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Detergent and skin irritation
ELSEVIER
Detergent and Skin Irritation ISAAK EFFENDY, MD HOWARD I. MAIBACH,
MD
U
ntil the late 19th century, the only man-made surfactant was soap. Soaps are the sodium or potassium salts of fatty acids or similar products formed by the saponification or neutralization of fats or oils with organic or inorganic bases. Soaps are less useful, however, in hard water, which is high in content of multivalent ions, such as calcium and magnesium. Despite this, its critical shortage in Germany after World War I provided an incentive for the development of synthetic soap substitutes, detergents.’ A synthetic process for sodium lauryl sulfate was described in Germany 6 decades ago.2 The term “deterge” derived from the Latin detergere, meaning to wipe off; the term “detergent,” which has existed at least since 1676, is used to mean a cleansing agent. Nowadays, a detergent includes almost any surface-active agent (surfactant) that concentrates at oilwater interfaces and holds cleansing as well as emulsifying properties. Since the late 194Os, synthetic surfactants have been used in ever-growing proportions in consumer and industrial cleaning formulations; among the various classes, anionic surfactants have been used most frequently.3 Recent figures for the United States indicate that anionic surfactants represent between 43 and 67% of the active ingredients in household, personal care, and industrial formulations. In 1992, total surfactant use was 2.3 billion kg, of which anionic surfactants made up 53%.3
Classification
of Surfactants
A surfactant possesses polar and nonpolar regions. The polar or hydrophilic region of the molecule may carry a positive or negative charge, giving rise to cationic or anionic surfactants, respectively. The presence in the same molecule of two moieties, one of which has affinity for the solvent and the other of which is antipathetic to it, is termed amphipathy. This dual nature is responsible for the phenomenon of surface activity and for micellization and solubilization.4 The classification of surfactants is somewhat arbitrary. It is generally convenient, however, to From the Department of Dermatology, University of Marburg, Germany (I.E.), and the Department of Dermatology, University of California, San Francisco, California (H.1.M.). Address correspondence to Howard I. Maibach, MD, Department of Dermatology, School of Medicine, University of California, San Francisco, Box 0989, Surge 110, San Francisco, CA 94143-0989.
Q 1996 by Etsevier Science Inc. 655 Avenue of the Americas, New
York, NY 10020
categorize the chemicals according to their polar portions, since the nonpolar portion is usually made up to alkyl or aryl groups. p6 The major polar groups found in most surfactants may be divided into four types (Table 1).
Anionic Agents The most commonly used anionic surfactants are those containing carboxylate, sulfonate, and sulfate ions. Those containing carboxylate ions are known as soaps. Numerous alkyl sulfates are available as surfactants, but by far the most popular member of this group is sodium lauryl sulfate (SLS). Unlike soaps, SLS is compatible with dilute acid and with calcium and magnesium ions. The lower-chain-length compounds, around C12, have better wetting properties, whereas the higher members, Cl6 to C20, have better detergent properties.6 SLS is an anionic emulsifying, detergent, and wetting agent in ointments, personal care products, and other pharmaceutical preparations. In its own right, however, SLS is a potent antimicrobial, and toothpastes containin SLS exhibit antibacterial effects in vitro and in vivo.7, i
Cationic Agents Many long-chain cations, such as amine salts and quaternary ammonium salts, are used as surfactants when dissolved in water. Their use in pharmaceutical preparations is limited to that of antimicrobial preservatives rather than as surfactants because of their bactericidal activity against a wide range of grampositive and some gram-negative organisms.4s They may be used on the skin, however, especially in the cleansing of wounds. Aqueous solutions are used for cleaning contaminated medical utensils.
Amphoteric Agents An amphoteric surfactant possesses at least one anionic and one cationic group in its molecule. Amphoteric surfactants have the detergent properties of anionic surfactants and the disinfectant properties of cationic surfactants. Their activity depends on the pH of the media in which they are used. Balanced amphoteric surfactants are reputed to be nonirritant to the eyes and skin and therefore have been used in so-called baby shampoos.’ 0738-081X/96/$32.00 SSDlO738-081X~95~00103-4
Table 1. Classification
Cationic Amphoteric
Nonionic
ad Their Utilization
Freqzrcntly Used Compounds (selection)”
Type qt’ Surfnctant Anionic
of Swfactants
Sodium lauryl sulfate, sodium laureth sulfate, TEA-lauryl sulfate, ammonium lauryl sulfate, sodium stearate Quaternium-15 quaternium-19, stearalkonium chloride, quaternium-23, stearalkonium hectoritr Cocamidopropylbetaine, coca-betaine, disodium cocamphodiacetate, CAP-hydroxisulfataine, disodium lauroamphodipropionatr Polysorbate 20, cocamide DEA, lauramide DEA, polysorbate 60, laureth-33
Non ionic Amen fs These surfactants have the advantage over ionic surfactants in that they are compatible with all other types of surfactants and their properties are generally minimally affected by pH. Hence, in the past decade, they have become the major class of compounds used in pharmaceutical systems. Moreover, the toxicity potential of these surfactants is low. The nonionic surfactants have been used as industrial, cosmetic, pharmaceutical, and food emulsifiers, as textile detergents, as foam stabilizers in laundry and dishwashing detergents, and as thickeners for liquid detergents and shampoos.”
Irritant Properties Despite the need for surfactants in everyday life, most surfactants elicit irritant skin reactions, which have been recognized since the problem of soap irritations was first reported (for review, see Blank”). For this reason, the effects of surfactants on the skin have been extensively studied under in vitro and in vivo conditions.“-15 As a result, it was shown that surfactants induced biochemical changes of the skin when applied topically. Since then, surfactants have become widely used model irritants in the investigation of skin irritation.‘6-24 Numerous uses of certain surfactants in biologic and biomedical research stem from their ability to solubilize lipid membranes. Such effects depend on both absolute concentration and surfactant-lipid molar ratios. At low surfactant concentrations, membranes lose their barrier capacity, greatly increasing permeability,25 while at higher concentrations, generally above the critical micelle concentration, cell lysis occursz6 Thus, the overall effect of a surfactant on membrane permeability is the result of two opposing events, interaction with the membrane and that of the permeant with the micelle.27 The physicochemical properties of surfactants appear a crucial factor for eliciting irritant skin reactions.4*5,20,27 Binding of surfactants to keratin and con-
Utilzzatiori
-.--._ Emulsifying,
soIubilizing,
Hair
conditioning
Foam
boosters,
Emulsitying, detergent
agent, emulsifying
solubilizing,
wetting antimicrobial agent,
suspending
agent,
_-.-_-_--__..~ detergent agent,
preservati\
v’-
detergent
agent,
foam
booster!.,.
comitant protein denaturation result in swelling of the membrane and are directly related to induction of cutaneous responses.” Anionic surfactants prove to be potent primary irritants to human and animal skin.‘“.“’ Cationic surfactants are reputedly at least equally irritatingz0j3” but more cytotoxic than anionics,““3’ while the irritation potential of nonionic surfactants is be lieved to be the lowest.“20~“3’“” Many surfactants are primary irritants-substances that are alleged to damage the skin by direct cytotoxic action and without prior immunologic sensitization (delayed hypersensitivity).3” Some important properties for experimentally used irritants have been postu. lated by Wahlberg & Maibach: lack of systemic toxicity, no carcinogenicity, no allergenicity, good chemical definition, no extreme pH value, and causing no cosmetic inconveniences to exposed subjects.3” Moreover, such an irritant should be obtainable in relatively pure form, and its irritant response should be reproducible.
Irritant
Skin Responses
Atziouic Surfactants Sodium Lau yl Sulfate Since the introduction of the sodium alkyl sulfates, particularly sodium lauryl sulfate (SLS), in modern personal care products substituting for ordinary soaps,” SLS has often used in skin irritant investigations. SLS can interact strongly with the skin, causing large alterations in barrier properties. It swells and disrupts fhhe stratum corneum; both lipid and protein structures are affected.37,38 SLS has been recommended as a reference irritant because it is fast acting, nonallergenic, and consistent in its toxicity.“’ Such properties make the surfactant suitable and useful in studies on irritant skin reactions.3”J40-42 The use of SE in studies on irritant contact dermatitis has been reviewed by Agner4s and by Lee and Maibach.44
Clinics in Dermatology
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1996;14:15--21
Surfactants
Cetrimide Centrimide is a mixture consisting mainly of tetradecyl (approximately 68%), dodecyl(22%), and hexadecyl trimethyl ammonium bromides (7%). Cetrimide solutions 0.1 to 1% are used for cleansing the skin, wounds, and burns and for storage of sterilized surgical instruments. The surfactant is also used in shampoos to remove scales in seborrhea.4 When topically applied to mice skin, cetrimide caused more severe skin damage in a relatively short time than did SLS.” The authors of the study suggested that the protein-binding ability of the substance is of primary significance in eliciting irritant reactions. Cetyl trimethyl ammonium bromide and SLS caused toxic effects on cultured human keratinocytes at concentrations as low as 3 gm/mg, but SLS was the less toxic of the two.45 Wilhelm et a146demonstrated that 0.5% dodecyl trimethyl ammonium bromide was less irritant than 0.5% SLS as assessedwith an evaporimeter and capacitance meter. Betzzalkonium Cldoride Benzalkonium Chloride (BAC) is a mixture of alkyldimethylbenzylammonium chlorides of the general formula in which R represents a mixture of alkyls from &Hi7 to C,8H3F47 In dilute solution (1:lOOOto 1:2000), it may be used for the disinfection of skin and mucous membranes and for cleansing polyethylene, nylon tubing, and catheters. BAC is widely used as a preservative for ophthalmics. A 1% solution of BAC was reported to alter the permeability of the skin3’ and to cause similar damage to SLS.29Bjornberg showed that SLS (0.5 to 3%) and BAC (0.5 to 2.0%) had the same irritant effect when evaluated clinically according to erythema scores.48Willis et al, however, found that BAC produced inflammatory changes that histologically differed from those of SLS.33 Parakeratosis and lipid accumulation were not seen, but necrotic damage was evident, even in the skin site judged clinically to be mild. The authors suggested, therefore, that the mechanisms of skin irritation between the two types of surfactant are different. Further studies by Willis et a149,50 and others5’ supported this hypothesis. Berardesca et al showed that 1% BAC influenced the water-holding capacity of the stratum corneum to a lesser extent than did 7% SLS (anionic) and 7% cocoamidopropyl betaine (amphoteric) as evaluated from the skin surface water 10~s.~’Among anionic and cationic surfactants, solvents, and emulsifiers, however, BAC had the greatest hyperplasiogenic effect, indicating a stronger irritancy potential.53 Similarly, Harvell et al reported that 0.5% BAC induced a stronger clinical skin irritation than 0.5% SLS and 0.5% cocoamidopro-
DETERGENT
AND SKIN IRRITATION
17
pyl betaine.32 Furthermore, BAC was more cytotoxic to both cultured human oral and skin keratinocytes than sLs.54
Amphoteric
Surfactants
CocoamidopropylBetaine Like all amphoteric agents, cocoamidopropyl betaine (CAPB) is compatible with all other types of surfactants. Hard water has no effect on its foaming properties in aqueous solution. The chemical is one of the most frequently used amphoteric surfactants in shampoos, partly because it is less irritating to skin and eyes than other typess5 CAPB induced less skin surface water loss than SLS but a higher rate than BAC: 7% SLS >l% CAPB >7% BAC.52 On the other hand, CAPB caused less clinical skin irritation than SLS and BAC: 0.2% BAC >0.5% SLS >0.5% CAPB.32 Korting et al, however, reported that CAPB possesseda higher irritation potential than polyethylene glycol (nonionic surfactant) as measured by an evaporimeter and chromameter.31 It is interesting to note that CAPB in vitro proved to be highly cytotoxic compared with other surfactants3’ The investigators ranked the cytotoxicity of different classesof surfactant evaluated by both in vitro neutral red release and cell growth/protein assays as follows: cationic = amphoteric > anionic > nonionic (according to decreasing cytotoxicity). The frequency of CAPB allergic contact dermatitis is currently being defined. 56 The researchers suggest that the parent compound dimethylaminopropylamine, present as an impurity in the commercial product, is responsible for CAPB allergy.
Nonionic
Surfactants
Propylene Glycol Propylene Glycol (PG) is increasingly used as a vehicle for therapeutic formulations and cosmetics, as well as in many personal care and food products. The potential for irritant reactions and sensitization to PG was reported 4 decades ago.57 Although Frosch and Kligman, using the chamber scarification test, classified 100% PG as a moderate skin irritant,58 other authors concluded that PG, among some surfactants and solvents, displayed only marginal irritant properties.59-62 Indeed, further studies showed that a 48-hour occlusive application with 100% PG failed to produce clinical and histologic irritation when compared with anionic (5% SLS) and cationic surfactant (0.5% BAC). Specifically by light microscopy, a striking “basket weave” pattern to the stratum comeum of the PC-treated skin was evident in all biopsies, due to the osmotic hydration of cornea1 cells.33 The mechanism of the skin response to PG has not
entirely been elucidated. The question whether irritation or allergy is involved in a reacting subject remains problematic; “PG dermatitis” still provides a dermatologic crux (for review, see Fisher63 and Catanzaro and Smith@). Funk and Maibach proposed classifying skin reactions to PG into four different mechanisms, which may allow a partial explanation of effects observed by different authorsb5 Similar issues must be clarified with another nonionic surfactant, butylene glycol. Polyethylene Glycol 200 Glyceryl Monotallowate In a soap chamber assay the surfactant, applied twice a day, induced only minimal changes as evaluated with an evaporimeter and chromameter when compared with some anionic and amphoteric surfactants.“’ Moreover, with the use of both in vitro cytotoxicity assays (neutral red release and cell growth/protein), PEG 200 glyceryl monotallowate proved to be less cytotoxic than other surfactants investigated. Sorbitan Mouolaluate When applied (open) once daily for 3 days to the skin, 10% sorbitan monolaurate marginally influenced the epidermal water barrier as evaluated by skin surface water loss rates (water-holding capacity) compared to anionic (7% SLS) and amphoteric (7% CAPB) surfactants.”
Combination of Surfactants: Possible Decrease in Irritation
Potential
Antagonism or mutual inhibition occurs in the process of acid-base neutralization and anionic-cationic surfactant reaction; however, less appreciated interactions between anionic, nonionic, and amphoteric surfactants can also greatly alter the irritation potential of detergents to the skin.6&ds SLS and linear C9-i3 alkylbenzene sufonate (LAS), when applied alone at 20% occlusively for 4 hours, induced erythema in human volunteers,@ but decreased erythema was obtained for combination of 20% SLS with 10% sodium lauryl ether-2E0 sulfate (SLES), 10% CAPB, or 10% cocodiethanolamine. Similarly, a combination of 20% LAS + 10% SLES + 10% C9-11 alcohol 8 EO (nonionic), a total surfactant level of 40%, was substantially lessirritant than 20% LAS alone. The investigators suggested that skin irritation is related not simply to the total concentration of surfactants but rather to the combination of surfactants present.6Y Similarly, it has also been demonstrated that a combination of sodium lauroyl glutamate (SLG), a mild surfactant, with SLS induced less skin irritation than did SLS alone as assessedby visual scoring and an evaporimeter. ‘” A possible exp lanation is that reduced skin response might be caused by replacement of SLS with the milder SLG, or that SLG might compete with SLS
for surtace area on the skin. Alternatively, the critical micelle concentration level of SLS was possibly lowered by addition of SLG and the level of surfactant monomer may decrease, resulting in reduced skin response.70 Effects of serial applications of surfactant on the skm seem to be different from those of mixed surfactants Malten and Thiele proposed that partial exposure of the skin to the same or different detergent, which was preexposed to certain deter ents, might influence the in5* The partial overlapping of tensity of skin irritation. preexposed skin exhibited a milder reaction than adjacent, newly exposed skin. Recent studies, however, showed that this overlapping region exhibits an intense irritation effect characteristic of cumulative irritation induced by SLS.72 Moreover, the newly exposed skin shows the higher transepidermal waterless (TEWL) values, which could be explained by a possible spread~crf SLS after prolonged treatment, irritating the skin adjacent to the treated site (“the overlap phenomenon”) “’
Irritancy Potential of Frequently Used Surfactants Different models have been developed to define the irritation potential of a given compound.73*74The objectivity and reproducibility of such in vivo tests have been improved b the use of noninvasive bioengineering techniques.4”,Y5-79With these methods, a ranking of the irritant potency of some recurrently used surfactant has been obtained (Table 2). Numerous in vitro alternative tests have been developed. Such promising assays should provide an objective means of predicting the irritation potential of che~cals.“‘,74,8&“’ Rougier et al summarize extensive documentation of this approach.“’ One should keep in mind, however, that it is unlikely that an in vitro system could ever be devebped to mimic the complex cascade of reactions that occur in the human skin. In vivo testing in human volunteers is therefore still crucial, at least to confirm in vitro results.
Conclusions Because detergents hold certain beneficial properties: their use in everyday life becomes nearly indispensable; however, the irritation potential of surfactants may relatively limit their employment. Visualization and possibly development of less irritant, mild, consumerfriendly single surfactants or surfactant systems are therefore of general interest. Differences in the irritation potential between types of surfactants exist, but the arbitrary classification of surfactants does not necessarily correspond with the irritancy of each compound. Hence, improved assays to predict the irritation potential of surfactant are still required. Our theoretical and practical insights have significantly improved, yet the complexity of the skin and
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1996;14:15-21
DETERGENT
AND
SKIN
IRRITATION
19
Table2. Irritant Potencyof SomeFrequently UsedSurfactants Rankingof Irritation Potential
In Vivo Test
Assessment
LAS > SLS > AEOS-3E0 > polysorbate 20 (Tween 20) SLS > SLES > CPAB > LESS > RMSS > PEG (concentrations: 1%)
Epidermis curling test & 5-day soap chamber test 2-day soap chamber test
5% SLS > 0.5% BAC > 100% I’G” 5% SLS = 0.5% BAC > 100% PGh
48-h patch test
SLS > cocobetaine > CAPB (concentrations: 2%) 0.5% SLS > 0.5% dodecyl trimethyl ammonium bromide > potassium soap N-alkyl-sulfatec,, > C,,,, C,,,, 7% SLS > 7% CAPB
> 1% BAC
> 10%
Ref.
gauge & visual scoring
79
TEWL, skin reflective color using chromameter (SRC) “visual scoring ‘histology
31
48-h patch test
TEWL
78
24-h patch test
TEWL, skin capacitance
46
24-h patch test 24-h plastic occlusion stress test
TEWL, SRC skin surface water loss (SSWL)
74 52
5-day repeated occlusive application test (2x daily)
TEWL, SRC, capacitance, skin replica, spectroscopic and visual scoring
77
33
sorbitan monolaurate 2% SLS > 2.9% LAS > 7.9% PEG-20
glyceryl monotallowate
AEOS-SE0 = alkyl (C12-,4 average) ethoxy sulfates; BAC = benzalkonium chloride; CAPB = cocoamidopropyl betaine; LAS = linear alkyl (CIz average) benzene sulfonate; LESS = disodium laureth sulfate; PEG = polyethyene nlycol; PC = propylene nlycol; RMSS = disodium ricinoleamido monoethanolamido sulfosuccinate; SLES = sodium lauyl ether sulfate; SLS = sodium lauyl sulfate. ” ” - 1 ” - ”
the surfactant suggests that future development will flourish with a multifactorial approach that combines the advancing techniques of physical chemistry with the more slowly evolving insights into animal and human skin biology.
13. 14. 15.
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tients with hand eczema, atopic dermatitis and controls. Acta Derm Venereol (Stockh) 1992;Suppl. 173:1-26. Lee CH, Maibach HI. The sodium lauryl sulfate irritant dermatitis model. Contact Dermatitis 1995;33:1-7. Bigliardi PL, Herron NJ, Nelson RD, Dahl MV. Effects 0~ detergents on proliferation and metabolism of human kt;ratinocytes. Exp Dermatol 1994;3:89-94. Wilhelm KP, Freitag G, Wolff HH. Surfactant-induced skin irritation and skin repair. J Am Acad Dermatol 1994; 30:944-9. Budavari S, O’Neil MJ, Smith A, Heckelman PI-. Tht: Merck index: An encyclopedia of chemicals, drugs, and biologicals. 11th ed. Rahway, NJ: Merck & Co., 1989. Bjiirnberg A. Skin reactions to primary irritants in patientx with hand eczema: An investigation with matched cartrols. Thesis. Gbteborg: Oscar Isacsons, 1968. Willis CM, Stephens CJM, Wilkinson JD. Differential ctfects of structurally unrelated chemical irritants on the density of proliferating keratinocytes in 48 h patch test reactions. J Invest Dermatol 1992;99:449-53, Willis CM, Stephens CJM, Wilkinson JD. Differential patterns of epidermal leukocyte infiltration in patch test reactions to structurally unrelated chemical irritants. J Irrvest Dermatol 1993;101:364-70. Wilmer JL, Burleson FG, Kayama F, et al. Cytokine induction in human epidermal keratinocytes exposed to contact irritants and its relation to chemical-induced inflammation in mouse skin. J Invest Dermatol 3994;102:915-22. Berardesca E, Fideli D, Gabba I’, et al. Ranking of surtaictant skin irritancy in vivo in man using the plastic occlnsion stress test (POST). Contact Dermatitis 1990;23:1--!. Lesnik RH, Kligman LH, Kligman AM. Agents that calfit* enlargement of sebaceous glands in hairless mice: I Topical substances. Arch Dermatol Res 1992;284:100-5 Eun HC, Chung JH, Jung SY, et al. A comparative study cjt the cytotoxicity of skin irritants on cultured human oral and skin keratinocytes. Br J Dermatol 1994;130:24-8. De Groot AC, Weyland JW, Nater JP. Unwanted effects ot cosmetics and drugs used in dermatology. 3rd ed. Amsterdam: Elsevier, 1994. Angelini G, Foti C, Rigano L, Vena GA. 3-Dimethylaminopropylamine: A key substance in contact allergy to cocamidopropylbetaine? Contact Dermatitis 1995;32:96-Y. Warshaw TG, Herrmann F. Studies of skin reactions Lo propylene glycol. J Invest Dermatol 1952;19:423-9. Frosch I’J, Kligman AM. The chamber-scarification test fur assessing irritancy of topically applied substances, In: Drill VA, Lazar P, editors. Cutaneous toxicity. New York Academic, 1977:127-39. Willis CM, Stephens CJM, Wilkinson JD. Experimentally induced irritant contact dermatitis. Contact Dermatitis 1988;18:20-4 Wahlberg JE, Nilsson G. Skin irritancy from propylene glycol. Acta Derm Venereol (Stockh) 7982;64:286-90. Trancik RJ, Maibach HI. Propylene glycol: Irritation or sensitization? Contact Dermatitis 1982;8:185-9. Hannuksela M, Piril& V, Salo OP. Skin reactions to propylene glycol. Contact Dermatitis 1975;1:112-6. Fisher AA. Propylene glycol dermatitis. Cutis 1978;31: 166-78.
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64. Catanzaro JM, Smith GJ. Propylene glycol dermatitis. J Am Acad Dermatol 1991;24:90-5. 65. Funk JO, Maibach HI. Propylene glycol dermatitis: Reevaluation of an old problem. Contact Dermatitis 1994;31: 23641. 66. Rhein LD, Simion FA, Hill R, et al. Human cutaneous response to a mixed surfactant system: Role of solution phenomena in controlling surfactant irritation. Dermatologica 1990;180:18-23. 67. Dominguez JG, Balaguer F, Parra JL, Pelejero CM. The inhibitory effects of some amphoteric surfactants on skin irritation by alkyl sulfates. Int J Cosmet Sci 1981;3:57-68. 68. Imokawa G. Comparative study on the mechanism of irritation by sulfate and phosphate type of anionic surfactants. J Sot Cosmet Chem 1980;31:45-66. 69. Dillarstone A, Paye M. Antagonism in concentrated surfactant systems. Contact Dermatitis 1993;28:198. 70. Lee HL, Kawasaki Y, Maibach HI. Effect of surfactant mixtures on irritant contact dermatitis potential in man: Sodium lauroyl glutamate and sodium luryl sulphate. Contact Dermatitis 1994;30:205-9. 71. Malten KE, Thiele FAJ. Some measuring methods for the evaluation of orthoergic contact dermatitis: Some theoretical aspects of “orthoergic” (irritant) dermatitis. Arch Belg Dermatol 1973;28:9-21. 72. Patil SM, Singh I’, Maibach HI. Cumulative irritancy in man to sodium lauryl sulfate: The overlap phenomenon. Int J Pharmacol 1994;110:147-55. 73. Harvell J, Bason MM, Maibach HI. In vitro skin irritation assays: Relevance to human skin. Clin Toxic01 1992;30: 359-69. 74. Wilhelm KP, Samblebe M, Siegers Cl’. Quantitative in
DETERGENT
75.
76.
77.
78.
79. 80.
81.
82.
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IRRITATION
21
vitro assessment of N-alkyl sulphate-induced cytotoxicity in human keratinocytes (HaCaT): Comparison with in vivo human irritation tests. Br J Dermatol 1994;130:18-23. Tupker RA. Prediction of irritancy. In: Elsner I’, Berardesca E, Maibach HI, editors. Bioengineering of the skin: Water and the stratum corneum. Boca Raton, FL: CRC, 1994:73-85. Berardesca E, Elsner I’, Maibach HI, editors. Bioengineering of the skin: Cutaneous blood flow and erythema. Boca Raton, FL: CRC, 1994. Zhou J, Mark R, Stoudemayer T, et al. The value of multiple instrumental and clinical methods, repeated patch applications, and daily evaluations for assessing stratum corneum changes induced by surfactants. J Sot Cosmet Chem 1991;42:105-28. Van der Valk PGM, Nater JP, Bleumink E. Vulnerability of the skin to surfactants in different groups of eczema patients and controls as measured by water vapour loss. Clin Exp Dermatol 1985;10:98-103. Tavss E, Eigen E, Kligman AM. Letter to the editor. J Sot Cosmet Chem 1985;36:251-4. Osborne R, Perkins MA. An approach for development of alternative test methods based on mechanisms of skin irritation. Food Chem Toxic01 1994;32:13342. Mtiller-Decker K, Furstenberger G, Marks F. Keratinocyte-derived proinflammatory key mediators and cell viability as in vitro parameters of irritancy: A possible alternative to the Draize skin irritation test. Toxic01 Appl Pharmacol 1994;127:99-108. Rougier A, Goldberg AM, Maibach HI, editors. In vitro skin toxicology: Irritation, phototoxicity, sensitization. New York: Mary Ann Liebert, 1994.
Detergent and Skin Irritation ISAAK EFFENDY, MD HOWARD I. MAIBACH,
MD
U
ntil the late 19th century, the only man-made surfactant was soap. Soaps are the sodium or potassium salts of fatty acids or similar products formed by the saponification or neutralization of fats or oils with organic or inorganic bases. Soaps are less useful, however, in hard water, which is high in content of multivalent ions, such as calcium and magnesium. Despite this, its critical shortage in Germany after World War I provided an incentive for the development of synthetic soap substitutes, detergents.’ A synthetic process for sodium lauryl sulfate was described in Germany 6 decades ago.2 The term “deterge” derived from the Latin detergere, meaning to wipe off; the term “detergent,” which has existed at least since 1676, is used to mean a cleansing agent. Nowadays, a detergent includes almost any surface-active agent (surfactant) that concentrates at oilwater interfaces and holds cleansing as well as emulsifying properties. Since the late 194Os, synthetic surfactants have been used in ever-growing proportions in consumer and industrial cleaning formulations; among the various classes, anionic surfactants have been used most frequently.3 Recent figures for the United States indicate that anionic surfactants represent between 43 and 67% of the active ingredients in household, personal care, and industrial formulations. In 1992, total surfactant use was 2.3 billion kg, of which anionic surfactants made up 53%.3
Classification
of Surfactants
A surfactant possesses polar and nonpolar regions. The polar or hydrophilic region of the molecule may carry a positive or negative charge, giving rise to cationic or anionic surfactants, respectively. The presence in the same molecule of two moieties, one of which has affinity for the solvent and the other of which is antipathetic to it, is termed amphipathy. This dual nature is responsible for the phenomenon of surface activity and for micellization and solubilization.4 The classification of surfactants is somewhat arbitrary. It is generally convenient, however, to From the Department of Dermatology, University of Marburg, Germany (I.E.), and the Department of Dermatology, University of California, San Francisco, California (H.1.M.). Address correspondence to Howard I. Maibach, MD, Department of Dermatology, School of Medicine, University of California, San Francisco, Box 0989, Surge 110, San Francisco, CA 94143-0989.
Q 1996 by Etsevier Science Inc. 655 Avenue of the Americas, New
York, NY 10020
categorize the chemicals according to their polar portions, since the nonpolar portion is usually made up to alkyl or aryl groups. p6 The major polar groups found in most surfactants may be divided into four types (Table 1).
Anionic Agents The most commonly used anionic surfactants are those containing carboxylate, sulfonate, and sulfate ions. Those containing carboxylate ions are known as soaps. Numerous alkyl sulfates are available as surfactants, but by far the most popular member of this group is sodium lauryl sulfate (SLS). Unlike soaps, SLS is compatible with dilute acid and with calcium and magnesium ions. The lower-chain-length compounds, around C12, have better wetting properties, whereas the higher members, Cl6 to C20, have better detergent properties.6 SLS is an anionic emulsifying, detergent, and wetting agent in ointments, personal care products, and other pharmaceutical preparations. In its own right, however, SLS is a potent antimicrobial, and toothpastes containin SLS exhibit antibacterial effects in vitro and in vivo.7, i
Cationic Agents Many long-chain cations, such as amine salts and quaternary ammonium salts, are used as surfactants when dissolved in water. Their use in pharmaceutical preparations is limited to that of antimicrobial preservatives rather than as surfactants because of their bactericidal activity against a wide range of grampositive and some gram-negative organisms.4s They may be used on the skin, however, especially in the cleansing of wounds. Aqueous solutions are used for cleaning contaminated medical utensils.
Amphoteric Agents An amphoteric surfactant possesses at least one anionic and one cationic group in its molecule. Amphoteric surfactants have the detergent properties of anionic surfactants and the disinfectant properties of cationic surfactants. Their activity depends on the pH of the media in which they are used. Balanced amphoteric surfactants are reputed to be nonirritant to the eyes and skin and therefore have been used in so-called baby shampoos.’ 0738-081X/96/$32.00 SSDlO738-081X~95~00103-4
Table 1. Classification
Cationic Amphoteric
Nonionic
ad Their Utilization
Freqzrcntly Used Compounds (selection)”
Type qt’ Surfnctant Anionic
of Swfactants
Sodium lauryl sulfate, sodium laureth sulfate, TEA-lauryl sulfate, ammonium lauryl sulfate, sodium stearate Quaternium-15 quaternium-19, stearalkonium chloride, quaternium-23, stearalkonium hectoritr Cocamidopropylbetaine, coca-betaine, disodium cocamphodiacetate, CAP-hydroxisulfataine, disodium lauroamphodipropionatr Polysorbate 20, cocamide DEA, lauramide DEA, polysorbate 60, laureth-33
Non ionic Amen fs These surfactants have the advantage over ionic surfactants in that they are compatible with all other types of surfactants and their properties are generally minimally affected by pH. Hence, in the past decade, they have become the major class of compounds used in pharmaceutical systems. Moreover, the toxicity potential of these surfactants is low. The nonionic surfactants have been used as industrial, cosmetic, pharmaceutical, and food emulsifiers, as textile detergents, as foam stabilizers in laundry and dishwashing detergents, and as thickeners for liquid detergents and shampoos.”
Irritant Properties Despite the need for surfactants in everyday life, most surfactants elicit irritant skin reactions, which have been recognized since the problem of soap irritations was first reported (for review, see Blank”). For this reason, the effects of surfactants on the skin have been extensively studied under in vitro and in vivo conditions.“-15 As a result, it was shown that surfactants induced biochemical changes of the skin when applied topically. Since then, surfactants have become widely used model irritants in the investigation of skin irritation.‘6-24 Numerous uses of certain surfactants in biologic and biomedical research stem from their ability to solubilize lipid membranes. Such effects depend on both absolute concentration and surfactant-lipid molar ratios. At low surfactant concentrations, membranes lose their barrier capacity, greatly increasing permeability,25 while at higher concentrations, generally above the critical micelle concentration, cell lysis occursz6 Thus, the overall effect of a surfactant on membrane permeability is the result of two opposing events, interaction with the membrane and that of the permeant with the micelle.27 The physicochemical properties of surfactants appear a crucial factor for eliciting irritant skin reactions.4*5,20,27 Binding of surfactants to keratin and con-
Utilzzatiori
-.--._ Emulsifying,
soIubilizing,
Hair
conditioning
Foam
boosters,
Emulsitying, detergent
agent, emulsifying
solubilizing,
wetting antimicrobial agent,
suspending
agent,
_-.-_-_--__..~ detergent agent,
preservati\
v’-
detergent
agent,
foam
booster!.,.
comitant protein denaturation result in swelling of the membrane and are directly related to induction of cutaneous responses.” Anionic surfactants prove to be potent primary irritants to human and animal skin.‘“.“’ Cationic surfactants are reputedly at least equally irritatingz0j3” but more cytotoxic than anionics,““3’ while the irritation potential of nonionic surfactants is be lieved to be the lowest.“20~“3’“” Many surfactants are primary irritants-substances that are alleged to damage the skin by direct cytotoxic action and without prior immunologic sensitization (delayed hypersensitivity).3” Some important properties for experimentally used irritants have been postu. lated by Wahlberg & Maibach: lack of systemic toxicity, no carcinogenicity, no allergenicity, good chemical definition, no extreme pH value, and causing no cosmetic inconveniences to exposed subjects.3” Moreover, such an irritant should be obtainable in relatively pure form, and its irritant response should be reproducible.
Irritant
Skin Responses
Atziouic Surfactants Sodium Lau yl Sulfate Since the introduction of the sodium alkyl sulfates, particularly sodium lauryl sulfate (SLS), in modern personal care products substituting for ordinary soaps,” SLS has often used in skin irritant investigations. SLS can interact strongly with the skin, causing large alterations in barrier properties. It swells and disrupts fhhe stratum corneum; both lipid and protein structures are affected.37,38 SLS has been recommended as a reference irritant because it is fast acting, nonallergenic, and consistent in its toxicity.“’ Such properties make the surfactant suitable and useful in studies on irritant skin reactions.3”J40-42 The use of SE in studies on irritant contact dermatitis has been reviewed by Agner4s and by Lee and Maibach.44
Clinics in Dermatology
Cationic
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1996;14:15--21
Surfactants
Cetrimide Centrimide is a mixture consisting mainly of tetradecyl (approximately 68%), dodecyl(22%), and hexadecyl trimethyl ammonium bromides (7%). Cetrimide solutions 0.1 to 1% are used for cleansing the skin, wounds, and burns and for storage of sterilized surgical instruments. The surfactant is also used in shampoos to remove scales in seborrhea.4 When topically applied to mice skin, cetrimide caused more severe skin damage in a relatively short time than did SLS.” The authors of the study suggested that the protein-binding ability of the substance is of primary significance in eliciting irritant reactions. Cetyl trimethyl ammonium bromide and SLS caused toxic effects on cultured human keratinocytes at concentrations as low as 3 gm/mg, but SLS was the less toxic of the two.45 Wilhelm et a146demonstrated that 0.5% dodecyl trimethyl ammonium bromide was less irritant than 0.5% SLS as assessedwith an evaporimeter and capacitance meter. Betzzalkonium Cldoride Benzalkonium Chloride (BAC) is a mixture of alkyldimethylbenzylammonium chlorides of the general formula in which R represents a mixture of alkyls from &Hi7 to C,8H3F47 In dilute solution (1:lOOOto 1:2000), it may be used for the disinfection of skin and mucous membranes and for cleansing polyethylene, nylon tubing, and catheters. BAC is widely used as a preservative for ophthalmics. A 1% solution of BAC was reported to alter the permeability of the skin3’ and to cause similar damage to SLS.29Bjornberg showed that SLS (0.5 to 3%) and BAC (0.5 to 2.0%) had the same irritant effect when evaluated clinically according to erythema scores.48Willis et al, however, found that BAC produced inflammatory changes that histologically differed from those of SLS.33 Parakeratosis and lipid accumulation were not seen, but necrotic damage was evident, even in the skin site judged clinically to be mild. The authors suggested, therefore, that the mechanisms of skin irritation between the two types of surfactant are different. Further studies by Willis et a149,50 and others5’ supported this hypothesis. Berardesca et al showed that 1% BAC influenced the water-holding capacity of the stratum corneum to a lesser extent than did 7% SLS (anionic) and 7% cocoamidopropyl betaine (amphoteric) as evaluated from the skin surface water 10~s.~’Among anionic and cationic surfactants, solvents, and emulsifiers, however, BAC had the greatest hyperplasiogenic effect, indicating a stronger irritancy potential.53 Similarly, Harvell et al reported that 0.5% BAC induced a stronger clinical skin irritation than 0.5% SLS and 0.5% cocoamidopro-
DETERGENT
AND SKIN IRRITATION
17
pyl betaine.32 Furthermore, BAC was more cytotoxic to both cultured human oral and skin keratinocytes than sLs.54
Amphoteric
Surfactants
CocoamidopropylBetaine Like all amphoteric agents, cocoamidopropyl betaine (CAPB) is compatible with all other types of surfactants. Hard water has no effect on its foaming properties in aqueous solution. The chemical is one of the most frequently used amphoteric surfactants in shampoos, partly because it is less irritating to skin and eyes than other typess5 CAPB induced less skin surface water loss than SLS but a higher rate than BAC: 7% SLS >l% CAPB >7% BAC.52 On the other hand, CAPB caused less clinical skin irritation than SLS and BAC: 0.2% BAC >0.5% SLS >0.5% CAPB.32 Korting et al, however, reported that CAPB possesseda higher irritation potential than polyethylene glycol (nonionic surfactant) as measured by an evaporimeter and chromameter.31 It is interesting to note that CAPB in vitro proved to be highly cytotoxic compared with other surfactants3’ The investigators ranked the cytotoxicity of different classesof surfactant evaluated by both in vitro neutral red release and cell growth/protein assays as follows: cationic = amphoteric > anionic > nonionic (according to decreasing cytotoxicity). The frequency of CAPB allergic contact dermatitis is currently being defined. 56 The researchers suggest that the parent compound dimethylaminopropylamine, present as an impurity in the commercial product, is responsible for CAPB allergy.
Nonionic
Surfactants
Propylene Glycol Propylene Glycol (PG) is increasingly used as a vehicle for therapeutic formulations and cosmetics, as well as in many personal care and food products. The potential for irritant reactions and sensitization to PG was reported 4 decades ago.57 Although Frosch and Kligman, using the chamber scarification test, classified 100% PG as a moderate skin irritant,58 other authors concluded that PG, among some surfactants and solvents, displayed only marginal irritant properties.59-62 Indeed, further studies showed that a 48-hour occlusive application with 100% PG failed to produce clinical and histologic irritation when compared with anionic (5% SLS) and cationic surfactant (0.5% BAC). Specifically by light microscopy, a striking “basket weave” pattern to the stratum comeum of the PC-treated skin was evident in all biopsies, due to the osmotic hydration of cornea1 cells.33 The mechanism of the skin response to PG has not
entirely been elucidated. The question whether irritation or allergy is involved in a reacting subject remains problematic; “PG dermatitis” still provides a dermatologic crux (for review, see Fisher63 and Catanzaro and Smith@). Funk and Maibach proposed classifying skin reactions to PG into four different mechanisms, which may allow a partial explanation of effects observed by different authorsb5 Similar issues must be clarified with another nonionic surfactant, butylene glycol. Polyethylene Glycol 200 Glyceryl Monotallowate In a soap chamber assay the surfactant, applied twice a day, induced only minimal changes as evaluated with an evaporimeter and chromameter when compared with some anionic and amphoteric surfactants.“’ Moreover, with the use of both in vitro cytotoxicity assays (neutral red release and cell growth/protein), PEG 200 glyceryl monotallowate proved to be less cytotoxic than other surfactants investigated. Sorbitan Mouolaluate When applied (open) once daily for 3 days to the skin, 10% sorbitan monolaurate marginally influenced the epidermal water barrier as evaluated by skin surface water loss rates (water-holding capacity) compared to anionic (7% SLS) and amphoteric (7% CAPB) surfactants.”
Combination of Surfactants: Possible Decrease in Irritation
Potential
Antagonism or mutual inhibition occurs in the process of acid-base neutralization and anionic-cationic surfactant reaction; however, less appreciated interactions between anionic, nonionic, and amphoteric surfactants can also greatly alter the irritation potential of detergents to the skin.6&ds SLS and linear C9-i3 alkylbenzene sufonate (LAS), when applied alone at 20% occlusively for 4 hours, induced erythema in human volunteers,@ but decreased erythema was obtained for combination of 20% SLS with 10% sodium lauryl ether-2E0 sulfate (SLES), 10% CAPB, or 10% cocodiethanolamine. Similarly, a combination of 20% LAS + 10% SLES + 10% C9-11 alcohol 8 EO (nonionic), a total surfactant level of 40%, was substantially lessirritant than 20% LAS alone. The investigators suggested that skin irritation is related not simply to the total concentration of surfactants but rather to the combination of surfactants present.6Y Similarly, it has also been demonstrated that a combination of sodium lauroyl glutamate (SLG), a mild surfactant, with SLS induced less skin irritation than did SLS alone as assessedby visual scoring and an evaporimeter. ‘” A possible exp lanation is that reduced skin response might be caused by replacement of SLS with the milder SLG, or that SLG might compete with SLS
for surtace area on the skin. Alternatively, the critical micelle concentration level of SLS was possibly lowered by addition of SLG and the level of surfactant monomer may decrease, resulting in reduced skin response.70 Effects of serial applications of surfactant on the skm seem to be different from those of mixed surfactants Malten and Thiele proposed that partial exposure of the skin to the same or different detergent, which was preexposed to certain deter ents, might influence the in5* The partial overlapping of tensity of skin irritation. preexposed skin exhibited a milder reaction than adjacent, newly exposed skin. Recent studies, however, showed that this overlapping region exhibits an intense irritation effect characteristic of cumulative irritation induced by SLS.72 Moreover, the newly exposed skin shows the higher transepidermal waterless (TEWL) values, which could be explained by a possible spread~crf SLS after prolonged treatment, irritating the skin adjacent to the treated site (“the overlap phenomenon”) “’
Irritancy Potential of Frequently Used Surfactants Different models have been developed to define the irritation potential of a given compound.73*74The objectivity and reproducibility of such in vivo tests have been improved b the use of noninvasive bioengineering techniques.4”,Y5-79With these methods, a ranking of the irritant potency of some recurrently used surfactant has been obtained (Table 2). Numerous in vitro alternative tests have been developed. Such promising assays should provide an objective means of predicting the irritation potential of che~cals.“‘,74,8&“’ Rougier et al summarize extensive documentation of this approach.“’ One should keep in mind, however, that it is unlikely that an in vitro system could ever be devebped to mimic the complex cascade of reactions that occur in the human skin. In vivo testing in human volunteers is therefore still crucial, at least to confirm in vitro results.
Conclusions Because detergents hold certain beneficial properties: their use in everyday life becomes nearly indispensable; however, the irritation potential of surfactants may relatively limit their employment. Visualization and possibly development of less irritant, mild, consumerfriendly single surfactants or surfactant systems are therefore of general interest. Differences in the irritation potential between types of surfactants exist, but the arbitrary classification of surfactants does not necessarily correspond with the irritancy of each compound. Hence, improved assays to predict the irritation potential of surfactant are still required. Our theoretical and practical insights have significantly improved, yet the complexity of the skin and
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1996;14:15-21
DETERGENT
AND
SKIN
IRRITATION
19
Table2. Irritant Potencyof SomeFrequently UsedSurfactants Rankingof Irritation Potential
In Vivo Test
Assessment
LAS > SLS > AEOS-3E0 > polysorbate 20 (Tween 20) SLS > SLES > CPAB > LESS > RMSS > PEG (concentrations: 1%)
Epidermis curling test & 5-day soap chamber test 2-day soap chamber test
5% SLS > 0.5% BAC > 100% I’G” 5% SLS = 0.5% BAC > 100% PGh
48-h patch test
SLS > cocobetaine > CAPB (concentrations: 2%) 0.5% SLS > 0.5% dodecyl trimethyl ammonium bromide > potassium soap N-alkyl-sulfatec,, > C,,,, C,,,, 7% SLS > 7% CAPB
> 1% BAC
> 10%
Ref.
gauge & visual scoring
79
TEWL, skin reflective color using chromameter (SRC) “visual scoring ‘histology
31
48-h patch test
TEWL
78
24-h patch test
TEWL, skin capacitance
46
24-h patch test 24-h plastic occlusion stress test
TEWL, SRC skin surface water loss (SSWL)
74 52
5-day repeated occlusive application test (2x daily)
TEWL, SRC, capacitance, skin replica, spectroscopic and visual scoring
77
33
sorbitan monolaurate 2% SLS > 2.9% LAS > 7.9% PEG-20
glyceryl monotallowate
AEOS-SE0 = alkyl (C12-,4 average) ethoxy sulfates; BAC = benzalkonium chloride; CAPB = cocoamidopropyl betaine; LAS = linear alkyl (CIz average) benzene sulfonate; LESS = disodium laureth sulfate; PEG = polyethyene nlycol; PC = propylene nlycol; RMSS = disodium ricinoleamido monoethanolamido sulfosuccinate; SLES = sodium lauyl ether sulfate; SLS = sodium lauyl sulfate. ” ” - 1 ” - ”
the surfactant suggests that future development will flourish with a multifactorial approach that combines the advancing techniques of physical chemistry with the more slowly evolving insights into animal and human skin biology.
13. 14. 15.
References 1. Kirk-Othmer. Encyclopedia of chemical technology. New York: John Wiley & Sons, 1984. 2. Lottermoser A, Stoll F. The surface and interfacial activities of salts of the fatty acid alcohol sulfuric acid esters. Kolloid-Z 1933;63:49-61. 3. Ainsworth SJ, Soaps and detergents. Chem Engin News 1992;70(3):27-63. 4. Attwood D, Florence AT. Surfactant system: Their chemistry, pharmacy and biology. London: Chapman and Hall, 1983:1-11. 5. Zografi G, Schott H, Swarbrick J. Interfacial phenomena. In: Gennaro AR, editor. Remington’s pharmaceutical sciences. Easton PA: Mack, 1990:257-72. 6. Rosen MJ. Surfactants and interfacial phenomena. New York: John Wiley & Sons, 1978:1-25. 7. Moran J, Addy M, Wade WG. Determination of minimum inhibitory concentrations of commercial toothpastes using an agar dilution method. J Dent 1988;16:27-31. 8. Wade WG, Addy M. Antibacterial activity of some tricloSan-containing toothpastes and their ingredients. J Periodontol 1992;63:280-2. 9. Reynold EF, editor. Martindale: The extra pharmacopoeia. 30th ed. London: Pharmaceutical, 1993:1215-6. 10. Blank IH. Action of soap on the skin. Arch Dermatol1939; 39:811-7. 11. Emery 8, Edwards L. The pharmacology of soaps: III. Irritant action of sodium alkyl sulphates on human skin. J Am Pharm Assoc 1940;29:254-60. 12. Van Scott EJ, Lyon JB. A chemical measure of the effect of
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MAIBACM
toxicity of sodium dodecyl sulfate in sea water. Biochem Biophys Acta 1992;1103:148-56. Partearroyo MA, Ostolaza H, Goni FM, Barbera-Guillem M. Surfactant-induced cell toxicity and cell lysis. Biochem Pharmacol 1990;40:1323-8. Walters KA, Bialik W, Brain KR. The effects of surfactants on penetration across the skin. Int J Cosmet Sci 1993;lF;: 260-70. Rhein LD, Simion FA. Surfactant interactions with skin. Surfact Sci Ser 1991;32:33-49. Gisslen H, Magnusson B. Effects of detergents on guineapig skin. Acta Derm Venereol (Stockh). 1966;46:269-74. Scala J, McOsker DE, Reller HH. The percutaneous absorption of ionic detergents. J Invest Dermatol 1968;50: 370-7. Korting HC, Herzinger T, Hartinger A, et al. Discrimination of the irritancy potential of surfactants in vitro by two cytotoxicity assays using normal human keratinocytes, HaCaT cells and 3T3 mouse fibroblast: Correlation with in vivo data from a soap chamber assay. J Dermatol Sci 1994; 7119-29. Harvell J, Tsai YC, Maibach HI, et al. An in vivo correlation with three in vitro assays to assess skin irritation potential. J Toxic Cut Ocular Toxic 1994;13:171-83. Willis CM, Stephens CJM, Wilkinson JD. Epidermal damage induced by irritants in man: a light and electron microscopic study. J Invest Dermatol 1989;93:695-9. Imokawa G, Mishima Y. Cumulative effect of surfactants on cutaneous horny layers: Lysosome IabiIizing action. Contact Dermatitis 1979;5:151-62. Kligman AM, Wooding WM. A method for the measurement and evaluation of irritants on human skin. J Invest Dermatol 1967;49:78-94. Wahlberg JE, Maibach HI. Nonanoic acid irritation: A positive control at routine patch tetsing. Contact Dermatitis 1980;6:128-30. Goodman M, Barry BW. Action of penetration enhancers on human stratum corneum as assessed by differential scanning calorimetry. In: Bronaugh RL, Maibach HI, editors. Percutaneous absorption: Mechanism-Methodology-Drug Delivery. New York: Marcel Dekker, 1989:567-95. Scheuplein R, Ross L. Effects of surfactants and solvents on the permeability of epidermis. J Sot Cosmet Chem 1970;21:853-73. LaRoche G, Eisler R, Tarzwell CM. Bioassay procedures for oil and oil dispersant toxicity evaluation. J Water Pollut Control Fed 1970;42:1982-9. Varani J, Fligiel SEC, Perone P, et al. Effects of sodium lauryl sulfate on human skin in organ culture: Comparison with all-trans-retinoic acid and epidermal growth factor. Dermatology 1993;187:19-25. Griffiths CEM, Finkel LJ, Tranfaglia MG, et al. An in vivo experimental model for effects of topical retinoic acid in human skin. Br J Dermatol 1993;129:389-94. Berardesca E, Herbst R, Maibach HI. Plastic occlusion stress test as a model to investigate the effects of skin delipidization on the stratum corneum water holding capacity in vivo. Dermatology 1993;187:914. Agner T. Noninvasive measuring methods for the investigations of irritant patch test reactions: A study of pa-
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59.
60. 61. 62. 63.
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