SCCS Scientific Opinion on Acid Yellow 3 (submission II) - SCCS/1631/21.

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on Acid Yellow 3 - C054 (CAS Number 8004-92-0, EC No 305-897-5), submission II, preliminary version of 7 May 2021, final version of 23 July 2021, SCCS/1631/21.

The SCCS scientific advice on the safety of nanomaterials in cosmetics.

The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment.

Interventions for hand eczema.

BACKGROUND: Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social stigma, and impairment in employment. Many different interventions of unknown effectiveness are used to treat hand eczema. OBJECTIVES: To assess the effects of topical and systemic interventions for hand eczema in adults and children. SEARCH METHODS: We searched the following up to April 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, AMED, LILACS, GREAT, and four trials registries. We checked the reference lists of included studies for further references to relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared interventions for hand eczema, regardless of hand eczema type and other affected sites, versus no treatment, placebo, vehicle, or active treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were participant- and investigator-rated good/excellent control of symptoms, and adverse events. MAIN RESULTS: We included 60 RCTs, conducted in secondary care (5469 participants with mild to severe chronic hand eczema). Most participants were over 18 years old. The duration of treatment was short, generally up to four months. Only 24 studies included a follow-up period. Clinical heterogeneity in treatments and outcome measures was evident. Few studies performed head-to-head comparisons of different interventions. Risk of bias varied considerably, with only five studies at low risk in all domains. Twenty-two studies were industry-funded.Eighteen trials studied topical corticosteroids or calcineurin inhibitors; 10 studies, phototherapy; three studies, systemic immunosuppressives; and five studies, oral retinoids. Most studies compared an active intervention against no treatment, variants of the same medication, or placebo (or vehicle). Below, we present results from the main comparisons.Corticosteroid creams/ointments: when assessed 15 days after the start of treatment, clobetasol propionate 0.05% foam probably improves participant-rated control of symptoms compared to vehicle (risk ratio (RR) 2.32, 95% confidence interval (CI) 1.38 to 3.91; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 8; 1 study, 125 participants); the effect of clobetasol compared to vehicle for investigator-rated improvement is less clear (RR 1.43, 95% CI 0.86 to 2.40). More participants had at least one adverse event with clobetasol (11/62 versus 5/63; RR 2.24, 95% CI 0.82 to 6.06), including application site burning/pruritus. This evidence was rated as moderate certainty.When assessed 36 weeks after the start of treatment, mometasone furoate cream used thrice weekly may slightly improve investigator-rated symptom control compared to twice weekly (RR 1.23, 95% CI 0.94 to 1.61; 1 study, 72 participants) after remission is reached. Participant-rated symptoms were not measured. Some mild atrophy was reported in both groups (RR 1.76, 95% CI 0.45 to 6.83; 5/35 versus 3/37). This evidence was rated as low certainty.Irradiation with ultraviolet (UV) light: local combination ultraviolet light therapy (PUVA) may lead to improvement in investigator-rated symptom control when compared to local narrow-band UVB after 12 weeks of treatment (RR 0.50, 95% CI 0.22 to 1.16; 1 study, 60 participants). However, the 95% CI indicates that PUVA might make little or no difference. Participant-rated symptoms were not measured. Adverse events (mainly erythema) were reported by 9/30 participants in the narrow-band UVB group versus none in the PUVA group. This evidence was rated as moderate certainty.Topical calcineurin inhibitors: tacrolimus 0.1% over two weeks probably improves investigator-rated symptom control measured after three weeks compared to vehicle (14/14 tacrolimus versus 0/14 vehicle; 1 study). Participant-rated symptoms were not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well-tolerated application site burning/itching.A within-participant study in 16 participants compared 0.1% tacrolimus to 0.1% mometasone furoate but did not measure investigator- or participant-rated symptoms. Both treatments were well tolerated when assessed at two weeks during four weeks of treatment.Evidence from these studies was rated as moderate certainty.Oral interventions: oral cyclosporin 3 mg/kg/d probably slightly improves investigator-rated (RR 1.88, 95% CI 0.88 to 3.99; 1 study, 34 participants) or participant-rated (RR 1.25, 95% CI 0.69 to 2.27) control of symptoms compared to topical betamethasone dipropionate 0.05% after six weeks of treatment. The risk of adverse events such as dizziness was similar between groups (up to 36 weeks; RR 1.22, 95% CI 0.80 to 1.86, n = 55; 15/27 betamethasone versus 19/28 cyclosporin). The evidence was rated as moderate certainty.Alitretinoin 10 mg improves investigator-rated symptom control compared with placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; 2 studies, n = 781) and alitretinoin 30 mg also improves this outcome compared with placebo (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; 2 studies, n = 1210). Similar results were found for participant-rated symptom control: alitretinoin 10 mg RR 1.73 (95% CI 1.25 to 2.40) and 30 mg RR 2.75 (95% CI 2.18 to 3.48). Evidence was rated as high certainty. The number of adverse events (including headache) probably did not differ between alitretinoin 10 mg and placebo (RR 1.01, 95% CI 0.66 to 1.55; 1 study, n = 158; moderate-certainty evidence), but the risk of headache increased with alitretinoin 30 mg (RR 3.43, 95% CI 2.45 to 4.81; 2 studies, n = 1210; high-certainty evidence). Outcomes were assessed between 48 and 72 weeks. AUTHORS' CONCLUSIONS: Most findings were from single studies with low precision, so they should be interpreted with caution. Topical corticosteroids and UV phototherapy were two of the major standard treatments, but evidence is insufficient to support one specific treatment over another. The effect of topical calcineurin inhibitors is not certain. Alitretinoin is more effective than placebo in controlling symptoms, but advantages over other treatments need evaluating.Well-designed and well-reported, long-term (more than three months), head-to-head studies comparing different treatments are needed. Consensus is required regarding the definition of hand eczema and its subtypes, and a standard severity scale should be established.The main limitation was heterogeneity between studies. Small sample size impacted our ability to detect differences between treatments.

The significance of batch and patch test method in establishing contact allergy to fragrance mix I-EDEN Fragrance Study Group.

BACKGROUND: A fragrance mix consisting of eight separate fragrance ingredients (fragrance mix I [FM I]) is present in most baseline patch test series. Patch testing with the TRUE Test technique is considered to detect less contact allergy to FM I than testing with the Finn Chamber technique. OBJECTIVE: To investigate the possible significance of batch and patch test method in establishing contact allergy to FM I. METHODS: Three thousand one hundred and nineteen individuals representing a sample of the general population were patch tested with two batches of FM I with two patch test techniques at six dermatology clinics in five European countries. The TRUE Test technique and the Finn Chamber technique with pet. preparations were used. McNemar's test was used for statistical calculations. RESULTS: The contact allergy prevalences varied between 0.7% and 2.6%. The patch tests with the mixes containing Evernia prunastri (oak moss) with a high content of chloratranol/atranol resulted in substantially more positive reactions than the corresponding tests with the mixes containing oak moss with a low content of chloratranol/atranol. The Finn Chamber technique detected significantly more contact allergic reactions than the TRUE Test technique (P < 0.001). CONCLUSION: The Finn Chamber technique detects more contact allergy to FM I than the TRUE Test technique.

Two decades of p-phenylenediamine and toluene-2,5-diamine patch testing - focus on co-sensitizations in the European baseline series and cross-reactions with chemically related substances.

BACKGROUND: Cross-reactions and co-sensitizations are of great importance in understanding contact allergy and exposure sources. OBJECTIVES: To investigate common cross-reactions and co-sensitizations in p-phenylenediamine (PPD)-sensitized and toluene-2,5-diamine (TDA)-sensitized individuals. METHODS: From our patch test population, 8036 patients patch tested with the European baseline series were extracted. Readings had to be performed at least on day 3 according to ICDRG guidelines. RESULTS: Two hundred and fifty-one patients were sensitized to PPD and/or TDA; 231 patients were sensitized to PPD, and 109 to TDA. Significant differences were observed regarding the strengths of patch test reactions to PPD and number of cross-reactions. For TDA, a difference was found between all reaction strengths, except between + and ++ strengths. PPD-sensitized individuals were more likely to be sensitized to carba mix, cobalt chloride, colophonium, p-tert-butyl phenolformaldehyde resin, paraben mix, and methylisothiazolinone. TDA-sensitized individuals were more often sensitized to carba mix. CONCLUSIONS: Cross-reactivity was commonly found among individuals sensitized to PPD or TDA, and was strongly related to the strength of the patch test reaction. Regarding co-sensitizations, a frequently appearing or common exposure source could not be determined. However, modification of the allergen by, for example, the skin microbiota may have caused the formation of molecules that are, for the human immune system, indistinguishable from PPD.

Alitretinoin and acitretin in severe chronic hand eczema; results from a retrospective daily practice study.

Acitretin has been used off-label for years to treat chronic hand eczema, but acitretin is less often prescribed as alitretinoïne was approved. This study evaluates both retinoids in a daily practice cohort of patients with severe chronic hand eczema in terms of drug survival and reasons for discontinuation. Patients using alitretinoin or acitretin between 01-01-1994 and 01-08-2015 were included in this retrospective daily practice study and analyzed by Kaplan-Meier drug survival curves. Potential determinants were analyzed by Cox regression analyses. Ninety-five patients were treated with alitretinoin and 109 patients with acitretin. The main reasons for discontinuation were adverse events and cleared hand eczema, 29.5 and 27.4% in alitretinoin versus 43.1 and 23.9% in acitretin. Patients with hyperkeratotic hand eczema had most often a good effect of treatment: 68.3% in alitretinoin and 50.7% in acitretin treatment. The drug survival rates of alitretinoin and acitretin after 12, 24, 36, and 52 weeks were 69.3, 45.1, 19.6, 7.0% and 74.3, 45.5, 33.8, 23.2%, respectively. Alitretinoin and acitretin are effective treatment options for patients with hand eczema. However, both treatments were more effective in patients with hyperkeratotic hand eczema. Fewer patients discontinued alitretinoin compared with acitretin due to adverse events.

Opinion of the Scientific Committee on Consumer Safety (SCCS) - Opinion on the fragrance ingredients Tagetes minuta and Tagetes patula extracts and essential oils (phototoxicity only) in cosmetic products.

CONCLUSION OF THE OPINION: The SCCS considers a maximum level of 0.01% Tagetes minuta and Tagetes patula extracts and essential oils in leave-on products (except sunscreen cosmetic products) as safe, provided that the alpha terthienyl (terthiophene) content of the Tagetes extracts and oils does not exceed 0.35%. The Tagetes extracts and oils should not be used as ingredients of sunscreen products.

The role of the antioxidant ascorbic acid in the elicitation of contact allergic reactions to p-phenylenediamine.

BACKGROUND: An allergic contact reaction is accompanied by high oxidative stress in the skin. Pretreatment of the skin with antioxidative substances could reduce the elicitation reaction. OBJECTIVES: To investigate, in a proof-of-principle study, whether pretreatment of the skin with the antioxidant ascorbic acid reduces the elicitation reaction to a p-phenylenediamine (PPD)-containing hair dye in sensitized subjects. METHODS: Twelve subjects with contact allergy to PPD, a documented skin reaction to a hair dye simulation exposure model and a history of hair dye-related skin complaints were included in this study. Skin areas on the forearms were, in a left versus right design, exposed to an emulsion with ascorbic acid and an emulsion without ascorbic acid, and then to a 2% PPD-containing hair dye testing formulation. In addition, control areas were exposed to the emulsions and to the PPD-containing hair dye formulation without pretreatment. Skin reactions were graded on day (D)2 and D3. RESULTS: Pretreatment with ascorbic acid emulsion resulted in a reduction in the elicitation reaction in 7 of 12 subjects at D3 (p = 0.046). No statistically significant difference was observed at D2. CONCLUSIONS: Pretreatment of the skin with the antioxidant ascorbic acid had an attenuating effect on the elicitation reaction to PPD in sensitized individuals.

Real-time detection of p-phenylenediamine penetration into human skin by in vivo Raman spectroscopy.

BACKGROUND: Penetration, autoxidation and N-acetylation of p-phenylenediamine (PPD) have been studied in vitro and ex vivo. However, a clear understanding of in vivo PPD penetration and the formation of PPD derivatives is lacking. OBJECTIVES: To obtain insights into the in vivo penetration, clearance and formation of PPD derivatives in human skin. METHODS: Patch test chambers containing PPD 1% pet. were applied to the forearms of two human volunteers, with increasing application times. Non-invasive Raman microspectroscopy was used for detection of PPD (derivatives) in skin at several follow-up times. RESULTS: Application of a PPD 1% pet. patch for 30 min resulted in substantial amounts of PPD in the stratum corneum of 90 mg PPD/g keratin. PPD contents were highest after three applications for 1 h each (330 mg PPD/g keratin), followed by single applications for 2 h 40 min, 2 h, and 23 h. The PPD half-time in the skin was 3 h. No spectral contributions of Bandrowski's base, monoacetyl-PPD and diacetyl-PPD were detected. CONCLUSIONS: We have gained insights into the in vivo penetration of PPD in human skin by using non-invasive Raman spectroscopy. Penetration into the skin was fast, and the PPD concentrations detected in the stratum corneum were high. PPD was detected in both the stratum corneum and the viable epidermis. Oxidized or acetylated PPD derivatives could not be detected.

Hand eczema.

Hand eczema is an inflammation of the skin; the cause is often multifactorial. Initial management includes avoiding causative irritants or allergens (e.g., by wearing impermeable gloves) and applying emollients and potent topical glucocorticoids.

p-Phenylenediamine exposure in real life - a case-control study on sensitization rate, mode and elicitation reactions in the northern Netherlands.

BACKGROUND: The prevalence of p-phenylenediamine (PPD) sensitization is 4% in the patch tested population and varies between zero and 1.5% in the general population. Hair dye is a recognised sensitization source. OBJECTIVES: To define the prevalence rates of PPD sensitization in the general and patch tested populations of The Netherlands, and to gain insights into relationships between patch test strength and exposure sources. METHODS: Patch test database cases were matched with population-based controls. Analyses were performed based on demographic details, patch test reactions, and potential PPD exposure. RESULTS: PPD sensitization occurred in 3.3% of the patch tested population and in 1.3% of the general population. Hairdressers had a 4.4-fold increased chance of being sensitized to PPD (p = 0.041), and black henna tattoos showed a tendency for a 2.3-fold increased chance of sensitization (p = 0.081). Weak elicitation reactions were present in hairdressers and consumers. However, cases who had had black henna tattoos showed significantly more (extremely) strong patch test reactions upon elicitation (p = 0.015). CONCLUSIONS: The prevalence rates in the patch tested and general population of The Netherlands are comparable with the prevalence rates of other mid-European centres. PPD sensitization is often attributed to hair dye. However, this study shows that subjects sensitized by black henna tattoos present with very severe elicitation reactions, emphasizing the need for more strict policing the prohibition.

Hands4U: the effects of a multifaceted implementation strategy on hand eczema prevalence in a healthcare setting. Results of a randomized controlled trial.

BACKGROUND: Healthcare workers have an increased risk of developing hand eczema. A multifaceted implementation strategy was developed to implement a guideline to prevent hand eczema among healthcare workers. OBJECTIVES: To investigate the effects of the implementation strategy on self-reported hand eczema and preventive behaviour. METHODS: A randomized controlled trial was performed. A total of 48 departments (n = 1649) were randomly allocated to the multifaceted implementation strategy or the control group. The strategy consisted of education, participatory working groups, and role models. Outcome measures were self-reported hand eczema and preventive behaviour. Data were collected at baseline, and 3, 6, 9 and 12 months of follow-up. RESULTS: Participants in the intervention group were significantly more likely to report hand eczema [odds ratio (OR) 1.45; 95% confidence interval (CI) 1.03-2.04], and they reported significantly less hand washing (B, - 0.38; 95%CI: - 0.48 to - 0.27), reported significantly more frequent use of a moisturizer (B, 0.30; 95%CI: 0.22-0.39) and were more likely to report wearing cotton undergloves (OR 6.33; 95%CI: 3.23-12.41) than participants in the control group 12 months after baseline. CONCLUSIONS: The strategy implemented can be used in practice, as it showed positive effects on preventive behaviour. More research is needed to investigate the unexpected effects on hand eczema.

Hands4U: the effectiveness of a multifaceted implementation strategy on behaviour related to the prevention of hand eczema-a randomised controlled trial among healthcare workers.

OBJECTIVES: To investigate the effects of a multifaceted implementation strategy on behaviour, behavioural determinants, knowledge and awareness of healthcare workers regarding the use of recommendations to prevent hand eczema. METHODS: The Hands4U study is a randomised controlled trial. A total of 48 departments (n=1649 workers) were randomly allocated to the multifaceted implementation strategy or the control group (minimal implementation strategy). Within the departments designated to the multifaceted implementation strategy, participatory working groups were set up to enhance the implementation of the recommendations for hand eczema. In addition, working group members were trained to become role models, and an education session was given within the department. Outcome measures were awareness, knowledge, receiving information, behaviour and behavioural determinants. Data were collected at baseline, with a 3- and 6-month follow-up. RESULTS: Statistically significant effects were found after 6 months for awareness (OR 6.30; 95% CI 3.41 to 11.63), knowledge (B 0.74; 95% CI 0.54 to 0.95), receiving information (OR 9.81; 95% CI 5.60 to 17.18), washing hands (B -0.40; 95% -0.51 to -0.29), use of moisturiser (B 0.29; 95% CI 0.20 to 0.38), cotton under gloves (OR 3.94; 95% CI 2.04 to 7.60) and the overall compliance measure (B 0.14; 95% CI 0.02 to 0.26), as a result of the multifaceted implementation strategy. No effects were found for behavioural determinants. CONCLUSIONS: The multifaceted implementation strategy can be used in healthcare settings to enhance the implementation of recommendations for the prevention of hand eczema. TRIAL REGISTRATION NUMBER: NTR2812.

Implementation of recommendations for hand eczema through a multifaceted strategy. A process evaluation among health care workers.

Process data give important insights into how an intervention is implemented. The aim of the present study is to conduct a process evaluation, alongside a randomised controlled trail, on the implementation of recommendations for the prevention of hand eczema. The intervention was carried out in healthcare workers' departments and consisted of working groups and role models. The role models were selected based on their representativeness, their influence on colleagues, and their motivation. The focus of the working group was to implement recommendations for hand eczema at the department by choosing solutions to overcome barriers for implementation. Out of the 104 solutions, 87 were realised. Solutions regarding moisturisers and use of cotton under gloves, were used by 90.9% and 30.8% of the employees, respectively. Of all participants, 58.2% actively engaged with the role models. This process evaluation showed that the intervention was executed according to protocol and that the solutions were implemented well. However, the role model component in the intervention should be improved.

Occupational skin hazards and prevalence of occupational skin diseases in shoe manufacturing workers in Indonesia.

PURPOSE: Shoe manufacturing workers are exposed daily to an extensive range of potential physical and chemical occupational hazards. Shoe manufacturing in Indonesia is one of the industrial sectors that has shown sustained growth amongst the newly industrialized countries (NICs). In this study, we investigated the possible potential exposure of the workers to physical and occupational hazards and determined the prevalence of occupational skin diseases at a shoe manufacturing factory in Indonesia. METHODS: A cross-sectional study on the observation of the working process and an inventory and risk assessment of exposure to the chemicals used. Classification of chemicals as potential sensitizers/irritants and qualitative assessments of these chemicals were done. Workers were examined and interviewed using the Nordic Occupational Skin Questionnaire-2002/LONG. RESULTS: The risk of Occupational skin diseases (OSD) at the shoe factory was mainly related to the exposure of the workers' skin to potential physical and chemical hazards in hot and humid environmental conditions. From a total of 514 workers, 8.5 % reported current OSD and 4.8 % reported a history of OSD. Occupational skin diseases were diagnosed in 29 % of the workers by dermatologists and 7.6 % had an occupational contact dermatitis (OCD). Of the 39 workers with contact dermatitis, 33 consented to being patch tested, 14 (3 %) workers showed a positive results and considered as having an occupational allergic contact dermatitis (OACD) and 25 (4.9 %) had an occupational irritant contact dermatitis (OICD). CONCLUSION: We observed a repeated and prolonged exposure of the workers to numerous physical and chemical skin hazards at this factory.

The optimal patch test concentration for ascaridole as a sensitizing component of tea tree oil.

BACKGROUND: Tea tree oil is used as a natural remedy, but is also a popular ingredient in household and cosmetic products. Oxidation of tea tree oil results in degradation products, such as ascaridole, which may cause allergic contact dermatitis. OBJECTIVES: To identify the optimal patch test concentration for ascaridole, and to investigate the relationship between a positive reaction to ascaridole and a positive reaction to oxidized tea tree oil. PATIENTS/MATERIALS/METHODS: Three hundred and nineteen patients with eczema were patch tested with ascaridole 1%, 2%, and 5%, and 250 patients were patch tested with oxidized tea tree oil 5%. Readings were performed on D3 and D7 according to a patch test calibration protocol. RESULTS: With an increasing ascaridole test concentration, the frequency of positive reactions increased: ascaridole 1%, 1.4%; ascaridole 2%, 5.5%; and ascaridole 5%, 7.2%. However, the frequencies of irritant and doubtful reactions also increased, especially for ascaridole 5%. A positive reaction to ascaridole was related to a positive reaction to tea tree oil. CONCLUSIONS: This study is in support of ascaridole being a sensitizer. We recommend patch testing with ascaridole at 2%. The finding that every positive reaction to oxidized tea tree oil is accompanied by a positive reaction to ascaridole suggests that ascaridole might be a contact allergen in oxidized tea tree oil.

Penetration and haptenation of p-phenylenediamine.

Although p-phenylenediamine (PPD) has been recognized as an extreme sensitizer for many years, the exact mechanism of sensitization has not been elucidated yet. Penetration and the ability to bind to proteins are the first two hurdles that an allergen has to overcome to be able to sensitize. This review is an overview of studies regarding PPD penetration through skin (analogues) and studies on the amino acids that are targeted by PPD. To complete this review, the auto-oxidation and N-acetylation steps involved in PPD metabolism are described. In summary, under normal hair dyeing exposure conditions, <1% of the applied PPD dose penetrates the skin. The majority (>80%) of PPD that penetrates will be converted into the detoxification products monoacetyl-PPD and diacetyl-PPD by the N-acetyltransferase enzymes. The small amount of PPD that does not become N-acetylated is susceptible to auto-oxidation reactions, yielding protein-reactive PPD derivatives. These derivatives may bind to specific amino acids, and some of the formed adducts might be the complexes responsible for sensitization. However, true in vivo evidence is lacking, and further research to unravel the definite mechanism of sensitization is needed.