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..Detailed statistical analysis of the results indicated that the most important factor driving the induction of skin sensitization was the number of exposures...

..p-Phenylenediamine (PPD) is an important hair dye allergen, but there remains a reasonable suspicion that other hair dye chemicals may also be responsible for a proportion of the clinical burden of hair dye allergy...

..These and other examples are discussed with particular reference to the fabrication of a gold standard dataset that is required for the validation of in vitro alternatives...

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..2 +/- 0.6%. Given that EC3 values for a variety of contact allergens range over several orders of magnitude, these results further endorse the utility of EC3 values as a reliable indicator of human contact allergenic potency...

..As a consequence, this substance should not normally be regarded as, or classified as, a significant skin sensitizer...

..Consequently, in vitro or in silico alternatives which can identify the significant acute human skin irritants in this group may well represent suitable alternatives to the rabbit...

..How this can be achieved using the LLNA and employed in safety evaluation is discussed in detail, together with practical suggestions for the deployment of such processes in regulatory toxicology...

..Examples are given for substances falling into various potency groups for skin sensitization relating to results from the local lymph node assay, the guinea pig maximization test, the Buehler method and human experience...

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..Thus, recommendations can be made concerning how these considerations can be embraced by those responsible for safety evaluation and for the shaping of regulations for skin sensitizing chemicals/formulations...

..A key perspective is that no predictive test is without limitations; having a good appreciation of these limitations is necessary for making the best use of the information derived from these methods...

..In addition, it is possible that irritancy alone does not represent a complete surrogate marker for the ability of a chemical to produce danger signals relevant to the induction of skin sensitization...

..A new method, the local lymph node assay, replaces the guinea-pig as a tool for hazard identification and offers the real prospect of accurate prediction of allergen potency, the missing link in skin sensitization risk assessment...

..To explore critically the potential merits of this approach, one specific example is examined in detail...

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..These data show the importance of adherence to test guidelines and aligns the clinical experience with resorcinol with that obtained in predictive animal methods...

..It is concluded that the OECD Guideline as currently written embodies the necessary flexibility to permit conduct of the LLNA in a manner necessary to meet the varying needs of regulatory agencies and toxicologists around the world...

..These results support further the utility of EC3 determinations in the LLNA as a measure of the relative potency of a contact allergen...

..A key consideration when undertaking risk assessments should be the potential for synergy between contact allergens. Previously, this concept has only been investigated during elicitation in contact allergic individuals...

..These data underscore the need to consider vehicle effects in the context of skin-sensitization risk assessments...

..Thus, proactive use of QRA, used conservatively and in combination with expert judgment, would have limited the problem of ACD to this new preservative that is known to have caused problems on the consumer market...

..The Deductive Estimation of Risk from Existing Knowledge (DEREK) is one such expert system which is described in further detail...

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..Accordingly, the evaluation of an additional group of similar aldehydes is now underway to assess the robustness of these models, with some emphasis being based on ensuring a wider spread of chemical reactivity...

..Education for healthcare professionals could usefully be enhanced to take this on board...

..In addition to this, the need for performance standards and an agreed 'gold standard' dataset against which to validate both alternatives and new prediction models is discussed...

..Previously, a quantitative risk assessment suggested there was no risk of induction of fragrance allergy from minor residues of fragrance chemicals on washed fabrics...

..Nevertheless, where risk assessment for skin irritation was critical, then at the population level, these differences might be relevant, both for safety in use of substances and products and for skin acceptability...

..Clinically, clothing pattern dermatitis associated with fragrance allergy is almost never observed, although this could be investigated clinically by exposing sensitized individuals to the relevant fragrance allergen...

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..It is envisaged that the data from such assays will be integrated with outputs from other in vitro assays in the future to give a prediction of the sensitisation potential of novel chemicals...

..Therefore, at least for this model protein, non-covalent interactions appear not to be a key determinant of allergen potency...

..A positive stinging response on the nasolabial fold may not necessarily predict subjective responses to a product when used on other areas of the face...

..Whether such individuals are those who experience problems with skin care products remains to be addressed...

..Deriving such information is relevant to our understanding of antigen formation in the immunobiology of skin sensitisation and in the development of in vitro protein haptenation assays...

..It is important to document in the literature the outcome of historical studies that were performed to assess the risk of adverse skin effects associated with their use...

..Elicitation response characteristics to complete permanent hair dye products in paraphenylenediamine (PPD)-allergic volunteers have not previously been explored in detail...

..Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK)...

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..g. 0.01 ng/m(3)) are commonly associated with other types of safe exposure. Consumer limits typically will lie between these values and depend on the actual exposure associated with product use...

..As a result, risk assessment for contact of protein with skin must take into account potential barrier impairment and thus the possibility of both the induction and the elicitation of allergic skin reactions...

..The use of proteomics has identified a number of proteins which could be used as general markers for skin irritation and which may in particular be of value for the development of in vitro predictive models...

..However, its proper use and interpretation are necessary if those consumers most at risk are to have the information necessary to avoid serious adverse reactions to hair dyes...

..However, for the very large majority of HRIPTs conducted concerning the risk of skin sensitization, there is neither scientific justification nor any other merit...

..p.m. Then, where consumer products meet this guideline fully, modern quantitative risk assessment shows clearly that elicitation of ACD is highly improbable, and the chance of the induction of sensitization is even lower...

..Both possibilities are consistent with what is understood of the chemistry and composition of commercially available linalool...

..Consequently, it is concluded that there is no scientific justification for removing the option to use a 4-animal version of the LLNA...

..However, a detailed evaluation will be necessary to provide reassurance that a reduction in group size would provide adequate sensitivity across a range of skin sensitization potencies...

..In addition to accurately identifying skin sensitizers, the LLNA can also provide a reliable measure of relative sensitization potency, information that is pivotal to the successful management of human health risks...

..It is hoped that this dataset will accelerate the development, evaluation and eventual validation of new approaches to skin-sensitization testing...

..Results of LLNA studies have been interpreted in the context of historical clinical data on occupational allergic contact dermatitis associated with exposure to MMA...

..The purpose of this brief review article is to consider the approaches available and to highlight key procedural issues...

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..06%), Disperse Blue 3 (1.56%) and Disperse Red 11 (2.13%). We interpreted the simultaneous patch test reactions to PPD and DO3 as due either to cross-sensitivity proper, or to metabolic conversion of textile dyes in the skin to PPD...

..This observation is the basis for the hypothesis concerning cross-reactivity and the effect of simultaneous exposure. The study found that fragrance allergy could be a common problem in patients with eczema on the hands...

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..Such knowledge can then be used in order that effective and appropriate in vitro/in silico tools for predicting sensitization potential, with a high confidence, can be developed...

..Existing data on formaldehyde may conflict with this theory, though this could be explained by allergen specificity. We propose that further work in this area is needed...

..Hence, intermittent exposure to lower concentrations of PPD may be equivalent to higher concentration, one-off exposure...

..This paper reports information that was presented during the Workshop...

..This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed...

..Judicious use of this approach for extrapolating EC3 values can provide information on a likely potency classification for use in risk assessment and may avoid the need for repeat animal testing...

..An alternative explanation may be the increasing use of permanent hair dyes...

..This article seeks to consider skin sensitization and ACD in holistic fashion, bridging experimental observations with clinical disease and basic mechanisms with practical toxicology...

..Collectively, these studies show that pPD, but not BB, selectively activates human dendritic cells in vitro...

..The outcomes from this collaboration demonstrate the importance of updating and refining computer models for the prediction of skin sensitization as new information from experimental and theoretical studies becomes available...

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..It is concluded that a rLLNA with two mice/group would display decreased sensitivity and is inappropriate for use in hazard identification...

..This paper provides an overview of each of these areas with an evaluation of the available scientific database to support an uncertainty factor in the range of 1-10 for each area...

..Further risk factors included leg dermatitis and old age. The frequency of sensitization remains low. It is very unlikely that exposure to cosmetics or personal care products may have played a role in the few cases sensitized...