title: NTP Toxicity Studies of Cadmium Oxide (CAS No. 1306-19-0) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.
abstract: Three thousand tons of cadmium are imported or produced annually in the United States, and approximately 90% of this is cadmium oxide. Cadmium oxide is used in batteries, electroplating baths, pigments, plastics, synthetic products, and a variety of other materials. Cadmium oxide was nominated for study by the National Cancer Institute because of its widespread use and to obtain toxicity and carcinogenicity information. This report describes toxicity studies of cadmium oxide aerosol in F344/N rats and B6C3F1 mice, including sperm motility and vaginal cytology evaluations, and developmental toxicity studies of cadmium oxide aerosol in Sprague-Dawley rats and Swiss (CD-1(R)) mice. Genetic toxicology studies were done in Salmonella typhimurium and B6C3F1 mice erythrocytes. Cadmium oxide has been evaluated by other investigators for long-term carcinogenic effects, and recently the International Agency for Research on Cancer (IARC) evaluated cadmium and cadmium compounds for carcinogenic risks to humans. IARC (1993) classified cadmium and cadmium compounds as human carcinogens (Group I chemicals). GENETIC TOXICITY: Cadmium oxide was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation, and did not induce micronuclei in erythrocytes of mice exposed by inhalation for 13 weeks. DEVELOPMENTAL TOXICITY STUDIES: For these studies, sperm-positive Sprague-Dawley rats and Swiss (CD-1(R)) mice were exposed to 0, 0.05, 0.5, or 2 mg/m(3) cadmium oxide 6 hours per day, 7 days per week, on gestation Day 4 through 19 (rats) or gestation Day 4 through 17 (mice). Maternal toxicity was observed in Sprague-Dawley rats exposed to 2 mg/m(3) cadmium oxide for 16 days and included body weights lower than those of the controls and clinical signs of toxicity (dyspnea and hypoactivity). There was no evidence of embryolethality in rats at any exposure level. However, in rats exposed to 2 mg/m(3), developmental toxicity was evidenced by lower fetal weights and a significant increase in the incidence of reduced skeletal ossifications. Maternal toxicity was also observed in Swiss (CD-1(R)) mice exposed to 2 mg/m(3) cadmium oxide for 14 days. Clinical signs were dyspnea, hypoactivity, lower body weight, and a lower pregnancy rate (30% vs. 97% in the control group). The total number of resorptions per litter was increased at the 2 mg/m(3) level. Developmental toxicity was evidenced by lower fetal weights in the 0.5 and 2 mg/m(3) groups and an increase in the incidence of reduced sternebral ossification in the 2 mg/m(3) group. TOXICITY STUDIES: Male and female F344/N rats and B6C3F1 mice were exposed to cadmium oxide aerosol (MMAD=1.1-1.6 mm) for 6 hours per day, 5 days per week, for 2 or 13 weeks. Exposure levels were 0.1 to 10 mg/m(3) for the 2-week studies and 0.025 to 1 mg/m(3) for the 13-week studies. The current Occupational Safety and Health Administration (OSHA) standards for cadmium, based on the results of these and other studies, are 2.5 mg/m(3) for the action level (AL) and 5 mg/m(3) for the permissible exposure limit (PEL) (29 CFR &sec; 1910.1027). The AL and PEL are calculated as an 8-hour, time-weighted average exposure. In the 2-week studies, all rats and mice at the highest exposure level (10 mg/m(3)) died from respiratory toxicity characterized by inflammation, necrosis, and fibrosis of the lung. Toxicity to the nasal cavity and tracheobronchial lymph nodes was also observed in the 10 mg/m(3) groups. At the lower exposure levels, treatment-related toxic lesions were not life threatening, and all body weights were within 10% of controls. In the 13-week studies, all rats and mice (with the exception of one control mouse) survived to the end of the studies. The final mean body weight of rats in the highest exposure groups (1 mg/m(3)) was 93% of the control value. For all other exposed rat and mouse groups, final mean body weights corresponded to those of the respective controls. For rats and mice in the 13-week studies, the major toxicity was to the respiratory system. Treatment-related lesions were observed in the lung, tracheobronchial lymph node, larynx, and nose. The no-observed-adverse-effect level (NOAEL) in the lungs was 0.025 mg/m(3) for rats. A NOAEL was not found in the lungs or larynx of mice or in the larynx of rats. At the 0.025 and 0.05 mg/m(3) levels in mice, lung lesions were minimal and not considered life threatening. A NOAEL in the nasal cavity was 0.05 mg/m(3) for rats and mice. Reproductive toxicity was observed in the 1 mg/m(3) groups of rats and was evidenced by a reduced number of spermatids per testis and an increase in the length of the estrous cycle. Reproductive toxicity was not observed at any exposure level in mice.