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Safrole

Safrole is an organic compound with the formula CH2O2C6H3CH2CH=CH2. It is a colorless oily liquid, although impure samples can appear yellow. A member of the phenylpropenoid family of natural products, it is found in sassafras plants among others. Small amounts are found in a wide variety of plants, where it functions as a natural antifeedant. Ocotea pretiosa, which grows in Brazil, and Sassafras albidum, which grows in eastern North America, are the main natural sources of safrole. It has a characteristic "sweet-shop" aroma.
Safrole can be obtained through natural extraction from Sassafras albidum and Ocotea cymbarum. Sassafras oil for example is obtained by steam distillation of the root bark of the sassafras tree. The resulting steam distilled product contains about 90% safrole by weight. The oil is dried by mixing it with a small amount of anhydrous calcium chloride. After filtering-off the calcium chloride, the oil is vacuum distilled at 100 C under a vacuum of 11 mmHg or frozen to crystallize the safrole out. This technique works with other oils in which safrole is present as well.
Safrole is a member of the methylenedioxybenzene group, of which many compounds are used as insecticide synergists; for example, safrole is used as a precursor in the synthesis of the insecticide piperonyl butoxide. Safrole is also used as a precursor in the synthesis of the drug N-methyl-3,4-methylenedioxyamphetamine (MDMA, Ecstasy). Before safrole was banned by the FDA in 1960 for use in food, it was used as a food flavour for its characteristic candy-shop aroma. It was used as an additive in root beer, chewing gum, toothpaste, soaps, and certain pharmaceutical preparations.
Isosafrole is produced synthetically from safrole. It is not found in nature. Isosafrole comes in two forms, trans-isosafrole and cis-isosafrole. Isosafrole is used as a precursor for the psychoactive drug MDMA. When safrole is metabolized several metabolites can be identified. Some of these metabolites have been shown to exhibit toxicological effects, such as 1-hydroxysafrole and 3-hydroxysafrole in rats. Further metabolites of safrole that have been found in urine of both rats and human include 1,2-dihydroxy-4-allylbenzene or 1(2)-methoxy-2(1)hydroxy-4- allylbenzene.
Toxicological studies have shown that safrole is a weak hepatocarcinogen at higher doses in rats and mice. Safrole requires metabolic activation before exhibiting toxicological effects. Metabolic conversion of the allyl group in safrole is able to produce intermediates which are directly capable of binding covalently with DNA and proteins. Metabolism of the methylenedioxy group to a carbene allows the molecule to form ligand complexes with cytochrome P450 and P448. The formation of this complex leads to lower amounts of available free cytochrome P450. Safrole can also directly bind to cytochrome P450, leading to competitive inhibition. These two mechanisms result in lowered mixed function oxidase activity.
Safrole is still regarded by FDA to be a weak carcinogen in rats. However, according to a 1977 study of the metabolites of safrole in both rats and humans, two carcinogenic metabolites of safrole found in the urine of rats, 1'-hydroxysafrole and 3'-hydroxyisosafrole, were not found in human urine. The European Commission on Health and consumer protection assumes safrole to be genotoxic and carcinogenic. It occurs naturally in a variety of spices, such as cinnamon, nutmeg, and black pepper, and herbs such as basil. In that role, safrole, like many naturally occurring compounds, may have a small but measurable ability to induce cancer in rodents. Despite this, the effects in humans were estimated by the Lawrence Berkeley National Laboratory to be similar to risks posed by breathing indoor air or drinking municipally supplied water. In the United States, it was once widely used as a food additive in root beer, sassafras tea, and other common goods, but was banned by the FDA after its carcinogenicity in rats was discovered. Today, safrole is also banned for use in soap and perfumes by the International Fragrance Association.
The root bark of American sassafras contains a low percentage of steam-volatile oil, which is typically 75% safrole. Attempts to refine safrole from sassafras bark in mass quantities are generally not economically viable due to low yield and high effort. However, smaller quantities can be extracted quite easily via steam distillation (about 10% of dry sassafras root bark by mass, or about 2% of fresh bark). Demand for safrole is causing rapid and illicit harvesting of the Cinnamomum parthenoxylon tree in Southeast Asia, in particular the Cardamom Mountains in Cambodia. However, it is not clear what proportion of illicitly harvested safrole is going toward MDMA production, as over 90% of the global safrole supply (about 2000 metric tons per year) is used to manufacture pesticides, fragrances, and other chemicals. Sustainable harvesting of safrole is possible from leaves and stems of certain plants.