United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/023F
Final
9-20-2010
Provisional Peer-Reviewed Toxicity Values for
Titanium
(CASRN 7440-32-6)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER:
Jon Reid, National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY:
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)
l
Titanium

-------
FINAL
9-20-2010
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
Background	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	3
DERIVATION 01 PROVISIONAL VALUES	3
CANCER WEIGHT OF EVIDENCE DESCRIPTOR	3
MODE-OF-ACTION DISCUSSION	3
REFERENCES	5
li
Titanium

-------
FINAL
9-20-2010
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
NOAELhec
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
111
Titanium

-------
FINAL
9-20-2010
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
TITANIUM (CASRN 7440-32-6)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
>	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
>	California Environmental Protection Agency (CalEPA) values, and
>	EPA Health Effects Assessment Summary (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by two
EPA scientists and external peer review by three independently selected scientific experts.
PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram consensus
review provided for IRIS values. This is because IRIS values are generally intended to be used
in all EPA programs, while PPRTVs are developed specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
1
Titanium

-------
FINAL
9-20-2010
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI.
INTRODUCTION
No reference dose (RfD), reference concentration (RfC), or cancer assessment for
titanium is included on the United States Environmental Protection Agency (U.S. EPA) IRIS
database (U.S. EPA, 2010) or on the Drinking Water Standards and Health Advisories List
(U.S. EPA, 2006). The HEAST did not report any RfD or RfC values for titanium (U.S. EPA,
2003), and the Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1994) does
not contain any assessments for titanium. The toxicity of titanium has not been reviewed by
ATSDR (2008). CalEPA (2008) has not derived toxicity values for exposure to titanium. No
occupational exposure limits for titanium have been derived by the American Conference of
Governmental Industrial Hygienists (ACGIH, 2010), the National Institute of Occupational
Safety and Health (NIOSH, 2005), or the Occupational Safety and Health Administration
(OSHA, 2010).
Titanium has not been evaluated under the 2005 Guidelines for Carcinogen Risk
Assessment (U.S. EPA, 2005). The HEAST (U.S. EPA, 2003) does not report any
carcinogenicity values for titanium. The International Agency for Research on Cancer (IARC,
1999) has reviewed the carcinogenic potential of titanium as a surgical implant and has
determined that there is inadequate evidence to classify the carcinogenicity of such implants.
Therefore, IARC has designated titanium as a Group 3 agent, which is defined as an agent "Not
Classifiable as to Their Carcinogenicity to HumansTitanium has been reviewed by the World
Health Organization (WHO, 1982), and intramuscular injection of titanium metal was found to
induce fibrosarcomas and lymphosarcomas in rats. However, the WHO has concluded that the
available data on the carcinogenicity of titanium do not indicate that this effect occurs in humans.
Titanium is not included in the 11th Report on Carcinogens (NTP, 2005). CalEPA (2002) has
not prepared a quantitative estimate of the carcinogenic potential of titanium.
Literature searches were conducted on sources published from 1900 through May 2010
for studies relevant to the derivation of provisional toxicity values for titanium, CAS No.
7440-32-6. Searches were conducted using EPA's Health and Environmental Research Online
2
Titanium

-------
FINAL
9-20-2010
(HERO) evergreen database of scientific literature. HERO searched 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 toxicity
assessment values: ACGM, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW,
EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 1 provides information for all of the potentially relevant studies.
Though three sources containing information on titanium exposure were identified in
Table 1, the literature search revealed no human or animal studies, acute, short term, or chronic,
that are useful for developing toxicity values for titanium. Intramuscular information cannot be
translated to meaningful data for development of toxicity values.
DERIVATION OF PROVISIONAL VALUES
Limitations in the available data preclude development of both cancer and noncancer
toxicity values.
CANCER WEIGHT OF EVIDENCE DESCRIPTOR
Limitations in the data preclude development of a weight-of-evidence descriptor.
MODE-OF-ACTION DISCUSSION
Limitations in the data preclude determination of a mode-of-action discussion.
3
Titanium

-------
FINAL
9-20-2010
Table 1. Summary of Potentially Relevant Data for Titanium (CASRN 7440-32-6)
Category
Number of Male/Female,
Species, Study Type,
Study Duration
Dosimetry
Critical Effects
NOAEL
BMDL/
BMCL
LOAEL
Reference
Comments
Human
1. Oral (mg/kg-day)
None
2. Inhalation (mg/m )
Subchronic
None
Chronic
1 Male (type of study and
duration not reported)
Not
provided
Fibrosis
None
Not run None
Husten, 1959
A worker in the hard metal industry
reported fibrosis; however, this
worker was also exposed to other
elements more likely responsible
for fibrosis.
Developmental
None
Reproductive
None
Carcinogenic
None
Animal
1. Oral (mg/kg-day)
None
2. Inhalation (mg/m )
None
4
Titanium

-------
FINAL
9-20-2010
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2010) Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH
ATSDR (Agency for Toxic Substances and Disease Registry). (2008) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Available online at http://www.atsdr.cdc.gov/toxpro2.html. Accessed on May 5, 2010.
Beder O.E.; Eade G. (1956) An investigation of tissue tolerance to titanium metal implants in
dogs. Surgery, 39: 470-473.
CalEPA (California Environmental Protection Agency). (2002) Office of Environmental Health
Hazard Assessment. Hot Spots Unit Risk and Cancer Potency Values. Available online at
http://www.oehha.ca.gov/air/hot spots/pdf/TSDlookup2002.pdf and
http://www.oehha.ca.gov/air/hot spots/pdf/Appendix%20I2002.pdf. Accessed on May 10, 2010.
CalEPA (California Environmental Protection Agency). (2008) Office of Environmental Health
Hazard Assessment. Search Chronic RELs. Available online at
http ://www. arb. ca. gov/toxics/healthval/chronic.pdf and
http://www.oehha.ca.gov/air/chronic rets/AllChrels.html. Accessed on May 5, 2010.
Furst A. (1971) Trace elements related to specific chronic diseases: Cancer. In HL Cannon; HC
Hopps (Ed.),Enviromental geochemistry in health and disease (pp. 109-130). Boulder, CO: The
Geological Society of America.
Husten K (1959) Hard metal fibrosis of the lung. IntArch Occup Environ Health, 16: 721-732.
IARC (International Agency for Research on Cancer). (1999) IARC Monographs on the
evaluation of carcinogenic risks to humans. Available online at
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed on May 10, 2010.
NIOSH (National Institute for Occupational Safety and Health). (2005) NIOSH Pocket Guide
to Chemical Hazards. Index by CASRN. Available online at
http://www.cdc.gov/niosh/npg/npgdcas.html. Accessed on May 5, 2010.
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp.ni ehs.nih.gov/?obi ectid=7DA86165-BDB5-
82F8-F7E4FB36737253D5. Accessed on May 5, 2010.
OSHA (Occupational Safety and Health Administration). (2010) OSHA Standard 1915.1000
for Air Contaminants. Part Z, Toxic and Hazardous Substances. Available online at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p id=102
86. Accessed on May 5, 2010.
5
Titanium

-------
FINAL
9-20-2010
U.S. EPA (U.S. Environmental Protection Agency). (1994) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
December. Accessed on May 5, 2010.
U.S. EPA (U.S. Environmental Protection Agency). (2003) Health Effects Assessment
Summary Tables (HEAST). Prepared by the Office of Research and Development, National
Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial
Response, Washington, DC; EPA 540-R-97-036. Available online at http://epa-fa.east.ornl.gov/.
Accessed April 23, 2010.
U.S. EPA (U.S. Environmental Protection Agency). (2005) Guidelines for carcinogen risk
assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register
70(66): 17765-17817.
U.S. EPA (U.S. Environmental Protection Agency). (2006) 2006 Edition of the Drinking Water
Standards and Health Advisories. Office of Water, Washington, DC; EPA 822-R-06-013.
Available online at http://www.epa.gov/waterscience/drinkine/standards/dwstandards.pdf.
Accessed May 5, 2010.
U.S. EPA (U.S. Environmental Protection Agency). (2010) Integrated Risk Information System
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http://www.epa.gov/iris/. Accessed May 5, 2010.
WHO (World Health Organization). (1982) Online catalogs for the Environmental Health
Criteria Series. Available online at http://www.inchem.org/documents/ehc/ehc/ehc24.htm.
Accessed May 5, 2010.
6
Titanium

-------