title: NTP Toxicology and Carcinogenesis Studies of Titanocene Dichloride (CAS No. 1271-19-8) in F344/N Rats (Gavage Studies).
abstract: Titanocene dichloride is an organometallic compound composed of two cyclopentadienyl rings, titanium, and chloride. It is used as a cocatalyst in polymerization reactions. Toxicology and carcinogenesis studies were conducted by administering titanocene dichloride (greater than 98% pure) in corn oil by gavage to groups of F344/N rats for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary cells. 14-Day and 13-Week Studies: In the 14-day studies, titanocene dichloride was administered at doses of 0, 65, 125, 250, 500, or 1,000 mg/kg. All high-dose rats and four of the five male and two of the five female rats given 500 mg/kg died during the studies. A dose-related decrease in body weight gain was seen in rats given 125, 250, 500, and 1,000 mg/kg. Lesions related to chemical administration included hepatocellular necrosis, tubule necrosis in the kidney, erosions and ulcers of the glandular stomach, and hyperplasia of the forestomach epithelium. The 13-week studies were conducted by administering titanocene dichloride at doses of 0, 8, 16, 31, 62, or 125 mg/kg. One female rat in the 125 mg/kg dose group died from chemical toxicity during the fourth week of the studies. Body weight gain was lower in rats given 62 or 125 mg/kg than in control groups. Treatment-associated histopathologic lesions were seen in the stomachs of high-dose males and all groups of females given titanocene dichloride. These lesions included hyperplasia and metaplasia of the glandular stomach and hyperplasia and hyperkeratosis of the forestomach. Body Weight and Survival in the 2-Year Studies: The doses selected for the 2-year studies in rats (0, 25, and 50 mg/kg) were based on the potentially life-threatening nature of the glandular stomach lesions and the decreased body weight gain compared to controls seen in the 62 and 125 mg/kg dose groups in the 13-week studies. The final mean body weights of high-dose males and females were 91% and 89% of controls, respectively. The 2-year survival rates for males in the control, low-, and high-dose groups were 41/60, 30/60, and 24/60; survival rates for female rats were 37/60, 30/61, and 31/60. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: The principal toxic effects associated with the administration of titanocene dichloride for 2 years occurred in the stomach. The lesions in the stomach were seen at the 15-month interim evaluations and were similar to, but less severe than, those observed at 2 years. The lesions included focal erosions of the glandular mucosa with an associated inflammatory response, hyperplasia and metaplasia of the epithelium of the fundic glands, and fibrosis of the lamina propria and submucosa. Forestomach lesions included focal acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium. Squamous cell papillomas of the forestomach were seen in four low-dose males, one high-dose male, one low-dose female, and two high-dose females; none were observed in controls. A squamous cell carcinoma of the forestomach occurred in one low-dose male and a benign basosquamous tumor occurred in one high-dose male. Accumulations of macrophages with blue-gray pigment believed to contain titanium were present in many organs of dosed rats including the gastrointestinal tract, liver, lung, and lymph nodes. A dose-related increase in the incidence of inflammation of the nasal mucosa and lung also occurred and was attributed to reflux and/or regurgitation and aspiration of gavage solution due to the severe stomach lesions. Genetic Toxicology: Titanocene dichloride was mutagenic in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation (S9); it was not mutagenic in TA100 with S9, nor was it mutagenic in TA1535, TA1537, or TA98 with or without S9. Titanocene dichloride did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Conclusions: Under the conditions of these 2-year gavage studies, there was equivocal, there was equivocal evidence of carcinogenic activity of titanocene dichloride in male F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas, squamous cell carcinoma, and basosquamous tumor benign. There was equivocal evidence of carcinogenic activity of titanocene dichloride in female F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas. Nonneoplastic lesions associated with the administration of titanocene dichloride for up to 2 years included erosions and inflammation of the gastric mucosa, hyperplasia and metaplasia of the fundic glands with fibrosis of the lamina propria in the glandular stomach, and acanthosis (hyperplasia) and hyperkeratosis of the forestomach epithelium. Synonyms: Titanium ferrocene; biscyclopentadienyltitanium dichloride; dichlorodi-p-cyclopentadienyltitanium; dichlorobis(h5-2,4-cyclopentadien-1-yl)titanium; dicyclopentadienyltitanium dichloride; dichlorodicyclopentadienyltitanium; dichlorotitanocene; dicyclopentadienyldichlorotitanium; dichlorobis(p-cyclopentadienyl)titanium; bis (h5-cyclopentadienyl) titanium dichloride; dichlorobis(h5-cyclopentadienyl)titanium; dichlorobiscyclopentadienyl titanium; dichlorobis(1,3-cyclopentadiene)titanium; bis(cyclopentadienyl)dichlorotitanium