Hemolytic activity of ethylene glycol phenyl ether (EGPE) in rabbits.

Studies were conducted to characterize the hemolytic effects of EGPE in rabbits following oral and dermal exposure, and to evaluate the in vitro hemolytic potential of EGPE and its major metabolite using rabbit red blood cells (RBC). Gavage administration of EGPE to female New Zealand White rabbits at 100, 300, 600, or 1000 mg/kg/day for up to 10 consecutive days (one dose/day) resulted in a dose-related intravascular hemolytic anemia. The hemolytic anemia was characterized by decreased RBC count, hemoglobin concentration, packed cell volume, hemoglobinuria, splenic congestion, renal tubule damage, and a regenerative erythroid response in the bone marrow. The hemolytic anemia was observed without alterations in RBC glutathione or methemoglobin. Phenoxyacetic acid (PAA) was identified as a major blood metabolite of EGPE. In vitro exposure of female rabbit erythrocytes indicated EGPE to be considerably more hemolytic than PAA. In a 90-day dermal study in which EGPE was applied to the skin of male and female New Zealand White rabbits 6 hr/day, 5 days/week, at doses up to 500 mg/kg/day, there was no indication of a hemolytic response. The only treatment-related effects were sporadic occurrences of slight erythema and scaling of skin at the site of test material application in high dose group male and female rabbits. However, erythema and scaling were not associated with gross or histopathologic changes and were not considered toxicologically significant.

Chlorpyrifos: a 13-week nose-only vapor inhalation study in Fischer 344 rats.

Fischer 344 rats were exposed by the nose-only inhalation route to chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or 20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrations were limited by the low vapor pressure of chlorpyrifos (theoretical maximum vapor concentration of 25 ppb at 25 degrees C). No treatment-related signs of toxicity or changes in body weights were detected during the course of the study. Urinalysis, hematology, clinical chemistry, organ weights, gross pathologic, and histopathologic evaluations were performed at the end of the study with no treatment-related effects observed. In addition, no differences from controls were noted in plasma, red blood cell, or brain cholinesterase activities. The results of this study indicate that the no-observed-effect level for chlorpyrifos vapor was the highest attainable concentration, 20.6 ppb, in male and female Fischer 344 rats.

The effects of inhalation exposure to sulfuryl fluoride on fetal development in rats and rabbits.

Sulfuryl fluoride is a fumigant insecticide used for soils and permanent structures. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0, 25, 75, or 225 ppm of sulfuryl fluoride vapor via inhalation for 6 hr/day on Days 6-15 and 6-18 of gestation, respectively. Among rats, maternal water consumption was increased in the 225 ppm exposure group, but there were no indications of embryotoxicity, fetotoxicity, or teratogenicity in any of the exposed groups. Among rabbits, maternal weight loss during the exposure period (Days 6-18) was observed in the 225 ppm group. Decreased fetal body weights, considered secondary to maternal weight loss, were also observed at 225 ppm. However, no evidence of embryotoxicity or teratogenicity was observed among rabbits in any exposure group. Thus, inhalation exposure to sulfuryl fluoride was not teratogenic in either rats or rabbits exposed to levels of up to 225 ppm, and fetotoxic effects (reduced body weights) were observed among fetal rabbits only at an exposure level that produced maternal weight loss.

The chronic toxicity and oncogenicity of inhaled technical-grade 1,3-dichloropropene in rats and mice.

Male and female Fischer 344 rats and B6C3F1 mice were exposed by inhalation to target concentrations of 0, 5, 20, or 60 ppm (0, 22.7, 90.8, or 272 mg/m3) technical-grade 1,3-dichloropropene (DCPT) 6 hr/day, 5 days/week, for up to 2 years. Ancillary groups of rats and mice were exposed for 6- and 12-month periods. Significant treatment-related nonneoplastic changes following exposure for 2 years were morphological alterations in the nasal tissues of rats exposed to 60 ppm and mice exposed to 20 or 60 ppm DCPT. In addition, mice exposed to 20 or 60 ppm had hyperplasia of the transitional epithelium lining the urinary bladder. Survival of male and female rats and mice exposed to DCPT was similar to that of the corresponding controls. No statistically increased tumor incidence was observed in treated rats. The only neoplastic response observed in mice was an increased incidence of benign lung tumors (bronchioloalveolar adenomas) in male mice exposed to 60 ppm DCPT (22/50 versus 9/50 in controls).

1,1,1-trichloroethane formulation: a chronic inhalation toxicity and oncogenicity study in Fischer 344 rats and B6c3F1 mice.

Groups of male and female Fischer 344 rats and B6C3F1 mice (80/sex/group) were exposed to vapor concentrations of 0, 150, 500, or 1500 ppm 1,1,1-trichloroethane formulation 6 hr/day, 5 days/week, for 2 years. Ten rats and mice/sex from each group were predesignated for interim sacrifices after 6, 12, and 18 months of exposure. Fifty rats and mice/sex/group were assigned to the study to be terminated after 24 months. Parameters measured during the study included mortality, in-life clinical signs of toxicity, hematology, urinalysis (rats only), clinical chemistry, body weight, organ weights (liver, kidneys, brain, heart, testes), gross pathology, and histopathology. Inhalation exposure of male and female Fischer 344 rats to 1500 ppm vapor of the 1,1,1-trichloroethane formulation for 2 years resulted in a significant decrease in body weights of females. In addition, very slight microscopic hepatic effects were seen in the liver of 1500 ppm-exposed male and female rats necropsied at 6, 12, and 18 months. The hepatic effects could not be discerned at 24 months due to confounding geriatric changes. In the rats exposed to 150 and 500 ppm there were no changes that were considered due to exposure to the 1,1,1-trichloroethane formulation. There were no toxic effects noted in male or female mice at any exposure concentration tested. There were no indications of an oncogenic effect in rats or mice following 2 years of exposure to this 1,1,1-trichloroethane formulation.

Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice.

In order to provide a comprehensive subchronic inhalation toxicity study of the soil fumigant, technical grade 1,3-dichloropropene (DCPT), male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 10, 30, 90, or 150 ppm DCPT vapors 6 hr/day, 5 days/week for 13 weeks. The primary target tissues of inhaled DCPT were identified as the nasal mucosa of both sexes of rats and mice, and the urinary bladder of female mice. In addition, depressed growth rates of all animals exposed to 90 or 150 ppm DCPT (up to 20% in rats and 12% in mice) resulted in a variety of alterations in hematologic and clinical chemistry parameters, and changes in organ weights relative to controls. Nasal mucosal effects consisted of a dose-related slight degenerative effect of nasal olfactory epithelium or a mild hyperplasia of the respiratory epithelium or both in all animals exposed to 90 or 150 ppm and 2 of 10 male rats exposed to 30 ppm DCPT. Some focal areas of respiratory metaplasia were also noted in high exposure group mice. Urinary bladder effects consisted of a diffuse, moderate hyperplasia of the transitional epithelium in female mice exposed to 90 or 150 ppm DCPT. No treatment-related effects were observed in rats or mice exposed to 10 ppm DCPT vapors.

Evaluation of the effects of inhalation exposure to 1,3-dichloropropene on fetal development in rats and rabbits.

1,3-Dichloropropene (DCP), which has found widespread use as a soil fumigant, was evaluated for its potential effects on embryonal and fetal development in rats and rabbits. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropene for 6 hr/day during gestation Days 6-15 (rats) or 6-18 (rabbits). Exposure-related decreases in maternal weight gain and feed consumption were observed in rats at all treatment levels. Decreased weight gain was also observed among rabbits at 60 and 120 ppm. A slight, but statistically significant, increase in the incidence of delayed ossification of the vertebral centra in rats exposed in utero to 120 ppm of DCP was considered of little toxicologic significance in light of the maternal toxicity observed at this exposure concentration. No evidence of a teratogenic or embryotoxic response was observed in either species at any exposure level tested. Thus, it was concluded that DCP was not teratogenic at exposure levels up to 120 ppm in either rats or rabbits.

Metabolism and disposition of propylene glycol monomethyl ether (PGME) beta isomer in male rats.

Male Fischer 344 rats were given a single po dose of approximately 1 or 8.7 mmol/kg of radiolabelled propylene glycol monomethyl ether (PGME) beta isomer (2-methoxy-1-propanol). After dosing, expired air, excreta, and tissues were analyzed for 14C activity and metabolites in urine were isolated and identified. Approximately 70 to 80% of the 14C was excreted in urine while about 10 to 20% was eliminated as 14CO2 within 48 hr after dosing. The major urinary metabolite was 2-methoxypropionic acid, which accounted for approximately 93 and 79% of the radioactivity in urine from high- and low-dose animals, respectively. A glucuronide conjugate of the PGME beta isomer was also identified in urine; this metabolite accounted for approximately 3 to 4% of the radioactivity in the urine at both dosages. These results indicate that the PGME beta isomer is metabolized via different routes to different types of metabolites in comparison to the PGME alpha isomer. While the two isomers are biotransformed differently, there is a substantial toxicological data base which clearly shows that the commercial grade PGME mixture (2 to 5% beta isomer) has a low degree of biological activity.

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).

Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice.

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 25 or 75 ppm (0, 0.10 or 0.31 mg/l) ethyl acrylate vapors, 6 hours per day, 5 days per week, for a total of 27 months. Additional rats and mice were exposed to 225 ppm (0.92 mg/l) for 6 months and then held for 21 additional months post-exposure. Histopathologic changes in olfactory portions of the nasal mucosa were present in animals in all of these three exposure groups. These microscopic exposure-related changes were concentration-dependent, primarily in terms of distribution of the lesions within the nasal cavity. Generally those areas of the nasal mucosa normally lined by olfactory epithelium were altered, while the regions lined by respiratory epithelium were relatively unaffected. There was no indication of an oncogenic response in any organ or tissue in either rats or mice. A follow-up study in which Fischer 344 rats and B6C3F1 mice were exposed to 5 ppm (0.02 mg/l) for 24-months revealed no treatment-related changes in the nasal mucosa.

Teratologic evaluation of inhaled propylene glycol monomethyl ether in rats and rabbits.

Pregnant Fischer 344 rats and New Zealand White rabbits were exposed via inhalation to 0, 500, 1500, or 3000 ppm of propylene glycol monomethyl ether (PGME) for 6 hr/day on Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Initial exposure to 3000 ppm of PGME produced signs of mild central nervous system depression which were more pronounced and of a longer duration in rats than in rabbits. Postexposure recovery was rapid and accomodation to the test atmosphere developed following subsequent exposures. Rats and rabbits exposed to 3000 ppm had decreased weight gains over the exposure period and rats had decreased food consumption during the first 3 days of exposure. Fetal examination revealed no embryotoxic or teratogenic effects among rats or rabbits in any exposure group. Slight fetotoxicity among rats, in the form of delayed sternebral ossification, was observed at 3000 ppm. Thus, it was concluded that PGME was not teratogenic at exposure levels up to 3000 ppm.

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.