy 3 (1.3) 7 (1.0) 27** (1.2) 42** (1.8) Follicular Cell, Mineralization 25 (1.0) 26 (1.0) 40** (1.3) 44** (2.1)
Follicular Cell, Adenomal 0002
Follicular Cell, Carcinomam 1012
Follicular Cell, Adenoma or Carcinoman

Overall rate 1/47 (2%) 0/47 (0%) 1/43 (2%) 4/46 (9%) Adjusted rate 2.3% 0.0% 2.6% 9.1% Terminal rate 1/36 (3%) 0/36 (0%) 0/32 (0%) 2/40 (5%) First incidence (days) 729 (T) — 703 644 Poly-3 test P=0.026 P=0.503N P=0.741 P=0.189

* Significantly different (P # 0.05) from the control group by the Poly-3 test ** P # 0.01 (T)Terminal sacrifice a Number of animals with lesion b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked c Historical incidence for 2-year drinking water studies with controls given NTP-2000 diet (mean ± standard deviation): 3/139 (2. 2% ± 0.3%), range 2% d Historical incidence: 1/139 (1.0% ± 1.4%), range 0%-2% e Number of animals with neoplasm per number of animals with thyroid gland examined microscopically f Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality g Observed incidence at terminal kill h Not applicable; no neoplasms in animal group i Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidences are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A lower incidence in an exposed group is indicated by N

. j Value of statistic cannot be computed. k Historical incidence: 4/139 (3.2% ± 1.1%), range 2%-4% l Historical incidence: 1/142 (1.0% ± 1.4%), range 0%-2%
m Historical incidence: 3/142 (2.1% ± 0.2%), range 2%
n Historical incidence: 4/142 (3.1% ± 1.3%), range 2%-4%

### Sodium Chlorate, NTP TR 517 39



### 50 microns) containing little colloid to relatively large (several hundred microns) filled with colloid. In smaller follicles, the epithelium is generally cuboidal, while more attenuated in glands distended with colloid. Following sodium chlorate administration, there was anexposure concentration-related increase in the percentage of smaller follicles, and these follicles contained sparse amounts of generally pale, often vacuolatedappearing colloid (colloid depletion). The lining epithelium of affected glands appeared more prominent, ranging from cuboidal to somewhat columnar (Plate 4).

The incidences of focal follicle mineralization in 1,000 and 2,000 mg/L females were significantly greater than that in the control group (Tables 8 and B5), and the severity was increased in the 2,000 mg/L group. This lesion consisted of basophilic, ovoid-shaped bodies in the colloid of some of the thyroid follicles. This is a common aging change, but the increased incidences may have been exacerbated by exposure to sodium chlorate.

Spleen : The incidence of hematopoietic cell proliferation was significantly increased in 2,000 mg/L males when compared to the control group (0 mg/L, 2/48, severity grade 2.5; 125 mg/L, 6/49, severity grade 2.3; 1,000 mg/L, 4/49, severity grade 2.5; 2,000 mg/L, 11/50, severity grade 2.5; Table A5). Histologically, this lesion was characterized by an increase in erythroid and myeloid cells within the red pulp. While the increase in hematopoietic cell proliferation was modest and not observed in the 3-week study, this finding is consistent with hematological effects observed in humans and other animal species administered sodium chlorate.

Bone Marrow : The incidences of bone marrow hyperplasia were significantly increased in 1,000 and 2,000 mg/L males when compared to the control group (0 mg/L, 28/48; 125 mg/L, 35/48; 1,000 mg/L, 41/50; 2,000 mg/L, 40/49; Table A5). The severity grades of this lesion were greater in all treatment groups when compared to controls (1.9, 2.3, 2.4, 2.7).Microscopically, bone marrow hyperplasia was characterized by an increase of hematopoietic cells in the marrow cavity. Though histological evaluation of bone marrow sections is generally a crude assessment of erythroid and/or myeloid response, the increases in hyperplasia incidence and severity suggest this was a treatment-related effect.

Mononuclear Cell Leukemia : The incidence of mononuclear cell leukemia was significantly increased in the male 2,000 mg/L group when compared to controls (13/50, 21/50, 16/50, 23/50; Table A3). However, the incidences of this lesion in all exposed groups fell within the historical range in controls (all routes) [514/1,159 (43.1% ± 12.8%), range 22% to 68%]. Because the incidence of mononuclear cell leukemia in the control group was at the low end of the historical control range and near average in the exposed groups, this lesion was not attributed to sodium chlorate administration.

### 40 Sodium Chlorate, NTP TR 517



### TABLE 

### 9 Survival, Body Weights, and Water Consumption of Mice in the 3-Week Drinking Water Study of Sodium Chlorate

Final Weight Mean Body Weightb 

### (g) Relative Water Concentration Survivala 

### Initial Final Change to Controls Consumption c 

### (mg/L) (%) Week 1 Week 3

Male 0 10/10 24.5 ± 0.2 27.7 ± 0.3 3.3 ± 0.2 4.6 4.9 125 10/10 24.2 ± 0.3 28.0 ± 0.3 3.8 ± 0.2 101 4.6 4.7 250 10/10 24.4 ± 0.2 28.0 ± 0.4 3.7 ± 0.2 101 4.6 4.5 500 10/10 23.9 ± 0.4 28.0 ± 0.3 4.1 ± 0.5 101 4.6 4.6 1,000 10/10 24.2 ± 0.3 27.5 ± 0.3 3.3 ± 0.2 99 4.4 4.7 2,000 10/10 24.3 ± 0.3 27.9 ± 0.4 3.6 ± 0.2 101 4.3 5.0



### Female

0 10/10 19.1 ± 0.2 21.3 ± 0.3 2.2 ± 0.3 2.8 3.6 125 10/10 18.9 ± 0.3 21.3 ± 0.2 2.4 ± 0.3 100 2.8 3.5 250 10/10 18.8 ± 0.3 20.9 ± 0.1 2.1 ± 0.2 98 3.3 3.7 500 10/10 19.1 ± 0.1 20.4 ± 0.2 1.3 ± 0.2* 96 3.0 4.7 1,000 10/10 19.0 ± 0.3 21.1 ± 0.3 2.1 ± 0.2 99 3.5 4.8 2,000 10/10 18.3 ± 0.2 20.7 ± 0.3 2.3 ± 0.3 97 2.7 3.8

* Significantly different (P # 0.05) from the control group by Dunnett’s test a Number of animals surviving at 22 days/number initially in group b Weights and weight changes are given as mean ± standard error. c Water consumption is expressed as grams per animal per day. 

# MICE 

# 3-WEEK 

# S TUDY All mice survived to the end of the study (Table 9). Final mean body weights and body weight gains (except body weight gain of 500 mg/L females) of all exposed groups of mice were similar to those of the controlgroups. Water consumption by exposed mice was generally similar to that by the control groups throughout the study. Drinking water concentrations of 125, 250, 500, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 20, 45, 90, 175, and 350 mg/kg per day for male mice and 20, 45, 95, 190, and 365 mg/kg per day for female mice. No clinical findings attributed to sodium chlorate exposure were observed. At the exposure concentrations selected, no chemicalrelated changes in hematology parameters occurred (Table F2). There were no significant differences in organ weights between control and exposed groups (Table G2). No exposure-related lesions occurred in male or female mice.
Exposure Concentration Selection Rationale: Because sodium chlorate produced no biologically significant changes in any of the parameters examined in male or female B6C3F 1 

### mice, exposure concentrations of 500, 1,000, and 2,000 mg/L were selected for the 2-year study in B6C3F 1 

### mice.

### Sodium Chlorate, NTP TR 517 41



# 2-YEAR 

# S TUDY 

## Survival Estimates of 2-year survival probabilities for male and female mice are shown in Table 10 and in the Kaplan-Meier survival curves (Figure 3). Survival of exposed mice was similar to that of the control groups.

TABLE 

### 10 Survival of Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

Male

Animals initially in study 50 50 50 50

Moribund 5 5 4 10 Natural deaths 7 4 5 7 Animals surviving to study termination 38 41 41 33 Percent probability of survival at end of studya 76 82 82 66 Mean survival (days)b 694 712 708 689

Survival analysis c P=0.192 P=0.538N P=0.577N P=0.423



### Female

Animals initially in study 50 50 50 50

Accidental deathd 100 0 Otherd 001 0 Moribund 3 5 6 8 Natural deaths 10 10 12 7 Animals surviving to study termination 36 35 e 31 35 Percent probability of survival at end of study 74 70 63 70 Mean survival (days) 687 700 679 682

Survival analysis P=0.728 P=0.937 P=0.426 P=0.871

a Kaplan-Meier determinations b Mean of all deaths (uncensored, censored, and terminal sacrifice) c The result of the life table trend test (Tarone, 1975) is in the control column, and the results of the life table pairwise comparisons (Cox, 1972) with the controls are in the exposed group columns. Lower mortality in an exposed group is indicated by N

. d Censored from survival analysis e Includes one moribund sacrifice animal from the last week of the study

### 42 Sodium Chlorate, NTP TR 517



### F IGURE 

### 3 Kaplan-Meier Survival Curves for Male and Female Mice Exposed to Sodium Chlorate in Drinking Water for 2 Years

### Sodium Chlorate, NTP TR 517 43



## Body Weights, Water and Compound Consumption, and Clinical Findings The mean body weights of exposed groups of males were similar to those of the control group throughout the study (Table 11 and Figure 4). Body weights of 500 and 1,000 mg/L females were less than those of the controls after week 84, and those of 2,000 mg/L females were less after week 88 of the study (Table 12 and Figure 4). Water consumption by exposed mice was generally similar to that by controls throughout the study (Tables I3 and I4). Drinking water concentrations of 500, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 40, 80, and 160 mg/kg per day for male mice and 30, 60, and 120 mg/kg per day for female mice. No clinical findings related to sodium chlorate exposure were observed.

### 44 Sodium Chlorate, NTP TR 517



### TABLE 

### 11 Mean Body Weights and Survival of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

Weeks 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

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 22 50 22 101 50 22 100 50 22 101 50 4 28 50 28 99 50 28 100 50 28 100 50 8 34 50 33 98 50 34 99 50 34 100 50 12 39 50 38 99 50 38 99 50 39 100 50 16 44 50 43 99 50 44 100 50 44 100 50 20 47 50 47 99 50 47 101 50 47 100 50 24 50 50 49 99 50 49 99 50 50 100 50 28 51 50 50 99 50 50 99 50 50 99 50 32 51 50 50 98 50 50 98 50 50 99 50 36 51 50 51 99 50 51 99 50 51 100 50 40 52 50 51 99 50 51 99 50 52 100 50 44 52 49 51 98 50 51 98 50 52 100 49 48 53 49 52 98 50 52 98 50 53 100 49 52 53 49 52 99 50 52 99 50 53 101 49 56 53 49 52 99 50 52 99 50 53 100 49 60 53 49 52 99 50 53 99 50 53 100 49 64 53 49 53 100 49 53 99 50 53 100 49 68 53 49 54 101 49 53 100 50 55 102 48 72 54 48 53 99 49 53 98 50 54 100 48 76 54 48 53 99 49 52 97 50 54 101 48 80 53 48 52 100 49 52 99 49 53 101 47 84 53 45 52 99 47 53 100 46 52 98 46 88 52 44 51 99 46 52 101 45 51 98 44 92 51 41 51 99 46 51 101 45 50 97 42 96 51 39 50 98 45 50 99 44 50 98 37 100 49 39 47 97 45 48 99 41 48 99 36 104 47 38 45 97 41 47 100 41 49 104 33

Mean for weeks 1-13 31 30 99 31 100 31 100 14-52 50 50 99 50 99 50 100 53-104 52 51 99 51 99 52 100

### Sodium Chlorate, NTP TR 517 45



### TABLE 

### 12 Mean Body Weights and Survival of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

Weeks 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

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 18 50 18 99 50 18 100 50 18 100 50 4 22 50 22 100 50 22 100 50 22 99 50 8 27 50 27 97 50 27 99 48 26 96 50 12 32 50 31 98 50 32 99 48 30 94 50 16 37 50 36 98 50 36 99 48 35 96 50 20 42 50 42 99 50 42 100 48 41 97 50 24 47 50 47 99 50 47 100 48 45 96 49 28 50 50 50 100 50 50 101 48 49 97 49 32 53 50 52 99 50 53 100 48 51 98 49 36 54 50 54 100 50 54 100 48 53 97 49 40 58 49 58 100 50 57 99 48 56 97 49 44 58 49 59 100 50 57 98 48 57 97 49 48 60 49 60 99 50 59 97 48 59 98 49 52 61 49 61 100 50 60 98 48 61 99 49 56 61 49 61 100 50 60 98 48 61 100 49 60 62 49 61 98 50 61 98 48 62 100 49 64 63 48 62 99 50 63 100 48 62 99 49 68 63 48 62 98 49 63 99 48 64 101 47 72 64 48 62 96 48 63 98 47 65 101 46 76 65 47 64 98 47 64 99 45 65 99 46 80 67 47 65 97 46 65 98 44 65 98 44 84 66 46 65 99 44 64 98 43 65 99 44 88 66 41 63 95 44 62 94 42 64 97 43 92 65 39 60 93 44 62 96 39 62 95 42 96 64 38 58 90 44 60 94 37 59 91 41 100 63 37 56 89 41 57 91 36 59 93 36 104 61 36 54 88 36 55 90 31 55 90 35

Mean for weeks 1-13 25 25 99 25 100 24 97 14-52 52 52 99 52 99 51 97 53-104 64 61 95 61 96 62 97

### 46 Sodium Chlorate, NTP TR 517



### F IGURE 

### 4 Growth Curves for Male and Female Mice Exposed to Sodium Chlorate in Drinking Water for 2 Years

### Sodium Chlorate, NTP TR 517 47



## Pathology and Statistical Analyses This section describes the statistically significant or biologically noteworthy changes in the incidences of neoplasms and/or nonneoplastic lesions of the pancreatic islets, liver, thyroid gland, bone marrow, and ovary.Summaries of the incidences of neoplasms and nonneoplastic lesions, individual animal tumor diagnoses, statistical analyses of primary neoplasms that occurred with an incidence of at least 5% in at least one animal group, and historical incidences for the neoplasms mentioned in this section are presented in Appendix C for male mice and Appendix D for female mice.

Pancreatic Islets : There was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined) (Tables 13, D1, and D3) in female mice thatwas composed primarily of adenomas (three of four neoplasms in the 2,000 mg/L group). The incidences of pancreatic islet adenoma and adenoma or carcinoma(combined) in 2,000 mg/L females exceeded the historical ranges for drinking water controls (Tables 13, D1, D3, and D4a). The incidences of hyperplasia decreased with increasing exposure concentration. Histologically, islet cell adenomas were characterized by enlarged islets composed of focal accumulations of well-differentiatedislet cells with variable stromal components that compressed the adjacent parenchyma. On occasion, normal acinar cells were entrapped within the tumor. Becausesize is often considered an important criterion for discerning adenomas of endocrine organs, including the islets, it was noted that adenomas diagnosed in this study were significantly larger than those considered to be hyperplastic. In general, the hyperplastic lesions were smaller, affected multiple islets, and did not compress surrounding acinar tissue.

Liver : The incidences of hepatocellular carcinoma were significantly greater in 500 and 1,000 mg/L females than in the control group (0 mg/L, 3/49; 500 mg/L, 13/50; 1,000 mg/L, 15/49; 2,000 mg/L, 9/50; Tables D1 and D3). Although not statistically significant, the incidencein 2,000 mg/L females was also increased. The incidences in all exposed groups of females exceeded the historical range for drinking water controls [12/149 (8%), range 4% to 14%; Table D4b]. Microscopically, these neoplasms were not well demarcated, primarily trabecular in growth pattern, and characterized by cordsof atypical hepatocytes. When incidences of hepatocellular adenoma (30/49, 19/50, 26/49, 23/50) and carcinoma were combined (31/49, 26/50, 31/49, 26/50), there was no chemical effect. Due to this fact and because the increases were not exposure concentration-related, these carcinomas were not considered to be induced by sodium chlorate.

Thyroid Gland: The incidence of minimal follicular cell hypertrophy was significantly increased in 2,000 mg/L female mice when compared to the control group(0 mg/L, 3/48, severity grade 1.3; 500 mg/L, 2/50, severity grade 2.0; 1,000 mg/L, 5/49, severity grade 1.0; 2,000 mg/L, 14/50, severity grade 1.4; Table D5). Histologically, affected follicles appeared small and were lined by slightly enlarged epithelial cells. The lumens of these follicles contained sparse amounts of generally pale colloid.

The incidence of thyroid gland cystic degeneration was significantly increased in 1,000 mg/L females when compared to the control group (25/48, 28/50, 34/49,32/50; Table D5). Microscopically, there were variations in follicle size, often with coalescence of contiguous, large follicles to form multilocular cysts. Thesecysts were usually lined by flattened epithelial cells, separated by variable amounts of connective tissue, andfilled with pale colloid. Thyroid gland cystic degeneration was considered an aging change and not related to sodium chlorate administration.

Bone Marrow : The incidences of bone marrow hyperplasia were significantly increased in all exposed groups of female mice when compared to the control group (14/50, 28/50, 29/50, 31/50; Table D5). The severity of this lesion in exposed females was slightly greater than in the controls (2.4, 2.6, 2.9, 2.7). Microscopically, bone marrow hyperplasia was characterized by an increase of hematopoietic cells in the marrow cavity. As in the rat, the increases in incidence and severity suggest a treatment-related effect.

Ovary : The incidence of granulosa cell hyperplasia of the ovary was significantly increased in 2,000 mg/L female mice when compared to the control group (0/45, 0/45, 3/47, 7/50; Table D5). Microscopically, granulosa cell hyperplasia was characterized by one or more foci or a diffuse increase in the number of granulosa or luteal cells as pure or mixed populations. It was often difficult to discern focal hyperplastic changes from enlarged copora lutea. In general, these were not considered to be preneoplastic lesions.

### 48 Sodium Chlorate, NTP TR 517



### TABLE 

### 13 Incidences of Neoplasms and Nonneoplastic Lesions of the Pancreatic Islets in Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

Male

Number Examined Microscopically 48 50 50 50

Hyperplasiaa 31 (2.4)b 25 (2.3) 28 (2.5) 23 (2.3)



### Female

Number Examined Microscopically 46 47 49 49

Hyperplasia 9 (1.7) 6 (2.0) 4 (2.3) 3 (2.0)

Adenomac

Overall rate d 0/46 (0%) 2/47 (4%) 2/49 (4%) 3/49 (6%) Adjusted rate e 0.0% 4.5% 4.8% 6.8% Terminal rate f 0/36 (0%) 1/35 (3%) 2/31 (7%) 1/35 (3%) First incidence (days) —g 706 729 (T) 475 Poly-3 testh P=0.112 P=0.248 P=0.235 P=0.125

Adenoma or Carcinomac

Overall rate 0/46 (0%) 2/47 (4%) 2/49 (4%) 4/49 (8%) Adjusted rate 0.0% 4.5% 4.8% 9.1% Terminal rate 0/36 (0%) 1/35 (3%) 2/31 (7%) 2/35 (6%) First incidence (days) — 706 729 (T) 475 Poly-3 test P=0.045 P=0.248 P=0.235 P=0.065

(T)Terminal sacrifice a Number of animals with lesion b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked c Historical incidence for 2-year drinking water studies with controls given NTP-2000 diet (mean ± standard deviation): 2/146 (1.4% ± 2.3%), range 0%-4%. d Number of animals with neoplasm per number of animals with pancreatic islets examined microscopically e Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality f Observed incidence at terminal kill g Not applicable; no neoplasms in animal group h Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidences are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal sacrifice.

### Sodium Chlorate, NTP TR 517 49



# GENETIC 

# T OXICOLOGYSodium chlorate (100 to 10,000 μg/plate) was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA102, TA104, and TA1535, with or without induced rat or hamster liver S9 enzymes. In vivo, no increases in the frequencies of micronucleated normochromatic erythrocytes (NCEs) were seen in peripheral blood samples from male and female B6C3F 1 

### mice exposed to concentrations of 125 to 2,000 mg/L sodium chlorate in drinking water for 3 weeks. The abbreviated exposure duration of 3 weeks may not have allowed steady state to be reached in the circulating NCE population, but thedata are clearly negative, with no indication of an exposure concentration-related increase in NCEs. Steady state is usually established by day 35 of continuous
exposure.

### 50 Sodium Chlorate, NTP TR 517P LATE 1 Follicular cell adenoma (arrows) in the thyroid gland of a male F344/N rat exposed to 2,000 mg/L sodium chlorate in drinking water for 2 years. Note the normal portion of the thyroid gland to the upper left (asterisk). H&E; 4× P LATE 2 Follicular cell carcinoma in the thyroid gland of a male F344/N rat exposed to 2,000 mg/L sodium chlorate in drinking water for 2 years. H&E; 8×

P LATE 3 Thyroid gland of a control male F344/N rat in the 2-year drinking water study of sodium chlorate. Note the variably-sized follicles lined by cuboidal (arrowhead) to attenuated (arrow) epithelium. H&E; 40× P LATE 4 Follicular cell hypertrophy in the thyroid gland of a male F344/N rat exposed to 2,000 mg/L sodium chlorate in drinking water for 2 years. Note the predominance of small follicles lined by enlarged epithelial cells (arrows) when compared to follicles in Plate 3. H&E; 40×

### 51



### Sodium chlorate is found as a stable by-product in drinking water that has been disinfected with chlorine dioxide. Disinfection with chlorine dioxide, a strong oxidant, is being considered as an alternative to chlorine, which produces trihalomethanes in finished drinking water. Chlorine dioxide is more effective than chlorinefor killing most microorganisms, produces fewer chlorinated by-products, and does not produce significant levels of trihalomethanes (Richardson, 1998). However, sodium chlorate has been identified as a by-product of chlorine dioxide disinfection. Sodium chlorate was nominated for study by the United States EnvironmentalProtection Agency (USEPA) because of widespread consumer exposure to treated drinking water and a lack of carcinogenicity data.

In the 3-week and 2-year rat studies, there were no chemical-related deaths. Administration of sodium chlorate did not produce any clinical findings of toxicity and had no significant effect on body weights or water consumption of rats of either sex. The thyroid gland wasconsidered to be a target organ for sodium chlorate toxicity in the 3-week study because of the significantly increased incidences of thyroid gland follicular cell hypertrophy in 500 mg/L or greater males and females.

Administration of sodium chlorate to male and female rats caused significant exposure concentration-related decreases in serum concentrations of triiodothyronine (T 3 

### ) and thyroxine (T 4

### ) and significant increases in serum concentrations of thyroid stimulating hormone (TSH) that were evident by day 4 and persisted through week 3 of the 2-year study. The higher concentrations of circulating TSH appear to have effectively restored T 3 

### and T 4 

### concentrations nearly to control levels by week 14 in all exposed groups. By week 14, serum TSHconcentrations in 2,000 mg/L rats had declined significantly from the peak levels observed at week 3 but remained slightly elevated compared to control animals. Hormone levels may return to normal becauseof a homeostatic compensatory increase in cell proliferation with subsequent thyroid hormone production. Hood et al. (1999) demonstrated that small increases in serum TSH (between 10 and 20 ng/mL) can be sufficient to stimulate thyroid cell proliferation and thyroid gland growth. In fact, several special study rats had enlarged thyroid glands at the 14-week evaluation, indicating increased cellular growth. Although thyroid hormonelevels were not measured after week 14, chronic stimulation of the thyroid gland by TSH has been shown toincrease the susceptibility of rats to follicular-cellderived tumors in long-term bioassays (Capen, 1997).

Significant changes in serum hormone levels were observed within a few days of exposure, providing early evidence that sodium chlorate disrupts the hypothalamic-thyroid-pituitary axis. Bercz et al. (1982) reported that exposure of African green monkeys to chlorine dioxide, but not chlorate, resulted in decreased serum T 4 

### levels. In a subsequent study, Harrington et al. (1986) noted a decrease in T 4 

### levels in both Sprague-Dawley rats and African green monkeys exposed to drinking water containing 0.1 g/L chlorine dioxide. Decreased T 4 

### levels were associated with increased binding of dietary iodide to gastrointestinal tissue and contents. These observations led to the hypothesis that chlorine dioxide oxidizes iodide in food to a reactive species that binds to tissues of the digestive tract, preventing absorption of dietary iodide. This effect produces a functional state of iodine deficiency that promotes increased iodide uptake by the thyroid gland.

In the 2-year rat study, there were positive trends in the incidences of thyroid gland follicular cell carcinoma in males and in follicular cell adenoma or carcinoma (combined) in males and females. The incidences offollicular cell adenoma, carcinoma, and adenoma or carcinoma (combined) in 2,000 mg/L males and femalesexceeded the historical ranges for drinking water controls. Additional thyroid gland effects were observed,including alterations in thyroid hormone levels, follicular cell hypertrophy in males and females in the 3-week study, follicular cell hypertrophy at 3 and 14 weeks in special study rats, and increased incidences of follicular cell hypertrophy in all exposed groups of males and in 

# DISCUSSION AND CONCLUSIONS

### 52 Sodium Chlorate, NTP TR 517



### 1,000 and 2,000 mg/L females in the 2-year study. Furthermore, the incidence of follicular cell hypertrophy was significantly increased in 2,000 mg/L female mice. Based on these data, the increased incidences of thyroid gland neoplasms were considered to be related to sodium chlorate exposure.

Chlorate is chemically similar to perchlorate and bromate; both are thyroid gland toxicants and chemical oxidants. Perchlorate (ClO 4–

### ) is an anion that originates as a contaminant in groundwater and surface water fromthe dissolution of its ammonium, potassium, magnesium, or sodium salt. The primary target tissue for perchlorate toxicity is the thyroid gland, as indicated by perturbations of T 3 

### , T 4 

### , and TSH and by histopathology. Benign tumors and follicular cell carcinomas have been reported in the thyroid gland of male Wistar rats and female BALB/c mice after repeated high exposures (2 years at 1,339 mg/kg per day and 46 weeks at 2,147 mg/kg per day, respectively) of potassium perchlorate in drinking water (Kessler and Krunkemper, 1966; Pajer and Kalisnik, 1991). The mode-of-action for perchlorate toxicity is the competitive inhibition of iodide anion uptake by the sodium-iodide symporter, a carrier protein responsible for the active transport of iodide across the basolateral membrane of the thyroid gland epithelialcells (Wolff, 1998). Thyroid hormone synthesis is inhibited, resulting in decreased levels of T 3 

### and T 4 

### , increased TSH levels, and stimulation of thyroid cell proliferation.

Bromate is one of the most prevalent water disinfection by-products associated with ozonation (Glaze, 1986; Cavanagh et al. , 1992). Potassium bromate is carcinogenic in the rat thyroid gland, producing adenomas and carcinomas at water concentrations as low as 0.02 g/L (20 ppm; 1.5 mg/kg/day; DeAngelo et al ., 1998; Wolf et al. , 1998). The mechanism by which potassium bromate induces thyroid gland tumors is not known. Bromide binds to the sodium-iodide symporter of the thyroid gland with low affinity (Van Sande et al. , 2003). High levels of bromide result in a decrease in iodide accumulation in the thyroid gland and a rise in iodide excretion by the kidneys, resulting in decreased thyroidhormone synthesis and stimulation of thyroid cell proliferation (Pavelka, 2004).

The mechanism by which sodium chlorate induces thyroid gland follicular cell adenomas and carcinomas has not been determined. Chlorate may interfere with iodideuptake indirectly or directly, in a similar manner to chlorine dioxide or perchlorate, respectively, resulting in stimulation of thyroid follicular cell proliferation mediated by TSH secondary to decreases in T 3 

### and T 4 

### . Sodium chlorate was not mutagenic in several strains of Salmonella typhimurium , with or without exogenous metabolic activation, and did not induce chromosomal aberrations in the bone marrow of CD-1 mice (Meier et al., 1985) or micronucleated erythrocytes in peripheral blood of B6C3F 1 

### mice (Table E2). Therefore, it is unlikely that sodium chlorate induces thyroid glandfollicular cell tumors through a direct genotoxic mechanism. However, sodium chlorate could potentially alter genes via oxidative damage.

Investigators at USEPA conducted a 90-day study on sodium chlorate administered in the drinking water to male F344 rats and B6C3F 1 

### mice (Hooth et al., 2001). However, hematology and clinical chemistry were not included in this study. For this reason, a 3-week study of sodium chlorate was initiated by NTP for the collection of hematology and clinical chemistry data on days 4 and 22, the early time points for these data collections inNTP 13-week toxicity studies. Hematotoxicity, primarily methemoglobin formation, is a characteristic symptom of chlorate poisoning in humans and animals, including horses, pigs, cows, sheep, chickens, and dogs (Gregory et al., 1993). Sodium chlorate is a potent oxidizing agent and oxidizes ferrous hemoglobin (Fe 2+

### ) to ferric-hemoglobin (Fe 3+ 

### or methemoglobin), which isunable to bind oxygen. The formation of methemoglobin is prevented by reduction of Fe 3+ 

### to Fe 2+ 

### by methemoglobin reductase. There were minimal effects on hematological parameters in rats in the 3-week sodium chlorate study. The effects were similar to those reported previously (Couri et al. , 1982; Abdel-Rahman et al. , 1985; McCauley et al. , 1995). However, there were no effects on methemoglobin formation in rats or mice in the 3-week studies. Rat and mouse erythrocytes have high rates of methemoglobin reductase compared to human erythrocytes (Smith, 1996), with the mouse having 9.5-fold activity relative to that in human erythrocytes. There was also no evidence of the subsequent kidney damage described in other species, including humans, poisoned with sodium chlorate.

Although hematological effects were not observed in the3-week studies, nonneoplastic lesions of the hematopoietic system were evident in the 2-year rat and mouse studies. The incidences of bone marrow hyperplasia were significantly increased in 1,000 and 2,000 mg/L male rats and all exposed groups of female mice when

### Sodium Chlorate, NTP TR 517 53



### compared to the control groups. Hematopoietic cell proliferation of the spleen was significantly increased in2,000 mg/L male rats. Although the severities were minimal to mild, these lesions were considered to be related to sodium chlorate administration and indicated potential hematotoxicity.

In the 3-week and 2-year studies in mice, there were no chemical-related deaths. Administration of sodium chlorate did not produce any clinical findings of toxicity and had no significant effect on body weights of males or water consumption by mice of either sex. Male mice may have been able to tolerate slightly higher exposureconcentrations. Target organs for sodium chlorate toxicity in the 2-year study included the pancreatic islets and thyroid gland in female mice. The thyroid gland was considered to be a target organ for sodium chloratetoxicity because of the increases in the incidences of follicular cell hypertrophy in 1,000 and 2,000 mg/L female mice; the incidence was significantly increased at 2,000 mg/L. There was no evidence of thyroid gland effects in male or female mice after 3 weeks of exposure.

Several arguments support an association of pancreatic islet neoplasms with sodium chlorate administration. Spontaneous pancreatic islet cell tumors are rare in the B6C3F 1 

### mouse (Boorman and Sills, 1999). In the 2-year mouse study, there was a positive trend in the incidencesof pancreatic islet cell adenoma or carcinoma (combined) in females. The incidences of adenoma and adenoma or carcinoma (combined) in the 2,000 mg/L group exceeded the NTP historical range for drinking water controls. However, the incidences of these lesionswere not increased in male mice. Furthermore, the incidences of pancreatic islet hyperplasia were not increased significantly in exposed mice of either sex. Based on these data, the pancreatic islet cell response in female mice was considered an equivocal finding. Only one other NTP study, 2,4- and 2,6-toluene diisocyanate (NTP, 1986), demonstrated clear or some evidence of carcinogenicity in female rats based on an increased incidence of pancreatic islet adenomas.



# C ONCLUSIONS Under the conditions of this 2-year drinking water study, there was some evidence of carcinogenic activity * of sodium chlorate in male and female F344/N rats based on increased incidences of thyroid gland neoplasms. There was no evidence of carcinogenic activity of sodium chlorate in male B6C3F 1 

### mice exposed to 500, 1,000, or 2,000 mg/L. There was equivocal evidence of carcinogenic activity of sodium chlorate in female B6C3F 1 

### mice based on marginally increased incidences of pancreatic islet neoplasms.

Exposure to sodium chlorate resulted in nonneoplastic lesions in the thyroid gland of male and female rats and female mice, bone marrow of male rats and female mice, and spleen of male rats.

__________ * Explanation of Levels of Evidence of Carcinogenic Activity is on page 9. A summary of the Technical Reports Review Subcommittee comments and public discussion on this Technical Report appears on page 11.

### 54 Sodium Chlorate, NTP TR 517

### 55



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### Sodium Chlorate, NTP TR 517 59



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### 60 Sodium Chlorate, NTP TR 517



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### 61



# APPENDIX A SUMMARY OF LESIONS IN MALE RATS IN THE 2-YEAR DRINKING WATER STUDY OF SODIUM CHLORATE

TABLE 

### A1 Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 TABLE 

### A4 Historical Incidence of Thyroid Gland Neoplasms in Control Male F344/N Rats . . . . . . . . 95 TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

### Sodium Chlorate, NTP TR 517 62



### TABLE 

### A1 Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Accidental death 1 Moribund 10 13 11 14 Natural deaths 3 10 8 8 Survivors

Terminal sacrifice 36 27 31 28

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, colon (48) (47) (44) (49) Intestine large, cecum (47) (46) (43) (47) Intestine small, duodenum (49) (46) (46) (47) Intestine small, jejunum (47) (46) (42) (44) Intestine small, ileum (47) (46) (42) (47) Liver (50) (50) (48) (50)

Hemangiosarcoma 1 (2%) Hepatocellular adenoma 3 (6%) Histiocytic sarcoma 1 (2%) 1 (2%) Mesentery (19) (20) (19) (23)

Carcinoma, metastatic, pancreas 1 (5%) Hemangiosarcoma, metastatic, liver 1 (5%) Histiocytic sarcoma 1 (5%) 1 (5%) Osteosarcoma 1 (5%) Pancreas (49) (49) (49) (50)

Hemangiosarcoma, metastatic, liver 1 (2%) Acinus, adenoma 2 (4%) 1 (2%) Acinus, adenoma, multiple 1 (2%) Acinus, carcinoma 1 (2%) Salivary glands (49) (50) (50) (50)

Fibrosarcoma 1 (2%) Stomach, forestomach (50) (50) (50) (50)

Schwannoma malignant 1 (2%) Squamous cell papilloma 1 (2%) Stomach, glandular (49) (48) (48) (50) Tongue (1) (1) (1) (1)

Sarcoma 1 (100%) Squamous cell carcinoma 1 (100%) Squamous cell papilloma 1 (100%)



### Cardiovascular System Blood vessel (1) (2)

Aorta, osteosarcoma 1 (100%) Heart (50) (50) (50) (50)

Carcinoma, metastatic, Zymbal’s gland 1 (2%) Schwannoma benign 1 (2%)

### 63 Sodium Chlorate, NTP TR 517



### TABLE 

### A1 Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Endocrine System Adrenal cortex (49) (49) (50) (50)

Carcinoma 1 (2%) Osteosarcoma, metastatic, bone 1 (2%) Adrenal medulla (49) (49) (50) (50)

Ganglioneuroma 1 (2%) Pheochromocytoma malignant 3 (6%) 1 (2%) 1 (2%) Pheochromocytoma benign 6 (12%) 3 (6%) 3 (6%) 5 (10%) Bilateral, ganglioneuroma 1 (2%) Bilateral, pheochromocytoma benign 1 (2%) 3 (6%) Islets, pancreatic (50) (49) (49) (50)

Adenoma 3 (6%) 4 (8%) 3 (6%) 5 (10%) Carcinoma 2 (4%) 1 (2%) 2 (4%) Pituitary gland (48) (50) (49) (50)

Pars distalis, adenoma 16 (33%) 15 (30%) 20 (41%) 15 (30%) Pars intermedia, adenoma 1 (2%) 1 (2%) Thyroid gland (47) (44) (43) (47)

Bilateral, C-cell, adenoma, multiple 1 (2%) C-cell, adenoma 9 (19%) 9 (20%) 5 (12%) 9 (19%) C-cell, carcinoma 2 (4%) 2 (5%) 1 (2%) Follicular cell, adenoma 1 (2%) 2 (4%) Follicular cell, carcinoma 4 (9%)



### General Body System Peritoneum (1) (1) Tissue NOS (5) (6) (2) (7)

Abdominal, paraganglioma 1 (20%) Mediastinum, carcinoma, metastatic, Zymbal’s gland 1 (17%) Mediastinum, squamous cell carcinoma, metastatic, lung 1 (17%) Pelvic, leiomyoma 1 (20%) Thoracic, fibroma 1 (14%)



### Genital System Epididymis (50) (50) (50) (50) Preputial gland (48) (49) (50) (50)

Adenoma 1 (2%) 6 (12%) 5 (10%) 5 (10%) Carcinoma 3 (6%) 1 (2%) 2 (4%) 2 (4%) Prostate (50) (49) (50) (50) Seminal vesicle (50) (49) (50) (50) Testes (50) (50) (50) (50)

Bilateral, interstitial cell, adenoma 1 (2%) Bilateral, interstitial cell, adenoma, multiple 40 (80%) 43 (86%) 42 (84%) 39 (78%) Interstitial cell, adenoma 2 (4%) 1 (2%) 2 (4%) Interstitial cell, adenoma, multiple 3 (6%) 5 (10%) 2 (4%) 3 (6%)



### Hematopoietic System Bone marrow (48) (48) (50) (49) Lymph node (34) (24) (26) (34)

Histiocytic sarcoma 1 (3%) Deep cervical, histiocytic sarcoma 1 (3%) Mediastinal, carcinoma, metastatic, Zymbal’s gland 1 (4%) Lymph node, mandibular (3) (2) (3) (4)

### Sodium Chlorate, NTP TR 517 64



### TABLE 

### A1 Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Hematopoietic System (continued) Lymph node, mesenteric (49) (50) (49) (50) Spleen (48) (49) (49) (50)

Histiocytic sarcoma 1 (2%) Capsule, carcinoma, metastatic, pancreas 1 (2%) Thymus (48) (48) (49) (47)

Carcinoma, metastatic, Zymbal’s gland 1 (2%) Thymoma benign 1 (2%)



### Integumentary System Mammary gland (45) (43) (47) (44)

Carcinoma 1 (2%) 1 (2%) Fibroadenoma 2 (4%) 1 (2%) 4 (9%) 4 (9%) Skin (50) (50) (50) (50)

Basal cell carcinoma 1 (2%) 2 (4%) Basal cell carcinoma, multiple 1 (2%) Keratoacanthoma 4 (8%) 2 (4%) 1 (2%) 1 (2%) Trichoepithelioma 1 (2%) Subcutaneous tissue, fibroma 9 (18%) 9 (18%) 4 (8%) 7 (14%) Subcutaneous tissue, fibroma, multiple 1 (2%) 1 (2%) 1 (2%) Subcutaneous tissue, fibrosarcoma 1 (2%) 2 (4%) Subcutaneous tissue, histiocytic sarcoma 1 (2%) Subcutaneous tissue, lipoma 1 (2%) Subcutaneous tissue, neural crest tumor 1 (2%) Subcutaneous tissue, osteosarcoma 1 (2%) Subcutaneous tissue, sarcoma 1 (2%) Subcutaneous tissue, schwannoma malignant 1 (2%) 1 (2%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Osteosarcoma 1 (2%) Periosteum, cranium, fibrosarcoma, metastatic, skin 1 (2%)



### Nervous System Brain (50) (50) (50) (50)

Carcinoma, metastatic, Zymbal’s gland 1 (2%) Glioma malignant 1 (2%)



### Respiratory System Lung (50) (50) (50) (50)

Alveolar/bronchiolar adenoma 1 (2%) 1 (2%) 2 (4%) Alveolar/bronchiolar carcinoma 2 (4%) 2 (4%) 1 (2%) Alveolar/bronchiolar carcinoma, multiple 1 (2%) Carcinoma, metastatic, Zymbal’s gland 1 (2%) Histiocytic sarcoma, metastatic, uncertain primary site 1 (2%) Osteosarcoma, metastatic, bone 1 (2%) Squamous cell carcinoma 1 (2%) Nose (49) (49) (49) (50) Trachea (50) (49) (50) (50)

### 65 Sodium Chlorate, NTP TR 517



### TABLE 

### A1 Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Special Senses System Eye (50) (48) (46) (50)

Retrobulbar, fibrosarcoma, metastatic, skin 1 (2%) Harderian gland (49) (49) (49) (50)

Carcinoma 1 (2%) Zymbal’s gland (1) (1) (3)

Carcinoma 1 (100%) 1 (100%) 1 (33%)



### Urinary System Kidney (47) (46) (49) (49)

Lipoma 1 (2%) 1 (2%) Mesenchymal tumor benign 1 (2%) Renal tubule, adenoma 1 (2%) Urinary bladder (48) (49) (47) (50)



### Systemic Lesions Multiple organsb (50) (50) (50) (50)

Histiocytic sarcoma 1 (2%) 1 (2%) Leukemia mononuclear 13 (26%) 21 (42%) 16 (32%) 23 (46%) Lymphoma malignant 1 (2%) Mesothelioma malignant 1 (2%) 2 (4%) 2 (4%)



### Neoplasm Summary Total animals with primary neoplasms c 49 50 50 50

Total primary neoplasms 135 152 124 150 Total animals with benign neoplasms 48 49 47 47

Total benign neoplasms 100 112 97 108 Total animals with malignant neoplasms 27 32 24 32

Total malignant neoplasms 34 40 27 42 Total animals with metastatic neoplasms 2 5 1

Total metastatic neoplasms 3 10 3 Total animals with malignant neoplasms of uncertain primary site 1 Total animals with uncertain neoplasms benign or malignant 1 Total uncertain neoplasms 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 c Primary neoplasms: all neoplasms except metastatic neoplasms

### Sodium Chlorate, NTP TR 517 66

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon + A + A +++++++++++++++++++++ Intestine large, rectum + A + A +++++++++++++++++++++ Intestine large, cecum + A + A ++++++++A++++++++++++ Intestine small, duodenum + + + A +++++++++++++++++++++ Intestine small, jejunum + A + A ++++++++A++++++++++++ Intestine small, ileum + A + A ++++++++A++++++++++++ Liver +++++++++++++++++++++++++

Histiocytic sarcoma X Mesentery ++++++ ++ ++

Histiocytic sarcoma X Osteosarcoma X Pancreas + + + A +++++++++++++++++++++ Salivary glands + + + A +++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++

Schwannoma malignant X Stomach, glandular + + + A +++++++++++++++++++++ Tongue


### Cardiovascular System Blood vessel +

Aorta, osteosarcoma X Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex + + + A +++++++++++++++++++++

Osteosarcoma, metastatic, bone X Adrenal medulla + + + A +++++++++++++++++++++

Pheochromocytoma malignant X Pheochromocytoma benign X Islets, pancreatic +++++++++++++++++++++++++

Adenoma X Carcinoma Parathyroid gland + + + A +++++++++++++++++++++ Pituitary gland ++++A+++++++A++++++++++++

Pars distalis, adenoma X X X X Thyroid gland + A + A +++++++++A+++++++++++

C-cell, adenoma X X X X X X C-cell, carcinoma Follicular cell, adenoma X


### General Body System Tissue NOS + + +

Abdominal, paraganglioma X Pelvic, leiomyoma X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3445555666667777777777777 

### Number of Days on Study 8260147333990022222233333 1393154066595699999900000

0000000000000000000000000 

### Carcass ID Number 1332330424254411111100000 2910827560401634567812389

+: Tissue examined microscopically M: Missing tissue X: Lesion present A: Autolysis precludes examination. I: Insufficient tissue Blank: Not examined

### 67 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Mesentery + + + + + + + + + 19

Histiocytic sarcoma 1 Osteosarcoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 49 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Schwannoma malignant 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 Tongue + 1


### Cardiovascular System Blood vessel 1

Aorta, osteosarcoma 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49

Osteosarcoma, metastatic, bone 1 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49

Pheochromocytoma malignant X X 3 Pheochromocytoma benign X X X X X 6 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X 3 Carcinoma X X 2 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 48

Pars distalis, adenoma X X X X X X X X X X X X 16 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47

C-cell, adenoma X X X 9 C-cell, carcinoma XX 2 Follicular cell, adenoma 1


### General Body System Tissue NOS + +5

Abdominal, paraganglioma 1 Pelvic, leiomyoma 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000111111111111111144444

0000000000000000000000000 T otal 

### Carcass ID Number 2234111222333334444400022 Tissues/ 5739019189045672347845623 T umors

### Sodium Chlorate, NTP TR 517 68

Genital System Epididymis +++++++++++++++++++++++++ Preputial gland + + + A +++++++++++++++++++++

Adenoma Carcinoma X X Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++

Bilateral, interstitial cell, adenoma, multiple X X X X XXXXXXXXXXXXXXX Interstitial cell, adenoma X Interstitial cell, adenoma, multiple X X


### Hematopoietic System Bone marrow + + A +++++++++++++++++++++ Lymph node +++++++++ +++ +++ + +

Histiocytic sarcoma X Deep cervical, histiocytic sarcoma X Lymph node, mandibular MMMM + + MMMMMMMMMMMMMMM + MMM Lymph node, mesenteric + + + M +++++++++++++++++++++ Spleen + A ++++++++++A++++++++++++

Histiocytic sarcoma X Thymus + + + A + + + +M+ + + + + + + + + + + + + + + +


### Integumentary System Mammary gland M + + A + + + +M+ + + + + + + + + + + + + + + +

Fibroadenoma Skin +++++++++++++++++++++++++

Keratoacanthoma X X X Trichoepithelioma X Subcutaneous tissue, fibroma X X X X X Subcutaneous tissue, fibrosarcoma X Subcutaneous tissue, neural crest tumor


### Musculoskeletal System Bone +++++++++++++++++++++++++

Osteosarcoma X Skeletal muscle


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + + Spinal cord + + 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3445555666667777777777777 

### Number of Days on Study 8260147333990022222233333 1393154066595699999900000

0000000000000000000000000 

### Carcass ID Number 1332330424254411111100000 2910827560401634567812389

### 69 Sodium Chlorate, NTP TR 517

Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + M 48

Adenoma X 1 Carcinoma X 3 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50

Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X X X 40 Interstitial cell, adenoma X 2 Interstitial cell, adenoma, multiple X 3


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 48 Lymph node + + + + + + + + + + + + + + + + + 34

Histiocytic sarcoma 1 Deep cervical, histiocytic sarcoma 1 Lymph node, mandibular MMMMMMMMMMMMMMMMMMMMMMMMM 3 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 49 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 48

Histiocytic sarcoma 1 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Integumentary System Mammary gland + + M + + + + + + + + + M + + + + + + + + + + + + 45

Fibroadenoma X X 2 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Keratoacanthoma X 4 Trichoepithelioma 1 Subcutaneous tissue, fibroma X X X X 9 Subcutaneous tissue, fibrosarcoma 1 Subcutaneous tissue, neural crest tumor X 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma 1 Skeletal muscle + 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 2 Spinal cord 2 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000111111111111111144444

0000000000000000000000000 T otal 

### Carcass ID Number 2234111222333334444400022 Tissues/ 5739019189045672347845623 T umors

### Sodium Chlorate, NTP TR 517 70

Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma Alveolar/bronchiolar carcinoma Alveolar/bronchiolar carcinoma, multiple Histiocytic sarcoma, metastatic,

uncertain primary site X Osteosarcoma, metastatic, bone X Nose 

### + + A + + + + + + + + + + + + + + + + + + + + + + Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland + + + A +++++++++++++++++++++

Carcinoma


### Urinary System Kidney + A + A ++++++++A++++++++++++ Urinary bladder + A + A +++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X Leukemia mononuclear X X X X X X X X Lymphoma malignant X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3445555666667777777777777 

### Number of Days on Study 8260147333990022222233333 1393154066595699999900000

0000000000000000000000000 

### Carcass ID Number 1332330424254411111100000 2910827560401634567812389

### 71 Sodium Chlorate, NTP TR 517

Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 1 Alveolar/bronchiolar carcinoma XX 2 Alveolar/bronchiolar carcinoma, multiple X 1 Histiocytic sarcoma, metastatic,

uncertain primary site 1 Osteosarcoma, metastatic, bone 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Carcinoma X 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 47 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Leukemia mononuclear X X X X X 13 Lymphoma malignant 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000111111111111111144444

0000000000000000000000000 T otal 

### Carcass ID Number 2234111222333334444400022 Tissues/ 5739019189045672347845623 T umors

### Sodium Chlorate, NTP TR 517 72

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon ++++A+A+A++++++++++++++++ Intestine large, rectum ++++A+A+A++++++++++++++++ Intestine large, cecum + + A + A + A + A ++++++++++++++++ Intestine small, duodenum + + A + A + A + A ++++++++++++++++ Intestine small, jejunum + + A + A + A + A ++++++++++++++++ Intestine small, ileum + + A + A + A + A ++++++++++++++++ Liver +++++++++++++++++++++++++

Hemangiosarcoma Hepatocellular adenoma X Histiocytic sarcoma Mesentery + + + + + + + + + + +

Carcinoma, metastatic, pancreas Hemangiosarcoma, metastatic, liver Histiocytic sarcoma Pancreas ++++++A++++++++++++++++++

Hemangiosarcoma, metastatic, liver Acinus, adenoma X X Acinus, adenoma, multiple Acinus, carcinoma Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular + + A + + + A ++++++++++++++++++ Tongue +

Squamous cell carcinoma X Tooth +


### Cardiovascular System Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex ++++++A++++++++++++++++++ Adrenal medulla ++++++A++++++++++++++++++

Ganglioneuroma X Pheochromocytoma benign X Bilateral, pheochromocytoma benign X Islets, pancreatic ++++++A++++++++++++++++++

Adenoma XX X Carcinoma Parathyroid gland +++++++++++++++++++++++++ Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma X X X X Pars intermedia, adenoma X Thyroid gland + + A + A + A + A + + A ++++++++++A++

C-cell, adenoma X X X C-cell, carcinoma 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

5555566666666666677777777 

### Number of Days on Study 4567801135666799901112222 2524254982038235934441699

0000000000000000000000000 

### Carcass ID Number 5877986656568959858896655 2518236244550119488943937

### 73 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma X 1 Hepatocellular adenoma X X 3 Histiocytic sarcoma X 1 Mesentery + + + + + + + + + 20

Carcinoma, metastatic, pancreas X 1 Hemangiosarcoma, metastatic, liver X 1 Histiocytic sarcoma X 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hemangiosarcoma, metastatic, liver X 1 Acinus, adenoma 2 Acinus, adenoma, multiple X 1 Acinus, carcinoma X 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48 Tongue 1

Squamous cell carcinoma 1 Tooth 1


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49

Ganglioneuroma 1 Pheochromocytoma benign XX 3 Bilateral, pheochromocytoma benign 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X 4 Carcinoma X 1 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pars distalis, adenoma X X X X X X X X X X X 15 Pars intermedia, adenoma 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 44

C-cell, adenoma X X X X X X 9 C-cell, carcinoma X X 2 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000000000011111

0000000000000000000100000 T otal 

### Carcass ID Number 5777888999566777999066778 Tissues/ 9234127035678567678001096 T umors

### Sodium Chlorate, NTP TR 517 74

General Body System Peritoneum + Tissue NOS + + + + + +

Mediastinum, carcinoma, metastatic,

Zymbal’s gland X Mediastinum, squamous cell carcinoma,

metastatic, lung X


### Genital System Epididymis +++++++++++++++++++++++++ Penis + Preputial gland ++++++A++++++++++++++++++

Adenoma X Carcinoma Prostate ++++++A++++++++++++++++++ Seminal vesicle ++++++A++++++++++++++++++ Testes +++++++++++++++++++++++++

Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X Interstitial cell, adenoma X Interstitial cell, adenoma, multiple X X X X


### Hematopoietic System Bone marrow ++++++++A++A+++++++++++++ Lymph node + ++++ + ++ ++++ ++

Mediastinal, carcinoma, metastatic,

Zymbal’s gland X Lymph node, mandibular MMMMMMMMMMMMMMMMM + MMMMMMM Lymph node, mesenteric +++++++++++++++++++++++++ Spleen ++++++A++++++++++++++++++

Capsule, carcinoma, metastatic, Pancreas Thymus + + + + + + + + + + + + + +MI + + + + + + + + +

Carcinoma, metastatic, Zymbal’s gland X


### Integumentary System Mammary gland + M + M A M M + + + +M+ + + + + +M+ + + + + +

Carcinoma X Fibroadenoma Skin +++++++++++++++++++++++++

Basal cell carcinoma Basal cell carcinoma, multiple Keratoacanthoma X X Subcutaneous tissue, fibroma X X X Subcutaneous tissue, fibroma, multiple X Subcutaneous tissue, fibrosarcoma X Subcutaneous tissue, histiocytic sarcoma Subcutaneous tissue, lipoma X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

5555566666666666677777777 

### Number of Days on Study 4567801135666799901112222 2524254982038235934441699

0000000000000000000000000 

### Carcass ID Number 5877986656568959858896655 2518236244550119488943937

### 75 Sodium Chlorate, NTP TR 517

General Body System Peritoneum 1 Tissue NOS 6

Mediastinum, carcinoma, metastatic,

Zymbal’s gland 1 Mediastinum, squamous cell carcinoma,

metastatic, lung 1


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Penis + 2 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X X X X 6 Carcinoma X 1 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 49 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 49 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50

Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X X X X X X 43 Interstitial cell, adenoma 1 Interstitial cell, adenoma, multiple X 5


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 48 Lymph node + + + + + + + + + + 24

Mediastinal, carcinoma, metastatic,

Zymbal’s gland 1 Lymph node, mandibular MMMMMMMMMMMMMMMMMMMM + MMMM 2 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49

Capsule, carcinoma, metastatic, Pancreas X 1 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48

Carcinoma, metastatic, Zymbal’s gland 1


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 43

Carcinoma 1 Fibroadenoma X 1 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Basal cell carcinoma X 1 Basal cell carcinoma, multiple X 1 Keratoacanthoma 2 Subcutaneous tissue, fibroma X X X X X X 9 Subcutaneous tissue, fibroma, multiple 1 Subcutaneous tissue, fibrosarcoma X 2 Subcutaneous tissue, histiocytic sarcoma X 1 Subcutaneous tissue, lipoma 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000000000011111

0000000000000000000100000 T otal 

### Carcass ID Number 5777888999566777999066778 Tissues/ 9234127035678567678001096 T umors

### Sodium Chlorate, NTP TR 517 76

Musculoskeletal System Bone +++++++++++++++++++++++++

Periosteum, cranium, fibrosarcoma,

metastatic, skin X


### Nervous System Brain +++++++++++++++++++++++++

Glioma malignant X Peripheral nerve + Spinal cord +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma Alveolar/bronchiolar carcinoma X Squamous cell carcinoma X Nose ++++++A++++++++++++++++++ Trachea ++++++A++++++++++++++++++


### Special Senses System Eye + + + + A + A + + + + + + + + + + + + + + + + + +

Retrobulbar, fibrosarcoma, metastatic, skin X Harderian gland ++++++A++++++++++++++++++ Lacrimal gland + Zymbal’s gland +

Carcinoma X


### Urinary System Kidney ++++++A+A++A++++++++++A++

Lipoma Renal tubule, adenoma X Urinary bladder ++++++A++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++ Histiocytic sarcoma

Leukemia mononuclear X X X X X X XXXXX XX X Mesothelioma malignant X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

5555566666666666677777777 

### Number of Days on Study 4567801135666799901112222 2524254982038235934441699

0000000000000000000000000 

### Carcass ID Number 5877986656568959858896655 2518236244550119488943937

### 77 Sodium Chlorate, NTP TR 517

Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Periosteum, cranium, fibrosarcoma,

metastatic, skin 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50

Glioma malignant 1 Peripheral nerve 1 Spinal cord 1


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 1 Alveolar/bronchiolar carcinoma X 2 Squamous cell carcinoma 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 48

Retrobulbar, fibrosarcoma, metastatic, skin 1 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lacrimal gland 1 Zymbal’s gland 1

Carcinoma 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 46

Lipoma X 1 Renal tubule, adenoma 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 1 Leukemia mononuclear X X X X X X X 21 Mesothelioma malignant 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000000000011111

0000000000000000000100000 T otal 

### Carcass ID Number 5777888999566777999066778 Tissues/ 9234127035678567678001096 T umors

### Sodium Chlorate, NTP TR 517 78

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon + A + A A + A A + + + A +++++++++++++ Intestine large, rectum + + + + + +AA+ + +A+ + + + + + + + + + + + + Intestine large, cecum + A A + A + A A + + + A + + A ++++++++++ Intestine small, duodenum + A + + + +AA+ + + + + +A+ + + + + + + + + + Intestine small, jejunum + A A A + + A A A + + A + + A ++++++++++ Intestine small, ileum + AAAA+AA+ + +A+ +A ++++++++++ Liver + A ++++A++++++++++++++++++ Mesentery + + +++++ + + ++ Pancreas + A +++++++++++++++++++++++

Acinus, adenoma X Salivary glands +++++++++++++++++++++++++

Fibrosarcoma Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular + A ++++A++++++++++++++++++ Tongue +

Sarcoma X Tooth


### Cardiovascular System Blood vessel + + Heart +++++++++++++++++++++++++

Schwannoma benign X


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma malignant X Pheochromocytoma benign X X Islets, pancreatic + A +++++++++++++++++++++++

Adenoma X Parathyroid gland +++++++++++++++++++++++++ Pituitary gland + M +++++++++++++++++++++++

Pars distalis, adenoma X X X X X X X X X X X Thyroid gland + A A A + + A A + + + A + + A ++++++++++

Bilateral, C-cell, adenoma, multiple C-cell, adenoma X X X


### General Body System Peritoneum + Tissue NOS +


### Genital System Epididymis +++++++++++++++++++++++++ Preputial gland +++++++++++++++++++++++++

Adenoma X X X Carcinoma X X Prostate +++++++++++++++++++++++++ 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

2455566666666667777777777 

### Number of Days on Study 0766700246677990012222222 9516657670735583341999999



### Carcass ID Number 1111111111111111111111111 0401342400113101300222224 6572645842594786031234893

### 79 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 43 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 42 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 42 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 48 Mesentery + + + + + + + + 19 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49

Acinus, adenoma 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50

Fibrosarcoma X 1 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48 Tongue 1

Sarcoma 1 Tooth + 1


### Cardiovascular System Blood vessel 2 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50

Schwannoma benign 1


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma malignant 1 Pheochromocytoma benign X 3 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X 3 Parathyroid gland M + + + M + M + + + + + + + + + + + + + + + + + + 47 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Pars distalis, adenoma X X X X X X X X X 20 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 43

Bilateral, C-cell, adenoma, multiple X 1 C-cell, adenoma X X 5


### General Body System Peritoneum 1 Tissue NOS + 2


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma XX 5 Carcinoma 2 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000000011111111111111

1111111111111111111111111 T otal 

### Carcass ID Number 1133334444500111222233344 Tissues/ 3412350129059018016778967 T umors

### Sodium Chlorate, NTP TR 517 80

Genital System (continued) Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++

Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X Interstitial cell, adenoma, multiple X


### Hematopoietic system Bone marrow +++++++++++++++++++++++++ Lymph node + + + + + + + +++++ ++ + Lymph node, mandibular MMMM + MMMM + MMMM + MMMMMMMMMM Lymph node, mesenteric +++++++++++++++++++++++++ Spleen ++++++A++++++++++++++++++ Thymus +++++++++I+++++++++++++++

Thymoma benign


### Integumentary system Mammary gland + + + + + + + +M+ + + +M+ + + + + + + + + + +

Carcinoma Fibroadenoma X X Skin +++++++++++++++++++++++++

Keratoacanthoma Subcutaneous tissue, fibroma X X Subcutaneous tissue, fibroma, multiple X Subcutaneous tissue, sarcoma X Subcutaneous tissue, schwannoma malignant X


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + + + + Spinal cord + + + +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X Nose ++++++A++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + M + A + + A A + + + + + + + + + + + + + + + + + Harderian gland + A +++++++++++++++++++++++ Lacrimal gland + Zymbal’s gland +

Carcinoma X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

2455566666666667777777777 

### Number of Days on Study 0766700246677990012222222 9516657670735583341999999

1111111111111111111111111 

### Carcass ID Number 0401342400113101300222224 6572645842594786031234893

### 81 Sodium Chlorate, NTP TR 517

Genital System (continued) Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50

Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X X X X X 42 Interstitial cell, adenoma, multiple X 2


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lymph node + + + + + + + + + + + 26 Lymph node, mandibular MMMMMMMMMMMMMMMMMMMMMMMMM 3 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + I + + + + + 49 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 49

Thymoma benign X 1


### Integumentary System Mammary gland + + + + + M + + + + + + + + + + + + + + + + + + + 47

Carcinoma X 1 Fibroadenoma XX 4 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Keratoacanthoma X 1 Subcutaneous tissue, fibroma X X 4 Subcutaneous tissue, fibroma, multiple 1 Subcutaneous tissue, sarcoma 1 Subcutaneous tissue, schwannoma malignant 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle + 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 4 Spinal cord + 5


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 2 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 46 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lacrimal gland 1 Zymbal’s gland 1

Carcinoma 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000000011111111111111

1111111111111111111111111 T otal 

### Carcass ID Number 1133334444500111222233344 Tissues/ 3412350129059018016778967 T umors

### Sodium Chlorate, NTP TR 517 82

Urinary System Kidney + A +++++++++++++++++++++++

Mesenchymal tumor benign X Urinary bladder + A + + + +AA+ + + + + + + + + + + + + + + + +


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Leukemia mononuclear X X X X X X X X X X X Mesothelioma malignant X X 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

2455566666666667777777777 

### Number of Days on Study 0766700246677990012222222 9516657670735583341999999

1111111111111111111111111 

### Carcass ID Number 0401342400113101300222224 6572645842594786031234893

### 83 Sodium Chlorate, NTP TR 517

Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49

Mesenchymal tumor benign 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 47


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Leukemia mononuclear X X X X X 16 Mesothelioma malignant 2 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000000011111111111111

1111111111111111111111111 T otal 

### Carcass ID Number 1133334444500111222233344 Tissues/ 3412350129059018016778967 T umors

### Sodium Chlorate, NTP TR 517 84

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon + + A ++++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum + + A + A +++++++A++++++++++++ Intestine small, duodenum + + A ++++A+++++++++++++A+++ Intestine small, jejunum A + A + A + + A ++++A++++++++A+++ Intestine small, ileum + + A +++++++++++++A++++A+++ Liver +++++++++++++++++++++++++ Mesentery +++++++ + +++ + ++++ Pancreas +++++++++++++++++++++++++ Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++

Squamous cell papilloma Stomach, glandular +++++++++++++++++++++++++ Tongue

Squamous cell papilloma


### Cardiovascular System Heart +++++++++++++++++++++++++

Carcinoma, metastatic, Zymbal’s gland X


### Endocrine System Adrenal cortex +++++++++++++++++++++++++

Carcinoma Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma malignant Pheochromocytoma benign X X Bilateral, ganglioneuroma X Bilateral, pheochromocytoma benign X Islets, pancreatic +++++++++++++++++++++++++

Adenoma X Carcinoma X Parathyroid gland +++++++++++++++++++++++++ Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma X X X X X X X X X Pars intermedia, adenoma X Thyroid gland + + A + A ++++++++++++++++A+++

C-cell, adenoma X C-cell, carcinoma X Follicular cell, adenoma Follicular cell, carcinoma X


### General Body System Tissue NOS + + + + +

Thoracic, fibroma 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4445556666666666777777777 

### Number of Days on Study 4684693455777899000112222 3525209411128199133080999

1111111111111111111111111 

### Carcass ID Number 9858665556797658557877666 2477795491391586126584023

### 85 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 Mesentery + + + + + + + 23 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell papilloma X 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 Tongue + 1

Squamous cell papilloma X 1


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, Zymbal’s gland 1


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma X 1 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma malignant X 1 Pheochromocytoma benign X X X 5 Bilateral, ganglioneuroma 1 Bilateral, pheochromocytoma benign X X 3 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X X 5 Carcinoma X 2 Parathyroid gland + + + + + + + + + + + + + + + + M + + + + + + + + 49 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pars distalis, adenoma X X X X X X 15 Pars intermedia, adenoma 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47

C-cell, adenoma X X X X X X X X 9 C-cell, carcinoma 1 Follicular cell, adenoma X X 2 Follicular cell, carcinoma X X X 4


### General Body System Tissue NOS + + 7

Thoracic, fibroma X 1 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000001111111111

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 T otal 

### Carcass ID Number 6788899999778885566779990 Tissues/ 4212301678090893668573450 T umors

### Sodium Chlorate, NTP TR 517 86

Genital System Epididymis +++++++++++++++++++++++++ Preputial gland +++++++++++++++++++++++++

Adenoma X X Carcinoma X Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++

Bilateral, interstitial cell, adenoma Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X Interstitial cell, adenoma X X Interstitial cell, adenoma, multiple X X


### Hematopoietic System Bone marrow + + + A +++++++++++++++++++++ Lymph node ++++ +++ ++++++++ ++++ Lymph node, mandibular M M + MMMMM + MMMMMMMMMMMMMMMM Lymph node, mesenteric +++++++++++++++++++++++++ Spleen +++++++++++++++++++++++++ Thymus + + + I + + + + + + + + + + + + + + + +M+M+ +


### Integumentary system Mammary gland + + + + + + + M + + + + M + MM + + M + + + + + +

Fibroadenoma X Skin +++++++++++++++++++++++++

Basal cell carcinoma Keratoacanthoma X Subcutaneous tissue, fibroma X X X Subcutaneous tissue, fibroma, multiple Subcutaneous tissue, osteosarcoma X Subcutaneous tissue, schwannoma malignant


### Musculoskeletal System Bone +++++++++++++++++++++++++


### Nervous System Brain +++++++++++++++++++++++++

Carcinoma, metastatic, Zymbal’s gland X Peripheral nerve + + + Spinal cord + + +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar carcinoma Carcinoma, metastatic, Zymbal’s gland X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++ 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4445556666666666777777777 

### Number of Days on Study 4684693455777899000112222 3525209411128199133080999

1111111111111111111111111 

### Carcass ID Number 9858665556797658557877666 2477795491391586126584023

### 87 Sodium Chlorate, NTP TR 517

Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X 5 Carcinoma X 2 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50

Bilateral, interstitial cell, adenoma X 1 Bilateral, interstitial cell, adenoma, multiple X X X X X X X X X X X X X X X X X X X X X X 39 Interstitial cell, adenoma 2 Interstitial cell, adenoma, multiple X 3


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lymph node ++++++++ + + + + + + + 34 Lymph node, mandibular MMMMMMMM + MMMMMMMMM + MMMMMM 4 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 47


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + M 44

Fibroadenoma X X X 4 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Basal cell carcinoma X X 2 Keratoacanthoma 1 Subcutaneous tissue, fibroma X X X X 7 Subcutaneous tissue, fibroma, multiple X 1 Subcutaneous tissue, osteosarcoma 1 Subcutaneous tissue, schwannoma malignant X 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, Zymbal’s gland 1 Peripheral nerve 3 Spinal cord + + 5


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar carcinoma X 1 Carcinoma, metastatic, Zymbal’s gland 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000001111111111

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 T otal 

### Carcass ID Number 6788899999778885566779990 Tissues/ 4212301678090893668573450 T umors

### Sodium Chlorate, NTP TR 517 88

Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++ Lacrimal gland + Zymbal’s gland + + +

Carcinoma X


### Urinary System Kidney + + + A +++++++++++++++++++++

Lipoma Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Leukemia mononuclear XXXX XX X X XX X XX X Mesothelioma malignant 

### TABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4445556666666666777777777 

### Number of Days on Study 4684693455777899000112222 3525209411128199133080999

1111111111111111111111111 

### Carcass ID Number 9858665556797658557877666 2477795491391586126584023

### 89 Sodium Chlorate, NTP TR 517

Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lacrimal gland 1 Zymbal’s gland 3

Carcinoma 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49

Lipoma X 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Leukemia mononuclear X X X X X X X X X 23 Mesothelioma malignant X X 2 

### T ABLE 

### A2 Individual Animal Tumor Pathology of Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2222222222333333333333333 9999999999000001111111111

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 T otal 

### Carcass ID Number 6788899999778885566779990 Tissues/ 4212301678090893668573450 T umors

### Sodium Chlorate, NTP TR 517 90



### TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Adrenal Medulla: Benign Pheochromocytoma Overall rate a 6/49 (12%) 4/49 (8%) 3/50 (6%) 8/50 (16%) Adjusted rateb 13.8% 9.1% 6.8% 18.3% Terminal rate c 6/36 (17%) 3/27 (11%) 2/31 (7%) 5/28 (18%) First incidence (days) 729 (T) 555 698 699 Poly-3 testd P=0.229 P=0.364N P=0.236N P=0.391


### Adrenal Medulla: Malignant Pheochromocytoma Overall rate 3/49 (6%) 0/49 (0%) 1/50 (2%) 1/50 (2%) Adjusted rate 6.9% 0.0% 2.3% 2.3% Terminal rate 3/36 (8%) 0/27 (0%) 0/31 (0%) 1/28 (4%) First incidence (days) 729 (T) —e 667 729 (T) Poly-3 test P=0.404N P=0.119N P=0.300N P=0.305N


### Adrenal Medulla: Benign or Malignant Pheochromocytoma Overall rate 9/49 (18%) 4/49 (8%) 4/50 (8%) 9/50 (18%) Adjusted rate 20.7% 9.1% 9.1% 20.6% Terminal rate 9/36 (25%) 3/27 (11%) 2/31 (7%) 6/28 (21%) First incidence (days) 729 (T) 555 667 699 Poly-3 test P=0.331 P=0.110N P=0.107N P=0.598N


### Liver: Hepatocellular Adenoma Overall rate 0/50 (0%) 3/50 (6%) 0/48 (0%) 0/50 (0%) Adjusted rate 0.0% 6.9% 0.0% 0.0% Terminal rate 0/36 (0%) 3/27 (11%) 0/31 (0%) 0/28 (0%) First incidence (days) — 729 (T) — — Poly-3 test P=0.141N P=0.119 —f

— 

### Lung: Alveolar/bronchiolar Carcinoma Overall rate 3/50 (6%) 2/50 (4%) 0/50 (0%) 1/50 (2%) Adjusted rate 6.9% 4.6% 0.0% 2.3% Terminal rate 3/36 (8%) 2/27 (7%) 0/31 (0%) 1/28 (4%) First incidence (days) 729 (T) 729 (T) — 729 (T) Poly-3 test P=0.159N P=0.499N P=0.118N P=0.307N


### Lung: Alveolar/bronchiolar Adenoma or Carcinoma Overall rate 4/50 (8%) 3/50 (6%) 2/50 (4%) 1/50 (2%) Adjusted rate 9.2% 6.9% 4.6% 2.3% Terminal rate 4/36 (11%) 3/27 (11%) 2/31 (7%) 1/28 (4%) First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) Poly-3 test P=0.119N P=0.499N P=0.337N P=0.180N


### Mammary Gland: Fibroadenoma Overall rate 2/50 (4%) 1/50 (2%) 4/50 (8%) 4/50 (8%) Adjusted rate 4.6% 2.3% 9.0% 9.2% Terminal rate 2/36 (6%) 1/27 (4%) 3/31 (10%) 3/28 (11%) First incidence (days) 729 (T) 729 (T) 566 718 Poly-3 test P=0.118 P=0.499N P=0.343 P=0.334


### Mammary Gland: Fibroadenoma or Carcinoma Overall rate 2/50 (4%) 2/50 (4%) 5/50 (10%) 4/50 (8%) Adjusted rate 4.6% 4.6% 11.3% 9.2% Terminal rate 2/36 (6%) 1/27 (4%) 4/31 (13%) 3/28 (11%) First incidence (days) 729 (T) 726 566 718 Poly-3 test P=0.173 P=0.693N P=0.221 P=0.334

### 91 Sodium Chlorate, NTP TR 517

Pancreas: Adenoma Overall rate 0/49 (0%) 3/49 (6%) 1/49 (2%) 0/50 (0%) Adjusted rate 0.0% 6.9% 2.3% 0.0% Terminal rate 0/36 (0%) 3/27 (11%) 1/31 (3%) 0/28 (0%) First incidence (days) — 729 (T) 729 (T) — Poly-3 test P=0.214N P=0.118 P=0.500 —



### Pancreas: Adenoma or Carcinoma Overall rate 0/49 (0%) 4/49 (8%) 1/49 (2%) 0/50 (0%) Adjusted rate 0.0% 9.3% 2.3% 0.0% Terminal rate 0/36 (0%) 4/27 (15%) 1/31 (3%) 0/28 (0%) First incidence (days) — 729 (T) 729 (T) — Poly-3 test P=0.138N P=0.059 P=0.500 —



### Pancreatic Islets: Adenoma Overall rate 3/50 (6%) 4/49 (8%) 3/49 (6%) 5/50 (10%) Adjusted rate 6.9% 9.2% 6.9% 11.5% Terminal rate 3/36 (8%) 2/27 (7%) 2/31 (7%) 4/28 (14%) First incidence (days) 729 (T) 663 714 681 Poly-3 test P=0.335 P=0.498 P=0.661 P=0.355



### Pancreatic Islets: Adenoma or Carcinoma Overall rate 5/50 (10%) 5/49 (10%) 3/49 (6%) 7/50 (14%) Adjusted rate 11.4% 11.5% 6.9% 16.0% Terminal rate 5/36 (14%) 3/27 (11%) 2/31 (7%) 5/28 (18%) First incidence (days) 729 (T) 663 714 681 Poly-3 test P=0.331 P=0.629 P=0.358N P=0.379


### Pituitary Gland (Pars Distalis): Adenoma Overall rate 16/48 (33%) 15/50 (30%) 20/49 (41%) 15/50 (30%) Adjusted rate 37.2% 33.8% 43.8% 33.6% Terminal rate 13/36 (36%) 11/27 (41%) 12/31 (39%) 8/28 (29%) First incidence (days) 630 652 561 651 Poly-3 test P=0.516N P=0.457N P=0.337 P=0.449N


### Preputial Gland: Adenoma Overall rate 1/48 (2%) 6/49 (12%) 5/50 (10%) 5/50 (10%) Adjusted rate 2.4% 13.7% 11.3% 11.3% Terminal rate 1/35 (3%) 5/27 (19%) 3/31 (10%) 3/28 (11%) First incidence (days) 729 (T) 542 626 465 Poly-3 test P=0.287 P=0.060 P=0.111 P=0.111


### Preputial Gland: Carcinoma Overall rate 3/48 (6%) 1/49 (2%) 2/50 (4%) 2/50 (4%) Adjusted rate 7.0% 2.3% 4.6% 4.6% Terminal rate 2/35 (6%) 1/27 (4%) 1/31 (3%) 1/28 (4%) First incidence (days) 511 729 (T) 721 590 Poly-3 test P=0.555N P=0.304N P=0.492N P=0.491N


### Preputial Gland: Adenoma or Carcinoma Overall rate 4/48 (8%) 7/49 (14%) 7/50 (14%) 6/50 (12%) Adjusted rate 9.3% 16.0% 15.8% 13.4% Terminal rate 3/35 (9%) 6/27 (22%) 4/31 (13%) 3/28 (11%) First incidence (days) 511 542 626 465 Poly-3 test P=0.461 P=0.270 P=0.276 P=0.395 

### TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 92

Skin: Keratoacanthoma Overall rate 4/50 (8%) 2/50 (4%) 1/50 (2%) 1/50 (2%) Adjusted rate 9.1% 4.6% 2.3% 2.3% Terminal rate 2/36 (6%) 0/27 (0%) 1/31 (3%) 0/28 (0%) First incidence (days) 636 695 729 (T) 718 Poly-3 test P=0.132N P=0.338N P=0.181N P=0.183N


### Skin: Keratoacanthoma, Trichoepithelioma, or Basal Cell Carcinoma Overall rate 5/50 (10%) 4/50 (8%) 1/50 (2%) 3/50 (6%) Adjusted rate 11.3% 9.1% 2.3% 6.9% Terminal rate 3/36 (8%) 2/27 (7%) 1/31 (3%) 2/28 (7%) First incidence (days) 636 695 729 (T) 718 Poly-3 test P=0.224N P=0.502N P=0.103N P=0.364N



### Skin: Fibroma Overall rate 9/50 (18%) 10/50 (20%) 5/50 (10%) 8/50 (16%) Adjusted rate 20.5% 22.1% 11.3% 18.2% Terminal rate 7/36 (19%) 6/27 (22%) 3/31 (10%) 5/28 (18%) First incidence (days) 695 555 607 651 Poly-3 test P=0.300N P=0.528 P=0.187N P=0.498N



### Skin: Fibroma, Fibrosarcoma, or Sarcoma Overall rate 10/50 (20%) 12/50 (24%) 6/50 (12%) 8/50 (16%) Adjusted rate 22.3% 26.4% 13.3% 18.2% Terminal rate 7/36 (19%) 7/27 (26%) 3/31 (10%) 5/28 (18%) First incidence (days) 381 555 209 651 Poly-3 test P=0.180N P=0.420 P=0.198N P=0.412N



### Testes: Adenoma Overall rate 45/50 (90%) 49/50 (98%) 44/50 (88%) 45/50 (90%) Adjusted rate 93.8% 99.1% 93.3% 92.8% Terminal rate 34/36 (94%) 27/27 (100%) 30/31 (97%) 27/28 (96%) First incidence (days) 469 542 561 443 Poly-3 test P=0.198N P=0.164 P=0.644N P=0.593N


### Thyroid Gland (C-Cell): Adenoma Overall rate 9/47 (19%) 9/44 (20%) 6/43 (14%) 9/47 (19%) Adjusted rate 21.1% 22.2% 15.0% 21.6% Terminal rate 7/36 (19%) 7/27 (26%) 4/31 (13%) 8/28 (29%) First incidence (days) 636 619 660 718 Poly-3 test P=0.485N P=0.553 P=0.334N P=0.583


### Thyroid Gland (C-Cell): Carcinoma Overall rate 2/47 (4%) 2/44 (5%) 0/43 (0%) 1/47 (2%) Adjusted rate 4.7% 5.0% 0.0% 2.4% Terminal rate 2/36 (6%) 2/27 (7%) 0/31 (0%) 1/28 (4%) First incidence (days) 729 (T) 729 (T) — 729 (T) Poly-3 test P=0.254N P=0.673 P=0.251N P=0.505N


### Thyroid Gland (C-Cell): Adenoma or Carcinoma Overall rate 11/47 (23%) 11/44 (25%) 6/43 (14%) 10/47 (21%) Adjusted rate 25.7% 27.2% 15.0% 23.9% Terminal rate 9/36 (25%) 9/27 (33%) 4/31 (13%) 9/28 (32%) First incidence (days) 636 619 660 718 Poly-3 test P=0.339N P=0.539 P=0.174N P=0.524N 

### TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 93 Sodium Chlorate, NTP TR 517

Thyroid Gland (Follicular Cell): Carcinoma Overall rate 0/47 (0%) 0/44 (0%) 0/43 (0%) 4/47 (9%) Adjusted rate 0.0% 0.0% 0.0% 9.6% Terminal rate 0/36 (0%) 0/27 (0%) 0/31 (0%) 4/28 (14%) First incidence (days) — — — 729 (T) Poly-3 test P=0.003 — — P=0.058


### Thyroid Gland (Follicular Cell): Adenoma or Carcinoma Overall rate 1/47 (2%) 0/44 (0%) 0/43 (0%) 6/47 (13%) Adjusted rate 2.4% 0.0% 0.0% 14.4% Terminal rate 0/36 (0%) 0/27 (0%) 0/31 (0%) 6/28 (21%) First incidence (days) 705 — — 729 (T) Poly-3 test P=0.002 P=0.512N P=0.513N P=0.052


### All Organs: Mononuclear Cell Leukemia Overall rate 13/50 (26%) 21/50 (42%) 16/50 (32%) 23/50 (46%) Adjusted rate 28.5% 45.0% 35.0% 48.4% Terminal rate 8/36 (22%) 8/27 (30%) 8/31 (26%) 10/28 (36%) First incidence (days) 545 574 561 465 Poly-3 test P=0.111 P=0.074 P=0.328 P=0.036


### All Organs: Osteosarcoma Overall rate 3/50 (6%) 0/50 (0%) 0/50 (0%) 1/50 (2%) Adjusted rate 6.7% 0.0% 0.0% 2.3% Terminal rate 0/36 (0%) 0/27 (0%) 0/31 (0%) 1/28 (4%) First incidence (days) 469 — — 729 (T) Poly-3 test P=0.344N P=0.122N P=0.122N P=0.315N


### All Organs: Benign Neoplasms Overall rate 48/50 (96%) 49/50 (98%) 47/50 (94%) 47/50 (94%) Adjusted rate 99.3% 99.1% 97.7% 96.3% Terminal rate 36/36 (100%) 27/27 (100%) 31/31 (100%) 27/28 (96%) First incidence (days) 469 542 561 443 Poly-3 test P=0.128N P=0.955N P=0.608N P=0.346N


### All Organs: Malignant Neoplasms Overall rate 27/50 (54%) 32/50 (64%) 24/50 (48%) 32/50 (64%) Adjusted rate 55.4% 66.7% 49.7% 66.5% Terminal rate 16/36 (44%) 14/27 (52%) 11/31 (36%) 16/28 (57%) First incidence (days) 381 562 209 465 Poly-3 test P=0.365 P=0.175 P=0.360N P=0.181 

### TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 94

All Organs: Benign or Malignant Neoplasms Overall rate 49/50 (98%) 50/50 (100%) 50/50 (100%) 50/50 (100%) Adjusted rate 99.6% 100.0% 100.0% 100.0% Terminal rate 36/36 (100%) 27/27 (100%) 31/31 (100%) 28/28 (100%) First incidence (days) 381 542 209 443 Poly-3 test P=0.987 P=1.000 P=1.000 P=1.000

(T)Terminal sacrifice a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, liver, lung, pancreas, pancreatic islets, pituitary gland, preputial gland, testes, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality c Observed incidence at terminal kill d Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for the differential mortality in animals that do not reach terminal sacrifice. A negative trend or a lower incidence in an exposed group is indicated by N

. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 

### TABLE 

### A3 Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 95 Sodium Chlorate, NTP TR 517



### TABLE 

### A4 Historical Incidence of Thyroid Gland Neoplasms in Control Male F344/N Rats a



### Incidence in Controls Follicular Cell Follicular Cell Follicular Cell

Adenoma Carcinoma Adenoma Study or Carcinoma

Historical Incidence in Drinking Water Controls Given NTP-2000 Diet

Dipropylene glycol 1/42 0/42 1/42 Sodium chlorate 1/47 0/47 1/47 Sodium nitrite 1/50 1/50 2/50



### Overall Historical Incidence: Drinking Water Studies Total (%) 3/139 (2.2%) 1/139 (0.7%) 4/139 (2.9%) Mean ± standard deviation 2.2% ± 0.3% 1.0% ± 1.4% 3.2% ± 1.1% Range 2% 0%-2% 2%-4%



### Overall Historical Incidence: All Routes Total (%) 12/1,140 (1.1%) 11/1,140 (1.0%) 23/1,140 (2.0%) Mean ± standard deviation 1.0% ± 1.3% 0.9% ± 1.2% 1.9% ± 1.5% Range 0%-4% 0%-4% 0%-4%

a Data as of April 19, 2004

### Sodium Chlorate, NTP TR 517 96

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Accidental death 1 Moribund 10 13 11 14 Natural death 3 10 8 8 Survivors

Terminal sacrifice 36 27 31 28

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, colon (48) (47) (44) (49)

Edema 2 (4%) Intestine large, rectum (48) (47) (47) (50)

Congestion 1 (2%) Edema 1 (2%) Hemorrhage 1 (2%) Intestine large, cecum (47) (46) (43) (47)

Edema 1 (2%) 1 (2%) Ulcer 1 (2%) Intestine small, duodenum (49) (46) (46) (47)

Ulcer 1 (2%) Epithelium, hyperplasia 1 (2%) Intestine small, jejunum (47) (46) (42) (44)

Epithelium, necrosis 1 (2%) Intestine small, ileum (47) (46) (42) (47)

Ulcer 1 (2%) Liver (50) (50) (48) (50)

Angiectasis, focal 2 (4%) 1 (2%) 1 (2%) 3 (6%) Basophilic focus 27 (54%) 30 (60%) 33 (69%) 29 (58%) Cholangiofibrosis 2 (4%) 1 (2%) 1 (2%) 1 (2%) Clear cell focus 21 (42%) 18 (36%) 29 (60%) 15 (30%) Congestion 2 (4%) Degeneration, cystic, focal 13 (26%) 9 (18%) 12 (25%) 14 (28%) Eosinophilic focus 2 (4%) 3 (6%) 2 (4%) Fibrosis, focal 1 (2%) 1 (2%) Hemorrhage, focal 1 (2%) Hepatodiaphragmatic nodule 6 (12%) 2 (4%) 3 (6%) 5 (10%) Hyperplasia, focal, histiocytic 6 (12%) 2 (4%) 8 (17%) 5 (10%) Hyperplasia, focal, lymphoid 1 (2%) 1 (2%) Infarct 1 (2%) Infiltration cellular, mixed cell 36 (72%) 29 (58%) 33 (69%) 28 (56%) Mixed cell focus 13 (26%) 11 (22%) 3 (6%) 8 (16%) Bile duct, hyperplasia 48 (96%) 49 (98%) 46 (96%) 50 (100%) Centrilobular, congestion 1 (2%) Hepatocyte, necrosis, focal 1 (2%) 2 (4%) Hepatocyte, vacuolization cytoplasmic, diffuse 3 (6%) 3 (6%) 4 (8%) Hepatocyte, vacuolization cytoplasmic, focal 26 (52%) 15 (30%) 14 (29%) 18 (36%) Hepatocyte, periportal, necrosis 1 (2%)

a Number of animals examined microscopically at the site and the number of animals with lesion 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 97 Sodium Chlorate, NTP TR 517

Alimentary System (continued) Liver (continued) (50) (50) (48) (50)

Hepatocyte, periportal, vacuolization cytoplasmic 1 (2%) 1 (2%) Hepatocyte, centrilobular, atrophy 1 (2%) Hepatocyte, centrilobular, necrosis 1 (2%) 3 (6%) 6 (13%) 4 (8%) Hepatocyte, centrilobular, vacuolization cytoplasmic 4 (8%) 9 (18%) 12 (25%) 11 (22%) Hepatocyte, midzonal, necrosis 1 (2%) Hepatocyte, midzonal, vacuolization cytoplasmic 6 (12%) 1 (2%) 1 (2%) Hepatocyte, midzonal, vacuolization cytoplasmic, focal 1 (2%) Portal, fibrosis 1 (2%) Portal, hemorrhage 1 (2%) Mesentery (19) (20) (19) (23)

Angiectasis 1 (5%) Hemorrhage 1 (5%) 1 (5%) Inflammation, chronic 1 (5%) Inflammation, chronic, focal 1 (4%) Fat, necrosis 2 (11%) 2 (11%) 2 (9%) Fat, necrosis, focal 12 (63%) 10 (50%) 13 (68%) 14 (61%) Pancreas (49) (49) (49) (50)

Inflammation, chronic 1 (2%) Acinus, atrophy, diffuse 1 (2%) Acinus, atrophy, focal 23 (47%) 23 (47%) 27 (55%) 15 (30%) Acinus, hyperplasia, focal 1 (2%) 1 (2%) Duct, cyst, focal 1 (2%) 1 (2%) Duct, cyst, focal, multiple 15 (31%) 13 (27%) 18 (37%) 15 (30%) Salivary glands (49) (50) (50) (50)

Atrophy 1 (2%) Hyperplasia, focal, histiocytic 1 (2%) Stomach, forestomach (50) (50) (50) (50)

Edema 1 (2%) 1 (2%) 4 (8%) Erosion 1 (2%) Inflammation, chronic 4 (8%) 1 (2%) Inflammation, chronic, focal 1 (2%) Inflammation, focal 1 (2%) 1 (2%) Ulcer 1 (2%) 5 (10%) 2 (4%) 4 (8%) Epithelium, cyst 1 (2%) Epithelium, hyperplasia 2 (4%) 8 (16%) 1 (2%) 7 (14%) Epithelium, hyperplasia, focal 1 (2%) Stomach, glandular (49) (48) (48) (50)

Erosion 3 (6%) 2 (4%) 4 (8%) 4 (8%) Perforation 1 (2%) Pigmentation, focal 1 (2%) 1 (2%) Ulcer 1 (2%) 3 (6%) Epithelium, hyperplasia, focal 1 (2%) Tongue (1) (1) (1) (1)

Epithelium, hyperplasia 1 (100%) Tooth (1) (1)

Malformation 1 (100%) Peridontal tissue, hyperplasia, squamous 1 (100%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 98

Cardiovascular System Heart (50) (50) (50) (50)

Cardiomyopathy 6 (12%) 3 (6%) 7 (14%) 10 (20%) Infiltration cellular, mixed cell 2 (4%) 1 (2%) 2 (4%) Inflammation, chronic, focal 1 (2%) Thrombosis 1 (2%) 1 (2%) 2 (4%) 2 (4%) Artery, inflammation, chronic, focal 1 (2%) Endocardium, valve, inflammation, chronic, focal 1 (2%)



### Endocrine System Adrenal cortex (49) (49) (50) (50)

Accessory adrenal cortical nodule 1 (2%) 7 (14%) 4 (8%) 3 (6%) Atrophy 1 (2%) Cytoplasmic alteration, focal 3 (6%) 3 (6%) 2 (4%) 4 (8%) Degeneration, cystic, focal 2 (4%) Hyperplasia, diffuse 1 (2%) Infiltration cellular, mixed cell 1 (2%) Necrosis, focal 1 (2%) Vacuolization cytoplasmic, diffuse 1 (2%) Vacuolization cytoplasmic, focal 12 (24%) 8 (16%) 7 (14%) 6 (12%) Capsule, fibrosis, focal 1 (2%) Adrenal medulla (49) (49) (50) (50)

Hyperplasia, focal 5 (10%) 12 (24%) 9 (18%) 13 (26%) Islets, pancreatic (50) (49) (49) (50)

Hyperplasia 2 (4%) Hyperplasia, focal 1 (2%) 1 (2%) Parathyroid gland (49) (50) (47) (49)

Hyperplasia, focal 1 (2%) Pituitary gland (48) (50) (49) (50)

Angiectasis 2 (4%) 4 (8%) 1 (2%) 3 (6%) Hemorrhage 1 (2%) Hemorrhage, focal 1 (2%) Pars distalis, cyst 2 (4%) 1 (2%) 1 (2%) 1 (2%) Pars distalis, cytoplasmic alteration, focal 3 (6%) 7 (14%) 3 (6%) 8 (16%) Pars distalis, degeneration, cystic, focal 2 (4%) 2 (4%) Pars distalis, hemorrhage, focal 2 (4%) 2 (4%) 1 (2%) 3 (6%) Pars distalis, hyperplasia, focal 4 (8%) 2 (4%) 3 (6%) 1 (2%) Pars distalis, pars nervosa, hemorrhage, focal 1 (2%) Pars intermedia, hemorrhage, focal 1 (2%) Rathke’s cleft, cyst 1 (2%) Rathke’s cleft, hemorrhage 1 (2%) 2 (4%) 2 (4%) Rathke’s cleft, hyperplasia, cystic 1 (2%) Thyroid gland (47) (44) (43) (47)

C-cell, hyperplasia 45 (96%) 42 (95%) 41 (95%) 44 (94%) C-cell, hyperplasia, focal 1 (2%) Follicle, cyst 1 (2%) 1 (2%) 2 (4%) Follicle, degeneration, cystic, focal 2 (4%) Follicle, mineralization, focal 45 (96%) 43 (98%) 42 (98%) 42 (89%) Follicular cell, hypertrophy 4 (9%) 13 (30%) 33 (77%) 40 (85%) Follicular cell, hypertrophy, focal 1 (2%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 99 Sodium Chlorate, NTP TR 517

General Body System Tissue NOS (5) (6) (2) (7)

Abdominal, fibrosis 1 (50%) Mediastinum, hemorrhage 1 (17%)



### Genital System Epididymis (50) (50) (50) (50)

Fibrosis 1 (2%) Inflammation, chronic 1 (2%) 1 (2%) 2 (4%) Penis (2)

Thrombosis 1 (50%) Preputial gland (48) (49) (50) (50)

Atrophy 1 (2%) Cyst 1 (2%) 1 (2%) Degeneration, cystic 2 (4%) 1 (2%) 2 (4%) Hyperplasia, cystic 1 (2%) 1 (2%) Inflammation, chronic 22 (46%) 12 (24%) 18 (36%) 20 (40%) Necrosis 1 (2%) Prostate (50) (49) (50) (50)

Inflammation, chronic 21 (42%) 23 (47%) 29 (58%) 30 (60%) Mineralization, focal 3 (6%) 2 (4%) 3 (6%) 4 (8%) Epithelium, hyperplasia, focal 11 (22%) 4 (8%) 2 (4%) 11 (22%) Testes (50) (50) (50) (50)

Atrophy 4 (8%) 10 (20%) 9 (18%) 6 (12%) Bilateral, atrophy 1 (2%) Germinal epithelium, atrophy 1 (2%) Germinal epithelium, degeneration 1 (2%) Interstitial cell, hyperplasia, focal 1 (2%) 1 (2%) 1 (2%) 3 (6%)



### Hematopoietic System Bone marrow (48) (48) (50) (49)

Angiectasis 1 (2%) Atrophy 1 (2%) Fibrosis 2 (4%) Hyperplasia 28 (58%) 35 (73%) 41 (82%) 40 (82%) Myeloid cell, erythroid cell, hyperplasia 2 (4%) Lymph node (34) (24) (26) (34)

Ectasia 1 (3%) Hemorrhage 1 (3%) Deep cervical, hemorrhage 1 (4%) Deep cervical, hyperplasia, plasma cell 1 (3%) Mediastinal, angiectasis 1 (4%) Mediastinal, ectasia 5 (15%) 7 (29%) 5 (19%) 3 (9%) Mediastinal, hemorrhage 3 (9%) 2 (8%) 2 (8%) 1 (3%) Mediastinal, hyperplasia, histiocytic 3 (13%) 2 (8%) 1 (3%) Mediastinal, hyperplasia, lymphoid 1 (3%) 1 (4%) 3 (9%) Mediastinal, hyperplasia, plasma cell 1 (3%) 2 (8%) Mediastinal, infiltration cellular, polymorphonuclear 1 (4%) Mediastinal, inflammation, chronic active 1 (3%) Mediastinal, inflammation, suppurative 1 (4%) Pancreatic, angiectasis 2 (6%) Pancreatic, ectasia 3 (9%) 3 (13%) 3 (12%) 6 (18%) Pancreatic, hemorrhage 5 (15%) 3 (13%) 1 (4%) 1 (3%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 100

Hematopoietic System (continued) Lymph node (continued) (34) (24) (26) (34)

Pancreatic, hyperplasia, histiocytic 8 (24%) 5 (21%) 9 (35%) 6 (18%) Pancreatic, hyperplasia, lymphoid 1 (3%) 1 (4%) Pancreatic, pigmentation 1 (3%) 1 (4%) 1 (4%) Renal, hemorrhage 1 (4%) Renal, hyperplasia, focal, histiocytic 1 (4%) Renal, hyperplasia, lymphoid 1 (4%) Lymph node, mesenteric (49) (50) (49) (50)

Amyloid deposition 1 (2%) Ectasia 1 (2%) 1 (2%) 1 (2%) 3 (6%) Hemorrhage 2 (4%) 3 (6%) Hyperplasia, focal, histiocytic 1 (2%) Hyperplasia, histiocytic 3 (6%) 3 (6%) 1 (2%) Hyperplasia, lymphoid 2 (4%) 1 (2%) 1 (2%) Spleen (48) (49) (49) (50)

Amyloid deposition 1 (2%) Angiectasis, focal 2 (4%) 1 (2%) 3 (6%) Atrophy 1 (2%) Congestion 1 (2%) 1 (2%) Fibrosis, focal 2 (4%) 2 (4%) 4 (8%) Hematopoietic cell proliferation 2 (4%) 6 (12%) 4 (8%) 11 (22%) Hemorrhage 1 (2%) 1 (2%) Hyperplasia, focal, histiocytic 1 (2%) 1 (2%) 2 (4%) 1 (2%) Infarct, multiple 1 (2%) Metaplasia, focal, lipocyte 1 (2%) Necrosis 1 (2%) Pigmentation 1 (2%) Pigmentation, focal 1 (2%) Capsule, accessory spleen, focal 1 (2%) Capsule, fibrosis, focal 1 (2%) Lymphoid follicle, atrophy 1 (2%) Thymus (48) (48) (49) (47)

Angiectasis 1 (2%) Cyst 1 (2%) Hemorrhage 1 (2%) 2 (4%) 3 (6%) Hyperplasia, lymphoid 2 (4%) 1 (2%)



### Integumentary System Mammary gland (45) (43) (47) (44)

Cyst 1 (2%) Dilatation 7 (16%) 7 (16%) 7 (15%) 2 (5%) Hyperplasia 1 (2%) 2 (4%) 2 (5%) Inflammation, chronic, focal 1 (2%) 1 (2%) Skin (50) (50) (50) (50)

Cyst epithelial inclusion 3 (6%) 1 (2%) 3 (6%) 1 (2%) Fibrosis, focal 2 (4%) Hyperkeratosis, focal 1 (2%) 1 (2%) Inflammation, chronic, focal 2 (4%) Ulcer 1 (2%) Artery, subcutaneous tissue, thrombosis 1 (2%) Epidermis, hyperplasia, focal 1 (2%) Lip, inflammation, chronic, focal 1 (2%) Subcutaneous tissue, cyst 1 (2%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 101 Sodium Chlorate, NTP TR 517

Integumentary System (continued) Skin (continued) (50) (50) (50) (50)

Subcutaneous tissue, cyst epithelial inclusion 1 (2%) Subcutaneous tissue, hyperplasia, focal, histiocytic 1 (2%) Subcutaneous tissue, inflammation, chronic, focal 1 (2%) Subcutaneous tissue, inflammation, chronic,

focal, suppurative 1 (2%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Cranium, hyperostosis 1 (2%)



### Nervous System Brain (50) (50) (50) (50)

Compression, focal 6 (12%) 6 (12%) 7 (14%) 6 (12%) Hemorrhage, focal 2 (4%) 2 (4%) 4 (8%) 6 (12%) Cerebrum, ventricle, hydrocephalus 1 (2%)



### Respiratory System Lung (50) (50) (50) (50)

Congestion 2 (4%) 1 (2%) 3 (6%) Foreign body, focal 1 (2%) Hemorrhage 1 (2%) Hemorrhage, focal 3 (6%) 1 (2%) 2 (4%) 2 (4%) Hyperplasia, focal, histiocytic 1 (2%) 1 (2%) Hyperplasia, histiocytic 2 (4%) 1 (2%) 1 (2%) 2 (4%) Infiltration cellular, mixed cell 1 (2%) 3 (6%) 1 (2%) 2 (4%) Inflammation, chronic, focal 5 (10%) 2 (4%) 3 (6%) 3 (6%) Inflammation, focal, suppurative 1 (2%) Alveolar epithelium, hyperplasia, focal 8 (16%) 5 (10%) 3 (6%) 4 (8%) Alveolar epithelium, metaplasia, squamous 1 (2%) Alveolus, edema, focal 1 (2%) Alveolus, hyperplasia, focal, histiocytic 1 (2%) Interstitium, edema 1 (2%) 1 (2%) Mediastinum, edema 1 (2%) 1 (2%) Nose (49) (49) (49) (50)

Foreign body 1 (2%) 2 (4%) 1 (2%) Inflammation, chronic 1 (2%) Inflammation, suppurative 1 (2%) 1 (2%) 6 (12%) 1 (2%) Nasolacrimal duct, inflammation 1 (2%) 3 (6%) 1 (2%) Olfactory epithelium, hyperplasia, focal 1 (2%) Respiratory epithelium, hyperplasia, focal 1 (2%) Trachea (50) (49) (50) (50)

Peritracheal tissue, edema 1 (2%)



### Special Senses System Eye (50) (48) (46) (50)

Atrophy 2 (4%) Cataract 2 (4%) 1 (2%) 2 (4%) Exudate 1 (2%) Cornea, inflammation, chronic 1 (2%) Cornea, retrobulbar, inflammation, chronic active 1 (2%) Retina, degeneration 2 (4%) 1 (2%) 2 (4%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 102

Special Senses System (continued) Harderian gland (49) (49) (49) (50)

Fibrosis, focal 1 (2%) Hyperplasia, focal, histiocytic 1 (2%) 1 (2%) 1 (2%) Inflammation, chronic, focal 1 (2%) 1 (2%) 1 (2%) Inflammation, chronic active, diffuse 1 (2%) Epithelium, hyperplasia, focal 1 (2%)



### Urinary System Kidney (47) (46) (49) (49)

Cyst 1 (2%) Cyst, multiple 1 (2%) Hydronephrosis 1 (2%) Infarct 1 (2%) Infarct, multiple 1 (2%) 1 (2%) Metaplasia, focal, lipocyte 1 (2%) Nephropathy 45 (96%) 44 (96%) 48 (98%) 47 (96%) Cortex, medulla, atrophy 1 (2%) Pelvis, infiltration cellular, mixed cell 1 (2%) Pelvis, transitional epithelium, hyperplasia 1 (2%) 1 (2%) Renal tubule, accumulation, hyaline droplet 1 (2%) 4 (8%) 2 (4%) Renal tubule, hyperplasia, focal 1 (2%) Renal tubule, pigmentation 4 (9%) 4 (9%) 1 (2%) 4 (8%) Urinary bladder (48) (49) (47) (50)

Calculus microscopic observation only 1 (2%) Edema 2 (4%) Hemorrhage 2 (4%) Inflammation, chronic 1 (2%) Serosa, inflammation, focal 1 (2%) Transitional epithelium, hyperplasia, diffuse 1 (2%) 

### TABLE 

### A5 Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 103



# APPENDIX B SUMMARY OF LESIONS IN FEMALE RATS IN THE 2-YEAR DRINKING WATER STUDY OF SODIUM CHLORATE

TABLE 

### B1 Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 TABLE 

### B3 Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 TABLE 

### B4 Historical Incidence of Thyroid Gland Neoplasms in Control Female F344/N Rats . . . . . . 134 TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

### Sodium Chlorate, NTP TR 517 104



### TABLE 

### B1 Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Moribund 10 11 11 4 Natural deaths 3 3 6 5 Survivors

Died last week of study 2 1 1 Terminal sacrifice 37 34 32 40

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, colon (50) (48) (46) (49)

Leiomyosarcoma 1 (2%) Intestine small, jejunum (49) (47) (44) (45)

Leiomyoma 1 (2%) Liver (50) (50) (50) (50)

Cholangiocarcinoma 1 (2%) Histiocytic sarcoma 1 (2%) Histiocytic sarcoma, metastatic, skeletal muscle 1 (2%) Mesentery (18) (10) (13) (16)

Carcinoma 1 (6%) Oral mucosa (1) (1)

Squamous cell carcinoma 1 (100%) Pancreas (50) (49) (49) (49)

Acinus, adenoma 2 (4%) Salivary glands (50) (50) (50) (50) Stomach, forestomach (50) (50) (50) (50) Tooth (2) (2) (1)

Odontoma 1 (50%)



### Cardiovascular System Heart (50) (50) (50) (50)



### Endocrine System Adrenal cortex (50) (50) (50) (50) Adrenal medulla (50) (50) (50) (50)

Pheochromocytoma malignant 1 (2%) 1 (2%) Pheochromocytoma complex 1 (2%) Pheochromocytoma benign 2 (4%) 1 (2%) 1 (2%) 1 (2%) Islets, pancreatic (50) (49) (49) (50)

Adenoma 2 (4%) 1 (2%) Carcinoma 1 (2%) 1 (2%) 1 (2%) Pituitary gland (49) (49) (50) (50)

Pars distalis, adenoma 23 (47%) 18 (37%) 17 (34%) 24 (48%) Pars distalis, adenoma, multiple 1 (2%) Pars distalis, carcinoma 1 (2%) 3 (6%) Pars intermedia, adenoma 1 (2%) 1 (2%) 1 (2%) Thyroid gland (47) (47) (43) (46)

Bilateral, C-cell, adenoma 1 (2%) 2 (4%) C-cell, adenoma 11 (23%) 8 (17%) 11 (26%) 9 (20%) C-cell, carcinoma 1 (2%) 3 (6%) 1 (2%) 3 (7%) Follicular cell, adenoma 2 (4%) Follicular cell, carcinoma 1 (2%) 1 (2%) 2 (4%)

### 105 Sodium Chlorate, NTP TR 517

General Body System Tissue NOS (1) (2) (4) (6)

Mediastinum, carcinoma, metastatic, thyroid gland 1 (50%) Mediastinum, carcinoma, metastatic, Zymbal’s gland 1 (25%) Mediastinum, histiocytic sarcoma 1 (25%) Mediastinum, sarcoma 1 (17%)



### Genital System Clitoral gland (49) (50) (50) (49)

Adenoma 11 (22%) 5 (10%) 12 (24%) 4 (8%) Carcinoma 3 (6%) 1 (2%) Sarcoma 1 (2%) Ovary (50) (50) (49) (50)

Granulosa cell tumor benign 1 (2%) Sarcoma 1 (2%) Oviduct (2) Uterus (50) (50) (49) (50)

Carcinoma, metastatic, mesentery 1 (2%) Sarcoma stromal 1 (2%) Endometrium, polyp stromal 8 (16%) 8 (16%) 7 (14%) 7 (14%) Endometrium, polyp stromal, multiple 1 (2%) 2 (4%) Endometrium, sarcoma 1 (2%)



### Hematopoietic System Bone marrow (50) (49) (50) (50) Lymph node (36) (34) (30) (39)

Mediastinal, histiocytic sarcoma 1 (3%) Mediastinal, sarcoma 1 (3%) Lymph node, mandibular (4) (6) (4) (5) Lymph node, mesenteric (50) (49) (49) (50) Spleen (50) (50) (50) (50)

Sarcoma 1 (2%) Thymus (49) (48) (48) (48)

Sarcoma 1 (2%)



### Integumentary System Mammary gland (50) (50) (50) (50)

Adenoma 3 (6%) 2 (4%) Carcinoma 2 (4%) 1 (2%) 2 (4%) Carcinoma, multiple 1 (2%) Fibroadenoma 23 (46%) 26 (52%) 23 (46%) 27 (54%) Fibroadenoma, multiple 10 (20%) 3 (6%) 8 (16%) 6 (12%) Histiocytic sarcoma, metastatic, skeletal muscle 1 (2%) Skin (50) (50) (50) (50)

Basal cell carcinoma 1 (2%) Keratoacanthoma 1 (2%) Trichoepithelioma 2 (4%) Pinna, neural crest tumor 1 (2%) Subcutaneous tissue, carcinoma, metastatic,

mammary gland 1 (2%) Subcutaneous tissue, fibroma 4 (8%) 1 (2%) 1 (2%) 1 (2%) 

### TABLE 

### B1 Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 106

Integumentary System (continued) Skin (continued) (50) (50) (50) (50)

Subcutaneous tissue, fibrosarcoma 1 (2%) Subcutaneous tissue, histiocytic sarcoma 1 (2%) Subcutaneous tissue, histiocytic sarcoma,

metastatic, skeletal muscle 1 (2%) Subcutaneous tissue, lipoma 1 (2%) Subcutaneous tissue, sarcoma 1 (2%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Osteosarcoma 1 (2%) Skeletal muscle (2) (1) (1)

Histiocytic sarcoma 1 (50%) Rhabdomyosarcoma 1 (50%)



### Nervous System Brain (49) (50) (50) (50)

Carcinoma, metastatic, pituitary gland 2 (4%)



### Respiratory System Lung (50) (50) (50) (50)

Alveolar/bronchiolar adenoma 1 (2%) 1 (2%) Alveolar/bronchiolar carcinoma 1 (2%) Carcinoma, metastatic, mammary gland 1 (2%) Histiocytic sarcoma 1 (2%) Histiocytic sarcoma, metastatic, skeletal muscle 1 (2%) Sarcoma 1 (2%) Nose (50) (50) (50) (50)



### Special Senses System Eye (50) (49) (47) (50) Harderian gland (50) (50) (50) (50)

Histiocytic sarcoma 1 (2%) Squamous cell carcinoma, metastatic, oral mucosa 1 (2%) Zymbal’s gland (1) (1) (1)

Carcinoma 1 (100%)



### Urinary System Kidney (50) (49) (47) (47)

Sarcoma 1 (2%) Urinary bladder (50) (48) (50) (50)

Transitional epithelium, papilloma 1 (2%)



### Systemic Lesions Multiple organsb (50) (50) (50) (50)

Histiocytic sarcoma 2 (4%) 1 (2%) Leukemia mononuclear 11 (22%) 9 (18%) 13 (26%) 9 (18%) Lymphoma malignant 1 (2%) Mesothelioma malignant 1 (2%) 

### TABLE 

### B1 Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 107 Sodium Chlorate, NTP TR 517

Neoplasm Summary Total animals with primary neoplasms c 49 48 46 48

Total primary neoplasms 133 102 101 118 Total animals with benign neoplasms 46 42 44 47

Total benign neoplasms 107 77 82 87 Total animals with malignant neoplasms 21 22 19 22

Total malignant neoplasms 25 25 19 31 Total animals with metastatic neoplasms 1 5 2 2

Total metastatic neoplasms 1 8 2 2Total animals with uncertain neoplasmsbenign or malignant 1 Total uncertain neoplasms 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 c Primary neoplasms: all neoplasms except metastatic neoplasms 

### TABLE 

### B1 Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 108

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon +++++++++++++++++++++++++

Leiomyosarcoma Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum +++++++++++++++++++++++++ Intestine small, duodenum +++++++++++++++++++++++++ Intestine small, jejunum ++++++A++++++++++++++++++ Intestine small, ileum ++++++A++++++++++++++++++ Liver +++++++++++++++++++++++++ Mesentery + + + + + + + + + + + + Pancreas +++++++++++++++++++++++++

Acinus, adenoma X Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular +++++++++++++++++++++++++


### Cardiovascular System Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma benign Islets, pancreatic +++++++++++++++++++++++++

Adenoma Carcinoma Parathyroid gland + + + + + + + + + + + + + + + + + +M+ +M+ + + Pituitary gland + + + + + + + + + + + + + + + + + +M+ + + + + +

Pars distalis, adenoma X X X X X X X X X XXXX Pars distalis, carcinoma X Pars intermedia, adenoma Thyroid gland + + + + +AA+ + + + + + + + + + +M+ + + + + +

Bilateral, C-cell, adenoma C-cell, adenoma X X X X X C-cell, carcinoma X Follicular cell, carcinoma


### General Body System Tissue NOS +


### Genital System Clitoral gland +++++++++++++++++++++++++

Adenoma X X X X Carcinoma X Ovary +++++++++++++++++++++++++

Granulosa cell tumor benign X 

### T ABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

4455555666777777777777777 

### Number of Days on Study 2615699246112333333333333 3215645341787444444444444

2222222222222222222222222 

### Carcass ID Number 4110434240431000111122222 2803567765001124234512345

+: Tissue examined microscopically M: Missing tissue X: Lesion present A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined

### 109 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50

Leiomyosarcoma X 1 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 Mesentery + + + + + + 18 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50

Acinus, adenoma X 2 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma benign X X 2 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X 2 Carcinoma X 1 Parathyroid gland + + + + + + + + + M + + + + + + + + + + + + + + + 47 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Pars distalis, adenoma X X X X X X X X X X 23 Pars distalis, carcinoma 1 Pars intermedia, adenoma X 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47

Bilateral, C-cell, adenoma X 1 C-cell, adenoma X X X X X X 11 C-cell, carcinoma 1 Follicular cell, carcinoma X 1


### General Body System Tissue NOS 1


### Genital System Clitoral gland + + + + M + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X X X X X X 11 Carcinoma XX 3 Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50

Granulosa cell tumor benign 1 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

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 3333333333333333333333333 4444445556666666677777777

2222222222222222222222222 T otal 

### Carcass ID Number 3334452220000111233333444 Tissues/ 7898906896789679012345134 T umors

### Sodium Chlorate, NTP TR 517 110

Genital System (continued) Uterus +++++++++++++++++++++++++

Sarcoma stromal Endometrium, polyp stromal X X Endometrium, polyp stromal, multiple X Vagina + + + +


### Hematopoietic System Bone marrow +++++++++++++++++++++++++ Lymph node + + ++++ +++++ +++++ ++ Lymph node, mandibular MMMMMM + MMMMMMMMMMMMMMMMMM Lymph node, mesenteric +++++++++++++++++++++++++ Spleen +++++++++++++++++++++++++ Thymus + + + + + + + + + + + + + + + + + +M+ + + + + +


### Integumentary System Mammary gland +++++++++++++++++++++++++

Adenoma X Carcinoma X X Carcinoma, multiple X Fibroadenoma X X X X XXXX X Fibroadenoma, multiple X XXXX X Skin +++++++++++++++++++++++++

Basal cell carcinoma X Trichoepithelioma X Pinna, neural crest tumor X Subcutaneous tissue, fibroma X Subcutaneous tissue, lipoma


### Musculoskeletal System Bone +++++++++++++++++++++++++


### Nervous System Brain + + + + + + + + + +M+ + + + + + + + + + + + + + Peripheral nerve + Spinal cord +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma Alveolar/bronchiolar carcinoma Carcinoma, metastatic, mammary gland X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++ Zymbal’s gland + 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

4455555666777777777777777 

### Number of Days on Study 2615699246112333333333333 3215645341787444444444444

2222222222222222222222222 

### Carcass ID Number 4110434240431000111122222 2803567765001124234512345

### 111 Sodium Chlorate, NTP TR 517

Genital System (continued) Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Sarcoma stromal X 1 Endometrium, polyp stromal X X X X X X 8 Endometrium, polyp stromal, multiple 1 Vagina + + 6


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lymph node + + + + + + + + + + + + + + + + + + 36 Lymph node, mandibular MMMMM + MMMMMMMM + MMMMM + MMMM 4 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma XX 3 Carcinoma 2 Carcinoma, multiple 1 Fibroadenoma XXXXX XXX X X X X X X 23 Fibroadenoma, multiple X X X X 10 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Basal cell carcinoma 1 Trichoepithelioma X 2 Pinna, neural crest tumor 1 Subcutaneous tissue, fibroma X X X 4 Subcutaneous tissue, lipoma X 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 49 Peripheral nerve 1 Spinal cord 1


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 1 Alveolar/bronchiolar carcinoma X 1 Carcinoma, metastatic, mammary gland 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Zymbal’s gland 1 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

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 3333333333333333333333333 4444445556666666677777777

2222222222222222222222222 T otal 

### Carcass ID Number 3334452220000111233333444 Tissues/ 7898906896789679012345134 T umors

### Sodium Chlorate, NTP TR 517 112

Urinary System Kidney +++++++++++++++++++++++++ Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Leukemia mononuclear X X X X X X X X 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

4455555666777777777777777 

### Number of Days on Study 2615699246112333333333333 3215645341787444444444444

2222222222222222222222222 

### Carcass ID Number 4110434240431000111122222 2803567765001124234512345

### 113 Sodium Chlorate, NTP TR 517

Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Leukemia mononuclear X X X 11 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

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 3333333333333333333333333 4444445556666666677777777

2222222222222222222222222 T otal 

### Carcass ID Number 3334452220000111233333444 Tissues/ 7898906896789679012345134 T umors

### Sodium Chlorate, NTP TR 517 114

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon +++++A+++A+++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum +++++A+++A+++++++++++++++ Intestine small, duodenum +++++++++A+++++++++++++++ Intestine small, jejunum + + + + +AA+ +A+ + + + + + + + + + + + + + +

Leiomyoma X Intestine small, ileum +++++A+++A+++++++++++++++ Liver +++++++++++++++++++++++++

Cholangiocarcinoma X Histiocytic sarcoma X Histiocytic sarcoma, metastatic, skeletal muscle Mesentery + + + + + + + Pancreas +++++++++A+++++++++++++++ Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular +++++++++A+++++++++++++++ Tooth + +

Odontoma X


### Cardiovascular System Blood vessel + Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma malignant X Pheochromocytoma benign Islets, pancreatic +++++++++A+++++++++++++++

Adenoma Carcinoma Parathyroid gland + + + + + + + + + + + + + + + + +M+ + + + + + + Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + +

Pars distalis, adenoma X X X X X X X Pars distalis, carcinoma X X Pars intermedia, adenoma Thyroid gland + + + + +AA+ +A+ + + + + + + + + + + + + + +

Bilateral, C-cell, adenoma C-cell, adenoma X X X X C-cell, carcinoma X X


### General Body System Tissue NOS +

Mediastinum, carcinoma, metastatic,

thyroid gland X 

### T ABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

3445556666667777777777777 

### Number of Days on Study 6231462233451233333333333 5331133669474734444444455

2222222222222222222222222 

### Carcass ID Number 6987858598567755556666966 5066781452201871351234967

### 115 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Leiomyoma 1 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 48 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Cholangiocarcinoma 1 Histiocytic sarcoma 1 Histiocytic sarcoma, metastatic, skeletal muscle X 1 Mesentery + + + 10 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 Tooth 2

Odontoma 1


### Cardiovascular System Blood vessel 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma malignant 1 Pheochromocytoma benign X 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X 1 Carcinoma X 1 Parathyroid gland + + + + M + + + + + + + + + + + + + + + + + M + + 47 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Pars distalis, adenoma X X X X X X X X X X X 18 Pars distalis, carcinoma X 3 Pars intermedia, adenoma X 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47

Bilateral, C-cell, adenoma X X 2 C-cell, adenoma X X X X 8 C-cell, carcinoma X 3


### General Body System Tissue NOS + 2

Mediastinum, carcinoma, metastatic,

thyroid gland 1 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555556666666666667777

2222222222222222222222223 T otal 

### Carcass ID Number 6678899995577777788889990 Tissues/ 8908912346923457903456780 T umors

### Sodium Chlorate, NTP TR 517 116

Genital System Clitoral gland +++++++++++++++++++++++++

Adenoma X X Carcinoma X Ovary +++++++++++++++++++++++++ Uterus +++++++++++++++++++++++++

Endometrium, polyp stromal X X Vagina + +


### Hematopoietic System Bone marrow +++++++++A+++++++++++++++ Lymph node ++++ + ++ +++++ +++++++ Lymph node, mandibular MMMMMMM + MMMMMMM + + MMMMMMMM Lymph node, mesenteric +++++++++A+++++++++++++++ Spleen +++++++++++++++++++++++++ Thymus + + + + + + + + +A+ + + + + + + + + + + +M+ +


### Integumentary System Mammary gland +++++++++++++++++++++++++

Carcinoma X Fibroadenoma X X X X X XXXXX X Fibroadenoma, multiple X Histiocytic sarcoma, metastatic,

skeletal muscle Skin +++++++++++++++++++++++++

Subcutaneous tissue, carcinoma, metastatic, mammary gland X Subcutaneous tissue, fibroma X Subcutaneous tissue, fibrosarcoma X Subcutaneous tissue, histiocytic sarcoma X Subcutaneous tissue, histiocytic sarcoma, metastatic, skeletal muscle


### Musculoskeletal System Bone +++++++++++++++++++++++++

Osteosarcoma X Skeletal muscle

Histiocytic sarcoma Rhabdomyosarcoma


### Nervous System Brain +++++++++++++++++++++++++

Carcinoma, metastatic, pituitary gland X Peripheral nerve + + Spinal cord + + 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

3445556666667777777777777 

### Number of Days on Study 6231462233451233333333333 5331133669474734444444455

2222222222222222222222222 

### Carcass ID Number 6987858598567755556666966 5066781452201871351234967

### 117 Sodium Chlorate, NTP TR 517

Genital System Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X 5 Carcinoma 1 Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Endometrium, polyp stromal X X X X X X 8 Vagina + 3


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lymph node + + + + + +++ + + + + + + + 34 Lymph node, mandibular M M + MMMMMMMM + MMMMMMMMMM + MM 6 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 49 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma 1 Fibroadenoma X X X X X X X X X X X X X X X 26 Fibroadenoma, multiple XX 3 Histiocytic sarcoma, metastatic,

skeletal muscle X 1 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Subcutaneous tissue, carcinoma, metastatic, mammary gland 1 Subcutaneous tissue, fibroma 1 Subcutaneous tissue, fibrosarcoma 1 Subcutaneous tissue, histiocytic sarcoma 1 Subcutaneous tissue, histiocytic sarcoma, metastatic, skeletal muscle X 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma 1 Skeletal muscle + +2

Histiocytic sarcoma X 1 Rhabdomyosarcoma X 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, pituitary gland X 2 Peripheral nerve + 3 Spinal cord + 3 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555556666666666667777

2222222222222222222222223 T otal 

### Carcass ID Number 6678899995577777788889990 Tissues/ 8908912346923457903456780 T umors

### Sodium Chlorate, NTP TR 517 118

Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma Histiocytic sarcoma X Histiocytic sarcoma, metastatic,

skeletal muscle Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + A + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Histiocytic sarcoma X


### Urinary System Kidney +++++++++A+++++++++++++++ Urinary bladder +++++++++A+++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X Leukemia mononuclear X X X X 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

3445556666667777777777777 

### Number of Days on Study 6231462233451233333333333 5331133669474734444444455

2222222222222222222222222 

### Carcass ID Number 6987858598567755556666966 5066781452201871351234967

### 119 Sodium Chlorate, NTP TR 517

Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 1 Histiocytic sarcoma 1 Histiocytic sarcoma, metastatic,

skeletal muscle X 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 49 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49 Urinary bladder + + + + + + + + M + + + + + + + + + + + + + + + + 48


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 2 Leukemia mononuclear X X X X X 9 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 125 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555556666666666667777

2222222222222222222222223 T otal 

### Carcass ID Number 6678899995577777788889990 Tissues/ 8908912346923457903456780 T umors

### Sodium Chlorate, NTP TR 517 120

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon + + + A + + + A A +++++A++++++++++ Intestine large, rectum + + + A + + + A A +++++A++++++++++ Intestine large, cecum + + + A A + + A A +++++A+++A++++++ Intestine small, duodenum + + + A + + + A A +++++A+++A++++++ Intestine small, jejunum + + + A A + + A A +++++A+++A++++++ Intestine small, ileum + + + A A + + A A +++++A+++A++++++ Liver +++++++++++++++++++++++++ Mesentery + + +++++ + + Oral mucosa + Pancreas ++++++++++++++++++A++++++ Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular + + + + A + + + + + + + + + + + + + + + + + + + + Tooth + +


### Cardiovascular System Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma benign Islets, pancreatic ++++++++++++++++++A++++++ Parathyroid gland + + + + + + + + + + + + + + + + + +M+ + + + + + Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma X X X X X X X X X Thyroid gland + + A A A + + A A +++++A+++A++++++

C-cell, adenoma XXXX C-cell, carcinoma X Follicular cell, carcinoma X


### General Body System Tissue NOS + + + +

Mediastinum, carcinoma, metastatic,

Zymbal’s gland X Mediastinum, histiocytic sarcoma X


### Genital System Clitoral gland +++++++++++++++++++++++++

Adenoma X X X X X X X Ovary ++++++++++++++++++A++++++ Oviduct + + Uterus ++++++++++++++++++++++++

Endometrium, polyp stromal X X X Endometrium, polyp stromal, multiple X X Vagina + + 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

4555555666666667777777777 

### Number of Days on Study 0114788112335990033333333 1147377556661993344444444

3333333333333333333333333 

### Carcass ID Number 5201234243002141322233334 0848451594690162867906790

### 121 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 45 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 44 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 Mesentery + + + + 13 Oral mucosa 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49 Tooth 2


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma benign X 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + M + + 48 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pars distalis, adenoma X X X X X X X X 17 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 43

C-cell, adenoma X X X X X X X 11 C-cell, carcinoma 1 Follicular cell, carcinoma 1


### General Body System Tissue NOS 4

Mediastinum, carcinoma, metastatic,

Zymbal’s gland 1 Mediastinum, histiocytic sarcoma 1


### Genital System Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X X X 12 Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 49 Oviduct 2 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 49

Endometrium, polyp stromal X X X X 7 Endometrium, polyp stromal, multiple 2 Vagina + 3 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 4444445556666666666777777

3333333333333333333333333 T otal 

### Carcass ID Number 4444443330000111222001111 Tissues 2345781231235679123780345 T umors

### Sodium Chlorate, NTP TR 517 122

Hematopoietic System Bone marrow +++++++++++++++++++++++++ Lymph node ++++++++ ++ +++ +++ +

Mediastinal, histiocytic sarcoma X Lymph node, mandibular M M M + MMMMMMMMMMM + MMMMMMMMM Lymph node, mesenteric + + + + + + +M+ + + + + + + + + + + + + + + + + Spleen +++++++++++++++++++++++++ Thymus + + + + + + + + + + +M+ + + + + +M+ + + + + +


### Integumentary System Mammary gland +++++++++++++++++++++++++

Fibroadenoma X X X X X X X X X X Fibroadenoma, multiple X X X X X Skin +++++++++++++++++++++++++

Subcutaneous tissue, fibroma X


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle +

Mesothelioma malignant, metastatic, mesentery X


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve


### Respiratory System Lung +++++++++++++++++++++++++ Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + A + + + + + + A + + + A + + + + + + Harderian gland +++++++++++++++++++++++++ Lacrimal gland Zymbal’s gland +

Carcinoma X


### Urinary System Kidney ++++A+++A+++++++++A++++++ Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X Leukemia mononuclear X X X X X X X X Lymphoma malignant X Mesothelioma malignant X 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

4555555666666667777777777 

### Number of Days on Study 0114788112335990033333333 1147377556661993344444444

3333333333333333333333333 

### Carcass ID Number 5201234243002141322233334 0848451594690162867906790

### 123 Sodium Chlorate, NTP TR 517

Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lymph node + + + + + + ++ + + + + + 30

Mediastinal, histiocytic sarcoma 1 Lymph node, mandibular MMMMMMMMMMMMMMMMMMMM + M + MM 4 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 49 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Fibroadenoma X X X X X X X X X X X X X 23 Fibroadenoma, multiple X X X 8 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Subcutaneous tissue, fibroma 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle 1

Mesothelioma malignant, metastatic, mesentery 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve + 1


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 47 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lacrimal gland + 1 Zymbal’s gland 1

Carcinoma 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 47 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Leukemia mononuclear X X X X X 13 Lymphoma malignant 1 Mesothelioma malignant 1 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 4444445556666666666777777

3333333333333333333333333 T otal 

### Carcass ID Number 4444443330000111222001111 Tissues 2345781231235679123780345 T umors

### Sodium Chlorate, NTP TR 517 124

Alimentary System Esophagus +++++++++++++++++++++++++ Intestine large, colon +++++++A+++++++++++++++++ Intestine large, rectum + + A + + + A A +++++++++A+++++++ Intestine large, cecum + + + + + +AA+ + + + + + + + +A+ + + + + + + Intestine small, duodenum ++++++A++++++++++++++++++ Intestine small, jejunum + + A + A + A A +++++++++A+++++++ Intestine small, ileum + + A + + + A A +++++++++++++++++ Liver +++++++++++++++++++++++++ Mesentery + + + + + + + +

Carcinoma X Oral mucosa +

Squamous cell carcinoma X Pancreas + + A ++++++++++++++++++++++ Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular +++++++++++++++++++++++++ Tooth +


### Cardiovascular System Blood vessel Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma malignant X Pheochromocytoma complex Pheochromocytoma benign X Islets, pancreatic +++++++++++++++++++++++++

Carcinoma X Parathyroid gland + + + + + + + + + + + + +M+M+ + + + + + + + + Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma X X X X X X X X X X X X X X Pars distalis, adenoma, multiple X Pars intermedia, adenoma Thyroid gland + + A + + + A A +++++++++A+++++++

C-cell, adenoma X X X C-cell, carcinoma X Follicular cell, adenoma X X Follicular cell, carcinoma X


### General Body System Tissue NOS + + + + +

Mediastinum, sarcoma X 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4566666677777777777777777 

### Number of Days on Study 7433467902222222233333333 5256480339999999905555555

3333333333333333333333333 

### Carcass ID Number 5898696787777888995555555 1018375016789679052345678

### 125 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine large, rectum + + + + + + + + + + + + I + + + + + + + + + + + + 45 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 45 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 Mesentery + + + + + + + + 16

Carcinoma 1 Oral mucosa 1

Squamous cell carcinoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 Tooth 1


### Cardiovascular System Blood vessel + 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma malignant 1 Pheochromocytoma complex X 1 Pheochromocytoma benign 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma 1 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + M + + 47 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pars distalis, adenoma XXXX X X X X X X 24 Pars distalis, adenoma, multiple 1 Pars intermedia, adenoma X 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 46

C-cell, adenoma X X X X X X 9 C-cell, carcinoma X X 3 Follicular cell, adenoma 2 Follicular cell, carcinoma X 2



### General Body System Tissue NOS + 6

Mediastinum, sarcoma 1 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555555566666666667777

3333333333433333333333333 T otal 

### Carcass ID Number 5677777999066688889996666 Tissues/ 9012345689012423452346789 T umors

### Sodium Chlorate, NTP TR 517 126

Genital System Clitoral gland +++++++++++++++++++++++++

Adenoma X Sarcoma X Ovary +++++++++++++++++++++++++

Sarcoma X Uterus +++++++++++++++++++++++++

Carcinoma, metastatic, mesentery X Endometrium, polyp stromal X X X X X Endometrium, sarcoma X Vagina


### Hematopoietic System Bone marrow +++++++++++++++++++++++++ Lymph node +++++++++++ ++++++++ ++

Mediastinal, sarcoma X Lymph node, mandibular MMMMMMMMMM + M + MMMM + MMMMMMM Lymph node, mesenteric +++++++++++++++++++++++++ Spleen +++++++++++++++++++++++++

Sarcoma X Thymus + + + + +M+ + + + + + + + + + + + + + + + + + +

Sarcoma X


### Integumentary System Mammary gland +++++++++++++++++++++++++

Adenoma Carcinoma X Fibroadenoma X X X X X X X XXXXXXX Fibroadenoma, multiple X X Skin +++++++++++++++++++++++++

Keratoacanthoma X Subcutaneous tissue, fibroma X Subcutaneous tissue, sarcoma X


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle +


### Nervous System Brain +++++++++++++++++++++++++


### Respiratory System Lung +++++++++++++++++++++++++

Sarcoma X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++ 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4566666677777777777777777 

### Number of Days on Study 7433467902222222233333333 5256480339999999905555555

3333333333333333333333333 

### Carcass ID Number 5898696787777888995555555 1018375016789679052345678

### 127 Sodium Chlorate, NTP TR 517

Genital System Clitoral gland + + + + + + + + + + M + + + + + + + + + + + + + + 49

Adenoma X X X 4 Sarcoma 1 Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50

Sarcoma 1 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, mesentery 1 Endometrium, polyp stromal X X 7 Endometrium, sarcoma 1 Vagina + 1


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lymph node + + + + + + + + + + + + + + + + + + 39

Mediastinal, sarcoma 1 Lymph node, mandibular M M M + MMMMMMMMMMMM + MMMMMMMM 5 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50

Sarcoma 1 Thymus + + + + + + + + + + + + + + + + + + + + + I + + + 48

Sarcoma 1


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X 2 Carcinoma X 2 Fibroadenoma X X X X X X X X X X X X X 27 Fibroadenoma, multiple X X X X 6 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Keratoacanthoma 1 Subcutaneous tissue, fibroma 1 Subcutaneous tissue, sarcoma 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Sarcoma 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555555566666666667777

3333333333433333333333333 T otal 

### Carcass ID Number 5677777999066688889996666 Tissues/ 9012345689012423452346789 T umors

### Sodium Chlorate, NTP TR 517 128

Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Squamous cell carcinoma, metastatic,

oral mucosa X Lacrimal gland + Zymbal’s gland +


### Urinary System Kidney + + A + A ++++++++++++A+++++++

Sarcoma X Urinary bladder +++++++++++++++++++++++++

Transitional epithelium, papilloma


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Leukemia mononuclear X X X X X X 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

4566666677777777777777777 

### Number of Days on Study 7433467902222222233333333 5256480339999999905555555

3333333333333333333333333 

### Carcass ID Number 5898696787777888995555555 1018375016789679052345678

### 129 Sodium Chlorate, NTP TR 517

Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell carcinoma, metastatic,

oral mucosa 1 Lacrimal gland + 2 Zymbal’s gland 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 47

Sarcoma 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50

Transitional epithelium, papilloma X 1


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Leukemia mononuclear X X X 9 

### TABLE 

### B2 Individual Animal Tumor Pathology of Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555555555566666666667777

3333333333433333333333333 T otal 

### Carcass ID Number 5677777999066688889996666 Tissues/ 9012345689012423452346789 T umors

### Sodium Chlorate, NTP TR 517 130



### TABLE 

### B3 Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

Adrenal Medulla: Benign, Complex, or Malignant Pheochromocytoma Overall rate a 2/50 (4%) 2/50 (4%) 1/50 (2%) 3/50 (6%) Adjusted rateb 4.5% 4.5% 2.3% 6.4% Terminal rate c 2/37 (5%) 1/36 (3%) 1/33 (3%) 3/41 (7%) First incidence (days) 729 (T) 541 729 (T) 729 (T) Poly-3 testd P=0.430 P=0.690 P=0.512N P=0.522



### Clitoral Gland: Adenoma Overall rate 11/49 (22%) 5/50 (10%) 12/50 (24%) 4/49 (8%) Adjusted rate 24.9% 11.4% 26.9% 8.7% Terminal rate 10/36 (28%) 5/36 (14%) 8/33 (24%) 4/40 (10%) First incidence (days) 595 729 (T) 511 729 (T) Poly-3 test P=0.131N P=0.085N P=0.512 P=0.035N



### Clitoral Gland: Carcinoma Overall rate 3/49 (6%) 1/50 (2%) 0/50 (0%) 0/49 (0%) Adjusted rate 6.9% 2.3% 0.0% 0.0% Terminal rate 3/36 (8%) 1/36 (3%) 0/33 (0%) 0/40 (0%) First incidence (days) 729 (T) 729 (T) —e

— Poly-3 test P=0.054N P=0.305N P=0.120N P=0.110N



### Clitoral Gland: Adenoma or Carcinoma Overall rate 14/49 (29%) 6/50 (12%) 12/50 (24%) 4/49 (8%) Adjusted rate 31.7% 13.7% 26.9% 8.7% Terminal rate 13/36 (36%) 6/36 (17%) 8/33 (24%) 4/40 (10%) First incidence (days) 595 729 (T) 511 729 (T) Poly-3 test P=0.036N P=0.037N P=0.395N P=0.005N


### Mammary Gland: Fibroadenoma Overall rate 33/50 (66%) 29/50 (58%) 31/50 (62%) 33/50 (66%) Adjusted rate 69.8% 63.5% 68.7% 69.0% Terminal rate 26/37 (70%) 25/36 (69%) 24/33 (73%) 29/41 (71%) First incidence (days) 423 365 547 636 Poly-3 test P=0.437 P=0.333N P=0.544N P=0.557N


### Mammary Gland: Adenoma Overall rate 3/50 (6%) 0/50 (0%) 0/50 (0%) 2/50 (4%) Adjusted rate 6.7% 0.0% 0.0% 4.3% Terminal rate 3/37 (8%) 0/36 (0%) 0/33 (0%) 2/41 (5%) First incidence (days) 729 (T) — — 729 (T) Poly-3 test P=0.609 P=0.123N P=0.125N P=0.478N


### Mammary Gland: Fibroadenoma or Adenoma Overall rate 35/50 (70%) 29/50 (58%) 31/50 (62%) 34/50 (68%) Adjusted rate 74.0% 63.5% 68.7% 71.1% Terminal rate 28/37 (76%) 25/36 (69%) 24/33 (73%) 30/41 (73%) First incidence (days) 423 365 547 636 Poly-3 test P=0.466 P=0.184N P=0.362N P=0.464N


### Mammary Gland: Carcinoma Overall rate 3/50 (6%) 1/50 (2%) 0/50 (0%) 2/50 (4%) Adjusted rate 6.5% 2.3% 0.0% 4.3% Terminal rate 0/37 (0%) 0/36 (0%) 0/33 (0%) 2/41 (5%) First incidence (days) 462 541 — 729 (T) Poly-3 test P=0.483N P=0.323N P=0.132N P=0.495N

### 131 Sodium Chlorate, NTP TR 517

Mammary Gland: Adenoma or Carcinoma Overall rate 6/50 (12%) 1/50 (2%) 0/50 (0%) 4/50 (8%) Adjusted rate 12.9% 2.3% 0.0% 8.5% Terminal rate 3/37 (8%) 0/36 (0%) 0/33 (0%) 4/41 (10%) First incidence (days) 462 541 — 729 (T) Poly-3 test P=0.494N P=0.064N P=0.019N P=0.362N


### Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma Overall rate 37/50 (74%) 30/50 (60%) 31/50 (62%) 35/50 (70%) Adjusted rate 76.0% 64.9% 68.7% 73.2% Terminal rate 28/37 (76%) 25/36 (69%) 24/33 (73%) 31/41 (76%) First incidence (days) 423 365 547 636 Poly-3 test P=0.466 P=0.161N P=0.280N P=0.466N



### Pancreatic Islets: Adenoma or Carcinoma Overall rate 3/50 (6%) 2/49 (4%) 0/49 (0%) 1/50 (2%) Adjusted rate 6.7% 4.7% 0.0% 2.1% Terminal rate 3/37 (8%) 2/36 (6%) 0/32 (0%) 1/41 (2%) First incidence (days) 729 (T) 729 (T) — 729 (T) Poly-3 test P=0.153N P=0.518N P=0.129N P=0.288N


### Pituitary Gland (Pars Distalis): Adenoma Overall rate 23/49 (47%) 18/49 (37%) 17/50 (34%) 25/50 (50%) Adjusted rate 49.9% 41.0% 36.5% 51.3% Terminal rate 16/36 (44%) 15/36 (42%) 9/33 (27%) 20/41 (49%) First incidence (days) 511 626 511 475 Poly-3 test P=0.367 P=0.261N P=0.134N P=0.526


### Pituitary Gland (Pars Distalis): Carcinoma Overall rate 1/49 (2%) 3/49 (6%) 0/50 (0%) 0/50 (0%) Adjusted rate 2.3% 6.8% 0.0% 0.0% Terminal rate 0/36 (0%) 1/36 (3%) 0/33 (0%) 0/41 (0%) First incidence (days) 644 636 — — Poly-3 test P=0.074N P=0.304 P=0.504N P=0.487N


### Pituitary Gland (Pars Distalis): Adenoma or Carcinoma Overall rate 24/49 (49%) 21/49 (43%) 17/50 (34%) 25/50 (50%) Adjusted rate 51.7% 47.1% 36.5% 51.3% Terminal rate 16/36 (44%) 16/36 (44%) 9/33 (27%) 20/41 (49%) First incidence (days) 511 626 511 475 Poly-3 test P=0.527N P=0.409N P=0.099N P=0.566N


### Skin: Trichoepithelioma or Basal Cell Carcinoma Overall rate 3/50 (6%) 0/50 (0%) 0/50 (0%) 0/50 (0%) Adjusted rate 6.7% 0.0% 0.0% 0.0% Terminal rate 3/37 (8%) 0/36 (0%) 0/33 (0%) 0/41 (0%) First incidence (days) 729 (T) — — — Poly-3 test P=0.084N P=0.123N P=0.125N P=0.110N


### Skin: Keratoacanthoma, Trichoepithelioma, or Basal Cell Carcinoma Overall rate 3/50 (6%) 0/50 (0%) 0/50 (0%) 1/50 (2%) Adjusted rate 6.7% 0.0% 0.0% 2.1% Terminal rate 3/37 (8%) 0/36 (0%) 0/33 (0%) 0/41 (0%) First incidence (days) 729 (T) — — 635 Poly-3 test P=0.337N P=0.123N P=0.125N P=0.285N 

### TABLE 

### B3 Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 132

Skin: Fibroma Overall rate 4/50 (8%) 1/50 (2%) 1/50 (2%) 1/50 (2%) Adjusted rate 8.9% 2.3% 2.3% 2.1% Terminal rate 3/37 (8%) 0/36 (0%) 1/33 (3%) 1/41 (2%) First incidence (days) 623 714 729 (T) 729 (T) Poly-3 test P=0.175N P=0.188N P=0.191N P=0.167N



### Skin: Fibroma, Fibrosarcoma, or Sarcoma Overall rate 4/50 (8%) 2/50 (4%) 1/50 (2%) 2/50 (4%) Adjusted rate 8.9% 4.6% 2.3% 4.2% Terminal rate 3/37 (8%) 0/36 (0%) 1/33 (3%) 1/41 (2%) First incidence (days) 623 714 729 (T) 670 Poly-3 test P=0.277N P=0.351N P=0.191N P=0.316N


### Thyroid Gland (C-Cell): Adenoma Overall rate 12/47 (26%) 9/47 (19%) 11/43 (26%) 9/46 (20%) Adjusted rate 28.0% 21.2% 28.3% 20.6% Terminal rate 10/36 (28%) 6/36 (17%) 11/32 (34%) 9/40 (23%) First incidence (days) 661 644 729 (T) 729 (T) Poly-3 test P=0.368N P=0.317N P=0.585 P=0.292N


### Thyroid Gland (C-Cell): Carcinoma Overall rate 1/47 (2%) 3/47 (6%) 1/43 (2%) 3/46 (7%) Adjusted rate 2.3% 7.1% 2.5% 6.9% Terminal rate 1/36 (3%) 2/36 (6%) 0/32 (0%) 3/40 (8%) First incidence (days) 729 (T) 626 587 729 (T) Poly-3 test P=0.394 P=0.302 P=0.743 P=0.314


### Thyroid Gland (C-Cell): Adenoma or Carcinoma Overall rate 13/47 (28%) 11/47 (23%) 12/43 (28%) 12/46 (26%) Adjusted rate 30.3% 25.7% 30.5% 27.5% Terminal rate 11/36 (31%) 7/36 (19%) 11/32 (34%) 12/40 (30%) First incidence (days) 661 626 587 729 (T) Poly-3 test P=0.526N P=0.406N P=0.588 P=0.479N


### Thyroid Gland (Follicular Cell): Adenoma or Carcinoma Overall rate 1/47 (2%) 0/47 (0%) 1/43 (2%) 4/46 (9%) Adjusted rate 2.3% 0.0% 2.6% 9.1% Terminal rate 1/36 (3%) 0/36 (0%) 0/32 (0%) 2/40 (5%) First incidence (days) 729 (T) — 703 644 Poly-3 test P=0.026 P=0.503N P=0.741 P=0.189


### Uterus: Stromal Polyp Overall rate 9/50 (18%) 8/50 (16%) 9/50 (18%) 7/50 (14%) Adjusted rate 20.0% 18.2% 20.0% 14.7% Terminal rate 8/37 (22%) 7/36 (19%) 4/33 (12%) 5/41 (12%) First incidence (days) 644 636 514 635 Poly-3 test P=0.318N P=0.521N P=0.603 P=0.347N


### Uterus: Stromal Polyp or Stromal Sarcoma Overall rate 10/50 (20%) 8/50 (16%) 9/50 (18%) 7/50 (14%) Adjusted rate 22.2% 18.2% 20.0% 14.7% Terminal rate 9/37 (24%) 7/36 (19%) 4/33 (12%) 5/41 (12%) First incidence (days) 644 636 514 635 Poly-3 test P=0.255N P=0.417N P=0.501N P=0.255N 

### TABLE 

### B3 Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 133 Sodium Chlorate, NTP TR 517

All Organs: Mononuclear Cell Leukemia Overall rate 11/50 (22%) 9/50 (18%) 13/50 (26%) 9/50 (18%) Adjusted rate 24.0% 20.4% 29.0% 18.8% Terminal rate 7/37 (19%) 8/36 (22%) 7/33 (21%) 6/41 (15%) First incidence (days) 594 623 615 636 Poly-3 test P=0.408N P=0.437N P=0.385 P=0.359N


### All Organs: Benign Neoplasms Overall rate 46/50 (92%) 42/50 (84%) 44/50 (88%) 47/50 (94%) Adjusted rate 94.3% 88.7% 90.1% 95.1% Terminal rate 35/37 (95%) 33/36 (92%) 29/33 (88%) 39/41 (95%) First incidence (days) 423 365 511 475 Poly-3 test P=0.319 P=0.248N P=0.342N P=0.609


### All Organs: Malignant Neoplasms Overall rate 21/50 (42%) 22/50 (44%) 19/50 (38%) 22/50 (44%) Adjusted rate 44.2% 47.3% 40.4% 45.5% Terminal rate 14/37 (38%) 14/36 (39%) 8/33 (24%) 17/41 (42%) First incidence (days) 462 541 547 635 Poly-3 test P=0.497N P=0.465 P=0.432N P=0.533


### All Organs: Benign or Malignant Neoplasms Overall rate 49/50 (98%) 48/50 (96%) 46/50 (92%) 48/50 (96%) Adjusted rate 98.0% 97.5% 93.6% 97.1% Terminal rate 36/37 (97%) 35/36 (97%) 30/33 (91%) 40/41 (98%) First incidence (days) 423 365 511 475 Poly-3 test P=0.429N P=0.706N P=0.271N P=0.652N

(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, pancreatic islets, pituitary gland, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality c Observed incidence at terminal kill d Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for the differential mortality in animals that do not reach terminal sacrifice. A negative trend or a lower incidence in an exposed group is indicated by N

. e Not applicable; no neoplasms in animal group 

### TABLE 

### B3 Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 134



### TABLE 

### B4 Historical Incidence of Thyroid Gland Neoplasms in Control Female F344/N Rats a



### Incidence in Controls Follicular Cell Follicular Cell Follicular Cell

Adenoma Carcinoma Adenoma Study or Carcinoma

Historical Incidence in Drinking Water Controls Given NTP-2000 Diet

Dipropylene glycol 0/45 1/45 1/45 Sodium chlorate 0/47 1/47 1/47 Sodium nitrite 1/50 1/50 2/50



### Overall Historical Incidence: Drinking Water Studies Total (%) 1/142 (0.7%) 3/142 (2.1%) 4/142 (2.8%) Mean ± standard deviation 1.0% ± 1.4% 2.1% ± 0.2% 3.1% ± 1.3% Range 0%-2% 2% 2%-4%



### Overall Historical Incidence: All Routes Total (%) 3/1,192 (0.3%) 13/1,192 (1.1%) 16/1,192 (1.3%) Mean ± standard deviation 0.2% ± 0.6% 1.2% ± 1.2% 1.5% ± 1.3% Range 0%-2% 0%-4% 0%-4%

a Data as of April 19, 2004

### 135 Sodium Chlorate, NTP TR 517

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Moribund 10 11 11 4 Natural deaths 3 3 6 5 Survivors

Died last week of study 2 1 1 Terminal sacrifice 37 34 32 40

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine small, duodenum (50) (49) (45) (49)

Amyloid deposition 1 (2%) Epithelium, cyst 1 (2%) Liver (50) (50) (50) (50)

Angiectasis, focal 2 (4%) Basophilic focus 42 (84%) 44 (88%) 41 (82%) 42 (84%) Cholangiofibrosis 1 (2%) 1 (2%) 3 (6%) Clear cell focus 6 (12%) 16 (32%) 18 (36%) 10 (20%) Congestion 6 (12%) 2 (4%) 2 (4%) 1 (2%) Degeneration, cystic, focal 1 (2%) 1 (2%) 3 (6%) Eosinophilic focus 1 (2%) 1 (2%) 2 (4%) Fibrosis, focal 1 (2%) Hemorrhage 1 (2%) Hepatodiaphragmatic nodule 7 (14%) 4 (8%) 8 (16%) 3 (6%) Hyperplasia, focal, histiocytic 20 (40%) 19 (38%) 16 (32%) 23 (46%) Hyperplasia, focal, regenerative 1 (2%) 1 (2%) Hyperplasia, regenerative 2 (4%) Infarct, multiple 1 (2%) Infiltration cellular, focal, polymorphonuclear 1 (2%) Infiltration cellular, polymorphonuclear 1 (2%) Infiltration cellular, mixed cell 39 (78%) 38 (76%) 35 (70%) 41 (82%) Mixed cell focus 12 (24%) 6 (12%) 7 (14%) 8 (16%) Thrombosis 1 (2%) Bile duct, cyst 1 (2%) Bile duct, hyperplasia 29 (58%) 24 (48%) 34 (68%) 26 (52%) Capsule, cyst 1 (2%) Hepatocyte, karyomegaly 1 (2%) Hepatocyte, necrosis, focal 2 (4%) 1 (2%) Hepatocyte, vacuolization cytoplasmic 2 (4%) Hepatocyte, vacuolization cytoplasmic, diffuse 1 (2%) 2 (4%) 1 (2%) 2 (4%) Hepatocyte, vacuolization cytoplasmic, focal 17 (34%) 10 (20%) 10 (20%) 10 (20%) Hepatocyte, periportal, vacuolization cytoplasmic 2 (4%) Hepatocyte, periportal, centrilobular,

vacuolization cytoplasmic 1 (2%) Hepatocyte, centrilobular, necrosis 2 (4%) 1 (2%) 1 (2%) 2 (4%) Hepatocyte, centrilobular, vacuolization cytoplasmic 5 (10%) 3 (6%) 8 (16%) 3 (6%) Hepatocyte, midzonal, vacuolization cytoplasmic 2 (4%)

a Number of animals examined microscopically at the site and the number of animals with lesion 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 136

Alimentary System (continued) Mesentery (18) (10) (13) (16)

Inflammation, chronic, focal 1 (10%) Fat, necrosis 4 (22%) 2 (20%) 1 (8%) Fat, necrosis, focal 12 (67%) 5 (50%) 9 (69%) 13 (81%) Pancreas (50) (49) (49) (49)

Lipomatosis 1 (2%) Acinus, atrophy, diffuse 1 (2%) Acinus, atrophy, focal 15 (30%) 8 (16%) 9 (18%) 16 (33%) Duct, cyst, focal 1 (2%) 2 (4%) 4 (8%) 1 (2%) Duct, cyst, focal, multiple 10 (20%) 14 (29%) 11 (22%) 18 (37%) Duct, hyperplasia, focal 1 (2%) Salivary glands (50) (50) (50) (50)

Atrophy, focal 2 (4%) Stomach, forestomach (50) (50) (50) (50)

Edema 1 (2%) 1 (2%) 1 (2%) Erosion 1 (2%) Inflammation, chronic 2 (4%) 1 (2%) Inflammation, chronic, focal 1 (2%) Perforation 1 (2%) Ulcer 2 (4%) 7 (14%) 1 (2%) Epithelium, hyperplasia 2 (4%) 4 (8%) 6 (12%) 1 (2%) Stomach, glandular (50) (49) (49) (50)

Erosion 2 (4%) 2 (4%) 2 (4%) Erosion, focal 1 (2%) Inflammation, chronic 1 (2%) Necrosis, focal 1 (2%) Pigmentation, focal 1 (2%) Ulcer 1 (2%) Tooth (2) (2) (1)

Malformation 1 (50%) Dentine, malformation 1 (50%) Peridontal tissue, inflammation, chronic 1 (50%) 2 (100%) Peridontal tissue, inflammation, chronic, focal 1 (100%)



### Cardiovascular System Blood vessel (1) (1)

Thrombosis 1 (100%) Heart (50) (50) (50) (50)

Cardiomyopathy 4 (8%) 2 (4%) 2 (4%) Infiltration cellular, mixed cell 1 (2%) 1 (2%) 4 (8%) Thrombosis 1 (2%)



### Endocrine System Adrenal cortex (50) (50) (50) (50)

Accessory adrenal cortical nodule 2 (4%) 3 (6%) 5 (10%) 2 (4%) Angiectasis 2 (4%) 1 (2%) 1 (2%) 2 (4%) Cytoplasmic alteration, focal 1 (2%) 2 (4%) 3 (6%) 2 (4%) Degeneration, cystic, focal 1 (2%) 1 (2%) Fibrosis, focal 1 (2%) Hematopoietic cell proliferation 1 (2%) 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 137 Sodium Chlorate, NTP TR 517

Endocrine System (continued) Adrenal cortex (continued) (50) (50) (50) (50)

Hemorrhage 1 (2%) 1 (2%) 2 (4%) Infiltration cellular, mixed cell 1 (2%) Necrosis, focal 1 (2%) Vacuolization cytoplasmic, focal 7 (14%) 13 (26%) 7 (14%) 8 (16%) Adrenal medulla (50) (50) (50) (50)

Angiectasis 1 (2%) Hyperplasia, focal 3 (6%) 4 (8%) 1 (2%) 1 (2%) Infiltration cellular, focal, lymphoid 1 (2%) Islets, pancreatic (50) (49) (49) (50)

Hyperplasia, focal 1 (2%) Parathyroid gland (47) (47) (48) (47)

Hyperplasia, focal 1 (2%) Pituitary gland (49) (49) (50) (50)

Angiectasis 10 (20%) 6 (12%) 2 (4%) 13 (26%) Pigmentation, focal 1 (2%) Pars distalis, angiectasis 1 (2%) 2 (4%) 2 (4%) Pars distalis, cyst 2 (4%) 2 (4%) 1 (2%) 2 (4%) Pars distalis, cytoplasmic alteration, focal 3 (6%) 1 (2%) 2 (4%) 3 (6%) Pars distalis, degeneration, cystic, focal 11 (22%) 14 (29%) 11 (22%) 3 (6%) Pars distalis, hemorrhage, focal 9 (18%) 6 (12%) 10 (20%) 2 (4%) Pars distalis, hyperplasia, focal 7 (14%) 5 (10%) 10 (20%) 4 (8%) Pars distalis, infiltration cellular, focal 1 (2%) Pars nervosa, hyperplasia, atypical, focal 1 (2%) Rathke’s cleft, cyst 1 (2%) 2 (4%) Rathke’s cleft, hemorrhage 1 (2%) 2 (4%) 2 (4%) 6 (12%) Rathke’s cleft, hyperplasia, cystic 1 (2%) Thyroid gland (47) (47) (43) (46)

Congestion 1 (2%) Ultimobranchial cyst 1 (2%) 1 (2%) C-cell, hyperplasia 43 (91%) 45 (96%) 43 (100%) 44 (96%) Follicle, mineralization, focal 25 (53%) 26 (55%) 40 (93%) 44 (96%) Follicular cell, hyperplasia, cystic, focal 1 (2%) Follicular cell, hypertrophy 3 (6%) 7 (15%) 27 (63%) 42 (91%)



### General Body System Tissue NOS (1) (2) (4) (6)

Mediastinum, cyst 1 (25%) Mediastinum, thrombosis 1 (17%) Oral, foreign body, focal 1 (17%) Oral, necrosis, focal 1 (17%)



### Genital System Clitoral gland (49) (50) (50) (49)

Cyst 1 (2%) Degeneration, cystic 5 (10%) 2 (4%) 6 (12%) 1 (2%) Hyperplasia 1 (2%) Hyperplasia, cystic 1 (2%) 4 (8%) 3 (6%) 1 (2%) Hyperplasia, cystic, focal 1 (2%) Inflammation, chronic 6 (12%) 2 (4%) 1 (2%) 3 (6%) Duct, inflammation, chronic 1 (2%) 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 138

Genital System (continued) Ovary (50) (50) (49) (50)

Cyst 5 (10%) 1 (2%) 1 (2%) 4 (8%) Corpus luteum, hyperplasia 1 (2%) Interstitial cell, hyperplasia 1 (2%) 1 (2%) Periovarian tissue, cyst 4 (8%) 4 (8%) 2 (4%) 1 (2%) Uterus (50) (50) (49) (50)

Hemorrhage 1 (2%) 1 (2%) Hydrometra 1 (2%) Inflammation, chronic 1 (2%) Inflammation, focal, suppurative 1 (2%) Inflammation, suppurative 1 (2%) 1 (2%) Ulcer, chronic active 1 (2%) Endometrium, hyperplasia, cystic 16 (32%) 7 (14%) 16 (33%) 11 (22%) Vagina (6) (3) (3) (1)

Cyst 2 (33%) 1 (33%) 1 (33%) 1 (100%) Inflammation, chronic 1 (17%) Inflammation, suppurative 1 (33%) 1 (33%)



### Hematopoietic System Bone marrow (50) (49) (50) (50)

Angiectasis 1 (2%) Hemorrhage 1 (2%) Hyperplasia 2 (4%) 1 (2%) 1 (2%) Hyperplasia, focal, histiocytic 2 (4%) 2 (4%) Myeloid cell, hyperplasia 7 (14%) 3 (6%) 2 (4%) 6 (12%) Myeloid cell, erythroid cell, hyperplasia 2 (4%) 2 (4%) 3 (6%) Lymph node (36) (34) (30) (39)

Hyperplasia, plasma cell 1 (3%) Pigmentation 1 (3%) Deep cervical, hemorrhage 1 (3%) Deep cervical, hyperplasia, lymphoid 1 (3%) Deep cervical, hyperplasia, plasma cell 1 (3%) Mediastinal, angiectasis 1 (3%) Mediastinal, congestion 1 (3%) Mediastinal, ectasia 2 (6%) 4 (12%) 2 (7%) 4 (10%) Mediastinal, hemorrhage 6 (17%) 6 (18%) 5 (17%) 3 (8%) Mediastinal, hyperplasia, histiocytic 1 (3%) 4 (12%) 2 (7%) 3 (8%) Mediastinal, hyperplasia, lymphoid 1 (3%) 2 (6%) 2 (7%) 3 (8%) Mediastinal, hyperplasia, plasma cell 1 (3%) Mediastinal, infiltration cellular, mixed cell 1 (3%) Mediastinal, pigmentation 1 (3%) Pancreatic, angiectasis 1 (3%) Pancreatic, ectasia 1 (3%) 1 (3%) Pancreatic, hemorrhage 5 (14%) 3 (9%) 5 (13%) Pancreatic, hyperplasia, histiocytic 31 (86%) 22 (65%) 15 (50%) 25 (64%) Pancreatic, hyperplasia, lymphoid 1 (3%) Pancreatic, pigmentation 1 (3%) 7 (21%) 3 (10%) 6 (15%) Lymph node, mandibular (4) (6) (4) (5)

Ectasia 1 (17%) 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 139 Sodium Chlorate, NTP TR 517

Hematopoietic System (continued) Lymph node, mesenteric (50) (49) (49) (50)

Hemorrhage 1 (2%) Hyperplasia, focal, histiocytic 1 (2%) Hyperplasia, histiocytic 2 (4%) 4 (8%) 4 (8%) Hyperplasia, lymphoid 1 (2%) Spleen (50) (50) (50) (50)

Angiectasis, focal 1 (2%) 1 (2%) Fibrosis, focal 1 (2%) 1 (2%) Hematopoietic cell proliferation 16 (32%) 21 (42%) 8 (16%) 17 (34%) Hemorrhage 1 (2%) 1 (2%) 1 (2%) 2 (4%) Hyperplasia, focal, histiocytic 2 (4%) 4 (8%) 2 (4%) 5 (10%) Infarct 1 (2%) Pigmentation, focal 1 (2%) Red pulp, fibrosis, diffuse 1 (2%) Thymus (49) (48) (48) (48)

Angiectasis 2 (4%) 1 (2%) Cyst 1 (2%) Hemorrhage 1 (2%) 2 (4%) 1 (2%) Hyperplasia, lymphoid 1 (2%) 1 (2%)



### Integumentary System Mammary gland (50) (50) (50) (50)

Dilatation 37 (74%) 39 (78%) 34 (68%) 38 (76%) Ectasia 4 (8%) 1 (2%) 3 (6%) 2 (4%) Fibrosis 2 (4%) 1 (2%) 1 (2%) 4 (8%) Fibrosis, focal 1 (2%) Hyperplasia 7 (14%) 11 (22%) 10 (20%) 9 (18%) Hyperplasia, focal 1 (2%) 1 (2%) Inflammation, chronic 1 (2%) Skin (50) (50) (50) (50)

Inflammation, chronic, focal 1 (2%) Ulcer 1 (2%) Subcutaneous tissue, fibrosis, focal 1 (2%)



### Musculoskeletal System None



### Nervous System Brain (49) (50) (50) (50)

Compression, focal 9 (18%) 9 (18%) 10 (20%) 9 (18%) Hemorrhage, focal 4 (8%) 3 (6%) 2 (4%) Necrosis, focal 1 (2%) Thalamus, mineralization, focal 1 (2%) Thalamus, necrosis, focal 1 (2%) 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 140

Respiratory System Lung (50) (50) (50) (50)

Congestion 2 (4%) 1 (2%) Hemorrhage, focal 1 (2%) 1 (2%) 2 (4%) Hyperplasia, focal, histiocytic 1 (2%) 1 (2%) 2 (4%) Hyperplasia, histiocytic 4 (8%) 6 (12%) 5 (10%) 2 (4%) Infiltration cellular, polymorphonuclear 1 (2%) Infiltration cellular, mixed cell 2 (4%) 3 (6%) 2 (4%) 1 (2%) Inflammation, chronic, focal 2 (4%) 4 (8%) 2 (4%) Metaplasia, focal, osseous 1 (2%) Alveolar epithelium, hyperplasia 1 (2%) Alveolar epithelium, hyperplasia, focal 4 (8%) 2 (4%) 3 (6%) 2 (4%) Interstitium, edema 1 (2%) Mediastinum, edema 1 (2%) Peribronchiolar, hyperplasia, lymphoid 1 (2%) Nose (50) (50) (50) (50)

Inflammation, suppurative 1 (2%) 2 (4%) Nasolacrimal duct, inflammation 1 (2%) 1 (2%) Respiratory epithelium, metaplasia, focal, squamous 1 (2%)



### Special Senses System Eye (50) (49) (47) (50)

Atrophy 1 (2%) Cataract 2 (4%) 3 (6%) 1 (2%) 2 (4%) Hemorrhage 1 (2%) Retinal detachment 1 (2%) Bilateral, atrophy 1 (2%) Cornea, inflammation, chronic 1 (2%) 1 (2%) Cornea, necrosis, focal 1 (2%) Retina, degeneration 1 (2%) 2 (4%) 1 (2%) 2 (4%) Harderian gland (50) (50) (50) (50)

Hyperplasia, cystic, focal 1 (2%) Hyperplasia, focal 1 (2%) Hyperplasia, focal, histiocytic 2 (4%) 1 (2%) Inflammation, chronic, focal 1 (2%) 1 (2%) 2 (4%) Metaplasia, focal, squamous 1 (2%) Epithelium, hyperplasia, focal 1 (2%)



### Urinary System Kidney (50) (49) (47) (47)

Atrophy, diffuse 1 (2%) Atrophy, focal 1 (2%) 2 (4%) Cyst 1 (2%) 1 (2%) Hyperplasia, lymphoid 1 (2%) Infarct 1 (2%) 1 (2%) Infiltration cellular, polymorphonuclear 1 (2%) Inflammation, chronic 1 (2%) 2 (4%) Inflammation, chronic, focal, granulomatous 1 (2%) Nephropathy 43 (86%) 41 (84%) 37 (79%) 38 (81%) Pelvis, inflammation, chronic 1 (2%) Pelvis, transitional epithelium, hyperplasia 1 (2%) Renal tubule, accumulation, hyaline droplet 5 (10%) 12 (24%) 11 (23%) 5 (11%) Renal tubule, pigmentation 2 (4%) 1 (2%) 4 (9%) 4 (9%) 

### TABLE 

### B5 Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L

### 141



# APPENDIX C SUMMARY OF LESIONS IN MALE MICE IN THE 2-YEAR DRINKING WATER STUDY OF SODIUM CHLORATE

TABLE 

### C1 Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 TABLE 

### C3 Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

### Sodium Chlorate, NTP TR 517 142



### TABLE 

### C1 Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Moribund 5 5 4 10 Natural deaths 7 4 5 7 Survivors

Terminal sacrifice 38 41 41 33

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, colon (48) (50) (50) (50)

Histiocytic sarcoma, metastatic, liver 1 (2%) Intestine large, cecum (47) (49) (49) (48)

Carcinoma 1 (2%) Histiocytic sarcoma 1 (2%) Histiocytic sarcoma, metastatic, liver 1 (2%) Intestine small, duodenum (48) (50) (49) (49)

Adenoma 1 (2%) Carcinoma 1 (2%) Carcinoma, metastatic, islets, pancreatic 1 (2%) Polyp adenomatous 2 (4%) Intestine small, jejunum (47) (49) (50) (50)

Adenoma 1 (2%) 1 (2%) Carcinoma 2 (4%) 2 (4%) 2 (4%) Liver (48) (50) (50) (50)

Carcinoma, metastatic, islets, pancreatic 1 (2%) Cholangiocarcinoma 1 (2%) 1 (2%) Hemangioma 1 (2%) Hemangiosarcoma 1 (2%) 2 (4%) 1 (2%) 2 (4%) Hemangiosarcoma, metastatic, spleen 1 (2%) Hepatoblastoma 5 (10%) 3 (6%) 1 (2%) 3 (6%) Hepatoblastoma, multiple 1 (2%) Hepatocellular carcinoma 14 (29%) 13 (26%) 14 (28%) 12 (24%) Hepatocellular carcinoma, multiple 6 (13%) 1 (2%) 5 (10%) 1 (2%) Hepatocellular adenoma 16 (33%) 15 (30%) 13 (26%) 14 (28%) Hepatocellular adenoma, multiple 14 (29%) 17 (34%) 23 (46%) 16 (32%) Histiocytic sarcoma 1 (2%) 2 (4%) 2 (4%) Ito cell tumor malignant 1 (2%) Leiomyosarcoma, metastatic, mesentery 1 (2%) Mesentery (9) (10) (10) (8)

Cholangiocarcinoma, metastatic, liver 1 (11%) Hepatocellular carcinoma, metastatic, liver 1 (10%) 1 (13%) Histiocytic sarcoma 2 (25%) Histiocytic sarcoma, metastatic, liver 1 (11%) Ito cell tumor malignant, metastatic, liver 1 (10%) Leiomyosarcoma 1 (11%) Liposarcoma 1 (10%) Pancreas (48) (50) (50) (50)

Cholangiocarcinoma, metastatic, liver 1 (2%) Hepatocellular carcinoma, metastatic, liver 1 (2%) 1 (2%) Histiocytic sarcoma, metastatic, liver 1 (2%) Salivary glands (50) (50) (50) (50)

Histiocytic sarcoma 1 (2%)

### 143 Sodium Chlorate, NTP TR 517

Alimentary System (continued) Stomach, forestomach (49) (50) (50) (50)

Leiomyosarcoma, metastatic, mesentery 1 (2%) Squamous cell papilloma 2 (4%) 2 (4%) Stomach, glandular (48) (50) (50) (50)

Adenoma 2 (4%) Histiocytic sarcoma, metastatic, liver 1 (2%) Leiomyosarcoma, metastatic, mesentery 1 (2%)



### Cardiovascular System Heart (50) (50) (50) (50)

Cholangiocarcinoma, metastatic, liver 1 (2%)



### Endocrine System Adrenal cortex (50) (50) (50) (50)

Adenoma 1 (2%) 1 (2%) 1 (2%) 1 (2%) Hepatocellular carcinoma, metastatic, liver 1 (2%) Bilateral, subcapsular, adenoma 1 (2%) Subcapsular, adenoma 1 (2%) 3 (6%) 4 (8%) 2 (4%) Islets, pancreatic (48) (50) (50) (50)

Adenoma 1 (2%) 1 (2%) Carcinoma 1 (2%) Pituitary gland (47) (47) (45) (49)

Pars distalis, adenoma 1 (2%)



### General Body System None



### Genital System Epididymis (50) (50) (50) (50)

Cholangiocarcinoma, metastatic, liver 1 (2%) Histiocytic sarcoma, metastatic, liver 1 (2%) Prostate (50) (50) (50) (50) Seminal vesicle (50) (50) (50) (50)

Histiocytic sarcoma, metastatic, liver 1 (2%) Testes (50) (50) (50) (50)

Interstitial cell, adenoma 2 (4%)



### Hematopoietic System Bone marrow (49) (50) (50) (50)

Hemangiosarcoma, metastatic, spleen 1 (2%) Histiocytic sarcoma 1 (2%) Lymph node (3) (1) (3)

Mediastinal, carcinoma, metastatic, harderian gland 1 (33%) Mediastinal, hepatocellular carcinoma, metastatic, liver 1 (100%) 1 (33%) Mediastinal, histiocytic sarcoma, metastatic, liver 1 (33%) Mediastinal, leiomyosarcoma, metastatic, mesentery 1 (33%) Pancreatic, hepatocellular carcinoma, metastatic, liver 1 (100%) Pancreatic, histiocytic sarcoma, metastatic, liver 1 (33%) Renal, hepatocellular carcinoma, metastatic, liver 1 (100%) Renal, histiocytic sarcoma, metastatic, liver 1 (33%) Renal, leiomyosarcoma, metastatic, mesentery 1 (33%) 

### TABLE 

### C1 Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 144

Hematopoietic System (continued) Lymph node, mandibular (49) (48) (45) (49)

Histiocytic sarcoma 1 (2%) Lymph node, mesenteric (47) (50) (50) (50)

Hepatocellular carcinoma, metastatic, liver 1 (2%) Histiocytic sarcoma 1 (2%) Leiomyosarcoma, metastatic, mesentery 1 (2%) Spleen (48) (50) (50) (50)

Hemangiosarcoma 1 (2%) Histiocytic sarcoma 1 (2%) 1 (2%) Histiocytic sarcoma, metastatic, liver 1 (2%) Leiomyosarcoma, metastatic, mesentery 1 (2%) Thymus (43) (43) (40) (44)

Alveolar/bronchiolar carcinoma, metastatic, lung 1 (3%) Hepatocellular carcinoma, metastatic, liver 1 (3%) Leiomyosarcoma, metastatic, mesentery 1 (2%)



### Integumentary System Skin (50) (50) (50) (50)

Subcutaneous tissue, fibrous histiocytoma 1 (2%) Subcutaneous tissue, lipoma 1 (2%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Carcinoma, metastatic, harderian gland 1 (2%) Skeletal muscle (3) (1) (3) (2)

Alveolar/bronchiolar carcinoma, metastatic, lung 2 (67%) Hepatocellular carcinoma, metastatic, liver 1 (50%) Histiocytic sarcoma, metastatic, liver 1 (33%) Leiomyosarcoma, metastatic, mesentery 1 (33%) Rhabdomyosarcoma 1 (50%)



### Nervous System None



### Respiratory System Lung (50) (50) (50) (50)

Alveolar/bronchiolar adenoma 6 (12%) 4 (8%) 7 (14%) 6 (12%) Alveolar/bronchiolar carcinoma 4 (8%) 5 (10%) 6 (12%) 4 (8%) Alveolar/bronchiolar carcinoma, multiple 1 (2%) Carcinoma, metastatic, harderian gland 1 (2%) Carcinoma, metastatic, kidney 1 (2%) Hemangiosarcoma 1 (2%) Hepatoblastoma, metastatic, liver 1 (2%) 2 (4%) Hepatocellular carcinoma, metastatic, liver 9 (18%) 2 (4%) 4 (8%) 6 (12%) Histiocytic sarcoma 1 (2%) 1 (2%) Histiocytic sarcoma, metastatic, liver 1 (2%) Leiomyosarcoma, metastatic, mesentery 1 (2%) 

### TABLE 

### C1 Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 145 Sodium Chlorate, NTP TR 517

Special Senses System Harderian gland (50) (50) (50) (49)

Adenoma 6 (12%) 4 (8%) 4 (8%) 6 (12%) Carcinoma 1 (2%) 1 (2%)



### Urinary System Kidney (49) (50) (50) (50)

Alveolar/bronchiolar carcinoma, metastatic, lung 1 (2%) Hepatocellular carcinoma, metastatic, liver 1 (2%) Renal tubule, adenoma 1 (2%) Renal tubule, carcinoma 1 (2%)



### Systemic Lesions Multiple organsb (50) (50) (50) (50)

Histiocytic sarcoma 1 (2%) 2 (4%) 3 (6%) Lymphoma malignant 3 (6%) 1 (2%) 3 (6%)



### Neoplasm Summary Total animals with primary neoplasms c 45 45 47 45

Total primary neoplasms 86 76 95 87 Total animals with benign neoplasms 34 38 37 34

Total benign neoplasms 47 48 59 51 Total animals with malignant neoplasms 29 22 30 27

Total malignant neoplasms 39 28 36 36 Total animals with metastatic neoplasms 12 5 9 8

Total metastatic neoplasms 38 5 20 14

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 c Primary neoplasms: all neoplasms except metastatic neoplasms 

### TABLE 

### C1 Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 146

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder A + + + A + A M + + M M +++++++++++++ Intestine large, colon A +++++A++++++++++++++++++

Histiocytic sarcoma, metastatic, liver X Intestine large, rectum A +++++++++++++I++++++++++ Intestine large, cecum A +++++A+++A++++++++++++++

Histiocytic sarcoma, metastatic, liver X Intestine small, duodenum A +++++A++++++++++++++++++

Adenoma Intestine small, jejunum A ++++A+++++A+++++++++++++

Carcinoma Intestine small, ileum A +++++A++++++++++++++++++ Liver A +++++A++++++++++++++++++

Cholangiocarcinoma X Hemangiosarcoma Hepatoblastoma X X X Hepatoblastoma, multiple Hepatocellular carcinoma X X X X X X X Hepatocellular carcinoma, multiple X X Hepatocellular adenoma X X X X X X X X X Hepatocellular adenoma, multiple X X X X X Histiocytic sarcoma X Leiomyosarcoma, metastatic, mesentery X Mesentery + + + + + +

Cholangiocarcinoma, metastatic, liver X Histiocytic sarcoma, metastatic, liver X Leiomyosarcoma X Pancreas A +++++A++++++++++++++++++

Cholangiocarcinoma, metastatic, liver X Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma, metastatic, liver X Salivary glands +++++++++++++++++++++++++ Stomach, forestomach A ++++++++++++++++++++++++

Leiomyosarcoma, metastatic, mesentery X Stomach, glandular A +++++A++++++++++++++++++

Histiocytic sarcoma, metastatic, liver X Leiomyosarcoma, metastatic, mesentery X Tooth +


### Cardiovascular System Heart +++++++++++++++++++++++++

Cholangiocarcinoma, metastatic, liver X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3455566666667777777777777 

### Number of Days on Study 0866602236692222222233333 1411233581399999999900000

0000000000000000000000000 

### Carcass ID Number 0513122303110233444402223 7048585991088656258922372

+: Tissue examined microscopically M: Missing tissue X: Lesion present A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined

### 147 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48

Histiocytic sarcoma, metastatic, liver 1 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Histiocytic sarcoma, metastatic, liver 1 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 48

Adenoma X 1 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Carcinoma X X 2 Intestine small, ileum + + + + + M + + + + + + + + + + + + + + + + + + + 47 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 48

Cholangiocarcinoma 1 Hemangiosarcoma X 1 Hepatoblastoma XX 5 Hepatoblastoma, multiple X 1 Hepatocellular carcinoma X X X X X X X 14 Hepatocellular carcinoma, multiple X X X X 6 Hepatocellular adenoma X X X X X X X 16 Hepatocellular adenoma, multiple X X X X X X X X X 14 Histiocytic sarcoma 1 Leiomyosarcoma, metastatic, mesentery 1 Mesentery + + + 9

Cholangiocarcinoma, metastatic, liver 1 Histiocytic sarcoma, metastatic, liver 1 Leiomyosarcoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 48

Cholangiocarcinoma, metastatic, liver 1 Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma, metastatic, liver 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49

Leiomyosarcoma, metastatic, mesentery 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48

Histiocytic sarcoma, metastatic, liver 1 Leiomyosarcoma, metastatic, mesentery 1 Tooth + 2


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50

Cholangiocarcinoma, metastatic, liver 1 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0011111111111111111444444

0000000000000000000000000 T otal 

### Carcass ID Number 4400000111112223344123344 Tissues/ 4713456236790194706140313 T umors

### Sodium Chlorate, NTP TR 517 148

Endocrine System Adrenal cortex +++++++++++++++++++++++++

Adenoma X Bilateral, subcapsular, adenoma X Subcapsular, adenoma Adrenal medulla ++++++A++++++++++++++++++ Islets, pancreatic A +++++A++++++++++++++++++

Adenoma Parathyroid gland M + + + + MM + + + + + + + + + + + + + + + + + + Pituitary gland + + + + + +M+ + + +M+ + + + + + + + +M+ + + Thyroid gland I + + + + +M+ + + + + + + + + + + + + + + + + +


### General Body System None


### Genital System Epididymis +++++++++++++++++++++++++

Histiocytic sarcoma, metastatic, liver X Preputial gland +++++++++++++++++++++++++ Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++

Histiocytic sarcoma, metastatic, liver X Testes +++++++++++++++++++++++++


### Hematopoietic System Bone marrow A ++++++++++++++++++++++++ Lymph node + + +

Mediastinal, histiocytic sarcoma,

metastatic, liver X Mediastinal, leiomyosarcoma,

metastatic, mesentery X Pancreatic, histiocytic sarcoma, metastatic, liver X Renal, histiocytic sarcoma, metastatic, liver X Renal, leiomyosarcoma, metastatic, mesentery X Lymph node, mandibular + + + + + + + M + + + + + + + + + + + + + + + + + Lymph node, mesenteric A + + I + + A ++++++++++++++++++

Hepatocellular carcinoma, metastatic, liver X Leiomyosarcoma, metastatic, mesentery X Spleen A +++++A++++++++++++++++++

Histiocytic sarcoma, metastatic, liver X Leiomyosarcoma, metastatic, mesentery X Thymus M + + + + + + + + MM + + + + + + + + + M + + + +

Leiomyosarcoma, metastatic, mesentery X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3455566666667777777777777 

### Number of Days on Study 0866602236692222222233333 1411233581399999999900000

0000000000000000000000000 

### Carcass ID Number 0513122303110233444402223 7048585991088656258922372

### 149 Sodium Chlorate, NTP TR 517

Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma 1 Bilateral, subcapsular, adenoma 1 Subcapsular, adenoma X 1 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 48

Adenoma X 1 Parathyroid gland + + + + + M + + + + + + + + + + + + + + + + + + + 46 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48


### General Body System None


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma, metastatic liver 1 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma, metastatic, liver 1 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lymph node 3

Mediastinal, histiocytic sarcoma,

metastatic, liver 1 Mediastinal, leiomyosarcoma,

metastatic, mesentery 1 Pancreatic, histiocytic sarcoma, metastatic, liver 1 Renal, histiocytic sarcoma, metastatic, liver 1 Renal, leiomyosarcoma, metastatic, mesentery 1 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 49 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 47

Hepatocellular carcinoma, metastatic, liver 1 Leiomyosarcoma, metastatic, mesentery 1 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 48

Histiocytic sarcoma, metastatic, liver 1 Leiomyosarcoma, metastatic, mesentery 1 Thymus M + + + + + + + M + + + + + + + + + + + + M + + + 43

Leiomyosarcoma, metastatic, mesentery 1 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0011111111111111111444444

0000000000000000000000000 T otal 

### Carcass ID Number 4400000111112223344123344 Tissues/ 4713456236790194706140313 T umors

### Sodium Chlorate, NTP TR 517 150

Integumentary System Mammary gland +++++++++++++++++++++++++ Skin +++++++++++++++++++++++++


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle + +

Histiocytic sarcoma, metastatic, liver X Leiomyosarcoma, metastatic, mesentery X


### Nervous System Brain +++++++++++++++++++++++++


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X X Alveolar/bronchiolar carcinoma X X X X Hepatoblastoma, metastatic, liver Hepatocellular carcinoma, metastatic, liver X X X X X X X Histiocytic sarcoma, metastatic, liver X Leiomyosarcoma, metastatic, mesentery X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + M + + + + + + + + + + + + + + + Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + +

Adenoma X X X


### Urinary System Kidney A ++++++++++++++++++++++++ Urinary bladder ++++++A++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++ Histiocytic sarcoma X

Lymphoma malignant X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

3455566666667777777777777 

### Number of Days on Study 0866602236692222222233333 1411233581399999999900000

0000000000000000000000000 

### Carcass ID Number 0513122303110233444402223 7048585991088656258922372

### 151 Sodium Chlorate, NTP TR 517

Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle + 3

Histiocytic sarcoma, metastatic, liver 1 Leiomyosarcoma, metastatic, mesentery 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X X X X 6 Alveolar/bronchiolar carcinoma 4 Hepatoblastoma, metastatic, liver X 1 Hepatocellular carcinoma, metastatic, liver X X 9 Histiocytic sarcoma, metastatic, liver 1 Leiomyosarcoma, metastatic, mesentery 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 49 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X 6


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Lymphoma malignant X X 3 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0011111111111111111444444

0000000000000000000000000 T otal 

### Carcass ID Number 4400000111112223344123344 Tissues/ 4713456236790194706140313 T umors

### Sodium Chlorate, NTP TR 517 152

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder + M M + M A + + + + + + + + + + + + + + +M+ I + Intestine large, colon +++++++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum +++++++++++++++++++++++++ Intestine small, duodenum +++++++++++++++++++++++++ Intestine small, jejunum M ++++++++++++++++++++++++

Carcinoma Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + +M Liver +++++++++++++++++++++++++

Hemangiosarcoma X X Hepatoblastoma X X Hepatocellular carcinoma X X X X X Hepatocellular carcinoma, multiple Hepatocellular adenoma X X X X Hepatocellular adenoma, multiple X X X X X X X X X X Ito cell tumor malignant X Mesentery + + + +

Ito cell tumor malignant, metastatic, liver X Pancreas +++++++++++++++++++++++++ Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++ Stomach, glandular +++++++++++++++++++++++++

Adenoma X X Tooth + +


### Cardiovascular System Heart +++++++++++++++++++++++++


### Endocrine system Adrenal cortex +++++++++++++++++++++++++

Adenoma Subcapsular, adenoma X X Adrenal medulla +++++++++++++++++++++++++ Islets, pancreatic +++++++++++++++++++++++++ Parathyroid gland + + + +M+ + + +M+ + + + + + + + + + + + + + + Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma Thyroid gland +++++++++++++++++++++++++


### General Body System None


### Genital System Epididymis +++++++++++++++++++++++++ Preputial gland +++++++++++++++++++++++++ Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++ 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

4556667777777777777777777 

### Number of Days on Study 3770691222222223333333333 1474883129999990000000000

0000000000000000000000000 

### Carcass ID Number 6899658587788995555677779 1529513923478683478456791

### 153 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + M + + + + + + + + + + M + I + + 41 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + M + + + + + + + + + + + + + 49 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 49

Carcinoma X X 2 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 2 Hepatoblastoma X 3 Hepatocellular carcinoma X X X X X X X X 13 Hepatocellular carcinoma, multiple X 1 Hepatocellular adenoma X X X X X X X X X X X 15 Hepatocellular adenoma, multiple X X X X X X X 17 Ito cell tumor malignant 1 Mesentery + + + + + + 10

Ito cell tumor malignant, metastatic, liver 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma 2 Tooth + + 4


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X 1 Subcapsular, adenoma X 3 Adrenal medulla + + + + + + + + + + + + + + + + + + + M + + + + M 48 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 Pituitary gland + M + + + + + + M + + + + + I + + + + + + + + + + 47

Pars distalis, adenoma X 1 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50


### General Body System None


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0111111111111114444444444

1000000000000000000000000 T otal 

### Carcass ID Number 0555666677888896667789999 Tissues/ 0256026901046943782810357 T umors

### Sodium Chlorate, NTP TR 517 154

Hematopoietic System Bone marrow +++++++++++++++++++++++++ Lymph node, mandibular M + I ++++++++++++++++++++++ Lymph node, mesenteric +++++++++++++++++++++++++ Spleen +++++++++++++++++++++++++ Thymus M + + + I + + + + +M+ + + + + + + + + + +M+ +


### Integumentary System Mammary gland +++++++++++++++++++++++++ Skin +++++++++++++++++++++++++


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle +


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + Spinal cord +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X Alveolar/bronchiolar carcinoma X X Hepatoblastoma, metastatic, liver X Hepatocellular carcinoma, metastatic, liver X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Adenoma X X


### Urinary System Kidney +++++++++++++++++++++++++

Renal tubule, adenoma Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Lymphoma malignant 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

4556667777777777777777777 

### Number of Days on Study 3770691222222223333333333 1474883129999990000000000

0000000000000000000000000 

### Carcass ID Number 6899658587788995555677779 1529513923478683478456791

### 155 Sodium Chlorate, NTP TR 517

Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 48 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 Thymus + + + + + + + + M + + I + + M + + + + + + + + + + 43


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 1 Spinal cord 1


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X X X 4 Alveolar/bronchiolar carcinoma X X X 5 Hepatoblastoma, metastatic, liver X 2 Hepatocellular carcinoma, metastatic, liver X 2 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X 4


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50

Renal tubule, adenoma X 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Lymphoma malignant X 1 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0111111111111114444444444

1000000000000000000000000 T otal 

### Carcass ID Number 0555666677888896667789999 Tissues/ 0256026901046943782810357 T umors

### Sodium Chlorate, NTP TR 517 156

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder + + I + + + + +M+ + + + +M+ + + + + + + + + + Intestine large, colon +++++++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum +++++A+++++++++++++++++++ Intestine small, duodenum +++++A+++++++++++++++++++

Polyp adenomatous Intestine small, jejunum +++++++++++++++++++++++++

Adenoma Intestine small, ileum +++++++++++++++++++++++++ Liver +++++++++++++++++++++++++

Cholangiocarcinoma X Hemangioma X Hemangiosarcoma X Hemangiosarcoma, metastatic, spleen X Hepatoblastoma X Hepatocellular carcinoma X X X X X X X X X Hepatocellular carcinoma, multiple X X X Hepatocellular adenoma X X X X X X X Hepatocellular adenoma, multiple X X X X X X X X X X Histiocytic sarcoma X Mesentery + + + + + +

Hepatocellular carcinoma, metastatic, liver X Liposarcoma X Pancreas +++++++++++++++++++++++++

Hepatocellular carcinoma, metastatic, liver X Salivary glands +++++++++++++++++++++++++ Stomach, forestomach +++++++++++++++++++++++++

Squamous cell papilloma X Stomach, glandular +++++++++++++++++++++++++ Tooth


### Cardiovascular System Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + +

Adenoma Subcapsular, adenoma X Adrenal medulla +++++++++++++++++++++++++ Islets, pancreatic +++++++++++++++++++++++++ Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + +M Pituitary gland + + M M + + + + + + + +M+ + + + + + + + + + + + Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + +M 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

5555666667777777777777777 

### Number of Days on Study 4567066772222222222223333 3820778239999999999990000

1111111111111111111111111 

### Carcass ID Number 0224132000112233344440011 9480707438266914912482503

### 157 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, rectum + + + + + I + + + + + + + + + + + + + + + + + + + 49 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49

Polyp adenomatous X X 2 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X 1 Intestine small, ileum + + + + + + + + + + + + + + + M + + + + + + + + + 49 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Cholangiocarcinoma 1 Hemangioma 1 Hemangiosarcoma 1 Hemangiosarcoma, metastatic, spleen 1 Hepatoblastoma 1 Hepatocellular carcinoma X X X X X 14 Hepatocellular carcinoma, multiple XX 5 Hepatocellular adenoma X X X X X X 13 Hepatocellular adenoma, multiple X X X X X X X X X X X X X 23 Histiocytic sarcoma X 2 Mesentery + + + + 10

Hepatocellular carcinoma, metastatic, liver 1 Liposarcoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hepatocellular carcinoma, metastatic, liver 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell papilloma X 2 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 Tooth + 1


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X 1 Subcapsular, adenoma X X X 4 Adrenal medulla + + + + + + + + M + + + + + + + + + + + + + + + + 49 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 Parathyroid gland + + + + + + M + + + + + + + + + + + + M + + + + + 47 Pituitary gland + + + + + + + + + + + + + + + + + + M + M + + + + 45 Thyroid gland + + + + + + M + + + + + + + + + + + + + + + + + + 48 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000011111111144444444

1111111111111111111111111 T otal 

### Carcass ID Number 1223344400112334501122334 Tissues/ 5032656717192579064815383 T umors

### Sodium Chlorate, NTP TR 517 158

General Body System None


### Genital System Epididymis +++++++++++++++++++++++++

Cholangiocarcinoma, metastatic, liver X Preputial gland +++++++++++++++++++++++++ Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++


### Hematopoietic System Bone marrow +++++++++++++++++++++++++

Hemangiosarcoma, metastatic, spleen X Lymph node +

Mediastinal, hepatocellular Carcinoma, metastatic, liver X Pancreatic, hepatocellular carcinoma,

metastatic, liver X Renal, hepatocellular carcinoma,

metastatic, liver X Lymph node, mandibular + + + M ++++++++++++ MMMM +++++ Lymph node, mesenteric +++++++++++++++++++++++++ Spleen +++++++++++++++++++++++++

Hemangiosarcoma X Histiocytic sarcoma X Thymus + + M + + + M + + + M + + + +M+ + +M+ + + +M

Alveolar/bronchiolar carcinoma, Metastatic, lung X Hepatocellular carcinoma, metastatic, liver X


### Integumentary System Mammary gland +++++++++++++++++++++++++ Skin +++++++++++++++++++++++++

Subcutaneous tissue, fibrous Histiocytoma Subcutaneous tissue, lipoma


### Musculoskeletal System Bone +++++++++++++++++++++++++

Carcinoma, metastatic, harderian gland Skeletal muscle + + +

Alveolar/bronchiolar carcinoma, Metastatic, lung X X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

5555666667777777777777777 

### Number of Days on Study 4567066772222222222223333 3820778239999999999990000

1111111111111111111111111 

### Carcass ID Number 0224132000112233344440011 9480707438266914912482503

### 159 Sodium Chlorate, NTP TR 517

General Body System None


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50

Cholangiocarcinoma, metastatic, liver 1 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma, metastatic, spleen 1 Lymph node 1

Mediastinal, hepatocellular carcinoma,

metastatic, liver 1 Pancreatic, hepatocellular carcinoma,

metastatic, liver 1 Renal, hepatocellular carcinoma,

metastatic, liver 1 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 45 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 1 Histiocytic sarcoma 1 Thymus + + M + + + + + + + + + + + + M + + M + M + + + + 40

Alveolar/bronchiolar carcinoma,

metastatic, lung 1 Hepatocellular carcinoma, metastatic, liver 1


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Subcutaneous tissue, fibrous Histiocytoma X 1 Subcutaneous tissue, lipoma X 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, harderian gland X 1 Skeletal muscle 3

Alveolar/bronchiolar carcinoma,

metastatic, lung 2 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000011111111144444444

1111111111111111111111111 T otal 

### Carcass ID Number 1223344400112334501122334 Tissues/ 5032656717192579064815383 T umors

### Sodium Chlorate, NTP TR 517 160

Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + + Spinal cord + +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X X X Alveolar/bronchiolar carcinoma X X X X X X Alveolar/bronchiolar carcinoma, multiple Carcinoma, metastatic, kidney Hepatocellular carcinoma, metastatic, liver X X X Histiocytic sarcoma X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Adenoma X X Carcinoma


### Urinary System Kidney +++++++++++++++++++++++++

Alveolar/bronchiolar carcinoma,

metastatic, lung X Hepatocellular carcinoma, metastatic, liver X Renal tubule, carcinoma Urethra + Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

5555666667777777777777777 

### Number of Days on Study 4567066772222222222223333 3820778239999999999990000

1111111111111111111111111 

### Carcass ID Number 0224132000112233344440011 9480707438266914912482503

### 161 Sodium Chlorate, NTP TR 517

Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 2 Spinal cord 2


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X X X X 7 Alveolar/bronchiolar carcinoma 6 Alveolar/bronchiolar carcinoma, multiple X 1 Carcinoma, metastatic, kidney X 1 Hepatocellular carcinoma, metastatic, liver X 4 Histiocytic sarcoma 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X 4 Carcinoma X 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar carcinoma,

metastatic, lung 1 Hepatocellular carcinoma, metastatic, liver Renal tubule, carcinoma X 1 Urethra 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 2 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 0000000011111111144444444

1111111111111111111111111 T otal 

### Carcass ID Number 1223344400112334501122334 Tissues/ 5032656717192579064815383 T umors

### Sodium Chlorate, NTP TR 517 162

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder + + + + I + + IM+ + +A+ + + + + + + + + + + + Intestine large, colon +++++++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum +++++A++++++A++++++++++++

Carcinoma Histiocytic sarcoma X Intestine small, duodenum +++++I+++++++++++++++++++

Carcinoma Carcinoma, metastatic, islets, pancreatic Intestine small, jejunum +++++++++++++++++++++++++

Adenoma X Carcinoma X X Intestine small, ileum +++++A+++++++++++++++++++ Liver + + + + + + + + + + + + + + + + + + + + + + ++ +

Carcinoma, metastatic, islets, pancreatic Hemangiosarcoma Hepatoblastoma X Hepatocellular carcinoma X X X X X X X X X Hepatocellular carcinoma, multiple X Hepatocellular adenoma X X X X X X X X X Hepatocellular adenoma, multiple X X X X X Histiocytic sarcoma X X Mesentery + + + + + +

Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma X Pancreas +++++++++++++++++++++++++ Salivary glands +++++++++++++++++++++++++

Histiocytic sarcoma X Stomach, forestomach +++++++++++++++++++++++++

Squamous cell papilloma X X Stomach, glandular +++++++++++++++++++++++++ Tooth +


### Cardiovascular System Blood vessel Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++

Adenoma Hepatocellular carcinoma, metastatic, liver X Subcapsular, adenoma X Adrenal medulla +++++++++++++++++++++++++ Islets, pancreatic +++++++++++++++++++++++++

Adenoma X Carcinoma 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

2455566666666677777777777 

### Number of Days on Study 8637901144556911222222222 8550556800274419199999999

1111211111111111111111111 

### Carcass ID Number 5799066769858778556778889 6719070138244569819243570

### 163 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + + + + + + + + + + + I + + + 45 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, rectum + M + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 48

Carcinoma X 1 Histiocytic sarcoma 1 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 49

Carcinoma X 1 Carcinoma, metastatic, islets, pancreatic X 1 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma 1 Carcinoma 2 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 49 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma, metastatic, islets, pancreatic X 1 Hemangiosarcoma X X 2 Hepatoblastoma X X 3 Hepatocellular carcinoma X X X 12 Hepatocellular carcinoma, multiple 1 Hepatocellular adenoma X X X X X 14 Hepatocellular adenoma, multiple X X X X X X X X X X X 16 Histiocytic sarcoma 2 Mesentery ++ 8

Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma X 2 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell papilloma 2 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 Tooth + + 3


### Cardiovascular System Blood vessel + 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X 1 Hepatocellular carcinoma, metastatic, liver 1 Subcapsular, adenoma X 2 Adrenal medulla + + + + + + + + + + + + + + + + + I + + + + + + + 49 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma 1 Carcinoma X 1 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2233333333333333333333333 9900000001111111114444444

1111111111111111111111111 T otal 

### Carcass ID Number 9956788995666777895556689 Tissues/ 2671001352246389873595864 T umors

### Sodium Chlorate, NTP TR 517 164

Endocrine System (continued) Parathyroid gland + + + + + + + +M+ + + + + + + + + + + + + + + + Pituitary gland + + + + + + + + + + + + + + + + + + +M+ + + + + Thyroid gland +++++++++++++++++++++++++


### General Body System None


### Genital System Epididymis +++++++++++++++++++++++++ Preputial gland +++++++++++++++++++++++++ Prostate +++++++++++++++++++++++++ Seminal vesicle +++++++++++++++++++++++++ Testes +++++++++++++++++++++++++

Interstitial cell, adenoma X


### Hematopoietic System Bone marrow +++++++++++++++++++++++++

Histiocytic sarcoma X Lymph node + + +

Mediastinal, carcinoma, metastatic,

Harderian gland X Mediastinal, hepatocellular carcinoma,

metastatic, liver X Lymph node, mandibular + + + + + + + + + + + + + +M+ + + + + + + + + +

Histiocytic sarcoma X Lymph node, mesenteric +++++++++++++++++++++++++

Histiocytic sarcoma X Spleen +++++++++++++++++++++++++

Histiocytic sarcoma X Thymus + + + + +M+ + + I + + + +M+ + + + + + + + + +


### Integumentary System Mammary gland +++++++++++++++++++++++++ Skin +++++++++++++++++++++++++


### Musculoskeletal System Bone +++++++++++++++++++++++++ Skeletal muscle + +

Hepatocellular carcinoma, metastatic, liver X Rhabdomyosarcoma X


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + Spinal cord + 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

2455566666666677777777777 

### Number of Days on Study 8637901144556911222222222 8550556800274419199999999

1111211111111111111111111 

### Carcass ID Number 5799066769858778556778889 6719070138244569819243570

### 165 Sodium Chlorate, NTP TR 517

Endocrine System (continued) Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50


### General Body System None


### Genital System Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50

Interstitial cell, adenoma X 2


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Lymph node 3

Mediastinal, carcinoma, metastatic,

Harderian gland 1 Mediastinal, hepatocellular carcinoma

metastatic, liver 1 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 49

Histiocytic sarcoma 1 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Thymus + + + M + M + + + + + + + + + + + + + + + + M + + 44


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skeletal muscle 2

Hepatocellular carcinoma, metastatic, liver 1 Rhabdomyosarcoma 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 1 Spinal cord 1 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2233333333333333333333333 9900000001111111114444444

1111111111111111111111111 T otal 

### Carcass ID Number 9956788995666777895556689 Tissues/ 2671001352246389873595864 T umors

### Sodium Chlorate, NTP TR 517 166

Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X X X X Alveolar/bronchiolar carcinoma X X Carcinoma, metastatic, harderian gland X Hemangiosarcoma Hepatocellular carcinoma, metastatic, liver X X X X X X Histiocytic sarcoma X Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland ++++++++I++++++++++++++++

Adenoma X X X Carcinoma X


### Urinary System Kidney +++++++++++++++++++++++++ Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X X Lymphoma malignant X 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

2455566666666677777777777 

### Number of Days on Study 8637901144556911222222222 8550556800274419199999999

1111211111111111111111111 

### Carcass ID Number 5799066769858778556778889 6719070138244569819243570

### 167 Sodium Chlorate, NTP TR 517

Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X X 6 Alveolar/bronchiolar carcinoma X X 4 Carcinoma, metastatic, harderian gland 1 Hemangiosarcoma X 1 Hepatocellular carcinoma, metastatic, liver 6 Histiocytic sarcoma 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X X 6 Carcinoma 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 3 Lymphoma malignant X X 3 

### TABLE 

### C2 Individual Animal Tumor Pathology of Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 2233333333333333333333333 9900000001111111114444444

1111111111111111111111111 T otal 

### Carcass ID Number 9956788995666777895556689 Tissues/ 2671001352246389873595864 T umors

### Sodium Chlorate, NTP TR 517 168

Adrenal Cortex: Adenoma Overall rate a 3/50 (6%) 4/50 (8%) 5/50 (10%) 3/50 (6%) Adjusted rateb 6.7% 8.5% 10.8% 6.9% Terminal rate c 3/38 (8%) 4/41 (10%) 5/41 (12%) 3/33 (9%) First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) Poly-3 testd P=0.566 P=0.532 P=0.379 P=0.654



### Harderian Gland: Adenoma Overall rate 6/50 (12%) 4/50 (8%) 4/50 (8%) 6/50 (12%) Adjusted rate 13.2% 8.4% 8.5% 13.5% Terminal rate 4/38 (11%) 3/41 (7%) 2/41 (5%) 3/33 (9%) First incidence (days) 562 698 543 605 Poly-3 test P=0.478 P=0.344N P=0.345N P=0.606



### Harderian Gland: Adenoma or Carcinoma Overall rate 6/50 (12%) 4/50 (8%) 5/50 (10%) 7/50 (14%) Adjusted rate 13.2% 8.4% 10.6% 15.6% Terminal rate 4/38 (11%) 3/41 (7%) 3/41 (7%) 3/33 (9%) First incidence (days) 562 698 543 595 Poly-3 test P=0.335 P=0.344N P=0.473N P=0.491


### Intestine Small (Duodenum or Jejunum): Carcinoma Overall rate 2/50 (4%) 2/50 (4%) 0/50 (0%) 3/50 (6%) Adjusted rate 4.5% 4.2% 0.0% 6.8% Terminal rate 2/38 (5%) 2/41 (5%) 0/41 (0%) 1/33 (3%) First incidence (days) 729 (T) 729 (T) —e 570 Poly-3 test P=0.418 P=0.673N P=0.228N P=0.498


### Intestine Small (Duodenum or Jejunum): Adenoma or Carcinoma Overall rate 3/50 (6%) 2/50 (4%) 1/50 (2%) 4/50 (8%) Adjusted rate 6.7% 4.2% 2.2% 9.0% Terminal rate 3/38 (8%) 2/41 (5%) 1/41 (2%) 2/33 (6%) First incidence (days) 729 (T) 729 (T) 729 (T) 570 Poly-3 test P=0.362 P=0.473N P=0.291N P=0.497


### Liver: Hepatocellular Adenoma Overall rate 30/48 (63%) 32/50 (64%) 36/50 (72%) 30/50 (60%) Adjusted rate 64.5% 67.6% 74.9% 65.5% Terminal rate 25/38 (66%) 31/41 (76%) 32/41 (78%) 24/33 (73%) First incidence (days) 484 722 543 535 Poly-3 test P=0.478 P=0.459 P=0.184 P=0.546


### Liver: Hepatocellular Carcinoma Overall rate 20/48 (42%) 14/50 (28%) 19/50 (38%) 13/50 (26%) Adjusted rate 43.3% 28.6% 39.2% 28.4% Terminal rate 14/38 (37%) 10/41 (24%) 14/41 (34%) 5/33 (15%) First incidence (days) 484 431 558 570 Poly-3 test P=0.159N P=0.099N P=0.421N P=0.100N


### Liver: Hepatocellular Adenoma or Carcinoma Overall rate 41/48 (85%) 42/50 (84%) 44/50 (88%) 40/50 (80%) Adjusted rate 86.0% 85.8% 89.2% 84.2% Terminal rate 32/38 (84%) 37/41 (90%) 37/41 (90%) 27/33 (82%) First incidence (days) 484 431 543 535 Poly-3 test P=0.477N P=0.604N P=0.434 P=0.517N 

### TABLE 

### C3 Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 169 Sodium Chlorate, NTP TR 517

Liver: Hepatoblastoma Overall rate 6/48 (13%) 3/50 (6%) 1/50 (2%) 3/50 (6%) Adjusted rate 13.5% 6.3% 2.1% 6.8% Terminal rate 5/38 (13%) 1/41 (2%) 0/41 (0%) 2/33 (6%) First incidence (days) 561 577 668 719 Poly-3 test P=0.179N P=0.207N P=0.048N P=0.248N


### Liver: Hepatocellular Carcinoma or Hepatoblastoma Overall rate 23/48 (48%) 16/50 (32%) 20/50 (40%) 16/50 (32%) Adjusted rate 49.2% 32.7% 41.0% 34.9% Terminal rate 16/38 (42%) 11/41 (27%) 14/41 (34%) 7/33 (21%) First incidence (days) 484 431 558 570 Poly-3 test P=0.180N P=0.074N P=0.276N P=0.117N


### Liver: Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastoma Overall rate 41/48 (85%) 43/50 (86%) 45/50 (90%) 40/50 (80%) Adjusted rate 86.0% 87.7% 90.8% 84.2% Terminal rate 32/38 (84%) 37/41 (90%) 37/41 (90%) 27/33 (82%) First incidence (days) 484 431 543 535 Poly-3 test P=0.448N P=0.522 P=0.337 P=0.517N


### Lung: Alveolar/bronchiolar Adenoma Overall rate 6/50 (12%) 4/50 (8%) 7/50 (14%) 6/50 (12%) Adjusted rate 13.5% 8.4% 14.9% 13.7% Terminal rate 6/38 (16%) 3/41 (7%) 6/41 (15%) 4/33 (12%) First incidence (days) 729 (T) 604 570 711 Poly-3 test P=0.423 P=0.328N P=0.540 P=0.610


### Lung: Alveolar/bronchiolar Carcinoma Overall rate 4/50 (8%) 5/50 (10%) 7/50 (14%) 4/50 (8%) Adjusted rate 8.9% 10.6% 14.7% 9.1% Terminal rate 2/38 (5%) 5/41 (12%) 4/41 (10%) 2/33 (6%) First incidence (days) 638 729 (T) 543 640 Poly-3 test P=0.534 P=0.528 P=0.293 P=0.631


### Lung: Alveolar/bronchiolar Adenoma or Carcinoma Overall rate 10/50 (20%) 8/50 (16%) 13/50 (26%) 9/50 (18%) Adjusted rate 22.1% 16.8% 27.0% 20.3% Terminal rate 8/38 (21%) 7/41 (17%) 9/41 (22%) 5/33 (15%) First incidence (days) 638 604 543 640 Poly-3 test P=0.505 P=0.349N P=0.383 P=0.520N


### All Organs: Hemangioma or Hemangiosarcoma Overall rate 1/50 (2%) 2/50 (4%) 3/50 (6%) 2/50 (4%) Adjusted rate 2.2% 4.2% 6.4% 4.6% Terminal rate 1/38 (3%) 2/41 (5%) 2/41 (5%) 2/33 (6%) First incidence (days) 729 (T) 729 (T) 667 729 (T) Poly-3 test P=0.386 P=0.520 P=0.322 P=0.494


### All Organs: Histiocytic Sarcoma Overall rate 1/50 (2%) 0/50 (0%) 2/50 (4%) 3/50 (6%) Adjusted rate 2.2% 0.0% 4.3% 6.8% Terminal rate 0/38 (0%) 0/41 (0%) 2/41 (5%) 1/33 (3%) First incidence (days) 661 — 729 (T) 595 Poly-3 test P=0.097 P=0.489N P=0.512 P=0.301 

### TABLE 

### C3 Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 170

All Organs: Malignant Lymphoma Overall rate 3/50 (6%) 1/50 (2%) 0/50 (0%) 3/50 (6%) Adjusted rate 6.6% 2.1% 0.0% 6.8% Terminal rate 2/38 (5%) 1/41 (2%) 0/41 (0%) 2/33 (6%) First incidence (days) 301 729 (T) — 616 Poly-3 test P=0.514 P=0.292N P=0.115N P=0.649


### All Organs: Benign Neoplasms Overall rate 34/50 (68%) 38/50 (76%) 37/50 (74%) 34/50 (68%) Adjusted rate 70.7% 79.4% 76.7% 72.5% Terminal rate 27/38 (71%) 35/41 (85%) 32/41 (78%) 24/33 (73%) First incidence (days) 484 604 543 535 Poly-3 test P=0.528N P=0.223 P=0.330 P=0.515


### All Organs: Malignant Neoplasms Overall rate 29/50 (58%) 22/50 (44%) 30/50 (60%) 27/50 (54%) Adjusted rate 59.1% 44.9% 60.0% 56.7% Terminal rate 19/38 (50%) 17/41 (42%) 21/41 (51%) 14/33 (42%) First incidence (days) 301 431 543 535 Poly-3 test P=0.435 P=0.113N P=0.544 P=0.487N


### All Organs: Benign or Malignant Neoplasms Overall rate 45/50 (90%) 45/50 (90%) 47/50 (94%) 45/50 (90%) Adjusted rate 90.7% 91.0% 94.0% 93.1% Terminal rate 34/38 (90%) 38/41 (93%) 38/41 (93%) 30/33 (91%) First incidence (days) 301 431 543 535 Poly-3 test P=0.355 P=0.618 P=0.402 P=0.470

(T)Terminal sacrifice a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, liver, and lung; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality c Observed incidence at terminal kill d Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for the differential mortality in animals that do not reach terminal sacrifice. A negative trend or a lower incidence in an exposed group is indicated by N

. e Not applicable; no neoplasms in animal group 

### TABLE 

### C3 Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 171 Sodium Chlorate, NTP TR 517

Disposition Summary

Animals initially in study 50 50 50 50 Early deaths

Moribund 5 5 4 10 Natural deaths 7 4 5 7 Survivors

Terminal sacrifice 38 41 41 33

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, cecum (47) (49) (49) (48)

Edema 1 (2%) 3 (6%) 4 (8%) 2 (4%) Inflammation, chronic 1 (2%) 1 (2%) Intestine small, duodenum (48) (50) (49) (49)

Ulcer 1 (2%) 1 (2%) Epithelium, hyperplasia 1 (2%) 1 (2%) Intestine small, jejunum (47) (49) (50) (50)

Epithelium, hyperplasia 2 (4%) Intestine small, ileum (47) (49) (49) (49)

Cyst 1 (2%) Liver (48) (50) (50) (50)

Angiectasis 2 (4%) 2 (4%) Basophilic focus 2 (4%) 3 (6%) 4 (8%) Clear cell focus 12 (25%) 19 (38%) 19 (38%) 13 (26%) Cyst 1 (2%) 1 (2%) Eosinophilic focus 11 (23%) 10 (20%) 5 (10%) 11 (22%) Hematopoietic cell proliferation 1 (2%) 4 (8%) Hemorrhage 1 (2%) 1 (2%) Hyperplasia, lymphoid 1 (2%) 1 (2%) Infarct 1 (2%) Infiltration cellular, mixed cell 2 (4%) 1 (2%) 1 (2%) Mixed cell focus 2 (4%) 9 (18%) 8 (16%) 7 (14%) Necrosis, focal 4 (8%) 6 (12%) 7 (14%) 6 (12%) Regeneration, focal 1 (2%) Tension lipidosis 1 (2%) 1 (2%) Bile duct, hyperplasia 2 (4%) Centrilobular, necrosis 1 (2%) 2 (4%) Hepatocyte, karyomegaly 1 (2%) 1 (2%) Hepatocyte, vacuolization cytoplasmic 2 (4%) 3 (6%) Kupffer cell, pigmentation 2 (4%) 1 (2%) Mesentery (9) (10) (10) (8)

Infarct 1 (10%) Inflammation, chronic 1 (11%) 2 (25%) Fat, necrosis 3 (33%) 8 (80%) 6 (60%) 5 (63%) Pancreas (48) (50) (50) (50)

Cyst 2 (4%) Acinus, cytoplasmic alteration 1 (2%) 1 (2%) Salivary glands (50) (50) (50) (50)

Atrophy 1 (2%) 2 (4%) Hyperplasia, lymphoid 7 (14%) 3 (6%) 6 (12%) 4 (8%)

a Number of animals examined microscopically at the site and the number of animals with lesion 

### TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 172

Alimentary System (continued) Stomach, forestomach (49) (50) (50) (50)

Cyst 2 (4%) Diverticulum 1 (2%) 1 (2%) 2 (4%) Erosion 1 (2%) Inflammation, chronic active 2 (4%) 2 (4%) 4 (8%) 2 (4%) Ulcer 1 (2%) 1 (2%) 2 (4%) 1 (2%) Epithelium, hyperplasia 3 (6%) 7 (14%) 2 (4%) 4 (8%) Stomach, glandular (48) (50) (50) (50)

Cyst 1 (2%) 2 (4%) 1 (2%) Ulcer 1 (2%) Tooth (2) (4) (1) (3)

Malformation 2 (100%) 4 (100%) 2 (67%)



### Cardiovascular System Heart (50) (50) (50) (50)

Cardiomyopathy 2 (4%) Inflammation, chronic 2 (4%) 1 (2%) 1 (2%) 1 (2%) Mineralization 1 (2%) 2 (4%) Thrombosis 1 (2%) 1 (2%)



### Endocrine System Adrenal cortex (50) (50) (50) (50)

Accessory adrenal cortical nodule 6 (12%) 5 (10%) 3 (6%) 5 (10%) Degeneration, fatty 1 (2%) 1 (2%) 2 (4%) Hyperplasia, focal 4 (8%) 6 (12%) 7 (14%) 9 (18%) Hypertrophy 1 (2%) Hypertrophy, focal 9 (18%) 16 (32%) 11 (22%) 11 (22%) Capsule, hyperplasia 5 (10%) 3 (6%) 1 (2%) 8 (16%) Adrenal medulla (49) (48) (49) (49)

Hyperplasia 1 (2%) 1 (2%) 1 (2%) Islets, pancreatic (48) (50) (50) (50)

Hyperplasia 31 (65%) 25 (50%) 28 (56%) 23 (46%) Parathyroid gland (46) (48) (47) (49)

Cyst 1 (2%) 2 (4%) 1 (2%) Pituitary gland (47) (47) (45) (49)

Pars distalis, cyst 1 (2%) 1 (2%) 2 (4%) 5 (10%) Pars intermedia, cyst 1 (2%) Thyroid gland (48) (50) (48) (50)

Degeneration, cystic 13 (27%) 17 (34%) 14 (29%) 15 (30%) Follicular cell, hypertrophy 2 (4%) 1 (2%) 2 (4%)



### General Body System None



### Genital System Epididymis (50) (50) (50) (50)

Atypia cellular 1 (2%) 6 (12%) 4 (8%) 3 (6%) Granuloma sperm 1 (2%) 1 (2%) Inflammation, chronic 1 (2%) 1 (2%) 1 (2%) 

### TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 173 Sodium Chlorate, NTP TR 517

Genital System (continued) Preputial gland (50) (50) (50) (50)

Cyst 22 (44%) 26 (52%) 15 (30%) 29 (58%) Inflammation, chronic 28 (56%) 27 (54%) 18 (36%) 21 (42%) Prostate (50) (50) (50) (50)

Inflammation, chronic 1 (2%) 4 (8%) 3 (6%) 5 (10%) Seminal vesicle (50) (50) (50) (50)

Degeneration 1 (2%) 2 (4%) Dilatation 1 (2%) Inflammation, chronic 3 (6%) 1 (2%) Testes (50) (50) (50) (50)

Angiectasis 1 (2%) 1 (2%) Atrophy 1 (2%) 1 (2%) 1 (2%) Necrosis 1 (2%) Germinal epithelium, atrophy 1 (2%) 5 (10%) 3 (6%) 4 (8%)



### Hematopoietic System Bone marrow (49) (50) (50) (50)

Hyperplasia 21 (43%) 12 (24%) 13 (26%) 15 (30%) Lymph node (3) (1) (3)

Mediastinal, hemorrhage 1 (33%) Lymph node, mandibular (49) (48) (45) (49)

Atrophy 1 (2%) 1 (2%) Hyperplasia, lymphoid 14 (29%) 14 (29%) 16 (36%) 16 (33%) Pigmentation 7 (14%) 10 (21%) 9 (20%) 9 (18%) Lymph node, mesenteric (47) (50) (50) (50)

Atrophy 2 (4%) 1 (2%) 1 (2%) Hematopoietic cell proliferation 2 (4%) 4 (8%) 1 (2%) Hemorrhage 4 (9%) 6 (12%) 2 (4%) 4 (8%) Hyperplasia, lymphoid 11 (23%) 6 (12%) 6 (12%) 9 (18%) Spleen (48) (50) (50) (50)

Depletion lymphoid 1 (2%) Hematopoietic cell proliferation 21 (44%) 17 (34%) 18 (36%) 21 (42%) Hyperplasia, lymphoid 8 (17%) 9 (18%) 10 (20%) 8 (16%) Pigmentation 3 (6%) 1 (2%) 1 (2%) Lymphoid follicle, atrophy 1 (2%) 1 (2%) 3 (6%) Thymus (43) (43) (40) (44)

Atrophy 11 (26%) 13 (30%) 4 (10%) 13 (30%) Cyst 1 (2%) 3 (7%) 4 (10%) 4 (9%) Hyperplasia, lymphoid 2 (5%) 1 (2%)



### Integumentary System Skin (50) (50) (50) (50)

Cyst epithelial inclusion 1 (2%) Edema 3 (6%) Inflammation, chronic 1 (2%) 1 (2%) Ulcer 2 (4%) Epidermis, hyperplasia 1 (2%) 1 (2%) 

### TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 174

Musculoskeletal System Bone (50) (50) (50) (50)

Fracture 1 (2%) 1 (2%) 2 (4%) Hyperostosis 1 (2%) 1 (2%) Skeletal muscle (3) (1) (3) (2)

Atrophy 1 (100%) Infiltration cellular, lipocyte 1 (33%)



### Nervous System Peripheral nerve (1) (2) (1)

Atrophy 1 (100%)



### Respiratory System Lung (50) (50) (50) (50)

Edema 6 (12%) 11 (22%) 7 (14%) 8 (16%) Foreign body 1 (2%) 1 (2%) Hemorrhage 5 (10%) 3 (6%) 4 (8%) 5 (10%) Hyperplasia, lymphoid 4 (8%) 5 (10%) 7 (14%) 6 (12%) Infiltration cellular, histiocyte 8 (16%) 5 (10%) 9 (18%) 10 (20%) Metaplasia, osseous 2 (4%) Alveolar epithelium, hyperplasia 2 (4%) 3 (6%) 1 (2%) 5 (10%) Nose (50) (50) (50) (50)

Foreign body 1 (2%) 1 (2%) 2 (4%) Inflammation, chronic 1 (2%) 2 (4%) 1 (2%) 5 (10%) Respiratory epithelium, hyperplasia 1 (2%) 1 (2%)



### Special Senses System Eye (49) (50) (50) (50)

Cataract 1 (2%) Inflammation, chronic 3 (6%) Harderian gland (50) (50) (50) (49)

Hyperplasia, focal 1 (2%) 1 (2%) Inflammation, chronic 1 (2%) 3 (6%) 3 (6%) 2 (4%)



### Urinary System Kidney (49) (50) (50) (50)

Cyst 14 (29%) 10 (20%) 9 (18%) 10 (20%) Hydronephrosis 1 (2%) 2 (4%) 2 (4%) 1 (2%) Hyperplasia, lymphoid 8 (16%) 6 (12%) 4 (8%) 11 (22%) Infarct 5 (10%) 1 (2%) 4 (8%) 5 (10%) Inflammation, chronic 1 (2%) 1 (2%) Metaplasia, osseous 7 (14%) 5 (10%) 3 (6%) 4 (8%) Nephropathy 37 (76%) 42 (84%) 43 (86%) 36 (72%) Renal tubule, accumulation, hyaline droplet 1 (2%) 1 (2%) Renal tubule, dilatation 1 (2%) 2 (4%) 3 (6%) Renal tubule, hyperplasia 1 (2%) 1 (2%) 1 (2%) Renal tubule, necrosis 1 (2%) 2 (4%) Renal tubule, pigmentation 2 (4%) 1 (2%) 1 (2%) Urethra (1)

Angiectasis 1 (100%) 

### TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 175 Sodium Chlorate, NTP TR 517

Urinary System (continued) Urinary bladder (49) (50) (50) (50)

Edema 1 (2%) 1 (2%) Hyperplasia, lymphoid 1 (2%) 1 (2%) Inflammation, chronic 1 (2%) Transitional epithelium, hyperplasia 2 (4%) 1 (2%) 

### TABLE 

### C4 Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 176

### 177



# APPENDIX D SUMMARY OF LESIONS IN FEMALE MICE IN THE 2-YEAR DRINKING WATER STUDY OF SODIUM CHLORATE

TABLE 

### D1 Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 TABLE 

### D3 Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 TABLE 

### D4a Historical Incidence of Pancreatic Islet Neoplasms in Control Female B6C3F 1 

### Mice . . . . . 210 TABLE 

### D4b Historical Incidence of Liver Neoplasms in Control Female B6C3F 1 

### Mice . . . . . . . . . . . . . . 210 TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

### Sodium Chlorate, NTP TR 517 178



### TABLE 

### D1 Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Accidental death 1 Moribund sacrifice 3 5 6 8 Natural deaths 10 10 12 7 Survivors

Died last week of study 1 Terminal sacrifice 36 34 31 35 Other 1

Animals examined microscopically 50 50 50 50



### Alimentary System Esophagus (49) (50) (50) (50) Gallbladder (40) (44) (44) (48) Intestine large, cecum (44) (47) (47) (47)

Hemangioma 1 (2%) Intestine small, duodenum (46) (47) (47) (50)

Adenoma 1 (2%) Polyp adenomatous 1 (2%) Intestine small, jejunum (45) (47) (47) (47)

Histiocytic sarcoma 1 (2%) Intestine small, ileum (42) (45) (46) (47) Liver (49) (50) (49) (50)

Hemangioma 2 (4%) Hemangiosarcoma 1 (2%) 2 (4%) Hemangiosarcoma, metastatic, spleen 1 (2%) Hepatoblastoma 1 (2%) Hepatocellular carcinoma 2 (4%) 6 (12%) 11 (22%) 6 (12%) Hepatocellular carcinoma, multiple 1 (2%) 7 (14%) 4 (8%) 3 (6%) Hepatocellular adenoma 15 (31%) 9 (18%) 14 (29%) 8 (16%) Hepatocellular adenoma, multiple 15 (31%) 10 (20%) 12 (24%) 15 (30%) Histiocytic sarcoma 1 (2%) 1 (2%) Mesentery (30) (32) (27) (24)

Fibrosarcoma 1 (4%) Fibrous histiocytoma 1 (3%) Hemangiosarcoma 1 (4%) Hepatocellular carcinoma, metastatic, liver 1 (4%) Histiocytic sarcoma 1 (4%) Sarcoma, metastatic, skin 1 (4%) Schwannoma malignant, metastatic, skin 1 (3%) Oral mucosa (2) (1)

Squamous cell carcinoma 1 (50%) Squamous cell papilloma 1 (100%) Pancreas (46) (47) (49) (48)

Fibrosarcoma, metastatic, mesentery 1 (2%) Histiocytic sarcoma 1 (2%) Sarcoma, metastatic, skin 1 (2%) Acinus, sarcoma 1 (2%) Salivary glands (48) (47) (49) (50)

Hepatocellular carcinoma, metastatic, liver 1 (2%) Histiocytic sarcoma 1 (2%)

### 179 Sodium Chlorate, NTP TR 517

Alimentary System (continued) Stomach, forestomach (49) (50) (50) (49)

Squamous cell carcinoma 1 (2%) 1 (2%) Squamous cell papilloma 1 (2%) 1 (2%) Squamous cell papilloma, multiple 1 (2%) Stomach, glandular (49) (48) (50) (49)

Hepatocellular carcinoma, metastatic, liver 1 (2%) Tongue (2)



### Cardiovascular System Heart (49) (50) (49) (50)

Hemangiosarcoma, metastatic, spleen 1 (2%) Hepatocellular carcinoma, metastatic, liver 1 (2%)



### Endocrine System Adrenal cortex (50) (49) (49) (50)

Histiocytic sarcoma 1 (2%) Osteosarcoma, metastatic, bone 1 (2%) Subcapsular, adenoma 1 (2%) Adrenal medulla (50) (49) (49) (50)

Pheochromocytoma malignant 2 (4%) Pheochromocytoma complex 1 (2%) Pheochromocytoma benign 1 (2%) 1 (2%) Islets, pancreatic (46) (47) (49) (49)

Adenoma 2 (4%) 2 (4%) 3 (6%) Carcinoma 1 (2%) Pituitary gland (46) (45) (48) (50)

Histiocytic sarcoma 1 (2%) Pars distalis, adenoma 3 (7%) 2 (4%) 4 (8%) 4 (8%) Thyroid gland (48) (50) (49) (50)

Follicular cell, adenoma 1 (2%)



### General Body System None



### Genital System Clitoral gland (47) (47) (47) (49) Ovary (45) (45) (47) (50)

Choriocarcinoma 2 (4%) Cystadenoma 1 (2%) 4 (9%) 1 (2%) 1 (2%) Granulosa cell tumor malignant 1 (2%) Granulosa cell tumor benign 1 (2%) 1 (2%) 1 (2%) 5 (10%) Histiocytic sarcoma 2 (4%) 1 (2%) Luteoma 3 (7%) 1 (2%) Yolk sac carcinoma 1 (2%) Uterus (50) (50) (50) (50)

Hemangiosarcoma 1 (2%) Histiocytic sarcoma 2 (4%) 1 (2%) Leiomyosarcoma 1 (2%) Polyp stromal 1 (2%) 3 (6%) Yolk sac carcinoma, metastatic, ovary 1 (2%) 

### TABLE 

### D1 Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 180

Hematopoietic System Bone marrow (50) (50) (50) (50)

Hemangiosarcoma 1 (2%) 1 (2%) 2 (4%) Histiocytic sarcoma 1 (2%) Lymph node (7) (5) (11) (9)

Histiocytic sarcoma 1 (9%) Liposarcoma, metastatic, skin 1 (20%) Iliac, histiocytic sarcoma 2 (18%) Iliac, liposarcoma, metastatic, skin 1 (20%) Mediastinal, sarcoma, metastatic, pancreas 1 (9%) Pancreatic, histiocytic sarcoma 1 (9%) Renal, histiocytic sarcoma 1 (9%) 1 (11%) Lymph node, mandibular (46) (46) (49) (49)

Histiocytic sarcoma 2 (4%) Squamous cell carcinoma, metastatic,

uncertain primary site 1 (2%) Lymph node, mesenteric (47) (49) (49) (49)

Histiocytic sarcoma 1 (2%) 2 (4%) Histiocytic sarcoma, metastatic, mesentery 1 (2%) Yolk sac carcinoma, metastatic, ovary 1 (2%) Spleen (49) (48) (49) (50)

Hemangiosarcoma 2 (4%) 1 (2%) 1 (2%) Histiocytic sarcoma 2 (4%) Sarcoma, metastatic, skin 1 (2%) Thymus (48) (44) (48) (48)

Hepatocellular carcinoma, metastatic, liver 1 (2%) Histiocytic sarcoma 1 (2%) 1 (2%)



### Integumentary System Mammary gland (50) (50) (50) (50)

Adenoma 1 (2%) Carcinoma 1 (2%) Skin (48) (50) (50) (50)

Hemangioma 1 (2%) Squamous cell carcinoma 1 (2%) Subcutaneous tissue, fibrosarcoma 1 (2%) 2 (4%) Subcutaneous tissue, hemangioma 1 (2%) Subcutaneous tissue, hemangiosarcoma 1 (2%) Subcutaneous tissue, liposarcoma 1 (2%) Subcutaneous tissue, sarcoma 1 (2%) Subcutaneous tissue, schwannoma malignant 3 (6%) 1 (2%) 1 (2%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Osteosarcoma 1 (2%) 1 (2%) 2 (4%) Sarcoma 1 (2%) Skeletal muscle (2) (4) (6)

Histiocytic sarcoma, metastatic, mesentery 1 (25%) Rhabdomyosarcoma 1 (50%) 1 (25%) 2 (33%) Sarcoma, metastatic, pancreas 1 (25%) Sarcoma, metastatic, skin 1 (17%) Yolk sac carcinoma, metastatic, ovary 1 (17%) 

### Table D1 Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 181 Sodium Chlorate, NTP TR 517

Nervous System Brain (50) (50) (50) (50)

Osteosarcoma, metastatic, bone 1 (2%)



### Respiratory System Lung (50) (50) (49) (50)

Alveolar/bronchiolar adenoma 3 (6%) 1 (2%) 3 (6%) Alveolar/bronchiolar carcinoma 1 (2%) 1 (2%) 1 (2%) 1 (2%) Alveolar/bronchiolar carcinoma, multiple 1 (2%) Hepatocellular carcinoma, metastatic, liver 1 (2%) 3 (6%) 5 (10%) 2 (4%) Histiocytic sarcoma 1 (2%) 1 (2%) Liposarcoma, metastatic, skin 1 (2%) Osteosarcoma, metastatic, bone 1 (2%) Sarcoma, metastatic, skin 1 (2%) Nose (50) (50) (50) (50)

Carcinoma 1 (2%) Histiocytic sarcoma 1 (2%)



### Special Senses System Eye (50) (48) (50) (50) Harderian gland (50) (50) (50) (49)

Adenoma 11 (22%) 9 (18%) 5 (10%) 6 (12%) Carcinoma 1 (2%) 1 (2%) Histiocytic sarcoma 1 (2%)



### Urinary System Kidney (50) (49) (49) (50)

Hepatocellular carcinoma, metastatic, liver 1 (2%) Histiocytic sarcoma 1 (2%) Osteosarcoma, metastatic, bone 1 (2%) Urinary bladder (49) (50) (50) (50)



### Systemic Lesions Multiple organsb (50) (50) (50) (50)

Histiocytic sarcoma 1 (2%) 4 (8%) 2 (4%) Leukemia granulocytic 1 (2%) Lymphoma malignant 23 (46%) 19 (38%) 28 (56%) 27 (54%)



### Neoplasm Summary Total animals with primary neoplasms c 47 45 46 47

Total primary neoplasms 99 87 108 105 Total animals with benign neoplasms 38 27 33 31

Total benign neoplasms 58 40 44 53 Total animals with malignant neoplasms 33 38 41 41

Total malignant neoplasms 41 47 64 52 Total animals with metastatic neoplasms 2 5 10 5

Total metastatic neoplasms 2 8 20 11

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 c Primary neoplasms: all neoplasms except metastatic neoplasms 

### Table D1 Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 182

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder A A + + A + + A + AAAAA +++++++++++ Intestine large, colon A ++++++++A+++++++++++++++ Intestine large, rectum ++++++++A++++++++++++++++ Intestine large, cecum + A + + A + + + AAAA +++++++++++++ Intestine small, duodenum A ++++++A+A+A+++++++++++++ Intestine small, jejunum A A + + + + + + I AA+ + + + + + + + + + + + + + Intestine small, ileum A M + + A + + A M A A + + + + + + + + + + + +M+ Liver A ++++++++++++++++++++++++

Hemangioma X Hemangiosarcoma Hepatoblastoma Hepatocellular carcinoma X Hepatocellular carcinoma, multiple Hepatocellular adenoma X X X X Hepatocellular adenoma, multiple X X X X X X Mesentery A +++++++ +++++ + +++++

Fibrous histiocytoma Schwannoma malignant, metastatic, skin X Oral mucosa + +

Squamous cell carcinoma X Pancreas A A + + A + + M +++++++++++++++++ Salivary glands + + + +M+ + +M+ + + + + + + + + + + + + + + + Stomach, forestomach A ++++++++++++++++++++++++ Stomach, glandular A ++++++++++++++++++++++++


### Cardiovascular System Blood vessel Heart + + + + + + + +M+ + + + + + + + + + + + + + + +


### Endocrine System Adrenal cortex +++++++++++++++++++++++++

Subcapsular, adenoma Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma malignant X Pheochromocytoma benign X Islets, pancreatic A A + + A + + M +++++++++++++++++ Parathyroid gland M M +++++++++++++++++++++++ Pituitary gland M + + + I M +++++++++++++++++++

Pars distalis, adenoma Thyroid gland M ++++++++++++++++++++++++

Follicular cell, adenoma 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

2455555566666777777777777 

### Number of Days on Study 7427899903367133333333333 1046811760904055555555555

2222222222222222222222222 

### Carcass ID Number 1122004023432400011111112 3787456653202512312456890

+: Tissue examined microscopically M: Missing tissue X: Lesion present A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined

### 183 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + M + + + + + + + + + + + 49 Gallbladder + + + + + + + + + + + + + + M + + + + + + + + + + 40 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, rectum + + + + + + + + + + + + + + + + + + I + + + + + + 48 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 45 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 42 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hemangioma X 2 Hemangiosarcoma X 1 Hepatoblastoma X 1 Hepatocellular carcinoma X 2 Hepatocellular carcinoma, multiple X 1 Hepatocellular adenoma X X X X X X X X X X X 15 Hepatocellular adenoma, multiple X X X X X X X X X 15 Mesentery + + + + + + + + + + + + 30

Fibrous histiocytoma X 1 Schwannoma malignant, metastatic, skin 1 Oral mucosa 2

Squamous cell carcinoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 46 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 48 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Cardiovascular System Blood vessel + 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50

Subcapsular, adenoma X 1 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma malignant X 2 Pheochromocytoma benign 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 46 Parathyroid gland M M + + + + + + + + + + + + + + + + M + + + + + + 45 Pituitary gland + + + + + + + + + + + + + + + + + + + M + + + + + 46

Pars distalis, adenoma X X X 3 Thyroid gland + + + + + + + + + + + + + + + + + + M + + + + + + 48

Follicular cell, adenoma X 1 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555556666666666666667777

2222222222222222222222222 T otal 

### Carcass ID Number 2244450001222333344443333 Tissues/ 6978907890134678901341245 T umors

### Sodium Chlorate, NTP TR 517 184

General Body System None


### Genital System Clitoral gland I ++++++++++++++++++++++++ Ovary A + + + + + + + + + + + + + + +MIM+ + + + + +

Cystadenoma Granulosa cell tumor benign Luteoma X X Uterus +++++++++++++++++++++++++

Polyp stromal


### Hematopoietic System Bone marrow +++++++++++++++++++++++++

Hemangiosarcoma X Lymph node + + + + Lymph node, mandibular + + + +M+ + +M+ + + + + + + + + + + + + + + + Lymph node, mesenteric A + + + + + + + + + + + + + + + + +M+ + +M+ + Spleen A ++++++++++++++++++++++++

Hemangiosarcoma X Thymus + + + + + + + +M+ + + + + + + + + + + + + + + +


### Integumentary System Mammary gland +++++++++++++++++++++++++ Skin ++++++I++++++++++++++++++

Subcutaneous tissue, schwannoma malignant X X


### Musculoskeletal System Bone +++++++++++++++++++++++++


### Nervous System Brain +++++++++++++++++++++++++


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X X Alveolar/bronchiolar carcinoma Hepatocellular carcinoma, metastatic, liver Nose +++++++++++++++++++++++++

Carcinoma X Trachea I + + + M ++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Adenoma X X X X Carcinoma X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

2455555566666777777777777 

### Number of Days on Study 7427899903367133333333333 1046811760904055555555555

2222222222222222222222222 

### Carcass ID Number 1122004023432400011111112 3787456653202512312456890

### 185 Sodium Chlorate, NTP TR 517

General Body System None


### Genital System Clitoral gland + M + I + + + + + + + + + + + + + + + + + + + + + 47 Ovary + + + + + + + + + + + + + + + + + + + + + + + I + 45

Cystadenoma X 1 Granulosa cell tumor benign X 1 Luteoma X 3 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Polyp stromal X 1


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 1 Lymph node + + + 7 Lymph node, mandibular + + + + + + + + I + + + + + + + + I + + + + + + + 46 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 47 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hemangiosarcoma X 2 Thymus + + + + + + + + + + + + + + + + I + + + + + + + + 48


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + I + + + + + + + + 48

Subcutaneous tissue, schwannoma malignant X 3


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 3 Alveolar/bronchiolar carcinoma X 1 Hepatocellular carcinoma, metastatic, liver X 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma 1 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma X X X X X X X 11 Carcinoma 1 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555556666666666666667777

2222222222222222222222222 T otal 

### Carcass ID Number 2244450001222333344443333 Tissues/ 6978907890134678901341245 T umors

### Sodium Chlorate, NTP TR 517 186

Urinary System Kidney +++++++++++++++++++++++++ Urinary bladder A ++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Lymphoma malignant X X X X X X X X X X X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

2455555566666777777777777 

### Number of Days on Study 7427899903367133333333333 1046811760904055555555555

2222222222222222222222222 

### Carcass ID Number 1122004023432400011111112 3787456653202512312456890

### 187 Sodium Chlorate, NTP TR 517

Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Lymphoma malignant X X X X X X X X X X X X 23 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 0 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5555556666666666666667777

2222222222222222222222222 T otal 

### Carcass ID Number 2244450001222333344443333 Tissues/ 6978907890134678901341245 T umors

### Sodium Chlorate, NTP TR 517 188

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder + M A A + + + + + + + +MAA + + + + + + + + + + Intestine large, colon + + + A +++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum + A + A ++++++++++A++++++++++ Intestine small, duodenum + A + A ++++++++++A++++++++++

Adenoma X Intestine small, jejunum + + + A ++++++++A+A++++++++++ Intestine small, ileum + A A A +++++++A++A++++++++++ Liver +++++++++++++++++++++++++

Hemangiosarcoma X Hemangiosarcoma, metastatic, spleen X Hepatocellular carcinoma X X X Hepatocellular carcinoma, multiple X X X Hepatocellular adenoma X X X X Hepatocellular adenoma, multiple X X Mesentery + + + + +++++++ + +++ + Pancreas + A A A +++++++++++++++++++++ Salivary glands + M M + + + + + + + + + +M+ + + + + + + + + + + Stomach, forestomach +++++++++++++++++++++++++

Squamous cell carcinoma Stomach, glandular + A + A +++++++++++++++++++++


### Cardiovascular System Blood vessel + + + Heart +++++++++++++++++++++++++

Hemangiosarcoma, metastatic, spleen X


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + +M+ Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + +M+ Islets, pancreatic + A A A +++++++++++++++++++++

Adenoma X Parathyroid gland + + + + + +M+ + + + +M+ + + + + + + + +M+ + Pituitary gland + M + + + + +M+ + + + + + + + + +M+ + + + + +

Pars distalis, adenoma X X Thyroid gland +++++++++++++++++++++++++


### General Body System None


### Genital System Clitoral gland + + M +++++++++++++++I++++++ Ovary + M + I + + + + + +M+ +M+ + + + + + + + + + +

Cystadenoma X Granulosa cell tumor benign Uterus +++++++++++++++++++++++++

Hemangiosarcoma X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

4455556667777777777777777 

### Number of Days on Study 6915667780111123333333333 1232183426347973444444445

2222223222222222222222222 

### Carcass ID Number 9698960788958995556666795 3868930765284707690679081

### 189 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 44 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Adenoma 1 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 45 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma X 2 Hemangiosarcoma, metastatic, spleen 1 Hepatocellular carcinoma X X X 6 Hepatocellular carcinoma, multiple X X X X 7 Hepatocellular adenoma X X X X X 9 Hepatocellular adenoma, multiple X X X X X X X X 10 Mesentery + ++++ + + + + ++ + + + + + 32 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 47 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 47 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell carcinoma X 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 48


### Cardiovascular System Blood vessel 3 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma, metastatic, spleen 1


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 47

Adenoma X 2 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 Pituitary gland + + M + + + + + + + + + + + M + + + + + + + + + + 45

Pars distalis, adenoma 2 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50


### General Body System None


### Genital System Clitoral gland + + + + + + + + + + + + + M + + + + + + + + + + + 47 Ovary + + + + + + + + + I + + + + + + + + + + + + + + + 45

Cystadenoma X X X 4 Granulosa cell tumor benign X 1 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 1 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

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 3333333333333333333333333 5555555555555566666667777

2222222222222222222222222 T otal 

### Carcass ID Number 5555777888899977777886666 Tissues/ 2345689012314512345791245 T umors

### Sodium Chlorate, NTP TR 517 190

Hematopoietic System Bone marrow +++++++++++++++++++++++++

Hemangiosarcoma X Lymph node + + + +

Liposarcoma, metastatic, skin X Iliac, liposarcoma, metastatic, skin X Lymph node, mandibular + M M + + + + + + + + + +M+ + + + + + + + + + + Lymph node, mesenteric + + + M +++++++++++++++++++++

Histiocytic sarcoma Spleen + A + A +++++++++++++++++++++

Hemangiosarcoma X Thymus + + M + M + + + + + I + + MM + + + + + + + + + +


### Integumentary System Mammary gland +++++++++++++++++++++++++

Carcinoma X Skin +++++++++++++++++++++++++

Hemangioma Subcutaneous tissue, fibrosarcoma X Subcutaneous tissue, liposarcoma X Subcutaneous tissue, schwannoma malignant X


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + +

Osteosarcoma X Skeletal muscle + +

Rhabdomyosarcoma X


### Nervous System Brain +++++++++++++++++++++++++


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma Alveolar/bronchiolar carcinoma Hepatocellular carcinoma, metastatic, liver X X Liposarcoma, metastatic, skin X Nose +++++++++++++++++++++++++ Trachea + + + + + + + + + + + + + + + + + + + + + + + + +


### Special Senses System Eye + A + A + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Adenoma X X X Carcinoma X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

4455556667777777777777777 

### Number of Days on Study 6915667780111123333333333 1232183426347973444444445

2222223222222222222222222 

### Carcass ID Number 9698960788958995556666795 3868930765284707690679081

### 191 Sodium Chlorate, NTP TR 517

Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 1 Lymph node + 5

Liposarcoma, metastatic, skin 1 Iliac, liposarcoma, metastatic, skin 1 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + M + + + + 46 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 49

Histiocytic sarcoma X 1 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 48

Hemangiosarcoma 1 Thymus + + + + + + + + + + + + + + + + + I + + + + + + + 44


### Integumentary system Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Carcinoma 1 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangioma X 1 Subcutaneous tissue, fibrosarcoma 1 Subcutaneous tissue, liposarcoma 1 Subcutaneous tissue, schwannoma malignant 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma 1 Skeletal muscle 2

Rhabdomyosarcoma 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X 1 Alveolar/bronchiolar carcinoma X 1 Hepatocellular carcinoma, metastatic, liver X 3 Liposarcoma, metastatic, skin 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 48 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma XXXX X X 9 Carcinoma 1 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

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 3333333333333333333333333 5555555555555566666667777

2222222222222222222222222 T otal 

### Carcass ID Number 5555777888899977777886666 Tissues/ 2345689012314512345791245 T umors

### Sodium Chlorate, NTP TR 517 192

Urinary System Kidney + + + A +++++++++++++++++++++ Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma Lymphoma malignant X X X X X X X X X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

4455556667777777777777777 

### Number of Days on Study 6915667780111123333333333 1232183426347973444444445

2222223222222222222222222 

### Carcass ID Number 9698960788958995556666795 3868930765284707690679081

### 193 Sodium Chlorate, NTP TR 517

Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 1 Lymphoma malignant X X X X X X X X X X 19 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 500 mg/L

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 3333333333333333333333333 5555555555555566666667777

2222222222222222222222222 T otal 

### Carcass ID Number 5555777888899977777886666 Tissues/ 2345689012314512345791245 T umors

### Sodium Chlorate, NTP TR 517 194

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder + + + A + + + + + +M+ +AAA+ + + + + + + + + Intestine large, colon + + + A + + + A +++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum + + + A ++++++A+++A++++++++++

Hemangioma Intestine small, duodenum + + + A + + + + + +M+ +A+ + + + + + + + + + + Intestine small, jejunum + A + + + + + + + + + + +AA+ + + + + + + + + +

Histiocytic sarcoma Intestine small, ileum + + + A + + + + + +A+ +AA+ + + + + + + + + + Liver + + + A +++++++++++++++++++++

Hepatocellular carcinoma X X X X X Hepatocellular carcinoma, multiple X Hepatocellular adenoma X X X X X X X Hepatocellular adenoma, multiple X X X Histiocytic sarcoma X Mesentery + + +++++++++++ ++ + +

Fibrosarcoma X Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma X Pancreas + + + A +++++++++++++++++++++

Fibrosarcoma, metastatic, mesentery X Histiocytic sarcoma Acinus, sarcoma X Salivary glands +++++++++++++++++I+++++++

Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma Stomach, forestomach +++++++++++++++++++++++++

Squamous cell carcinoma Squamous cell papilloma Squamous cell papilloma, multiple X Stomach, glandular +++++++++++++++++++++++++

Hepatocellular carcinoma, metastatic, liver X Tongue + +


### Cardiovascular System Heart + + + + + + + + + +M+ + + + + + + + + + + + + +

Hepatocellular carcinoma, metastatic, liver X


### Endocrine System Adrenal cortex + + + A +++++++++++++++++++++

Histiocytic sarcoma Osteosarcoma, metastatic, bone X Adrenal medulla + + + A +++++++++++++++++++++ Islets, pancreatic + + + A +++++++++++++++++++++

Adenoma Parathyroid gland + + + M + + + + + + + + + + + + + + + + + + + +M 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

0045555666666677777777777 

### Number of Days on Study 2380047011266811122333333 7463324288212312903444444

3333333333333333333333333 

### Carcass ID Number 3021230044102213234223444 9343651739625244930780678

### 195 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + + + + + I + + + + + + + + + 44 Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 48 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Hemangioma X 1 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47

Histiocytic sarcoma X 1 Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 46 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hepatocellular carcinoma X X X X X X 11 Hepatocellular carcinoma, multiple X X X 4 Hepatocellular adenoma X X X X X X X 14 Hepatocellular adenoma, multiple X X X X X X X X X 12 Histiocytic sarcoma 1 Mesentery + + + + + + + + + + 27

Fibrosarcoma 1 Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 49

Fibrosarcoma, metastatic, mesentery 1 Histiocytic sarcoma X 1 Acinus, sarcoma 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma X 1 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell carcinoma X 1 Squamous cell papilloma X 1 Squamous cell papilloma, multiple 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hepatocellular carcinoma, metastatic, liver 1 Tongue 2


### Cardiovascular System Heart + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hepatocellular carcinoma, metastatic, liver 1


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49

Histiocytic sarcoma X 1 Osteosarcoma, metastatic, bone 1 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X 2 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 4555556666666666677777777

3333333333333333333333333 T otal 

### Carcass ID Number 5111220000013333311124444 Tissues/ 0125134568901267878901245 T umors

### Sodium Chlorate, NTP TR 517 196

Endocrine System (continued) Pituitary gland + + + + + + + + + +M+ + + + + + + + + + + + + +

Histiocytic sarcoma Pars distalis, adenoma Thyroid gland + + + M +++++++++++++++++++++


### General Body System None


### Genital System Clitoral gland + + + + + + + + + + + +M+ + + + + + + + + + + + Ovary + + + M + + + + + + + +M+ + + + + + + + + + + +

Choriocarcinoma X Cystadenoma X Granulosa cell tumor benign Histiocytic sarcoma X Luteoma Uterus +++++++++++++++++++++++++

Histiocytic sarcoma X Leiomyosarcoma Vagina +


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + +

Hemangiosarcoma X X Lymph node + + + + + +

Histiocytic sarcoma Iliac, histiocytic sarcoma X Mediastinal, sarcoma, metastatic, pancreas X Pancreatic, histiocytic sarcoma Renal, histiocytic sarcoma Lymph node, mandibular + + + + + + + + + + + + + + + + +M+ + + + + + +

Histiocytic sarcoma X Lymph node, mesenteric +++++++++++++++++++++++++

Histiocytic sarcoma X Histiocytic sarcoma, metastatic, mesentery X Spleen + + + A +++++++++++++++++++++

Hemangiosarcoma X Histiocytic sarcoma X Thymus + + + + + + + + + +M+ + + + + + + + + + + + + +

Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma



### Integumentary System Mammary gland +++++++++++++++++++++++++

Adenoma X Skin +++++++++++++++++++++++++

Squamous cell carcinoma Subcutaneous tissue, hemangiosarcoma X 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

0045555666666677777777777 

### Number of Days on Study 2380047011266811122333333 7463324288212312903444444

3333333333333333333333333 

### Carcass ID Number 3021230044102213234223444 9343651739625244930780678

### 197 Sodium Chlorate, NTP TR 517

Endocrine System (continued) Pituitary gland + + + + + + + + + + + + + + + I + + + + + + + + + 48

Histiocytic sarcoma X 1 Pars distalis, adenoma X X X X 4 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49


### General Body System None


### Genital System Clitoral gland + + + + + I + + + + + + I + + + + + + + + + + + + 47 Ovary + + + + + + + + + + + + + + + + + + + + I + + + + 47

Choriocarcinoma X 2 Cystadenoma 1 Granulosa cell tumor benign X 1 Histiocytic sarcoma X 2 Luteoma X 1 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 2 Leiomyosarcoma X 1 Vagina 1


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hemangiosarcoma 2 Lymph node + + + + + 11

Histiocytic sarcoma X 1 Iliac, histiocytic sarcoma X 2 Mediastinal, sarcoma, metastatic, pancreas 1 Pancreatic, histiocytic sarcoma X 1 Renal, histiocytic sarcoma X 1 Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 49

Histiocytic sarcoma X 2 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + I 49

Histiocytic sarcoma X 2 Histiocytic sarcoma, metastatic, mesentery 1 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hemangiosarcoma 1 Histiocytic sarcoma X 2 Thymus + + + + + + + + + + + + M + + + + + + + + + + + + 48

Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma X 1


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma 1 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Squamous cell carcinoma X 1 Subcutaneous tissue, hemangiosarcoma 1 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 4555556666666666677777777

3333333333333333333333333 T otal 

### Carcass ID Number 5111220000013333311124444 Tissues/ 0125134568901267878901245 T umors

### Sodium Chlorate, NTP TR 517 198

Musculoskeletal System Bone +++++++++++++++++++++++++

Osteosarcoma X Sarcoma X Skeletal muscle + + +

Histiocytic sarcoma, metastatic, mesentery X Rhabdomyosarcoma Sarcoma, metastatic, pancreas X


### Nervous System Brain +++++++++++++++++++++++++

Osteosarcoma, metastatic, bone X Peripheral nerve + + Spinal cord + + +


### Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar carcinoma X Alveolar/bronchiolar carcinoma, multiple Hepatocellular carcinoma, metastatic, liver X X Histiocytic sarcoma X Osteosarcoma, metastatic, bone X Nose +++++++++++++++++++++++++

Histiocytic sarcoma Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland +++++++++++++++++++++++++

Adenoma X XX Histiocytic sarcoma


### Urinary System Kidney + + + A +++++++++++++++++++++

Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma Osteosarcoma, metastatic, bone X Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X X X Leukemia granulocytic X Lymphoma malignant X X X X X XXXXXX 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

0045555666666677777777777 

### Number of Days on Study 2380047011266811122333333 7463324288212312903444444

3333333333333333333333333 

### Carcass ID Number 3021230044102213234223444 9343651739625244930780678

### 199 Sodium Chlorate, NTP TR 517

Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma 1 Sarcoma 1 Skeletal muscle + 4

Histiocytic sarcoma, metastatic, mesentery 1 Rhabdomyosarcoma X 1 Sarcoma, metastatic, pancreas 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma, metastatic, bone 1 Peripheral nerve 2 Spinal cord 3


### Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + 49

Alveolar/bronchiolar carcinoma 1 Alveolar/bronchiolar carcinoma, multiple X 1 Hepatocellular carcinoma, metastatic, liver X X X 5 Histiocytic sarcoma 1 Osteosarcoma, metastatic, bone 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 1 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Adenoma XX 5 Histiocytic sarcoma X 1


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 49

Hepatocellular carcinoma, metastatic, liver 1 Histiocytic sarcoma X 1 Osteosarcoma, metastatic, bone 1 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma X 4 Leukemia granulocytic 1 Lymphoma malignant XXXX X XXXX X X X X X X X X 28 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 1,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 4555556666666666677777777

3333333333333333333333333 T otal 

### Carcass ID Number 5111220000013333311124444 Tissues/ 0125134568901267878901245 T umors

### Sodium Chlorate, NTP TR 517 200

Alimentary System Esophagus +++++++++++++++++++++++++ Gallbladder ++++++++++++++A++++++++++ Intestine large, colon +++++++++++++++++++++++++ Intestine large, rectum +++++++++++++++++++++++++ Intestine large, cecum + + + +M+A+ + +A+ + + + + + + + + + + + + + Intestine small, duodenum +++++++++++++++++++++++++

Polyp adenomatous X Intestine small, jejunum +++++A++++A+++A++++++++++ Intestine small, ileum + + + + +A+ + + + + + + + + + + + + + +M+ + + Liver +++++++++++++++++++++++++

Hepatocellular carcinoma X X Hepatocellular carcinoma, multiple X X Hepatocellular adenoma X X X X Hepatocellular adenoma, multiple X X X X X Histiocytic sarcoma X Mesentery + + +++++ + ++++

Hemangiosarcoma Sarcoma, metastatic, skin Oral mucosa +

Squamous cell papilloma X Pancreas + + + + +MA + + + + + + + + + + + + + + + + + +

Sarcoma, metastatic, skin Salivary glands +++++++++++++++++++++++++ Stomach, forestomach + + + M +++++++++++++++++++++

Squamous cell papilloma X Stomach, glandular + + + M +++++++++++++++++++++


### Cardiovascular System Blood vessel Heart +++++++++++++++++++++++++


### Endocrine System Adrenal cortex +++++++++++++++++++++++++ Adrenal medulla +++++++++++++++++++++++++

Pheochromocytoma complex X Pheochromocytoma benign X Islets, pancreatic ++++++A++++++++++++++++++

Adenoma X X Carcinoma Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + MM Pituitary gland +++++++++++++++++++++++++

Pars distalis, adenoma X X Thyroid gland +++++++++++++++++++++++++


### General Body System None 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

1444555666666677777777777 

### Number of Days on Study 4457349146888802222222223 2755507867155859999999995

3333333333333333333333333 

### Carcass ID Number 5599987696878685555666678 2929796053890171345678906

### 201 Sodium Chlorate, NTP TR 517

Alimentary System Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 Gallbladder + + + + + + + + + + + I + + + + + + + + + + + + + 48 Intestine large, colon M + + + + + + + + + + + + + + + + + + + + + + + + 49 Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50

Polyp adenomatous 1 Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 47 Intestine small, ileum + + + + + + + + + + + + + + + + + + M + + + + + + 47 Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50

Hepatocellular carcinoma X X X X 6 Hepatocellular carcinoma, multiple X 3 Hepatocellular adenoma X X X X 8 Hepatocellular adenoma, multiple X X X X X X X X X X 15 Histiocytic sarcoma 1 Mesentery + + + + + + + + + + + + 24

Hemangiosarcoma X 1 Sarcoma, metastatic, skin X 1 Oral mucosa 1

Squamous cell papilloma 1 Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 48

Sarcoma, metastatic, skin X 1 Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 49

Squamous cell papilloma 1 Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 49


### Cardiovascular System Blood vessel + 1 Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Endocrine System Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pheochromocytoma complex 1 Pheochromocytoma benign 1 Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X 3 Carcinoma X 1 Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + M + 47 Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50

Pars distalis, adenoma X X 4 Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50


### General Body System None 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5666666666666677777777777

3333333333333333333333334 T otal 

### Carcass ID Number 9666778888899955577777990 Tissues/ 0245781234513467812345680 T umors

### Sodium Chlorate, NTP TR 517 202

Genital System Clitoral gland +++++++++++++++++++++++++ Ovary +++++++++++++++++++++++++

Cystadenoma X Granulosa cell tumor malignant X Granulosa cell tumor benign Histiocytic sarcoma X Yolk sac carcinoma X Uterus +++++++++++++++++++++++++

Histiocytic sarcoma X Polyp stromal Yolk sac carcinoma, metastatic, ovary X


### Hematopoietic System Bone marrow +++++++++++++++++++++++++

Histiocytic sarcoma X Lymph node + + + + +

Renal, histiocytic sarcoma X Lymph node, mandibular +++++++++++++++++++++++++

Squamous cell carcinoma, metastatic, uncertain primary site Lymph node, mesenteric +++++++++++++++++++++++++

Yolk sac carcinoma, metastatic, ovary X Spleen +++++++++++++++++++++++++

Sarcoma, metastatic, skin Thymus + + + +M+ + + + + + + + +M+ + + + + + + + + +

Histiocytic sarcoma X


### Integumentary System Mammary gland +++++++++++++++++++++++++ Skin +++++++++++++++++++++++++

Subcutaneous tissue, fibrosarcoma X X Subcutaneous tissue, hemangioma X Subcutaneous tissue, sarcoma Subcutaneous tissue, schwannoma malignant X


### Musculoskeletal System Bone +++++++++++++++++++++++++

Osteosarcoma X X Skeletal muscle + + + + +

Rhabdomyosarcoma X X Sarcoma, metastatic, skin Yolk sac carcinoma, metastatic, ovary X


### Nervous System Brain +++++++++++++++++++++++++ Peripheral nerve + + Spinal cord + + 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

1444555666666677777777777 

### Number of Days on Study 4457349146888802222222223 2755507867155859999999995

3333333333333333333333333 

### Carcass ID Number 5599987696878685555666678 2929796053890171345678906

### 203 Sodium Chlorate, NTP TR 517

Genital System Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + I 49 Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50

Cystadenoma 1 Granulosa cell tumor malignant 1 Granulosa cell tumor benign X X X X X 5 Histiocytic sarcoma 1 Yolk sac carcinoma 1 Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Polyp stromal X X X 3 Yolk sac carcinoma, metastatic, ovary 1


### Hematopoietic System Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 1 Lymph node + + + + 9

Renal, histiocytic sarcoma 1 Lymph node, mandibular + + + + + + + + + + + + + M + + + + + + + + + + + 49

Squamous cell carcinoma, metastatic, uncertain primary site X 1 Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + M + + + + 49

Yolk sac carcinoma, metastatic, ovary 1 Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50

Sarcoma, metastatic, skin X 1 Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 48

Histiocytic sarcoma 1


### Integumentary System Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50

Subcutaneous tissue, fibrosarcoma 2 Subcutaneous tissue, hemangioma 1 Subcutaneous tissue, sarcoma X 1 Subcutaneous tissue, schwannoma malignant 1


### Musculoskeletal System Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50

Osteosarcoma 2 Skeletal muscle + 6

Rhabdomyosarcoma 2 Sarcoma, metastatic, skin X 1 Yolk sac carcinoma, metastatic, ovary 1


### Nervous System Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 Peripheral nerve 2 Spinal cord 2 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5666666666666677777777777

3333333333333333333333334 T otal 

### Carcass ID Number 9666778888899955577777990 Tissues/ 0245781234513467812345680 T umors

### Sodium Chlorate, NTP TR 517 204

Respiratory System Lung +++++++++++++++++++++++++

Alveolar/bronchiolar adenoma X Alveolar/bronchiolar carcinoma Hepatocellular carcinoma, metastatic, liver X Histiocytic sarcoma X Sarcoma, metastatic, skin Nose +++++++++++++++++++++++++ Trachea +++++++++++++++++++++++++


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + Harderian gland + + + +M+ + + + + + + + + + + + + + + + + + + +

Adenoma X X X X


### Urinary system Kidney +++++++++++++++++++++++++ Urinary bladder +++++++++++++++++++++++++


### Systemic Lesions Multiple organs +++++++++++++++++++++++++

Histiocytic sarcoma X X Lymphoma malignant X X X X X XXXXXX 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

1444555666666677777777777 

### Number of Days on Study 4457349146888802222222223 2755507867155859999999995

3333333333333333333333333 

### Carcass ID Number 5599987696878685555666678 2929796053890171345678906

### 205 Sodium Chlorate, NTP TR 517

Respiratory System Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50

Alveolar/bronchiolar adenoma X X 3 Alveolar/bronchiolar carcinoma X 1 Hepatocellular carcinoma, metastatic, liver X 2 Histiocytic sarcoma 1 Sarcoma, metastatic, skin X 1 Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Special Senses System Eye + + + + + + + + + + + + + + + + + + + + + + + + + 50 Harderian gland + + + + + + + + + + + + + + + + + + + + + + + + + 49

Adenoma X X6


### Urinary System Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50


### Systemic Lesions Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50

Histiocytic sarcoma 2 Lymphoma malignant X X X X X X X X X X X X X X X X 27 

### TABLE 

### D2 Individual Animal Tumor Pathology of Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate: 2,000 mg/L

7777777777777777777777777 

### Number of Days on Study 3333333333333333333333333 5666666666666677777777777

3333333333333333333333334 T otal 

### Carcass ID Number 9666778888899955577777990 Tissues/ 0245781234513467812345680 T umors

### Sodium Chlorate, NTP TR 517 206

Adrenal Medulla: Benign, Complex, or Malignant Pheochromocytoma Overall rate a 3/50 (6%) 0/49 (0%) 0/49 (0%) 2/50 (4%) Adjusted rateb 6.8% 0.0% 0.0% 4.6% Terminal rate c 2/36 (6%) 0/34 (0%) 0/31 (0%) 1/35 (3%) First incidence (days) 660 —e — 681 Poly-3 testd P=0.538N P=0.117N P=0.126N P=0.503N



### Harderian Gland: Adenoma Overall rate 11/50 (22%) 9/50 (18%) 5/50 (10%) 6/50 (12%) Adjusted rate 24.9% 19.7% 11.8% 13.7% Terminal rate 10/36 (28%) 7/35 (20%) 4/31 (13%) 5/35 (14%) First incidence (days) 576 673 712 597 Poly-3 test P=0.093N P=0.368N P=0.095N P=0.142N



### Harderian Gland: Adenoma or Carcinoma Overall rate 12/50 (24%) 10/50 (20%) 5/50 (10%) 6/50 (12%) Adjusted rate 27.2% 21.7% 11.8% 13.7% Terminal rate 11/36 (31%) 7/35 (20%) 4/31 (13%) 5/35 (14%) First incidence (days) 576 568 712 597 Poly-3 test P=0.053N P=0.358N P=0.060N P=0.094N


### Liver: Hepatocellular Adenoma Overall rate 30/49 (61%) f 19/50 (38%) 26/49 (53%) 23/50 (46%) Adjusted rate 66.1% 41.5% 59.9% 51.4% Terminal rate 26/36 (72%) 17/35 (49%) 19/31 (61%) 20/35 (57%) First incidence (days) 524 674 602 475 Poly-3 test P=0.252N P=0.013N P=0.348N P=0.108N


### Liver: Hepatocellular Carcinoma Overall rate 3/49 (6%) 13/50 (26%) 15/49 (31%) 9/50 (18%) Adjusted rate 6.9% 28.5% 35.6% 20.3% Terminal rate 2/36 (6%) 9/35 (26%) 12/31 (39%) 7/35 (20%) First incidence (days) 710 682 711 475 Poly-3 test P=0.158 P=0.007 P<0.001 P=0.061


### Liver: Hepatocellular Carcinoma or Hepatoblastoma Overall rate 4/49 (8%) 13/50 (26%) 15/49 (31%) 9/50 (18%) Adjusted rate 9.2% 28.5% 35.6% 20.3% Terminal rate 3/36 (8%) 9/35 (26%) 12/31 (39%) 7/35 (20%) First incidence (days) 710 682 711 475 Poly-3 test P=0.219 P=0.018 P=0.002 P=0.119


### Liver: Hepatocellular Adenoma or Carcinoma Overall rate 31/49 (63%) f 26/50 (52%) 31/49 (63%) 26/50 (52%) Adjusted rate 68.1% 56.7% 71.3% 57.9% Terminal rate 26/36 (72%) 21/35 (60%) 23/31 (74%) 22/35 (63%) First incidence (days) 524 674 602 475 Poly-3 test P=0.287N P=0.174N P=0.461 P=0.207N


### Lung: Alveolar/bronchiolar Adenoma Overall rate 3/50 (6%) 1/50 (2%) 0/49 (0%) 3/50 (6%) Adjusted rate 6.8% 2.2% 0.0% 6.9% Terminal rate 2/36 (6%) 1/35 (3%) 0/30 (0%) 3/35 (9%) First incidence (days) 630 729 (T) — 729 (T) Poly-3 test P=0.513 P=0.294N P=0.130N P=0.657 

### TABLE 

### D3 Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 207 Sodium Chlorate, NTP TR 517

Lung: Alveolar/bronchiolar Adenoma or Carcinoma Overall rate 4/50 (8%) 2/50 (4%) 2/49 (4%) 4/50 (8%) Adjusted rate 9.1% 4.4% 4.8% 9.2% Terminal rate 3/36 (8%) 2/35 (6%) 1/30 (3%) 4/35 (11%) First incidence (days) 630 729 (T) 712 729 (T) Poly-3 test P=0.482 P=0.323N P=0.365N P=0.636


### Ovary: Cystadenoma Overall rate 1/45 (2%) 4/45 (9%) 1/47 (2%) 1/50 (2%) Adjusted rate 2.5% 9.6% 2.5% 2.3% Terminal rate 1/32 (3%) 3/34 (9%) 1/30 (3%) 1/35 (3%) First incidence (days) 729 (T) 682 729 (T) 729 (T) Poly-3 test P=0.336N P=0.196 P=0.757N P=0.740N


### Ovary: Benign Granulosa Cell Tumor Overall rate 1/45 (2%) 1/45 (2%) 1/47 (2%) 5/50 (10%) Adjusted rate 2.5% 2.4% 2.5% 11.5% Terminal rate 1/32 (3%) 1/34 (3%) 1/30 (3%) 5/35 (14%) First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) Poly-3 test P=0.031 P=0.749N P=0.757N P=0.123


### Ovary: Benign or Malignant Granulosa Cell Tumor Overall rate 1/45 (2%) 1/45 (2%) 1/47 (2%) 6/50 (12%) Adjusted rate 2.5% 2.4% 2.5% 13.5% Terminal rate 1/32 (3%) 1/34 (3%) 1/30 (3%) 5/35 (14%) First incidence (days) 729 (T) 729 (T) 729 (T) 142 Poly-3 test P=0.012 P=0.749N P=0.757N P=0.075


### Ovary: Luteoma Overall rate 3/45 (7%) 0/45 (0%) 1/47 (2%) 0/50 (0%) Adjusted rate 7.5% 0.0% 2.5% 0.0% Terminal rate 2/32 (6%) 0/34 (0%) 1/30 (3%) 0/35 (0%) First incidence (days) 674 — 729 (T) — Poly-3 test P=0.079N P=0.110N P=0.300N P=0.103N


### Ovary: Benign Granulosa Cell Tumor, Malignant Granulosa Cell Tumor, or Luteoma Overall rate 4/45 (9%) 1/45 (2%) 2/47 (4%) 6/50 (12%) Adjusted rate 10.1% 2.4% 5.0% 13.5% Terminal rate 3/32 (9%) 1/34 (3%) 2/30 (7%) 5/35 (14%) First incidence (days) 674 729 (T) 729 (T) 142 Poly-3 test P=0.185 P=0.164N P=0.331N P=0.440



### Pancreatic Islets: Adenoma Overall rate 0/46 (0%) 2/47 (4%) 2/49 (4%) 3/49 (6%) Adjusted rate 0.0% 4.5% 4.8% 6.8% Terminal rate 0/36 (0%) 1/35 (3%) 2/31 (7%) 1/35 (3%) First incidence (days) — 706 729 (T) 475 Poly-3 test P=0.112 P=0.248 P=0.235 P=0.125



### Pancreatic Islets: Adenoma or Carcinoma Overall rate 0/46 (0%) 2/47 (4%) 2/49 (4%) 4/49 (8%) Adjusted rate 0.0% 4.5% 4.8% 9.1% Terminal rate 0/36 (0%) 1/35 (3%) 2/31 (7%) 2/35 (6%) First incidence (days) — 706 729 (T) 475 Poly-3 test P=0.045 P=0.248 P=0.235 P=0.065 

### TABLE 

### D3 Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 208

Pituitary Gland (Pars Distalis): Adenoma Overall rate 3/46 (7%) 2/45 (4%) 4/48 (8%) 4/50 (8%) Adjusted rate 7.2% 4.9% 9.8% 9.2% Terminal rate 3/35 (9%) 2/32 (6%) 4/30 (13%) 3/35 (9%) First incidence (days) 729 (T) 729 (T) 729 (T) 688 Poly-3 test P=0.356 P=0.503N P=0.489 P=0.526



### Skin: Fibrosarcoma or Sarcoma Overall rate 0/50 (0%) 1/50 (2%) 0/50 (0%) 3/50 (6%) Adjusted rate 0.0% 2.2% 0.0% 6.9% Terminal rate 0/36 (0%) 0/35 (0%) 0/31 (0%) 2/35 (6%) First incidence (days) — 513 — 705 Poly-3 test P=0.041 P=0.511 —g P=0.118


### Skin: Schwannoma Malignant Overall rate 3/50 (6%) 1/50 (2%) 0/50 (0%) 1/50 (2%) Adjusted rate 6.8% 2.2% 0.0% 2.3% Terminal rate 2/36 (6%) 0/35 (0%) 0/31 (0%) 0/35 (0%) First incidence (days) 591 561 — 685 Poly-3 test P=0.207N P=0.291N P=0.126N P=0.309N


### Stomach (Forestomach): Squamous Cell Papilloma or Squamous Cell Carcinoma Overall rate 0/50 (0%) 1/50 (2%) 3/50 (6%) 1/50 (2%) Adjusted rate 0.0% 2.2% 7.0% 2.3% Terminal rate 0/36 (0%) 1/35 (3%) 2/31 (7%) 1/35 (3%) First incidence (days) — 729 (T) 574 729 (T) Poly-3 test P=0.343 P=0.508 P=0.115 P=0.499


### Uterus: Stromal Polyp Overall rate 1/50 (2%) 0/50 (0%) 0/50 (0%) 3/50 (6%) Adjusted rate 2.3% 0.0% 0.0% 6.9% Terminal rate 1/36 (3%) 0/35 (0%) 0/31 (0%) 3/35 (9%) First incidence (days) 729 (T) — — 729 (T) Poly-3 test P=0.081 P=0.492N P=0.506N P=0.303


### All Organs: Hemangiosarcoma Overall rate 3/50 (6%) 4/50 (8%) 2/50 (4%) 1/50 (2%) Adjusted rate 6.8% 8.8% 4.7% 2.3% Terminal rate 2/36 (6%) 3/35 (9%) 1/31 (3%) 1/35 (3%) First incidence (days) 606 674 662 729 (T) Poly-3 test P=0.170N P=0.518 P=0.515N P=0.310N


### All Organs: Hemangioma or Hemangiosarcoma Overall rate 5/50 (10%) 5/50 (10%) 3/50 (6%) 2/50 (4%) Adjusted rate 11.4% 11.0% 7.1% 4.6% Terminal rate 4/36 (11%) 4/35 (11%) 2/31 (7%) 1/35 (3%) First incidence (days) 606 674 662 618 Poly-3 test P=0.134N P=0.609N P=0.375N P=0.218N


### All Organs: Histiocytic Sarcoma Overall rate 0/50 (0%) 1/50 (2%) 4/50 (8%) 2/50 (4%) Adjusted rate 0.0% 2.2% 9.3% 4.6% Terminal rate 0/36 (0%) 1/35 (3%) 1/31 (3%) 1/35 (3%) First incidence (days) — 729 (T) 503 535 Poly-3 test P=0.163 P=0.508 P=0.058 P=0.239 

### TABLE 

### D3 Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 209 Sodium Chlorate, NTP TR 517

All Organs: Malignant Lymphoma Overall rate 23/50 (46%) 19/50 (38%) 28/50 (56%) 27/50 (54%) Adjusted rate 50.5% 41.0% 63.8% 59.5% Terminal rate 19/36 (53%) 16/35 (46%) 23/31 (74%) 22/35 (63%) First incidence (days) 440 492 503 447 Poly-3 test P=0.089 P=0.238N P=0.138 P=0.254


### All Organs: Benign Neoplasms Overall rate 38/50 (76%) 27/50 (54%) 33/50 (66%) 31/50 (62%) Adjusted rate 81.6% 58.6% 74.5% 67.9% Terminal rate 31/36 (86%) 22/35 (63%) 24/31 (77%) 25/35 (71%) First incidence (days) 524 673 574 475 Poly-3 test P=0.234N P=0.010N P=0.273N P=0.090N


### All Organs: Malignant Neoplasms Overall rate 33/50 (66%) 38/50 (76%) 41/50 (82%) 41/50 (82%) Adjusted rate 69.9% 76.9% 88.8% 84.1% Terminal rate 24/36 (67%) 24/35 (69%) 27/31 (87%) 29/35 (83%) First incidence (days) 440 461 503 142 Poly-3 test P=0.041 P=0.289 P=0.018 P=0.073


### All Organs: Benign or Malignant Neoplasms Overall rate 47/50 (94%) 45/50 (90%) 46/50 (92%) 47/50 (94%) Adjusted rate 95.8% 91.0% 98.5% 95.4% Terminal rate 34/36 (94%) 31/35 (89%) 31/31 (100%) 33/35 (94%) First incidence (days) 440 461 503 142 Poly-3 test P=0.439 P=0.288N P=0.427 P=0.659N

(T)Terminal sacrifice a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, liver, lung, ovary, pancreatic islets, and pituitary gland; for other tissues, denominator is number of animals necropsied. b Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality c Observed incidence at terminal kill d Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly-3 test accounts for the differential mortality in animals that do not reach terminal sacrifice. A negative trend or a lower incidence in an exposed group is indicated by N

. e Not applicable; no neoplasms in animal group f A single incidence of hepatoblastoma occurred in an animal that also had an adenoma. g Value of statistic cannot be computed. 

### TABLE 

### D3 Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 210



### TABLE 

### D4b Historical Incidence of Liver Neoplasms in Control Female B6C3F 1 

### Mice a



### Incidence in Controls Hepatocellular Hepatocellular Hepatocellular

Adenoma Carcinoma Adenoma Study or Carcinoma

Historical Incidence in Drinking Water Controls Given NTP-2000 Diet

Dipropylene glycol 11/50 7/50 17/50 Sodium chlorate 30/49 3/49 31/49 Sodium nitrite 9/50 2/50 10/50



### Overall Historical Incidence: Drinking Water Studies Total (%) 50/149 (33.6%) 12/149 (8.1%) 58/149 (38.9%) Mean ± standard deviation 20% ± 2.8% 9% ± 7.1% 27% ± 9.9% Range 18%-61% 4%-14% 20%-63%



### Overall Historical Incidence: All Routes Total (%) 214/1,251 (17.1%) 90/1,251 (7.2%) 286/1,251 (22.9%) Mean ± standard deviation 18.0% ± 11.6% 7.6% ± 4.4% 24.1% ± 12.8% Range 6%-61% 0%-16% 8%-63%

a Data as of April 19, 2004 

### TABLE 

### D4a Historical Incidence of Pancreatic Islet Neoplasms in Control Female B6C3F 1 

### Mice a



### Incidence in Controls Adenoma Carcinoma Adenoma Study or Carcinoma

Historical Incidence in Drinking Water Controls Given NTP-2000 Diet

Dipropylene glycol 2/50 0/50 2/50 Sodium chlorate 0/46 0/46 0/46 Sodium nitrite 0/50 0/50 0/50



### Overall Historical Incidence: Drinking Water Studies Total (%) 2/146 (1.4%) 0/146 2/146 (1.4%) Mean ± standard deviation 1.4% ± 2.3% 1.3% ± 2.3% Range 0%-4% 0%-4%



### Overall Historical Incidence: All Routes Total (%) 8/1,230 (0.7%) 1/1,230 (0.1%) 9/1,230 (0.7%) Mean ± standard deviation 0.7% ± 1.2% 0.1% ± 0.4% 0.8% ± 1.2% Range 0%-4% 0%-2% 0%-4%

a Data as of April 19, 2004

### 211 Sodium Chlorate, NTP TR 517

Disposition Summary Animals initially in study 50 50 50 50 Early deaths

Accidental death 1 Moribund 3 5 6 8 Natural death 10 10 12 7 Survivors

Died last week of study 1 Terminal sacrifice 36 34 31 35 Other 1

Animals examined microscopically 50 50 50 50



### Alimentary System Intestine large, colon (48) (49) (48) (49)

Hemorrhage 1 (2%) Intestine large, cecum (44) (47) (47) (47)

Edema 4 (9%) 6 (13%) 6 (13%) 6 (13%) Hemorrhage 1 (2%) Inflammation, chronic 1 (2%) Ulcer 1 (2%) Intestine small, duodenum (46) (47) (47) (50)

Ulcer 1 (2%) 1 (2%) Epithelium, hyperplasia 2 (4%) Intestine small, ileum (42) (45) (46) (47)

Inflammation, chronic 1 (2%) 1 (2%) Epithelium, hyperplasia 1 (2%) 1 (2%) Liver (49) (50) (49) (50)

Angiectasis 2 (4%) 2 (4%) 1 (2%) Basophilic focus 5 (10%) 4 (8%) 1 (2%) Clear cell focus 3 (6%) 1 (2%) Eosinophilic focus 9 (18%) 9 (18%) 13 (27%) 7 (14%) Hematopoietic cell proliferation 7 (14%) 4 (8%) 3 (6%) 8 (16%) Hemorrhage 1 (2%) Hepatodiaphragmatic nodule 1 (2%) Hyperplasia, lymphoid 4 (8%) 7 (14%) 3 (6%) 5 (10%) Infarct 1 (2%) Infiltration cellular, mixed cell 7 (14%) 7 (14%) 8 (16%) 7 (14%) Mixed cell focus 7 (14%) 2 (4%) 3 (6%) 3 (6%) Necrosis, focal 5 (10%) 1 (2%) 4 (8%) 1 (2%) Tension lipidosis 2 (4%) 3 (6%) 1 (2%) Centrilobular, necrosis 2 (4%) 2 (4%) 2 (4%) 2 (4%) Hepatocyte, karyomegaly 3 (6%) Hepatocyte, vacuolization cytoplasmic 4 (8%) 3 (6%) 6 (12%) 4 (8%) Kupffer cell, hyperplasia 1 (2%) 1 (2%) 2 (4%) Kupffer cell, pigmentation 3 (6%) 4 (8%) 4 (8%) 7 (14%) Mesentery (30) (32) (27) (24)

Angiectasis 1 (3%) 1 (4%) Hemorrhage 1 (3%) Inflammation, chronic 1 (4%) Fat, necrosis 21 (70%) 24 (75%) 20 (74%) 16 (67%)

a Number of animals examined microscopically at the site and the number of animals with lesion 

### TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate a



### 0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 212

Alimentary System (continued) Pancreas (46) (47) (49) (48)

Atrophy 2 (4%) 1 (2%) 1 (2%) Cyst 1 (2%) 1 (2%) Acinus, hyperplasia, focal 1 (2%) Salivary glands (48) (47) (49) (50)

Hyperplasia, lymphoid 16 (33%) 21 (45%) 15 (31%) 18 (36%) Stomach, forestomach (49) (50) (50) (49)

Diverticulum 2 (4%) 1 (2%) 1 (2%) 2 (4%) Edema 3 (6%) Erosion 1 (2%) 2 (4%) 2 (4%) Hyperplasia 1 (2%) Inflammation, chronic active 2 (4%) 2 (4%) Ulcer 2 (4%) 3 (6%) 3 (6%) Epithelium, hyperplasia 3 (6%) 4 (8%) 9 (18%) 6 (12%) Stomach, glandular (49) (48) (50) (49)

Erosion 1 (2%) 2 (4%) Ulcer 1 (2%)



### Cardiovascular System Blood vessel (1) (3) (1)

Aorta, mineralization 1 (33%) Heart (49) (50) (49) (50)

Cardiomyopathy 1 (2%) 1 (2%) 1 (2%) Mineralization 1 (2%) 1 (2%) 2 (4%)



### Endocrine System Adrenal cortex (50) (49) (49) (50)

Accessory adrenal cortical nodule 4 (8%) 2 (4%) 7 (14%) 7 (14%) Hyperplasia, focal 1 (2%) Capsule, hyperplasia 1 (2%) 2 (4%) Zona reticularis, vacuolization cytoplasmic 1 (2%) 1 (2%) Adrenal medulla (50) (49) (49) (50)

Hyperplasia 2 (4%) 2 (4%) 1 (2%) Islets, pancreatic (46) (47) (49) (49)

Hyperplasia 9 (20%) 6 (13%) 4 (8%) 3 (6%) Parathyroid gland (45) (47) (48) (47)

Cyst 1 (2%) 1 (2%) 2 (4%) 2 (4%) Pituitary gland (46) (45) (48) (50)

Pars distalis, angiectasis 1 (2%) 2 (4%) 2 (4%) Pars distalis, cyst 1 (2%) Pars distalis, hyperplasia, focal 3 (7%) 3 (7%) 3 (6%) 1 (2%) Thyroid gland (48) (50) (49) (50)

Degeneration, cystic 25 (52%) 28 (56%) 34 (69%) 32 (64%) Follicle, cyst 1 (2%) 1 (2%) 1 (2%) Follicular cell, cyst 2 (4%) Follicular cell, hypertrophy 3 (6%) 2 (4%) 5 (10%) 14 (28%)



### General Body System None 

### TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 213 Sodium Chlorate, NTP TR 517

Genital System Clitoral gland (47) (47) (47) (49)

Inflammation, chronic 2 (4%) 4 (8%) Ovary (45) (45) (47) (50)

Angiectasis 3 (7%) 2 (4%) 4 (9%) 3 (6%) Cyst 9 (20%) 14 (31%) 14 (30%) 13 (26%) Cyst, hemorrhagic 1 (2%) Hemorrhage 1 (2%) Thrombosis 3 (7%) 1 (2%) 1 (2%) Bilateral, cyst 1 (2%) Follicle, hemorrhage 1 (2%) 4 (9%) 4 (9%) 9 (18%) Granulosa cell, hyperplasia 3 (6%) 7 (14%) Uterus (50) (50) (50) (50)

Angiectasis 1 (2%) 2 (4%) 1 (2%) Hyperplasia, atypical 1 (2%) Hyperplasia, cystic 45 (90%) 45 (90%) 40 (80%) 41 (82%) Inflammation, chronic 2 (4%) Inflammation, suppurative 1 (2%) Metaplasia, squamous 2 (4%) 1 (2%) Endometrium, hyperplasia, atypical 1 (2%)



### Hematopoietic System Bone marrow (50) (50) (50) (50)

Hyperplasia 14 (28%) 28 (56%) 29 (58%) 31 (62%) Myelofibrosis 1 (2%) 2 (4%) 1 (2%) 2 (4%) Lymph node (7) (5) (11) (9)

Iliac, hemorrhage 1 (9%) Iliac, hyperplasia, lymphoid 1 (14%) 1 (11%) Mediastinal, hyperplasia, lymphoid 1 (14%) 1 (20%) 2 (18%) Mediastinal, pigmentation 1 (14%) Pancreatic, hemorrhage 1 (11%) Renal, hemorrhage 1 (14%) 1 (11%) Lymph node, mandibular (46) (46) (49) (49)

Atrophy 1 (2%) 1 (2%) Hematopoietic cell proliferation 1 (2%) 1 (2%) 1 (2%) Hyperplasia, lymphoid 12 (26%) 7 (15%) 7 (14%) 10 (20%) Pigmentation 18 (39%) 16 (35%) 18 (37%) 15 (31%) Lymph node, mesenteric (47) (49) (49) (49)

Atrophy 1 (2%) 1 (2%) 2 (4%) Ectasia 2 (4%) 1 (2%) Hematopoietic cell proliferation 2 (4%) 2 (4%) 1 (2%) 2 (4%) Hemorrhage 4 (9%) 2 (4%) 1 (2%) Hyperplasia, lymphoid 10 (21%) 8 (16%) 11 (22%) 6 (12%) Pigmentation 1 (2%) 2 (4%) Spleen (49) (48) (49) (50)

Accessory spleen 1 (2%) Hematopoietic cell proliferation 39 (80%) 39 (81%) 35 (71%) 39 (78%) Hyperplasia, lymphoid 11 (22%) 10 (21%) 5 (10%) 9 (18%) Pigmentation 28 (57%) 30 (63%) 28 (57%) 27 (54%) Lymphoid follicle, atrophy 1 (2%) 2 (4%) 1 (2%) 2 (4%) Thymus (48) (44) (48) (48)

Atrophy 5 (10%) 7 (16%) 5 (10%) 9 (19%) Cyst 3 (6%) 1 (2%) 1 (2%) Hyperplasia, lymphoid 5 (10%) 3 (7%) 4 (8%) 2 (4%) 

### TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 214

Integumentary System Mammary gland (50) (50) (50) (50)

Hyperplasia 5 (10%) 11 (22%) 8 (16%) 10 (20%) Skin (48) (50) (50) (50)

Edema 1 (2%) 1 (2%) Epidermis, hyperplasia 1 (2%) 1 (2%) Subcutaneous tissue, edema 1 (2%) 2 (4%)



### Musculoskeletal System Bone (50) (50) (50) (50)

Callus 1 (2%) Fracture 1 (2%) 1 (2%) Hyperostosis 1 (2%) 1 (2%) 4 (8%) 3 (6%) Cranium, osteopetrosis 1 (2%) Femur, osteopetrosis 1 (2%) 1 (2%) Skeletal muscle (2) (4) (6)

Angiectasis 1 (17%) Atrophy 1 (17%)



### Nervous System Brain (50) (50) (50) (50)

Compression 1 (2%) 1 (2%) 1 (2%) Inflammation, chronic 1 (2%) Necrosis 1 (2%) 1 (2%) Peripheral nerve (2) (2)

Atrophy 1 (50%) 2 (100%)



### Respiratory System Lung (50) (50) (49) (50)

Edema 5 (10%) 8 (16%) 3 (6%) 5 (10%) Foreign body 2 (4%) Hemorrhage 5 (10%) 8 (16%) 6 (12%) 4 (8%) Hyperplasia, lymphoid 10 (20%) 8 (16%) 3 (6%) 9 (18%) Infiltration cellular, polymorphonuclear 1 (2%) Infiltration cellular, histiocyte 1 (2%) 1 (2%) 3 (6%) 5 (10%) Metaplasia, osseous 1 (2%) 2 (4%) Thrombosis 1 (2%) 4 (8%) 1 (2%) Alveolar epithelium, hyperplasia 2 (4%) 2 (4%) 1 (2%) 2 (4%)



### Special Senses System Eye (50) (48) (50) (50)

Inflammation, chronic 3 (6%) 3 (6%) Cornea, hyperplasia 2 (4%) 1 (2%) Harderian gland (50) (50) (50) (49)

Cyst 1 (2%) Hyperplasia, focal 1 (2%) 1 (2%) 1 (2%) 

### TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 215 Sodium Chlorate, NTP TR 517

Urinary System Kidney (50) (49) (49) (50)

Hydronephrosis 1 (2%) 1 (2%) Hyperplasia, lymphoid 8 (16%) 9 (18%) 6 (12%) 8 (16%) Infarct 3 (6%) 2 (4%) 4 (8%) 5 (10%) Metaplasia, osseous 1 (2%) 3 (6%) 2 (4%) Nephropathy 14 (28%) 11 (22%) 14 (29%) 12 (24%) Renal tubule, accumulation, hyaline droplet 2 (4%) 1 (2%) 2 (4%) 1 (2%) Renal tubule, dilatation 1 (2%) 1 (2%) Renal tubule, necrosis 1 (2%) 1 (2%) Renal tubule, pigmentation 3 (6%) 1 (2%) 1 (2%) Transitional epithelium, hyperplasia 1 (2%) Urinary bladder (49) (50) (50) (50)

Hyperplasia, lymphoid 4 (8%) 12 (24%) 4 (8%) 5 (10%) Transitional epithelium, hyperplasia 1 (2%) 

### TABLE 

### D5 Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 216

### 217



# APPENDIX E GENETIC TOXICOLOGY

S

ALMONELLA TYPHIMURIUM 

### MUTAGENICITY 

### T EST 

### P ROTOCOL 

### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 M OUSE 

### P ERIPHERAL 

### B LOOD 

### MICRONUCLEUS 

### T EST 

### P ROTOCOL 

### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 E VALUATION 

### P ROTOCOL


### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 RESULTS


### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 T ABLE 

### E1 Mutagenicity of Sodium Chlorate in Salmonella typhimurium . . . . . . . . . . . . . . . . . . . . . . . . 220 T ABLE 

### E2 Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice Following Administration of Sodium Chlorate in Drinking Water for 3 Weeks . . . . . . . . . 222

### 218 Sodium Chlorate, NTP TR 517



# GENETIC TOXICOLOGY

S

ALMONELLA TYPHIMURIUM 

# MUTAGENICITY 

# T EST 

# P ROTOCOL Testing was performed as reported by Zeiger et al. (1992). Sodium chlorate was sent to the laboratory as a coded aliquot. It was incubated with the Salmonella typhimurium tester strains TA97, TA98, TA100, TA102, TA104, and TA1535 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 37° 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 37° C.

Each trial consisted of triplicate plates of concurrent positive and negative controls and at least five doses of sodium chlorate. In the absence of toxicity, 10,000 μ g/plate was selected as the high dose. All trials were repeated at the same or a higher S9 fraction.

In this assay, a positive response is defined as a reproducible, dose-related increase in histidine-independent (revertant) colonies in any one strain/activation combination. An equivocal response is defined as an increase in revertants that is not dose related, is not reproducible, or is not of sufficient magnitude to support a determination of mutagenicity. A negative response is obtained when no increase in revertant colonies is observed following chemical treatment. There is no minimum percentage or fold increase required for a chemical to be judged positive or weakly positive.



# M OUSE 

# P ERIPHERAL 

# B LOOD 

# MICRONUCLEUS 

# T EST 

# P ROTOCOL A detailed discussion of this assay is presented by MacGregor et al. (1990). At the end of the 3-week toxicity study, peripheral blood samples were obtained from male and female mice. Smears were immediately prepared and fixed in absolute methanol. The methanol-fixed slides were stained with acridine orange and coded. Slides were scanned to determine the frequency of micronuclei in 2,000 normochromatic erythrocytes (NCEs) in each of 10 animals per exposure group. In addition, the percentage of polychromatic erythrocytes (PCEs) in a population of 1,000 erythrocytes was determined as a measure of bone marrow toxicity.

The results were tabulated as the mean of the pooled results from all animals within a treatment group plus or minus the standard error of the mean. The frequency of micronucleated cells among NCEs was analyzed by astatistical software package that tested for increasing trend over exposure groups with a one-tailed CochranArmitage trend test, followed by pairwise comparisons between each exposure group and the control group (ILS, 1990). In the presence of excess binomial variation, as detected by a binomial dispersion test, the binomial variance of the Cochran-Armitage test was adjusted upward in proportion to the excess variation. In the micronucleus test, an individual trial is considered positive if the trend test P value is less than or equal to 0.025 or if the P value for any single exposed group is less than or equal to 0.025 divided by the number of exposed groups. A final call of positive for micronucleus induction is preferably based on reproducibly positive trials (as noted above). Results of the 3-week studies were accepted without repeat tests, because additional test data could not be obtained. Ultimately, the final call is determined by the scientific staff after considering the results of statistical analyses, the reproducibility of any effects observed, and the magnitudes of those effects.



# E VALUATION 

# P ROTOCOL These are the basic guidelines for arriving at an overall assay result for assays performed by the National Toxicology Program. Statistical as well as biological factors are considered. For an individual assay, the statistical procedures for data analysis have been described in the preceding protocols. There have been instances, however,

### Sodium Chlorate, NTP TR 517 219



### in which multiple aliquots of a chemical were tested in the same assay, and different results were obtained among aliquots and/or among laboratories. Results from more than one aliquot or from more than one laboratory are not simply combined into an overall result. Rather, all the data are critically evaluated, particularly with regard to pertinent protocol variations, in determining the weight of evidence for an overall conclusion of chemical activity in an assay. In addition to multiple aliquots, the in vitro assays have another variable that must be considered in arriving at an overall test result. In vitro assays are conducted with and without exogenous metabolic activation. Results obtained in the absence of activation are not combined with results obtained in the presence of activation; each testing condition is evaluated separately. The summary table in the Abstract of this Technical Report presents a result that represents a scientific judgement of the overall evidence for activity of the chemical in an assay.



# RESULTS Sodium chlorate (100 to 10,000 μg/plate) was not mutagenic in S. typhimurium strains TA97, TA98, TA100, TA102, TA104, or TA1535, with or without induced rat or hamster liver S9 enzymes. In vivo, no increases in the frequencies of micronucleated NCEs were seen in peripheral blood samples from male and female B6C3F 1 

### mice exposed to concentrations of 125 to 2,000 mg/L sodium chlorate in drinking water for 3 weeks. The abbreviated exposure duration of 3 weeks may not have allowed steady state to be reached in the circulating NCE population, but the data are clearly negative, with no indication of an exposure concentration-related increase in NCEs. Steady state is usually established by day 35 of continuous exposure.

### 220 Sodium Chlorate, NTP TR 517



### TABLE 

### E1 Mutagenicity of Sodium Chlorate in Salmonella typhimurium a



### Revertants/Plateb


### Strain Dose –S9 hamster S9 rat S9 (μg/plate) Trial 1 Trial 2 + 10% + 30% + 10% + 30%

TA102 0 216 ± 5.2 233 ± 20.7 331 ± 9.8 264 ± 4.3 309 ± 27.7 275 ± 11.5 100 210 ± 5.2 220 ± 16.4 359 ± 16.0 250 ± 3.3 340 ± 40.5 264 ± 23.0 333 219 ± 3.3 225 ± 14.6 331 ± 7.2 259 ± 13.9 347 ± 31.0 254 ± 20.0 1,000 233 ± 12.5 233 ± 16.9 305 ± 13.3 286 ± 5.8 357 ± 23.1 291 ± 9.6 3,333 242 ± 22.7 238 ± 6.5 349 ± 4.5 291 ± 6.5 373 ± 34.6 274 ± 8.6 10,000 209 ± 5.2 248 ± 19.3 392 ± 7.9 252 ± 20.8 322 ± 32.4 257 ± 11.6

Trial summary Negative Negative Negative Negative Negative Negative Positive control c 737 ± 24.1 898 ± 41.7 1,211 ± 42.0 784 ± 15.3 1,110 ± 60.9 768 ± 24.3



### TA104 0 298 ± 8.0 334 ± 16.8 430 ± 10.4 430 ± 11.2 397 ± 15.2 405 ± 10.0 100 289 ± 29.1 328 ± 6.4 411 ± 2.7 432 ± 14.7 377 ± 25.2 411 ± 1.7 333 285 ± 32.8 324 ± 26.7 426 ± 12.2 408 ± 11.4 368 ± 22.2 399 ± 7.5 1,000 262 ± 18.1 364 ± 28.0 365 ± 2.3 406 ± 16.6 425 ± 20.0 398 ± 17.3 3,333 314 ± 9.8 326 ± 16.2 363 ± 12.3 411 ± 3.8 427 ± 22.8 416 ± 9.8 10,000 302 ± 8.2 342 ± 17.9 384 ± 40.0 407 ± 1.5 410 ± 4.9 412 ± 0.9

Trial summary Negative Negative Negative Negative Negative Negative Positive control 939 ± 17.9 921 ± 42.5 1,254 ± 25.9 974 ± 31.5 1,266 ± 29.0 826 ± 47.6



### TA100 0 145 ± 6.9 137 ± 8.7 120 ± 7.3 126 ± 9.5 133 ± 5.2 122 ± 12.4 100 125 ± 3.8 117 ± 4.4 130 ± 1.3 130 ± 9.3 162 ± 2.0 124 ± 9.5 333 134 ± 7.3 127 ± 9.1 124 ± 0.0 135 ± 5.5 131 ± 3.3 148 ± 2.9 1,000 131 ± 7.6 126 ± 9.1 137 ± 7.4 152 ± 8.5 134 ± 7.0 125 ± 2.0 3,333 135 ± 8.7 121 ± 3.8 126 ± 11.2 134 ± 8.8 139 ± 13.4 134 ± 9.5 10,000 144 ± 4.9 132 ± 5.5 128 ± 8.9 126 ± 10.1 122 ± 1.7 131 ± 12.5

Trial summary Negative Negative Negative Negative Negative Negative Positive control 900 ± 12.3 844 ± 5.1 695 ± 18.5 664 ± 21.1 635 ± 24.8 624 ± 15.4



### TA1535 0 13 ± 2.4 11 ± 2.3 12 ± 0.9 12 ± 2.0 12 ± 1.5 13 ± 1.2 100 11 ± 0.3 8 ± 1.2 10 ± 0.3 12 ± 0.7 13 ± 0.6 15 ± 2.0 333 9 ± 0.6 11 ± 2.3 9 ± 1.2 15 ± 1.8 9 ± 0.0 10 ± 1.8 1,000 12 ± 2.0 11 ± 1.3 10 ± 2.7 10 ± 1.2 7 ± 0.6 10 ± 1.2 3,333 11 ± 1.7 7 ± 0.7 9 ± 0.6 12 ± 3.4 8 ± 0.7 10 ± 3.2 10,000 9 ± 1.0 9 ± 1.7 10 ± 1.8 8 ± 0.7 6 ± 1.9 12 ± 2.7

Trial summary Negative Negative Negative Negative Negative Negative Positive control 938 ± 15.5 940 ± 16.2 126 ± 14.0 141 ± 5.0 130 ± 15.1 115 ± 6.9



### TA97 0 128 ± 10.5 139 ± 9.5 146 ± 4.5 169 ± 3.3 154 ± 5.3 174 ± 6.3 100 117 ± 11.1 147 ± 14.3 148 ± 18.1 151 ± 7.5 157 ± 9.8 191 ± 13.8 333 127 ± 14.3 132 ± 10.8 157 ± 12.1 177 ± 10.4 132 ± 3.3 191 ± 14.0 1,000 145 ± 11.4 126 ± 9.6 136 ± 5.2 155 ± 3.7 140 ± 15.5 167 ± 25.2 3,333 121 ± 7.8 149 ± 10.6 138 ± 13.3 160 ± 6.6 158 ± 13.2 210 ± 9.3 10,000 121 ± 6.1 125 ± 4.0 88 ± 45.6 142 ± 10.7 131 ± 8.2 173 ± 19.8

Trial summary Negative Negative Negative Negative Negative Negative Positive control 572 ± 16.9 640 ± 21.1 710 ± 8.9 660 ± 6.7 653 ± 15.0 650 ± 23.7

### Sodium Chlorate, NTP TR 517 221



### TABLE 

### E1 Mutagenicity of Sodium Chlorate in Salmonella typhimurium

Revertants/Plate Strain Dose –S9 hamster S9 rat S9 (μg/plate) Trial 1 Trial 2 + 10% + 30% + 10% + 30%

TA98 0 12 ± 0.9 21 ± 2.7 18 ± 2.4 11 ± 1.5 30 ± 3.2 15 ± 2.6 100 12 ± 1.5 22 ± 1.8 19 ± 5.0 13 ± 1.7 26 ± 1.8 10 ± 1.2 333 10 ± 0.3 19 ± 4.1 24 ± 1.5 9 ± 2.6 23 ± 1.2 12 ± 1.2 1,000 11 ± 2.1 21 ± 3.2 25 ± 0.7 14 ± 2.4 21 ± 2.0 8 ± 0.9 3,333 12 ± 1.0 24 ± 4.3 26 ± 2.3 10 ± 1.9 30 ± 0.9 13 ± 1.9 10,000 13 ± 1.5 21 ± 6.1 27 ± 1.7 10 ± 1.2 27 ± 4.3 13 ± 2.7

Trial summary Negative Negative Negative Negative Negative Negative Positive control 380 ± 8.3 443 ± 16.9 534 ± 11.4 478 ± 6.7 466 ± 15.8 431 ± 7.8

a Study performed at SRI International. The detailed protocol is presented by Zeiger et al. (1992). 0 μg/plate was the solvent control. b Revertants are presented as mean ± standard error from three plates. c The positive controls in the absence of metabolic activation were sodium azide (TA100 and TA1535), 9-aminoacridine (TA97), 4-nitro- o
phenylenediamine (TA98), mitomycin-C (TA102), and methyl methanesulfonate (TA104). The positive control for metabolic activation with all strains was 2-aminoanthracene, and 2-aminoanthracene or sterigmatocystin was used for TA102.

### 222 Sodium Chlorate, NTP TR 517



### TABLE 

### E2 Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice Following Administration of Sodium Chlorate in Drinking Water for 3 Weeks a



### Number of Mice Concentration with Erythrocytes Micronucleated NCEs/ P Value c 

### PCEs (%) (mg/L) Scored 1,000 NCEsb



### Male

Tap waterd 10 1.20 ± 0.20 2.510 ± 0.15

Sodium chlorate 125 10 1.25 ± 0.13 0.4432 2.350 ± 0.10 250 10 1.10 ± 0.16 0.6160 2.190 ± 0.08 500 10 0.75 ± 0.21 0.9253 2.260 ± 0.11 1,000 10 1.05 ± 0.14 0.6727 2.080 ± 0.11 2,000 10 1.25 ± 0.23 0.4432 2.040 ± 0.08

P=0.406 e



### Female

Tap water 10 0.95 ± 0.16 1.890 ± 0.07

Sodium chlorate 125 10 1.05 ± 0.24 0.3759 1.820 ± 0.11 250 10 1.00 ± 0.18 0.4364 1.750 ± 0.14 500 10 0.65 ± 0.18 0.8557 1.680 ± 0.10 1,000 10 0.85 ± 0.17 0.6306 1.840 ± 0.10 2,000 10 1.15 ± 0.18 0.2684 2.040 ± 0.12

P=0.285

a Study was performed at SITEK Research Laboratories, Inc. The detailed protocol is presented by MacGregor et al. (1990). NCE=normochromatic erythrocyte; PCE=polychromatic erythrocyte b Mean ± standard error c Pairwise comparison with the vehicle control, significant at P # 0.005 (ILS, 1990) d Vehicle control e Significance of micronucleated NCEs/1,000 NCEs tested by the one-tailed trend test, significant at P # 0.025 (ILS, 1990)

### 223



# APPENDIX F CLINICAL PATHOLOGY RESULTS

TABLE 

### F1 Hematology and Clinical Chemistry Data for Rats in the 3-Week Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 TABLE 

### F2 Hematology Data for Mice in the 3-Week Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

### Sodium Chlorate, NTP TR 517 224

Male

Hematology

n 10 10 10 10 10 10

Hematocrit (%) Day 4 42.7 ± 1.1 41.8 ± 0.8 42.4 ± 0.8 42.9 ± 1.2 42.5 ± 1.2 41.2 ± 0.8 Day 22 44.7 ± 0.5 44.8 ± 0.5 44.1 ± 0.7 43.3 ± 0.8 44.1 ± 0.5 42.1 ± 0.6** Hemoglobin (g/dL) Day 4 14.1 ± 0.3 13.8 ± 0.2 14.1 ± 0.2 14.3 ± 0.4 14.1 ± 0.4 13.7 ± 0.2 Day 22 14.9 ± 0.2 15.1 ± 0.1 14.9 ± 0.2 14.7 ± 0.2 14.7 ± 0.2 14.0 ± 0.2** Erythrocytes (10 6/μL) Day 4 7.22 ± 0.17 7.08 ± 0.13 7.24 ± 0.11 7.24 ± 0.18 7.21 ± 0.18 7.04 ± 0.14 Day 22 8.05 ± 0.09 8.05 ± 0.07 7.91 ± 0.14 7.80 ± 0.11 7.86 ± 0.09 7.53 ± 0.11** Reticulocytes (10 6/μL) Day 4 0.76 ± 0.02 0.74 ± 0.02 0.73 ± 0.03 0.77 ± 0.03 0.77 ± 0.03 0.73 ± 0.02 Day 22 0.43 ± 0.01 0.44 ± 0.01 0.44 ± 0.01 0.46 ± 0.01 0.46 ± 0.01 0.41 ± 0.01 Mean cell volume (fL) Day 4 59.1 ± 0.4 59.0 ± 0.4 58.6 ± 0.3 59.3 ± 0.2 58.9 ± 0.3 58.5 ± 0.2 Day 22 55.5 ± 0.3 55.6 ± 0.2 55.7 ± 0.2 55.4 ± 0.4 56.1 ± 0.2 55.9 ± 0.2 Mean cell hemoglobin (pg) Day 4 19.6 ± 0.1 19.5 ± 0.1 19.5 ± 0.1 19.7 ± 0.1 19.6 ± 0.2 19.5 ± 0.1 Day 22 18.6 ± 0.1 18.7 ± 0.1 18.9 ± 0.1 18.9 ± 0.1 18.7 ± 0.1 18.6 ± 0.1 Mean cell hemoglobin concentration (g/dL) Day 4 33.1 ± 0.2 33.1 ± 0.1 33.3 ± 0.3 33.2 ± 0.2 33.3 ± 0.2 33.2 ± 0.2 Day 22 33.4 ± 0.3 33.7 ± 0.2 33.8 ± 0.3 34.1 ± 0.2 33.3 ± 0.2 33.3 ± 0.1 Platelets (10 3 /μL) Day 4 850.4 ± 14.0 859.4 ± 15.7 820.7 ± 9.1 866.1 ± 20.0 888.2 ± 13.4 869.2 ± 20.5 Day 22 925.5 ± 16.4 958.0 ± 19.0 934.4 ± 18.7 954.9 ± 13.0 908.9 ± 19.7 837.3 ± 11.8** Leukocytes (10 3 /μL) Day 4 8.05 ± 0.39 7.91 ± 0.27 8.20 ± 0.21 7.89 ± 0.30 7.06 ± 0.45 7.71 ± 0.29 Day 22 10.82 ± 0.50 10.28 ± 0.14 9.73 ± 0.29 10.10 ± 0.25 9.52 ± 0.31 9.71 ± 0.33 Segmented neutrophils (10 3 /μL) Day 4 1.09 ± 0.05 1.01 ± 0.04 0.91 ± 0.05* 0.63 ± 0.04** 0.48 ± 0.04** 0.47 ± 0.04** Day 22 1.05 ± 0.04 0.85 ± 0.04** 0.70 ± 0.03** 0.66 ± 0.04** 0.54 ± 0.03** 0.38 ± 0.02** Lymphocytes (10 3 /μL) Day 4 6.69 ± 0.36 6.63 ± 0.26 7.01 ± 0.19 6.98 ± 0.30 6.34 ± 0.43 6.96 ± 0.26 Day 22 9.49 ± 0.47 9.15 ± 0.12 8.77 ± 0.26 9.20 ± 0.27 8.74 ± 0.30 9.10 ± 0.31 Activated lymphocytes (10 3 /μL) Day 4 0.10 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.12 ± 0.01 0.10 ± 0.01 0.14 ± 0.01* Day 22 0.09 ± 0.02 0.08 ± 0.01 0.07 ± 0.01 0.08 ± 0.01 0.08 ± 0.01 b 0.10 ± 0.01 Monocytes (10 3 /μL) Day 4 0.12 ± 0.01 0.11 ± 0.00 0.12 ± 0.01 0.10 ± 0.01 0.10 ± 0.01 0.10 ± 0.01 Day 22 0.15 ± 0.02 0.15 ± 0.01 0.15 ± 0.02 0.12 ± 0.01 0.12 ± 0.01 b 0.07 ± 0.01** Basophils (10 3 /μL) Day 4 0.005 ± 0.002 0.006 ± 0.002 0.008 ± 0.002 0.013 ± 0.004 0.007 ± 0.002 0.007 ± 0.002 Day 22 0.012 ± 0.003 0.012 ± 0.001 0.010 ± 0.001 0.010 ± 0.002 0.010 ± 0.002b 0.012 ± 0.001 Eosinophils (10 3 /μL) Day 4 0.05 ± 0.01 0.04 ± 0.01 0.05 ± 0.01 0.07 ± 0.03 0.03 ± 0.00 0.04 ± 0.00 Day 22 0.04 ± 0.01 0.04 ± 0.00 0.03 ± 0.00 0.04 ± 0.01 0.05 ± 0.01 0.04 ± 0.00 Methemoglobin (g/dL) Day 4 0.17 ± 0.04 0.34 ± 0.15 0.20 ± 0.04 0.20 ± 0.05 b 0.27 ± 0.04 0.22 ± 0.04 Day 22 0.20 ± 0.03 0.27 ± 0.02 0.20 ± 0.03 0.18 ± 0.03 0.17 ± 0.03 0.21 ± 0.06 

### TABLE 

### F1 Hematology and Clinical Chemistry Data for Rats in the 3-Week Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 225 Sodium Chlorate, NTP TR 517

Male (continued)

Clinical Chemistry

Day 4 10 10 10 10 9 10 Day 22 10 10 10 10 10 10

Urea nitrogen (mg/dL) Day 4 10.0 ± 0.9 11.2 ± 0.7 9.5 ± 0.5 9.1 ± 0.7 10.3 ± 0.8 10.8 ± 0.5 Day 22 10.7 ± 0.4 10.4 ± 0.4 10.7 ± 0.5 10.9 ± 0.4 10.1 ± 0.4 10.3 ± 0.5 Creatinine (mg/dL) Day 4 0.39 ± 0.01 0.38 ± 0.02 0.34 ± 0.02 0.38 ± 0.02 0.40 ± 0.02 0.38 ± 0.01 Day 22 0.41 ± 0.01 0.42 ± 0.01 0.42 ± 0.02 0.41 ± 0.01 0.40 ± 0.02 0.44 ± 0.02 Total protein (g/dL) Day 4 5.4 ± 0.1 5.5 ± 0.1 5.4 ± 0.1 5.4 ± 0.1 5.5 ± 0.2 5.6 ± 0.1 Day 22 5.8 ± 0.1 5.9 ± 0.1 5.8 ± 0.1 5.8 ± 0.1 5.8 ± 0.1 5.8 ± 0.1 Albumin (g/dL) Day 4 4.0 ± 0.1 4.0 ± 0.1 3.9 ± 0.1 b 3.9 ± 0.1 4.0 ± 0.1 4.1 ± 0.1 Day 22 4.3 ± 0.1 4.5 ± 0.0 4.3 ± 0.0 4.3 ± 0.0 4.3 ± 0.0 4.4 ± 0.0 Alanine aminotransferase (IU/L) Day 4 69 ± 2 66 ± 1 64 ± 1 69 ± 2 62 ± 2 64 ± 2 Day 22 52 ± 1 54 ± 2 52 ± 1 54 ± 1 54 ± 1 51 ± 1 Alkaline phosphatase (IU/L) Day 4 740 ± 21 720 ± 34 682 ± 17 730 ± 31 733 ± 26 706 ± 16 Day 22 536 ± 8 548 ± 8 531 ± 6 541 ± 7 544 ± 9 489 ± 10* Creatine kinase (IU/L) Day 4 236 ± 23 224 ± 27 238 ± 27 274 ± 26 252 ± 39 228 ± 25 Day 22 104 ± 19 78 ± 11 b 83 ± 10 109 ± 17 c 68 ± 7b 99 ± 17 c Sorbitol dehydrogenase (IU/L) Day 22 6 ± 0 d 8 ± 0* d 8 ± 2b 8 ± 2 c 7 ± 1 c 6 ± 1 c Bile acids (μmol/L) Day 4 34.3 ± 5.7 28.1 ± 2.3 27.5 ± 1.9 30.4 ± 4.2 30.5 ± 2.5 26.0 ± 2.6 Day 22 32.6 ± 2.7 28.5 ± 3.0 28.0 ± 1.9 25.3 ± 1.1 26.0 ± 1.0 38.6 ± 4.3



### Female

n 10 10 10 10 10 10

Hematology

Hematocrit (%) Day 4 43.4 ± 0.6 43.6 ± 0.7 43.9 ± 0.9 42.1 ± 0.9 43.1 ± 0.8 42.7 ± 0.6 Day 22 43.9 ± 0.6 43.7 ± 0.6 44.1 ± 1.1 44.4 ± 0.6 44.8 ± 0.3 43.4 ± 0.7 Hemoglobin (g/dL) Day 4 14.2 ± 0.2 14.2 ± 0.2 14.6 ± 0.3 13.8 ± 0.3 14.2 ± 0.3 14.0 ± 0.1 Day 22 14.8 ± 0.2 14.6 ± 0.2 14.8 ± 0.3 14.9 ± 0.2 14.9 ± 0.1 14.3 ± 0.2 Erythrocytes (10 6/μL) Day 4 7.60 ± 0.09 7.61 ± 0.13 7.65 ± 0.17 7.30 ± 0.15 7.51 ± 0.14 7.40 ± 0.08 Day 22 8.41 ± 0.13 8.28 ± 0.11 8.34 ± 0.24 8.47 ± 0.12 8.47 ± 0.08 8.20 ± 0.13 Reticulocytes (10 6/μL) Day 4 0.60 ± 0.03 0.63 ± 0.02 0.60 ± 0.02 0.66 ± 0.02 0.62 ± 0.02 0.60 ± 0.03 Day 22 0.24 ± 0.01 b 0.24 ± 0.01 0.29 ± 0.07 0.24 ± 0.01 0.25 ± 0.01 0.26 ± 0.01 Mean cell volume (fL) Day 4 57.1 ± 0.3 57.4 ± 0.1 57.5 ± 0.3 57.8 ± 0.1 57.5 ± 0.3 57.7 ± 0.3 Day 22 52.3 ± 0.2 52.8 ± 0.1 53.0 ± 0.5 52.4 ± 0.2 52.8 ± 0.2 52.9 ± 0.2 

### TABLE 

### F1 Hematology and Clinical Chemistry Data for Rats in the 3-Week Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 226

Female (continued)

n 10 10 10 10 10 10

Hematology (continued)

Mean cell hemoglobin (pg) Day 4 18.7 ± 0.1 18.7 ± 0.1 19.0 ± 0.1 19.0 ± 0.1 18.9 ± 0.1 18.9 ± 0.1 Day 22 17.6 ± 0.1 17.6 ± 0.1 17.7 ± 0.2 17.6 ± 0.1 17.6 ± 0.1 17.5 ± 0.1 Mean cell hemoglobin concentration (g/dL) Day 4 32.8 ± 0.2 32.6 ± 0.2 33.1 ± 0.2 32.8 ± 0.3 32.9 ± 0.1 32.8 ± 0.3 Day 22 33.7 ± 0.2 33.4 ± 0.2 33.5 ± 0.2 33.5 ± 0.1 33.3 ± 0.1 33.0 ± 0.1* Platelets (10 3 /μL) Day 4 834.0 ± 19.3 846.3 ± 21.4 832.7 ± 7.6 818.1 ± 18.5 866.9 ± 24.6 843.4 ± 10.2 Day 22 846.0 ± 16.9 871.8 ± 14.2 844.3 ± 13.7 803.3 ± 17.8 842.2 ± 19.3 860.5 ± 18.8 Leukocytes (10 3 /μL) Day 4 8.83 ± 0.41 8.57 ± 0.47 8.94 ± 0.40 8.44 ± 0.30 8.24 ± 0.51 8.53 ± 0.34 Day 22 10.14 ± 0.35 9.32 ± 0.29 9.71 ± 0.61 10.63 ± 0.39 10.28 ± 0.51 10.63 ± 0.43 Segmented neutrophils (10 3 /μL) Day 4 1.02 ± 0.08 0.87 ± 0.08 0.82 ± 0.03* 0.67 ± 0.04** 0.58 ± 0.05** 0.46 ± 0.03** Day 22 0.93 ± 0.05 0.63 ± 0.03** 0.66 ± 0.05** 0.61 ± 0.04** 0.57 ± 0.07** 0.46 ± 0.04** Lymphocytes (10 3 /μL) Day 4 7.54 ± 0.37 7.50 ± 0.42 7.84 ± 0.39 7.51 ± 0.28 7.40 ± 0.47 7.80 ± 0.31 Day 22 8.94 ± 0.31 8.45 ± 0.26 8.75 ± 0.56 9.72 ± 0.35 9.40 ± 0.46 9.88 ± 0.40 Activated lymphocytes (10 3 /μL) Day 4 0.10 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.10 ± 0.02 0.13 ± 0.01 Day 22 0.08 ± 0.01 0.07 ± 0.01 0.09 ± 0.01 0.09 ± 0.01 0.10 ± 0.01 0.10 ± 0.01* Monocytes (10 3 /μL) Day 4 0.12 ± 0.02 0.11 ± 0.01 0.11 ± 0.01 0.10 ± 0.01 0.08 ± 0.01* 0.09 ± 0.01* Day 22 0.11 ± 0.01 0.10 ± 0.01 0.13 ± 0.01 0.14 ± 0.01 0.13 ± 0.01 0.10 ± 0.01 Basophils (10 3 /μL) Day 4 0.006 ± 0.002 0.008 ± 0.002 0.007 ± 0.002 0.008 ± 0.002 0.010 ± 0.001 0.008 ± 0.001 Day 22 0.016 ± 0.003 0.013 ± 0.003 0.017 ± 0.003 0.015 ± 0.002 0.019 ± 0.004 0.016 ± 0.003 Eosinophils (10 3 /μL) Day 4 0.05 ± 0.01 0.03 ± 0.01 0.05 ± 0.01 0.05 ± 0.01 0.06 ± 0.01 0.05 ± 0.01 Day 22 0.06 ± 0.01 0.06 ± 0.01 0.07 ± 0.01 0.06 ± 0.01 0.06 ± 0.01 0.07 ± 0.01 Methemoglobin (g/dL) Day 4 0.14 ± 0.02 0.14 ± 0.03 0.19 ± 0.03 0.15 ± 0.02 0.14 ± 0.02 0.18 ± 0.02 Day 22 0.21 ± 0.03 0.20 ± 0.03 0.21 ± 0.02 0.21 ± 0.02 0.21 ± 0.03 0.19 ± 0.02

Clinical Chemistry

Urea nitrogen (mg/dL) Day 4 11.1 ± 0.7 10.6 ± 7.5 11.6 ± 0.6 10.0 ± 0.6 10.3 ± 0.7 11.4 ± 0.7 Day 22 15.0 ± 0.4 14.3 ± 0.4 14.0 ± 0.6 13.8 ± 0.3 13.9 ± 0.5 12.53 ± 0.4** Creatinine (mg/dL) Day 4 0.37 ± 0.02 0.37 ± 0.02 0.37 ± 0.02 0.37 ± 0.02 0.36 ± 0.02 0.38 ± 0.01 Day 22 0.51 ± 0.01 0.54 ± 0.01 0.52 ± 0.02 0.50 ± 0.02 0.53 ± 0.02 0.50 ± 0.00 Total protein (g/dL) Day 4 5.4 ± 0.1 5.3 ± 0.1 5.3 ± 0.1 5.3 ± 0.1 5.4 ± 0.1 5.4 ± 0.1 Day 22 6.1 ± 0.1 5.9 ± 0.1 6.1 ± 0.1 5.8 ± 0.1 6.1 ± 0.1 6.0 ± 0.1 Albumin (g/dL) Day 4 4.2 ± 0.1 4.2 ± 0.1 4.2 ± 0.1 4.1 ± 0.1 4.2 ± 0.1 4.2 ± 0.1 Day 22 4.7 ± 0.1 4.7 ± 0.0 4.7 ± 0.1 4.5 ± 0.0 4.7 ± 0.0 4.6 ± 0.1 

### TABLE 

### F1 Hematology and Clinical Chemistry Data for Rats in the 3-Week Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### 227 Sodium Chlorate, NTP TR 517

Female (continued)

n 10 10 10 10 10 10

Clinical Chemistry (continued)

Alanine aminotransferase (IU/L) Day 4 49 ± 2 51 ± 2 49 ± 2 47 ± 1 57 ± 6b 52 ± 2 Day 22 40 ± 2 41 ± 1 43 ± 1 42 ± 1 41 ± 1 39 ± 1 Alkaline phosphatase (IU/L) Day 4 557 ± 17 564 ± 12 554 ± 15 572 ± 14 551 ± 13 570 ± 20b Day 22 388 ± 11 377 ± 6 367 ± 10 374 ± 7 360 ± 8 366 ± 8 Creatine kinase (IU/L) Day 4 294 ± 63 254 ± 30 242 ± 36 208 ± 19 298 ± 76 248 ± 30 Day 22 152 ± 15 116 ± 8 160 ± 26 120 ± 19 148 ± 18 114 ± 12 Sorbitol dehydrogenase (IU/L) Day 22 4 ± 1 3 ± 0 3 ± 0 4 ± 0 4 ± 0 3 ± 0 Bile acids (μmol/L) Day 4 30.6 ± 3.0 30.2 ± 2.2 28.9 ± 1.2 29.4 ± 2.1 30.8 ± 2.4 31.6 ± 2.2 Day 22 23.3 ± 2.6 23.1 ± 1.8 22.8 ± 1.9 20.4 ± 1.1 24.8 ± 1.9 17.9 ± 1.0

* Significantly different (P # 0.05) from the chamber 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 c n=8 d n=7 

### TABLE 

### F1 Hematology and Clinical Chemistry Data for Rats in the 3-Week Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

### Sodium Chlorate, NTP TR 517 228



### TABLE 

### F2 Hematology Data for Mice in the 3-Week Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

Male

n 10 10 10 10 10 10

Hematocrit (%) 49.6 ± 1.1 48.0 ± 0.5 47.7 ± 0.5 48.9 ± 0.6 49.2 ± 0.8 49.1 ± 0.4 Hemoglobin (g/dL) 16.5 ± 0.4 16.0 ± 0.1 15.9 ± 0.2 16.3 ± 0.2 16.1 ± 0.3 15.9 ± 0.1 Erythrocytes (10 6/μL) 10.46 ± 0.25 10.16 ± 0.11 10.09 ± 0.11 10.44 ± 0.13 10.38 ± 0.17 10.21 ± 0.08 Reticulocytes (10 6/μL) 0.33 ± 0.00 0.34 ± 0.01 0.35 ± 0.01 0.34 ± 0.01 0.34 ± 0.01 0.34 ± 0.01 Mean cell volume (fL) 47.5 ± 0.2 47.2 ± 0.2 47.3 ± 0.1 46.9 ± 0.2 47.4 ± 0.2 48.1 ± 0.1 Mean cell hemoglobin (pg) 15.8 ± 0.1 15.8 ± 0.1 15.7 ± 0.1 15.6 ± 0.1 15.6 ± 0.1 15.6 ± 0.1 Mean cell hemoglobin

concentration (g/dL) 33.3 ± 0.1 33.4 ± 0.1 33.2 ± 0.2 33.3 ± 0.3 32.8 ± 0.2* 32.5 ± 0.2** Platelets (10 3 /μL) 1,204.5 ± 55.6 1,182.6 ± 37.7 1,224.0 ± 39.9 1,197.4 ± 49.1 1,198.5 ± 53.0 1,273.0 ± 43.0 Leukocytes (10 3 /μL) 5.38 ± 0.32 5.04 ± 0.44 5.41 ± 0.56 5.36 ± 0.59 5.12 ± 0.29 4.39 ± 0.51 Segmented neutrophils

(10 3 /μL) 0.61 ± 0.10 0.58 ± 0.09 0.53 ± 0.07 0.63 ± 0.14 0.44 ± 0.05 0.40 ± 0.05 Lymphocytes (10 3 /μL) 4.64 ± 0.29 4.32 ± 0.35 4.74 ± 0.49 4.59 ± 0.51 4.57 ± 0.25 3.89 ± 0.45 Activated lymphocytes

(10 3 /μL) 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.0 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 Monocytes (10 3 /μL) 0.07 ± 0.01 0.07 ± 0.01 0.08 ± 0.01 0.08 ± 0.01 0.07 ± 0.01 0.06 ± 0.01 Basophils (10 3 /μL) 0.003 ± 0.002 0.000 ± 0.000 0.004 ± 0.002 0.005 ± 0.002 0.000 ± 0.000 0.002 ± 0.001 Eosinophils (10 3 /μL) 0.04 ± 0.01 0.05 ± 0.01 0.05 ± 0.01 0.05 ± 0.01 0.03 ± 0.00* 0.02 ± 0.01* Methemoglobin (g/dL) 0.23 ± 0.02 0.19 ± 0.02 0.21 ± 0.03 0.23 ± 0.02 0.19 ± 0.03 0.26 ± 0.01



### Female

n 9 10 10 10 10 10

Hematocrit (%) 49.0 ± 0.6 48.4 ± 0.8 49.4 ± 0.4 49.1 ± 0.7 47.5 ± 0.8 48.1 ± 0.5 Hemoglobin (g/dL) 16.2 ± 0.3 15.9 ± 0.2 16.0 ± 0.1 16.0 ± 0.2 15.6 ± 0.2 15.4 ± 0.2 Erythrocytes (10 6/μL) 10.21 ± 0.17 10.14 ± 0.16 10.27 ± 0.10 10.20 ± 0.15 9.83 ± 0.17 9.86 ± 0.14 Reticulocytes (10 6/μL) 0.31 ± 0.01 0.30 ± 0.01 0.31 ± 0.01 0.31 ± 0.01 0.33 ± 0.02 0.33 ± 0.02 Mean cell volume (fL) 48.0 ± 0.3 47.7 ± 0.2 48.1 ± 0.2 48.2 ± 0.2 48.4 ± 0.2 48.8 ± 0.2* Mean cell hemoglobin (pg) 15.8 ± 0.1 15.7 ± 0.1 15.6 ± 0.1 15.7 ± 0.1 15.9 ± 0.1 15.6 ± 0.1 Mean cell hemoglobin

concentration (g/dL) 33.0 ± 0.3 33.0 ± 0.3 32.5 ± 0.2 32.7 ± 0.2 32.8 ± 0.2 32.0 ± 0.1** Platelets (10 3 /μL) 888.6 ± 34.5 970.8 ± 50.0 879.70 ± 56.5 863.7 ± 49.6 961.1 ± 56.5 948.1 ± 41.6 Leukocytes (10 3 /μL) 4.61 ± 0.45 4.44 ± 0.20 4.90 ± 0.34 4.64 ± 0.44 4.76 ± 0.28 4.39 ± 0.28 Segmented neutrophils

(10 3 /μL) 0.43 ± 0.06 0.49 ± 0.04 0.48 ± 0.05 0.49 ± 0.05 0.46 ± 0.05 0.40 ± 0.04 Lymphocytes (10 3 /μL) 4.04 ± 0.39 3.81 ± 0.19 4.28 ± 0.29 4.02 ± 0.39 4.16 ± 0.24 3.86 ± 0.26 Activated lymphocytes

(10 3 /μL) 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 Monocytes (10 3 /μL) 0.07 ± 0.01 0.06 ± 0.01 0.06 ± 0.01 0.07 ± 0.01 0.07 ± 0.01 0.06 ± 0.01 Basophils (10 3 /μL) 0.004 ± 0.002 0.003 ± 0.002 0.006 ± 0.002 0.005 ± 0.002 0.003 ± 0.002 0.007 ± 0.002 Eosinophils (10 3 /μL) 0.06 ± 0.01 0.06 ± 0.01 0.07 ± 0.01 0.05 ± 0.01 0.06 ± 0.01 0.06 ± 0.01 Methemoglobin (g/dL) 0.18 ± 0.02 0.13 ± 0.04 0.19 ± 0.04 0.19 ± 0.05 0.15 ± 0.03 0.15 ± 0.04

* Significantly different (P # 0.05) from the chamber control group by Dunn’s or Shirley’s test ** P # 0.01 a Mean ± standard error. Statistical tests were performed on unrounded data.

### 229



# APPENDIX G ORGAN WEIGHTS AND ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS

TABLE 

### G1 Organ Weights and Organ-Weight-to-Body-Weight Ratios for F344/N Rats in the 3-Week Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 TABLE 

### G2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 3-Week Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

### Sodium Chlorate, NTP TR 517 230



### TABLE 

### G1 Organ Weights and Organ-Weight-to-Body-Weight Ratios for F344/N Rats in the 3-Week Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

n 10 10 10 10 10 10



### Male

Necropsy body wt 184 ± 3 183 ± 4 191 ± 4 189 ± 3 183 ± 2 177 ± 2

Heart Absolute 0.644 ± 0.012 0.631 ± 0.014 0.650 ± 0.018 0.669 ± 0.026 0.623 ± 0.010 0.544 ± 0.015** Relative 3.509 ± 0.056 3.444 ± 0.036 3.411 ± 0.057 3.538 ± 0.105 3.402 ± 0.037 3.071 ± 0.067** R. Kidney Absolute 0.705 ± 0.013 0.700 ± 0.017 0.733 ± 0.023 0.740 ± 0.012 0.702 ± 0.012 0.637 ± 0.020* Relative 3.842 ± 0.064 3.822 ± 0.063 3.846 ± 0.075 3.925 ± 0.069 3.834 ± 0.043 3.593 ± 0.087 Liver Absolute 7.680 ± 0.191 7.920 ± 0.206 8.110 ± 0.266 8.562 ± 0.345 7.868 ± 0.169 7.501 ± 0.240b
Relative 41.856 ± 1.050 43.210 ± 0.592 42.514 ± 0.728 45.248 ± 1.262 42.959 ± 0.696 42.612 ± 1.349b Lung Absolute 1.123 ± 0.081 b 1.113 ± 0.062 1.169 ± 0.041 1.245 ± 0.095 1.172 ± 0.052 0.988 ± 0.030 Relative 6.141 ± 0.492b 6.078 ± 0.315 6.154 ± 0.231 6.562 ± 0.424 6.399 ± 0.270 5.584 ± 0.171 R. Testis Absolute 1.085 ± 0.036 1.075 ± 0.030 1.091 ± 0.023 1.100 ± 0.026 1.089 ± 0.024 1.036 ± 0.032 Relative 5.893 ± 0.131 5.863 ± 0.093 5.735 ± 0.094 5.835 ± 0.135 5.949 ± 0.113 5.850 ± 0.162 Thymus Absolute 0.384 ± 0.013 0.349 ± 0.028 0.385 ± 0.012 0.397 ± 0.016 0.377 ± 0.012 0.378 ± 0.012 Relative 2.089 ± 0.065 1.915 ± 0.156 2.025 ± 0.065 2.100 ± 0.068 2.058 ± 0.066 2.133 ± 0.062



### Female

Necropsy body wt 130 ± 1 132 ± 2 130 ± 1 131 ± 2 132 ± 2 131 ± 2

Heart Absolute 0.468 ± 0.012 0.482 ± 0.019 0.469 ± 0.008 0.482 ± 0.009 0.486 ± 0.007 0.464 ± 0.011 Relative 3.611 ± 0.078 3.649 ± 0.133 3.623 ± 0.064 3.693 ± 0.061 3.704 ± 0.086 3.541 ± 0.069 R. Kidney Absolute 0.531 ± 0.010 0.539 ± 0.018 0.518 ± 0.009 0.537 ± 0.010 0.553 ± 0.012 0.523 ± 0.012 Relative 4.099 ± 0.071 4.077 ± 0.106 4.003 ± 0.077 4.111 ± 0.045 4.204 ± 0.061 3.990 ± 0.070 Liver Absolute 5.046 ± 0.089 5.010 ± 0.126 4.963 ± 0.064 5.091 ± 0.110 5.171 ± 0.163 5.035 ± 0.177 Relative 38.941 ± 0.539 37.918 ± 0.748 38.338 ± 0.444 38.992 ± 0.691 39.284 ± 0.975 38.390 ± 1.171 Lung Absolute 0.821 ± 0.030 0.821 ± 0.031 0.804 ± 0.025 0.895 ± 0.034 0.807 ± 0.025 0.785 ± 0.027 Relative 6.338 ± 0.230 6.210 ± 0.197 6.207 ± 0.174 6.838 ± 0.182 6.129 ± 0.134 5.990 ± 0.192 Thymus Absolute 0.314 ± 0.010 0.322 ± 0.007 0.329 ± 0.008 0.333 ± 0.011 0.316 ± 0.013 0.313 ± 0.010 Relative 2.423 ± 0.081 2.440 ± 0.044 2.539 ± 0.057 2.545 ± 0.070 2.399 ± 0.090 2.388 ± 0.085

* Significantly different (P # 0.05) from the chamber 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) aregiven as mg organ weight/g body weight (mean ± standard error). b n=9

### 231 Sodium Chlorate, NTP TR 517



### TABLE 

### G2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 3-Week Drinking Water Study of Sodium Chlorate a



### 0 mg/L 125 mg/L 250 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L

n 10 10 10 10 10 10



### Male

Necropsy body wt 29.8 ± 0.3 29.8 ± 0.3 30.0 ± 0.5 29.8 ± 0.4 29.8 ± 0.4 30.2 ± 0.4

Heart Absolute 0.155 ± 0.005 0.146 ± 0.004 0.150 ± 0.006 0.148 ± 0.004 0.149 ± 0.004 0.144 ± 0.004 Relative 5.209 ± 0.172 4.894 ± 0.177 4.999 ± 0.182 4.970 ± 0.107 4.996 ± 0.145 4.769 ± 0.131 R. Kidney Absolute 0.283 ± 0.006 0.274 ± 0.005 0.282 ± 0.010 0.285 ± 0.008 0.284 ± 0.007 0.276 ± 0.007 Relative 9.506 ± 0.176 9.182 ± 0.117 9.410 ± 0.332 9.570 ± 0.190 9.522 ± 0.216 9.151 ± 0.268 Liver Absolute 1.438 ± 0.058 1.399 ± 0.036 1.443 ± 0.043 1.439 ± 0.035 1.427 ± 0.041 1.369 ± 0.026 Relative 48.321 ± 1.956 46.832 ± 0.832 48.080 ± 1.172 48.327 ± 0.838 47.777 ± 1.043 45.392 ± 1.010 Lung Absolute 0.207 ± 0.014 0.181 ± 0.010 0.189 ± 0.014 0.196 ± 0.012 0.201 ± 0.019 0.178 ± 0.006 Relative 6.986 ± 0.549 6.066 ± 0.324 6.308 ± 0.452 6.599 ± 0.424 6.711 ± 0.589 5.881 ± 0.138 R. Testis Absolute 0.107 ± 0.002b 0.110 ± 0.002 0.111 ± 0.002 0.110 ± 0.002 0.110 ± 0.002 0.111 ± 0.002 Relative 3.610 ± 0.051 b 3.689 ± 0.057 3.709 ± 0.046 3.700 ± 0.063 3.688 ± 0.070 3.663 ± 0.052 Thymus Absolute 0.046 ± 0.001 0.042 ± 0.001 0.047 ± 0.001 0.044 ± 0.003 0.043 ± 0.002 0.044 ± 0.002 Relative 1.548 ± 0.053 1.389 ± 0.039 1.562 ± 0.030 1.475 ± 0.079 1.439 ± 0.055 1.464 ± 0.069



### Female

Necropsy body wt 22.8 ± 0.4 22.8 ± 0.1 23.0 ± 0.3 22.5 ± 0.2 23.4 ± 0.5 22.6 ± 0.6

Heart Absolute 0.118 ± 0.003 0.118 ± 0.004 0.118 ± 0.002 0.119 ± 0.004 0.121 ± 0.004 0.117 ± 0.002 Relative 5.185 ± 0.122 5.178 ± 0.181 5.134 ± 0.110 5.292 ± 0.136 5.183 ± 0.149 5.197 ± 0.134 R. Kidney Absolute 0.167 ± 0.004 0.171 ± 0.004 0.170 ± 0.005 0.170 ± 0.003 0.173 ± 0.005 0.166 ± 0.005 Relative 7.332 ± 0.146 7.505 ± 0.189 7.387 ± 0.209 7.568 ± 0.157 7.407 ± 0.205 7.351 ± 0.200 Liver Absolute 1.048 ± 0.026 1.024 ± 0.021 1.025 ± 0.039 1.006 ± 0.024 1.020 ± 0.038 1.038 ± 0.030 Relative 46.035 ± 0.975 44.940 ± 0.893 44.446 ± 1.292 44.733 ± 0.863 43.521 ± 0.927 45.895 ± 0.562 Lung Absolute 0.167 ± 0.010 0.168 ± 0.006 0.175 ± 0.010 0.187 ± 0.009 0.165 ± 0.008 0.175 ± 0.010 Relative 7.400 ± 0.575 7.377 ± 0.282 7.579 ± 0.363 8.318 ± 0.372 7.082 ± 0.372 7.745 ± 0.396 Thymus Absolute 0.061 ± 0.001 0.056 ± 0.003 0.063 ± 0.002 0.062 ± 0.002 0.061 ± 0.001 0.061 ± 0.002 Relative 2.677 ± 0.075 2.461 ± 0.148 2.722 ± 0.072 2.773 ± 0.111 2.632 ± 0.087 2.708 ± 0.078

a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) aregiven as mg organ weight/g body weight (mean ± standard error). b n=9

### Sodium Chlorate, NTP TR 517 232

### 233



# APPENDIX H CHEMICAL CHARACTERIZATION AND DOSE FORMULATION STUDIES

P ROCUREMENT AND 

### C HARACTERIZATION OF 

### S ODIUM 

### C HLORATE 

### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 P REPARATION AND 

### ANALYSIS OF 

### D OSE 

### F ORMULATIONS 

### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 F IGURE 

### H1 Infrared Absorption Spectrum of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 TABLE 

### H1 Preparation and Storage of Dose Formulations in the 3-Week and 2-Year Drinking Water Studies of Sodium Chlorate . . . . . . . . . . . . . . . 237 TABLE 

### H2 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 3-Week Drinking Water Studies of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . 238 TABLE 

### H3 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 2-Year Drinking Water Studies of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . 239

### 234 Sodium Chlorate, NTP TR 517



# CHEMICAL CHARACTERIZATION AND DOSE FORMULATION STUDIES

P ROCUREMENT AND 

# C HARACTERIZATION OF 

# S ODIUM 

# C HLORATE A single lot of sodium chlorate (14019PQ) was obtained from Aldrich Chemical Company, Inc. (Milwaukee, WI), by the analytical chemistry laboratory, Battelle Columbus (Columbus, OH), and provided to the study laboratory, Southern Research Institute (Birmingham, AL). Lot 14019PQ was used in the 3-week and 2-year studies. Identity, purity, and stability analyses were conducted by the analytical chemistry laboratory and the study laboratory. Reports on analyses performed in support of the sodium chlorate studies are on file at the National Institute of Environmental Health Sciences.

Lot 14019PQ, a white crystalline solid, was identified as sodium chlorate by the analytical chemistry laboratory and the study laboratory using infrared spectroscopy and by Galbraith Laboratories, Inc. (Knoxville, TN) using melting point determination. All spectra were consistent with a literature spectrum ( Aldrich , 1985) of sodium chlorate. The infrared spectrum is presented in Figure H1. The determined melting point agreed with the range of values reported in the literature (MSDS, 1986; Sax’s , 1996; Hawley’s , 1997; MDL, 1997)

The moisture content of lot 14019PQ was determined by Galbraith Laboratories, Inc., using Karl Fischer titration. The purity of lot 14019PQ was determined by the analytical chemistry laboratory using argentimetric titration, by the analytical chemistry laboratory and the study laboratory using anion exchange ion chromatography (IC), and by Galbraith Laboratories, Inc., using elemental analysis. Argentimetric titration was performed by heating samples of sodium chlorate in solutions of sulfurous and nitric acids, adding solutions of 0.1 N silver nitrate and ferric ammonium sulfate indicator after cooling, and titrating to the end point with 0.1 N ammonium thiocyanate. IC was performed by the analytical chemistry laboratory using system A and by the study laboratory using system B.

A) Dionex Corp. (Sunnyvale, CA), an Ionpac AS9-SC ion exchange column (250 mm × 

### 4 mm; and a mobile phase of A) 40 mM boric acid and 20 mM sodium hydroxide and B) 200 mM boric acid and 100 mM NaOH. Following 6 minutes of isocratic elution with 50% A:50 % B, the mobile phase was linearly changed to 30% A and 70% B in 2 minutes; and to 100% B in 2 minutes Following a 3-minute hold, the gradient was linearly changed to 50% A:50% B in 1 minute, followed by a 4-minute hold. The flow rate was 1.5 mL/minute and suppressed conductivity detection was used.

B) Alltech Associates, Inc. (Deerfield, CA), Odyssey Basic Ion Chromatograph, an Alltech Anion HC ion exchange column (150 mm × 

### 4.6 mm, Alltech Associates), using an isocratic mobile phase of 2.8 mM sodium bicarbonate and 4.4 mM sodium carbonate in deionized organic-free water. The flow rate was 1.4 mL/minute, the column temperature was 50° C, and suppressed conductivity detection was used.

Karl Fischer titration indicated a moisture content of less than 0.05%. Elemental analysis for chlorine was in agreement with the theoretical value for sodium chlorate; however, elemental analysis for sodium was higher (108%) than the theoretical value. Argentimetric titration indicated a purity of 99.7%. IC by system A indicated one major peak with no reportable impurities. IC by system B indicated a relative purity of 101% based on major peak comparison with a frozen reference standard of the same lot. Major peak area percent indicated a purity of 100%. The overall purity of lot 14019PQ was determined to be greater than 99%.

Stability studies of the bulk chemical were performed by the analytical chemistry laboratory. IC by system A indicated that sodium chlorate was stable as a bulk chemical for 15 days when stored under a minimal headspace protected from light at temperatures up to 60° C. To ensure stability, the bulk chemical was stored at room temperature, protected from light, in amber glass containers with Teflon® 

### -lined lids. Stability was monitored by

### Sodium Chlorate, NTP TR 517 235



### the study laboratory during the 2-year studies with IC by system B. No degradation of the bulk chemical was detected.



# P REPARATION AND 

# ANALYSIS OF 

# D OSE 

# F ORMULATIONS The dose formulations were prepared once during the 3-week studies and every 4 weeks during the 2-year studies by mixing sodium chlorate with tap water (Table H1). Formulations were stored at room temperature in NALGENE ® 

### containers and protected from light.

Homogeneity studies of 125 and 2,000 mg/L dose formulations were performed by the study laboratory with IC by a system similar to system B. Stability studies of a 2 mg/L dose formulation were performed by the analytical chemistry laboratory with IC by a system similar to system A. Homogeneity was confirmed and stability was confirmed for at least 44 days for dose formulations stored in sealed NALGENE ® 

### containers at temperatures up to 25° C, and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.

Periodic analyses of the dose formulations of sodium chlorate were conducted by the study laboratory using IC by systems similar to system B. During the 3-week studies, the dose formulations were analyzed once; all five of the dose formulations for rats and mice were within 10% of the target concentrations (Table H2). Animal room samples of these dose formulations were also analyzed; all five of the animal room samples for rats and mice were within 10% of the target concentrations.

During the 2-year studies, the dose formulations were analyzed approximately every 10 weeks (Table H3). Of the dose formulations used for rats and mice, 40 of 42 were within 10% of the target concentrations. One dose formulation for rats and one dose formulation for mice were inadvertently used at 14% and 11% of target, respectively. All 12 of the animal room samples analyzed for rats and mice were within 10% of the target concentrations.

### 236 Sodium Chlorate, NTP TR 517



### F IGURE 

### H1 Infrared Absorption Spectrum of Sodium Chlorate

### Sodium Chlorate, NTP TR 517 237



### TABLE 

### H1 Preparation and Storage of Dose Formulations in the 3-Week and 2-Year Drinking Water Studies of Sodium Chlorate

Preparation A premix was prepared in a beaker with tap water and then thoroughly mixed with additional tap water in a NALGENE ® mixing tank for approximately 15 minutes. Dose formulations were prepared once during the 3-week studies and every 4 weeks during the 2-year studies.



### Chemical Lot Number 14019PQ


### Maximum Storage Time 44 days


### Storage Conditions Stored in NALGENE ® containers at room temperature in the dark


### Study Laboratory Southern Research Institute (Birmingham, AL)

### 238 Sodium Chlorate, NTP TR 517



### TABLE 

### H2 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 3-Week Drinking Water Studies of Sodium Chlorate

Target Determined Difference Date Prepared Date Analyzed Concentration Concentration a 

### from Target (mg/L) (mg/L) (%)

Rats

May 11, 1998 May 13, 1998 125 131 +5 250 253 +1 500 510 +2 1,000 1,015 +2 2,000 1,976 –1

June 11, 1998 b 125 133 +7 250 260 +4 500 522 +4 1,000 1,027 +3 2,000 2,022 +1



### Mice

May 11, 1998 May 13, 1998 125 131 +5 250 253 +1 500 510 +2 1,000 1,015 +2 2,000 1,976 –1

June 12, 1998 b 125 134 +8 250 265 +6 500 528 +6 1,000 1,032 +3 2,000 2,075 +4

a Results of duplicate analyses b Animal room samples

### Sodium Chlorate, NTP TR 517 239



### TABLE 

### H3 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 2-Year Drinking Water Studies of Sodium Chlorate

Target Determined Difference Date Prepared Date Analyzed Concentration Concentration a 

### from Targetb 

### (mg/L) (mg/L) (%)

Rats

September 10, 1998 September 11, 1998 125 125 +1 1,000 1,041 +4 2,000 2,025 +1

October 19-20, 1998 c 125 123 –2 1,000 990 –1 2,000 1,963 –2

November 6, 1998 November 9, 1998 125 127 +2 1,000 1,004 0 1,000 995 –1 2,000 1,976 –1 2,000 1,976 –1

January 29, 1999 February 1, 1999 125 142 +14 1,000 1,095 +10 2,000 2,125 +6

March 26, 1999 March 29-31, 1999 125 128 +3 1,000 991 –1 d 2,000 1,982 –1 d

April 30, 1999 c 125 137 +10 1,000 1,042 +4 2,000 2,103 +5

April 1, 1999 April 1, 1999 1,000 993 –1 e 2,000 1,966 –2 e

June 18, 1999 June 21-22, 1999 125 125 0 1,000 973 –3 2,000 1,963 –2

August 13, 1999 August 16-17, 1999 125 132 +5 1,000 1,016 +2 2,000 2,045 +2

November 5, 1999 November 8, 1999 125 125 0 1,000 1,004 0 2,000 1,994 0

December 13, 1999 c 125 129 +3 1,000 1,037 +4 2,000 2,045 +2

December 28, 1999 January 3, 2000 125 135 +8 1,000 1,076 +8 2,000 2,133 +7

March 23, 2000 March 24, 2000 125 127 +1 1,000 1,007 +1 2,000 1,991 0

### 240 Sodium Chlorate, NTP TR 517

Rats (continued) May 18, 2000 May 19, 2000 125 127 +2 1,000 1,047 +5 2,000 2,014 +1

June 26, 2000 c 125 122 –2 1,000 1,034 +3 2,000 2,016 +1

August 10, 2000 August 11, 2000 125 113 –10 1,000 985 –2 2,000 1,955 –2



### Mice

September 10, 1998 September 11, 1998 500 504 +2 1,000 1,041 +4 2,000 2,025 +1

October 19-20, 1998 c 500 493 –1 1,000 1,013 +1 2,000 1,971 –1

November 6, 1998 November 9, 1998 500 506 +1 1,000 1,004 0 1,000 995 –1 2,000 1,976 –1 2,000 1,976 –1

January 29, 1999 February 1, 1999 500 556 +11 1,000 1,095 +10 2,000 2,125 +6

March 26, 1999 March 29-31, 1999 500 537 +7 1,000 991 –1 d 2,000 1,982 –1 d

April 30, 1999 c 500 544 +9 1,000 1,051 +5 2,000 2,076 +4

April 1, 1999 April 1, 1999 1,000 993 –1 e 2,000 1,966 –2 e

June 18, 1999 June 21-22, 1999 500 471 –6 1,000 973 –3 2,000 1,963 –2

August 13, 1999 August 16-17, 1999 500 503 +1 1,000 1,016 +2 2,000 2,045 +2 

### TABLE 

### H3 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 2-Year Drinking Water Studies of Sodium Chlorate

Target Determined Difference Date Prepared Date Analyzed Concentration Concentration from Target (mg/L) (mg/L) (%)

### Sodium Chlorate, NTP TR 517 241

Mice (continued) November 5, 1999 November 8, 1999 500 509 +2 1,000 1,004 0 2,000 1,994 0

December 13, 1999 c 500 512 +2 1,000 1,020 +2 2,000 2,008 0

December 28, 1999 January 3, 2000 500 534 +7 1,000 1,076 +8 2,000 2,133 +7

March 23, 2000 March 24, 2000 500 527 +5 1,000 1,007 +1 2,000 1,991 0

May 18, 2000 May 19, 2000 500 527 +5 1,000 1,047 +5 2,000 2,014 +1

June 26, 2000 c 500 535 +7 1,000 1,036 +4 2,000 2,052 +3

August 10, 2000 August 11, 2000 500 478 –4 1,000 985 –2 2,000 1,955 –2

a Results of duplicate analyses b Reported percentages are based on unrounded raw data; therefore, some percentages may not be reproducible when calculated from the rounded concentration values presented here. c Animal room samples d Remixed, not used in study e Results of remix; not used in study 

### TABLE 

### H3 Results of Analyses of Dose Formulations Administered to Rats and Mice in the 2-Year Drinking Water Studies of Sodium Chlorate

Target Determined Difference Date Prepared Date Analyzed Concentration Concentration from Target (mg/L) (mg/L) (%)

### 242 Sodium Chlorate, NTP TR 517

### 243



# APPENDIX I WATER AND COMPOUND CONSUMPTION IN THE 2-YEAR DRINKING WATER STUDIES OF SODIUM CHLORATE

TABLE 

### I1 Water and Compound Consumption by Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 TABLE 

### I2 Water and Compound Consumption by Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 TABLE 

### I3 Water and Compound Consumption by Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 TABLE 

### I4 Water and Compound Consumption by Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

### 244 Sodium Chlorate, NTP TR 517



### TABLE 

### I1 Water and Compound Consumption by Male Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L Water Body Water Body Dose Water Body Dose Water Body Dose

(g) a Weight (g) Weight (mg/kg)b (g) Weight (mg/kg) (g) Weight (mg/kg) Week (g) (g) (g) (g)

4 15.9 187 16.8 187 11.3 16.2 185 87.5 17.1 186 183.5 8 16.4 261 16.3 263 7.8 17.2 266 64.7 17.5 270 129.3 12 16.0 312 15.9 315 6.3 16.5 319 51.7 16.6 322 103.2 16 15.6 348 14.6 351 5.2 15.5 357 43.5 15.3 358 85.6 20 15.3 373 15.5 374 5.2 15.6 379 41.2 15.8 382 83.0 24 14.8 393 14.7 396 4.6 15.3 402 38.1 15.8 403 78.4 28 15.3 420 15.6 423 4.6 16.3 429 37.9 17.4 428 81.3 32 14.1 437 14.2 439 4.1 14.3 445 32.2 14.7 446 66.2 36 13.5 442 13.4 445 3.8 13.2 452 29.3 14.1 451 62.5 40 14.3 459 14.8 461 4.0 14.4 466 30.9 14.6 468 62.4 44 13.2 467 14.4 474 3.8 14.4 477 30.3 14.6 478 61.2 48 13.3 475 13.7 479 3.6 13.8 482 28.7 13.8 486 56.7 52 13.4 487 13.8 491 3.5 13.5 493 27.4 13.8 494 55.7 56 14.2 489 14.7 493 3.7 14.7 497 29.6 15.1 498 60.8 60 15.0 495 15.2 499 3.8 15.4 501 30.7 15.6 501 62.1 64 15.2 499 15.1 503 3.8 15.2 505 30.1 15.7 505 62.1 68 14.8 500 15.0 503 3.7 15.1 504 30.0 15.5 505 61.2 72 14.7 497 15.4 502 3.8 15.8 506 31.3 15.5 504 61.5 76 15.4 508 15.6 506 3.9 16.1 508 31.7 16.1 509 63.3 80 14.6 508 14.4 506 3.6 14.8 507 29.1 15.6 508 61.4 84 15.2 512 15.6 508 3.8 16.1 513 31.4 16.7 510 65.6 88 15.7 509 15.7 501 3.9 15.8 516 30.6 17.2 510 67.5 92 14.8 514 15.8 501 3.9 15.1 514 29.4 16.2 508 63.9 96 14.9 507 14.9 500 3.7 15.2 505 30.1 15.7 498 63.0 100 14.1 497 14.7 486 3.8 15.5 504 30.7 16.4 488 67.2 104 15.0 490 16.5 497 4.2 15.7 500 31.4 17.2 496 69.3

Mean for weeks 1-13 16.1 254 16.4 255 8.5 16.6 257 68.0 17.1 259 138.7 14-52 14.3 430 14.5 433 4.2 14.6 438 34.0 15.0 439 69.3 53-104 14.9 502 15.3 500 3.8 15.4 506 30.5 16.0 503 63.8

a Grams of water consumed per animal per day b Milligrams of sodium chlorate consumed per kilogram body weight per day

### Sodium Chlorate, NTP TR 517 245



### TABLE 

### I2 Water and Compound Consumption by Female Rats in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 125 mg/L 1,000 mg/L 2,000 mg/L Water Body Water Body Dose Water Body Dose Water Body Dose

(g) a Weight (g) Weight (mg/kg)b (g) Weight (mg/kg) (g) Weight (mg/kg) Week (g) (g) (g) (g)

4 12.7 140 12.9 141 11.5 12.8 140 91.8 12.6 138 182.8 8 12.2 169 12.5 171 9.1 12.6 170 74.2 12.8 169 151.6 12 11.5 186 12.0 187 8.0 11.8 188 62.6 11.6 186 124.8 16 11.1 197 11.3 200 7.1 11.1 199 55.6 10.6 196 107.7 20 10.6 205 11.3 208 6.8 10.9 208 52.6 10.9 204 106.6 24 10.8 213 11.1 215 6.4 10.8 216 50.3 11.3 212 106.3 28 11.5 228 11.7 230 6.3 11.7 232 50.5 11.9 226 105.6 32 10.5 232 11.1 236 5.9 10.9 237 45.9 11.0 231 94.8 36 10.1 235 10.4 239 5.5 9.7 240 40.5 10.1 236 86.0 40 10.7 246 10.9 250 5.4 10.8 248 43.4 10.9 244 89.4 44 10.1 259 10.9 268 5.1 10.5 265 39.8 11.0 259 84.6 48 10.4 260 10.6 266 5.0 10.3 263 39.3 10.4 259 80.4 52 10.5 271 11.3 277 5.1 10.3 276 37.2 10.5 267 79.1 56 11.1 278 11.5 283 5.1 11.9 284 41.8 11.7 276 85.0 60 11.3 285 12.0 287 5.2 12.6 293 43.1 12.8 283 90.3 64 11.9 294 12.3 301 5.1 12.5 304 41.2 12.7 291 87.2 68 11.8 304 12.1 310 4.9 12.0 309 38.9 12.4 298 83.3 72 12.1 308 12.4 313 4.9 12.8 316 40.5 12.7 305 83.2 76 12.8 322 13.2 325 5.1 12.8 328 39.1 13.3 317 83.8 80 12.4 327 11.8 331 4.5 12.0 332 36.1 12.4 323 76.6 84 12.9 331 13.1 337 4.8 13.2 337 39.1 13.7 330 83.0 88 13.4 337 13.6 338 5.0 13.7 341 40.1 13.7 331 83.2 92 13.2 340 12.4 342 4.5 13.4 345 38.9 13.5 339 79.5 96 13.8 340 14.0 343 5.1 13.5 352 38.5 14.2 332 85.5 100 13.5 342 13.4 350 4.8 13.9 351 39.5 14.5 337 86.0 104 13.4 339 13.1 351 4.7 14.7 359 41.0 14.1 341 82.5

Mean for weeks 1-13 12.1 165 12.5 166 9.5 12.4 166 76.2 12.3 164 153.1 14-52 10.6 235 11.1 239 5.9 10.7 238 45.5 10.9 234 94.1 53-104 12.6 319 12.7 324 4.9 13.0 327 39.8 13.2 316 83.8

a Grams of water consumed per animal per day b Milligrams of sodium chlorate consumed per kilogram body weight per day

### 246 Sodium Chlorate, NTP TR 517



### TABLE 

### I3 Water and Compound Consumption by Male Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L Water Body Water Body Dose Water Body Dose Water Body Dose

(g) a Weight (g) Weight (mg/kg)b (g) Weight (mg/kg) (g) Weight (mg/kg) Week (g) (g) (g) (g)

4 3.6 28.1 4.0 27.7 72 3.8 28.2 136 3.9 28.2 274 8 3.3 33.9 3.6 33.3 54 3.3 33.5 100 3.3 33.8 197 12 3.1 38.7 3.3 38.2 43 3.0 38.4 78 3.3 38.6 171 16 3.2 43.6 3.2 43.0 37 3.1 43.5 71 2.9 43.6 134 20 2.8 47.1 2.9 46.5 31 2.9 47.4 61 2.8 47.0 120 24 3.0 49.5 3.0 48.8 31 3.0 49.1 61 3.1 49.6 125 28 3.4 50.5 3.3 49.8 33 3.3 49.9 67 3.4 50.2 135 32 3.3 50.7 3.3 49.7 33 3.3 49.8 67 3.4 50.4 137 36 3.5 51.3 3.6 50.7 35 3.6 50.6 72 3.6 51.2 141 40 3.8 51.8 3.7 51.1 37 4.0 51.4 79 3.8 51.8 145 44 3.7 52.2 3.7 50.9 36 3.6 51.3 71 3.7 52.1 140 48 3.9 53.0 3.7 51.8 36 3.8 51.7 73 3.8 52.8 142 52 3.8 52.6 3.6 51.8 34 3.7 52.1 71 3.7 52.9 140 56 4.1 52.7 3.9 52.1 38 4.0 52.2 76 4.0 52.5 151 60 4.1 53.0 4.1 52.2 39 4.3 52.6 81 4.0 53.0 152 64 4.2 53.4 4.2 53.2 39 4.5 52.7 85 4.2 53.4 157 68 4.2 53.2 4.3 53.5 40 4.3 53.2 81 4.2 54.5 153 72 3.8 54.1 4.0 53.4 37 4.0 52.8 75 3.9 54.2 144 76 3.9 53.6 4.0 53.0 38 4.1 52.2 79 4.0 54.0 149 80 4.2 52.5 4.0 52.4 39 4.4 51.8 84 4.1 52.9 155 84 4.1 53.0 4.2 52.4 40 4.1 53.0 77 4.1 51.7 157 88 4.1 51.7 3.9 51.4 38 3.9 52.3 74 3.9 50.6 156 92 4.9 50.9 4.3 50.6 43 4.3 51.4 83 4.2 49.6 169 96 4.8 50.7 4.3 49.7 43 4.0 50.3 80 4.1 49.6 164 100 4.3 48.6 4.0 47.1 43 3.8 48.1 79 3.9 48.1 161 104 4.2 46.6 4.2 45.1 46 4.1 46.5 89 4.0 48.5 166

Mean for weeks 1-13 3.4 33.6 3.6 33.1 57 3.4 33.3 105 3.5 33.5 214 14-52 3.5 50.2 3.4 49.4 34 3.4 49.7 69 3.4 50.2 136 53-104 4.2 51.8 4.1 51.2 40 4.1 51.5 80 4.0 51.7 156

a Grams of water consumed per animal per day b Milligrams of sodium chlorate consumed per kilogram body weight per day

### Sodium Chlorate, NTP TR 517 247



### TABLE 

### I4 Water and Compound Consumption by Female Mice in the 2-Year Drinking Water Study of Sodium Chlorate

0 mg/L 500 mg/L 1,000 mg/L 2,000 mg/L Water Body Water Body Dose Water Body Dose Water Body Dose

(g) a Weight (g) Weight (mg/kg)b (g) Weight (mg/kg) (g) Weight (mg/kg) Week (g) (g) (g) (g)

4 3.5 22.3 3.4 22.2 78 3.4 22.4 151 3.9 22.0 356 8 2.9 27.3 3.1 26.6 58 3.2 27.1 117 3.5 26.3 266 12 3.1 32.0 3.2 31.4 51 3.1 31.6 98 3.5 30.2 234 16 3.0 36.5 3.1 35.9 43 3.6 36.0 100 3.1 35.0 175 20 2.4 42.3 2.4 41.9 29 2.4 42.3 57 2.5 41.2 123 24 2.5 46.9 2.3 46.5 25 2.3 46.8 50 2.4 45.1 106 28 2.4 49.9 2.7 49.7 27 2.3 50.3 46 2.9 48.6 118 32 2.5 52.5 2.4 51.9 23 2.4 52.7 45 2.4 51.4 93 36 2.3 54.4 2.5 54.2 23 2.3 54.3 43 2.5 53.0 94 40 2.3 57.8 2.3 58.0 20 2.2 57.4 39 2.4 56.1 87 44 2.5 58.4 2.7 58.5 23 2.4 57.2 42 2.8 56.6 99 48 2.3 60.2 2.4 59.6 20 2.4 58.6 41 2.7 59.0 90 52 2.4 61.0 2.4 60.8 19 2.4 59.9 40 2.5 60.5 82 56 2.5 61.2 2.5 61.0 20 2.5 60.1 42 2.6 61.4 83 60 2.6 62.2 2.6 61.1 22 2.8 60.9 46 2.8 62.1 89 64 2.8 62.8 2.7 62.4 22 2.7 62.7 43 3.2 62.0 103 68 2.6 63.4 2.7 62.3 21 2.8 62.9 44 2.5 63.7 80 72 2.4 64.2 2.8 61.8 23 2.5 63.1 40 2.7 64.5 84 76 2.7 65.0 2.8 63.9 22 2.9 64.3 44 2.8 64.6 86 80 2.9 66.5 2.8 64.7 22 3.0 65.0 46 2.9 65.2 89 84 2.8 65.7 2.8 64.9 22 3.1 64.3 49 2.8 65.1 87 88 2.6 65.9 3.0 62.9 24 3.3 61.7 54 2.7 63.7 86 92 3.1 64.9 3.8 60.2 32 3.7 62.3 60 3.0 61.9 96 96 3.2 64.3 3.5 57.8 30 4.0 60.1 67 3.2 58.5 110 100 3.4 63.3 4.2 56.3 37 4.5 57.3 79 3.4 58.6 116 104 3.6 61.0 3.7 53.7 35 5.1 55.0 93 4.1 54.6 150

Mean for weeks 1-13 3.2 27.2 3.2 26.7 62 3.2 27.0 122 3.6 26.2 285 14-52 2.5 52.0 2.5 51.7 25 2.5 51.6 50 2.6 50.7 107 53-104 2.9 63.9 3.1 61.0 25 3.3 61.5 54 3.0 62.0 97

a Grams of water consumed per animal per day b Milligrams of sodium consumed per kilogram body weight per day

### 248 Sodium Chlorate, NTP TR 517

### 249



# APPENDIX J INGREDIENTS, NUTRIENT COMPOSITION, AND CONTAMINANT LEVELS IN NTP-2000 RAT AND MOUSE RATION

TABLE 

### J1 Ingredients of NTP-2000 Rat and Mouse Ration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 TABLE 

### J2 Vitamins and Minerals in NTP-2000 Rat and Mouse Ration . . . . . . . . . . . . . . . . . . . . . . . . . 250 TABLE 

### J3 Nutrient Composition of NTP-2000 Rat and Mouse Ration . . . . . . . . . . . . . . . . . . . . . . . . . . 251 TABLE 

### J4 Contaminant Levels in NTP-2000 Rat and Mouse Ration . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

### 250 Sodium Chlorate, NTP TR 517



### TABLE 

### J1 Ingredients of NTP-2000 Rat and Mouse Ration

Ingredients Percent by Weight

Ground hard winter wheat 22.26 Ground #2 yellow shelled corn 22.18 Wheat middlings 15.0 Oat hulls 8.5 Alfalfa meal (dehydrated, 17% protein) 7.5 Purified cellulose 5.5 Soybean meal (49% protein) 5.0 Fish meal (60% protein) 4.0 Corn oil (without preservatives) 3.0 Soy oil (without preservatives) 3.0 Dried brewer’s yeast 1.0 Calcium carbonate (USP) 0.9 Vitamin premixa 0.5 Mineral premixb 0.5 Calcium phosphate, dibasic (USP) 0.4 Sodium chloride 0.3 Choline chloride (70% choline) 0.26 Methionine 0.2

a Wheat middlings as carrier b Calcium carbonate as carrier



### TABLE 

### J2 Vitamins and Minerals in NTP-2000 Rat and Mouse Ration a



### Amount Source

Vitamins A 4,000 IU Stabilized vitamin A palmitate or acetate D 1,000 IU D-activated animal sterol K 1.0 mg Menadione sodium bisulfite complex

" -Tocopheryl acetate 100 IU Niacin 23 mg Folic acid 1.1 mg d

-Pantothenic acid 10 mg d -Calcium pantothenate Riboflavin 3.3 mg Thiamine 4 mg Thiamine mononitrate B 12 52 μg Pyridoxine 6.3 mg Pyridoxine hydrochloride Biotin 0.2 mg d -Biotin



### Minerals Magnesium 514 mg Magnesium oxide Iron 35 mg Iron sulfate Zinc 12 mg Zinc oxide Manganese 10 mg Manganese oxide Copper 2.0 mg Copper sulfate Iodine 0.2 mg Calcium iodate Chromium 0.2 mg Chromium acetate

a Per kg of finished product

### Sodium Chlorate, NTP TR 517 251



### TABLE 

### J3 Nutrient Composition of NTP-2000 Rat and Mouse Ration

Mean ± Standard Nutrient Deviation Range Number of Samples

Protein (% by weight) 13.5 ± 0.44 12.7 – 14.5 25 Crude fat (% by weight) 8.1 ± 0.26 7.6 – 8.6 25 Crude fiber (% by weight) 9.2 ± 0.66 7.9 – 10.5 25 Ash (% by weight) 4.9 ± 0.19 4.7 – 5.4 25


### Amino Acids (% of total diet) Arginine 0.748 ± 0.053 0.670 – 0.850 12 Cystine 0.223 ± 0.027 0.150 – 0.250 12 Glycine 0.702 ± 0.043 0.620 – 0.750 12 Histidine 0.343 ± 0.023 0.310 – 0.390 12 Isoleucine 0.534 ± 0.041 0.430 – 0.590 12 Leucine 1.078 ± 0.059 0.960 – 1.140 12 Lysine 0.729 ± 0.065 0.620 – 0.830 12 Methionine 0.396 ± 0.053 0.260 – 0.460 12 Phenylalanine 0.611 ± 0.038 0.540 – 0.660 12 Threonine 0.492 ± 0.045 0.430 – 0.590 12 Tryptophan 0.129 ± 0.016 0.110 – 0.160 12 Tyrosine 0.378 ± 0.054 0.280 – 0.460 12 Valine 0.658 ± 0.049 0.550 – 0.710 12


### Essential Fatty Acids (% of total diet) Linoleic 3.89 ± 0.278 3.49 – 4.54 12 Linolenic 0.30 ± 0.038 0.21 – 0.35 12



### Vitamins Vitamin A (IU/kg) 5,694 ± 1,010 3,700 – 7,790 25 Vitamin D (IU/kg) 1,000 a



### " -Tocopherol (ppm) 84.3 ± 17.06 52.0 – 110.0 12 Thiamine (ppm)b 7.9 ± 0.83 6.3 – 9.3 25 Riboflavin (ppm) 6.4 ± 2.11 4.20 – 11.20 12 Niacin (ppm) 78.6 ± 10.86 66.4 – 98.2 12 Pantothenic acid (ppm) 23.1 ± 3.61 17.4 – 29.1 12 Pyridoxine (ppm)b 8.88 ± 2.05 6.4 – 12.4 12 Folic acid (ppm) 1.84 ± 0.56 1.26 – 3.27 12 Biotin (ppm) 0.337 ± 0.13 0.225 – 0.704 12 Vitamin B 12 (ppb) 64.8 ± 50.9 18.3 – 174.0 12 Choline (ppm)b 3,094 ± 292 2,700 – 3,790 12



### Minerals Calcium (%) 0.998 ± 0.045 0.903 – 1.090 25 Phosphorus (%) 0.564 ± 0.028 0.505 – 0.618 25 Potassium (%) 0.668 ± 0.023 0.627 – 0.694 12 Chloride (%) 0.368 ± 0.033 0.300 – 0.423 12 Sodium (%) 0.189 ± 0.016 0.160 – 0.212 12 Magnesium (%) 0.200 ± 0.009 0.185 – 0.217 12 Sulfur (%) 0.176 ± 0.026 0.116 – 0.209 12 Iron (ppm) 177 ± 46.2 135 – 311 12 Manganese (ppm) 53.4 ± 6.42 42.1 – 63.1 12 Zinc (ppm) 52.5 ± 6.95 43.3 – 66.0 12 Copper (ppm) 6.64 ± 1.283 5.08 – 9.92 12 Iodine (ppm) 0.535 ± 0.242 0.233 – 0.972 12 Chromium (ppm) 0.545 ± 0.125 0.330 – 0.751 12 Cobalt (ppm) 0.23 ± 0.041 0.20 – 0.30 12

a From formulation b As hydrochloride (thiamine and pyridoxine) or chloride (choline)

### 252 Sodium Chlorate, NTP TR 517



### TABLE 

### J4 Contaminant Levels in NTP-2000 Rat and Mouse Ration a



### Mean ± Standard Nutrient Deviationb 

### Range Number of Samples

Contaminants Arsenic (ppm) 0.16 ± 0.070 0.10 – 0.33 25 Cadmium (ppm) 0.04 ± 0.006 0.04 – 0.07 25 Lead (ppm) 0.11 ± 0.104 0.05 – 0.54 25 Mercury (ppm) <0.02 25 Selenium (ppm) 0.19 ± 0.033 0.14 – 0.28 25 Aflatoxins (ppb) <5.00 25 Nitrate nitrogen (ppm) c 10.8 ± 2.98 9.04 – 21.1 25 Nitrite nitrogen (ppm) c <0.61 25 BHA (ppm) d <1.0 25 BHT (ppm) d <1.0 25 Aerobic plate count (CFU/g) 10 ± 2 10 – 20 25 Coliform (MPN/g) 0.4 ± 1.2 0.0 – 3.6 25 Escherichia coli (MPN/g) <10 25 Salmonella (MPN/g) Negative 25 Total nitrosoamines (ppb) e 4.6 ± 1.64 2.1 – 8.8 25 N

-Nitrosodimethylamine (ppb) e 1.8 ± 0.86 1.0 – 5.1 25 N

-Nitrosopyrrolidine (ppb) e 2.8 ± 1.10 1.0 – 5.6 25


### Pesticides (ppm)



### " -BHC <0.01 25 

### $ -BHC <0.02 25 

### (-BHC <0.01 25 

### * -BHC <0.01 25 Heptachlor <0.01 25 Aldrin <0.01 25 Heptachlor epoxide <0.01 25 DDE <0.01 25 DDD <0.01 25 DDT <0.01 25 HCB <0.01 25 Mirex <0.01 25 Methoxychlor <0.05 25 Dieldrin <0.01 25 Endrin <0.01 25 Telodrin <0.01 25 Chlordane <0.05 25 Toxaphene <0.10 25 Estimated PCBs <0.20 25 Ronnel <0.01 25 Ethion <0.02 25 Trithion <0.05 25 Diazinon <0.10 25 Methyl chlorpyrifos 0.145 ± 0.124 0.023 – 0.499 25 Methyl parathion <0.02 25 Ethyl parathion <0.02 25 Malathion 0.217 ± 0.188 0.020 – 0.826 25 Endosulfan I <0.01 25 Endosulfan II <0.01 25 Endosulfan sulfate <0.03 25

a All samples were irradiated. 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. c Sources of contamination: alfalfa, grains, and fish meal d Sources of contamination: soy oil and fish meal e All values were corrected for percent recovery.

### 253



# APPENDIX K SENTINEL ANIMAL PROGRAM

METHODS


### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 RESULTS


### . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

### 254 Sodium Chlorate, NTP TR 517



# 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.

During the 2-year studies, serum samples were collected from randomly selected sentinel rats and mice at 6, 12, and 18 months and 2,000 mg/L rats and mice at study termination. Blood from each animal was collected and allowed to clot, and the serum was separated. Samples were processed appropriately and sent to BioReliance Corporation, Rockville, 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 

# R

ATS

ELISA Mycoplasma arthritidis 6 months, study termination M

ycoplasma pulmonis 6 months, study termination PVM (pneumonia virus of mice) 6, 12, and 18 months, study termination RCV/SDA (rat coronavirus/sialodacryoadentis virus) 6, 12, and 18 months, study termination Sendai 6, 12, and 18 months, study termination

Immunofluorescence Assay Parvovirus 6, 12, and 18 months, study termination

### Sodium Chlorate, NTP TR 517 255



### Method and Test Time of Analysis 

# MICE

ELISA Ectromelia virus 6, 12, and 18 months, study termination EDIM (epizootic diarrhea of infant mice) 6, 12, and 18 months, study termination GDVII (mouse encephalomyelitis virus) 6, 12, and 18 months, study termination LCM (lymphocytic choriomeningitis virus) 6, 12, and 18 months, study termination Mouse adenoma virus-FL 6, 12, and 18 months, study termination MHV (mouse hepatitis virus) 6, 12, and 18 months, study termination M. arthritidis 6 months, study termination M. pulmonis 6 months, study termination PVM 6, 12, and 18 months, study termination Reovirus 3 6, 12, and 18 months, study termination Sendai 6, 12, and 18 months, study termination

Immunofluorescence Assay Ectromelia virus 18 months EDIM 18 months GDVII 18 months LCM 18 months Mouse adenoma virus-FL 12 and 18 months MCMV (mouse cytomegalovirus) 6 months, study termination MHV 18 months M. arthritidis 6 months, study termination Parvovirus 6, 12, and 18 months, study termination PVM 18 months Reovirus 3 18 months



# RESULTS For the 2-year studies in rats and mice, all serology tests were negative.

### 256 Sodium Chlorate, NTP TR 517