Skin sensitization

A summary of in vitro approaches to assessment of immune-mediated skin effects is shown in Table 12.1. 

Industrial operations and chemical processing provide a suitable atmosphere for the induction of immunologic reactions as seen with skin sensitization and the respiratory tract. The antigen antibody reaction with a complex cascade-type system of serum proteins results in a variety of sensitizing reactions of the worker and disturbs his or her normal health. 

Substances when applied to human skin might exert a sensitizing potential on the skin and need, therefore, to be evaluated and classified for their possible toxicity. Every substance that provokes immunologically mediated cutaneous reactions (i.e., skin sensitization or allergic contact dermatitis) is referred to as skin sensitizer. Several tests are recommended, but no single method is able to identify all potential substances capable of inducing sensitization of human skin. Widely used test methods for the investigation of skin sensitization, the so-called adjuvant and nonadjuvant tests, are described below. 

The guinea pig maximization test (GPMT) is a preferred method for the detection of skin sensitizers. It belongs to the class of adjuvant-tests, where the substance will be applied in Freund s complete adjuvant (FCA). The test is based on the possible induction of an immune response of the skin during an induction period (at least 1 week). This pretreatment of the subject will eventually result in a hypersensitive reaction during a further exposure, the so-called challenging phase. 

The dose used for the induction exposure is chosen in such a way that it is systemically well tolerated and causes only mild-to-moderate skin irritations. The dose during the challenging period should be the highest nonirritating dose. Both doses need to be determined in preliminary tests, in case no other information on the test substances is available. 

The test is started with an intradermal and/or epidermal application of the test substance, using the induction dose on young adult guinea pigs of either gender. In the case of female animals, these have to be nulliparous and nonpregnant. For 5 days prior to the test, animals are kept at (20 3)°C with 30-70% relative humidity, conventional laboratory diet, and unlimited access to water. The induction dose is administered to the shoulder region and is followed by the induction period (10-14 days), in which the animals can rest and a possible immune response may develop. It should be noted that the location of the induction dose is kept occluded for the first 48 h after administration. 

Along with the testing of the materials of interest, control experiments with reference substances need to be performed. At least every 6 month, the control test needs to be carried out using mild-to-moderate skin sensitizers [recommended substances are a-hexylcinnamaldehyde, benzothiazole-2-thiol (mercaptobenzothiazole), and benzocaine] to evaluate the testing procedure. 

For those materials that RIFM has shown to be sensitizers, IFRA has either applied a restriction or banned their use (Table 10.1). In some 

The first two products can be used in their crude form after the usual washing procedures, but may be further purified. In the last case, distillation is necessary to give a suitable product. 

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Irritant Skin Sensitive Mild eye Irritant Inhalation, mg/m Oral, mg/kg... 

Repeated exposures to acryhc monomers can produce allergic dermatitis (or skin sensitization) resulting in rash, itching, or sweUing. After exposure to one monomer, this dermatitis may arise upon subsequent exposure to the same or even a different acryhc monomer. 

Primary human skin irritation of tetradecanol, hexadecanol, and octadecanol is nil they have been used for many years ia cosmetic creams and ointments (24). Based on human testing and iudustrial experience, the linear, even carbon number alcohols of 6—18 carbon atoms are not human skin sensitizers, nor are the 7-, 9- and 11-carbon alcohols and 2-ethylhexanol. Neither has iudustrial handling of other branched alcohols led to skin problems. Inhalation hazard, further mitigated by the low vapor pressure of these alcohols, is slight. Sustained breathing of alcohol vapor or mist should be avoided, however, as aspiration hazards have been reported (25). 

Formaldehyde causes eye, upper respiratory tract, and skin irritation and is a skin sensitizer. Although sensory irritation, eg, eye irritation, has been reported at concentrations as low as 0.1 ppm in uncontrolled studies, significant eye/nose/throat irritation does not generally occur until concentrations of 1 ppm, based on controlled human chamber studies. Odor detection has commonly been reported to occur in the range of 0.06—0.5 ppm (133—135). 

The importance of hydrolysis potential, ie, whether moisture or water is present, is illustrated by the following example. In the normal dermal toxicity test, namely dry product on dry animal skin, sodium borohydride was found to be nontoxic under the classification of the Federal Hazardous Substances Act. Furthermore, it was not a skin sensitizer. But on moist skin, severe irritation and bums resulted. 

Uncured resins are skin sensitizers and contact should be avoided, as weU as breathing the vapor, mist, or dust. Novolak-based pulverized products generally contain hexamethylenetetramine, which may cause rashes and dermatitis. PhenoHc molding compounds and pulverized phenoHc adhesives must be controUed as potentially explosive dusts. In addition, they contain irritating or toxic additives. 

Health and Safety Factors. Both pyromellitic acid and its dianhydride irritate skin, eyes, and mucous membranes, and they cause skin sensitization (156). When it comes in contact with moist tissue the dianhydride converts to the acid. Direct contact with should be avoided and protective clothing should be worn in areas where it is used. The LD q for intergastric administration in rats is 2.2—2.6 g/kg (157). In 6-mo experiments, the maximum nontoxic dose was 0.07 mg/kg/d, and it affected the fiver, kidney, and reproductive tract. Precautions against fire and dust explosions as explained in the terephthafic acid section should be foUowed. 

Bacitracin given parenteraHy is sufftciendy nephrotoxic that it is rarely used in human medicine for other than topical indications (80). Thus safe and effective use, especially as the zinc salt, is limited almost completely to ointments, sprays, and solutions for skin and ophthalmic use in concentrations of 250 to 1000 units per milliliter. Bacitracin is only rarely skin sensitizing. As in the case of polymyxin, bacitracin is usually combined with other antibiotics to enlarge its spectmm of activity, or with corticoids or analgesics to reUeve pain or itching. 

Other toxicological effects that may be associated with exposure to benzyl chloride based on animal studies are skin sensitization and developmental embryo and/or fetal toxicity. A 1980 OSHA regulation has estabhshed a national occupational exposure limit for benzyl chloride of 5 mg/m (1 ppm). Concentrations of 160 mg/m (32 ppm) in air cause severe irritation of the eyes and respiratory tract (68). 

Some skin sensitization to low molecular-weight DGEBPA resins (mol wt - 340) has been shown in animals and humans. Skin sensitization decreases with an increase in molecular weight but the presence of low molecular-weight fractions in the advanced resins may present a hazard to skin sensitization (43). 

Epoxy Phenol Novolak Resins. Acute oral studies indicate low toxicity for these resins (49). Eye studies indicate only minor irritation in animals (49). The EPN resins have shown weak skin-sensitizing potential in humans. 

The greater the degree of cyanoethylation the higher the viscosity of the adduct, the larger the pot life and the lower the peak exotherm. The products are skin sensitive. 

As a very general rule it may be said that the amines are fast curing and give good chemical resistance but most are skin sensitive. The organic anhydrides are less toxic and in some cases give cured resins with very high heat distortion temperatures. They do not cross-link the resins at room temperature. 

Thus with industrial skin sensitizers, e.g. ehromates or amine euring agents, no effeet is usually observed on first exposure subsequent exposure results in inflammation of the skin, not restrieted to the areas of eontaet. Refer to Table 5.5. 

Indicators of toxicity hazards include LD50, LC50, plus a wide range of in vitro and in vivo techniques for assessment of skin and eye indtation, skin sensitization, mutagenicity, acute and chronic dermal and inhalation toxicity, reproductive toxicology, carcinogenicity etc. 

Nickel compounds Hydrogenations (e.g. Raney nickel) Conversion of synthesis gas to methane Reduction of organo nitro compounds to amines Carcinogenic (nickel subsulphide). Skin sensitization... 

SEN Capable of causing respiratory sensitization skin sensitizers have not been given a separate notation SK Can be absorbed through skin... 

Polymeric ethyl cyanoacrylate exhibits very low toxicity properties. In tests with laboratory rats, oral administration of 6400 mg/kg of the polymer failed to harm the test animals. Some skin irritation did occur in tests on guinea pigs, but skin sensitization or absorption through the skin was not observed [45]. 

Although poloxamers show poor biodegradability, they exhibit very low acute toxicity [92] and are reported as having low potential for causing irritation and skin sensitization [26]. Toxicity decreases as ethylene oxide content increases, and the least toxic poloxamers are approved as food additives [80]. 

The amount of residual sulfonate ester remaining after hydrolysis can be determined by a procedure proposed by Martinsson and Nilsson [129], similar to that used to determine total residual saponifiables in neutral oils. Neutrals, including alkanes, alkenes, secondary alcohols, and sultones, as well as the sulfonate esters in the AOS, are isolated by extraction from an aqueous alcoholic solution with petroleum ether. The sulfonate esters are separated from the sultones by chromatography on a silica gel column. Each eluent fraction is subjected to saponification and measured as active matter by MBAS determination measuring the extinction of the trichloromethane solution at 642 nra. (a) Sultones. Connor et al. [130] first reported, in 1975, a very small amount of skin sensitizer, l-unsaturated-l,3-sultone, and 2-chloroalkane-l,3-sultone in the anionic surfactant produced by the sulfation of ethoxylated fatty alcohol. These compounds can also be found in some AOS products consequently, methods of detection are essential. 

Generally speaking, up to now the importance of a-sulfo fatty acid esters in cosmetic products has been low [1 p. 367], In the future they may become more interesting because of their mildness. a-Sulfomethyl laurate and most other ester sulfonates are mild to the skin also, they are not human skin sensitizers or primary skin irritants. Tests have shown that a-sulfomethyl laurate is mild enough to be in bath products, such as bubble bath [62]. Three patents for different applications are given to show how ester sulfonates can be used in cosmetics. 

The only study located regarding immunological effects in humans after dermal exposure to endosulfan was an account of the results of patch tests on the backs of 14 farm workers with work-related dermatitis and 8 controls who were not exposed to pesticides (Schuman and Dobson 1985). Skin sensitization was not observed in any of the subjects following a 48-hour, closed-patch exposure to an unspecified amount of 0.1 % endosulfan in petrolatum. 

Glycolic acid peels are contraindicated in contact dermatitis, pregnancy and in patients with glycolate hypersensitivity. Moreover, they can increase skin sensitivity to ultraviolet light. 

Sampson HA, Mendelson L, Rosen JP Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992 327 380-384. De Bilderling G, Mathot M, Agustsson S, Tuerlinckx D. Jamart J. Bodart E Early skin sensitization to aeroallergens. Clin Exp Allergy 2008 38 643-648. 

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