Abstract
Background
Preservatives are often necessary components of commercial products. Large scale North American studies on preservative allergy are limited.
Objective
To evaluate demographics, positive patch test reactions (PPTR), clinical relevance and trends for preservatives tested by the North American Contact Dermatitis Group (NACDG).
Methods
We conducted retrospective cross-sectional analysis of NACDG patch testing results of preservatives from 1994–2016.
Results
50,799 patients were tested; 11,338 (22.3%) had a PPTR to ≥1 preservative. The most frequent reactions were to methylisothiazolinone (MI) 0.2% aqueous (aq) (12.2%), formaldehyde 2% aq (7.8%), formaldehyde 1% aq (7.8%), quaternium-15 2% petrolatum (pet) (7.7%) and methyldibromo glutaronitrile/phenoxyethanol (MDBGN/PE) 2% pet (5.1%). Paraben mix 12% pet (1%), iodopropynyl butylcarbamate (IPBC) 0.1% pet (0.4%), benzyl alcohol 1% pet (0.3%) and phenoxyethanol 1% pet (0.2%) had the lowest PPTRs. Linear regression analysis of preservatives tested revealed that only MCI/MI 0.01% aq (parameter estimate (PE) 0.42; CI 0.17–0.66; p<0.005) had a significant increase in PPTRs over time.
Limitations
Collected variables are dependent on clinical judgment. Results may be prone to referral selection bias.
Conclusion
This large North American study provides insight on preservative PPTRs and trends from 1994–2016.
Keywords: contact dermatitis, preservative, patch test, NACDG, allergic contact dermatitis, methylisothiazolinone, methylchloroisothiazolinone/methylisothiazolinone, formaldehyde, formaldehyde releaser, iodopropynyl butylcarbamate, methyldibromo glutaronitrile/phenoxyethanol, paraben, benzyl alcohol, phenoxyethanol, preservative allergy
Introduction
Preservatives are chemicals added to cosmetic, household and industrial products to prevent or eliminate microbial growth and delay chemical degradation.1,2 Preservatives are indispensable components of commercial products due to their ability to prolong shelf-life and prevent infections. They have also been recognized as important skin sensitizers worldwide.3–7
Large-scale epidemiologic studies on preservative allergy in North America are few. In this study, we sought to characterize demographics, patch test reactions, relevance and trends associated with preservatives in the North American Contact Dermatitis Group (NACDG) data set.
Methods
This retrospective study was approved by the Duke University Institutional Review Board. The NACDG consists of contact dermatitis experts in the United States and Canada. We included NACDG data from 1994–2016; methodology has been reported previously.8 Patients were tested with the NACDG screening series (Chemotechnique, Sweden; Allergeaze, Smartpractice, Canada); allergen composition and duration of testing for individual allergens varied. Allergens were applied with patch test chambers (Smartpractice, USA) and Scanpor tape (Norgesplaster, Norway). Readings were designated as +++ (very strong), ++ (strong), +(mild), +/− (weak/doubtful), irritant and negative in accordance with NACDG criteria.8 In addition, final interpretation for each allergen was determined and documented as allergic, unknown, irritant or negative. For each reaction designated allergic, investigators determined clinical relevance as definite, probable, possible or past.8 For the purposes of this study, positive patch test reaction (PPTR) is defined as a final patch test interpretation of allergic.
Two subgroups were defined a priori: 1) those with a PPTR to ≥1 preservative (PP) and 2) those with PPTRs to only non-preservative allergens (other positive — OP); both groups excluded patients who had no PPTR.
Data were entered into Access or Excel (Microsoft, USA) and analyzed using SAS 9.4 (SAS Institute Incorporated, USA). Descriptive statistics were performed to summarize patient demographics and frequency and percentage of PPTR. Odds ratio (the ratio of the odds of having an outcome in the PP group to the odds of the outcome in the OP group), with its 95% confidence interval, was estimated. Significance-prevalence index number (SPIN), a weighted calculation of clinical relevance combined with prevalence, where SPIN = (proportion of population allergic) × (1 × % definite relevance + 0.66 × % probable relevance + 0.33 × % possible relevance) × 100, was calculated for each test cycle.9 Trend of PPTRs over time was analyzed with a simple linear regression model, with the formula: Positive rate = β0 + β1Time + ε. Regression diagnostics were performed to evaluate model assumptions. Preservatives tested for fewer than 6 cycles were excluded. The parameter estimate represented the average increase or decrease of the percentage of PPTR with one test cycle increase. Significance of tests was assessed at alpha = 0.05.
Results
50,799 patients (mean age 48 years [SD 16.9]) were included. 33,901 patients (66.7% of total tested) had at least one PPTR. 11,338 subjects had ≥1 PPTR to preservatives; this represented 22.3% of the total tested population and 33.4% of subjects with ≥1 PPTR. Demographic characteristics are summarized in Table 1.
Table 1.
Demographics*
| Characteristic | Total Tested Population | Any Positive Patch Test Reaction | Positive Patch Test Reaction to Preservatives |
||
|---|---|---|---|---|---|
| Yes | No | OR (95% CI) | |||
| n=50799 Number (%) | n=33901 Number (%) | n=11338 Number (%) | n=22563 Number (%) | ||
| Male | 17119 (33.7) | 10746 (31.7) | 4210 (37.1) | 6536 (29.0) | 1.45 (1.38, 1.52) |
| Race | |||||
| Caucasian | 43653 (86.4) | 29187 (86.6) | 9977 (88.6) | 19210 (85.6) | 1.30 (1.22, 1.40) |
| Black | 3042 (6.0) | 1969 (5.8) | 513 (4.6) | 1456 (6.5) | 0.69 (0.62, 0.76) |
| Asian | 2186 (4.3) | 1501 (4.5) | 475 (4.2) | 1026 (4.6) | 0.92 (0.82, 1.03) |
| Hispanic | 924 (1.8) | 564 (1.7) | 165 (1.5) | 399 (1.8) | 0.82 (0.68, 0.99) |
| Occupational# | n/a | 3570 (10.5) | 721 (6.4) | 2286 (10.1) | 0.60 (0.55, 0.66) |
| Atopic Triad | |||||
| Hay Fever | 14131 (27.9) | 9356 (27.7) | 2994 (26.5) | 6362 (28.3) | 0.91 (0.87, 0.96) |
| Eczema | 11054 (21.8) | 7375 (21.8) | 2405 (21.3) | 4970 (22.1) | 0.96 (0.90, 1.01) |
| Asthma | 7269 (14.3) | 4761 (14.1) | 1509 (13.4) | 3252 (14.4) | 0.91 (0.85, 0.97) |
| Hand Dermatitis | 12319 (24.3) | 8524 (25.2) | 3280 (28.9) | 5244 (23.3) | 1.34 (1.28, 1.41) |
| Leg Dermatitis | 2103 (4.1) | 1375 (4.1) | 472 (4.2) | 903 (4.0) | 1.04 (0.93, 1.17) |
| Face Dermatitis | 7965 (15.7) | 5419 (16.0) | 1662 (14.7) | 3757 (16.7) | 0.86 (0.81,0.92) |
| Age >40 years | 33931 (66.8) | 23081 (68.1) | 8432 (74.4) | 14649 (64.9) | 1.57 (1.49, 1.65) |
| Positivity rate (≥1PPTR) | 33901 (66.7) | n/a | n/a | n/a | n/a |
Only patients with non-missing values for these variables were included
Calculated only for patients with positive patch test reactions.
Patients with preservative PPTRs were more likely to be male, Caucasian, > 40 years and have hand dermatitis as compared to those with non-preservative PPTR (Table 1). Preservative-positive patients were less likely to be Black, Hispanic, and have occupational dermatitis, facial involvement, hay fever and asthma. There were no statistical differences between the two groups with respect to Asian race, history of eczema, or leg dermatitis.
Preservatives and test cycles are summarized in Table 2. Pooled preservative patch test results are summarized in Table 3. There were 24,114 PPTRs to preservatives among 11,339 patients. Preservatives with the highest positive reaction frequencies were methylisothiazolinone (MI) 0.2% aqueous (aq) (12.2%); formaldehyde [2% aq (7.8%) and 1% aq (7.8%)]; quaternium-15 2% petrolatum (pet) (7.7%) and methyldibromo glutaronitrile (MDBGN)/phenoxyethanol 2% pet (5.1%). The lowest frequencies of PPTRs included paraben mix 12% pet (1%); iodopropynyl butylcarbamate (IPBC) 0.1% pet (0.4%); benzyl alcohol 1% pet (0.3%) and phenoxyethanol 1% pet (0.2%). Several preservatives, benzalkonium chloride 0.1% aq, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) 0.01% pet, MI 0.2% aq, formaldehyde 2% aq and phenoxyethanol 1% pet, were tested for limited cycles.
Table 2:
Preservatives Tested 1994–2016
| Preservative Type | 1994–1996 | 1996–1998 | 1998–2000 | 2001–2002 | 2003–2004 | 2005–2006 | 2007–2008 | 2009–2010 | 2011–2012 | 2013–2014 | 2015–2016 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Formaldehyde & Formaldehyde Releasers | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq | Formaldehyde 1% aq |
| Formaldehyde 2% aq | Formaldehyde 2% aq | ||||||||||
| 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane-1,3-diol 0.5% pet | 2-Bromo-2-nitropropane -1,3- diol 0.5% pet | 2-Bromo-2-nitropropane -1,3- diol 0.5% pet | 2-Bromo-2-nitropropane -1,3- diol 0.5% pet | 2-Bromo-2-nitropropane -1,3- diol 0.5% pet | 2-Bromo-2-nitropropane -1,3 diol 0.5% pet | |
| Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | Diazolidinyl Urea 1% pet | |
| Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | Diazolidinyl Urea 1% aq | |||||
| DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | DMDM Hydantoin 1% pet | |
| DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | DMDM Hydantoin 1% aq | |||||
| Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | Imidazolidinyl Urea 2% pet | |
| Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | Imidazolidinyl Urea 2% aq | |||||
| Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | Quaternium-15 2% pet | |
| Isothiazolinones | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01 % aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq | Methylchloroisothiazolone/ methylisothiazolone 0.01% aq |
| Methylchloroisothiozolone/ methylisothiazolone 0.01% pet | |||||||||||
| Methylisothiazolinone 0.2% aq | Methylisothiazolinone 0.2% aq |
||||||||||
| Others | Benzalkonium Chloride 0.1% aq | ||||||||||
| Benzyl alcohol 1% pet | Benzyl alcohol 1% pet | Benzyl alcohol 1% pet | |||||||||
| Iodopropynyl butylcarbamate 0.1% pet | Iodopropynyl butylcarbamate 0.1% pet | Iodopropynyl butylcarbamate 0.1% pet | Iodopropynyl butylcarbamate 0.1% pet | ||||||||
| Iodopropynyl butyl carbamate 0.5% pet | Iodopropynyl butylcarbamate 0.5% pet | Iodopropynyl butylcarbamate 0.5% pet | Iodopropynyl butylcarbamate 0.5% pet | Iodopropynyl butylcarbamate 0.5% pet | Iodopropynyl butylcarbamate 0.5% pet | ||||||
| Methyldibromo glutaronitrile / phenoxyethanol 2.5% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | Methyldibromo glutaronitrile / phenoxyethanol 2% pet | ||
| Methyldibromo glutaronitrile / phenoxyethanol 1% pet | Methyldibromo glutaronitrile / phenoxyethanol 1% pet | Methyldibromo glutaronitrile 0.4% pet & | Methyldibromo glutaronitrile 0.4% pet & | ||||||||
| Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | Paraben Mix 12% pet | |
| Phenoxyethanol 1% pet | Phenoxyethanol 1% pet | ||||||||||
NACDG allergens are tested in 2-year cycles. Table includes preservatives tested 1994–2016.
Included in analysis for methyldibromo glutaronitrile / phenoxyethanol 2%
Included in analysis for methyldibromo glutaronitrile / phenoxyethanol 1%
Table 3 –
Percentage, Strength and Clinical Relevance of Positive Patch Test Reactions to Preservatives 1994–2016
| Preservative | n | Final Interpretation Allergic n (%)a | Second Read Code n (%) | Relevance n (%)b | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| +++ | ++ | + | +/− | Definite | Probable | Possible | Past | |||
| MI 0.2% (2000 ppm) aq. | 10613 | 1294 (12.2) | 364 (26.5) | 411 (29.9) | 443 (32.2) | 147 (10.7) | 88 (6.9) | 626 (48.8) | 470 (36.6) | 28 (2.2) |
| Formaldehyde 2% aq. | 10613 | 826 (7.8) | 101 (8.4) | 329 (27.4) | 480 (39.9) | 187 (15.6) | 6 (0.7) | 184 (22.3) | 481 (58.3) | 17 (2.1) |
| Formaldehyde 1% aq. | 50050 | 3880 (7.8) | 251 (5.7) | 1278 (29.0) | 2184 (49.5) | 655 (14.8) | 77 (2.0) | 847 (22.1) | 2112 (55.1) | 95 (2.5) |
| Quaternium-15 2% pet. | 50042 | 3827 (7.7) | 665 (16.4) | 1319 (32.6) | 1620 (40.0) | 437 (10.8) | 148 (3.9) | 1139 (30.0) | 2056 (54.2) | 139 (3.7) |
| MDBGN/phenoxyethanol 2% pet. | 48550 | 2491 (5.1) | 102 (2.8) | 556 (15.2) | 1710 (46.7) | 1121 (30.6) | 69 (2.8) | 493 (20.1) | 1102 (45.0) | 93 (3.8) |
| Benzalkonium chloride 0.1% aq.c | 4892 | 212 (4.3) | 3 (0.7) | 54 (12.0) | 173 (38.4) | 138 (30.7) | 2 (1.0) | 11 (5.2) | 44 (21.0) | 18 (8.6) |
| IPBC 0.5% pet. | 28676 | 1086 (3.8) | 51 (2.6) | 190 (9.6) | 751 (37.9) | 808 (40.8) | 28 (2.6) | 358 (33.6) | 515 (48.4) | 15 (1.4) |
| MCI/MI 0.01% (100 ppm) aq. | 50588 | 1907 (3.8) | 170 (8.4) | 743 (36.8) | 910 (45.1) | 182 (9.0) | 152 (8.1) | 800 (42.4) | 739 (39.2) | 68 (3.6) |
| MCI/MI 0.01% (100 ppm) pet.d | 2012 | 65 (3.2) | 0 (0) | 26 (34.2) | 37 (48.7) | 13 (17.1) | 10 (15.4) | 32 (49.2) | 15 (23.1) | 5 (7.7) |
| MDBGN/phenoxyethanol 1 % pet. | 16762 | 499 (3.0) | 11 (1.7) | 103 (15.5) | 306 (46.0) | 235 (35.3) | 28 (5.7) | 74 (15.0) | 220 (44.7) | 7 (1.4) |
| Diazolidinyl urea 1% pet. | 50638 | 1393 (2.8) | 118 (7.9) | 363 (24.4) | 753 (50.6) | 250 (16.8) | 84 (6.1) | 394 (28.7) | 774 (56.3) | 34 (2.5) |
| Diazolidinyl urea 1% aq. | 31424 | 833 (2.7) | 45 (5.0) | 202 (22.3) | 483 (53.2) | 173 (19.1) | 40 (4.9) | 264 (32.1) | 425 (51.7) | 12 (1.5) |
| 2-bromo-2-nitropane-1,3-diol 0.5% pet. | 50623 | 1249 (2.5) | 83 (5.2) | 273 (17.1) | 832 (52.0) | 387 (24.2) | 21 (1.7) | 161 (13.2) | 696 (56.9) | 38 (3.1) |
| Imidazolidinyl urea 2% pet. | 50616 | 1199 (2.4) | 121 (9.4) | 301 (23.3) | 639 (49.4) | 233 (18.0) | 49 (4.1) | 334 (28.1) | 703 (59.2) | 31 (2.6) |
| DMDM hydantoin 1% pet. | 50634 | 997 (2.0) | 45 (4.2) | 210 (19.4) | 57 (53.0) | 249 (23.0) | 52 (5.3) | 292 (29.5) | 572 (57.8) | 22 (2.2) |
| Imidazolidinyl urea 2% aq. | 31542 | 576 (1.8) | 41 (6.1) | 108 (16.1) | 357 (53.1) | 161 (23.9) | 33 (5.8) | 167 (29.6) | 291 (51.5) | 14 (2.5) |
| DMDM hydantoin 1% aq. | 31417 | 520 (1.7) | 17 (2.8) | 121 (20.2) | 308 (51.4) | 150 (25.0) | 26 (5.0) | 144 (28.0) | 280 (54.4) | 14 (2.7) |
| Paraben mix 12% pet. | 50645 | 527 (1.0) | 38 (5.3) | 153 (21.5) | 303 (42.5) | 203 (28.5) | 49 (9.5) | 211 (40.7) | 207 (40) | 14 (2.7) |
| IPBC 0.1% pet. | 20238 | 81 (0.4) | 4 (3.0) | 15 (11.1) | 56 (41.5) | 49 (36.3) | 5 (6.3) | 17 (21.5) | 40 (50.6) | 1 (1.3) |
| Benzyl alcohol 1% pet. | 13628 | 44 (0.3) | 1 (1.5) | 8 (12.1) | 39 (59.1) | 16 (24.2) | 7 (16.3) | 17 (39.5) | 10 (23.3) | 1 (2.3) |
| Phenoxyethanol 1% pet. | 6900 | 12 (0.2) | 1 (3.7) | 3 (11.1) | 9 (33.3) | 11 (40.7) | 1 (8.3) | 0 (0.0) | 6 (50.0) | 1 (8.3) |
First and second readings were designated as +++ (very strong), ++ (strong), +(mild), +/− (weak/doubtful), irritant and negative in accordance with ICDRG criteria. Final interpretation for each allergen was coded as allergic, unknown, irritant or negative. For each reaction designated allergic, clinical relevance was described as definite, probable, possible and past. Discrepancies in final interpretation and second read code will differ due to interpretation of results.
Excludes unknown/uncertain.
Excludes those with “not tested” or “not applicable”. Percentages were calculated for patients who had PPTR. Relevance category “unknowns” was included in the denominator for percentage calculation. However, “unknowns” not shown.
Allergen tested only during the 2001–2002 cycle.
Allergen tested only during the 1994–1996 cycle.
Abbreviations: Aq, aqueous; Pet, petrolatum; MI, methylisothiazolinone; MCI, methylchloroisothiazolinone; MDBGN, methyldibromo glutaronitrile; IPBC, iodopropynyl butylcarbamate; DMDM, dimethylol dimethyl.
Preservative trends over time are documented in Figure 1A and B. SPIN trends are plotted in Figure 1C and D. Interestingly, SPIN trends mirror allergen percentage trends.
Figure 1 — Trends of PPTR for Preservatives 1994 — 2016.
(A) Positive patch test reactions for formaldehyde and formaldehyde releasing preservatives.
(B) Positive patch test reactions for isothiazolinones, parabens and other preservatives.
(C) Significance-prevalence index number (SPIN) for formaldehyde and formaldehyde releasing preservatives.
(D) SPIN for isothiazolinones, parabens and other preservatives.
SPIN = Prevalence*(1*Definite+0.66*Probable+0.33*Possible).
Abbreviations: Aq, aqueous; Pet, petrolatum; MI, methylisothiazolinone; MCI, methylchloroisothiazolinone; MDBGN, methyldibromo glutaronitrile; IPBC, iodopropynyl butylcarbamate; DMDM, dimethylol dimethyl.
The linear regression model of trends recorded parameter estimates (PE) (Table 4); these represent the average increase or decrease in reactions with each test cycle increase. This model identified only one preservative, MCI/MI 0.01% aq (p<0.005) with a significant increase in PPTRs. Formaldehyde 1% aq and several formaldehyde releasers (FR) (quaternium-15, diazolidinyl urea, imidazolidinyl urea, DMDM hydantoin, 2-bromo-2-nitropropane-1,3-diol) demonstrated a decreasing trend, with quaternium-15 2% pet showing the largest decrease (p<0.001). MDBGN/phenoxyethanol 2% pet (p<0.001) and paraben mix 12% pet (p=0.038) also showed a significant trend for decrease in PPTRs. MI 0.2% aq (first cycle 10.9%, last cycle 13.4%) and formaldehyde 2% aq (first cycle 7%, last cycle 8.4%) both showed considerable increases, but were not included in the linear regression model as they were only tested for two cycles.
Table 4.
Linear Regression Analysis of Positive Patch Test Reactions 1994–2016
| Preservative | Parameter estimate (%) with 95% CI | p-value |
|---|---|---|
| MCI/MI 0.01% (100 ppm) aq | 0.42 [0.17, 0.66] | 0.005 |
| IPBC 0.5% pet | 0.35 [−0.07, 0.76] | 0.080 |
| Paraben mix 12% pet | −0.08 [−0.16, −0.01] | 0.038 |
| 2-bromo-2-nitropropane-1,3-diol 0.5% pet | −0.18 [−0.33, −0.03] | 0.024 |
| DMDM hydantoin 1% pet | −0.19 [−0.29, −0.09] | 0.002 |
| DMDM hydantoin 1% aq | −0.21 [−0.37, −0.05] | 0.021 |
| Imidazolidinyl urea 2% pet | −0.23 [−0.29, −0.16] | <0.001 |
| Imidazolidinyl urea 2% aq | −0.24 [−0.34, −0.15] | 0.001 |
| Diazolidinyl urea 1% pet | −0.26 [−0.36, −0.17] | <0.001 |
| Diazolidinyl urea 1% aq | −0.33 [−0.55, −0.12] | 0.011 |
| Formaldehyde 1% aq | −0.42 [−0.56, −0.28] | <0.001 |
| MDBGN/phenoxyethanol 2% pet | −0.43 [−0.56, −0.30] | <0.001 |
| Quaternium-15 2% pet | −0.57 [−0.84, −0.31] | <0.001 |
Trend of PPTRs over time was analyzed with a simple linear regression model, where Positive rate = β0 + β1Time + ε.
Abbreviations: CI, Confidence Interval; Aq, aqueous; Pet, petrolatum; MI, methylisothiazolinone; MCI, methylchloroisothiazolinone; MDBGN, methyldibromo glutaronitrile; IPBC, iodopropynyl butylcarbamate; DMDM, dimethylol dimethyl.
Discussion
This study examined preservative allergy trends in North America. Patients with preservative PPTRs were more likely to be age >40 years, male, and have hand involvement. Fasth reported demographics for 8463 patients with contact sensitivity to formaldehyde and FR (2007–2016), compared them to 8350 patients without reactions, and found that patients with PPTRs to formaldehyde 1% aq (83.5%) and diazolidinyl urea 2% pet (90.2%) were more likely to be >40 years.10 Similar to our study, patients with PPTRs to formaldehyde 1% aq (63%), formaldehyde 2% aq (50%), quaternium-15 1% pet (68.1%), diazolidinyl urea 2% pet (61%) and DMDM hydantoin 2% aq (61.9%) were more likely to have hand dermatitis. However, they identified only one preservative, formaldehyde 2% aq (22.4% males allergic vs 31.5% males not allergic) with a difference in sex prevalence. Buckley reported increasing fragrance allergy with age and theorized that this was due to repeat environmental exposure and age-related susceptibility;11 perhaps a similar phenomenon exists for preservatives. It is not surprising that hand dermatitis was more common in preservative positive patients as compared to those with non-preservative PPTRs, given the ubiquitous exposure of hands to products. Patients with PPTRs to preservatives, as compared to non-preservatives, were more likely to be male. This could simply be because females had greater numbers of positives to non-preservatives allergens, or could be related to differences in occupational exposures, hobbies, or other factors.
Common Preservative Allergens
Methylisothiazolinone
Of the tested preservatives, MI 0.2% aq had the highest overall PPTRs (12.2%). Cycle frequencies increased from 10.9% (2013–2014) to 13.4% (2015–2016).8,12 The 2015–16 SPIN of 685, the highest recorded, confirms that MI usually has clinical relevance.8 These data are consistent with international studies of MI 0.2% aq: Mayo Clinic 13.6% (2011–2015, n=964); International Contact Dermatitis Research Group 7.3% (2014, n=3865); Australia 14.5% (2011–2017, n=2787).13–15 Due to this epidemic of contact allergy, MI was named the 2013 Allergen of the Year by the American Contact Dermatitis Society (ACDS).16
In 2016, the European Commission banned MI in leave-on products and allowed a maximum of 15 ppm in rinse-off products.17 Similarly, Canada’s Cosmetic Ingredient Hotlist (CIH) prohibits MI in leave-on products and mandates a maximum of 15ppm in rinse-off products.18 In comparison, in 2010 the United States based Cosmetic Ingredient Review (CIR) panel recommends a maximum of 100 ppm.19 The 2014 CIR update recommended a maximum of 100 ppm in rinse-off products and described MI as “safe in leave-on products when formulated to be non-sensitizing based on the results of a quantitative risk assessment (QRA) or similar methodology”.20 Groups in Australia and the United Kingdom have noted recent downtrends in PPTRs to MI.15,21 It is possible that this is related to regulations; this has not been identified in North America.
Prior to 2013, the NACDG tested MI only via MCI/MI 0.01% aq. This hapten includes 76.7% MCI and 23.3% MI; at this formulation, MI is tested at 0.002% aq. Higher test concentrations are required to detect sensitization;22 MI 0.2% aq is recommended. Because TRUE Test includes MCI/MI but not MI, users should add MI 0.2% aq to confirm contact allergy.23 Patients with MI allergy should avoid any product that contains MI, regardless of reported MI product concentration.
Methylcholoroisothiazolinone/methylisothiazolinone
Reaction frequencies were 3.8% for MCI/MI 0.01% aq and 3.2% for MCI/MI 0.01% pet, with a significant upward trend for MCI/MI 0.01% aq (2009–10 to 2015–16). MCI/MI had it’s highest frequency 2015–2016 (7.3%).8
Similar to MI, increasing reactions to MCI/MI are an international phenomenon. On 9/30/2019, the US CIR panel described MCI/MI as “safe in cosmetics when formulated to be non-sensitizing, based on the results of a QRA or similar methodology” with a recommendation of <15ppm for rinse-off products and <7.5ppm leave-on products.24 The CIH prohibits MCI/MI in leave-on products, with a maximum of 15ppm in rinse-off products;18 when MCI/MI and MI are formulated together, the total concentration of the combined chemicals may not exceed 15ppm in rinse-off products. As with MI, patients with MCI/MI allergy should avoid products containing MCI/MI.
Formaldehyde and Formaldehyde Releasers
Formaldehyde (1% aq and 2% aq) and quaternium-15 2% pet had the highest frequencies of formaldehyde-related PPTRs (7.8%, 7.8% and 7.7%). Linear regression analysis revealed that formaldehyde 1% aq and FR had statistically significant decreasing trends. Therefore, the high PPTRs to formaldehyde and quaternium-15 over the study period do not reflect current trends for these preservatives. Europe has experienced a similar downward trend.10
Positive patch test reactions to formaldehyde and FRs are more frequent in North America than in Europe, where reports of PPTRs include formaldehyde 2% at 2.4–3.3% and FR at <1%.25–27 The reason for these discrepancies is unknown; potential contributors may be differences in patch test technique28 and investigator interpretation of results.29 It has also been argued that variances may be due to regulatory differences, even though the required (European Union) and recommended (US) maximum concentrations of formaldehyde and FRs in cosmetic products are almost identical, with exceptions of slightly higher US allowances for imidazolidinyl urea (0.6% EU, 1% US) and DMDM hydantoin (0.6% EU, ≤0.8% US).30–35 One might also theorize that continental differences in PPTRs are due to divergent rates of preservative utilization in products. However, a 2010 study identified a similar number of FRs in US-based cosmetic products (23.8%) vs Netherlands products (24.6%), and by 2017, FRs were only present in 9.9% of products catalogued by CAMP.36,37 This conversation is not complete without a final caution that undeclared formaldehyde has been identified in North American and European consumer products; for this reason our ability to comprehensively understand consumer formaldehyde and FR exposure remains incomplete.38,39
The ideal patch test allergen identifies the highest number of relevant PPTRs, with the lowest possible irritant reactions. Formaldehyde 2% aq identifies more positive patch test reactions than formaldehyde 1% aq, with similar irritant frequencies.26,27,40 Importantly 2% aq should be aliquoted with a micropipette, when possible, to avoid irritant reactions.28
Methyldibromo glutaronitrile
MBDGN/phenoxyethanol 2% pet, with MDBGN the likely allergen, had an overall higher PPTR prevalence (5.1%) as compared to several other preservatives, but prevalence has significantly decreased over time. For comparison, Mayo Clinic (2011–2015) MDBGN 0.5% pet was 4.3%,13 and in Europe, Giménez-Arnau (2009–2012) MDBGN/phenoxyethanol 1.5% pet was 2.04%.25 MDBGN was originally marketed as a less-sensitizing alternative to formaldehyde and MCI/MI. However, numerous reports highlighted its sensitizing potential, resulting in more stringent regulations and a decreased frequency of PPTRs in Europe beginning in the early 2000s.41,42 The US allows up to MDBGN 0.025% in leave-on products and 0.06% in rinse-off products43. A 2017 CAMP database analysis identified MDBGN in only 0.02% of products.37 The decreasing trend for PPTRs may be due to the fact that MDBGN is now only rarely used as a preservative in personal care products.
Uncommon Preservative Allergens
Parabens
Parabens are inexpensive, odorless, colorless and biodegradable.44 Because of their low prevalence of allergy despite pervasive consumer concerns, parabens were selected as the 2019 ACDS (NON) Allergen of the Year.45
In this study, the overall reaction frequency to paraben mix 12% pet was 1%. Like the formaldehyde preservatives, paraben PPTRs have steadily declined from 2% in 1994–1996 to 0.6% in 2015–2016. A consistent trend is also observed in the European population, with recent estimated paraben PPTR ranges of 0.5%-1%.5,25
Parabens are tightly regulated in Europe, with a ban on isopropylparaben, isobutylparaben, phenylparaben, benzylparaben and pentylparaben since 2014 and a limit on the combined concentration of propylparaben and butylparaben (0.19%) since 2015.1 In comparison, the US CIR panel states that 20 of 21 reviewed parabens are recommended as safe for use in cosmetic products when used at a combined concentration of up to 0.8%; data were insufficient to determine safety of benzylparaben.46 Parabens are regularly utilized as preservatives in US-based personal products; in 2017 parabens were present in 20.8% of ACDS CAMP personal products.37
Benzyl Alcohol and Phenoxyethanol
Two other preservatives had consistently low reactions, benzyl alcohol 1% pet (0.3%) and phenoxyethanol 1% pet (0.2%). Few large series report the reaction frequencies to these preservatives. However, Schnuch (1996–2009, Europe) documented benzyl alcohol 1% pet as 0.28% (n=79,770) and phenoxyethanol 1% pet as 0.24% (n=6932);6 these numbers coincide with our results. Phenoxyethanol was the most commonly identified preservative (23.9%) in the 2017 ACDS CAMP database. Benzyl alcohol came in at #4, present in 12.7% of products.37
Both benzyl alcohol 10% and phenoxyethanol 1% pet were added to the 2019–2020 NACDG screening series. Benzyl alcohol was added because of its increasing use in products. Phenoxyethanol was included because of its frequent use in cosmetic products and to better differentiate MBDGN vs phenoxyethanol in methyldibromo glutaronitrile/phenoxyethanol reactions. The data demonstrate that these are rare allergens.
Iodopropynyl butylcarbamate
Discussion of iodopropynyl butylcarbamate is challenging, because although IPBC 0.1% had one of the lowest reaction frequencies at 0.4%, and although IPBC 0.5% pet does not represent one of the most common preservative allergens (3.8%), IPBC 0.5% pet did, in fact, have a marginal increase in reactions over time. Directly comparable data are not available, because other patch test groups test IPBC at lower concentrations (Mayo Clinic and Europe 0.1%-0.2).13,25
As IPBC is a known marginal irritant47, it is possible that the higher reported reactions in North America are due to false-positive reactions; ongoing and additional studies are needed. Stricter regulations for the use of IPBC in cosmetics in Europe, with a maximum concentration of 0.02% in rinse-off products and 0.01% in leave-on products, could also explain differences in reaction frequencies between North America and Europe.13,25
Limitations
Interpretation of patch test reactions and other collected variables are dependent on clinical judgment. Results may be prone to referral population selection bias; results may not be representative of the general dermatology population or population at large.
Conclusion
The most common preservative allergens were methylisothiazolinone, formaldehyde, quaternium-15 and methyldibromo glutaronitrile/phenoxyethanol. Parabens, benzyl alcohol, iodopropynyl butylcarbamate 0.1% and phenoxyethanol had consistently low reactions. There was a significant increasing trend for methylchloroisothiazolinone/methylisothiazolinone; methylisothiazolinone and formaldehyde 2% also increased. Formaldehyde and FR had significant downward trends, as did methyldibromo glutaronitrile/phenoxyethanol and parabens.
Funding sources:
This study was supported in part by Duke Dermatology, which provided statistical funding. This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Medical Center. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.
Footnotes
Conflicts of interests: Dr. Atwater received a Pfizer Independent Grant for Learning & Change. Dr Taylor owns non-controlling shares of common stock in Cigna, Merck, Johnson and Johnson, and Opko Health. He has consulted for Bayer and Kao Brands. A non-dependent child is an employee of Pfizer. He is a Steering Committee Member of the Cosmetic Ingredient Review and an FDA Special Government Employee for the Center for Devices and Radiologic Health.
IRB approval status: Reviewed and approved by Duke University IRB: approval #00092478.
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