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Abstract for TOX-93

Toxicity Study of Chitosan Administered in Feed to Sprague Dawley [Crl:CD(SD)] Rats

CASRN: 9012-76-4
Chemical Formula: (C6H11NO4)n
Molecular Weight: 1526.45
Synonyms/Common Names: 2-Amino-2-deoxy-beta-D-glucosamine; deacetylated chitin; poliglusam; poly (D-glucosamine)
Report Date: December 2017

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Abstract

Chitosan is a cationic carbohydrate polymer that is commercially derived from the deacetylation of chitin obtained from seafood shells. The most widespread route of human exposure to chitosan is as a dietary supplement for body weight reduction. Chitosan was nominated by the National Cancer Institute for mechanistic studies designed to measure the potential for vitamin E depletion and osteoporosis following ingestion. Male and female Sprague Dawley rats were exposed to chitosan (86.5% deacetylated, with an average molecular weight of approximately 82 kilodaltons and estimated to be approximately 94% pure) in feed for 6 months.

In this 6-month study, groups of 10 male and 10 female core study rats (Group A) were fed control diets (AIN-93M) or diets containing chitosan at concentrations of 1%, 3%, or 9%, for up to 25 weeks. Two additional groups of 10 male and 10 female rats (Groups B and C) were given the same dietary concentrations for up to 26 weeks. All male and female Group A rats survived to the end of the study. Mean body weights and feed consumption of exposed Group A groups were similar to those of the control groups. Dietary concentrations of 1%, 3%, and 9% resulted in average daily doses of approximately 450, 1,500, and 5,200 mg chitosan/kg body weight per day to males and 650, 1,800, and 6,000 mg/kg per day to females. There were no treatment-related clinical findings in core study animals.

The 9% male and female rats had significantly decreased cholesterol values (26% to 48%), compared to the controls, at all time points. Triglycerides were significantly decreased in 9% male and female rats, but not at every time point.

Phosphorus levels were significantly decreased in 9% male rats at weeks 13, 19, and 25; a decrease also occurred in 3% males at week 13. Phosphorus levels were significantly decreased in 3% and 9% females at weeks 13 and 25.

Compared to those of the controls, serum vitamin A concentrations were significantly decreased (approximately 30%) at weeks 13, 19, and 26 in 9% males, at weeks 13 and 26 in 3% males (approximately 15%), and at weeks 19 and 26 in 9% females (approximately 20%). Serum vitamin E concentrations were significantly decreased at all time points in 3% (33% to 42%) and 9% (79% to 82%) males, in 1% (17%) males at week 13, and in 9% (62% to 65%) females at all time points. Hepatic vitamin E concentrations were significantly decreased at week 26 in 3% (48%) and 9% (87%) males and 9% (80%) females. Serum concentrations of 1,25(OH)2 vitamin D were significantly increased in 9% (105% to 142%) males and (100% to 180%) females at weeks 7, 19, and 26.

Compared to the control groups, percent fat digested was significantly decreased during week 6 in 9% males and females, during week 12 in 3% and 9% males, during week 18 in 9% males and females, and during week 24 in all exposed groups of males and females. Calcium absorption was significantly increased in 9% females during weeks 12 and 24. Fecal weight was significantly increased in 3% and 9% males and females during each collection period, and in 1% females during weeks 12, 18, and 24. Fecal moisture was significantly increased in 9% males (up to 170%) and 9% females at all time points, in 3% males during week 6, and in 3% females during weeks 12 and 18.

Results of this study did not support chitosan as a cause of bone resorption. Significant elevation of parathyroid hormone levels occurred occasionally and inconsistently, while calcium levels remained relatively stable. Bone calcium, bone length, and the histology findings did not indicate calcium loss from the bone following chitosan exposure.

The absolute and relative liver weights of 9% males and females and the absolute and relative thymus weights of 3% males and 9% males and females were significantly less than those of the control groups.

There was a treatment-related decrease in the incidence of periportal fatty change in the liver of 9% females relative to the control group. A decreased incidence of periportal fatty change was observed in the liver of 9% males relative to the control group as well, but this decrease was not significant, and it was the same as that observed in 1% males. The appearance of periportal fatty change was similar in both males and females and in both exposed and control groups.

Under the conditions of the 6-month feed study of chitosan, male and female rats fed 3% and 9% chitosan in the diet had significantly decreased levels of serum vitamin A and serum and hepatic vitamin E and increased levels of serum 1,25(OH)2 vitamin D. Consumption of high levels of chitosan decreased percentage fat digestion and increased fecal weight and moisture, as well as reduced levels of phosphorous, cholesterol, and triglycerides. Female rats exposed to 9% chitosan also had significant liver weight and histologic changes. Based on the above results, the lowest-observed-effect level for chitosan exposure was 1% (approximately equivalent to 450 mg/kg) in male and 9% (approximately equivalent to 6,000 mg/kg) in female rats.

Studies

Summary of Findings Considered to be Toxicologically Relevant in Sprague Dawley Rats Exposed to Chitosan in Feed for 6 Months
  Male
Sprague Dawley Rats
Female
Sprague Dawley Rats
Concentrations in feed 0%, 1%, 3%, 9% 0%, 1%, 3%, 9%
Survival rates Group A: 10/10, 10/10, 10/10, 10/10
Group B: 9/10, 10/10, 10/10, 8/10
Group C: 10/10, 10/10, 10/10, 10/10
Group A: 10/10, 10/10, 10/10, 10/10
Group B: 10/10, 10/10, 9/10, 10/10
Group C: 10/10, 9/10, 10/10, 10/10
Body weights Exposed groups similar to the control group Exposed groups similar to the control group
Clinical findings None None
Clinical pathology ↓ Phosphorus
↓ Cholesterol
↓ Triglycerides
↓ Phosphorus
↓ Cholesterol
↓ Triglycerides
Vitamin concentrations ↓ Serum vitamin A
↑ Serum 1,25(OH)2 vitamin D
↓ Serum vitamin E
↓ Hepatic vitamin E
↓ Serum vitamin A
↑ Serum 1,25(OH)2 vitamin D
↓ Serum vitamin E
↓ Hepatic vitamin E
Digestive parameters ↓ Percent fat digested
↑ Fecal weight
↑ Fecal moisture
↓ Percent fat digested
↑ Fecal weight
↑ Fecal moisture
↑ Calcium absorbed
Bone parameters None None
Reproductive toxicity None Not determined
Organ weights ↓ Absolute and relative liver weights
↓ Absolute and relative thymus weights
↓ Absolute and relative liver weights
↓ Absolute and relative thymus weights
Nonneoplastic effects None Liver: periportal, fatty change (7/10, 4/10, 4/10, 0/10)