Paraquat disposition in rats, guinea pigs and monkeys

LD50 doses of ¹⁴C-labeled paraquat were administered to rats, guinea pigs and monkeys by gavage, and radioactivity was determined in excreta and tissues. Rat urine was analyzed for paraquat metabolites by thin-layer chromatography. [¹⁴C]Paraquat was absorbed from the gastrointestinal tract and reached highest serum values 0.5–1 hr after administration. Disappearance of [¹⁴C]paraquat from serum was characterized by a rapid initial decline followed by a prolonged slow decline. Tissue paraquat values were higher than serum values in rats and guinea pigs. Relative to other tissues, paraquat accumulated transiently in the lung and reached peak concentration 32 hr after administration. In rats a major portion of administered paraquat was not absorbed from the gastrointestinal tract. At 32 hr after paraquat, 52% of the administered dose remained in the gastrointestinal tract and 17 and 14% of the administered dose was excreted in the feces and urine, respectively. No radioactivity was recovered in expired air or flatus. Excretion of paraquat in urine and feces was prolonged in all species. In monkeys paraquat was measured in urine and feces 21 days after administration. Chromatography of urine from [¹⁴C]paraquat-treated rats revealed no metabolites. The primary pathologic changes induced by paraquat in the lung may be related to the transient uptake of the chemical by that organ.     

Metabolism and disposition of isomers of dinitro- and mononitroglycerol in the rat.

Approximately 59 to 82% of an oral dose of ¹⁴C-labeled dinitro- (DNG) or mononitroglycerol (MNG) was absorbed by the rat. The absorption was similar for 1,2-DNG, 1,3-DNG, and 1-MNG, but less for 2-MNG. Most of the absorbed radioactivity was excreted in the expired air and in the urine. The ¹⁴C recovered in the expired air was similar for the DNGs and 1-MNG averaging 20 to 30% of the dose in 24 hr, whereas only 7% was present in the air after administration of 2-MNG. Radioactivity excreted in the urine accounted for about 50% of the 1,2-DNG and 2-MNG doses in 24 hr, but only 25 to 30% of the 1,3-DNG and 1-MNG doses. The liver contained 2 to 9% of the administered DNGs and MNGs at 4 hr and these values remained essentially unchanged at 24 hr. Only small amounts of radioactivity were recovered in various other tissues. Urine from DNG-treated rats contained mainly free MNGs, glucuronide conjugates of DNGs and MNGs, glycerol and other polar metabolites, and only small amounts of DNG. After administration of MNGs, considerable amounts of unchanged MNGs were excreted in the urine along with glycerol and other polar components. Unlike the DNGs, no MNG-glucuronides were present in the urine.     

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to rats and dogs

Clearance of ¹⁴C activity from the plasma and its elimination from the body of rats and dogs were determined after single oral doses of [carboxy-¹⁴C]2,4,5-T. The half-life values for the clearance of ¹⁴C activity from the plasma of rats given doses of 5, 50, 100 or 200 mg/kg were 4.7, 4.2, 19.4 and 25.2 hr, respectively; half-lives for elimination from the body were 13.6, 13.1, 19.3 and 28.9 hr, respectively. The apparent volume of distribution also increased with dose. Urinary excretion of unchanged 2,4,5-T accounted for most of the ¹⁴C activity eliminated from the body of rats. A small amount of unidentified metabolite was detected in the urine when rats were given 100 or 200 mg/kg but not 5 or 50 mg/kg. These results show that the distribution, metabolism and excretion of 2,4,5-T are markedly altered when large doses are administered.In dogs given 5 mg/kg, the half-life values for clearance from plasma and elimination from the body were 77.0 and 86.6 hr, respectively, offering a plausible explanation of why 2,4,5-T is more toxic in dogs than in rats. Appreciable excretion in the feces was noted and three unidentified metabolites were detected in urine of dogs, indicating a considerable difference in metabolism of 2,4,5-T by dogs and rats given the same dose.     

Metabolism and disposition of ferbam in the rat.

Approximately 40–70% of an oral dose of ferric [³⁵S]dimethyldithiocarbamate ([³⁵S]ferbam) or ferric [¹⁴C]dimethyldithiocarbamate ([¹⁴C]ferbam) was absorbed through the gastrointestinal tract of the rat during a 24-hr period. In rats receiving [³⁵S]ferbam, 22.7, 18.1, and 1.0% of the radioactivity was found in urine, expired air, and bile, respectively. Only small amounts of ³⁵S were found in the various tissues, including blood, kidneys, muscle, and brain. In rats receiving [¹⁴C]ferbam 42.9 and 1.4% of the ¹⁴C was found in the urine and bile, respectively; whereas only 0.6% of the radioactivity was recovered in the expired air. The other tissues contained only small amounts of ¹⁴C. Analysis of expired air indicated that the only expired ferbam metabolite was carbon disulfide. Major metabolites in the urine included inorganic sulfate, a salt of dimethylamine and a glucuronide conjugate of dimethyldithiocarbamate. Unchanged ferbam was not excreted in the urine. In pregnant rats given [¹⁴C]ferbam a small but significant amount of radioactivity readily crossed the placenta into the fetus. In lactating rats given [¹⁴C]ferbam, radioactivity was secreted into milk, absorbed by the pups and excreted in the pups' urine.     

Chlophentermine-induced abnormalcytoplasmic inclusions in peripheral blood cells of rats and guinea pigs.

The metabolic fate of [¹⁴C]gossypol was studied in the pig following a single oral dose of 6.7 mg/kg (3.7 μCi). Radioactivity was rapidly excreted from the animal body via feces. After 20 days, the total radioactivity recovered in the feces was 94.6% of the administered dose. A total of 2.1% of the radioactivity of administered dose was recovered in the expired CO₂ collected continually for 20 days. This indicates that decarbonilation of gossypol is not a major route of gossypol metabolism in the pig. Radioactivity was least excreted via urine; only 0.7% of the administered dose was recovered in the urine. One day after the administration, the tissues had 32.9% of the administered dose, which was decreased to 1.2% at 20 days. The conceptration of gossypol and its metabolites in the tissues (as indicated by radioactivity) was highest in the muscle, followed by liver, adipose tissues, and the blood. The half-life for the disappearance of radioactivity from the animal body following the administration of [¹⁴C]gossypol was 78 hr. Identification of metabolites was carried out by ultraviolet, infrared, and mass spectrometry in connection with thin-layer autoradiography. Compounds isolated from pig liver were characterized as gossypol, gossypolone, gossypolonic acid, demethylated gossic acid, and presumably apogossypol. Gossypol and metabolites may be conjugated to form glucuronides, sulfates, or hybrids.     

Disposition of tetrachloro(14C)ethylene following oral and inhalation exposure in rats

Tetrachloro[¹⁴C]ethylene (Perc) was administered to adult, male Sprague-Dawley rats by gavage (1 or 500 mg/kg) or by inhalation (10 or 600 ppm, 6 hr duration). Within 72 hr following oral administration of 1 mg/kg or inhalation of 10 ppm [¹⁴C]Perc, approximately 70% of the body burden of radioactivity was excreted in expired air as Perc, 26% as ¹⁴CO₂ and nonvolatile metabolites in urine and feces, and 3 to 4% remained in the carcass. After oral administration of 500 mg/kg or inhalation of 600 ppm [¹⁴C]Perc, 89% of the radioactivity was recovered in expired air as Perc, 9% as ¹⁴CO₂ and urinary and fecal metabolites, and 1 to 2% remained in the carcass. The major urinary metabolite of Perc was identified as oxalic acid. Pulmonary elimination of Perc was monophasic with a half life ($\text{t}\text{1}\text{2}$) of approximately 7 hr independent of dose or route of administration. Radioactivity remaining in the carcass 72 hr after exposure by either route was primarily distributed within liver, kidney and fat tissue. In liver, 85 to 90% of the total radioactivity was cleared within 72 hr following inhalation exposure to 10 or 600 ppm. Nonextractable radioactivity, either bound or incorporated into hepatic macromolecular material, was cleared at a slower rate. The tissue concentration of nonextractable radioactivity was dependent upon body burden and metabolic capacity but apparently not upon route of administration. Thus, the data indicate that disposition of Perc is a saturable, primarily dose-dependent process in rats.     

Excretion,distribution and metabolism of 1,2,4-trichlorobenzene in rats

1,2,4-Trichlorobenzene (TCB) labeled with C-14 was given perorally to rats at a dosage of 50 mg/kg for excretion and distribution studies.About 66% and 17% of the oral dose was excreted in the urine and feces, respectively, within 7 days. Trapped radioactivity in the expired air amounted to 2.1% of the dose, but production of labeled carbon dioxide was negligible. Tissue residues were evenly distributed throughout the organs and tissues examined, except for the adipose tissue which consistently had a little higher concentration.The urinary, fecal and expiratory metabolites were identified. Free 2,4,5- and 2,3,5-trichlorophenol (TCP) and their conjugates were mainly detected in the urine. 5- or 6-Sulfhydryl, methylthio, methylsulfoxide and methylsulfone derivatives of TCB were also detected as minor metabolites. Dichlorobenzenes and unchanged TCB were confirmed in the expired air. Reductive dechlroination seems to be catalysed by intestinal microflora enzymes.     

Author Index to Volume 22

Abstract

In vivo percutaneous penetration and tissue distribution of radioactivity following a topical application of ¹⁴C-labeled butyl 2-chloroethyl sulfide (BCS) were determined in the laboratory rat. Up to 70% of the topical BCS was lost by evaporation. Only a portion of BCS in the skin was extracted with ethanol. At 1 hr, approximately two-thirds of the applied BCS was ethanol-extractable. This level decreased to about 6% at 24 hr. Radioactivity in blood was detected 5 min after application. Thereafter, a linear increase in blood radioactivity was observed throughout the entire 4 hr experimental period. Topical BCS was absorbed into the circulation and was incorporated into various organs and tissues. The liver, kidneys, heart, lungs, skeletal muscle, brain, eyes, and bone marrow were radioactive. On an equal weight basis, the kidneys and lungs contained the highest level of radioactivity. Following a subcutaneous injection of BCS, over 2% of the dose appeared in expired air. No radioactivity was detected in expired carbon dioxide. In 24 hr, up to 70% of the applied radioactivity was excreted in the urine. Four urinary metabolites of BCS were found. This study demonstrates that skin contact with BCS forms an extensive reservoir of ethanol-extractable labeled BCS and/or its metabolites in the affected skin site.     

Disposition of [14C]methyl bromide in rats after inhalation

Methyl bromide is used as a disinfectant to fumigate soil and a wide range of stored food commodities in warehouses and mills. Human exposure occurs during the manufacture and use of the chemical. The purpose of this investigation was to determine the disposition and metabolism of [14C]methyl bromide in rats after inhalation. Male Fischer-344 rats were exposed nose only to a vapor concentration of 337 nmol [14C]methyl bromide/liter air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Elimination of 14C as 14CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total [14C]methyl bromide absorbed excreted by this route. CO2 excretion exhibited a biphasic elimination pattern with 85% of the 14CO2 being excreted with a half-time of 3.9 +/- 0.1 hr (means +/- SE) and 15% excreted with a half-time of 11.4 +/- 0.2 hr. Half-times for elimination of 14C in urine and feces were 9.6 +/- 0.1 and 16.1 +/- 0.1 hr, respectively. By 65 hr after exposure, about 75% of the initial radioactivity had been excreted with 25% remaining in the body. Radioactivity was widely distributed in tissues immediately following exposure with lung (250 nmol equivalents/g), adrenal (240 nmol equivalents/g), kidney (180 nmol equivalents/g), liver (130 nmol equivalents/g), and nasal turbinates (110 nmol equivalents/g) containing the highest concentrations of 14C. Radioactivity in livers immediately after exposure accounted for about 17% of the absorbed methyl bromide. Radioactivity in all other tissues examined accounted for about 10% of the absorbed methyl bromide. Elimination half-times of 14C from tissues were on the order of 1.5 to 8 hr. In all tissues examined, over 90% of the 14C in the tissues was methyl bromide metabolites. The data from this study indicate that after inhalation methyl bromide is rapidly metabolized in tissues and readily excreted.     

Excretion of 14C-labeled cyanide in rats exposed to chronic intake of potassium cyanide

The excretion of an acute dose of 14C-labeled cyanide in urine, feces, and expired air was studied in rats exposed to daily intake of unlabeled KCN in the diet for 6 weeks. Urinary excretion was the main route of elimination of cyanide carbon in these rats, accounting for 83% of the total excreted radioactivity in 12 hr and 89% of the total excreted radioactivity in 24 hr. The major excretion metabolite of cyanide in urine was thiocyanate, and this metabolite accounted for 71 and 79% of the total urinary activity in 12 hr and 24 hr, respectively. The mean total activity excreted in expired air after 12 hr was only 4%, and this value did not change after 24 hr. Of the total activity in expired air in 24 hr, 90% was present as carbon dioxide and 9% as cyanide. When these results were compared with those observed for control rats, it was clear that the mode of elimination of cyanide carbon in both urine and breath was not altered by the chronic intake of cyanide.     

Fate of Erythritol after Single Oral Administration to Rats and Dogs

The absorption and distribution of radiolabeled erythritol were studied in Wistar rats and beagle dogs after a single oral administration in doses ranging from 0.125 to 2.0 g erythritol/kg body wt. Erythritol concentrations in blood and plasma of rats reached their maxima 1 hr after administration and then declined biexponentially. In the blood and plasma of dogs, the highest concentrations occurred after 1/2 hr followed by a similar decline. Blood plasma distribution ratios and plasma protein binding ratios increased as blood plasma levels declined. At 120 hr after administration, 95.68 ± 2.25% of the radioactivity had been excreted in the urine of dogs and 92.70 ± 0.44% in the urine of rats; 0.33 ± 0.05% had been excreted in the feces of dogs and 1.19 ± 0.09% in the feces of rats; 1.17 ± 0.04% had been excreted in expired air from dogs and 4.80 ± 0.32% in expired air from rats. The results demonstrate that erythritol is rapidly absorbed and excreted, principally through the urinary pathway.     

Disposition of 3,3′-dichlorobenzidine in the rat

The disposition of the carcinogen 3,3′-dichlorobenzidine (DCB) was studied in the male rat following oral administration. [¹⁴C]DCB was well absorbed by the rat with the maximum plasma radioactivity levels being found within 8 hr after dosing. The radioactivity was well distributed in the tissues 24 hr after administration with the highest levels found in the liver, followed by kidney, lung, and spleen. Repeated administration (six doses) of [¹⁴C]DCB to animals did not result in a substantial accumulation of ¹⁴C in the tissues. The elimination of radioactivity from the plasma, liver, kidney, and lung was biphasic showing an initial rapid decline (half-lives 1.68, 5.78, 7.14, and 3.85 hr, respectively) followed by a slower disappearance phase (half-lives 33.0, 77.0, 138.6, and 43.3 hr, respectively). Approximately half of the total ¹⁴C in the liver and kidney was covalently bound to cellular macromolecules 72 hr after dosing. [¹⁴C]DCB-derived radioactivity was extensively excreted by rats, mainly via the feces. Approximately 23–33% of the administered dose was recovered in the urine and 58–72% in the feces of rats within 96 hr. More than 65% of the administered ¹⁴C was eliminated in the bile of bile duct-cannulated rats within 24 hr after dosing. The radioactivity excreted in the urine and bile was primarily in the form of free (urine 71.2%, bile 25.5%) and conjugated (urine 19.6%, bile 57.9%) metabolites of DCB. Thus DCB is readily absorbed following oral administration, and then metabolized and excreted mainly via the feces.     

Distribution,excretion, and binding of radioactivity in the rat after intraperitoneal administration of the lung-toxic furan, [14C]4-ipomeanol

4-Ipomeanol [1-(3-furyl)-4-hydroxypentanone] is a poisonous metabolite produced in the mold-damaged sweet potato (Ipomoea batatas). In experimental animals the compound characteristically exhibits lung toxicity, producing prominent pulmonary edema and congestion. The distribution and excretion of radioactivity in rats after administration of [¹⁴C]4-ipomeanol has been studied. The toxin was given ip at doses of 2, 10, and 30 mg/kg. Approximately half of the administered radioactivity appeared in the urine within 2 hr, with only traces occurring in the feces and expired air. The greatest tissue concentration of radioactivity occurred in the lungs. Other organs showing significant concentrations were liver, kidney, and gastrointestinal tract. The maximal accumulation of activity occurred in the tissues within 0.5–1 h. The values declined over the next 1–2 hr, then reached a plateau representing residual activity. This residual activity is particularly high in lung, liver, and kidney, and represents the toxin or its metabolite(s) which has become tightly bound to tissue macromolecules. Binding occurs maximally in lung, and therefore may indicate that the binding phenomenon is involved in the toxic mechanism of 4-ipomeanol.     

Biotransformation of the immunomodulator, 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2a]benzimidazole-2-acetic acid,and its relationship to tyroid toxicity

Wy-13,876, 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2a]benzimidazole-2-acetic acid, causes enlargement of the thyroids of rats and dogs. Radioactivity was accumulated in the thyroids, but not in other tissues of dogs given the ¹⁴C-labeled drug. Uptake of ¹⁴C by the thyroid of the rat was time dependent; there was little or no accumulation until 8 hr after drug administration. Biotransformation of Wy-13,876 is extensive. Two metabolites, benzimidazolethiol and benzimidazole, account for most of the radioactivity in the thyroid but almost no unchanged drug was detected. The two metabolites were also detected in liver, plasma, and urine, however, they represented little of the drug-related substances. Recovery of radiolabel in theexcreta of rats given [¹⁴C]Wy-13,876 was 79 ± 7.9% ± SD and was about evenly divided between feces and urine. Radioactivity, primarily benzimidazolethiol and benzimidazole, also accumulated in the thyroids of rats given labeled benzimidazolethiol. Chronic treatment with either the thiol metabolite or the parent compound reduced the plasma concentration of thyroid hormone and caused enlargement of the thyroid. Thus, the biotransformation of Wy-13,876 to benzimidazolethiol followed by accumulation of this metabolite in the thyroid initiates a sequence of events which begins with the inhibition of thyroid hormone synthesis. Reduced concentrations of circulating thyroid hormones stimulate the release of TSH which in turn increases thyroid activity leading to the hyperplasia and enlargement. Treatment of rats with l-thyroxine prior to administration of [¹⁴C]Wy-13,876 partially prevented the accumulation of radioactivity by the thyroid. Wy-18,251, an analog of Wy-13,876, was not metabolized to benzimidazolethiol and was not thyrotoxic.     

[14C]Methyl chloroform (1,1,1-trichloroethane): Pharmacokinetics in rats and mice following inhalation exposure

Studies on the pharmacokinetics of [¹⁴C]methyl chloroform (1,1,1-trichloroethane) in male Fischer 344 rats and B6C3F1 mice were undertaken to characterize the disposition of the inhaled chemical over a wide range of exposure concentrations. The animals were exposed to 150 or 1500 ppm of [¹⁴C]methyl chloroform vapor for 6 hr and the elimination of ¹⁴C activity was followed for 72 hr. Following exposure to either concentration of methyl chloroform, both species excreted >96% of the total recovered radioactivity during the first 24 hr. The major route of elimination of methyl chloroform was via exhalation of unchanged chemical in the expired air which constituted approximately 94–98% of the total recovered radioactivity in rats and 87–97% in mice at 150 and 1500 ppm, respectively. Mice were found to eliminate methyl chloroform in the expired air more rapidly than did rats. The remaining radioactivity (approximately, 2–13%) was detected as metabolized methyl chloroform in the expired air (¹⁴CO₂) and as nonvolatile radioactivity in the urine, feces, carcass, and cage wash. Although mice were found to metabolize two to three times more methyl chloroform on a body weight basis, the biotransformation of methyl chloroform was shown to be a saturable, dose-dependent process in both species. Since the biotransformation of methyl chloroform occurred to such a limited extent, saturation of its metabolism did not impact markedly on the distribution or elimination of the parent chemical. The body burden, end-exposure blood level, and tissue concentration of methyl chloroform were found overall to increase in direct proportion with the exposure concentration. [¹⁴C]Methyl chloroform was more concentrated in the fat of both species than in the liver or kidneys immediately after exposure. However it was rapidly cleared from the fat so that by 24 hr <2% of the initial radioactivity remained. Thus, methyl chloroform shows little potential for significant bioaccumulation in rodents.     

The Fate of Ultra-Low Viscosity 14C-Hydroxypropyl Methylcellulose in Rats Following Gavage Administration

ABSTRACT

The disposition of ¹⁴C-Hydroxypropyl methylcellulose (HPMC) with a viscosity of 2.25 centipoise was studied in male and female Sprague-Dawley rats following a single 500 mg/kg body weight gavage dose, or five consecutive daily doses. Recoveries for the single dose were: feces, >99%; urine, ～1%; carcass and tissues, ?0.2%; expired air, 0.07%; and bile, 0.05%. Plasma radioactivity had a monophasic excretion half-life of approximately 2 hours for either sex. The majority of the residual radioactivity in the tissues was found in the gastrointestinal tract. The absorbed radioactivity in the urine, based on thin layer chromatography (TLC) analyses, represented methyl ethers of glucose and oligomers; this amounted to 0.56% recovered in a study in which urine samples were isolated from possible contamination by radioactivity in the feces. The 0.56% correlated well with the 0.53% portion of the original dosing solution which consisted of cellulose units with an average molecular weight of < 1000. Recovery of radioactivity in the feces of rats on the 5-day dosing regimen was 97% and 102% for males and females, respectively, without any evidence for accumulation in tissues. Approximately 1% was recovered in the urine. Thus, the results of this work show that ultra-low viscosity 2.25 centipoise HPMC was only minimally absorbed with essentially all of a single 500 mg/kg gavage dose, or 5 daily consecutive doses, being excreted unabsorbed in the feces.     

Distribution and biomarker of carbon‐14 labeled fullerene C60 ([14C(U)]C60) in pregnant and lactating rats and their offspring after maternal intravenous exposure

A comprehensive distribution study was conducted in pregnant and lactating rats exposed to a suspension of uniformly carbon‐14 labeled C₆₀ ([¹⁴C(U)]C₆₀). Rats were administered [¹⁴C(U)]C₆₀ (~0.2 mg [¹⁴C(U)]C₆₀ kg^–1 body weight) or 5% polyvinylpyrrolidone (PVP)‐saline vehicle via a single tail vein injection. Pregnant rats were injected on gestation day (GD) 11 (terminated with fetuses after either 24 h or 8 days), GD15 (terminated after 24 h or 4 days), or GD18 (terminated after 24 h). Lactating rats were injected on postnatal day 8 and terminated after 24 h, 3 or 11 days. The distribution of radioactivity in pregnant dams was influenced by both the state of pregnancy and time of termination after exposure. The percentage of recovered radioactivity in pregnant and lactating rats was highest in the liver and lungs. Radioactivity was quantitated in over 20 tissues. Radioactivity was found in the placenta and in fetuses of pregnant dams, and in the milk of lactating rats and in pups. Elimination of radioactivity was < 2% in urine and feces at each time point. Radioactivity remained in blood circulation up to 11 days after [¹⁴C(U)]C₆₀ exposure. Biomarkers of inflammation, cardiovascular injury and oxidative stress were measured to study the biological impacts of [¹⁴C(U)]C₆₀ exposure. Oxidative stress was elevated in female pups of exposed dams. Metabolomics analysis of urine showed that [¹⁴C(U)]C₆₀ exposure to pregnant rats impacted the pathways of vitamin B, regulation of lipid and sugar metabolism and aminoacyl‐tRNA biosynthesis. This study demonstrated that [¹⁴C(U)]C₆₀ crosses the placenta at all stages of pregnancy examined, and is transferred to pups via milk. Copyright © 2015 John Wiley & Sons, Ltd.     

Studies on the toxicology of hexachlorobenzene I. Pharmacokinetics

In female rats dosed orally with ¹⁴C-hexachlorobenzene the extent of intestinal absorption of carbon-14 has been found to be dependent on the form of application. When the substance was given as a solution in oil about 80% of the dose administered was absorbed, but when given as an aqueous suspension only 6%.In animals treated with ¹⁴C-hexachlorobenzene dissolved in oil, all tissues contained radioactivity. Highest levels were found in adipose tissue, lowest in blood and muscle. Peak values of radioactivity were reached between 2 to 5 days after application.Elimination was studied after intraperitoneal application of 4 mg/kg ¹⁴C-hexachlorobenzene dissolved in oil. Two weeks after administration, 34% of the radioactivity administered was recovered in the feces and 5% in urine. About 80% of carbon-14 excreted in feces and about 4% in urine was contained in the unchanged drug. This indicates that biodegradation of hexachlorobenzene in the rat is not insignificant. No radioactivity was detected in the expired air.The authors are indebted to Prof. J. Portig for many helpful suggestions. Miss A. Springer gave valuable technical assistance.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Metabolic disposition and irreversible binding of 1-phenylcyclohexene in rats

The metabolic disposition of l-[¹⁴C]phenylcyclohexene ([¹⁴C]PC) was examined in rats after ip or iv drug administration. Radioactivity, which was accumulated by various organs, peaked within 30 min after ip administration of [¹⁴C]PC (0.21 mg/kg). A significant amount of this radioactivity was not extractable by repeated methanol extractions, indicating irreversible binding of [¹⁴C]PC metabolite(s) to tissue proteins. Following iv administration of [¹⁴C]PC (0.42 mg/kg), [¹⁴C]PC concentrations in blood declined biphasically with time; the blood elimination half-life of [¹⁴C]PC is 77 min. About 83% of the dose given was excreted in urine and feces within 54 hr of administration. About 35% of the dose was excreted in the bile in 1 hr. At least four [¹⁴C]PC metabolites were detected in the urine or bile. The bulk of the urinary radioactivity was composed of metabolites since less than 6% of [¹⁴C]PC given was excreted unchanged in the urine.