(e) Spectroscopy data: Infrared, ultraviolet and nuclear magnetie resonance spectral
data have been reported (Sadtler Research Laboratories, 1980; Pouchert, 1981,
1983, 1985).
if Solubility: Soluble in ethanol, benzene, diethyl ether, acetone, chloroform, gla-
cial acetic acid and carbn disulfide; insoluble in water (Hawley, 1981;
Sandmeyer, 1981; Windholz, 1983; Weast, 1985)
(g) Volatility: Vapour pressure: 28.4 mm Hg at 25°C (Eller, 1984)
(h) Flash-point: 4.4°C (Sandmeyer, 1981)
(i) Reactivity: Quite stable in air (Clement Associates, 1977). Reacts photochemical-ly with nitrogen oxides or halogens to form nitrotoluene, nitrobenzene and nitro-
-79-
80 IAC MONOGRAHS VOLUME 47
phenol and halogenated products, respectively (Merian & Zander, 1982; US En-vironmental Protection Agency, 1983)
Trade Names: Antisal la; CP 25; MethacideToluene Is marketed pricipally as nitration and industrial grades, its purity being de-
pendent on the specific gravity and boiling range of the product (Hoff, 1983). Reagent-gradetoluene is available with a purity of greater than 99% (Aldrich Chemical Co., 1988). Techni-cal grades (901200 C boiling range) are less pure and may con tain up to 25% benzene as wellas other hydrocrbons (Clement Associates, 1977; Fishbein, 1985).
2. Production, Use, Occurrence and Analysis
2.1 Production and use
(a) Production
Toluene is produced durig petroleum refining operations, directly as a by-product ofstyrene manufacture and indirectly as a by-product of coke-oven operations.
It is produced from petroleum as an aromatic mixure with benzene and xylene priari-Iy by catalytic reforming and pyrolytic crackig. Catalytic reforming processes accunt forabout 87% of the total amount of toluene produced in the USA This process involves dehy-drogenation of selected petroleum fractions containing abundant naphthenic hydrocrbnsto yield a mixure of aromaties and paraffins. Reforming processes are used to produce abenzene-toluene-xylene reformate from which the individual aromatics are recovered bydistillation, washing with nitric acid and redistilation. Onlya small fraction of the reformateis used for isolation of the toluene; the bulk of the unseparated toluene in the reformate isused for gasoline blending.
The second largest source of toluene is from pyrolysis gasoline, formed as a by-productdurig pyrolytic crackig (steam crackig) of heavier hydrocrbns for the manufacture ofolefins. Toluene is isolated from pyrolysis gasoline by distilation, removal of olefins and di-olefins and redistilation.
lCacuIated from: mglm3 = (molecIa weihU24.45) x ppm, asumi standard temprature (25'C) an presre (760 mm Hg)
TOLUENE 81
Toluene is also obtained as a by-product durig styene manufacture when ethylben-zene is dehydrogenated. The toluene isolated from the by-product is used for gasolineblending or as feed for benzene manufacture by the hydrodealkylation process. The produc-tion of toluene from coke-oven operations is minimal (Hoff, 1983).
The amounts of isolated toluene (and of total toluene) produced in these different waysin the USA in 1978 were as follows: from catalytic reformate, 3.6 (29.5) milion tonnes; frompyrolysis gasoline, 376.8 (708) thousand tonnes; as a styene by-product, 99.8 (145) thousandtonnes; and denved from coal, 65.8 (79.5) thousand tonnes. These quantities represent atotal of 4.2 (30) milion tonnes (Fishbein, 1985).
Western Europe and Japan are also major producers of this compound. ln 1980, over85% of the toluene produced in the world was accunted for by the USA, western Europeand Japan. ln Japan and western Europe, toluene is produced mainly from pyrolysis gaso-line. ln all three areas, coke-oven light oil provided less than 10% of the toluene supply in1980 (Fishbein, 1985).
Data on the production of toluene in the major producing countries are presented inThble 1. World production of toluene in 1980 was estimated at more than 5 million tonnes -
approxiately one-third of the amount of benzene produced. However, an additional 30
million tonnes of toluene are consumed annuallyas a constituent of motor fuel (Merian &Zander, 1982).
Table 1. Annual production data for tolueneB (thousands of tonnes)
Country 1983 1984 1985 1986 1987
Canada 411 395 472 393 396
France 41 39 40 38 33
Germany, Federal Republic of 314 371 391 478 4021 taly 299 313 348 233 178
Japan 831 784 803 805 882
Mexico 223 216 220 238 313
USA 2560b 2390b 2300b 2640 3050
aprom US International 1fade Commission (1984,1985, 1986); Anon. (1987a, 1988)bpetroleum-derived, not including tar distilation and coke-oven derived toluene
(b) UseThe largest single use of islated toluene is in the production ofbenzene via the hydro-
demethylation process, in which toluene and hydrogen (a reformate by-procuct) are reactedunder high temperature and pressure to yield benzene and methane (Hoff, 1983). This pro-cess has been used to balance the supply and demand for benzene (Mannsvle ChemicalProducts Corp., 1981).
The second largest use of toluene is in solvent applications, especilly in the paint andcoating industiy. Significant amounts are also used in inks, adhesives, the leather industiy(lARC, 1981), pharmaceuticals and other formulated products. Solvents accunted for 40%
82 !AC MONOGRAHS VOLUME 47
or more of the nonfuel use of toluene in Japan and western Europe in 1980. ln the USA in1981, the use of toluene as a solvent was secnd only to its use in benzene production viahydrodemethylation and accunted for about 26% of nonfuel consumption (Fishbein, 1985).
lsolated toluene is also used directly in several consumer products, such as sanitizingagents, household aerosols, paints and varnishes, paint thinners and antirst preservatives
(Fishbein, 1985).
Most of the toluene in the benzene-toluene-xylene mixures, which is never islatedand remains in various refinery streams, is used in gasoline blending. Toluene has severaladvantages as a blending agent in gasoline: a high octane number and low volatilty, and itblends easily with other inexpensive materials such as n-butane, which is highly volatile(Hoff, 1983). It is anticipated that the use of toluene in unleaded gasolie wil continue toincrease. ln 1985, 73-75% of the gasoline used in the USA was unleaded. By 199, this per-centage is expected to rie to 95-100% (Mannsvle Chemical Products Corp., 1981). Thetoluene concentrations in US gasolines are estimated to range from 5 to 22% (wt%; IARC,1989).
Toluene is used as an intermediate in the production of toluene diianate for use in
polyurethane production, and of benzoic acid for use in the manufacture of benzoate andbenzyl esters and salts for foo preservatives and cosmetic articles such as soaps, penumes,flavours, creams and lotions. Catalytic disroportionation of toluene has been used to pro-duce benzene and paa-xylene, with little or no ethylbenzene or ortho- or meta-xylene. Vi-nyl toluene, which is produced byalkylation of toluene with ethylene followed by dehydroge-nation of ethyltoluene, is used as a modifier in unsaturated polyester resins. Other impor-tant chemical products made from toluene include triitrotoluene and related explosives,benzaldehyde (an important chemical intermediate) and sacchar (Hoff, 1983; US Envion-mental Protecion Agency, 1983; Fishbein, 1985). Small amounts of toluene are used for themanufacture of paa-cesol, which is used priariy for the manufacture of butylated hy-
droxyoluene (US Envionmental Protection Agency, 1983).ln western Europe, phenol (see monograph, p. 263) is the most importnt derivative of
toluene, followed by toluene diianate and caprolactm. ln Japan, toluene is use pn-mariy for benzene and paa-cesol production (Fishbein, 1985).
Of the estimated 3.3 milion tonnes of toluene produced in the USA in 1980, 44% wasused to make benzene, 34% to make gasoline, 10% in solvents, 6% to make toluene dnsa-nate, and 6% for misllaneous use (Mannsvle Chemical Corp., 1981).
(c) Regulatory status an guideline
Occupational expsure limits for toluene in 34 countnes or regions are presented inThble 2.
2.2 Occurrence
(a) Natral occurrence
Toluene ocrs in nature in crde oil (US Envionmenta Protecion Agency, 1983),
natural gas deposits and the volatile emisions from volcaoes and forest fires (National Re-search Counci, 1976).
TOLUENE 83
Table 2. Occupational exposure limits for toluenea
Country or region Year Concentrationb InterpretationC
( mg/m3)
Australia 1984 380 1WAAustria 1985 750 1WABelgium 1985 375 1WABrazil 1985 S 290 1WABulgaria 1984 50 1WACommission of the European 1986 375 1WA
Communities 1875 MaxmumChile 1985 S 300 1WAChina 1985 100 1WACzechoslovakia 1985 200 Average
600 STELGermany, Federal Republic of 1988 380 1WAHungary 1985 100 1WA
500 STELIndia 1985 S 375 1WA
S 560 STELIndonesia 1985 375 1WAItaly 1985 S 300 1WAJapan 1988 375 1WAKorea, Republic of 1985 375 1WA
560 STELMexico 1985 S 750 1WANetherlands 1986 S 375 1WANoiway 1981 280 1WAPoland 1985 100 1WARomania 1985 300 Average
400 MaxmumSweden 1987 200 1WA
400 STELSwitzrland 1985 S 380 1WA'Tiwan 1985 S 375 1WAUK 1987 S 375 1WA
S 560 STEL (10 min)
84 IAC MONOGRAHS VOLUME 47
Table 2 (contd)
ACGIH
Year Concentrationb InterpretationC
(mg/m3)
1988 430 1WA1986 375 1WA
750 Ceilng1988 375 1WA
560 STEL (15 min)1986 50 Ceilng1985 S 375 1WA
S 560 Ceilng1985 200 1WA
Country or region
USAdOSHANIOSH
USSRVenezuela
Yugoslavia
tlrom Direktoratet for AridstiIset (1981); International Labour Office (1984); Arid-
sinspetie (1986); Commission of the European Communities (1986); Institut National de Re-cherche et de Sécurité (1986); National Institute for Ocupational Safety and Health (1986);Cok (1987); Health and Safety Executive (1987); National Swedish Bord of OcupationalSafety and Health (1987); 1Yõsuojeluhalltus (1987); American Conference of GovemmentalIndustrial Hygienists (1988); Arjdtilsyet (1988); Deutshe Forshungsgemeinschaft(1988)bS, skin notation9WA, 8-h time-weighted average; STEL, short-term expure limittiSHA, Ocupational Safety and Health Administration; NIOSH, National Institute for Oc-cupational Safety and Health; ACGIH, American Conference ofGovemmental Industrial Hy-gienists
(b) Occupationa exsure
On the basis of a US National Occupational Expsure Survey, the National Institutefor Occupational Safety and Health (1983) estimated that 1278 () workers were potentially
exposed to toluene in the USA in 1981-83.Levels of toluene measured in the air in work envionments are summaried in Thble 3.
ln the majority of these envionments, concurrent expsure to other solvents is likely to havetaken place.
Biological monitorig measurements have also been made. Expsures in the manufac-ture of trapezoid belts resulted in uriaiy hippuric acid concentrations of 2.1 g/l in workers inthe belt department and 9 g/l in those in the weighing room (Capellini & AIessio, 1971).
Exposures to toluene on automatic spray finishing machines in a leather finishing operationresulted in uriaiy hippuric acid levels ranging from 1.5 to 3.66 g/l, witii an average of 2.38 g/L.Ali nine samples were taken: at the end of the work shift. Expsures in the washing and top-ping department in the same plant resulted in uriaiy hippuric acid levels of 2.16-5.85 g/l,with an average of 4.48 g/l. Concentrations of toluene in a rubber coating plant resulted in
post-shift uriaiy hippuric acid levels of 2.75-6.8 g/l (average, 3.66; Pagnoito & Lieberman,1967). Post-shift results of biological monitorig of 35 toluene-expsed priting workersranged from 0.09 to 3.13 mg/l toluene in bloo (average, 1.55 mg/l), 0.33 to 11.6 g/l hippuric
Table 3 . Occupational exposures to toluene
Environment Sampling4 Concentratio in air Reference
Environment SamplingQ Concentration in air Reference
R.b.. sh mamafacre (UK) 1WA persnal 3-280 ppm (11-1050 mg/m3)
Mean, 57 ppm (215 mg/m3)Campbell et ai.
(1987)
Paet ßoo (FRG) 8-h 1WA persnal Mean, 86.7 mg/m3
(max 750 mg/m3)
15-200 ppm (57-754 mg/m3,
average)
Denkhaus et ai.
(1986)Sbke (Japan) Matsushita et ai.
(1975)arA, time-weighted average
i1D, not detected
i-oE
~
00..
88 IAC MONOGRAHS VOLUME 47
acid in urie (average, 5.03 g/l), .; 0.1 to 10.6 mg/l ortho-cresol in urie (average, 3.11 mgll)and 0.1 to 27.1 mg/l phenol in urie (average, 5.29 mg/l; Angerer, 1985). ln workers in afactoiy in the UK that manufactured rubber sheets used in the priting industiy, bloo tolu-
ene levels were 10-18 llmol (0.9-1.6 mg)/l; pre- and post-shift levels of exhaled tolueneranged from 320 to 542 nmol (30-50 llg)1l and uriaiy hippuric acid levels were 0.72-1.01mmol (6693 mg)/mmol creatinine over four years (Campbell et al., 1987). The average con-centration of toluene in the bloo of parquet fIoorers was 99 llg/l (max, 2550 .lg/l) (Denkhauset al., 1986).
Occupational expsure of painters and paint manufacturig workers to toluene is de-scribed in the monograph on ocupational expsures in paint manufacture and painting (seep. 329). Occupational expsures to toluene in petroleum refing and in the production anduse of petroleum fuels are described in Volume 45 of the Monographs (IARC, 1989).
(c) Air
Toluene is released into the envionment durig its production, processing (via distila-tion vents), loading and handling and in transprtation and storage operations.
Merian (1982) estimated worldwide atmospheric emissions of toluene to be 6.2 milliontonnes. Contributions included losses from refineries (40%), automobile exhausts (32%),solvents (16% ), petroleum losses to the sea (8% ), losses from the chemical industiy (2% ) andgasoline evaporation (0.8%).
ln the USA, total annual emissions of toluene were estimated to be about 450 thousandtonnes, 99.3% of whieh was released into the atmosphere and 0.7% into waste waterways
(Clement Assoiates, 1977). The US Envionmental Protection Agency (1983) estimatedthat atmospheric emissions of toluene in the USA durig its production in 1979 were 3.0tonnes/year from catalytic reforming, 0.5 tonnes/year from pyrolytic crackig, 0.1 tonnes/
year as a styene by-product and and 0.2 tonnes/year as a coke oven by-product. ln 1979, USemissions were estimated to be about 1 milion tonnes, 90% of the loss being due to evapora-tion of gasoline and automobile exhaust emissions (Fishbein, 1985). ln Japan, 250 and 60thousand tonnes of toluene were lost to the environment in 1976 and 1974, respectively,
through its use as a solvent in paint and priting ink industries (Merlan & Zander, 1982).Toluene is transprted rapidly from water (where it has low solubilty) into the atmo-
sphere. Its half-life in water (1 m deep) is about 5 h; that in the atmosphere is 13 h. It isremoved from the atmosphere priariy by reactions with atomic oxygen, aryl- or alkyl-per-oxy or hydroxyl radicals, and ozone. Because of its rapid oxidation, toluene would not remainlong enough in the atmosphere to be inuenced by air-to-sudace transfer mechanisms (In-ternational Programme on Chemical Safety, 1985r'
The tropospheric lifetime of toluene is four days, and average worldwide distribution isapproxiately 0.0075 mg/m3 air. Average atmospheric concentrations of 0.005-1.31 mg/m3 have been measured, with the highest level being 5.5 mg/m3, in studies from Europe,Canada and the USA, between 1971 and 1980. ln the viciity of ån automobile paintingplant, levels of 0.06.6 mg/m3 were reported 16.5-1.6 kmdowÌwid from the painting faci-ity, compared with 0.00 mg/m3 upwid (International Programme for Chemical Safety,1985). Concentrations of 42 mg/m3 were recorded in the air in the vicity of a chemical
TOLUENE 89
reclamation plant after residents had complained of odour and ilnesses (US EnvionmentalProtection Agency, 1983).
Mean atmospheric concentrations of toluene in urban areas around the world in1971-80 include (in mg/m3): 0.04 in Canada, 0.002-0.2 in the Federal Republic of Germany,0.03 in Finland, 0.02 in Japan, 0.02-0.07 in the Netherlands, 0.03-0.05 in South Africa, 0.005in Sweden, 0.04-0.06 in Switzerland and 0.02-0.06 in the UK (Merian & Zander, 1982; USEnvionmental Protection Agency, 1983). De Bortoli et al. (1984) reported 0.007-0.156 mg/m3 toluene in 15 samples collected in outdoor air in northern Italy. ln the USA, measure-ments were recorded between 1967 and 1978 for atmospheric concentrations in both urbanand rural sites in five major regions of the countiy. The highest mean concentration wasreported in the eastern region (0.15 mg/m3 in New York and New Jersey), followed by 0.14mg/m3 in Los Angeles and urban Alabama. Values reported for other regions were muchlower (0.001 and 0.002 mg/m3 in urban Oklahoma and rural AIabama, respectively), andnone was detected in several midwestern states (US Envionmental Protection Agency,1983). Toluene was also detected in the expired air of individuals from a US urban popula-tion (mean, 0.0084 mg/m3; Krotoszyski et aL., 1979) and in the interior of cars before (0.5mg/m3) and after drivig (1.0 mg/m3; Merian & Zander, 1982). A range of 0.02-0.412 mg/m3was found in 48 samples collected at German traffic intersections (Seifert & Abraham,1982). Levels of 0.00 mg/m3 toluene were measured in two rural areas in the USA between1971 and 1978; .c 0.001 mg/m3 was measured in six others (Holzer et al., 1977; Merian &Zander, 1982; US Envionmental Protection Agency, 1983). Levels of 97-891 mg/m3 weremeasured in the smoke of forest fires (Merln & Zander, 1982).
De Bortoli et al. (1984) measured 0.017-0.378 mg/m3 toluene in 14 homes and in oneoffice building in northern ltaly. LevelsofO.I5-.9 mg/m3 toluene werefound in US homespolluted with tobacc smoke (US Envionmental Protection Agency, 1983). Toluene hasbeen detected in tobacc smoke (IARC, 1986). Seifert and Abraham (1982) found an aver-age concentration of 0.061 mg/m3 (range, 0.017-0.116 mg/m3) in kitchens and other rooms of15 homes in West Berlin; just outside the walls of these dwellings, the measured concentra-tions averaged 0.035 mg/m3 (range, 0.016-.06 mg/m3). Mølhave (1979) reported a peak lev-el of 0.61 mg/m3, based on measurements in 14 rooms in homes in Denmark; and Mølhaveand Møller (1979) reported an average concentration in 39 homes of 0.09 mg/m3.
(d) Water
Drikig-water in Prague, Czechoslovakia, in 1973 contained .c 0.1 J.g/I toluene (Mer-ian & Zander, 1982), whereas in Toronto, Canada, in 1980 drikig-water contained an aver-
age of 2 J.g/l (compared to .c 1 J.gll before treatment; Otson et al., 1982). Levels of 42-100J.g/I were reported in well water in the viciity of landfil sites in the USA (US Envionmen-tal Protection Agency, 1983). The concentration of toluene in rain water in the Federal Re-public of Germany has been reported to be 0.13-0.70 J.gll (US Envionmental ProtectionAgency, 1983; International Programme on Chemical Safety, 1985).
Toluene has been found at concentrations of 1-5 J.g/I in water samples from a numberof rivers in eastern and midwestern USA, with concentrations ranging up to 12 J.g/l in theMississippi River near New Orleans. Concentrations of 0.8 J.g/l have been reported inthe
90 !AC MONOGRAHS VOLUME 47
Rhine River in the Federal Republic of Germany and of 1.9 l.gll in Switzerland (Merin &Zander, 1982).
Concentrations of 0.005-.376 l.gll (mean, 0.061 l.gll) were reported at several coastalsites along the Gulf of Mexico (US Envionmental Protection Agency, 1983).
(e) Soit
Toluene exits in an adsorbed state in soil. ln assiciation with clay minerais, its adsorp-tion is inversely proportional to the pH of the soil. Approxiately 4070% of tolueneapplied to the sudace of sandy soils is volatilized. The biodegradation of toluene by mieroor-ganisms in the soil ranged from 63-86% after 20 days (Wilson et aI., 1981; US EnvionmentalProtection Agency, 1983; Wilson et al., 1983).
if FoodThe US Envionmental Protection Agency (1983) reported toluene concentrations of
.c 1 mg/kg in 56 of 59 samples of fish tested; one fish had a level of 35 mg/kg toluene. rIt wasnot clear to the Workig Group whether these concentrations were found in whole fish oronly in the edible part.)
Toluene was also detected at low concentrations (0.08-.11 mg/kg) in a few samples ofmaple syp packaged in plastie containers (Hollifield et al., 1980).
2.3 Analysis
Methods for the analysis of toluene and its metabolites have recently been reviewedand compiled (Fishbein & O'Neil, 1988) and are summaried in Thble 4. Colorietric detec-
tion systems have been developed for toluene in air (ENMET Corp., undated; MathesonGas Products, undated; Roxan, Inc., undated; The Foxbro Co., 1983; Sensidye, 1985; Na-tional Draeger, Inc., 1987; SKC Inc., 1988).
3. Biological Data Relevant to the Evaluation of
earcinogenic Risk to Humans
3.1 CarciDogeDicity studies iD aDimals1
(a) Oral administration
Rat: Groups of 40 male and 40 female Sprague-Dawley rats, seven weeks old, wereadministered 500 mg/kg bw toluene (purity, 98.34%)in olive oil by stomach tube on four tofive days per week for 104 weeks. Groups of 50 males and 50 females :eceived olive oil atoneand served as controls. Ali rats were maintained until death, and the study was terminated at
lThe Working Group was aware of a study in progress by inhalation in mice and rats (lARe, 1988).
TOLUENE 91
Table 4. Analytical methods for determining toluene and its metabolites iD variousmatrices
Pasive sam- Desrb (carbn disul- GC-FID 0.2 ppm Otsn et al.pler with fide); inject aliquot; (0.8 mg/m3) (1983)charcoal analy on packed
column
Water Exract with hexane; in- GC-FID 5 IJglI Otsn &ject aliquot Willams (1981)
Heat in water bath at GC-MS 1 IJglI Otson et al.25°C for 1 h; injet (1982)headspace aliquots
Foo Bulk Sparge 10 ml with ni- Headspace 10-275 IJglI Fazio & Sherma(maple trogen; incuba te 2 h at GC; GC/MS (1987)syp) 90.C; inject 2 ml of ( confirm)
headspace vapours
Soil Wash with distiled wa- GC-FT-IR Not given Gurka &ter; acidify, steam distil Betowski (1982)with hexane; removehexane layer; dry andreduce to 1 ml (nitro-gen)
Automo- lènax GC Desorb thermally into GC-MS Not given Hampton et al.bile exhaust polymer ad- liquid nitrogen-coled (1982)gas sorbant capilary trap
Alveolar Charcoal Desorb thermally; in- GC-MS Not given Apotoli et al.air jet into glass column (1982)Bloo Hepariniz Add redistiled ethyl GC-FID 0.05 IJg/g Oliver (1982)
benzne disslved inmethanol and water;equilibrate at 60.C for45 min; remove aliquotheadspace and inject
Hepariniz Purge (nitrogen) at GC-MS -c 1 IJglI Cramer et al.room temperature; trap (1988)(Inax TA); desorbthermally; analy vola-tiles on column
Acidify and extract hip- TL-UV 6 J.g Bieniek et al.puric acid with chloro- (1982)fonn; separate on TL(pra-dimethylamino-benzldehyde for co-lour development); ex-tract azlactones withethanol; detennine UVabsorbancy
Add soium hydroxide GC-FID 2 J.g/g Miyaura & Isonoand olive oil with inter- (1985)nal standard (ethylben-zene); incuba te at 35°Cfor 2.5 h; inject aliquotof headspace vapour
Urine(hippuricacid)
Tissue Mince(muscle,liver)
aAbbreviations: GC, gas chromatography; FID, flame ioniztion detection; MS, mass spetrometry; Fr-IR,Fourier transfonn/infrared spetrometry; TL, thin-Iayer chromatography; ~ ultraviolet spectrometry
week 141. At week 141, thymomas were reported in 1137 treated males and 2/40 treated fe-males compared to 0/45 and 0/49 controls. Other haemolymphoreticular tumours were re-ported in 2/37 treated males and 5/40 treated females compared to 3/45 and 1149 controls
(denominators are numbers of rats alive in each group at 58 weeks, when the first haemolym-phoreticular tumour was observed). The authors reported an increase in the total numbersof animais with malignant tumours (tyes unspecified) at 141 weeks: 18/40 treated males and21140 treated females compared to 11/45 and 10/49 controls (denominators are numbers ofrats alive in each group at 33 weeks, when the first malignant tumour was observed; Maltoniet al., 1983, 1985). (The Workig Group noted the incomplete reporting of tumour pathologyin this study and that combining different tyes of tumours is not usually the most appropri-ate method for evaluating carcinogenicity (lARC, 1980; Montesano et al., 1986).)
(b) Inhalation
Rat: Groups of 120 male and 120 female Fischer 344 rats, about seven weeks of age,were exposed by inhalation to 0, 30, 100 or 300 ppm (0, 113,377 or 1131 mg/m3) toluene (puri-
ty, ~ 99.98%) for 6 h per day on five days per week for up to 24 months. Interi kils were
made in all groups at six months (five rats), 12 months (five rats) and 18 months (20 rats). Ailsurvvig rats were kiled at 24 months; these compried 71 male and 70 female control s, 73males and 75 females given the low dose, 68 males and 76 females given the mid-dose, and 67males and 75 females given thehigh dose. No increase in the incidence of tumours was re-
ported in the treated groups (Gibson & Hardisty, 1983). (Te Workig Group noted theincomplete reporting of data on pathology and that the level of expsure was low.)
TOLUENE 93
(c) Skin application
Mouse: Toluene was tested as a vehicle control or in combination with various carcino-gens in a number ofski painting studies in mice. No ski tumour attributable to toluenealone was observed (poel, 1962; Frei & Kigsley, 1968; Lijinsky & Garcia, 1972; Doak et aL.,1976; Weiss et al., 1986). (Te Workig Group noted either the small number of animais usedin these exprients and the short duration or incomplete reporting of the studies. J
A group of 50 male C3H/HeJ mice, six to ten weeks of age, received applications of 25i.iJ (21.7 mg) toluene (purity unspecified) on clipped interscpular ski three tImes a weekuntil death. Mean survval time was 83 weeks. No ski tumour was reported at terminationof the study (unspecified), and complete histological examination revealed no treatment-re-lated tumour at other sites (McKee & Lewi, 1987). ln a similar study with 50 C3H/HeJ mice(mean survval time, 77 weeks), one ski papiloma was found (McKee et aL., 1986).
Seven groups of vehicle controls used for different experients, each consisting of 50
male C3H/HeJ mice, six to eight weeks old, received applications of 50 mg toluene on theinterscpular ski twice a week for 73-120 weeks. Ski tumours (by gross observation J oc-curred in 3/350 mice (Blackburn et al., 1986).
3.2 Other relevant data
The toxicology of toluene has been reviewed (National Institute for Occupational Safe-ty and Health, 1973; Cohr & Stokholm, 1979; Benignus, 1981a,b; World Health Organiz-tion, 1981; International Programme on Chemical Safety, 1985; Anon., 1987b; Low et al.,1988).
(a) Exrimental systems
(i) Absorption, distribution, exretion an metabolismWhen dogs were expsed to 0.4-.6 J.g/ml toluene vapour, 91-94% was taken up in the
lungs (Egle & Gochberg, 1976). Absorption was Cömplete when toluene was given orally todogs (Koop & Gehrke, 1925); the bloo level in rats increased more slowly after oral admin-istration than after inhalation (Pkkö et al., 1977). Absorption through the ski of mice invivo was 4.59 J.g/cm2 per hour (Turuta et al., 1987). Toluene penetrated rat ski excised
three days after clipping and depilation with cream at a rate one-tenth that of benzene andten times that of ortho-xylene (Turuta, 1982).
When 3H-toluene was given to rats either orally or by inhalation, radioactivity 2 h afteradministration was highest in the adipose tissue, followed by the liver, kidneys and brain(Pkkö et al., 1977). Similar results were obtained after intramusclar injection of (rig-Ia-belled 14C)toluene to mice (Ogata et al., 1974) and after intraperitoneal injection of (meth-yl-14C)toluene to mice (Koga, 1978). Levels in the cerebrum, cerebellum and spinal cordwere comparable to those in bloo of rats after intraperitoneal injecion (Savolainen, 1978).Toluene levels in brain and bloo were linearly related to toluene levels in inhaled air afterrats were expsed to 50, 100, 50 or 100 ppm (189, 377, 1885 or 3770 mg/m3) toluene for 3 h
(Benignus et al., 1984). The toluene concentration was higher in brain than in bloo immedi-ately after expsure. The decrease after termation of expsure was almost parallel in thetwo tissues but slightly faster in brain than in bloo (Benignus et al., 1981). Less than 2%
94 IAC MONOGRAHS VOLUME 47
radioactivity was excreted in bile within 24 h after intraperitoneal injection of 50 mg/kg bw(14C)toluene to rats (Abu-EI-Makarem et al., 1967).
When rabbits were given a single oral dose of 350 mg/kg bw toluene, 19% was exhaledunchanged within 12 h (Smith et al., 1954). ln rats given 3H-toluene orally or by inhalation,only 1% or less of the initial radioactivity was found in various tissues 24 h after dosing, ex-cept for white adipose tissue which contained 3.5-5% (Pkkö et al., 1977). Similar resultswere obtained in mice (Koga, 1978).
Toluene is excreted into the urie priariy as hippuric acid (after side-chain oxidation
followed by glycine conjugation) and, to a minute extent, as conjugated cresols (after aromat-ic hydroxylation and sulfation/glucuronidation; International Programme on Chemical Safe-
ty, 1985). Of an orally administered dose of 0.3 g/kg bw given to rabbits, 74% was excreted inurie as hippuric acid within 24 h (El Masiy et al., 1956). ln rats, 0.04.11 % and 0.4- 1.0% ofan oral dose of 100 mg/kg bw toluene were excreted in urie as ortho-cesol and paa-cresol,
respectively (Bake & Scheline, 1970); the ratio of ortho- and paa-cesol:hippuric acid var-ied depending on expsure intensity and strain of rats (lnoue et al., 1984).
Intraperitoneal injection of 370 mg/kg bw toluene to rats resulted in decreased hepaticglutathione levels and increased uriaiy thioether excretion, suggesting the formation ofmercapturic acid(s) as a minor metabolite(s) (van Doorn et al., 1980). Activation of tolueneto covalently binding metabolites has been reported. Wh en (methyI14C)-toluene was incu-bated with rat liver microsomes in the presence of an NADPH-generating system, part ofthe radioactivity remained in microsomal components after extensive extraction with varioussolvents and trichloroacetic acid. Treatment with ribonuclease and protease indicated thatthe radioactivity bound preferentially to proteins (Pthiratne et al., 1986).
Pregnant C57BI mice were expsed by inalation to 14C-toluene (theoretical concen-tration, 20 ppm (754 mg/m3)) for 10 min on days 11, 14 or 17 of gestation, and distnbutionof the label was determined 0, 0.5, 1,4 and 24 h after expsure. The label quickly entered theembiyo, but uptake was low relative to that in maternai tissues. Ail fetal activitywas extract-able, indicating that no firly bound metabolite was present (Ghantous & Danielson, 1986).
(n) Toxic effects
The oral LD50 of toluene in rats has been reported to be about 5 g/kg bw (range, 2.6-7g/kg bw) depending on age and strain (Wolf et al., 1956; Kiura et al., 1971; Withey & Hall,1975). The intraperitoneal LDso was reprted to be about 1.6 g/kg bw in different strains ofrats (Ikeda & Ohtsuji, 1971; Lundbrg et al., 1986) and about 1.2 g/kg bw in mice (Schumacher& Grandjean, 196). The LC50 in rats expsed for 6 h was 50 () mg/m3 (Cameron et al.,1938), and that in mice exsed for 7 h was 19950 mg/m3 (Svielyet al., 1943). The estimateddermal LDso in rabbits was about 12 mg/kg bw (Smyth et al., 1969). Toluene is only slightly tomoderately irtating for ski and eyes of rabbits (Wolf et al., 1956; International Programmeon Chemical Safety, 1985).
Minor weight loss was noted in rats exsed to 50 ppm (190 mg/m3) toluene for 7 hper day on five days per week for five weeks and in mice exsed to 40 ppm (15 00 mg/m3)toluene for 3 h per day for ten weeks (Benignus, 1981a).
TOLUENE 95
Acute inhalation of high concentrations of toluene resulted, depending on species, ageand concentration, in more or less pronounced central nervous system depression (Carpen-ter et al., 1976). Inhalation of concentrations of 26 ppm (980 mg/m3) for several hours ledto signs of narcotic effects. Inhalation of 12 00 ppm (45 20 mg/m3) for 5 min producedmarked central nervous system depression in mice and rats (Bruckner & Peterson, 1981a,b).
ln rats, subchronic inhalation of toluene (100 ppm (3770 mg/m3), 12 h per day for 16weeks) resulted in reversible reduction of mixed nerve conduction velocty (Ikeuchi et al.,1981). Disturbance of circardian rhythm was seen with 40 ppm (1500 mg/m3) 4 h per dayfor four weeks (Hisnaga & 1àkeuchi, 1983), and behavioural effects were seen with 40ppm (1500 mg/m3), 2 h per day for 60 days (Ikeda & Miyake, 1978). Behavioural effectshave been reported at expsures as low as 150 ppm (56 mg/m3) for 30 min in rats (Geller etal., 1979; Woo et aL., 1983) and 4 mg/m3 for ten days in mice (Horiguchi & Inoue, 1977).N eurological signs have been recorded in cats expsed to 25 50 mg/m3 for 10 min per day for40 days (Contreras et al., 1979). Expsure disturbed the turnover of neurotransmitters (do-pamine, norepinephrie and 5-hydroxyiytamine) in the central nervous system of rats af-ter expsure to 300375 mg/m3 for one or a few days (Fuxe et al., 1982; Rea et al., 1984).
No significant toxicity (as determined bybloo parameters, uriaiy parameters, organweights and histopathological examinations of major organs) was se en after oral administra-tion of up to 590 mglkg bw toluene to female rats for periods of up to six months (Wolf et al.,1956) or daily 6-8-h inhalation expsures to concentrations below 40 ppm (150 mg/m3) forup to 24 months in rats (Jenkis et al., 1970; Gibson & Hardisty, 1983) or for up to 127 days indogs (Jenkis et al., 1970; Carpenter et al., 1976) or monkeys (Jenkis et al., 1970).
ln rats expsed to 80 mg/m3 toluene for 8 h per day on six days per week for sevenweeks, lung irtation but no systematic haematological change was noted. Signs of centralnervous system intoxication, incordination and paralysis of the hind legs, and congestivechanges in lung, liver, kidney, heart and spleen were seen in two dogs expsed to tolueneconcentrations of 750 mg/m3 th en 10 00 mg/m3 for 8 h per day on six days per week for sixmonths; both animals.died after 180 days (Fabre et al., 1955).
An increase in the number of kidney casts was noted in rats expsed by inhalation to 750mg/m3 toluene for 7 h per day on five days per week for five weeks (International Programmeon Chemical Safety, 1985). Hyperaemic glomeruli and albuminuria were reported in twodogs expsed to 750 mg/m3 then 10 00 mg/m3 for 8 h per day on si days per week for sixmonths (Fabre et al., 1955).
Changes in the activity of drug-metabolizing enzyes in the liver were reported in ratsexpsed to 50 ppm (1875 mg/m3) for 6 h per day for three days (foftgård et al., 1982) andfollowig oral administration of 0.7 mllkg bw for two days (Mungikr & Pawar, 1976; Pykkö,1980). Reduction in boy weight gain and increases in liver weight and in cyochrome P450and cyochrome bs concentrations, but no toxicity-related specific ultrastructural change inthe liver, were observed in male rats expsed to toluene at 60 mg/m3 for 8 h per day for
fourweeks and in male and female rats expsed to up to 350 mg/m3 for 8 h per day for six months
(Ungváiy et al., 1980).
96 IAC MONOGRAHS VOLUME 47
(ii) Effects on reproduction and prenaal toxicity
Toluene (5-100 J.mol (0.5-9.2 mg)/egg) was injected into the air sac of white LeghornSK 12 cruck embiyos on day 2 or 6 of incubation; control eggs received an injection of thevehicle (olive oil). The LDso was reported to be in excess of 100 J.moll egg, although this dosecaused 100% mortlity when given on day 6 (Elovaara et al., 1979).
Toluene was injected into the yolk sac of fresh fertile chicken eggs prior to incubation.Hatchabilty of the eggs was 85%, 25% and 0 with expsures of 4.3, 8.7 and 17.4 mg/ egg, re-spectively (McLaughlin et al., 196).
As reported in an abstract, CD-l mice were expsed by gavage to 0.3 (0.27), 0.5 (0.45) or1.0 ml (0.9 mg)lkg bw toluene in cottonseed oil on days 6-15 of gestation or to 1.0 ml/kg ondays 12-15. No maternai effect was observed in the groups expsed on days 6-15, but signifi-cant embiyo lethality was se en at all dose levels, and fetal weight was reduced at 0.5 and 1.0ml/kg hw. Cleft palates were seen at the highest expsure leveL. ln the groups expsed ondays 12-15, only maternai toxicity was se en (Nawrot & Staples, 1979).
ln a teratology sceening assay, two groups of 30 ICR/SIM mice recived 0 or 180 mg/kg bw per day toluene by oral intubation on days 8-12 of gestation. Dams were allowed todeliver, and the offsprig were evaluated for growth and vibility in the early neonatal peri-od. No effect was observed in either the dams or the offsprig (Seidenberg et al., 1986; Sei-denberg & Becker, 1987). Using the same basic protocl, CD-1 mice received 0 or 2350 mg/
kg bw per day (50 mice per group) or 0 and 300 mglkg bw per day (groups of 46 and 49 mice,respectively) toluene by oral intubation on days 6-13 of gestation. ln the first experient,
expsure to toluene was lethal to one dam; no control died, and there was no other effect ondams or offsprig. ln the second experient, 3/49 treated dams died; there was no death in
the control group, and no other sign of toxicity was observed in dams or their offsprig (Har-din et aL., 1987).
ln four studies, mice were expsed by inhalation to up to 3770 mg/m3 du rig various
periods of gestation. Expsure to 150 mg/m3 resulted in maternai mortlity after continu-ous (24 h/day) but not after intermittent (7 h/day) expsure. Fetal vibilty was not affectedin any study. Fetal growth retardation was noted in one study at 50 mg/m3 (24 h/day on days6-13), but not in another at 150 mg/m3 (7 h/day on days 6-16). An increased incidence ofextra ribs was seen at 3770 mg/m3 (6 h/day on days 1-17) but a lower incidence was reported at150 mg/m3 (7 h/day on days 6-16). No treatment-related malformation was seen in anystudy. ln the two studies in which offsprig were followed postnatally after expsure at 3770mg/m3 for 6 h per day on days 1-17, and 150 mg/m3 for 7 h per day on days 6-16, no effect onpostnatal growth or vibilty was observed (Hudák & Ungváiy, 1978; Shigeta et al., 1982;Ungváiy & Tátrai, 1985; Courtney et al., 1986). (The Workig Group noted that, on the basisof a non-dose-related increase in the frequency of enlarged renal pelvi and a decreasedvariabilty in nb profile, Courtenay et al. (1986) concluded that toluene was teratogenic tomice. )
CFY rats were expsed by inhalation to 150 mg/m3 toluene (analytical purity) for 24 hper day on days 9-14 of gestation (19 rats), to 150mg/m3 on days 1-8 of gestation (nine rats)or to 100 mg/m3 for 8 h per day on days 1-21 of gestation (ten rats). There were 26 controlfemales for expsure on days 9-14 and ten control females for the expsures starting on day 1
TOWENE 97
of gestation. Expsure to 150 mg/m3 caused mortlity in 2/19 and 5/9 dams in the groupsexpsed on days 9-14 and 1-8, respectively; no other maternai effect was reported. Absenceof the tail was reported in 2/213 fetuses expsed on days 9-14 as compared to 0/348 fetuses inthe control group. On skeletal examination of the group expsed on days 9-14, 7/102 treatedfetuses had fused sternebrae and 22/102 had extra ris; the incidences in the control group
were 2/169 and 0/169, respectively. High expsure levels early in development were accm-panied by lower fetal bo weights at term but no abnormality; the only effect noted follow-ing expsure to low levels throughout gestation (days 1-21) was an increased incidence ofsigns of skeletal retardation (prly ossified sternebrae, bipartite vertebra centra and short-ened 13th nb). No effect on feta vibilty was noted with any expsure regimen (Hudák &Ungváiy, 1978).
ln a subsequent study, groups of 22 or 20 CFY rats were expsed by inhalation to air orto 100 mg/m3 toluene for 24 h per day on days 7-14 of gestation. Animais were kiled on day21 of pregnancy and the fetuses were examined by routine teratological techniques. No ma-ternai toxicity was observed in the treated group; an increaed incidence of supernumerarynbs was the only effect reported (p .( 0.10) in the fetuses (rátrai et al., 1980). (Te WorkigGroup noted that it is not clear how the latter data were analysed; it appears that the individ-ual fetus was used as the unit of comparison. i ln a further study, expsure by inhalation to 0or 36 mg/m3 toluene (analytical purity) for 24 h per day on days 10-13 of gestation did notappear to affect fetal development adversely although it did potentiate the maternai andembiyonic toxic effects of acetylsalicylic acid (Ungváiy et al., 1983).
Groups of 12 female Nya:NYLAR mice were given 0, 16, 80 or 40 mg/l toluene in thedrikig-water from mating throughout gestation and lactation, and the offsprig continuedto receive toluene in the drikig-water from weaning unti the end of testing. Offsprigwere observed for vibility, sudace righting abilty at seven days of age, eye and ear openingand startle respnse at 13-14 days of age, open field activity at 35 days of age and rotorodpedormance at 45-55 days of age. No treatment-related effect was observed for fluid con-sumption, growth, vibilty or apperance of developmentallandmarks. Mice expsed to 40mg/l displayed decreased habituation in the open field apparatus; a non-dose-related im-pairent of rotonxI pedormance was also observed (Kostas & Hotchin, 1981).
Rats of an inbred strain (rokai high avoiders) were expsed to 0, 100 or 50 ppm (0, 377or 1885 mg/m3) toluene for 7 h per day from day 13 of gestation to postnatal day 48. Develop-mental endpoints examined included age at pinna detachment, the presence of downy fur,incisor eruption, eye opening, bo weight, a righting reflex and respnses in a rotorod test.A learning test (Sidman avoidance) was conducted daily for ten days beginning on day 49, 100or 150. There was no significant diference between the treated groups with respect to acqui-sition of developmentallandmarks, but boy growth was greater in the group expsed to 100ppm. Treated male offsprig in both expsure groups were deficient in acquisition of thelearning task at initial, but not later, ages; no consistent effect was noted in the learning be-haviour of treated female offsprig (Shigeta et al., 1986).
Groups of New Zealand white rabbits were expsed to 0 (60 animais), 50 (ten rabbits)or 100 (eight rabbits) mg/m3 toluene for 24 h per day on days 7-20 of gestation. Fetuses wereexamined by routine teratological techniques on day 30 of gestation. Females that received
98 IAC MONOGRAHS VOLUME 47
the high dose either died, aborted or had no live fetuses at term. One female in the low-dosegroup aborted, but no significant fetal effect was noted (Ungváiy & Tátrai, 1985). (TheWorkig Group noted that this paper is a compendium of data on rats, miee and rabbits fromone laboratoiy and presents little detail on experiental results.)
(iv) Genetic and related effectsThe genetic and related effects of toluene have been reviewed (Dean, 1978, 1985; Fish-
bein, 1985).
Toluene induced a permanent loss of initiation of DNA replication in Bacillus subtÜiscells (Winston & Matsushita, 1975). It did not produce differential kiling in DNA repair-proficient compared to repair-deficient strains of B. subtilis rec + 1- (McCarroll et aL., 1981a)or Eschenchia coli (McCarroll et al., 1981b). Toluene did not induce SOS activity in Salmonel-la typhimunum TAI535/pSKl002 (Nakamura et al., 1987) and was not mutagenic to S. typhi-munum TA1535, TA1537, TA1538, TA98, TAlOO, UT8413 or UT8414 either in the pres-ence or absence of an exogenous metabolic system from uninduced or Aroclor-induced ratand Syran hamster livers (Lebowitz et al., 1979 (abstract); Nestmann et al., 1980; Bos et al.,1981; Spanggord et al., 1982; Haworth et aL., 1983; Connor et al., 1985).
As reported in an abstract, toluene induced chromosomal anaphase alterations in Viciafaba (Gomez-Aroyo & Vilalobos-Pietrii, 1981).
Toluene induced mitotic arrest (C-mitosis) in embiyos of the grasshopper, Melanoplussanguinipes (Liang et aL., 1983). It did not induce sex-linked recessive lethal mutations ortransloctions, but did induce sex-chromosome loss and nondisjunction in male Drosophila
melanogaster at a dose of 1-1.5% toluene administered in foo (Rodriguez Amaiz & Villalo-bos-Pietrii, 1985a,b). As reported in an abstract, toluene did not induce recessive lethal
mutations in D. melanogaster expsed to 50 and 100 mg/kg for 24 h by feeding (Donner etal., 1981).
Toluene induced DNA single-strand breaks (as measured by alkaline elution) in pria-iy cultures of rat hepatoces (Sina et al., 1983), but did not cause DNA damage or repair, asmeasured by the 'nick-translation' assay, in cultured human fibroblasts (Snyder & Mathe-son, 1985). As reported in an abstract, toluene did not induce mutations in mouse lymphomaL5178Y TK + /- cells in vitro or chromosomal aberrations in rat bone marrow in vivo (Lebo-witz et al., 1979). It did not induce sister chromatid exchange or chromosomal aberrations incultured human lymphoces in vitro (Gerner-Smidt & Friedrich, 1978). (Te WorkigGroup noted that the human lymphoces were tested without an exogenous metabolic sys-tem.)
Toluene was reported to induce chromosomal aberrations in the bone-marrow cells ofmale albino rats after chronic inhalation expsure to 5.4 or 50.7 mg/m3 on 4 h per day, five
days a week for four months (Arstovet al., 1981) or after subctaneous injection of 0.8 g/kgbw (Dobrokhotov, 1972). Chromosomal aberrtions in bone-marrow cells were reportedfollowig suhcutaneous injection of 1 g/kg bw daily for 12 days to male albino rats (Lyapkalo,1973). N either micronuclei nor chromosomal aberrations were observed in male and femaleCD-l. mice administered two doses of 1720 mg/kg bw toluene (99% pure) at a 24-h intervalby oral gavage (Gad-EI-Kari et al., 1984). Increases in the frequency of IDicronuclei and of
TOLUENE 99
chromosomal aberrations in rat bone-marrow cells were reported after two intraperitonealinjections of 217 mg/kg bw and 435 mglkg bw (Roh et al., 1987).
Toluene induced micronuclei in bone-marrow polychromatic eiyhroces of male
NMRI and B6C3Fl mice after two intraperitoneal doses of 0.12-0.5 ml/kg bw (0.1-0.44 mg/kg) at a 24-h interval (Mohtashamipur et al., 1985). Pretreatment of male NMRI miee withinducers (phenobarbital, Aroclor 1254, 3-methylcholanthrene) or inhibitors (metyapone,a-naphthoflavone) of cyochrome P450 enhanced the frequency of micronuclei induced bytoluene, while simultaneous injections of toluene and inhibitors decreased the observedclastogenic activities (Mohtashamipur et al., 1987).
Toluene and benzene administered concurrently were reported to have an additive ef-fect on induction of chromosomal aberrations (Dobrokhotov, 1972; Dobrokhotov & En-ikeev, 1977). Toluene reduced the number of sister chromatid exchanges induced by ben-zene when both compounds were administered intraperitoneally to DBA/2 mice (fce et al.,1982) and reduced the clastogenic activity of benzene when the two compounds were simul-taneously administered orally to CD-1 mice (Gad-EI-Kari et al., 1984), intraperitoneallyto Sprague-Dawley rats (Roh et al., 1987) or subcutaneously to NMRI mice (Ilmek et al.,1982).
As reported in an abstract, expsure of male rats by inhalation to 300 ppm (1130 mg/m3)toluene for 6 h per day on five days per week for 15 weeks did not induce chromosomal aber-rations in bone-marrow cells (Donner et al., 1981). As reported in an abstract, oral adminis-tration of toluene did not induce chromosomal aberrtions in bone-marrow cells or domi-nant lethal mutations in random-bred male SHR mice (Feldt et al., 1985).
As reported in an abstract, toluene did not inhibit intracellular communication (asmeaured by metabolic coperation) in Chinese hamster V79 cells (Awogi et al., 1986).
Toluene did not enhance morphological transformation of Syrn hamster embiyo cellsby the SA7 adenovis (Casto, 1981).
It did not induce sperm-head abnormalities in mice (fopham, 1980).
(b) Huma(i) Absorption, distriution, exretion an metabolism
Inhalation is a major route of human expsure to toluene, although ski absorptionmay ocur in ocpational settings. An average lung uptake of 53.3% was obtained durig
expsure of volunteers to 271-1177 mg/m3 toluene for 5 h (Srbvá & Teisinger, 1952). Simi-lar results were obtained in later studies: e.g., 57-72% (Potrowski, 1967),53% (Nomiyama &Nomiyama, 1974) and 3050% (Carlssn, 1982) lung uptake. When volunteers immersedtheir hands in liquid toluene, ski penetration took place at a rate of 14-23 mg/cm2 per hour(Dutkiewicz & Tyras, 196). (Te Workig Group noted that the absorbed amount of tolu-ene was calculated as the difference between the applied and the remaining amount of tolu-ene, and therefore, the absorption rate may be overestimated.) Immersion of one hand inliquid toluene for 30 min resulted in a bloo level (taken from the unexpsed arm) of toluenetwce as high as that after inalation of 100 ppm (377 mg/m3) for 4 h (Sato & Nakajima, 1978),indicating that both respirtoiy and percutaneous absorption are importnt. Toluene was
100 IAC MONOGRAHS VOLUME 47
detected in exhaled air after whole-boy ski expsure (with no inhalation) to 60 ppm (226mg/m3) toluene for 3.5 h (Riiimäki & Pfåffli, 1978).
After expsure of volunteers to 100 ppm (377 mg/m3) toluene for 2 h, the fall in theconcentration of toluene in bloo paralleled that in exhaled air. The decay curve consisted of
three components with half -times of 1.7, 30 and 180 min (calculated by the Workig Group)for the initiaiS min, 5-120 min and 180300 min, respectively (Sato & Fujiwara, 1972). Thebiological half-time for the excretion of uriaiy metabolites among toluene workers wasabout 7.5 h (fokunaga et al., 1974). A shorter half-time was observed after expsure of vol-unteers (Baelum et al., 1987). The half -time of toluene in adipose tissue of expsed workerswas 0.5-2.7 days (Carlsson & Ljungquist, 1982). Toluene was present in the bloo of priters
several days after the end of expsure (Nise & 0rbaek, 1988).
Most (e.g., 68% (Ogata et al., 1970)) of the toluene absorbed undergoes side-chain oxi-dation followed by glycine conjugation and is excreted in the urie as hippuric acid. ortho-,
meta- and para-Cresols were also identified as minor metabolites of toluene (Angerer, 1979;Woiwode et al., 1979; Woiwode & Diysch, 1981). ortho-Cresollevels are about 1/100 ofhippuric acid levels in the urie of workers expsed to toluene (Hasegawa et al., 1983; Inoueet al., 1986). The toluene level in bloo is closely related to the level in alveolar air; the con-centration of metabolites in urie is correlated with both, but less closely (Brugnone et al.,1976).
Levels of hippuric acid, and to a lesser extent ortho-cresol, in urie have been studiedintensively as indicators of expsure to (De Rosa et al., 1987), and their validity has been es-tablished (Pgnotto & Lieberman, 1967; Ikeda & Ohtsuji, 1969; Capellini & AIessio, 1971;Pfåffli et al., 1979; Bergert et al., 1980; AIessio et al., 1981; Hasegawa et al., 1983; De Rosa etal., 1985, 1987). Metabolite levels in urie samples collected near the end of a workig dayshift (AIessio et al., 1981; Hasegawa et al., 1983; De Rosa et al., 1985) correlated best with thetime-weighted average expsure to toluene; toluene accumula tes in the boy towards theend of a workig week (Konietzko et al., 1980) as a reflection of its biological half -time (Toku-naga et al., 1974). Levels of toluene in the bloo have also been used since these are lowamong nonexpsed subjects (Szadkowskiet al., 1973). The biological monitorig of expsureto toluene has been reviewed (Luwerys, 1983).
No significant change in toluene metabolism is induced by expsure to toluene underusual ocupational conditions (Wallért, 1986). Simultaneous expsure to other solvents,such as benzene, is known to suppress toluene metabolism (lnoue et al., 1988). Toluene me-tabolism may differ among populations (lnoue et al., 1986).
When a large dose of ethanol was taken in combination with expsure to toluene, tolu-ene metabolim was inhibited due to metabolic competition between the two chemicals.Bloo toluene levels were lower in workers who drank regularly, indicating induction of tol-uene metabolism by continued ethanol intake-induce metabolism (Waldron et al., 1983). Amore rapid apparent clearance of toluene from the bloo was seen in smokers compared tononsmokers ocpationally expsed to toluene (Wallén, 1986).
TOLUENE 101
(ü) Toxic effects
Subjects who intentionally abuse toluene and workers expsed ocupationally (mainlypriters and painters) are generally also expsed to other organic solvents (International
Programme on Chemical Safety, 1985). Metabolic and toxic interactions between tolueneand other solvents may enhance or reduce any adverse effect (Swedish Criteria Group forOccupational Standards, 1985).
Slight hypsmia has been noted in priters (Baelum et al., 1982). Moderate and tran-sient effects on the eye (conjunctival irtation and corneal damage) ocurred in workerssplashed with liquid toluene (Grant, 1962). Eye and upper airay irtation ocurred after a
6.5-h expsure to an air level of 100 ppm (377 mg/m3) toluene (Baelum et aL., 1985), andlachiyation was seen at 150 mg/m3 (International Programme on Chemical Safety, 1985).An obstructive ventilatoiy pattern has been recorded in inhalation abusers of spray paintcontaining toluene (Reyes de la Rocha et al., 1987). Prolonged expsure of the ski to tolu-
ene may cause contact dermatitis (Matsushita et al., 1975).Volunteers expsed to 100 ppm (377 mg/m3) toluene for 6 h per day for four days suf-
fered from subjective complaints of headache, dizziness and a sensation of intoxication(Andersen et al., 1983). ln subjects expsed to 750 mg/m3 for 8 h, fatigue, muscular weak-ness, confusion, impaired cordination, enlarged pupils and accmmodation disturbanceswere experienced; at about 30 mg/m3, severe fatigue, pronounced nausea, mental confu-sion, considerable incordination with staggerig gait and strongly affected pupilaiy lightreflexes were observed. After expsure at the high level, muscular fatigue, nervousness andinsomnia lasted for several days (International Programme for Chemical Safety, 1985).Heavy accidental exposure leads to coma (Longley et aL., 1967; Grifithset al., 1972; Bakison& Jones, 1985).
Similar effects have been observed in cross-sectional studies of workers, includingpainters (see also the monograph on ocupational expsures in paint manufacture and paint-ing) exposed to corresponding or lower levels of toluene (Wilson, 1943; Matsushita et al.,1975; Elofsson et al., 1980; Husman, 1980; Baelum et al., 1982; Winchester & Madjar, 1986).
(Te Working Group noted that there is probably confounding by other agents.)Initial signs and syptoms of central nervous system effects with an excitatoiy stage,
followed by central nervous system depression, ataxa, depressed consciousness and comahave also been observed in glue sniffers, who may be expsed to very high levels of toluene(Streicher et al., 1981). Generally, these signs and syptoms are reversible (Benignus,1981a); however, prolonged glue sniffing (two years or more) may result in permanent ence-phalopathy (Malm & Lyig- Thnell, 1980; Kig et al., 1981; Schiker et al., 1982; Fornazzari etal., 1983). ln particular, cerebellar signs have been reported (Fornazzariet al., 1983). Effectson the peripheral nervous system have also been observed in 'sniffers' (Korobki et aL., 1975).
(The Workig Group noted that the relationship with toluene is severely confounded by con-comitant exposure to other solvents (including alcohol) and drugs with known neurotoxicity(e.g., sedatives and neuroleptics).)
ln volunteers exposed to 300 ppm (1130 mg/m3) toluene for a few hours, impairent of
simple reaction times was observed (Gamberale & Hultengren, 1972; Winneke, 1982),whereas 300375 mg/m3 caused no such effect (Andersen et al., 1983; Dick et al., 1984;
102 lAC MONOGRAHS VOLUME 47
Anshelm Oison et al., 1985; Iregren, 1986). Disturbances of psychomotor pedormance havebeen noted in cross-sectional studies of car and industrial painters expsed to a mixure ofsolvents including toluene (Hänninen et aL., 1976; Elofsson et al., 1980; Biscldi et al., 1981;Winchester & Madjar, 1986; see also the monograph on ocupational expsures in paintmanufacture and painting). Changes in short-term memoiy, in other intellectual functionsand in moo have also been reported in painters expsed to a mixure of solvents containingtoluene (Hänninen et al., 1976; Elofssn et al., 1980; Winchester & Madjar, 1986). However,the data are not consistent: in one study of toluene-expsed factoiy workers, there was nosuch effect (Cherr et al., 1985). Neurobehavioural effects have also been found in subjectsmostly expsed to toluene, such as in the priting industiy (lregren, 1986; Hänninen et al.,1987), at levels of 300 mg/m3 (Iregren, 1986). However, in one study of priters, no sucheffect was observed (Struwe & Wennberg, 1983). (Te Workig Group noted that tests haveusually been pedormed within 24 h after the last expsure, so it cannot be determined if theeffects are of short duration or may be prolonged).
After three days of intense expsure (in sorne cases to the point of unconsciousness) toa mixure containing toluene, workers in a factoiy suffered memory disturbances that contin-ued for months (Stolleiy & Flindt, 1988). ln one study, there were indications of dyschroma-lopsia in priters expsed to a mixure of solvents, including toluene (Mergler et al., 1988).
Further indications of effects on the central and peripheral nervous systems, have beenreported in car and industril painters (Seppäläinen et al., 1978; Elofsson et al., 1980; Hus-man & Karli, 1980) and other workers (friebig et al., 1983) expsed to mixures of solvents,including toluene (see also the monograph on ocupational expsures in paint manufactureand painting). ln a study of toluene workers (Cherr et al., 1985) and in priters expsedalmost exclusively to toluene (Struwe & Wennberg, 1983; Antti-Poik et al., 1985), no effecton the peripheral nervous system was observed.
'Sniffers' (Bennett & Forman, 1980; Kroeger et al., 1980; Moss et al., 1980; Voigts &Kaufman, 1983; Batlle et al., 1988) and workers expsed accidentally to toluene (Reisin et al.,1975) have been reported to develop both renal tubular damage (e.g., acidosis) and signs ofglomerular damage, with haematuri, pyuri and proteinuri (Voigts & Kaufman, 1983).
However, severe toluene poisoning has been reported without kidney disease (Brugnone &Perbellini, 1985), and, in a study of industril spray painters expsed to a mixure of solventscontaining toluene, there was no indication of kidney disease (Greenburg et al., 1942). Laterreports of workers (mostly painters but also a series of reports that included photogravureworkers) expsed to toluene have indicated slight adverse effects on the kidney (Askergren,1981; Askergren et al., 1981a,b,c; Franchini et al., 1983), although another study showed noeffect (Luweiys et al., 1985; see also the monographs on sorne petroleum solvents and onocupational expsures in paint manufacture and painting).
Transient effects on the liver have been reported in a few 'sniffers' (Fomaziari et al.,1983; Suzuki et al., 1983); however, no disernable effect was observed in two subjects incoma followig acute toluene intoxication (Brugnone & Perbellini, 1985). Slight effects onthe liver have been noted in toluene-expsed workers (Greenburg et al., 1942), includingpriting workers (Szadkowski et al., 1976) and workers using tolueì1e-based glues (Shiojima
TOLUENE 103
et al., 1983), but not among other priters and painters expsed to toluene (Kurppa &Husman, 1982; Waldron et al., 1982; Lundberg & Håkansson, 1985; Boewer et al., 1988).
ln one proportionate mortlity study (Pganini-Hil et al., 1980) and in one cohort study(Loyd et al., 1977) of priters, who may be expsed to toluene, there was an excess of livercirhosis. (Te Workig Group noted that the effect cannnot be ascbed with certinty totoluene, since expsure to many other agents had ocurred.)
Some early studies (Wilson, 1943; Gattner & May, 1963; Klavis & Wile, 1967) relatedmajor myelotoxic effects (leukopenia, anaemia, thromboopenia and bone-marrowchanges) to expsure to toluene, which were generally assoiated with benzene contamina-tion of the toluene. Other cross-sectional studies (Bänfer, 1961; Tähti et al., 1981) have dis-played no such effect. Sorne recent studies have shown slightly increased haemoglobin lev-els (Elofsson et al., 1980) and thromOOopenia (Bevig et al., 1983, 1984) in car painters andworkers in paint manufacture expsed to toluene, among other chemicals. Minor changesinwhite bloo cells have also been reported followig expsure to toluene (Fnborská, 1973;
Matsushita et al., 1975).
ln human volunteers expsed to 20 ppm (750 mg/m3) toluene for 6 h per day for twodays, the heart rate was increased significantly (Suzuki, 1973).
(ii) Effects on ferti/ty an on pregn outcomeln the study of Holmberg (1979), descbed in the monograph on some petroleum sol-
vents, three mothers of children with central nervous system defects, but no control mother,reported havig worked with toluene du rig the first triester of pregnancy. Two of the
mothers of cases had also been expsed to other solvents. ln the study of Holmberg et al.(1982), described in the monograph on sorne petroleum solvents, three mothers of childrenwith oral clefts but no control mother reported havig worked with toluene durig the firsttriester of pregnancy. Ail three had also been expsed to other solvents.
Ericson et al. (1984) linked records of female laboratoiy workers from the 1975 Swedishcensus to maternity records for 1976. Among the 1161 birh records identified in the labora-toiy workers, 44 (3.5%) of the children were either born dead or had a significant malforma-tion. Among the 98354 deliveries in Sweden durig the same year, 250 (2.6%) had a similaroutcome. A case-cntrol study of 26 of the children who had died within seven days or whohad severe malformations and of 50 con trois chosen from among children of laboratoryworkers was then pedormed. Expsure to toluene was similar in mothers of cases (8%) andof con trois (8%); they had also been expsed to many solvents and other substances.
Axelsson et al. (1984) studied the outcome of pregnancy for 745 women born in 1935 andlater, who had been engaged in laboratoiy work at the University of Gothenberg, Sweden,between 1968 and 1979. Data on outcome of pregnancy was obtained by postal survey andfrom the Medical Birh Register and the Register of Congenital Malformations in Sweden;data on expsure to specific substances were obtained by questionnaire. Toluene expsuredurg the first triester of pregnancy was reported by 140 women, 17 of whom (10.2%) had
had a spontaneous abortion. This compares with spontaneous ahortion rates of 11.5%among women who had not worked in a laboratoiy durig the first triester and 9.0% among
104 !AC MONOGRAHS VOLUME 47
women who had worked in a laboratory but not with solvents durig the first triester.Cases and con trois had been expsed to many solvents and other substances.
Thskien et al. (1986) studied the histoiy of spontaneous abortions in women employedin eight Finnish pharmaceutical factories in 1973-80. The identity numbers of the womenwere linked to the nationwide hospital discharge data for 1973-81; 1795 pregnancies werethus identified, 142 of which were spontaneous abortions. A case-cntrol study was carredout on women with spontaneous abortions who had been employed durig the first triester
and three age-matched controls. Toluene expsure durig the first triester was reported byfactoiy physicians for seven of 38 (18%) cases, compared with 14 of 119 (12%) controls. Thecorresponding overall relative risk (RR) was 1.6 (95% confidence interval (CI), 0.6-.5); for
those exposed less than once a week, the RR was 1.2 (0.2-6.9), and for those expsed morethan once a week, the RR was 1.9 (0.6-.4). Cases and controls had had expsure to manysol vents and other substances.
McDonald et al. (1987) compared the chemical expsures of 301 women who had givenbirh to a child with a severe malformation to that of 301 controls, matched by hospital, gra-vidity, educationallevel, maternai age and date of deliveiy. Cases and controls were re-stricted to women who had given birh in Montréal in 1982-84 and who had worked for atleast 30 h per week durig the first 12 weeks of pregnancy. Chemical expsure was assessedby visiting the workplace or by telephone intervew with the employer. Overall chemicalexposure was assessed to have been more frequent in cases (21%) than in controls (16%).Wh en the solvents were divided into nine chemical categories and the malformation into sixanatomical sites, the strongest association was between aromatic solvents and uriaiy tractabnormalities (nine expsed cases, six of which were hypspadias, versus no expsed control).Six of the nine cases were assessed to have been expsed to toluene.
(iv) Genetic and related effectsNo significant difference in the frequency of chromosomal changes was observed in
peripheral bloo lymphoces of 24 workers (aged 29-6) at a rotogravure plant in Italy whowere expsed to toluene (mean value, around 20 ppm (750 mg/m3)) for three to 15 yearscompared with 24 controls matched for age and sex (Forni et al., 1971). (Te Workig Groupnoted that smokig habits were not considered.)
An excess of chromosomal aberrations (chromatid and ishromatid breaks) was re-
ported in the lymphoces of 14 Swedish workers (aged 23-54) expsed only to toluene for1.5-26 years (average level, 10020 ppm (377-750 mg/m3)) in a rotogravure priting factoiyin comparison with 49 unexpsed workers (Funes-Cravioto et al., 1977). (Te WorkigGroup noted that smokig habits were not considered, and details of controls were not giv-en.)
No increase in the frequency of chromosomal aberrtions or sister chromatid exchangewas found in the peripheral bloo lymphoces of 32 rotogravure workers in Finland (aged21-50) expsed to toluene (7-112 ppm) for three to 35 years compared to 15 unexpsed sub-jects (Mäki-Pakknen et al., 1980). No increase in the frequency of sister chromatid ex-changes was observed in seven workers in the Swedish paint industry expsed to various sol-vents, including more than 100 mg/m3 toluene (Haglund et al., 1980; see also the monograph
TOLUENE 105
on ocupational expsures in paint manufacture and painting). (The Workig Group notedthe small number of workers studied.)
Increases in the frequency of sister chromatid exchange, chromatid breaks, chromatidexchanges and gaps were reported in the peripherallymphoces of 20 workers (aged 32-6)at a rotogravure plant in the Federal Republic of Germany who had been expsed to toluene(20300 ppm (7501130 mg/m3)) for more than 16 years, compared to 24 matched con trois(Bauchinger et al., 1982). ln an abstract, a syergistic effect of smokig and expsure to tolu-ene on the frequency of sister chromatid exchange was also reported (Bauchinger et al.,1983). ln the same plant, a higher incidence of chromatid-tye aberrations than in con troiswas observed up to two years after cessation of expsure to toluene; longer after expsure,
the aberration yields reached background level (Schmid et al., 1985).The frequency of chromosomal aberrations in 20 employees at a rotogravure plant ex-
posed mainly to toluene in various priting inks was no different from that in 23 controlworkers; an increased frequency was observed in smokers in both groups (pelclová et al.,1987).
3.3 Epidemiological studies of carcinogenicity iD humans
ln each of the studies described below, expsures were mixed and overlapping, andthese studies are cited in several monographs.
Olsson and Brandt (1980) pedormed a study on solvent expsure among 25 cases ofHodgki's disease and 50 controls in Sweden (see the monograph on some petroleum sol-vents). Expsure to toluene was mentioned by six cases and three controls. Ail exposedcases and con trois were expsed to other solvents.
Austin and Schnatter (1983) pedormed a case-cntrol study on 21 deceased brain tu-mour patients and two control groups (80 employees in each) from a cohort of employees at aUS petrochemical plant, investigating 37 chemicals. Expsure to 12 of these chemicals wasmore frequent among cases than controls, but toluene was not among the se.
Wilcosky et al. (1984) pedormed a case-cntrol study of rubber workers in the USA,descbed in detail in the monograph on some petroleum solvents. Expsure to toluene wasassoiated with an increased rik for prostatic cancer (relative rik (RR), 2.6; three cases) andlymphatic leukaemia (3.0; two cases). Exsure to 'solvent it (a proprietaiy mixure contain-
ing mostly toluene) was assoted with increased RRs for stomach cancer (1.4; 15 cases),lymphosarcoma (2.6; six cases) and lymphatic leukaemia (2.8; seven cases). (The WorkigGroup noted that the number of cases in each categoiy is small, multiple expsures wereevaluated independently of other expsures, and none of the assoiations is significant.)
Carpenter et al. (1988) evaluated the possible assotion with expure to 26 chemitalsor chemical groups in 89 cases of priaiy cancers of the central nervous system and 356
matched controls in cohorts of workers at two US nuclear faciities. Toluene, xylene (seemonograph,. p. 125) and methyl ethyl ketone were evaluated as one chemical group; the
matched RR was 2.0 (28 cases; 95% Ci, 0.7-5.5) in comparin with nonexpsed workers.AImost all cases had had low expsure accrding to the classification used. The authors re-
ported that the RRs were adjusted for internai and external expsure to radiation. fle
kajo
Rectangle
106 !AC MONOGRAHS VOLUME 47
Workig Group noted that no separate analysis was reported for the three solvents, norwereexpsure levels quantified, and that there were many concurrent expsures. i
4. Summary of Data Reported and Evaluation
4.1 Exposures
Toluene is a major industril chemical derived mainly from petroleum refining. Majoruses of toluene are in the production of benzene and as a solvent in paints, inks and adhe-sives. Toluene-cntaining petroleum distilates are extensively and increasingly used in gas-oline blending. Toluene is ubiquitous in the envionment and is present at high levels inmany ocupational settings.
4.2 Experimental carcinogenicity data
Toluene was tested for carcinogenicity in one stra of rats by gastric intubation at onedose level and in one strain of rats by inhalation. These studies were inadequate for evalua-tion. Toluene was used as a vehicle control in a number of ski painting studies. Sorne ofthe se studies were inadequate for evaluation; in others, repeated application of toluene tothe ski of mice did not result inan increased incidence of ski tumours.
4.3 "uman carcinogenicity data
Toluene was mentioned as an expsure in four case-cntrol studies involvig severalanatomical sites of cancer. The results could not be evaluated with regard to toluene itself.
4.4 Other relevant data
ln humans, prolonged ski contact with toluene may cause nonallergic contact derma-titis. Exsure to toluene also causes nervous system syptoms and signs. Excessive exp-sure to toluene may cause adverse effects on the kidney and liver.
Adverse effects on the nervous system have been observed in experiental animais.
ln the available studies on spntaneous abortion, periatal mortity and congenitalmalformations in humans, the numbers of cases were small and the mothers had also beenexpsed to other substances.
Embiyotoxicity has been seen in some studies in mire and rats but not in rabbits. Em-biyotoxic effects generally ocrred concurrently with maternai toxicity.
Increased frequencies of sister chromatid exchange and chromosomal aberrations inperipheral lymphoces were observec in one study of workers expse to toluene but not intwo studies of chromosomal aberrtions, one of sister chromatid exchange and one in whichboth effects were investigated. These studies are inconclusive with regard to expsure totoluene.
TOLUENE 107
Toluene induced chromosomal aberrtions in rats and micronuclei in mice and rats.Sister chromatid exchange and chromosomal aberrations were not induced in cultured hu-man lymphoces, in the absence of an exogenous metabolic system. Toluene did not inducemorphological transformation in cultured animal cells. Toluene induced DNA damage incultured animal cells. It did not induce mutation or chromosomal aberrations but-inducedaneuploidy in Drosophila. It did not induce DNA damage or mutation in bacteria. (See Ap-pendix 1.)
4.5 Evaluation 1
There is inadequate evdence for the carcinogenicity of toluene in humans.There is inadequate evidence for the carciogenicity of toluene in experiental animais.
Overall evaluationToluene is not classifiable as to its carcinogenicity to humans (Group 3).
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