Percutaneous absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from soil

Eight dermal absorption experiments (two in vivo; six in vitro) and one intravenous experiment were conducted using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either neat (high dose at approximately 250 microg/cm(2) and low dose at 10 ng/cm(2)) or sorbed on a low organic soil (LOS) or high organic soil (HOS) at 1 ppm (10 ng TCDD/10 mg soil/cm(2)). After 96 h the percent of applied dose absorbed (PADA) for the neat low dose was 78% in vivo (rat) and 76% in vitro (rat). PADA for the equivalent TCDD dose sorbed on LOS were 16.3% (rat in vivo), 7.7% (rat in vitro) and 2.4% (human in vitro). The PADA for TCDD sorbed on HOS (1 ppm) was 1.0% (rat in vitro). Generally, rat skin was observed to be three to four times more permeable to TCDD than human skin. At steady state, the dermal flux of TCDD in neat form, sorbed on LOS at 1 ppm, and sorbed on HOS at 1 ppm (all in vitro, rat) was 120, 0.007, and 0.0007 ng/cm(2)/h, respectively (ratio = 1.7 x 10(5):10:1). Making adjustments to account for differences between in vitro and in vivo results and adjusting for application to monolayer loads, the 24-h TCDD absorption for human skin is estimated as 1.9% from LOS (1 ppm) and 0.24% from HOS (1 ppm).     

Comparative dermal absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin and three polychlorinated dibenzofurans

Polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) are toxic environmental contaminants which have the potential to accumulate in human tissues. In order to examine the potential for systemic exposure following dermal exposure, the absorption, distribution, and elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), and 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) were evaluated in male F344 rats. TCDD (0.00015, 0.001, 0.01, 0.1, 0.5, and 1.0 mumol/kg) and the three PCDFs (0.1, 0.5, and 1.0 mumol/kg) were applied to a preclipped region on the back of the rat and covered with a perforated cap. The rats were held in individual metabolism cages for 3 days. In animals administered 0.1 mumol/kg, the absorption of TCDF was greater than that of 4PeCDF, 1PeCDF, and TCDD. Relative absorption (percentage of administered dose) declined with increasing dose while the absolute absorption (microgram/kg) increased nonlinearly with dose. Absorption of TCDF at 0.1 mumol/kg was 48% of the administered dose which was significantly greater than that of the other compounds. At this dose, absorption of 4PeCDF was greater than that of TCDD. Absorption at the higher doses was similar for all four compounds. Maximum relative absorption of TCDD (approximately 40% of the administered dose) was obtained at 0.001 and 0.00015 mumol/kg. Major tissue depots for these four chemicals included liver, adipose, skin, and muscle tissue; however, the liver:fat ratio for 4PeCDF was approximately fourfold higher than that for the other three compounds. When normalized to 100% of dose absorbed, the distribution of 4PeCDF-derived radioactivity in liver and adipose tissue was similar to that previously observed after oral and iv administration. In animals administered 0.1 mumol TCDF or 1PeCDF/kg, 56 and 32% of the respective absorbed dose was excreted as polar metabolites within 3 days. Very little of the absorbed dose of either TCDD (approximately 10%) or 4PeCDF (approximately 2%) was eliminated. Results indicate that the dermal absorption of these compounds is incomplete and that systemic toxicity following acute dermal exposure to levels found in the environment is unlikely.     

Penetration,distribution and kinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human skin in vitro

The in vitro penetration of³H-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into human cadaver skin was studied at concentrations of 65 and 6.5 ng TCDD per cm² of skin surface. Vehicles used were acetone to simulate exposure to TCDD as a dry material, and mineral oil to simulate exposure to TCDD in an oily medium. Penetration was performed for 30, 100, 300, and 1000 min in improved Franz cells. Skin was used either intact, or with stripped horny layer. Skin was sectioned along its natural layers and radioactivity determined in epidermis and dermis. TCDD did not readily penetrate into human skin in vitro. The vehicle of exposure to TCDD played an important role in dermal penetration. The rapidly evaporating acetone allowed TCDD to penetrate deeply into the loose surface lamellae of the horny layer, but then appeared to be poorly available for further penetration. Mineral oil as the vehicle, on the other hand, represented a lipophilic compartment which competed with lipophilic constituents of the stratum corneum for TCDD and hence slowed its penetration even more. The stratum corneum acted as a protective barrier, as its removal increased the amount of TCDD absorbed into layers of the skin. Hourly rates of absorption of TCDD per unit area of skin were calculated in two ways: a worst case scenario where TCDD absorbed into any layer of skin including the stratum corneum was used for regression analysis; and a physiological approach where only that amount of TCDD was considered absorbed which had penetrated beyond the epidermis into the region of dermal vascularization. Under worst case scenario conditions the stratum corneum appeared to mediate dermal absorption of TCDD, since calculated rates of absorption decreased when skin stripped of its stratum corneum was exposed to TCDD. This was, however, not the case with the physiological approach. There was a consistent relationship between concentration of TCDD applied and concentration of TCDD found in skin. Also, a clear-cut correlation was found between the amount of TCDD that penetrated and the time of exposure. The rate of penetration into intact skin of different concentrations of TCDD from acetone ranged from 100 to 800 pg TCDD per hour and cm² of skin (worst case scenario), or 6 to 170 pg per hour and cm² with the physiological approach. With mineral oil as the vehicle the rate of penetration into intact skin was lower, ranging from 20 to 220 pg and 1.4 to 18 pg, respectively, per hour and cm² of skin. Our results on the distribution of TCDD in human skin also suggest that as yet unknown constituents of epidermis and upper dermis have a somewhat higher affinity towards TCDD than those of the lower dermis.Presented in part at the 28th Annual Meeting of the Society of Toxicology, Atlanta, GA, 1989     

Effect of dose on the percutaneous absorption of 2- and 4-chloronitrobenzene in rats.

The effect of dose on the dermal absorption of 2- and 4-chloronitrobenzene (2- and 4-CNB) has been investigated in rats following nonocclusive protective dermal application on an area of 4 cm2 per animal at approximately 0.0325, 0.325, and 3.25 mg/cm2 (0.65, 6.5, and 65 mg/kg, respectively). At the three-dose levels, 33-40% and 51-62% of the dose of 2- and 4-CNB, respectively, was absorbed from the skin within 72 hr. The balance of the dose was recovered in the protective device and the organic trap (i.e. that portion unavailable for dermal absorption). The absorbed radioactivity was excreted in urine (21-28% of dose, 2-CNB; 43-45%, 4-CNB) and feces (11-15%, 2-CNB; 5-12%, 4-CNB). The extent and rate of dermal absorption and urinary and fecal excretion of 2-CNB were linear over the 0.65-65 mg/kg dose range; for 4-CNB they were linear over the 0.65-6.5 mg/kg dose, and nonlinear at the 65 mg/kg dose.     

Age-Related Changes in Dermal Absorption of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-Pentachlorodibenzofuran

Age-Related Changes in Dermal Absorption of 2,3,7,8-Tetrachlorodibenzo-p-dioxinand 2,3,4,7,8-Pentachlorodibenzofuran. BANKS, Y. B., BREWSTER,D. W., AND BIRNBAUM, L. S. (1990). Fundam. Appl. Toxicol. 15,163–173. Changes in the structure and function of agedskin may alter percutaneous absorption of environmental compoundssuch as the halogenated aromatic hydrocarbons. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)and 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) were previouslyfound to be poorly absorbed in 3 month male Fischer 344 ratswithin 3 days after dermal administration. In order to examineage-related changes in dermal absorption and changes in potentialfor systemic exposure, the absorption, distribution, and eliminationof TCDD and 4PeCDF were examined in male Fischer 344 rats ofvarious ages (TCDD: 10, 36, and 96 week; 4PeCDF: 10, 36, 64,96, and 120 week). Each compound was applied at a dose of 0.1µmol/kg and/or 0.04 µmol in 60 µ1 acetoneto a preclipped region of the back and covered with a stainless-steelperforated cap. Rats were housed in individual metabolism cagesfor 3 days. Dermal absorption of both compounds was decreasedin older age groups compared to 10 week rats. The major tissuedepots for both compounds were liver, adipose, skin, and muscleand in comparable age groups, the liver.fat ratio was greaterin 4PeCDF-treated animals. Age-related changes in the distributionof the administered dose and the absorbed dose varied with thecompound as well as the depot. Elimination of TCDD and 4PeCDFwas limited at all ages. Results indicate that percutaneousabsorption of these compounds is decreased in older animals,suggesting that systemic bioavailability may be decreased inolder organisms following dermal exposure to TCDD or 4PeCDF.     

Absorption and disposition of 14C-labelled Kathon biocide, a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, following intravenous or dermal administration to male Sprague-Dawley rats

Kathon biocide (KB), a 75:25 mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (KI) and 2-methyl-4-isothiazolin-3-one (KII), is a broad-spectrum antimicrobial agent. The absorption and disposition of 14C label were studied in male Sprague-Dawley rats following iv or dermal administration of KB 14C labelled in the carbonyl carbon of either KI or KII. KI-labelled Kathon was distributed rapidly following an iv dose (0.8 mg/kg). Total 14C label in the plasma was rapidly eliminated, with the data best described by a three-compartment model. Total 14C label concentration in the blood, however, remained constant at 3 ppm from 6 to 96 hr after administration and represented 29% of the dose, indicating that KI-labelled Kathon and/or metabolites was sequestered by the cellular fraction of blood. Elimination of 14C label from the tissues examined was biphasic, with a terminal half-life of more than 4 days; by 96 hr, faeces, urine and CO2 accounted for 35, 31 and 4% of the dose, respectively. Following a single 24-hr dermal application of 0.2 ml of an aqueous solution containing 2000 ppm [14C]KB (400 micrograms), rats absorbed 94% of KI-labelled KB and 82% of KII-labelled KB. However, the systemic bioavailability of KB was substantially less than this, since approximately half of the absorbed KB was associated with the skin at the application site 24 hr after the application. Percutaneous absorption was not affected by concentration over the range 500-4000 ppm. As the concentration of KI-labelled KB in the applied solution increased from 500 to 4000 ppm, the relative amount of 14C label associated with the skin decreased, while that in the excreta increased, indicating greater systemic penetration at higher concentrations. Low amounts of 14C label were found in the testes (less than 2 ppb) and blood (24 ppb) 28 days after a single dermal application of KI-labelled KB. Four consecutive daily applications of KI-labelled KB did not influence the proportion of the dose absorbed from the skin. However, the proportion of the dose excreted was higher than after a single application of an equivalent amount of KB.     

Dermal absorption of dihalomethane vapors

The dermal absorption of dibromomethane (DBM) and bromochloromethane (BCM) vapors was studied in rats placed in a specially designed chamber incorporating individual respiratory protection to avoid pulmonary uptake. Exposures (DBM: 500 to 10,000 ppm; BCM: 2500 to 40,000 ppm) lasted 4 hr during which time five blood samples were drawn from jugular cannulae for analysis of the parent dihalomethane by gas chromatography. Estimates of the amounts of chemicals stored in tissues and exhaled were based on concentrations in the blood and tissue partition coefficients, tissue volumes, and ventilation rate. Total metabolism was estimated from the amount of bromide released during the 4-hr exposure. The total amount of vapor absorbed through the skin was calculated from the estimates of the amount of parent chemical in blood and tissues, and the amounts exhaled and metabolized. The dermal flux for each concentration (DBM: 0.004 to 0.078 mg/cm2/hr; BCM: 0.011 to 0.164 mg/cm2/hr) was calculated by dividing the amount absorbed by exposed surface area and duration of exposure. Flux was divided by exposure concentration to calculate a permeability constant. With each dihalomethane the permeability constants (DBM: congruent to 1.12 cm/hr; BCM: congruent to 0.79 cm/hr) were essentially independent of exposure concentration. This study shows that a whole-body dermal vapor exposure in rodents is technically possible, and quantitation of penetration can be accomplished using calculations based on achieved blood concentrations and some measure of metabolism.     

Bioavailability of Soil-Bound TCDD: Dermal Bioavailability in the Rat

Bioavailability of Soil-Bound TCDD: Dermal Bioavailability inthe Rat. SHU, H., TEITELBAUM, T., WEBB, A. S., MARPLE, L., BRUNCK,B. DEI ROSSI, D., MURRAY, J., AND PAUSTENBACH, D. (1988). Fundam.Appl. Toxicol. 10, 335-343. 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD), an unwanted by-product formed during the manufactureof hexachlorophene and phenoxyherbicides, has been found asan environmental contaminant in many U.S. and Western Europeansites. This study examines in the rat the degree of dermal absorptionof TCDD bound to soil. Such information would assist regulatoryagencies in evaluating the degree of exposure of humans whocome in contact with TCDD-contaminated soil. Several parameterswhich may influence dermal absorption were studied, includingTCDD dose, duration of contact, presence of crankcase oil asa co-contaminant, and environmentally contaminated vs laboratory-preparedsoil. The dermal penetration of TCDD following 4 hr of contactwith skin was approximately 60% of that following 24 hr of contact(P 0.05). Following 24 hr of contact with the skin, the degreeof dermal uptake of TCDD contaminated soil was approximately1% of the administered dose. Under the conditions of the presentstudy, the degree of uptake does not appear to be influencedto any significant extent by the concentration of TCDD on soil,the presence of crankcase oil as co-contaminants, or by environmentallyvs laboratory-contaminated soil. Although a number of parametersexamined in this study did not significantly influence the degreeof dermal absorption of TCDD in the rat following 24 hr of contactwith the contaminated soil, the unqualified use of the 1% valueto estimate human exposure would overestimate human exposure,since there is general agreement among researchers that ratskin tends to be more permeable than human skin to highly lipid-solublecompounds such as TCDD.     

Pharmacokinetics and bioavailability of diisopropanolamine (DIPA) in rats following intravenous or dermal application.

This study was conducted to determine the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA), an alcohol amine used in a number of industrial and personal care products. Groups of 4 female Fischer 344 rats received either a single bolus i.v. dose of 19.0mg/kg (14)C-DIPA in water or a dermal application of 19.5mg/kg (14)C-DIPA in acetone to an area of 1cm(2) on the back and covered with a bandage. Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA). Following i.v. administration, DIPA was rapidly cleared from the plasma and excreted into urine in a biexponential manner (t(1/2alpha), 0.4h; t(1/2beta), 2.9h). The levels of radioactivity in plasma dropped below the limit of detection 12h post-dosing. A total of 97+/-4% of the dose was actively excreted in urine by kidney, most ( approximately 71%) within 6h of dosing, virtually all as parent compound; renal clearance exceeded the glomerular filtration rate. Following dermal application, approximately 20% of the dose was absorbed in 48 h with the steady-state penetration rate of approximately 0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine at a relatively constant rate due to the presence of large amount of the (14)C-DIPA at the application site. Fecal elimination was <0.2% of the dose. The absorbed DIPA did not accumulate in tissues; only approximately 0.1% of the administered dose was found in liver and kidney. The absolute systemic dermal bioavailability (dose corrected AUC(dermal)/AUC(i.v.)) of (14)C-DIPA was 12%. The ADME of DIPA contrasts that of its diethanol analogue, diethanolamine, which displays a broad spectrum of toxicity in rats and mice. Toxicologically significant concentrations of DIPA are unlikely to be achieved in the systemic circulation and/or tissues as a result of repeated dermal application of products containing DIPA due to slow absorption from the skin, rapid unchanged elimination in urine, and majority of the products contain 相似文献   

Percutaneous absorption of benzyl acetate through rat skin in vitro. 1. Validation of an in vitro model against in vivo data

The percutaneous absorption in vitro of the fragrance agent benzyl acetate has been evaluated in flow-through diffusion cells using shaved full-thickness skin from male Fischer 344 rats. After the application of neat [methylene-14C]benzyl acetate to the epidermal surface of the skin and occlusion with parafilm 1.3 cm above the skin surface, the absorption of the chemical across the skin and into the receptor fluid was rapid and extensive, commencing within 1 hr of application, and reaching 49.8 +/- 3.2% (mean +/- SD, n = 4) of the applied dose after 48 hr. The coefficient of variation for absorption at 48 hr between four identical experiments was 6.4%. The extent of absorption at 48 hr of benzyl acetate applied in 50% (v/v) ethanol was not significantly different from that after application neat, although absorption at earlier times was enhanced, with a maximum increase of 8.5% of the applied dose at 12 hr. Over the dose range studied there was a linear relationship (r = 0.996) between the amount of benzyl acetate applied to the skin (1.66-33.13 mg benzyl acetate/cm2) and the amount absorbed into the receptor fluid at 24 hr (0.66 +/- 0.04-10.27 +/- 0.51 mg/cm2). The extent of absorption of benzyl acetate through rat skin in vitro was compared with the extent of absorption in vivo at 24 hr and a correlation coefficient of 0.993 was obtained. These data support the use of this in vitro system as a model to predict in vivo absorption and indicate the suitability of the system to study factors influencing the disposition of topically applied benzyl acetate.     

Effects of Dose and Routes of Exposure on the Disposition of 2,3,7,8-[H]Tetrabromodibenzo-p-dioxin (TBDD) in the Rat

Polybrominated dibenzo-p-dioxins and dibenzofurans are of major concern because of potential occupational and environmental exposures and their structural similarity to the highly toxic chlorinated analogues. 2,3,7,8-Tetrabromodibenzo-p-dioxin (TBDD) is a closely related analogue in both structure and activity to the most toxic isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The objectives of this study were to characterize the effects of dose and routes on absorption, excretion, and terminal tissue distribution of [³H]TBDD in the rat 72 hr after dosing. Rats were treated orally by gavage with 1, 10, 100, or 500 nmol/kg, intratracheally with 1 nmol/kg, or dermally with 1 nmol/kg (200 pmol/l.8 cm²). TBDD exhibited nonlinear oral absorption kinetics with maximum absorption (80%) occurring at dose ≤10 nmol/kg. similar to the transpulmonary absorption. In contrast, dermal absorption of TBDD was low (12%). The major tissue depots of radioactivity were liver, adipose tissue, and skin. Tissue distribution of the oral dose was dose-dependent, with disproportionally greater hepatic concentrations occurring at absorbed doses of >8 nmol/kg. Liver:adipose tissue (L:F) concentration ratios were 2.9 to 6.6 (lowest to highest oral dose, respectively). The lower L:F ratios obsened for the dermal and intratracheal doses at 1 nmol/kg (1.5 and 2, respectively) were likely due to differences in absorbed dose and dose-related tissue distribution. Elimination of radioactivity in feces, the major route of excretion for all dose groups and routes, and urine was also nonlinear with respect to the oral dose. The results of the present study provide important considerations for high- to low-dose and route-to-route extrapolations with TBDD and other dioxins and furans in human risk assessments.     

Percutaneous absorption of co-administered N-methyl-2-[14C]pyrrolidinone and 2-[14C]pyrrolidinone in the rat.

The percutaneous absorption has been investigated in rats of a mixture (3:2, w/w) of N-methyl-2-pyrrolidinone (NMP) and 2-pyrrolidinone (2-P), a combination intended for use as a vehicle in the formulation of an antimycotic drug to enhance skin penetration on dermal application, following co-administration of the two 14C-radiolabelled compounds by the dermal and oral routes. Radioactivity was excreted predominantly in the urine after either route of administration, and comparison of the respective excretion profiles indicated that about three-quarters of the applied dose was absorbed through the skin. Plasma concentrations of each parent compound, as determined by radio-HPLC, reached peak values at 2 hr after oral dosing, and remained relatively uniform during 1-6 hr after application to the skin, suggesting constant percutaneous absorption during this period. NMP appeared to be absorbed through the skin more extensively and at a slightly faster rate than 2-P; total percutaneous absorption tended to be more extensive in female than in male rats. Together, these two 14C-compounds accounted for most of the plasma radioactivity up to 6-8 hr post-administration. However, by 12 hr (when plasma levels were relatively low), most of the radioactivity was associated with unknown polar metabolites. In view of the extensive percutaneous absorption and little first-pass metabolism of the two pyrrolidinones, the oral route was considered to represent a valid alternative to the dermal route for the assessment of the systemic toxicity of the two compounds.     

Percutaneous absorption of triadimefon in the adult and young male and female rat

The percutaneous absorption of 14C-phenoxy ring labeled triadimefon was studied in adult and young male and female Sprague-Dawley rats. Triadimefon was applied (41.1 to 46.4 micrograms/cm2) in 0.2 ml of acetone to areas comprising 3% of the body surface (7.0 to 14.5 cm2). Thirty-six animals were treated at the initiation of each study. Groups of three animals were subsequently killed at 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hr after treatment. Skin from the treated area as well as blood, heart, liver, kidneys, remaining carcass, urine, and feces were analyzed for 14C by scintillation counting techniques. Based on 14C counts, triadimefon was lost more rapidly from the skin of young animals (t 1/2, 20 to 25 hr) than from the skin of adult animals (t 1/2, 29 to 53 hr). Recovery studies indicated that adult males, adult females, young males, and young females, respectively, absorbed 53, 82, 57, and 52% of the dose. The rest of the dose based on material balance was presumably lost by evaporation. Approximately 2.5 to 3.9% of the dose penetrated the skin in one hour and was available for absorption. The rate of entry triadimefon into blood was 2 to 2.5 times faster for young than that observed in adult animals. Elimination of it from blood was faster in the case of the young animals. Triadimefon was absorbed through the skins of the adult male, adult female, young male, and young female rats, respectively, at rates of 0.20, 0.50, 0.58, and 0.48 micrograms/hr/cm2 of skin.     

Relative toxicity and tumor-promoting ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) in hairless mice

2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.     

Dermal uptake and excretion of 14C-toluene diisocyante (TDI) and 14C-methylene diphenyl diisocyanate (MDI) in male rats. Clinical signs and histopathology following dermal exposure of male rats to TDI

Polyurethanes (PU) are polymers made with diisocyanates such as MDI (4,4'-methylene diphenyl diisocyanate) and TDI (2,4-toluene diisocyanate and 2,6-toluene diisocyanate). Investigations have been undertaken with MDI and TDI to assess dermal uptake and resulting systemic exposure. Absorption, distribution and excretion of MDI was studied in rats using a single dermal administration of (14)C-MDI dissolved in acetone at nominal 165 mg/kg body weight and 15 mg/kg bw (4.0 and 0.4 mg/cm(2)) and intradermal injection of (14)C-MDI dissolved in corn oil at nominal 1.4 mg/kg bw. Dermal absorption of (14)C-MDI (at both doses) was low; at or below 1% of the applied dose. Considerable amounts of the applied radioactivity were found at the application site which could not be washed off. By intradermal administration of (14)C-MDI approximately 66% of applied radioactivity remained at the application site with approximately 26% recovered in excreta, cage wash, tissues and carcass. The absorption, distribution and excretion of 2,4-TDI was studied in rats following a single dermal administration of radiolabelled (14)C-2,4-TDI at nominal 350 mg/kg body weight (12 mg/cm(2)). Dermal absorption of (14)C-2,4-TDI was at or below 1% of the applied dose. Considerable amounts of the applied radioactivity were found at the application site which could not be washed off. In summary the results show that dermal uptake of MDI and TDI is very low. Due to the chemical reactivity of isocyanates it can be expected that small amounts which might be absorbed will react with tissue constituents directly at the exposed skin area, or will be converted to adducts with biomacromolecules or to biologically inactive oligoureas. Overall it is concluded that, following dermal exposure to MDI and TDI, systemic exposures and resulting toxicity, other than the known sensitization, can be expected to be very low. In addition studies were performed with dermal application of unlabelled 2,4 and 2,6 TDI to check the availability and fate of this chemical on rat skin surface and to assess possible tissue damage. These experiments showed that unchanged test material can be detected on rat skin for up to 8h if not washed off. Dermal treatment with 2,4 or 2,6 TDI was associated with irritation with increased severity over a 48 h period after washing with a decontaminant solution.     

Absorption, distribution, metabolism and excretion of intravenously and dermally administered triethanolamine in mice.

Triethanolamine (TEA) is an amino alcohol having widespread applications in consumer goods and as an industrial chemical. A number of relatively high-dose dermal toxicity studies have been conducted in rats and mice reflecting the principal route of human exposure to TEA. The absorption, distribution, metabolism and excretion (ADME) of (14)C-TEA derived radioactivity were determined in male C3H/HeJ mice following dermal application of 2000 mg/kg (neat) or, to characterize blood kinetics, intravenous (iv) injection of 1 mg/kg (14)C-TEA. Balance and excretion data were also collected in mice utilizing several dermal dosing scenarios (1000 mg/kg in acetone, 2000 mg/kg neat, 2000 mg/kg in water) and, for comparative purposes, in male Fischer 344 rats dosed dermally with 1000 mg/kg neat (14)C-TEA. Urine, feces, expired CO(2) (iv) and, where appropriate, blood were collected over a 24- or 48-hour period post-dosing. The half-life for dermal absorption of radioactivity was estimated to be 1.3 hours. Intravenously administered radioactivity was eliminated in a biphasic manner with a prominent initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr). Radioactivity was excreted primarily via the urine (49-69%) as unmetabolized TEA, regardless of dosage, route or vehicle used. Fecal excretion of radioactivity comprised 16-28% of dose administered. The body burden at sacrifice (sum of liver, kidney, carcass and non-application site skin) ranged from 3 to 6% of the dose. It was concluded that TEA is absorbed extensively following dermal application to mice at dosages relevant to toxicity testing and that acetone or water vehicles do not appear to significantly alter total uptake. Significantly, the blood kinetics and ADME of TEA in mice and/or rats differs from that of a related chemical, diethanolamine, which appears to be more toxic to rodents than TEA.     

Absorption,Metabolism, and Disposition of [14C]SDZ ENA 713, an Acetylcholinesterase Inhibitor,in Minipigs Following Oral,Intravenous, and Dermal Administration

Purpose. SDZ ENA 713 (rivastigmine) is an acetylcholinesterase inhibitor intended for therapeutic use in Alzheimer's disease. The present study compared the pharmacokinetics of [¹⁴C]SDZ ENA 713 after intravenous, oral, and dermal administration to male minipigs, and also examined the effects of dose level and skin abrasion on transdermal absorption. Methods. Four groups of 3 minipigs each received a single intravenous (0.1 mg/kg), single oral (1.0 mg/kg), or topical doses of 18 mg or 54 mg of [¹⁴C]SDZ ENA 713. Topical doses were administered as dermal patches on two occasions 10 days apart. On Study Day 1, test patches were applied to a virgin skin site. Placebo patches were applied to a separate skin site and were replaced daily during Days 1–10. On Study Day 11, test patches were applied to the site on which the placebo patches had been previously applied. After each dose, serial blood and quantitative urine and feces were collected at designated intervals for 7 days. Concentrations of radioactivity, parent drug, and metabolite ZNS 114–666 were measured in whole blood. Radioactivity was also determined in excreta, skin application sites (at study termination), and on used dermal patches (at 24 hr after application). Results. Oral doses of [¹⁴C]SDZ ENA 713 were rapidly (t_max = 0.83 hr) and efficiently (ca. 93%) absorbed, although the bioavailability of the parent drug was low, ca. 0.5%, apparently due to extensive first-pass metabolism. Radioactivity was excreted mainly in the urine (90%) with a half-life of 56 hr, slightly longer than that observed after an intravenous dose, 46 hr. After dermal administration of [¹⁴C]SDZ ENA 713 to a virgin skin site, absorption was 8% at both dose levels investigated. Following daily application of placebo patches for 10 days, absorption from a [¹⁴C]SDZ ENA 713 dermal patch increased by approximately twofold, 17% and 19% of the 18 mg and 54 mg doses, respectively. The increase is possibly due to hydration or abrasion of the skin as a result of repeated application and removal of the adhesive patches. Whereas total absorption from the dermal dose was smaller than that from the oral dose, essentially all of the absorbed drug via the dermal route reached the systemic circulation intact, thus yielding a SDZ ENA 713 bioavailability 20–40 times greater than that of the oral dose. Metabolite ZNS 114–666 was rapidly formed and accounted for <4% of total drug-related material in the systemic circulation. Conclusions. Dermal administration in minipigs provided a markedly greater bioavailability of SDZ ENA 713 than the oral route. The extent of absorption was independent of dose within the range tested, and appeared to be enhanced by hydration or abrasion of the skin application site.     

Dermal absorption and disposition of 1,3-diphenylguanidine in rats

Dermal absorption, distribution, and metabolism of 1,3-diphenylguanidine (CAS 102-06-7) (DPG), widely used as an accelerator in processing rubber and in food packaging, was studied in adult female Sprague-Dawley rats. DPG shows 10% penetration through clipped back skin of the rats in 5 d. The first-order dermal absorption rate constant as determined by least square method was 0.021 +/- 0.002 d-1 (T1/2 = 33.6 d). Approximately 13% of the absorbed dose remained in the body in 5 d. Retention in skin, muscle, liver, intestine and fat contributed most to the body burden of DPG-derived radioactivity in 5 d. All tissues showed tissue to blood ratios greater than 1, with liver and intestine ratios of 26 at 5 d. Approximately 61% of the absorbed dose was eliminated into urine and 27% into feces in 5 d showing rapid clearance of absorbed DPG from the body. High-pressure liquid chromatography (HPLC) analysis of urine revealed two major peaks [parent compound and metabolite(s)]. Within 72 h, approximately 50% of the DPG-derived radioactivity excreted in the urine was parent compound. After 72 h, the DPG-derived radioactivity in the urine was present in the form of a single metabolite, and no parent compound was detected. No parent compound was detected in feces. Two metabolites, neither of which occurred in urine, were detected in feces. The HPLC analysis of the radioactivity at the application site showed only parent compound. Even though DPG shows slow dermal penetration, this route of exposure needs to be considered in the risk assessments because of the suspected chronic toxicity of DPG.     

A physiologically based pharmacokinetic model of organophosphate dermal absorption.

The rate and extent of dermal absorption are important in the analysis of risk from dermal exposure to toxic chemicals and for the development of topically applied drugs, barriers, insect repellents, and cosmetics. In vitro flow-through cells offer a convenient method for the study of dermal absorption that is relevant to the initial processes of dermal absorption. This study describes a physiologically based pharmacokinetic (PBPK) model developed to simulate the absorption of organophosphate pesticides, such as parathion, fenthion, and methyl parathion through porcine skin with flow-through cells. Parameters related to the structure of the stratum corneum and solvent evaporation rates were independently estimated. Three parameters were optimized based on experimental dermal absorption data, including solvent evaporation rate, diffusivity, and a mass transfer factor. Diffusion cell studies were conducted to validate the model under a variety of conditions, including different dose ranges (6.3-106.9 microg/cm2 for parathion; 0.8-23.6 microg/cm2 for fenthion; 1.6-39.3 microg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5-120 microl for ethanol; 20-80 microl for 2-propanol and acetone), occlusion versus open to atmosphere dosing, and corneocyte removal by tape-stripping. The study demonstrated the utility of PBPK models for studying dermal absorption, which can be useful as explanatory and predictive tools that may be used for in silico hypotheses generation and limited hypotheses testing. The similarity between the overall shapes of the experimental and model-predicted flux/time curves and the successful simulation of altered system conditions for this series of small, lipophilic compounds indicated that the absorption processes that were described in the model successfully simulated important aspects of dermal absorption in flow-through cells. These data have direct relevance to topical organophosphate pesticide risk assessments.     

Fate of ethion in goats after intravenous, oral and dermal administration

Toxicokinetic parameters and cumulative excretion were studied in goats after intravenous, oral and dermal administration of unlabelled and 14C-ethion. Plasma concentration-time data was subjected to non-compartmental analysis. IV injection studies showed an effective half-life (t1/2) of 2 hr, a total body clearance (ClT) of 3.21.kg-1.hr-1 and a volume of distribution (Vd(ss) of 9.4 1.kg-1. Plasma levels of 14C-ethion (ethion + metabolites) were much higher and more persistent than those of unchanged ethion. Cumulative excretion of 14C-ethion was 78% of the dose with 66% in urine, 8% in faeces and 4% in milk. Oral administration resulted in low plasma levels of unchanged ethion, an absorption half-life (t1/2 abs) of 10 hr and a bioavailability of less than 5%. Cumulative excretion was 80% of the dose with 64% in urine, 14% in faeces and 1.7% in milk. Dermal application showed a t1/2 abs of 85 hr and a bioavailability of 20%. Only 0.05% of the dose was excreted unchanged in milk. It is concluded that (1) orally administered ethion is extensively metabolized in the GIT, (2) dermal application results in prolonged and limited absorption and (3) absorbed ethion is rapidly eliminated through metabolism.