Irritation evaluation

The design of vaginal, rectal, and nasal irritation studies is less formalized, but follows the same basic pattern as the primary dermal irritation test. The rabbit is the preferred species for vaginal and rectal irritation studies, but the monkey and dog have also been used for these (Eckstein et al., 1969). Both the rabbit and rat have commonly seen use for nasal irritation evaluations. Defined quantities (typically 1.0 ml) of test solutions or suspensions are instilled into the orifice in question. For the vagina or rectum inert bungs are usually installed immediately thereafter to continue exposure for a defined period of time (usually the same period of hours as future human exposure). The orifice is then flushed clean, and 24 h after exposure it is examined and evaluated (graded) for irritation using the scale in Table 11.1. 

Intravenous irritation is evaluated as follows Rabbits are sacrificed by a lethal dose of barbiturate following the 72-h irritation evaluation. The injection site and surrounding tissue are grossly evaluated at approximately 24 and 72 h after dosing on a scale of 0 to 3 as follows. 

Williams, S.J. (1985). Changing concepts of ocular irritation evaluation pitfalls and progress. Food. Chem. Toxicol. 23 189-193. 

Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation evaluation of potential parenteral vehicles. Drug Dev Commun 1974-75 1(5) 471-477. 

Over the years, several people have proposed a dermal irritation evaluation model based on the test material being applied to the inside surface of the rabbit ear. The advantages are that this site does not have to be shaved and the results may not over predict the toxicity as much. Seemingly no formal evaluation of a method based on this site has been performed and published. 

Finally, the researcher performs a clinical trial with human volunteer subjects to compare the two products antibacterial efficacy, as well as their skin irritation potential. Although the antimicrobial portion of the study had revealed activity equivalence, the skin irritation evaluation demonstrates that... 

Fig. 3. Application of a barrier cream by 150 volunteers with occupational contact to irritants evaluated using a fluorescence technique. Results are given as average percentage of sufficient application for all volunteers, indicating skipped areas at the dorsal aspects of the fingers, the interdigital spaces and the wrist (Wigger-Alberti et al. 1997a)...

Evaluation of the irritation eUcited from 0.1 ml. of the material appHed to the eyes without rinsing. 

Evaluation of the irritation eUcited from an appHcation of hiU-strength alcohol left ia contact with the skin for 24 h. 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Sensitization. The skin irritation and sensitization potentials of 9.0% thioglycolic acid were evaluated usiag the open epicutaneous test. Reactions were not observed dutiag the challenge phase. ThioglycoHc acid was an irritant, but not a sensitizer (20). 

Health and Safety. Cinnamyl alcohol has been evaluated by FEMA and given GRAS status (FEMA No. 2294). Two of its esters, cinnamyl cinnamate (FEMA No. 2298) and cinnamyl acetate (FEMA No. 2293), ate also used extensively in flavor and fragrance compositions. Cinnamyl alcohol has also been tested by RIFM (48) and found to be safe for use. There have been reported cases of irritation and several manufacturers market a desensitized alcohol for use in fragrance appHcations. 

Methods of testing for eye and skin irritation potential have been reviewed (137). The official FHSA procedure for evaluating ocular irritation potential of detergent products is a modified Drai2e rabbit eye test (138). Some controversy surrounds this method at present, and a search for a procedure less injurious to test animals is in progress. In general, the order of irritation is cationic > anionic > nonionic (139). 

The acute oral toxicity and the primary skin and acute eye irritative potentials of dimer acids, distilled dimer acids, trimer acids, and monomer acids have been evaluated based on the techniques specified ia the Code of Eederal Regulatioas (CER) (81). The results of this evaluatioa are showa ia Table 7. Based oa these results, monomer acids, distilled dimer acids, dimer acids, and trimer acids are classified as nontoxic by ingestion, are not primary skin irritants or corrosive materials, and are not eye irritants as these terms are defined ia the Eederal regulatioas. 

Smoke pellets are produced in a range of sizes and are commonly used tor the resting of household flues and chimneys. The pellet is ignited and will burn for about 10 seconds producing a dense white smoke. Because this is a combustion process there are obvious restrictions on its use (nonflammable atmo spheres, nonflammable surfaces, etc.). In addition the smoke is buoyant because of the heat generated. The smoke can also be an irritant and/or toxic. The production of smoke cannot be controlled, but pellets are inexpensive, easy to use, and readily available, and the smoke is produced in sufficient quantities to make them useful in the evaluation, for example, of fume cupboards and Ixroths. 

As new compounds, very limited research has been done to evaluate the biological effects of ionic liquids. The topical effect of [EMIM]C1/A1C13 melts and [EMIMjCl on the integument of laboratory rat has been investigated. The study reports that [EMIMjCl is not in itself responsible for tissue damage. However, the chloroaluminate salt can induce tissue irritation, inflammation, and necrosis, due to the presence of aluminium chloride. However, treatments for aluminium chloride and hydrochloric acid are well documented. This study needs to be expanded to the other ionic liquids, and their toxicity need to be investigated [46]. 

The ocular irritation caused by cosmetic ingredients has been evaluated by the determination of the amount of histamine contained in tears. Contact of surfactants and the eye tissue cause an immediate dose-dependent release of histamine through direct cytotoxic damage of cell membranes. This method has been tested with sodium lauryl sulfate with volunteers [187]. 

More recent publications on sulfosuccinates have confirmed the minimal or close to zero skin and eye irritation caused by these products. In a general screening of product safety evaluation methods the authors [16] rejected the sulfosuccinate from further consideration in the statistical analysis of experimental data (variance analysis) because the product had not shown any irritation in the Duhring-Chamber test. The sulfosuccinate (based on fatty alcohol ethoxy late) was tested in a screening with 14 other surfactants, namely, alkyl sulfates, sulfonates, ether sulfates, and a protein fatty acid condensation product. 

In a broad evaluation also the sulfosuccinate disodium laureth sulfosuccinate (DLSS) was a part of a variety of surfactants tested for their dermatological mildness, and some different test methods were applied [16]. Products were compared applying in vitro methods (Zein test, hemolysis) and in vivo methods (Duhring-Chamber test, skin mildness by intracutaneous test on mice and topical application on hairless mice, mucous membrane irritation according to the Draize procedure on rabbit eyes). In the Duhring-Chamber test the DLSS elicited no reactions in the animal tests it ranged in the least irritant third of the 15 products tested. 

Chitosan acetate and lactate salt films have been tested as wound-healing materials. Mechanical, bioadhesive and biological evaluation of the films were carried out. The results were compared to Omiderm . Chitosan lactate exhibited a lower tensile strength, however, it was more flexible and bioadhesive than chitosan acetate. Chitosan lactate and Omiderm did not cause any allergic reactions in contrast, chitosan acetate produced skin irritation clearly due to the anion. Nevertheless, no sign of toxicity was encountered when the extracts of three preparations were administered parenterally [244]. 

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

Lethal concentrations and doses are parameters of acute, systemic poisoning. There are also specific protocols to evaluate the irritant and corrosive effects on skin, eyes and mucous membranes. 

Irritability stimulant Verify diagnosis/comorbidity Evaluate time of occurrence ... 

Theoretically, the risk of serious GI adverse events should be less than with oral NSAIDs, but long-term studies evaluating these events are lacking.38 Studies comparing topical NSAIDs with other topical products, including counterirritants, are also needed.35 Local cutaneous adverse reactions (e.g., erythema, pruritus, and irritation) occur in 1% to 2% of patients and may be due in part to the vehicle used.38... 

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