Metabolism and disposition of dipropylene glycol monomethyl ether (DPGME) in male rats.

Male Fischer 344 rats were given a single oral dose of approximately 1289 mg/kg (8.7 mmol/kg) of [14C]DPGME. After dosing, expired air, excreta, and tissues were analyzed for 14C activity, and metabolites in urine were isolated and identified. Approximately 60% of the administered 14C activity was excreted in urine, while 27% was eliminated as 14CO2 within 48 hr after dosing. DPGME, PGME, dipropylene glycol, propylene glycol, as well as sulfate and glucuronide conjugates of DPGME were identified in urine of animals given [14C]DPGME. Results of the study indicate that DPGME is metabolized via the same routes to the same general types of metabolites as previously identified for propylene glycol monomethyl ether (PGME).

Propylene glycol monomethyl ether acetate (PGMEA) metabolism, disposition, and short-term vapor inhalation toxicity studies.

Male Fischer 344 rats were given a single po dose of approximately 8.7 mmol/kg of [1-14C]propylene glycol monomethyl ether acetate (PGMEA) or exposed to 3000 ppm [1-14C]PGMEA for 6 hr. After dosing, expired air, excreta, and tissues were analyzed for 14C activity, and metabolites in urine were isolated and identified. Approximately 64% of the administered 14C activity was eliminated as 14CO2 and about 24% was excreted in urine within 48 hr after a single po dose of radiolabeled PGMEA. Similarly, 53% was eliminated as 14CO2 and 26% was excreted in urine within 48 hr after the inhalation exposure. Propylene glycol, propylene glycol monomethyl ether (PGME), and the sulfate and glucuronide conjugates of PGME were identified as urinary metabolites after po dosing, as well as after inhalation exposure to PGMEA. The urinary metabolite profile and disposition of [14C]PGMEA were nearly identical to results previously obtained with propylene glycol monomethyl ether (PGME), indicating that PGMEA is rapidly and extensively hydrolyzed to PGME in vivo. A short-term vapor inhalation toxicity study in which male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 300, 1000, or 3000 ppm PGMEA confirmed that there were no substantial differences in the systemic effects of PGMEA as compared to PGME. However, histopathologic examination did reveal changes in the olfactory portions of the nasal mucosa of rats and mice exposed to PGMEA, which may be related to acetic acid resulting from hydrolysis of PGMEA in the nasal epithelium.

Ethylene glycol monomethyl ether and propylene glycol monomethyl ether: metabolism, disposition, and subchronic inhalation toxicity studies.

Short-term and subchronic vapor inhalation studies have shown that there are pronounced differences in the toxicological properties of ethylene glycol monomethyl ether (EGME) and propylene glycol monomethyl ether (PGME). Overexposure to EGME has resulted in adverse effects on testes, bone marrow and lymphoid tissues in laboratory animals. PGME does not affect these tissues, and instead, overexposure to PGME has been associated with increases in liver weight and central nervous system depression. EGME is primarily oxidized to methoxyacetic acid in male rats, while PGME apparently undergoes O-demethylation to form propylene glycol. Since methoxyacetic acid has been shown to have the same spectrum of toxicity as EGME in male rats, the observed differences in the toxicological properties of EGME and PGME are thought to be due to the fact that the two materials are biotransformed via different routes to different types of metabolites.

Biochemical factors involved in the effects of orthophenylphenol (OPP) and sodium orthophenylphenate (SOPP) on the urinary tract of male F344 rats.

Carbon-14 labeled sodium orthophenylphenate (SOPP) was incubated with purified microsomes isolated from rat liver. During this incubation, macromolecular binding of radioactivity (MMB) was observed. MMB was dependent upon the presence of both active microsomes and NADP. In vivo studies of MMB were also conducted. MMB was measured in the liver, kidney, and bladder of male F344 rats administered SOPP (0.19 to 1.88 mM/kg) or orthophenylphenol (OPP) (0.29 to 2.97 mM/kg). The levels of MMB were not linearly related to administered dose. Disproportionate increases in MMB were observed in each tissue after administration of 0.75 to 1.88 mM/kg of SOPP. Disproportionate increases in MMB in liver and bladder tissue were also observed with OPP at somewhat higher doses. These studies indicate that the intermediate(s) produced by the oxidative pathway for metabolism of SOPP and OPP are capable of binding to biological macromolecules. The disproportionate increases in MMB observed in vivo after high doses are probably associated with saturation of the primary (conjugative) metabolic pathway for SOPP and OPP metabolism.

Determination of cis- and trans-1,3-dichloropropene in whole rat blood by gas chromatography and gas chromatography-chemical ionization mass spectrometry with selected ion monitoring.

An analytical method was developed for quantitating low concentrations of the isomers cis- and trans-1,3-dichloropropene in whole rat blood by gas chromatography and gas chromatography-chemical ionization mass spectrometry with selected ion monitoring.

Comparative metabolism and disposition of ethylene glycol monomethyl ether and propylene glycol monomethyl ether in male rats.

Male Fischer 344 rats were given a single po dose of approximately 1 or 8.7 mmol/kg of [14C]EGME (ethylene glycol monomethyl ether) or [14C]PGME (propylene glycol monomethyl ether). After dosing, expired air, excreta, and tissues were analyzed for 14C; metabolites in urine were isolated and identified. There were pronounced differences in the metabolism and disposition of [14C]EGME and [14C]PGME. Approximately 50 to 60% of the administered 14C was excreted in urine, and about 12% was eliminated as 14CO2 within 48 hr after a single po dose of [14C]EGME. For PGME, only 10 to 20% of the administered 14C was excreted in urine, while 50 to 60% was eliminated as 14CO2 within 48 hr. Methoxyacetic acid was identified as the primary urinary metabolite of EGME, accounting for 80 to 90% of the total 14C in urine. PGME, propylene glycol(1,2-propanediol), and the sulfate and glucuronide conjugates of PGME were identified in urine of rats given PGME. Since methoxyacetic acid causes the same spectrum of toxicity as EGME in male rats, it is likely that the adverse effects of EGME are the result of its in vivo bioactivation to methoxyacetic acid. Hence, differences in routes of metabolism and types of metabolites appear to be the underlying basis for the remarkably different toxicologic properties of EGME and PGME, respectively.

Quantitative determination of 1,2-dibromo-3-chloropropane in whole rat blood and drinking water by gas chromatography.

1,2-Dibromo-3-chloropropane (DBCP) in an amber-colored liquid that has been used as a soil fumigant for nematodes since 1957 in agricultural cropland. Formulations containing DBCP have been primarily sold under the trademarks Fumazone (Dow Chemical, Midland, MI, U.S.A.) and Nemagon (Shell, THe Hague, The Netherlands). Recent reports have associated exposure to DBCP with disruption of spermatogenesis and azoospermia or oligospermia in male workers. Tests on laboratory animals have indicated that DBCP has an adverse effect on spermatogenesis and leads to testicular atrophy. In support of DBCP studies in animals, an analytical method was developed to determine low-level concentrations of DBCP in whole blood. Previous analytical methods for DBCP in blood required extensive sample preparation and steam distillation which limits the number of analysis per time period. This paper describes a simple gas chromatographic-electron-capture detection (GC-ECD) method that is both specific and sensitive to DBCP blood levels at concentrations as low as 2.28 x 10(-1) ng/ml DBCP. In addition, a quantitative analytical method was developed to measure levels of DBCP in drinking water which parallels the method in blood.

Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recovery.

Groups of male and female Fischer 344 rats were administered acrylamide in their drinking water at 0, 0.05, 0.2, 1, 5, or 20 mg/kg/day for up to 93 days. Following the administration of acrylamide in the drinking water, male rats from each dose level were held for up to 144 days of recovery. The 20 mg/kg/day groups had definite treatment-related effects after 92 (males) and 93 (females) days. They were dragging the rear limbs, body weights were decreased, serum cholinesterase activity was decreased in top dose females, and packed cell volume, red blood cell, and hemoglobin values were slightly decreased in males and females. In the 20 mg/kg/day groups, the primary target tissue was the peripheral nerve with lesions consisting of severe degeneration characterized by demyelinization and axonal loss. Slight spinal cord degeneration was observed. Other effects included atrophy of skeletal muscle, testicular atrophy, and distended urinary bladders; these were probably secondary to the nerve degeneration. After 144 days of recovery, the lesions had partially or completely reversed. Parameters affected at the 5 mg/kg/day dose level after 92 (males) and 93 (females) days consisted of peripheral nerve degeneration which were of a lesser degree of severity than those seen in the 20 mg/kg/day groups and appeared to have completely reversed after 111 days of recovery. In rats given 1 mg/kg/day, a minimal treatment-related effect was observed in males after 92 days, and this was limited to very slight nerve degeneration using electron microscopy (females were not examined by electron microscopy). This observed effect appeared to have reversed after 25 days of recovery. No treatment-related effects were seen in any of the parameters monitored in the rats given 0.05 or 0.2 mg/kg/day of acrylamide.