Registration Dossier

Administrative data

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
Skin sensitization is referred to as allergic contact dermatitis (ACD) in a clinical setting. This is a cell mediated type IV delayed hypersensitivity. The cellular mechanisms involved with ACD have been reviewed (1, 2). To behave as a skin sensitizer, a substance must first penetrate the stratum corneum, partition into the epidermis and react there with proteins, probably on the surface of the Langerhans cells, to form a hapten-carrier conjugate. The skin sensitization potential of enzymes has been reviewed in several publications indicating that enzymes should not be considered skin sensitizers. (3-7; 13, 14). In addition, there is an unequivocal statement from AMFEP (www.amfep.org) on this topic indicating that enzymes do not have skin sensitizing potential. The lack of skin sensitizing potential is substantiated by evidence from robust human experimental data and extensive in-use human studies performed with detergents containing enzymes (ref. 8-12; 14 -19). Together, these studies confirm that the presence of enzymes in the detergents doesn’t result in ACD, including those conducted with atopic individuals.

After review of the available evidence, it can be concluded that enzymes should not be classified as skin sensitizers according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. This conclusion is based on the following considerations:

1. The results of predictive testing in man demonstrate that enzymes do not have significant skin sensitization potential.

2. In a clinical setting, enzymes have only very rarely been suggested as a possible cause of allergic contact dermatitis. Even in these few cases, a causal relationship has never been proven. More commonly clinical studies have demonstrated that enzymes are not a cause of ACD.

3. ACD has never been reported where there has been extensive occupational enzyme exposure in the detergent enzyme industries which, in the past, has led to respiratory sensitization and/or irritant dermatitis.

4. A few cases of contact dermatitis had occurred in occupational settings in response to irritating enzyme preparations (e.g. proteases), but this is a non-immunologic phenomenon (also known as irritant contact dermatitis) unrelated to allergic contact hypersensitivity, which is a cell mediated delayed type hypersensitivity.

5. Contact urticaria has been reported in occupational settings but this is also a non-immunologic event or antibody mediated type I hypersensitivity; Contact urticaria (also known as protein contact dermatitis) is unrelated to allergic contact hypersensitivity, which is a cell-mediated delayed type hypersensitivity.

6. Over a 45-year period, billions of consumers have had skin exposure to enzymes but there is no evidence that this exposure has given rise to skin sensitization.


References

1. Kimber, I. (1994), Cytokines and regulation of allergic sensitization to chemicals, Toxicology, 93:1-11.

2. Scheper, R.J., and B. M.E. von Blomberg (1992), Cellular mechanisms in allergic contact dermatitis, in Textbook of Contact Dermatitis, R. J.G. Rycroft, T. Menne, P.J. Frosch, and C. Benezra, Eds., Springer-Verlag, Berlin, p. 11-27.

3. Association Internationale de la Savonnerie et de la Detergence (AISE)/AMFEP, Enzymes: Lack of skin sensitisation potential. 1995.

4. Basketter DA, English JS, Wakelin SH, White IR. (2008) Enzymes, detergents and skin: facts and fantasies. Br.J.Dermatol. 158(6):1177-81.
5. Basketter, N. Berg, C. Broekhuizen, M. Fieldsend, S. Kirkwood, C. Kluin, S. Mathieu, C.Rodriguez. (2012). Enzymes in cleaning products: An overview of toxicological properties and risk assessment/management. Regulatory Toxicology and Pharmacology 64:117-123.

6. HERA Human and environmental risk assessment on ingredients of household cleaning products -alpha-amylases, cellulases and lipases. 2005.

7. HERA Human and environmental risk assessment on ingredients of household cleaning products - Subtilisins (Proteases). Edition 2.0. 2007.

8. Bannan,E.A., Griffith,J.F., Nusair,T.L., and L.J.Sauers (1983) Skin testing of laundered fabrics in the dermal safety assessment of enzyme containing detergents. Journal of Toxicology - Cutaneous and Ocular Toxicology 11, 327-339.

9. Griffith,J.F., Weaver,J.E., Whitehouse,H.S., Poole,R.L., and Newmann EANixon,G.A. (1969) Safety Evaluation of Enzyme Detergents Oral and Cutaneous Toxicity, Irritancy and Skin Sensitization Studies. Food and Cosmetics Toxicology 7, 581-593.

10. Rodriguez,C., Calvin,G., Lally,C., and LaChapelle,J.M. (1994) Skin effects associated with wearing fabrics washed with commercial laundry detergents. Journal of Toxicology - Cutaneous and Ocular Toxicology 13, 39-45.

11. Cormier,E.M., Sarlo,K., Scott,L.A., MacKenzie,D.P., Payne,N.S., Carr,G.J., Smith,L.A., Cua-Lim,F., Bunag,F.C., and Vasunia,K. (2004) Lack of type 1 sensitization to laundry detergent enzymes among consumers in the Philippines: results of a 2-year study in atopic subjects. Annals of Allergy Asthma and Immunology 92, 549-557.

12. White,I.R., Lewis,J., and el,A.A. (1985) Possible adverse reactions to an enzyme-containing washing powder. Contact Dermatitis 13, 175-179.

13. Basketter D.; N. Berg; F. Kruszewski; K. Sarlo; B. Concoby. The Toxicology and Immunology of Detergent Enzymes. 2012b. J. Immunotox., 9, 320-326.

14. Andersen,P.H., Bindslev-Jensen,C., Mosbech,H., Zachariae,H., and Andersen,K.E. (1998) Skin symptoms in patients with atopic dermatitis using enzyme-containing detergents. A placebo-controlled study. Acta dermato-venereologica 78, 60-62.

15. Belsito,D.V., Fransway,A.F., Fowler,J.F., Jr., Sherertz,E.F., Maibach,H.I., Mark,J.G., Jr., Mathias,C.G., Rietschel,R.L., Storrs,F.J., and Nethercott,J.R. (2002) Allergic contact dermatitis to detergents: a multicenter study to assess prevalence. Journal of the American Academy of Dermatology 46, 200-206.

16. Lee,M.Y., Park,K.S., Hayashi,C., Lim,H.H., Lee,K.H., Kwak,I., and Laurie,R.D. (2002) Effects of repeated short-term skin contact with proteolytic enzymes. Contact Dermatitis 46, 75-80.

17. Pepys,J., Wells,I.D., D'souza,M.F., and Greenberg,M. (1973) Clinical and Immunological Responses to Enzymes of Bacillus Subtilis in Factory Workers and Consumers. Clinical Allergy 3, 143-160.

18. Peters,G., Johnson,G.Q., and Golembiewski,A. (2001) Safe use of detergent enzymes in the workplace. Appl.Occup Environ.Hyg. 16, 389-395.

19. Zachariae,H., Thomsen,K., and Rasmussen,O.G. (1973) Occupational enzyme dermatitis. Results of patch testing with Alcalase. Acta dermato-venereologica 53, 145-148

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion