To Synthesize or Not to Synthesize...that is the question


The Food Babe, The Environmental Working Group, The Center for Public Integrity, Natural News, The Campaign for Safe Cosmetics and even Scientific American would all have us believe there is no substitute for natural. If we were to believe the websites, blogs and other communications from individuals or bodies such as these, we could believe anything that hasn’t been immediately derived from a cultivated source is going to kill us – and anything that has been labeled artificial is toxic and will cause us serious harm.

This misinformation makes an impact on consumer perception. Over recent years, several large consumer product manufacturers—particularly in the food and beverage arenas—have made moves to eliminate anything artificial from a wide number of consumer products. At the same time, there is significant pressure on the natural sources of key ingredients in the flavor and fragrance supply chain.

A Natural Challenge

Not everything is simple in the world of naturals. For example, Huanglongbing (HLB; citrus greening), thought to be caused by the bacterium Candidatus Liberibacter asiaticus, has seriously affected citrus production in a number of countries in Asia, Africa, Brazil, USA, the Indian subcontinent and the Arabian Peninsula. Wherever the disease has appeared, citrus production has been compromised with the loss of millions of trees. In August 2005, the disease was found in the south Florida region of Homestead and Florida City. Since that time, HLB was found in commercial and residential sites in all counties with commercial citrus.

In addition to citrus, there were recent challenges with vanilla, lavender, sandalwood and other materials derived from plants, flowers and other cultivated sources, which affected availability and cost. While some organizations in the F&F world have formed sustainable partnerships with growers and farmers in an attempt to combat supply volatility, this does not address the situation on a macro level – and the challenges around natural materials continue.

Moreover the safety of the oils, extracts and absolutes created from cultivated products has been questioned. At the recent International Federation of Essential Oils and Aroma Trades (IFEAT) 2016 Conference in Dubai, Sean V. Taylor, scientific secretary to the Flavor Extracts and Manufacturers Association (FEMA) expert panel and the International Organization of the Flavor Industry (IOFI) scientific director, presented on the FEMA Generally Recognized as Safe (GRAS) evaluation and re-evaluation of flavoring complex mixtures. He indicated, “despite their incredible importance as food flavorings, there has not yet been significant scientifically based safety evaluations of essential oils.” He also continued to outline a rigorous and comprehensive evaluation and re-evaluation program to cover more than 250 natural complex substances (NCS).

Can We Live Only in a Natural World?

Let’s start by seeing if we can actually define what natural is. This is something I’ve tried to cover previously in other articles – and while it should be relatively simple in reality, it isn’t because consumer perception of natural compared to the legislative definitions are widely different.

If we take the world of flavors for example, different regions of the world abide by different definitions of what would constitute a natural product. Take the U.S. definition outlined in 21 CFR. Chapter 1, Parts 101.22(a) .1 and .3 (see Panel 1) then this allows us to define anything which started its journey from a natural source can be labeled as natural in the consumer product.

The Europeans complicate matters further as the EEC Council Directive on Flavorings and source materials for their production (88/388/EEC) shows (see Panel 2). This legislation gives greater restrictions to what can be defined as natural, by restricting the processes which can be involved in creating a natural product.

What Makes an NCS?

Turning our attention to the world of fragrances, the International Fragrance Association (IFRA) only allows fragrances marked as “natural” if they contain fragrance ingredients corresponding to the terms and definitions laid down in the International Organization for Standardization’s (ISO) 9235:1997 (Aromatic natural raw materials – Vocabulary) or if substances are already present in them and isolated from them by purely physical means. For example, a substance such as menthol—which is naturally present in peppermint oil—can be called natural if it is isolated from the peppermint oil by physical methods only.

In general, ISO 9235 defines natural aromatic raw materials as being physically obtained from plants using distillation, expression and extraction. Natural fragrances are complex compositions of natural aromatic raw materials such as essential oils, fractions of essential oils, isolates, exudates such as resins, distillates, extracts and volatile concentrates. Synthetically reconstituted essential oils, synthetic nature-identical ingredients and intentionally chemically modified natural raw materials (e.g. chemical acetylation of essential oil) cannot be used in fragrance compounds described as natural. The Natural Products Association goes one step further to forbid the use of petrochemical solvents in the extraction process—so concretes and absolutes made using hexane are not permitted.

While I am certainly not a lawyer, it’s my impression these guidelines are in place to protect the public from materials, which could cause them harm. However, do these guidelines make the assumption that everything immediately derived from a cultivated source is safe and therefore exempt from testing and regulation? There is also the added belief from the majority of consumers that, “natural = healthy or safe” and consequently, everything naturally derived must be better for you.

This kind of consumer pressure has led to companies such as General Mills and Nestle to commit to removing artificial flavors from its products. The one clear thing that is when the majority of consumers refer to natural, they are thinking of an ingredient, which was immediately derived from the cultivated source, i.e. an NCS. This brings me back to the point: Do we really know and control with repeatable accuracy exactly what makes up an NCS?

From the perspective of the humble chemist, determining the safety of an NCS compared to an individual molecule seems to be a far more complicated and rigorous task. In addition, policing the chemicals, which are present in an NCS to ensure the dosage of chemicals in a consumer product are safe, is even more complicated. This would potentially require significant analysis and cost to ensure that should the required limits of each individual component be adhered to.

A World without Synthetics?

Looking at the FEMA GRAS list of ingredients, whether artificial or natural, gives us some surprising insights. Of the 2,809 GRAS ingredients, only 403 could be described as NCS (see F-1), while the remaining 2,406 are clearly defined molecules. Interestingly, of these 2,406 molecules, 522 are not actually found in nature, but could in theory be synthesized from a naturally occurring starting molecule using naturally occurring reagents to give us a “natural” aroma chemical. Regardless of this, it is interesting for the flavorist adhering to the FEMA GRAS list, around 85% of the ingredients that could be used are distinct molecules, which need to be synthesized in some way.

Seeing the evolution of materials submitted to FEMA over time is also interesting. Looking at a complete FEMA GRAS list from 2001 up to 4838 (the highest number on the interim GRAS 28 list), it is clear from the alphabetical nature of the list that the first FEMA GRAS lists were populated by materials, which were currently in use: FEMA# 2001 being acacia gum and FEMA# 3124 being zingerone. Of these initial materials, 360 of the total 403 NCS are included in these early FEMA GRAS lists. In the subsequent 1704 additions, only 43 materials that could be considered NCS were added. Is this because the world has run out of natural materials to extract or distill? Highly unlikely, I would suggest.

A combination of other factors are the more likely contributors to this observation. Firstly, flavorists and perfumers have recognized while natural oils and extracts have complex and interesting notes, which add greatly to the products they create, the reproducibility of these materials can leave a lot to be desired. Year on year variations, regional variation and even local variation from farmer to farmer all have an effect on the constituents of an oil or extract. Add the changes which occur to this as we move from botanical species to botanical species and we introduce a huge number of variables, all of which could have an effect on the odor and taste profile of the material being used.

Analytical techniques have also become much improved. The ability to analyze an oil, extract, distillate or even fruit, vegetables, meat and fish and subsequently, detect and identify the chemical constituents down to the ppb level has increased dramatically over the last few decades. This means some of the key odor constituents are the materials they were using—which were a mystery to flavorists and perfumers previously—which could be synthesized and utilized in formulations. This, along with other factors such as greater access and focus on molecular synthesis has led to an increase on the FEMA GRAS list. One example is materials with lower odor thresholds, which previously could not be characterized, but certainly could be identified by the trained nose.

Take a look at the more recently published GRAS lists and you will see them more highly populated with molecules containing sulfur, nitrogen and oxygen. Additionally, while the early GRAS lists contained a large number of esters and similarly, simple molecules to synthesize, the more recent GRAS lists saw a greater diversity in chemical structure. A greater focus on synthesis, rather than isolation, enabled greater access to not only research and development on a lab scale, but also greater access to more complex engineering solutions to producing these molecules on a large scale. These, and other molecules, which occur naturally at lower levels, are now recognized as being the key components in the creation of truly outstanding formulations.

Molecules are Important

The ability of synthetic chemistry to come up with either cost effective routes to molecules identified in nature or to novel molecules with interesting odor profiles has increased significantly in the last 20-30 years. This is one of the major factors behind the rapid increase in the number of molecules, which have found their way on to the flavorist or perfumer’s palette. In just about all areas of flavor and fragrance creation the identification and production of synthetic molecules has been a critical factor in the creation of more elaborate and pleasurable products.

While the consumer may be prejudiced against synthetics, the perfumer and flavorist certainly are not. Even in the world of fine fragrance, synthetics are recognized for what they are, namely the essential tools for creation. For example, the secret of Dior’s Eau Sauvage is methyl dihydrojasmonate. Without hydroxycitronellal, the cult perfume Quelque Fleurs would be missing its heart and the more recent Calvin Klein fragrance, CK One would have a huge hole in it without dihydromyrcenol (see F-2). Synthetics are obviously not exclusively used in fine fragrance (see F-3). All three of the materials just mentioned, while being the key ingredients to some of the most successful fine fragrances are also the staples used in detergents, body wash and shampoo. This also does not mean synthetics are cheap either. Some materials cost over $500-1000 per kilo.

Even though there was an increase in the range of synthetic molecules in more recent decades, this does not mean the use of synthetics is a recent phenomenon. The French perfume house, Guerlain could claim to have begun the synthetics revolution in 1889 in its fragrance, Jicky. The classic, L’Heure Bleue (1912) contains methyl anthranilate (yes, of the Concord grape flavor), Mitsouko (1919) uses the so called aldehyde C14 and the immortal Shalimar (1925) has a variety of synthetics, such as ethyl vanillin and a number of different quinolines.

The ability of chemistry to design and create synthetics it seems is essential to both the perfumer and the flavorist. So why do consumers have bad opinions of them?

Natural Carbon Source

Recently, there was a rise in articles and blogs, which refer to the starting point of the ingredients in our food. The disdain to which anything derived from petrochemicals is held and the leverage, which can be used in the mind of the consumer, is a clear link to the lack of understanding on just what a chemical is. Clearly petrochemicals link strongly to more industrial processes and application and for the average consumer, the thought of having a petrochemical in their food or their fragrance is a highly unappealing idea. From the point of view of the chemist, however, the source of the material does not matter. For the flavorist or perfumer, if they have an interesting and cost effective molecule, which allows for the creation of something wonderful, then why should they care?

We should not however ignore the will of the consumer, regardless of how poorly or narrowly informed they are. This brings me to something, which in my view, is going to play an increasingly important role in the next few years in the fragrance and flavor world and that is ... just where do you get your carbons from?

The industry started to look at sustainability with increasing frequency in recent years. There are obvious reasons from both environmental and business continuity standpoints to do this. Business sustainability and environmental sustainability are heavily linked in the fragrance and flavor worlds – if even from the simple perspective there are a large number of critical ingredients, which are cultivated. If we acknowledge there is a limited amount of petrochemically derived feedstock available to us then at some point in the future we will have to face a different challenge. We should recognize formulating a flavor or fragrance using only NCS’s is difficult and limiting and therefore the use of synthetics in flavor and fragrance creation is essential.

For example, dihydromyrcenol is one of those molecules the fragrance industry would find difficult to live without. Not only is it a staple detergent and, as previously mentioned, a key component of CK One, but it also appears in other fine fragrances such as Drakkar Noir (at 10%), Polo and Cool Water to name a few. The material does not appear in nature, but it could be said to be one of the most, “natural synthetics” available in the market currently. Natural synthetic seems to be something of an oxymoron, however what we need to consider is where our carbons have come from.

Let’s take a look at the synthesis of dihydromycenol (see F-4). Produced by the pyrolysis of pinane to dihydromyrcene and subsequent hydration to dihydromycrenol, the starting point for this is typically alpha pinene, which originally is sourced either directly or indirectly from pine trees. By sourcing the initial raw material from a natural, sustainable source we do two things: First, we start with “natural” carbons and second, we begin with a renewable source. Finally, through clever chemical synthesis, we create a molecule, which has a reproducible, interesting, useful and desirable odor profile.

There are other molecules, which can take their starting points from cultivated sources. Some are from the bottom end of the cost spectrum such as citronellol and geraniol and some from the top end. What most of these materials have in common is, in general, they belong to the same or similar groups of molecules. Terpenes are prevalent in the materials, which could claim, depending on their synthesis, “natural” carbons as their starting point. This particular family is an easy starting point due to the ease of availability of its precursors. It is not always easy to find accessible sources of raw materials from which to start, especially as there are a significant amount of crops, which do not already have demand.

There are two potential solutions to this. One is waste valorization, which is fast becoming an increasingly important area of R&D for academics and beyond. Chemists, such as Avtar Matharu, Ph.D. and Thomas Farmer, Ph.D. from the University of York’s Green Chemistry department, are able to tap into a regional network of industries in their search for potential areas where the discarded materials from larger scale areas of the food and agricultural chains could be utilized. They then use their chemical expertise to isolate and synthesize materials of value, which could be useful to other areas of the chemical industry.

The second has received a lot of attention in the F&F world already. Biotechnology has for some time been seen as a potentially cost effective source of creating either existing molecules for the fragrance and flavor market, as well as a potentially novel way of coming up with intermediate molecules for further derivatization. Biotech also offers the potential to utilize natural carbons as its feedstock and has the advantages of comparatively low cost feedstocks such as sugar. The F&F world clearly sees biotech as being an important part of the production and creation of future synthetics. Firmenich, Givaudan, Mane, Robertet and Symrise have all invested in this area in recent years, and while the technology still has more areas to explore it is not the exclusive domain of the larger companies as the recent announcement of the REG Life Sciences and ACS International collaboration shows.

The fragrance and flavor world knows it cannot exist without synthetics, but perhaps it is time to shift our definitions of what is natural and what is not in order to help the conscience of the consumer. Instead of thinking about the nature of the material we are using, perhaps it is time to start thinking about the nature of the feedstock we are using and put the method of production to one side.

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