Dermal administration

The primary systemic targets of endosulfan toxicity in animals following dermal exposure are the liver and kidney. Adverse hematological effects have also been observed following dermal administration of endosulfan. No studies were located regarding musculoskeletal effects in humans or animals after dermal exposure to endosulfan. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

Woollen BH, Marsh JR, Laird WJD, Lesser JE (1992) The metabolism of cypermethrin in man differences in urinary metabolite profiles following oral and dermal administration. Xenobiotica 22 983-991... 

The rate and extent to which a xenobiotic entity enters the systemic circulation intact, following oral or dermal administration. It is sometimes expanded to include therapeutically active metabolites. Also known as the comparative bioavailability. 

J. M. Mathews, K. Decosta, B. E Thomas, Lauramide Diethanolamine Absorption, Metabolism, and Disposion in Rats and Mice after Oral, Intravenous, and Dermal Administration , Drug Metab. Dispos. 1996, 24, 702-710. 

Similar to Voltaren" Emulgel, oily droplets of an eutectic mixture of lidocaine and prilocaine are dispersed in a hydrogel to provide local anesthesia to the skin for injections and siugical treatment (Emla cream). A further possibility is the dermal administration of a liposome dispersion as a spray (Heparin PUR ratiopharm Spriih-gel "). After administration, water and isopropylic alcohol evaporate partially resulting in an increase of concentration and in a transition from the initial liposome dispersion into a lamellar liquid crystal [32]. The therapeutic effect appears to be influenced favorably by the presence of lecithins rather than by the degree of liposome dispersion. 

Absolute systemic bioavailabUity (absorbed fraction of the dose or concentration administered) can only be calculated by comparing the so-called Area Under the Plasma Curve (AUC, the area under the curve in a plot of the concentration of a substance in the plasma against time) after oral, inhalation, or dermal administration with the AUC after direct administration into the systemic circulation, e.g., after intravenous administration. In order to obtain a rehable estimate for AUC after single administration, it is necessary to have blood samples for 3-5 half-hves. In case data are not available for a calculation of the AUC, the absorbed fraction can be indicated from data on the amount of the parent compound and its metabohte(s) excreted in the urine, feces, and exhaled air. It should be noted that the amount excreted in the feces stems from both the unabsorbed fraction as well as from the fraction of the substance following bUiary excretion. 

Initial toxicity data on an uncharacterized agent usually are obtained by oral, intraperi-toneal, or dermal administration to laboratory animals. This provides an estimate of the lethal potency of the material. Observation of the animals after administration of the material often provides valuable information concerning the effects that may occur in humans. Autopsy of the animals will show the likely target organs in humans. 

Available data indicate that 2-hexanone is readily absorbed by humans and various animal species after inhalation, oral, or dermal administration (Di Vencenzo et al. 1977, 1978). However, information on the rates of absorption via the inhalation and oral routes, as well as estimates of the fraction of the applied dermal dose that is absorbed, would be useful in assessing potential absorption by exposed humans. In addition, information on potential determinants of absorption such as dose level and nutritional status would also be helpful. 

Mathews, J.M., Gamer, C.E. Matthews, H.B. (1995) Metabolism, bioaccumulation, and incorporation of diethanolamine into phosphohpids. Chem. Res. Toxicol, 8, 625-633 Mathews, J.M., Gamer, C.E., Black, S.L. Matthews, H.B. (1997) Diethanolamine absorption, metabolism and disposition in rat and mouse following oral, intravenous and dermal administration. Xenobiotica, 27, 733-746... 

Verschueren, K. (1996) Handbook of Environmental Data on Organic Chemicals, 3rd Ed., New York, Van Nostrand Reinhold, pp. 1823-1825 Waechter, J.M. Rick, D.L. (1988) Triethanolamine Pharmacokinetics in C3H/HeJMice and Fischer-344 Rats Following Dermal Administration, Midland, MI, Dow Chemical Company WesL R.J. Gonsior, S.J. (1996) Biodegradation of triethanolamine. Environ. Toxicol. Chem., 15, 472 80... 

This paper discusses some of the investigative steps taken to develop an analytical procedure by which urinary levels of chlorobenzilate (CB), dicofol (DC) and suitable metabolites, especially p,p -dichlorobenzo-phenone (DBP) can be determined. The approach is classical rat-dosing experimentation involving both oral and dermal administration of the two acaricides of interest. 

Dermal. Dermal administration is required for estimation of toxicity of chemicals that may be absorbed through the skin, as well as for estimation of skin irritation and photosensitization. Compounds are applied, either directly or in a suitable solvent, to the skin of experimental animals after hair has been removed by clipping. Often dry materials are mixed with water to make a thick paste that can be applied in a manner that ensures adequate contact with the skin. Frequently the animals must be restrained to prevent licking and hence oral uptake of the material. Solvent and restraint controls should be considered when stress is involved. Skin irritancy tests may be conducted on either animals or humans, using volunteer test panels for human tests. 

Excretion data in orally and parenterally exposed humans indicate that feces is the major route of radium excretion and that biliary excretion is probably also involved. Some urinary elimination also takes place in persons exposed via inhalation, oral, and dermal routes. Continued excretion for months after exposure has been attributed to the release of radium from the lungs in persons exposed via inhalation and from the turnover of bone matrix in persons exposed orally or via parenteral administration. It would be useful to have quantitative information on the excretion patterns of radium administered to animals via inhalation, oral, and dermal administration and to more clearly elucidate the role of biliary excretion in the elimination process. 

Within 120 hours after dermal administration of 0.32 g/kg 2,3,7,8-TCDD to the clipped back skin of male Fischer 344 rats, 4% of the administered dose was excreted in the feces and <1% was excreted in the urine (Banks and Bimbaum 1991). The rate of 2,3,7,8-TCDD elimination significantly increased overtime. 

Chromium compounds are absorbed after dermal administration by guinea pigs. Measurement of 51chromium in the organs and body fluids revealed distribution, due to dermal absorption of... 

Cossum PA,Troung L, Owens SR, Markham PM, Shea JP, Crooke ST. Pharmacokinetics of a 14C-labeled phosphorothioate oligonucleotide, ISIS 2105, after intra-dermal administration to rats. J Pharmacol Exp Therapeut 1994 269(l) 89-94. 

Dix KJ, Coleman DP, Fossett JE et al. (2001) Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure. Xenobiotica 31 357-375 Mathews JM, Black SR, Burka LT (1998) Disposition of butanal oxime in rat following oral, intravenous and dermal administration. Xenobiotica 28 767-777 Okuyama Y, Momota K, Morino A (1997) Pharmacokinetics of Prulifloxacin. Arzneim Forsch/Drug Res 47 276-284 Simonsen L, Petersen MB, Benfeldt E, Serup J (2002) Development of an in vivo animal model for skin penetration in hairless rats assessed by mass balance. Skin Pharmacol Appl Skin Physiol 15 414 124... 

Capsaicin in humans has a very low oral bioavailability, not because of lack of absorption, but because it is almost completely metabolized in the liver before reaching the general circulation, where it exists almost exclusively as metabolites. The very poor oral bioactivity is also responsible for the large difference in LD50 between oral and dermal administration of capsaicin (LD50 about 190 and >510 mg/kg... 

Fire Master BP-6 appears to have a similar acute toxicity to rats as the PCB mixtures Aroclor 1254 and Kanechlor 500 [5].The LD50 values of commercial mixtures show a relatively low order of acute toxicity (LDS0 > 1 g/kg body weight) in rats, rabbits and quails, following oral or dermal administration. The toxicity of PBBs was higher with multiple dose rather than single dose administration. The few studies performed with commercial octabrominated biphenyl mixtures and BB-209 did not result in mortality in rats and fish. On the basis of the limited available data, octabrominated biphenyls and BB-209 appear to be less toxic than other lower brominated PBB mixtures, probably because they are less efficiently absorbed [2]. 

Acute toxicity refers to those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours. 

If a drug is intended for use by ocular or dermal administration, one of the first requirements is to determine whether it could cause irritation upon contact with those tissues. Drugs or drug formulations that may inadvertently come into contact with the eye... 

Sulfhemoglobinemia has been reported after trans-dermal administration of dimethylsulfoxide (12). 

Octyidodecanol has been used in the preparation of oil/ water microemulsions investigated as the vehicle for the dermal administration of drugs having no or low skin penetration. Octyidodecanol has also been evaluated as a solvent for naproxen when applied topically. ... 

It has been difficult to demonstrate arsenic carcinogenicity in animal experiments. Oral and dermal administrations of arsenic trioxides and pentoxides have not resulted in carcinogenic outcomes in animal studies. Likewise, animal studies on organic arsenic compounds have been negative. Inorganic arsenic compounds induce deletion mutations and some chromosomal abnormalities, but no point mutations. 

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