Cinnamic aldehyde: A survey of consumer patch-test sensitization

k]l Chem. Toxic. Voh 21. No. 6. pp. 721 725. 1983

0278-6915 83S3.00+11.00 Cop?right , 1983 Pergamon Pres> lad

Printed in Great Britain. All rights reserved

C I N N A M I C A L D E H Y D E : A S U R V E Y OF C O N S U M E R PATCH-TEST SENSITIZATION P. J. DANNEMAN,K. A. BOOMAN, J. DORSKY, K. A. KOHRMAN, A. S. ROTHI'NSTEIN, R. I. St','DLAK, R. J. STELTENKAMP and G. R. THOMPSON Fragrance Raw Material Subcommittee to the Biomedical Research Committee of The Soap and Detergent Association*, 475 Park Avenue South, New York, NY 10016, USA (Received 18 Januart' 1983)

The potential for cinnamic aldehyde, an important fragrance and flavour ingredient, to induce or to elicit delayed contact hypersensitivity reactions in man was evaluated by analysing patch-test data. Results of studies involving a total of4117 patch tests on various consumer products and fragrance blends containing cinnamic aldehyde and on the material itself were collected from fragrance and formulator companies. The data indicate that cinnamic aldehyde contained in consumer products and fragrance blends at concentrations up to 6 x 10 I°C, and patch-tested at concentrations up to 8 × 10 >',,, has no detectable potential to induce hypersensitivity. Cinnamic aldehyde when tested alone induced a doserelated hypersensitivity response. According to published reports, cinnamic aldehyde elicited positive delayed hypersensitivity responses in dermatitic patients. However, results of the current survey show that when cinnamic aldehyde was tested alone or as part of a mixture in subjects in the general population, no pre-existing hypersensitivity reactions to the fragrance material were observed in any of the 4117 patch tests which constituted the survey. Cinnamic aldehyde at the concentrations contained in consumer products and fragrances, has a very low potential to induce hypersensitivity ('induced" reactions) or to elicit sensitization reactions ('elicited' reactions) in the general population. Abstract

INTRODUCTION A survey of h u m a n skin sensitization data from patch tests on materials c o n t a i n i n g c i n n a m i c aldehyde has been c o n d u c t e d u n d e r the auspices of The Soap a n d Detergent Association (SDA). M e m b e r c o m p a n i e s and fragrance suppliers s u b m i t t e d the results of h u m a n patch tests on a variety of commercial and experimental products c o n t a i n i n g c i n n a m i c aldehyde, on neat cinnamic aldehyde tested in a vehicle and on fragrance blends that c o n t a i n e d c i n n a m i c aldehyde. The object of publishing these cumulative data is to provide guidance and perspective for the safe use of cinnamic aldehyde in c o n s u m e r products. Similar surveys by the SDA have been published on hydroxycitronellal, citral a n d c i n n a m i c alcohol (Steltenkamp, B o o m a n , Dorsky et al. 1980a, b, c). Surveys conducted on eugenol and clove leaf oil (Rothenstein, Booman, Dorsky et al. 1983), isoeugenol ( T h o m p s o n , *The addresses of the individual authors are: P. J. Dannemann and K. A. Kohrman, The Proctor & Gamble Co., Cincinnati, OH 45217: K. A. Booman and R. h Sedlak, The Soap & Detergent Association, New York, NY 10016: J. Dorsky, Givaudan Corp., Clifton, NJ 07014; A. S. Rothenstein, Lever Brothers Co., Edgewater, NJ 07020: R. J. Steltenkamp, Colgate-Palmolive Co., Piscataway, NJ 08854, G. R. Thompson, International Flavors & Fragrances, Union Beach, NJ 07735. Ahbret'ialions: EOA - Essential Oil Association: FEMA - Flavoring Extract Manufacturers" Association: H R I P T - human repeat insult patch test: S D A - The Soap and Detergent Association.

B o o m a n , Dorsky et ul. 1983) and benzyl salicylate ( K o h r m a n , B o o m a n , Dorsky et al. 1983) are published in this issue o f F o o d a n d C h e m i c a l Toxicology. C i n n a m i c aldehyde (/3-phenylacrolein: 3-phenylpropenal; cinnamal" CAS 10,~54-1) is an i m p o r t a n t fragrance raw material, used in the soap and detergent industry in m a n y different types of fragrances for its strong and spicy cinnamon-like odour. It has been in public use since before 1900. An estimated 100,000 lb are currently used per a n n u m in perfumes and flavours in the USA. C i n n a m i c aldehyde is generally recognized as safe ( G R A S ) for food additive applications ( F E M A , 1965) and was approved for food use by the Food and Drug A d m i n i s t r a t i o n (21 C F R 182.6/)). C i n n a m i c aldehyde occurs naturally in the oils of cassia, which may contain up to 80,I~i cinnamic aldehyde, Ceylon and Japanese cinnam o n bark, and Ceylon and M a d a g a s c a r c i n n a m o n leaves, and in other essential oils such as hyacinth, m y r r h a n d Patchouli. Commercial cinnamic aldehyde is m a d e by the c o n d e n s a t i o n of acetaldehyde with benzaldehyde and is >98'I,1 pure (EOA, 1975). C i n n a m i c aldehyde was selected for this survey because of recent reports of its potential to induce and elicit sensitization reactions when applied to m a n (Opdyke, 1979). W h e n tested alone under the exaggerated conditions of predictive patch-testing, cinnamic aldehyde was shown to have a potential to induce hypersensitivity at c o n c e n t r a t i o n s >0.5'!i, (Table 1: Opdyke, 1976, 1977 & 1979). However, Opdyke (1976 & 1977) has also observed that when cinnamic aldehyde was tested at high c o n c e n t r a t i o n s in natural 721

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P . J . DANNEMAN et al.

toothpaste induced the hypersensitivity or merely elicited a pre-existing sensitization, since cinnamic aldehyde and cinnamon oil are widely used in flavours and fragrances, and cinnamic aldehyde is used as a chewing gum flavouring at a concentration of about 5000ppm (Collins & Mitchell, 1975). In many of the cases shown in Table 2, patients involved in the tests were simultaneously exposed to multiple ingredients. Many of the dermatitic patients also reacted to at least one other fragrance ingredient in addition to cinnamic aldehyde. This report, using previously unpublished data on human patch tests, examines the extent of existing sensitization to cinnamic aldehyde as well as the potential of the material to induce delayed contact hypersensitivity among non-dermatitic subjects tested with a variety of consumer products and fragrance blends containing cinnamic aldehyde .

Table I. Summary of sensitization reactions induced by neat* cinnamic aldehyde in normal subjectst Test concn (% in petrolatum) 3 2 (I.5

Test method KM KM KM x 4++

Incidence of positive reactions 3/25 11/25 2/25

KM = Kligman maximization *Cinnamic aldehyde not mixed with any other essential oils. tData from tests by Kligman (1974, 1973 & 1977) respectively, summarized by Opdyke (1979). +In this test, instead of the standard five consecutive 48-hr patch-test exposures, the subjects received 20 (i.e. four sets of five) consecutive 48-hr patch-test exposures,

oils such as cinnamon leaf oil or mixed 1:1 (v/v) with eugenol or d-limonene, its sensitizing capacity was "quenched", i.e. the natural oils and synthetic mixtures appeared to inhibit the induction and/or elicitation of hypersensitivity to cinnamic aldehyde. Previously published results of cinnamic aldehyde diagnostic patch tests in dermatitic patients are summarized in Table 2. The reports of elicited hypersensitivity to cinnamic aldehyde include those of perioral allergic stomatitis and dermatitis attributed to cinnamic aldehyde flavouring in a toothpaste (Drake & Maibach, 1976; Kirton & Wilkinson, 1975; Magnusson & Wilkinson, 1975). An earlier report described the skin reactions of three patients with allergic stomatitis who were patch-test positive to 0.5~i cinnamon oil in petrolatum (Millard, 1973). However, the author could not establish whether the

EXPERIMENTAL

This survey was initiated in 1979 to collect data from human patch tests conducted in the USA by member companies of the SDA and fragrance suppliers. Participants were requested to submit all their available data on patch tests conducted on commercial and experimental consumer products, on concentrated fragrance blends containing cinnamic aldehyde and on cinnamic aldehyde tested alone. Consumers are not exposed to concentrated fragrance blends or to cinnamic aldehyde alone. The data requested in this survey included the same type of information as was gathered in previous surveys on hydroxycitronellal, citral and cinnamic alcohol (Steltenkamp et al. 1980a, b, c). The screen-

Table 2. Summary of sensitization reactions elicited by neat* cinnamic aldehyde in dermatitic patients tested by the 48-hr diagnostic patch test

Details of subjects tested Patients sensitive to balsam of Peru{ Contact dermatitis patients++. ca use unknown Patients tested by North American Contact Dermatitis Group{_ Patients sensitive to balsam of Peru{_ Patients with eczema, cosmetic sensitivity, young atopics, or cooks, chemical workers Patients with suspected allergic stomatitis Patients with allergic contact dermatitis to proprietary ointment Patient sensitive to aftershave+ Patient with acute stomatitis and dermatitis

Cinnamic aldehyde concn in vehiclet C;)

Incidence of positive reactions

Reference

2

15,71

Hjorth, 1961

2

1/34 (M) 5/55 (F)

Schorr, 1975

NS

7/202

Rudner, 1977

NS

14/142

Mitchell, 1975

I

3/63

Kirton & Wilkinson. 1975

I

15/16

Magnusson & Wilkinson, 1975

I

3;3

Calnan, 1976

I

I/I

Calnan, 1979

1

I/I

Drake & Maibach, 1976

M - Males F = Females NS = Not specified in the published report *Cinnamic aldehyde not mixed with any other essential oils. +The vehicle was petrolatum except in the studies by Hjorth (vaseline) and Rudner (NS). {_Patients received multiple and simultaneous exposure to other test materials and often showed multiple positive responses.

Cinnamic aldehyde: sensitization survey

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Table 3. Cinnamic aldehyde in consumer products and in fragrance blends

Product type or fragrance blend Personal care Household Fragrance blends

In patch test mixture

In product or blend

Concn (%) of product or blend in patch-test vehicle

31 x 10 s-8 x 10 3 4 x 10-7-6 x 10 -3 4 x 10-9-2 x 10 -3

2 x 10 3-6 x 10 ~ 8 x 10-s 6 x 10 3 2 × 10-7-5 x 10 3

0.3 10 0.5 100 1 50

Concn (%) of cinnamic aldehyde

No. of sensitizations No, of tests*

Elicited

Induced

645 1519 1823

0 0 0

0 0 0

*Fragrance blends were tested by the human repeat insult patch test and the consumer products by the human repeat insult patch test or the prophetic patch test procedure.

ing and selection of the test subjects were also the same as described previously, as were the patch test procedures (Steltenkamp et al. 1980a). Reported cinnamic aldehyde concentrations were from the direct use of the material itself and did not include any amounts that might be present due to the use of natural products or specialities in which it was a constituent.

mic aldehyde induced hypersensitivity in five out of 41 test subjects, although the results were not conclusive since the reactions during challenge occurred only at the original (induction) site and not at the site of cinnamic aldehyde challenge. At a concentration of 1.25~o, cinnamic aldehyde induced hypersensitivity in five out of ten subjects. Cinnamic aldehyde did not elicit pre-existing hypersensitivity reactions in any of the 130 subjects at any of the concentrations tested.

RESULTS

Results were collected from 4117 patch tests of products or test materials containing a wide range of cinnamic aldehyde concentrations. Since some subjects participated in more than one test, it is estimated that a total of approximately 3294 different subjects were involved in the studies reported in this survey. Results were reported from tests involving 34 different product and fragrance blend formulations and also on patch tests of cinnamic aldehyde tested alone. Vehicles used in these tests included water, ethanol, petrolatum and dimethylphthalate. In some cases a finished product was applied directly to the skin. Results were reported from a total of 2164 patch tests on personal care and household products. The applied concentrations of cinnamic aldehyde ranged f r o m 4 x l0 7to8 x 10 3% (Table 3). No induced or elicited hypersensitivity reactions attributable to cinnamic aldehyde were observed in any of the 2164 tests. Results from 1823 patch tests were reported on fragrance blends that contained cinnamic aldehyde at concentrations ranging from 4 x 10 -9 to 2 X 10 3~o (Table 3). Again, no hypersensitivity reactions were induced or elicited by any of the fragrance blends tested. In human repeat insult patch tests (HRIPT), cinnamic aldehyde, tested alone using ethanol as the vehicle, failed to induce or elicit hypersensitivity at concentrations of 0.1~o (41 subjects) and 0.5~o (38 o/ subjects: Table 4). At a concentration of 1.0/o, cinnaTable 4. Hmnan sensitization survey: human repeat insult patch tests on pure cinnamic aldehyde in ethanol Cinnamic aldehyde in ethanol (%)

Elicited*

1.25 1.0 0.5 0.1

0/10 0/41 0/38 0/41

Incidence of positive reactions Induced 5/10 5",/41 0/38 0/41

*Elicited reactions are those tests that were positive at the first, second or third patch application. fThe five subjects reacted during challenge only at the original (induction) site and not at the site of primary challenge.

DISCUSSION

To assess the sensitization potential of a fragrance material, the potential of the material both to elicit pre-existing sensitization and to induce new sensitization must be considered. The magnitude of preexisting sensitization is defined by the frequency and severity of hypersensitivity reactions elicited under given conditions of exposure. Similarly, the potential for a material to cause (i.e. induce) new sensitization responses is indicated by the frequency and severity of hypersensitivity reactions induced under various conditions of exposure. Previous reports have shown that neat cinnamic aldehyde (i.e. cinnamic aldehyde not mixed with any other essential oils) will elicit reactions in diagnostic patch testing of dermatitic subjects (Calnan, 1976 & 1979; Drake & Maibach, 1976; Hjorth, 1961: Kirton & Wilkinson, 1975; Magnusson & Wilkinson, 1975: Rudner, 1977: Schorr, 1975). In the present survey, no elicited reactions indicative of pre-existing sensitization to cinnamic aldehyde occurred in 4117 tests conducted in subjects taken from the general population. The absence of elicited reactions to cinnamic aldehyde in these subjects indicates that the incidence of pre-existing sensitization to cinnamic aldehyde in the general (non-dermatitic) population is very low to non-existenC The sensitization potential of a new material is assessed by examining the ability of the material to induce hypersensitivity in prophetic patch tests. In order to make the tests more sensitive, exaggerated conditions of exposure are used, as in the Kligman maximization test (Kligman, 1966: Kligman & Epstein, 1975) and in the HRIPT (Steltenkamp et al. 1980a). Under conditions of exaggerated exposure, cinnamic aldehyde tested alone in a vehicle at concentrations ~>1.0°~oinduced hypersensitivity responses in normal volunteers. At 0.5 and 0.1'~,i, cinnamic aldehyde failed to induce hypersensitivity responses under HRIPT conditions in 38 to 41 volunteers, respectively. Using 0.51~ii cinnamic aldehyde in the maximization test (five consecutive 48-hr patch applications), Kligman (reported by Opdyke, 1979) induced hypersensitivity in one out of 25 subjects alter

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P.J. DANNEMAN el al.

one set of patch applications, and in a second subject after four s t a n d a r d sets of patch applications. Thus a d o s e - d e p e n d e n t hypersensitivity response appears io be induced by neat cinnamic aldehyde. However, tests involving such exaggerated exposure to neat cinnamic aldehyde may give misleading data regarding the sensitization potential of the materiah Results of tests on fragrance blends a n d product formulations c o n t a i n i n g cinnamic aldehyde provide data of more practical significance. The results of the present survey show that fragrance blends that contain cinnamic aldehyde at concentrations up to 0.005'(o (i.e. patch-tested at concentrations tip to 0.002";) or household or personal care products that contain cinnamic aldehyde at concentrations up to 0.6";i (i.e. patch-tested at concentrations up to 0.006!,), did not induce hypersensitivity reactions. Experimental evidence has indicated that the sensitization potential of a simple c o m p o u n d may be different from the sensitization potential of mixtures containing the c o m p o u n d (Opdyke, 1976). As shown by O p d y k e (1976 & 1979) the capacity of cinnamic aldehyde to induce hypersensitivity in m a n is diminished when it is tested as the n a t m a l (citmamon) oil and even when it is mixed (1:1, v/v) with other simple c o m p o u n d s such as cugenol and d-limonene. The absence of pre-existing sensitization to cinnamic aldehyde t b u n d in subjects in this survey suggests that there is a low probability that cinnamic aldehyde will induce hypersensitivity under normal conditions of exposure to c o n s u m e r products c o n t a i n i n g the ingredient. This conchtsion is supported by the obserwttion that no cases of induced hypersensitivity occurred in 2164 tests on c o n s u m e r products or in 1823 tests on fragrance blends which c o n t a i n e d cinnamic aldehyde. A l t h o u g h there are isolated reports of allergic stomatitis and perioral dermatitis attributed to a t o o t h p a s t e that c o n t a i n e d cinnamic aldehyde as a llavouring ingredient (Drake & Maibach, 1976: Kirton & Wilkinson, 1975: Millard, 1973), there is no p r o o f that the t o o t h p a s t e actually induced the hypersensitivity. Since cinnamic aldehyde, structurally similar cinnamyl derivatives and natural oils c o n t a i n i n g these materials are widely used in such products as oral antiseptics, chewing gum, beverages and ice cream (Collins & Mitchell, 1975), people are exposed to cinnamic aldehyde in a variety of ways. The properties of the vehicle in i m p a r t i n g a stickiness to the t o o t h p a s t e may have played a role in eliciting the gingival reactions ( M a g n u s s o n & Wilkinson, 1975). Despite the wide use of cinnamic aldehyde in m a n y types of c o n s u m e r products, the frequency of reports of clinical hypersensitivity reactions a t t r i b u t a b l e to this c o m p o u n d is low (Drake & M a i b a c h , 1976). The c o n t r a s t between the incidence of elicited reactions to cinnamic aldehyde in dermatitic patients reported m the literature and the incidence observed in non-dermatitic subjects in the current survey is striking. The incidence of elicited responses in dermatitic patients tested with neat cinnamic aldehyde ranged from 3.4",, (Rudner, 1977) to 21711 (Hjorth, 1961). A l t h o u g h the cinnamic aldehyde concentrations used in the present survey were generally lower than the c o n c e n t r a t i o n s used by the der-

matologists, the absence of elicited reactions in any of the 4117 tests reported here indicates that there may also be differences in the test populations. In the present survey, individuals k n o w n to be under treatment for skin disease at the time of testing were excluded. In contrast, in the dermatitic patient surveys and in case reports described in the lilentture, the subjects in whom reactions to cinnamic aldehyde were elicited were generally those k n o w n to bc sensitized previously to perfumes or to be under care for contact dermatitis. It may be that such dermatitic patients represent a unique segment of the popuhttion and do not provide valid data of the incidence oF hypersensitivity to a given c o m p o t t n d in the general population. The patch-test data presented here, a data base which is significantly larger than has been avaihtble before, indicate that the potential for sensitization t h r o u g h c o n s u m e r - p r o d u c t use of cinnanaic aldehyde is very low.

RFFERENCES Calnan C. D. (19761. Cinnanion dernmtitis from an omt lnent. ('o#llacl Dermalili.v 2, 167.

Calnan C. D. (1979). Unusual hydroxycitronellal pert'unae dermatitis. ('ontacl DernlatitL~ 5, 123. Collins F. W. & Mitchcll J. C. (1975). Aroma chemicals. Reference sources for perftune and flavour ingredients with special reference to cinnamic aldehyde. ('onta, v Dermaliti,s' l, 43. Drake T. E. & Maibach H. 1. (1976). Allergic contact dermatitis and stomatitis caused by a cinnamic aldehyde flavoured toothpaste. /lrch.v Derm. 112, 202. Essential Oil Association of U.S.A.. lnc (It)751 Specificatkms: Standard No. 204. [2OA, Nc~ 5ork. NY Flavouring Extract Manulhcturers' Association 11965). Survey of flavouring mgredienl usage levels. No. 2286. t'W Technol., Champa&,l 19 (2). part 2, 155. Hjorth N. (1961). Ecze,talous ,4//urg 3" to Ba/.~am~. -lI,pliud Perfumes and Flavouring Agunts. Munksgaard. ('openhagen. Kirton V. & Wilkinson D. S. (I 975). Sensitivity to cinnamic aldehyde in a toothpaste. 2. Eurther studies. (',mtacl Dermaliliv I, 77. Kligman A. M. (1966). The identilication ol contact allergens by human assay. 1II. The maxinaization l e s l . . \ procedure [br screening and rating contact sensilizers..I ire'eft. Derm. 47, 3t,~3. Kligman A. M. & Epstein W. (1975L t!pdating the maximization test for identifying contact allergens. Co,zact Dermatitis I, 231. Kohrman K. A., Booinan K. A.. Dorsk~ J.. Rothenstem A. S., Schwoeppe E. A., Sedlak R. I., Steltenkamp R..I. & Thompson G. R. (1983). Benzyl salievlatc: a stu'xe~ or consumer patch-test sensitization, lql ('lw,1. I , x i c . 21. 741. Magnusson B. & Wilkinson D. S. /1975). Cinnzunic al dehyde in toothpaste. I. Clinical aspects and patch tests. COIIICICt DermatitLv l, 70. Millard k. G. (19731. Contact sensitivit3 to Ioothpasle. Hr meal. J. I. 676. Mitchell J. C. (1975). F'atch testing x,,ith some components of balsam of Peru. Contact O{'rmaliliv l, 19I. Opdyke D. L J. (I 976). Inhibition oi" sensitization reactions induced by certain alddlydes, t:d ('o.',,,m,l. lD~icol. 14, 197.

Opdyke I). L. J. (1977). Safety testing of fragrances: problems and implications. ('fin. 7uvicol. lit I I ), 61.

Cinnamic aldehyde: sensitization survey Opdyke D. L. J. (1979), Monographs on fragrance raw materials: cinnamic aldehyde. Fd Cosmet. Toxicol. 17, 253. Rothenstein A. S., Booman K. A., Dorsky J., Kohrman K. A., Schwoeppe E. A., Sedlak R. I., Steltenkamp R, J. & 'Thompson G. R. (1983). Eugenol and clove leaf oil: a survey of consumer patch-test sensitization. Fd Chem. Toxic. 21, 727. Rudncr E. J. ( 19771. North American group results. Contact Dermalilix 3, 208. Schorr W. F. (19751. Cinnamic aldehyde allergy. Contact Dermatitis 1, 108. Steltenkamp R. J., Booman K. A., Dorsky J., King T. O., Rothcnstcin A. S.. Schwoeppe E. A., Sedlak R. I., Smith T. H. F. & Thompson G. R. (1980a). Hydroxycitronellal: a survey of consumer patch-test sensitization. Fd Cosmet. i"o.vicol. 18, 407.

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Steltenkamp R. J., Booman K. A., Dorsky J., King T. O.. Rothenstein A. S., Schwoeppe E. A., Sedlak R. I., Smith T. H. F. & Thompson G. R. (1980b). Citral: a survey of consumer patch-test sensitization. Fd Cosmet. Toxicol. 18, 413. Steltenkamp R. J., Booman K. A., Dorsky J., King T. O., Rothenstein A. S.~ Schwoeppe E. A., Sedlak R. I., Smith T. H. F. & Thompson G. R. (1980c). Cinnamic alcohol: a survey of consumer patch-lest sensitization. Fd Cosmet. Toxicol. 18, 419. Thompson G. R., Booman K. A., Dorsky J., Kohrman K. A., Rothenstein A. S., Schwoeppe E. A., Sedlak R. 1. & Steltenkamp R. J. (1983). lsoeugenol: a survey of consumer patch-test sensitization. Fd C72em. Toxic. 21, 735.