TITANIUM DioxinE

1. ehemical and Physical Data

1.1 Synonyms

Chem. Abstr. Services Reg. No.: 13463-67-7 - Titanium dioxide1317-70- - Anatase titanium dioxide1317-802 - Rutile titanium dioxide

Chem. Abstr. Nam: Titanium dioxideIUP AC Systematic Name: Titanium dioxide

Synonym: CI 77891; E 171; NCI-C04240; Pigment White 6; titania; titanium (IV)oxide

1.2 Molecular formula and molecular weight

Ti02 MoL. wt: 79.90

1.3 Chemical and physical properties of the pure substance

(a) Description: Fine white powder (Windholz, 1983); ciystal structure is tetragonalwith the titanium ion octahedrally bonded to six oxygen ions; position of octahe-dra in the lattice and number of molecules per unit cell differ for anatase and ru-tie forms: anatase titanium dioxide contains four molecules per unit cell, rutilecon tains only two (Schiek, 1982).

(b) Density: Anatase, 3.84 g/cm3; rutile, 4.26 glcm3 (Weast, 1985)

(c) Spectroscopy: X-ray diffraction patterns for anatase and rutile titanium dioxidehave been reported (Roberts et al., 1974).

(d) Refractive index: Anatase, 2.554, 2.493; rutie, 2.616, 2.903 (Weast, 1985)

(e) Solubility: Soluble in sulfuric acid and alkalis; insoluble in water (Weast, 1985)

1.4 Technical products and impurities

Trade names: A-Fil Cream; Atlas white titanium dioxide; Austiox; Bayertitan; Calco-tone White T; Cosmetic White C47-5175; Cosmetic White C47-9623; C-Weiss 7; Flamenco;

-307-

308 IAC MONOGRAHS VOLUME 47

Hombitan; Horse Head A-410; Horse Head A-420; Horse Head R-71O; KR 360; Kronostitanium dioxide; Levnox White RKB; Rayox; Runa RH2O; Rutile; Tichlor; Tiofine; Tiona'fD.; Tioxide; Tipaque; Ti-Pure; Titafrance; Titandioxid; Titanox; Titanox 2010; Trioxide(s);

Tronox; Unitane products (various); 1700 White; ZopaqueThe technical products that incorporate titanium dioxide require a component that is

essentially free from coloured impurities in order to produce the desired whitening and op-acifying effect. International standards have been established for four tyes of titaniumdioxide pigments. Type 1 (minimum, 94% titanium dioxide) is an anatase, freely chalkigpigment used in white interior and exterior hou

se paints, chal kig being the formation of alayer of loose pigment powder on the sudace of weathered paint film (Schurr, 1981). Type II

(minimum, 92% titanium dioxide) is a rutile pigment with medium chalkig resistance usedin vaiying amounts in aU tyes of interior paints, enamels and lacquers. Type III (minimum,80% titanium dioxide) is also a rutile pigment with medium chalking resistance, used prici-paUy in alkyd and emulsion flat wall paints. Type IV (minimum, 80% titanium dioxide) isanother rutile pigment, but with high chalking resistance; it is used in exterior paints and hasexcellent durability and gloss retention (American Society for Testing and Materials, 1988).Typical median particle sizes for anatase and rutie pigments range from 0.2-0.3 J.m (LeS ota,1978; Schurr, 1981).

Aluminium, silicon and zinc oxides may be added to either form of the pigment to en-hance specific properties such as increased dispersibility and ultraviolet light resistance. Ti-tanium dioxide pigments must remain free of extenders such as barium sulfate, clay, magne-sium silcate and calcium carbnate; however, the pigment may be extended by blending withanhydrous calcium sulfate (Lowenheim & Moran, 1975; American Society for Testing andMaterials, 1988).

2. Production, Use, Occurrence and Analysis

2.1 Production and use

(a) Production

Titanium dioxide is the pricipal white pigment used commerciaUy, due to its high re-fractive index, its ease of dispersion into a variety of matrices, and its inertness towardsthosematrices durig processing and throughout product life (Considine, 1974).

Two main processes exist for makig titanium dioxide pigments: the sulfate process and

the chloride process. The sulfate process, the older of the two, was first used in Europe andthe USA around 1930 and was the priaiy process until the early 1950s, when the chlorideprocess was developed. By 1981, the chloride process accunted for approxiately 78% ofUS production and by 1982 for 68% of world titanium dioxide pigment production (Consi-dine, 1974; Lynd & Lefond, 1983).

ln the sulfate process, rutile or anatase titanium dioxide is produced by digesting ilme-nite (iron titanate) or titanium slag with sulfuric acid. The major concern in selecting the

TITANUM DIOXIDE 309

starting material for use in the process is that it contain as little as possible of impurities suchas chromium, vanadium, manganese, niobium and phosphorus, which impair pigment prop-erties. Ilmenite containing as little as 40% titanium dioxide can be used to produce pigment-grade titanium dioxide. Titanium slag may also be used as the starting mate riaL. Slag is pro-duced by smelting ilmenite in an electric furnace and tyically con tains about 70% titaniumdioxide, although concentrations may reach 85% (Considine, 1974; Lowenheim & Moran,1975; Lynd & Lefond, 1983). Some tyical materils used for pigment production through-

out the world are shown in Thble 1.

The sulfate process is a batch process in whieh concentrated sulfuric acid is added toground ilmenite or titanium slag in proportions of 1.5: 1 (acid to ore). An organic floculentor antimony oxide may be added to induce aggregation of suspended titanyl and Iron sulfatesinto a solid porous cake. The cake is dissolved in a dilute acid solution to release the sulfateagglomeration into solution. If necessaiy, scrap iron is added to reduce iron (III) to iron (II).Also durig this step, small amounts of titanium (IV) are reduced to titanium (III) to preventlater oxidation of iron (II). The solution is clariied by settling and filtration. The resultingmother liquor is concentrated and subjected to steam for 6 h. Seed ciystals may be added toaid nucleation. Abut 95% of the titanium in the mother liquor is hydrolysed to titaniumhydrate or metatitanic acid (H2 Ti03), which is collected on a filter and washed. The finalfiter cake is calcined at 90100°C to form titanium dioxide. The product is ground,quenched and dispersed in water; the coarse particles are separated in the thickener, re-ground and filtered; and the cake is dried in a rotaiy steam diyer and pulveried. The result-ing product is anatase titanium dioxide. The rutile form is made by seeding the mother liquorwith rutile seed ciystals and conditioning the precipitated pigment with phosphates, potas-sium, antimony, aluminium or zinc compounds prior to calcination. The recveiy of pig-

ment-grade titanium dioxide in sulfate process plants is approxiately 80% (Lwenheim &Moran, 1975; Lynd & Lefond, 1983; Lynd, 1985).

The chloride process is a continuous procss that requires ores with a high content oftitanium dioxide or concentra tes such as natural or sythetic rutile. Natural rutile contains

approxiately 95% titanium dioxide; sythetic rutile or ilmenite (iron titanate) concentratesmust have a minimum titanium dioxide content of 60% to produce economical yields of pig-ment in this process. The titanium dioxide content in ilmenite may be increased by reducingiron to its elemental form, followed by chemical or physical separation. Another method ofenrichment is reducing iron (III) to iron (II) and chemically leaching it out of the mineraI. Athird method involves prior selective chloriation to remove iron and other impurities (Con-sidine, 1974; Lowenheim & Moran, 1975; Lynd & Lefond, 1983).

ln the chloride process, ore is ground and mixed with coke in a fluidized or static bedreactor and chloriated at temperatures of 850100°C. Titanium tetrachlorideis pro-duced, along with chlorides of impurities present in the starting materil, which include chlo-rides of iron, vanadium and silcon; these are removed chemically and through fractionaldistilation.. Hydrogen chloride and carbn dioxide are present after chloriation and arevented prior to fractional distilation. Conversion to titanium dioxide is accmplished byburning titanium tetrachloride with air or oxygen at temperatures of 1201370°C. The re-sulting fine-grained oxide is sometimes calcied at about 5O°C to remove any residual

V.-CI

Table 1. Composition of typical commercial ilmenite concentrates and titaniferous slagQ (weight percent)

Material USA Australia Norway India Malaysia Canada South Africa(AmangC) (Québec) (Richards

Bay slag)

New York Florida Company A Company B Quilon MKdeposit depoitb

TI02 (total) .46.1 64.00 54.4 55.4 45.0 60.6 54.2 53.1 70-74 85.0 (min)

~TI203 10-15 25.0 (max)Fe203 6.7 28.48 19.0 11.1 12.5 24.2 14.2 8.7 s:FeO 39.3 1.33 19.8 22.5 34.0 9.3 26.6 33.6 12-15 0

ZAl203 1.4 1.23 1.5 0.6 1.0 1.3 4-6 0Si02 1.5 0.28 0.7 1.4 2.8 0.7 3.5-5 0CaO 0.5 0.007 0.04 0.25 1.2 (max) 0.15 (max) ~MgO 1.9 0.20 0.45 5.0 0.9 1.0 4.5-5.5 1.3 (max) ""

::Cr203 0.00 0.2 0.03 -= 0.076 0.12 0.07 0.005 0.25 0.3 (max) v.V20e 0.05 0.12 0.13 0.16 0.15 0.16 0.02 0.5-0.6 0.6 (max) -i0zr02 0.01 0.9 0.8

ES 0.6 -= 0.01 -= 0.05 0.21 0.12 0.03-0.10 s:PzOe 0.008 0.12 0.02 -= 0.04 0.085 0.025 (max) t'MnO 0.5 1.4 0.25 0.4 0.4 4.0 0.2-0.3 2.5 (max) :!H20 (los on ignition) 1.3 0.4 2.0 0.3Rare earths trace 0.12C 0.22 -= 0.055 0.03-0.10

aprom Lynd & Lefond (1983)11K, Manavalakwchi areacAmang, a crude mixure of heavy minerais that must be treated further to recover ilmenite

TITANUM DIOXIDE 311

chlorie or hydrogen chloride. These gases are separated, and the chlorie is collected andrecirculated to the chloriator. Approxiately 90% of the chlorie may be recycled. Alu-minium chloride is added to titanium tetrachloride to assure near-total conversion to rutiletitanium dioxide. A tyical yield from this process is 90% (Lowenheim & Moran, 1975; Lynd& Lefond, 1983; Lynd, 1985).

CUITent worldwide demand for titanium dioxide is about 2.8 million tonnes (Anon.,1988a,b,c). Production volumes in 1978-86 in seve rai countries are given in Thble 2.

Table 2. Titanium dioxide pigment production by country in 1978-86 (thousand tonnes)"

Country 1978 1979 1980 1981 1982 1983 1984 1985 1986

Brazil NA NA 29.9 32.8 30.9 45.3 45.0 NA NA

Czechoslavakia 19.1 18.8 16.6 16.7 20.0 21.0 20.4 NA NA

Finland NA 270.7 355.2 402.1 366.3 420.7 502.2 NA NA

India 9.9 NA NA NA NA NA NA NA NA

Italyb 60.0 59.0

Japan 171.4 185.4 172.8 176.2 184.0 195.9 204.7 217.7 222.9

Korea, Republic of 9.2 5.1 8.0 9.8 11.1 14.4 NA NA NA

Mexico 28.5 35.0 39.1 40.0 37.5 40.5 44.7 NA NA

Spain 53.9 66.1 51.4 66.6 67.5 64.9 70.0 74.7 NA

UK 205.3 192.9 186.7 169.6 172.3 193.9 206.0 219.1 230.0

USA 635.8 673.1 659.4 690.2 598.6 689.3 757.3 780 844.7

USSR 7.1 7.1 6.0 4.7 5.0 5.0 6.4 NA NA

Yugoslavia 19.2 19.6 19.6 21.9 21.4 25.6 21.7 NA NA

tlrom Anon. (1988d,e); NA, not availabIe~ot produced after 1979

(b) Use

The pricipal use of titanium dioxide is as a whitening and opacifing agent in paints,varnishes, lacquers, paper, plastics, ceramics, rubber and priting ink (Ible 3). These indus-tries accunted for 93-95% of the titanium dioxide pigment used in the USA durig 1982-86(Mannsville Chemical Products Corp., 1983; Lynd & Hough, 1986).

Titanium dioxide is the most common white synthetic pigment used in the paint indus-tiy. Modern paint plants often handle titanium dioxide as a sluri for convenience and toavoid airbrne particulates (SchuIT, 1981). ln the paper industiy, both anatase and rutiletitanium dioxides are used to improve opacity. The total amount of pigment varies with thegrade of paper but may comprise 2-40% of the final sheet, of which as much as 25% may betitanium dioxide. The pigment is dispersed during the pulping process and retained in thesheet during formation with organic polymers. The optical efficiency of titanium pigment isimproved by sythetic silcas and silcates (Baum et aL., 1981). Paper is waterproofed by coat-ing the sheets with polyethylene resins whitened with titanium dioxide (Locker, 1982).

312 IAC MONOGRAHS VOLUME 47

Table 3. Percent distribution ortitanium dioxide pigment used within US indus-tries, 1982-86a

Industiy 1982 1983 1984 1985 1986

Paint, vamish, lacquer 48.1 48.9 54.8 54.3 52.6

Paper 27.4 27.3 19.9 20.5 20.7

Plastics 12.7 13.2 15.4 16.2 15.8

Ceramics 1.2 1.0 1.0 0.7 2.2

Rubber 2.6 1.8 2.0 1.7 2.0

Prnting inks 1.0 1.1 1.2 1.0 1.4

Other 7.0 6.7 5.7 5.6 5.3

tlrom Lynd & Hough (1986)

Titanium oxide is incorprated into various plastic products to confer opacity andwhiteness, and also because it resists degradation by ultraviolet light and is chemically inert(Lynd, 1985).

Commercial use of anatase titanium dioxide as an opacifier for ceramic and enamelproducts began in 1946. Rutie pigments may also be used for this purpse (Friedberg, 1980;Lynd, 1985).

Titanium dioxide is also incorprated into rubber tyes to make whitewall tyes (Lynd,1985). ln priting inks, titanium dioxide is mixed with coloured pigments to add opacity orlighten the hue. ln a tyical nitrocellulose ink formulation, titanium pigment is present at 35wt%. An aciylic-based ink formulation contained 30 wt% titanium dioxide (Burachinsky etal., 1981).

Other uses for titanium dioxide are as a catalyst in the production of alcohol fuels(Klass, 1984), as a delusterant in a variety of sythetic fibres at up to 2 wt% (Davis & Hil,1982), as a component of flame-retardant formulations for woo (Wegner et al., 1984), incosmetics as a physical sunscreening agent (Isacoff, 1979), as a component of gums, resinsand waxes used for makig dental impressions (Pfenbarger & Rupp, 1979), and as a pig-ment in floor coverigs, leather products and soaps (Mannsvle Chemical Products Corp.,1983).

(c) Regulatory status and guidelines

Occupational expsure limits for titanium dioxide in 13 countries or regions are pres-ented in Thble 4.

Titanium dioxide may be used as a foo colour additive with the followig specifications

limiting impurities: antimony compounds, -: 100 mg/kg; zinc compounds, -: 50 mg/kg; solu-ble barium compounds, -: 5 mg/kg; and hydrochloric acid-soluble compounds, -: 3.4 g/kg(Commission of the European Communities, 1962).

TITANUM DIOXIDE

Table 4. Occupational exposure limits for titanium dioxide"

Country or region Year Concentrationb InterpretationC(mg/m3)

8 1WA6 1WA

10 1WA5 1WA

10 STEL6d 1WA

10 1WA10 1WA6 1WA

S 10 1WA

10 1WA5 1WA

15 1WAiot 1WA10 1WA20 Ceiling

AustriaDenmarkFinlandGennan Democratie Republic

1985198819871985

Gennany, Federal Republic ofNetherlandsNorwaySwitzrlandThiwanUK

Thtal inhalable dustRespirable dust

USAeOSHAACGIH

USSRVenezuela

198819861981198519851987

1985198819861985

aprom Direktoratet for Areidstilsynet (1981); Arbeidsinspectie (1986); Institut National de Re-cherche et de Sécurité (1986); Cook (1987); Health and Safety Executive (1987); 1Yõsuojeluhall-tus (1987); American Conference of Govemmental Industrial Hygienists (1988); Arejdstiisyet

(1988); Deutsche Forshungsgemeinschaft (1988)hS, skin notationcrA, 8-h time-weighted average; STEL, short-tenn exposure limit

dJotal dust containing no asbestos and -: 1 % free silicaeoSHA, Occupational Safety and Health Administration; ACGIH, American Conference of Gov-emmental Industrial Hygienists-Measured as fine dust

2.2 Occurrence

313

(a) Natural occurrence

Titaniurndioxide ocurs naturally in three ciystalline forms: anatase, rutile and brook-ite. Only anatase and rutie are of commercial importance. Rutile can be mined directly, butanatase is obtained through the processing of ilmenite, a natural iron titanate (Lynd, 1985).

Rutile is a widespread accessoiy minerai found in high-grade metamorphic gneiss esand schists anò in igneous rocks. It also ocurs in black sand deposits in many parts of theworld. Typically, the composition of rutile is 95% titanium dioxide, the remaining 5% beingsilcon, chromium, vanadium, aluminium and iron oxides (Lynd & Lefond, 1983).

Ilmenite is a common accessoiy grain in igneous rocks such as anorthosites, gabbrosand basic lavas; it may also ocur as an intergrowth in magnetite and haematite. Weatherig

314 IARC MONOGRAPHS VOLUME 47

and alterations along grain boundaries result in the removal of iron from the ilmenite lattiee,producing leucoxene or pseudorutie. Ilmenite is also found in sand deposits (Lynd & Le-fond, 1983).

The pricipal producing cou nt ries for rutie and ilmenite are Australia, Brazil, Canada,China, Finland, India, Malaysia, Mexico, Norway, Sierra Leone, South Africa, Sri Lanka andthe USA (Lynd & Lefond, 1983).

(b) Occupational expsure

On the basis of a US National Occupational Expsure Survey, the National Institutefor Occupational Safety and Health (1983) estimated that 127000 workers were potentiallyexposed to titanium dioxide in the USA in 1981-83.

Although it is apparent that ocupational expsure to titanium dioxide is extensive,there are few data on levels and sources of expsure (Santodonato et al., 1985), and the dataavailable in the literature are reported as total dust or nuisance dust and not as titaniumdioxide. Concentrations ranged from 10 to 40 mg/m3 during the griding of titaium diox-

ide pigment, but documentation of these levels was not provided (Elo et al., 1972). Long-term exposures to titanium dioxide dust in a titanium pigment production factoiy ocsional-ly exceeded 10 mg/m3, and exposures greater than 10 mg/m3 were common during the repairof production machineiy (Rode et al., 1981).

2.3 Analysis

No inormation was available to the Working Group on methods for the quantitativedetermination of titanium dioxide in envionmental samples. Occupational expsures to ti-tanium dioxide have been estimated gravietrically as total or respirable dust (Lee et al.,1986).

3. Biological Data Relevant to the Evaluation of

earcinogenic Risk to Humans

3.1 Carcinogenicity studies in animais

(a) Oral administration

Mouse: Groups of 50 male and 50 female B6C3F1 mice, five weeks old, were fed dietscontaining 0, 2.5% or 5.0% titanium dioxide (anatase; purity, ::98%) daily for 103 weeks.Mice were kiled at 109 weeks of age, one week after expsure was stopped. At terminalsacriice, there was no significant difference in survval between treated and control males:32, 40 and 40 control s, low-dose and high-dose males were stil alive at that time. ln femalemice, a dose-related trend for decreased survival was significant in treated groups (p =0.001, Throne test); survval at terminal sacriice was 45, 39 and 33 among control, low-doseand high-dose females, respectively. No difference in boy weights between treated and

TITANUM DIOXIDE 315

control groups and no significant increase in the incidence of tumours was observed intreated mice of either sex (National Cancer Institute, 1979).

Rat: Groups of 50 male and 50 female Fischer 344 rats, nine weeks old, were fed dietscontaining 0, 2.5% or 5.0% titanium dioxide (anatase; purity, ~98%) daily for 103 weeks.Rats were kiled at 113 weeks of age, one week after expsure was stopped. There was nosignificant difference in survval between treated and control groups of either sex; survivalofmales at terminal sacriice was 31,37 and 36 among control, low-dose and high-dose groups,respectively, and that of females was 36, 36 and 34 in control, low-dose and high-dosegroups, respectively. No difference in boy weights between treated and control groups andno significant increase in the incidence of tumours was observed in treated mice of either sex(National Cancer Institute, 1979).

(b) Inhlation/intratracheal administration

Rat: Groups of 50 male and 50 female Sprague-Dawley rats, eight weeks of age, wereexpsed by inhalation to 0 or 15.95 mg/m3 titanium dioxide (purity unspecified) for 6 h perdayon five days per week for 12 weeks. After 140 weeks (128 weeks after the end of exp-

sure), all survvig rats were sacriiced. Average survval was 116 and 113 weeks for controland treated males and 114 and 120 weeks for control and treated females, respectively. Atterminal sacriice, 39 control males, 44 treated males, 45 control females and 45 treated fe-

males were stil alive. No difference in boy weights between treated and control groups andno significant increase in the incidence of tumours was observed in treated mice of either sex(Tyssen et al., 1978). (Te Workig Group noted the short duration of expsure and therelatively low expsure leveL.)

Groups of 100 male and 100 female CD rats, five weeks of age, were expsed by inhala-tion to 0, 10,,50 or 250 mg/m3 titanium dioxide (rutile; 99% pure; 84% of dust particles ofrespirable size) for 6 h per day on five days per week for two years. At three, six and 12months, five, five and ten rats of each sex at each dose, respectively, were removed for inter-im kils. No difference in mortlity, boy weight or clinical signs was observed. Nasal cavities

were examined histologically, and no tumour was observed. Lung tumours were observedpriariy in high-dose rats of each sex. The inçidences of lung adenomas were: males - con-

trol, 2/79; low-dose, 1/71; mid-dose, 1/75; and high-dose, 12/77; females - control, 0/77; low-dose, 0/75; mid-dose, 0/74; and high-dose, 13/74. The incidences of cystic keratinizing squa-mous-cell carcinomas were: males - 0/79, 0/71, 0/75 and 1/77; females - 0/77, 1/75, 0/74 and13/74. One anaplastic carcioma ocurred in a low-dose male. The lung tumours ocurredin the bronchioloalveolar region, and no evidence of metastasis was observed. The authorsnoted difficulty in distinguishing between the squamous-cell carcinomas and keratinizingsquamous metaplasia (Lee et al., 1985a,b, 1986).

Hamer: Groups of 24 male and 24 female Syrn golden hamsters, six to seven weeksold, receivedintratracheal administrations of 0 or 3 mg titanium dioxide ((purity unspeciied)particle size, 97% c: 5 J.m) in 0.2 ml saline once a week for 15 weeks. AnimaIs were observeduntil spntaneous death and all control and treated hamsters died by 120 and 80 weeks, re-

spectively, after the beginning of treatment. Therespirtoiy tract and other organs withgross Iesions were examined microscpically; no respirtoiy tract tumour ocrred in treated

316 IAC MONOGRAHS VOLUME 47

hamsters, but two tracheal papilomas were found in untreated con trois (Stenbäck et aL.,1976).

(c) Subcutaneous injection

Rat: Groups of 20 male and 20 female Sprague-Dawley rats, 13 weeks old, received asingle subcutaneous injection of 1 ml saline or 30 mg of one of three preparations of titanium

dioxide (~99%, ~95% or ~85% pure) in 1 ml saline into the fIank. Ali rats were observedunti spontaneous death, which ocurred as late as 136, 126, 146 and 133 weeks in the controland titanium dioxide-treated groups, respectively. No tumour was observed at the site of theinjection in any group (Maltoni et al., 1982). (The Workig Group noted the inadequate re-porting of the study.)

(d) Intraperitoneal injection

Mouse: Groups of 30 or 32 male Marsh-Buffalo miee, five to six months old, received asingle intraperitoneal injection of 0 or 25 mg titanium dioxide (purity, ~98%; manuallyground) in 0.25 ml saline. Ail survvors (ten control and 13 treated mice) were kiled 18months after treatment. No difference in the incidence of locl or distant tumours was ob-served between treated and control animais (Bischoff & Biyson, 1982). (The WorkigGroup noted the small number of animais used.)

Rat: As part of a large study on various dusts, three groups of female Wistar rats, nine,four and five weeks of age, received intraperitoneal injections of granular titanium dioxide(purity unspecified) in 2 ml 0.9% soium chloride solution. The first group received a totaldose of 90 mg per animal by five weekly injections; the second group received a single injec-tion of 5 mg per animal; and the third group received three weekly injections of 2, 4 and 4 mgper animaL. One concurrent group of 32 five-weék-old Wistar rats received a single injec-tion of saline atone. Average lifespans were 120, 102, 130 and 120 weeks. No intra-abdomi-nal tumour was reported in 47 and 32 rats from the second and third groups that were ex-amined; six of 113 rats examined from the firt group had sarcomas, mesotheliomas or carci-nomas of the abdominal cavity (numbers unspeciied). Two controls had abdominal tumours.ln a similar experient with female Sprague-Dawley rats given single intraperitoneal injec-tions of 5 mg per animal titanium dioxide, 2/52 rats developed abdominal tumours (averagelifespan, 99 weeks). Controls were not available for comparin (Pott et al., 1987).

(e) Administration with known carcinogens

Hamer: Groups of 24 male and 24 female Syrn golden hamsters, six to seven weeksold, received intratracheal administrations of 3 mg titanium dioxide ((purity unspecified)particle size, 97% ,5 J.) plus benzol a )pyrene in 0.2 ml saline, or benw( a )pyrene in saline

(controls) once a week for 15 weeks. Aniials were observed until spntaneous death; aUcontrol and treated hamsters had died by 100 and 70 weeks, respectively. ln the 48 hamsters(number of tumours per sex unspecified) treated with titanium dioxide plus benzol a )pyrene,tumours ocurred in the lary (11 papilomas, five squamous-cU carciomas), trachea

(three papilomas, 14 squamous-cll carcinomas, one adenocrcioma) and lung (one ade-noma, one adenocrcioma, 15 squamous-cll carcinomas, one anaplastic carcinoma). Twopapilomas ocurred in the lary of benw( a )pyrene-treated controls. ln the same study,

TITANUM DIOXIDE 317

ferrc oxide and benzo(alpyrene induced a similar spectrum of tumours as that induced by

the combination with titanium dioxide; aluminium oxide and benzo(alpyrene produced noincrease in tumour incidence compared with benzo( a lpyrene-treated con trois (Stenbäck etal., 1976).

3.2 Other relevant data

(a) Exprimental systems

The toxicology of titanium dioxide has been reviewed (World Health Organization,1982).

(i) Absorption, distribution, exretion and metabolismThe pattern of deposition of titanium dioxide (anatase) dust in the lungs of rats was

similar to that seen with other particles (Feri et al., 1983). After rats were expsed to 16.5mg/m3 anatase and 19.3 mg/m3 rutile aerosols (mass median aerodynamie diameters, about 1Jlm) for 7 h, the half-lives of pulmonaiy clearance were 51 and 53 days, respectively (Feri &Oberdörster, 1985). Pulmonaiy clearance of titanium dioxide was significantly decreasedafter long-term exposure to 1 ppm (2.6 mg/m3) sulfur dioxide (Feri & Leach, 1973).

Followig intratracheal instilation of titanium dioxide to miee and rapid partial remov-al of partic1es by ciliaiy clearance within the first 15 min, subsequent pulmonaiy clearancehad a half-life of about 20 days; the slow phase was assumed to be due to uptake of the par-ticles and removal by macrophages (Finch et al., 1987).

After exposure of rats by inhalation to 10,50 and 250 mg/m3 titanium dioxide (rutile;mass median aerodynamic diameter, 1.5- 1. 7 Jlm) for 6 h per day on five days per week for twoyears, inhaled particles were found to be engulfed by macrophages, and dense accumulationof dust-Iaden macrophages was seen in perivascular and peribronchial lymphoid tissue.Massive accumulation of these dust-containing cells was also seen in tracheobronchiallymph nodes and, to a lesser extent, in cervicallymph nodes. The ocurrence of dust par-ticles in mesenteric lymph nodes, in the liver and in the spleen suggests that small amountscou Id have entered the general circulation from the lungs (Lee et al., 1985a). Also after in-travenous injection to rats, titanium dioxide particles were found to accumulate in abdomi-nallymph nodes (coeliac nodes) which drain the liver (Huggins & Froehlich, 196). Pulmo-naiy accumulation increased considerably in rats expsed by inhalation to 250 mg/m3 as com-pared to 10 and 50 mg/m3, indicating that pulmonaiy clearance mechanisms can be over-loaded at the highest dose (Lee et al., 1986).

(ii) Toxic effects

Titanium dioxide pigments (anatase and others) caused significant mobiliztion of peri-toneal macrophages when injected into the peritoneal cavity of mice (Nuuja et al., 1982).They decreased the level of acid phosphatase in mouse peritoneal macrophages in vitro; sili-ca-cated particles were the most effective (Nuuja & Arstila, 1982). ln both studies, tita-nium Qioxide had minimal cytotoxicity in comparison to quartz and asbestos. ln vivo, titaniumdioxide (anatase and rutie) failed to induce proline hydroxylase in the lungs of rats fourweeks after they had been exposed by inhalation (Zitting & Skyttä, 1979).

318 IAC MONOGRAHS VOLUME 47

Anatase, rutile and rutile containing trace amounts of nickel or chromium had no fi-brotic potential in either an in-vitro test for cell vibilty using bovie alveolar macrophagesor followig instilation into rat lungs in vivo; a-quartz gave positive results in both assays

(Richards et al., 1985). Similarly, injection of an untreated anatase form of titanium dioxide(particle size, 0.8-16 J.m) into the pleura of rats caused no pleural effusion and only a fewstrands of connective tissue surrounding the collections of macrophages (Grasso et al., 1983).Additional studies in vivo have all failed to demonstrate any fibrotic potential in rats or rab-bits (Grandjean et al., 1956; Chritie et al., 1963; Dale, 1973; Sethi et al., 1973; Feri &Oberdörster, 1985); however, one study showed that intratracheal instilations of 3 mg tita-nium dioxide to hamsters once a week for 15 weeks resulted in slight pulmonaiy inamma-tion and, subsequently, interstitial fibrosis (Stenbäck et al., 1976). Infammatoiy changes andformation of collagen fibres were also seen after intratracheal instilation into rats of ilme-nite (iron titanate) or titanium dioxide dusts (Shevtsova, 1968).

Followig overloading of lung clearance in rats expsed to 250 mg/m3 rutile for 6 h perday on five days per week for two years, there was massive accumulation of dust-Iaden ma-crophages; free particles and cellular debri were found in the alveoli, and alveolar proteino-sis and cholesterol granulomas developed. Lung weights increased, and white patches ofaccumulated dusts were seen in the lungs at autopsy (Lee et al., 1985b, 1986).

(ii) Effects on reproduction an prenatal toxicityNo data were available to the Workig Group.

(iv) Genetic an related effectsTitanium dioxide did not induce differential kiling in DNA repair-proficient com-

pared to repair-deficient strains of Bacillus subtils rec+/- (details not givenJ (Kda et al.,1980).

Titanium dioxide was not mutagenic to Salmonella typhimurium TA1535, TA1537,

TA1538, TA97, TA98 or TA100 (Dunkel et al., 1985; Zeiger et al., 1988) or to Escherichia coliWP2, either in the presence or absence of an exogenous metabolic system from the livers ofuninduced and Aroclor-induced rats, mice and Syran hamsters (Dunkel et al., 1985).

It did not induce morphological transformation in Syran hamster embiyo cells (Di Pao-lo & Casto, 1979) and did not enhance transformation of Syrn hamster embiyo cells by theSA7 adenovis (Casto et al., 1979).

(b) Human

(i) Absorption, distribution, exretion an metabolismPulmonaiy retention of titanium dioxide dusts has been documented in several studies.

The lungs usually contain higher levels of titanium than any other organ analysed (Schroederet aL., 1963). ln lung tissue obtained from one autopsy and two thoracotomies performed onworkmen employed in a factoiy that processed titanium dioxide, titanium dioxide was foundin lysosomes of alveolar macrophages and in lymphatic macrophages (BIo et al., 1972). Dust-laden macrophages were seen in sputum samples from current titanium dioxide workers andfrom retired workers who had left the factoiy three years earlier; in lung biopsies from re-tired workers, macrophages were loaded with titanium dioxide and with silcon, which possi-

TITANUM DIOXIDE319

bly originated from the titanium dioxide coating (Määttä & Arstila, 1975). Massive deposi-tion of rutile was also reported at autopsy in the lungs of a man who had been employed at atitanium dioxide production plant until fouryears before his death (Rode et al., 1981). Tita-nium dioxide deposition has also been reported in regionallymph nodes (Schmitz-Moor-mann et al., 196; Yamadori et al., 1986).

The pattern of regional deposition of titanium dioxide in the lungs and the relative con-tents in lymph nodes suggest that titanium dioxide is removed relatively slowly via the lym-phatic system. The lungs of 35 miners contained an average of 71 mg titanium dioxide, but atotal of only 4 mg was found in the regionallymph nodes (Einbrodt & Liffers, 1968).

(ü) Toxic effects

At an ilmenite (iron titanate) extraction plant, where workers were also expsed to ru-tie, chest X-rays (70 mm) were abnormal in 3/136 workers, of whom 24 had had more thanten years' expsure. The prevalence was similar to that (4/170) seen in a control group (Ura-goda & Pito, 1972). (Te Workig Group noted that the X-ray technique used would havedetected only cases with severe pneumocniosis.)

A man who was employed to pack titanium dioxide into cans developed pneumocnio-sis after nine years of expsure; lung tissue examined five years later revealed slight fibrosisof interstitial tissue surrounding bronchioles and alveolar spaces (Yamadori et al., 1986). ln astudy of lung tissue obtained from an autopsy and from two thoracotomies pedormed ontitanium dioxide workers, deposits of titanium dioxide in interstitiallung tissue were also

assoiated with cell destruction and slight fibrosis (Elo et al., 1972). Määttä and Arstia (1975)suggested that the fibrogenic effect might be due to the presence of silcon compounds asso-ciated with the titanium dioxide dust. Another worker in titanium pigment production, how-ever, had massive deposition of rutile in the lungs but no inammation or fibrosis (Rode etal., 1981). The absence offibrotic changes has also been reported in a case after 15 years ofexpsure at a titanium dioxide mil (Schmitz-Moormann et al., 196).

As reported in an abstract, in a cross-sectional study of 207 workers producing titaniumdioxide from ilmenite ore, the predominant signs were obstructive airay changes. ln 26workers, chest X-rays showed iregular or nodular opacities of limited extent; eight of theseworkers were known also to have been expsed to silca or asbestos (Daum et al., 1977). (TeWorkig Oroup noted that when titanium dioxide is produced from ilmenite ore the driedore is digested by sulfuric acid, causing expsure to both sulfuric acid mist and titanium diox-ide dust. The possible role of titanium dioxide could not be assessed.)

ln a cross-sectional study of 20 titanium metal production workers, including 78 work-ers involved in the reduction process who were expsed to titanium tetrachloride vapour,titanium oxychloride and titanium dioxide particles, reductions in lung function (forced expi-ratoiy volume in one minute) were found. The authors noted that this finding could be dueto expsure to titanium tetrachloride, which reacts violently with water to liberate heat andproduce hydrochloric acid, titanium oxychloride and titanium dioxide. Pleural disease withplaques and pleural thickening was observed in 36 of the 20 workers, including eight of the

78 reduction process workers. Sorne cases were probably caused by prior expsure to asbes-

tos; however, among workers not known to have been expsed to asbestos, the risk for pleu-

320 !AC MONOGRAHS VOLUME 47

rai disease after more than ten years of employment was 3.8 times' the rik in those who hadbeen employed for fewer than five years. The authors noted that past expsure to asbestos atthe titanium production facilty may have contributed to the rik (Garabrant et al., 1987).

A chest X -ray study of 336 workers at two titanium dioxide-producing plants showed 19cases of pleural abnormalities (thiekening/plaques), as compared to 3/62 among unexpsedworkers at thesame plants. The odds ratio for chest X-ray abnormality assoiated with tita-nium dioxide expsure was 1.4. No lung fibrosis was observed. Expsures at the plants in-c1uded titanium tetrachloride, potassium titanate and asbestos (Chen & Fayerweather,1988).

A case of granulomatous lung disease was reported in a worker with possible expsureto titanium dioxide at an aluminium smelting plant where he worked near a firebrick fur-nace. A lymphoce transformation test showed proliferative response to titanium chloridebut not to any other metal tested, suggesting a possible link with titanium hypersensitivity(Redline et aL., 1986).

(ii) Effects on fertility and on pregnany outcomeNo data were available to the Workig Group.

(iv) Genetic and related effectsNo data were available to the Workig Group.

3.3 Case reports and epidemiological studies of carcinogenicity to humans

Titanium dioxide was foundin the lungs of three patients who died of cancers at varioussites (Schmitz-Moormann et al., 196; Ophus et al., 1979; Rode et al., 1981; Yamadori et al.,1986), one of which was a papilaiy adenocrcinoma in the right lung. The latter had been

engaged in packig titanium dioxide for about 13 years prior to his death at the age of 53 andhad smoked about 17 cigarettes per day for 40 years; he had been diagnosed at the age of 48 ashavig pneumocniosis.

Chen and Fayerweather (1988) studied mortality and cancer incidence among 1576male employees who had been expsed to titanium dioxide for more than one year in twoplants in the USA. Information on cancer incidence was obtained from the company cancerregistiy, which was started in 1956. Information on deaths among active and pensioned em-ployees was obtained from the company mortlity registry, which was started in 1957: vitalstatus was determined for about 94% of the cohort, and death certificat es were av~ilabie forabout 94% of those known to be deceased. Observed numbers of incident cancer cases werecompared with expected numbers based on company rates, and the observed numbers ofdeaths were compared with both company and US rates. Mortlity from all cancers was low-er than expected. For lung cancer, nine deaths were observed, with 17.3 expected on the

basis of national rates (stanctrdized mortlity ratio (SMR), 52; (95% confidence interval,24-99D and 15.3 expected on the basis of company rates (59; (27-112D. There was a slight

. excess of incident cancer cases, 38 versus 32.6 (117; (83-160D, due mainly to ten cases of tu-mours of the genitouriaiy system ver sus 6.3 expected (159; (76-292)); there were eight casesof lung cancer with 7.7 expected (104; (45-205D. (Te Workig Group noted that details of

TITANUM DIOXIDE 321

expsure to titanium dioxide and other factors were not described, that cancer mortality andspecific cancer sites were not reported in detail, that incident cancer cases only in activelyemployed persons were used for both observed and company reference rates, and that thenumbers of incident cases were compared only with company rates.)

4. Summary of Data Reported and Evaluation

4.1 Exposures

Titanium dioxide is a white pigment produced mainly from ilmenite (iron titanate) andnatural rutile (titanium dioxide). It is widely used in paints, paper, plasties, ceramics, rubber,inks and a variety of other products. Occupational expsure to titanium dioxide durig itsproduction, the production of paints, in painting trades and durig other industrial use islikely to be extensive, but there is a paucity of data on levels, both ocupational and envion-mental.

4.2 Experimental carcinogenicity data

Titanium dioxide was tested for carcinogenicity by oral administration in one strain ofmice and in one strain of rats, by inhalation in two strains of rats, by intratracheal administra-tion in one strain of hamsters, by subcutaneous injection in one strain of rats and by intraperi-toneal administration in one strain of male mice and two strains of female rats. Increasedincidences of lung adenomas in rats of both sexes and of cystic keratinizing lesions diagnosedas squamous-cell carcinomas in female rats were observed in animais that had inhaled thehigh but not the low doses of titanium dioxide. Oral, subcutaneous, intratracheal and intra-

peritoneal administration did not produce a significant increase in the frequency of any tyeof tumour in any species. Intratracheal administration of titanium dioxide in combinationwith benw(a)pyrene to hamsters resulted in an increase in the incidence ofbenign and ma-lignant tumours of the lary, trachea and lungs over that in benzo(a)pyrene-treated con-

trois.

4.3 Human carcinogenicity data

The only available epidemiological study provided inconclusive results.

4.4 Other relevant data

Titanium dioxide did not induce morphological transformationin mammalin cells ormutation in bacteri. (See Appendix 1.)

322 IAC MONOGRAHS VOLUME 47

4.5 Evaluation 1

There is inadequate evidence for the carcinogenicity of titanium dioxide in humans.There is limited evidence for the carciogenicity of titanium dioxide in experiental ani-

mais.

Overall evaluatioD

Titanium dioxide is not classifiable as 10 its carcinogenicity to huma (Group 3).

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