acalculated from mg/m3 = (molecular weight/24.45) X ppm, assuming standard temperature (25 . C) and pres-sure (760 mm Hg)
Infrared, ultraviolet and nuclear magne tic resonance spetraldata have been reported
Soluble in ethanol, diethyl ether, acetone, benzne; insoluble inwater
6.8 at 25.C 8.3 at 25.C 8.9 at 25.C
1.4 Technical products and impurities
Trade Nam: Chromar; Dilan; ScintilarXylene is marketed pricipally as a mixure of ortho, meta and para isomers, generally
referred to as 'mixed xylenes'. The individual ismers are also available commercially. Mostmixed xylenes contain ethylbenzene, except for a small volume produced by toluene dispro-portionation (Ransley, 1984). Commercial-grade (mixed) xylene tyically is composed of ap-proxiately 20% ortho-xylene, 40% meta-xylene and 20% paa-xyle,e, with about 15%
ethylbenzene and smaller amounts of toluene, triethylbenzene (pseudocumene), phenol,thiophene, pyrdine and non-aromatic hydrocrbns (National Institute for OccupationalSafety and Health, 1975; Clement Assoiates, 1977). A product of higher purity is reportedto contain a minimum of 97% xylene isomer with maxum impurities of 3% ethylbenzene,0.1% benzene, 0.1% toluene and 0.01% water (Riedel-de Haën, 1984).
32
2.77-3.12
29
3.2
27
3.15
mg/m3 = 4.34 X ppma
Highly inflammable
XYLNE 127
Typical para-xylene products (99.5% pure) contain 0.3% ethylbenzene, 0.1 % meta-xy-lene and 0.1 % ortho-xylene (Rnsley, 1984). Ali three ismers are available at 99.9% mini-
mal high purity, spectrophotometric grade as well as in 'chemically pure' grades, as follows:ortho-xylene, 98% pure; paa-xylene, 99%; and meta-xylene, 99% (Riedel-de Haen, 1984).
2. Production, Use, Occurrnce and Analysis
2.1 Production and use
(a) Production
Xylene ocurs in petroleum stock, but in veiy small quantities. It is produced priariyby the catalytic reforming of naphtha streams, which are rich in alicyclic hydrocrbns. Thearomatic reformate fractions consist mainly of benzene, toluene and mixed xylenes, xylenesrepresenting the largest fraction. The xylene ismers are separated from the reformate byextraction and distilation on the basis of differences in boiling-point. ortho- Xylene, whichhas the highest boiling point, is separated as the bOttom distilate; paa-xylene is separated bycontinuous ciystalliztion or adsorption from the mixed xylenes or isomeried from themeta-xylene/paa-xylene distilate; and meta-xylene is obtained by selective ciystalliztionor solvent extraction of meta-pra mixures (Mannsvle Chemical Products Corp., 1981;Ransley, 1984).
Another source of mixed xylenes is pyrolysis gasoline, a by-product that results fromcrackig of hydrocrbn feeds durig olefin manufacture (Fishbein, 1985). The mixed xylene
content of pyrolysis gasoline varies, depending upon the feed and the severity of the crackigprocess. Pyolysis gasoline is a less efficient source for recoveiy of mixed xylene than catalyt-ic reformate because it contains large amounts of ethylbenzene.
Mixed xylenes may also be produced from petroleum refining operations by the ToyoRayon.and Atlantic-Riehfield processes, in which toluene is transalkylated or disproportion-ated. Benzene and toluene are the pricipal products (Fishbein, 1985). Xylenes obtainedfrom this source are 'ethylbenzene free', provided the transalkylationfeed stocks are limitedto toluene and (plymethyl)benzene (Ransley, 1984).
Less than 1 % of the mixed xylenes in the USA are derived from coal. Coal subjected tohigh-pressure carbniztion (coke manufacture) yields crude light oil containing 3-6%mixed xylenes. Eveiy tonne of coal yields 2-3 gallons (7.6-11.41) of crude light oil (Ransley,1984), which may be used as a supplementaiy source of aromatic compounds in petroleumrefining, processed for recovery of light naphtha containing mixed xylenes and styene, orburned as fueL.
The Mitsubishi Gas Chemical Company (MG CC) process is another commercialmethod for separating the meta ismer from mixed xylenes using a hydrofluoric acid-boro-fluoride separation technique. It is also a straightforward means of separating the other Caaromatic isomers (Ransley, 1984).
The total quantities of mixed xylenes (and the percentages isolated as xylene) producedin the USA in 1978 in the ways descnbed above were as follows: catalytic reformate, 34.9
IARC MONOGRAPHS VOLUME 47
million tonnes (10%); pyrolysis gasoline, 375 thousand tonnes (52%); toluene disproportion- ation, 90 thousand tonnes (54%); and coal-derived, 15 thousand tonnes (88%). Of the total 35.44 million tonnes produced in 1978, about 11% was isolated (Fishbein, 1985).
Mixed xylenes are also produced in large quantities in Europe and Japan. Data on pro- duction of xylenes in a number of areas are presented in Tmble 2.
Table 2. Annual production of xylenes (thousands of tonnes)"
Country or region 1981
~ r a z i l ~
Bulgaria
Canada
China
Czechoslovakia
France
Germany, Federal Republic of
Hungary
India
Italy
Japan
Korea, Republic of
Mexico
Portugal
Romania
Spain
l3iwan
Tbrkey
USA
USSR
Yugoslavia
"From US International Bade Commission (1982, 1983, 1984); Anon. (1985); US International Bade Com- mission (1985, 1986); Anon. (1987); US International Bade Commission (1987); Anon. (1988a,b) bortho-~ylene %A, not available
XYLENE 129
(b) Use
Mixed xylenes recovered from all sources (petroleum refineries, pyrolysis gasoline,coal-tar) are used in the chemical and solvent industries (Rnsley, 1984). AIthough islatedxylenes are also blended into gasoline to improve octane rating, the refoimate without isola-tion of mixed xylenes or other aromatics is priariy used for gasoline blending. Unleadedpremium gasoline has been reported to contain 10-22% xylenes (Korte & Boedefeld, 1978;Ikeda et al., 1984).
Mixed xylenes are also used in the manufacture of perfumes (Sittig, 1985), insecticides,pharmaceuticals and adhesives and in painting, priting, rubber, plastics (Sandmeyer, 1981) .and leather industries (IARC, 1981).
ln the USA most of the production of islated mixed xylenes is separated into the indi-vidual ismers for use as chemical intermediates or as solvents (Mannsvile Chemical Prod-ucts Corp., 1981). The approxiate distributions of the production of mixed xylenes in theUSA are as follows: paa-xylene, 50%; gasoline blending, 10-25%; ortho-xylene,10-15%; solvents, 10%; ethylbenzene, 3%; andmeta-xylene, 1% (Ransley, 1984). para-Xy-lene is used pricipally to manufacture terephthalic acid and dimethylterephthalate, used inthe production of saturated polyester resins and fibres (Mannsvile Chemical ProductsCorp., 1981). The remaining small amount of para-xylene produced is used as a pharmaceu-tical or pesticide intermediate and in solvents for adhesives and coatings (Hawley, 1981;Anon., 1986). ortho-X ylene is used priariy as a feedstock for the manufacture of phthalic
anhydride: almost 60% of the ortho-xylene produced in the USA in 1978 was used in this way(Fishbein, 1985). It is also used as a chemical intermediate in sythesis of dyes, pharmaceuti-cals and insecticides (Hawley, 1981; Ransley, 1984). meta-Xylene is used in the manufactureof isphthalic acid for polyester resins (Mannsvile Chemical Products Corp., 1981) and as achemical intermediate for dyes and insecticides (Hawley, 1981).
(c) Regulatory status and guidelines
Occupational expsure limits for xylenes in 32 countries or regions are presented inThble 3.
Table 3. Occupational exposure limits for xylenes (ail isomers)a
Country or region Year Concentrationb InterpretationC( mg/m3)
Austria 1985 435 1WABelgium 1985 S 435 1WABrazl 1985 S 340 1WABulgaria 1985 50 1WACommision of the Europen 1986 435 AverageCommunities 2175 MaxmumChile 1985 S 348 1WAChina 1985 100 1WA
130 !AC MONOGRAHS VOLUME 47
Table 3 (contd)
Country or region Year Concentrationb InterpretationC(mg/m3)
655 STELMexico 1985 S 435 1WANetherlands 1986 S 435 1WANorway 1981 435 1WAPoland 1985 100 1WARomania 1985 S 300 1WA
S 400 MaxmumSweden 1987 S 200 1WA
S 450 STEL (15 min)Switzrland 1985 S 435 1WA1àiwan 1985 435 1WAUK 1987 S 435 1WA
S 650 STL(10 min)USAd
OSHA 1988 200 1WA300 Ceiling
NIOSH 1986 434 1WA868 Ceilig (10 min)
ACGIH 1988 435 lWA655 STL (15 min)
USSR 1985 50 Ceiling
XYLENE 131
Table 3 (contd)
Country or region Year Concentrationb InterpretationC( mg/m3)
Venezuela 1985 S 435 1WAS 655 Ceilng
Yugoslavia 1985 50 1WA
tlrom Direktoratet for Aridstilsynet (1981); National Swedish Board of Ocupational Safety and
HeaIth (1984); Areidsinspectie (1986); Commission of the European Communities (1986); Institut Na-tional de Recherche et de Sécurité (1986); National Institute for Ocupational Safety and HeaIth (1986);Cook (1987); Health and Safety Executive (1987); i:õsuojeluhaIItus (1987); American Conference ofGovemmental Industrial Hygienists (1988); Arjdstilsyet (1988); Deutshe Forshungsgemeinschaft(1988); US Ocupational Safety and Health Administration (1988)iJ, skin notation9WA, 8-h time-weighted average; STEL, short-tenn expure limit"OSHA, Occupational Safety and HeaIth Administration; NIOSH, National Institute for Occupation-al Safety and Health; ACGIH, American Conference of Govemmental Industrial Hygienists
2.2 Occurrence
(a) Naturaloccurrence
Mixed xylenes are present in coal-tar, petroleum stocks (Fishbein, 1985) and naturalgas (Hilard, 1980) in small quantities.
(h) Occupational expsure
On the basis of a US National Occupational Expsure Survey, the National Institutefor Occupational Safety and Health (1983) estimated that 1106 80 workers were potentiallyexpsed to xylene in the USA in 1981-83.
Levels of xylene to which workers have been expsed are summaried in Thble 4. Lev-els determined durig the manufacture and application of paints are described in the mono-graph on ocupational expsures in paint manufacture and painting (see p. 329). Levels ofexpsure to xylene in petroleum refining and in the manufacture and use of petroleum fuelsare reported in Volume 45 of the Monographs (lARC, 1989).
Pre- and post-shift concentrations of methyl hippuric acid in the urie of workers in a
shipbuilding yard were 0.2-7.1 mg/mL. The workers were using a thinner in spray-paintingoperations that contained 32.8% meta- or para-xylene (Ogata et aL., 1971). Mean uriaiyconcentrations of methyl hippuric acid in workers in a photograph album manufacturigplant who used a c1eaning solvent (complex mixure of 90% C7-C9 aliphatic hydrocrbons,5% toluene and 5% xylene) to rem ove excess glue were 0.07 g/g creatinine before a shift and0.48 g/g creatinine afterwards (Baker & Fannick, 1983).
(c) Air
Mixed xylenes are emitted to the ambient air durig their production and use from
reactor, distilation and ciystalliztion vents. Emissions mayalso ocur durig storage, load-ing and handling. Total emissions of mixed xylenes in the USA in 1978 were estimated to be
132 lAC MONOGRAHS VOLUME 47
4100 tonnes from catalytic reformate, 150 tonnes froID pyrolysis gasoline, 18 tonnes fromtoluene disproportionation and 19 tonnes from coal-derived production. Emissions of totalindividual isomers were estimated to be 1180 tonnes of ortho-xylene, 290 tonnes of paa-xy-lene and 80 tonnes of meta-xylene (Fishbein, 1985). Merian (1982) reported that worldwidelosses of xylenes into air froID refineries, evaporation of gasoline, automobile exhaust andsolvent losses are approxiately 3 milion tonnes.
Table 4. Occupational exposure to xylene
Environment ReferenceSamplinga Concentration in airb
Mixed xylene are also lost durig use, as in the processing of chemicals and solvents,evaporation durig transprttion, distnbution, storage and use of gasoline, in motor vehicle
emissions and from agricultural sprayig (Fishbein, 1985).
Atmospheric concentrations of total mixed xylenes have been determined at variousloctions around the world. Mean values and ranges measured between 1961 and 1980 are as
follows: (in mg/m3): France (0.003-0.01), Federal Republic of Germany (rural, 0.001-0.04;urban, 0.15), Japan (0.06.39), the Netherlands (urban, 0.07), South Africa (0.02-0.03) andSwitzerland (urban, 0.02-0.05). ln the USA, mean concentrations of atmospheric xylene aturban sites in California, Texas and New York/New Jersey in 1961-74 were 0.08-0.12,0.04-0.07 and 0.15 mg/m3, respectively (Merln & Zander, 1982). Xylene levels of 116-84mg/m3 have been reported in smoke from forest fires (Merln & Zander, 1982), and xylenehas been detected in cigarette smoke (Holzer et al., 1976). Concentrations of meta-xylene inoutdoor air in the USA have been reported to range from 0.016 to 0.061 ppm (0.069-0.265mg/m3; Fishbein, 1985).
Xylene has been detected in indoor envionments as a consequence of cokig, fuel
burning and tobacc smokig. The mean concentrations of combined meta- and para-xy-lenes in indoor air were 0.029, 0.021 and 0.014 mg/m3 in kitchens, other rooms and bedrooms,respectively (Seifert & Abraham, 1982; Wallace et al., 1983). Holzer et al. (1976) found ap-proxiately 50 ppb (0.2 mg/m3) meta- plus paa-xylene in nonventilated cigarette smoke-
filed room air and 18 ppb (0.08 mg/m3) in the air of a room where no cigarettes had beensmoked.
Outdoor air next to dwellings contained 0.00-0.028 mg/m3 combined meta- and para-
xylenes and that in backyards, 0.0011 mg/m3 (Seifert & Abraham, 1982; Wallace et aL., 1983);0.002 mg/m3 ortho-xylene was measured in backyards (Wallace et al., 1983), and 0.1 mg/m3meta- and paa-xylenes was measured at trafic intersections (Seifert & Abraham, 1982).
Krotoszyski. et al. (1979) reported mean levels of 0.001, 0.003 and 0.0031 mg/m3ortho-, meta- and paa-xylene, respectively, in expired air of 54 normal, healthy volunteersfrom an urban population in Chicago, IL, USA. Xylene was also found in breath samplesfrom urban residents of two New Jersey cities in the USA; mean values were 0.0034 mg/m3for ortho-xylene and 0.00 mg/m3 for combined meta- and paa-xylene. Levels were higherin persons who pumped their own gasoline or were expsed to auto and truck exhaust (Wal-lace et al., 1984).
(d) Water
Xylenes have been identified in sudace and drikig-waters, for example in the river
Glatt, a tnbutaiy of the Rhine. ln the USA, levels of 2-8 ,.g/l were reported in sudace waterfrom the Florida Bay and 3-8 ,.g/l in drikig- and tap-water in New Orleans, LA (Merian &Zander, 1982).
(e) Anma tissuesOgata and Miyake (1973) measured mean concentrations of 21.7,30.1 and 25.0 mg/kg
meta-,para- and ortho-xylene in the muscles and 5.2, 26.6 and 6.1 mg/kg of the three ismers,respectively, in the liver of eels (Agilla japonica) expsed to sea water containing 14.1 mg/kgmeta-xylene and 13.1 mg/kg ortho-xylene.
134 IAC MONOGRAPHS VOLUME 47
2.3 Analysis
Selected methods for the analysis of xylene in various matrices are listed in Thble 5.Methods for the analysis of xylene have recently been reviewed and compiled (Fishbein &O'N eil, 1988).
Colorietric detection systems have been developed for xylenes in air (Te FoxboroCo., 1983; Sensidyne, 1985; National Draeger, Inc., 1987; SKC, 1988; ENMET Corp., un-dated; Matheson Gas Products, undated; Roxan, Inc., undated).
3. Biological Data Relevant to the Evaluation of
earcinogenic Risk to Humans
3.1 Carcinogenicity studies in animais
Oral administration
Mouse: Groups of 50 male and 50 female B6C3F1 mice, eight weeks of age, received 0,500 or 100 mg/kg bw technical-grade xylene (comprising 60.2% meta-, 13.6% para- and9.1 % ortho-xylene with 17% ethylbenzene; purity, 99.7% with 2.8 ppm (0.0028%) benzeneas contaminant) in corn oil by stomach tube on five days per week for 103 weeks. The animaiswere kiled in weeks 104105. No significant difference in mean boy weights or survval wasobserved between control and treated miee. Survval at termination of the experient was:males - 27 controls, 35 low-dose and 36 high-dose; and females - 36 controls, 35 low-doseand 31 high-dose. No treatment-related increase in the incidence of any tumourwas seen inanimais of either sex (National Toxicology Program, 1986; Huff et al., 1988).
Rat: Groups of 40 male and 40 female Sprague-Dawley rats, seven weeks of age, wereadministered 50 mg/kg bw mixed xylenes (ortho-, meta- and para-; purities, :: 99% (sourceand percentage composition unspecifiedD in olive oil by stomach tube on four to five days perweek for 104 weeks. A group of 50 males and 50 females received olive oil only. Rats weremaintained until natural death; all rats had died by week 141. At that time, thymomas werereported in 1/34 treated males and 0/36 treated females, compared to 0/45 and 0/49 in thecontrol groups. Other haemolymphoreticular tumours (histology unspeciied) were re-ported in 4/34 treated males and 3/36 treated females, compared to 3/45 and 1/49 controls.(Te denominators are numbers of rats alive in each group at 58 weeks when the first haemo-lymphoreticular tumour was observed.) The authors reported an increase in the total num-ber of animais with malignant tumours (tye unspecified) at 141 weeks: in 14/38 treatedmales and 22/40 treated females compared to 11/45 and 10/49 controls. (Te denominatorsare the number of rats alive in each group at 33 weeks when the first malignant tumour wasobserved.) (Maltoniet al., 1983, 1985). f1e Workig Group noted the incomplete reportingof the composition of the test materil and of tumour pathology, and that combining differ-ent tyes of tumours is not usually the most approprite method for evaluating carciogenic-ity (lARC, 1980; Montesano et al., 1986). J
XYLENE 135
Table 5. Analytical methods for the determiDatioD of xyleDe and its metabolites iD varionsmatrices
Water Extract with hexane; Ge-FID S Ilgll Otsn & Wil-inject aliquot liams (1981)
Heat samples in wa- Ge-MS 1 J.gll Otson et al.ter bath at 2S-C for (1982)1 h; inject head-space aliquots
Automotive ex- Tenax GC poly- Desrb thennally GC-MS Not given Hampton et al.haust gas mer adsorbant into liquid nitrogen- (1982)
cartridge cooled capilaiy trap
Breath (air) S pecially de- Diy cartridge over GC-MS Not given Wallace et al.signed spirome- calcium sulfate; de- (1983, 1984,ter containing sorb thennally in a 1986)Tenax-GC car- fused silica capilaiytridge column
Bloo Hepariniz or Purge (nitrogen) at GC-MS 10 ppt Cramer et al.antifoam emul- room temperature;
(J.gll ) (1988)sion B trap (lnax TA); de-
sorb thennally; ana-
ly volatiles on col-umn
TIssue (musle, Mince tissue Heat with ethanol Ge-FID Not given Ogata & Miy-liver) and potassium hy- ake (1973,
droxide; extract with 1978)n-hexane; apply ex-tract to silca gel/-
Urine (methyl- After alkaline hy- Ge-FID Not given Engstrõm &hippuric acid) drolyis, extract with Riihimãki
diethyl ether at acid- (1988)ic pH; silylate andinjet onto Ge
4Abbreviations Ge, ga chromatography; FID, flame-ionition detection; MS, mas spectrometry
136 lAC MONOGRAHS VOLUME 47
Groups of 50 male and 50 female Fisher 344/N rats, seven weeks of age, received 0,250or 50 mg/kg bw technical-grade xylene (containing 60.2% meta-, 13.6% paa- and 9.1%ortho-xylene with 17% ethylbenzene; purity, 99.7% with 2.8 ppm (0.0028%) benzene as con-taminant) in corn oil by stomach tube on five days per week for 103 weeks. The animais werekiled in weeks 104-105. High-dose males had lower mean bo weights from week 59 on-wards; body weights of low-dose males and treated females were comparable to those of con-trois. At termination of the experient, 36 male controls and 25 males at the low dose and 20
at the high dose were stil alive; the differences were due in part to accidental kiling of ani-mais. Survval in control and treated females was similar at termination (38 controls, 3310w-dose and 35 high-dose). The incidences of tumours in treated animais of either sex were notsignificantly higher than that in the control group (National Toxicology Program, 1986; Huffet al., 1988).
3.2 Other relevant data
The toxicology of xylenes has been reviewed (Riiimäki & Engström, 1979; WorldHealth Organiztion, 1981; Fishbein, 1985; European Chemical Industiy Ecology and Toxi-
cology Centre, 1986).
Ca) Exprimental systems
(i) Absorption, distribution, excretion and metabolismortho- Xylene was found to penetrate rat ski excised three days after clipping and depi-
lation with cream at a rate that was 1/10 that of toluene and 1/100 that ofbenzene (Iuruta,1982).
ln rats expsed to 208 mg/m3 (methyl-14C)pa-xylene for 1 h, distnbution of radioac-tivity immediately after termination of the expsure was highest in the kidneys, followed bysubcutaneous fat, ischiatic nerve, bloo, liver and lungs. Activity was 1/5 to 1/30 of theselevels 6 h after the end of expsure (Carlsson, 1981). -
Xylenes are metabolized both in the liver and lungs (Carlone & Fouts, 1974; Smith etal., 1982; Toftgård et al., 1986), priariy at a side-chain, to form methylhippuric acid andtoluic acid (methylbenzoic acid) glucuronide as major metabolites and methylbenzyl mercap-turic acid as a minor metabolite (Carlone & Fouts, 1974; Ogata et al., 1980; van Doorn et al.,1980). They are metabolized to a lesser extent at the aromatic rig to form dimethylphenol(e.g., Toftgård et al., 1986). The ratio among the metabolttes varies depending on the isomer(Bray et al., 1949; Bakke & Scheline, 1970) and the species of animal (e.g., Ogata et al., 1980).
Most of the xylene that is absorbed is excreted rapidly into the urie as metabolites.
When rabbits were given oral doses of up to 1.8 g each of the three ismers, separately, wellover 50% of the radioactivity was recovered in urie within 24 h (Bray et al., 1949).
When 3 mmol/kg ortho-, meta- or paa-xylene were given intraperitoneally to rats, un-naiy excretion of thiocmpounds was highest with ortho-xylene and much lower with meta-
xylene and para-xylene (van Doorn et al., 1980).ln male rats expsed to meta-xylene vapour at concentrations of 20, 1700 or 320 mg/
m3 for 6 h per day on five days per week for two weeks, xylene concentrations in brain and
XYLENE 137
perienal fat were increased durig the second week of expsure (Savolainen & pfåffli,1980).
Pregnantmice were expsed by inhalation to 14C-paa-xylene (theoretical concentra-tion, 20 ppm (8680 mg/m3)l for 10 min on days 11, 14 or 17 of gestation, and distnbution ofthe label was determined 0, 0.5, 1 and 4 h after expsure. The label quickly entered the em-biyo, but uptake was low relative to maternai tissues. Ali fetal activity was extractable, indi-cating that no firly bound metabolite was present (Ghantous & Danielsson, 1986).
(ii) Toxic effects
Oral LDso values for ortho-xylene, meta-xylene, paa-xylene and the isomer mixure inrats range between 360 and 580 mg/kg bw (Wolf et al., 1956; European Chemical IndustiyEcology and Toxicology Centre, 1986). The intraperitoneal LDsos of the pure isomers in
male mice ranged from 1360 to 2100 mg/kg bw (Mohtashampur et al., 1985). An inhalationLCso (4 h) for the isomer mixure in male rats has been determined as 6700 ppm (29078mg/m3; Carpenter et al., 1975). The 6 h-inhalation LCsos of the pure isomers in female mIcewere 390-5300 ppm (17 0023 () mg/m3; Bonnet et al., 1979).
A 4-h percutaneous administration of 44 mg/kg bw of mixed xylenes to three male
rabbits resulted in the death of one rabbit on the fifth day after expsure. At dose levels of1700 mg/kg bw, none of three rabbits died (Bine & Zuidema, 1970).
Ten to 20 applications of undiluted mixed xylenes on the ears or shaved abdomen ofrabbits for two or four weeks resulted in moderate to marked eiyhema and oedema, withsupedicial necrosis at both sites. Mter introduction of two drops of mixed xylenes into therabbit eye, slight conjunctival irtation and transient corneal injuiy were observed (Wolf etal., 1956). Application of undiluted xylene to the eye caused corneallesions in cats (Schmid,1956).
Rats were expsed by inhalation for 4 h to 250, 580, 12 00, 26 () and 43 () mg/m3mixed xylenes. Ail rats at the highest concentration and 4/10 at 26 () mg/m3 died; xylene-induced pneumonitis was noted in two of the rats that died. Prostration was noted with43 00 and 12 () mg/m3 and poor cordination with 580 mg/m3; no such sign was observed
at the lowest expsure concentration. Expsure of four male cats to 4100 mg/m3 mixedxylene vapour for 2 h resulted in ataxa, spasms and anaesthesia, followed by death (Carpen-ter et al., 1975).
Expsure of rats by inhalation to meta-xylene at concentrations of 200, 1700 or 3200mg/m3 for 6 h per day on five days per week for two weeks resulted in changes in the activitiesof brain enzyes (NADPH-diaphorase, azoreductase and superoxide dismutase), whichwere reversible two weeks after cessation of expsure (Savolainen & pfäffli, 1980). Changesin open-field behaviour were observed in rats expsed by inhalation to 300 ppm (1300 mg/m3) for 6 h per day for five to 18 weeks (Savolainen et al., 1979).
Intraperitoneal administration of 1 g/kg bw xylene resulted in an increase in serum or-nithine carbamyl transferase activity and lipid accumulation in the liver of rabbits and gui-nea-pigs, indicating liver damage (DiVincenzo & Krasavage, 1974). Similarly, increases inliver enzye activities in the serum of rats expsed by inhalation to 150 ppm (6510 mg/m3)para-xylene for 4 h (Patel et al., 1979) and to 40 ppm (1730 mg/m3) meta-xylene for 6 h per
138 IAC MONOGRAHS VOLUME 47
day on five days per week for two weeks (Elovaara, 1982) are indicative of xylene-inducedliver damage. Expsure of rats to 60 ppm (26 mg/m3) xylene durig the light period of theday for four weeks (Toftgård et al., 1981) or to 20 ppm (8680 mg/m3) ortho-,paa- or meta-
xylene for 6 h per day for three days (Toftgård & Nielsen, 1982) induced microsomal cyoch-rome P450. Repeated oral administration (1 g/kg per day) of ortho-, meta- or paa-xylene torats for three days (Pkkö, 1980) or intermittent expsure of rats by inhalation to 300 ppm(1300 mg/m3) xylene on 6 h per day for two weeks (Savolainen et al., 1978) also increased theactivities of drug metabolizing enzyes in the liver and kidney. Inhalation expsure ofgroups of rats to 300 mg/m3 paa-xylene on day 10 or on days 9 and 10 of gestation (dailyduration was presumably for 24 hl reduced concentrations of progesterone and 17ß-oestra-diol in the maternai circulation (Ungváiy et al., 1981).
ln sorne rats expsed to 300 mg/m3 mixed xylenes for 8 h per day on six days per weekfor 110-130 days, expsure resulted in paralysis of the hind legs, weight loss, a slight decreasein leukoces, increases in bloo urea, uriaiy bloo and albumin, and hyperplasia of the
bone marrow. Slight congestion of kidney, liver, heart, adrenal, lung and spleen were ob-served. Cellular desquamation of glomeruli and necrosis of the convoluted tubules werealso reported (Fabre et al., 196).
Rats, guinea-pigs, monkeys and dogs were expsed either to 780 ppm (3368 mg/m3)ortho-xylene for 8 h per day on five days per week for six weeks or to 78 ppm (337 mg/m3)continuously for 90 days. No significant change in boy weight or in haematological parame-ters and no significant toxicity were observed after histopathological examination of all ma-jor organs (Jenkis et al., 1970).
Groups of four male rats and four male dogs were expsed for 6 h per day on five daysper week for 13 weeks to 180, 46 or 810 ppm (770, 20 or 350 mg/m3) mixed xylenes. Nosignificant effect was reported on boy weight, haematology, bloo chemistiy, urie chemis-tiy, organ weight or macroscpic and microscpic pathology at any concentration tested(Carpenter et al., 1975).
Groups of 15 male rats were expsed by inhalation to 350 ppm (15 20 mg/m3) ortho-xylene for 8 h per day for one or six weeks. Slight decreases in boy weight gain and increasedliver weight were observed in both groups (Tátrai & Ungváiy, 1980).
(ii) Effects on reproduction and prenatal toxicity
The teratogenic and developmental effects of xylene have been reviewed (Hoo &Otley, 1985).
Groups of 30 Mallard eggs were expsed by immersion for 30 sec in a 1 or 10% aqueoussuspension of xylene on day 3 or 8 of incubation; control eggs were immersej in distiledwater. No significant effect was observed on the growth, survval or development of embiyosexamined at day 18 of incubation (Hoffman &Eastin, 1981).
ln one study reported in an abstract (Nawrot & Staples, 1980), expsure of CD-l miceto 0.75 or 1.0 ml/kg bw of any of the three ismers on days 6-15 of gestation was reported tocause maternai toxicity and fetal death; cleft palates were also reported in fetuses expsed tothe ortho- and paa-isomers. Wh en the experient was repeated with meta-xylene, a low
but statistically significant incidence of cleft palates ocurred after repeated expsures to 1.0
XYLENE 139
ml/kg bw in the absence of overt maternai effects. (Te Workig Group noted that the doseswere incorrectly expressed as mg, rather than ml, in the abstract.) Marks et al. (1982) expsedCD-l mice to ,0.52-4.13 g/kg bw mixed xylenes on days 6-15 of gestation. Ail dams and fe-tuses at the highest dose died, and dams died at 3.1 g/kg bw. Fetal vibility was reduced at thisdose, and growth at 2.06 g/kg bw. Cleft palate and wavy nbs were seen with 2.06 g/kg bw andabove. (Te Workig Group noted an error in the paper in converting the dose from volumeper kiogram to mass per kiogram.) ln ICR/SIM mice given meta-xylene at 20 mg/kg bwon days 8-12 of gestation, no significant effect was seen on maternai toxicity or postnatalgrowth or on viatilty of the offsprig (Seidenberg et al., 1986).
ln one study reported as an abstract, ICR mice were expsed to 0,50, 100 and 20ppm (2170, 4340 and 8680 mg/m3) xylene on days 6-12 of gestation. It was stated that fetalgrowth was retarded at the two highest dose levels and that there was a dose-related increasein the frequency of supernumeraiy nbs and delayed ossification of the sternebrae. At thehigh dose, growth retardation persisted into the postnatal period (Shigeta et al., 1983). (TeWorkig Group noted that the reporting of the experiental design and results were insuffi-cient to evaluate many of the parameters.) CFLP miee were expsed to 0, 50 or 100 mg/m3xylene or to 50 mg/m3 ortho-, meta- or paa-xylene for 24 h per day on days 6-15 of gesta-tion. Fetal growth and skeletal retardation were reported at the highest doses (Ungváiy &Tátrai, 1985). (Te Workig Group noted that this paper is a compendium of data on rats,mice and rabbits from one laboratoiy and presents few details of experiental results.)
ln CFY rats, fused sternebrae and extra ribs were observed in fetuses of dams expsedto 100 mg/m3 xylene for 24 h per day on days 9-14 of pregnancy, in the absence of maternaieffects (Hudák & Ungváiy, 1978). ln another study in CFY rats using levels of 0,250, 190 or340 mg/m3 xylene given on days 7-15 of gestation, it was stated that maternai effects weremoderate and dose-dependent; the highest dose resulted in decreased embiyonIc viabilityand fetal growth as well as an increased incidence of extra ribs; skeletal retardation was seenwith all three doses (Ungváiy & Tátrai, 1985). (Te Workig Group had the same reserva-tions about this paper as expressed above.) Mirkova et al. (1983) reported fetal growth retar-dation followig expsure ofWistar rats to 50 and 50 mg/m3 xylene on days 1-21 of gesta-
tion; these effects were not seen with 10 mg/m3. The growth retardation persisted throughpostnatal day 21. (Te Working Group noted that the reporting of the experiental designand results were insufficient to evaluate many of the parameters.)
CFY rats were expsed via inhalation to ortho-, meta- or pdra-xylene (analytical purity)at concentrations of 0, 150, 150 and 300 mg/m3 for 24 h per day on days 7-14 of gestation.Foo consumption was reduced at the two higher concentrations of ortho-xylene and in thegroups expsed to the highest level of meta- and of para-xylene. Expsure to 300 mg/m3meta-xylene kiled 4/30 dams and reduced weight gain in the survvig dams; 2/20 and 7/20 of
the females receivig the high doses of ortho- and para-xylene, respectively, resorbed theirentire litters. Increased maternalliverweightboy weight ratios were observed in all groupsexpsed to ortho-xylene. Fetal boy weights were reduced by the two highest levels of ortho-
xylene and by the highest level of meta- and of para-xylene; fetal viabiltywas affected only by
the highest dose level of paa-xylene. There was no indication that anyxylene isomer causedvisceral abnormalities in fetuses in a dose-related manner, but skeletal development. was
140 IAC MONOGRAHS VOLUME 47
retarded by the high concentration of onho-xylene and by all concentrations of para-xylene.Extra ribs were seen in significantly more fetuses in the groups expsed to the high doses ofmeta- and para-xylene (látrai et al., 1979; Hudák et al., 1980; Ungváry et al., 1980). (TeWorkig Group noted that the analysis supporting this observation is based on data on fe-tuses, rather than on data on litters, the customaiy unit of comparison.)
Groups of 25 Sprague-Dawley rats were expsed by inhalation to 0,350 or 700 mg/m3para-xylene (purity, 99%) for 6 h per day on days 7-16 of gestation, and the offsprig wereevaluated for growth, viabilty and neurobehavioural development. The high dose level re-duced maternai weight gain durig the expsure period, but growth, viabilty, locmotor ac-tivity and the acoustic startle response of the offsprig were not affected (Ros en et al., 1986).
Groups of New Zealand white rabbits were expsed to 0 (60 animais in a poled controlgroup), 500 or 100 mg/m3 of onho-xylene, meta-xylene, para-xylene or xylene (compositionunspecified) for 24 h per day on days 7-20 of gestation. Fetuses were examined by routineteratological techniques on day 30 of gestation. It was stated that for each solvent the high-dose level produced mild maternai toxicity (no data were presented for the 100mg/m3ortho- and meta-xylene group). Maternai death and abortion were noted with both xylene
andpara-xylene at 100 mg/m3. The boy weights of female fetuses expsed to 50 mg/m3xylene were significantly reduced, but no other effect on fetuses was reported (Ungváiy &Tátrai, 1985). fle Workig Group noted that this paper is a compendium of data on rats,mice and rabbits from one laboratoiy and presents few details on experiental results.)
(iv) Genetic and related effectsThe genetic and related effects of xylene have been reviewed (Dean, 1978, 1985; Fish-
bein, 1985).
Technical-grade xylene did not produce differential kiling in DNA repair-proficientcompared. to repair-deficient strains of Bacillus subtilis rec+ 1- (McCarroll et al., 1981a) orEschenchia coli (McCarroll et aL., 1981b). Xylene (grade unspecified) did not induce SOSactivity in Salmonella typhimurium TA1535/pSK 1002 (Nakamura et al., 1987). paa-Xylenewas not mutagenic to E. coli WP2uvr A in the presence or absence of an exogenous metabolic
system from Aroclor-induced rat liver (Shimizu et al., 1985). ortho-, meta- and paa-Xylene,xylene (grade unspecified) andmixed xylenes were not mutagenic to S. typhmurium TA1535,TA1537, TA1538, TA98, TA100, UT8413 or UT8414 in the presence or absence of an ex-ogenous metabolic system from uninduced or Aroclor-induced rat and Syrn hamster livers
(Lebowitz et aL., 1979 (abstract); Bos et al., 1981; Haworth et al., 1983; Connor et aL., 1985;Shimizu et al., 1985; Zeiger et al., 1987).
As reported in an abstract, expsure to technical-grade xylene (contaminated with18.3% ethylbenzene), but not expsure to meta- or ortho-xylene, caused recessive lethal mu-tations in Drosophila melanogaser (Donner et al., 1980).
As reported in an abstract, xylene (grade unspecified) did not induce mutation inmouse lymphoma L5178Y TK+ 1- cells or chromoSomal aberrations in rat bone marrow (Le-bowitz et al., 1979). Xylene (grade unspecied) did not inducesister chromatid exchange orchromosomal aberrtions in human lymphoces in vitro (Gerner-Smidt & Friedrich, 1978).
XYLENE 141
(The Workig Group noted that the study of human lymphoces was pedormed without anexogenous metabolic system.)
None of the three ismers induced micronuclei in the bone marrow of male NMRImice after two intraperitoneal administrations of 0.12-0.75 ml!kg bw (0.11-0.65 mg/kg bw) at
a 24-h interval (Mohtashamipur et al., 1985); however, theyenhanced the induction of mi-cronuclei by toluene (lohtashamipur et al., 1987).
As reported in an abstract, expsure of rats to mIxed ismers (300 ppm; 1300 mg/m3) for6 h per day on five days per week for nine, 14 and 18 weeks did not induce chromosomalaberrations in bone-marrow cells (Donner et al., 1980).
As reported in an abstract, xylene did not inhibit intercellular communication (as mea-sured by metabolic coperation) in Chine se hamster V79 cells (Awogi et al., 1986).
Xylene (grade unspecified) did not enhance morphological transformation of Syranhamster embiyo cells by the SA7 adenovis (Casto, 1981).
Rats injected intraperitoneally with 0.5 and 1.5 ml/kg bw (0.44 and 1.32 mg/kg bw)ortho-xylene showed a significant increase in the percentage of abnormal sperm whenhoused at temperatures of 24-30°C (control: 2.94::1.36; treated: 4.17:11.41) but not at2O24°C (Washington et al., 1983). The authors interpreted this as a syergistic effect be-tween xylene and temperature.
(h) Humans
(i) Absorption, distribution, exretion an metabolismMost of the available inormation on xylene metabolism in humans deals withmeta-xy-
lene.ln volunteers expsed by inhalation, lung retention was practically identical (64%) for
the three ismers (Šedivec & Flek, 1976a). ln other studies with volunteers, lung retentionof meta-xylene was about 60% (Riiimäki et al., 1979) to 75% (Senczuk & Or.1owski 1978).When volunteers immersed their hands in liquid meta-xylene, it was absorbed at 2 Jlg/cm2per min (Engström et al., 1977). A nine-fold interidiviual varition in ski absorption rate
was observed among volunteers (Luweiys et al., 1978). The amount of meta-xylene ab-sorbed after whole-bo expsure of volunteers to 60 ppm (26 mg/m3) vapour, excluding
inhalation, for 3.5 h was equivalent to the amount absorbd after inhalation expsure to 20ppm (87 mg/m3) for the same duration (Riiimäki & Pfåffli, 1978).
More than 70% of meta-xylene absorbed was excreted into the urie as metabolites(Ogata et al., 1970; Engström et al., 1~84). A minor portion ("' 5%, apparently irespective ofthe ismer) was exhaled unchanged (Sedivec & Flek, 1976a; Riiimäki et al., 1979; Astrand etal., 1978).
Elimination of meta-xylene from the bo via excretion and inhalation is rapid, with abiological half -time of 1 h for a rapid phase after 6-16 h of expsure and of about 20 h for aslow phase (Riiimäki et al., 1979). Abut 72% of total uriaiy metabolites was excreted inthe urie within 24 h after termination of expsure to the three isomers (Sedivec & Flek,
1976a). Removal of irdustrial xylene froID subcutaneous adipose tissue, however, is slow(Engström & Bjurström, 1978), with a half -time of 25-128 h for the meta ismer (Engström& Riiimäki 1979).
142 IAC MONOGRAHS VOLUME 47
Xylenes are priariy metabolized in humans to the correspnding methylhippuric
acid (toluric acid); and glycine conjugation is considered to be a rate-limiting step (Riiimäki,1979). Wh en volunteers were expsed to ortho-, meta- or paa-xylene vapour, more than95% of the absorbed compound was excreted as methylhippuric acid, and onlya small por-tion was excreted as dimethylphenol: 0.86% as 2,3-dimethylphenol and 3,4-dimethylphenol,after expsure to ortho-xylene (the ratio between the two dimethylphenols varied dependingon individuals), 1.98% as 2,4-imethylphenol aftervexpsure to meta-xylene and 0.05% as2,5-dimethylphenol after expsure to paa-xylene (Sedivec & Flek, 19700). ln other experi-ments in which volunteers were expsed to meta-xylene, meta-methylhippuric acid in theurie accunted for 72% (Ogata et al., 1970) to 97% (Engström et al., 1984) of the meta-xy-lene absorbed, whereas 2,4-imethylphenol and 3-methylbenzyl alcohol accunted for 2.5
and 0.05%, respectively (Engström et al., 1984). Similar results were found for paa-xylene
(Ogata et al., 1970). ortho-Xylene was metabolized almost exclusively to ortho-methylhippu-ricacid; only trace amounts of ortho-toluieacid (ortho-methylbenwicacid) glucuronide weredetected in the urie of volunteers expsed to ortho-xylene vapour (Ogata et al., 1980).
Methylhippuric acid has therefore been proposed as a marker uriaiy metabolite for
the biological monitorig of factory workers expsed to xylene, and urie collected in thelatte! half of a shift is recommended for analysis (Lundberg & Sollenberg, 1986; for reviews,see Sedivec & Flek, 1976b; Riiimäki, 1979).
(n) Toxic effects
Sorne of the inormation on the adverse effects of xylene on the central and peripheralnervous systems originates from studies of workers expsed ocupationally (mainly paint-ers); such workers are generally also expsed to other organic solvents (Seppäläinen et aL.,1978; Elofsson et aL., 1980; Ekberg et al., 1986). For further inormation, see the monographon ocupational expsures in paint manufacture and painting.
Most volunteer subjects expsed to 20 mg/m3 technical xylene for 15 min had eyeirtation (Carpenter et al., 1975); workers expsed to a mixure of solvents, inc1udingxylene,displayed corneal vacuoles (Schmid, 1956). Similar effects have been descbed in spraypainters expsed to almost pure xylene as a lacquer-diluting agent (Matthäus, 196).
Exsure of volunteers to technical xylene by inhalation caused irtation of the airays(Carpenter et al., 1975); veiy high accdental expsure caused pneumonitis (Morley et al.,1970). Ingestion of xylene caused irtation of the gastrointestinal tract (Gosselin et al.,1976).
Ski contact caused a burning sensation and reversible eiyhema (Lauweiys et al.,1978). Prolonged expsure may cause contact dermatitis (European Chemical IndustiyEcology and Toxicology Centre, 1986).
ln studies of volunteers expsed to 20 ppm (870 mg/m3) xylene fpr 8 h, simple reactiontime was slowed (Ogata & Nagao, 1970). Heavy accdental expsure may cause narcosis (Ba-kison & Jones, 1985) and death (Morley et al., 1970). Goldie (196) suggested that ocpa-tional expsure to xylene in paints provoked epileptic seizures in one case.
ln volunteers expsed to 390 mg/m3 or more technical xylene or meta-xylene, with orwithout physical exercise, reaction time, manual cordination, bo equilibrium and
XYLENE 143
electroencephalogram were affected (Gamberale et al., 1978; Savolainen & Linnavuo, 1979;Savolainen, 1980; Savolainenet al., 198Oa,b; Savolainen & Riiimäki, 1981a,b; Seppäläinenetal., 1981; Savolainen et al., 1984, 1985a,b). ln particular, concentration peaks affected per-formance. Tolerance developed after expsure for a week and disappeared durig the week-end.
Transient kidney damage has ocsionally been reported in cases of severe, acute xy-lene poisoning (Morley et al., 1970; Bakison & Jones, 1985). Furthermore, indications ofslight adverse effects on the kidney (Askergren, 1981; Askergren et al., 1981a,b,c; Franchiniet al., 1983) have been reported in workers expsed mainly to xylene and toluene (see also themonograph on ocupational expsures in paint manufacture and painting).
ln cases of severe, acute poisning, signs of liver damage have been reported (Morley etaL., 1970; Bakison & Jones, 1985).
Aplastic anaemia was reported in one laboratoiy worker and decreased platelet counts
in 12/27 other laboratoiy workers expsed to technical xylene (containing 0.2% benzene).Wh en expsure to xylene was interrpted, platelet counts returned to normal (Forde, 1973).(The Workig Group noted several early reports of effects on bloo and bloo forming or-gans, which might have been due to benzene contamination of xylene.)
(iii) Effects on fertility and on pregny outcomeln their study of female pharmaceutical workers in Finland, Thskien et aL. (1986; see
the monograph on toluene) also assessed expsure to xylene. Expsure durig the first tri-mester of pregnancy was reported by three of 38 (8%) women who had had a spontaneousabortion compared to four of 199 (3% ) control women who had had live birhs. The corre-sponding relative risk (RR) was 2.0 (95% confidence interval (Ci), 0.4-10.6). Cases and con-trois had been expsed to many solvents and other substances.
ln the study of Swedish female laboratoiy workers (Axelsson et al., 1984; see the mono-graph on toluene), 160 women reported havig worked in a laboratoiy with expsure to xy-lene durig the first triester of pregnancy. The miscrrage rate of 10.3% compares with
that of 11.5% among women who had not worked in a laboratoiy durig the first triester
and that of 9.0% among women who had worked in a laboratoiy but not with solvents durigthe first triester. Cases and controls had been expsed to many solvents and other sub-
stances.Ericson et al. (1984; see the monograph on toluene) reported that expsure to xylene
had been similar for Swedish laboratoiy workers who had given birh to children who died inearly infancy or were malformed (8%) and for women who had had normal birhs (8%).Cases and controls were exposed to many solvents and other substances.
ln the study of Holmberg (1979; described in the monograph on some petroleum sol-vents), the mother of one child with central nervous system d~fects and one control motherreported havig worked with xylene durig the first triester of pregnancy. Both mothershad also been expsed to other solvents. ln the study of Holmberg et al. (1982), described inthe monograph on some petroleum solvents, three mothers of children with oral clefts butno control mother were reported to have worked with xylenes òurig the first triester of
pregnancy. The mothers had also been expsed to other solvents.
144 lAC MONOGRAHS VOLUME 47
(iv) Genetic and related effectsNo increase in the frequency of sister chromatid exchange was observed in ten workers
in the Swedish paint industiy expsed to various solvents, including more than 100 mg/m3xylene (Haglund et al., 1980; see also the monograph on ocupational expsures in paintmanufacture and painting). (Te Workig Group noted the small number of workers ob-served.) No increase in sister chromatid exchange was observed in 46 workers at a Hungarinchemical plant expsed to technical xylene (ortho-, meta- and paa-xylene, 6-15% ethylben-zene) with an average expsure of nine years to an average of 50 mg/m3, compared with 34clerical workers from the factoiy who were used as controls (Pp & Varga, 1987).
3.3 Epidemiological studies of carciDogeDicity iD humaDs
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 expsure to organic solvents among 25cases of Hodgki's disease and 50 controls in Sweden (see the monograph on some petro-leum solvents). Expsure to xylene was mentioned by four cases but no referent. Ali ex-posed cases and referents were expsed to other solvents.
Wilcosky et al. (1984) pedormed a case-cntrol study of rubber workers in the USA (seethe monograph on some petroleum solvents). Expsure to xylene was assoiated with in-creased risks for prostatic cancer (relative risk (RR), 1.5, eight cases), lymphosarcoma (3.7,four cases) and lymphatic leukaemia (3.3, four cases). (Te Workig Group noted that thenumber of cases in each categoiy is small and that multiple expsures were evaluated inde-pendently of other expsures. Although the risk for lymphosarcoma in xylene-expsedworkers was significantly raised, four significant assotions were reported out of the 20 sub-stances, and these assoiations are based on larger numbers of expsed cases. It was there-fore impossible to determine whether a single substance was asiated with the rik.)
Carpenter et aL. (1988) evaluated the possible assoation with expure to 26 chemicalsor chemical groups in 89 cases of priaiy cancers of the central nervous system and 356matched controls in cohorts of workers at two US nuclear faciities. Toluene (see mono-graph, p. 79), xylene and methyl ethyl ketone were evaluated as one chemical group; thematched RR was 2.0 (28 cases; 95% confidence interval, 0.7-5.5) in comparin with non ex-posed workers. AImost all cases had had low expsure accrding to the classification used.The authors reported that the RRs were adjusted for internai and external expsure to radi-ation. (The Workig Group noted that no separate analysis was pedormed for the threesolvents, nor were expsure levels quantified, and that there were many concurrent exp-sures. )
XYLENE 145
4. Summary of Data Reported and Evaluation
4.1 Exposures
Xylene is a major industril chemical derived mainly from petroleum refining. It oc-curs in three ismeric forms (ortho, meta and paa) and is produced and used both as 'mixedxylenes' (usually containing 10-15% ethylbenzene) and as the individual Ismers. Xylene isused as a solvent in paints, inks, adhesives and insecticides. Xylene-cntaining petroleumdistilat es are used extensively and increasingly in gasoline blending.
The individual ismers are used mainly as chemica intermedìates in the manufactureof derivatives of phthalic anhydride (from ortho-xylene), isphthalic acid (from meta-xylene)and terephthalic acid (from paa-xylene).
Xylene is ubiquitous in the envionment. Occupational expsure has been reported inpetroleum refining, in the production of xylene and in the use of xylene and its end products.
4.2 Experimental carcinogenicity data
Xylene (technical grade or mixed xylenes) was tested for carcinogenieity in one strain ofmice and in two strains of rats by gastric intubation. One study in rats with mixed xylenes wasconsidered inadequate for evaluation. No increase in the incidence of tumours was observedin either mice or rats followig the administration of a technical-grade xylene.
No data were available on the individual isomers.
4.3 Human carcinogenicity data
Expsure to xylene has been assoiated with increased risks for haematopoietic malig-nancies in two case-cntrol studìes, but the number of cases was limited and expsure was toa variety of compounds.
4.4 Other relevant data
ln humans, expsure to xylene causes irtant and central nervous system effects. Ad-verse effects have been observed on the kidney and liver in cases of accidental poisoning.Similar effects have been se en in experiental animais after expsure to xylene at high lev-els.
ln sorne studies of the reproductive outcome of women expsed to xylene durig thefirst triester of pregnancy, small excess riks for spontaneous abortion and for congenital
malormation were reported. ln all of these studies, the numbers of cases were small and themothers had also been expsed to other substances.
Maternally toxic or near-toxic amounts of xylene have been assoiated with malforma-tions in mice after oral administration and with embiyotoxicity in rabbits, rats and mice afterexpsure by inhalation.
146 IAC MONOGRAHS VOLUME 47
Sister chromatid exchange was not induced in peripherallymphoces of workers in twostudies; however, expsure was to a variety of compounds.
N one of the three isomers of xylene induced mieronuclei in mice in vivo. Sister chroma-tid exchange and chromosomal aberrations were not induced in cultured human lympho-cyes, in the absence of an exogenous metabolic system. Xylene of unspecified grade did notinduce morphological transformation in cultured animal cells. None of the three isomers or
xylene, either alone or in combination, induced mutation in bacteria. Technical-grade xy-lene did not induce DNA da mage in bacteria. (See Appendix 1.)
4.5 Evaluation 1
There is inadequate evidence for the carcinogenicity of xylene in humans.There is inadequate evidence for the carcinogenicity of xylene in experiental animais.
Ove rail evaluationXylene is not classifiable as to its carcinogenicity to humans (Group 3).
5. Referenèes
American Conference of Govemmental Industrial Hygienists (1988) Threhold Limit Values and Biologi-cal Exsure Indices for 1988-1989, Cincinnati, OH, p. 38
Angerer, J. & Lehnert, G. (1979) Occpational chronic expsure to organic solvents. VIII. Phenoliccompounds - metabolites of alkylbenzenes in man. Simultaneous expure to ethylbenzene and
xylenes. Int. Arh. occup. environ. Health, 43, 145-150Anon. (1985) Facts and figures from the chemical industry. Chem. Eng. News, 63, 22-6Anon. (1986) Chemical profile: para-xylenes. Chem. Maret. Rep., September, p. 54Anon. (1987) Facts and figures from the chemical industry. Chem. Eng. News, 65, 2476Anon. (1988a) Facts and figures from the chemical industry. Chem Eng. News, 66,34-82Anon. (1988b) CHEM-INFELL Database, Dunstable, UK, Reed TelepublishingLtd, Chemical Intell-
gence ServceArbeidsinspectie (Lbour Inspetion) (1986) De Nationale MAC-Lijst 1986 (National MAC-Lit 1986)
(P145), Voorburg, Ministry of Social Afairs and Work Environment, p. 21Arbejdstilsynet (Lbour Inspection) (1988) Gransevaerdier for StofJer og Materier (Limit Values for
Substances and Materials) (At-avisning No. 3.1.0.2), Copenhagen, p. 32Askergren, A. (1981) Studies ofkidney function in subjects exp to organic solvents. III. Excretion of
cens in the urine. Acta med. scand., 210, 103-106Askergren, A., Allgén, L-G. & Bergström, J. (1981a) Studies ofkiney function in subjects expd to
organic solvents. II. The effect of desmopressin in a concentration test and the effect of expureto organic solvents on renal concentrating abilty. Acta med. scand., 209, 485-4
lFor definitions of the italicizd tenus, see Preamble, pp. 27-30.
XYLENE 147
Askergren, A, Allgén, L-G., Karlsson, e., Lundberg, 1. & Nyberg, E. (1981b )Studies ofkidney function
in subjects expd to organic solvents. 1. Excretion of albumin and ß-2-microglobulin in theurine. Acta med. scand., 209, 479-43
Askergren, A, Brandt, R, Gullquist, R, Silk, B. & Strandell, T (198lc) Studies of kidney function insubjects expd to organic solvents. IV Effect on 51-Cr-EDTA clearance. Acta med. scand., 210,
373-376
Åstrand, 1., Engström, J. & Dvrm, P. (1978) Exure to xylene and ethylbenzene. 1. Uptake, distribu-tion and elimination in man. Scand. 1 Worl Environ. Heath,4, 185-194
Awogi, T, Itoh, T & Tsushimoto, G. (1986) The effect ofbenzene and its derivatives on metaboliccop-eration (Abstract No. 2). Mutat. Re., 164, 263
Axelsson, G., Lütz, e. & Rylander, R (1984) Exure to solvents and outcome of pregnancy in univer-sity laboratory employees. Br. 1 ind. Med., 41, 305-312
Baker, D. & Fannick, N. (1983)LeatherCraftsman, Lynbro, NY(Health Hazd Evaluation Detennina-lion Report No. 80-601367), Cincinnati, OH, National Institute for Occpational Safety andHealth
Baknson, M.A & Jones, RD. (1985) Gasings due to methylene chloride, xylene, toluene, and styenereported to Her Majesty's Factory Inspetorate 1961-80. Br. 1 ind. Med., 42, 184-190
Bake, O.M. & Scheline, RR (1970) Hydroxylation of aromatic hydrocarbons in the rat. Toxicol. appl.Phanacol., 16, 691-700
Bonnet, P., Raoult, G. & Gradiski, G. (1979) LCro of major aromatic hydrocbons (Fr.). Arh. Mal.prot Méd. Tra Sée. SOC., 40,805-810
Bo, R.P., Brouns, RM.E., van Doom, R, Theuws, J.LG. & Hendersn, P.T (1981) Non-mutagenicityof toluene, 0-, m- and p-xylene, o-methylbenzylalcohol and o-methylbenzylsulfate in the Amesasay. Mutat. Re., 88, 273-279
bon toxicity studies. V Animal and hum an response to vapors of mixed xylenes. Toxiol. appl.P~oL, 33, 543-558
Casto, Re. (1981) Detection of chemical cacinogens and mutagens in hamster celIs by enhancement ofadenoviru transformation. ln: Mishra, N., Dunkel, V & Mehlman, 1., ed, Advances in ModemEnvironmental Toxiology, Vol. 1, Prnceton, NJ,.Senate Pres, pp. 241-271
Clement Asiates (1977) Xylene. ln: Informion Dossers on SubstancesDesignated by TSCA (Toxic
Substances Control Act) Interagency Testing Committee (October, 1977) (Contrat NSF-C-ENV7-15417), Washington DC
Commision of the European Communities (1986) Occpational limit values. Off 1 Eur. Commun., 164,6-7
148 !AC MONOGRAHS VOLUME 47
Connor, 1:e., Theiss, J.e., Hanna, H.A, Monteith, D.K. & Matney, 1:S. (1985) Genotoxicity of organicchemicals frequently found in the air of mobile homes. Toxiol. LeU., 25,33-40
Cook, W.A (1987) Occupational Exsure Limits - Worldwide, Washington DC, American IndustrialHygiene Asociation, pp. 37, 126, 157,224
Cramer, P.H., Boggess, K.E., Hosnfeld, J.M., Remtners, J.e., Breen, J.J., Robinson, P.E. & Stroup, e.(1988) Determination of organic chemicals of human whole bloo: preliminary method develop-ment for volatile organics. Bull. environ. Contam. Toxicol., 40, 612-618
Dean, B.J. (1978) Genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Re., 47, 75-97Dean, B.J. (1985) Recnt findings on the genetic toxicology ofbenzene, toluene, xylenes and phenols.
Mutat. Re., 154, 153-181
Deutsche Forshungsgemeinschaft (German Research Society) (1988) Maxmale Areitsplatzkonzentra-tionen und Biologiche Aritsstoffolerazwerle 1988 (Maxmal Concentrations in the Work Placeand Biological Tolerance Values for Working Materials 1988) (Reporl No. XX, Weinheim,VCH Verlagsgesellschaf, p. 61
Direktoratet for Arbeidstilsynet (Directorate for Labour Inspetion) (1981) Administraive Nomier forForurensning i Aridsatmosfaere 1981 (Administrative Norms for Pollution in Work Atmosphere1981) (No. 361), Olso, p. 22
DiVincenzo, G.D. & Krasavage, w.J. (1974) Serum omithine cabamyl transferas as a liver responsetest for expure to organic solvents. Am. ind. Hyg. ksoc.l, 35,21-29
Donner, M., Mäk-Paakkanen, J., Norppa, H., Sorsa, M. & Vainio, H. (1980) Genetic toxicology ofxy-lenes (Abstract No. 9). Mutat. Re., 74, 171-172
van Doom, R, Bo, RP., Brouns, RM.E., Leijdekkers, e.-M. & Hendersn, P.1: (1980) Effect of tolu-ene and xylenes on liver glutathione and their urinar excretion as mercapturic acids in the rat.Arh. Toxiol., 43, 293-304
Ekberg, K., Baregård, L, Hagberg, S. & Sällsten, G. (1986) Chronic and acute effects of solvents oncentral nervous system functions in floorlayers. Br. 1 ind. Med., 43, 101-106
Eller, P.M. (1984) NIOSH Manua of Ana/ytica/ Methods, 3rd 00., VoL. 1 (DHHS (NIOSH) Publ. No.84-100), Washington De, US Government Prnting Offce, pp. 15001-15007, 1501-1-1501-7
Elofsson, S.-A, Gamberale, F., Hindmarh, 1:, Iregren, A, Isakn, A., Johnsn, 1., Knave, B.,
Lydahl, E., Mindus, p., Persn, H.E., Philpsn, B., Steby, M., Struwe, G., Söerman, E., Wenn-berg, A & Widén, L (1980) Exure to organic solvents. A cros-seional epidemiologic inves-tigation on ocpationally exp ca and industrial spray painters with speial reference to thenervous system. Scand. 1 Worl Environ. Reath, 6, 239-273
Elovaara, E. (1982) Dos-relatOO effects of m-xylene inhalation on the xenobiotic metabolism of the rat.Xenobiotica, 12, 345-352
Engström, J. & Bjurström, R (1978) Exure to xylene and ethylbenzene. II. Concentration in subc-taneous adipo tisue. Scand. 1 Worl Environ. Reath, 4, 195-203
Engström, J. & Riihimäk, V. (1979) Distribution of m-xylene to subctaneous adipo tisue in short-term exprimental hum an exure. Scand.l Worl Environ. Reath, 5,12134
Engström, J. & Riihimäk, V. (1988) Method 11- detennination of methyl hippuric acids in urine by gaschromatography. ln: Fishbein, L & O'Neil, I.K., ed, Environmenta/ Carinogens. Methods of
Ana/ysis and Exsure Mearement, Vol. 10, Benzne and Alkylated Benzne (IARC Scientiji Pub-lications No. 85), Lyon, International Agency for Resarch on Cancer, pp. 313-318
Engström, J., Husman, K. & Riihimäk, V. (1977) Percutaneous absrption of m-xylene in man. lnt.Arh. occup. environ. Rea/th, 39, 181-189
XYlENE 149
Engström, K., Riihimil, V & Lane, A (1984) Urinar dispoition of ethylbenzene and m-xylene inman following separate and combined expure. lnt. Arh. oceup. environ. Heath, 54,355-363
ENMET Corp. (undated) ENMET -Kitagaa Toxi Gas Deteetor Tubes, Ann Arbor, MIEricson, A, Källén, R, Zetterström, R, Eriksn, M. & Westerholm, P. (1984) Delivery outcome of
women working in laboratories during pregnancy. Arh. environ. Health, 39, 5-10European Chemical Industry Eclogy and Toxicology Centre (1986) Joint Assessment of Commodity
Chemieals, No. 6, Xylenes, Brussls
Fabre, R., Truhaut, R. & Laham, S. (196) Toxicological studies on benzene replacement solvents. IvXylenes (Fr.). Arh. Mal. prof, 21,301-313
Fishbein, L (1985) An overvew of environmental and toxicological aspects of aromatic hydrocbons.III. Xylene. Sei total Environ., 43, 165-183
Fishbein, L & O'Neil, I.K., eds (1988) Environmental Carinogens. Methods of Analysis and ExsureMeasurement, Vol. 10, Benzene and Alkylaled Benznes (IARC Scientifie Publications No. 85), Lyon,International Agency for Research on Cancer
Foxboro, MAFranchini, 1., Cavatorta, A, Falzoi, M., Lucertini, S. & Mutt, A (1983) Early indicators of renal damage
in workers expd to organic solvents. lnt. Arh. oceup. environ. Health, 52, 1-9Gamberale, F., Görel Annwall, RA & Hultengren, M. (1978) Expure to xylene and ethylbenzene. III.
Effects on central nervous functions. Seand. 1 Worl Environ. Health, 4, 20211Gerner-Smidt, P. & Friedrich, U. (1978) The mutagenic effect ofbenzene, toluene and xylene studied by
the SCE technique. Mutal. Re., 58,313-316Ghantous, H. & Danielsson, RRG. (1986) Placental transfer and distribution of toluene, xylene and
benzene, and their metabolites during gestation in mice. Biol. Re. Preg., 7, 98-105Goldie, 1. (1960) Can xylene (xylol) provoke convulsive seizures? lnd. Med. Surg., 29, 33-35
London, Her Majesty's Stationery Office, p. 22Hilard,J.H. (1980) Gas, natural. ln: Mark, H.F., Othmer,D.F., Overberger, c.G.,Seaborg, G.T & Gray-
son, M., eds, Kirl-Othmer Eneyclopedia ofChemieal Teehnology, 3rd ed., Vol. 11, New York, JohnWiley & Sons, pp. 630-52
150 IAC MONOGRAHS VOLUME 47
Hine, C.H. & Zuidema, H.H. (1970) The toxcological properties of hydrocbon 8Olvents. lnd. Med.,39, 215-220
Hoffan, D.J. & Eastin, w.c., Jr (1981) Effects of industral effuents, heavy metaIs, and organic 801-vents on mallard embryo development. Toxiol. Leu., 9, 35-
Holmberg, P.c. (1979) Central-nervus-system defects in children bom to mothers exp to organic80lvents during pregnancy. Lancet, ii, in-l79
Holmberg, p.c., Hemberg, S., Kurppa, K, Rantala, K & Riala, R (1982) Oral cleft and organic 80lventexpure during pregnancy.Int. Ark occup. environ. Heath, 50, 371-376
Holzer, G., Oró, J. & Berth, W. (1976) Gas chromatogrphie mas-spetrometric evaluation of ex-haled tobacc smoke. 1 Chromaogr, 126, nl-785
Hoo, RD. & Ottley, M.S. (1985) Developmental effec asiate with expure to xylene: a review.Dmg. chem. Toxiol., 8, 281-297
Hudák, A. & Ungv, G. (1978) Embryotoxic effects of benzene and its methyl derivatives: toluene,xylene. Toxiology, 11, 55-63
Hudák, A, Tátra, E., Lõrincz, M., Barcza, G. & Ungv, G. (1980) Study of the embryotoxic effect oforlho-xylene (Hung.). Morp. és.lg. OTV Szemle, 20, 2020
Huff, J.E., Eastin, w., Roycroft, J., Eustis, S.L & Hasman, J.K (1988) Carcinogenesis studies of ben-zene, methyl benzene, and dimethyl benzenes. Ann. N.Y. Acad Sei., 534, 427-4
IAC (1980) lARC Monogrph on the Evaluaion of the Carinogenic Ri of Chemicals to Humo,'Suppl. 2, Long-term and Shorl-term Screening Ass for Carinogenesis: A Critical Appraisal, Lyon
IAC(1981)lARC Monogrphon the Evaluaion of the Carinogenic Ris ofChemical toHuma, Vol.25, Wood, Leather and Some Asociaed Indusri, Lyon
IAC(1989)lARC Monogrphon theEvaluaionofCarinogenic RistoHum, Vol. 45, Occupation-al Exsure in Petroleum Refining Cmde Où and Major Petroleum Fue/s, Lyon
Ikeda, M., Kumai, M:, Watanabe, 1: & Fujita, H. (1984) Aromatic and other contents in automobilegasline in Japan. lnd. Heath, 22, 235-241
Institut National de Recherche et de Sérité (National Institute for Resarch and Safety) (1986) Valeurs
Limites pour les Concentraions des Substanes Dangereus Dan l'Air des Lieux de Traai (LimitValues for Concentrations of Dangerous Substance in the Air of Work Places) (ND1609-125-86), Par, p. 581
Jenkins, LJ., Jr, Jones, RA & Siegel, S. (1970) Long-term inhalation screening studies of benzene,toluene,o-xylene and cumene in exprimental animaIs. Toxicol. appl. Phaacol., 16, 818-823
Kilbum, KH., Seidman, B.c. & Warhaw, R (1985) Neurobehavioral and respiratory symptoms offormaldehyde and xylene expure in histology technicians. Ark environ. Heath, 40, 229-233
Klaucke, D., Johansen, M. & Vogt, RL(1982) An outbreakofxylene intoxication in a hospitaL. Am. 1ind. Med., 3,173-178
Korte, E & Boefeld, E. (1978) Ectoxicological review of global impact of petroleum industry and itsproducts. Ecotoxicol. environ. Sal., 2, 55-103
Krotoszyki, B.K, Bruneau, G.M. & O'Neil, H.J. (1979) Measurement of chemical inhalation expsure in urban population in the presnce of endogenous effuents. 1 an. Toxiol., 3, 225-234
Lauwery, RR, Dath, 1:, Lachapelle, J.-M., Buchet, J.-P. & Roels, H. (1978) The influence of tw bar-er creams on the percutaneous absrption of m-xylene in man. 1 occup. Med., 20,17-20
Lebowitz, H., Bruick, D., Mathesn, D., J agannath, D.R, Ree, M., Gooe, S. & Roy, G. (1979) Com-monly us fueIs and 80lvents evaluated in a battery of short-term bioaays (Abstrct Eb-). En-viron. Mutagenes, 1, 172-173
XYlENE 151
Lundberg,I. & Sollenberg, J. (1986) Correlation ofxylene expure and methyl hippuric acid excretionin urine among paint industry workers. Scand.l Worl Environ. Heath, 12, 149-153
Maltoni, c., Conti, B. & Cotti, G. (1983) Benzene: a multipotential cacinogen. Results of long-termbioasays performed at the Bologna Institute of Oncology. Am. 1 ind. Med., 4, 589-630
Maltoni, c., Conti, B., Cotti, G. & Belpogg, E (1985) Exrimental studies on benzene cacinogenicityat the Bologna Institute of Oncology current results and ongoing research. Am. 1 ind. Med., 7,415-4
Mannsville Chemical Products Corp. (1981) Chemical Products Synopsis: Xylenes, Cortland, NYMarks, LA., Leoux, LA. & Moore, J.A. (1982) Teratogenicity of a comemrcial xylene mixre in the
mouse.l Toxicol. environ. Heath, 9, 97-105Mathesn Gas Products (undated) The Matheson-Kitagaa Toxic Gas Deteetor System, East Rutherford,
NJMatthãus, W (196) Contribution to the comeal lesion of workers involved in surface vaishing in the
fumiture industry (Ger.). Klin. Mbl. Augenheilk., 144, 713-717McCaroll, N.E., Keeh, RH. & Piper, c.E. (1981a) A microsuspension adaptation of the Bacillus subti-
lis 'rec' asay. Environ. Mutagenesis, 3, 607-616McCaroll, N.E., Piper, C.E. & Keeh, RH. (1981b) An E. coli microsuspension asay for the detection
of DNA damage induce by direct-acting agents and promutagens. Environ. Mutagenesis,3,429-4
Merian, E. (1982) The environ mental chemistry of volatile hydrocbons. Toxicol. environ. Chem., 5,167-175
Merian, E. & Zander, M. (1982) Volatile aromatics. ln: Hutzinger, O., ed., Handbok of EnvironmentalChemistry, VoL. 3, Par B, Anthropogenic Compounds, Berlin (West), Springer, pp. 117-161
Mirkova, E., Zakov, c., Antov, G., Mikhailova, A., Khinkova, L & Benchev, 1. (1983) Prenataltoxicityof xylene. 1 Hyg. Epidemiol. Microbiol. lmmunol., 27, 337-343
Mohtashamipur, E., Norpth, K, Woelke, U. & Huber, P. (1985) Effects of ethylbenzene, toluene, and
xylene on the induction of micronuclei in bone marrow polychromatic eryhroces of mice. Arh.Toxicol., 58, 106109
Mohtashamipur, E., Strãter, H., Triebel, R. & Norpth, K (1987) Effects ofpretreatment of male NMRImice with enzye inducers or inhibitors on clastogenicity of toluene. Arh. Toxicol., 60, 463
Montesano, R., Barh, H., Vainio, H., Wilboum, J. & Yamasaki, H., ed (1986) Long-term and Short-term Ats for Carinogens: A Critical Appraal (IARC Scientiftc Publications No. 83), Lyon, Inter-national Agency for Research on Cancer
Morley, R., Ecleston, D.W, Douglas, c.P., Greville, WE.J., Sctt, D.J. & Anderson, J. (1970)Xylenepoisoning: a report on one fatal ca and tw ca of recovery afer prolonged unconsciousness.Br. med. 1., iii, 442-43
Moszczyski, P. & Usiewicz, J. (1985) Occpation al expure to benzene, toluene and xylene and thelymphoce lysmal N-acetyl-beta-D-glucoaminidas. lnd. Heath, 23, 47-51
Nakamura, S., Oda, Y., Shimada, L, Oki, 1. & Sugimoto, K (1987) SOS-inducing activity of chemicalcacinogens and mutagens in Salmonella typhimurium TAI535/pSk100: examination with 151chemicals. Mutai. Re., 192, 239-24
National Draeger, Inc. (1987) Deteetor Tube Products for Gas and Vapor Detection, Pittsburgh, PANational Institute for Occpational Safety and Health (1975) Criteri for a Recommended Standard ...
Occupaional Exsure to Xylene (DHEW (NIOSH) Publ. No. 75-168), Washington DC, US De-parment of Health, Education, and Welfare
152 IAC MONOGRAHS VOLUME 47
National Institute for Occpational Safety and lIealth (1983) National Occupational Exsure Survey1981-83, Cincinanti, OH
National Institute for Occpation al Safety and Health (1986) NIOSH recmmendations for ocpa-tional safety and health standards. Morbid. Morfal. U'ly Rep. Suppl., 35, 33S
National Swedish Board of Occpation al Safety and Health (1987) Hygienisa Gräärden (HygienicLimit Values), (Ordinance 1987:12), Solna, p. 38
National Toxicology Program (1986) Toxicology and Carinogenesis Studies of Xylenes (Mixd) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene)(CAS No. 1330-20-7) in F344/ N Ratsand B6C3F1 Mice (Gavage Studies) (NTP TR 327; NIH Publ. No. 87-2583), Research TrianglePark, NC, US Deparment of Health and Human Servce
Nawrot, P.S. & Staples, R.E. (1980) Embryofetal toxicity and teratogenicity of isomers of xylene in themouse (Abstract No. 65). ln: 19th Annual Meeting of the Society ofToxicology Marh 9-13, 1980,Washington DC, Society of Toxicology
Ogata, M. & Miyake, Y (1973) Identification of substances in petroleum causing objection able ooour infish. Water Re., 7, 1493-1504
Ogata, M. & Miyake, Y (1978) Disappearance of aromatic hydrocbons and organic sulfur compoundsfrom fish flesh rearOO in crude oH suspension. Water Re., 12, 1041-104
Ogata, M. & Nagao, I. (1970) Urinar m-methyl hippuric acid excretion and physiological changes inpersons expsed to 20 ppm m-xylene in an expure chamber(Jpn.). lpn.l ind. Health, 10, 75-79
Ogata, M., Tomokuni, K. & Takatsuka, l: (1970) Urinary excretion ofhippuric acid and m- or p-methyl-hippuric acid in the urine of persns expd to vapours of toluene and ni- or p-xylene as a test ofexpsure. Br. 1 ind. Med., 27, 43-50
Ogata, M., Takatsuka, Y. & Tomokuni, K. (1971) Excretion ofhippuric acid and m- or p-methylhippuricacid in the urine of persons expd to vapours of toluene and m- or p-xylenein an expurechamber and in workshops with speific reference to repeatOO expure. Br. 1 ind. Med., 28,382-385
Ogata, M., Yamazak, Y, Sugihara, R., Shimada, Y & Meguro, l: (1980) Quantitation ofurinar o-xy-
lene metabolites ofrats and human beings by high performance liquid chromatography. Int. Arh.occup. environ. Heath, 46, U7-139
Olsson, H. & Brandt, L (1980) Occpation al expure to organic solvents and Hoogkn's disas inmen. A ca-referent study. Scand. 1 Work Environ. Health, 6, 302-305
Otson, R & Wiliams, D.l: (1981) Evaluation of a liquid-liquid extraction technique for water pollut-ants. 1 Chromatogr, 212, 187-197
Otson, R, WilIams,D.T & Bothwell, P.D. (1982) Volatile organic compounds in water in thirt Cana-dian potable water treatment facilties. 1 Aroc. off anal. Chem., 65, 1370-1374
Pap, M. & Varga, C. (1987) Sister-chromatid exchanges in peripheral lymphoes of workers ocpa-tionallyexpd to xylenes. Mutai. Re., 187, 22-225
. Chemical Co., pp. 740B, 74IA, 742APouchert, c.J., ed. (1985) The Aldrih LibraofFT -IR Spetra, Vol. 1, Milwaukee, WI, Aldrich Chemical
Co., pp. 936D, 938A, 939A, 941B
XYLENE 153
Pyykkö, K (1980) Effects of methylbenzenes on microsmal enzyes in rat liver, kidney and lung. Bio-chim. biophys. Acta, 633, 1-9
Ransley, D.L (1984) Xylenes and ethylbenzene. ln: Mark, H.E, Othmer, D.F., Overberger, c.G.,Seaborg, G:r & Graysn, M., eds, Kirl-Othmer Encyclopedia of Chemical Technology, 3rd ed.,
Vol. 24, New York, John Wiley & Sons, pp. 709-744Riedel-de Haën (1984) Laboratory Chemicals, Hanover
Riihimak, v: (1979) Conjugation and urinar excretion of toluene and m-xylene metabolites in a man.Scand.l Worl Environ. Heath,5, 135-142
Riihimak, v: & Engström, K (1979)Xylene (Swe.) (Arete och Hälsa 1997:35), Nordic Exprt Groupfor Criteria Docments
Riihimak, v: & Pfäi, P. (1978) Percutaneous absrption of solvent vapors in man. Scand.l Worl Envi-
ron. Heath, 4, 73-85
Riihimak, V:, Pfäi, P., Savolainen, K & Pekar, K (1979) Kinetics of m-xylene in man. General fea-
tures of absorption, distribution, biotransformation and excretion in repetitive inhalation expsure. Scand. 1 Worl Environ. Heath, 5, 217-231
Rivera, R. & Rostand, R. (1975) Hillerich & Bradsby Co., Jeffersonville, Indiana (Hea/th Hazd Evalua-tion Detemiination Repon No. 74-121-203), Cincinnati, OH, National Institute for OccpationalSafety and Health
Roper, P. (1980) Emory University Pathology Depament, Atlanta, Georg (Health Hazd EvaluationDetemiination Repon No. 80-31-693), Cincinnati, OH, National Institute for Occpational Safetyand Health
Rosn, M.B., Crofton, KM. & Chernoff, N. (1986) Postnatal evaluation of prenatal expure to p-xy_lene in the rat. Toxiol. LeU., 34, 223-229
Roxan, Ine. (undated) Precision Gas Detector, Wooland Hils, CASadtler Research Laboratories (1980) Standad Spetra Collection, 1980 Cumulative Index, Philadelphia,
PA
Sandmeyer, E. (1981) Aromatic hydrocbons. ln: Clayton, G.D. & Clayton, EE., eds, PaUy's IndustrialHygine and Toxiology, 3rd rev. 00., Vol. 2B, New York, John Wiley & Sons, p. 3256,3291-3292
Savolainen, K (1980) Combined effec of xylene and alcohol on the central nervous system. Acta ph_maol. toxicol., 46, 366372
Savolainen, K & Unnavuo, M. (1979) Effects of m-xylene on human equilbrium measurOO with aquantitative method. Acta phol. toxiol.,44, 315-318
Savolainen, K & Pfafi, P. (1980) Dos-dependent neurochemical changes during short-term inhala-tion expure to m-xylene. Arh. Toxiol., 45, 117-122
Savolainen, K & Riihimak, v: (1981a) An early sign of xylene effect on human equilibrium. Acta phar-maol. toxiol., 48, 279-283
Savolainen, K & Riihimak, v: (1981b)Xylene and alcohol involvement ofthe hum an equilibrium sys-tem. Acta phol. toxiol., 49, 447-451
Savolainen, K, Vainio, H., Helojoki, M. & Elovaar, E. (1978) Biochemical and toxicological effects ofshort-term, intermittentxylene inhalation expure and combined ethanol intake. Arh. Toxiol.,41, 195-205
Savolainen, H., Pfä, P., Helojoki, M. & Tengén, M. (1979) Neurochemical and behavioural effects of
long-term intermittent inhalation of xylene vapour and simultaneous ethanol intake. Acta ph_maol. toxiol., 44, 20207
154 IAC MONOGRAHS VOLUME 47
Savolainen, K, Riihimäk, V, Seppaläinen, AM. & ünnoila, M. (1980a) Effects of short-term m-xy-lene expure and physical exercise on the central nervous system. ¡nt. Arh occup. environ.lf~th, 45, 105-121
Savolainen, K, Riihimäk, V, Vaheri, E. & ünnoila, M. (1980b) Effects of xylene and alcohol on vestib-ular and visual functions in man. Scand. 1 Wolk Environ. Health, 6, 94-103
Savolainen, K, Kekoni, J., Riihimäk, V & Lane, A (1984) Immediate effects of m-xylene on the hu-man central nervous system. Anh Toxicol., Suppl. 7,412-417
Savolainen, K, Riihimäk, V, Luukkonen, R & Muona, O. (1985a) Changes in the sens of balancecorrelate with concentrations of m-xylene in venous bloo. Br. 1 ind. Med., 42, 765-769
Savolainen, K, Riihimäk, V, Muona, O., Kekoni, J., Luukkonen, R & Lane, A (1985b) Converslyexpure-related effects betwen atmospheric m-xylene concentrations and human lxy senseof balance. Acta phacol. toxiol., 57, 67-71
Schmid, E. (1956) Comeal injuries in fumiture polishers (Ger.). Anh Gewerbpahol. Gewerbyg.,15,37-4
v
Sedivec V & Flek, J. (1976a) The absorption, metabolism, and excretion ofxylenes in man. ¡nt. Arh.occup. environ. H~th, 37, 205-217
v
Sedivec V & Flek, J. (1976b) Expure test for xylenes. ¡nt. Anh. occup. environ. lf~th, 37, 219-232Seidenberg, J.M., Andersn, D.G. & Beker, RA (1986) Validation of an in vivo developmental toxicity
screen in the mous. Teratog. Carinog. Mutagenesis, 6, 361-374
Seifert, B. & Abraham, H.J. (1982) Indoor air concentrations ofbenzene and sorne other aromatic hy-drocbons. Ecotoxiol. environ. Sa!, 6, 190192
Seifert, B. & Abraham, H.J. (1983) Use of pasive samplers for the determination of gasus organicsubstances in indoor air at low concentration leveIs. ¡nt. 1 environ. an. Chem, 13,237-253
Senczuk, W. & Orlowski, J. (1978) Absrption of m-xylene vapours through the respiratory tract andexcretion of m-methylhippuric acid in urine. Br. 1 ind. Med., 35, 5055
Sensidyne (1985) The First Tmly Simple Preisn Gas Detector System, Lago, FL
SeppäIäinen, AM., Husman, K. & Mårensn, C. (1978) Neurophysiological effects of long-term expsure to a mixre of organic solvents. Scand. 1 Worl Environ. lf~th, 4,30314
Seppaläinen, AM., Savolainen, K. & Kovala, 1: (1981) Changes induce by xylene and alcohol in humanevoked potentials. Electronceph. clin. Neurophysiol., 51, 148-155
Shigeta, S., Aikawa H., Misawa 1: & Suzuki, K. (1983) Fetotoxicity of inhaled xylene in mice (Abstract).Teraology, 28, 22
Shimizu, H., Suzuki, Y., Takemura, N., Goto, S. & Matsushita, H. (1985) The results of microbial muta-tion tet for fort-three industrial chemicaIs. Jpn. 1 ind. H~th, 27,4019
Sittig, M. (1985) lfandbo ofToxi and lfazdous Chemicals and Carinogens, 2nd 00., Park Ridge, NJ,Noyes, pp. 931-933
SKC (1988) Compreensve Cata/og and Guide, Eighty Fòur, PA
Smith, B.R, Plummer, J.L, Wolf, C.R, Philpot, RM. & Bend, J.R. (1982) p-Xylene metabolism byrabbit lung and liver and its relationship to the selective destruction of pulmonar cyochromeP-450.1 Phol. ex. 11rap., 223, 736742
Sukhanova V, Mar eva LM. & Boiko, VI. (1969) Investigation of functional properties ofleukocesof workers engagOO in manufacture of xylene. lfyg Sanit.,34, 44-450
Taskinen, H., ündbohm, M.-L & Hemminki, K. (1986) Spontaneous abortions among women workingin the pharaceutical industr. Br. 1 ind. Med., 43, 199-205, 432
XYIENE 155
Tátra, E. & Ungvár, G. (1980) Changes induce by o-xylene inhalations in the rat liver. Acta med.acad. sei hung., 37, 211-216
Tátra, E., Hudák, A, Barcza, G. & Ungvár, G. (1979) Study of embryotoxic effect of the meta-xylene(Hung.). Egeegtudomany, 23, 147-151
Toftgård, R & Nielsn, O.G. (1982) Effects ofxylene and xylene ismers on cyochrome P-450 and invitro enzyatic activities in rat lIver, kidney and lung. Toxicology, 23, 192-212
Toftgård, R, Nielsen, O.G. & Gustafssn, J.-Å. (1981) Changes in the rat lIver microsomal cyochromeP-450 and enzyatic aetivities afer the inhalation of n-hexane, xylene, methyl ethyl ketone andmethylchloroform for four weeks. Scand. 1 Work Environ. HeaIth, 7,31-37
Toftgård, R, Haaparanta, 'I & Halpert, J. (1986) Rat lung and lIver cyochrome P-450 isozyes in-volved in the hydroxylation of m-xylene. Toxiology, 39, 225-231
Tsuruta, H. (1982) Percutaneous absorption of organie solvents. III. On the penetration rates of hydro-phobie solvents through the excise rat skin. Ind. Heath,20, 335-345
Työsuojeluhalltu (National Finnish Board of Ocpational Safety and Health) (1987)HTP-Arot 1987(TLV Values 1987) (Safety Bulletin 25), Helsinki, Valtion Painatuskeskus, p. 19
Ungvár, G. & Tátrai, E. (1985) On the embryotoxie effeets ofbenzene and its alkyl derivatives in mice,rats and rabbits. Arh. Toxicol., Suppl. 8,425-430
Ungvár, G., Tátrai, E., Hudák,A., Barcza, G. & Lõrinez, M. (1980)Studiesofthe embryotoxieeffeets oforlho-, meta- andpa-xylene. Toxicology, 18, 61-74
Ungváry, G., Varga, R, Horváth, E., Tátrai, E. & Folly, G. (1981) Study of the role of maternaI sex ste-roid production and metabolism in the embryotoxicity of pa-xylene. Toxicology, 19, 262-26
US International Trade Commission (1982)Synthetic Orgic Chemicals, US Production and Sales, 1981
(USITC Publ. 1292) Washington DC, US Government Prnting OffceUS International Trade Commission (1983)Synthetic Organic Chemicals, US Production and Sales, 1982
(USITC Publ. 1422) Washington DC, US Government Prnting OffceUS International Trade Commission (1984) Synthetic Organic Chemicals, US Production and Sales, 1983
(USITC Publ. 1588) Washington DC, US Government Prnting OffceUS International Trade Commission (1985) Synthetic Orgic Chemicals, US Production and Sales, 1984
(USITC Publ. 1745) Washington DC, US Government Prnting OffceUS International Trade Commission (1986) Synthetic Organic ChemicaIs, US Production and Sales, 1985
(USITC Publ. 1892) Washington DC, US Government Prnting OfficeUS International Trade Commission (1987) Synthetic Organic ChemicaIs, US Production and Sales, 1986
(USITC Publ. 2009) Washington DC, US Government Prnting OfficeUS Occpation al Safety and Health Administration (1988) Labor. US Code Fed. Regul., Title 29, Par
1910.100
Wallace, LA, Pellzzar, E.D., Harll, 'ID., Sparacino, C. & Zelon, H. (1983) Personal expure to
volatile organics and other compounds indoors and outdoors - the TEAM (total expure ass-sment methodology) study. ln: Proeedings of the 76th Annual Meeting of the Air Pollution ControlAssociation, Atlanta, GA, Atlanta, GA, Air Pollution Control Assoiation, pp. 1-29
Wallace, LA, Pellzzar, E.D., Harell, 'ID., Zelon, H., Sparacino, C. & Whitmore, R. (1984)Analysis
of exhaled breath of 355 urban residents for volatile organie compounds. ln: Bergland, B.,lJndvall, 'I & Sundell, J., eds, Indoor Air. Proeedingsofthe 3rd International Conference on Indoor
Air Quality and Climate, Vol. 4, Stockholm, Swedish Couneil for Building Researeh, pp. 15-20
156 IAC MONOGRAHS VOLUME 47
Wallace, LA, Pellzzar, E.D., Harll, 'ID., Whitrnore, R, Sparcino, e. & Zelon, H. (1986) Total
expure asrnent rnethodology (fAM) study: persnal exures, indoor-outdoor relation-sliips, and breath levels of volatile organic cornpounds in New Jersy. Environ. int., 12, 369-387
Washington, WJ., Murthy, Re., Doye, A, Eugene, K., Brown, D. & Bradley, 1. (1983) Induction ofrnorphologically abnorral sperr in rats expd to o-xylene. Arh. Andro/., 11, 233-237
Weast, Re., ed. (1985) Handbok of Chemistry and Physis, 66th ed., Cleveland, OH, CRC Pres, pp.C-549-C-550
Wilcoky, 'Ie., Checkoway, H., Marhall, E.G. & Tyroler, H.A (1984) Cancer rnortality and solventexpsures in the rubber industry. Am ind. Hyg. At. 1.,45,80-811
Windholz, M., ed. (1983) The Merck Index, 10th ed., Rahway, NJ, Merck & Co., pp. 1447-144Wolf, M.A, Rowe, VK., McCollster, D.D., Hollngsworth, R.L & Oyen, F. (1956) Toxicological studies
of certain alkylated benzenes and benzene. Arh. ind. Heath, 14, 387-398World Health Organization (1981) Reommended Heath-basd Limits in Occupaiona Exsure to Se-
/ected Organic So/vents. Report of a WHO Study Group (WHO tech. Rep. SeT. 664, Geneva pp.25-38
Zeiger, E., Andersn, B., Haworth, S., Lawlor, 'I, Mortelrnans, K. & Spek, W (1987) Salmonella muta-genicity tests: III. Results frorn the testing of 255 chernicals. Environ. Mutagenes, 9 (Supp/. 9),1-110
