Dihydroxyacetone: An Updated Insight into an Important Bioproduct

Abstract Currently obtained from glycerol through microbial fermentation, the demand of 1,3‐dihydroxyacetone (DHA) has significantly grown during the course of the last decade, driven by the consumer passion for a tan and increasing awareness of UV photodamage to the skin caused by prolonged exposure to the sun. We provide an updated bioeconomy perspective into a valued bioproduct (DHA), whose supply and production from glycerol, we argue in this study, will rapidly expand and diversify, with important global health benefits.


Introduction
Commercially obtained from glycerol through microbial fermentation,o ver the acetic acid bacteria, 1,3-dihydroxyacetone (DHA;1 ,3-dihydroxy-2-propanone) is the simplest ketone form of sugars( ketoses) and an important intermediate in carbohydrate metabolism in higherp lants and animalsf ormed during glycolysis. [1] In the solid-state, DHA exists as ad imer with a dioxan structure, which, upon dissolution,r eadily dissociates into am ixture of free carbonyl and hydrated monomers (Scheme 1). [2] In at ypical Maillardr eaction (the reaction of sugars with amino acids, ubiquitous in cookinga nd, thus, in dailyl ife), [3] DHA reacts with the protein keratin on the skin surface, producing pigmentsc alled melanoidins,p olymericc ompounds that are linked by lysine chains to the proteins of the stratum corneum. [4] Its browning effects, exploited also to mask the effects of vitiligo (treatment with a6%D HA cream,l eadingt o9 0% satisfactiono fv itiligo patients), [5] were discovered by accident in the 1930s:a ttempts to treat diabetes patients with oral doses of DHA resultedi nadeep yellow coloring of gums. [6] The first self-tanning lotion is said to have been commercialized in 1945 in California, [6] thoughm ost reports agree that sunless tanning products debuted on the US cosmetic market in 1959. [7] In any case, in the 1950s, Wittgenstein rediscovered the skin browning caused by DHA while studying the effect of large oral doses of DHA in children with glycogen storage disease. The skin of the children that casually and accidentally came into contact with DHA in solution turned brown, whereas textiles didn ot. [8] Wittgenstein and Berry concluded their 1960 "artificialt an" study [9] by reporting findings on the mechanism of skin staining with DHA, stating that it "appears to proceed through combination with free amino groups in skin proteins, and particularly by combination of DHA with the free guanido group in arginine". [9] Fifty five years later (in 2015), driven by consumer demand for af ashionable tan throughout the whole year and by concomitanti ncreasing awareness of UV photodamage hazards, [10] one of the leading self-tanning product manufacturers sold out ay ear's worth of stock of its in-shower tanning lotion in only one day. [11] Already in 2011, 41 %o fw omen in the UK were reported to use self-tanning products. [12] In this study, we provide an updated bioeconomyp erspective into av alued bioproduct (DHA), whose supply and productionf rom readily available glycerol, we argue, will rapidlye xpand and diversify.

Quality and Health Aspects
DHA has been approved across the world for use in self-tanning products for several decades. To quote an industry's practitioner "no other substance, so far,h as been capable to provide more satisfactory or more lasting results". [6] In the EU, for example, the Scientific Committee on Consumer Safety evaluated the safety of DHA as as elf-tanningi ngredient in cosmetic Currently obtained from glycerol through microbial fermentation, the demand of 1,3-dihydroxyacetone (DHA)h as significantly grown during the course of the last decade, driven by the consumer passion for at an and increasing awareness of UV photodamage to the skin caused by prolonged exposure to the sun.W ep rovidea nu pdated bioeconomy perspective into av alued bioproduct (DHA), whose supply and production from glycerol, we argue in this study,w ill rapidly expand and diversify,w ith importantglobal health benefits. formulations, in 2010, and concluded that the use of DHA in skin formulations at concentrationsu pt o1 0% will not pose a risk to the health of the consumer. [13] Several medicala ssociations recommend it as as afer alternative to UV radiationf rom the sun or from hazardoust anning beds ("we don't callt hose UV tanning booths;w ecall them tanning coffins"). [14] Exposure to UV radiation and, in particular,t oi ndoor tanning beds can cause skin cancer, skin burns, and premature skin aging.C urrent misconceptions among the general public about the established risks of DHA-containings unless tanning products, as well as guidelines for their proper use,h ave been reviewed lately. [15] Sunless tanning products containing DHA produce, within a few hours, ar elativelyl ong-lasting tan (from 3t o1 0days, depending on the formulation), withoutt he risks of photodamage. As mentioned above, this reactioni sl imited to the stratum corneum (the outer layer of human skin comprised of dead cells), and in vitro skin absorption studies have found no significant systemic absorption of DHA when appliedt opically to the skin. [16] On the other hand, the Maillard reaction between DHA and amino acids generates reactive oxygen species (ROS), namely highly reactive free radicals, [17] that may attack the cell structures and degrade collagen and elastin fibers,p romoting premature skin aging andw rinkle formation.T he process is accelerated under sun radiation,w ith more than 180 % additional radicals generatedd uring sun exposure with respect to untreated skin, thus requiring short or no sun exposure when self-tannersa re used. [18] It is also relevant here to notice how,w hen appliedo nt he skin, at ypical DHA-based creama ttenuatest he sunlight-induced formation of vitamin D. [19] Owing to the formationo fR OS, it is perhaps not surprising that DHA induces DNA damage. [20] More recently,s cholars in the US confirmed and expandedt hese results, showingt hat exposing viable cells to DHA significantly alters the cell microenvironment, promoting the induction of cell death, in particular through internal exposures from inhalation, absorption into mucous membranes, or through broken skin. [21] The team concluded that more work is necessary to understand the complex metabolic eventsi nduced by exposure to DHA.
Meanwhile, as DHA continuest ob ea pproved as as elf-tanning ingredient, this is ac lear case in which chemical innovation aimed at product quality improvement, concomitantly leads to minimized potential health and safety risks, while still avoidingt he UV-induceds kin photodamage of conventional tanning.
Conventional self-tanning formulationsu se relatively high levels of DHA (up to 15 %), causingu nnatural orange tones, smell due to the Maillard reaction (a burnt biscuit stench), and unevend eposition of color and skind ryness. Successful efforts devotedt os olve these issues and improvet he artificial tanning process include:i ncreased stability (avoiding incompatible ingredients in the final formulation,w hose pH must be below 5f or DHA stability);r educed damage from free radicals (throught he addition of powerful natural antioxidants);e nhanced tan, lastingl onger and providing am ore pleasing color tone (by addinge rythrulose, another keto-sugar occurring in red, to the formulation).
Further improvements originate from purer DHA made available by suppliers, preferably in powder form (the degradation of DHA in this form is negligible when stored at room temperature for one year;w hereas a1 0% DHA aqueous solution stored at 40 8Cf or 6months shows al oss of approximately 25 %o ft he active ingredient). [22] An on-exhaustive Review [23] of recent progress startedi n 2011, when research chemists at al arge chemical company introducedanew formulation, in which DHA wasadded in al ow amount (from ac oncentration of ca. 0.01 %t oc a. 0.9 %) to a topical cosmetic base comprisingm oisturizers, vitamins, botanicals,o ils, and sunscreen agents. This was formulated as an emulsion with the aid of an emulsifier suitable for topical use on skin, such as cetearyl glucoside, whichs trengthens the lipid structure within the skin, establishing ab arriert om oisture loss. [23] Other examples of similar commercial formulations include hyaluronic acid (to keep the skin hydrated), hemp seed oil extract containinga ll 21 amino acids for ah ealthys kin, black tea, and Aloe Vera antioxidantsw ith soothingp roperties. [24] Furthermore, some of the DHA added to the formulation is microencapsulated, so as to provide al ong-lasting tan through the slow releaseo ft he entrapped molecules as well as to assureal onger shelf life.
Another new formulation consists of tailor-made tanning products based on liquid concentrates,b lending DHA with raspberryo il and Aloe Vera, which users can combine with their moisturizer to create multi-tasking skincare products, with even sleep-mask tan formulations to replace conventional nightly skincare masks. [25] The list concludes with as elf-tanning product that includes ab lend of EcoCert-certified DHA and erythrulose with cardamom seed oil and five aromatic teas, so as to avoid the use of any phthalate-containing fragrance to mask the unpleasant smell that often characterizes sunless tanners:n atural pigmentsb eet root, blue green algae, caramel, and cocoa powder. [26] In general, the new formulations make the skin appear more moisturized, and the color more naturala nd more radiant over an extended period of time, thereby solving the old orangelookingand odor issues typical of former self-tanning compositions. [23] With today's advanced formulations, no professional application of sunless tanning products or complex skin preparation steps are required, with products ranging from portable lotions to post-shower formulations.

Market and Production
The globals elf-tanning product market was recently forecast to generate $1.011millionr evenuei n2 017. [27] For comparison, global revenue in 2014 was around$ 775 million. [27] In the US, from 2011to2016, the market grew by 27 %(from $135 million to $171 million), and by another 19 %in2 017 alone. [11] In 2013, Dobos emphasized how improved self-tanning products that were capable of gradually providing am ore natural color had become so successfult hat consumer demand resultedi np roduct shortages, causing "bidding wars" [7] on a well-known online shop. By the same token, with several million cases of non-melanoma skin cancert reated every year ChemistryOpen 2018, 7,233 -236 www.chemistryopen.org across the world, the use of self-tanning products by increasingly aware consumers, willing to avoid the hazards of longterm sun exposure, will only increase. This means that there is an eed to expand and renew the conventional production of DHA. Accordingly,b ya nalyzing the global DHA industry,a market research company recently concluded that the "development of technology is the key". [28] The industrialp roduction of DHA involves the biotransformationo fp ure glyceroli n aqueous solution through the free cells of the acetic acid bacteria Gluconobactero xydans in ar eactionc atalyzed by glycerol dehydrogenase. [29] This microbial process typicallyr equires reaction times of up to 70 h, with amaximum yield of 40 %, leading to ahigh production cost.
Concomitantt om arket expansion, numerous attempts have been devoted to improving the conventionalm ethod. Suffice it to mention here, the conversion of glycerol to DHA has been mediated by the glycerold ehydrogenase enzyme encapsulatedi nm agnetic mesoporouss ilica, with the solidc atalyst being easily separated from the reactionm ixture (by using a simple magnet) and recycled in seven consecutive cycles. [30] The use of ar aw biodiesel glycerol by-product in place of pure glycerolh as also been converted over an alginate-immobilized biocatalyst (cell extract), resulting in as imilar concentrationo f DHA (8.7 gL À1 )i no nly half the time. [31] Figures on the DHA market volume greatly differ.A2010s cientific article from Japanese scholars [32] suggests that the annualp roduction of DHA would amountt o2 000 tons. Indeed,a sachemical imported in the EU market in quantities of 1000-10000 tons per year,D HA appears in the European Chemicals Agencyr egister,i nw hich two new suppliers registered as of late 2017. [33] Similarly,p ubliclya vailable prices forD HA differ greatly. Scholars in South Korea in 2015 reported ap rice of $150 kg À1 , [30 ] emphasizing how attractive this made the conversion of glycerolt oD HA, given the low price of glycerol ($0.35 kg À1 ). Glycerol derived in huge amountsf rom biodiesel manufacturing has become an inexpensive platform chemical. [34] All of these arguments anticipate the forthcomingd evelopment and commercialization of chemical catalysis affording high yields of DHA, especiallyi nv iew of low capital and operational costs.
Af irst major advance was reported by Koper and co-workers in 2012, as they obtained 100 %s electivity in the electro-oxidation of glycerolt oD HA at the surface of aP tBi/C electrode modifiedw ith bismuth. [35] No chemical oxidantw as required besides the electric current.
Thoughl ess selective, mediating the electrocatalytic oxidation of glycerolt oD HA in 61.4 %y ield (anda bout 15 %y ield of glyceraldehyde) at ag lycerolc onversion of 90.3 %u nder moderate voltage (0.797 Vv s. SHE, standard hydrogen electrode), the PtSb/C electrocatalytic electrode was shown,b ys cholars in South Korea in 2016, to be highly stable. Reusedf or five consecutive reactionc ycles, after washings everalt imes with water and drying in an oven at 343 Kf or 2hprior to reuse, the electrocatalytic electrode retained its high original activity and selectivity,a ffording glycerol conversion and selectivity values with variations of only around 5% (Figure 1). [36] Another major advance was reported by Xu and co-workers in 2013, [37] when they showed how to heterogeneously oxidize glyceroltoD HA by using O 2 as the primary oxidantinw ater,a t room temperature and atmospheric pressure, over an anostructured flower-like Bi 2 WO 6 photocatalyst, under visible-light irradiation. Though carried out in ad iluted 0.067 m solution, the new photocatalytic process afforded unprecedented yield (87 %) and selectivity (91 %) values. The process was even im-proved2years later with the sol-gel encapsulation of the photocatalyst,w hich resulted in at hreefold enhanced reaction rate, while retaining the striking selectivity to DHA. [38] Almost concomitantly,asimilar technology was developed in Germany,b ased on ah eterogeneously photocatalyzed process under normalc onditions (room temperature, ambient pressure) using a-Bi 2 O 3 /Pt powder as the visible-light photocatalyst from a concentrated aqueous solution of glycerol( 1:1g lycerol/water by volume). [39] Remarkably,acompany in Germany already offers the technology for transfer to industry. [40]

Outlook and Conclusions
Since the 1920s,w hen tanning was made trendy by Coco Chanel, [41] at an has become highly fashionable across the world. Based on the use of new bioproducts and microencapsulation technology,s ignificant progress in self-tanning products using DHA as the active ingredient has been able to solve the main issues of former self-tan formulations.A st hese new formulations penetrate the market, the negative reputationo f self-tanning products will becomeo bsolete, and self-tan utilization may become as commonplace as the use of lipsticks and other makeup. Advanced producerse ven offer online applications (TanM irror), allowing users to take ap hotograph and see how they will look after application.D riven by product quality,s uch progress has afforded benefits to health and safety issues, as new formulations comprise muchl ower amountsofD HA, containing powerful naturala ntioxidants that are capable to quencht he ROS free radicals generatedo nt he skin upon the application. This resulted in anet positivec ontribution to health by avoiding prolonged exposure to the UV radiation, both under the sun and in tanning booths and beds. Globally,t his has led to ab ooming demand of high-purity and possibly even certified DHA. Although market figures are generally not publicly available, we assume that the current annualD HA production has more than doubled from the 2000 tons produced in 2009/2010. Along with advances in conventional DHA manufacturing through glycerol microbial oxidation, the aforementioned high demand and sustained high prices open the route to the introduction of industrial DHA catalytic syntheses. In particular,w ea rgue, in this study, that the oxidant-free electrocatalytic oxidationo fg lycerol over new and highly stable electrodes [37] and the aerobic photooxidation driven by solar light [35] are ideally suited for industrialization. Thisa rticle offers an updated bioeconomyp erspective that will be useful to researchers and industry practitioners in accelerating the progress of DHA manufacturing and the productiono fs elf-tan formulations capable of deploying the full potentialoft his unique molecule.