NTP TECHNICAL REPORT 

ON THE 

TOXICOLOGY AND CARCINOGENESIS 

STUDIES OF 

TRIETHANOLAMINE 

(CAS NO. 102-71-6) 

IN F344/N RATS AND B6C3F1 MICE

(DERMAL STUDIES) 

NATIONAL TOXICOLOGY PROGRAM 

P.O. Box 12233 

Research Triangle Park, NC 27709 

November 1999 

NTP TR 449 

NIH Publication No. 00-3365 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

National Institutes of Health 
FOREWORD 

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

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

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

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

Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. In July 1981, the 

Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. The NTP coordinates the 

relevant programs, staff, and resources from these Public Health Service agencies relating to basic and 

applied research and to biological assay development and validation. 

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

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

prevention of disease. 

The studies described in this Technical Report were performed under the direction of the NIEHS and were 

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

applicable federal, state, and local health and safety regulations. Animal care and use were in accordance 

with the Public Health Service Policy on Humane Care and Use of Animals. The prechronic and chronic 

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

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

before being presented for public review. 

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

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

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

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

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

species and quantitative risk analyses for humans require wider analyses beyond the purview of these 

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

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

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

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

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

ON THE 

TOXICOLOGY AND CARCINOGENESIS 

STUDIES OF 

TRIETHANOLAMINE 

(CAS NO. 102-71-6) 

IN F344/N RATS AND B6C3F1 MICE

(DERMAL STUDIES) 

NATIONAL TOXICOLOGY PROGRAM 

P.O. Box 12233 

Research Triangle Park, NC 27709 

November 1999 

NTP TR 449 

NIH Publication No. 00-3365 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

National Institutes of Health 
2 Triethanolamine, NTP TR 449 

CONTRIBUTORS 

National Toxicology Program 

Evaluated and interpreted results and reported findings 

D.A. Bridge, B.S. 

J.R. Bucher, Ph.D. 

R.E. Chapin, Ph.D. 

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

T.J. Goehl, Ph.D. 

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

J.K. Haseman, Ph.D. 

R.L. Melnick, Ph.D. 

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

J.H. Roycroft, Ph.D. 

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

D.B. Walters, Ph.D. 

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

Battelle Columbus Laboratories 

Conducted studies, evaluated pathology findings 

P.J. Kurtz, Ph.D., Principal Investigator (2-year studies) 

A.C. Peters, D.V.M., 

Principal Investigator (13-week studies) 

M.R. Hejtmancik, Ph.D. 

L.E. Mezza, D.V.M., M.S. 

R.L. Persing, D.V.M. 

J.D. Toft, II, D.V.M., M.S. 

Experimental Pathology Laboratories, Inc. 

Provided pathology quality assurance 

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

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

B.F. Hamilton, D.V.M., Ph.D. 

Dynamac Corporation 

Prepared quality assurance audits 

S. Brecher, Ph.D., Principal Investigator 

Analytical Sciences, Inc. 

Provided statistical analyses 

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

S.R. Lloyd, M.S. 

NTP Pathology Working Group 

Evaluated slides, prepared pathology report on rats 

(26 February 1993) 

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

PATHCO, Inc. 

F. Chatani, Ph.D. 

National Toxicology Program, Observer 

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

National Toxicology Program 

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

National Toxicology Program 

B.F. Hamilton, D.V.M., Ph.D. 

Experimental Pathology Laboratories, Inc. 

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

National Toxicology Program 

D. Meuten, D.V.M., Ph.D. 

North Carolina State University 

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

National Toxicology Program 

Evaluated slides, prepared pathology report on mice 

(26 February 1993) 

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

PATHCO, Inc. 

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

Experimental Pathology Laboratories, Inc. 

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

Chemical Industry Institute of Toxicology 

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

National Toxicology Program 

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

National Toxicology Program 

K. Takahashi, D.V.M., M.S., Ph.D. 

National Toxicology Program 

Biotechnical Services, Inc. 

Prepared Technical Report 

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

G. Gordon, M.A. 

L.M. Harper, B.S. 

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

E.S. Rathman, M.S. 

W.D. Sharp, B.A., B.S. 

S.M. Swift, B.S. 
3 

CONTENTS 

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

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ............. 11 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE ................................ 12 

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

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

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

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

DISCUSSION AND CONCLUSIONS ............................................ 63 

REFERENCES ........................................................... 67 

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

of Triethanolamine ............................................. 75 

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

of Triethanolamine ............................................. 117 

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

of Triethanolamine ............................................. 147 

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

of Triethanolamine ............................................. 179 

APPENDIX E Genetic Toxicology ............................................. 219 

APPENDIX F Organ Weights and Organ-Weight-to-Body-Weight Ratios .................. 229 

APPENDIX G Hematology, Clinical Chemistry, and Urinalysis Results .................... 237 

APPENDIX H Reproductive Tissue Evaluations and Estrous Cycle Characterization ........... 245 

APPENDIX I Chemical Characterization and Dose Formulation Studies ................... 249 

APPENDIX J Ingredients, Nutrient Composition, and Contaminant Levels 

in NIH-07 Rat and Mouse Ration ................................... 267 
4 Triethanolamine, NTP TR 449 

APPENDIX K Sentinel Animal Program ......................................... 271 

APPENDIX 1 L Impact of Helicobacter hepaticus Infection in B6C3F Mice

from 12 NTP 2-Year Carcinogenesis Studies ............................ 275 
5 

ABSTRACT 

HOCH2CH2	 N CH2CH2OH 

CH2CH2OH 

TRIETHANOLAMINE 

CAS No. 102-71-6 

Chemical Formula: C 6 15 3 H NO Molecular Weight: 149.19

Synonyms:	 Nitrilo-2,2N,2NN-triethanol; 2,2N,2NN-nitrilotriethanol; 2,2N,2NN-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; 

triethylolamine; tri(hydroxyethyl)amine; 2,2N,2NN-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; 

tris(2-hydroxyethyl)amine; triethylolamine; trolamine 

Trade Names:	 Daltogen; Sterolamide; Thiofaco T-35 

Triethanolamine is widely used as an ingredient in 

emulsifiers, thickeners, wetting agents, detergents, 

and alkalinizing agents in cosmetic products; as a 

chemical intermediate for anionic and nonionic 

surfactants and surface active agents in household 

cleaning agents, textiles, herbicides, pharmaceutical 

ointments, and other products; as a vulcanization 

accelerator in the manufacture of rubber; and in many 

other industrial applications. The National Cancer 

Institute nominated triethanolamine for study because 

of its widespread use in cosmetics and other consumer 

products, its high potential for worker exposure due 

to its many industrial uses, and its potential for 

conversion to the carcinogen N-nitrosodiethanolamine. 

Dermal application was chosen as the route of exposure to mimic the principal means of human exposure 

to triethanolamine and because considerable systemic 

exposure is achieved with this route. Male and female 

F344/N rats and B6C3F1 mice received triethanolamine (purity 98% or greater) by dermal application 

for 13 weeks or 2 years. Genetic toxicology studies 

were conducted in Salmonella typhimurium, cultured 

Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. 

13-WEEK STUDY IN RATS 

Groups of 10 male and 10 female rats were topically 

administered 0, 125, 250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or 

2,000 mg/kg neat triethanolamine, 5 days per week, 

for 13 weeks. All rats survived to the end of the 

study. Final mean body weights and weight gains of 

males and females administered 2,000 mg/kg and the 

mean body weight gain of females administered 

1,000 mg/kg were significantly less than those of the 

vehicle controls. Clinical observations included 

irritation, scaliness, and crustiness of the skin at the 

site of application for males and females. Males also 

had discoloration, and two males administered 

2,000 mg/kg had ulceration at the site of application. 

Changes in clinical pathology parameters were minor 

and consistent with inflammation at the site of 

application. 

Kidney weights were generally greater in males and 

females administered 500, 1,000, or 2,000 mg/kg 

than in the vehicle controls. Microscopic lesions 

attributed to triethanolamine administration included 

acanthosis and inflammation at the site of application, 
6 Triethanolamine, NTP TR 449 

nephropathy in females, and hypertrophy of the 

pituitary gland pars intermedia in males and females. 

These lesions generally occurred with dose-related 

increases in incidence and severity in males and 

females. 

13-WEEK STUDY IN MICE 

Groups of 10 male and 10 female mice were topically 

administered 0, 250, 500, 1,000, or 2,000 mg 

triethanolamine per kilogram body weight in acetone 

or 4,000 mg/kg neat triethanolamine, 5 days per 

week, for 13 weeks. All mice survived to the end of 

the study. The final mean body weight and weight 

gain of males in the 250 mg/kg group were less than 

those of the vehicle controls. Clinical findings were 

observed only in mice in the 4,000 mg/kg groups and 

included scaliness, irritation, and discoloration at the 

site of triethanolamine application for males and 

females and skin erosion at this site in one male. 

The absolute kidney and liver weights of males and 

females administered 4,000 mg/kg were greater than 

those of the vehicle controls; relative kidney weights 

of males administered 1,000 mg/kg or greater and 

females in all dosed groups were also greater than 

those of the vehicle controls. 

Microscopic examination of the skin of dosed mice 

indicated acanthosis and inflammation at the site of 

application. Acanthosis occurred in all dosed groups 

and in one vehicle control female; the severity 

increased with increasing dose in males and females. 

Inflammation was observed in males and females in 

the 4,000 mg/kg groups and in one female in the 

2,000 mg/kg group. 

2-YEAR STUDY IN RATS 

Based on the presence of acanthosis and inflammation 

at the site of application at the higher doses in the 

13-week study, triethanolamine doses selected for the 

2-year study in rats were 32, 63, and 125 mg/kg for 

males and 63, 125, and 250 mg/kg for females. 

Groups of 60 male and 60 female rats were topically 

administered triethanolamine in acetone 5 days per 

week for 103 weeks. Ten male and ten female rats 

from each group were evaluated at 15 months for 

organ weights and histopathology. 

Survival, Body Weights, Clinical Findings, 

and Organ Weights 

The survival rate of females in the 250 mg/kg group 

was slightly less than that of the vehicle controls. The 

mean body weight of females administered 250 mg/kg 

ranged from 9% to 12% less than that of the vehicle 

controls between weeks 73 and 93. Male and female 

rats receiving triethanolamine had irritated skin at the 

site of application; in dosed females, the site of 

application also had a crusty appearance. The number 

of animals in which these findings were observed 

increased with increasing dose. At the 15-month 

interim evaluation, the absolute left and right kidney 

weights and relative right kidney weight of females 

administered 250 mg/kg were significantly greater 

than those of the vehicle controls. 

Pathology Findings 

The incidence of acanthosis at the site of application 

in males administered 125 mg/kg and the incidences 

of acanthosis, inflammation, and ulceration in dosed 

females were greater than in the vehicle controls at the 

15-month interim evaluation and at the end of the 

2-year study. Males in the 125 mg/kg group also had 

greater incidences of inflammation and ulceration than 

the vehicle controls, and females receiving 125 or 

250 mg/kg had greater incidences of epidermal 

erosion than the vehicle controls at 2 years. There 

were no skin neoplasms at or away from the site of 

application that were considered related to treatment 

with triethanolamine. 

At the end of the study, renal tubule adenomas were 

observed in seven dosed males and in one vehicle 

control female and one female in the 63 mg/kg group. 

One male in the 125 mg/kg group and one female in 

the 250 mg/kg group had renal tubule hyperplasia. 

Extended (step-section) evaluation of the kidneys of 

all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 

32 mg/kg group, two males in the 63 mg/kg group, 

and three males in the 125 mg/kg group (including 

one male from the 15-month interim evaluation). An 

oncocytoma was also identified in one male in the 

32 mg/kg group. Hyperplasia was identified in eight 

additional vehicle control males and in 19 additional 

dosed males. The total incidences (combined standard 

and extended evaluations) of renal tubule adenoma in 

dosed male rats were slightly greater than the vehicle 
Triethanolamine, NTP TR 449 7 

control incidence (vehicle control, 1/50; 32 mg/kg, 

2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total 

incidence of hyperplasia in dosed and vehicle control 

males was similar (9/50, 8/50, 7/49, 6/50). The 

severity of hyperplasia in males in the 32 and 

125 mg/kg groups was greater than that in the vehicle 

controls. 

2-YEAR STUDY IN MICE 

Based on dose-related inflammation at the site of 

application in the 13-week study, triethanolamine 

doses selected for the 2-year study in mice were 200, 

630, and 2,000 mg/kg for males and 100, 300, and 

1,000 mg/kg for females. Groups of 60 male and 

60 female mice were topically administered triethanolamine in acetone 5 days per week for 103 weeks. 

Ten male and ten female mice from each group were 

evaluated at 15 months for organ weights and 

histopathology. 

Survival, Body Weights, Clinical Findings, 

and Organ Weights 

Survival rates of all dosed groups of males and 

females were similar to those of the vehicle controls. 

The mean body weight of males administered 

2,000 mg/kg ranged from 8% to 10% less than that of 

the vehicle controls from week 69 through the end of 

the study. Clinical findings included irritation and 

discoloration of the skin at the site of application for 

most males in the 2,000 mg/kg group and a few 

females in the 1,000 mg/kg group; males administered 

200 or 630 mg/kg also had skin irritation. At the 

15-month interim evaluation, the right kidney weights 

of male mice that received 630 or 2,000 mg/kg and 

the left kidney weights of males that received 

2,000 mg/kg were significantly greater than those of 

the vehicle controls. 

Pathology Findings 

Acanthosis and inflammation of the skin were 

observed at the site of application in male and female 

mice at the 15-month interim evaluation and at the end 

of the 2-year study. In males in the 2,000 mg/kg 

group, the incidences of both lesions were significantly greater than those in the vehicle controls at 

both time points; however, the severities of acanthosis 

and inflammation did not increase with dose. At the 

end of the study, the incidence of inflammation in 

females in the 1,000 mg/kg group was significantly 

greater than that in the vehicle controls. One vehicle 

control male and two males in each of the 630 and 

2,000 mg/kg groups had ulcers at the site of 

application. 

At the 15-month interim evaluation, hepatocellular 

carcinomas were observed in dosed and vehicle 

control males and hepatocellular adenomas in dosed 

and vehicle control males and females; however, the 

incidences were not dose related. Nonneoplastic 

lesions observed at 15 months included foci of cellular 

alteration in a few dosed males and females; eosinophilic foci were also observed in two vehicle control 

females. 

At the end of the 2-year study, females in the 

1,000 mg/kg group had significantly greater incidences of hepatocellular adenoma and multiple 

adenomas and a greater combined incidence of 

hepatocellular adenoma and carcinoma than the 

vehicle controls (adenoma: vehicle control, 22/50; 

100 mg/kg, 22/50; 300 mg/kg, 24/50; 1,000 mg/kg, 

40/50; multiple adenomas: 11/50, 9/50, 13/50, 

29/50; combined adenoma and carcinoma: 23/50, 

26/50, 28/50, 41/50). Females in the 300 mg/kg 

group had significantly greater incidences of hepatocellular carcinoma (1/50, 4/50, 7/50, 5/50) and 

eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the 

vehicle controls. 

Incidences of hepatocellular adenoma and multiple 

adenomas in males in the 2,000 mg/kg group were 

significantly greater than those in the vehicle controls 

(adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 

630 mg/kg, 29/50; 2,000 mg/kg, 37/50; multiple 

adenomas: 17/50, 18/50, 17/50, 29/50). Three 

males in the 2,000 mg/kg group had hepatoblastomas, 

and males in this group also had significantly greater 

incidences of hepatocellular neoplasms (combined) 

(adenoma, carcinoma, and hepatoblastoma: 31/50, 

34/50, 33/50, 42/50) and eosinophilic foci (10/50, 

17/50, 11/50, 23/50) than the vehicle controls. 

Male mice had a pattern of nonneoplastic liver lesions 

along with silver-staining helical organisms within the 

liver which suggested an infection with Helicobacter 

hepaticus. With polymerase chain reaction-based 

assays and culture, the presence of an organism 

compatible with H. hepaticus was confirmed. An 

increased incidence of hepatocellular neoplasms in 

male mice has been shown to be associated with 
 

_________ 

8 Triethanolamine, NTP TR 449 

H. hepaticus infection when hepatitis is also present. 

Therefore, interpretation of the increased incidence of 

hepatocellular neoplasms in mice was confounded. 

GENETIC TOXICOLOGY 

Triethanolamine was not mutagenic in any of the 

in vitro or in vivo short-term tests performed by the 

NTP. It did not induce mutations in Salmonella 

typhimurium, and no induction of sister chromatid 

exchanges or chromosomal aberrations in cultured 

Chinese hamster ovary cells exposed to triethanolamine was noted. These in vitro tests were conducted 

with and without S9 metabolic activation. 

Triethanolamine did not induce sex-linked recessive 

lethal mutations in germ cells of adult male 

Drosophila melanogaster exposed by feeding or 

injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral 

blood samples of male and female mice that received 

dermal applications of triethanolamine for 13 weeks. 

CONCLUSIONS 

Under the conditions of these dermal studies, there 

was equivocal evidence of carcinogenic activity* of 

triethanolamine in male F344/N rats based on a 

marginal increase in the incidence of renal tubule cell 

adenoma. There was no evidence of carcinogenic 

activity in female F344/N rats receiving 63, 125, or 

250 mg triethanolamine per kilogram body weight. 

The study in male and female B6C3F1 mice was 

considered inadequate, because the presence of a 

Helicobacter hepaticus infection complicated interpretation of the relationship between triethanolamine 

administration and liver neoplasms in these animals. 

Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, 

and dosed female rats had epidermal erosion at the 

site of skin application. 

* Explanation of Levels of Evidence of Carcinogenic Activity is on page 11. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 14. 
Triethanolamine, NTP TR 449 9 

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

Male Female Male Female 

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

Doses in acetone by 

dermal application 

0, 32, 63, or 

125 mg/kg 

0, 63, 125, or 

250 mg/kg 

0, 200, 630, or 

2,000 mg/kg 

0, 100, 300, or 

1,000 mg/kg 

Body weights Dosed groups similar 

to vehicle controls 

250 mg/kg group 

slightly less than 

vehicle controls 

2,000 mg/kg group 

slightly less than 

vehicle controls 

Dosed groups similar 

to vehicle controls 

2-Year survival 

rates 

21/50, 11/50, 18/49, 

19/50 

25/50, 29/50, 25/50, 

18/50 

46/50, 40/50, 39/50, 

41/50 

39/50, 40/50, 38/50, 

37/50 

Nonneoplastic 

effects 

Skin, site of 

application: acanthosis 

(1/50, 1/50, 1/49, 

9/50); inflammation 

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

8/50); ulcer (0/50, 

0/50, 0/49, 5/50) 

Kidney: severity of 

hyperplasia (standard 

and extended 

evaluations - 1.7, 2.6, 

1.5, 2.5) 

Skin, site of 

application: acanthosis 

(2/50, 10/50, 30/50, 

32/50); inflammation 

(2/50, 10/50, 30/50, 

32/50); ulcer (2/50, 

7/50, 22/50, 27/50); 

epidermal erosion 

(1/50, 6/50, 16/50, 

14/50) 

Skin, site of 

application: acanthosis 

(2/50, 1/50, 6/50, 

11/50); inflammation 

(2/50, 0/50, 7/50, 

11/50) 

Liver: eosinophilic 

foci (10/50, 17/50, 

11/50, 23/50) 

Skin, site of 

application: acanthosis 

(0/50, 2/50, 1/50, 

3/50); inflammation 

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

5/50) 

Liver: eosinophilic 

foci (9/50, 10/50, 

18/50, 16/50) 

Neoplastic effects None None None None 

Uncertain findings Kidney: renal tubule 

adenoma (standard 

evaluation - 0/50, 

1/50, 4/49, 2/50; 

standard and extended 

evaluations combined ­

1/50, 2/50, 6/49, 4/50) 

None Liver: hepatocellular 

adenoma (27/50, 

27/50, 29/50, 37/50); 

hepatoblastoma (0/50, 

0/50, 0/50, 3/50); 

hepatocellular 

adenoma, 

hepatocellular 

carcinoma, or 

hepatoblastoma (31/50, 

34/50, 33/50, 42/50) 

Liver: hepatocellular 

adenoma (22/50, 

22/50, 24/50, 40/50); 

hepatocellular 

carcinoma (1/50, 4/50, 

7/50, 5/50); 

hepatocellular adenoma 

or carcinoma (23/50, 

26/50, 28/50, 41/50) 

Incidences of liver neoplasms in mice could not be 

interpreted due to the presence of Helicobacter 

hepaticus infection. 

Level of evidence 

of carcinogenic 

activity 

Equivocal evidence No evidence Inadequate study 

(H. hepaticus 

infection) 

Inadequate study 

(H. hepaticus 

infection) 
10 Triethanolamine, NTP TR 449 

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

Genetic toxicology 

Salmonella typhimurium gene mutations: Negative in strains TA98, TA100, TA1535, and TA1537 with and 

without S9 

Sister chromatid exchanges 

Cultured Chinese hamster ovary cells in vitro: Negative with and without S9 

Chromosomal aberrations 

Cultured Chinese hamster ovary cells in vitro: Negative with and without S9 

Sex-linked recessive lethal mutations 

Drosophila melanogaster: Negative when administered in feed or by injection 

Micronucleated erythrocytes 

Mouse peripheral blood in vivo: Negative 
Triethanolamine, NTP TR 449 11 

EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

evidence. 

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

neoplasms that may be chemical related. 

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

malignant or benign neoplasms. 

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

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

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

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

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

two adjacent levels. These considerations should include: 

• adequacy of the experimental design and conduct; 

• occurrence of common versus uncommon neoplasia; 

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

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

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

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

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

•	 latency in tumor induction; 

•	 multiplicity in site-specific neoplasia; 

•	 metastases; 

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

another sex or species); 

•	 presence or absence of dose relationships; 

•	 statistical significance of the observed tumor increase; 

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

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

•	 structure-activity correlations; and 

•	 in some cases, genetic toxicology. 
_________ 

12 Triethanolamine, NTP TR 449 

NATIONAL TOXICOLOGY PROGRAM BOARD OF SCIENTIFIC COUNSELORS 

TECHNICAL REPORTS REVIEW SUBCOMMITTEE 

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. 

November 29, 1994 

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

University of Wisconsin Medical School Fox Chase Cancer Center 

Madison, WI Philadelphia, PA 

Thomas L. Goldsworthy, Ph.D. Louise Ryan, Ph.D. 

Department of Experimental Pathology and Toxicology Division of Biostatistics 

Chemical Industry Institute of Toxicology Harvard School of Public Health and 

Research Triangle Park, NC Dana-Farber Cancer Institute 

Boston, MA 

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

Department of Environmental Occupational Health Robert E. Taylor, M.D., Ph.D. 

University of Pittsburgh Department of Pharmacology 

Pittsburgh, PA Howard University College of Medicine 

Washington, DC 

Curtis D. Klaassen, Ph.D. 

Department of Pharmacology and Toxicology Mary Jo Vodicnik, Ph.D.* 

University of Kansas Medical Center Lilly MSG Development Center 

Kansas City, KS Belgium 

Claudia S. Miller, M.D., M.S., Principal Reviewer Jerrold M. Ward, D.V.M., Ph.D., Principal Reviewer 

University of Texas Health Sciences Center National Cancer Institute 

San Antonio, TX Frederick, MD 

Janardan K. Reddy, M.D.* 

Department of Pathology 

Northwestern University Medical School 

Chicago, IL 

* Did not attend 
_________ 

Triethanolamine, NTP TR 449 13 

October 30, 1998 

Gary P. Carlson, Ph.D., Chairperson 

School of Health Sciences 

Purdue University 

West Lafayette, IN 

A. John Bailer, Ph.D. 

Department of Mathematics and Statistics 

Miami University 

Oxford, OH 

Steven A. Belinsky, Ph.D., Principal Reviewer 

Inhalation Toxicology Research Institute 

Kirkland Air Force Base 

Albuquerque, NM 

James S. Bus, Ph.D. 

Health and Environmental Sciences 

Dow Chemical Company 

Midland, MI 

Linda A. Chatman, D.V.M.* 

Pfizer, Inc. 

Groton, CT 

John M. Cullen, Ph.D., V.M.D. 

Department of Microbiology, Parasitology, and Pathology 

College of Veterinary Medicine 

North Carolina State University 

Raleigh, NC 

* Did not attend 

Susan M. Fischer, Ph.D.*, Principal Reviewer 

M.D. Anderson Cancer Center 

The University of Texas 

Smithville, TX 

Thomas L. Goldsworthy, Ph.D.* 

Integrated Laboratory Systems 

Research Triangle Park, NC 

Stephen S. Hecht, Ph.D., Principal Reviewer 

University of Minnesota Cancer Centers 

Minneapolis, MN 

Michele Medinsky, Ph.D. 

Chemical Industry Institute of Toxicology 

Research Triangle Park, NC 

Jose Russo, M.D.* 

Fox Chase Cancer Center 

Philadelphia, PA 
14 Triethanolamine, NTP TR 449 

SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS 

November 29, 1994: The draft Technical Report on 

the toxicology and carcinogenesis studies of triethanolamine first received public review by the 

National Toxicology Program’s Board of Scientific 

Counselors’ Technical Reports Review Subcommittee 

on 29 November 1994. The review meeting was held 

at the National Institute of Environmental Health 

Sciences, Research Triangle Park, NC. 

Dr. J.R. Bucher, NIEHS, introduced the toxicology 

and carcinogenesis studies of triethanolamine by 

discussing the uses of the chemical, describing the 

experimental design, reporting on survival and body 

weight effects, and commenting on possible chemicalrelated neoplasms and nonneoplastic lesions in rats 

and mice. The proposed conclusions were equivocal 

evidence of carcinogenic activity in male F344/N rats 

and male B6C3F mice, no evidence of carcinogenic 1 

activity in female F344/N rats, and some evidence of 

carcinogenic activity in female B6C3F mice. 1 

Dr. Bucher noted that Helicobacter hepaticus had first 

been described in the literature in 1994 by a member 

of the Subcommittee, Dr. Ward. He said the infection 

is associated with a chronic active hepatitis in many 

strains of mice and appears to affect males more than 

females. It causes a focal necrosis and inflammation 

progressing to hepatocytomegaly, oval cell hyperplasia, and cholangitis. In male mice this appears to 

lead to an increase in the incidence of liver 

neoplasms. Dr. J.R. Hailey, NIEHS, described the 

histopathologic appearance of livers from infected 

animals and the stain used to identify the bacteria. He 

reported that infection with H. hepaticus was suspected or confirmed in four other NTP studies in mice 

and that the impact on study interpretation was being 

assessed. Dr. G.N. Rao, NIEHS, said the presence of 

the bacteria has been reported in a number of laboratories and animal production facilities around the 

country. However, he stated that the NTP management procedure in production colonies of terminating 

and restarting colonies every 2 to 3 years made the 

problem self-limiting in NTP laboratories and believed 

that the colonies have been free of H. hepaticus since 

1991 or before. 

Dr. Ward, a principal reviewer, agreed with the 

proposed conclusions. He suggested that because of 

the infection, further information on sources of mice 

should be made clear in the Technical Report and 

would help to indicate that the infection is limited to 

certain suppliers of mice. Dr. Ward thought the 

rationale for using the dermal route was adequate but 

said the report should indicate that the skin application 

study was approximately equivalent to a low-dose oral 

study because of significant skin absorption. 

Dr. Bucher said there was not sufficient dose-response 

information to make quantitative comparison of oral 

versus skin absorption of the chemical. 

Dr. Miller, the second principal reviewer, agreed with 

the proposed conclusions, although she said more 

clarification was needed on why the level of evidence 

for carcinogenicity in female mice was some evidence 

rather than clear evidence. Because triethanolamine 

is used extensively in more than 2,500 cosmetics, she 

said the chemical may also contact mucous membranes, especially around the eyes and mouth, and 

suggested consideration be given to oral/mucous 

membrane testing. Dr. Bucher said that Japanese 

studies using 1% and 2% drinking water solutions did 

not give any strong indication of carcinogenicity. 

Dr. Miller wondered how the doses used would 

compare with doses humans might encounter, e.g., in 

a 5% cream applied daily to the face. Dr. Bucher 

estimated from a personal communication that such a 

human dose would not differ greatly from the dose in 

rats. 

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

attend the meeting but had submitted her review, 

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

Dr. Karol agreed with the proposed conclusions. She 

said that justification was needed for selection of 

acetone as the solvent for the studies. Dr. Karol also 

said that in view of reports that the chemical has 

sensitization potential, the skin lesions and “active 

inflammation” should be discussed in connection with 

possible contact dermatitis. Dr. Bucher agreed that a 

case could be made for contact dermatitis being 

associated, but in looking at the lesions histologically, 

there was little evidence that the inflammatory process 

had an allergic component. There were no perivascular lymphoid infiltrates or edematous reactions 

with eosinophilic infiltrates which might be expected 

if contact dermatitis were present. 
 

Triethanolamine, NTP TR 449 15 

There was further discussion about the possible impact 

of H. hepaticus in female mice and whether or not 

infection could be a confounder in the etiology of the 

liver lesions as in male mice. Dr. Bucher said the 

diagnosis of oval cell hyperplasia or karyomegaly was 

observed in only one mid-dose female mouse, and 

although an exhaustive evaluation was not performed, 

the bacteria were not believed to be a factor in female 

mice. 

Dr. Miller moved that the Technical Report on 

triethanolamine be accepted with the revisions discussed and with the conclusions as written: for male 

rats and mice, equivocal evidence of carcinogenic 

activity, for female rats, no evidence of carcinogenic 

activity, and for female mice, some evidence of 

carcinogenic activity. Dr. Russo seconded the 

motion, which was accepted unanimously with seven 

votes. 

Subsequent Investigations: Subsequent to the 

29 November 1994 public review, the NTP carried 

out an extensive investigation into the extent of 

evidence of H. hepaticus infection in NTP studies as 

well as the apparent influence of this infection on 

neoplasm rates in all organs in male and female mice 

(see Appendix L). B6C3F mice from 12 NTP 2-year 1 

carcinogenesis studies were found to be infected with 

H. hepaticus. Many of the male mice from nine of 

these studies had an associated hepatitis, and these 

nine studies were considered “affected” studies. The 

incidences of neoplasms (both hepatocellular neoplasms and hemangiosarcoma) of the liver, but not of 

other organs, were found to be increased in control 

male mice in the affected studies compared to the 

incidences in control males from 26 unaffected 

contemporary studies. Other observations further 

differentiated control male mice from affected and 

unaffected studies. H-ras codon 61 CAA-to-AAA 

mutations were less common in liver neoplasms in 

males from affected studies compared to historical and 

unaffected study controls. In addition, increases in 

cell proliferation rates and apoptosis were observed in 

the livers of male mice with H. hepaticus-associated 

hepatitis. These data support the hypothesis that the 

increased incidence of liver neoplasms is associated 

with H. hepaticus and that hepatitis may be important 

in the pathogenesis. Therefore, it was concluded that 

the interpretation of carcinogenic effects in the liver of 

B6C3F1 mice may be confounded if H. hepaticusassociated hepatitis is present, and that studies in 

which liver neoplasia was the only effect in male mice 

with evidence of H. hepaticus-associated hepatitis 

should be considered inadequate for evaluation of 

carcinogenesis. 

This evaluation did not reveal a significant influence 

of H. hepaticus infection on the occurrence of any 

neoplasm type in female mice. Nonetheless, it was 

decided that to repeat the study with uninfected mice 

was the only way to rigorously rule out an effect of 

H. hepaticus on the triethanolamine-induced incidence 

of hepatocellular neoplasms in female mice. Therefore, in 1998 a second evaluation of triethanolamine 

was begun using the same study design and same 

chemical in the same laboratory as the study reported 

in this Technical Report. This study is being performed with male and female B6C3F mice. 1 

October 30, 1998: The proposal to change the level 

of evidence for the male mouse study from equivocal 

evidence of carcinogenic activity to inadequate study 

was brought before the NTP’s Board of Scientific 

Counselors’ Technical Reports Review Subcommittee 

on 30 October 1998. Dr. Bucher briefly reviewed the 

study findings and outlined the NTP’s position concerning the interpretation of studies in which there 

was evidence of H. hepaticus infection. This position 

and the lines of evidence which led to its adoption 

were presented to the Subcommittee at their meeting 

on 11 and 12 December 1996 by Dr. Hailey. 

Dr. Belinsky, a principal reviewer, began his comments with several suggestions concerning the discussion of the kidney neoplasm findings in male rats and 

then turned to concerns regarding the H. hepaticus 

issue. He said that while he understood the NTP’s 

position, he was uncomfortable concluding that the 

evidence was sufficient to rule out a possible influence 

of H. hepaticus infection on the liver neoplasm 

response in female mice. He suggested that the study 

may not, in fact, have been totally adequate and that 

the conclusion of some evidence of carcinogenic 

activity in female mice be amended to indicate that 

these animals were infected with H. hepaticus. 

Dr. Hecht, the second principal reviewer, also said 

that he had not fully understood that female mice also 
16 Triethanolamine, NTP TR 449 

were infected with the organism in studies where male Dr. Fischer, the third principal reviewer, was unable 

mice were infected and manifested microscopic to attend the meeting, but Dr. Hart read her written 

changes in the liver from the infection. Dr. Hecht comments. She agreed with the proposal to designate 

suggested that the conclusion for female mice should the male mouse study as inadequate and questioned 

be reconsidered. Both he and Dr. Belinsky indicated whether the doses administered to the female mice 

that their proposal to reconsider the conclusion was were high enough to adequately reveal possible 

influenced by the fact that the female mouse study was neoplastic effects in the kidney. 

being repeated. Dr. Hecht also asked that additional 

information be added to the report concerning the The panel then returned to the discussion of the 

possibility that N-nitrosodiethanolamine, a potential adequacy of the female mouse study. After listening 

contaminant, might have influenced the results. to public comment on this issue, Dr. Carlson called 

for a motion. Dr. Belinsky moved that the conclusions of equivocal evidence of carcinogenic activity in 

Dr. Bucher responded that the NTP had had technical male rats, no evidence of carcinogenic activity in 

difficulty with the assessment of possible N-nitroso- female rats, and inadequate study in male mice, as 

diethanolamine contamination in the triethanolamine proposed by the NTP, be accepted by the panel and 

and diethanolamine stocks used in the NTP studies. that the study in female mice be judged inadequate. 

He pointed out that the potential carcinogenicity of Dr. Hecht seconded the motion, which was accepted 

N-nitrosodiethanolamine in mice has not been estab- by three yes votes (Drs. Belinsky, Hecht, and 

lished, so it was difficult to predict the impact of this Medinsky) to two no votes (Drs. Bailer and Cullen), 

contaminant. with one abstention (Dr. Bus). 
 

 

17 

INTRODUCTION 

HOCH2CH2	 N CH2CH2OH 

CH2CH2OH 

TRIETHANOLAMINE 

CAS No. 102-71-6 

Chemical Formula: C 6 15 3 H NO Molecular Weight: 149.19

Synonyms:	 Nitrilo-2,2N,2NN-triethanol; 2,2N,2NN-nitrilotriethanol; 2,2N,2NN-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; 

triethylolamine; tri(hydroxyethyl)amine; 2,2N,2NN-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; 

tris(2-hydroxyethyl)amine; triethylolamine; trolamine 

Trade Names:	 Daltogen; Sterolamide; Thiofaco T-35 

CHEMICAL 

AND PHYSICAL PROPERTIES 

Triethanolamine, with a melting point of 21.6E C, is 

a colorless to pale yellow, viscous, hygroscopic liquid 

with a slight ammonia-like odor. It has a boiling 

point of 335.4E C at 760 mm, a specific gravity of 

1.124 (20/4E C), and a vapor pressure less than 

0.01 mm at 20E C. Triethanolamine is miscible with 

water, methanol, or acetone and is slightly soluble in 

ether or benzene; it readily forms salts with organic 

and inorganic acids and turns brown on exposure to 

air and light (Remington’s Pharmaceutical Sciences, 

1980; CIR, 1983; Merck Index, 1989). It is combustible when heated and may decompose to oxides of 

nitrogen (Lewis, 1990). 

PRODUCTION, USE, 

AND HUMAN EXPOSURE 

Triethanolamine is commercially produced, together 

with mono- and diethanolamine, by aminating ethylene oxide with ammonia; triethanolamine is separated 

from the mixture by distillation (Kirk-Othmer, 1978). 

The reported annual production of triethanolamine in 

the United States during 1991 was 86 million kilograms (USITC, 1993). 

Ethanolamines are chemically bifunctional and 

undergo reactions typical of both amines and alcohols 

(CIR, 1983). Industrially significant reactions of the 

ethanolamines include the reaction with long-chain 

fatty acids to form neutral ethanolamine soaps and 

“sweetening” of natural gas through reactions with 

sulfuric acid, carbon dioxide, or other acid constituents to form water-soluble salts (Kirk-Othmer, 1978; 

Melnick and Tomaszewski, 1990). Ethanolamines 

can also act as antioxidants in the autoxidation of 

animal and vegetable fats (CIR, 1983). Triethanolamine, in combination with fatty acids, is used extensively in cosmetic formulations including emulsifiers, 

thickeners, wetting agents, detergents, and alkalizing 

agents. In 1981, triethanolamine was reported to be 

present in 2,757 cosmetic products at concentrations 

of up to 5%; these products included creams, lotions, 

skin cleansers, shampoos, hair care and coloring 

agents, permanent wave lotions, deodorants, fragrances, makeup, nail polish and polish remover, and 

cuticle softeners and removers (CIR, 1983). 
18 Triethanolamine, NTP TR 449 

Triethanolamine is a chemical intermediate for both 

anionic and nonionic surfactants. It is widely used in 

the manufacture of emulsifiers and dispersing agents 

for household detergents and polishes; textiles (lubricants, dyes, and antistatic agents), agricultural chemicals (herbicides), mineral and vegetable oils, paraffin 

and waxes, pharmaceutical ointments, and petroleum 

demulsifiers. Triethanolamine is used in the rubber 

industry as a vulcanization accelerator, in the tanning 

of hides as a humectant and softening agent, and in 

the manufacture of synthetic resins, plasticizers, 

adhesives, and sealants. It is a solvent for casein, 

shellac, and dyes. It also increases the penetration of 

organic liquids into wood and paper. The metalchelating properties of triethanolamine are used in 

many industrial applications such as corrosion inhibition, electroplating, metal cleaning and rust removal, 

and the preparation of photographic chemicals and 

soldering fluxes. The fatty acid salts of triethanolamine are used extensively in lubricating and metalworking fluids (cutting oils). Addition of small 

amounts of triethanolamine or its salts reduces particle 

agglomeration during the grinding of cement and 

reduces set time and increases the early strength of 

concrete (Kirk-Othmer, 1978; Hawley’s Condensed 

Chemical Dictionary, 1987; Merck Index, 1989; 

Melnick and Tomaszewski, 1990). Articles intended 

for use in the production, processing, and packaging 

of food may contain triethanolamine (21 CFR, 

Parts 175, 176, 177, and 178). 

The most widespread human exposure to ethanolamines occurs through the use of cosmetics (CIR, 

1983). Dermal exposure also results from contact 

with household detergents, other surfactants containing this compound, pharmaceutical ointments, 

cutting fluids, adhesives, and sealants. Although the 

Pollutant Strategies Branch of the United States 

Environmental Protection Agency (USEPA) identified 

triethanolamine as an air pollutant (Melnick and 

Tomaszewski, 1990), significant industrial exposure 

to triethanolamine by inhalation of adhesives, sealants, 

or cutting fluids appears unlikely due to its low vapor 

pressure; the chief risk would be from direct local 

contact of the skin or eyes with the undiluted, 

unneutralized liquid (Patty’s, 1981). The National 

Occupational Exposure Survey for 1981 to 1983 has 

estimated that more than 1.7 million workers were 

potentially exposed to triethanolamine in the United 

States (NIOSH, 1990). The threshold limit value for 

triethanolamine, adopted in 1993, was based primarily 

3 on skin and eye irritation and is 5 mg/m (ACGIH, 

1994). 

The Cosmetic Ingredient Review (CIR) Expert Panel 

(1983) concluded that the use of mono-, di-, and 

triethanolamine is safe in cosmetic formulations 

designed for brief, discontinuous use followed by 

thorough rinsing of the skin. They further concluded 

that the concentration of ethanolamine should not 

exceed 5% in cosmetic products intended for 

prolonged contact with the skin. In the presence of 

nitrite, oxides of nitrogen, or 2-bromo-2-nitropropane1,3-diol, an antimicrobial agent used in cosmetics, diand triethanolamine may be readily nitrosated to 

N-nitrosodiethanolamine (CIR, 1983), which is a 

known liver, kidney, and nasal carcinogen in laboratory animals (Hoffmann et al., 1982; Preussmann 

et al., 1982; Lijinsky and Kovatch, 1985). N-Nitrosodiethanolamine has been identified in a variety of 

cosmetic products at concentrations up to 48,000 ppb 

(Fan et al., 1977a); the CIR panel concluded, therefore, that di- and triethanolamines should not be used 

in cosmetic products that contain N-nitrosating agents 

as intentional ingredients or potential contaminants 

(CIR, 1983). 

Fan et al. (1977b) reported that before 1977, the 

majority of synthetic cutting (metalworking) fluids 

used in the United States contained up to 45% triethanolamine and 18% sodium nitrite, with N-nitrosodiethanolamine present as an impurity at concentrations of up to 3%. Concern about potential human 

health risks posed by exposure to nitrosamines in 

metalworking fluids led the USEPA to issue a regulation prohibiting the use of nitrosating agents in any 

metalworking fluid containing a triethanolamine salt 

of a tricarboxylic acid complex (40 CFR, § 747.200). 

Furthermore, questions about the safety of hair color 

products containing di- and triethanolamine have been 

raised as a result of studies showing mutagenic 

activity in 89% (150/169) of oxidative-type hair dye 

formulations tested in Salmonella typhimurium (Ames 

et al., 1975). 

ENVIRONMENTAL IMPACT 

Triethanolamine may be released into the environment 

in emissions or effluents from manufacturing or industrial sites, from the disposal of consumer products 

containing triethanolamine, from the application of 

agricultural chemicals in which triethanolamine is 
 

Triethanolamine, NTP TR 449 19 

used as a dispersing agent, or during use of an aquatic 

herbicide containing a copper-triethanolamine complex (Hawley’s Condensed Chemical Dictionary, 

1987). Residual triethanolamine in soil may also 

leach into the groundwater. The half-life of 

triethanolamine in soil and water ranges from days to 

weeks; it biodegrades fairly rapidly following acclimation (HSDB, 1994). Ethanolamines have been shown 

to be selectively toxic to green algae (Scenedesmus 

quadricauda) (Bringmann and Kühn, 1980). In the 

atmosphere, triethanolamine primarily exists in the 

vapor phase; the vapor, which has a half-life of 

4 hours, is expected to react with photochemically 

generated hydroxyl radicals in the atmosphere. The 

complete solubility of triethanolamine in water suggests that this compound may also be removed from 

the atmosphere by precipitation. Volatilization of 

triethanolamine from water and moist soil surfaces has 

been estimated to be negligible (Eisenreich et al., 

1981; Atkinson, 1987; HSDB, 1994). 

ABSORPTION, DISTRIBUTION, 

METABOLISM, AND EXCRETION 

Experimental Animals 

Triethanolamine may be absorbed through the skin 

and in the gastrointestinal tract. In a comparative 

pharmacokinetics and metabolism study, dermal 14 absorption of [ C]-triethanolamine was slower and

less extensive in F344 rats than in C3H/HeJ mice, 

although the tissue distribution of radioactivity was 

similar (cited by Melnick and Tomaszewski, 1990; no 

further details were given). In mice that received a 

single 1,000 mg/kg dermal application, approximately 

60% of the radioactivity was recovered from the urine 

and 20% was recovered from the feces 48 hours after 

dosing; less than 10% was detected in the skin at the 

site of application. More than 95% of the radioactivity recovered in the urine was identified as the 

parent compound, indicating that triethanolamine does 

not undergo extensive biotransformation in mice. The 14 serum half-life of [ C]-triethanolamine in mice was

approximately 9.5 hours after either a 1 mg/kg 

intravenous injection or a 1,000 mg/kg dermal 

application (cited by Melnick and Tomaszewski, 

1990). In rats, a single oral dose (2 to 3 mg/kg) of 

[ C]-triethanolamine was rapidly absorbed and 

excreted mainly in the urine as unchanged parent 

compound (Kohri et al., 1982). Twenty-four hours 

after dosing, 53% of the radioactivity was recovered 

in the urine and 20% was recovered in the feces. A 

small amount of a metabolite, triethanolamine glucuronide, was also detected. 

Humans 

No information on the pharmacokinetics and metabolism of triethanolamine in humans was found in the 

literature. 

TOXICITY 

Experimental Animals 

The toxicity of triethanolamine was the subject of a 

review by Knaak et al. (1997). The acute and chronic 

toxicity of triethanolamine is generally considered 

to be low (Kindsvatter, 1940; Melnick and 

Tomaszewski, 1990). Triethanolamine toxicity has 

been demonstrated in animals following administration 

by inhalation, injection, oral routes (gavage, feed, and 

drinking water), and dermal application. In a study 

comparing the relative toxicities of the ethanolamines 

(Patty’s, 1981), symptoms in dogs following intravenous injection included increased blood pressure, 

diuresis, salivation, and pupillary dilation; larger 

doses caused sedation, coma, and death following a 

decrease in blood pressure and cardiac collapse. 

Symptoms were most severe with monoethanolamine 

and least severe with triethanolamine. 

The acute oral LD50 of triethanolamine was reported 

to be 8 to 9 g/kg in albino rats and 8 g/kg in guinea 

pigs (Kindsvatter, 1940; Smyth et al., 1951). Gross 

lesions in the animals that died were confined to the 

gastrointestinal tract and included gastric dilatation, 

congestion, and focal hemorrhage in the stomach and 

dilatation of intestinal blood vessels. Kindsvatter 

(1940) suggested that the acute toxicity of triethanolamine was related to its alkalinity, based on the 

survival of one guinea pig fed 10 g/kg neutralized 

with hydrochloric acid; this dose exceeds the oral 

LD50 (8 g/kg) of triethanolamine when administered as 

the free base. The acute oral LD50 values for 

triethanolamine ranged from 4.2 to 11.3 g/kg in rats 

and 5.4 to 7.8 g/kg in mice (BIBRA, 1990). 14 
 

20 Triethanolamine, NTP TR 449 

In a 90-day study in Carworth-Wistar rats administered triethanolamine in feed at daily doses of 5 to 

2,610 mg/kg, the no-observed-effect level (NOEL) 

was 80 mg/kg. Decreased body weight gains were 

observed in rats administered 1,270 mg/kg or above. 

Microscopic lesions of the kidney, liver, lung, or 

small intestine and a low incidence of mortality 

occurred at a concentration of 730 mg/kg or above. 

Liver and kidney weight effects occurred at concentrations as low as 170 mg/kg (Smyth et al., 1951). In 

other studies (Kindsvatter, 1940), doses ranging from 

200 to 1,600 mg/kg were administered to albino rats 

daily in feed for up to 17 weeks or to guinea pigs 

5 days per week by gavage for up to 120 doses. 

Slight, reversible changes were present in the kidney 

(cloudy swelling of the convoluted tubules and 

Henle’s loop) at all doses and in the liver (hepatocellular cloudy swelling and fatty change) at doses of 

400 mg/kg and higher. Although liver toxicity was 

not apparent in a more recent 2-year study with 

Fischer 344/DuCrj rats administered 1% or 2% 

triethanolamine in drinking water ad libitum, the 

occurrence of dose-related kidney toxicity (acceleration of chronic nephropathy, mineralization of the 

renal papilla, nodular hyperplasia of the pelvic 

mucosa, and pyelonephritis with or without papillary 

necrosis) indicated that even the 1% dose level was 

not well tolerated by rats (Maekawa et al., 1986); 

effects were more severe in females than in males. 

Due to increased mortality and decreased body weight 

gains in females that received 2% triethanolamine, 

doses administered to females were halved from 

week 69 to the end of the study. In contrast, B6C3F1 

mice tolerated the same concentrations of triethanolamine in drinking water for 82 weeks without adverse 

effects on survival or organ weights and with no 

increased incidences of histopathologic lesions 

(Konishi et al., 1992); body weights of mice receiving 

2% were slightly less than those of the controls, 

however. 

The dermal toxicity of triethanolamine has been 

evaluated in mice, rats, rabbits, and guinea pigs under 

various experimental conditions. Guinea pigs dosed 

with 8 g/kg of undiluted triethanolamine daily by 

dermal application, 5 days per week, died after 2 to 

17 applications (Kindsvatter, 1940). Histopathologic 

changes included generalized congestion of the lungs, 

kidneys, liver, adrenal glands, and peritoneum; 

extravasation of fibrin into the alveoli of the lungs; 

cloudy swelling of the kidneys and liver; fatty change 

in the liver; and cellular infiltration and inflammation 

at the site of application, indicating that dermal 

absorption of triethanolamine is capable of producing 

systemic toxicity (Kindsvatter, 1940; Melnick and 

Tomaszewski, 1990). 

The acute dermal toxicity of a single 2 g/kg application of undiluted triethanolamine was evaluated over 

a 24-hour period with a closed-patch test in rabbits 

(CIR, 1983). Triethanolamine was applied to six 

rabbits with intact skin and six with abraded skin. 

Mild to moderate erythema without edema occurred 

on both intact and abraded skin and resolved within 

10 days. In another dermal study, a single application 

of 560 mg/kg to rabbits resulted in erythema and 

slight edema at the application site. Dermal applications of 2 mL/kg per day of a 2.5% aqueous solution 

of triethanolamine for 28 days produced only mild 

dermatitis in New Zealand rabbits (CIR, 1983). 

Triethanolamine (1% to 100%), applied dermally to 

male C3H mice 5 days per week for 2 weeks in 50 μL 

acetone, caused mild epidermal hyperplasia at the site 

of application with dosage solutions as low as 25% 

(cited by Melnick and Tomaszewski, 1990). In a 

follow-up study in which male and female C3H mice 

received dermal applications of 0%, 10%, 33%, or 

100% triethanolamine in 50 μL acetone three times 

per week for 13 weeks, mild hyperplasia at the 

application site was observed in all dosed groups 

(Melnick and Tomaszewski, 1990; DePass et al., 

1995). 

In a combined dermal and drinking water study, 

CBA × C Bl 57 6 mice received dermal applications of 

a 6.5% or 13% aqueous solution of triethanolamine, 

1 hour per day, 5 days per week for 6 months, with or 

without additional oral administration of 1.4 mg/L in 

the drinking water (Kostrodymova et al., 1976; CIR, 

1983). No toxic effects were present in mice receiving the 6.5% solution. However, functional changes 

in the liver and central nervous system occurred 

1 month after treatment began with the 13% solution, 

with or without additional triethanolamine in the 

drinking water, indicating that systemic toxicity had 

resulted from percutaneous absorption. Clinical 

pathology changes at 3 months included elevated 

lymphocyte and segmented neutrophil counts. 
Triethanolamine, NTP TR 449 21 

The eye irritation potential of triethanolamine or 

cosmetics containing the chemical has been evaluated 

in rabbits and rhesus monkeys; these studies have 

been reviewed by the CIR Expert Panel (1983). In a 

study with albino rabbits, moderate irritation occurred 

when 0.1 mL triethanolamine was instilled (Griffith 

et al., 1980); application of 0.01 mL caused only 

negligible damage. Application of 0.02 mL undiluted 

triethanolamine to the cornea of the rabbit eye with 

the lids retracted caused necrosis of 63% to 87% of 

the cornea; this reaction was graded as 5 on a scale of 

1 to 10 (Carpenter and Smyth, 1946). Application of 

a 0.023 M aqueous solution of triethanolamine to 

rabbit eyes, following removal of the corneal epithelium to facilitate penetration, caused essentially no 

injuries when the solution was adjusted to pH 10; 

application of the same solution adjusted to pH 11 

caused moderate corneal swelling and hyperemia of 

the iris and conjunctiva that reversed within 1 week 

(Grant, 1974). 

Skin and eye irritation in rabbits were evaluated in a 

study comparing the effects of ethanolamines (mono-, 

di-, and triethanolamine) and three mixtures 

containing 69%, 74%, or 87% triethanolamine plus 

varying proportions of other ethanolamines 

(Dutertre-Catella et al., 1982). Eye irritation was 

rated maximum for monoethanolamine, severe for 

diethanolamine, mild for the 69% and 74% mixtures, 

and minimum for triethanolamine and the 87% mixture. Skin irritation was rated severe for monoethanolamine, moderate for diethanolamine and the 

69% mixture, and slight for triethanolamine and the 

74% and 87% mixtures. Although skin sensitization 

occurs in humans, no skin sensitizing responses or 

delayed hypersensitivity reactions occurred in studies 

of guinea pigs treated dermally with 5% to 100% 

triethanolamine (one application per week for 

3 weeks; up to 6 hours per application) and subsequently challenged with 25% to 100% triethanolamine 

after 1 to 3 weeks (CIR, 1983). 

No clinical evidence of systemic toxicity or histopathology was observed when hair dye preparations 

containing 0.1% to 1.5% triethanolamine were 

applied to the clipped backs and sides of New Zealand 

white rabbits at doses of 1 mg/kg twice weekly for 

13 weeks, with or without prior abrasion of the skin 

(Burnett et al., 1976). However, in a similar 13-week 

rabbit study in which cosmetic formulations 

containing 14% triethanolamine stearate were applied 

to the clipped back five times per week in doses of 1 

or 3 mg/kg, mild to moderate skin irritation occurred; 

the irritation, which cleared within 72 hours, was 

followed by moderate to heavy scaling (CIR, 1983). 

Signs of systemic toxicity included lower body weight 

and significantly greater kidney weights at the 

3 mg/kg dose. 

Humans 

There is no appreciable hazard to workers from 

normal industrial use of ethanolamines (Kirk-Othmer, 

1978). However, these compounds may cause serious 

toxic effects when ingested, as well as causing local 

injury to the mouth, throat, and digestive tract. At 

ordinary temperatures, triethanolamine presents no 

hazard from vapor inhalation, but excessive vapor 

concentrations may occur when triethanolamine is 

heated. These vapors are irritating to the eyes and 

nose. Triethanolamine is a skin and eye irritant; 

however, it is less irritating to the skin and mucous 

membranes than most amines. 

In a series of patch tests on healthy volunteers, the 

highest nonirritant concentration of triethanolamine, 

applied in petrolatum for 48 hours, was determined to 

be 50% (Meneghini et al., 1971). In a different test, 

the irritancy potential of triethanolamine was designated as slight (5% concentration) or marked 

(10% concentration) when applied topically in ethanol 

within a chamber to the scarified forearm skin of 

volunteers once daily for 3 days; the threshold 

concentration for skin irritation was 100% on intact 

skin and 5% (in ethanol) on scarified skin (Frosch and 

Kligman, 1976). 

There have been no reports of industrial injuries from 

triethanolamine (Patty’s, 1981). However, Shrank 

(1985) reported that a lathe operator became sensitized to triethanolamine, which was an ingredient in a 

cutting oil, and 47 positive reactions to triethanolamine (10% in an aqueous solution) occurred in patch 

tests of 230 metal workers with occupational dermatitis (Alomar et al., 1985). In this study, 43% of all 

positive responses were to triethanolamine. Triethanolamine was also found to be the most frequent 

sensitizer in a study in which patients with suspected 

cosmetic- or medicine-related contact dermatoses were 

patch tested with common emulsifying agents (Tosti 

et al., 1990). It has been identified as a causative 

agent in patients with eczema or allergic contact 

dermatitis (Venediktova and Gudina, 1976; Angelini 
22 Triethanolamine, NTP TR 449 

et al., 1985; Jones and Kennedy, 1988) and in a 

curious case of intractable sneezing caused by exposure to a laundry detergent (Herman, 1983). 

In a study designed to evaluate allergic contact dermatitis to substances commonly found in pharmaceutical 

ointments, a 24-hour patch test with a 1% aqueous 

solution of triethanolamine in 773 patients gave 

positive reactions in four (0.5%) of these patients 

(Iden and Schroeter, 1977). Positive reactions also 

occurred in 2% of 100 subjects in another study with 

a 48-hour patch test using 5% triethanolamine in 

petrolatum (Fisher et al., 1971; Iden and Schroeter, 

1977). In clinical tests with triethanolamine and 

cosmetic products containing triethanolamine, mild 

skin irritation occurred at concentrations above 5%, 

but there was little skin sensitization. In addition, 

there was no evidence of phototoxicity or photosensitization reactions with products containing up to 20% 

triethanolamine (CIR, 1983). However, based on 

positive skin sensitivity reactions (patch-test results) in 

1.6% of a patient population with eczematous dermatitis who were tested with 5% triethanolamine in 

petrolatum, Meneghini et al. (1971) recommended 

restricting the use of triethanolamine in cosmetics and 

pharmaceutical preparations. 

Triethanolamine has been given a toxic hazard rating 

of slightly toxic, with a probable oral lethal dose in 

humans of 5 to 15 g/kg, which corresponds to 

between 1 pint and 1 quart for a 70 kg (150 lb) person 

(Gosselin et al., 1984). Dreisbach (1980) estimated 

the lethal dose in humans to be 50 g. Assuming 

complete dermal absorption, a human weighing 50 kg 

would receive an approximate dose of 10 mg/kg 

through the use of 10 g of cosmetics containing 

5% triethanolamine. 

REPRODUCTIVE 

AND DEVELOPMENTAL TOXICITY 

Experimental Animals 

Triethanolamine has been shown to stimulate neuritogenesis in cultured chick embryo ganglia 

(Sisken et al., 1985). However, it was embryotoxic 

when injected into 3-day chick embryos; the LD50 

value (the dose causing early death in 50% of the 

embryos) was 3 μmole (447 μg) per egg. Eleven days 

after the triethanolamine injection, there was no 

significant increase in the incidence of chick embryo 

malformations (Korhonen et al., 1983; cited by 

Melnick and Tomaszewski, 1990). 

In an in vivo assay for potential adverse reproductive 

effects in mice, di- and triethanolamine, administered 

daily by gavage on gestation days 6 through 15 in 

doses of 1,125 mg/kg per day, had no effect on 

maternal mortality, the number of viable litters, litter 

size, or survival and body weight of the pups. However, similar administration of 850 mg/kg per day of 

monoethanolamine resulted in 16% mortality in dams 

and fewer viable litters (NIOSH, 1987). A preliminary developmental toxicity test in mice, used in 

conjunction with a scoring system of indices of 

developmental toxicity, resulted in a classification of 

low priority for further study of monoethanolamine, 

intermediate priority or “no decision” for triethanolamine, and high priority for diethanolamine (York 

et al., 1988). 

In mating trial studies in male and female Fisher 344 

rats, 0.5 g/kg of triethanolamine in acetone, applied 

dermally to the interscapular area of the clipped back 

in an approximate volume of 1.8 mL/kg daily for 

10 weeks prior to mating, during breeding, and 

through gestation and lactation for females, had no 

effect on mating, fertility, or offspring growth and 

survival. In similar studies with Swiss (CD-1®) mice 

administered daily applications of 2 g/kg in an 

approximate volume of 3.6 mL/kg, no chemicalrelated effects occurred other than ruffled fur in 

females and irritation at the application site of males 

and females (Battelle, 1988a,b). 

No embryotoxic or teratogenic effects were produced 

by topical administration of semipermanent hair dye 

preparations (2 mL/kg) containing 0.1% to 1.5% 

triethanolamine to the shaved backs of pregnant 

Charles River CD rats on gestation days 1, 4, 7, 10, 

13, 16, and 19 (Burnett et al., 1976). 

Humans 

No information related to the reproductive or developmental toxicity of triethanolamine in humans was 

found in the literature. 
Triethanolamine, NTP TR 449 23 

CARCINOGENICITY 

Experimental Animals 

Triethanolamine was not carcinogenic in Fischer 

F344/DuCrj rats when administered ad libitum in 

drinking water at dose levels of 1% or 2%, but was 

nephrotoxic, especially in females (Maekawa et al., 

1986). Due to increased mortality associated with 

nephrotoxicity in females and decreased body weight 

gain in females in the 2% group, the doses of triethanolamine administered to the female groups were 

reduced by half after week 68 of the study. There 

were no statistically significant increased incidences of 

primary neoplasms in exposed groups compared to the 

controls when analyzed by the chi-square test. 

Because of nephrotoxicity, which appeared to have an 

adverse effect on the life expectancy of exposed 

animals, an age-adjusted statistical analysis was 

performed. The results showed a positive trend 

(P<0.05) in the incidence of hepatic neoplasms in 

males and uterine endometrial sarcomas and renal 

tubule adenomas in females. However, the incidence 

of these neoplasms in the control groups were lower 

than those in historical controls. In a similar study, 

triethanolamine had no carcinogenic activity in 

B6C3F mice when administered in drinking water at 1 

a concentration of 1% or 2% for 82 weeks (Konishi 

et al., 1992). Triethanolamine was not carcinogenic 

in male CBA × C Bl 57 6 mice when applied dermally 

for 14 to 18 months (Kostrodymova et al., 1976; CIR, 

1983). 

Incidences of malignant lymphoma, particularly 

thymic lymphoma, were increased in female, but not 

in male, ICR-JCL mice fed diets containing 0.03% or 

0.3% triethanolamine throughout their life span 

(Hoshino and Tanooka, 1978). The total incidences 

of malignant neoplasms in treated female mice were 

significantly greater than the control incidence 

(P<0.01); the incidences were 1/36 in controls, 

10/37 in the 0.03% group, and 13/36 in the 0.3% 

group. In another long-term study with ICR mice 

(Inai et al., 1979), the incidence of thymic lymphoma 

and nonthymic leukemia in control females at 

109 weeks was 5/15. This rate is 10 times greater 

than the rate observed in the female control group of 

the Hoshino and Tanooka study, and is similar to that 

reported for triethanolamine-treated females. 

Rust-proofing cutting fluid (containing low levels of 

triethanolamine, sodium nitrite, and polyethylene 

glycol) was carcinogenic in male Wistar rats (Wang 

et al., 1988). Groups of 40 rats were administered 

either undiluted cutting fluid or a threefold dilution of 

the fluid in water ad libitum for 2 years. Treated rats 

had increased incidences of neoplasms, particularly 

pancreatic carcinoma. The total incidences of malignant neoplasms were 0% in the control group, 10% in 

the group given diluted cutting fluid, and 27.5% in 

the group that received the undiluted fluid. In another 

group of rats exposed to undiluted cutting fluid 

supplemented with ascorbic acid, the total incidence 

of malignant neoplasms was 1/40 (2.5%). Based on 

the protective action of ascorbic acid in this study, 

Wang et al. (1988) concluded that the carcinogenic 

agent was a nitrosamine formed in vivo; the inhibitory 

action of ascorbic acid on the in vivo formation of 

nitroso compounds has been documented (Mirvish 

et al., 1975). Because the cutting fluid contained 

triethanolamine and sodium nitrite, the most probable 

nitrosamine formed during this study was N-nitrosodiethanolamine. However, the neoplasms induced in 

rats in previous experiments with N-nitrosodiethanolamine were primarily hepatocellular carcinomas, 

not pancreatic carcinomas (Lijinsky and Kovatch, 

1985). 

Humans 

In an epidemiology study conducted by Järvholm 

et al. (1986), the mortality and cancer morbidity in 

219 men exposed to cutting fluids for at least 5 years, 

including at least 1 year of exposure to a cutting fluid 

containing both amines and nitrites (primarily ethanolamines and sodium nitrite), were not significantly 

different from those of the general population. The 

authors concluded that although the results indicate 

that the use of cutting fluids in this industry did not 

lead to an increased risk of cancer, they were unable 

to exclude the possibility of an increased risk for 

cancer of a specific site because of the small sample 

population. 

GENETIC TOXICITY 

The limited information on the mutagenicity of 

triethanolamine indicates that the chemical is not 

genotoxic. Triethanolamine did not induce DNA 

damage in Escherichia coli (Inoue et al., 1982), 

mutations in Salmonella typhimurium (Inoue et al., 

1982; Dean et al., 1985; Mortelmans et al., 1986), or 

gene conversion in Saccharomyces cerevisiae (Dean 

et al., 1985). No induction of sister chromatid 
24 Triethanolamine, NTP TR 449 

exchanges occurred in cultured Chinese hamster ovary 

cells treated with triethanolamine (Galloway et al., 

1987), and results of tests for induction of chromosomal aberrations in cultured rat liver cells (Dean 

et al., 1985) and cultured Chinese hamster cells 

(Inoue et al., 1982; Galloway et al., 1987) were also 

negative. The S. typhimurium tests and the rodent cell 

cytogenetic tests were conducted with and without S9 

metabolic activation enzymes. No increase in the 

frequency of sex-linked recessive lethal mutations was 

observed in germ cells of male Drosophila 

melanogaster administered triethanolamine by feeding 

or injection (Yoon et al., 1985). 

STUDY RATIONALE 

The National Cancer Institute nominated triethanolamine for study because of its widespread use in 

cosmetics and other consumer products, its high 

potential for worker exposure due to its many industrial uses, and its potential for conversion to the 

carcinogen N-nitrosodiethanolamine. Concern was 

also prompted by the increased incidences of 

lymphoma and total malignant neoplasms in female 

ICR-JCL mice receiving 0.03% or 0.3% triethanolamine in the diet (Hoshino and Tanooka, 1978). 

Dermal application was chosen as the route of exposure to mimic the principal means of human exposure 

to triethanolamine and because considerable systemic 

exposure is achieved with this route. 
 

25 

MATERIALS AND METHODS 

PROCUREMENT 

AND CHARACTERIZATION 

OF TRIETHANOLAMINE 

Triethanolamine was obtained from Texaco Chemical 

Company (Division of Texaco, Inc., Bellaire, TX) in 

two lots (3B-1-84 and 7G-60). Lot 3B-1-84 was used 

during the 13-week studies and lot 7G-60 was used 

during the 2-year studies. Identity, purity, and 

stability analyses were conducted by the analytical 

chemistry laboratory, Midwest Research Institute 

(Kansas City, MO; Appendix I). Reports on analyses 

performed in support of the triethanolamine studies 

are on file at the National Institute of Environmental 

Health Sciences (NIEHS). 

The chemical, a clear, colorless, viscous liquid, was 

identified as triethanolamine by infrared, ultraviolet/ 

visible, and nuclear magnetic resonance spectroscopy. 

The purity of both lots was determined by elemental 

analysis, Karl Fischer water analysis, functional group 

titration, thin-layer chromatography, and gas chromatography. Elemental analyses for carbon, hydrogen, and nitrogen were in reasonable agreement with 

theoretical values for triethanolamine. Karl Fischer 

water analysis indicated less than 0.5% water in either 

lot. Functional group titrations were performed to 

identify the presence of primary and secondary 

amines, which were assumed to be monoethanolamine 

and diethanolamine. Functional group titration 

indicated less than 0.4% primary or secondary 

amines. Thin-layer chromatography indicated a major 

spot and only trace impurities. For lot 3B-1-84, gas 

chromatography by two systems indicated a major 

peak and one to three impurities with areas totaling no 

more than 1.4% of the major peak area. For 

lot 7G-60, gas chromatography by two systems 

indicated a major peak and no impurities or one 

impurity with an area of 0.16% relative to the major 

peak. The overall purities of lot 3B-1-84 and 

lot 7G-60 were determined to be approximately 98% 

and 99%, respectively. 

Lot 3B-1-84 was further characterized by National 

Formulary methods (USP XX/NF XV) of testing for 

trolamine, a mixture of alkanolamines consisting 

largely of triethanolamine, along with diethanolamine, 

and monoethanolamine. All results were consistent 

with NF XV requirements for trolamine. 

The concentrations of nonpolar nitrosamines 

(N-nitrosodimethylamine, N-nitrosomethylethylamine, 

N-nitrosodiethylamine, N-nitrosodi-n-propylamine, 

N-nitrosodi-n-butylamine, N-nitrosopiperidine, 

N-nitrosopyrrolidine, and N-nitrosomorpholine) and 

the polar nitrosamine N-nitrosodiethanolamine in 

lot 7G-60 were determined by Covance Laboratories, 

Inc. (Madison, WI). No nonpolar nitrosamines or 

N-nitrosodiethanolamine were present at concentrations greater than the limits of detection. 

Stability studies of the bulk chemical were performed 

by the analytical chemistry laboratory with gas chromatography. These studies indicated that triethanolamine was stable as a bulk chemical for 2 weeks when 

stored under a nitrogen headspace, protected from 

light, at temperatures up to 60E C. To ensure stability, the bulk chemical was stored at room temperature 

in amber glass containers under a nitrogen headspace 

during the 2-year studies. Stability was monitored by 

the study laboratory during the 13-week studies with 

gas chromatography and nonaqueous amine titration 

and during the 2-year studies with gas chromatography. No degradation of the bulk chemical was 

detected. 

PREPARATION AND ANALYSIS 

OF DOSE FORMULATIONS 

In the 13-week studies, the highest doses were applied 

neat. The lower concentrations in the 13-week studies 

and all dose formulations in the 2-year studies were 

prepared by mixing triethanolamine and acetone to 

give the required concentration (Table I1). Acetone 

was chosen as the vehicle for these studies because it 

is miscible with triethanolamine and because acetone 

rapidly evaporates. The dose formulations were 

prepared once every 2 weeks and were stored at 5E C 

in amber glass bottles under a nitrogen head space, 
26 Triethanolamine, NTP TR 449 

protected from light, for up to 3 weeks. Stability 

studies of the dermal dose formulations were performed by the analytical chemistry laboratory; stability was confirmed for at least 3 weeks at room temperature in sealed glass vials, under a nitrogen head 

space, in the dark and for at least 3 hours under 

animal room conditions (open to air and light). 

Periodic analyses of dose formulations of triethanolamine were conducted by the study laboratory and the 

analytical chemistry laboratory with gas chromatography. For the 13-week studies, the dose formulations were analyzed at the beginning, midpoint, and 

end of the studies; animal-room samples of the same 

dose formulations were also analyzed (Table I2). All 

dose formulations and animal-room samples were 

within 10% of the target concentrations. For the 

2-year studies, the dose formulations were analyzed at 

the beginning of the studies and every 6 to 10 weeks 

thereafter; animal-room samples were analyzed every 

22 to 26 weeks (Table I3). Of the doses analyzed, 

95% (59/62) of the formulations for rats and all of the 

formulations for mice were within 10% of the target 

concentrations. All animal-room samples for rats and 

97% (29/30) of the animal-room samples for mice 

were within 10% of the target concentrations. Results 

of periodic referee analyses performed by the analytical chemistry laboratory agreed with the results 

obtained by the study laboratory (Table I4). 

13-WEEK STUDIES 

The 13-week studies were conducted to evaluate the 

cumulative toxic effects of repeated exposure to 

triethanolamine and to determine the appropriate doses 

to be used in the 2-year studies. 

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

obtained from Simonsen Laboratories (Gilroy, CA). 

On receipt, the rats and mice were 4 weeks old. 

Animals were quarantined for 11 to 14 days and were 

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

studies began, five male and six female rats and mice 

were randomly selected for parasite evaluation and 

gross observation for evidence of disease. At the 

beginning of quarantine and at the beginning and the 

end of the studies, serologic analyses were performed 

on five male and five female rats and mice using the 

protocols of the NTP Sentinel Animal Program 

(Appendix K). 

Doses for the 13-week studies were based on the 

results of 14- and 16-day comparative studies in which 

F344/N rats and B6C3F1 mice received triethanolamine by the dermal route in acetone, in drinking 

water, or by inhalation. The results of the dermal 

studies included skin irritation of a severity that 

limited the highest dose for the 13-week studies to 

2,000 mg/kg for rats and 4,000 mg/kg for mice. The 

14- and 16-day triethanolamine studies are unpublished but are available from the NTP. 

Based on the results of the earlier NTP studies, groups 

of 10 male and 10 female rats were topically 

administered 0, 125, 250, 500, 1,000, or 2,000 mg 

triethanolamine per kilogram body weight. Groups of 

10 male and 10 female mice were topically administered 0, 250, 500, 1,000, 2,000, or 4,000 mg 

triethanolamine per kilogram body weight. Except for 

the highest dose, which was applied neat, all doses 

were administered in acetone. Dose volumes were 

adjusted weekly, if necessary, according to the 

average body weights of the dosed groups. For rats, 

if the dose volume exceeded 320 μL, half the total 

volume was administered in the morning and the 

remainder was administered in the afternoon. Doses 

were applied 5 days per week for 13 weeks to an area 

extending from the animal’s mid-back to the dorsal 

intrascapular region; the site of application was 

clipped weekly during the studies. Additional groups 

of 10 male and 10 female rats and mice designated for 

clinical pathology evaluations received the same 

dermal exposures as the core study rats and mice. 

Feed and water were available ad libitum. Rats and 

mice were housed individually. Clinical findings 

were recorded weekly for core study rats and mice. 

All 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. 

Clinical pathology studies were performed on rats and 

mice designated for clinical pathology testing. Hematology and clinical chemistry analyses were conducted 

during week 12 for rats and week 13 for mice. Blood 

for hematology and clinical chemistry analyses was 

drawn from the retroorbital sinus of rats and mice 

anesthetized with a mixture of 70%:30% carbon 

dioxide:air. Blood for hematology determinations was 

placed in tubes containing potassium EDTA as an 

anticoagulant. Blood for serum analyses was collected in tubes without anticoagulant, allowed to clot 

at room temperature, and centrifuged, and the serum 
Triethanolamine, NTP TR 449 27 

was separated. Hematology parameters were measured on an Ortho ELT-8/ds hematology analyzer 

(Ortho Instruments, Westwood, MA). Differential 

leukocyte counts and morphologic evaluation of blood 

cells were determined by light microscopic examination of blood films stained with a modified 

Romanowsky stain. Reticulocyte counts were determined by light microscopy from smears of whole 

blood stained with new methylene blue. Clinical 

chemistry parameters were measured on a Hitachi 704 

chemistry analyzer (Boehringer Mannheim, 

Indianapolis, IN). Table 1 lists the hematology and 

clinical chemistry parameters measured. 

Urinalysis studies were performed during weeks 1, 3, 

7, and 13 for rats and weeks 7 and 12 for mice. For 

all urine studies, rats and mice were housed individually in polycarbonate metabolism cages (Maryland 

Plastics, New York) for a 16-hour collection period. 

The urine collection containers were immersed in an 

ice water bath during the sampling period to minimize 

evaporation and to suppress bacterial growth. Food 

was withheld, but water was available ad libitum 

during the collection period. Urine volume was 

measured and specific gravity was determined with a 

refractometer (American Optical, Buffalo, NY). 

Urine chemistry variables were measured on a 

Hitachi 704 chemistry analyzer; parameters measured 

are listed in Table 1. 

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

collected for sperm morphology and vaginal cytology 

evaluations from all rats in the 0, 500, 1,000, and 

2,000 mg/kg groups and all mice in the 0, 1,000, 

2,000, and 4,000 mg/kg groups. The parameters 

evaluated are listed in Table 1. Methods used were 

those described in the NTP’s sperm morphology and 

vaginal cytology evaluations protocol (NTP, 1983). 

For 7 consecutive days before the scheduled terminal 

sacrifice, the vaginal vaults of the females were 

moistened with saline, if necessary, and samples of 

vaginal fluid and cells were stained. Relative 

numbers of leukocytes, nucleated epithelial cells, and 

large squamous epithelial cells were determined and 

used to ascertain estrous cycle stage (i.e., diestrus, 

proestrus, estrus, and metestrus). Male animals were 

evaluated for sperm morphology, count, and motility. 

The right epididymis and right testis were isolated and 

weighed. The tail of the epididymis (cauda epididymis) was then removed from the epididymal body 

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

modified Tyrode’s buffer (mice) was applied to slides, 

and a small incision was made at the distal border of 

the cauda epididymis. The sperm effluxing from the 

incision were dispersed in the buffer on the slides, and 

the numbers of motile and nonmotile spermatozoa 

were counted for five fields per slide by two 

observers. Following completion of sperm motility 

estimates, each right cauda epididymis was placed in 

buffered saline solution. Caudae were finely minced, 

and the tissue was incubated in the saline solution and 

then heat fixed at 65E C. Sperm density was then 

determined microscopically with the aid of a hemacytometer. Four sperm morphology slides were prepared for each animal evaluated. An aliquot of killed 

sperm suspension was stained in a test tube, spread on 

a microscope slide under a coverslip, and examined. 

A necropsy was performed on all core study animals. 

The brain, left epididymis, heart, right kidney, liver, 

lungs, spleen, left testis, and thymus were weighed. 

Tissues for microscopic examination were fixed and 

preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned 

to a thickness of 5 to 6 μm, and stained with hematoxylin and eosin. A complete histopathologic examination was performed on core study rats in the vehicle 

control and 2,000 mg/kg groups and core study mice 

in the vehicle control and 4,000 mg/kg groups; the 

tissues and organs routinely examined are listed in 

Table 1. Additionally, the skin (site of application) of 

rats and mice and the kidney of female rats in the 

lower exposure groups were examined until a noeffect level was determined. 

2-YEAR STUDIES 

Study Design 

Groups of 60 male and 60 female rats and mice were 

topically administered triethanolamine in acetone. 

Male rats received 0, 32, 63, or 125 mg/kg. Female 

rats received 0, 63, 125, or 250 mg/kg. Male mice 

received 0, 200, 630, or 2,000 mg/kg. Female mice 

received 0, 100, 300, or 1,000 mg/kg. Dose volumes 

were adjusted weekly according to the average body 

weights of the dosed groups. Dose volumes ranged 

from 61 to 272 μL for male rats, 55 to 173 μL for 

female rats, 39 to 105 μL for male mice, and 33 to 

102 μL for female mice. Doses were applied 5 days 

per week for 103 weeks to an area extending from the 

animal’s mid-back to the intrascapular region; the site 

of application was clipped approximately once per 
28 Triethanolamine, NTP TR 449 

week during the studies. Ten male and ten female 

rats and mice from each group were evaluated at 

15 months for histopathology and organ weights. 

Source and Specification of Animals 

Male and female F344/N rats and B6C3F1 mice were

obtained from Simonsen Laboratories, Inc. (Gilroy, 

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

were quarantined for 11 days before the studies 

began. Five male and five female rats and mice were 

selected for parasite evaluation and gross observation 

of disease. Serology samples were collected for viral 

screening. Rats and mice were approximately 

6 weeks old at the beginning of the studies. The 

health of the animals was monitored during the studies 

according to the protocols of the NTP Sentinel Animal 

Program (Appendix K). 

Animal Maintenance 

Rats and mice were housed individually. Feed and 

water were available ad libitum. Cages and racks 

were rotated every 2 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 monthly; body weights were 

recorded at the beginning of the study, weekly for 

13 weeks, monthly thereafter, and at the end of the 

studies. 

A complete necropsy and microscopic examination 

were performed on all rats and mice. At the 

15-month interim evaluation necropsy, the left kidney, 

right kidney, and liver of rats and mice were weighed. 

At necropsy, all organs and tissues were examined for 

grossly visible lesions, and all major tissues were 

fixed and preserved in 10% neutral buffered formalin, 

processed and trimmed, embedded in paraffin, 

sectioned to a thickness of 5 to 6 μm, and stained with 

hematoxylin and eosin for microscopic examination. 

For all paired organs (i.e., adrenal gland, kidney, 

ovary), samples from each organ were examined. 

Complete histopathologic examinations were performed on all animals. The tissues and organs routinely examined are listed in Table 1. 

Microscopic evaluations were completed by the study 

laboratory pathologist, and the pathology data were 

entered into the Toxicology Data Management System. The slides, paraffin blocks, and residual wet 

tissues were sent to the NTP Archives for inventory, 

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

individual animal data records, and pathology tables 

were evaluated by an independent quality assessment 

laboratory. The individual animal records and tables 

were compared for accuracy, the slide and tissue 

counts were verified, and the histotechnique was 

evaluated. For the 2-year studies, quality assessment 

pathologists evaluated slides from all tumors and all 

potential target organs, which included the skin and 

kidneys of male and female rats, the adrenal glands of 

male rats, and the skin, liver, lymph nodes, spleen, 

and thymus of male and female mice. Additionally, 

the livers of male and female rats were examined 

when the diagnosis of nodular hyperplasia had been 

made; the adrenal glands of male mice were examined 

when the diagnosis of adenomatous hyperplasia had 

been made. The standard evaluation of the kidneys in 

these studies included microscopic examination of a 

longitudinal section of the central portion of the left 

kidney and a cross section of the central portion of the 

right kidney. Step sections were made from the 

residual kidney wet tissue from all male rats because 

microscopic examination of the original kidney 

sections showed increased incidences of proliferative 

lesions. Kidneys were sectioned in increments of 

0.5 mm to produce four additional sections per 

kidney, or eight sections per animal. 

The quality assessment report and the reviewed slides 

were submitted to the NTP Pathology Working Group 

(PWG) chairperson, who reviewed the selected tissues 

and addressed any inconsistencies in the diagnoses 

made by the laboratory and quality assessment pathologists. Representative histopathology slides containing examples of lesions related to chemical 

administration, examples of disagreements in 

diagnoses between the laboratory and quality 

assessment pathologists, or lesions of general interest 

were presented by the chairperson to the PWG for 

review. The PWG consisted of the quality assessment 

pathologist and other pathologists experienced in 

rodent toxicologic pathology. This group examined 

the tissues without any knowledge of dose groups or 
 

 

Triethanolamine, NTP TR 449 29 

previously rendered diagnoses. When the PWG cedures have been described, in part, by Maronpot 

consensus differed from the opinion of the laboratory and Boorman (1982) and Boorman et al. (1985). For 

pathologist, the diagnosis was changed. Final subsequent analyses of the pathology data, the decidiagnoses for reviewed lesions represent a consensus sion of whether to evaluate the diagnosed lesions for 

between the laboratory pathologist, reviewing patholo- each tissue type separately or combined was generally 

gist(s), and the PWG. Details of these review pro- based on the guidelines of McConnell et al. (1986). 

TABLE 1 

Experimental Design and Materials and Methods in the Dermal Studies of Triethanolamine 

13-Week Studies 2-Year Studies 

Study Laboratory 

Battelle Columbus Laboratories Battelle Columbus Laboratories 

(Columbus, OH) (Columbus, OH) 

Strain and Species 

Rats: F344/N Rats: F344/N 

Mice: B6C3F 1 Mice: B6C3F 1 

Animal Source 

Simonsen Laboratories, Inc. Simonsen Laboratories, Inc. 

(Gilroy, CA) (Gilroy, CA) 

Time Held Before Studies 

11 to 14 days 11 days 

Average Age When Studies Began 

6 weeks 6 weeks 

Date of First Dose 

Rats: 30 June - 1 July (clinical pathology) or 2-3 July 1986 Rats: 14 November 1988 

Mice: 11-12 August (clinical pathology) or 13-14 August 1986 Mice: 31 October 1988 

Duration of Dosing 

13 weeks (5 days/week) 103 weeks (5 days/week) 

Date of Last Dose 

Rats: 1 October (clinical pathology) or 2 October 1986 Rats: 2 November 1990 

Mice: 12-13 November 1986 Mice: 19 October 1990 

Necropsy Dates 

Rats: 2-3 October 1986 Rats: 15-Month interim evaluation -

Mice: 13-14 November 1986 12 February (males) or

 13 February (females) 1990 

Terminal -

12-14 November 1990 

Mice: 15-Month interim evaluation -

29 January (males) or

 30 January (females) 1990 

Terminal -

29 October - 1 November and

 5 November 1990 
 

 

 

30 Triethanolamine, NTP TR 449 

TABLE 1 

Experimental Design and Materials and Methods in the Dermal Studies of Triethanolamine (continued) 

13-Week Studies	 2-Year Studies 

Average Age at Necropsy 

19 weeks	 15-Month interim evaluation -

Rats and mice: 72 weeks 

Terminal -

Rats: 111 weeks 

Mice: 111 weeks (males)

 110-111 weeks (females) 

Size of Study Groups 

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

Terminal - 50 males and 50 females 

Method of Distribution 

Animals were distributed randomly into groups of approximately Same as 13-week studies 

initial mean body weights. 

Animals per Cage 

1 1 

Method of Animal Identification 

Toe mark	 Tail tattoo 

Diet 

NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Same as 13-week studies 

Gardners, PA), available ad libitum, changed weekly 

Water Distribution 

Tap water (City of Columbus municipal supply) via automatic Same as 13-week studies 

watering system (Edstrom Industries, Waterford, WI), available 

ad libitum 

Cages 

Polycarbonate (Lab Products, Inc., Garfield, NJ), changed weekly	 Polycarbonate (Lab Products, Inc., Maywood, NJ), changed 

weekly 

Bedding 

Beta-Chips® hardwood chips (Northeastern Products, Inc., Sani-Chips® hardwood chips (P.J. Murphy Forest Products, 

Warrensburg, NY), changed weekly Montville, NJ), changed weekly 

Cage Filters 

DuPont 2024 spun-bonded polyester filter (Snow Filtration Co., Same as 13-week studies 

Cincinnati, OH), changed every 2 weeks 

Racks 

Stainless steel (Lab Products, Inc., Garfield, NJ), changed every Stainless steel (Lab Products, Inc., Maywood, NJ), changed every 

2 weeks 2 weeks 

Animal Room Environment 

Temperature: 19.4E to 23.9E C (rats), 20.0E to 23.9E C (mice) Temperature: 20.0E to 23.9E C (rats), 20.0E to 24.4E C (mice) 

Relative humidity: 35% to 65% Relative humidity: 35% to 76% (rats), 24% to 82% (mice) 

Fluorescent light: 12 hours/day Fluorescent light: 12 hours/day 

Room air: minimum of 15 changes/hour Room air: minimum of 10 changes/hour 
Triethanolamine, NTP TR 449 31 

TABLE 1 

Experimental Design and Materials and Methods in the Dermal Studies of Triethanolamine (continued) 

13-Week Studies 2-Year Studies 

Doses 

Rats: 0, 125, 250, 500, or 1,000 mg/kg in acetone; 2,000 mg/kg Rats: 0, 32, 63, or 125 mg/kg (males) and 0, 63, 125, or 

neat 250 mg/kg (females) in acetone 

Mice: 0, 250, 500, 1,000, or 2,000 mg/kg in acetone; Mice: 0, 200, 630, or 2,000 mg/kg (males) and 0, 100, 300, or 

4,000 mg/kg neat 1,000 mg/kg (females) in acetone 

Type and Frequency of Observation 

Observed twice daily; animals were weighed initially, weekly, and Observed twice daily; clinical findings were recorded monthly. 

at the end of the studies; clinical findings of core study animals Animals were weighed initially, weekly for 13 weeks, monthly 

were recorded weekly. Dorsal skin lesions were diagramed. thereafter, and at the end of the studies. 

Method of Sacrifice 

CO asphyxiation 2 CO asphyxiation 2 

Necropsy 

Necropsy performed on all core study animals. Organs weighed Necropsy performed on all animals. Organs weighed were left 

were brain, left epididymis, heart, right kidney, liver, lungs, and right kidneys and liver. 

spleen, left testis, and thymus. 

Clinical Pathology 

Blood was collected from all clinical pathology group animals None 

from the retroorbital sinus for hematology and clinical chemistry. 

Urine was collected overnight (16 hours) from clinical pathology 

group rats during weeks 1, 3, 7, and 13 and from clinical 

pathology group mice during weeks 7 and 12. 

Hematology: hematocrit; hemoglobin concentration; erythrocyte, 

reticulocyte, and nucleated erythrocyte counts; mean cell volume; 

mean cell hemoglobin; mean cell hemoglobin concentration; 

platelet count; and total leukocyte count and differentials 

Clinical chemistry: urea nitrogen, creatinine, glucose, total 

protein, albumin, alanine aminotransferase, aspartate 

aminotransferase, and sorbitol dehydrogenase 

Urinalysis: glucose, protein, volume, and specific gravity 

Histopathology 

Complete histopathology was performed on core study rats in the Complete histopathology was performed on all rats and mice. In 

vehicle control and 2,000 mg/kg groups and mice in the vehicle addition to gross lesions and tissue masses, the tissues examined 

control and 4,000 mg/kg groups. In addition to gross lesions and included: adrenal gland, bone and marrow, brain, clitoral gland, 

tissue masses, the tissues examined included: adrenal gland, bone epididymis, esophagus, gallbladder (mice), heart, kidney, large 

and marrow, brain, clitoral gland, epididymis, esophagus, intestine (cecum, colon, and rectum), liver, lung, lymph nodes 

gallbladder (mice), heart, kidney, large intestine (cecum, colon, (mandibular and mesenteric), mammary gland, nose, ovary, 

and rectum), liver, lung, lymph nodes (mandibular and pancreas, parathyroid gland, pituitary gland, preputial gland, 

mesenteric), mammary gland, nose, ovary, pancreas, parathyroid prostate gland, salivary gland, seminal vesicle, skin (lesions and 

gland, pituitary gland, preputial gland, prostate gland, salivary unaffected skin from site of application; inguinal skin), small 

gland, seminal vesicle, skin (lesions and unaffected skin from site intestine (duodenum, jejunum, and ileum), spinal cord and sciatic 

of application; inguinal skin), small intestine (duodenum, jejunum, nerve (if neurologic signs were present), spleen, stomach 

and ileum), spinal cord and sciatic nerve (if neurologic signs were (forestomach and glandular stomach), testis, thymus, thyroid 

present), spleen, stomach (forestomach and glandular stomach), gland, trachea, urinary bladder, and uterus. 

testis, thymus, thyroid gland, trachea, urinary bladder, uterus, and 

vagina (females in vaginal cytology studies only). Additionally, 

the kidney of female rats, pituitary gland of male and female rats, 

and skin (site of application) of male and female rats and mice in 

the lower exposure groups were examined until a no-effect level 

was reached. 
32 Triethanolamine, NTP TR 449 

TABLE 1 

Experimental Design and Materials and Methods in the Dermal Studies of Triethanolamine (continued) 

13-Week Studies 2-Year Studies 

Sperm Morphology and Vaginal Cytology Evaluations 

Rats in the 0, 500, 1,000, and 2,000 mg/kg groups and mice in None 

the 0, 1,000, 2,000, and 4,000 mg/kg groups were evaluated. 

Sperm samples were collected at the end of the studies and 

evaluated for sperm count, motility, and morphology. The right 

cauda, epididymis, and testis were weighed. Vaginal samples 

were collected for 7 consecutive days before the end of the studies 

and evaluated for the relative frequency of estrous stages and for 

estrous cycle length. 

STATISTICAL METHODS 

Survival Analyses 

The probability of survival was estimated by the 

product-limit procedure of Kaplan and Meier (1958) 

and is presented in the form of graphs. Animals 

found dead of other than natural causes or missexed 

were censored from the survival analyses; animals 

dying from natural causes were not censored. Statistical analyses for possible dose-related effects on 

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

groups for equality and Tarone’s (1975) life table test 

to identify dose-related trends. All reported P values 

for the survival analyses are two sided. 

Calculation of Incidence 

The incidences of neoplasms or nonneoplastic lesions 

as presented in Tables A1, A5, B1, B4, C1, C5, D1, 

and D5 are given as the number of animals bearing 

such lesions at a specific anatomic site and the number 

of animals with that site examined microscopically. 

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

D3) and all nonneoplastic lesions are given as the 

numbers of animals affected at each site examined 

microscopically. However, when macroscopic 

examination was required to detect neoplasms in 

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

and mammary gland) before microscopic evaluation, 

or when neoplasms had multiple potential sites of 

occurrence (e.g., leukemia or lymphoma), the 

denominators consist of the number of animals on 

which a necropsy was performed. Tables A3, B3, 

C3, and D3 also give the survival-adjusted neoplasm 

rate for each group and each site-specific neoplasm, 

i.e., the Kaplan-Meier estimate of the neoplasm incidence that would have been observed at the end of the 

study in the absence of mortality from all other 

competing risks (Kaplan and Meier, 1958). 

Analysis of Neoplasm Incidences 

The majority of neoplasms in these studies were 

considered to be incidental to the cause of death or not 

rapidly lethal. Thus, the primary statistical method 

used was logistic regression analysis, which assumed 

that the diagnosed neoplasms were discovered as the 

result of death from an unrelated cause and thus did 

not affect the risk of death. In this approach, neoplasm prevalence was modeled as a logistic function 

of chemical exposure and time. Both linear and 

quadratic terms in time were incorporated initially, 

and the quadratic term was eliminated if the fit of the 

model was not significantly enhanced. The neoplasm 

incidences of exposed and control groups were 

compared on the basis of the likelihood score test for 

the regression coefficient of dose. This method of 

adjusting for intercurrent mortality is the prevalence 

analysis of Dinse and Lagakos (1983), further 

described and illustrated by Dinse and Haseman 

(1986). When neoplasms are incidental, this comparison of the time-specific neoplasm prevalences also 

provides a comparison of the time-specific neoplasm 

incidences (McKnight and Crowley, 1984). 

In addition to logistic regression, other methods of 

statistical analysis were used, and the results of these 

tests are summarized in the appendixes. These 

methods include the life table test (Cox, 1972; 

Tarone, 1975), appropriate for rapidly lethal 

neoplasms, and the Fisher exact test and the CochranArmitage trend test (Armitage, 1971; Gart et al., 
Triethanolamine, NTP TR 449 33 

1979), procedures based on the overall proportion of 

neoplasm-bearing animals. 

Tests of significance included pairwise comparisons of 

each exposed group with controls and a test for an 

overall dose-related trend. Continuity-corrected tests 

were used in the analysis of neoplasm incidence, and 

reported P values are one sided. The procedures 

described in the preceding paragraphs were also used 

to evaluate selected nonneoplastic lesions. For further 

discussion of these statistical methods, refer to 

Haseman (1984). 

Analysis of Nonneoplastic 

Lesion Incidences 

Because all nonneoplastic lesions in this study were 

considered to be incidental to the cause of death or not 

rapidly lethal, the primary statistical analysis used was 

a logistic regression analysis in which nonneoplastic 

lesion prevalence was modeled as a logistic function 

of chemical exposure and time. For lesions detected 

at the interim evaluation, the Fisher exact test, a 

procedure based on the overall proportion of affected 

animals, was used. 

Analysis of Continuous Variables 

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

control groups in the analysis of continuous variables. 

Organ and body weight data, which have approximately normal distributions, were analyzed using the 

parametric multiple comparison procedures of Dunnett 

(1955) and Williams (1971, 1972). Clinical chemistry, hematology, and epididymal spermatozoal data, 

which have typically skewed distributions, were 

analyzed using the nonparametric multiple comparison 

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

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

assess the significance of the dose-related trends and 

to determine whether a trend-sensitive test (Williams’ 

or Shirley’s test) was more appropriate for pairwise 

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

Average severity values were analyzed for significance using the Mann-Whitney U test (Hollander and 

Wolfe, 1973). Because the vaginal cytology data are 

proportions (the proportion of the observation period 

that an animal was in a given estrous stage), an 

arcsine transformation was used to bring the data into 

closer conformance with a normality assumption. 

Treatment effects were investigated by applying a 

multivariate analysis of variance (Morrison, 1976) to 

the transformed data to test for simultaneous equality 

of measurements across doses. 

Historical Control Data 

Although the concurrent control group is always the 

first and most appropriate control group used for 

evaluation, historical control data can be helpful in the 

overall assessment of neoplasm incidence in certain 

instances. Consequently, neoplasm incidences from 

the NTP historical control database, which is updated 

yearly, are included in the NTP reports for neoplasms 

appearing to show compound-related effects. 

QUALITY ASSURANCE METHODS 

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

compliance with Food and Drug Administration Good 

Laboratory Practice Regulations (21 CFR, Part 58). 

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

submitted to the NTP Archives, these studies were 

audited retrospectively by an independent quality 

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

this NTP Technical Report. Audit procedures and 

findings are presented in the reports and are on file at 

NIEHS. The audit findings were reviewed and 

assessed by NTP staff, so all comments had been 

resolved or were otherwise addressed during the preparation of this Technical Report. 

GENETIC TOXICOLOGY 

The genetic toxicity of triethanolamine was assessed 

by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium, 

sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, sexlinked recessive lethal mutations in Drosophila 

melanogaster, and increases in the frequency of 

micronucleated erythrocytes in peripheral blood of 

mice. The protocols for these studies and the results 

are given in Appendix E. 

The genetic toxicity studies of triethanolamine are part 

of a larger effort by the NTP to develop a database 

that would permit the evaluation of carcinogenicity in 

experimental animals from the molecular structure and 

the effects of the chemical in short-term in vitro and 
34 Triethanolamine, NTP TR 449 

in vivo genetic toxicity tests. These genetic toxicity 

tests were originally developed to study mechanisms 

of chemical-induced DNA damage and to predict 

carcinogenicity in animals, based on the electrophilicity theory of chemical carcinogenesis and the 

somatic mutation theory of cancer (Miller and Miller, 

1977; Straus, 1981; Crawford, 1985). 

There is a strong correlation between a chemical’s 

potential electrophilicity (structural alert to DNA 

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

correlated with the induction of carcinogenicity in rats 

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

Tennant, 1991). Other in vitro genetic toxicity tests 

correlate less well with rodent carcinogenicity 

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

these other tests can provide information on the types 

of DNA and chromosome effects that can be induced 

by the chemical being investigated. Data from NTP 

studies show that a positive response in Salmonella is 

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

carcinogens), and that there is no complementarity 

among the in vitro genetic toxicity tests. That is, no 

battery of tests that included the Salmonella test 

improved the predictivity of the Salmonella test alone. 

The predictivity for carcinogenicity of a positive 

response in bone marrow chromosome aberration or 

micronucleus tests appears to be less than the 

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

1995). Positive responses in long-term peripheral 

blood micronucleus tests have not been formally 

evaluated for their predictivity for rodent carcinogenicity. But, because of the theoretical and observed 

associations between induced genetic damage and 

adverse effects in somatic and germ cells, the 

determination of in vivo genetic effects is important to 

the overall understanding of the risks associated with 

exposure to a particular chemical. 
 

35 

RESULTS 

RATS 

group was also significantly less than that of the 

13-WEEK STUDY vehicle controls. Clinical findings related to triethAll rats survived to the end of the study (Table 2). anolamine administration occurred only at the site of 

Final mean body weights and weight gains of males application and included irritation, scaliness, and 

and females in the 2,000 mg/kg groups were signifi- crustiness for males and females. Males also had 

cantly less than those of the vehicle controls; the mean discoloration, and two males administered 

body weight gain of females in the 1,000 mg/kg 2,000 mg/kg had ulceration at the site of application. 

TABLE 2 

Survival and Body Weights of Rats in the 13-Week Dermal Study of Triethanolamine 

Dose 

(mg/kg) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

125 

250 

500 

1,000 

2,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

98 ± 2 

94 ± 2 

95 ± 2 

96 ± 2 

98 ± 3 

95 ± 3 

296 ± 6 

279 ± 5 

279 ± 6 

288 ± 5 

290 ± 10 

252 ± 9** 

198 ± 6 

185 ± 5 

184 ± 5 

193 ± 5 

192 ± 9 

156 ± 8** 

94 

94 

97 

98 

85 

Female 

0 

125 

250 

500 

1,000 

2,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

84 ± 2 

84 ± 2 

86 ± 2 

85 ± 2 

87 ± 2 

82 ± 1 

176 ± 3 

171 ± 3 

175 ± 3 

173 ± 3 

170 ± 3 

156 ± 2** 

92 ± 3 

87 ± 2 

89 ± 2 

88 ± 3 

83 ± 3* 

74 ± 2** 

97 

100 

98 

97 

89 

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

** P#0.01 a Number of animals surviving at 13 weeks/number initially in group b Weights and weight changes are given as mean ± standard error. 
36 Triethanolamine, NTP TR 449 

Clinical pathology results are listed in Table G1. In Kidney weights were generally greater in males and 

general, changes were minimal to mild, occurred only females administered 500, 1,000, or 2,000 mg/kg 

in the 2,000 mg/kg groups, and are consistent with the than in the vehicle controls (Table F4). Other differmarked chronic active skin inflammation observed ences in organ weights of males and females 

microscopically. Mild increases in segmented neutro- administered 2,000 mg/kg were considered secondary 

phil counts occurred in male and female rats in the to the lower body weights of these groups. There 

2,000 mg/kg groups; in males, this change was were no biologically significant differences in sperm 

accompanied by increased leukocyte and eosinophil morphology or vaginal cytology parameters between 

counts. These findings are consistent with the pres- dosed and vehicle control rats (Table H1). 

ence of a mild inflammatory leukogram related to the 

skin inflammation. Minimal decreases occurred in Gross lesions attributed to triethanolamine application 

mean red cell volume in male and female rats admin- included crust at the site of application for males and 

istered 2,000 mg/kg and in hematocrit in females females administered 1,000 or 2,000 mg/kg. Yellow 

administered 2,000 mg/kg. These changes are con- skin coloration in the lumbar region of vehicle control 

sistent with a minimal depression of hematopoiesis and treated males was attributed to the application of 

related to chronic inflammation. acetone. Microscopic lesions at the site of application 

included acanthosis and inflammation, which varied 

Minimal increases in albumin and urea nitrogen from minimal or mild in the lower dose groups to 

concentrations, likely representing minimal dehydra- marked in the 2,000 mg/kg groups (Table 3). In rats 

tion, occurred in females that received 2,000 mg/kg. with minimal acanthosis, the epidermis was as much 

Additionally, increased urine specific gravity in as twice the normal thickness. The more severe 

females in the 1,000 and 2,000 mg/kg groups at lesions were focal to multifocal and included a 

weeks 7 (day 44) and 13 and in male rats in the thickened epidermis (three to four times the normal 

2,000 mg/kg group at week 13 would be consistent thickness); chronic active inflammation; and erosion, 

with dehydration. Dehydration can be a sequela of ulceration, or both. The underlying dermis was often 

inflammation. Serum aspartate aminotransferase thickened by chronic active inflammation, including 

activities were mildly increased in male rats receiving fibrosis. 

250 mg/kg or greater and in females receiving 

2,000 mg/kg. Aspartate aminotransferase has a wide Dosed females had greater incidences of nephropathy 

tissue distribution, and, in the rat, the greatest tissue than did the vehicle controls (Table 3). Nephropathy 

concentrations are found in the heart, liver, skeletal consisted of minimal to mild, focal or multifocal 

muscle, brain, and kidney (Boyd, 1983). In this cortical tubules lined by hyperchromatic, basophilic 

study, the cause of the increased aspartate amino- tubule epithelium (regeneration). Mineralization, 

transferase activity is unknown, but this increase which also occurred with greater incidences and 

could indicate mild cardiac/skeletal muscle or hepatic severity in dosed females, consisted of tiny lamellated 

injury. Serum alanine aminotransferase activity was concretions within tubule lumina and/or epithelium. 

minimally increased in males in the 1,000 and The incidences of nephropathy were not increased in 

2,000 mg/kg groups. This enzyme is liver specific in dosed males. The incidences of hypertrophy of the 

the rat, and increases in serum activity would be pituitary gland pars intermedia were significantly 

consistent with a hepatic effect. However, the activity greater in males and females in the 2,000 mg/kg 

of sorbitol dehydrogenase, which is also liver specific, group than in the vehicle controls (Table 3). The pars 

decreased minimally in females administered 500 or intermedia is a thin section of tissue composed of 

1,000 mg/kg. Additionally, there was no microscopic compact clusters of polygonal cells that lies between 

evidence of hepatic injury or change in absolute liver the pars distalis and the pars nervosa. Because of its 

weight in dosed rats. Urine protein excretion was small size and because of some variation in sectioning 

decreased in males in the 2,000 mg/kg group on of the pituitary gland, the pars intermedia was not 

day 16, in males administered 500 mg/kg or greater always present in the section examined. In the 

at week 7, and in males in the 1,000 and 2,000 mg/kg animals with hypertrophy, the pars intermedia was as 

groups at week 13. The cause for the decreased much as twice the normal size, with a somewhat 

protein excretion is unknown. nodular appearance. Individual cells were moderately 
 

37 

c 

Triethanolamine, NTP TR 449 

enlarged, apparently due to an increase in the amount acanthosis and inflammation at the site of application 

of cytoplasm. at higher doses in the 13-week studies, triethanolamine doses selected for use in the 2-year dermal 

Dose Selection Rationale: Based on decreased body study in rats were 32, 63, and 125 mg/kg for males 

weight gain and progression in the severity of and 63, 125, and 250 mg/kg for females. 

TABLE 3 

Incidences of Selected Nonneoplastic Lesions in Rats in the 13-Week Dermal Study of Triethanolamine 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

Male 

Skin, Site of Applicationa 

Acanthosisb 

10 

0 

10 

0 

10 

6** (1.2) c 10 9** (1.2) 

10 

10** (2.0) 

10 

10** (3.5) 

Inflammation, Chronic Active 0 0 2 (1.5) 2 (2.0) 10** (2.7) 10** (4.0) 

Pituitary Gland, Pars Intermedia 9 6 7 8 9 8 

Hypertrophy 0 0 0 0 0 5** (1.0) 

Female 

Skin, Site of Application 10 10 10 10 10 10 

Acanthosis 0 0 0 4* (1.3) 8** (1.6) 10** (2.8) 

Inflammation, Chronic Active 0 0 0 1 (2.0) 5* (2.6) 10** (3.9) 

Kidney, Renal Tubule 10 10 10 10 10 10 

Regeneration (Nephropathy) 2 (1.0) 3 (1.0) 5 (1.0) 7* (1.0) 10** (1.4) 8* (1.4) 

Mineralization 3 (1.0) 9** (1.1) 6 (1.0) 7 (1.6) 9** (1.9) 9** (1.4) 

Pituitary Gland, Pars Intermedia 6 8 8 8 6 9 

Hypertrophy 0 0 0 0 1 (1.0) 9** (1.7) 

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

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

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

38 Triethanolamine, NTP TR 449 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male and 

female rats are shown in Table 4 and in the KaplanMeier survival curves (Figure 1). The survival rates 

of males receiving 32 mg/kg and females receiving 

250 mg/kg were slightly less than those of the vehicle 

controls. 

Body Weights and Clinical Findings 

Mean body weights are given in Figure 2 and 

Tables 5 and 6. The mean body weight of females 

administered 250 mg/kg ranged from 9% to 12% less 

than that of the vehicle controls between weeks 73 and 

93; however, at the end of the study, the mean body 

weight of this group was only 7% less than that of 

the vehicle controls. Mean body weights of dosed 

males were similar to those of the vehicle controls 

throughout the study. Male and female rats receiving 

triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had 

a crusty appearance. The number of animals in which 

these findings were observed increased with 

increasing dose. 

Organ Weights 

At the 15-month interim evaluation, the absolute left 

and right kidney weights and relative right kidney 

weight of females administered 250 mg/kg were 

slightly greater than those of the vehicle controls 

(Table F2); the organ weights of dosed males were 

similar to those of the vehicle controls. 
39 

c 

Triethanolamine, NTP TR 449 

TABLE 4 

Survival of Rats in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Male 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Accidental deathsa 2 0 0 0 

Missexeda 0 0 1 0 

Moribund 18 27 25 23 

Natural deaths 9 12 6 8 

Animals surviving to study termination 

Percent probability of survival at the end of studyb 

21 

45 

11 

22 

18 

37 

19 

38 

Mean survival (days)c 651 641 653 

645 

Survival analysisd P=0.861 P=0.053 P=0.645 P=0.481 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Female 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Moribund 11 4 12 17 

Natural deaths 14 17 13 15 

Animals surviving to study termination 25 29 25 18e 

Percent probability of survival at the end of study 50 58 50 36 

Mean survival (days) 678 676 672 605 

Survival analysis P=0.017 P=0.658N P=1.000 P=0.056 

a Censored from survival analyses b	 Kaplan-Meier determinations 

Mean of all deaths (uncensored, censored, and terminal sacrifice) d	 The result of the life table trend test (Tarone, 1975) is in the vehicle control column, and the results of the life table pairwise comparisons 

(Cox, 1972) with the vehicle controls are in the dosed group columns. A lower mortality in a dose group is indicated by N. e Includes one animal that died during the last week of the study 
1.0 

0 .1 

o.e 

... 

..J 0.7 

~ 

0: > 0 .6 

"' 

:::J 

.... 

0 

.... 

>- M 

::; 

... 

iii 0.4 m 

0 

0: 

"- O.l 

0.2 • OWG/1<0 

0 l2 WC/I(C 

l::J. 0.1 I) WG/KG 

0 12$ WG/I<G 

o.o 0 

·~ 30 eo 75 10 10~ 120 

WEEKS ON STUDY 

1.0 

O.t 

0.8 

0.7 ..J 

~ ;;: 

0: 0.1 :::J 

.... 

111 

0 

.... 

>- 0.5 

::; 

iii 

< 0.4 m 

0 

0: 

"- 0.3 

fEMALE RATS 0.2 • OUC/kC 

0 ll W0/1(0 

6, 125 UG/KC 0. 1 0 2SDMO/XG 

0.0 

0 IS JO 45 75 to lOS 120 

WEEKS ON STUDY 

40 Triethanolamine, NTP TR 449 

FIGURE 1 

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

in Acetone by Dermal Application for 2 Years 
Triethanolamine, NTP TR 449 41 

FIGURE 2 

Growth Curves for Male and Female Rats Administered Triethanolamine 

in Acetone by Dermal Application for 2 Years 
42 Triethanolamine, NTP TR 449 

TABLE 5 

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

Weeks 0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

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

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

1 110 60 107 97 60 110 100 59 108 98 60 

2 151 60 148 98 60 150 100 59 147 98 60 

3 177 59 173 98 60 176 100 59 173 98 60 

4 209 59 205 98 60 209 100 59 205 98 60 

5 225 59 219 97 60 226 101 59 220 98 60 

6 242 59 235 97 60 241 100 59 234 97 60 

7 253 59 247 98 60 253 100 59 247 98 60 

8 265 59 259 98 60 265 100 59 259 98 60 

9 279 59 274 98 60 279 100 59 274 98 60 

10 287 59 283 99 60 287 100 59 281 98 60 

11 297 59 293 99 60 294 99 59 289 97 60 

12 301 59 297 99 60 299 99 59 294 98 60 

13 306 59 303 99 60 302 99 59 298 98 60 

17 328 59 325 99 60 324 99 59 320 98 60 

21 347 59 342 99 60 342 99 59 338 97 60 

25 355 59 351 99 60 352 99 59 345 97 60 

29 369 59 362 98 60 361 98 59 356 96 60 

33 382 59 375 98 60 375 98 59 368 96 60 

37 388 59 384 99 60 382 98 59 374 96 60 

41 395 59 389 99 60 390 99 59 379 96 60 

45 404 59 393 97 60 394 98 59 383 95 60 

49 404 59 398 98 60 396 98 59 387 96 60 

53 411 59 402 98 60 401 98 57 389 95 60 

57 415 59 405 98 60 410 99 56 396 95 60 

61 420 59 411 98 58 413 98 56 399 95 59 

65 424 59 420 99 57 422 99 55 404 95 57 

69a 433 47 420 97 46 425 98 45 413 95 46 

73 437 47 425 97 44 430 98 44 417 95 44 

77 437 46 424 97 44 432 99 43 418 96 43 

81 430 41 420 98 41 423 98 42 415 97 37 

85 419 37 412 99 37 426 102 37 412 98 34 

89 414 35 405 98 30 419 101 35 410 99 33 

93 408 32 402 99 26 423 104 30 405 99 30 

97 406 27 392 97 24 410 101 28 404 100 25 

101 395 26 382 97 19 380 96 26 398 101 21 

104 382 22 375 98 13 398 104 18 388 101 19 

Mean for weeks 

1-13 239 234 98 238 100 233 97 

14-52 375 369 98 368 98 361 96 

53-104 417 407 98 415 100 405 97 

a Interim evaluation occurred during week 66. 
Triethanolamine, NTP TR 449 43 

TABLE 6 

Mean Body Weights and Survival of Female Rats in the 2-Year Dermal Study of Triethanolamine 

Weeks 0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

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 95 60 95 100 60 94 100 60 95 100 60 

2 117 60 118 101 60 117 101 60 118 101 60 

3 127 60 128 100 60 127 100 60 126 99 60 

4 141 60 140 100 60 140 100 60 140 99 60 

5 147 60 148 101 60 148 101 60 146 99 60 

6 153 60 154 100 60 152 100 60 151 99 60 

7 158 60 157 100 60 157 99 60 155 98 60 

8 162 60 161 100 60 161 99 60 158 98 60 

9 167 60 168 101 60 167 100 60 164 99 60 

10 170 60 170 100 60 169 99 60 167 98 60 

11 176 60 175 100 60 173 99 60 171 98 60 

12 175 60 176 100 60 173 99 60 171 98 60 

13 177 60 178 100 60 176 99 60 173 98 60 

17 184 60 185 100 60 182 99 60 179 97 60 

21 193 60 193 100 60 190 99 60 187 97 59 

25 196 60 197 101 60 194 99 60 191 97 59 

29 202 60 204 101 60 201 99 60 196 97 59 

33 211 60 210 100 60 208 99 59 201 96 59 

37 214 60 217 101 60 212 99 59 208 97 58 

41 222 60 221 100 60 217 98 59 211 95 58 

45 230 60 227 99 60 222 96 59 215 94 58 

49 234 59 231 99 60 226 97 59 217 93 58 

53 239 59 235 99 60 231 97 59 223 93 55 

57 243 58 238 98 60 234 96 59 227 93 53 

61 250 58 246 99 59 241 97 58 233 93 52 

65 255 58 251 99 57 248 97 58 240 94 50 

69a 264 47 257 97 47 252 95 47 242 92 38 

73 267 47 260 97 46 256 96 46 241 90 38 

77 271 47 262 97 45 258 95 46 246 91 36 

81 268 45 263 98 44 259 97 44 243 91 35 

85 270 43 265 98 41 261 96 42 245 90 33 

89 274 42 268 98 39 264 96 40 241 88 31 

93 273 38 270 99 38 270 99 36 248 91 26 

97 277 34 272 98 35 270 98 34 253 92 22 

101 280 32 274 98 32 268 96 32 254 91 20 

104 276 26 273 99 30 267 97 27 257 93 18 

Mean for weeks 

1-13 151 151 100 150 99 149 99 

14-52 210 209 100 206 98 201 96 

53-104 265 260 98 256 97 242 91 

a Interim evaluation occurred during week 66. 
44 Triethanolamine, NTP TR 449 

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 skin, 

kidney, thyroid gland, uterus, and pituitary gland. 

Summaries of the incidences of neoplasms and nonneoplastic lesions, individual animal tumor diagnoses, 

statistical analyses of primary neoplasms that occurred 

with an incidence of at least 5% in at least one animal 

group, and historical incidences for the neoplasms 

mentioned in this section are presented in Appendix A 

for male rats and Appendix B for female rats. 

Skin: Gross lesions attributed to triethanolamine 

administration consisted of multiple, small, randomly 

located, red or brown lesions or crusts at the site of 

application in females. Increased incidences of 

nonneoplastic lesions at the site of application in 

dosed rats were observed at the 15-month interim 

evaluation and at the end of the 2-year study 

(Table 7). Lesions occurred more frequently in 

females than in males receiving equivalent doses. 

Lesions consisted of thickened epidermis (acanthosis) 

and ulceration with associated chronic active inflammation in dosed males and females, as well as erosion 

in dosed females. 

At the 15-month interim evaluation, two males in the 

125 mg/kg group had minimal acanthosis at the site of 

application. Females receiving 125 or 250 mg/kg had 

acanthosis, inflammation, and ulceration. Acanthosis 

and inflammation were of mild average severity; the 

average severity of ulceration was mild in the 

125 mg/kg group and moderate in the 250 mg/kg 

group. At 2 years, the incidence of acanthosis in 

males administered 125 mg/kg and the incidences of 

acanthosis, inflammation, and ulceration in dosed 

females were greater than in the vehicle controls; 

additionally, males in the 125 mg/kg group had 

greater incidences of inflammation and ulceration than 

the vehicle controls. The incidences of erosion, 

which was diagnosed only in areas distinctly removed 

from ulceration, were significantly greater in females 

receiving 125 or 250 mg/kg than in the vehicle 

controls at 2 years. 

The epidermis covering the entire site of application 

was generally mildly thickened (two to four times) 

relative to that of the vehicle controls (Plates 1 and 2), 

with neutrophils occasionally observed within the 

epidermis. Ulcers were random and multifocal and 

were of mild to moderate severity. Ulcers were 

characterized by complete segmental necrosis of 

epidermis, with variable erosion of the dermis and 

associated chronic active inflammation (neutrophils, 

lymphocytes, and macrophages). Ulcerated areas 

were covered with cellular debris, keratin, fibrin, and 

inflammatory cells composing the “crusts” noted 

grossly. Erosion consisted of necrosis of the superficial layers of epidermis and did not extend into the 

dermis. 

At 2 years, one male in the 125 mg/kg group had a 

keratoacanthoma at the site of application (Tables 7 

and A1). However, the incidences of keratoacanthoma and squamous cell papilloma of the skin (all 

sites) were slightly less in dosed males than in the 

vehicle controls (Table A3). No keratoacanthomas or 

squamous cell papillomas occurred in vehicle control 

male rats in the only other dermal study with an 

acetone vehicle in the NTP database; however, the 

incidences of keratoacanthoma (10%) and squamous 

cell papilloma (6%) in the vehicle controls in the 

present study fall within the historical range for these 

neoplasms in male rats in NTP feed studies (keratoacanthoma, 0%-10%; squamous cell papilloma, 

0%-8%). One vehicle control male had a basal cell 

adenoma at the site of application; this neoplasm did 

not occur in dosed males (Tables 7 and A1). Additionally, one vehicle control female had a squamous 

cell papilloma and one female in the 63 mg/kg group 

had a keratoacanthoma away from the site of application; no skin neoplasms occurred in females administered 125 or 250 mg/kg triethanolamine (Table B1). 

Squamous cell papillomas were observed in 6 of 

1,202 females in NTP feed studies (range 0%-2%) but 

did not occur in the other dermal study. 
Triethanolamine, NTP TR 449 45 

TABLE 7 

Incidences of Neoplasms and Nonneoplastic Lesions of the Skin at the Site of Application in Rats 

in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 

Acanthosisa 10 0 

10 

0 

10 

0 

10 

2 (1.0)b 

2-Year Study 

Number Examined Microscopically 50 50 49 50 

Acanthosis 1 (1.0) 1 (1.0) 1 (1.0) 9** (1.7) 

Inflammation, Chronic Active 0 2 (1.0) 0 8** (1.9) 

Ulcer 0 0 0 5* (3.2) 

Erosion 0 0 0 1 (3.0) 

Basal Cell Adenoma 1 0 0 0 

Keratoacanthoma 0 0 0 1 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Acanthosis 0 1 (2.0) 7** (2.3) 6** (2.0) 

Inflammation, Chronic Active 0 1 (2.0) 7** (2.1) 6** (2.0) 

Ulcer 0 1 (2.0) 7** (2.1) 6** (2.5) 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Acanthosis 2 (2.0) 10* (2.1) 30** (2.1) 32** (2.0) 

Inflammation, Chronic Active 2 (2.5) 10* (2.3) 30** (2.1) 32** (2.2) 

Ulcer 2 (3.5) 7 (3.4) 22** (3.2) 27** (2.7) 

Erosion 1 (3.0) 6 (3.0) 16** (3.0) 14** (2.7) 

* Significantly different (P#0.05) from the vehicle control group by the logistic regression test (2-year study) 

** Significantly different (P#0.01) from the vehicle control group by the Fisher exact test (15-month interim evaluation) or by the logistic 

regression test (2-year study) a Number of animals with lesion 

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

 

46 Triethanolamine, NTP TR 449 

Kidney: No kidney lesions were observed at the completely filled the tubule lumens and that usually 

15-month interim evaluation; however, the absolute caused slight dilatation of the tubule. The hyperkidney weights of females in the 250 mg/kg group plastic cells were generally slightly larger than normal 

were greater than those of the vehicle controls. At epithelial cells and were polygonal, with abundant 

2 years, the incidence of adenoma of the renal tubule eosinophilic cytoplasm. All adenomas were small 

epithelium in males in the 63 mg/kg group was (less than 0.9 cm) and expansile and usually consisted 

marginally greater than that in the vehicle controls of multiple, variably sized tubule profiles, some with 

(Tables 8 and A3). No renal tubule adenomas necrotic centers. Cells of adenomas were generally 

occurred in vehicle control male F344/N rats in the larger than normal and polygonal, with abundant 

other dermal study in the NTP database with an eosinophilic cytoplasm. 

acetone vehicle; the incidence of this neoplasm in 

untreated control males ranged from 0% to 6% Thyroid Gland: The incidence of C-cell adenoma or 

(Table A4). Although the neoplasm incidence carcinoma (combined) was marginally greater in 

observed in the 63 mg/kg group exceeds the incidence female rats in the 250 mg/kg group than in the vehicle 

in untreated controls in the NTP database, an equal or controls (0 mg/kg, 1/50; 63 mg/kg, 2/50; 125 mg/kg, 

greater incidence did not occur in males in the 2/50; 250 mg/kg, 6/49; Tables B1 and B3). This 

125 mg/kg group, and the neoplasms in all groups greater incidence was not considered to be related to 

were small and were detected only microscopically. the administration of triethanolamine. Thyroid gland 

Additionally, the incidences of hyperplasia were not C-cell neoplasms are relatively common, spontaincreased in dosed males (Tables 8 and A5). Because neously occurring neoplasms in male and female rats, 

of these uncertain findings, an extended evaluation of occurring in 6 of 46 vehicle control females (13%) in 

the kidneys of vehicle control and dosed males was the other NTP dermal study with an acetone vehicle 

conducted. In this extended evaluation, additional and in 175 of 1,196 untreated control females (15%) 

proliferative lesions (hyperplasia and adenoma) were in NTP feed studies. Further, of the 24 feed studies 

identified, with similar incidences in all groups in the database, no control group had an incidence of 

(Table 8); however, the incidence of adenoma was less than 6% for C-cell neoplasms. Additionally, 

marginally, although not significantly, greater in the proliferative lesions of the thyroid gland C-cells 

125 mg/kg group than in the vehicle controls. generally represent a morphological and biological 

Nephropathy was observed in nearly all male rats in continuum, with progression from hyperplasia to 

all groups (Table 8); there was no apparent difference adenoma to carcinoma. In this study, there was often 

in the severity of this lesion between dosed and difficulty in determining whether the proliferative 

vehicle control groups. lesions were adenomas or hyperplasia. The incidences of hyperplasia in dosed females (8/50, 4/50, 

The proliferative lesions were phenotypically similar 10/50, 2/49; Table B4) did not support a treatment 

to those spontaneously occurring in F344/N rats. effect, and when the incidences of hyperplasia and 

Focal renal tubule hyperplasia consisted of single or neoplasms were combined, the results indicated no 

multiple adjacent tubule profiles containing three or increased incidences of proliferative thyroid gland 

more layers of epithelial cells that partially or C-cell lesions in dosed female rats. 
Triethanolamine, NTP TR 449 47 

TABLE 8 

Incidences of Neoplasms and Nonneoplastic Lesions of the Renal Tubule in Rats 

in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Male 

15-Month Interim Evaluation 

Single Sections (Standard Evaluation) 

Number Examined Microscopically 

Nephropathy, Chronica 10 

10 (2.0) b 

10 

9 (2.0) 

10 

10 (2.0) 

10 

10 (1.6) 

Step Sections (Extended Evaluation) 

Number Examined Microscopically 

Adenoma 

10 

0 

10 

0 

10 

0 

10 

1 

Single Sections and Step Sections (Combined) 

Number Examined Microscopically 10 

Nephropathy, Chronic 10 (2.0) 

Adenoma 0 

10 

9 (2.0) 

0 

10 

10 (2.0) 

0 

10 

10 (1.6) 

1 

2-Year Study 

Single Sections (Standard Evaluation) 

Number Examined Microscopically 

Hyperplasiac 

Nephropathy, Chronic 

Adenomad 

50 

1 (3.0) 

48 (2.6) 

0 

50 

0 

49 (2.6) 

1 

49 

1 (1.0) 

49 (2.6) 

4 

50 

1 (3.0) 

50 (2.7) 

2 

Step Sections (Extended Evaluation) 

Number Examined Microscopically 

Hyperplasia 

Adenoma 

Oncocytoma 

50 

8 (1.5) 

1 

0 

50 

8 (2.6) e 

1 

1 

49 

6 (1.6) 

2 

0 

50 

5 (2.4) 

2 

0 

Single Sections and Step Sections (Combined) 

Number Examined Microscopically 50 

Hyperplasia 9 (1.7) c 

Nephropathy, Chronic 48 (2.6) 

Adenoma 1 

Oncocytoma 0 

50 

8 (2.6) 

49 (2.6) 

2 

1 

49 

7 (1.5) 

49 (2.6) 

6 

0 

50 

6 (2.5) 

50 (2.7) 

4 

0 

(continued) 
48 

c 

Triethanolamine, NTP TR 449 

TABLE 8 

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats 

in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 

Nephropathy, Chronic 

10 

9 (1.0) 

10 

8 (1.0) 

10 

8 (1.0) 

10 

4* (1.3) 

2-Year Study 

Number Examined Microscopically 

Hyperplasia 

Nephropathy, Chronic 

Adenoma 

50 

0 

45 (1.7) 

1 

50 

0 

44 (1.5) 

1 

50 

0 

41 (1.7) 

0 

50 

1 

42 

0 

(1.0) 

(1.5) 

* Significantly different (P#0.05) from the vehicle control group by the Fisher exact test a Number of animals with lesion 

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

Includes hyperplasia and renal tubule hyperplasia d Historical incidence for 2-year NTP dermal studies with acetone vehicle control groups (mean ± standard deviation): 0/100. Historical 

incidence for 2-year NTP feed studies with untreated control groups: 9/1,200 (0.8% ± 1.5%); range, 0%-6%. e Severity grade was not given for one animal in this group. 

Uterus: The incidence of stromal polyp of the uterus Pituitary Gland: The incidences of hemosiderin 

was marginally increased in females in the 125 mg/kg pigment in the pituitary gland pars distalis increased 

group, but not in the 250 mg/kg group (2/50, 1/50, with increasing dose in male rats (0 mg/kg, 23/50; 

8/50, 5/50; Tables B1 and B3). Stromal polyps are 32 mg/kg, 24/50; 63 mg/kg, 32/48; 125 mg/kg, 

relatively common, spontaneously occurring, benign 35/50), and the incidence of angiectasis was also 

neoplasms in female rats, occurring in 3 of 50 vehicle marginally greater in males administered 125 mg/kg 

control females (6%) in the other dermal study with than in the vehicle controls (30/50, 36/50, 29/48, 

an acetone vehicle in the NTP database and in 39/50) (Table A5). These are minimal changes in the 

178/1,202 untreated control females (16%) in NTP incidence of common incidental lesions of uncertain 

feed studies. Also, the vehicle control incidence of biological significance. Conversely, the incidences of 

4% is well below the historical incidence for untreated these lesions were lower in females administered 

controls, and the incidence in the 125 mg/kg group is 250 mg/kg than in the vehicle controls (hemosiderin 

the same as the historical incidence for untreated pigmentation: 33/50, 29/50, 27/50, 22/50; angieccontrols. Therefore, the increased incidence of tasis: 37/50, 35/50, 36/50, 29/50) (Table B4). 

stromal polyp in females in the 125 mg/kg group was 

not considered to be related to triethanolamine 

administration. 
 

Triethanolamine, NTP TR 449 49 

MICE 

13-WEEK STUDY 

All mice survived to the end of the study (Table 9). 

The final mean body weight and weight gain of males 

in the 250 mg/kg group were less than those of the 

vehicle controls; the final mean body weights and 

weight gains of dosed females were similar to those of 

the vehicle controls. Clinical findings were observed 

only in mice in the 4,000 mg/kg groups and included 

scaliness, irritation, and discoloration at the site of 

triethanolamine application for males and females and 

skin erosion at this site in one male. 

Clinical pathology results are listed in Table G2. The 

most prominent difference from vehicle control values 

involved serum sorbitol dehydrogenase activity; 

treatment-related decreases in sorbitol dehydrogenase 

activities occurred in all dosed groups of males and 

females. Typically, an increase in serum sorbitol 

dehydrogenase activity indicates an increase in hepatocellular leakage or permeability; decreases in enzyme 

activity are often seen but can be explained only 

infrequently. Decreases in enzyme activity could 

reflect altered enzyme synthesis, release from hepatocytes, catabolism, inactivation, inhibition, or excretion 

(Schmidt and Schmidt, 1987, 1989; Pappas, 1989). 

TABLE 9 

Survival and Body Weights of Mice in the 13-Week Dermal Study of Triethanolamine 

Dose 

(mg/kg) 

Survivala Initial 

Mean Body Weight (g) b 

Final Change 

Final Weight 

Relative to Controls 

(%) 

Male 

0 

250 

500 

1,000 

2,000 

4,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

23.3 ± 0.6 

22.5 ± 0.5 

22.6 ± 0.5 

22.7 ± 0.5 

22.9 ± 0.3 

22.4 ± 0.4 

33.8 ± 0.5 

30.7 ± 0.7** 

31.8 ± 0.6 

32.7 ± 0.7 

32.2 ± 0.8 

31.9 ± 0.6 

10.5 ± 0.3 

8.2 ± 0.7* 

9.2 ± 0.8 

9.9 ± 0.4 

9.3 ± 0.5 

9.4 ± 0.5 

91 

94 

97 

95 

94 

Female 

0 

250 

500 

1,000 

2,000 

4,000 

10/10 

10/10 

10/10 

10/10 

10/10 

10/10 

18.7 ± 0.4 

19.0 ± 0.3 

18.5 ± 0.2 

18.9 ± 0.3 

19.0 ± 0.4 

18.7 ± 0.3 

28.3 ± 0.7 

28.2 ± 0.5 

28.8 ± 0.6 

28.8 ± 0.7 

28.4 ± 0.5 

27.5 ± 0.7 

9.6 ± 0.5 

9.2 ± 0.4 

10.2 ± 0.6 

9.9 ± 0.5 

9.4 ± 0.4 

8.7 ± 0.6 

100 

102 

102 

100 

97 

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

** P#0.01 a Number of animals surviving at 13 weeks/number initially in group b Weights and weight changes are given as mean ± standard error. 
 

50 Triethanolamine, NTP TR 449 

Differences in other hematology and clinical chemistry parameters were minimal or transient and were 

not considered to be biologically relevant. 

The absolute kidney and liver weights of males and 

females in the 4,000 mg/kg groups were significantly 

greater than those of the vehicle controls; relative 

kidney weights of males administered 1,000 mg/kg or 

greater and of all dosed groups of females were also 

greater than those of the vehicle controls (Table F9). 

The absolute and relative spleen weights of females in 

the 4,000 mg/kg group were significantly greater than 

those of the vehicle controls. Males administered 

4,000 mg/kg had a greater relative heart weight than 

the vehicle controls. 

No statistically significant differences in sperm 

morphology or vaginal cytology parameters occurred 

between dosed and vehicle control mice (Table H2). 

At necropsy, the skin of males and females administered 4,000 mg/kg was crusted (7/10 males, 

4/10 females) and white (1/10 males, 8/10 females), 

scaly (1/10 males), or both (5/10 males, 2/10 females) 

at the site of application. One female in the 

2,000 mg/kg group also had crusted skin. Minimal 

epidermal thickening (acanthosis), up to twice the 

normal thickness, occurred in nearly all dosed animals 

and in one vehicle control female (Table 10); the 

severity of acanthosis was greater in the 4,000 mg/kg 

groups than in the lower dose groups. Chronic active 

inflammation occurred in the 4,000 mg/kg groups and 

in one female in the 2,000 mg/kg group, with some 

animals having erosion, inflammation, or both. In 

these animals, the underlying dermis was often 

thickened by chronic active inflammation, including 

fibrosis. 

Dose Selection Rationale: Based on the presence of 

chronic inflammation at the site of application in the 

higher dose groups in the 13-week study, triethanolamine doses selected for use in the 2-year dermal 

study in mice were 200, 630, and 2,000 mg/kg for 

males and 100, 300, and 1,000 mg/kg for females. 

TABLE 10 

Incidences of Selected Nonneoplastic Lesions of the Skin at the Site of Application in Mice 

in the 13-Week Dermal Study of Triethanolamine 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Male 

Number Examined Microscopically 

Acanthosisa 10 0

10 

 8** (1.0)b 

10 

 9** (1.0) 

10 

10** (1.0) 

10 

10** (1.0) 

10 

10** (2.0) 

Inflammation, Chronic Active 0 0 0 0 0 7** (2.9) 

Female 

Number Examined Microscopically 10 10 10 10 10 10 

Acanthosis 1 (1.0) 10** (1.0) 9** (1.0) 10** (1.1) 9** (1.1) 10** (2.4) 

Inflammation, Chronic Active 0 0 0 0 1 (4.0) 4* (3.0) 

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

** P#0.01 a Number of animals with lesion 

b Average severity of lesions in affected rats: 1=minimal; 2=mild; 3=moderate; 4=marked 
Triethanolamine, NTP TR 449 51 

2-YEAR STUDY 

Survival 

Estimates of 2-year survival probabilities for male and 

female mice are shown in Table 11 and in the KaplanMeier survival curves (Figure 3). Survival rates of all 

dosed groups of males and females were similar to 

those of the vehicle controls. 

Body Weights and Clinical Findings 

The mean body weight of males administered 

2,000 mg/kg ranged from 8% to 10% less than that of 

the vehicle controls from week 69 through the end of 

the study; mean body weights of dosed and vehicle 

control females were similar throughout the study 

(Tables 12 and 13 and Figure 4). 

Clinical findings included irritation and discoloration 

of the skin at the site of application for most males in 

the 2,000 mg/kg group and a few females in the 

1,000 mg/kg group; males administered 200 or 

630 mg/kg also had skin irritation. In the 

2,000 mg/kg group, one male had thin skin and one 

male had crusty skin at the site of application. Clinical findings at sites other than the site of application 

included hair discoloration for males in the 

2,000 mg/kg group and females in the 1,000 mg/kg 

group. 

Organ Weights 

At the 15-month interim evaluation, the right kidney 

weights of male mice in the 630 and 2,000 mg/kg 

groups and the left kidney weights of males in the 

2,000 mg/kg group were significantly greater than 

those of the vehicle controls (Table F4). 
52 

c 

Triethanolamine, NTP TR 449 

TABLE 11 

Survival of Mice in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Male 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Moribund 2 5 3 6 

Natural deaths 2 5 8 3 

Animals surviving to study termination 

Percent probability of survival at the end of studyb 

46 

92 

40e 

80 

39 

78 

41 

82 

Mean survival (days)c 718 712 700 715 

Survival analysisd P=0.623 P=0.151 P=0.087 P=0.231 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Female 

Animals initially in study 60 60 60 60 

15-Month interim evaluationa 10 10 10 10 

Moribund 7 4 5 11 

Natural deaths 4 6 7 2 

Animals surviving to study termination 39e 40 38 37 

Percent probability of survival at the end of study 78 80 76 74 

Mean survival (days) 669 695 697 694 

Survival analysis P=0.661 P=0.915N P=1.000 P=0.895 

a Censored from survival analyses b	 Kaplan-Meier determinations 

Mean of all deaths (uncensored, censored, and terminal sacrifice). d	 The result of the life table trend test (Tarone, 1975) is in the vehicle control column, and the results of the life table pairwise comparisons 

(Cox, 1972) with the vehicle controls are in the dosed group columns. A lower mortality in a dose group is indicated by N. e Includes one animal that died during the last week of the study 
Triethanolamine, NTP TR 449 53 

FIGURE 3 

Kaplan-Meier Survival Curves for Male and Female Mice Administered Triethanolamine 

in Acetone by Dermal Application for 2 Years 
54 Triethanolamine, NTP TR 449 

TABLE 12 

Mean Body Weights and Survival of Male Mice in the 2-Year Dermal Study of Triethanolamine 

Weeks 0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

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 21.3 60 21.2 100 60 20.6 97 60 20.7 97 60 

2 23.3 60 23.6 101 60 23.3 100 60 23.6 101 60 

3 25.5 60 25.2 99 60 25.1 98 60 25.6 100 60 

4 26.1 60 25.9 99 60 26.0 100 60 26.6 102 60 

5 26.4 60 26.4 100 60 26.7 101 60 26.8 102 60 

6 27.0 60 27.0 100 60 27.0 100 60 27.3 101 60 

7 27.7 60 27.5 99 60 27.7 100 60 28.1 101 60 

8 28.5 60 28.6 100 60 28.8 101 60 29.1 102 60 

9 29.7 60 29.7 100 60 29.7 100 60 30.1 101 60 

10 30.2 60 30.2 100 60 30.4 101 60 30.9 102 60 

11 30.2 60 30.4 101 60 30.5 101 60 31.0 103 60 

12 31.1 60 31.3 101 60 31.3 101 60 31.6 102 60 

13 31.8 60 32.0 101 60 31.9 100 60 32.0 101 60 

17 34.1 60 34.5 101 60 34.6 102 60 34.5 101 60 

21 36.3 60 36.2 100 60 36.4 100 60 36.6 101 60 

25 38.1 60 38.2 100 60 38.3 101 60 38.5 101 60 

29 39.4 60 39.5 100 60 39.6 101 60 40.1 102 60 

33 43.3 60 43.4 100 60 43.4 100 60 43.7 101 60 

37 45.6 60 45.6 100 60 46.0 101 60 45.9 101 60 

41 46.0 60 46.5 101 60 46.4 101 60 46.7 102 60 

45 48.1 60 48.1 100 60 48.0 100 60 48.6 101 60 

49 48.0 60 48.3 101 60 47.8 100 60 48.7 102 60 

53 48.4 59 48.2 100 60 48.2 100 60 48.9 101 60 

57 48.6 59 48.6 100 60 48.5 100 59 49.3 101 60 

61 50.5 59 50.0 99 60 49.9 99 59 50.3 100 60 

65 49.7 59 49.3 99 60 49.7 100 59 49.5 100 60 

69a 49.9 49 49.2 99 50 49.6 99 49 46.9 94 50 

73 50.0 49 49.4 99 50 49.8 100 47 44.9 90 50 

77 50.2 49 48.7 97 49 49.0 98 47 46.3 92 50 

81 50.2 49 48.9 97 48 49.3 98 46 45.8 91 50 

85 50.5 49 48.6 96 48 49.2 97 46 46.5 92 48 

89 50.8 48 48.3 95 48 49.8 98 45 46.6 92 47 

93 50.1 48 46.7 93 47 48.1 96 44 45.0 90 47 

97 48.7 48 45.1 93 44 46.8 96 42 44.9 92 44 

101 48.6 47 44.9 92 41 46.5 96 39 43.5 90 43 

104 48.4 46 45.0 93 40 47.0 97 39 44.0 91 42 

Mean for weeks 

1-13 27.6 27.6 100 27.6 100 28.0 101 

14-52 42.1 42.3 100 42.3 100 42.6 101 

53-104 49.6 47.9 97 48.7 98 46.6 94 

a Interim evaluation occurred during week 66. 
Triethanolamine, NTP TR 449 55 

TABLE 13 

Mean Body Weights and Survival of Female Mice in the 2-Year Dermal Study of Triethanolamine 

Weeks 0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

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 17.6 60 17.4 99 60 17.6 100 60 17.4 99 60 

2 19.4 59 19.4 100 59 19.7 102 60 19.4 100 60 

3 21.1 59 21.1 100 59 21.0 100 60 21.0 100 60 

4 21.6 59 21.8 101 59 22.1 102 60 22.1 102 60 

5 22.8 59 23.0 101 59 23.1 101 60 23.2 102 60 

6 23.5 59 23.4 100 59 23.4 100 60 23.9 102 60 

7 24.9 59 24.4 98 59 24.9 100 60 25.1 101 60 

8 25.6 59 25.6 100 59 26.0 102 60 25.9 101 60 

9 26.4 59 26.2 99 59 26.6 101 60 26.5 100 60 

10 26.7 59 26.6 100 59 27.0 101 60 26.7 100 60 

11 27.2 59 26.9 99 59 27.3 100 60 27.4 101 60 

12 27.7 59 27.7 100 59 28.1 101 60 28.0 101 60 

13 28.5 59 28.1 99 59 29.0 102 60 28.6 100 60 

17 30.8 59 30.8 100 59 30.8 100 60 30.7 100 60 

21 32.7 59 32.8 100 59 32.8 100 60 32.5 99 60 

25 34.1 59 34.1 100 59 34.6 102 60 34.6 102 60 

29 35.7 58 35.9 101 59 35.8 100 60 36.1 101 60 

33 38.9 58 38.8 100 59 39.2 101 60 39.3 101 60 

37 41.9 58 41.1 98 59 41.3 99 60 41.8 100 60 

41 42.7 58 42.4 99 59 42.6 100 60 42.8 100 60 

45 45.0 57 44.6 99 59 44.6 99 60 45.3 101 60 

49 46.2 57 45.4 98 59 45.8 99 59 46.1 100 59 

53 46.4 56 45.2 97 59 46.3 100 59 46.1 99 59 

57 46.8 56 45.8 98 59 46.5 99 59 47.2 101 59 

61 49.6 56 48.2 97 58 48.9 99 59 49.3 99 58 

65 49.3 56 47.8 97 58 48.5 98 58 48.9 99 58 

69a 48.7 46 47.9 98 48 49.2 101 48 48.6 100 48 

73 49.4 45 48.4 98 48 49.8 101 48 48.2 98 48 

77 49.8 43 48.4 97 48 49.1 99 48 48.2 97 47 

81 50.0 43 48.5 97 47 49.0 98 47 49.1 98 45 

85 50.6 42 49.5 98 46 49.9 99 46 50.0 99 44 

89 51.6 42 49.2 95 46 51.1 99 44 51.0 99 44 

93 50.5 42 48.7 96 45 50.0 99 43 49.2 97 44 

97 49.6 42 47.8 96 43 49.3 99 41 47.9 97 41 

101 49.3 39 46.9 95 41 47.6 97 40 46.4 94 39 

104 49.2 39 46.7 95 40 48.2 98 38 46.1 94 37 

Mean for weeks 

1-13 24.1 24.0 100 24.3 101 24.2 100 

14-52 38.7 38.4 99 38.6 100 38.8 100 

53-104 49.3 47.8 97 48.8 99 48.3 98 

a Interim evaluation occurred during week 66. 
56 Triethanolamine, NTP TR 449 

FIGURE 4 

Growth Curves for Male and Female Mice Administered Triethanolamine 

in Acetone by Dermal Application for 2 Years 
Triethanolamine, NTP TR 449 57 

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 skin, 

liver, hematopoietic system, and bone. 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. 

Skin: Acanthosis and inflammation of the skin were 

observed at the site of application in male and female 

mice at the 15-month interim evaluation and at the end 

of the 2-year study (Tables 14, C5, and D5). In 

males in the 2,000 mg/kg group, the incidences of 

both lesions were significantly greater than those in 

the vehicle controls at both time points; however, the 

severity of acanthosis and inflammation did not 

increase with increasing dose. 

After 2 years, the incidences of minimal to mild 

chronic inflammation at the site of application were 

generally greater in dosed males and females than in 

the vehicle controls (Table 14). Additionally, the 

incidences of thickened epidermis (acanthosis) and 

segmental atrophy of hair follicles and associated 

sebaceous glands were significantly greater in males 

in the 2,000 mg/kg group than in the vehicle controls. 

The acanthosis in male mice was mild (thickness two 

to three times normal) and had a focal to segmental 

distribution. The minimal infiltrates of chronic 

inflammatory cells in the dermis often occurred in 

conjunction with the acanthosis. The adnexal atrophy 

was minimal to mild and usually occurred without 

concurrent acanthosis and dermal inflammation. It 

was characterized by an absence or reduced number 

of hair follicles and sebaceous glands in a distinct 

segment of the site of application; the hair follicles 

and sebaceous glands that were present appeared 

relatively normal to slightly hypertrophic. The 

incidences of skin neoplasms in dosed mice were 

similar to those in the vehicle controls at and away 

from the site of application. 

Liver: The incidences of hepatocellular neoplasms in 

females receiving 1,000 mg/kg were significantly 

greater than those in the vehicle controls (Tables 15, 

C3, and D3). The historical incidences of these 

neoplasms in recent NTP feed studies range from 3% 

to 56% (Tables 15 and D4). The historical rates for 

dermal studies include only two other studies with an 

acetone vehicle; the incidences of hepatocellular 

neoplasms in females in these studies were 14% and 

20%. While the greater neoplasm incidences in dosed 

mice were for benign (adenoma) rather than malignant 

(carcinoma) hepatocellular neoplasms, the number of 

females in the 1,000 mg/kg group with multiple 

adenomas was significantly greater than that in the 

vehicle controls. The incidences of eosinophilic foci 

in females in the 300 and 1,000 mg/kg groups were 

slightly greater than the incidence in the vehicle 

controls, although the difference was statistically 

significant only in the 300 mg/kg group (Table 15). 

In males, the incidences of hepatocellular neoplasms 

in the 2,000 mg/kg group were significantly greater 

than those in the vehicle controls (Tables 15 and C3). 

The historical incidences of these neoplasms range 

from 10% to 68% (Tables 15 and C4). In the other 

dermal studies in the historical database with an 

acetone vehicle, the incidences of hepatocellular 

neoplasms in males were 18% and 46%. The number 

of males in the 2,000 mg/kg group with multiple 

adenomas was significantly greater than that in the 

vehicle controls. Additionally, the incidence of 

eosinophilic foci was significantly greater in males in 

the 2,000 mg/kg group than in the vehicle controls 

(Table 15). Hepatoblastomas, which do not commonly occur spontaneously, were observed in the 

livers of three males in the 2,000 mg/kg group. 

The hepatocellular adenomas were well-demarcated 

nodular proliferations (Plate 3) that often occupied 

several lobules and caused compression of the surrounding parenchyma (Plate 4). There was loss of 

normal lobular architecture, and hepatic cords 

abruptly intersected with those of the surrounding 

tissue. Although the cellular morphology within 

neoplasms varied, generally the neoplastic cells were 

large and variably vacuolated, with abundant eosinophilic cytoplasm and large round nuclei. The eosinophilic foci were variably sized; the largest occupied 

several hepatic lobules, with limited compression of 

the adjacent parenchyma. The foci were composed of 

large cells as described for the adenomas. 
58 Triethanolamine, NTP TR 449 

TABLE 14 

Incidences of Nonneoplastic Lesions of the Skin at the Site of Application in Mice 

in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Acanthosisa 0 1 (1.0) b 1 (3.0) 6** (1.7) 

Inflammation, Chronic 0 0 2 (2.0) 5* (1.4) 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Acanthosis 2 (2.0) 1 (1.0) 6 (1.3) 11** (1.9) 

Inflammation, Chronic 2 (1.5) 0 7 (1.1) 11** (1.6) 

Ulcer 1 (1.0) 0 2 (2.0) 2 (2.5) 

Hair Follicle, Sebaceous Gland, Atrophy 0 0 1 (1.0) 15** (1.7) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Acanthosis 0 1 (1.0) 0 2 (1.5) 

Inflammation, Chronic 0 0 0 3 (1.0) 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Acanthosis 0 2 (2.0) 1 (1.0) 3 (1.3) 

Inflammation, Chronic 0 2 (1.5) 2 (1.0) 5* (1.4) 

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

regression test (2-year study) 

** P#0.01 a Number of animals with lesion 

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked 
Triethanolamine, NTP TR 449 59 

TABLE 15 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice in the 2-Year Dermal Study 

of Triethanolamine 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Male 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Basophilic Focusa 0 1 1 0 

Clear Cell Focus 0 1 0 0 

Eosinophilic Focus 0 0 0 1 

Mixed Cell Focus 0 0 0 2 

Karyomegaly 2 1 1 2 

Oval Cell, Hyperplasia 2 1 1 3 

Hepatocellular Adenoma 1 2 1 4 

Hepatocellular Carcinoma 1 2 0 1 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Basophilic Focus 7 2 3 3 

Clear Cell Focus 13 10 7 5 

Eosinophilic Focus 10 17 11 23** 

Karyomegaly 11 17 9 16 

Oval Cell, Hyperplasia 10 14 9 16 

Hepatocellular Adenoma 

Overall rateb 27/50 (54%) 27/50 (54%) 29/50 (58%) 37/50 (74%) 

Adjusted ratec 

Terminal rated 

54.0% 

23/46 (50%) 

62.7% 

24/40 (60%) 

67.4% 

25/39 (64%) 

78.6% 

31/41 (76%) 

First incidence (days) 367 665 607 572 

Logistic regression teste P=0.012 P=0.571 P=0.359 P=0.034 

Hepatocellular Adenoma, Multiple 17 18 17 29* 

Hepatocellular Carcinoma 

Overall rate 15/50 (30%) 20/50 (40%) 15/50 (30%) 14/50 (28%) 

Adjusted rate 31.2% 43.0% 33.2% 30.0% 

Terminal rate 13/46 (28%) 14/40 (35%) 9/39 (23%) 9/41 (22%) 

First incidence (days) 678 537 507 572 

Logistic regression test P=0.175N P=0.207 P=0.585 P=0.494N 

Hepatocellular Carcinoma, Multiple 6 8 7 5 

Hepatoblastoma 0 0 0 3 

Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastomaf 

Overall rate 31/50 (62%) 34/50 (68%) 33/50 (66%) 42/50 (84%) 

Adjusted rate 62.0% 72.2% 73.3% 85.7% 

Terminal rate 27/46 (59%) 27/40 (68%) 27/39 (69%) 34/41 (83%) 

First incidence (days) 467 537 507 572 

Logistic regression test P=0.009 P=0.359 P=0.377 P=0.018 

* Significantly different (P#0.05) from the vehicle control group by the logistic regression test 

** P#0.01 
60 Triethanolamine, NTP TR 449 

TABLE 15 

Incidences of Neoplasms and Nonneoplastic Lesions of the Liver in Mice in the 2-Year Dermal Study 

of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Female 

15-Month Interim Evaluation 

Number Examined Microscopically 10 10 10 10 

Basophilic Focus 0 0 1 0 

Clear Cell Focus 0 1 0 0 

Eosinophilic Focus 2 0 0 1 

Hepatocellular Adenoma 2 2 1 1 

2-Year Study 

Number Examined Microscopically 50 50 50 50 

Basophilic Focus 0 2 1 1 

Clear Cell Focus 1 0 0 1 

Eosinophilic Focus 9 10 18* 16 

Karyomegaly 0 1 0 0 

Hepatocellular Adenoma 

Overall rate 22/50 (44%) 22/50 (44%) 24/50 (48%) 40/50 (80%) 

Adjusted rate 54.9% 53.6% 58.3% 95.2% 

Terminal rate 21/39 (54%) 21/40 (53%) 21/38 (55%) 35/37 (95%) 

First incidence (days) 681 650 597 647 

Logistic regression test P<0.001 P=0.496N P=0.480 P<0.001 

Hepatocellular Adenoma, Multiple 11 9 13 29** 

Hepatocellular Carcinoma 

Overall rate 1/50 (2%) 4/50 (8%) 7/50 (14%) 5/50 (10%) 

Adjusted rate 2.6% 9.0% 16.0% 12.8% 

Terminal rate 1/39 (3%) 2/40 (5%) 4/38 (11%) 4/37 (11%) 

First incidence (days) 729 (T) 557 434 591 

Logistic regression test P=0.204 P=0.176 P=0.024 P=0.110 

Hepatocellular Adenoma or Carcinomag 

Overall rate 23/50 (46%) 26/50 (52%) 28/50 (56%) 41/50 (82%) 

Adjusted rate 57.4% 60.2% 64.7% 95.3% 

Terminal rate 22/39 (56%) 23/40 (58%) 23/38 (61%) 35/37 (95%) 

First incidence (days) 681 557 434 591 

Logistic regression test P<0.001 P=0.457 P=0.276 P<0.001 

(T)Terminal sacrifice 

a	 Number of animals with lesion 

b	 Number of animals with neoplasm per number of animals with liver examined microscopically 

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

the pairwise comparisons between the vehicle controls and that dosed group. The logistic regression test regards neoplasms in animals dying 

prior to terminal kill as nonfatal. For all tests, a negative trend or a lower incidence in a dose group is indicated by N. f	 Historical incidence for 2-year NTP dermal studies with acetone vehicle control groups (mean ± standard deviation): 63/150 

(42.0% ± 22.3%); range, 18%-62%. Historical incidence for 2-year NTP feed studies with untreated control groups: 509/1,316 

(38.7% ± 13.9%); range, 10%-68% 

g	 Historical incidence (dermal): 40/150 (26.7% ± 17.0%); range, 14%-46%. Historical incidence (feed): 260/1,312 (19.8% ± 12.8%); 

range, 3%-56% 

c 
Triethanolamine, NTP TR 449 61 

Hepatoblastomas are uncommon neoplasms in mice; 

these neoplasms may occur spontaneously or may be 

chemically induced in the liver of several mouse 

strains (Turusov et al., 1973; Nonoyama et al., 

1988), including the B6C3F1 mouse used in NTP 

studies. It is considered to be a malignant neoplasm, 

and in NTP studies, its metastatic potential appears 

similar to that of hepatocellular carcinomas. Hepatoblastomas are easily diagnosed on hematoxylin- and 

eosin-stained sections because of their distinctive 

morphology and were typical in this study. The neoplasms were sharply demarcated from surrounding 

tissue (Plate 5) and were composed of deep 

basophilic-staining pleomorphic (small spindle to large 

ovoid) cells arranged in compact sheets, islands, or 

trabeculae (Plate 6). Cells generally contained a scant 

amount of eosinophilic cytoplasm and had round to 

oval nuclei. Two of the hepatoblastomas were less 

than 5 mm in diameter, while the third was 2 cm in 

diameter, with trabeculae and large, cystic, hemorrhagic areas and a thick fibrous capsule. 

Hepatoblastomas almost always occur within an 

existing proliferative lesion, most often a hepatocellular carcinoma. In NTP studies, the diagnosis of 

hepatoblastoma is made whenever this distinctive 

lesion is observed. To avoid duplicate diagnoses, no 

separate diagnosis is made for the lesion within which 

the hepatoblastoma occurs. The cell of origin of the 

hepatoblastoma has not been clearly defined in rodents 

or humans but may be a very primordial cell 

(Abenoza et al., 1987; Nonoyama et al., 1988; Van 

Eyken et al., 1990). To determine the significance of 

increases in the incidences of neoplasms that may be 

related to chemical treatment, the NTP generally 

performs statistical analyses on benign and malignant 

neoplasms of like histogenesis both independently and 

in combination. Although the biology of hepatoblastomas is not fully understood, the NTP considers 

this neoplasm to be part of the spectrum of liver 

neoplasms that occurs spontaneously and as a result of 

chemical treatment. Therefore, the NTP considers the 

combined analyses (hepatocellular carcinoma and 

hepatoblastoma; hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) the most 

important analyses in evaluating the carcinogenic 

potential of an agent on the liver. 

The livers of many of the male mice in all groups, 

including the vehicle controls, had mild to moderate 

karyomegaly of hepatocytes and oval cell hyperplasia 

(Table 15). These lesions occurred with greater 

incidences and/or severities than spontaneous occurrences. Individual hepatocytes in periportal areas 

were variably, and often markedly, enlarged, including nuclear enlargement (karyomegaly). Enlarged 

cells had varying degrees of cytoplasmic vacuolization, and frequently the cytoplasm was invaginated 

into the nucleus. Near the portal triads, along sinusoidal channels, were increased numbers of small, 

dark, ovoid- to spindle-shaped cells that were presumed to be “oval cells” or bile duct epithelium. 

These changes are consistent with those described by 

Ward et al. (1994a,b) as occurring in animals with 

livers containing Helicobacter hepaticus bacterial 

organisms. A Warthin-Starry histologic staining 

procedure was performed on sections of liver from 

12 affected males, three unaffected males, and four 

unaffected females. Bacterial organisms were identified in affected, but not in unaffected, livers. The 

organisms were generally thin, elongate (2 to 10 μm), 

often spiraled rods observed singly or in small clusters. The bacteria were between and at the periphery 

of hepatocytes, which is consistent with localization 

within bile canaliculi as described by Ward et al. 

(1994a,b). Frozen livers from four male mice with 

characteristic liver lesions were evaluated with a 

polymerase chain reaction (PCR)-based assay and 

culture (Fox et al., 1998); all were confirmed to be 

infected with H. hepaticus. In a larger subsequent 

analysis of 44 male and female mice without characteristic liver lesions, H. hepaticus-specific DNA was 

amplified from the livers of 21 of 44 mice (47%) 

compared to 14 of 44 mice (32%) having H. hepaticus 

cultured from frozen liver. Similar PCR assay results 

were obtained in frozen liver from a smaller subset of 

these same mice at a different laboratory (Malarkey 

et al., 1997; Appendix L). 

Hematopoietic System: The incidence of malignant 

lymphoma (all types) was significantly greater in 

females administered 1,000 mg/kg than in the vehicle 

controls (0 mg/kg, 6/50; 100 mg/kg, 10/50; 

300 mg/kg, 6/50; 1,000 mg/kg, 15/50; Table D3). 

Malignant lymphoma in mice, especially females, is 

a commonly occurring neoplasm with a variable 

incidence. These neoplasms occurred in 324 of 

1,320 (24.5%) untreated female mice in NTP feed 

studies in the historical database; in the two other 

dermal studies with acetone as the vehicle, malignant 

lymphomas occurred in 22 of 100 vehicle control 

females. In this study, the incidences were not 
62 Triethanolamine, NTP TR 449 

increased in other dosed groups, and the incidence in 

the 300 mg/kg group was the same as in the vehicle 

control group. Also, the vehicle control incidence of 

12% is well below the historical control incidences, 

while the incidence of 30% in the 1,000 mg/kg group 

is close to the average historical control incidence. 

Although male mice received triethanolamine at doses 

that were twice those administered to females, the 

incidences of malignant lymphoma in dosed and 

vehicle control males were similar (0 mg/kg, 4/50; 

200 mg/kg, 1/50; 630 mg/kg, 9/50; 2,000 mg/kg, 

1/50). Therefore, the increased incidence of malignant lymphoma in female mice in the 1,000 mg/kg 

group was not considered to be related to triethanolamine administration. 

Bone: Osteosarcomas were observed in two female 

mice administered 1,000 mg/kg (Table D1). In one 

female, the osteosarcoma involved the right scapula, 

while in the other female, the lumbar vertebrae were 

involved. An additional osteosarcoma occurred in the 

inguinal skin of a female in the 300 mg/kg group; 

there was no evidence of a primary site in the bone of 

this mouse. These osteosarcomas were composed of 

variably sized and shaped spindle cells with multifocal 

areas of osteoid formation. Osteosarcoma is an 

uncommon neoplasm in mice, occurring in 7 of 

1,320 untreated control females. These neoplasms are 

not considered to be related to triethanolamine 

administration because of their low incidences, the 

lack of statistical significance, and the lack of other 

information that would suggest an effect of triethanolamine on bone. 

GENETIC TOXICOLOGY 

Triethanolamine (33 to 3,333 μg/plate) was negative 

for induction of mutations in Salmonella typhimurium 

strains TA98, TA100, TA1535, and TA1537 when 

tested with or without S9 metabolic activation 

(Table E1; Mortelmans et al., 1986). In cytogenetic 

tests with cultured Chinese hamster ovary cells, no 

induction of sister chromatid exchanges (Table E2) or 

chromosomal aberrations (Table E3) was observed 

with or without S9 (Galloway et al., 1987). In the 

sister chromatid exchange test without S9, the first of 

two trials was negative. In the second trial, a significant increase in sister chromatid exchanges was 

observed at the highest dose tested (2,520 μg/mL), 

but the trend test was negative (P$0.025), and the trial 

was concluded to be equivocal. Severe cytotoxicity 

limited the number of cells that could be scored at this 

high dose. Overall, the sister chromatid exchange test 

was considered to be negative. Cytotoxicity was also 

noted at the highest dose tested (4,030 μg/mL) in the 

chromosomal aberrations test without S9. 

Triethanolamine administered by feeding or injection 

at doses up to 30,000 ppm did not induce sex-linked 

recessive lethal mutations in germ cells of male 

Drosophila melanogaster (Table E4; Yoon et al., 

1985). Results of an in vivo peripheral blood micronucleus test in mice were also negative (Table E5). In 

this test, blood samples were obtained from male and 

female mice after 13 weeks of dermal applications of 

1,000 to 4,000 mg/kg triethanolamine. No significant 

increases in the frequencies of micronucleated normochromatic or polychromatic erythrocytes were 

observed at any dose tested. 
63 

DISCUSSION AND CONCLUSIONS 

Triethanolamine has use patterns that could lead to findings of very mild but generally dose-related 

human exposure through a variety of routes. Clearly increases in serum alanine and aspartate aminotransits use in cosmetics results in dermal exposure, but its ferase activities were suggestive of liver injury. 

presence in cutting fluids and in other industrial However, sorbitol dehydrogenase activity, which is 

applications could also lead to inhalation of mists. generally considered to be a better gauge of liver 

The chemical is also approved for use in food pack- damage, was not increased, and histopathology 

aging, potentially resulting in oral ingestion. Because revealed no evidence of hepatic injury. Aspartate 

of this, comparative 2-week studies were performed aminotransferase has a wider tissue distribution than 

with triethanolamine administered to rats and mice at sorbitol dehydrogenase, and increased serum activity 

concentrations up to 80,000 ppm in drinking water, could be related to minor injury at another site, such 

2,000 mg/m3 by whole body inhalation, and as the muscle, rather than to hepatotoxicity. Addi3,370 mg/kg by dermal application (NTP, unpub- tionally, some compounds can cause increases in 

lished data). The results of these short-term studies alanine aminotransferase activity in the liver or serum 

gave little evidence of significant systemic toxicity by without causing hepatic injury. 

any route. Triethanolamine was toxic at the site of 

application, resulting in hemorrhage and necrosis of Kidney weights increased with increasing dose in male 

the glandular stomach of rats in the drinking water and female rats in the 13-week study. Dosed males 

study, inflammation of the laryngeal submucosa in had decreased urinary protein excretion which likely 

rats and mice in the inhalation studies, and inflam- reflected a change in renal function or an increase in 

mation of the skin of rats and mice in the dermal protein reabsorption, as serum protein concentrations 

studies. Poor palatability led to the deaths of rats were not affected. Although these findings suggest 

receiving 80,000 ppm triethanolamine in drinking the possibility of protein droplet accumulation or some 

water. other form of renal dysfunction or injury, no evidence 

of hyaline droplet nephropathy or other histopathoThe dermal route of exposure was chosen for further logic changes that might account for the weight 

studies because of the predominant potential for changes was noted. 

dermal exposure to humans through the use of cosmetics. Studies of absorption and metabolism of Lesions at the site of application in rats in the 13-week 

triethanolamine have indicated quite extensive dermal study ranged from no discernable change, through 

absorption of doses similar to those used in the minimal to mild epidermal thickening (acanthosis), to 

13-week studies, with little evidence of significant chronic active inflammation, erosion, and ulceration. 

metabolism prior to excretion in urine and feces The dermis was also thickened with inflammation and 

(Melnick and Tomaszewski, 1990). Thus, dermal fibrosis at the higher doses. There was no histologic 

studies were expected to provide a systemic challenge evidence to suggest the development of skin sensitizaand yield information applicable to exposure by other tion or contact dermatitis. This does not, however, 

routes. rule out the possibility that triethanolamine might 

cause contact sensitization in a more sensitive animal 

In the 13-week rat study, topical application of model, such as the guinea pig. Doses selected for the 

2,000 mg triethanolamine per kilogram body weight 2-year study were lower than those that caused 

resulted in a significant decrease in body weight gain, inflammation in the 13-week study. 

and grossly visible crusts at the site of application 

were noted in males and females administered 1,000 The findings in the 13-week mouse study were similar 

or 2,000 mg/kg. Hematologic changes were consis- to those in the rat study. Clinical pathology and 

tent with the presence of skin inflammation in rats in histopathology evaluations provided no evidence of 

the 2,000 mg/kg groups, and clinical chemistry significant systemic toxicity, although liver and kidney 
64 Triethanolamine, NTP TR 449 

weights were increased in the 4,000 mg/kg groups. the standard histopathologic evaluation, and thus this 

Dose-related decreases in serum sorbitol dehydro- incidence may be compared to historical control data. 

genase activities occurred in male and female mice. The 8% incidence in the 63 mg/kg group exceeds the 

The cause of this change, and any possible biological historical mean (0.8%) and range (0%-6%) observed 

relevance it may have, are unclear. Doses selected in previous untreated control groups from feed 

for the 2-year mouse study were lower than those that studies. However, the lack of both a clear dose 

caused inflammation at the site of application in the response and an increase in incidences of total prolif13-week study. erative lesions in dosed rats leaves doubt that this 

result could be attributed to triethanolamine adminisAlthough the results of the 13-week rat study led to tration with certainty. Other examples of the use of 

the selection of doses for female rats in the 2-year an extended evaluation of the kidney and their interstudy that were twice those administered to males, the pretation have been discussed by Eustis et al. (1994). 

females were clearly more sensitive to triethanolamine 

administration, as shown by the much greater inci- In a previous carcinogenicity study in which triethdences and severities of inflammation and irritation at anolamine was administered in drinking water at 

the site of application in females compared to males in concentrations of 1% and 2% to groups of 47 to 

the 2-year study. Ulceration occurred in about half 50 F344/DuCrj rats (Maekawa et al., 1986), two 

the female rats receiving 125 or 250 mg/kg, while renal tubule adenomas were observed in females in 

only 5 of 50 males receiving 125 mg/kg had similar the 2% group; none occurred in the controls or in the 

lesions. The survival rate of female rats receiving 1% group. This finding was discounted by the 

250 mg/kg was less than that of the other groups, authors because renal toxicity was observed in females 

although the mean body weight of this group was only in the 2% group. Doses were halved for females after 

slightly decreased during the study, and this decrease week 68 because of toxicity. The total triethanolwas observed only around week 90. There were no amine intake during the study was reported to be 119 

skin neoplasms in male or female rats at or away from or 232 mg (actually grams) for female rats. For 

the site of application that were considered to be comparison, assuming 100% absorption of material 

related to triethanolamine administration. from the skin and average body weights of 350 g for 

males and 200 g for females, rats in the 125 (male) 

Histopathologic findings which were evaluated to and 250 mg/kg (female) groups in the current studies 

determine their relationship with triethanolamine would have received total doses of approximately 23 g 

exposure included renal tubule adenomas in male rats for males and 26 g for females. Thus, the lack of 

and thyroid gland C-cell adenomas and carcinomas kidney toxicity in the current study is consistent with 

and uterine stromal polyps in female rats. The the findings of Maekawa et al. (1986). These authors 

increased incidences of thyroid gland C-cell neo- also reported increased incidences of hepatic neoplasms and uterine stromal polyps were not con- plasms in males and uterine endometrial sarcoma in 

sidered to be related to triethanolamine administration. females. However, these findings were not attributed 

The evidence for a relationship between the renal to triethanolamine administration because in compartubule neoplasms in male rats and triethanolamine ison to historical incidences, the neoplasm trends 

administration was considered equivocal. The total reflected low incidences in the control groups rather 

number of male rats identified in the combined single than increased incidences in the exposed groups. 

and step-section evaluations as having proliferative 

lesions (hyperplasia and adenoma) of the renal tubule In the current 2-year mouse study, the doses were 

epithelium was 10/50 (vehicle controls), 8/50 much greater than those administered to rats in 

(32 mg/kg), 11/49 (63 mg/kg), and 8/50 (125 mg/kg). relation to body weight. Inflammation and acanthosis 

Although the proliferative lesions were observed only of the skin were seen in the mouse study but were 

microscopically, those that were identified as ade- much less severe than the lesions in dosed rats, and 

nomas were clearly larger lesions; these appeared in there was little evidence of progression of the lesions. 

one vehicle control male, two males in the 32 mg/kg Treatment-related skin neoplasms did not occur at or 

group, six males in the 63 mg/kg group, and four away from the site of application. Survival rates were 

males in the 125 mg/kg group. Four of the six 74% or greater in all groups, and possible treatmentadenomas in the 63 mg/kg group were noted during related effects on body weights were observed only in 
Triethanolamine, NTP TR 449 65 

males in the 2,000 mg/kg group after week 65. The 

maximum mean body weight of males and females 

was approximately 50 g, which is moderately heavy 

but is consistent with other recent studies in which 

mice were housed individually. It is likely that male 

and female mice could have tolerated somewhat 

higher doses, but the selection of doses was appropriate, based on the findings of the 13-week studies. 

The incidences of proliferative lesions of the liver 

were increased in male and female mice receiving 

triethanolamine for 2 years. In females, the incidences of hepatocellular carcinoma and eosinophilic 

foci were significantly greater in the 300 mg/kg group 

and the incidences of hepatocellular adenoma and 

multiple adenomas were significantly greater in the 

1,000 mg/kg group than in the vehicle controls. In 

male and female mice, the combined incidences of 

hepatocellular neoplasms showed a positive, doserelated trend and were significantly greater in males in 

the 2,000 mg/kg group and females in the 

1,000 mg/kg group than in the vehicle controls. The 

incidences of hepatocellular neoplasms in dosed and 

vehicle control females exceeded the historical control 

range for untreated controls. In males, increased 

incidences were limited to hepatocellular adenomas, 

multiple adenomas, and eosinophilic foci in animals 

receiving 2,000 mg/kg. In addition, three males in 

this group each had a hepatoblastoma, a rare and 

atypical form of hepatocellular carcinoma. However, 

the incidence of hepatocellular carcinoma was not 

increased in this group. 

Based on retrospective analyses, Helicobacter 

hepaticus was determined to have infected mice in 

12 recent NTP 2-year studies (Appendix L). Of the 

12 studies, mice (primarily males) from nine studies, 

including the current study of triethanolamine, had 

H. hepaticus-associated hepatitis. Qualitatively, the 

hepatitis and the silver-staining organisms within the 

liver were similar among the nine studies. In studies 

from which adequately preserved (frozen) liver tissue 

was available, including the triethanolamine study, an 

organism compatible with H. hepaticus was identified 

with assays based on polymerase chain reaction (PCR) 

(Malarkey et al., 1997; Fox et al., 1998). In general, 

efforts to identify H. hepaticus from tissue that had 

been fixed in formalin for longer than a week were 

not successful (Malarkey et al., 1997). Because of 

the presence of the typical liver lesions, silver-staining 

helical organisms, and confirmation with PCR-based 

assays and culture, mice from the current study of 

triethanolamine were determined to be infected with 

H. hepaticus. 

Increases in the incidences of hepatocellular neoplasms in male mice have been shown to be associated 

with H. hepaticus infection when hepatitis is also 

present (Ward et al., 1994a; Fox et al., 1996; 

Appendix L). Additionally, in NTP studies in which 

the H. hepaticus-associated hepatitis was observed, 

there was an increased incidence of hemangiosarcoma 

of the liver in male mice (Appendix L). Because of 

the former association, interpretation of the increased 

incidences of hepatocellular neoplasms in male mice 

in the triethanolamine study was confounded. Other 

findings in this study were not considered to have 

been significantly impacted by the infection with 

H. hepaticus or its associated hepatitis. 

In female mice, there were also significantly increased 

incidences of hepatocellular neoplasms. The association of triethanolamine with liver neoplasms in female 

mice is more certain, and NTP staff originally 

proposed that this constituted “some evidence” of 

carcinogenicity. The Technical Reports Review 

Subcommittee considered the female mouse study to 

be inadequate, however, because of uncertainty about 

the potential for H. hepaticus infection to influence 

the liver neoplasm incidence (see pages 15 and 16). 

As mentioned earlier, there have been several other 

carcinogenicity studies of triethanolamine in mice. 

Konishi et al. (1992) found that triethanolamine was 

not carcinogenic or toxic in B6C3F1 mice receiving 

1% or 2% in drinking water for 82 weeks. Incidences 

of liver neoplasms were reported, and the only suggestive finding was a nonsignificant increase in the 

incidences of hyperplastic nodules in female mice 

(vehicle controls, 4%; 1% group, 8%; 2% group, 

12%). Whether treatment-related liver neoplasia 

would have developed if the study had progressed for 

2 years is unknown. There was no evidence of 

increased incidences of liver neoplasms at 15 months 

in the present study, although the doses used by 

Konishi et al. likely resulted in a greater total exposure to triethanolamine than occurred in this study. 

Hoshino and Tanooka (1978) reported increased incidences of malignant lymphoma in female ICR-JCL 

mice receiving a relatively low dose of 0.03% or 

0.3% triethanolamine in feed in a lifetime study. 
_________ 

66 Triethanolamine, NTP TR 449 

Other studies with this strain have reported much 

greater control incidences of malignant lymphoma 

(Konishi et al., 1992) than was found in the Hoshino 

and Tanooka study, and this may account for these 

findings. Incidences of malignant lymphoma, 

although not thymic lymphoma as reported by 

Hoshino and Tanooka, were also increased in the 

present study. This was also attributed to a lower 

than expected vehicle control incidence of this rather 

common and variable neoplasm. 

The results of a variety of in vitro and in vivo assays 

for genetic toxicity of triethanolamine were negative. 

Potential mechanisms accounting for the increased 

incidence of liver neoplasms in female mice will 

require further study. 

CONCLUSIONS 

Under the conditions of these dermal studies, there 

was equivocal evidence of carcinogenic activity* of 

triethanolamine in male F344/N rats based on a 

marginal increase in the incidences of renal tubule cell 

adenoma. There was no evidence of carcinogenic 

activity in female F344/N rats receiving 63, 125, or 

250 mg triethanolamine per kilogram body weight. 

The study in male and female B6C3F1 mice was 

considered inadequate, because the presence of a 

Helicobacter hepaticus infection complicated interpretation of the relationship between triethanolamine 

administration and liver neoplasms in these animals. 

Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, 

and dosed female rats had epidermal erosion at the 

site of skin application. 

* Explanation of Levels of Evidence of Carcinogenic Activity is on page 11. A summary of the Technical Reports Review Subcommittee 

comments and the public discussion on this Technical Report appears on page 14. 
67 

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74 Triethanolamine, NTP TR 449 
75 

APPENDIX A 

SUMMARY OF LESIONS IN MALE RATS 

IN THE 2-YEAR DERMAL STUDY 

OF TRIETHANOLAMINE 

TABLE A1 

TABLE A2 

TABLE A3 

TABLE A4 

TABLE A5 

Summary of the Incidence of Neoplasms in Male Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 

Individual Animal Tumor Pathology of Male Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 

Statistical Analysis of Primary Neoplasms in Male Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 

Historical Incidence of Renal Tubule Adenomas in Control Male F344/N Rats ........ 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 

76 

82 

104 

108 

109 
 

 

 

 

 

76 Triethanolamine, NTP TR 449 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Accidental deaths 

Moribund 

Natural deaths 

Survivors 

Terminal sacrifice 

Missexed 

60 

10 

2 

18 

9 

21 

60 

10 

27 

12 

11 

60 

10 

25 

6 

18 

1 

60 

10 

23 

8 

19 

Animals examined microscopically 60 60 59 60 

15-Month Interim Evaluation 

Endocrine System 

Adrenal medulla 

Pheochromocytoma benign

Pituitary gland 

Pars distalis, adenoma

Thyroid gland 

C-cell, adenoma

(10) 

(10) 

 3 (30%) 

(10) 

 1 (10%) 

(10) 

(10) 

 3 (30%) 

(10) 

(10) 

 1 (10%) 

(10) 

 5 (50%) 

(10) 

 1 (10%) 

(10) 

(10) 

 2 (20%) 

(10) 

Genital System 

Epididymis 

Prostate 

Testes 

Bilateral, interstitial cell, adenoma

Interstitial cell, adenoma

(10) 

(10) 

(10) 

 1 (10%) 

 2 (20%) 

(10) 

(10) 

(10) 

 3 (30%) 

 4 (40%) 

(10) 

(10) 

(10) 

 1 (10%) 

 3 (30%) 

(10) 

(10) 

(10) 

 4 (40%) 

Integumentary System 

Skin 

Subcutaneous tissue, fibroma

(10) (10) 

 1 (10%) 

(10) (10) 

Systemic Lesions 

Multiple organsb 

Leukemia mononuclear

Mesothelioma NOS

(10) 

 1 (10%) 

 1 (10%) 

(10) (10) 

 1 (10%) 

(10) 

 1 (10%) 

Systems Examined with No Neoplasms Observed 

Alimentary System 

Cardiovascular System 

General Body System 

Hematopoietic System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Special Senses System 

Urinary System 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 77 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (49) (50) 

Leiomyosarcoma 1 (2%) 

Intestine small, duodenum (50) (50) (49) (50) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (2%) 

Leiomyosarcoma, metastatic, stomach, 

glandular 1 (2%) 

Intestine small, jejunum (50) (50) (49) (50) 

Fibrous histiocytoma, metastatic, spleen 1 (2%) 

Mast cell tumor malignant 1 (2%) 

Intestine small, ileum (50) (50) (49) (50) 

Fibrous histiocytoma, metastatic, spleen 1 (2%) 

Liver (50) (50) (49) (50) 

Hepatocellular carcinoma 1 (2%) 

Hepatocellular adenoma 3 (6%) 1 (2%) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (2%) 

Leiomyosarcoma, metastatic, stomach, 

glandular 1 (2%) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Mesentery (9) (9) (10) (5) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (11%) 

Leiomyosarcoma, metastatic, stomach, 

glandular 1 (10%) 

Pancreas (50) (50) (49) (50) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (2%) 

Leiomyosarcoma, metastatic, stomach, 

glandular 1 (2%) 

Salivary glands (50) (50) (48) (50) 

Neurofibrosarcoma, metastatic, skin 1 (2%) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Stomach, forestomach (50) (50) (49) (50) 

Squamous cell papilloma 1 (2%) 1 (2%) 1 (2%) 

Stomach, glandular (50) (50) (49) (50) 

Leiomyosarcoma 1 (2%) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (2%) 

Tongue (1) 

Squamous cell papilloma 1 (100%) 

Cardiovascular System 

Blood vessel (50) (50) (49) (49) 

Heart (50) (50) (49) (50) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

78 Triethanolamine, NTP TR 449 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Endocrine System 

Adrenal cortex (50) (50) (49) (50) 

Adrenal medulla (50) (50) (49) (50) 

Pheochromocytoma complex 1 (2%) 

Pheochromocytoma benign 2 (4%) 8 (16%) 4 (8%) 3 (6%) 

Bilateral, pheochromocytoma benign 1 (2%) 

Islets, pancreatic (50) (50) (49) (50) 

Adenoma 1 (2%) 3 (6%) 3 (6%) 5 (10%) 

Parathyroid gland (49) (47) (44) (47) 

Adenoma 1 (2%) 

Pituitary gland (50) (50) (48) (50) 

Pars distalis, adenoma 34 (68%) 37 (74%) 30 (63%) 37 (74%) 

Pars distalis, adenoma, multiple 1 (2%) 1 (2%) 2 (4%) 4 (8%) 

Thyroid gland (50) (50) (49) (50) 

Neurofibrosarcoma, metastatic, skin 1 (2%) 

Bilateral, C-cell, adenoma 1 (2%) 

C-cell, adenoma 5 (10%) 4 (8%) 7 (14%) 6 (12%) 

C-cell, carcinoma 1 (2%) 1 (2%) 

Follicular cell, adenoma 1 (2%) 

Follicular cell, carcinoma 1 (2%) 

General Body System 

None 

Genital System 

Epididymis (50) (50) (49) (50) 

Preputial gland (50) (50) (48) (50) 

Adenoma 1 (2%) 1 (2%) 

Carcinoma 1 (2%) 1 (2%) 

Fibrosarcoma 1 (2%) 

Prostate (50) (49) (49) (50) 

Adenocarcinoma 1 (2%) 1 (2%) 

Sarcoma 1 (2%) 

Seminal vesicle (50) (50) (49) (50) 

Testes (50) (50) (49) (50) 

Bilateral, interstitial cell, adenoma 15 (30%) 11 (22%) 15 (31%) 9 (18%) 

Interstitial cell, adenoma 16 (32%) 22 (44%) 18 (37%) 16 (32%) 

Hematopoietic System 

Bone marrow (50) (50) (49) (50) 

Lymph node (14) (10) (16) (9) 

Deep cervical, carcinoma, metastatic, 

thyroid gland 1 (6%) 

Lymph node, mandibular (50) (50) (49) (50) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Lymph node, mesenteric (50) (50) (49) (49) 

Spleen (50) (50) (49) (50) 

Fibrous histiocytoma 1 (2%) 

Thymus (46) (49) (48) (49) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 79 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Integumentary System 

Mammary gland (48) (43) (45) (45) 

Carcinoma 1 (2%) 1 (2%) 

Fibroadenoma 1 (2%) 

Skin (50) (50) (49) (50) 

Basal cell adenoma 1 (2%) 

Keratoacanthoma 1 (2%) 

Abdominal, ventral, keratoacanthoma 1 (2%) 

Dorsal, keratoacanthoma 1 (2%) 

Face, basosquamous tumor malignant 1 (2%) 

Face, squamous cell papilloma 2 (4%) 1 (2%) 

Head, basosquamous tumor benign 1 (2%) 

Hindlimb, subcutaneous tissue, fibroma 1 (2%) 

Inguinal, keratoacanthoma 1 (2%) 

Inguinal, subcutaneous tissue, fibrosarcoma 1 (2%) 

Inguinal, subcutaneous tissue, sarcoma 1 (2%) 

Neck, subcutaneous tissue, schwannoma

 malignant 1 (2%) 

Pinna, sarcoma 1 (2%) 

Pinna, squamous cell papilloma 1 (2%) 

Site of application-mass, basal cell adenoma 1 (2%) 

Site of application-mass, keratoacanthoma 1 (2%) 

Subcutaneous tissue, fibroma 1 (2%) 

Subcutaneous tissue, fibrous histiocytoma, 

metastatic, spleen 1 (2%) 

Subcutaneous tissue, liposarcoma 1 (2%) 

Subcutaneous tissue, neurofibrosarcoma 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 

Subcutaneous tissue, ventral, fibroma 1 (2%) 

Tail, fibrosarcoma 1 (2%) 

Thoracic, keratoacanthoma 2 (4%) 1 (2%) 

Thoracic, subcutaneous tissue, fibroma 1 (2%) 1 (2%) 

Ventral, keratoacanthoma 1 (2%) 

Musculoskeletal System 

Skeletal muscle (1) (1) (1) (1) 

Neurofibrosarcoma, metastatic, skin 1 (100%) 

Nervous System 

Brain (50) (50) (48) (50) 

Astrocytoma NOS 1 (2%) 

Spinal cord (2) (2) 
 

 

 

 

 

 

 

 

 

 

80 Triethanolamine, NTP TR 449 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Respiratory System 

Lung (50) (50) (49) (50) 

Carcinoma, metastatic, thyroid gland 1 (2%) 

Carcinoma, metastatic, uncertain primary site 1 (2%) 

Schwannoma malignant, metastatic, skin 1 (2%) 

Nose (50) (50) (49) (50) 

Squamous cell carcinoma 1 (2%) 

Special Senses System 

Ear (1) (2) (2) (1) 

Zymbal’s gland (2) (2) (1) 

Carcinoma 2 (100%) 1 (50%) 1 (100%) 

Urinary System 

Kidney (50) (50) (49) (50) 

Hemangiosarcoma 1 (2%) 

Leiomyosarcoma, metastatic, 

intestine large, colon 1 (2%) 

Renal tubule, adenoma 1 (2%) 4 (8%) 2 (4%) 

Urinary bladder (50) (50) (48) (49) 

Systemic Lesions 

Multiple organs (50) (50) (49) (50) 

Leukemia mononuclear 24 (48%) 16 (32%) 21 (43%) 22 (44%) 

Mesothelioma NOS 2 (4%) 1 (2%) 1 (2%) 
81 

c 

Triethanolamine, NTP TR 449 

TABLE A1 

Summary of the Incidence of Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 6 9 9 5 

2-Year study 47 49 48 50 

Total primary neoplasms 

15-Month interim evaluation 9 11 12 7 

2-Year study 125 120 120 117 

Total animals with benign neoplasms 

15-Month interim evaluation 5 9 9 5 

2-Year study 44 49 47 48 

Total benign neoplasms 

15-Month interim evaluation 7 11 11 6 

2-Year study 93 90 91 88 

Total animals with malignant neoplasms 

15-Month interim evaluation 1 

2-Year study 26 23 27 26 

Total malignant neoplasms 

15-Month interim evaluation 1 

2-Year study 30 30 28 27 

Total animals with metastatic neoplasms 

2-Year study 5 2 1 

Total metastatic neoplasms 

2-Year study 15 5 3 

Total animals with malignant neoplasms

 of uncertain primary site 

2-Year study 1 

Total animals with uncertain neoplasmsbenign or malignant 

15-Month interim evaluation 1 1 1 

2-Year study 2 1 2 

Total uncertain neoplasms 

15-Month interim evaluation 2 1 2 

2-Year study 14 5 10 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

 

 

82 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

Number of Days on Study 

0 4 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 7 7 

1 5 7 3 3 3 5 5 5 7 8 8 9 0 1 2 3 4 5 5 7 7 7 0 0 

2 2 6 5 6 8 0 4 4 7 6 9 1 9 8 1 1 2 4 6 0 0 0 2 5 

Carcass ID Number 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

4 3 5 4 4 0 1 0 5 0 3 4 4 5 5 0 0 3 2 2 1 2 5 5 2 

4 8 3 9 0 5 8 7 4 8 4 7 1 6 7 2 1 7 9 7 6 3 9 2 0 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular adenoma 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

Tongue 

Squamous cell papilloma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

+ + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Bilateral, pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + + + + + + + + + + + + + + M + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X 

Pars distalis, adenoma, multiple X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, C-cell, adenoma 

C-cell, adenoma X 

General Body System 

Tissue NOS 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Penis + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenocarcinoma 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 83 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 0 0 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 5 0 7 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 1 1 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 3 3 2 1 1 1 2 3 3 4 5 0 1 1 2 3 4 4 5 0 0 2 3 4 6 Tissues/ 

2 5 6 2 1 3 2 3 9 2 5 3 0 5 1 1 5 6 0 4 6 4 0 3 0 Tumors 

Alimentary System 

Esophagus + + + + M + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular adenoma X 3 

Mesentery + + + + 9 

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 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 2 

Bilateral, pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X 34 

Pars distalis, adenoma, multiple 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, C-cell, adenoma X 1 

C-cell, adenoma X X X X 5 

General Body System 

Tissue NOS +

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Penis + 2 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma X 1 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenocarcinoma X 1 

 1 
 

 

 

 

 

 

 

 

 

 

 

84 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

0 4 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 1 5 7 3 3 3 5 5 5 7 8 8 9 0 1 2 3 4 5 5 7 7 7 0 0 

2 2 6 5 6 8 0 4 4 7 6 9 1 9 8 1 1 2 4 6 0 0 0 2 5 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 4 3 5 4 4 0 1 0 5 0 3 4 4 5 5 0 0 3 2 2 1 2 5 5 2 

4 8 3 9 0 5 8 7 4 8 4 7 1 6 7 2 1 7 9 7 6 3 9 2 0 

Genital System (continued) 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X X 

Interstitial cell, adenoma X X X X X X X X X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + + + + + + 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + + + + + + + + + + + + + + + + + + + M M M + 

Integumentary System 

Mammary gland + + + + + + + + M + + + + + + + + + + + + + + + + 

Carcinoma 

Fibroadenoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Keratoacanthoma 

Face, squamous cell papilloma X X 

Hindlimb, subcutaneous tissue, fibroma X 

Inguinal, keratoacanthoma 

Pinna, squamous cell papilloma 

Site of application-mass, basal cell, adenoma 

Subcutaneous tissue, fibroma 

Subcutaneous tissue, sarcoma 

Tail, fibrosarcoma X 

Thoracic, keratoacanthoma X 

Ventral, keratoacanthoma 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Skeletal muscle 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Peripheral nerve + + 

Spinal cord + + 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell carcinoma 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 85 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 0 0 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 5 0 7 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 1 1 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 3 3 2 1 1 1 2 3 3 4 5 0 1 1 2 3 4 4 5 0 0 2 3 4 6 Tissues/ 

2 5 6 2 1 3 2 3 9 2 5 3 0 5 1 1 5 6 0 4 6 4 0 3 0 Tumors 

Genital System (continued) 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X X X X X X 15 

Interstitial cell, adenoma X X X X X X X 16 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + 14 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + M 46 

Integumentary System 

Mammary gland + + + + + M + + + + + + + + + + + + + + + + + + + 48 

Carcinoma X 1 

Fibroadenoma X 1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Keratoacanthoma X 1 

Face, squamous cell papilloma 2 

Hindlimb, subcutaneous tissue, fibroma 1 

Inguinal, keratoacanthoma X 1 

Pinna, squamous cell papilloma X 1 

Site of application-mass, basal cell, adenoma X 1 

Subcutaneous tissue, fibroma X 1 

Subcutaneous tissue, sarcoma X 1 

Tail, fibrosarcoma 1 

Thoracic, keratoacanthoma X 2 

Ventral, keratoacanthoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle + 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve 2 

Spinal cord 2 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell carcinoma X 1 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

86 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

0 4 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 7 7 

Number of Days on Study 1 5 7 3 3 3 5 5 5 7 8 8 9 0 1 2 3 4 5 5 7 7 7 0 0 

2 2 6 5 6 8 0 4 4 7 6 9 1 9 8 1 1 2 4 6 0 0 0 2 5 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

Carcass ID Number 4 3 5 4 4 0 1 0 5 0 3 4 4 5 5 0 0 3 2 2 1 2 5 5 2 

4 8 3 9 0 5 8 7 4 8 4 7 1 6 7 2 1 7 9 7 6 3 9 2 0 

Special Senses System 

Ear 

Eye + + 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X X 

Mesothelioma NOS X 
 

 

 

 

Triethanolamine, NTP TR 449 87 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 0 0 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 5 0 7 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 1 1 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 3 3 2 1 1 1 2 3 3 4 5 0 1 1 2 3 4 4 5 0 0 2 3 4 6 Tissues/ 

2 5 6 2 1 3 2 3 9 2 5 3 0 5 1 1 5 6 0 4 6 4 0 3 0 Tumors 

Special Senses System 

Ear + 1 

Eye 2 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X 24 

Mesothelioma NOS X 2 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

88 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

4 4 4 4 4 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 2 4 6 8 0 4 5 5 6 7 7 7 9 0 0 0 1 1 2 2 3 3 3 4 

6 0 3 7 4 7 9 8 8 4 2 3 8 9 4 6 8 3 9 0 1 1 4 5 9 

1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 1 0 1 0 0 0 1 1 0 0 

Carcass ID Number 1 8 6 9 0 7 8 6 0 9 9 9 6 8 7 1 6 0 9 6 9 2 1 9 6 

6 6 9 9 1 4 9 8 5 2 6 7 4 2 7 5 5 7 1 7 4 0 4 5 6 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic,

 intestine large, colon X 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic,

 intestine large, colon X 

Schwannoma malignant, metastatic, skin 

Mesentery + + + + 

Leiomyosarcoma, metastatic,

 intestine large, colon X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic,

 intestine large, colon X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Neurofibrosarcoma, metastatic, skin X 

Schwannoma malignant, metastatic, skin 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma X 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic,

 intestine large, colon X 

Tooth 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + + + + + + + + + + + + + M + + + + M + M + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X X X 

Pars distalis, adenoma, multiple 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Neurofibrosarcoma, metastatic, skin X 

C-cell, adenoma X X X 

C-cell, carcinoma X 

Follicular cell, carcinoma 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 89 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

(continued) 

6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 7 8 9 9 0 1 1 1 1 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 

7 7 4 0 4 2 0 8 9 9 4 4 6 7 9 0 0 0 0 0 0 1 1 1 1 

0 0 0 1 0 0 0 0 1 1 1 1 1 0 1 0 0 0 0 1 1 0 0 1 1 Total 

Carcass ID Number 7 8 6 1 7 7 7 6 0 1 0 1 0 9 0 6 8 8 8 0 1 7 8 1 1 Tissues/ 

1 3 3 3 6 2 9 2 4 0 6 9 9 3 0 1 4 5 8 2 2 3 1 7 8 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma 1 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic,

 intestine large, colon 1 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic,

 intestine large, colon 1 

Schwannoma malignant, metastatic, skin X 1 

Mesentery + + + + + 9 

Leiomyosarcoma, metastatic,

 intestine large, colon 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic,

 intestine large, colon 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Neurofibrosarcoma, metastatic, skin 1 

Schwannoma malignant, metastatic, skin X 1 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyosarcoma, metastatic,

 intestine large, colon 1 

Tooth + 1 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X X X X 8 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X X 3 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X 37 

Pars distalis, adenoma, multiple X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Neurofibrosarcoma, metastatic, skin 1 

C-cell, adenoma X 4 

C-cell, carcinoma 1 

Follicular cell, carcinoma X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

90 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

(continued) 

4 4 4 4 4 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 

6 

2 

0 

4 

3 

6 

7 

8 

4 

0 

7 

4 

9 

5 

8 

5 

8 

6 

4 

7 

2 

7 

3 

7 

8 

9 

9 

0 

4 

0 

6 

0 

8 

1 

3 

1 

9 

2 

0 

2 

1 

3 

1 

3 

4 

3 

5 

4 

9 

Carcass ID Number 

1 

1 

6 

0 

8 

6 

0 

6 

9 

0 

9 

9 

1 

0 

1 

0 

7 

4 

0 

8 

9 

0 

6 

8 

1 

0 

5 

0 

9 

2 

0 

9 

6 

0 

9 

7 

0 

6 

4 

0 

8 

2 

0 

7 

7 

1 

1 

5 

0 

6 

5 

1 

0 

7 

0 

9 

1 

0 

6 

7 

0 

9 

4 

1 

2 

0 

1 

1 

4 

0 

9 

5 

0 

6 

6 

General Body System 

None 

Genital System 

Epididymis 

Penis 

Preputial gland 

Carcinoma 

Fibrosarcoma 

Prostate 

Adenocarcinoma 

Sarcoma 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X X X X X X X X 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Schwannoma malignant, metastatic, skin 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Carcinoma 

Skin 

Basal cell adenoma 

Face, basosquamous tumor malignant 

Neck, subcutaneous tissue,

 schwannoma malignant 

Subcutaneous tissue, liposarcoma 

Subcutaneous tissue, neurofibrosarcoma 

Thoracic, subcutaneous tissue, fibroma 

+ + + + + + + + + + M + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

X 

Musculoskeletal System 

Bone 

Skeletal muscle 

Neurofibrosarcoma, metastatic, skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 91 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

(continued) 

6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 

7 

7 

7 

8 

4 

9 

0 

9 

4 

0 

2 

1 

0 

1 

8 

1 

9 

1 

9 

2 

4 

2 

4 

2 

6 

2 

7 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

0 0 0 1 0 0 0 0 1 1 1 1 1 0 1 0 0 0 0 1 1 0 0 1 1 Total 

Carcass ID Number 7 

1 

8 

3 

6 

3 

1 

3 

7 

6 

7 

2 

7 

9 

6 

2 

0 

4 

1 

0 

0 

6 

1 

9 

0 

9 

9 

3 

0 

0 

6 

1 

8 

4 

8 

5 

8 

8 

0 

2 

1 

2 

7 

3 

8 

1 

1 

7 

1 

8 

Tissues/ 

Tumors 

General Body System 

None 

Genital System 

Epididymis 

Penis 

Preputial gland 

Carcinoma 

Fibrosarcoma 

Prostate 

Adenocarcinoma 

Sarcoma

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

+ + + + + + + + + + + + + + + + + + + + M + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X 

X X X X X X X X X X X X X X 

50 

1 

50 

1 

1 

49 

1 

1 

50 

50 

11 

22 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Schwannoma malignant, metastatic, skin 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + M + + + + 

50 

10 

50 

1 

50 

50 

49 

Integumentary System 

Mammary gland 

Carcinoma 

Skin 

Basal cell adenoma 

Face, basosquamous tumor malignant 

Neck, subcutaneous tissue,

 schwannoma malignant 

Subcutaneous tissue, liposarcoma

Subcutaneous tissue, neurofibrosarcoma 

Thoracic, subcutaneous tissue, fibroma 

M + + M + + + + + + + M + + + + + M + M M + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

X 

43 

1 

50 

1 

1 

1 

1 

1 

1 

Musculoskeletal System 

Bone 

Skeletal muscle

Neurofibrosarcoma, metastatic, skin

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

92 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

(continued) 

4 4 4 4 4 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 

Number of Days on Study 1 

6 

2 

0 

4 

3 

6 

7 

8 

4 

0 

7 

4 

9 

5 

8 

5 

8 

6 

4 

7 

2 

7 

3 

7 

8 

9 

9 

0 

4 

0 

6 

0 

8 

1 

3 

1 

9 

2 

0 

2 

1 

3 

1 

3 

4 

3 

5 

4 

9 

Carcass ID Number 

1 

1 

6 

0 

8 

6 

0 

6 

9 

0 

9 

9 

1 

0 

1 

0 

7 

4 

0 

8 

9 

0 

6 

8 

1 

0 

5 

0 

9 

2 

0 

9 

6 

0 

9 

7 

0 

6 

4 

0 

8 

2 

0 

7 

7 

1 

1 

5 

0 

6 

5 

1 

0 

7 

0 

9 

1 

0 

6 

7 

0 

9 

4 

1 

2 

0 

1 

1 

4 

0 

9 

5 

0 

6 

6 

Respiratory System 

Lung 

Carcinoma, metastatic, thyroid gland 

Carcinoma, metastatic, uncertain

 primary site 

Schwannoma malignant, metastatic, skin 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Zymbal’s gland 

Carcinoma 

+ 

X 

Urinary System 

Kidney 

Leiomyosarcoma, metastatic,

 intestine large, colon 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 
 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 93 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 32 mg/kg 

(continued) 

6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 

7 

7 

7 

8 

4 

9 

0 

9 

4 

0 

2 

1 

0 

1 

8 

1 

9 

1 

9 

2 

4 

2 

4 

2 

6 

2 

7 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

Carcass ID Number 

0 

7 

1 

0 

8 

3 

0 

6 

3 

1 

1 

3 

0 

7 

6 

0 

7 

2 

0 

7 

9 

0 

6 

2 

1 

0 

4 

1 

1 

0 

1 

0 

6 

1 

1 

9 

1 

0 

9 

0 

9 

3 

1 

0 

0 

0 

6 

1 

0 

8 

4 

0 

8 

5 

0 

8 

8 

1 

0 

2 

1 

1 

2 

0 

7 

3 

0 

8 

1 

1 

1 

7 

1 

1 

8 

Total 

Tissues/ 

Tumors 

Respiratory System 

Lung 

Carcinoma, metastatic, thyroid gland

Carcinoma, metastatic, uncertain

 primary site

Schwannoma malignant, metastatic, skin 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

1 

1 

50 

50 

Special Senses System 

Ear 

Zymbal’s gland 

Carcinoma 

+

X

+ + 2 

2 

2 

Urinary System 

Kidney 

Leiomyosarcoma, metastatic,

 intestine large, colon 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

1 

50 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X 

50 

16 
 

 

 

 

 

 

 

 

 

 

 

 

 

94 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

3 3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 

Number of Days on Study 5 6 7 3 0 2 6 7 7 7 8 8 1 1 2 3 3 3 4 4 5 0 0 1 1 

3 5 9 1 0 2 2 4 5 9 4 6 6 7 3 1 1 4 2 9 2 2 2 0 0 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 4 6 3 4 3 6 6 3 6 2 4 8 7 5 6 5 6 2 4 4 5 4 7 6 7 

8 1 1 4 4 6 5 8 8 9 6 0 7 7 2 9 9 8 3 9 1 7 3 3 0 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, stomach, glandular X 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hepatocellular carcinoma 

Leiomyosarcoma, metastatic, stomach, glandular X 

Mesentery + + + + + + + 

Leiomyosarcoma, metastatic, stomach, glandular X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma, metastatic, stomach, glandular X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + M + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Squamous cell papilloma 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyosarcoma X 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma complex X 

Pheochromocytoma benign X X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Parathyroid gland + + + + + + + + + + M M 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 X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X X X X 

C-cell, carcinoma 

Follicular cell, adenoma X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 95 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 9 2 4 4 4 9 9 9 9 0 0 0 0 0 0 0 1 1 1 1 1 1 1 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 3 3 2 2 5 4 5 6 7 2 2 3 5 6 7 7 2 2 3 4 5 7 7 Tissues/ 

8 6 2 1 2 0 5 6 7 4 5 7 9 4 0 1 5 3 4 0 0 3 2 6 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + 49 

Leiomyosarcoma, metastatic, stomach, glandular 1 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + 49 

Liver + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hepatocellular carcinoma X 1 

Leiomyosarcoma, metastatic, stomach, glandular 1 

Mesentery + + + 10 

Leiomyosarcoma, metastatic, stomach, glandular 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + 49 

Leiomyosarcoma, metastatic, stomach, glandular 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + 48 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + 49 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + 49 

Leiomyosarcoma 1 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + 49 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pheochromocytoma complex 1 

Pheochromocytoma benign X X 4 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X X 3 

Parathyroid gland + + + M + + + + + + + + + + + + + + + + + + + + 44 

Pituitary gland + + + + + + + + M + + + + + + + + + + + + + + + 48 

Pars distalis, adenoma X X X X X X X X X X X X X X X X 30 

Pars distalis, adenoma, multiple 2 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X 7 

C-cell, carcinoma X 1 

Follicular cell, adenoma 1 
 

 

 

 

 

 

 

 

 

 

 

 

96 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

3 3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 

Number of Days on Study 5 

3 

6 

5 

7 

9 

3 

1 

0 

0 

2 

2 

6 

2 

7 

4 

7 

5 

7 

9 

8 

4 

8 

6 

1 

6 

1 

7 

2 

3 

3 

1 

3 

1 

3 

4 

4 

2 

4 

9 

5 

2 

0 

2 

0 

2 

1 

0 

1 

0 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 4 6 3 4 3 6 6 3 6 2 4 8 7 5 6 5 6 2 4 4 5 4 7 6 7 

8 1 1 4 4 6 5 8 8 9 6 0 7 7 2 9 9 8 3 9 1 7 3 3 0 

General Body System 

None 

Genital System 

Epididymis 

Preputial gland 

Adenoma 

Prostate 

Seminal vesicle 

Testes 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

X X X X X X X X X 

Hematopoietic System 

Bone marrow 

Lymph node 

Deep cervical, carcinoma, metastatic,

 thyroid gland 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + M + + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

Dorsal, keratoacanthoma 

Face, squamous cell papilloma 

Inguinal, subcutaneous tissue, fibrosarcoma 

Subcutaneous tissue, ventral, fibroma 

Thoracic, keratoacanthoma 

Thoracic, subcutaneous tissue, fibroma 

+ M + + + + + + + + + + + + + M + + + M + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

Musculoskeletal System 

Bone 

Skeletal muscle 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + M + 

Peripheral nerve + + 

Spinal cord + + 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 97 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 9 2 4 4 4 9 9 9 9 0 0 0 0 0 0 0 1 1 1 1 1 1 1 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 3 3 2 2 5 4 5 6 7 2 2 3 5 6 7 7 2 2 3 4 5 7 7 Tissues/ 

8 6 2 1 2 0 5 6 7 4 5 7 9 4 0 1 5 3 4 0 0 3 2 6 Tumors 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + 49 

Preputial gland M + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma 1 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + 49 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + 49 

Testes + + + + + + + + + + + + + + + + + + + + + + + + 49 

Bilateral, interstitial cell, adenoma X X X X X X X X X 15 

Interstitial cell, adenoma X X X X X X X X X 18 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + 49 

Lymph node + + + + + + + + 16 

Deep cervical, carcinoma, metastatic,

 thyroid gland X 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + 49 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + 49 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + 48 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + M 45 

Skin + + + + + + + + + + + + + + + + + + + + + + + + 49 

Dorsal, keratoacanthoma X 1 

Face, squamous cell papilloma X 1 

Inguinal, subcutaneous tissue, fibrosarcoma 1 

Subcutaneous tissue, ventral, fibroma 1 

Thoracic, keratoacanthoma X 1 

Thoracic, subcutaneous tissue, fibroma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + 49 

Skeletal muscle 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + 48 

Peripheral nerve 2 

Spinal cord 2 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + 49 

Nose + + + + + + + + + + + + + + + + + + + + + + + + 49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + 49 
 

 

 

 

 

 

98 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

3 3 3 4 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 

Number of Days on Study 5 6 7 3 0 2 6 7 7 7 8 8 1 1 2 3 3 3 4 4 5 0 0 1 1 

3 5 9 1 0 2 2 4 5 9 4 6 6 7 3 1 1 4 2 9 2 2 2 0 0 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

Carcass ID Number 4 6 3 4 3 6 6 3 6 2 4 8 7 5 6 5 6 2 4 4 5 4 7 6 7 

8 1 1 4 4 6 5 8 8 9 6 0 7 7 2 9 9 8 3 9 1 7 3 3 0 

Special Senses System 

Ear + + 

Eye + 

Zymbal’s gland + + 

Carcinoma X 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Renal tubule, adenoma X X X 

Urinary bladder + + + + + + + + + + + + M + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X X 

Mesothelioma NOS X 
 

 

 

 

 

Triethanolamine, NTP TR 449 99 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 9 2 4 4 4 9 9 9 9 0 0 0 0 0 0 0 1 1 1 1 1 1 1 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 7 3 3 2 2 5 4 5 6 7 2 2 3 5 6 7 7 2 2 3 4 5 7 7 Tissues/ 

8 6 2 1 2 0 5 6 7 4 5 7 9 4 0 1 5 3 4 0 0 3 2 6 Tumors 

Special Senses System 

Ear 2 

Eye + + 3 

Zymbal’s gland 2 

Carcinoma 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + 49 

Hemangiosarcoma X 1 

Renal tubule, adenoma X 4 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + 48 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + 49 

Leukemia mononuclear X X X X X X X X X X X X 21 

Mesothelioma NOS 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

100 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

Number of Days on Study 

4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 

0 2 4 5 0 0 3 4 4 5 5 6 6 7 7 7 1 4 4 4 4 6 6 6 7 

4 4 4 9 2 2 5 3 6 8 8 2 3 2 2 9 7 2 2 5 9 4 5 7 0 

Carcass ID Number 

2 2 2 1 1 2 2 2 2 1 1 2 2 2 2 2 2 1 2 2 2 1 2 1 2 

2 0 2 9 8 1 3 2 1 8 9 2 0 3 3 3 0 9 2 4 1 8 2 8 0 

5 6 4 8 2 0 6 7 9 7 9 6 3 2 3 0 2 0 0 0 5 3 9 6 9 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Fibrous histiocytoma, metastatic, spleen 

Mast cell tumor malignant 

Intestine small, ileum 

Fibrous histiocytoma, metastatic, spleen 

Liver 

Hepatocellular adenoma 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + M + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Parathyroid gland + + + + + + + M + + + M + + + + + + + + + + M + + 

Adenoma 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X 

Pars distalis, adenoma, multiple X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X X X 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Penis + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma X X X 

Interstitial cell, adenoma X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 101 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 8 8 9 9 1 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 8 0 1 8 2 9 9 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 1 1 

2 2 2 1 2 2 1 1 1 2 2 2 1 1 2 2 2 2 1 1 1 1 2 2 2 Total 

Carcass ID Number 0 3 3 9 3 3 8 8 9 1 1 2 8 9 1 2 2 3 8 8 9 9 0 0 1 Tissues/ 

5 5 8 2 7 4 1 8 6 2 3 8 5 1 8 1 3 9 4 9 5 7 0 8 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Fibrous histiocytoma, metastatic, spleen 1 

Mast cell tumor malignant X 1 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Fibrous histiocytoma, metastatic, spleen 1 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular adenoma X 1 

Mesentery + + 5 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X X 3 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X X X 5 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Adenoma X 1 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X X 37 

Pars distalis, adenoma, multiple X X X 4 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X 6 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Penis + 2 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X X X X X X 9 

Interstitial cell, adenoma X X X X X X X X X 16 
 

 

 

 

 

 

 

 

 

 

 

 

 

102 Triethanolamine, NTP TR 449 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 

Number of Days on Study 0 

4 

2 

4 

4 

4 

5 

9 

0 

2 

0 

2 

3 

5 

4 

3 

4 

6 

5 

8 

5 

8 

6 

2 

6 

3 

7 

2 

7 

2 

7 

9 

1 

7 

4 

2 

4 

2 

4 

5 

4 

9 

6 

4 

6 

5 

6 

7 

7 

0 

Carcass ID Number 

2 

2 

5 

2 

0 

6 

2 

2 

4 

1 

9 

8 

1 

8 

2 

2 

1 

0 

2 

3 

6 

2 

2 

7 

2 

1 

9 

1 

8 

7 

1 

9 

9 

2 

2 

6 

2 

0 

3 

2 

3 

2 

2 

3 

3 

2 

3 

0 

2 

0 

2 

1 

9 

0 

2 

2 

0 

2 

4 

0 

2 

1 

5 

1 

8 

3 

2 

2 

9 

1 

8 

6 

2 

0 

9 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Fibrous histiocytoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + M + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + M + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

Abdominal, ventral, keratoacanthoma 

Head, basosquamous tumor benign 

Inguinal, subcutaneous tissue, sarcoma 

Pinna, sarcoma 

Site of application-mass, keratoacanthoma 

Subcutaneous tissue, fibrous

 histiocytoma, metastatic, spleen 

+ + + + + + M M M + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

Musculoskeletal System 

Bone 

Skeletal muscle 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

Nervous System 

Brain 

Astrocytoma NOS 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Eye 

Zymbal’s gland 

Carcinoma 

+ 

X 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

Mesothelioma NOS 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 103 

TABLE A2 

Individual Animal Tumor Pathology of Male Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 8 8 9 9 1 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 

4 8 0 1 8 2 9 9 9 9 9 9 0 0 0 0 0 0 1 1 1 1 1 1 1 

2 2 2 1 2 2 1 1 1 2 2 2 1 1 2 2 2 2 1 1 1 1 2 2 2 Total 

Carcass ID Number 0 3 3 9 3 3 8 8 9 1 1 2 8 9 1 2 2 3 8 8 9 9 0 0 1 Tissues/ 

5 5 8 2 7 4 1 8 6 2 3 8 5 1 8 1 3 9 4 9 5 7 0 8 7 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + + + 9 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Fibrous histiocytoma 1 

Thymus + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Integumentary System 

Mammary gland + M + + + + + + + + + M + + + + + + + + + + + + + 45 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Abdominal, ventral, keratoacanthoma X 1 

Head, basosquamous tumor benign X 1 

Inguinal, subcutaneous tissue, sarcoma X 1 

Pinna, sarcoma 1 

Site of application-mass, keratoacanthoma X 1 

Subcutaneous tissue, fibrous

 histiocytoma, metastatic, spleen 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Astrocytoma NOS 1 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear + 1 

Eye + + 2 

Zymbal’s gland 1 

Carcinoma 1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X X 2 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + M + 49 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leukemia mononuclear X X X X X X X X X X X X X X X X X 22 

Mesothelioma NOS 1 
104 Triethanolamine, NTP TR 449 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Adrenal Medulla: Benign Pheochromocytoma a Overall rate 3/50 (6%) 8/50 (16%) 4/49 (8%) 3/50 (6%) b Adjusted rate 11.8% 44.9% 16.8% 11.8% c Terminal rate 1/21 (5%) 4/11 (36%) 2/18 (11%) 1/19 (5%) 

First incidence (days) 702 573 586 558 

d Life table test P=0.357N P=0.025 P=0.473 P=0.592 

d Logistic regression test P=0.354N P=0.069 P=0.489 P=0.641 

d Cochran-Armitage test P=0.340N 

d Fisher exact test P=0.100 P=0.489 P=0.661N 

Adrenal Medulla: Benign or Complex Pheochromocytoma 

Overall rate 3/50 (6%) 8/50 (16%) 5/49 (10%) 3/50 (6%) 

Adjusted rate 11.8% 44.9% 18.9% 11.8% 

Terminal rate 1/21 (5%) 4/11 (36%) 2/18 (11%) 1/19 (5%) 

First incidence (days) 702 573 584 558 

Life table test P=0.379N P=0.025 P=0.335 P=0.592 

Logistic regression test P=0.371N P=0.069 P=0.343 P=0.641 

Cochran-Armitage test P=0.359N 

Fisher exact test P=0.100 P=0.346 P=0.661N 

Kidney (Renal Tubule): Adenoma (Single Sections) 

Overall rate 0/50 (0%) 1/50 (2%) 4/49 (8%) 2/50 (4%) 

Adjusted rate 0.0% 5.6% 15.2% 10.5% 

Terminal rate 0/21 (0%) 0/11 (0%) 1/18 (6%) 2/19 (11%) e First incidence (days) — 718 649 729 (T) 

Life table test P=0.179 P=0.460 P=0.060 P=0.215 

Logistic regression test P=0.155 P=0.454 P=0.060 P=0.215 

Cochran-Armitage test P=0.165 

Fisher exact test P=0.500 P=0.056 P=0.247 

Kidney (Renal Tubule): Adenoma (Single and Step Sections) 

Overall rate 1/50 (2%) 2/50 (4%) 6/49 (12%) 4/50 (8%) 

Adjusted rate 4.3% 9.8% 25.2% 21.1% 

Terminal rate 0/21 (0%) 0/11 (0%) 3/18 (17%) 4/19 (21%) 

First incidence (days) 710 690 649 729 (T) 

Life table test P=0.127 P=0.432 P=0.054 P=0.150 

Logistic regression test P=0.099 P=0.441 P=0.054 P=0.140 

Cochran-Armitage test P=0.113 

Fisher exact test P=0.500 P=0.053 P=0.181 

Liver: Hepatocellular Adenoma 

Overall rate 3/50 (6%) 0/50 (0%) 0/49 (0%) 1/50 (2%) 

Adjusted rate 8.9% 0.0% 0.0% 5.3% 

Terminal rate 0/21 (0%) 0/11 (0%) 0/18 (0%) 1/19 (5%) 

First incidence (days) 550 — — 729 (T) 

Life table test P=0.256N P=0.160N P=0.129N P=0.343N 

Logistic regression test P=0.249N P=0.119N P=0.125N P=0.307N 

Cochran-Armitage test P=0.248N 

Fisher exact test P=0.121N P=0.125N P=0.309N 
Triethanolamine, NTP TR 449 105 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 3/50 (6%) 0/50 (0%) 1/49 (2%) 1/50 (2%) 

Adjusted rate 8.9% 0.0% 4.5% 5.3% 

Terminal rate 0/21 (0%) 0/11 (0%) 0/18 (0%) 1/19 (5%) 

First incidence (days) 550 — 722 729 (T) 

Life table test P=0.304N P=0.160N P=0.316N P=0.343N 

Logistic regression test P=0.301N P=0.119N P=0.312N P=0.307N 

Cochran-Armitage test P=0.297N 

Fisher exact test P=0.121N P=0.316N P=0.309N 

Pancreatic Islets: Adenoma 

Overall rate 1/50 (2%) 3/50 (6%) 3/49 (6%) 5/50 (10%) 

Adjusted rate 4.8% 17.1% 14.5% 23.1% 

Terminal rate 1/21 (5%) 1/11 (9%) 2/18 (11%) 4/19 (21%) 

First incidence (days) 729 (T) 667 710 563 

Life table test P=0.088 P=0.167 P=0.275 P=0.080 

Logistic regression test P=0.070 P=0.243 P=0.300 P=0.084 

Cochran-Armitage test P=0.079 

Fisher exact test P=0.309 P=0.301 P=0.102 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 35/50 (70%) 38/50 (76%) 32/48 (67%) 41/50 (82%) 

Adjusted rate 87.0% 88.5% 82.5% 95.1% 

Terminal rate 16/21 (76%) 7/11 (64%) 11/17 (65%) 17/19 (89%) 

First incidence (days) 536 416 379 404 

Life table test P=0.251 P=0.043 P=0.557N P=0.110 

Logistic regression test P=0.132 P=0.305 P=0.460N P=0.081 

Cochran-Armitage test P=0.142 

Fisher exact test P=0.326 P=0.445N P=0.121 

Skin: Squamous Cell Papilloma 

Overall rate 3/50 (6%) 0/50 (0%) 1/49 (2%) 0/50 (0%) 

Adjusted rate 9.7% 0.0% 5.6% 0.0% 

Terminal rate 1/21 (5%) 0/11 (0%) 1/18 (6%) 0/19 (0%) 

First incidence (days) 550 — 729 (T) — 

Life table test P=0.091N P=0.180N P=0.343N P=0.134N 

Logistic regression test P=0.088N P=0.120N P=0.312N P=0.120N 

Cochran-Armitage test P=0.087N 

Fisher exact test P=0.121N P=0.316N P=0.121N 

Skin: Keratoacanthoma 

Overall rate 5/50 (10%) 0/50 (0%) 2/49 (4%) 2/50 (4%) 

Adjusted rate 21.7% 0.0% 11.1% 10.5% 

Terminal rate 4/21 (19%) 0/11 (0%) 2/18 (11%) 2/19 (11%) 

First incidence (days) 670 — 729 (T) 729 (T) 

Life table test P=0.252N P=0.100N P=0.273N P=0.257N 

Logistic regression test P=0.273N P=0.052N P=0.213N P=0.255N 

Cochran-Armitage test P=0.264N 

Fisher exact test P=0.028N P=0.226N P=0.218N 
106 Triethanolamine, NTP TR 449 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Skin (Subcutaneous Tissue): Fibroma, Fibrosarcoma, Neurofibrosarcoma, or Sarcoma 

Overall rate 3/50 (6%) 2/50 (4%) 3/49 (6%) 1/50 (2%) 

Adjusted rate 11.4% 6.6% 10.2% 5.3% 

Terminal rate 1/21 (5%) 0/11 (0%) 1/18 (6%) 1/19 (5%) 

First incidence (days) 586 613 431 729 (T) 

Life table test P=0.271N P=0.641N P=0.611 P=0.353N 

Logistic regression test P=0.264N P=0.508N P=0.652 P=0.327N 

Cochran-Armitage test P=0.264N 

Fisher exact test P=0.500N P=0.651 P=0.309N 

Testes: Adenoma 

Overall rate 31/50 (62%) 33/50 (66%) 33/49 (67%) 25/50 (50%) 

Adjusted rate 85.3% 100.0% 86.0% 76.1% 

Terminal rate 16/21 (76%) 11/11 (100%) 13/18 (72%) 12/19 (63%) 

First incidence (days) 538 558 353 459 

Life table test P=0.157N P=0.020 P=0.294 P=0.351N 

Logistic regression test P=0.108N P=0.203 P=0.338 P=0.205N 

Cochran-Armitage test P=0.095N 

Fisher exact test P=0.418 P=0.365 P=0.157N 

Thyroid Gland (C-cell): Adenoma 

Overall rate 6/50 (12%) 4/50 (8%) 7/49 (14%) 6/50 (12%) 

Adjusted rate 25.8% 17.3% 23.4% 20.1% 

Terminal rate 5/21 (24%) 1/11 (9%) 2/18 (11%) 2/19 (11%) 

First incidence (days) 591 573 584 459 

Life table test P=0.464 P=0.626 P=0.431 P=0.566 

Logistic regression test P=0.450 P=0.413N P=0.483 P=0.607 

Cochran-Armitage test P=0.454 

Fisher exact test P=0.370N P=0.484 P=0.620N 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

Overall rate 6/50 (12%) 5/50 (10%) 8/49 (16%) 6/50 (12%) 

Adjusted rate 25.8% 19.3% 26.9% 20.1% 

Terminal rate 5/21 (24%) 1/11 (9%) 2/18 (11%) 2/19 (11%) 

First incidence (days) 591 558 584 459 

Life table test P=0.493 P=0.495 P=0.328 P=0.566 

Logistic regression test P=0.480 P=0.527N P=0.368 P=0.607 

Cochran-Armitage test P=0.484 

Fisher exact test P=0.500N P=0.371 P=0.620N 

All Organs: Mononuclear Cell Leukemia 

Overall rate 24/50 (48%) 16/50 (32%) 21/49 (43%) 22/50 (44%) 

Adjusted rate 72.3% 57.6% 64.3% 77.5% 

Terminal rate 13/21 (62%) 2/11 (18%) 8/18 (44%) 13/19 (68%) 

First incidence (days) 452 558 500 424 

Life table test P=0.512 P=0.493N P=0.493N P=0.559 

Logistic regression test P=0.466 P=0.102N P=0.378N P=0.506N 

Cochran-Armitage test P=0.506 

Fisher exact test P=0.076N P=0.378N P=0.421N 
107 

c 

Triethanolamine, NTP TR 449 

TABLE A3 

Statistical Analysis of Primary Neoplasms in Male Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

All Organs: Benign Neoplasms 

Overall rate 45/50 (90%) 49/50 (98%) 48/49 (98%) 48/50 (96%) 

Adjusted rate 100.0% 100.0% 100.0% 100.0% 

Terminal rate 21/21 (100%) 11/11 (100%) 18/18 (100%) 19/19 (100%) 

First incidence (days) 535 416 353 404 

Life table test P=0.400 P=0.011 P=0.227 P=0.192 

Logistic regression test P=0.124 P=0.033 P=0.032 P=0.067 

Cochran-Armitage test P=0.195 

Fisher exact test P=0.102 P=0.107 P=0.218 

All Organs: Malignant Neoplasms 

Overall rate 26/50 (52%) 24/50 (48%) 27/49 (55%) 26/50 (52%) 

Adjusted rate 76.8% 68.9% 72.4% 82.5% 

Terminal rate 14/21 (67%) 2/11 (18%) 9/18 (50%) 14/19 (74%) 

First incidence (days) 452 467 379 424 

Life table test P=0.473 P=0.218 P=0.365 P=0.398 

Logistic regression test P=0.449 P=0.475N P=0.458 P=0.516 

Cochran-Armitage test P=0.466 

Fisher exact test P=0.421N P=0.457 P=0.579N 

All Organs: Benign or Malignant Neoplasms 

Overall rate 48/50 (96%) 49/50 (98%) 48/49 (98%) 50/50 (100%) 

Adjusted rate 100.0% 100.0% 100.0% 100.0% 

Terminal rate 21/21 (100%) 11/11 (100%) 18/18 (100%) 19/19 (100%) 

First incidence (days) 452 416 353 404 

Life table test P=0.418 P=0.031 P=0.366 P=0.238 

Logistic regression test P=0.117 P=0.442 P=0.403 P=0.293 

Cochran-Armitage test P=0.154 

Fisher exact test P=0.500 P=0.508 P=0.247 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for adrenal gland, kidney, 

liver, pancreatic islets, pituitary gland, skin, testis, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill d Beneath the control incidence are the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise 

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

indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the 

overall incidence rates. For all tests, a negative trend or a lower incidence in a dose group is indicated by N. e Not applicable; no neoplasms in animal group 
108 Triethanolamine, NTP TR 449 

TABLE A4 

Historical Incidence of Renal Tubule Adenomas in Control Male F344/N Ratsa 

Study Incidence in Controls 

Historical Incidence in Dermal Studies (with Acetone Vehicle) at Battelle Columbus Laboratories 

4-Vinyl-1-cyclohexene diepoxide 0/50 

Triethanolamine 0/50 

Overall Historical Incidence in Feed Studies 

Total 9/1,200 (0.8%) 

Standard deviation 1.5% 

Range 0%-6% 

a Data as of 17 June 1994 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 109 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Accidental deaths 2 

Moribund 18 27 25 23 

Natural deaths 9 12 6 8 

Survivors 

Terminal sacrifice 21 11 18 19 

Missexed 1 

Animals examined microscopically 60 60 59 60 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, colon (10) (10) (10) (10) 

Parasite metazoan 1 (10%) 

Intestine large, rectum (10) (10) (10) (10) 

Parasite metazoan 2 (20%) 3 (30%) 

Liver (10) (10) (10) (10) 

Basophilic focus 1 (10%) 

Clear cell focus 1 (10%) 

Eosinophilic focus 1 (10%) 

Hepatodiaphragmatic nodule 1 (10%) 2 (20%) 1 (10%) 

Inflammation, chronic 5 (50%) 7 (70%) 9 (90%) 8 (80%) 

Bile duct, hyperplasia 8 (80%) 10 (100%) 9 (90%) 5 (50%) 

Hepatocyte, degeneration, cystic 1 (10%) 

Mesentery (1) (1) 

Fat, inflammation, necrotizing 1 (100%) 1 (100%) 

Pancreas (10) (10) (10) (10) 

Inflammation, subacute 1 (10%) 

Acinus, atrophy 2 (20%) 2 (20%) 5 (50%) 3 (30%) 

Artery, inflammation, chronic active 1 (10%) 1 (10%) 

Stomach, glandular (10) (10) (10) (10) 

Hyperplasia, glandular 1 (10%) 

Cardiovascular System 

Heart (10) (10) (10) (10) 

Cardiomyopathy, chronic 5 (50%) 10 (100%) 7 (70%) 9 (90%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Hypertrophy 1 (10%) 1 (10%) 

Adrenal medulla (10) (10) (10) (10) 

Hyperplasia 1 (10%) 

Parathyroid gland (6) (10) (9) (9) 

Hyperplasia 1 (17%) 

Pituitary gland (10) (10) (10) (10) 

Pars distalis, cyst 1 (10%) 1 (10%) 

Pars distalis, hyperplasia 3 (30%) 3 (30%) 2 (20%) 8 (80%) 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

110 Triethanolamine, NTP TR 449 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

15-Month Interim Evaluation (continued) 

Endocrine System (continued) 

Thyroid gland (10) 

Cyst

C-cell, hyperplasia 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

 2 (20%) 

Genital System 

Epididymis 

Mineralization

Preputial gland 

Hyperplasia

Inflammation, chronic active

Duct, dilatation

Prostate 

Inflammation, chronic active

Testes 

Interstitial cell, hyperplasia

Seminiferous tubule, atrophy

(10) 

 1 (10%) 

(10) 

 10 (100%)

(10) 

 7 (70%) 

(10) 

 6 (60%) 

(10) 

(10) 

 2 (20%) 

 9 (90%) 

(10) 

 8 (80%) 

(10) 

 5 (50%) 

(10) 

(10) 

 10 (100%)

 1 (10%) 

(10) 

 8 (80%) 

(10) 

 7 (70%) 

(10) 

(10) 

 10 (100%) 

(10) 

 9 (90%) 

(10) 

 9 (90%) 

 1 (10%) 

Integumentary System 

Mammary gland 

Cyst

Hyperplasia, cystic

Skin 

Site of application-no mass, acanthosis

(10) 

 1 (10%) 

 2 (20%) 

(10) 

(10)

 2 (20%) 

(10) 

(9)

 1 (11%) 

(10) 

(9) 

(10) 

 2 (20%) 

Musculoskeletal System 

Bone 

Femur, cyst

(10) (10) (10) (10) 

 1 (10%) 

Nervous System 

Brain 

Compression

Hemorrhage

Hydrocephalus

(10) 

 1 (10%) 

(10) 

 1 (10%) 

 1 (10%) 

(10) (10) 

Respiratory System 

Lung 

Inflammation, chronic active

Alveolus, infiltration cellular, 

mononuclear cell

Nose 

Inflammation, chronic

Nasolacrimal duct, inflammation, 

suppurative

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

 3 (30%) 

(10) 

(10) 

 2 (20%) 

 2 (20%) 

(10) 

 1 (10%) 

(10) 

 3 (30%) 

 4 (40%) 

(10) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 111 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

15-Month Interim Evaluation (continued) 

Special Senses System 

Eye (1) 

Lens, cataract 1 (100%) 

Retina, atrophy 1 (100%) 

Urinary System 

Kidney (10) (10) (10) (10) 

Necrosis, coagulative 1 (10%) 

Nephropathy, chronic 10 (100%) 9 (90%) 10 (100%) 10 (100%) 

Systems Examined with No Lesions Observed 

General Body System 

Hematopoietic System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (49) (50) 

Inflammation, necrotizing 1 (2%) 

Parasite metazoan 4 (8%) 4 (8%) 2 (4%) 3 (6%) 

Intestine large, rectum (50) (50) (49) (50) 

Parasite metazoan 6 (12%) 4 (8%) 8 (16%) 8 (16%) 

Intestine large, cecum (50) (50) (49) (50) 

Inflammation, necrotizing 1 (2%) 

Inflammation, suppurative 2 (4%) 

Parasite metazoan 1 (2%) 

Intestine small, duodenum (50) (50) (49) (50) 

Inflammation, necrotizing 2 (4%) 

Intestine small, ileum (50) (50) (49) (50) 

Parasite metazoan 1 (2%) 

Liver (50) (50) (49) (50) 

Angiectasis 1 (2%) 2 (4%) 

Basophilic focus 7 (14%) 7 (14%) 4 (8%) 9 (18%) 

Clear cell focus 5 (10%) 3 (6%) 4 (8%) 1 (2%) 

Congestion 1 (2%) 

Eosinophilic focus 2 (4%) 4 (8%) 2 (4%) 2 (4%) 

Hepatodiaphragmatic nodule 3 (6%) 5 (10%) 5 (10%) 2 (4%) 

Hyperplasia, nodular 1 (2%) 

Inflammation, chronic 7 (14%) 17 (34%) 10 (20%) 7 (14%) 

Leukocytosis 1 (2%) 

Mixed cell focus 1 (2%) 3 (6%) 2 (4%) 

Necrosis, coagulative 1 (2%) 2 (4%) 2 (4%) 2 (4%) 

Bile duct, hyperplasia 48 (96%) 39 (78%) 44 (90%) 47 (94%) 

Hepatocyte, degeneration, cystic 8 (16%) 5 (10%) 6 (12%) 8 (16%) 

Hepatocyte, vacuolization cytoplasmic 6 (12%) 7 (14%) 5 (10%) 6 (12%) 

Mesentery (9) (9) (10) (5) 

Fat, inflammation, necrotizing 6 (67%) 6 (67%) 5 (50%) 4 (80%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

112 Triethanolamine, NTP TR 449 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Alimentary System (continued) 

Pancreas (50) (50) (49) (50) 

Acinus, atrophy 21 (42%) 19 (38%) 14 (29%) 14 (28%) 

Acinus, hyperplasia, nodular 1 (2%) 3 (6%) 

Artery, inflammation, chronic active 1 (2%) 1 (2%) 

Artery, thrombosis 1 (2%) 

Perivascular, inflammation, chronic active 1 (2%) 

Stomach, forestomach (50) (50) (49) (50) 

Foreign body, multiple 1 (2%) 

Granuloma 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Inflammation, necrotizing 4 (8%) 3 (6%) 8 (16%) 6 (12%) 

Mineralization 1 (2%) 

Epithelium, hyperplasia 6 (12%) 6 (12%) 9 (18%) 5 (10%) 

Stomach, glandular (50) (50) (49) (50) 

Cyst epithelial inclusion 1 (2%) 

Erosion 5 (10%) 3 (6%) 1 (2%) 

Inflammation, necrotizing 2 (4%) 2 (4%) 3 (6%) 

Mineralization 1 (2%) 

Necrosis, coagulative 1 (2%) 1 (2%) 

Tongue (1) 

Cyst 1 (100%) 

Tooth (1) 

Inflammation, chronic active 1 (100%) 

Cardiovascular System 

Blood vessel (50) (50) (49) (49) 

Mineralization 1 (2%) 1 (2%) 

Mesenteric artery, polyarteritis, chronic 1 (2%) 

Mesenteric artery, thrombosis 1 (2%) 

Heart (50) (50) (49) (50) 

Cardiomyopathy, chronic 46 (92%) 42 (84%) 45 (92%) 46 (92%) 

Inflammation, chronic active 1 (2%) 

Inflammation, suppurative 1 (2%) 

Mineralization 1 (2%) 

Atrium, thrombosis 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Endocardium, atrium, proliferation 1 (2%) 

Valve, bacterium 1 (2%) 

Valve, inflammation, chronic active 2 (4%) 

Endocrine System 

Adrenal cortex (50) (50) (49) (50) 

Accessory adrenal cortical nodule 1 (2%) 

Degeneration, fatty 21 (42%) 17 (34%) 20 (41%) 22 (44%) 

Hyperplasia 15 (30%) 17 (34%) 19 (39%) 24 (48%) 

Hypertrophy 6 (12%) 5 (10%) 5 (10%) 5 (10%) 

Karyomegaly 1 (2%) 

Necrosis, coagulative 1 (2%) 

Adrenal medulla (50) (50) (49) (50) 

Hyperplasia 28 (56%) 21 (42%) 22 (45%) 21 (42%) 

Islets, pancreatic (50) (50) (49) (50) 

Hyperplasia 2 (4%) 3 (6%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 113 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Endocrine System (continued) 

Parathyroid gland (49) (47) (44) (47) 

Cyst 1 (2%) 1 (2%) 1 (2%) 

Hyperplasia 2 (4%) 3 (6%) 3 (7%) 1 (2%) 

Pituitary gland (50) (50) (48) (50) 

Craniopharyngeal duct, pars distalis, cyst 1 (2%) 

Pars distalis, angiectasis 30 (60%) 36 (72%) 29 (60%) 39 (78%) 

Pars distalis, cyst 4 (8%) 2 (4%) 2 (4%) 3 (6%) 

Pars distalis, hyperplasia 6 (12%) 13 (26%) 13 (27%) 10 (20%) 

Pars distalis, infarct 1 (2%) 1 (2%) 1 (2%) 

Pars distalis, pigmentation, hemosiderin 23 (46%) 24 (48%) 32 (67%) 35 (70%) 

Pars intermedia, hyperplasia 1 (2%) 

Thyroid gland (50) (50) (49) (50) 

Hyperplasia 1 (2%) 

C-cell, hyperplasia 7 (14%) 6 (12%) 7 (14%) 7 (14%) 

Follicle, cyst 1 (2%) 1 (2%) 1 (2%) 

Follicular cell, hyperplasia 1 (2%) 

General Body System 

Tissue NOS (1) 

Ectasia 1 (100%) 

Genital System 

Epididymis (50) (50) (49) (50) 

Atrophy 26 (52%) 25 (50%) 27 (55%) 20 (40%) 

Fibrosis 1 (2%) 

Granuloma sperm 1 (2%) 

Inflammation, chronic active 1 (2%) 

Mineralization 1 (2%) 

Fat, necrosis 1 (2%) 

Preputial gland (50) (50) (48) (50) 

Hyperplasia 1 (2%) 

Inflammation, chronic active 44 (88%) 44 (88%) 41 (85%) 48 (96%) 

Duct, dilatation 5 (10%) 4 (8%) 4 (8%) 2 (4%) 

Prostate (50) (49) (49) (50) 

Hyperplasia, cystic 1 (2%) 

Inflammation, chronic active 45 (90%) 44 (90%) 42 (86%) 47 (94%) 

Inflammation, hemorrhagic 1 (2%) 1 (2%) 

Epithelium, hyperplasia 1 (2%) 

Seminal vesicle (50) (50) (49) (50) 

Atrophy 24 (48%) 22 (44%) 23 (47%) 13 (26%) 

Mineralization 1 (2%) 

Testes (50) (50) (49) (50) 

Polyarteritis 9 (18%) 4 (8%) 9 (18%) 6 (12%) 

Interstitial cell, hyperplasia 15 (30%) 17 (34%) 12 (24%) 16 (32%) 

Seminiferous tubule, atrophy 10 (20%) 8 (16%) 14 (29%) 8 (16%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

114 Triethanolamine, NTP TR 449 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Hematopoietic System 

Bone marrow (50) (50) (49) (50) 

Hyperplasia 1 (2%) 3 (6%) 5 (10%) 4 (8%) 

Myelofibrosis 1 (2%) 1 (2%) 

Lymph node (14) (10) (16) (9) 

Inguinal, sinus, ectasia 1 (10%) 

Mediastinal, sinus, hemorrhage 1 (6%) 

Lymph node, mandibular (50) (50) (49) (50) 

Hyperplasia, lymphoid 1 (2%) 

Necrosis, coagulative 1 (2%) 

Lymph node, mesenteric (50) (50) (49) (49) 

Sinus, ectasia 1 (2%) 1 (2%) 

Spleen (50) (50) (49) (50) 

Congestion 1 (2%) 1 (2%) 

Developmental malformation 1 (2%) 

Fibrosis 10 (20%) 3 (6%) 5 (10%) 7 (14%) 

Hematopoietic cell proliferation 1 (2%) 2 (4%) 1 (2%) 

Necrosis, coagulative 3 (6%) 1 (2%) 2 (4%) 2 (4%) 

Thrombosis 1 (2%) 

Red pulp, atrophy 1 (2%) 

Thymus (46) (49) (48) (49) 

Cyst 1 (2%) 

Developmental malformation 1 (2%) 

Integumentary System 

Mammary gland (48) (43) (45) (45) 

Hyperplasia, cystic 44 (92%) 35 (81%) 36 (80%) 42 (93%) 

Inflammation, chronic 1 (2%) 

Inflammation, chronic active 2 (4%) 2 (5%) 1 (2%) 

Inflammation, proliferative 1 (2%) 1 (2%) 

Skin (50) (50) (49) (50) 

Dermis, site of application-no mass, fibrosis 1 (2%) 1 (2%) 1 (2%) 

Dermis, site of application-mass, fibrosis 1 (2%) 

Epidermis, site of application-no mass,

 erosion 1 (2%) 

Foot, acanthosis 1 (2%) 

Foot, hyperkeratosis 1 (2%) 

Foot, inflammation, chronic active 1 (2%) 

Foot, ulcer 1 (2%) 

Inguinal, acanthosis 2 (4%) 1 (2%) 1 (2%) 

Inguinal, inflammation, chronic active 2 (4%) 1 (2%) 

Inguinal, ulcer 1 (2%) 

Neck, ventral, inflammation, chronic active 1 (2%) 

Prepuce, inflammation, suppurative 1 (2%) 

Site of application-no mass, acanthosis 1 (2%) 1 (2%) 1 (2%) 9 (18%) 

Site of application-no mass, inflammation,

 chronic active 2 (4%) 8 (16%) 

Site of application-no mass, ulcer 4 (8%) 

Site of application-no mass, ulcer, multiple 1 (2%) 

Tail, acanthosis 1 (2%) 

Tail, hyperkeratosis 1 (2%) 

Tail, inflammation, chronic active 1 (2%) 1 (2%) 

Tail, ulcer 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 115 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Musculoskeletal System 

Bone (50) (50) (49) (50) 

Fibrous osteodystrophy 1 (2%) 1 (2%) 

Maxilla, abscess 1 (2%) 1 (2%) 1 (2%) 

Maxilla, fibrosis 2 (4%) 1 (2%) 1 (2%) 

Nervous System 

Brain (50) (50) (48) (50) 

Compression 15 (30%) 18 (36%) 10 (21%) 21 (42%) 

Gliosis 1 (2%) 

Hemorrhage 4 (8%) 1 (2%) 

Hydrocephalus 14 (28%) 18 (36%) 9 (19%) 18 (36%) 

Peripheral nerve (2) (2) 

Sciatic, myelin, degeneration 1 (50%) 

Spinal cord (2) (2) 

Hemorrhage 1 (50%) 

White matter, degeneration 1 (50%) 

Respiratory System 

Lung (50) (50) (49) (50) 

Inflammation, chronic active 7 (14%) 4 (8%) 4 (8%) 2 (4%) 

Inflammation, suppurative 1 (2%) 

Metaplasia, osseous 1 (2%) 

Mineralization 1 (2%) 

Alveolar epithelium, hyperplasia 2 (4%) 3 (6%) 1 (2%) 

Alveolus, infiltration cellular, 

mononuclear cell 17 (34%) 20 (40%) 18 (37%) 9 (18%) 

Fat, mediastinum, atrophy 1 (2%) 

Mediastinum, fibrosis 1 (2%) 

Perivascular, edema 1 (2%) 

Nose (50) (50) (49) (50) 

Fungus 1 (2%) 1 (2%) 

Inflammation, chronic active 5 (10%) 4 (8%) 3 (6%) 9 (18%) 

Nasolacrimal duct, inflammation, 

suppurative 12 (24%) 11 (22%) 7 (14%) 8 (16%) 

Respiratory epithelium, hyperplasia 2 (4%) 1 (2%) 

Special Senses System 

Ear (1) (2) (2) (1) 

Cyst epithelial inclusion 1 (50%) 

Eye (2) (3) (2) 

Lens, cataract 3 (100%) 2 (100%) 

Retina, atrophy 3 (100%) 2 (100%) 

Zymbal’s gland (2) (2) (1) 

Abscess 1 (50%) 
 

 

 

 

 

 

 

 

 

 

116 Triethanolamine, NTP TR 449 

TABLE A5 

Summary of the Incidence of Nonneoplastic Lesions in Male Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

2-Year Study (continued) 

Urinary System 

Kidney (50) (50) (49) (50) 

Hydronephrosis 1 (2%) 1 (2%) 

Hyperplasia 1 (2%) 1 (2%) 

Inflammation, suppurative 1 (2%) 

Mineralization 1 (2%) 

Necrosis, coagulative 1 (2%) 

Nephropathy, chronic 48 (96%) 49 (98%) 49 (100%) 50 (100%) 

Pigmentation, hemosiderin 1 (2%) 

Cortex, cyst 2 (4%) 1 (2%) 

Renal tubule, hyperplasia 1 (2%) 

Urinary bladder (50) (50) (48) (49) 

Dilatation 1 (2%) 

Inflammation, hemorrhagic 2 (4%) 1 (2%) 
117 

APPENDIX B 

SUMMARY OF LESIONS IN FEMALE RATS 

IN THE 2-YEAR DERMAL STUDY 

OF TRIETHANOLAMINE 

TABLE B1 Summary of the Incidence of Neoplasms in Female Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 118 

TABLE B2 Individual Animal Tumor Pathology of Female Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 122 

TABLE B3 Statistical Analysis of Primary Neoplasms in Female Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 138 

TABLE B4 Summary of the Incidence of Nonneoplastic Lesions in Female Rats 

in the 2-Year Dermal Study of Triethanolamine ............................ 141 
 

 

 

 

 

 

 

118 Triethanolamine, NTP TR 449 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Moribund 

Natural deaths 

Survivors 

Died last week of study 

Terminal sacrifice 

60 

10 

11 

14 

25 

60 

10 

4 

17 

29 

60 

10 

12 

13 

25 

60 

10 

17 

15 

1 

17 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Endocrine System 

Adrenal medulla 

Pheochromocytoma benign

Islets, pancreatic 

Adenoma

Pituitary gland 

Pars distalis, adenoma

Thyroid gland 

Follicular cell, adenoma

(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

 1 (10%) 

(10) 

(10) 

(10) 

(10) 

 2 (20%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 4 (40%) 

(10) 

 1 (10%) 

Genital System 

Uterus 

Polyp stromal

(10) 

 2 (20%) 

(10) 

 1 (10%) 

(10) (10) 

 2 (20%) 

Special Senses System 

Zymbal’s gland

Carcinoma

 (1) 

 1 (100%) 

Systems Examined with No Neoplasms Observed 

Alimentary System 

Cardiovascular System 

General Body System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Urinary System 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 119 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study 

Alimentary System 

Esophagus (50) (50) (50) (50) 

Periesophageal tissue, lipoma 1 (2%) 

Liver (50) (50) (50) (50) 

Hepatocellular adenoma 1 (2%) 

Mesentery (3) (2) (2) (2) 

Rhabdomyosarcoma, metastatic, 

skeletal muscle 1 (50%) 

Pancreas (50) (50) (50) (50) 

Stomach, forestomach (50) (50) (50) (50) 

Squamous cell papilloma 1 (2%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Schwannoma benign 1 (2%) 

Schwannoma malignant 1 (2%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Adenoma 1 (2%) 1 (2%) 

Adrenal medulla (50) (50) (50) (49) 

Pheochromocytoma benign 1 (2%) 

Bilateral, pheochromocytoma benign 1 (2%) 

Islets, pancreatic (50) (50) (50) (50) 

Adenoma 2 (4%) 1 (2%) 

Carcinoma 1 (2%) 

Parathyroid gland (41) (48) (47) (43) 

Adenoma 1 (2%) 

Pituitary gland (50) (50) (50) (50) 

Pars distalis, adenoma 32 (64%) 25 (50%) 29 (58%) 23 (46%) 

Pars distalis, adenoma, multiple 1 (2%) 1 (2%) 1 (2%) 

Thyroid gland (50) (50) (50) (49) 

C-cell, adenoma 1 (2%) 2 (4%) 2 (4%) 5 (10%) 

C-cell, carcinoma 1 (2%) 

Follicular cell, adenoma 2 (4%) 1 (2%) 1 (2%) 1 (2%) 

Follicular cell, carcinoma 1 (2%) 1 (2%) 

General Body System 

None 

Genital System 

Clitoral gland (48) (49) (50) (50) 

Adenoma 2 (4%) 6 (12%) 2 (4%) 2 (4%) 

Carcinoma 1 (2%) 

Bilateral, carcinoma 1 (2%) 

Ovary (50) (50) (50) (50) 

Granulosa cell tumor malignant 1 (2%) 

Uterus (50) (50) (50) (50) 

Leiomyoma 1 (2%) 

Polyp stromal 2 (4%) 1 (2%) 8 (16%) 5 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

120 Triethanolamine, NTP TR 449 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study (continued) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Lymph node (6) (5) (6) (3) 

Mediastinal, rhabdomyosarcoma,

 metastatic, skeletal muscle 1 (33%) 

Mediastinal, schwannoma malignant, 

metastatic, heart 1 (20%) 

Lymph node, mandibular (49) (50) (50) (50) 

Lymph node, mesenteric (50) (50) (49) (50) 

Spleen (50) (50) (50) (50) 

Thymus (49) (47) (47) (48) 

Rhabdomyosarcoma, metastatic, 

skeletal muscle 1 (2%) 

Thymoma benign 1 (2%) 

Thymoma malignant 1 (2%) 

Mediastinum, schwannoma malignant, 

metastatic, heart 1 (2%) 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Adenoma 1 (2%) 1 (2%) 

Carcinoma 1 (2%) 

Fibroadenoma 12 (24%) 13 (26%) 7 (14%) 6 (12%) 

Fibroadenoma, multiple 1 (2%) 3 (6%) 2 (4%) 

Skin (50) (50) (50) (50) 

Face, squamous cell papilloma 1 (2%) 

Inguinal, keratoacanthoma 1 (2%) 

Subcutaneous tissue, neurofibrosarcoma 1 (2%) 

Musculoskeletal System 

Skeletal muscle (1) (2) 

Hemangiosarcoma 1 (100%) 

Rhabdomyosarcoma 1 (50%) 

Nervous System 

Brain (50) (50) (50) (50) 

Medulloblastoma NOS 1 (2%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Mediastinum, rhabdomyosarcoma,

 metastatic, skeletal muscle 1 (2%) 

Nose (50) (50) (50) (50) 
 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 121 

TABLE B1 

Summary of the Incidence of Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study (continued) 

Special Senses System 

Ear (1) (2) (1) 

Middle ear, carcinoma, metastatic, 

Zymbal’s gland 1 (100%) 

Pinna, fibrosarcoma 1 (50%) 

Zymbal’s gland (1) (1) 

Carcinoma 1 (100%) 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Renal tubule, adenoma 1 (2%) 1 (2%) 

Urinary bladder (49) (50) (50) (50) 

Leiomyoma 1 (2%) 

Transitional epithelium, papilloma 1 (2%) 

Systemic Lesions 

Multiple organsb (50) (50) (50) (50) 

Leukemia mononuclear 13 (26%) 14 (28%) 13 (26%) 16 (32%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 3 2 3 7 

2-Year study 47 42 44 37 

Total primary neoplasms 

15-Month interim evaluation 3 2 3 9 

2-Year study 76 77 74 67 

Total animals with benign neoplasms 

15-Month interim evaluation 2 2 3 7 

2-Year study 43 37 39 30 

Total benign neoplasms 

15-Month interim evaluation 2 2 3 9 

2-Year study 57 59 59 46 

Total animals with malignant neoplasms 

15-Month interim evaluation 1 

2-Year study 16 17 13 18 

Total malignant neoplasms 

15-Month interim evaluation 1 

2-Year study 19 18 15 20 

Total animals with metastatic neoplasms 

2-Year study 1 2 

Total metastatic neoplasms 

2-Year study 2 5 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 1 

Total uncertain neoplasms 

2-Year study 1 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms c 
 

 

 

 

 

 

 

 

 

122 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

Number of Days on Study 

3 

3 

8 

3 

9 

0 

4 

6 

6 

5 

4 

2 

5 

5 

5 

5 

6 

7 

5 

8 

2 

5 

9 

3 

6 

3 

4 

6 

3 

6 

6 

3 

8 

6 

3 

9 

6 

6 

3 

6 

7 

1 

6 

7 

4 

6 

7 

4 

6 

9 

1 

6 

9 

9 

7 

1 

0 

7 

1 

0 

7 

1 

3 

7 

1 

8 

7 

1 

9 

7 

1 

9 

7 

2 

8 

Carcass ID Number 

2 

5 

8 

2 

8 

5 

2 

5 

1 

2 

5 

6 

3 

0 

0 

2 

4 

6 

2 

8 

0 

2 

7 

6 

2 

9 

0 

2 

4 

2 

2 

9 

4 

2 

8 

4 

2 

4 

1 

2 

9 

3 

2 

5 

3 

2 

6 

0 

2 

7 

8 

2 

4 

7 

2 

6 

5 

2 

9 

5 

2 

8 

6 

2 

7 

2 

2 

6 

4 

2 

9 

7 

2 

7 

9 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

Cardiovascular System 

Blood vessel + 

Heart + 

Endocrine System 

Adrenal cortex + 

Adrenal medulla + 

Islets, pancreatic + 

Parathyroid gland + 

Adenoma 

Pituitary gland + 

Pars distalis, adenoma 

Pars distalis, adenoma, multiple 

Thyroid gland + 

C-cell, adenoma 

Follicular cell, adenoma 

Follicular cell, carcinoma 

General Body System 

None 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

M 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

+ 

X 

+ 

Genital System 

Clitoral gland + + + + + + + + + + + + M + + + + + M + + + + + + 

Adenoma 

Carcinoma X 

Bilateral, carcinoma X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Granulosa cell tumor malignant 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyoma X 

Polyp stromal X 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 123 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Total 

Carcass ID Number 4 4 5 6 6 6 7 8 9 9 4 4 5 6 7 7 8 9 9 4 5 6 8 8 8 Tissues/ 

3 9 4 1 2 3 0 2 6 9 5 8 7 7 1 4 1 1 8 4 2 8 7 8 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + 3 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + M + + + + + M M M + + + M M + 41 

Adenoma 1 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X 32 

Pars distalis, adenoma, multiple X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X 1 

Follicular cell, adenoma X 2 

Follicular cell, carcinoma X 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Adenoma X X 2 

Carcinoma 1 

Bilateral, carcinoma 1 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Granulosa cell tumor malignant X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Leiomyoma 1 

Polyp stromal X 2 
 

 

 

 

 

 

 

 

 

124 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

Number of Days on Study 

3 

3 

8 

3 

9 

0 

4 

6 

6 

5 

4 

2 

5 

5 

5 

5 

6 

7 

5 

8 

2 

5 

9 

3 

6 

3 

4 

6 

3 

6 

6 

3 

8 

6 

3 

9 

6 

6 

3 

6 

7 

1 

6 

7 

4 

6 

7 

4 

6 

9 

1 

6 

9 

9 

7 

1 

0 

7 

1 

0 

7 

1 

3 

7 

1 

8 

7 

1 

9 

7 

1 

9 

7 

2 

8 

Carcass ID Number 

2 

5 

8 

2 

8 

5 

2 

5 

1 

2 

5 

6 

3 

0 

0 

2 

4 

6 

2 

8 

0 

2 

7 

6 

2 

9 

0 

2 

4 

2 

2 

9 

4 

2 

8 

4 

2 

4 

1 

2 

9 

3 

2 

5 

3 

2 

6 

0 

2 

7 

8 

2 

4 

7 

2 

6 

5 

2 

9 

5 

2 

8 

6 

2 

7 

2 

2 

6 

4 

2 

9 

7 

2 

7 

9 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

+ + + + + + + + + + + + + + + M + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Face, squamous cell papilloma 

Subcutaneous tissue, neurofibrosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Musculoskeletal System 

Bone 

Skeletal muscle 

Hemangiosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

+ 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Eye 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 
 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 125 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

Number of Days on Study 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

1 

7 

3 

1 

7 

3 

1 

7 

3 

1 

7 

3 

1 

7 

3 

1 

Carcass ID Number 

2 

4 

3 

2 

4 

9 

2 

5 

4 

2 

6 

1 

2 

6 

2 

2 

6 

3 

2 

7 

0 

2 

8 

2 

2 

9 

6 

2 

9 

9 

2 

4 

5 

2 

4 

8 

2 

5 

7 

2 

6 

7 

2 

7 

1 

2 

7 

4 

2 

8 

1 

2 

9 

1 

2 

9 

8 

2 

4 

4 

2 

5 

2 

2 

6 

8 

2 

8 

7 

2 

8 

8 

2 

8 

9 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + M + + + + + 

50 

6 

49 

50 

50 

49 

Integumentary System 

Mammary gland 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

Face, squamous cell papilloma 

Subcutaneous tissue, neurofibrosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

12 

1 

50 

1 

1 

Musculoskeletal System 

Bone 

Skeletal muscle

Hemangiosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

1 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

50 

2 

1 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

50 

Special Senses System 

Eye + 1 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + M + + + + + 

50 

1 

49 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X 

50 

13 
 

 

 

 

 

 

 

 

 

 

126 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

Number of Days on Study 

4 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 

0 3 4 0 3 6 7 7 8 9 0 4 6 6 7 7 9 9 0 1 2 2 2 2 2 

0 4 3 4 6 2 6 9 3 5 0 9 2 4 3 8 1 9 8 5 7 9 9 9 9 

Carcass ID Number 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

5 0 1 0 2 4 5 2 5 1 3 3 4 2 3 4 3 4 0 2 4 0 1 2 2 

1 5 0 6 4 6 2 3 7 9 0 5 4 5 3 1 4 9 9 1 0 3 3 2 8 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel 

Heart 

Schwannoma benign 

Schwannoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Bilateral, pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Parathyroid gland + + + + M M + + + + + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X X X X X X X X X 

Pars distalis, adenoma, multiple 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma 

Follicular cell, adenoma X 

Follicular cell, carcinoma X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + M + + + + + + + + + + 

Adenoma X X X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal 
 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 127 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 4 4 5 5 5 0 1 1 1 1 2 3 4 0 0 0 0 3 3 3 3 4 5 5 6 Tissues/ 

3 7 4 5 9 7 2 4 5 7 9 1 5 1 2 4 8 2 6 8 9 2 3 6 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery + + 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Schwannoma benign 1 

Schwannoma malignant 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign 1 

Bilateral, pheochromocytoma benign 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 2 

Parathyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X 25 

Pars distalis, adenoma, multiple X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X 2 

Follicular cell, adenoma 1 

Follicular cell, carcinoma 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adenoma X X X 6 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X 1 
 

 

 

 

 

 

 

 

 

 

128 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

Number of Days on Study 

4 

0 

0 

4 

3 

4 

4 

4 

3 

5 

0 

4 

5 

3 

6 

5 

6 

2 

5 

7 

6 

5 

7 

9 

5 

8 

3 

5 

9 

5 

6 

0 

0 

6 

4 

9 

6 

6 

2 

6 

6 

4 

6 

7 

3 

6 

7 

8 

6 

9 

1 

6 

9 

9 

7 

0 

8 

7 

1 

5 

7 

2 

7 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

Carcass ID Number 

3 

5 

1 

3 

0 

5 

3 

1 

0 

3 

0 

6 

3 

2 

4 

3 

4 

6 

3 

5 

2 

3 

2 

3 

3 

5 

7 

3 

1 

9 

3 

3 

0 

3 

3 

5 

3 

4 

4 

3 

2 

5 

3 

3 

3 

3 

4 

1 

3 

3 

4 

3 

4 

9 

3 

0 

9 

3 

2 

1 

3 

4 

0 

3 

0 

3 

3 

1 

3 

3 

2 

2 

3 

2 

8 

Hematopoietic System 

Bone marrow 

Lymph node 

Mediastinal, schwannoma malignant,

 metastatic, heart 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

Mediastinum, schwannoma malignant,

 metastatic, heart 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + M + + + + + 

X 

Integumentary System 

Mammary gland 

Adenoma 

Carcinoma 

Fibroadenoma 

Skin 

Inguinal, keratoacanthoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Eye 

Harderian gland 

Zymbal’s gland 

Carcinoma 

+ 

X 

+ 

+ 

+ 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 129 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 63 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

Carcass ID Number 

3 

4 

3 

3 

4 

7 

3 

5 

4 

3 

5 

5 

3 

5 

9 

3 

0 

7 

3 

1 

2 

3 

1 

4 

3 

1 

5 

3 

1 

7 

3 

2 

9 

3 

3 

1 

3 

4 

5 

3 

0 

1 

3 

0 

2 

3 

0 

4 

3 

0 

8 

3 

3 

2 

3 

3 

6 

3 

3 

8 

3 

3 

9 

3 

4 

2 

3 

5 

3 

3 

5 

6 

3 

6 

0 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Mediastinal, schwannoma malignant,

 metastatic, heart

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

Mediastinum, schwannoma malignant,

 metastatic, heart

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ +

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + M + + M 

50 

5 

1 

50 

50 

50 

47 

1 

Integumentary System 

Mammary gland 

Adenoma 

Carcinoma 

Fibroadenoma 

Skin 

Inguinal, keratoacanthoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

X X X X X X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

1 

1 

13 

50 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

50 

Special Senses System 

Ear

Eye 

Harderian gland

Zymbal’s gland

Carcinoma

+

 1 

2 

1 

1 

1 

Urinary System 

Kidney 

Renal tubule, adenoma

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

50 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X 

50 

14 
 

 

 

 

 

 

 

 

 

 

130 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

2 3 4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

Number of Days on Study 2 9 7 8 4 4 7 9 0 1 3 3 3 4 7 7 9 0 1 1 1 1 2 2 2 

2 9 7 4 4 4 4 3 0 9 1 9 9 8 0 3 1 0 0 4 8 9 4 5 8 

3 3 4 4 3 3 4 4 3 3 4 3 4 3 3 3 3 3 3 3 3 4 4 3 4 

Carcass ID Number 8 8 0 0 6 9 2 0 7 8 1 7 1 7 9 7 9 7 9 6 9 0 0 6 1 

9 0 2 4 1 3 0 0 7 1 0 0 6 2 0 9 1 4 8 3 4 3 8 2 2 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Periesophageal tissue, lipoma X 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Mesentery + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma 

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 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma 

Follicular cell, adenoma 

General Body System 

Tissue NOS + 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 131 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 

3 3 3 3 3 4 4 4 3 3 3 3 3 3 3 4 4 4 4 4 3 3 3 3 4 Total 

Carcass ID Number 6 6 7 8 9 0 1 1 6 6 7 8 8 9 9 0 0 0 1 1 7 8 9 9 1 Tissues/ 

6 8 5 3 7 6 5 7 4 5 6 4 5 2 6 1 5 7 1 9 8 2 5 9 4 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Periesophageal tissue, lipoma 1 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Mesentery 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma X 1 

Parathyroid gland + + + + + + M + + + + + + + + + + + + + + + + + + 47 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X 29 

Pars distalis, adenoma, multiple 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

C-cell, adenoma X X 2 

Follicular cell, adenoma X 1 

General Body System 

Tissue NOS

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X X 2 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X X X X X X 8 

 1 
 

 

 

 

 

 

 

 

 

 

 

132 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

2 3 4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 

Number of Days on Study 2 9 7 8 4 4 7 9 0 1 3 3 3 4 7 7 9 0 1 1 1 1 2 2 2 

2 9 7 4 4 4 4 3 0 9 1 9 9 8 0 3 1 0 0 4 8 9 4 5 8 

3 3 4 4 3 3 4 4 3 3 4 3 4 3 3 3 3 3 3 3 3 4 4 3 4 

Carcass ID Number 8 8 0 0 6 9 2 0 7 8 1 7 1 7 9 7 9 7 9 6 9 0 0 6 1 

9 0 2 4 1 3 0 0 7 1 0 0 6 2 0 9 1 4 8 3 4 3 8 2 2 

Hematopoietic System 

Blood 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + + + 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node, mesenteric M + + + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Thymus + + + + + + + + + + + + + + + + M + + M + + + + + 

Thymoma benign X 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Fibroadenoma X X X X X 

Fibroadenoma, multiple X X 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Pinna, fibrosarcoma X 

Eye + + + 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 

Leiomyoma X 

Transitional epithelium, papilloma 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 

Leukemia mononuclear X X X X X X X X 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 133 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 125 mg/kg 

(continued) 

Number of Days on Study 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

1 

7 

3 

1 

7 

3 

1 

7 

3 

1 

7 

3 

1 

Carcass ID Number 

3 

6 

6 

3 

6 

8 

3 

7 

5 

3 

8 

3 

3 

9 

7 

4 

0 

6 

4 

1 

5 

4 

1 

7 

3 

6 

4 

3 

6 

5 

3 

7 

6 

3 

8 

4 

3 

8 

5 

3 

9 

2 

3 

9 

6 

4 

0 

1 

4 

0 

5 

4 

0 

7 

4 

1 

1 

4 

1 

9 

3 

7 

8 

3 

8 

2 

3 

9 

5 

3 

9 

9 

4 

1 

4 

Total 

Tissues/ 

Tumors 

Hematopoietic System 

Blood 

Bone marrow 

Lymph node

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

Thymoma benign

+

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + M + + + + + + 

1 

50 

6 

50 

49 

50 

47 

1 

Integumentary System 

Mammary gland 

Adenoma 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

7 

3 

50 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Lung 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

50 

Special Senses System 

Ear 

Pinna, fibrosarcoma

Eye + 

+

+ +

 2 

1 

6 

Urinary System 

Kidney 

Urinary bladder 

Leiomyoma

Transitional epithelium, papilloma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

50 

1 

1 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X 

50 

13 
 

 

 

 

 

 

 

 

 

 

 

134 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 250 mg/kg 

Number of Days on Study 

1 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6 6 

2 5 5 5 5 8 9 2 2 3 5 6 2 2 5 8 8 1 1 2 3 3 4 4 5 

5 0 3 3 8 9 4 0 9 9 9 3 2 4 6 8 8 0 7 4 1 3 4 9 7 

Carcass ID Number 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

5 4 3 4 7 4 5 7 6 4 5 3 6 4 7 4 6 2 5 7 5 3 5 7 2 

8 9 7 5 1 4 1 6 4 0 2 9 7 3 2 8 3 3 5 7 0 8 4 8 2 

Alimentary System 

Esophagus 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular adenoma 

Mesentery 

Rhabdomyosarcoma, metastatic,

 skeletal muscle 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla M + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + M + + + + + M + + + + M + + + + + + M + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

C-cell, adenoma X X 

C-cell, carcinoma 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal X X X 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 135 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 250 mg/kg 

(continued) 

6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 7 7 9 0 1 1 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 

7 0 0 0 0 3 8 9 9 9 9 9 9 9 0 0 0 0 1 1 1 1 1 1 1 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 2 2 7 4 3 4 6 3 3 3 7 7 7 8 3 6 6 6 2 4 5 5 6 6 7 Tissues/ 

1 7 0 2 0 7 1 3 5 6 3 4 9 0 4 0 2 5 4 1 6 7 6 8 5 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular adenoma X 1 

Mesentery + 2 

Rhabdomyosarcoma, metastatic,

 skeletal muscle 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Parathyroid gland + + M + + + + M + M + + + + + + + + + + + + + + + 43 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pars distalis, adenoma X X X X X X X X X X X X X X X X X X 23 

Thyroid gland + + M + + + + + + + + + + + + + + + + + + + + + + 49 

C-cell, adenoma X X X 5 

C-cell, carcinoma X 1 

Follicular cell, adenoma 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 2 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X X 5 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

136 Triethanolamine, NTP TR 449 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 250 mg/kg 

(continued) 

1 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6 6 

Number of Days on Study 2 

5 

5 

0 

5 

3 

5 

3 

5 

8 

8 

9 

9 

4 

2 

0 

2 

9 

3 

9 

5 

9 

6 

3 

2 

2 

2 

4 

5 

6 

8 

8 

8 

8 

1 

0 

1 

7 

2 

4 

3 

1 

3 

3 

4 

4 

4 

9 

5 

7 

Carcass ID Number 

4 

5 

8 

4 

4 

9 

4 

3 

7 

4 

4 

5 

4 

7 

1 

4 

4 

4 

4 

5 

1 

4 

7 

6 

4 

6 

4 

4 

4 

0 

4 

5 

2 

4 

3 

9 

4 

6 

7 

4 

4 

3 

4 

7 

2 

4 

4 

8 

4 

6 

3 

4 

2 

3 

4 

5 

5 

4 

7 

7 

4 

5 

0 

4 

3 

8 

4 

5 

4 

4 

7 

8 

4 

2 

2 

Hematopoietic System 

Blood 

Bone marrow 

Lymph node 

Mediastinal, rhabdomyosarcoma,

 metastatic, skeletal muscle 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

Rhabdomyosarcoma, metastatic,

 skeletal muscle 

Thymoma malignant 

+ 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

M + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Integumentary System 

Mammary gland 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone 

Skeletal muscle 

Rhabdomyosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

Nervous System 

Brain 

Medulloblastoma NOS 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ 

+ 

Respiratory System 

Lung 

Mediastinum, rhabdomyosarcoma,

 metastatic, skeletal muscle 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Middle ear, carcinoma, metastatic,

 Zymbal’s gland 

Eye 

Zymbal’s gland 

Carcinoma 

+ 

X 

+ 

X 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 137 

TABLE B2 

Individual Animal Tumor Pathology of Female Rats in the 2-Year Dermal Study of Triethanolamine: 250 mg/kg 

(continued) 

6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 6 

7 

7 

0 

7 

0 

9 

0 

0 

0 

1 

3 

1 

8 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 2 

1 

2 

7 

7 

0 

4 

2 

3 

0 

4 

7 

6 

1 

3 

3 

3 

5 

3 

6 

7 

3 

7 

4 

7 

9 

8 

0 

3 

4 

6 

0 

6 

2 

6 

5 

2 

4 

4 

1 

5 

6 

5 

7 

6 

6 

6 

8 

7 

5 

Tissues/ 

Tumors 

Hematopoietic System 

Blood

Bone marrow 

Lymph node 

Mediastinal, rhabdomyosarcoma,

 metastatic, skeletal muscle 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

Rhabdomyosarcoma, metastatic,

 skeletal muscle 

Thymoma malignant 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ +

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + M + + + + + + + + + + + + + 

X

 1 

50 

3 

1 

50 

50 

50 

48 

1 

1 

Integumentary System 

Mammary gland 

Fibroadenoma 

Fibroadenoma, multiple 

Skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

6 

2 

50 

Musculoskeletal System 

Bone 

Skeletal muscle 

Rhabdomyosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

50 

2 

1 

Nervous System 

Brain 

Medulloblastoma NOS

Peripheral nerve

Spinal cord

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

1 

1 

Respiratory System 

Lung 

Mediastinum, rhabdomyosarcoma,

 metastatic, skeletal muscle 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

50 

50 

Special Senses System 

Ear

Middle ear, carcinoma, metastatic,

 Zymbal’s gland

Eye 

Zymbal’s gland

Carcinoma

+

 1 

1 

1 

1 

1 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

Systemic Lesions 

Multiple organs 

Leukemia mononuclear 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X X X 

50 

16 
138 Triethanolamine, NTP TR 449 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Clitoral Gland: Adenoma a Overall rate 2/48 (4%) 6/49 (12%) 2/50 (4%) 2/50 (4%) b Adjusted rate 8.0% 17.3% 8.0% 7.7% c Terminal rate 2/25 (8%) 3/29 (10%) 2/25 (8%) 1/18 (6%) 

First incidence (days) 729 (T) 579 729 (T) 389 

d Life table test P=0.512N P=0.170 P=0.697 P=0.595 

d Logistic regression test P=0.383N P=0.139 P=0.697 P=0.693N 

d Cochran-Armitage test P=0.325N 

d Fisher exact test P=0.141 P=0.676N P=0.676N 

Clitoral Gland: Adenoma or Carcinoma 

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

Adjusted rate 13.3% 17.3% 8.0% 7.7% 

Terminal rate 2/25 (8%) 3/29 (10%) 2/25 (8%) 1/18 (6%) 

First incidence (days) 593 579 729 (T) 389 

Life table test P=0.276N P=0.421 P=0.336N P=0.480N 

Logistic regression test P=0.166N P=0.381 P=0.323N P=0.328N 

Cochran-Armitage test P=0.138N 

Fisher exact test P=0.383 P=0.319N P=0.319N 

Mammary Gland: Fibroadenoma 

Overall rate 13/50 (26%) 13/50 (26%) 10/50 (20%) 8/50 (16%) 

Adjusted rate 40.8% 44.8% 28.4% 32.1% 

Terminal rate 7/25 (28%) 13/29 (45%) 3/25 (12%) 4/18 (22%) 

First incidence (days) 636 729 (T) 619 459 

Life table test P=0.383N P=0.451N P=0.335N P=0.460N 

Logistic regression test P=0.275N P=0.584N P=0.327N P=0.345N 

Cochran-Armitage test P=0.102N 

Fisher exact test P=0.590N P=0.318N P=0.163N 

Mammary Gland: Fibroadenoma, Adenoma, or Carcinoma 

Overall rate 13/50 (26%) 13/50 (26%) 11/50 (22%) 8/50 (16%) 

Adjusted rate 40.8% 44.8% 31.7% 32.1% 

Terminal rate 7/25 (28%) 13/29 (45%) 4/25 (16%) 4/18 (22%) 

First incidence (days) 636 729 (T) 619 459 

Life table test P=0.404N P=0.451N P=0.418N P=0.460N 

Logistic regression test P=0.296N P=0.584N P=0.420N P=0.345N 

Cochran-Armitage test P=0.109N 

Fisher exact test P=0.590N P=0.408N P=0.163N 

Pituitary Gland (Pars Distalis): Adenoma 

Overall rate 33/50 (66%) 26/50 (52%) 30/50 (60%) 23/50 (46%) 

Adjusted rate 81.3% 66.1% 74.5% 78.3% 

Terminal rate 18/25 (72%) 16/29 (55%) 15/25 (60%) 12/18 (67%) 

First incidence (days) 390 504 544 429 

Life table test P=0.433 P=0.082N P=0.380N P=0.516N 

Logistic regression test P=0.259N P=0.112N P=0.354N P=0.175N 

Cochran-Armitage test P=0.051N 

Fisher exact test P=0.111N P=0.339N P=0.035N 
Triethanolamine, NTP TR 449 139 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Thyroid Gland (C-cell): Adenoma 

Overall rate 1/50 (2%) 2/50 (4%) 2/50 (4%) 5/49 (10%) 

Adjusted rate 4.0% 6.9% 8.0% 20.9% 

Terminal rate 1/25 (4%) 2/29 (7%) 2/25 (8%) 3/18 (17%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 429 

Life table test P=0.015 P=0.552 P=0.500 P=0.053 

Logistic regression test P=0.027 P=0.552 P=0.500 P=0.081 

Cochran-Armitage test P=0.047 

Fisher exact test P=0.500 P=0.500 P=0.098 

Thyroid Gland (C-cell): Adenoma or Carcinoma 

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

Adjusted rate 4.0% 6.9% 8.0% 26.2% 

Terminal rate 1/25 (4%) 2/29 (7%) 2/25 (8%) 4/18 (22%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 429 

Life table test P=0.004 P=0.552 P=0.500 P=0.024 

Logistic regression test P=0.009 P=0.552 P=0.500 P=0.037 

Cochran-Armitage test P=0.019 

Fisher exact test P=0.500 P=0.500 P=0.053 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 3/50 (6%) 2/50 (4%) 1/50 (2%) 1/49 (2%) 

Adjusted rate 10.1% 5.5% 4.0% 2.7% 

Terminal rate 2/25 (8%) 0/29 (0%) 1/25 (4%) 0/18 (0%) 

First incidence (days) 582 562 729 (T) 524 

Life table test P=0.285N P=0.465N P=0.308N P=0.411N 

Logistic regression test P=0.192N P=0.499N P=0.308N P=0.305N 

Cochran-Armitage test P=0.204N 

Fisher exact test P=0.500N P=0.309N P=0.316N 

Uterus: Stromal Polyp 

Overall rate 2/50 (4%) 1/50 (2%) 8/50 (16%) 5/50 (10%) 

Adjusted rate 6.1% 3.4% 30.2% 17.5% 

Terminal rate 1/25 (4%) 1/29 (3%) 7/25 (28%) 2/18 (11%) 

First incidence (days) 555 729 (T) 700 353 

Life table test P=0.023 P=0.468N P=0.046 P=0.137 

Logistic regression test P=0.061 P=0.500N P=0.045 P=0.300 

Cochran-Armitage test P=0.079 

Fisher exact test P=0.500N P=0.046 P=0.218 

All Organs: Mononuclear Cell Leukemia 

Overall rate 13/50 (26%) 14/50 (28%) 13/50 (26%) 16/50 (32%) 

Adjusted rate 39.7% 39.8% 36.2% 54.1% 

Terminal rate 7/25 (28%) 9/29 (31%) 5/25 (20%) 6/18 (33%) 

First incidence (days) 636 443 484 439 

Life table test P=0.055 P=0.569N P=0.581 P=0.079 

Logistic regression test P=0.155 P=0.494 P=0.582 P=0.142 

Cochran-Armitage test P=0.297 

Fisher exact test P=0.500 P=0.590N P=0.330 
140 

c 

Triethanolamine, NTP TR 449 

TABLE B3 

Statistical Analysis of Primary Neoplasms in Female Rats in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

All Organs: Benign Neoplasms 

Overall rate 43/50 (86%) 38/50 (76%) 39/50 (78%) 33/50 (66%) 

Adjusted rate 95.4% 90.3% 92.8% 91.2% 

Terminal rate 23/25 (92%) 25/29 (86%) 22/25 (88%) 15/18 (83%) 

First incidence (days) 390 400 544 353 

Life table test P=0.268 P=0.109N P=0.323N P=0.417 

Logistic regression test P=0.230N P=0.151N P=0.233N P=0.130N 

Cochran-Armitage test P=0.017N 

Fisher exact test P=0.154N P=0.218N 0.017N 

All Organs: Malignant Neoplasms 

Overall rate 17/50 (34%) 17/50 (34%) 13/50 (26%) 18/50 (36%) 

Adjusted rate 47.6% 46.0% 36.2% 56.6% 

Terminal rate 8/25 (32%) 10/29 (34%) 5/25 (20%) 6/18 (33%) 

First incidence (days) 466 443 484 439 

Life table test P=0.122 P=0.470N P=0.280N P=0.142 

Logistic regression test P=0.342 P=0.581 P=0.259N P=0.352 

Cochran-Armitage test P=0.490 

Fisher exact test P=0.583N P=0.257N P=0.500 

All Organs: Benign or Malignant Neoplasms 

Overall rate 47/50 (94%) 43/50 (86%) 44/50 (88%) 39/50 (78%) 

Adjusted rate 97.9% 93.4% 95.6% 95.0% 

Terminal rate 24/25 (96%) 26/29 (90%) 23/25 (92%) 16/18 (89%) 

First incidence (days) 390 400 484 353 

Life table test P=0.133 P=0.155N P=0.391N P=0.238 

Logistic regression test P=0.263N P=0.153N P=0.267N P=0.193N 

Cochran-Armitage test P=0.020N 

Fisher exact test P=0.159N P=0.243N P=0.020N 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for clitoral gland, pituitary 

gland, thyroid gland, and uterus; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill d Beneath the control incidence are the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise 

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

indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the 

overall incidence rates. For all tests, a negative trend or a lower incidence in a dose group is indicated by N. 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 141 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 11 4 12 17 

Natural deaths 14 17 13 15 

Survivors 

Died last week of study 1 

Terminal sacrifice 25 29 25 17 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Intestine large, colon (10) (10) (10) (10) 

Parasite metazoan 1 (10%) 1 (10%) 

Intestine large, rectum (10) (10) (10) (10) 

Parasite metazoan 1 (10%) 1 (10%) 3 (30%) 

Liver (10) (10) (10) (10) 

Basophilic focus 1 (10%) 2 (20%) 

Hepatodiaphragmatic nodule 3 (30%) 2 (20%) 2 (20%) 

Inflammation, chronic 7 (70%) 8 (80%) 6 (60%) 6 (60%) 

Necrosis, coagulative 1 (10%) 

Bile duct, hyperplasia 5 (50%) 4 (40%) 3 (30%) 2 (20%) 

Pancreas (10) (10) (10) (10) 

Acinus, atrophy 1 (10%) 1 (10%) 

Duct, ectasia 1 (10%) 

Cardiovascular System 

Heart (10) (10) (10) (10) 

Cardiomyopathy, chronic 9 (90%) 9 (90%) 9 (90%) 10 (100%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Degeneration, fatty 1 (10%) 

Pituitary gland (10) (10) (10) (10) 

Pars distalis, cyst 6 (60%) 8 (80%) 8 (80%) 3 (30%) 

Pars distalis, hyperplasia 3 (30%) 6 (60%) 2 (20%) 3 (30%) 

Pars intermedia, cyst 1 (10%) 1 (10%) 

Thyroid gland (10) (10) (10) (10) 

C-cell, hyperplasia 1 (10%) 1 (10%) 

Genital System 

Clitoral gland (10) (10) (10) (10) 

Hyperplasia 1 (10%) 

Inflammation, chronic active 3 (30%) 2 (20%) 2 (20%) 

Ovary (10) (10) (10) (10) 

Cyst 1 (10%) 

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

 

 

 

 

 

 

 

 

 

 

142 Triethanolamine, NTP TR 449 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

15-Month Interim Evaluation (continued) 

Hematopoietic System 

Bone marrow (10) 

Hyperplasia

(10) 

 1 (10%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

Integumentary System 

Mammary gland 

Hyperplasia, cystic

Skin 

Site of application-no mass, acanthosis

Site of application-no mass, inflammation,

 chronic active

Site of application-no mass, ulcer

Site of application-no mass, ulcer, multiple

(10) 

 5 (50%) 

(10) 

(10) 

 5 (50%) 

(10) 

 1 (10%) 

 1 (10%) 

 1 (10%) 

(10) 

 8 (80%) 

(10) 

 7 (70%) 

 7 (70%) 

 3 (30%) 

 4 (40%) 

(10) 

 7 (70%) 

(10) 

 6 (60%) 

 6 (60%) 

 1 (10%) 

 5 (50%) 

Respiratory System 

Lung 

Inflammation, chronic active

Alveolus, infiltration cellular, 

mononuclear cell

Nose 

Nasolacrimal duct, inflammation, 

suppurative

(10) 

 2 (20%) 

 5 (50%) 

(10) 

(10) 

 2 (20%) 

 8 (80%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

 7 (70%) 

(10) 

(10) 

 4 (40%) 

 8 (80%) 

(10) 

Special Senses System 

Eye

Lens, cataract

Retina, atrophy

 (1)

 1 (100%)

 1 (100%)

 (2) 

 2 (100%) 

 2 (100%) 

Urinary System 

Kidney 

Nephropathy, chronic

Cortex, cyst

(10) 

 9 (90%) 

(10) 

 8 (80%) 

(10) 

 8 (80%) 

 1 (10%) 

(10) 

 4 (40%) 

Systems Examined with No Lesions Observed 

General Body System 

Musculoskeletal System 

Nervous System 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 143 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study 

Alimentary System 

Esophagus (50) (50) (50) (50) 

Perforation 2 (4%) 

Intestine large, colon (50) (50) (50) (50) 

Parasite metazoan 1 (2%) 4 (8%) 2 (4%) 2 (4%) 

Intestine large, rectum (50) (50) (50) (50) 

Parasite metazoan 2 (4%) 7 (14%) 6 (12%) 5 (10%) 

Intestine large, cecum (50) (50) (50) (50) 

Inflammation, suppurative 1 (2%) 

Parasite metazoan 1 (2%) 

Intestine small, jejunum (50) (50) (50) (50) 

Necrosis, coagulative 1 (2%) 

Liver (50) (50) (50) (50) 

Angiectasis 1 (2%) 3 (6%) 3 (6%) 

Basophilic focus 21 (42%) 27 (54%) 29 (58%) 11 (22%) 

Clear cell focus 1 (2%) 2 (4%) 

Eosinophilic focus 2 (4%) 1 (2%) 5 (10%) 5 (10%) 

Hepatodiaphragmatic nodule 8 (16%) 11 (22%) 10 (20%) 2 (4%) 

Inflammation, chronic 14 (28%) 14 (28%) 23 (46%) 17 (34%) 

Inflammation, necrotizing 1 (2%) 1 (2%) 

Mixed cell focus 2 (4%) 1 (2%) 1 (2%) 

Necrosis, coagulative 2 (4%) 1 (2%) 1 (2%) 

Bile duct, hyperplasia 11 (22%) 11 (22%) 15 (30%) 11 (22%) 

Hepatocyte, vacuolization cytoplasmic 3 (6%) 2 (4%) 5 (10%) 4 (8%) 

Kupffer cell, hypertrophy 1 (2%) 

Mesentery (3) (2) (2) (2) 

Fat, inflammation, necrotizing 2 (67%) 2 (100%) 

Perivascular, inflammation, chronic active 1 (50%) 1 (50%) 

Pancreas (50) (50) (50) (50) 

Acinus, atrophy 5 (10%) 8 (16%) 17 (34%) 5 (10%) 

Artery, inflammation, chronic active 1 (2%) 1 (2%) 

Perivascular, inflammation, chronic active 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Duct, ectasia 1 (2%) 

Stomach, forestomach (50) (50) (50) (50) 

Inflammation, necrotizing 2 (4%) 4 (8%) 2 (4%) 3 (6%) 

Epithelium, hyperplasia 3 (6%) 2 (4%) 1 (2%) 3 (6%) 

Stomach, glandular (50) (50) (50) (50) 

Erosion 1 (2%) 3 (6%) 1 (2%) 1 (2%) 

Inflammation, necrotizing 1 (2%) 

Cardiovascular System 

Blood vessel (50) (50) (50) (50) 

Aorta, polyarteritis, chronic 1 (2%) 

Mesenteric artery, polyarteritis, chronic 1 (2%) 

Heart (50) (50) (50) (50) 

Cardiomyopathy, chronic 32 (64%) 24 (48%) 32 (64%) 26 (52%) 

Inflammation, chronic active 1 (2%) 

Atrium, thrombosis 2 (4%) 3 (6%) 4 (8%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

144 Triethanolamine, NTP TR 449 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study (continued) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Degeneration, fatty 15 (30%) 15 (30%) 19 (38%) 11 (22%) 

Hyperplasia 15 (30%) 21 (42%) 17 (34%) 6 (12%) 

Hypertrophy 2 (4%) 2 (4%) 1 (2%) 

Karyomegaly 1 (2%) 

Necrosis, coagulative 1 (2%) 1 (2%) 

Adrenal medulla (50) (50) (50) (49) 

Hyperplasia 9 (18%) 8 (16%) 4 (8%) 4 (8%) 

Islets, pancreatic (50) (50) (50) (50) 

Hyperplasia 1 (2%) 

Parathyroid gland (41) (48) (47) (43) 

Cyst 1 (2%) 

Hyperplasia 1 (2%) 

Pituitary gland (50) (50) (50) (50) 

Craniopharyngeal duct, pars distalis, cyst 1 (2%) 1 (2%) 

Pars distalis, angiectasis 37 (74%) 35 (70%) 36 (72%) 29 (58%) 

Pars distalis, cyst 24 (48%) 14 (28%) 25 (50%) 17 (34%) 

Pars distalis, hyperplasia 15 (30%) 18 (36%) 18 (36%) 12 (24%) 

Pars distalis, pigmentation, hemosiderin 33 (66%) 29 (58%) 27 (54%) 22 (44%) 

Thyroid gland (50) (50) (50) (49) 

C-cell, hyperplasia 8 (16%) 4 (8%) 10 (20%) 2 (4%) 

Follicle, cyst 1 (2%) 

Follicular cell, hyperplasia 1 (2%) 

General Body System 

None 

Genital System 

Clitoral gland (48) (49) (50) (50) 

Hyperplasia 2 (4%) 8 (16%) 4 (8%) 1 (2%) 

Inflammation, chronic active 11 (23%) 16 (33%) 18 (36%) 8 (16%) 

Duct, dilatation 2 (4%) 1 (2%) 4 (8%) 3 (6%) 

Ovary (50) (50) (50) (50) 

Atrophy 1 (2%) 

Cyst 2 (4%) 4 (8%) 4 (8%) 2 (4%) 

Hematocyst 1 (2%) 

Uterus (50) (50) (50) (50) 

Hyperplasia, cystic, glandular 1 (2%) 

Horn, dilatation 3 (6%) 

Lumen, hemorrhage 1 (2%) 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 145 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study (continued) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Hyperplasia 2 (4%) 2 (4%) 1 (2%) 4 (8%) 

Myelofibrosis 1 (2%) 

Lymph node (6) (5) (6) (3) 

Mediastinal, pigmentation, hemosiderin 1 (17%) 

Mediastinal, sinus, infiltration cellular,

 mononuclear cell 1 (17%) 

Lymph node, mandibular (49) (50) (50) (50) 

Inflammation, necrotizing 1 (2%) 

Inflammation, suppurative 1 (2%) 

Sinus, ectasia 1 (2%) 

Lymph node, mesenteric (50) (50) (49) (50) 

Inflammation, chronic active 1 (2%) 

Spleen (50) (50) (50) (50) 

Fibrosis 2 (4%) 2 (4%) 

Hematopoietic cell proliferation 2 (4%) 1 (2%) 1 (2%) 

Infiltration cellular, lipocyte 1 (2%) 

Red pulp, atrophy 1 (2%) 1 (2%) 

Thymus (49) (47) (47) (48) 

Fibrosis 1 (2%) 

Granuloma 1 (2%) 

Integumentary System 

Mammary gland (50) (50) (50) (50) 

Hyperplasia, cystic 42 (84%) 39 (78%) 42 (84%) 37 (74%) 

Inflammation, chronic active 1 (2%) 

Skin (50) (50) (50) (50) 

Epidermis, site of application-no mass,

 erosion 1 (2%) 6 (12%) 16 (32%) 14 (28%) 

Face, abscess 1 (2%) 

Head, acanthosis 2 (4%) 

Head, inflammation, chronic active 1 (2%) 2 (4%) 

Head, ulcer 1 (2%) 

Inguinal, acanthosis 1 (2%) 1 (2%) 

Inguinal, inflammation, chronic active 2 (4%) 1 (2%) 2 (4%) 1 (2%) 

Site of application-no mass, acanthosis 2 (4%) 10 (20%) 30 (60%) 32 (64%) 

Site of application-no mass, inflammation,

 chronic active 2 (4%) 10 (20%) 30 (60%) 32 (64%) 

Site of application-no mass, ulcer 4 (8%) 8 (16%) 

Site of application-no mass, ulcer, multiple 2 (4%) 7 (14%) 18 (36%) 19 (38%) 

Tail, acanthosis 1 (2%) 

Tail, hyperkeratosis 1 (2%) 

Tail, inflammation, chronic active 1 (2%) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Osteopetrosis 3 (6%) 1 (2%) 

Maxilla, abscess 1 (2%) 

Skeletal muscle (1) (2) 

Fibrosis 1 (50%) 
 

 

 

 

 

 

 

 

 

 

 

 

146 Triethanolamine, NTP TR 449 

TABLE B4 

Summary of the Incidence of Nonneoplastic Lesions in Female Rats in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

2-Year Study (continued) 

Nervous System 

Brain (50) (50) (50) (50) 

Compression 18 (36%) 15 (30%) 15 (30%) 12 (24%) 

Hemorrhage 3 (6%) 1 (2%) 

Hydrocephalus 10 (20%) 9 (18%) 10 (20%) 13 (26%) 

Necrosis 1 (2%) 

Peripheral nerve (2) (1) 

Sciatic, myelin, degeneration 1 (100%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Inflammation, chronic active 14 (28%) 16 (32%) 16 (32%) 18 (36%) 

Inflammation, necrotizing 1 (2%) 

Metaplasia, osseous 1 (2%) 

Pigmentation, hemosiderin 1 (2%) 

Alveolar epithelium, hyperplasia 4 (8%) 1 (2%) 1 (2%) 

Alveolus, infiltration cellular, 

mononuclear cell 29 (58%) 35 (70%) 30 (60%) 26 (52%) 

Artery, mediastinum, polyarteritis, chronic 1 (2%) 

Perivascular, edema 1 (2%) 

Nose (50) (50) (50) (50) 

Inflammation, chronic active 9 (18%) 5 (10%) 8 (16%) 1 (2%) 

Nasolacrimal duct, inflammation, 

suppurative 11 (22%) 8 (16%) 9 (18%) 8 (16%) 

Special Senses System 

Eye (1) (2) (6) (1) 

Lens, cataract 1 (100%) 1 (50%) 5 (83%) 1 (100%) 

Retina, atrophy 1 (100%) 1 (50%) 6 (100%) 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Nephropathy, chronic 45 (90%) 44 (88%) 41 (82%) 42 (84%) 

Cortex, cyst 1 (2%) 

Renal tubule, hyperplasia 1 (2%) 
147 

APPENDIX C 

SUMMARY OF LESIONS IN MALE MICE 

IN THE 2-YEAR DERMAL STUDY 

OF TRIETHANOLAMINE 

TABLE C1	 Summary of the Incidence of Neoplasms in Male Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 148 

TABLE C2 Individual Animal Tumor Pathology of Male Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 152 

TABLE C3 Statistical Analysis of Primary Neoplasms in Male Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 168 

TABLE C4 Historical Incidence of Liver Neoplasms in Control Male B6C3F1 Mice ............. 172

TABLE C5	 Summary of the Incidence of Nonneoplastic Lesions in Male Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 173 
 

 

 

 

 

 

 

 

 

 

 

148 Triethanolamine, NTP TR 449 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 2 5 3 6 

Natural deaths 2 5 8 3 

Survivors 

Died last week of study 1 

Terminal sacrifice 46 39 39 41 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver (10) (10) (10) (10) 

Hepatocellular carcinoma 1 (10%) 2 (20%) 1 (10%) 

Hepatocellular adenoma 2 (20%) 1 (10%) 4 (40%) 

Hepatocellular adenoma, multiple 1 (10%) 

Systems Examined with No Neoplasms Observed 

Cardiovascular System 

Endocrine System 

General Body System 

Genital System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Special Senses System 

Urinary System 

2-Year Study 

Alimentary System 

Intestine small, duodenum (50) (50) (50) (50) 

Polyp adenomatous 1 (2%) 

Intestine small, jejunum (50) (50) (50) (50) 

Carcinoma 1 (2%) 

Liver (50) (50) (50) (50) 

Carcinoma, metastatic, pancreas 1 (2%) 

Hemangioma 1 (2%) 1 (2%) 

Hemangiosarcoma 3 (6%) 1 (2%) 1 (2%) 

Hemangiosarcoma, multiple 2 (4%) 

Hepatoblastoma 3 (6%) 

Hepatocellular carcinoma 9 (18%) 12 (24%) 8 (16%) 9 (18%) 

Hepatocellular carcinoma, multiple 6 (12%) 8 (16%) 7 (14%) 5 (10%) 

Hepatocellular adenoma 10 (20%) 9 (18%) 12 (24%) 8 (16%) 

Hepatocellular adenoma, multiple 17 (34%) 18 (36%) 17 (34%) 29 (58%) 

Histiocytic sarcoma 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 149 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Alimentary System (continued) 

Mesentery (3) (1) 

Carcinoma, metastatic, pancreas 1 (33%) 

Hepatoblastoma, metastatic, liver 1 (100%) 

Pancreas (50) (50) (50) (50) 

Carcinoma 1 (2%) 

Stomach, forestomach (50) (49) (50) (50) 

Squamous cell carcinoma 1 (2%) 

Stomach, glandular (50) (50) (50) (50) 

Carcinoid tumor NOS 1 (2%) 

Cardiovascular System 

None 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Capsule, spindle cell, adenoma 1 (2%) 1 (2%) 

Adrenal medulla (50) (50) (50) (50) 

Pheochromocytoma benign 1 (2%) 1 (2%) 1 (2%) 

Islets, pancreatic (50) (50) (50) (50) 

Adenoma 1 (2%) 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Bilateral, follicular cell, adenoma 1 (2%) 

Follicular cell, adenoma 2 (4%) 

General Body System 

Tissue NOS (1) 

Hemangioma 1 (100%) 

Genital System 

Epididymis (50) (50) (50) (50) 

Sarcoma 1 (2%) 

Prostate (50) (50) (50) (50) 

Hemangiosarcoma 1 (2%) 

Seminal vesicle (50) (50) (50) (50) 

Carcinoma, metastatic, pancreas 1 (2%) 

Testes (50) (50) (50) (50) 

Bilateral, interstitial cell, adenoma 1 (2%) 

Interstitial cell, adenoma 1 (2%) 

Hematopoietic System 

Lymph node (2) (2) (3) (1) 

Lumbar, histiocytic sarcoma 1 (33%) 

Mediastinal, carcinoma, metastatic, pancreas 1 (50%) 

Mediastinal, hepatocellular carcinoma, 

metastatic, liver 1 (50%) 

Pancreatic, hepatoblastoma, metastatic, liver 1 (100%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

150 Triethanolamine, NTP TR 449 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Hematopoietic System (continued) 

Lymph node, mandibular 

Lymph node, mesenteric 

Hepatoblastoma, metastatic, liver

Histiocytic sarcoma

Spleen 

Hemangiosarcoma

Histiocytic sarcoma

Thymus 

(47) 

(46) 

(50) 

 1 (2%) 

(44) 

(47) 

(47) 

(50) 

(36) 

(48) 

(47) 

(50) 

(47) 

(48) 

(48) 

 1 (2%) 

 1 (2%) 

(50) 

 1 (2%) 

 1 (2%) 

(43) 

Integumentary System 

Skin 

Neck, basal cell carcinoma

Neck, subcutaneous tissue, hemangiosarcoma

Neck, subcutaneous tissue, fat, hemangioma

Subcutaneous tissue, sarcoma

(50) 

 1 (2%) 

(50) 

 1 (2%) 

(50) (50) 

 1 (2%) 

 1 (2%) 

Musculoskeletal System 

Skeletal muscle

Carcinoma, metastatic, pancreas

Hemangiosarcoma

 (1)

 1 (100%) 

(1)

 1 (100%) 

(1) 

Nervous System 

None 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar adenoma, multiple

Alveolar/bronchiolar carcinoma

Carcinoma, metastatic, pancreas

Hepatocellular carcinoma, metastatic, liver

(50) 

 14 (28%) 

 1 (2%) 

 2 (4%) 

 4 (8%) 

(50) 

 11 (22%) 

 4 (8%) 

 5 (10%) 

 1 (2%) 

 6 (12%) 

(50) 

 14 (28%) 

 1 (2%) 

 3 (6%) 

(50) 

 8 (16%) 

 2 (4%) 

 1 (2%) 

 2 (4%) 

Special Senses System 

Harderian gland

Adenoma

 (4)

 4 (100%)

 (5)

 5 (100%)

 (6)

 5 (83%) 

(1) 

 1 (100%) 

Urinary System 

Kidney 

Histiocytic sarcoma

Renal tubule, adenoma

(50) 

 1 (2%) 

(50) (50) (50) 

 1 (2%) 

 2 (4%) 
 

 

 

 

151 

c 

Triethanolamine, NTP TR 449 

TABLE C1 

Summary of the Incidence of Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Systemic Lesions 

Multiple organsb (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Leukemia lymphocytic 1 (2%) 

Lymphoma malignant lymphocytic 3 (6%) 

Lymphoma malignant mixed 4 (8%) 1 (2%) 5 (10%) 1 (2%) 

Lymphoma malignant undifferentiated cell 1 (2%) 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 2 4 1 5 

2-Year study 39 45 42 48 

Total primary neoplasms 

15-Month interim evaluation 2 4 1 5 

2-Year study 80 83 79 80 

Total animals with benign neoplasms 

15-Month interim evaluation 1 2 1 4 

2-Year study 35 38 35 41 

Total benign neoplasms 

15-Month interim evaluation 1 2 1 4 

2-Year study 54 51 50 54 

Total animals with malignant neoplasms 

15-Month interim evaluation 1 2 1 

2-Year study 19 28 25 23 

Total malignant neoplasms 

15-Month interim evaluation 1 2 1 

2-Year study 26 31 29 26 

Total animals with metastatic neoplasms 

2-Year study 4 7 3 3 

Total metastatic neoplasms 

2-Year study 4 13 3 5 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 1 

Total uncertain neoplasms 

2-Year study 1 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

 

 

152 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

Number of Days on Study 

3 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

6 1 7 1 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 

7 6 8 2 9 9 9 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 

Carcass ID Number 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

2 0 0 5 0 0 1 1 2 3 3 4 5 5 5 5 0 2 2 3 4 4 4 5 5 

3 5 3 4 2 7 6 7 5 2 5 7 0 1 6 7 1 1 2 9 0 2 5 5 8 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Polyp adenomatous 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma, multiple 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X X 

X X 

X X X X X X 

X X X X X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + M + + + + M + + + + M + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, spindle cell, adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Parathyroid gland + + + + + + + + + + + + + + + + + M + + M + + + + 

Pituitary gland + + + M + + + + + + + + + + + + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma X X 

General Body System 

Tissue NOS 

Hemangioma 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 153 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 0 0 1 1 1 2 3 3 4 4 4 4 4 5 6 0 0 1 1 2 2 2 3 3 5 Tissues/ 

4 6 3 4 9 6 6 7 1 3 6 8 9 3 0 8 9 1 2 4 8 9 1 3 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp adenomatous 1 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma, multiple X 2 

Hepatocellular carcinoma X X X X X 9 

Hepatocellular carcinoma, multiple X X X X 6 

Hepatocellular adenoma X X X X 10 

Hepatocellular adenoma, multiple X X X X X X X X 17 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, spindle cell, adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma X 1 

Parathyroid gland + + + + + + + + + + + + M + + + + + + + + + + + + 47 

Pituitary gland + + + + + + + M + + + + + + + + + + + + + + + + + 48 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma 2 

General Body System 

Tissue NOS + 1 

Hemangioma X 1 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

154 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

3 6 6 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 6 

7 

1 

6 

7 

8 

1 

2 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

Carcass ID Number 

0 

2 

3 

0 

0 

5 

0 

0 

3 

0 

5 

4 

0 

0 

2 

0 

0 

7 

0 

1 

6 

0 

1 

7 

0 

2 

5 

0 

3 

2 

0 

3 

5 

0 

4 

7 

0 

5 

0 

0 

5 

1 

0 

5 

6 

0 

5 

7 

0 

0 

1 

0 

2 

1 

0 

2 

2 

0 

3 

9 

0 

4 

0 

0 

4 

2 

0 

4 

5 

0 

5 

5 

0 

5 

8 

Hematopoietic System 

Bone marrow 

Lymph node 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Hemangiosarcoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + M + + 

+ + + + + + + + M + + + + + + + + M + + M + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + M + + + + + + + + M + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

Neck, basal cell carcinoma 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Musculoskeletal System 

Bone 

Skeletal muscle 

Hemangiosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma,

 multiple 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X 

+ 

X 

+ 

X 

Urinary System 

Kidney 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Lymphoma malignant mixed 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 
 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 155 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total 

Carcass ID Number 0 0 1 1 1 2 3 3 4 4 4 4 4 5 6 0 0 1 1 2 2 2 3 3 5 Tissues/ 

4 6 3 4 9 6 6 7 1 3 6 8 9 3 0 8 9 1 2 4 8 9 1 3 9 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + 2 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + M 47 

Lymph node, mesenteric + + + + + + + + M + + + + + + + + + + + + + + + + 46 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 1 

Thymus M + + + + + + + + + + + + M + + + + M + + + M + + 44 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Neck, basal cell carcinoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle + 1 

Hemangiosarcoma X 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X X X X X X 14 

Alveolar/bronchiolar adenoma,

 multiple 1 

Alveolar/bronchiolar carcinoma X X 2 

Hepatocellular carcinoma, metastatic, liver X X X X 4 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Harderian gland + 4 

Adenoma X 4 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Renal tubule, adenoma X 1 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymphoma malignant mixed X X X 4 

50 
 

 

 

 

 

 

 

 

 

 

 

156 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 200 mg/kg 

5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 3 2 6 6 6 8 8 8 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 

5 7 1 5 6 7 2 3 8 6 9 9 9 9 9 9 9 9 9 9 0 0 0 0 0 

0 0 0 1 0 0 1 1 1 1 0 0 0 0 0 1 1 1 1 1 0 0 0 1 1 

Carcass ID Number 6 9 7 1 7 7 0 1 1 1 7 7 8 9 9 0 0 0 1 1 7 7 9 0 0 

9 3 6 1 4 1 7 4 6 5 0 2 0 0 6 0 1 8 0 7 8 9 7 3 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + + + + + + + M + + M + + + + + + + + + + + + + + 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, pancreas X 

Hemangioma X 

Hemangiosarcoma X X 

Hepatocellular carcinoma X X X X X X X 

Hepatocellular carcinoma, multiple X X X X 

Hepatocellular adenoma X X X X 

Hepatocellular adenoma, multiple X X X X X X X X X 

Mesentery + + 

Carcinoma, metastatic, pancreas X 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoid tumor NOS 

Cardiovascular System 

Blood vessel 

Heart 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, spindle cell, adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + M + + + + + + + + + + M + + + + + + + + + + M 

Pituitary gland + + + + + + + + + + + + + M + + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma, metastatic, pancreas X 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, interstitial cell, adenoma 

Interstitial cell, adenoma 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 157 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 200 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 

1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 1 Total 

Carcass ID Number 0 1 1 6 6 6 8 8 8 8 8 8 8 9 9 9 0 2 6 6 6 6 9 0 1 Tissues/ 

6 2 3 3 5 7 2 4 5 6 7 8 9 1 5 8 4 0 1 2 4 8 9 9 8 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, pancreas 1 

Hemangioma 1 

Hemangiosarcoma X 3 

Hepatocellular carcinoma X X X X X 12 

Hepatocellular carcinoma, multiple X X X X 8 

Hepatocellular adenoma X X X X X 9 

Hepatocellular adenoma, multiple X X X X X X X X X 18 

Mesentery + 3 

Carcinoma, metastatic, pancreas 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + 49 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoid tumor NOS X 1 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, spindle cell, adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + M + + + + + + + + M + + M + + + + + + + + + + 44 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma, metastatic, pancreas 1 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, interstitial cell, adenoma X 1 

Interstitial cell, adenoma X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

158 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 200 mg/kg 

(continued) 

5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 

5 

3 

7 

2 

1 

6 

5 

6 

6 

6 

7 

8 

2 

8 

3 

8 

8 

1 

6 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

0 0 0 1 0 0 1 1 1 1 0 0 0 0 0 1 1 1 1 1 0 0 0 1 1 

Carcass ID Number 6 9 7 1 7 7 0 1 1 1 7 7 8 9 9 0 0 0 1 1 7 7 9 0 0 

9 3 6 1 4 1 7 4 6 5 0 2 0 0 6 0 1 8 0 7 8 9 7 3 5 

Hematopoietic System 

Bone marrow 

Lymph node 

Mediastinal, carcinoma, metastatic,

 pancreas 

Mediastinal, hepatocellular carcinoma,

 metastatic, liver 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + M + 

+ + 

X 

X 

+ + + + M M + + + + + + + + + + + + + + + + + + + 

+ + + + M + + + M + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + M M M + M + + + + + + M + + + + + M + + + 

Integumentary System 

Mammary gland 

Skin 

Neck, subcutaneous tissue,

 hemangiosarcoma 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone 

Skeletal muscle 

Carcinoma, metastatic, pancreas 

+ + + + + + + + + + + + + + + + + + + + + + + M + 

+ 

X 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

+ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, pancreas 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X 

X X 

X 

X X 

+ + + + + + + + + + + + + + + + + + + + + + + M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Eye 

Harderian gland 

Adenoma 

+ 

+ 

X 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Lymphoma malignant mixed 

+ + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 159 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 200 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 1 Total 

Carcass ID Number 0 

6 

1 

2 

1 

3 

6 

3 

6 

5 

6 

7 

8 

2 

8 

4 

8 

5 

8 

6 

8 

7 

8 

8 

8 

9 

9 

1 

9 

5 

9 

8 

0 

4 

2 

0 

6 

1 

6 

2 

6 

4 

6 

8 

9 

9 

0 

9 

1 

8 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Lymph node

Mediastinal, carcinoma, metastatic,

 pancreas

Mediastinal, hepatocellular carcinoma,

 metastatic, liver

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + M + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + M + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

M + + + + + + + + M + M M M + + + + + M + + M + M 

2 

1 

1 

47 

47 

50 

36 

Integumentary System 

Mammary gland 

Skin 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

Neck, subcutaneous tissue,

 hemangiosarcoma X 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Skeletal muscle 1 

Carcinoma, metastatic, pancreas 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve

Spinal cord

 1 

1 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Carcinoma, metastatic, pancreas

Hepatocellular carcinoma, metastatic, liver 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X 

X X X 

X X X

X X X X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

11 

4 

5 

1 

6 

49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 1 

Eye + + + 3 

Harderian gland + + + + 5 

Adenoma X X X X 5 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

Systemic Lesions 

Multiple organs 

Lymphoma malignant mixed 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

50 

1 
 

 

 

 

 

 

 

 

 

 

160 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 630 mg/kg 

Number of Days on Study 

3 4 5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

7 9 0 4 0 4 5 7 7 9 9 2 2 2 2 2 2 2 2 3 3 3 3 3 3 

3 3 7 0 7 5 2 0 7 4 7 9 9 9 9 9 9 9 9 0 0 0 0 0 0 

Carcass ID Number 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 

5 3 6 2 2 7 5 2 7 5 6 2 3 3 4 5 5 7 7 2 4 4 5 5 5 

2 3 2 2 9 3 8 7 1 1 4 1 5 8 0 6 9 0 5 6 2 3 0 3 7 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + M + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X 

X X X X X 

X X X X X X 

X X X X X X X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + M + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma X 

Parathyroid gland + + + + + + + + + M + + + + + + + + + + + + + + + 

Pituitary gland + + M + + + M + + + M + + + + + + + + + + + M + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

General Body System 

None 

Genital System 

Epididymis 

Sarcoma 

Preputial gland 

Prostate 

Seminal vesicle 

Testes 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Hematopoietic System 

Bone marrow 

Lymph node 

Lumbar, histiocytic sarcoma 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

X 

+ + + + + M + + + + + + + + + + + + + + + + M + + 

+ M + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + M + + + + + M + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 161 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 630 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total 

Carcass ID Number 6 7 7 2 3 4 4 4 5 5 6 6 6 8 2 2 3 3 4 4 6 6 6 7 7 Tissues/ 

6 4 6 4 2 4 8 9 4 5 0 3 9 0 3 5 1 6 1 7 1 5 7 7 9 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma X 1 

Hepatocellular carcinoma X X X X 8 

Hepatocellular carcinoma, multiple X X 7 

Hepatocellular adenoma X X X X X X 12 

Hepatocellular adenoma, multiple X X X X X X X X X 17 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adenoma 1 

Parathyroid gland + + + M + + + + + + + + + + + + + + + + + + + + + 48 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 46 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma 1 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hematopoietic System 

Bone marrow + + + M + + + + + + + + + + + + + + + + + + + M + 48 

Lymph node + 3 

Lumbar, histiocytic sarcoma 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Lymph node, mesenteric + + + M + + + + + + + + + + + + + + + + + M + + + 47 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Thymus + + + + + + + + + + + + + + + + + + + + M + + + + 47 
 

 

 

 

 

 

 

 

 

 

 

 

 

162 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 630 mg/kg 

(continued) 

3 4 5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 7 

3 

9 

3 

0 

7 

4 

0 

0 

7 

4 

5 

5 

2 

7 

0 

7 

7 

9 

4 

9 

7 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

Carcass ID Number 

1 

5 

2 

1 

3 

3 

1 

6 

2 

1 

2 

2 

1 

2 

9 

1 

7 

3 

1 

5 

8 

1 

2 

7 

1 

7 

1 

1 

5 

1 

1 

6 

4 

1 

2 

1 

1 

3 

5 

1 

3 

8 

1 

4 

0 

1 

5 

6 

1 

5 

9 

1 

7 

0 

1 

7 

5 

1 

2 

6 

1 

4 

2 

1 

4 

3 

1 

5 

0 

1 

5 

3 

1 

5 

7 

Integumentary System 

Mammary gland 

Skin 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Musculoskeletal System 

Bone 

Skeletal muscle 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic,

 liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Eye 

Harderian gland 

Adenoma 

+ 

+ 

X 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Leukemia lymphocytic 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated

 cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

X X 

X X X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 163 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 630 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

Carcass ID Number 

1 

6 

6 

1 

7 

4 

1 

7 

6 

1 

2 

4 

1 

3 

2 

1 

4 

4 

1 

4 

8 

1 

4 

9 

1 

5 

4 

1 

5 

5 

1 

6 

0 

1 

6 

3 

1 

6 

9 

1 

8 

0 

1 

2 

3 

1 

2 

5 

1 

3 

1 

1 

3 

6 

1 

4 

1 

1 

4 

7 

1 

6 

1 

1 

6 

5 

1 

6 

7 

1 

7 

7 

1 

7 

9 

Total 

Tissues/ 

Tumors 

Integumentary System 

Mammary gland 

Skin 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

Musculoskeletal System 

Bone 

Skeletal muscle

+ + + M + + + + + + + + + + + + + + + + + + + M + 48 

1 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+

+

50 

1 

2 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma

Hepatocellular carcinoma, metastatic,

 liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X X X X X 

X X

+ + + M + + + + + + + + + + + + + + + + + + + M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

14 

1 

3 

48 

50 

Special Senses System 

Ear 

Eye 

Harderian gland 

Adenoma 

+ 

+

+ + 

X X 

+

+ 

X 

+

X

 2 

1 

6 

5 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma

Leukemia lymphocytic

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated

 cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X

X 

50 

1 

1 

3 

5 

1 
 

 

 

 

 

 

 

 

 

 

 

 

 

164 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 2,000 mg/kg 

Number of Days on Study 

5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

7 7 0 5 7 7 7 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 

2 9 6 5 0 5 8 2 4 9 9 9 9 9 9 9 9 9 9 9 9 9 9 0 0 

Carcass ID Number 

2 2 2 1 2 2 2 2 2 1 1 1 1 1 1 1 2 2 2 2 2 2 2 1 1 

1 1 1 8 0 1 3 0 2 8 8 9 9 9 9 9 0 1 2 2 2 2 3 8 9 

0 9 8 1 5 4 9 2 2 3 4 0 5 6 7 8 6 7 0 7 8 9 4 8 9 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Carcinoma 

Intestine small, ileum 

Liver 

Hemangioma 

Hemangiosarcoma 

Hepatoblastoma 

Hepatocellular carcinoma 

Hepatocellular carcinoma, multiple 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Hepatoblastoma, metastatic, liver 

Pancreas 

Salivary glands 

Stomach, forestomach 

Squamous cell carcinoma 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + M + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

X X 

X X X X 

X X X X X 

X X X X X X 

X X X X X X X X X X X X 

X 

+ 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel M + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign X 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + + + + + M + + + + + + + + + + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, follicular cell, adenoma 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 165 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 2,000 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 1 1 2 2 2 2 2 2 2 2 1 1 2 2 2 2 Total 

Carcass ID Number 0 0 0 1 1 1 3 3 4 8 9 1 1 2 2 2 2 3 3 8 8 0 2 3 3 Tissues/ 

0 1 4 2 5 6 1 5 0 6 2 1 3 3 4 5 6 0 2 2 5 3 1 6 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma X 1 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma 1 

Hemangiosarcoma 1 

Hepatoblastoma X 3 

Hepatocellular carcinoma X X X X X 9 

Hepatocellular carcinoma, multiple 5 

Hepatocellular adenoma X X 8 

Hepatocellular adenoma, multiple X X X X X X X X X X X X X X X X X 29 

Histiocytic sarcoma 1 

Mesentery 1 

Hepatoblastoma, metastatic, liver 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell carcinoma 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland M M + + + + M + + + + + M + + + + + + + + + + + + 45 

Pituitary gland + + + + + + + + + + + + + + + + + + + I + + + + + 49 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, follicular cell, adenoma X 1 

General Body System 

None 

Genital System 

Epididymis + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Preputial gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Prostate + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Seminal vesicle + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Testes + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

166 Triethanolamine, NTP TR 449 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 2,000 mg/kg 

(continued) 

5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 7 

2 

7 

9 

0 

6 

5 

5 

7 

0 

7 

5 

7 

8 

1 

2 

2 

4 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

2 2 2 1 2 2 2 2 2 1 1 1 1 1 1 1 2 2 2 2 2 2 2 1 1 

Carcass ID Number 1 1 1 8 0 1 3 0 2 8 8 9 9 9 9 9 0 1 2 2 2 2 3 8 9 

0 9 8 1 5 4 9 2 2 3 4 0 5 6 7 8 6 7 0 7 8 9 4 8 9 

Hematopoietic System 

Bone marrow 

Lymph node 

Pancreatic, hepatoblastoma,

 metastatic, liver 

Lymph node, mandibular 

Lymph node, mesenteric 

Hepatoblastoma, metastatic, liver 

Histiocytic sarcoma 

Spleen 

Hemangiosarcoma 

Histiocytic sarcoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

X 

+ + + + + + + M + + + + + + + + + + + + + + + + + 

+ + M + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

M I + M + + + M + + + + + + + + + + + + + + + + + 

Integumentary System 

Mammary gland 

Skin 

Neck, subcutaneous tissue, fat,

 hemangioma 

Subcutaneous tissue, sarcoma 

M M M M M M M M M M M M M M M M M M M M M M M M M 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

+ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar adenoma, multiple 

Alveolar/bronchiolar carcinoma 

Hepatocellular carcinoma, metastatic, liver 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X 

X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Harderian gland 

Adenoma 

+ 

X 

+ + 

Urinary System 

Kidney 

Histiocytic sarcoma 

Renal tubule, adenoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant mixed 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 167 

TABLE C2 

Individual Animal Tumor Pathology of Male Mice in the 2-Year Dermal Study of Triethanolamine: 2,000 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 1 1 2 2 2 2 2 2 2 2 1 1 2 2 2 2 Total 

Carcass ID Number 0 0 0 1 1 1 3 3 4 8 9 1 1 2 2 2 2 3 3 8 8 0 2 3 3 Tissues/ 

0 1 4 2 5 6 1 5 0 6 2 1 3 3 4 5 6 0 2 2 5 3 1 6 7 Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + M + + + + + 49 

Lymph node 1 

Pancreatic, hepatoblastoma,

 metastatic, liver 1 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + M 48 

Lymph node, mesenteric + + + + + M + + + + + + + + + + + + + + + + + + + 48 

Hepatoblastoma, metastatic, liver 1 

Histiocytic sarcoma 1 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Histiocytic sarcoma 1 

Thymus M + M + + + + + + M + + + + + + + + + + + + + + + 43 

Integumentary System 

Mammary gland M M M M M M M M M M M M M M M M M M M M M M M M M 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Neck, subcutaneous tissue, fat,

 hemangioma X 1 

Subcutaneous tissue, sarcoma 1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + M + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve 1 

Spinal cord 1 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X X X X 8 

Alveolar/bronchiolar adenoma, multiple X X 2 

Alveolar/bronchiolar carcinoma 1 

Hepatocellular carcinoma, metastatic, liver 2 

Nose + + + + + + + + + + + + + + + + + + + M + + + + + 49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear

Harderian gland

Adenoma

 2 

1 

1 

Urinary System 

Kidney + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Renal tubule, adenoma X 2 

Urinary bladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Systemic Lesions 

Multiple organs + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Lymphoma malignant mixed X 1 

49 
168 Triethanolamine, NTP TR 449 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Harderian Gland: Adenoma 

Overall ratea 

Adjusted rateb 4/50 (8%) 

8.7% 

5/50 (10%) 

12.5% 

5/50 (10%) 

12.4% 

1/50 (2%) 

2.1% 

Terminal ratec 4/46 (9%) 5/40 (13%) 4/39 (10%) 0/41 (0%) 

First incidence (days) 

Life table testd 729 (T) 

P=0.113N 

729 (T) 

P=0.413 

694 

P=0.400 

606 

P=0.212N 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

P=0.097N 

P=0.096N 

P=0.413 

P=0.500 

P=0.432 

P=0.500 

P=0.180N 

P=0.181N 

Liver: Hemangiosarcoma 

Overall rate 2/50 (4%) 3/50 (6%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 4.3% 7.5% 2.6% 2.4% 

Terminal rate 2/46 (4%) 3/40 (8%) 1/39 (3%) 1/41 (2%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) 

Life table test P=0.333N P=0.436 P=0.558N P=0.540N 

Logistic regression test P=0.333N P=0.436 P=0.558N P=0.540N 

Cochran-Armitage test P=0.311N 

Fisher exact test P=0.500 P=0.500N P=0.500N 

Liver: Hepatocellular Adenoma 

Overall rate 27/50 (54%) 27/50 (54%) 29/50 (58%) 37/50 (74%) 

Adjusted rate 54.0% 62.7% 67.4% 78.6% 

Terminal rate 23/46 (50%) 24/40 (60%) 25/39 (64%) 31/41 (76%) 

First incidence (days) 367 665 607 572 

Life table test P=0.009 P=0.320 P=0.158 P=0.013 

Logistic regression test P=0.012 P=0.571 P=0.359 P=0.034 

Cochran-Armitage test P=0.013 

Fisher exact test P=0.579N P=0.420 P=0.030 

Liver: Hepatocellular Carcinoma 

Overall rate 15/50 (30%) 20/50 (40%) 15/50 (30%) 14/50 (28%) 

Adjusted rate 31.2% 43.0% 33.2% 30.0% 

Terminal rate 13/46 (28%) 14/40 (35%) 9/39 (23%) 9/41 (22%) 

First incidence (days) 678 537 507 572 

Life table test P=0.347N P=0.118 P=0.396 P=0.545 

Logistic regression test P=0.175N P=0.207 P=0.585 P=0.494N 

Cochran-Armitage test P=0.274N 

Fisher exact test P=0.201 P=0.586N P=0.500N 

Liver: Hepatoblastoma 

Overall rate 0/50 (0%) 0/50 (0%) 0/50 (0%) 3/50 (6%) 

Adjusted rate 0.0% 0.0% 0.0% 7.0% 

Terminal rate 0/46 (0%) 0/40 (0%) 0/39 (0%) 2/41 (5%) 

First incidence (days) 

Life table test 

—e 

P=0.008 

— 

—f — 

— 

675 

P=0.106 

Logistic regression test P=0.009 — — P=0.121 

Cochran-Armitage test P=0.009 

Fisher exact test — — P=0.121 
Triethanolamine, NTP TR 449 169 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Liver: Hepatocellular Carcinoma or Hepatoblastoma 

Overall rate 15/50 (30%) 20/50 (40%) 15/50 (30%) 16/50 (32%) 

Adjusted rate 31.2% 43.0% 33.2% 34.4% 

Terminal rate 13/46 (28%) 14/40 (35%) 9/39 (23%) 11/41 (27%) 

First incidence (days) 678 537 507 572 

Life table test P=0.528N P=0.118 P=0.396 P=0.376 

Logistic regression test P=0.344N P=0.207 P=0.585 P=0.505 

Cochran-Armitage test P=0.462N 

Fisher exact test P=0.201 P=0.586N P=0.500 

Liver: Hepatocellular Adenoma, Hepatocellular Carcinoma, or Hepatoblastoma 

Overall rate 31/50 (62%) 34/50 (68%) 33/50 (66%) 42/50 (84%) 

Adjusted rate 62.0% 72.2% 73.3% 85.7% 

Terminal rate 27/46 (59%) 27/40 (68%) 27/39 (69%) 34/41 (83%) 

First incidence (days) 367 537 507 572 

Life table test P=0.011 P=0.139 P=0.137 P=0.006 

Logistic regression test P=0.009 P=0.359 P=0.377 P=0.018 

Cochran-Armitage test P=0.009 

Fisher exact test P=0.338 P=0.418 P=0.012 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 15/50 (30%) 15/50 (30%) 14/50 (28%) 10/50 (20%) 

Adjusted rate 32.6% 36.4% 35.9% 23.7% 

Terminal rate 15/46 (33%) 14/40 (35%) 14/39 (36%) 9/41 (22%) 

First incidence (days) 729 (T) 621 729 (T) 675 

Life table test P=0.160N P=0.410 P=0.465 P=0.274N 

Logistic regression test P=0.137N P=0.503 P=0.465 P=0.224N 

Cochran-Armitage test P=0.123N 

Fisher exact test P=0.586N P=0.500N P=0.178N 

Lung: Alveolar/bronchiolar Carcinoma 

Overall rate 2/50 (4%) 5/50 (10%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 4.3% 11.7% 2.4% 2.0% 

Terminal rate 2/46 (4%) 3/40 (8%) 0/39 (0%) 0/41 (0%) 

First incidence (days) 729 (T) 666 677 579 

Life table test P=0.210N P=0.175 P=0.554N P=0.527N 

Logistic regression test P=0.194N P=0.217 P=0.505N P=0.525N 

Cochran-Armitage test P=0.191N 

Fisher exact test P=0.218 P=0.500N P=0.500N 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 16/50 (32%) 19/50 (38%) 15/50 (30%) 11/50 (22%) 

Adjusted rate 34.8% 43.9% 37.4% 25.2% 

Terminal rate 16/46 (35%) 16/40 (40%) 14/39 (36%) 9/41 (22%) 

First incidence (days) 729 (T) 621 677 579 

Life table test P=0.113N P=0.186 P=0.453 P=0.286N 

Logistic regression test P=0.081N P=0.287 P=0.489 P=0.193N 

Cochran-Armitage test P=0.078N 

Fisher exact test P=0.338 P=0.500N P=0.184N 
170 Triethanolamine, NTP TR 449 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

All Organs: Hemangiosarcoma 

Overall rate 2/50 (4%) 4/50 (8%) 1/50 (2%) 1/50 (2%) 

Adjusted rate 4.3% 10.0% 2.6% 2.4% 

Terminal rate 2/46 (4%) 4/40 (10%) 1/39 (3%) 1/41 (2%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) 

Life table test P=0.265N P=0.275 P=0.558N P=0.540N 

Logistic regression test P=0.265N P=0.275 P=0.558N P=0.540N 

Cochran-Armitage test P=0.244N 

Fisher exact test P=0.339 P=0.500N P=0.500N 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 3/50 (6%) 5/50 (10%) 1/50 (2%) 3/50 (6%) 

Adjusted rate 6.5% 12.0% 2.6% 7.3% 

Terminal rate 3/46 (7%) 4/40 (10%) 1/39 (3%) 3/41 (7%) 

First incidence (days) 729 (T) 667 729 (T) 729 (T) 

Life table test P=0.513N P=0.289 P=0.366N P=0.609 

Logistic regression test P=0.493N P=0.341 P=0.366N P=0.609 

Cochran-Armitage test P=0.485N 

Fisher exact test P=0.357 P=0.309N P=0.661N 

All Organs: Malignant Lymphoma (Lymphocytic, Mixed, or Undifferentiated Cell Type) 

Overall rate 4/50 (8%) 1/50 (2%) 9/50 (18%) 1/50 (4%) 

Adjusted rate 8.7% 2.5% 22.3% 2.4% 

Terminal rate 4/46 (9%) 1/40 (3%) 8/39 (21%) 1/41 (2%) 

First incidence (days) 729 (T) 729 (T) 645 729 (T) 

Life table test P=0.251N P=0.224N P=0.068 P=0.216N 

Logistic regression test P=0.232N P=0.224N P=0.086 P=0.216N 

Cochran-Armitage test P=0.225N 

Fisher exact test P=0.181N P=0.117 P=0.181N 

All Organs: Benign Neoplasms 

Overall rate 36/50 (72%) 38/50 (76%) 35/50 (70%) 41/50 (82%) 

Adjusted rate 72.0% 84.4% 81.4% 85.4% 

Terminal rate 32/46 (70%) 33/40 (83%) 31/39 (79%) 34/41 (83%) 

First incidence (days) 367 621 607 572 

Life table test P=0.093 P=0.123 P=0.231 P=0.061 

Logistic regression test P=0.152 P=0.391 P=0.551 P=0.191 

Cochran-Armitage test P=0.153 

Fisher exact test P=0.410 P=0.500N P=0.171 

All Organs: Malignant Neoplasms 

Overall rate 20/50 (40%) 28/50 (56%) 25/50 (50%) 23/50 (46%) 

Adjusted rate 41.7% 58.2% 53.2% 47.7% 

Terminal rate 18/46 (39%) 20/40 (50%) 17/39 (44%) 16/41 (39%) 

First incidence (days) 678 537 507 572 

Life table test P=0.497 P=0.038 P=0.089 P=0.222 

Logistic regression test P=0.353N P=0.163 P=0.297 P=0.351 

Cochran-Armitage test P=0.507N 

Fisher exact test P=0.080 P=0.211 P=0.343 
171 

c 

Triethanolamine, NTP TR 449 

TABLE C3 

Statistical Analysis of Primary Neoplasms in Male Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

All Organs: Benign or Malignant Neoplasms 

Overall rate 40/50 (80%) 45/50 (90%) 42/50 (84%) 48/50 (96%) 

Adjusted rate 80.0% 91.8% 89.4% 96.0% 

Terminal rate 36/46 (78%) 36/40 (90%) 34/39 (87%) 39/41 (95%) 

First incidence (days) 367 537 507 572 

Life table test P=0.039 P=0.029 P=0.068 P=0.008 

Logistic regression test P=0.028 P=0.130 P=0.311 P=0.025 

Cochran-Armitage test P=0.028 

Fisher exact test P=0.131 P=0.398 P=0.014 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver and lung; for other 

tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill d Beneath the control incidence are the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise 

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

indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the 

overall incidence rates. For all tests, a negative trend or a lower incidence in a dose group is indicated by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
172 Triethanolamine, NTP TR 449 

TABLE C4 

Historical Incidence of Liver Neoplasms in Control Male B6C3F a 1 Mice

Incidence in Controls 

Study Hepatocellular Hepatocellular Hepatoblastoma Hepatocellular Adenoma, 

Adenoma Carcinoma Hepatocellular Carcinoma, 

or Hepatoblastoma 

Historical Incidence in Dermal Studies (with Acetone Vehicle) at Battelle Columbus Laboratories 

4-Vinyl-1-cyclohexene diepoxide 18/50 6/50 0/50 23/50 

Triethanolamine 27/50 15/50 0/50 31/50 

Overall Historical Incidence in Dermal Studies (with Acetone Vehicle) 

Total 51/150 (34.0%) 25/150 (16.7%) 0/150 63/150 (42.0%) 

Standard deviation 21.1% 11.7% 22.3% 

Range 12%-54% 8%-30% 18%-62% 

Overall Historical Incidence in Feed Studies 

Total 344/1,316 (26.1%) 220/1,316 (16.7%) 0/1,316 509/1,316 (38.7%) 

Standard deviation 13.2% 7.2% 13.9% 

Range 4%-60% 3%-29% 10%-68% 

Data as of 17 June 1994 a 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 173 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 2 5 3 6 

Natural deaths 2 5 8 3 

Survivors 

Died last week of study 1 

Terminal sacrifice 46 39 39 41 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver (10) (10) (10) (10) 

Basophilic focus 1 (10%) 1 (10%) 

Clear cell focus 1 (10%) 

Eosinophilic focus 1 (10%) 

Karyomegaly 2 (20%) 1 (10%) 1 (10%) 2 (20%) 

Mixed cell focus 2 (20%) 

Hepatocyte, cytoplasmic alteration 2 (20%) 1 (10%) 1 (10%) 2 (20%) 

Hepatocyte, cytoplasmic alteration, focal 1 (10%) 

Hepatocyte, vacuolization cytoplasmic,

 multifocal 4 (40%) 6 (60%) 3 (30%) 6 (60%) 

Oval cell, hyperplasia 2 (20%) 1 (10%) 1 (10%) 3 (30%) 

Pancreas (10) (10) (10) (10) 

Acinus, atrophy 1 (10%) 

Stomach, forestomach (10) (10) (10) (10) 

Acanthosis 1 (10%) 

Stomach, glandular (10) (10) (10) (10) 

Dysplasia 1 (10%) 

Endocrine System 

Adrenal cortex (10) (10) (10) (10) 

Capsule, accessory adrenal cortical nodule 1 (10%) 

Capsule, hyperplasia 1 (10%) 

Parathyroid gland (8) (8) (8) (9) 

Cyst 1 (13%) 

Pituitary gland (10) (10) (10) (10) 

Pars distalis, cyst 1 (10%) 

Genital System 

Preputial gland (10) (10) (10) (10) 

Duct, ectasia 1 (10%) 3 (30%) 1 (10%) 1 (10%) 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

174 Triethanolamine, NTP TR 449 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

15-Month Interim Evaluation (continued) 

Integumentary System 

Skin (10) 

Ulcer

Site of application-no mass, acanthosis

Site of application-no mass, inflammation,

 chronic

(10) 

 1 (10%) 

(10) 

 1 (10%) 

 1 (10%) 

 2 (20%) 

(10) 

 6 (60%) 

 5 (50%) 

Respiratory System 

Lung 

Alveolus, hemorrhage, multifocal

(10) 

 1 (10%) 

(10) (10) (10) 

Urinary System 

Kidney 

Nephropathy, chronic

(10) 

 7 (70%) 

(10) 

 9 (90%) 

(10) 

 10 (100%)

(10) 

 9 (90%) 

Systems Examined with No Lesions Observed 

Cardiovascular System 

General Body System 

Hematopoietic System 

Musculoskeletal System 

Nervous System 

Special Senses System 

2-Year Study 

Alimentary System 

Gallbladder (50) (48) (49) (49) 

Cyst 1 (2%) 

Intestine small, jejunum (50) (50) (50) (50) 

Peyer’s patch, hyperplasia, lymphoid 1 (2%) 

Liver (50) (50) (50) (50) 

Basophilic focus 7 (14%) 2 (4%) 3 (6%) 3 (6%) 

Clear cell focus 13 (26%) 10 (20%) 7 (14%) 5 (10%) 

Congestion 1 (2%) 

Cyst 1 (2%) 

Cytoplasmic alteration 10 (20%) 17 (34%) 10 (20%) 16 (32%) 

Eosinophilic focus 10 (20%) 17 (34%) 11 (22%) 23 (46%) 

Fatty change 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 1 (2%) 1 (2%) 

Infiltration cellular, lymphocyte 1 (2%) 

Karyomegaly 11 (22%) 17 (34%) 9 (18%) 16 (32%) 

Mixed cell focus 2 (4%) 1 (2%) 

Necrosis 1 (2%) 2 (4%) 

Thrombosis 1 (2%) 

Bile duct, hyperplasia 2 (4%) 2 (4%) 1 (2%) 

Hepatocyte, cytoplasmic alteration 1 (2%) 

Hepatocyte, necrosis 1 (2%) 

Kupffer cell, hyperplasia 1 (2%) 

Oval cell, hyperplasia 10 (20%) 14 (28%) 9 (18%) 16 (32%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 175 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Alimentary System (continued) 

Mesentery (3) (1) 

Fat, inflammation, chronic 2 (67%) 

Pancreas (50) (50) (50) (50) 

Infiltration cellular, histiocyte 1 (2%) 

Acinus, atrophy 3 (6%) 

Artery, inflammation, chronic 1 (2%) 

Duct, cyst 1 (2%) 

Stomach, forestomach (50) (49) (50) (50) 

Acanthosis 1 (2%) 1 (2%) 

Ulcer 2 (4%) 

Stomach, glandular (50) (50) (50) (50) 

Dysplasia 1 (2%) 

Hyperplasia 1 (2%) 

Pigmentation 1 (2%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Degeneration, chronic 1 (2%) 1 (2%) 1 (2%) 

Atrium, thrombosis 1 (2%) 

Coronary artery, polyarteritis, chronic 2 (4%) 

Endocrine System 

Adrenal cortex (50) (50) (50) (50) 

Angiectasis 1 (2%) 

Developmental malformation 1 (2%) 1 (2%) 

Hyperplasia 1 (2%) 2 (4%) 1 (2%) 3 (6%) 

Hypertrophy 17 (34%) 14 (28%) 16 (32%) 7 (14%) 

Necrosis 1 (2%) 2 (4%) 

Thrombosis 1 (2%) 

Vacuolization cytoplasmic 7 (14%) 1 (2%) 2 (4%) 

Capsule, accessory adrenal cortical nodule 1 (2%) 1 (2%) 1 (2%) 

Capsule, cyst 1 (2%) 

Capsule, spindle cell, hyperplasia 10 (20%) 4 (8%) 7 (14%) 4 (8%) 

Adrenal medulla (50) (50) (50) (50) 

Hyperplasia 2 (4%) 3 (6%) 1 (2%) 

Necrosis 1 (2%) 

Parathyroid gland (47) (44) (48) (45) 

Cyst 1 (2%) 

Pituitary gland (48) (49) (46) (49) 

Pars distalis, cyst 2 (4%) 1 (2%) 3 (6%) 

Pars distalis, hyperplasia 2 (4%) 1 (2%) 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Infiltration cellular, lymphocyte 1 (2%) 

Polyarteritis, chronic 1 (2%) 

Follicle, cyst 1 (2%) 

Follicular cell, hyperplasia 14 (28%) 12 (24%) 10 (20%) 9 (18%) 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

176 Triethanolamine, NTP TR 449 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Genital System 

Epididymis (50) (50) (50) (50) 

Granuloma sperm 1 (2%) 2 (4%) 1 (2%) 2 (4%) 

Artery, inflammation, chronic 1 (2%) 

Preputial gland (50) (50) (50) (50) 

Inflammation, chronic 2 (4%) 1 (2%) 2 (4%) 

Inflammation, chronic active 1 (2%) 2 (4%) 

Duct, ectasia 35 (70%) 40 (80%) 30 (60%) 23 (46%) 

Prostate (50) (50) (50) (50) 

Infiltration cellular, histiocyte 1 (2%) 

Inflammation, chronic 1 (2%) 1 (2%) 

Seminal vesicle (50) (50) (50) (50) 

Inflammation, chronic 1 (2%) 1 (2%) 

Artery, inflammation, chronic 1 (2%) 

Testes (50) (50) (50) (50) 

Congestion 1 (2%) 

Germinal epithelium, atrophy 1 (2%) 1 (2%) 

Germinal epithelium, mineralization 1 (2%) 

Hematopoietic System 

Bone marrow (50) (49) (48) (49) 

Myelofibrosis 1 (2%) 1 (2%) 

Lymph node, mandibular (47) (47) (48) (48) 

Hyperplasia, lymphoid 1 (2%) 

Lymph node, mesenteric (46) (47) (47) (48) 

Fibrosis 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 3 (6%) 1 (2%) 1 (2%) 

Spleen (50) (50) (50) (50) 

Congestion 1 (2%) 

Hematopoietic cell proliferation 4 (8%) 6 (12%) 4 (8%) 8 (16%) 

Thymus (44) (36) (47) (43) 

Atrophy 14 (32%) 25 (69%) 19 (40%) 16 (37%) 

Cyst 1 (2%) 

Infiltration cellular, histiocyte 1 (2%) 

Integumentary System 

Skin (50) (50) (50) (50) 

Ulcer 1 (2%) 

Hair follicle, sebaceous gland, site of

 application-no mass, atrophy 1 (2%) 15 (30%) 

Inguinal, acanthosis 1 (2%) 

Inguinal, inflammation, chronic 2 (4%) 

Inguinal, ulcer 1 (2%) 

Inguinal, subcutaneous tissue, edema 1 (2%) 

Site of application-no mass, acanthosis 2 (4%) 1 (2%) 6 (12%) 11 (22%) 

Site of application-no mass, inflammation,

 chronic 2 (4%) 7 (14%) 11 (22%) 

Site of application-no mass, ulcer 1 (2%) 2 (4%) 2 (4%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 177 

TABLE C5 

Summary of the Incidence of Nonneoplastic Lesions in Male Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

2-Year Study (continued) 

Musculoskeletal System 

Bone (50) (49) (48) (49) 

Cranium, hyperostosis 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Pons, necrosis, chronic, focal 1 (2%) 

Peripheral nerve (1) (1) (1) 

Sciatic, degeneration 1 (100%) 1 (100%) 

Spinal cord (1) (2) (1) 

Nerve, degeneration 1 (50%) 1 (100%) 

White matter, degeneration 1 (100%) 

Respiratory System 

Lung (50) (50) (50) (50) 

Inflammation, chronic 1 (2%) 2 (4%) 

Alveolar epithelium, hyperplasia 3 (6%) 4 (8%) 2 (4%) 2 (4%) 

Alveolar epithelium, hyperplasia, macrophage 1 (2%) 1 (2%) 

Mediastinum, infiltration cellular, histiocyte 1 (2%) 

Special Senses System 

Eye (3) (1) 

Cornea, inflammation, chronic 3 (100%) 

Cornea, inflammation, chronic, proliferative 1 (100%) 

Harderian gland (4) (5) (6) (1) 

Hyperplasia 1 (17%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Hydronephrosis 2 (4%) 1 (2%) 

Metaplasia, osseous 1 (2%) 

Mineralization 1 (2%) 

Nephropathy, chronic 48 (96%) 45 (90%) 45 (90%) 47 (94%) 

Cortex, cyst 4 (8%) 4 (8%) 2 (4%) 
178 Triethanolamine, NTP TR 449 
179 

APPENDIX D 

SUMMARY OF LESIONS IN FEMALE MICE 

IN THE 2-YEAR DERMAL STUDY 

OF TRIETHANOLAMINE 

TABLE D1	 Summary of the Incidence of Neoplasms in Female Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 181 

TABLE D2 Individual Animal Tumor Pathology of Female Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 186 

TABLE D3 Statistical Analysis of Primary Neoplasms in Female Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 208 

TABLE D4 Historical Incidence of Hepatocellular Neoplasms in Control Female B6C3F1 

 Mice ..... 212

TABLE D5	 Summary of the Incidence of Nonneoplastic Lesions in Female Mice 

in the 2-Year Dermal Study of Triethanolamine ............................ 213 
180 Triethanolamine, NTP TR 449 
 

 

 

Triethanolamine, NTP TR 449 181 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Disposition Summary 

Animals initially in study 

15-Month interim evaluation 

Early deaths 

Moribund 

Natural deaths 

Survivors 

Died last week of study 

Terminal sacrifice 

60 

10 

7 

4 

1 

38 

60 

10 

4 

6 

40 

60 

10 

5 

7 

38 

60 

10 

11 

2 

37 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver 

Hepatocellular adenoma

(10) 

 2 (20%) 

(10) 

 2 (20%) 

(10) 

 1 (10%) 

(10) 

 1 (10%) 

Genital System 

Uterus 

Polyp stromal

(10) (10) (9) 

 1 (11%) 

(10) 

 2 (20%) 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

(10) (10) 

 1 (10%) 

(10) (10) 

Systems Examined with No Neoplasms Observed 

Cardiovascular System 

Endocrine System 

General Body System 

Hematopoietic System 

Integumentary System 

Musculoskeletal System 

Nervous System 

Special Senses System 

Urinary System 

2-Year Study 

Alimentary System 

Intestine small, duodenum (50) (50) (50) (50) 

Intestine small, jejunum (50) (50) (50) (50) 

Sarcoma, metastatic, skin 1 (2%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

182 Triethanolamine, NTP TR 449 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Alimentary System (continued) 

Liver (50) (50) (50) (50) 

Hemangioma 1 (2%) 

Hemangiosarcoma 3 (6%) 

Hepatocellular carcinoma 1 (2%) 4 (8%) 7 (14%) 5 (10%) 

Hepatocellular adenoma 11 (22%) 13 (26%) 11 (22%) 11 (22%) 

Hepatocellular adenoma, multiple 11 (22%) 9 (18%) 13 (26%) 29 (58%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 3 (6%) 

Ito cell tumor NOS, multiple 1 (2%) 

Mesentery (2) (5) (5) (5) 

Histiocytic sarcoma 1 (20%) 

Fat, sarcoma, metastatic, skin 1 (20%) 

Pancreas (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 

Salivary glands (50) (50) (50) (50) 

Stomach, forestomach (50) (50) (50) (50) 

Squamous cell papilloma 1 (2%) 

Stomach, glandular (50) (50) (50) (50) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Sarcoma, metastatic, skin 1 (2%) 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Capsule, spindle cell, adenoma 1 (2%) 1 (2%) 1 (2%) 

Adrenal medulla (50) (50) (50) (50) 

Pheochromocytoma benign 1 (2%) 

Islets, pancreatic (50) (50) (50) (50) 

Carcinoma 1 (2%) 

Pituitary gland (44) (49) (49) (49) 

Adenoma 1 (2%) 

Pars distalis, adenoma 4 (9%) 5 (10%) 4 (8%) 5 (10%) 

Pars intermedia, adenoma 1 (2%) 2 (4%) 

Thyroid gland (50) (50) (50) (50) 

Bilateral, follicular cell, adenoma 1 (2%) 

Follicular cell, adenoma 4 (8%) 2 (4%) 5 (10%) 5 (10%) 

Follicular cell, carcinoma 1 (2%) 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 183 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Genital System 

Ovary (50) (50) (50) (50) 

Cystadenoma 5 (10%) 3 (6%) 2 (4%) 

Granulosa cell tumor benign 1 (2%) 1 (2%) 

Hemangioma 1 (2%) 

Hemangiosarcoma 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 

Luteoma 3 (6%) 2 (4%) 

Teratoma NOS 1 (2%) 1 (2%) 

Follicle, cystadenoma 1 (2%) 

Uterus (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 1 (2%) 1 (2%) 

Polyp stromal 1 (2%) 1 (2%) 1 (2%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Hemangiosarcoma 1 (2%) 

Lymph node (4) (8) (6) (9) 

Bronchial, hemangiosarcoma, metastatic, 

uncertain primary site 1 (25%) 

Bronchial, sarcoma, metastatic, skin 1 (17%) 

Mediastinal, sarcoma, metastatic, skin 1 (17%) 

Mediastinal, teratoma NOS, metastatic, ovary 1 (13%) 

Pancreatic, histiocytic sarcoma 1 (11%) 

Lymph node, mandibular (47) (49) (49) (49) 

Histiocytic sarcoma 1 (2%) 2 (4%) 

Lymph node, mesenteric (46) (49) (48) (49) 

Histiocytic sarcoma 2 (4%) 

Spleen (50) (50) (50) (50) 

Hemangiosarcoma 3 (6%) 1 (2%) 

Histiocytic sarcoma 2 (4%) 1 (2%) 2 (4%) 

Capsule, sarcoma, metastatic, skin 1 (2%) 

Thymus (46) (47) (49) (48) 

Histiocytic sarcoma 1 (2%) 2 (4%) 

Sarcoma, metastatic, skin 1 (2%) 1 (2%) 

Thymoma NOS 1 (2%) 

Integumentary System 

Mammary gland (48) (48) (50) (47) 

Adenoma 1 (2%) 

Hemangiosarcoma 1 (2%) 

Skin (50) (50) (50) (50) 

Inguinal, subcutaneous tissue, osteosarcoma 1 (2%) 

Neck, subcutaneous tissue, sarcoma 1 (2%) 

Pinna, sarcoma 1 (2%) 1 (2%) 

Subcutaneous tissue, fibrosarcoma, multiple 1 (2%) 

Subcutaneous tissue, sarcoma 1 (2%) 2 (4%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

184 Triethanolamine, NTP TR 449 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Lumbar, vertebra, sarcoma 1 (2%) 

Scapula, osteosarcoma 1 (2%) 

Vertebra, osteosarcoma 1 (2%) 

Skeletal muscle (2) (2) 

Fibrosarcoma 1 (50%) 

Diaphragm, sarcoma, metastatic, skin 1 (50%) 1 (50%) 

Nervous System 

None 

Respiratory System 

Lung (50) (50) (50) (49) 

Alveolar/bronchiolar adenoma 2 (4%) 4 (8%) 2 (4%) 5 (10%) 

Alveolar/bronchiolar carcinoma 1 (2%) 2 (4%) 

Fibrosarcoma, metastatic, skin 1 (2%) 

Hemangiosarcoma, metastatic, uncertain

 primary site 1 (2%) 

Hepatocellular carcinoma, metastatic, liver 1 (2%) 

Histiocytic sarcoma 1 (2%) 1 (2%) 2 (4%) 

Osteosarcoma, metastatic, bone 1 (2%) 

Osteosarcoma, metastatic, skin 1 (2%) 

Osteosarcoma, metastatic, tissue NOS 1 (2%) 

Sarcoma, metastatic, bone 1 (2%) 

Sarcoma, metastatic, skin 1 (2%) 1 (2%) 

Mediastinum, sarcoma, metastatic, skin 1 (2%) 

Special Senses System 

Harderian gland (1) (2) (1) 

Adenoma 1 (100%) 1 (50%) 1 (100%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Histiocytic sarcoma 1 (2%) 

Urinary bladder (50) (50) (50) (50) 

Systemic Lesions 

Multiple organsb (50) (50) (50) (50) 

Histiocytic sarcoma 2 (4%) 2 (4%) 3 (6%) 

Leukemia lymphocytic 1 (2%) 1 (2%) 

Lymphoma malignant 1 (2%) 

Lymphoma malignant lymphocytic 1 (2%) 5 (10%) 3 (6%) 4 (8%) 

Lymphoma malignant mixed 4 (8%) 4 (8%) 1 (2%) 7 (14%) 

Lymphoma malignant undifferentiated cell 1 (2%) 1 (2%) 2 (4%) 3 (6%) 
185 

c 

Triethanolamine, NTP TR 449 

TABLE D1 

Summary of the Incidence of Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Neoplasm Summary 

Total animals with primary neoplasmsc 

15-Month interim evaluation 2 3 2 3 

2-Year study 37 43 42 49 

Total primary neoplasms 

15-Month interim evaluation 2 3 2 3 

2-Year study 58 70 66 92 

Total animals with benign neoplasms 

15-Month interim evaluation 2 3 2 3 

2-Year study 34 33 31 43 

Total benign neoplasms 

15-Month interim evaluation 2 3 2 3 

2-Year study 44 43 43 62 

Total animals with malignant neoplasms 

2-Year study 11 22 21 25 

Total malignant neoplasms 

2-Year study 14 25 22 29 

Total animals with metastatic neoplasms 

2-Year study 1 3 3 3 

Total metastatic neoplasms 

2-Year study 2 10 8 3 

Total animals with malignant neoplasms

 of uncertain primary site 

2-Year study 1 

Total animals with uncertain neoplasmsbenign or malignant 

2-Year study 2 1 1 

Total uncertain neoplasms 

2-Year study 2 1 1 

a Number of animals examined microscopically at the site and the number of animals with neoplasm b Number of animals with any tissue examined microscopically 

Primary neoplasms: all neoplasms except metastatic neoplasms 
 

 

 

 

 

 

 

 

 

 

186 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

Number of Days on Study 

0 1 2 3 4 5 5 5 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

0 9 8 5 8 1 3 7 8 9 0 2 2 2 2 2 2 2 2 3 3 3 3 3 3 

9 7 9 0 7 2 4 2 1 8 0 9 9 9 9 9 9 9 9 0 0 0 0 0 0 

Carcass ID Number 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

6 6 6 8 6 5 8 4 4 7 5 4 5 6 7 7 9 9 9 4 4 4 6 7 7 

9 8 1 6 2 5 5 2 8 5 6 4 2 5 6 9 0 1 7 1 3 6 4 1 2 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Mesentery 

Pancreas 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X X 

X X X X 

+ + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + M + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, spindle cell, adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + + + + + M M + + + + + + + M + M + + + + 

Pituitary gland M + + + + + + + + + + + + + + + + + + + + + + M + 

Pars distalis, adenoma X X X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma X 

General Body System 

None 

Genital System 

Clitoral gland + M + + + + + + + + + + + + + + + + + + + + + + + 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Cystadenoma X 

Granulosa cell tumor benign 

Hemangiosarcoma 

Luteoma 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Polyp stromal 

+: Tissue examined microscopically M: Missing tissue X: Lesion present 

A: Autolysis precludes examination I: Insufficient tissue Blank: Not examined 
 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 187 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 Total 

Carcass ID Number 8 8 8 8 9 4 5 5 6 7 7 8 8 9 9 5 5 5 6 7 7 8 9 9 0 Tissues/ 

1 3 7 8 6 5 7 8 3 4 7 0 2 2 9 1 4 9 0 3 8 4 4 5 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma X 1 

Hepatocellular adenoma X X X X X X 11 

Hepatocellular adenoma, multiple X X X X X X X 11 

Mesentery 2 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + M M + + + 47 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, spindle cell, adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + M + + M + + + + M + + + + + + + + + + + + 43 

Pituitary gland + + + M + + + M I + M + + + + + + + + + + + + + + 44 

Pars distalis, adenoma 4 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X X X 4 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cystadenoma X X X X 5 

Granulosa cell tumor benign X 1 

Hemangiosarcoma X 1 

Luteoma X X X 3 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Polyp stromal X 1 
 

 

 

 

 

 

 

 

 

 

 

188 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

0 1 2 3 4 5 5 5 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 0 9 8 5 8 1 3 7 8 9 0 2 2 2 2 2 2 2 2 3 3 3 3 3 3 

9 7 9 0 7 2 4 2 1 8 0 9 9 9 9 9 9 9 9 0 0 0 0 0 0 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

Carcass ID Number 6 6 6 8 6 5 8 4 4 7 5 4 5 6 7 7 9 9 9 4 4 4 6 7 7 

9 8 1 6 2 5 5 2 8 5 6 4 2 5 6 9 0 1 7 1 3 6 4 1 2 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Lymph node 

Bronchial, hemangiosarcoma,

 metastatic, uncertain primary site 

Lymph node, mandibular + + + + + + + M + + + + + + + + + M + + + + + M + 

Lymph node, mesenteric M + + + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Thymus + + + + + M + + + + + + + + + + + + + + + + M M + 

Integumentary System 

Mammary gland + M + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Subcutaneous tissue, sarcoma X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Peripheral nerve + + 

Spinal cord + + 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Hemangiosarcoma, metastatic,

 uncertain primary site 

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Harderian gland 

Adenoma 

Urinary System 

Kidney 

Urinary Bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 189 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 0 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 Total 

Carcass ID Number 8 

1 

8 

3 

8 

7 

8 

8 

9 

6 

4 

5 

5 

7 

5 

8 

6 

3 

7 

4 

7 

7 

8 

0 

8 

2 

9 

2 

9 

9 

5 

1 

5 

4 

5 

9 

6 

0 

7 

3 

7 

8 

8 

4 

9 

4 

9 

5 

0 

0 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Hemangiosarcoma

Lymph node 

Bronchial, hemangiosarcoma,

 metastatic, uncertain primary site 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Hemangiosarcoma 

Thymus 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + +

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + M + + + + + + + + + + + + + + + + M + M + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

+ + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

4 

1 

47 

46 

50 

3 

46 

Integumentary System 

Mammary gland 

Hemangiosarcoma 

Skin 

Subcutaneous tissue, sarcoma

+ + + + + + + + + + + + + + + + + + + + + M + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

48 

1 

50 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Nervous System 

Brain 

Peripheral nerve

Spinal cord

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

2 

2 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Hemangiosarcoma, metastatic,

 uncertain primary site 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

2 

1 

50 

50 

Special Senses System 

Ear

Harderian gland 

Adenoma 

+

X

 1 

1 

1 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

Systemic Lesions 

Multiple organs 

Lymphoma malignant lymphocytic

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X X

X 

50 

1 

4 

1 
 

 

 

 

 

 

 

 

 

 

 

190 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

Number of Days on Study 

0 4 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

0 1 5 7 3 5 7 7 8 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 

9 4 7 8 9 0 5 5 5 3 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 

Carcass ID Number 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 1 4 5 3 4 1 3 2 1 1 1 3 3 4 4 5 5 5 0 1 2 2 2 3 

7 4 1 6 0 5 3 2 2 1 7 9 4 6 0 3 3 5 9 4 8 1 3 8 1 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Sarcoma, metastatic, skin 

Intestine small, ileum 

Liver 

Hemangiosarcoma 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Ito cell tumor NOS, multiple 

Mesentery 

Fat, sarcoma, metastatic, skin 

Pancreas 

Sarcoma, metastatic, skin 

Salivary glands 

Stomach, forestomach 

Squamous cell papilloma 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X X 

X X X X X X X X 

X X X 

X 

X 

+ + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Pheochromocytoma benign 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Carcinoma X 

Parathyroid gland + + + + M + + M + + + + + + + + + + M + + + + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Adenoma 

Pars distalis, adenoma X X 

Pars intermedia, adenoma 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 191 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 3 3 4 4 4 5 5 5 6 2 2 4 4 5 5 0 0 0 0 0 2 2 2 3 5 Tissues/ 

7 8 4 6 7 2 4 7 0 0 9 2 8 1 8 1 2 3 5 9 4 5 6 5 0 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, skin 1 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 3 

Hepatocellular carcinoma X X 4 

Hepatocellular adenoma X X X X X 13 

Hepatocellular adenoma, multiple X X X X X X 9 

Histiocytic sarcoma X 2 

Ito cell tumor NOS, multiple 1 

Mesentery + + + 5 

Fat, sarcoma, metastatic, skin 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, skin 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Squamous cell papilloma X 1 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel M + + + + + + + + + + + + + + + + + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pheochromocytoma benign X 1 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Carcinoma 1 

Parathyroid gland M + M + + + + + + + + M + + + + + + + + + + M + + 43 

Pituitary gland + + + + + + M + + + + + + + + + + + + + + + + + + 49 

Adenoma X 1 

Pars distalis, adenoma X X X 5 

Pars intermedia, adenoma X 1 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X X 2 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

192 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

(continued) 

0 4 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 0 1 5 7 3 5 7 7 8 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 

9 4 7 8 9 0 5 5 5 3 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

Carcass ID Number 0 1 4 5 3 4 1 3 2 1 1 1 3 3 4 4 5 5 5 0 1 2 2 2 3 

7 4 1 6 0 5 3 2 2 1 7 9 4 6 0 3 3 5 9 4 8 1 3 8 1 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Granulosa cell tumor benign 

Hemangioma 

Histiocytic sarcoma X 

Luteoma 

Teratoma NOS 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Polyp stromal X 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 

Lymph node + + + + 

Mediastinal, teratoma NOS,

 metastatic, ovary 

Lymph node, mandibular + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + + + + + + 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangiosarcoma X 

Histiocytic sarcoma X 

Capsule, sarcoma, metastatic, skin X 

Thymus + + M + + + + + + + + + M + + + + + + + + + + + + 

Sarcoma, metastatic, skin X 

Integumentary System 

Mammary gland + + M + + + M + + + + + + + + + + + + + + + + + + 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 

Pinna, sarcoma 

Subcutaneous tissue, sarcoma X X 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 

Skeletal muscle + + 

Fibrosarcoma X 

Diaphragm, sarcoma, metastatic, skin X 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Peripheral nerve + 

Spinal cord + 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 

Alveolar/bronchiolar adenoma X X 

Hepatocellular carcinoma, metastatic, liver X 

Histiocytic sarcoma 

Sarcoma, metastatic, skin X 

Mediastinum, sarcoma, metastatic, skin X 

Nose + + + + M + + + + + + + + + + + + + + + + + + + + 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 193 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Total 

Carcass ID Number 3 3 4 4 4 5 5 5 6 2 2 4 4 5 5 0 0 0 0 0 2 2 2 3 5 Tissues/ 

7 8 4 6 7 2 4 7 0 0 9 2 8 1 8 1 2 3 5 9 4 5 6 5 0 Tumors 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + M M + 48 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Granulosa cell tumor benign X 1 

Hemangioma X 1 

Histiocytic sarcoma 1 

Luteoma X X 2 

Teratoma NOS X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Polyp stromal 1 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node + + + + 8 

Mediastinal, teratoma NOS,

 metastatic, ovary X 1 

Lymph node, mandibular + + + + + M + + + + + + + + + + + + + + + + + + + 49 

Histiocytic sarcoma X 1 

Lymph node, mesenteric + + + + + + + + + + + + + + + + + + + + M + + + + 49 

Spleen + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangiosarcoma 1 

Histiocytic sarcoma X 2 

Capsule, sarcoma, metastatic, skin 1 

Thymus + + + + + + + + + + + + + + + + M + + + + + + + + 47 

Sarcoma, metastatic, skin 1 

Integumentary System 

Mammary gland + + + + + + + + + + + + + + + + + + + + + + + + + 48 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Pinna, sarcoma X 1 

Subcutaneous tissue, sarcoma 2 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Skeletal muscle 2 

Fibrosarcoma 1 

Diaphragm, sarcoma, metastatic, skin 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Peripheral nerve 1 

Spinal cord 1 

Respiratory System 

Lung + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Alveolar/bronchiolar adenoma X X 4 

Hepatocellular carcinoma, metastatic, liver 1 

Histiocytic sarcoma X 1 

Sarcoma, metastatic, skin 1 

Mediastinum, sarcoma, metastatic, skin 1 

Nose + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 
 

 

 

 

 

194 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

(continued) 

Number of Days on Study 

0 

0 

9 

4 

1 

4 

5 

5 

7 

5 

7 

8 

6 

3 

9 

6 

5 

0 

6 

7 

5 

6 

7 

5 

6 

8 

5 

7 

1 

3 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

2 

9 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

7 

3 

0 

Carcass ID Number 

3 

0 

7 

3 

1 

4 

3 

4 

1 

3 

5 

6 

3 

3 

0 

3 

4 

5 

3 

1 

3 

3 

3 

2 

3 

2 

2 

3 

1 

1 

3 

1 

7 

3 

1 

9 

3 

3 

4 

3 

3 

6 

3 

4 

0 

3 

4 

3 

3 

5 

3 

3 

5 

5 

3 

5 

9 

3 

0 

4 

3 

1 

8 

3 

2 

1 

3 

2 

3 

3 

2 

8 

3 

3 

1 

Special Senses System 

Harderian gland 

Adenoma 

Urinary System 

Kidney 

Histiocytic sarcoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X X X X 

X 

X 
 

 

 

 

 

 

Triethanolamine, NTP TR 449 195 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 100 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

Carcass ID Number 

3 

3 

7 

3 

3 

8 

3 

4 

4 

3 

4 

6 

3 

4 

7 

3 

5 

2 

3 

5 

4 

3 

5 

7 

3 

6 

0 

3 

2 

0 

3 

2 

9 

3 

4 

2 

3 

4 

8 

3 

5 

1 

3 

5 

8 

3 

0 

1 

3 

0 

2 

3 

0 

3 

3 

0 

5 

3 

0 

9 

3 

2 

4 

3 

2 

5 

3 

2 

6 

3 

3 

5 

3 

5 

0 

Total 

Tissues/ 

Tumors 

Special Senses System 

Harderian gland 

Adenoma 

+ 

X

+ 2 

1 

Urinary System 

Kidney 

Histiocytic sarcoma 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

1 

50 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X

X X X

50 

2 

5 

4 

1 
 

 

 

 

 

 

 

 

 

 

196 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

3 4 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 3 4 7 9 0 2 6 7 8 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 

0 4 0 9 7 3 4 9 4 2 2 6 9 9 9 9 9 9 9 9 9 0 0 0 0 

3 3 4 4 3 4 3 3 4 3 3 4 3 3 3 3 3 3 4 4 4 3 3 3 3 

Carcass ID Number 9 9 1 1 8 1 9 9 0 7 8 0 6 7 7 7 7 9 0 0 2 6 7 8 8 

6 2 1 4 2 8 5 9 6 5 3 9 2 6 7 8 9 0 0 4 0 8 2 4 5 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + M 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 

Hemangioma 

Hepatocellular carcinoma X X X X 

Hepatocellular adenoma X X X X X 

Hepatocellular adenoma, multiple X X X X 

Histiocytic sarcoma X 

Mesentery + + + + + 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Sarcoma, metastatic, skin X 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, spindle cell, adenoma X 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland M + + + + M M + + M + + + + M + + + + M M M + + + 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Follicular cell, adenoma 

Follicular cell, carcinoma 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + M M + + + M + + + + + + + + + + + + + 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Cystadenoma X X 

Teratoma NOS 

Follicle, cystadenoma 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma 
 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 197 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 6 

3 3 4 4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 3 Total 

Carcass ID Number 8 9 0 0 0 0 1 1 6 6 6 6 7 8 8 6 9 9 0 0 1 1 1 1 9 Tissues/ 

9 3 1 2 5 8 2 5 1 3 5 6 1 0 1 4 7 8 3 7 0 6 7 9 4 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hemangioma X 1 

Hepatocellular carcinoma X X X 7 

Hepatocellular adenoma X X X X X X 11 

Hepatocellular adenoma, multiple X X X X X X X X X 13 

Histiocytic sarcoma 1 

Mesentery 5 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Sarcoma, metastatic, skin 1 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, spindle cell, adenoma 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + + M + + + + + + + M + + + + + 40 

Pituitary gland + + + + + + + + + + + + + + M + + + + + + + + + + 49 

Pars distalis, adenoma X X 4 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Follicular cell, adenoma X X X X X 5 

Follicular cell, carcinoma X 1 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + + + + + + + + + + + + + + + + + 47 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cystadenoma X 3 

Teratoma NOS X 1 

Follicle, cystadenoma X 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma X 1 
 

 

 

 

 

 

 

 

 

 

 

 

 

198 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

(continued) 

3 4 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 

0 

3 

4 

4 

0 

7 

9 

9 

7 

0 

3 

2 

4 

6 

9 

7 

4 

8 

2 

1 

2 

1 

6 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

3 3 4 4 3 4 3 3 4 3 3 4 3 3 3 3 3 3 4 4 4 3 3 3 3 

Carcass ID Number 9 9 1 1 8 1 9 9 0 7 8 0 6 7 7 7 7 9 0 0 2 6 7 8 8 

6 2 1 4 2 8 5 9 6 5 3 9 2 6 7 8 9 0 0 4 0 8 2 4 5 

Hematopoietic System 

Bone marrow 

Lymph node 

Bronchial, sarcoma, metastatic, skin 

Mediastinal, sarcoma, metastatic, skin 

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Histiocytic sarcoma 

Thymus 

Histiocytic sarcoma 

Sarcoma, metastatic, skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + 

X 

X 

+ + + + + M + + + + + + + + + + + + + + + + + + + 

+ M + + + M + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + M + + + + + + + + + + + + + 

X 

X 

Integumentary System 

Mammary gland 

Adenoma 

Skin 

Inguinal, subcutaneous tissue, osteosarcoma 

Neck, subcutaneous tissue, sarcoma 

Pinna, sarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

X 

Musculoskeletal System 

Bone 

Lumbar, vertebra, sarcoma 

Skeletal muscle 

Diaphragm, sarcoma, metastatic, skin 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + 

X 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Histiocytic sarcoma 

Osteosarcoma, metastatic, skin 

Sarcoma, metastatic, bone 

Sarcoma, metastatic, skin 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

X 

X 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear 

Harderian gland 

Adenoma 

+ 

X 

+ 
 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 199 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

6 

3 3 4 4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 3 Total 

Carcass ID Number 8 

9 

9 

3 

0 

1 

0 

2 

0 

5 

0 

8 

1 

2 

1 

5 

6 

1 

6 

3 

6 

5 

6 

6 

7 

1 

8 

0 

8 

1 

6 

4 

9 

7 

9 

8 

0 

3 

0 

7 

1 

0 

1 

6 

1 

7 

1 

9 

9 

4 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lymph node 

Bronchial, sarcoma, metastatic, skin

Mediastinal, sarcoma, metastatic, skin

Lymph node, mandibular 

Lymph node, mesenteric 

Spleen 

Histiocytic sarcoma 

Thymus 

Histiocytic sarcoma

Sarcoma, metastatic, skin

+ + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

6 

1 

1 

49 

48 

50 

1 

49 

1 

1 

Integumentary System 

Mammary gland 

Adenoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

Skin + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Inguinal, subcutaneous tissue, osteosarcoma

Neck, subcutaneous tissue, sarcoma

Pinna, sarcoma

 1 

1 

1 

Musculoskeletal System 

Bone + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Lumbar, vertebra, sarcoma

Skeletal muscle

 1 

2 

Diaphragm, sarcoma, metastatic, skin 1 

Nervous System 

Brain + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma

Alveolar/bronchiolar carcinoma 

Histiocytic sarcoma

Osteosarcoma, metastatic, skin

Sarcoma, metastatic, bone

Sarcoma, metastatic, skin

Nose 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

2 

1 

1 

1 

1 

1 

50 

Trachea + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Special Senses System 

Ear 1 

Harderian gland 1 

Adenoma 1 
 

 

 

200 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

(continued) 

3 4 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 2 

0 

3 

4 

4 

0 

7 

9 

9 

7 

0 

3 

2 

4 

6 

9 

7 

4 

8 

2 

1 

2 

1 

6 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

3 

0 

3 

0 

Carcass ID Number 

3 

9 

6 

3 

9 

2 

4 

1 

1 

4 

1 

4 

3 

8 

2 

4 

1 

8 

3 

9 

5 

3 

9 

9 

4 

0 

6 

3 

7 

5 

3 

8 

3 

4 

0 

9 

3 

6 

2 

3 

7 

6 

3 

7 

7 

3 

7 

8 

3 

7 

9 

3 

9 

0 

4 

0 

0 

4 

0 

4 

4 

2 

0 

3 

6 

8 

3 

7 

2 

3 

8 

4 

3 

8 

5 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Leukemia lymphocytic 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

X 
 

 

 

 

Triethanolamine, NTP TR 449 201 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 300 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

6 

Carcass ID Number 

3 

8 

9 

3 

9 

3 

4 

0 

1 

4 

0 

2 

4 

0 

5 

4 

0 

8 

4 

1 

2 

4 

1 

5 

3 

6 

1 

3 

6 

3 

3 

6 

5 

3 

6 

6 

3 

7 

1 

3 

8 

0 

3 

8 

1 

3 

6 

4 

3 

9 

7 

3 

9 

8 

4 

0 

3 

4 

0 

7 

4 

1 

0 

4 

1 

6 

4 

1 

7 

4 

1 

9 

3 

9 

4 

Total 

Tissues/ 

Tumors 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Leukemia lymphocytic

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X

X

X X 

50 

2 

1 

3 

1 

2 
 

 

 

 

 

 

 

 

 

 

 

 

202 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

Number of Days on Study 

3 4 5 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

1 1 2 3 5 9 4 6 7 8 9 1 1 2 2 2 2 2 2 2 2 2 2 3 3 

7 5 1 7 1 1 7 1 0 0 9 2 2 9 9 9 9 9 9 9 9 9 9 0 0 

Carcass ID Number 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

2 7 6 3 6 7 5 7 2 8 4 5 6 2 2 3 4 4 5 6 6 7 7 2 3 

3 9 4 6 1 3 8 6 8 0 7 6 2 1 5 9 0 1 4 8 9 5 8 6 0 

Alimentary System 

Esophagus 

Gallbladder 

Intestine large, colon 

Intestine large, rectum 

Intestine large, cecum 

Intestine small, duodenum 

Intestine small, jejunum 

Intestine small, ileum 

Liver 

Hepatocellular carcinoma 

Hepatocellular adenoma 

Hepatocellular adenoma, multiple 

Histiocytic sarcoma 

Mesentery 

Histiocytic sarcoma 

Pancreas 

Histiocytic sarcoma 

Salivary glands 

Stomach, forestomach 

Stomach, glandular 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X X X X X X 

X X X X X X X X X X X 

X X X 

+ + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + + + + + + + + + + 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 

Capsule, spindle cell, adenoma 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 

Parathyroid gland + + + + + + + + + + + + + + + + + M + + + + + + + 

Pituitary gland + + + + + M + + + + + + + + + + + + + + + + + + + 

Pars distalis, adenoma X X X 

Pars intermedia, adenoma X X 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 

Bilateral, follicular cell, adenoma 

Follicular cell, adenoma X X 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + + + + M + + + + + + + + + + + + + + + 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 

Cystadenoma 

Histiocytic sarcoma X 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 

Histiocytic sarcoma X 

Polyp stromal X 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 203 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 

0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 5 5 6 2 2 4 4 5 5 7 7 2 2 3 3 3 3 4 4 4 6 6 6 7 7 Tissues/ 

0 3 7 2 9 2 5 1 9 2 4 4 7 1 2 3 7 3 4 9 0 5 6 1 7 Tumors 

Alimentary System 

Esophagus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Gallbladder + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, colon + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, rectum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine large, cecum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, duodenum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, jejunum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Intestine small, ileum + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Liver + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Hepatocellular carcinoma X X 5 

Hepatocellular adenoma X X X X X 11 

Hepatocellular adenoma, multiple X X X X X X X X X X X X X X X X X X 29 

Histiocytic sarcoma 3 

Mesentery + 5 

Histiocytic sarcoma 1 

Pancreas + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Salivary glands + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, forestomach + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Stomach, glandular + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cardiovascular System 

Blood vessel + + + + + + + + + + + + + + + + M + + + + + + + + 49 

Heart + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Endocrine System 

Adrenal cortex + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Capsule, spindle cell, adenoma X 1 

Adrenal medulla + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Islets, pancreatic + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Parathyroid gland + + + + + + + + + + + + + M M + M + + + + + M + + 45 

Pituitary gland + + + + + + + + + + + + + + + + + + + + + + + + + 49 

Pars distalis, adenoma X X 5 

Pars intermedia, adenoma 2 

Thyroid gland + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Bilateral, follicular cell, adenoma X 1 

Follicular cell, adenoma X X X 5 

General Body System 

None 

Genital System 

Clitoral gland + + + + + + M + + + + + + + + + + + + + + + + + + 48 

Ovary + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Cystadenoma X X 2 

Histiocytic sarcoma 1 

Uterus + + + + + + + + + + + + + + + + + + + + + + + + + 50 

Histiocytic sarcoma 1 

Polyp stromal 1 
 

 

 

 

 

 

 

 

 

 

 

204 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

(continued) 

3 4 5 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 

7 

1 

5 

2 

1 

3 

7 

5 

1 

9 

1 

4 

7 

6 

1 

7 

0 

8 

0 

9 

9 

1 

2 

1 

2 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 2 7 6 3 6 7 5 7 2 8 4 5 6 2 2 3 4 4 5 6 6 7 7 2 3 

3 9 4 6 1 3 8 6 8 0 7 6 2 1 5 9 0 1 4 8 9 5 8 6 0 

Hematopoietic System 

Bone marrow 

Lymph node 

Pancreatic, histiocytic sarcoma 

Lymph node, mandibular 

Histiocytic sarcoma 

Lymph node, mesenteric 

Histiocytic sarcoma 

Spleen 

Histiocytic sarcoma 

Thymus 

Histiocytic sarcoma 

Thymoma NOS 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + 

X 

+ + + + + + + + + M + + + + + + + + + + + + + + + 

X X 

+ + + + + + + + + + + + M + + + + + + + + + + + + 

X X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X 

+ + + M + + + + + + + + + + + + + + + + + + + + + 

X X 

Integumentary System 

Mammary gland 

Skin 

Subcutaneous tissue, fibrosarcoma, multiple 

+ + + M + + + + + + M + M + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

Musculoskeletal System 

Bone 

Scapula, osteosarcoma 

Vertebra, osteosarcoma 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X 

X 

Nervous System 

Brain 

Peripheral nerve 

Spinal cord 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ 

+ 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Fibrosarcoma, metastatic, skin 

Histiocytic sarcoma 

Osteosarcoma, metastatic, bone 

Osteosarcoma, metastatic, tissue NOS 

Nose 

Trachea 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X 

X 

X X 

X 

X 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

Special Senses System 

Ear + 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 
 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 205 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 5 

0 

5 

3 

6 

7 

2 

2 

2 

9 

4 

2 

4 

5 

5 

1 

5 

9 

7 

2 

7 

4 

2 

4 

2 

7 

3 

1 

3 

2 

3 

3 

3 

7 

4 

3 

4 

4 

4 

9 

6 

0 

6 

5 

6 

6 

7 

1 

7 

7 

Tissues/ 

Tumors 

Hematopoietic System 

Bone marrow 

Lymph node 

Pancreatic, histiocytic sarcoma

Lymph node, mandibular 

Histiocytic sarcoma

Lymph node, mesenteric 

Histiocytic sarcoma

Spleen 

Histiocytic sarcoma

Thymus 

Histiocytic sarcoma

Thymoma NOS 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + M + + + + + + + + + + 

X

50 

9 

1 

49 

2 

49 

2 

50 

2 

48 

2 

1 

Integumentary System 

Mammary gland 

Skin 

Subcutaneous tissue, fibrosarcoma, multiple

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

47 

50 

1 

Musculoskeletal System 

Bone 

Scapula, osteosarcoma

Vertebra, osteosarcoma

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

1 

Nervous System 

Brain 

Peripheral nerve

Spinal cord

+ + + + + + + + + + + + + + + + + + + + + + + + + 50 

1 

1 

Respiratory System 

Lung 

Alveolar/bronchiolar adenoma 

Alveolar/bronchiolar carcinoma 

Fibrosarcoma, metastatic, skin

Histiocytic sarcoma

Osteosarcoma, metastatic, bone

Osteosarcoma, metastatic, tissue NOS

Nose 

Trachea 

+ + + + + + + M + + + + + + + + + + + + + + + + + 

X X

X

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

49 

5 

2 

1 

2 

1 

1 

50 

50 

Special Senses System 

Ear 1 

Urinary System 

Kidney 

Urinary bladder 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

50 

50 
 

 

 

 

 

206 Triethanolamine, NTP TR 449 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

(continued) 

3 4 5 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 1 

7 

1 

5 

2 

1 

3 

7 

5 

1 

9 

1 

4 

7 

6 

1 

7 

0 

8 

0 

9 

9 

1 

2 

1 

2 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

2 

9 

3 

0 

3 

0 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 

Carcass ID Number 2 7 6 3 6 7 5 7 2 8 4 5 6 2 2 3 4 4 5 6 6 7 7 2 3 

3 9 4 6 1 3 8 6 8 0 7 6 2 1 5 9 0 1 4 8 9 5 8 6 0 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma 

Leukemia lymphocytic 

Lymphoma malignant 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X X X 

X 

X 

X X 

X 
 

 

 

 

Triethanolamine, NTP TR 449 207 

TABLE D2 

Individual Animal Tumor Pathology of Female Mice in the 2-Year Dermal Study of Triethanolamine: 1,000 mg/kg 

(continued) 

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 

Number of Days on Study 3 

0 

3 

0 

3 

0 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

1 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

3 

2 

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Total 

Carcass ID Number 5 

0 

5 

3 

6 

7 

2 

2 

2 

9 

4 

2 

4 

5 

5 

1 

5 

9 

7 

2 

7 

4 

2 

4 

2 

7 

3 

1 

3 

2 

3 

3 

3 

7 

4 

3 

4 

4 

4 

9 

6 

0 

6 

5 

6 

6 

7 

1 

7 

7 

Tissues/ 

Tumors 

Systemic Lesions 

Multiple organs 

Histiocytic sarcoma

Leukemia lymphocytic

Lymphoma malignant 

Lymphoma malignant lymphocytic 

Lymphoma malignant mixed 

Lymphoma malignant undifferentiated cell type 

+ + + + + + + + + + + + + + + + + + + + + + + + + 

X

X X X

X X X X X

X X 

50 

3 

1 

1 

4 

7 

3 
208 Triethanolamine, NTP TR 449 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Liver: Hemangiosarcoma 

Overall ratea 

Adjusted rateb 0/50 (0%) 

0.0% 

3/50 (6%) 

7.5% 

0/50 (0%) 

0.0% 

0/50 (0%) 

0.0% 

Terminal ratec 0/39 (0%) 3/40 (8%) 0/38 (0%) 0/37 (0%) 

First incidence (days) 

Life table testd —e 

P=0.289N 

729 (T) 

P=0.126 

— 

—f — 

— 

Logistic regression testd 

Cochran-Armitage testd 

Fisher exact testd 

P=0.289N 

P=0.276N 

P=0.126 

P=0.121 

— 

— 

— 

— 

Liver: Hepatocellular Adenoma 

Overall rate 22/50 (44%) 22/50 (44%) 24/50 (48%) 40/50 (80%) 

Adjusted rate 54.9% 53.6% 58.3% 95.2% 

Terminal rate 21/39 (54%) 21/40 (53%) 21/38 (55%) 35/37 (95%) 

First incidence (days) 681 650 597 647 

Life table test P<0.001 P=0.537N P=0.379 P<0.001 

Logistic regression test P<0.001 P=0.496N P=0.480 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.580N P=0.421 P<0.001 

Liver: Hepatocellular Carcinoma 

Overall rate 1/50 (2%) 4/50 (8%) 7/50 (14%) 5/50 (10%) 

Adjusted rate 2.6% 9.0% 16.0% 12.8% 

Terminal rate 1/39 (3%) 2/40 (5%) 4/38 (11%) 4/37 (11%) 

First incidence (days) 729 (T) 557 434 591 

Life table test P=0.203 P=0.201 P=0.038 P=0.098 

Logistic regression test P=0.204 P=0.176 P=0.024 P=0.110 

Cochran-Armitage test P=0.218 

Fisher exact test P=0.181 P=0.030 P=0.102 

Liver: Hepatocellular Adenoma or Carcinoma 

Overall rate 23/50 (46%) 26/50 (52%) 28/50 (56%) 41/50 (82%) 

Adjusted rate 57.4% 60.2% 64.7% 95.3% 

Terminal rate 22/39 (56%) 23/40 (58%) 23/38 (61%) 35/37 (95%) 

First incidence (days) 681 557 434 591 

Life table test P<0.001 P=0.395 P=0.187 P<0.001 

Logistic regression test P<0.001 P=0.457 P=0.276 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.345 P=0.212 P<0.001 

Lung: Alveolar/bronchiolar Adenoma 

Overall rate 2/50 (4%) 4/50 (8%) 2/50 (4%) 5/49 (10%) 

Adjusted rate 5.1% 10.0% 5.3% 13.0% 

Terminal rate 2/39 (5%) 4/40 (10%) 2/38 (5%) 4/36 (11%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 521 

Life table test P=0.173 P=0.348 P=0.686 P=0.196 

Logistic regression test P=0.201 P=0.348 P=0.686 P=0.217 

Cochran-Armitage test P=0.200 

Fisher exact test P=0.339 P=0.691N P=0.210 
Triethanolamine, NTP TR 449 209 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Lung: Alveolar/bronchiolar Adenoma or Carcinoma 

Overall rate 2/50 (4%) 4/50 (8%) 3/50 (6%) 7/49 (14%) 

Adjusted rate 5.1% 10.0% 7.9% 17.4% 

Terminal rate 2/39 (5%) 4/40 (10%) 3/38 (8%) 5/36 (14%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 415 

Life table test P=0.044 P=0.348 P=0.488 P=0.074 

Logistic regression test P=0.055 P=0.348 P=0.488 P=0.071 

Cochran-Armitage test P=0.054 

Fisher exact test P=0.339 P=0.500 P=0.075 

Ovary: Cystadenoma 

Overall rate 5/50 (10%) 0/50 (0%) 4/50 (8%) 2/50 (4%) 

Adjusted rate 12.3% 0.0% 10.5% 5.4% 

Terminal rate 4/39 (10%) 0/40 (0%) 4/38 (11%) 2/37 (5%) 

First incidence (days) 572 — 729 (T) 729 (T) 

Life table test P=0.435N P=0.031N P=0.508N P=0.234N 

Logistic regression test P=0.402N P=0.031N P=0.476N P=0.204N 

Cochran-Armitage test P=0.406N 

Fisher exact test P=0.028N P=0.500N P=0.218N 

Ovary: Luteoma 

Overall rate 3/50 (6%) 2/50 (4%) 0/50 (0%) 0/50 (0%) 

Adjusted rate 7.7% 5.0% 0.0% 0.0% 

Terminal rate 3/39 (8%) 2/40 (5%) 0/38 (0%) 0/37 (0%) 

First incidence (days) 729 (T) 729 (T) — — 

Life table test P=0.088N P=0.488N P=0.126N P=0.130N 

Logistic regression test P=0.088N P=0.488N P=0.126N P=0.130N 

Cochran-Armitage test P=0.082N 

Fisher exact test P=0.500N P=0.121N P=0.121N 

Pituitary Gland (Pars Distalis or Unspecified Site): Adenoma 

Overall rate 4/44 (9%) 6/49 (12%) 4/49 (8%) 5/49 (10%) 

Adjusted rate 10.1% 15.4% 10.8% 12.8% 

Terminal rate 2/34 (6%) 6/39 (15%) 4/37 (11%) 4/37 (11%) 

First incidence (days) 487 729 (T) 729 (T) 647 

Life table test P=0.563 P=0.443 P=0.606N P=0.537 

Logistic regression test P=0.571N P=0.451 P=0.579N P=0.568 

Cochran-Armitage test P=0.580N 

Fisher exact test P=0.441 P=0.581N P=0.569 

Spleen: Hemangiosarcoma 

Overall rate 3/50 (6%) 1/50 (2%) 0/50 (0%) 0/50 (0%) 

Adjusted rate 7.7% 2.5% 0.0% 0.0% 

Terminal rate 3/39 (8%) 1/40 (3%) 0/38 (0%) 0/37 (0%) 

First incidence (days) 729 (T) 729 (T) — — 

Life table test P=0.117N P=0.296N P=0.126N P=0.130N 

Logistic regression test P=0.117N P=0.296N P=0.126N P=0.130N 

Cochran-Armitage test P=0.110N 

Fisher exact test P=0.309N P=0.121N P=0.121N 
210 Triethanolamine, NTP TR 449 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Thyroid Gland (Follicular Cell): Adenoma 

Overall rate 4/50 (8%) 2/50 (4%) 5/50 (10%) 6/50 (12%) 

Adjusted rate 10.3% 5.0% 13.2% 16.2% 

Terminal rate 4/39 (10%) 2/40 (5%) 5/38 (13%) 6/37 (16%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) 

Life table test P=0.150 P=0.325N P=0.484 P=0.335 

Logistic regression test P=0.149 P=0.325N P=0.484 P=0.335 

Cochran-Armitage test P=0.182 

Fisher exact test P=0.339N P=0.500 P=0.370 

Thyroid Gland (Follicular Cell): Adenoma or Carcinoma 

Overall rate 4/50 (8%) 2/50 (4%) 6/50 (12%) 6/50 (12%) 

Adjusted rate 10.3% 5.0% 15.8% 16.2% 

Terminal rate 4/39 (10%) 2/40 (5%) 6/38 (16%) 6/37 (16%) 

First incidence (days) 729 (T) 729 (T) 729 (T) 729 (T) 

Life table test P=0.162 P=0.325N P=0.352 P=0.335 

Logistic regression test P=0.162 P=0.325N P=0.352 P=0.335 

Cochran-Armitage test P=0.197 

Fisher exact test P=0.339N P=0.370 P=0.370 

All Organs: Hemangiosarcoma 

Overall rate 4/50 (8%) 3/50 (6%) 0/50 (0%) 0/50 (0%) 

Adjusted rate 10.3% 7.5% 0.0% 0.0% 

Terminal rate 4/39 (10%) 3/40 (8%) 0/38 (0%) 0/37 (0%) 

First incidence (days) 729 (T) 729 (T) — — 

Life table test P=0.042N P=0.486N P=0.066N P=0.070N 

Logistic regression test P=0.042N P=0.486N P=0.066N P=0.070N 

Cochran-Armitage test P=0.038N 

Fisher exact test P=0.500N P=0.059N P=0.059N 

All Organs: Hemangioma or Hemangiosarcoma 

Overall rate 4/50 (8%) 4/50 (8%) 1/50 (2%) 0/50 (0%) 

Adjusted rate 10.3% 10.0% 2.6% 0.0% 

Terminal rate 4/39 (10%) 4/40 (10%) 1/38 (3%) 0/37 (0%) 

First incidence (days) 729 (T) 729 (T) 729 (T) — 

Life table test P=0.037N P=0.630N P=0.187N P=0.070N 

Logistic regression test P=0.037N P=0.630N P=0.187N P=0.070N 

Cochran-Armitage test P=0.033N 

Fisher exact test P=0.643N P=0.181N P=0.059N 

All Organs: Malignant Lymphoma (Lymphocytic, Mixed, NOS, or Undifferentiated Cell Type) 

Overall rate 6/50 (12%) 10/50 (20%) 6/50 (12%) 15/50 (30%) 

Adjusted rate 15.4% 23.1% 15.1% 37.0% 

Terminal rate 6/39 (15%) 7/40 (18%) 5/38 (13%) 12/37 (32%) 

First incidence (days) 729 (T) 639 624 317 

Life table test P=0.013 P=0.231 P=0.607 P=0.020 

Logistic regression test P=0.019 P=0.241 P=0.597N P=0.029 

Cochran-Armitage test P=0.018 

Fisher exact test P=0.207 P=0.620N P=0.024 
211 

c 

Triethanolamine, NTP TR 449 

TABLE D3 

Statistical Analysis of Primary Neoplasms in Female Mice in the 2-Year Dermal Study of Triethanolamine (continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

All Organs: Histiocytic Sarcoma 

Overall rate 0/50 (0%) 2/50 (4%) 2/50 (4%) 3/50 (6%) 

Adjusted rate 0.0% 4.5% 4.7% 6.7% 

Terminal rate 0/39 (0%) 1/40 (3%) 1/38 (3%) 0/37 (0%) 

First incidence (days) — 414 579 521 

Life table test P=0.165 P=0.250 P=0.249 P=0.133 

Logistic regression test P=0.123 P=0.206 P=0.220 P=0.087 

Cochran-Armitage test P=0.162 

Fisher exact test P=0.247 P=0.247 P=0.121 

All Organs: Benign Neoplasms 

Overall rate 34/50 (68%) 34/50 (68%) 32/50 (64%) 44/50 (88%) 

Adjusted rate 79.0% 80.9% 76.0% 100.0% 

Terminal rate 30/39 (77%) 32/40 (80%) 28/38 (74%) 37/37 (100%) 

First incidence (days) 487 650 579 521 

Life table test P=0.001 P=0.508N P=0.465N P=0.007 

Logistic regression test P=0.003 P=0.385N P=0.275N P=0.019 

Cochran-Armitage test P=0.006 

Fisher exact test P=0.585N P=0.417N P=0.014 

All Organs: Malignant Neoplasms 

Overall rate 11/50 (22%) 22/50 (44%) 21/50 (42%) 25/50 (50%) 

Adjusted rate 27.5% 46.6% 43.9% 52.8% 

Terminal rate 10/39 (26%) 15/40 (38%) 12/38 (32%) 15/37 (41%) 

First incidence (days) 698 414 320 317 

Life table test P=0.024 P=0.030 P=0.038 P=0.005 

Logistic regression test P=0.037 P=0.021 P=0.025 P=0.004 

Cochran-Armitage test P=0.021 

Fisher exact test P=0.016 P=0.026 P=0.003 

All Organs: Benign or Malignant Neoplasms 

Overall rate 37/50 (74%) 43/50 (86%) 42/50 (84%) 50/50 (100%) 

Adjusted rate 86.0% 89.6% 87.4% 100.0% 

Terminal rate 33/39 (85%) 35/40 (88%) 32/38 (84%) 37/37 (100%) 

First incidence (days) 487 414 320 317 

Life table test P=0.003 P=0.207 P=0.180 P=0.002 

Logistic regression test P<0.001 P=0.202 P=0.266 P<0.001 

Cochran-Armitage test P<0.001 

Fisher exact test P=0.105 P=0.163 P<0.001 

(T)Terminal sacrifice 

a Number of neoplasm-bearing animals/number of animals examined. Denominator is number of animals examined microscopically for liver, lung, ovary, 

pituitary gland, spleen, and thyroid gland; for other tissues, denominator is number of animals necropsied. b Kaplan-Meier estimated neoplasm incidence at the end of the study after adjustment for intercurrent mortality 

Observed incidence at terminal kill d Beneath the control incidence are the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise 

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

indirectly) the cause of death. The logistic regression test regards these lesions as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the 

overall incidence rates. For all tests, a negative trend or a lower incidence in a dose group is indicated by N. e Not applicable; no neoplasms in animal group f Value of statistic cannot be computed. 
212 Triethanolamine, NTP TR 449 

TABLE D4 

Historical Incidence of Hepatocellular Neoplasms in Control Female B6C3F a 1 Mice

Incidence in Controls 

Study Adenoma Carcinoma Adenoma or Carcinoma 

Historical Incidence in Dermal Studies (with Acetone Vehicle) at Battelle Columbus Laboratories 

4-Vinyl-1-cyclohexene diepoxide 8/50 2/50 10/50 

Triethanolamine 22/50 1/50 23/50 

Overall Historical Incidence in Dermal Studies (with Acetone Vehicle) 

Total 34/150 (22.7%) 7/150 (4.7%) 40/150 (26.7%) 

Standard deviation 18.9% 3.1% 17.0% 

Range 8%-44% 2%-8% 14%-46% 

Overall Historical Incidence in Feed Studies 

Total 194/1,312 (14.8%) 90/1,312 (6.9%) 260/1,312 (19.8%) 

Standard deviation 10.5% 6.1% 12.8% 

Range 2%-50% 0%-20% 3%-56% 

a Data as of 17 June 1994 
 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 213 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Disposition Summary 

Animals initially in study 60 60 60 60 

15-Month interim evaluation 10 10 10 10 

Early deaths 

Moribund 7 4 5 11 

Natural deaths 4 6 7 2 

Survivors 

Died last week of study 1 

Terminal sacrifice 38 40 38 37 

Animals examined microscopically 60 60 60 60 

15-Month Interim Evaluation 

Alimentary System 

Liver (10) (10) (10) (10) 

Basophilic focus 1 (10%) 

Clear cell focus 1 (10%) 

Eosinophilic focus 2 (20%) 1 (10%) 

Pancreas (10) (10) (10) (10) 

Acinus, atrophy 2 (20%) 

Stomach, forestomach (10) (10) (10) (10) 

Acanthosis 1 (10%) 

Endocrine System 

Thyroid gland (10) (10) (10) (10) 

Follicular cell, hyperplasia 3 (30%) 

Genital System 

Ovary (9) (10) (9) (10) 

Thrombosis 1 (10%) 

Follicle, cyst 2 (22%) 2 (20%) 2 (22%) 

Follicle, cyst, multiple 1 (11%) 

Uterus (10) (10) (9) (10) 

Endometrium, hyperplasia, cystic, glandular 10 (100%) 10 (100%) 9 (100%) 9 (90%) 

Hematopoietic System 

Bone marrow (10) (10) (10) (10) 

Myelofibrosis 1 (10%) 1 (10%) 1 (10%) 

Lymph node, mesenteric (8) (10) (8) (10) 

Hyperplasia, lymphoid 1 (13%) 

Spleen (10) (10) (10) (10) 

Hyperplasia, lymphoid 1 (10%) 

Thymus (9) (10) (9) (10) 

Hyperplasia, lymphoid 1 (11%) 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

214 Triethanolamine, NTP TR 449 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

15-Month Interim Evaluation (continued) 

Integumentary System 

Skin (10) (10) (10) (10) 

Site of application-no mass, acanthosis 1 (10%) 2 (20%) 

Site of application-no mass, inflammation,

 chronic 3 (30%) 

Urinary System 

Kidney (10) (10) (10) (10) 

Nephropathy, chronic 6 (60%) 3 (30%) 2 (20%) 4 (40%) 

Systems Examined with No Lesions Observed 

Cardiovascular System 

General Body System 

Musculoskeletal System 

Nervous System 

Respiratory System 

Special Senses System 

2-Year Study 

Alimentary System 

Intestine large, colon (50) (50) (50) (50) 

Inflammation, chronic active 1 (2%) 

Intestine small, jejunum (50) (50) (50) (50) 

Peyer’s patch, hyperplasia, lymphoid 2 (4%) 

Liver (50) (50) (50) (50) 

Basophilic focus 2 (4%) 1 (2%) 1 (2%) 

Clear cell focus 1 (2%) 1 (2%) 

Congestion 1 (2%) 

Cytoplasmic alteration 1 (2%) 

Eosinophilic focus 9 (18%) 10 (20%) 18 (36%) 16 (32%) 

Fatty change 1 (2%) 

Hematopoietic cell proliferation 1 (2%) 

Hepatodiaphragmatic nodule 1 (2%) 

Hypertrophy 1 (2%) 

Infiltration cellular, lymphocyte 2 (4%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Karyomegaly 1 (2%) 

Leukocytosis 1 (2%) 

Necrosis 2 (4%) 3 (6%) 2 (4%) 1 (2%) 

Kupffer cell, hyperplasia 1 (2%) 

Mesentery (2) (5) (5) (5) 

Fat, infiltration cellular, lymphocyte 1 (20%) 

Fat, inflammation, chronic 2 (100%) 4 (80%) 3 (60%) 3 (60%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 215 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Alimentary System (continued) 

Pancreas (50) (50) (50) (50) 

Cyst 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Acinus, atrophy 2 (4%) 2 (4%) 1 (2%) 

Artery, inflammation, chronic 1 (2%) 

Duct, cyst 1 (2%) 

Stomach, forestomach (50) (50) (50) (50) 

Acanthosis 1 (2%) 1 (2%) 

Stomach, glandular (50) (50) (50) (50) 

Hyperplasia 1 (2%) 1 (2%) 1 (2%) 

Inflammation, chronic active 1 (2%) 

Pigmentation 1 (2%) 1 (2%) 

Ulcer 1 (2%) 

Cardiovascular System 

Heart (50) (50) (50) (50) 

Artery, thrombosis 1 (2%) 

Coronary artery, inflammation, chronic 1 (2%) 

Endocrine System 

Adrenal cortex (50) (49) (50) (50) 

Hyperplasia 1 (2%) 

Hypertrophy 3 (6%) 2 (4%) 3 (6%) 1 (2%) 

Infiltration cellular, lymphocyte 1 (2%) 

Necrosis 1 (2%) 

Capsule, accessory adrenal cortical nodule 2 (4%) 2 (4%) 

Capsule, cyst 1 (2%) 1 (2%) 

Capsule, spindle cell, hyperplasia 1 (2%) 1 (2%) 

Adrenal medulla (50) (50) (50) (50) 

Cyst 1 (2%) 

Hyperplasia 1 (2%) 3 (6%) 3 (6%) 

Pituitary gland (44) (49) (49) (49) 

Pars distalis, angiectasis 1 (2%) 

Pars distalis, cyst 1 (2%) 2 (4%) 1 (2%) 

Pars distalis, hyperplasia 3 (7%) 7 (14%) 8 (16%) 5 (10%) 

Pars intermedia, hyperplasia 1 (2%) 

Rathke’s cleft, cyst 1 (2%) 

Rathke’s cleft, hemorrhage 1 (2%) 

Thyroid gland (50) (50) (50) (50) 

Infiltration cellular, lymphocyte 1 (2%) 

Inflammation, chronic active 1 (2%) 

Follicle, cyst 1 (2%) 2 (4%) 

Follicular cell, hyperplasia 23 (46%) 20 (40%) 18 (36%) 24 (48%) 

General Body System 

None 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

216 Triethanolamine, NTP TR 449 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Genital System 

Clitoral gland (49) (48) (47) (48) 

Inflammation, chronic 1 (2%) 

Duct, ectasia 3 (6%) 1 (2%) 2 (4%) 3 (6%) 

Ovary (50) (50) (50) (50) 

Atrophy 34 (68%) 37 (74%) 34 (68%) 29 (58%) 

Cyst 1 (2%) 

Thrombosis 1 (2%) 2 (4%) 1 (2%) 

Follicle, cyst 13 (26%) 17 (34%) 16 (32%) 14 (28%) 

Periovarian tissue, cyst 1 (2%) 1 (2%) 

Periovarian tissue, infiltration cellular,

 lymphocyte 1 (2%) 

Periovarian tissue, inflammation, chronic

 active 1 (2%) 

Uterus (50) (50) (50) (50) 

Hemorrhage 1 (2%) 

Infiltration cellular, lymphocyte 1 (2%) 

Inflammation, chronic 1 (2%) 

Endometrium, hyperplasia, cystic, glandular 47 (94%) 48 (96%) 47 (94%) 44 (88%) 

Lymphatic, ectasia 1 (2%) 

Hematopoietic System 

Bone marrow (50) (50) (50) (50) 

Myelofibrosis 6 (12%) 15 (30%) 4 (8%) 6 (12%) 

Myeloid cell, atrophy 1 (2%) 

Lymph node (4) (8) (6) (9) 

Mediastinal, hyperplasia, lymphoid 1 (25%) 1 (17%) 

Lymph node, mandibular (47) (49) (49) (49) 

Hyperplasia, lymphoid 1 (2%) 2 (4%) 1 (2%) 

Lymph node, mesenteric (46) (49) (48) (49) 

Hematopoietic cell proliferation 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 

Spleen (50) (50) (50) (50) 

Hematopoietic cell proliferation 3 (6%) 9 (18%) 3 (6%) 6 (12%) 

Hyperplasia, lymphoid 5 (10%) 4 (8%) 

Necrosis 1 (2%) 

Thymus (46) (47) (49) (48) 

Atrophy 19 (41%) 28 (60%) 28 (57%) 22 (46%) 

Cyst 1 (2%) 

Hyperplasia, lymphoid 1 (2%) 1 (2%) 

Integumentary System 

Mammary gland (48) (48) (50) (47) 

Hyperplasia, glandular 1 (2%) 

Skin (50) (50) (50) (50) 

Acanthosis 1 (2%) 

Inguinal, inflammation, chronic 1 (2%) 

Site of application-no mass, acanthosis 2 (4%) 1 (2%) 3 (6%) 

Site of application-no mass, inflammation,

 chronic 2 (4%) 2 (4%) 5 (10%) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 217 

TABLE D5 

Summary of the Incidence of Nonneoplastic Lesions in Female Mice in the 2-Year Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

2-Year Study (continued) 

Musculoskeletal System 

Bone (50) (50) (50) (50) 

Vertebra, coccygeal, fracture 1 (2%) 

Nervous System 

Brain (50) (50) (50) (50) 

Compression 3 (6%) 3 (6%) 1 (2%) 1 (2%) 

Hemorrhage 2 (4%) 

Medulla, hemorrhage 1 (2%) 

Peripheral nerve (2) (1) (1) 

Sciatic, degeneration 1 (100%) 

Spinal cord (2) (1) (1) 

Nerve, degeneration 1 (50%) 1 (100%) 1 (100%) 

White matter, degeneration 1 (100%) 

Respiratory System 

Lung (50) (50) (50) (49) 

Hemorrhage, focal 1 (2%) 

Inflammation, chronic active 1 (2%) 1 (2%) 

Mineralization, focal 1 (2%) 

Alveolar epithelium, hyperplasia 1 (2%) 1 (2%) 

Alveolar epithelium, hyperplasia, macrophage 1 (2%) 

Pleura, hyperplasia 1 (2%) 

Special Senses System 

Ear (1) (1) (1) 

Internal ear, hyperplasia, glandular 1 (100%) 

Harderian gland (1) (2) (1) 

Acinus, hyperplasia 1 (50%) 

Urinary System 

Kidney (50) (50) (50) (50) 

Amyloid deposition 1 (2%) 

Inflammation, chronic active 1 (2%) 

Nephropathy, chronic 16 (32%) 27 (54%) 28 (56%) 21 (42%) 

Cortex, cyst 1 (2%) 

Cortex, infarct 3 (6%) 2 (4%) 

Pelvis, inflammation, acute 1 (2%) 

Renal tubule, hyperplasia, cystic 1 (2%) 

Renal tubule, necrosis 1 (2%) 

Urinary bladder (50) (50) (50) (50) 

Inflammation, chronic active 1 (2%) 1 (2%) 
218 Triethanolamine, NTP TR 449 
219 

APPENDIX E 

GENETIC TOXICOLOGY 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL ............................. 220 

CHINESE HAMSTER OVARY CELL CYTOGENETICS PROTOCOLS ............................ 220 

DROSOPHILA MELANOGASTER TEST PROTOCOL ....................................... 221 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOL ............................ 222 

EVALUATION PROTOCOL ..................................................... 222 

RESULTS ................................................................ 223 

TABLE E1 Mutagenicity of Triethanolamine in Salmonella typhimurium .................... 224 

TABLE E2 Induction of Sister Chromatid Exchanges in Chinese Hamster Ovary Cells 

by Triethanolamine ................................................ 225 

TABLE E3 Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells 

by Triethanolamine ................................................ 226 

TABLE E4 Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster 

by Triethanolamine ................................................ 226 

TABLE E5 Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice 

Following Treatment with Triethanolamine by Dermal Application for 13 Weeks ...... 227 
 

220 Triethanolamine, NTP TR 449 

GENETIC TOXICOLOGY 

SALMONELLA TYPHIMURIUM MUTAGENICITY TEST PROTOCOL 

Testing was performed as reported by Mortelmans et al. (1986). Triethanolamine was sent to the laboratory 

as a coded aliquot from Radian Corporation (Austin, TX). It was incubated with the Salmonella 

typhimurium tester strains TA98, TA100, TA1535, and TA1537 either in buffer or S9 mix (metabolic 

activation enzymes and cofactors from Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster 

liver) for 20 minutes at 37E C. Top agar supplemented with L-histidine and d-biotin was added, and the 

contents of the tubes were mixed and poured onto the surfaces of minimal glucose agar plates. Histidineindependent mutant colonies arising on these plates were counted following incubation for 2 days at 37E C. 

Each trial consisted of triplicate plates of concurrent positive and negative controls and five doses of 

triethanolamine. The high dose was limited by toxicity. All trials were repeated. 

In this assay, a positive response is defined as a reproducible, dose-related increase in histidine-independent 

(revertant) colonies in any one strain/activation combination. An equivocal response is defined as an 

increase in revertants that is not dose related, 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. 

CHINESE HAMSTER OVARY CELL CYTOGENETICS PROTOCOLS 

Testing was performed as reported by Galloway et al. (1987). Triethanolamine was sent to the laboratory 

as a coded aliquot by Radian Corporation. It was tested in cultured Chinese hamster ovary (CHO) cells for 

induction of sister chromatid exchanges (SCEs) and chromosomal aberrations (Abs), both in the presence 

and absence of Aroclor 1254-induced male Sprague-Dawley rat liver S9 and cofactor mix. Cultures were 

handled under gold lights to prevent photolysis of bromodeoxyuridine-substituted DNA. Each test consisted 

of concurrent solvent and positive controls and of at least three doses of triethanolamine. In the trials 

conducted without S9, the high dose was limited by toxicity; in the trials with S9, the high dose was limited 

to 10,100 μg/mL. A single flask per dose was used, and tests yielding equivocal or positive results were 

repeated. 

Sister Chromatid Exchange Test: In the SCE test without S9, CHO cells were incubated for up to 26 hours 

with triethanolamine in supplemented McCoy’s 5A medium. Bromodeoxyuridine (BrdU) was added 

2 hours after culture initiation. After 26 hours, the medium containing triethanolamine was removed and 

replaced with fresh medium plus BrdU and Colcemid, and incubation was continued for up to 2 hours. 

Cells were then harvested by mitotic shake-off, fixed, and stained with Hoechst 33258 and Giemsa. In the 

SCE test with S9, cells were incubated with triethanolamine, serum-free medium, and S9 for 2 hours. The 

medium was then removed and replaced with medium containing serum and BrdU and no triethanolamine 

and incubation proceeded for an additional 25.8 hours, with Colcemid present for the final 2 hours. 

Harvesting and staining were the same as for cells treated without S9. All slides were scored blind and 

those from a single test were read by the same person. Fifty second-division metaphase cells were scored 

for frequency of SCEs/cell from each dose level. 

Statistical analyses were conducted on the slopes of the dose-response curves and the individual dose points 

(Galloway et al., 1987). An SCE frequency 20% above the concurrent solvent control value was chosen as 

a statistically conservative positive response. The probability of this level of difference occurring by chance 

at one dose point is less than 0.01; the probability for such a chance occurrence at two dose points is less 

than 0.001. An increase of 20% or greater at any single dose was considered weak evidence of activity; 
 

Triethanolamine, NTP TR 449 221 

increases at two or more doses resulted in a determination that the trial was positive. A statistically 

significant trend (P<0.005) in the absence of any responses reaching 20% above background led to a call 

of equivocal. 

Chromosomal Aberrations Test: In the Abs test without S9, cells were incubated in McCoy’s 5A medium 

with triethanolamine for 8.5 hours; Colcemid was added, and incubation continued for 2 hours. The cells 

were then harvested by mitotic shake-off, fixed, and stained with Giemsa. For the Abs test with S9, cells 

were treated with triethanolamine and S9 for 2 hours, after which the treatment medium was removed and 

the cells were incubated for 8.5 hours in fresh medium, with Colcemid present for the final 2 hours. Cells 

were harvested in the same manner as for the treatment without S9. 

Cells were selected for scoring on the basis of good morphology and completeness of karyotype 

(21 ± 2 chromosomes). All slides were scored blind and those from a single test were read by the same 

person. One hundred first-division metaphase cells were scored at each dose level. Classes of aberrations 

included simple (breaks and terminal deletions), complex (rearrangements and translocations), and other 

(pulverized cells, despiralized chromosomes, and cells containing 10 or more aberrations). 

Chromosomal aberration data are presented as percentage of cells with aberrations. To arrive at a statistical 

call for a trial, analyses were conducted on both the dose response curve and individual dose points. For a 

single trial, a statistically significant (P#0.05) difference for one dose point and a significant trend 

(P#0.015) were considered weak evidence for a positive response; significant differences for two or more 

doses indicated the trial was positive. A positive trend test in the absence of a statistically significant 

increase at any one dose resulted in an equivocal call (Galloway et al., 1987). Ultimately, the trial calls 

were based on a consideration of the statistical analyses as well as the biological information available to the 

reviewers. 

DROSOPHILA MELANOGASTER TEST PROTOCOL 

The assays for induction of sex-linked recessive lethal (SLRL) mutations were performed with adult flies as 

described by Yoon et al. (1985). Triethanolamine was supplied as a coded aliquot by Radian Corporation. 

It was assayed in the SLRL test by feeding for 3 days to adult Canton-S wild-type males no more than 

24 hours old at the beginning of treatment. Because no response was obtained, triethanolamine was retested 

by injection into adult males. Three dose levels were tested to ensure adequate testing of the chemical. 

To administer a chemical by injection, a glass Pasteur pipette was drawn out in a flame to a microfine 

filament, and the tip was broken off to allow delivery of the test solution. Injection was performed either 

manually, by attaching a rubber bulb to the other end of the pipette and forcing through sufficient solution 

(0.2 to 0.3 μL) to slightly distend the abdomen of the fly, or by attaching the pipette to a microinjector 

which automatically delivered a calibrated volume. Flies were anesthetized with ether and immobilized on a 

strip of tape. Injection into the thorax, under the wing, was performed with the aid of a dissecting 

microscope. 

Toxicity tests were performed to set concentrations of triethanolamine at a level that would induce 30% 

mortality after 72 hours of feeding or 24 hours after injection, while keeping induced sterility at an 

acceptable level. Oral exposure was achieved by allowing Canton-S males to feed for 72 hours on a 

solution of triethanolamine in 5% sucrose. In the injection experiments, 24- to 72-hour-old Canton-S males 

were treated with a solution of triethanolamine dissolved in saline or peanut oil and allowed to recover for 

24 hours. A concurrent saline or peanut oil control group was also included. In the adult exposures, 

treated males were mated to three Basc females for 3 days and given fresh females at 2-day intervals to 

produce three matings of 3, 2, and 2 days (in each case, sample sperm from successive matings were treated 

at successively earlier post-meiotic stages). F1 heterozygous females were mated with their siblings and
222 Triethanolamine, NTP TR 449 

then placed in individual vials. F1 daughters from the same parental male were kept together to identify

clusters. (A cluster occurs when a number of mutants from a given male result from a single spontaneous 

premeiotic mutation event and is identified when the number of mutants from that male exceeds the number 

predicted by a Poisson distribution.) If a cluster was identified, all data from the male in question were 

discarded. Clusters were identified in four dose groups in this series of experiments. These are noted in 

Table E4. Presumptive lethal mutations were identified as vials containing fewer than 5% of the expected 

number of wild-type males after 17 days; these were retested to confirm the response. 

SLRL data were analyzed by simultaneous comparison with the concurrent and historical controls, using a 

normal approximation to the binomial test (Margolin et al., 1983). A test result was considered positive if 

the P value was less than or equal to 0.01 and the mutation frequency in the tested group is greater than 

0.10%, or if the P value was less than or equal to 0.05 and the frequency in the treatment group was greater 

than 0.15%. A test was considered to be inconclusive if (a) the P value was between 0.05 and 0.01 but the 

frequency in the treatment group was between 0.10% and 0.15% or (b) the P value was between 0.10 and 

0.05 but the frequency in the treatment group was greater than 0.10%. A test was considered negative if 

the P value was greater than or equal to 0.10 or if the frequency in the treatment group was less than 

0.10%. 

MOUSE PERIPHERAL BLOOD MICRONUCLEUS TEST PROTOCOL 

A detailed discussion of this assay is presented by MacGregor et al. (1990). Peripheral blood samples were 

obtained from male and female B6C3F mice at the end of the 13-week toxicity study. Smears were 1 

immediately prepared and fixed in absolute methanol and were later stained with a chromatin-specific 

fluorescent dye mixture of Hoechst 33258/pyronin Y (MacGregor et al., 1983) and coded. Slides were 

scanned to determine the frequency of micronuclei in 2,000 polychromatic erythrocytes (PCEs) and 

10,000 normochromatic erythrocytes (NCEs) in each animal per dose group. 

Log transformation of the NCE data, testing for normality by the Shapiro-Wilk test, and testing for 

heterogeneity of variance by Cochran’s test were performed before statistical analyses. The frequency of 

micronucleated cells among NCEs was analyzed by analysis of variance using the SAS GLM procedure. 

The NCE data for each dose group were compared with the concurrent solvent control with a Student’s 

t-test. The frequency of micronucleated cells among PCEs was analyzed by the Cochran-Armitage trend 

test, and individual dose groups were compared to the concurrent solvent control by Kastenbaum-Bowman’s 

binomial test. 

EVALUATION PROTOCOL 

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, in which multiple aliquots of a chemical were tested in the same assay, and differing 

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. 
Triethanolamine, NTP TR 449 223 

RESULTS 

Triethanolamine (33 to 3,333 μg/plate) was negative for induction of mutations in S. typhimurium strains 

TA98, TA100, TA1535, and TA1537 when tested with or without S9 metabolic activation (Table E1; 

Mortelmans et al., 1986). In cytogenetic tests with cultured CHO cells, no induction of SCEs (Table E2) or 

Abs (Table E3) was observed with or without S9 (Galloway et al., 1987). In the SCE test without S9, the 

first of two trials was negative. In the second trial, a significant increase in SCEs was observed at the 

highest dose tested (2,520 μg/mL), but the trend test was negative (P$0.025), and the trial was concluded to 

be equivocal. Severe cytotoxicity limited the number of cells that could be scored at this high dose. 

Overall, the SCE test was considered to be negative. Cytotoxicity was also noted at the highest dose tested 

(4,030 μg/mL) in the Abs test without S9. 

Triethanolamine administered by feeding or injection at doses up to 30,000 ppm did not induce SLRL 

mutations in germ cells of male D. melanogaster (Table E4; Yoon et al., 1985). Results of an in vivo 

peripheral blood micronucleus test in mice were also negative (Table E5). In this test, blood samples were 

obtained from male and female mice after 13 weeks of dermal applications of 1,000 to 4,000 mg/kg 

triethanolamine. No significant increases in the frequencies of micronucleated NCEs or PCEs were 

observed at any dose tested. 
224 Triethanolamine, NTP TR 449 

TABLE E1 

Mutagenicity of Triethanolamine in Salmonella typhimuriuma 

Revertants/Plateb 

Strain Dose -S9 +10% hamster S9 +10% rat S9 

(μg/plate) Trial 1 Trial 2 Trial 1 Trial 2 Trial 1 Trial 2 

TA100 0 

33 

100 

333 

1,000 

3,333 

89 ± 2.6 

96 ± 8.5 

87 ± 3.1 

74 ± 12.7 

73 ± 3.2 

74 ± 4.8 

104 ± 11.8 

112 ± 6.1 

98 ± 2.2 

93 ± 5.2 

106 ± 10.6 

96 ± 5.3 

192 ± 13.5 

180 ± 7.9 

215 ± 26.7 

188 ± 10.0 

145 ± 5.2 

155 ± 3.8 

163 ± 14.8 

145 ± 4.2 

162 ± 11.0 

154 ± 4.6 

148 ± 13.6 

137 ± 2.6 

159 ± 15.2 

162 ± 9.9 

151 ± 6.1 

165 ± 3.7 

152 ± 6.1 

153 ± 14.2 

164 ± 8.4 

143 ± 14.5 

157 ± 4.4 

147 ± 12.2 

149 ± 5.4 

122 ± 20.8 

Trial summary 

Positive controlc Negative 

359 ± 21.0 

Negative 

425 ± 29.6 

Negative 

668 ± 41.6 

Negative 

935 ± 188.8 

Negative 

299 ± 30.2 

Negative 

293 ± 1.2 

TA1535 0 

33 

100 

333 

1,000 

3,333 

7 ± 

5 ± 

5 ± 

10 ± 

7 ± 

7 ± 

0.9 

1.7 

2.1 

1.5 

0.9 

0.6 

4 ± 

2 ± 

3 ± 

3 ± 

3 ± 

4 ± 

1.3 

0.3 

0.3 

1.5 

0.7 

0.6 

9 ± 

9 ± 

6 ± 

6 ± 

7 ± 

8 ± 

1.5 

0.9 

0.9 

1.8 

1.8 

1.8 

6 ± 

4 ± 

2 ± 

4 ± 

6 ± 

3 ± 

1.5 

1.2 

1.2 

0.0 

0.7 

1.5 

11 ± 

8 ± 

8 ± 

9 ± 

9 ± 

8 ± 

1.9 

2.2 

2.3 

1.5 

1.9 

2.1 

7 ± 

3 ± 

4 ± 

7 ± 

4 ± 

5 ± 

2.0 

1.2 

1.0 

2.1 

1.2 

1.5 

Trial summary 

Positive control 

Negative 

193 ± 19.5 

Negative 

291 ± 39.0 

Negative 

61 ± 11.8 

Negative 

47 ± 7.7 

Negative 

71 ± 4.6 

Negative 

19 ± 2.0 

TA1537 0 

33 

100 

333 

1,000 

3,333 

9 ± 

6 ± 

7 ± 

7 ± 

9 ± 

3 ± 

2.4 

2.2 

1.2 

1.2 

0.9 

0.3 

6 ± 

5 ± 

6 ± 

6 ± 

6 ± 

5 ± 

1.5 

0.7 

0.6 

1.3 

0.9 

2.7 

8 ± 

10 ± 

10 ± 

8 ± 

7 ± 

9 ± 

1.5 

1.3 

3.0 

3.5 

2.4 

1.8 

9 ± 

9 ± 

10 ± 

8 ± 

7 ± 

8 ± 

0.3 

2.5 

1.0 

1.3 

1.0 

1.5 

8 ± 

11 ± 

8 ± 

12 ± 

7 ± 

9 ± 

2.0 

1.8 

1.2 

2.5 

0.9 

1.5 

5 ± 

5 ± 

4 ± 

5 ± 

6 ± 

8 ± 

1.8 

1.2 

1.2 

1.7 

0.9 

1.9 

Trial summary 

Positive control 

Negative 

300 ± 35.1 

Negative 

198 ± 22.5 

Negative 

37 ± 10.7 

Negative 

44 ± 3.2 

Negative 

35 ± 5.8 

Negative 

19 ± 1.2 

TA98 0 

33 

100 

333 

1,000 

3,333 

18 ± 

13 ± 

14 ± 

15 ± 

9 ± 

14 ± 

2.3 

1.7 

2.3 

1.5 

1.5 

1.9 

15 ± 

12 ± 

11 ± 

12 ± 

12 ± 

12 ± 

2.0 

2.6 

0.7 

0.9 

2.2 

1.2 

23 ± 

18 ± 

31 ± 

23 ± 

25 ± 

17 ± 

2.7 

1.0 

9.4 

4.4 

2.0 

3.5 

18 ± 

15 ± 

18 ± 

17 ± 

19 ± 

13 ± 

2.9 

1.3 

3.1 

0.3 

0.6 

0.9 

23 ± 

20 ± 

27 ± 

17 ± 

18 ± 

16 ± 

1.0 

3.7 

1.7 

1.7 

3.4 

0.7 

19 ± 

15 ± 

18 ± 

13 ± 

15 ± 

11 ± 

2.1 

1.5 

3.5 

2.6 

0.9 

0.9 

Trial summary 

Positive control 

Negative 

261 ± 25.1 

Negative 

245 ± 30.7 

Negative 

330 ± 15.5 

Negative 

420 ± 7.1 

Negative 

94 ± 2.5 

Negative 

166 ± 1.2 

a The study was performed at Case Western Reserve University. The detailed protocol and these data are presented by Mortelmans et al. 

(1986). b	 Revertants are presented as mean ± standard error from three plates. 

The positive controls in the absence of metabolic activation were sodium azide (TA100 and TA1535), 9-aminoacridine (TA1537), and 

4-nitro-o-phenylenediamine (TA98). The positive control for metabolic activation with all strains was 2-aminoanthracene. 

c 
 

Triethanolamine, NTP TR 449 225 

TABLE E2 

Induction of Sister Chromatid Exchanges in Chinese Hamster Ovary Cells by Triethanolaminea 

Total No. of SCEs/ Relative 

Dose Cells Chromo- No. of Chromo- SCEs/ Hrs Change of SCEs/ 

Compound (μg/mL) Scored somes SCEs some Cell in BrdU Chromosomeb 

(%) 

-S9 

Trial 1 

Summary: Negative 

c Medium 50 1,047 398 0.38 8.0 25.8 

Mitomycin-Cd 0 50 1,049 1,887 1.79 37.7 25.8 373.22 

Triethanolamine 100 50 1,050 443 0.42 8.9 25.8 10.99 

330 50 1,050 417 0.39 8.3 25.8 4.47 

1,010 50 1,048 387 0.36 7.7 25.8 -2.86 

P=0.745e 

Trial 2 

Summary: Equivocal 

Medium 50 1,043 435 0.41 8.7 25.5 

Mitomycin-C 0.005 50 1,036 1,648 1.59 33.0 25.5 281.42 

Triethanolamine 630 50 1,041 447 0.42 8.9 25.5 2.96 

1,260 50 1,043 438 0.41 8.8 25.5 0.69 

2,520 8 163 84 0.51 10.5 28.0 23.56* 

P=0.174 

+S9 

Summary: Negative 

Medium 50 1,034 426 0.41 8.5 25.8 

Cyclophosphamided 1.5 50 1,039 1,389 1.33 27.8 25.8 224.49 

Triethanolamine 330 50 1,031 446 0.43 8.9 25.8 5.00 

1,010 50 1,045 453 0.43 9.1 25.8 5.22 

10,100 50 1,039 463 0.44 9.3 25.8 8.16 

P=0.130 

* Positive response ($20% increase over solvent control) a The study was performed at Litton Bionetics, Inc. A detailed description of the protocol and these data are presented by Galloway et al. 

(1987). SCE=sister chromatid exchange; BrdU=bromodeoxyuridine b SCEs/chromosome in treated cells versus SCEs/chromosome in solvent control cells 

Solvent control 

d Positive control e Significance of SCEs/chromosome tested by the linear regression trend test versus log of the dose 

c 
226 

c 

Triethanolamine, NTP TR 449 

TABLE E3 

Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells by Triethanolaminea 

-S9 +S9 

Dose Total No. of Abs/ Cells with Dose Total No. of Abs/ Cells with 

(μg/mL) Cells Abs Cell Abs (%) (μg/mL) Cells Abs Cell Abs (%) 

Scored Scored 

Harvest time: 10.5 hours 

Summary: Negative 

Harvest time: 10.5 hours 

Summary: Negative 

Dimethylsulfoxideb 

100 7 0.07 5.0 

Dimethylsulfoxide 

100 2 0.02 2.0 

Mitomycin-Cc 

0.5 100 24 0.24 20.0 

Cyclophosphamidec 

25 100 32 0.32 26.0 

Triethanolamine 

1,510 

2,010 

4,030 

100 

100 

56 

2 

1 

0 

0.02 

0.01 

0.00 

2.0 

1.0 

1.0 

Triethanolamine 

6,040 

8,060 

10,070 

100 

100 

100 

3 

6 

2 

0.03 

0.06 

0.02 

3.0 

5.0 

2.0 

P=0.985d P=0.373 

a The study was performed at Litton Bionetics, Inc. The detailed protocol and these data are presented by Galloway et al. (1987). 

Abs=aberrations 

b Solvent control 

Positive control 

d Significance of percent cells with aberrations tested by the linear regression trend test versus log of the dose 

TABLE E4 

Induction of Sex-Linked Recessive Lethal Mutations in Drosophila melanogaster 

by Triethanolaminea 

Route of 

Exposure 

Dose 

(ppm) 

Incidence of 

Death (%) 

Incidence of 

Sterility (%) 

No. of Lethals/No. of X Chromosomes Tested 

Mating 1 Mating 2 Mating 3 Totalb 

Injection 10,000 12 0 0/1,016 0/1,185 2/1,000 2/3,201 (0.06%) 

0c 0/1,024 0/1,179 0/981 0/3,184 (0.00%) 

Feeding 20,000c 2 3 0/1,011 1/1,262 1/570 2/2,843 (0.07%) 

0c 1/909 2/1,467 1/735 4/3,111 (0.13%) 

Injection 20,000 8 0 0/524 0/1,127 1/984 1/2,635 (0.04%) 

0 0/374 0/1,268 2/871 2/2,513 (0.08%) 

Feeding 30,000 48 20 0/1,190 1/1,924 0/739 1/3,853 (0.03%) 

0c 2/2,091 2/2,509 2/1,989 6/6,589 (0.09%) 

Injection 30,000 56 30 1/247 0/113 1/108 2/468 (0.43%) 

0 1/864 2/1,078 1/1,091 4/3,033 (0.13%) 

a The study was performed at Brown University. A detailed protocol of the sex-linked recessive lethal assay is presented by Yoon et al. 

(1985). Results were not significant at the 5% level (Margolin et al., 1983). b Combined total number of lethal mutations/number of X chromosomes tested for three mating trials 

Data were corrected for the occurrence of spontaneous clusters. c 
227 

c 

Triethanolamine, NTP TR 449 

TABLE E5 

Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice Following Treatment 

with Triethanolamine by Dermal Application for 13 Weeksa 

Dose Micronucleated Cells/1,000 Cellsb Number of 

(mg/kg) PCEs NCEs Mice 

Male 

0 2.13 ± 0.40 1.75 ± 0.20 10 

1,000 1.04 ± 0.36 1.88 ± 0.17 10 

2,000 2.41 ± 0.40 1.36 ± 0.10 10 

4,000 2.00 ± 0.48 1.90 ± 0.30 10 

Trend test P=0.337c P=0.785c 

Female 

0 2.06 ± 0.35 1.16 ± 0.12 10 

1,000 1.60 ± 0.34 1.20 ± 0.08 10 

2,000 2.38 ± 0.43 1.08 ± 0.12 10 

4,000 2.12 ± 0.39 0.99 ± 0.11 10 

Trend test P=0.355 P=0.145 

a The detailed protocol is presented by MacGregor et al. (1990); 10,000 NCEs (normochromatic erythrocytes) and 2,000 PCEs (polychromatic 

erythrocytes) were scored per animal. b Data are presented as mean ± standard error. 

Cochran-Armitage trend test for PCEs and analysis of variance by the SAS GLM procedure for NCEs 
228 Triethanolamine, NTP TR 449 
229 

APPENDIX F 

ORGAN WEIGHTS 

AND ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS 

TABLE F1 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats 

in the 13-Week Dermal Study of Triethanolamine ........................... 230 

TABLE F2 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats 

at the 15-Month Interim Evaluation in the 2-Year Dermal Study 

of Triethanolamine ................................................ 232 

TABLE F3 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice 

in the 13-Week Dermal Study of Triethanolamine ........................... 233 

TABLE F4 Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice 

at the 15-Month Interim Evaluation in the 2-Year Dermal Study 

of Triethanolamine ................................................ 235 
230 Triethanolamine, NTP TR 449 

TABLE F1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

Male 

n 10 10 10 10 10 10 

Necropsy body wt 299 ± 6 284 ± 7 286 ± 6 287 ± 7 295 ± 11 248 ± 11** 

Brain 

Absolute 1.911 ± 0.021 1.867 ± 0.021 1.868 ± 0.019 1.900 ± 0.011 1.919 ± 0.018 1.880 ± 0.030 

Relative 6.41 ± 0.11 6.60 ± 0.15 6.55 ± 0.12 6.65 ± 0.18 6.58 ± 0.19 7.74 ± 0.39** 

L. Epididymis 

Absolute 0.443 ± 0.008 0.438 ± 0.011 0.442 ± 0.007 0.453 ± 0.010 0.449 ± 0.012 0.411 ± 0.014 

Relative 1.49 ± 0.03 1.55 ± 0.05 1.55 ± 0.04 1.59 ± 0.06 1.53 ± 0.04 1.68 ± 0.08 

Heart 

Absolute 0.993 ± 0.030 0.907 ± 0.017 0.961 ± 0.037 0.953 ± 0.023 0.983 ± 0.032 0.898 ± 0.022 

Relative 3.32 ± 0.06 3.20 ± 0.07 3.36 ± 0.09 3.33 ± 0.08 3.35 ± 0.10 3.68 ± 0.17 

R. Kidney 

Absolute 1.187 ± 0.025 1.134 ± 0.026 1.188 ± 0.031 1.264 ± 0.028 1.366 ± 0.039** 1.366 ± 0.051** 

Relative 3.97 ± 0.05 4.00 ± 0.06 4.16 ± 0.06 4.41 ± 0.06* 4.65 ± 0.09** 5.58 ± 0.24** 

Liver 

Absolute 13.949 ± 0.446 12.404 ± 0.443 13.418 ± 0.693 15.174 ± 0.382 15.516 ± 0.421 12.517 ± 0.405 

Relative 46.58 ± 0.86 43.68 ± 1.14 46.73 ± 1.61 53.12 ± 1.90* 52.92 ± 1.05* 51.18 ± 2.14* 

Lung 

Absolute 1.870 ± 0.054 1.740 ± 0.062 1.761 ± 0.083 1.674 ± 0.037 1.817 ± 0.060 1.569 ± 0.039** 

Relative 6.28 ± 0.23 6.15 ± 0.25 6.15 ± 0.25 5.88 ± 0.25 6.18 ± 0.08 6.49 ± 0.41 

Spleen 

Absolute 0.666 ± 0.016 0.646 ± 0.013 0.626 ± 0.009 0.666 ± 0.013 0.690 ± 0.028 0.612 ± 0.024 

Relative 2.23 ± 0.03 2.28 ± 0.05 2.19 ± 0.04 2.33 ± 0.05 2.34 ± 0.03 2.50 ± 0.11** 

L. Testis 

Absolute 1.409 ± 0.028 1.362 ± 0.026 1.349 ± 0.019 1.369 ± 0.013 1.394 ± 0.033 1.372 ± 0.032 

Relative 4.71 ± 0.06 4.82 ± 0.13 4.73 ± 0.09 4.79 ± 0.10 4.76 ± 0.09 5.61 ± 0.22** 

Thymus 

Absolute 0.326 ± 0.015 0.298 ± 0.010 0.318 ± 0.013 0.330 ± 0.014b 0.338 ± 0.020 0.256 ± 0.017** 

Relative 1.09 ± 0.04 1.06 ± 0.05 1.12 ± 0.05 1.13 ± 0.05b 1.14 ± 0.04 1.03 ± 0.04 
Triethanolamine, NTP TR 449 231 

TABLE F1 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

Female 

n 10 10 10 10 10 10 

Necropsy body wt 174 ± 4 170 ± 4 174 ± 4 174 ± 3 170 ± 3 158 ± 4** 

Brain 

Absolute 1.748 ± 0.020 1.712 ± 0.023 1.754 ± 0.014 1.759 ± 0.024 1.761 ± 0.022 1.770 ± 0.013 

Relative 10.14 ± 0.35 10.17 ± 0.33 10.14 ± 0.23 10.11 ± 0.12 10.35 ± 0.14 11.27 ± 0.19** 

Heart 

Absolute 0.649 ± 0.016 0.659 ± 0.014 0.661 ± 0.015 0.652 ± 0.016b 0.673 ± 0.022 0.619 ± 0.011 

Relative 3.76 ± 0.12 3.91 ± 0.13 3.81 ± 0.06 3.75 ± 0.08b 3.95 ± 0.11 3.95 ± 0.10 

R. Kidney 

Absolute 0.744 ± 0.017 0.745 ± 0.017 0.758 ± 0.019 0.810 ± 0.015* 0.847 ± 0.019** 0.891 ± 0.019** 

Relative 4.31 ± 0.14 4.41 ± 0.11 4.37 ± 0.08 4.66 ± 0.08* 4.98 ± 0.12** 5.67 ± 0.15** 

Liver 

Absolute 6.982 ± 0.290 6.860 ± 0.188 7.154 ± 0.222 7.340 ± 0.289 7.483 ± 0.342 7.067 ± 0.272 

Relative 40.28 ± 1.52 40.52 ± 0.71 41.15 ± 0.68 42.10 ± 1.37 43.88 ± 1.76 44.96 ± 1.64* 

Lung 

Absolute 1.199 ± 0.032 1.283 ± 0.023 1.357 ± 0.072 1.253 ± 0.055 1.261 ± 0.037 1.146 ± 0.039 

Relative 6.94 ± 0.23 7.60 ± 0.20 7.82 ± 0.37 7.18 ± 0.23 7.40 ± 0.17 7.31 ± 0.30 

Spleen 

Absolute 0.468 ± 0.010 0.461 ± 0.010 0.462 ± 0.009 0.456 ± 0.011 0.461 ± 0.013 0.427 ± 0.009* 

Relative 2.71 ± 0.08 2.73 ± 0.08 2.67 ± 0.03 2.62 ± 0.04 2.71 ± 0.09 2.72 ± 0.07 

Thymus 

Absolute 0.261 ± 0.013 0.269 ± 0.011 0.279 ± 0.022 0.268 ± 0.010 0.275 ± 0.019 0.250 ± 0.009 

Relative 1.51 ± 0.08 1.59 ± 0.07 1.60 ± 0.11 1.54 ± 0.06 1.61 ± 0.09 1.59 ± 0.06 

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

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/ 

g body weight (mean ± standard error). b n=9 
232 Triethanolamine, NTP TR 449 

TABLE F2 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Rats at the 15-Month Interim Evaluation 

in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 32 mg/kg 63 mg/kg 125 mg/kg 

n 10 10 10 10 

Male 

Necropsy body wt 423 ± 13 440 ± 8 429 ± 13 408 ± 13 

L. Kidney 

Absolute 1.652 ± 0.044 1.726 ± 0.035 1.690 ± 0.047 1.619 ± 0.047 

Relative 3.92 ± 0.09 3.93 ± 0.06 3.95 ± 0.08 3.97 ± 0.06 

R. Kidney 

Absolute 1.627 ± 0.030 1.717 ± 0.045 1.680 ± 0.057 1.574 ± 0.046 

Relative 3.86 ± 0.07 3.90 ± 0.08 3.92 ± 0.08 3.86 ± 0.05 

Liver 

Absolute 17.991 ± 0.709 18.037 ± 0.687 17.809 ± 0.609 16.669 ± 0.695 

Relative 42.92 ± 2.43 40.90 ± 1.03 41.55 ± 0.75 40.82 ± 1.01 

0 mg/kg 63 mg/kg 125 mg/kg 250 mg/kg 

Female 

Necropsy body wt 242 ± 6 260 ± 6 245 ± 9 255 ± 6 

L. Kidney 

Absolute 1.008 ± 0.017 1.058 ± 0.018 1.064 ± 0.034 1.133 ± 0.020** 

Relative 4.18 ± 0.12 4.09 ± 0.10 4.36 ± 0.09 4.46 ± 0.09 

R. Kidney 

Absolute 0.982 ± 0.021 1.026 ± 0.016 1.031 ± 0.027 1.113 ± 0.022** 

Relative 4.06 ± 0.10 3.96 ± 0.06 4.23 ± 0.08 4.38 ± 0.10* 

Liver 

Absolute 9.735 ± 0.189 10.217 ± 0.213 9.952 ± 0.300 10.393 ± 0.228 

Relative 40.22 ± 0.41 39.42 ± 0.48 40.77 ± 0.79 40.85 ± 0.72 

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

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/ 

g body weight (mean ± standard error). 
Triethanolamine, NTP TR 449 233 

TABLE F3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Male 

n 10 10 10 10 10 10 

Necropsy body wt 34.2 ± 0.7 30.9 ± 0.7** 32.1 ± 0.7 32.5 ± 0.7 32.0 ± 0.8 32.0 ± 0.6 

Brain 

Absolute 0.455 ± 0.007 0.446 ± 0.003 0.448 ± 0.006 0.449 ± 0.004 0.446 ± 0.009 0.458 ± 0.005 

Relative 13.37 ± 0.35 14.49 ± 0.30 14.03 ± 0.29 13.90 ± 0.28 14.02 ± 0.45 14.35 ± 0.30 

L. Epididymis 

Absolute 0.052 ± 0.002 0.054 ± 0.003 0.055 ± 0.003 0.053 ± 0.003 0.053 ± 0.002 0.051 ± 0.002 

Relative 1.52 ± 0.06 1.75 ± 0.12 1.71 ± 0.08 1.62 ± 0.07 1.67 ± 0.07 1.61 ± 0.07 

Heart 

Absolute 0.171 ± 0.007 0.158 ± 0.003 0.158 ± 0.005 0.168 ± 0.004 0.176 ± 0.004 0.186 ± 0.008 

Relative 5.01 ± 0.19 5.13 ± 0.11 4.97 ± 0.21 5.21 ± 0.21 5.51 ± 0.14 5.82 ± 0.25** 

R. Kidney 

Absolute 0.320 ± 0.009 0.306 ± 0.005 0.311 ± 0.010 0.326 ± 0.006 0.325 ± 0.008 0.347 ± 0.010* 

Relative 9.37 ± 0.18 9.93 ± 0.12 9.73 ± 0.26 10.07 ± 0.20* 10.17 ± 0.16* 10.85 ± 0.30** 

Liver 

Absolute 1.685 ± 0.041 1.633 ± 0.054 1.667 ± 0.033 1.654 ± 0.041 1.719 ± 0.035 1.875 ± 0.041** 

Relative 49.37 ± 1.03 52.81 ± 0.82* 52.08 ± 0.73* 51.01 ± 0.91* 53.78 ± 0.47** 58.60 ± 0.89** 

Lung 

Absolute 0.350 ± 0.014 0.327 ± 0.012 0.309 ± 0.010 0.319 ± 0.017 0.334 ± 0.019 0.328 ± 0.013 

Relative 10.22 ± 0.30 10.59 ± 0.29 9.71 ± 0.41 9.82 ± 0.44 10.44 ± 0.57 10.27 ± 0.41 

Spleen 

Absolute 0.073 ± 0.002 0.068 ± 0.002 0.071 ± 0.002 0.073 ± 0.002 0.074 ± 0.003 0.077 ± 0.003 

Relative 2.14 ± 0.09 2.19 ± 0.06 2.21 ± 0.06 2.25 ± 0.05 2.32 ± 0.09 2.42 ± 0.10 

L. Testis 

Absolute 0.112 ± 0.004 0.109 ± 0.003 0.113 ± 0.002 0.113 ± 0.003 0.109 ± 0.002 0.110 ± 0.004 

Relative 3.29 ± 0.13 3.54 ± 0.09 3.52 ± 0.07 3.48 ± 0.09 3.41 ± 0.05 3.43 ± 0.09 

Thymus 

Absolute 0.044 ± 0.002 0.035 ± 0.003 0.043 ± 0.003 0.046 ± 0.005 0.044 ± 0.003 0.043 ± 0.002 

Relative 1.30 ± 0.06 1.14 ± 0.10 1.33 ± 0.10 1.43 ± 0.17 1.38 ± 0.08 1.33 ± 0.06 
234 Triethanolamine, NTP TR 449 

TABLE F3 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Female 

n 10 10 10 10 10 10 

Necropsy body wt 28.2 ± 0.6 28.2 ± 0.5 28.7 ± 0.6 28.2 ± 0.7 27.4 ± 0.5 28.2 ± 0.5 

Brain 

Absolute 0.469 ± 0.006 0.459 ± 0.004 0.473 ± 0.005 0.478 ± 0.006 0.469 ± 0.004 0.467 ± 0.004 

Relative 16.70 ± 0.38 16.29 ± 0.25 16.58 ± 0.34 17.03 ± 0.47 17.19 ± 0.28 16.60 ± 0.32 

Heart 

Absolute 0.149 ± 0.007 0.161 ± 0.008 0.150 ± 0.005 0.156 ± 0.008 0.159 ± 0.006 0.167 ± 0.005 

Relative 5.30 ± 0.23 5.74 ± 0.34 5.23 ± 0.12 5.55 ± 0.25 5.80 ± 0.15 5.93 ± 0.15 

R. Kidney 

Absolute 0.217 ± 0.005 0.234 ± 0.004* 0.230 ± 0.006 0.231 ± 0.004 0.230 ± 0.003 0.253 ± 0.008** 

Relative 7.69 ± 0.11 8.32 ± 0.15* 8.03 ± 0.15* 8.22 ± 0.17* 8.41 ± 0.15** 8.95 ± 0.21** 

Liver 

Absolute 1.590 ± 0.061 1.548 ± 0.027 1.600 ± 0.041 1.566 ± 0.031 1.576 ± 0.051 1.833 ± 0.047** 

Relative 56.37 ± 1.78 54.96 ± 1.00 55.81 ± 0.79 55.63 ± 1.09 57.58 ± 1.19 64.92 ± 1.11** 

Lung 

Absolute 0.314 ± 0.020 0.305 ± 0.018 0.329 ± 0.014 0.326 ± 0.013 0.310 ± 0.013 0.302 ± 0.018 

Relative 11.11 ± 0.62 10.86 ± 0.71 11.53 ± 0.53 11.56 ± 0.43 11.34 ± 0.42 10.70 ± 0.63 

Spleen 

Absolute 0.093 ± 0.004 0.095 ± 0.003 0.098 ± 0.003 0.099 ± 0.005 0.100 ± 0.003 0.109 ± 0.005** 

Relative 3.32 ± 0.16 3.37 ± 0.11 3.42 ± 0.08 3.53 ± 0.17 3.66 ± 0.12 3.85 ± 0.18* 

Thymus 

Absolute 0.049 ± 0.004 0.056 ± 0.003 0.052 ± 0.002 0.052 ± 0.004 0.059 ± 0.002 0.056 ± 0.002 

Relative 1.76 ± 0.15 1.98 ± 0.07 1.80 ± 0.06 1.85 ± 0.13 2.16 ± 0.08* 1.97 ± 0.07 

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

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/ 

g body weight (mean ± standard error). 
Triethanolamine, NTP TR 449 235 

TABLE F4 

Organ Weights and Organ-Weight-to-Body-Weight Ratios for Mice at the 15-Month Interim Evaluation 

in the 2-Year Dermal Study of Triethanolaminea 

0 mg/kg 200 mg/kg 630 mg/kg 2,000 mg/kg 

n 10 10 10 10 

Male 

Necropsy body wt 49.5 ± 1.9 49.5 ± 1.5 50.0 ± 1.9 52.0 ± 1.2 

L. Kidney 

Absolute 0.439 ± 0.013 0.459 ± 0.012 0.476 ± 0.015 0.517 ± 0.014** 

Relative 8.92 ± 0.13 9.32 ± 0.26 9.58 ± 0.25 9.98 ± 0.26** 

R. Kidney 

Absolute 0.452 ± 0.015 0.473 ± 0.014 0.504 ± 0.015* 0.549 ± 0.016** 

Relative 9.19 ± 0.23 9.61 ± 0.32 10.14 ± 0.27* 10.56 ± 0.23** 

Liver 

Absolute 2.850 ± 0.330 2.950 ± 0.216 2.538 ± 0.149 3.088 ± 0.197 

Relative 57.29 ± 5.93 59.82 ± 4.16 50.53 ± 1.38 59.37 ± 3.59 

0 mg/kg 100 mg/kg 300 mg/kg 1,000 mg/kg 

Female 

Necropsy body wt 50.9 ± 1.8 48.4 ± 1.3 47.7 ± 1.3 49.8 ± 1.9 

L. Kidney 

Absolute 0.292 ± 0.008 0.294 ± 0.006 0.311 ± 0.005 0.308 ± 0.007 

Relative 5.76 ± 0.13 6.11 ± 0.18 6.58 ± 0.20* 6.26 ± 0.26 

R. Kidney 

Absolute 0.312 ± 0.010 0.318 ± 0.006 0.330 ± 0.004 0.328 ± 0.005 

Relative 6.16 ± 0.11 6.60 ± 0.15 6.96 ± 0.18** 6.67 ± 0.24 

Liver 

Absolute 2.074 ± 0.066 2.104 ± 0.100 2.098 ± 0.032 2.178 ± 0.077 

Relative 40.89 ± 0.79 43.52 ± 1.53 44.34 ± 1.45 43.93 ± 1.27 

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

** P#0.01 a Organ weights (absolute weights) and body weights are given in grams; organ-weight-to-body-weight ratios (relative weights) are given as mg organ weight/ 

g body weight (mean ± standard error). 
236 Triethanolamine, NTP TR 449 
237 

APPENDIX G 

HEMATOLOGY, CLINICAL CHEMISTRY, 

AND URINALYSIS RESULTS 

TABLE G1 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats 

in the 13-Week Dermal Study of Triethanolamine ........................... 

Hematology, Clinical Chemistry, and Urinalysis Data for Mice 

in the 13-Week Dermal Study of Triethanolamine ........................... 

238 

241 
238 Triethanolamine, NTP TR 449 

TABLE G1 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

n 10 10 10 10 10 10 

Male 

Hematology 

Hematocrit (%) 50.6 ± 0.5 50.0 ± 0.5 51.0 ± 0.8 50.8 ± 1.0 50.1 ± 1.0 49.2 ± 1.0 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 15.6 ± 0.1 

9.58 ± 0.09 

15.5 ± 0.1 

9.50 ± 0.08 

15.8 ± 0.2 

9.70 ± 0.15 

15.9 ± 0.3 

9.67 ± 0.17 

15.6 ± 0.2 

9.55 ± 0.16 

15.2 ± 0.3 

9.53 ± 0.16 

Mean cell volume (fL) 52.8 ± 0.2 52.6 ± 0.2 52.5 ± 0.2 52.4 ± 0.2 52.3 ± 0.4 51.8 ± 0.3** 

Mean cell hemoglobin (pg) 16.3 ± 0.1 16.3 ± 0.1 16.3 ± 0.1 16.5 ± 0.1 16.4 ± 0.2 16.0 ± 0.1 

Mean cell hemoglobin 

concentration (g/dL) 

Platelets (10 /μL) 3 

Reticulocytes (10 /μL) 6 

Leukocytes (10 /μL) 3 

30.8 ± 0.2 

638.4 ± 9.0 

0.1 ± 0.0 

6.26 ± 0.34 

30.9 ± 0.1 

617.4 ± 17.4 

0.1 ± 0.0 

7.22 ± 0.39 

31.0 ± 0.2 

615.4 ± 7.7 

0.2 ± 0.0 

7.32 ± 0.50 

31.3 ± 0.3 

599.3 ± 18.8b 

0.1 ± 0.0 

7.30 ± 0.42 

31.3 ± 0.4 

637.6 ± 12.9 

0.2 ± 0.0 

7.04 ± 0.34 

31.0 ± 0.2 

647.6 ± 10.1 

0.1 ± 0.0 

9.04 ± 0.40** 

Segmented 

 neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

1.21 ± 0.13 

4.98 ± 0.30 

0.01 ± 0.01 

0.06 ± 0.02 

1.16 ± 0.15 

5.94 ± 0.38 

0.02 ± 0.01 

0.10 ± 0.04 

1.26 ± 0.12 

6.01 ± 0.47 

0.00 ± 0.00 

0.06 ± 0.02 

1.18 ± 0.12 

6.00 ± 0.38 

0.00 ± 0.00 

0.12 ± 0.04 

1.24 ± 0.13 

5.69 ± 0.32 

0.02 ± 0.01 

0.09 ± 0.02 

2.64 ± 0.20** 

6.14 ± 0.40 

0.00 ± 0.00 

0.26 ± 0.05** 

Nucleated 

 erythrocytes (10 /μL) 3 0.00 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 0.00 ± 0.00 0.01 ± 0.01 0.01 ± 0.01 

Clinical Chemistry 

Urea nitrogen (mg/dL) 20.8 ± 0.4 19.5 ± 0.3 19.7 ± 0.5 19.9 ± 0.6 20.6 ± 0.5 21.2 ± 0.4 

Creatinine (mg/dL) 0.58 ± 0.02 0.56 ± 0.02 0.57 ± 0.02 0.57 ± 0.03 0.58 ± 0.02 0.54 ± 0.02 

Glucose (mg/dL) 112 ± 2 111 ± 2 110 ± 3 113 ± 7 111 ± 3 107 ± 3 

Total protein (g/dL) 6.7 ± 0.1 6.7 ± 0.2 6.9 ± 0.1 6.8 ± 0.2 7.0 ± 0.2 6.7 ± 0.1 

Albumin (g/dL) 5.0 ± 0.1 5.0 ± 0.1 5.1 ± 0.1 5.2 ± 0.1 5.2 ± 0.1 4.9 ± 0.1 

Alanine 

aminotransferase (IU/L) 45 ± 2 45 ± 2 51 ± 3 53 ± 4 52 ± 4* 69 ± 5** 

Aspartate 

aminotransferase (IU/L) 76 ± 4 74 ± 2 96 ± 7* 98 ± 10* 90 ± 7* 127 ± 7** 

Sorbitol 

dehydrogenase (IU/L) 16 ± 1 14 ± 1 16 ± 2 15 ± 1 15 ± 1 15 ± 2 
Triethanolamine, NTP TR 449 239 

TABLE G1 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

n 10 10 10 10 10 10 

Male (continued) 

Urinalysis 

Glucose (mg/hr) 

Day 3 0.018 ± 0.003 0.016 ± 0.003 0.017 ± 0.004 0.014 ± 0.003 0.012 ± 0.004 0.015 ± 0.003 

Day 16 0.039 ± 0.002 0.041 ± 0.002 0.042 ± 0.007 0.042 ± 0.003 0.040 ± 0.002 0.042 ± 0.002 

Day 44 

Week 13 

0.037 ± 0.005 

0.054 ± 0.003b 

0.021 ± 0.005 

0.055 ± 0.004 

0.031 ± 0.007 

0.051 ± 0.003 

0.029 ± 0.006 

0.035 ± 0.007 

0.029 ± 0.007 

0.033 ± 0.007* 

0.031 ± 0.005 

0.036 ± 0.007 

Protein (mg/hr) 

Day 3 0.013 ± 0.001 0.014 ± 0.002 0.018 ± 0.002 0.024 ± 0.004 0.016 ± 0.002 0.014 ± 0.002 

Day 16 0.085 ± 0.012 0.090 ± 0.010 0.080 ± 0.008 0.065 ± 0.004 0.063 ± 0.009 0.046 ± 0.009* 

Day 44 

Week 13 

0.104 ± 0.008 

0.598 ± 0.024b 

0.087 ± 0.008 

0.663 ± 0.045 

0.102 ± 0.007 

0.637 ± 0.019 

0.062 ± 0.009** 

0.510 ± 0.060 

0.066 ± 0.010** 

0.407 ± 0.050** 

0.045 ± 0.008** 

0.269 ± 0.029** 

Volume (mL/16 hr) 

Day 3 9.2 ± 1.2 8.7 ± 1.4 8.9 ± 1.1 11.2 ± 1.6 10.1 ± 0.9 7.8 ± 1.1 

Day 16 14.1 ± 1.3 12.7 ± 1.9 12.7 ± 1.8 15.2 ± 1.3 16.3 ± 1.3 14.7 ± 1.9 

Day 44 

Week 13 

13.3 ± 1.3 

9.2 ± 0.7b 

13.2 ± 2.3 

8.2 ± 1.0b 

15.5 ± 1.8 

12.2 ± 1.8 

14.9 ± 1.6 

11.8 ± 1.0 

16.1 ± 1.3 

11.2 ± 1.5b 

15.3 ± 1.9 

9.5 ± 1.6 

Specific gravity 

Day 3 1.017 ± 0.002 1.018 ± 0.002 1.016 ± 0.002 1.015 ± 0.002 1.015 ± 0.001 1.023 ± 0.002 

Day 16 1.012 ± 0.001 1.016 ± 0.003 1.014 ± 0.002 1.012 ± 0.001 1.012 ± 0.001 1.017 ± 0.002 

Day 44 1.016 ± 0.001 1.017 ± 0.003 1.015 ± 0.002 1.014 ± 0.001 1.015 ± 0.001 1.023 ± 0.002 

Week 13 1.021 ± 0.001 1.026 ± 0.003 1.023 ± 0.003 1.019 ± 0.001 1.023 ± 0.002 1.035 ± 0.004* 

Female 

Hematology 

Hematocrit (%) 50.5 ± 0.4 50.7 ± 0.6 51.0 ± 0.7 50.2 ± 0.4 49.3 ± 0.6 48.4 ± 0.6* 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 15.7 ± 0.2 

8.87 ± 0.08 

15.6 ± 0.2 

8.87 ± 0.11 

15.7 ± 0.3 

8.96 ± 0.14 

15.5 ± 0.1 

8.83 ± 0.07 

15.4 ± 0.2 

8.77 ± 0.10 

15.0 ± 0.2 

8.67 ± 0.11 

Mean cell volume (fL) 56.9 ± 0.3 57.3 ± 0.3 57.0 ± 0.3 56.9 ± 0.3 56.4 ± 0.2 55.7 ± 0.3** 

Mean cell hemoglobin (pg) 17.7 ± 0.1 17.6 ± 0.1 17.6 ± 0.2 17.6 ± 0.1 17.5 ± 0.1 17.3 ± 0.1 

Mean cell hemoglobin 

concentration (g/dL) 

Platelets (10 /μL) 3 

Reticulocytes (10 /μL) 6 

Leukocytes (10 /μL) 3 

31.1 ± 0.1 

613.8 ± 19.2 

0.1 ± 0.0 

5.08 ± 0.38 

30.8 ± 0.2 

601.2 ± 22.3 

0.1 ± 0.0 

5.14 ± 0.36 

30.8 ± 0.2 

640.2 ± 16.4 

0.1 ± 0.0 

5.96 ± 0.40 

30.9 ± 0.2 

606.0 ± 35.8 

0.1 ± 0.0 

5.86 ± 0.49 

31.2 ± 0.1 

609.0 ± 17.4 

0.1 ± 0.0 

5.38 ± 0.23 

31.1 ± 0.1 

641.4 ± 18.7 

0.1 ± 0.0 

6.36 ± 0.44 

Segmented

 neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.68 ± 0.07 

4.31 ± 0.40 

0.02 ± 0.01 

0.07 ± 0.03 

0.67 ± 0.10 

4.38 ± 0.33 

0.00 ± 0.00 

0.08 ± 0.01 

0.74 ± 0.08 

5.16 ± 0.34 

0.01 ± 0.01 

0.05 ± 0.01 

0.87 ± 0.16 

4.92 ± 0.44 

0.01 ± 0.01 

0.09 ± 0.02 

0.84 ± 0.11 

4.42 ± 0.15 

0.03 ± 0.01 

0.10 ± 0.03 

1.46 ± 0.24** 

4.77 ± 0.29 

0.02 ± 0.01 

0.12 ± 0.03 

Nucleated 

 erythrocytes (10 /μL) 3 0.02 ± 0.01 0.00 ± 0.00 0.00 ± 0.00 0.01 ± 0.01 0.02 ± 0.01 0.01 ± 0.01 
240 Triethanolamine, NTP TR 449 

TABLE G1 

Hematology, Clinical Chemistry, and Urinalysis Data for Rats in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 125 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 

n 10 10 10 10 10 10 

Female (continued) 

Clinical Chemistry 

Urea nitrogen (mg/dL) 20.5 ± 0.6 19.9 ± 0.5 21.1 ± 0.4 21.5 ± 0.5 20.5 ± 0.4 23.0 ± 0.6** 

Creatinine (mg/dL) 0.60 ± 0.02 0.57 ± 0.02 0.58 ± 0.02 0.59 ± 0.02 0.57 ± 0.02 0.58 ± 0.02 

Glucose (mg/dL) 113 ± 6 110 ± 6 102 ± 2 107 ± 3 105 ± 3 103 ± 3 

Total protein (g/dL) 6.4 ± 0.1 6.5 ± 0.1 6.5 ± 0.1 6.5 ± 0.1 6.5 ± 0.1 6.7 ± 0.1 

Albumin (g/dL) 4.9 ± 0.1 4.9 ± 0.1 4.9 ± 0.1 5.0 ± 0.1 5.0 ± 0.1 5.2 ± 0.1* 

Alanine 

aminotransferase (IU/L) 43 ± 2 43 ± 3 45 ± 2 45 ± 2 42 ± 2 53 ± 3 

Aspartate 

aminotransferase (IU/L) 85 ± 6 88 ± 10 96 ± 6 84 ± 4 87 ± 4 126 ± 12** 

Sorbitol

 dehydrogenase (IU/L) 21 ± 1 19 ± 1 18 ± 1 16 ± 1* 16 ± 1* 18 ± 1 

Urinalysis 

Glucose (mg/hr) 

Day 3 0.011 ± 0.003 0.013 ± 0.002 0.013 ± 0.004 0.011 ± 0.003 0.012 ± 0.004 0.010 ± 0.003 

Day 16 0.029 ± 0.002 0.025 ± 0.002 0.025 ± 0.003 0.024 ± 0.003 0.025 ± 0.003 0.017 ± 0.003* 

Day 44 0.013 ± 0.004 0.013 ± 0.003 0.016 ± 0.007 0.018 ± 0.006 0.028 ± 0.005 0.027 ± 0.008 

Week 13 0.009 ± 0.003 0.011 ± 0.003 0.021 ± 0.002** 0.023 ± 0.003** 0.026 ± 0.002** 0.025 ± 0.003** 

Protein (mg/hr) 

Day 3 0.016 ± 0.002 0.014 ± 0.004 0.007 ± 0.001** 0.008 ± 0.001* 0.005 ± 0.000** 0.008 ± 0.001** 

Day 16 0.008 ± 0.003 0.005 ± 0.001 0.009 ± 0.001 0.008 ± 0.001 0.009 ± 0.002 0.010 ± 0.002 

Day 44 

Week 13 

0.004 ± 0.002 

0.029 ± 0.005b 

0.004 ± 0.001 

0.051 ± 0.006 

0.012 ± 0.005 

0.036 ± 0.008 

0.013 ± 0.002* 

0.042 ± 0.008 

0.005 ± 0.001 

0.039 ± 0.006 

0.010 ± 0.002 

0.039 ± 0.009 

Volume (mL/16 hr) 

Day 3 9.1 ± 0.9 8.6 ± 1.1 10.8 ± 1.1 9.6 ± 1.3 8.2 ± 0.6 9.8 ± 1.3 

Day 16 11.4 ± 1.6 7.6 ± 1.3 9.6 ± 0.7 10.4 ± 0.9 8.3 ± 0.7 8.3 ± 1.3 

Day 44 10.1 ± 1.4 10.0 ± 1.7 11.3 ± 1.2 9.2 ± 1.2 7.4 ± 0.9 7.6 ± 0.8 

Week 13 6.0 ± 1.0 7.5 ± 1.2 6.3 ± 0.7 8.1 ± 1.0 6.2 ± 0.6 5.4 ± 0.9 

Specific gravity 

Day 3 1.013 ± 0.002 1.016 ± 0.002 1.012 ± 0.001 1.015 ± 0.001 1.016 ± 0.001 1.018 ± 0.002 

Day 16 1.013 ± 0.002 1.017 ± 0.002 1.014 ± 0.001 1.013 ± 0.001 1.018 ± 0.001* 1.021 ± 0.004c 

Day 44 1.016 ± 0.002 1.015 ± 0.002 1.013 ± 0.002 1.016 ± 0.002 1.024 ± 0.003* 1.026 ± 0.002** 

Week 13 1.017 ± 0.001 1.016 ± 0.002 1.020 ± 0.003 1.017 ± 0.002 1.023 ± 0.002* 1.032 ± 0.005** 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error. Statistical tests were performed on unrounded data. b n=9 

n=6 c 
Triethanolamine, NTP TR 449 241 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Mice in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Male 

Hematology 

n 10 10 10 10 10 10 

Hematocrit (%) 53.6 ± 0.6 53.5 ± 0.7 55.4 ± 0.5 54.1 ± 0.9 53.7 ± 0.4 51.5 ± 0.5 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 15.6 ± 0.3 

10.02 ± 0.12 

15.3 ± 0.2 

9.85 ± 0.16 

16.0 ± 0.3 

10.33 ± 0.10 

15.4 ± 0.3 

10.08 ± 0.15 

15.4 ± 0.2 

9.91 ± 0.08 

14.8 ± 0.2 

9.64 ± 0.10 

Mean cell volume (fL) 53.5 ± 0.2 54.3 ± 0.3 53.7 ± 0.3 53.4 ± 0.3 54.2 ± 0.3 53.5 ± 0.3 

Mean cell hemoglobin (pg) 15.6 ± 0.2 15.6 ± 0.2 15.5 ± 0.1 15.3 ± 0.1 15.6 ± 0.1 15.4 ± 0.1 

Mean cell hemoglobin 

concentration (g/dL) 

Platelets (10 /μL) 3 

Reticulocytes (10 /μL) 6 

Leukocytes (10 /μL) 3 

29.0 ± 0.2 

721.6 ± 37.9 

0.2 ± 0.0 

6.40 ± 0.28 

28.6 ± 0.3 

785.6 ± 30.9 

0.2 ± 0.0 

5.64 ± 0.30 

28.9 ± 0.3 

741.8 ± 42.6 

0.2 ± 0.0 

6.22 ± 0.37 

28.5 ± 0.2 

773.0 ± 32.3 

0.2 ± 0.0 

5.90 ± 0.63 

28.7 ± 0.2 

767.8 ± 31.0 

0.2 ± 0.0 

5.74 ± 0.25 

28.7 ± 0.3 

855.6 ± 40.1 

0.2 ± 0.0 

5.22 ± 0.72* 

Segmented

 neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

1.01 ± 0.14 

5.15 ± 0.23 

0.01 ± 0.01 

0.24 ± 0.05 

0.86 ± 0.07 

4.60 ± 0.24 

0.02 ± 0.01 

0.15 ± 0.05 

1.12 ± 0.22 

4.91 ± 0.31 

0.01 ± 0.01 

0.18 ± 0.06 

1.02 ± 0.13 

4.75 ± 0.56 

0.01 ± 0.01 

0.12 ± 0.02 

0.85 ± 0.10 

4.77 ± 0.22 

0.01 ± 0.01 

0.12 ± 0.03 

0.74 ± 0.10 

4.33 ± 0.60 

0.01 ± 0.01 

0.15 ± 0.04 

Nucleated 

 erythrocytes (10 /μL) 3 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.01 ± 0.01 0.01 ± 0.01 0.00 ± 0.00 

Clinical Chemistry 

n 9 9 10 9 8 10 

Urea nitrogen (mg/dL) 25.7 ± 2.4 23.7 ± 1.2 22.5 ± 0.9 23.0 ± 1.1 22.5 ± 0.9 24.0 ± 1.9 

Creatinine (mg/dL) 0.39 ± 0.03 0.36 ± 0.02 0.40 ± 0.02 0.37 ± 0.02 0.35 ± 0.02 0.40 ± 0.02 

Glucose (mg/dL) 151 ± 7 159 ± 5 149 ± 6 149 ± 5 150 ± 6 168 ± 15 

Total protein (g/dL) 5.6 ± 0.1 5.5 ± 0.1 5.6 ± 0.1 5.5 ± 0.1 5.7 ± 0.1 5.6 ± 0.1 

Albumin (g/dL) 3.9 ± 0.1 3.8 ± 0.0 3.9 ± 0.1 3.7 ± 0.1 4.0 ± 0.1 3.8 ± 0.1 

Alanine

 aminotransferase (IU/L) 33 ± 4b 34 ± 2 41 ± 3 37 ± 4c 38 ± 6d 31 ± 2d 

Aspartate

 aminotransferase (IU/L) 59 ± 11 57 ± 10 59 ± 5 53 ± 6c 65 ± 11 63 ± 9d 

Sorbitol

 dehydrogenase (IU/L) 49 ± 3 36 ± 1** 34 ± 2** 30 ± 2**c 30 ± 2**d 25 ± 2** 
242 Triethanolamine, NTP TR 449 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Mice in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Male (continued) 

Urinalysis 

n 10 10 9 10 10 10 

Glucose (mg/hr) 

Day 46 0.006 ± 0.001 0.008 ± 0.003d 0.006 ± 0.001 0.005 ± 0.001 0.004 ± 0.001 0.004 ± 0.001d 

Week 13 0.007 ± 0.001 0.006 ± 0.001 0.007 ± 0.002c 0.010 ± 0.002 0.007 ± 0.001 0.010 ± 0.002 

Protein (mg/hr) 

Day 46 0.175 ± 0.041 0.168 ± 0.051d 0.162 ± 0.041 0.139 ± 0.041 0.129 ± 0.035 0.108 ± 0.026d 

Week 13 0.198 ± 0.032 0.148 ± 0.026 0.173 ± 0.053c 0.187 ± 0.028 0.160 ± 0.027 0.238 ± 0.043 

Volume (mL/16 hr) 

Day 46 1.1 ± 0.2 1.0 ± 0.3d 1.6 ± 0.5 0.9 ± 0.2 0.8 ± 0.2 0.7 ± 0.2d 

Week 13 1.2 ± 0.2 0.7 ± 0.1 1.0 ± 0.3 1.3 ± 0.3 1.1 ± 0.2 1.3 ± 0.2 

Specific gravity 

Day 46 1.029 ± 0.004 1.028 ± 0.002d 1.020 ± 0.004 1.026 ± 0.004 1.029 ± 0.003b 1.031 ± 0.006e 

Week 13 1.028 ± 0.002 1.039 ± 0.005 1.025 ± 0.006c 1.029 ± 0.003 1.027 ± 0.003 1.038 ± 0.005 

Female 

Hematology 

n 10 10 10 9 9 10 

Hematocrit (%) 53.6 ± 1.2 53.1 ± 0.7 53.9 ± 0.5 53.9 ± 1.0 54.2 ± 0.5 53.8 ± 1.3 

Hemoglobin (g/dL) 

Erythrocytes (10 /μL) 6 14.7 ± 0.4 

9.76 ± 0.26 

15.0 ± 0.2 

9.71 ± 0.15 

15.4 ± 0.1 

9.80 ± 0.12 

15.4 ± 0.2 

9.86 ± 0.19 

15.5 ± 0.2 

10.03 ± 0.12 

15.7 ± 0.3 

9.88 ± 0.30 

Mean cell volume (fL) 55.1 ± 0.3 54.8 ± 0.4 55.1 ± 0.5 54.6 ± 0.3 54.1 ± 0.3* 54.6 ± 1.0* 

Mean cell hemoglobin (pg) 15.1 ± 0.4 15.5 ± 0.1 15.7 ± 0.1 15.7 ± 0.2 15.5 ± 0.1 16.0 ± 0.4 

Mean cell hemoglobin 

concentration (g/dL) 

Platelets (10 /μL) 3 

Reticulocytes (10 /μL) 6 

Leukocytes (10 /μL) 3 

27.6 ± 0.6 

620.6 ± 46.9 

0.2 ± 0.0 

4.40 ± 0.32 

28.3 ± 0.2 

655.6 ± 41.6 

0.2 ± 0.0 

4.72 ± 0.34 

28.5 ± 0.2 

627.8 ± 45.3 

0.2 ± 0.0 

4.04 ± 0.34 

28.7 ± 0.4 

684.2 ± 27.4 

0.2 ± 0.0 

4.96 ± 0.29 

28.6 ± 0.2 

714.4 ± 24.1 

0.2 ± 0.0 

5.16 ± 0.29 

29.3 ± 0.2** 

722.0 ± 53.5 

0.2 ± 0.0 

5.68 ± 0.43 

Segmented 

 neutrophils (10 /μL) 3 

Lymphocytes (10 /μL) 3 

Monocytes (10 /μL) 3 

Eosinophils (10 /μL) 3 

0.56 ± 0.07 

3.78 ± 0.27 

0.00 ± 0.00 

0.05 ± 0.02 

0.62 ± 0.07 

4.02 ± 0.29 

0.01 ± 0.01 

0.08 ± 0.01 

0.49 ± 0.09 

3.46 ± 0.31 

0.01 ± 0.01 

0.07 ± 0.02 

0.58 ± 0.07 

4.28 ± 0.25 

0.01 ± 0.01 

0.10 ± 0.02 

0.66 ± 0.07 

4.37 ± 0.25 

0.02 ± 0.01 

0.11 ± 0.02 

0.75 ± 0.15 

4.80 ± 0.33 

0.01 ± 0.01 

0.13 ± 0.02* 

Nucleated

 erythrocytes (10 /μL) 3 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 
243 

c 

Triethanolamine, NTP TR 449 

TABLE G2 

Hematology, Clinical Chemistry, and Urinalysis Data for Mice in the 13-Week Dermal Study of Triethanolamine 

(continued) 

0 mg/kg 250 mg/kg 500 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

Female (continued) 

Clinical Chemistry 

n 10 10 9 9 10 10 

Urea nitrogen (mg/dL) 

Creatinine (mg/dL) 

Glucose (mg/dL) 

23.9 ± 1.6 

0.41 ± 0.02 

138 ± 5 

18.8 ± 1.1 

0.39 ± 0.01d 

151 ± 7 

20.0 ± 1.8 

0.42 ± 0.02 

153 ± 11 

20.4 ± 1.4b 

0.41 ± 0.01b 

145 ± 5b 

18.4 ± 1.6 

0.42 ± 0.02 

143 ± 4 

19.6 ± 1.5 

0.40 ± 0.02 

144 ± 5 

Total protein (g/dL) 5.5 ± 0.1 5.7 ± 0.1 5.7 ± 0.1 5.7 ± 0.1 5.8 ± 0.1* 5.6 ± 0.1 

Albumin (g/dL) 4.1 ± 0.1 4.2 ± 0.1 4.2 ± 0.1 4.1 ± 0.0 4.3 ± 0.1 4.2 ± 0.1 

Alanine

 aminotransferase (IU/L) 35 ± 4 44 ± 9d 32 ± 4c 24 ± 1 27 ± 2 42 ± 9 

Aspartate 

aminotransferase (IU/L) 50 ± 3 66 ± 15 52 ± 3c 44 ± 3 59 ± 6 77 ± 14 

Sorbitol 

dehydrogenase (IU/L) 44 ± 3 32 ± 4** 27 ± 1**c 20 ± 1** 20 ± 1** 17 ± 1** 

Urinalysis 

n 10 10 10 10 10 10 

Glucose (mg/hr) 

Day 46 

Week 13 

0.008 ± 0.001 

0.011 ± 0.002 

0.010 ± 0.001 

0.007 ± 0.002 

0.009 ± 0.001 

0.008 ± 0.001 

0.011 ± 0.002 

0.007 ± 0.001d 

0.008 ± 0.001 

0.005 ± 0.000* 

0.012 ± 0.001* 

0.008 ± 0.001 

Protein (mg/hr) 

Day 46 

Week 13 

0.073 ± 0.010 

0.071 ± 0.011 

0.087 ± 0.011 

0.055 ± 0.008 

0.090 ± 0.012 

0.073 ± 0.013 

0.108 ± 0.015 

0.065 ± 0.011d 

0.077 ± 0.012 

0.061 ± 0.010 

0.131 ± 0.017* 

0.066 ± 0.009 

Volume (mL/16 hr) 

Day 46 

Week 13 

1.4 ± 0.2 

1.5 ± 0.2 

1.7 ± 0.5 

1.2 ± 0.2 

1.2 ± 0.1 

1.4 ± 0.3 

1.6 ± 0.3 

1.3 ± 0.3d 

1.0 ± 0.2 

1.0 ± 0.2d 

2.7 ± 0.4 

1.5 ± 0.3 

Specific gravity 

Day 46 

Week 13 

1.021 ± 0.002 

1.025 ± 0.002 

1.026 ± 0.002 

1.023 ± 0.002 

1.026 ± 0.002 

1.028 ± 0.004 

1.027 ± 0.003 

1.025 ± 0.003d 

1.031 ± 0.003 

1.032 ± 0.005 

1.031 ± 0.004 

1.037 ± 0.004 

* Significantly different (P#0.05) from the control group by Dunn’s or Shirley’s test 

** P#0.01 a Mean ± standard error. Statistical tests were performed on unrounded data. b n=8 

n=10 d n=9 e n=6 
244 Triethanolamine, NTP TR 449 
245 

APPENDIX H 

REPRODUCTIVE TISSUE EVALUATIONS 

AND ESTROUS CYCLE CHARACTERIZATION 

TABLE H1 Summary of Reproductive Tissue Evaluations for Male Rats 

in the 13-Week Dermal Study of Triethanolamine ........................... 246 

TABLE H2 Summary of Estrous Cycle Characterization for Female Rats 

in the 13-Week Dermal Study of Triethanolamine ........................... 246 

TABLE H3 Summary of Reproductive Tissue Evaluations for Male Mice 

in the 13-Week Dermal Study of Triethanolamine ........................... 247 

TABLE H4 Summary of Estrous Cycle Characterization for Female Mice 

in the 13-Week Dermal Study of Triethanolamine ........................... 247 
246 Triethanolamine, NTP TR 449 

TABLE H1 

Summary of Reproductive Tissue Evaluations for Male Rats in the 13-Week Dermal Study of Triethanolaminea 

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

n 10 10 10 10 

Weights (g) 

Necropsy body weight 299 ± 6 287 ± 7 295 ± 11 248 ± 11** 

R. cauda epididymis 0.150 ± 0.003 0.154 ± 0.005 0.153 ± 0.006 0.143 ± 0.006 

R. epididymis 0.421 ± 0.007 0.413 ± 0.005 0.405 ± 0.008 0.388 ± 0.011* 

R. testis 1.369 ± 0.026 1.345 ± 0.017 1.426 ± 0.077 1.326 ± 0.041 

Epididymal spermatozoal measurements 

Motility (%) 73.50 ± 1.09 74.95 ± 1.49 74.97 ± 1.65 78.26 ± 1.65 

Abnormal (%) 1.220 ± 0.205 0.780 ± 0.070 1.160 ± 0.299 1.200 ± 0.176 

Concentration (10 /g cauda epididymal tissue) 6 650 ± 35 572 ± 48 674 ± 36 588 ± 29 

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

** Significantly different (P#0.01) from the control group by Williams’ test a Data are presented as mean ± standard error. Differences from the control group are not significant by Dunnett’s test (right cauda epididymis and testis 

weights) or Dunn’s test (epididymal spermatozoal measurements). 

TABLE H2 

Summary of Estrous Cycle Characterization for Female Rats in the 13-Week Dermal Study of Triethanolaminea 

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

n 10 10 10 10 

Necropsy body weight (g) 

Estrous cycle length (days) 

174 ± 4 

4.70 ± 0.21 

174 ± 3 

4.40 ± 0.22 

170 ± 3 

4.75 ± 0.25b 

158 ± 4** 

4.50 ± 0.27b 

Estrous stages (% of cycle) 

Diestrus 25.7 28.6 38.6 42.9 

Proestrus 17.1 7.1 11.4 12.9 

Estrus 37.1 37.1 35.7 27.1 

Metestrus 18.6 25.7 11.4 17.1 

Uncertain diagnoses 1.4 1.4 2.9 0.0 

** Significantly different (P#0.01) from the control group by Williams’ test a Necropsy body weight and estrous cycle length data are presented as mean ± standard error. Differences from the control group for estrous cycle length are 

not significant by Dunn’s test. By multivariate analysis of variance, dosed females do not differ significantly from the control females in the relative length of 

time spent in the estrous stages. b Estrous cycle was longer than 7 days or unclear in 2 of 10 rats. 
Triethanolamine, NTP TR 449 247 

TABLE H3 

Summary of Reproductive Tissue Evaluations for Male Mice in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

n 10 10 10 10 

Weights (g) 

Necropsy body weight 34.2 ± 0.7 32.5 ± 0.7 32.0 ± 0.8 32.0 ± 0.6 

R. cauda epididymis 0.022 ± 0.004 0.021 ± 0.002 0.016 ± 0.001 0.017 ± 0.001 

R. epididymis 0.052 ± 0.003 0.052 ± 0.003 0.047 ± 0.002 0.046 ± 0.002 

R. testis 0.121 ± 0.003 0.117 ± 0.003 0.115 ± 0.003 0.113 ± 0.006 

Epididymal spermatozoal measurements 

Motility (%) 71.83 ± 1.84 74.35 ± 1.58 74.11 ± 1.82 71.79 ± 1.84 

Abnormal (%) 1.62 ± 0.12 1.52 ± 0.12 1.44 ± 0.14 1.92 ± 0.43 

Concentration (10 /g cauda epididymal tissue) 6 628 ± 105 603 ± 63 617 ± 68 676 ± 108 

a Data are presented as mean ± standard error. Differences from the control group are not significant by Dunnett’s test (weights) or Dunn’s test (epididymal 

spermatozoal measurements). 

TABLE H4 

Summary of Estrous Cycle Characterization for Female Mice in the 13-Week Dermal Study of Triethanolaminea 

0 mg/kg 1,000 mg/kg 2,000 mg/kg 4,000 mg/kg 

n 10 10 10 10 

Necropsy body weight (g) 28.2 ± 0.6 28.2 ± 0.7 27.4 ± 0.5 28.2 ± 0.5 

Estrous cycle length (days) 4.00 ± 0.00b 4.00 ± 0.00 4.20 ± 0.13 4.20 ± 0.25 

Estrous stages (% of cycle) 

Diestrus 37.1 27.1 32.9 32.9 

Proestrus 8.6 12.9 20.0 12.9 

Estrus 28.6 30.0 25.7 31.4 

Metestrus 22.9 30.0 21.4 20.0 

Uncertain diagnoses 2.9 0.0 0.0 2.9 

a Necropsy body weight and estrous cycle length data are presented as mean ± standard error. Differences from the control group are not significant by 

Dunnett’s test (necropsy body weight) or Dunn’s test (estrous cycle length). By multivariate analysis of variance, dosed females do not differ significantly 

from the control females in the relative length of time spent in the estrous stages. b Estrous cycle was unclear in 2 of 10 mice. 
248 Triethanolamine, NTP TR 449 
249 

APPENDIX I 

CHEMICAL CHARACTERIZATION 

AND DOSE FORMULATION STUDIES 

PROCUREMENT AND CHARACTERIZATION OF TRIETHANOLAMINE ........................... 250 

PREPARATION AND ANALYSIS OF DOSE FORMULATIONS .................................. 252 

FIGURE I1 Infrared Absorption Spectrum of Triethanolamine ........................... 254 

FIGURE I2 Nuclear Magnetic Resonance Spectrum of Triethanolamine ..................... 255 

TABLE I1 Preparation and Storage of Dose Formulations in the Dermal Studies 

of Triethanolamine ................................................. 256 

TABLE I2 Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week Dermal Studies of Triethanolamine ........................... 257 

TABLE I3 Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine ............................ 259 

TABLE I4 Results of Referee Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week and 2-Year Dermal Studies of Triethanolamine ................... 265 
250 Triethanolamine, NTP TR 449 

CHEMICAL CHARACTERIZATION 

AND DOSE FORMULATION STUDIES 

PROCUREMENT AND CHARACTERIZATION OF TRIETHANOLAMINE 

Triethanolamine was obtained from Texaco Chemical Company (Division of Texaco, Inc., Bellaire, TX) in 

two lots (3B-1-84 and 7G-60). Lot 3B-1-84 was used in the 13-week studies and Lot 7G-60 was used 

during the 2-year studies. Identity, purity, and stability analyses were conducted by the analytical chemistry 

laboratory, Midwest Research Institute (Kansas City, MO). Reports on analyses performed in support of 

the triethanolamine studies are on file at the National Institute of Environmental Health Sciences. 

The chemical, a clear, colorless, viscous liquid, was identified as triethanolamine by infrared, ultraviolet/ 

visible, and nuclear magnetic resonance spectroscopy. All spectra were consistent with the literature spectra 

(Sadtler Standard Spectra, 1970) of triethanolamine (Figures I1 and I2). 

The purity of Lot 3B-1-84 was determined by elemental analyses, Karl Fischer water analysis, functional 

group titration, thin-layer chromatography (TLC), and gas chromatography. For functional group titration, 

triethanolamine samples were reacted with excess acetic anhydride to identify the presence of 

monoethanolamine or diethanolamine; the samples were then heated in a steam bath for 10 minutes and 

cooled. Glacial acetic acid was added, and the samples were titrated with 0.1 N perchloric acid in glacial 

acetic acid. Additional samples of triethanolamine were prepared by the same method but without the 

addition of acetic anhydride. All titrations were monitored potentiometrically with a combination pH/mV 

electrode filled with 0.1 M lithium perchlorate in acetic anhydride. TLC was performed on Silica Gel 

60 F-254 plates with two solvent systems: 1) chloroform:methanol:concentrated ammonium hydroxide 

(55:40:5) and 2) toluene:methanol:concentrated ammonium hydroxide (55:40:5). Diethanolamine was used 

as a reference standard. The plates were examined with two visualization methods: 1) iodine vapor and 

2) a spray of 0.5% ninhydrin in butanol followed by heating. Gas chromatography was performed with a 

flame ionization detector and a nitrogen carrier gas. Two systems were used: 

A) 60/80 mesh Tenax GC column, with an oven temperature program of 50E C for 5 minutes, 

then 50E to 300E C at 10E C per minute, and a carrier gas flow rate of 15 mL/minute, and 

B) 3% SP-2100 DB on 100/120 Supelcoport, with an oven temperature program of 50E C for 

5 minutes, then 50E to 250E C at 10E C per minute, and a carrier gas flow rate of 

70 mL/minute. 

Elemental analyses for hydrogen and nitrogen were in agreement with the theoretical values for 

triethanolamine; the results for carbon were slightly low. Karl Fischer water analysis indicated 

0.45% ± 0.06(s)% water. Functional group titration of triethanolamine samples treated with acetic 

anhydride indicated 98.4% ± 0.3% total tertiary amines. Titration of samples not pretreated with acetic 

anhydride indicated 99.0% ± 0.2% total titratable amines; the difference between the two titration values 

indicated an impurity equivalent to 0.04 mEq/g sample (0.4% w/w, based on diethanolamine being the most 

likely impurity). TLC by system 1 indicated a major spot and a very slight trace impurity; system 2 

indicated a major spot and a trace, a slight trace, and a very slight trace impurity. Gas chromatography 

with system A indicated one major peak and three impurities with areas totaling 1.43% of the major peak 

area; system B indicated one major peak and one impurity with an area less than 0.2% relative to the major 

peak. The overall purity of triethanolamine was determined to be approximately 98%. 

Lot 3B-1-84 was further characterized by National Formulary methods (USP XX/NF XV) of testing for 

trolamine, a mixture of alkanolamines consisting largely of triethanolamine, with some diethanolamine and 
Triethanolamine, NTP TR 449 251 

monoethanolamine. The bulk chemical produced a deep blue color when reacted with cupric sulfate, 

followed by the addition of 1 N sodium hydroxide, and produced a carmine red color when reacted with 

cobaltous chloride. Vapors produced by a heated sample turned moistened red litmus paper blue. A 

specific gravity of 1.124 ± 0.000 was determined for the bulk chemical. The refractive index was 

determined to be 1.484 ± 0.000 at 20E C. Karl Fischer water analysis indicated 0.45% ± 0.06% water. 

After being charred, ignited in a muffle furnace, and then cooled in a desiccator, a 1-gram sample of 

triethanolamine produced 0.03% ± 0.02% residue. Titration with 1 N hydrochloric acid, with methyl red 

indicator, indicated 101.2% ± 0.2% alkanolamines. All results were consistent with NF XV requirements 

for trolamine. 

The purity of Lot 7G-60 was also determined by elemental analyses, Karl Fischer water analysis, functional 

group titration, TLC, and gas chromatography. Functional group titration and TLC methods were the same 

as those used for Lot 3B-1-84. Two gas chromatographic systems with a flame ionization detector were 

used: 

A) 60/80 mesh Tenax GC column, with an oven temperature program of 50E C for 5 minutes, 

then 50E to 300E C at 10E C per minute, and a nitrogen carrier gas at a flow rate of 

15 mL/minute, and 

B) DB-5 Megabore fused silica column, with an oven temperature program of 100E C for 

5 minutes, then 100E to 250E C at 10E C per minute, a helium carrier gas at a flow rate of 

9 mL/minute, and a nitrogen make-up gas at a flow rate of 23 mL/minute. 

Elemental analyses for carbon, hydrogen, and nitrogen were in agreement with the theoretical values for 

triethanolamine. Karl Fischer water analysis indicated 0.09% ± 0.01% water. Functional group titration 

indicated 99.3% ± 0.6% total tertiary amines and 100.2% ± 0.4% total titratable amines; the difference 

between the two titration values indicated an impurity equivalent to 0.04 mEq/g sample (0.4% w/w based 

on diethanolamine being the most likely impurity). TLC by system 1 indicated a major spot and two trace 

impurities; system 2 indicated a major spot, a trace impurity, and three slight trace impurities. Gas 

chromatography by system A indicated one major peak and one impurity, with an area of 0.16% relative to 

the major peak; system B indicated one major peak and no impurities with areas of 0.1% or greater relative 

to the major peak. The overall purity of Lot 7G-60 was determined to be approximately 99%. 

The concentrations of nonpolar nitrosamines (N-nitrosodimethylamine, N-nitrosomethylethylamine, 

N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitrosodi-n-butylamine, N-nitrosopiperidine, 

N-nitrosopyrrolidine, and N-nitrosomorpholine) and the polar nitrosamine N-nitrosodiethanolamine in 

lot 7G-60 were determined by Covance Laboratories, Inc. (Madison, WI). To measure nonpolar 

nitrosamines, samples were diluted with high-performance liquid chromatography (HPLC)-grade water and 

then partitioned three times with dichloromethane:pentane (35:65); samples were vortexed and centrifuged 

between each partitioning. The pentane fractions were transferred to a Kuderna-Danish concentrator tube 

with an attached concentrator flask, and dichloromethane, isooctane, and an ebullator were added. A threeball Snyder column prewet with dichloromethane was attached to the concentrator tube, and the entire 

apparatus was placed in a hot water bath until the volume of the solvent was reduced to 4 to 8 mL. The 

sample was allowed to cool, and the concentrated extract was collected with dichloromethane. The sample 

was then heated under a stream of nitrogen until the concentration was less than 1 mL; the volume was 

adjusted to 1.0 mL with isooctane. The samples were then analyzed for nonpolar nitrosamines by gas 

chromatography with a thermal energy detector, a 10% Carbowax 1540 100/120 WHP in 5% KOH column, 

and an argon carrier gas at a flow rate of 25 mL/minute. The oven temperature program was 120° C for 

4 minutes, then 120° to 180° C at 4° C per minute, with a final hold of 8 minutes at 180° C. No nonpolar 

nitrosamines were present at concentrations greater than the limit of detection (0.1 ppm). 
252 Triethanolamine, NTP TR 449 

To measure the polar nitrosamine N-nitrosodiethanolamine, samples were diluted with distilled water, and 

1 N hydrogen chloride was added. The samples were mixed and shaken, then further diluted with distilled 

water and remixed. Two cation exchange columns were prepared; first the solvent, then 0.05 N hydrogen 

chloride, then distilled water was drained in the column to the top of the resin bed. The columns were 

connected in a series with a ChemElut-extraction column. The sample, followed by distilled water, was 

allowed to drip through the three columns and allowed to be absorbed onto the dry column for 10 minutes. 

The columns were then rinsed with 10% acetone in ethyl acetate; N-nitrosodiethanolamine was eluted with 

additional acetone in ethyl acetate, and the samples were concentrated to complete dryness on a rotary 

evaporator with a hot water bath. The dry column was rinsed with methanol three times, and the collected 

samples were dried under a stream of nitrogen; 1 mL of methanol was added, and the samples were then 

analyzed for N-nitrosodiethanolamine by HPLC with a thermal energy detector, an Alltech platinum 5μ CN 

column, and an isocratic solvent system of isooctane:dichloromethane:methanol (71:18:11). The flow rate 

was 0.4 mL/minute. No N-nitrosodiethanolamine was present at a concentration greater than the limit of 

detection (1.0 ppm). 

Stability studies of the bulk chemical were performed on Lot 3B-1-84 with gas chromatography by the 

analytical chemistry laboratory. System A, as described for the purity analyses for this lot, was used, but 

with an isothermal oven temperature of 240E C, and with triethylene glycol added as an internal standard. 

These studies indicated that triethanolamine was stable as a bulk chemical for 2 weeks when stored under a 

nitrogen headspace, protected from light, at temperatures up to 60E C. To ensure stability, the bulk 

chemical was stored at room temperature in amber glass containers under a nitrogen headspace during the 

2-year studies. Stability was monitored by the study laboratory during the 13-week studies with gas 

chromatography and nonaqueous amine titration and during the 2-year studies with gas chromatography. 

No degradation of the bulk chemical was detected. 

PREPARATION AND ANALYSIS OF DOSE FORMULATIONS 

During the 13-week studies, the highest exposure concentrations were applied neat. The lower 

concentrations in the 13-week studies and all dose formulations in the 2-year studies were prepared by 

mixing triethanolamine and acetone to give the required concentration (Table I1). The dose formulations 

were prepared once every 2 weeks and were stored at 5E C in amber glass bottles under a nitrogen 

headspace, protected from light, for up to 3 weeks. 

Stability studies of the 70 mg/mL (125 mg/kg - rats; 250 mg/kg - mice) dose formulation were performed 

with gas chromatography. System A as described for the purity analyses of Lot 3B-1-84 was used, but with 

an isothermal oven temperature of 220E C. The stability of the dose formulations was confirmed for at least 

3 weeks when stored at room temperature in sealed glass vials, under a nitrogen headspace, in the dark and 

for at least 3 hours under animal room conditions (open to air and light). The stability of 10 mg/mL 

triethanolamine in acetone was also confirmed under these conditions by gas chromatography with flame 

ionization detection, a DB-1 column, and an oven temperature program of 80E C for 5 minutes, then 80E to 

190E C at 15E C per minute, with a 3-minute hold. A helium carrier gas at a flow rate of 26 mL/minute 

was used. 

Periodic analyses of the dose formulations of triethanolamine were conducted at the study laboratory and 

analytical chemistry laboratory with gas chromatography. For the 13-week studies, the formulations were 

analyzed at the beginning, midpoint, and end of the studies; animal-room samples of the same dose 

formulations were also analyzed (Table I2). All dose formulations and animal-room samples were within 

10% of the target concentrations. For the 2-year studies, the dose formulations were analyzed at the 

beginning of the studies and every 6 to 10 weeks thereafter; additionally, animal-room samples were 

analyzed every 22 to 26 weeks (Table I3). Of the dose formulations analyzed, 95% (59/62) for rats and all 

formulations for mice were within 10% of the target concentration. All animal-room samples for rats and 
Triethanolamine, NTP TR 449 253 

97% (29/30) for mice were within 10% of the target concentrations. Results of periodic referee analyses 

performed by the analytical chemistry laboratory agreed with the results obtained by the study laboratory 

(Table I4). 
254 Triethanolamine, NTP TR 449 

FIGURE I1 

Infrared Absorption Spectrum of Triethanolamine 
Triethanolamine, NTP TR 449 255 

FIGURE I2 

Nuclear Magnetic Resonance Spectrum of Triethanolamine 
256 Triethanolamine, NTP TR 449 

TABLE I1 

Preparation and Storage of Dose Formulations in the Dermal Studies of Triethanolamine 

13-Week Studies 2-Year Studies 

Preparation 

The highest doses (rats, 2,000 mg/kg; mice, 4,000 mg/kg) were 

applied neat; other doses were prepared by mixing triethanolamine 

with acetone and inverting repeatedly. Doses were prepared every 

2 weeks. 

Same as 13-week studies 

Chemical Lot Number 

3B-1-84 7G-60 

Maximum Storage Time 

3 weeks 3 weeks 

Storage Conditions 

Neat chemical stored at room temperature; triethanolamine:acetone 

mixtures stored at 5E C, protected from light 

Same as 13-week studies 

Study Laboratory 

Battelle Columbus Laboratories 

(Columbus, OH) 

Battelle Columbus Laboratories 

(Columbus, OH) 

Referee Laboratory 

Midwest Research Institute 

(Kansas City, MO) 

Midwest Research Institute 

(Kansas City, MO) 
Triethanolamine, NTP TR 449 257 

TABLE I2 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week Dermal Studies of Triethanolamine 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentrationa 

(mg/mL) 

Difference 

from Target 

(%) 

Rats 

23 June 1986 26 June 1986 70 

140 

280 

560 

70.8 

141 

279 

560 

+1 

+1 

0 

0 

16 July 1986b 70 

140 

280 

560 

72.3 

145 

284 

571 

+3 

+4 

+1 

+2 

4 August 1986 7 August 1986 70 

140 

280 

560 

67.2 

143 

283 

561 

!4 

+2 

+1 

0 

2 September 1986b 70 

140 

280 

560 

73.1 

143 

283 

567 

+4 

+2 

+1 

+1 

15 September 1986 16 September 1986 70 

140 

280 

560 

71.1 

136 

271 

559 

+2 

!3 

!3 

0 

7 October 1986b 70 

140 

280 

560 

67.8 

144 

297 

568 

!3 

+3 

+6 

+1 

Mice 

4 August 1986 7 August 1986 70 

140 

280 

560 

67.9 

144 

279 

561 

!3 

+3 

0 

0 

2 September 1986b 70 

140 

280 

560 

75.1 

143 

285 

551 

+7 

+2 

+2 

!2 

15 September 1986 16 September 1986 70 

140 

280 

560 

69.6 

134 

258 

535 

!1 

!4 

!8 

!5 

7 October 1986b 70 

140 

280 

560 

67.3 

144 

284 

562 

!4 

+3 

+1 

0 
258 Triethanolamine, NTP TR 449 

TABLE I2 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week Dermal Studies of Triethanolamine (continued) 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentration 

(mg/mL) 

Difference 

from Target 

(%) 

Mice (continued) 

27 October 1986 28 October 1986 70 

140 

280 

560 

68.6 

138 

277 

544 

!2 

!1 

!1 

!3 

19 November 1986b 70 

140 

280 

560 

66.9 

140 

284 

563 

!4 

0 

+1 

+1 

a Results of duplicate analyses. For rats, 70 mg/mL=125 mg/kg; 140 mg/mL=250 mg/kg; 280 mg/mL=500 mg/kg; 

560 mg/mL=1,000 mg/kg. For mice, 70 mg/mL=250 mg/kg; 140 mg/mL=500 mg/kg; 280 mg/mL=1,000 mg/kg; 

560 mg/mL=2,000 mg/kg. b Animal room samples 
Triethanolamine, NTP TR 449 259 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentrationa 

(mg/mL) 

Difference 

from Target 

(%) 

Rats 

7 November 1988 9 November 1988 50 

100b 

100c 

200b 

200c 

400 

48.9 

98.1 

98.0 

195 

195 

393 

!2 

!2 

!2 

!2 

!2 

!2 

1-2 December 1988d 50 

100b 

100c 

200b 

200c 

400 

53.0 

108 

106 

197 

198 

395 

+6 

+8 

+6 

!1 

!1 

!1 

20 December 1988 23-24 December 1988 50 

100b 

100c 

200b 

200c 

400 

50.3 

103 

101 

203 

197 

396 

+1 

+3 

+1 

+2 

!1 

!1 

14 February 1989 16-18 February 1989 50 

100b 

100c 

200b 

200c 

400 

47.8 

97.4 

100 

201 

203 

391 

!4 

!3 

0 

+1 

+2 

!2 

11 April 1989 14-15 April 1989 50 

100 

200 

400 

48.8 

103 

193 

386 

!2 

+3 

!3 

!3 

25-26 April 1989d 50 

100b 

100c 

200b 

200c 

400 

50.4 

103 

99.0 

203 

207 

397 

+1 

+3 

!1 

+2 

+4 

!1 

6 June 1989 7-8 June 1989 50 

100 

200 

400 

50.0 

104 

213 

408 

0 

+4 

+7 

+2 

1 August 1989 3 August 1989 50 

100 

200 

400 

55.2 

109 

203 

403 

+10 

+9 

+2 

+1 

4 August 1989e 50 50.8 +2 
260 Triethanolamine, NTP TR 449 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine (continued) 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentration 

(mg/mL) 

Difference 

from Target 

(%) 

Rats (continued) 

26 September 1989 29 September 1989 50 

100 

200 

400 

55.5 

123 

210 

400 

+11 

+23 

+5 

0 

30 September ­

1 October 1989e 50 

100 

48.1 

98.0 

!4

!2 

19 October 1989d 50 

100b 

100c 

200b 

200c 

400 

48.7 

103 

102 

211 

209 

414 

!3 

+3 

+2 

+6 

+5 

+4 

20 November 1989 22 November 1989 50 

100 

200 

400 

53.1 

107 

212 

405 

+6 

+7 

+6 

+1 

16 January 1990 18 January 1990 50 

100 

200 

400 

51.1 

102 

206 

402 

+2 

+2 

+3 

+1 

13 March 1990 16 March 1990 50 

100 

200 

400 

48.8 

98.0 

199 

402 

!2 

!2 

0 

+1 

23 April 1990 26 April 1990 50 

100 

200 

400 

49.6 

96.2 

192 

382 

!1 

!4 

!4 

!4 

9 May 1990d 50 

100b 

100c 

200b 

200c 

400 

50.9 

103 

104 

206 

208 

408 

+2 

+3 

+4 

+3 

+4 

+2 

18 June 1990 19 June 1990 50 

100 

200 

400 

50.9 

103 

202 

415 

+2 

+3 

+1 

+4 
Triethanolamine, NTP TR 449 261 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine (continued) 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentration 

(mg/mL) 

Difference 

from Target 

(%) 

Rats (continued) 

13 August 1990 15 August 1990 50 

100 

200 

400 

50.2 

101 

209 

434 

0 

+1 

+5 

+9 

8 October 1990 10 October 1990 50 

100 

200 

400 

52.9 

108 

405 

420 

+6 

+8 

+103 

+5 

12 October 1990f 12 October 1990 200 199 0 

8 and 12 October 1990 31 October 1990d 50 

100b 

100c 

200b 

200c 

400 

53.0 

109 

109 

211 

214 

436 

+6 

+9 

+9 

+6 

+7 

+9 

Mice 

25 October 1988 27-28 October 1988 50 

100 

150 

300 

500 

1,000 

49.4 

99.9 

147 

294 

486 

1,030 

!1 

0 

!2 

!2 

!3 

+3 

11 November 1988d 50 

100 

150 

300 

500 

1,000 

52.2 

103 

154 

306 

511 

999 

+4 

+3 

+3 

+2 

+2 

0 

20 December 1988 23-24 December 1988 50 

100 

150 

300 

500 

1,000 

50.4 

102 

154 

305 

492 

1,060 

+1 

+2 

+3 

+2 

!2 

+6 

14 February 1989 16-18 February 1989 50 

100 

150 

300 

500 

1,000 

48.6 

97.5 

146 

298 

503 

977 

!3 

!2 

!3 

!1 

+1 

!2 
262 Triethanolamine, NTP TR 449 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine (continued) 

Date Prepared Date Analyzed 

Target 

Concentration 

(mg/mL) 

Determined 

Concentration 

(mg/mL) 

Difference 

from Target 

(%) 

Mice (continued) 

11 April 1989 14-15 April 1989 50 

100 

150 

300 

500 

1,000 

50.0 

98.9 

146 

294 

510 

956g 

0 

!1 

!3 

!2 

+2 

!4 

15 April 1989f 16 April 1989 1,000 1,030 +3 

11 and 15 April 1989 25-26 April 1989d 50 

100 

150 

300 

500 

1,000 

52.0 

107 

157 

311 

515 

1,060 

+4 

+7 

+5 

+4 

+3 

+6 

6 June 1989 7-8 June 1989 50 

100 

150 

300 

500 

1,000 

49.3 

101 

153 

308 

513 

1,030 

!1 

+1 

+2 

+3 

+3 

+3 

1 August 1989 3 August 1989 50 

100 

150 

300 

500 

1,000 

54.4 

108 

161 

316 

530 

1,100 

+9 

+8 

+7 

+5 

+6 

+10 

4 August 1989e 50 

100 

1,000 

53.9 

107 

1,050 

+8 

+7 

+5 

26 September 1989 29 September 1989 50 

100 

150 

300 

500 

1,000 

52.9 

107 

165 

337 

537 

1,060 

+6 

+7 

+10 

+12 

+7 

+6 

30 September ­

1 October 1989e 150 

300 

153 

304 

+2

+1 

19 October 1989d 50 

100 

150 

300 

500 

1,000 

49.4 

101 

158 

304 

538 

1,050 

!1 

+1 

+5 

+1 

+8 

+5 
Triethanolamine, NTP TR 449 263 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine (continued) 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Mice (continued) 

20 November 1989 22 November 1989 50 52.5 +5 

100 109 +9 

150 159 +6 

300 315 +5 

500 522 +4 

1,000 1,090 +9 

16 January 1990 18 January 1990 50 51.7 +3 

100 103 +3 

150 154 +3 

300 303 +1 

500 505 +1 

1,000 1,030 +3 

13 March 1990 16 March 1990 50 49.4 !1 

100 98.5 !1 

150 150 0 

300 302 +1 

500 505 +1 

1,000 945 !5 

23 April 1990 26 April 1990 50 45.8 !8 

100 103 +3 

150 139 !7 

300 275 !8 

500 466 !7 

1,000 939 !6 

9 May 1990d 50 52.0 +4 

100 100 0 

150 151 +1 

300 291 !3 

500 498 0 

1,000 975 !2 

18 June 1990 19 June 1990 50 49.9 0 

100 99.1 !1 

150 149 !1 

300 299 0 

500 499 0 

1,000 1,030 +3 

13 August 1990 15 August 1990 50 50.3 +1 

100 107 +7 

150 162 +8 

300 324 +8 

500 530 +6 

1,000 1,050 +5 
264 

c 

Triethanolamine, NTP TR 449 

TABLE I3 

Results of Analysis of Dose Formulations Administered to Rats and Mice 

in the 2-Year Dermal Studies of Triethanolamine (continued) 

Target Determined Difference 

Date Prepared Date Analyzed Concentration Concentration from Target 

(mg/mL) (mg/mL) (%) 

Mice (continued) 

8 October 1990 11 October 1990 50 52.6 +5 

100 107 +7 

150 156 +4 

300 311 +4 

500 514 +3 

1,000 1,100 +10 

d 31 October 1990 50 51.5 +3 

100 111 +11 

150 160 +7 

300 324 +8 

500 519 +4 

1,000 1,030 +3 

a Results of duplicate analyses. For rats, 50 mg/mL=32 mg/kg; 100 mg/mL=63 mg/kg; 200 mg/mL=125 mg/kg; 400 mg/mL=250 mg/kg. 

For mice, 50 mg/mL=100 mg/kg; 100 mg/mL=200 mg/kg; 150 mg/mL=300 mg/kg; 300 mg/mL=630 mg/kg; 

500 mg/mL=1,000 mg/kg; 1,000 mg/mL=2,000 mg/kg. b Dose formulations for males 

Dose formulations for females 

d Animal-room samples e Dose formulations were reanalyzed due to problems associated with a changing baseline (3 August 1989 formulations) or integration 

problems resulting from solvent peak tailing. f Results of remix of dosing solutions prepared on 8 October 1990 (rats) and 11 April 1989 (mice) 

g Duplicate and triplicate analyses indicated E/O (expected/observed) was less than 0.90; dose formulation was remixed. 
265 

c 

Triethanolamine, NTP TR 449 

TABLE I4 

Results of Referee Analysis of Dose Formulations Administered to Rats and Mice 

in the 13-Week and 2-Year Dermal Studies of Triethanolamine 

Determined Concentration (mg/mL) 

Target Concentration Study Referee a b c Date Prepared (mg/mL) Laboratory Laboratory 

13-Week Study 

Rats 

23 June 1986 280 279 288 ± 2 

15 September 1986 70 71.1 69.8 ± 0.3 

2-Year Studies 

Rats 

7 November 1988 400 393 401 ± 3 

11 April 1989 50 48.8 52.6 ± 2.0 

26 September 1989 200 210 207 ± 1 

Mice 

25 October 1988 150 147 154 ± 1 

a For 13-week study rats, 70 mg/mL=125 mg/kg; 280 mg/mL=500 mg/kg. For 2-year study rats, 50 mg/mL=32 mg/kg; 

200 mg/mL=125 mg/kg; 400 mg/mL=250 mg/kg. For mice, 150 mg/mL=300 mg/kg. b Results of duplicate analyses 

Results of triplicate analyses (mean ± standard error) 
266 Triethanolamine, NTP TR 449 
267 

APPENDIX J 

INGREDIENTS, NUTRIENT COMPOSITION, 

AND CONTAMINANT LEVELS 

IN NIH-07 RAT AND MOUSE RATION 

TABLE J1 

TABLE J2 

TABLE J3 

TABLE J4 

Ingredients of NIH-07 Rat and Mouse Ration .............................. 

Vitamins and Minerals in NIH-07 Rat and Mouse Ration ...................... 

Nutrient Composition of NIH-07 Rat and Mouse Ration ...................... 

Contaminant Levels in NIH-07 Rat and Mouse Ration ........................ 

268 

268 

269 

270 
268 Triethanolamine, NTP TR 449 

TABLE J1 

Ingredients of NIH-07 Rat and Mouse Rationa 

Ingredientsb Percent by Weight 

Ground #2 yellow shelled corn 24.50 

Ground hard winter wheat 23.00 

Soybean meal (49% protein) 12.00 

Fish meal (60% protein) 10.00 

Wheat middlings 10.00 

Dried skim milk 5.00 

Alfalfa meal (dehydrated, 17% protein) 4.00 

Corn gluten meal (60% protein) 3.00 

Soy oil 2.50 

Dried brewer’s yeast 2.00 

Dry molasses 1.50 

Dicalcium phosphate 1.25 

Ground limestone 0.50 

Salt 0.50 

Premixes (vitamin and mineral) 0.25 

a NCI, 1976; NIH, 1978 b Ingredients were ground to pass through a U.S. Standard Screen No. 16 before being mixed. 

TABLE J2 

Vitamins and Minerals in NIH-07 Rat and Mouse Rationa 

Amount Source 

Vitamins 

A 5,500,000 IU Stabilized vitamin A palmitate or acetate 

D3 4,600,000 IU D-activated animal sterol 

K3 2.8 g Menadione 

d-"-Tocopheryl acetate 20,000 IU 

Choline 560.0 g Choline chloride 

Folic acid 2.2 g 

Niacin 30.0 g 

d-Pantothenic acid 18.0 g d-Calcium pantothenate 

Riboflavin 3.4 g 

Thiamine 10.0 g Thiamine mononitrate 

B12 4,000 μg 

Pyridoxine 1.7 g Pyridoxine hydrochloride 

Biotin 140.0 mg d-Biotin 

Minerals 

Iron 120.0 g Iron sulfate 

Manganese 60.0 g Manganous oxide 

Zinc 16.0 g Zinc oxide 

Copper 4.0 g Copper sulfate 

Iodine 1.4 g Calcium iodate 

Cobalt 0.4 g Cobalt carbonate 

a Per ton (2,000 lb) of finished product 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Triethanolamine, NTP TR 449 269 

TABLE J3 

Nutrient Composition of NIH-07 Rat and Mouse Ration 

Mean ± Standard 

Nutrient Deviation Range Number of Samples 

Protein (% by weight) 23.16 ± 0.68 21.80 - 24.20 24 

Crude fat (% by weight) 5.30 ± 0.22 4.60 - 5.60 24 

Crude fiber (% by weight) 3.63 ± 0.41 2.80 - 4.30 24 

Ash (% by weight) 6.50 ± 0.21 6.11 - 7.00 24 

Amino Acids (% of total diet) 

Arginine 1.287 ± 0.084 1.100 - 1.390 10 

Cystine 0.306 ± 0.075 0.181 - 0.400 10 

Glycine 1.160 ± 0.050 1.060 - 1.220 10 

Histidine 0.580 ± 0.024 0.531 - 0.608 10 

Isoleucine 0.917 ± 0.034 0.867 - 0.965 10 

Leucine 1.972 ± 0.052 1.850 - 2.040 10 

Lysine 1.273 ± 0.051 1.200 - 1.370 10 

Methionine 0.437 ± 0.115 0.306 - 0.699 10 

Phenylalanine 0.994 ± 0.125 0.665 - 1.110 10 

Threonine 0.896 ± 0.055 0.824 - 0.985 10 

Tryptophan 0.223 ± 0.160 0.107 - 0.671 10 

Tyrosine 0.677 ± 0.105 0.564 - 0.794 10 

Valine 1.089 ± 0.057 0.962 - 1.170 10 

Essential Fatty Acids (% of total diet) 

Linoleic 2.389 ± 0.233 1.830 - 2.570 9 

Linolenic 0.277 ± 0.036 0.210 - 0.320 9 

Vitamins 

Vitamin A (IU/kg) 6,690 ± 2,011 4,180 - 12,140 24 

Vitamin D (IU/kg) 4,450 ± 1,382 3,000 - 6,300 4 

"-Tocopherol (ppm) 36.92 ± 9.32 22.5 - 48.9 9 

Thiamine (ppm) 19.20 ± 2.30 16.0 - 28.0 24 

Riboflavin (ppm) 7.92 ± 0.93 6.10 - 9.00 10 

Niacin (ppm) 100.95 ± 25.92 65.0 - 150.0 9 

Pantothenic acid (ppm) 30.30 ± 3.60 23.0 - 34.6 10 

Pyridoxine (ppm) 9.25 ± 2.62 5.60 - 14.0 10 

Folic acid (ppm) 2.51 ± 0.64 1.80 - 3.70 10 

Biotin (ppm) 0.267 ± 0.049 0.19 - 0.35 10 

Vitamin B (ppb) 40.14 ± 20.04 10.6 - 65.0 10 12 

Choline (ppm) 3,068 ± 314 2,400 - 3,430 9 

Minerals 

Calcium (%) 1.22 ± 0.11 1.00 - 1.54 24 

Phosphorus (%) 0.95 ± 0.03 0.90 - 1.00 24 

Potassium (%) 0.887 ± 0.067 0.772 - 0.971 8 

Chloride (%) 0.526 ± 0.092 0.380 - 0.635 8 

Sodium (%) 0.315 ± 0.344 0.258 - 0.370 10 

Magnesium (%) 0.168 ± 0.008 0.151 - 0.180 10 

Sulfur (%) 0.274 ± 0.063 0.208 - 0.420 10 

Iron (ppm) 356.2 ± 90.0 255.0 - 523.0 10 

Manganese (ppm) 92.24 ± 5.35 81.70 - 99.40 10 

Zinc (ppm) 58.14 ± 9.91 46.10 - 81.60 10 

Copper (ppm) 11.50 ± 2.40 8.090 - 15.39 10 

Iodine (ppm) 3.70 ± 1.14 1.52 - 5.83 10 

Chromium (ppm) 1.71 ± 0.45 0.85 - 2.09 9 

Cobalt (ppm) 0.80 ± 0.23 0.490 - 1.150 6 
 

 

 

 

 

 

270 Triethanolamine, NTP TR 449 

TABLE J4 

Contaminant Levels in NIH-07 Rat and Mouse Rationa 

Mean ± Standard 

Deviationb Range Number of Samples 

Contaminants 

Arsenic (ppm) 0.27 ± 0.18 0.06 - 0.06 24 

Cadmium (ppm) 0.08 ± 0.02 0.05 - 0.10 24 

Lead (ppm) 0.23 ± 0.09 0.10 - 0.40 24 

Mercury (ppm) 0.04 ± 0.02 0.02 - 0.11 24 c Selenium (ppm) 0.42 ± 0.25 0.20 - 1.21 24 

Aflatoxins (ppb)d <5.0 24 e Nitrate nitrogen (ppm) 16.70 ± 4.10 8.60 - 24.0 24 e Nitrite nitrogen (ppm) 0.25 ± 0.20 <0.10 - 0.70 24 

BHA (ppm)f 1.42 ± 0.58 <1.00 - 3.00 24 

BHT (ppm)f 1.38 ± 0.58 <1.00 - 3.00 24 

Aerobic plate count (CFU/g) 41,892 ± 25,056 6,700 - 120,000 24 

Coliform (MPN/g) 4.60 ± 5.40 3.00 - 23.00 24 

Escherichia coli (MPN/g) <3.00 24 

Salmonella (MPN/g) Negative 13 

Total nitrosoamines (ppb)g 7.70 ± 2.90 3.60 - 16.5 24 

N-Nitrosodimethylamine (ppb)g 5.90 ± 2.60 2.60 - 13.0 24 

N-Nitrosopyrrolidine (ppb)g 1.81 ± 0.90 1.00 - 3.9 24 

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 <0.1 25 

Estimated PCBs <0.2 25 

Ronnel <0.01 25 

Ethion <0.02 25 

Trithion <0.05 25 

Diazinon <0.1 25 

Methyl parathion <0.02 25 

Ethyl parathion <0.02 25 

h Malathion 0.23 ± 0.20 <0.05 - 1.00 24 

Endosulfan I <0.01 25 

Endosulfan II <0.01 25 

Endosulfan sulfate <0.03 25 

a CFU=colony-forming units; MPN=most probable number; BHC=hexachlorocyclohexane or benzene hexachloride b For values less than the limit of detection, the detection limit is given as the mean. 

One lot milled 2 March 1989 and one lot milled 2 June 1989 contained more than 0.6 ppm. d No aflatoxin measurement was recorded for the lot milled 2 October 1989. e Sources of contamination: alfalfa, grains, and fish meal f Sources of contamination: soy oil and fish meal 

g All values were corrected for percent recovery. h One lot milled 1 September 1989 contained more than 0.51 ppm. 

c 
271 

APPENDIX K 

SENTINEL ANIMAL PROGRAM 

METHODS ............................................................... 

RESULTS ................................................................ 

272 

274 
272 Triethanolamine, NTP TR 449 

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 all subject to identical 

environmental conditions. The sentinel animals come from the same production source and weanling groups as 

the animals used for the studies of chemical compounds. 

Serum samples were collected from randomly selected rats and mice during the 13-week and 2-year studies. 

During the 2-year mouse study, the evaluations usually performed at 6 months were performed at 51⁄2 months, 

and an extra mouse hepatitis virus screening was performed at 6 months. Blood from each animal was collected, 

allowed to clot, and the serum separated. The samples were processed appropriately and sent to Microbiological 

Associates, Inc. (Bethesda, MD), for determination of antibody titers. The laboratory serology methods and 

viral agents for which testing was performed are tabulated below; the times at which blood was collected during 

the studies are also listed. 

Method and Test Time of Analysis 

RATS 

13-Week Study 

ELISA 

Mycoplasma arthritidis 

Mycoplasma pulmonis 

PVM (pneumonia virus of mice) 

RCV (rat coronavirus) 

RCV/SDA 

(rat coronavirus/sialodacryoadenitis virus) 

Sendai 

Quarantine and study initiation 

Quarantine and study initiation 

Quarantine, study initiation, and study termination 

Study initiation and study termination 

Quarantine 

Quarantine, study initiation, and study termination 

Hemagglutination Inhibition 

H-1 (Toolan’s H-1 virus) 

KRV (Kilham rat virus) 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

2-Year Study 

ELISA 

M. arthritidis 

M. pulmonis 

PVM 

RCV/SDA 

Sendai 

24 months 

24 months 

Quarantine, 6, 12, 18, and 24 months 

Quarantine, 6, 12, 18, and 24 months 

Quarantine, 6, 12, 18, and 24 months 

Immunofluorescence Assay 

RCV/SDA 12, 18, and 24 months 

Hemagglutination Inhibition 

H-1 

KRV 

Quarantine, 6, 12, 18, and 24 months 

Quarantine, 6, 12, 18, and 24 months 
Triethanolamine, NTP TR 449 273 

MICE 

13-Week Study 

Complement Fixation 

LCM (lymphocytic choriomeningitis virus) 

ELISA 

CARB (cilia-associated respiratory bacillus) 

Ectromelia virus 

GDVII (mouse encephalomyelitis virus) 

M. arthritidis 

M. pulmonis 

Mouse adenoma virus 

MHV (mouse hepatitis virus) 

PVM 

Reovirus 3 

Sendai 

Immunofluorescence Assay 

EDIM (epizootic diarrhea of infant mice) 

LCM 

Hemagglutination Inhibition 

K (papovavirus) 

MVM (minute virus of mice) 

Polyoma virus 

2-Year Study 

ELISA 

Ectromelia virus 

EDIM 

GDVII 

LCM 

M. arthritidis 

M. pulmonis 

MVM 

Mouse adenoma virus 

Mouse adenoma virus-FL 

MHV 

PVM 

Reovirus 3 

Sendai 

Immunofluorescence Assay 

EDIM 

GDVII 

LCM 

Mouse adenoma virus-FL 

MVM 

MHV 

Reovirus 3 

Quarantine and study initiation 

Quarantine and study initiation 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine and study initiation 

Quarantine and study initiation 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, study initiation, and study termination 

Quarantine, 51⁄2, 12, 18, and 24 months 

18 and 24 months 

Quarantine, 51⁄2, 12, 18, and 24 months 

12, 18, and 24 months 

24 months 

24 months 

Quarantine and 51⁄2 months 

Quarantine, 51⁄2, 12, and 18 months 

24 months 

Quarantine, 51⁄2, 6, 12, 18, and 24 months 

Quarantine, 51⁄2, 12, 18, and 24 months 

Quarantine, 51⁄2, 12, 18, and 24 months 

Quarantine, 51⁄2, 12, 18, and 24 months 

Quarantine, 51⁄2, 12, and 18 months 

24 months 

Quarantine and 51⁄2 months 

12 and 24 months 

12 and 18 months 

51⁄2 months 

24 months 
274 Triethanolamine, NTP TR 449 

MICE (continued) 

2-Year Study (continued) 

Hemagglutination Inhibition 

K Quarantine, 51⁄2, 12, 18, and 24 months 

MVM 24 months 

Polyoma virus Quarantine, 51⁄2, 12, 18, and 24 months 

RESULTS 

One rat had positive titers to M. arthritidis at the beginning of the 13-week study; one rat and one mouse also 

had positive titers to M. arthritidis at the end of the 2-year studies. Further evaluation of serum positive for 

M. arthritidis by immunoblot and Western blot procedures indicated that the positive titers may have been due to 

cross reaction with antibodies of nonpathogenic Mycoplasma or other agents. Only sporadic samples were 

positive, and there were no clinical findings or histopathologic changes of M. arthritidis infection in animals with 

positive titers. Accordingly, M. arthritidis-positive titers were considered to be false positives. 
 

 

275 

APPENDIX L 

IMPACT OF HELICOBACTER HEPATICUS 

INFECTION IN B6C3F1  MICE

FROM 12 NTP 2-YEAR CARCINOGENESIS STUDIES 

1	 1 1 1 James R. Hailey , Joseph K. Haseman , John R. Bucher , Ann E. Radovsky , 2 2 1	 1 David E. Malarkey , Richard T. Miller , Abraham Nyska , and Robert R. Maronpot

1

National Institute of Environmental Health Sciences 

Research Triangle Park, North Carolina 

2

Department of Microbiology, Pathology, and Parasitology 

College of Veterinary Medicine 

North Carolina State University 

Raleigh, North Carolina 

ABSTRACT ............................................................... 276 

INTRODUCTION ............................................................ 276 

MATERIALS AND METHODS .................................................... 277 

RESULTS AND DISCUSSION ..................................................... 279 

REFERENCES ............................................................. 286 

TABLE L1 Incidence of Helicobacter hepaticus-Associated Hepatitis in Control B6C3F1 

 Mice

from Nine NTP 2-Year Studies ....................................... 290 

TABLE L2 Identification of Helicobacter hepaticus with PCR-RFLP-Based Assays 

in Control B6C3F Mice from 32 NTP 2-Year Studies 1 

and Three NTP 13-Week Studies ...................................... 290 

TABLE L3 Comparison of Neoplasm Incidences in Control B6C3F1 

 Mice

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies .......... 291 

TABLE L4 Liver Neoplasm Incidences and Body Weights of Control B6C3F1 

 Mice

in Relation to Study Start Dates of Helicobacter hepaticus-Affected 

and Unaffected NTP 2-Year Studies .................................... 292 

TABLE L5 Association of Liver Neoplasm Incidence 

and Severity of Helicobacter hepaticus-Associated Hepatitis 

in Control B6C3F1  Mice from Nine Affected NTP 2-Year Studies ................ 293

TABLE L6	 H-ras Codon 61 AAA Mutations in Spontaneous Liver Neoplasms 

in Control B6C3F1  Mice from Helicobacter hepaticus-Affected

and Unaffected NTP 2-Year Studies .................................... 293 

TABLE L7 Proliferating Cell Nuclear Antigen Labeling Indices in the Liver 

of Control B6C3F1  Mice ............................................ 294

TABLE L8	 Summary of Target Sites of Carcinogenicity in B6C3F Mice 1 

from NTP 2-Year Studies with Helicobacter hepaticus-Associated Hepatitis ......... 295 
276 Triethanolamine, NTP TR 449 

IMPACT OF HELICOBACTER HEPATICUS 

INFECTION IN B6C3F MICE 1 

FROM 12 NTP 2-YEAR CARCINOGENESIS STUDIES 

ABSTRACT 

Male and female B6C3F1 mice from 12 NTP 2-year carcinogenesis studies were found to be infected with

Helicobacter hepaticus. Many of the male mice from nine of these studies (“affected” studies) had an 

associated hepatitis. The current evaluations were performed in an attempt to determine if the data from the 

H. hepaticus-affected NTP B6C3F1 mouse studies were compromised and unsuitable for cancer hazard

identification. The incidences of neoplasms of the liver (both hepatocellular neoplasms and 

hemangiosarcoma), but not of other organs in control male B6C3F1 mice, were found to be increased in

affected studies compared to control males from unaffected studies. The increased incidence of 

hepatocellular neoplasms was observed in those males exhibiting H. hepaticus-associated hepatitis. Other 

observations further differentiated control male mice from affected and unaffected studies. H-ras codon 61 

CAA-to-AAA mutations were less common in liver neoplasms in males from affected studies compared to 

historical and unaffected study controls. In addition, increases in cell proliferation rates and apoptosis were 

observed in the livers of male mice with H. hepaticus-associated hepatitis. These data support the 

hypothesis that the increased incidence of liver neoplasms is associated with H. hepaticus and that hepatitis 

may be important in the pathogenesis. Therefore, interpretation of carcinogenic effects in the liver of 

B6C3F mice may be confounded if there is H. hepaticus-associated hepatitis. 1 

INTRODUCTION 

Helicobacter-Induced Diseases 

Since the bacterium H. pylori was isolated from humans in 1983, numerous Helicobacter species have been 

identified in several laboratory and domestic animal species. Their pathogenicity varies, with some species 

inducing significant disease while others appear merely to colonize the gastrointestinal tract. H. pylori is 

known to cause chronic gastritis and peptic ulcers in humans (Marshall and Warren, 1984; Graham, 1989; 

Lee et al., 1993) and, more recently, has been linked to adenocarcinoma and mucosa-associated lymphoma 

of the stomach (Fox et al., 1989; Nomura et al., 1991; Parsonnet et al., 1991; Wotherspoon et al., 1993). 

Based on epidemiological and pathology findings, the International Agency for Research on Cancer (1994) 

has classified H. pylori as a group 1 carcinogen in humans. H. hepaticus is associated with an increase in 

liver neoplasm incidences in A/JCr mice (Ward et al., 1994a; Fox et al., 1996). 

H. hepaticus commonly colonizes the gastrointestinal tract of many strains of mice from many sources (Fox 

et al., 1994; Ward et al., 1994b; Shames et al., 1995). It has been shown to be pathogenic, with hepatitis 

highly prevalent in some strains of mice (A/JCr, BALB/cAnNCr, C3H/HeNCr, SJL/NCr, and SCID/NCr) 

(Ward et al., 1994b). Intestinal colonization does not necessarily result in subsequent hepatitis, and the 

conditions that lead to migration of the organism from the intestine to the liver have not been determined. 

H. hepaticus appears to reside primarily within the bile canaliculi. Male mice were reported to have a 

greater incidence and severity of hepatitis than female mice, and this finding occurred in NTP studies as 

well. The recently identified H. bilis, like H. hepaticus, colonizes the biliary tract, liver, and intestine of 

mice. While H. bilis has been identified in animals with chronic hepatitis, whether it caused the hepatitis is 

not known (Fox et al., 1995). 

The pathogenesis of H. hepaticus-induced disease has not been fully characterized. In susceptible strains of 

mice, H. hepaticus can cause acute, focal, nonsuppurative, necrotizing hepatitis, which progresses to 

chronic, active hepatitis characterized by minimal necrosis, hepatocytomegaly, oval cell hyperplasia, and 
Triethanolamine, NTP TR 449 277 

cholangitis. H. hepaticus has been found to possess high levels of urease (Fox et al., 1994). H. hepaticus 

is often isolated from the cecum and colon but is not necessarily isolated from the liver of A/JCr mice, even 

though these animals develop severe hepatitis. Culture supernatants from several strains of H. hepaticus 

and several other Helicobacter species were shown to cause cytopathic effects in a rodent hepatocyte cell 

line (Taylor et al., 1995). Ward et al. (1996) suggested that autoimmunity may play a role in the 

progressive hepatitis and carcinogenesis in livers infected with H. hepaticus. 

NTP Infectious Disease Surveillance 

In 1993, during the histological evaluation of an NTP 2-year study, pathologists identified a constellation of 

liver lesions (hepatitis) in control and treated male mice that was consistent with what would later be 

described in mice infected with H. hepaticus (Ward et al., 1993, 1994a; Fox et al., 1994). Subsequently, 

pathology results from all mouse studies begun since 1984 (67 two-year studies) were reviewed for 

diagnoses of the characteristic hepatitis; the lesions were identified in nine studies (NTP, 1998a,b,c,d, 

1999a,b). Silver stains revealed helical bacteria consistent with Helicobacter present in the liver of male 

mice in the nine studies. 

Every reasonable measure is taken to prevent the occurrence of infectious diseases during NTP 2-year 

carcinogenicity studies. When infections occasionally occur, care is taken to identify the causal agent and 

its source, measures are taken to ensure that animals in later studies will not be infected, and the potential 

impact on biological parameters (primarily neoplastic endpoints) important in interpretation of the study is 

determined. To date, animals (control and treated) from a few studies have had a mild pulmonary 

inflammatory response presumed to be caused by an infectious agent. In other studies, there have been 

utero-ovarian infections with Klebsiella sp. (Rao et al., 1987) and fungal infections of the nasal cavity. For 

scientifically valid reasons, interpretation of chemical-related effects was not considered significantly 

compromised in any of these studies. Unlike the previous infections, H. hepaticus involves the liver, the 

major metabolic organ, and has been associated with an increase in incidences of liver neoplasms in the 

A/JCr mouse (Ward et al., 1994a). Therefore, when the contemporary epizootic of H. hepaticus infection 

in the United States affected several NTP studies, use of the data for hazard identification was questioned. 

The first step was to determine the extent of the infection within NTP studies and then evaluate the impact 

the infection had on biological parameters important in interpretation of the carcinogenic potential of test 

chemicals. 

MATERIALS AND METHODS 

Histologic Examination 

Studies in which mice were potentially infected with H. hepaticus were identified by reviewing the summary 

pathology tables for characteristic diagnoses: oval and/or biliary epithelial hyperplasia, hepatocyte 

enlargement (often diagnosed as karyomegaly), chronic inflammation, and regenerative hyperplasia. All 

13-week and 2-year studies begun by the NTP since 1984 and for which complete pathology data were 

available (67 two-year studies) were examined. Eight contemporary studies in which the characteristic 

lesions were not identified from pathology tables were randomly selected for histologic reevaluation. Slides 

containing sections of hematoxylin- and eosin-stained livers from 20 to 25 control and 20 to 25 high-dose 

male mice from each of seven 2-year studies and one 13-week study (10 animals from each group) were 

reexamined microscopically for the presence of hepatitis potentially related to H. hepaticus infection. 

Hepatitis consistent with that observed with H. hepaticus infection was not observed in any of these studies. 

Liver sections from five or more animals from each of nine 2-year studies in which hepatitis was observed 

were prepared using the Warthin-Starry silver stain or Steiner’s modification to identify silver-positive 

helical bacteria. 
278 Triethanolamine, NTP TR 449 

PCR-RFLP Detection of Helicobacter DNA 

Assays based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were 

conducted at the NIEHS (Malarkey et al., 1997) and the University of Missouri Research Animal 

Diagnostic and Investigative Laboratory (MU-RADIL) (Riley et al., 1996) on liver tissue from 

approximately 20 animals from each of 32 NTP 2-year studies (including the nine affected studies) and three 

NTP 13-week studies. The majority of these studies were selected because they were begun at 

approximately the same time (1988-1990) as the nine affected studies. Also, two earlier studies 

(1984-1985; mouse life-span and p-nitroaniline studies) and one later study (1993; methyleugenol) were 

selected. The mouse life-span study was designed to evaluate the incidences of spontaneous changes 

associated with age; therefore, there is no NTP Technical Report. Frozen tissue was available from 22 of 

these studies, while only formalin-fixed tissue was available for the remaining ten 2-year studies and the 

three 13-week studies. Most of the assays were conducted by MU-RADIL, which used Helicobacter genusspecific primers; MU-RADIL used restriction endonucleases on a subset of positives to determine if the 

species was H. hepaticus. DNA was isolated from frozen liver samples with a QIAamp Tissue Kit (Qiagen 

Inc., Chatsworth, CA) according to the manufacturer’s recommendations or routine phenol/chloroform 

extraction (Malarkey et al., 1997). DNA content and purity were determined spectrophotometrically by 

measuring the A260/A280 optical density ratio. To isolate DNA from paraffin-embedded samples, five 10-μm 

sections were washed twice with 1 mL xylene and twice with 500 μL ethanol. Tissues were then dried 

within a vacuum centrifuge prior to DNA isolation as described above. Routine measures were taken to 

avoid contamination at every step from tissue collection to PCR amplification, and concurrently run controls 

without DNA were consistently negative. 

Statistical Analyses 

Multiple regression procedures were used to compare control neoplasm rates in the nine affected studies 

with the 26 unaffected contemporary studies which had no histologic evidence of H. hepaticus-associated 

liver disease. While frozen liver tissue was unavailable from 13 of these 26 studies, none showed the 

hepatitis indicative of H. hepaticus and thus were assumed to be unaffected. Potential confounding factors 

such as body weight, date study was begun, route of administration, and animal supplier were included as 

covariables in the statistical analysis. 

Analysis for H-ras Codon 61 CAA-to-AAA Mutations 

For analyses of formalin-fixed tissue, three to five unstained serial sections (10 μm thick) were cut from 

paraffin blocks containing hepatocellular adenomas or carcinomas. Paraffin-embedded tissues were 

deparaffinized and rehydrated prior to being digested with proteinase k overnight at 55E C to isolate DNA. 

Frozen tissues were digested with 10 mg/mL pronase in 1% sodium dodecyl sulfate in TNE buffer (10 mM 

TRIS, 150 mM NaCl, and 2 mM EDTA; pH 7.5) overnight at 37E C; DNA was isolated by phenol 

chloroform extraction and precipitated with ethanol (Marmur, 1961; Sills et al., 1995). 

Nested primers were used for amplification of exon 2 of H-ras by PCR. The outer primers were 5'-CCA 

CTA AGC CTG TTG TGT TTT GCA G-3' (forward primer) and 5'-CTG TAC TGA TGG ATG TCC 

TCG AAG GA-3' (reverse primer). The inner primers (second round of amplification) were 5'-GAC ATC 

TTA GAC ACA GCA GTT-3' (forward primer) and 5'-GGT GTT GTT GAT GGC AAA TAC-3' (reverse 

primer). Although the normal sequence of codon 60 is GCT, the forward PCR primer is made with a T at 

the penultimate 3' base to create the restriction site for Mse1. 

A nonradioactive RFLP method was employed to identify CAA-to-AAA mutations in the H-ras gene at 

codon 61 in liver neoplasms (Lee and Drinkwater, 1995). This was based on Mse1 enzyme restriction 

cutting only the sequence 5'-TTAA-3'. Thus, Mse1 will detect CÿA conversion mutation at the first 

position of codon 61. 
Triethanolamine, NTP TR 449 279 

Analysis of PCNA and Apoptosis 

Detailed methods are included in a report by Nyska et al. (1997). Cell proliferation was assessed in 

nonneoplastic areas of the liver, kidney, and lung by determining a PCNA S-phase labeling index (the 

percentage of cells in S phase). The identification of apoptotic cells was based on morphologic criteria 

(Garewal et al., 1996; Goldsworthy et al., 1996) and confirmed immunohistochemically by the terminal 

deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure (Gavrieli et al., 

1992). 

RESULTS AND DISCUSSION 

Identification of H. hepaticus Infection in NTP Studies 

Determining the extent of H. hepaticus infection involved a three-pronged approach of histologic evaluation, 

silver stains, and PCR-RFLP based assays; all were necessary because of the limitations identified for each. 

In NTP studies, and as reported in other studies (Ward et al., 1994b), there were no obvious clinical signs 

of infection, and the only significant histologic lesion (hepatitis) was observed in the liver, primarily in 

males. Therefore, summary pathology tables were reviewed to identify studies that may have been affected 

by H. hepaticus-associated hepatitis. Male mice from nine studies were identified (Table L1) as having the 

hepatitis. Eight of the nine studies were begun during a time span of about 6 months (July 1990 to 

January 1991), while the other study was begun much earlier (October 1988). The hepatitis was not 

observed in any 13-week studies. Use of histologic evaluation for identification of infected animals has 

limitations, however. It is somewhat insensitive, as H. hepaticus has been cultured and identified by PCRRFLP methods within livers of animals with no histological evidence of infection (Fox et al., 1999). This 

may be explained in part by the limited sampling (two liver sections) and the sometimes focal nature of 

H. hepaticus-associated hepatitis. Also, while in the more severely affected animals the hepatitis appears 

somewhat characteristic, component lesions of the hepatitis are not pathognomonic, and, when the hepatitis 

is subtle in 2-year old animals, it is more difficult to recognize or attribute to H. hepaticus. 

Within affected studies, the incidences of the hepatitis in male mice varied from 16% to 78% (Table L1). 

While generally mild to moderate, the hepatitis varied in severity from barely detectable in some animals to 

extensive liver involvement and regeneration in others. Only a few females were identified as having the 

characteristic hepatitis (Table L1). In general, the incidences and severities of H. hepaticus-associated 

hepatitis were similar between control and treated groups. This constellation of nonneoplastic liver lesions, 

while not pathognomonic, was certainly suggestive of an H. hepaticus infection, particularly when observed 

in control animals. Characteristic lesions included proliferation of oval and/or biliary epithelial cells, 

hepatocyte enlargement (diagnosed as karyomegaly), and chronic inflammation. In many instances, areas of 

regenerative hyperplasia were identified within diseased liver. 

Helicobacter spp. are not usually observed on routine histologic examination of hematoxylin and eosinstained sections of liver. The methods for confirmation of infection with Helicobacter include WarthinStarry silver stain or Steiner’s modification (Garvey et al., 1985) of this stain for direct microscopic 

observation of the organisms in tissue; however, this can be a relatively insensitive technique when few 

organisms are present. In most instances, histologic differentiation between Helicobacter species is not 

possible. Speciation can usually be accomplished with electron microscopy, but this technique is both time 

consuming and labor intensive. Microbiologic culture of feces, cecal smears, and fresh or frozen liver is 

also possible. Currently, assays involving amplification of the DNA of the organism using PCR are the 

most rapid and perhaps the most sensitive methods of detection, and the use of restriction endonucleases has 

allowed a determination of the species present. PCR-based methods also can be used on feces, cecal 

contents, or liver homogenates and are most sensitive when using fresh or frozen tissue (Riley et al., 1996; 

Malarkey et al., 1997). 
280 Triethanolamine, NTP TR 449 

Using Warthin-Starry silver stains or Steiner’s modification on the livers of five or more animals per study, 

helical bacteria (Helicobacter) were identified in animals from the nine affected studies. In some animals, 

helical bacteria were numerous, suggesting a heavy bacterial burden in these infected animals. However, 

even in these animals with abundant organisms, few to none were observed in proliferative hepatic lesions 

such as foci and neoplasms. Helical bacteria were not identified in approximately 25% of males with 

moderate hepatitis and were rarely identified in males without hepatitis or in females. The absence of 

identification of helical organisms by silver stains does not preclude infection, nor does the presence of 

organisms confirm H. hepaticus. Based upon current knowledge, however, the characteristic liver lesions 

in B6C3F mice, coupled with the presence of silver-positive helical organisms, are highly suggestive of 1 

H. hepaticus infection. 

As the NTP evaluation evolved, PCR-based assays were developed that appeared more sensitive than 

histologic evaluation and silver stains for identification and speciation of Helicobacter. Therefore, 

PCR-RFLP-based assays were used to confirm the presence of pathogenic Helicobacter (primarily 

H. hepaticus) within the nine affected studies and to determine whether there was H. hepaticus infection in 

other NTP studies. Unfortunately, none of the PCR-based assays had been specifically developed for, or 

proven reliable for use with, formalin-fixed tissue. Frozen tissue was available from a limited number of 

animals from a limited number of NTP studies, including only three of the nine affected studies. 

Furthermore, available frozen liver was almost always limited to tissue from a neoplasm, and, based upon 

results obtained with silver stains, organisms are generally not readily observed within proliferative hepatic 

lesions, even when organisms are abundant in adjacent liver tissue. Because the availability of frozen tissue 

was limited, a PCR-RFLP-based assay was developed and evaluated (Malarkey et al., 1997) for use with 

frozen or formalin-fixed tissue. 

The NIEHS and MU-RADIL laboratories conducted PCR-RFLP-based assays on 32 NTP 2-year studies and 

three NTP 13-week studies (data not shown); frozen tissues from 22 of the 2-year studies were available. 

All three bioassays in which hepatitis was identified and for which frozen tissue was available were positive 

for H. hepaticus by the PCR-RFLP-based assays (Table L2). At a third laboratory, H. hepaticus was also 

cultured from the liver tissue of animals in one of these studies (Fox et al., 1999). Formalin-fixed tissues 

from two of the three studies were evaluated and were also positive; these tissues had been fixed in formalin 

for less than 48 hours. In the other six affected studies, for which only formalin-fixed tissue was available, 

H. hepaticus was identified in only 1 of 120 animals (Table L2). This decreased sensitivity was considered 

to be related to the prolonged formalin fixation (Malarkey et al., 1997) rather than proof of an absence of 

H. hepaticus. The presence or absence of H. hepaticus apparently cannot be confirmed with current 

PCR-RFLP-based assays in liver that has been fixed in formalin for long periods (weeks or months). In the 

three 13-week studies with formalin-fixed tissue, only 1 of 30 animals was positive for H. hepaticus. 

Within the three affected, PCR-RFLP-positive 2-year studies, H. hepaticus was often identified by PCR in 

frozen livers of mice that had no overt hepatitis. In fact, based upon the combined data from two studies 

(including PCR results from three laboratories), of 57 animals without characteristic liver lesions, 13 of 

24 male mice (54%) and 17 of 33 female mice (52%) were positive for H. hepaticus. Furthermore, 

H. hepaticus was identified by PCR in frozen liver of several animals from three “unaffected” studies in 

which hepatitis typical of that associated with H. hepaticus was not observed (Table L2). Apparent 

variability occurs between various strains of mice and between individual mice from affected studies in 

developing hepatitis in response to H. hepaticus infection. One would assume that, within affected studies, 

most or all animals have been exposed to the organism, and even animals resistant to developing hepatitis 

may have organisms within the liver. This assumption is supported by the fact that animals without hepatitis 

are often positive with PCR-RFLP-based assays. Therefore, although alternative explanations are possible, 

the three PCR-RFLP-positive studies in which liver lesions are absent are assumed to be true positives. In 

fact, helical organisms were identified with a silver stain in one animal from one of these studies (Malarkey 

et al., 1997). Therefore, in addition to assessing the affect of H. hepaticus in the nine affected 2-year 
Triethanolamine, NTP TR 449 281 

studies, the significance of a positive PCR-RFLP assay for H. hepaticus in the absence of liver lesions is 

also an important question. 

Inconsistent Results with PCR-Based Methods 

As with any technique, the PCR-RFLP-based assays have limitations even when used to assay fresh and 

frozen tissue. One assessment of the variability in results of PCR and serologic analyses for Helicobacter 

among three commercial laboratories revealed significant inconsistencies (Dew et al., 1997). Others 

(J.M. Ward and J. Thigpen, personal communications) have obtained similarly inconsistent results when 

sending replicate samples to different laboratories. Though the number of samples evaluated by both the 

NIEHS and MU-RADIL laboratories was limited, there was good, but not complete, correlation of 

PCR-RFLP results. Also, within the affected studies, the PCR assays were not positive in some animals 

with liver disease. This result may be explained, in part, by the fact that the only frozen tissues available 

were neoplasms; as described above, neoplasms are expected to have fewer organisms. 

Analysis of H. hepaticus-Affected and Unaffected Studies 

for Incidence of Common Neoplasms 

To determine whether the incidences of various neoplasms were different between control groups from 

affected and unaffected studies, the nine affected studies were compared to 26 unaffected studies begun at 

relatively similar times (Table L3). There were no statistically significant differences in body weight or 

survival among the affected and unaffected studies. The neoplasms evaluated represent those that occurred 

at high enough incidences in various organs for statistically significant differences to be detected. Using 

multiple regression procedures, male mice in the nine affected studies were demonstrated to have a 

significantly (P<0.05) increased incidence of only two neoplasm types, both of which were in the liver 

(hepatocellular neoplasms and hemangiosarcoma), when compared to the unaffected studies. Because of 

these differences, there was also a corresponding significant difference in the overall incidence of malignant 

neoplasms (all sites) as well as in the overall proportion of neoplasm-bearing animals. No other tissue site 

showed a significant difference in the incidence of neoplasms. For female mice, the slightly increased 

incidence of hepatocellular neoplasms observed in the affected studies was not statistically significant. 

This seemingly simple analysis is complicated by several potential confounding variables. There have been 

coordinate, time-related increases in body weight and in the incidence of liver neoplasms in mice in NTP 

studies (Haseman, 1992). Table L4 presents the liver neoplasm incidences in relation to the dates the 

studies began and clearly shows the increases in liver neoplasm incidences and body weights (Seilkop, 

1995). In assessing differences in neoplasm incidences between H. hepaticus-affected and unaffected 

studies, the most relevant comparison would be between studies begun at approximately the same time. The 

starts of 20 of the 26 unaffected studies were clustered near the early part of the time frame (April 1988 to 

June 1990), while the starts of the affected studies were clustered toward the later end, with eight of the 

nine studies begun between July 1990 and January 1991; incidences of liver neoplasms in these later studies 

are expected to be higher based on trends in body weight alone. While the slightly increased incidences of 

liver neoplasms observed in female control mice in the nine affected studies is likely due to clustering in 

time, clearly, this alone cannot account for the increased liver neoplasm incidences observed in control male 

mice in the affected studies (Table L3). 

Ideally, unaffected studies used in the above comparison should not only be free of histologic evidence of 

infection with H. hepaticus but should be confirmed as negative by PCR assays. Thirteen of these 

26 studies could not be confirmed as negative by PCR because frozen tissue was not available; however, 

H. hepaticus-associated hepatitis was not present in any of the 26 studies. Because these and other data 

reported to date suggest that hepatitis is associated with neoplasm development in the liver, it seems 

reasonable to include those 13 studies, unconfirmed by PCR, in this analysis. The majority of the 

13 studies confirmed as negative by PCR were begun much earlier than the clearly affected studies, and, 

therefore, comparing them alone to the nine affected studies is not reasonable. Although not presented 
282 Triethanolamine, NTP TR 449 

here, a number of comparisons were made with various groupings of studies based on the degree of 

confidence in their infection status. Although the outcomes of the various comparisons varied somewhat, 

incidences of hepatocellular neoplasms and hemangiosarcomas of the liver were consistently increased in 

control male mice from affected studies compared to control males from unaffected studies. Significantly 

increased liver neoplasm incidences generally were not observed in females. Importantly, the following 

data corroborate the findings and association with H. hepaticus identified in these analyses. 

Analysis of Hepatitis-Positive and Hepatitis-Negative Mice 

for Liver Neoplasm Incidence 

Several infectious agents known to be associated with increased incidences of neoplasms cause chronic 

inflammation in the target tissue or organ. It is commonly hypothesized that this inflammatory process may 

cause or contribute to the development of neoplasms. One approach to address this was to stratify the mice 

from the affected studies according to the severity of hepatitis and examine liver neoplasm incidences in 

relation to these groupings. Thus, animals within the nine affected studies were placed into three groups: 

1) animals with mild to moderate hepatitis considered related to H. hepaticus infection (+), 2) animals with 

minimal to mild hepatitis that may have been associated with H. hepaticus (±), and 3) animals with no 

hepatitis that was considered to be associated with H. hepaticus (S). Within these groupings, the incidence 

of liver neoplasms was significantly increased (P<0.05) in males with mild to moderate H. hepaticusassociated hepatitis (+) when compared to animals without such hepatitis (Table L5). The neoplasm 

incidence in animals with minimal lesions (±) was also increased. The liver neoplasm incidence in males 

without hepatitis (58%) was similar to the incidence (54.8%) in males from the 26 unaffected studies 

(Table L3). This analysis clearly suggests an association of H. hepaticus-associated hepatitis with increased 

liver neoplasm incidences. Females showed a similar trend, albeit not significant; however, these 

comparisons are weak because of the low numbers of females with hepatitis. 

Analysis of H-ras Oncogene Mutations in Liver Neoplasms in Mice 

from Affected and Unaffected Studies 

Liver neoplasms commonly occur in control B6C3F mice in 2-year studies. In the historical database of 1 

333 male and female mice with liver neoplasms, 106 (32%) had H-ras codon 61 CAA-to-AAA mutations 

(Maronpot et al., 1995). This historical control database is composed primarily of male data; however, 

adequate numbers of females have been assayed, and there was no significant difference in the incidences of 

CAA-to-AAA mutations between males and females. 

In an attempt to examine further whether H. hepaticus infection had an effect on the development of 

hepatocellular neoplasms, neoplasms from control male mice from selected affected (NTP, 1998a,b, 1999a) 

and unaffected (NTP, 1993, 1999c) studies were evaluated for H-ras codon 61 CAA-to-AAA mutations 

(Table L6). Only 6% (2/33) of the hepatocellular neoplasms from control males with hepatitis from three 

affected studies had this mutation. This percentage is significantly (P<0.01) less than the 32% (11/34) 

observed in males from the two unaffected studies and less than the 32% (106/333) that occurred in 

historical control animals. In addition, neoplasms from males without hepatitis from the affected, PCRpositive triethanolamine study (NTP, 1999a) and the unaffected, PCR-positive methyleugenol study (NTP, 

1999d) were evaluated; the incidences of mutations in those groups were 3/14 (21%) and 2/17 (12%), 

respectively. 

Neoplasms from control female mice (none had hepatitis) from affected and unaffected studies were 

evaluated for the CAA-to-AAA mutation (Table L6). The mutation rate was low in both the affected studies 

(1/25; 4%) and the unaffected study (1/11; 9%) when compared to the 32% observed in the historical 

control groups. 

The finding of a different H-ras mutation profile in neoplasms of male mice from affected studies tends to 

support the association of increased neoplasm incidences with H. hepaticus, although there is no mechanistic 
Triethanolamine, NTP TR 449 283 

understanding behind this observation. In a study of H. hepaticus-infected A/JCr mice, ras mutations were 

not detected in the 25 hepatocellular neoplasms analyzed using a PCR/single-strand conformation 

polymorphism assay (Sipowicz et al., 1997). Because of the low spontaneous rate of liver neoplasms in the 

A/JCr mouse, there are few or no conclusive data on ras mutations in uninfected animals, however. Point 

mutations at codons 12, 13, and 61 of the Ki-, Ha- and N-ras genes were not identified in 45 early gastric 

carcinomas in humans, whether or not H. pylori was present (Craanen et al., 1995). If the increased 

incidence of hepatocellular neoplasms is associated with hepatitis, as many suspect, then one would expect 

the neoplasms from animals without hepatitis to have a similar mutational profile as that of the historical 

controls. The data do not provide a clear answer, because the hepatitis-free males from the affected 

triethanolamine study (NTP, 1999a) and the males from the methyleugenol study (NTP, 1999d), which were 

positive by PCR but lacked hepatitis, had mutation frequencies between those of the unaffected controls and 

the hepatitis-positive mice. Furthermore, mutations in neoplasms from females, none of which had 

hepatitis, from two affected and one unaffected study were very low compared to the historical controls. 

These findings were unexpected, and their significance is not understood. 

H. hepaticus-Associated Alterations in Cell Kinetics 

Studies evaluating cell kinetics were completed to explore further the link between hepatitis and the 

increased incidence of liver neoplasms (Table L7; Nyska et al., 1997). One of the major objectives was to 

determine whether there were differences between PCNA labeling indices in the livers of animals with 

hepatitis from three affected studies, cobalt sulfate heptahydrate, chloroprene, and triethanolamine (NTP, 

1998a,b, 1999a), compared to animals without hepatitis, whether from the same three affected studies or 9 from an unaffected study, 1-trans-delta -tetrahydrocannabinol (NTP, 1996). Male mice with hepatitis from 

the three affected studies had a significantly increased (P<0.001) labeling index, with a 24-fold increase 

over males from the unaffected study and a sixfold increase over males without hepatitis from the same 

three affected studies (Table L7). The labeling index increase in these mice was substantial and was 

considered biologically significant. Male mice without hepatitis from the three affected studies had a 

significantly greater labeling index (increased fourfold) than male mice from the unaffected study 

(Table L7). The significance of this finding is uncertain, as differences of a similar magnitude were 

observed in other comparisons. For example, the labeling index of females from the unaffected 1-trans­ 9 delta -tetrahydrocannabinol study (Table L7; NTP, 1996) was increased fivefold over females from the

PCR-positive, hepatitis-negative scopolamine hydrobromide trihydrate study (NTP, 1997). Such differences 

may be within the limits of normal variability for 2-year-old animals. 

A second objective of the cell proliferation studies of the liver was to determine if labeling indices were 

increased in animals from the PCR-positive, hepatitis-negative methyleugenol (NTP, 1999d), scopolamine 

hydrobromide trihydrate (NTP, 1997), and mouse life-span studies compared to an unaffected PCR-negative 9 and hepatitis-negative 1-trans-delta -tetrahydrocannabinol study (NTP, 1996). The scopolamine 

hydrobromide trihydrate study was evaluated and included in the study by Nyska et al. (1997), while the 

methyleugenol and mouse life-span studies were completed later and are included in Table L7. The labeling 

indices of males from two of these three studies were almost identical to those of males from the unaffected 

study. However, the labeling index of males from the mouse life-span study is increased approximately 

fivefold over that of males from the unaffected study as well as fivefold over the labeling indices of males 

from the two like studies of scopolamine hydrobromide trihydrate and methyleugenol. This finding suggests 

that the increase observed in the mouse life-span study is not attributable to the presence of H. hepaticus, as 

two other studies also positive for H. hepaticus did not show a similar increase. 

The cell proliferation data for the liver from NTP studies are consistent with data from a study by Fox et al. 

(1996) in which cell proliferation indices were evaluated at 8, 10, and 13 months in the A/JCr mouse, 

which is generally believed to be more susceptible to H. hepaticus-associated hepatitis than the B6C3F1 

mouse. In the study by Fox et al. (1996), cell proliferation rates were significantly increased at all time 

points in males. Some increases were observed in females in that study but did not reach statistical 
284 Triethanolamine, NTP TR 449 

significance. An increased incidence of hepatocellular neoplasms was observed only in the males. Though 

liver lesions were observed in females in that study, they were less severe than those in males. 

In addition to the liver, cell proliferation indices (PCNA) were evaluated in the kidneys and lungs of male 

and female mice in affected studies versus those in unaffected studies (Nyska et al., 1997). No apparent 

effect of H. hepaticus infection or the presence of hepatitis on PCNA indices was observed for the kidneys 

or lungs. 

Apoptosis (programmed cell death) is another important parameter in evaluations of cell kinetics. The 

apoptotic index in the liver of male mice with hepatitis from an affected study, cobalt sulfate heptahydrate 

(NTP, 1998a), was significantly (P<0.01) greater than that observed in males from the unaffected 1-trans­ 9 delta -tetrahydrocannabinol study and the PCR-positive, hepatitis-negative scopolamine hydrobromide

trihydrate study (Nyska et al., 1997). For females, there were no significant differences among the three 

studies. 

Two 13-week studies which were begun during the same time as the nine affected studies were randomly 

selected for evaluation of PCNA indices. H. hepaticus was not identified in either of the studies by 

PCR-RFLP; however, as with all NTP 13-week studies, only tissue fixed in formalin for an unspecified 

period was available. Because of this, no true negative control group was available; therefore, the labeling 

index of these 19- to 20-week-old animals was compared to values cited in the literature (Eldridge and 

Goldsworthy, 1996) for 20-week-old B6C3F mice. The labeling index in the NTP studies clearly was not 1 

increased (data not shown). 

The Impact of H. hepaticus on the Interpretation of 2-Year Carcinogenesis Studies 

Increases in the incidences of neoplasms are associated with a number of infectious agents. The chronic 

inflammation caused by these agents has been hypothesized to be important in the pathogenesis of the 

increased neoplasm incidences (e.g., gastric cancer associated with H. pylori). The increased incidences of 

liver neoplasms in male mice from the nine affected NTP studies were observed in the animals with 

H. hepaticus-associated hepatitis. Neoplasms from males with hepatitis tended to have an H-ras mutation 

profile different from that of animals from unaffected studies. Further, cell replication rates at 2 years were 

significantly higher in males with hepatitis compared to those in males without hepatitis. The data suggest 

that H. hepaticus-associated hepatitis is associated with the increased incidences of liver neoplasms in the 

male B6C3F1 mouse. Therefore, the most important consideration in evaluating the impact of H. hepaticus 

infection on the interpretation of study results appears to be the presence or absence of significant hepatitis. 

For any carcinogenicity study, data within and specific to the individual study provide the greatest basis for 

an accurate interpretation. However, it is prudent to consider and evaluate all data or information which 

may affect the interpretation. Based upon the data presented in this and other reports, general guidelines 

emerge that may be useful in interpreting potential chemical-associated carcinogenic effects in H. hepaticusinfected B6C3F mice. In a study with sufficient evidence of H. hepaticus-associated hepatitis (>10% of 1 

the animals having the characteristic hepatitis may be a reasonable guideline), interpretation of increased 

incidences of liver neoplasms (hepatocellular neoplasms and hemangiosarcoma) of male mice is considered 

to be potentially confounded. 

Altered chemical uptake and metabolism, due to the intestinal load of H. hepaticus and to H. hepaticusassociated liver disease, respectively, are possible reasons for considering that the male mouse response to 

chemical administration at sites other than the liver should also be considered confounded. Data do not 

currently exist that definitively answer this question. In this group of nine studies, however, there is no 

evidence to suggest that affected mice responded to chemical treatment in organs other than the liver in a 

manner different from mice in nonaffected studies. Within each study, there was excellent concordance in 

chemical-associated neoplasms between the male mice and the females, which had little or no hepatitis 
Triethanolamine, NTP TR 449 285 

(Table L8). Furthermore, analyses indicate that H. hepaticus is not associated with neoplastic responses 

outside the liver; incidences of neoplasms at sites other than the liver were not different between control 

groups from affected and unaffected studies (Table L3). Cell replication rates in two major organs (lung 

and kidney) also were not increased in control groups from affected studies compared to those from 

unaffected studies. 

One of the more difficult issues to address is whether interpretation of a treatment-related increase in liver 

neoplasm incidences in the female mouse is confounded when H. hepaticus-associated hepatitis is present 

within the male mice in the study. Most evidence to date links hepatitis with the increased liver neoplasm 

incidences observed in males, and female B6C3F mice in affected studies do not have significant hepatitis 1 

at 2 years. The lack of hepatitis in females, however, is based on an analysis in which only late time points 

were evaluated histologically. Therefore, it is conceivable that hepatitis along with increased cell 

proliferation could have occurred earlier and resolved by 18 months to 2 years. Data collected to date, 

however, suggest that H. hepaticus-associated hepatitis is a late-developing and persistent disease in the 

B6C3F1 mouse. H. hepaticus-associated hepatitis has never been observed in any NTP 13-week studies, 

including five begun during the same 6-month time span as eight of the nine affected 2-year studies. Also, 

within affected 2-year studies, more males (51%) that were 18 to 24 months of age had hepatitis than those 

(34%) that were 12 to 18 months of age. This is consistent with a report by Ward et al. (1994b) that 

H. hepaticus-associated liver lesions are not observed at early time points in the B6C3F1 mouse. 

Nonetheless, within affected studies, female control mice did have a slightly elevated incidence of liver 

neoplasms when compared to control mice from unaffected studies, and the data derived from the H-ras 

mutation frequency analysis were inconclusive. The possibility that H. hepaticus-infected female mice from 

affected studies may respond differently to a liver carcinogen than mice from unaffected studies cannot be 

eliminated at this time. However, because within an affected study hepatitis is observed only rarely in 

females, until definitive data suggest otherwise, it is concluded that the interpretation of an apparent 

chemical-induced neoplastic effect in the liver of female mice is not confounded. To censor the few females 

with H. hepaticus-associated hepatitis from any statistical analyses of hepatocellular neoplasms would be 

prudent. Studies in the ostensibly more sensitive A/JCr mouse (Fox et al., 1996) also showed significant 

increases in neoplasm incidences and cell proliferation rates in the liver of H. hepaticus-infected males, but 

not females. 

Another concern is how to interpret possible chemical-related effects in a study in which the status of 

H. hepaticus infection cannot be determined by PCR-RFLP because only tissues fixed in formalin for more 

than 48 hours are available. While histologic evaluation is inadequate to identify infection, it appears 

adequate for identifying hepatitis severe enough to alter the outcome of the study. Therefore, in the absence 

of significant histologic evidence of H. hepaticus-associated hepatitis, the outcome of a 2-year study should 

not be considered potentially compromised. 

The causality between H. hepaticus infection and neoplasia has not been proven in the B6C3F1 mouse in

these studies, nor has the mechanism of this association been determined; further studies are needed. 

However, sufficient information exists to make reasonable scientific judgments relative to the interpretation 

of data from the nine 2-year carcinogenicity studies in the B6C3F1 mouse. Refinements to the above 

interpretive positions may occur if warranted by future information. 
286 Triethanolamine, NTP TR 449 

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290 Triethanolamine, NTP TR 449 

TABLE L1 

Incidence of Helicobacter hepaticus-Associated Hepatitis in Control B6C3F Mice 1 

from Nine NTP 2-Year Studiesa 

Incidence of Hepatitis (%) 

Study Males Females 

Sodium xylenesulfonate 78 4 

AZT/5,000 U "-interferon A/D 76 4 

Cobalt sulfate heptahydrate 72 8 

AZT/500 U "-interferon A/D 66 0 

Chloroprene 54 0 

Theophylline 32 0 

"-Interferon A/D 22 4 

Triethanolamine 20 0 

AZT 16 2 

Average 48 2 

a Includes regeneration and mild to marked (excludes minimal) chronic inflammation, karyomegaly, oval cell hyperplasia, and bile duct 

hyperplasia. AZT=3N-azido-3N-deoxythymidine 

TABLE L2 

Identification of Helicobacter hepaticus with PCR-RFLP-Based Assays in Control B6C3F Mice 1 

from 32 NTP 2-Year Studies and Three NTP 13-Week Studiesa 

H. hepaticus-Positive Studiesb 

Type of Sample Total Affected Unaffected 

Studies Studies Studies 

13-Week Studies 

Formalin-fixed liver 3 — 1/3c 

2-Year Studies 

Frozen liver 22 3/3 3/19 

Formalin-fixed liver 10 1/6c 0/4 

a PCR-RFLP=polymerase chain reaction-restriction fragment length polymorphism b	 Number of H. hepaticus-positive studies/number of affected or unaffected studies. Affected studies are those in which hepatitis typical of 

that associated with H. hepaticus infection occurred in many male mice. 

Only one animal in the positive study was positive for H. hepaticus. c 
Triethanolamine, NTP TR 449 291 

TABLE L3 

Comparison of Neoplasm Incidences in Control B6C3F1 Mice

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies 

Males Females 

Affected Unaffected Affected Unaffected 

Studiesa Studies Studies Studies 

Number of studies 9 26 9 26 

Survival (%) 64 71 68 68 

12-Month body wt (g) 48.0 48.3 48.1 47.0 

Neoplasm incidence (%) 

Liver 71.3* 54.8 50.3 40.5 

Lung 26.6 23.2 7.6 10.3 

Pituitary gland 0.4 0.8 14.7 14.3 

Harderian gland 5.6 6.1 6.0 4.9 

Lymphoma 6.9 6.3 16.2 15.5 

Circulatory system 9.8 6.0 5.3 4.7

 liver only 7.1* 2.5 — — 

All benign 61.8 57.2 59.1 54.6 

All malignant 61.3* 40.9 50.0 44.2 

All neoplasms 88.0* 77.4 82.7 75.4 

* Significantly different (P#0.05) from the unaffected studies a Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice. 
292 Triethanolamine, NTP TR 449 

TABLE L4 

Liver Neoplasm Incidences and Body Weights of Control B6C3F Mice 1 

in Relation to Study Start Dates of Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studiesa 

Liver Neoplasm Incidence (%) Mean Body Weight (g) 

Study Start Date Affected Unaffected Affected Unaffected 

Studiesa Studies Studies Studies 

Male 

April to September 1988 — 43.8 (8)b — 46.2 (8) 

October 1988 62.0 (1) — 48.3 (1) — 

November 1988 to September 1989 — 52.6 (7) — 48.7 (7) 

October 1989 to June 1990 — 61.2 (5) — 48.9 (5) 

July 1990 to January 1991 72.5 (8) 66.2 (4) 48.0 (8) 49.0 (4) 

February 1991 to April 1992 — 68.0 (2) — 52.8 (2) 

Average 71.3 54.8 48.0 48.3 

Female 

April to September 1988 — 31.1 (8) — 44.8 (8) 

October 1988 46.0 (1) — 46.4 (1) — 

November 1988 to September 1989 — 39.9 (7) — 47.2 (7) 

October 1989 to June 1990 — 38.6 (5) — 45.9 (5) 

July 1990 to January 1991 50.9 (8) 54.2 (4) 48.3 (8) 48.0 (4) 

February 1991 to April 1992 — 58.0 (2) — 55.6 (2) 

Average 50.3 40.5 48.1 47.0 

a Includes nine affected studies (those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice) and 

26 unaffected studies 

b Number of studies is given in parentheses. 
Triethanolamine, NTP TR 449 293 

TABLE L5 

Association of Liver Neoplasm Incidence and Severity of Helicobacter hepaticus-Associated Hepatitis a in Control B6C3F Mice from Nine Affected NTP 2-Year Studies 1 

Liver Neoplasm Incidence 

Severity of Hepatitis Males Females 

Absent 

Minimal 

Mild/moderate 

Significance of association 

101/175 (58%) 

44/57 (77%) 

176/218 (81%) 

P<0.05 

196/396 (49%) 

23/42 (55%) 

7/11 (64%) 

NSb 

a Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection occurred in many male mice. b NS=not significant 

TABLE L6 

H-ras Codon 61 AAA Mutations in Spontaneous Liver Neoplasms in Control B6C3F Mice 1 

from Helicobacter hepaticus-Affected and Unaffected NTP 2-Year Studies 

a Study Affected H-ras AAA Mutations 

Male 

Cobalt sulfate heptahydrate + 0/10 (0%) 

Chloroprene + 1/13 (8%) 

Triethanolamine + 1/10 (10%) 

Oxazepam — 7/18 (39%) 

Diethanolamine — 4/16 (25%) 

Historical control database 106/333 (32%) 

Female 

Chloroprene + 0/10 (0%) 

Triethanolamine + 1/15 (7%) 

Diethanolamine — 1/11 (9%) 

Historical control database 106/333 (32%) 

a +=affected; — =not affected. Affected studies are those in which hepatitis typical of that associated with H. hepaticus infection occurred 

in many male mice. 
294 

c 

Triethanolamine, NTP TR 449 

TABLE L7 a Proliferating Cell Nuclear Antigen Labeling Indices in the Liver of Control B6C3F1 Mice

Hepatitis No. of PCNA Labeling Average PCNA 

Animals Indexb Labeling Indexc 

Male 

Cobalt sulfate heptahydrated + 15 0.535 ± 0.129 

Chloroprened + 12 1.452 ± 0.386 

d Triethanolamine	 + 9 1.215 ± 0.374 1.011 

Cobalt sulfate heptahydrate — 7 0.175 ± 0.117 

Chloroprene — 10 0.296 ± 0.124 

Triethanolamine — 12 0.100 ± 0.042 0.186 

9 e 1-Trans-delta -tetrahydrocannabinol — 15 0.042 ± 0.011 

Scopolamine hydrobromide trihydratef — 14 0.043 ± 0.012 

Methyleugenolf — 14 0.077 ± 0.020 

Mouse life-span studyf — 15 0.217 ± 0.880 

Female 

Cobalt sulfate heptahydrate + 5 0.161 ± 0.062 

Cobalt sulfate heptahydrate — 17 0.055 ± 0.015 

Chloroprene — 12 0.154 ± 0.050 

Triethanolamine — 12 0.138 ± 0.053 0.108 

9 1-Trans-delta -tetrahydrocannabinol — 13 0.156 ± 0.047 

Scopolamine hydrobromide trihydrate — 15 0.032 ± 0.009 

a A portion of these data are presented in Nyska et al. (1997). +=hepatitis present; — =no hepatitis present b	 Mean ± standard error; PCNA=proliferating cell nuclear antigen 

Average of the mean labeling indices for animals from all three studies d	 Affected study (one in which hepatitis typical of that associated with H. hepaticus occurred in many male mice) e Unaffected study (one in which the typical hepatitis did not occur in mice) f	 Unaffected study with no typical hepatitis, but positive for H. hepaticus by polymerase chain reaction-restriction fragment length 

polymorphism-based assay 
295 

c 

Triethanolamine, NTP TR 449 

TABLE L8 

Summary of Target Sites of Carcinogenicity in B6C3F Mice from NTP 2-Year Studies 1 

with Helicobacter hepaticus-Associated Hepatitis 

Males	 Females 

Chloroprene Lung Lung 

Circulatory systema Circulatory system 

Harderian gland Harderian gland 

Forestomach Forestomach 

Kidney Liver 

Skin 

Mesentery 

Zymbal’s gland 

Mammary gland 

Cobalt sulfate heptahydrateb Lung Lung 

Triethanolamine Liver Liver 

AZTc None Vagina 

Sodium xylenesulfonate None None 

Theophylline None None 

a Hemangioma and hemangiosarcoma of the liver were excluded from the analysis in males. b	 An apparent treatment-related increase in the incidence of hemangiosarcoma of the liver was discounted in male mice because of the presence 

of H. hepaticus. 

AZT=3N-azido-3N-deoxythymidine. Includes four studies: AZT; "-interferon A/D; AZT/500 U "-interferon A/D; and 

AZT/5,000 U "-interferon A/D 
296 Triethanolamine, NTP TR 449