Cumulative Irritation Research Articles

Skin risk assessment of metalworking fluids: a survey among Swiss suppliers.

Metalworking fluids (MWF) are the most important cause of hand dermatitis in the metal industry. The substitution of noxious products by less aggressive MWFs is therefore an important measure to reduce the incidence of hand eczema in this type of industry. In order to do so, producers and suppliers have to evaluate the skin risk of such products by predictive allergenicity and irritancy testing. The aim of the study is to evaluate if predictive testing is performed in MWF products that are currently offered in the Swiss market and what kind of tests are applied. A questionnaire was sent to 11 Swiss MWF suppliers in order to collect information on the actual practice of skin risk testing. Nine of 11 suppliers returned the questionnaire. Five suppliers report some kind of allergenicity testing in some of the products. Seven companies test for irritancy by a single application method, but only two perform cumulative irritancy testing in some products. The methods of testing (animal, human, field studies) vary greatly among the different companies. It is concluded that the practice of predictive testing for sensitization and irritancy of MWF is unsatisfactory and does not allow the user to compare products based on their skin risk. Occupational dermatologists should strive for standardization of MWF testing including so far scarcely performed repeated insult tests.

Final Report on the Safety Assessment of Polyquaternium-7

The quaternary ammonium compound Polyquaternium-7 is used as an antistatic agent, film former, and hair fixative in a wide variety of cosmetics. This ingredient is formed by the polymerization of acrylamide with dimethyl dialylammonium chloride; residual acrylamide monomer can be found at levels as high as 10 ppm. An 8% aqueous solution of Polyquaternium-7 is typically supplied and this solution may be used in cosmetic formulations at a concentration as high as 5%. Most uses are at lower concentrations. Rats were fed up to 50,000 ppm of an 8% aqueous solution for 30 days; a decrease in organ weight was noted in the higher exposure groups. Dermal exposure of rats to 2.25 ml/kg per day for 14 weeks was nonirritating to both intact and abraded skin. Dermal exposure of rabbits to an 8% solution produced no irritation, and ocular exposure showed mild irritation that cleared after 24 h. Polyquaternium-7 was not mutagenic in an Ames test. Repeated insult patch test data suggest that 8% Polyquaternium-7 is at best a mild cumulative irritant, but not a sensitizer. Clinical tests with an 8% solution indicated that Polyquaternium-7 is not a photosensitizer. Given its structure, this material is considered not likely to be significantly absorbed in the skin and therefore is unlikely to produce general toxicity, developmental toxicity, or mutagenic/carcinogenic effects under use conditions. The presence of unreacted acrylamide monomer is considered sufficiently low so as to have no toxicologic significance. Based on the available data, it is concluded that Polyquaternium-7 is safe for use in cosmetic formulations.

A study of skin responses to follow-up, rechallenge and combined effects of irritants using non-invasive measurements

Irritant contact dermatitis is a common clinical problem. Primary irritation can be easily recognized, but cumulative irritation by daily exposure is hard to be diagnosed and the condition may fail to be clear even away from work. The mechanism of irritant dermatitis produced by repeated or combined exposure to clinical or subclinical doses of irritants is still poorly understood. In order to find out whether the subclinical doses of irritants affect each other by repeated or combined exposure according to their concentrations, non-invasive measurements, transepidermal water loss and laser Doppler flowmetry were used. Sodium lauryl sulfate, sodium hydroxide and benzalkonium chloride were serially diluted and patch-tested with large Finn chambers on Scanpor tape on the back of normal human volunteers and responses were followed up for 7 days. Twice repeated exposure with subclinical doses of irritants at 1 day intervals were also performed. Repeated daily applications for 5 days with subclinical doses of single or premixed irritants were performed to know the combined irritating effect. The irritant response was well correlated to the concentration of the irritants. However, increased response was not observed when subclinical doses were rechallenged on the previously patch tested sites. Twice-repeated exposure of subclinical doses of irritants increased skin irritancy when measured by transepidermal water loss and laser Doppler flowmetry. Some correlation and some discrepancies were observed between different evaluation methods in combined and repeated application tests with irritants of subclinical doses. Responses of skin irritancy induced by subclinical doses showed somewhat different pattern from that given strong irritants. So, when evaluating the patients suspicious of irritant dermatitis, patch testing with the possible combination of the irritants or repeated test may be helpful to verify their effect on the skin even at a weak concentration.

The sodium lauryl sulfate model: an overview.

Irritant contact dermatitis is a complex entity with several clinical forms (acute, cumulative, etc.) and multiple mechanisms. Sodium lauryl sulfate (SLS), the most widely utilized model for studying acute and cumulative irritation, has proved highly practical and informative for such studies. This article summarizes several decades of investigation, and provides details of dosing, application method (closed versus open), and biologic endpoints (visual grading, transepidermal water loss) that may be utilized in future studies.

Cumulative irritancy in man to sodium lauryl sulfate: The overlap phenomenon

Repeated contact of skin with surfactants causes irritation often characterized by dryness, erythema and scaliness. Morphologically healed skin after preexposure can still evoke a stronger reaction to any subsequent exposure of an irritant. Cumulative irrtancy using the overlap phenomenon was studied. The effects of repeated and prolonged application of sodium lauryl sulfate (SLS) on human skin in vivo (healthy adult volunteers) were evaluated using non-invasive techniques of TEWL and skin capacitance measurements and visual scoring. The inability of TEWL and skin capacitance to achieve pretreatment values 2 weeks post SLS treatment suggests the possible detrimental effects of SLS on skin lipids. The surfactant effect was cumulative and dehydrating effects on prolonged and repeated application were observed.

Final Report on the Safety Assessment of Lauramine Oxide and Stearamine Oxide

Lauramine Oxide and Stearamine Oxide are aliphatic tertiary amine oxides that are used mostly in hair care products as foam builders and stabilizers, viscosity enhancers, emollients, conditioners, emulsifiers, antistatic agents, and wetting agents. Both compounds are susceptible to nitrosation and can form nitrosamines in the presence of nitrosating agents. In rats, up to 40% of Lauramine Oxide applied to the skin was absorbed. In two human volunteers, 92% of the dose applied to the skin was recovered from the skin. The oral LD50 in rats for a formulation containing 0.3% Lauramine Oxide was estimated to be >20 g/kg. At a concentration of 30%, Lauramine Oxide produced severe dermal reactions in rabbits, but at 0.3% only slight to moderate erythema with slight edema, Assuring, and slight to moderate epithelial desquamation were found. Stearamine Oxide applied to rabbit skin at 5% did not cause irritation. Both ingredients caused mild, transient ocular irritation in rabbits. Clinical data showed dermal exposure to 3.7% Lauramine Oxide to be a mild irritant, with a slight potential for mild cumulative skin irritation at concentrations as low as 2%. At 0.3%, Lauramine Oxide was not a sensitizer in clinical studies. Lauramine Oxide was nonmutagenic in the Ames assay, but was mutagenic after nitrosation. Lauramine Oxide at 0.1% in drinking water was not carcinogenic in rats, but at 0.1% with 0.2% sodium nitrate did increase the incidence of liver neoplasms. Based on this animal data, neither ingredient should contain N-ni-troso compounds nor be used in formulations containing nitrosating agents. On the basis of the available animal and clinical data, it is concluded that Lauramine Oxide and Stearamine Oxide are safe as cosmetic ingredients for rinse-off products, but that the concentration in Lauramine Oxide leave-on products should be limited to 3.7% and that of Stearamine Oxide limited to 5%.

Study of cumulative irritant contact dermatitis in man utilizing open application on subclinically irritated skin

We evaluated the effect of subclinical irritation on the cutaneous reaction elicited by cumulative short-term (30-min) application of sodium lauryl sulphate (SLS), by measuring transepidermal water loss (TEWL) and assigning visual scores. 11 healthy adult volunteers, free of skin disease and with no history of atopic dermatitis, were treated with SLS solution (1%, 2%, 5%, 7.5%). On a Monday, we applied 80 microliters of 1% SLS solution and deionized water (control), using large aluminium chambers with filter paper discs, for 30 min. We measured TEWL values 2 x before and after patch application of control and 1% SLS solution, and then applied 80 microliters of SLS solution (2%, 5%, 7.5%) using filter paper discs. From Tuesday to Friday, we applied 80 microliters of each solution, using filter paper discs, and measured TEWL before and after open application of test solutions. Compared with each corresponding group, TEWL values of SLS patch groups (S-2.0, S-5.0, S-7.5) were higher than those of water patch groups (W-2.0, W-5.0, W-7.5), respectively. TEWL values of each groups increased stepwise and the final (hour 97) TEWL values were higher than those of baseline (hour 0) TEWL. The mean visual scores of the vehicle control were lower than those of other test groups, but there were no statistically significant differences in visual scores between each test group. These findings suggested that impaired skin barrier function, elicited by subclinical irritation from short-duration contact with some irritants, might augment the cumulative irritant contact dermatitis caused by repeated open exposure to other surfactants.(ABSTRACT TRUNCATED AT 250 WORDS)

Faecal enzymes: in vivo human skin irritation

Digestive enzymes in faeces have been reported to possess skin irritation potential. The present study was designed to investigate the in vivo irritant potentials of faecal concentrations of proteolytic and lipolytic digestive enzymes in bile salt mixtures. In a 21-day cumulative irritation assay, clinical evaluation and noninvasive bioengineering techniques were used. 5 days occlusive exposure to phosphate buffer (pH = 8) caused no visual skin damage but reflectance spectroscopy demonstrated significant vasodilation (p < 0.01) and increases in transepidermal water loss (TEWL) and skin pH were also observed (p < 0.01). These increases were still present at days 12 and 19. Occlusive exposure to physiologic concentrations of faecal enzymes resulted in significant visual and objective scores at day 5, 12, and 19, with increased readings as a function of exposure time (p < 0.01). The enzyme mixture containing lipase caused delayed onset of skin erythema and epidermal barrier disruption compared to elastase and chymotrypsin containing solutions. Prolonged occlusive exposure to digestive enzymes in faecal concentrations caused severe skin erythema and epidermal barrier disruption in a human model, suggesting a possible etiologic role of digestive enzymes in perianal, circumstomal or diaper dermatitis.

An in Vivo Correlation with Three in Vitro Assays to Assess Skin Irritation Potential

We have tested the irritancy of 10 materials of various chemical composition in three in vitro toxicity assays: the Skintex Dermal Assay system (In Vitro International, Irvine, CA, USA), the silicon microphysiometer (Molecular Devices Inc., Menlo Park, CA), and the Living Skin Equivalent (Organogenesis Inc., Cambridge, MA). The purpose was to discover to what degree the in vitro results predict in vivo skin irritation as seen in nine female volunteers over the course of a 5 day cumulative irritancy patch test. Two in vivo assessments of irritancy were made and compared to the in vitro results, a visual scoring system, and a potentially more objective bioengineering assessment: the chromameter. Measures of sensitivity, specificity, positive predictive value, and negative predictive value were used to compare in vitro with in vivo results. Comparison of results using correlation coefficients was avoided since statistically significant rank orders could not be demonstrated for either in vitro or in vivo data. For these in vitro systems, sensitivity ranged from 60 to 100%, specificity from 80 to 100%, positive predictive value from 75 to 100%, and negative predictive value from 67 to 100%. The assay that exhibited the best measures of sensitivity, specificity, and other parameters was the Living Skin Equivalent. This assay is also the one that most closely simulates human skin. The nonionic surfactant triton X-100 gave a false-positive result in both the Living Skin Equivalent and the silicon microphysiometer. False-positive results with nonionic surfactants are consistent with observations made in other cell-based in vitro systems. We caution that the results not be overinterpreted to imply superiority for any one system.

The Toxicology of Moisturizers

AbstractMoisturizers are applied to dry skin on such a frequent and daily basis that key toxicologic questions must be asked regarding exposure to these emollients and their ingredients. The toxicologic variables are the composition of the moisturizers themselves, how long the moisturizer is in contact with the skin, how frequently the moisturizer is applied and reapplied, the area and skin site of the application, the skin's physiological response to such products, occasional responses of the body itself, and measuring and interpreting results from various prognostic tests on moisturizers. The actual skin condition and misuse of moisturizers are also important to know. Patients' reactions to moisturizers include, but are not limited to, irritant and allergic contact dermatitis, photocontact dermatitis from sunscreen-containing moisturizers, and, occasionally, contact urticaria. Dermatologists are recently describing reactions that can be called cumulative subclinical irritation to such products as well. ...

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumuor incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evudebce for a non-genotoxic mechanism. Examples of such substances include croton oil, 12- O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.

Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy

Skin absorption of benzoyl peroxide from a topical lotion containing freely dispersed drug was compared with that from the same lotion in which the drug was entrapped in a controlled-release styrene-divinylbenzene polymer system. In an in vitro diffusion system, statistically significant (p = 0.01) differences were found in the content of benzoyl peroxide in excised human skin and in percutaneous absorption. In vivo, significantly (p = 0.002) less benzoyl peroxide was absorbed through rhesus monkey skin from the polymeric system. This controlled release of benzoyl peroxide to skin can alter the dose relation that exists between efficacy and skin irritation. Corresponding studies showed reduced skin irritation in cumulative irritancy studies in rabbits and human beings, whereas in vivo human antimicrobial efficacy studies showed that application of the formulations containing entrapped benzoyl peroxide significantly reduced counts of Propionibacterium acnes (p less than 0.001) and aerobic bacteria (p less than 0.001) and the free fatty acid/triglyceride ratio in skin lipids. These findings support the hypothesis that, at least for this drug, controlled topical delivery can enhance safety without sacrificing efficacy.

Human Cutaneous Response to a Mixed Surfactant System: Role of Solution Phenomena in Controlling Surfactant Irritation

Exposure of the skin to surfactant-based products can result in irritation. To control this effect researchers are probing mechanisms of surfactant action. In vitro studies show that mixing surfactants often results in less denaturation (swelling) of stratum corneum. We have explored the in vivo human irritation response (using a 21-day cumulative irritation test) to two of these surfactants-sodium lauryl sulfate (SLS) and (C12-C14) alkyl, 7-ethoxy sulfate (AEOS-7EO). Results demonstrate that addition of AEOS-7EO to a constant dose of SLS results in a significant reduction in erythema, hence producing a milder system. The reason for the synergism is unclear, but may related to experimentally determined alterations in the micellar solution properties of the SLS upon addition of AEOS-7EO.

The transient and cumulative effect of sodium lauryl sulphate on the epidermal barrier assessed by transepidermal water loss: inter-individual variation

The aims of the investigation were: 1) to study the inter-individual variation in time course of TransEpidermal Water Loss and of clinical manifestations after a 24-h single exposure to Sodium Lauryl Sulphate. This TEWL time course (expressed as the difference in TEWL between the day of patch removal and a subsequent day) reflected the epidermal barrier response to the damage caused by SLS; 2) to investigate the association between the TEWL time course after the single SLS exposure and the TEWL value after 4-day repeated SLS exposure (as a model for cumulative irritation). The 35 healthy subjects tested could be divided into four sub-groups according to the day of their maximum TEWL value after the single SLS exposure (days 2 to 5). For the whole group, inter-individual variation in TEWL course was most pronounced in the first days following the single SLS application. Moreover, there was an inverse relationship (R = -0.61) between TEWL course during the first days after the single exposure and the TEWL value after 4-day repeated exposures. It is concluded that this association illustrates the importance of an adequately responding barrier function against the continuous exposure to irritants in daily life. The aims of the investigation were: 1) to study the inter-individual variation in time course of TransEpidermal Water Loss and of clinical manifestations after a 24-h single exposure to Sodium Lauryl Sulphate. This TEWL time course (expressed as the difference in TEWL between the day of patch removal and a subsequent day) reflected the epidermal barrier response to the damage caused by SLS; 2) to investigate the association between the TEWL time course after the single SLS exposure and the TEWL value after 4-day repeated SLS exposure (as a model for cumulative irritation). The 35 healthy subjects tested could be divided into four sub-groups according to the day of their maximum TEWL value after the single SLS exposure (days 2 to 5). For the whole group, inter-individual variation in TEWL course was most pronounced in the first days following the single SLS application. Moreover, there was an inverse relationship (R = -0.61) between TEWL course during the first days after the single exposure and the TEWL value after 4-day repeated exposures. It is concluded that this association illustrates the importance of an adequately responding barrier function against the continuous exposure to irritants in daily life. The aims of the investigation were: 1) to study the inter-individual variation in time course of TransEpidermal Water Loss and of clinical manifestations after a 24-h single exposure to Sodium Lauryl Sulphate. This TEWL time course (expressed as the difference in TEWL between the day of patch removal and a subsequent day) reflected the epidermal barrier response to the damage caused by SLS; 2) to investigate the association between the TEWL time course after the single SLS exposure and the TEWL value after 4-day repeated SLS exposure (as a model for cumulative irritation). The 35 healthy subjects tested could be divided into four sub-groups according to the day of their maximum TEWL value after the single SLS exposure (days 2 to 5). For the whole group, inter-individual variation in TEWL course was most pronounced in the first days following the single SLS application. Moreover, there was an inverse relationship (R = -0.61) between TEWL course during the first days after the single exposure and the TEWL value after 4-day repeated exposures. It is concluded that this association illustrates the importance of an adequately responding barrier function against the continuous exposure to irritants in daily life.

Irritant Dermatitis Syndrome

The clinical aspects of irritant CD are summarized as follows. Irritant dermatitis syndrome includes multiple acute and slowly developing symptoms and those induced by repeated cumulative irritation. The clinical symptoms are related to the eliciting irritant agents. Irritation is influenced by the quantity and quality of the exposure. Environmental and endogenous factors are important in the development and course of irritant dermatitis syndrome. There is wide interindividual variation in irritation reactivity. Tools for the diagnosis of irritant contact dermatitis are lacking.

Cutaneous Irritant and Sensitizing Potential Of 2-Ethyl-1,3-Hexanediol in Human Subjects

AbstractStudies in paid human volunteer subjects indicated that undiluted 2-ethyl-1,3-hexanediol may produce minor primary skin irritation by single sustained contact in 4 of 30 (13%) subjects, and slight to moderate cumulative skin irritation by recurrent sustained dermal contact in 25 of 27 (93%) subjects. Evidence for skin sensitization was obtained in only 1 of 203 (0.5%) subjects, and was seen only when the agent was used under occluded conditions. 2-Ethyl-1,3-hexanediol may be a weak skin sensitizer.

Anionic Surfactants as Detergents for Scalp and Hair

The influences of six representative surfactants on hair and the scalp were investigated under various conditions such as : irritation, protein denaturation, sorption onto commercial hide powder or keratin powder, change in turnover time of the stratum corneum, dandruff and disintegration of the cuticle.1. Influence of surfactants on scalp.Although the cumulative irritation test, 48-hour closed patch test, and immersion test were performed to assess the irritating effects of surfactants, the results did not agree with each other. The immersion test, which makes essentially the same use of surfactants, gave results in close agreement with those for sorption of sufactants or protein denaturation by surfactants.Amounts of surfactants sorbed by hide powder.Irritation score of immersion test : r=0.671.Amounts of surfactants sorbed by keratin powder.Irritation score of immersion test : r=0.930.Per cent denaturation of OVA by surfactants.Irritation score of immersion test : r=0.880.Turnover times of the stratum corneum due to the surfactants were found to follow the order, AMT≤AGS≤L-Soap≤AP<LS≤ES.Examination of the amounts of dandruff as observed when using AMT shampoo and ES shampoo, each with a different effect on the turnover time of the stratum corneum, showed the amounts to differ remarkably according to the surfactant used.2. Influence of surfactants on hair.The extent of disintegration of cuticle by a surfactant supersonic treatment was found to have the following order : AMT≤AGS≤AP≤ES<LS<L-Soap.Based on the above results, AMT can be a good surfactant as a detergent for the hair and scalp.

Alkane-induced edema formation and cutaneous barrier dysfunction.

Certain mineral oils and hydrocarbons require repeated topical application to cause irritation. A structure activity relationship of pure n-alkanes was undertaken in a mouse ear edema model to investigate the mechanism of cumulative irritancy. Alkanes were applied twice daily over a 4-day period. Dodecane was found to be non-irritating, while tridecane elicited a response only at 96 h. Tetradecane was the strongest irritant with significant increases (p less than 0.05) in ear thickness observed at 48 h. Hexadecane, octadecane, and eicosane exhibited progressively decreasing activity. Permeability of the ears to hydrocortisone was monitored in vitro during tridecane- and tetradecane-induced irritation. Significant increases in permeability were observed 24 h before edema formation. A positive correlation was found between the extent of edema formation and enhancement of permeability. Loss of barrier function would result in increased cutaneous availability of the alkanes. Increased permeability prior to edema formation indicates that induction of barrier dysfunction may be a factor in the mechanism of alkane-induced irritation.

Irritant reactivity in males and females.

Repeated, daily, open sodium lauryl sulfate (SLS) applications caused slight alterations in transepidermal water loss (TEWL) and dielectric water content (DEWC) in males and females. No erythema developed. Inter-individual variation in skin reactivity was demonstrated; sex-related patterns in reactivity to open cumulative irritant exposure did not exist. In patch testing with 0.5 and 1% SLS, reflecting acute irritation capacity, the reaction pattern, assessed by TEWL, DEWC, laser Doppler velocimetry (LDV) and visual scoring (VS), differed from that induced by open, cumulative SLS irritation. Again, inter-individual variation in the reactivity was demonstrated; significant sex-related differences did not develop. Individual reactivity showed considerable variation in acute and cumulative irritant response and was greater than the sex-related variation. We did not identify responses demonstrating that women have delicate (easily irritated) skin, nor that males have "tougher" skin than females.

3: Final Report on the Safety Assessment of Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid, and Stearic Acid

Oleic, Lauric, Palmitic, Myristic, and Stearic Acids are fatty acids with hydrocarbon chains ranging in length from 12 to 18 carbons with a terminal carboxyl group. These fatty acids are absorbed, digested, and transported in animals and humans. Little acute toxicity was observed when Ofeic, Lauric, Palmitic, Myristic, or Stearic Acid or cosmetic formulations containing these fatty acids were given to rats orally at doses of 15-19 g/kg body weight. Feeding of 15% dietary Oleic Acid to rats in a chronic study resulted in normal growth and health, but reproductive capacity of female rats was impaired. Results from topical application of Oleic, Palmitic, and Stearic Acid to the skin of mice, rabbits, and guinea pigs produced little or no apparent toxicity. Studies using product formulations containing Oleic and Stearic acids indicate that neither is a sensitizer or photosensitizing agent. Animal studies also indicate that these fatty acids are not eye irritants. Lauric, Stearic, and Oleic Acids were noncarcinogenic in separate animal tests. In primary and cumulative irritation clinical studies, Oleic, Myristic, and Stearic Acids at high concentrations were nonirritating. Cosmetic product formulations containing Oleic, Lauric, Palmitic, and Stearic Acids at concentrations ranging up to 13% were not primary or cumulative irritants, nor sensitizers. On the basis of available data from studies using animals and humans, it is concluded that Oleic, Lauric, Palmitic, Myristic, and Stearic Acids are safe in present practices of use and concentration in cosmetics.