Irritant responses

Soap as used in personal cleansing products has a long safe history of use. Modem soaps have been specifically formulated to be compatible with skin and to be used on a daily basis with minimal side effects. Excessive use of soap for skin cleansing can dismpt the natural barrier function of skin through the removal of skin oils and dismption of the Hpid bdayer in skin. This can result in imperfect desquamation or a dry appearance to skin and cause an irritation response or erythema, ie, reddening of the skin. Neither of these is a permanent response and the eHcitation of this type of skin reaction depends on the individual s skin type, the product formulation, and the frequency of use. 

Marginal irritant A material that is capable of causing an irritation response after repeated exposures. 

Polyhydroxy Acids (PHAs) provide similar effects as AHASjbut do not cause the sensory irritation responses that limit the use of AHAs. PHAs have also been found to have some addi-... 

However, in the presence of particulate catalysts and sunlight, conversion to sulphur trioxide occurs and the irritant response is much more severe. 

For example, sulphur dioxide is highly water soluble and tends to be absorbed in the airways above the larynx. Responses at various concentrations are summarized in Table 5.3. However, in the presence of particulate catalysts and sunlight, conversion to sulphur trioxide occurs and the irritant response is much more severe. 

Babiuk, C., W.H. Steinhagen, and C.S. Barrow. 1985. Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment. Toxicol. Appl. Pharmacol. 79 143-149. 

FACTORS AFFECTING IRRITATION RESPONSES AND TEST OUTCOME 371... 

B. The physical nature of solids must be carefully considered both before testing and in interpreting results. Shape (sharp edges), size (small particles may abrade the skin by being rubbed back and forth under the occlusive wrap), and rigidity (stiff fibers or very hard particles will be physically irritating) of solids may all enhance an irritation response. 

Murphy JC, Osterberg RE, Seabaugh VM, et al. 1982. Ocular irritancy responses to various pHs of acids and bases with and without irrigation. Toxicology 23 281-291. 

Nethercott JR, Lawrence M. 1983. The effect of the guinea pig maximization protocol on the irritant response to deodorized kerosene The excited skin syndrome. Contact Dermatitis 9(6) 439-443. 

As mentioned above, a NOAEL can usually not be derived from the classic test guideline methods for skin and eye irritation. Based on information from acute and/or repeated dose toxicity smdies using inhalation, it may be possible to derive a NOAEL and/or LOAEL for respiratory tract irritation. In such smdies, the slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the irritative response the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

In rats exposed to 3 000-5000 ppm there was an immediate irritant response, followed by labored breathing, pulmonary edema, and death within minutes to hours. ... 

Whether or not chlorothalonil is a true dermal sensitizer in humans or strictly a skin irritant remains controversial. Some investigators suggest that repeated exposure results in an enhanced irritant response, whereas others suggest that it is a potent contact allergen. It is noted that relatively few cases of allergy to chlorothalonil have been reported despite widespread use for over 20 years. Furthermore, at a plant that produces the chemical cases of work-related contact dermatitis have not been reported for years after adoption of good hygienic practices. ... 

Clinical expressions of cutaneous allergic reactions include eczematous, indurate-inflammatory, and urticarial eruptions. Irritant responses causing direct damage to the skin may be confused with allergic responses involving immune mechanisms. An important difference is that allergic reactions require an initial exposure to sensitize the individual dermatitis is then elicited by minimal subsequent exposure to the agent. 

Comparison of Threshold Irritant Response of Eyes of Guinea Pig and Rabbit and Eyes and Tongue of Man to CR Solutions ... 

To demonstrate the ability of HDI to be a direct irritant to the skin, HDI was applied to the non-oeeluded intaet skin of adult male albino guinea pigs either undiluted (100%) or in solutions of 0.05, 0.5, 5, or 25% in 1 1 aeetone-dioxane eontaining 13% guinea pig fat. HDI was demonstrated to produce severe-eiythema and edema when applied to the skin at concentrations of 5, 25, and 100%. Applieation of undiluted material resulted in frank skin necrosis. Moderate irritation to intaet skin was noted at the 0.5% HDI dose, while a 0.05% solution failed to produce any perceptible eutaneous irritation response (Haskell Laboratory 1961). 

Phototoxicity irritant response to a combination of a chemical and sunlight. 

Dermal Effects. Dermal exposure to diazinon resulted in contact dermatitis in farm workers (Matsushita et al. 1985). But in another human dermal exposure study, diazinon failed to elicit an irritation response (Lisi et al. 1987). In laboratory animal studies, diazinon was also not irritating to guinea pigs in a 24-hour occluded skin patch test (Matsushita et al. 1985). 

The persistence of residues at intramuscular injection sites may be due in part to the irritant response produced in the muscle (52). Chloramphenicol, tylosin, penicillins, dihydrostreptomycin, and oxytetracycline have been shown to produce local irritation at the site of injection, leading to residue persistence this may be exacerbated by the solvent used. However, residues do not persist with proper injection of drugs and use of formulations that do not cause severe irritation (52), as has been demonstrated with one oxytetracycline product that produced little irritation (53-55). 

Blankschtein et al. have concluded that micelle size is a major factor in surfactant induced irritation.37 As the micelle size increases, penetration of the surfactant into deeper layers decreases and therefore increasing the micelle size is an approach to enhancing mildness. In principle, factors that reduce the micelle charge will increase the micelle size and therefore have the potential to reduce swelling and penetration under cleansing conditions. Note, however, that the inherent tendency of the molecule to cause an irritation response may be related to the charge density of the molecule rather than the micelle size. 

Metabonomics (the quantitative measurement of time-related responses to stimuli within the body)17,18 may prove to be of some use to assess the potential of a material to elicit an irritant response following topical application. The concept being that certain stimuli change the metabolite profile in intermediate biochemical pathways. Analysis of body fluids such as urine, saliva, plasma, biopsy material, etc. produces a fingerprint of biochemical changes characteristic of the nature or site of a toxic (or other) effect. 

In order to ensure that the visual assessment captures all irritant responses, it may be necessary to record more than one assessment for any given skin site. This is particularly true for use tests, where topical application is likely to cover a large area of skin. The area of application may need to be divided into several discrete sites, which are assessed separately. For example, the axilla may be split into three sites the peak (generally identified as the mounded area in the centre of the axilla, where the majority of hair growth occurs), the around (skin around the peak which usually receives some treatment) and the creases (creases that are found crossing through the axilla). Treatment may be discontinued due to a reaction (e.g. well-developed erythema) in any of the three sites. 

Perfumes and fragrances can be complexed with cyclodextrins. On application to the skin, the perfume is released over a longer time than perfume applied to the skin in a non-complexed form. Some perfumes are irritating to the skin. Because the perfume is contained within the cavity of the cyclodextrin, contact with the skin is minimized, resulting reduction or elimination of irritation. Moisture and oils in the skin release the perfume slowly, so that the minimum concentration of perfume needed to elicit an irritable response is not reached. 

C.S. Barrow, Y. Alarie, J.C. Warrick, and M.F. Stock, Comparison of the sensory irritant response in mice to chlorine and hydrogen chloride, Archives of Environmental Health, 32(2), 68-76, 1977. 

It must be stressed that the primary mechanism of many topical irritants (e.g., organic solvents, corrosives) is the impairment to the stratum corneum barrier properties discussed above, reflected by an increase in transepidermal loss (TEWL). If the stratum corneum barrier is perturbed, the feedback response mediated by cytokines (especially TNFa) may be initiated whereby regeneration of the barrier occurs. However, additional responses to these inflammatory mediators may in themselves launch an irritation response mediated by the keratinocytes or lead to an immune reaction if the antigen is recognized. Regardless of the initiating mechanism, the sequelae to many irritants is the same, namely, epidermal cell death. 

There are two primary mechanisms of cell death that occur in response to an irritant response apoptosis or necrosis (Figure 35.4). Apoptosis is a form of programmed... 

---