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https://ntp.niehs.nih.gov/go/tox095abs

Abstract for TOX-95

Toxicity Studies of Myristicin Administered to F344/NTac Rats and B6C3F1 Mice

CASRN: 607-91-0
Chemical Formula: C11H12O3
Molecular Weight: 192.21
Synonyms/Common Names: 1-Allyl-5-methoxy-2,3-methylenedioxybenzene; 5-allyl-1-methoxy-2,3,-(methylenedioxy)benzene; 1-methoxy-2,3-methylenedioxy-5-allyl benzene; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole
Report Date: March 2019

FULL REPORT PDF

Abstract

Myristicin is derived from the tropical evergreen tree Myristica fragrans. It is a major constituent in essential oil extracted from either the seed, which is the source of the spice nutmeg, or the aril covering the seed, which is the source of the spice mace. Myristicin was nominated for study by the National Cancer Institute due to widespread human exposure from natural sources and extensive consumer exposure. Male and female F344/NTac rats and B6C3F1/N mice received myristicin (greater than 94% pure) in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 600 mg/kg body weight 5 days per week for 13 weeks. Additional groups of 10 male and 10 female clinical pathology study rats were administered the same doses for 21 days. Genetic toxicology studies were conducted in Salmonella typhimurium and in rat and mouse peripheral blood erythrocytes.

All core study male rats survived to the end of the study. Three 600 mg/kg core study female rats died within 4 days of the start of the study. The mean body weights of 600 mg/kg males were significantly less than those of the vehicle controls. The livers of all 300 and 600 mg/kg rats surviving to the end of the study were enlarged at necropsy.

Small but significant increases in segmented neutrophil counts occurred in 300 and 600 mg/kg male rats at study termination and could be related to the liver necrosis or lesions in the glandular stomach observed microscopically at 600 mg/kg. Alanine aminotransferase and sorbitol dehydrogenase activities were significantly elevated in several dosed groups of males and females, but most consistently at 600 mg/kg, consistent with the observed liver necrosis. At week 14, cholesterol was significantly increased in the 100 mg/kg or greater males and in all dosed groups of females. Triglycerides were significantly increased in 300 and 600 mg/kg males and 600 mg/kg females at week 14. The reason for the alterations is not known, but they may be related to changes in lipid metabolism.

The absolute and relative liver weights of 100 mg/kg or greater male and female rats and the relative liver weight of 30 mg/kg males were significantly increased compared to those of the vehicle controls. The absolute and relative kidney weights of 100 mg/kg or greater males were significantly increased compared to the vehicle controls. The relative kidney weights of 300 and 600 mg/kg females were significantly greater than that of the vehicle control group.

Treatment-related lesions in the liver of rats included centrilobular hepatocyte hypertrophy, fatty change, and hepatocyte necrosis. Treatment-related lesions in the glandular stomach included epithelium atrophy and hyperplasia in male and female rats and necrosis in female rats. Treatment-related lesions in the submandibular salivary gland included secretory depletion in males and females. Treatment-related lesions in the kidney of male rats included renal tubule hyaline droplet accumulation and a slight increase in the severity of nephropathy.

Male rats in the 600 mg/kg group had significantly lower absolute left cauda and left epididymis weights and mean total number of sperm per cauda epididymis compared to those of the vehicle controls. Treatment-related lesions in the male rat reproductive system include germinal epithelium degeneration and elongated spermatid retention in seminiferous tubules of the testis and exfoliated germ cells in the duct lumina of the epididymis. Myristicin exposure via gavage exhibited the potential to be a reproductive toxicant in male F344/NTac rats.

All mice survived to the end of the study. The mean body weights of 300 and 600 mg/kg males and females were significantly less than those of the vehicle control groups. As in rats, the livers of all 300 and 600 mg/kg male and female mice were enlarged at necropsy. A few treated mice had white or tan foci in the forestomach.

Leukocyte counts were significantly increased in 300 and 600 mg/kg male and 600 mg/kg female mice. Segmented neutrophil counts were significantly increased in 300 and 600 mg/kg males and females, the lymphocyte count was significantly increased in 600 mg/kg males, and the monocyte count was significantly increased in 600 mg/kg females. The increase in the leukon was consistent with the chronic inflammation observed in the stomach.

The absolute and relative liver weights of male mice administered 100 mg/kg or greater and all dosed groups of females were significantly greater than those of the vehicle control groups.

Treatment related lesions in the liver of mice included fatty change, centrilobular hepatocyte hypertrophy, hepatocyte necrosis, and oval cell hyperplasia. Treatment-related lesions in the nose of mice included epithelial atrophy, nerve atrophy, glands hyperplasia, and hyaline droplet accumulation of the olfactory epithelium and hyaline droplet accumulation and cytoplasmic vacuolization of the respiratory epithelium. The incidences of atrophy and hyperplasia in the epithelium of the glandular stomach were significantly increased in 600 mg/kg males and females compared to the vehicle controls. In the forestomach, the incidences of chronic and epithelial suppurative inflammation were significantly increased in 600 mg/kg males compared to vehicle controls.

Myristicin was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535, when tested with or without exogenous metabolic activation. In the 3-month in vivo studies, male and female rats had significant increases in micronucleated immature erythrocytes (polychromatic erythrocytes; PCEs) in the peripheral blood as well as significant increases in the percentage of circulating PCEs, suggesting that myristicin may have stimulated erythropoiesis in rats. No increases in micronucleated red blood cells were seen in peripheral blood of male or female mice from the 3-month study, but significant decreases in the percentage of PCEs in peripheral blood were seen in both sexes, suggesting toxicity to the bone marrow.

Under the conditions of the 3-month oral gavage studies, there were treatment-related lesions in male and female rats and mice. The major targets from myristicin administration in rats and mice included the liver and glandular stomach. In rats, additional targets included salivary glands in males and females, and the kidney, testis, and epididymis in males. Additional targets in the mice included the nose in males and females and the forestomach in males. The most sensitive measure of myristicin toxicity in male rats was a higher relative liver weight (lowest-observable-effect level (LOEL) = 30 mg/kg), and in female rats, the most sensitive measures were clinical chemistry findings (LOEL = 10 mg/kg) including increased cholesterol and alanine aminotransferase. In male mice, the most sensitive measures of myristicin toxicity included higher absolute and relative liver weights and a significantly increased incidence of fatty liver (LOEL = 100 m/kg). The most sensitive measure of myristicin toxicity in female mice was an increase in absolute and relative liver weight (LOEL = 10 mg/kg). No-observed-effect levels were 10 mg/kg for male rats and 30 mg/kg for male mice, but none was reached for female rats or mice.

NTP technical report on the toxicity studies of Myristicin administered by gavage to F344/NTac rats and B6C3F1/N mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 95.

Studies

Summary of Findings Considered to be Toxicologically Relevant in Rats and Mice Administered Myristicin by Gavage for 3 Months
  Male
F344/NTac Rats
Female
F344/NTac Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Doses in corn oil

0, 10, 30, 100, 300, or 600 mg/kg

0, 10, 30, 100, 300, or 600 mg/kg

0, 10, 30, 100, 300, or 600 mg/kg

0, 10, 30, 100, 300, or 600 mg/kg

Survival rates 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 10/10, 10/10, 10/10, 10/10, 10/10, 7/10 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 10/10, 10/10, 10/10, 10/10, 10/10, 10/10
Body weights

600 mg/kg group 20% less than the vehicle control group

Dosed groups similar to the vehicle control group 300 mg/kg group 12% less than the vehicle control group; 600 mg/kg group 24% less than the vehicle control group

300 mg/kg group 11% less than the vehicle control group; 600 mg/kg group 16% less than vehicle control group

Clinical findings None None None None
Organ weights ↑ Liver (absolute and relative [a])
↑ Kidney (absolute and relative)
↑ Liver (absolute and relative)
↑ Kidney (relative)
↑ Liver (absolute and relative) ↑ Liver (absolute and relative)
Clinical pathology ↑ Neutrophil count
↑ Alanine aminotransferase activity
↑ Sorbitol dehydrogenase activity
↑ Cholesterol
↑ Triglycerides
↑ Alanine aminotransferase activity
↑ Sorbitol dehydrogenase activity
↑ Cholesterol
↑ Triglycerides
↑ Leukocyte counts
↑ Neutrophil counts
↑ Lymphocyte counts
↑ Leukocyte counts
↑ Neutrophil counts
↑ Monocyte counts
Reproductive toxicity ↓ Cauda epididymis wt.
↓ Epididymis wt.
↓ Sperm per cauda
Not determined None Not determined
Nonneoplastic effects

Liver: fatty change (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); centrilobular, hepatocyte, hypertrophy (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); hepatocyte, necrosis (0/10, 0/10, 0/10, 0/10, 0/10, 8/10)

Glandular stomach: epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 0/10, 10/10); epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 10/10)

Salivary glands: submandibular gland, depletion secretory (0/10, 0/0, 0/0, 0/0, 0/10, 7/10)

Kidney
: renal tubule, accumulation, hyaline droplet (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); severity of nephropathy (1.0, 1.0, 1.0, 1.0, 1.0,1.8)

Testes: germinal epithelium, degeneration (5/10, 5/10, 3/10, 6/10, 8/10, 10/10);  elongated spermatid, retention (5/10, 3/10, 0/10, 1/10, 6/10, 10/10)

Epididymis: exfoliated germ cell (1/10, 3/10,1/10, 2/10, 4/10, 10/10)

Liver: fatty change (0/10, 0/10, 0/10, 0/10, 1/10, 10/10); centrilobular, hepatocyte, hypertrophy (0/10, 0/10, 0/10, 0/10, 10/10, 7/10); hepatocyte, necrosis (0/10, 0/10, 0/10, 0/10, 0/10, 6/10)

Glandular stomach: epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 5/10, 7/10); epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 7/10); epithelium, necrosis (0/10, 0/10, 0/10, 0/10, 0/10, 2/10)

Salivary glands: submandibular gland, depletion secretory (0/10, 0/0, 0/10, 0/10, 10/10, 7/10)

Liver: fatty change (0/10, 0/10, 0/10, 8/10, 5/10, 10/10); centrilobular, hepatocyte, hypertrophy (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); hepatocyte, necrosis (0/10, 0/10, 0/10, 0/10, 1/10, 10/10); oval cell, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 10/10)

Glandular stomach: epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 0/10, 10/10); epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 10/10)

Nose: olfactory epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); nerve, atrophy (0/10, 0/10, 0/10, 0/10, 8/10, 10/10); glands, olfactory epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 7/10); olfactory epithelium, accumulation, hyaline droplet (0/10, 0/10, 0/10, 0/10, 2/10, 9/10); respiratory epithelium, accumulation, hyaline droplet (4/10, 5/10, 1/10, 5/10, 10/10, 10/10); respiratory epithelium, vacuolization, cytoplasmic (1/10, 1/10, 0/10, 0/10, 0/10, 6/10)

Forestomach: inflammation, chronic (0/10, 0/10, 0/10, 0/10, 2/10, 4/10): epithelium, inflammation, suppurative (0/10, 0/10, 0/10, 0/10, 0/10, 4/10)

Liver: fatty change (0/10, 0/10, 0/10, 0/10, 0/10, 10/10); centrilobular, hepatocyte, hypertrophy (0/10, 0/10, 0/10, 10/10, 10/10, 10/10); hepatocyte, necrosis (0/10, 0/10, 0/10, 1/10, 10/10, 10/10); oval cell, hyperplasia (0/10, 0/10, 0/10, 0/10, 10/10, 10/10)

Glandular stomach: epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 0/10, 10/10); epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 10/10)

Nose: olfactory epithelium, atrophy (0/10, 0/10, 0/10, 0/10, 10/10, 10/10); nerve, atrophy (0/10, 0/10, 0/10, 0/10, 9/10, 10/10); glands, olfactory epithelium, hyperplasia (0/10, 0/10, 0/10, 0/10, 0/10, 10/10); olfactory epithelium, accumulation, hyaline droplet (0/10, 1/10, 0/10, 3/10, 8/10, 10/10); respiratory epithelium, accumulation, hyaline droplet (5/10, 3/10, 1/10, 7/10, 10/10, 10/10); respiratory epithelium, vacuolization, cytoplasmic (0/10, 0/10, 0/10, 0/10, 2/10, 4/10)

Genetic Toxicology
Assay Results
Bacterial gene mutations:
 
Negative in TA97, TA98, TA100, and TA1535 with or without S9
Micronucleated erythrocytes
Rat peripheral blood in vivo:
Mouse peripheral blood in vivo:

Positive in males and females
Negative in males and females


a = Relative to body weight