The antimicrobial effect of parabens and their potential utility as preservatives were first reported in 1924 by Sabalitschka.1 Their use has steadily increased; they are now among the most common biocides present in cosmetics, foods, and pharmaceuticals. This favored status has been achieved because of documented minimal toxicity, low cost, chemical inertness, and near worldwide acceptance (although that status is currently being challenged). Cosmetic chemists use parabens in their formulations because they have no perceptible odor or taste, are effectively pH neutral, and do not discolor or harden.2 Within this family, methylparaben, ethylparaben, propylparaben, and butylparaben are the most commonly used members, independently and in combination with each other or other biocides. Methylparaben and propylparaben are by far the most used, generally at concentrations of 0.4% or less and frequently much lower.3,4 Parabens are assessed as nonmutagenic.5
Without preservation, cosmetic products and pharmaceuticals rapidly become contaminated with mold, fungi, and bacteria, resulting in spoilage and increased infection risk. The cleaner the manufacturing process and site, the less preservation required. Particularly problematic microbes are the gram-positive Staphylococcus aureus and the gram-negative Escherichia coli. Product preservation is an absolute necessity. Despite the misguided apprehension about and public fear of preservatives being “bad for you” or “not natural,” parabens have been classified as generally regarded as safe by the US Food and Drug Administration (FDA).6
PHYSICOCHEMICAL PROPERTIES AND METABOLISM
Parabens are homologous esters of p-hydroxybenzoic acid and represent an aromatic carboxylic acid containing a carboxyl group bonded directly to a benzene ring; a hydroxy group is present on position 4 with varying alkyl radicals as side chain. Parabens in general are stable and nonvolatile; absorbed via the gastrointestinal tract and, to a degree, percutaneously; hydrolyzed to p-hydroxybenzoic acid; and conjugated with rapid urinary excretion. There is no solid evidence of accumulation within body tissues or organs, although detectable tissue and organ levels of indeterminate duration have been reported. One study has shown that parabens weakly interact with human serum albumin, thus suggesting that they are present to some degree in free form in plasma and available to reach or, theoretically, even accumulate in internal organs and tissues.7 Notwithstanding, parabens have not been proven to be carcinogenic or cytotoxic. Parabens are white, odorless, and crystalline and exhibit adequate water solubility to achieve preservative activity. Increasing oil and organic solvent solubility is seen with increasing alkyl chain length (the same increase of chain length decreases water solubility and therefore the desired preservation activity). They are used in cosmetics, pharmaceuticals, and foods, but a strong, undesirable metallic taste occurs at concentrations of more than 0.08%, which (along with the understandable desire to minimize systemic exposure) results in limiting concentration used in foods.8 They are biodegradable by a number of nonspecific enzymes in nature, a fact that would suggest a potential environmental benefit in their use.9
Paraben biocidal mechanism, in general, and propyl paraben, in particular, may be linked to mitochondrial failure dependent on induction of membrane permeability transition accompanied by the mitochondrial depolarization and depletion of cellular adenosine triphosphate through uncoupling of oxidative phosphorylation.10 At the root of antimicrobial activity is the disruption of membrane transport processes, although some investigators have identified the inhibition of DNA and RNA synthesis; action upon key enzymes such as adenosine triphosphatases and phosphotransferases may also play a role.11–13 On the macroscopic level, the mechanism of antibacterial action of parabens is linked to the membrane with disruption of the lipid bilayer, thereby interfering with bacterial membrane transport processes and perhaps causing the leakage of intracellular constituents.14
The paraben family has excellent coverage against fungi and gram-positive bacteria. They are more effective against fungi than bacteria, and antibacterial activity is most effective against gram-positive organisms.15 Evidence of antimicrobial activity for commonly used parabens shows broad inhibition of E. coli, Pseudomonas aeruginosa, Aspergillus niger, and Candida albicans, with higher inhibition of staphylococcal species, particularly S. aureus.16 The potency of cosmetic preservatives has been studied, and minimal inhibitory concentration (MIC) determinations reveal parabens to be less powerful biocides in comparison to other common agents as evidenced by much higher MIC concentrations (Table 1).17 Antimicrobial activity also differs to a significant degree between parabens (Table 2).18 Within a bacterial genus, MIC levels may vary greatly; such is the case with Salmonella species.19
Combinations of parabens are often found in final formulations, depending on solubility differentials, desired shelf life, and spectrum of activity. Evidence exists for improved antimicrobial efficacy with the use of lower concentrations of multiple parabens. Methylparaben and ethylparaben are the 2 most frequently paired.20 Paraben biocidal activity increases with the length of the hydrocarbon alkyl chain, while solubility simultaneously drastically decreases. This is another rationale behind using parabens in combination.10,21 The issue of solubility of individual parabens when used in combination is complex. Propylparaben exhibits a peculiar solubility behavior in aqueous solution, with approximately 50% decreased solubility in mixtures also containing ethylparaben, a finding substantiated by solubility experiments on tertiary and quaternary combinations of parabens.22
Because coverage against gram-negative bacteria is limited, a second nonparaben biocide is often added to final formulations. Phenoxyethanol is the most commonly found synergistic biocide, but formaldehyde-releasing biocides and isothiazolinones are also frequently used.23 These combination biocides often allow effective preservation with lower concentrations of all preservative components.
Thirty-five different parabens have been identified. Excluding p-hydroxybenzoic acid and structures with deuterium and carbon 13, and including complex structures, calcium, sodium, and potassium salts and sulfates, there are at least 24 different paraben moieties. Their relevant side chains, common names, chemical formulas, and structures may be compared (Table 3).24 Up to 10 have been identified as present in a single cosmetic formulation, although use of 2 to 5 is not uncommon.25,26
SYNONYMS FOR PARABEN
Marks et al27 identified 14 synonyms for paraben preservatives. Similar synonym lists may been found in other references. PubChem, an online compendium of chemical substances, maintains a list of depositor-supplied synonyms for parabens in cosmetics and industrial products.28 Thirty synonyms and trade names for the 5 most commonly used paraben derivatives are displayed (Table 4). Including all tabulated nomenclature from this list and similar names notwithstanding, there are many names by which paraben derivatives may be identified in occupational applications: methylparaben has 220 synonyms29; propylparaben, 179 synonyms30; ethylparaben, 175 synonyms31; butylparaben, 173 synonyms32; and benzylparaben, 100 synonyms.33 In cosmetic products, the International Nomenclature for Cosmetic Ingredients name, as listed in the column headers of Table 4, must be used.
SOURCES OF EXPOSURE TO PARABENS
Parabens are ubiquitous.34,35 They have been documented in house dust, pond water, and even trace amounts in mineral and treated water samples.36 The 3 major sources of parabens are cosmetics, medications, and food stuffs, and these will be examined separately.35,36 Estimates in the United States suggest that the average total paraben exposure per individual is approximately 76 mg/d (up to 1.3 mg/kg per day for a person weighing 70 kg).10 Cosmetics and personal care products provide roughly two thirds of this at 50 mg/d, whereas pharmaceutical products supply 25 mg/d, and food contributes only 1 mg/d. The concentration of parabens in foods is usually less than 1%. However, given their poor percutaneous absorption, parabens applied to the skin may account for a significantly lower systemic burden than does exposure from foods or systemic medicaments.37
One European study found parabens in 99% of leave-on products and 77% of rinse-off products.38 Zirwas and Moennich39 found parabens as the seventh most common allergen in shampoos, behind the more frequently positive preservative isothiazolinone. Uter et al40 in 2014 reported that, of 4680 German products, 39% contained between 1 and 5 parabens; most often, parabens were found with phenoxyethanol. Our personal internet database searches have identified German products that contained up to 7 parabens.41
Gabb and Blake42 looked at 38,975 consumer products and found that 4435 contained methylparaben (11.4%), 1356 contained ethylparaben (3.5%), and 1008 contained butylparaben (2.6%) (Fig. 1). They found parabens to be rarely used in household products. Only methylparaben was identified in ingested products, whereas hair, oral, and personal care products enjoy relatively broad application at 10% to 30%. Bronzers, tanners, eye makeups, and foundations had methylparaben present more than 40% of the time.
In 1 comprehensive US series, Scheman et al43–46 and the American Contact Alternatives Group chronicled the frequency of paraben utilization in a widespread array of 5416 cosmetic products. Parabens were found in 66% to 87% of women's cosmetics, 30% of shampoos, 77% to 82% of lipsticks and lip liners, 30% of sunblocks, and 23% of wipes. Notably, none of the 195 deodorants and antiperspirants examined contained parabens.
The American Contact Dermatitis Society maintains a database of cosmetic and household products, known as the Contact Allergen Management Program (CAMP).47 By using this interface, a search for products safe to use for the solely paraben-sensitive patient provides a wealth of information (Table 5).48 As of May 28, 2018, the CAMP tabulates ingredients in 4612 products; overall, 874 contain parabens (19%). The CAMP database has 90 categories of products, so relevant information has been regrouped for highlighting purposes. Facial cosmetics and products average 30% paraben presence, with face makeup (other) (52.1%) and face powder (43.4%) having the highest percentages. One hundred thirty-three of 376 moisturizers (35.4%) contain parabens. Eye care products and makeups also average just more than 30%, with mascara and eyeliner as the most frequent products to contain parabens (53.3% and 42.9%, respectively). Less than 10% of hair care products, shampoos, and conditioners contain parabens. Lip and mouth care products average less than 15%, with a mere 1.3% of toothpastes containing parabens. Lip liner, however, contains it more than 30% of the time.
The CAMP household products, a total of 283 catalogued, contain parabens only 1.1% of the time. Topical medicaments frequently contain parabens (45.6% acne/rosacea, 37.5% topical antibiotics, and 35.5% of pain, first aid, and numbing products). Seborrhea therapies frequently contain parabens (66.7%), as do products for aging and wrinkling (39.3%). Products that are applied to potentially inflamed skin regions for comfort or healing have parabens at frequencies which could be interpreted as worrisome (in light of the information about increased incidence of paraben sensitivity in patients with stasis dermatitis or skin integrity issues); these include barrier products (46.2%), perianal products (62.5%), and personal hygiene lubricants and fresheners (48%). This concern regarding allergic sensitization from anogenital paraben exposure has not been confirmed in a subsequent study.49
Additional CAMP reports and alternative databases are available for product ingredient review; SkinSAFE and a database compiled by the Environmental Working Group (EWG) are 2 examples.26,50,51 The comparison of preservative use in these 3 databases provides useful information (although data set sources are not equivalent) (Table 6).
Parabens are frequently found in products in all 3 databases, at a rate between 17% and 21%. In the CAMP, parabens were the second most frequently used preservative, present in a total of 983 products (20.75%). Only phenoxyethanol was more heavily represented at 23.9%, whereas methylisothiazolinone (MI) was present in 12.9% and the 2-part biocide methylchloroisothiazolinone/MI was present in 8.8%. The rare allergens benzyl alcohol and benzoic acid were also represented at more than 10%, whereas all other biocides were seen in less than 10% of products. The SkinSAFE database has similar proportions, with slightly lower paraben utilization by percentage compared with CAMP. The frequencies of the different parabens used in cosmetics as documented by the EWG and SkinSAFE are remarkably similar. Phenoxyethanol is seen in 20% more products than are parabens in CAMP and in nearly twice as many products in SkinSAFE; parabens are more commonly used than phenoxyethanol (16.8% vs 7.7%, respectively) in the EWG tabulation. These data are roughly equivalent to those in a published study from 2005.52
The Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives (JECFA) established a total paraben (the sum of methylparaben, ethylparaben, and propylparaben) acceptable daily intake (ADI) of 0 to 10 mg/kg of body weight, although propylparaben and other parabens with yet longer alkyl side chains were later recommended for exclusion from the total paraben ADI because of endocrine disruptor activity potential.53 There are no other defined regulations regarding the use of parabens in domestic foods, although recommended use parameters have been proposed at concentrations not to exceed 0.1% in medications.54 In the United States, parabens are listed as such on the label of ingredients; in Europe, parabens are not generally identified but given E-numbers instead. The most commonly used parabens in food are methylparaben (food additive E218) and ethylparaben (E214), with the European Food Safety Authority setting an acceptable daily intake of 0 to 10 mg/kg of bodyweight per day for methylparaben and ethylparaben. Other less commonly found parabens preserving foods include propylparaben (E216), heptylparaben, butylparaben, and isobutylparaben.55
Absolute amount and extent of paraben utilization in ingestibles are unknown but expected to vary greatly. For example, 50 fresh-cut vegetable samples from different farmer markets in Beijing, China, were collected to measure parabens, and only 1 sample tested positive to methylparaben with concentration at 81 μg/kg as determined by the QuEChERS technique (perhaps the optimal assay for detecting chemical residues in fruits and vegetables).54 Conversely, a separate study in China found nearly all of the food sources to contain at least 1 kind of paraben (cereal products, meat, seafood, eggs, dairy products, bean products, vegetables, and fruits). Levels determined using high-performance liquid chromatography–tandem mass spectrometry detection revealed the total paraben sum of concentrations to range from undetectable to 2530 ng/g of fresh food weight (mean, 39 ng/g).56 It seems predictable that fresh foods would have low-paraben content in comparison with processed foods.
Detailed lists of foods that contain parabens are frequently published, and the summary data are presented (Table 7). Not previously reported is the quantification of paraben content in different foods. Wang et al57 examining foods from Albany, New York, found 90% of foods across all categories to contain a mean of 9.67-ng/g parabens; methylparaben, ethylparaben, and propylparaben predominated. They estimated the mean daily ingestion rates of food items to be 940, 879, 470, 273, and 307 ng/kg of body weight per day for infants, toddlers, children, teenagers, and adults, respectively; the daily ingestion for a 70-kg man calculates to 21 μg, well below the levels used in many in vivo and in vitro studies with no observed adverse effects.4 Foods with particularly high levels of methylparaben include pancake syrup, muffins, iced tea, pudding, and turkey roast; propylparaben and ethylparaben were highest in turkey breasts, turkey roast, yogurt, apple pie, and red wine. Chinese consumption may be yet higher, converting to approximately 27 mg/d in adults.4 Additional studies to look at paraben content in food are indicated. Although the margin of safety (MOS) has been estimated for multiple topical cosmetic product use at 3000 for infants and 840 for adults, an equivalent determination has not been made for the ingestion of parabens.4
A list of oral medications that contain parabens is maintained in a compendium generated by Drugs.com (Table 8).58 Although not an exhaustive tabulation, methylparaben, propylparaben, and butylparaben are the 3 most common.59–61 Isobutylparaben, propylparaben sodium, and methylparaben sodium are found in a handful of products.62–64 Enteral and parenteral medications that tend to include these preservatives include multidose vial antibiotics, local anesthetics, corticosteroids, enteral and parenteral vitamins, diuretics, insulin, heparin, antihypertensives, chemotherapeutic agents, haloperidol, and other syrups.15,48,65 Topical prescription agents include formulations of benzoyl peroxide, clindamycin, clocortolone, desonide, eflornithine, fluocinolone acetonide, fluorouracil, fluticasone, hydrocortisone, hydroquinone, imiquimod, metronidazole, salicylic acid, sertaconazole, sodium sulfacetamide, tretinoin, and urea.66
Evaluation of the excretion of parabens resulting from their ingestion in pharmaceuticals has been undertaken. In 1 small study without control population and with a small sample size, paraben-containing medication ingestion on the same day as urine sampling (range, 0.75–7.0 hours) was associated with a nearly 14-fold increase in mean urinary methylparaben concentration. Dodge and colleagues67 measured the temporal relationship between paraben-containing medication ingestion and levels of urinary excretion of parabens. Ingestion of a medication containing parabens within 7 hours was associated with 8.7- and 7.5-fold increases in mean methylparaben and propylparaben concentrations, respectively.
Individuals sensitized to parabens rarely, if ever, have to avoid foods or pharmaceuticals that contain parabens to control their dermatitis; flares of eczema are not reported with their ingestion. However, paraben-sensitive cooks and food handlers who prepare foods containing the preservative may develop hand dermatitis.15,65 Veien et al68 performed peroral challenge with 100 mg of mixture 50/50 methylparaben and propylparaben in 14 paraben-allergic patients; dermatitis flared in 2, but neither improved with paraben avoidance in foods, suggesting that no direct cause and effect existed. Systemic contact dermatitis to parabens has been reported but is believed to be exceedingly rare.69,70
SENSITIZATION POTENTIAL OF PARABENS
The sensitization potential of an antigen has traditionally been evaluated by the Buehler guinea pig and the guinea pig maximization tests (with injection of test material in Freund complete adjuvant). These techniques, bypassing the cutaneous barrier and antigen processing cell contact, have been reported to both overestimate the risk of weak antigens71 and underestimate the risk of strong antigens.72 For the past several decades, the murine local lymph node assay (LLNA) has been the criterion standard for testing materials for allergenicity in animals, because it not only uses fewer animals but also can be used to classify the potency of a given material.73 In their excellent review of testing procedures with human skin sensitization test methodologies (including repeat insult patch testing, provocative use test, or extended product use test), Robinson et al74 stressed the need for a comprehensive, balanced approach to all sensitization risk assays. Basketter75 also reviewed skin sensitization methodology in detail and observed its essential nature to be that of comparative toxicology, because various substances are evaluated in a relative fashion.76 Parabens have been classified as nonsensitizing in these 3 predictive assays.
The murine LLNA is based on measurement of the proliferative activity of draining lymph node cells on day 7 after 3 consecutive days of index chemical application. Degree of activation is determined by incorporation of one of several different radiolabels, is seen to be an alternative from the methods hereinbefore, and is more animal friendly. Basketter et al,77 using the LLNA, have ranked parabens as a human class 4 antigen with very weak or no sensitization risk. Comparatively, parabens are less sensitizing than class 2 and 3 antigens, dominated by fragrances, and class 1 with potent antigens such as dinitrochlorobenzene.
The European Union (EU) has banned animal testing for cosmetic ingredients, making alternative reliable testing methodology necessary. One approach that emulates the in vivo situation of human skin, known as the loose-fit coculture-based sensitization assay, cocultures primary human keratinocytes and allogenic dendritic cell–related cells.78 Sensitization potency of parabens was assessed by flow cytometric analysis of the dendritic cell–related cell maturation marker CD86 as indicators of dendritic cell activation. Parabens exhibited weak (methylparaben, ethylparaben, propylparaben, and isopropylparaben) or strong (butylparaben, isobutylparaben, pentylparaben, and benzylparaben) effects, with phenylparaben exhibiting an intermediate effect; as with cutaneous penetration capabilities, sensitization potencies of parabens correlate with side chain length. Parabens used in cosmetics showed no (methylparaben and ethylparaben) or weak (propylparaben, isopropylparaben, butylparaben, isobutylparaben, phenylparaben, and benzylparaben) irritative potencies; only pentylparaben was rated to be an irritant.
A novel modification of this technique adds lymphocyte surface marker determination, with antigens differentially affecting these markers based on potency: strong antigens raised interleukin-4 concentrations in coculture supernatants, whereas interferon gamma levels decreased, indicating T helper 2 (Th2) cell activation in vitro.79
The Genomic Allergen Rapid Detection involves the assessment of transcriptional changes of selected genomic biomarkers (Genomic Allergen Rapid Detection predication signal) induced in a myeloid cell line in response to chemical stimulation.80 Propylparaben was predicted as a sensitizer by this assay, whereas in the LLNA and human potency studies, it was not. Overall predictive performance of the test is estimated at 83% to 90%.81 Developments such as these are hoped to improve the evaluation of sensitization potential of new products and established allergens, including parabens.
These assays and similar in vitro methods are, like the LLNA, alleged to define hazard, rather than risk. Their predictive power (false negatives and false positives) remains in an early evaluation stage.82
Schnuch and colleagues83 of the Informationsverbund Dermatologischer Kliniken (IVDK or Information Network of Dermatology Clinics) identified the importance of relating the frequency of sensitization to the probable exposure to preservatives via leave-on cosmetics, which they quantified by the number of products containing the preservative in question (n = 3566, as documented by the Chemisches und Veterinaruntersuchungsamt Karlsruhe/Germany). By dividing the relative percentage of products containing a biocide (product share) by the percentage of “allergy share” of a product in screening (percent positive of all positive biocides), they were able to quantify exposure risk for preservatives in light of allergen potency; they labeled this the sensitization exposure quotient (SEQ). Parabens ranked third lowest of 10 preservatives and biocide families studied (0.36). Only phenoxyethanol (significantly lower, 0.06) and benzoic acid (slightly lower, 0.30) have lower SEQ. Sorbates and benzoates were intermediate, whereas all of the biocides that contact dermatitis investigators examine in a standard screening fashion have SEQ values between 1.6 and 13. This evaluation would indicate that parabens are allergologically safer than all other preservatives evaluated except for phenoxyethanol and benzoic acid.
PATCH TEST PROCEDURE
A paraben mix is used to screen for contact allergy to parabens across the globe, using a combination of 4 or 5 different parabens at 3% to 4% concentration, depending on the testing system used (Table 9).65 The North American Contact Dermatitis Group (NACDG) uses a 12% concentration with methylparaben, ethylparaben, propylparaben, and butylparaben, each at 3%; until 1996, the test concentration used was 15% and contained hexylparaben. In Europe and in many other parts of the world, parabens were tested in a 15% concentration (methyl, ethyl, propyl, butyl, and benzyl, each at 3%) until 1994; thereafter, test concentration was 16% (deletion of benzylparaben and other parabens raised to 4% concentration in petrolatum). This higher concentration is proposed by European investigators to be necessary to overcome the epidermal barrier and avoid false-negative results. The converse of the weak positive reaction must be interpreted with caution because this higher concentration approaches irritancy threshold. Patch testing with the paraben-allergic patient's own products is frequently negative because the concentration within the formulation is well below elicitation threshold. Repeated open application testing (also called provocative use testing) of the product on dermatitic or uninvolved skin may be positive and should be considered an important part of the evaluation.
Although the concentration of the paraben mix has varied for geographical area and time, mixes have been used since the earliest patch testing to parabens was undertaken. The recommendation that parabens be tested individually (as true-positive patch test reactions may be missed with the mix) has not been widely adopted by the contact dermatologic community.84
In a comprehensive study by the IVDK, patch test results were correlated to clinical causation and comparison of Reaction Index (relating the number of allergic reactions to the number of doubtful or irritant reactions) and the positivity ratio (relating the frequency of positive reactions to the total number of allergic reactions).85 Problematic allergens included the paraben mix, which had a negative reaction index (−0.22) at a positivity ratio of 84.8%. This indicates a potential problem with the patch test material as irritating. Only 0.2% of their 121,247 patients tested had 2 to 3(+) strength reactions to paraben mix, with the remaining 1.1% having 1(+) reactions or weaker. Up to 50% of paraben mix reactions were false positives, which was verified as negative reactions when subsequently tested individually.
PARABENS AS CONTACT ALLERGENS
There are numerous excellent paraben contact dermatitis reviews.1,15,65,86–91 The gestalt among these studies is that, despite parabens being a ubiquitous group of preservatives with a remarkably high degree of exposure in the general public, the prevalence of positive patch tests is low. Despite being the most frequently used biocide, a general overall positivity rate in screening studies of 1% is frequently quoted, and the interpretation of the acceptance of this benchmark threshold varies by author and continent. Because we are discussing comparable sensitization risks to other available preservatives, paraben's performance as (non)allergenic is stellar.
North American Experience
The monitoring of paraben allergy has been ongoing for nearly as long as they have been used as biocides, with the first reported studies of paraben testing as an allergen and contact sensitivity dating to 1940.92 Schorr and Mohajerin93 published the first case of contact dermatitis to parabens in the United States in 1966. Schorr also published one of the earliest reports of routine screening of parabens (tested at 5% in petrolatum) in 21 patients for 2 years and found 0.8% to be allergic.94 Epstein95 published his early experience 2 months earlier in 1968.
A report of 927 patients tested at 1 US institution showed a positivity rate of 2.9% for parabens for a 2-year period; they identified an increased risk of co-sensitization to other preservatives, including formaldehyde and quaternium 15.96 Nethercott97 found parabens as rare sensitizers in 200 patients in Toronto (0.5%, 1 patient).
The Mayo Clinic Experience
The second largest body of data in North America comes from the Mayo Clinic. Testing at the higher “European” concentration of 16% paraben mix, the Mayo Clinic Contact Dermatitis Group reported paraben positivity in 1.6% of 1318 patients from 1998 to 2000,98 1.7% of 3841 patients from 2001 to 2005,99 and 1.2% of 4439 patients from 2006 to 2010.100 Irritant patch test frequency at this higher concentration was reported for the 2001 to 2005 data set at 0.7%, significantly higher than the NACDG irritancy rate during the overlapping period (0.2% from 2001 to 2002, P = 0.0001). A total of 98.5% of positives were relevant or of “questionable relevance.” By comparing the Mayo and NACDG data, 16% paraben mix is shown to have a higher frequency of irritant responses than the 12% concentration.
The North American Contact Dermatitis Group Experience
The NACDG, currently a consortium of 18 contact dermatitis specialists in the United States and Canada, periodically publishes the results of testing to its current standard screening tray, a set of chemicals that changes over time under the effects of emerging allergens and cumulative experience. The first report in this fashion was published by Rudner et al101 in 1973, with follow-up reports of subsequent data cycles by the same lead author in 1975 and 1977.102,103 The paraben positivity rate from 1971 to 1972 was 3.0% in 1200 patients, 3.5% from 1972 to 1974 in 2366 patients, 3.7% in 1900 patients from 1974 to 1975, and 2.7% in 1975 to 1976. The 1989 to 1990 data cycle showed paraben allergy in 1.3%,104 whereas Storrs et al105 reported paraben screening in a preservatives and vehicles series, positive in 7 of 661 patients (1.1%) tested from 1984 to 1985. Parabens were not reported in the summary of NACDG screening data from 1985 to 1989.106
The NACDG has reported its experience with parabens routinely at 2-year cycles beginning in 1992.107–117 (Fig. 2, Table 10). What can be readily appreciated is that allergy to parabens is exceedingly uncommon.
Beginning in 1994, the NACDG began including relevancy data in its publications; this was reported in every 2-year data cycle except for 1996 to 1998 and 2003 to 2004 (Table 11). Definite relevance is uncommon because it necessitates positive testing to an actual product or item containing the allergen; probable relevance requires that the allergen be identified as an ingredient or component of an item used by the patient, and possible relevance is ascribed when the patient is exposed to circumstances where skin contact with the type of materials known to contain the allergen in question is possible. Confidence in the significance of the positive reaction is highest with definite relevance, high with probable relevance, and less certain with possible relevance.118
The highest reported positivity rate was the first data cycle between 1992 and 1994 at 2.3% (interestingly, the first 2 data cycles from 1992 to 1996 had the highest rates reported, during which time the higher total concentration of paraben mix (15%) was used). Since that time, positivity rates have progressively fallen, with a positivity rate between 0.6% and 1.4% for the past 18 years. This would lead one to the assumption that this decrease may be due to the decrease in testing concentration. However, if one compares the 2 decades since 1996 (both sets containing five 2-year data cycles, 1996–2006 vs 2006–2016), the null hypothesis is still refuted at P = 0.02. The decline in positivity rates cannot be related solely to the decrease in testing concentration. The mean positivity rate for the entire period from 1992 to 2016 is 1.1% in a total of 55,013 patients. Relevancy data reveal that, when a positive nonirritant paraben reaction is identified, 67.5% to 100% of the time, it was interpreted as relevant (mean, 87.0%); in most patients, retesting to confirm true allergy was either not performed or not reported. Probable and possible relevance were the most common interpretations, with definite relevance ascribed for 0% to 16.7% of patients. The paraben mix is rarely irritating as tested by the NACDG, with the 1994 to 1996 data set showing 5.7% irritancy rate (using 15% paraben mix) and all subsequent reported rates for the 12% paraben mix being from 0.1% to 0.2% when reported, equivalent to that seen by European investators.119
Another method of data assessment may be used by the selective weighting of definite/probable/possible relevance categories (the SPIN calculation or significance-prevalence index number).120 This mathematic calculation allows one to incorporate the allergenicity and relevance of the allergen into 1 measure.120 The SPIN indices for parabens for the past 10 years of the NACDG data period reports spanned 28 to 83, which ranks the paraben mix for that period 22nd to 52nd for all allergens tested. With parabens near the bottom of the list of antigen positivity in all study periods, their higher SPIN compared with their lower rate of positivity indicates higher-than-average certainty of relevancy (Table 12).
In interpretation of these data and those of other investigators, it behooves one to assess the burden of disease represented. In absolute numbers for the 24-year NACDG investigation in 55,023 patients, only 618 patients (1.0%) were identified with positive paraben mix reactions. This is in stark comparison with the data for all other biocides tested in the standard screening tray now and during the course of time. As an example, consider the 2 data sets between January 1, 2013, and December 31, 2016, when the NACDG evaluated a total of 10,452 patients for preservative allergy (Table 13). There were a total of 63 paraben reactions (0.6%). Conversely, MI was positive in 1249 patients (11.9%). Thus, positive reactions were nearly 20 times as common for MI in comparison with the paraben mix. The perspective of having more isothiazolinone allergic reactions in the last 2-year data cycle (749) as compared with paraben reactions for the entire 24 years that the NACDG has monitored for paraben allergy (618) is significant.
The SEQ as described by the IVDK can be roughly applied to the NACDG data by comparing paraben allergy in one 2-year data set (2014–2016) to the relative proportion of products used in the United States as determined by the SkinSAFE experience (Table 14).51 The quotient again is calculated by dividing “product share” (the relative percentage of products containing a biocide) by the “allergy share” (the relative percentage of all biocide allergies). Using this formula, parabens account for 1.3% of the total “allergy share” and 19.6% of the “product share.” The SEQ for parabens is 0.04, up to a thousandfold less than that of methyldibromo glutaronitrile (allowing for possible irritant responses) (80) and significantly less than that of quaternium 15 (7.45) and MI (1.56). Extending this interpretive line of study, by dividing the SEQ for an individual preservative by the sum of the quotients would provide an additional perspective not addressed by Schnuch119: that of relative share of each allergen to the quotient and that one might term “quotient load.” The quotient load for parabens with this calculation is 0.0001. If one were to remove products that might skew this formula, those being allergens contained in few products per se (formaldehyde) or decreasing in use because of industry reaction to reported past allergenicity and lasting sensitization issues (quaternium 15 and methyldibromo glutaronitrile), the quotient load (although higher) remains low at 0.007. Parabens are both widely used and safe allergologically.
The actual prevalence of paraben sensitivity in the general population is unknown and is suspected to vary by geographic location because of genetic and exposure degree differences. Two studies from Denmark and Germany examining 1146 and 1141 patients reported 0.1% and 0.6% paraben positivity, respectively, in their nondermatitic cohorts.121,122 Mirshahpanah and Maibach123 provided another estimate through pooled epidemiologic studies and computed model examination. Their novel approach suggests the incidence rate in patch test evaluation/prevalence in general public ratio to be a median of 5:1 across all allergens, with as high as 11.6 for formaldehyde ratios and as low as 1 for parabens when examining NACDG data. The corresponding International Contact Dermatitis Research Group ratio for parabens is 1.9, suggesting that the incidence of allergy in eczema patient evaluation is nearly twice that estimated for the general community. Limitations of this study include the exclusion of differences in antigen exposure in diverse population subsets and inherent genetic reactivity differences.
The International Experience
There are no domestic or international contact dermatitis groups other than the NACDG that routinely report screening series data at regular intervals. International reports published sporadically for the past 5 decades largely confirm the NACDG paraben experience. Smaller series outside the United States (<500 tested) are not included in these tables but are mentioned here for completeness and positivity rates, which ranged from 0.7% to 10.9%, in Eastern Europe (0.2% of 405),124 Lithuania (0.3% of 297),125 France (1.5% of 131),126 Belgium (10.9% of 330),127 Belgium (1.5% of 400),128 United Kingdom (0.7% of 403),129 India (8% of 63),130 Brazil (20.9% of 134),131 United Arab Emirates (5.1% of 373),132 Japan (3.1% of 256),133 and India (6% of 100).134
Analysis of the data set reveals that, aside from the studies where the patient population is cosmetic in nature, the frequency of paraben allergy is low. In the 26 years between 1965 and 1991, 24 studies were performed on general populations of eczema patients (Table 15). A total of 89,402 patients were tested to a paraben mix at concentrations between 12% and 16%; 1499 reacted positively (1.7%), and paraben positivity in these studies for 26 years ranged from 0.2% (de Groot) to 3.8% (Fransway) (Table 15). The average positivity percentage of these older studies was 1.7%.1,102,135–157
The data from outside the United States since 1992 affirm the North American experience of low reactivity (Table 16). A total of 300,544 patients have been tested, with 3020 patients reactive to paraben mix at concentrations of 12% to 16% (1.0%); the mean percentage of reactivity among studies was 0.93%. The highest percentage of patients reacting came from Lithuania (3.4% of 680 tested, suspected because of a “highly selected patient population”), and the lowest came from Turkey (0% of 542 tested, speculated because of infrequent use of cosmetics by Turkish women at the time).119,158–174
More than 40% of the population in Table 16 originated from 1 IVDK study, and 2 additional studies from this group were excluded because of data and year overlap; a positivity rate for parabens of 1.3% in all 3 studies is maintained.175,176 These authors confirmed the experience of the NACDG that, even at the higher concentration of 16% of 66,835 patients, paraben mix is not frequently reported to be irritating (0.2%), although negative repeat patch test results might suggest a higher value. No other studies in Tables 15 and 16 specifically addressed irritation frequency on patch testing. Relevance of the positive patch test was only addressed by the Australian study and reported to be 20.8%.172
Several aspects of these international studies deserve specific mention. At least 3 studies, from the United Kingdom, Denmark, and the IVDK, observed reaction rates in men tested to be often higher than those of women by 15% to 30%.119,164,165 One of these groups relates this to a lower threshold for irritancy in men.119 Another Danish study found men nearly twice as likely to be allergic to parabens.168
The multicenter experience authored by Jong et al164 demonstrates significant variation of positivity rate by geographic location (0%–2.8%), presumably because of differences in exposure or, less likely, genetic differences in allergenic reactivity; reaction rates overall in the study decreased over time. Yin et al170 and Helsing et al169 report a similar multicenter variability experience (0.1%–3.4% and 0%–5.0%, respectively). Thyssen and colleagues168 point out increasing incidence of paraben allergy with increasing age (0.3% younger than 18 years to 0.9% older than 60 years). In the Singapore study, more than 50% of patients tested had facial contact dermatitis, which might explain the higher-than-average positivity rate.171 The formidable database from the European Surveillance System on Contact Allergies network showed a low paraben positivity of 0.7% in 52,586 patients; the positivity rate in the T.R.U.E. Test assay in 2362 patients from this data set was half of that (0.35%).169
Comparing the first 25 years of paraben sensitivity data (Table 15) with the second 25 years (Table 16), there has been a significant decrease in the frequency of paraben allergy for the 2 periods, indeed multiple powers greater than significance of less than 0.05% (P = 0.0000015).
Surveying the cumulative world experience (Tables 11, 15, and 16), beginning with the first studies screening for paraben allergy 50 years ago to the present, 444,969 patients have been evaluated. A total of 5137 patients exhibited positive reactions (1.2%); decreasing positivity rates are found over time. Allergologically, parabens are remarkably safe biocides.
There are a number of studies where the actual number of patients tested or the exact percentage of positivity was not listed (Table 17).95,103,133,147,157,177–183 Much like Tables 15 and 16, the studies before 1992 tend to have a higher rate of reactivity overall (0%–2.7%; mean, 1.4%) than do the more recent studies after 1995 (<0.5%–1.0%).
Cosmetic Dermatitis Studies
Studies in which the patient population was suspected of having an allergic contact dermatitis to cosmetic products are tabulated in Table 18.151,162,184–194 In a total of 14 studies, 21,132 patients have been evaluated across the world, with 508 allergic to parabens (total, 2.3%; mean, 3.85%). Populations in Asian countries seem to have increased rates of sensitization because of the extensive use of cosmetics containing parabens at concentrations that may not be as closely monitored as in Europe or America; in 1 study from Thailand, parabens were identified in more than 80% of makeup and oral care items, with 20% to 65% of other cosmetic products containing 1 or more parabens.195 The cosmetic nature of the patients in the 3 Asian studies reported the extensive use of parabens in cosmetics, and higher used concentrations in these products may account for this higher rate of reactivity.
Not all studies of cosmetic allergy indicated a high frequency of paraben sensitivity. Goossens194 found only 1 of 597 patients to be paraben allergic and asserts that “the withdrawal of parabens from cosmetics is merely a consumer, publicity, and political issue.”
CLINICAL PRESENTATIONS OF PARABEN ALLERGY
Because of the dominance of paraben use in leave-on formulation exposure, it comes as no surprise that populations using cosmetics and presenting with facial dermatitis would have a higher reaction rate to such a common biocide than the general and contact dermatitis clinic populations as a whole. Numerous studies have all shown that makeups, moisturizers, hair care products, and eye cosmetics are the most common sources.196,197 The average woman uses 12 personal care products daily with 168 new unique ingredients (6 and 85 are corresponding figures for men).198 With this level of exposure, it is not surprising that, in 7 pooled studies involving 30,207 contact dermatitis patients, 9.8% of positive reactions were due to cosmetic allergens.199
Studies confirm that parabens rarely cause cosmetic allergy despite their extensive use in cosmetics.194 In a Swedish compilation of complaints of cosmetic reactions to the Medical Products Agency for a 5-year period between 1989 and 1994, 191 reports concerning adverse effects of 253 cosmetics and toiletries were examined.200 Ninety percent of the reports concerned women, and the top-ranking product category was moisturizers, followed by hair care products and nail products. Fragrances, toluenesulfonamide formaldehyde resin, and preservatives were the causative agents in 79 patch-tested patients; 7 preservatives were implicated in 19 adverse effects, with none of them paraben based. The important NACDG study of causes of cosmetic allergy failed to show the paraben mix in the top 20 causes of dermatitis.201 They did find it 19th in their list of causes of moisturizer-induced dermatitis, with the rate in men roughly half of that in women. Overall, parabens were implicated as causative in only 1% of all cosmetic allergic patients (slightly higher in men than women). This level is not statistically different than the NACDG results for the population as a whole during the same 4-year period of 2001 to 2004 (0.9%). In an earlier 1985 report by the NACDG, 19 paraben-allergic patients were identified of 713 patients with cosmetic allergy (2.7%), a slightly higher rate than their noncosmetic dermatitis patients for the period.186 Goossens and colleagues202 examined 475 patients with cosmetic allergy and concur that preservatives and perfume components are the most common culprits; 16 were paraben allergic (3.4%).
In their excellent review of cosmetics and dermatitis, Alani and colleagues203 from the Mayo Clinic did not identify parabens as a common cause for allergic contact dermatitis and labeled them weak sensitizers. They did recommend its screening in a standard or cosmetics tray, if sensitivity to a cosmetic product is suspected, and included it in their list of antigens that can cause dermatitis in eye shadow products (but not eyeliners, concealers, mascaras, and nail or hair care series). The previously referenced CAMP database has a total of 342 ophthalmic medications, contact lens solutions, and eyelid makeups, with mascara (64/120, 53.3%) and eyeliner (33/77, 42.9%) more frequently containing parabens than do eye shadow products (6/33, 18.2%) (Table 5). Other reviews of cosmetic allergy mention parabens as rarely problematic in passing fashion only.204
The definitive study of patients identified as having cosmetics, sunscreens, and moisturizers as the only identified allergen sources was performed by the IVDK.205 Parabens were positive in 1.0% of 10,124 patients and 0.9% of 14,728 controls (P = 0.73); their evidence-based statement was that parabens are safe preservatives in cosmetics. These same authors cite one of their own studies asserting that up to half of these paraben reactions are believed to be irritant responses.206 Summarizing these cosmetic studies, it would seem that, generally, parabens do not cause cosmetic dermatitis at a significantly greater rate than the general eczema population, although differences in exposure load geographically may account for certain studies showing higher rates.
SPECIFIC EXPOSURES AND POPULATIONS
As water-based leave-on formulations, the need for long-lasting broad-spectrum preservation of moisturizers is self-evident. Zirwas and Stechschulte,207 using a major pharmacy database, identified 276 moisturizers, 62% of which contained parabens (bested only by fragrance at 68%). The CAMP has 133 moisturizers of a total of 376 (35.4%) that contain parabens (Table 5).
The NACDG examined a 10-year experience with sunscreen product testing and identified 3 of 124 patients with allergy to sunscreens to be paraben sensitive (2.4%).208 In the CAMP database, 37 of 201 products contained parabens (Table 5).
In the Yu et al209 analysis in 2016, parabens (predominantly methylparaben) were found in 9.5% of diaper wipes and 24.4% of topical preparations. The authors noted a trend of substitution of parabens with ethylhexylglycerin in diaper products. There are isolated reports of diaper allergy in infants due to parabens.210 The CAMP database has a high prevalence of parabens in products used in the perianal region (10/16 products, 62.5%) (Table 5).
In their examination of product inserts for corticosteroid formulations dispensed more than 20,000 times in 1 calendar year, Coloe and Zirwas211 found parabens to be present in 7 of 46 steroid formulations (15%); parabens were the most common preservative allergen identified in such formulations. The CAMP database showed an overall prevalence of 17% (44/259), with over-the-counter formulations more frequently containing parabens (9/12, 75%) than branded prescription products (18/92, 19.6%) and generic prescription corticosteroids (17/155, 11%) (Table 5). Perioperative use of corticosteroids may cause contact dermatitis; 1 group of authors suggests that preservatives and other inactive ingredients may be more frequently problematic than active ingredients.212 Ointments are less likely to contain parabens (or any preservatives because of the lack of aqueous phase) than are cream and lotion formulations.
Using a database from a major pharmacy chain, Zirwas and Moennich39 found 43 of 179 shampoos to contain parabens, the eighth most common allergen identified. The CAMP database has 13 of 270 (7.6%). Hair dyes, stylers, and conditioners are all also low in frequency (7.6%–13.1%) (Table 5).
As the major preservatives in imiquimod cream, parabens were found to be positive at no higher rate than in the general patch test population in patients who had been treated with imiquimod.213
Aschenbeck and Warshaw214,215 compared the prevalence of parabens in facial wet wipes and in personal hygiene wet wipes and found no significant difference between the two (23.6% of 178 facial wipes and 20.4% of 132 personal hygiene wet wipes contained parabens, the 15th most common allergen in facial wipes). In the CAMP registry, facial products and cosmetics contain parabens 31.8% of the time, with powder makeup (20/46, 43.4%) and other facial makeup leading the way (25/48 products, 52.1%) (Table 5). Foundation concealers and blushers all have prevalence of roughly 30%.
A study from the Mayo Clinic, examining the most common causes of vulvar contact dermatitis, identified the top 5 allergens to be fragrances (3), benzocaine, and quaternium 15.216 Only 1 of the 90 women reacted to paraben mix, which was deemed no higher incidence than baseline. A recent review of genital dermatitis tabulated the results from four investigations, with paraben positivity found in between 0.4% and 1.7% of patients.217 As referenced previously, in the NACDG experience, parabens were not identified as a significant cause for anogenital dermatitis.49
Leg Ulcers and Stasis Dermatitis
There is significant variation by geographic location with respect to paraben allergy prevalence in the leg ulcer and chronic venous insufficiency population. A Canadian study of 100 patients with chronic venous disease and leg ulceration failed to identify parabens as a relevant allergen, with 18 other allergens more often problematic at frequencies of more than 4%.218 Another North American population showed a similar low frequency of positivity at 2%.219 A Croatian study, on the other hand, found 17% of their patients with leg ulceration to be paraben allergic.220 Although many studies report that the incidence of contact dermatitis is increased in patients with venous disease, dermatitis, or leg ulceration, a recent German study found that patients with leg ulcer were less frequently sensitized than historical controls (16.9% of 5264 patients with stasis change; 25.9 of 4881 controls). Paraben sensitization was significantly elevated from control groups, however, at 2.6%.221 Notwithstanding these mixed results, the overall perceived increased rate of sensitization in patients with leg ulceration, stasis dermatitis, and occluded skin (eg, Unna boot) may be an indication of the paraben paradox and the result of increased penetration of allergen and differential loss of hydrolysis of esters due to missing or dysfunctional cutaneous esterases.15,65
Periorbital and Eyelid Dermatitis
Definitive studies have been performed on the subject of eyelid dermatitis. The NACDG reported its experience in 278 cases of isolated contact dermatitis of the eyelids examined in the 2003 to 2004 data cycle. Twenty-six allergens, including 4 preservatives, were identified as causative in between 1.1% and 8.2% of cases; parabens did not make this list of problematic antigens.222 Similarly, Amin and Belsito223 did not identify parabens as an issue in 46 cases of eyelid dermatitis; 37 other antigens including 10 preservatives were found in 2.2% to 28% in this 10-year study. Herbst and colleagues,224 using the Information Network of the IVDK, did not list parabens as allergens in their top 30 causes of periorbital dermatitis in 1053 cases. In 204 patients with isolated allergic contact dermatitis of the eyelids, Herro and colleagues225 found 1 to 2 cases of paraben allergy. Indeed, in light of these data, parabens may be the preferred biocide for periocular products and instillation medicaments. A study from the ophthalmology literature demonstrated that, as opposed to benzalkonium chloride, parabens do not affect cell viability of keratinocytes.226 Landeck and colleagues,227 although finding 3% of their periorbital dermatitis patients to be paraben sensitive (8/266), noted that 3.2% of the control population for this period without periorbital dermatitis were paraben sensitive (not statistically significant). An isolated case has been reported of paraben allergy in an eyedrop.228
A retrospective examination from 2008 to 2015 in Japan showed 2 of 21 patients (9.3%) to be allergic to paraben 15% in petrolatum.229
Pediatric Contact Dermatitis
Paraben reactions are rare in children. Hogeling and Pratt230 neither mentioned paraben mix nor listed it as a top 10 allergen in their study of 100 children. In an excellent review of pediatric contact dermatitis, parabens are not listed as a relevant allergen in any of the 16 studies reviewed. Unpublished data provided by the authors revealed 1 of 440 children (0.2%) positive to parabens in New Delhi.231 Another review from 2011 detailed 9275 children tested in 20 series over 11 years.232 Paraben mix was identified as a top 3 allergen in only 1 small series of 70 children in India (43%).233
Noting abrogated barrier function as an issue for contact sensitization, a Kuwaiti study examined 103 patients with palmoplantar pustulosis and 100 regular psoriasis controls; no cases of paraben allergy were identified in either group.234
Although there is limited reference to parabens being photosensitizers, we could find no references reporting routine photopatch testing; parabens are not included on screening photopatch trays in North America or Europe. Methylparaben has been shown to be photosensitizing in vitro, with dose-dependent decrease in cell viability in keratinocyte culture cell line HaCaT along with a 40% reduction in antimicrobial activity. Intracellular generation of reactive oxygen species and multiple organelle disruption were also identified. Oxidative stress led to DNA damage and apoptosis via mitochondrial and endoplasmic reticulum damage, leading the authors to call for parabens to be removed from products exposed to UV light.235 Another study failed to show photoreactivity (either photoallergy or phototoxicity), but the authors found that butylparaben products may induce hyperpigmentation and intensification of preexistent dermatitis upon exposure to sunlight.236
Excited Skin Syndrome
In a 2002 retrospective analysis of 39 patients with excited skin syndrome (of 630 total patients tested), 9 (23%) were positive to paraben mix on the first patch test experience; on retesting at further distance on the back from p-phenylenediamine (PPD), only 3 remained positive.237 The authors assumed that proximity of positive reactions on excited skin to each other and to cross-reacting antigens is an important consideration.
Systemic Contact Dermatitis
Five isolated cases of systemic contact dermatitis to parabens administered enterally or parenterally exist, clearly a rare phenomenon in light of the extensive use of parabens in medicaments and foods.15,69,70,238,239 Parabens were not included in Jacob and Zapolanski's240 2008 review article on the subject.
Immediate Hypersensitivity to Parabens
Isolated cases of type 1 hypersensitivity to parabens have been reported.241 Fisher242 found 0.2% of patients with paraben allergy to react to scratch and intradermal testing of parabens. Pruritus, urticaria, localized angioedema, and bronchospasm have been rarely reported, with the cause often parenteral administration.15,65
The Paraben Paradox
The paraben paradox, as classically proposed by Fisher,243 described parabens in topical therapeutic agents sensitizing roughly 1% of the population while rarely, if ever, inductive to those using paraben-containing cosmetics. He postulated that paraben-preserved therapeutic agents generally are used on inflamed, eczematous, excoriated skin, whereas other formulations such as cosmetics are used on normal skin; differential concentrations and penetration/barrier dysfunction are believed to explain this phenomenon. Schorr and Mohajerin93 reiterated the paradox, postulating that the hydrolysis of the ester parent molecule to p-hydroxybenzoic acid in the skin by esterases was the cause of this phenomenon. The extension and corollary of this situation are where patch tests may be negative on uninvolved skin, yet parabens applied to involved skin can elicit dermatitis. The explanation of this paradoxical response is yet to be determined.
Hervella and colleagues,244 along with a case report, claim that the classic “paraben paradox” as described by Fisher is now rarely seen and that the most common picture of paraben allergy presently is sensitization through contact with cosmetics and subsequent intolerance of even minimal concentrations of parabens. They proposed that the predominance of weak positive patch test reactions to parabens is relevant when investigated adequately.244
Various other versions of the “paraben paradox” have been suggested:
- The (in)frequency of cross-reactions to p-aminobenzoic acid derivatives and other structurally related molecules;
- Lesser concentrations of 2 or more parabens are more effective than a larger concentration of a single paraben (this is postulated to be due to relative and complimentary oil and water partitioning);
- Predictive patch testing with paraben-containing cosmetics has yielded no cases of allergic dermatitis, whereas there is a larger number (roughly 1%) among patients undergoing patch testing for suspected allergic contact dermatitis (the paradox questioned in this scenario is how, with the extensive testing performed, this could occur)245; and
- Patch testing with individual esters (at the same concentration as that present in the mix) may be positive despite paraben mix negativity.84
CROSS-REACTIVITY OF PARABENS TO OTHER “PARA GROUP” ANTIGENS AND TO EACH OTHER
p-Phenylenediamine seems to be the allergen most frequently cited as at risk for cross-reaction in paraben-sensitive patients. Turchin and colleagues246 found that 2.37% of 253 PPD-sensitive patients also reacted to the paraben mix, whereas overall paraben sensitivity in 4115 PPD-negative patients was 0.68%. Patients allergic to PPD were 3.4 times more likely to be sensitive to parabens. Similarly, paraben-positive patients were 3.1 times more likely to have a positive reaction to PPD mix than those negative to the paraben mix. None of the 37 benzocaine-allergic patients reacted to parabens. These differences were statistically significant, but clinical relevance was indeterminate.246 Rudzki and Kleniewska179 identified 20 paraben-allergic individuals (13.9%) among 144 PPD-sensitive patients; 20 of 63 benzocaine-sensitive individuals (31.7%) were allergic to parabens. In a much larger European series, 231 patients allergic to PPD were more frequently reactive to parabens (2.2%) than PPD-negative individuals (0.3%), P < 0.001.174 Taking a conservative exposural approach, the CAMP database includes all hydroxybenzoates and PPD derivatives as cross-reactors to parabens. However, an analysis of 46 PPD- and 6 paraben-sensitive patients showed no cross-reactivity.247
p-Aminobenzoic acid derivatives, sulfonamides, and caine derivatives, other than benzocaine, may rarely cross-react with parabens, but these reports are exceedingly scarce because of the exclusion of these allergens from most standard screening series; isolated reports of cross-reactions between parabens, PPD, and, specifically p-aminobenzoic acid are found in the literature.248
OCCUPATION AND PARABENS
In a cohort of 5112 occupational cases, Dickel and colleagues249 identified 69 allergic to parabens; only 6 of these (0.1%) were occupational. Not surprisingly, parabens did not rank in the top 25 occupationally related or top 17 nonoccupationally related allergens in the NACDG study of 2732 production workers or as a relevant occupational allergen in 132 print machine operators.250,251 It was not among the 46 standard series allergens identified to be relevant in 691 mechanics and repair workers.252 Kucenic and Belsito253 did not find paraben mix to be a notable allergen in their report of 135 occupational dermatitis cases. Jain et al254 tested 500 nurses in their northern India population and found the most common reactivity to be to their gloves (50%); 5% of this population was paraben sensitive.
REGULATIONS REGARDING PARABEN USE IN COSMETICS
United States Regulations
In the United States, individual parabens have been interpreted as safe individually in cosmetics at a concentration of up to 0.4% and in mixtures of parabens of up to 0.8%; amounts of 0.3% or less are typically used in cosmetic formulations. The Cosmetic Ingredient Review (CIR) has identified a wide range of paraben concentrations in cosmetic products, but concentrations exceeding the 0.4% guideline in place at the time have been exceedingly infrequent. Cosmetic manufacturers with occasional exception seem to adhere to recommended guidelines and regulations, with CIR-Safety assessment of parabens37 and Rastogi and colleagues38 finding similar concentrations.
Recommendations for infant exposures are addressed separately from adult exposures in determining MOS; ranges from approximately 6000 MOS for single-paraben products to approximately 3000 MOS for multiple-paraben products in adults have been determined and are interpreted as conservative estimates.4
The question regarding CIR determination of safety levels deserves mention. The 2 most important laws pertaining to cosmetics marketed in the United States are the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act; the FDA regulates cosmetics under the authority of these laws. The law does not require cosmetic products and ingredients, other than color additives, to have FDA approval before they go on the market.
Final CIR reports on a chemical substance are the result of literature search and review of government sources and databases. The CIR is a panel of 9 voting members with dermatological, veterinarian pathology, toxicologic, and pharmacologic expertise. In addition, there is 1 nonvoting member each from industry, the FDA, and the Consumer Federation of America. The expert panel of the CIR has examined parabens on 10 different occasions for the period spanning 1984 to June 2018. On each occasion, it has been the opinion of the expert panel that parabens in cosmetics are safe for use, reiterating the guidelines for concentration, which have not changed over the 34-year period.37
The most frequently used parabens, methyl and n-propyl, may be added (up to 0.1%) as antimicrobials to preserve food; these parabens, as well as ethylparaben, can also be used in food packaging.3,10,21 The FDA approved the use of parabens in foods in the specific Code of Federal Regulations (CFR); methylparaben (21 CFR 184.1490) and propylparaben (21 CFR 184.1670) are generally recognized as safe when used as chemical preservatives in foods, with use limits of 0.1% for each. The JECFA has placed the acceptable daily intake for methylparaben, ethylparaben, and propylparaben at 0 to 10 mg/kg per day. This was seconded by the European Food Safety Authority in 2004 for all, except propylparaben, “due to recent research demonstrating its effects on certain reproductive parameters in rats.” Specifically, the JECFA cited studies demonstrating propylparaben to have adverse effects in tissues of reproductive organs in male rats at dietary doses of as little as 10 mg/kg of body weight per day, which is within the range of the paraben allowable dietary intake at the time.255 Although noting that propylparaben exposure through diet is limited, the issue of adopted parameters was referred to the EU and propylparaben was removed from foodstuffs in Europe in the 2007 JECFA report.256
At maximum concentrations rarely exceeding 0.1%, parabens are allowed as preservatives in various pharmaceutical products. These are guidelines and recommendations and are not restrictions that are currently enforced in the United States. Outliers from the CIR report include oral solutions and syrups as well as rectal solutions at concentrations of 5% to 20%.257
European Union Regulations
When it comes to preservatives used in cosmetic formulations outside the United States, the EU has become the primary regulator. The organization determining preservative policy in the EU is the European Commission, which seeks the input of the Scientific Committee on Consumer Safety, as well as industry and other interested parties. Like the CIR, the Scientific Committee on Consumer Safety has reiterated its previous conclusion that the continued use of 4-methylparaben and ethylparaben as preservatives in cosmetics at the maximum authorized concentrations is considered safe for human health at 0.4% for 1 ester or 0.8% when used in combination; propylparaben and butylparaben as preservatives in cosmetic products are considered as safe to the consumer as long as the sum of their individual concentrations does not exceed 0.14%, because of “weak endocrine-modifying potential and quantitative risk assessment.” No additional restrictions were placed upon the use of parabens at that time for infants and children with or without active flexural dermatitis.258 The EU has a list of 59 allowable preservatives, known as Annex V, that not only governs preservative use in the 28-nation alliance but also influences regulations in many other countries.259 Formulators find that often 2 or 3 options are appropriate for a particular formulation. Annex V was last updated on September 14, 2017. Entry 12 allows the use of 4-hydroxybenzoic acid, methylparaben and ethylparaben, and their potassium, calcium, and sodium salts at 0.4% for 1 ester or 0.8% when used in combination; butylparaben, propylparaben, and their sodium and potassium salts may not exceed the total sum of more than 0.14%. The Danish government, however, has subsequently banned the use of larger-molecule parabens (propylparaben, isopropylparaben, butylparaben, and isobutylparaben) in products for children up to 3 years old as a precautionary measure, because children might be especially vulnerable to these endocrine effects, particularly on broken skin.
In April 2014, the European Commission amended Annex II and V of the EU cosmetic regulation, adding the following 5 parabens to the list of substances prohibited in cosmetic products: isopropylparaben, isobutylparaben, phenylparaben, benzylparaben, and pentylparaben. They also banned the use of propylparaben and butylparaben in the nappy area in children younger than 3 years.260
There are those who would suggest that the European Commission is slow in reacting to scientific documentation involving trends in preservative allergy as evidenced by the perceived sluggish response to methyldibromo glutaronitrile and methylisothiazolinone.261 The decision to allow cosmetic preservatives to come to market and be listed on Annex V as safe until proven otherwise has been brought into question. Schwensen and colleagues262 indicted the process as lacking. Their statement: “The introduction of new preservatives in Europe with inadequate premarket risk assessment has rapidly increased the overall burden of cutaneous disease caused by preservatives. We suggest that the cosmetic industry has a responsibility to react faster and replace troublesome preservatives when a preservative contact allergy epidemic is recognized, but the European Commission has the ultimate responsibility for failures in risk management after new, major sensitizing preservatives are introduced onto the market.”262
In 2014, after the EU decision on limits and bans on parabens, the Association of Southeast Asian Nations' Cosmetics Committee decided to ban the use of isopropylparaben, isobutylparaben, phenylparaben, benzylparaben, and pentylparaben as preservatives in cosmetics and had already adopted the guidelines recommended for paraben derivatives according to Europe's lead; their statutes are identical to those in place in Europe.
The Canadians have not specifically placed restrictions or bans on any parabens but have weighed in stating that convincing hormonal mimicry and oncogenic potential data are lacking. In all other recommendations, Health Canada has agreed with the FDA position on parabens.263,264
ALTERNATIVES TO PARABENS AND THE ISSUE OF HYPOALLERGENICITY
Parabens have been vilified by a number of consumer watchdog organizations and consumer product manufacturers. However, are there alternatives that are safer and as effective? A variety of approaches have been proposed, including but not limited to citrus extracts such as ascorbic acid, benzyl alcohol, synergistic blends of multifunctional natural ingredients including botanical extracts, honeysuckle extract, spice extracts, and fragrances. Pure essential oils, such as rosemary, lavender, clove, and plant extracts such as Calendula, exhibit variable microbistatic and microbicidal activities. The replacement of the aqueous component of creams with Aloe vera has been used, eliminating the need for the typical preservation required for the aqueous component. Natural antimicrobial enzyme systems and combinations with biocidal activity, such as the combination of benzoic acid with glycereth-2 cocoate and gluconolactone and sodium benzoate, are under study. Dissolvable film technology using single-dose separation and administration decreases preservative requirements, but it is expensive and currently rarely used. Other approaches include decreasing the pH of cosmetic formulations and using emollients with membrane-disrupting properties, chelating agents, or glycolics. A water-soluble mixture of citric acid with silver citrate with preservative activity has been developed, but the European Commission Scientific Committee on Consumer Products was unable to confirm safety without performance of an in vitro mammalian gene mutation assay. They also voiced concerns regarding the development of argyria.265
Airless packaging may also decrease the need for strong chemical biocides. Unfortunately, these systems are much more expensive to produce, obtain, and use than are the safe, effective, inexpensive, and formulation-friendly parabens. Stability and safety issues are also often associated with such systems, which makes large-scale production problematic. Refrigerated cosmetics are another consideration.52 Preservative-free, single-dose packaging is attractive albeit expensive.
For those unready to throw the biocide out of the cosmetic water, synergists added to aqueous formulations such as sorbitan caprylate serve to augment activity of established agents with preservative function such as phenoxyethanol, benzyl alcohol, and even parabens; this allows for lower concentrations of these synthetic biocides to act against microbial overgrowth effectively.266
Health and safety concerns and the natural origin of ingredients continue to rise in the public consumer conscience. Investigators looking at the consumer mindset failed to identify a relationship between attitudes toward chemical safety and purchasing. Fragrances generally do not elicit concern in the buyer, whereas there was a significant association regarding product concern and the presence of several potential or perceived toxicants including mercury, bisphenol A, and parabens.267 It would seem that the negative mantle in which parabens have been cloaked is having an impact on buyer selection. An additional issue, which arises in the alluring nature of the “natural” and “organic” claim, is that often fair trade organizations and manufacturers do not live up to their organic claims when scrutinized. The degree of claim deviation is geographically dependent, with European companies generally scoring highest in fidelity to claim.268 In their excellent study of products claiming “dermatologist tested,” “hypoallergenic,” “fragrance free,” and “paraben free” (buzzwords in the hypoallergenic marketing package), Hamann and colleagues269 found that 79% to 89% of the 186 products they studied contained at least 1 proven contact allergen and more than 50% contained 2 or more. Five or more allergens were found in up to 12% of products made by manufacturers using such claims.269
From early on, the voice of restraint when evaluating the antiparaben bandwagon could be heard. Lorenzetti and Wernnet270 reviewed data available in 1977 and advised parabens as useful with minimal risks in light of the alternatives available. From another viewpoint with a similar perspective, certain manufacturers are staying with traditional preservative products that are, in their opinion, tried and proven in order not to disappoint their established consumer base. Reformulation inevitably requires the changing of successful product constitution, cost, and shelf life concerns that could upset the end user.271,272
At the present time, there is not a definitive, clear understanding of the potential risks that parabens may possess to Homo sapiens; the toxicology of parabens is intensively being examined, and an overview of the safety aspects of parabens will be the subject of subsequent publication. Significant in vitro and laboratory animal data have indicated that there may be valid reasons for concern. However, sectors of the scientific community feel that the crusade against chemical preservation is unwarranted. In 2012, Castelain and Castelain9 reviewed the literature and concluded the assertions that parabens posed risks of endocrine disruption (minimal risk at approved use concentrations) and carcinogenesis (breast cancer causation lacking definitive evidence), and effects on fertility in men (under investigation) were unwarranted based on existing scientific information. They argue that elimination of proven, safe preservatives based on inadequate evidence opens the door to preservative misadventure via the unknown or substitution without adequate evidence of safety (such as in the case of isothiazolinones). Lundov and colleagues273 advise balance in the approach to product versus preservation, making the observation that the potential harm to consumers is not insignificant and that cosmetics and toiletries can be contaminated via 2 different means: direct from the manufacturer or after purchase by the consumer in (occasionally greatly prolonged) use. Numerous examples of such contamination have been catalogued, but truly, this represents the “tip of the iceberg” of the actual problem scope. It is also their opinion that many products are “overpreserved” by manufacturers and make the observation of differences of even a hundredfold for the concentration of preservatives in products of similar nature. Their call that additional studies be performed by manufacturers to evaluate the efficacy of preservation systems in products and to use realistic, scientifically and investigationally determined amounts rather than biocide overkill is well stated. Handwashing by consumer, maintaining products at appropriate temperature limits, and recognition by the consumer that toiletries and cosmetics are not eternal and should be consumed before their expiration would also lift some of the burden from manufacturers.
SUMMARY AND CONCLUSIONS
Parabens have been used safely in cosmetic products, pharmaceuticals, and foods for more than 70 years and have admirably fulfilled their role as inexpensive, effective biocides. They are rarely problematic as contact allergens, and it is for this reason that parabens have been designated (non)allergen of the year (the second allergen designated); thimerosal was the first such allergen because of the converse experience of very frequent but typically irrelevant reactions. In the 20th century, it was the potential allergenicity of parabens that was at issue; the past 15 years have brought forth a large number of additional concerns to fuel the paraben controversy and provide new life to the “paraben-free” mantra for those who wish to embrace it. Concerns include endocrine disruption, carcinogenicity (specifically breast cancer), neonatal and perinatal exposure risks, fertility, spermatogenesis disturbance, emotional disorders, and environmental impact. These issues have been repeatedly addressed by industry and a number of regulatory authorities, most of whom have found parabens to be safe as cosmetic and food preservatives, as summarized by this article. Suffice to say that this nonallergen of the year's emerging potential pariah status, despite the well-documented scientific evidence to the contrary, may be the newest incarnation of the “paraben paradox.”
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