Abstract:

Parabens are among the most widely used preservatives in cosmetic formulations. The aim of this study was to investigate the relationship between allergic contact dermatitis (ACD) and the use of parabens in cosmetics. A systematic review was performed with searches in PubMed, Scopus and Science Direct, in addition to a manual search. Interventional or observational studies that assessed the incidence of ACD in individuals using parabens were included. The quality of the articles was assessed and the data were extracted for a qualitative synthesis and single-arm meta-analysis. Fourteen studies (8 longitudinal, 3 cross-sectional, 1 quasi experimental and 2 case reports) were included in the systematic review and had their data extracted. Twelve studies reported ACD after the use of parabens and were included in the single-arm meta-analysis, resulting in an ACD incidence of 0.9%[95%CI: 0.4-2.0%], thus classified as a rare event. This result was related to already sensitized skin in most cases. In addition, the concentration of parabens in the contact test was above that recommended in cosmetics. The incidence of ACD due to parabens is rare, but further studies with control groups and at the usual concentrations of parabens are needed to better evaluate the results.

Keywords:
Dermatitis; Allergic Contact; Parabens; Systematic review; Safety

HIGHLIGHTS

HIGHLIGHTS

INTRODUCTION

Among the most common preservatives in cosmetic and pharmaceutical formulations are the alkyl esters of parahydroxybenzoic acid, classified as methylparaben, ethylparaben, propylparaben, butylparaben and benzylparaben (the latter banned in the new cosmetic ingredient review - CIR expert panel because it is considered unsafe). However, according to the CIR expert panel, 21 types of parabens are currently known [¹1 Cosmetic Ingredient Review. Expert panel cosmetic ingredient review. 2019 oct. Available from: <https://www.cir-safety.org/sites/default/files/Admin_5.pdf>.
https://www.cir-safety.org/sites/default... ]. According to the food and drug administration (FDA), the parabens most commonly used as preservatives are methylparaben, ethylparaben, propylparaben and butylparaben [²2 Food and drug administration. Parabens in cosmetics. 2020 apr. Available from: https://www.fda.gov/cosmetics/cosmetic-ingredients/parabens-cosmetics
https://www.fda.gov/cosmetics/cosmetic-i... ].

Due to the high efficiency of parabens, their concentrations in formulations often do not exceed 0.3% individually, or 0.3% methylparaben and 0.1% propylparaben [³3 Soni MG, Taylor SL, Greenberg NA, Burdock GA. Evaluation of the health aspects of methyl paraben: a review of the published literature. Food Chem Toxicol, 2002, 40(10):1335-73.]. Despite this, there is a worldwide controversy over the safety of these products regarding human health. A study published in 2005 showed that the use of parabens in cosmetic products can cause skin allergies [⁴4 Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis, 2005, 16(2): 57-66; quiz 55-6.]. However, in a retrospective observational study published in 2014 evaluating 69,487 individuals already suspected of having allergic contact dermatitis (ACD), only 1% had positive reactions to parabens [⁵5 Dinkloh A, Worm M, Geier J, Schnuch A and Wollenberg A. Contact sensitization in patients with suspected cosmetic intolerance: results of the IVDK 2006-2011. J Eur Acad Dermatol Venereol, 2015, 29(6): 1071-81.].

ACD is an inflammatory dermatosis of exogenous etiology; it is more frequent in industrialized countries, and is considered one of the most common occupational diseases [⁶6 Duarte IAG, Lazzarini R, Bedrikow RB, Pires MC. Dermatite de contato. Anais Brasileiros de Dermatologia, 2000, 75(5): 529-48., ⁷7 Saint-Mezard P, Rosieres A, Krasteva M, Berard, F. Allergic contact dermatitis. Eur J Dermatol, 2004, 14(5): 284-95.]. It is caused by external agents that trigger an inflammatory reaction in contact with the skin, and the disease is usually manifested as eczema [⁷7 Saint-Mezard P, Rosieres A, Krasteva M, Berard, F. Allergic contact dermatitis. Eur J Dermatol, 2004, 14(5): 284-95.]. External agents that can trigger ACD include preservatives, acidulants or emulsifiers, which are commonly found in cosmetic formulations [⁸8 Lazzarini T, Duarte I, Ferreira AL. Patch tests. An Bras Dermatol, 2013, 88(6): 879-88.].

Considering the contradictions in several countries regarding the safety of using parabens as preservatives in cosmetic products, the objective of this study was to conduct a systematic review of the literature in order to assess the incidence of ACD related to the use of parabens in cosmetics.

MATERIAL AND METHODS

The research was designed using the cochrane collaboration recommendations for systematic reviews [⁹9 Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Matthew J.. Cochrane handbook for systematic reviews of interventions, 2 nd ed. 2019, Chichester (UK): John Wiley & Sons.] and reported according to the preferred reporting items for systematic reviews and meta-analysis (prisma) [¹⁰10 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021, 372: n71.].

Study search

Electronic searches were performed in pubmed, scopus and science direct, in addition to manual searches in the references of included studies and in non-indexed records. The following descriptors were used: dermatitis, paraben, 4-hydroxybenzoic acid, toxicity, safety and allergy. The terms were combined using the Boolean operators “and” and “or”. The detailed search can be found in supplementary material 1 (https://osf.io/v4fuy/?view_only=3a076c1726ec4cfd86e852cc964f7c3a)

Inclusion and exclusion criteria

The acronym “PICOS” was used to assess study eligibility criteria [⁹9 Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Matthew J.. Cochrane handbook for systematic reviews of interventions, 2 nd ed. 2019, Chichester (UK): John Wiley & Sons.]. (P) participants: participants with healthy skin or with suspected allergic contact dermatitis or other dermatological reactions. (I) intervention: parabens in any concentration. (C) comparator: placebo or without comparator. (O) outcome: allergic contact dermatitis. (S) study design: observational or interventional studies. Articles published until February 2021 were included.

Studies that were not available in full in any database and that were not found after attempts to contact the authors were excluded, as well as articles published in non-roman characters. Studies conducted in patients with already diagnosed dermatological reactions (including ACD) were also excluded from this systematic review.

Study selection

After the search, two independent reviewers read the titles and abstracts of the studies retrieved (screening). Then, the articles selected in the screening stage were read in full by the two reviewers (eligibility stage), again independently, and those that met the established inclusion criteria were selected for data extraction. Disagreements between reviewers were resolved by consensus or by the decision of a third independent reviewer. For the organization of references and screening, the EndNote version X7 was used.

Data extraction and synthesis

Studies that met the inclusion criteria were used for data extraction, which was also performed in duplicate by two independent reviewers with the help of pre-prepared spreadsheets in Microsoft Excel®. Baseline information was extracted from the studies (authors, year of publication, country), type of study, number of individuals, age, sex, type of cosmetic, type of paraben, percentage and characteristics of the paraben, time of exposure, type of test and outcomes.

Quality assessment

Observational studies and quasi-experimental studies were evaluated regarding their methodological quality using the Newcastle Ottawa scale (NOS). This scale contains eight items segmented into three parts: selection, comparability, exposure (case-control) or outcome (cohort study) [¹¹11 Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [2013 october 2019]; Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.as
http://www.ohri.ca/programs/clinical_epi... ]. Studies scored ≥7 were considered to be of high quality.

To assess the quality of case reports, the tool proposed by Murad et al. Was used, composed of eight questions that can be separated into four domains: selection, investigation, causality and reports. In this tool, the suggestion is not to use an aggregate score, instead making an overall judgement about methodological quality based on the questions deemed most critical [¹²12 Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMG Evid Based Med, 2018, 23(2): 60-3.].

Meta-analysis

The quantitative analysis of the studies included in this systematic review was performed using CMA® software (comprehensive meta-analysis version 2.0 Biostat, Englewood, NJ), in a single-arm meta-analysis using a random effects model and 95% confidence interval (ci). Heterogeneity was assessed by calculating the i-square (i2); values of i2>75% were considered to indicate high heterogeneity [⁹9 Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Matthew J.. Cochrane handbook for systematic reviews of interventions, 2 nd ed. 2019, Chichester (UK): John Wiley & Sons.].

Subgroup analyses were performed according to the country of the study.

Publication bias

Publication bias was assessed with the CMA® software (comprehensive meta-analysis) - (version 2.0 biostat, Englewood, NJ) using a funnel plot graph.

This study was recorded on the PROSPERO database (registration number CRD42019135888 - https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019135888)

RESULTS

A total of 3,570 records were initially identified by searching electronic databases (Figure 1). After removing 44 duplicates, the titles and abstracts of 3,526 articles were screened, 113 of which were selected for reading in full. After this stage, 14 articles were eligible for analysis, comprising 8 longitudinal studies [⁵5 Dinkloh A, Worm M, Geier J, Schnuch A and Wollenberg A. Contact sensitization in patients with suspected cosmetic intolerance: results of the IVDK 2006-2011. J Eur Acad Dermatol Venereol, 2015, 29(6): 1071-81., ¹³13 Adams RM, Maibach HI. A five-year study of cosmetic reactions. J Am Acad Dermatol, 1985,13(6):1062-9.

14 Akasya-Hillenbrand E, Özkaya-Bayazit E. Patch test results in 542 patients with suspected contact dermatitis in Turkey. Contact Dermatitis, 2002,46(1):17-23.

15 Duarte I, Antonio Jabur da Cunha J, Lazzarini R. Allergic contact dermatitis in private practice: what are the main sensitizers? Dermatitis, 2011,22(4):225-6.

16 Romaguera C, Camarasa JMG, Alomar A, Grimalt F. Patch tests with allergens related to cosmetics. Contact Dermatitis, 1983,9(2):167-8.

17 Sarma N, Ghosh S. Clinico-allergological pattern of allergic contact dermatitis among 70 indian children. Indian J Dermatol Venereol Leprol, 2010,76(1):38-44.

18 Schnuch A, Lessmann H and Geier J and Uter W. Contact allergy to preservatives. Analysis of IVDK data 1996-2009. Br J Dermatol, 2011,164(6):1316-25.-¹⁹19 Zhao l, Li IF. Contact sensitization to 34 common contact allergens in university students in Beijing. Contact Dermatitis, 2015,73(5):323-4.], 3 cross-sectional studies [²⁰20 Gómez Vázquez M, Fernández-Redondo V, Toribio J. Allergic contact eczema/dermatitis from cosmetics. Allergy, 2002,57(3):268-9.

21 Lee SS, Hong DK, Jeong NJ, Lee JH, Choi Y, Lee A. Multicenter study of preservative sensitivity in patients with suspected cosmetic contact dermatitis in Korea. J Dermatol, 2012, 39(8): 677-81.-²²22 Rodrigues DF, Goulart EM. Patch test results in children and adolescents. Study from the Santa Casa de Belo Horizonte dermatology clinic, Brazil, from 2003 to 2010. An Bras Dermatol, 2015, 90(5): 671-83.], 2 case reports [²³23 Cooper SM, Shaw S. Allergic contact dermatitis from parabens in a tar shampoo. Contact Dermatitis, 1998,39(3):140., ²⁴24 Henry JC, Tschen EH, Becker LE. Contact urticaria to parabens. Arch Dermatol, 1979,115(10):1231-2.] and one quasi-experimental study [²⁵25 Dogra A, Minocha YC, Sood VK and Dewan SP. Contact dermatitis due to cosmetics and their ingredients. Indian J Dermatol Venereol Leprol, 1994, 60(2):72-5.]. No study was retrieved through the manual search. The reasons for the exclusion of studies after reading in full are described in supplementary material 2: (https://osf.io/v4fuy/?view_only=3a076c1726ec4cfd86e852cc964f7c3a)

The study characteristics and participants baseline characteristics are described in Table 1.

Two studies were conducted in three countries, and the rest of the studies were conducted in only one country each. The publication period varied between 1979 and 2015. Two studies evaluated only one individual (case reports), and among the other 12 studies the number of individuals ranged between 70 and 281,100. The age of the individuals included ranged from 1 to 83 years. One of the case reports refers to a man and the other to a woman. Of the other studies, five reported the gender of the individuals, and of these, 69.5% (1,252) were women. The time elapsed between the application of the paraben and the evaluation of the skin reaction varied between immediately and 2 days after the application (eight studies did not provide this data).

Of the studies detailing which paraben was used (eight studies), all used more than one paraben, or a mixture of parabens (table 2). Four studies used parabens at a concentration of 16%, two studies 15%, one study 12% and one study 5%. Only two studies have been carried out in healthy patients [¹⁹19 Zhao l, Li IF. Contact sensitization to 34 common contact allergens in university students in Beijing. Contact Dermatitis, 2015,73(5):323-4., ²⁴24 Henry JC, Tschen EH, Becker LE. Contact urticaria to parabens. Arch Dermatol, 1979,115(10):1231-2.]; the other studies included patients with suspected allergic skin reactions.

Quality assessment

For observational and quasi-experimental studies, the average of the results obtained was 6.3, and only two studies were considered of high quality with a score of 9 [⁵5 Dinkloh A, Worm M, Geier J, Schnuch A and Wollenberg A. Contact sensitization in patients with suspected cosmetic intolerance: results of the IVDK 2006-2011. J Eur Acad Dermatol Venereol, 2015, 29(6): 1071-81., ²¹21 Lee SS, Hong DK, Jeong NJ, Lee JH, Choi Y, Lee A. Multicenter study of preservative sensitivity in patients with suspected cosmetic contact dermatitis in Korea. J Dermatol, 2012, 39(8): 677-81.]. The other studies scored 5 or 6, indicating moderate quality.

The results obtained in the evaluation of the methodological quality of the case reports indicate that the studies were of good quality, as both presented the answer “no” in only one of the items.

Meta-analysis

Twelve studies (1,802 individuals) were selected for the single-arm meta-analysis. As these were heterogeneous studies, the random effects model was chosen in the analysis. Figure 2 shows the result of the overall ACD occurrence rate (0.9% [95%ci 0.4-2.0%]. The results demonstrate high heterogeneity (99.4%) among the studies.

In the subgroup analyses according to the country of the study (Table 3), it was not possible to evaluate the studies conducted in North America as this comprised only one study. Studies conducted in Asia had an incidence of ACD of 48 positive cases per 1000 individuals (i2 = 97.79%). Studies conducted in South America resulted in an incidence of 11 positive cases per 1000 individuals (i2 = 0). In the European region, the incidence was 4 positive cases per 1000 individuals (i2 = 98.883%).

Publication bias

Figure 3 presents the funnel graph, suggesting the presence of publication bias.

DISCUSSION

Although parabens are popular, since the 1960s, their use and safety according to ACD is questionable. Therefore, its use as a preservative in cosmetic, pharmaceutical and industrial products raises concerns about the possible risk to human health [⁴4 Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis, 2005, 16(2): 57-66; quiz 55-6., ²⁶26 Hafeez F, Maibach H. An overview of parabens and allergic contact dermatitis. Skin Therapy Lett, 2013, 18(5): 5-7.]. Although there is controversy regarding the use of parabens in cosmetics, this class of chemical preservatives has withstood extensive tests carried out by some north american and european organizations. It is noticeable that the use of a “claim” (paraben-free) has been highlighted in the media, but the use of this term may be limited to marketing, since the use of these substances within the indicated concentration is allowed by competent agencies. However, the fear that parabens may induce ACD has remained persistent [¹⁵15 Duarte I, Antonio Jabur da Cunha J, Lazzarini R. Allergic contact dermatitis in private practice: what are the main sensitizers? Dermatitis, 2011,22(4):225-6., ²⁷27 Pedersen S, Marra F, Nicoli S, Santi P. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci, 2007, 29(5): 361-7.]. Therefore, the FDA continues to assess the safety of parabens [²2 Food and drug administration. Parabens in cosmetics. 2020 apr. Available from: https://www.fda.gov/cosmetics/cosmetic-ingredients/parabens-cosmetics
https://www.fda.gov/cosmetics/cosmetic-i... ].

This is the first systematic review published in the literature on the safety of parabens regarding the incidence of ACD. We evaluated 14 studies that addressed the use of some type of cosmetic containing parabens as a preservative and its possible relationship with ACD. The included studies were carried out in different countries on different continents, showing that studies assessing these substances have been conducted in different regions of the world. Most of the studies found in the present systematic review showed low ACD rates in individuals using parabéns [⁵5 Dinkloh A, Worm M, Geier J, Schnuch A and Wollenberg A. Contact sensitization in patients with suspected cosmetic intolerance: results of the IVDK 2006-2011. J Eur Acad Dermatol Venereol, 2015, 29(6): 1071-81.,¹³13 Adams RM, Maibach HI. A five-year study of cosmetic reactions. J Am Acad Dermatol, 1985,13(6):1062-9.,¹⁵15 Duarte I, Antonio Jabur da Cunha J, Lazzarini R. Allergic contact dermatitis in private practice: what are the main sensitizers? Dermatitis, 2011,22(4):225-6.,¹⁶16 Romaguera C, Camarasa JMG, Alomar A, Grimalt F. Patch tests with allergens related to cosmetics. Contact Dermatitis, 1983,9(2):167-8.,¹⁸18 Schnuch A, Lessmann H and Geier J and Uter W. Contact allergy to preservatives. Analysis of IVDK data 1996-2009. Br J Dermatol, 2011,164(6):1316-25.

19 Zhao l, Li IF. Contact sensitization to 34 common contact allergens in university students in Beijing. Contact Dermatitis, 2015,73(5):323-4.

20 Gómez Vázquez M, Fernández-Redondo V, Toribio J. Allergic contact eczema/dermatitis from cosmetics. Allergy, 2002,57(3):268-9.-²¹21 Lee SS, Hong DK, Jeong NJ, Lee JH, Choi Y, Lee A. Multicenter study of preservative sensitivity in patients with suspected cosmetic contact dermatitis in Korea. J Dermatol, 2012, 39(8): 677-81.,²⁴24 Henry JC, Tschen EH, Becker LE. Contact urticaria to parabens. Arch Dermatol, 1979,115(10):1231-2.], both for individuals with suspected ACD and healthy subjects.

Two studies included in this systematic review were carried out in a population in India, totalling 270 individuals. Of these, 89% were women. In these studies, the incidence rates of ACD in relation to exposure to parabens were approximately four times higher when compared to the other studies [¹⁷17 Sarma N, Ghosh S. Clinico-allergological pattern of allergic contact dermatitis among 70 indian children. Indian J Dermatol Venereol Leprol, 2010,76(1):38-44., ²⁵25 Dogra A, Minocha YC, Sood VK and Dewan SP. Contact dermatitis due to cosmetics and their ingredients. Indian J Dermatol Venereol Leprol, 1994, 60(2):72-5.]. This may have occurred because the concentration of parabens used in Indian goods may be above the permitted standard level (0.1-0.3%), leading to greater skin sensitization, so these results obtained need to be validated in further studies [¹⁷17 Sarma N, Ghosh S. Clinico-allergological pattern of allergic contact dermatitis among 70 indian children. Indian J Dermatol Venereol Leprol, 2010,76(1):38-44.].

Sensitization to parabens, whether immediate or delayed hypersensitivity, presents a difficult diagnosis and a therapeutic challenge for physicians. When detected, individuals should be advised to avoid cosmetics or other products containing these preservatives [²⁴24 Henry JC, Tschen EH, Becker LE. Contact urticaria to parabens. Arch Dermatol, 1979,115(10):1231-2.]. There are reports that ACD caused by parabens contained in shampoo formulations is uncommon, except for damaged skin. Therefore, it is possible to conclude that on skin already damaged by some type of irritation, dermatitis is more likely to occur due to contact with the use of cosmetic products containing parabens, since the skin is already sensitized [²³23 Cooper SM, Shaw S. Allergic contact dermatitis from parabens in a tar shampoo. Contact Dermatitis, 1998,39(3):140.].

In the single-arm meta-analysis, the incidence of ACD was 0.9%. As recommended by the Council for International Organizations of Medical Sciences (CIOMS), this is considered a rare reaction [²⁸28 World Health Organization. Guidelines for preparing core clinical-safety information on drugs. Report of CIOMS working groups III and V, Ed. 2. 1999, Geneva: CIOMS. 101.]. In addition, it was observed that the heterogeneity among the studies included in the analysis was high. The cause of this heterogeneity may be related to clinical, methodological and statistical variations of the included studies. The subgroup analysis carried out by region showed that Asia had a higher prevalence of ACD associated with parabens, which can be explained by the studies carried out in India that presented a significant number of positive cases. In addition, all studies used doses of parabens above recommended levels, which may overestimate the incidence of ACD.

One of the latest studies carried out by the CIR panel of experts concluded that 20 different types of parabens are safe in cosmetics, as long as they are within the current practice of use and in concentrations considered safe [¹1 Cosmetic Ingredient Review. Expert panel cosmetic ingredient review. 2019 oct. Available from: <https://www.cir-safety.org/sites/default/files/Admin_5.pdf>.
https://www.cir-safety.org/sites/default... ]. Although the different types of parabens evaluated through contact testing in the studies included in this systematic review are within the list of parabens allowed by the CIR panel, it is known that the concentrations used in contact tests are much higher than those recommended by the agencies, which leads us to conclude that the incidence of ACD would be even lower if recommended concentrations of parabens were used.

The CIR panel of experts is concerned about the bioaccumulation potential of parabens, which can be distributed throughout tissues. In addition, despite recent studies using sensitive analytical tests demonstrating the presence of parabens in different human tissues, the data are still unclear about permanent accumulation in tissues, so further studies are needed. It has been shown that, after parabens are applied to the skin, they are metabolized into 4-hydroxybenzoic acid, which is safe under the typical conditions of use [²⁹29 Cosmetic Ingredient Review. Procedures & support to the expert. Panel for cosmetic ingredient safety. 2019, Washington: Cosmetic Ingredient Review. 23.].

Limitations

The present study was limited to investigating the relationship between the use of parabens in cosmetics and the incidence of ACD; therefore, other problems related to parabens were not the subject of this study.

Another limitation of this study is that only two of the studies had a control group. Thus, the meta-analysis was conducted without comparison with another group. For more robust results, controlled studies are necessary.

In view of all the data collected and analyzed in this systematic review with a meta-analysis, we observed that, in the few cases in which ACD was associated with the use of cosmetics containing parabens, the reaction was often attributed to the application of parabens on already damaged skin and at concentrations much higher than recommended. Therefore, skin reactions to cosmetic products containing parabens in their formulations are rare and, when they occur, it is recommended to discontinue use of the product containing this preservative. This fact does not justify the interruption of the use of this class as preservatives in cosmetics. These data would be better evaluated in studies with a control group, at the usual concentrations of parabens and in individuals without suspected ACD.

CONCLUSION

According to the results obtained in this study, considering the advantages, facility of use, compatibility with different cosmetic formulations, low cost and good effectiveness, the incidence of ACD after using cosmetics with parabens is observed as a rare event. Therefore, we can consider that paraben-free products do not appear to be advantageous to the consumer, since they generally have a higher cost on the market. However, as a safety measure, consumers who have already been diagnosed with ACD can be advised to avoid the use of cosmetic products containing parabens, since the chance of increasing dermatitis with the use of parabens may be greater because the skin is already be sensitized.

REFERENCES

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History