EPA-540/1-86-006
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
£EPA
'HEALTH EFFECTS ASSESSMENT
FOR XYLENE
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EPA/540/1-86-006
September 1984
HEALTH EFFECTS ASSESSMENT
FOR XYLENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
V-~ *>-^v.";.:< ! ».\.bct;on Agency
r 'r ,'-<>'' j,
C.'VCSL-.O, SiHncis -00604': '
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DISCLAIMER
This report has been funded wholly or In part by the UnHed States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
Prefe'cltorf 'AgsrTcy
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with xylene.
All estimates of acceptable Intakes and carcinogenic potency presented 1n
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-Hne literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Hazard Assessment Report on Xylene. Prepared by
Syracuse Research Corporation under Contract No. 68-03-3112 for the
Environmental Criteria and Assessment Office, Research Triangle
Park, NC.
U.S. EPA. 1985. Drinking Water Criteria Document for Xylenes.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Drinking Water, Washington,
DC. (Final draft)
i
The Intent 1n these assessments 1s to suggest acceptable exposure levels
; whenever sufficient data were available. Values were not derived or larger
c uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e. protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
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The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment 1n proper context, the reader Is
referred to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates.
Inhalation data for mixed xylenes as well as the o-, m- and p-lsomers
are fragmented. Mixed xylenes and the o-1somer have been evaluated 1n sub-
chronic studies with adult animals. All of these compounds have been evalu-
ated 1n teratology studies. NOELs for fetotoxldty have been established
for all Isomers except p-xylene. Additional clarification of the lowest
fetotoxldty effect level for mixed xylenes Is needed. An Inhalation AIS
for o-xylene of 67 mg/day 1s estimated based on fetotoxldty. An AIS for
m-xylene which 1s less fetotoxlc Is based on analogy to nonreproductlve
effects of o-xylene and 1s estimated as 71 mg/day. The AIS for mixed
xylenes 1s based on a fetotoxldty NOEL and estimated to be 48 mg/day. No
value 1s estimated for p-xylene. For chronic exposure, an AIC for o-xylene
and by analogy, m-xylene 1s estimated as 14 mg/day based on a 1-year Inhala-
tion study 1n rats. For mixed xylenes an AIC of 28 mg/day 1s estimated
based on a rat 90-day Inhalation study. No AIC for Inhalation 1s estimated
for p-xylene.
Only one oral administration study was located. This study exposed rats
to o-xylene by their diet for 6 months at one dose level and defined a
LOAEL. Based on this study, an oral AIS of 7 mg/day and an pral AIC of 0.7
mg/day were estimated for o-xylene and by analogy for m- and'mixed xylenes.
An AIC was not estimated for p-xylene. A CS of 9 was calculated based on
teratogenldty and fetotoxldty 1n mice at a level also associated with
maternal toxldty.
These estimates, especially for the oral route, should be reviewed as
additional data become available.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's- Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball waskthe Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati. OH
Technical support services for the document series was provided by:
t
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati. OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
ENVIRONMENTAL CHEMISTRY AND FATE ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . ,
2.1. ORAL ,
2.2. INHALATION ,
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral ,
3.1.2. Inhalation ,
3.2. CHRONIC ,
3.2.1. Oral ,
3.2.2. Inhalation ,
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . ,
3.3.1. Oral ,
3.3.2. Inhalation ,
3.4. TOXICANT INTERACTIONS ,
CARCINOGENICITY ,
*
4.1. HUMAN DATA ,
4.2. BIOASSAYS ,
4.3. OTHER RELEVANT DATA ,
4.4. WEIGHT OF EVIDENCE ,
REGULATORY STANDARDS AND CRITERIA ,
RISK ASSESSMENT ,
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) ,
6.1.1. Oral
6.1.2. Inhalation
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) ' . . . ,
6.2.1. Oral
6.2.2. Inhalation
6.3. CARCINOGENIC POTENCY (q-^*)
REFERENCES
Page
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14
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17
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APPENDIX: Summary Table for Xylene 28
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Services
CS Composite score
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RQ Reportable quantity
RVjj Dose-rating value
RVe Effect-rating value
SCE Sister chromatld exchange
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Xylene can exist 1n three IsomeMc forms. Commercial xylene 1s a
mixture of three Isomers In the following percent ranges: o-xylene, 10-25%;
m-xylene, 45-70%; and p-xylene, 6-15% (NIOSH, 1975). The relevant physical
and chemical properties of the Individual xylenes and their environmental
fate are as follows:
Chemical class
CAS Registry No.
Molecular weight
Vapor pressure 1n
mm Hg at 20°C
Water solubility In
mg/1 at 25°C
Octanol/water partition
coefficient
BCF
(estimated]
Half-life 1n air:
Half-life 1n water:
monocycllc aromatic hydrocarbon
o-xlene, 95-47-6; m-xylene, 108-38-3
p-xylene, 106-42-3
106.17
o-xylene, 5; m-xylene, 6;
p-xylene, 6.5 (Verschueren, 1983)
o-xylene, 170.5; m-xylene, 146;
p-xylene, 156 (Sutton and Calder, 1975)
>
o-xylene, 589; m-xylene, 1585;
p-xylene, 1413 (Leo et al., 1971)
o-xylene, 45; m-xy-lene, 105;
p-xylene, 95
o-xylene, 13 hours; m-xylene, 8 hours;
p-xylene, 15 hours (Singh et al., 1981)
2.6-11 days for the three xylenes
(estimated)
The BCFs for the three xylenes have been estimated by using the equation
of Velth et al. (1979) and the octanol/water partition coefficient values
stated above.
The dominant process for the removal of xylenes from water 1s volatili-
zation (U.S. EPA, 1985). The half-lives for the three xylenes are based on
an EXAMS model because of evaporation (Burns et al., 1981), with the appro-
priate Input parameter given In U.S. EPA (1985).
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The half-lives for the three xylenes 1n soil could not be located 1n the
available literature; however, based upon the characteristics of their
evaporation from water, volatilization 1s expected to be the predominant
loss mechanism from the soil surface. In subsurface soil, blodegradatlon of
xylenes 1s likely to be a slow process (U.S. EPA, 1985). The persistence of
xylenes 1n soils has been reported to be >6 months (NRC, 1980). Therefore,
In subsurface soils with low organic carbon content, xylenes may Infiltrate
Into groundwater from soil (U.S. EPA, 1985).
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Although explicit data regarding the absorption of xylenes from the
gastrointestinal tract of animals or humans were not located, H can be
Inferred that absorption by this route 1s nearly complete. In the rabbit,
85-90% of an administered oral dose of xylene Isomers (ranging from 0.9-1.7
g/an1mal) was accounted for In the urine, while pulmonary excretion may have
accounted for the remaining xylene (Bray et a!., 1949).
2.2. INHALATION
Studies evaluating the Inhalation absorption rate 1n humans exposed to
doses ranging from 100-1300 mg/m3 Indicated that ~60% of the xylene
present 1n the Inspired air, regardless of the Isomer or Isomer mixture
used, 1s absorbed (Astrand et al., 1978; R11h1mak1 et al., 1979a; Sedlvec
and Flek, 1974, 1976; Gamberale et al., 1978; Se'nczuk and Orlowskl, 1978).
»
Exercise Increases the relative amount of xylene absorbed (Astrand et al.,
1978; R11h1mak1 et al., 1979b).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
Table 3-1 summarizes experiments regarding subchronlc xylene exposure.
3.1.1. Oral. The only animal study of subchronlc oral exposure to xylene
was performed by Bowers et al. (1982). Twenty male Long-Evans rats weighing
0.8-0.9 kg were fed xylene at a dose of 200 mg/kg of food (200 ppm). Groups
of five animals were killed after 1, 2, 3 and 6 months. The Hvers were
grossly normal, but two types of vesicles were seen with the transmission
electron microscope In the hepatocytes of the xylene-treated animals. These
vesicles were not present 1n the control group. The authors (Bowers et al.,
1982) noted that the vesicles were Involved 1n the elimination of xylene or
Us metabolites or both. The purpose of one type of vesicle may have been
to Increase the surface area of hepatocytes. The focus of this experiment
seemed to be exclusively on the liver; no other effects were reported.
3.1.2. Inhalation. Although Ungvary et al. (1981) presented some
evidence 1n acute toxldty studies that females may be more sensitive to
»
xylene exposure than males, most of the subchronlc Inhalation studies have
been done on males (Carpenter et al., 1975; Jenkins et al., 1970; Savolalnen
et al., 1979). Male rats were exposed to mixed xylenes (p-xylene. 8%;
m-xylene, 65%; o-xylene, 8%; ethylbenzene, 19%) at a dose of 180, 460 and
810 ppm (770, 2000 and 3500 mg/m3, respectively) for 6 hours/day, 5 days/
week for 13 weeks (Carpenter et al., 1975). There were 25 rats In each
group. No biochemical effects (blood levels of urea, nitrogen, glutamlc
oxalacetlc transamlnase, glutamlc pyruvlc transamlnase and alkaline phospha-
tase) or hlstologlcal effects (lung, liver, kidney, brain, pituitary,
trachea, thyroid, parathyroid, heart, spleen, gastrointestinal tract,
muscle, nerve and bone marrow) were seen 1n rats treated at the two lower
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TABU 3-1
Subchronlc Exposure to Xylene
Route
Oral
Inhalation
Dose
200 mg/kg
180 pp« (770 mg/m»)
460 ppm (2000 mg/m»)
810 ppm (3500 mg/m»)
Exposure
1. 2. 3 and
6 Months
6 hours/day,
5 days/week,
13 weeks
Species
Long-Evans
rats
(0.8-0.9 kg)
rats
Sex
N
N
N
M
Number
20
25
25
25
Effect
Livers were grossly
normal; ultra-strut -
turally. vesicles were
present.
No effects were
seen biochemically
or histologlcally at
Reference
Bowers et al., 1982
Carpenter et al..
1975
Inhalation
Inhalation
180 ppm (770 mg/m*)
460 ppm (2000 mg/m*)
810 ppm (3500 mg/m*)
78 ppm (337 mg/m*)
6 hours/day,
5 days/week.
13 weeks
continuous
for
90 days
dogs
rats
guinea pigs
dogs
monkeys
H
N
N
H/f
H/F
M
14
15
2
3
180 or 460 ppm.
Transitory changes
In blood cell counts
and slight changes
In renal tubules at
810 ppm.
No effect on blood cell
counts, clinical chem-
istry, body weight.
liver and kidney weights.
No effect on hematology
or body weight gain.
Jenkins et al.. 1970
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dose levels. In rats exposed to xylene at the highest dose level, there was
an Increase 1n erythrocyte and monocyte counts after 3 weeks of xylene Inha-
lation, which disappeared during weeks 7-13 of the experiment. The authors
did not consider this an adverse effect (Carpenter et a!., 1975). Male dogs
were exposed to mixed xylenes at concentrations of 180, 460 or 810 ppm (770,
2000 and 3500 mg/m3, respectively) for 6 hours/day, 5 days/week for 13
weeks (Carpenter et al., 1975). There were four dogs 1n each group. No
effect on blood cell count, clinical chemistry, urlnalysls, body weight or
"liver and kidney weight was reported.
In another study, 20 male Wlstar rats were exposed to 300 ppm (1300
mg/m3) xylene for 6 hours/day, 5 days/week for <18 weeks (Savolalnen et
al., 1979). Some rats were killed at 5, 9, 14 and 18 weeks. Brain super-
oxide dlsmutase decreased after 5 weeks of xylene exposure, but Increased
after 18 weeks of xylene exposure. Brain cytosollc glutath^one peroxldase
activity was significantly decreased after 14 weeks, but was not signifi-
cantly different from control levels after 18 wefiks of xylene exposure.
Some behavioral changes (decreased preening and reduced activity) were seen
1n the xylene-treated rats (Savolalnen et al., 1979).
Jenkins et al. (1970) exposed NMRI:0(SD) Sprague-Oawley or NMRI:(LE)
Long-Evans derived rats (apparently mixed strains and sexes), NMRI:(ASH)
Princeton derived guinea pigs (mixed sexes), squirrel monkeys and beagle
dogs to o-xylene (purity not specified) for either 30 Intermittent exposures
(8 hours/day, 5 days/week) or continuously for 90 days. Group sizes were:
12 rats 1n the Intermittent protocol, 14 rats 1n the continuous protocol, 15
guinea pigs for each exposure condition, 2 male dogs for each exposure
condition, 2 male monkeys on the Intermittent protocol and 3 exposed contin-
uously. Exposure concentrations were: 3358 mg/m3 for the Intermittent
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protocol and 337 mg/m3 for the continuous protocol. Blood counts, hemo-
globin and hematocrlt were monitored In addition to body weight. H1sto-
pathologlcal evaluation was conducted on heart, lung, liver, spleen and
kidney of all species at the end of exposure and brain and spinal cord from
dogs and monkeys.
Apparently statistics were not run on body weights. Rats continuously
exposed gained more weight than controls. Guinea pigs and dogs also gained
more weight on the contluous protocol than did controls. Both control and
exposed dogs lost equal amounts of weight. Statistics were not reported for
blood chemistries, but none of the values appeared different. Hlstopathol-
ogy apparently yielded negative results although data were not shown. Organ
weights were not reported. Two rats died on the third exposure day and both
a rat and a monkey died on day 7 on the Intermittent protocol, while one rat
died on day 56 of the continuous protocol. If necropsies* were done the
results were flot reported, making It Impossible to ascertain whether the
deaths were treatment related.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the chronic oral toxldty of
xylene could not be located 1n the available literature.
3.2.2. Inhalation. Male CFY rats were exposed to 4750 mg/m3 of xylene
for 8 hours/day, 7 days/week for 1 year (Tatral et al., 1981). Although the
xylene-exposed animals ate more, they had decreased body weights. Xylene-
exposed rats also had hepatomegaly and an altered hepatic enzyme pattern.
Cytochrome P-450, NADPH-cytochrome c reductase, aniline hydroxylase and
am1nopyr1n-N-demethylase activity were Increased, while bromosulfophthalein
retention time 1n the liver was decreased. Ultrastructurally, the centrl-
lobular hepatocytes of xylene-treated rats had moderate smooth endoplasmlc
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retlculum proliferation, an Increased number of peroxlsomes and autophagous
bodies, glycogen depletion and, occasionally, damaged mitochondria. Pro-
liferation of the smooth endoplasmlc retlculum has been correlated with
Increased mixed function oxldase activity. Liver enlargement was attributed
to functlnal hypertrophy.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Oral exposure to 3.10 or 4.13 g/kg/day on days 6-15 of
gestation was toxic to pregnant CD-I mice, producing a mortality Incidence
of 12/38 at 3.10 g/kg/day (Marks et al., 1982). Doses of 2.06 and 2.58
g/kg/day caused Increased resorptlons and fetal malformations, and decreased
fetal body weights (Marks et al., 1982). Doses of 1.03 and 0.52 g/kg/day
had no apparent effects on fetal or maternal toxlclty.
3.3.2. Inhalation. Shlgeta et al. (1983) reported that IRC mice exposed
to 500, 1000, 2000 or 4000 ppm xylene for 6 hours/day on days 6-12 of gesta-
tion did not differ from controls 1n the number of Implantation sites or the
number of resorbed or dead fetuses. At dose levels of 2000 and 4000 ppm,
*
fetal weights were decreased and skeletal ossification was delayed.
Continuous exposure of 26 pregnant CF4 rats to 1000 mg/m3 mixed
xylenes (10% o-xylene, 50/4 m-xylene, 20% p-xylene, 20% ethylbenzene) on days
9-14 of gestation resulted 1n an Increased Incidence of fused sternebrae and
extra ribs 1n the offspring. The Incidence of retarded skeletal development
appeared higher but was not significantly different (Hudak and Ungvary,
1978). There was no effect on maternal weight gain, mean Utter size, mean
placenta! weight, mean fetal weight, fetal resorptlon or fetal mortality.
Pregnant CF4 rats were exposed to 150, 1500 or 3000 mg/m3 of each of
the Isomers of xylene continuously on days 7-14 of gestation (Ungvary et
al., 1980). The number of rats 1n each exposed group was 20 except for the
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3000 mg/m3 m-xylene group which contained 30 rats. Groups of 15, 25 or 20
rats served as controls for the o-, m- and p-1somers, respectively. Signs
of maternal toxlclty Included decreased food consumption In all 3000 mg/m3
groups and 1n the 1500 mg/m3 o-xylene-exposed group. The 3000 mg/m3
group exposed to m-xylene exhibited Increased mortality (4/30). The authors
state that maternal weight gain decreased as a function of exposure concen-
tration during the early days of exposure (data not shown). The only sig-
nificant effect on weight gain by day 21 of gestation was 1n the m-xylene
group exposed to 3000 mg/m3. An Increase In maternal liver:body weight
ratio was reported for all o-xylene exposed groups. Dams exposed to
p-xylene at all dose levels had significantly lower placental weights.
Utters from dams exposed to p-xylene at 3000 mg/m3 showed signifi-
cantly Increased fetal loss (69% vs. 4X 1n controls), The number of rats
pregnant was decreased In dams exposed to 3000 mg/m3 of o-xylene or
m-xylene. The average number of Implants per rat was decreased 1.n the group
exposed to m-xylene at 3000 mg/m3.
Mean fetal weight was significantly reduced following exposure to all
three Isomers at the 3000 mg/m3 concentration. Additionally, exposure to
o-xylene at 1500 mg/m3 resulted 1n significant fetal weight reductions.
There were no Indications of Increased Incidence of external, soft tissue or
skeletal malformations. An Increase 1n the Incidence of extra Mbs, classi-
fied by the authors as a skeletal anomaly, was seen In Utters from dams
exposed to 3000 mg/m3 of either m-xylene or p-xylene. . Skeletal retarda-
tion occurred 1n fetuses from dams exposed to 3000 mg/m3 o-xylene and 1n
all p-xylene-exposed groups.
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' In addition, the number of alkaline phosphatase positive proximal con-
voluted tubules as well as the number and Intensity of the positive staining
nephrons for sucdnlc dehydrogenase, add phosphatase and glucose-6-phospha-
tase was reduced 1n the o- and p-xylene fetuses from dams exposed to 3000
mg/m3. In the liver and thymus cells from fetuses of dams exposed to all
three Isomers at 3000 mg/m3 there was a decrease In sucdnlc dehydrogenase
and glucose-6-phosphatase activities. The enzyme changes 1n the kidneys
were Interpreted by the authors as an Indication of a delay In maturation.
In summary, exposure to 1500 mg/m3 produced no adverse effects on
Utters exposed to m-xylene, 150 mg/m3 produced no adverse effects on
Utters exposed to o-xylene, and p-xylene resulted 1n fetotoxldty as
evident by delays 1n skeletal ossification following exposure to the lowest
concentration tested (150 mg/m3).
Charles River CD female rats were exposed to mixed xylenes (11%
o-xylene, 52% m-xylene, 0.31% p-xylene, 36.IX ethylbenzene) at concentra-
tions of 0, 433 and 1733 mg/m3 on days 6 through 15 of gestation, 6 hours/
day (LHton B1onet1cs, 1978). There were 25 pregnant dams per exposure
group. Animals were sacrificed on day 20 of gestation. The number of
Implantation sites, resorptlon sites, live and dead fetuses, fetal weights
and external abnormalities were recorded. One-third of the fetuses from
each Utter were examined for soft-tissue anomalies, with the remainder
examined for skeletal abnormalities. The only effect apparent was a
significant Increase In the number of offspring with "unusual skeletal
variations". Incidences of fetuses were 19 1n the control, 24 1n the low-
dose group and 37 1n the high-dose group; however, the number of Utters
affected were 9, 6 and 10. The authors did not judge this effect to be
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treatment related because the majority of the affected fetuses were from
three Utters and because all fetuses from these Utters were "small".
3.4. TOXICANT INTERACTIONS
The Interaction of xylene with ethanol (Savolalnen et al., 1978;
Elovaara et al., 1980; Savolalnen and R11h1mak1, 1981; Seppalalnen et al.,
1981; R11h1mak1 et al., 1982a,b), 1,1,l-tr1chloroethane (Savolalnen et al.,
1982} and carbon tetrachlorlde (Tatral et al., 1979) have been studied. In
rats, oral 1ngest1on of alcohol (15% of drinking fluid) potentiates the
effect of Inhalation exposure to 300 ppm of xylene given 6 hours/day, 5
days/week (Savolalnen et al., 1978; Elovaara et al., 1980). After 2 weeks
of simultaneous exposure, changes 1n hepatic and renal enzyme activities
(7-ethoxycoumar1n, o-deethylase, UOP-glucuronosyltransferase and cytochrome
P-450) were noted. After 18 weeks of exposure. Increased numbers of Intra-
cellular I1p1d droplets were present In the livers of rats exposed to both
xylene and ethanol, but were absent from the livers of rats exposed to
xylene or ethanol separately. In humans, alcohol Ingestlon (0.8 g/kg), In
»
conjuncton with xylene exposure (290 ppm for 4 hours), Increased the effect
of alcohol on central equilibrium control mechanisms (Savolalnen and R11h1-
makl, 1981). Xylene doubled the volume of centMlobular liver necrosis
caused by Ingestlon of 2 mi/kg bw of carbon tetrachlorlde In rats (Tatral
et al., 1979). Xylene and 1,1 ,l-tr1chloroethane each depressed the metabo-
lism of the other 1n humans, but no hlstopathologlcal effects were described
(Savolalnen et al., 1982).
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the human cardnogenldty of xylene could not
be located 1n the available literature.
4.2. BIOASSAYS
A bloassay of the cardnogenldty of xylene 1s being conducted on rats
and mice orally exposed to xylene (NTP, 1983), but a complete and final
report of the study 1s not available at this time.
4.3. OTHER RELEVANT DATA
m-Xylene, p-xylene and o-xylene were not mutagenlc 1n Salmonella
typh1mur1um strains TA98, TA100, TA1535, TA1537 and TA1538 In the presence
or absence of the rat liver mlcrosomal fraction (Florin et al., 1980; Bos et
al., 1981). Mixed xylenes were not mutagenlc 1n Escher1ch1a coll strains
WP2, WP2uvrA, CM611, WP67, HP100, W3110 and p3478 (McCarroll^et al., 1981).
Xylene was not mutagenlc In the Drosophlla recessive lethal test (Donner et
al., 1980), and did not Increase chromosomal aberrations In hematopoletic
cells (Donner et al., 1980) or SCEs In human lymphocytes .In. vitro (Gerner-
Smldt and Fr1edr1ch, 1978).
4.4. WEIGHT OF EVIDENCE
The results of the NTP (1983) bloassay are not available, but H should
be noted that tumors were not observed 1n rats that were exposed to xylene
vapor (4750 mg/m3) for 1 year (Tatral et al., 1981). IARC has not evalu-
ated the risk to humans associated with oral or Inhalation exposures to
xylene. Using the criteria for evaluating the overall weight of evidence of
cardnogenldty to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), xylene 1s most appropriately designated
as a Group D - Not Classified chemical.
-12-
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1983) recommends a TWA-TLV of 100 ppm (435 mg/m3) and a
STEL-TLV of 150 ppm (655 mg/m3). NIOSH (1975) recommends a I0-m1nute
celling of 200 ppm xylene because the attention, Judgment and perception of
the worker can be altered due to the depressant effect of xylene on the
CNS. OSHA (Code of Federal Regulations, 1981) has promulgated a TWA limit
of 100 ppm for occupational exposure to xylene.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. In the only study (Bowers et al., 1982) on oral exposure to
xylene one dietary level (200 ppm) of o-xylene was given to 20 male Long-
Evans rats. Groups of five rats were killed after 1, 2, 3 and 6 months of
o-xylene exposure. No gross or light microscopic effects were seen;
however, 200 ppm appeared to be a NOAEL because ultrastructural changes 1n
liver morphology, which did not appear to be adverse, were noted. Assuming
a rat consumes 5% of Us body weight per day, the estimated NOAEL from this
study 1s 10 mg/kg/day. Applying an uncertainty factor of 100 results 1n an
estimated AIS of 7 mg/day for a 70 kg human. This study Is flawed by small
group sizes and the use of only one exposure level. However, the effects
observed are consistent with those following Inhalation exposure to
o-xylene. Tatra! et al. (1981) exposed male rats to 4750 mg/m3 o-xylene 8
hours/day, 7 days/week for 1 year. Effects noted Included decreased body
weights, minimal liver damage apparent only following electron microscopy
and hepatomegaly attributed to functional hypertrophy. For purposes of
comparison a dose may be estimated from this Inhalation study. Assuming
rats breath 0.223 mV24 hours, weigh 0.35 kg and that 50% of the Inhaled
xylene 1s absorbed (U.S. EPA, 1985), the following dose 1s estimated: 4750
mg/m3 x 0.223 mV24 hours x 8/24 hours x 0.50 * 0.35 = 504 mg/kg.
Applying an uncertainty factor of 1000 (10 to estimate a NOAEL from a LOAEL,
10 for Interspedes extrapolation, and 10 for 1nter1nd1v1dual variability)
results 1n an alternate AIS estimate of 35 mg/day. This estimate 1s within
a factor of 5 of the estimate derived from the Bowers et al. (1982) study.
As a result of the Inherent uncertainty 1n route to route extrapolation, the
more conservative estimate of 7 mg/day based on the oral data 1s proposed as
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the AIS for o-xylene. This value should be reevaluated when more complete
oral data become available.
Jenkins et al. (1970) conducted an additional Inhalation evaluation of
o-xylene In rats, monkeys and dogs either as 3358 mg/m9 8 hours/day, 5
days/week for 30 exposures or 389 mg/m3 continuously for 90 days.
Unexplained deaths 1n rats preclude use of the Intermittent exposure data.
Organ weights were not reported and apparently electron microscopic evalua-
tions of livers were not conducted. Pathology data were reported as a
single sentence which stated results were essentially negative. This study
would suggest an AIS of 87 mg/day. However, the protocol as reported
suggests that subtle liver effects documented by Bowers et al. (1982) and
Tatra! et al. (1981) could have been missed. Therefore, this study 1s not
recommended as a basis for quantitative risk assessment.
Data are not available for oral exposure of adult an1ma>s to commercial
mixed xylenes nor for the m- or p-1somers. An oral teratology evaluation of
mixed xylenes 1n mice Indicated no effects on offspring at doses <1.03 g/kg/
day. Acute tox1cH1es of the three Isomers and commercial mixed xylenes are
similar (U.S. EPA, 1985). In the absence of additional experimental data It
may be appropriate to apply the AIS for o-xylene to mixed xylenes and
m-xylene. The p-lsomer Is the most severely fetotoxlc of the xylenes 1n rat
teratology studies by Inhalation and the only Isomer for which a NOEL for
fetotoxldty has not been established. Although xylene appears to exhibit a
greater potential for fetotoxldty by the Inhalation route, the oral evalua-
tion was conducted with mice and the Inhalation evaluations with rats; thus
complicating Interpretations. Until these questions are resolved H 1s sug-
gested that the o-xylene based AIS may not be appropriate for the p-xylene
Isomer.
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6.1.2. Inhalation. As discussed 1n Section 6.1.1. a 1-year evaluation of
the toxldty of Inhaled o-xylene has been conducted (Tatral et a!., 1981).
This study 1s considered more appropriate for assessment of adult Inhalation
toxlclty than Jenkins et al. (1970) as discussed 1n Section 6.1.1. In
addition, an Inhalation teratology study has been conducted In rats which
defined a NOEL for fetotoxldty of 96 mg/kg (extrapolated from an exposure
concentration of 150 mg/m3) (Ungvary et al., 1980). The LOAEL from Tatral
et al. (1981) 1s estimated to be 1009 mg/kg, estimated as 1n Section 6.1.1.
with the omission of the absorption factor which was applied to estimate
absorbed dose for purposes of route:route extrapolation. Applying an
uncertainty factor of 10 to estimate a NOAEL from a LOAEL results 1n an
estimated NOAEL of 101 mg/kg/day, essentially the same as the fetotoxldty
NOEL of 96 mg/kg/day. Using the NOEL for the most sensitive endpolnt, feto-
toxldty, results 1n an estimated Inhalation AIS of o-xylene, of 67.2 mg/day
[96 mg/kg/day * 100 (uncertainty factor) x 70 kg].
m-Xylene was less fetotoxlc than o-xylene wlth^a NOEL of 956 mg/kg/day
(exposure concentration 1500 mg/m3). Therefore, for m-xylene the LOAEL of
1009 from Tatral et al. (1981) represents the lowest LOAEL assuming that the
o- and m-lsomers exhibit comparable tox1cH1es. Applying an uncertainty
factor of 1000 (10 to estimate a NOAEL, 10 for Interspedes extrapolation
and 10 for 1nter1nd1v1dual variability) results 1n an AIS of 70.7 that Is
essentially Indistinguishable from the value based on fetotoxldty.
For mixed xylenes, Ungvary et al. (1980) established a fetotoxldty FEL
of 637 mg/kg. Litton B1onet1cs (1978) established a NOAEL/LOAEL of 276
mg/kg/day based on Increased numbers of fetuses, but not Utters with
skeletal abnormalities. The lower exposure concentration In the Litton
B1onet1cs study clearly defined a NOEL of 69 mg/kg/day. Carpenter et al.
-16-
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(1975) exposed male rats to 770, 2000 or 3500 mg/m3, 6 hours/day, 5 days/
week. The highest exposure level appeared to represent a NOAEL. The esti-
mated dose Is 398 mg/kg. This dose 1s higher than the LOAEL/NOAEL for feto-
toxldty In the LHton B1onet1cs (1978) study. Although the effect at this
dose level was questionable, skeletal abnormalities are the endpolnts
observed following higher levels of xylene exposure. It 1s suggested that
mixed xylenes be reevaluated for Inhalation teratology utilizing doses
around this possible threshold level. As an Interim approach, the dose of
276 mg/kg will be considered a LOAEL. As a result, the NOEL for fetotox-
1dty of 69 mg/kg/day may be used to estimated an AIS. Dividing by an
uncertainty factor of 100 and multiplying by 70 kg results 1n an estimated
AIS for mixed xylenes of 48.3 mg/day.
A fetotoxldty NOEL for p-xylene has not been established. Significant
fetotoxldty was seen at the lowest exposure concentration,' 150 mg/m3 (96
mg/kg) (Ungvary et al., 1980). .Since this dose 1s similar to the estimated
NOAEL for other endpolnts, an AIS for p-xylene Is not proposed.
In conclusion, an AIS for o-xylene of 67 mg/day 1s proposed based upon
fetotoxldty, and an AIS of 70.7 mg/day for mixed xylenes and m-xylene,
while an AIS 1s not suggested for p-xylene. These values should be reevalu-
ated when additional data become available.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. Although pertinent data regarding chronic oral exposure to
xylenes were not located 1n the available literature, an AIC for oral expo-
sure of 0.7 mg/day can be derived from the AIS for oral exposure by dividing
the AIS {7 mg/day) by an uncertainty factor of 10, applied to reflect the
unknowns Involved 1n extrapolating from subchronlc to chronic expsoure. As
described 1n Section 6.1.1., this value 1s suggested for mixed xylenes,
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o-xylene and m-xylene, but not p-xylene. This AIC 1s substantially lower
than that derived from the TLV (161 mg/day) using an uncertainty factor of
10 or that derived from an Inhalation study 1n many species (4.43) (U.S.
EPA, 1985). Both of these latter ADIs Involve route-to-route extrapolation
with Us Inherent uncertainties.
An RQ was derived for the teratogenldty (cleft palates) and fetotox-
1c1ty observed 1n mice treated by gavage with a mixture of xylenes and
ethylbenzene at 2.58 g/kg/day on days 6-,15 of gestation. A human MED 1s
calculated by multiplying the animal dose by the cube root of the ratio of
the body weight of mice (assumed: 0.03 kg) to that of humans (assumed: 70
kg) and multiplying the result by 70 to express the MED In mg/day for a 70
kg human. A human MED of 13616 mg/day, corresponding to an RV of 1, 1s
calculated. Teratogenldty In the presence of maternal toxldty 1s assigned
an RVg of 9. A CS of 9 1s calculated as the product o,f the RV and
RVe.
6.2.2. Inhalation. In the only subchronlc Inhalation study on o-xylene
»
(Tatral et al., 1981) considered adequate for risk assessment (see Section
6.1.2.), rats were exposed to one dose level of xylene (4750 mg/m3) for 1
year. This exposure level produced signs of toxldty, such as changes 1n
body and organ weights, ultrastructural alterations and enzyme Induction,
without producing gross changes 1n the morbidity or mortality of the
animals, and Is considered to be a LOAEL. An AIS of 70.7 mg/day was
estimated as described 1n Section 6.1.2. Applying an additional uncertainty
factor of 5 to account for the duration of the study results 1n an estimated
AIC of 14.1 mg/day. As outlined In Section 6.1.2., this AIS 1s proposed for
o-xylene and by analogy to m-xylene. Carpenter et al. (1975) defined an
Inhalation subchronlc NOAEL of 398 mg/kg for mixed xylenes. Applying an
-18-
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uncertainty factor of 1000 and multiplying by 70 kg results 1n an estimated
AIC of 27.9 nig/day. An AIC 1s not estimated for p-xylene. This value 1s
lower than an estimate based on the TLV. (This estimate using an uncer-
tainty factor of 10 would be 310 mg/day.)
6.3. CARCINOGENIC POTENCY (q *)
Derivation of a q * Is precluded by the lack of cardnogenldty data.
An NCI gavage study has been completed 1n rats and mice using a commercial
mixture of xylene but the first draft of this report Is not yet available
(May, 1985).
-19-
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7. REFERENCES
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Threshold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment with Intended Changes for 1983-84. Cincinnati, OH.
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Astrand, I., J. Engstrom and P. Ovrum. 1978. Exposure to xylene and ethyl-
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Environ. Health. 4(3): 185-194. (Cited 1n U.S. EPA, 1985)
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1981. Non-mutagen1dty of toluene, o-xylene, m-xylene and p-xylene,
o-methylbenzylalcohol and o-methylbenzylsulfate 1n the Ames assay. Mutat.
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Bowers, D.E., Jr., M.S. Cannon and D.H. Jones. 1982. Ultrastructural
changes In livers of young and aging rats exposed to methylated benzenes.
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Bray, H.G., B.G. HumphMs and W.V. Thorpe. 1949. Metabolism of derivative
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Burns, L.H., D.M. CUne and R.R. Lasslter. 1981. Exposure Analysis Model-
Ing System (EXAMS). Environmental Research Lab, ORD, U.S. EPA, Athens, GA.
-20-
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Carpenter, C.P., E.R. Klnkead, D.L. Geary, Jr., L.J. Sullivan and J.M. King.
1975. Petroleum hydrocarbon toxldty studies. V. Animal and human response
to vapors of mixed xylenes. Toxlcol. Appl. Pharmacol. 33(3): 543-558.
(Cited 1n U.S. EPA, 1985)
Code of Federal Regulations. 1981. OSHA Safety and Health Standards. 29
CFR 1910.1000.
Oonner, M., J. Haekl-Paakkanen, H. Norppa, M. Sorsa and H. Va1n1o. 1980.
Genetic toxicology of xylenes. Mutat. Res. 74: 171-172. (Cited In U.S.
EPA, 1985)
Elovaara, E., Y. Collan, P. Pfaffll and H. Va1n1o. 1980. The combined
toxldty of technical grade xylene and ethanol In the rat. Xenoblotlca.
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10(6): 435-446. (Cited 1n U.S. EPA, 1985)
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guidelines for carcinogenic risk assessment. 49 FR 46294-46299.
Florin, I., L. Rutberg, M. Curvall and C.R. Enzell. 1980. Screening of
tobacco smoke constituents for mutagenUHy using the Ames' test. Toxicol-
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Gamberale, F., G. Annual! and M. Hultengren. 1978. Exposure to xylene and
ethylbenzene. III. Effects on central nervous functions. Scand. J. Work,
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Gerner-Smldt, P. and U. FMedMch. 1978. The mutagenlc effect of benzene,
toluene and xylene studied by the SCE technique. Mutat. Res. 58: 313-316.
(Cited 1n U.S. EPA, 1985)
Hudak, A. and 6. Ungvary. 1978. Embryotoxlc effects of benzene and Its
methyl derivatives: Toluene, xylene. Toxicology. 11: 55-63. (Cited In
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Jenkins, L.J., Jr., R.A. Jones and J. Slegal. 1970. Long-term Inhalation
screening studies on benzene, toluene, o-xylene and cumene on experimental
animals. Toxlcol. Appl. Pharmacol. 16(3): 818-823. (Cited In U.S. EPA,
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Leo, A., C. Hansch and 0. Elklns. 1971. Partition coefficients and their
uses. Chem. Rev. 71: 525-616.
LHton Blonetlcs. 1978. Teratology study 1n rats: Xylene. Final report to
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Marks, T.A., T.A. Ledoux and J.A. Moore. 1982. Teratogenldty of a com-
mercial xylene mixture 1n the mouse. J. Toxlcol. Environ. Health. 9(1):
97-106. (Cited In U.S. EPA, 1985)
McCarroll, N.E., C.E. Piper and B.H. Keech. 1981.- An E.. coll mlcrosuspen-
slon assay for the detection of DNA damage Induced by direct-acting agents
and promutagens. Environ. Mutagen. 3: 429-444. (Cited In U.S. EPA, 1985)
-22-
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NIOSH (National Institute for Occupational Safety and Health). 1975.
Criteria for a Recommended Standard...Occupational Exposure to Xylene. U.S.
DHEW Pub. No. (NIOSH) 75-168, PHS, CDC, Rockvllle, MO. p. 101. (Cited 1n
U.S. EPA, 1980b)
NRC (National Research Council). 1980. The Alky! Benzenes. Committee on
Alkyl Benzene Derivatives. Board on Toxicology and Environmental Health
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R11h1mak1, V., P. PfaffH, K. Savolalnen and K. PekaM. 1979a. Kinetics of
i
m-xylene In man: General features of absorption, distribution, blotransfor-
matlon and excretion In repetitive Inhalation exposure. Scand. J. Work,
•
Environ. Health. 5(3): 217-231. (Cited 1n U.S. EPA, 1985)
R11h1mak1, V., P. PfaffH and K. Savolalnen. 1979b. Kinetics of m-xylene
1n man: Influence of Intermittent physical exercise and changing environ-
mental concentrations on kinetics. Scand. J. Work Environ. Health. 5(3):
232-248. (Cited 1n U.S. EPA, 1985)
R11h1mak1, V., K. Savolalnen, P. PfaffH, K. Pekarl, H.W. Slppel and A.
Lalne. 1982a. Metabolic Interaction between m-xylene and ethanol. Arch.
Toxlcol. 49(3-4): 253-264. (CHed In U.S. EPA, 1985)
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R11h1mak1, V., A. Lalne, K. Savolalnen and H. Slppel. 1982b. Acute solvent-
ethanol Interactions with special reference to xylene. Scand. J. Work
Environ. Health. 8(1): 77-79. (Cited 1n U.S. EPA, 1985)
Savolalnen, K. and V. R11h1mak1. 1981. Xylene and alcohol Involvement of
the human equilibrium. Acta. Pharmacol. Toxlcol. 48(3): 279-283. (Cited
1n U.S. EPA, 1985)
Savolalnen, K., H. Valnlo, M. Helojokl and E. Elovaara. 1978. Biochemical
and toxlcologlcal effects of short-term, Intermittent xylene Inhalation
exposure and combined ethanol Intake. Arch. Toxlcol. 41(3): 195-205.
Savolalnen, K., P. PfaffH, M. Helojokl and M. Tengen. 1979. Neurochemlcal
and behavioral effects of long-term Intermittent Inhalation of xylene vapor
and simultaneous ethanol Intake. Acta. Pharmacol. Toxlcol. 44(3): 200-207.
(Cited 1n U.S. EPA, 1985)
Savolalnen, K., V. R11h1mak1, A. Lalne and J. Kekonl. 1982. Short-term
exposure of human subjects to m-xylene and 1,1 ,l-tr1chloroethane. Arch.
Toxlcol. (Suppl.) 5: 96-99. (Cited 1n U.S. EPA, 1985)
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xylenes 1n man. Int. Arch. Occup. Environ. Health. 37(3): 205-217. (Cited
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Se'nczuk, W. and J. Orlowskl. 1978. Absorption of m-xylene vapors through
the respiratory tract and excretion of m-methylh1ppur1c acid 1n urine. Br.
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xylene and alcohol 1n human evoked potentials. Electroencephalogr. CUn.
Neurophyslol. 51(2): 148-155. (Cited 1n U.S. EPA, 1985}
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Inhaled xylene 1n mice. Teratology. 28(1): 22A. (Cited In U.S. EPA, 1985)
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of some potentially hazardous organic chemicals In urban environments.
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t
Sutton, C. and J.A. Calder. 1975. Solubility of alkylbenzenes 1n distilled
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liver of benzene, toluene, xylene and CC1.. Acta. Physlol. Acad. Sc1.
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Tatral, E., G. Ungvary, I.R. Cseh, et al. 1981. The effect of long-term
Inhalation of o-xylene on the liver. Ind. Environ. Xenob'1ot1cs, Proc. Int.
Conf. p. 293-300. (CHed 1n U.S. EPA, 1984}
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Ungvary, G., J. Cseh, S. Manyal, A. Molnar, S. Szeberenyl and E. Tatral.
1980. Enzyme Induction by o-xylene Inhalation. Acta. Med. Acad. Sd. Hung.
37(1): 115-120. (Cited 1n U.S. EPA, 1985)
Ungvary, G., B. Varga, E. Horvath, E. Tatral and G. Folly. 1981. Study on
the role of maternal sex steroid production and metabolism 1n the embryotox-
IcHy of para-xylene. Toxicology. 19: 263-268. (Cited 1n U.S. EPA, 1985)
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Criteria. Federal Register. 45:79347-79357.
U.S. EPA. 1980b. Hazard Assessment Report on Xylene. Prepared by Syracuse
Research Corporation under Contract No. 68-03-3112 .for U.S. EPA, ECAO,
Research Triangle Park, NC.
•
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
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U.S. EPA. 1985. Drinking Water Criteria Document on Xylenes. Prepared by
the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for
the Office of Drinking Water, Washington, DC. (Final draft)
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Velth, G.D., D.L. Defoe and B.V. Bergstadt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals In fish. J. F1sh Res. Board Can.
36: 1040-1048.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemistry,
2nd ed. Van Nostrand Relnhold Co., New York. p. 1310.
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APPENDIX
Summary Table for Xylene
CD
Inhalation
AIS
o-xylene
m-xylene
mixed xylenes
p-xylene
AIC
o-xylene
m-xylene
mixed xylenes
p-xylenes
Species
rat
rat
rat
NA
rat
rat
rat
NA
Experimental
Dose/Exposure
150 mg/m9
4750 mg/m»
8 hours/day
433 mg/m"
6 hours/day
NA
4750 mg/m"
8 hours/day
4750 mg/ma
8 hours/day
3500 mg/m'
6 hours/day
NA
Effect
fetotoxlclty
NOEL
hepatomegaly
weight loss
fetotoxlclty
NOEL
NA
hepatomegaly
Wight loss
hepatomegaly
weight loss
transient blood
alterations
NA
Acceptable Intake
(AIS or AIC)
67.2 mg/day
70.7 mg/day
48.3 mg/day
ND
14.1 mg/day
14.1 mg/day
27.9 mg/day
ND
Reference
Ungvary et al.,
1980
Tatral et al. ,
1981
Litton
Blonetlcs. 1978
NA
Tatral et al. ,
1981
Tatral et al.,
1981
Carpenter
et al., 1975
NA
-------
i * V
APPENDIX (cont.)
I
rs>
Species
Oral
AIS
o-, m- and rat
mixed xylenes
p-xylene NA
AIC
o-, m- and rat
mixed xylenes
p-xylene NA
Experimental
Dose/Exposure
200 ppm
food
NA
200 ppm
food
NA
Effect
ultrastructural
liver changes
NA
ultrastructural
liver changes
NA
Acceptable Intake
(AIS or AIC)
7 mg/day
ND
0.7 mg/day
ND
Reference
Bower et al.t
1982
NA
Bowers et al..
1982
NA
NA = Not applicable; ND = not derived
r (jo o ;..
- o 09. •
• I oo § m
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i §-
OQ
O
a
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