Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) (CAS no. [31906-04-4]) or Lyral® is a synthetic fragrance that is patch-tested independently (5% pet.) or as part of the fragrance mix II (FM II) within the European baseline series of patch tests,1 and also as part of fragrance series in patients with suspected allergic contact dermatitis (ACD). FM II (14% pet.) is composed of a total of 6 fragrances: hexyl cinnamic aldehyde (5% pet.), HICC (2.5% pet.), coumarin (2.5% pet.), farnesol (2.5% pet.), citral (1% pet.), and citronellol (0.5% pet.). Because of their importance, HICC and FM II were added as allergens to the European baseline series in 2008.2 In Spain, both have been included as allergens in the Spanish baseline series since 2012,3 although HICC was removed from the Spanish baseline series in 2022, becoming part of the Spanish extended series.4

The most recent European studies indicate a decrease in the prevalence of sensitization to HICC in recent years, currently around 1%.5–9 In most studies, the percentage of HICC-positive patients who would be missed if only FM II were patch-tested within a baseline series is approximately 15–20%. For this reason, some authors have recommended eliminating HICC from European and national baseline series.8–13

The primary endpoint of this study is to evaluate the frequency of sensitization to HICC in Spain during the period 2018–2023 and the simultaneous positivity to FM II to determine whether HICC should remain part of the Spanish baseline series. Secondary endpoints include assessing the clinical relevance of sensitization and the clinical–epidemiological characteristics of the sensitized population.

The Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy (REIDAC) prospectively collects clinical information from all patients studied with patch tests in participating hospitals in Spain.14 We conducted an observational, cross-sectional study including unselected patients from REIDAC, consecutively and simultaneously patch-tested with HICC (5% pet.) and FM II (14% pet., of which 2.5% is HICC), as part of the Spanish baseline and the 2022 Spanish extended series, from June 1st, 2018 to December 31st, 2023.

Allergens were obtained from Chemotechnique Diagnostics® (Vellinge, Sweden) and allergEAZE® (SmartPractice, Calgary, Canada), depending on center availability. Patch tests were performed according to the clinical practice guidelines of the European Society of Contact Dermatitis (ESCD).15 Reactions scored as (+), (++), or (+++) were considered positive. Relevance (current, past, irritant, active sensitization, cross-reactivity, unknown) was determined based on clinical history. Data collected included MOAHLFA index variables (Male, Occupational dermatitis, Atopic dermatitis, Hand dermatitis, Leg dermatitis, Face dermatitis, Age>40 years), the patient's main occupation, and the main site of dermatitis.

Continuous variables (age) were expressed as arithmetic mean (standard deviation), and categorical variables as counts (proportions). Fisher's exact test was used as univariate analysis to study the association between MOAHLFA variables and positivity to HICC and FM II, expressed as odds ratios (OR) with 95% confidence intervals (95%CI). Results were considered significant when p≤0.05. Statistical analyses were performed using Stata® 16 (StataCorp. 2019. Stata® Statistical Software: Release 16. College Station, TX: StataCorp LLC, RRID: SCR_012763).

The prevalence of sensitization to HICC in our study was 0.8%, lower than the 1.1% observed by Silvestre et al. in 2011–2015.16 In contrast, the frequency of FM II positivity remained stable at 3.3%.

In 1999, Frosch et al.17 recommended routine patch testing of HICC, and in 2005 defended the utility of FM II to detect more fragrance-sensitized patients,18 which led Bruze et al. to recommend inclusion of both in the European baseline series in 2008.2 Since then, European studies in consecutive patients have shown a progressive decrease in HICC positivity and, to a lesser extent, FM II positivity, with current prevalences near 1% and 3%, respectively.5–9 This decrease relates to the 2009 recommendation of the International Fragrance Association (IFRA) to reduce HICC concentration in cosmetics19 and the European Commission's definitive ban on its use in cosmetics in 2017, effective August 23rd, 2021.20

Significant variability exists in the prevalence of allergy to fragrance markers across European centers.21 Within the Information Network of Departments of Dermatology (IVDK), Geier et al.,6,22 Uter et al.,23 Krautheim et al.,24 and Schnuch et al.25,26 demonstrated a decline in HICC and FM II positivity from 2.6% and 5% in 1995 down to 1.1% and 3% in 2021, respectively. Similarly, though less markedly, HICC sensitization decreased significantly in the European Surveillance System on Contact Allergies (ESSCA), as shown by Uter et al.,7,27,28 Ahlström et al.,8 and Frosch et al.,29 from 1.7% in 2009 down to 1.3% in 2020, with FM II remaining stable at 3.8%. In an International Contact Dermatitis Research Group (ICDRG) study from 2012 to 2016, Bruze et al.9 found HICC and FM II positivity frequencies of 1.6% and 3.9%, respectively. In another multicenter European cohort (2008–2011), Diepgen et al.30 observed respective frequencies of 1.5% and 1.9%.

In Sweden, HICC and FM II allergy prevalence was studied by Andernord et al.,31 Engfeldt et al.,12 and Isaksson et al.10 within the Swedish Contact Dermatitis Research Group (SCDRG), and by Sukakul et al.13 and Mowitz et al.32 in Malmö Hospital, decreasing from peaks of 1.7% and 3.4% in 2006 down to lows of 1% and 2.3% in 2020, respectively. Within SIDAPA (Società Italiana Dermatologia Allergologica Professionale Ambientale) during 2016–2021, Stingeni et al.5 reported respective prevalences of 1% and 2.1%. At Gentofte Hospital (Copenhagen, Denmark), Ahlström et al.8 observed a decrease in HICC sensitization from >2% in 2009 down to 1% in 2019. At St. John's Hospital (London, UK), Mann et al.33 and Ung et al.34 found HICC and FM II prevalences stable at 1.4% and 2.9%, respectively. At Leuven Hospital (Belgium), Nardelli et al.35 observed decreasing HICC sensitization from 2007 to 2011 (mean 2.1%), while FM II remained stable (mean 6%).

In our study, allergy to HICC and FM II was clinically relevant in over half of patients, which is consistent with prior reports.2,8,21,30 The proportion of moderate/strong (++/+++) reactions was 58% and 56% for HICC and FM II, respectively, with low rates of irritant/doubtful reactions.

Of all HICC positives, 75% were detected by FM II, a percentage similar to that observed in cases with clinically relevant allergy to both allergens. In the literature, the proportion of FM II-positive, HICC-negative patients ranges from 10%34,35 to 24%,5,8,29 averaging 15–20% in most studies.9,10,12,22,24 Given these findings and the decline in HICC sensitization, several authors have advocated removal of HICC from national and European baseline series (except Stingeni et al.5). Indeed, the SCDRG eliminated HICC from the Swedish baseline series in 2014,10 and the ICDRG adopted the same decision for the international baseline series in 2020.11 This ultimately led to exclusion of HICC from the new 2022 Spanish baseline series,4 moving it to the Spanish extended series—a decision supported by our findings. Considering the European Commission's ban on HICC in cosmetics,36 sensitization is expected to continue declining. Nonetheless, to continue documenting this trend and given the lack of regulation of HICC use in cosmetics in non-European markets, we recommend continuing HICC patch testing within the Spanish and European extended series.

In our study, no MOAHLFA variables were associated with HICC positivity, while FM II positivity was significantly associated with age>40 years and inversely with facial dermatitis. In the literature, female sex and age>40 years are often associated with positivity to HICC5,8,10,25,29,30,37 and FM II.5,10,24,38 Occupational dermatitis, atopic dermatitis, and facial dermatitis have been occasionally associated with HICC8,37 and FM II.6,24,38 In our patients, the most frequent sites were hands, trunk, and face for both HICC (Table 3) and FM II (Table 4), consistent with fragrance ACD typically affecting hands, face, neck, and axillae.21,38,39 Interestingly, in our cohort facial dermatitis was negatively associated with FM II positivity, possibly because we only analyzed the main site without considering multiple locations. Additionally, several studies link hand involvement with FM II positivity,6,16,24,38 while leg involvement has been negatively associated with HICC sensitization.8,16,25,37,40

In our population, occupational ACD cases were rare, at 3% for HICC and 10% for FM II. The most frequent occupations were administrative staff, service sector employees, homemakers, and healthcare workers, with no major differences by relevance (Tables 3 and 4). In general, occupational ACD due to fragrances is uncommon, mainly involving the perfume/cosmetics, domestic cleaning, esthetics/hairdressing, health care, food, metalworking, and aromatherapy industries.21,39 However, Montgomery et al.41 observed a gradual increase in occupational fragrance ACD cases reported in the UK during 1996–2015.

The prevalence of sensitization to HICC in Spain has decreased in recent years, currently standing at 0.8%. Half of the cases are clinically relevant. FM II detects 3 of every 4 patients sensitized to HICC. Our results support keeping HICC outside the Spanish baseline series and within the Spanish extended series and highlight the need to consider its transfer from the European baseline series to the European extended series.

REIDAC is promoted by the Spanish Academy of Dermatology and Venereology (AEDV, Fundación Piel Sana), which has received funding from the Spanish Agency of Medicines and Medical Devices (AEMPS) (BOE reference) and Sanofi®. The funding sources had no role in study conception, design, data collection, analysis, interpretation, manuscript preparation, review, approval, or logistical support.

None declared.