Application of molecular encapsulation for toxicology studies: comparative toxicity of p-Chloro-alpha, alpha, alpha-trifluorotoluene in alpha-cyclodextrin vehicle versus corn oil vehicle in male and female Fischer 344 rats and B6C3F1 mice.
The application of alpha-cyclodextrin (alpha-CD) as an alternative vehicle for water insoluble and volatile chemicals was investigated in toxicity studies of p-chloro-alpha, alpha, alpha-trifluorotoluene (CTFT). Groups of F344 rats and B6C3F1 mice of each sex were administered CTFT (97% pure) by gavage in either corn oil or alpha-CD aqueous formulations daily for 14 consecutive days. The dose levels used were 10 (mice only), 50, 400, and 1000 mg/kg for corn oil vehicle and 10, 50, and 400 mg/kg (maximum achievable dose at gavage volume of 5 ml/kg) for alpha-CD vehicle. With both vehicles CTFT and alpha 2u-globulin were found to accumulate in the male rat kidney after 14 days of exposure and a dose-related toxic nephropathy was observed at dose of 50 mg/kg or higher. The hepatocellular hypertrophy and cytoplasmic vacuolation of the adrenal cortex which appeared in dosed male and female rats were also found to be independent of vehicle. Clinical pathology findings suggested a mild anemia and cholestasis in rats. With both vehicles no tissue bioaccumulation of CTFT was found in male or female mice. Vehicle-independent hepatocellular hypertrophy and cholestasis were also observed in mice at doses of 400 and 1000 mg/kg. In conclusion, the alpha-CD vehicle does not affect the toxic responses of CTFT in both sexes of both species. The results of the studies suggest that alpha-CD may be an appropriate alternative vehicle for toxicity studies.
Yuan
J
J
National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Jameson
C W
CW
Goehl
T J
TJ
Elwell
M R
MR
Leininger
J R
JR
Thompson
M B
MB
Corniffe
G
G
Carlton
T
T
D000510:Alpha-Globulins / Q000096:biosynthesis / Q000276:immunology; D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D002214:Capsules; D003314:Corn Oil; D003505:Cyclodextrins; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D047391:alpha-Cyclodextrins
D000510:Alpha-Globulins; D002214:Capsules; D003505:Cyclodextrins; D014677:Pharmaceutical Vehicles; D011506:Proteins; C013803:alpha 2u globulin; D047391:alpha-Cyclodextrins; D014050:Toluene; C037723:4-chloro-alpha,alpha,alpha-trifluorotoluene; D003314:Corn Oil; C032613:alpha-cyclodextrin