The scent of roses, a bouquet of fragrance diversity.

Roses have been domesticated since antiquity for their therapeutic, cosmetic, and ornamental properties. Their floral fragrance has great economic value, which has influenced the production of rose varieties. The production of rose water and essential oil is one of the most lucrative activities, supplying bioactive molecules to the cosmetic, pharmaceutical, and therapeutic industries. In recent years, major advances in molecular genetics, genomic, and biochemical tools have paved the way for the identification of molecules that make up the specific fragrance of various rose cultivars. The aim of this review is to highlight current knowledge on metabolite profiles, and more specifically on fragrance compounds, as well as the specificities and differences between rose species and cultivars belonging to different rose sections and how they contribute to modern roses fragrance.

Sniffing Out the Sustainable Future: The Renewability Revolution in Fragrance Chemistry.

In this review, the impact of the transition from today's resource-wasting petrochemical economy towards a 100/100 renewable and biodegradable future is discussed with respect to the fragrance families: "citrus", "green", "fruity", "floral", "floriental", "oriental", "woody", "chypre" and "fougère". After benchmark data on ingredients usage, definitions on biodegradation and sustainability are given. Celebrating the 150th anniversary of synthetic vanillin, its historic synthesis from renewable starting materials serves as introduction. In the grand scheme of things, citrus scents upcycled from the beverages industry, are already an ideal case for 100/100 with new opportunities for artificial essential oils. In the fruity domain, transparent and lactonic ingredients are available in a sustainable manner. However, in the domain of green odorants, there is a lack of green chemistry for important key materials. In the floral family, renewability is more critical than biodegradability, but cost is an issue. Thanks to Ambrox and maltol, florientals and orientals will persist, while woody notes severely lack an Iso E Super replacer. In the chypre genre, patchouli became the new moss, but more musks are increasingly in demand. With their high percentage of linalool and dihydromyrcenol, the construction of fougères could well become a precedent for other families, despite challenges in vetiver and salicylates. Still, the challenges exemplified here create immense opportunities for new perfumery materials.

Contact sensitization to fragrance mix I and fragrance mix II among European dermatitis patients: A systematic review.

BACKGROUND: Fragrance substances are a frequent cause of contact allergy worldwide. Fragrance exposure varies by sex, age and possibly country, influenced by cosmetic availability, environmental conditions and cultural practices. OBJECTIVES: To systematically review and gather prevalence of sensitization to fragrance mix I (FM I) and fragrance mix II (FM II) in consecutively patch tested European dermatitis patients. METHOD: A total of 4134 publications on patch test results of European dermatitis patients, published from 1981 to 2022, were systematically reviewed according to a previously registered and published PROSPERO protocol. RESULTS: Eighty-four eligible original articles were analysed. Overall prevalence of sensitization to fragrance mix I (FM I) was 6.81% (95% CI: 6.37-7.28), and FM II was 3.64% (95% CI: 3.3-4.01). Sensitization to FM I was most prevalent in Central and Eastern Europe and to FM II in Western Europe. No clear time trends were observed. Among paediatric dermatitis patients, sensitization prevalence for FM I and FM II was 4.09% (95% CI: 3.37-4.96) and 2.17% (95% CI: 1.53-3.07). CONCLUSION: The frequency of positive patch test results for both FMI and FMII remains high. Sensitization is also prevalent among children. Enhanced regulation and labelling of cosmetic products play a vital role in averting exposure and sensitization to fragrance allergens.

Analysis of preservatives and fragrances in topical medical devices: The need for more stringent regulation.

INTRODUCTION: Medical devices (MDs) have a long history of use, and come with regulatory frameworks to ensure user safety. Although topically applied MDs in the form of gels and creams might be used on damaged skin, their composition is often similar to that of cosmetic products applicable to intact skin, especially in terms of preservatives and fragrances. However, unlike cosmetics, these products are not subject to compound-specific restrictions when used in MDs. OBJECTIVE: This study aimed to identify and quantify preservatives and fragrances in topically applied MDs and assess their safety towards the Cosmetic Regulation (EC) 1223/2009. METHOD: Sixty-nine MDs available on the EU market were subjected to previously validated liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) methods to identify and quantify occurring preservatives and fragrances. RESULTS: Findings revealed that 32% of the examined MDs did not provide comprehensive ingredient lists, leaving users uninformed about potential risks associated with product use. Furthermore, 30% of these MDs would not meet safety standards for cosmetic products and, most significantly, 13% of the analysed samples contained ingredients that are prohibited in leave-on cosmetics. CONCLUSION: Results highlight the pressing demand for more stringent requirements regarding the labelling and composition of MDs to enhance patient safety. Improved regulation and transparency can mitigate potential risks associated with the use of topically applied MDs.

Frequency and clinical relevance of contact allergy in dental patients.

BACKGROUND: While many studies have reported on occupational allergic contact dermatitis amongst dental personnel, studies on the relevance of patch testing in dental patients are scarce. OBJECTIVES: To determine the frequency and clinical relevance of contact allergy in patients with intra- and perioral complaints. METHODS: A total of 360 patients with intra- and perioral complaints suspected of having a contact allergy were patch-tested with the dental allergen series, European Baseline Series, and extended Amsterdam Baseline Series at Amsterdam University Medical Centers between January 2015 and November 2021. RESULTS: A total of 285 patients (79.2%) had a positive patch test reaction for either one (18.6%) or multiple allergens (60.6%). Sodium tetrachloropalladate was the most sensitising allergen with 98 patients (27.2%) testing positive, followed by nickel sulphate (23.3%), methylisothiazolinone (15.6%), and fragrance mix I (14.2%). Clinical relevance was found in 68 of 208 patients (32.7%), with patients having one (15.4%) or multiple (17.3%) patch test reactions clinically relevant to their (peri)oral complaints. CONCLUSIONS: Clinically relevant patch test reactions were frequently seen in dental patients. Although this study provides us with a better understanding on the frequency and clinical relevance of contact allergy in dental patients, further studies are needed to confirm our results.

Aromas: Lovely to Smell and Nice Solvents for Polyphenols? Curcumin Solubilisation Power of Fragrances and Flavours.

Natural aromas like cinnamaldehyde are suitable solvents to extract curcuminoids, the active ingredients found in the rhizomes of Curcuma longa L. In a pursuit to find other nature-based solvents, capable of solving curcumin, forty fragrances and flavours were investigated in terms of their solubilisation power. Aroma compounds were selected according to their molecular structure and functional groups. Their capabilities of solving curcumin were examined by UV-Vis spectroscopy and COSMO-RS calculations. The trends of these calculations were in accordance with the experimental solubilisation trend of the solubility screening and a list with the respective curcumin concentrations is given; σ-profiles and Gibbs free energy were considered to further investigate the solubilisation process of curcumin, which was found to be based on hydrogen bonding. High curcumin solubility was achieved in the presence of solvent (mixtures) with high hydrogen-bond-acceptor and low hydrogen-bond-donor abilities, like γ- and δ-lactones. The special case of DMSO was also examined, as the highest curcumin solubility was observed with it. Possible specific interactions of selected aroma compounds (citral and δ-hexalactone) with curcumin were investigated via 1H NMR and NOESY experiments. The tested flavours and fragrances were evaluated regarding their potential as green alternative solvents.

Mass-Spectrometry-Based Research of Cosmetic Ingredients.

Cosmetic products are chemical substances or mixtures used on the skin, hair, nails, teeth, and the mucous membranes of the oral cavity, whose use is intended to clean, protect, correct body odor, perfume, keep in good condition, or change appearance. The analysis of cosmetic ingredients is often challenging because of their huge complexity and their adulteration. Among various analytical tools, mass spectrometry (MS) has been largely used for compound detection, ingredient screening, quality control, detection of product authenticity, and health risk evaluation. This work is focused on the MS applications in detecting and quantification of some common cosmetic ingredients, i.e., preservatives, dyes, heavy metals, allergens, and bioconjugates in various matrices (leave-on or rinse-off cosmetic products). As a global view, MS-based analysis of bioconjugates is a narrow field, and LC- and GC/GC×GC-MS are widely used for the investigation of preservatives, dyes, and fragrances, while inductively coupled plasma (ICP)-MS is ideal for comprehensive analysis of heavy metals. Ambient ionization approaches and advanced separation methods (i.e., convergence chromatography (UPC2)) coupled to MS have been proven to be an excellent choice for the analysis of scented allergens. At the same time, the current paper explores the challenges of MS-based analysis for cosmetic safety studies.

Encapsulation of Fragrances in Micro- and Nano-Capsules, Polymeric Micelles, and Polymersomes.

Fragrances are ubiquitously and extensively used in everyday life and several industrial applications, including perfumes, textiles, laundry formulations, hygiene household products, and food products. However, the intrinsic volatility of these small organic molecules leaves them particularly susceptible to fast depletion from a product or from the surface they have been applied to. Encapsulation is a very effective method to limit the loss of fragrance during their use and to sustain their release. This review gives an overview of the different materials and techniques used for the encapsulation of fragrances, scents, and aromas, as well as the methods used to characterize the resulting encapsulation systems, with a particular focus on cyclodextrins, polymer microcapsules, inorganic microcapsules, block copolymer micelles, and polymersomes for fragrance encapsulation, sustained release, and controlled release.

Enzymatic properties of a non-classical aldoxime dehydratase capable of producing alkyl and arylalkyl nitriles.

Nitriles are of significant interest in the flavor and fragrance industries with potential application in cosmetics due to their higher stability than analogous aldehydes. However, the traditional methods to prepare nitriles need toxic reagents and hash conditions. This work aimed to develop a chemoenzymatic strategy to synthesize nitriles from natural aldehydes with aldoxime as the intermediate. A non-classical aldoxime dehydratase (Oxd) was discovered from the fungus Aspergillus ibericus (OxdAsp) to catalyze the dehydration of aldoximes to corresponding nitriles under mild conditions. The amino acid sequence of OxdAsp exhibits an approximately 20% identity with bacterial Oxds. OxdAsp contains a heme prosthetic group bound with the axial H287 in the catalytic pocket. The structure models of OxdAsp with substrates suggest that its catalytic triad is Y138-R141-E192, which is different from the classically bacterial Oxds of His-Arg-Ser/Thr. The catalytic mechanism of OxdAsp was proposed based on the mutagenesis of key residues. The hydroxyl group of the substrate is fixed by E192 to increase its basicity. Y138 acts as a general acid-based catalyst, and its phenolic proton is polarized by the adjacent R141. The protonated Y138 would donate a proton to the hydroxyl group of the substrate and eliminate a water molecule from aldoxime to produce nitrile. The recombinant OxdAsp can efficiently dehydrate citronellal oxime and cinnamaldoxime to citronellyl nitrile and cinnamonitrile in aqueous media, which are applied as fragrance ingredients in the food and cosmetic fields. KEY POINTS: • A novel aldoxime dehydratase from the Aspergillus genus was first characterized as a heme-binding protein. • The catalytic mechanism was predicted based on the molecular interactions of the catalytic pocket with the substrate. • A chemoenzymatic strategy was developed to synthesize nitriles from natural aldehydes with aldoxime as the intermediate.

Common fragrance chemicals activate dendritic cells in coculture with keratinocytes.

BACKGROUND: Fragrances are important contact allergens; however, investigation of their skin sensitization potency has been challenging in new approach methods (NAMs). Many fragrance chemicals are susceptible to autoxidation or can be metabolized by enzymes constitutively expressed in skin keratinocytes. Strong sensitizers can be formed in both of these processes. Further, keratinocytes can modulate the dendritic cell (DC) activation and maturation potential, a key event in the acquisition of contact allergy. OBJECTIVES: To evaluate the 2D coculture model consisting of keratinocytes and DCs using different weak to moderate sensitizing fragrance chemicals. Further, to investigate fragrances and related oxidation products in the in vitro model and compare to in vivo data. METHODS: Chemicals were tested in the coculture activation test (COCAT), consisting of HaCaT keratinocytes and THP-1 cells. THP-1 cell surface expression of costimulatory and adhesion molecules (CD86 and CD54) collected after 24 h incubation with the chemicals was analysed using flow cytometry. RESULTS: Twenty-four molecules were tested positive, three were negative (n = 27). Four pairs were evaluated, with aldehydes showing a 6- to 13-fold stronger responses compared to their corresponding alcohols. CONCLUSIONS: Results provide insight into the activation of DC in their natural environment of keratinocytes. α,ß-Unsaturated alcohols were classified as weaker sensitizers compared to their corresponding aldehydes. In sum, testing of fragrances retrieved results in good agreement with in vivo data.

The use of carvone in consecutive patch testing.

BACKGROUND: Carvone (l-carvone) is a mint-tasting flavour additive that most of us is exposed to and can cause allergic contact reactions. OBJECTIVES: To analyse the frequency and the relevance of positive carvone reactions in a dermatitis population. METHOD: A retrospective analysis of dermatitis patients consecutively tested with carvone from 2017 to 2021. Data were retrieved from the department's patch-test database. RESULTS: Of 3554 patients tested with carvone, 28 (0.79%) had a positive reaction. Carvone-positive patients had higher mean age, were significantly more likely female (p < 0.001) and had often an intraoral/lip involvement (p < 0.001). In the carvone-positive group, 50% (n = 14) had a relevant reaction, and in 4 of 14, the relevance was first revealed after test reading. Of the carvone-positive patients, 18 of 28 did not have a coexisting allergy to a fragrance/flavour allergen and of these 44% had a relevant allergy. CONCLUSIONS: The study suggests that a significant fraction of relevant carvone contact allergies may be overlooked if the allergen is not tested. Furthermore, as the exposure is widespread, inclusion of carvone in the Swedish baseline series may be justified even if the contact allergy prevalence is below 1%.

Contact sensitizations in massage therapists with occupational contact dermatitis: Patch test data of the Information Network of Departments of Dermatology, 2008-2020.

BACKGROUND: Massage therapists are particularly exposed to constituents of massage preparations, wet work and mechanical strain and therefore, at high risk to develop occupational dermatitis (OD). OBJECTIVES: To describe the sensitization spectrum of massage therapists with OD. PATIENTS AND METHODS: In a retrospective study, patch test data of patients with OD (128 massage therapists and 24 374 patients working in other professions) collected by the Network of Departments of Dermatology (IVDK, 2008-2020) were analysed. RESULTS: Hand dermatitis (91.4%) and allergic contact dermatitis (34.4%) were common in massage therapists with OD. Most frequent were sensitizations to fragrances/essential oils which were found in 54 (42.2%) massage therapists and thus, more often than in other patients with OD. Concomitant positivity to several fragrances/essential oils was frequent. In 8 (14.8%) of the 54 massage therapists, sensitizations to fragrances/essential oils were not detected with the baseline series, but only with special fragrance series. CONCLUSIONS: Allergic contact dermatitis is common in massage therapists with OD and is mainly caused by fragrances and essential oils. Hence, massage therapists should be aware of this risk. When OD is suspected, not only the baseline series, but also special fragrance series should be patch tested in this occupational group.

Fragrance allergens in cosmetic products marketed for children in Denmark.

BACKGROUND: Fragrances are among the most common contact allergens in children. Cosmetic products are the most frequent source of skin exposure. OBJECTIVE: To investigate exposure to fragrance allergens among Danish children, based on a sample of 1179 cosmetic products marketed for children. METHODS: Information regarding cosmetic products marketed to children was obtained using a non-profit smartphone application registry, with data from December 2015 to November 2022. RESULTS: The number of validated products was 26 537, of which 1349 marketed for children. After elimination of duplicates, 1179 (4.4%) individual products remained. The majority 53.8% (634/1179) of the products were fragranced. The highest frequency of declared fragrances was found in 'Facial care'-products: 93.0% (80/86), of which 97.7% were lip balms. The highest number of labelled fragrances in one single product (n = 16) was found in a baby perfume. Fragrance mix I (FMI) or II (FMII) allergens were found in 25.3% (298/1179) of the products. Limonene and linalool were the two most frequently labelled fragrance allergens. CONCLUSION: Children can be exposed to a vast number of fragrance allergens from scented cosmetic products. Allergens from FM I and FMII are widely used in cosmetic products marketed to children. Patch testing with FMI and FMII remains relevant in children.

Forgotten Perfumery Plants - Part II: New Insights into the Development of Novel Fragrant Ingredients - Hawthorn Case Study.

Naturalness is gaining ground among perfumers and the use of natural raw materials is spreading in perfumery. Forgotten perfumery plants are of concern to develop innovative and natural ingredients for modern perfume industries. The main purpose of this study was to evaluate the potential interest of Crataegus monogyna Jacq. extracts as fragrance ingredient. To this end, various extractions, phytochemical characterizations and organoleptic evaluations of hawthorn were conducted on fresh, frozen, and dried flowering aerial parts, to identify those most likely to be of interest. More than a hundred compounds, anisaldehyde being the predominant one, were characterized for the first time in the volatile fraction, using HS-SPME-GC-MS technology. Impact of plant treatment and harvest year on the extracts were also discussed. From this work, a new and natural hawthorn-based ingredient was developed to complete the perfumers' palette.

Biotechnologies in Perfume Manufacturing: Metabolic Engineering of Terpenoid Biosynthesis.

The fragrance industry is increasingly turning to biotechnology to produce sustainable and high-quality fragrance ingredients. Microbial-based approaches have been found to be particularly promising, as they offer a more practical, economical and sustainable alternative to plant-based biotechnological methods for producing terpene derivatives of perfumery interest. Among the evaluated works, the heterologous expression of both terpene synthase and mevalonate pathway into Escherichia coli has shown the highest yields. Biotechnology solutions have the potential to help address the growing demand for sustainable and high-quality fragrance ingredients in an economically viable and responsible manner. These approaches can help compensate for supply issues of rare or impermanent raw materials, while also meeting the increasing demand for sustainable ingredients and processes. Although scaling up biotransformation processes can present challenges, they also offer advantages in terms of safety and energy savings. Exploring microbial cell factories for the production of natural fragrance compounds is a promising solution to both supply difficulties and the demand for sustainable ingredients and processes in the fragrance industry.

Release of Volatile Cyclopentanone Derivatives from Imidazolidin-4-One Profragrances in a Fabric Softener Application.

Imidazolidin-4-ones were investigated as hydrolytically cleavable profragrances to increase the long-lastingness of perfume perception in a fabric softener application. The reaction of different amino acid amides with 2-alkyl- or 2-alkenylcyclopentanones as the model fragrances to be released afforded the corresponding bi- or tricyclic imidazolidin-4-ones as mixtures of diastereoisomers, which were separated by column chromatography. In polar solution, the different stereoisomers equilibrated under thermodynamic conditions to form mixtures with constant isomeric distributions, as shown by NMR spectroscopy. Dynamic headspace analysis on dry cotton demonstrated the controlled fragrance release from the precursors in practical application. Under non-equilibrium conditions (continuous evaporation of the fragrance) and depending on the structure and stereochemistry of the profragrances, the recorded headspace concentrations of the fragrance released from the precursors increased by a factor of 2 up to 100 with respect to the unmodified reference. Prolinamide-based precursors released the highest amount of fragrance and were thus found to be particularly suitable for prolonging the evaporation of cyclopentanone-derived fragrances on a dry cotton surface.

GC-MS Determination of Undeclared Phthalate Esters in Commercial Fragrances: Occurrence, Profiles and Assessment of Carcinogenic and Non-Carcinogenic Risk Associated with Their Consumption among Adult Consumers.

Phthalates are chemicals that are extensively used in the manufacturing of cosmetic products. The occurrence of phthalate esters in personal care products may pose adverse effects on consumers' health. In this work, a simple, fast and reliable GC-MS method was developed and validated for concurrent determination of phthalate esters in fragrances. Simple procedures were employed for sample preparation and clean up. The recoveries achieved were in the range of 94.9% to 105.6% with RSD ≤ 4.06. The detection limits were in the range of 0.0010 to 0.0021 µg/mL. The GC-MS method was utilized to investigate the occurrence of phthalate esters in different brands of perfumes sold in the Saudi Arabian market. Diethyl phthalate was detected in all analyzed samples, with a maximum concentration of 5766 µg/mL, and di (2-ethylhexyl) phthalate was detected in the majority of the analyzed samples (95%), with a mean concentration of 55.9 µg/mL and a highest concentration of 377.7 µg/mL. Additionally, the exposure to phthalate esters due to the consumption of perfumes was investigated among the adult Saudi population for the first time. It was found that the systemic exposure dose, measured at mean concentrations, ranged from 4.59 × 10-4 to 4.29 × 10-2 (mg/kg/day) and from 5.00 × 10-4 to 4.68 × 10-2 (mg/kg/day) for male and female users, respectively. Moreover, the non-carcinogenic risk of the investigated phthalate esters and the carcinogenic risk of DEHP were also evaluated. The non-carcinogenic risk values of the detected phthalate esters were greater than 100, which indicates that exposure to these phthalate esters is unlikely to produce non-carcinogenic health effects to consumers. However, at maximum DEHP concentrations, the carcinogenic risk values were 5.49 × 10-5 for male users and 5.98 × 10-5 for female users, which indicates the possibility of DEHP to pose a carcinogenic health effect if present at high levels. Regular monitoring of undeclared chemicals such as phthalate esters in personal care products marketed in Saudi Arabia is extremely important to ensure consumers' safety. To the best of the authors' knowledge, this is the first study to assess the health risk associated with consumption of perfumes in Saudi Arabia.

An Enantiospecific Synthesis of 5-epi-α-Bulnesene.

As a result of its unique fragrance and wider role in traditional medicine, agarwood produced in Aquilaria spp. and certain other trees has been harvested to near extinction as a natural phenomenon. Artificially induced agarwood production in Aquilaria plantations has sated some of the demand although the product quality is variable. Synthetic chemistry may have a role to play in providing sustainable routes to many of the fragrant components identified in agarwood and its smoke when burnt as incense. In this work, we report efforts towards a total synthesis of the guaiane sesquiterpene α-bulnesene, which is found, along with its more fragrant oxidised derivatives, in agarwood. Following the ring-expansion of (R)-carvone using reported procedures, α-butenylation gave a substrate for samarium diiodide mediated reductive cyclisation, the two butenyl epimers of the substrate each leading to a single bicyclic alcohol (24 and 25). Overall homoconjugate hydride reduction of one of these alcohols was achieved by Lewis acid-mediated ionisation and then hydride transfer from triethylsilane to complete an overall seven-step synthesis of 5-epi-α-bulnesene. This new synthesis paves the way for short routes to both α-bulnesene enantiomers and a study of their aerial and enzymatic oxidation products.

Biotechnology - A Tool to Transform Givaudan's Fragrance Ingredients Palette.

To support perfumers in their creation of olfactive signatures resulting in unique and instantly recognizable perfumes, there is a constant demand for the development of new odorant molecules and of novel processes for their production. Increasing the sustainability of both the molecules and the processes is a crucial activity at Givaudan. Biocatalysis has the potential to positively influence metrics applied at Givaudan that drive and measure our ambition to innovate responsibly, which is summarized in the FiveCarbon Path™. It targets an increased use of renewable carbon, carbon efficiency in synthesis, and the production of powerful and biodegradable odorant molecules while maximizing the use of upcycled carbon available from waste and side streams. This review illustrates with some examples how enzymes selected from the oxidoreductase and isomerase enzyme classes are applied at Givaudan for the preparation of odorant molecules both at laboratory and industrial scale.

Biomimetic Synthesis of Nor-Cedrene and Nor-Isozizaene Sesquiterpenoids and Exploration of Their Olfactive Properties.

We report the preparation of nor-bisabolyl epoxide 13 and its use as a common biomimetic intermediate for the synthesis of nor-sesquiterpenoids. Through a cationic cyclization cascade pathway, we prepared nor-isozizaenol 25, ultimately constituting an eight-step access to this complex sesquiterpenoid from inexpensive and abundant starting materials. Using a radical cyclization cascade pathway, we prepared nor-cedryl alcohol 26 from the same intermediate. Derivatization of these two products led to the discovery of two potent woody odorants of interest in perfumery.