Dermal application studies

Wlmersteiger, R. and Juan. H. (1991), Resorption Study of Tyrasou after Dermal Application (study performed or healthy subjects). J.S.W. - Experimental Research, Stndic Analytik. 01/91 p.l. 

There are no available carcinogenicity data in humans or animals using any route of exposure. Data from the CUT inhalation bioassay should provide valuable information on the carcinogenic potential of airborne nitrobenzene. There is currently no apparent need for studies using the oral or dermal route. However, as stated above, the results of the CUT bioassay may provide insight into the possible need for dermal application studies. 

The effect on the eyes was more noticeable. A single application of the solution mentioned above produced moderate redness and short and minor swelling of conjunctiva. Radiotracer studies with Hostapur SAS [102] revealed that after oral (up to 50 mg/kg) and dermal application on rats, the product and its metabolites were very quickly excreted either in completely oxidized form as carbon dioxide or in the urine and feces. Residues in organs and tissues after 7 days were well below 1 ppm. 

LD50 values for the dermal route of exposure to methyl parathion have been established in acute studies for rats 67 mg/kg for males and females (Gaines 1960), 110 mg/kg for males, and 120 mg/kg for females (EPA 1978e). The LD50 in male mice exposed by dermal application of methyl parathion to their hind feet (rather than shaved backs) was 1,200 mg/kg (Skinner and Kilgore 1982a). The mice were muzzled to prevent oral exposure from grooming. 

In a study of pregnant rats that were exposed to radiolabeled methyl parathion by single dermal application, half-life elimination rate constants for various tissues ranged from 0.04 to 0.07 hour, highest values noted in plasma, kidneys, and fetus. Of the applied radioactivity, 14% was recovered in the urine in the first hour postapplication. By the end of the 96-hour study, 91% of the applied dose had been recovered in the urine. Fecal excretion accounted for only 3% of the administered dose (Abu-Qare et al. 2000). 

Three animal studies were located regarding distribution of endosulfan in animals following dermal exposure (Dikshith et al. 1988 Hoechst 1986 Nicholson and Cooper 1977). Endosulfan was detected in the brain (0.73 ppm), liver (3.78 ppm), and rumen contents (0.10 ppm) of calves that died after dermal exposure to a dust formulation of endosulfan (Nicholson and Cooper 1977). Following a single dermal application of aqueous suspensions of 0.1, 0.83, and 10.13 mg/kg C-endosulfan to male Sprague-Dawley rats, low concentrations of endosulfan (ng/g levels) appeared in the blood and tissues (other than skin at and around the application site) after 1 hour (Hoechst 1986). The concentrations of endosulfan in the blood and tissues increased with the time of exposure and were proportional to the dose applied. The liver and kidney appeared to sequester radiolabel relative to the concentrations of radiolabel in the blood or fat. Endosulfan levels were approximately 10 times higher in the liver and kidney than in the fat, blood, and brain throughout the study (Hoechst 1986). 

JP-8-induced systemic immunosuppression is explained in part by modulation of cytokine and inflammatory pathways. Within 48 hours of a single dermal application of JP-8 (300 pL), serum IL-10 levels increase significantly to nearly 3000 pg/mL [36], As IL-10 is known to suppress DTH responses [64,65], it is likely that modulation of this cytokine contributes to JP-8 s immunotoxicity. Furthermore, splenic T-cell proliferative responses are significantly decreased in JP-8 exposed mice, yet this effect is reversed following neutralization of IL-10, administration of IL-12, or inhibition of prostaglandin E2 (PGE2) production [60], Additional studies demonstrated suppression... 

In the pharmaceutical industry, the two most common routes of administration are via diet and gavage (PMA, 1988). Some compounds are given by drinking water, topical (dermal) application, or injection, depending on the expected clinical exposure route, which is the primary criterion for determining the route of administration in carcinogenicity studies. When more than one clinical route is anticipated for a drug, the dietary route is often chosen for practical reasons. 

Dermal Effects. No studies were located regarding the dermal effects in humans after dermal exposure to endrin. No damage to the skin at the site of application was observed in rabbits exposed to a single or repeated dermal application of dry endrin (Treon et al. 1955) however, the rabbits had convulsions. 

Phenol has been tested in animals for carcinogenicity by the oral and dermal routes, but results are equivocal. In a chronic NCI cancer bioassay (NCI 1980), a significant incidence of tumors (pheochro-mocytomas of the adrenal gland, leukemia, or lymphomas) occurred only in male rats exposed to the lowest dose level (2,500 ppm, 277 mg/kg/day) of phenol but not in male or female mice or male rats exposed to a higher dose level (5,000 ppm, 624 mg/kg/day). Since tumors occurred only in males in one of the two species tested, and since a positive dose-response relationship was not established, this study does not provide sufficient evidence to conclude that phenol is carcinogenic when administered by the oral route. Dermal application of phenol has been shown to result in tumors in mice phenol is a tumor promoter when it is applied after the application of the tumor initiator DMBA (Boutwell and Bosch 1959 Salaman and Glendenning 1957 Wynder and Hoffmann 1961). However, this effect occurs at dose levels of phenol that produce severe skin... 

No studies were located regarding the metabolism of 3,3 -dichlorobenzidine in humans following dermal exposure. In a 24-hour urine sample of rats given a single dermal application of 3,3 -dichlorobenzidine (50 mg/kg/day), -diacetyl 3,3 -dichlorobenzidine (but not/V-acetyl 3,3 -dichlorobenzidine or the unchanged chemical) was detected (Tanaka 1981). Since the mutagenicity of diacetylated product is much less than either the monoacetylated or parent compoimd (Lazear et al. 1979 Reid et al. 1984 ... 

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