Subchronic and chronic inhalation toxicity of antimony trioxide in the rat.
Fischer 344 rats were exposed by inhalation to Sb2O3 (antimony trioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and 23.46 mg/m3 for 6 hr/day, 5 days/week for 13 weeks followed by a 27-week observation period. Subsequently, an inhalation oncogenicity study was conducted at exposure levels of 0, 0.06, 0.51, and 4.50 mg/m3 for 12 months followed by a 12-month observation period. The Sb2O3 in the subchronic study had a mass median aerodynamic diameter (MMAD) of 3.05 +/- 0.21 microns (mean +/- SD) with a geometric standard deviation (GSD) of 1.57 +/- 0.06. In the chronic study, the MMAD was 3.76 +/- 0.84 and the GSD was 1.79 +/- 0.32. Except for the eyes, no adverse clinical observations were attributed to Sb2O3 in either study. In the subchronic study, corneal irregularities were seen after about 2 weeks of exposure and did not abate during the observation period. In the chronic study, ophthalmoscopic evaluation at 24 months revealed a dose-related increase in cataracts of 11, 24, 28, and 32% (both sexes combined) for each group, respectively. Body weights were significantly lower (6%) than the control group's weights in the 23.46 mg/m3 males in the subchronic study. These rats did not recover this weight during the 27-week observation period. Body weights of the females in both studies and males in the chronic study were unaffected. There were no Sb2O3 effects on clinical chemistry or hematology in either study. Mean absolute and relative lung weights were significantly increased in the 4.92 and 23.46 mg/m3 groups in the subchronic study. The 23.46 mg/m3 group's lung weights did not recover to control levels during the 27-week observation period. Lung weights for rats in the chronic study were unaffected. Microscopic changes in the lungs in the subchronic and chronic study were limited to subacute-chronic interstitial inflammation, increased numbers of alveolar-intraalveolar macrophages, foreign material in the alveolar-intraalveolar macrophages in the peribronchial and perivascular (chronic study only) lymphoid aggregates and in the peribronchial lymph nodes, granulomatous inflammation/granulomas, and fibrosis. In the chronic study, any observed neoplasms occurred with comparable incidence among all groups and were within the historical range for controls. Clearance of Sb2O3 from the lung was burden dependent and was reduced by 80% in the 4.50 mg/m3 group in the chronic study. The previously reported studies, which found Sb2O3 to be a carcinogen, were run at higher lung burdens. Under the exposure conditions of the current study, Sb2O3 was not a carcinogen.
Newton
P E
PE
Pharmaco LSR Inc., East Millstone, New Jersey 08875-2360.
Bolte
H F
HF
Daly
I W
IW
Pillsbury
B D
BD
Terrill
J B
JB
Drew
R T
RT
Ben-Dyke
R
R
Sheldon
A W
AW
Rubin
L F
LF
D000280:Administration, Inhalation; D000818:Animals; D000965:Antimony / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001273:Atmosphere Exposure Chambers; D001835:Body Weight / Q000187:drug effects; D005128:Eye Diseases / Q000139:chemically induced; D005260:Female; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000965:Antimony; C037554:antimony trioxide