Estragole

Biological Agents -> Plant Oils and Extracts

Volatile Organic Compound (VOC)

0.9645 at 70 °F (NTP, 1992) - Less dense than water; will float

0.965 g/cu cm at 25 °C

0.960-0.968

Liquid

Colorless to light yellow liquid

Insoluble (<1 mg/ml) (NTP, 1992)

In water, 178 mg/L at 25 °C

Very soluble in ethanol, chloroform

0.178 mg/mL at 25 °C

Insoluble in water; soluble in alcohols

Soluble (in ethanol)

178 °F (NTP, 1992)

81 °C (178 °F) - closed cup

This chemical does not meet GHS hazard criteria for < 0.1% (1 of 1959) of reports.

Warning

H302 (99.8%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P261, P264, P270, P272, P273, P280, P301+P317, P302+P352, P318, P321, P330, P332+P317, P333+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 1959 reports by companies from 22 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

Chemical: Benzene, 1-methoxy-4-(2-propenyl)-

Hazard Traits - Carcinogenicity

Regulation (EC) No 1831/2003 (amended)

Benzene, 1-methoxy-4-(2-propen-1-yl)- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Benzene, 1-methoxy-4-(2-propen-1-yl)- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 09-03-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/26786

Benzene, 1-methoxy-4-(2-propenyl)-: Does not have an individual approval but may be used under an appropriate group standard

Emergency treatment: Essential oils; Essential oils can cause CNS depression and aspiration pneumonia after ingestion; Commercial products of essential oils usually contain concentrations of 1% to 20%, and a potentially toxic exposure is 5-15 mL; No sensitization when tested at 3% in petrolatum on 25 volunteers; Minor liver damage found in rats fed 605 mg/kg/day for four days; [HSDB] Moderate irritant on rabbit skin; Causes somnolence and coma at lethal doses in rats; [RTECS];

Synthetic flavoring substances and adjuvants may be safely used in food in accordance with the following conditions. (a) They are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice. (b) They consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. Estragole is included on this list.

Essential oils, oleoresins (solvent-free), and natural extractives (including distillates) that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Estragole is included on this list.

Essential oils, oleoresins (solvent-free), and natural extractives (including distillates) that are generally recognized as safe for their intended use, within the meaning of section 409 of the act. Estragole is included on this list.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Unsuitable extinguishing media: Do NOT use water jet.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Use water spray to cool unopened containers.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Contain spillage, and then collect with non-combustible absorbent material, (e.g. sand, earth, diatomaceous earth, vermiculite) and place in container for disposal according to local / national regulations. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, use absorbent paper to pick up all liquid spill material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with alcohol followed by washing with a strong soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. This combustible material may be burned in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapor or mist. Keep away from sources of ignition - No smoking. Take measures to prevent the build up of electrostatic charge.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

BACKGROUND: Anethole and estragole are monoterpene position isomers and constituents of essential oils from aromatic plants and were used in this study with the aim of analyzing their anti-inflammatory activity. METHODS: The anti-edematogenic effects of anethole and estragole were evaluated through plethysmometry in Swiss mice. RESULTS: Anethole inhibited carrageenan-induced edema at doses of 3, 10 and 30 mg/kg from 60 to 240 min after induction. However, the inhibitory effects of estragole were observed only from 60 to 120 min at the two highest doses. Anethole and estragole similarly inhibited edema elicited by substance P, bradykinin, histamine and TNF-alpha but were different in the inhibition of serotonin-elicited edema. In addition, only estragole inhibited sodium nitroprusside-induced edema. CONCLUSIONS: Anethole and estragole showed different profiles in the anti-inflammatory response to substance P, bradykinin, histamine, serotonin and TNF-alpha NO is involved only in the inhibition mechanism of estragole.

SCOPE: The present work investigates whether the previous observation that the basil flavonoid nevadensin is able to inhibit sulfotransferase (SULT)-mediated estragole DNA adduct formation in primary rat hepatocytes could be validated in vivo. METHODS AND RESULTS: Estragole and nevadensin were co-administered orally to Sprague-Dawley rats, at a ratio reflecting their presence in basil. Moreover, previously developed physiologically based biokinetic (PBBK) models to study this inhibition in rat and in human liver were refined by including a submodel describing nevadensin kinetics. Nevadensin resulted in a significant 36% reduction in the levels of estragole DNA adducts formed in the liver of rats. The refined PBBK model predicts the formation of estragole DNA adducts in the liver of rat with less than twofold difference compared to in vivo data and suggests more potent inhibition in the liver of human compared to rat due to less efficient metabolism of nevadensin in human liver and intestine. CONCLUSION: Given the role of the SULT-mediated DNA adduct formation in the hepatocarcinogenicity of estragole, the results of the present study suggest that the likelihood of bioactivation and subsequent adverse effects in rodent bioassays may be lower when estragole is dosed with nevadensin compared to dosing of pure estragole.

Estragole is a natural constituent of several herbs and spices including sweet basil. In rodent bioassays, estragole induces hepatomas, an effect ascribed to estragole bioactivation to 1'-sulfooxyestragole resulting in DNA adduct formation. The present paper identifies nevadensin as a basil constituent able to inhibit DNA adduct formation in rat hepatocytes exposed to the proximate carcinogen 1'-hydroxyestragole and nevadensin. This inhibition occurs at the level of sulfotransferase (SULT)-mediated bioactivation of 1'-hydroxyestragole. The Ki for SULT inhibition by nevadensin was 4 nM in male rat and human liver fractions. Furthermore, nevadensin up to 20 uM did not inhibit 1'-hydroxyestragole detoxification by glucuronidation and oxidation. The inhibition of SULT by nevadensin was incorporated into the recently developed physiologically based biokinetic (PBBK) rat and human models for estragole bioactivation and detoxification. The results predict that co-administration of estragole at a level inducing hepatic tumors in vivo (50 mg/kg bw) with nevadensin at a molar ratio of 0.06, representing the ratio of their occurrence in basil, results in almost 100% inhibition of the ultimate carcinogen 1'-sulfooxyestragole when assuming 100% uptake of nevadensin. Assuming 1% uptake, inhibition would still amount to more than 83%. Altogether these data point at a nevadensin-mediated inhibition of the formation of the ultimate carcinogenic metabolite of estragole, without reducing the capacity to detoxify 1'-hydroxyestragole via glucuronidation or oxidation. These data also point at a potential reduction of the cancer risk when estragole exposure occurs within a food matrix containing SULT inhibitors compared to what is observed upon exposure to pure estragole.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a structure estimation method(2), indicates that 1-methoxy-4-(2-propenyl)benzene is expected to have low mobility in soil(SRC). Volatilization of 1-methoxy-4-(2-propenyl)benzene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.6X10-4 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). 1-Methoxy-4-(2-propenyl)benzene has an estimated vapor pressure of 0.17 mm Hg(SRC), determined from a fragment constant method(2) and exists as a liquid under environmental conditions; therefore, 1-methoxy-4-(2-propenyl)benzene may volatilize from dry soil(SRC). Utilizing the OECD 301F ready Biodegradability test, 48% O2 consumption was reached in 4 weeks(3) indicating that biodegradation may be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a structure estimation method(2), indicates that 1-methoxy-4-(2-propenyl)benzene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 4.6X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 6 hrs and 6 days, respectively(SRC). According to a classification scheme(4), an estimated BCF of 90(SRC), from an estimated log Kow of 3.47(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Utilizing the OECD 301F ready Biodegradability test, 48% O2 consumption was reached in 4 weeks(5) indicating that biodegradation may be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1-methoxy-4-(2-propenyl)benzene, which has an estimated vapor pressure of 0.17 mm Hg at 25 °C((SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-methoxy-4-(2-propenyl)benzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7 hrs(SRC), calculated from its rate constant of 5.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase 1-methoxy-4-(2-propenyl)benzene is degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 23 hrs(SRC), calculated from its rate constant of 1.2X10-17 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). 1-Methoxy-4-(2-propenyl)benzene does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: 1-Methoxy-4-(2-propenyl)benzene (Estragole) is a liquid. It is used in perfumes and as flavor in foods and liqueurs. It has been tested as an experimental therapy. HUMAN STUDIES: When tested as 3% in petrolatum, it produced no irritation after a 48-hr closed-patch test on human subjects. A maximization test was carried out on 25 volunteers. The material was tested at a concentration of 3% in petrolatum and produced no sensitization reactions. It was not mutagenic when tested on human cells in vitro. ANIMAL STUDIES: Rats given 4 daily oral doses of 605 mg/kg estragole showed minor liver damage, consisting of discoloration, mottling and blunting of lobe edge. Applied full strength to intact or abraded rabbit skin for 24 hr under occlusion estragole was moderately irritating. Estragole is a rodent liver carcinogen which requires bioactivation. It induced hepatocellular carcinomas by 15 months in 23 and 39% of the mice that received total doses of 4.4 and 5.2 umoles, respectively. In rats estragole induced dose-dependent increases in DNA damage following EndoIII or hOGG1 digestion and without enzyme treatment in liver, the cancer target organ. The formation of estragole-specific DNA adducts following conversion from estragole to the nucleophilic metabolite by sulfotransferase 1A1 (SULT1A1) has been reported.

1-Methoxy-4-(2-propenyl)benzene was detected in volatiles typical for 91 US woodland landscapes, represented by 49 tree genre(1). The compound was reported as a volatile component of chickpea (Cicer arietinum L.) seed(2). 1-Methoxy-4-(2-propenyl)benzene is a volatile flavor component of Kogyoku apples, harvested in Iwate Prefecture, Japan(3). The compound was tentatively identified in emissions of organics from vegetation in California's Central Valley, sampled during summer 1988 and 1989(4).

1-Methoxy-4-(2-propenyl)benzene occurrence in plants(1).

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for 1-methoxy-4-(2-propenyl)benzene is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

1-Methoxy-4-(2-propenyl)benzene was tested for but not detected in wells following groundwater infiltration by wastewater at a rapid infiltration pond system located at Ft. Devens, Massachusetts, sampled in 1978(1). The compound was identified at a concentration range of not detected to 0.045 mg/L and not detected to 0.030 mg/L in unbleached wastewater from two kraft paper mills in Georgia, sampled in 1972(2).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 1-methoxy-4-(2-propenyl)benzene can be estimated to be 520(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1-methoxy-4-(2-propenyl)benzene is expected to have low mobility in soil(SRC).

1-Methoxy-4-(2-propenyl)benzene is found in many plants, in particular spices(1). The compound was isolated initially from the rind of Persea gratissima Garth and from the Oil of Estragon. It has been found in oils of Russian anise, basil, fennel, turpentine and others(2). 1-Methoxy-4-(2-propenyl)benzene is the main constituent of tarragon oil (Artemisia dracunculus L, (Compositae)), present to an extent of 60-75%. The compound has also been reported in pine oil and in American turpentine oil(3).

/HUMAN EXPOSURE STUDIES/ Tested as 3% in petrolatum, it produced no irritation after a 48-hr closed-patch test on human subjects. ... A maximization test was carried out on 25 volunteers. The material was tested at a concentration of 3% in petrolatum and produced no sensitization reactions.

/GENOTOXICITY/ The present study was undertaken to evaluate, in the HepG2 human hepatoma cell line, the in vitro cytotoxic, genotoxic, and apoptotic activities of estragole (1), contained in the essential oil of Foeniculum vulgare (fennel) and suspected to induce hepatic tumors in susceptible strains of mice. Toward this end, an MTT cytotoxicity assay, a trypan blue dye exclusion test, a double-staining (acridine orange and DAPI) fluorescence viability assay, a single-cell microgel-electrophoresis (comet) assay, a mitochondrial membrane potential (delta-psi-m) assay, and a DNA fragmentation analysis were conducted. In terms of potential genotoxic effects, the comet assay indicated that estragole (1) was not able to induce DNA damage nor apoptosis under the experimental conditions used.

/GENOTOXICITY/ Estragole, a common component of herbs and spices, is a well-known genotoxic hepatocarcinogen in rodents, whereas its potential toxic effect in humans is still debated. In the European contest, one of the major sources of human exposure to this phytochemical is Foeniculum vulgare Mill. (fennel). Therefore, the aim of this study was to evaluate the in vitro toxicity of estragole in the context of two complex phytochemical mixtures derived from fennel: fennel seed powder (FSPw) and fennel seed essential oil (FSEO). The estragole-containing preparations were analyzed for their ability to cause cytotoxicity, genotoxicity, apoptosis and cell cycle perturbation in the human hepatoma (HepG2) cell line. None of the tested concentrations of FSPw induced DNA damage, nor apoptosis or cell cycle perturbation. Although FSEO did not induce any genetic damage as well, it exerted marked dose-dependent apoptotic effects on HepG2 cells with a concurrent cell cycle arrest in G2/M at the highest tested dose. Although prospective analyses are required to clarify the observed toxic effects of FSEO, our results support the hypothesis that the genotoxicity of estragole may be significantly reduced or null in the context of botanical mixtures.

/OTHER TOXICITY INFORMATION/ Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions.

1-Methoxy-4-(2-propenyl)benzene's production and use as a flavoring in foods and liqueurs(1) will result in its release to the environment through various waste streams(SRC). Its use in perfumes(1) will result in its direct release to the environment(SRC).

Synthetic flavoring substances and adjuvants may be safely used in food in accordance with the following conditions. (a) They are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice. (b) They consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. Estragole is included on this list.

Essential oils, oleoresins (solvent-free), and natural extractives (including distillates) that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Estragole is included on this list.

Essential oils, oleoresins (solvent-free), and natural extractives (including distillates) that are generally recognized as safe for their intended use, within the meaning of section 409 of the act. Estragole is included on this list.

Protein phosphatase 2A (PP2A) is a serine-threonine phosphatase that regulates cell signaling pathways. Its inactivation is correlated with tumor malignancy, possibly due to the effects on cell differentiation and malignant cell transformation. Therefore, it has been noted that PP2A could be a promising target for cancer therapy. In our previous study of the hepatocarcinogen estragole (ES), cell proliferation may be required to convert ES-specific DNA adducts to mutations. To explore the trigger for cell proliferation, gpt delta rats were administered ES by gavage at doses of 3, 30 and 300 mg/kg/day for 4 weeks. ES-induced cell proliferation and gene mutations were observed at only the high dose whereas ES-specific DNA adducts were detected in a dose-dependent manner. Western blot analyses revealed activation of the Akt and ERK pathways without activation of upstream regulators, such as c-Raf, PKC and, PI3K. Phosphorylation of the PP2A C subunit at Tyr307 was found along with phosphorylation of Src. The overall data might imply that PP2A inactivation is responsible for cell cycle progression through activation of the Akt and ERK pathways at high doses of ES. Based on gamma-H2AX immunohistochemistry and Western blot analysis for Rad51 protein, the resultant mutation spectra showed large deletion mutations that might result from double strand breaks of DNA. Thus, it is likely that inactivation of PP2A resulted in acceleration and exacerbation of gene mutations. We conclude that PP2A might contribute to an early stage of chemical carcinogenesis, suggesting that PP2A could be a molecular target of primary cancer prevention.

The present study investigates interindividual variation in liver levels of the proximate carcinogenic metabolite of estragole, 1'-hydroxyestragole, due to variation in two key metabolic reactions involved in the formation and detoxification of this metabolite, namely 1'-hydroxylation of estragole and oxidation of 1'-hydroxyestragole. Formation of 1'-hydroxyestragole is predominantly catalyzed by P450 1A2, 2A6, and 2E1, and results of the present study support that oxidation of 1'-hydroxyestragole is catalyzed by 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2). In a first approach, the study defines physiologically based biokinetic (PBBK) models for 14 individual human subjects, revealing a 1.8-fold interindividual variation in the area under the liver concentration-time curve (AUC) for 1'-hydroxyestragole within this group of human subjects. Variation in oxidation of 1'-hydroxyestragole by 17beta-HSD2 was shown to result in larger effects than those caused by variation in P450 enzyme activity. In a second approach, a Monte Carlo simulation was performed to evaluate the extent of variation in liver levels of 1'-hydroxyestragole that could occur in the population as a whole. This analysis could be used to derive a chemical-specific adjustment factor (CSAF), which is defined as the 99th percentile divided by the 50th percentile of the predicted distribution of the AUC of 1'-hydroxyestragole in the liver. The CSAF was estimated to range between 1.6 and 4.0, depending on the level of variation that was taken into account for oxidation of 1'-hydroxyestragole. Comparison of the CSAF to the default uncertainty factor of 3.16 for human variability in biokinetics reveals that the default uncertainty factor adequately protects 99% of the population.

The extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite 1'-sulfooxyestragole depends on the relative levels of bioactivation and detoxification pathways. The present study investigated the kinetics of the metabolic reactions of both estragole and its proximate carcinogenic metabolite 1'-hydroxyestragole in humans in incubations with relevant tissue fractions. Based on the kinetic data obtained a physiologically based biokinetic (PBBK) model for estragole in human was defined to predict the relative extent of bioactivation and detoxification at different dose levels of estragole. The outcomes of the model were subsequently compared with those previously predicted by a PBBK model for estragole in male rat to evaluate the occurrence of species differences in metabolic activation. The results obtained reveal that formation of 1'-oxoestragole, which represents a minor metabolic route for 1'-hydroxyestragole in rat, is the main detoxification pathway of 1'-hydroxyestragole in humans. Due to a high level of this 1'-hydroxyestragole oxidation pathway in human liver, the predicted species differences in formation of 1'-sulfooxyestragole remain relatively low, with the predicted formation of 1'-sulfooxyestragole being two-fold higher in human compared with male rat, even though the formation of its precursor 1'-hydroxyestragole was predicted to be fourfold higher in human. Overall, it is concluded that in spite of significant differences in the relative extent of different metabolic pathways between human and male rat there is a minor influence of species differences on the ultimate overall bioactivation of estragole to 1'-sulfooxyestragole.

1. The metabolic fates of the naturally occurring food flavors trans-anethole and estragole, and their synthetic congener p-propylanisole, have been investigated in human volunteers using the [methoxy-(14)C]-labelled compounds. The doses used were close to those encountered in the diet, 1 mg, 100 micrograms and 100 micrograms respectively. 2. In each case, the major routes of elimination of (14)C were in the urine and in the expired air as (14)CO2. 3. Urinary metabolites were separated by solvent extraction, t.l.c. and h.p.l.c., and characterized by comparison of chromatographic mobilities with standards and by radioisotope dilution. Nine (14)C urinary metabolites were found after trans-anethole administration, four after p-propylanisole and five after estragole. All were products of side chain oxidations. 4. The principal metabolites of p-propylanisole were 4-methoxyhippuric acid (12%) and 1-(4'-methoxyphenyl)propan-1-ol (2%) and -2-ol (8%). 5. The major metabolite of trans-anethole was 4-methoxyhippuric acid (56% of dose), accompanied by much smaller amounts of the two isomers of 1-(4'-methoxyphenyl)propane-1,2-diol (together 3%). 6. After estragole administration, the two volunteers eliminated 0.2 and 0.4% of the dose respectively as 1'-hydroxyestragole. 7. The human metabolic data is discussed with reference to the comparative metabolic disposition of these compounds in the mouse and rat, species commonly used in their safety assessment.

The metabolism of the potent carcinogen estragole was investigated in humans after consumption of fennel tea by analyses of its metabolites in blood plasma and urine. Stable isotope dilution assays based on LC-MS/MS detection revealed that 1'-hydroxylation of estragole happened very fast as the concentration of conjugated 1'-hydroxyestragole in urine peaked after 1.5 hr, whereas it was no longer detectable after 10 hr. Besides the formation of less than 0.41% conjugated 1'-hydroxyestragole of the estragole dose administered, the further metabolite p-allylphenol was generated from estragole in a higher percentage (17%). Both metabolites were also detected in blood plasma in less than 0.75-2.5 hr after consumption of fennel tea. In contrast to this, no estragole was present in these samples above its detection limit. From the results, it can be concluded that an excess of the major fennel odorant trans-anethole principally does not interfere with estragole metabolism, whereas influences on the quantitative composition of metabolites cannot be excluded. The presence of a sulfuric acid conjugate of estragole could not be confirmed, possibly due to its high reactivity and lability.

For more Metabolism/Metabolites (Complete) data for 1-Methoxy-4-(2-propenyl)benzene (11 total), please visit the HSDB record page.

Naturally occurs in tarragon oil, basil oils, anise bark oil, and others; [Hawley] Used as a flavoring ingredient and a fragrance in perfumes and soaps; [HSDB]

For 1-methoxy-4-(2-propenyl)benzene (USEPA/OPP Pesticide Code: 062150) there are 0 labels match. /SRP: Not registered for current use in the USA, but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

In perfumes and as flavor in foods and liqueurs.

Reported uses (ppm):

MEDICATION

(1979) No Data

(1981) No Data

(1979) 3.60X10+5 GRAMS (PRINCPL CUSTMS DISTS)

(1981) 7.88X10+6 GRAMS (PRINCPL CUSTMS DISTS)

2023: 1,731,806 lb

(1979) PROBABLY GREATER THAN 9.08X10+6 GRAMS

(1981) PROBABLY GREATER THAN 9.08X10+6 GRAMS

Non-confidential 2016 Chemical Data Reporting (CDR) information on the production and use of chemicals manufactured or imported into the United States. Chemical: Benzene, 1-methoxy-4-(2-propen-1-yl)-:

Estragole

Estragole; p-Allylanisole; 4-Allylanisole; 1-Allyl-4-methoxybenzene; Benzene, 1-methoxy-4-(2-propenyl)-; Chavicyl methyl ether; Isoanethole; p-Methoxyallylbenzene; 1-Methoxy-4-(2-propen-1-yl)benzene; Methyl chavicol

IFRA_STD_099.pdf

51

IFRA 51st Amendment - Guidance for the use of IFRA Standards

Restriction: This material should be used only in the limited quantity as stated in the Standard

Obtained by fractional distillation of the oil of turpentine or by treating a solution of the same oil in ether with an aqueous solution of mercuric acetate and subsequently heating the aqueous phase with zinc and sodium hydroxide; forms allyl bromide and magnesium p-methoxy phenate in ether.

Fragrance Ingredients

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

All Other Basic Organic Chemical Manufacturing

Benzene, 1-methoxy-4-(2-propen-1-yl)-: ACTIVE

Concentrations in final products (%): soap usual 0.02, max 0.25; detergent usual 0.002, max 0.03; creams, lotions usual 0.01, max 0.03; perfume usual 0.08, max 0.30.

Main constituent of tarragon oil (estragon oil), the oil from Artemisia dracunculus L., Compositae (esdragon) where it occurs to an extent of 60-75%. ... Occurs also in pine oil and in American turpentine oil.

0.00031 [Products applied to the lips]

0.0025 [Products applied to the axillae]

0.00063 [Products applied to the face/body using fingertips]

0.014 [Products related to fine fragrances]

0.0022 [Products applied to the body using the hands (palms), primarily leave-on (Body lotion)]

0.00063 [Products applied to the face using the hands (palms), primarily leave-on (Face moisturizer)]