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PubMed2006

Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.

There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.

Animals↗

PubMed2006

Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the schiff base applicability domain for skin sensitization.

Several recent (1999 onward) publications on skin sensitization to aldehydes and ketones, which can sensitize by covalent binding to skin protein via Schiff base formation, present QSARs based on the Taft sigma parameter to model reactivity and log P to model hydrophobicity. Here, all of the data are reanalyzed together in a stepwise self-consistent way using the parameters log P (octanol/water) and Sigmasigma, the latter being the sum of Taft sigma values for the two groups R and R' in RCOR'. A QSAR is derived: pEC3 = 1.12(+/-0.07) Sigmasigma + 0.42(+/-0.04) log P - 0.62(+/-0.13); n = 16 R(2) = 0.952 R(2)(adj) = 0.945 s = 0.12 F = 129.6, based on mouse local lymph node assay (LLNA) data for 11 aliphatic aldehydes, 1 alpha-ketoester and 4 alpha,beta-diketones. In developing this QSAR, an initial regression equation for a training set of 10 aldehydes was found to predict a test set consisting of the other 6 compounds. The QSAR is found to be well predictive for LLNA data on a series of alpha,gamma-diketones and also correctly predicts the nonsensitizing properties of simple dialkylketones. It is shown to meet all of the criteria of the OECD principles for applicability within regulatory practice. In view of the structural diversity within the sets of compounds considered here, the present findings confirm the view that within the mechanistic applicability domain the differences in sensitization potential are dependent solely on differences in chemical reactivity and partitioning.

Benzaldehydes↗

PubMed1997

Skin sensitization to eugenol and isoeugenol in mice: possible metabolic pathways involving ortho-quinone and quinone methide intermediates.

With the aim of providing further mechanistic insights into the mode of action of eugenol (4-allyl-2-methoxyphenol) and isoeugenol (4-propenyl-2-methoxyphenol), we have synthesized two series of modified compounds which were tested in the mouse local lymph node assay for their skin sensitizing potential. The replacement of the methoxy group by an isopropoxy group led to a complete loss of sensitization for the eugenol derivative 6a, while no significant effect was observed for the isoeugenol derivative 6b. In the eugenol series, when methyl groups were present in the 3-, 5-, or 6-position a significant reduction in sensitization potential was observed while in the isoeugenol series only methyl substitution in the 3- and 5-position had a discernable effect. Introduction of three methyl groups on the aromatic ring of eugenol (3,5,6-trimethyl-4-allyl-2-methoxyphenol, 7) and of a tert-butyl substituent at the gamma-position of the alkyl chain of isoeugenol (4-[3',3',3'-trimethylpropenyl]-2-methoxyphenol, 8) led to a strong decrease of the sensitizing capacity. Our findings indicate that, at least in the mouse, eugenol could sensitize via a demethylation pathway followed by oxidation to the o-quinone which could act directly as a hapten even if we cannot exclude a reaction via its tautomeric p-quinone methide. Isoeugenol, on the other hand, could act via a mechanism not involving demethylation and for which the evidence is consistent with a direct oxidation to the p-quinone methide.

Animals↗

PubMed1997

Skin sensitization to linalyl hydroperoxide: support for radical intermediates.

In order to better understand the skin sensitization mechanism of allylic hydroperoxides, linalyl hydroperoxide (1) and several of its potential rearrangement products-epoxylinalool (2), epoxynerol (3), epoxygeraniol (4), and furan (5) and pyran (6) derivatives-were synthesized. The sensitizing properties of these molecules have been screened on mice using the local lymph node assay (LLNA) and further evaluated on guinea pigs using the Freund's complete adjuvant test (FCAT). Linalyl hydroperoxide (1) and linalyl epoxide (2) were found to be sensitizers, while the other compounds were classified as mild sensitizers or nonsensitizers. In the guinea pigs, no cross-reactions were observed between skin sensitizers 1 and 2. Radical-trapping experiments were carried out on linalyl hydroperoxide (1) using TTBP as trapping agent and Fe(3+)-TPP as radical inducer. The major reaction taking place is the formation of a furan ring by intramolecular reaction of the oxygen-centered radical with the isoprenyl double bond with the formation of a tertiary radical. Reaction of this intermediate with radicals derived from TTBP gave compounds 10a,b in 25% yield. The second important reaction, accounting for 14%, is taking place on the allylic double bond with the formation of a less stable primary radical which is not trapped by a TTBP-derived radical but by a hydroxy radical to give a mixture of epoxides 3 and 4. These results are in favor of the formation of a carbon-centered reactive radical as intermediate in the skin sensitization to linalyl hydroperoxide.

Animals↗

PubMed2002

Investigation of the skin sensitizing activity of linalool.

An increasing range of chemicals appears to be capable of causing skin sensitization as a result of their capacity to undergo air oxidation (autoxidation) with the consequent formation of reactive species such as epoxides and hydroperoxides. In this small investigation, the ability of linalool, a common fragrance ingredient, to cause such effects was quantified using the local lymph node assay before and after careful purification by vacuum distillation. The commercially available grade of linalool (97% purity) was shown to be a weak skin sensitizer. Various impurities, including linalool oxide, dihydrolinalool, epoxylinalool, 3-hexenyl butyrate and 3,7-dimethyl-1,7-octadiene-3,6-diol were identified and were completely removed (except for the dihydrolinalool remaining at 1.4%) and the re-purified linalool retested. Neither linalool or dihydrolinalool are protein-reactive compounds. The sensitization potency of the re-purified linalool sample was considerably reduced, but not entirely eliminated, suggesting either that an allergenic impurity could be very quickly reformed by mechanisms of activation or that certain potent undetectable allergens remained. Both possibilities are consistent with what is understood of the chemistry and composition of commercially available linalool.

Acyclic Monoterpenes↗

PubMed2002

Structure-activity relationships for selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals, a proportion of them providing not only desirable aroma characteristics, but also being associated with adverse effects, notably the ability to cause allergic reactions in the skin. However, efforts to find substitute materials are hampered by the need to undertake animal testing to evaluate both the presence and the degree of skin sensitization hazard. One potential route to avoid such testing is to understand the relationships between chemical structure and skin sensitization. In the present work we have evaluated two groups of fragrance chemicals, saturated aldehydes (aryl substituted and aliphatic aldehydes) and alpha,beta-unsaturated aldehydes. Data on their skin sensitization potency defined using the local lymph node assay has been evaluated in relation to their physicochemical properties. The initial outcome has been consistent with the concept that alpha,beta-unsaturated aldehydes react largely via Michael addition, whilst the group of saturated aldehydes form Schiff bases with proteins. Simple models of chemical reactivity based on these mechanisms suggest that it may be possible to predict allergenic potency. 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.

Aldehydes↗

PubMed2000

A skin sensitization risk assessment approach for evaluation of new ingredients and products.

Skin sensitization risk assessment of new ingredients or products is critical before their introduction into the marketplace. The risk assessment process described in this article involves evaluation of skin sensitization hazard, consideration of all potential human exposures, comparative ingredient/product benchmarking, and, when appropriate, the management of the risk. In this article, a risk assessment process is reviewed along with a description of the risk assessment tools that are employed for evaluating a new ingredient or product. The basic process we use for evaluating the skin sensitization risk of a new product or ingredient is considered a no effect/safety factor approach. The tools used for conducting a risk assessment include structure activity relationship analysis, exposure assessment, preclinical testing (e.g., local lymph node assay [LNNA]) and clinical testing (e.g., human repeat insult patch testing [HRIPT]). The skin sensitization risk assessment process described in this paper has been used successfully for many years for the safe introduction of new products into the marketplace. This process is dynamic--it can be applied to a diversity of product categories (e.g., shampoo, transdermal drug). In summary, the skin sensitization risk assessment process described in this article allows one to carefully assess the skin sensitization potential of a new ingredient or product so that it can be safely introduced into the marketplace.

Allergens↗

PubMed2002

Mechanism based structure-activity relationships for skin sensitisation--the carbonyl group domain.

The biological activity of skin-sensitising chemicals is related to their ability to react either directly or after metabolic activity with appropriate skin proteins. For direct-acting electrophilic compounds, this ability can be modelled by the Relative Alkylation Index (RAI) by a combination of electrophilicity and hydrophobicity parameters. Several SARs based on this approach are reported. In this present work, electrophilicity parameters based on Taft substituent constants are used together with Leo and Hansch log P fragment values to calculate RAI values for hard electrophiles having a reactive carbonyl group. These are then applied to analysis of sensitisation data obtained in the murine Local Lymph Node Assay (LLNA) for two series of diketones as well as a homologous series of alpha, beta-unsaturated aldehydes. The sensitisation potentials of these reactive electrophiles show good correlations with the RAI. These findings re-affirm the view that physicochemical parameters are the key to eliciting the relationship between chemical structure and a toxic endpoint. They provide further evidence of the value of SAR studies in identifying mechanisms of sensitisation and aiding risk assessments without the need for extensive animal testing.

Aldehydes↗

PubMed2005

Final report on the safety assessment of potassium silicate, sodium metasilicate, and sodium silicate.

Potassium Silicate, Sodium Metasilicate, and Sodium Silicate combine metal cations with silica to form inorganic salts used as corrosion inhibitors in cosmetics. Sodium Metasilicate also functions as a chelating agent and Sodium Silicate as a buffering and pH adjuster. Sodium Metasilicate is currently used in 168 formulations at concentrations ranging from 13% to 18%. Sodium Silicate is currently used in 24 formulations at concentrations ranging from 0.3% to 55%. Potassium Silicate and Sodium Silicate have been reported as being used in industrial cleaners and detergents. Sodium Metasilicate is a GRAS (generally regarded as safe) food ingredient. Aqueous solutions of Sodium Silicate species are a part of a chemical continuum of silicates based on an equilibrium of alkali, water, and silica. pH determines the solubility of silica and, together with concentration, determines the degree of polymerization. Sodium Silicate administered orally is readily absorbed from the alimentary canal and excreted in the urine. The toxicity of these silicates has been related to the molar ratio of SiO2/Na2O and the concentration being used. The Sodium Metasilicate acute oral LD50 ranged from 847 mg/kg in male rats to 1349.3 mg/kg in female rats and from 770 mg/kg in female mice to 820 mg/kg in male mice. Gross lesions of variable severity were found in the oral cavity, pharynx, esophagus, stomach, larynx, lungs, and kidneys of dogs receiving 0.25 g/kg or more of a commercial detergent containing Sodium Metasilicate; similar lesions were also seen in pigs administered the same detergent and dose. Male rats orally administered 464 mg/kg of a 20% solution containing either 2.0 or 2.4 to 1.0 ratio of sodium oxide showed no signs of toxicity, whereas doses of 1000 and 2150 mg/kg produced gasping, dypsnea, and acute depression. Dogs fed 2.4 g/kg/day of Sodium Silicate for 4 weeks had gross renal lesions but no impairment of renal function. Dermal irritation of Potassium Silicate, Sodium Metasilicate, and Sodium Silicate ranged from negligible to severe, depending on the species tested and the molar ratio and concentration tested. Sodium Metasilicate was negative in the local lymph node assay (LLNA), but a delayed-type hypersensitivity response was observed in mice. Potassium Silicate was nonirritating in two acute eye irritation studies in rabbits. Sodium Metasilicate (42.4% H2O) was corrosive to the rabbit eye. Sodium Silicate was a severe eye irritant in some eye irritation studies, but was irritating or nonirritating in others. A skin freshener containing Sodium Silicate was nonirritating. Sodium Metasilicate was nonmutagenic in bacterial cells. Rats given Sodium Silicate (600 and 1200 ppm of added silica) in the drinking water in reproductive studies produced a reduced number of offspring: to 67% of controls at 600 ppm and to 80% of controls at 1200 ppm. Three adult rats injected intratesticularly and subcutaneously with 0.8 mM/kg of Sodium Silicate showed no morphological changes in the testes and no effect on the residual spermatozoa in the ductus deferens. Sodium Metasilicate (37% in a detergent) mixed with water was a severe skin irritant when tested on intact and abraded human skin, but 6%, 7%, and 13% Sodium Silicate were negligible skin irritants to intact and abraded human skin. Sodium Silicate (10% of a 40% aqueous solution) was negative in a repeat-insult predictive patch test in humans. The same aqueous solution of Sodium Silicate was considered a mild irritant under normal use conditions in a study of cumulative irritant properties. The Cosmetic Ingredient Review (CIR) Expert Panel recognized the irritation potential of these ingredients, especially in leave-on products. However, because these ingredients have limited dermal absorption and Sodium Metasilicate is a GRAS direct food substance, the Panel deemed the ingredients safe for use in cosmetic products in the practices of use and concentration described in this safety assessment, when formulated to avoid irritation.

Animals↗

PubMed2004

Inhibition of mast cell-dependent allergy reaction by extract of black cohosh (Cimicifuga racemosa).

Black cohosh (Cimicifuga racemosa) has been used as therapeutics for pain and inflammation in Korean folk medicine. The potential effects of black cohosh extract (BCE) on mast cell-dependent allergy reaction, however, have not been well elucidated yet. In the present study, we investigated the effect of BCE on the allergy reaction using mast cell-dependent in vivo and in vitro models. BCE showed no potential of skin sensitization in local lymph node assay (LLNA). The oral administration of BCE significantly inhibited the anti-IgE-induced passive cutaneous anaphylaxis (PCA) reaction. BCE also showed inhibitory potential on the compound 48/80-induced histamine release from rat peritoneal mast cells. In addition, BCE inhibited the IL-4, IL-5 and TNF-alpha mRNA induction by PMA and A23187 in human leukemia mast cells, HMC-1. These results demonstrated that BCE has an anti-allergic potential and it may be due to the inhibition of histamine release and cytokine gene expression in the mast cells.

Animals↗

PubMed2006

Aniline--a 'historical' contact allergen? Current data from the IVDK and review of the literature.

OBJECTIVES: To assess whether aniline should be regarded as potential cause of contact allergy (CA). METHODS: Retrospective analysis of clinical data collected in a CA surveillance network (IVDK, www.ivdk.org) between 01/1992 and 06/2004 and review of pertinent literature. RESULTS: In the above period, 25 of the 1119 patients patch tested with aniline had positive (allergic) reactions; in 24 of these 25 patients, CA to p-phenylenediamine, p-aminoazobenzene or (in one case) another para-amino compound was additionally diagnosed. Exposure to aniline could not be ascertained in any of the cases, based on the available data. DISCUSSION: Previous clinical results, which have been summarized and tabulated, are partly difficult to evaluate, as they may lack detail, or test concentrations are higher than those currently recommended, possibly yielding false-positive reactions. In none of the studies had previous exposures to aniline been unequivocally identified. CONCLUSION: Based on clinical data it is unlikely that aniline is an independent sensitizer of current importance. However, it may elicit allergic reactions in subjects pre-sensitized to para-substituted amino compounds. In summary, supported by recent experimental evidence employing the local lymph node assay as a validated animal test system, it appears probable that aniline is a weak allergen.

Adult↗

PubMed2003

Dermal exposure to 3-amino-5-mercapto-1,2,4-triazole (AMT) induces sensitization and airway hyperreactivity in BALB/c mice.

A cluster of occupational asthma (OA) cases associated with occupational exposure to 3-amino-5-mercapto-1,2,4-triazole (AMT) and N-(2,6-difluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide (DE498) in a herbicide producing plant was previously reported by the National Institute for Occupational Safety and Health. Due to the limited toxicological data available for these chemicals, murine studies were undertaken to evaluate the toxicity and sensitization potential of these two agents. No signs of systemic toxicity as evaluated by body and selected organ weights or irritancy were observed following dermal exposure to concentrations up to 25% (w/v) AMT in BALB/c mice. DE498 tested negative for sensitization potential in both the TOPKAT QSAR model and in vivo in the Local Lymph Node Assay (LLNA), while AMT tested positive in both TOPKAT QSAR and the LLNA. Evaluation of the potential for AMT to induce contact hypersensitivity using the MEST yielded negative results. Cytokine evaluation and phenotypic analysis of draining lymph node (DLN) cells demonstrated an increase in IL-4 and IgE+B220+ cells 4 and 10 days post initial exposure, respectively. Following dermal exposure 7 days a week for 35 days, animals exposed to up to 25% AMT demonstrated a dose-dependent elevation in total serum IgE and an increase in airway hyperreactivity upon methacholine challenge. Following intratracheal challenge with AMT, pulmonary histopathology revealed a dose-dependent suppurative and histiocytic alveolitis in these animals. These studies indicate that DE498 does not induce sensitization following dermal exposure; however, AMT was identified as a sensitizer with the potential to induce airway hyperreactivity.

Administration, Cutaneous↗

PubMed2005

Interactions of contact allergens with dendritic cells: opportunities and challenges for the development of novel approaches to hazard assessment.

The identification of potential skin sensitizing chemicals is a key step in the overall skin safety risk assessment process. Traditionally, predictive testing has been conducted in guinea pigs. More recently, the murine local lymph node assay (LLNA) has become the preferred test method for assessing skin sensitization potential. However, even with the significant animal welfare benefits provided by the LLNA, there is a need to develop non-animal test methods for skin sensitization. Mechanistic understanding of allergic contact dermatitis has increased substantially in recent years. For example, a number of changes are known to occur in epidermal Langerhans cells, the principal antigen-presenting dendritic cell in the skin, as a result of exposure to chemical allergens, including the internalization of surface major histocompatibility complex (MHC) class II molecules via endocytosis, the induction of tyrosine phosphorylation, the modulation of cell surface markers, and cytokine expression. The application of this knowledge to the design of predictive in vitro alternative tests provides both unique opportunities and challenges. In this review, we have focused specifically on the impact of chemical exposure on dendritic cells and the potential use of that information in the development of cell-based assays for assessing skin sensitization potential of chemicals in vitro.

Allergens↗

PubMed2005

Clinical update on contact allergy.

PURPOSE OF REVIEW: The aim of this article is to review recent findings in contact allergy, regarding clinical research. RECENT FINDINGS: The biocide methyldibromo glutaronitrile was identified to be an important sensitizer. Subsequently, it was banned from leave-on cosmetics in the European Union. Another group of important allergens that have been studied extensively included the fragrances oak moss absolute, isoeugenol, hydroxyisohexyl 3-cyclohexene carboxaldehyde and farnesol. A new fragrance mix II has been developed for standard testing, which includes the two latter compounds. Dose response studies have demonstrated broad individual variation of elicitation thresholds, dependent on the allergen concentration during induction, and other factors. Some unsuspected routes of exposure to allergens include oral, inhalational, connubial or airborne contact. Experimental studies provide a classification of newly introduced chemicals; increasingly, the local lymph node assay is supplementing and potentially replacing the guinea pig maximization test. Recent advances in occupational contact allergy include, for example, some attempts to improve diagnostics for epoxy resin and other plastic, glue, and cutting fluid components. SUMMARY: Constant awareness for new allergens, confirmed by critical evaluation, standardization of patch test materials, and the identification of temporal patterns and subgroups at risk will improve both the diagnosis and prevention of allergic contact dermatitis.

Allergens↗

PubMed2004

Characterization of the sensitizing potential of chemicals by in vitro analysis of dendritic cell activation and skin penetration.

Development of in vitro models to identify sensitizing chemicals receives public interest since animal testing should be avoided whenever possible. In this article we analyze two essential properties of sensitizing chemicals: skin penetration and dendritic cell (DC) activation. Activation of immature DC derived from peripheral blood monocytes was evaluated by flow cytometric analysis of CD86 positive cells and quantitative measurement of interleukin-1beta and aquaporin P3 gene expression. The sensitizer 2,4,6-trinitrobenzenesulfonic acid induced a concentration-dependent response for all parameters, whereas the irritant sodium lauryl sulfate did not. When two related aromatic amines, p-toluylenediamine (PTD) and hydroxyethyl-p-phenylenediamine (HE-PPD) were tested, both induced substantial DC activation indicating their potential sensitizing properties. These findings contrasted with in vivo results: in murine local lymph node assays (LLNA) PTD, but not HE-PPD, was sensitizing using acetone/aqua/olive oil as vehicle. Skin penetration measurement revealed that this was due to bioavailability differences. On retesting HE-PPD in the LLNA using the penetration enhancer dimethylsulfoxide as vehicle, it induced a specific response. We conclude that in vitro analysis of DC activation capability of the two selected chemicals demonstrates that prediction of skin sensitization potential is possible provided that skin penetration data indicate sufficient bioavailability of the test compound.

Amines↗

PubMedDate not supplied

Ranking of hair dye substances according to predicted sensitization potency: quantitative structure-activity relationships.

Allergic contact dermatitis following the use of hair dyes is well known. Many chemicals are used in hair dyes and it is unlikely that all cases of hair dye allergy can be diagnosed by means of patch testing with p-phenylenediamine (PPD). The objectives of this study are to identify all hair dye substances registered in Europe and to provide their tonnage data. The sensitization potential of each substance was then estimated by using a quantitative structure-activity relationship (QSAR) model and the substances were ranked according to their predicted potency. A cluster analysis was performed in order to help select a number of chemically diverse hair dye substances that could be used in subsequent clinical work. Various information sources, including the Inventory of Cosmetics Ingredients, new regulations on cosmetics, data on total use and ChemId (the Chemical Search Input website provided by the National Library of Medicine), were used in order to identify the names and structures of the hair dyes. A QSAR model, developed with the help of experimental local lymph node assay data and topological sub-structural molecular descriptors (TOPS-MODE), was used in order to predict the likely sensitization potential. Predictions for sensitization potential were made for the 229 substances that could be identified by means of a chemical structure, the majority of these hair dyes (75%) being predicted to be strong/moderate sensitizers. Only 22% were predicted to be weak sensitizers and 3% were predicted to be extremely weak or non-sensitizing. Eight of the most widely used hair dye substances were predicted to be strong/moderate sensitizers, including PPD - which is the most commonly used hair dye allergy marker in patch testing. A cluster analysis by using TOPS-MODE descriptors as inputs helped us group the hair dye substances according to their chemical similarity. This would facilitate the selection of potential substances for clinical patch testing. A patch-test series with potent, frequently used, substances representing various chemical clusters is suggested. This may prove useful in diagnosing PPD-negative patients with symptoms of hair dye allergy and would provide some clinical validation of the QSAR predictions.

Allergens↗

PubMed2005

Evaluation of the skin sensitizing potency of chemicals by using the existing methods and considerations of relevance for elicitation.

The Technical Committee of Classification and Labelling dealing with harmonized classification of substances and classification criteria under Directive 67/548/EEC on behalf of the European Commission nominated an expert group on skin sensitization in order to investigate further the possibility for potency consideration of skin sensitizers for future development of the classification criteria. All substances and preparations should be classified on the basis of their intrinsic properties and should be labelled accordingly with the rules set up in the Directive 67/548/EEC. The classification should be the same under their full life cycle and in the case that there is no harmonized classification the substance or preparation should be self-classified by the manufacturer in accordance with the same criteria. The Directive does not apply to certain preparations in the finished state, such as medical products, cosmetics, food and feeding stuffs, which are subject to specific community legislation. The main questions that are answered in this report are whether it would be possible to give detailed guidance on how to grade allergen potency based on the existing methods, whether such grading could be translated into practical thresholds and whether these could be set for both induction and elicitation. 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.

Advisory Committees↗

PubMed2006

Allergenicity and cross-reactivity of naphthenic acid and its metallic salts in experimental animals.

The allergenicity and the cross-reactivity of naphthenic acid (NA) and its metallic salts were evaluated in experimental animals. In the guinea pig maximization test, sensitizing skin reactions were observed with cobalt naphthenate (CoN), zinc naphthenate (ZnN) and NA, but not with copper naphthenate, with CoN being the most potent sensitizer. Animals sensitized with 1 naphthenic compound cross-reacted to the other 3 as well. Furthermore, animals in the CoN-sensitized group reacted to the relevant metallic salt cobalt chloride (CoCl2). A dose-response study using the CoN-sensitized group showed that the concentration of CoCl2 required to elicit a skin reaction of similar extent in comparison with CoN was more than 10 times higher, when skin-reaction scores were compared on the basis of cobalt content. In the local lymph node assay, significant increases in stimulation index values without skin irritation were observed with CoN and ZnN, where the former was more potent than the latter. Although CoN is a reported skin sensitizer, this study showed that skin allergenicity of naphthenic compounds is not restricted solely to CoN. In addition, the results suggest the main antigenic determinant of naphthenic compounds to be the structure of NA, even though metal moieties modulate their allergenicity.

Allergens↗