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https://ntp.niehs.nih.gov/go/tox099abs

Abstract for TOX-99

Toxicity Studies of a Gum Guggul Extract Formulation Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats and B6C3F1/N Mice

CASRN: GUMGUGGULEXT
Report Date: June 2020

FULL REPORT PDF

Abstract

Gum guggul extracts (GGEs) are botanical preparations derived from the oleoresin of the Commiphora mukul tree. The preparations are traditionally used in Ayurvedic medicine to treat hyperlipidemia, obesity, diabetes, atherosclerosis, and inflammatory conditions such as arthritis. In the United States, GGEs are marketed as dietary supplements. GGE toxicity was evaluated due to widespread human exposure through increasing dietary supplement use, demonstrated metabolic and hormone-altering effects, and a lack of available information to adequately assess safe use in humans. Male and female Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice were administered a GGE formulation in corn oil by gavage for 28 days or 3 months. Oral gavage was chosen as the route of exposure for these studies because human exposure primarily occurs by ingestion of encapsulated GGE supplements.

Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg GGE formulation/kg body weight/day in corn oil by gavage, 5 days per week for 3 months. Additional groups of 10 male and 10 female rats were administered the same doses for an interim 28-day study. All rats survived to the end of the study with the exception of three female rats, with a single death occurring in each of the 0, 125, and 500 mg/kg/day groups. Terminal mean body weights of all dosed groups of rats for both the 28-day and 3-month studies were within 5% of vehicle controls. No treatment-related clinical findings were observed. Dose‑related increases in absolute and relative liver weights were evident in male and female rats at 28 days and 3 months. There were no dose-related microscopic findings at 28 days or 3 months. Clinical pathology changes observed at 28 days or 3 months in male and/or female rats were increased globulin concentration and decreased bile acid, cholesterol, and phospholipid concentrations. Increased hepatic cytochrome P450 (CYP) 2B and CYP3A activities were observed at 28 days and 3 months in all dosed groups of male and female rats.

Groups of 15 male and 15 female mice were administered 0, 15.5, 31, 62.5, 125, or 250 mg GGE formulation/kg body weight/day in corn oil by gavage, 5 days per week for 3 months. Additional groups of 10 male and 10 female mice were administered the same doses for an interim 28-day study. All mice survived to the end of the study. Terminal mean body weights of all dosed groups of mice for both 28-day and 3-month studies were within 7% of vehicle controls. No treatment-related clinical findings were observed. No treatment-related effects on organ weights were observed, and there were no dose-related microscopic findings in mice at 28 days or 3 months. In the 3-month study, elevated serum cholesterol and phospholipid concentrations were noted in female mice. Administration of the tested GGE formulation did not result in significant changes in reproductive organ histopathology of male and female mice. Male mice administered ≥62.5 mg/kg/day exhibited statistically significant lower mean total number of homogenization-resistant spermatids and mean total number of homogenization-resistant spermatids/mg testis relative to the vehicle control group. Mice dosed with 250 mg/kg/day also displayed lower testicular weights (approximately 12%, significant trend) and lower caudal sperm counts relative to vehicle controls, collectively indicating that the GGE formulation examined exhibits the potential to be a male reproductive toxicant. Increased hepatic CYP2B and CYP3A activities were observed in male and female mice at the highest tested dose, 250 mg/kg/day.

The genotoxic potential of the administered GGE formulation was evaluated by quantifying micronucleated reticulocytes or erythrocytes in rat and mouse peripheral blood samples, following 3 months of dosing. No apparent increases in the frequency of micronucleated erythrocytes/reticulocytes or changes in the percentage of immature erythrocytes were noted in rats or mice, suggesting that the tested GGE formulation did not induce bone marrow toxicity or alter erythropoiesis in rodents.

The potential effects of a GGE formulation on endogenous metabolism were evaluated using human in vitro models. Treatment with a marketed GGE formulation decreased CYP2C9, CYP3A4-mediated testosterone 6β-hydroxylase, and CYP2C19 metabolic activity in human microsomal preparations. Additionally, treatment decreased taurocholate uptake in a human Na+ taurocholate cotransporting polypeptide activity assay and heightened ATPase activity by human P-glycoprotein. Taken together, these data suggest that GGE constituents may act as substrates or cofactors that modify the activity of human metabolic enzymes and transporters.

Under the conditions of the 3-month gavage studies, administration of the selected GGE formulation resulted in increased globulin concentrations and decreased bile acid, cholesterol, and phospholipid concentrations in rats, whereas increases in cholesterol and phospholipid concentrations were observed in mice. Decreased mean number of homogenization-resistant spermatids was evident in mice administered the GGE formulation, suggesting the testes might be a target organ of GGE toxicity (lowest-observed-effect level [LOEL] = 62.5 mg/kg/day). Male and female rats displayed significantly increased absolute and relative liver weights relative to the GGE formulation dose administered. Additionally, increased hepatic CYP3A and CYP2B activity was observed in both test species, and metabolic potential was altered in human in vitro assays, suggesting an increased potential for dietary supplement-drug pharmacokinetic interactions.

National Toxicology Program (NTP). 2020. NTP technical report on the toxicity studies of a gum guggul extract formulation administered by gavage to Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 99. https://doi.org/10.22427/NTP-TOX-99

Studies

Summary of Findings Considered Toxicologically Relevant in Rats and Mice Administered a Gum Guggul Extract Formulation by Gavage for Three Months
  Male
Sprague Dawley Rats
Female
Sprague Dawley Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Doses in corn oil 0, 62.5, 125, 250, 500, or 1,000 mg/kg/day 0, 62.5, 125, 250, 500, or 1,000 mg/kg/day 0, 15.5, 31, 62.5, 125, or 250 mg/kg/day 0, 15.5, 31, 62.5, 125, or 250 mg/kg/day
Survival rates 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 9/10, 10/10, 9/10, 10/10, 9/10, 10/10 15/15, 15/15, 15/15, 15/15, 15/15, 15/15 15/15, 15/15, 15/15, 15/15, 15/15, 15/15
Body weights Dosed groups similar to the vehicle control group Dosed groups similar to the vehicle control group Dosed groups similar to the vehicle control group Dosed groups similar to the vehicle control group
Clinical findings None[a] None None None
Organ weights ↑ Absolute and relative liver weight
↑ Relative kidney weight
↓ Absolute and relative thymus weight
↑ Absolute and relative liver weight None None
Nonneoplastic effects None None None None
Clinical pathology None ↑ Globulin
↑ A:G ratio
↓ Bile acids
None ↑ Cholesterol
↑ Phospholipids
Reproductive findings None Not assessed

↓ Number of spermatid heads
↓ Cauda epididymal sperm count
↓ Number of sperm/mg cauda
↓ Testis weight

Not assessed
CYP2B/CYP3A enzyme activity ↑ CYP2B
↑ CYP3A
↑ CYP2B
↑ CYP3A
↑ CYP2B
↑ CYP3A
↑ CYP2B
↑ CYP3A
Genetic Toxicology
Assay Results
Micronucleated erythrocytes (in vivo):
Rat:
Mouse:


Negative in males and females
Negative in males and females

[a] None = no toxicologically relevant effects for this endpoint.