Dermatology

Allergic Contact Dermatitis: Preservatives

Preservatives are ubiquitous in many chemicals and toiletries and are a common cause of acute and chronic allergic contact dermatitis. In one series, up to 50% of patch-tested individuals had at least one reaction to at least one preservative.

  • Formaldehyde

Rarely used in topical personal care products, many industrial or workplace exposures

  • Formaldehyde-releasing agents

The most commonly used agents are listed below. These agents release formaldehyde molecules into the product as they degrade. In some cases, the base molecule itself is allergenic, in others the formaldehyde sensitivity is the cause of the reaction.

Quaternium-15

Diazolidinyl urea

Imidazolidinyl urea

2-bromo-2-nitropropane-1,3-diol

DMDM hydantoin

  • Other preservatives

Isothiazolinones (methylchloroisothiazolinone [MCI] and methylisothiazolinone [MI] most common)

Non-formaldehyde-releasing preservative in cosmetics, frequently used in wash-on/wash-off products, cosmetics, moistened toilet paper, and laundry detergents. AKA: Methylchloroisothiazolinine/Methylisothiazolinone [MCI/MI] (Euxyl® K100 not 400), Grotan K, and many more. MCI/MI was banned in the EU in 2015 in wash off products.

Often in hair care products and wet wipes for adults.

Becoming a very common cause of preservative dermatitis in the US.

Methyldibromoglutaronitrile

Banned by the European Union (EU) in 2007. Use in the United States (US) is rare.

Parabens: Minimally estrogenic. Questioned as cause of breast carcinoma. FDA states that this is "improbable." Despite this, many individuals question its safety. A rare cause (<1%) of ACD.

Iodopropynyl butylcarbamate

A halogenated, unsaturated carbamate - questionable cross-reaction with other carbamate rubber accelerators

Broad spectrum coverage-–fungicide/bactericide

Widely used in industry: polymer emulsions/pigments, wood preservatives, metalworking

Ethylenediamine dihydrochloride

Stabilizer in steroid creams and latex rubber, inhibitor in antifreeze/cooling fluids

Entire family of antihistamines based on ethylenediamine molecule; ingestion can cause localized or generalized dermatitis

–hydroxyzine, cetirizine, aminophylline

Cross-reactions: EDTA, antazoline, aminophylline, cetirizine, promethazine, piperazines

Sodium benzoate

In acidic environments (especially vitamin C), degrades to benzene

Bacteriostatic and fungistatic under acidic conditions

Used mostly in acidic foods such as:

  • salad dressings (vinegar)

  • carbonated drinks (carbonic acid)

  • jams and fruit juices (citric acid)

  • pickles (vinegar)

  • condiments

On labels as sodium benzoate or E211

Worsens urticaria in 10% to 40% of chronic urticaria patients

Benzyl alcohol

Fragrance, local anesthetic and preservative

Excellent gram positive coverage

Component of cocoa

Triclosan

Phenolic antibacterial. Recently questioned as teratogen, though this is not definitive.

Propylene glycol

Preservative in foods and cosmetics

Topical steroids; added to increase steroid penetration/efficacy

Causes both irritant and allergic dermatitis

Thimerosal

Rarely used in the US and EU. Mercurial preservative. Occasionally still used in vaccines.

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Episodic or sustained dermatitis on areas exposed to topical products/medicaments is the most common history.

  • Characteristic findings on physical examination

Like any other dermatitis, the acute phase consists of erythematous, vesicular papules and often coalescing plaques on exposed surfaces. Common sites are hands, arms, and face/eyelids. Chronic dermatitis may develop on any chronically exposed site--leading to hyperkeratosis, crusting, excoriations as well as erythema and possibly active vesiculation.

  • Expected results of diagnostic studies

Histopathology is nonspecific but helpful in general classification. The most common read is spongiotic dermatitis with superficial perivascular infiltrate, often with lymphocytes and eosinophils. Serologic and genetic tests are not recommended. Imaging is not necessary. In cases of widespread, recalcitrant dermatitis, a biopsy for direct immunofluorescence (DIF) may be helpful. The DIF biopsy would evaluate for a pre-blistering stage of a primary blistering disorder such as dyshidrosiform bullous pemphigoid. Patch testing is the gold standard for diagnosis of allergic contact dermatitis. A broad screening panel will provide a thorough evaluation of the many causes of ACD, including preservatives.

  • Diagnosis confirmation

The differential diagnosis is broad, encompassing all of the "eczema" family. The most common differential is that of atopic dermatitis vs allergic contact dermatitis (ACD) vs drug hypersensitivity reaction. Rarely, prebullous pemphigoid may present with a pattern similar to generalized ACD.

Who is at Risk for Developing this Disease?

Anyone using topical products or consuming preserved foods is at risk for developing preservative ACD. Essentially all commercially prepared personal care products (such as shampoos, conditioners, lotions/creams and topical medicaments) use various additives to prevent spoilage due to bacterial/fungal overgrowth. Without these agents, the product will become rancid, usually within 30 to 60 days of preparation. Considering the overall widespread exposure we all have to these chemicals, development of ACD to preservatives is rare, but for those it affects it is a significant problem.

Individuals often will use the same product for years. As opposed to medication allergies, the products one has been exposed to the longest are the greatest suspects. Development of a type IV reaction (sensitization) may occur when the offending product is used on damaged skin (atopic dermatitis, xerosis, skin injuries).

What is the Cause of the Disease?

Like all other forms of allergic contact dermatitis, this is a type IV delayed type immunologic reaction. For dermatitis to occur, the individual must have prior exposure to the allergen (sensitization). This occurs when the epidermal Langerhans cell or dermal dendritic cell is exposed to the chemical hapten. This is then phagocytized, processed and the cell migrates to the regional lymph node.

The processed hapten is presented to T-cells, thus leading to memory T-cell development. With a subsequent exposure, these memory T-cells start the complex cascade of cutaneous inflammation. Usually this occurs within 24 to 72 hours following re-exposure, thus the "delayed-type" label. These rashy reactions do not occur within minutes, as compared with the type I immediate type histamine-modulated reactions.

Systemic Implications and Complications

There are no clear systemic implications/complications for cutaneous exposures causing allergic contact dermatitis. Some allergen groups such as the formaldehyde-based and the benzene-based preservatives may be carcinogens. Parabens and triclosan are less clearly problematic, though there is concern.

Treatment Options

  • MILD DERMATITIS

  1. Topical therapy is adequate for mild cases. Fluocinolone 0.5% or triamcinolone 0.1% to the involved sites in appropriate amounts will speed healing.

  2. Oral therapy is rarely necessary. Over-the-counter diphenhydramine 12.5 or 25mg by mouth as necessary may be used if pruritus is bothersome.

  • MODERATE OR SEVERE DERMATITIS

Topical therapy

For localized, smaller area dermatitis with significant symptoms, clobetasol 0.05% used twice daily until symptoms/dermatitis resolves or for 3 weeks. Widespread dermatitis responds to triamcinolone 0.1% cream used twice daily. When dispensed in a 454g jar, this will provide adequate amounts of medication for a large surface area. Over-the-counter oatmeal baths may be soothing.

Oral therapy

For widespread, symptomatic dermatitis in amenable individuals, oral prednisone will alleviate symptoms and speed recovery. One tapering dosage regimen is prednisone 10mg tabs by mouth: 6 tabs daily for 4 days, then 4 tabs daily for 4 days, then 2 tabs daily for 4 days, finally 1 tab daily for 4 days. Oral antihistamine agents are useful for sedation when sleep is desired. Hydroxyzine 12.5 to 25 mg by mouth, as necessary up to 4 times daily, is often helpful for symptomatic relief.

Topical antipruritic agents containing diphenhydramine or pramoxine are not recommended due to the risk for development of type IV allergy.

Considering the self-limited nature of these conditions, in most cases, physical modalities such as phototherapy are not necessary. For longer duration chronic dermatitis, possibly caused by topical products, phototherapy may be useful in clearing dermatitis after an allergen has been identified. Surgical therapy for these conditions is not necessary or desired.

Optimal Therapeutic Approach for this Disease

For all severity of dermatitis from preservatives, topical therapy is preferable for first-line treatment. Topical corticosteroids are safe and effective with appropriate use for self-limited dermatitides such as preservative ACD. For mild disease, oral therapy is rarely warranted. For most, symptomatic relief (decreased pruritus) begins within 6 hours of application of an appropriate strength topical corticosteroid. Often, full resolution of dermatitis will take 1 to 2 weeks.

Severe, widespread and symptomatic cases may require additional oral therapy with antipruritics and corticosteroids in addition to topical therapy. Some symptomatic relief with oral corticosteroids often begins within 6 hours of the first dose. Severe dermatitis may take longer to resolve, but many cases will be clear or nearly clear within 2 weeks. Oral corticosteroids should be carefully used in those with hypertension or diabetes.

Patient Management

These conditions are self limited in most cases. For most, as-necessary follow-up is all that is required. For suspected preservative dermatitis that you are not able to figure out clinically, consider referral for patch testing.

If the allergen(s) have been identified by patch testing, it is essential that the patient be educated on the chemical names that they would see on a label. Info sheets are available from several sources. Extensive allergen information is available at no cost at: http://www.dormer.com/Allergens/PatientInfoSeriesEng.aspx

The American Contact Dermatitis Society (ACDS) offers the Contact Allergen Management Program (CAMP) to its members. The patient's allergen(s) are entered into the CAMP and it returns an extensive list of products that are safe to use (allergen-free). Access is limited to members of the ACDS.

Unusual Clinical Scenarios to Consider in Patient Management

In rare cases, a widespread dermatitis in non-exposed areas may develop. The primary ACD progresses in the typical pattern on exposed sites. Autoeczematization is a flare of pruritic morbilliform dermatitis, often generalized, which develops in non-allergen exposed areas. These flares occur infrequently. Treatment is the same as with other allergic dermatitis.

What is the Evidence?

Rietschel, RL, Fowler, JF, Rietschel, RL, Fowler, JF. "Preservatives and vehicles in cosmetics and toiletries". Fisher's contact dermatitis. BC Decker. 2008. pp. 266-318.

(An excellent discussion of all things related to preservative allergic contact dermatitis.)

Lundov, MD, Moesby, L, Zachariae, C, Johansen, JD. "Contamination versus preservation of cosmetics: a review on legislation, usage, infections, and contact allergy". Contact Derm. vol. 60. 2009. pp. 70-8.

(An interesting discussion of appropriate preservative use.)

Wetter, DA, Yiannias, JA, Prakash, AV, Davis, MD, Farmer, SA, el-Azhary, RA. "Results of patch testing to personal care product allergens in a standard series and a supplemental cosmetic series: an analysis of 945 patients from the Mayo Clinic Contact Dermatitis Group, 2000-2007". J Am Acad Dermatol. vol. 63. 2010. pp. 789-98.

(An analysis of patch test results of 945 patients from the Mayo Clinic Contact Dermatitis Group.)

Kasemsarn, P, Iamphonrat, T, Boonchai, W. "Risk factors and common contact allergens in facial allergic contact dermatitis patients". Int J Dermatol. vol. 55. 2016 Apr. pp. 417-24.

(Women have facial ACD more often than men. The most common causes are personal care products.)

Sasseville, D, Alfalah, M, Lacroix, JP. "“Parabenoia” Debunked, or “Who's Afraid of Parabens?”". Dermatitis. vol. 26. 2015 Nov-Dec. pp. 254-9.

(Review of the safety of parabens in products.)

Yu, SH, Sood, A, Taylor, JS. "Patch Testing for Methylisothiazolinone and Methylchloroisothiazolinone-Methylisothiazolinone Contact Allergy". JAMA Dermatol. vol. 152. 2016 Jan. pp. 67-72.

(Review of the increasing prevalence of MCI and MI allergy.)
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