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H B Matthews

Publications and source records attributed to H B Matthews.

At least 55 records · Page 3Linked to original sources
PubMed1990

The interaction of methanol, rat-liver S9 and the aromatic amine 2,4-diaminotoluene produces a new mutagenic compound.

Methanol is a widely used solvent for organic compounds and a human toxicant. In our studies of the metabolism of aromatic amines in the Ames/Salmonella assay, we observed a rapid and quantitative conversion of the mutagenic and carcinogenic aromatic amine 2,4-diaminotoluene (2,4-DAT) to a single product. This product was only produced in the presence of methanol, and not other organic solvents. Isolation of this product showed that it was highly mutagenic in Salmonella TA98 with S9 activation. Characterization of the product of the interaction of methanol and 2,4-DAT indicated that methanol is activated to a reactive intermediate, probably formaldehyde, by the 9000 X g supernatant used in the Ames/Salmonella assay. The formaldehyde subsequently reacts with 2,4-DAT to form the mutagenic product, identified as bis-5,5'(2,4,2',4'-tetraaminotolyl)methane. Results of this study demonstrate that methanol may be an inappropriate solvent for mutation and metabolism studies of aromatic amines and possibly other chemicals, and that solvent-xenobiotic interactions may in some cases lead to the misinterpretation of results.

Animals↗
PubMed1990

Subchronic toxicity studies indicate that tris(2-chloroethyl)phosphate administration results in lesions in the rat hippocampus.

Tris(2-chloroethyl)phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams and synthetic fibers, was studied as part of the National Toxicology Program's class study of phosphate flame-retardants. TRCP was administered at 0, 22, 44, 88, 175 and 350 mg/kg to both sexes of rats and 0, 44, 88, 175, 350 and 700 mg/kg to both sexes of mice in both fourteen day repeat dose and sixteen week subchronic studies. Results of these studies showed that TRCP toxicity in the 14-day studies was limited to modest increases in male rat kidney and female rat liver weights. Little evidence of toxicity was observed in mice in the 14 day studies. Toxicity observed in mice in the sixteen week studies was limited to increased liver weights in both sexes and decreased kidney weights in males. Administration of TRCP to rats for sixteen weeks resulted in increased mortality of both males and females, increased liver and kidney weights and a lesion in the hippocampal region of the brain. The lesion observed in rat brain appeared as loss of the pyramidal neurons of the CA1 region of the hippocampus and was both more common and more severe in female rats. This lesion, which was not observed in mice, is unusual for any chemical and is unique for a trialkyl phosphate such as TRCP. It is speculated that this highly directed toxicity of TRCP might be used as a chemical probe to investigate the role of the hippocampus in behavior and other functions.

Animals↗
PubMed1990

Vaginal absorption of polyvinyl alcohol in Fischer 344 rats.

Polyvinyl alcohol (PVA) is a polymer with a wide range of molecular weights and uses. Recently, low molecular weight formulations of PVA have been used as components of contraceptive products designed for intravaginal administration in human females. Previous studies in animals have determined that little or no absorption of PVA occurs from the gastrointestinal (GI) tract. However, there is some concern that PVA of lower molecular weights might be absorbed across membranes of the reproductive tract. Consequently, this work has investigated the absorption of low molecular weight PVA across biological membranes of the reproductive and GI tracts of Fischer 344 rats. Oral administration of ten consecutive daily doses of 14C PVA resulted in little apparent absorption of the dose from the GI tract. In contrast, intravaginal administration of 14C PVA resulted in increasing concentrations of PVA-derived radioactivity in major tissues following one, three or ten daily doses of the estimated human dose of 3 mg/kg. PVA-derived radioactivity was concentrated mainly in the liver, reaching a peak greater than 1750 ng equivalents/g tissue 24 hours following ten daily doses. Over 300 ng equivalents/g tissue were still present in the liver 30 days following the last dose.

Absorption↗
PubMed1990

The carcinogenic activity of commercial grade toluene diisocyanate in rats and mice in relation to the metabolism of the 2,4- and 2,6-TDI isomers.

Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene diisocyanate (TDI) in corn oil for 5 days per week for 105 or 106 weeks. Female rats and mice were given doses of 60 or 120 mg/kg body weight, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The TDI reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concentrations. The chemical product used was commercial grade TDI, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metabolism studies were conducted with each of the radiolabelled TDI isomers in male rats. Absorption of both of the TDI isomers occurred, with the highest concentrations found in the stomach, cecum, large intestine, and bladder. Excretion occurred via the feces and urine. The major metabolic products from the metabolism of 2,4-TDI were shown to be identical with those from the metabolism of the carcinogen, 2,4-diaminotoluene, whereas the metabolism of the 2,6-TDI isomer yielded one major product, identified as 2,6-bis(acetylamino)toluene. Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the TDI-exposed rats were dose-related increases in acute broncho-pneumonia, characterized as chemical pneumonitis, with incidences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males. Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not commence until 70 weeks of exposure, demonstrating that toluene diisocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls. Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant increases in tumor incidences were observed in many different target organs. TDI was carcinogenic in F344/N rats, causing subcutaneous fibromas and fibrosarcomas in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites.

Acute exposure to 2-butoxyethanol (BE) causes dose- and age-dependent hemolytic anemia in rats. Recently, we have shown that butoxyacetic acid (BAA) is the proximate hemolytic agent and that inhibition of alcohol or aldehyde dehydrogenases protected rats against BE-induced hemolytic anemia. In the present investigations, the kinetics of 14C-BE metabolism and clearance were studied in control adult (3-4 months old) and old (12-13 months old) male F344 rats and in adult male F344 rats treated with pyrazole, cyanamide or probenecid. Our results showed that the area under the curve (AUC), maximum plasma concentration (Cmax) and systemic clearance (Cls) of BE were dose-dependent. In contrast, there was no effect of dose on half-life (T1/2) or volume of distribution (Vd) of BE. These results also showed that there was no age effect on T1/2, Vd or Cls of BE. However, Cmax and AUC of BE increased as a function of age. Also, analysis of variance indicated no significant interactions (P less than or equal to .05) between dose and age in relation to BE kinetics. As expected, inhibition of BE metabolism by pretreatment of rats with pyrazole or cyanamide resulted in a significant increase in the T1/2 and AUC of BE, whereas it caused a significant decrease in the Cls. Furthermore, pyrazole had no effect, whereas cyanamide had decreased Vd of BE. Analysis of the toxicokinetic parameters of BAA revealed that T1/2, AUC and Cmax of BAA were directly related to the age of the rats and the dose of BE administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1989

Structure-activity relationships for the in vitro hematotoxicity of N-alkoxyacetic acids, the toxic metabolites of glycol ethers.

Ethylene glycol mono-n-alkyl ethers are a major class of industrial chemicals which cause a wide range of toxic effects in laboratory animals including reproductive and developmental toxicity, as well as hematotoxicity. Alkoxyacetic acids are the major metabolites of ethylene glycol ethers and are considered to be the proximate toxic metabolites. The structure-toxicity relationships of these acids are well documented in the reproductive and developmental systems. Therefore, current studies were conducted to investigate the structure-activity relationships of these acids for hematotoxicity in rat blood in vitro. Results presented here indicate that the effects of various alkoxyacetic acids on rat erythrocytes are qualitatively similar and comprise early swelling followed by hemolysis. The ranking of the activity of these acids was as follows: butoxyacetic acid (BAA) greater than propoxyacetic acid approximately equal to pentoxyacetic acid greater than ethoxyacetic acid greater than methoxyacetic acid. Furthermore, this effect of alkoxyacetic acids was associated with a parallel decrease in blood ATP levels. It is currently unknown if swelling or ATP depletion is the primary effect of these acids. In addition, at equimolar concentrations neither heptanoic, butoxypropionic, nor propoxypropionic acids caused any significant effect on rat erythrocytes in vitro. This suggests that the presence and position of the ether linkage, as it is in BAA, are critical for the development of hematotoxicity. Studies of the relationship between the toxic effect of BAA and its partitioning between erythrocytes and plasma showed that the concentration of [14C]BAA in plasma remained relatively constant while that in the erythrocytes increased as a function of time. This pattern of BAA distribution between plasma and erythrocytes was parallel to erythrocyte swelling. Incubation of BAA with rat blood for 30 min followed by removal of BAA by washing the erythrocytes twice and then continuing the incubation revealed that erythrocyte swelling was not reversible, however, the rate of swelling declined significantly.

Acetates↗
PubMed1989

Comparative metabolism and disposition of ethyl carbamate (urethane) in male Fischer 344 rats and male B6C3F1 mice.

The metabolism, disposition, and excretion of ethyl carbamate (EC) was investigated following oral or iv administration of a wide range of doses to male rats and mice. At a low dose, 4.75 mg/kg, administered iv, approximately 98% was exhaled as CO2 within 8 or 12 hr by mice or rats, respectively. However, as the dose increased, the percentage of dose eliminated as CO2 decreased in a dose-dependent manner which was much more pronounced in rats than mice. At all doses studied, mice eliminated EC as CO2 (as % dose) more rapidly than rats. Evidence of saturation of metabolism and elimination was observed at doses greater than 4.75 mg/kg in rats and greater than 47.5 mg/kg in mice. Following iv administration of 47.5 or 475 mg/kg, EC was initially evenly distributed in all tissues of each species except fat. After the initial time point (15 min), rat tissues contained higher concentrations of 14C compared to tissues of mice receiving the same dose. The disappearance of 14C from blood and various tissues followed monoexponential kinetics with rates dependent upon the species and the dose but independent of the tissue. Following oral administration, EC was completely absorbed from the gastrointestinal tracts of rats and mice at all doses studied. Approximately 5, 0.7, and 1% of the doses were excreted in urine, in feces, and as volatile organics, respectively. EC was neither an inducer nor an inhibitor of its own metabolism to CO2 following daily treatment of rats with oral doses of 47.5 mg/kg for 9 days. Only the parent compound was present in blood, lungs, skin, liver, kidney, muscle, and bile of treated rats. The urinary metabolic profile of EC was not affected by the route of administration in either species; however, in the rat but not in the mouse it was influenced by dose. Pretreatment of rats with piperonyl butoxide or SKF 525A (cytochrome P-450 inhibitors) or tri-o-cresyl phosphate (TOCP) or paraoxon (carboxylesterase inhibitors) or methyl carbamate (competitive substrate) did not greatly alter the metabolism of EC to CO2. The in vitro metabolism of EC to CO2 was not highly localized in any particular tissue or subcellular fraction of liver and was not affected by NADPH, GSH, NADH, or combinations of these cofactors. This work indicates that a number of studies of EC carcinogenicity have used doses that exceed the capacity of rats and mice to metabolize this chemical in a linear fashion.

Animals↗
PubMed1987

Calcium channel blockers protect against ethanol- and indomethacin-induced gastric lesions in rats.

The current studies were designed to investigate the effect of calcium channel blockers on chemically induced gastric lesions in rats. Results of this study indicate that pretreatment of male F344 rats with the calcium channel blockers verapamil, diltiazem, or Mg2+ significantly protected against ethanol- and indomethacin-induced gastric lesions as demonstrated by gross and histopathologic evaluation. Treatment of rats with calcium channel blockers before ethanol or indomethacin administration resulted in a significant decline in the mean number of lesions per glandular stomach, the damaged area of the glandular stomach, and the severity of lesions. Calcium channel blockers also caused a significant decline in the incidence of indomethacin-induced gastric lesions, but had no effect on the incidence of ethanol-induced gastric lesions. These results offer the first evidence that calcium channel blockers may play an important role in the protection against chemically induced gastric lesions and thereby offer insight into the mechanism of gastric ulcer formation. It is speculated that this knowledge may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.

Animals↗
PubMed1987

Absorption and metabolism of 5-(4-nitrophenyl)-2,4-pentadienal (Spydust).

5-(4-Nitrophenyl)-2,4-pentadienal (NPPD) was recently alleged to have been used as a tracking agent to monitor the activities of U.S. citizens in the Soviet Union. In order to better assess human risk from possible exposure to this compound the absorption and metabolism of [14C]NPPD has been investigated in male F344 rats. These studies have revealed that NPPD was readily and quantitatively absorbed from the gastrointestinal tract, distributed throughout the tissues, metabolized, and rapidly excreted primarily in urine. NPPD was sparingly absorbed following dermal administration of 0.01, 0.1, and 1.0 mg/cm2. The amount absorbed increased as the dose increased but the percentage of the dose absorbed decreased as the dose increased, e.g., 50% (5 of 10 micrograms applied) of the low dose was absorbed but only 5% (50 of 100 micrograms applied) of the high dose was absorbed. The material absorbed after dermal administration was rapidly excreted and the distribution and metabolism of the dermally administered compound was no different from oral administration. A total of five metabolites, 4-nitrocinnamic acid, 4-acetamidobenzoic acid, 4-nitrohippuric acid, 4-acetamidocinnamic acid, and 4-nitrobenzoic acid, were identified by cochromatography with authentic standards and comparison of UV spectra. These metabolites are formed by oxidative metabolism of the pentadienal side chain, reduction of the nitro group, and/or conjugation of the resulting amino group with acetate or carboxylic acid with glycine.

Administration, Cutaneous↗
PubMed1987

Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats.

Heavy production as well as the diversity of 2-butoxyethanol (BE) uses, which include preparation of products intended for household uses, pose a high risk of human exposure to BE. The current studies were designed to investigate the acute toxicity of BE and to evaluate the effect of age on BE-induced toxicity in F344 male rats. Data presented in this report show that BE causes severe acute hemolytic anemia resulting in significant increases in the concentration of free plasma hemoglobin. Secondary to the hemolytic effects, BE also caused hemoglobinuria as well as histopathologic changes in the liver and kidney. These effects of BE were dose- and time-dependent. Further, both the hemolytic effects and the secondary effects of BE were age dependent with older rats being more sensitive than younger rats. The metabolic basis of the greater susceptibility of older rats to BE-induced toxicity was investigated by comparing BE metabolism in adult (9- to 13-week-old) and young (4- to 5-week-old) rats. These studies revealed that there was a significantly higher portion of the administered dose eliminated by young rats as CO2 as compared to that eliminated by older rats. Similarly, a significantly higher portion of the administered dose was excreted in the urine of young rats. HPLC analysis of the urinary metabolites of BE in adult and young rats showed that the ratio of butoxyacetic acid (BAA)/BE-glucuronide + BE - sulfate (previously thought to reflect an activation/detoxification index of BE; see text) was significantly higher in older rats. We currently believe that the increase in the activation/detoxification index in older rats is caused by decreased degradation of BAA to CO2 (as evident by the lower percentage of the dose excreted as CO2 by older rats) and by depressed urinary excretion of BAA (as evident from the lower percentage of the dose excreted in the urine of older rats.

Administration, Oral↗
PubMed1987

Ethyl acrylate distribution, macromolecular binding, excretion, and metabolism in male Fisher 344 rats.

We have demonstrated previously that ethyl acrylate causes severe acute forestomach (nonglandular portion of the stomach) toxicity in rats. Ethyl acrylate was also shown to cause forestomach tumors when administered to rats chronically by gavage. The current studies were designed to investigate ethyl acrylate distribution, excretion, and metabolism, as well as the macromolecular interactions of ethyl acrylate (EtAc) in the forestomach (target organ) and liver (nontarget organ). 2,3-[14C]Ethyl acrylate was administered in corn oil at 100, 200, or 400 mg/kg by gavage. Data presented here show that the radioactivity derived from EtAc is rapidly absorbed after gavage administration and distributed into all major tissues of male F344 rats. The highest concentration of EtAc-derived radioactivity was detected in the forestomach, glandular stomach, intestine, liver, and kidney at 4 and 24 hr after dosing. The highest percentage of EtAc-derived radioactivity was found in the lipid fraction of the liver. In the forestomach, the highest percentage of EtAc-derived radioactivity was found in the protein fraction. The major route of EtAc excretion was CO2 exhalation (approximately 70% of the administered dose in 24 hr) followed by the urinary excretion. Two metabolites were identified in the urine, namely, N-acetyl-s-(2-carboxyethyl)cysteine and N-acetyl-s-(2-carboxyethyl) cysteine ethyl ester. This suggests that Michael-like addition of sulfhydryls to acrylate is a pathway of EtAc metabolism. Hydrolysis of the ethyl ester may occur before or after conjugation. Further degradation of the GSH conjugates resulted in the formation of the mercapturic acids detected in the urine of EtAc-treated rats.

Acrylates↗
PubMed1987

Comparative metabolism and excretion of resorcinol in male and female F344 rats.

Following oral administration, resorcinol was readily absorbed from the gastrointestinal tract, rapidly metabolized, and excreted by male and female rats. In both sexes, most of the dose of resorcinol (greater than 90%) was excreted in the urine within 24 hr after oral administration of 112 mg/kg, indicating little potential for bioaccumulation in animal tissues. Less than 3% of an oral dose was excreted in feces. An analysis of bile indicated that at least 50% of the dose excreted in bile undergoes enterohepatic circulation to be eventually excreted in urine. Little (less than 5%) of the parent compound was excreted in urine; most of the dose was in the form of three major and one minor metabolite. The relative amounts of metabolites excreted changed only slightly with time and dose administered. Approximately 70% of the total radioactivity in the urine of both sexes was in the form of a glucuronide conjugate. Female rats excreted a greater portion of the dose as a sulfate conjugate than males. Males excreted more of a diconjugate containing both sulfate and glucuronide groups. Repeated exposure to up to five daily doses resulted in no apparent alteration of the pattern of resorcinol absorption, metabolism, and excretion observed after a single dose.

Animals↗
PubMed1987

Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases.

2-Butoxyethanol (BE) is a massively produced glycol ether of which more than 230 million pounds was produced in the United States in 1983. It is extensively used in aerosols and cleaning agents intended for household use. This creates a high potential for human exposure during its manufacturing and use. A single exposure of rats to BE causes severe hemolytic anemia accompanied by secondary hemoglobinuria as well as liver and kidney damage. Butoxyacetic acid (BAA) was earlier identified as a urinary metabolite of BE. In addition, we have recently identified two additional urinary metabolites of BE, namely, BE-glucuronide and BE-sulfate conjugates. The current studies were undertaken to investigate the metabolic basis of BE-induced hematotoxicity in male F344 rats. Treatment of rats with pyrazole (alcohol dehydrogenase inhibitor) protected rats against BE-induced hematotoxicity and inhibited BE metabolism to BAA. Pyrazole inhibition of BE metabolism to BAA was accompanied by increased BE metabolism to BE-glucuronide and BE-sulfate as determined by quantitative high-performance liquid chromatography analysis of BE metabolites in urine. There was approximately a 10-fold decrease in the ratio of BAA to BE-glucuronide + BE-sulfate in the urine of rats treated with pyrazole + BE compared to rats treated with BE alone. Pretreatment of rats with cyanamide (aldehyde dehydrogenase inhibitor) also significantly protected rats against BE-induced hematotoxicity and modified BE metabolism in a manner similar to that caused by pyrazole. Administration of equimolar doses of BE, the metabolic intermediate butoxyacetaldehyde, or the ultimate metabolite BAA caused similar hematotoxic effects. Cyanamide also protected rats against butoxyacetaldehyde-induced hematotoxicity. Further evidence of the involvement of metabolism in hematotoxicity was demonstrated by the administration of deuterium-labeled BE (1,1-dideuterio-2-BE) which resulted in a significant delay in the development of hematotoxicity. It is therefore concluded that: a) there is a strong correlation between the amount of BAA in the urine and BE-induced hematotoxicity; b) metabolic activation of BE via alcohol and aldehyde dehydrogenases is a prerequisite for the development of BE-induced hematotoxicity; and c) hematotoxicity induced by BE can be attributed to its metabolite BAA. Finally, the current studies may prove beneficial in the treatment of acute glycol ethers poisoning with alcohol dehydrogenase inhibitors.

Acetaldehyde↗
PubMed1986

Ethyl acrylate-induced gastric toxicity. III. Development and recovery of lesions.

Rats receiving 14 daily gavage doses of 100 or 200 mg/kg ethyl acrylate (EtAc) and killed at varying times following the end of dosing exhibited dose-dependent lesions and recovery from lesions in the forestomach. The glandular stomach which was previously shown to be affected by acute exposure to EtAc appeared to have adapted to resist EtAc toxicity with repeat exposure and appeared normal in all animals. Adaptation of the forestomach was characterized by increased papillomatous thickening with dose. Lesions observed in acute exposure to EtAc were still present with repeat dosing and were more pronounced at the high dose. Forestomachs of rats which received 100 mg/kg EtAc for 14 days were recovered to normal within 2 weeks following the last dose. Forestomachs of rats receiving 200 mg/kg EtAc still exhibited numerous lesions 2 weeks following the last dose, and mucosal hyperplasia was present in the forestomachs at 4 weeks postexposure. Two lesions, submucosal fibrosis and foreign body reaction, became more prevalent in high-dose animals with time. Foreign body reaction, which was present in all animals 4 weeks postexposure, appeared to have resulted from entrapment of hair and/or feed particles in forestomach lesions in the course of healing. It is speculated that the increased cell proliferation and the induced foreign body reactions may contribute to the previously demonstrated carcinogenic effect of EtAc on the rat forestomach.

Acrylates↗
PubMed1986

Association of chemically induced forestomach cell proliferation and carcinogenesis.

A number of chemicals have been shown to cause malignant neoplasms in the forestomach of Fischer 344 rats when administered chronically by gavage. The present study was designed to identify early forestomach lesions following 2-week repeated gavage administration of some of these forestomach carcinogens. In this manner, we attempted to examine the hypothesis that early cell proliferation is associated with repetitive gavage administration of these chemicals. Groups of 8 or more male F344 rats received 1 of 6 reported forestomach carcinogens (ethyl acrylate (EtAc), diglycidyl resorcinol ether(DGRE), 1,2-dibromoethane (DBE), 1,2-dibromo-3-chloro-propane (DBCP), 1-chloro-2-methylpropene (dimethylvinyl chloride, DMVC) and 3-chloro-2-methylpropene (CMP)), 1 of 2 structurally related chemicals (methyl methacrylate (MMA) and dichloroethane (DCE)) which were negative in chronic carcinogenicity studies or the vehicle (corn oil) alone 5 days/week for 2 weeks. Histopathologic examination of forestomachs of rats killed 24 h after the last dose indicated no significant difference in the incidence or severity of epithelial cell proliferation in the rat forestomach between the vehicle control group and the 2 negative control groups. In contrast, the incidence and severity of epithelial cell proliferation of the rat forestomach in every group treated with a forestomach carcinogen was significantly higher than the incidence in the vehicle or negative control groups. These results suggest that early epithelial cell proliferation of the forestomach may be associated with at least some chemicals that induce forestomach neoplasia following chronic administration by gavage.

Animals↗
PubMed1986

Disposition and metabolism of 2-bromo-4,6-dinitroaniline in the male F344 rat.

The disposition of [14C]-2-bromo-4,6-dinitroaniline (BDNA) was studied in male F344 rats following oral or intravenous (iv) administration. The gastrointestinal absorption of BDNA was nearly complete and was not affected by dose in the range (10-100 mumol/kg body weight) studied. Following either oral or iv administration, BDNA was rapidly distributed throughout the tissues and showed no marked affinity for any particular tissue. Clearance of [14C]BDNA-derived radioactivity from various tissues was rapid and was best described by two-component decay curves. The whole-body half-life of BDNA was approximately 7 h. Within 72 h, clearance of [14C]BDNA-derived radioactivity from the body was 98% complete. [14C]BDNA was rapidly cleared by metabolism to 13 metabolites, which were excreted in urine (62%) and feces (33%). Most (66%) of the urinary radioactivity was excreted in the form of sulfate conjugates of two metabolites of BDNA; excretion of unmetabolized BDNA was minimal (less than 2%). Biliary excretion of [14C]BDNA was significant; however, some of this BDNA-derived radioactivity underwent enterohepatic circulation and was subsequently excreted in urine. Results of this study indicate that, if metabolism is a detoxification process, the rapid metabolism and excretion of this compound should minimize the likelihood of chronic toxicity from repeated exposure to BDNA beyond that predicted by data from acute or short-term exposures.

Aniline Compounds↗
PubMed1986

Disposition of 2,4-dinitroaniline in the male F-344 rat.

The disposition and metabolism of 2,4-dinitroaniline was studied in male F-344 rats following oral and i.v. administration. Gastrointestinal absorption was near complete and was not affected by dose (10-90 mumol/kg). Following either oral or i.v. administration, dinitroaniline was rapidly distributed throughout the tissues and showed no marked affinity for any particular tissue. 14C-dinitroaniline was readily cleared by metabolism to at least nine metabolites; radioactivity was excreted primarily in urine (70% dose) and to a lesser extent in faeces (25-30% dose). Clearance of radioactivity from the body was near complete in 3 days. As the whole-body half-life of dinitroaniline derived radioactivity in the rat was less than 3 h and there was no evidence for saturation of any mechanism of absorption, distribution, metabolism or excretion in the dose range studied, 2,4-dinitroaniline appears to have little potential for bioaccumulation in animal tissues. Analysis of urine and bile detected nine metabolites of 2,4-dinitroaniline. The major metabolite was excreted in urine as a sulphate conjugate and in bile as a glucuronide. This metabolite was characterized by combined h.p.l.c./mass spectrometry as 2,4-dinitrophenylhydroxylamine.

Administration, Oral↗