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PubMed1995

A local lymph-node assay validation study of a structure-activity relationship model for contact allergens.

A structure-activity relationship model for prediction of contact allergenic potential of chemicals had previously been developed. The model had been shown to be able to classify known allergens and nonallergens using data on physicochemical and reactivity parameters of functional groups by discriminant two-value multiple regression analysis. To investigate the model, six selected chemicals which had not been previously investigated for allergenicity were studied with both the model and a murine local lymph-node assay. The same compounds were predicted to be allergens (3-bromo-2-coumaranone, 1-nitrocyclohexene and alpha-acryloyloxy-beta, beta-dimethyl-beta-butyrolactone) and nonallergens (1-carbethoxy-4-piperidone, 6,7-dimethoxy-2-tetralone and 9-acetylanthracene) by both the model and the local lymph-node assay.

Allergens↗
PubMed2002

Respiratory hypersensitivity to trimellitic anhydride in Brown Norway rats: evidence for different activation pattern of immune cells following topical and respiratory induction.

The elicitation of respiratory allergy in animal models is exquisitely complex and interpretation of results from different laboratories cannot readily be compared due to variability in testing protocols, biomarkers and techniques used to identify 'positive' responses. On the one hand, guinea-pigs have been proposed as a good model with which to study allergic and irritant bronchial hyperresponsiveness. On the other hand, considerable efforts have been made to develop animal models that take the immunological mechanisms into account to reduce the complexity as well as duration of the guinea-pig assays. In principle, local skin reactions can easily be determined by the local lymph node assay (LLNA) introduced by Kimber and Weisenberger. In contrast to lung sensitization there are already simplified and reliable models available to test for and discriminate contact sensitizers from skin irritants, i.e. the modified local lymph node assay IMDS (integrated model for the differentiation of skin reactions). Modifications of this assay verified that methods other than radioactive labelling may be comparably sensitive, and that it is possible to eliminate 'false positive' results induced by irritants (IMDS). Thus, we asked whether there could be a similar simplified model like the modified LLNA or IMDS for investigations of respiratory allergens. Therefore, we analysed immune reactions induced by the dermal and respiratory route, respectively. Analyses of the draining lymph nodes of the lung and the ear were carried out before and after challenge via the pulmonary tract. The results clearly support that (1) the reactions in the lung draining lymph nodes could be used as early indicators of respiratory sensitization, and (2) the specificity of the immune competent cells seem to be dependent of the route of administration during induction.

Administration, Inhalation↗
PubMed2006

The skin allergenic properties of chemicals may depend on contaminants--evidence from studies on coumarin.

BACKGROUND/AIMS: Positive patch tests are considered representative of a contact allergy to the tested chemical. However, contaminants and derivatives rather than the suspected chemical itself could be responsible for the allergic skin reactions. Here, we tested the importance of contaminants in the sensitizing and allergenic properties of coumarin in mice and humans. Coumarin, an ingredient in cosmetics and fragrances, was chosen as the reference chemical since conflicting results have been obtained regarding its ability to induce contact allergy. In some chemical preparations, this could be explained by the presence of coumarin derivatives endowed with allergenic properties. METHODS: In mice, three different coumarin preparations were tested in the local lymph node assay. In humans, we assessed the irritant and allergenic properties of highly pure coumarin in nonallergic and fragrance-allergic patients. RESULTS: Pure coumarin did not exhibit irritant or sensitizing properties in the local lymph node assay. In contrast, two other commercially available coumarins and three contaminants that were detected in these coumarin preparations were identified as weak and moderate sensitizers, respectively. In humans, pure coumarin was extremely well tolerated since only 1 out of 512 patients exhibited a positive patch test to the chemical. CONCLUSIONS: These results indicate that coumarin cannot be considered as a common contact allergen and further emphasize that purity of chemicals is mandatory for the assessment of their allergenicity.

Adult↗
PubMed1993

Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity.

Twenty organic Salmonella mutagens, seven of which (including benzo[a]pyrene) are established skin carcinogens, and one of which (2-chloroethanol) is a well-defined noncarcinogen to skin, have been evaluated for skin-sensitizing activity using the local lymph node assay. The relative mutagenicity of the agents to Salmonella was also established. Fourteen of the chemicals were positive in the local lymph node assay, including the seven skin carcinogens. 2-Chloroethanol was inactive as a sensitizing agent. We suggest that a variety of factors contributes to the lack of sensitizing activity of the remaining six bacterial mutagens: extremes of intrinsic chemical reactivity, high water solubility reducing dermal translocation, and inappropriate dermal metabolism. Two reference skin-sensitizing agents (an oxazolinone and fluorescein isothiocyanate) were established as in vitro clastogens after their recognition as nonmutagens to Salmonella. These data imply that mutagenicity, rather than simply activity in the Salmonella assay, is a primary stimulus for electrophilic sensitization and carcinogenic initiation in the skin. We conclude that genotoxicity data for an agent can provide indications of the agent's potential to induce skin sensitization and that genotoxins which are skin-sensitizing agents have an enhanced potential to initiate skin carcinogenesis. We suggest that common, albeit individually distinct, structure-activity relationships underpin genotoxicity, skin sensitization, and the initiation of skin carcinogenesis. These relationships should simplify the hazard evaluation of chemicals and contribute to a reduction in animal usage. Several predictions of skin carcinogenicity are made based on the data presented.

Animals↗
PubMed1976

Disseminated systemic expression of the "local" popliteal lymph node assay in rats.

In contrast to the traditional belief that the popliteal lymph node (PLN) assay of graft-versus-host (GVH) reactivity is a local phenomenon, this study describes significant systemic components of both donor and host lymphoid cell activity. Not only are host radiosensitive lymphocytes of systemic origin necessary for the manifestation of normal PLN hypertrophy, but as few as 2.5 X 10(6) parental lymph node cells (LNCs) injected into the hind footpad of adult F1 hybrid rats disseminate widely, provoking significant systemic GVH reactions, as measured by splenomegaly, and distant lymphadenopathy. Futhermore, locally injected donor LNCs ultimately engender three forms of attenuated GVH reactivity: (1) the dissipation of potentially unlimited GVH reactivity, (2) refractoriness of the host to subsequent rechallenge by GVH-inducing cells, and (3) progressive loss of GVH reactivity in donor LNCs when serially transferred to secondary F1 recipients. Whether this modulation of the cell-mediated immune response is the expression of an anti-recognition structure response by the host or the activation of some other immunoregulatory protein, it is absent or reduced in splenectomized recipients. The data suggest that the spleen provides an immunoregulatory microenvironment in which cell-mediated immune responses, such as the GVH reaction, are modulated.

Animals↗
PubMed2003

Validity of methods to predict the respiratory sensitizing potential of chemicals: A study with a piperidinyl chlorotriazine derivative that caused an outbreak of occupational asthma.

A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test. In addition, respiratory hyper-reactivity was assessed following a novel protocol involving dermal sensitization (20 microl of a 3% solution on each ear for three days) and intranasal challenge (0.1% or 1%, 10 microl per nostril on day 10), followed, after 24 h, by a methacholine challenge (using whole-body plethysmography), bronchoalveolar lavage, and histology. PCT was also used for structure-activity relationship (SAR) models for (respiratory) sensitization. High concentrations of PCT (10 and 20%) resulted in significant responses in the local lymph node assay (LLNA; stimulation indices (SI) of 2.7 +/- 0.9 and 3.2 +/- 0.6, respectively). The mouse IgE test was positive with 20% PCT only. Methacholine responsiveness was increased only in previously sensitized mice receiving a challenge with TDI or PCT. However, there was no evidence for pulmonary inflammation. The SAR studies indicated that PCT could be a respiratory sensitizer. Based on an approved test protocol such as the LLNA and the mouse IgE test, PCT proved to be a weak sensitizer when compared to TDI and oxazolone. However, in a protocol involving an intranasal challenge, PCT appeared to be a respiratory sensitizer of similar potency to TDI.

Adjuvants, Immunologic↗
PubMed1999

Immune responses to contact allergens: novel approaches to hazard evaluation.

Progress in our understanding of the immunobiological mechanisms that cause skin sensitization and allergic contact dermatitis has facilitated consideration of alternative approaches to hazard evaluation. One such is the murine local lymph node assay in which, in contrast to more traditional guinea pig tests, sensitizing activity is measured as a function of events associated with the induction, rather than the elicitation, phase of contact hypersensitivity. Activity in the local lymph node assay is dependent upon all of those immunological events that are initiated following first encounter with chemical allergen and which result in the stimulation of T lymphocyte proliferative responses in lymph nodes draining the site of exposure. In this respect the assay embraces in an holistic way the induction of skin sensitization. With the objective of developing in vitro approaches to hazard identification, consideration has been given to discrete immunological responses that characterize the induction of skin sensitization. Most attention has focused upon the changes induced by chemical allergens in the phenotype and function of epidermal Langerhans cells and in cytokine expression. In addition, attempts have been made to identify contact allergens as a function of their ability to provoke in vitro specific responses by unprimed T lymphocytes. These novel approaches to skin sensitization testing and their potential utility in the context of toxicological evaluations are reviewed in this article.

Allergens↗
PubMed1999

Contact sensitivity to selected acrylate compounds in B6C3F1 mice: relative potency, cross reactivity, and comparison of test methods.

Given the increasing prevalence of occupational sensitization to acrylate compounds, n-butyl acrylate (BAC), ethyl acrylate (EAC), and trimethylol propane triacrylate (TMT) were recommended by the National Toxicology Program for hypersensitivity testing in female B6C3F1 mice. The objectives of these studies were to determine the irritating and sensitizing potential of these three compounds using an irritation assay, the murine Local Lymph Node Assay (LLNA), and the Mouse Ear Swelling Test (MEST). The minimal irritating concentration for TMT was determined to be 1.0%, whereas BAC and EAC demonstrated no irritation up to 30%, the highest concentration tested. TMT tested positive in the LLNA at concentrations as low as 0.1% whereas an induction concentration of 0.3% was required to elicit a positive response in the MEST. Furthermore, BAC tested negative in the MEST at induction concentrations as high as 30%, but yielded positive results in the LLNA at concentrations as low as 20%. EAC, at all concentrations tested, was negative in both the MEST and the LLNA. Cross reactivity was only seen when mice were sensitized with TMT and challenged with BAC. In these studies, the LLNA was a more sensitive indicator of the allergic potential of these three acrylates when compared to the MEST.

Acrylates↗
PubMed2004

Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. 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).

Aldehydes↗
PubMed1995

Streptozotocin: inherent but not expressed skin sensitizing activity.

We have shown previously that the alkylating agent streptozotocin (STZ) fails to induce responses in the murine local lymph node assay, a predictive test for contact sensitizing potential. In the present study, we demonstrate that this same compound when injected intradermally into the ears of mice provokes a dose-dependent induction of draining lymph node cell proliferation. These data indicate that the intrinsic immunogenicity of STZ is not displayed in the local lymph node assay under conditions of conventional topical exposure, secondary to a failure to cross the lipophilic stratum corneum in sufficient quantities. This finding has implications for the discernment of structure-activity relationships in contact sensitization.

Animals↗
PubMed1992

Differences of draining lymph node cell proliferation among mice, rats and guinea pigs following exposure to metal allergens.

Contact sensitivities of three well known metal allergens (nickel sulfate, potassium dichromate and cobalt chloride) were examined using the local lymph node assay in CBA/N mice, F344 rats and Hartley guinea pigs. The effect of various species sera on lymph node cell (LNC) proliferation was also investigated. Exposure to potassium dichromate and cobalt chloride induced significant LNC proliferative responses in the three species. The LNC responses to potassium dichromate in the rats were higher than those in the mice and guinea pigs. Mice exhibited the highest response to cobalt chloride among the three species, whereas, exposure to nickel sulfate failed to induce a marked LNC proliferation. Increased draining lymph node weights and LNC numbers were also observed following exposure to the metal salts. However, these parameters were less sensitive compared with the LNC proliferative response. There was a large difference in the lymph node weight between individual guinea pigs. The [methyl-3H]thymidine incorporation into LNC of each species cultured in the presence of the homologous serum in vitro was lower than in the presence or absence of fetal calf serum. However, there was no significant difference in stimulation indices among the different culture conditions. The local lymph node assay may be performed in rats as well as in mice for the detection of metal allergens.

Allergens↗
PubMed2005

Assessment of potency of allergenic activity of low molecular weight compounds based on IL-1alpha and IL-18 production by a murine and human keratinocyte cell line.

Assessment of allergenic potency of low molecular weight compounds is generally performed using animal models, such as the guinea pig maximisation test and the murine local lymph node assay (LLNA). Progress in unravelling the mechanisms of skin sensitisation, including effects on the production of cytokines by the different cell types of the skin, provides us with the opportunity to develop in vitro tests as an alternative to in vivo sensitisation testing. The aim of the present study was to establish an in vitro method to assess the potency of allergens, on the basis of their induction of cytokine production by murine and human keratinocytes. In the present study we used test systems comprised of the murine epidermal keratinocyte cell line HEL-30 and the human keratinocyte cell line HaCaT. We exposed these cell lines to the allergens ethyl-p-aminobenzoate (benzocaine), diethylamine (DEA), 2,4-dinitrochlorobenzene (DNCB), and phthalic anhydride (PA). IL-1alpha and IL-18 dose-response data were evaluated by non-linear regression analysis and at a stimulation index of 3 of cytokine production of treatment versus control, the corresponding allergen concentration was calculated. For HEL-30, for both cytokines DNCB showed the strongest potency followed in this order by PA, benzocaine, and DEA. This classification was similar to our previous findings obtained in the LLNA. For HaCaT, unfortunately, such ranking proved to be much less feasible. In conclusion, to assess the potency of allergens the murine keratinocyte cell line HEL-30 may be a useful in vitro test system, alternative to in vivo models, although this requires further testing using a much wider range of compounds.

Allergens↗
PubMed2003

Occupational issues of allergic contact dermatitis.

Occupational contact dermatitis is often of multifactorial origin, and it is difficult to determine the relative significance of the various contributing factors. Contact allergies are relevant in 20-50% of recognised occupational contact dermatitis cases. The reported frequency in different studies varies, depending on differences in how occupational diseases are notified and recognised, in types of occupation in a geographical area, and the "quality" of the dermatological examination, including the accuracy of the diagnostic patch-test investigation. However, the clinical relevance of the reported contact allergies is often uncertain. Many occupational contact dermatitis patients with documented contact allergies develop chronic eczema, in spite of work changes and attempted allergen avoidance. Recognition/non-recognition of a notified case may be based on circumstantial evidence, because of difficulties in the establishing of a firm proof of work exposure and subsequent development of skin disease. Reliable quantitative exposure measuring techniques are needed. Methods are developed for the measurement of exposure to allergens such as nickel and acrylates, which makes it possible for exposure-effect relationships to be established with increased certainty. For prevention of allergic contact dermatitis it was a major step forward, with mandatory ingredient labelling of cosmetic products. However, improved labelling of the presence of contact allergens in household and industrial products is needed. For the identification of hazardous contact allergenic compounds, guinea pig or mice assays are still required. The local lymph node assay (LLNA), which is an objective and sensitive mouse assay has now been internationally validated and accepted.

Dermatitis, Allergic Contact↗
PubMed2003

Impact of exposure duration by low molecular weight compounds on interferon-gamma and interleukin-4 mRNA expression and production in the draining lymph nodes of mice.

The local lymph node assay (LLNA) is used to identify allergens by means of dermal exposure. For hazard identification, besides identification also the distinction between contact and respiratory allergens is of importance. We have previously shown that a modified LLNA can be used to identify respiratory allergens, on the basis of Con A induced IL-4 production. Here we show a good qualitative correlation between mRNA expression and production of IFN-gamma and IL-4. This suggests that distinction between contact and respiratory allergens may also be studied at the mRNA expression level. Secondly, another assay, similar to the modified LLNA but differing in the duration and the number of allergen applications as well as in the ex vivo culture conditions, here denoted as 'longer' assay, has been reported to be able to identify contact allergens, on the basis of (spontaneous) IFN-gamma production. In the present study we have compared these assays. Similar to our previous findings, in the modified LLNA exposure to the respiratory allergen trimellitic anhydride (TMA) resulted in a approximately 10-fold higher Con A induced IL-4 production compared with the contact allergen dinitrochlorobenzene (DNCB), while exposure to both allergens resulted in a similar Con A induced IFN-gamma production. In the 'longer' assay, TMA exposure resulted in Con A induced IL-4 production whereas DNCB exposure did not. Importantly, only a 2-fold higher spontaneous IFN-gamma production was induced by DNCB compared with TMA, the difference being not statistically significant. Thus, although the 'longer' assay indeed showed a somewhat higher IFN-gamma induction by DNCB compared with TMA, the magnitude and robustness of this effect question its applicability. These results favor the modified LLNA since it is shorter, and combines identification of allergens (by cell proliferation) with identification of respiratory allergens (by IL-4 production). Compounds that induce cell proliferation with a low concomitant IL-4 production may thus be identified as contact allergens, although the need to positively identity such allergens remain.

Allergens↗
PubMed2004

Development of a peptide reactivity assay for screening contact allergens.

Allergic contact dermatitis resulting from skin sensitization is a common occupational and environmental health problem. In recent years, the local lymph node assay (LLNA) has emerged as a practical option for assessing the skin sensitization potential of chemicals. In addition to accurate identification of skin sensitizers, the LLNA can also provide a reliable measure of relative sensitization potency; information that is pivotal in successful management of human health risks. However, even with the significant animal welfare benefits provided by the LLNA, there is still interest in the development of nonanimal test methods for skin sensitization testing. One characteristic of a chemical allergen is its ability to react with proteins prior to the induction of skin sensitization. The majority of chemical allergens is electrophilic and as such reacts with nucleophilic amino acids like cysteine or lysine. In order to determine if reactivity correlates with sensitization potential, 38 chemicals representing allergens of different potencies (weak to extreme) and nonsensitizers were evaluated for their ability to react with glutathione or three synthetic peptides containing either cysteine, lysine, or histidine. Following a 15-min reaction time for glutathione or a 24 h reaction period for the three synthetic peptides, the samples were analyzed by HPLC. UV detection was used to monitor the depletion of glutathione or the peptide following reaction. The results demonstrate that a significant correlation (Spearman correlation) exists between allergen potency and the depletion of glutathione (p = 0.001), lysine (p = 0.025), and cysteine (p = 0.020), but not histidine. The peptide with the highest sensitivity was cysteine (80.8%) whereas histidine was the least sensitive (11.5%). The data presented show that measuring peptide reactivity has utility for screening chemicals for their skin sensitization potency and thus potential for reducing our reliance on animal test methods.

Algorithms↗
PubMed2005

Non-enzymatic glutathione reactivity and in vitro toxicity: a non-animal approach to skin sensitization.

The development of non-animal methods to predict the potential of chemicals to cause skin sensitization is of great importance. On the basis of many published studies into the underlying chemical mechanisms skin sensitization, the immunological priming which leads to the disease allergic contact dermatitis, is recognized as a reactive chemistry endpoint. Consequently, the combination of chemical assays with in vitro techniques may provide a useful surrogate to animal testing for skin sensitization. This study attempts to investigate the relationship between skin sensitization assessed in the local lymph node assay (LLNA) initially and a thiol reactivity index based on glutathione (GSH), pEC(50) thiol (EC(50) being defined as the concentration of the test substance which gives 50% depletion of free thiol under standard conditions) in combination with a measure of cytotoxicity (pIGC(50)) to Tetrahymena pyriformis (TETRATOX). The pEC(50) thiol values and the pIGC(50) values were determined for twenty-four compounds for which LLNA test data were available. Thiol reactivity was found to discriminate sensitizers from non-sensitizers according to the rule: pEC(50) thiol>-0.55 indicates that the compound will be a skin sensitizer. However, because of metabolic activation a pEC(50) thiol<-0.55 does not necessarily mean that the compound will be a non-sensitizer. Excess toxicity to T. pyriformis (i.e. the extent of toxic potency over that expected by non-polar narcosis) was determined in order to assess biological reactivity. The best discrimination based on excess toxicity in the TETRATOX assay was given by the "rule": excess toxicity>0.50 indicates that the compound will be a skin sensitizer. These approaches become more powerful when combined. When taken together, the thiol and TETRATOX assays predict the sensitization potential of 23 of the 24 compounds correctly. alpha-Hexylcinnamic aldehyde is incorrectly predicted to be a non-sensitizer, whereas LLNA results suggest it may be a weak sensitizer, this inaccuracy being rationalized in terms of its high hydrophobicity. Due to the selectivity of electro(nucleo)philic reactions some sensitizing compounds will not be identified using a single nucleophile such as thiol.

Allergens↗
PubMed2003

Identifying airway sensitizers: cytokine mRNA profiles induced by various anhydrides.

Exposure to low molecular weight (LMW) chemicals in the workplace has been linked to a variety of respiratory effects. Within the LMW chemicals, one of the major classes involved in these effects are the acid anhydrides. The immunological basis of respiratory hypersensitivity involves CD4+ cells. By virtue of their induction of cytokines typical of CD4+ T-helper type 2 (Th2) cells-interleukin (IL)-4, 10, and 13-respiratory sensitizers may be identified and differentiated from contact sensitizers which induce Th1 cytokines (IL-2 and IFN-gamma). Our previous work suggested that the ribonuclease protection assay (RPA) was useful in identifying the respiratory sensitizer, trimellitic anhydride (TMA), based on quantitative differences in Th2 cytokine mRNA as compared to the contact sensitizer dinitrochlorobenzene (DNCB). Therefore, the purpose of the studies described in this report was to expand the chemicals tested in the RPA. To this end, four acid anhydrides with known respiratory sensitization potential, TMA, maleic anhydride (MA), phthalic anhydride (PA) and hexahydrophthalic anhydride (HHPA), were tested. Although previously determined to induce immunologically equivalent responses in a local lymph node assay (LLNA), the initial dose chosen (2.5%) failed to induce Th2 cytokine mRNA expression. To determine if the lack of cytokine expression was related to dose, LLNAs were conducted at higher doses for each of the anhydrides. The highest doses evaluated (four- to six-fold higher than those used in the initial RPA) gave equivalent proliferative responses for the various anhydrides and were used for subsequent RPA testing. At these higher doses, significant increases in Th2 versus Th1 cytokine mRNA were observed for all anhydrides tested. These results suggest that the RPA has the potential to serve as a screen for the detection of LMW airway sensitizing chemicals. However, the basis for selecting immunologically equivalent doses may require some modification.

Anhydrides↗
PubMed2004

Allergenicity evaluation of Bioban CS-1135 in experimental animals.

An industrial preservative, Bioban CS-1135, was evaluated for its contact allergenicity by means of multiple-dose guinea-pig maximization test and non-radioactive murine local lymph node assay. In the guinea-pig test, an induction dose of 0.5% Bioban CS-1135 sensitized all animals of the group. The dose-response study of the elicitation phase determined a minimum elicitation dose of 5% for positive skin reactions. In the murine assay, Bioban CS-1135 at doses of 10% and more exerted significant effects on lymphoid cell proliferation. Although the data clearly designated Bioban CS-1135 as a skin sensitizer, its relative potency was ranked lowest among skin-sensitizing biocides previously evaluated in this laboratory.

Allergens↗