Suspensions dermal

For liquid or semisolid drug products such as parenterals, emulsions, suspensions, dermal creams, etc., the issue of "direct exposure" is not clearly addressed and can be somewhat confusing. The ICH guideline states, "Where practicable when testing samples of the drug product outside the primary pack, these should be presented in a way similar to the conditions mentioned for the drug substance."... 

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). 

Overview. Humans living in areas surrounding hazardous waste sites may be exposed to endosulfan primarily via dermal contact with or ingestion of contaminated soils since this compound is found bound to soil particles. Although endosulfan can be found in water as colloidal suspensions adsorbed to particles, ingestion of contaminated finished drinking water is not expected to be a major route of exposure since endosulfan is not very water soluble. Likewise, inhalation exposure to endosulfan via volatilization from contaminated media is not a major route of exposure since endosulfan is not very... 

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. 

High ophthalmic solutions and suspensions, trans-dermal ointments and patches, nasal aerosols and sprays... 

Table 1 shows the number and types of workers and the various situations in which these workers were monitored for dermal exposure to carbaryl. Formulations of carbaryl that were evaluated included 80S, a wettable powder containing 80% active carbaryl 50W, a wettable powder containing 50% active carbaryl Sevimol 4, a liquid suspension of carbaryl in molasses containing 40% active ingredient and XLR, a water based flowable containing 4 lbs active carbaryl per gallon. 

Published acute oral LD50 values (mg/kg) for chlorobenzilate administered to rats have included 700, form unstated (2) 702 for technical material (3) 735 for xylene emulsion (3) 960-A850 for suspensions (4) 1500 for other emulsions (A) and 3100-A850, form unspecified (2). Acute dermal LD q values for rabbits include >2550 for 25WP wettable powder and >5000 for 4E emulsion (3). 

No lethality was reported among rabbits when a saline suspension of 5,000 mg 4-nitrophenol/kg was applied to the abraded dorsal surface for 24 hours (Monsanto 1983b). The animals were observed for 15 days. No treatment-related deaths were observed in rats treated dermally with doses between 50 and 250 mg/kg/day of 4-nitrophenol for 120 days (Angerhofer 1985). In mice, application of a 47 mg/kg/day dose of 2-nitrophenol or 4-nitrophenol to shaved skin for 12 weeks did not alter the survival rate (Boutwell and Bosch 1959). The NOAELs are recorded in Table 2-3. 

The dermal absorption of C-3,3, 4,4 -tetraCB (PCB 77) and 2,2, 4,4, 5,5 -tetraCB (PCB 153) in female F344 rats was assessed under conditions where the PCB was appUed as either a solid, aqueous paste, aqueous suspension, or dissolved in ethanol (Hughes et al. 1992). The chemicals were applied to the clipped mid-dorsal region of the rat. The treatment area was then occluded, and urine and feces were... 

Hughes MF, Shrivastava SP, Sumler MR, et al. 1992. Dermal absorption of chemicals Effect of application of chemicals as a solid, aqueous paste, suspension, or in volatile vehicle. J Toxicol Environ Health. 37 57-71. 

Dermal absorption was tested in eight women at a maximum dose of 0.0029 mg selenium/kg as selenomethionine (0.05% L-selenomethionine in a lotion). No detectable increase in serum selenium concentrations was observed but because the concentrations tested were so low, absorption cannot be ruled out (Burke et al. 1992a). Absorption of selenium disulfide was examined using a monthly 24-hour urine specimen in 16 persons who washed their hair weekly with a 1% selenium disulfide shampoo. No differences were found from control urinary selenium levels over the 1-year exposure period (Cummins and Kimura 1971). No absorption of selenium from selenium sulfide was seen in 15 persons who applied a 2.5% selenium sulfide suspension to their torsos and allowed it to remain on the body overnight (Kalivas 1993). 

DDT, Velsicol AR50, and triton X-100 mixed together in the form of a suspension. After a woman spilled the suspension on the front of her clothes, she became confused, developed convulsions, and died within minutes after exposure (Derbes et al. 1955). At autopsy, the brain, lungs, and kidneys were found to have nonspecific pathological changes. Deaths were not reported in a compilation of cases and personal reports of acute human dermal exposure to chlordane (ERA 1980a). 

Only one case report was available that described reproductive effects in humans after dermal exposure to chlordane. In this study, a woman accidentally spilled an unknown quantity of suspension containing chlordane down the front of her clothes and died shortly afterwards (Derbes et al. 1955). An autopsy of the woman revealed endometrial hemorrhage and superficial ulceration of the vaginal mucosa. Because of an inadequate medical history, these lesions may not be treatment-related. 

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