INHALATION TOXICITY, NEUROTOXICITY, AND TOXICOKINETIC STUDIES OF p-CHLOROBENZOTRIFLUORIDE

Abstract

Sprague-Dawley rats (10/sex/group) were exposed via whole-body inhalation exposure 6 h/ day, 5 days/wk for 13 wk, to exposure levels (mean SD) of 0, 10 1, 51 1, or 252 5 ppm of para -chlorobenzotrifluoride (PCBTF, CAS number 98-56-6). Additional animals were included for evaluation after a 13-wk recovery (5/sex/ group), neuropathology (5/sex/group/interval), and for toxicokinetic analyses (45 females, 51 ppm group only). The high exposure level was set based upon results of a 4-wk study, which found tremors, hyperactivity, and increases in total protein, calcium, albumin, globulin, and phosphorus at 1044 ppm, and increases in absolute or relative organ weights in the kidney at 262 ppm and above and in the liver at 494 ppm and above. In the 13-wk study, there were no untoward observations recorded either during the exposures or during weekly detailed clinical evaluations. There was no indication of any PCBTF-related ocular disease or changes seen in any measured hematological and clinical chemistry parameters. Body weight gain was not affected by these exposures. A possible but minimal decrease in food consumption (6% in the 252 ppm group) was seen during the first few weeks of exposure. There were no PCBTF effects on the nervous system as measured by motor activity, a functional observational battery of assessments, or neuropathology. In the 252 ppm exposure group, an 11% increase in relative liver weights in both males and females correlated with the centrilobular hypertrophy seen microscopically. There were no PCBTF-related macroscopic observations. Microscopically, PCBTF-related centrilobular hypertrophy was present in 3 males and 3 females in the 252 ppm group at the time of the terminal sacrifice but not in the 10 or 51 ppm groups. Centrilobular hypertrophy was not present among recovery animals at any exposure level. This effect was considered to be an adaptive response. Toxicokinetic samples drawn pre-and postexposure on day 5 of exposure every other week showed an increasing level of PCBTF in the preexposure bloods and a decreasing level of PCBTF in postexposure bloods over the course of the study. Multiple tissue samples obtained during a single nose-only exposure after completion of the 13-wk of whole-body exposures found the PCBTF level to be initially 10-fold higher in the fat. The PCBTF level in the brain, kidney, liver, lungs, muscle, fat, and blood approximately doubled in each tissue during the nose-only exposure, but the PCBTF fat level did not decay during the 24-h postexposure period.