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Abstract for TR-558 - 3,3',4,4'-Tetrachloroazobenzene (CASRN 14047-09-7)

Abstract

TR-558
Toxicology and Carcinogenesis Studies of 3,3',4,4'-Tetrachloroazobenzene (TCAB) (CAS No. 14047-09-7) in Harlan Sprague-Dawley Rats and B6C3F1 Mice (Gavage Studies)

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Abstract

Chemical Formula: C12H6C14 N2 -- Molecular Weight: 320.0

3,3',4,4'-Tetrachloroazobenzene (TCAB) is not commercially manufactured but is formed as an unwanted by-product in the manufacture of 3,4-dichloroaniline and its herbicidal derivatives Propanil®, Linuron®, and Diuron®. It occurs from the degradation of chloroanilide herbicides (acylanilides, phenylcarbamates, and phenylureas) in soil by peroxide-;producing microorganisms; and is formed by the photolysis and biolysis of 3,4-dichloroaniline. Humans may be exposed to TCAB during the manufacture as well as the application of herbicides containing TCAB as a contaminant. TCAB was nominated by the United States Environmental Protection Agency for toxicity and carcinogenicity testing based on its structural and biological similarity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the potential for human exposure from the consumption of crops contaminated with 3,4-;dichloroaniline-derived herbicides. Male and female Harlan Sprague-Dawley rats and B6C3F1 mice were administered TCAB (at least 97.8% pure) in corn oil:acetone (99:1) by gavage for 3 months (rats only) or 2 years.

3-MONTH STUDY IN RATS

Groups of 10 male and 10 female Harlan Sprague-Dawley rats were administered 0.1, 0.3, 1, 3, 10, 30, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 14 weeks; groups of 10 male and 10 female rats received the corn oil:acetone vehicle alone. Special study groups of 30 (dosed groups) or 6 (vehicle control group) female Harlan Sprague-Dawley rats were administered 0.1, 3, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 13 weeks; vehicle controls received the corn oil:acetone vehicle alone.

All male and female rats survived to the end of the study. Terminal mean body weights of males were not significantly different from vehicle controls in any group. Terminal mean body weights of females administered 10 mg/kg or greater were significantly less than those of the vehicle controls. Mean body weight gains of all dosed groups of females were significantly less than those of the vehicle controls. The hematology results indicate that TCAB induced a microcytic normochromic responsive anemia in male Sprague-Dawley rats. Serum concentrations of total thyroxine (T4) and free T4 were significantly decreased in a dose-related manner in all dosed groups in both sexes compared to their respective vehicle controls; total triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations were generally unaffected. There were no statistically significant differences in the BrdU labeling indices in the liver of males or females exposed to TCAB compared to their respective vehicle controls. Significant induction of hepatic 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-deethylase activities was observed in all dosed groups of males and females. Significant induction of hepatic acetanilide-4-hydroxylase activity was observed in males exposed to 3 mg/kg or greater and all treated groups of females. EROD activities in the lung generally increased with increasing dose and were significantly greater in all treated groups of males and females compared to their respective vehicle controls. The highest concentrations of TCAB were observed in fat tissue with lower concentrations in the liver and lung. TCAB concentrations were significantly increased in a dose-dependent manner in all tissues from dosed groups relative to vehicle controls.

At the end of the 3-month study, absolute and relative liver weights were significantly greater than those of the vehicle controls in all dosed groups of males and in females administered 10 mg/kg or greater. Absolute and relative lung weights were significantly greater in 100 mg/kg males and 3 mg/kg or greater females. Absolute and relative right kidney and spleen weights were generally significantly greater for all dosed groups of males. Absolute thymus weights of 10 mg/kg or greater males and absolute and relative thymus weights of 1 mg/kg or greater females were significantly less than those of the vehicle controls.

In the liver, the incidences of midzonal to diffuse hepatocytic hypertrophy in males administered 1 mg/kg or greater and in females administered 10 mg/kg or greater were significantly greater than the vehicle control incidences. Hematopoietic cell proliferation occurred in most males administered 3 mg/kg or greater and most females administered 10 mg/kg or greater. The incidences of midzonal hepatocytic cytoplasmic fatty vacuolization were significantly increased in males administered 3 mg/kg or greater. In the lung, significantly increased incidences of bronchiolar metaplasia of the alveolar epithelium and interstitial mononuclear cell infiltration occurred in 10, 30, and 100 mg/kg males. The incidence of interstitial mononuclear cell infiltration was also significantly increased in 100 mg/kg females. Significantly increased incidences of hematopoietic cell proliferation of the spleen occurred in males administered 10 mg/kg or greater. The incidences of hemosiderin pigment of the spleen were significantly increased in 10 mg/kg or greater females. Atrophy in the thymus was significantly increased in all dosed groups of females, except the 0.1 mg/kg group, and in males administered 10 mg/kg or greater.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female Harlan Sprague-Dawley rats were administered 10, 30, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 2 years; groups of 50 male and 50 female rats received the corn oil:acetone vehicle alone. The survival of all dosed groups of males was significantly less than that of the vehicle controls. Mean body weights of 100 mg/kg males were less than those of the vehicle control group throughout the study. Mean body weights of 30 mg/kg males were 6% less than those of the vehicle control group after week 24, and those of 10 mg/kg males were 7% less than the vehicle control group after week 80. Mean body weights of 100 mg/kg females were less than those of the vehicle control group throughout the study, and those of 30 mg/kg females were 6% less than the vehicle control group after week 36.

In the lung, the incidences of multiple cystic keratinizing epithelioma and single or multiple cystic keratinizing epithelioma (combined) in males and females were significantly increased in all dosed groups (except multiple epithelioma in 10 mg/kg females). Significantly increased incidences of pigmentation, alveolar epithelium squamous metaplasia (except 10 mg/kg females), and alveolar epithelium bronchiolar metaplasia occurred in all dosed groups of males and females. The incidences of histiocytic cellular infiltration in all dosed groups of males were significantly increased.

In the liver, the incidences of cholangiocarcinoma (single or multiple) occurred in a positive trend in males and were significantly greater than that in the vehicle control group; the incidence in 100 mg/kg females was also increased. A significant dose-related increase in hepatic toxicity was observed in dosed rats and was characterized by increased incidences of numerous lesions including hepatocyte hypertrophy, centrilobular degeneration, hepatocellular necrosis, pigmentation, fatty change, bile duct hyperplasia, oval cell hyperplasia, nodular hyperplasia, hematopoietic cell proliferation, eosinophilic focus, mixed cell focus, multinucleated hepatocytes, bile duct cyst, toxic hepatopathy, and cholangiofibrosis.

Significantly increased incidences of gingival squamous cell carcinoma within the oral mucosa occurred in 10 mg/kg males and 100 mg/kg males and females. The incidences of gingival squamous hyperplasia and cystic keratinizing hyperplasia in dosed groups of males and females were generally significantly increased.

The incidences of follicular cell adenoma (single or multiple) of the thyroid gland in 30 and 100 mg/kg males were significantly greater than that in the vehicle control group. The incidences of follicular cell hypertrophy, follicular cell hyperplasia, and inflammation were significantly increased in 30 and 100 mg/kg males.

Three incidences of single or multiple squamous cell papilloma of the forestomach occurred in 100 mg/kg females, and single incidences of squamous cell carcinoma of the forestomach occurred in 10 and 100 mg/kg females. Significantly increased incidences of epithelial hyperplasia occurred in all dosed groups of males and females.

There were three incidences of malignant schwannoma in the thoracic cavity in 100 mg/kg males and a single incidence in 30 mg/kg males.

In the adrenal cortex of 30 and 100 mg/kg females, there were slightly increased incidences of adenoma. In all dosed groups of males, the incidences of degeneration, cytoplasmic vacuolization, and hyperplasia of the zona fasciculata were significantly increased. Increased incidences and severities of necrosis occurred in 30 and 100 mg/kg males. Incidences of cytoplasmic vacuolation in 10 and 100 mg/kg females and hyperplasia of the zona fasciculata in 30 mg/kg females were significantly greater than those in the vehicle controls.

Numerous nonneoplastic effects were seen in other organs including atrophy, acinar cytoplasmic vacuolization, and inflammation of the pancreas; blood vessel inflammation; lymphoid follicle atrophy and pigmentation of the spleen; pigmentation and atrophy of the mesenteric lymph node; germinal epithelial degeneration of the testes; and inflammation of the nose.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were administered 3, 10, or 30 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 2 years; groups of 50 male and 50 female rats received the corn oil:acetone vehicle alone. Survival of 10 and 30 mg/kg males and 30 mg/kg females was significantly less than that of vehicle controls. All 30 mg/kg males died before the end of the study. Mean body weights of treated males were similar to or greater than those of the vehicle controls throughout most of the study. Mean body weights of 10 and 30 mg/kg males were 10% and 8% less than those of the vehicle controls at the last weighing at weeks 101 and 73, respectively. Mean body weights of 3 mg/kg females were 7% greater than those in the vehicle controls after week 64. The only chemical-related clinical finding was the appearance of ulcers or abscesses, primarily on the head and neck and exacerbated by scratching. These skin lesions appeared as areas of discoloration, ulceration, or thickening. In both sexes, the time when these lesions first appeared was dose related, with lesions appearing first in the 30 mg/kg groups.

The incidences of transitional epithelial carcinoma of the urethra were significantly increased in all dosed groups of males, and two of these neoplasms were observed in 30 mg/kg females. Transitional epithelial hyperplasia of the urethra and urinary bladder occurred in male and female mice. One 10 mg/kg male and one 30 mg/kg female had transitional epithelial carcinoma of the ureter. The incidences of dilatation and chronic active inflammation of the ureter were significantly increased in 10 and 30 mg/kg males.

In the lung, significantly increased incidences of alveolar/bronchiolar adenoma occurred in all dosed groups of males, and a significantly increased incidence of alveolar/bronchiolar carcinoma occurred in 30 mg/kg females. Significantly increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) occurred in 3 and 10 mg/kg males and 30 mg/kg females. A single incidence of cystic keratinizing epithelioma (CKE) and a single incidence of multiple CKE occurred in 30 mg/kg females. The incidences of chronic active inflammation were significantly increased in 10 and 30 mg/kg females.

In the forestomach, the incidences of squamous cell carcinoma in the 30 mg/kg groups were significantly greater than those in the vehicle control groups. Significantly increased incidences of hyperplasia at the limiting ridge occurred in all dosed groups. In the glandular stomach, incidences of focal epithelial hyperplasia, epithelial cyst (except 10 mg/kg females), and subtle mucosal lymphoid cell infiltration were significantly increased in dosed groups of males and females; the incidences of mineralization were significantly increased in all dosed groups of males.

The incidences of subcutaneous fibrosarcoma and fibrosarcoma or malignant schwannoma (combined) of the skin were significantly increased in 30 mg/kg females. The skin lesions observed grossly were characterized histologically as chronic active inflammation, dermal fibrosis, and epidermal hyperplasia and ulcers. The incidences of these lesions in females were dose related, and all were significantly greater in the 30 mg/kg group than in the vehicle control group; the incidences of these lesions in all male dosed groups, except dermal fibrosis at 30 mg/kg, were significantly increased. The incidences of follicular dilatation were significantly increased in 10 and 30 mg/kg males and females. The incidences of sebaceous gland atrophy were significantly increased in 10 and 30 mg/kg males and 30 mg/kg females.

Statistically significant increased incidences of malignant lymphoma occurred in 10 and 30 mg/kg females. The lymphoma involved the spleen and various lymph nodes (i.e., mesenteric, mediastinal, and mandibular).

Numerous nonneoplastic effects were seen in other organs including urinary bladder transitional epithelial hyperplasia; atrophy, cystic ducts, and chronic inflammation of the clitoral gland; ovarian atrophy; bone marrow hyperplasia; atrophy and hematopoietic cell proliferation of the spleen; atrophy of the thymus; hematopoietic cell proliferation of the liver; cardiomyopathy; and aorta mineralization.

CONCLUSIONS

Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of TCAB in male Harlan Sprague-Dawley rats based on increased incidences of cystic keratinizing epithelioma of the lung, cholangiocarcinoma of the liver, and gingival squamous cell carcinoma of the oral mucosa. The increased incidences of follicular cell adenoma of the thyroid gland were also considered to be related to TCAB administration. The marginally increased incidence of malignant schwannoma may have been related to TCAB administration. There was clear evidence of carcinogenic activity of TCAB in female Harlan Sprague-Dawley rats based on increased incidences of cystic keratinizing epithelioma of the lung and gingival squamous cell carcinoma of the oral mucosa. The increased incidences of cholangiocarcinoma of the liver and squamous cell papilloma or squamous cell carcinoma (combined) of the forestomach were also considered to be related to TCAB administration. The marginally increased incidences of adenoma of the adrenal cortex may have been related to TCAB administration. There was clear evidence of carcinogenic activity of TCAB in male B6C3F1 mice based on increased incidences of carcinoma of the urethra and alveolar/bronchiolar neoplasms of the lung. The increased incidences of squamous cell carcinoma of the forestomach were also considered to be related to TCAB administration. The marginally increased incidence of carcinoma of the ureter may have been related to TCAB administration. There was clear evidence of carcinogenic activity of TCAB in female B6C3F1 mice based on increased incidences of fibrosarcoma and fibrosarcoma or malignant schwannoma (combined) of the skin. The increased incidences of  carcinoma of the urethra, alveolar/bronchiolar neoplasms and cystic keratinizing epithelioma of the lung, and squamous cell carcinoma of the forestomach were also considered to be related to TCAB administration. The marginally increased incidences of carcinoma of the ureter and malignant lymphoma may have been related to TCAB administration.

TCAB administration caused increased incidences of nonneoplastic lesions of the lung, liver, oral mucosa, forestomach, adrenal cortex, pancreas, blood vessel, spleen, and mesenteric lymph node in male and female rats; the thyroid gland and testis in male rats; the nose in female rats; the urinary bladder, forestomach, glandular stomach, skin, spleen, thymus, liver, and heart in male and female mice; the urethra, ureter, and blood vessel in male mice; and the lung, clitoral gland, ovary, and bone marrow in female mice.

Synonyms: Azobenzene, 3,3',4,4'-tetrachloro-(8CI); 3,3',4,4'-tetrachloroazobenzene diazene, bis(3,4-dichlorophenyl)-(9CI); TCAB


Summary of the 2-Year Carcinogenesis Carcinogenesis Studies of TCAB
  Male
Harlan Sprague-Dawley Rats
Female
Harlan Sprague-Dawley Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Concentrations in corn oil/acetone by gavage 0, 10, 30, or 100 mg/kg 0, 10, 30, or 100 mg/kg 0,  3, 10, or 30 mg/kg 0, 3, 10, or 30 mg/kg
Body weights 100 mg/kg group 7% less than the vehicle control group after week 2; 30 mg/kg group 6% less than the vehicle control group after week 24; 10 mg/kg group 7% less than the vehicle control group after week 80 100 mg/kg group 6% less than the vehicle control group after week 3; 30 mg/kg group 6% less than the vehicle control group after week 36 10 mg/kg group 10% less than the vehicle control at week 101; 30 mg/kg group 8% less than the vehicle control group at week 73 3 mg/kg group 7% greater than the vehicle control group after week 64
Survival Rates 28/50, 9/50, 4/50, 2/50 25/50, 30/50, 19/50, 17/50 35/50, 31/50, 5/49, 0/50 35/50, 30/50, 32/50, 20/50
Nonneoplastic effects Lung: pigmentation (3/50, 16/50, 12/50, 16/50); alveolar epithelial metaplasia, squamous (0/50, 14/50, 22/50, 22/50); alveolar epithelium, metaplasia, bronchiolar (1/50, 32/50, 32/50, 34/50); alveolus, infiltration cellular, histiocyte (23/50, 34/50, 35/50, 35/50)
Liver: hepatocyte hypertrophy (0/50, 6/50, 11/50, 22/50); centrilobular degeneration (0/50, 10/50, 23/50, 24/50); necrosis (1/50, 7/50, 18/50, 21/50); pigmentation (1/50, 4/50, 5/50, 6/50); diffuse fatty change (3/50, 9/50,18/50, 34/50); oval cell hyperplasia (0/50, 4/50, 8/50, 5/50); hematopoietic cell proliferation (5/50, 40/50, 37/50, 30/50); eosinophilic focus (3/50, 9/50, 4/49, 12/50); bile duct cyst (0/50, 0/50, 1/50, 4/50); toxic hepatopathy 0/50, 0/50, 5/50, 8/50)
Oral Mucosa: gingival squamous hyperplasia (2/50, 21/50, 24/50, 31/50); gingival cystic keratinizing hyperplasia (0/50, 4/50, 18/50, 11/50)
Thyroid Gland: follicular cell hypertrophy (2/50, 2/50, 6/50, 6/50); follicular cell hyperplasia (0/50, 2/50, 10/50, 12/50); inflammation (0/50, 3/50, 9/50, 14/50)
Forestomach: epithelium hyperplasia (8/50, 36/50, 44/50, 45/50)
Adrenal Cortex: degeneration (4/50, 14/50, 14/50, 9/50); vacuolization cytoplasmic (20/50, 29/50, 31/50, 25/50); zona fasciculata, hyperplasia (14/50, 22/50, 19/50, 21/50); necrosis (0/50, 2/50, 4/50, 13/50)
Pancreas: atrophy (4/50, 13/49, 10/50, 10/50); acinar vacuolization cytoplasmic (0/50, 16/49, 30/50, 13/50); inflammation (1/50, 7/49, 7/50, 3/50)
Blood Vessel: inflammation (21/50, 29/50, 30/50, 29/50)
Spleen: lymphoid follicle, atrophy (5/50, 4/50, 5/50, 12/50)
Lymph Node, Mesenteric: pigmentation (1/50, 24/48, 25/50, 20/50); atrophy (0/50, 1/48, 1/50, 5/50)
Testis: germinal epithelial degeneration (15/50, 16/50, 18/50, 21/50)
Lung: pigmentation (1/50, 11/50, 21/49, 26/49); alveolar epithelium, metaplasia, squamous (2/50, 4/50, 18/49, 30/49); alveolar epithelium, metaplasia, bronchiolar (0/50, 21/50, 26/49, 35/49)
Liver: hepatocyte hypertrophy (4/50, 33/50, 38/49, 42/49); centrilobular degeneration (1/50, 2/50, 18/49, 17/49); necrosis (3/50, 6/50, 10/49, 10/49); pigmentation 1/50, 17/50, 32/49, 40/49); focal fatty change (2/50, 2/50, 2/49, 9/49); diffuse fatty change (0/50, 3/50, 10/49, 10/49); bile duct hyperplasia (12/50, 26/50, 29/49, 38/49); oval cell hyperplasia (0/50, 7/50, 24/49, 36/49); nodular hyperplasia (1/50, 3/50, 11/49, 22/49); hematopoietic cell proliferation (28/50, 42/50, 32/49, 37/49); eosinophilic focus (3/50, 27/50, 31/49, 38/49); mixed cell focus (6/50, 16/50, 14/49, 16/49); bile duct cyst (3/50, 4/50, 5/49, 12/49); multinucleated hepatocyte (0/50, 2/50, 1/49, 28/49); toxic hepatopathy (0/50, 4/50, 14/49, 25/49); cholangiofibrosis (0/50, 1/50, 0/49, 11/49)
Oral Mucosa: gingival squamous hyperplasia (0/50, 8/50, 24/50, 24/50); gingival cystic keratinizing hyperplasia (0/50, 4/50, 9/50, 13/50)
Forestomach: epithelial hyperplasia (0/50, 32/50, 46/50, 46/50)
Adrenal Cortex: vacuolization cytoplasmic (7/50, 16/50, 13/50,15/49); zona fasciculata, hyperplasia (14/50, 20/50, 25/50, 21/49)
Pancreas: atrophy (0/50, 11/49, 12/49, 13/49); acinar vacuolization cytoplasmic (0/50, 27/49, 33/49, 40/49)
Blood Vessel: inflammation (1/50, 10/50, 14/50, 16/50)
Spleen: lymphoid follicle, atrophy (3/50, 4/50, 8/49, 10/49); pigmentation (31/50, 44/50, 42/49, 47/49)
Lymph Node, Mesenteric: pigmentation (14/50, 32/49, 32/50, 30/49); atrophy (0/50, 0/49, 4/50, 6/49)
Nose: inflammation (0/50, 7/50, 6/50, 8/50)
Urethra: transitional epithelial hyperplasia (0/50, 17/50, 2/49, 0/50)
Ureter: dilatation 0/43, 6/45, 22/47, 42/50); chronic active inflammation (0/43, 3/45, 24/47, 39/50)
Urinary Bladder: transitional epithelial hyperplasia (0/50, 1/50, 0/49, 4/50)
Forestomach: epithelial hyperplasia (8/50, 21/50, 33/49, 44/50)
Glandular Stomach: focal epithelial hyperplasia (0/50, 10/50, 20/49, 34/50); gland epithelium cyst (5/50, 18/50, 21/49, 26/50); lymphoid cellular infiltration (3/50, 20/50, 19/49, 15/50); mineralization (0/50, 4/50, 6/49, 13/50)
Skin: chronic active inflammation (3/50, 13/50, 12/49, 5/50); dermal fibrosis (3/50, 12/50, 12/49, 4/50); epidermal hyperplasia (3/50, 13/50, 12/49, 6/50); epidermal ulcer (3/50, 13/50, 11/49, 6/50); hair follicle dilatation (7/50, 10/50, 13/49, 28/50); sebaceous gland atrophy (13/50, 10/50, 20/49, 29/50)
Spleen: atrophy (2/50, 9/50, 30/49, 39/49)
Thymus: atrophy (11/41, 15/42, 30/40, 45/49)
Liver: hematopoietic cell proliferation (2/50, 9/50, 9/49, 3/50)
Heart: cardiomyopathy (5/50, 5/50, 17/49, 9/50)
Blood Vessel: aorta mineralization (0/50, 0/50, 6/49, 8/50)
Urinary Bladder: transitional epithelial hyperplasia (0/49, 0/50, 0/50, 4/50)
Lung: chronic active inflammation (0/49, 3/50, 5/50, 7/50)
Forestomach: epithelial hyperplasia (8/50, 27/50, 38/50, 43/50)
Glandular Stomach: focal epithelial hyperplasia (1/50, 19/50, 26/50, 28/50); gland epithelial cyst (8/50, 19/50, 13/50, 22/50); lymphoid cellular infiltration (1/50, 14/50, 30/50, 28/50)
Skin: chronic active inflammation (0/50, 2/50, 6/50, 11/50); dermal fibrosis (0/50, 1/50, 4/50, 11/50); epidermal hyperplasia (1/50, 2/50, 4/50, 11/50); epidermal ulcer (0/50, 1/50, 4/50, 11/50); hair follicle dilatation (2/50, 0/50, 11/50, 23/50); sebaceous gland atrophy (6/50, 10/50, 11/50, 15/50)
Clitoral Gland: atrophy (25/49, 44/50, 37/49, 40/50); cyst duct (5/49, 46/50, 43/49, 43/50); chronic active inflammation (3/49, 4/50, 17/49, 25/50)
Ovary: atrophy (29/49, 44/50, 47/50, 45/50)
Bone Marrow: hyperplasia (2/50, 8/50, 9/50, 16/50)
Spleen: hematopoietic cell proliferation (10/49, 25/50, 21/50, 33/50)
Thymus: atrophy (7/48, 15/48, 12/45, 25/48)
Liver: hematopoietic cell proliferation (3/49, 9/50, 9/50, 21/50)
Heart: cardiomyopathy (3/49, 5/50, 4/50, 9/50)
Neoplastic effects Lung: cystic keratinizing epithelioma (0/50, 14/50, 31/50, 37/50)
Liver: cholangiocarcinoma (0/50, 4/50, 4/50, 6/50)
Oral Mucosa: gingival squamous cell carcinoma (1/50, 5/50, 4/50, 5/50)
Thyroid Gland: follicular cell adenoma (0/50, 3/50, 4/50, 4/50
Lung: cystic keratinizing epithelioma (0/50, 6/50, 26/49, 39/49)
Liver: cholangiocarcinoma (1/50, 1/50, 1/49, 3/49)
Oral Mucosa: gingival squamous cell carcinoma (0/50, 0/50, 4/50, 6/50)
Forestomach: squamous cell papilloma or squamous cell carcinoma (0/50, 1/50, 0/50, 4/50)
Urethra: transitional epithelial carcinoma (0/50, 32/50, 46/49, 49/50) Lung: alveolar/ bronchiolar adenoma (5/50, 16/50, 12/49, 6/50); alveolar/ bronchiolar adenoma or carcinoma (7/50, 17/50, 15/49, 6/50) Forestomach: squamous cell carcinoma (0/50, 1/50, 1/49, 3/50) Skin: fibrosarcoma (1/50, 6/50, 5/50, 8/50); fibrosarcoma or malignant schwannoma (2/50, 8/50, 7/50, 12/50)
Urethra: transitional epithelial carcinoma (0/50, 0/50, 0/50, 2/50)
Lung: alveolar/ bronchiolar carcinoma (0/49, 2/50, 1/50, 4/50); alveolar/bronchiolar adenoma or carcinoma (3/49, 8/50, 5/50, 10/50); cystic keratinizing epithelioma (0/49, 0/50, 0/50, 2/50)
Forestomach: squamous cell carcinoma (0/50, 1/50, 1/50, 4/50)
Equivocal findings Malignant Schwannoma: (0/50, 0/50, 1/50, 3/50) Adrenal Cortex: adenoma (1/50, 1/50, 3/50, 4/49)
Ureter: epithelial carcinoma (0/50, 1/50, 0/50, 0/50) Ureter: epithelial carcinoma (0/50, 0/50, 1/50, 0/50)

Malignant Lymphoma: (2/50, 5/50, 8/50, 7/50)
Level of evidence of carcinogenic activity Clear evidence Clear evidence Clear evidence Clear evidence

Date: November 2010

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies