Cutaneous Irritation Research Articles

The Effect of Surfactants on Metabolism of Choline Phospholipids in Human Epidermal Keratinocytes in Culture

AbstractThe pathophysiology of surfactant-induced cutaneous primary irritancy most likely involves surfactant interaction with phospholipids of skin cell membranes. The effect of such agents on membrane choline (Ch) phospholipid metabolism was investigated in human epidermal keratinocytes in culture. Cells were prelabeled with [3H]Ch and then treated with four surfactants: linear alkyl benzene sulfonate (LAS), sodium lauryl sulfate (SLS), alkyl ethoxylate sulfate (AEOS-3EO). and TWEEN-20. Media were assayed for release of labeled Ch metabolites. All four surfactants stimulated release of label in a dose-dependent manner in concentrations between 5 × 10−3 and 5 × 10−5 M.

Racial differences in sodium lauryl sulphate induced cutaneous irritation: black and white.

The different reactivity of black and white skin after exposure to sodium lauryl sulphate (SLS) has been investigated. 9 white and 10 black male volunteers entered the study. The tests were performed on the back at 3 sites: untreated skin, skin pre-treated with occlusion and skin pre-delipidized. Irritant reactions were elicited applying 0.5% and 2.0% SLS via Finn chamber patch tests and monitored by means of laser Doppler velocimetry (LDV), transepidermal water loss (TEWL) and stratum corneum water content (WC). Higher TEWL, LDV, and WC values were recorded for 2.0% SLS when compared to 0.5% SLS and baselines. Pre-treatment with short-term occlusion generally increased values, while delipidization produced flattening of the data more detectable in whites than in blacks. Significant TEWL differences for the two concentrations were recorded in whites for the occluded site (P less than 0.02) while in blacks in the untreated (P less than 0.04) and delipidized (P less than 0.03) sites. LDV revealed significant changes in the untreated and pre-occluded white skin (P less than 0.05 and 0.01, respectively). In blacks, the values were significantly different only in the pre-occluded skin (P less than 0.01). Water content correlated with the visual score and was greatly increased in sites with strongly positive reactions (P less than 0.01). It appears that there are significant differences in the modulation of irritation, in the behavior of water barrier function and of the erythematous response between blacks and whites. Clinical correlations are discussed.

Human cutaneous irritation: induced hyporeactivity.

The variation in human skin response to sodium lauryl sulfate (SLS) was determined with patch and open applications. Reactions in different subjects and in multiple simultaneous patch tests were compared. Skin responses were assessed with visual scoring (VS), laser Doppler velocimetry (LDV) and transepidermal water loss (TEWL). Previous open, unpatched SLS exposure decreased patch test reactivity to 1% SLS assessed with VS (p less than 0.05) or LDV (p less than 0.05). Corresponding TEWL alteration was inconstant. Variation in reactivity at different test sites in multiple simultaneous tests was considerable, though less than the variation at different test times (p less than 0.05). Inter-subject variation in test reactivity was greater than the variation between different test times or adjacent test sites. Repeated open applications and the subclinical dermatitis appear to have produced a hyporeactive state. The results suggest that non-specific skin inflammation is elicited by multiple factors, e.g., stratum corneum integrity and vascular reactivity. Their balance determines the ensuing reactions. The induced hyporeactivity may be one of many causes of false negative diagnostic patch tests.

Use of lanthanum to detect changes in the permeability barrier of rat skin after dermal exposure to organic chemicals

Occupational dermal exposures to organic solvents are of importance due to local effects in the skin and systemic toxicity if penetration occurs through the skin. Repeated or prolonged contact with organic solvents may cause dry skin and cutaneous irritation. Although organic solvents have been shown to penetrate the skin, little information is available concerning the effects on the barrier properties of skin after dermal exposure to solvents. The purpose of this investigation was to examine the ultra- structural changes in rat skin after exposure to 3 organic chemicals and to correlate changes with the location of an electron dense tracer, lanthanum, which is normally excluded by the permeability barrier in the stratum corneum.Male rats, 6 for saline and 6 for each chemical, were exposed for 24 h to sterile saline, trichloroethylene (TCE), perchloroethylene (PERC), or toluene using dermal exposure cells developed in this laboratory. The cells were filled with 2 mL of saline or the neat chemical.

Variation in cutaneous perfusion due to synthetic pyrethroid exposure.

Synthetic pyrethroids are neurotoxic insecticides with a low mammalian toxicity. Prior investigations have found these agents to be neither cutaneous irritants nor sensitisers. Clinically demonstrable inflammation, as judged by erythema, oedema, or vesiculation, has not been apparent. Nevertheless, paraesthesia does result from cutaneous exposure. In this investigation technical grade flucythrinate was applied to the forearms of human participants twice daily for five consecutive days. Laser Doppler velocimeter measurements were made before each topical application, with histamine phosphate being intradermally injected on termination of the study. Results of both laser Doppler velocimetry and histamine induced axon reflex vasodilatation were not statistically significant at an alpha = 0.05 level. This investigation suggests that the synthetic pyrethroids have little influence on neurogenic vasodilatation on topical exposure.

1 Final Report on the Safety Assessment of Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol

Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol are long-chain saturated or unsaturated (Oleyl) fatty alcohols. They are used in numerous cosmetic product categories at concentrations of less than 0.1 percent to greater than 50 percent. The metabolism of Stearyl Alcohol and Oleyl Alcohol in rats is described. The results of acute oral toxicity studies indicate a very low order of toxicity. In rabbit irritation tests, these alcohols produced minimal ocular irritation and minimal to mild cutaneous irritation. Stearyl Alcohol produced no evidence of contact sensitization or comedogenicity. Clinical patch testing indicates a very low order of skin irritation potential and sensitization. Photoreactivity studies on products containing these ingredients were negative for phototoxicity or photosensitization. Based on the available data, it is concluded that Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol are safe as currently used in cosmetics.

Disturbances in toxicological experiments caused by Microsporum canis.

Cutaneous lesions which can lead to false positive results have been observed in several rabbits used for the determination of the cutaneous irritation capacity of a product (ITA, PII). The responsible agent was Microsporum canis. A preventive treatment by an antifungal agent did not modify toxicological experimental results.

Evaluation of the protective value of an antisolvent gel by laser Doppler flowmetry and histology.

In a previous histological study, we observed the protective efficiency of an antisolvent gel (Antixol) against the skin irritation induced by epicutaneous application of n-hexane for 15 and 30 min. In the present study, we tried to evaluate the protective efficiency of the Antixol gel against the cutaneous irritation induced by the application of toluene for 10 min. The possible application of laser Doppler flowmetry as a new objective method to test skin irritation and to evaluate the protective efficiency of barrier creams and gels was confirmed by the histological findings.

3 Final Report on the Safety Assessment of Sorbitan Stearate, Sorbitan Laurate, Sorbitan Sesquioleate, Sorbitan Oleate, Sorbitan Tristearate, Sorbitan Palmitate, and Sorbitan Trioleate

The Sorbitan esters, including Sorbitan Stearate, Sorbitan Laurate, Sorbitan Sesquioleate, Sorbitan Oleate, Sorbitan Tristearate, Sorbitan Palmitate, and Sorbitan Trioleate, are used in cosmetic products as emulsifiers and stabilizers at concentrations normally under 5 percent. Toxicity was reported in subchronic and chronic studies at concentrations above that normally used in cosmetics. They are generally mild skin irritants but nonsensitizers in animals. They have the potential to induce cutaneous irritation in humans but not sensitization to normal skin. Carcinogenic studies using Sorbitan Stearate and Laurate were negative. At concentrations of 10 percent or greater, Sorbitan Laurate is a tumor promoter in mouse skin. It is concluded that the latter is not relevant to the use of the Sorbitan esters at low concentrations in cosmetics and that the Sorbitan esters reviewed in the report are safe as cosmetic ingredients under present conditions of concentration and use.

Assessment of the Skin Irritancy Potential of Synthetic Detergents (Syndets)

Summary Among the factors which determine the degree of damage to the skin are (a) the resistance of the stratum corneum to the solubilisation of its components, (b) the intrinsic toxicity of the compound, and (c) the susceptibility of the viable cell layers to damage. In this study of the toxicity of syndets we have attempted to compare their properties in vivo and in vitro and relate these to cutaneous irritancy studies in normal volunteers. The “solubilising” effect of a series of syndets has been studied using the forced desquamation technique. Although no differences could be determined in terms of the corneocytes released from the skin surface, the protein solubilised did differ according to the syndet used and a rank order could be obtained. The susceptibility of viable cells to lysis by syndets has been studied in vitro, using human skin fibroblasts. This test system was able to discriminate between the different syndets and gave the same rank order as the in vivo human test. Comparison with the standard cutaneous irritancy test indicated some correlation between the two test systems and the irritancy test. However, the rank order correlation did show some discrepancy, and the use of such test systems as predictors of cutaneous irritancy is still being investigated.

1 Final Report on the Safety Assessment of Laureths 4 and 23

The Laureths, polyethoxyethers of lauryt alcohol, are used in a wide variety of cosmetic products. Laureth-4 was “practically nontoxic” when administered orally to rats and mice. Acute, subchronic, and chronic dermal tests with diluted formulations on rabbits were negative for systemic toxicity. In eye irritation studies in rabbits, undiluted Laureth-4 was moderately and minimally irritating in the unrinsed and rinsed eye, respectively; 10 and 20% dilutions were both classified as minimally and nonirritating. The acute oral LD50s for Laureth-23 were 8.6 and 3.5 g/kg for fasted male rats and mice, respectively. Undiluted Laureth-23 caused no primary irritation when applied to the rabbit skin. Undiluted Laureth-23 caused a slight conjunctival reaction in rabbits. Review of safety test data on closely-related Laureths and other lauryl alcohol ethoxylated compounds indicated no teratological, multiple generation and fertility, and mutagenicity effects for these compounds. No skin irritation or sensitization was reported in clinical studies with undiluted Laureth-4. A 6% Laureth-4 product produced no evidence of phototoxicity. No primary cutaneous irritation was observed in clinical studies using 60% Laureth-23. No evidence of sensitization was reported when a 25% solution of Laureth-23 was used in a repeated insult patch test on 168 subjects, nor was there evidence of phototoxicity when tested on a subset of this population. It is concluded that Laureth-4 and Laureth-23 are safe as cosmetic ingredients in the present practices of use and concentration.

Anti‐irritant potential of cosmetic raw materials and formulations

Synopsis The investigation studied the anti-irritant potential of several substances commonly employed in cosmetic formulations as basic components of the emulsion or as active ingredients, and evaluated the effect of the emulsifier. Five different emulsions were made irritating by addition of croton oil, in sufficient quantity to provoke a clearly adverse reaction in the rabbit, i.e. primary cutaneous irritation index (PII) close to 2. The PII was determined according to the official French methods by applying to symmetrical areas of the back, the irritant base as control and the same base containing the test substance. Fifty-five ingredients were evaluated: gelling agents, plant extracts, molecules defined as healing, anti-inflammatory substances or anaesthesic compounds, etc. The test substances were added to the emulsion at concentrations close to the ones generally found in cosmetics. The qualitative and the quantitative composition of the oil phase was similar for each emulsion. Several gelling agents, thickeners and polymers which notably reduce skin contact with an irritant, gave good results. Some of the usual healing, anti-inflammatory, local anaesthesic compounds gave the expected results. Some ingredients, though well known, were ineffective. The type of emulsifier, by modifying cutaneous penetration and bio-availability of the active ingredients, may play an important role.

Percutaneous absorption of clindamycin in the pig and the rat.

Clindamycin HCl in a 3% formulation was applied twice daily to the back skin of three white (Yorkshire) and three black (Hampshire) pigs for 22 days. Partial thickness samples of skin were obtained by use of a dermatome on shaved opposite sides at 4 hours and 5 days posttreatment. More than twice the antibiotic activity (P less than or equal to .001) was found in thinner (254 micrometers epidermis) samples than in thicker (1016 micrometers epidermis and dermis, 1 to 3) samples. A significantly higher content of antibiotic (P = 0.015) was retained in the skin of black pigs at five days posttreatment. Groups of ten Upjohn Sprague-Dawley rats were treated similarly with clindamycin phosphate in a 3% formulation three times daily for 22 days. At termination of treatment antibiotic activity was widely distributed, whereas at five days posttreatment residual activity was confined largely to samples of treated skin. No cutaneous irritation due to treatment was observed in either study.

An Experimental Study on Cutaneous Irritability and Allergenicity Due to Some Constituents of an Epoxy Resin

An Experimental Study on Cutaneous Irritability and Allergenicity Due to Some Constituents of an Epoxy Resin

Safety evaluation of some humectants and moisturizers used in cosmetic formulations

Synopsis Safety tests have been carried out on some humectants and moisturizers, continuing a study involving commonly used cosmetic ingredients (1-6). The test substances (listed in Table I) were products from various suppliers and of different types and grades. The ocular and cutaneous tolerance tests have been conducted on animals following the official French methods but with some complements or modifications (28-36). Each compound has been tested as supplied and diluted in water. Pathological lesions of the ocular mucous membrane were provoked by lactic acid at 20 and 10% concentrations. A slight corneal opacity was also noted with ethoxydiglycol and polyamino sugar condensate and a significant irritation with hexylene glycol (non-diluted). In dilutions of 10 or 20%, these substances were non-irritating. Only one product (lactic acid) has given a moderate primary cutaneous irritation (PII = 2.50), when applied undiluted. The indices obtained with the other raw materials correspond to a non-irritating application. With the exception of lactic acid (the study being terminated after 1 week), no significant adverse reaction was macroscopically and histologically observed after daily application (neat) for 6 weeks. Finally, the predictive sensitizing tests (guinea-pig) carried out with two samples of propylene glycol proved to be negative.

Safety evaluation of gums and thickeners used in cosmetic formulations

Synopsis Safety tests have been carried out on gums and thickeners, continuing a study involving commonly used cosmetic ingredients (1, 2, 3, 4). The ocular and cutaneous tolerance tests have been conducted on the rabbit following the official French methods (5, 6) but with some complements or modifications (1, 2, 3, 4, 7). The test substances (listed in Table 1) were products from various suppliers and of different types and grades. None of the fifty samples tested provoked pathological lesions of the ocular mucous membrane; nevertheless, corneal irritation was noted with silicates, silica and bentonite, probably due to mechanical effect, when applied at relatively high concentration. The highest score on the primary cutaneous irritancy test (moderately irritant) was that for the gelled volatile hydrocarbon solvents. The repeated application test was continued for 6 weeks: no significant pathological reaction was observed. Only a slight intolerance was noted with the gels of volatile hydrocarbons and isopropyl myristate, but the irritant reactions were significantly reduced compared to those previously observed with the pure oils (1, 2). Consequently, based on these data, it can be concluded that the use of gums and thickeners involved in this publication presents no hazard for the skin.

Cutaneous sensitivity to ultraviolet light and chemical irritants.

This investigation examines the relationship between the sun sensitivity of human skin and its response to chemical irritants. Forty-four Caucasoid subjects with normal back skin were studied. The minimal erythema dose (MED) was determined with the sunburning spectrum of a high-pressure mercury lamp. Cutaneous irritability was quantified using a series of seven irritants of different chemical structure, solubility, and concentrations. The response was either expressed as a threshold value of exposure time (ammonium hydroxide, sodium hydroxide) or was graded after a standard exposure in intensity of whealing (dimethyl sulphoxide) or erythema (sodium lauryl sulphate, quaternium 1, croton oil, kerosene). A significant correlation between the MED and the response to all seven primary irritants was found. The relationship was better for water-soluble irritants than for lipid-soluble ones. Despite marked individual variations the determination of the MED is suggested as a valuable tool in identifying hyperirritable skin. Skin typing based on complexion and sunburn history proved to be less reliable.

Evaluation of the cutaneous-irritation potential of 56 compounds

The primary cutaneous irritation of 56 chemicals was tested in the rabbit using three different procedures. The three protocols selected for the tests were the method published by the French authorities for the testing of cosmetics and toiletries (Journal Officiel 21 April 1973, p. 3862; ibid 5 June 1973, p. 3953) and the methods proposed for the testing of chemicals by the Association Française de Normalisation (AFNOR) and, in 1979, by the Organisation for Economic Co-operation and Development. The results of the three sets of tests were compared and the effects of differences in procedure and numbers of animals were studied, together with the possible relation between irritancy and the pH of the test material. It was concluded that the AFNOR protocol best met the requirements for such tests and that gloves should be worn for the handling of all substances classified as moderately or severely irritant on that scale.

Antigenicity and cutaneous toxicity of N-(4′-(9-acridinylamino)-3-methoxyphenyl)-methanesulfonamide (AMSA; NSC-249992) in guinea pigs and rabbits

Dermal rashes appearing in personnel involved in the bulk formulation of the antineoplastic agent AMSA prompted this investigation of the allergenicity and cutaneous irritation potential of the drug in rabbits and guinea pigs. Maximization testing of AMSA in guinea pigs resulted in a 100% skin sensitization rate. A 14-day cutaneous irritation study using a modified Draize test did not show any potential of AMSA to produce skin irritation on intact or abraded skin. AMSA did not induce antibodies in rabbits which could be detected by passive hemagglutination, cutaneous anaphylaxis, Arthus reactivity, or delayed hypersensitivity in rabbits. AMSA also failed to sensitize guinea pigs for systemic anaphylaxis.

Cutaneous Irritation in the Topical Application of 30 Antineoplastic Agents to New Zealand White Rabbits

Cutaneous Irritation in the Topical Application of 30 Antineoplastic Agents to New Zealand White Rabbits