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Abstract for TR-588 - Glycidamide

Abstract

Toxicology and Carcinogenesis Studies of Glycidamide (CASRN 5694-00-8) in F344/N Nctr Rats and B6C3F1/Nctr Mice (Drinking Water Studies)

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Abstract

Glycidamide is a reactive electrophile that occurs primarily as a metabolite of acrylamide. Because acrylamide can be formed as a by-product during the cooking of starchy foods (including French fries, potato chips, and bread) and the roasting of coffee, the National Toxicology Program performed simultaneous studies to determine and compare the long-term effects of acrylamide and glycidamide in male and female F344/N Nctr rats and B6C3F1/Nctr mice. The data from the animals exposed to acrylamide formed the basis for NTP Technical Report 575. The results from the studies with glycidamide form the basis for the current report.

2-WEEK STUDY IN RATS

Groups of four male and four female F344/N Nctr rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM glycidamide in the drinking water (0, 12.2, 30.6, 61.2, 122, 306, or 612 ppm glycidamide) for 14 days. One female rat given 7.03 mM glycidamide in the drinking water died after 12 days of treatment. Male rats administered 3.52 and 7.03 mM glycidamide weighed 84% and 60% of the control rats; female rats weighed 87% and 58% of the control rats. All male rats and one of four female rats receiving 7.03 mM glycidamide in drinking water exhibited hind limb paresis on day 14. Mild-to-moderate dilatation of the urinary bladder was observed in three of four male rats and one of four female rats given 7.03 mM glycidamide 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 glycidamide in drinking water.

2-WEEK STUDY IN MICE

Groups of four male and four female B6C3F1/Nctr mice were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM glycidamide in the drinking water (0, 12.2, 30.6, 61.2, 122, 306, or 612 ppm glycidamide) for 14 days. Mice administered 7.03 mM glycidamide in the drinking water for 14 days showed marked decreases in body weight (>30% compared to control mice). A single female mouse treated with 7.03 mM glycidamide in the drinking water displayed an abnormal posture and gait after 14 days of treatment. Male mice given 3.52 mM glycidamide in the drinking water for 14 days showed a modest decrease (8-13%) in body weight. There were no other adverse effects in either male or female mice administered 3.52 mM glycidamide in the drinking water for 14 days.

3-MONTH STUDY IN RATS

Groups of eight male and eight female F344/N Nctr rats were administered 0.0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM glycidamide in the drinking water (0, 12.2, 30.6, 61.2, 122, or 306 ppm glycidamide) for 3 months. After 3 months, male rats administered 1.41 and 3.52 mM glycidamide weighed 86% and 78% of the control rats; female rats weighed 88% and 78% of the control rats. Hind limb paresis was observed in all rats administered 3.52 mM glycidamide in the drinking water. A low incidence of peripheral neuropathy involving the sciatic nerve and axonal degeneration of the lumbar spinal cord was noted in male and female rats administered 3.52 mM glycidamide. The neuronal degenerative changes were accompanied by luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in all male rats given 1.41 or 3.52 mM glycidamide. A lower incidence of this lesion was also detected in all other doses of glycidamide.

3-MONTH STUDY IN MICE

Groups of eight male and eight female B6C3F1/Nctr mice were administered 0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM glycidamide in the drinking water (0, 12.2, 30.6, 61.2, 122, or 306 ppm glycidamide) for 3 months. One female mouse administered 1.41 mM glycidamide died before the end of the experiment. After 3 months, the male mice given 3.52 mM glycidamide weighed 90% of the control male mice; none of the other groups had significant changes in body weight gain. Hind limb paresis was observed in two of eight male mice administered 3.52 mM glycidamide. Peripheral neuropathy, involving primarily the sciatic nerve, was noted in male and female mice treated with 3.52 mM glycidamide. 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 seven of eight male mice given 3.52 mM glycidamide.

2-YEAR STUDY IN RATS

Groups of 48 male and 48 female F344/N Nctr rats were administered 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) in the drinking water ad libitum for 2 years resulting in average daily consumptions for the entire 2-year period of 0.39, 0.79, 1.56, and 3.34 mg glycidamide per kg body weight in male F344/N Nctr rats and 0.54, 1.08, 2.23, and 4.65 mg glycidamide per kg body weight in female F344/N Nctr rats.

There were significant dose-related decreasing trends in body weight in both male and female F344/N Nctr rats exposed to glycidamide in the drinking water. At the end of the 2-year period, F344/N Nctr rats administered 0.70 mM glycidamide weighed 79%-82% of the control groups. Food and water consumption were generally not affected by glycidamide. Male and female F344/N Nctr rats administered 0.35 and 0.70 mM glycidamide had decreased survival compared to control F344/N Nctr rats.

In male F344/N Nctr rats, the incidence of epididymal malignant mesothelioma, testicular malignant mesothelioma, and combined epididymal or testicular malignant mesothelioma was increased significantly in the 0.35 and 0.70 mM glycidamide dose groups. Malignant schwannoma of the heart, squamous cell papilloma of the tongue, combined squamous cell papilloma or carcinoma of the oral mucosa or tongue, follicular cell adenoma, follicular cell carcinoma, and combined follicular cell adenoma or carcinoma of the thyroid gland, and mononuclear cell leukemia were increased significantly in the 0.70 mM glycidamide dose group.

In female F344/N Nctr rats, the incidence of mammary gland fibroadenoma was increased significantly in all glycidamide dose groups. The incidence of follicular cell adenoma of the thyroid gland increased at 0.70 mM and the incidence of combined follicular cell adenoma or carcinoma of the thyroid gland was increased significantly in the 0.175, 0.35, and 0.70 mM glycidamide dose groups; the incidence of clitoral gland carcinoma was increased significantly in the 0.35 and 0.70 mM glycidamide dose groups; and the incidence of combined squamous cell papilloma or carcinoma of the oral mucosa or tongue, squamous cell papilloma of the forestomach, and mononuclear cell leukemia was increased significantly at 0.70 mM glycidamide.

2-YEAR STUDY IN MICE

Groups of 48 male and 48 female B6C3F1/Nctr mice were administered 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM glycidamide resulted in an average daily consumption for the entire 2-year period of 1.20, 2.65, 5.13, and 9.55 mg glycidamide per kg body weight in male B6C3F1/Nctr mice and 1.37, 2.89, 5.64, and 12.99 mg glycidamide per kg body weight in female B6C3F1/Nctr mice.

There were no consistent body weight changes in either male or female B6C3F1/Nctr mice exposed to glycidamide. Food and water consumption were generally not affected by glycidamide, except toward the end of the study. There were dose-related decreasing trends in survival in B6C3F1/Nctr mice, with survival being significantly decreased in male B6C3F1/Nctr mice administered 0.175, 0.35, and 0.70 mM glycidamide and female B6C3F1/Nctr mice given 0.35 and 0.70 mM glycidamide.

In male B6C3F1/Nctr mice, the incidence of Harderian gland adenoma and alveolar/bronchiolar adenoma of the lung was increased significantly in all glycidamide dose groups. The incidence of squamous cell papilloma and combined squamous cell papilloma or carcinoma of the skin, and squamous cell papilloma and combined squamous cell papilloma or carcinoma of the forestomach was increased significantly at 0.70 mM glycidamide.

In female B6C3F1/Nctr mice, the incidence of Harderian gland adenoma was increased significantly in all glycidamide dose groups. Mammary gland adenoacanthoma increased at 0.70 mM and the incidence of adenocarcinoma and combined adenocarcinoma or adenoacanthoma of the mammary gland increased at 0.35 and 0.70 mM glycidamide. Fibrosarcoma of the skin increased significantly at 0.70 mM and combined fibrosarcoma or sarcoma of the skin was increased significantly at 0.35 and 0.70 mM glycidamide. The incidence of alveolar/bronchiolar adenoma of the lung and squamous cell papilloma of the forestomach was increased significantly at 0.70 mM glycidamide.

CONCLUSIONS

Under the conditions of this 2-year drinking water study, there was clear evidence of carcinogenic activity of glycidamide in male F344/N Nctr rats based upon increased incidences of malignant mesothelioma of the epididymis and testis tunica, malignant schwannoma of the heart, follicular cell adenoma or carcinoma of the thyroid gland, and oral cavity (oral mucosa or tongue) squamous cell neoplasms (primarily papilloma). An increased incidence of mononuclear cell leukemia may have been related to glycidamide exposure. There was clear evidence of carcinogenic activity of glycidamide in female F344/N Nctr rats based upon increased incidences of mammary gland fibroadenoma, oral cavity (oral mucosa or tongue) squamous cell neoplasms (primarily papilloma), follicular cell adenoma or carcinoma of the thyroid gland, and carcinoma of the clitoral gland. Increased incidences of squamous cell papilloma of the forestomach and mononuclear cell leukemia were also considered to be related to glycidamide exposure.

There was clear evidence of carcinogenic activity of glycidamide in male B6C3F1/Nctr mice based upon increased incidences of adenoma of the Harderian gland, alveolar/bronchiolar adenoma of the lung, squamous cell neoplasms (primarily papilloma) of the skin and forestomach. There was clear evidence of carcinogenic activity of glycidamide in female B6C3F1/Nctr mice based upon increased incidences of adenoma of the Harderian gland, alveolar/bronchiolar adenoma of the lung, adenoacanthoma and adenocarcinoma of the mammary gland, squamous cell papilloma of the forestomach, and malignant mesenchymal neoplasms of the skin. The occurrence of granulosa cell tumors of the ovary may have been related to glycidamide exposure.

In F344/N Nctr rats, exposure to glycidamide was associated with increased incidence of brain gliosis (males and females), exfoliated germ cells within the epididymis (males), hepatocyte degeneration (males), liver necrosis (males), bone marrow hyperplasia (females), axonal degeneration of the lumbar spinal cord (females), and uterine endometrial hyperplasia (females).

In B6C3F1/Nctr mice, exposure to glycidamide was associated with increased incidences of cataracts (males and females), corneal inflammation (males and females), forestomach squamous cell hyperplasia (males and females), hematopoietic cell proliferation of the spleen (males and females), preputial gland lesions (degeneration, ductal dilatation, inflammation) (males), ovarian cysts (females), hepatic angiectasis and necrosis (females), and axonal degeneration of the cervical spinal cord (females).

The results of this bioassay, when compared to those previously reported for acrylamide, indicate that acrylamide is efficiently metabolized to glycidamide in both sexes of both species. Based upon the concordance of tumor sites between the two bioassays, the data also indicate that carcinogenic activity of acrylamide is due to its metabolic conversion to glycidamide.

Synonyms: 2,3-epoxypropanamide; glycidic acid amide; oxirane-2-carboxamide; oxiranecarboxamide


Summary of the 2-Year Carcinogenesis Study of Glycidamide
  Male
F344/N Nctr Rats
Female
F344/N Nctr Rats
Male
B6C3F1/Nctr Mice
Female
B6C3F1/Nctr Mice
Doses in drinking water 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) ad libitum for 2 years 0, 0.0875, 0.175, 0.35, or 0.70 mM glycidamide (0, 7.65, 15.3, 30.6, and 61.2 ppm glycidamide) ad libitum for 2 years
Body weights 0.70 mM glycidamide exposure group weighed 82% of control group after 2 years 0.70 mM glycidamide exposure group weighed 79% of control group after 2 years No significant body weight changes Only sporadic changes, with magnitude ≤ 5% of controls
Survival rates 21/48, 18/48, 15/48, 7/48, 2/48 35/48, 26/48, 27/48, 17/48, 2/48 45/48, 41/48, 34/48, 26/48, 25/48 41/48, 42/48, 38/48, 31/48, 8/48
Nonneoplastic effects Brain: gliosis (0/48, 1/48, 0/48, 0/47, 4/48)
Epididymis: exfoliated germ cells (0/48, 1/45, 2/48, 3/47, 4/47)
Liver: hepatocyte degeneration (2/47, 6/47, 6/48, 10/47, 8/47); necrosis (1/47, 5/47, 2/48, 7/47, 5/47)
Brain: gliosis (0/48, 0/48, 4/48, 4/48, 4/48)
Bone marrow: hyperplasia (2/48, 6/48, 7/46, 8/47, 14/47)
Spinal cord (lumbar): axonal degeneration (5/48, 6/48, 5/47, 6/48, 9/48)
Uterus: endometrial hyperplasia (11/48, 17/48, 14/48, 14/48, 23/48)
Eye: cataract (1/47, 3/45, 7/46, 8/44, 17/42); corneal inflammation (0/47, 0/45, 2/46, 0/44, 8/42)
Preputial gland: degeneration (4/47, 10/47, 5/46, 12/46, 9/44); ductal dilatation (0/47, 0/47, 1/46, 0/46, 4/44); inflammation (1/47, 6/47, 2/46, 3/46, 9/44)
Spleen: hematopoietic cell proliferation (6/47, 6/47, 12/47, 14/46, 17/44)
Stomach (forestomach): epithelial hyperplasia (5/47, 2/45, 5/48, 5/45, 12/41)
Eye: cataract (1/45, 2/44, 8/47, 8/44, 9/43); corneal inflammation (0/45, 2/44, 1/47, 3/44, 5/43)
Liver: angiectasis (0/47, 0/48, 1/47, 0/46, 5/43); necrosis (0/47, 0/48, 0/47, 0/46, 5/43)
Ovary: cyst (14/45, 17/47, 25/47, 22/46, 18/44)
Spinal cord (cervical): axonal degeneration (4/45, 9/44, 10/47, 9/45, 10/43)
Spleen: hematopoietic cell proliferation (6/46, 10/47, 11/47, 14/47, 29/45)
Stomach (forestomach): epithelial hyperplasia (4/45, 4/45, 10/47, 11/45, 5/44)
Neoplastic effects Epididymis: malignant mesothelioma (0/48, 1/45, 3/48, 10/47, 17/47)
Testes: malignant mesothelioma (0/48, 1/47, 3/48, 6/47, 13/48)
Epididymis or testes: malignant mesothelioma (0/48, 1/48, 3/48, 10/47, 17/48)
Heart: malignant schwannoma (2/48, 3/48, 3/48, 7/47, 8/48)
Oral mucosa: squamous cell papilloma (1/48, 1/48, 0/48, 2/47, 3/48); squamous cell carcinoma (1/48, 0/48, 1/48, 1/47, 0/48)
Tongue: squamous cell papilloma (0/48, 1/48, 0/48, 1/47, 4/48); squamous cell carcinoma (0/48, 0/48, 1/48, 0/47, 0/48)
Oral mucosa or tongue: squamous cell papilloma or carcinoma (2/48, 2/48, 2/48, 3/47, 7/48)
Thyroid gland: follicular cell adenoma (2/47, 1/42, 3/48, 3/47, 8/46); follicular cell carcinoma (0/47, 2/42, 3/48, 1/47, 5/46); follicular cell adenoma or carcinoma (2/47, 3/42, 6/48, 4/47, 13/46)
Clitoral gland: carcinoma (4/48, 6/48, 7/48, 11/48, 14/47)
Mammary gland: fibroadenoma (16/48, 26/48, 35/48, 33/48, 36/48)
Oral mucosa: squamous cell papilloma (1/48, 1/48, 2/48, 0/48, 4/48); squamous cell carcinoma (0/48, 0/48, 0/48, 1/48, 2/48)
Tongue: squamous cell papilloma (0/48, 1/48, 0/48, 1/48, 0/48); squamous cell carcinoma (0/48, 0/48, 0/48, 0/48, 1/48)
Oral mucosa or tongue: squamous cell papilloma or carcinoma (1/48, 2/48, 2/48, 2/48, 7/48)
Stomach: forestomach squamous cell papilloma (0/48, 1/48, 0/48, 0/47, 3/46)
Thyroid gland: follicular cell adenoma (0/48, 3/48, 3/46, 1/46, 5/47); follicular cell carcinoma (0/48, 0/48, 2/46, 3/46, 3/47); follicular cell adenoma or carcinoma (0/48, 3/48, 5/46, 4/46, 8/47)
Mononuclear cell leukemia: (14/48, 11/48, 21/48, 19/48, 27/48)
Harderian gland: adenoma (3/47, 17/47, 23/47, 32/46, 42/47)
Lung: alveolar/bronchiolar adenoma (0/47, 7/46, 7/47, 13/47, 17/47)
Skin: squamous cell papilloma (0/47, 1/48, 2/47, 1/47, 8/46); squamous cell carcinoma (0/47, 0/48, 0/47, 0/47, 2/46); squamous cell papilloma or carcinoma (0/47, 1/48, 2/47, 1/47, 9/46)
Stomach: forestomach squamous cell papilloma (0/47, 2/45, 3/48, 2/45, 10/41); forestomach squamous cell carcinoma (0/47, 0/45, 0/48, 0/45, 2/41); forestomach squamous cell papilloma or carcinoma (0/47, 2/45, 3/48, 2/45, 12/41)
Harderian gland: adenoma (2/45, 19/47, 20/47, 24/46, 40/46)
Lung: alveolar/bronchiolar adenoma (3/46, 5/48, 3/47, 7/47, 9/44)
Mammary gland: adenoacanthoma (0/45, 0/48, 0/47, 1/47, 8/45); adenocarcinoma (1/45, 1/48, 2/47, 9/47, 11/45); adenoacanthoma or adenocarcinoma (1/45, 1/48, 2/47, 9/47, 18/45)
Skin: fibrosarcoma (0/45, 1/48, 2/47, 2/47, 9/45); sarcoma (0/45, 0/48, 1/47, 3/47, 3/45); fibrosarcoma or sarcoma (0/45, 1/48, 3/47, 5/47, 12/45)
Stomach: forestomach squamous cell papilloma (1/45, 1/45, 1/47, 5/45, 9/44)
Equivocal findings Mononuclear cell leukemia: (21/48, 26/48, 27/48, 27/47, 31/48) None None Ovary: granulosa cell tumor – benign or malignant (0/45, 0/47, 0/47, 3/46, 3/44)
Level of evidence of carcinogenic activity Clear evidence Clear evidence Clear evidence Clear evidence

Date: November 2014

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

Target Organs & Incidences from 2-year Studies