CHAPTER THIRTEEN
Titanium, Zirconium, and Hafnium
Barbara Malczewska-Toth, Ph.D., DABT
Titanium, zirconium, and hafnium belong to the group IVB
of the periodic table. A characteristic feature of these transi-
tion elements is the ease with which they form stable complex
ions. Features that contribute to this ability are favorably high
charge-to-radius ratios and the availability of unfilled
d orbitals. The ability of forming metallic bonds is demon-
strated by the existence of a wide variety of alloys among
different transition metals. Other features of these metals are
high densities, high melting points, and low vapor pressures.
Within this group, these properties tend to increase with
increasing atomic weight.
This chapter discusses the chemical and physical proper-
ties followed by the toxicity of each chemical and compound
in three sections: the first section provides details on titanium,
the second section on zirconium, and the third section on
hafnium. Table 13.1 presents the atomic number, atomic
weight, and natural isotopes of titanium, zirconium, and
hafnium.
TITANIUM AND TITANIUM COMPOUNDS
Titanium (Ti) [7440-32-6] is a silvery gray metal that
resembles polished steel. Titanium, a transition element,
was first discovered as its oxide by William Gregor in 1791
and named in 1795 by Martin H. Klaproth after the Titans,
the giants of Greek mythology. Nevertheless, the pure metal
was not isolated until 1910 and remained a laboratory
curiosity until an economical purification process was
developed in 1946.
Because titanium is as strong as steel and 45% lighter in
weight, it is especially suitable for use in aviation and
astronautics. About 50% of the titanium produced is used
Patty’s Toxicology, Sixth Edition. Volume 1, Edited by Eula Bingham and Barbara Cohrssen.

2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.
for jet engine components (rotors, fins, and compressor
parts). Titanium alloys readily with other metals such as
aluminum and tin. The alloy composition Ti þ 2.5% tin þ 5%
aluminum is used when high strength at high temperatures is
required, and the alloy Ti þ 8% aluminum þ molybdenum
þ vanadium is used in low-temperature applications. Each
supersonic transport contains about 270,000 kg of titanium.
The most important titanium compound is titanium
dioxide, TiO2 [13463-67-7], a white substance that has a
high reflective index. TiO2 forms the basis of the titanium
pigment industry because of its opacifying property, ready
availability, and relatively low cost. TiO2 is processed at
very high temperatures into artificial rutile, which is used
as a semiprecious stone (titania). Titania has a light yellow
color and a higher index of refraction than diamond, but is
rather soft. TiO2 has been used to some degree since 1918,
but its use expanded after technological improvements in
ore processing and because of expanded industrial need.
Fifty percent of the TiO2 used is as pigments, 20% in paper,
and 12% in plastics. It is also used in paints, inks, foods (as
food additive to whiten flour, in dairy products and con-
fections), medicines (pills), toothpaste, and as an additive
in sunscreen cosmetics. Additional uses of TiO2 are as a
catalyst, a dielectric in capacitors, a functional part in some
oxygen sensors, a component of surgical implants and
prostheses (for bone/medical implant integration), cleav-
ing proteins at proline sites, odor controller in cat litter, as a
semiconductor, and a source of titanium metal. In recent
years, with the development of nanotechnology, TiO2 uses
increased as the TiO2 is converted to nanomaterials
through engineering. TiO2 nanobelts are increasingly
used as photocatalysts and TiO2 nanowires are used in
solar cells.
427
428 BARBARA MALCZEWSKA-TOTH

Table 13.1. The Atomic Number, Atomic Weight, and Natural The toxicology of two other titanium compounds, titanium
Isotopes of Titanium, Zirconium, and Hafnium diboride and titanium carbide, is not discussed in this chapter.
Atomic Atomic Natural Titanium diboride [12045-63-5], an extremely hard sub-
Element Symbol Number Weight Isotopes stance (Mohs hardness 9þ) with oxidative resistance up to
46 1400 C, is used as a metallurgical additive for superalloys
Titanium Ti 22 47.90 Ti (8.0%)
47 and nuclear steels, as a high-temperature electrical conduc-
Ti (11.2%)
48
Ti (17.1%) tor, and in coatings resistant to attack by molten metals.
49
Ti (17.4%) Titanium carbide is extremely hard and as a crystalline solid
50
Ti (2.8%) has its chief use as an additive to tungsten carbide in cutting
Zirconium Zr 40 91.22 90
Zr (51.5%) tools and other parts that are subjected to thermal shock.
91
Zr (11.2%)
92
Zr (17.1%)
94 1.0 Titanium
Zr (17.4%)
96
Zr (2.8%) 1.0.1 CAS Number
174
Hafnium Hf 72 178.49 Hf (0.2%)
176 [7440-32-6]
Hf (5.2%)
177
Hf (18.6%)
178
Hf (27.3%) 1.0.2 Synonyms
179
Hf (13.6%) Titanium rod; titanium powder; titanium wire
180
Hf (35.1%)
1.0.3 Trade Names

The remaining titanium compounds have a variety of NA

special uses.
Titanium trichloride, a dark-violet deliquescent solid that
decomposes in air and water, is used as a cocatalyst for
polyolefin polymerization and in organometallic synthesis.
The tetrachloride is a colorless liquid that fumes in moist air
and forms a dense, persistent, white cloud used in smoke
screens. The tetrachloride is used extensively in TiO2
production.
Titanium disulfide, a yellow solid, is used as a solid
lubricant, and titanous sulfate, green in the crystalline
state but dark purple in acid solution, is used in the textile
industry as a reducing agent for stripping or discharging
colors.
The toxicity of titanium varies with the chemical form.
Metallic titanium and TiO2 are insoluble, unreactive, non-
metabolized, and virtually devoid of acute toxicity, though
prolonged exposure to high concentrations of TiO2 causes
lung tumors in rats. With expansion of nanotechnology, the
TiO2 material has been engineered in terms of shapes and
sizes resulting in significant particle size reduction. The
reduction of the particle size leads to increased specific
surface area, which contributes to increased potential for
toxicity of the engineered TiO2 nanomaterials. In contrast,
the soluble inorganic titanium salts are absorbed and metab-
olized and do show appreciable acute toxicity. A third
titanium form, the oil-soluble organotitanium complex, tita-
nocene, is metabolized by a still different pathway and is both
toxic and tumorigenic in animals. Both titanium compounds
and titanocene complexes show chemotherapeutic activity
and have been used for treatment of gastrointestinal, breast,
lung, and skin cancers.
1.0.4 Molecular Weight
47.87
1.0.5 Molecular Formula
Ti
1.1 Chemical and Physical Properties
The physical and chemical characteristics of titanium [7440-
32-6] and the most industrially important compounds of
titanium are presented in Table 13.2.
The chief valence form of titanium is 4þ (titanic), but 3þ
(titanous) and 2þ are known, including a peroxy-type
compound. Oxy compounds such as TiOCl2, called titanyl,
exist, but the existence of TiO2þ ion is doubtful. Tetravalent
titanium compounds hydrolyze to yield hydrous titanium
oxide, which forms the basis of the TiO2 pigment industry.
Intermediate valence stages disproportionate to higher and
lower forms, a property that is used in producing reduced
titanium halides. Organic derivatives of titanium are known,
but as yet have little industrial significance. The most
common types are the alkyl and aryl titanates of the general
formula Ti(OR)4, where R stands for alkyl or aryl radical.
A commercially available complex organic coordination
compound, titanocene (dicyclopentadienyl titanium
dichloride), is used as a catalyst, ultraviolet absorber, reduc-
ing agent, free radical scavenger, and as cancer chemo-
therapeutic agent in the treatment of gastrointestinal,
breast, lung, and skin cancers (1–3).
 TITANIUM, ZIRCONIUM, AND HAFNIUM 429

Table 13.2. Physical and Chemical Properties of Titanium (Ti) and Its Compounds
Molecular Molecular Boiling Melting Specific
Compound CAS Number Formula Weight Point ( C) Point ( C) Gravity Solubility
Titanium [7440-32-6] Ti 47.87 3287 1660 4.5 Insol. cold water;
dec. hot water
Titanium dioxide [13463-67-7] TiO2 79.87 2500–3000 1830–1850 3.90 (anatase); Sol. hot H2SO4,
4.23 (rutile) HF, alkali; insol.
HCl, water,
alcohol
Titanium carbide [12070-08-5] TiC 59.88 4820 3140 4.93 Insol. water; sol.
aqua regia, HNO3
Titanium trichloride [7705-07-9] TiCl3 154.23 660 Dec. 440 2.64 Sol. water; HCl; v.
sol. alcohol;
insol. ether
Titanium tetrachloride [7550-45-0] TiCl4 189.68 136.4 25 Liq. 1.726 Sol. cold water,
HCl, alcohol
Titanium hydride [7704-98-5] TiH2 49.88 Dec. 450 — 3.75 —
Titanium(IV) sulfide [12039-13-3] TiS2 112.00 — — 3.37 Hyd. sl. colder; dec.
in steam, HCl;
sol. dil. HNO3,
H2SO4
Titanium(III) sulfate [10363-61-0] Ti2(SO4)3 383.93 — — — Insol. water,
alcohol; sol.
dil. HCl

Dust clouds of titanium metal powder, average particle
diameter 10.5 mm, that contain 0.08% H, 0.82% O, and
0.062% N by weight experimentally ignite at 330 C in air
but are not combustible at temperatures below 850 C in CO2
or N2 gas (4). Titanium hydride (TiH2) containing 2.83% H,
0.24% O, and 0.071% N, and 70% theoretical H for TiH2
ignited at 440 C under similar test conditions. Neither dust
layers nor clouds ignited in an atmosphere of helium or argon
up to 850 C, but layers of both powders ignited in a mixture
of 50% air and 50% helium at 850 C. Layers of both powders
were ignited by a weak electric spark. Both titanium metal
powders and turnings can be ignited, but flammability is
highly dependent on particle size and surface area. Coarse
particles of titanium metal powder, probably of the order of
greater than 100 mm, show no tendency to ignite (5). A
serious explosion occurred from friction of commercially
pure titanium samples that had been undergoing corrosion
tests in red fuming nitric acid (6).
and Finland). Ilmenite accounts for about 91% of the world’s
consumption of titanium minerals and world resources of
anatase, ilmenite, and rutile total more than 2 billion tons (8).
Rutile (a form of TiO2) is less abundant; its chief source is
certain Australian beach sands. Two other less prominent
forms of TiO2 exist, anatase and brookite. The ores vary
around the world in TiO2 content from 39% to 96%. Anatase
is used as a food color (7).
Metallic titanium is widely used in the aerospace industry
because of its outstanding strength-to-weight ratio. Although
the most extensive usage is in military aircraft, the use of
titanium in commercial aircraft has also increased. For
example, the Boeing 777 consists of nearly 10% by weight
of titanium. Additional uses for titanium are based on its
corrosion resistance, as in heat exchangers, and its biocom-
patibility in medical and dental implants. Both pure titanium
and nickel–titanium alloy (NiTi) have shown excellent tissue
compatibility (9, 10).

1.2 Production and Use 1.3 Exposure Assessment

Titanium is the ninth most abundant element and accounts for
about 0.63% of the Earth’s crust. Analyses of rock samples
from the moon indicate that titanium is far more abundant
there; some lunar rocks consist of 12% titanium by weight.
World production of titanium sponge metal was estimated at
69,000 metric tons in 1991 (7). The most important titanium-
bearing minerals are ilmenite, rutile, and leucoxene. Ilmenite
(FeTiO3) is found in beach sands (Australia, India, and
Florida) and in rock deposits associated with iron (Norway
Humans can be exposed to titanium and its compounds
through many potential exposure routes, including inhala-
tion, ingestion, and skin absorption.
1.4 Toxic Effects
Little information exists on the way titanium acts at the
biochemical level. An early study reported that titanium
dichloride (TiCl2) inhibits serum alkaline phosphatase
430 BARBARA MALCZEWSKA-TOTH
(53%) at a concentration of 0.46 mM in vitro but has no effect
on trypsin even at a 1.1 mM concentration (11). However, a
more recent study has found that aqueous titanium(IV)
inhibits trypsin class (but not chymotrypsin class) pro-
teases (12). Soluble titanium salts injected subcutaneously
reportedly inhibit transaminase but activate lipase (13).
Another interaction involves the complexing of soluble
titanium salts (e.g., titanium lactate) and catechols, including
DOPA (3,4-dihydroxyphenylalanine). DOPA has an intense,
yellow-orange color (14). A greenish coloration of the
surfaces of a lung that had large accumulations of TiO2
was found in a pigment worker of 9 years. In another
case, the pulmonary surfaces were a grayish white (15).
These titanium salts inhibit the action of tyrosinase on
DOPA by competing with tyrosinase for the substrate.
1.4.1 Human Experience
The distribution of titanium is reported to be general in all
organs of the human body but in low concentrations. In the
mid-1930s, Maillard and Ettori (16) found concentrations
ranging from 0.015 to 0.11 ppm among Frenchmen. Tipton
and Cook (17) and Tipton et al. (18) analyzed 29 tissues of
150 adults in the United States in the late 1950s by spectro-
graphic methods and also found titanium in all tissues, but the
median concentrations of 5 ppm or greater were found in only
7 of the 29. Lung tissue headed the list with 220 ppm,
followed by skin (32 ppm), omentum (21 ppm), and adrenal
glands (15 ppm), and thyroid, cecum, and rectum had a
median value of 5 ppm each. Titanium was not found,
however, with equal frequency in the tissues of all indivi-
duals; frequencies varied from a low of 9% for the brain to
99% for lungs, showing that pulmonary tissue has a special
affinity for titanium. Not unexpectedly, wide ranges of
variation were found for most tissues. Daily intake of tita-
nium from food, commonly a major contributor, has been
estimated to vary as much as 30-fold, depending on diet
selection (100–3000 mg Ti per day) (19). Geographic resi-
dence and occupation can make even larger contributions to
intake (20); analysis (mass spectrometry) of bituminous coal
dust from certain areas showed as much as 860 ppm Ti,
360 ppm chrysotile asbestos, and 3600 ppm cement. For
example, workers at a cement plant or persons living nearby
might experience high environmental titanium intake, result-
ing in high titanium levels in body tissues. Actual determina-
tions (mass spectroscopy) of tissue titanium from coal miners
and residents of coal mining areas show values considerably
greater than those found generally in nonmining areas (20).
The lung of a coal miner had a titanium content of 3800 ppm,
compared to 380 ppm Ti in the lung of an area nonminer, and
compared with the general U.S. median of 220 ppm noted
before. Another coal miner’s lung, less heavily contaminated
with Ti (480 ppm), had a pulmonary lymph node containing
2400 ppm Ti, indicating phagocytosis of titanium-containing
particles from the lungs. Two samples of urine from
coal miners also showed high values—110 and 490 mg
Ti/L urine—compared with an average 1959 value for
U.S. adults of 10.2 mg/L urine (21).
Less conspicuous, but nevertheless definite, is the varia-
tion in tissue titanium content of individuals who reside in
urban areas with differing environmental titanium expo-
sure. Five tissues, lung, liver, kidney, heart, and spleen, from
seven cities in the United States showed that titanium in
organs other than the lung was highest in residents from
New York City and Chicago; titanium was found, however,
in the lungs of all residents analyzed in all seven cities (19).
Similarly, differences in racial and geographic area were
found in the titanium content of lung, liver, and kidney of
residents of 17 localities around the world. Contrary to
findings in the United States, titanium was not detected in
the lungs of some individuals in Berne, Switzerland; Vel-
lore, India; and Lambarene, Gabon (then known as French
Equatorial Africa). Geographic differences were striking;
although titanium was found in the kidney and liver in 60%
of the Tokyo residents analyzed, no titanium was found in
the organs of residents of Kyoto, a less industrialized
Japanese city. Titanium was not found in the kidneys and
only occasionally in the livers of residents of Bangkok or
Uganda (19).
Important in the understanding of the body disposition of a
trace element is the determination whether (1) it is present in
the newborn (passes the placental barrier), (2) the element
accumulates in the body with age, and (3) if so, in which
organs and tissues. Investigations by Schroeder et al. (19)
have shown that titanium does not invariably occur in the
newborn; titanium was not detected in two-fifths of the
samples taken from the lungs of babies and children. Accu-
mulation in the lungs of Americans was easily demonstrable;
the concentration rises to high levels after the third decade.
No such phenomenon, however, was evident in the kidney,
skin, or aorta; both the percentage occurrence and concen-
tration were fairly constant throughout eight decades. The
prevalence of this metal in other organs (except for skin,
where it is always present) was generally less than 40% and
often less than 20%, and accumulations or decreases with age
were not demonstrable. Concentrations in the skin of 17
white and 6 black persons were comparable. Therefore, it
appears that titanium accumulates markedly in lung tissue
with age, but has no special predilection for other internal
organs.
An intestinal barrier to absorption of whatever form in
which titanium is ingested is inferred from the low urinary
output. Very few reports in this area have appeared. Schroe-
der et al. (19) compared the titanium tissue distribution when
administered to mice as the soluble potassium titanium
oxalate at a level of 5 ppm for 208–268 days in drinking
water. At the end of the exposure, 4–15 times more titanium
had accumulated in the lungs, heart, and kidneys of exposed

animals than in the controls. This indicates that, for mice at
least, soluble titanium compounds are readily absorbed from
the gastrointestinal tract, in contrast to essentially nonab-
sorbed insoluble forms.
1.5 Standards, Regulations, or Guidelines of Exposure
None established.
2.0 Titanium Dioxide
2.0.1 CAS Number
[13463-67-7]
2.0.2 Synonyms
Titanium(IV) oxide; rutile; anatase; brookite; titanium(IV)
dioxide; titanium oxide; tioxide; Atlas white titanium
dioxide; Bayertitan; Baytitan; Calcotone white t; Comet;
Hombitan; Kronos titanium dioxide; Levanox white rkb;
Runa rh20; Tiofine; titania; tiona t.d.; Tipaque; Titafrance;
Titanox; Titanox 2010; zopaque; cosmetic white C47-9623;
horse head a-410; horse head a-420; horse head r-710;
Unitane o-110; Unitane o-220; Unitane or-150; Unitane
or-340; Unitane or-342; Unitane or-350; Unitane or-540;
Unitane or-640; C.I. 77891; C.I. pigment white 6; cosmetic
white C47-5175; 1700 white; a-fil cream; Aeroxide;
Austiox; Bayeritian; Flamenco; Hitox; Kronos; KH360;
Rayox; Rutiox cr; ti-pure; titanium peroxide; titan white;
trioxide (s); Tronox; tioxide rhd; Kronos cl 220; tioxide
rsm; Titanox ranc; Austiox r-cr 3; R 680; RO 2; ti-pure
r 900; Tioxide ad-m; Tioxide r.xl; cab-o-ti; ti-pure r 901;
tipaque r 820; kronos rn 56; kronos rn 40p; bayertitan a;
bayertitan r-u-f; tioxide r-cr; p 25 (oxide); Unitane or-650;
Unitane or-450; zopaque ldc; Runa arh 20; Runa arh 200;
hombitan r 101d; hombitan r 610k; kronos 2073; P 25;
Unitane or-572; UV-Titan; ti-pure r 101; ti-pure r 915; titanic
anhydride; titanic acid anhydride; titanic oxide; titanium
white; octahedrite; Unitane; titanium dioxide P25.
2.0.3 Trade Names
NA
2.0.4 Molecular Weight
79.87
2.0.5 Molecular Formula
O2Ti
2.0.6 Molecular Structure
O¼Ti¼O
TITANIUM, ZIRCONIUM, AND HAFNIUM 431
2.1 Chemical and Physical Properties
See Table 13.2.
2.2 Production and Use
Approximately 95% of all titanium is used as TiO2 (22). TiO2
is produced commercially from ilmenite, leucoxene, rutile,
titaniferous slag, and synthetic rutile (18). Two major com-
mercial production processes are used: the sulfate process,
which uses TiOSO4 as an intermediate, and the chloride
process, which uses TiCl4 as an intermediate. World produc-
tion of TiO2 was estimated at approximately 2.5 million
metric tons in 1992 (23) and 4.4 million metric tons in
2004 (24). The U.S. production of TiO2 was at approximately
1.3 million metric tons in 2005, 1.4 million metric tons in
2007, and 1.2 million metric tons in 2009 (8). In recent years,
TiO2 is among the most commonly produced and utilized
nanomaterials. Recent estimates of annul global production
of ultrafine TiO2 particles or nanomaterials (one dimension
,100 nm) range between 5000 and 6400 metric tons (25, 26).
This large amount of produced nanomaterials may result in
occupational and environmental exposures.
Commercial pigments contain almost no particles
,100 nm. Ultrafine TiO2 particles range in size from 1 to
100 nm, with a modal primary size of 10–50 nm. TiO2 has
also been produced as engineered nanomaterials that are
composed of either TiO2 rutile or TiO2 anatase. Due to
greatly reduced demand from the construction and automo-
tive industries, global production of TiO2 pigment decreased
to approximately 5.6 million metric tons in 2009 (8). In 2009,
TiO2 pigment was produced by four companies at eight
facilities in seven states in the United States, at estimated
1.5 million metric tons (8). The estimated use of pigment (by
the end use) was paint 59% (includes lacquers and varnishes),
plastic 25%, paper 10%, and other 6%. Other uses of TiO2
included catalysts, ceramics, coated fabrics and textiles, floor
coverings, printing ink, and roofing granules (8).
2.3 Exposure Assessment
Humans can be exposed to TiO2 through many exposure
routes, including inhalation, swallowing, ingestion, and
absorption through the skin. NIOSH method #S385 recom-
mends that airborne concentrations of TiO2 should be
collected on a filter, eluted with acid, and measured by
inductively coupled argon plasma atomic emission spectros-
copy (27). The OSHA analytical method for TiO2 is based on
gravimetric analysis (28).
2.4 Toxic Effects
TiO2 is not readily absorbed and has been considered virtu-
ally inert. Until the mid-1980s, only a few case reports
432 BARBARA MALCZEWSKA-TOTH
suggested adverse effects as a result of industrial expo-
sure (15, 29). Even these studies indicated that the pulmonary
effects could have been caused by other materials that were
found in the lungs. The pulmonary changes induced by TiO2
were characterized by Moran et al. (30) as being fibrotic and
having numerous macrophages with deposits of black pig-
ment. Energy dispersion X-ray analysis demonstrated the
presence of large amounts of titanium in the pigment gran-
ules. Toxicity of TiO2 increases with decreasing particle size
and nano-TiO2-mediated toxicity (especially inflammatory
responses of the airways) has been increasingly reported to be
greater than that of the same mass of larger particles of
similar chemical composition. The toxic effects include
hyperresponsiveness and inflammation of the airways, pul-
monary fibrosis, cardiovascular, neurodegenerative effects,
or neurobehavioral changes resulting from prenatal expo-
sure. As compared to fine or coarse-sized particles, inhalation
exposure to nanoparticles having smaller aerodynamic para-
meters and extremely high surface area per unit mass ratio
results in greater efficiency of lung deposition and translo-
cation to distant tissues and organs, as well as an increased
potential for biological interactions. In addition to surface
area, other physicochemical characteristics of TiO2 nano-
particles can influence their toxicity. These characteristics
include particle coating, solubility, shapes, and the ability to
generate reactive oxidative species and react with biological
macromolecules.
2.4.1 Experimental Studies
In an early study, Christie et al. (31) found no adverse
pulmonary effects due to airborne exposure of Wistar rats
to TiO2. However, an inhalation study that exposed rats to
TiO2 for 7 h/day, 5 days/week, for up to 16 weeks produced
no measurable inflammation (as indicated by neutrophil
recruitment) at low TiO2 concentrations, but higher concen-
trations (30, 50, and 90 mg/m3) caused the transfer of dust to
lymph nodes and the first evidence of inflammation (32).
After rats were intratracheally instilled with 5–100 mg/kg
of TiO2 dust, lactate dehydrogenase (LDH) and total protein
(TP) were measured in bronchoalveolar lavage fluid (BALF),
and ex vivoalveolar macrophage (AM) fibronectin release
was assessed at days 7, 14, and 28 following exposure. Lung
dust burdens were determined on days 1, 7, and 28 after
instillation. TiO2 elicited dose-related increases in LDH and
TP in BALF and stimulated persistent increases in AM
fibronectin release at greater than or equal to 50 mg/kg.
Transient or no effects occurred at less than or equal to
10 mg/kg. Only TiO2 doses greater than or equal to 50 mg/kg
resulted in fibrosis. Increased dust retention, enzyme release,
and activation of AM fibronectin release were associated
with the development of fibrosis. The correlation of the
BALF markers of lung injury and the increase in AM
fibronectin release with the development of fibrosis suggests
that these end points may be used as biomarkers of dust-
induced interstitial lung disease (33).
Pulmonary toxicity of ultrafine TiO2 particles has exten-
sively been investigated in experimental studies in rodents (in
vivo animal models) and in vitro cell cultures. Several studies
compared particle sizes and species responses to TiO2 inha-
lation exposure and demonstrated that at equivalent mass
basis ultrafine insoluble particles produced greater toxicity
(pulmonary inflammation, tissue damage, and lung tumors)
than larger particles of similar chemical composition. Acute
intratracheal instillation exposure of male Wistar rats to
500 mg of ultrafine particles of TiO2 (29 nm) but not fine
particles (250 nm) increased epithelial permeability, epithe-
lial damage, and inflammation (34). The chemotactic activity
of macrophages was significantly increased by exposure to
ultrafine particles at the 500 mg dose but was similar to saline
control for fine particles. However, subchronic exposure to
high concentration of TiO2 aerosols affected alveolar clear-
ance to varying degrees in Fisher 344 rats, B3C3F1 mice, and
hamsters (35, 36). Female Fisher 344 rats, B3C3F1 mice, and
hamsters were exposed by inhalation to fine (rutile; 250 nm
primary particles) and ultrafine (21 nm primary particles)
TiO2 (35, 36). Decreased pulmonary clearance rates were
observed in both rats and mice after subchronic exposure to
high concentrations of fine TiO2 particles; however, for
ultrafine particles of TiO2, pulmonary clearance rates were
decreased to a greater extent. No effect of subchronic expo-
sure to TiO2 on clearance was observed in hamsters. All rats,
mice, and hamsters manifested acute inflammatory responses
following exposure to fine and ultrafine particles of TiO2;
however, the response was greater for ultrafine particles on a
mass basis. Also, rats and mice, but not hamsters, showed
increased epithelial permeability that affects the transport of
TiO2 from the luminal surfaces into the circulatory system
and other tissues.
Indeed, studies have demonstrated the rapid (approxi-
mately 1 h) translocation of free ultrafine TiO2 particles
across pulmonary cell membranes (37). Following inhalation
exposure of Wistar rats (adult, male), approximately 80% of
22 nm TiO2 particles remained on the luminal side of the
airway surfaces, 5% were in epithelial or endothelial cells,
5% were in connective tissues, and 10% were within
capillaries 24 h after inhalation (37). TiO2 particles found
within cells were not membrane bound. Both ultrafine and
fine particles (78 and 200 nm in diameter) crossed cellular
membranes by nonendocytic mechanisms, including adhe-
sive interaction and diffusion, whereas larger particles
(1000 nm) undergo ligand receptor-mediated phagocytosis.
Grassian et al. (38) evaluated inflammatory toxicity to the
lung from acute and subacute inhalation exposure of 6-week-
old male C57B1/6 mice to some of the smallest manufactured
nanoparticles of TiO2 (a primary particle size of 2–5 nm).
The study examined the toxicity by enumeration of total and
differential cells, determination of total protein, LDH

activity, and inflammatory cytokines in BALF. Lungs were
also examined for histopathologic changes. Mice exposed
acutely to 0.77 or 7.22 mg/m3 TiO2 nanoparticles showed
minimal lung toxicity or inflammation. Mice exposed sub-
acutely to 8.88 mg/m3 TiO2 nanoparticles and necropsied
immediately and at week 1 or 2 postexposure had higher
counts of total cells and alveolar macrophages in the BAL
fluid compared with sentinels. This significant but moderate
inflammatory response resolved by week 3 postexposure; all
other toxicity indicators were negative. Similar pulmonary
effects of TiO2 nanoparticles were observed in a short-term
study of male Wistar rats exposed to aerosols of 0 (control), 2,
10, and 50 mg/m3 nano-TiO2 exposed by inhalation for 6 h/
day for 5 days (39). Treatment with nanoparticles of TiO2
resulted in morphological changes in the lung, with 50 mg/m3
TiO2 producing an increase in lung weight. Lung inflamma-
tion was associated with dose-dependent increases in BALF
total cell and neutrophil counts, total protein content, enzyme
activities, and levels of cell mediators. Measurements of
clinical pathology parameters did not reveal presence of
systemic effects. Cell replication was increased at all TiO2
dose levels in large and medium bronchi and terminal
bronchioles, as determined by incorporation of 5-bromo-
20 -deoxyuridine (39). In another study, which investigated
the effects of TiO2 nanoparticle aggregation in inhalation and
instillation studies (40), the authors demonstrated the impor-
tance of the size and nature of nanoparticle aggregates in
evaluating their toxicity.
Particle surface area (but not particle mass or number of
particles) influences inflammatory effects and explains differ-
ences in inflammatory responses between fine and ultrafine
particles of TiO2 (41, 42). On the basis of instilled particle
mass, ultrafine TiO2 particles (20 nm; anatase) caused greater
influx of polymorphonuclear neutrophils than fine particles
(250 nm, anatase) in both Fisher 344 rats and C57BL/6J
mice (41). The surface properties of TiO2 particles, such as
roughness/smoothness, may also affect protein binding, with
smoother TiO2 surface being more hydrophobic (43). Other
studies reported minimal pulmonary toxicity of the base
pigment grade and ultrafine TiO2 particles that was indepen-
dent of particle size and surface area (44–46). However,
exposure to ultrafine TiO2 particle types (such as TiO2 anatase
or rutile uf-3) produced differential pulmonary effects and
these effects depended on the particle composition and crystal
structure (46). Therefore, the lung toxicity from exposure to
ultrafine anatase/rutile uf-3 particles cannot be viewed as
representative for all ultrafine TiO2 particle types.
Generation of reactive oxidant species on the particle
surface influences lung inflammatory response to particles.
A reduction of TiO2 particle size was associated with
increased proinflammatory properties (34) and DNA oxida-
tive damage to human bronchial epithelial cells in the
absence of photoactivation (47). TiO2 nanoparticles have
been shown to exhibit the adjuvant effect in mice (48, 49).
TITANIUM, ZIRCONIUM, AND HAFNIUM 433
Immune adjuvant activity of ultrafine TiO2 particles (14 and
29 nm diameter) on allergic airway inflammation in a mouse
model has been demonstrated to increase with decreasing
particle size (49).
Inhaled nanosized particles of TiO2 may enter the
bloodstream and translocate to other organs and tissues,
including the fetus. Specific pathogen-free male Sprague–
Dawley [H1a:(SD)CVF] rats (10–12 weeks old) were
exposed by inhalation to filtered air (control) or TiO2
nanoparticles (primary particle diameter about 21 nm) at
aerosol concentrations of 6 mg/m3 for 240 min (50). Inha-
lation exposure to TiO2 nanoparticles produced an increase
in spontaneous tone in coronary arterioles and impaired
endothelium-dependent flow-induced dilation. Thus, the
study demonstrates that exposure to TiO2 nanoparticles
significantly impairs endothelium-dependent vasodilation
in subepicardial arterioles, the findings consistent with the
cardiac events associated with particulate matter pollution
exposure.
Inhaled nanoparticles of TiO2 (UV-titan L181) induced
chronic lung inflammation in time-mated adult female
mice and affected development of their offspring (51).
Moderate neurobehavioral toxicity has been observed in
gestationally exposed offspring of adult female mice inhal-
ing nanoparticles of UV-titan. The study used UV-titan, a
rutile modified with unspecified amounts of zirconium,
silicon, aluminum, and coated with polyalcohols. Time-
mated, nulliparous adult C57BL/6BomTac mice were
exposed by inhalation (1 h/day) to 40 mg TiO2/m3 aerosol-
ized powder of TiO2 (average crystallite size: 21 nm; peak
size: 97 nm) on gestational days 8–18. (This dose corre-
sponds to the 8 h Danish TWA occupational exposure
limit.) Studied toxicity end points included maternal
lung inflammation, gestational and litter parameters, off-
spring neurological function, and fertility. In exposed adult
mice, 38 mg Ti/kg was measured in their lungs on day 5
and differential cell counts of BALF revealed lung inflam-
mation at 5 and 26–27 days following termination of
exposure, compared to control mice. Prenatally exposed
offspring tended to avoid the central zone of the open field,
as young adults. Also, prenatally exposed female offspring
showed prepulse inhibition, as young adults. Cognitive
function was unaffected, as measured by the Morris
water maze test (51). Although recent studies attempted
to explore the biological mechanisms involved or specific
pathways leading to the observed effects on fetal develop-
ment in rats (52), their relevance to humans is to be
determined.
Scuri et al. (52) studied effects of TiO2 nanoparticles on
neuroimmune responses in rat airways under invivo inhalation
exposure. As compared to controls, TiO2 exposure (12 mg
TiO2/m3, for 5.6 h/day for 3 days) produced upregulation of
lung neutrophins in weaning (2 weeks old) and newborn
(2 days old) but not in adult (12 weeks old) animals. The
434 BARBARA MALCZEWSKA-TOTH
effect was associated with increased airway responsiveness
and upregulation of growth-related oncogene/keratine-
derived chemokine [GRO/KC; CXCL1, rat equivalent of
human interleukin (IL)-8] in BALF. The results demonstrate
that exposure to TiO2 nanoparticles upregulates the expres-
sion of lung neutrophins in an age-dependent manner and that
this effect is associated with hyperresponsiveness and inflam-
mation of the airways. Furthermore, the results suggest the
presence of a critical window of vulnerability in earlier stages
of lung development that may lead to an increased risk of
developing asthma later in life (52).
Administration of TiO2 at concentrations of 25,000 and
50,000 ppm in the diet of F334 rats and B6C3F1 mice caused
no remarkable changes in the survival of the rats or the male
mice. The survival in the female mice was adversely affected.
In female rats, the incidences of C-cell adenomas or carci-
nomas in the thyroid gland were increased at the high dose
(control 1/48, 25,000 ppm 0/47, 50,000 ppm 6/44). The
tumor rate among the male rats was not affected by treat-
ment (53). White feces were noted in the groups of test
animals, suggesting that the absorption of the test material
was limited.Following acute oral exposure of adult mice to
TiO2 nanoparticles (25 and 80 nm) and fine particles
(155 nm) at 5 g/kg dose, TiO2 particles of all sizes were
distributed mainly to the liver, spleen, lungs, and kidneys,
2 weeks after exposure (54). Also, the subacute study of
oral toxicity of TiO2 nanoparticles in Wistar rats revealed
biochemical effects (disturbances in energy and amino
acid metabolism) indicative of slight injury to the liver
and heart (55).
The effects of particle size, coating, and shape on TiO2 skin
penetration have recently been investigated in in vitro
models (56, 57) and minipigs (58). The findings from
available studies demonstrate that the penetration of TiO2
nanoparticles is negligible within the intact skin and within
the damaged skin in vitro.
2.4.1.1 Carcinogenesis. In a 1985 study, rats (CD) were
exposed to graded airborne concentrations (0, 10, 50, and
250 mg/m3) of TiO2 6 h/day, 5 days/week, for 2 years. The
majority of the particles were in the respirable range (84%
,13 mm MMD). All responses were confined to the lungs. At
the lowest dose, the histopathological evaluation of the lungs
revealed dust-laden macrophages in the alveolar ducts and
adjacent alveoli with pneumocyte hyperplasia. At the two
highest concentrations, there were increases in lung weight,
accumulation of dust in the macrophages, foamy macrophage
responses, type II pneumocyte hyperplasia, alveolar proteino-
sis, alveolar bronchiolization, cholesterol granulomas, focal
pleurisy, and dust deposition in the tracheobronchiolar lymph
nodes. At the 250 mg/m3 exposure concentration, bronchiole
alveolar adenomas (males: control 2/79, 250 mg/m3 12/79;
females: control 0/79, 250 mg/m3 13/79) increased.
Additionally, 13/79 females at the 250 mg/m3 dose showed
squamous cell carcinoma, compared with none in 79 controls.
The authors noted that this response might have little biological
relevance to humans because of the overload of respiratory
clearance mechanisms and also pointed out that the type,
location, and development of the tumors were different from
those in human lung tumors (59). It is not clear that the nasal
cavity epithelium was examined. However, the nasal cavity
load would be expected to be higher in the rats because of
anatomic structure, whereas the lung deposition should be
higher in humans because we are, in part, mouth breathers.
The observation of lung tumors in rats in response to TiO2
was surprising because TiO2 has been regarded as inert and
has commonly been used as a negative control dust in rat
inhalation studies. However, the tumorigenicity of TiO2 in
the rat was supported in a subsequent study. A chronic
inhalation study of “ultrafine” TiO2 in Wistar rats produced
a 32% incidence of lung tumors, versus 0.5% in controls.
The rats were exposed to a concentration of 10 mg/m3 for
18 h/day, 5 days/week, for 24 months, followed by a 6-month
observation period. The “ultrafine” TiO2 particles used in this
study were 15–40 nm, which is an order of magnitude smaller
than typical pigment grade TiO2. NMRI mice exposed to
TiO2 under the same conditions did not develop lung
tumors (60).
Comparison of the inflammatory properties of pigment
grade TiO2 (250 nm particle size) with ultrafine TiO2 (20 nm
particle size) has demonstrated that the ultrafine particles are
retained to a greater degree in the lung, translocated to a
greater degree to the pulmonary interstitium, are more
inflammatory, and yield more cell proliferation than pigment
grade TiO2 (61). A 1997 study has shown that, at high lung
burdens (following a 4-week exposure, 6 h/day, 5 day/week
at 250 mg/m3), both pigment grade TiO2 and carbonyl iron,
another material generally regarded as inert, can also produce
a sustained inflammatory response in the rat lung (62).
Intratracheal instillation of two types of hydrophilic TiO2
(P25, mostly anatase, 25 nm mean particle size, and AL 23
203-1 anatase, 200 nm particle size), but not hydrophobic
P805 (21 nm mean particle size), produced an increased
incidence of both benign and malignant lung tumors in
female SPF Wistar rats (63). These data suggest that the
induction of lung tumors by TiO2 in the rat may not be a
compound-specific response but rather a generic response of
the rat lung to excessive burdens of low-solubility dusts.
Some authors have argued that this response may be unique
to the rat (62, 64). Therefore, the significance of the TiO2-
induced lung tumors in the rat to humans who are exposed to
TiO2 is unclear currently.
Some studies suggest that TiO2 induces lung tumor
development through a secondary genotoxic mechanism
that involves chronic pulmonary inflammation, initiating
a pathway of genetic changes, which result from the oxida-
tive damage of DNA by reactive oxygen and nitrogen
species (ROS/RNS) produced during particle-initiated

inflammation (46, 65). TiO2 nanoparticles have recently
been demonstrated to have the potential to convert benign
tumor cells into malignant cells through generation of ROS
in the target cells (66). These effects of nanoparticles of
TiO2 (rutile crystal phase) on poorly tumorigenic and non-
metastatic regressive tumor cells (QR-32 clones), fibrosar-
coma cells, were examined in a C57BL/6 mouse. Two types
of nano-TiO2 with different surface modifications were
used: TiO2-1 treated with ZrO2Al (OH)3, which is hydro-
philic, and TiO2-2 treated with ZrO2Al (OH)3 and stearic
acid, which is hydrophobic. Mice that were cotransplanted
subcutaneously with QR-32 clone cells and nano-TiO2,
either uncoated (TiO2-1) or coated with stearic acid
(TiO2-2), did not form tumors. However, QR-32 cells
became tumorigenic after injection into sites previously
implanted with TiO2-1 but not TiO2-2, and these developing
tumors acquired metastatic phenotypes. Neither histological
nor inflammatory cytokine mRNA expression was observed
between TiO2-1 and TiO2-2 treatments. However, TiO2-2
but not TiO2-1 generated high levels of ROS in cell-free
conditions and TiO2-2 produced a stronger response that
resulted in cytotoxicity to the QR-32 cells. In addition,
TiO2-2 but not TiO2-1 led to the development of nuclear
interstices and multinucleate cells. Cells that survived the
TiO2 toxicity acquired a tumorigenic phenotype. Addition
of antioxidant N-acetyl-L-cysteine inhibited the TiO2-
induced ROS formation and related cell injury (66).
2.4.2 Human Experience
Since Blina (67) reported in 1928 on the toxicological
inertness of TiO2 during production and handling, subse-
quent reports (68, 69) of similar industrial experiences have
been published. These findings are similar to those in
animals that inhale TiO2 (31, 70). Elo et al. (15), however,
concluded that TiO2 behaves as a mild pulmonary irritant on
the basis of a combined analytical and pathological study
of the lungs of three workers who had processed TiO2 for
8–9 years. Their investigation was no doubt spurred by a
Russian investigator’s report of fibrotic and inflammatory
changes in rat lungs from inhalation of crude ilmenite and
rutile ore dusts (71). The evidence of Elo et al. is uncon-
vincing because of incomplete medical histories. In one
case, recurrent bouts of bronchitis from smoking undoubt-
edly contributed to the dyspnea and were aggravated by the
dusty environment. The subpleural fibrosis in the second
and third cases may have resulted from previous tuberculo-
sis. It should also be noted that TiO2 used in the dye industry
may be coated with other elements, such as Al and Si, rather
than being pure TiO2 (72).
In a study of 67 workers in a Nigerian TiO2 paint factory,
airway symptoms were present in 50–54%; 20–40% had
neurological symptoms, and 10–27% had other symptoms.
These manifestations were correlated with exposure and
TITANIUM, ZIRCONIUM, AND HAFNIUM 435
pulmonary function tests. Among the workers, 42% had
restrictive lung impairment. Although the smoking rate
was low among these workers, there may have been some
exposure to cotton dust that confounded the results of the
study (72). In another study, no respiratory effects, fibrosis, or
lung cancers were evident among 1576 TiO2 workers (73).
Also, other epidemiological studies (three occupational
cohort studies and one population-based case–control
study) did not find an association between inhalation
exposure to TiO2 and increased risk of lung cancer, kidney
cancer, or any other cancer site or chronic respiratory
diseases (74–77). The results of the most recent cohort
study of mortality among TiO2 workers employed at three
titanium dioxide plants in the United States (77) are compa-
rable with those from previous TiO2 cohort studies. The study
found no indications of increased mortality from any cause;
the mortality rates were comparable with those for the
general U.S. population.
2.4.2.1 Pharmacokinetics, Metabolism, and Mechan-
isms. The kinetics of TiO2 elimination in the rat lung
following its deposition after 7 h exposures at 10 and
50 mg/m3 were determined for periods up to 140 days
(78). The TiO2 particles had a mass median diameter of
1.48 mm. Irrespective of exposure concentration, deposi-
tion was linear, placing 75 mg TiO2 in the lung after 7 h at
10 mg/m3 and 370 mg at 50 mg/m3. The retention half-time
was 14 days for the first clearance phase and 88 days
thereafter. Papain-produced emphysema (78) and SO2,
even at 1 ppm, after a prolonged 170 h exposure reduced
clearance rates by more than 50% (79). Studies have also
indicated that TiO2 particles can be transported via sys-
temic circulation to other tissues and organs (mainly liver,
spleen, lungs, kidneys, and heart) following absorption
from the gastrointestinal tract (54, 55).
Several in vitro studies have shown that TiO2-produced
reactive oxygen/nitrogen species (ROS/RNS) at the site of
nanoparticles interaction with tissue/biological material are
responsible for oxidative cell damage, resulting in inflam-
matory, cytotoxic, and genotoxic effects (47, 54). However,
the results of these studies are somehow contradictory.
Particle size (including its surface area), crystallinity
(including photocatalytic activity), surface chemistry, and
particle aggregation/agglomeration tendency affect biologi-
cal activity and toxicity of TiO2 (80). TiO2 nanosphere,
short (,5 mm) and long ( . 15 mm) nanobelts (NB-1 and
NB-2, respectively) were tested for biological activity using
primary murine alveolar macrophages and in vivo in 2-
month-old male C57BL/6 mice (81). These fiber-shaped
nanoparticles (NB-2) initiated an inflammatory response
by alveolar macrophage. The inflammatory response was
produced by inflammasome activation and release of inflam-
matory cytokines through a cathepsin B-mediated mecha-
nism. Interaction of long TiO2 nanobelts with lung
436 BARBARA MALCZEWSKA-TOTH
macrophages was similar to that of asbestos or silica expo-
sure. This study demonstrated that toxicity and pathogenic
potential of TiO2 change dramatically as the shape of a
particle is altered into one that a lung macrophage (a
phagocytic cell) has difficulty processing, which results
in lysosomal disruption and inability to form functional
lysosomes that leads to a cycle of cell death, inflammation,
and consequently lung disease such as fibrosis, with long-
term exposure (81).
In another study (82), TiO2 nanoparticles (15 nm) induced
apoptotic cell death in bronchial epithelial cells (16HBE14o
cell line and NHBE primary cells). TiO2-exposed cells
demonstrated typical both morphological and biochemical
attributes of apoptotic cell death. The morphological char-
acteristics included decreased cell size, cell membrane
blebbing, peripheral chromatin condensation, and apoptotic
body formation and the biochemical features included cas-
pase activation and DNA fragmentation. TiO2 nanoparticles
produced lipid peroxidation, lysosomal membrane destabi-
lization, and cathepsin B release during apoptotic pro-
cess (82). Production of reactive oxygen species was also
involved in apoptosis induction by exposure to TiO2 nano-
particles. In summary, TiO2 nanoparticles induce apoptotic
cell death through the lysosomal membrane destabilization
and lipid peroxidation (81, 82).
The mechanisms for apoptosis induced by TiO2 nanopar-
ticles were further studied in human airway epithelial cell line
(BEAS-2B cells) (83), in a mouse epidermal (JB6) cell
line (84), and in mouse splenocytes (85). Exposure of
BEAS-2B cells to TiO2 nanoparticles resulted in a dose-
dependent increase of the levels of ROS and morphological
apoptosis as well as a dose-dependent decrease of cell
viability (83). The study demonstrated that apoptosis in
BEAS-2B cells occurred through a mitochondrial pathway
independent of caspase 8/t-Bid pathways. However, in JB6
epidermal cells, TiO2 nanoparticles showed higher cytotox-
icity and apoptotic induction compared to fine particles;
caspase-8/Bid and mitochondrial signaling appeared to
play a major role in apoptosis involving the intrinsic
mitochondrial pathway (84). Intraperitoneal injection of
mice with TiO2 nanoparticles for 45 consecutive days resulted
in TiO2 nanoparticles accumulation in the mouse spleen,
leading to congestion and lymph node proliferation of spleen
tissue and splenocyte apoptosis (85). TiO2 nanoparticles
induced the splenocyte apoptosis through mitochondrial-
mediated pathway.
The in vitro genotoxicity of TiO2 nanoparticles (rutile and
anatase) was compared with fine TiO2 rutile in human
bronchial epithelial cells (BEAS-2B) using the comet
assay and the cytokinesis-block micronucleus test (86).
The study showed greater efficiency of uncoated nanosized
anatase TiO2 and fine rutile TiO2 than silica-coated nano-
sized rutile TiO2 in inducing DNA damage. Only nanopar-
ticles of anatase TiO2 slightly induced micronuclei (86).
However, no cytotoxicity or genotoxicity of nanoparticles
of TiO2 was demonstrated in vitro in human nasal mucosa
cells obtained from 10 donors (87). The cells were exposed to
nanoparticles of TiO2 in increasing concentrations of 10, 25,
50, and 100 mg/mL. TiO2 particles were mainly nanosized
(,100 nm) but showed a strong tendency to aggregated in
spite of sonication of the suspension. Eleven percent of
particles entered the cytoplasm and 4% of particles entered
the cell nucleus. There was no loss of cell viability observed
by the trypan blue exclusion test and fluorescein diacetate
assay. The comet assay failed to provide an evidence of DNA
fragmentation and cytotoxicity in human nasal epithelial
cells (87).
Mechanisms of neurotoxic potential of TiO2 nanoparticles
(up 120 ppm) were investigated in vitro in nerve cells critical
to the pathophysiology of neurodegeneration [brain cultures
of immortalized mouse microglia (BV2), rat dopaminergic
(DA) neurons (N27), and primary cultures of embryonic rat
striatum] following exposure to commercially available TiO2
nanomaterial, Degussa P25 (88). Degussa P35 appeared to be
nontoxic to isolated N27 neurons but stimulated BV2 micro-
glia to release ROS and damaged OS-sensitive neurons in
cultures of brain striatum through affecting genomic path-
ways associated with cell cycling, inflammation, apoptosis,
and mitochondrial bioenergetics (88). In another study, expo-
sure to TiO2 nanoparticles induced acute functional neuro-
toxicity at low particle concentrations of 1 mg/cm2 (89). The
effects were observed in cocultures of primary neurons and
glial cells, which form stable and electrically active neuronal
networks on microelectrode array (MEA) neurochips.
2.5 Standards, Regulations, or Guidelines of Exposure
Titanium has a considerable occupational exposure, primar-
ily as TiO2. It is estimated by NIOSH that 363,640 workers
are exposed to TiO2 on a full-time basis. Of 86 combined
federal and state OSHA samples between 1979 and 1988,
1.2% samples were above the OSHA permissible exposure
level (PEL), and 23% were above half of the PEL (90). The
OSHA PEL for TiO2 is 15 mg/m3 (91). ATLV-TWA has been
developed by ACGIH. This is the equivalent of any inert dust.
NIOSH has not established a numerical recommended expo-
sure level (REL) for TiO2, but has classified this substance as
a potential occupational carcinogen (93). TiO2 was evaluated
as possibly carcinogenic to humans (Group 2B) based on
sufficient evidence in experimental animals and inadequate
evidence of carcinogenicity in humans (94). The dioxide is
the only titanium compound for which standards have been
established.
3.0 Titanium Tetrachloride
3.0.1 CAS Number
[7550-45-0]
 TITANIUM, ZIRCONIUM, AND HAFNIUM 437

3.0.2 Synonyms 3.4.2 Human Experience

Titanic chloride; tetrachlorotitanium; titanium chloride; tita- Experience with TiCl4 has been reviewed by Lawson (96).
nium(IV) tetrachloride; titanium(IV) chloride; titanium The serious effects of TiCl4 liquid on the skin and eye,
chloride (T-4); titanium chloride (TiCl4) (T-4) reported earlier by Zapp (97, 98), were found amply true.
Second- and third-degree burns and lasting deep brown
3.0.3 Trade Names pigmentation occur about the periphery of the scars and in
areas of healed burns. The condition suggested that a reaction
NA product had penetrated the damaged epithelium and
remained there after healing (96). TiCl4 can cause severe
3.0.4 Molecular Weight burns to the eyes and also to the lungs if the fumes are
inhaled (99). However, a study of 969 workers occupation-
189.68
ally exposed to TiCl4 showed no elevation of lung cancer or
other respiratory diseases (100).
3.0.5 Molecular Formula
Cl4Ti
3.5 Standards, Regulations, or Guidelines
of Exposure
3.0.6 Molecular Structure
TiCl4 is extremely dangerous when combined with water,
including perspiration, due to the formation of HCl and heat.
Cl– Therefore, it is essential that TiCl4 be removed from the skin
Cl– Ti4+ Cl–
Cl–
by wiping with a clean dry cloth before flushing the skin with
water (101).

3.1 Chemical and Physical Properties

4.0 Titanocene
See Table 13.2.
4.0.1 CAS Number
[1271-19-8]
3.2 Production and Use
TiCl4 is used in TiO2 production, the manufacture of artificial 4.0.2 Synonyms
pearls and iridescent glass, and, by the military, to create
Titanium, dichlorobis(h5-2,4-cyclopentadien-1-yl)-; dichlor-
smoke screens.
odi-p-cyclopentadienyltitanium; dichlorobis(h5-2,4-cyclo-
pentadien-1-yltitanium);dichlorodicyclopentadienyltitanium;
3.3 Exposure Assessment dichlorotitanocene; titanium ferrocene; biscyclopentadienyl-
titanium(IV) dichloride; biscyclopentadienyltitanium
Inhalation of the fumes and absorption through the skin are
dichloride; bis(cyclopentadienyl)dichlorotitanium.
the predominant potential routes of human exposure to TiCl4.
4.0.3 Trade Names
3.4 Toxic Effects
NA
3.4.1 Carcinogenesis
4.0.4 Molecular Weight
Rats exposed to 10 mg TiCl4/m3 for 6 h/day, 5 days/week, for
2 years developed rhinitis, tracheitis, hyperplasia, foamy dust 248.99
cell accumulation, and alveolar bronchiolization. In addition,
5/150 animals developed squamous cell carcinoma, com-
4.1 Chemical and Physical Properties
pared to 0/156 in the controls. Two of the squamous cell
carcinomas were described as cystic keratinizing lesions, See Table 13.2.
whose relevance to humans was questioned by the authors.
However, the remaining three squamous cell tumors were
4.2 Production and Use
described as microscopic, well-differentiated carcino-
mas (95). Therefore, TiCl4 may be regarded as potentially Titanocene dichloride is used as an experimental cancer
carcinogenic in the rat. chemotherapeutic agent (102).
438 BARBARA MALCZEWSKA-TOTH
4.3 Exposure Assessment
Humans can be exposed to titanocene dichloride chiefly by
inhalation and absorption thorough the skin.
4.4 Toxic Effects
4.4.1 Experimental Studies
4.4.1.1 Pharmacokinetics, Metabolism, and Mechanisms.
Titanocene dichloride accumulates preferentially in the liver
and intestines of rats, after intraperitoneal injection (103).
4.4.1.2 Reproductive and Developmental. Titanocene
dichloride crossed the placental barrier only to a minimal
degree in pregnant mice and was not teratogenic (104).
4.4.1.3 Carcinogenesis. Titanocene administered by
intramuscular injection produced tumors both at the injection
site and at sites distant from the injection site (105, 106).
Titanocene dichloride showed equivocal evidence of carci-
nogenicity in male and female Fischer 244 rats in a 2-year
oral gavage study (107).
ZIRCONIUM AND ZIRCONIUM COMPOUNDS
Zirconium is a grayish-white, lustrous metal that is classified
in the second series of transition metals in subgroup IVB
of the periodic table. Impure zirconium was isolated in
1824 by heating a mixture of potassium zirconium fluoride
with potassium in an iron tube (108). Zirconium occurs
abundantly in stars and has been identified in the sun and
in meteorites. It is present as a minor impurity during the
extraction of beryllium from its ore, bertrandite.
Occurrence
Zirconium, one of the more abundant elements, is widely
distributed in the Earth’s crust and occurs as the oxide,
baddeleyite (ZrO2), or as part of a complex of oxides as in
zircon, ZrO2SiO2, elpidite, Na2ZrSi6O133H2O, and eudia-
lyte, Na13(CaFe)6(ZrSi)20O52Cl (109). Zircon is the most
important commercial ore and baddeleyite also has some
importance. It has been estimated that zirconium constitutes
about 0.017% of the lithosphere.
Major world sources of zircon are Australia, the Republic
of South Africa, and the United States. France, Japan, and
the United States are producers of nuclear and commercial
grade zirconium metals. Global production of zirconium
concentrates (excluding the United States) decreased in
2009 by 4% compared with that in 2008 (from approxi-
mately 1.3 million metric tons in 2008 to 1.2 million tons in
2009) (8). About 50,000 tons of the world demand of
184,000 tons (27%) of zircon was consumed by the United
States in 1983. Zircon occurs worldwide as an accessory
mineral in igneous, metamorphic, and sedimentary rocks
from which it is mined.
Commercial deposits occur only in Brazil and the Republic
of South Africa, but it is also found in East Africa, Sri Lanka,
and the former Soviet Union. Zircon sand is produced in
Australia, Republic of China, Korea, South Africa, India, and
Brazil. All commercial sources of zircon are derived from
mining ancient, unconsolidated beach deposits, the largest of
which are in Kerala, India, in Sri Lanka, the east and west
coasts of Australia, on the Trail Ridge in Florida, and at
Richards Bay in the Republic of South Africa. These heavy
mineral sands are processed to recover the titanium-bearing
minerals ilmenite, rutile, and leucoxene, and zircon is
obtained as a coproduct. The output of zircon depends mainly
on the market for titanium minerals used in producing tita-
nium oxide white pigment and titanium metal (108, 110). The
production of zirconium metal is only a minor use of zircon.
In the United States, the zirconium content of zircon in
beach sand and placer deposits in Florida and Georgia is
estimated at 4 million tons. In addition, 4 million tons of
marginal reserves and subeconomic resources are located
principally in Tennessee, New Jersey, South Carolina, and
California. Zircon is recovered from mineral sands by dredg-
ing and mining.
Zirconium is associated with other metals in many minerals
but is recovered only from zircon (ZrO4SiO2), baddeleyite
(brazilite) (ZrO2), and eudialyte [Na13(CaFe)6(ZrSi)20O52Cl].
Hafniumisinvariablyassociatedwithzirconium.Zirconoccurs
in all igneous rocks but is more common in granite, sylnite
(complex silicates), and diorite (alkaline earth silicates). Zircon
is a common constituent of river gravels and beach sands, from
where it is recovered as a coproduct of ilmenite (FeO4TiO2),
rutile (TiO2), and monazite (thorium and lanthanum phos-
phates). Baddeleyite usually occurs in phenolite and is also
found in river gravels and beach sands (108).
Because of its very high chemical activity at temperatures
just above normal ambient temperature, zirconium occurs
only in the combined state (110). Zirconium is found in at least
37 different mineral forms (111), but the predominant com-
mercial source is the mineral zircon, zirconium orthosilicate.
Baddeleyite, a natural zirconium oxide, has been found in
Brazil and in Transvaal, South Africa. The Brazilian ore
occurs frequently with zircon and may contain 65–85%
zirconium oxide, 12–18% silica, and 0.5% uranium oxide.
Currently, very little Brazilian ore is exported because all
radioactive minerals are under the close scrutiny of the
Brazilian government. The Transvaal ore is a complex ore
composed of different sections; these are mined to recover
magnetite, apatite (a copper concentrate), vermiculite, and
baddeleyite. The baddeleyite ore contains a zirconium
oxide concentration of 0.2% but when concentrated, it
yields about 96% zirconium oxide with a hafnium content
(Hf/Zr þ Hf) of about 2%. Zirconium and hafnium are
 TITANIUM, ZIRCONIUM, AND HAFNIUM 439

geochemically associated in the principal ore mineral, 5.0.2 Synonyms

zircon, in a ratio of 50:1. The two elements are separated
Zirconium powder; zirconium plate; zirconium rod; zirco-
only for nuclear applications.
nium wire; zirconium foil
Eudialyte [Na13(CaFe)6(ZrSi)20O52Cl], a third ore, is the
source of pure zirconium oxide from large deposits in
southwest Greenland. Two zirconium-containing minerals 5.0.3 Trade Names
have been discovered in the past 20 years, welognite NA
(Sr2.8Ca0.2)ZrNa2(CO3)63H2O and gittinsite CaZrSi2O7.
Unlike zircon, the zirconium content of these minerals and 5.0.4 Molecular Weight
eudialyte can be dissolved by strong acid.
Zircon is the primary zirconium mineral of commercial 91.22
significance. It is recovered solely as a by-product of mining
and extracting of the titanium minerals, ilmenite and rutile, 5.0.5 Molecular Formula
for which there is a much larger demand. Zircon has been
Zr
known as a gem mineral since biblical times and was called
Jargon in Sri Lanka and Hyacinth in France. The name
zircon comes from the Arabic “zargun,” meaning gold 5.1 Chemical and Physical Properties
color, describing the gemstone now known as zircon.
The physical and chemical properties of zirconium and some
Zircons may be colorless, amber, red, reddish brown,
of its compounds are listed in Table 13.3.
blue, green, or black. Analysis of the gemstone Jargon
Zirconium is a hard, shiny, ductile metal, similar to
from Sri Lanka in 1789 by Klaproth revealed 68% of
an unknown earth that he called zirkonerde (112). In stainless steel in appearance. It can be hot-worked to form
slabs, rods, and rounds from arc melted ingot. Cold working
1797, Vauquelin studied this new earth, gave it the name
of zirconium yields sheets, foil, bar, wire, and tubing. The
zirconia, and published the preparation and properties of
chemistry of zirconium is almost identical to that of hafnium,
some of its compounds (113). It was only in 1824 that
as similar as deuterium is to hydrogen.
Berzelius prepared the first crude zirconium metal, a black
The most common valence of zirconium is 4þ, and in rare
powder, by heating potassium and potassium hexafluoro-
instances it has a valence of 3þ or 2þ. Zirconium has a
zirconate in a closed pot (110).
maximal covalence of 8, but covalences of 5, 6, and 7 are
The mineral zircon is mainly used for facings on foundry
molds; foundries consume approximately one-half of the common. Zirconium probably does not exist in compounds
as a monoatomic ion but is frequently found as the central
domestic zirconium production, and the remaining one-half
atom of complex anions and cations.
is consumed by refractory, abrasive, ceramic, metal, and
Zirconium forms three categories of compounds: (1)
other industries. Domestic zirconium is marketed in propri-
complex zirconium cations, (2) complex zirconium anions,
etary mixtures for use as weighting agents, Zr–TiO2 blends
for welding rod manufacture, and zirconium refractory and (3) zirconium in nonionized groups. The simplest zirco-
heavy-mineral (kyanite, sillimanite, and staurolite) sand nium cations are ZrO2þ and ZrCl22þ; an example of anions of
the hypothetical HZrO4 and H2ZrO3 is hexafluorozirconate,
blends for foundry sand and sandblasting applications.
The zirconium-bearing foundry sand was reportedly (ZrF6)2. Zirconium alkoxides, (Zr(OR)4), are examples of
nonionic zirconium compounds. Further information on
designed to provide consistent high-quality performance
the chemistry of zirconium is provided by Tanner (115),
at low cost for critical casting applications (114).
Blumenthal (116), and Miller (117).
Zircon is widely used in furnaces and hearths as refractory
Zirconium is a highly active metal but seems passive
bricks and blocks for containing molten metals. Zircon is also
because of the stable, protective oxide film that is formed
used in manufacturing fused cast and bonded AZS
on exposure to air or water. Bulk zirconium does not burn in
(alumina–zirconia–silica base) refractories for glass tank
air but oxidizes rapidly at 700 C in air; however, it combines
furnace use and in alumina–zirconia snagging wheels used
in heavy grinding on rough metal surfaces. Zircon is also with chlorine at lower temperatures. Pure sponge zirconium
is pyrophoric and violently explosive when impure. Fires so
used as a refractory material for dies used to extrude various
started cannot be extinguished by ordinary means and require
materials (108).
quenching by smothering with some pulverized mineral
carbonate such as dolomite. Serious explosions have
5.0 Zirconium occurred from moist exposure of metal scrap containing
zirconium as a contaminant. Zirconium metal dust dispersed
5.0.1 CAS Number
with uranium and uranium hydride as a cloud ignites under
[7440-67-7] certain conditions.
440
Table 13.3. Physical and Chemical Properties of Zirconium and Its Compoundsa
CAS Molecular Molecular Boiling Melting Specific Solubility in
Compound Number Formula Weight Point ( C) Point ( C) Gravity Water (68 F) References
a
Zirconium [7440-67-7] Zr 91.22 4409 1855 6.52 Insoluble
a
Zirconium beryllide [12010-33-2] ZrBe13 1925 2.72
a
Zirconium beryllide ZrBe17 1980 3.08
a,b
Zirconium diboride [12045-64-6] ZrB2 112.85 3040 6.17
b
Zirconium boride [12045-28-2] ZrB 2800
b
Zirconium boride (1:12) [12046-91-2] ZrB12 Decomposes at 2250
b
Zirconium bromide, [13777-25-8] ZrBr4 410.84 360c 450d 3.98
zirconium tetrabromide
a
Zirconium carbide [12020-14-3] ZrC 103.24 3532 6.73
c a
Zirconium chloride, [10026-11-6] ZrCl4 233.04 331 437d 2.80 Reacts with water
zirconium tetrachloride
e
Zirconium dichloride [13762-26-0] ZrCl2 162.13 Decomposes at 350 3.6
c a
Zirconium fluoride, zirconium [7783-64-4] ZrF4 167.22 912 932d 4.43 Slightly sol
tetrafluoride
a
Zirconium hydride [7704-99-6] ZrH2 92.34 5.6 Insoluble
a
Zirconium hydroxide [14475-63-9] Zr(OH)4 159.25 Decomposes 3.25 Insoluble
c a
Zirconium iodide [13986-26-0] ZrI4 598.84 431 499d 4.85 Very soluble
a
Zirconium nitrate, [13746-89-9] Zr(NO3)45H2O 429.32 Decomposes at 100 Very soluble
pentahydrate
a
Zirconium nitride [25658-42-8] ZrN 105.23 2960 7.09
a
Zirconium orthosilicate [10101-52-7] ZrSiO4 183.31 Decomposes at 1540 4.56 Insoluble
a
Zirconium oxide [1314-23-4] ZrO2 123.22 2710 5.68 Insoluble
a
Zirconium silicide [12039-90-6] ZrSi2 147.40 1620 4.88 Insoluble
a
Zirconium sulfide [12039-15-5] ZrS2 155.36 1480 3.82 Insoluble
a
Zirconium sulfate, [7446-31-3] Zr(SO4)24H2O 355.41 Decomposes at 100 2.8 Very soluble
tetrahydrate
f
Zirconium sulfate [14644-61-2] Zr(SO4)2 283.3 Decomposes at 410 3.2
a
Zirconium chloride, [13520-92-8] ZrOCl28H2O 322.25 Decomposes at 400 1.91 Very soluble
octahydrate
f
Zirconium oxychloride [7699-43-6] ZrOCl2 178.13
a
Adapted from CRC Handbook of Chemistry and Physics, CRC Press, 78th ed., Boca Raton, FL, 1997–1998.
b
Adapted from Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed., Vol. 4, Wiley, New York, 1992.
c
Sublimation point.
d
Triple point.
e
Adapted from CRC Handbook of Chemistry and Physics, CRC Press, 67th ed., Boca Raton, FL, 1986–1987.
f
Adapted from CHEMFINDER.com.

Clean zirconium plate ignites spontaneously in oxygen of
about 2 MPa (300 psi); the autoignition pressure drops as the
metal thickness decreases (109). Finely divided zirconium in
the form of powder or chips is extremely pyrophoric and
hazardous to handle and store. Spontaneous explosions have
been reported with both the wetted sponge and the wet and
dry stored scrap metal. The spontaneous ignition pressure for
thin sheets of zirconium metal in oxygen varies depending
upon the oxygen content of the specimen. The reaction with
nitrogen is slower than with oxygen. When heated in nitrogen
at 700 C for 3 min, it forms a 0.3 mm layer of zirconium
nitride and a 1.2 mm layer at 900 C.
Zirconium is readily attacked by acidic solutions contain-
ing fluorides. As little as 3 ppm fluoride ion in 50% boiling
sulfuric acid corrodes zirconium at 1.25 mm/year. Solutions
of ammonium hydrogen fluoride or potassium hydrogen
fluoride have been used for pickling and electroplating
zirconium. However, commercial pickling is done with
nitric–hydrofluoric acid mixtures.
Molten zirconium is also extremely reactive. Zirconium
fires and explosions have occurred in the presence of, or in
circumstances involving, carbon tetrachloride, nitrogen,
zirconium tetrachloride, magnesium chloride, and potassium
bisulfate. The mechanism in these reactions may not be
known, but if the principles of (1) the importance of particle
size and surface area, (2) the nature of the contact or mixture
of zirconium with any oxidant, (3) the character and insta-
bility of the protective oxide layer, and (4) the limitations of
amounts and personnel exposures are applied in any use or
handling of zirconium, the unfavorable experiences of the
past may be averted (108).
Zirconium metal has excellent corrosion resistance to
water and steam, mineral acids, strong alkalies, organic
acids, salt solutions, and molten salts. This property is
attributed to the dense, adherent, oxide film that forms at
ambient temperatures. Zirconium is completely resistant to
sulfuric acid up to boiling temperatures at concentrations of
70 wt%, in the absence of fluoride ion. It is also resistant to
attack by nitric acid at concentrations up to 70 wt% and up to
250 C. The corrosion rate is less than a mil per year in acetic,
boric, carbolic, chromic, citric, formic, hydrochloric, lactic,
monochloroacetic, nitric, oxalic, tannic, tartaric, and tri-
chloroacetic acids, aqueous phenol, caustic alkali solutions,
ammonium hydroxide, many solvents, and aqueous salt
solutions. It is resistant to molten sodium hydroxide up
to 1000 C but is less resistant to potassium hydrox-
ide (108, 109). However, the metal is attacked by hydro-
fluoric acid. Resistance to hot water and steam is also not as
satisfactory as required for nuclear plant use; hence, the alloy
Zircaloy-2 (Zr containing 1.5% Sn, 0.12% Fe, 0.05% Ni, and
0.01% Cr) was developed for use in nuclear plants. Another
alloy, Zircaloy-4, that contains less nickel has also been
used in nuclear plants and is sometimes preferred to
Zircaloy-2 (108, 109).
TITANIUM, ZIRCONIUM, AND HAFNIUM 441
Substitutes for zirconium may be employed for many end-
use applications with minor inconvenience or quality
sacrifices. Conversely, zirconium may substitute for other
substances that are in less abundant supply or find a variety
of expanded applications where oxidation resistance, low
neutron absorption, and other properties may be significant
factors.
The free energies of its compounds indicate that zirconium
should react with any nonmetal, other than inert gases, at
ordinary temperatures. In practice, the metal is unreactive
near room temperature because of an invisible, impervious
oxide film on its surface. This film renders the metal passive,
and it remains bright and shiny indefinitely even when
exposed to air. At elevated temperatures, it is very reactive
to nonmetallic elements and to many of the metallic elements
and forms either solid solutions or compounds. At 1290 C, as
much as 30 atmospheric % oxygen, 20 atmospheric %
nitrogen, and 50 atmospheric % hydrogen will dissolve in
the metal (108).
Zirconium forms alloys with almost all metals except
mercury and those of the alkali and alkaline earth groups.
Zirconium alloys resist neutron bombardment and corrosion
and have a low neutron-capture cross section; traces of
hafnium destroy this property (110).
5.2 Production and Use
5.2.1 Production
Zirconium was first produced in elemental form in 1824 by
Berzelius, but it was brittle because it contained impurities
such as oxygen, nitrogen, and hydrogen. In 1914, the first
relatively pure zirconium was prepared by reducing zirco-
nium tetrachloride with sodium in a bomb furnace. High-
purity zirconium was produced by Van Arkel and de Boer in
1925 by vaporizing zirconium tetraiodide into a bulb contain-
ing a hot tungsten filament, which caused the tetraiodide to
dissociate, depositing zirconium on the filament. The zirco-
nium is recovered as bright extremely pure metal crystals. This
procedure was later used for the commercial production of
zirconium in the United States. Dr. Kroll from the Bureau of
Mines conducted research and produced high-purity zirco-
nium on a commercial scale in 1944; the Kroll method is now
used for large-scale commercial production of zirconium.
In 2009, resources of zircon in the United States included
about 14 million tons associated with titanium resources in
heavy-mineral sand deposits (8). Phosphate and sand and
gravel deposits have the potential to yield substantial amount
of zircon as a future by-product. Eudialyte and gittinsite are
zirconium silicate minerals that have a potential for zirconia
production. Currently, identified world resources of zircon
exceed 60 million tons (8).
The production of zirconium metal must be carried out in
an atmosphere from which water vapor, oxygen, and nitrogen
442 BARBARA MALCZEWSKA-TOTH

Table 13.4. Statistics of Zirconium Imports and Exports—United States, 2005–2009a

Metric Tons
2005 2006 2007 2008 2009 (est.)
Imports
Zirconium ores and concentrates (ZrO2) 24,800 23,500 13,000 22,300 20,300
Zirconium, unwrought, powder, and waste and scrap 283 256 299 318 690
Zirconium oxide (ZrO2) 3160 2820 3740 5060 3,100
Exports
Zirconium ores and concentrates (ZrO2) 65,600 49,600 43,000 27,400 22,000
Zirconium, unwrought, powder, waste and scrap 321 271 328 591 210
Zirconium oxide (ZrO2) 2260 3340 2400 2970 1700
Prices
Zircon (dollars per metric ton)
Domestic 570 785 763 788 830
Imported 674 791 872 773 890
Zirconium, unwrought (dollars per kg) 22 23 24 26 58
a
Adapted from U.S. Geological Survey, Mineral Commodity Summaries, 2010.

are rigorously excluded; otherwise, the metal becomes brittle
and impossible to fabricate.
The statistics of U.S. zirconium imports and exports for
the years 2005–2009 are presented in Table 13.4. In the year
2000, U.S. demand for zirconium has reached about
116,000 tons. The average annual growth rate was 5.7%
since 1983. The rest-of-world demand for zirconium may be
346,000 tons of zirconium in 2000, representing an average
annual growth of 5.6% since 1983. In 2009, global financial
difficulties led to decreased demand for ceramic, foundry,
opacifiers, and refractory products (8). Consequently, con-
sumption of zircon was expected to recover with average
growth of 3% per year through 2015.
5.2.2 Current Processing Steps
Zircon is a highly refractory mineral as shown by its geolog-
ical stability; the ore is cracked only at high temperatures
with strong reagents.
5.2.2.1 Electric Furnace. Zircon and coke are reacted in
an electric arc furnace to produce crude zirconium carbide
nitride. With a deficiency of carbon, silica is not reduced to
carbide but forms silicon monoxide that is vaporized at the
reaction temperature of about 2500 C. When more coke is
added, the silica forms the carbide in the fused ingot. The
mixed zircon, coke, iron oxide, and lime produce zirconium
ferrosilicon that is an alloy agent.
5.2.2.2 Caustic Soda Fusion. Fusion of finely ground
zircon with caustic soda at 600 C or with soda ash produces
a frit containing sodium silicate, sodium zirconate, and some
sodium silicozirconate. Treatment with water removes most
of the sodium and silica, leaving a hydrous zirconium oxide
that is soluble in most mineral acids.
5.2.2.3 Fluorosilicate Fusion. This method was used to
separate hafnium from zirconium by the fused reaction of
milled zircon with potassium hydrogen fluoride or potassium
hexafluorosilicate at 700 C. The potassium moiety was used
rather than the sodium moiety because of the lower tendency
of potassium to dissociate and lose silicon tetrafluoride by
sublimation.
5.2.2.4 Chlorination. Historically, zircon and coke were
reacted in an electric arc furnace to form carbide nitride, and
the crushed product was treated with chlorine gas to form
zirconium tetrachloride. Currently, milled zircon and coke
are chlorinated in fluidized beds using chlorine as the fluid-
izing medium.
5.2.2.5 Thermal Dissociation. The thermal dissociation
of zircon into zirconia and cristobalite or liquid silica
above 1650 C was used to produce zirconia, but the two
phases partially recombine during cooling.
5.2.2.6 Separation of Hafnium from Zirconium. Zirco-
nium (Zr) and hafnium (Hf) always occur together in
natural minerals, and all zirconium compounds contain
about 2 wt% Hf. The only applications where Zr should be
free from Hf are zirconium components of water-cooled
nuclear reactors. Details of the separation of Zr and Hf and
the qualitative differences in chemical behavior between
hafnium and zirconium are presented in the section on
hafnium.
Ductile metal is prepared commercially by two methods.
5.2.2.7 Kroll Process. Zircon is heated with carbon in an
arc furnace to form zirconium cyanonitride Zr(CNO), which
is an interstitial solution of carbon, nitrogen, and oxygen

(mostly carbon) in the metal. Silicon disappears from the
system by evaporation, largely as silicon monoxide. The hot
cyanonitride is treated with a stream of chlorine causing the
formation and volatilization of zirconium tetrachloride.
The tetrachloride is next purified by resublimation in an
inert atmosphere. This step separates it from contaminating
oxides that, if carried through to the metal, would make it
nonductile. The tetrachloride vapor is passed into a chamber
containing liquid magnesium. Suitable control of conditions
of the reaction leads to recovery of metal sponge rather
than powder, which would be more difficult to handle.
The magnesium chloride by-product is separated from
the metal by melting and draining it off, and residues are
removed by vacuum distillation. The isolated zirconium
sponge is crushed, pressed into bars, and arc melted under
an inert atmosphere. The melt is formed into ingots, whose
quality is evaluated by hardness tests.
5.2.2.8 Van Arkel–de Boer Process. Crude zirconium
metal, too high in oxygen content to be suitable for commer-
cial uses, is placed in a heated vessel containing iodine and an
electrically heated refractory metal wire. The crude metal
reacts with the iodine at a relatively low temperature to form
volatile iodides of zirconium, which are thermolyzed on the
heated wire at about 1300 C depositing zirconium metal and
liberating iodine. The metal is recovered as bright, extremely
pure, metal crystals.
Zirconium is also prepared by reducing its oxide or fluoride
with calcium metal, an excellent reducing agent (118, 119).
5.2.3 Uses
Because of its low thermal neutron absorption cross section
and low radioactivity after radiation exposure, hafnium-free
zirconium is used as cladding for uranium fuel elements in
nuclear reactors. For this purpose, the zirconium must be free
of hafnium, which occurs with it in the mineral, because
hafnium has about 600 times the cross section of thermal
(slow) neutrons of zirconium.
Consumption of zirconium sponge is mainly for military
purposes, but substantial amounts are used in private power
reactors. Zirconia refractories are used by the aluminum,
brass, and glass industries; a small amount is used to prepare
zirconium metal powder. Because it is a powerful deoxidizer
(scavenger), zirconium is used as an additive in iron and steel.
Zirconium compounds are used in the ceramics industry.
Zirconium is used as an amorphous alloy with titanium,
copper, nickel, and beryllium to produce a variety of bulk
metallic glasses that can be cast and machined into useful
components such as gears or even structural uses (120).
Zirconium is also used in the development of reserve
batteries; the heat pellet used in the activation of these
batteries is usually a mixture of zirconium and an oxidant
such as potassium perchlorate. Such batteries have been
TITANIUM, ZIRCONIUM, AND HAFNIUM 443
manufactured for military ordinance for use in rockets,
bombs, missiles, and so on (121). Zirconium is used as an
abrasive either as the fused oxide or in combination with
aluminum oxide (122). It is also used in defluoridating well
water and wastewaters (123).
Zirconium was banned from use in aerosol preparations
of antiperspirants because skin changes were noted in
animal experiments (124). However, it is still used in topical
antiperspirants in the form of aluminum zirconium chlor-
ohydrate preparations that are less toxic (D. R. Miller and
M. Kazel cited in Ref. 75; D. G. Spoerke Jr. cited in
Ref. 124).
Inorganic zirconium compounds have widely varying uses
in the preparation of other zirconium compounds, as
pigments, textile water repellents (carbonate, hydroxide,
tetra- and oxychlorides), catalysts, lubricants, in white
leather tanning (sulfate), and as preservatives (nitrate).
The nitrate is a strong oxidizing agent and constitutes a
dangerous fire and explosive hazard when in contact with
organic combustibles.
Zirconium forms alkoxides with alcohols, for example,
methoxide, ethoxide, isopropoxide, and tertiary butoxide;
however, the thermal stability decreases from primary to
tertiary alkoxide. Zirconium also forms double alkoxides
with some alkali metals, as well as chloroalkoxides from
the chloride. The zirconium alkoxides, zirconium tetra-n-
propylate [23519-77-9], and zirconium tetra-n-butylate
[1071-76-7] are used for cross-linking and hardening isocy-
anate, epoxy, silicon, urea, melamine, and terephthalate
resins. They are also used in the sol–gel process, as catalysts
in condensation reactions, and as water repellents (125).
5.2.4 By-products and Coproducts
Zircon, manazite, staurolite, and xenotime are recovered as
by-products during the processing of heavy-mineral-bearing
sands for ilmenite and rutile in Florida. In Australia and
South Africa, zircon is recovered from mining operations for
titaniferous minerals.
5.2.5 Zirconium Alloys
Zirconium forms two intermetallic compounds with beryl-
lium called beryllides (ZrBe13 [12010-33-2] and ZrBe17).
Beryllides are usually prepared by a solid-state reaction of
the two metals in powdered form at about 1260 C. These
beryllides exhibit excellent oxidation resistance at 1260 C
but not at lower temperatures; however, high strength at
elevated temperature, good thermal conductivity, and low
densities make these beryllides suitable for applications in
high-temperature aerospace technology (126).
Zirconium also combines with boron to form three types of
borides that have metallic characteristics such as high elec-
trical conductivity and positive coefficients of electrical
resistivity. The melting points of these borides are presented
444 BARBARA MALCZEWSKA-TOTH
in Table 13.3; only the zirconium boride 1:12 variety decom-
poses at its melting point.
5.3 Exposure Assessment
Exposures to dust and fume of zirconium and its compounds,
as well as to SiO2, occur during milling and during other uses.
5.3.1 Workplace Methods
The method of choice in the past for determining zirconium
and its compounds was by using atomic absorption spectros-
copy (AAS) (127) because it can quantitatively determine
zirconium in the presence of hafnium, which is impossible by
chemical methods. The ICP method that is particularly suited
for determining the refractory zirconium oxide was also used
in 1974 (128) and is superior to AAS in many ways. Its
advantages are simultaneous, multielement determination at
the ultratrace level on microliter or microgram samples with
minimal interelement effects. For zirconium, the detection
limit is about 0.005 mg/mL, and for hafnium, an invariable
contaminant, about 0.01 mg/mL (128).
However, Method 7300 using inductively coupled argon
plasma atomic emission spectroscopy (ICP-AES) has been
recommended by NIOSH for determining zirconium in air
samples (27). This method has a range of 0.005–2 mg Zr/m3
and a precision for total sampling and analysis of
0.049 mg Zr/m3 s.d. at the TLV of 5 mg Zr/m3, but it is not
without interferences. Spectral interferences are the primary
interferences encountered in ICP-AES analyses. These are
minimized by judicious wavelength selection, interelement
correction factors, and background correction. This method
replaces the earlier method used by NIOSH for trace ele-
ments. Flame atomic absorption spectroscopy (FAAS;
NIOSH Method 7013-7082) is an alternate analytical tech-
nique used for many trace metals (129).
Another method (Method 8005) has been developed by
NIOSH for determining Zr in blood or tissue and also uses the
ICP-AES method (130).
OSHA has also developed an analytic method for deter-
mining Zr using gravimetric analysis as well as an atomic
absorption method (28).
A colorimetric method using a rapid dilution procedure and
alizarin red S has been adopted by the FDA (131) as an official
first action for determining the antiperspirant zirconyl hydro-
xychloride containing aluminum hydroxychloride (132).
Recoveries for zirconium-spiked samples are 99.8%. A
combined morin fluorescence (MF) and energy dispersive
X-ray (EDXA) procedure is useful for screening lung sections
for the presence of antiperspirants containing zirconium and
aluminum. Although MF does not distinguish between zirco-
nium and aluminum, EDXA can confirm the identity of the
two at the MF sites. EDXA, however, is unsuitable for
screening, because of the small mass sampled (ca. 1012 g).
It should be noted in passing that the Talvitie method (133)
for silica (SiO2) does not distinguish SiO2 from ZrO2.
Modifications have been made in the Bricker–Waterbury
colorimetric method to adapt it to routine analyses of zirco-
nium in air for samples of 1–10 mg Zr (127), but zirconium
cannot be determined in urine by this method unless it is first
isolated.
5.3.2 Community Methods
An early study of Greek lignites and power plant ashes had
shown the presence of trace metals. Another study was
conducted to determine the amount of trace metals, including
zirconium. Instrumental neutron activation analysis (INAA)
was used to determine the trace metal content. The amount of
zirconium in wet bottom ash dried at 106 C, in inlet and
outlet fly ash, and in fly ash from the electrostatic precipitator
ranged from 175.6 to 248.9 ppm. The content of zirconium in
these fly ashes was approximately 200 times the content of 28
other trace metals. The only trace metal that was also high
was strontium that ranged from 176.7 to 589 ppm. Similarly,
in another power plant, the content of zirconium in the fly ash
(wet, inlet, and electrostatic precipitator) ranged from 195.6
to 291.1 ppm (134).
A study that focused on determining trace element con-
centrations in total suspended particulate by instrumental
neutron activation analysis in two different areas in north-
eastern Spain (a rural area influenced by the emissions of a
large coal-fired power station and the urban and industrial
areas of Castellon) was described in 1997. Total suspended
particulate was sampled by standard medium volume captor
(MVC) high- and medium-volume captors, using cellulose
membrane filters of 0.8 and 0.45 mm pore size. Preliminary
research was performed on the homogeneous distribution of
elements in the sample filters and on the study of blank filters
for calculating the background average element contents.
The results obtained allowed distinguishing different major
anthropogenic sources of trace elements in the atmosphere at
the sampling sites: (1) Zr, Hf, Sc, U, and Th were related to
atmospheric pollution derived from the ceramic industry of
the Castellon area; (2) As, Cr, Cs, Rb, Sb, Se, and Zn were
related to traffic and other industrial emission in the Castellon
area, and (3) As, Cr, Sb, and Zn were related to power
generation emissions in the rural area (135).
Theaccumulationofzirconium(Zr)as(Zr4(OH)8(H2O)16)8þ
by cyanobacteria and microalgae was characterized. In all of
the cyanobacteria and microalgal species examined, accu-
mulation consisted of a single rapid energy-independent
phase (“biosorption”), and no energy-dependent accumula-
tion was observed. Biosorption of Zr was concentration
dependent, followed a Freundlich adsorption isotherm,
depended on pH, and showed decreased accumulation
with decreased pH. Prior treatment with Naþ, Kþ, Csþ,
Ca2þ, Mg2þ, and Sr2þ (added as chlorides) also decreased Zr

accumulation by cyanobacteria and microalgae, probably a
result of competition between Zr ions and other cations,
including Hþ, for available binding sites on the cell walls.
Zirconium desorption from microalgae and cyanobacteria
was increased by increasing external cation concentrations
or by decreasing the pH of the desorption agent (136).
In 1993, inductively coupled plasma atomic emission
spectroscopy was used to determine a number of toxic
heavy metals and other pollutants in the aquatic environment
of the El Manzala area (137). Mean values and standard
deviations were tabulated for lead, cobalt, copper, chromium,
cadmium, zinc, zirconium, and strontium determinations in
three different zones that represented the whole area. The
results indicated a several-fold increase compared to those
reported for other surface waters in Egypt or in the Mediter-
ranean Sea. Peak values occurred toward the north part of the
lake, west of Port Said city (Egypt). Zinc and cadmium
concentrations were extremely low. Continual monitoring
control of pollutants in surface waters and primary treatment
of waste effluents on the waste generation sites were recom-
mended by the researchers (137).
5.3.3 Biomonitoring/Biomarkers
Very little information exists on the metabolism of zirconium
chiefly because zirconium compounds are mostly insoluble
and thus very poorly absorbed from their deposition site from
either oral or inhalation routes. Similarly, though the water-
insoluble basic carbonate is soluble in stomach acids, it is
likewise theoretically converted to an insoluble colloidal
form in the gastrointestinal tract.
Until the mid-1970s, there was little information available
on normal zirconium values in either the environment or
animal tissues, presumably because of the analytic difficulties
encountered with the highly refractory ZrO2 (128). Scattered
data on zirconium were obtained by spark source mass
spectrometry in a few inorganic and human biological tissues
and fluids. A sample of crocidolite asbestos had 0.90 ppm Zr,
whereas a sample of chrysotile asbestos (origins unknown)
had twice that concentration and a cement sample had
9.0 ppm Zr. The zirconium content of bituminous coal sam-
ples varied widely from 16 to 270 ppm from two different
Pennsylvania mines, and 29 ppm in a coal sample from a Utah
mine. Just as zirconium values ranged widely in coal dust,
zirconium concentrations in coal miners’ lungs ranged from
1.0 ppm in a normal functioning miner’s lung to 3.8 ppm in a
lightly pigmented section of a lung and 14 ppm in a heavily
pigmented section. A lung of a male nonminer had 3.6 ppm,
and that of a female resident near mining operations had
1.5 ppm. Pulmonary lymph nodes of miners had concentra-
tions as high as 22 ppm Zr, indicating phagocytosis of the
zirconium-bearing particles. Two samples of coal miners’
blood had Zr values of 0.3 and 10 mg/100 g, and urine values
were 3 and 12 mg/L (20).
TITANIUM, ZIRCONIUM, AND HAFNIUM 445
5.4 Toxic Effects
Binary alloys of zirconium with antimony, beryllium, boron,
niobium, gallium, indium, nickel, silver, thorium, titanium,
uranium, and zinc, and ternary alloys with iron and tin,
tantalum and niobium, silicon and boron, and copper and
chromium were prepared and physical characteristics (melt-
ing point, thermal conductivity, electrical resistance, etc.)
were studied (115).
5.4.1 Experimental Studies
Oral toxicity of zirconium is considered low in laboratory
animals and inhalation studies resulted in limited toxicity.
5.4.2 Human Experience
5.4.2.1 Clinical Cases. Despite suspicion that inhalation
of zirconium could cause human pulmonary disease, docu-
mentation of zirconium pneumoconiosis in humans has been
lacking. Bartter et al. (138) studied a likely case of zirconium
compound-induced (unspecified) pulmonary fibrosis. Their
diagnosis was based on the following: (1) a history of a
gradual increase in symptoms and slowly progressing pul-
monary fibrosis identified by chest roentgenograms compat-
ible with pneumoconiosis; (2) an appropriate history of
exposure and a latency period of about 15 years before the
onset of dyspnea and of roentgenographic changes; (3) an
analysis of open-lung biopsy material revealing end-stage
fibrosis and honeycombing, a moderate number of birefrin-
gent particles, and extremely high levels of a variety of
zirconium compounds; and (4) no other potential cause of
fibrosis. Bartter et al. (138) concluded that zirconium should
be considered a likely cause of pneumoconiosis and that
appropriate precautions should be taken to limit exposures in
the workplace.
The new and unique clinical entity of zirconium granu-
lomas of allergic epithelioid origin in humans, first
described by Rubin et al. in 1956 (139), has since been
reported repeatedly, both clinically (140) and experimen-
tally (141–144). Grossly, they consist of dusky, reddish
brown, discrete papules 1–4 mm in diameter, closely set in
the domes of the axillae, and sparsely at the periphery.
Histologically, they are granulomas composed of epitheli-
oid cells and Langerhans giant cells surrounded by lym-
phocytes in a typical tuberculoid pattern. Problems also
arose from the use of a deodorant containing an organic
zirconium salt, commonly NaZr lactate. Removal of the
sensitizing zirconium salt resulted in healing.
Pulmonary granuloma in zirconium workers has been
reported; however, the reports do not specify whether it
was due to zirconium metal or a specific compound of
zirconium (145). In addition, dermal granulomatous lesions,
probably of allergic epithelioid origin, have been observed
446 BARBARA MALCZEWSKA-TOTH

following the use of deodorant sticks and poison ivy lotions 5.6 Studies on Environmental Impact
containing zirconium; the latter chemical may have been
In the city of Esslingen (Baden-Wurttemberg, southwest
used as a compound and not as the metal per se.
Germany), the outer bark layers of Aesculus hippocastanum
Two case reports pertaining to zirconium-related inter-
trees were analyzed by X-ray fluorescence analysis in
stitial lung disease were presented. The first case was a
1988–1989 for the contents of various trace elements.
49-year-old male admitted to the hospital with suspected
Because of its physical and biochemical properties, tree
pneumoconiosis. He had been employed at a refractory
bark retains and accumulates high amounts of diverse pollu-
brick production factory for 28 years since age 20 and
tants. In this study, the stem bark of horse chestnut showed
had worked on furnaces and on refractory lining production.
elevated levels of nickel, selenium, iron, titanium, and zir-
(Zirconium compounds have been found in foundry sands,
conium presumably due to automobile exhausts and abrasion
refractory brick, abrasives, and ceramics.) Chest X-rays
of wearing (151).
revealed diffuse bilateral opacities. Neutron activation
Trace elements, including Zr, have been determined in
analysis (NAA) of particles showed Zr levels of 715 ppm.
seaweed samples by inductively coupled plasma atomic
Histological study of biopsy tissue showed fibrosis and
emission spectrometry (AES). The results obtained by quad-
hyperplasia and weakly birefringent particles in alveolar
rupole (Q)-ICP-MS after acid digestion agreed well with
and interstitial histiocytes (146).
certified reference and reported values (152).
The second case was a 29-year-old male who had
Using bioassays on bacteria (Photobacterium phosphor-
worked as a coremaker in a foundry for 8 years. He
eum), microscopic algae (Selenastrum capricornutum),
was admitted for suspected pneumoconiosis. X-rays
and fish (Salmo gairdneri), a study confirmed the hypoth-
showed diffuse opacities, and histology revealed granulo-
esis that Zr has low toxicity. According to the author, the
mas and birefringent particles in histiocytes. NAA showed
toxic effects noted by the Microtox test may have
that Zr levels in a lung biopsy were less than 5 ppm. The
been attributed to pH rather than specifically to Zr
authors concluded that even though it was not possible to
(5 min EC50 . 4.3 mg/L). Fish assays also confirmed
definitely confirm that Zr exposure produced the lung
the low toxicity of Zr (96 h LC50 . 20 mg/L; 96 h minimal
disease in these patients, it seemed to be the most likely
stress concentration was . 20 mg/L). Mutagenicity (fluc-
cause (146).
tuation test) and genotoxicity (SOS chromotest) assays
failed to show any DNA-related effects linked to this
5.4.2.1.1 Chronic and subchronic toxicity. There are very
metal. Only the algal assays (ATP energy stress) demon-
few studies conducted to determine the chronic and sub-
strated genuine toxicity at Zr concentrations between 1.3
chronic adverse effects of zirconium in the workplace.
and 2.5 mg/L (153).
A study of 22 workers exposed to fumes during the
zirconium reduction process for 1–5 years revealed no
striking abnormalities referable to zirconium exposure (147). 6.0 Zirconium Tetrachloride
Also, 32 male hand finishers of zirconium metal reactor
components who had worked for 1–17 years in that job 6.0.1 CAS Number
showed no significant differences from the control [10026-11-6]
group (148).
6.0.2 Synonyms
5.5 Standards, Regulations, or Guidelines of Exposure
Zirconium chloride, tetra-; tetrachlorozirconium; zirconium
A TLV for exposure to zirconium compounds was set by the chloride (ZrCl4); zirconium(IV) chloride (1:4); zirconium
ACGIH in 1959 on the basis of a no-effect level of ZrO2 dust chloride (T-4); zirconium(IV) chloride; zirconium chloride,
and ZrCl4 mist, as well as the recognized low toxicity of 99.9%
zirconium compounds by routes normally experienced in
industrial situations (149). A TLV-TWA has been developed 6.0.3 Trade Names
by ACGIH (92). NIOSH has a REL of 5 mg/m3 as Zr and a
STEL value of 10 mg/m3 (93). NA
OSHA adopted the 1968 ACGIH TLV as an 8 h time-
weighted average (TWA) that has subsequently been adopted 6.0.4 Molecular Weight
by Finland, West Germany, and Italy. As of June 2005, the
233.02
OSHA TWA has remained at 5 mg/m3 (91). The former
Soviet Union adopted a MAK of 6 mg/m3 for zirconium
6.0.5 Molecular Formula
metal and its insoluble compounds, the dioxide, and carbide,
and 1 mg/m3 for fluorozirconate (150). Cl4Zr

6.0.6 Molecular Structure
Cl–
Cl– Zr4+ Cl–
Cl–
6.1 Chemical and Physical Properties
Zirconium tetrachloride forms lustrous, white, monoclinic
crystals that melt at 437 C. It is a corrosive powder. It is
hygroscopic, and thus soluble in cold water, alcohol, ether,
and concentrated hydrochloric acid. It reacts vigorously with
water forming hydrogen chloride (irritating vapor) and zir-
conium oxychloride. When moist, zirconium tetrachloride
reacts with common materials to form hydrochloric acid that
is corrosive to many metals. Through hydrolysis to HCl,
zirconium tetrachloride can irritate the respiratory tract and
other superficial surfaces of the body on exposure (150).
Zirconium tetrachloride readily forms coordinate bonds with
oxygen and nitrogen in organic molecules. When heated to
decomposition, it emits fumes of hydrogen chloride (154).
Some physical properties of zirconium tetrachloride are
presented in Table 13.3.
6.2 Toxic Effects
6.2.1 Chronic and Subchronic Toxicity
Inhalation of ZrCl4 mist at an airborne concentration of 6 mg
of Zr/m3 was perceptibly toxic after a 2-month exposure, as
shown by slight decreases in hemoglobin and erythrocyte
count in dogs. There was some increase in mortality over that
of controls. Apparently, the toxicity of zirconium compounds
is not altered by the low percentage of hafnium normally
present in zirconium compounds. However, zirconium oxide
dust and ZrCl4 mist inhaled at respirable particle sizes for 1
year at 3.5 mg of Zr/m3 failed to have any adverse effect on
laboratory animals (155, 156).
6.2.2 Pharmacokinetics, Metabolism, and Mechanisms
6.2.2.1 Distribution. Tracer studies of oral absorption of
89
ZrC l4 with the stable chloride as carrier show that less than
0.001% of the dose passes from the gastrointestinal tract to
the bloodstream (157).
6.2.3 Other: Neurological, Pulmonary, and Skin
Sensitization
The contact sensitization capacities of four metal salts, nickel
sulfate (NiSO4), potassium dichromate (K2Cr2O7), titanium
chloride (TiCl4), and zirconium chloride (ZrCl4), were eval-
uated using guinea pigs and mice. In the guinea pig sensiti-
zation tests, an injection concentration of 1% was set up for
all chemicals, and the challenge concentration was changed.
TITANIUM, ZIRCONIUM, AND HAFNIUM 447
Guinea pigs were sensitized with NiSO4, K2Cr2O7, and
TiCl4. Among the test metal salts, K2Cr2O7 showed the
highest sensitization rate and strongest skin reactions.
ZrCl4 did not cause any sensitization responses under
experimental conditions. The minimum challenge concen-
tration to cause a skin response was ,0.25% for K2Cr2O7,
0.5% for NiSO4, and 2% for TiCl4, respectively. A sensi-
tive mouse lymph node assay (SLNA) also showed that
NiSO4 and K2Cr2O7 were sensitizers. In the SLNA, TiCl4
as well as ZrCl4 caused mild lymph node responses but
were classified as nonsensitizers. According to the
researchers of the study, the order of sensitization potential
was K2Cr2O7 . NiSO4 . TiCl4 . ZrCl4. The NiSO4-
and K2Cr2O7-sensitized animals did not show any reac-
tions to ZrCl4 and TiCl4. No cross-reaction among these
metal salts was found (158).
6.3 Standards, Regulations, or Guidelines of Exposure
NIOSH has not recommended an exposure limit for
zirconium tetrachloride but believes that the 5 mg/m3 as
that TWA mandated by OSHA is adequate (91, 93). A
TLV-TWA has been developed by ACGIH (92).
7.0 Zirconium Dioxide
7.0.1 CAS Number
[1314-23-4]
7.0.2 Synonyms
Zirconia; zirconium oxide; ZrO2; zirconic anhydride; zirco-
nium(IV) oxide; zirconium(IV) oxide, calcined; zirconium
oxide, 99%
7.0.3 Trade Names
NA
7.0.4 Molecular Weight
123.22
7.0.5 Molecular Formula
O2Zr
7.0.6 Molecular Structure
O¼Zr¼O
7.1 Chemical and Physical Properties
Zirconium dioxide is a white, amorphous powder, insoluble
in water but slightly soluble in acid. Some of its properties are
448 BARBARA MALCZEWSKA-TOTH

Table 13.5. The Supply/Demand for Zirconia (Zirconium Oxide) in Metric Tons for 1991 and 1994a
United States Western Europe Japan Totalb
1991 1994 1991 1994 1991 1994 1991 1994
c
Number of producers 5 5 5 4 9 9 19 18
Production 9747 12,100 4100 4400 6750 6280 19,850 22,780
Importsd 1536 2404 6100 nae 650 900 8286 nae
Exportsf 1495 1222 300 nae 718 nae 3213 nae
Consumption 9788 13,282 9,845 10,175 7400 7190 23,421 30,641
a
Adapted from Chemical Economics Handbook, SRI International, Menlo Park, CA, August 1996.
b
Totals may not equal the sums of categories because of rounding.
c
Data for the United States and Western Europe do not include producers of zirconia metal and reprocessors of baddeleyite. Data for Japan include manufactured
zirconia producers that use baddeleyite as a raw material.
d
Data for the United States and Western Europe include baddeleyite but not for Japan.
e
Japan’s export figures include germanium oxide that represents less than 5% of total volume.
f
Not available.

presented in Table 13.3. The supply and demand for zirconia
for 1991 and 1994 are presented in Table 13.5.
7.2 Uses
Zirconia (ZrO2) has been used as a reflective surface agent
on satellites. Zirconia is also used as a supporting substrate
for high-performance liquid chromatography (HPLC) anal-
yses because it is a stable substrate and resists dissolution
from pH 0 to 14, does not shrink or swell in any chromato-
graphically interesting solvent or ionic strength, and does
not further sinter and thus lose pore volume or structure
upon heating to 800–900 C. Thus, it is effective for sepa-
rating low molecular weight species, especially those that
are health hazards in the agrochemical workplace, including
insecticides, herbicides, and their metabolites.
7.3 Toxic Effects
7.3.1 Chronic and Subchronic Toxicity
The toxicity of ZrO2 dust by inhalation is of a very low order;
neither 75 mg of Zr/m3 inhaled by laboratory animals daily
for 1 month nor 11 mg of Zr/m3 for 2 months produced any
significant alterations in growth rate, mortality, hematologi-
cal values, biochemical constituents, or morphological struc-
tures of the respiratory system (159).
A comparative determination of the fibrogenicity of two
novel mineral fibers, zirconia (ZrO2) and alumina (Al2O3),
under the trade names of Saffil zirconia and Saffil alumina
(ICI Ind. Ltd.), showed that when the two fiber types were
injected intraperitoneally into rats, (1) the deposition of
connective tissue containing collagen around zirconia was
considerably less than that around alumina and (2) Saffil
zirconia was eliminated more readily than Saffil alumina and
was seen more frequently in the lungs and lymph
nodes (160).
7.3.2 Pharmacokinetics, Metabolism, and Mechanisms
7.3.2.1 Distribution. Deposition and retention of zirco-
nium in the lung and pulmonary lymph nodes following
inhalation of ZrO2 dust are typical of that of an insoluble
substance (161); however, deposition of the soluble ZrOCl2
in the lung following inhalation of the ZrCl4 mist was equally
great and showed a similar distribution in other body tissues,
in keeping with the theoretical formation of an insoluble
colloidal complex mentioned earlier. However, zirconium
deposition in the bone was less than 1% of that in the lung,
and the soft tissue content was a fraction of that in bone.
Overall, the retention of zirconium in all tissues of the rat was
high; little, if any, decrease in deposited zirconium occurred
in 6 months.
7.3.3 Carcinogenesis
To simulate the chronic alpha radiation of Thorotrast, the
liver of female Wistar rats was exposed to fractionated
neutron irradiation at 14-day intervals (0.2 Gy per fraction)
over 2 years to a total dose of 10.0 Gy. Before the start of
irradiation, half of the animals received 120 mL of nonra-
dioactive Zirconotrast (ZrO2), which is comparable to
Thorotrast in all other physical and chemical properties.
The first liver tumor was detected 1 year after the begin-
ning of irradiation. At the end of the life span study, the
incidence of irradiated animals with liver tumors was about
40%. In the animals treated additionally with ZrO2, the
incidence, time of onset, and overall number of liver
tumors were nearly equal, indicating that the fractionated
neutron irradiation was the exclusive cause of tumor
development. The lifelong-deposited ZrO2 colloid had
no influence on tumor induction or development. Histo-
logical types of benign and malignant liver tumors seen in
this study were the same as those seen in animals treated
with Thorotrast (162).
 TITANIUM, ZIRCONIUM, AND HAFNIUM 449

The foreign body tumorigenic potentials of alkyl-alpha- matic glycation, or in the fluorescence intensity, as indicated
cyanoacrylate (cyanoacrylate), zirconia, polyvinyl chlo- by the late stage, because the tumor had low values relative to
ride (PVC), silicone, and cellulose were studied in those for the capsule collagens. The results confirmed the
rats (163). Silicone, cellulose, polyvinyl chloride, zirconia, biochemical characteristics of fibril collagen surrounding the
and alkyl-alpha-cyanoacrylate were implanted into the implanted material. These characteristics of collagen in
subcutaneous tissue of female Fisher 344 rats. The animals capsules and tumors may be related to the production and
were observed weekly for subcutaneous tumor develop- progression of the tumor (164).
ment. Tumor-bearing rats were killed 741 days after
implantation, and the tumors were removed and examined 7.3.4 Human Experience
by electron microscopy and immunohistochemical techni-
7.3.4.1 Chronic and Subchronic Toxicity. A case of pul-
ques. Tumors classified as malignant fibrous histiocytomas
monary fibrosis was described that was likely to have been
were induced in 27.3%, 54.5%, 100%, and 63.6% of rats by
caused by exposure to zirconium dioxide. The victim was a
silicone rubber, polyvinyl chloride, zirconia, and alkyl-
62-year-old man with a chief complaint of dyspnea that had
alpha-cyanoacrylate, respectively, but not by cellulose.
been increasing gradually during the preceding 25 years,
Almost all tumors were composed of a mixture of cells
even though he had stopped smoking cigarettes. He started
that resembled fibroblasts with numerous rough-surfaced
working at age 24 in the lens grinding department of an
endoplasmic reticulum and Golgi apparatus, histiocytes
optical company and continued to work there for 39 years.
characterized by developed endoplasmic reticulum and
His work involved grinding, polishing, pitting, and blocking
abundant lysosomes, myofibroblasts characterized by the
of lenses. In this capacity, he had been exposed to a variety of
presence of both myofibrils and fibroblast-like structures,
compounds. He had not worn any respiratory protection at
and immature mesenchymal cells. In some tumors, the
work. His greatest dust exposure occurred during blocking
cells exhibited a storiform pattern. Some tumor cells were
operations that involved the use of talc powder and mixing
positively stained by ED2 or antimuscle actin antibody. All
dry Zirox-B powder with water. Zirox-B contained 90%
tumors were limited to the implantation sites. No metasta-
zirconium as zirconium oxide and 10% respirable quartz.
ses were observed. The features of induced tumors in rats
Analysis of lung tissue revealed markedly elevated quantities
were consistent with those of human malignant fibrous
of a variety of zirconium compounds. The authors concluded
histiocytoma. A rat malignant fibrous histiocytoma trans-
that zirconium was a possible cause of pulmonary fibrosis
planted into the subcutaneous tissue of the syngeneic
and recommended that appropriate precautions be taken in
female Fisher 344 rats grew and metastasized to the
the workplace wherever and whenever workers are exposed
lungs (163).
to zirconium (138). However, the researchers have not taken
Biochemical investigations were made into changes in
into consideration the exposure of the worker to respirable
tumors induced by subcutaneous implantation of disks of
quartz that is known to cause fibrosis and that was present in
lanthanum and zirconium oxide containing hydroxyapatites.
Zirox-B to the extent of 10%.
Fibril collagen from tumor tissues was compared with fibrous
capsules formed around discs of various apatites, based on
cross-links and types. The amount of collagen in the tumor as 7.4 Standards, Regulations, or Guidelines of Exposure
hydroxyproline was less than that in the capsules. Further-
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
more, the collagen in the tumor could be solubilized by
10 mg/m3 (93). As of June 2005, the OSHA TWA has
pepsin digestion. Although there was no qualitative differ-
remained at 5 mg/m3 (91). ATWL-TWA has been developed
ence in the hydroxylation ratio of proline among tissue
by ACGIH (92).
collagens, the hydroxylation ratio of lysine in the tumor
collagen was higher than that in the capsule collagens.
Various methods for analyzing the type of pepsin-solubilized 8.0a Zirconium Sulfate
collagen, including differential salt precipitation, amino acid
8.0.1a CAS Number
analysis, and SDS-PAGE, revealed that tumor collagen con-
sisted mainly of type I and small amounts of types III and V. [14644-61-2]
Although the capsule collagens included types I and III, type
V was not present. Cross-linking in the insoluble collagen 8.0.2a Synonyms
was investigated using three different methods: modified
Zirconium tetrasulfate; zirconium sulfate; sulfuric acid,
amino acid analysis, HPLC, and fluorescence analysis.
zirconium(4þ) salt (2:1)
The tumor collagen contained considerable pyridinoline
and histidinoalanine as nonreducible cross-links. No differ-
8.0.3a Trade Names
ence was seen among tumor and capsule collagens in the
furosine level, as indicated by the early stage of nonenzy- NA
450 BARBARA MALCZEWSKA-TOTH

8.0.4a Molecular Weight delayed hypersensitivity and the production of T-cell-medi-

ated immunologic granulomas by these metals in vivo (165).
283.3
8.2.1.1 Chronic and Subchronic Toxicity. Zr(SO4)2 was
8.0.5a Molecular Formula administered at a level of 5 ppm in drinking water in lifetime
O8S2Zr studies of rats. The diet contained an additional 2.66 ppm of
an unknown Zr moiety. No evidence was found of any
biological or toxicological activity of zirconium, except to
8.0.6a Molecular Structure
affect inconsistently the body weight of older animals. There
was also no evidence that zirconium was tumorigenic in a rat
O
– strain (Long–Evans) with appreciable (20%) tumor inci-
– –
–O – S – O
– dence. The researchers (166) also found that zirconocene
O– was nontumorigenic in C57 BL mice.
Zr4+
O– After exposing several hundred Long–Evans rats to drink-
– –

O–
– S – O– ing water containing 5 ppm Zr(SO4)2 for a lifetime, Schroe-
–

O der et al. (167) could find no analytic evidence by a

spectrophotometric method using chloranilic acid that zirco-
nium was consistently absorbed from the gastrointestinal
8.0b Zirconium Sulfate, Tetrahydrate tract; indeed, the zirconium concentration in the male rat
kidney was less than that of controls whose diet, like that
8.0.1b CAS Number of the treated, contained 2.66 ppm Zr. The liver and lung
[7446-31-3] showed a slight increase of 0.7% and 1%, respectively, over
that of controls; the heart and spleen showed increases of
8.0.2b Synonyms 9.4% and 32%, and an average deposition in the five tissues of
9.9%. Females that had an average tissue distribution of only
Zirconium tetrasulfate4H2O; zirconium sulfate tetrahydrate 2.6% showed the striking difference of 2.4% less zirconium
in the spleen than in the controls (167).
8.0.3b Trade Names
NA 8.2.1.2 Genetic and Related Cellular Effects Studies. In
the literature, two elements, beryllium and zirconium, have
been described as inducing identical tissue lesions consisting
8.0.4b Molecular Weight
of immune-mediated granulomas. Intracellular lesions
355.41 induced by beryllium sulfate have been studied previously.
Injection of low doses of zirconium sulfate showed that the
8.0.5b Molecular Formula intracellular concentration sites are very different between
the two elements and zirconium was uniquely localized in the
O12S2ZrH8
lysosomes of the lymph node macrophages and associated
with phosphorus (168).
8.1 Chemical and Physical Properties Both beryllium and zirconium salts, BeSO4 and Zr(SO4)2,
exerted a concentration-dependent stimulation of mouse
Zirconium sulfate forms white, tetrahedral crystals. It is very
spleen cell proliferation, as measured by an increase in
soluble in water. Some of the properties of zirconium sulfate
(3 H )thymidine incorporation into lymphocyte DNA,
are presented in Table 13.3.
although the maximal response (four- to fivefold at
100–200 mM) induced by Zr(SO4)2 was greater than that
8.2 Toxic Effects by BeSO4 (two- to threefold at 1–5 mM). Preincubation of
splenocytes with low concentrations of BeSO4 (,1 mM) or a
8.2.1 Experimental Studies
broad range of Zr(SO4)2 concentrations (2–100 mM) also
The formation of immune-mediated granulomas has previ- assisted subsequent lectin (concanavalin A; ConA)-mediated
ously been reported with beryllium exposure. It is interest- lymphocyte proliferation. The results indicated that, at
ing to note that the in vitro results on mouse splenocytes defined concentrations, Be and Zr salts can both act as
indicate that BeSO4 and Zr(SO4)2 can act as lymphocyte lymphocyte mitogens and augment the functional responsive-
mitogens, as well as to augment the functional responsive- ness of immune cells, which may help explain the character-
ness of B-cell-mediated immune cells. This may help to istic induction of delayed hypersensitivity and production of
explain the characteristic induction of T-cell-mediated immunologic granulomas by these metals in vivo (165).
 TITANIUM, ZIRCONIUM, AND HAFNIUM 451

8.3 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
9.0a Zirconium Oxychloride
9.0.1a CAS Number
zirconium oxide (ZrO2) at 250 C. It is also formed as the
octahydrate [13520-92-8] as white, tetrahedral crystals that
are very soluble in water, ethyl alcohol, ether, and methanol,
among others, but only slightly soluble in hydrochloric acid.
When heated to decomposition, it emits toxic fumes of
hydrogen chloride. Some physical properties are presented
in Table 13.3.
9.2 Toxic Effects

[7699-43-6] 9.2.1 Chronic and Subchronic Toxicity

Schroeder and Nason (156) called attention to a little appre-
9.0.2a Synonyms ciated fact, namely, the way in which nonessential metals, in
Chlorozirconyl; basic zirconium chloride; dichlorooxozir- this case zirconium, interact with essential trace metals in the
conium; zirconium chloride oxide; zirconium chloride oxide body to change the normal concentrations of essential metals
(ZrCl2O); zirconium chloride, basic; zirconium oxide in the body’s various organs. At 5 ppm, zirconium, as a
chloride; zirconium oxydichloride; zirconium, dichlor- simple salt (presumably the oxychloride) in the drinking
ooxo-; zirconyl chloride; zirconyl oxide (ZrOCl2). water of rats for their lifetime, caused a reduction of the
chromium concentration, an element in short supply in aging
mammals. The physiological significance of these changes
9.0.3a Trade Names:
for overall body functioning in health and disease and in toxic
NA states is yet to be discerned.
The effect of zirconium (Zr) on the humoral immune
9.0.4a Molecular Weight response was studied by measuring the level of IgM
plaque-forming cells (IgM-PFCs) against sheep red
178.13 blood cells (SRBCs) in the spleen of C57BL mice intra-
peritoneally injected with zirconium oxychloride. Two
9.0.5a Molecular Formula experiments were carried out: (1) a single injection of
Cl2OZr zirconium oxychloride of 1/5, 1/10, 1/50, and 1/100 of the
LD50 for intraperitoneal injection and (2) continuous
injection of 1/20, 1/40, and 1/80 of the LD50 every
9.0.6a Molecular Structure
other day for 2 or 4 weeks in mice. In the case of a single
injection, zirconium oxychloride was intraperitoneally
O
injected on days 1, 0, þ1, þ2, and þ3 in relation to
Zr
Cl Cl SRBC immunization. The following conclusions were
drawn by the author from this study: (1) Zr has an adjuvant-
like activity in relation to the humoral immune response, at
9.0b Zirconium Oxychloride, Octahydrate least to IgM antibody production; (2) this effect was recog-
nized with a single injection with Zr and also after continuous
9.0.1b CAS Number
injection; (3) a single injection of Zr was more effective when
[13520-92-8] the mice were treated with Zr 24 h before or after SRBC
immunization; and (4) a lower dose (1/50, 1/100 of the LD50
9.0.2b Synonym for a single injection, and 1/40, 1/80 of the LD50 for continu-
ous injection) led to a more enhanced level of IgM-PFCs than
Zirconium chloride, basic, aqueous soln. carc. a higher dose (1/5, 1/10 of the LD50 for a single injection, and
1/20 of the LD50 for continuous injection) (169).
9.1 Chemical and Physical Properties
9.2.2 Pharmacokinetics, Metabolism, and Mechanisms
9.1.1 General
9.2.2.1 Absorption. A study (170) of pharmacological
Zirconium oxychloride exists as white silky crystals, soluble actions of pure zirconyl chloride (ZrOCl2) on smooth and
in water and alcohol. With water, the octahydrate is formed striated muscle in rabbits and cats indicated that the normal
as tetragonal white needles. It is extremely hygroscopic peristaltic action in rabbits slowed at 1 mM concentration,
and decomposes to zirconium tetrachloride (ZrCl4) and but the effect was less noticeable in cats. The change was
452 BARBARA MALCZEWSKA-TOTH
reversible on washing with Ringer’s solution. ZrOCl2 at
0.006 mM concentration shortened the amplitude of
the contraction of the rabbit heart auricle and ventricle
and constricted the coronary arteries. The latter effect
appeared irreversible. No effect on blood pressure, however,
was noted below 1 mol% concentration of ZrOCl2 in injected
rabbits and 3–7 mol% was required to lower the blood
pressure appreciably. No electrocardiographic changes
were noted (170).
9.2.3 Genetic and Related Cellular Effects Studies
Zirconium oxychloride was administered as a single oral
dose to Swiss albino mice corresponding to 1/2, 1/6, and 1/20
of the LD50 values. Bone marrow cells were screened after 6,
12, and 24 h for chromosomal aberrations following an air-
drying-Giemsa schedule. The frequency of chromosomal
breaks and aberrations induced increased at a rate directly
proportional to the concentration used. The increase was also
related to the period after exposure, though to a lesser extent
than the concentration used. There was no direct relationship
to the sex of the animal (171).
The effect of a single oral exposure to different concentra-
tions of zirconium oxychloride was studied on bone marrow
cell chromosomes of Swiss albino mice. The mice were
sacrificed 24 h after exposure. Dose levels of 2250 or
750 mg/kg in males and 2200 or 734 mg/kg in females
increased the mitotic frequency compared to control mice.
Mitotic frequency was not enhanced appreciably by the lowest
dose used, 225 mg/kg for males and 220 mg/kg for females.
These findings indicated that the metal may not stimulate
division in lymphocytes at concentrations below 220 mg/kg.
These single-dose exposures significantly enhanced the fre-
quency of aberrant metaphases. The percentages of total
abnormalities increased in both sexes at all concentrations.
The degree of increase was directly related to the con-
centration used. In general, the abnormalities produced
were relatively higher in females than in males. The authors
indicated that this is the first report of the clastogenicity of
zirconium (172).
The interaction between two group IV metals, highly toxic
lead and relatively inactive and low toxicity zirconium, was
studied in the bone marrow chromosomes of mice in vivo.
Low and high doses of zirconium oxychloride were fed orally
to the experimental mice (1) 2 h before, (2) 2 h after, or (3)
together with different doses of lead nitrate. Protection
against lead-induced clastogenicity was observed only
when the lower dose of zirconium was administered before
lead. All other combinations gave an additive or synergistic
effect as seen by significant increases in the frequencies of
chromosomal aberrations (173).
The viability and DNA synthesis in cultured spleen cells
from C57BL mice were studied in vitro (174). An 80–400 mM
concentration of zirconium oxychloride decreased the viability
of spleen cells. On the other hand, with zirconium dioxide
and zirconium sulfate, there was no change in viability at
1–400 mM. The degree of DNA synthesis in spleen cells
treated with zirconium dioxide or zirconium sulfate was no
different from controls. Zirconium oxychloride enhanced
DNA synthesis at 1–20 mM concentrations, but inhibited it
at 40–400 mM. These studies showed that the effect of
zirconium on the cytotoxicity of mouse cells depends
upon the solubility of zirconium salts. Zirconium oxychlor-
ide was also weakly mitogenic for lymphocytes at 1–20 mM
concentrations (174).
9.2.4 Human Experience
9.2.4.1 Acute Toxicity. Acute poisoning from ingestion
of Zr oxychloride resulted in the following symptoms:
burning pain in the mouth and throat, vomiting, watery or
bloody diarrhea, tenesmus, retching, hemolysis, hematuria,
anuria, liver damage with jaundice, convulsions, hypoten-
sion, and collapse (175). Through its hydrolysis to hydro-
chloric acid, zirconium oxychloride can irritate the
respiratory tract and other superficial surfaces of the
body on exposure (150).
9.2.4.2 Genetic and Related Cellular Effects Studies. The
addition of different concentrations of aqueous zirconium
oxychloride solution to human peripheral blood leukocyte
cultures obtained from healthy donors increased the fre-
quency of chromosomal aberrations in cells compared
with untreated controls. The degree of enhancement of
aberrations and sister chromatid exchanges was directly
related to the concentrations used. The most common aber-
rations were chromatid breaks (176).
9.3 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
9.4 Studies on Environmental Impact
The swimming rate of Tetrahymena pyriformis strain HSM
was measured by stroboscopic photography, in aqueous
solutions of each of three metallic substances: Se as selenous
acid, V as vanadyl sulfate, and Zr as zirconyl chloride. The
swimming rate was measured over 45 min periods, moni-
tored every 15 min, in concentrations of each metal, singly, at
0, 5, 10, 20, 30, and 50 ppm. A significant decrease in
swimming rate was recorded for each metal at concentrations
of 20 ppm or more. The method provided a useful bioassay to
determine the presence of pollutants in freshwater quickly
and easily (177).

10.0 Zirconium Silicate
10.0.1 CAS Number
[10101-52-7]
10.0.2 Synonym
Silicic acid, zirconium salt
10.0.3 Trade Names
NA
10.0.4 Molecular Weight
183.31
10.1 Chemical and Physical Properties
Zirconium silicate is used as an additive to glass, in ceramic
tiles, in ultrafiltration membranes, and as a dental abrasive.
10.2 Toxic Effects
10.2.1 Human Experience
10.2.1.1 Clinical Cases. A 25-year-old nonsmoking male
ceramic tile worker developed a worsening dry cough and
dyspnea after 3.5 years as a sorter and glazer of tiles.
Microscopic examination of an open lung biopsy revealed
an intense granulomatous interstitial pneumonia with mild
fibrosis, compatible with hypersensitivity pneumonitis, and
numerous very small birefringent crystals around the termi-
nal airways and occasionally in granulomas. Pulmonary
particle analysis revealed an inhaled dust burden nearly
100-fold the background level, consisting mainly of clay
minerals and zirconium silicate. The patient had no history of
clinical or laboratory findings suggesting any organic etio-
logic agent. A sarcoid granulomatosis type of chronic
pulmonary hypersensitivity reaction occurs after long-term
exposure to zirconium, but this case demonstrated that
zirconium can also cause an acute and fulminant allergic
alveolitis-like hypersensitivity reaction (178).
A case of hypersensitivity pneumonitis in a ceramic tile
worker exposed to zirconium silicate was reported. A 25-
year-old previously healthy female presented with a history
of 2 months of dry cough and dyspnea upon exertion. Coarse
crepitations were heard in both lungs, and bilateral inter-
stitial fibrosis and discrete nodules were seen in a chest
radiograph. Marked decreases in respiratory function were
seen on pulmonary function tests. Chest radiographs and
lung function tests had been normal 7 years earlier. The
patient had a 3.5-year history of working in a ceramic tile
factory as a glazer and sorter and had not generally used
personal protective equipment. Up to 30% zirconium sili-
cate was found in the glazing material used in the tile factory
TITANIUM, ZIRCONIUM, AND HAFNIUM 453
along with dust concentrations up to 5.8 mg/m3. Silicate
particles were identified in factory air samples. Treatment of
the patient with prednisolone for 9 months was ineffective,
and the patient died 1 week after an open lung biopsy.
Interstitial inflammation along with fibrosis of the alveolar
walls was seen in the biopsy and autopsy samples. The walls
of the terminal and respiratory bronchioli were severely
inflamed by ulceration of the epithelium, and granulomas
were seen close to the lumen of the airway and in the
alveolar parenchyma. No evidence of an infectious process
or systemic disorder was seen. Particle analysis of lung
tissue samples demonstrated an inhaled dust burden con-
sisting primarily of clay particles and zirconium silicate that
was almost 100 times that of the normal background level.
The authors concluded that zirconium exposure can cause
an acute allergic pulmonary alveolitis-like hypersensitivity
reaction (178).
10.3 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
11.0 Zirconium Dichloride
11.0.1 CAS Number:
[13762-26-0]
11.0.2 Molecular Weight
162.13
11.1 Chemical and Physical Properties
Zirconium dichloride is formed by the decomposition of
zirconium tetrachloride.
11.2 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
12.0a Zirconium Oxynitrate
12.0.1a CAS Number
[13826-66-9]
12.0.2a Synonym
Nitric acid, zirconium salt
454 BARBARA MALCZEWSKA-TOTH
12.0.3a Molecular Weight
231.23
12.0b Zirconium Nitrate Pentahydrate
12.0.1b CAS Number
[13746-89-9]
12.0.2b Synonym
Nitric acid, zirconium salt, pentahydrate
12.0.3b Molecular Weight
429.32
12.1 Chemical and Physical Properties
Zirconium nitrate also occurs as the pentahydrate
[13746-89-9] (Zr(NO3)45H2O) that forms white, hygro-
scopic crystals. The latter is very soluble in water and
soluble in ethyl alcohol. Other physical properties are
presented in Table 13.3.
12.2 Toxic Effects
12.2.1 Human Experience
Because it is relatively physiologically inert, the effects of
zirconium ion on enzyme systems have been little tested. In
1936, Gould (11) showed that Zr(NO3)4 produced a slight
(10.5%) inhibition of amylase activity at 0.53 mM concen-
tration in vitro, a 20% inhibition of yeast invertase at 0.7 mM,
and a 50% inhibition of serum alkaline phosphatase at
0.9 mM, but trypsin was not inhibited at 1 mM concentration.
The rather low inhibitory effects produced on these enzymes
at the zirconium concentrations used indicate no specific
effect of zirconium on these particular enzymes (11).
12.3 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of July 1999, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
95
13.0 Z irconium Particles
13.1 Toxic Effects
13.1.1 Pharmacokinetics, Metabolism, and Mechanisms
13.1.1.1 Absorption. A differential deposition of inhaled
95
Zr particles that depended on the temperature of their
generation was reported by Thomas et al. (179). Aerosols
that contained 95 Zr and 95 Nb at near equilibrium pro-
duced particles of four different chemical compositions at
100, 250, 600, and 1100 C. When the particles at the two
highest temperatures were inhaled by mice, they were
retained tenaciously in the lung and maintained the starting
95
Zr to 95 Nb ratio of about 1:9. At 100 C, the radio-
nuclides were translocated from the lung to the skeleton at
a ratio of about 1:3, indicative of an excess burden of 95 Zr .
At 250 C, the pattern was similar but less pronounced. The
differential patterns of retention resulted in significant
differences in the radiation dose pattern; at the lowest
temperature, the highest radiation doses were received
by the skeleton, lung, and liver, whereas at the higher
temperatures, the radiation dose was delivered almost
exclusively to the lung (179).
13.1.1.2 Distribution. The age of the animal seemed to
affect absorption and retention of 95 Zr –95 Nb according
to a study published in 1972 (180). Although these
nuclides were poorly absorbed by adult rats, they were
absorbed to a considerable extent by suckling rats, result-
ing in a 10–1000 times higher retention than in adults.
The initial rapid loss of the nuclides from suckling rats
decreased at weaning age and was followed by a consid-
erably slower exponential decrease. Though the adult rats
showed a much steeper and larger initial loss, a similar rate
of exponential decrease was observed thereafter. The
whole-body retention curves of these nuclides for suckling
rats previously treated with cortisone acetate showed much
steeper initial loss and significantly lower retention than
those for controls. The ratio of 95 Zr –95 Nb in the bone of
suckling rats was approximately 4–5, whereas that in most
of their soft tissues was almost unity. The authors con-
cluded that the substantial absorption of these nuclides by
suckling rats was mainly due to the more active pinocytosis
in younger animals (180).
13.1.1.3 Excretion. Schubert (181) showed that zirco-
nium moves 91 Y and 239 Pu out of the skeleton, enhancing
their excretion. This shows that metal shifts are not confined
to those of nonessential metals; for example, ozone, as well as
glutathione, causes large shifts in zinc lung concentration
following brief, 3 h exposures of rats at slightly toxic levels of
3 ppm ozone (182).
13.2 Standards, Regulations, or Guidelines of
Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).

14.0 Aluminum Zirconium Compounds
14.1 Toxic Effects
14.1.1 Human Experience
14.1.1.1 General Information. Human exposure to alu-
minum zirconium compounds has been associated with the
development of hypersensitivity reactions.
14.1.1.2 Clinical Cases. Zirconium compounds have been
associated with the development of hypersensitivity granu-
lomas. However, aluminum zirconium complexes have not
previously been shown to induce sensitization. The clinical
and histological findings of a case were described in which a
patient developed an acute hypersensitivity reaction to an
aluminum zirconium complex (183).
14.2 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
15.0 Zirconium Compounds (Combination Studies)
15.1 Toxic Effects
15.1.1 Human Experience
15.1.1.1 Clinical Cases. Men who worked with zirconium
compounds at one site in the North of England were moni-
tored since 1975 to evaluate the effects of exposure on the
lung (mainly ,10 mg/m3) over many years. Chest radio-
graphs (in 1975, 1978, and 1982) and lung function measure-
ments (from 1975 to 1988) were carried out on all 178 men
known to have worked with the compounds; an estimate of
cumulative exposure was computed from job title and likely
exposures. No evidence was found that zirconium exposure
resulted in abnormal chest radiographs or impaired pulmo-
nary function (184).
15.2 Standards, Regulations, or Guidelines of
Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
16.0 Sodium Zirconium Lactate
16.1 Toxic Effects
16.1.1 Human Experience
16.1.1.1 Clinical Cases. By 1959 there were numerous
reports of axillary granulomas following the use of stick
TITANIUM, ZIRCONIUM, AND HAFNIUM 455
deodorants containing NaZr lactate (185). These granulomas
appear as underarm eruptions of small, indolent, flesh-
colored papules, often in linear streaks. Several years
later, zirconium oxide, as a cream, introduced as a treatment
for poison ivy dermatitis, produced small papules in the skin
that, on microscopic examination, revealed epithelioid cell
granulomas (186). When the sensitizing Zr salt was removed
from the preparation, healing occured.
16.2 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
17.0 Zirconium-Containing Aerosol Spray
17.1 Toxic Effects
17.1.1 Human Experience
17.1.1.1 Clinical Cases. Epstein (187) developed a
zirconium-containing aerosol spray that did not produce
granulomas of the skin in an unsensitized person. However,
Zr-containing antiperspirant sprays were ultimately banned
following a panel statement of the FDA and subsequent
hearings that concluded that (1) the respiratory tract is the
deposition site for the antiperspirant in spray form, (2) no
proof was presented on the metabolic fate or integrity of the
deposited spray in the respiratory tract, and (3) zirconium
chlorhydrate can elicit a hypersensitivity granulomatous
response in sensitized persons.
17.2 Standards, Regulations, or Guidelines of
Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
18.0 Lead Titanate Zirconate
18.1 Toxic Effects
18.1.1 Human Experience
18.1.1.1 Clinical Cases. An Ontario plant with 101 work-
ers who produced and used the ceramic compound lead
titanate zirconate (LTZ) was the site of an investigation (188).
Although air lead levels were high in most plant areas,
82 workers who were not exposed to lead oxide but to
LTZ in the process had normal blood lead levels. In addition,
no radiographic changes or abnormal pulmonary function
456 BARBARA MALCZEWSKA-TOTH
test results were detected in 61 workers examined. The
particle size of LTZ was less than 5 mm, and the solubility
of LTZ in body fluids was significantly less than lead oxide.
The authors postulated that the observed low toxicity of LTZ
could be due to its low solubility in body fluids. Further
studies of the toxicity of LTZ and other less soluble lead
compounds were recommended by the authors (188).
18.2 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
19.0 Zircaloy
19.1 Toxic Effects
19.1.1 Human Experience
19.1.1.1 Clinical Cases. A 51-year-old nonsmoking
female suffered from relapsing progressive pneumonia for
several years. She had worked for 16 years in the nuclear
industry and was exposed to grinding particles and welding
fumes from working with Zircaloy, an alloy that contains tin,
iron, chromium, and zirconium. During an exacerbation of
the pneumonia, radiography showed interstitial infiltration of
both lower lobes. In addition, nodular and painful thicken-
ings appeared in old operation scars on various parts of her
body. Persistent infiltrations of the lung led to lobectomy of
the right lower lobe to exclude a malignant disease in the
worker. The histological picture of the lung tissue showed
different stages of alterations and pronounced proliferation
of the alveolar epithelium, epithelioid cell granulomas
between well-preserved alveolar walls, and additional
large areas of scar tissue (189). This observation was similar
to that noted in another study published a few years previ-
ously, where the authors called it “Zirconium lung” (190).
19.2 Standards, Regulations, or Guidelines of Exposure
NIOSH has a REL of 5 mg/m3 as Zr and a STEL value of
10 mg/m3 (93). As of June 2005, the OSHA TWA has
remained at 5 mg/m3 (91). A TLV-TWA has been developed
by ACGIH (92).
19.3 Studies on Environmental Impact
Zircaloy hazards associated with the shear/leach operation at
the second Thermal Oxide Reprocessing Plant (THORP) at
the Sellafield factory were examined. Potential hazards of the
process include Zircaloy dust explosions in the vicinity of the
shear and either dry or submerged ignition layers. With
respect to the development of the safety case for layer
ignitions, the reaction kinetics were experimentally investi-
gated by reproducing the conditions under which a thermal
runaway could be seen. A mathematical model of the settled
layer heat transfer characteristics was developed. It was
shown that an oxide layer formed on particles of Zircaloy
resulted in a slowing of explosive reactions of particulate
Zircaloy (191).
HAFNIUM AND HAFNIUM COMPOUNDS
Hafnium (Hf) [7440-58-6], one of the transition elements,
belongs to group IVB of the periodic table along with
titanium and zirconium. Hafnium is never found free in
nature but is always associated with the more plentiful
zirconium in natural minerals. Hafnium and zirconium are
almost identical in nature and hence show close similarity in
chemical properties not seen in any other pair of elements
in the periodic table.
Hafnium is one of the less abundant elements in the Earth’s
crust. It makes up 2% of the combined weight of hafnium and
zirconium in zircon, (ZrHf)O2SiO2, which is recovered from
certain beach sands. Hafnium makes up about 0.5–2% of the
combined weight with zirconium in the ore, baddeleyite,
(ZrHf)O2 (192). Because of its similarity to zirconium, no
qualitative differences have been found that would permit
separating them except for the production of hafnium-free
nuclear grade zirconium (110).
Hafnium was positively identified only in 1923 though
zirconium was discovered in 1789. The theory that element
72 was tetravalent and not trivalent like the rare earth series
elements was postulated by the Bohr atomic theory and by
Moseley’s X-ray spectra of several zircon concentrates (193).
The name hafnium comes from Hafnia, the Latin name for
Copenhagen where the discovery was made.
Hafnium was also identified by X-ray fluorescence analy-
sis and by neutron activation analysis in a chronosequence of
soils in the Indiana Dunes. It was leached along with tita-
nium, selenium, and heavy lanthanides associated with heavy
minerals, particularly, iron oxides, in the very fine sand
fraction (0.05–0.1 mm) of the Indiana Dunes soils (194).
The primary commercial source of hafnium is zircon,
zirconium orthosilicate, which is inert and refractory and
is obtained during the mining of rutile and ilmenite mineral
sands. Zircon sands contain 2% hafnium oxide but higher
concentrations are found in altered zircons such as cyrtolite,
malacon, alvite, and na€egite. Resources of hafnium in the
United States are estimated at about 130,000 tons in 2009,
available in the 14million ton domestic resources of zircon
(8). World resources of hafnium are associated with those of
zircon and baddeleyite and exceeded 1 million tons in 2009.
The statistics of hafnium imports and prices for 2005–2009
are presented in Table 13.6.
 TITANIUM, ZIRCONIUM, AND HAFNIUM 457

Table 13.6. Statistics of Hafnium Imports and Prices—United States, 2005–2009a

2005 2006 2007 2008 2009 (est.)
Imports (metric tons)
Hafnium, unwrought, waste, and scrap 4 4 4 12 5
Prices
Hafnium sponge (dollars per kg) 235 194 250 343 648
a
Adapted from U.S. Geological Survey, Mineral Commodity Summaries, 2010.

It is extremely difficult to separate hafnium from zirco- tributyl phosphate, and (3) fractional crystallization of the
nium. Some of the methods used in the laboratory for double fluorides (195). Three industrial methods are nor-
separating it from zirconium are (1) solvent extraction of mally used to separate hafnium and zirconium: (1) liquid–
thiocyanates by hexone, (2) solvent extraction of nitrates by liquid extraction (2) molten salt distillation, and (3) fluor-
ozirconate crystallization. Different hafnium compounds are
obtained from zircon using different procedures. Figure 13.1
Zircon
presents a flowchart for obtaining the various hafnium
(ZrHf)SiO4
compounds, as well as the different forms of hafnium
Cracking from zircon.
(coke + Cl2) SiCl4 Another method used a pressurized ion-exchange column
to separate hafnium from zirconium. Basically, the hafnium
(ZrHf)Cl4 and zirconium sulfate complex was separated by chro-
a. Liquid–liquid extraction
matographic elution from Dowex 50W-X8 (15–25 mm)
a. Sublimation resin with sulfuric acid solutions. Fluorometric and colori-
b. Precipitation
b. Distillation
ZrCl2 c. Calcination metric reagents were used to monitor the column effluents
ZrO2
continuously. Because neither the fluorometric nor the colori-
a. Chlorination
Various hafnium metric reagent was specific for either hafnium or zirconium,
HfCl4 HfO4
chemicals peak patterns were identified using the stable isotopes 90 Zr
b. Sublimation and 180Hf as “fingerprints” of their elution position (196). An
a. Molten salt a. Magnesium reduction unseparated fraction was also obtained that was thought to be a
electrolysis b. Vacuum distillation polymeric hydrolytic product.
b. Salt leach
Some physical properties of hafnium and its compounds
are presented in Table 13.7.
Hf metal Hf metal
crystals sponge

20.0 Hafnium
20.0.1 CAS Number
[7440-58-6]
Iodine bar refining Electron beam refining

20.0.2 Synonyms
Celtium; elemental hafnium; hafnium metal; hafnium plate;
Vacuum arc melting hafnium foil; hafnium wire

20.0.3 Trade Names

Hf ingot
NA

Forging, rolling, extrusion, drawing 20.0.4 Molecular Weight

178.49
Hafnium bar, plate, strip, foil, tube, wire
20.0.5 Molecular Formula
Figure 13.1. Flowchart of hafnium production from zircon. Hf
458
Table 13.7. Physical and Chemical Properties of Hafnium and Its Compounds
CAS Molecular Molecular Boiling Melting Specific Solubility in
Compound Number Formula Weight. Point ( C) Point ( C) Gravity Water (68 F) Reference
a
Hafnium [7440-58-6] Hf 178.49 4603 2233 13.31 Insoluble
a
Hafnium beryllide HfBe13 1595 3.93
a
Hafnium beryllide HfBe17 ,1750 4.78
a
Hafnium diboride [12007-23-7] HfB2 200.11 3100 10.5
b
Hafnium boride [12228-27-2] HfB 189.3 Dec. at 210
a
Hafnium dodecaboride [32342-52-2]
c d a
Hafnium bromide, hafnium tetrabromide [13777-22-5] HfBr4 498.11 323 424 4.90
a
Hafnium carbide [12069-85-1] HfC 190.50 3000 12.2
c a
Hafnium chloride [13499-05-3] HfCl4 320.30 317 432d Reacts with water
a
Hafnium fluoride, hafnium tetrafluoride [13709-52-9] HfF4 254.48 970c . 970 7.1
a
Hafnium hydride [12770-26-2] HfH2 180.51 11.4
c d a
Hafnium iodide, hafnium tetraiodide [13777-23-6] HfI4 686.11 394 449 5.6
a
Hafnium nitride [25817-87-2] HfN 192.50 3305 13.8
a
Hafnium orthosilicate [13870-13-8] HfSiO4 270.57 7.0
a
Hafnium oxide [12055-23-1] HfO2 210.49 2774 9.68 Insoluble
a
Hafnium oxychloride octahydrate [14456-34-9] HfOCl28H2O 409.52 Decomposes Soluble
a
Hafnium phosphide [12325-59-6] HfP 209.46 9.78
a
Hafnium selenide [12162-21-9] HfSe2 336.41 7.46
a
Hafnium silicide [12401-56-8] HfSi2 234.66 1700 7.6
a
Hafnium sulfate [15823-43-5] Hf(SO4)2 370.62 Decomposes . 500
a
Hafnium sulfide [18855-94-2] HfS2 242.62 6.03
a
Adapted from CRC Handbook of Chemistry and Physics, CRC Press, 78th ed., Boca Raton, FL, 1997–1998.
b
Adapted from CRC Handbook of Chemistry and Physics, CRC Press, 67th ed., Boca Raton, FL, 1986–1987.
c
Sublimation point.
d
Triple point.

20.1 Chemical and Physical Properties
Hafnium is a gray, ductile metal that melts at 2227  20 C.
It is insoluble in water but soluble (presumably by reaction)
in hydrofluoric acid.
The normal stable valence of hafnium is four, which is also
its maximum valence. However, hafnium forms compounds
with coordination numbers of six, seven, and eight, thus
forming numerous complex ions.
In powder or granular form, hafnium may spontaneously
ignite on contact with air at room temperature to form a more
stable oxide film. It also ignites on contact with nitrogen,
phosphorus, and sulfur at higher temperatures. It may also
explosively decompose due to shock, friction, concussion, or
on violent reaction with strong oxidizing agents and with
halogens (197–199).
Hafnium is readily soluble in hydrofluoric acid, is slowly
attacked by concentrated sulfuric acid, but is unaffected by
nitric acid, dilute hydrochloric or sulfuric acids, or by alkalis.
However, if traces of fluoride are present, all mineral acids
attack hafnium.
Hafnium reacts with carbon, nitrogen, or oxygen at high
temperatures to form a fine dispersion of hafnium carbide,
nitride, or oxide that provides a second-phase particle
dispersion strengthening. Small additions of hafnium and
carbon react to form second-phase dispersions in tantalum,
molybdenum, and tungsten alloys (200–202).
The chemistry of hafnium is almost identical with that of
zirconium, just like deuterium is similar to hydrogen. The
separation process for hafnium and zirconium depends upon
the difference in equilibrium constants of the same reaction
rather than upon different reactions of the two elements. A
few qualitative differences in chemical behavior exist
between hafnium and zirconium (192):
1. Rufigallic acid gives a red solution with either hafnium
or zirconium in a moderately acidic solution of hydro-
chloric acid, but on increasing the acidity, only the
hafnium solution turns yellow.
2. Both hafnium and zirconium form 1:1 complexes with
beta-hydronaphthazarin, but only zirconium also
forms a 1:2 complex.
3. The compound Hf(NO3)4N2O5 is obtained as a subli-
mate that contains only hafnium when reagents con-
taining both hafnium and zirconium are sublimed.
4. In strong hydrochloric acid solution, Neothorin gives a
red-violet solution or precipitate with hafnium but a
blue-violet one with zirconium. Hydrogen peroxide
alters the color of the zirconium complex to orange and
that of the hafnium complex to pink.
5. Addition of diarsine to a solution of zirconium tetra-
chloride in tetrahydrofuran leads to the rapid precipi-
tation of an adduct. The hafnium analog precipitates
only after a delay.
TITANIUM, ZIRCONIUM, AND HAFNIUM 459
20.2 Production and Use
Almost all of the hafnium metal currently produced in the
United States is obtained by reducing its tetrachloride or
hydrofluorohafniate with magnesium or with sodium using
the Kroll process (203). It is then followed by a refining
process, whereby electron beam melting of the hafnium in
high vacuum removes all impurities whose partial pressure at
the surface of the melt is greater than the vapor pressure of
hafnium.
Hafnium is also extracted from cyrtolite (204) and as a
by-product during the production of hafnium-free nuclear
grade zirconium. Other methods of production of hafnium
are thermal decomposition of its iodide and reduction of its
oxide with a mixture of calcium and sodium (118, 195).
Hafnium is prepared by reducing its oxide or fluoride with
calcium metal that is an excellent reducing agent (118).
The formulations and preparations of hafnium are avail-
able in sponge, iodide bar, ingot, wrought products from bar
to foil, wire (205), or in chunk or particulate form, specifi-
cally for alloying (206).
The largest use of hafnium is in superalloys (with 1–2%
hafnium) that are used for cast vanes and turbine blades in the
hottest stages following the combustion zone of jet aircraft
engines. It is extensively used as shielding material and as
control rods in thermal nuclear reactors because (1) of its
thermal neutron cross section (it is about 600 times that of
zirconium) and (2) it can absorb and give up heat twice as fast
as zirconium or titanium. Hafnium is also used in control rods
in pressurized water reactors to power many naval vessels
because of its excellent hot water (450 C) corrosion resis-
tance, good ductility and machinability, and large neutron
absorption cross section (207). It also has an advantage over
many other neutron absorbers, including boron, because its
cross section does not decrease markedly after long periods
of irradiation. This stability permits the formation of many
stable isotopes of hafnium, whereby the neutron absorption
by one hafnium isotope results in the formation of a new
hafnium isotope that also has a large absorption cross section.
Hafnium is also used as construction material in space
technology and in jet engines (200). Because of its neutron
absorption capabilities, alloys of hafnium are used as
separator sheets for spent nuclear fuel rods in interim
holding ponds. It is also used in high-temperature applica-
tion alloys, for example, superalloys and refractory metal
alloys, to improve the high-temperature tensile and creep
strength (207).
Hafnium acts as a strengthening agent in refractory alloys;
the addition of small quantities of hafnium to molybdenum,
niobium, tantalum, and tungsten alloys imparts a dispersed
second-phase strengthener. The addition of 1–2% hafnium in
solid solution to nickel-based superalloys yielded significant
improvements in high-temperature ductility, as well as ten-
sile and creep strength (120).
460 BARBARA MALCZEWSKA-TOTH
Another application for hafnium is in cemented carbide
cutting tools. Hafnium–niobium carbide solid solutions are
a satisfactory replacement for increasingly scarce tantalum
carbide in steel cutting grades of cemented carbides in both
roughing and light finishing grades (208).
Potential exposures to hafnium can be determined by using
NIOSH method #S194 found in NIOSH Manual of Analytical
Methods, 2nd ed., Vol. 5, August 1979.
20.3 Toxic Effects
20.3.1 Experimental Studies
20.3.1.1 Chronic and Subchronic Toxicity. The lungs
may be affected by repeated or prolonged exposure to
hafnium. The liver may also be affected (209).
20.3.2 Human Experience
Inhalation (209): Hafnium can be absorbed into the body
by inhalation of its aerosol.
Prevention: Avoid inhaling fine dust and mist by using
local exhaust ventilation or appropriate breathing
protection.
Skin: Prevention: Use protective gloves. First aid:
Remove contaminated clothes; rinse and wash skin
with soap and water.
Eyes: Acute hazards: irritant; causes redness. Prevention:
Use safety spectacles.
Ingestion: Prevention: Do not eat, drink, or smoke during
work. Always wash hands before eating.
Spillage disposal: Evacuate danger area. Eliminate all
sources of ignition. Do not wash away into sewer
because it is flammable. Do not absorb in sawdust
or other combustible absorbents. Wet the powder to
prevent formation of dust or ignition; carefully collect
the powder into sealable containers, and remove it to a
safe place. During this procedure, use extra personal
protection, for example, a P2 filter respirator for
harmful particles.
Storage: Store hafnium in a fireproof area. Keep it sepa-
rate from strong oxidizing agents, strong bases,
halogens, phosphorus, and sulfur. Keep it stored
under water (210).
20.4 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3, and the OSHA PEL and
TWA is 0.5 mg/m3 (91).
Compounds of Hafnium and Their Properties
Most of the hafnium compounds have no commercial value
except as intermediates in the production of hafnium metal.
The carbide, nitride, and oxide of hafnium are more refrac-
tory than their counterparts of the other group IV elements in
the periodic table.
21.0 Hafnium Tetrachloride
21.0.1 CAS Number
[13499-05-3]
21.0.2 Synonym
Hafnium chloride
21.0.3 Trade Names
NA
21.0.4 Molecular Weight
320.30
21.0.5 Molecular Formula
Cl4Hf
21.0.6 Molecular Structure
Cl–
Cl– Hf4+ Cl–
Cl–
21.1 Chemical and Physical Properties
21.1.1 General
Hafnium tetrachloride is a white, monoclinic crystalline solid
that volatilizes at 250 C. It reacts immediately with water to
form hafnium oxychloride and hydrogen chloride. It also
reacts with almost all oxygen-containing organic compounds
and molten alkaline halides to form addition compounds.
It reacts with steam or air to form finely divided hafnium
dioxide. Hafnium tetrachloride can be reduced to lower
chlorides by reaction with hafnium metal or by reaction
with aluminum metal in liquid aluminum chloride (211).
Some physical properties of hafnium tetrachloride are pre-
sented in Table 13.7.
Hafnium tetrachloride is made (1) by reacting chlorine
with hafnium at 317 C, (2) from a mixture of hafnium
oxide and carbon above 700 C, or (3) by reacting carbon
tetrachloride with hafnium oxide above 450 C.

21.2 Toxic Effects
21.2.1 Experimental Studies
21.2.1.1 Acute Toxicity
Skin irritation: The application of hafnium tetrachloride
to the intact skin of six rabbits for 24 h caused mild
irritation that lasted for 3 days. When applied similarly
to abraded skin of rabbits, severe irritation and ulcera-
tion were noted (209).
Eye irritation: Transient irritation and redness were
observed in three rabbits following the instillation of
1 mg hafnium tetrachloride; this was due to the con-
version of hafnium tetrachloride to hafnium oxychlor-
ide in the eye fluid (209).
21.2.1.2 Chronic and Subchronic Toxicity
Oral: When hafnium tetrachloride was added to the diet of
groups of six male and six female rats at 0.01%, 0.1%, or 1%
for 12 weeks (ca. 500 mg/kg body weight), there were no
adverse effects on survival, growth, or blood parameters.
Microscopic examination of a limited range of major tissues
revealed liver effects (vacuolization and granulation) in
almost all animals at the 1% dietary level and only in
some animals at the lower levels (122). Hafnium tetrachlo-
ride would also have transformed into hafnium oxychloride
in the gastrointestinal tract.
21.3 Standards, Regulations, or Guidelines
of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal. The
NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL and
TWA is 0.5 mg/m3 as Hf (91).
22.0 Hafnium Dioxide
22.0.1 CAS Number
[12055-23-1]
22.0.2 Synonyms
Hafnium(IV) oxide; hafnium oxide, 99.9%; hafnium oxide;
hafnia
22.0.3 Trade Names
NA
22.0.4 Molecular Weight
210.49
TITANIUM, ZIRCONIUM, AND HAFNIUM 461
22.0.5 Molecular Formula
HfO2
22.0.6 Molecular Structure
O
Hf
O
22.1 Chemical and Physical Properties
Hafnium monoxide and hafnium dioxide are known but only
the dioxide is stable under ordinary conditions. Hafnium
dioxide is formed as white, cubic crystals and is insoluble in
water. Some properties of hafnium dioxide are presented in
Table 13.7.
Hafnium monoxide may be formed at temperatures higher
than 2000 C, particularly when the partial pressure of oxy-
gen is low. When hafnium metal is melted in an electron
beam melting furnace, the monoxide is probably formed. The
dioxide is formed by the ignition of hafnium metal or its
carbide, tetrachloride, sulfide, boride nitride, or hydrous
oxide.
Hafnium dioxide melts at 2774 C. At room temperature,
hafnium dioxide is slowly dissolved by hydrofluoric acid.
At elevated temperatures, hafnium dioxide reacts with con-
centrated sulfuric acid or with alkali bisulfates to form various
sulfates. It also reacts with carbon tetrachloride or with
chlorine in the presence of carbon to form hafnium tetrachlo-
ride and with alkalies to form alkaline hafnates. Above
1500 C, it reacts with carbon to form hafnium carbide.
22.2 Toxic Effects
22.2.1 Experimental Studies
22.2.1.1 Chronic and Subchronic Toxicity. Oral admin-
istration of hafnium dioxide at 2 g/kg body weight for
1 month to an unspecified number of guinea pigs showed
no changes in survival, growth, or blood parameters (210).
Only slightly increased liver weight and decreased kidney
and spleen weights were noted, but they were not statistically
significant. Microscopic examination showed a diffuse thick-
ening of the alveolar walls and some granulation of the
cytoplasm in the liver (210).
22.3 Standards, Regulations, or Guidelines of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA
PPEL and TWA is 0.5 mg/m3 as Hf (91).
462 BARBARA MALCZEWSKA-TOTH

23.0 Hafnium Sulfate water or by dissolving hydrous hafnium oxide in hydrochlo-

ric acid. Repeated crystallization of hafnium oxide chloride
23.0.1 CAS Number
using concentrated hydrochloric acid is the classical method
[15823-43-5] of obtaining hafnium salts free of all metallic impurities
except zirconium. On heating, it rapidly loses both water and
23.0.2 Synonym hydrochloric acid. On continued heating, it decomposes
further to yield hafnium dioxide. Hafnium oxide chloride
Sulfuric acid, hafnium (4þ) salt (2:1)
is soluble in water. Its solubility in hydrochloric acid
decreases with increasing acid strength but increases greatly
23.0.3 Trade Names
at higher temperatures. Hafnium oxide chloride is the starting
NA material for preparing other hafnium compounds. Some
properties of hafnium oxychloride octahydrate are presented
23.0.4 Molecular Weight in Table 13.7.
370.62
24.2 Toxic Effects

23.1 Chemical and Physical Properties 24.2.1 Experimental Studies

Hafnium sulfate is a white, crystalline solid that decomposes
at temperatures above 500 C (204, 211). Some properties of
hafnium sulfate are presented in Table 13.7.
23.2 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal. The
NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL and
TWA is 0.5 mg/m3 as Hf (91).
24.0 Hafnium Oxychloride Octahydrate
24.0.1 CAS Number
[14456-34-9]
24.0.2 Synonyms
Hafnium chloride oxide octahydrate; hafnium oxide chloride
octahydrate; hafnium dichloride octahydrate; hafnium
dichloride oxide, 98þ% (metals bais) (Zr 1.5%)
24.0.3 Trade Names
NA
24.2.1.1 Acute Toxicity.
Eye irritation: Transient irritation and redness were
observed in three rabbits following the instillation of
1 mg hafnium tetrachloride; the hafnium tetrachloride
would have been converted to hafnium oxychloride in
the eye fluid. However, the instillation of 0.1 mL of
0.1% hafnium oxychloride at pH 2.1 did not irritate the
eyes of six rabbits (209).
In groups of five guinea pigs, intradermal injection
of 0.001% hafnium oxychloride (solvent, unspecified)
caused mild irritation, and severe irritation with scar
formation was noted at concentrations of 1% and
higher (209).
Intradermal: A single intradermal injection of 0.02 mL of
0.08% hafnium oxychloride (ca. 0.8 mg/kg body
weight) in saline into the ear lobe of 20 mice caused
local dysplasia and hyperplasia and produced a chon-
dral mass in all animals after 2 months (214).
24.2.2 Human Experience
24.2.2.1 General Information. An intradermal injection
of 0.02 mL of a 0.001% solution of hafnium oxychloride in
saline induced no local reactions in 77 subjects when checked
up to 9 months after the injection (215).

24.0.4 Molecular Weight 24.3 Standards, Regulations, or Guidelines of

409.52
24.1 Chemical and Physical Properties
Hafnium oxychloride octahydrate occurs as white tetragonal
crystals that form when hafnium tetrachloride reacts with
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).

25.0 Hafnium Beryllides
25.1 Chemical and Physical Properties
25.1.1 General
Hafnium forms two kinds of beryllides (HfBe13 and HfBe17)
by a solid-state reaction of the blended powder constituents at
1200 C. Further fabrication of the reacted powders into
specific shapes is carried out by vacuum hot pressing or
hot isostatic pressing. Some properties of the two beryllides
are presented in Table 13.7.
The beryllides are intermetallic compounds and are hard,
strong materials that exhibit little ductility at room tempera-
ture. Strength properties increase gradually as a function of
temperature up to about 870 C, above which a sharp increase
in strength occurs that peaks at about 1260 C. These ber-
yllides exhibit excellent oxidation resistance, high strength at
elevated temperature, good thermal conductivity, and low
densities (216).
25.2 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal. The
NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL and
TWA is 0.5 mg/m3 as Hf (91).
26.0 Hafnium Borides
26.0.1 CAS Numbers
[12228-27-2] (hafnium boride); [12007-23-7] (hafnium
diboride); [32342-52-2] (hafnium dodecaboride).
26.0.2 Synonyms
Hafnium boride, 99% (metals basis); hafnium diboride.
26.0.3 Trade Names
NA
26.0.4 Molecular Weights
189.3 (hafnium boride); 200.11 (hafnium diboride)
26.0.5 Molecular Formula
BHf (hafnium boride); B2Hf (hafnium diboride); B12Hf
(hafnium dodecaboride)
26.0.6 Molecular Structure
Hf B
TITANIUM, ZIRCONIUM, AND HAFNIUM 463
26.1 Chemical and Physical Properties
26.1.1 General
Hafnium is formed into Hf borides to obtain high electrical
conductivity and positive coefficients of electrical resistiv-
ity. Such borides have high melting points, great hardness,
low coefficients of thermal expansion, and good chemical
stability (217). Hafnium diboride (HfB2) is a gray, crystal-
line solid. It is usually prepared by reacting hafnium oxide
with carbon and either boron oxide or boron carbide.
Hafnium diboride can also be prepared from mixtures of
hafnium tetrachloride, boron trichloride, and hydrogen
above 2000 C or by direct synthesis from the respective
elements. Hafnium diboride is attacked by hydrofluoric acid
but is resistant to nearly all other reagents at room tempera-
ture (110). Hafnium dodecaboride (HfB12) is prepared by
direct synthesis from the elements hafnium and boron.
Some properties of hafnium boride are presented in
Table 13.7.
26.2 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal. The
NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL and
TWA is 0.5 mg/m3 as Hf (91).
27.0 Hafnium Borohydride
27.0.1 CAS Number
[25869-93-6]
27.1 Chemical and Physical Properties
Hafnium borohydride is the most volatile hafnium compound
(mp 29 C, bp 118 C). It is prepared by reacting sodium
fluorohafniate with aluminum borohydride for several days at
room temperature, followed by distillation of the hafnium
borohydride by fractionation to separate it from the alumi-
num borohydride (218).
27.2 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
464 BARBARA MALCZEWSKA-TOTH

28.0 Hafnium Carbide 29.0 Hafnium Tetrafluoride

28.0.1 CAS Number 29.0.1 CAS Number
[12069-85-1] [13709-52-9]

28.0.2 Synonyms
29.0.2 Synonyms
NA
Hafnium fluoride; hafnium fluoride, 99.99%
28.0.3 Trade Names
NA 29.0.3 Trade Names
NA
28.0.4 Molecular Weight
190.50 29.0.4 Molecular Weight
254.48
28.1 Chemical and Physical Properties
Hafnium carbide is formed as refractory cubic crystals. Some 29.0.5 Molecular Formula
properties of hafnium carbide are presented in Table 13.7. F4Hf

29.0.6 Molecular Structure

28.2 Production and Use
Hafnium carbide is a dark gray, brittle solid. It can be
prepared by heating a mixture of the elements or by reacting
hafnium tetrachloride with methane at 2100 C. Sufficient
quantities of hafnium oxide or hafnium metal sponge are
obtained during the large-scale production of pure zirconium
for nuclear reactors. On an industrial scale, hafnium carbide
can be produced from the hydrided hafnium sponge at
1500–1700 C or from hafnium oxide at 2000–2200 C by
carburization in vacuo in the presence of hydrogen.
The resulting carbide contains almost the theoretical quantity
of carbon (6.30% C) and a maximum of 0.1% free car-
bon (219). The hafnium carbide obtained is not a true
stoichiometric compound as much as a solution of carbon
at specific interstitial sites of a face-centered cubic hafnium
lattice (220).
Hafnium carbide is inert to most reagents at room temper-
ature but is dissolved by hydrofluoric acid solutions.
Hafnium carbide reacts exothermally with halogens at
250–500 C to form hafnium tetrahalide, and to form hafnium
oxide with oxygen above 500 C. In the presence of hydrogen,
hafnium carbide slowly loses some of its carbon at higher
temperatures (220).
F–
F– Hf4+ F–
F–
29.1 Chemical and Physical Properties
Hafnium tetrafluoride forms white, monoclinic crystals.
Some properties of hafnium tetrafluoride are presented in
Table 13.7.
29.2 Production and Use
Hafnium tetrafluoride is prepared by careful thermal
decomposition of ammonium fluorohafniate in an oxy-
gen-free atmosphere or by passing anhydrous hydrogen
fluoride over hafnium tetrachloride at 300 C. Direct syn-
thesis from the elements is incomplete because the product
merely forms a film on the metal. Ammonium fluorohafni-
ate can be prepared by crystallization from an aqueous
hydrofluoric acid solution by adding ammonium
fluoride (110).

28.3 Standards, Regulations, or Guidelines of 29.3 Standards, Regulations, or Guidelines of

Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
 TITANIUM, ZIRCONIUM, AND HAFNIUM 465

30.0 Hafnium Tetrabromide 31.0.3 Trade Names

30.0.1 CAS Number NA
[13777-22-5]
31.0.4 Molecular Weight:
30.0.2 Synonyms 686.11
Hafnium bromide; hafnium bromide, ultra dry, anhydrous,
31.0.5 Molecular Formula
98.5% (metals basis).
HfI4
30.0.3 Trade Names
31.0.6 Molecular Structure
NA

30.0.4 Molecular Weight I–

I– Hf4+ I–
498.11 I–

30.0.5 Molecular Formula

31.1 Chemical and Physical Properties
Br4Hf
Hafnium tetraiodide forms yellow-orange cubic crystals that
30.0.6 Molecular Structure are produced by the reaction of iodine with hafnium metal at
or above 300 C. Above 1200 C, the iodide dissociates to
form hafnium metal and iodine, which is the method used
Br–
Br– Hf4+ Br–
in the iodide bar refining process. Hafnium tetraiodide is
Br– reported to have three stable crystalline forms at
263–405 C (221). Some properties of hafnium tetraiodide
are presented in Table 13.7.
30.1 Chemical and Physical Properties
30.1.1 General 31.2 Standards, Regulations, or Guidelines of
Hafnium tetrabromide forms white, cubic crystals and is very Exposure
similar to the tetrachloride in both its physical and chemical A TLV-TWA has been developed by ACGIH (92). Evapora-
properties. Some properties of hafnium tetrabromide are tion at 20 C is negligible; however, a harmful concentration
presented in Table 13.7. of airborne particles can be reached quickly on dispersal. The
NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL and
TWA is 0.5 mg/m3 as Hf (91).
30.2 Standards, Regulations, or Guidelines of
Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora- 32.0 Hafnium Sulfide
tion at 20 C is negligible; however, a harmful concentration 32.0.1 CAS Number
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL [18855-94-2]
and TWA is 0.5 mg/m3 as Hf (91).
32.0.2 Synonym
31.0 Hafnium Tetraiodide Hafnium disulfide
31.0.1 CAS Number
32.0.3 Trade Names
[13777-23-6]
NA
31.0.2 Synonyms
32.0.4 Molecular Weight
Hafnium iodide; hafnium iodide, ultra dry, anhydrous, 98.5%
(metals basis). 242.62
466 BARBARA MALCZEWSKA-TOTH
32.1 Chemical and Physical Properties
Hafnium sulfide is formed as purple-brown hexagonal crystals.
Several sulfides (Hf2S, HfS, and HfS2) have been prepared by
reacting hafnium and sulfur at 500 C or by passing hydrogen
sulfide over heated platinum powder. Only the disulfide is
well characterized and has good lubricating properties. Some
properties of hafnium sulfide are presented in Table 13.7.
32.2 Standards, Regulations, or Guidelines of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
33.0 Hafnium Hydride
33.0.1 CAS Number
[12770-26-2]
33.0.2 Synonyms
NA
33.0.3 Trade Names
NA
33.0.4 Molecular Weight
180.51
33.1 Chemical and Physical Properties
Hafnium hydride is formed as refractory, tetrahedral crystals.
Hafnium hydride is usually produced as an intermediate in
the process of making hafnium powder from mass hafnium
metal. Hafnium reacts reversibly with hydrogen to form
hydride, and the proportion of hydrogen depends upon the
temperature and pressure of hydrogen used. As hydrogen is
absorbed, the hafnium transforms from the hexagonal metal
to the face-centered cubic hydride and then to the face-
centered tetragonal hydride. Hafnium hydride is brittle
and is easily crushed to very fine particles sizes (110).
Some properties of hafnium hydride are presented in
Table 13.7.
33.2 Standards, Regulations, or Guidelines of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
34.0 Hafnium Nitride
34.0.1 CAS Number
[25817-87-2]
34.0.2 Synonym
Hafnium mononitride
34.0.3 Trade Names
NA
34.0.4 Molecular Weight
192.50
34.0.5 Molecular Formula
HfN
34.0.6 Molecular Structure
Hf N
34.1 Chemical and Physical Properties
Hafnium nitride is formed as yellow-brown, cubic crystals
and is prepared by heating hafnium metal to 1000–1500 C
in an atmosphere of nitrogen or ammonia. It can also be
prepared by reacting hafnium tetrachloride vapor with nitro-
gen in a hydrogen atmosphere at temperatures higher than
1000 C. Some properties of hafnium nitride are presented in
Table 13.7.
Hafnium nitride is a brittle solid. The deposition of a thin
layer of hafnium nitride on steel grade, cemented carbide,
cutting tools reduces frictional forces and wear, thus increas-
ing the life of the tool by a factor of 6–8 (110).
34.2 Standards, Regulations, or Guidelines of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
35.0 Hafnium Dihydride
35.1 Toxic Effects
35.1.1 Chronic and Subchronic Toxicity
The instillation of 50 mg hafnium dihydride in rats increased
levels of serum enzymes after 3–6 months, indicating a
possible effect on liver function. After 6 months, there was
biochemical evidence of mild fibrotic changes in the lungs.

The researchers also mentioned that microscopic examina-
tion revealed muscular swelling in the heart; fatty changes
in the liver; and damage to the lungs, kidneys, and
spleen (222).
35.2 Standards, Regulations, or Guidelines of Exposure
A TLV-TWA has been developed by ACGIH (92). Evapora-
tion at 20 C is negligible; however, a harmful concentration
of airborne particles can be reached quickly on dispersal.
The NIOSH REL (93) is 0.5 mg/m3 as Hf, and the OSHA PEL
and TWA is 0.5 mg/m3 as Hf (91).
Other Miscellaneous Data on Hafnium Compounds
Nonhuman Single Exposure
Oral: Rat LD50 (compound not mentioned) was reported
as 2362 mg/kg body weight (body weight) (165).
Groups of five rats survived when given a 5 mg dose
(approximately 25 mg/kg body weight) of hafnium
tetrachloride, hafnium citrate, or hafnium nitilotriace-
tate by stomach tube (223). Groups of 7–10 hamsters
also survived when given hafnium dioxide or hafnium
carbide “orally” (10 mL of solution was placed at the
back of the tongue) at a dose of 1 mg/kg body
weight (223).
According to a translated Soviet study, an unspeci-
fied number of mice survived treatment with hafnium
dioxide or hafnium carbide up to 10 g/kg body weight
by stomach tube (210).
Intravenous: Rat LD50 for a hafnium sodium mandelate
complex was reportedly equivalent to 75–100 mg haf-
nium/kg body weight (224, 225). A group of 17 rats
also survived when given approximately 3.06 mg haf-
nium (ca. 10 mg/kg body weight) as hafnium sodium
mandelate (225). An intravenous injection of 0.5–2 mg
hafnium oxychloride/kg body weight produced no
overt effects in an undisclosed number of cats. At
5 mg/kg body weight, blood pressure and blood flow
were temporarily decreased, and the electrical activity
of the heart was altered. Cardiovascular collapse,
respiratory paralysis, and death occurred at 10 mg/kg
body weight (209).
Intraperitoneal: Mouse LD50 (chemical not reported) was
reported to be 112 mg/kg body weight. Treatment
resulted in immediate urination and lethargy (209).
According to a translated Soviet study, an unspeci-
fied number of mice survived treatment with hafnium
dioxide or hafnium carbide up to 10 g/kg body weight
by stomach tube (210).
Groups of six mice survived treatment with bis(1-
phenyl-1,3-butanedionato)hafnium dichloride, bis(1-
TITANIUM, ZIRCONIUM, AND HAFNIUM 467
phenyl-1,3-butanedionato)hafnium bromide, or tris
(1-phenyl-1,3-butanedionato)hafnium monochloride
at 80, 132, or 223 mg/kg body weight, respec-
tively (227).
Muscular weakness, reduced activity, eye closing,
and weight loss were observed in mice given hafnocene
dichloride at a dose of 20 mg/kg body weight or
higher (227, 228).
Intratracheal: Nine months following the instillation of
50 mg hafnium dioxide or hafnium carbide into the
windpipe of rats, the lungs showed a pronounced cell
reaction accompanied by moderate fibrosis of the
alveolar walls (air sac) (210).
Repeated Exposure
Intraperitoneal: When a hafnium gluconate complex was
administered to rats at about 2–3 g hafnium/kg body
weight/day for apparently 10 days, half of the treated
animals died (224).
Intravenous: Slower growth was reported in 30 rats given
bis(1-phenyl-1,3-butanedionato)hafnium dichloride at
14 mg/kg body weight, twice weekly for 10 weeks.
Though one of the treated rats died compared to none in
controls (0/30), the death was thought to have been due
to a bacterial infection (229).
Other Genotoxicity
Treatment of DNA derived from mammalian thymus or
salmon testes with hafnocene dichloride resulted in
metal–DNA adduct formation (230).
BIBLIOGRAPHY
1. I. Melendez, Titanium complexes in cancer treatment. Crit.
Rev. Oncol. Hematol. 42, 309–315 (2002).
2. F. Caruso and M. Rossi, Antitumor titanium compounds. Mini
Rev. Med. Chem. 4, 49–60 (2004).
3. B. Desoize, Metals and metal compounds in cancer treatment.
Anticancer Res. 24, 1529–1544 (2004).
4. I. Hartman, Rep. Invest. U.S. Bur. Mines 3202, 1951.
5. Communication from J. Butler and V. P. Kawecki, Berylco
Industries, January 15, 1979.
6. P. M. Ambrose et al., Inf. Circ. U.S. Bur. Mines 7777, 1955.
7. R. Rahman, Titanium metal. In The Chemical Economics
Handbook, SRI International, Menlo Park, CA, 1997.
8. U.S. Geological Survey, Mineral Commodity Summaries
2010, U.S. Geological Survey, Washington, DC, 2010, p 193.
9. I. Gotman, Characteristics of metals used in implants. J.
Endocrinol. 11, 383–389 (1997).
10. D. J. Wever et al., Cytotoxic, allergic, and genotoxic activity of
a nickel–titanium alloy. Biomaterials 18, 1115–1120 (1997).
468 BARBARA MALCZEWSKA-TOTH
11. B. S. Gould, Effects of thorium, zirconium, titanium and
cerium on enzyme action. Proc. Soc. Exp. Biol. Med. 34,
381 (1936).
12. B. Duffy et al., Transition metals as protease inhibitors. Biol.
Trace Elem. Res. 641, 197–213 (1998).
13. S. Y. Margolin, Chem. Abstr. 74, 138748 (1971).
14. D. J. Cavanaugh et al., J. Am. Chem. Soc. 77, 1531 (1955).
15. R. Elo et al., Pulmonary deposits of titanium dioxide in man.
Arch. Pathol. 94, 417–424 (1972).
16. L. C. Maillard and J. Ettori, Bull. Acad. Med. (Paris) 115, 631
(1936).
17. I. H. Tipton and M. J. Cook, Trace elements in human tissue.
Part II. Adult subjects from the United States. Health Phys. 9,
103–145 (1963).
18. I. H. Tipton et al., Trace elements in human tissue. Part III.
Subjects from Africa, the Near and Far East, and Europe.
Health Phys. 11, 403–451 (1965).
19. H. A. Schroeder et al., Abnormal trace metals in Man.
J. Chronic Dis. 16, 55 (1963).
20. M. L.Jacobs, Evaluation of Spark Source Mass Spectrometry
in the Analysis of Biologic Samples, HEW Publication
(NIOSH) No. 75-186, 1975.
21. H. M. Perry and E. F. Perry, Normal concentrations of some
trace metals in human urine: changes produced by ethylene-
diaminetetraacetate. J. Clin. Invest. 38, 1452 (1959).
22. J. Gambogi, Titanium. Minerals Information, U.S. Geological
Survey, Washington, DC, 1996.
23. E. Thiers et al., Titanium dioxide pigments—CEH Marketing
Research Report, In The Chemical Economics Handbook, SRI
International, Menlo Park, CA, 1995, pp. 788.5000A–788.
5002X.
24. D. R. Swiler, Pigments, inorganic, In Kirk-Othmer Encyclo-
pedia of Chemical Technology, Wiley, New York, 2005 (online
version).
25. N. C. Mueller and B. Nowack, Exposure modeling of
engineered nanoparticles in the environment. Environ. Sci.
Technol. 42, 4447–4453 (2008).
26. C. D. Robichaud et al., Estimates of upper bounds and trends in
nano-TiO2 production as a basis for exposure assessment.
Environ. Sci. Technol. 43, 4227–4233 (2009).
27. National Institute for Occupational Safety and Health
(NIOSH), Manual of Analytical Methods, 2nd ed., Vol. 3
S385, NIOSH Publication 77-157-C, U.S. Department of
Health and Human Services, Cincinnati, OH, 1994.
28. Occupational Safety and Health Administration (OSHA),
Chemical Information Manual, OSHA Instruction CPL 2-
2.43A, OSHA, Directorate of Technical Support, OSHA
Salt Lake City Center 4T, 1991.
29. K. Maatta and A. U. Arstila, Pulmonary deposits of titanium
dioxide in cytologic and lung biopsy specimens. Light and
electron microscopic X-ray analysis. Lab. Invest. 33, 342–346
(1975).
30. C. A. Moran et al., Identification of titanium in human tissues:
probable role in pathologic processes. Hum. Pathol. 22,
450–454 (1991).
31. H. Christie, R. J. MacKay, and A. M. Fisher, Pulmonary effects
of inhalation of titanium dioxide by rats. Am. Ind. Hyg. Assoc.
J. 24, 42–46 (1963).
32. J. H. Vincent and K. Donaldson, A dosimetric approach to
relating the biological response of the lung to the accumula-
tion of inhaled mineral dust. Br. J. Ind. Med. 47, 302–307
(1990).
33. K. E. Driscoll et al., Respiratory tract responses to dust:
relationships between dust burden, lung injury, alveolar
macrophage fibronectin release, and the development of
pulmonary fibrosis. Toxicol. Appl. Pharmacol. 106, 88–101
(1990).
34. L. C. Renwick et al., Increased inflammation and altered
macrophage chemotactic responses caused by two ultrafine
particle types. Occup. Environ. Med. 61, 442–447 (2004).
35. E. Bermudez et al., Long-term pulmonary responses of three
laboratory rodent species to subchronic inhalation of pig-
mentary titanium dioxide particles. Toxicol. Sci. 70, 86–97
(2002).
36. E. Bermudez et al., Pulmonary responses of mice, rats, and
hamsters to subchronic inhalation of ultrafine titanium dioxide
particles. Toxicol. Sci. 77, 347–357 (2004).
37. M. Geiser et al., Ultrafine particles cross cellular membranes
by nonphagocytotic mechanisms in lungs and in cultured cells.
Environ. Health Perspect. 113, 1555–1560 (2005).
38. V. H. Grassian et al., Inhalation exposure study of titanium
dioxide nanoparticles with primary particle size of 2 and 5 nm.
Environ. Health Perspect. 115, 397–402 (2007).
39. L. Ma-Hock et al., Development of a short-term inhalation test
in the rat using nano-titanium dioxide as a model substance.
Inhal. Toxicol. 21, 102–118 (2009).
40. V. H. Grassian et al., Inflammatory response of mice to
manufactured titanium dioxide nanoparticles: comparison
of size effects through different exposure routes. Nanotox-
icology 1, 211–226 (2007).
41. F. Oberdorster et al., Acute pulmonary effects of ultrafine
particles in rats and mice. Res. Rep. Health Eff. Inst. 96, 5–86
(2000).
42. C. L. Tran et al., Inhalation of poorly soluble particles. II.
Influence of particle surface area on inflammation and clear-
ance. Inhal. Toxicol. 12, 1113–1126 (2000).
43. S. R. Sousa et al., Human serum albumin adsorption on TiO2
from single protein solutions and from plasma. Langmuir 20,
9745–9754 (2004).
44. D. B. Warheit et al., Comparative pulmonary toxicity inhala-
tion and instillation studies with different TiO2 particle for-
mulations: impact of surface treatments on particle toxicity.
Toxicol. Sci. 88, 514–524 (2005).
45. D. B. Warheit et al., Pulmonary instillation studies with
nanoscale TiO2 rods and dots in rats: toxicity is not dependent
upon particle size and surface area. Toxicol. Sci. 91, 227–236
(2006).
46. D. B. Warheit et al., Pulmonary toxicity study in rats with
three forms of ultrafine-TiO2 particles: differential
responses related to surface properties. Toxicology 230,
90–104 (2007).

47. J. R. Gurr et al., Ultrafine titanium dioxide particles in the
absence of photoactivation can induce oxidative damage to
human bronchial epithelial cells. Toxicology 213, 66–73
(2005).
48. S. T. Larsen et al., Nano titanium dioxide particles promote
allergic sensitization and lung inflammation in mice. Basic
Clin. Pharmacol. Toxicol. 106, 114–117 (2009).
49. C. de Haar et al., Ultrafine but not fine particulate matter
cause airway inflammation and allergic airway sensitization
to co-administered antigen in mice. Clin. Exp. Allergy 36,
1469–1479 (2006).
50. A. J. LeBlanc et al., Nanoparticle inhalation impairs endo-
thelium-dependent vasodilation in subepicardial arterioles.
J. Toxicol. Environ. Health A 72, 1576–1584 (2009).
51. K. S. Hougaard et al., Effects of prenatal exposure to surface-
coated nanosized titanium dioxide (UV-Titan). A study in
mice. Part. Fibre Toxicol 7, 1–15 (2010).
52. M. Scuri et al., Effects of titanium dioxide nanoparticle
exposure on neuroimmune responses in rat airways. J. Toxicol.
Environ. Health A 73, 1353–1369 (2010).
53. National Cancer Institute (NCI), Bioassay of Titanium Dioxide
for Possible Carcinogenicity, DHEW (NIH) Publication No.
78-1347, NCI, Bethesda, MD, 1979.
54. J. Wang et al., Acute toxicity and biodistribution of different
sized titanium dioxide particles in mice after oral administra-
tion. Toxicol. Lett. 168, 176–185 (2007).
55. Q. Bu et al., NMR-based metabonomic study of the sub-acute
toxicity of titanium nanoparticles in rats after oral adminis-
tration. Nanotechnology 21, 105–125 (2010).
56. B. Kiss et al., Investigation of micronized titanium dioxide
penetration in human skin xenografts and its effect on cellular
functions of human skin-derived cells. Exp. Dermatol. 8,
659–667 (2008).
57. M. Senzui et al., Study on penetration of titanium dioxide
(TiO2) nanoparticles into intact and damaged skin in vitro.
J. Toxicol. Sci. 35, 107–113 (2010).
58. N. Sadrieh et al., Lack of significant dermal penetration of
titanium dioxide from sunscreen formulations containing
nano- and submicron-size TiO2 particles. Toxicol. Sci. 115,
156–166 (2010).
59. K. P. Lee, H. J. Trochimowicz, and C. F. Reinhardt, Pulmonary
response of rats exposed to titanium dioxide (TiO2) by inha-
lation for two years. Toxicol. Appl. Pharmacol. 79, 179–192
(1985).
60. U. Heinrich et al., Chronic inhalation exposure of Wistar rats
and two different strains of mice to diesel engine exhaust,
carbon black, and titanium dioxide. Inhal. Toxicol. 7,
533–556 (1995).
61. G. Oberd€orster, J. Ferin, and B. Lehnert, Correlation
between particle size, in vivo particle persistence, and lung
injury. Environ. Health Perspect. 102(Suppl. 5), 173–179
(1994).
62. D. B. Warheit et al., Inhalation of high concentrations of low
toxicity dusts in rats results in impaired pulmonary clearance
mechanisms and persistent inflammation. Toxicol. Appl. Phar-
macol. 145, 10–22 (1997).
TITANIUM, ZIRCONIUM, AND HAFNIUM 469
63. F. Pott and M. Roller, Carcinogenicity study with nineteen
granular dusts in rats. Eur. J. Oncol. 10, 249–281 (2005).
64. A. Watson and P. Valberg, Particle-induced lung tumors in
rats: evidence for species specificity in mechanisms. In J. L.
Mauderly and R. J. McCunney, eds., Particle Overload in the
Rat Lung and Lung Cancer, Taylor & Francis, Washington,
DC, 1996, pp. 227–257.
65. R. P. Schins and A. M. Knaapen, Genotoxicity of poorly
soluble particles. Inhal. Toxicol. 19 (Suppl. 1), 189–198
(2007).
66. K. Onuma et al., Nano-scaled particles of titanium dioxide
convert benign mouse fibrosarcoma cells into aggressive
tumor cells. Am. J. Pathol. 175, 2171–2183 (2009).
67. L. V. Blina, Riforma Med. 44, 1516 (1928).
68. P. Schmitz-Moormann, H. Hoerlein, and F. Hanefeld, Lung
changes in exposure to titanium dioxide. Beitr. Silikose-
Forsch. 80, 1–17 (1964).
69. R. L. Hervin and J. B. Lucas, Occupational health case report.
No. 8. Monoisopropanolamine. J. Occup. Med. 16, 355–357
(1974).
70. O. J. Mogilevskaja, Gig. Sanit. 3, 20 (1956).
71. V. M. Shevtsova, The effect of dust from titanium and zirco-
nium ores on workers and also on animals during a long-
duration experiment. Gig. Tr. Prof. Zabol. 12, 24–30 (1968).
72. U. G. Oleru, Respiratory and nonrespiratory morbidity in a
titanium oxide paint factory in Nigeria. Am. J. Ind. Med. 12,
173–180 (1987).
73. J. L. Chen and W. E. Fayerweather, Epidemiologic study of
workers exposed to titanium dioxide. J. Occup. Med. 30,
937–942 (1988).
74. J. P. Fryzek et al., A cohort mortality study among titanium
dioxide manufacturing workers in the United States. J. Occup.
Environ. Med. 45, 400–409 (2003).
75. P. Boffeta et al., Exposure to titanium dioxide and risk of lung
cancer in a population-based study from Montreal. Scand. J.
Work Environ. Health 27, 227–232 (2001).
76. P. Boffetta et al., Mortality among workers employed in the
titanium dioxide production industry in Europe. Cancer
Causes Control 15, 697–706 (2004).
77. E. D. Ellis et al., Mortality among titanium dioxide workers at
three DuPont plants. J. Occup. Environ. Med. 52, 303–309
(2010).
78. J. Ferin, Papain-induced emphysema and the elimination of
TiO2 particulates from the lungs. Am. Ind. Hyg. Assoc. J. 32,
157–162 (1971).
79. J. Ferin and L. J. Leach, The effect of sulfur dioxide on lung
clearance of titanium dioxide particles in rats. Am. Ind. Hyg.
Assoc. J. 34, 260–263 (1973).
80. H. J. Johnston et al., Identification of the mechanisms that
drive the toxicity of TiO2 particulates: the contribution of
physicochemical characteristics. Part. Fibre Toxicol. 6(33),
1–27 (2009).
81. R. F. Hamilton et al., Particle length-dependent titanium
dioxide nanomaterials toxicity and bioactivity. Part. Fibre
Toxicol. 6(35), 1–11 (2009).
470 BARBARA MALCZEWSKA-TOTH
82. S. Hussain et al., Carbon black and titanium dioxide nano-
particles elicit distinct apoptotic pathways in bronchial epi-
thelial cells. Part. Fibre Toxicol. 7(10), 1–17 (2010).
83. Y. Shi et al., Titanium dioxide nanoparticles cause apoptosis
in BEAS-2B cells through the caspase 8/t-Bid-independent
mitochondrial pathway. Toxicol. Lett. 196, 21–27 (2010).
84. J. Zhao et al., Titanium dioxide (TiO2) nanoparticles induce
JB6 cell apoptosis through activation of the caspase-8/Bid and
mitochondrial pathways. J. Toxicol. Environ. Health A 72,
1141–1149 (2009).
85. N. Li et al., Spleen injury and apoptotic pathway in mice caused
by titanium dioxide nanoparticules. Toxicol. Lett. 195, 161–168
(2010).
86. G. C. Falck et al., Genotoxic effects of nanosized and fine
TiO2. Hum. Exp. Toxicol. 28, 339–3552 (2009).
87. S. Hackenberg et al., Intracellular distribution, geno- and
cytotoxic effects of nanosized titanium dioxide particles in
the anatase crystal phase on human nasal mucosa cells.
Toxicol. Lett. 195, 9–14 (2010).
88. T. C. Long et al., Nanosize titanium dioxide stimulates reac-
tive oxygen species in brain microglia and damages neurons
in vitro. Environ. Health Perspect. 115, 1631–1637 (2007).
89. A. Gramowski et al., Nanoparticles induce changes of the
electrical activity of neuronal networks on microelectrode
array neurochips. Environ. Health Perspect. 118, 1363–1369
(2010).
90. D. H. Wegman and L. J. Fine, Occupational health in the
1990s. Annu. Rev. Public Health 11, 89–103 (1990).
91. Occupational Health and Safety Administration (OSHA),
Code of Federal Regulations (CFR), 29 CFR Part 1910
(1910.1000 to end) (revised as of June 1, 2005). U.S. Govern-
ment Printing Office, Washington, DC, 2005.
92. American Conference of Governmental Industrial Hygienists
(ACGIH), Threshold Limit Values and Biological Exposure
Indices, ACGIH, Cincinnati, OH, 2000.
93. National Institute for Occupational Safety and Health
(NIOSH), Recommendations for Occupational Safety and
Health. Compendium of Policy Documents and Statements,
DHHS (NIOSH) Publication No. 92-100, U.S. Department of
Health and Human Services, Public Health Service, Centers
for Disease Control, Division of Standards Development and
Technology Transfer, Cincinnati, OH, 1992.
94. International Agency for Research on Cancer (IARC), Mono-
graphs on the Evaluation of Carcinogenic Risks to Humans:
Carbon Black, Titanium Dioxide, and Talc, Vol. 93, World
Health Organization, Lyon, France, 2010.
95. K. P. Lee et al., Inhalation toxicity study on rats exposed
to titanium tetrachloride atmospheric hydrolysis products for
two years. Toxicol. Appl. Pharmacol. 83, 30–45 (1986).
96. J. J. Lawson, The toxicity of titanium tetrachloride. J. Occup.
Med. 3, 7–12 (1961).
97. J. A. Zapp, Toxicity of Titanium Tetrachloride, In-House
Report, Medical Research Project No. MR-176, DuPont
Haskell Laboratory, Wilmington, DE, 1948.
98. J. A. Zapp, Further Studies, Medical Research Project No.
MR-199, DuPont Haskell Laboratory, Wilmington, DE, 1949.
99. D. K. Chitkara and B. J. McNeela, Titanium tetrachloride
burns to the eye. Br. J. Ophthalmol. 76, 380–382 (1992).
100. W. E. Fayerweather et al., Epidemiologic study of lung cancer
mortality in workers exposed to titanium tetrachloride. J.
Occup. Med. 34, 164–169 (1992).
101. S. M. Paulsen, L. B. Nanney, and J. B. Lynch, Titanium
tetrachloride: an unusual agent with the potential to create
severe burns. J. Burn Care Rehabil. 19, 377–381 (1998).
102. P. K€opf-Maier and H. K€ opf, Non-platinum-group metal anti-
tumor agents: history, current status, and perspectives. Chem.
Rev. 87, 1137–1152 (1987).
103. P. K€opf-Maier, U. Brauchle, and A. Henssler, Organ distribu-
tion and pharmacokinetics of titanium after treatment with
titanocene dichloride. Toxicology 51, 291–298 (1988).
104. P. K€opf-Maier, U. Brauchle, and A. Heussler, Transplacental
passage of titanium after treatment with titanocene dichloride.
Toxicology 48, 253–260 (1988).
105. A. Furst and R. T. Haro, A survey of metal carcinogenesis.
Prog. Exp. Tumor Res. 12, 103 (1969).
106. A. Furst and R. T. Haro, 10th International Cancer Congress,
Houston, TX, 1970, Abstract, p. 28.
107. National Toxicology Program (NTP), Toxicology and Carci-
nogenesis Studies of Titanocene Dichloride (CAS No. 1271-
19-8) in F344/N Rats (Gavage Studies), NTP Technical
Report No. 399, NIH Publication No. 91-2854, NTP,
Washington, DC, 1991.
108. R. P. Beliles, Zirconium, In Patty’s Industrial Hygiene and
Toxicology, 3rd ed., Vol. II, Part C, Wiley, New York, 1994,
pp. 2342–2352.
109. W. B. Blumenthal, Zirconium, In McGraw-Hill Encyclopedia
of Science & Technology, 7th ed., Vol. 19, McGraw-Hill, New
York, 1992, pp. 630–633.
110. R. H. Nielsen, J. H. Schlewitz, and H. Nielsen, Zirconium and
zirconium compounds, In Kirk-Othmer Encyclopedia of
Chemical Technology, 3rd ed., Vol. 24, Wiley, New York,
1984, pp. 863–902.
111. H. D. Hess, Rep. Invest. U.S. Bur. Mines RI-5856, 1962.
112. M. H. Klaproth, Kirk-Othmer Encyclopedia of Chemical
Technology, 3rd ed., Vol. 24, Wiley, New York, 1984, p. 863.
113. L. N. Vauquelin, Kirk-Othmer Encyclopedia of Chemical
Technology, 3rd ed., Vol. 24, Wiley, New York, 1984,
pp. 863–864.
114. H. E. Stokinger, Zirconium, In Patty’s Industrial Hygiene and
Toxicology, 3rd ed., Vol. IIA, Wiley, New York, 1981,
pp. 2049–2060.
115. L. E. Tanner, Armour Research Foundation Report ARF-
20685, 1958.
116. W. B. Blumenthal, The Chemical Behavior of Zirconium, Van
Nostrand, Princeton, NJ, 1958.
117. G. L. Miller, Zirconium, 2nd ed., Academic Press, New York,
1958.
118. O. N. Carlson, F. A. Schmidt, and H. A. Wilhelm, J. Electro-
chem. Soc. 104, 51 (1957).
119. C. J. DeCroly, J. Gerard, and D. Tytgat, Rev. Metall. (Paris) 56,
143 (1959).

120. G. J. Shiflet, Kirk-Othmer Encyclopedia of Chemical Tech-
nology, 4th ed., Vol. 12, Wiley, New York, 1994, p. 663.
121. G. Blomgren and J. Hunter, Kirk-Othmer Encyclopedia of
Chemical Technology, 4th ed., Vol. 3, Wiley, New York, 1992,
p. 1025.
122. C. V. Rue, Kirk-Othmer Encyclopedia of Chemical Technol-
ogy, 4th ed., Vol. 1, Wiley, New York, 1991, pp. 17–18.
123. C. A. Babu et al., Removal of fluoride from pickling waste
with zirconium. Waste Manage. 13(3), 279–283 (1993).
124. D. M. Lisi, Availability of zirconium in topical antiperspirants.
Arch. Intern. Med. 152, 421–426 (1992).
125. H. Horn and U. Horns, Kirk-Othmer Encyclopedia of Chemi-
cal Technology, 4th ed., Vol. 2, Wiley, New York, 1992, p. 48.
126. R. L. Flescher and R. J. Zabala, Metall. Trans. A 20(7),
1279–1282 (1989).
127. E. E. Campbell, The determination of zirconium in air. Am.
Ind. Hyg. Assoc. J. 20, 281–283 (1959).
128. V. A. Fassel and R. N. Kniseley, Anal. Chem. 46, 1110A (1974).
129. National Institute for Occupational Safety and Health
(NIOSH), Manual of Analytical Methods, Trace Elements
by FAAS Method: Zirconium, Method 7013-7082, 4th ed.,
NIOSH, Cincinnati, OH, 1994.
130. National Institute for Occupational Safety and Health
(NIOSH), Manual of Analytical Methods, Elements in
Blood or Tissue: Zirconium, Method 8005, 4th ed., Issue 2,
NIOSH, Cincinnati, OH, 1994.
131. P. Bearin, J. Assoc. Off. Anal. Chem. 59, 830 (1976).
132. P. Bearin, J. Assoc. Off. Anal. Chem. 60, 663 (1977).
133. N. A. Talvitie, Determination of free silica: gravimetric and
spectrophotometric procedures applicable to air-borne and
settled dust. Am. Ind. Hyg. Assoc. J. 25, 169–178 (1964).
134. P. N. Dimotakis et al., Trace metals in lignites and ashes of
Greek power plants. J. Radioanal. Nucl. Chem. Lett. 127(2),
133–141 (1988).
135. X. Querol et al., Trace element contents in atmospheric
suspended particles: inferences from instrumental neutron
activation analysis. Fresenius’ J. Anal. Chem. 357(7),
934–940 (1997).
136. G. W. Girnham, G. A. Codd, and G. M. Gadd, Accumulation of
zirconium by microalgae and cyanobacteria. Appl. Microbiol.
Biotechnol. 39(4–5), 666–672 (1993).
137. S. El Alfy and A. A. Abdel-Rassoul, Trace metal pollutants in
El Manzala lakes by inductively coupled plasma spectroscopy.
Water Res. 27(7), 1253–1256 (1993).
138. T. Bartter et al., Zirconium compound-induced pulmonary
fibrosis. Arch. Intern. Med. 151(6), 1197–1201 (1991); also
see comments: Arch. Intern. Med. 152 (2), 421–422, 426 (1992).
139. L. Rubin et al., Granulomas of the axillas caused by deodor-
ants. J. Am. Med. Assoc. 162(10), 953–955 (1956).
140. Editorial, Lancet, May 31 (1958).
141. J. T. Prior, H. Rustad, and G. A. Cronk, Pathological changes
associated with deodorant preparations containing sodium
zirconium lactate: an experimental study. J. Invest. Dermatol.
29, 449–463 (1957).
TITANIUM, ZIRCONIUM, AND HAFNIUM 471
142. J. T. Prior and G. A. Cronk, Pathological changes associated
with aluminum and zirconium compounds. Arch. Dermatol.
80, 105–112, 447–454, (1959).
143. R. M. Williams and G. B. Skipworth, Zirconium granulomas
of the glabrous skin following treatment of rhus dermatitis.
Arch. Dermatol. 80, 273–276 (1959).
144. W. B. Shelley and H. J. Hurley, The allergic origin of zirco-
nium deodorant granulomas. Br. J. Dermatol. 70, 75–101
(1958).
145. J. Doull, C. D. Klaassen, and M. D. Amdur, eds., Casarett and
Doull’s Toxicology, 2nd ed., Macmillan, New York, 1980.
146. L. Romeo et al., Zirconium interstitial lung disease: case
reports, In J. Hurych, M. Lesage, and A. David, eds., Proceed-
ings of the 8th International Conference on Occupational
Lung Diseases, Prague, Czechoslovakia, 1992, Vol. III,
Czech Medical Society, Prague, Czech Republic, 1993,
pp. 1016–1020.
147. C. E. Reed, A study of the effects on the lung of industrial
exposure to zirconium dusts. Arch. Ind. Health 13, 578–580
(1956).
148. O. C. Hadjimichael and R. E. Brubaker, Evaluation of an
occupational respiratory exposure to a zirconium-containing
dust. J. Occup. Med. 23(8), 543–547 (1981).
149. American Conference of Governmental and Industrial Hygie-
nists (ACGIH), Documentation of Threshold Limit Values and
Biological Exposure Indices, 5th ed., ACGIH, Cincinnati, OH,
1986.
150. H. E. Stokinger, In G. Clayton and F. Clayton, eds., Patty’s
Industrial Hygiene and Toxicology, 3rd ed., Vol. 2A, Wiley,
New York, 1981, pp. 1493–2060.
151. E. Ebbinghaus, K. H. Kreeb, and R. Weinmann-Kreeb, GIS
supported monitoring long-termed urban trace element loads
with bark of Aesculus hippocastanum L. J. Appl. Bot. 71(5–6),
205–211 (1997).
152. S. Sakao, Y. Ogawa, and H. Uchida, Determination of trace
elements in sea weed samples by inductively coupled plasma
mass spectrometry. Anal. Chim. Acta 355(2–3), 121–127
(1997).
153. P. Couture et al., Zirconium toxicity assessment using bacte-
ria, algae and fish assays. Water Air Soil Pollut. 47(1–2),
87–100 (1989).
154. N. I. Sax, Dangerous Properties of Industrial Materials, 6th
ed., Van Reinhold Nostrand, New York, 1984.
155. H. C. Hodge et al., Atomic Energy Commission Project,
University of Rochester, Rochester, NY, 1955 (unpublished
results).
156. H. A. Schroeder and A. P. Nason, Interactions of trace metals
in mouse and rat tissues; zinc, chromium, copper, and
manganese with 13 other elements. J. Nutr. 106(2),
198–203 (1976).
157. J. G. Hamilton, Report No. MDDC-1001, U.S. Atomic Energy
Commission, Washington, DC, 1944.
158. Y. Ikarashi et al., Evaluation of skin sensitization potential of
nickel, chromium, titanium and zirconium salts using guinea-
pigs and mice. Biomaterials 17(21), 2103–2108 (1996).
472 BARBARA MALCZEWSKA-TOTH
159. C. J. Spigel et al., Inhalation Toxicity of Zirconium Com-
pounds. I. Short-Term Studies, Report No. UR-460, Atomic
Energy Project, University of Rochester, Rochester, New
York, 1956.
160. J. A. Styles and J. Wilson, Comparison between in vitro
toxicity of two novel fibrous mineral dusts and their tissue
reactions in vivo. Ann. Occup. Hyg. 19(1), 63–68 (1976).
161. Anonymous, Zirconium Powder, National Safety Council,
Chicago, IL, 1986.
162. A. Spiethoff et al., The combined and separate action of
neutron radiation and zirconium dioxide on the liver of
rats. Health Phys. 63(1), 111–118 (1992).
163. S. Hatanaka et al., Induction of malignant fibrous histiocytoma
in female Fisher rats by implantation of cyanoacrylate, zirco-
nia, polyvinyl chloride or silicone. In Vivo 7(2), 111–116
(1993).
164. M. Uchida and A. Fujita, Fibril collagen in tumors induced by
lanthanum and zirconium oxide containing hydroxyapatites.
J. Osaka Odontol. Soc. 56(5), 361–375 (1993).
165. R. J. Price and D. N. Skilleter, Mitogenic effects of beryllium
and zirconium salts on mouse splenocytes in vitro. Toxicol.
Lett. 30(1), 89–95 (1986).
166. R. T. Haro, A. Furst, and H. L. Falk, Studies on the acute
toxicity of nickelocene. Proc. West. Pharmacol. Soc. 11,
39–42 (1968).
167. H. A. Schroeder, M. Mitchener, and A. P. Nason, Zirconium,
niobium, antimony, vanadium and lead in rats: life term
studies. J. Nutr. 100, 59–68 (1970).
168. J. P. Berry, F. Bertrand, and P. Galle, Subcellular localization
of zirconium in nodular lymphatic cells after administration of
soluble salts. Study by electron microprobe. Toxicology 62(2),
239–246 (1990).
169. S. Shima et al., IgM antibody production in mice intraperito-
neally injected with zirconium oxychloride. Br. J. Ind. Med. 44
(9), 633–637 (1987).
170. J. van Niekirk, Naunyn-Schmiedebergs Arch. Exp. Pathol.
Pharmakol. 184, 686 (1937).
171. S. Ghosh, A. Sharma, and G. Talukder, Relationship of
clastogenic effects of zirconium oxychloride to dose and
duration of exposure in bone marrow cells of mice in vivo.
Toxicol. Lett. 55(2), 195–201 (1991).
172. S. Ghosh, A. Sharma, and G. Talukder, Cytotoxic effects of
zirconium oxychloride on bone marrow cells of mice. Mutat.
Res. 243(1) 29–33 (1990).
173. H. Dhir et al., Interaction between two group IV metals—lead
and zirconium—in bone marrow cells of Mus musculus
in vivo. Biometals 5(2), 81–86 (1992).
174. S. Shima et al., Experimental study of cytotoxicity of zirco-
nium compounds in vitro. Nippon Eiseigaku Zasshi 43(4),
895–900 (1988).
175. R. H. Dreisbach, Handbook of Poisoning, 9th ed., Lange
Medical Publications, Los Altos, CA, 1977.
176. S. Ghosh, G. Talukder, and A. Sharma, Cytogenetic effects
of exposure to zirconium oxychloride in human leukocyte
cultures. Toxicol. In Vitro 5(4), 295–300 (1991).
177. E. C. Bovee and T. L. O’Brien, Some effects of selenium,
vanadium and zirconium on the swimming rate of Tetrahy-
mena pyriformis: a bioassay study. Univ. Kans. Sci. Bull. 52
(4), 39–44 (1982).
178. K. K. Liippo et al., Hypersensitivity pneumonitis and exposure
to zirconium silicate in a young ceramic tile worker. Am. Rev.
Respir. Dis. 148, 1089–1092 (1993)
179. R. G. Thomas, S. A. Walker, and R. O. McClellan, Relative
hazards for inhaled 95 Zr and 95 Nb particles formed under
various thermal conditions. Proc. Soc. Exp. Biol. Med. 138(1),
228–234 (1971).
180. Y. Shiraishi and R. Ichikawa, Absorption and retention of Ce-
144 and Zr-95–Nb-95 in newborn, juvenile and adult rats.
Health Phys. 22(4), 373–378 (1972).
181. J. Schubert, An experimental study of the effect of zirco-
nium and sodium citrate treatment on the metabolism of
plutonium and radioyttrium. J. Lab. Clin. Med. 34, 313–325
(1949).
182. J. R. Dixon et al., Metal shifts as early indicators of response
from low-grade pulmonary irritation. Appl. Pharmacol. 9(2),
225–233 (1966).
183. H. G. Skelton 3rd et al., Zirconium granuloma resulting
from an aluminum zirconium complex: a previously unrec-
ognized agent in the development of hypersensitivity
granulomas. J. Am. Acad. Dermatol. 28(5), 874–876
(1993).
184. R. L Marcus, S. Turner, and N. M. Cherry, A study of lung
function and chest radiographs in men exposed to zirconium
compounds. Occup. Med. 46(2), 109–113 (1996).
185. W. B. Shelley and H. J. Hurley, The immune granuloma: late
delayed hypersensitivity to Zr and Be, In M. Samter, ed.,
ImmunologicDiseases,Little,Brown,& Co.,Boston,MA,1971.
186. G. R. Baler, Granulomas from topical zirconium in poison ivy
dermatitis. Arch. Dermatol. 91, 145–148 (1965).
187. W. L. Epstein, Granulomatous hypersensitivity. Prog. Allergy
11, 36–88 (1967).
188. M. L. Roy et al., Worker exposure to lead titanate zirconate in
an Ontario companyJ. Occup. Med. 31(12), 986–989 (1989).
Comment in: J. Occup. Med. 32 (7), 645–646 (1990).
189. U. Werfel et al., Sarcoid granulomatosis after zirconium
exposure with multiple organ involvement. Eur. Respir. J.
12, 750 (1998).
190. J. M. Kotter and G. Zieger, Zirconium-lunge. Pathologe 13,
104–109 (1992).
191. N. J. James, J. Rutherford, and G. T. Sheppard, Zircaloy
hazards in nuclear fuel reprocessing. Hazards in the process
industries: Hazards IX. Inst. Chem. Eng. Symp. Ser. 97,
143–157 (1986).
192. W. B. Blumenthal, Hafnium, In McGraw-Hill Encyclopedia
of Science & Technology, 7th ed., Vol. 8, McGraw-Hill,
New York, 1992, pp. 286–287.
193. D. Coster and von Hevesy, Nature (London) 111, 252 (1923).
194. K. B. Esser, J. G. Bockheim, and P. A. Helmke, Trace element
distribution in soils formed in the Indiana dunes, U.S.A. Soil
Sci. 152, 340–350 (1991).

195. N. I. Sax and R. J. Lewis, eds., Hawley’s Condensed
Chemical Dictionary, 11th ed., Van Nostrand Reinhold,
New York, 1987, p. 583.
196. F. J. Hurst, Separation of Hafnium from Zirconium in Sulfuric
Acid Solutions Using Pressurized Ion Exchange, Government
Reports Announcements Index, Issue 17, 1981.
197. U.S. Department of Transportation, Emergency Response
Guidebook, DOT P 5800.4, U.S. D.O.T., Washington, DC,
1987.
198. National Institute for Occupational Safety and Health
(NIOSH), Pocket Guide to Chemical Hazards, U.S. Depart-
ment of Health and Human Services, Washington, DC, 1998,
pp. 156–157 and CD ROM, 2000.
199. L. Bretherick, Handbook of Reactive Chemical Hazards, 6th
ed., Vol. 1, Butterworth, Heinemann, 1999.
200. B. Venugopal and T. D. Luckey, Metal Toxicity in Mammals,
Vol. 2, Plenum, New York, 1978, p. 203.
201. J. Schemel, ASTM Manual on Zirconium and Hafnium, ASTM
STP 639, American Standards for Testing and Materials,
Philadelphia, PA, 1977.
202. American Conference of Governmental Industrial Hygienists
(ACGIH), Documentation of the Threshold Limit Values and
Biological Exposure Indices, 6th ed., Vol. 2, ACGIH, Cincin-
nati, OH, 1991.
203. D. R. Lide, ed., CRC Handbook of Chemistry and Physics,
71st ed., CRC Press, Boca Raton, FL, 1990–1991, pp. 4–15.
204. S. Budavari, ed., The Merck Index: Encyclopedia of Chemicals,
Drugs and Biologicals, Merck & Co., Rahway, NJ, 1989, p. 723.
205. Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 12,
Wiley, New York, 1978–1984.
206. Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed., Vol.
A1, VCH Publishers, Deerfield Beach, FL, 1985 to present.
207. R. H. Nielsen, Hafnium and hafnium compounds, In Kirk-
Othmer Encyclopedia of Chemical Technology, 4th ed.,
Vol. 12, Wiley, New York, 1994, p. 872.
208. P. H. Booker and R. E. Curtis, Cutting Tool Eng. 30(9–10), 18
(1976).
209. T. J. Haley et al., The toxicologic and pharmacologic effects of
hafnium salts. Toxicol. Appl. Pharmacol. 4, 238–246 (1962).
210. N. A. Zhilova, Experimental study of the toxicity of some
hafnium compounds. Hyg. Sanit. 29, 132–134 (1964).
211. R. E. Lenga, ed., The Sigma Aldrich Library of Chemical Safety
Data, 1st ed., Sigma Aldrich Corp., Milwaukee, WI, 1985.
212. E. M. Larsen, Zirconium and hafnium chemistry, In H. J.
Emelius and A. F. Sharpe, eds., Advances in Inorganic Chem-
istry and Radiochemistry, Academic Press, New York, 1970,
pp. 92–97.
213. American Conference of Governmental and Industrial Hygie-
nists (ACGIH), Documentation of the Threshold Limit Values
TITANIUM, ZIRCONIUM, AND HAFNIUM 473
and Biological Exposure Indices, 6th ed., on CD-ROM,
ACGIH, Cincinnati, OH, 1991.
214. W. B. Shelley, Chondral dysplasia induced by zirconium and
hafnium. Cancer Res. 33(2), 287–292 (1973).
215. W. B. Shelley et al., Intradermal test with metals and other
inorganic elements in sarcoidosis and anthraco-silicosis.
J. Invest. Dermatol. 31, 301 (1958).
216. A. J. Stonehouse and M. N. Emily, Beryllium compounds, In
Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.,
Vol. 4, Wiley, New York, 1978, p. 149.
217. W. G. Moffat, Handbook of Binary Phase Diagrams, General
Electric Co., Schenectady, New York, 1976.
218. H. R. Hoekstra and J. J. Katz, J. Am. Chem. Soc. 71, 2488 (1949).
219. Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.,
Vol. 4, Wiley, New York, 1978, p. 498.
220. E. Rudy, Ternary Phase Equilibria in Transition-Metal-Boron-
Carbon-Silicon Systems. Part V. Compendium of Phase Dia-
gram Data, AFML-TR-65-2, Air Force Materials Laboratory,
Wright-Patterson Air Force Base, Dayton, OH, 1969.
221. F. D. Stevenson and C. E. Wicks, J. Chem. Eng. Data. 10, 33
(1965).
222. I. T. Brakhnova et al., Gig. Sanit. 37, 36 (1972).
223. D. M. Taylor, A. Seidel, and H. Doertfel, The metabolism of
radioactive hafnium in marmosets and hamsters. Int. J. Nucl.
Med. Biol. 12(5), 387–392 (1985).
224. C. F. Kittle et al., J. Pharmacol. Exp. Ther. 101, 21 (1951).
225. C. F. Kittle et al., Distribution and excretion of radioactive
181-hafnium sodium mandelate in the rat. Proc. Soc. Exp.
Biol. Med. 76, 278–282 (1951).
226. B. K. Keppler and K. Michels, Antitumor activity of 1.3-
diketonato zirconium(IV) and hafnium(IV) complexes.
Arzneim. Forsch. 35, 1837- 1839 (1985)
227. P. Kopf-Maier, B. Hesse, and H. Kopf, Tumor inhibition by
metallocenes: effect of titanocene, zirconocene, and haf-
nocene dichlorides on Ehrlich ascites tumor in mice
(author’s transl.). J. Cancer Res. Clin. Oncol. 96(1),
43–51 (1980).
228. P. Kopf-Maier, W. Wagner, and H. Kopf, In vitro cell growth
inhibition by metallocene dichlorides. Cancer Chemother.
Pharmacol. 5(4), 237–241 (1981).
229. H. Bischoff et al., Efficacy of beta-diketonato complexes of
titanium, zirconium, and hafnium against chemically induced
autochthonous colonic tumors in rats. J. Cancer Res. Clin.
Oncol. 113(5), 446–450 (1987).
230. M. L. McLaughlin et al., DNA-metal binding by antitumor-
active metallocene dichlorides from inductively coupled
plasma spectroscopy analysis: titanocene dichloride forms
DNA–Cp2Ti or DNA–CpTi adducts depending on pH.
J. Am. Chem. Soc. 112, 8949–8953 (1990).