Dermal dose, excretion

Urinary excretion of radioactivity after a dermal dose of [14C]tributyl phosphate was 29-44% of the applied dose in rats (Gatz 1992b). A large proportion of the dose (24-43%) was recovered in the site wash at the end of the exposure. 

In addition, the use of biological monitoring has the advantage that skin penetration under particular conditions of protective clothing is included as well in the approach. The results of a dose-excretion study of propoxur by Meuling et al. (1991) using volunteers indicate a significant increase of the dermal uptake of the compound under conditions of occlusion, where there is increased blood flow, skin temperature, and skin moisture. 

Carbon tetrachloride was rapidly excreted in expired air of volunteers who immersed their thumbs in liquid carbon tetrachloride (Stewart and Dodd 1964). The half-life of expiration was about 30 minutes, but no quantitative estimate of the fraction of the absorbed dose excreted in air was performed. No studies were located regarding excretion in animals after dermal exposure to carbon tetrachloride. 

Dermal application of 14C-labeled 4-nitrophenol to dogs resulted in 11% of the dose (radioactive label) excreted in the urine over a period of 7 days. Fecal elimination was negligible. In rabbits, 78% of an absorbed dermal dose of C-labeled 4-nitrophenol appeared in the urine in 1 day. As in dogs, fecal elimination accounted for less than 1% of the absorbed dose (Snodgrass 1983). 

In vivo experiments on 4 human volunteers, to whom 0.0026 mg/cm2 of 14C-benzene was applied to forearm skin, indicated that approximately 0.05% of the applied dose was absorbed (Franz 1984). Absorption was rapid, with more than 80% of the total excretion of the absorbed dose occurring in the first 8 hours after application. Calculations were based on urinary excretion data and no correction was made for the amount of benzene that evaporated from the applied site before absorption occurred. In addition, the percentage of absorbed dose excreted in urine that was used in the calculation was based only on data from rhesus monkeys and may not be accurate for humans. In another study, 35-43 cm2 of the forearm was exposed to approximately 0.06 g/cm2 of liquid benzene for 1.25-2 hours (Hanke et al. 1961). The absorption was estimated from the amount of phenol eliminated in the urine. The absorption rate of liquid benzene by the skin (under the conditions of complete saturation) was calculated to be low, approximately 0.4 mg/cm2/hour. The absorption due to vapors in the same experiment was negligible. The results indicate that dermal absorption of liquid benzene is of concern, while dermal absorption from vapor exposure may not be of concern because of the low concentration of benzene in vapor form at the point of contact with the skin. No signs of acute intoxication due to liquid benzene dermally absorbed were noted. These results confirm that benzene can be absorbed through skin. However, non-benzene-derived phenol in the urine was not accounted for. 

Hexachlorophene is well absorbed orally and dermal-ly and through mucosal surfaces. In rats, up to 55% of dermally applied hexachlorophene is absorbed in 24 h. Dermal absorption is enhanced by dimethylsulf-oxide and dermatitis or skin abrasions. Placental transfer has been demonstrated in rats. Hexachlorophene is converted to hexachlorophene-jS-o-glucuro-nide in the rat and rabbit. Some hexachlorophene has been found in the blood and adipose tissue. Hexachlorophene was administered intraperitoneally to rats and rabbits excretion was slow and most (48-83%) was excreted unchanged in the feces. Hepatic function is an important determinant in the removal of hexachlorophene. In a rat study, within 3h after administration, 50% was excreted in the bile. Rats given intraperitoneal doses excreted 5 % of the dose in the urine and none as CO2 more than 70% of the material was excreted in feces. 

Data in animals regarding the excretion of hydrazines are limited to two studies. In dogs administered a single dermal dose of 300-1,800 mg/kg 1,1-dimetliylhydrazine, levels of up to 600 pg/mL... 

In rats, approximately 60% of a single dermal dose of 157 pmol/kg was excreted in the urine during a... 

Male Sprague-Dawley rats were treated with a single dermal dose of 2.5 mg MBOCA or C-MBOCA within 72 hours, 2.54% of the administered radioactive MBOCA was excreted as C, while only... 

The percents of the total dose excreted In urine over the 10 days averaged (high and low dose) dlmethoate, 12% dlchlorvos, 10% ronnel, 11% dlchlofenthlon, 57% carbophenothlon, 66% parathlon, 40% and leptophos, 50%. Very little of this excretion occurred beyond the third day post exposure. Intact residues of ronnel, dlchlofenthlon, carbophenothlon, and leptophos were found In fat on day 3 and day 8 post exposure. In another rat experiment, animals were dosed once dermally and Intramuscularly with azlnphosmethyl (44). About 78% of the dermal dose had been excreted In urine In 24 hr. Its rate of excretion peaked In 8-16 hr., continued at about the same rate for another 16 hr., and declined to a steady level 16 hr. thereafter. There was a linear relationship between dermal dose and urinary excretion. The Intramuscular dose was excreted much more rapidly than the dermal dose. No apparent relationship existed between the Intramuscular dose and urinary excretion. 

Because these experiments illustrate the excretion differences between dermal. Intramuscular, and oral dose excretion, the excretion differences between compounds, and also problems about which urinary metabolite to monitor (see 44). a very comprehensive experimental design would be necessary to correctly model dermal exposure, absorption, and urinary metabolite levels. Statistical problems, centering around replicate variation and the resulting necessity for abnormally large numbers of replications, could drive the costs of such an experiment In small animals, and certainly in humans, to prohibitively high levels. 

The Issues of how r whether to measure dermal dose versus urinary excretion is another Important research need which also leads into the absorption submodel. The external dose measurement has two potential advantages over urinary excretion ... 

Unresolved Issues Include how many samples of each are required and how can one relate dose to absorption, excretion to AAChE, or (of academic Interest) dose to excretion. The difficulty in correlating dermal dose and excretion (2,26,27) is related in part to the differences mentioned earlier between measuring dose with pads-and-gloves and washing the skin (2,18). The correlation difficulty is most severe with the skin wash technique because it measures the dose that isn t absorbed. Depending upon the time-history of exposure and the kinetics of absorption, it should be equally expected that dermal dose by washing and urinary excretion will even... 

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). 

Siddiqui et al. 1987a Tyagi et al. 1984). Limited data from an acute dermal study showing a dose-related decrease in excretion with increasing dose indicate that the metabolism of endosulfan is saturable (Hoechst 1986). 

Elevated trichloroethylene levels in expired air were measured in subjects who immersed one hand in an unspecified concentration of trichloroethylene for 30 minutes (Sato and Nakajima 1978). Guinea pigs, exposed to dilute concentrations of aqueous trichloroethylene (-0.020 to 0.110 ppm) over a majority of their body surface area for 70 minutes, excreted 59% of the administered dose in the urine and feces 95% of the metabolized dose was excreted in 8.6 days (Bogen et al. 1992). No other studies were located for humans or animals regarding excretion after dermal exposure to trichloroethylene. 

No animal or human data were available for inhalation exposure. There are no data regarding effects in humans after oral exposure. Information is available in animals regarding health effects following acute, intermediate, and chronic oral ingestion of diisopropyl methylphosphonate. The animal data obtained after oral exposure indicate that diisopropyl methylphosphonate is moderately toxic after acute bolus exposure but has a lower order of toxicity after intermediate and chronic exposures in food. No data were found on the toxicity of diisopropyl methylphosphonate after exposure in drinking water. Further, diisopropyl methylphosphonate is rapidly metabolized and excreted and does not accumulate. It does not appear to have reproductive or developmental effects. At the doses tested, it does not appear to be an acetylcholinesterase inhibitor, although this issue has not been resolved yet. Limited data are available for dermal exposure in humans and animals. Diisopropyl methylphosphonate does not appear to be a... 

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. 

Urinary excretion of radioactivity was measured in human volunteers during and after a 3.5-hour period of dermal exposure to 0.11 or 0.22 g 32P-labeled TOCP (Hodge and Sterner 1943). The specific activity of the test substance was not reported. Radioactivity in urine was measured with a Geiger-Muller counter, but the limits of detection were not reported. Maximum estimated excretion rates, 10 and 43 pg TOCP/hour for the respective dosage levels, were measured within 24 hours of initiation of exposure. Radioactivity was not detected 48 or 72 hours after dosing ceased. Cumulative radioactivity detected in urine accounted for 0.13% and 0.36% of the dermally applied radioactivity. 

The relationship between exposure and internal dose is known only for a few pyrethroids. Human volunteer studies have shown that, after a single oral administration, pyrethroids and the respective metabolites are excreted in urine within 24 hr and do not accumulate in the body. In field workers exposed to cypermetrin through the dermal route, urine excretion of the intact compound and its metabolites peaked 36 hr after exposure had ceased (WHO, 1989). 

The internal dose of propoxur was measured by assessing the total amount of 2-isopropoxyphenol (IPP) excreted in the urine, collected over a period of 24 hr from the start of exposure, and described in detail in previous studies (Brouwer et al., 1993 Meuling et al., 1991). Volunteer kinetics studies revealed a one-to-one relationship of absorbed propoxur and excreted IPP on a mole basis. Based on the results by Machemer et al. (1982), a pulmonary retention of 40% was used to calculate the relative contribution of the respiratory exposure to the internal exposure. To estimate the contribution of the dermal exposure, the calculated respiratory portion was subtracted from the total amount of IPP excreted in urine. 

Mirex is excreted in human milk. Mirex was identified in 3 of 14 milk samples obtained from Canadian women (Mes et al. 1978). The dose was not reported, but exposure was assumed to be of chronic duration via the diet or via dermal contact (Mes et al. 1978). 

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the absorption, distribution, metabolism, and excretion of disulfoton by humans or animals after inhalation or dermal exposure. Limited data exist regarding the absorption, distribution, and excretion after oral exposure to disulfoton. Data on levels of disulfoton and metabolites excreted in urine and expired air suggest that some almost complete absorption of an administered dose of disulfoton over 3-10 days (Lee et al. 1985 Puhl and Fredrickson 1975). The data are limited regarding the relative rate and extent of absorption. Animal data suggest that disulfoton and/or its metabolites are rapidly distributed to the liver, kidney, fat, skin, muscle, and brain, with peak levels occurring within 6 hours (Puhl and Fredrickson 1975). Elimination of disulfoton and metabolites occurs primarily in the urine, with >90% excreted in the urine in 3-10 days (Lee et al. 1985 Puhl and Fredrickson 1975). 

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