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TOXICOLOGICAL PROFILE FOR
TITANIUM TETRACHLORIDE

Prepared by:

Clement International Corporation
Under Contract No. 205-88-0608

Prepared for:

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service
Agency for Toxic Substances and Disease Registry

June 1994

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CAT. FOR

I HEALTH DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the
Agency for Toxic Substances and Disease Registry.

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UPDATE STATEMENT

Toxicological profiles are revised and republished as necessary, but no less than once every three
years. For information regarding the update status of previously released profiles, contact
ATSDR at:

Agency for Toxic Substances and Disease Registry K A / Z 3 /
Division of Toxicology/Toxicology Information Branch

1600 Clifton Road NE, E-29 T 6 o 7 6 4

Atlanta, Georgia 30333
y #
1 97Y

PUBL

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a hakt csi DEF a

 
FOREWORD

The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) amended the
Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund). Section
211 of SARA also amended Title 10 of the U. S. Code, creating the Defense Environmental Restoration
Program. Section 2704(a) of Title 10 of the U. S. Code directs the Secretary of Defense to notify the Secretary

of Health and Human Services of not less than 25 of the most commonly found unregulated hazardous
substances at defense facilities.

Section 2704(b) of Title 10 of the U. S. Code directs the Administrator of the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare a toxicological profile for each substance on the list
provided by the Secretary of Defense under subsection (b). Each profile must include the following:

(A) The examination, summary, and interpretation of available toxicological information and
epidemiological evaluations on a hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute, and chronic health effects.

(B) A determination of whether adequate information on the health effects of each substance is
available or in the process of development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic health effects.

(C) Where appropriate, identification of toxicological testing needed to identify the types or levels of
exposure that may present significant risk of adverse health effects in humans.

This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The
original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary.

The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse
health effects information for the hazardous substance being described. Each profile identifies and reviews the
key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties.
Other pertinent literature is also presented but described in less detail than the key studies. The profile is not

intended to be an exhaustive document; however, more comprehensive sources of specialty information are
referenced.

Each toxicological profile begins with a public health statement, which describes in nontechnical language
a substance’s relevant toxicological properties. Following the public health statement is information concerning
levels of significant human exposure and, where known, significant health effects. The adequacy of information
to determine a substance’s health effects is described in a health effects summary. Data needs that are of
significance to protection of public health will be identified by ATSDR and the Environmental Protection

Agency (EPA). The focus of the profiles is on health and toxicological information; therefore, we have included
this information in the beginning of the document.

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Foreword

The principal audiences for the toxicological profiles are health professionals at the Federal, state, and
local levels, interested private sector organizations and groups, and members of the public. We plan to revise
these documents in response to public comments and as additional data become available. Therefore, we

encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent
to:

Agency for Toxic Substances and Disease Registry
Division of Toxicology

Mail Stop E-29

Atlanta, Georgia 30333

This profile reflects our assessment of all relevant toxicological testing and information that has been peer
reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control and Prevention
(CDC), and other Federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and
is being made available for public review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.

David Satcher, M.D., Ph.D.
Administrator
Agency for Toxic Substances and
Disease Registry

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vii

CONTRIBUTORS

CHEMICAL MANAGERS(S)/AUTHOR(S):

Edward Murray, Ph.D.
ATSDR, Division of Toxicology, Atlanta, GA

Roberta Wedge, M.S.
Clement International Corporation, Fairfax, VA

THIS PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:
1. Green Border Review. Green Border review assures the consistency with ATSDR policy.

2 Health Effects Review. The Health Effects Review Committee examines the health effects
chapter of each profile for consistency and accuracy in interpreting health effects and
classifying endpoints.

3. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to
substance-specific minimal risk levels (MRLs), reviews the health effects database of each
profile, and makes recommendations for derivation of MRLs.

4, Quality Assurance Review. The Quality Assurance Branch assures that consistency across

profiles is maintained, identifies any significant problems in format or content, and establishes
that Guidance has been followed.

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CONTENTS
FOREWORD us: vnbssnrsssass ss ssisoassneats ss vbnsasssassesssnsssdavassess sas v
CONTRIBUTORS ...ocsenssssstossssressssans tosassssnsasesss bassssbasvnvnsee vase vii
LISTOR FIGURES .uvsssnnsivsssananstssssspressssssbosssupnonnsnssdsstessnnne xiii
LIST OF TABLES .cvunsosvspussssasavcssssssnssssnssuse sts bsdbassunestynrnsnnneses Xv
1. PUBLIC HEALTH STATEMENT ........ccctetenrrnrnnnresenenaananesensancnsnnns 1
1.1 WHAT IS TITANIUM TETRACHLORIDE? ..........ciuiunenrnrnrncnonnnncncenes 1
12 WHAT HAPPENS TO TITANIUM TETRACHLORIDE WHEN IT ENTERS THE
ENVIRONMENT? ....0ovvvvnsusnsssaasasnsansssosesasassassssesnansacnens 2
1.3 HOW MIGHT I BE EXPOSED TO TITANIUM TETRACHLORIDE? .........c0tvvenenn 2
1.4 HOW CAN TITANIUM TETRACHLORIDE ENTER AND LEAVE MY BODY? ........... 2
1.5 HOW CAN TITANIUM TETRACHLORIDE AFFECT MY HEALTH? .........ccovvinnns 2
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
TITANIUM TETRACHLORIDE? ....... civ ittntntnrsannnnenssosasnsnsassecns 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTHY + vevnvnatsstssnnsssnssnssssnesssssssnsesspsnssssvesanns 3
1.8 WHERE CAN I GET MORE INFORMATION? . .......iivnnennnnnnnnnnennnerenes 4
5 HEALUTHEFFECTS ..vvusunrsrisssunsasnsnss rrrprsss ARENAS sosmsansannssss snes 5
1 INTRODUCTION i curt rsramnssconss ss sda susssnasaasses sossonssnainnres vee 5
22 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .......ciinienennnnns 5
72.1] INhalaHON EXPOSUTE ..:cvvsns rr sssssnnvsnasssesssvsnnsassrasvannnnsas 9
DO1L DOOM vuusnrncssissmassasssastsstssinsussssonsyrrransnsss 9
2212 SySemiCEectS . . ccvovusssaunnarsrrrsrastananis sssssanennss 10
22.13 Immunological Effects ...........civirirnnritirniannenonenes 13
22.14 Neurological Effects ..........ccevesnrnrarrtrsrnrnnrarcccnnss 14
22.15 Reproductive Effects ..........c.oovnienirnrrnrnarneenrneen, 14
22.1.6 Developmental Effects . .........ovuieuenreirinnnannnnnnens 14
22.17 GenotoxXiC Effects . .. vv vvvt niente 14
22.18 CANCET ....vvvvvnnessansssnnsanssesesssannssassssassnanesns 14
337 OrlEXpOSUIE «onvrssnansssrsvbtsssssansnsssdrssssssdtss btinuvnsnnss 15
D991 Deal ...cvvncrsrrrrararrrrrrarateteer arate erases 16
2222 SySemiCEffects .......ovvvererrnnnnrrrantittarna eens 16
2223 Immunological Effects ...........covivirininriiiinrntnrnenenn 16
2224 Neurological Effects ........ co cvvrensnnnrcicsnrnnnnacnnrnns 16
2225 Reproductive Effects ..........couiiniinnniirnninnrnnnnannennn. 16
2226 Developmental Effects . ........coviiuniennieiinainernes 16
2227 GenotoXiC Effects . .. vou ve nnnrnnes snr eenteenntcnaananens 16
D098 CONCOT + vrsveunssastsitsssrssssssnnsssvonsdfbasnsssversons 16
223 DermalExposure ..........viviirieiirrriiiiirittiiir ssn 16
D931 DOIN suenvearsiits sasssnssssesstsnmstsnndsssrervansasss 16
2332 SystemdCEIectS ...vvuvusuasstrrirnnarssssrrssiinssassrrnens 16
2233 Immunological Effects . ........ovuiuiierneneirennnennnns 18
2234 Neurological Effects ............ eevunrvnreretrrnsnnrrarenees 19
2235 Reproductive Effects ..........coivrunnrnntinnrnnnnnnnenneens 19
2236 Developmental Effects . .......covuiiiinennirnrnranansenenns 19
7937 GenoloXiCEMectS ......ccovvsvrnernerersnrracrcessnnarrscnes 19

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RAB Cor vovvscannnmenssrvrenssdinssnnnn ss sis soe centes sss dune 19

23 TOXICORINBTICS wu''viunnuvvnunersts nunantnssssnes een enns messes 19
23.1 ABSOTPHON oti 20
2.3.1.1 Inhalation EXPOSUTE . ............uueeesnssee 20

23.1.2 Oral EXPOSUIE . . out tui t tees eee eee 20

2.3.1.3 Dermal EXPOSUIe . ...........ouueeenen 20

23.2 Distribution ............. 20
2.3.2.1 Inhalation EXPOSUTE . ............ouueesnsaee 20

2.32.2 Oral EXPOSUIE . . . o.oo ieee eee ee eee ee 20

2.3.23 Dermal EXPOSUIE . .......uuuiitse see 20

2.3.3 Metabolism . .. LLL 20

2.34 BXCTEHON ... o.oo itt 21

2.3.5 Mechanisms of ACHON . ...............ouuuuiuienn i 21
2.3.5.1 Inhalation EXPOSUTE . .............oouuunsni 21

2.3.52 Oral EXPOSUIE . . ..o.vvvvitte eee eee eee 21

2.3.53 Dermal EXPOSUIe . .............c.ooiunsea 21

24 RELEVANCE TO PUBLIC HEALTH . ............couiiiiiii 21
2.5.1 Biomarkers Used to Identify or Quantify Exposure to Titanium Tetrachloride . . .. .. ... 30

2.5.2 Biomarkers Used to Characterize Effects Caused by Titanium Tetrachloride . ......... 30

2.6 INTERACTIONS WITH OTHER SUBSTANCES .............o'''o'ooeo 30
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..............ooooooo.. 30
28 METHODS FOR REDUCING TOXIC EFFECTS ............ooo'io 31
2.8.1 Reducing Peak Absorption Following EXpOSUTE . . . ...............oo'o''ooonn 31

28.2 Reducing Body Burden ......................o.iiii 31

2.8.3 Interfering with the Mechanism of Action for Toxic Effects ..................... 31

29 ADEQUACY OF THE DATABASE ............c0oiuiiiiiia 32
29.1 Existing Information on Health Effects of Titanium Tetrachloride . . ............... 32

29.2 Identification of Data Needs .................couuuursuronnn 32

29.3 On-going SAEs . ........ Li 36

3. CHEMICAL AND PHYSICAL INFORMATION . .............00ueosei 37
3.1 CHEMICAL IDENTITY ...........coouiiiiinininiiinai 37
32 PHYSICAL AND CHEMICAL PROPERTIES ............0o'oo'i 37
4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ...............o'o'oeononn 41
41 PRODUCTION . .uuunnmnntssanonsnesnnnsessnnsnsssnstonennesonmme sy 41
42 IMPORT/EXPORT ............iuuinianieiniea 41
83 USE turcuiniininuiurnstniniarttustsaretrnrnrrertereen rer 41
44 DISPOSAL... 41
5. POTENTIAL FOR HUMAN EXPOSURE . ..............ouuuiiinn 45
5.1 OVERVIEW o.oo 45
5:2 RELEASES TO THE ENVIRONMENT ............c.ouuuurininn 45
cE 45

322 WAET «oot 45

523 Soil LL. 45

53 ENVIRONMENTAL FATE ..........oiuiniininnin ina 45
5.3.1 Transport and Partitioning . .......................... i 45

5.3.2 Transformation and Degradation .....................ouuurioinnnn. 45
co JE 45

33.22 WAT Luisi niiinraara rset rrr nase ren... eso 48

5.323  Sedimentand Soil ................ 48

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Xi

54 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ..........cccvnnnnn 48

SA1 All conupenns is nEpppsassasss ss suassmsnnas rrssssenrnce shy rree ani 48

SHS WHEE wun vei riiabsnnnune 55 Kans saknpiine 1s rorreshdaststinusnnsaees 48

543 Sedimentand Soll ........ceeisvrecarrinai er tnve aa eran 48

54.4 Other Environmental Media .........ooorunoerrrnnnaennnrrnnnnrerenrrs 48

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .........cconnooeccons 48

5.6 POPULATIONS WITH POTENTIALLY HIGHEXPOSURES . ...cciiiienncnnnnnanssns 48

57 ADEQUACY OF THE DATABASE ...........cueurreennnnnmnnrnreennnnneres 49

57.1 Identification of Data Needs .........cooeevnnoerrnnnaennnerrnrecnnsees 49

572 On-going SAILS . oo. ouvert iia 50

6. ANALYTICAL METHODS . ....0vtverrennnnnnnnnnsssnnrrnnes ss annnnrresssansns 51

61 BIOLOGICAL MATERIALS .....vvvuuusvsrrvrnntenanrssssssnnsnosnsnnnss: 51

62 ENVIRONMENTAL SAMPLES .........ccivnnnrenennnnnnnnnnnnnnnnnnneneness 51

6.3 ADEQUACY OF THE DATABASE .........coonnnnnnrennnnnrrrrennnnnssss 56

6.3.1 Identification of Data Needs ...........cooeeeennnnnererrrnnnnnnnn ress 56

632 On-going SWIEs . ...covvvrriirrenrrrrsrsrnnrrrrsasnnnar assay 57

7. REGULATIONS AND ADVISORIES . ....ootinnnnineen anne ese emmsssssnmme es 59

8 REFERENCES ......vvtrrseeeesssrsacessssrssssssassrsssssnnurssraassnnnssres 65

9 GLOSSARY ....ivvsennsssoensessvasssassssrasssesasnssssvsssasandunsernnnnn 73
APPENDICES

A USER'SGUIDE ......vvrvuuuerrssssrnsunnssassssssesnsnasssassrnnnncnssyrrs A-1

B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS . ...ivvvvvneenrnnnsssonsnnnnsanes B-1

C. PEERREVIEW ..cuovurvicvnsnussssnnrsessvssnannsssscsstssstsnncnerunenees C-1

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xiii

LIST OF FIGURES

2-1 Levels of Significant Exposure to Titanium Tetrachloride - INDAIAGON «vivo mum nw ain repos FRbwes

2-2 Existing Information on Health Effects of Titanium Tetrachloride . ........ coin,

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2-2

3-1

3-2

4-1

5-1

6-1

6-2

LIST OF TABLES

Levels of Significant Exposure to Titanium Tetrachloride - Inhalation .........cceenvnnnveennnn
Genotoxicity of Titanium Tetrachloride In Vitro ..........coouunnnernneernnnnnrroneees
Chemical Identity of Titanium Tetrachloride . . .. .....ovievnrrnnnrrrren enero
Physical and Chemical Properties of Titanium Tetrachloride . .......covovvv iene cncocoannnns
Facilities That Manufacture or Process Titanium Tetrachloride ...........cooevenerenreenes
Releases to the Environment from Facilities That Manufacture or Process Titanium Tetrachloride . ..

Analytical Methods for Determining Titanium Tetrachloride and Titanium Dioxide in Biological
IVEAIBIIALE + «cv ummuas ss bh dsssanasastsssraonsddaais sh sa papuavesesssssbsvesvnns

Analytical Methods for Determining Titanium Dioxide in Environmental Samples ..............

Regulations and Guidelines Applicable to Titanium Tetrachloride . ........c.ccveeeeiennens

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|]

 
1. PUBLIC HEALTH STATEMENT

This Statement was prepared to give you information about titanium tetrachloride and to
emphasize the human health effects that may result from exposure to it. The
Environmental Protection Agency (EPA) has identified 1,350 hazardous waste sites as the
most serious in the nation. These sites comprise the "National Priorities List" (NPL):
Those sites which are targeted for long-term federal cleanup activities. Titanium
tetrachloride has not been found in any of the sites on the NPL. However, the number
of NPL sites evaluated for titanium tetrachloride is not known. As EPA evaluates more
sites, the number of sites at which titanium tetrachloride is found may increase. This
information is important because exposure to titanium tetrachloride may cause harmful
health effects and because these sites are potential or actual sources of human exposure
to titanium tetrachloride.

When a substance is released from a large area, such as an industrial plant, or from a
container, such as a drum or bottle, it enters the environment. This release does not
always lead to exposure. You can be exposed to a substance only when you come in
contact with it. You may be exposed by breathing, eating, or drinking substances
containing the substance or by skin contact with it.

If you are exposed to a substance such as titanium tetrachloride, many factors will
determine whether harmful health effects will occur and what the type and severity of
those health effects will be. These factors include the dose (how much), the duration
(how long), the route or pathway by which you are exposed (breathing, eating, drinking,
or skin contact), the other chemicals to which you are exposed, and your individual
characteristics such as age, gender, nutritional status, family traits, life-style, and state of
health.

1.1 WHAT IS TITANIUM TETRACHLORIDE?

Titanium tetrachloride is a colorless to pale yellow liquid that has fumes with a strong
odor. It rapidly forms hydrochloric acid, as well as titanium compounds if it comes in
contact with water. In 1990, approximately 1.5 million tons of titanium tetrachloride
were produced in the United States.

Titanium tetrachloride is not found naturally in the environment and is made from
minerals that contain the metal titanium. It is used to make titanium metal and other
titanium-containing compounds, such as titanium dioxide, which is used as a white
pigment in paints and other products, and as an intermediate to produce other chemicals.

Chapter 3 contains more information on the physical and chemical properties of titanium
tetrachloride, and Chapter 4 contains more information its production and use.

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1. PUBLIC HEALTH STATEMENT

1.2 WHAT HAPPENS TO TITANIUM TETRACHLORIDE WHEN IT ENTERS THE
ENVIRONMENT?

Titanium tetrachloride enters the environment primarily as air emissions from facilities
that make or use it in various chemical processes or as a result of spills. In the air, if
moisture is present, titanium tetrachloride reacts with the moisture to form hydrochloric
acid and other titanium compounds, such as titanium dioxide and titanium oxychloride.
The hydrochloric acid may break down or be carried in the air. The titanium compounds
may settle out to soil or to water. In water they then sink to the bottom sediments.

They may remain for a long time in the soil or sediments. Titanium compounds, such as
titanium dioxide, are also found in the air and water. For further information on what
happens to titanium tetrachloride in the environment, refer to Chapters 4 and 5.

1.3 HOW MIGHT | BE EXPOSED TO TITANIUM TETRACHLORIDE?

Titanium tetrachloride has not been found in water, soil, food, or air other than in the
workplace. Because titanium tetrachloride breaks down so rapidly in the environment, it
is unlikely that you would be exposed to it unless you worked in a facility that made or
used it or if you were exposed to it as a result of a spill. If you work at such a facility,
you may breathe in air that contains it or breathe fumes of hydrochloric acid. You could
also breathe in particles of the titanium compound, titanium dioxide, or titanium metal
dust. If titanium tetrachloride spills, you may get it on your skin.

At disposal sites for titanium tetrachloride, you may be exposed to fumes of it or its
breakdown product, hydrochloric acid. In 1980, about 2,100 workers may have been
exposed to titanium tetrachloride in the workplace.

No other information has been found on the presence of titanium tetrachloride in air,
water, soil, or foods that would suggest that you may be exposed to it from these sources.
For more information on the potential for exposure to titanium tetrachloride, refer to
Chapter 5.

1.4 HOW CAN TITANIUM TETRACHLORIDE ENTER AND LEAVE MY BODY?

Titanium tetrachloride can easily enter your body if you breathe air that is contaminated
with its fumes. In your nose and lungs, the titanium tetrachloride will react with the
moist air and form hydrochloric acid, which may cause burns. Titanium metal particles
may remain in your lungs or nearby tissue. Titanium tetrachloride and its breakdown
products do not appear to enter other parts of your body. Refer to Chapter 2 for more
information on how titanium tetrachloride may enter and leave your body.

1.5 HOW CAN TITANIUM TETRACHLORIDE AFFECT MY HEALTH?
Titanium tetrachloride can be very irritating to the skin, eyes, mucous membranes, and

the lungs. The corrosive action of titanium tetrachloride stems from its vigorous reaction
with water. The reaction products, especially hydrochloric acid, are responsible for

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3

1. PUBLIC HEALTH STATEMENT

harmful health effects and burns that can occur after exposure to titanium tetrachloride.
Breathing in or swallowing large amounts of titanium tetrachloride can cause death.
However, it is not known how much of the compound is necessary to cause death.
Inhaling large amounts of titanium tetrachloride fumes can cause serious injury to the
lungs and can result in death. After short-term exposure to titanium tetrachloride, less
serious respiratory system effects can include cough and tightness in the chest. More
severe effects can include chemical bronchitis or pneumonia, and congestion of the
mucous membranes of the upper respiratory tract resulting in long-term effects such as
the narrowing of the larynx, trachea, and upper bronchi.

Accidental exposure to liquid titanium tetrachloride can result in skin burns and can
cause permanent damage to the eyes if they are not protected.

Some laboratory animals that breathed high concentrations of titanium tetrachloride
fumes for 2 years developed lung tumors of a special type. However, there is no
evidence that exposure to titanium tetrachloride causes cancer in humans. Information is
insufficient to determine if titanium tetrachloride causes birth defects or affects
reproduction. The International Agency for Research on Cancer, a National Cancer
Institute-supported facility, has indicated that titanium dioxide is not classifiable as to its
potential for causing cancer in humans; however, other government agencies have not
classified titanium tetrachloride for its potential to cause cancer. For more information
on the health effects of titanium tetrachloride, see Chapter 2.

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN
EXPOSED TO TITANIUM TETRACHLORIDE?

There is no medical test to indicate whether you have been exposed to titanium
tetrachloride. However, exposure to titanium dioxide or titanium metal, possible
breakdown products of titanium tetrachloride, can be determined by examining lung
tissue for titanium metal particles with electron microscopes. This test is not specific for
titanium tetrachloride exposure, nor does it indicate whether you may have potential
health effects resulting from such exposure or the amount of titanium compound to
which you were exposed. For more information on determining exposure to titanium
tetrachloride, refer to Chapters 2 and 6.

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?

The federal government has developed regulations and guidelines for release and
transportation of titanium tetrachloride. Congress has determined that titanium
tetrachloride is a hazardous air pollutant, and EPA has established that it is an extremely
hazardous substance.

Releases of more than 1 pound of titanium tetrachloride must be reported to EPA.

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1. PUBLIC HEALTH STATEMENT

Maximum levels have not been established for titanium tetrachloride exposure in the
workplace. See Chapter 7 for more information on the regulations and guidelines that
have been established for titanium tetrachloride.

1.8 WHERE CAN | GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state
health or environmental quality department or:

Agency for Toxic Substances and Disease Registry
Division of Toxicology

1600 Clifton Road NE, E-29

Atlanta, Georgia 30333

(404) 639-6000

This agency can also provide you with information on the location of occupational and
environmental health clinics. These clinics specialize in the recognition, evaluation, and
treatment of illness resulting from exposure to hazardous substances.

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2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and
other interested individuals and groups with an overall perspective of the toxicology of titanium
tetrachloride. It contains descriptions and evaluations of toxicological studies and epidemiological
investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data

to public health.
A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near
hazardous waste sites, the information in this section is organized first by route of exposure — inhalation,
oral, and dermal; and then by health effect — death, systemic, immunological, neurological, reproductive,
developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure
periods — acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in figures.
The points in the figures showing no-observed-adverse-effect levels (NOAELSs) or lowest-observed-adverse-
effect levels (LOAELS) reflect the actual doses (levels of exposure) used in the studies. LOAELSs have
been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a
biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less
serious" effects are those that are not expected to cause significant dysfunction or death, or those whose
significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of
judgment may be required in establishing whether an end point should be classified as a NOAEL, "less
serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide
whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines
and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in
this approach to warrant an attempt at distinguishing between "less serious" and "serious" effects. The
distinction between "less serious" effects and "serious" effects is considered to be important because it helps
the users of the profiles to identify levels of exposure at which major health effects start to appear.
LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or
duration, and place into perspective the possible significance of these effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and
figures may differ depending on the user’s perspective. Public health officials and others concerned with
appropriate actions to take at hazardous waste sites may want information on levels of exposure associated
with more subtle effects in humans or animals (LOAELS) or exposure levels below which no adverse
effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk
Levels or MRLs) may be of interest to health professionals and citizens alike.

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of titanium
tetrachloride are indicated in Table 2-1 and Figure 2-1. Because cancer effects could occur at lower
exposure levels, Figure 2-1 also shows a Tnge for the upper, bound of estimated excess risks, ranging from
a risk of 1 in 10,000 to 1 in 10,000,000 (10™ to 107), as developed by EPA.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been

made for titanium tetrachloride. An MRL is defined as an estimate of daily human exposure 10 a
substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a

***x DRAFT FOR PUBLIC COMMENT ***
»»» INSJWNOD ONBNd HOH 14VHA ves

TABLE 2-1. Levels of Significant Exposure to Titanium Tetrachloride - Inhalation

 

 

 

Exposure LOAEL (effect)
Key to duration/ NOAEL Less serjous Seri
figure" Species frequency System (mg/m™) (mg/m) (mg/m™) Reference
ACUTE EXPOSURE
Death
1 Rat 4 hr 460 (LCgq) EPA 1984
Systemic
2 Rat 10 min Resp 1466 (nasal discharge, 5112 (discrete inflamma- Karlsson et al.
Once dyspnea) tory residue in the 1986
lungs, coarsened
alveolar septa)
Derm/oc 1466 (swollen eyelids)
CHRONIC EXPOSURE
Systemic
3 Rat 2 yr Resp 0.1°(tracheitis and EPA 1986; Lee et
5d/wk rhinitis) al. 1986
6hr/d
Immunological
A Rat 2 yr 1.0 (increased incidence EPA 1986; Lee et
5d/wk of foamy lung al. 1986
6hr/d macrophages with
increased TiCl4
dust deposition)
Cancer
5 Rat 2 yr 10.0 (CEL-differentiated EPA 1984
5d/wk squamous cel |
6hr/d carcinoma in lungs

of 3/150, keratin-
ized squamous

cell carcinoma in
2/150)

S103443 H1TV3H 2
xxx INTGWWOO O1N8Nd HOH 14VHA »xx

TABLE 2-1. Levels of Significant Exposure to Titanium Tetrachloride - Inhalation (continued)

 

 

 

Exposure LOAEL (effect)
Key to duration/ NOAEL Less serious Serioys
figure® Species frequency System (mg/m™) (mg/m”) (mg/m”) Reference
6 Rat 2 yr 10.0 (CEL-squamous cell EPA 1986; Lee
5d/wk carcinoma in lung- et al. 1986
6hr/d 2/69 males and 3/74

females)

 

“The number corresponds to entries in Figure 2-1.

Used to derive a chronic inhalation Minimum Risk Level (MRL) of 0.001 mg/m’; concentration divided by an uncertainty factor

of 90 (3 for extrapolation from animals to humans, 10 for human variability, and 3 for use of a minimal LOAEL).

CEL = cancer effect level; d = day(s); Derm/oc

LOAEL
Ticl,

titanium tetrachloride; wk = week(s); yr

= dermal/ocular; hr = hour(s); LCs, = lethal concentration, 50% kill;
lowest -observed-adverse-effect level; min

= minute(s); NOAEL = no-observed-adverse-effect level; Resp = respiratory;

year(s)

S103443 H1TVaH 2

 
ss» INJWWNOD OMN8Nd HOH 14VHA sss

FIGURE 2-1. Levels of Significant Exposure to Titanium Tetrachloride - Inhalation

 

 

 

 

 

ACUTE CHRONIC
(<14 Days) (> 365 Days)
Systemic Systemic
(mg/m?)
10,000
@
1,000 | Oz Oa
Br
100 |
10 ®s5 Gu
1F Qu
01 | Par
1
1
0.01 | 1
1
|
0.001 | |
<
0.0001 L
Key
r Rat HB cso ' Minimal risk level for
@ LOAEL for serious effects (animals) | effects other than cancer

 

* Doses represent the lowest dose tested per study that produced a tumorigenic

( LOAEL for less serious effects (animals)
@ CEL - Cancer Effect Level
The number next to each point corresponds to entries in Table 2-1.

/

 

response and do not imply the existence of a threshold for the cancer end point.

 

S103443 HITVaH 2

 
9

2. HEALTH EFFECTS

specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the
target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of
exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects.
MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral
routes. Appropriate methodology does not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a),
uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an
example, acute inhalation MRLs may not be protective for health effects that are delayed in development
or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic
bronchitis. As these kinds of health effects data become available and methods to assess levels of
significant human exposure improve, these MRLs will be revised.

A User’s Guide has been provided at the end of this profile (see Appendix A). This guide should aid in
the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

2.2.1 Inhalation Exposure

Titanium tetrachloride can be highly irritating to the mucous membranes (including the upper respiratory
tract), to the skin, and to the eyes (Mogilevskaja 1983). Titanium tetrachloride is a colorless to light
yellow liquid with a penetrating acid odor (Haddad and Winchester 1990). Titanium tetrachloride is a
highly corrosive acute irritant to the skin, eyes, mucous membranes, and respiratory tract (EPA 1985b).
Titanium tetrachloride readily hydrolyzes in the presence of water or moist air via an exothermic reaction
that occurs in two stages. First, titanium tetrachloride condenses into fine droplets that form a highly
dispersed particulate smoke. This smoke is very hygroscopic and reacts with the moisture in the air to
form secondary smoke, which contains hydrolytic products of titanium tetrachloride such as hydrochloric
acid, titanium oxychloride, and titanium dioxide. Titanium tetrachloride is used as an intermediate in the
production of metallic titanium and titanium dioxide when it is reduced in the presence of metallic sodium
to yield a solid mixture of titanium and sodium chloride (Garabrant et al. 1987). Titanium tetrachloride
can also be used for the generation of white smoke screens in military operations (Wilms et al. 1992), in
the pigment and mordant dye industry, and in glass and pearl manufacturing (EPA 1985b). Because of its
rapid hydrolysis and smoke or fume formation, exposure to titanium tetrachloride aerosol is most likely to
occur via the inhalation route. The highly corrosive properties of titanium tetrachloride that have been
described in accidental occupational exposure studies are probably due to its rapid hydrolysis by water
(EPA 19850).

All of the human studies discussed in the section on inhalation exposure are either epidemiological reports
of occupational exposure or case reports of accidental exposure. In occupational studies and in reports of
accidental exposure, the exact levels of exposure are not known. Furthermore, in many of the
occupational studies, inhalation exposure occurred simultaneously with dermal exposure. Therefore, some
of the effects reported in this section may be due partially to dermal exposure to titanium tetrachloride.

2.2.1.1 Death

One death was reported of a worker who was accidentally splashed over his whole body with titanium
tetrachloride (Chitkara and McNeela 1992). He suffered extensive burns to his facial skin, nasopharynx,
and larynx, and both his eyes were severely injured. His corneas were thick and opaque with extensive
swelling of the bulbar conjunctiva and episclera. Over the next 14 days, some of the opacity in the right
eye cleared, but there was no improvement in the left eye. The patient died from the complications of
severe pulmonary injury caused by inhalation of titanium tetrachloride fumes (Chitkara and McNeela
1992).

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Except for the single case described above, no increase in mortality from any cause was reported in
workers occupationally exposed to titanium tetrachloride from 1 day to over 5 years (EPA 1990b;
Fayerweather et al. 1992). However, these studies are limited because they are focused to some extent on
the incidence of and mortality from lung cancer and because of the potential exposure of the subjects to
other chemicals in the chemical manufacturing complex.

Limited information was located regarding lethal effects in animals after inhalation exposure to titanium
tetrachloride. A 4-hour inhalation LCs, of 460 mg/m? in rats was reported (EPA 1984), but the primary
study for this lethal concentration was not cited. After a single 2-hour inhalation exposure to low,
medium, and high levels of titanium tetrachloride and its hydrolysis products (titanium oxychloride,
titanium dioxide and hydrochloric acid), 9 out of 15 mice died (Mezentseva et al. 1963). The results
indicate that death following exposure was dose-dependent; of the 9 animals that died following exposure
to titanium tetrachloride, 4 were from the high-dose group, 3 were from the middle-dose group, and 2
were from the low-dose group. This study also included three groups of mice exposed to hydrochloric acid
alone (the doses were 0.012-0.06 mg/L, 0.036-0.11 mg/L, and 0.03-0.24 mg/L). Only one mouse died in
the group exposed to the high dose of hydrochloric acid. These results are important because they
compare the toxic effects of titanium tetrachloride and its hydrolysis products with those of hydrochloric
acid, and they indicate that hydrolysis products of titanium tetrachloride are more toxic to mice than
hydrochloric acid alone. Although the cause of death in this study is not known, it appeared that in both
cases (exposure to hydrolysis products of titanium tetrachloride and exposure to hydrochloric acid alone)
the active component was hydrochloric acid. One possible explanation for the more severe effects seen
from exposure to titanium tetrachloride compared with hydrochloric acid is that hydrochloric acid, because
of its high solubility, is dissolved in the moisture of the nasopharynx and trachea and thus penetrates the
lungs to only a very limited extent. However, in the case of exposure to titanium tetrachloride, the
hydrolysis occurs in several steps; one of the hydrolysis products, titanium oxide hydrate, is a particulate
that can absorb some of the hydrochloric acid vapors that are also generated during hydrolysis and carry
they into the deeper parts of the lungs. In the lungs, the hydrolysis process is repeated with the further
release of hydrochloric acid, resulting ultimately in larger amounts of hydrochloric acid being carried
deeper into the lung and to the alveoli (Mezentseva et al. 1963). This study is limited in that the precise
exposure levels are not known since the titanium tetrachloride concentrations were communicated as
separate titanium concentrations and hydrochloric acid concentrations. The study also did not give
detailed information on the exposed animals.

2.2.1.2 Systemic Effects

No studies were located regarding cardiovascular, gastrointestinal, musculoskeletal, hepatic, and renal
effects in humans or animals after inhalation exposure to titanium tetrachloride. The systemic effects
observed after inhalation exposure are discussed below.

The LOAEL values from each reliable study for systemic effects in each species and duration category are
recorded in Table 2-1 and plotted Figure 2-1.

Respiratory Effects. Case studies of humans acutely exposed to titanium tetrachloride fumes have shown
the irritant nature of the inhaled chemical. Since titanium tetrachloride undergoes hydrolysis almost
immediately when in contact with water or moisture in the air (forming fumes that contain titanium
oxychloride and hydrochloric acid), its main effect on the lungs is corrosive. Although the degree of
pulmonary injury can vary, exposure can result in an intense chemical bronchitis or pneumonia (Lawson
1961). Following an accidental acute exposure, three research workers experienced only mild irritant
symptoms consisting of cough, and tightness in the chest, which both lasted only a couple of hours and left
no abnormalities on the chest x-ray (Ross 1985). More severe pulmonary effects were reported in two
other incidents of accidental exposure to titanium tetrachloride. One worker that was splashed with hot
titanium tetrachloride suffered marked congestion of the mucous membranes of the pharynx, vocal cords,
and trachea (Ross 1985). This exposure had long-term effects that included stenosis of the larynx, trachea,

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2. HEALTH EFFECTS

and upper bronchi. The second worker accidentally exposed to titanium tetrachloride hydrolysis fumes
developed cough and dyspnea 20 minutes after exposure (Park et al. 1984). His symptoms progressed to
severe upper airway distress that required intubation and ventilation. Further symptoms included hypoxia
and diffuse pulmonary infiltrates suggestive of adult respiratory distress syndrome. He gradually improved,
but fiberoptic bronchoscopy 5 weeks after admission revealed erythema of the entire bronchial tree and the
presence of 35-40 fleshy polypoid lesions. The presence of the polyps, according to the authors, was a
sign of an exaggerated but normal reparative process of the tracheobronchial injury. This delayed
complication has been seen in thermal respiratory injuries, indicating that the severe adverse respiratory
effects seen in this case are in part due to the exothermic nature of the titanium tetrachloride hydrolysis
reaction. One year after the injury, his lungs appeared normal but some degree of mild stenosis remained.

The results of occupational exposure of 209 workers employed at a metals reduction facility in Ashtabula,
Ohio, were reported in two retrospective studies (Garabrant et al. 1987; NIOSH 1980). The results
suggest that pulmonary impairment may be caused by exposure to titanium tetrachloride. Medical
examinations, chest x-rays, and pulmonary function tests were done on all workers. Medical and
occupational histories were also obtained. Personal and area air samples were analyzed for titanium
particulates, asbestos, welding fumes, and hydrochloric acid. NIOSH determined that the hydrochloric acid
concentration in the air was negligible (below the OSHA standard of 5 mg/m?). Workers were divided
into three groups (two experimental and one control) based on their jobs and duration of employment in
specific jobs. The use of a group of maintenance workers as a control may have caused the
underestimation of the true association between respiratory symptoms and pleural disease because the
controls were exposed to everything the other two groups were exposed to. Of the 209 workers, 78 were
engaged in the titanium tetrachloride reduction process and were also exposed to sodium, titanium dioxide,
titanium oxychloride, and dust. There were no significant differences regarding symptoms, results of
functional tests, and results of chest radiographs among the three groups. The symptoms included cough,
phlegm production, chronic bronchitis, and wheezing with dyspnea. Logistic regression analysis of the
chest radiograph data showed that pleural thickening was strongly related to the length of time working in
titanium production (p<0.001). The initial estimate of loss of pulmonary function, taking smoking into
account, was 45 mL/year leading to a deficit of 1.8 L/40-year employment period (NIOSH 1980). Further
analysis of the employees, based on job and duration of employment, confirmed large decreases in forced
vital capacity (FVC) in workers employed in titanium tetrachloride reduction for at least 10 years
(Garabrant et al. 1987). A regression analysis of the data adjusted for age, height, and smoking revealed
that the rate of loss of FVC was 24 mL per year for the titanium tetrachloride workers (Garabrant et al.
1987). The results also showed that previous asbestos exposure and cigarette smoking were not
significantly related to pleural thickening. These results suggest that chronic exposure to titanium
tetrachloride may result in restrictive pulmonary changes and that there is no clear association between
pleural thickening and reduction in ventilatory capacity. It is difficult to determine the precise cause of
these pulmonary abnormalities, and further studies are needed to clarify this issue. The limitations of both
studies include the lack of information on the duration, route, and exposure levels, the concomitant
exposure to a mixture of chemicals, and the use of maintenance workers who were exposed to one or more
chemicals as a control group.

Since titanium tetrachloride is rapidly hydrolyzed in the presence of water, some of the pulmonary
depositions in occupationally exposed workers may be due to metallic titanium. In a study of three
workers who worked for 9-10 years in a titanium dioxide procéssing factory, electron microscopy and
spectrometric and spectrographic analyses of lung tissue showed the presence of considerable amounts of
titanium (Elo et al. 1972). Electron microscopy first identified 0.1-0.4-um-diameter black particles in
lysosomes of phagocytic cells filling the alveolar lumen. The black particles were very similar to the
titanium dioxide particles that were layered on top of the grid and examined under the electron
microscope, and further spectrographic analyses using x-ray fluorescence confirmed the presence of
titanium. Large quantities of titanium were also present in the lymph nodes. Similar findings were made
in the case of a 55-year-old man who worked for 3 years in a titanium pigment processing factory (Ophus

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2. HEALTH EFFECTS

et al. 1979). He died of lung metastasis from an undifferentiated tumor in the right ileal bone, and his
lungs were analyzed for the presence of titanium. Macroscopic and microscopic examinations revealed
large amounts of white, birefractive pigment in all parts of the lungs without obvious fibrotic changes.
Further analysis confirmed the presence of titanium and occasionally iron, and also showed that the crystal
modification of titanium was in the form of rutile, a mineral of titanium dioxide that also contains some
iron. Ash weight determinations of lung tissue revealed an increased concentration of titanium dust
particulates in the right middle lobe (43.3-49%) and lower lobe (39.2-47%) as compared to <0.2% found
in two control specimens. The absence of any pulmonary response to the deposits of titanium dust may be
due to the fact that rutile is a biologically inert crystalline modification of titanium/titanium dioxide. None
of the techniques used in this study can unequivocally identify the presence of titanium dioxide. In a study
of a 45-year-old man who worked for 13 years as a furnace feeder in an aluminum smelting company,
scanning electron microscopy and enc dispersive x-ray analysis Showed that the lung tissue biopsy from
the lower right lobe contained 1.39x10” exogenous particulates/cm® of tissue (Redline et al. 1986). The
particulates contained various metallic alloys; 61% of the particulates consisted of aluminum and other
metals such as titanium, zinc, and nickel, 35% contained various aluminum silicates, and 2% of the
particles were silica. This finding confirms the possibility of titanium deposition in the lung tissue and, in
this case, lends support to the association of granulomatous lung disease with metallic particle deposition.
The results of these three case reports indicate that metallic titanium can be deposited in the lungs of
occupationally exposed workers, and that these deposits do not necessarily cause histopathological changes.
It is also possible that these deposits do cause local pulmonary tissue irritation, which can progress to
granulomatous lung disease. Further studies are needed to establish the causal relationship between
deposits of titanium dust particulates and granulomatous lung disease.

Findings in animals support the observations made i humans. Female Sprague-Dawley rats were exposed
by inhalation to 1,466, 5,112, 7,529, and 11,492 mg/m? of titanium tetrachloride for 10 minutes (Karlsson
et al. 1986). None of the animals died from exposure, but signs of toxicity included wet noses, nasal
discharge, swollen eyelids, and dyspnea. These signs disappeared 48-72 hours after exposure, and lung
histopathology done 7 days later showed minor lesions. The lungs in 1/3 and 2/2 rats exposed to 5,112 and
11,492 mg/m”, respectively, showed discrete inflammatory residues, coarsened alveolar septa, and sparse
accumulation of phagocytes. Similar observations were made in chronically exposed Crl:CD rats

(EPA 1986; Lee et 2k 1986). Groups of 100 rats/sex/concentration were exposed by inhalation to 0, 0.1,
1.0, and 10.0 mg/m? respectively, of hydrolyzed titanium tetrachloride for 6 hours/day, 5 days/week for

104 weeks (2 years). Five males and five females from each group were sacrificed after 3 and 6 months,
10 animals of each sex were killed after 1 year, and the remaining animals were sacrificed at the end of the
2nd year for gross and microscopic evaluation. The primary clinical finding was an increased incidence of
irregular respiration and abnormal lung noises in exposed animals. The incidence was concentration-
related (5%, 12%, 24%, and 36% in males and 8%, 16%, 44%, and 41% in females at 0, 0.1, 1.0, and

10.0 mg/m3, respectively). The major health effects of exposure to titanium tetrachloride were observed in
the respiratory tract of exposed rats. The incidence of rhinitis increased with concentration and duration
of exposure. In the control animals, the incidence ranged from 3.9% to 31.6% and was usually higher at

2 years. In the low-concentration group, the incidence of rhinitis at 1 year ranged from 4.3% to 15%, and
at 2 years it ranged from 21.9% to 64.4%. In the mid- and high-concentration groups, the incidences were
4.5-31.8% and 25-33.3%, respectively, at 1 year, and 16.9-56.2% and 23.2-65.8%, respectively, after

2 years of exposure. Tracheitis also increased with duration and to a lesser degree with concentration.
The two highest groups had an increased incidence of tracheitis as early as 3 months; after 2 years,
tracheitis was increased in the lowest exposure group. The incidences of tracheitis at the end of the

2 years were 0-2.5%, 12-20%, 41-40%, and 30-44% for the control, low-, mid-, and high-exposure
groups, respectively. The 0.1- -mg/m> level is considered a less serious LOAEL for adverse effects in the
extrathoracic/tracheobronchial region. Gross pathology and histopathology revealed compound-related
changes in the lungs and thoracic lymph nodes of the treated animals. Mean absolute and relative lung
weights were increased significantly (p<0.05) after 1 and 2 years of treatment compared to untreated
controls. In male rats, relative lung weight was increased significantly (p<0.05) after 6 months of
treatment. The increase in lung weight ranged from 1.23 to 1.55 times control values for females, and

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2. HEALTH EFFECTS

from 1.13 to 1.35 for males. Foci laden with yellow titanium tetrachloride hydrolysis product were present
on the lung pleural surface and on the slightly enlarged tracheobronchial lymph nodes in the mid- and
high-exposure groups. The pulmonary response in these two groups also included the presence of the
dust-laden macrophages and hyperplasia of the alveolar lining. The incidence and severity of alveolar
hyperplasia increased with concentration; incidences were 0% in the control and low-exposure groups, and
32-63% and 92-97% in the mid- and high-exposure groups, respectively. The concentration of 0.1 mg/m>
is considered a LOAEL for the pulmonary effects and was used for the derivation of a chronic inhalation
exposure MRL of 0.001 mg/m? as described in the footnote in Table 2-1.

Hematological Effects. Limited information is available regarding hematological effects in humans
following inhalation exposure to titanium tetrachloride. No abnormal values for hemoglobin, white blood
cells, neutrophils, monocytes, and basophils were found in 10 workers exposed for 4-17 years to low levels
of titanium tetrachloride fumes (Lawson 1961). The level of titanium tetrachloride in the fumes was not
reported. Three of the workers had mild eosinophilia, and four had relative lymphocytosis. Since there
were no data from control subjects, it is difficult to estimate whether these changes are significant or not.
According to the author, the observed lymphocytosis may have been caused by the influenza present
among the workers at the time of the study. Another limitation of the study is the lack of a detailed
description of the other chemicals to which the workers may have been exposed.

In a chronic inhalation exposure study, Crl:CD rats were exposed to 0, 0.1, 1.0, and 10.0 mg/m> of titanium
tetrachloride 6 hours/day, 5 days/week for 2 years (EPA 1986; Lee et al. 1986). After 18 months of
exposure, high-dose rats had a significant increase in neutrophils (p<0.05) and a decrease in lymphocytes.
Males at this concentration had a significant decrease in erythrocytes and significant increases in mean cell
volume and mean cell hemoglobin.

Dermal/Ocular Effects. Mild symptoms of toxicity developed in a case in which three research workers
were accidentally exposed to titanium tetrachloride fumes (Ross 1985). One person developed eye
irritation that lasted about 2 hours. Upon medical examination several hours after the accident, no
abnormalities were found. In another case of accidental exposure, a 50-year-old chemical engineer was
sprayed with titanium tetrachloride over his head, chest, neck, and back (Park et al. 1984). When he
removed his mask to clean himself, he was exposed to vapor formed when titanium tetrachloride came in
contact with air. He developed erythema of the conjunctivae, tongue, and pharynx with other signs of
respiratory toxicity. His ocular symptoms were more severe than the ones described in the first case
because he used water to clean himself. That led to the formation of hydrochloric acid, which caused
second- and third-degree burns over the parts of his body that came in contact with titanium tetrachloride.
No information was given about the dose or the course of his eye injury. Use of water in cases of titanium
tetrachloride is contraindicated because of their vigorous interaction and formation of hydrochloric acid.

Eye injury after titanium tetrachloride exposure was also observed in acutely exposed rats. In the acute
inhalation exposure sty, female Sprague-Dawley rats were exposed to concentrations of 1,466, 5,112,
7,529, and 11,492 mg/m> of titanium tetrachloride for 10 minutes (Karlsson et al. 1986). No animals died
from the exposure, but the signs of toxicity included swollen eyelids, irritation, wet noses, nasal discharge,
and dyspnea. Although the animals were observed for 7 days, the symptoms disappeared within

48-72 hours.

2.2.1.3 Immunological Effects

Very limited information is available regarding immunological effects in humans or animals following
inhalation exposure to titanium tetrachloride. An elevated lymphocyte count of 23,700 cells/mm> was
found in a worker after an accidental exposure to titanium tetrachloride (Park et al. 1984). No further
information or details of exposure were provided, but the worker also suffered second- and third-degree
burns over 25% of his body. In another study, 4/10 workers chronically exposed to low levels of titanium
tetrachloride fumes had relative lymphocytosis (Lawson 1961). However, it is difficult to interpret this

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2. HEALTH EFFECTS

finding because no controls were available, and there was influenza among the workers at the time the
study was conducted.

The immune status in humans is most commonly evaluated by in vitro testing of peripheral blood
lymphocytes (PBLs). Impaired cellular immune function was found in a 45-year-old man who worked for
13 years as a furnace feeder in an aluminum smelting company (Redline et al. 1986). The in vitro
responses of his PBLs to selected mitogens (phytohemagglutinin, pokeweed mitogen, and concanavalin A)
were below the mean values for normal responses established in 50 control subjects. Since he presented
with pulmonary granuloma containing different metallic particles, his PBLs were tested four times over an
11-month period for responsiveness to titanium tetrachloride, nickel sulfate, and aluminum chloride. This
was done to establish a possible causal relationship between the metallic particulates in the pulmonary
granuloma and the immune response of the delayed hypersensitivity type. Only the response to titanium
tetrachloride was positive in two out of four tests. The controls used in the experiment were three
painters exposed to titanium-based paints for 15-28 years; their response to all three metallic salts was
negative. These results indicate that chronic exposure to titanium in this one patient may have led to his
sensitization and may be related to the pulmonary granulomatous disease that he developed. Important to
note, however, is that three other chronically exposed individuals used as controls were not sensitive to
titanium. The limitations of the study are that exposure occurred to several metals, that the dose or
precise duration are not known, and that the in vitro response of the patient to titanium tetrachloride was
positive in two out of four tests.

In an inhalation exposure study, Crl:CD rats were exposed to 0, 0.1, 1.0, and 10.0 mg/m> of hydrolyzed
titanium tetrachloride for 6 hours/day, 5 days/week for 2 years (EPA 1986; Lee et al. 1986). The study
focused on lung injuries and revealed the presence of two types of macrophages in the lung alveoli. Both
types contained particles; one type had densely aggregated particles (dust-laden macrophages), and the
other contained a small amount of particles (foamy dust macrophages). The incidence of these latter
macrophages was increased in rats receiving 10.0 mg/> of hydrolyzed titanium tetrachloride. Dose-related
changes observed in the tracheobronchial lymph nodes of rats exposed to 1.0 and 10.0 mg/m> included
slight enlargement of the nodes and foci laden with yellow titanium tetrachloride hydrolysis product.
These tracheobronchial lymph nodes were also slightly enlarged. The two types of macrophages seen in
treated rats were not present in any of the control animals. The results indicate that compound-related
lung injury evoked an immune reaction in the form of increased macrophage infiltration. The limitations
of the study are that other immune functions were not tested and that no information is available
regarding the numbers of lymphoid cells. It is therefore difficult to estimate the extent of immunologic
injury in rats following chronic inhalation exposure to titanium tetrachloride.

All LOAEL values from each reliable study for immunological effects in rats in chronic-duration studies
are recorded in Table 2-1 and plotted Figure 2-1.

No studies were located regarding the following health effects in humans or animals after inhalation
exposure to titanium tetrachloride:

2.2.1.4 Neurological Effects

2.2.1.5 Reproductive Effects

2.2.1.6 Developmental Effects

2.2.1.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.4.

2.2.1.8 Cancer

A few epidemiological studies have examined cancer mortality in workers employed in industries using
titanium tetrachloride. No association between titanium tetrachloride exposure and lung cancer mortality

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was found in 969 male workers occupationally exposed to <0.5->3.0 mg/m? of titanium tetrachloride for
periods up to more than 5 years (EPA 1990b; Fayerweather et al. 1992). Of these workers, 24 lung cancer
cases and 96 controls were included in the statistical analyses. Data on the incidence of lung cancer and
chronic respiratory disease (from 1956 through 1985) and mortality (from 1935 through 1983) were
included in the study. The smoking status, year of birth, and year of hire of the workers were also taken
into account. No titanium tetrachloride exposure monitoring data were available before 1975, and the use
of respirators for protection against titanium tetrachloride during routine operations was introduced in
1984. Statistical analysis of the available mortality and lung cancer incidence data showed that there was
no association between titanium tetrachloride and lung cancer mortality (odds ratio, 1.1). The results
showed that only cigarette smoking was a strong predictor of lung cancer mortality. There were no graded
dose-response trends for titanium tetrachloride and lung cancer mortality for the exposure indices of time-
weighted average, exposure duration, and cumulative exposure index.

Although lung squamous cell carcinoma and keratinizing squamous cell carcinoma were observed in rats
chronically exposed to titanium tetrachloride, it is difficult to estimate their relevance to lung tumors in
humans (EPA 1984, 1986; Lee et al. 1986). One hundred male and 100 female Crl:CD rats were exposed
to 0, 0.1, 1.0, and 10.0 mg/m? of hydrolyzed titanium tetrachloride vapors 6 hours/day, 5 days/week for

104 weeks (2 years). Chronic toxicity was evaluated by sacrificing 20 rats per group at 3, 6, and 12 months.
Histopathology was done on all major tissues and organs, and no changes were observed except in the
respiratory tract. Two types of lung squamous cell carcinoma were found. Well-differentiated squamous
cell carcinoma was found in 1/75 males and 2/75 females exposed to 10.0 mg/m? of titanium tetrachloride
(EPA 1984). The other lung tumor type was a keratinized, cystic, squamous cell carcinoma found in

1/75 males and 1/75 females from the same exposure group. No tumors were present in the lower
exposure groups or in the controls. The limitation of this study is that it reported only the
histopathological findings without any further details on other adverse effects. The results of this study
were also reported elsewhere (EPA 1986; Lee et al. 1986). No abnormal clinical signs, changes in body
weights, or excess mortality were observed in any of the exposed groups. Histopathology revealed no
changes in the thyroid, adrenal glands, testes, kidneys, or other organs (not specified). The results showed
that the only compound-related changes occurred in the lungs and thoracic lymph nodes. Morphological
analysis of the exposure vapors revealed fine, round, transparent particles (<1 pm in diameter) and large
aggregated particles (up to 400 ym in diameter). Energy-dispersive x-ray analysis of the particulates
showed two peaks characteristic of titanium and chlorine. Although it is the same set of animals as in the
EPA (1984) study, the incidence of lung squamous cell carcinomas was reported differently in this report.
The total number of lung carcinomas was the same, five (in 2/69 males and 3/74 females). Three of the
five were microscopic in size (but the type was not specified, although it was probably a well-differentiated
lung squamous cell carcinoma), and two were keratinizing cystic squamous cell carcinomas. The
carcinomas occurred in the alveoli with squamous metaplasia and next to the alveolar ducts with
aggregated dust-laden macrophages and were probably a result of chronic tissue irritation from dust-laden
macrophages and cellular debris. No metastases were found in any of the rats. According to the authors,
these lung carcinomas are a unique type of experimentally induced tumors that are not usually seen in
humans or other animals. Their etiology is also different from human squamous cell carcinoma. Lung
squamous cell carcinomas in humans arise in the basal cells of the bronchial epithelium, while cystic
keratinizing squamous cell carcinomas observed in this study developed from the alveolar lining cells that
are close to the alveolar duct region. It is therefore difficult to estimate the relevance of these keratinizing
carcinomas to humans.

The lowest dose of titanium tetrachloride that produced a tumorigenic response (Cancer Effect Level,
CEL) in rats after chronic-duration exposure is recorded in Table 2-1 and plotted in Figure 2-1.

2.2.2 Oral Exposure

No studies were located regarding the following health effects in humans or animals after oral exposure to
titanium tetrachloride:

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2.2.2.1 Death

2.2.2.2 Systemic Effects
2.2.2.3 Immunological Effects
2.2.2.4 Neurological Effects
2.2.2.5 Reproductive Effects
2.2.2.6 Developmental Effects
2.2.2.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.4.
2.2.2.8 Cancer

No studies were located regarding cancer in humans or animals after oral exposure to titanium
tetrachloride.

2.2.3 Dermal Exposure

As indicated in the section on inhalation exposure, the chemical and physical characteristics of titanium
tetrachloride make it difficult to clearly distinguish dermal from inhalation exposure in cases of accidental
occupational exposures. Therefore, many of the findings described in the inhalation section will be
repeated in this section.

2.2.3.1 Death

One death was reported of a worker who was accidentally splashed over his whole body with titanium
tetrachloride (Chitkara and McNeela 1992). He suffered extensive burns to facial skin, nasopharynx, and
larynx, and both his eyes were severely injured. His corneas were thick and opaque with extensive swelling
of the bulbar conjunctiva and episclera. Over the next 14 days, some of the opacity in the right eye
cleared, but there was no improvement in the left eye. The patient died from the complications of severe
pulmonary injury caused by inhalation of titanium tetrachloride fumes.

No increase in mortality from any cause was reported in workers occupationally exposed to titanium
tetrachloride from 1 day to over 5 years (EPA 1990b; Fayerweather et al. 1992). The studies are limited,
however, because they usually do not report the dose or duration of exposure, because they are focused
somewhat on the mortality from lung cancer, and because of the potential exposure of the subjects to
other chemicals in the chemical manufacturing complex.

No studies were located regarding death in animals after dermal exposure to titanium tetrachloride.
2.2.3.2 Systemic Effects

No studies were located regarding cardiovascular, gastrointestinal, musculoskeletal, hematological, hepatic,
or renal effects in humans or animals after dermal exposure to titanium tetrachloride. The systemic effects
observed after dermal exposure are discussed below.

Respiratory Effects. Only mild adverse pulmonary effects were observed in workers following an
accidental exposure to titanium tetrachloride (Ross 1985). The precise concentration and duration of
exposure are not known. The mild symptoms included ticklish cough and tightness in the chest that lasted
about 2 hours. Chest x-rays performed several hours later did not reveal any abnormalities. The lungs are
the target organ for titanium tetrachloride exposure as is shown by a study of a 45-year-old man who
worked for 13 years as a furnace feeder in an aluminum smelting company and was diagnosed with
granulomatous lung disease (Redline et al. 1986). The scanning electron microscopy and energy
dispersive x-ray analysis of his lung tissue biopsy showed that the lower right lobe contained 1.39x10°

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exogenous particulates/cm> of tissue. Further analysis showed that the particulates contained various
metallic alloys: 61% of the particulates consisted of aluminum and other metals such as titanium, zinc,
and nickel; 35% contained various aluminum silicates; 2% of the particles were silica. This finding
confirms the possibility of titanium deposition in the lung tissue, and in this case lends support to the
association of granulomatous lung disease with metallic particle deposition. It is also possible that these
deposits cause local pulmonary tissue irritation, which can progress to granulomatous lung disease.
Further studies are needed to establish the causal relationship between deposits of titanium dust
particulates and granulomatous lung disease.

No studies were located regarding respiratory effects in animals after dermal exposure to titanium
tetrachloride.

Dermal/Ocular Effects. Titanium tetrachloride is a highly corrosive acute irritant to the skin, eyes,
mucous membranes, and respiratory tract (EPA 1985b). In a study of acute accidental occupational
exposure to liquid titanium tetrachloride, three workers suffered chemical and thermal skin injuries from
the treatment that followed their exposure (Lawson 1961). The precise dose and duration of exposure
were not known, but all three workers were extensively sprayed with water, which was a contraindicated
treatment. The corrosive and thermal dermal injuries did not come from titanium tetrachloride alone but
resulted from the reaction of titanium tetrachloride and water. This extremely vigorous reaction is
exothermal, generating large quantities of heat and producing hydrochloric acid responsible for the highly
corrosive dermal effects. Therefore, the titanium tetrachloride hydrolysis resulted in the third-degree burns
in all three workers. In all three cases, the most severe burns occurred in areas that were occluded by
either belts or shoes. The burns were deep, occasionally required skin grafting, and took a long time to
heal. In all three cases the scars were surrounded by dark-brown pigmentation. Although the cause of
this scar coloration is not known, it may represent accumulations of metallic titanium. Nine additional
cases with less severe outcomes were also noted but were not described in this report. The effects ranged
from mild second-degree burns to transitory erythema. It is postulated that the initial thermal burn
exposes the deeper tissue layers to the effects of hydrochloric acid, resulting in severe burns (Chitkara and
McNeela 1992).

In another case of acute accidental exposure, three research workers were exposed to titanium
tetrachloride fumes and suffered minor symptoms (Ross 1985). The workers were using titanium
tetrachloride to assess a welding torch when a brass tap flew off, spilling liquid titanium tetrachloride, and
filling the 8.5x17 foot room with fumes. One of the workers developed a cough, tightness in the chest,
and eye irritation. The second worker complained of a ticklish cough and unpleasant taste in his mouth,
while the third worker had no symptoms. All these symptoms, which were considered mild, lasted for
about 2 hours. No abnormalities were present in a chest x-ray taken a few hours later. In order to see the
effects of titanium tetrachloride on skin, 10 volunteers were exposed to 0.5 mL of purified anhydrous
titanium tetrachloride for 1 minute (Lawson 1961). Assuming that the chemical was 100% pure, the
concentration would be 860 mg, or 12.3 mg/kg/day of titanium tetrachloride. It was not possible to remove
all the chemical by wiping the skin with dry towels; a whitish-yellow granular deposit was still present on
the site of exposure. This remaining deposit was washed off with cold water. In this experiment, the
subjects reported a stinging sensation between S and 32 seconds after exposure. This sensation
disappeared after washing with cold water. According to the author, the experiment confirmed that the
titanium tetrachloride dermal injury must be treated as a thermal burn, as has been observed in previous
cases of accidental exposure (Lawson 1961).

In cases of acute accidental eye exposure to liquid titanium tetrachloride, the injury to the eye depends on
the degree of the burn and the treatment that follows (Chitkara and McNeela 1992). In the description of
eight cases of acute eye injury, the exposure concentrations were not reported. On the basis of these eight
cases, four grades of eye burns were identified. Grade I and grade II eye burns resolve without
complications, while grade III and grade IV burns result in eye loss. Grade I eye injuries usually consist of
mild defects of inferior corneal and conjunctival epithelium that heal within 2-3 days after the exposure.

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Grade II injuries affect the same eye structures but are more severe and take longer to heal. No
information on grade III eye injuries was given. The grade IV eye injuries have corneal and conjunctival
burns accompanied by conjunctival ischemia and lens opacity. Over a period of time (up to 2 months),
this injury progresses to severe corneal stromal lysis and ultimately corneal perforation resulting in
blindness (Chitkara and McNeela 1992).

It has been postulated that harmful effects of titanium tetrachloride are due to its extremely vigorous
reaction with water in any form (perspiration on the skin, tears, moisture in the air) resulting in liberation
of large quantities of heat. The mechanism of injury involves the thermal burn, which exposes the deeper
tissue layers to other titanium tetrachloride hydrolysis products such as hydrochloric acid resulting in even
more severe and deeper burns. In other words, the extremely serious effects observed following exposure
to titanium tetrachloride are the result of combined thermal and acid burns (Chitkara and McNeela 1992).

No studies were located regarding dermal or ocular effects in animals after dermal exposure to titanium
tetrachloride.

2.2.3.3 Immunological Effects

There is limited information regarding immunological effects in humans following dermal exposure to
titanium tetrachloride. An elevated lymphocyte count of 23,700 cells/mm? was found in a worker after an
accidental exposure to titanium tetrachloride (Park et al. 1984). There was no information on the precise
dose. This worker had suffered second- and third-degree burns over 25% of his body. Relative
lymphocytosis was observed in 4/10 workers chronically exposed to low levels of titanium tetrachloride
fumes (Lawson 1961). The meaning of this finding is not clear because there were no controls and there
was influenza among the workers at the time the study was conducted. Based on these results, it is not
clear if lymphocytosis is an adverse effect of titanium tetrachloride exposure.

PBLs are commonly used in the assessment of the immune status in humans. Impaired cellular immune
function was found in a 45-year-old man who worked for 13 years as a furnace feeder in an aluminum
smelting company (Redline et al. 1986). The in vitro response of his PBLs to selected mitogens
(phytohemagglutinin, pokeweed mitogen, and concanavalin A) was below the mean values established in
50 control subjects. His PBLs were also tested four times over an 11-month period for responsiveness to
titanium tetrachloride, nickel sulfate, and aluminum chloride. This was done to establish a possible causal
relationship between the metallic particulates in the pulmonary granuloma and the immune response of
the delayed hypersensitivity type. All the responses were negative except for the response to titanium
tetrachloride, which was positive in two out of four tests. The controls used in the experiment were three
painters exposed to titanium-based paints for 15-28 years; their response to all three metallic salts was
negative. These results indicate that chronic exposure to titanium in this one patient may have led to his
sensitization. They also suggest that the accumulation of metallic particulates of titanium in the lungs may
be related to the pulmonary granulomatous disease that this patient developed. Important to note,
however, is that the three other chronically exposed individuals used as controls were not sensitive to
titanium. The limitations of the study are that the subject was exposed to several metals, that the dose
and precise duration are not known, and that the in vitro response of the patient to titanium tetrachloride
was positive in two out of four tests.

No studies were located regarding immunological effects in animals after dermal exposure to titanium
tetrachloride.

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No studies were located regarding the following health effects in humans or animals after dermal exposure
to titanium tetrachloride:

2.2.3.4 Neurological Effects
2.2.3.5 Reproductive Effects
2.2.3.6 Developmental Effects
2.2.3.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.4.

2.2.3.8 Cancer

No studies were located regarding carcinogenic effects in humans after dermal exposure to titanium
tetrachloride. However, as stated at the beginning of Section 2.2.1, the precise route of exposure in studies
of occupational exposure to titanium tetrachloride is not known. The exposure most likely occurs by
inhalation, although dermal exposure is also possible. The incidences of cancer, chronic respiratory
disease, pleural thickening/plaques, and pulmonary fibrosis were investigated from 1956 through 1985 in a
group of 1,576 workers occupationally exposed to titanium dioxide (Chen and Fayerweather 1988). There
were no monitoring data for titanium dioxide exposure prior to 198. The time- jhe average Janges
for dont dioxide exposure (by quartile) were: >0-<5.0 mg/m>, 5.0-<10 mg/m?>, 10-<20 mg/m3, and
>20 mg/m>. Exposure durations were not specified for individual workers; however, 25% of them were
exposed for less than 0.2 years, 25% were exposed for between 0.2 and 1 year, 25% were exposed for
between 1 and 4 years, and 25% were exposed for more than 4 years. Although the results indicate that
both the incidence of cancer cases and the incidence of lung cancer specifically were slightly higher in
titanium dioxide-exposed groups as compared to the control group (901 nonexposed workers); this increase
was not statistically significant. Nested case-control analyses based on 16 lung cancers and 898 control
subjects showed that there was also no statistically significant association between titanium dioxide
exposure and risk of lung cancer after adjusting for age and exposure to titanium tetrachloride, pigmentary
potassium titinate (PKT), and asbestos (Chen and Fayerweather 1988). Similar observations were made
with respect to the incidence of lung cancer (based on 27 cases of lung cancer deaths and 331 noncancer
decedent controls) and chronic respiratory disease (based on 88 chronic respiratory disease cases and 898
noncancerous nonrespiratory disease controls). No cases of pulmonary fibrosis were observed in any of the
exposed workers. The results indicate that exposure to titanium dioxide was not associated with an
increased incidence of lung cancer. These results are important for two reasons: because titanium dioxide
is one of the hydrolysis products of titanium tetrachloride and because the results support the observations
made regarding the incidence of lung cancer among titanium tetrachloride-exposed workers discussed in
Section 2.2.1.2 (EPA 1990b; Fayerweather et al. 1992). The results indicate that exposure to titanium
tetrachloride and exposure to its hydrolysis product, titanium dioxide, do not increase lung cancer
incidence.

No studies were located regarding carcinogenic effects in animals after dermal exposure to titanium
tetrachloride.

2.3 TOXICOKINETICS

No studies were located regarding absorption, distribution, metabolism, or excretion of titanium
tetrachloride in humans or animals following exposure to titanium tetrachloride. Because of the physico-
chemical characteristics of titanium tetrachloride, the major route of exposure is by inhalation, and the
major target organ is the lung. Exposure can also occur by the dermal route, especially in cases of
accidental occupational exposures. Although there are no studies on absorption or distribution by any of
the three routes, it was shown that particles of metallic titanium are present in the lungs of occupationally
exposed individuals (Elo et al. 1972; Ophus et al. 1979; Redline et al. 1986).

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2.3.1 Absorption
2.3.1.1 Inhalation Exposure

Studies that directly measure the absorption of titanium tetrachloride in humans following inhalation
exposure were not located.

2.3.1.2 Oral Exposure

No studies were located regarding absorption in humans or animals after oral exposure to titanium
tetrachloride.

2.3.1.3 Dermal Exposure

No studies were located regarding absorption in humans or animals after dermal exposure to titanium
tetrachloride.

2.3.2 Distribution
2.3.2.1 Inhalation Exposure

No studies were located regarding distribution in humans or animals following inhalation exposure to
titanium tetrachloride. However, in a case report of chronic inhalation exposure to titanium dioxide,
which is one of the titanium tetrachloride hydrolysis products, metallic particulates similar to titanium
dioxide were found in lysosomes of phagocytes within the alveolar lumen (Elo et al. 1972). Spectrometric
and spectrographic analysis showed accumulation of metallic titanium in the lungs. Analysis of tissues
from one worker who drowned showed that titanium was also present in the lymph nodes adjacent to the
lung. No titanium was found in the tissue specimens from brain, thyroid gland, myocardium, spleen, liver,
kidneys, and nerve ganglia of the sympathetic trunk. These results suggest that metallic titanium
selectively accumulates in the lung and adjacent lymph nodes, but additional studies are needed to show
that this accumulation occurs also after exposure to titanium tetrachloride.

2.3.2.2 Oral Exposure

No studies were located regarding distribution in humans or animals after oral exposure to titanium
tetrachloride.

2.3.2.3 Dermal Exposure

In a case study of accidental occupational exposure to titanium tetrachloride, three workers suffered
third-degree burns because they were extensively sprayed with water following the exposure (Lawson 1961).
The wounds took a long time to heal, and in all three workers the scars were surrounded by dark brown

pigmentation. The authors suggested that the pigmentation may have been due to the metallic titanium
deposits.

2.3.3 Metabolism

No studies were located regarding metabolism in humans or animals following inhalation, oral, or dermal
exposure to titanium tetrachloride.

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2.3.4 Excretion

No studies were located regarding excretion in humans or animals following inhalation, oral, or dermal
exposure to titanium tetrachloride.

2.3.5 Mechanisms of Action
2.3.5.1 Inhalation Exposure

The chemical properties of titanium tetrachloride are responsible for effects observed following both
inhalation and dermal exposures. The instability of titanium tetrachloride in the presence of water leads
to its rapid hydrolysis, which generates heat and various hydrolysis products. One of these hydrolysis
products, hydrochloric acid, is partially responsible for the corrosive effects observed following exposure to
titanium tetrachloride. In a study that compared the effects of titanium tetrachloride and hydrochloric acid
in mice after acute inhalation exposure, it was concluded that the active component in both cases was
hydrochloric acid (Mezentseva et al. 1963). The results showed that 9/15 and 1/15 mice exposed to
titanium tetrachloride and hydrochloric acid, respectively, died. One possible explanation for the more
severe effects seen from exposure to titanium tetrachloride compared with hydrochloric acid is that
hydrochloric acid, because of its high solubility, is dissolved in the moisture of the nasopharynx and
trachea and thus penetrates into the lungs to only a very limited extent. However, in the case of exposure
to titanium tetrachloride, the hydrolysis occurs in several steps; one of the hydrolysis products, titanium
oxide hydrate, is a particulate that can absorb some of the hydrochloric acid vapors that are also generated
during hydrolysis and carry them into the deeper parts of the lungs. In the lungs, the hydrolysis process is
repeated with the further release of hydrochloric acid, resulting ultimately in larger amounts of
hydrochloric acid being carried deeper into the lung and to the alveoli (Mezentseva et al. 1963). This
study is limited in that the precise exposure levels are not known, since the titanium tetrachloride
concentrations were communicated as separate titanium concentrations and hydrochloric acid
concentrations. The study also did not give detailed information on the exposed animals.

2.3.5.2 Oral Exposure

No studies were located regarding the mechanism of action of titanium tetrachloride in humans or animals
after oral exposure.

2.3.5.3 Dermal Exposure

As in the case of inhalation injuries, the harmful effects of titanium tetrachloride to the skin and the eyes
are due to its extremely vigorous reaction with water in any form (perspiration on the skin, tears, moisture
in the air) resulting in the generation of heat. The mechanism of injury involves a thermal burn, which
exposes the deeper tissue layers to hydrolysis products of titanium tetrachloride such as hydrochloric acid,
resulting in even more severe and deeper burns. In other words, the extremely serious effects observed
following exposure to titanium tetrachloride are the result of combined thermal and acid burns (Chitkara
and McNeela 1992).

2.4 RELEVANCE TO PUBLIC HEALTH

The major and most common ways of exposure to titanium tetrachloride are via the inhalation and dermal
routes. Titanium tetrachloride is not very stable and undergoes rapid hydrolysis. In the presence of water,
titanium tetrachloride is hydrolyzed through a vigorous exothermic reaction generating a large quantity of
heat and several hydrolysis products, including hydrochloric acid. Therefore, this reaction causes thermal
and chemical burns in both exposed humans and animals. Monitoring data for titanium tetrachloride in
environmental media are non-existent, but its chemical properties suggest that titanium tetrachloride

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partitions to the air in the form of its hydrolysis products. Therefore, the most likely route of human
exposure to titanium tetrachloride hydrolysis products is inhalation.

The most significant effect of acute or chronic inhalation exposure to titanium tetrachloride is mild-to-
severe pulmonary injuries. The corrosive effects of acute exposure can also affect the skin, eyes, and the
mucous membranes of the upper respiratory tract. These effects have been observed in humans and
animals. Since the cases of acute or chronic exposure in humans are usually accidental or occupational
and the precise exposure concentrations are not known, it is difficult to determine whether the observed
pulmonary effects are concentration-related. However, the results of both acute and chronic exposure in
animals suggest that adverse respiratory effects in animals are dose-dependent. The eye injuries resulting
from acute dermal exposure to titanium tetrachloride in humans have four degrees of severity indicating
that they are dose-dependent. It is not known if the animal data support this finding because of the
limited information available regarding eye injuries in animals. In cases of acute animal exposure to
titanium tetrachloride, only mild eye injuries such as eyelid swelling have been observed.

Very few studies have addressed the question of the mechanism of pulmonary toxicity and the role
hydrochloric acid plays in it. The results of a study in mice showed that titanium tetrachloride was more
lethal than hydrochloric acid. One possible explanation for the more severe effects seen from exposure to
titanium tetrachloride compared with hydrochloric acid is that hydrochloric acid, because of its high
solubility, is dissolved in the moisture of the nasopharynx and trachea and thus penetrates into the lungs
to only a very limited extent. However, in the case of exposure to titanium tetrachloride, the hydrolysis
occurs in several steps; one of the hydrolysis products, titanium oxide hydrate, is a particulate that can
absorb some of the hydrochloric acid vapors that are also generated during hydrolysis and carry them into
the deeper parts of the lungs. In the lungs, the hydrolysis process is repeated with the further release of
hydrochloric acid, resulting ultimately in larger amounts of hydrochloric acid being carried deeper into the
lung and to the alveoli and thus causing tissue burns at a much deeper level (Mezentseva et al. 1963).
This mechanism of toxicity can also explain the second- and third-degree burns observed after acute dermal
exposure to titanium tetrachloride.

Only one case of delayed toxic pulmonary effects was described in humans following acute inhalation
exposure. The exposure caused severe toxic lung effects, but 5 weeks after exposure, fiberoptic
bronchoscopy revealed erythema of the entire bronchial tree and the presence of 35-40 fleshy polypoid
lesions. The presence of the polyps, according to the authors, was a sign of an exaggerated, but normal,
reparative process of the tracheobronchial injury. This delayed complication has been seen in thermal
respiratory injuries, indicating that the severe adverse respiratory effects seen in this case are in part due
to the exothermal nature of the titanium tetrachloride hydrolysis reaction. One year after the injury his
lung appeared normal with some degree of mild stenosis.

The adverse hematological effects in humans following acute inhalation exposure include mild eosinophilia
and relative lymphocytosis. Because of the very limited database, it is difficult to assess the significance of
these findings. These observations could not be verified in animal systems because of the lack of
information on hematological effects following acute exposure. However, the results of chronic exposure
in rats do not support the observations in humans. After 18 months of exposure, a significant increase in
the number of neutrophils and a decrease in lymphocytes were observed in exposed rats. Resolution of
these contradictory findings will be possible when additional animal studies are available.

Insufficient information is available regarding adverse immunological effects in humans following titanium
tetrachloride exposure. In an effort to elucidate the etiology of granulomatous lung disease, lymphocytes
from a chronically exposed worker with the disease were tested for their responsiveness to titanium
tetrachloride. The results were compared to those from three subjects chronically exposed to titanium-
containing paints. The results were inconclusive because the response of the controls was always negative
while the response of the patient was positive in two out of four tests done over an 11-month period. The
results of chronic inhalation exposure in rats indicate that compound-related lung injury evoked an

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immune response in the form of an increased macrophage infiltration. The limitation of the study is that
other immune functions were not tested. As in the case of studies in humans, insufficient information is
available to estimate the true extent of immunologic injury in rats following chronic inhalation exposure to
titanium tetrachloride.

Since no toxicokinetic information is available on titanium tetrachloride, it is not possible to estimate if
there is a potential for bioaccumulation of the compound in humans. Because of its chemical
characteristics and rapid hydrolysis in the presence of water, however, it seems unlikely that it would
bioaccumulate in the body.

It is not possible to assess the reproductive or developmental effects in humans or animals because no
information was located regarding these effects in humans or animals.

Of major concern to individuals occupationally exposed to titanium tetrachloride is potential acute
exposure to large quantities of the compound via inhalation or dermal contact. The degree of respiratory
or dermal injury depends greatly on the amount of titanium tetrachloride to which workers are exposed,
the protective clothing they use, and the treatment measures undertaken after the exposure. The
treatment should avoid the use of water in order to prevent rapid hydrolysis of titanium tetrachloride and
the generation of heat and hydrolysis products such as corrosive hydrochloric acid. It is very unlikely that
titanium tetrachloride would be found at hazardous waste sites because of its instability and rapid
hydrolysis.

The limited information available indicates that titanium tetrachloride is not genotoxic in bacteria
(Kanematsu et al. 1980; Ogawa et al. 1987).

Since the major route of exposure to titanium tetrachloride is inhalation, the sensitive population includes
persons with bronchitis, pneumoconiosis, bronchial asthma, pulmonary tuberculosis, and diseases of the
upper respiratory tract who are at risk because of the toxic nature of titanium tetrachloride fumes
(Mezentseva et al. 1963). For the same reason, work with titanium tetrachloride is contraindicated in
persons who have other pulmonary or cardiovascular conditions that make it difficult for them to wear a
protective mask (Mezentseva et al. 1963).

Minimal Risk Levels for Titanium Tetrachloride
Inhalation MRLs

° An MRL of 0.001 mg/m has been derived for chronic inhalation exposure (365 days or more) to the
reactive Vapor of titanium tetrachloride. This chronic inhalation MRL was based on a LOAEL of
0.1 mg/m? for trachigivis and rhinitis seen in groups of 100 male and female Crl:CD rats exposed to 0,
0.1, 1.0, or 10 mg/m> for up to 2 years. An increased incidence of rhinitis was seen in the low-
exposure group after 1 year. An increased incidence of tracheitis was not seen in the low-exposure
group prior to 2 years of exposure, although the higher exposure groups showed this effect after 3
months. Adverse respiratory effects, including alveolar hyperplasia, were concentration dependent
(EPA 1986; Lee et al. 1986).

No acute- or intermediate-duration inhalation MRLs have been derived for titanium tetrachloride because

there are no adequate dose-response data available in humans or animals that identify threshold levels for
noncancer health effects.

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Oral MRLs

No MRLs have been derived for oral exposure to titanium tetrachloride because there are no dose-
response data available in humans or animals for any duration of exposure that identify threshold levels for
noncancer health effects.

Death. One death was reported of a worker who was accidentally splashed over his whole body with
titanium tetrachloride (Chitkara and McNeela 1992). He suffered extensive burns to facial skin,
nasopharynx, and larynx, and both his eyes were severely injured. His corneas were thick and opaque with
extensive swelling of the bulbar conjunctiva and episclera. Over the next 14 days, some of the opacity in
the right eye cleared, but there was no improvement in the left eye. The patient died from the
complications of severe pulmonary injury caused by inhalation of titanium tetrachloride fumes (Chitkara
and McNeela 1992).

Except for the single case described above, no increase in mortality from any cause was reported in
workers occupationally exposed to titanium tetrachloride for 1 day to over 5 years (EPA 1990b;
Fayerweather et al. 1992). However, these studies are limited because they are focused somewhat on the
incidence of and mortality from lung cancer and because of the potential exposure of the subjects to other
chemicals in the chemical manufacturing complex.

There is little information on the lethal effects of titanium tetrachloride in animals. A 4-hour inhalation
LCs, of 460 mg/m? in rats was reported (EPA 1984), but the primary study for this lethal concentration
was not cited. In mice, single acute inhalation exposure to low, medium, and high levels of titanium
tetrachloride and its hydrolysis products, titanium oxychloride and hydrochloric acid, caused dose-
dependent death in 9 out of 15 mice (Mezentseva et al. 1963). The study also shows that titanium
tetrachloride was more lethal than hydrochloric acid, which was also used in the study. One possible
explanation is that hydrochloric acid, because of its high solubility, dissolves in the moisture of the
nasopharynx and trachea, penetrating the lungs to a very small extent. In the case of titanium
tetrachloride exposure, the hydrolysis occurs in several steps, and at each step, the products can absorb the
hydrochloric acid that is also generated during hydrolysis, and carry it into the deeper parts of the lungs.
There the process is repeated, resulting ultimately in a larger amount of hydrochloric acid being carried
deeper into the lung and to the alveoli (Mezentseva et al. 1963).

Systemic Effects

Respiratory Effects. The lungs are the major target organ following inhalation exposure and to some extent
dermal exposure to titanium tetrachloride. The case studies of humans acutely exposed to titanium
tetrachloride fumes have shown the irritant nature of the inhaled chemical. Since titanium tetrachloride
undergoes hydrolysis almost immediately when in contact with water or moisture in the air (forming fumes
that contain titanium oxychloride and hydrochloric acid), its main effect on the lungs is corrosive, and
although the degree of pulmonary injury can vary, it can result in intense chemical bronchitis or
pneumonia (Lawson 1961). The mild irritant symptoms include cough and tightness in the chest, which
last only a short time and usually leave no abnormalities visible on a chest x-ray (Ross 1985).

More severe pulmonary effects consisted of marked congestion of the mucous membranes of the pharynx,
vocal cords, and trachea (Ross 1985). Although this exposure was acute, it had long-term effects that
included stenosis of the larynx, trachea, and upper bronchi. In some cases of accidental exposure, these
symptoms progressed to severe upper airway distress that required intubation and ventilation (Park et al.
1984). Additional symptoms may include hypoxia and diffuse pulmonary infiltrates suggestive of adult
respiratory distress syndrome. The improvement is gradual, and may go through different stages. In one
case of accidental exposure to titanium tetrachloride fumes, fiberoptic bronchoscopy performed 5 weeks
after exposure revealed erythema of the entire bronchial tree and the presence of 35-40 fleshy polypoid
lesions (Park et al. 1984). The presence of the polyps was a sign of an exaggerated, but normal, reparative

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process of the tracheobronchial injury seen in thermal respiratory injuries. This delayed complication
provides support to the theory that the severe adverse respiratory effects observed after exposure to
titanium tetrachloride are in part due to the exothermal nature of the titanium tetrachloride hydrolysis
reaction. Only some degree of mild pulmonary stenosis was evident in this case after 1 year. Impairment
of the pulmonary function may result from chronic occupational exposure to titanium tetrachloride. The
results of occupational exposure of 209 workers employed in a metal reduction facility in Ashtabula, Ohio,
were reported in two retrospective studies (Garabrant et al. 1987; NIOSH 1980). The results suggest that
pulmonary impairment may be caused by exposure to titanium tetrachloride. Of the 209 workers, 78 were
engaged in the titanium tetrachloride reduction process and were also exposed to sodium, titanium dioxide,
titanium oxychloride, and dust. Logistic regression analysis of the chest radiograph data showed that
pleural thickening was strongly related to the duration of work in titanium production (p<0.001). The
initial estimates of loss of pulmonary function, taking smoking into account, was 45 mL/year leading to a
deficit of 1.8 L/40-year employment period (NIOSH 1980). Further analysis of the employees based on job
and duration of employment confirmed large decreases in FVC in workers employed in titanium
tetrachloride reduction for at least 10 years (Garabrant et al. 1987). A regression analysis of the data
adjusted for age, height, and smoking revealed that the rate of loss of FVC was 24 mL per year for the
titanium tetrachloride workers (Garabrant et al. 1987). The results also showed that previous asbestos
exposure and cigarette smoking were not significantly related to pleural thickening. These results suggest
that chronic exposure to titanium tetrachloride may result in restrictive pulmonary changes and that there
is no clear association between pleural thickening and reduction in ventilatory capacity. It is difficult to
determine the precise cause of these pulmonary abnormalities, because of the lack of information on the
duration, route, exposure levels, and concomitant exposure to a mixture of chemicals.

Since titanium tetrachloride is rapidly hydrolyzed in the presence of water, it is difficult to measure the
substance in the body. However, there is a possibility that some of the pulmonary depositions in
occupationally exposed workers may be due to metallic titanium. Indeed, considerable amounts of
titanium were found in lung tissue of three workers who worked for 9-10 years in a titanium dioxide
processing factory (Elo et al. 1972). Electron microscopy identified 0.1-0.4-ym-diameter titanium particles
in lysosomes of phagocytic cells filling the alveolar lumen. Large quantities of titanium were also present
in the lymph nodes. Similar findings were made the case of a 55-year-old man who worked for 3 years in a
titanium pigment processing factory (Ophus et al. 1979). Macroscopic and microscopic examinations
revealed large amounts of white, birefractive pigment in all parts of the lungs without obvious fibrotic
changes. Further analysis confirmed the presence of titanium and occasionally iron and also showed that
the crystal modification of titanium found in the lung was rutile. The absence of any pulmonary response
to the titanium dust deposits may be due to the fact that rutile is a biologically inert crystalline
modification of titanium/titanium dioxide. None of the techniques used in this study can unequivocally
identify the presence of titanium dioxide. Particulate titanium was also present in the lungs of a
45-year-old man who worked for 13 years as a furnace feeder in an aluminum smelting company (Redline
et al. 1986). The particulates contained various metallic alloys: 61% of the particulates consisted of
aluminum and other metals such as titanium, zinc, and nickel; 35% contained various aluminum silicates;
2% of the particles were silica. This finding confirms the possibility of titanium deposition in the lung
tissue. Furthermore, since the worker had a case of pulmonary granulomatous disease, the identification
of metallic particulates lends support to the possible association between granulomatous lung disease and
metallic particle deposition. These results indicate that metallic titanium can be deposited in the lungs of
occupationally exposed workers, and that these deposits do not necessarily cause histopathological changes.
It is also possible that these deposits do cause local pulmonary tissue irritation, which can progress to
granulomatous lung disease. These results indicate that the severity of the pulmonary injury following
exposure to titanium tetrachloride is related to the inhaled amount of the compound. It is also reasonable
to assume that individuals with impaired respiratory function will be more susceptible to the effects of
titanium tetrachloride. Minor adverse pulmonary effects may be present in persons chronically exposed to
low levels of titanium tetrachloride in the vicinity of a hazardous waste site.

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The results of acute and chronic exposure studies to titanium tetrachloride in animals support the
observations made in humans. In female Sprague-Dawley rats, signs of pulmonary toxicity included wet
noses, nasal discharge, swollen eyelids, and dyspnea following an acute inhalation exposure to titanium
tetrachloride (Karlsson et al. 1986). These signs disappeared 48-72 hours after exposure, and lung
histopathology 7 days later showed only minor lesions. Similar observations were made in chronically
exposed Crl:CD rats (EPA 1986; Lee et al. 1986). The primary clinical finding was a concentration-related
increase in the incidence of irregular respiration and abnormal lung noises in exposed animals. The major
health effects of exposure to titanium tetrachloride were observed in the respiratory tract. The incidence
of rhinitis increased with concentration and duration of exposure. Tracheitis also increased with duration
and to a lesser degree with concentration. The 0.1 mg/m? in this study was considered a less serious
LOAEL for adverse effects in the extrathoracic/tracheobronchial region. Gross pathology and
histopathology showed compound-related changes in the lungs and thoracic lymph nodes in the form of
foci laden with yellow titanium tetrachloride hydrolysis product. These foci were present on the lung
pleural surface and on the slightly enlarged tracheobronchial lymph nodes. The pulmonary response also
included the presence of the dust-laden macrophages, and the concentration-related hyperplasia of the
alveolar lining.

Hematological Effects. No abnormal values for hemoglobin, white blood cells, neutrophils, monocytes, and
basophils were found in 10 workers exposed for 4-17 years to low levels of titanium tetrachloride fumes
(Lawson 1961). However, three of the workers had mild eosinophilia, and four had relative lymphocytosis.
The significance of these effects is not known; there were no controls in the study, and the observed
lymphocytosis may have been caused by the influenza present among the workers at the time of the study.
Since the doses that produced the observed effects are not known, it is possible that persons living in the
vicinity of hazardous waste sites may be chronically exposed to amounts of titanium tetrachloride sufficient
to induce such effects.

The results from animal studies do not support the observations made in humans. A significant increase
in neutrophils (p<0.05) and a decrease in lymphocytes were observed in Crl:CD rats after chronic
inhalation exposure to titanium tetrachloride (EPA 1986; Lee et al. 1986). In addition, a significant
decrease in erythrocytes and a significant increase in the mean cell volume and mean cell hemoglobin were
observed in males after 18 months of exposure.

Dermal/Ocular Effects. Titanium tetrachloride is a highly corrosive irritant to the skin, eyes, mucous
membranes, and respiratory tract (EPA 1985b). Exposure to liquid titanium tetrachloride results in
chemical and thermal skin injuries, unless appropriate treatment is used following the exposure (Lawson
1961). The corrosive thermal dermal injuries are not solely due to titanium tetrachloride, but result from
the contact of titanium tetrachloride and water. This extremely vigorous reaction is exothermal, generating
large quantities of heat. It also produces hydrochloric acid as one of the hydrolysis products which is
responsible for the highly corrosive dermal effects. Therefore, the accidental exposure to titanium
tetrachloride and its subsequent hydrolysis can result in the third-degree burns. The most severe burns in
reported cases occurred in the areas that were occluded by either belts or shoes (Lawson 1961). These
burns were deep, occasionally required skin grafting, and took a long time to heal. In all three cases the
scars were surrounded by dark brown pigmentation. Although the reason for this scar coloration is not
known, it is possible that is represents accumulations of metallic titanium. Avoiding the use of water in
the treatment following exposure to titanium tetrachloride is the single most important factor in
preventing the hydrolysis that leads to thermal and chemical burns. Exposure to liquid titanium
tetrachloride can cause severe eye injuries depending on the degree of the burn and the treatment that
follows. Four grades of eye burns were identified based on the description of eight cases of accidental
occupational exposure (Chitkara and McNeela 1992). Grade I and grade II eye burns resolve without
complications, while grade III and grade IV burns result in eye loss. Grade I eye injuries usually consist of
mild defects of inferior corneal and conjunctival epithelium which heal within 2-3 days after the exposure.
Grade II injuries affect the same eye structures but are more severe and take longer to heal. No
information of grade III eye injuries was given. The grade IV eye injuries have corneal and conjunctival

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burns accompanied with conjunctival ischemia and lens opacity. Over a period of time (up to 2 months),
this injury progresses to severe corneal stromal lysis and ultimately corneal perforation resulting in
blindness. The exposures causing dermal and eye injuries of this extent are very unlikely to occur at the
hazardous waste sites because of the excessive quantities of titanium tetrachloride needed to produce such
corrosive effects.

Immunological Effects. Two studies reported lymphocytosis in humans following inhalation exposure to
titanium tetrachloride. In one case, an elevated lymphocyte count was found in a worker after an
accidental exposure to titanium tetrachloride (Park et al. 1984) in the other case, 4/10 workers chronically
exposed to low levels of titanium tetrachloride fumes had relative lymphocytosis (Lawson 1961). However,
it is difficult to interpret these findings because no controls were available, and there was influenza among
the workers at the time the study was conducted. The results of in vitro evaluation of the immune status
of exposed workers are also inconclusive. Impaired cellular immune function was found in a 45-year-old
man who had decreased responses to selected mitogens (phytohemagglutinin, pokeweed mitogen, and
concanavalin A) commonly used for the assessment of immune status (Redline et al. 1986). It was also
not possible to determine if prolonged exposure to titanium tetrachloride could cause sensitization of the
delayed hypersensitivity type because the response was positive in two out of four tests performed over an
11-month period. Although unlikely, it is possible that susceptible individuals living in the vicinity of
hazardous waste sites may be chronically exposed to sufficient amounts of titanium tetrachloride to cause
sensitization.

The studies in animals indicate that dust-laden macrophage infiltration of the lung and adjacent lymph
nodes is the prevalent adverse immune effect following chronic inhalation exposure to titanium
tetrachloride (EPA 1986; Lee et al. 1986). The results indicate the beginning of an active cell-mediated
immune response in the exposed animals due to the accumulation of titanium tetrachloride hydrolysis
products. These data are insufficient to determine if individuals chronically exposed to low levels of
titanium tetrachloride at hazardous waste sites would develop an active cell-mediated immune response to
titanium tetrachloride.

Genotoxic Effects. No studies investigating the potential of titanium tetrachloride to induce genetic
damage in humans or whole animals were found. As the data presented in Table 2-2 indicate, the in vitro
testing of titanium tetrachloride for adverse effects on genetic material has been limited to several
bacterial strains. In the available studies, titanium tetrachloride, at unspecified doses, was not mutagenic
in Salmonella typhimurium strains TA1537, TA2637, TA98, TA100, or TA102; exogenous metabolic
activation was not included in the assay (Ogawa et al. 1987). The same investigators did not observe an
enhancement of mutagenesis when S. typhimurium strains TA1537 or TA2637 were exposed simultaneously
to titanium tetrachloride doses ranging from 1 to 10,000 pmol/plate and 100 ymol/plate 9-aminoacridine
(9-AA). The well-known mutagen 9-AA was included in the experiment because the findings from earlier
studies conducted by these investigators suggested that 9-AA may serve as a carrier of metal cations across
cellular membranes. Titanium tetrachloride was determined to be toxic to the bacteria since, even after
washing to remove the chemical, no revertant colonies grew.

Nonactivated doses of titanium tetrachloride ranging from 0.005 to 0.5 molal did not cause preferential
inhibition of recombination repair-deficient (rec”) Bacillus subtilis strain M45 as compared to
deoxyribonucleic acid (DNA) repair-proficient (rec™) strain H17 (Kanematsu et al. 1980). Similarly,
unspecified concentrations of titanium tetrachloride in the absence of metabolic activation were reported
to be negative in the B. subtilis rect’ assay (Kada et al. 1980).

Because titanium tetrachloride rapidly hydrolyzes upon contact with water, the findings from the limited

microbial assay are insufficient to reach any conclusions regarding the potential, if any, of titanium
tetrachloride to induce genotoxic effects.

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ws INSJWWOD OMENd HOH L4VHA xxx

TABLE 2-2. Genotoxicity of Titanium Tetrachloride /n Vitro

 

 

Results
With Without

Species (test system) End point activation activation Reference
Prokaryotic organisms:

Salmonella typhimurium Gene mutation NT — Ogawa et al. 1987

(TA1537, TA2637, TA98, TA100)
S. typhimurium (TA1537, TA2637) Gene mutation NT - Ogawa et al. 1987
Bacillus subtilis (H17, M45) DNA damage NT — Kada et al. 1980;

Kanematsu et al. 1980

 

"Bacterial strains were simultaneously exposed to titanium tetrachloride and 9-aminoacridine.

— = negative result; DNA = deoxyribonucleic acid; NT = not tested

S103443 HLTVAH 2

82
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2. HEALTH EFFECTS

Cancer. Epidemiological studies are inadequate to determine if titanium tetrachloride causes cancer in
occupationally exposed individuals. However, statistical analysis of the available mortality and lung cancer
incidence data indicate that there is no association between titanium tetrachloride exposure and lung
cancer mortality (EPA 1990b; Fayerweather et al. 1992).

Lung squamous cell carcinoma and keratinizing squamous cell carcinoma were observed in rats chronically
exposed to titanium tetrachloride (EPA 1984, 1986; Lee et al. 1986). The carcinomas occurred following
chronic inhalation exposure of rats in the alveoli with squamous metaplasia and next to the alveolar ducts
with aggregated dust-laden macrophages and were probably a result of chronic tissue irritation from
dust-laden macrophages and cellular debris. No metastases were found in any of the rats. According to
the study authors, these lung carcinomas are a unique type of experimentally induced tumors that is not
usually seen in humans or other animals. Their etiology is also different from human squamous cell
carcinomas. Human lung squamous cell carcinomas arise in the basal cells of the bronchial epithelium,
while cystic keratinizing squamous cell carcinomas observed in this study developed from the alveolar
lining cells that are close to the alveolar duct region. It is therefore difficult to estimate the relevance of
these keratinizing carcinomas to humans.

2.5 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have
been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

A biomarker of exposure is a xenobiotic substance or its metabolite(s), or the product of an interaction
between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment
of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself
or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors
can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may
be the result of exposures from more than one source. The substance being measured may be a metabolite
of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several
different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and
environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites
may have left the body by the time samples can be taken. It may be difficult to identify individuals
exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral
nutrients such as copper, zinc, and selenium). Biomarkers of exposure to titanium tetrachloride are
discussed in Section 2.5.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an
organism that, depending on magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of
tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial
cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung
capacity. Note that these markers are not often substance specific. They also may not be directly adverse,
but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by
titanium tetrachloride are discussed in Section 2.5.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability
to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or
other characteristic or a preexisting disease that results in an incyease in absorbed dose, a decrease in the
biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are
discussed in Section 2.7, "Populations That Are Unusually Susceptible.”

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2.5.1 Biomarkers Used to Identify or Quantify Exposure to Titanium Tetrachloride

Because of the chemical characteristics of titanium tetrachloride, namely its very rapid hydrolysis in the
presence of small amounts of water, it is not possible to determine its levels in the blood. Also, no
methods for the measurement of titanium tetrachloride in biological samples were located. Although very
little information is available, some of the titanium tetrachloride hydrolysis products could be used as
biomarkers to identify or possibly to quantify the exposure to titanium tetrachloride. One of the more
stable hydrolysis products of titanium tetrachloride is titanium dioxide. The use of electron microscopy
and/or spectrometric and spectrographic analysis using x-ray fluorescence showed the presence of carbon-
like, birefractive, pigment aggregations under the pleura that consisted of 0.1-0.4-ym-diameter black
particles very similar to titanium dioxide in the lysosomes of alveolar and lymph node macrophages of
three titanium dioxide processing factory workers (Elo et al. 1972). Also present in the lung and lymph
node tissue samples were large quantities of titanium metal. Following accidental exposure to titanium
tetrachloride, scars formed after second- or third-degree burns were surrounded by dark pigmentation
(Lawson 1961). The burns are the result of the vigorous interaction of titanium tetrachloride and water,
which was used following the exposure. Although the nature of this dark pigmentation is not known, it is
possible that it is due to the presence of metallic titanium deposits. These observations suggest that both
titanium dioxide and metallic titanium could be used as biomarkers of titanium tetrachloride exposure.

Another useful indication of dermal exposure to titanium tetrachloride is low pH of the skin (Lawson
1961). This low skin pH results from the presence of hydrochloric acid, which is one of the titanium
tetrachloride hydrolysis products. The low pH may indicate that additional decontamination is needed to
prevent the thermal burns.

2.5.2 Biomarkers Used to Characterize Effects Caused by Titanium Tetrachloride

No description of biomarkers that could be used to characterize the effects caused by exposure to titanium
tetrachloride was found in the course of the literature search. As mentioned in the paragraph above, the
early studies of the occupational exposure described the interaction of titanium tetrachloride and water
that resulted in the second- and third-degree skin burns (Lawson 1961). These severe burns are the result
of vigorous hydrolysis reaction of titanium tetrachloride in the presence of water and can be considered
effects of titanium tetrachloride exposure.

2.6 INTERACTIONS WITH OTHER SUBSTANCES

Limited information is available regarding the influence of other substances on the toxicity of titanium
tetrachloride, except for water. Titanium tetrachloride interacts vigorously with water in an exothermic
reaction that produces heat and hydrochloric acid. Under those circumstances, exposure to titanium
tetrachloride results in a severe thermal and chemical injury.

Acute exposure of Sprague-Dawley rats and Syrian hamsters to the reactant products of aerosolized
titanium tetrachloride and ammonium hydroxide did not cause any significant changes in either species
(DOE 1978). The status of the animals was evaluated 1 hour after exposure or 30 days after exposure.
The mixture of the two chemicals was used to generate cold smoke, which is produced by the reaction of
titanium tetrachloride with concentrated ammonium hydroxide; the resulting products are titanium dioxide
and ammonium chloride (Smith et al. 1980).

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
A susceptible population will exhibit a different or enhanced response to titanium tetrachloride than will
most persons exposed to the same level of titanium tetrachloride in the environment. Reasons include

genetic make-up, developmental stage, age, health and nutritional status (including dietary habits that may
increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history

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(including smoking). These parameters result in decreased function of the detoxification and excretory
processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target
organs (including effects or clearance rates and any resulting end-product metabolites). For these reasons
we expect the elderly with declining organ function and the youngest of the population with immature and
developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations
who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations
With Potentially High Exposure."

Persons with bronchitis, pneumoconiosis, bronchial asthma, pulmonary tuberculosis, and diseases of the
upper respiratory tract are at risk because of the toxic nature of titanium tetrachloride fumes (Mezentseva
et al. 1963). For the same reason, work with titanium tetrachloride is contraindicated in persons with
pulmonary or cardiovascular conditions that make it difficult for them to wear a protective mask
(Mezentseva et al. 1963).

2.8 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of
exposure to titanium tetrachloride. However, because some of the treatments discussed may be
experimental and unproven, this section should not be used as a guide for treatment of exposures to
titanium tetrachloride. When specific exposures have occurred, poison control centers and medical
toxicologists should be consulted for medical advice.

2.8.1 Reducing Peak Absorption Following Exposure

In cases of acute dermal exposure to liquid titanium tetrachloride, immediate rinsing with water should not
be used as a treatment (Lawson 1961). Rather, dry wiping of the skin with towels or cotton gauze is the
best way to minimize the effects of exposure. After dermal exposure and dry wiping, a light-yellow-to-
white granular deposit may still remain on the skin surface (HSDB 1992). At this stage, copious amounts
of cool water should be used to completely decontaminate the exposed skin. In the case of eye exposure,
immediate rinsing of the eye with water or neutralizing solutions such as sodium bicarbonate should be
avoided (HSDB 1992). Protective clothing and goggles should be worn as a preventative measure
(Chitkara and McNeela 1992). Since inhalation is the most probable route of exposure, early prophylactic
treatment may include oxygen to prevent possible pulmonary complications (HSDB 1992). Although
corticosteroid therapy improved the pulmonary status in one patient (Park et al. 1984), and prednisone can
be used at 1-2 mg/kg/day, the benefits of the use of steroids are debatable (HSDB 1992).

2.8.2 Reducing Body Burden

No information was located regarding reduction of body burden following exposure to titanium
tetrachloride by any route.

2.8.3 Interfering with the Mechanism of Action for Toxic Effects

The precise mechanism of titanium tetrachloride is not known, but it is believed that its toxicity stems
from its vigorous hydrolysis in the presence of water; this reaction generates heat and hydrochloric acid
(Chitkara and McNeela 1992; Lawson 1961). To interfere successfully with the possible mechanism of
titanium tetrachloride toxicity, the chemical and thermal injury that follows exposure in the presence of
water should be prevented. That is done by wiping of the exposed site with a dry cloth as thoroughly as
possible and avoiding rinsing with water at all costs. One study suggests topical steroids and ascorbate,
antibiotics, and mydratics, as well as oral ascorbate in cases of very severe injuries (Chitkara and McNeela
1992).

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2.9 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of titanium tetrachloride is available. Where adequate
information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to determine the health effects (and
techniques for developing methods to determine such health effects) of titanium tetrachloride.

The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would
reduce the uncertainties of human health assessment. This definition should not be interpreted to mean
that all data needs discussed in this section must be filled. In the future, the identified data needs will be
evaluated and prioritized, and a substance-specific research agenda will be proposed.

2.9.1 Existing Information on Health Effects of Titanium Tetrachloride

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to
titanium tetrachloride are summarized in Figure 2-2. The purpose of this figure is to illustrate the existing
information concerning the health effects of titanium tetrachloride. Each dot in the figure indicates that
one or more studies provide information associated with that particular effect. The dot does not imply
anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data
needs." A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data
Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to
conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as
any substance-specific information missing from the scientific literature.

The vast majority of literature reviewed regarding the health effects of titanium tetrachloride in humans
concerned case reports and chronic-duration epidemiological studies of workers employed in industries
using titanium tetrachloride and case reports of accidental exposure of workers to titanium tetrachloride.
For workers employed in industries using titanium tetrachloride, the major route of exposure is by
inhalation. In cases of accidental spills, the predominant route of exposure is dermal. Therefore, the
information on acute-duration exposure comes from inhalation and dermal exposure data, and information
on chronic-duration exposure comes almost exclusively from inhalation exposure data. The occupational
exposure data are often limited by exposures to other chemicals, by the lack of information on the dose,
and by lack of detail on the duration of exposure. No information is available regarding neurological,
developmental, or reproductive effects in humans after exposure by any route, and no information is
available regarding any effects in humans following oral exposure.

All of the information regarding health effects of titanium tetrachloride in animals was obtained from
studies in which the exposure to titanium tetrachloride occurred by the inhalation route. There is no
information concerning health effects in animals following oral or dermal exposures.

Because titanium tetrachloride rapidly hydrolyzes in the presence of water, the major potential route of
exposure is inhalation for persons involved in industries utilizing titanium tetrachloride. In the case of

accidental spills that may occur in the manufacturing process, it is possible to be exposed via the dermal
route. Therefore, additional information on health effects via these two routes would be of value.

2.9.2 Identification of Data Needs
Acute-Duration Exposure. Acute-duration inhalation exposure data in humans indicate that the lungs

are the major target organ of titanium tetrachloride toxicity. Symptoms of pulmonary toxicity range from
mild such as ticklish cough and tightness in the chest (Ross 1985) to more severe such as shallow

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FIGURE 2-2. Existing Information on Health Effects of
Titanium Tetrachloride

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SYSTEMIC / o/
SSeS & & && S &/
S/S ESSE S/S
Inhalation ® ® oO ®
Oral
Dermal ®
HUMAN
SYSTEMIC / 3/
s/o ESE & & & $ ) & 5
&/ ES&S SSS
Inhalation | @ | ® oo 0 %
Oral
Dermal

 

 

 

 

 

 

 

 

 

 

 

 

ANIMAL

@ Existing Studies

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2. HEALTH EFFECTS

breathing, upper airway stridor progressing to hypoxia, and formation of pulmonary infiltrates that are
Characteristic of respiratory distress syndrome (Park et al. 1984). Lymphocytosis was reported in several
cases of accidental inhalation exposure, but the results are not sufficient to conclude that they were a
consequence of the exposure (Lawson 1961; Park et al. 1984). The data in animals support the
observations made in humans regarding respiratory injury following acute inhalation exposure to titanium
tetrachloride; irritation, wet nose, nasal discharge, and dyspnea were observed in rats following a 10-minute
inhalation exposure to titanium tetrachloride (Karlsson et al. 1986). Insufficient information was available
to calculate an acute-duration inhalation MRL for titanium tetrachloride. Additional studies on the acute
exposure to titanium tetrachloride in animals are needed to examine the histopathologic effects in various
regions of the respiratory system.

No information was available regarding acute-duration oral exposure of titanium tetrachloride in either
humans or animals. This is not expected to be a major route of exposure to titanium tetrachloride
because of its rapid hydrolysis in moist air.

The skin and the eyes are target organs following acute dermal exposure to titanium tetrachloride
(Chitkara and McNeela 1992; Lawson 1961; Ross 1985). Results from these studies indicate that the eyes
may be the most sensitive target organ for the effects of brief dermal exposure to titanium tetrachloride.
The injury to the eye depends on the degree of the burn (caused by exothermal hydrolysis reaction of
titanium tetrachloride) and of the treatment that follows the exposure. Studies examining the effects of
acute dermal exposure to titanium tetrachloride in animals would be useful in establishing the possible
threshold levels for eye injuries.

Intermediate-Duration Exposure. No information is available regarding effects of intermediate-duration
exposure to titanium tetrachloride in humans. There are two reports of the effects of intermediate-
duration inhalation exposure in rats (EPA 1986; Lee et al. 1986). These reports describe effects, such as
nasal irritation and lung abnormalities that are almost identical to those observed following chronic
exposure (see Chronic-Duration Exposure and Cancer, below). Given the similar findings following
intermediate- and chronic-duration exposure, additional intermediate-duration inhalation studies are not
necessary at this time.

No information was available regarding intermediate-duration oral or dermal exposure of titanium
tetrachloride in either humans or animals. Studies examining the effects of intermediate dermal exposure
to titanium tetrachloride would help determine if toxic effects would occur as a result of intermediate
exposure to titanium tetrachloride.

Chronic-Duration Exposure and Cancer. Two epidemiological studies were conducted on workers who
were chronically exposed to titanium tetrachloride. Doses were not well defined, concomitant inhalation
and possible dermal exposures occurred, and there may have been exposure to other chemicals. It may be
possible to recommend a population from DuPont Laboratories that has been already studied for future
investigation of effects caused by chronic exposures since they do have the records of all of their
employees potentially exposed to titanium tetrachloride. Data from the existing epidemiological studies
indicate that the pulmonary system is the main target for chronic inhalation exposure in humans. Further
studies on the causes of the pulmonary abnormalities seen in some workers with chronic exposure to
titanium tetrachloride would be useful in determining long-term lung damage that may be indicative of
exposure to the chemical (Garabrant et al. 1987). Similarly, chronic inhalation exposure in animals also
indicates that lungs are the primary target organ for chronic toxicity in rats (EPA 1986; Lee et al. 1986).
No studies on chronic oral exposure in humans or animals were located.

Epidemiological studies that examine the incidence of cancer in workers exposed to titanium tetrachloride
did not show that this compound is carcinogenic in humans. These studies are limited by lack of data on
dose and precise duration of exposure and by possible exposure of workers to other chemicals (EPA

1990b; Fayerweather et al. 1992). Although lung squamous cell carcinoma and keratinizing squamous cell

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35

2. HEALTH EFFECTS

carcinoma were observed in rats after chronic inhalation exposure to titanium tetrachloride, it is difficult
to estimate their relevance to lung tumors in humans because they have a different etiology (EPA 1984,
1986; Lee et al. 1986). Additional studies in the mouse by the inhalation route would help clarify the
carcinogenic potential of titanium tetrachloride. These studies would also elucidate the possibility that the
accumulation of titanium metallic particles in the lungs may cause a sufficient degree of irritation to lead
to cancer formation or lung granulomatous disease.

Genotoxicity. No conclusions can be reached regarding the potential, if any, of titanium tetrachloride to
induce genetic damage. It is probable that valid results cannot be obtained in any in vivo or in vitro test
systems because of the rapid hydrolysis of titanium tetrachloride in aqueous environments.

Reproductive Toxicity. No information was located regarding reproductive toxicity in humans or animals
following exposure to titanium tetrachloride. Studies examining the reproductive effects of titanium
tetrachloride would help determine if toxic effects would occur as a result of acute- or chronic-duration
inhalation or dermal exposure to titanium tetrachloride.

Developmental Toxicity. No information was located regarding developmeéntal toxicity in humans or
animals following exposure to titanium tetrachloride. Studies examining the developmental effects of
titanium tetrachloride would help determine if toxic effects would occur as a result of acute- or chronic-
duration inhalation or dermal exposure to titanium tetrachloride.

Immunotoxicity. Isolated cases of titanium tetrachloride-induced lymphocytosis have been reported in
humans exposed by the inhalation route (Lawson 1961; Park et al. 1984). The interpretation of these
results is limited because no details of the exposure were provided (Park et al. 1984) and no controls were
provided (Lawson 1961). Impaired cellular immune function evident in reduced mitogen responsiveness
was present in a chronically exposed worker (Redline et al. 1986). In two out of four assays done with
PBLs from this worker, the response to titanium tetrachloride was positive indicating the possible
sensitization against titanium tetrachloride. More information is needed to confirm this finding and
establish the relationship between the delayed hypersensitivity observed in this worker and the
accumulation of metallic titanium in the pulmonary granuloma also found in this case. Additional studies
of dermal and inhalation exposure examining the potential effects of the longer exposure in animals would
help elucidate the immunotoxicity of titanium tetrachloride.

Neurotoxicity. No information was located regarding neurotoxicity in humans or animals following
exposure to titanium tetrachloride. However, studies on the neurotoxicity of this compound are probably
not warranted because of the corrosive nature of the compound and because effects are most likely to be
localized.

Epidemiological and Human Dosimetry Studies. Human studies on titanium tetrachloride consist of
either case reports of accidental occupational exposure or epidemiological studies of workers employed in
the manufacture of metallic titanium, titanium salts, titanium pigments, or mordant dyes. Because of the
rapid hydrolysis of titanium tetrachloride in the presence of small amounts of water, the exposures in case
reports and epidemiological studies are virtually all by the inhalation route, with two accidental exposures
via the dermal route. A good database of occupationally exposed workers (EPA 1990b; Fayerweather et al.
1992) exists at DuPont Laboratories and was used to evaluate the association between the exposure to
titanium tetrachloride and lung cancer incidence and mortality. Locating populations for future
epidemiological studies may be difficult if exposure records of potentially exposed workers are not
maintained. Since titanium tetrachloride is used to generate smoke screens, the records of potentially
exposed individuals may be available from the military. If such groups of exposed individuals are located,
investigation regarding systemic, immunological, neurological, developmental, and reproductive effects and
correlation of these effects with the exposure levels of titanium tetrachloride would provide useful
information. Further studies on occupationally exposed workers may be useful in determining chronic
effects of this compound.

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36

2. HEALTH EFFECTS

Because of its rapid hydrolysis, very few persons are likely to be exposed to titanium tetrachloride at
hazardous waste sites.

Biomarkers of Exposure and Effect

Exposure. It is not possible to determine the levels of titanium tetrachloride in the blood because there
are no available methods. Also, titanium tetrachloride is very rapidly hydrolyzed in the presence of small
amounts of water. However, some titanium tetrachloride hydrolysis products could be used as biomarkers
to identify or possibly quantify the exposure to titanium tetrachloride. One of the more stable hydrolysis
products of titanium tetrachloride is titanium dioxide. The use of electron microscopy, and spectrometric
and spectrographic analysis using x-ray fluorescence, showed the presence of carbon-like particles that were
very similar to titanium dioxide in the lysosomes of alveolar and lymph node macrophages of three
titanium dioxide processing factory workers (Elo et al. 1972). Also present in the lung and lymph node
tissue samples were large quantities of metallic titanium. Further studies would be useful.

Effect. Following accidental occupational exposure to titanium tetrachloride, the scars left from the
second- or third-degree burns were surrounded by dark pigmentation (Lawson 1961). Although the nature
of this dark pigmentation is not known, it may be due to the presence of metallic titanium deposits. These
observations suggest that both titanium dioxide and metallic titanium could be used as a biomarkers of
titanium tetrachloride exposure.

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding absorption,
distribution, metabolism, or excretion of titanium tetrachloride; however, further studies are not warranted
because of the very reactive nature of this compound.

Comparative Toxicokinetics. No studies were located regarding toxicokinetics in any animal species;
however, further studies are not warranted for titanium tetrachloride because of the very reactive nature of
this compound.

Methods for Reducing Toxic Effects. The most important way to prevent toxic effects of titanium
tetrachloride in the occupational setting is to use protective clothing and a respirator. If exposure occurs,
the use of water for decontamination is dangerous. To prevent thermal and chemical injuries that result
from the vigorous hydrolysis of titanium tetrachloride, wiping with dry towels or cotton gauze are
recommended to minimize the effects of exposure. After dermal exposure and dry wiping, a light-yellow-
to-white granular deposit may remain on the skin surface (HSDB 1992). At this stage, copious amounts of
cool water should be used to decontaminate the exposed skin completely. Since inhalation is the most
probable route of exposure, early prophylactic treatment may include oxygen to prevent possible
pulmonary complications. Further exposure should also be avoided (HSDB 1992). Although
corticosteroid therapy improved the pulmonary status in one patient (Park et al. 1984), and prednisone can
be used at 1-2 mg/kg/day, the use of steroids is debatable (HSDB 1992). One study suggested the use of
topical steroids and ascorbate, the use of antibiotics and mydratics, and the use of oral ascorbate in cases
of very severe injuries (Chitkara and McNeela 1992).

2.9.3 On-going Studies

No on-going studies regarding the health effects of titanium tetrachloride were reported in the Federal
Research in Progress File database.

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37

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Information regarding the chemical identity of titanium tetrachloride is located in Table 3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES

Information regarding the physical and chemical properties of titanium tetrachloride is located in
Table 3-2.

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38

3. CHEMICAL AND PHYSICAL INFORMATION

TABLE 3-1. Chemical Identity of Titanium Tetrachloride

 

 

Characteristic Information Reference
Chemical name Titanium tetrachloride HSDB 1992
Synonym(s) Tetrachlorotitanium, HSDB 1992
titanic chloride, titanium
chloride
Registered trade name(s) No data
Chemical formula TiCl, HSDB 1992
Chemical structure OHM/TADS 1992
Cl
|
Cl— Ti—Cl
Cl
Identification numbers:
CAS registry 7550-45-0 HSDB 1992
NIOSH RTECS XR 1925000 HSDB 1992
EPA hazardous waste No data
OHM/TADS 7217310 HSDB 1992
DOT/UN/NA/IMCO shipping IMCO/UN: #8.0/1838; CHRIS 1985
DOT: #1838
HSDB 870 HSDB 1992
NCI No data

 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental
Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute;
NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous
Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical
Substances

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39

3. CHEMICAL AND PHYSICAL INFORMATION

TABLE 3-2. Physical and Chemical Properties of Titanium Tetrachloride

 

 

Property Information Reference
Molecular weight 189.70 Sax and Lewis 1989
Color Colorless Budavari et al. 1989
Physical state Liquid CHRIS 1985
Melting point -24.1°C Budavari et al. 1989
Boiling point 136.4°C Budavari et al. 1989
Density:

at 20°C 1.726 g/cm’ Budavari et al. 1989

at 25°C No data

at 30°C No data .
Odor Penetrating acid odor Budavari et al. 1989
Odor threshold:

Water No data

Air No data
Solubility:

Water at 20°C
Organic solvent(s)
Partition coefficients:
Log Koy
Log K,.
Vapor pressure at 20°C
Henry’s law constant:
at 20°C
at 30°C
Autoignition temperature
Flashpoint
Flammability limits
Conversion factors
Explosive limits

Soluble in cold water
Soluble in alcohol

No data
No data
10.0 mmHg

No data

No data

No data

No data

Nonflammable

1 mg/m> = 7.76 ppm?

Reactive only under
extreme conditions

Budavari et al. 1989
Budavari et al. 1989

Whitehead 1983

OHM/TADS 1992

OHM/TADS 1992

 

a | mg/m® = 1 ppm x 189.73/24.45

*** DRAFT FOR PUBLIC COMMENT ***
 
41

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

41 PRODUCTION

Titanium tetrachloride is a colorless-to-light-yellow watery liquid that is produced by the chlorination of
titanium compounds by a continuous process in a fluid-bed reactor. Minerals with a high titanium
content, such as beneficiated ilmenite, mineral rutile, and leucoxene, are used in the production of
titanium tetrachloride. Carbon is also added during the chlorination process as a reducing agent because
the titanium compounds contain oxygen (Whitehead 1983).

Production capacity in the United States in 1980 was 2,500,000 tons (Whitehead 1983). The aggregate
production volume for titanium tetrachloride reported in the Toxic Substances Control Act Inventory for
1990 was 3,150,556,000 pounds (1,575,278 metric tons) (CICIS 1993). A list of titanium tetrachloride
production and processing facilities in the United States along with the production or processing volume
for each facility are provided in Table 4-1 (TRI91 1993).

4.2 IMPORT/EXPORT

No information on import or export volumes for titanium tetrachloride was located.

4.3 USE

Titanium tetrachloride is used in the manufacture of titanium metal, titanium dioxide pigments, iridescent
glass, artificial pearls, and as a starting material for a variety of organic and inorganic titanium compounds.
It is also used as a mordant dye, a polymerization catalyst, and as a catalyst in several types of organic
syntheses (Budavari et al. 1989; EPA 1985b; Nordman and Berlin 1986; OHM/TADS 1992; Stokinger 1981;
Whitehead 1983).

Titanium tetrachloride was formerly used with potassium bitartrate as a mordant, with dyewoods to dye
leather, and as a smoke-producing screen for the military (Budavari et al. 1989; Whitehead 1983).

4.4 DISPOSAL

Titanium (including its container) should be disposed of in an incinerator or burned in a furnace.
Alternatively, titanium tetrachloride may be spread on a thin layer on the ground and dispersed into a
sewer by large amounts of water. Spill areas should be washed thoroughly. The local waste-water
treatment authority should be notified of any discharge. Small spills of titanium tetrachloride should be
covered with a sufficient amount of sodium bicarbonate. The mixture should be placed in an appropriate
container such as fiber drum, plastic bag, or carton and incinerated or burned (HSDB 1992; OHM/TADS
1992).

No other information on methods for the industrial disposal of titanium tetrachloride was located.

*** DRAFT FOR PUBLIC COMMENT ***
»»» INJWWOD OIN8Nd HOA 14VHA xx»

TABLE 4-1.

Facilities That Manufacture or Process Titanium Tetrachloride®

 

b

Range of
maximum amounts

 

Facility Location on site in pounds Activities and uses
DU PONT MOBILE PLANT MOBILE PLANT AXIS, AL 100,000-999,999 As a formulation component
HITECH INC. HAMPTON, AR 1,000-9,999 As an article component

DU PONT ANTIOCH ANTIOCH
CHEVRON USA PRODUCTS CO. RICHMOND

REFINERY
DU PONT EDGEMOOR EDGE MOOR

KEMIRA INC.

AMERICAN SYNTHETIC RUBBER CORPCORP.

LAROCHE CHEMICALS INC.

HIMONT USA INC. LAKE CHARLES PLANT
SCM CHEMICALS HAWKINS POINT PLANT

ANDERSON DEVELOPMENT CO.
AKZO CHEMICALS INC.
KERR-MCGEE CHEMICAL CORP.

DU PONT DELISLE DELISLE PLANT

DU PONT CHAMBERS WORKS CHAMBERS
WORKS

AKZO CHEMICALS INC.

HUNTSMAN POLYPROPYLENE CORP.

TITANIUM METALS CORP. OF AMERICA

CORNING GLASS WORKS CANTON PLANT

TAM CERAMICS INC.

RMI TITANIUM CO. METALS REDUCTION
PLANT

SCM CHEMICALS ASHTABULA PLANT 1

SCM CHEMICALS ASHTABULA PLANT II
OREGON METALLURGICAL CORP.

DU PONT JOHNSONVILLE PLANT
JOHNSONVILLE PLANT

ANTIOCH, CA
RICHMOND, - CA

EDGEMOOR, DE

SAVANNAH, GA

LOUISVILLE, KY
BATON ROUGE, LA

LAKE CHARLES, LA
BALTIMORE, MD
ADRIAN, MI

WESTON, MI
HAMILTON, MS

PASS CHRISTIAN, MS
DEEPWATER, NJ
EDISON, NJ

WEST DEPTFORD TWP, NJ
HENDERSON, NV

CANTON, NY
NIAGARA FALLS, NY
ASHTABULA, OH
ASHTABULA, OH
ASHTABULA, OH

ALBANY, OR
NEW JOHNSONVILLE, TN

100, 000-999, 999
10,000-99, 999

1,000, 000-9,999,999

1,000, 000-9, 999,999

1,000-9,999
10, 000-99, 999

100, 000-999, 999
1,000, 000-9, 999,999
10,000-99,999
10,000-99,999
1,000,000-9, 999,999
1,000, 000-9,999,999
10,000-99, 999
100, 000-999, 999

10, 000-99, 999
1,000, 000-9,999,999

10,000-99, 999
10,000-99,999
1,000, 000-9,999,999
100, 000-999,999
1,000,000-9, 999,999

1,000,000-9,999,999
1,000,000-9,999,999

Produce, for on-site use/processing,
as a reactant

Produce, for on-site use/processing,
as a reactant

Produce, for on-site use/processing,
for sale/distribution, as a
reactant

Produce, for on-site use/processing,
for sale/distribution, as a
reactant

As a processing aid

Import, for on-site use/processing,
as a formulation component, as a
manufacturing aid

As a reactant

Produce, for on-site use/processing,
as a reactant

As a reactant

In re-packaging

Produce, for on-site use/processing,
as a reactant

Produce, for on-site use/processing,
as a reactant

As a reactant

As a reactant

As. a processing aid

Produce, for on-site use/processing,
for sale/distribution, as a
reactant

As a formulation component

As a reactant

As a reactant

Produce, for on-site use/processing,
as a reactant

Produce, for on-site use/processing,
as a reactant

As a reactant

Produce, for on-site use/processing,
as a reactant

IVSOdSIA NV ‘Asn ‘1HOdWI ‘NOILONAOHd ‘v

ey
sss INSWWNOOD OMNBNd HO 14VHA w=»

TABLE 4-1. Facilities That Manufacture or Process Titanium Tetrachloride (Continued)

 

Facility

Range of
maximum amounts

Location” on site in pounds

Activities and uses

 

AMOCO CHEMICAL CO. CEDAR BAYOU PLANT

CHEVRON CHEMICAL CoO.

GOODYEAR TIRE & RUBBER CO. BEAUMONT
CHEMICAL PLANT

SOLVAY POLYMERS INC.

CATALYST RESOURCES INC.

ETHYL CORP. HOUSTON PLANT

HIMONT USA INC.

HOECHST CELANESE BAYPORT WORKS

QUANTUM CHEMICAL CORP. USI DIV.
DU PONT VICTORIA SITE
OCCIDENTAL CHEMICAL co.
OCCIDENTAL CHEMICAL CORP.

AKZO CHEMICALS INC.

BAYTOWN, TX 10,000-99,999
BAYTOWN, TX 10,000-99,999
BEAUMONT, TX 10,000-99,999
DEER PARK, TX 10, 000-99, 999
PASADENA, TX 100, 000-999, 999
PASADENA, TX 10, 000-99, 999
PASADENA, TX 10, 000-99, 999
PASADENA, TX 100, 000-999, 999
PORT ARTHUR, TX 100,000-999,999
VICTORIA, TX 10,000-99, 999
VICTORIA, TX 1,000-9,999

WADSWORTH, TX 10, 000-99, 999
GALLIPOLIS FERRY, WV 10,000-99,999

As a processing aid
As a processing aid
As a processing aid

As a processing aid

As a reactant

As a processing aid

As a reactant

Import, for on-site use/processing,
as a formulation component, as a
processing aid

As a processing aid

As a processing aid

As a processing aid

As a processing aid

As a processing aid

 

iDerived from TRI91 (1993)
Post Office state abbreviations used

vS0dSia NV ‘3sn ‘1HOdI ‘NOLLONAOoHd '¥
=

&
3
b;

ho

 
45

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Titanium tetrachloride is an inorganic compound that rapidly hydrolyzes upon contact with water. It may
be released to air during production and/or use or as a result of spills. Because it hydrolyzes upon contact
with water, it is unlikely to be transported significant distances in any environmental media. However, one
of its hydrolysis products, titanium dioxide, may persist in soils or sediments. The other hydrolysis
product, hydrochloric acid, dissociates in water and air.

Exposure to titanium tetrachloride is primarily occupational, with titanium industry workers having the
greatest potential exposure.

Titanium tetrachloride has not been identified at any of the 1,350 hazardous waste sites on the EPA NPL
(HAZDAT 1993).

5.2 RELEASES TO THE ENVIRONMENT

5.2.1 Air

According to the Toxics Release Inventory (TRI) (Table 5-1), an estimated total of 54,360 pounds
(approximately 25 metric tons) of titanium tetrachloride, amounting to 100% of the total environmental
release, was discharged to the air from manufacturing and processing facilities in the United States in 1990
(TRI91 1993). The TRI data listed in Table 5-1 should be used with caution since only certain types of
facilities are required to report. This is not an exhaustive list.

5.2.2 Water

No information was found regarding releases of titanium tetrachloride to surface water or groundwater.
5.2.3 Soil

No information was located regarding releases of titanium tetrachloride to soils.

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

Titanium tetrachloride hydrolyzes upon contact with moist air to form a vapor of hydrochloric acid,
titanium dioxide, and titanium oxychloride (Whitehead 1983; Wilms et al. 1992). Consequently,
environmental transport of this compound is negligible; however, the atmospheric transport of the
hydrolysis products may be substantial.

5.3.2 Transformation and Degradation

5.3.2.1 Air

Upon contact with moist air, titanium tetrachloride hydrolyzes with fuming into hydrogen chloride,
titanium dioxide, and titanium oxychloride (Whitehead 1983; Wilms et al. 1992).

*** DRAFT FOR PUBLIC COMMENT ***
sss INSWNOOD OMN8Nd HOH 14VHA =»

TABLE 5-1.

Releases to the Enviroment from Facilities
That Manufacture or Process Titanium Tetrachloride®

 

Reported amounts released in pounds

 

 

off-site
- Underground Total POTW waste
Facility Location Air injection Water Land environment transfer transfer
DU PONT MOBILE PLANT AXIS, AL 0 0 0 0 0 0 2,020,000
MOBILE PLANT
HITECH INC. HAMPTON, AR 525 0 0 0 525 0 0
DU PONT ANTIOCH ANTIOCH ANTIOCH, CA 1,400 0 0 0 1,400 0 0
CHEVRON USA PRODUCTS CO. RICHMOND, CA 0 0 0 0 0 0 0
RICHMOND REFINERY
DU PONT EDGEMOOR EDGE EDGEMOOR, DE 410 0 0 0 410 0 0
MOOR
KEMIRA INC. SAVANNAH, GA 3,800 0 0 0 3,800 0 0
AMERICAN SYNTHETIC LOUISVILLE, KY S 0 0 0 5 0 0
RUBBER CORPCORP.
LAROCHE CHEMICALS INC. BATON ROUGE, LA 0 0 0 0 0 0 0
HIMONT USA INC. LAKE LAKE CHARLES, LA 100 0 0 0 100 0 0
CHARLES PLANT }
SCM CHEMICALS HAWKINS BALTIMORE, MD 3 0 0 0 31 0 0
POINT PLANT
andERSON DEVELOPMENT CO. ADRIAN, MI 23 0 0 0 23 0 0
AKZO CHEMICALS INC. WESTON, MI 10 0 0 0 10 0 0
KERR-MCGEE CHEMICAL HAMILTON, MS 1,900 0 0 0 1,900 0 0
CORP.
DU PONT DELISLE DELISLE PASS CHRISTIAN, MS 5,800 0 0 0 5,800 0 0
PLANT
DU PONT CHAMBERS WORKS DEEPWATER, NJ 476 0 0 0 476 0 0
CHAMBERS WORKS
AKZO CHEMICALS INC. EDISON, NJ 869 0 0 0 869 0 2,640
HUNTSMAN POLYPROPYLENE WEST DEPTFORD, NJ 0 0 0 0 0 0 0
CORP.
TITANIUM METALS CORP. OF HENDERSON, NV 250 0 0 0 250 0 0
AMERICA
CORNING GLASS WORKS CANTON, NY 0 0 0 0 0 0 0
CANTON PLANT
TAM CERAMICS INC. NIAGARA FALLS, NY 16 0 0 0 16 0 0
RMI TITANIUM CO. METALS ASHTABULA, OH 210 0 0 0 210 0 0
REDUCTION PLANT
SCM CHEMICALS ASHTABULA ASHTABULA, OH 420 0 0 0 420 0 0
PLANT 1
SCM CHEMICALS ASHTABULA ASHTABULA, OH 1 0 0 0 1" 0 0

PLANT 11

34NSOdX3 NVWNH HO4 TVLIN3LOd 'S
TABLE 5-1. Releases to the Environment from Facilities
That Manufacture or Process Titanium Tetrachloride (continued)

 

Reported amounts released in pounds

»»s INSWWNOO ONENd HO LIVHA sx»

 

 

 

off-site
5 Underground Total POTW waste
Facility Location Air injection Water Land environment® transfer transfer
OREGON METALLURGICAL ALBANY, OR 500 0 0 0 500 0 0
CORP.
DU PONT JOHNSONVILLE NEW JOHNSONVIL, TN 3,000 0 0 0 3,000 0 0
PLANT JOHNSONVILLE
PLANT
AMOCO CHEMICAL CO. CEDAR BAYTOWN, TX 0 0 0 0 0 0 0
BAYOU PLANT
CHEVRON CHEMICAL CoO. BAYTOWN, TX 0 0 0 0 0 0 0
GOODYEAR TIRE & RUBBER BEAUMONT, TX 0 0 0 0 0 0 0
CO. BEAUMONT CHEMICAL
PLANT
SOLVAY POLYMERS INC. DEER PARK, TX 0 0 0 0 0 0 0
CATALYST RESOURCES INC. PASADENA, TX 7,540 0 0 0 7,540 0 958
ETHYL CORP. HOUSTON PASADENA, TX 4,250 0 0 0 4,250 0 0
PLANT
HIMONT USA INC. PASADENA, TX 500 0 0 0 500 1 2,688
HOECHST CELANESE BAYPORT PASADENA, TX 0 0 0 0 0 0 130,000
WORKS
QUANTUM CHEMICAL CORP. PORT ARTHUR, TX 1,550 0 0 0 1,550 0 0
USI DIV.
DU PONT VICTORIA SITE VICTORIA, TX 0 0 0 0 0 0 0
OCCIDENTAL CHEMICAL CoO. VICTORIA, TX 0 0 0 0 0 0 0
OCCIDENTAL CHEMICAL WADSWORTH, TX 10 0 0 0 10 0 214,500
CORP.
AKZO CHEMICALS INC. GALLIPOLIS FER, WV 0 0 0 0 0 0 0
Totals 33,606 0 0 0 33,606 1 2,370,786

 

"Derived from TRI91 (1993)

Post Office state abbreviations used
“The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility

POTW = publicly owned treatment works

3HNSOdX3 NVWNH HO4 TVIIN3LOd °S

Ly
48

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2.2 Water
When titanium tetrachloride is released to water it hydrolyzes to hydrochloric acid, titanium oxychloride,
and titanium dioxide. Titanium oxychloride usually further hydrolyzes to hydrochloric acid and titanium

dioxide (Wilms et al. 1992). In water, hydrochloric acid dissociates to the hydrogen and chloride ions.
Titanium dioxide is insoluble in water and may settle out to sediment.

5.3.2.3 Sediment and Soil
No information was located on the degradation of titanium tetrachloride released to soils or sediments;
however, based on the ready hydrolysis of this compound in moist air or water, it may be expected that

titanium tetrachloride will also hydrolyze upon contact with moisture in the soil. Residues of titanium
dioxide, a very inert compound, are likely to remain in the soil or settle out to sediment.

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

No information was located on levels of titanium tetrachloride in air.

5.4.2 Water

No information was located on levels of titanium tetrachloride in surface water or groundwater.
5.4.3 Sediment and Soll

No information was located on levels of titanium tetrachloride in sediment or soil.

5.4.4 Other Environmental Media

No information was located on levels of titanium tetrachloride in other environmental media.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Information on the potential for general population exposure to titanium tetrachloride as a result of its
manufacture, use, disposal, or presence at a waste site was not located. The lack of data on concentrations
of titanium tetrachloride in foods, water, air, and other sources of general population exposure suggests
that such exposure is limited.

Preliminary data from a workplace survey, the National Occupational Exposure Survey (NOES), conducted
by the National Institute for Occupational Safety and Health (NIOSH) from 1980 to 1983, indicated that
2,107 workers, including 131 women, were potentially exposed to titanium tetrachloride in the workplace
in 1980 (NIOSH 1993).

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Workers in the titanium industry have the greatest potential for exposure to titanium tetrachloride.
Workers who are involved in the process of producing titanium metal from titanium tetrachloride receive
the most exposure, particularly those involved in the reduction process where they are exposed to vapors
of titanium tetrachloride, titanium oxychloride, and titanium dioxide particulates (Garabrant et al. 1987).
Maintenance and repair workers at these facilities are exposed to high concentrations of titanium
tetrachloride vapors containing its hydrolysis products, titanium oxide and hydrochloric acid (Mogilevskaja

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49

5. POTENTIAL FOR HUMAN EXPOSURE

1983). Workers who may use titanium tetrachloride for examining welding machinery may be exposed as a
result of accidental spills (Ross 1985).

5.7 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA as amended directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of titanium tetrachloride is available. Where adequate
information is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a
program of research designed to determine the health effects (and techniques for developing methods to
determine such health effects) of titanium tetrachloride.

The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would
reduce or eliminate the uncertainties of human health assessment. This definition should not be
interpreted to mean that all data needs discussed in this section must be filled. In the future, the
identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be
proposed.

5.7.1 Identification of Data Needs

Physical and Chemical Properties. Although it has been determined that titanium tetrachloride
hydrolyzes upon contact with water, it is not a well-defined chemical in terms of its physical and chemical
properties (Budavari et al. 1989). Further information on its water solubility, octanol/water partition
coefficient, soil adsorption coefficient, and Henry's law constant would be helpful in determining the
environmental fate of this chemical and the rate at which it degrades in air, water, soil, and sediments.

Production, Import/Export, Use, and Release and Disposal. The available use, production, and
release information for titanium tetrachloride is insufficient to determine the amount of titanium
tetrachloride that may be present in the environment (CICIS 1993; OHM/TADS 1992; Whitehead 1983).
In addition, there is a lack of data on how much titanium tetrachloride may be stored at waste sites,
methods of industrial disposal, and environmental releases that may result from its use as a dye, as a
catalyst, and in the titanium metal industry. This type of information, along with data on production
trends, would be useful in determining whether significant releases occur, what the proper disposal
methods are, and the potential for environmental contamination.

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section
11023, industries are required to submit chemical release and off-site transfer information to the EPA.
The Toxics Release Inventory (TRI), which contains this information for 1991, became available in May of
1992. This database will be updated yearly and should provide a list of industrial production facilities and
emissions.

Environmental Fate. Titanium tetrachloride readily hydrolyzes upon contact with moisture to form
hydrochloric acid, titanium dioxide, and titanium oxychloride (Whitehead 1983; Wilms et al. 1992).
Information on the degradation rates, persistence, and fate of these degradation products would be helpful
in determining levels of titanium tetrachloride that may have an impact on various environmental media.
This is particularly true for releases of titanium tetrachloride to soil as a result of spills. Because it is a
liquid at room temperature, it would be helpful to know if the compound permeates the soil, particularly
in low- moisture situations.

Bioavailability from Environmental Media. Information is lacking on the bioavailability of titanium
tetrachloride from environmental media as there is no information available on titanium tetrachloride

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50

5. POTENTIAL FOR HUMAN EXPOSURE

levels in environmental media. The rapid hydrolysis of titanium tetrachloride in water (Wilms et al. 1992)
suggests that human exposure via contaminated drinking water or surface waters is unlikely, and no further
studies on the bioavailability of this compound in water are indicated at this time. Studies of the
persistence of titanium tetrachloride and its degradation products in soils would be helpful in determining
whether there is potential for human exposure, particularly at hazardous waste sites.

Food Chain Bioaccumulation. No information was found on the bioaccumulation potential of titanium
tetrachloride in aquatic or terrestrial ecosystems. However, its rapid hydrolysis upon contact with moisture
(Wilms et al. 1992) suggests that there is little potential for bioaccumulation in aquatic or terrestrial
organisms. Further studies on the bioaccumulation of this compound are not required.

Exposure Levels in Environmental Media. No monitoring studies of titanium tetrachloride levels in
any environmental media were located. Such studies, particularly for arid soils and atmospheres in which
titanium tetrachloride is less likely to hydrolyze, would assist health officials in determining the length of
time that the compound may persist and levels that may be found at some hazardous waste sites.
Furthermore, determination of titanium tetrachloride levels in all media at hazardous waste sites should be
undertaken.

Reliable monitoring data for the levels of titanium tetrachloride in contaminated media at hazardous waste
sites are needed so that the information obtained on levels of titanium tetrachloride in the environment
can be used in combination with the known body burden of titanium tetrachloride to assess the potential
risk of adverse health effects in populations living in the vicinity of hazardous waste sites.

Exposure Levels in Humans. Most human exposures to titanium tetrachloride occur in the workplace
as a result the production of titanium or because of accidental spills. Data on workplace exposures do
exist (Garabrant et al. 1987; Ross 1985); however, exposure levels for the general population or persons
living near hazardous waste sites are not available. Studies to determine the potential for exposure of
people living near areas where titanium tetrachloride is stored or disposed of would be useful in
determining whether there is a risk to this population. This information is necessary for assessing the
need to conduct health studies on these populations.

Exposure Registries. No exposure registries for titanium tetrachloride were located. This substance is
not currently one of the substances for which a subregistry has been established in the National Exposure
Registry. The substances will be considered in the future when chemical selection is made for subregistries
to be established. The information that is amassed in the National Exposure Registry facilitates the
epidemiological research needed to assess adverse health outcomes that may be related to the exposure to
this substance.

5.7.2 On-going Studies

No on-going studies on the potential for human exposure to titanium tetrachloride were located.

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6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or
measuring, and/or monitoring titanium tetrachloride, its metabolites, and other biomarkers of exposure and
effect to titanium tetrachloride. The intent is not to provide an exhaustive list of analytical methods.
Rather, the intention is to identify well-established methods that are used as the standard methods of
analysis. Many of the analytical methods used for environmental samples are the methods approved by
federal agencies and organizations such as EPA and the National Institute for Occupational Safety and
Health (NIOSH). Other methods presented in this chapter may be those that are approved by groups

such as the Association of Official Analytical Chemists (AOAC) and the American Public Health
Association (APHA). Additionally, analytical methods may be included that modify previously used
methods to obtain lower detection limits, and/or to improve accuracy and precision.

6.1 BIOLOGICAL MATERIALS

Titanium tetrachloride hydrolyzes into titanium dioxide and hydrochloric acid upon contact with water or
moisture in the air. Titanium tetrachloride cannot be detected in biological materials; however, titanium
dioxide and titanium metal can be detected and may be used as indicators of exposure to titanium
tetrachloride, although the presence of these materials in biological tissue does not necessarily mean the
exposure occurred. See Table 6-1 for a summary of the analytical methods most commonly used to detect
titanium tetrachloride and titanium dioxide in biological materials. The primary method used to detect
titanium dioxide in lung tissue is scanning and/or transmission electron microscopy (STEM). Electron
probe x-ray microanalysis (ARL EMX-SM) and energy dispersive x-ray analysis (EDXA) have been used in
conjunction with STEM (Ferin et al. 1976; Redline et al. 1986). Sample preparation consists of extraction
of the lung tissue, fixation in osmium tetroxide and/or glutaraldehyde, dehydration in ethanol, embedment
in epoxy, followed by sectioning and staining with uranyl acetate and lead citrate (Ferin et al. 1976; Ophus
et al. 1979). The detection limit is 0.2 pmol/L. A limitation of this method is that it cannot differentiate
between titanium dioxide and titanium dioxide pigments.

No analytical methods were found for determining titanium dioxide in urine. However, titanium metal can
be determined by inductively coupled argon plasma, atomic emission spectroscopy (ICP-AES). This
method is very sensitive, with a detection level of 2 ppb and a good recovery of 86% (NIOSH 1984).

No information was located on detecting titanium dioxide in blood, adipose tissue, feces, or human milk.

6.2 ENVIRONMENTAL SAMPLES

No methods for detecting titanium tetrachloride in environmental samples were located. However,
titanium dioxide may be used as an indicator of titanium tetrachloride presence in air and some food
samples, but its presence does not necessarily mean that titanium tetrachloride is or was present in the
environmental sample. See Table 6-2 for a summary of the analytical methods used to determine titanium
dioxide in environmental samples.

The primary method for detecting titanium dioxide in air is by gravimetric filter weight (G/FW) (NIOSH
1980, 1984). Air sampling may be performed by collection of a sample on a polyvinyl chloride membrane
or DMSO filter, drying or heating, followed by equilibration of the sample in an environmental chamber.
Detection limits are in the ppm range (NIOSH 1980, 1984). Spectrophotometric methods can detect
titanium metal in air at a detection level of 2 pg, and atomic absorption spectrophotometry (AAS) can
detect titanium metal at 1.9 pg/mL for 1% absorption (Anonymous 1975). Samples for both methods are
collected on an electrostatic precipitator (ESP), filter paper, standard impinger, or a membrane filter. The
sample is reacted with hydrogen peroxide for the general spectrophotometric method, or acidified with
hydrochloric acid solution for the AAS method (Anonymous 1975). ICP-AES is an alternative method to

*** DRAFT FOR PUBLIC COMMENT ***
sss INSJWINOD OMNENd HO4 14VHA ss»

TABLE 6-1. Analytical Methods for Determining Titanium Tetrachloride
and Titanium Dioxide in Biological Materials

 

 

Sample
detection Percent

Sample matrix Preparation method Analytical method limit recovery Reference
Urine Perform creatine ICP-AES 2 ppb 86% NIOSH 1984
(Ti metal) determination, adjust (NIOSH Method

pH, add polydithio- 8310)

carbamate resin,

ash filter
Lung tissue Extract sample SEM/EDXA NR NR Redline et al. 1986
(TiO)
Lung tissue Extract sample, fix TEM/ARL EMX-SM; 0.2 um NR Ferin et al. 1976
(TiO,) in osmium tetroxide, STEM

dehydrate in ethanol,

embed in epoxy, section

and stain with uranyl

acetate and lead citrate
Lung tissue Extract sample, dry OES NR NR Elo et al. 1972

(TiOy)

grind

SAOH.L3IN TVOLLATYNY ‘9
»sx INGWNOO OMNBNd HOH LIVHA x»

TABLE 6-1. Analytical Methods for Determining Titanium Tetrachloride

and Titanium Dioxide in Biological Materials (continued)

 

 

Sample
detection Percent

Sample matrix Preparation method Analytical method limit recovery Reference
Lung tissue Extract sample, fix TEM/EDS NR NR Ophus et al. 1979
(TiO, and in glutaraldehyde and
Ti pigments) osmium tetroxide,

dehydrate in ethanol,

embed in epoxy resin,

section and stain with

uranyl acetate and lead

citrate
Lung tissue Extract sample, dehydrate, SEM/EDS NR NR Ophus et al. 1979
(TiO, and mount on carbon stub with
Ti pigments) carbon cement
Lung tissue Filter lung tissue; ash XD NR NR Ophus et al. 1979
(TiO, and dispersions through
Ti pigments) silver membrane

 

ARL EMX-SM = electron probe x-ray microanalyzer; EDS = energy dispersive x-ray microanalysis; EDXA = energy dispersive
x-ray analysis; ICP-AES = inductively coupled argon plasma, atomic emission spectroscopy; NIOSH = National Institute for
Occupational Safety and Health; NR = not reported; OES = optic emission spectrograph; SEM = scanning electron microscopy;
STEM = scanning transmission electron microscopy; TEM = transmission electron microscopy; Ti = titanium; TiO, = titanium

dioxide; XD = x-ray diffractometry

SAOH13NW TYOULATVNY "9
sss INSJWWOD OMN8Nd HOH 14VHA ss»

TABLE 6-2. Analytical Methods for Determining Titanium Dioxide in Environmental Samples

 

 

Sample
detection Percent
Sample matrix Preparation method Analytical method limit recovery Reference
Air Collect sample on G/FW 0.2 ppm NR NIOSH 1984
filter, dry, (NIOSH Method
equilibrate 0500)
Air Collect sample on G/FW 0.25-2.6ppm NR NIOSH 1984
filter, dry, (NIOSH Method
equilibrate 0600)
Air Collect sample on filter, ICP-AES 2 ppb 96% NIOSH 1984
heat with ashing acid, (NIOSH Method
dissolve residue in 7300)
dilution acid
Air Collect sample with ESP, SP 2 ug NR Anonymous 1975
(Ti metal) react with H,0,
Air Collect sample with ESP, AAS 1.9 pg/mL for NR Anonymous 1975
(Ti metal) acidify 1% absorption
Air Collect sample on filter G/FW 0.01 ppm NR Moseley et al. 1982
(Ti compounds in personal sampling pump

except TiCly)

at 1.5-1.7 L/min

SAOHLIN TVOLLATYNY 9
ss» INSWNOO OMNENd HO 14VHA ss

TABLE 6-2. Analytical Methods for Determining Titanium Dioxide
in Environmental Samples (continued)

 

 

Sample
detection Percent
Sample matrix Preparation method Analytical method limit recovery Reference
Cheese Char under IR lamp, SP NR NR Leone 1973
add Na,SO, and H,SO,,
clarify

 

AAS = atomic absorption spectrophotometry; ESP = electrostatic precipitator; G/FW = gravimetric filter weight; H,0, =
hydrogen peroxide; H,SO, = sulfuric acid; ICP-AES = inductively coupled argon plasma, atomic emission spectroscopy; ; IR
infrared; Na,SO, = sodium sulfate; NIOSH = National Institute for Occupational Safety and Health; NR = not reported; SP
spectrophotometry; Ti = titanium; TiCl, = titanium tetrachloride

SAOHLINW TYOLLATYNY 9
56

6. ANALYTICAL METHODS

determine titanium dioxide in air, with detection limits in the ppb range and an excellent recovery of 96%
(NIOSH 1984).

Hydrochloric acid is a hydrolysis product of titanium tetrachloride and can be detected in air. Gaseous
hydrochloric acid must first be separated from aerosols that contain chloride ions. Filter packs, diffusion
denuders, and diffusion samplers are the most common methods used to determined hydrochloric acid in
air (Kamrin 1992). However, if hydrochloric acid is found in air, it is not necessarily indicative of exposure
to titanium tetrachloride.

The presence of titanium dioxide in cheese has been studied (Leone 1973). Sample preparation included

Charring and ashing, followed by dissolution of the sample in sulfuric acid. A yellow-orange complex was
produced by adding hydrogen peroxide to the sample. The colorimetric method detected titanium dioxide
by comparing the spectrophotometric response of the sample to the response of titanium dioxide (Leone

1973).

The addition of hydrogen peroxide to a cheese or air sample to colorimetrically determine titanium dioxide
may cause interference from nickel, copper, cobalt, molybdenum, vanadium, and chromium, if present. It
is unlikely, however, that these elements are present in cheese. Interferences in air samples can be
overcome by the use of treated and untreated standards, or by precipitating the titanium dioxide
(Anonymous 1975; Leone 1973).

No information was located on detecting titanium tetrachloride or titanium dioxide in water, soil, or
sediment.

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of titanium tetrachloride is available. Where adequate
information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a
program of research designed to determine the health effects (and techniques for developing methods to
determine such health effects) of titanium tetrachloride.

The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would
reduce the uncertainties of human health assessment. This definition should not be interpreted to mean
that all data needs discussed in this section must be filled. In the future, the identified data needs will be
evaluated and prioritized, and a substance-specific research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. Methods exist for measuring titanium
dioxide and titanium dioxide pigment in lung tissue (Elo et al. 1972; Ferin et al. 1976; Ophus et al. 1979;
Redline et al. 1986) and for measuring titanium metal in urine (NIOSH 1984). However, no methods
were identified for detecting titanium tetrachloride in any biological materials. Most methods can only
detect the presence, and not the levels, of titanium dioxide or titanium dioxide pigments in lung tissue
(Elo et al. 1972; Ophus et al. 1979; Redline et al. 1986). STEM, EDXA, and x-ray diffraction (XD)
methods cannot differentiate between titanium dioxide and titanium dioxide pigment. ARL EMX-SM in
conjunction with STEM can detect titanium dioxide levels more accurately in lung tissue. However, no
method exists for determining background levels of titanium tetrachloride or titanium dioxide in the
general population, or levels at which biological effects occur.

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6. ANALYTICAL METHODS

More sensitive methods for detecting long-term exposure to titanium dioxide or titanium metal in
biological tissue are desirable in order to monitor levels of titanium dioxide, titanium dioxide pigment, or
metal in titanium industry workers. In addition, methods should be developed that could easily
differentiate between titanium dioxide and titanium dioxide pigments in lung tissue.

No biomarkers of effect of titanium tetrachloride exist. However, after a worker’s accidental exposure to
titanium tetrachloride, a dark pigmentation formed around the scars left by the burns, suggesting that
titanium metal may be a biomarker of exposure (Lawson 1961). Additional study is required to determine
the cause of the dark pigmentation. Further development of methods for determining biomarkers of effect
for titanium tetrachloride would be beneficial to determine whether or not an individual has been exposed
to the compound.

Methods for Determining Parent Compounds and Degradation Products in Environmental Media.
Human exposure to titanium tetrachloride is most likely to result from being splashed with the liquid.
Titanium dioxide, a hydrolysis product of titanium tetrachloride, or titanium metal in workplace air may be
indicative of exposure to titanium tetrachloride, titanium metal, or titanium dioxide. G/FW is the most
common method for determining titanium dioxide in air (NIOSH 1980, 1984), and spectrophotometric
methods are most common for detecting titanium metal in air (Anonymous 1975; NIOSH 1984). The
sensitivity of the gravimetric methods is in the ppm range, and the sensitivity of the spectrophotometric
methods is in the ppb range with good recovery. Both methods can measure background levels in the
environment and levels at which health effects may occur. A colorimetric method to determine the
presence of titanium dioxide in cheese has also been developed (Leone 1973). The reliability and
specificity of many of these methods have not been determined; therefore, methods to improve the
reliability and specificity of titanium dioxide and titanium metal in air would be useful.

No methods for determining titanium tetrachloride or titanium dioxide in water, soil, or sediment were
found.

6.3.2 On-going Studies

No on-going studies regarding analytical methods were located for titanium tetrachloride.

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7. REGULATIONS AND ADVISORIES

International, national, and state regulations and guidelines pertinent to human exposure to titanium
tetrachloride are summarized in Table 7-1.

Titanium effluent limitations are in effect for discharges from the production of titanium at primary and
secondary titanium facilities. The following existing point sources are subject to regulation: chlorination
off-gas wet air pollution control, titanium tetrachloride handling wet air pollution control, reduction area
wet air pollution control, melt cell wet air pollution control, chlorine liquefaction wet air pollution
control, sodium reduction container reconditioning wash water, chip crushing wet air pollution control,
acid leachate and rinse water, sponge crushing and screening wet air pollution control, acid pickle and
wash water, scrap milling wet air pollution control, scrap detergent wash water, casting crucible wash
water, and casting contact cooling water (EPA 1985a).

ATSDR has derived one MRL value for titanium tetrachloride. A chronic inhalation MRL of

0.001 mg/m> was derived for titanium tetrachloride based on its ability to cause irregular breathing and
lung noises in rats, along with rhinitis, tracheitis, and alveolar hyperplasia (Lee et al. 1986).

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60

7. REGULATIONS AND ADVISORIES

TABLE 7-1. Regulations and Guidelines Applicable to Titanium Tetrachloride

 

 

Agency Description Information References
INTERNATIONAL
IARC Cancer classification IARC 1989
Titanium dioxide Group 32
NATIONAL
Regulations:
a. Air:
CAA Clean Air Act and Amendments 1990 listed CAA 1990 (42 USC
as a hazardous air pollutant 7412); CAAA 1990
Titanium tetrachloride Yes (Title III. Section
112 B)
OSHA Limits for air contaminants OSHA 1992 (29 CFR
(titanium dioxide, total dust) 1910.1000)
PEL, TWA (8-hour) 15 mg/m3
b. Water:
EPA Effluent limitation guidelines EPA 1985a (40 CFR
representing the degree of 421.300-421.306)

effluent reduction attainable

by the application of best
practicable control technology,

best available technology
economically achievable, standards
of performance for new sources, and
pretreatment standards for existing
and new sources

Titanium Yes
c. Food:

EPA FIFRA exemptions from tolerances for pesticide EPA 1971 [40 CFR
chemicals in or on raw agricultural 180.1001(d)]
commodities

Titanium dioxide Yes

FDA Titanium dioxide regulations for use in food Yes FDA 1982 (21 CFR
packaging cellophane 177.1200)

FDA Color additive mixtures for food use Yes FDA 1984 (21 CFR
made with titanium dioxide may 73.575)

contain only those diluents that
are suitable and must conform to the
following specifications:

Lead <10 ppm
Arsenic <1 ppm
Antimony <2 ppm
Mercury <1 ppm

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7. REGULATIONS AND ADVISORIES

TABLE 7-1. Regulations and Guidelines Applicable to Titanium Tetrachloride (continued)

 

 

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Agency Description Information References
NATIONAL (cont.)
Loss on ignition at 800°C (after 20.5%
drying for 3 hours at 105°C)
Water-soluble substances 20.3%
Acid-soluble substances 20.5%
Titanium dioxide after drying for <99.0%
3 hours at 105°C
FDA The color additive titanium dioxide Yes FDA 1984 (21 CFR
may be safely used for coloring 73.575)
foods but is subject to the
following restrictions:
Quantity of titanium dioxide <1% by weight of food
FDA Titanium dioxide is exempt from Yes FDA 1977c [176.170
regulation as a food additive in (b) (2)]; FDA
its use as a component in the paper 1989 (21 CFR
and paperboard food packing industry 181.30)
d. Other:
EPA List of extremely hazardous substances EPA 1990c (40 CFR,
Titanium tetrachloride Yes Appendix A, Part
355)
EPA Titanium tetrachloride EPA 1990c (40 CFR,
Reportable quantity 1 pound Appendix A, Part
Threshold planning quantity 100 pounds 355)
EPA Toxic Chemical Release Inventory reporting: EPA 1991 (40 CFR
Community-Right-to-Know 372)
Titanium tetrachloride Yes
FDA Regulations concerning titanium dioxide No FDA 1983 (21 CFR
used as a component in adhesives 175.105)
FDA Federal Food, Drug and Cosmetic Act Yes FDA 1989a [Sections
regulations for titanium dioxide 510(k), 515,
use in contact lens coloring 520(g) of the Act]
Guidelines:
a. Air
ACGIH TLV-TWA, total dust (titanium dioxide) 10 mg/m3 ACGIH 1986
NIOSH REL LOQ (titanium dioxide) cab; 0.2 mg/m NIOSH 1992
62

7. REGULATIONS AND ADVISORIES

TABLE 7-1. Regulations and Guidelines Applicable to Titanium Tetrachloride (continued)

 

 

levels of toxic air pollutants
Titanium dioxide (8-hour)
Acceptable ambient limit

1276x103 gous hous
20.00 mg/m

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Agency Description Information References
NATIONAL (cont.)
b. Other:
DOT Packaging and labelling requirements Yes DOT 1987 (49 CFR
Titanium tetrachloride, anhydrous Corrosive 172.102); DOT 1989
(49 CFR 171.101)
DOT Maximum net quantity in one package DOT 1989 (49 CFR
Passenger aircraft/train 1 quart 172.101)
Cargo plane 10 gallons
DOT Elevated temperature material regulations DOT 1991 (49 CFR
Titanium tetrachloride Yes 173.247)

FDA The color additive titanium dioxide may Yes FDA 1977a (21 CFR
be safely used in drugs, contact lenses 73.2575); FDA
and cosmetic coloring 1977 (21 CFR

73.1575); FDA
1986 (21 CFR
73.3126)

FDA Certification requirements for Yes FDA 1977a (21 CFR
titanium dioxide used as a color 73.2575). FDA
additive in food, drugs, contact 1986 (21 CFR
lenses, and cosmetics 73.3126); FDA

FDA 19776

(21 CFR 73.1575);
FDA 1984 (21 CFR
73.575)

FDA Titanium dioxide labeling regulations Yes FDA 1987 (21 CFR
for food, drugs, contact lenses and 70.25)
cosmetic coloring

STATE
Regulations and
Guidelines:
a. Air:
Average acceptable ambient air concentrations NATICH 1993
Oklahoma 0.00
Texas 30-minute average 1.00x10" ug/m3
Annual 1.00x10! ug/m3
Kentucky Acceptable ambient limits and significant emission NREPC 1986 (401

KAR 63:022)
63

7. REGULATIONS AND ADVISORIES

TABLE 7-1. Regulations and Guidelines Applicable to Titanium Tetrachloride (continued)

 

Agency Description Information References

 

STATE (cont.)

b. Other:
Wisconsin List of toxic pollutants CELDS 1993
Titanium Yes

 

3Not classifiable as to its carcinogenicity in humans
bcancer potential; lung tumors in animals

ACGIH = American Conference of Governmental Industrial Hygienists; Ca = Cancer Potential; CAA = Clean Air Act; DOT =
Department of Transportation; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; FIFRA = Federal
Insecticide, Fungicide, and Rodenticide Act; IARC = International Agency for Research on Cancer; LOQ = Limit of Quantitation;
NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration; PEL =
Permissible Exposure Limit; REL = Recommended Exposure Limit; TLV = Threshold Limit Value; TWA = Time-Weighted Average

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65

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*ACGIH. 1986. Threshold limit values for chemical substances and physical agents in the work
environment with intended changes for 1986. American Conference of Governmental Industrial
Hygienists. Cincinnati, OH.

*Anonymous. 1975. Analytical guide for Ti metal and Ti dioxide. Am Ind Hyg Assoc J 36:707-708.

Anonymous. 1990. Liquefied gaseous fuels spill test facility program: Eleven additional chemicals:
Environmental assessment. Govt Reports Announcements & Index (GRA&I) 15. NTIS/DES0008109.

Anson BJ, Harper DG, Winch TR. 1956. Intra-osseous blood supply of the auditory ossicles in man.
Ann Otolaryngol 73:645-650.

Ashby J, Mohammed R. 1986. Slide preparation and sampling as a major source of variability in the
mouse micronucleus assay. Mutat Res 164:217-235.

*Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments.
Regul Toxicol Pharmacol 8:471-486.

Browning E. 1969. Toxicity of industrial metals. 2nd ed. New York, NY: Appleton-Century-Crofts,
331-335.

*Budavari S, O’Neill MJ, Smith A, et al., eds. 1989. The Merck index. Rathway, NJ: Merck & Co., Inc.
*CAA. 1990. Clean Air Act. United States Code 42 USC 7412.

*CAAA. 1990. Clean Air Act Amendments. Washington, DC: Public Law 101-549, Title III,
Section 112 B.

Casto BC, Meyers J, DiPaulo JA. 1979. Enhancement of viral transformation for evaluation of the
carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res 39:193-198.

*CELDS. 1993. Computer-aided Environmental Legislative Data Systems. University of Illinois, Urbana,
IL. March 9, 1993.

Chakrabarti CL, Katyal M. 1971. Indirect determination of titanium by atomic absorption
spectrophotometry. Anal Chem 43(10):1302-1303.

*Chen JL, Fayerweather WE. 1988. Epidemiologic study of workers exposed to titanium dioxide.
J Occup Med 30(12):937-942.

*Chitkara DK, McNeela BJ. 1992. Titanium tetrachloride burns to the eye. Br J Ophthalmol
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*CHRIS. 1985. Chemical Hazard Response Information System. Hazard assessment handbook.
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*Cited in text

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*Kanematsu N, Hara M, Kada T. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat
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*Lawson JJ. 1961. The toxicity of titanium tetrachloride. J Occup Med 3(1):7-12.

*Lee KP, Trochimowicz HJ, Reinhardt CF. 1985. Pulmonary response of rats exposed to titanium dioxide
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*Lee KP, Kelly DP, Schneider PW, et al. 1986. Inhalation toxicity study on rats exposed to titanium
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*NATICH. 1993. Titanium chloride. National Air Toxics Information Clearinghouse. Data base report
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Institute for Occupational Safety and Health. Publication no. 84-100, Methods 7300 and 8310.

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9. GLOSSARY

Acute Exposure — Exposure to a chemical for a duration of 14 days or less, as specified in the
Toxicological Profiles.

Adsorption Coefficient (K,) — The ratio of the amount of a chemical adsorbed per unit weight of organic
carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd) — The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase)
divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a
fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or
sediment.

Bioconcentration Factor (BCF) — The quotient of the concentration of a chemical in aquatic organisms at
a specific time or during a discrete time period of exposure divided by the concentration in the
surrounding water at the same time or during the same period.

Cancer Effect Level (CEL) — The lowest dose of chemical in a study, or group of studies, that produces
significant increases in the incidence of cancer (or tumors) between the exposed population and its
appropriate control.

Carcinogen — A chemical capable of inducing cancer.
Ceiling Value — A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure — Exposure to a chemical for 365 days or more, as specified in the Toxicological
Profiles.

Developmental Toxicity — The occurrence of adverse effects on the developing organism that may result
from exposure to a chemical prior to conception (either parent), during prenatal development, or
postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point
in the life span of the organism.

Embryotoxicity and Fetotoxicity — Any. toxic effect on the conceptus as a result of prenatal exposure to a
chemical; the distinguishing feature between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and variations, altered growth, and in
utero death.

EPA Health Advisory — An estimate of acceptable drinking water levels for a chemical substance based on
health effects information. A health advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.

Immediately Dangerous to Life or Health (IDLH) — The maximum environmental concentration of a
contaminant from which one could escape within 30 min without any escape-impairing symptoms or
irreversible health effects.

Intermediate Exposure — Exposure to a chemical for a duration of 15-364 days, as specified in the
Toxicological Profiles.

Immunologic Toxicity — The occurrence of adverse effects on the immune system that may result from
exposure to environmental agents such as chemicals.

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74

9. GLOSSARY

In Vitro — Isolated from the living organism and artificially maintained, as in a test tube.
In Vivo — Occurring within the living organism.

Lethal Concentration) (LC;,) — The lowest concentration of a chemical in air which has been
reported to have caused death in humans or animals.

Lethal Concentration sy (LCsy) — A calculated concentration of a chemical in air to which exposure for a
specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose; ,) (LD; ) — The lowest dose of a chemical introduced by a route other than inhalation
that is expected to have caused death in humans or animals.

Lethal Dose sy) (LDsy) — The dose of a chemical which has been calculated to cause death in 50% of a
defined experimental animal population.

Lethal Times, (LTs,) — A calculated period of time within which a specific concentration of a chemical
is expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL) — The lowest dose of chemical in a study, or group of
studies, that produces statistically or biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.

Malformations — Permanent structural changes that may adversely affect survival, development, or
function.

Minimal Risk Level — An estimate of daily human exposure to a dose of a chemical that is likely to be
without an appreciable risk of adverse noncancerous effects over a specified duration of exposure.

Mutagen — A substance that causes mutations. A mutation is a change in the genetic material in a body
cell. Mutations can lead to birth defects, miscarriages, or cancer.

Neurotoxicity — The occurrence of adverse effects on the nervous system following exposure to chemical.

No-Observed-Adverse-Effect Level (NOAEL) — The dose of chemical at which there were no statistically
or biologically significant increases in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this dose, but they are not considered
to be adverse.

Octanol-Water Partition Coefficient (K ,) — The equilibrium ratio of the concentrations of a chemical in
n-octanol and water, in dilute solution.

Permissible Exposure Limit (PEL) — An allowable exposure level in workplace air averaged over an 8-
hour shift.

q;* — The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the
multistage procedure. The q;* can be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually ug/L for water, mg/kg/day for food, and pg/m>
for air).

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9. GLOSSARY

Reference Dose (RfD) — An estimate (with uncertainty spanning perhaps an order of magnitude) of the
daily exposure of the human population to a potential hazard that is likely to be without risk of
deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and
human studies) by a consistent application of uncertainty factors that reflect various types of data used to
estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire
database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer.

Reportable Quantity (RQ) — The quantity of a hazardous substance that is considered reportable under
CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount
established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities
are measured over a 24-hour period.

Reproductive Toxicity — The occurrence of adverse effects on the reproductive system that may result
from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior,
fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of
this system.

Short-Term Exposure Limit (STEL) — The maximum concentration to which workers can be exposed for
up to 15 min continually. No more than four excursions are allowed per day, and there must be at least
60 min between exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity — This term covers a broad range of adverse effects on target organs or
physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen — A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV) — A concentration of a substance to which most workers can be exposed
without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL.

Time-Weighted Average (TWA) — An allowable exposure concentration averaged over a normal 8-hour
workday or 40-hour workweek.

Toxic Dose (TDgy) — A calculated dose of a chemical, introduced by a route other than inhalation, which
is expected to cause a specific toxic effect in 50% of a defined experimental animal population.

Uncertainty Factor (UF) — A factor used in operationally deriving the RfD from experimental data. UFs
are intended to account for (1) the variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating
from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10.

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A-1

APPENDIX A

USER’S GUIDE

Chapter 1
Public Health Statement

This chapter of the profile is a health effects summary written in nontechnical language. Its intended
audience is the general public especially people living in the vicinity of a hazardous waste site or
substance release. If the Public Health Statement were removed from the rest of the document, it
would still communicate to the lay public essential information about the substance.

The major headings in the Public Health Statement are useful to find specific topics of concem. The
topics are written in a question and answer format. The answer to each question includes a sentence
that will direct the reader to chapters in the profile that will provide more information on the given
topic.

Chapter 2
Tables and Figures for Levels of Significant Exposure (LSE)

Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration
of exposure and end point and to illustrate graphically levels of exposure associated with those effects.
All entries in these tables and figures represent studies that provide reliable, quantitative estimates of
No-Observed-Adverse-Effect Levels (NOAELSs), Lowest-Observed-Adverse-Effect Levels (LOAELS)
for Less Serious and Serious health effects, or Cancer Effect Levels (CELSs). In addition, these tables
and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for
noncancer end points, and EPA’s estimated range associated with an upper-bound individual lifetime
cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick
review of the health effects and to locate data for a specific exposure scenario. The LSE tables and
figures should always be used in conjunction with the text.

The legends presented below demonstrate the application of these tables and figures. A representative
example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends
correspond to the numbers in the example table and figure.

LEGEND
See LSE Table 2-1

(1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance
using these tables and figures should be the relevant and appropriate route of exposure. When
sufficient data exist, three LSE tables and two LSE figures are presented in the document. The
three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and
dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation
(LSE Figure 2-1) and oral (LSE Figure 2-2) routes.

(2). Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to
364 days); and chronic (365 days or more) are presented within each route of exposure. In this
example, an inhalation study of intermediate duration exposure is reported.

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3).

CF

(5).
(6).

@.

(8).

9).

(10).

(11).

(12),

A-2

APPENDIX A

Health Effect The major categories of health effects included in LSE tables and figures are
death, systemic, immunological, neurological, developmental, reproductive, and cancer.
NOAELs and LOAELSs can be reported in the tables and figures for all effects but cancer.
Systemic effects are further defined in the "System" column of the LSE table.

Key to Figure Each key number in the LSE table links study information to one or more data
points using the same key number in the corresponding LSE figure. In this example, the study
represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL
(also see the two "18r" data points in Figure 2-1).

Species The test species, whether animal or human, are identified in this column.

Exposure Frequency/Duration The duration of the study and the weekly and daily exposure
regimen are provided in this column. This permits comparison of NOAELs and LOAELSs from
different studies. In this case (key number 18), rats were exposed to [substance x] via
inhalation for 13 weeks, 5 days per week, for 6 hours per day.

System This column further defines the systemic effects. These systems include: respiratory,
cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and
dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not
covered in these systems. In the example of key number 18, one systemic effect (respiratory)
was investigated in this study.

NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which
no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of
3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation
MRL of 0.005 ppm (see footnote "b").

LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used
in the study that caused a harmful health effect. LOAELSs have been classified into "Less
Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at
which adverse health effects first appear and the gradation of effects with increasing dose. A
brief description of the specific end point used to quantify the adverse effect accompanies the
LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia)
occurred at a LOAEL of 10 ppm.

Reference The complete reference citation is given in Chapter 8 of the profile.

CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of
carcinogenesis in experimental or epidemiological studies. CELs are always considered serious
effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report
doses which did not cause a measurable increase in cancer.

Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found
in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to
derive an MRL of 0.005 ppm.

LEGEND

See LSE Figure 2-1

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the
reader quickly compare health effects according to exposure levels for particular exposure duration.

*** DRAFT FOR PUBLIC COMMENT ***
«+» LINJWWNOD 0178Nd HOH 14VHQA wes

 

 

 

 

» TABLE 2-1. Levels of significant Exposure to [Chemical x] - Inhalation

 

 

 

   

 

 

 

 

Exposure LOAEL (effect)
Key to frequency/ NOAEL Less serious Serious
figure* Species duration System (ppm) (ppm) (ppm) Reference
INTERMEDIATE EXPOSURE
Systemic
18 Rat 13 wk Resp 3° 10 (hyperplasia) Nitschke et al.
5d/wk 1981
6hr/d
CHRONIC EXPOSURE
>
Cancer 2
0
38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 Mm
5d/wk organs) Oo
7hr/d x
>
39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982
5d/wk nasal tumors)
6hr/d
40 Mouse 79-103 wk 10 (CEL, lung tumors, NTP 1982
5d/wk hemangiosarcomas)
6hr/d

 

* The number corresponds to entries in Figure 2-1.

» Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10 ppm; dose adjusted for intermittent exposure
and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).

CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest -observed-adverse-effect level; mo = month(s); NOAEL =
no-observed-adverse-effect level; Resp = respiratory; wk = week(s)

ev
«x» LINGJAWWOD 0178Nd HOH 14VHQA ...

SAMPLE

FIGURE 2-1. Levels of Significant Exposure to [Chemical X] - Inhalation

 

 

INTERMEDIATE CHRONIC
(15-364 Days) (> 365 Days)
Systemic Systemic

 

 

 

Vd >
& & 5 2 Fp ef 7

 

 

 

 

 

 

 

 

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Ff <f 2 3* Ff FF Ff < <¢
(ppm)
10,000 =
1,000
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25m ior 38¢ 38r
wo kb O2sm Par @33m Osx (Psem @ Os« Os Osa O3¢r (Parr Pom ®3er
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1
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1
1
oo I 1 10-5 4 Estimated Upper- <=— |
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0.001 Cancer Risk
o x, 10-¢ 1 Levels
0.0001 p=
Key 10-7
r Rat @ LOAEL for serious effects (animals) .
0.00001 Lk m Mouse  LOAEL for less serious effects (animals) 1 Minimal risk level for
h Rabbit O NOAEL (animals) : effects other than cancer
g Guinea pig @ CEL - Cancer Effect Level (animals) ~r
h Monkey
The number next to each point corresponds to entries in Table 2-1.
* Doses represent the lowest dose tested per study that produced a tumorigenic
response and do not imply the existence of a threshold for the cancer end point.

 

 

 

 

 

 

 

V XION3ddVv

vv
A-5

APPENDIX A

(13). Exposure Duration The same exposure periods appear as in the LSE table. In this example,
health effects observed within the intermediate and chronic exposure periods are illustrated.

(14). Health Effect These are the categories of health effects for which reliable quantitative data
exist. The same health effects appear in the LSE table.

(15). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically
displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis.
Inhalation exposure is reported in mg/m’ or ppm and oral exposure is reported in mg/kg/day.

(16). NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate
inhalation exposure MRL is based. As you can see from the LSE figure key, the
open-circle symbol indicates a NOAEL for the test species (rat). The key number 18
corresponds to the entry in the LSE table. The dashed descending arrow indicates the
extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of
0.005 ppm (see footnote "b" in the LSE table).

17). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were
derived. The diamond symbol refers to a CEL for the test species (rat). The number 38
corresponds to the entry in the LSE table.

(18). Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the
upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are
derived from EPA’s Human Health Assessment Group's upper-bound estimates of the slope
of the cancer dose response curve at low dose levels a).

(19). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure.
Chapter 2 (Section 2.4)
Relevance to Public Health
The Relevance to Public Health section provides a health effects summary based on evaluations of
existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to
present interpretive, weight-of-evidence discussions for human health end points by addressing the
following questions.

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around
hazardous waste sites?

The section discusses health effects by end point. Human data are presented first, then animal data.
Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute,
intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous,
subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a
table of genotoxicity information is included.

*** DRAFT FOR PUBLIC COMMENT ***
A-6

APPENDIX A

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using
existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer
potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end
points from which they were derived are indicated and discussed in the appropriate section(s).

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to
public health are identified in the Identification of Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for
route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can
be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral -
acute, -intermediate, - chronic). These MRLs are not meant to support regulatory action, but to
acquaint health professionals with exposure levels at which adverse health effects are not expected to
occur in humans. They should help physicians and public health officials determine the safety of a
community living near a substance emission, given the concentration of a contaminant in air or the
estimated daily dose received via food or water. MRLs are based largely on toxicological studies in
animals and on reports of human occupational exposure.

MRL users should be familiar with the toxicological information on which the number is based.
Section 2.4, "Relevance to Public Health," contains basic information known about the substance.
Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "Populations that are
Unusually Susceptible" provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a
modified version of the risk assessment methodology used by the Environmental Protection Agency
(EPA) (Bames and Dourson 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure.

To derive an MRL, ATSDR generally selects the end point which, in its best judgement, represents the
most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this
judgement or derive an MRL unless information (quantitative or qualitative) is available for all poten-
tial effects (e.g., systemic, neurological, and developmental). In order to compare NOAELSs and
LOAELS for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all
intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted
for continuous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the
chosen end point are available, ATSDR derives an MRL using the most sensitive species (when infor-
mation from multiple species is available) with the highest NOAEL that does not exceed any adverse
effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is
not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor of (1,
3, or 10) is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors
of (1, 3, or 10 ) are used for human variability to protect sensitive subpopulations (people who are
most susceptible to the health effects caused by the substance) and (1, 3, or 10) are used for inter-
species variability (extrapolation from animals to humans). In deriving an MRL, these individual
uncertainty factors are multiplied together. Generally an uncertainty factor of 10 is used; however, the
MRL workgroup reserves the right to use uncertainty factors of (1, 3, or 10) based on scientific
judgement. The product is then divided into the adjusted inhalation concentration or oral dosage
selected from the study. Uncertainty factors used in developing a substance-specific MRL are
provided in the footnotes of the LSE Tables.

*** DRAFT FOR PUBLIC COMMENT ***
TITANIUM TETRACHLORIDE B-1

ACGIH
ADME
atm
ATSDR
BCF
BSC

C

CDC
CEL
CERCLA
CFR
CLP

cm

CNS

d
DHEW
DHHS
DOL
ECG
EEG
EPA
EKG

F

Fy

FAO
FEMA
FIFRA

fpm
ft

APPENDIX B

ACRONYMS, ABBREVIATIONS, AND SYMBOLS

American Conference of Governmental Industrial Hygienists
Absorption, Distribution, Metabolism, and Excretion
atmosphere

Agency for Toxic Substances and Disease Registry
bioconcentration factor

Board of Scientific Counselors

Centigrade

Centers for Disease Control

Cancer Effect Level

Comprehensive Environmental Response, Compensation, and Liability Act
Code of Federal Regulations }
Contract Laboratory Program

centimeter

central nervous system

day

Department of Health, Education, and Welfare
Department of Health and Human Services
Department of Labor

electrocardiogram

electroencephalogram

Environmental Protection Agency

see ECG

Fahrenheit

first filial generation

Food and Agricultural Organization of the United Nations
Federal Emergency Management Agency

Federal Insecticide, Fungicide, and Rodenticide Act
feet per minute

foot

Federal Register

gram

gas chromatography

generation

high-performance liquid chromatography

hour

Immediately Dangerous to Life and Health
International Agency for Research on Cancer
International Labor Organization

inch

adsorption ratio

kilogram

metric ton

organic carbon partition coefficient

octanol-water partition coefficient

liter

liquid chromatography

lethal concentration, low

lethal concentration, 50% Kill

*** DRAFT FOR PUBLIC COMMENT ***
TITANIUM TETRACHLORIDE

LD;
LDs
LOAEL
LSE

m

mg

min

mL

mm
mmHg
mmol
mo
mppcf
MRL
MS
NIEHS
NIOSH
NIOSHTIC
ng

nm
NHANES
nmol
NOAEL
NOES
NOHS
NPL
NRC
NTIS
NTP
OSHA
PEL.

pg
pmol
PHS
PMR
ppb
ppm
ppt
REL
RfD
RTECS
sec
SCE
SIC
SMR
STEL
STORET
TLV
TSCA
TRI
TWA
us.
UF

APPENDIX B

lethal dose, low

lethal dose, 50% kill
lowest-observed-adverse-effect level

Levels of Significant Exposure

meter

milligram

minute

milliliter

millimeter

millimeters of mercury

millimole

month

millions of particles per cubic foot

Minimal Risk Level

mass spectrometry

National Institute of Environmental Health Sciences
National Institute for Occupational Safety and Health
NIOSH’s Computerized Information Retrieval System
nanogram

nanometer

National Health and Nutrition Examination Survey
nanomole

no-observed-adverse-effect level

National Occupational Exposure Survey
National Occupational Hazard Survey

National Priorities List

National Research Council

National Technical Information Service
National Toxicology Program

Occupational Safety and Health Administration
permissible exposure limit

picogram

picomole

Public Health Service

proportionate mortality ratio

parts per billion

parts per million

parts per trillion

recommended exposure limit

Reference Dose

Registry of Toxic Effects of Chemical Substances
second

sister chromatid exchange

Standard Industrial Classification

standard mortality ratio

short term exposure limit

STORAGE and RETRIEVAL

threshold limit value

Toxic Substances Control Act

Toxics Release Inventory

time-weighted average

United States

uncertainty factor

*** DRAFT FOR PUBLIC COMMENT ***

B-2
TITANIUM TETRACHLORIDE

yr
k

£

RXR O®R KAA II V

pum
He

APPENDIX B

year
World Health Organization
week

greater than

greater than or equal to
equal to

less than

less than or equal to
percent

alpha

beta

delta

gamma

micron

microgram

*** DRAFT FOR PUBLIC COMMENT ***
 

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TITANIUM TETRACHLORIDE C-1

APPENDIX C

PEER REVIEW

A peer review panel was assembled for titanium tetrachloride. The panel consisted of the following
members: Dr. Dominic Cataldo, Staff Scientist, Battelle Northwest Laboratories, Richland, Washington;
Mr. Bruce Jacobs, Manager, Environmental Health Engineering, General Physics Corporation, Edgewood,
Maryland; and Mr. Lyman Skory, Skory Consulting, Midland, Michigan. These experts collectively have
knowledge of titanium tetrachloride’s physical and chemical properties, toxicokinetics, key health end
points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of
the Comprehensive Environmental Response, Compensation, and Liability Act, as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer
reviewers’ comments and determined which comments will be included in the profile. A listing of the peer
reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their
exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a
list of unpublished documents cited are also included in the administrative record.

The citation of the peer review panel should not be understood to imply its approval of the profile’s final
content. The responsibility for the content of this profile lies with the ATSDR.

w U.S. GOVERNMENT PRINTING OFFICE:1994-537-974

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