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EC number: 215-035-9
CAS number: 1271-19-8
The NTP performed a series
of studies with the substance. A 2 -year carcinogenicity study was
performed where rats were dose by gavage on a daily basis at 25 and 50
Under the conditions of
these 2-year gavage studies, there was equivocal evidence of
carcinogenic activity' of titanocene dichloride in male F344/N rats
based on a marginal increase in the incidence of fore-stomach 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 fore-stomach squamous cell papillomas.
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.
these 2-year studies of titanocene dichloride, the forestomach tumors in
dosed male and female rats given titanocene dichloride by oral gavage
were considered equivocal evidence of carcinogenic activity because:
the numbers of tumors were small and only slightly above historical
there was no dose-related increase in tumor incidence in male rats;
the tumors were mostly benign (the only squamous cell carcinoma occurred
in a low dose male); and,
the biological potential of the relationship of hyperplasia and the
papillomas is not clear.
2 year study shows that the
parent compound, titanocene dichloride, was toxic at the site of
exposure, whereas the titanium-containing metabolite reaching other
organs was relatively nontoxic. Recent
studies by Kopf-Maier and Martin (1989) have shown that following the
intraperitoneal injection of titanium dichloride, titanium accumulates
in both the cytoplasm and nucleus of cells. Other studies suggest that
the cytotoxicity of this compound results from the interaction with
nucleic acid constituents (Toney et al.,1986).
effects may be explained by what occurs when the substance comes into
contact with water. According to an assessment of the water solubility
of the test item (Envigo Study Number FD03TF), no determination of the
water solubility of the parent test item was possible or relevant due to
rapid hydrolysis in contact with water. Analysis of saturated solutions
resulted in a mean solution concentration equivalent to 103g/L of
solution at 20.0+0.5 ◦C, monitoring the response attributed to soluble
hydrolysis products formed on dissolution. Extreme low pH values for the
solution were noted, pH 0.8, consistent with the liberation of
hydrochloric acid during hydrolysis as which is supported by Toney et al
also in contact with the forestomach of a rat such a reaction may occur.
The pH in the forestomach of the rat is between 4.5 -6 and there is no
protection from mucus secretion as there is in the human stomach
(Proctor et al., 2007). Furthermore, the dosing is done in bulk by
gavage. The severity of the reaction would probably less in the human
since humans have no squamous epithelium in the stomach, the potential
risk from non-genotoxic forestomach carcinogens involves exposure of the
mouth, pharynx and oesophagus at dose levels that exert irritating
action. It seems very unlikely that exposure to concentrations far below
those having irritating potential is hazardous to man (Kroes and Wester,
In case of
workers oral exposure is not expected. The major routes of exposure for
workers are inhalation and dermal. In case of exposure on skin these
effects observed in the stomach are not relevant. Skin irritation
studies and an acute dermal study do not show any effects on the skin.
substance is positive in the Ames test and in the MLA. Due to the
complex structure QSAR predictions are not relevant for this substance.
For in vivo genotoxicity a study is proposed to further elucidate this
25 mg/kg bw/d are:
of the study:
high incidence of abnormal respiratory sounds.The
respiratory sounds were probably due to exudate in the upper respiratory
tract and were related to the pulmonary and nasal cavity lesions present
in dosed animals.
inflammation of the nasal mucosa and Acute
and/or granulomatous inflammation of the lung in male and female rats.
The lung and nose lesions were considered to be causally related to the
reflux and aspiration of the gavage solution due to degenerative and
inflammatory lesions in the stomach.
proliferation was seen in the stomach. Nonneoplastic lesions in the
forestomach were observed: epithelial hyperplasia and hyperkeratosis and
inflammation was seen in the glandular stomach.
50 mg/kg bw/d are:
lesions associated with the administration of titanocene dichloride
occurred in stomach and were similar to those seen at two years.
same except the effects on the glandular
stomach are more severe: inflammation, hyperplasia/dysplasia, erosion,
fibrosis and metaplasia.
following systemic effects were observed in this study at both dose
the 15 month interim evaluation a statistically significant decrease in
body weight for males given 25 or 50 mg/kg and for females given 50
liver weights were significantly decreased in males given 50 mg/kg and
significantly increased in females given 50 mg/kg. In
males asignificantly decreased organ to body weight ratios
at 50mg/kg dose of the brain and liver and at 25mg/kg of the brain. In
females a significantly decreased organ to body weight ratios at 50mg/kg
dose of the brain, heart, liver and lung and at 25mg/kg of the liver.At
the end of the study decreased body weights were observed and final
bodyweight were 91-96% for males and females.
the end of the study in both males and females and dose levels
granulomatous inflammation/pigmentation of the liver was seen and in
males at the high dose lesions with eosinophilic focus and mixed focus.
significantly lower survival rates were seen at the end of the study.
the 15 month evaluations at both dose levels accumulations of
macrophages laden withblue-gray to
gray-green pigment were seen in several organs of dosed male and female
rats, but occurred predominantly in mesenteric lymph nodes and lungs.In
selected animals, special stains were employed in an effort to further
characterize the pigment. In these animals, the pigment was negative for
the periodic acid-Schiff reaction and Perl’siron stainand
was not believed to be hemosiderin or lipofuscin. The pigment was
thought to containtitanium.
parameters were measured in the 15 month interim evaluation and
significant dose-related decreases in hematocrit, haemoglobin, meancellvolume,
and meancell hemoglobin values were observed for male andfemale
titanocene dichloride at both dose levels. These changes
in hematology values are consistent with a mild microcytic
anemia of the type commonly accompanying various chronic inflammatory processes.
the results of this study the LOAEL is, for local and systemic effects,
25 mg/kg bw/d.
Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Titanocene Dichloride
Male F344/N Rats
Female F344/N Rats
0, 25, or 50 mg/kg in corn oil
0, 25, or 50 mg/kg in corn oil by gavage
Dosed lower than controls
2-year survival rates
41/60, 30/60, 24/60
37/60, 30/61, 31/60
erosions -1/58, 9/59, 13/58;
inflammation -0/58, 9/59, 10/58;
hyperplasia -0/58, 10/59,
metaplasia -0/58, 26/59,
fibrosis -0/58, 30/59, 37/58; fat proliferation -0/59, 2/59, 14/60
Forestomach acanthosis (epithelial hyperplasia) -8/57, 25/59, 26/59;
hyperkeratosis -5/57, 13/59, 17/59
Liver granulomatous inflammation -0/60, 16/59, 14/60
Various organs: pigmentation
erosions -2/60, 11/60, 10/60;
inflammation -0/60, 4/60,2/60,
hyperplasia -0/60, 24/60,23/60;
metaplasia -0/60, 36/60, 51/60;
fibrosis -0/60, 39/60,51/60;
fat proliferation -0/60, 15/60, 41/60
Forestomach acanthosis (epithelial
hyperplasia) -11/60,20/60, 27/60;
hyperkeratosis -10/60, 23/60, 21/60
Liver: granulomatous inflammation - 6/60,24/60, 33/60
squamous cell papilloma - 0/60, 4/60,1/60;
squamous cell carcinoma - 0/60, 1/60,0/60;
basosquamous tumor benign - 0/60, 0/60, 1/60
squamous cell papilloma -0/60, 1/61,2/60
Level of evidence of carcinogenic activity
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 2 years. Body Weight
and Survival in the 2-Year Studies The doses selected for the 2-year
studies in rats (0, 25, and 50 mgkg) were based on the potentially
life-threatening nature of the glandular stomach lesions and the
decreased body weight gain seen in 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. Non-neoplastic 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-dosefemales; 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 gastro-intestinal
tract, liver, lung, and lymph nodes. A doserelated
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
Under the conditions of these 2-year gavage
- There was equivocal evidence of
carcinogenic activity of titanocene dichloride in male F344/N rats based
on a marginal increase in the incidence of fore-stomach 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 fore-stomach squamous
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.
Based on the available information the
substance is not classified for this endpoint.
et al., (1985) Hydrolysis chemistry of the metallocene dichlorides
M(ƞ5-C5H5)2Cl2, M = titanium, vanadium, or zirconium. Aqueous kinetics,
equilibria, and mechanistic implications for a new class of antitumor
agents. J. Am. Chem. Soc., 1985, 107 (4), pp 947–953.
et al., (2007) REVIEW Mode-of-Action Framework for Evaluating the
Relevance of Rodent Forestomach Tumors in Cancer Risk Assessment.
TOXICOLOGICAL SCIENCES 98(2), 313–326
R. and Wester, P. W. (1986)Forestomach
carcinogens: possible mechanisms of action.Fd
Chern. Toxic.Vol. 24, No.l0/11, pp. 1083-1089
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