National Toxicology Program

National Toxicology Program

Abstract for TR-575 - Acrylamide (CASRN 79-06-1)

http://ntp.niehs.nih.gov/go/36330

Toxicology and Carcinogenesis Studies of Acrylamide (CASRN 79-06-1) in F344/N Rats and B6C3F1 Mice (Feed and Drinking Water Studies)

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Abstract

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years.

2-WEEK STUDY IN RATS

Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male rats given 3.52 mM acrylamide in drinking water. Mild to moderate degeneration of the germinal epithelium in the seminiferous tubules of the testes was noted microscopically in all male rats given 7.03 mM acrylamide in drinking water and in two of four male rats fed 370 mg acrylamide per kg diet.

2-WEEK STUDY IN MICE

Groups of four male and four female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. None of the mice administered 7.03 mM acrylamide in the drinking water survived the 14-day study. Mice administered 7.03 mM acrylamide in the drinking water showed marked decreases in body weight (greater than 25% compared to control mice) after seven days of treatment, and two of the mice displayed hind leg paralysis. No significant adverse effects were observed in mice administered 3.52 mM acrylamide in the drinking water for 14 days.

Female B6C3F1 mice given 370 mg acrylamide per kg diet for 14 days showed a modest decrease (11%) in body weight. No other significant adverse effects were observed in mice administered any dose of acrylamide in the diet.

3-MONTH STUDY IN RATS

Groups of eight male and eight female F344/N rats were administered 0.0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, or 185 mg acrylamide per kg diet for 13 weeks. After 13 weeks, male and female rats administered 3.52 mM acrylamide weighed 73% and 71% of the control rats, respectively. Male and female rats fed 185 mg acrylamide per kg diet for 13 weeks weighed 86% and 82% of the control rats, respectively. Hind-leg paralysis was observed in all rats administered 3.52 mM acrylamide in the drinking water or 185 mg acrylamide per kg diet. Four of eight female rats administered 1.41 mM acrylamide also displayed hind-leg paralysis. Radiculoneuropathy (a degenerative lesion) involving the sciatic nerve and lumbar spinal cord was observed in all male and female rats administered 3.52 mM acrylamide or 185 mg acrylamide per kg diet. A low incidence of radiculoneuropathy was also noted in female rats fed 74 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. All rats treated with 3.52 mM acrylamide displayed increased hemosiderin pigment in their spleens and hyperplasia of red blood cell precursors in their bone marrow. Two of eight male rats fed 185 mg acrylamide per kg diet also had increased hemosiderin pigment in their spleens.

Degeneration of the germ cells in the testes was observed in all male rats given 1.41 or 3.52 mM acrylamide, or 185 mg acrylamide per kg diet. A lower incidence of this lesion was also detected in all other doses of acrylamide in the diet.

3-MONTH STUDY IN MICE

Groups of eight male and eight female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet. After 13 weeks, the male and female mice given 3.52 mM acrylamide weighed 86% and 94% of their respective control mice; male mice administered 1.41 mM acrylamide weighed 91% of the control male mice; and male and female mice fed 370 mg acrylamide per kg diet weighed 87% and 81% of their respective control groups. Hind-limb paralysis was observed in all mice administered 3.52 mM acrylamide or 370 mg acrylamide per kg diet. Radiculoneuropathy involving the sciatic nerve, lumbar spinal cord, or both was observed in all male and female mice administered 3.52 mM acrylamide. Radiculoneuropathy, involving primarily the sciatic nerve, was also noted in one of eight female mice fed 185 mg acrylamide per kg diet and in mice fed 370 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in six of eight male mice given 3.52 mM acrylamide and seven of seven mice fed 370 mg acrylamide per kg diet.

2 YEAR STUDY IN RATS

Groups of 48 male and 48 female F344/N rats were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in an average daily consumption of approximately 0.33, 0.66, 1.32, and 2.71 mg acrylamide per kg body weight in male F344/N rats and 0.44, 0.88, 1.84, and 4.02 mg acrylamide per kg body weight in female F344/N rats.

Acrylamide had no effect upon the survival of male F344/N rats. Female F344/N rats administered 0.175, 0.35, or 0.70 mM acrylamide had decreased survival compared to control female F344/N rats. Acrylamide caused significant dose-related decreasing trends in body weight in F344/N rats. At the end of the 2 year period, male and female F344/N rats administered 0.70 mM acrylamide weighed 86% and 85% of their respective control groups. Feed consumption was generally not affected by acrylamide; water consumption in female F344/N rats was increased at later time points.

In male F344/N rats, the incidence of epididymis malignant mesothelioma, combined epididymis or testicular tunica malignant mesothelioma, heart malignant incidences of schwannoma, pancreatic islets adenoma, thyroid gland follicular cell carcinoma, and combined thyroid gland follicular cell adenoma or carcinoma was increased significantly in the 0.70 mM acrylamide group.

In female F344/N rats, the incidence of clitoral gland carcinoma was increased significantly in the 0.0875, 0.175, and 0.70 mM acrylamide groups. The incidence of mammary gland fibroadenoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide. Significant increases in neoplasm incidences were also observed in oral mucosa squamous cell papilloma, combined oral mucosa or tongue squamous cell papilloma or carcinoma, combined skin fibroma, fibrosarcoma, or sarcoma, and combined thyroid gland follicular cell adenoma or carcinoma at 0.70 mM acrylamide.

2-YEAR STUDY IN MICE

Groups of 48 male and 48 female B6C3F1 mice were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in average daily consumption of approximately 1.04, 2.20, 4.11, and 8.93 mg acrylamide per kg body weight in male B6C3F1 mice and 1.10, 2.23, 4.65, and 9.96 mg acrylamide per kg body weight in female B6C3F1 mice.

Acrylamide caused dose-related decreasing trends in survival in B6C3F1 mice, with the survival being significantly decreased in male B6C3F1 mice administered 0.70 mM acrylamide and female B6C3F1 mice given 0.35 and 0.70 mM acrylamide. Acrylamide caused only sporadic changes in body weight in B6C3F1 mice, with the magnitude of the change never exceeding 6% of the respective control body weight. Food and water consumption was generally not affected by acrylamide, except for an increased consumption by female B6C3F1 mice in the 0.70 mM acrylamide group toward the end of the study.

In male B6C3F1 mice, the incidence of harderian gland adenoma and combined harderian gland adenoma or adenocarcinoma was increased significantly in all acrylamide dose groups. The incidence of lung alveolar/bronchiolar adenoma and combined lung alveolar/bronchiolar adenoma or carcinoma was increased significantly at 0.175 and 0.70 mM acrylamide, and the incidence of stomach (forestomach) squamous cell papilloma and combined stomach (forestomach) squamous cell papilloma or carcinoma was increased significantly at 0.35 and 0.70 mM acrylamide.

In female B6C3F1 mice, the incidence of harderian gland adenoma was increased significantly in all dosed groups. The combined incidence of mammary gland adenoacanthoma or adenocarcinoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide, and the incidence of mammary gland adenocarcinoma was increased significantly at 0.175 and 0.70 mM acrylamide. Incidences of lung alveolar/bronchiolar adenoma, combined lung alveolar/bronchiolar adenoma or carcinoma, and malignant mesenchymal skin tumors (fibrosarcoma, hemangiosarcoma, liposarcoma, myxosarcoma, neurofibrosarcoma, or sarcoma) were increased significantly at 0.35 and 0.70 mM acrylamide. A significant increase was also observed in the incidence of ovary granulosa cell tumor (benign) and mammary gland adenoacanthoma at 0.70 mM.

CONCLUSIONS

Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of acrylamide in male F344/N rats based on increased incidences of malignant mesothelioma of the epididymis and testis tunica, malignant schwannoma of the heart, and follicular cell adenoma or carcinoma of the thyroid gland. An increased incidence of pancreatic islet adenoma was also considered related to acrylamide exposure.

There was clear evidence of carcinogenic activity of acrylamide in female F344/N rats based on increased incidences of fibroadenoma of the mammary gland, squamous cell neoplasms (primarily papilloma) of the oral cavity (mucosa or tongue), mesenchymal neoplasms (fibroma, fibrosarcoma, or sarcoma) of the skin, and follicular cell neoplasms (adenoma or carcinoma) of the thyroid gland. Increased incidences of hepatocellular adenoma of the liver and carcinoma of the clitoral gland were also considered to be related to acrylamide exposure. The occurrence of malignant schwannoma of the heart may have been related to acrylamide exposure.

There was clear evidence of carcinogenic activity of acrylamide in male B6C3F1 mice based on increased incidences of neoplasms (primarily adenoma) of the harderian gland, alveolar/bronchiolar neoplasms (primarily adenoma) of the lung and squamous cell neoplasms (primarily papilloma) of the forestomach.

There was clear evidence of carcinogenic activity of acrylamide in female B6C3F1 mice based on increased incidences of harderian gland adenoma, alveolar/ bronchiolar adenoma of the lung, adenoacanthoma and adenocarcinoma of the mammary gland, benign granulosa cell neoplasms of the ovary, and malignant mesenchymal neoplasms of the skin. Increased incidences of squamous cell papilloma of the forestomach were also considered to be related to acrylamide exposure.

Exposure to acrylamide was associated with increased incidences of degeneration of the retina and sciatic nerve in male and female rats; preputial gland duct ectasia in male rats; adrenal cortex hypertrophy and cytoplasmic vacuolization, bone marrow hyperplasia, ovarian atrophy, and spleen hematopoietic cell proliferation in female rats; cataracts of the eye, spleen hematopoietic cell proliferation, and forestomach epithelial hyperplasia in male and female mice; preputial gland inflammation and lung epithelial hyperplasia in male mice; and ovarian cysts in female mice.  

Synonyms: 2-Propenamide, acrylagel, acrylic acid amide, acrylic amide, ethylenecarboxamide, propenamide, vinyl amide.


Summary of the 2-Year Carcinogenesis Study of Acrylamide
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Doses in drinking water 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide (0, 6.25, 12.5, 25, or 50 ppm acrylamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide  (0, 6.25, 12.5, 25, or 50 ppm acrylamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide (0, 6.25, 12.5, 25, or 50 ppm acrylamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide  (0, 6.25, 12.5, 25, or 50 ppm acrylamide) ad libitum for 2 years
Body weights 0.70 mM acrylamide exposure group weighed 86% of control group after 2 years 0.70 mM acrylamide exposure group weighed 85% of control group after 2 years Only sporadic changes, with magnitude 4% of controls Only sporadic changes, with magnitude 6% of controls
Survival rates 17/48, 14/48, 19/48, 16/48, 9/48 34/48, 28/48, 21/48, 23/48, 13/48 39/48, 39/48, 37/48, 38/48, 28/48 39/48, 36/48, 36/48, 25/48, 15/48
Nonneoplastic effects Eye: retina degeneration (2/44, 2/47, 3/47, 2/46, 10/45)
Peripheral nerve (sciatic): axon degeneration (5/48, 7/48, 7/48, 11/48, 23/48)
Preputial gland: duct ectasia (4/48, 6/47, 11/48, 14/48, 10/48)
Adrenal cortex: hypertrophy (4/48, 5/48, 5/48, 4/48, 10/48); cytoplasmic vacuolization (2/48, 5/48, 5/48, 5/48, 9/48)
Bone marrow: hyperplasia (0/48, 1/48, 1/48, 3/47, 4/48)
Eye: retina degeneration (14/45, 16/48, 16/47, 21/45, 23/46)
Ovary: atrophy (38/48, 41/48, 43/48, 44/48, 43/48)
Peripheral nerve (sciatic): axon degeneration (4/48, 3/48, 1/48, 4/48, 19/48)
Spleen: hematopoietic cell proliferation (8/48, 10/48, 7/48, 7/48, 15/48)
Eye: cataract (3/44, 6/44, 5/45, 6/44, 9/41)
Lung: alveolar epithelium hyperplasia (0/47, 0/46, 3/47, 4/45, 9/48)
Preputial gland: inflammation (3/44, 6/46, 3/47, 14/47, 15/46)
Spleen: hematopoietic cell proliferation (5/45, 6/47, 9/46, 6/47, 14/45)
Stomach: forestomach epithelium hyperplasia (0/46, 1/45, 3/46, 3/47, 8/44)
Eye: cataract (3/45, 2/44, 7/47, 11/45, 13/38)
Ovary: cyst (8/46, 18/45, 12/48, 20/45, 18/42)
Spleen: hematopoietic cell proliferation (5/46, 10/46, 6/48, 14/45, 18/44)
Stomach: forestomach epithelium hyperplasia (5/46, 9/46, 4/48, 4/45, 11/42)
Neoplastic effects Epididymis: malignant mesothelioma (2/48, 2/48, 1/48, 5/48, 8/48)
Testes: malignant mesothelioma (1/48, 2/48, 1/48, 1/48, 5/48)
Epididymis or Testes: malignant mesothelioma (2/48, 2/48, 1/48, 5/48, 8/48)
Heart: malignant schwannoma (1/48, 2/48, 3/48, 4/48, 6/48)
Pancreatic islets: adenoma (1/46, 2/48, 4/48, 1/48, 6/48); carcinoma (0/46, 0/48, 0/48, 1/48, 0/48); adenoma or carcinoma (1/46, 2/48, 4/48, 2/48, 6/48)
Thyroid gland: follicular cell adenoma (0/47, 1/48, 1/47, 1/48, 3/48); follicular cell carcinoma (1/47, 2/48, 3/47, 6/48, 6/48); follicular cell adenoma or carcinoma (1/47, 3/48, 4/47, 6/48, 9/48)
Clitoral gland: carcinoma (1/48, 6/48, 12/47, 3/48, 8/47)
Heart: malignant schwannoma (2/48,1/48, 0/48, 2/48, 4/48)
Liver: hepatocellular adenoma (0/48, 0/48, 1/48, 1/48, 3/48)
Mammary gland: fibroadenoma (16/48, 18/48, 24/46, 22/47, 31/48)
Oral mucosa or tongue: squamous cell papilloma or carcinoma (0/48, 2/48, 1/48, 3/48, 5/48)
Skin: subcutaneous tissue fibroma, fibrosarcoma, or sarcoma (1/48, 0/48, 0/48, 1/48, 5/48)
Thyroid gland: follicular cell adenoma (0/48, 0/48, 1/48, 0/48, 2/47); follicular cell carcinoma (0/48, 0/48, 1/48, 3/48, 2/47); follicular cell adenoma or carcinoma (0/48, 0/48, 2/48, 3/48, 4/47)
Harderian gland: adenoma (2/46, 13/46, 27/47, 36/47, 39/47); adenocarcinoma (0/46, 0/46, 0/47, 1/47, 1/47); adenoma or adenocarcinoma (2/46, 13/46, 27/47, 37/47, 39/47)
Lung: alveolar/bronchiolar adenoma (5/47, 6/46, 13/47, 10/45, 19/48); alveolar/bronchiolar adenoma or carcinoma (6/47, 6/46,14/47, 10/45, 20/48)
Stomach: forestomach squamous cell papilloma (0/46, 2/45, 2/46, 6/47, 6/44); forestomach squamous cell carcinoma (0/46, 0/45, 0/46, 1/47, 2/44); forestomach squamous cell papilloma or carcinoma (0/46, 2/45, 2/46, 7/47, 8/44)
Harderian gland: adenoma (0/45, 8/44, 20/48, 32/47, 31/43)
Lung: alveolar/bronchiolar adenoma (1/47, 4/47, 6/48, 11/45, 19/45)
Mammary gland: adenoacanthoma (0/47, 1/46, 1/48, 2/45, 4/42); adenocarcinoma (0/47, 4/46, 6/48, 2/45, 13/42); adenoacanthoma or adenocarcinoma (0/47, 4/46, 7/48, 4/45, 17/42)
Ovary: benign granulose cell tumor (0/46, 1/45, 0/48, 1/45, 5/42)
Skin: fibrosarcoma, hemangiosarcoma, liposarcoma, myxosarcoma, neurofibrosarcoma, or sarcoma (0/48, 0/46, 3/48, 10/45, 6/43) 
Stomach: forestomach squamous cell papilloma (4/46, 0/46, 2/48, 5/45, 8/42)
Level of evidence of carcinogenic activity Clear evidence Clear evidence Clear evidence Clear evidence

Date: July 2012


 

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