treatment related because the majority of the affected fetuses were from
three litters and because all fetuses from these litters were “small”.
3.4. TOXICANT INTERACTIONS

The interaction of xylene with ethanol (Savolainen et al., 1978;
Elovaara et al., 1980; Savolainen and Riihimaki, 1981; Seppalainen et al.,
1981; Riihimakt et al., 1982a,b), 1,1,1]-trichloroethane (Savolainen et al.,
1982) and carbon tetrachloride (Tatrai et al., 1979) have been studied. In
rats, oral ingestion of alcohol (15% of drinking fluid) potentiates the
effect of inhalation exposure to 300 ppm of xylene given 6 hours/day, 5
days/week (Savolainen et al., 1978; Elovaara et al., 1980). After 2 weeks
of simultaneous exposure, changes in hepatic and renal enzyme activities
(7-ethoxycoumarin, o-deethylase, UDP-glucuronosyltransferase and cytochrome
P-450) were noted. After 18 weeks of exposure, increased numbers of intra-
cellular lipid 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 ingestion (0.8 g/kg), in
conjuncton with xylene exposure (290 ppm for 4 hours), increased the effect
of alcohol on central equilibrium control mechanisms (Savolainen and Riihi-
maki, 1981). Xylene doubled the volume of centrilobular liver necrosis
caused by ingestion of 2 m&/kg bw of carbon tetrachloride in rats (Tatrai
et al., 1979). Xylene and 1,1,1-trichloroethane each depressed the metabo-
lism of the other in humans, but no histopathological effects were described

(Savolainen et al., 1982).


-92-

Summary Table for Xylene

APPENDIX

Exper imental Acceptable Intake
Species Dose/Exposure Effect (AIS or AIC) Reference
Inhalation
AIS
o-xy lene rat 150 mg/m? Fetotoxicity 67.2 mg/day Ungvary et al.,
NOEL 1980
m-xylene rat 4750 mg/m? hepatomegaly 710.7 mg/day Tatral et al.,
8 hours/day weight loss 1981
mixed xylenes rat 433 mg/m? fetotoxicity 48.3 mg/day Litton
6 hours/day NOEL Bionetics, 1978
p-xylene NA NA NA ND NA
AIC
o-xylene rat 4750 mg/m? hepatomegaly 14.1 mg/day Tatrat et al.,
8 hours/day Weight loss 1981
m-xylene rat 4750 mg/m? hepatomegaly 14.1 mg/day Tatral et al.,
. 8 hours/day weight loss 1981
mixed xylenes rat 3500 mg/m? transient blood 27.9 mg/day Carpenter
6 hours/day alterations et al., 1975
p-xylenes NA NA NA ND NA

re a


-s-

TABLE 3-1

Subchronic Exposure to Xylene

Route Dose Exposure Species Sex Number Effect Reference
Oral 200 mg/kg 1, 2, 3 and Long-Evans ® 20 Livers were grossly Bowers et al., 1982
6 months rats normal; ultra-struc-
(0.8-0.9 kq) turally, vesicles were
present.
Inhalation 160 ppm (770 mg/m?) 6 hours/day, rats J 25 Mo effects were Carpenter et al.,
460 ppm (2000 mg/m?) 5 days/week, a 25 seen biochemically 1975
810 ppm (3500 mg/m?) 13 weeks " 25 or histologically at
180 or 460 ppm.
Transitory changes
‘n blood cell counts
and slight changes
1n renal tubules at
810 ppm.
Inhalation 180 ppm (770 mg/m*) 6 hours/day, dogs a 4 No effect on blood cell
460 ppm (2000 mg/m?) 5 days/week, a 4 counts, clinical chem-
810 ppm (3500 mg/m*) 13 weeks “ 4 istry, body weight,
liver and kidney wetghts.
Inhalation 78 ppm (337 mg/m?) continuous. rats i Ww No effect on hematology Jenkins et at., 1970
for quinea pigs W/F 18 or body weight gain.
90 days dogs " 2
monkeys. 3



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/m? 8 hours/day, 5
days/week for 30 exposures or 389 mg/m? continuously for 90 days.
Unexplained deaths in 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
Tatrai et al. (1981) could have been missed. Therefore, this study is not
recommended as a basis for quantitative risk assessment.

Data are not available for oral exposure of adult animabs to commercial
mixed xylenes nor for the m- or p-isomers. An oral teratology evaluation of
mixed xylenes in mice indicated no effects on offspring at doses <1.03 g/kg/
day. Acute toxicities 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-isomer 1s the most severely fetotoxic of the xylenes in rat
teratology studies by inhalation and the only isomer for which a NOEL for
fetotoxicity has not been established. Although xylene appears to exhibit a
greater potential for fetotoxicity 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 it is sug-
gested that the o-xylene based AIS may not be appropriate for the p-xylene

isomer.

-15-


The AIC, acceptable intake chronic, is similar in concept to the ADI
(acceptable daily intake). It 4s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the lifespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC is route specific and estimates acceptable
exposure for a given route with the implicit assumption that exposure by
other routes is insignificant.

Composite scores (CSs) for noncarcinogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development is explained in U.S. EPA (1983).

For compounds for which there is sufficient evidence of carcinogenicity,
AIS and AIC values are not derived. for a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer is a
process that is 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 if available.

iv


Ungvary, G., J. Cseh, S. Manyai, A. Molnar, S. Szeberenyi and E. Tatrai.
1980. Enzyme induction by o-xylene inhalation. Acta. Med. Acad. Sci. Hung.
37(1): 115-120. (Cited in U.S. EPA, 1985)

Ungvary, G., B. Varga, E. Horvath, £. Tatrai and G. Folly. 1981. Study on
the role of maternal sex steroid production and metabolism in the embryotox-

icity of para-xylene. Toxicology. 19: 263-268. (Cited in U.S. EPA, 1985)

U.S. EPA. 1980a. Guidelines and Methodology Used in the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
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 Toxicity Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid

Waste and Emergency Response, Washington, DC.
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)

-26-


4. CARCINOGENICITY

4.1. HUMAN DATA

Pertinent data regarding the human carcinogenicity of xylene could not
be located in the available literature.
4.2. BIOASSAYS

A bioassay of the carcinogenicity of xylene is being conducted on rats
and mice orally exposed to xylene (NTP, 1983), but a complete and final
report of the study is not available at this time.
4.3. OTHER RELEVANT DATA

m-Xylene, p-xylene and o-xylene were not mutagenic in Salmonella
typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 in the presence
or absence of the rat liver microsomal fraction (Florin et al., 1980; Bos et
al., 1981). Mixed xylenes were not mutagenic in Escherichia coli strains
WP2, WP2uvrA, CM671, WP67, WP100, W3110 and p3478 (McCarroll, et al., 1981).
Xylene was not mutagenic in the Drosophila recessive lethal test (Donner et
al., 1980), and did not increase chromosomal aberrations in hematopoietic

cells (Donner et ai., 1980) or SCEs in human lymphocytes in vitro (Gerner-

Smidt and Friedrich, 1978).
4.4. WEIGHT OF EVIDENCE

The results of the NTP (1983) bioassay are not available, but it should
be noted that tumors were not observed in rats that were exposed to xylene
vapor (4750 mg/m?) for 1 year (Tatrai 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
carcinogenicity to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), xylene is most appropriately designated

as a Group D - Not Classified chemical.

-12-


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 in many species (4.43) (U.S.
EPA, 1985). Both of these latter ADIs involve route-to-route extrapolation
with its inherent uncertainties.

An RQ was derived for the teratogenicity (cleft palates) and fetotox-
icity observed in mice treated by gavage with a mixture of xylenes and
ethylbenzene at 2.58 g/kg/day on days 6515 of gestation. A human MED ts
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, is

d
calculated. Teratogenicity in the presence of maternal toxicity is assigned
an RV, of 9. A CS of 9 is calculated as the product of the RVA and
RV,.

6.2.2. Inhalation. In the only subchronic inhalation study on o-xylene
(Tatrai et al., 1981) considered adequate for risk assessment (see Section
6.1.2.), rats were exposed to one dose level of xylene (4750 mg/m?) for 1
year. This exposure level produced signs of toxicity, such as changes in
body and organ weights, ultrastructural alterations and enzyme induction,
without producing gross changes in 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 in Section 6.1.2. Applying an additional uncertainty
factor of 5 to account for the duration of the study results in an estimated
AIC of 14.1 mg/day. As outlined in Section 6.1.2., this AIS is proposed for
o-xylene and by analogy to m-xylene. Carpenter et al. (1975) defined an

inhalation subchronic NOAEL of 398 mg/kg for mixed xylenes. Applying an

-18-


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 in
liver morphology, which did not appear to be adverse, were noted. Assuming
a rat consumes 5% of its body weight per day, the estimated NOAEL from this
study 1s 10 mg/kg/day. Applying an uncertainty factor of 100 results in 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. Tatrai et al. (1981) exposed male rats to 4750 mg/m® 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
Tats breath 0.223 m?/24 hours, weigh 0.35 kg and that 50% of the inhaled
xylene is absorbed (U.S. EPA, 1985), the following dose is estimated: 4750
mg/m? x 0.223 m?/24 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 interspecies extrapolation, and 10 for inter individual variability)
results in an alternate AIS estimate of 35 mg/day. This estimate is within
a factor of 5 of the estimate derived from the Bowers et al. (1982) study.
As a result of the inherent uncertainty in route to route extrapolation, the

more conservative estimate of 7 mg/day based on the oral data 1s proposed as

-14-


ete

Veith, G.D., D.L. Defoe and B.V. Bergstadt. 1979. Measuring and estimating
the bioconcentration factor of chemicals in fish. J. Fish Res. Board Can

36: 1040-1048.

Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemistry,

2nd ed. Van Nostrand Reinhold Co., New York. p. 1310.

-27-


3000 mg/m? m-xylene group which contained 30 rats. Groups of 15, 25 or 20
rats served as controls for the o-, m- and p-isomers, respectively. Signs
of maternal toxicity included decreased food consumption in a1} 3000 mg/m?
groups and in the 1500 mg/m? o-xylene-exposed group. The 3000 mg/m?
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 in the m-xylene
group exposed to 3000 mg/m?. An increase in maternal liver:body weight
ratio was reported for all o-xylene exposed groups. Dams exposed to
p-xylene at al] dose levels had significantly lower placental weights.

Litters from dams exposed to p-xylene at 3000 mg/m? showed signifi-
cantly increased fetal loss (69% vs. 4% in controls), The number of rats
pregnant was decreased in dams exposed to 3000 mg/m? of o-xylene or
m-xylene. The average number of implants per rat was decreased in the group
exposed to m-xylene at 3000 mg/m?. .

Mean fetal weight was significantly reduced following exposure to all
three isomers at the 3000 mg/m? concentration. Additionally, exposure to
o-xylene at 1500 mg/m? resulted in significant fetal weight reductions.
There were no indications of increased incidence of external, soft tissue or
skeletal malformations. An increase in the incidence of extra ribs, classi-
fied by the authors as a skeletal anomaly, was seen in litters from dams
exposed to 3000 mg/m? of either m-xylene or p-xylene. . Skeletal retarda-
tion occurred in fetuses from dams exposed to 3000 mg/m? o-xylene and in

all p-xylene-exposed groups.

-9-


1. ENVIRONMENTAL CHEMISTRY AND FATE

Xylene can exist in three isomeric forms. Commercial xylene is 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 monocyclic aromatic hydrocarbon

CAS Registry No. o-xlene, 95-47-6; m-xylene, 108-38-3
p-xylene, 106-42-3

Molecular weight 106.17

Vapor pressure in o-xylene, 5; m-xylene, 6;

mm Hg at 20°C p-xylene, 6.5 (Verschueren, 1983)

Water solubility in o-xylene, 170.5; m-xylene, 146;

mg/2 at 25°C p-xylene, 156 (Sutton and Calder, 1975)

in

Octanol/water partition o-xylene, 589; m-xylene, 1585;

coefficient p-xylene, 1413 (Leo et al., 1971)”

BCF o-xylene, 45; m-xylene, 105;

(estimated) : p-xylene, 95

Half-life in air: o-xylene, 13 hours; m-xylene, 8 hours;
p-xylene, 15 hours (Singh et al., 1981)

Half-life in water: 2.6-11 days for the three xylenes
(estimated)

The BCFs for the three xylenes have been estimated by using the equation
of Veith et al. (1979) and the octanol/water partition coefficient values
stated above.

The dominant process for the removal of xylenes from water is volatili-
zation (U.S. EPA, 1985). The half-lives for the three xylenes are based on
an EXAMS model because of evaporation (Burns et a1., 1981), with the appro-

priate input parameter given in U.S. EPA (1985).

-1-


Rithimaki, V., A. Laine, K. Savolainen and H. Sippel. 1982b. Acute solvent-
ethanol interactions with special reference to xylene. Scand. J. Work

Environ. Health. 8(1): 77-79. (Cited in U.S. EPA, 1985)

Savolainen, K. and V. Riihimaki. 1981. Xylene and alcoho) involvement of
the human equilibrium. Acta. Pharmacol. Toxicol. 48(3): 279-283. (Cited
in U.S. EPA, 1985)

Savolainen, K., H. Vainio, M. Helojoki and E. Elovaara. 1978. Biochemical
and toxicological effects of short-term, intermittent xylene inhalation

exposure and combined ethanol intake. Arch. Toxicol. 41(3): 195-205.

Savolainen, K., P. Pfaffll, M. Helojoki and M. Tengen. 1979. Neurochemical
and behavioral effects of long-term intermittent inhalation of xylene vapor
and simultaneous ethanol intake. Acta. Pharmaco). Toxicol. 44(3): 200-207.
(Cited in U.S. EPA, 1985)

Savolainen, K., V. Riihimaki, A. Laine and J. Kekoni. 1982. Short-term
exposure of human subjects to m-xylene and 1,1,1-trichloroethane. Arch.

Toxicol. (Suppl.) 5: 96-99. (Cited in U.S. EPA, 1985)

Sedivec, V. and J. Flek. 1974. Absorption and excretion of xylenes in man.

Prac. Lek. 26(7): 243-248. (Cited in U.S. EPA, 1985)
Sedivec, V. and J. Flek. 1976. The absorption, metabolism and excretion of

xylenes in man. Int. Arch. Occup. Environ. Health. 37(3): 205-217. (Cited
in U.S. EPA, 1985)

-24-


Carpenter, C.P., £.R. Kinkead, D.L. Geary, Jr., L.J. Sullivan and J.M. King.
1975. Petroleum hydrocarbon toxicity studies. V. Animal and human response
to vapors of mtxed xylenes. Toxicol. Appl. Pharmacol. 33(3): 543-558.
(Cited in U.S. EPA, 1985)

Code of Federal Regulations. 1981. OSHA Safety and Health Standards. 29
CFR 1910.1000.

Donner, M., J. Maeki-Paakkanen, H. Norppa, M. Sorsa and H. Vainio. 1980.
Genetic toxicology of xylenes. Mutat. Res. 74: 171-172. (Cited in U.S.
EPA, 1985)

Elovaara, £., Y. Coltan, P. Pfaffli and H. Vainio. 1980. The combined
toxicity of technical grade xylene and ethanol in the rat. Xenobiotica.
10(6): 435-446. (Cited in U.S. EPA, 1985)

Federal Register. 1984. Environmental Protection Agency. Proposed

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 mutagenicity using the Ames' test. Toxicol-

ogy. 15: 219-232. (Cited in U.S. EPA, 1985)
Gamberale, F., G. Annwa]l and M. Hultengren. 1978. Exposure to xylene and

ethylbenzene. III. Effects on central nervous functions. Scand. J. Work,

Environ. Health. 4(3): 204-211. (Cited in U.S. EPA, 1985)

-21-


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 was,the Project
Officer. The final documents in 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:
,
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon

Environmental Criteria and Assessment Office
Cincinnati, OH

vi


ABSTRACT

In order to place the risk assessment tn proper context, the reader 1s
referred to the preface of this document. The preface outlines limitations
applicable to al? 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-tsomers
are fragmented. Mixed xylenes and the o-isomer have been evaluated in sub~
chronic studies with adult animals. All of these compounds have been evalu-
ated in teratology studies. NOELs for fetotoxicity have been established
for all isomers except p-xylene. Additional clarification of the lowest
fetotoxicity effect level for mixed xylenes is needed. An inhalation AIS
for o-xylene of 67 mg/day is estimated based on fetotoxicity. An AIS for
m-xylene which is less fetotoxic 4s based on analogy to nonreproductive
effects of o-xylene and is estimated as 71 mg/day. The AIS for mixed
xylenes is based on a fetotoxicity NOEL and estimated to be 48 mg/day. No
value is estimated for p-xylene. for chronic exposure, an AIC for o-xylene
and by analogy, m-xylene is estimated as 14 mg/day based on a 1-year inhala-
tion study in rats. For mixed xylenes an AIC of 28 mg/day is estimated
based on a rat 90-day inhalation study. No AIC for inhalation is 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
teratogenicity and fetotoxicity in mice at a level also associated with
maternal toxicity. .

These estimates, especially for the oral route, should be reviewed as
additional data become available.


“In addition, the number of alkaline phosphatase positive proximal con-
voluted tubules as wel] as the number and intensity of the positive staining
nephrons for succinic dehydrogenase, acid phosphatase and glucose-6-phospha-
tase was reduced in the o- and p-xylene fetuses from dams exposed to 3000
mg/m?. In the liver and thymus cells from fetuses of dams exposed to all
three isomers at 3000 mg/m? there was a decrease in succinic dehydrogenase
and glucose-6-phosphatase activities. The enzyme changes in the kidneys
were interpreted by the authors as an indication of a delay in maturation.

In summary, exposure to 1500 mg/m? produced no adverse effects on
litters exposed to m-xylene, 150 mg/m? produced no adverse effects on
litters exposed to o-xylene, and p-xylene resulted in fetotoxicity as
evident by delays in skeletal ossification following exposure to the lowest
concentration tested (150 mg/m?).

Charles River CD female rats were exposed to mixed xylenes (11%
o-xylene, 52% m-xylene, 0.31% p-xylene, 36.1% ethylbenzene) at concentra-
tions of 0, 433 and 1733 mg/m? on days 6 through 15 of gestation, 6 hours/
day (Litton Bionetics, 1978). There were 25 pregnant dams per exposure
group. Animals were sacrificed on day 20 of gestation. The number of
implantation sites, resorption sites, live and dead fetuses, fetal weights
and external abnormalities were recorded. One-third of the fetuses from
each litter 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 in the control, 24 in the low-
dose group and 37 in the high-dose group; however, the number of litters

affected were 9, 6 and 10. The authors did not judge this effect to be

-10-


LIST OF ABBREVIATIONS

ADI Acceptable daily intake

AIC Acceptable intake chronic

AIS Acceptable intake subchronic

BCF Bioconcentration 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

RVg Dose-rating value

RVe Effect-rating value -
SCE Sister chromatid exchange

STEL Short-term exposure limit

TLV Threshold limit value

TWA Time-weighted average

vali


6.1.2. Inhalation. As discussed in Section 6.1.1. a 1-year evaluation of
the toxicity of inhaled o-xylene has been conducted (Tatrai et al., 1981).
This study is considered more appropriate for assessment of adult Inhalation
toxicity than Jenkins et al. (1970) as discussed in Section 6.1.1. In
addition, an inhalation teratology study has been conducted in rats which
defined a NOEL for fetotoxicity of 96 mg/kg (extrapolated from an exposure
concentration of 150 mg/m?) (Ungvary et al., 1980). The LOAEL from Tatrai
et al. (1981) is estimated to be 1009 mg/kg, estimated as in 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 in an
estimated NOAEL of 101 mg/kg/day, essentially the same as the fetotoxicity
NOEL of 96 mg/kg/day. Using the NOEL for the most sensitive endpoint, feto-
toxicity, results in 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 fetotoxic than o-xylene with a NOEL of 956 mg/kg/day
(exposure concentration 1500 mg/m?). Therefore, for m-xylene the LOAEL of
1009 from Tatrai et al. (1981) represents the lowest LOAEL assuming that the
o- and m-isomers exhibit comparable toxicities. Applying an uncertainty
factor of 1000 (10 to estimate a NOAEL, 10 for interspecies extrapolation
and 10 for interindividual variability) results in an AIS of 70.7 that is
essentially indistinguishable from the value based on fetotoxicity.

For mixed xylenes, Ungvary et al. (1980) established a fetotoxicity FEL
of 637 mg/kg. Litton Bionetics (1978) established a NOAEL/LOAEL of 276
mg/kg/day based on increased numbers of fetuses, but not litters with
skeletal abnormalities. The lower exposure concentration in the Litton

Bionetics study clearly defined a NOEL of 69 mg/kg/day. Carpenter et al.

-16-


EPA-540/1-86-006

Office of Emergency and Off'ce of Research and Development
rete wrrreriae serene Remedial Response Office of Health and Environmental
Agency Washington DC 20460 Assessment

Environmental Criteria and
Assessment Office
Cincinnati OH 45268

Superfund

SEPA
HEALTH EFFECTS ASSESSMENT
FOR XYLENE ;



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, it can be
inferred that absorption by this route is nearly complete. In the rabbit,
85-90% of an administered oral dose of xylene isomers (ranging from 0.9-1.7
g/animal) was accounted for in the urine, while pulmonary excretion may have
accounted for the remaining xylene (Bray et al., 1949).
2.2. INHALATION

Studies evaluating the inhalation absorption rate in humans exposed to
doses ranging from 100-1300 mg/m? indicated that ~60% of the xylene
present in the inspired air, regardless of the isomer or ‘tsomer mixture
used, 1s absorbed (Astrand et al., 1978; Riihimaki et al., 1979a; Sedivec
and Flek, 1974, 1976; Gamberale et al., 1978; Se'nczuk and Orlowski, 1978).
Exercise increases the relative amount of xylene absorbed (Astrand et al.,

1978; Riihimaki et al., 1979b).

~3-


The half-lives for the three xylenes in soil could not be located in 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, biodegradation of
xylenes is likely to be a slow process (U.S. EPA, 1985). The persistence of
xylenes in 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).

-2-


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, COC, Rockville, MD. p. 101. (Cited in
U.S. EPA, 1980b)

NRC (National Research Council). 1980. The Alkyl Benzenes. Committee on
Alkyl Benzene Derivatives. Board on Toxicology and Environmental Health

Hazards, Assembly of Life Sciences, National Academy Press, Washington, DC.

NTP (National Toxicology Program). 1983. National Toxicology Program/
Toxicology Testing Program. Chemicals on standard protocol. Management

Status 12/6/83. (Cited in U.S. EPA, 1985)

Riihimaki, V., P. Pfaffli, K. Savolainen and K. Pekari. 1979a. Kinetics of
,

m-xylene in man: General features of absorption, distribution, biotransfor-

Mation and excretion in repetitive inhalation exposure. Scand. J. Work,

Environ. Health. 5(3): 217-231. (Cited in U.S. EPA, 1985)

Riihimaki, V., P. Pfaffli and K. Savolainen. 1979b. Kinetics of m-xylene
in man: Influence of intermittent physical exercise and changing environ-
mental concentrations on kinetics. Scand. J. Work Environ. Health. 5(3):

232-248. (Cited in U.S. EPA, 1985)
Rithimakt, V., K. Savolainen, P. Pfaffli, K. Pekari, H.W. Sippel and A.

Laine. 1982a. Metabolic interaction between m-xylene and ethanol. Arch.

Toxicol. 49(3-4): 253-264. (Cited in U.S. EPA, 1985)

-23-


Gerner-Smidt, P. and U. Friedrich. 1978. The mutagenic effect of benzene,
toluene and xylene studied by the SCE technique. Mutat. Res. 58: 313-316.
(Cited in U.S. EPA, 1985)

Hudak, A. and G. Ungvary. 1978. Embryotoxic effects of benzene and its
methy] derivatives: Toluene, xylene. Toxicology. 11: 55-63. (Cited tn
U.S. EPA, 1985)

Jenkins, L.J., dr., R.A. Jones and J. Stegal. 1970. Long-term inhalation
screening studies on benzene, toluene, o-xylene and cumene on experimental
animals. Toxicol. Appl. Pharmacol. 16(3): 818-823. (Cited in U.S. EPA,
1985)

Leo, A., C. Hansch and D. Elkins. 1971. Partition coefficients and their
uses. Chem. Rev. 71: 525-616.

Litton Bionetics. 1978. Teratology study in rats: Xylene. Final report to
American Petroleum Institute, Washington, DC. LBI Project No. 20698-5.

Marks, T.A., T.A. Ledoux and J.A. Moore. 1982. Teratogenicity of a com-
mercial xylene mixture in the mouse. J. Toxicol. 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. coli microsuspen-
sion 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-


TABLE OF CONTENTS

1. ENVIRONMENTAL CHEMISTRY AND FATE. 2... 1 1 ee ee ee ee ee
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS... ..
2.1. ORAL 2 2 we ee ee ee
2.2. INHALATION . 2 1 1 1 ee ee ee ee ee ee
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS. 2... 2.2. eee
3.1. SUBCHRONIC 2. 1 1 ee ee ee
Oral. 2 ee ee ee eee
Inhalation. . 2. 2 6 ee ee ee ee ee ee ee
3.2. CHRONIC. ©. 2... ee eee eee
Oral, ee ee
Inhalation see
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS... ....
3.3.1. Orale 2 ee ee ee ee ee ee
3.3.2. Inhalation. .. 2... 2 ee ee ee ee ee ee

,
3.4. TOXICANT INTERACTIONS. . 2 2 2 1 eee ee ee eee ee
4. CARCINOGENICITY . 2. 2 2 ee ee ee ee eee
4.1 HUMAN DATA. 2... we ee ee ee See ee
4.2 BIOASSAYS. © 2 6 we ee ee ee we ee ee
4.3. OTHER RELEVANT DATA. © 2 2 2 2 eee ee ee ee ee eee
4.4 WEIGHT OF EVIDENCE. 2... ee ee ee ee ee ee ee
5. REGULATORY STANDARDS AND CRITERIA. 2... 2 1. ee ee eee
6. RISK ASSESSMENT © 2 2 wee ee ee eee
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)... 2.2.2.2 ee eee
6.1.1. Oral... ee ee ee
6.1.2. Inhalation... 2... 2 ee ee ee ee ee eee
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)... 2... 2. ee ee ee
6.2.1. Oral. 2. we ee ee ee
6.2.2. Inhalation... 1... ee ee ee ee ee ee
6.3. CARCINOGENIC POTENCY (qjy*) ~~... 2.2. eee tees
7. REFERENCES. © 6 ww ee ee ee ee
APPENDIX: Summary Table for Xylene... 2... ee ee ee eee eee

~

o


5. REGULATORY STANDARDS AND CRITERIA

The ACGIH (1983) recommends a TWA-TLV of 100 ppm (435 mg/m?) and a
STEL-TLV of 150 ppm (655 mg/m?). NIOSH (1975) recommends a 10-minute
ceiling 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.

-13-


uncertainty factor of 1000 and multiplying by 70 kg results in an estimated
AIC of 27.9 mg/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 carcinogenicity data.
An NCI gavage study has been completed in rats and mice using a commercial
mixture of xylene but the first draft of this report is not yet available
(May, 1985).

-19-


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 in
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxicologic and environmental
data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document is current up to
September, 1984. Secondary sources of information have also been relied
upon in 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 (QHEA) 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)

,

The intent in these assessments is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited in
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 is not the endpoint of concern).
The first, the AIS or acceptable intake subchronic, is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time interval (1.e., for an interval that
does not constitute a significant portion of the lifespan). 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 in ambient air or water where lifetime exposure is
assumed. Animal data used for AIS estimates generally include exposures
with durations of 30-90 days. Subchronic human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.

wi


dose levels. In rats exposed to xylene at the highest dose level, there was
an increase in 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 al., 1975). Male dogs
were exposed to mixed xylenes at concentrations of 180, 460 or 810 ppm (770,
2000 and 3500 mg/m?, respectively) for 6 hours/day, 5 days/week for 13
weeks (Carpenter et a1., 1975). There were four dogs in each group. No
effect on blood cell count, clinical chemistry, urinalysis, body weight or
liver and kidney weight was reported.

In another study, 20 male Wistar rats were exposed to 300 ppm (1300
mg/m?) xylene for 6 hours/day, 5 days/week for <18 weeks (Savolainen et
al., 1979). Some rats were killed at 5, 9, 14 and 18 weeks. Brain super-
oxide dismutase decreased after 5 weeks of xylene exposure, but increased
after 18 weeks of xylene exposure. Brain cytosolic glutathfone peroxidase
activity was significantly decreased after 14 weeks, but was not signifi-
cantly different from control levels after 18 weeks of xylene exposure.
Some behavioral changes (decreased preening and reduced activity) were seen
in the xylene-treated rats (Savolainen et al., 1979).

Jenkins et al. (1970) exposed NMRI:0(SD) Sprague-Dawley 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 in the intermittent protocol, 14 rats in 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/m? for the intermittent

-6-


reticulum proliferation, an increased number of peroxisomes and autophagous
bodies, glycogen depletion and, occasionally, damaged mitochondria. Pro-
liferation of the smooth endoplasmic reticulum has been correlated with
increased mixed function oxidase activity. Liver enlargement was attributed
to functinal 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-1 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 resorptions 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 toxicity.
3.3.2. Inhalation. Shigeta 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 in 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/m? mixed
xylenes (10% o-xylene, 50% m-xylene, 20% p-xylene, 20% ethylbenzene) on days
9-14 of gestation resulted in an increased incidence of fused sternebrae and
extra ribs in 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 litter size, mean
placental weight, mean fetal weight, fetal resorption or fetal mortality.
Pregnant CF4 rats were exposed to 150, 1500 or 3000 mg/m? of each of
the isomers of xylene continuously on days 7-14 of gestation (Ungvary et

al., 1980). The number of rats in each exposed group was 20 except for the

-8-


DISCLAIMER

This report has been funded wholly or in part by the United 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 it 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.

‘At Protection Agency

Wi


1

n

wo
1

prhae

APPENDIX (cont.)

Exper tmental Acceptable Intake
Species Oose/Exposure Effect (AIS or AIC) Reference
Oral
AIS
o-, m- and rat 200 ppm ultrastructural 7 mg/day Bower et al.,
mixed xylenes food liver changes 1982
p-xylene NA NA NA ND NA
AIC .
o-, m- and rat 200 ppm ultrastructural 0.7 mg/day Bowers et al.,
mixed xylenes food liver changes 1982
p-xylene NA NA NA ND NA

NA = Not applicable; ND = not derived

‘quasy vos d


(1975) exposed male rats to 770, 2000 or 3500 mg/m*, 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-
toxicity in the Litton Bionetics (1978) study. Although the effect at this
dose level was questionable, skeletal abnormalities are the endpoints
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-
icity 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 in an estimated
AIS for mixed xylenes of 48.3 mg/day.

A fetotoxicity NOEL for p-xylene has not been established. Significant
fetotoxicity was seen at the lowest exposure concentration,’ 150 mg/m? (96
mg/kg) (Ungvary et al., 1980). _Since this dose is similar to the estimated
NOAEL for other endpoints, an AIS for p-xylene 1s not proposed.

In conclusion, an AIS for o-xylene of 67 mg/day is proposed based upon
fetotoxicity, and an AIS of 70.7 mg/day for mixed xylenes and m-xylene,
while an AIS is 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 in 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 in extrapolating from subchronic to chronic expsoure. As

described in Section 6.1.1., this value is suggested for mixed xylenes,

-17-


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

@o tection Agency


Se'nczuk, W. and J. Orlowski. 1978. Absorption of m-xylene vapors through
the respiratory tract and excretion of m-methylhippuric acid tn urine. Br.

J. Ind. Med. 35(1): 50-55. (Cited in U.S. EPA, 1985)

Seppalainen, A.M., K. Savolainen and T. Kovala. 1981. Changes induced by
xylene and alcohol in human evoked potentials. Electroencephalogr. Clin.

Neurophysiol. 51(2): 148-155. (Cited in U.S. EPA, 1985)

Shigeta, S., H. Aikawa, T. Misawa and K. Suzuki. 1983. Fetotoxicity of
inhaled xylene in mice. Teratology. 28(1): 22A. (Cited in U.S. EPA, 1985)

Singh, H.B., L.J. Salas, A.J. Smith and H. Shigeishi. 1981. Measurements
of some potentially hazardous organic chemicals in urban environments.

Atmos. Environ. 15: 601-612.

’

Sutton, C. and J.A. Calder. 1975. Solubility of alkylbenzenes in distilled

water and seawater at 25°C. J. Chem. Eng. Data. 20: 232.

Tatrai, E., A. Hudak and G. Ungvary. 1979. Simultaneous effect on the rat
liver of benzene, toluene, xylene and cCl,. Acta. Physiol. Acad. Sci.

Hung. 53: 261. (Cited in U.S. EPA, 1985)
Tatrat, &., G. Ungvary, I.R. Cseh, et al. 1981. The effect of long-term

inhalation of o-xylene on the liver. Ind. Environ. Xenobiotics, Proc. Int.

Conf. p. 293-300. (Cited in U.S. EPA, 1984)

~25-


7. REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents in the
Workroom Environment with Intended Changes for 1983-84. Cincinnati, OH.
p. 35.

Astrand, I., J. Engstrom and P. Ovrum. 1978. Exposure to xylene and ethyl-
benzene. I. Uptake, distribution and elimination in man. Scand. J. Work

Environ. Health. 4(3): 185-194. (Cited in U.S. EPA, 1985)

Bos, R.P., R.M.E. Brouns, R. Van Doorn, J.L.G. Theuws and P.T. Henderson.
1981. Non-mutagenicity of toluene, o-xylene, m-xylene and p-xylene,
o-methylbenzylalcohol and o-methylbenzylsulfate in the Ames ;assay. Mutat.
Res. 88(3): 273-280. (Cited in U.S. EPA, 1985)

Bowers, D.E., dr.,; M.S. Cannon and D.H. Jones. 1982. Ultrastructural
changes in livers of young and aging rats exposed to methylated benzenes.

Am. J. Vet. Res. 43(4): 679-683. (Cited in U.S. EPA, 1985)

Bray, H.G., B8.G. Humphris and W.V. Thorpe. 1949. Metabolism of derivative
of toluene: 3. o-, m- and p-xylenes. Biochem. J. 45: 241-244. (Cited in
U.S. EPA, 1985)

Burns, L.H., D.M. Cline and R.R. Lassiter. 1981. Exposure Analysis Model-
ing System (EXAMS). Environmental Research Lab, ORD, U.S. EPA, Athens, GA.

-20-


3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
Table 3-1 summarizes experiments regarding subchronic xylene exposure.

3.1.1. Oral. The only animal study of subchronic 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 livers 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 in the control group. The authors (Bowers et al.,
1982) noted that the vesicles were involved in the elimination of xylene or
its 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 in acute toxicity studies that females may be more sensitive to
xylene exposure than males, most of the subchronic inhalation studies have
been done on males (Carpenter et al., 1975; Jenkins et al., 1970; Savolainen
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/m?, 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, glutamic
oxalacetic transaminase, glutamic pyruvic transaminase and alkaline phospha-
tase) or histological effects (lung, liver, kidney, brain, pituitary,
trachea, thyroid, parathyroid, heart, spleen, gastrointestinal tract,

muscle, nerve and bone marrow) were seen in rats treated at the two lower

-4-


protocol and 337 mg/m? for the continuous protocol. Blood counts, hemo-
globin and hematocrit were monitored in addition to body weight. Histo-
pathological evaluation was conducted on heart, lung, Jiver, 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 contiuous 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. Histopathol-
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 necropstes’ were done the
results were not 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 toxicity of
xylene could not be located in the available literature.

3.2.2. Inhalation. Male CFY rats were exposed to 4750 mg/m? of xylene
for 8 hours/day, 7 days/week for 1 year (Tatrai 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
aminopyrin-N-demethylase activity were increased, while bromosulfophthalein
retention time in the liver was decreased. Ultrastructurally, the centri-

lobular hepatocytes of xylene-treated rats had moderate smooth endoplasmic

-T-