Overview and history
Safrole is a phenylpropene that usually extracted from the root-bark or the fruit of sassafras plants in the form of sassafras oil or is synthesized from catechol or other related methylenedioxy-compounds
[1]. It is the key component of brown camphor oil, and also exists in small amounts in a wide variety of plants, where it functions as a natural pesticide. The major source of safrole includes Ocotea cymbarum oil made from Ocotea pretiosa(a plant growing in Brazil), and sassafras oil made from Sassafras albidum(a tree growing in eastern North America)
[2, 3].
Safrole is one of the natural components of refined oils in more than fifty kinds of vegetables
[4]. Many of them can be made into seasonings and are one of the major components of essential oils, such as sassafras, camphor, nutmeg, black pepper, sweet basil, mace, cinnamon, anise and piper betle flower
[4]. Safrole is a precursor chemical of ring-substituted amphetamine-type substances such as MDMA or Ecstasy, MDA, MDE
[5]. Safrole and isosafrole(S-isomer of safrole) were once used extensively as a seasoning in soft drinks. For example, Sarsaparilla and Coke have used sassafras oil as seasoning, which contained nearly 85% safrole and isosafrole. Intake estimates of flavoring substances are generally very poor because of the lack of data on the concentrations of these chemicals naturally occurring or voluntarily added in foodstuffs. Within the Council of Europe, UK and France provided calculations based on their respective food consumption data and on concentration levels documented or assumed
[6, 7].
Since safrole and isosafrole are carcinogens, adding sassafras oil in soft drinks has been prohibited in the US since 1970, while it was defined as a kind of food additive and treated as a special element of seasonings in the Republic of China with limited usage
[8, 9].
Physiochemical properties
Safrole appears as a colorless or slightly yellow oily liquid. It has a characteristic "sweet-shop" aroma. As a naturally occurring substance, it is a derivative of the aromatic phenol ether 1,3-benzodioxole(HSDB 2009)
[12]. It exists at room temperature as colorless or pale-yellow oil with an odor of sassafras. It is practically insoluble in water, insoluble in glycerine, slightly soluble in propylene glycol, soluble in alcohol, and miscible with chloroform and ether
[11].
Synthesis
Safrole is produced by distillation of oils rich in safrole(such as sassafras, nutmeg, mace, cinnamon, anise, black pepper and sweet basil). It is nearly impossible to obtain large quantities of safrole and/or sassafras oil without arousing the suspicion of law enforcement, as Safrole is currently a List I chemical
[12]. U.S. production of safrole was 257,000 lb in 1969 and 277,000 lb in 1970, but had fallen to 12,000 lb by 1977(HSDB 2009)
[10]. In 2009, safrole was manufactured by only one facility worldwide, in the United States[SRI 2009]
[13], and was available from 11 U.S. suppliers(ChemSources 2009)
[14]. U.S. imports of safrole were 36,000 lb in 1980(HSDB 2009)
[10] and ranged from 11,000 to 132,000 lb in 1997, 2003, 2004, and 2005(USITC 2009)
[15]. U.S. exports of safrole were 6,600 lb in 1996 and 35,200 lb in 1998.
Application
Safrole can be 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)(HSDB 2009)
[10]. 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 use or any other addition of safrole or oil of sassafras to food was banned in the United States in 1960(IARC1976, HSDB 2009)
[10, 16]. Safrole has also been used in the illicit production of the drug 3,4-methylenedioxymethamphetamine(MDMA, or ecstasy), and the U.S. Drug Enforcement Administration has designated safrole a List I Chemical(DEA 2009)
[17].
Warning and risk
Safrole are carcinogens
[7, 8], therefore, adding sassafras oil in soft drinks has been prohibited in the US since 1970, while it was defined as a kind of food additive and treated as a special element of seasonings in the Republic of China. However, it can be used only in soft drinks with the use limit below 1μg/mL, according to food additive regulations
[18]. Safrole and isosafrole were once used extents have a connection with inductive liver tumors
[19]. A high concentration(0.5%) of safrole and isosafrole has been shown to increase the occurrence rate of malignant tumors in mice Safrole or 4-allyl-l; 2-methylenedioxybenzene is a plant constituent that is a hepatotoxin for animals and man. The major toxicity of safrole and isosafrole come from their carcinogenic nature after oxidation. Safrole is oxidized into1-hydroxysafrole by many mammals and whose derivatives including isosafrole and dihydrosafrole, which are all both carcinogenic
[20, 21].
References
- Perkin, William Henry & Trikojus, Victor Martin[1927]. "CCXII. —A synthesis of safrole and o-safrole". Journal of the Chemical Society: 1663–1666. doi:10.1039/JR9270001663. Retrieved 28 December 2013.
- Hickey, Michael J.[1948]. "Investigation of the chemical constituents of Brazilian sassafras oil". Journal of Organic Chemistry. 13[3]: 443–6.
- Kamdem, Donatien; Gage, Douglas[2007]. "Chemical Composition of Essential Oil from the Root Bark of Sassafras albidum". Planta Medica. 61[6]: 574–5.
- Choong Y M and Lin H J, 2000, A Rapid and Simple Gas chromatographic Method for Direct Determination of safrole in soft drinks, Journal of Food and Drug Analysis, vol. 9, No. 1, Pages: 27-32.
- Rianjanu, A., Roto, R., Julian, T., Hidayat, S. N., Kusumaatmaja, A., & Suyono, E. A., et al.[2018]. Polyacrylonitrile nanofiber-based quartz crystal microbalance for sensitive detection of safrole. Sensors, 18(4], 1150.
- https://ec.europa.eu/food/sites/food/files/safety/docs/fs_food-improvement-agents_flavourings-out116.pdf
- Borchert, Wislocki and Miller, 2012, The Metabolism of the Naturally Occurring Hepatocarcinogen,
- https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+2653
- https://www.fda.gov.tw/tc/includes/GetFile.ashx?id=f636695477623841313
- HSDB. 2009. Hazardous Substances Data Bank. National Library of Medicine.
- Report on Carcinogens, 2011, Twelfth Edition, National Toxicology Program, Department of Health and Human Services, and Page 374.
- The Chemistry Encyclopedia,[2005] Safrole http://www.chemistrydaily.com/chemistry/Safrole
- SRI. 2009. Directory of Chemical Producers. Menlo Park, CA: SRI Consulting. Database edition. Last accessed: 7/14/09.
- ChemSources. 2009. Chem Sources Chemical Search. Chemical Sources International.
- USITC. 2009. USITC Interactive Tariff and Trade DataWeb. United States International Trade Commission.
- IARC. 1976. Safrole, isosafrole, and dihydrosafrole. In Some Naturally Occurring Substances. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 10. Lyon, France: International Agency for Research on Cancer. pp. 231-244.
- DEA. 2009. Safrole and Sassafras Oil are used in the Illicit Manufacture of MDMA. Drug Enforcement Administration.
- https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/sassafras
- Long, E. L., Nelson, A. A., Fitzhugh, O. G., & Hansen, W. H.[1963]. Liver tumours produced in rats by feeding safrole. Journal of the American Medical Association, 184, 159-159.
- Borchert, P, et al. "The metabolism of the naturally occurring hepatocarcinogen safrole to 1'-hydroxysafrole and the electrophilic reactivity of 1'-acetoxysafrole. " Cancer Research 33.3(1973]: 575-589.
- Borchert, P, et al. "1'-Hydroxysafrole, a proximate carcinogenic metabolite of safrole in the rat and mouse." Cancer Research 33.3(1973]:590-600.
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
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.
Chemical Properties
Safrole is a colorless to yellow liquid with an
odor of camphor or sassafras.
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.
Uses
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.
Uses
A naturally occurring methylenedioxyphenyl compound found in black peppers and in oil of sassafras;
safrole has been used as a flavoring and in perfumery.
Uses
In perfumery; denaturing fats in soap manufacture; also in manufacture of heliotropin. Formerly as flavoring agent in foods, drugs and beverages.
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.
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.
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.
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 5×10
5 hydroxyl radicals per cm3. The rate
constant for the vapor-phase reaction of safrole with ozone has
been estimated as 1.2 × 10
17 cm3 mol1 s at 25 °C. This
corresponds to an atmospheric half-life of about 23 days at an
atmospheric concentration of 7 × 10
11 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.
