Preservatives

ELSEVIER

Preservatives BIRGITTA MAGNUS

GRUVBERGER, MSc BRUZE, MD, PhD

T

he need of preservatives has increased since water-based products have become more common. Organic solvents and mineral oil are nowadays often replaced with water. To prevent growth of bacteria, fungi, yeasts, and algae in water-based products/ systems it is necessary to add preservatives. Thus medicaments, toiletries, cosmetics, detergents as well as paints, glues, adhesives, and cutting fluids are products that may contain preservatives. Several preservatives are available, but new, more effective ones have been introduced on the market. Besides paying attention to microbiological and economical aspects, the manufacturer must pay attention to health aspects as well as to environmental hazards when developing preservatives. Most preservatives are low-molecular-weight compounds and biologically active, so they can be expected to be contact sensitizers. When performing patch testing, proper test preparations must be used. A recent textbook includes a list of patch test concentrations of many contact antigens.l Test concentrations and vehicles of the listed preservatives are given in Table 1. Many reports on contact allergy to preservatives have been published. During the late 1980s methylisothiazolinones (MIT) were reported to sensitize many people, especially when used in leave-on products.2 Still, MITcontaining preservatives are frequently used not only in industrial products but also in cosmetics and toiletries. Several studies and case reports concerning MIT have been published during the last years. Then, what is new? We have chosen to discuss (1) new preservatives reported to be sensitizers, (2) an old preservative with an increased frequency of contact allergy, and (3) an old preservative with a renewed clinical relevance.

New Sensitizers Kathon 930 In the early 1990s a group of investigators reported on occupational contact dermatitis from Kathon 930@, which was used as a biocide in a textile finishing factory.3 Like other Kathons, this new one is based on an isothiazolinone. Kathon 930 consists of 4,5-dichloro-2-n-octyylFrom the Department of Occupational and Environmental Dermafology, Malmd Uniwrsify Hospital, Malm0, Sweden. Address correspondence to Dr. Birgittu Gruvberger, Department of Occupational and Environmenfal Dermatology, Malmd University Hospital, S-205 02 MalmB. Sweden.

0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York,

NY 10010

4-isothiazolin-3-one at 30% in xylene. The new isothiazolinone is chemically related to another preservative, 2-n-octyl-4-isothiazolin-3-one (Kathon 893). The structures of various isothiazolinones are shown in Fig 1. Eight out of 19 workers developed itchy reddish eruptions on skin exposed to the finishing agent containing Kathon 930. Open tests were performed on 6 patients with both the finishing agent without a biocide and with the Kathon 930-containing finishing agent [600 parts per million (ppm) active ingredients (a.i.)]. Five patients showed strong positive test reactions to the biocide-containing finishing agent. None reacted to the finishing agent. No controls were tested, so it is difficult to evaluate the test reactions. No reactions to Kathon CG 50 ppm a.i. could be demonstrated when closed test was performed.

2-Methyl-4,5-trimethylene-4-isothiazolin-3-one

(MI/T)

Another new isothiazolinone derivative is MT1 (Fig 1). In 1994, a group of investigators reported on contact hypersensitivity to MTI.4 A laboratory technician who was handling a variety of concentrated biocides including MTI, 1,2-benzisothiazolin-3-one (BIT), and Kathon WT became sensitized to MTI. Patch testing revealed positive reactions to 0.01% MT1 in water and to BIT 0.1%. Since the patient was exposed to both isothiazolinones, is it impossible to draw any conclusions about cross-reactions. Fifty controls were negative to the test preparation with MTI. Recently, 2 preservatives based on MTI, Promexal W50 and X50 (Zeneca Specialities, UK) with 5% MT1 in water have been launched as biocides to paints, polymer emulsions, pigment dispersions, adhesives, metalworking fluids, printing inks, fountain solutions and household products.

A Preservative with an Increased Frequency of Contact Allergy Euxyl 2-C400 Euxyl K 400 was introduced in Europe in the middle of 1980s and in the United States in 1990 by the manufacturer Schiilke and Mayr (Hamburg, Germany). This preservative is effective at low concentrations against bacteria, yeasts, and fungi. It is recommended for cosmetics and personal care products, with a use concentration of 0.05-0.2%. 0738-081x/97/$32.00 PII SO738-081X(97)00052-7

L94

GRUVBERGER

rable 1.

AND

Clinics

BRUZE

Proper test concentrations

ill Dermatology

9 _I!w:;15:493-4iyi

and vehicles of ywservatives* Substamr

L-Aza-3,7-dioxa-5-ethyl-bicycle-(3,3,0)-octane 1,2-Benzisothiazolin-3-one 3enzoic acid 3enzyl alcohol 3enzyl-4-hydroxybenzoate !-Bromo-Z-nitropropane-1,3-diol Sutyl-4-hydroxybenzoate l-Chloroacetamide 1-(3-Chloroaflyl)-3,5,7-triaza-l-azonia-adamantane chloride I-Chloro-3-cresol i-Chloro-2,methyl-&sothiazolin-3-one (MCI) + 2-methyl-4-isothiazolin-3-one &Chloro-3,5-xylenol !,5-Diazolidinylurea 1,2-Dibromo-2,4-dicyanobutane + 2-phenoxyethanol 1,4-Dimethyloxazolidine + 3,4,4+imethyloxazolidine 1,3-Dimethylol-5,5-dimethyl hydantion Ethyl-4hydroxybenzoate 1,4(2-Ethyl-2-nitrotrimethylene)-dimorpholine + 4-(2-nitrobutyl)-morpholine Formaldehyde hnidazolidinyl urea Methyl-4-hydroxy benzoate ‘J-Methylolchloroacetamide !-n-Octyl-4-isothiazolin-3-one Propyl4hydroxybenzoate Sodium benzoate sodium-2-pyridinethiol-l-oxide Sorbic acid Sodium ethylmercurithiosalicyiate Triclosan Zinc pyrithione Hexahydro-1,3,5-tris-(2-hydroxyethyl)-triazine --

7-c t soncentratiorl

‘Trade name Bioban

i~&kit

CS 1246

Benzylparaben Bronopol Butylparaben Quaternium (MI)

Kathon

15, Dowicil

200

CG

Germall II Euxyl K 400 Bioban 1135 DMDM hydantoin Ethylparaben Bioban I’ 1487 Germall 115 Methylparaben Parmetol K 50, Grotan HD Skane M-8, Kathon 893 Propylparaben Sodium

-

omadine

Thimerosal, Merthiolate Irgasan DP 300 Zinc omadine Grotan BK

pet = petrolntum; uq = nqtmtrs. ‘According to Niklasson.’

Euxyl K 400 consists of the 2 active ingredients 1,2dibromo-2,4-dicyanobutan (BCB) 20% and 2-phenoxyethanol (PE) 80% (Fig 2). PE has been used for a long time as a preservative in the cosmetic industry, and BCB is known as a preservative for technical applications such as latex paints, adhesives, and metal-working fluids under the trade name Tektamer 38@ (Calgon).” Methyldibromoglutaronitril is the adopted name

for BCB in the International Nomenclature of Cosmetic Ingredients (INCI). Guinea pig maximization test with the 2 individual ingredients of Euxyl K 400 was performed by a group of

a.

Yry--CH2-yH2 7’

H,C-

CN

Figure 2. The structure of various isothiazolinones. u: Z-methyl4-isothiazolin-3-one. b: 5-chloro-2-methyl-4isothiazolin-3-one. c: 2-n-octyl-4-isothiazolin-3-one. d: 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one. e: 2-methyl-4,5-trimethylene-4-isothiazolin-3-one. f: 1,2-benzisothiazolin-3-one.

b.

CN

0-C2H40H

Figure 2. Structures of a) 1,2-dibromo-2,4-dicyanobutane 2-phenoxyethanol.

and bi

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1997;15:493-497

PRESERVATIVES

investigators, and no sensitizing capacity of the 2 ingredients could be demonstrated;6 however, the authors emphasized that this result did not exclude the possibility that Euxyl K 400 could sensitize humans when used in commercial products.6 After its introduction, many manufacturers of cosmetics started to use Euxyl K 400 as an alternative to the sensitizing preservative Kathon CG. The first report on contact allergy to Euxyl K 400 was published in 1989.6 A woman developed contact dermatitis on her face and neck after application of a lotion containing Euxyl K 400. Patch testing with the lotion and the preservative Euxyl K 400 revealed strong positive reactions. Patch tests with the a.i. showed a positive reaction to BCB 0.004% in water.7 Since this report on hypersensitivity to Euxyl K 400, there have been many case reports on contact allergy to this preservative. 5,8-13 Lotions, eye gels, cleansing creams, ultrasonic gel and moist toilet paper have been the most common causes to Euxyl K 400- induced allergic contact dermatitis. Contact allergy frequency figures for Euxyl K 400 and or its active ingredients have been published from many European countries (Table 2). Both Euxyl K 400

and BCB have been used to screen hypersensitivity to Euxyl K 400. Several groups found that a positive test reaction to Euxyl K 400 did not necessarily correlate with positive reactions to the active ingredientsl5J9 The most proper test preparation to detect hypersensitivity to Euxyl K 400 has not yet been determined. Recently, a group of investigators recommended patch testing with BCB alone, because this active ingredient seems to be the only sensitizer in Euxyl K 400;z4 however, the optimal test concentration and vehicle for BCB are still unknown. The authors of the study recommend 0.3-0.5% in petrolatum.24

A Preservative with a Renewed Clinical Relevance Thimerosal

(TIM)

Thimerosal (TIM) is a common sensitizer. High frequencyies of positive test reactions (4.7%-21.5%) have been demonstrated when dermatitis patients as well as healthy subjects have been tested with TIM.2533 All ages may be involved, but there is a predominance in young adults among the dermatitis patients;33,% however, positive patch tests often lack clinical rele-

Table 2. Prevalence of contact allergy to Euxyl K 400 and/or 1,2-dibromo-2,4-dicyanobutan dermatitis vatients

Chemical Euxyl

K 400

Euxyl Euxyl BCB PE Euxyl Euxyl BCB Euxyl

K 400 K 400

Euxyl

K 400

PE BCB BCB Euxyl BCB FE BCB

K 400 K 400

Test concentration %

Numberof Vehicle

pet

2.5 2.5 0.15

0.2 0.05

Pet = petrolatum;

0.15 2.5 0.5 1.5 5 0.5

pet aq aq/PG

0.5 0.1 0.3 0.1 0.05 0.1 PG = propylene

310

pet PG PG

0.1

BCB

Pet

aq pet pet pet aq aq/alc

K 400

K 400

pet pet pet pet pet pet pet+SL

2057 2057 1033 >1800 3726 3726 3726 400 889 1142 1033 1033 3455 3022/3455 729/3455 3455 919/3455 814 1019 1019 1019 2943

ale PG

0.5 0.1 0.4

glycoi;

patients

ak = ethanol,

aq = aqueous,

495

Positive reactions (Number) (%) 24 24 18 0 36 30 1

0 5 6 21 18 99 54 5 2 21 16 24 24

0 119

6 SL = soy lecithin.

(BCB) and 2-phenoxyethanol

(PE) in

Year of study Author

1.2 1.2 1.7 0.0 1.0 0.8 0.0 0.0 0.6 0.5 2.0 1.7 2.8 1.8 0.7 0.06 2.3 2.0 2.4 2.4 0.0 4.0

Tosti

1.9

Vigan

et at

Country

Crefl

Italy

1988-1990(14)

Ross et at Fuchs et at

U.K. Germany

1989(9) 1889-1990(15)

Torres et at Corazza et at de Groot et at Motolesi et at

Portugal Italy Netherlands Italy

Tosti

Italy

Wl-1994(19)

Netherlands Netherlands

1993-1994(20) 1993-1995(21)

et at

van Ginkel et at Okkerse et at

de Groot

et at

et at

1990(10) 1993(16) 1991(17) 1991(18)

1994(22)

France

1994(23)

496

GRUVBERGER

AND

BRLJZE

c.

COOH

HS

b. C,H$-lg

Cl

+

I

+

-

HCI

r&OH

+

H,O

Figure 3. The synthesis of (a) thimerosal (sodium ethylmercurifhiosalicylafe) from (b) ethylmercuric chloride (c) thiosnlz’cylic acid, and sodium hydroxide (NaOH).

vance.33-36Recently, a review article about positive tests to TIM was published.33 The author concluded that TIM should be retained in the standard test series for scientific purposes, but its inclusion does not seem to be indicated on clinical grounds.?” TIM is synthesized from ethylmercuric chloride (EM) and thiosalicylic acid (TSA; Fig 3).37 Now and then these compounds, in addition to other organic as well as inorganic mercury compounds, have been tested on TIM-hypersensitive patients. The investigator found that 18 out of 23 TIMsensitized were positive to EM.“O At an early stage it was understood that a positive patch test with TIM was not a marker for mercury allergy.33 There has been an increasing interest in characterizing the sensitizing moiety of TIM. Recently, a group of investigators reported on simultaneous patch testing with the 2 components EM and TSA in TIM-sensitized individuals.s7 Nineteen out of 23 TIM-hypersensitive patients revealed positive test reactions to EM, but none reacted to TSA.s7 In another study TIM-sensitized patients were tested with the same components and with the same concentrations.38 Hypersensitivity to EM was demonstrated in 87.2% of the TIM-sensitive patients; however, in contrast to other studies, it was found that 44.5% of the patients reacted positively to TSA.“fi A group of investigators found a relationship between piroxicam-induced photosensitivity and contact sensitivity to TSA .39Three patients developed a photocontact dermatitis after application of a piroxicam gel with a subsequent positive photopatch test to the gel, while patch testing revealed positive test reactions to TIM and TSA.“9 Another group found that many patients allergic to TIM and with no history of taking piroxicam had positive photopatch tests to piroxicam, in contrast to controls.4o These findings were followed

by a renewed interest in TSA, because all patients with contact allergy to TIM and concomitant photoallergy to piroxicam tested positively to TSA.39,4” This result has been considered a primary sensitization to TIM and its TSA part, which then cross-reacts with the piroxicam photoproducts. This interpretation has been strongly supported by a recent animal study.4L Animals that were contact sensitized to TIM or TSA tested positively at challenge to irradiated piroxicam invivo, while arti-. mals photosensitized to piroxicam tested positively at challenge to TIM and TSA.J’ Thus, contact allergy to TSA can be used to predict the risk of photoallergic reactions to piroxicam. Clinically, this means that patients known or suspected to be TIM-hypersensitive should not be given piroxicam unless it is shown that their TIM-hypersensitivity is -rt~ lated to EM and not to TSA.

Conclusion There is an increased use of preservatives in waterbased products, both in the occupational and the non-. occupational environment. Allergic contact dermatitis from preservatives is common. Some of the problems are related to new preservatives, others to an increased use of a certain preservative or may be due to new relations to other substances. As examples of these 3 situations we have discussed the new preservatives Kathon 930 and MTJ, the increased frequency of contact allergy to Euxyl K 400, and finally the relationship between photosensitizing piroxicam and contact allergy to TIM and TSA.

References Niklasson BJ. Patch-test concentrations. ln: Guin JD, editor. Practical contact dermatitis. A handbook for the Practitioner. New York: McGraw-Hill, 1995705-69. 2. Bruze M, Gruvberger B, Bjiirkner B, Kathon CG-an unusualcontact sensitizer.In: Men& T, Maibach HI, editors. Exogenousdermatoses.BocaRaton: CRC Press,1991:283-W 98. L3 Kawai K, Nakagawa M, Sasaki Y, et al. 0ccupation;rl contact dermatitis from Kathon 930. Contact Dermatitis 1.

1993;28:117-8. 4. Burden AD, O’Driscoll

JB, Page FC, et al. Contact hype?

sensitivity to a new isothiazolinone. Contact Dermatitis 1994;30:179-80. 5. de Croot AC, Weyland JW. Contact allergy to methyldibromoglutaronitrile in the cosmetics preservative Euxyl K 400. Am J Contact Dermatitis 1991;2:31-2. 6. Bruze M, Gruvberger B, Agrup G. Sensitization studiesin the guinea pig with the active ingredients of Euxyl K 400. Contact Dermatitis 1988;18:37-9. 7. Senff H, Exner M, Gortz J, et al: Kontaktallergie auf &en neuen Konservierungsstoff. Dermatosen 1989;37:45-7. 8. Pigatto PD, Bigardi A, Legori A, et al. Allergic contact dermatitis from Tektamer 38 (dibromodicyanobutane). Contact Dermatitis 1991;25:138-9.

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9. Ross JS, Cronin E, White IR, et al. Contact dermatitis from Euxyl K 400 in cucumber eye gel. Contact Dermatitis 1992;26:60. 10. Torres V, Soares AI’. Contact allergy to dibromodicyanobutane in a cosmetic cream. Contact Dermatitis 1992; 27:114-5. 11. Gebhart M, Stuhlert A, Knopf 8. Allergic contact dermatitis due to Euxyl K 400 in an ultrasonic gel. Contact Dermatitis 1993;29:272. 12. Fernandez E, Navarro JA, de1 Pozo L, et al. Allergic contact dermatitis due to dibromodicyanobutane in cosmetics. Contact Dermatitis 1995;32:109-110. 13. O’Donnell BF, Foulds IS. Contact dermatitis due to dibromodicyanobutane in cucumber eye gel. Contact Dermatitis 1993;29:99-100. 14. Tosti A, Guerra L, Bardazzi F, et al. Euxyl K 400: a new sensitizer in cosmetics. Contact Dermatitis 1991;25:89-93. 15. Fuchs Th, Enders F, Przybilla B, et al. Contact allergy to Euxyl K 400. Results of a multicenter study of the German Contact Allergy Group (DKG). Dermatosen 1991;39: 151-3. 16. Corazza M, Mantovani L, Roveggio C, et al. Frequency of sensitization to Euxyl K 400 in 889 cases. Contact Dermatitis 1993;28:298-9. 17. de Groot AC, Bruynzeel DP, Coenraads PJ, et al. Frequency of allergic reactions to methyldibromoglutaronitrile (1,2-dibromo-2,4-dicyanobutane) in The Netherlands. Contact Dermatitis 1991;25:270-1. 18. Motolese A, Seidenari S, Truzzi M, et al. Frequency of contact sensitization to Euxyl K 400. Contact Dermatitis 1991;25:128. 19. Tosti A, Vincenzi C, Trevisi I’, et al. Euxyl K 400: incidence of sensitization, patch test concentration and vehicle. Contact Dermatitis 1995;33:193-5. 20. van Ginkel CJW, Rundervoort GJ. Increasing incidence of contact allergy to the new preservative 1,2-dibromo-2,4dicyanobutane (methyldibromoglutaronitrile). Br J Dermatol 1995;132:918-20. 21. Okkerse A, Geursen-Reitsma AM, van Joost Th. Contact allergy to methyldibromoglutaronitrile and certain other preservatives. Contact Dermatitis 1996;34:151-2. 22. de Groot AC, de Cock PAJJM, Coenraads PJ, et al. Methyldibromoglutaronitrile is an important contact allergen in The Netherlands. Contact Dermatitis 1996;34:118-20. 23. Vigan M, Brechat N, Girardin P, et al. Un nouvel allergene: Le dibromodicyanobutane. Compte rendu d’une etude portant sur 310 malades de janvier a decembre 1994. Ann Dermatol Venereol 1996;123:322-4. 24. de Groot AC, van Ginkel CJW, Weyland JW. How to

PRESERVATIVES

25.

26. 27.

28. 29. 30.

31.

32.

33. 34.

35.

36. 37.

38.

39.

40.

41.

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detect sensitization to Euxyl K 400. Letter to the Editor. Contact Dermatitis 1996;34:373-4. Osawa J, Kitamura K, Ikezawa Z, et al. A probable role for vaccines containing thimerosal in thimerosal hypersensitivity. Contact Dermatitis 1991;24:178-82. Aberer W. Vaccination despite thimerosal sensitivity. Contact Dermatitis 1991;24:6-10. Aberer W, Reiter E, Ziegler V, et al. The importance of including Thimerosal, an increasingly frequent allergen in Europe, in standard screening series for allergic contact dermatitis. Am J Contact Dermatitis 1991;2:110-2. Wantke F, Demmer CM, Gijtz M, et al. Contact dermatitis from thimerosal. Contact Dermatitis 1994;30:115-7. Hansson H, Moller H. Patch test reactions to merthiolate in healthy young subjects, Br J Dermatol 1970;83:349-56. Mijller H, Merthiolate allergy: A nationwide iatrogenic sensitization. Acta Derm Venereol (Stockh) 1977;57:50917. Seidenari S, Manzini BM, Danese P, et al. Patch and prick test study of 593 healthy subjects. Contact Dermatitis 1990;23:162-7. Barros MA, Baptista A, Correia TM, et al. Patch testing in children: a study of 562 schoolchildren. Contact Dermatitis 1991;25:156-9. Miiller H. All these positive tests to thimerosal. Contact Dermatitis 1994;31:209-13. van’t Veen AJ, van Joost Th. Sensitization to thimerosal (Merthiolate) is still present today. Contact Dermatitis 1994;31:293-8. Schafer T, Endres F, Przybilla B. Sensitization to thimerosal and previous vaccination. Contact Dermatitis 1995; 32:114-6. Goncalo S, Goncalo M, Azenha A, et al. Allergic contact dermatitis in children. Contact Dermatitis 1992;26:112-5. Pirker C, M&linger T, Wantke F, et al. Ethylmercuric chloride: the responsible agent in thimerosal hypersensitivity. Contact Dermatitis 1993;29:152-4. Goncalo M, Figueiredo A, Goncalo S. Hypersensitivity to thimerosal: the sensitizing moiety. Contact Dermatitis 1996;34:201-3. Serrano G, Bonillo J, Aliaga A, et al. Piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. J Am Acad Dermatol 1990;23:479-83. Cime de Castro JL, Freitas JP, Menezes Brandao F, et al. Sensitivity to thimerosal and photosensitivity to piroxicam. Contact Dermatitis 1991;24:187-92. Ikezawa Z, Kitamura K, Osawa J, et al. Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate. J Invest Dermatol 1992;98:918-22.