_ TECHNICAL REPORT DATA
(Pltue mdinitmcuont on tht rtvtru btfort compltnnf)
1. REPORT NO.
EPA/600/8-89/098
a.
4, ilTLE AND SUBTITLE
Updated Health Effects Assessment for Xylenes
3. RECIPIENT? ACCESSION NO
PB90-142506/AS
6 REPORT DATE
. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
r PERFORMING ORGANIZATION REPORT NO
PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15 SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order ]2991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
t.his document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. 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 systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is 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. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATi Field/Croup
8. DISTRIBUTION STATEMENT
Public
1*. SECURITY CLASS (Thu Rtport)
Unrlassified
21. NO. OF PAGES
M. SECURITY CLASS (This ptftl
Unclassified
22. PRICE
EPA Fw* 2220-1 (**. 4-77) PRKVIOUS EDITION i* OMOLCTK
-------
EPA/600/8-89/098
August, 1989
HEALTH EFFECTS ASSESSMENT
FOR XYLENES
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
-------
DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with o-, m-,
p-xylene and mixed xylenes. All estimates of acceptable Intakes and
carcinogenic potency presented 1n this document should be considered as
preliminary and reflect limited resources allocated to this project.
Pertinent toxlcologlc and environmental data were located through on-Hne
literature searches of the TOXLINE. CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document Is current up
to Hay, 1987. Secondary sources of Information have also been relied upon
In the preparation of this report and represent large-scale health assess-
ment 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. 1987. Drinking Water Criteria Document for Xylene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH, for
the Office of Drinking Water, Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
Xylenes (o-, m-, p-). Prepared for the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH, for the Office of Solid Waste and Emergency
Response, Washington, DC. EPA/600/X-86/216. NTIS PB88-246/86/AS.
The Intent 1n these assessments Is to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
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.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose. Is
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 llfespan).
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 1s assumed. Animal data used for RFD$ 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. These
values are developed for both Inhalation (RfOgj) and oral (RfD$0)
exposures.
111
-------
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfD0) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
For protection against toxldty from Inhalation exposure, an RfD$j and
RfDj of 0.3 mg/m3 for o-, m-, p- and mixed xylenes has been estimated
for human CNS efects (Hake et al., 1981). The Hake et al. (1981) study
Identified CNS effects (100 ppm p-xylene) as acute exposure. However, the
RfD Workgroup, because of other supporting studies, verified the RfDj of
0.3 mg/m3 on May 18, 1989.
An RfD$o of 250 mg/day for o-, m-, p- and mixed xylenes was estimated
from a NOAEL of 357 mg/kg/day for reduced body weights of rats 1n a 13-week
gavage study (NTP, 1986). An RfD0 of 126 mg/day for o-, m-, p- and mixed
xylenes was based on a NOAEL of 180 mg/kg/day for reduced survival In male
rats In a 103-week gavage study (NTP, 1986). A CS of 10 was based on the
mortality seen at the higher dose, 357 mg/kg/day.
These RfD values should be considered provisional and subject to change
as subchronlc oral testing sponsored by OSW and OTS 1s completed.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for ERA'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 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 the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Trlna Porter
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3
2.1. ORAL 3
2.2. INHALATION 3
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 4
3.1. SUBCHRONIC 4
3.1.1. Oral 4
3.1.2. Inhalation 5
3.2. CHRONIC 9
3.2.1. Oral 9
3.2.2. Inhalation 10
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 10
3.3.1. Oral 10
3.3.2. Inhalation 11
3.4. TOXICANT INTERACTIONS 16
4. CARCINOGENICITY 17
4.1. HUMAN DATA 17
4.2. BIOASSAYS 17
4.2.1 Oral 17
4.2.2 Inhalation 17
4.3. OTHER RELEVANT DATA 18
4.4. WEIGHT OF EVIDENCE 18
5. REGULATORY STANDARDS AND CRITERIA 19
6. RISK ASSESSMENT 20
6.1. SUBCHRONIC REFERENCE DOSES (RfDs) 20
6.1.1. Oral (RfDso) 20
6.1.2. Inhalation (RfDsi) 21
vll
-------
TABLE OF CONTENTS (cent.)
Page
6.2. REFERENCES DOSE (RfD) 26
6.2.1. Oral (RfD0) 26
6.2.2. Inhalation (RfDj) 27
6.3. CARCINOGENIC POTENCY (q-,* or Unit Risk Slope) 28
7. REFERENCES 29
APPENDIX: Summary Table for Xylene 41
-------
LIST OF ABBREVIATIONS
BCF Bloconcentratlon factor
bw Body weight
CAS Chemical Abstract Services
CNS Central nervous system
CS Composite score
EEG Electroencephalogram
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RfDi Inhalation reference dose
RfDo Oral reference dose
RfDg Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfDso Subchronlc oral reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
SCE Sister chromatld exchange
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
VER Visual evoked response
1x
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
Xylene can exist In three IsomeMc forms. Commercial xylene Is a
mixture of three Isomers 1n the following percent ranges: o-xylene, 10-25%;
m-xylene, 45-7054; 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 In
mm Hg at 20°C
Water solubility 1n
mg/8. at 25°C
Log octanol/water
partition coefficient
BCF
Half-lives 1n
A1r:
Water:
monocycllc aromatic hydrocarbon
o-xylene, 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, 3.12; m-xylene, 3.20;
p-xylene, 3.15 (U.S. EPA, 1986a)
o-xylene, 7.3-21.4; m-xylene, 6.4-23.6;
p-xylene, 23.6 (U.S. EPA, 1986a)
o-xylene, 48-68; o-, m- and p-xylene, 350
(estimated) (U.S. EPA, 1986a)
o-xylene, 13 hours; m-xylene, 8 hours;
p-xylene, 15 hours (Singh et al., 1981)
o-, m- and p-xylene, 1.5-11.0 days
(estimated) (U.S. EPA, 1985, 1986a)
The predominant removal mechanism for xylenes In the atmosphere Is
reaction with photochemically generated hydroxyl radicals. Detection of
xylenes 1n rainwater suggests that small amounts of these compounds may also
be removed from the atmosphere by washout (U.S. EPA, 1986a).
0006H
-1-
08/21/87
-------
The dominant process 1n the removal of xylenes from water appears to be
volatilization (U.S. EPA, 1987). The aquatic half-life (1.5-11.0 days) Is
the volatilization half-life estimated using an EXAMS model and the data
given In U.S. EPA (1986a). Volatilization rates vary depending on the depth
of water, temperature, oxygen exchange rate and the amount of organic matter
1n the sediments (U.S. EPA, 1987).
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, blodegradatlon of
xylenes 1s likely to be a slow process (U.S. EPA, 1987). The persistence of
xylenes 1n soils has been reported to be >6 months (NRC, 1980). Therefore,
1n subsurface soils with low organic carbon content, xylenes may Infiltrate
Into groundwater from soil. This has been substantiated by the widespread
occurrence of xylenes 1n groundwater (U.S. EPA, 1986a).
0006H -2- 08/14/89
-------
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 Is nearly complete. In the rabbit,
85-90% of an administered oral dose of xylene Isomers (ranging from 0.9-1.7
g/anlmal) was accounted for as metabolites In the urine, while pulmonary
excretion may have accounted for the remaining xylene (Bray et al., 1949).
2.2. INHALATION
Studies that evaluate the Inhalation absorption In humans exposed to
doses ranging from 100-1300 mg/m3 Indicated that -60% (43-74%) of the
xylene present 1n the Inspired air, regardless of the Isomer or Isomer
mixture used, Is absorbed (Astrand et al., 1978; RUhlmakl et al., 1979a;
Sedlvec and Flek, 1974, 1976; Gamberale et al., 1978; Se'nczuk and Orlowskl,
1978). Exercise may Increase slightly the relative amount of xylene
absorbed (Astrand et al., 1978; R11h1mak1 et al., 1979b).
0006H -3- 08/01/89
-------
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Twenty male Long-Evans rats, 12-19 months old and weighing
0.8-0.9 kg, were fed a diet containing 200 ppm o-xylene (Bowers et a!.,
1982). 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 1n the control group. The authors
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 occurrence of these vesicles
appears to represent an adaptive rather than an adverse effect. The focus
of this experiment was exclusively on the liver; no other effects were
reported.
Borrlston Laboratories, Inc. (T983) performed a 4-week nephrotoxlclty
screening study with m-xylene 1n male F-344 rats. Groups of 10 rats
received 0.5 or 2.0 g/kg by gavage 5 days/week. There were no adverse
effects on the kidney at either treatment level.
NTP (1986) conducted a 13-week gavage study by feeding mixed xylenes (9%
o-, 60% m-, 14% p- and 17% ethylbenzene) In corn oil to groups of 10 male
and 10 female 6-week-old F344/N rats and to groups of 10 male and 10 female
7-week-old B6C3F1 mice. Five days/week doses of 0 (vehicle control), 62.5,
125, 250, 500 or 1000 mg/kg were administered to rats and 0 (vehicle
control), 125, 250, 500, 1000 or 2000 mg/kg were administered to mice. The
animals were observed twice dally, body weights were recorded weekly, all
animals were subjected to necropsy at termination and vehicle control and
high-dose animals were subjected to comprehensive hlstopathologlcal
examination.
0006H -4- 08/01/89
-------
All rats survived to termination of treatment. Terminal body weights of
high dose (1000 mg/kg) rats were 15% (male) and 8% (females) less than
controls. No signs of toxlclty were observed and there were no treatment-
related gross or hlstopathologlcal lesions. Two female mice In the high
dose (2000 mg/kg) group died during the study. Although cause of death was
not determined, gavage error was not ruled out. Neurological signs appeared
In mice In the 2000 mg/kg group at 5-10 minutes after dosing and persisted
for 15-60 minutes. Body weight gain at 2000 mg/kg was depressed 7% 1n male
mice and 17X In female mice. There were no treatment-related gross or
microscopic lesions.
3.1.2. Inhalation. Pertinent subchronlc Inhalation data for animals
exposed to the xylenes are summarized In Table 3-1. For mixed xylenes,
Carpenter et al. (1975) reported no adverse effects 1n rats or dogs exposed
to <3500 mg/m3, 6 hours/day, 5 days/week for 13 weeks. A comprehensive
hlstopathologlcal examination was performed. Fabre et al. (1960), however,
reported bone marrow hyperplasla and glomerulonephrHls 1n rats and rabbits
exposed to 3000 mg/m3, 8 hours/day, 6 days/week for 110-130 days. The
latter study, however, was available only from a secondary source and was
not available for critical evaluation. Savolalnen et al. (1979a) reported
altered brain biochemistry and decreased behavioral activity 1n rats exposed
to 1300 mg/ma, 6 hours/day, 5 days/week for <18 weeks. The lowest concen-
tration tested 1n the Carpenter et al. (1975) 13-week study, 770 mg/m3, 6
hours/day, 5 days/week, appears to be a NOEL for mixed xylenes In rats and
dogs.
For o-xylene, Tatral et al. (1981) observed Increased food and water
consumption, decreased body weight gain and mild effects on the liver 1n
male rats exposed to 4750 mg/ma, 8 hours/day, 7 days/week for 1 year.
0006H -5- 08/21/87
-------
01
c
Oi
*>
X
o
41
3
O
T *
n "
si -
i H
£
C
U
o
k
£
|
U
c
Ol
Ol
t
ae
u
o*
Ik
Ik
*
k
3
I/I
0.
IU
£
X
4>
CO
c
>9
u
VJ
VI
Of
U
41
C
3
O
1
y»
^
k f*
OJ
c
V »
Q IT9
«o -M
U *V
**
§,
$o>
£
>«*o
V **
0 VI
£
§k
VI
U k C
£"" £
III
«s -o x
78*
k r Ol
e »^i
oi >i e
E O> 41
* O£
!P
X £^
JK
41
§..*
if!
9 r
S * 0
in
i
t
IB
VI
^1
C
B
5
k
IB
Ol
C
X
*
X
£
5
c en
O* f
c
^B *
O IB
IB *»
CO Oi
o
w
ft>
u
*
u
t/l
K
ll
c u
01 IB
/ £
mff Ml
«£
4i
VI
C >>
n > 41
~^>.
l!i
s
i:
k
J£
?
2
^
v>
01
X
*
X
K
TB
»
w
k O
£ lO
IB V>
U. f
1
41
ex
C VI
o
u
IB £
"9 41
U C
VI O
B f
2*01
k VI
II
£ k
k l
en ^H
E «jO ^
a a>>e
«« 7
""we
meau.
5
ae
ae
k
u
VI
Ol
c
0)
x
4>
X
K
»
>
^5v,
!-.»
I its
"57
(A ^9
t k. 1
!!i
(M
^
*
DC
M
2"
IB
U
VI
01
c
01
*>»
X
g
X
K
in
on
k r
e T
S.^
k
IB «<
U 01
. .to
'&'§>"'
$$r
>>>»>
0 C >B
£ V C
O ^ 3
k
vi O -
Sti
«!
01 > U
f IB O
0)1- 0
k Of r
«rf
C k
ies
» 4> O
S = 0
k f *<
« o 5
vi E
O ^3 v
P
rs.
e IB
e -o
nir>
*??
__ rji w
?||
^
K
Ol
"ex
*o
f,
V*
^
VI
»
|
*>.
X
o
Oi
x
K
-
en
^ 7
IBI-
k fB
IB <
r- «
41
> VI 1
41 O
o i
fZ oT k
V U U O
Oi IB C
§*" «S 9; k el
oi 6
0££ UOS
Ol^
Ol Of O* fB Q Oi
vi in a o. o
Ol O> k £ U O
k k 41 41 £
U Ti Ik «<
5 S^
k
3 f-
O
£ k
O
COU-
J(
u
e IB
m-o
f*
oe
*
5^
U.
^
IB
g
«
X
O
s
V
IB «
^ ^
s?
IB C
r- =)
1
fl9
«*
3
IB
Ol
i.
»* 4>
S.C?
o> >.
it
V Ol
0 £
£
Ol k
vi 9
41 u
U k
a in
v>
^f
»,
Ife
«>tt>
1/1
& v
§1
kf>
n CD
S
K
ik
U
>»
>
O Ol
f- O
O f
£ 4>
C ^
&| g,?
£ IB » IB
.? ^ C
"i * T^
x 31 x
C 01 ft
°TI §^
vi .V 0>
M *rf VI ««
ll 11
oZ *I
e o> o oi
O CO
VI O » O
Ol £ Oi £
e TS
no »- o
k O
It 1
«£ I
ll ^f
si ^r
n no
n in r> u.
»
K K
01 01
L L
1C 1C
Oi >B 41 IB
9 > 3 >
CTiiiU 9*iM
1C 1 IB 1
a. c a. c
c/> o «/> o
IB k IB k
k O k O
a
en
(
C *
*"
c
Cf>
o
*o
««
1
«"c"
c o
*i
1,1
18
^o
> 0)
^ f
o
c
o
S** o>
0
«- o
Ol "
VI
» VI
II
VI
st
£ 0
CO
B"»
CD «B
g*
£
^
K
^^
^1
IB *
41 L>
c e
§,>
D>
O
f
O
1
S
»
I
$|
fl
11
Ol
Ol Oi
* £
»
VI
o
C
Iv,
4-S
gie
sl
in
^
K*
^k.
D>
*l
IB Ol
41 u
C C
9 k
ex a.
0006H
-6-
08/21/87
-------
*»
c
o
u
1
n
i
to
<
Ol
u
c
Oi
k
0)
01
at
««
u
Ol
Ik
Ik
htl
01
k
9
l/i
|
w
.
o
X.
X
%
c
*
k
£
VI
Of
8
a.
«v>
TS
c
1
u
0
^
en
'mm
i/i
c
i*
*
^^ &>
c
o-o
Ol
«* «
u ^-
01 E
Ik V
Ik ^"
a>
o >.
c o>
0
i?s
0 VI
^ £
C k
O
VI ><
if
Ol 'o
:1
B £
s .g
U C -
VI ^ **
§IB IB
Ol C
k >» E
9T> 5
01 0 X
X.O Ol
>> VI
IB *L
O Oi
"»
1-
£ k
e
09 u.
J«
Oi
£8
Ol<
*£
O9 IB
S'
com
CM
i
o>
Ol
£
>»
g1
^
01
C
01
*>l
X
1
e
o
f^
en
^
VI
c
J* IB
C
at f
^9 Of
k
o
>l
Ol
o
"o
il
^z **
IB
e
c -
IB IB
Ol X
01
«*
£ Tl
Oi Oi
$1
gl^
><
gg1
It- ^
U- O
ft) *-
Irt
O
K£
>»
^*
wi
§
9
C
4
C
e
U VI
>t
e5
?
fo
a>
r- k
n o
COlk
CM
Ol
o>
IB
1
o>
e
^
o
P.
o*
^*
VI
e
i'
a» -^
^ A*
v
ft>
^i*
^K
E
«M*
^^
f
O
«rf
£
O
«*
£
Ol
$
>>
"g
£
g~
c
e
4rf
£^
l VI
IB M
V 01
«$
1*
£ k
O
00 tn
CM
^r
Z
>
tl
Jt
01
k
k
"5
o-
VI
o
^
V
*
VI
C
i*
Or **
^^ Q>
w
ft*
«<
^
J
^
^^
J
o
«<
£
e
««
£
Ol
I
>>
*g
J3
S
e
o
«« 4^
£^
«- e
« *^
"I
o x
x a>
>t
9
O
9
e
««
e
o
U VI
>»
* IB
B V
If
Kfe
n »
>.
Ol
Jt
I
ft)
b.
U
₯
VI
00
CM
^3 ffl
C ^~
B
*
^£ ^E
«rf «^
II
V7 V
e
o
4^
IB
k
Ol
c
a>
o>
tt
v
k
Ol
>
r-
W
J^
E
e
o
1
E
IB
e
x
k
^
9
&
^^
_|
^^^^
« vi
e >»
>!
1 -
CO ><^
^ «9 Oi
"5S
C *
1=^
e
O £ k
O O
C0*i!
I'
ee
>.
Ol
A
|
^
o>
11
0>
^
>l
X
1
C
xs »^
e ^>
w
*
^z
fe £
«-> Ol
IB 0)
u -o
U k
_ IB
§f
9
k A
£ 9
w> "
^^
VI
E >
>» tJ2
C5|
*
IS?
S-fe
««£
r>
$'
ee
^
Ol
a.
|
^
Ol
«
c
Ol
>l
x
£
ft) O
N
e vi
ft* b>
- 1
>. 5
^C *^
** *^
* _
«?
^ 4k
V U
e 01
IB ex
VI
Ol C
e vi 9
Ol k
^ Ol < E e
x 5
1 VI Ol
ex. ^ i-
x k S
S * X
£ B
ie
Ol
K S
K K k
S - u.
«A 1
. *
i e
i E Oi
e N
Jt c
8K 01
CO 03
IB £ U
I
b»
g.
Ol
k
«*
e
e
g
oe
.^
Ol
a
u
o.
a.
IB
+*
o
it
<
X
0006H
-7-
08/21/87
-------
Although the group size was not mentioned, statistical analyses were
performed. No mortality was reported. Jenkins et al. (1970) exposed rats>
guinea pigs, dogs and monkeys to 3358 mg/ma, 8 hours/day, 5 days/week for
6 weeks or to 337 mg/ma continuously for 90 days. There were no effects
on body weight gain, hematology or hlstopathologlcal appearance of a limited
number of tissues. One (of two) dogs exposed to 3358 mg/m3 had neuro-
muscular tremors throughout the experiment. Among the rats, 3/12 exposed to
3358 mg/m3 died and 1/14 exposed to 337 mg/m3 died. Cause of death was
not reported.
Only one subchronlc Inhalation study was located for m-xylene. In
experiments with guinea pigs exposed to 1300 mg/m3, 4 hours/day, 6 days/
week for 10-11 weeks, Smyth and Smyth (1928) reported pulmonary Inflammation
and liver and kidney degeneration.
Several short-term studies with xylenes 1n humans, reviewed by U.S. EPA
(1986a), suggest that mildly adverse effects may be observed at or near the
ACGIH (1986a,b) TWA-TLV of 100 ppm (435 mg/m3) for mixed xylenes or the
Individual Isomers. Hake et al. (1981) exposed groups of male volunteers to
p-xylene at 20, 100 or 150 ppm (87, 435 or 651 mg/m3) for 1, 3 or 7.5
hours/day for 5 consecutive days at each exposure level. Males were
sedentary except for those exposed for 7.5 hours/day, who exercised for 11
minutes of day 4 of each exposure week. Groups of females were exposed at
rest to 100 ppm for 1, 3 or 7.5 hours/day for 5 consecutive days. There
were no effects on hematology, urlnalysls, EEG, VER, pulmonary ventilation
volume, heart rate, metabolic rate, blood pressure or results 1n various
cognitive or performance tests In either men or women, with the exception of
two of four men exposed to 150 ppm for 7.5 hours who had decreased perform-
ance In the Flanagan coordination test. Nose and throat Irritation and
headaches were reported 1n females exposed at 100 ppm for 7.5 hours/day.
0006H -8- 08/21/87
-------
Gamberale et al. (1978) exposed male subjects at rest to mixed xylenes
(54.4, T2.8, 12.1 and 20.7%, m-, p-, o-xylene and ethylbenzene) at 0, 435 or
1300 mg/m3 for 70 minutes. In a second experiment, eight men were exposed
to 1300 mg/m3 for 70 minutes; exercise was added to the first 30 minutes
of exposure. In both experiments, five neurological performance tests
(addition, simple and choice reaction times, short-term memory and critical
flicker fusion frequency) were administered during the last 35 minutes of
exposure. There were no effects on the performance tests In the first
experiment at either 435 or 1300 mg/m3. In the second experiment, exer-
cise that was associated with Increased uptake of xylenes at 1300 mg/m3
resulted 1n decreased performance In all five tests.
Several studies associate exposure to m-xylene with Impaired neuro-
logical performance. Savolalnen et al. (1979b) noted adverse effects on
reaction time and equilibrium 1n male students exposed to 4.1 ymol/J.
(435 mg/m3), 6 hours/day for 5 consecutive days for 2 weeks. Tolerance to
m-xylene appeared to develop during the first 5 days of the exposure.
Savolalnen et al. (1984) associated alterations In body balance and simple
visual reaction times In healthy males with exercise and exposures to 8.2
jjmol/l (870 mg/m3) fluctuating as high as 16.4 ymol/8. (1740
mg/m3). Exposures were for 4 hours; some of the subjects exercised for 10
minutes. In other reports from this laboratory with exposure to m-xylene
ranging from 90-400 ppm by various schedules for up to 6 weeks, alterations
1n body balance were noted (Savolalnen et al., 1980, 1982a,b; Savolalnen,
1980; R11h1mak1 and Savolalnen, 1980; Savolalnen and Llnnavuo, 1979).
3.2. CHRONIC
3.2.1. Oral. NTP (1986) performed a 103-week chronic toxlclty carclno-
genlcUy gavage study where mixed xylenes (60.2% m-, 9.1% o-, 13.6% p-xylene
0006H -9- 08/01/89
-------
arid 17.QX ethylbenzene) In corn oil were administered to 50 male and 50
female F344/N rats at 0 (vehicle control), 250 or 500 mg/kg and to 50 male
and 50 female B6C3F1 mice at 0 (vehicle control), 500 or 1000 mg/kg, 5
days/week. High-dose male rats had body weights 5-8% less than controls
starting at week 59. A dose-related Increase In mortality was also observed
In male rats, which became statistically significant at the high dose by
week 103. Although some of the deaths were attributed to gavage error. It
was possible that the treated rats more forcefully resisted Intubation,
which Indicated a treatment-related behavioral change. The only effect
observed In mice was a 5- to 30-m1nute period of hyperactlvlty In both sexes
In the high-dose group after dosing. No treatment-related hlstopathologlcal
lesions were observed 1n rats or mice.
3.2.2. Inhalation. U.S. EPA (1986a) reviewed several occupational
studies of workers exposed to xylene. Generally, exposure was to a mixture
of solvents or exposures were not sufficiently quantified for use 1n risk
assessment. These studies loosely associate exposure to solvents with renal
effects (Mlkulskl et a!., 1972; Askergren, 1981, 1982; Askergren et al.,
1981a,b; Franchlnl et al., 1983), liver effects (Kurppa and Husman, 1982;
Dossing et al., 1983), ocular and neurophyslologlcal effects (Kurppa and
Husman, 1982) and effects on Immunocompetency and hematopolesls (Sukhanova
et al., 1969; Moszychzynskl, 1981, 1982; Moszychzynskl and L1s1ew1cz, 1983,
1984).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Gavage treatment with mixed xylenes (60.2, 13.6, 9.1 and
17.0% m-, p-, o-xylene and ethylbenzene) at 3100 or 4130 mg/kg/day on days
6-15 of gestation was lethal to pregnant CD-I mice and produced a mortality
Incidence of 12/38 at 3100 mg/kg/day and of 15/15 at 4130 mg/kg/day (Marks
0006H -10- 08/01/89
-------
et al., 1982}'. Doses of 2060 and 2580 mg/kg/day caused Increased maternal
liver weight, Increased resorptlons and fetal malformations, and decreased
fetal body weights (Marks et al., 1982). Doses of 1030 and 520 mg/kg/day
had no apparent effects on fetal or maternal toxldty.
In an experiment with Individual xylene Isomers, Nawrot and Staples
(1981) treated pregnant mice with doses of -780, 1960 or 2610 mg/kg/day on
days 6-15 of gestation. Maternal toxldty, Increased fetal resorptlons and
cleft palate were observed with o- and p-xylene at 1960 and 2610 mg/kg/day,
but not at 780 mg/kg/day. No cleft palate or maternal toxldty were noted
with m-xylene at any dose. In a second experiment In this series, all
xylene Isomers were given at 2610 mg/kg/day on days 12-15 of gestation and
resulted In Increased prenatal deaths; the m- and p-lsomers resulted In
cleft palates. In further testing with m-xylene alone, a significant
Increase 1n cleft palates was observed at 2610 mg/kg/day during gestation
days 6-15.
3.3.2. Inhalation. Shlgeta et al. (1983) reported that IRC mice exposed
to 500, 1000, 2000 or 4000 ppm (2174, 4342, 8684 or 17,369 mg/m8) xylene
[1somer(s) not specified] for 6 hours/day on days 6-12 of gestation did not
differ from controls In the number of Implantation sites or the number of
resorbed, dead or externally malformed fetuses. At dose levels of 2000 and
4000 ppm, fetal weights were decreased and delayed skeletal ossification and
supranumerary ribs were observed. In neonates from dams allowed to deliver
(~l/3 of each group), decreased body weight gain and delayed body hair and
tooth development at 4000 ppm were attributed to xylene exposure.
Continuous exposure of 20 pregnant CFY rats to 1000 mg/m3 mixed
xylenes (10% o-xylene, 50% m-xylene, 20% p-xylene, 20% ethylbenzene) on days
9-14 of gestation resulted 1n an Increased Incidence of fused sternebrae and
0006H -11- 08/01/89
-------
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
placental weight, mean fetal weight, fetal resorptlon, fetal mortality or
visceral malformations.
Pregnant CFY 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
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-lsomers, respectively. Signs
of maternal toxlclty Included decreased food consumption In all 3000 mg/m3
groups and In the 1500 mg/m3 o-xylene-exposed group. The group exposed to
3000 mg/m3 m-xylene exhibited Increased mortality (4/30). The authors
stated that maternal weight gain decreased as a function of exposure concen-
tration during the early days of exposure (specific data not provided). The
only significant effect on weight gain by day 21 of gestation was 1n the
3000 mg/m3 m-xylene group. An Increase 1n maternal llver-to-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. 4% In controls). The number of pregnant
rats was decreased at 3000 mg/m3 o-xylene or m-xylene. The average number
of Implants per rat was decreased In the group exposed to 3000 mg/m3
m-xylene.
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 In significant fetal weight reductions.
0006H -12- 08/01/89
-------
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/m3 of either m-xylene or p-xylene. Skeletal retarda-
tion occurred 1n fetuses from dams exposed to 3000 mg/ma o-xylene and In
all p-xylene-exposed groups.
In addition, the number of alkaline phosphatase positive proximal convo-
luted tubules as well as the number and Intensity of the positive staining
nephrons for succlnlc dehydrogenase, add phosphatase and glucose-6-phos-
phatase 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 1n sucdnlc dehydrogenase
and glucose-6-phosphatase activities. The enzyme changes In the kidneys
were Interpreted by the authors as an Indication of a delay 1n maturation.
Exposure to 1500 mg/m3 produced no adverse effects on litters exposed
to m-xylene; 150 mg/m3 produced no adverse effects on litters exposed to
o-xylene; and p-xylene resulted In fetotoxldty as evident by delays In
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, 36.1% ethylbenzene) at concentra-
tions of 0, 433 and 1733 mg/m3 on days 6-15 of gestation for 6 hours/day
(Litton Blonetlcs, 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; the remaining fetuses were examined for
0006H -13- 08/01/89
-------
skeletal abnormalities. There was no evidence of maternal toxlclty. The
only effect apparent was a significant Increase 1n the number of offspring
with "unusual skeletal variations." Incidences 1n fetuses were 19 In the
control, 24 In the low-dose group and 37 In the high-dose group; however,
the number of Utters affected were 9, 6 and 10. The authors did not judge
this effect to be treatment-related because the majority of the affected
fetuses were from three Utters and because all fetuses from these Utters
were "small."
Delayed skeletal development, supranumerary ribs and Increased post-
Implantation loss were reported In rats exposed to an unspecified mixture of
xylene Isomers at 230, 1900 or 3360 mg/m3 continuously on days 7-14 of
gestation {Balogh et a!., 1982). There was no evidence of maternal toxlclty.
Hlrkova et al. (1983) exposed groups of mated Wlstar rats to a commer-
cial mixture of xylene Isomers (levels of Individual Isomers not stated) at
0, 10, 50 or 500 mg/m3, 6 hours/day, 5 days/week during the entire gesta-
tion period. At >50 mg/m3 postlmplantatlon, loss was Increased, fetal
body weights were decreased and Increased Incidences of fetal hemorrhages
were noted. High Incidences of fetal hemorrhages, however, were noted In
all groups Including controls. An Increased Incidence of Internal anomalies
was reported at 500 mg/ma and an Increased Incidence of defects 1n
skeletal ossification was reported at 50 and 500 mg/m3, but the data were
not provided for evaluation. In rats allowed to deliver, reduced body
weight and "functional Inferiority" of several organs were reported In pups
from the 50 and 500 mg/m3 groups.
B1o/Dynam1cs, Inc. (1982) performed an extensive reproduction-develop-
mental toxlclty study with a xylene mixture (20.42% o-, 44.2% m-, 20.3%
p-xylenes, 12.8% ethylbenzene and 2.4% toluene). Concentrations of 60, 250
0006H -14- 08/01/89
-------
or 500 ppm (261, 1086 or 2171 mg/m3), 6 hours/day were provided to groups
of 10-20 male and 20-40 female CD rats for 131 days before mating and during
a 20-day mating period (both sexes), and during days 1-20 of gestation and
days 5-20 of lactation (females). A control group of 30 males and 60
females were sham-exposed. After mating, five treated males were necrop-
sled; the remaining five males were killed after a 3-week recovery period.
Female F rats were necropsled and hlstopathologlcal examinations were
performed at weaning of their offspring on lactation day 21. Offspring were
sacrificed for necropsy and hlstopathology at weaning (1/sex/lHter) or at
postpartum day 49. In a second part of the study, additional groups of
males and females were exposed as described and the females were sacrificed
on gestation day 21 to evaluate developmental toxlclty. In a third part of
the study, males and females exposed to 500 ppm as described above were
mated to untreated rats.
There were no treatment-related effects on parental mortality, food con-
sumption, body weight gain or appearance at necropsy. No treatment-related
effects were observed on mating, fertility or pregnancy Indices, gestation
length, parturition data, litter size or pup survival. In the developmental
toxldty study, a slight but significant decrease was observed 1n the body
weight of female fetuses and delayed fetal skeletal ossification was
observed 1n both sexes from F rats exposed to 500 ppm. There was no
Increase 1n the Incidence of malformations 1n pups from treated parents. In
the reproduction part of the study, pup weights were reduced at 500 ppm on
postpartum day 21. Ovarian weights were reduced In female pups at 250 and
500 ppm sacrificed at day 21 but not at the day-49 sacrifice, and there were
no effects on necropsy or hlstopathology of the pups of either sex at post-
partum day 21 or 49.
0006H -15- 08/01/89
-------
3.4. TOXICANT INTERACTIONS
The Interaction of xylene with ethanol (Savolalnen et al., 1978;
Elovaara et al., 1980; Savolalnen and R11h1mak1, 1981; Seppalafnen et al.,
1981; R11h1mak1 et al., 1982a,b), 1,1,l-tr1chloroethane (Savolalnen et al.,
1982b) and carbon tetrachloMde (Tatral et al., 1979) has been studied. In
rats, oral 1ngest1on of alcohol (15% of drinking fluid) potentiates the
effect of Inhalation exposure to 300 ppm xylene given 6 hours/day, 5 days/
week (Savolalnen et al., 1978; Elovaara et al., 1980). After 2 weeks of
simultaneous exposure, changes In hepatic and renal enzyme activities
(7-ethoxycoumarln, o-deethylase, UDP-glucuronosyltransferase and cytochrome
P-450) were noted. After 18 weeks of exposure, Increased numbers of 1ntra-
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 1ngest1on (0.8 g/kg), 1n
conjunction with xylene exposure (290 ppm for 4 hours), Increased the effect
of alcohol on central equilibrium control mechanisms (Savolalnen and
R11h1mak1, 1981). Xylene doubled the volume of centrllobular Hver necrosis
caused by Ingestlon of 2 ml/kg bw of carbon tetrachlorlde 1n rats (Tatral
et al., 1979). Xylene and 1,1,1-trlchloroethane each depressed the metabo-
lism of the other In humans, but no hlstopathologlcal effects were described
(Savolalnen et al., 1982b).
0006H -16- 08/21/87
-------
4. CARCINOGENICITY
4.1. HUNAN DATA
McHlchael et al. (1975) performed a case-control study that associated
occupational exposure to organic solvents with a statistically significantly
Increased Incidence of leukemia. No attempt, however, was made to estimate
the relative risk associated with specific solvents. In a subsequent
analysis of data from the same company studied by McMUhael et al. (1975),
Arp et al. (1983) Indicated that coal-based xylene was the primary component
of the solvent mixture to which workers were exposed, but that other
(unspecified) solvents were also present.
4.2. BIOASSAYS
4.2.1. Oral. In an NTP (1986) chronic tox1c1ty-cardnogen1c1ty study
with mixed xylenes (see Section 3.2.1.), rats were treated with gavage doses
of 250 or 500 mg/kg and mice with 500 or 1000 mg/kg, 5 days/week for 103
weeks. NTP (1986) concluded that there was no evidence for the carclno-
genldty of mixed xylenes In rats or mice 1n this experiment.
NTP (1986) reviewed a study In which Sprague-Dawley rats were treated by
gavage with xylenes (not otherwise specified) 1n olive oil at 0 or 500
mg/kg, 4 or 5 days/week for 104 weeks (Maltonl et al., 1985). Observation
continued until week 141 at which time survivors were killed for examina-
tion. The number of male and female rats having malignant tumors was 11/50
and 10/50 for controls and 14/40 and 22/40 In the treated groups. NTP
(1986) stated that because of lack of Information on survival and specific
tumor types, the study Is difficult to Interpret.
4.2.2. Inhalation. Tatral et al. (1981) exposed rats to o-xylene at 4750
mg/m3, 8 hours/day, 7 days/week for 1 year to Investigate effects on the
liver (see Section 3.1.2.). No tumors were reported, and this study was
Inadequate for evaluation of carclnogenlclty.
0006H -17- 08/01/89
-------
4.3. OTHER RELEVANT DATA
m-Xylene, p-xylene and o-xylene were not mutagenlc In several strains of
Salmonella typhlmurlum 1n the presence or absence of the rat liver mlcro-
somal fraction (Florin et al., 1980; Bos et al.. 1981; Haworth et al.,
1983). Mixed xylenes were not mutagenlc In Escherlchla coll strains WP2,
WP2uvrA, CM611, WP67, WP100. 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 hematopoletlc
cells (Conner et al., 1980) or SCEs 1n human lymphocytes hi vitro (Gerner-
Smldt and FMedrlch, 1978).
4.4. HEIGHT OF EVIDENCE
Relevant animal data regarding the cardnogenldty of the xylenes
Include the NTP (1986) gavage study, which was an adequate study that was
negative 1n rats and mice, and the Maltonl et al. (1985) gavage study, which
suggested a carcinogenic response In rats. In a recent qualitative evalua-
tion, U.S. EPA (1986a) considered the animal data to be Inadequate for
assessing the cardnogenldty of xylenes. Human occupational data
(McMlchael et al., 1975; Arp et al., 1983), although these data suggest an
association of exposure to xylene with leukemia, are confounded by simulta-
neous exposure to other solvents and are also Inadequate for assessing the
cardnogenldty of xylenes. Using the CAG guidelines for cancer risk
assessment (U.S. EPA, 1986b), U.S. EPA (1986a) assigned xylenes to Group D
not classifiable as to human cardnogenldty. This classification Is
adopted In this analysis for mixed xylenes and the Individual (o-, m-, p-)
xylene Isomers.
0006H -18- 08/01/89
-------
6. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1986a,b) recommends a TWA-TLV of 100 ppm (435 mg/m3) and a
STEL-TLV of 150 ppm (655 mg/m3) for xylene CAS No. 1330-20-7, which Is the
mixture of Isomers, and also for the Individual o-, m- and p-lsomers. NIOSH
(1975) recommends a I0-m1nute celling of 200 ppm xylene because the
attention, judgment and perception of the worker can be altered by the
depressant effect of xylene on the CNS. OSHA (1985) has an occupational
standard PEL of 100 ppm (435 mg/m3) xylene.
0006H -19- 08/01/89
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSES (RfOc)
%>
6.1.1. Oral (RfDso). Bowers et al. (1982) examined the effects of
o-xylene at 200 ppm In the diet for <6 months on the livers of rats and
BorMston Laboratories, Inc. (1983) examined the effects of m-xylene at 0.5
and 2.0 g/kg, 5 days/week for 4 weeks on the kidneys of rats. Adverse
effects were not reported In either study. Although these studies Investi-
gated effects In key organs, they are considered too limited In scope to
serve as the basis for quantitative risk assessment.
In more comprehensive studies sponsored by NTP (1986), male and female
rats were treated by gavage with mixed xylenes at 0, 62.5, 125, 250, 500 or
1000 mg/kg, 5 days/week for 13 weeks, and mice were treated by an Identical
protocol with 0, 125, 250, 500, 1000 or 2000 mg/kg. The only effect
reported In rats was reduced terminal body weight, 15% In males and 8% In
females, at 1000 mg/kg. The next lower dosage, 500 mg/kg (357 mg/kg/day
when expanded to dally treatment) represents a NOEL 1n rats In this experi-
ment. Adverse effects 1n mice Included transient neurological signs (Imme-
diately after dosing) and reduced body weight gain. In addition, two
females at this dosage died, but the cause of death was not determined.
Xylenes at relatively high dosages have been associated with develop-
mental toxlclty In laboratory animals. Marks et al. (1982) administered
mixed xylenes to pregnant mice at dosages of 520-4130 mg/kg/day on days 6-15
of gestation. Doses of 3100 and 4130 mg/kg/day were associated with fetal
deaths, while doses of 2060 and 2580 mg/kg/day were associated with mild
maternal toxldty (Increased liver weight) and developmental toxlclty.
Neither maternal nor developmental toxlclty occurred at the two lowest
doses, 520 and 1030 mg/kg/day. In another developmental toxlclty study,
0006H -20- 08/01/89
-------
Nawrot and Staples (1981) treated pregnant mice with the Individual o-,
m- and p-1somers of xylenes at ~780, 1960 or 2610 mg/kg/day on days 6-15 of
gestation, at 2610 mg/kg/day on days 12-15 of gestation and In further
trials with m-xylene at 2610 mg/kg/day on gestation days 6-15. Although the
results were not reported clearly 1n the secondary source from which these
data were taken, H appears that all Isomers were associated with prenatal
death and an Increased Incidence of cleft palate, which was generally
accompanied by maternal toxldty. The lowest dosage tested, 780 mg/kg/day,
appears to be a NOAEL for fetotoxldty for all three xylene Isomers.
The NOAELs for developmental toxldty, 1030 mg/kg/day for mixed xylenes
(Marks et al., 1982) and 780 mg/kg/day for the Individual Isomers (Nawrot
and Staples, 1981), are sufficiently above the NOEL of 357 mg/kg/day for
subchronlc toxldty 1n rats that the latter may serve as the basis for an
RfDSQ. Application of an uncertainty factor of 100, 10 for Interspedes
extrapolation and 10 to protect unusually sensitive Individuals, results In
an RfDgQ of 4 mg/kg/day, or 250 mg/day for a 70 kg human. These values
are considered provisional for mixed xylenes and Individual Isomers, pending
the results of subchronlc testing of Individual Isomers (OSW) and mixed
xylenes (OTS) 1n progress (U.S. EPA, 1986a).
6.1.2. Inhalation (RfDgI). The subchronlc animal Inhalation studies
with xylenes (see Table 3-1), do not clearly define thresholds of toxldty
for mixed xylenes or any of the Individual Isomers. For mixed xylenes,
Carpenter et al. (1975) reported no adverse effects In rats or dogs exposed
to <3500 mg/m3, 6 hours/day, 5 days/week for 13 weeks. In contrast,
however, Fabre et al. (1960) reported several lesions Including glomerulo-
nephrltls In rats exposed to 3000 mg/m3, 8 hours/day, 6 days/week for
110-130 days, and Savolalnen et al. (1979a) reported decreased behavioral
0006H -21- 08/01/89
-------
activity In rats exposed to 1300 mg/m3, 6 hours/day, 5 days/week for <18
weeks. A NOAEL for behavior effects was not Identified.
In an experiment with o-xylene 1n rats, 4750 mg/m3, 6 hours/day, 5
days/week for 1 year was associated with decreased body weight gain and
Increased relative liver weight, but with no effects on biochemical Indi-
cators of liver damage or on hlstopathology of unspecified organs (Tatral et
al., 1981). Jenkins et al. (1970) exposed rats, guinea pigs, dogs and
monkeys to 3358 mg/m3, 8 hours/day, 5 days/week for 6 weeks or to 337
mg/m3 continuously for 90 days. No effects on weight gain, hematology or
a limited hlstologlcal examination were observed. Unexplained deaths
occurred In both treated groups of rats.
Smyth and Smyth (1928) observed pulmonary Inflammation and liver or
kidney degeneration (or both) 1n guinea pigs exposed to 1300 mg/m3
m-xylene, 4 hours/day, 6 days/week for 10-11 weeks.
The most comprehensive 1nhalat1orv study was a reproductive toxlcity
experiment In which rats were exposed to mixed xylenes at 0, 60, 250 or 500
ppm (0, 261, 1086 or 2171 mg/m3), 6 hours/day for -190 days before mating
and during mating, gestation and lactation (Blo/Dynanrtcs, Inc., 1982) (see
Section 3.3.2.). There were no effects on parameters of subchronlc toxlcity
In parental rats. Signs of fetal toxldty, which were limited to the 500
ppm group, Included delayed skeletal ossification 1n both sexes and reduced
body weights of female fetuses. Reduced pup weights on lactation day 21,
which Indicates reproductive toxldty, were also observed In this group.
Reduced ovarian weights of female pups were observed at 250 and 500 ppm on
day 21 but not on day 49. This appeared to be a transient nonadverse
effect. This experiment, therefore, appears to define a LOAEL for rats of
500 ppm for 6 hours/day that 1s associated with fetotoxldty and Impaired
0006H -22- 08/01/89
-------
neonatal growth, and a NOAEL of 250 ppm for 6 hours/day that Is associated
with transient reduction 1n ovarian weights 1n offspring.
With the exception of the unexplained death of one rat In a group of 14
exposed to o-xylene at 337 mg/m3 continuously for 90 days (Jenkins et al.,
1970), none of the subchronlc animal studies reviewed In Section 3.1.2.
define adverse effects below the NOAEL of 250 ppm (1086 mg/m3) for 6
hours/day In the Bio/Dynamics, Inc. (1982) study. Other Inhalation develop-
mental toxlclty studies, however, suggest that adverse effects may occur at
or below the NOAEL In the B1o/Dynam1cs, Inc. (1982) study. Hudak and
Ungvary (1978) observed an Increased Incidence of fused sternebrae and extra
ribs In offspring of rats exposed to mixed xylenes at 1000 mg/m3 continu-
ously on days 9-14 of gestation. Balogh et al. (1982) reported delayed
skeletal development, extra ribs and Increased postlmplantatlon loss In rats
exposed to an unspecified mixture of xylenes at >230 mg/m3 continuously on
days 7-14 of gestation, but data were not sufficient for evaluation.
Mlrkova et al. (1983) reported defects 1n skeletal ossification and
"functional Inferiority" of several organs of pups from rats exposed to a
commercial mixture of xylene Isomers at >50 mg/m3 but not at 10 mg/m3, 6
hours/day, 5 days/week. Ungvary et al. (1980) exposed pregnant rats to the
Individual Isomers of xylene at 150, 1500 or 3000 mg/m3 continuously on
days 7-14 of gestation. Adverse fetal effects were noted with m-xylene at
3000 mg/m3 but not at 1500 mg/m3, with o-xylene at >1500 mg/m3 but not
at 150 mg/m3 and with p-xylene at all exposure levels.
Benchmarks of toxUHy and transformed doses from studies (all In rats)
that are sufficient for quantitative risk assessment are presented In Table
6-1. The B1o/Dynam1cs, Inc. (1982) NOAEL for mixed xylenes of 250 ppm or
181 mg/kg/day appears to be challenged by a LOAEL of 5.7 mg/kg/day that Is
0006H -23- 08/01/89
-------
4"
*-
*o
oc
c
^
u
K
o
I 1C
VI O M
c a *s
2 I
Ol
3
VI
,,
3
1
5
»
*
c
,
U
1
o
^ CM
O 03
Z2
UJ
O
^
u
X
o
o
*
r>
VI
O
V
rg
tk
o
CM 1C
||
Sie
...
Ol
c
Ol
>>
X
Ol
X
K
03
iJ ^
C '""
VI >C
u
"S "Z
1C
C 1C
ca o
o eo k
OD i fX
UJ UJ
O O
ae i
VI
u
Ol
k y-
O u-
CJ
* »
1C
W *
li
o
u ^-
O Oi
k V U
"5 Oi "K
A vi O
3k *
vi oi e
0 V Ol
e re «k
*c
a
VI
5 --
^N 3
O*i *O £
6r- >» 01
V. 1 VI 3
01 k 0
O 0 JE
03
o >» ic je
~* .-is
E vi E >»
CL k ^ VI 4-»
Of V VI
m e oi
one u-im 01
03 S
Ol Ol
- -
1C 1C
5 f
k O>
c =
UJ UJ
o o
ii
u-
Ol -
> o
c o
O 01
C - «k
-L
f^ lA
in
on
.~ ^"»
>c o a i
^ oi a
vi 3 e vi
k 0 >i
15 §'
w§
Ol «-
.*$§ ^^
^^!= ffS
0»iiC Ol
E ic-w o o>
O vi O
e oi u-i e
^ m 01 i- o
Ol
c
01
K
1
O
g
&
:
It
Ol
=
UJ
0
u
Ol
«k
Ik
Ol
>
1C
o
c
4
ei
>>»
VI 1
a vi
e >.
i:
w o
II **
p
I*
£§
§
o>
-
''C
01
S
UJ
O
s
o
o
Ol
Ik
Ol
*«.
a i
o r~
a
C VI
H
11
1?
Ol
c
Ol
X
1
E
OS CD
Ol Ol
; ;
fO o
1C O
o t!
C Ik
4
A in
in 01
Ol
^» >.«
31 VI 1
OP- 3 1-
3 O
C IA 3 VI
e -S5
u e o c
o u o
m «- ^
E «< «->
^3 £2
gs rs
g01 e01
£§ Si
Ol
c
X
1
^
o
0
in
o
o
c
VI
VI
Ol
a.
X
Ol
o
S3
£
CO
£
** ,
01 J2
_= 0
a o>
VI «<
2 «
o "~
fc S
9)
** V
i« 0»
k V
ll
&
's
I5
g k
fi
^ a
^ «
Trt ^*
li
01
Ol J*
|g
U.
Vi O
3
!*§»
is
Sf
55
?*
^ *
C
CL *
x n
«»
*.i
^3 C*)
^ F-
£ei
^ **
u 01
1C 01
u 3
1C
1
a
,
o
3
Ol
^
4n
r>
0
ik
0
«j
1C
k
k
o
1.
S
o
ja
Ol
^
Ol
k
Ol
Ik
k
UJ
S
w
Ol
JP
-------
estimated from the Mlrkova et al. (1983) study. The nature of the xylene
mixture used In the Mlrkova et al. (1983) study, however, was not described
and Incidence data for Internal anomalies was not presented. Furthermore,
the Incidence of fetal hemorrhage was high 1n all groups Including controls,
which suggests that the health of the rats or the conduct of the experiment
was compromised. Therefore, the Mlrkova et al. (1983) study, 1n light of
the more comprehensive and more thoroughly reported Bio/Dynamics, Inc.
(1982) study, 1s not considered further 1n risk assessment.
The developmental toxlclty study by Ungvary et al. (1980) with different
xylene Isomers Indicates a similarity 1n Inhalation toxlclty between the
o- and m-1somers, but a markedly greater toxlclty for p-xylene. The study
defines fetotoxldty NOAELs for the o- and m-1somers but falls to define a
NOAEL for p-xylene.
Using the 181 mg/kg/day NOAEL for mixed Isomers, the Bio/Dynamics, Inc.
(1982) study can be used to approximate a NOAEL for p-xylene. The 18
mg/kg/day NOAEL dose Identified for mixed xylenes contain -20.3% or 36.7
mg/kg/day p-xylene, a dose that may be considered a NOAEL for p-xylene.
This estimation for a NOAEL for p-xylene Indicates that an RfD based on a
dose of -36.7 mg/kg/day should be applicable to mixed xylenes and to the
Individual Isomers. The level of 36.7 mg/kg/day 1s not used as the basis of
the RfD because short-term experiments In humans with m-xylene (Savolalnen
et al., 1980, 1982a,b; Savolalnen. 1980; R11h1mak1 and Savolalnen, 1980;
Savolalnen and Llnnavuo, 1979) and with p-xylene (Hake et al., 1981) suggest
that Impaired neurological performance 1n humans may be a more sensitive
endpolnt of xylene toxlclty than endpolnts evaluated 1n animals and that the
human data may be a more appropriate basis for an RfDj. Therefore, the
0006H -25- 08/01/89
-------
Dj of 0.3 mg/ma for a 70 kg human that 1s derived 1n Section 6.2.2.,
1s adopted as the RfDSJ for mixed xylenes and the Individual Isomers for
the purpose of this document.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDJ. Chronic oral toxldty data are restricted to the
103-week NTP (1986) gavage study of mixed xylenes In which rats were treated
with 0, 250 or 500 mg/kg and mice with 0, 500 or 1000 mg/kg, 5 days/week.
High-dose mice of both sexes experienced a transient period of hyperactlvlty
Immediately after dosing. High-dose male rats had body weights 5-8% less
than controls starting at week 59 and statistically significantly Increased
mortality at the end of the study. No effects were observed at 250 mg/kg,
which 1s a NOEL In this experiment. An RfD_ can be derived from the NOEL
of 250 mg/kg In this study. Multiplication by 5/7 to expand dosage over 7
days/week and application of an uncertainty factor of 100, 10 to extrapolate
from rats to humans and 10 to protect unusually sensitive Individuals,
results 1n an RfD. of 2 mg/kg/day or 126 mg/day for a 70 kg human. This
value, which agrees with that derived by U.S. EPA (1986a), 1s adopted as a
provisional RfDQ for mixed xylenes and the Individual Isomers of xylene
pending results of the subchronlc oral testing (see Section 6.1.1.). It Is
expected to be protective against developmental toxldty as discussed In
Section 6.1.1.
U.S. EPA (1986a) derived a CS for xylene based on the Increased mortal-
ity observed In male rats that were treated by gavage with mixed xylenes at
500 mg/kg, 5 days/week for 103 weeks 1n the NTP (1986) study. The 500 mg/kg
dose was transformed to 357 mg/kg/day. Multiplication by the cube root of
the ratio of the animal body weight (0.425 kg estimated from data provided)
to the reference human body weight (70 kg) resulted In a human equivalent
0006H -26- 08/01/89
-------
dose of 65 mg/kg/day or 4550 mg/day for a 70 kg human. The human MED of
4550 mg/day 1s equivalent to an RV, of 1, An RV of 10 was chosen for
the effect of Increased mortality. Multiplying the RVd by the RV&
results 1n a CS of 10. This CS 1s adopted for mixed xylenes and the
Individual xylene Isomers.
6.2.2. Inhalation (RfD.). Animal Inhalation data for the xylenes were
restricted to subchronlc and developmental toxlclty studies, which were
evaluated for risk assessment In Section 6.1.2. A NOAEL of 181 mg/kg/day
for mixed xylenes and an approximate NOAEL of 36.7 mg/kg/day for p-xylene
were Identified In a subchronlc toxlclty-reproductlon rat study (Bio/
Dynamics, Inc., 1982). The ACGIH (1986a,b) TWA-TLV of 100 ppm (435 mg/m3)
has been 1n effect since 1967 and Is regarded as protective against
Irritation, narcosis and chronic Injury. Recent human studies (Hake et a!.,
1981; Savolalnen et al., 1980, 1982a,b; Savolalnen, 1980; R11h1mak1 and
Savolalnen, 1980; Savolalnen and Llnnavuo, 1979), however, associated mild
neurophyslologlcal disorders with exposure at or near the TLV. Recently,
the U.S. EPA (1989) RfD Workgroup considered the CNS effects of the Hake et
al. (1981) study for the derivation of an RfDj. It was highly unusual
that an acute human study was used for the derivation of the RfD.;
however, the RfD Workgroup recognized that this study Is supported by other
human studies (even with their limitations). Based on the CNS effects, the
100 ppm dose was a LOAEL and the 20 ppm dose was a NOAEL. The 20 ppm (87
mg/m3) was adjusted to 27 mg/m3 as the human equivalent concentration.
By applying an uncertainty factor of 100 (10 for Intraspedes variability
and an additional factor of 10 to compensate for the use of a 5-day study)
to this NOEL, an RfD of 0.3 mg/m3 was derived and verified by the RfD
Workgroup on May 18, 1989.
0006H -27- 08/01/89
-------
6.3. CARCINOGENIC POTENCY (q.,* or Unit Risk Slope)
Negative results In the oral NTP (1986) cancer study with mixed xylenes
In rats and mice and no tumors reported 1n the 1-year Inhalation study with
o-xylene In rats (Tatral et al., 1981) preclude estimation of carcinogenic
potencies for oral or Inhalation exposure to xylene.
0006H -28- 08/21/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
Threshold Limit Values and Biological Exposure Indices for 1986-1987.
Cincinnati, OH. p. 33.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the Threshold Limit values and Biological Exposure Indices,
5th ed. Cincinnati, OH. p. 637-638.
Arp, E.W., Jr., P.H. Wolf and H. Checkoway. 1983. Lymphocytlc leukemia and
exposures to benzene and other solvents In the rubber Industry. 3. Occup.
Med. 25(8): 598-602. (CHed 1n U.S. EPA, 1986a)
Askergren, A. 1981. Studies on kidney function In subjects exposed to
organic solvents. III. Excretion of cells In the urine. Acta. Med. Scand.
210: 103-106. (Cited 1n U.S. EPA, 1986a)
Askergren, A. 1982. Organic solvents and kidney function. Adv. Mod.
Environ. Toxlcol. 2: 157-172. (CHed 1n U.S. EPA, 1986a)
Askergren, A., L.G. Allgen and J. Bergstrom. 1981a. Kidney function In
subjects exposed to organic solvents: 2. The effect of desmopressln 1n a
concentration test and the effect of exposure of organic to solvents on
renal concentrating ability. Acta. Med. Scand. 209: 485-488. (CHed In
U.S. EPA, 19863)
0006H -29- 08/21/87
-------
Askergren, A., L.G. Allgen, C. Karlsson, I. Lundberg and E. Nyberg. 1981b.
Kidney function 1n subjects exposed to organic solvents: 1. Excretion of
albumin and B-s-mlcroglobulIn In the urine. Acta. Med. Scand. 209:
479-484. (Cited 1n U.S. EPA, 1986a)
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 1n U.S. EPA, 1985)
Balogh, T., E. Tatral, G. Barcza, M. Lor Inez and G. Ungvary. 1982. Embryo-
toxic effect of xylene. Egeszsegtudomany. 26: 42-48. (Cited 1n U.S. EPA,
1986a)
Bio/Dynamics, Inc. 1982. Parental and fetal reproduction Inhalation
toxldty study In rats with mixed xylenes. FYI submission FY1-AX-0982-0209.
Submitted by the American Petroleum Institute to U.S. EPA, Washington, DC.
Microfiche No. 0209. (Cited In U.S. EPA, 1986a)
Borrlston Laboratories, Inc. 1983. Four-week oral nephrotoxlclty screening
study 1n male F-344 rats phases I and II pathology report. FYI submission
AX-1283-0280. Submitted by the American Petroleum Institute to U.S. EPA,
Washington, DC.
Bos, R.P., R.H.E. Brouns, R. Van Doom, J.L.G. Theuws and P.T. Henderson.
1981. Non-mutagenlclty of toluene, o-xylene, m-xylene and p-xylene,
o-methylbenzylalcohol and o-methylbenzylsulfate 1n the Ames assay. Hutat.
Res. 88(3): 273-280. (Cited In U.S. EPA, 1985)
0006H -30- 08/21/87
-------
Bowers, D.E., Jr., M.S. Cannon and D.H. Jones. 1982. UHrastructural
changes In livers of young and aging rats exposed to methylated benzenes.
Am. J. Vet. Res. 43(4): 679-683. (Cited 1n U.S. EPA, 1985)
Bray, H.G., B.G. Humphrls and W.V. Thorpe. 1949. Metabolism of derivative
of toluene: 3. o-, m- and p-xylenes. Blochem. J. 45: 241-244. (CHed In
U.S. EPA, 1985)
Carpenter, C.P., E.R. Klnkead, D.L. Geary, Jr., L.J. Sullivan and J.M. King.
1975. Petroleum hydrocarbon toxlclty studies. V. Animal and human response
to vapors of mixed xylenes. Toxlcol. Appl. Pharmacol. 33(3): 543-558.
Conner, M., J. Maekl-Paakkanen, H. Norppa, M. Sorsa and H. Va1n1o. 1980.
Genetic toxicology of xylenes. Mutat. Res. 74: 171-172. (CHed In U.S.
EPA, 1985)
Dossing, M., P. Arllen-Soborg, L.M. Petersen and L. Ranek. 1983. Liver
damage associated with occupational exposure to organic solvents 1n house
painters. Eur. J. CUn. Invest. 13(2): 151-158. (Cited 1n U.S. EPA, 1986a)
Elovaara, E., Y. Collan, P. PfaffH and H. Valnlo. 1980. The combined
toxlclty of technical grade xylene and ethanol In the rat. Xenob1ot1ca.
10(6): 435-446. (CHed 1n U.S. EPA, 1985)
Fabre, R., R. Truhaut and S. Laham. 1960. Toxlcologlcal research on
replacement solvents for benzene ~ IV. Study of xylenes. Arch. Mai Prof.
21: 301-313. (Fre.) (CHed 1n NIOSH, 1975)
0006H -31- 08/21/87
-------
Florin, I., L. Rutberg, M. Curvall and C.R. Enzell. 1980. Screening of
tobacco smoke constituents for mutagenlclty using the Ames' test.
Toxicology. 15: 219-232. (Cited In U.S. EPA, 1985)
Franch1n1, I., A. Cavatorta, M. Falzo, S. Lucertlnl and A. Muh1. 1983.
Early Indicators of renal damage In workers exposed to organic solvents.
Anter. Arch. Occup. Environ. Health. 52: 1-9. (Cited In U.S. EPA, 1986a)
Gamberale, F., G. Annwall 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, 1986a)
Gerner-Smldt, P. and U. Frledrlch. 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)
Hake, C.L., R.D. Steward, A. Wu, et al. 1981. p-Xylene: Development of a
biological standard for the Industrial worker by breath analysis.
NIOSH-MCOW-ENUM-XY-77-3. NTIS PB82-152844. (Cited 1n U.S. EPA, 1986a)
Haworth, S., T. Lawlor, K. Mortelmans, et al. 1983. Salmonella mutagen-
lclty test results for 250 chemicals. Environ. Hutagen. Suppl. 1: 3-142.
(Cited In NTP, 1986)
Hudak, A. and G. Ungvary. 1978. Embryotoxlc effects of benzene and Us
methyl derivatives: Toluene, xylene. Toxicology. 11: 55-63. (Cited 1n
U.S. EPA, 1985)
0006H -32- 08/21/87
-------
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.
Kurppa, K. and K. Husman. 1982. Car painters exposure to a mixture of
organic solvents: Serum activities of liver enzymes. Scand. J. Work
Environ. Health. 8(2): 137-140. (Cited In U.S. EPA, 1986a)
LHton Blonetlcs. 1978. Teratology study 1n rats: Xylene. Final report to
American Petroleum Institute, Washington, DC. LBI Project No. 20698-5.
FYI-AX-0183-0231.
Maltonl, C., B. Contll, G. Cottl and F. Belpoggl. 1985. Experimental
studies on benzene carclnogenlclty at the Bologna Institute of Oncology:
Current results of_ongoing research. Am. J. Ind. Med. 7: 415-446. (Cited
1n NTP, 1986)
Marks, T.A., T.A. Ledoux and J.A. Moore. 1982. TeratogenlcUy of a commer-
cial xylene mixture 1n the mouse. 0. Toxlcol. Environ. Health. 9(1):
97-106. (Cited 1n U.S. EPA, 1985)
McCarroll, N.E., C.E. Piper and B.H. Keech. 1981. An IE. coll mlcrosuspen-
slon assay for the detection of DNA damage Induced by direct-acting agents
and promutagens. Environ. Mutagen. 3: 429-444. (CHed 1n U.S. EPA, 1985)
McMlchael, A.J., R. Sp1r1tas, L.L. Kupper and J.F. Gamble. 1975. Solvent
exposure and leukemia among rubber workers: An epldemlologlc study. J.
Occup. Med. 17(4): 234-239. (Cited 1n U.S. EPA, 1986a)
0006H -33- 08/21/87
-------
M1kulsk1, P.I., R. Wlglusz, A. Bublewska and J. Usells. 1972. Investiga-
tion of exposure of ships painters to organic solvents. Br. J, Ind. Hed.
29(4): 450-453. (CHed In U.S. EPA, 1986a)
Hlrkova, E., C. Zalkov, G. Antov, A. Mlkhallova, L. Khlnkova and I. Benchev.
1983. Prenatal toxldty of xylene. 0. Hyg. Epldem. Mlcrob. Immun. 27:
337-343.
Moszczynskl, P. 1981. Organic solvents and T lymphocytes. Lancet. 1:
438. (CHed In U.S. EPA, 1986a)
Moszczynskl, P. 1982. Effect of organic solvents In the course of profes-
sional exposure on the E rosette test and skin reactions against dlstreptase
and tuberculin. Folia Haematol. 109: 224-229. (Cited In U.S. EPA, 1986a)
Moszczynskl, P. and J. Llslewlcz. 1983. Hematologlcal Indices of periph-
eral blood In workers occupatlonally exposed to benzene, toluene and xylene.
Zentralbl Bakterlol Mlkroblol Hyg Abt 1 Org B Hyg Umwelthyg Krankenhaushyg
Arbeltshyg praev Med. 178(4): 329-339. (CHed 1n U.S. EPA, 1986a)
Moszczynskl, P. and J. L1s1ew1cz. 1984. Occupational exposure to benzene,
toluene and xylene and the T lymphocyte functions. Haematologla. 17(4):
449-454. (Cited In U.S. EPA, 1986a)
Nawrot, P.S. and R.E. Staples. 1981. Embryofetal toxldty and teratogen-
1c1ty of Isomers of xylene In the mouse. lexicologist. 1: A22. (CHed 1n
U.S. EPA, 1986a)
0006H -34- 08/21/87
-------
N10SH (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, RockvUle, MO. p. 101.
NRC (National Research Council). 1980. The Alky! Benzenes. Committee on
Alky! Benzene Derivatives. Board on Toxicology and Environmental Health
Hazards, Assembly of Life Sciences, National Academy Press, Washington, DC.
NTP (National Toxicology Program). 1986. NTP technical report on the
toxicology and carclnogenesls of xylenes (mixed) (60.2% m-xylene, 13.6%
p-xylene, 17.0% ethylbenzene and 9.1% o-xylene) (CAS No. 1330-20-7) 1n F344
rats and B6C3F1 mice (gavage studies). U.S. DHHS, PHS, NIH, NTP, Research
Triangle Park, NC. NTP TR327. NIH Publ. No. 86-2583.
OSHA (Occupational Safety and Health Administration). 1985. OSHA Safety
and Health Standards. Code of Federal Regulations. 29: 1910.1000.
R11h1mak1, V. and K. Savolalnen. 1980. Human exposure to m-xylene kinetics
and acute effects on the central nervous system. Ann. Occup. Hyg. 23(4):
411-422. (Cited 1n U.S. EPA, 1986a)
R11h1mak1, V., P. PfaffH, K. Savolalnen and K. Pekarl. 1979a. Kinetics of
m-xylene 1n man: General features of absorption, distribution, blotransfor-
matlon and excretion In repetitive Inhalation exposure. Scand. J. Work
Environ. Health. 5(3): 217-231. (Cited In U.S. EPA, 1985)
0006H -35- 08/01/89
-------
RMhlmakl, V., P. Pfaffll and K. Savolalnen. 1979b. Kinetics of m-xylene
In man: Influence of Intermittent physical exercise and changing environ-
mental concentrations on kinetics. Scand. 3. Work Environ. Health. 5(3):
232-248. (Cited 1n U.S. EPA. 1985)
R11h1mak1, V., K. Savolalnen, P. Pfaffll, K. PekaM, H.W. Slppel and A.
Lalne. 1982a. Metabolic Interaction between m-xylene and ethanol. Arch.
Toxlcol. 49(3-4): 253-264. (Cited 1n U.S. EPA, 1985)
Rllhlmakl, 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. (CHed 1n U.S. EPA, 1985)
Savolalnen, K. 1980. Combined effects of xylene and alcohol on the central
nervous system. Acta. Pharmacol. Toxlcol. 46: 366-372. (CHed 1n U.S.
EPA, 1986a)
Savolalnen, K. and M. Llnnavuo. 1979. Effects of m-xylene on human
equilibrium measured with a quantitative method. Acta. Pharmacol. Toxlcol.
44(4): 315-318. (Cited In U.S. EPA, 1986a)
Savolalnen, K. and V. R11h1mak1. 1981. Xylene and alcohol Involvement of
the human equilibrium. Acta. Pharmacol. Toxlcol. 48(3): 279-283. (CHed
In 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.
0006H -36- 08/21/87
-------
Savolalnen, K., P. Pfaffll. M. Helojokl and M. Tengen. 1979a. Neurocheml-
cal and behavioral effects of long-term Intermittent Inhalation of xylene
vapor and simultaneous ethanol Intake. Acta. Pharmacol. Toxlcol. 44(3):
200-207. (Cited In U.S. EPA, 1985)
Savolalnen, H., I. R11h1mak1 and M. Llnnolla. 1979b. Effects of short term
xylene exposure on psychophyslologlcal functions 1n man. Int. Arch. Occup.
Environ. Health. 44(4): 201-212. (Cited 1n U.S. EPA, 1986a)
Savolalnen, K., V. R11h1mak1, A.M. Seppalalnen and H. Unnolla. 1980.
Effects of short-term m-xylene exposure and physical exercise on the central
nervous system. Int. Arch, occup. Environ. Health. 45(2): 105-122. (Cited
In U.S. EPA, 1986a)
Savolalnen, K., V. R11h1mak1 and A. Lalne. 1982a. Blphaslc effects of
Inhaled solvents on human equilibrium. Acta. Pharmacol. Toxlcol. 51(3):
237-242. (Cited 1n U.S. EPA, 1986a)
Savolalnen, K., V. Rllhlmakl, A. Lalne and J. Kekonl. 1982b. Short-term
exposure of human subjects to m-xylene and 1,1,1-trlchloroethane. Arch.
Toxlcol. (Suppl.) 5: 96-99. (Cited In U.S. EPA, 1986a)
Savolalnen, K., J. Kekonl, V. Rllhlmakl and A. Lalne. 1984. Immediate
effects of m-xylene on the human central nervous system. Arch. Toxlcol. 7:
412-417. (Cited 1n U.S. EPA, 1986a)
0006H -37- 08/21/87
-------
Sedlvec, V. and 3. Flek. 1974. Absorption and excretion of xylenes In man.
Prac. Lek. 26(7): 243-248. (Cited 1n U.S. EPA, 1985)
SedWec, V. and 3. Flek. 1976. The absorption, metabolism and excretion of
xylenes 1n man. Int. Arch. Occup. Environ. Health. 37(3): 205-217. (Cited
1n U.S. EPA, 1985)
Se'nczuk, W. and 3. Orlowskl. 1978. Absorption of m-xylene vapors through
the respiratory tract and excretion of m-methylhlppurlc acid 1n urine. Br.
3. Ind. Med. 35(1): 50-55. (Cited In U.S. EPA, 1985)
Seppalalnen, A.M., K. Savolalnen and T. Kovala. 1981. Changes Induced by
xylene and alcohol In human evoked potentials. Electroencephalogr. Clln.
Neurophyslol. 51(2): 148-155. (CHed 1n U.S. EPA, 1985)
Shlgeta, S., H. Alkawa, T. Mlsawa and K. Suzuki. 1983. Fetotox1c1ty of
Inhaled xylene 1n mice. Teratology. 28(1): 22A. (Cited In U.S. EPA, 1985)
Singh, H.B., L.3. Salas, A.3. Smith and H. Shlgelshl. 1981. Measurements
of some potentially hazardous organic chemicals In urban environments.
Atmos. Environ. 15: 601-612.
Smyth, H.F. and H.F. Smyth, Jr. 1928. Inhalation experiments with certain
lacquer solvents. 3. Ind. Hyg. 10: 261-271. (CHed In U.S. EPA, 1985)
Sukhanova, V.A., L.M. Makareva and V.S. Bocko. 1969. Investigation of
functional properties of leukocytes of workers engaged In the manufacture of
xylene. Hyg. SanH. 34: 448-450. (Cited 1n U.S. EPA, 1986a)
0006H -38- 08/21/87
-------
Sutton, C. and J.A. Calder. 1975. Solubility of alkylbenzenes 1n distilled
water and seawater at 25°C. J. Chem. Eng. Data. 20: 232.
Tatral, E. and 6. Ungvary. 1980. Changes Induced by o-xylene Inhalation 1n
the rat liver. Acta. Med. Acad. Scl. Hung. 37(2): 211-216. (CUed In U.S.
EPA, 1985)
Tatral, E., A. Hudak and G. Ungvary. 1979. Simultaneous effect on the rat
liver of benzene, toluene, xylene and CC1.. Acta. Physio!. Acad. Sd.
Hung. 53: 261. (Cited In U.S. EPA, 1985)
Tatral, E., 6. Ungvary, I.R. Cseh, et al. 1981. The effect of long-term
Inhalation of o-xylene on the liver. Ind. Environ. Xenob1ot1cs, Proc. Int.
Conf. p. 293-300.
Ungvary, 6., E. Tatral, A. Hudak, 6. Barcza and M. Lor Inez. 1980. The
embryotoxlc effects of o-, m- and p-xylene. Toxicology. 18(1): 61-74.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Ambient Water Quality Criteria
Documents. Federal Register. 45(321): 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxldty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
0006H -39- 08/14/89
-------
U.S. EPA. 1986a. Health and Environmental Effects Profile for Xylenes (o-,
m-, p-). Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-86/216.
NTIS PB88-246186/AS.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987. Drinking Water Criteria Document for Xylenes. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC.
U.S. EPA. 1989. Integrated Risk Information System (IRIS). Reference Dose
(RfD) for Inhalation Exposure for Xylenes. Online: Input pending. (Veri-
fication date 05/18/89.) Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemistry,
2nd ed. Van Nostrand Relnhold Co., New York. p. 1310.
0006H - -40- 08/14/89
-------
CU
CU
X
u
X O
a
Z CU
a. j=
a. 10
* ^~
^^
L.
1
i
S
c
01
Ol
01
at
01
i/i ^».
0 t/»
o a
Ol OC
u
C t-
cu o
t-
01 0
u- *k
cu at
at
u
Ol
ik
k
UJ
01
^- V*
ro o
a
c -s.
CU O
a. a.
x x
UJ UJ
VI
01
t/9
-
o a
10 CD CO
CU - C IO
C CM C C C
c en c jf c c
«- ^- - m -
ro ro E ro ro
0 0*0 J= O 0
IB 0) C/5
M
E
W
CO
o
t
o
«- c
5.E1
0.^
0 10
i- a.
01 «-
c
+*
CO 3
ta> 01 01
4-* E **
Q. VI tt w C
o^ tt£!
o -a o -o 3
i ro CM 10 f
c
|
E
>. C v>
10 01
CU 1 Ctf
>- >>
o - x
C Ik 1
J-> - X
ro v> \ «-
o o E
ro ik
j= oe
c
r ^
00 f- O O CO
o> 10 co co **cn
en p «»cn cn^en^-
en cu* c ro en .
C CM C C C
>"v 1o'~1o§1o1o>'cu
ro i «r - i r ro
cat ooo.cooc«>
E
Ol
CO
o
o
- c
vi Ol
>i E
"ci^
II
01 -
c
*-» *io
J= U 1
«- Ol «
i O O
vi - Z
c
0
IO
c
01
ft U
*. "E§
ft Ql V. U
e E ~|^
OIUD E C
E CO v.i^ 01
- OICMr-
» E 10
ro o o >
~ CO 3
V ^t3 O*
E oi 01 o>
CJ.-W E--
ex vi a. i/i c
3 & 3 ro
O -^ «-> E
O -D O 'O 3
r- ro CM IO J=
C
1
u
NN
C VI
>> ro a>
U 1 01
i°-i
U X
O 1
ik E -a
^ 0)
. X
o o 1
ae
CO CO CO
» » .
^ °I PI
Z Z Z
^> ^^
/O IO
a -a
^. "^ o
Ol Ol «
E E
u
m CM co
CM r- 0
** i
r U
IO
_J _l ' O>
UJ UJ L. >
z z i
J£ Jtf ^^
oi 01 ai >>
u ai oi ro
x a » -o
VI I/I I/I Ol
>> >. >. J£
10 » ro -^ ro »v.
o >> -o >> -o >> gi
10 vi ro vi 10 E
u-i 10 -o tn jt -o inj^'o
J< >« Ol >» Ol V. O
DlftlJtf O> 3 Jt C7I J J^ kO
^ Oi >Jcogi >J co 01 *~
oico E 010 E 010 E u u
r- O r o -o
Oh.w> Ofc-co Ok.muj>
ooco in o -- oocoKce
ro ro ro
o -o
cm c vi
10 oi 10 01 o
1 Ol 1 CU IO CU
>» *> 1 01
X « X CXr-
> !(/>>!
E V E 'O u - x
Ol Ol I
e»x >x E 6 -o
CO 1 O 1 *" 3 Ol
^ f=oe ooe E-X
10 ee ce x o E
o S
0006H
-41-
08/01/89
------- |