Safrole

Description

In the early 1990s, certain forest shrubs of the Piperaceae, indigenous to the humid forests of Central America and Greater Amazonia, were found to contain high levels of safrole in their leaves. The Brazilian Amazon contains a wide variety of Piper species but attention had focused on P. hispidinervum and P. callosum, two species with high safrole content. Subsequently, P. callosum has been dropped in the research work in favor of the more promising P. hispidinervum. The essential oil of P. hispidinervum contains high levels (83–93%) of safrole in leaves, which can be easily extracted by hydrodistillation.

Chemical properties

light yellow-green liquid

Chemical properties

Safrole is a colorless to yellow liquid with an odor of camphor or sassafras.

Chemical properties

Use in foods is prohibited. Safrole has characteristic odor of sassafras. FDA banned the use of oil of safrole and sassafras bark in food, but permits use of edible spices, such as nutmeg and mace, which contain very small quantities of naturally occurring safrole. There is sufficient evidence for the carcinogenicity of safrole in experimental animals. Safrole is combustible when exposed to heat or flame and, when heated to decomposition, it emits acrid smoke and fumes.

Occurrence

Originally isolated in the oil from roots of Sassafras officinale; constituent of several essential oils, such as camphor, nutmeg and cinnamon leaves; the essential oil from the roots of Nemuaron humboldtii contains up to 99% safrole; Brazilian sassafras oil, up to 93%; and American sassafras oil, up to 80%. Also reported found in banana, cinnamon bark and leaf, nutmeg, mace, tamarind, pepper, cocoa, coriander seed, dill herb, dried bonito, lemon balm, ashanti pepper and green maté.

The Uses of Safrole

Safrole, the main component of oil of sassafras, is widely used as a flavoring agent in drugs and in the manufacture of heliotropin, perfumes, soaps, and piperonyl butoxide (a compound used in a variety of insecticides to enhance the pesticidal properties of other active ingredients). Safrole has also been used as a preservative in mucilage and library paste and as a flotation frother. Oil of sassafras, which contains safrole, was formerly used to flavor some soft drinks, such as root beer. However, this was banned in the United States in 1960. Safrole has also been used in the illicit production of the drug 3,4- methylenedioxymethamphetamine (MDMA or ecstasy) and the US Drug Enforcement Administration has designated safrole a List I Chemical.

The Uses of Safrole

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

The Uses of Safrole

A naturally occurring methylenedioxyphenyl compound found in black peppers and in oil of sassafras; safrole has been used as a flavoring and in perfumery.

Definition

ChEBI: A member of the class of benzodioxoles that is 1,3-benzodioxole which is substituted by an allyl group at position 5. It is found in several plants, including black pepper, cinnamon and nutmeg, and is present in several essential oils, notably that of sass fras. It has insecticidal properties and has been used as a topical antiseptic. Although not thought to pose a significant carcinogenic risk to humans, findings of weak carcinogenicity in rats have resulted in the banning of its (previously widespread) use in perfumes and soaps, and as a food additive.

Preparation

By distillation and/or freezing of such oils as Cinnamomum micranthum, Octea cymharum and oil of sassafras.

Aroma threshold values

Detection: 10 to 160 ppb

General Description

Clear colorless or slightly yellow liquid with the odor of sassafras. Denser than water (density 1.09 g / cm3) and insoluble in water. Hence sinks in water. Obtained from oil of sassafras or oil of camphor.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Safrole, an acetal, is readily hydrolyzed in acidic solution to give 4-allylpyrocatechol and formaldehyde (or formaldehyde polymers).

Hazard

Toxic by ingestion, may not be used in food products (FDA), a possible carcinogen.

Fire Hazard

Safrole is combustible.

Safety Profile

Confirmed carcinogen with experimental carcinogenic and neoplastigenic data. Poison by intravenous route. Moderately toxic by ingestion and subcutaneous routes. Experimental reproductive effects. Human mutation data reported. A sktn irritant. Combustible when exposed to heat or flame. When heated to decomposition it emits acrid smoke and irritating fumes. See also ALDEHYDES and ALLYL COMPOUNDS.

Toxicology

Safrole is a colorless oily liquid possessing a sweet, warm-spicy flavor. It has been used as a flavoring agent for more than 60 years. Oil of sassafras, which contains 80% safrole, also has been used as a spice. In the United States, the FDA banned the use of safrole in 1958 and many other countries followed this lead and also banned the use of safrole in flavors. Safrole, either naturally occurring in sassafras oil or the synthetic chemical, has been shown to induce liver tumors in rats. The continuous administration of safrole at 5,000 ppm in the total diet of rats caused liver tumors. Studies in dogs showed extensive liver damage at 80 and 40 mg/kg, lesser damage at lower levels, but no tumors. In vivo, safrole metabolites into 1’-hydroxysafrole. The structures of safrole and 1’-hydroxysafrole are shown in Figure 10.14.

Synthesis

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.

Potential Exposure

This compound has been used to flavor beverages and foods. It is also reported to be used in soap manufacture, perfumery, sleep aids, sedatives, and pesticides. The FDA estimated exposure to safrole of the general public through food consumption was extremely low since the Agency prohibited its used in food. Derived from oil of sassafras or camphor. Minimal exposure may occur through the use of edible spices, including nutmeg and mace, which contain low levels of naturally occurring safrole.

Carcinogenicity

Safrole is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Environmental Fate

Log Kow ＝ 3.45
Solubility: miscible with chloroform, ether; soluble in alcohol, slightly soluble in propylene glycol; soluble in water ＝ 121 mg l1 at 25 °C
Henry’s Law constant ＝ 9.07 × 106 atm-m3 mol1 at 25°C
Partition Behavior in Water, Sediment, and Soil
If released to air, safrole will exist solely as a vapor in the ambient atmosphere. Vapor-phase safrole will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with a half-life of 5.1 h. Safrole does not absorb light with wavelengths >290 nm and is not expected to be susceptible to direct photolysis by sunlight. If released to soil, safrole is expected to have moderate mobility and may absorb to suspended solids and sediment if released into water. An estimated bioconcentration factor (BCF) of 90 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to be an important environmental fate process, since safrole did not hydrolyze under environmental conditions.
Environmental Persistency
The rate constant for the vapor-phase reaction of safrole with photochemically produced hydroxyl radicals has been estimated as 7.6 × 1011 cm3 mol1 s at 25°C. This corresponds to an atmospheric half-life of about 5.1 h at an atmospheric concentration of 5×10⁵ hydroxyl radicals per cm3. The rate constant for the vapor-phase reaction of safrole with ozone has been estimated as 1.2 × 10¹⁷ cm3 mol1 s at 25 °C. This corresponds to an atmospheric half-life of about 23 days at an atmospheric concentration of 7 × 10¹¹ ozone molecules per cm3. Safrole does not absorb light with wavelengths >290 nm and is not expected to be susceptible to direct photolysis by sunlight. Hydrolysis is not expected to be an important environment fate process, since safrole was not observed to undergo hydrolysis under acidic, neutral, or basic conditions.
Bioaccumulation and Biomagnification
As estimated BCF of 90 was calculated for safrole, this BCF suggests the potential for bioconcentration in aquatic organisms is moderate.

Metabolism

Rats and guinea-pigs, dosed orally or ip with safrole, excreted in the urine 3-N,N-dimethylamino-1 -(3',4'-methylenedioxyphenyl)-1 -propanone (Oswald, Fishbein, Corbett & Walker, 1971). In addition, the rats excreted in the urine a major metabolite,3-piperidyl-l-(3',4'-methylenedioxyphenyl)-l-propanone, and traces of 3-pyrrolidinyl-l-(3',4'-methylenedioxyphenyl)-l-propanone. All three aminoketones decomposed to form 1-(3',4-methylenedioxyphenyl)-3-propen-l-one. Two metabolites formed by the epoxide-diol pathway and excreted in the urine of rats and guinea-pigs dosed with safrole were identified as l,2-methylenedioxy-4-(2',3'-dihydroxypropyl)benzene and l,2-dihydroxy-4-(2',3'-dihydroxypropyl)benzene (Horning, Bell, Carman & Stillwell, 1974).

Shipping

Environmentally hazardous substances, liquid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous hazardous material, Technical Name Required.

Purification Methods

Safrole has been purified by fractional distillation, although it has also been recrystallised from low boiling pet ether at low temperatures. [IR: Briggs et al. Anal Chem 29 904 1957, UV: Patterson & Hibbert J Am Chem Soc 65 1962 1943.] The maleic anhydride adduct forms yellow crystals from toluene m 257o [Hickey J Org Chem 13 443 1948], and the picrate forms orange-red crystals from CHCl3 [Baril & Magrdichian J Am Chem Soc 58 1415 1936]. [Beilstein 19 H 39, 19 I 617, 19 II 29, 19 III/IV 275, 19/1 V 553.]

Toxicity evaluation

A review of studies on safrole metabolism shows that the compound gives rise to a large number of metabolites by two major pathways, oxidation of the allyl side chain and oxidation of the methylenedioxy group, with subsequent cleavage to form a catechol. The mechanism by which safrole exerts the weak hepatocarcinogenicity that has been demonstrated in rats and mice. 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 cytochromes P450 and P448. It is suggested that whereas the allyl group is responsible for the mutagenic potential of safrole, the methylenedioxy moiety may be associated with epigenetic aspects of carcinogenicity.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explo- sions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Safrole, an acetal, is read- ily hydrolyzed in acidic solution to give 4-allylpyrocatechol and formaldehyde (or formaldehyde polymers)

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office.