United States
Environmental Protection
1=1 m m Agency
EPA/690/R-12/038F
Final
12-27-2012
Provisional Peer-Reviewed Toxicity Values for
Soluble Zirconium Compounds
(CASRN 7440-67-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	3
HUMAN STUDIES	8
Oral Exposures	8
Inhalation Exposures	8
Other Exposures	9
ANIMAL STUDIES	10
Oral Exposures	10
Chronic Studies	10
Inhalation Exposures	11
Short-term Studies	12
Subchronic Studies	12
Chronic Studies	12
Developmental Studies	12
Reproductive Studies	12
Other Routes of Exposure	13
Injection	13
Implant	14
Other Data	14
Short-Term Studies	14
Toxicokinetics	15
Genotoxicity	15
DERIVATION 01 PROVISIONAL VALUES	17
Derivation of Oral Reference Doses	17
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	18
Derivation of Chronic Provisional RfD (Chronic p-RfD)	18
Derivation of Inhalation Reference Concentrations	18
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)	19
Derivation of Chronic Provisional RfC (Chronic p-RfC)	19
Cancer Weight-of-Evidence Descriptor	19
Derivation of Provisional Cancer Potency Values	19
Derivation of Provisional Oral Slope Factor (p-OSF)	19
Derivation of Provisional Inhalation Unit Risk (p-IUR)	19
APPENDIX A. PROVISIONAL SCREENING VALUES	20
APPENDIX B. DATA TABLES	22
APPENDIX C. BMD OUTPUTS	26
APPENDIX D. REFERENCES	27
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
SOLUBLE ZIRCONIUM COMPOUNDS (CASRN 7440-67-7)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Zirconium is a metallic element having the atomic number of 40, an atomic weight of
91.22, and the chemical symbol (Zr) (ChemlDplus, 2011). It exists as a soft, malleable ductile
solid or gray to gold, amorphous powder. It is resistant to corrosion by water and steam, mineral
acids, strong alkalis, organic acids, salt solutions, and molten salts. It forms alloys with almost
all metals—except mercury, alkali, and alkaline earth groups (HSDB, 2006). Table 1 provides a
table of physicochemical properties. In this document, "statistically significant" denotes a
p-value of <0.05.
Table 1. Physicochemical Properties Table for Zirconium (CASRN 7440-67-7)a
Property (unit)
Value
Boiling point (°C)
3577
Melting point (°C)
1857
Density (g/cm3)
6.5107
Vapor pressure (Pa at 25°C)
0 mmHg
pH (unitless)
Data not available
Solubility in water (g/100 mL at 25°C)
Data not available—Soluble in hot concentrated acid
Relative vapor density (air =1)
Data not available
Molecular weight (g/mol)
91.224
aValues from HSDB (2010) and ChemID plus (2011).
No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for
zirconium is included in the United States Environmental Protection Agency (U.S. EPA)
Integrated Risk Information System (IRIS) database (U.S. EPA, 2010) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 2009). No RfD or RfC values are reported in
the Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 2011). The Chemical
Assessments and Related Activities (CARA) list (U.S. EPA, 1994) includes a Health and
Environmental Effects Profile (HEEP) for zirconium (U.S. EPA, 1985) that declined to derive
noncancer and cancer toxicity values due to inadequate noncancer and cancer data, respectively.
The toxicity of zirconium has not been reviewed by the Agency for Toxic Substances and
Disease Registry (ATSDR, 2011) or the World Health Organization (WHO, 2010). The
California Environmental Protection Agency (CalEPA, 2008) has also not derived toxicity values
for exposure to zirconium.
Occupational exposure limits for zirconium have been established by the Occupational
Safety and Health Administration (OSHA, 2006), the National Institute of Occupational Safety
and Health (NIOSH, 1994), and the American Conference of Governmental Industrial Hygienists
(ACGIH, 2011). The OSHA permissible exposure limit (PEL) 8-hour time weighted average
(TWA) for zirconium is 5 mg/m3 (OSHA, 2010). NIOSH has set a recommended exposure limit
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(REL) TWA of 5 mg/m3 and a REL short-term exposure limit (STEL) of 10 mg/m3 that applies
to all zirconium compounds—except zirconium tetrachloride for which it has set no REL. The
NIOSH IDLH (Immediately Dangerous to Life or Health) concentration for zirconium is
25 mg Zr/m3 (NIOSH, 1994). The ACGIH has set a threshold limit value (TLV) TWA of
5 mg/m3 and a STEL of 10 mg/m3 for zirconium (ACGIH, 2011).
The HEAST (U.S. EPA, 2011) did not report a U.S. EPA (1986) cancer
weight-of-evidence (WOE) classification or an oral slope factor for Zirconium. The
International Agency for Research on Cancer (IARC, 2011) has not reviewed the carcinogenic
potential of zirconium. Zirconium is not included in the 12th Report on Carcinogens (NTP,
2011). The CAL EPA online database CalEPA (2002) does not include a quantitative estimate
of carcinogenic potential for zirconium. ACGIH has classified zirconium in the Group A4: "not
classifiable as a human carcinogen" (ACGIH, 2011).
Literature searches were conducted on sources published from 1900 through April 2012,
for studies relevant to the derivation of provisional toxicity values for zirconium (elemental),
CASRN 7440-67-7, zirconium oxychloride, CASRN 7699-43-6, zirconium tetrachloride,
CASRN 10026-11-6, zirconium compounds, no CASRN, zirconium nitrate,
CASRN 13746-89-9, zirconium picramate, CASRN 63868-82-6, zirconium acetate,
CASRN 7585-20-8, zirconium silicate, CASRN 14940-68-2, zirconium potassium fluoride,
CASRN 16923-95-8, and zirconium ammonium fluoride, CASRN 16919-31-6. Searches were
conducted using the U.S. EPA's Health and Environmental Research Online (HERO) database of
scientific literature. HERO searches the following databases: AGRICOLA; American Chemical
Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information
Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview;
GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science &
Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA
publications available through the National Service Center for Environmental Publications
(NSCEP) and National Environmental Publications Internet Site (NEPIS) database); PubMed:
MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink;
TOXNET (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART,
EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS,
ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for relevant health information: ACGIH, ATSDR, CalEPA, U.S. EPA
IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2,
NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for zirconium and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. Principal
studies are identified by the note PS, and entries for the principal studies are presented in bold.
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Table 2. Summary of Potentially Relevant Data for Soluble Zirconium Compounds (CASRN 7440-67-7)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAELab
Reference
(Comments)
Notes0
Human
1. Oral (mg/kg-day)a
None
2. Inhalation (mg/m3)a
Subchronic
None
Chronic
22 workers (sex not
reported), case report,
1-5 years
Not reported
No abnormalities
None
Not run
None
Reed et al.
(1956)

32 male, case report,
1-17 yrs
Not reported
No abnormalities
None
Not run
None
Bingham et al.
(2001)

150 workers (sex not
reported), survey, duration
not reported
Not reported
Respiratory irritation, dermatitis
None
Not run
None
Thoburn and
Straub (NIOSH)
(1976)

178 male, occupational
epidemiology, 10 years
(average)
<1 mg/m3;
1-2.5 mg/m3;
2.5-10 mg/m3;
>10 mg/m3;
No abnormalities
>10
mg/m3
Not run
None
Marcus et al.
(1996)

1 female, case report,
3.5 years
5.8 >30%
zirconium
silicate with clay
Interstitial inflammation, fibrosis of
alveolar walls
None
Not run
None
Liippo et al.
(1993)

1 male, case report,
39 years
Not reported
Pulmonary fibrosis
None
Not run
None
Bartter, et al.
(1991)

1 worker (sex not reported),
case report, duration not
reported
Not reported
Interstitial lung granuloma
None
Not run
None
Romeo et al.
(1994)

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Table 2. Summary of Potentially Relevant Data for Soluble Zirconium Compounds (CASRN 7440-67-7)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAELab
Reference
(Comments)
Notes0
Chronic
1 male, 20 yrs and 1 male,
8 years, case report
Not reported
Lung fibrosis
None
Not run
None
Bingham et al.
(2001)

Developmental
None
Reproductive
None
Carcinogenic
None
Animal
1. Oral (mg/kg-day)a
Subchronic
None
Chronic
56/58, Long-Evans rat,
drinking water
(zirconium sulfate), feed
(zirconium), lifetime
0,0.79 (M),
0.89 (F)
combined
drinking water
and feedd
Significantly increased incidence of
glycosuria, females had higher fasting
serum glucose levels and males had
higher cholesterol levels
No significant increase in tumor
incidence
None
Not run
0.79 (M),
0.89 (F)
Schroeder et al.
(1970);
Kanisawa and
Schroeder
(1969)
PS
54/54, Charles River CD-I
mouse, drinking water
(zirconium sulfate), feed
(zirconium), lifetime
0, 1.71 (M), 1.75
(F) combined
drinking water
and feedd
Significant difference in survival in
female mice, significant decrease in
body weight males and females
No significant increase in tumor
incidence.
None
Not run
1.71 (M),
1.75 (F)
(PEL)
Schroeder et al.
(1968);
Kanisawa and
Schroeder(1969)

Developmental
None
Reproductive
None
Carcinogenic
None
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Table 2. Summary of Potentially Relevant Data for Soluble Zirconium Compounds (CASRN 7440-67-7)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAELab
Reference
(Comments)
Notes0
2. Inhalation (mg/m3)"
Subchronic
12 Albino rabbit (sex not
reported), 20 minutes/day,
6 weeks
49,000 (sodium
zirconium
lactate)
Bronchiolar abscesses with a lobular
type of pneumonia or peribronchial
granulomas
None
Not run
None
Prior et al.
(1960)


10 hamster (strain and sex
not reported), 225 days
15, 150
(zirconium
lactate),
15 (barium
zirconate)
Poor weight gain, pathological changes
consistent with chronic interstitial
pneumonitis, increase in zirconium
content of lung tissue (at all doses)
None
Not run
None
Brown et al.
(1963)


10 rat (strain and sex not
reported), 225 days
15, 150
(zirconium
lactate),
15 (barium
zirconate)
Poor weight gain, pathological changes
consistent with chronic interstitial
pneumonitis, increase in zirconium
content of lung tissue (at all doses)
None
Not run
None
Brown et al.
(1963)


10 guinea pig (strain and
sex not reported), 225 days
15, 150
(zirconium
lactate),
15 (barium
zirconate)
Poor weight gain, pathological changes
consistent with chronic interstitial
pneumonitis, increase in zirconium
content of lung tissue (at all doses)
None
Not run
None
Brown et al.
(1963)


Guinea pig (strain and
number not reported), 2 to
6 months
NA
No pulmonary effects
None
Not run
None
Clayton and
Clayton
(1981-1982)


Guinea pig (strain and
number not reported),
60 days
6, 75 (zirconium
tetrachloride)
Increased mortality (not specified) at
6 mg/m3, no effect at 75 mg/m3
None
Not run
None
Seiler et al.
(1988)


Rat (strain and number not
reported), 60 days
6, 75 (zirconium
tetrachloride)
Increased mortality (not specified) at
6 mg/m3, no effect at 75 mg/m3
None
Not run
None
Seiler et al.
(1988)

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Table 2. Summary of Potentially Relevant Data for Soluble Zirconium Compounds (CASRN 7440-67-7)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL3
LOAEL3b
Reference
(Comments)
Notes0
Subchronic
Dog (strain and number not
reported), 60 days
6, 75 (zirconium
tetrachloride)
Slight decreases in hemoglobin and red
blood cell count at 6 mg/m3, no effect at
75 mg/m3
None
Not run
None
Seiler et al.
(1988)

Chronic
Laboratory animals
(species, strain, number not
reported), 1 year
3.5
No effect
None
Not run
None
Bingham et al.
(2001)

""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-day) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. All long-term exposure values (4 weeks and longer) are converted from a discontinuous to a continuous
(weekly) exposure. Values from animal developmental studies are not adjusted to a continuous exposure.
bNot reported by the study author, but determined from data.
°Notes: IRIS = Utilized by IRIS, date of last update; PS = Principal study, NPR = Not peer reviewed, SS = Secondary source.
Conversions for Schroeder et al. (1970) and Schroeder et al. (1968) are for combined drinking water and feed based on default values for body weights and food
consumption rates for male and female rats and mice, per U.S. EPA (1988) and days dosed and total days of study based on average longevity (in days) provided in the
study tables in Schroeder et al. (1970) and (1968) (since length of study is given as lifetime). Drinking water exposure was converted from zirconium sulfate to
zirconium exposure using the following equation: zirconium sulfate intake (ppm) x MW zirconium MW zirconium sulfate = 5 ppm x 91.224 g 355.4 g = 1.28 ppm.
(Note, the MW of zirconium sulfate tetrahydrate [355.4 g] was used since that compound is soluble in water.) Dosimetry is calculated using default values for rats and
default food and water consumption rates (U.S. EPA, 1988). For example, the default time weighted average body weight for chronically exposed male Long-Evans rats
is 0.472 kg, the water intake is .057 (L/day) (water factor 0.121 L water/kg BW/day) and the food intake is 0.034 (kg/day) (food factor 0.072 kg food/kg BW/day).
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HUMAN STUDIES
Oral Exposures
The only report on oral exposure to zirconium in humans stated that symptoms from
acute ingestion consisted of burning pain in mouth and throat, vomiting, watery or bloody
diarrhea, tenesmus, retching, hemolysis, hematuria, anuria, liver damage with jaundice,
hypotension, collapse, and convulsions (Dreisbach, 1977). However, no dose information was
provided.
Inhalation Exposures
A study of 22 workers (sex not reported) exposed for 1 to 5 years to zirconium along with
a variety of other compounds during the zirconium reduction process revealed no abnormalities
from the exposure (Reed et al., 1956).
A study of 32 males who had worked for 1 to 17 years as hand finishers of zirconium
metal reactor components showed no significant differences from the control group
(Bingham et al., 2001). Bingham et al. (2001) noted that pulmonary granuloma in a different set
of zirconium workers had been reported after long-term exposure to zirconium, but the reports
did not specify whether the granuloma was due to zirconium metal or a specific compound of
zirconium.
Thoburn and Straub (NIOSH, 1976) conducted a health hazard investigation of
150 workers (sex not reported) in a facility that produced nuclear-reactor-grade zirconium and
hafnium from crude zirconium tetrachloride. Based on medical interviews and cutaneous
examination of the workers, the study authors determined that respiratory tract irritation and
dermatitis existed in the workers and that these health effects were associated with the
company's production of zirconium and hafnium. No further information was provided on these
studies—including the concentrations of zirconium—and, therefore, neither NOAELs nor
LOAELs could be determined.
A study was reported by Marcus et al (1996) on 178 male workers (average age =
37.6 years) working with zirconium compounds in England. The men had been employed at a
facility for an average length of employment of 10 years where they were exposed to zirconium
compounds. Chest radiographs were done in 1975, 1978, and 1982 and lung-function
measurements were carried out at regular intervals. An estimate of cumulative exposure was
computed from job titles and the likely exposures in each time period. Four exposure categories
were estimated: no dust: <1 mg/m3; low dust: 1-2.5 mg/m3; medium dust: 2.5-10 mg/m3; high
dust: >10 mg/m3. The number of years spent in each job was multiplied by the score on the dust
scale and a cumulative dust exposure score calculated for each man. At the start of the study
51.1% were in low dust jobs, 44.8% in medium dust jobs, and 4.1%> in high dust jobs. The mean
cumulative exposure (years x dust level) was 12.9 'dust years' at the start and 22.3 at the end of
the study. Those exposures and categories were examined in relationship to the chest
radiographs and impaired lung function of the workers. No evidence was found that zirconium
exposure resulted in abnormal chest radiographs or impaired lung function. A NOAEL or
LOAEL could not be determined from this study because this is a retrospective study in which
the exposures was not adequately quantified.
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A number of case reports have reported pulmonary effects from zirconium exposure.
Liippo et al. (1993) reported on a case of hypersensitivity pneumonitis in a 25-year old female
ceramic tile worker exposed to zirconium. The woman had worked for 3.5 years in a ceramic
tile factory as a glazer and sorter and generally had not used protective equipment. Up to
30% zirconium silicate was found in the glazing material used in the tile factory and dust
concentrations were up to 5.8 mg/m3. She developed a worsening dry cough and dyspnea and
the woman died one week after an open lung biopsy, which revealed interstitial inflammation
and fibrosis of the alveolar walls. Analysis of lung tissue samples showed inhaled dust
consisting primarily of clay particles and zirconium-silicate that was almost 100 times that of the
normal background level. The authors concluded that zirconium exposure caused an acute
allergic alveolitis-like hypersensitivity reaction.
Bartter et al. (1991) reported on a 62-year old man with dyspnea that had gradually
increased during the preceding 25 years. He was diagnosed with pulmonary fibrosis. The man
had worked for 39 years in the lens grinding department of an optical company where he had
been involved in the grinding, polishing, pitting, and blocking of lenses and had been exposed to
a variety of compounds—including Zirox B (zirconium oxide and respirable quartz). He had not
worn protective equipment at work. Analysis of the lung tissue showed significant elevations of
various zirconium compounds—including zirconium oxide, zirconium silicate, and zirconium
aluminum silicate. The authors concluded that zirconium was the probable cause of the patient's
pulmonary fibrosis. A NOAEL or a LOAEL could not be determined from these studies because
these are case reports and there is no dose-response information available.
Romeo et al. (1994) reported on a case of interstitial lung granuloma in a worker exposed
to zirconium compounds. Histological examination of transbronchial biopsy tissue showed small
interstitial nonconfluent granulomas with epithelioid and giant cells showing no central necrosis.
No further information was provided.
Additionally, two case reports on interstitial lung disease related to zirconium exposure
were presented by Bingham et al. (2001). The first case was a 49-year old man who had been
employed at a refractory brick production factory for 20 years. Chest X-rays showed diffuse
bilateral opacities and a histological study of biopsy tissue showed fibrosis and hyperplasia and
weakly birefringent particles in alveolar and interstitial histiocytes. Neutron activation analysis
of particles showed zirconium levels of 715 ppm. The second case was a 29-year old man who
had worked as a coremaker in a foundry for 8 years. X-rays showed diffuse opacities and
histology revealed granulomas and birefringent particles in histiocytes. Because no exposure
information was provided, neither a NOAEL nor a LOAEL could be determined from these case
reports.
Other Exposures
Bingham et al. (2001) reported dermal granulomatous lesions, probably of allergic
epithelioid origin, after dermal exposure to deodorant sticks and poison ivy lotions containing
zirconium. In a case study of two subjects (gender not specified), daily application of an
aluminum deodorant stick did not produce an adverse reaction, but the subjects showed a
granulomatous response to intracutaneous injection of a dilute aqueous solution of sodium
zirconium lactate (Browning, 1969). Dermal lesions were reported in a 15-year old girl
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following treatment of poison ivy dermatitis with 4% zirconium oxide cream. No granulomas
appeared on intact skin areas (National Poisons Information Service, 1998).
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to zirconium have been evaluated in two
chronic-duration studies that also examined carcinogenic effects (Schroeder et al., 1970; and
Schroeder et al., 1968). Kanisawa and Schroeder (1969) summarized the results from
Schroeder et al. (1970) and Schroeder et al. (1968) with more details on the carcinogenicity of
zirconium than were provided in Schroeder et al. (1970) or Schroeder et al. (1968).
Chronic Studies
A study that administered one of five trace elements (zirconium, niobium, antimony,
vanadium, or lead) to 603 rats (approximately 50/gender/chemical) in both drinking water
and feed, simultaneously, is chosen as the principal study (Schroeder et al., 1970). This
study was performed before Good Laboratory Practice (GLP) guidance was established. The test
drinking water containing 5 ppm zirconium sulfate was provided to 56 male and 58 female
Long-Evans rats (the offspring of pregnant Long-Evans rats purchased for the study) from
weaning to natural death (a maximum of 1347 days). An equal number of rats served as
controls. The experimental rats also were fed a diet containing 2.66 |ig/g zirconium (thus
zirconium was in the food and water). Using time-weighted average body weight and default
water consumption in Long-Evans rats, the dose of 5 ppm zirconium sulfate in drinking water
was converted to 0.60 mg/kg-day for males (0.057 L/day x 5 mg/L/0.472 kg = 0.60 mg/kg-day)
and 0.67 mg/kg-day for females. The dose of 2.66 mg/kg zirconium in feed was converted (also
using time-weighted average body weights and food consumption) to 0.19 mg/kg-day for males
and 0.22 mg/kg-day for females. These doses were also adjusted for the fraction of zirconium
sulfate that is zirconium as shown in Footnote d of Table 2. Actual food consumption data was
not shown. Data related to the differential bioavailability between drinking water and dietary
zirconium was not available. Because the rats ingested both drinking water and feed, the doses
were summed for a total equivalent dose (TED) of 0.79 mg/kg-day in males and 0.89 mg/kg-day
in females. The rats were weighed weekly from weaning until 6 weeks of age, and then monthly.
As the rats died, they were weighed and dissected to identify grossly visible tumors and other
lesions in the heart, lung, kidney, liver, and spleen. During the study, an epidemic of virulent
pneumonia struck the rat colony, and killed 19 males and 12 females (controls) and 5 males and
4 females (zirconium-exposed) in a 3-week period. According to the authors, these animals were
removed from the series and survival numbers were corrected for that time period.
Zirconium did not consistently affect the growth rates of the rats (Schroeder et al., 1970).
Males administered zirconium were significantly heavier than controls at 30, 150, and 180 days
and lighter than controls at 360 and 540 days, while females were significantly heavier than
controls at 30, 150, and 540 days (see Table B.l). There was no significant difference in
survival of the zirconium-administered rats compared to controls (see Table B.2). Females
administered zirconium showed significantly higher fasting serum glucose levels than controls
and males administered zirconium had significantly higher cholesterol levels. Glycosuria
(glucose in the urine) was noted in 23% of the controls and in 52% of 56 rats (study does not say
whether in males or females) administered zirconium (significantly different by chi-square
analysis atp< 0.01) (see Table B.3). No differences were observed in the mean body weights of
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the rats administered zirconium compared to controls, while the hearts of males administered
zirconium weighed 14.6% less than controls, the hearts of females weighed 7.4% more (see
Table B.4). No significant increase was reported in the number of tumors in rats administered
zirconium compared to the controls (Schroeder et al., 1970; Kanisawa and Schroeder, 1969) (see
Table B.4). The study authors did not identify a NOAEL or LOAEL from this study. A LOAEL
of 0.79 mg/kg-day (males) and 0.89 mg/kg-day (females) is identified based on significantly
increased incidence of glycosuria, higher fasting glucose levels in females and higher cholesterol
levels in males. A NOAEL is not determined because only one dose (in addition to controls) was
tested.
Schroeder et al. (1968) administered one of four trace elements (i.e., zirconium, niobium,
antimony, or fluorine) to different groups of mice in both drinking water and feed. The test
drinking water containing 5 ppm zirconium sulfate was administered to 54 male and 54 female
Charles River CD-I mice (born from random-bred pregnant females) over the lifetime (from
weaning until death) of the mice. An equal number of mice served as controls. The
experimental mice also were fed a diet reported to contain 2.66 |ig/g zirconium. Using standard
assumptions for body weight and water consumption in mice, 5 ppm zirconium sulfate in
drinking water was calculated to be equivalent to 1.23 mg/kg-day for males and 1.26 mg/kg-day
for females. The dose of 2.66 |ig/g zirconium in feed was calculated, also using standard
assumptions, to represent 0.48 mg/kg-day for males and 0.49 mg/kg-day for females. Because
the experimental mice ingested both drinking water and feed, the doses were summed for a total
equivalent dose of 1.71 mg/kg-day in males and 1.75 mg/kg-day in females. This study was
conducted before GLP guidance was developed by EPA in 1983. The mice were weighed
weekly for 8 weeks and then at monthly intervals (see Table B.5). The dead animals were
dissected, grossly visible tumors and other lesions were noted, and abnormal tissues were
sectioned. For the elemental analysis, hearts, lungs, kidneys, livers, and spleens were pooled in
samples of 5 to 15 from the various age groups and analyzed.
Significantly decreased body weights were noted in male mice at 90 and 540 days and
female mice at 540 days. Schroeder et al. (1968) reported a significant increase in body weights
in females at 60 days (see Table B.5). The study authors noted that administration of zirconium
was associated with shortened life spans by 27 to 47 days in males and 67 to 85 days in females,
at 5 out of 6 intervals, and that the difference in females was statistically significant. As in
Schroeder et al. (1970), the study continued until natural death of each animal (see Table B.6).
Schroeder et al. (1968; Kanisawa and Schroeder, 1969) noted a significant change in body
weights of males at 540 days. No significant increase was noted in the number of tumors
compared with control mice (see Table B.7). The study authors did not identify a NOAEL or
LOAEL from this study. A LOAEL is identified by EPA because the decrease in body weight
was greater than 10%. The LOAEL in male mice is 1.71 mg/kg-day while the FEL (based on
significantly increased mortality) in female mice is 1.75 mg/kg-day.
Inhalation Exposures
The effects of inhalation exposure of animals to zirconium have been evaluated in four
subchronic studies (Seiler et al., 1988; Brown et al., 1963; Prior et al., 1960; Clayton and
Clayton, 1981-1982), and one chronic (Bingham et al., 2001) study. The aerodynamic diameters
of the particles/suspensions were generally not available, so direct comparisons between studies
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is difficult. The subchronic-duration data are summarized in Table 2 based on animal species;
however, they are discussed in the text below based on study reports.
Short-term Studies
No studies regarding the effects of short term inhalation exposure of animals to
zirconium were identified.
Subchronic Studies
Rats, guinea pigs, and dogs were exposed by inhalation to zirconium tetrachloride at
6 and 75 mg/m3 for 60 days (Seiler et al., 1988). Dogs showed slight decreases in hemoglobin
and red blood cell counts and rats and guinea pigs demonstrated increased mortality
(unspecified) at 6 mg/m3. No effects were noted with zirconium oxide at 75 mg/m3 (Seiler et al.,
1988). No further details were provided in the secondary source (HSDB, 2006) for this study.
Because equivocal effects were noted at the low dose but not the high dose, neither a NOAEL
nor a LOAEL is identified.
Prior et al. (1960) exposed 12 Albino rabbits to 0 or 0.049 mg sodium zirconium lactate
per cubic centimeter (49,000 mg/m3) of air, for 20 minute exposures per day for 6 weeks. All
exposed animals exhibited either bronchiolar abscesses with a lobular type of pneumonia or
peribronchial granulomas. These effects were not seen in the control animals. These data
suggest a LOAEL of 49,000 mg/m3 with no NOAEL.
In another study, guinea pigs exposed continuously to several steps in the zirconium
reduction process for 2 to 6 months did not exhibit any pulmonary changes after a histological
examination (Clayton and Clayton, 1981-1982). No further details were provided.
Chronic Studies
Zirconium tetrachloride inhaled by laboratory animals (unspecified) for 1 year at
3.5 mg/m3 showed no adverse effects (Bingham et al., 2001). No further details were provided
in the secondary source (HSDB, 2006) for this study. A NOAEL or LOAEL could not be
determined due to the lack of data available on this study
Brown et al. (1963) exposed groups of 10 rats, 10 hamsters, and 10 guinea pigs for
225 days to either 15 or 150 mg/m3 zirconium lactate, 15 mg/m3 barium zirconate, or to room air
(controls). The animals exposed to the compounds showed reduced weight gain, pathological
changes consistent with chronic interstitial pneumonitis, very little deposition of fibrous tissue,
no granuloma, and an increase in the zirconium content of the lung tissue.
Developmental Studies
No studies regarding the effects of inhaled zirconium on the fetal development of animals
were identified.
Reproductive Studies
No studies regarding the effects of inhaled zirconium on the reproduction of animals
were identified.
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Other Routes of Exposure
The effects of injection exposure of animals to zirconium have been evaluated in six
short-term studies (Stookey et al., 1967; Harding, 1948; Shima et al., 1987; Shelley and Raque,
1971; Ikarashi et al., 1996; Kang et al., 1977). The effects of implant exposure have been
evaluated in one chronic study (Takamura et al., 1994).
Injection
Stookey et al. (1967) determined the toxic reaction of rats and guinea pigs to zirconium
silicate (20% concentration) or sodium zirconium lactate injections (20% and 45%
concentration). In rats, zirconium silicate injections resulted in a mild inflammatory reaction in
the oral mucosa, subcutaneous tissues, and intramuscular tissues. Sodium zirconium lactate
injections resulted in a destructive granulomatous reaction in the above tissues, and also in the
periosteal tissue. In guinea pigs, zirconium silicate injections resulted in a mild inflammatory
reaction in the oral mucosa, subcutaneous tissues, periosteal tissue, and intramuscular tissue,
while sodium zirconium lactate injections resulted in a destructive granulomatous reaction in the
above tissues. In another study by Stookey et al. (1967), rats were injected with 50 mg
zirconium silicate to muscle tissue. A mild inflammatory reaction was noted in the subcutaneous
and intramuscular tissues, with no necrosis identified. In a third study, Stookey et al. (1967)
histologically examined gingival tissue in rats administered an oral paste containing
75%) zirconium silicate and 25%> distilled water. No unusual tissue response was observed and
only an occasional mild local inflammatory response was reported. No NOAEL or LOAEL are
established because of lack of relevance of this route of exposure to oral or inhalation routes.
Six rats were injected intratracheally with 1 mL of a 10%> solution of zirconium silicate
(Harding, 1948). Three rats were killed after 7 and 9 months and their lungs examined
microscopically. Most of the zirconium silicate was found within the alveoli and lymph vessels
of the lungs and a small amount was noted within phagocytic cells. Swollen histiocytes were
observed in a few alveoli. Fibrosis was not noted. In another study by Harding (1948), a rabbit
received 4 doses intravenously over 1 week of a 5 mL suspension of a 10%> solution of zirconium
silicate. The rabbit was killed 33 weeks later. Clumps of crystals were observed in the Kupfer
cells. Smaller clumps were also noted in the spleen and alveolar walls and fibrosis was detected.
Shima et al. (1987) studied the effects of zirconium oxychloride on the humoral immune
system in mice. This was done in two different experiments by measuring IgM antibody
production against sheep red blood cells by the method of hemolytic plaque formation. For both
experiments, splenic cells were collected from mice immunized with 10%> sheep red blood cells
and cell suspensions were prepared. In the first experiment, male mice were injected
intraperitoneally once with 0, 1.7, 3.4, 17, or 34 mg/kg zirconium oxychloride. The mean IgM
production at each dose was increased compared to controls, and was statistically significant at
1.7, 3.4, and 34 mg/kg. In the second experiment, male mice were injected with 0, 2.125, 4.25,
or 8.5 mg/kg zirconium oxychloride every other day for 2 or 4 weeks. The mean IgM production
in each dose showed an increase over the controls, but only the group injected with 2.125 mg/kg
was statistically significantly different than the controls. The study authors suggested that
long-term exposure to low levels of zirconium dust in the workplace of zirconium industries
could enhance the humoral immune response, or at least the IgM immune response, and could
induce a state of hypersensitivity in exposed workers.
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CBA/J mice were injected intradermally in the foot pads or intraperitoneally with
zirconium lactate or sodium zirconium lactate (Shelley and Racque, 1971). A biopsy at 1 week
showed a nonspecific inflammatory round cell infiltrate and after 6 months, varying degrees of a
granulomatous response were noted, consisting primarily of macrophages. However, none of the
mice showed evidence of a delayed immune type of epithelioid cell granulomatous
hypersensitivity.
A study assessed the contact sensitizing capability of zirconium chloride in guinea pigs
and mice (Ikarashi et al., 1996). No sensitization responses were observed in the guinea-pig
sensitization test (at an injection of 0.1 mL of 1% zirconium chloride) or in the sensitive mouse
lymph node assay (at an initial intradermal injection of 50 |iL of various concentrations of
zirconium chloride, followed by a topical application of 25 |iL of 5% zirconium chloride in
70% dimethylsulphoxide on both ears 5 days later).
In a study designed to assess the potential sensitizing ability of selected compounds,
rabbits were injected with zirconium aluminum glycinate and sodium zirconium lactate (100 |ig
in saline solution) intradermally two times a week for 6 weeks (Kang et al., 1977). The rabbits
were skin tested within 7 days following the last inoculation. Rabbits administered sodium
zirconium lactate showed some marginally positive macrophage migration inhibition and skin
reactivity. No positive skin reactivity was noted with zirconium aluminum glycinate. The study
authors stated that delayed hypersensitivity does not appear to be associated with zirconium
compounds, under the conditions of this experiment.
Implant
Solid rods containing zirconium oxide with yttrium oxide were implanted in the left thigh
muscle of mice for 24 months (Takamura et al., 1994). Histological examination of the lungs,
liver, heart, kidneys, spleen, pancreas, brain, adrenals, gonads, thyroid, and thighs was carried
out. No increase in tumors at the implantation site was reported. In Olmedo et al. (2002) dental
implants were placed in rats to observe distribution over time. The histological analysis revealed
the presence of abundant intracellular aggregates of metallic particles of Ti and Zr in peritoneum,
liver, lung, and spleen. No health effects were noted.
OTHER DATA
A few studies on the short-term toxicity, toxicokinetics, and genotoxicity of zirconium
are available.
Short-Term Studies
The oral LD50 was reported to be 1688 mg/kg in rats and 655 mg/kg in mice for
zirconium tetrachloride (O'Neil, 2001). The oral LD50 in rats was reported to be 3500 mg/kg for
zirconium oxychloride (O'Neil, 2001), >10,000 mg/kg for zirconium lactate and 1980 mg/kg for
barium zirconate (Brown et al., 1963).
Stookey et al. (1967) administered doses ranging from 70 to 200 g/kg body weight
zirconium silicate by oral intubation to 80 albino mice, with the purpose of determining the LD50
for zirconium silicate. A dosage of 200 g/kg of body weight resulted in a 37.5% mortality rate in
the mice. Doses greater than 200 g/kg were not tested due to limitations of the mouse
gastrointestinal tract, so the LD50 was not determined.
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Toxicokinetics
A few studies on the toxicokinetics of zirconium are available. Schroeder et al. (1970)
administered 5 ppm zirconium in the drinking water and 2.66 |ig/g in the feed to rats over a
lifetime, and examined the accumulation in the kidney, liver, heart, lung, and spleen.
Accumulation in the organs was not observed, except for male rats where significant
accumulation in the spleen was noted. Schroeder et al. (1968) administered 5 ppm zirconium in
the drinking water and 2.66 |ig/g in the feed to mice over a lifetime and determined that
zirconium accumulated in the spleen and heart.
A recent study investigated the behavior of zirconium tritide (a radioactive compound)
particles in rat lungs (Zhou et al., 2010). Zirconium tritide particles (approximately 43 |ig based
on a 0.5 mL instillate of a 3 mg ZrT/35 mL saline solution) were instilled in the lungs of rats and
the tritium clearance time was obtained by sacrificing 44 rats at 1 hour, and 1, 2, 3, 7, 14, 30, 60,
120, and 180 day postexposure to collect lungs, bronchial lymph nodes (BLN), blood, liver,
kidney, and muscle tissues. While the volume surface diameter (VSD) was given, the ZrT
particles was a respirable 1.73 |im, this is not directly relevant since the particles were instilled.
A biokinetic model of zirconium tritide particles in the rat lung was developed and the predicted
retention curves with various phases of tritium in each organ agreed with the experimental data.
Genotoxicity
Table 3 presents a summary of the genotoxicity studies on zirconium. Zirconium
oxychloride was negative when tested in Salmonella typhimurium TA97, TA98, TA1535,
TA1537, and TA100, with and without rat and hamster liver S-9 metabolic activation
(Mortelmans et al., 1986). Zirconium tetrachloride also was negative in Salmonella typhimurium
TA98, TA100, TA102, TA1537, and TA2637, without metabolic activation. When it was
combined with 9-amino-acridine, it was positive for mutagenicity (Ogawa et al., 1987).
Ghosh et al. (1990, 1991) administered oral doses of zirconium oxychloride at 225, 750, or
2250 mg/kg in male mice and 220, 734, or 2200 mg/kg in female mice to study the effects on
bone marrow chromosomes. No increase in mitotic division frequency or in chromosomal
aberrations and breaks per cell were noted at the lowest dose, while the division frequency and
the number of chromosomal aberrations was increased at the higher doses, in both males and
females, as compared to controls. The frequency of chromosomal aberrations was slightly
higher in females than in males, but was not statistically significant. The study authors
concluded that zirconium oxychloride was potentially clastogenic, the effect being directly
proportional to the dose used (Ghosh et al., 1991). In a study on human peripheral blood
lymphocytes (Ghosh et al., 1992), aqueous solutions of zirconium oxychloride (20 |ig/mL) were
added to cultures from male and female volunteers ranging in age from newborns to 60 years
old. The endpoints screened were chromosome and chromatid breaks, dicentrics, and
rearrangements. The frequencies of chromosomal aberrations and sister chromatid exchanges
were compared between the different age groups, in both males and females. The frequency of
sister chromatid exchanges increased with the age of the female volunteers, but not the males.
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Table 3. Other Studies for Soluble Zirconium Compounds (CASRN 7440-67-7)
Test
Materials and Methods
Results
Conclusions
References
Genotoxicity
Zirconium oxychloride: Salmonella
typhimurium TA97, TA98, TA1535, TA1537,
TA100 (with and with S-9 metabolic
activation) (In vitro)
Negative
None
Mortelmans et al. (1986)

Zirconium tetrachloride: Salmonella
typhimurium TA98, TA100, TA102, TA1537,
TA2637 (without S-9 metabolic activation^)
(In vitro)
Negative
None
Ogawa et al. (1987)

Zirconium oxychloride: Oral exposure of
Swiss albino mice to 225, 750, 2,250 mg/kg
(males), 220, 734, 2,200 mg/kg (females)
(In vivo)
Mitotic divisional frequency not increased
at 220-225 mg/kg, increased at higher
doses
The percentages of total
abnormalities was increased
in both sexes at all doses
Ghosh etal. (1990)

Zirconium oxychloride: Oral exposure of
Swiss albino mice to 225, 750, 2,250 mg/kg
(males), 220, 734, 2,200 mg/kg (females)
(In vivo)
Increase in chromosomal aberrations
directly proportional to dose
Zirconium as zirconium
oxychloride is potentially
clastogenic
Ghosh etal. (1991)

Zirconium oxychloride: Human peripheral
blood lymphocyte culture from males and
females (In vitro)
Frequency of sister chromatid exchanges
increased with age of female volunteers,
(not male,) the frequency of other
chromosomal aberrations was not related
to age in either males or females
Molecular mechanism for
increase in sister chromatid
exchanges is not known
Ghosh etal. (1992)
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DERIVATION OF PROVISIONAL VALUES
Table 4A presents a summary of noncancer reference values. Table 4B presents a
summary of cancer values for zirconium.
Table 4A. Summary of Noncancer Reference Values for
Soluble Zirconium Compounds (CASRN 7440-67-7)
Toxicity Type
(Units)
Species/Sex
Critical Effect
p-Reference
Dose
POD
Method
POD
UFc
Principal Study
Screening
chronic p-RfD
(mg/kg-day)
Rat/M,F
Glycosuria in
urine,
increased
glucose and
cholesterol
levels
8 x l(T5
LOAEL
0.79
mg/kg-day
10,000
Schroeder et al.
(1970)
Screening
subchronic
p-RfD
(mg/kg-day)
Rat/M,F
Glycosuria in
urine,
increased
glucose and
cholesterol
levels
8 x l(T5
LOAEL
0.79
mg/kg-day
10,000
Schroeder et al.
(1970)
Subchronic
p-RfC (mg/m3)
N/A
Chronic p-RfC
(mg/m3)
N/A
N/A = not available
Table 4B. Summary of Cancer Reference Values for
Soluble Zirconium Compounds (CASRN 7440-67-7)
Toxicity Value
Reference Value
Tumor Type or
Precursor Effect
Species/Sex
Principal Study
p-OSF
N/A
p-IUR
N/A
N/A = not available
DERIVATION OF ORAL REFERENCE DOSES
There are no human oral studies available on zirconium and no animal subchronic
studies. There are two oral chronic studies available in animals. Schroeder et al. (1970)
administered 5 ppm zirconium sulfate in drinking water and 2.66 |ig/g zirconium in the feed to
rats over a lifetime, with a significantly increased incidence of glycosuria (study did not say if
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this effect was noted in males or females or both), higher fasting serum glucose levels in females
and higher serum cholesterol levels in males (see Table B.3). In mice, Schroeder et al. (1968),
administered the same 5 ppm zirconium sulfate in drinking water and 2.66 |ig/g zirconium in the
feed over a lifetime, resulting in a significant difference in the survival rate in female mice,
significantly decreased body weight in male mice at 90 and 540 days and in female mice at
540 days, and significantly increased body weight in female mice at 60 days (see Table B.5) was
observed. Both studies used a single dose only (in addition to controls), and it is not clear in
Schroeder et al. (1970) whether the increased incidence of glycosuria occurred in male or female
rats. In Schroeder et al. (1970), there was an epidemic of virulent pneumonia in the rat colony,
killing a number of animals. The authors stated that these animals were removed from the series
and survival curves corrected from that time. However, the epidemic of pneumonia presents
additional uncertainty about the results. The authors stated that the results from both of these
studies "reveal no evidence that zirconium as fed has any biological activity, except possibly to
affect body weight of older animals inconsistently". The basis of this statement is unclear given
that there was increased mortality in mice. Glycosuria and higher fasting glucose levels in
females and higher cholesterol levels in males were noted in the rats after zirconium exposure
(Schroeder et al., 1970), and LOAELs of 0.79 mg/kg-day (males) and 0.89 mg/kg-day (females)
are identified.
Due to the limitations of the database, and these studies, as discussed above, the use of
these studies to derive a chronic p-RfD would result in the application of four full areas of
uncertainty. EPA practice is not to develop a p-RfD with these limitations. However,
Appendix A of this document contains screening values that may be useful in certain instances.
Please see the attached Appendix for details.
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
Due to insufficient data, no subchronic p-RfD can be derived. However, Appendix A of
this document contains a screening value that may be useful in certain instances.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
Due to insufficient data, no chronic p-RfD can be derived. However, Appendix A of this
document contains a screening value that may be useful in certain instances.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
There are several chronic-duration inhalation studies in humans on zirconium
(Bingham et al., 2001; Thoburn and Straub, 1976; Marcus et al., 1996; Liippo et al., 1993;
Bartter et al., 1991; Romeo et al., 1994). However, the concentration of the zirconium in air was
not reported in most of these studies or they were case reports on a single individual.
Marcus et al. (1996) estimated cumulative exposure to zirconium compounds by dividing
exposure into four general categories based on job titles and likely exposures in each time period.
However, this exposure data is insufficient to calculate a p-RfC.
There are four subchronic inhalation studies (i.e., Seiler et al., 1988; Prior et al., 1960;
Clayton and Clayton, 1981-1982; Brown et al., 1963) and one chronic (Bingham et al., 2001)
inhalation study in animals for zirconium. However, for three of these studies (Seiler et al.,
1988; Clayton and Clayton, 1981-1982; Bingham et al., 2001), the primary study was
unavailable, and there were very few details available in the secondary sources (such as the
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Hazardous Substances Data Bank [HSDB, 2006]). No details of the experimental design and
few details of the results, including the numbers of animals exposed, are reported in this
secondary source. The primary studies were obtained and reviewed for Prior et al. (1960) and
Brown et al. (1963). However, few details are reported in these studies, including the sex of the
animals in Prior et al. (1960) and the strain and the sex of the animals in Brown et al. (1963).
Therefore, neither a subchronic or chronic p-RfC—nor screening values—can be derived.
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
Due to insufficient data, no subchronic p-RfC can be derived.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
Due to insufficient data, no chronic p-RfC can be derived.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No human data are available on the carcinogenicity of zirconium. Two animal studies
reported no increase in tumor incidence after exposure to zirconium in the feed and drinking
water for a lifetime in rats and mice (Schroeder et al., 1968, 1970; Kanisawa and Schroeder,
1969) (see Table B.7). According to the Guidelines for Carcinogen Risk Assessment (U.S. EPA,
2005), there is "Inadequate Information to Assess Carcinogenic Potential" of zirconium (see
Table 5).
Table 5. Cancer WOE Descriptor for Zirconium (CASRN 7440-67-7)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans"
N/A
N/A

"Likely to Be Carcinogenic to
Humans "
N/A
N/A

"Suggestive Evidence of
Carcinogenic Potential"
N/A
N/A

"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No human cancer studies are available
for zirconium, and two animal studies
are inadequate to assess the
carcinogenic potential of zirconium
"Not Likely to Be
Carcinogenic to Humans "
N/A
N/A

DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
Due to a lack of carcinogenicity data, no p-OSF can be derived.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
Due to a lack of carcinogenicity data, no p-IUR can be derived.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for zirconium. However, information is available for this chemical which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
DERIVATION OF SCREENING ORAL REFERENCE DOSES
There are no adequate subchronic- or chronic-duration studies regarding the toxicity of
oral exposure to zirconium on which to derive provisional toxicity values. However,
Schroeder et al. (1970) administered 5 ppm zirconium sulfate in the drinking water and 2.66 |ig/g
zirconium in the feed over a lifetime to rats. A significantly increased incidence of glycosuria
(study did not say if this effect was noted in male or females or both) was noted. In addition,
higher fasting glucose levels in females and higher cholesterol levels in males were observed
(see Table B.3). In a second experiment, Schroeder et al. (1970) administered the same 5 ppm
zirconium sulfate in the drinking water and 2.66 |ig/g zirconium in the feed for a lifetime to
mice. The health effects noted were a significant difference in the survival rate in female mice
(reported in the text but not in the study table, see Table B.6). Significantly decreased body
weight was observed in male mice at 90 and 540 days and female mice at 540 days, while a
significant increase was observed in female mice at 60 days (see Table B.5). However, these
studies used only a single dose (in addition to controls), and there was an epidemic of virulent
pneumonia in the rat colony which killed a number of animals, and using these studies to derive
a p-RfD also results in the application of a composite UF (UFC) of 10,000. Thus, only a
screening chronic p-RfD can be developed based on the effects noted in rats and mice after
exposure to zirconium in drinking water and feed over a lifetime (Schroeder et al., 1968, 1970).
While the critical effect may appear to be of minor biological significance, there is clear
treatment-related mortality at higher doses. The dose provided in the study for exposure to
zirconium sulfate in drinking water (i.e., 5 ppm) was converted to mg/kg-day based on standard
values for body weights and food and water consumption in both male and female rats and mice
(U.S. EPA, 1988), and the exposure to zirconium in feed (2.66 jug/g) was also converted to
mg/kg-day using these standard values (see Table 2, see footnote d). Because the rats were
exposed via drinking water and feed, the converted values in mg/kg-day were added together to
obtain the total dose for both male and female rats and mice. A LOAEL of 0.79 mg/kg-day
(males) and 0.89 mg/kg-day (females) is identified based on significantly increased glycosuria in
the urine and higher fasting serum glucose levels in female rats and higher cholesterol levels in
male rats in Schroeder et al. (1970). A LOAEL in male mice of 1.71 mg/kg-day is identified
from Schroeder et al. (1968) for reduced mean body weight that was greater than 10% compared
to concurrent controls. The male mouse LOAEL of 1.71 mg/kg-day strengthens the decision to
use the male rat LOAEL of 0.79 mg/kg-day as the POD which, importantly, is also protective
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against frank effects observed in female mice. The screening chronic p-RfD for zirconium is
therefore derived based on the LOAEL in male rats (0.79 mg/kg-day) since this value was
slightly lower than that in female rats (0.89 mg/kg-day) (Schroeder et al., 1970) as follows:
Adjust for daily exposure:
LOAELadj = LOAEL x [conversion to daily dose]
= 0.79 mg/kg x (days dosed ^ 7 days in week)
= 0.79 mg/kg x (7 h- 7)
= 0.79 mg/kg-day x 1
= 0.79 mg/kg-day
Screening Chronic p-RfD = LOAELAdj UFC
= 0.79 mg/kg-day ^ 10,000
= 8 x 10~5 mg/kg-day Zirconium
Table A.l summarizes the uncertainty factors for the screening chronic p-RfD for
Zirconium.
Table A.l. Uncertainty Factors for Screening Chronic p-RfD of Zirconium
(CASRN 7440-67-7)
UF
Value
Justification
ufa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic
and toxicodynamic differences between rats and humans. There are no data to determine
whether humans are more or less sensitive than rats to the toxicity of zirconium.
ufd
10
A UFd of 10 is selected because there are no acceptable two-generation reproductive or
developmental toxicity studies.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of information on the variability of response in humans.
ufl
10
A UFl of 10 is applied because the POD was developed using a LOAEL.
UFS
1
A UFS of 1 is applied for using data from a chronic study to assess potential effects from
chronic exposure.
UFC
10,000

DERIVATION OF SCREENING SUBCHRONIC ORAL REFERENCE DOSE
In the absence of data from subchronic-duration studies, the chronic screening p-RfD of
8 x 10~5 mg/kg-day is adopted as the provisional screening subchronic p-RfD.
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APPENDIX B. DATA TABLES
Table B.l. Body Weights of Long-Evans Rats Administered Zirconium3 (CASRN 7440-67-7)
Age (Days)
Control (Grams)b
Zirconium (Grams)b
Males
30
72.1 ±4.2
88.5 ± 2.3°
60
189.5 ±6.0
204.0 ± 4.7
90
270.0 ±8.9
285.7 ±6.2
120
312 ± 9.3
313.7 ±8.7
150
341.5 ±8.9
377.5 ±6.32c
180
364.7 ±8.7
392.0 ±6.44e
360
443.8 ± 14.9
405.2 ±8.45f
540
507.4 ± 16.4
469.0 ± 8.13d
Females
30
64.7 ±2.1
82.1 ±2.12c
60
154.2 ±6.0
159.3 ± 1.9
90
197.1 ±5.4
204.4 ± 1.9
120
225.2 ±5.3
232.0 ±2.7
150
238.8 ±4.0
250.0 ±2.5e
180
250.5 ±4.9
263.7 ±4.3
360
262.6 ±5.9
267.0 ± 4.2
540
262.4 ±9.8
299.2 ±5.32c
aSchroeder et al. (1970).
bMean ± SEM.
cp < 0.005.
dp < 0.025.
><0.01.
fp < 0.05.
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Table B.2. Survival and Longevity of Rats Administered Zirconium"

No.
Rats
Mean Age
(Days)
50% Dead
(Days)
75% Dead
(Days)
90% Dead
(Days)
Last Dead
(Days)
Longevityb
(Days)
Control male
52
819
872
974
1057
1232
1160 ±27.8
Zirconium male
56
870
881
1019
1077
1189
1127 ±23.0
Control female
54
910
912
1050
1157
1347
1304 ±36.0
Zirconium female
58
935
947
1099
1187
1291
1247 ± 17.4
aSchroederet al. (1970).
''Mean ± SEM of last 10% of animals surviving.
Table B.3. Serum Glucose and Cholesterol Levels in Rats Administered Zirconium3

Age
(Days)
Glucoseb Fasting
(mg/100 mL)c
Glucoseb Nonfasting
(mg/100 mL)c
Cholesterol
(mg/100 mL)c
Control males
718
106.5 ±3.6
134.4 ±5.1
77.5 ±2.1
Zirconium males
921
106.1 ±9.9
133.3 ±4.7
89.7 ± 5.6d
Control females
698
79.6 ±8.2
114.2 ±5.4
116.0 ±6.0
Zirconium females
921
111.4 ±5.6e
120.5 ±3.3
100.7 ± 9.0
aSchroeder et al. (1970).
'Difference between fasting and nonfasting levels of glucose were significant in all groups of males.
°Mean ± SEM.
^<0.01.
> < 0.005.
Table B.4. Mean Heart and Body Weights of Rats and Gross Tumors3

No. Rats
Autopsied
Weight at
Death
(Grams)
Heart Weight
(mg)
Ratio x 1000
(Heart Wt/
Body Wt)
Tumors (No.)
Tumors (%)
Control males
50
334
1498
4.49
10
20.0
Zirconium males
46
324
1280
3.95
7
15.2
Control females
39
234
949
4.06
14
35.9
Zirconium females
53
244
1019
4.18
20
37.7
aSchroeder et al. (1970).
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Table B.5. Body Weights of Mice Administered Zirconium"
Age (Days)
Control (Wt-Grams)b
Zirconium (Wt-Grams)b
Males
30
26.0 ±0.68
26.6 ± 1.19
60
39.1 ±0.68
39.2 ±0.93
90
45.2 ±0.75
42.8 ± 0.90°
120
49.3 ± 1.06
48.2 ±0.93
150
52.0 ± 1.42
51.0 ±0.75
180
51.6 ± 1.38
51.1 ± 1.06
360
56.8 ±2.16
54.7 ± 1.40
540
58.0 ± 1.91
50.3 ± 2.59d
Females
30
22.1 ±0.42
20.1 ±0.49
60
28.6 ±0.54
30.4 ± 0.55°
90
35.1 ±0.56
35.1 ± 1.29
120
38.2 ±0.89
39.0 ± 1.03
150
44.0 ±0.98
42.6 ± 1.52
180
45.2 ±0.80
43.8 ±0.94
360
54.3 ± 1.48
53.5 ± 1.12
540
55.2 ± 1.45
50.7 ± 1.20d
aSchroeder et al. (1968).
bMean ± SEM.
><0.025.
d/?<0.01.
Table B.6. Life Span of Mice Administered Zirconium3

No.
Mice
Mean Age
(Days)
Median Age
(Days)
75% Dead
(Days)
90% Dead
(Days)
Last Dead
(Days)
Longevityb
(Days)
Control male
54
540
570
637
692
913
805 ±34.3
Zirconium male
54
520
543
599
645
832
760 ± 17.4°
Control female
54
618
625
745
770
951
855 ±29.3
Zirconium female
53
580
558
660
800
955
901 ±21.0
aSchroeder et al. (1968).
bMean ± SEM.
><0.025.
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Table B.7. Tumors in Mice Administered Zirconium3

Control
Zirconium
No. of mice
71
72
Type of tumor
Benign epithelial
16
10
Malignant epithelial
4
4
Benign nonepithelial
0
0
Malignant nonepithelial
4
1
Pretumorous, liver
1
0
Total lesions
25
15
Location of tumor
Lung
15(3)
9(3)
Liver
4
3(1)
Mammary gland
1(1)

Other
4(4)
3(1)
Total tumors
24 (8)
15(5)
% with tumors
33.8
20.8
"Kanisawa and Schroeder (1969).
Note: Numbers in parentheses indicate number malignant.
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APPENDIX C. BMD OUTPUTS
Appendix C is not applicable.
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