Specialty chemicals

Giuliana Miglierini

GIULIANA MIGLIERINI

Sassafras oil, a key raw material now largely banned from the market
Sassafras oil has been for a long time an important raw material for the production of chemicals used in the flavours & fragrances and insecticide industries. The main component of Sassafras oil is safrole (80-90% of the raw oil depending on the source), which can be then chemically converted to isosafrole. Although safrole and isosafrole have been widely employed as flavours and fragrances, their use has been now largely restricted by the health authorities as the two compounds are reputed to be carcinogenic and irritants for the skin (1, 2). Studies on mice have shown a potential effect of safrole to induce liver cancer, kidney disorders, and damages to the central nervous system. Despite its potential toxic effects, isosafrole remains a key starting compound for the chemical production of other widely used products, such as the fragrances piperonal (heliotropine) and Helional and piperonyl butoxide, which is used as a synergistic ingredient in the formulation of insecticides (Figure 1). Safrole and isosafrole, mainly obtained from the safrole oil from Sassafras albidum (3), are also the starting material for the illegal production of the drug Ecstasy (MDMA, 3,4-methylenedioxymethamphetamine), one of todays most diffused drugs. THE TRADITIONAL USE OF SASSAFRAS OIL Safrole is found in quite large quantities in different plants among which the camphor tree (Cinnamomum camphora), in the North America Sassafras tree (Sassafras officinalis) and in the Chinese Sassafras (Sassafras tzumu). Smaller quantities of safrole may also be obtained from cinnamon, nutmeg, aniseed, ginger, black pepper and cinnamomum. The traditional use of safrole-containing plants dates back to the Aztec civilisation, making use of Piper Sanctum in the religious rites. Native Americans used sassafras root bark as infusion and tonic (3). Spanish colonists discovered the American species of Sassafras (Sassafras officinalis) in Florida in 1538 and introduced it to Europe. Desiccated leaves of Sassafras were used as spice for food preparation, while the oil obtained from the bark was employed in the traditional medicine for its diuretic and carminative effects, especially to cure affections of the genito-urinary tract. The safrole molecule was discovered in 1886 as a component of the Japanese Shikimol oil; from its oxidation a product was obtained characterised by a smell very similar to that of the Heliotrope flower. The product, named heliotropine (now known as piperonal), is an almond-like flavour originally obtained by degradation from piperine, the alkaloid which is the active ingredient of pepper (Pepper nigrum), and has been commercialised starting from the second half of the 20th century. Also obtained by synthesis from safrole, starting from 1947, is piperonyl butoxide, a synergist used in insecticides production as it blocks the detoxification mechanisms of insects. THE ILLICIT USE OF SASSAFRAS OIL Safrole is a natural raw material also used to prepare the drug Ecstasy, whose first synthesis is attributed to the German chemist Fritz Haber in 1898. The 3,4-methylenedioxymethamphetamine is the main compound of a group of drugs belonging to the amphetamine family and characterised by the 3,4-methylenedioxy functionality. The Ecstasy molecule was patented by Merck in 1914, but its effects on human health and behaviour were extensively studied only from the early 70s. Methamphetamines drugs are also known with the term entactogens, to emphasize their power of touching inside and their effects on mood. Ecstasy can be easily synthetized starting from safrole and its cost is relatively low compared to classic drug such as cocaine or heroin. According to the annual report of the European monitoring centre for drugs and drugs addiction (EMCDDA) (4), global annual production of amphetamines and Ecstasy may be estimated in about 520 tons. Ecstasy is produced mainly in Europe (with the Netherlands being the leading country) and, more recently, in South East Asia (China, Indonesia, and Hong Kong) and in North America. According to the same report, 8,5 tons of Ecstasy have been seized in 2004 world-wide, 50% of those coming from Central and West Europe, 23% from the North America and 16% from Oceania. The average cost to consumer for an Ecstasy tablet was, in 2004, about 3 in Poland and eastern countries and 15-25 in Greece and Italy. Raw materials, such as Sassafras oil, used to produce Ecstasy and other methamphetamines, are often subjected to illicit commercial practices. In order to prevent and block this drug trafficking, international authorities have issued laws and rules to make available world-wide a uniform set of criteria for the control of drug precursors and chemical substances used for their transformation. The criteria are based on the preventive authorisation to produce and market these types of chemicals and to control their export-import and final use. Within Europe, these rules are included in three different regulations (5-7), all of which have been integrated in single

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Figure 1. Safrole, isosafrole and their main derivatives

national legislations. Bilateral agreements have also been signed within the European Union and third countries, such as Bolivia, Chile, Colombia, Ecuador, the US, Mexico, Peru, Venezuela and Turkey. Substances included in the Annex A to the agreements are subject to a preventive notification from the relevant authority of the exporting country to the counterpart of the importing one, which is due before shipping of goods may occur. Furthermore, according to international legislation, production, transformation, marketing and distribution of classified substances are all activities subject to preventive authorisation from the authorities. Substances classified in category 1 according to UE regulations, such as safrole, isosafrole and piperonal, need a specific export authorisation in order to be commercialised, while to import these substances within the UE the importer also needs a preventive import authorisation and has to demonstrate that they are intended to be used for legal purposes. HISTORICAL SOURCES OF SAFROLE The up-to-now most diffused source of Sassafras oil is extraction from the bark of different species of trees. Cinnamomum parthenoxylon, for example, is a plant typical of Indochina and particularly rich in safrole (up to 97%), which has been now included in the International union for the conservation of nature (IUCN) Red book of the endangered species. This is not the only example that could be mentioned. China is the largest consumer of sassafras oil, using around 2000 tons annually for the production of heliotropine and other derivatives. In addition to this, a further annual requirement may be estimated at around 500 tons for the world-wide production of piperonyl butoxide. Considered that more than 95% of the needed Sassafras oil comes from destructive harvesting of the trees, most of which is illegal, it can be estimated that more than 500.000 trees are destroyed annually, which means 5 million trees lost only in the past 10 years. Sources of Sassafras oil are now becoming more and more difficult to find both due to the more strict control on the illicit use of the product and, even more importantly, in order to prevent massive deforestation of tropical forests. China, Brazil and Vietnam, the three main historical producers of Sassafras oil, have now banned harvest of the trees to prevent depletion of the resource. Brazil was the first country to stop harvesting in 1990. Vietnam then took the place of Brazil as a producer, but in 1999 the Vietnamese government also banned harvesting, while exports stopped in 2000. Up to 2003, Vietnam followed a policy of import and re-export the raw Sassafras oil.

From 2003, production moved again to Cambodia, namely in the Cardamom Mountains controlled by the Khmer rouge, but just a couple of years later (in 2005), the Cambodian government also banned harvesting of Sassafras trees, which are now classified in the countr y as rare species. Apparently the stop to production didnt work too efficiently, since in 2005 more than 600 tons of oil were produced and exported. A more stringent control by the local authorities, also assisted by the US DEA, led to the seizure in a Thai port in October 2007 of three containers containing 50,4 tons of safrole ready for export to America and China. The last seizure occurred recently in June 2008: the cooperation of the Cambodian authorities with the Australian police blocked 33 tons of safrole-rich oil, an amount big enough to produce 245 million tablets of Ecstasy. According to a declaration of the Australian Embassy in Cambodia, the stockpile had a potential street value of more 7.3 billion US$. The oil was destroyed by the Cambodian National authority for combating drugs by burning it over a three-day period, under the supervision of the Australian Federal police. Cambodian authorities have been working since 2002 to stem the distillation of the oil and since then have succeeded in detecting and dismantling more than 50 clandestine laboratories capable of producing up to 15 gallons of oil a day, according to the Australian Federal police. Production of Sassafras oil in China is strictly controlled by the authorities, but the Chinese companies, as well as those in Vietnam, operate in Laos and Burma on a sporadic basis. The trade is illegal; despite this, a few tons of oil from these regions occasionally enter China. ALTERNATIVE SOURCES OF SAFROLE Being Sassafras oil an almost banned raw material for the production of safrole and of its derivatives for use in the flavour & fragrances and insecticides industries, alternatives sources of these compounds need to be identified in order to safeguard the production chain. The first alternative that has been studied after the banning of sassafras tree harvesting in Brazil in 1990 is a natural one. The British Overseas development administration funded research to find a sustainable natural replacement for the Sassafras tree, resulting in the exploratory development of the new species Piper hispidinervium. This plant grows very fast and its leafs contains up to 85% safrole (8). The project stopped due to the availability of the more economically convenient Sassafras oil from Vietnam. China also had an experience of this kind in the Yunnan province, but it proved to be too difficult to convince farmers to invest in a single application when faced with the competition of numerous alternative crops. A second natural substitute has been developed in the Chinese Sichuan region, being this the district with the highest production of heliotropine in the world. The use of the native species Cinnamomum petrophilum, a tree with safrole content in the leaf up to 90%, has been encouraged by authorities for reforestation of hilly areas. The drawback of this approach is that the tree needs seven years to become productive; at present, only 5% of the total safrole oil demand is covered by this

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source and it is estimated that up to 20 years would be needed to really make C. petrophilum a viable alternative for industry. Last but not least, considered the difficulties discussed above for natural alternatives to Sassafras oil, the chemical synthesis starting from catechol seems to be the only sustainable solution. In this instance, the starting material is widely used and does not present any inconvenience as per supplying or illicit use. Many companies are working in their R&D departments to develop economic and sustainable synthetic routes to manufacturing Sassafrass oil derivatives, bypassing the synthesis of safrole and isosafrole, in order to synthetize heliotropine, Helional, piperonyl butoxide and other derivatives. Many patents have been already filed by companies world-wide and industrial development of the environmentally friendly processes is undergoing. It appears reasonable to conclude that this last one will be the winning challenge to make Sassafras oil derivatives available on the industrial market in future years without having shortage and, above all, without the contamination of safrole and isosafrole.
REFERENCES AND NOTES
1. IARC monographs on the evaluation of carcinogenic risk of chemicals to man, safrole, isosafrole and dihydrosafrole. Vol 10, pp 231-244 (1976) HSDB (Hazardous substances data bank) and references cited therein

3. 4.

5. 6.

7.

8.

US Department of Agriculture Natural resources conservation service (NRCS) Plant Guide: Sassafras European monitoring centre for drugs and drugs addiction (EMCDDA), Annual report 2006: The state of the drugs problem in Europe Regulation (EC) No 273/2004 of the European Parliament and of the Council of 11 February 2004 on drug precursors Council Regulation (EC) No 111/2005 of 22 December 2004 laying down rules for the monitoring of trade between the Community and third countries in drug precursors Commission Regulation (EC) No 1277/2005 of 27 July 2005 laying down implementing rules for Regulation (EC) No 273/2004 of the European Parliament and of the Council on drug precursors and for Council Regulation (EC) No 111/2005 laying down rules for the monitoring of trade between the Community and third countries in drug precursors Text with EEA relevance Food and Agriculture Organization of the United Nations (FAO) Corporate document repository, Flavours and fragrances of plant origin, Chapter 3: Sassafras oil, and references cited therein

GIULIANA MIGLIERINI Free-lance scientific journalist

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