Skin-sensitisation

These regulations came into force in Europe in March 2005 for any cosmetic product leaving the manufacturer s premises. 

Amyl cinnamic alcohol [Amyl cinnamyl alcohol] 

Benzyl alcohol Benzyl benzoate Benzyl cinnamate Benzyl salicylate Cinnamic aldehyde [Cinnamal] 

Citral Citronellol Coumarin Eugenol Farnesol Geraniol Hexyl cinnamaldehyde [Hexyl cinnamal] 

Methyl ionone alpha iso [Alpha-isomethyl ionone] 

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The glycidyl adducts are skin irritants similar in behaviour in this respeet to the parent amines. The skin sensitisation effects in the primary aliphatic amine may be reduced by addition of groups at the nitrogen atom. The hydroxyethyl group and its alkyl and aryl derivatives are the most effective found so far. 

Both ethylene and propylene oxide have been used in the preparation of adducts from a variety of amines, including ethylene diamine and diethylene triamine. The latter amine provides adducts which appetu" free of skin sensitising effects. 

It is thus seen that as a class the primarily aliphatic amines provide fast-curing hardeners for use at room temperatures. With certain exceptions they are skin sensitisers. The chemical resistance of the hardened resins varies according to the hardener used but in the case of the unmodified amines is quite good. The hardened resins have quite low heat distortion temperatures and except with diethylenetriamine seldom exceed 100°C. The number of variations in the properties obtainable may be increased by using blends of hardeners. 

Barratt MD. The role of structure-activity relationships and expert systems in alternative strategies for the determination of skin sensitisation, skin corrosivity and eye irritation. ATLA 1995 23 111-22. 

Although these are all used across Europe, the hierarchy of these has altered slightly due to the influences of environmental legislation. For example, Chloro-isothiazolone has been identified as a skin sensitiser and hence therefore lost its number one position as a controlling agent. New actives such as the Octyl - isothiazolone have recently been introduced as a more stable molecule where it is hoped that lower levels can be used reducing environmental and human safety aspects. 

Lower skin sensitisation potential Long lasting efficacy... 

It does have a number of draw backs. It has poor thermal stability (a property common to most formaldehyde release biocides) and, in some instances, may cause blackening of metalworking fluid concentrates if heated above 50°C for a period of time. Recently, this active ingredient was placed on Annex 1 of the Dangerous Substances Directive having been identified as a potential skin sensitiser. This means that formulations containing efficacious levels of this class of triazine in them would have to be labelled with R43 - may cause sensitisation by skin contact. This is unacceptable to many UK customers. As this material is only bactericidal, it needs to be co-formulated with a fungicide to provide complete protection for a product. 

PCMC has been placed on Annex 1 of the Dangerous Substances Directive having been identified as a potential skin sensitiser. 

Incompatibility with fluid formulations is one disadvantage of this chemistry, another is its potential to induce skin sensitisation. Benzisothiazolinone, (see Figure 6) is a chemically more stable isothiazolinone. This material can be incorporated into most metalworking fluid concentrates, over coming the stability problems seen with other isothiazolinones. However, this higher stability is reflected in higher in-use levels required to control micro-organisms. Typical in-use levels are between. ... 

METHYLCHLORO- ISOTHIAZOLINONE Broad spectrum of activity Skin sensitiser... 

OECD Guideline for the Testing of Chemicals 429 Skin Sensitisation Local Lymph Node Assay. Adopted April 24, 2002). 

European Centre for Ecotoxicology and Toxicology of Chemicals, Skin Sensitisation Testing, Mono. No. 14, Brussels, 1990. 

Organisation of Economic Cooperation and Development, OECD Guideline for Testing of Chemicals Skin Sensitisation, No. 406, Paris, 1992. 

Organisation of Economic Cooperation and Development, Skin Sensitisation Testing Methodological Considerations, Tech. Rep. No. 78, Paris, 1999. 

Casati, S., et al., Dendritic cells as a tool for the predictive identification of skin sensitisation hazard, Altem. LabAnim., 33, 47, 2005. 

Basketter, D.A., Gerberick, G.F., and Kimber, I., Skin sensitisation, vehicle effects and, the local lymph node assay. Food Chem. Toxicol., 39, 621, 2001. 

In order to facilitate satisfactory dye uptake, the molecular size of a disperse dye must be kept small monoazo structures are therefore exceptionally important, particularly in the coloration of polyester and cellulose triacetate. In the yellow shade area, molecular size generally poses no problem and the various available coupling components can all be used without making the molecule too large. A very simple example of the type of structure employed using a phenolic coupling component is Cl Disperse Yellow 3 (4-72). This dye is known to cause skin sensitisation when on nylon [85] and can also provoke an allergic reaction [86]. 

Dyes for cellulose acetate are relatively simple molecules, typified by Cl Disperse Red 15 (6.39 X = OH), Cl Disperse Violet 4 (6.39 X = NHCH3) and Cl Disperse Blue 3 (6.40), the last-named being manufactured from leucoquinizarin and the appropriate amines. The unsymmetrically substituted product inevitably contains significant amounts of the related symmetrical compounds. The widely used Cl Disperse Blue 3 is known to cause skin sensitisation when on nylon [17] and can also provoke an allergic reaction [18]. Bright red 2-alkoxy-l-amino-4-hydroxyanthraquinones, such as Cl Disperse Red 4 (6.41), can be obtained from l-amino-2,4-dibromoanthraquinone by hydrolysis to give l-amino-2-bromo-4-hydroxyanthraquinone (Cl Disperse Violet 17), which is then condensed with the appropriate alcohol. 

Skin sensitisation evaluation or local lymph node assay... 

The only in vitro studies fully validated and included in the EU test methods (a.2) are for skin corrosivity and phototoxicity, but efforts are underway to speed up validation for other endpoints. An original aim was that there would be no animal studies for the basic level of registration, but as there is currently no suitable in vitro test for skin sensitisation, the mouse local lymph node assay is included in Annex V of the Regulation (Table 9). The in vitro tests for skin and eye irritation are not fully validated, so as a compromise they are accepted for registration at up to 10 tonnes per annum (i.e., they are in Annex V), but if the results are negative they have to be confirmed by a standard animal test at 10 tonnes per annum (i.e., the Annex VI data, as shown in Table 10). 

Skin Sensitisation (Updated Guideline, adopted 17 July 1992)... 

ECETOC. 2000. Skin sensitisation testing for the purpose of hazard identification and risk assessment. ECETOC Monograph No. 29. Brussels ECETOC. 

Recent guidelines entitled Non-clinical Local Tolerance Testing of Medicinal Product from the CPMP refer to the murine local l)unph node assay as a method for the assessment of the induction phase of skin sensitisation. This method measures the ability of compoimds to induce proliferative responses in skin-draining lymph nodes. This method uses fewer animals than alternative in vivo methods and reduces the trauma to which animals are potentially subjected. ... 

Kimber I. Skin sensitisation immunological mechanisms and novel approaches to predictive testing. In Balls M, Van Zeller A-M, Haider M, eds. Proceedings of the Third World Congress on Alternatives and... 

Roberts, D.W, Aptula, A.O., Cronin, M.T., Hulzebos, E. and Padewicz, G. (2007) Global (Q)SARs for skin sensitisation assessment against OECD principles. SAR and QSAR in Environmental Research, 18, 343-365. 

Jowsey, I.R., Basketter, D.A., Westmoreland, C. and Kimber, 1. (2006) A future approach to measuring relative skin sensitising potency a proposal. Journal of Applied Toxicology, 26, 341—350. 

Roberts, D.W. and Aptula, A.O. (2008) Determinants of skin sensitisation potential. Journal ojApplied Toxicology,... 

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