Single Dermal Dose Research Articles

Human metabolism and urinary excretion kinetics of the UV filter Uvinul A plus® after a single oral or dermal dosage.

Hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, better known under its trading name Uvinul A plus® is a UV filter mainly used in sunscreens, but also present in other cosmetic products with a maximum concentration of 10% (w/w) according to the EU directive. In this study we investigated the human metabolism after a single oral and a single dermal dose of Uvinul A plus®, respectively. Samples collected within 72h of administration were analyzed with a newly developed UHPLC-MS/MS method. Results of the study revealed three major urinary metabolites, namely 2-(4-amino-2-hydroxybenzoyl)benzoic acid (AHB), 2-(4-(ethylamino)-2-hydroxybenzoyl)benzoic acid (EHB) and 2-(4-(diethylamino)-2-hydroxybenzoyl)benzoic acid (DHB), representing 52% of the administered oral dose. The three major metabolites are further converted into four minor metabolites with an additional hydroxyl group in the aniline moiety. Toxicokinetic parameters (amount excreted, tmax, elimination constant and half-life t1/2) and conversion factors were determined for the three major metabolites. The conversion factors were used to estimate the mean daily exposure to Uvinul A plus® in spot urine samples from 58 volunteers not intentionally exposed to Uvinul A plus® derived from a pilot study. The three major metabolites were quantifiable in 26% of the samples. In 35% of the samples, at least one major metabolite could be quantified. The daily systemic exposure to Uvinul A plus® was estimated to approximately 8.1-9.3μg/d by applying the combined conversion factor for all three major metabolites. In conclusion, a very low systemic exposure to DHHB was observed with regard to the no observed adverse effect level (NOAEL) as an established threshold for chronic uptake.

Toxicokinetics of a urinary metabolite of tebuconazole following controlled oral and dermal administration in human volunteers

Tebuconazole (TEB) is a widely used triazole fungicide, but the toxicokinetics of its human metabolites are not fully described. For proper interpretation of biological monitoring data, knowledge on the metabolism and elimination of the compound is required. A human volunteer study was performed with the aim to describe the time courses of urinary excretion after controlled oral and dermal administration of TEB. Six healthy volunteers (three males and three females) received on separate occasions a single oral dose of 1.5 mg of TEB and a single dermal dose of 2.5 mg during 1 h. In addition to a pre-exposure urine sample, complete urine voids were collected over 48 h post-administration. The main metabolite hydroxy-tebuconazole (TEB-OH) was quantified in each urine sample. Peak excretion rates after oral and dermal administration were reached after 1.4 and 21 h, mean elimination half-lives were 7.8 and 16 h, and recoveries within 48 h were 38% and 1%, respectively. The time courses of excretion were compared to simulations with an established physiologically based toxicokinetic model for TEB that was extended with a parallel model for TEB-OH. Overall, TEB-OH was rapidly excreted into urine after oral exposure, and renal elimination was considerably slower after dermal exposure. Urinary time courses between individuals were similar. The model predictions were in good agreement with the observed time courses of excretion.

ACUTE DERMAL TOXICITY STUDY OF ARECA CATECHU LINN. EXTRACT IN SPRAGUE-DAWLEY RATS

ABSTRACTObjective: Areca catechu Linn. or biji pinang is one of the most widely used psychoactive substance with several hundred million users worldwide,predominantly in Southern Asia. However, details of the dermal toxicity of A. catechu L. are still undiscovered. The objective of this study is toinvestigate the in vivo acute dermal toxicity of aqueous extract of A. catechu L. at dose 15,000 mg/kg body weight in Sprague-Dawley rats.Methods: The acute dermal toxicity of A. catechu L. nut extract was investigated in rats, as per OECD Guidelines 402 for acute toxicity protocols. Thebody weight, possibility of death, general signs, and behavior activity parameters were measured for 14 days to ascertain the median lethal dose(LD50) of the extract. At the end of the study, all the animals in all the treated group were sacrificed.Results: The LD50 was found to be >15,000 mg/kg body weight. There was significant weight increase (p<0.05) in treated group when comparedto control group. No mortality was observed during whole 14 days study period. A single dose of 15,000 mg/kg of body weight did not producetreatment-related signs of toxicity in any of animal tested.Conclusion: A single dermal dose to A. catechu L. aqueous extract had no toxic effects on mortality, clinical signs, body weight changes, and grossfindings in female rats at a dose of 15,000 mg/kg of body weight. Subsequently, the concentrate can be employed for pharmaceuticals nutrient plants.Keywords: A. catechu L., Acute dermal toxicity, LD50.

Acute Dermal Toxicity Study of Bee Venom (Apis mellifera L.) in Rats

Bee venom (Apis mellifera L. BV) has been used as a cosmetic ingredient for anti-ageing, anti-inflammatory and antibacterial functions. The aim of this study was to evaluate the acute toxicity after a single dermal administration of BV, BV was administered to 2 groups of Sprague-Dawley (SD) male and female rats (5 animals/group) at doses of 0 and 1,500 mg/kg body weight (BW). Mortality, clinical signs, body weight changes and gross findings were continually monitored for 15 days following the single dose. There were no unscheduled deaths in any groups during the study period. No BV related clinical signs and body weight changes were observed in any groups during the study period. There were no abnormal gross findings at necropsy on day 15 after the treatment. On the basis of the above results, it was concluded that there were no treatment-related effect on mortality, clinical signs, body weight changes and gross findings in SD rats treated with a single dermal dose of BV at dose of 1,500 mg/kg BW. Therefore, the approximate lethal dose of BV was considered to be over 1,500 mg/kg/day for both sexes of rats. BV may provide a developmental basis for a cosmetic ingredient or external application for topical uses.

Abstract 5462: Single dose dermal irritation study of apaziquone in rabbits

Abstract Introduction and Objectives: Apaziquone is a novel bioreductive alkylating agent in development for intravesical therapy of nonmuscle invasive bladder cancer (NMIBC). The standard dose of apaziquone in all ongoing clinical studies is 4 mg/ 40 mL (0.1mg/mL). For clinical use, lyophilized apaziquone is reconstituted with diluent and instilled in the bladder. During the preparation and handling of the product, there is a possibility of accidental dermal contact for the healthcare professionals. To date, dermal irritation potential of apaziquone has not been investigated. The purpose of this study was to evaluate the dermal irritation potential of apaziquone in rabbits. Materials & Methods: Apaziquone was administered topically on the skin (non-occlusive) to New Zealand White (NZW) rabbits as a single dose for 4 hours followed by removal of excess material, and skin examination for up to 72 hours after removal of excess material. Each male NZW rabbits (3/group; one group) had three identified treatment sites on the back: (1) untreated (2) vehicle (diluent for apaziquone) and (3) apaziquone (0.1 mg/mL). Animals were treated with a single non-occlusive dermal dose of apaziquone (0.5 mL of 0.1 mg/mL) and vehicle for 4 hours followed by removal of excess material. No test material or vehicle was applied to the site designated as untreated. The treatment sites were observed and scored at baseline and at various times (4, 24, 48, and 72 hours) after removal of excess test article and vehicle. The following parameters were evaluated: viability, clinical observations, and dermal observations/scoring by modified Draize method. Results: No clinical signs of toxicity were observed during the study and no signs of dermal irritation related to test article or vehicle/diluent were observed at any of the dose sites in any of animals. The Primary Dermal Irritation Index for apaziquone, administered at clinically relevant exposures, had a value of zero (0) indicating no irritation at the concentration and for the duration of exposure. Conclusion: Apaziquone did not cause any dermal irritation in rabbits at a clinically relevant concentration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5462. doi:1538-7445.AM2012-5462

Antibacterial and dermal toxicological profiles of ethyl acetate extract from Crassocephalum bauchiense (Hutch.) Milne-Redh (Asteraceae)

BackgroundThe emergence in recent years of numerous resistant strains of pathogenic bacteria to a range of formerly efficient antibiotics constitutes a serious threat to public health. Crassocephalum bauchiense, a medicinal herb found in the West Region of Cameroon is used to treat gastrointestinal infections as well as liver disorders. The ethyl acetate extract from the leaves of C. bauchiense was evaluated for its antibacterial activity as well as acute and sub-acute toxicities.MethodsThe plant extract was prepared by maceration in ethyl acetate. Its phytochemical screening was done by standard methods. The broth microdilution method was used to evaluate the in vitro antibacterial activity. The in vivo antibacterial activity of a gel formulation (0.05, 1 and 2% w/v) of this extract was evaluated using a Staphylococcus aureus-induced dermatitis in a murine model. Selected haematological and biochemical parameters were used to evaluate the dermal sub-acute toxicity of the extract in rats.ResultsPhytochemical screening of the C. bauchiense extract revealed the presence of alkaloids, phenols, tannins and sterols. In vitro antibacterial activities were observed against all the tested microorganisms (MIC = 0.04-6.25 mg/ml). Formulated extract-gel (2% w/v) and gentamycin (reference drug) eradicated the microbial infection after five days of treatment. A single dermal dose of this extract up to 32 g/kg body weight (bw) did not produce any visible sign of toxicity. Also, daily dermal application of the C. bauchiense extract gel formulation for 28 days did not show any negative effect, instead some biochemical parameters such as alanine aminotransferase (ALT and AST), low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides were significantly (p < 0.05) affected positively.ConclusionThese results indicate that the C. bauchiense ethyl acetate extract can be used safely for the treatment of some bacterial infections.

The effect of chlorine substitution on the disposition of polychlorinated biphenyls following dermal administration

The fate of selected polychlorobiphenyls (PCBs) was investigated following single dermal administration (0.4 mg/kg) to determine the effects of chlorine content and position on the disposition of PCBs following dermal absorption. Single dermal doses of (14)C-labeled mono-, di-, tetra- and hexachlorobiphenyls were administered to 1 cm(2) areas on the backs of F-344 male rats. Distribution of radioactivity in selected tissues and excreta was determined by serial sacrifice at time points up to 2 weeks. Unabsorbed radioactivity was removed from the dose site at either sacrifice or 48 h post-dose. The time course of radioactivity in the tissues showed a dependence on rate and extent of absorption. The most rapidly absorbed PCBs reached peak tissue concentrations at early times and were cleared from the tissues rapidly. The higher chlorinated PCBs were slowly absorbed and tended to accumulate in the adipose and skin after removal of unabsorbed dose. Excretion of absorbed radioactivity varied with chlorine content ranging from 27% to ca. 100% at 2 weeks post-dose. Excretion profiles following dermal doses tended to differ from profiles following equivalent IV doses, as did the metabolite profiles in excreta. Skin slice incubation experiments suggested that first pass metabolism in the dermal dose site was responsible for metabolism and disposition differences between routes of administration. The data further suggest that the rate of absorption, and therefore the disposition of PCBs following dermal administration may be mediated, either in part or fully, by transdermal metabolism.

DEET ( N,N -DIETHYL- m -TOLUAMIDE) ALONE AND IN COMBINATION WITH PERMETHRIN INCREASED URINARY EXCRETION OF 6β-HYDROXYCORTISOL IN RATS, A MARKER OF HEPATIC CYP3A INDUCTION

In this study, the ratio of 6 g -hydroxycortisol (6 g -OHF) to free cortisol (F) was determined in urine following a single dermal dose of 400 mg/kg of DEET ( N,N -diethyl- m -toluamide), and 1.3 mg/kg of permethrin, alone and in combination, in rats. Urine samples were collected at 2, 4, 8, 16, 24, 48, and 72 h after application. Recoveries of 6 g -OHF and cortisol (F) from control urine samples were between 75 and 85%, with limits of detection at 30 and 10 ng/ml for cortisol and 6 g -OHF, respectively. A single dermal dose of DEET alone and in combination with permethrin significantly increased urinary excretion of 6 g -hydroxycortisol 24 h after dosing. Permethrin did not significantly alter the urinary excretion of 6 g -hydroxycortisol. These results indicate that DEET, alone and in combination with permethrin, increased urinary excretion of 6 g -OHF in rats following a single dermal dose application.

COMBINED EXPOSURE TO DEET (N,N-DIETHYL-m-TOLUAMIDE) AND PERMETHRIN-INDUCED RELEASE OF RAT BRAIN MITOCHONDRIAL CYTOCHROME c

The release of cytochrome c from the mitochondrial intermembrane space can induce apoptosis. The levels of mitochondrial cytochrome c in rat brain following a single dermal dose of 400 mg/kg of DEET, and of 1.3 mg/kg of permethrin, alone or in combination were determined. Rats were sacrificed at a time interval of 0.5, 1, 2, 4, 8, 16, 24, 48, or 72 h after dosing. Brain mitochondria were isolated and the levels of cytochrome c were measured using reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Average percentage recovery of cytochrome c

INHIBITION OF CHOLINESTERASE ENZYMES FOLLOWING A SINGLE DERMAL DOSE OF CHLORPYRIFOS AND METHYL PARATHION, ALONE AND IN COMBINATION, IN PREGNANT RATS

Pregnant Sprague-Dawley rats (14-18 d of gestation) were treated with either a single dermal subclinical dose of 30 mg/kg (15% of dermal LD50) chlorpyrifos (O,O-diethyl O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate) or a single dermal subclinical dose of 10 mg/kg (15% of dermal LD50) methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) or the two in combination. Chlorpyrifos inhibited maternal and fetal brain acetylcholinesterase (AChE) activity within 24 h of dosing, (48% and 67% of control activity, respectively). Following application of methyl parathion, peak inhibition of maternal and fetal brain AChE activity occurred at 48 h and 24 h after dosing (17% and 48% of control activity, respectively). A combination of chlorpyrifos and methyl parathion produced peak inhibition of maternal and fetal brain AChE activity at 24 h postdosing (35% and 73% of control activity, respectively). Maternal and fetal brain AChE activity recovered to various degrees of percentage of control 96 h after dosing. Application of methyl parathion or chlorpyrifos alone or in combination significantly inhibited maternal plasma butyrylcholinesterase (BuChE) activity. No significant inhibition of fetal plasma BuChE activity was detected. Peak inhibition of maternal liver BuChE occurred 24 h after application of methyl parathion or chlorpyrifos alone or in combination (64%, 80%, and 61% of control activity, respectively). Significant inhibition of placental AChE occurred within 24 h after application of methyl parathion or chlorpyrifos alone or in combination. The results suggest that methyl parathion and chlorpyrifos, alone or in combination, were rapidly distributed in maternal and fetal tissues, resulting in rapid inhibition of cholinesterase enzyme activities. The lower inhibitory effect of the combination could be due to competition between chlorpyrifos and methyl parathion for cytochrome P-450 enzymes, resulting in inhibition of the formation of the potent cholinesterase inhibitor oxon forms. The faster recovery of fetal plasma BuChE is attributed to the de novo synthesis of cholinesterase by fetal tissues compared to maternal tissues.

Induction of urinary excretion of 3-nitrotyrosine, a marker of oxidative stress, following administration of pyridostigmine bromide, DEET ( N, N-diethyl- m-toluamide) and permethrin, alone and in combination in rats

In this study, we determined levels of 3-nitrotyrosine in rat urine following administration of a single oral dose of 13 mg/kg pyridostigmine bromide (PB) (3-dimethylaminocarbonyloxy- N-methylpyridinum bromide), a single dermal dose of 400 mg/kg N,N-diethyl- m-toluamide (DEET) and a single dermal dose of 1.3 mg/kg permethrin, alone and in combination. Urine samples were collected from five treated and five control rats at 4, 8, 16, 24, 48, and 72 h following dosing. Solid-phase extraction coupled with high-performance liquid chromatography with ultraviolet detection at 274 nm was used for the determination of tyrosine and 3-nitrotyrosine. A single oral dose of PB and a single dermal dose of DEET or their combination significantly ( P<0.05) increased levels of 3-nitrotyrosine starting 24 h after dosing compared with control urine samples. The maximum increase of 3-nitroytyrosine was detected 48 h after combined administration of PB and DEET. The ratio of 3-nitrotyrosine to tyrosine in urine excreted 48 h after dosing was 0.19±0.04, 0.20±0.05, 0.28±0.03, 0.32±0.04, 0.19±0.05, 0.42±0.04, 0.27±0.03, 0.36±0.04, and 0.48±0.04 following administration of water, ethanol, PB, DEET, permethrin, PB+DEET, PB+permethrin, DEET+permethrin, and PB+DEET+permethrin, respectively. The results indicate that an oral dose of PB and a dermal administration of DEET, alone and in combination, could generate free radical species, and thus increase levels of 3-nitrotyrosine in rat urine. Induction of 3-nitrotyrosine, a marker of oxidative stress, following exposure to these compounds could be significant in understanding the proposed enhanced toxicity following combined exposure to these compounds.

Increased 8-hydroxy-2′-deoxyguanosine, a biomarker of oxidative DNA damage in rat urine following a single dermal dose of DEET ( N, N-diethyl- m-toluamide), and permethrin, alone and in combination

Levels of the biomarker of DNA oxidative damage 8-hydroxy-2′-deoxyguanosine (8-OHdG) in rat urine following dermal exposure to DEET ( N, N-diethyl- m-toluamide) and permethrin, alone and in combination have been determined. A group of five rats for each time point were treated with a single dermal dose of 400 mg/kg of DEET, 1.3 mg/kg of permethrin or their combination. Urine samples were collected 2, 4, 8, 16, 24, 48, and 72 h following application. Control urine samples of rats treated with ethanol were also collected at the same time intervals. Solid phase extraction coupled with high performance liquid chromatography (HPLC) with UV detection at 254 nm was used for determination of 2′-deoxyguanosine, and (8-OHdG). The limits of detection (LOD) were 0.5 ng of both 2′-deoxyguanosine and 8-OHdG. Their average percentage recoveries from urine samples were between 70–85%. A single dermal dose of DEET or in combination with permethrin significantly induced levels of (8-OHdG) that are excreted in the urine over the time course of the study compared to control urine samples. Permethrin did not cause significant increase in the amount of 8-OHdG in the urine. Levels of 8-OHdG in urine excreted at 24 h were 1009±342, 1701±321, 1140±316, and 1897±231 ng following treatment with ethanol, DEET, permethrin, and DEET+permethrin, respectively. The results indicate that dermal administration of DEET could generate free radical species hence cause DNA oxidative damage in rats.

Urinary excretion of metabolites following a single dermal dose of [ 14C]methyl parathion in pregnant rats

The identification and kinetics of urinary excretion of metabolites of uniformly phenyl-labeled O, O-dimethyl O-4-nitrophenyl phosphorothioate ([ 14C]methyl parathion) were carried out following a single dermal dose of 10.0 mg (10 μCi)/kg in pregnant Sprague–Dawley rats at 14–18 days of gestation. Urine was collected at each time interval of 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Total p-nitrophenol in the conjugated and non-conjugated metabolites was measured as a marker of methyl parathion exposure. Elimination of radioactivity in the urine was rapid. Of the total 14C urinary excretion, 30% of the dose was excreted within 4 h, while 50 and 90% of the dose were recovered in the urine by 24 and 96 h, respectively. Excretion rate of total radioactivity was 60 μg methyl parathion equivalent/h (1.4 mg/day). By the end of the 96-h experiment, conjugated and non-conjugated metabolites accounted for 78.1 and 21.9%, respectively. Of the non-conjugated metabolites, p-nitrophenol and O, O-dimethyl O-4-nitrophenyl phosphate (methyl paraoxon) were identified by high performance liquid chromatography (HPLC) that accounted for 20%, and 1.9% of total urinary excretion, respectively. Appearance and disappearance rate constants of p-nitrophenol in urine were 0.12 and 0.048 μg/h, respectively. Conjugated metabolites were classified as: glucuronides 12% of urinary excretion, sulfates 3%, hot sulfuric acid hydrolysable residues 47% and 16.1% remained as unidentified water soluble metabolites. Direct hot acid hydrolysis of urine yielded 49% of extractable 14C-radioactivity compared to 62% when hot acid hydrolysis followed the enzymatic hydrolysis. The presence of the conjugated metabolites as the major class of metabolites of the total excretion indicates that determining only unbound p-nitrophenol as a biological marker for methyl parathion exposure underestimates total urinary excretion of p-nitrophenol. Sequential enzymatic and acid hydrolyses of urine prior solvent extraction are necessary for complete recovery of p-nitrophenol. The results indicate that the present method would show that the pregnant field worker or a housewife being at a greater risk than previously thought.

Placental transfer and pharmacokinetics of a single dermal dose of [14C]methyl parathion in rats.

The pharmacokinetics and placental transfer of a single dermal 10.0 mg (10microCi)/kg dose of uniformly phenyl-labeled [14C] methyl parathion (0,0-dimethyl 0-4-nitrophenyl phosphorothioate) were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three rats were killed at each time interval: 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Radioactivity disappeared biexponentially from the administration sites, which retained 50% and 3% of the dose after 1 h and 96 h, respectively. Most of the absorbed radioactivity was excreted in the urine (91%). Only 3% of the 14C was recovered in the feces. One h after the administration, radioactivity was detected in all tissues, including fetal tissue. The peak maternal plasma concentration of radioactivity (ng methyl parathion equivalent/ml) was 1005 at 2 h, compared to 318 ng for fetal plasma at 12 h. The maximum concentrations of radioactivity (ng methyl parathion equivalent/g), detected in most tissues within 12 h of dosing, were, in descending order: adipose tissue (67,532), kidney (1,571), spleen (1,256), spinal cord (1,004), heart (729), liver (706), brain (546), placenta (389), and fetus (256). The metabolism studies showed that methyl parathion, detected by HPLC, was the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 513 ng/ml, and in the following tissues (ng/g fresh tissue): kidney (819), fetus (668), placenta (394), liver (375), and brain (282). The metabolite methyl paraoxon was detected in maternal brain and liver at maximum concentrations (ng/g fresh tissue) of 135 and 64 after 12 h and 4 h respectively, while p-nitrophenol was only detected in liver at a maximum concentration of 21 ng/g 72 h after dosing. Pharmacokinetic studies showed that methyl parathion disappeared monoexponentially from plasma and tissues. The half-life of elimination of methyl parathion from plasma was 11 h corresponding to a constant rate value of 0.06 h(-1). The results indicate that skin and placenta are poor barriers against methyl parathion permeability, resulting in a rapid and extensive dermal absorption of this insecticide and extensive placental transfer. This is indicated by the relative residence (R(R)) of methyl parathion in the plasma, which was largest in the placenta followed by the fetus. This study suggests that pregnant women and fetuses may be at risk of cholinergic toxicity following dermal exposure to methyl parathion.

Absorption, Distribution, Metabolism, and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Dermally to Rats

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns at different time intervals following a single or multiple dermal administration of [Hexyl-1-14C] MGK 264 (N-octylbicycloheptene dicarboximide).Two groups of fasted rats were administered [14C] MGK 264 at a single dermal dose of 10 mg/kg or at a daily dermal dosage of 10 mg/ kg of nonradiolabeled compound for 14 days followed by a single dose of 14C-labeled compound at 10 mg/kg. Each animal was administered approximately 15 μCi radioactivity.Five male rats were used in each of two groups to determine the blood kinetics of administered radioactivity following a single or multipie dermal administration at 10 mg/kg. Radioactivity peaked at approximately 6 h after both single and multiple dermal dosing, indicating slow dermal absorption. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity for both groups was found to be 31 h.Twenty male rats were used in each of the other two experiments. Five animals were euthanized at each of the following time intervals following dose administration: peak blood radioactivity (12 h), blood half-life of radioactivity (43 h), second half-life (74 h), and 168 h. Urine and feces were collected from all animals at predetermined time intervals. At the predetermined times, the rats were euthanized and selected tissues and organs, including the treated skin, were harvested. Samples of urine, feces, and tissues were subsequently analyzed for 14C content.The animals excreted the majority of the absorbed radioactivity in the urine with a significant amount in the feces. At the 168 h time interval the animals excreted 46.27-51.48% of the dosed radioactivity in the urine and 30.37-35.92% in the feces. Tissue residues of 14C were the highest at the 1 h time interval and decreased at the subsequent time intervals. The level of radiolabeled compound was found to be highest in the lungs, stomach, intestine, kidneys, prostate, seminal vesicle, and liver. The total mean recovered radioactivity of the administered dose ranged between 85.35 and 101.52%.The results from the study clearly show that the absorption of MGK 264 from the skin is slow. After 12 h, 88.62 and 85.57% of the applied radioactivity was accounted for as unabsorbed radioactivity on the skin for the single and multiple dose, respectively, The surface radioactivity accounted for 60.06 and 59.15% after 43 h and 38.25 and 46.78% after 74 h for the single and multiple dose, respectively.The daily application of MGK 264 did not significantly affect the blood kinetics or blood half-life of radioactivity. Residual radioactivity on the treated skin for the multiple dose regimen was higher than for the single dose but the absorbed radioactivity was excreted in both the urine and the feces in a similar manner. The very low level of blood radioactivity indicates that the absorbed radioactivity is very quickly eliminated from the systemic circulation. With the exception of a higher amount of radioactivity present in the skin following multiple dose administration, the patterns of absorption, tissue distribution, and elimination between the single and multiple doses are equivalent.

Absorption, Distribution, Metabolism, and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

AbstractExperiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns at different time intervals following a single or multiple dermal administration of [Hexyl-1-14C] MGK 264 (N-octylbicycloheptene dicarboximide).Two groups of fasted rats were administered [14C] MGK 264 at a single dermal dose of 10 mg/kg or at a daily dermal dosage of 10 mg/ kg of nonradiolabeled compound for 14 days followed by a single dose of 14C-labeled compound at 10 mg/kg. Each animal was administered approximately 15 μCi radioactivity.Five male rats were used in each of two groups to determine the blood kinetics of administered radioactivity following a single or multipie dermal administration at 10 mg/kg. Radioactivity peaked at approximately 6 h after both single and multiple dermal dosing, indicating slow dermal absorption. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity for both grou...

The Effect of Chlorine Substitution on the Dermal Absorption of Polychlorinated Biphenyls

The fate of selected mono-, di-, tetra-, and hexachlorobiphenyls was investigated following single dermal administration (0.4 mg/kg) to determine the effects of chlorine substitution on the dermal absorption and disposition of polychlorinated biphenyls (PCBs). Single dermal doses of14C-labeled mono-, di-, tetra-, and hexachlorobiphenyls were administered to 1-cm2areas on the backs of F-344 male rats. Unabsorbed radioactivity was removed from the dose site either at euthanasia or 48 h postdose. Distribution of radioactivity in the dose site and selected tissues was determined by serial sacrifice at time points up to 2 weeks. Dermal penetration varied inversely with degree of chlorination and at 48 h ranged from ca. 100% for monochlorobiphenyl to ca. 30% for the hexachlorobiphenyl. Penetration rate constants correlated well with logKow. PCBs were retained in the epidermis for up to 2 weeks postdose. The data from these studies suggest that systemic absorption of PCBs involves a combination of sequential processes including penetration across the stratum corneum, possibly metabolism in the epidermis and/or dermis, adsorption to proteins, and finally absorption into the systemic circulation. The skin favors the rapid absorption of less chlorinated PCBs, but the relatively rapid metabolism and elimination of these compounds would result in lower body burdens. More highly chlorinated PCBs penetrate less rapidly but remain in the site of exposure and slowly enter the systemic circulation. The dermal absorption of a commercial PCB mixture was modeled, and the results suggest that the net result of the differences in absorbance rates would be a greater body burden of higher chlorinated PCBs relative to those that have a lower chlorine content.

Dose dependent effects on lymphoid organs following a single dermal application of sulphur mustard in mice.

The effects of a single dermal application of sublethal doses [15.5, 7.75 and 3.88 mg kg-1] of bis(2-chloroethyl)sulphide [sulphur mustard, SM] on body weight, organ/body weight ratio, haematology, histology and cellularity of spleen and thymus were studied after 7 days, in Balb/c mice. A progressive fall in body weight was noticed from the fifth day onwards after SM treatment. A dose-dependent decrease in the relative weights of spleen, liver and peripheral lymph nodes, and an increase in adrenal weight were also seen. An increase in red blood cell count, packed cell volume and haemoglobin concentration following SM intoxication were also dose dependent. These changes, together with a significant reduction in the cellularity of the spleen and thymus and degenerative histological changes, show that a single sublethal dermal dose of SM can cause considerable dose dependent systemic effects in Balb/c mice.

A Physiologically Based Pharmacokinetic Model for 2,3,7,8-Tetrabromodibenzo- p-dioxin (TBDD) in the Rat: Tissue Distribution and CYP1A Induction

Biologically based models serve as valuable tools for integration of mechanistic pharmacokinetic data by their explicit definition of important determinants of chemical disposition. The objective of the present work was to develop a physiologically based pharmacokinetic model to describe the disposition and enzyme induction properties of 2,3,7,8-tetrabromodibenzo- p-dioxin (TBDD). The TBDD model, which was based on models previously developed for 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), incorporated: ternary interactions between TBDD, the Ah receptor, and specific DNA-binding sites; induction of a TBDD-binding protein specific to the liver; and diffusion-limited tissue uptake. In the model for TBDD, CYP1A2, which had been measured directly by radioimmunoassay, was assumed to be the hepatic binding protein. The model employed physiologic parameters based on recent data in unanesthetized rats, growing tissue compartments, transluminal excretion of parent TBDD via the gut into the feces, and a separate skin compartment. The model was developed using tissue distribution and excretion data following a single intravenous dose of 1 nmol [ 3H]TBDD per kilogram. The TBDD model was then used unchanged to analyze several experimental data sets illustrating the time, dose, and route of exposure dependency of TBDD disposition. The model successfully described the dose-dependent tissue distribution of [ 3H]TBDD following intravenous and oral administration and following a single dermal dose. These studies show that diffusional clearance from blood to tissue was slower for skin than for fat (PA sk ∼ 0.1 PA f). When compared with TCDD: (i) TBDD had a higher fat partition coefficient (P f = 1000 vs 400) and a lower diffusional clearance into fat (PA f = 0.1 vs 0.2) than TCDD; (ii) the binding affinity of CYP1A2 for TBDD was slightly lower than that for TCDD (9.0 vs 6.5 nM); and (iii) TBDD exhibited a slightly greater rate of metabolic elimination (2.0 vs 1.65). Small differences were noted in DNA binding parameters derived for the induction of CYPlAl and CYP1A2 for TBDD versus TCDD. With minor modifications, the biologically based model for TCDD accurately described the behavior of the brominated congener. The present model, which relied on measured values ofCYP1A2 and specified CYP1A2 as the hepatic dioxin binding species, successfully describes the hepatic disposition of TBDD, providing further evidence that CYP1A2 is the primary hepatic binding species in the rat.

Evaluation of the Acute Toxicity of Silahydrocarbon

Silahydrocarbon (SHC) is a base stock for a candidate high-temperature hydraulic fluid. Because United States Air Force personnel working with SHC may be exposed to potential health hazards, a complete battery of acute toxicity tests was performed with the fluid. A single neat dose of 0.1 mL SHC into New Zealand White (NZW) rabbit eyes resulted in slight conjunctival irritation 1 hr after treatment in all unflushed eyes and one of three flushed eyes. Conjunctival irritation persisted through 24 hr but dissipated by 48 hr. Rinsing the eyes after treatment was of questionable benefit. A single treatment of 0.5 mL neat SHC to rabbit skin produced negative results for all but a single animal, which had very slight erythema at the test site 48 hr after treatment. Guinea pigs failed to exhibit a sensitization response following repeated application of SHC. A single oral dose of 5 g SHC/kg body weight given to five male and five female F-344 rats and a single dermal dose of 2 g SHC/kg body weight applied to five male and five female NZW rabbits resulted in no deaths or signs of toxic stress. Five male and five female F-344 rats were exposed to 4.8 mg/L (near limit concentration) of aerosolized SHC for 4 hr. All male rats and four female rats survived. During exposure, the animals exhibited signs of eye and upper respiratory irritation.