key: cord-0785222-2zyz4vjc
authors: Tasar, Ramona; Wiegand, Cornelia; Elsner, Peter
title: How irritant are n‐propanol and isopropanol? – A systematic review
date: 2020-11-11
journal: Contact Dermatitis
DOI: 10.1111/cod.13722
sha: 6970303313b27efd9ee87dbf6ad25a27615da101
doc_id: 785222
cord_uid: 2zyz4vjc

BACKGROUND: The use of alcoholic‐based hand rubs (ABHRs) is an important tool for hand hygiene, especially in times of the COVID‐19 pandemic. Possible irritant effects of ABHR may prevent their use by persons at risk of infection. METHODS: This systematic review is based on a PubMed search of articles published between January 2000 and September 2019 in English and German, and a manual search, related to the irritation potential of alcohol‐based disinfectants restricted to n‐propanol (1‐propanol) and its structural isomer isopropanol (isopropyl alcohol, 2‐propanol). RESULTS: The majority of the included studies show a low irritation potential of n‐propanol alone. However, recent studies provide evidence for significant barrier damage effects of repeated exposure to 60% n‐propanol in healthy, as well as atopic skin in vivo. The synergistic response of combined irritants, (ie, a combination of n‐propanol or isopropanol with detergents such as sodium lauryl sulfate) is greater, compared with a quantitatively identical application of the same irritant alone. CONCLUSION: While recent studies indicate a higher risk of skin irritation for n‐propanol and isopropanol than reported in the past, this risk still seems to be lower than that for frequent handwashing with detergents, as recommended by some to prevent COVID‐19 infections.

hand hygiene (hand washing, ABHR, skin protection, and skin care) must be ascertained as early as possible to keep the level of irritative skin changes in working life as low as possible.

Today, ABHR have re-gained popularity and are now widely used for infection control in clinical practice. ABHRs were found to be a suitable alternative to traditional hand washing as they require less time, act faster, are less irritating to the skin, and contribute to significantly lower infection rates. 11 Currently, hand disinfectants are the most important prevention measure after face masks in the global SARS-CoV-2 pandemic. Among other things, virus containment and transmission reduction are of highest priority. Recently, it was proven that a mixture of isopropanol 12 led to complete viral inactivation without cytotoxic activity, at a minimal concentration of 30%. 13 Irritant contact dermatitis (ICD) is the most common form of occupational skin disease with a prevalence of approx. 21%-75% in occupational groups with high exposure to wet-work. [14] [15] [16] [17] Therefore, HCW with higher frequencies of hand washing and use of disinfectants are severely affected. 18 Several field studies have elucidated that ABHRs (short-chain aliphatic alcohols such as n-propanol or isopropyl alcohol, so called "rub-ins") have a low irritation potential compared to detergents. [19] [20] [21] This systematic review evaluated the clinical evidence of the irritation potential of n-propanol and isopropanol as components of ABHRs. We reviewed the reference lists of the full length articles to identify additional articles that met the predefined inclusion criteria (Figure 1 ).

A total of 156 articles were identified from the initial search and 10 additional articles were found by manual search. After the review of all articles, 166 full text articles were further evaluated. As we focused on the primary literature and avoided double counting, 34 reviews were excluded from our primary analysis. We also excluded articles without the relation to the irritation potential of ABHR and articles dealing with animal models.

Following these exclusion criteria, we finally considered 20 articles.

For each study included, we recorded the intervention, substance, population, measurements, author, year, location, and conclusion, shown in Tables 1-4 . We included prospective studies only.

A total of 166 citations were retrieved. Twenty articles (12.04%) met the inclusion criteria. The majority of the studies (11/20) Of the 20 studies, six studies examined the irritation effects of npropanol or isopropanol alone while using different application methods, as shown in Table 1 .

In a tandem application model with consecutively applied 60% aq. n-propanol or a propanol mixture (2-propanol 45% w/w, 1-propanol 30% w/w) with 0.5% aq. sodium lauryl sulfate (SLS),

bility of propanol alone. The resulting irritation was assessed by corneometry and transepidermal water loss (TEWL) measurements.

The alternating application of n-propanol (Prop/Prop) showed values identical to water (plain control field) or an empty chamber, which served as a negative control. 22 Biometric measurements demonstrated a significant exponential increase, including water loss and skin irritation after the single application of SLS/SLS. 23 Another study conducted repetitive patch testing with various concentrations of three different alcohols by the consecutive application of the same alcohol. Ethanol, 1-propanol and 2-propanol were applied in concentrations ranges from 60%-100%. Evaluated by bioengineering techniques, all three alcohols failed to induce irritation regarding erythema (chromameter values) and skin barrier (TEWL values) at all patches. 6 Clemmensen et al published a study comparing irritation induction by different concentrations of SLS and nonanoic acid (NAA) in two test models. Here, n-propanol served as a vehicle for NAA but was beyond that tested separately as a pure solution.

The authors demonstrated that 100% n-propanol had the same irritancy level as 1% SLS, but did not differ statistically significantly from NAA concentrations in the repeated open application model. However, in the wash test model, n-propanol was less irritating than SLS in all concentrations. 24 In a forearm controlled application test on 35 volunteers, using ethanol, n-propanol, and isopropanol in various concentrations from 0%-10%, the volunteers were randomized for a standard frequency application (20x) or high frequency application (100x), mimicking the in-use conditions of HCW in hospitals. According to Cartner et al, the highest drop-out rates were recorded with the use of n-propanol. By day 10, all treatments of n-propanol at 100x application were stopped and, equally, >50% of the subjects stopped at the 20x application rate.

Moreover, the maximum visual redness score of 5.0 was only seen with n-propanol. 25 Allergic reactions to ABHR are rarely found in the literature. It has been proposed by García-Gavín et al that 100% isopropyl alcohol in a patch test caused allergic reactions and that it should be considered as a potent allergen. 26 Stutz et al tested 50 volunteer nurses, who thought they were allergic to ABHR. A total of 80% aq. ethanol, 60% aq. 1-propanol and 70% aq. 2-propanol, as well as five conventional disinfectants were analyzed using patch tests. A delayed type sensitization to an ABHR could be excluded in all 50 nurses. 9 3.1.2 | The irritation potential of n-propanol or isopropanol in combination with detergents in a tandem model A valid method for the sequential application of two irritants is known as the tandem repeated irritation test (TRIT), which has been well established over time. 27 Highest skin barrier impairment and lowest skin hydration was found with n-propanol, followed by ispopropanol and ethanol, regardless of the application frequency (Continues) detergent and an ABHR in combination has been reported to produce an additional irritation response, compared to single alcohol application. In total, five studies described the irritation capability of npropanol when combined with SLS, which is summarized in Table 1 .

Prior to the application of alcohol, previous irritation of the skin was induced by SLS applied under occlusive conditions for several minutes up to several hours.

In a short term repeated tandem application of 60% aq. n- Recently, another study demonstrated enhanced barrier impairment and local erythema after repetitive application of n-propanol on previously damaged atopic and healthy skin, when preceded by exposure to water and occlusion. Hereby, the cumulative effect of repeated exposure to n-propanol (30%, 45%, 60%, and 75%) in atopic and healthy subjects, with or without preceded occlusion with water, was evaluated. Repeated exposure to water enhanced the irritantinduced effects of n-propanol. The lowest concentration of npropanol was sufficient to induce barrier impairment in atopic skin without previous trauma. 43 

In a repetitive occlusive exposure to n-propanol 60% aq. and SLS areas showed a significantly higher losses of natural moisturising factor (NMF) than test fields without pretreated occlusion. The relative reduction of NMF after exposure to Pro/Pro was −55.4% and after SLS −79.2%. In contrast, pretreatment with occlusion showed much higher losses, of −60.8% and − 87.4%, respectively. 30 Subsequently, an extended study was conducted by the same authors with the discovery of a significant decrease in NMF levels after cumulative exposure to various concentrations of n-propanol (30%, 45%, 60%, 75%) in healthy and atopic skin groups. Here, the relative NMF reduction in the healthy skin group was lower than in the atopic skin group, independent of previous barrier damage by occlusion. Occlusion with water alone had no impact on NMF levels in both groups. 43 This result is consistent with findings of Soltanipoor et al, which confirmed that 60% n-propanol reduces NMF levels in the stratum corneum (SC). Furthermore, the authors showed that n-propanol caused remarkable changes in corneocyte surface topography under repeated occlusive conditions and that this effect is strongly associated with a decrease in NMF and SC hydration. The reduction of NMF was inversely correlated with the increase in circular nano objects (CNO) and the dermal texture index (DTI) detected with atomic force microscopy (AFM). N-propanol showed significant changes in skin capacitance, but not in TEWL parameters, leading the authors to suggest that the decrease in skin hydration depends on the decrease of NMF rather than the effect of n-propanol on the corneocyte lipid bilayers. 44 In a prospective in vitro and in vivo study by Cartner et al, the cellular toxicity of three alcohol solutions was analyzed using neonatal human epidermal keratinocytes by evaluating the production of inflammatory cytokines. Ethanol, n-propanol, and isopropanol in various concentration ranges from 0% to 10% were used. It was found that n-propanol distinctly increased the expression of TNF-α and IL-1α, and to a lesser extent isopropanol and ethanol. 25 The findings of this section are summarized in Table 3 .

The benefits of adding emollients to a propanol-based hand rub supports the regeneration of the skin barrier and may minimize the risk of developing the sensation of skin dryness. 45 The application of moisturizers after repeated irritation with water and detergents improves skin hydration. 46 As early as 1995, MES was found to have protective properties in Sterillium and to reduce skin roughness. 47 Furthermore, glycerol, a well-known moisturizing substance used in commonly available hand disinfectants, increases the skin water content. 48 The drying effect of alcohol can be reduced or eliminated by adding emollients such as 1% to 3% glycerol or other skin-conditioning agents to alcohol-based formulations. 49 Of the 20 studies, six studies examined the beneficial effects of emollients in customary disinfecting agents and are shown in Table 4 .

This category deliberately includes studies that investigate the irritation potential of Sterillium, a globally known disinfectant with additive humectants.

Kampf et al published a study of 53 volunteers repetitively patch tested in two phases with Sterillium (2-propanol 45% w/w, 1-propanol 30% w/w and MES 0,2%) under occlusive conditions. In the first phase, the induction phase, Sterillium exerted a barely perceptible, minimalerythema in one of the nine included patients. In general, none of the remaining participants showed any skin changes at any time. During the second phase (the challenge phase), 72 hours after the application of the disinfectant, none of the subjects showed skin reactions. 50 Pietsch et al, who tested Sterillium (45% w/w propan-2-ol, 30%

w/w propan-1-ol % 0.2% w/w ethylhexadecyldimethyl ammonium ethylsulfate) and the water-based handwashing antiseptic Hibiscrub (4% chlorhexidine digluconate) in a long-term application form, came to the same conclusion. All biophysical parameters indicated a significantly higher compliance towards Sterillium than Hibiscrub. 51 Kramer Based on the findings of this systematic search, hand disinfectants should be continued as standard hygiene procedures in healthcare centers where ABHR are used routinely many times a day.

The tolerability of n-propanol and isopropanol with or without additives has been established in various studies. 6, 9, [22] [23] [24] [50] [51] [52] [53] [54] The current systematic review shows that hand disinfectants with n-propanol concentrations of 60%, or certain combinations of propan-1-ol and propan-2-ol showed little to no irritation in intact skin and previously irritated skin. 6, 22, 23, 29 Bioengineering measurements dem- Since the only two options for hand hygiene procedures are hand washing with antiseptic soaps or ABHR, it is necessary to consider and compare the existing evidences of the irritation potential of both hygiene modalities. With respect to our reviewed publications, SLS showed greater irritability in in vivo as well as in in vitro tests compared to n-propanol or isopropanol. While recent studies indicate a higher risk of skin irritation for n-propanol and isopropanol than reported in the past, this risk still seems to be lower than that for frequent handwashing with detergents.

In conclusion, it is extremely important to recall that alcoholbased formulations for hand disinfections (whether isopropyl alcohol or n-propanol in 60%-90% vol/vol) are less irritant on skin than most antiseptic or non-antiseptic detergents and that alcohol-base formulations, with the addition of appropriate humectants, are at least as tolerable and efficacious as detergents. Commercial ABHR (with only few exceptions) contain hydrating agents 59 that have re-fatting properties and provide moisture to the skin. It has been proved that humectants promote skin hydration and minimize the incidence of irritant dermatitis. 45, 46, [60] [61] [62] [63] Besides glycerol, which increases the skin water content and accelerates the recovery of the skin barrier function, 64 MES proved to protect the skin, even when the alcoholbased solution is applied regularly. In occupations where the repeated application of disinfectants is necessary in the long term, additional moisturizers in alcohol-based hand rubs is a benefit and may promote tolerability and compliance.

Hände-Hygiene im Gesundheitswesen

Hand hygiene and patient care: pursuing the Semmelweis legacy

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Nursing staff workload as a determinant of methicillinresistant Staphylococcus aureus spread in an adult intensive therapy unit

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Do wearable alcohol-based handrub dispensers increase hand hygiene compliance? -a mixedmethods study

WHO Guidelines Approved by the Guidelines Review Committee. WHO Guidelines on Hand Hygiene in Health Care: First Global Patient Safety Challenge Clean Care Is Safer Care

Nurses' perceptions of the benefits and adverse effects of hand disinfection: alcohol-based hand rubs vs. hygienic handwashing: a multicentre questionnaire study with additional patch testing by the German Contact Dermatitis Research Group

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Self-reported hand eczema in a hospital population

Skin irritation and dryness associated with two hand-hygiene regimens: soap-and-water hand washing versus hand antisepsis with an alcoholic hand gel

Surgical hand disinfection with alcohols at various concentrations: parallel experiments using the new proposed European standards method

Skin tolerance and effectiveness of two hand decontamination procedures in everyday hospital use

Effects of disinfectants and detergents on skin irritation

Tandem application of sodium lauryl sulfate and n-propanol does not lead to enhancement of cumulative skin irritation

The irritant potential of n-propanol (nonanoic acid vehicle) in cumulative skin irritation: a validation study of two different human in vivo test models

Effect of different alcohols on stratum corneum kallikrein 5 and phospholipase A2 together with epidermal keratinocytes and skin irritation

Allergic contact dermatitis caused by isopropyl alcohol: a missed allergen? Contact Dermatitis

Additive impairment of the barrier function by mechanical irritation, occlusion and sodium lauryl sulphate in vivo

The tandem repeated irritation test: a new method to assess prevention of irritant combination damage to the skin

Irritancy of the skin disinfectant n-propanol

Barrier function and natural moisturizing factor levels after cumulative exposure to short-chain aliphatic alcohols and detergents: results of occlusion-modified tandem repeated irritation test

Less skin irritation from alcohol-based disinfectant than from detergent used for hand disinfection

Short-term effects of alcohol-based disinfectant and detergent on skin irritation

Cutaneous reactions to lower aliphatic alcohols before and during disulfiram therapy

Risk for hand eczema in employees with past or present atopic dermatitis

Hospital employees and skin problems

Individual and environmental risk factors for hand eczema in hospital workers

Wet-work exposure: a main risk factor for occupational hand dermatitis

Wet work exposure and hand eczema among healthcare workers: a cross-sectional study

Exposures related to hand eczema: a study of healthcare workers

Atopy and hand dermatitis in hospital wet work

Do atopics tolerate alcoholbased hand rubs? A prospective, controlled, randomized double-blind clinical trial

Emollients in a propanol-based hand rub can significantly decrease irritant contact dermatitis

Barrier damaging effects of n-propanol in occlusion-modified tandem repeated irritation test: modulation by exposure factors and atopic skin disease

Specific barrier response profiles after experimentally induced skin irritation in vivo

Dermatological aspects of a successful introduction and continuation of alcohol-based hand rubs for hygienic hand disinfection

The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents

Die Hautverträglichkeit von Mecetroniumetilsulfat in einem Händedesinfektionsmittel -eine klinische Studie

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Arguments for alcoholic hand disinfection

Dermal tolerance of sterillium, a propanolbased hand rub

Hand antiseptics: rubs versus scrubs, alcoholic solutions versus alcoholic gels

Clinical double-blind trial on the dermal tolerance and user acceptability of six alcohol-based hand disinfectants for hygienic hand disinfection

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A systematic review on the effectiveness of alcohol-based solutions for hand hygiene

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Assessment of the potential irritancy of oleic acid on human skin: evaluation in vitro and in vivo

The influence of cosmetic additives on the acceptability of alcohol-based hand disinfectants

Glycerol content within the WHO ethanol-based handrub formulation: balancing tolerability with antimicrobial efficacy

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Experimentally induced chronic irritant contact dermatitis to evaluate the efficacy of protective creams in vivo

A double-blind, randomized study to assess the effectiveness of different moisturizers in preventing dermatitis induced by hand washing to simulate healthcare use

Glycerol accelerates recovery of barrier function in vivo

How irritant are n-propanol and isopropanol? -A systematic review

The authors have declared no conflicts of interest. investigation; project administration.

Data sharing not applicable -no new data generated.

https://orcid.org/0000-0001-9946-8217Peter Elsner https://orcid.org/0000-0001-7696-3274