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Abstract for TOX-82

3-Month Toxicity Studies of Estragole Administered by Gavage to F344/N Rats and B6C3F1 Mice

CASRN: 140-67-0
Chemical Formula: C10H12O
Molecular Weight: 148.204
Synonyms/Common Names: 1-methoxy-4-(2-propenyl)-benzene (9CI); 1-allyl-4-methoxybenzene; 3-(p-methoxyphenyl)propene; 4-allylanisole; 4-allyl-1-methoxybenzene; chavicol methyl ether; esdragol; 1-methoxy-4-(2-propenyl)-benzene; p-methoxyallylbenzene; 4-methoxy-2'-propenylbenzene; p-allyl-methyl chavicol; tarragon
Report Date: January 2011

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Abstract

Estragole is a natural organic compound that is used as an additive, flavoring agent, or fragrance in a variety of food, cleaning, and cosmetic products; as an herbal medicine; as an antimicrobial agent against acid-tolerant food microflora; and to produce synthetic anise oil. Estragole was nominated for toxicity testing by the National Institute of Environmental Health Sciences to characterize its toxicity when administered by gavage to F344/N rats and B6C3F1 mice and to determine how similar its effects  might be to those of the structurally related compound, methyleugenol. Male and female F344/N rats and B6C3F1 mice were given estragole (greater than 99% pure) in corn oil by gavage for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes.

Core and special study (rats only) groups of 10 male and 10 female rats and mice were administered 37.5, 75, 150, 300, or 600 mg estragole/kg body weight in corn oil by gavage, 5 days per week. The core study groups were given estragole for 3 months and the special study groups for 30 days.

All core study rats survived the 3-month exposure period. Mean body weights of the 300 and 600 mg/kg groups were 73% to 92%, respectively, of those of the vehicle control groups. A staining pattern on the ventral surface anterior to the genitalia beginning at week 9 in the 300 and 600 mg/kg groups was attributed to residue of estragole or metabolites in the urine. Alterations in the erythron related to estragole administration occurred in male and female rats; male rats demonstrated a stronger response. The changes in the erythron were characterized as a microcytic, normochromic, nonresponsive anemia. There were decreases in serum iron concentration in the 300 mg/kg females and 600 mg/kg males and females. The average percent saturation of total iron binding capacity was decreased in the 600 mg/kg males and females. Dose-related increases in platelet counts occurred in most of the dosed groups of rats; the effect appeared to be stronger in males. The increase could be consistent with a reactive thrombocytosis. Increases in the serum alanine aminotransferase and sorbitol dehydrogenase activities suggested a hepatocellular effect (increased leakage) and were consistent with the morphological liver changes observed. There were dose-related increases in serum bile salt concentration in most treated male rats at all time points; females were less affected.

Absolute and relative liver weights were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Relative kidney weights were significantly increased in all dosed groups of male rats and in female rats given 75 mg/kg or greater. Absolute and relative testis weights of 300 and 600 mg/kg males were significantly decreased.

Two 600 mg/kg male rats had multiple cholangiocarcinomas in the liver and a third had an hepatocellular adenoma. All 600 mg/kg males exhibited cholangiofibrosis. All 75 mg/kg or greater males and all 150 mg/kg or greater females had hepatocellular hypertrophy. Incidences of bile duct hyperplasia, oval cell hyperplasia, and chronic periportal inflammation were significantly increased in all dosed groups. Incidences of basophilic and mixed cell foci were significantly increased in 150 mg/kg or greater males and females. Incidences of eosinophilic focus were significantly increased in 300 and 600 mg/kg males and 600 mg/kg females. Incidences of cellular infiltration of the periportal region by histiocytes increased significantly in all dosed groups of males and in 150 mg/kg or greater females.

Incidences of bone marrow hyperplasia were significantly increased in 75, 300, and 600 mg/kg male rats. Incidences of renal tubule papillary mineralization were significantly increased in 300 mg/kg males and females and 600 mg/kg males. Incidences of cortical renal tubule pigmentation were significantly increased in 150 mg/kg or greater males, and the incidence of renal tubule regeneration was significantly increased in 600 mg/kg females. Incidences of degeneration of the olfactory epithelium in the nose were significantly increased in 300 and 600 mg/kg rats. Incidences of hypertrophied chromophobe cells in the pars distalis of the pituitary gland were significantly increased in 300 and 600 mg/kg males. Cytoplasmic alteration of the submandibular salivary gland occurred in all 75 mg/kg or greater rats. Incidences of atrophy of the gastric glands in the stomach were significantly increased in 150 mg/kg or greater rats. Bilateral degeneration of the germinal epithelium in the testes and bilateral hypospermia of the epididymis occurred in all 300 and 600 mg/kg males.

In the special study, serum gastrin concentration and stomach pH were significantly increased in rats exposed to 600 mg/kg for 30 days. Gastric gland atrophy was significantly increased in the stomach of 300 and 600 mg/kg rats. Hepatic 7-pentoxyresorufin-O-deethylase activity was significantly increased in all exposed groups except 37.5 mg/kg females, and the increases were generally dose related.

In the mouse core study, a 600 mg/kg male died during week 9, and all 600 mg/kg female mice died during week 1; the female deaths were attributed to liver necrosis caused by estragole exposure. Mean body weights of 300 and 600 mg/kg males and 75 mg/kg or greater females were 79% to 89% those of the vehicle control groups.

Liver weights were generally increased in 75 mg/kg or greater males and in 300 mg/kg females. Relative thymus weights were significantly increased in all dosed groups of female mice.

The incidences of hepatocellular hypertrophy and hepatocellular degeneration were significantly increased in 300 and 600 mg/kg male mice and 150 and 300 mg/kg female mice. Incidences of oval cell hyperplasia were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Liver necrosis occurred in all 600 mg/kg female mice, along with a significant increase in the incidence of diffuse fatty change. In addition, 600 mg/kg females exhibited significant increases in the incidences of degeneration of the gastric glands of the glandular stomach, as well as squamous hyperplasia, mineralization, and ulcer in the forestomach. Degeneration of the olfactory epithelium in the nose occurred in all 300 and 600 mg/kg mice.

Estragole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation enzymes. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male and female mice in the 3-month study.

Under the conditions of these 3-month studies, estragole showed carcinogenic activity based on the occurrence of two cholangiocarcinomas and one hepatocellular adenoma in the liver of three of 10 male F344/N rats in the high dose group. Because rats and mice were exposed for only 3 months, these studies do not access the full carcinogenic potential of estragole.

Nonneoplastic effects were observed in the liver, glandular stomach, nose, kidney, and salivary gland of male and female rats and in the testes, epididymides, and pituitary gland of male rats. Nonneoplastic effects were also observed in the liver and nose of male and female mice and in the stomach of female mice.

IUPAC Name: 1-methoxy-4-prop-2-enylbenzene 

IUPAC International Chemical Identifier: -InChI=1/C10H12O/c1-3-4-9-5-7-10(11-2)8-6-9/h3,5-8H,1,4H2,2H3

Canonical SMILES: c1(ccc(OC)cc1)CC=C