Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid.

The metabolic series approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. The metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol and n-butyric acid (the butyl series), was first demonstrated using a provisional physiologically based pharmacokinetic (PBPK) model for the butyl series. The objective of this work was to complete development of the PBPK model for the butyl series. Rats were administered test compounds by iv bolus dose, iv infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular, and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate (100% of alveolar ventilation) and n-butanol (50% of alveolar ventilation) was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following iv administration and inhalation exposure to n-butyl acetate and n-butanol in rats and arterial blood n-butanol kinetics following inhalation exposure to n-butanol in humans. These validated inhalation route models can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Human equivalent concentrations of 169 ppm and 1066 ppm n-butanol corresponding to the rat n-butyl acetate NOAELs of 500 and 3000 ppm were derived using the models.

Metabolism and disposition of hydroquinone in Fischer 344 rats after oral or dermal administration.

Studies were conducted to determine the absorption, tissue distribution, excretion, and metabolism of 14C-hydroquinone (HQ) in male and female rats following single oral, repeated oral, or 24-h dermal administration. The concentration of parent compound in blood was also determined following a single 50-mg/kg gavage administration. Absorption into the blood was rapid after oral dosing; the maximum concentration of parent compound was attained within 20 min after dosing, and the maximum concentration of total 14C was attained within 30 min. Parent compound represented 1% of total 14C in blood, indicative of extensive first-pass metabolism. Excretion was primarily via the urine within the first 8h of gavage. Typically, 87-94% of the 14C was excreted in urine. Dermal application of 14C-HQ (20 microCi) as a 5.4% aqueous solution resulted in near background levels of 14C in blood; the maximum mean blood concentration was 0.65 microg HQ equivalents/g in females and not quantifiable in males. The majority (61-71%) of the 14C was recovered from the skin surface by washing at 24 h. HQ was extensively metabolized following oral dosing with typically <3% of the dose excreted as parent compound. The major urinary metabolites of HQ were glucuronide and O-sulfate conjugates, which represented 45-53% and 19-33%, respectively, of an oral dose. A <5% metabolite was identified as a mercapturic acid conjugate of HQ.

In vivo metabolism and kinetics of ethylene glycol monobutyl ether and its metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid, as measured in blood, liver and forestomach of mice.

1. Ethylene glycol monobutyl ether (EGBE) causes forestomach hyperplasia and neoplasia in mice when administered chronically by inhalation. 2. The study was initiated to test the physiologically based pharmacokinetic (PBPK) model prediction that 2-butoxyacetaldehyde (BAL), a transient, labile intermediate in the oxidation of EGBE to butoxyacetic acid (BAA), is unlikely to achieve concentrations sufficient to cause DNA damage in target tissues. 3. Male and female B6C3F1 mice were administered a high oral dose of EGBE (600mgkg(-1)), and tissues were collected at 5, 15, 45 and 90min following the dose. The tissues were processed for determination of EGBE, BAL and BAA by gas chromatography-mass spectrometry. 4. BAL was detected at low concentrations in all tissues sampled and at all time points following EGBE administration (about 0.3-33 microM). BAL concentrations were highest in the initial samples (5 min) in all tissues and declined from that point. 5. BAL concentrations in liver and forestomach tissues corresponded to the peak concentrations predicted by an already published PBPK model, and are higher than BAL concentrations that could be achieved by inhalation exposure to EGBE. 6. Mouse inhalation exposure to EGBE is therefore unlikely to generate BAL concentrations in tissues sufficient to initiate a carcinogenic response.

Family approach for estimating reference concentrations/doses for series of related organic chemicals.

The family approach for related compounds can be used to evaluate hazard and estimate reference concentrations/doses using internal dose metrics for a group (family) of metabolically related compounds. This approach is based upon a simple four-step framework for organizing and evaluating toxicity data: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response. Expansion of the traditional exposure-response analysis has been increasingly incorporated into regulatory guidance for chemical risk assessment. The family approach represents an advancement in the planning and use of toxicity testing that is intended to facilitate the maximal use of toxicity data. The result is a methodology that makes toxicity testing and the development of acceptable exposure limits as efficient and effective as possible. An example is provided using butyl acetate and its metabolites (butanol, butyraldehyde, and butyrate), widely used chemicals produced synthetically by the industrial oxo process. A template pharmacokinetic model has been developed that comprises submodels for each compound linked in series. This preliminary model is being used to coordinately plan toxicity studies, pharmacokinetic studies, and analyses to obtain reference concentrations/doses. Implementation of the family approach using pharmacokinetic modeling to obtain tissue dose metrics is described and its applications are evaluated.

Bioavailability and metabolism of hydroquinone after intratracheal instillation in male rats.

The purpose of this study was to investigate the rate and extent of hydroquinone (HQ) absorption and first pass metabolism in the lungs of male rats in vivo. [14C]HQ in physiological saline was administered intratracheally via an indwelling endotracheal tube to simulate inhalation exposure to HQ dust. The bioavailability of HQ was determined by blood sampling simultaneously at arterial and venous sites beginning immediately after administration to conscious rats. Pulmonary absorption and metabolism, and systemic metabolism and elimination were determined by chromatographic analysis of parent compound and metabolites in blood samples after intratracheal administration of [14C]HQ at 0.1, 1.0, and 10 mg/kg. Pulmonary absorption of HQ was found to be very rapid with [14C]HQ detectable in arterial blood, and to a lesser extent in venous blood, within 5 to 10 s after dose administration. Only [14C]HQ was detected in the initial (5-10 s) arterial blood samples at all dose levels, indicating that pulmonary metabolism of HQ was not extensive. However, later blood samples (45-720 s) indicated rapid metabolism and elimination of the parent compound and metabolites after intratracheal absorption. The elimination half-life from the 0.1 mg/kg dose was allometrically scaled to human proportions and used to estimate the steady-state (maximum) human blood concentrations of HQ resulting from presupposed workplace exposures. The estimates indicated minimal levels of HQ in human blood after respiratory exposures of greater than 1 h at 0.1 or 2.0 mg/m3; these levels were less than background concentrations of HQ detected in human blood in previous studies.

Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat.

1. Excretion balance studies were conducted with 2-ethylhexanoic acid (EHA) in the female Fischer 344 rat following single high (1 g/kg) or low (0.1 g/kg) oral doses of [2-14C-hexyl]EHA, following repeated oral dosing with unlabelled EHA and a final [14C]EHA oral dose at the low dose level, following dermal exposure with a high (1 g/kg) and low (0.1 g/kg) applied dose of [14C]EHA, and following a 1 mg/kg i.v. dose of [14C]EHA. 2. Oral, i.v. and dermal doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 3. After oral dosing of 0.1 g/kg, the mean peak blood level was 85.1 micrograms equivalents EHA/g. Maximum blood concentrations were detected at either 15 or 30 min in individual animals. After dermal application of 0.1 g/kg, the mean peak blood level of 7.9 micrograms equivalents EHA/g was attained at 8 h. 4. Occlusive dermal exposure caused damage to the epidermis in the first 24 h after application and resulted in dermal absorption of 70% relative to i.v. dosing, based on the ratio of percent dose in excreta. 5. Dermal application followed by prompt washing of the skin resulted in recovery of 101.9% from the skin surface and < 0.2% in the excreta. 6. The major urinary metabolites were the glucuronide of EHA, 2-ethyl-1,6-hexanedioic acid (namely 2-ethyladipic acid), 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-6-hydroxyhexanoic acid and ethylketohexanoic acid. Evidence for metabolism via beta-oxidation was also found, consistent with the incorporation of EHA into normal cellular intermediary metabolism.

In vivo percutaneous absorption of [14C]DEHP from [14C]DEHP-plasticized polyvinyl chloride film in male Fischer 344 rats.

These studies investigated the migration of di(2-ethylhexyl) phthalate (DEHP) contained as a plasticizer in polyvinyl chloride (PVC) from plastic film and its absorption through rat skin in iivo. Sheets of PVC film (15 cm2) plasticized with [14C]DEHP were applied to the shaved backs of eight male rats in two separate experiments. For Study I, the PVC film was removed after 24 hr, the animals were rewrapped to prevent them from ingesting any residual DEHP at the exposure site, and urine and faeces were collected at regular intervals for 7 days. For Study II, the PVC film was removed after 24 hr, and the animals were immediately killed by CO2 inhalation. Urine and faeces were collected at 24 hr, and the exposure site was washed and rinsed to remove residual [14C]DEHP. In both studies, the amounts of radioactivity transferred from the film were extremely small, amounting to 0.0643% (Study I) and 0.126% (Study II) of that applied. The transferred radioactivity was found to be in three separate fractions. Radioactivity readily removed from the skin (mean 75% of the transferred radioactivity), radioactivity remaining at the application site at sacrifice. and absorbed radioactivity, that is, that distributed systemically or eliminated. The mean absorption rates for DEHP, calculated from the sum of the quantities absorbed plus that present in the exposure site, were: Study I, 0.239, and Study II, 0.242 microg/cm2/hr.

Human exposure to naturally occurring hydroquinone.

Hydroquinone (HQ) is a nonvolatile chemical used in the photographic, rubber, chemical, and cosmetic industries. HQ is also known to occur in nature as the beta-D-glucopyranoside conjugate (arbutin), and free HQ is a known component of cigarette smoke. Low concentrations of HQ have been detected in the urine and plasma of humans with no occupational or other known exposure to HQ. The studies reported here investigate dietary and other potential sources of HQ and their contribution to HQ concentrations in the plasma and urine of human volunteers. Analysis of possible food sources of HQ by GC indicated significant amounts of arbutin in wheat products (1-10 ppm), pears (4-15 ppm), and coffee and tea (0.1 ppm). Free HQ was found in coffee (0.2 ppm), red wine (0.5 ppm), wheat cereals (0.2-0.4 ppm), and broccoli (0.1 ppm). After consuming a meal including arbutin- and HQ-containing foods, volunteers showed significant increases in plasma and urinary levels of HQ and its conjugated metabolites (total HQ). Mean plasma concentrations of total HQ peaked at 5 times background levels at 2 h after the completion of the meal, and mean urinary excretion rates of total HQ peaked at 12 times background at 2-3 h after the meal. Immediately after smoking four cigarettes in approximately 30 min, mean plasma concentrations of total HQ were maximally 1.5 times background levels; mean urinary excretion rates of total HQ peaked at 2.5 times background at 1-3 h after smoking. These data indicate that considerable human exposure to HQ can result from plant-derived dietary sources and, to a lesser extent, from cigarette smoke.

Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat.

1. Excretion balance studies were conducted with 2-ethylhexanol (2-EH) in female Fischer 344 rats following single high (500 mg/kg) and low (50 mg/kg) oral doses of [14C]2-EH, following repeated oral dosing with unlabelled 2-EH at the low level, following dermal exposure for 6 h with a 1 g/kg applied dose of [14C]2-EH, and following a 1 mg/kg i.v. dose of [14C]2-EH. 2. The high, low and repeated low oral dose studies with 2-EH showed similar excretion balance profiles of [14C], with some evidence of metabolic saturation at the high dose. 3. No evidence of metabolic induction was seen following the repeated low oral dosing. 4. All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 5. The dermal dosing resulted in only about 5% absorption of the 1 g/kg dose, with the major portion of the dose recovered unabsorbed from the dermal exposure cell at 6 h. 6. Urinary metabolites eliminated following the oral and dermal doses were predominantly glucuronides of oxidized metabolites of 2-EH, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.

The metabolism and disposition of ethyl 3-ethoxypropionate in the rat.

1. The metabolism and disposition of ethyl 3-ethoxypropionate (EEP) in male Sprague-Dawley rats was studied following single oral gavage at 150 or 1500 mg/kg. The 14C-EEP was rapidly absorbed at both dose levels, and was excreted predominantly as metabolites in the urine within 24 h of administration. 2. The major urinary metabolites of EEP were monoethyl malonate and 3-ethoxypropionate. Other metabolites included malonic acid and the glycine conjugate of 3-ethoxypropionate. Trace amounts of 14C-EEP were detected after both doses. 3. 14CO2 in the expired air accounted for 34% and 20% of the dose at 150 and 1500 mg 14C-EEP/kg, respectively, mostly in the first 24 h following administration. The appearance of 14CO2 indicates extensive oxidation of the molecule, and the lower percentage of 14CO2 at the high dose possibly indicates saturation of an oxidative metabolic pathway. 4. No evidence was found for alkoxyacetic acid metabolites, such as those produced by metabolism of some low molecular weight ethylene glycol ethers.

Metabolic studies with diethylene glycol monobutyl ether acetate (DGBA) in the rat.

1. The in vitro hydrolysis of DGBA in rat blood and its in vivo metabolism and disposition in male Sprague-Dawley rats were studied. 2. DGBA (5 mM) was hydrolysed in rat blood to diethylene glycol monobutyl ether (DGBE) with a half-life of less than 3 min. 3. 14C-DGBA was rapidly absorbed from the gastrointestinal tract and eliminated predominantly in rat urine within 24 h following oral administration at 200 or 2000 mg/kg. The major urinary metabolite was 2-(2-butoxyethoxy)acetic acid. No unchanged DGBA or DGBE was detected in rat urine at either dose level. 4. No evidence was found for excretion of 2-butoxyacetic acid, which has been shown to exert haematological effects in rats.

Pulmonary and percutaneous absorption of 2-propoxyethyl acetate and 2-ethoxyethyl acetate in beagle dogs.

A comparison was made of the absorption and elimination rates of 2-propoxyethyl acetate (PEA) and 2-ethoxyethyl acetate (EEA) following inhalation, dermal application or IV administration. Male beagle dogs were exposed to 50 ppm PEA or EEA for 5 hr, and breath samples were collected during the exposure and a 3-hr recovery period. Both compounds were rapidly absorbed through the lungs. After 10 min of exposure, the concentrations of the parent compounds in the expired breath were 5 to 10 ppm (80-90% absorption) and reached plateau values at about 3 hr of 13 ppm for PEA (74% absorption) and 16 ppm for EEA (68% absorption). Post-exposure breath samples declined exponentially to 0.5 ppm and 2 ppm after 3 hr for PEA and EEA, respectively. Expired concentrations of PEA were slightly, but significantly (p less than 0.025), lower than those of EEA at corresponding times during the exposure. After IV dosing with 1 mg/kg [ethyl-1,2-14C]PEA, the urine contained 61% and 88% of the dose in 4 and 24 hr, respectively. [14C]EEA was eliminated more slowly, with 20% and 61% of the dose appearing in the urine in 4 and 24 hr, respectively. Blood elimination half-lives were 1.6 hr for [14C]PEA and 7.9 hr for [14C]EEA. Only trace amounts of 14CO2 (less than 1%) or volatile materials (less than 0.1%) were detected in the expired air with either compound. For studies of percutaneous absorption, [14C]PEA or [14C]EEA was added to undiluted compound and applied in a glass cell to a shaved area on a dog's thorax for 30 or 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)