Lilial
Lilial, chemically 2-(4-tert-butylbenzyl)propanal (CAS 80-54-6), is a synthetic aldehyde compound employed as a fragrance ingredient to impart a fresh, green-floral scent reminiscent of lily muguet in perfumes, cosmetics, and detergents.[1][2] Widely utilized for its diffusive and substantive properties that enhance floral accords, Lilial synergizes with notes like phenylethyl alcohol and citronellol to amplify radiance in compositions. However, empirical toxicological data indicating reproductive toxicity, including impaired fertility and developmental effects in animal models, led to its classification as a Category 1B reprotoxicant under EU regulations.[3] Consequently, Lilial was prohibited in cosmetic products across the European Union and Northern Ireland effective March 2022, prompting industry shifts toward alternatives despite its prior prevalence in up to 97% of certain fragrance formulations.[4] Additionally, it is recognized as a potential skin sensitizer associated with allergic contact dermatitis.[5]
Nomenclature and Chemical Identity
Synonyms and Classification
Lilial is the trade name for the synthetic fragrance compound 2-(4-tert-butylbenzyl)propanal, also known by synonyms including butylphenyl methylpropional (BMHCA), lysmeral, lily aldehyde, p-tert-butyl-α-methylhydrocinnamaldehyde, and Lilyal.[6][7][8] The compound bears CAS Registry Number 80-54-6 and EINECS number 201-289-8.[6][9] Chemically, Lilial belongs to the class of aromatic aldehydes, characterized by a benzene ring substituted with a tert-butyl group and an α-methylated propanal side chain, imparting a fresh, lily-of-the-valley odor profile used in perfumery.[6][10] It is produced industrially as a single enantiomer or racemate, with no significant natural occurrence documented beyond trace levels in certain plants.[6] Under the European Union Classification, Labelling and Packaging (CLP) Regulation (EC) No 1272/2008, Lilial is classified as a reprotoxic substance category 1B (H360FD: may damage fertility and the unborn child), leading to its prohibition in cosmetic products effective March 1, 2022.[7][11] This classification stems from animal studies indicating reproductive toxicity at doses around 150-500 mg/kg body weight per day, though human exposure levels in fragrances were typically far lower.[3] It is also recognized as a potential skin sensitizer associated with contact dermatitis in susceptible individuals.[12]Molecular Formula and Structure
Lilial has the molecular formula C14H20O.[1][2] Its IUPAC name is 2-(4-tert-butylphenyl)propanal, also known as 2-(4-tert-butylbenzyl)propionaldehyde.[6][13] The chemical structure consists of a benzene ring with a tert-butyl substituent (-C(CH3)3) at the 4-position and a side chain at the 1-position comprising a methylene group linked to a chiral carbon bearing a methyl group and a formyl group (-CH2-CH(CH3)CHO).[1][2] This aldehyde functionality imparts the characteristic lily-of-the-valley odor profile associated with the compound.[8] The molecular weight is 204.31 g/mol.[6][14]Physical and Chemical Properties
Appearance, Odor, and Sensory Characteristics
Lilial is a colorless to pale yellow clear oily liquid at room temperature.[15][13] Its odor is characterized as fresh, green, and floral, with prominent muguet (lily-of-the-valley) facets, accompanied by watery, powdery, and subtle cumin undertones.[15][13] In perfumery applications, it delivers a light, blooming floral profile with medium odor strength and notable substantivity, persisting up to 236 hours in formulations.[15] The compound's sensory appeal stems primarily from its (R)-enantiomer, which imparts the intense lily-like scent, whereas the (S)-enantiomer contributes minimally to the overall aroma in racemic mixtures.[16]Solubility, Stability, and Reactivity
Lilial exhibits low solubility in water, with values reported as 0.033 g/L at 20°C.[17] This hydrophobicity is reflected in its octanol-water partition coefficient (logP) of 4.2 at 24°C, facilitating solubility in organic solvents such as ethanol, paraffin oil, and vegetable oils.[18] The compound demonstrates chemical stability under standard storage conditions, including protection from excessive heat, light, and ignition sources, with no hazardous decomposition expected in properly handled formulations.[19] However, exposure to air induces slow oxidation, particularly in aqueous solutions at pH 7 and 25°C, leading to degradation products.[3] Lilial shows no significant hydrolytic instability but requires antioxidants like alpha-tocopherol in some applications to mitigate oxidative loss.[3] Reactivity is typical of aliphatic aldehydes, with incompatibility toward strong oxidizing agents, acids, and bases, which can promote oxidation to the corresponding carboxylic acid, acetal formation, or unintended condensations.[20] [21] No explosive or highly exothermal reactions occur under normal conditions, though contact with reducing agents or alkalies should be avoided to prevent potential polymerization or reduction.[22]Synthesis and Manufacturing
Synthetic Routes
The primary synthetic route to Lilial, chemically 2-(4-tert-butylbenzyl)propanal, involves a crossed aldol condensation between 4-tert-butylbenzaldehyde and propionaldehyde, yielding the intermediate 4-tert-butyl-α-methylcinnamaldehyde, followed by selective hydrogenation of the α,β-unsaturated double bond.[13] This process is the dominant industrial method, leveraging the aromatic aldehyde's lack of α-hydrogens to favor crossed product formation under basic conditions, such as 1-5 mol% NaOH in ethanol at 0-5°C, achieving yields exceeding 85% for the condensation step.[23] Hydrogenation employs catalysts like 5% Pd/C at 3 atm and room temperature, or noble metals such as Pd, Rh, or Pd-Pr₂O₃ on Al₂O₃ supports, delivering >95% conversion and >98% selectivity to the saturated aldehyde while preserving the carbonyl.[13][23] Industrial variants utilize continuous flow reactors with MgO/alumina for condensation at 80-100°C and Ni or Cu-chromite for hydrogenation at 100-150°C under 10-20 atm, supporting global production capacities over 5,000 metric tons annually.[23] Alternative laboratory-scale routes include acetal protection of 4-tert-butylbenzaldehyde as its dimethyl acetal, reaction with propionaldehyde enolate generated by LDA at -78°C, dehydration, and hydrogenation, which enables stereocontrol with chiral catalysts like proline derivatives for up to 92% enantiomeric excess.[23] Friedel-Crafts alkylation of 4-tert-butylbenzene with methacrolein or its diacetate provides another pathway, analogous to cyclamenaldehyde synthesis, though less selective industrially due to polyalkylation risks.[13] Specialized methods encompass Rh-catalyzed hydroformylation of 1-(4-tert-butylphenyl)-1-methoxypropene followed by partial hydrogenation, or Pd-catalyzed coupling of 4-tert-butylphenyl halides with methallyl alcohol; these are niche, offering higher purity but increased complexity and cost compared to the aldol route.[13] Dehydrogenation of 3-(4-tert-butylphenyl)-2-methylpropanol over silver catalysts represents a further variant, typically for small-scale refinement rather than primary production.[13]Industrial Production Methods
Lilial is manufactured on an industrial scale predominantly through a two-step process beginning with the base-catalyzed aldol condensation of 4-tert-butylbenzaldehyde and propanal (propionaldehyde), typically using sodium hydroxide in an alcoholic solvent to form the intermediate α,β-unsaturated aldehyde, 2-[(4-tert-butylphenyl)methylidene]propanal.[24] [13] This condensation step proceeds under controlled conditions to minimize side reactions, such as self-condensation of propanal, and is often conducted at temperatures around 20–40°C to achieve high selectivity toward the desired crossed aldol product.[25] The unsaturated intermediate undergoes selective hydrogenation, commonly using a palladium or nickel catalyst under hydrogen pressure (typically 1–5 bar) at moderate temperatures (50–100°C), to saturate the double bond and yield Lilial as a racemic mixture of (R)- and (S)-enantiomers in a 1:1 ratio.[5] [25] The process is optimized for high yield (often exceeding 90%) and purity through distillation, with major producers like BASF employing continuous flow or batch reactors scaled for tonnage production to meet fragrance industry demands.[26] Alternative routes, such as modifications involving different catalysts or solvents, exist but are less common due to lower efficiency compared to the standard aldol-hydrogenation sequence.[27]Commercial Applications
Use in Fragrances and Perfumery
Lilial serves as a key synthetic fragrance ingredient in perfumery, prized for its ability to evoke the subtle, fresh scent of lily-of-the-valley (muguet), with characteristic light green, floral, and aldehydic notes.[28][29] This aldehyde contributes watery, clean, and slightly powdery facets, enabling perfumers to construct white floral accords and enhance aldehydic compositions across fine fragrances, soaps, and household products. Its (R)-enantiomer delivers the primary odor intensity, while the compound's overall profile integrates seamlessly with rose, jasmine, violet, and green odorants for balanced, spring-like effects.[30] In formulation, Lilial is typically incorporated at levels of 0.5% to 3% in fine fragrance compounds for optimal impact without overpowering delicacy, though broader applications allow up to 15% in perfume bases depending on the category.[29] It exhibits high performance ratings (9/10) in alcoholic perfumes, lotions, shampoos, and bath gels, owing to its stability and longevity in diverse matrices.[29] Perfumers often pair it with hedione, citronellol, and phenylethyl alcohol to amplify floral hearts and add diffusion, making it suitable for both modern clean scents and classic floral blends.[31] Prior to regulatory restrictions, Lilial's scalability and consistent synthetic production from propionaldehyde precursors supported its widespread adoption in commercial perfumery since the mid-20th century, underpinning elegant, versatile accords in products ranging from eau de parfums to fabric softeners.[28][29] The International Fragrance Association (IFRA) previously capped its use at 1.4% in finished products to ensure safety margins, reflecting its established role in sensory-driven formulations.[6]Applications in Cosmetics and Household Products
Butylphenyl methylpropional, commonly known as Lilial, functions primarily as a synthetic fragrance ingredient in cosmetics, providing a fresh, floral muguet (lily-of-the-valley) odor profile that enhances product sensory appeal.[11] In cosmetic formulations, it has been employed in rinse-off products such as soaps, shampoos, shower gels, and bath cleansers, typically at concentrations up to 0.1% according to industry standards for safety evaluation.[3] Leave-on cosmetics, including body lotions (up to 0.06%), hand creams (up to 0.05%), face creams (up to 0.05%), and make-up products like foundations (up to 0.04%), have also incorporated Lilial to impart long-lasting scent without requiring rinsing.[3] Deodorants have utilized it at levels as low as 0.09% to avoid excessive dermal exposure.[3] These applications leverage Lilial's stability in aqueous and emulsified systems, though its use in sprayable cosmetics has been deemed unsafe due to potential inhalation risks.[3]| Product Category | Example Products | Maximum Proposed Concentration (IFRA Standards) |
|---|---|---|
| Rinse-off | Soaps, shampoos, shower gels | 0.1% |
| Leave-on dermal | Body lotions, hand/face creams | 0.05–0.06% |
| Make-up | Foundations, eye products | 0.04% |
| Deodorants | Antiperspirants | 0.09% |
Toxicological Studies
Acute and Subchronic Toxicity Data
Acute toxicity studies indicate low hazard potential for Lilial (p-t-Butyl-α-methylhydrocinnamaldehyde). Oral LD50 values in rats range from 1390 mg/kg body weight (bw) (95% confidence interval: 1019–1867 mg/kg bw) to 3700 mg/kg bw (95% confidence interval: 2600–5400 mg/kg bw), depending on the study protocol and analysis method.[3] Dermal LD50 in rabbits exceeds 2000 mg/kg bw, with no systemic toxicity or mortality observed.[3] Inhalation exposure data are limited due to low volatility (vapor pressure 0.0025 hPa at 20°C), but rats exposed to saturated atmospheres showed no mortality, though minor systemic effects were noted without reaching lethal thresholds.[3] Subchronic toxicity assessments, primarily via oral gavage in rats, reveal dose-dependent effects on systemic parameters and male reproductive organs. In a 90-day study compliant with good laboratory practice (GLP), the no-observed-adverse-effect level (NOAEL) for systemic toxicity (including liver hypertrophy, reduced body weight, and adrenal changes in females) was 5 mg/kg bw/day, while the NOAEL for testicular toxicity (atrophy and degeneration in males) was 25 mg/kg bw/day; adverse effects emerged at ≥50 mg/kg bw/day for testes and ≥25 mg/kg bw/day for systemic endpoints.[35] Shorter repeated-dose oral studies (5–14 days) in rats corroborated testicular effects at ≥50 mg/kg bw/day, with liver and body weight alterations at similar doses.[3] A dermal repeat-dose study (5 days in rats) showed testicular toxicity only at the high dose of 2000 mg/kg bw/day.[35] No dedicated 90-day dermal or inhalation subchronic studies were identified.[3] These findings stem from industry-submitted data reviewed by regulatory bodies, with effects mechanistically linked to hepatic enzyme induction and hormonal disruption at higher exposures.[36]Reproductive and Endocrine Effects in Animal Models
In male Wistar rats administered Lilial orally via gavage, repeated-dose toxicity studies (e.g., 90-day exposure) revealed testicular atrophy, reduced sperm motility, and impaired spermatogenesis at doses ≥50 mg/kg body weight per day (bw/day), with a no-observed-adverse-effect level (NOAEL) of 25 mg/kg bw/day for male reproductive endpoints.[3][36] Similar effects, including aspermia and testes degeneration, were noted in a one-generation reproduction study at ≥62.6 mg/kg bw/day, yielding a NOAEL of 28.7 mg/kg bw/day.[37] These findings indicate rats as the most sensitive species for male reproductive toxicity compared to dogs (NOAEL 40 mg/kg bw/day for testicular effects) and limited data in mice, rabbits, and monkeys showing lesser or no effects.[3][37] Developmental toxicity assessments in pregnant Wistar rats (OECD TG 414, gestational days 6-20 via gavage) demonstrated reduced fetal body weights, increased skeletal variations, and tissue malformations at ≥12.7 mg/kg bw/day, with a NOAEL of 4.1 mg/kg bw/day; these outcomes were associated with maternal toxicity rather than selective teratogenicity.[36][3] An extended one-generation reproduction toxicity study (OECD TG 443) in Wistar rats (doses up to 15.1 mg/kg bw/day via gavage, spanning pre-mating to lactation) found no impacts on fertility indices, estrous cycles, or reproductive organ histopathology up to the highest dose, but pup body weight reductions occurred at 15.1 mg/kg bw/day (developmental NOAEL 4.5 mg/kg bw/day), again tied to parental toxicity.[36][3] Multi-generation and screening studies (e.g., OECD TG 421) corroborated reduced litter sizes, pup survival, and body weights at ≥150 mg/kg bw/day, with NOAELs of 50 mg/kg bw/day.[37] Endocrine-related effects in animal models remain inconclusive, with no alterations in thyroid hormone levels (T3, T4, TSH) or reproductive hormones observed in the OECD TG 443 study up to 15.1 mg/kg bw/day.[3] However, higher-dose exposures (≥150 mg/kg bw/day) in rats induced increased thyroid gland weights and histopathological changes, suggesting potential disruption at non-reproductive thresholds.[37] Testicular toxicity in rats is considered species-specific, with low relevance to humans due to metabolic differences in aldehyde detoxification.[36] These data underpin the European harmonized classification of Lilial as Repr. 1B (may damage fertility; suspected of damaging the unborn child), though in vivo endocrine disruption mechanisms lack strong causal linkage beyond reprotoxicity endpoints.[7][3]| Study Type | Species | Key Effects | NOAEL (mg/kg bw/day) | LOAEL (mg/kg bw/day) | Source |
|---|---|---|---|---|---|
| Repeated-dose (90-day) | Male Wistar rats | Testicular atrophy, impaired spermatogenesis | 25 | 50 | SCCS/RIFM[3][36] |
| Developmental (OECD 414) | Pregnant Wistar rats | Reduced fetal weight, skeletal variations | 4.1 | 12.7 | RIFM/SCCS[36][3] |
| Extended one-generation (OECD 443) | Wistar rats (F0/F1) | Pup weight reduction; no fertility effects | Reproduction: 15.1; Development: 4.5 | 15.1 | RIFM/SCCS[36][3] |
| Screening/multi-generation | Wistar rats | Reduced litter size, pup survival | 50 | 150 | Canada assessment[37] |
Genotoxicity, Carcinogenicity, and Allergenicity Assessments
Genotoxicity assessments of Lilial (butylphenyl methylpropional, p-BMHCA) have consistently shown no evidence of mutagenic or genotoxic potential in standard in vitro assays. Bacterial gene mutation tests using Salmonella typhimurium and Escherichia coli strains, conducted both with and without metabolic activation, yielded negative results.[3] Similarly, mammalian cell gene mutation assays, such as those in mouse lymphoma L5178Y cells, and chromosomal aberration tests in human lymphocytes demonstrated no clastogenic or aneugenic effects.[3] A 2023 study further confirmed the absence of genotoxicity in additional in vitro models, including DNA damage assays, aligning with prior evaluations by the Scientific Committee on Consumer Safety (SCCS).[38] Carcinogenicity data for Lilial are limited to indirect evidence from repeated-dose toxicity studies, with no dedicated long-term rodent bioassays available. Subchronic and chronic oral exposures in rats and mice showed no induction of hyperplasia, neoplasia, or preneoplastic lesions in target organs such as testes, liver, or kidneys, even at doses up to 300 mg/kg body weight per day.[39] The SCCS (2015) concluded there was no evidence of carcinogenic potential from these studies, and structural analogies to non-carcinogenic aldehydes like cinnamaldehyde support this finding.[35] Regulatory classifications, including the EU's CMR Category 1B for reprotoxicity, do not extend to carcinogenicity, as empirical data lack support for such effects.[3] Allergenicity evaluations indicate Lilial acts as a skin sensitizer, with documented cases of contact dermatitis in humans. Bioassay-guided fractionation of perfumes identified Lilial as a causative agent in fragrance-induced allergic reactions, confirmed via structure-activity relationships predicting moderate sensitization potential.[40] The SCCS has affirmed a risk of skin sensitization, classifying it among 26 fragrance allergens requiring labeling in cosmetics when exceeding 0.01% in leave-on products.[3] Local lymph node assays in mice reported EC3 values (estimated concentration for 3-fold stimulation) around 5-10%, indicative of moderate potency, though human predictive tests like HRIPT show variability, with sensitization rates below 1% at typical use levels (0.1-1%).[3] No cross-reactivity with common haptens has been noted, but patch testing data link it to eczematous reactions in susceptible individuals.[40]Human Exposure and Risk Characterization
Exposure Pathways and Levels
The primary human exposure pathway to Lilial (butylphenyl methylpropional, p-BMHCA) is dermal absorption from cosmetic and personal care products, particularly leave-on formulations such as perfumes, body lotions, hand creams, and deodorants, where percutaneous absorption rates range from 1.4% (in vivo human data) to 8.5–13.5% (in vitro, formulation-dependent).[3] Inhalation contributes secondarily via sprayable products like fine fragrances or air fresheners, though volatility is low and specific inhalation data are limited; oral exposure is minor and typically indirect, such as from hand-to-mouth transfer after dermal application or incidental ingestion from lip products, with no significant use in oral cosmetics like toothpastes.[3][41] Concentrations of Lilial in finished products vary by category, with higher levels in fragrances: up to 1.42–1.86% in hydroalcoholic perfumes (IFRA standards), 0.09% in deodorants, 0.05% in face/hand creams, 0.06% in body lotions, and 0.1% in bath products.[3][42] Systemic exposure doses (SEDs) are estimated using dermal absorption assumptions (e.g., 5% for ethanolic solutions, 25% for creams) and application factors, yielding individual SEDs such as 13.7 μg/kg bw/day from perfumes and 6.6 μg/kg bw/day from body lotions, with aggregate SED across products at 0.028 mg/kg bw/day (28 μg/kg bw/day).[3] Biomonitoring studies confirm low-level population exposure, with urinary metabolites (e.g., tert-butylbenzoic acid, lysmerol) indicating median daily intakes of 1.63 μg/kg bw/day (95th percentile: 4.69 μg/kg bw/day) in adults from 2000–2018, declining over time due to reduced use; children and adolescents show higher exposures in females (e.g., from perfumes and fabric softeners), with peaks in ages 3–5 and 14–17 years.[43][41]| Product Category | Typical Lilial Concentration (%) | Key Exposure Notes |
|---|---|---|
| Hydroalcoholic Fragrances/Perfumes | 1.42–1.86 | Highest dermal load; IFRA-limited.[3][42] |
| Deodorants | 0.09 | Spray/roll-on application.[3] |
| Body/Hand Creams, Lotions | 0.05–0.06 | Leave-on; higher absorption in emulsions.[3] |
| Bath Products | 0.1 | Rinse-off; lower retention.[3] |