Dermal irritants

Human sensitization studies were negative at 10% solution (47). Undiluted benzyl alcohol produces moderate dermal irritation in guinea pigs and mild dermal irritation in rabbits (48,49). Severe eye irritation was noted in a rabbit study (50). Acute oral rat LD q values were reported between 1.23 and 3.10 g/kg (50—52). A dermal rabbit LD q value of 2.0 g/kg has been reported (49). Rats died after 2 h when exposed to a 200-ppm vapor concentration (53). Benzyl alcohol is readily oxidized in animals and humans to benzoic acid [65-85-0] which is then conjugated with glycine [56-40-6], and rapidly eliminated in the urine as hippuric acid [495-69-2] (54). 

Internal Reports Skin Corrosion Potential ofEiquid Citric Acid S0%,Jan. 19, 1979, Dermal Irritation of Citric Acid in the Rabbit, Dec. 20, 1990, Ocular Irritation of Citric Acid in the Rabbit, May 14, 1991, Miles Inc., Elkhart, Ind. 

Pereira, E.M. et al., Tabebuia avellanedae naphthoquinones activity against methi-cillin-resistant staphylococcal strains, cytotoxic activity and in vivo dermal irritability analysis, Ann. Clin. Microbiol. Antimicrob., 22, 5, 2006. 

Much toxicological data are available on this red pigment acute oral toxicity in mice, 90-day subchronic toxicological study, acute dermal irritation and corrosion, acute eye irritation and corrosion, anti-tumor effectiveness, micronucleus test in mice, AMES test Salmonella typhimurium reverse mutation assay), estimation of antibiotic activity, and results of estimation of five mycotoxins. A new patent on Arpink Red was filed in 2001 with claims of anti-cancer effects of the anthraquinone derivatives and apphcations in the food and pharmaceutical fields. 

Shortness of breath, chest tightness, wheezing, laryngeal spasm, mucosal and dermal irritation, and redness. 

Organophosphate Ester Hydraulic Fluids. Repeated application of a patch treated with 0.2 pL of Skydrol 500B-4 for 5 weeks (3 times/week) resulted in mild cumulative erythema confined to the contact site in 14 of 53 human test subjects, beginning with the third dose during the first week. No evidence of immediate primary dermal irritation was observed (Monsanto 1980). 

Based on these data, it is not likely that acute exposure of humans to environmental levels of polyalphaolefln hydraulic fluids will result in dermal irritation. There is insufficient information to determine if long-term exposure to polyalphaolefln hydraulic fluids will result in dermal irritation in humans. 

Gray, B.H., C.L. Gaworski, J. Horton, C.D. Flemming, and L.H. Lee. 1985. Comparative dermal irritation by tributyltin and organotin-containing antifouling paints. Jour. Toxicol. Cutan. Ocul. Toxicol. 4 105-116. 

Nessel, C.S., et al., The role of dermal irritation in the skin tumor promoting activity of petroleum middle distillates, Toxicol. Sci., 49, 48, 1999. 

Despite wearing protective equipment that included disposable overalls and compressed-air-fed visors or full-facepiece masks with filters for dusts and vapors, hexachloroethane was detected in the plasma of exposed workers (Selden et al. 1993). After 5 weeks of exposure, plasma levels of hexachloroethane in 12 workers were 7.3 + 6 pg/L. Mild dermal irritation was also noted. If the skin irritation was a response to hexachloroethane rather than trauma from the protective clothing, the irritation suggests that the principal exposure route may have been dermal. Absorption of a saturated hexachloroethane solution across human skin was estimated to be 0.0230 mg/cm2/hour based on the physical properties of hexachloroethane (Fiserova-Bergerova et al. 1990). 

Respiratory, hematological, liver, and renal effects were not observed in 11 hexachloroethane-exposed workers. The identification of hexachloroethane in the plasma of these workers confirmed exposure, although the workers were wearing protective equipment. Mild dermal irritation was noted that may have been from exposure or a result of a local trauma effect of the protective equipment. 

Acute-Duration Exposure. -Hcxanc appears to be of low acute toxicity. -Hcxane in air is not irritating to humans (Nelson et al. 1943) and the only human health effect reported after acute-duration exposure is dermal irritation with undiluted liquid -hcxane (Wahlberg 1984). No reports of oral toxicity to w-hexane in humans were located. Oral LD50 values in Sprague-Dawley rats range from 15,840 to... 

The use of screens in environmental assessment and occupational health is fairly straightforward. On the occupational side, the concerns (as addressed in Chapter 11 of this volume) address the potential hazards to those involved in making the bulk drug. The need to address potential environmental concerns covers both true environmental items (aquatic toxicity, etc.) and potential health concerns for environmental exposures of individuals. The resulting work tends to be either regulatorily defined tests (for aquatic toxicity) or defined endpoints such as dermal irritation and sensitization, which have been (in a sense) screened for already in other nonspecific tests. 

For the skin, this scale is used in the primary dermal irritation test, which is performed for those agents that are to be administered to patients by application to the skin. As with all local tolerance tests, it is essential that the material be evaluated in condition of use, that is, in the final formulated form, applied to test animals in the same manner that the agent is to be used clinically. 

PRIMARY DERMAL IRRITATION TEST 11.2.1. Rabbit Screening Procedure... 

When a test substance produces dermal irritation that persists 72 h postapplication, daily observations of test and control sites are continued on all animals until all irritation caused by the test substance resolves or until Day 14 postapplication. 

The Primary Dermal Irritation Index is calculated for the test substance or control substance by dividing the sum of the Total Irritation Scores by the number of observations (three days x six animals = 18 observations). 

The categories of the Primary Dermal Irritation Index (PDII) are as follows [this categorization of dermal irritation is a modification of the original classification described by Draize et al. (1944)] ... 

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. 

F. Both the age of the test animal and the application site (saddle of the back versus flank) can markedly alter test outcome. Both of these factors are also operative in humans, of course (Mathias, 1983), but in dermal irritation tests, the objective is to remove all such sources of variability. In general, as an animal ages, sensitivity to irritation decreases. For the dermal test, the skin middle of the back (other than directly over the spine) tends to be thicker (and therefore less sensitive to irritations) than that on the flanks. 

Some materials, by either their physicochemical or toxicological natures, generate difficulties in the performance and evaluation of dermal irritation tests. The most commonly encountered of these problems are presented below. 

C. Systemic Toxicity. On rare occasions, the dermal irritation study is begun only to have the animals die very rapidly after test material is applied. 

A primary dermal irritation test will be performed prior to the study. 

The test substance will not be studied for eye irritation if it is a strong acid (pH of 2.0 or less) or strong alkali (pH of 11.0 or greater), and/or if the test substance is a severe dermal irritant (with a PDII of 5 to 8) or causes corrosion of the skin. 

D. Analysis of data The data from the irradiated and nonirradiated sites are evaluated separately. The scores from erythema and eschar formation, and edema at 24, 48, and 72 hr, are added for each animal (six values). The six values are then divided by 3, yielding six individual scores. The mean of the six individual animal irritation scores represents the mean primary irritation score (maximum score = 8, as in the primary dermal irritation study). This method was developed after a human model had been developed. 

The reader should note that this scoring scheme is the same one used for dermal sensitization scoring, whereas the scoring method for the rabbit model discussed previously is that used for dermal irritation studies.)... 

Hatoum, N.S., Leach, C.L., Talmsa, D.M., Gibbons, R.D., and Garvin, P.F. (1990). A statistical basis for using fewer rabbits in dermal irritation testing. J. Amer. Coll. Toxicol. 9 49-59. 

Mannisto and coworkers (1984) have published a series of articles on the dermal toxicity of the anthralins in the minipig. In one experiment, 24 sites per minipig were used to assess the acute dermal irritation of various concentrations to four different chemicals per site. The range of concentrations tested permitted them to calculate the median erythema concentration and median irritation concentrations with relatively... 

Hanhijarvi, H., Nevalainen, T. and Mannisto, P. (1985). A six-month dermal irritation test with anthralins in the Gottinger miniature swine. Arch. Toxicol, 8 (Suppl.) 463 168. 

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