Safrole

Biological Agents -> Plant Toxins

Carcinogens

1.1 at 68 °F (NTP, 1992) - Denser than water; will sink

1.100 g/cu cm at 20 °C

1.095-1.099

1.0960 @ 20°C

Colorless or pale yellow oil

Monoclinic crystals

Colorless liquid, prisms, or crystals

less than 1 mg/mL at 64 °F (NTP, 1992)

Insoluble in water

Very soluble in ethanol; miscible with ethyl ether, chloroform

Soluble in alcohol; slightly soluble in propylene glycol; insoluble in glycerol

Practically insoluble to insoluble in water

Soluble (in ethanol)

208 °F (NTP, 1992)

212 °F (100 °C) (Closed cup)

450 to 453 °F at 760 mmHg (NTP, 1992)

235 °C

232–234 °C

232-234 °C

232.5 °C @760 [mm Hg]

Hazardous decomposition products formed under fire conditions. - Carbon oxides.

When heated to decomposition it emits acrid smoke and irritating fumes.

Danger

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Chemical: 1,3-Benzodioxole, 5-(2-propenyl)-

Hazard Traits - Carcinogenicity

List I Chemical: A chemical specified by regulation that, in addition to legitimate uses, is used in manufacturing a controlled substance in violation of the Act and is important to the manufacture of a controlled substance. (21 eCFR 1310.02)

Regulation (EC) No 1831/2003 (amended)

Safrole: Does not have an individual approval but may be used under an appropriate group standard

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

Safrole is the toxic agent in sassafras oil; Safrole is classified as 2B (possible human carcinogen) by IARC; Safrole is metabolized in the body to 1'-hydroxysafrole; Ingestion of 5 ml of sassafras oil can cause severe symptoms (tachycardia, hypotension, and respiratory paralysis) or death; Large doses may damage the liver; Drinking 10 cups of sassafras tea caused sweating in one adult subject; Emergency treatment: Sassafras oil; [HSDB] A skin irritant; Targets the liver; [MSDSonline]

The following chemicals have been specifically designated by the Administrator of the Drug Enforcement Administration as the listed chemicals subject to the provisions of this part and parts 1309 and 1313 of this chapter. Each chemical has been assigned the DEA Chemical Code Number set forth opposite it. Safrole (DEA Code: 8323) is included on this List I.

List I chemical means a chemical specifically designated by the Administrator in section 1310.02(a) of this chapter that, in addition to legitimate uses, is used in manufacturing a controlled substance in violation of the Act and is important to the manufacture of a controlled substance.

Exempt chemical mixtures. (a) The chemical mixtures meeting the criteria in paragraphs (c) or (d) of this section are exempted by the Administrator from application of sections 302, 303, 310, 1007, 1008, and 1018 of the Act (21 U.S.C. 822, 823, 830, 957, 958, and 971) to the extent described in paragraphs (b) and (c) of this section. (b) No exemption granted pursuant to this section 1310.12 or section 1310.13 affects the criminal liability for illegal possession, distribution, exportation, or importation of listed chemicals contained in the exempt chemical mixture or the civil liability for unlawful acts related to exempt chemical mixtures, including distribution in violation of 21 U.S.C. 842(a)(11). (c) Mixtures containing a listed chemical in concentrations equal to or less than those specified in the "Table of Concentration Limits" are designated as exempt chemical mixtures for the purpose set forth in this section. The concentration is determined for liquid-liquid mixtures by using the volume or weight and for mixtures containing solids or gases by using the unit of weight.[Table#4126]

(a) Safrole is the chemical 4-allyl-1,2-methylenedioxy-benzene, C10H10O2. It is a natural constituent of the sassafras plant. Oil of sassafras is about 80 percent safrole. Isosafrole and dihydrosafrole are derivatives of safrole, and have been used as flavoring compounds. (b) Food containing any added safrole, oil of sassafras, isosafrole, or dihydrosafrole, as such, or food containing any safrole, oil of sassafras, isosafrole, or dihydrosafrole, e.g., sassafras bark, which is intended solely or primarily as a vehicle for imparting such substances to another food, e.g., sassafras tea, is deemed to be adulterated in violation of the act based upon an order published in the Federal Register of December 3, 1960 (25 FR 12412).

NTP Report on Carcinogens, Fourteenth Edition. The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Safrole (94-59-7) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of October 12, 2018: https://ntp.niehs.nih.gov/pubhealth/roc/index-1.html]

U203; As stipulated in 40 CFR 261.33, when safrole, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

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.

Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Storage class (TRGS 510): 6.1D: Non-combustible, acute toxic Cat.3 / toxic hazardous materials or hazardous materials causing chronic effects

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe 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: Soak up with inert absorbent material and dispose of as hazardous waste. Keep in suitable, closed containers for disposal.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, 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 60-70% ethanol followed by washing with a 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.

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U203, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for Safrole (7 total), please visit the HSDB record page.

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.

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

Avoid contact with skin and eyes. Avoid inhalation of vapor or mist.

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

For more Preventive Measures (Complete) data for Safrole (13 total), please visit the HSDB record page.

5.9 [mg/m3]

64 [mg/m3]

390 [mg/m3]

MINIMUM PROTECTIVE CLOTHING: If Tyvek-type disposable protective clothing is not worn during handling of this chemical, wear disposable Tyvek-type sleeves taped to your gloves.

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).

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

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).

When admin to rats at concentrations of 5,000 ppm in diet for 15 days, safrole acted as a synergist with EPN /o-ethyl o-para-nitrophenyl phenylphosphonothioate/ or hexobarbital. Methods for testing enzyme effect were detoxication and sleeping time for o-ethyl o-para-nitrophenyl phenylphosphonothioate and sleeping time only for hexobarbital. /from table/

Safrole... shown experimentally to be active synergist for pyrethrum and 1-naphthyl methyl carbamate (Sevin) in common with other methylene-dioxyphenyl compounds.

Arachidonic acid-induced platelet aggregation was inhibited by safrole. The IC50 was 1.7x10-5 g/mL.

The metabolic oxidation of chlorpromazine was investigated after pretreatment of rats with safrole for 6 days. Safrole preferentially inhibited 7-hydroxylation.

For more Interactions (Complete) data for Safrole (6 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 210(SRC), determined from a structure estimation method(2), indicates that safrole is expected to have moderate mobility in soil(SRC). Volatilization of safrole from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.1X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Safrole has a vapor pressure of 0.0706 mm Hg(3) and exists as a liquid under environmental conditions: therefore, safrole may volatilize from dry soil(SRC). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 210(SRC), determined from a structure estimation method(2), indicates that safrole 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 9.1X10-6 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 5 and 52 days, respectively(SRC). According to a classification scheme(4), an estimated BCF of 86(SRC), from an estimated log Kow of 3.45(2)and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), safrole, which has a vapor pressure of 0.0706 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase safrole 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 5 hrs(SRC), calculated from its rate constant of 7.6X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Vapor-phase safrole 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(3). Safrole contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Safrole is a colorless or pale yellow oil. Safrole is a major chemical constituent of aromatic oil present in sassafras root bark. According to FDA, safrole and safrole-containing products cannot be recognized as being safe for human use. Oil of sassafras containing safrole was formerly used as flavoring agent in soft drinks. Safrole is the main precursor for producing the amphetamine-type stimulant drug, N-methyl-3,4-methylenedioxyamphetamine (MDMA), also known as ecstasy. HUMAN STUDIES: A maximization test (Kligman) was carried out on 25 volunteers. The material was tested at a concentration of 8% in petrolatum and produced no sensitization reactions. Safrole-DNA adducts were detected in in tissue specimens from esophageal cancer patients with a history of habitual areca chewing. Similarly, the presence of safrole-DNA adduct was demonstrated in two out of 28 hepatic tissues from hepatocellular carcinoma patients, and only these two patients had a history of betel quid chewing lasting more than 10 years. Safrole was a potent inhibitor of human CYP1A2, CYP2A6, and CYP2E1. With relatively less potency, CYP2D6 and CYP3A4 were also inhibited. ANIMAL STUDIES: Safrole applied at full strength to intact or abraded rabbit skin for 24 hr under occlusion was moderately irritating. Applied undiluted to the backs of hairless mice, it was not irritating. In a feeding study in dogs, groups of 2 males and 2 females fed 5 or 20 mg safrole/kg/day for 6 years showed liver enlargement, fatty change, minimal focal necrosis, mild post-necrotic cirrhosis, bile duct and Kupffer cell proliferation, hepatic cell atrophy and leucocytic infiltration. Similar liver changes were seen with higher doses of 40 and 80 mg/kg/day given over much shorter periods of 91-116 and 26-39 days, respectively. Dietary administration of safrole caused hepatocellular carcinoma in male mice and benign or malignant liver tumors (hepatocellular carcinoma or adenoma or cholangiocarcinoma) in rats of both sexes. Hepatocellular carcinoma was also observed in mice of both sexes administered safrole by stomach tube from 7 to 28 days of age, followed by dietary exposure for up to 82 weeks, and in infant male mice administered safrole by sc injection. The incidence of liver tumors (adenoma and carcinoma) was increased in male mice exposed during infancy via milk and in adult female mice administered safrole in the diet. Safrole did not increase sister chromatid exchange frequency in cultured Chinese hamster cells. Safrole was mutagenic in Salmonella typhimurium strain TA 100 at concentration of 10 and 25 ug/mL. Safrole showed positive results in the absence of metabolic activation when its mutagenicity was determined with DNA repair-deficient Escherichia coli rec- strains. Hepatic safrole-DNA adduct were detected in mice that were treated with safrole. In pregnant mice, safrole was bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus and placenta. Fetal adduct levels were lower than maternal, exhibiting the greatest difference (42-fold) in liver, but little difference in lung, brain, and intestines.

Safrole occurs in the roots of Sassafras officinale and is a constituent of several essential oils such as camphor, nutmeg and cinnamon leaves. It is found in the essential oil from the roots of Nemuaron humboldtii (up to 99% safrole), Brazillian sassafras oil (up to 93%) and American sassafras oil (up to 80%). Safrole is found in banana, cinnamon bark and leaf, nutmeg, mace, tamarind, pepper, cocoa, coriander seed, dill herb, dried bonito, lemon balm, ashanti pepper and green mate(1).

Safrole occurrence in plants(1).

Asarum heterotropoides oil, an ingredient of the Chinese traditional medicine hsi-hsin, contains safrole as a main component.

Safrole was identified in Michelia hedyosperma, a traditional medicine.

For more Plant Concentrations (Complete) data for Safrole (6 total), please visit the HSDB record page.

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 safrole 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/]

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of safrole can be estimated to be 210(SRC). According to a classification scheme(2), this estimated Koc value suggests that safrole is expected to have moderate mobility in soil(SRC).

Safrole (CAS # 94-59-7) was evaluated for mutagenicity. The test substance was positive in two independent mouse lymphoma studies. No further information was submitted.

Safrole (CAS # 94-59-7) was evaluated for chromosomal effects. Results for chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells were positive. No further information was submitted.

Safrole (CAS # 94-59-7) was evaluated for DNA effects. Dose levels representing 1x, 0.5x, and 0.25x the concentration producing a 50% reduction in plating efficiency were tested. The positive control of 1 ug/mL was 7,12-dimethylbenzanthracene. Concentrations from 12.5 to 100 ug/mL did not influence the frequency of structural chromosome aberrations or polyploidy. At 100 ug/mL, the test substance marginally reduced the plating efficiency (PE) of RL4 cells (derived from a 10-day old male Wistar rat) by 50%. In the sister chromatid exchange (SCE) assay, the mitotic index (MI) was significantly reduced from 7.6% in the controls to 1% in the 100 ug/mL cultures. At the highest dose, there was evidence of cytotoxicity, growth inhibition, and cell cycle delay.

Safrole (CAS # 94-59-7) was evaluated for clastogenic activity in the Rat Liver (RL1) Chromosome Assay. The test substance was used at dose levels of 0, 25, 50, and 100 ug/mL. The positive control was 1 ug/mL of 7,12-dimethylbenz(a)anthracene. The test substance did not increase the frequency of chromosomal damage in cultured RL1 cells derived from a 10-day old Carworth Farm E rat.

For more TSCA Test Submissions (Complete) data for Safrole (6 total), please visit the HSDB record page.

Safrole occurrs in plants such as sassafras, basil, dill, witch hazel and in essential oils of mace and cinnamon(1). Safrole is a constituent of several essential oils. Sassafras oil contains up to 93% and lesser quantities occur in essential oils from nutmeg, mace, ginger, cinnamon and black pepper, usually in the range of <1-10% of the oil. Star anise oil obtained from the Japanese tree Illicium anisatum Linn. also contains about 6% safrole, whereas no safrole was detected in star anise oil obtained from the Chinese tree Illicium(2).

The following chemicals have been specifically designated by the Administrator of the Drug Enforcement Administration as the listed chemicals subject to the provisions of this part and parts 1309 and 1313 of this chapter. Each chemical has been assigned the DEA Chemical Code Number set forth opposite it. Safrole (DEA Code: 8323) is included on this List I.

List I chemical means a chemical specifically designated by the Administrator in section 1310.02(a) of this chapter that, in addition to legitimate uses, is used in manufacturing a controlled substance in violation of the Act and is important to the manufacture of a controlled substance.

Exempt chemical mixtures. (a) The chemical mixtures meeting the criteria in paragraphs (c) or (d) of this section are exempted by the Administrator from application of sections 302, 303, 310, 1007, 1008, and 1018 of the Act (21 U.S.C. 822, 823, 830, 957, 958, and 971) to the extent described in paragraphs (b) and (c) of this section. (b) No exemption granted pursuant to this section 1310.12 or section 1310.13 affects the criminal liability for illegal possession, distribution, exportation, or importation of listed chemicals contained in the exempt chemical mixture or the civil liability for unlawful acts related to exempt chemical mixtures, including distribution in violation of 21 U.S.C. 842(a)(11). (c) Mixtures containing a listed chemical in concentrations equal to or less than those specified in the "Table of Concentration Limits" are designated as exempt chemical mixtures for the purpose set forth in this section. The concentration is determined for liquid-liquid mixtures by using the volume or weight and for mixtures containing solids or gases by using the unit of weight.[Table#4126]

(a) Safrole is the chemical 4-allyl-1,2-methylenedioxy-benzene, C10H10O2. It is a natural constituent of the sassafras plant. Oil of sassafras is about 80 percent safrole. Isosafrole and dihydrosafrole are derivatives of safrole, and have been used as flavoring compounds. (b) Food containing any added safrole, oil of sassafras, isosafrole, or dihydrosafrole, as such, or food containing any safrole, oil of sassafras, isosafrole, or dihydrosafrole, e.g., sassafras bark, which is intended solely or primarily as a vehicle for imparting such substances to another food, e.g., sassafras tea, is deemed to be adulterated in violation of the act based upon an order published in the Federal Register of December 3, 1960 (25 FR 12412).

U203; As stipulated in 40 CFR 261.33, when safrole, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV.D.3.b).

The mechanism by which safrole exerts the weak carcinogenicity that has been demonstrated in rats and mice is considered. Metabolic conversion of the allyl group gives rise to intermediates capable of covalent binding with DNA and protein, and recent findings are compatible with conversion of the methylenedioxy group to a carbene, which forms ligand complexes with the heme moiety of cytochrome P450 and P448.

Following oral or ip administration... to rats and guinea pigs, 3'-N,N-dimethylamino-1'-(3, 4-methylenedioxyphenyl)-1'-propanone was identified as major urinary metabolite in guinea pigs and as minor metabolite in rats. ...Oral or ip administration... to rats... 3'-pyrrolidinyl-1' -(3,4-methylenedioxyphenyl)-1'-propanone, a further minor metabolite, and 3'-piperidyl-1'-(3,4-methylenedioxyphenyl)-1'-propanone were found in urine of rats.

Yields 4-allylcatechol probably in mouse and housefly; 3, 4-methylenedioxybenzaldehyde probably in fly. /from table/

Metabolites resulting from incubation of safrole with adrenal homogenates were 1'-hydroxysafrole, 4-allyl-1,2-dihydroxybenzene, 3'-hydroxysafrole, 2',3'-epoxysafrole and 2',3'-dihydro-2',3'-dihydroxysafrole.

For more Metabolism/Metabolites (Complete) data for Safrole (22 total), please visit the HSDB record page.

Pregnant ICR mice were treated orally with 600 umol/kg safrole (SA) dissolved in 4 mL/kg trioctanoin, on day 18 of gestation. The mice were killed 24 hr after treatment and the fetuses were removed and prepared for tissue isolation. A sensitive (32)P-postlabeling method was used to study the binding of safrole to the DNA of various maternal and fetal tissues. The results showed that safrole bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus and placenta, and the quantitative and qualitative differences in binding were organ-specific. The covalent binding index (umol adducted nucleotides per molecule of DNA nucleotides/umol carcinogen administered per g body weight) 24 hr after safrole treatment, ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA, with brain DNA the least affected. Autoradiography fingerprints derived from maternal and fetal organs revealed DNA adduct spots that were identified as several metabolites of safrole. Fetal adduct levels were lower than maternal, exhibiting the greatest difference (42-fold) in liver, but little difference in lung, brain, and intestines.

/Factors affecting transplacental DNA damage were examined. Timed pregnant mice or monkeys were given a single dose of carcinogen on different gestation days, sacrificed 1-50 days later, and analyzed for DNA adducts by (32)P post labeling assay. The following results were obtained. The chemical types of carcinogen determine the fetal and fetal/maternal adduct levels and whether there is a gestation stage dependency in DNA binding. ... Safrole preferentially bound to fetal liver (as for adults) with strong gestation stage specificity. ... All carcinogens tested bound ubiquitously to all fetal and possible embryonic DNA with levels exhibiting little relationship to placental levels. Fetal adduct levels varied from 0.05-2 fold of maternal levels depending on the carcinogen tested. Thus, fetal competence in metabolism of a specific carcinogen is a determining factor for transplacental DNA damage. Placental adduct levels are a qualitative, but not a quantitative, indicator of fetal exposure.

In mice given (14)C-labeled /in methylene dioxy position/ safrole or dihydrosafrole orally, 96 and 101% of radioactivity were recovered; 64 and 61% were found in carbon dioxide, 18 and 23% in urine, 6 and 5% in feces and intestine, 2 and 2.5% in liver and 6 and 9% in carcasses... .

Safrole was absorbed from the gastrointestinal tract by passive diffusion, with the absorption kinetics apparently dependent on its lipid solubility as determined in an in situ perfusion method in the rat. In this same procedure, safrole, at a level of 2 mg/mL of perfusion medium, reduced the absorption of glucose and methionine but not butyric acid.

Small doses of [C14]-safrole were absorbed rapidly and excreted almost completely via the urine in 24 hours in both man (doses 0.165 mg or 1.655 mg) and the rat (dose 0.63 mg/kg). A large dose (750 mg/kg) in the rat resulted in a decrease in the rate of elimination, only 25% being excreted in 24 hours, and plasma and tissue levels of safrole and its metabolites were elevated for 48 hours.

Found in various essential oils (highest concentration in sassafras); [Merck Index] Used as a fragrance, preservative in mucilage and library paste, floatation frother, antiseptic, and to denature fats in soap manufacture and to make heliotropin and piperonyl butoxide; Formerly used as a flavoring agent in foods, drugs, and beverages; [HSDB]

Working with Glues and Adhesives [Category: Other]

For safrole (USEPA/OPP Pesticide Code: 097901) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Use in food is prohibited.

In manufacture of piperonyl butoxide.

In perfumery; denaturing fats in soap manufacture; also in manufacture of heliotropin. Formerly as flavoring agent in foods, drugs, and beverages.

(1977) AT LEAST 9.80X10+7 G

(1980) 1.65X10+7 G

Derivation: From oil of sassafras or camphor oil.

By distillation from the essential oils rich in safrole; an uneconomical synthesis starts with catechol methylene ether reacted with allyl chloride; also 4-allyl alcohol with methylene iodide.

Constituent of several essential oils, notably sassafras in which it is present to the extent of about 75%.

Grade: Technical.

Cosmetics product ingredient: Safrole (5-(2-propenyl)-1,3-benzodioxole)

Information on 1 consumer products that contain Safrole in the following categories is provided:

Safrole

A chemical specified by regulation that, in addition to legitimate uses, is used in manufacturing a controlled substance in violation of the Act and is important to the manufacture of a controlled substance. (21 eCFR 1310.02)

1,3-Benzodioxole, 5-(2-propen-1-yl)-: ACTIVE

Method of purification: rectification or freezing.

Safrole is a major chemical constituent of aromatic oil present in sassafras root bark.

Safrole was identified in antibacterial and antiviral oils from forsythia suspensa.

Safrole (1,2-methylenedioxy-4-allylbenzene) is the principal constituent of oil of sassafras and a minor constituent of many other essential oils. The related substance, isosafrole (1,2-methylene- dioxy-4-propenylbenzene), also occurs as a minor constituent of many essential oils with a distribution similar to that of safrole. Another related substance, dihydrosafrole (1,2-methylenedioxybenzene-4- propylbenzene), is not known to occur naturally but is formed in the production of piperonyl butoxide.