Acute and 2-Week Aerosol Inhalation Studies on 970 and 1700 Molecular Weight Ethylene Oxide/Propylene Oxide (EO/PO) Polymers

Abstract

Prior aerosol inhalation studies on heavier molecular weight members of this series of ethylene oxide/propylene oxide (EO/PO) polymers have demonstrated that the lung is the primary target organ in rats. These studies extended the toxicological data on the lower molecular weight (MW) members (970 and 1700) of this series. In the present group of studies, the 4-hr acute LC₅₀ value (95% confidence limits) for the 970 MW polymer (U-260) was determined to be 4770 (4260–5350) mg/m³ for the combined sexes of Sprague-Dawley rats. A previous study had determined the LC₅₀ value for the 1700 MW polymer (U-660) to be 4670 (4090–5320) mg/m³ in Wistar rats. Repeated exposure studies were also conducted on both polymers, in which Fischer 344 rats were exposed for 6 hr/day, 5 days/week, for 9 exposures. For U-660, repeated exposure to mean concentrations of 504, 982, or 2460 mg/m³ produced total mortality at 2460 mg/m³, while signs of ocular and nasal irritation, respiratory difficulties, and reduced body weight (BW) and/or BW gain occurred in the 504 and 982 mg/m³ groups. Many of the hematological, serum chemistry, and urinalysis parameters were abnormal for the 504 and 982 mg/m³ groups when compared to controls. Absolute and relative lung weights were increased for the 504 and 982 mg/m³ groups. Of the organs evaluated, only the lung had histopathological lesions, including interstitial pneumonitis, bron-chioalveolar cell hyperplasia, and intra-alveolar macrophage infiltrates. The severity of the lesions was concentration-related. In a subsequent U-660 study with exposure concentrations of 5, 51, 98, and 492 mg/m³, effects observed at 492 mg/m³ were consistent with those observed in the previous U-660 study at 504 mg/m³. The most notable effects of lower concentrations included increases in absolute and relative lung weight observed for male rats of the 51, 98, and 492 mg/m³ groups and female rats of the 98 and 492 mg/m³ groups, as well as increases in absolute and/or relative kidney weights noted for females for the 98 and 492 mg/m³ groups. Additionally, histological evaluation indicated an increased incidence or alveolar histiocytosis for male animals exposed to 51 mg/m³ or higher concentrations of U-660. However, the injury to the lung that resulted from exposure to 492 mg/m³ U-660 completely resolved during a 6-week recovery period. For U-260, repeated exposure to mean concentrations of 5, 52, or 512 mg/m³ produced decreased BW gain in the 52 and 512 mg/m³ groups and increased absolute kidney weights in the 512 mg/m³ group. There were no histopathological lesions in the kidneys or lungs. Thus, despite the similar LC₅₀ value for these compounds, data for the 1700 MW polymer (U-660) indicate that the toxicity is cumulative, while data for the 970 MW polymer (U-260) indicate that, in contrast to other higher MW members of this series, pulmonary toxicity is not produced in rats during a 2-week exposure to concentrations up to 512 mg/m³. Further, a clear no-observed-effect concentration of 5 mg/m³ was established for both U-660 and U-260.