Clinical review II I Propylene glycol dermatitis Joseph M. Catanzaro, MD, and J. Graham Smith, Jr., MD Augusta, Georgia Propylene glycol is a commonly used vehicle for topical preparations. Although it is well suited for this purpose, it is capable of producing both primary irritant skin reaction and allergic sensitization. The literature on propylene glycol is reviewed, with particular attention to the nature of these adverse cutaneous effects. Guidelines for patients sensitive to propylene gly- col are discussed. (J AM ACAD DERMATOL 1991;24:90-5.) Propylene glycol (1,2 propanediol) was originally described by Wurtz in 1859.1 Known for its indus- trial and commercial uses, propylene glycol was first considered for use in pharmaceutical preparations in 1932. It was at that time proposed as a potential sol- vent and vehicle for a bismuth product used in the treatment of syphilis. 2 Within the past two decades, propylene glycol has been increasingly used as a ve- hicle for therapeutic formulations and cosmetics. The tendency of propylene glycol to induce irri- tant or allergic skin reactions in some patients is well documented. Because of the nearly universal pres- ence of propylene glycol in topical preparations and cosmetics, we review the literature pertaining to propylene glycol and its adverse cutaneous effects. PHYSICAL AND CHEMICAL PROPERTIES Propylene glycol is a colorless, viscous, nearly odorless liquid. It is miscible with water, alcohol, chloroform, and acetone and is soluble in ether. 3 Propylene glycol is hygroscopic, with an isotonic concentration of 2% in water, and is a superior hu- mectant, capable of retaining moisture over a wide range of relative humidity. 4, 5 Short- and long-term toxicologic studies indicate that propylene glycol has a low toxicity when used as a solvent in pharmaceuticals. 6 Given these prop- erties, propylene glycol is an excellent vehicle and solvent for both derrnatologic and nondermatologic formulations. NONDERMATOLOGIC USES OF PROPYLENE GLYCOL Propylene glycol is used extensively for industrial and commercial purposes and in pharmaceutical From the Department of Dermatology, Medical College of Georgia. Reprint requests: J. Graham Smith, Jr., MD, Department of Derma- tology, Medical College of Georgia, Augusta, GA 30912-2900. 16/1/23713 Table I. Reported topicals causing patch test-proved propylene glycol dermatitis Corticosteroid preparations 17-Clobetasol cream (Dermovate) 24 Fluocinonide cream (Lidex) 25 Halcinonide cream (Halog) 26 Antifungal preparations Ketoconazole cream (Nizoral) 27 Nystatin/triamcinolone cream (Myeolog) 4 Emollients Cetaphil lotion 4 Keri lotion 4 Triple lanolin cocoa cream 4 Other preparations Ercoril lotion (an antiperspirant) 2s K-Y lubricating jelly 26 Keralyt gel 4 Neuromod conductive gel 29, 30 Spectra 360 electrode gel 31, 32 Silver sulfadiazine cream (Silvadene) 33 Topical minoxidil (Rogaine) 34, 3s preparations other than dermatologicals. Propylene glycol has been used as a nontoxic antifreeze in dairies and breweries] as a component of automo- tive brake fluids and antifreeze preparations, 8 and in the production of varnishes and synthetic resins. 9 It has also been used as a solvent for flavoring agents in baking and candy production 6 and as an emulsi- fier and nontoxic preservative in the foods industry] Propylene glycol can be found in many nonpre- scription medications and personal hygiene prod- ucts.10 These include certain antitussives, shampoos and conditioners, douches, contraceptive gels, shav- ing creams, and antiperspirants. Some otic and oph- thalmologic preparations also contain varying amounts of propylene glycol. 1~ Among prescription medications, propylene gly- col can be found in several oral antibiotics, and it is also a major ingredient in the formulation of several parenteral preparations, including diazepam (Vali- 9O
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`Volume 24 Number 1 January 1991 Propytene glycol 91 Table II. Propylene glycol patch test studies Propylene glycol concentration Author(s) (%) No. of persora tested Warshaw and Herrmann z3 100 866 Huriez et al) 6 38 183 Braun 37 10 78 Fisher et al. 21 10 100 Hannuksela et al) 8 100 1556 32 42* 10 42* 3.2 42* Hannuksela et al. 39 2 880 Nater et al. 4~ 100 98 Blondeel et al. 9 10 330 Angelini and Meneghini 4: 20 400 Romaguera et al. n2 5/10 1450 Andersen and Storrs 43 100 84 No. of positive reactions (%) 138 (15.7) 23 (12.5) 3 (4) 2 (2) 194 (12.5) 20 12 9 2 (0.2) ii (11.2) 13 (3.9) 6 (1.5) 15 (1) 12 (14.3) Angelini et al. 4n 5 3364 27 (0.8) Hannuksela and Salo ns 30 86 19 (22) 10 86 7 (8) 1 86 5 (5.8) Willis et al. 46 100 35 14 (40) 50 16 0 (0) Kinnunen and Hannuksela 47 30 823 31 (3.8) Investigator's interpretation of reaction Irritant Allergic Allergic Allergic "True allergy" in 4 cases; remainder irritant Allergic Irritant t Allergic t 5 cases allergic; 7 cases irritant Allergic Irritant *Selected from subjects reacting to 100% propylene glycol. "Hnvestigators did not state whether reactions were judged irritant or allergic. urn), lorazepam (Ativan), phenytoin (Dilantin), hy- dralazine (Apresoline), and some nitroglycerin and vitamin formulations.11 The concentration of pro- pylene glycol is as high as 40% in diazepam and phenytoin, a 1, : 2 DERMATOLOGIC USES Propylene glycol as a therapeutic agent Propylene glycol possesses several properties that have been tested in therapeutic trials. Studies have demonstrated that certain concentrations of propy- lene glycol can denature protein and induce keratolysis.13 Several investigators have applied this property in the treatment of dermatoses associated with hyperkeratosis. Propylene glycol has been re- ported as effective in the treatment of seborrheic dermatitis 14 and certain types of ichthyosis. 15 When combined with salicylic acid (Keralyt), propylene glycol has reported efficacy in the treatment of cal- luses, keratosis palmaris et plantaris, and other hy- perkeratotic disorders.16 Propylene glycol also has antimicrobial properties and is active in vitro and in vivo against certain bac- teria and dermatophytes, 17-19 including many of those found in common dermatoses. In addition, several investigators have found propylene glycol ef- fective in the treatment of tinea versicolor.17, 20 Propylene glycol as a vehicle Propylene glycol is an ideal vehicular component for many topical preparations. It is a superior solu- bilizer, spreader, and emollient 2t and has often been used as a replacement for glycerin in dermatologie and cosmetic preparations, s The low cost of propy- lene glycol provides an additional advantage. 22 Within the past decade there has been increased use of propylene glycol in topical corticosteroid for- mulations. We found propylene glycol in varying concentrations in approximately 55% of the topical steroids currently available.11 Propylene glycol can be found in a similar percentage 6 of topical antibac- terials, antifungals, benzoyl peroxide preparations, and emollients. 11 The concentration of propylene glycol in each therapeutic formulation is variable; the final percentage is determined according to optimal stratum corneum penetration and drug release. Small changes in the concentration of propylene glycol can adversely affect drug absorption.:, 5 Given this widespread presence of propylene gly-
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`92 Catanzaro and Smith Journal of the American Academy of Dermatology Table III. Propylene glycol-free topical corticosteroids I o I ~ Amcinonide Cyelocort Betamethasone dipropionate Alphatrex X Diprosone X Maxivate X Betamethasone valerate Betatrex X Desowen X Tridesflon X Valisone X Desonide Desowen X Tddesflon X Des0ximetasone Topicort Topicort LP Diflorasone diacetate Florone X Maxittor X Fluocinolone acetonide Synalar X Flurandrenolide Cordran X Halcinonide Halog X Hydrocortisone Hytone X Laeticare HC Nutracort Hydroeortisone acetate Pramosone X Hydrocortisone butyrate Locoid X Triamcinolone acetonide Aristocort X Aristocort A Kenalog X S X X X X X X X X X X X X X X X X X X X X X O, Ointment; G, gel; C, cream; L, lotion; S, solution. col, many persons are exposed to the substance. The potential for adverse skin reactions is therefore sig- nificant. CUTANEOUS REACTIONS TO PROPYLENE GLYCOL The potential for irritant reactions and sensitiza- tion to propylene glycol has been recognized since 1952, when Warshaw and Herrmann 23 noted reac- tions in patients in whom propylene glycol was used as a solvent for patch test allergens. Since then, au- thors have reported numerous cases of contact der- matitis from propylene glycol in a wide variety of topical preparations. Substances that have been associated with patch test-proved propylene glycol reactions are listed in Table I. Each preparation contains a unique con- centration of propylene glycol, ranging from approx- imately 2% to 60%. Investigators concluded that al- lergic sensitization to propylene glycol had occurred for each of the substances listed with the exception of fluocinonide cream; the authors judged this reac- tion to be a primary irritant response. 25 Investigators have performed a number of patch test studies designed to determine the incidence and nature of propylene glycol skin reactions. These studies are summarized in Table II. A commonly encountered problem in patch test-
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`Volume 24 Number 1 January 1991 Propylene glycol 93 Table IV. Propylene glycol-free emollients Alpha-Keri body oil Aqua A cream Aquaderm lotion Aquanil lotion Aquaphor ointment Aveeno lotion Complex 15 face cream DML forte cream Eucerin cream Lacticare lotion Lubriderm cream, lotion Moisturel cream, lotion Nivea lotion Nutraderm cream, lotion Nutraderm 30 lotion Nutraplus lotion Pen Kera cream Purpose lotion Sarna lotion Table V. Propylene glycol-free antifungal preparations Ciclopirox olamine Loprox cream, lotion Clotrimazole Lotrimin cream, lotion, suspension Mycelex cream Mycelex-G cream Econazole nitrate Spectazole cream Haloprogin Halotex cream, suspension Miconazole nitrate Monistat-Derm cream, lotion Naftifme hydrochloride Naftin cream ing, particularly with propylene glycol, is reliably differentiating an irritant from an allergic response, especially if the reaction is relatively weak. 8 In the majority of the studies listed, the subject group comprised patients with eczema; in such patients, the results of patch tests with propylene glycol 10% to 20% may be even more difficult to interpret. 41 Several authors were thus unable to conclude whether propylene glycol reactions in their subjects represented irritation or true allergic sensitization. Perhaps the most convincing evidence of allergic sensitization to propylene glycol is presented in studies in which oral provocation was used. In An- gelini et al.'s study 44 of 5% aqueous propylene gly- col patch tests, allergy was confirmed by repeated Table VI. Propylene glycd-tree benzoyl peroxide gels BenT_~c Benzagel Desquam-E Desquam-X Panoxyl AQ Table VII. Propylene glycol-free topical anti-infective preparations Acyclovir (Zovirax ointment) Bacitracin zinc (Cortisporin ointment; Neosporin ointment) Erythromycin (Akne-Mycin ointment; Eryderm solution; Erygel gel) Erythromycin/benzoyl peroxide (Benzamyein gel) Lindane (}(well cream, lotion, shampoo) Selenium sulfide lotion Tetracycline (Topicycline solution) patch testing, usage tests, and oral exposure tests. In one allergic patient reported by Fisher and Brancaccio, 26 ingestion of a salad dressing contain- ing propylene glycol induced a recurrence of the pa- tient's dermatitis in previously affected areas, in- cluding the positive patch test sites. Reactions to peroral propylene glycol have also been reported by Hannuksela and Forstrom. 48 In their series of 38 patients with "allergic-type" patch test reactions to propytene glycol, 15 developed an exanthem after ingestion of propylene glycol. Twenty control pa- tients experienced no adverse effects. True allergic sensitization to propylene glycol does occur, but its incidence is debated. Among the studies listed, the percentage of positive responses judged to represent allergy ranges from zero to 12.5% of the studied population. 36, 40 Certainly, a significant number of reactions to propylene glycol represent a primary irritant effect. In the studies listed, there is an increase in the num- ber of irritant reactions when propylene glycol is used in higher concentrations, and especially when it is used under occlusionY, 38 In addition, several investigators noted a seasonal variation in reactions, with the greater percentage of irritant reactions ob- served in the cooler, less humid winter months. 23, 38 This trend was likely related to increased transepi- dermal water loss because of the hygroscopic nature of propylene glycol. 47 In an effort to clarify the nature of propylene gly-
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`94 Catanzaro and Smith Journal of the American Academy of Dermatology col skin reactions, Trancik and Maibach 49 reported a study of irritation and sensitization patch tests with propylene glycol. In the Draize sensitization portion of their study, 13 of 203 subj ects elicited a significant response, but none of these patients reacted to pro- vocative use testing. They concluded that propylene glycol "intolerance" was more likely in their sub- jects, but that propylene glycol was at least a min- imal irritant. Frosch and Kligrnan 5~ have classified 100% propylene glycol as a moderate skin irritant. GUIDELINES FOR PROPYLENE GLYCOL-SENSITIVE PATIENTS The proper concentration of propylene glycol for patch tests in patients in whom allergy is suspected is understandably controversial. In the past the rec- ommended concentration has ranged from 2% to 20% aqueous propylene glycol. 4, s, 41, 42, 50 Of course, the ideal concentration of propylene glycol would be nonirritating but capable of eliciting allergic sensiti- zation. Meneghini et al.51 found the highest nonirri- tant concentration of propylene glycol for patch testing to be 20%. Even at this concentration, how- ever, sensitivity may not be optimal. For instance, in Hannuksela and Forstrom's study, 4s peroral chal- lenge test results were positive even in some patients with reactions to 100% but not to 32% propylene glycol. In their study of repeated open application testing (ROAT), Hannuksela and Salo 45 concluded that present use tests favor a patch test concentration of 10% to 30% propylene glycol. The North American Contact Dermatitis Group currently recommends a 10% aqueous propylene glycol solution for patch testing. Allergic sensitiza- tion may be confirmed by repeated patch testing, usage tests, or by oral provocation in select cases. Although the number of preparations containing propylene glycol is great, a person sensitive to pro- pylene glycol can, with some effort, avoid the substance and find a reasonable alternative product. One must be aware, however, that formulations for topical agents are occasionally revised. Improved product labeling would be helpful in this regard. A current listing of some topical preparations containing no propylene glycol is found in Tables III to VII.11 Persons sensitive to propylene glycol should be advised of those products that are propylene gly- col free and, of course, avoid exposure to the wide variety of formulations containing propylene glycol. DISCUSSION Propylene glycol is ideally suited for use as a ve- hicle; physicians should, however, be aware of the potential for allergic sensitization and irritant reac- tions to this substance. Controversy still exists re- garding the exact incidence of propylene glycol allergy. Given the data presented and our clinical experience, we suspect that the incidence of propy- lene glycol allergy among patients with eczema may be greater than 2%. The number of topical preparations containing propylene glycol is increasing, and their frequent use by large patient populations could lead to an increase in observed propylene glycol sensitization. Addition of propylene glycol to the current standard patch test series should be considered. REFERENCES l. Hanzlik P J, SeidenfeId MA, Johnson CC. General proper- ties, irritant and toxic actions of ethylene glycol. J Pharma- col Exp Ther 1931;61:387-406. 2. Seidenfeld MA, Hanzlik PJ. The general properties, ac- tions and toxicity of propylene glycol. J Pharmacol Exp Ther 1932;44:109-21. 3. Windholz M, ed. The Merck Index. 10 ed. Rahway, NJ: Merck & Co, 1983:1130-1. 4. FisherAA.Propyleneglycoldermatitis.Cutis 1978;21:166. 5. Lorenzetti OJ. Propylene glycol gel vehicles. Cutis 1979; 23:247. 6. Ruddick JA. Toxicology, metabolism, and .biochemistry of 1,2-propanediol. Toxieol Appl Pharmacol 1972;21:102-11. 7. Reynolds J, ed. Martindale: The Extra Pharmacopoeia. 29th ed. London: The Pharmaceutical Press, 1989. 8. Fisher AA. Contact dermatitis. 3rd ed. Philadelphia: Lea & Febiger, 1986:26;245-50. 9. Blondeel A, Oleffe J, Achten G. Contact allergy in 330 dermatological patients. Contact Dermatitis 1978;4:270-6. 10. Fine JD, Arndt KA. Propylene glycol: a review. Excerpta Medica 1980;1-14. 11. Physicians' Desk Reference. 44th ed. Oradell, NJ: Medical Economics Co, 1990. 12. Fisher AA. The management ofpropyleneglycol-sensitive patients. Cutis 1980;25:24. 13. Herskovits TT, Gadegbekw B, Jaillet H. On the structural stability and solvent denaturation of proteins. I. Denatur- ation by the alcohols and glycols. J Biol Chem 1970; 245:2588. 14. Faergemann J. Propylene glycol in the treatment of sebor- rheic dermatitis of the scalp: a double-blind study. Cutis 1988;42:69-71. 15. Goldsmith LA, Baden HP. Propylene glycol with occlusion for treatment of ichthyosis. JAMA 1972;220:579-80. 16. Goldsmith LA. Propylene glycol. Int J Dermatol 1978; 17:703-5. 17. Faergemann J, Fredriksson T. Propylene glycol in the treatment oftinea versicolor. Acta Derm Venereol (Stockh) 1980;60:92-3.
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`Volume 24 Number 1 January 1991 Propylene glycol 95 18. Olitsky I. Antimicrobial properties of a propylene glycol based topical therapeutic agent. Pharm Sci 1965;54:787-8. 19. Robertson OH, Appel EM, Puck TT, et al. A study of the bactericidal activity in vitro of certain glycols and closely related compounds. J Invest Dermatol 1948;83:124. 20. Faergemann J, Bernander S. The activity in vitro of five different antimycotics against Pityrosporum orbiculare. Acta Derm Venereol (Stock_h) 1979;59:519. 21. Fisher AA, Pascher F, Kanof NB. Allergic contact derma- titis due to ingredients of vehicles. Arch Dermatol 1971; 104:286-90. 22. Fisher AA. Reactions to popular cosmetic humectants, III. Glycerin, propylene glycol, and butylene glycol. Cutis 1980;26:243-4. 23. Warshaw TG, Herrmann F. Studies of skin reactions to propylene glycol. J Invest Dermatol 1952;19:423-9. 24. Oleffe JA, Blondeel A, Coninck AD. Allergy to chloro- cresol and propylene glycol in a steroid cream. Contact Dermatitis 1979;5:53-4. 25. Shore RN, Shelley WB. Contact dermatitis from stearyl alcohol and propylene glycol in fluocinonide cream. Arch Dermatol 1974;109:397-9. 26. Fisher AA, Brancaccio RR. Allergic contact sensitivity to propylene glycol in a lubricant jelly. Arch Derrnatol 1979; 115:1451. 27. Eun HC, Kim YC. Propylene glycol allergy from ketocon- azole cream. Contact Dermatitis 1989;21:274-5. 28. Agren-Jonsson S, Magnusson B. Sensitization to propan- theline bromide trichlorocarbanilide and propylene glycol in an antiperspirant. Contact Dermatitis 1976;2:79-80. 29. Castelain PY, Chabeau G. Contact dermatitis after trans- cutaneous electric analgesia. Contact Dermatitis 1986; 15:32-5. 30. Tomb RR, Rivara G, Foussereau J. Contact dermatitis af- ter ultrasonography and electrocardiography. Contact Der- matitis 1987;17:149-52. 31. Fisher AA. Dermatologic hazards of electrocardiography. Cutis 1977;20:686. 32. Fisher AA. Dermatitis associated with transcutaneous electrical nerve stimulation. Cutis 1978;21:24. 33. Degreef H, Dooms-Goosens A. Patch testing with silver sulfadiazine cream. Contact Dermatitis 1985;12:33-7. 34. Van Der Willigen AH, Dutree-Meulenberg RO, Stolz E, et al. Topical minoxidil sensitization in androgenic alopecia. Contact Dermatitis 1987;17:44-5. 35. Fisher AA. Use of glycerin in topical minoxidil solutions for patient allergic to propylene glycol. Cutis 1990;45:81-2. 36. Huriez A, Martin P, Vanoverschelde M. L'allergie au pro- pylene-glycol. Bull Soc Fr Dermatol Syph 1966;73:263-7. 37. Braun W. Kontaktallergien gegen poylaethylenglykole. Z Haut Geschleehtskr 1969;44:385-8. 38. Hannuksela M, Pirila V, Salo OP. Skin reactions to propy- lene glycol. Contact Dermatitis 1975; 1:112-6. 39. Hannuksela M, Kousa M, Pirila V. Allergy to ingredients of vehicles. Contact Dermatitis 1976;2:105-10. 40. Nater JP, Baar A J, Hoedemaeker PJ. I-Iostological aspects of skin reactions to propylene glycol. Contact Dermatitis 1977;3:181-5. 41. AngeliniG, MeneghiniCL. Contactallergy frompropylene glycol. Contact Dermatitis 1981;7:197-8. 42. Romaguera C, Garcia-Perez A, Moran M, et al. Propylene glycol in standard patch tests. Contact Dermatitis 1981; 7:346. 43. Andersen KE, Storrs FJ. Hautreizungen durch propyle- neglykol. Hautarzt 1982;33:12-4. 44. Angelini G, Vena GA, Meneghini CL. Allergic contact dermatitis to some medicaments. Contact Dermatitis 1985; 12:263-9. 45. Hannuksela M, Salo H. The repeated open application test (ROAT). Contact Dermatitis 1986;14.221-7. 46. Willis CM, Stephens C J, Wilkinson JD. Experimentally- induced irritant contact dermatitis. Contact Dermatitis 1988;18:20-4. 47. Kinnunen T, Hannuksela M. Skin reactions to hexylene glycol. Contact Dermatitis 1989;21:154-8. 48. Hannuksela M, Forstrom L. Reactions to peroral propylene glycol. Contact Dermatitis 1978;4:41-5. 49. Trancik R J, Maibach HI. Propylene glycol: irritant or sen- sitization? Contact Dermatitis 1982;8:185-9. 50. Frosch P, Kligman A. The chamber-scarification test for assessing irritancy to topically applied substances In: Drill V, ed. Cutaneous toxicity. New York: Academic Press, 1977:127-54. 51. Meneghini CL, Rantuccio F, Lomoto M. Additives, vehi- cles and active drugs of topical medicaments as causes of delayed-type allergic dermatitis. Dermatologica 1971; 143:137-47.
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