Dermal application

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. 

Obviously, if you wish to treat a skin condition or infection, a preparation that can be applied topically would be the preferred option. Similarly, inhalation would be the first choice if trying to treat a pulmonary or bronchial condition, such as asthma. Dermal application would also be the first choice for localized tissue treatments (e.g. muscle injury), provided that the drug can be absorbed through the skin. However, in most other situations it is necessary for drugs to enter the bloodstream in order for them to be transported to their site of action. This is most commonly achieved by ingestion, or by intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) injection when the oral route is not suitable. 

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. 

Following single dermal applications of 10 mg/kg of radiolabeled methyl parathion to pregnant rats, methyl parathion was found to be widely distributed to all major tissues and organs. Concentrations were highest in plasma and kidney, maximum levels measured 2 hours postapplication. Peak levels in liver, brain, fetus, and placenta, were measured 2 to 10 hours later, at which times the highest concentration of methyl parathion was in the fetus (Abu-Quare et al. 2000). 

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). 

Dermal application of 587 mg/kg/day of endosulfan 3 days/week, 6 hours/day for 3 weeks caused no erythema or edema in guinea pigs (Hoechst 1983b). 

Indirect evidence indicates that dermal absorption occurs in animals. Calves dusted with a 4% dust formulation of endosulfan had neurological symptoms (tremors, twitching, convulsions) and died within a day after exposure (Nicholson and Cooper 1977). Neurological effects have also been reported in preclipped rabbits and rats after repeated application of endosulfan to the skin (Dikshith et al. 1988 Gupta and Chandra 1975). Dikshith et al. (1988) reported levels of a-, [3-, and total endosulfan in liver, kidney, brain, testes, fatty tissue, and blood 30 days after dermal application of endosulfan. 

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). 

Dikshith TSS, Raizada RB, Kumar SN, et al. 1988. Effect of repeated dermal application of endosulfan to rats. Vet Hum Toxicol 30 219-224. 

As discussed imder dermal effects, people can develop hypersensitivity to trichloroethylene. The effects observed in hypersensitive individuals include skin effects (Conde-Salazar et al. 1983 Nakayama et al. 1988 Phoon et al. 1984 Waller et al. 1994) and liver effects (Phoon et al. 1984). Dermal sensitivity was confirmed with patch testing in only two cases (Conde-Salazar et al. 1983 Nakayama et al. 1988). The woman described by Conde-Salazaer et al. (1983) reacted positively to both vapor exposure and a dermal application of 5% trichloroethylene in olive oil. 

Dermal Absorption. To determine the toxicity of parathion following dermal application, the method of Draize, Woodard, and Calvery (3) was followed. Variables considered in the design of these experiments were concentration as a factor of area, solvent, exposure time, and number of exposures. In some cases the wettable powder was applied in the dry form, while in other cases sufficient water was added to produce a viscid paste. All doses in the table are presented as milligrams per kilogram of parathion, regardless of the concentration or solvent. 

Table II. Toxicity of Parathion Following Dermal Application to Rabbits...

Radioactivity was detected in the blood and urine of a single female dog, 1 hour after dermal application of a 2.094-g dose of TOCP labeled with radioactive phosphorus to a 300-cm2 area of clipped and depilated abdominal skin (Hodge and Sterner 1943). Gas chromatographic analysis of blood detected no parent material in male rats at 4, 24, or 48 hours after a 24-hour, occluded exposure to a hydraulic fluid containing 99.9% cyclotriphosphazene, but the presence of metabolites in the blood was not investigated (Kinkead and Bashe 1987). 

The title compound 188, currently under development for the treatment of acne, psoriasis and photoaging via a topical application, has been synthesized161 in two steps by reacting carboxyl-[14C]vitamin A, 189, with ethyl chloroformate and subsequent treatment of the mixed anhydride 190 with acetamidophenol in the presence of a catalytic amount of 4-dimethylaminopyridine (equation 68), Carbon- 14-labelled compound was needed to investigate its metabolism and the extent of systematic adsorption of 188 after dermal application. 

Dermal application of nickel sulfate hexahydrate causes skin and testicular damage. 

Dermal application of 81 mg silver nitrate to 3.1 cm2 of skin daily for 8 weeks... 

Rat, mouse 10 mg/kg BW Dermal application daily for 10 days causes severe effect on skin and bile duct 3... 

Rat 0.36-0.95 mg/kg BW Single dermal application causes skin irritation 3... 

Dermal application routes are also toxic. Some deaths were recorded in turkeys from dermal treatments of 15 to 20 mg chlorpyrifos/kg BW (Schlinke etal. 1969). Higher levels applied to feathers killed turkeys within 8 h (Marshall and Roberts 1978). Newborn piglets (Sus spp.) were especially more sensitive than those 30 to 36 h old to cutaneous applications of chlorpyrifos ... 

Famphur is administered to livestock by intramuscular or subcutaneous injection, through the diet, as a dermal pour-on, or as an oral bolus. In mammals, famphur induced mortality at concentrations as low as 11.6 mg/kg BW in intraperitoneal injection (mouse), 27 mg/kg BW in a single oral exposure (mouse), >33.3 mg/kg BW in an intramuscular injection (Brahman cattle, Bos indicus), and 400 mg/kg BW in a dermal application (rat, Rattus sp.). Latent effects of famphur exposure were reported in reindeer (Rangifer tarandus) hinds 1 year posttreatment (altered blood chemistry). Famphur is rapidly metabolized by mammals. The half-time persistence of famphur and famoxon in subcutaneous fat of cattle after a single pour-on application is 0.9 days and is independent of dose between 25 and 150 mg/kg BW or initial tissue residues between 1.8 and 2.3 mg/kg BW. 

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