Xylenes Category:
m-Xylene (CAS No. 108-38-3), o-Xylene (CAS No.
95-47-6), p-Xylene (CAS No. 106-42-3), Mixed
Xylenes (CAS No. 1330-20-7)
Voluntary Children's Chemical Evaluation
Program (VCCEP) Tier 1 Pilot Submission
Docket Number OPPTS - 00274D
American Chemistry Council
Benzene, Toluene, and Xylenes VCCEP Consortium
Sponsors:
BP
Chevron Phillips Chemical LP
ExxonMobil Chemical Company
Flint Hills Resources, LP
Marathon Petroleum LLC
Shell Chemical LP
Sunoco, Inc.
Total Petrochemicals U.S.A.
Contributing Consultants:
ChemRisk (Exposure and Risk Assessments)
C&C Consulting (Hazard Assessment)
Exponent (Hazard and Risk Assessments)
Kannan Krishnan, Ph.D. (PBPK Modeling)
Linea (Exposure Assessment)
October 6, 2005
TABLE OF CONTENTS
1 Executive Summary............................................................................................................ 1
2 Xylenes VCCEP Program Background .............................................................................. 7
2.1 Xylenes Category....................................................................................................... 7
2.2 VCCEP Pilot Selection Criteria for Xylenes............................................................... 7
3 Previous Assessments...................................................................................................... 10
3.1 Integrated Risk Information System (EPA, 2003A) ................................................. 10
3.2 Acute Exposure Guideline Levels (AEGLs)............................................................. 10
3.3 IARC......................................................................................................................... 11
3.4 Other Reviews/Assessments................................................................................... 12
4 Regulatory Overview......................................................................................................... 13
4.1 EPA Regulation........................................................................................................ 13
4.2 Consumer Product Labeling and Packaging Requirements ................................... 18
4.3 FDA Regulations ...................................................................................................... 19
4.4 Workplace Regulations and Standards ................................................................... 19
4.5 HUD Regulation ....................................................................................................... 20
4.6 State Regulation....................................................................................................... 20
5 Chemical Overview ..................................................................................................... 22
5.1 Commercial Xylenes Production and Demand ....................................................... 22
5.2 Commercial Xylenes Uses....................................................................................... 25
5.3 Production and Uses of Refined Petroleum Products............................................. 26
5.4 Releases of Xylenes to Ambient Air ........................................................................ 27
5.5 Releases of Xylenes to Soil and Water ................................................................... 30
6 Hazard Assessment.......................................................................................................... 32
6.1 Xylenes Hazard Assessment Summary.................................................................. 32
6.2 Acute Toxicity (see Table 6.2) ................................................................................. 39
6.3 Repeated Dose Toxicity - Subchronic Toxicity (See Table 6.3) ............................. 42
6.4 Genetic Toxicity - (See Table 6.4) ........................................................................... 46
6.5 Reproductive Toxicity (see Table 6.5) ..................................................................... 50
6.6 Developmental Toxicity (see Table 6.5) ................................................................. 52
6.7 Immunotoxicity (see Table 6.6) .............................................................................. 57
6.8 Adult Neurotoxicity (see Table 6.7) ........................................................................ 57
6.9 Auditory Toxicity (see Table 6.7) ............................................................................ 61
6.10 Developmental Neurotoxicity (see Table 6.8) ......................................................... 63
6.11 Chronic Toxicity (1-2 years) - (see Table 6.9) ......................................................... 66
Xylenes VCCEP Submission i
6.12 Toxicokinetics and Metabolism................................................................................ 68
6.13 Human Experience .................................................................................................. 69
7.0 Exposure Assessment...................................................................................................... 78
7.1 Methodology/Scope of Assessment........................................................................ 78
7.2 Sources of Xylenes Exposure.................................................................................. 82
7.3 Discussion of Biomonitoring Data.......................................................................... 129
7.4 Uncertainties in the Exposure Assessment........................................................... 131
7.5 Summary of Exposures.......................................................................................... 135
8.0 Risk Assessment .............................................................................................................. 78
8.1 Benchmarks Used to Characterize Chronic and Acute Adverse Health Effects of
Xylenes............................................................................................................................ 142
8.2 Risk Assessment Methodology ............................................................................. 150
8.3 Evaluation of the Risk of Chronic Effects .............................................................. 151
8.4 Evaluation of the Risk of Acute Effects from Short-Term Infrequent Sources of
Exposure ......................................................................................................................... 153
8.5 Occupational Exposures ........................................................................................ 154
8.6 Discussion of Uncertainties ................................................................................... 155
8.7 Conclusions............................................................................................................ 156
9.0 VCCEP Data Needs Assessment................................................................................... 157
10 References...................................................................................................................... 158
Xylenes VCCEP Submission ii
LIST OF APPENDICES
Appendix A:
A1 Exposure Parameters
A2 SCREEN3 Model Analysis
A3 FDA Market Basket Survey Analysis of Xylenes in Prepared Foods
A4 Lifeline Modeling of Xylenes in Food
A5 Lifeline Modeling of Drinking Water Exposures
A6 Consumer Products Containing Xylenes
A7 MSDS Verification of Xylenes Content in Consumer Product
A8 Residential Metal Parts Degreasing Scenario
A9 Residential Spray Painting Scenario
A10 Xylenes Exposure from Tobacco Smoke
A11 Consumer Product Exposure Modeling Sensitivity Analysis
Appendix B Robust Summaries for VCCEP Hazard Endpoints
Appendix C PBPK Modeling
Xylenes VCCEP Submission iii
GLOSSARY OF TERMS
礸 Microgram
ACGIH American Conference of Governmental Industrial Hygienists
ACH Air Changes per Hour
AEGL Acute Exposure Guideline Level
ATSDR Agency for Toxic Substances and Disease Registry
CAA Clean Air Act
CARB California Air Resources Board
CAS Chemical Abstract Service
CERCLA Comprehensive Environmental Response, Compensation, and
Liability Act
CFM cubic feet per minute
CNS Central Nervous System
CPSC Consumer Product Safety Commission
EHC Environmental Health Criteria
EPA Environmental Protection Agency
ETS Environmental Tobacco Smoke
FDA Food and Drug Administration
FHSA Federal Hazardous Substances Act
g Gram
GC/MS Gas Chromatograph/Mass Spectrometry
GD Gestation Day
HEC Human Equivalent Concentration
HI Hazard Index
High-end exposure An exposure that was calculated using exposure concentrations
representative of a 90th or 95th percentile of the range of values
in a given dataset, depending on availability in the published.
HQ Hazard Quotient
I-O Indoor-Outdoor (ratio)
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System
IUR Inventory Update Rule (TSCA)
kg Kilogram
kHz Kilohertz (thousands of cycles per second)
LD Lactation Day
LOAEL Lowest observable adverse effect level
m-xylene Meta-xylene (1,3-dimethylbenzene)
MACT Maximum Achievable Control Technology
MCL Maximum Contaminant Level
MCLG Maximum Contaminant Level Goal
mg Milligram
Mixed Xylenes A mixture of o-xylene, m-xylene, p-xylene, and ethylbenzene, in
varying concentrations. Also referred to as commercial xylene,
technical-grade xylene
mL Milliliter
MSDS Material Safety Data Sheet
MSHA Mine Safety and Health Administration
NCEA National Center for Environmental Assessment
NCOD National Drinking Water Contaminant Occurrence Database
NESCAUM Northeast States for Coordinated Air Use Management
Xylenes VCCEP Submission iv
NHANES National Health and Nutrition Examination Survey
NOAEL No Observed Adverse Effect Level
NTP National Toxicology Program
OECD Organization of Economic Cooperation and Development
OEHHA Office of Environmental and Human Health Assessment (Cal.)
OPPTS Office of Pollution Prevention and Toxic Substances (EPA)
OSHA Occupational Safety and Health Administration
o-xylene Ortho-xylene (1,2-dimethylbenzene)
NESHAPs National Emission Standards for Hazardous Air Pollutants
NIOSH National Institute of Occupational Safety and Health
PAMS Photochemical Assessment Monitoring Stations
PBPK Physiologically-Based Pharmacokinetic (models, modeling)
PEL Permissible Exposure Limit (OSHA)
ppb Part Per Billion
ppm Part Per Million
PPPA Poison Prevention Packaging Act
p-xylene Para-xylene (1,4-dimethylbenzene)
RCRA Resource Conservation and Recovery Act
REL Recommended Exposure Limit
RfC Inhalation Reference Concentration
RfD Oral Reference Dose
RFG Reformulated Gasoline
SARA Superfund Amendments and Reauthorization Act
SD Standard Deviation
SDWA Safe Drinking Water Ac t
SEM Standard Error of the Mean
SIAM SIDS Initial Assessment Meeting
SIAR Screening Information Assessment Report
SIDS Screening Information Data Set
STEL Short-Term Exposure Limit
TEAM Total Exposure Assessment Method
TLV Threshold Limit Value
TRI Toxic Release Inventory
TSCA Toxic Substances Control Act
TWA Time-Weighted Average
Typical Exposure An exposure that was calculated using the average or median
exposure concentrations in a given dataset (depending on
availability) and average or median values for exposure
parameters.
UF Uncertainty Factor
USGS United States Geological Survey
VOC Volatile Organic Compound
VCCEP Voluntary Children's Chemical Evaluation Program
WAGM Weighted Average Geometric Mean
WHO World Health Organization
Xylene/Xylenes Referring to any combination of the individual xylene isomers
and/or mixed xylenes
Xylenes VCCEP Submission v
1 Executive Summary
This submission by the American Chemistry Council Benzene, Toluene & Xylene VCCEP
Consortium (the "Consortium") covers the Tier 1 review of the xylenes category ?meta (m)-
xylene (CAS No. 108-38-3), ortho (o)-xylene (CAS No. 95-47-6), para (p)-xylene (CAS No.
106-42-3), and mixed xylenes (CAS No. 1330-20-8) - under the VCCEP Pilot Program.
Meta-xylene and ortho-xylene were included in the VCCEP Pilot Program because they
were included in several biomonitoring and environmental monitoring databases that the
EPA used to identify chemicals that may have the potential for children's exposure. The
Consortium has chosen to include p-xylene and mixed xylenes (a complex product of C8
aromatic hydrocarbons) in this assessment in order to present the full xylenes category that
was reviewed under the OECD SIDS program and other assessments (EPA, 2003A, AEGL,
etc). The treatment of the individual xylene isomers and mixed xylenes as a single category
is common throughout most of the previous xylenes assessments and is well supported by
their similar physical and chemical properties, hazard properties, potential health effects,
and exposure sources. In this VCCEP assessment, the terms "xylenes" or "xylene" refer to
the category as a whole.
Production and Use
Mixed xylenes, generally manufactured in petroleum refining processes, are produced in the
range of 6-7 million metric tonnes a year. The vast majority of the mixed xylenes production,
approximately 94%, is used in the manufacture of the o-, m-, and p-xylene isomers, with p-
xylene accounting for a large majority (approximately 88%) of isomer production. The
xylene isomers are used as intermediate feedstocks in the production of polyester fibers and
resins used in such products as fabric, molded plastic, films and beverage bottles. Some
mixed xylenes production, approximately 4%, is used in solvent applications such as paints
and coatings. Most of the small remaining portion of mixed xylenes production is added to
gasoline to improve octane ratings.
Hazard Assessment
A large number of toxicology studies have been conducted on xylenes, including studies
that address the endpoints considered in the VCCEP program.
Results from acute oral, dermal or inhalation toxicity studies in rats and mice indicate that
the acute toxicity of xylene isomers and mixed xylenes is very low. Acute toxicity was
typically characterized by central nervous system depression at high doses. Mixed xylenes
and xylene isomers are irritating to the skin and eyes.
The predominant effects of repeat exposures to xylenes administered by inhalation or orally
were mild hepatic alterations that were considered adaptive responses to hydrocarbon
exposure. NOAELs and LOAELs were determined primarily on decreases in body weight
and increased liver weight and liver enzyme changes. Inhalation studies performed by
different investigators and single dose levels over durations of exposure of 6 weeks to 6
months demonstrated NOAELs in the range of 800-1000 ppm. Oral administration of mixed
xylenes for 13 weeks (5 days/week) to rats or mice resulted in LOAELs of 1000 mg/kg/day
[rats] or 2000 [mice].
Xylenes VCCEP Submission 1
Xylenes do not induce gene mutation or DNA damage in bacteria, or gene mutation or
cytogenetic damage to mammalian cells in culture. No chromosome aberrations or
increased incidence of sister chromatid exchanges were seen in animal or human subjects.
Xylenes are not genotoxic.
Reproduction parameters in rats were not adversely affected by exposure to mixed xylenes
in a 1-generation study at concentrations up to 500 ppm or in two dominant lethal studies in
which male rats and mice were treated by injection and mated with untreated females,
weekly throughout the spermatogenic cycle. No adverse effects on testes, accessory sex
glands, or circulating male hormones were observed in rats exposed to 1000 ppm mixed
xylenes for 61 days. Extremely high anesthetizing doses of xylene, administered daily for 7
days did affect testes weight, testosterone levels, and spermatozoa counts in Wistar rats.
Multiple studies have examined standard developmental toxicity endpoints in offspring of
animals exposed to mixed xylenes or individual xylene isomers. Developmental effects in
offspring of pregnant animals exposed to xylenes have been observed although generally at
dose levels high enough to induce maternal stress and toxicity. Saillenfait et al. (2003)
conducted the most comprehensive developmental studies of xylenes in rats, evaluating all
three individual isomers (o-, m-, and p-xylene), and mixed xylenes under the same
laboratory conditions at concentrations of 0, 100, 500, 1000, or 2000 ppm, 6 hours/day
during gestation days (GD) 6-20, in accordance with OECD protocol 414 (2001) and EPA
OPPTS 870.3700 (1998) testing guideline. All materials caused maternal toxicity (reduction
in maternal body weight gain) at 1000 and 2000 ppm. Decreased corrected maternal weight
gain (without gravid uterus) and food consumption were observed at 1000 and 2000 ppm o-,
m-, and p-xylene and at 2000 ppm of mixed xylenes. No fetal malformations were induced
by any test material. Decreased fetal body weight occurred at the maternally toxic doses of
1000 and 2000 ppm for all materials, and also at 500 ppm and greater for o-xylene and
mixed xylenes. Significant increase in mean percent fetuses with skeletal variations of all
types/litter was seen at 2000 ppm concentrations of o- and p-xylene. No single skeletal
variation occurred at an incidence significantly higher than that in controls.
Xylenes do not appear to affect the immune system in animals and limited human data does
not demonstrate diminished immunological reactivity. Mice exposed by inhalation to para-
xylene at concentrations up to 1200 ppm did not exhibit adverse effects on natural killer [NK]
cells. Repeated oral exposure to meta-, para-, or ortho-isomers for 10 days at oral doses up
to 2000 mg/kg/day increased liver weight but slight decreases in thymus or spleen weight
were only seen with p-xylene exposure. Mixed xylenes did not induce any organ weight
changes.
Exposure to xylenes by the oral or inhalation routes can result in nervous system effects
such as tremors, incoordination, muscle spasms, respiratory distress, hearing loss or
elevated auditory thresholds, lethargy, hyperactivity, and changes in brain enzyme activity
and levels of brain protein. Auditory impairment in rats induced by xylenes exposure at high
inhalation concentrations (800-1800 ppm) for 5 days to 6 weeks have been reported.
Korsak et al. (1992, 1994) demonstrated that exposure to m-xylene for 3 months decreased
rotarod performance at 100 ppm in trained male rats beginning after 1 month of exposure
and continuing at the same level throughout the exposure period without altering body
weight, organ weight or clinical chemistry parameters; no effect was observed at 50 ppm m-
xylene. Xylenes are known to induce narcosis at high doses in humans and a range of CNS
effects at lower doses. Human experimental trials indicate acute effects on sensory-motor
Xylenes VCCEP Submission 2
and information processing functions with slight impairment at 100-200 ppm, and adaptation
at 200 ppm exposure over several days.
There are several studies that have assessed developmental neurotoxicity in xylenes. The
available studies have some limitations including the absence of dose response data, the
lack of definitive NOAEL levels, and the lack of consistency in results of some of the test
batteries. However, the study by Hass et. al. (1995, 1997), while only conducted at a single
dose of 500 ppm, was a well-conducted sophisticated evaluation of the postnatal
development and behavior of rats exposed prenatally to mixed xylenes. There were some
slight effects of performance on Morris Water Maze measured in female offspring that were
not measured in males or in females with various toys in their cages. In a study on p-xylene
in rats, there were no neurobehavioral effects on motor activity (figure-8 maze) or on
acoustic startle response in the offspring of dams exposed to 800 and 1600 ppm prenatally
(Rosen 1986). EPA concluded in the xylenes IRIS database that the LOAEL for
developmental neurobehavioral effects is 500 ppm, based primarily on the Hass 1995 study,
and that the developing organism is not more sensitive than the adult to xylene exposure.
Chronic oral toxicity/carcinogenicity studies have been performed in rats and mice. Studies
of 103 weeks duration completed by the National Toxicology Program (NTP) did not result in
significant toxicological changes beyond increased levels of hyperactivity after dosing in
high dose rats and mice and slightly lower body weight in high dose male rats exposed to
500 mg/kg mixed xylenes (top dose). Increased mortality in rats at the 500 mg/kg dose was
attributed to dosing errors but still was used as the basis for the establishing a tentative
LOAEL of 500 mg/kg and a NOAEL of 250 mg/kg. In mice, the LOAEL was set at the
maximum dose of 1000 mg/kg and the NOAEL was 500 mg/kg.
Xylenes are rapidly absorbed by the respiratory tract with uptake increased by physical
exercise. Absorption is also positively correlated with the amount of body fat. Liquid m-
xylene is well absorbed through the skin, but m-xylene vapor (up to 600 ppm) does not
appear to be appreciably dermally absorbed. Xylenes are highly soluble in blood and are
taken up primarily in lipid-rich tissues (e.g., fat, brain) and in organs highly perfused with
blood (e.g., liver, kidney). Small amounts of p-xylene and o-xylene have been reported to
cross the placenta and distribute in amnionic fluid and fetal tissue. Xylenes undergo
extensive metabolism, primarily side-chain oxidation and conjugation with glycine and
glucuronic acid for m- and p-xylenes and by glucuronide formation with a small amount of
sulfate conjugates for o-xylene. Metabolites are primarily excreted in urine with small
amounts of xylene released unchanged in expired air. About 90% of the absorbed dose is
excreted in the urine as methylhippuric acid, the glycine conjugate of methylbenzoic acid,
following inhalation or dermal (liquid) exposure.
Neurobehavioral effects are considered the critical endpoint to assess xylene toxicity and
assays for these effects are used by regulatory agencies to set acceptable levels for human
exposure. The work of Korsak et al. (1994) with m-xylene was used to establish the IRIS
RfC of 0.1 mg/m 3 (EPA 2003a) and to derive the chronic inhalation health benchmark in this
VCCEP Risk Assessment of 0.66 mg/m 3 (see Section 8.1).
Exposure Assessment
Information on releases and concentrations of xylenes in the environment indicates that
releases have been steadily decreasing since the mid 1980s. This trend can be seen with
Xylenes VCCEP Submission 3
the Toxic Release Inventory (TRI) data, as well as ambient air monitoring data from
locations throughout the U.S. A child-centered approach was used to define exposure
scenarios for children's interaction with xylenes exposure sources including environmental
(ambient) sources and use of consumer products. Both typical and high-end estimates of
exposure were made. The environmental background/ambient sources of exposure include
indoor air, outdoor air, diet, and water. In addition to these ubiquitous sources, certain
subpopulations of children may be exposed to xylenes in microenvironments from specific
activities such as transportation via gasoline powered vehicles, use of consumer products
containing xylenes, or living in a home where tobacco smoking occurs (either used by
parents or teenage children). Occupational exposure sources were also considered for
mothers to address the potential for exposure to a nursing infant. Xylenes exposure
scenarios were developed for different age groups to account for the potential differences in
the ways individual exposures vary with age. Five age groups have been chosen to
generally correspond with the infant, pre-school, school-age, teenager, and adult stages of
life, see Table 1.1.
The exposure assessment indicated that the inhalation pathway is the primary route of
exposure with systemic (absorbed) doses at least one order of magnitude higher than those
received via oral ingestion or dermal pathways, except for infant ingestion of human milk
from an occupationally exposed mother.
Of the inhalation sources of exposures, indoor air contributes the most to overall inhalation
doses. Representative indoor air concentrations of xylenes used in this assessment ranged
from 7.6 to 9.1 礸/m 3 for typical exposures and 32 to 36 礸/m 3 for high end exposures. The
impact of smoking on indoor air concentrations of xylenes was also assessed and it was
found that environmental tobacco smoke contributes less than 1 礸/m 3 to the indoor air load
for smoking households.
Oral intake of xylenes from diet and tap water ingestion ranged from 4.6 x 10-5 to 2.1 x 10-4
mg/kg/day for typical exposures and from 8.8 x 10-5 to 3.7 x 10- 4 mg/kg/day for high end
exposures. For infants of occupationally exposed mothers, oral intake of xylenes from
ingestion of breast milk was predicted to range from 5.6 x 10-5 mg/kg/day to 2.7 x 10-2
mg/kg/day.
Infrequent exposures to xylene were assessed in spray painting and metals parts
degreasing scenarios. Indoor air modeling estimates indicated that the highest 1 air
-hr
concentrations were 9.5 ppm and 30 ppm for typical and high end exposures respectively,
during metals parts degreasing. The highest 1-hr air concentrations for the spray painting
scenario were 27 ppm and 46 ppm for typical and high end exposures, respectively.
Xylenes VCCEP Submission 4
Table 1.1 Summary of Xylenes Exposure Scenarios
Age Group
Female
Exposure Scenarios <1 1-5 6-13 14-18
19-35
year old year old year old year old
year old
Ambient Exposures
Outdoor Air
? ? ? ? ?br>
Urban
? ? ? ? ?br>
Rural
Indoor Air
? ? ? ? ?br>
In-home
? ? ?br>
In-School
? ? ? ? ?br>
Food
? ? ? ? ?br>
Water
Source-Specific Exposures
Tobacco Smoke
? ? ? ? ?br>
ETS
? ?br>
Mainstream
Consumer Products
? ?br>
Users
? ? ?br>
Non-users
Gasoline Sources
? ? ? ? ?br>
In-Vehicle
?(16 ?18
?br>
Refueling years old)
Occupational
?br>
Production/Processing
?br>
Non-Production
?= Included in evaluation.
Risk Assessment
The risk assessment and the underlying hazard assessment and exposure assessment
demonstrate the following:
? Very low xylenes exposures are received from everyday background sources of
exposure such as ambient air, water, food and in-vehicle exposures. Aggregated
background doses result in hazard indices (HIs) that are less than 0.05 at the high
end; for all age groups; except the nursing infant of an occupationally exposed
mother;
Xylenes VCCEP Submission 5
? Total xylenes doses to the nursing infant of an occupationally exposed mother range
from a typical dose of 0.0005 mg/kg/day to a high end dose of 0.027 mg/kg/day,
which results in HQs ranging from 0.003 to 0.13;
? Chronic, source-specific, inhalation exposures to xylenes from tobacco smoking and
vehicle refueling scenarios do not result in exceedances of the health benchmark,
even when aggregated with background ambient doses. Tobacco smoke HIs range
from 0.0009 for a child exposed only to ETS to 0.034 for an adult exposed to ETS
and mainstream smoke. Refueling HIs do not exceed 0.003 for a high end exposure;
? Short term air concentrations of xylenes to which children may be exposed during
use of various consumer products are not expected to exceed the interim AEGL-1
value of 130 ppm under typical or high end exposure conditions.
The quantitative risk characterization indicates that reasonably anticipated children's
exposures to xylenes from the ambient background environment and specific sources such
as gasoline during refueling and consumer product use are unlikely to pose significant
health risks.
Data Needs
Given (1) the significant margins between the HIs and estimated exposures, and (2) the
extensive data covering the endpoints for the three VCCEP Tiers, this submis sion concludes
no further testing is needed on the VCCEP endpoints.
For chemicals, like xylenes, that are used in consumer products and occur in many
environments, additional exposure assessment work is always possible. The VCCEP
sponsors believe, however, that the information presented in this document is adequate to
demonstrate that reasonably anticipated exposures to xylenes from environmental sources
are not likely to present significant health risks to children. In addition, doses from typical
and reasonably worst case exposures from use of consumer products that are consistent
with product label information are not likely to present significant health risks to children.
Accordingly, the VCCEP sponsors believe additional exposure assessment work should be
a low priority.
Xylenes VCCEP Submission 6
2 Xylenes VCCEP Program Background
In selecting compounds for the VCCEP Pilot Program, EPA relied on biomonitoring and
environmental monitoring databases that it considered relevant to assessing the potential for
children's exposure. The availability of hazard data was an additional factor that influenced
chemical selection decisions. These selection criteria (discussed in Section 2.2) resulted in
two xylene isomers - m-xylene and o-xylene ?being selected for the VCCEP Pilot program.
The Consortium has chosen to include p-xylene and mixed xylenes (a complex product of
C8 aromatic hydrocarbons) in this assessment in order to present the full xylenes category
that was reviewed under the OECD SIDS program and other assessments (EPA, 2003A,
AEGL, etc - see Section 3 for further information about previous reviews/assessments).
2.1 Xylenes Category
The xylenes category for this VCCEP assessment includes:
? m-Xylene (CAS No. 108-38-3),
? o-Xylene (CAS No. 95-47-6),
? p-Xylene (CAS No. 106-42-3),
? Mixed Xylenes (CAS No. 1330-20-7)
The treatment of the individual xylene isomers and mixed xylenes as a single category is
common throughout most of the previous xylenes assessments and is well supported by
their similar physical and chemical properties, hazard properties, potential health effects,
and exposure sources. In this VCCEP assessment, the terms "xylenes" or "xylene" refer to
the category as a whole.
Mixed xylenes presents a somewhat unique situation because in addition to containing the
three individual xylene isomers, it also frequently contains ethylbenzene. The ethylbenzene
content in mixed xylenes varies, though it is generally in the range of 5-20% by weight. In
the hazard assessment when mixed xylenes data are presented the ethylbenzene content is
noted whenever possible. The xylenes VCCEP exposure assessment presents data on the
exposure to the three xylene isomers but does not consider ethylbenzene exposure that
might arise from mixed xylenes since ethylbenzene exposure is being evaluated separately
under VCCEP.
2.2 VCCEP Pilot Selection Criteria for Xylenes
The Pilot Program selection criteria are discussed in the VCCEP Federal Register Notice
(Dec. 26, 2000) at III.Q. Based on these selection criteria, m-xylene and o -xylene were
selected for the VCCEP Pilot because they were: (1) evaluated under the Organization for
Economic Cooperation and Development (OECD) SIDS Program; (2) found in human blood
in the NHANES biomonitoring study; (3) reported in human exhaled air in the TEAM study;
(4) detected in drinking water; and (5) detected in indoor air. Table 2.1 provides a summary
of the EPA review of the available biomonitoring and environmental monitoring database for
these xylenes.
Xylenes VCCEP Submission 7
Table 2.1 The results of EPA's VCCEP candidate chemical selection process for o-
Xylene and m-Xylene
Chemicals found in Human Tissues Chemicals Found in Human
CHEMICAL Environment
CAS No.
NAME NHANES NHAT NHEXAS TEAMS Human NCOD INDOOR AIR
Milk
95-47-5 o-Xylene Y Y Y Y
108-38-3 m-Xylene Y Y Y Y
Reference: EPA VCCEP Website (http://www.epa.gov/chemrtk/vccep/vccepmth.htm)
2.2.1 National Health and Nutrition Examination Survey III (NHANES III)
NHANES III was conducted between 1988 through 1994 on 33,994 people and focused
primarily on basic health and nutritional parameters such as blood pressure, immunization
status, and nutritional blood measures. NHANES III included a special study that looked at
the blood levels of 32 volatile organic compounds (VOCs) in a sample of about 800
volunteers from the overall NHANES study. Eleven compounds were found with high
frequency and the data on these 11 compounds were sufficient to establish reference levels
(e.g., median, 95th percentile) for the nonoccupationally exposed U.S. population. Another
five compounds were found in at least 10% of the samples.
Results on xylenes from NHANES III were published in Ashley et al. (1994) and are
presented in Table 2.2 (from the EPA VCCEP website). These blood concentrations are
consistent with low level xylene exposure and are discussed further in Section 7.3.
Table 2.2 Blood Concentrations for Xylenes from NHANES III Study reported on
EPA's VCCEP website
Table 6: Frequency of Detection and Tissue Concentration
of Select VCCEP Pilot Chemicals in Human Monitoring Studies
CHEMICAL DETECTION
CAS No. MEDIUM CONCENTRATION
NAME FREQUENCY
m,p-xylene blood > 75% of 649 med = 0.19 ppb
95-47-6 o-xylene blood > 75% of 711 med = 0.11 ppb
2.2.2 Total Exposure Assessment Methodology Data
The Total Exposure Assessment Methodology (TEAM) study was designed to develop
methods to measure individual total exposure (exposure through air, food, and water) and to
apply these methods within a probability-based sampling framework to estimate the
exposures of urban populations in several U.S. cities. The TEAM Study data for xylenes are
limited to air monitoring data collected from several communities in New Jersey and
California in 1982 and 1983. These studies found personal air exposures for m-, p-, and o-
xylenes ranged from 13 ug/m 3 to 46 ug/m 3 and indoor air concentrations ranged from 8.5
ug/m 3 to 36 mg/m 3 (Wallace et al., 1987). A detailed exposure assessment on xylenes is
presented in Section 7.
Xylenes VCCEP Submission 8
2.2.3 National Drinking Water Contaminant Occurrence Database
The National Drinking Water Contaminant Occurrence Database (NCOD) provides data on
the occurrence and concentration of u nregulated contaminants in drinking water. NCOD
was developed to satisfy the statutory requirements set by Congress in the 1996 SDWA
amendments. The purpose of the database is to support EPA's decisions related to
identifying contaminants for regulation and subsequent regulation development. The NCOD
contains occurrence data from both Public Water Systems and other sources (like the U.S.
Geological Survey National Water Information System) on physical, chemical, microbial, and
radiological contaminants for both detections and non-detects.
NCOD contains occurrence monitoring from sampling locations throughout a Public Water
System; therefore, a detection value does not necessarily mean the contaminant would be
found at the tap. There are some summary statistics, but no actual analysis of the data is
provided. Also, NCOD contains data for only unregulated contaminants required to be
monitored by public water systems, even though EPA has not set health-based drinking
water maximum contaminant levels for this subset of contaminants. This subset is covered
by the Unregulated Contaminant Monitoring Rule, or UCMR. Currently the NCOD does not
contain occurrence data for all water systems and all states. The only Public Water System
data contained in NCOD is data that has been reported by States to the Safe Drinking Water
Information System (SDWIS). Historical data goes back to 1983.
Information on xylenes in drinking water is addressed in Section 7.2.1.2 of the exposure
assessment.
2.2.4 Air Monitoring Data
Several of the air monitoring references cited by EPA for the VCCEP program provide data
on indoor and/or outdoor air concentrations of xylenes. The air data samples reported in
these studies were generally collected between the mid -1980's and 1991. The most recent
study was conducted by Shields et al. (1996) in March and April 1991 at telecommunication
centers, data centers, and administrative offices. Daisey et al. (1994) collected indoor and
outdoor air samples at 12 office buildings in the San Francisco Bay area between June and
September 1990, including several buildings with indoor air quality complaints. Brown et al.
(1994) compiled the results of several previous indoor air studies on established and new
buildings and reported xylenes air concentrations for dwellings, offices, and a hospital.
Samfield (1992) and Shah and Singh (1988) also compiled the results of numerous indoor
and outdoor air monitoring studies. These studies generally reported average air
concentrations in the low part per billion (ppb) range. The results of these and other
exposure studies, from the Consortium's exposure assessment, are presented in Section 7.
Xylenes VCCEP Submission 9
3 Previous Assessments
This section reviews several previous assessments on xylenes.
3.1 Integrated Risk Information System (EPA, 2003A)
The EPA's Integrated Risk Information System (EPA, 2003A) is an online database of human
health effects of various chemicals that may be present in the environment (www.epa.gov/EPA,
2003a/). EPA updated the EPA, 2003A database for xylenes in January 2003 (EPA, 2003a).
This update included the derivation of a chronic xylenes oral reference dose (RfD) and a chronic
xylenes inhalation reference concentration (RfC).
The oral RfD for xylenes is based on decreased body weights in male rats observed in the
National Toxicology Program (NTP 1986) 2-year rat oral gavage study of mixed xylenes (60%
m-xylene, 13.6% p-xylene, 9.1% o-xylene, and 17% ethylbenzene). The NOAEL of 250
mg/kg/day was adjusted by 5/7 to account for 5-days per week dosing and divided by a total
uncertainty factor of 1,000, resulting in an RfD of 0.2 mg/kg/day. The total uncertainty factor
includes a factor of 10X for interspecies differences, a factor of 10X for intraspecies differences
for sensitive subpopulations, and a factor of 10X for database uncertainties. The RfD is used
for assessing oral exposures in the Risk Assessment (see Section 8).
The inhalation RfC of 0.1 mg/m 3 for xylenes is based on a NOAEL of 50 ppm (217 mg/m3) for
rotarod performance in male Wistar rats following 3 months of exposure for 6 hours per day, 5
days per week (Korsak 1994). A LOAEL for decreased performance was observed at 100 ppm
m-xylene. The NOAEL as point of departure was adjusted to a continuous exposure
concentration of 39 mg/m 3 and divided by a combined uncertainty factor of 300 to derive a
reference concentration of 0.1 mg/m 3. The Risk Assessment (Section 8) discusses the
derivation of the RfC and alternative chronic inhalation health benchmarks using this same point
of departure.
3.2 Acute Exposure Guideline Levels (AEGLs)
The National Advisory Committee for Acute Exposure Guideline Levels (NAC/AEGL) first met in
June 1996 with the purpose of developing and recommending airborne guideline levels for
short-term exposures to hazardous substances to the U. S. Environmental Protection Agency
(EPA). It was intended that these levels could also be used by other federal, state, and local
agencies and the private sector for emergency planning, prevention, and response activities
(U.S. EPA http://www.epa.gov/oppt/aegl/history.htm). There are three AEGL levels:
AEGL-1 - is the airborne concentration above which it is predicted that the general
population, including susceptible individuals could experience notable discomfort,
irritation, or asymptomatic nonsensory effects; however, the effects are not
disabling and are transient and reversible upon cessation of exposure.
AEGL-2 - is the airborne concentration above which it is predicted that the general
population, including susceptible individuals could experience irreversible or
other serious, long-lasting adverse health effects or an impaired ability to escape.
Xylenes VCCEP Submission 10
AEGL-3 - is the airborne concentration above which it is predicted that the general
population, including susceptible individuals could experience life-threatening
health effects or death.
The AEGL development process consists of four basic stages: (1) draft AEGLs, (2) proposed
AEGLs, (3) interim AEGLs, and (4) final AEGLs. Xylenes have gone through the first two
stages of the AEGL process. In June 2005, the AEGL committee approved the interim AEGLs
presented in Table 3.1 (EPA 2005).
The AEGL-1 value is a based upon slight eye irritation in humans during 30-minute exposure to
400 ppm mixed xylenes (Hastings 1986). An intraspecies factor of 3X was applied because the
effect was slight, resulting in an AEGL-1 value of 130 ppm. As this was determined to be a
threshold effect, the same AEGL-1 value was applied to all durations. The AEGL-1 value is
supported by several other studies, including: no effects at 200 ppm for p-xylene after 3 hours
exposure (Ogata 1970); no effects at 200 ppm m-xylene after 3, 4, and 5.5 -hour exposures
(Ogata 1970, Savolainen 1981, Laine 1993); eye irritation in a contact lens wearer at 150 ppm
p-xylene (Hake 1981); and, mild eye irritation and dizziness in one individual following a 15-
minute exposure to 230 ppm mixed xylenes (Ogata 1970). The AEGL-1 value was used in the
Risk Assessment (Section 8) as a point of departure for a margin of safety assessment for acute
inhalation exposures.
The AEGL-2 values are based on poor coordination in rats following a 4-hour exposure to 1300
ppm mixed xylenes (Carpenter 1975). The AEGL-3 values are based on the same study,
though the endpoint of concern was prostration, followed by full recovery, exhibited after 4-hour
exposure to 2800 ppm mixed xylenes. PBPK modeling was conducted to develop the AEGL-2
and AEGL-3 values.
Table 3.1: Interim Xylenes AEGLs
(ppm)
10 min 30 min 60 min 4 hr 8 hr
AEGL 1 130 130 130 130 130
AEGL 2 2,500* 1,300* 920* 500 400
AEGL 3 7,200* 3,600* 2,500* 1,300* 1,000*
Lower Explosive Limit (LEL) = 9,000 ppm
* = >10% LEL
For values denoted as * safety considerations against the hazard(s) of explosion(s) must be taken into
account.
Source: EPA Website (2005): http://www.epa.gov/oppt/aegl/
3.3 IARC
IARC reviewed xylenes in 1999 and classified them as Class 3 "not classifiable as to its
,
carcinogenicity to humans." A summary of the xylenes IARC review can be viewed on the IARC
website (http://www-cie.iarc.fr/htdocs/monographs/vol71/052-xylenes.html).
Xylenes VCCEP Submission 11
3.4 Other Reviews/Assessments
Previous reviews of the xylenes category have been conducted by the International Programme
on Chemical Safety (IPCS), the Organization for Economic Cooperation and Development
(OECD), and the Agency for Toxic Substances and Disease Registry (ATSDR) and others. The
IPCS evaluated xylenes in the mid-1990's and in 1997 published an Environmental Health
Criteria Review on xylenes (EHC 190) evaluating toxicological and environmental effects from
xylenes. The OECD evaluated the xylenes category under the Screening Information Data Set
(SIDS) program in May 2003 and concluded that while xylenes were potentially hazardous to
human health and the environment, the hazards were being managed and as such xylenes are
a low priority for further work. The ATSDR released a Toxicology Profile on xylenes in August
1995, which provides a review of hazard, exposure, and pharmacokinetic data.
Xylenes VCCEP Submission 12
4 Regulatory Overview
This section provides an overview of the extensive federal environmental, health and safety,
and related regulations controlling xylenes exposures.
Xylenes are broadly regulated by many federal agencies, including the Environmental
Protection Agency ("EPA"), the Food and Drug Administration ("FDA"), the Consumer Product
Safety Commission ("CPSC"), the Occupational Safety & Health Administration ("OSHA"), and
the Department of Housing and Urban Development ("HUD"). Given the number and
complexity of these regulations, this overview is not an exhaustive survey of all regulations
relating to xylenes.
4.1 EPA Regulation
EPA regulates xylenes under numerous statutes, including the Clean Air Act, 42 U.S.C. Ё 7401
et seq.; the Clean Water Act, 33 U.S.C. Ё 1251 et seq.; the Safe Drinking Water Act, 42 U.S.C.
Ё 300f et seq. ("SDWA"); the Resource Conservation and Recovery Act, 42 U.S.C. Ё 321 et
seq. ("RCRA"); the Comprehensive Environmental Response, Compensation, and Liability Act,
42 U.S.C. Ё 9601 et seq. ("CERCLA" or "Superfund"); the Superfund Amendments and
Reauthorization Act, 42 U.S.C. Ё 9601 et seq. ("SARA"); the Emergency Planning &
Community Right-To-Know Act ("EPCRA"), 42 U.S.C. Ё 11011 et seq.; the Pollution Prevention
Act, 42 U.S.C. Ё 13101 et seq. ("PPA"); and the Toxic Substances Control Act, 15 U.S.C. Ё
2601 et seq. ("TSCA").
4.1.1 Clean Air Act
The Clean Air Act regulates emissions of xylenes from stationary sources (e.g., factories,
refineries, and power plants) and mobile sources (e.g., trucks, cars, motorcycles) and as volatile
organic compounds in products. Under the Clean Air Act, xylenes are alternately referred to as
Hazardous Air Pollutants ("HAPs"), volatile organic compounds ("VOCs"), or Mobile Source Air
Toxics ("MSATs").
Hazardous Air Pollutant Regulation
Section 112 of the Clean Air Act establishes a two-step process for protecting the public and the
environment from the effects of toxic air pollutant emissions from stationary sources. First, EPA
promulgates extensive National Emission Standards for Hazardous Air Pollutants ("NESHAPs"),
better known as Maximum Achievable Control Technology ("MACT") standards, as required by
section 112(d) of the Act. These technology-based MACT standards are imposed on specific
manufacturing sectors on a category-by-category basis. See generally 40 C.F.R. Parts 61, 63.
Second, within the eight years following the promulgation of each technology-based MACT
standard, EPA has to regulate any remaining (or "residual") risk with an "ample margin of
safety." CAA ?112(f), 42 U.S.C. ?7412(f). In this second phase, EPA applies a risk-based
approach to assess whether the MACT technology-based emission limits sufficiently reduce
health and environmental risks.
Thus, emissions of xylenes from stationary sources are subject to both stringent, manufacturing-
sector-specific MACT-based standards and any further regulation that EPA determines is
Xylenes VCCEP Submission 13
necessary to ensure an ample margin of safety. Virtually all of the MACT standards have been
published, and EPA is in the process of considering whether residual risk rules for facilities will
be needed.
Volatile Organic Compound Regulations
Numerous regulations affect VOCs in regions where ozone formation is a concern. While these
regulations are not necessarily specific to xylenes, they do affect many consumer and
commercial products that contain xylenes and many commercial or industrial operations that
use xylenes. See, e.g., 40 C.F.R. Part 59 (National VOC emission standards for consumer and
commercial products); 40 C.F.R. Part 60 (VOC standards for new stationary sources involving
certain activities). In general, the overriding effect of these regulations is a reduction in
emissions of xylenes.
Mobile Source Air Toxics, Reformulated Gasoline, and Limits on Gasoline
Volatility
"Nationwide, mobile sources represent the largest contributor to air toxics." See EPA, Mobile
Source Emissions - Past, Present, and Future. The Clean Air Act requires EPA to promulgate
regulations to control hazardous air pollutants from motor vehicles and motor vehicle fuels
which reflect the greatest degree of emission reduction achievable considering "the availability
and costs of the technology, and noise, energy, and safety factors, and lead time." CAA
?202(l)(2), 42 U.S.C. ?7521(l)(2). As a result, numerous regulations reduce emissions of
mobile source air toxics like xylenes, including EPA's reformulated gasoline ("RFG") program,
limitations on gasoline volatility, and other provisions affecting MSATs.
Upon passage of the 1990 CAA amendments, EPA established the RFG program. This
program requires the reformulation of gasoline to reduce emissions of smog-forming and toxic
pollutants. See generally 40 C.F.R. Part 80.
Other regulations limit gasoline volatility, thereby reducing evaporative emissions. See, e.g., 40
C.F.R. ?80.27. Volatility is a measure of how easily a substance (e.g., gasoline) evaporates.
When gasoline evaporates, chemicals such as xylenes that are present in gasoline get into the
air. EPA regulates the Reid vapor pressure of gasoline, a common measure of gasoline
volatility, from May through September each year for certain "designated volatility nonattainment
areas" and "designated volatility attainment areas" as defined in 40 C.F.R. ?80.2(cc) and 40
C.F.R. ?80.2(dd), respectively. See id. Moreover, certain classes of motor vehicles are
required to have evaporative emission controls, thereby further reducing the amount of gasoline
volatiles that get into the air. See, e.g., 40 C.F.R. Ё 86.1811-01(d), 86.1811-04(e), 86.1812-
01(d), 86-1813-01(d), 86.1814-01(d), 86.1814-02(d), 86.1815-01(d), 86.1815-02(d), 86.1816-
05(d), 86.1816-08(d).
In 2001, EPA promulgated a mobile source air toxics final rule that identified 21 MSATs,
including xylenes, and set new gasoline toxic emission performance standards. See 66 Fed.
Reg. 17230 (March 29, 2001). This rule establishes a framework for EPA's national mobile
source air toxics program and requires that refineries maintain the toxics performance of the
gasoline they produced during the baseline period 1998-2000. The rule also contains a plan for
continuing research and analysis on all MSATs. In addition, EPA has announced plans to
propose another mobile source air toxics rule no later then February 28, 2006, and to finalize it
by February 9, 2007 (see 70 Federal Register 46168 (August 9, 2005)).
Xylenes VCCEP Submission 14
Table 4.1: Timeline of Mobile Source Regulatory Actions Resulting in Reductions of
VOCs in Emissions
Year Description
The Clean Air Act Amendments of 1970 - sets the first standards for emissions from
1970
motor vehicles. The standards are phased in over the next 5 years.
1971 New cars must meet evaporative emissions standards for the first time.
1975 New cars are required to use catalytic converters.
1981 New cars meet the amended Clean Air Act standards for the fi rst time.
1983 Second generation catalytic converters required for new cars.
First inspection and maintenance programs established in areas with air pollution
1983
problems.
1989 EPA sets first fuel volatility limits aimed at reducing evaporative emissions.
Clean Air Act Amendments of 1990 require further reductions in hydrocarbons, lower
tailpipe standards, more stringent emission testing procedures, expanded I/M programs,
1990
new vehicle technologies, and clean fuels programs.
California adopts a low emission vehicle (LEV) program.
1991 EPA establishes lower tailpipe standards for hydrocarbons.
Winter oxygenated fuel program begins in cities with high carbon monoxide levels.
1992 California has a similar "Phase I gasoline" program (oxygenated fuel required to limit
carbon monoxide emissions also has a lower hydrocarbon content).
Progressive introduction begins of national Tier 1 emission limits for light duty vehicles.
1994
On board diagnostic systems become a requirement for light duty vehicles and trucks.
Phase I RFG is required to be sold in areas of ozone non-attainment (Phase I RFG has
1995 lower volatility, contain oxygenated compounds, and lower hydrocarbons). California
transitional gasoline introduced as a transition from Phase I to Phase II RFG.
California Phase II RFG is introduced. Phase II RFG has reduced vapor pressure and
lower hydrocarbon.
National Tier 1 emission limits introduced progressively from 1996 for light duty trucks.
1996
Phase-in begins of revised procedures and limits for evaporative emissions for light and
heavy-duty vehicles.
Dispensing rates for gasoline and methanol pumps are regulated.
Federal Tier 1 tailpipe emissions standards go into effect.
California's Low Emission Vehicles (LEV) fleet averaging program begins.
National hydrocarbon emission limits introduced for vehicles using clean alternative
fuels (provisions under LEV program).
1998
Voluntary Agreement for Cleaner Cars: Northeastern states agree to put cleaner cars
on the road before they could be mandated under the CAAA. The first Niles under this
agreement were released in New England in 1999 and were available nationwide in
2001.
1998 Phase-in begins of on-board refueling controls on passenger vehicles (1998 ?2000).
National Low Emissions Vehicle (NLEV) program starts.
2000 California hydrocarbon emission limits introduced for vehicles using clean alternative
fuels - provisions under LEV program.
2001 Phase-in begins of onboard refueling controls on light light-duty trucks (2001-2003)
2001 Japanese electric-gasoline hybrid automobiles become available.
2003 Federal Tier 2 tailpipe emissions standard phase-in begins.
2003 Phase-in of California's LEV II program begins.
Xylenes VCCEP Submission 15
Year Description
2003 California requires a maximum level of sulfur in RFG of 600 ppm.
2004 Phase-in begins of onboard on heavy light -duty trucks (2004-2006).
For refiners and importers, EPA requires a maximum level of sulfur in gasoline of 300
2004
ppm, and an average of 120 ppm.
For refiners, EPA requires an average level of sulfur in gasoline of 30 ppm. For
2005
importers, the average requirement is 90 ppm, and the maximum is 300 ppm.
2005 California requires a maximum level of sulfur in RFG of 30 ppm.
2006 Phase-in of California's LEV II program complete.
For refiners, EPA requires a maximum level of sulfur in gasoline of 80 ppm. For
2006
importers, the average is set at 150 ppm.
2007 Planned finalization of additional EPA rule on mobile source air toxics.
Importers must meet the 30 ppm average and 80 ppm maximum sulfur content in
2007
gasoline.
2010 Federal Tier 2 tailpipe emissions standard phase-in complete.
This list also includes regulatory actions that reduce sulfur in gasoline. Lower sulfur content increases catalytic converter
efficiency, thus decreasing hydrocarbon emissions. Therefore, the new sulfur regulations have also been included in the table.
4.1.2. Clean Water Act
The Clean Water Act, originally enacted as the Federal Water Pollution Control Act
Amendments of 1972, establishes the basic structure for regulating discharges of pollutants into
the navigable waters of the United States. It prohibits any person from discharging any pollutant
from a point source into navigable waters except as in compliance with the Act's permit
requirements, effluent limitations, and other relevant provisions. The Act also grants EPA the
authority to set wastewater standards for industry and water quality standards for all
contaminants in surface waters.
Xylenes have been designated hazardous substances under the Clean Water Act. See 40
C.F.R. ?116.4. Because of this designation, certain discharges and releases are regulated.
For example, releases in excess of 100 pounds of xylenes from any facility must be reported.
See 40 C.F.R. ?117.3. Other EPA regulations permit ocean dumping of wastewater containing
xylenes, but only when xylenes are present in concentrations below their solubility in seawater.
See 40 C.F.R. ?227.7(a).
In addition, EPA has established water quality standards, which vary by body of water, for states
not complying with federal guidance for establishing their own standards under the Clean Water
Act. See 40 C.F.R. Ё 131.31?40.
4.1.3. Safe Drinking Water Act
The Safe Drinking Water Act creates a comprehensive scheme for regulating drinking water and
its sources. Under the authority of the Act, EPA sets standards for approximately 90
contaminants in drinking water and its sources -- rivers, lakes, reservoirs, springs, and ground
water wells. For each of these contaminants, EPA sets an enforceable limit, called a Maximum
Contaminant Level ("MCL"), and a non-enforceable public health goal, called a Maximum
Contaminant Level Goal ("MCLG"), which allows for a margin of safety.
Xylenes VCCEP Submission 16
EPA has set both the MCLG and the MCL for xylenes in public drinking water sources at 10.0
mg/L. See 40 C.F.R. Ё 141.50, 141.61. This is also the permissible level for xylenes in bottled
water products. 21 C.F.R. ?165.110(b)(4)(iii)(B).
In addition to MCLGs, MCLs, and other similar drinking water standards, EPA also promulgates
health advisories, or guidance values, based on non-cancer health effects for different durations
of exposure (e.g., one-day, ten-day, and lifetime). These health advisories provide technical
guidance to EPA, state and local government, and other public health officials regarding health
effects, analytical methodologies, and treatment technologies associated with drinking water
contamination. EPA has promulgated several health advisory values for xylenes. See Office of
Water, EPA, 2004 Edition of the Drinking Water Standards and Health Advisories, EPA 822-R-
04-005 (Winter 2004).
4.1.4. Resource Conservation and Recovery Act
The Resource Conservation and Recovery Act (RCRA) regulates the transportation, storage,
treatment, and disposal of hazardous wastes. Xylenes and certain substances containing
xylenes are identified on two of RCRA's three hazardous waste lists -- hazardous wastes from
nonspecific sources (40 C.F.R. ?261.31) and commercial chemical products (40 C.F.R.
?261.33). Xylenes also are on the ground water monitoring list for owners and operators of
hazardous waste facilities. See 40 C.F.R. Pt. 264 App. IX. Thus, xylenes are subject to a
variety of RCRA controls relating to xylenes' transportation, storage, treatment, and disposal.
4.1.5. Comprehensive Environmental Response, Compensation, and Liability Act
The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), as
amended by the Superfund Amendments and Reauthorization Act (SARA), provides EPA broad
authority to respond directly to releases and threatened releases of hazardous substances,
pollutants, and contaminants that may endanger public health or the environment.
Xylenes have been designated as hazardous substances under CERCLA. See 40 C.F.R.
?302.4. As a result, xylenes are subject to monitoring and numerous other requirements
relating to releases and threatened releases. For example, releases of xylenes in excess of 100
pounds from any facility must be reported. See 40 C.F.R. Part 302. In addition, certain
amounts of spent solvents containing xylenes are reportable. See id. Moreover, xylenes
present at listed Superfund sites are subject to varying levels of cleanup.
4.1.6. The Emergency Planning & Community Right-To-Know Act and The Pollution
Prevention Act
The Emergency Planning & Community Right-To-Know Act, also known as Title III of SARA,
was enacted by Congress to help inform local communities of chemical hazards in their areas.
Section 313 of EPCRA requires EPA and state governments to annually collect data on
releases and transfers of certain toxic chemicals from industrial facilities. These data are
available to the public in the Toxics Release Inventory ("TRI"). In 1990, Congress amended
these reporting requirements by passing the Pollution Prevention Act ("PPA"). Section 6607 of
Xylenes VCCEP Submission 17
the PPA requires facilities to provide information on pollution prevention and recycling for each
toxic chemical subject to reporting under TRI. See 42 U.S.C. ?13106.
Xylenes are some of the more than 650 chemicals and chemical categories subject to reporting
under TRI. See 40 C.F.R. ?372.65; EPA, 2004 Reporting Year List of TRI Chemicals. Thus,
users of xylenes in many industries, such as manufacturers, miners, petroleum bulk terminals,
and chemical wholesalers, are subject to these reporting requirements.
4.1.7. Toxic Substance Control Act
The Toxic Substances Control Act authorizes EPA to obtain information on all new and existing
chemical substances that could cause an unreasonable risk to public health or the environment
and to regulate their manufacture, use, distribution, and disposal. Under TSCA, EPA classifies
chemical substances as either "existing" chemicals or "new" chemicals. Existing chemicals are
those listed on the Toxic Substances Control Act Chemical Substance Inventory, or TSCA
Inventory, which EPA must compile, keep current, and publish. All the chemicals in the xylenes
category are on the TSCA Inventory. See TSCA ?8(b), 15 U.S.C. ?2607(b). TSCA provides
authority to EPA to regulate and seek various kinds of safety and health data on existing
chemicals, which include mandatory reporting under Section 8, 15 U.S.C. ?2607, and testing
under Section 4, 15 U.S.C. ?2603.
4.2 Consumer Product Labeling and Packaging Regulation
The Consumer Product Safety Commission (CPSC) regulates xylenes under the Federal
Hazardous Substances Act, 15 U.S.C. Ё 1261 et seq. ("FHSA"), and the Poison Prevention
Packaging Act (PPPA), 15 U.S.C.Ё 1471 et seq. ("PPPA").
The FHSA requires precautionary labeling on the immediate containers of hazardous household
products to help consumers safely store and use these products and to provide consumers
information about immediate first aid steps in the event of an accident. The FHSA also
authorizes CPSC to ban certain products that are so dangerous or where the nature of the
hazard is such that the labeling required by the FHSA is not adequate to protect consumers.
Implementing regulations require special labeling of certain products containing xylenes and
recommend that hazardous chemicals such as xylenes not be used in children's products.
Given that substances containing 10 percent or more by weight of xylenes are "hazardous,"
products containing xylenes require special labels, including "danger," "Vapor harmful," "poison,"
and "Harmful or fatal if swallowed." 16 C.F.R. ?1500.14(a), (b).
To reduce the risk of exposure to hazardous chemicals such as xylenes found in liquid-filled
children's products, CPSC requests that manufacturers eliminate the use of such chemicals in
children's products. See 16 C.F.R. ?1500.231. CPSC also recommends that importers,
distributors, and retailers that purchase children's products for resale obtain assurances from
manufacturers that the products do not contain these hazardous chemicals. See id.
The PPPA requires that certain products be packaged in child-resistant packaging to protect
children under five from possible poisoning and death in the event that they open containers of
hazardous products and eat or drink the contents. CPSC regulations impose special packaging
Xylenes VCCEP Submission 18
requirements for numerous substances, including solvents for paint or other similar surface-
coating materials that contain 10 percent or more by weight of xylenes, or combinations of
xylenes and certain other solvents, and that have a viscosity of less than 100 Saybolt universal
seconds at 100 ?F. See 16 C.F.R. ?1700.14(a)(15).
4.3 FDA Regulations
Given that FDA regulates a myriad of products ranging from food ingredients and drugs to
medical and surgical devices, only a sample of FDA's regulations relating to xylenes are
discussed below.
In general, FDA limits the amount, if any, of xylenes that may occur in food and drugs. Xylenes
are not approved food additives that may be directly added to food for human consumption.
See 21 C.F.R. Part 172. Limited amounts of xylenes, however, are permitted as indirect food
additives, for example, as a result of processing equipment or packaging.
Although there is no specified limit to the amount of xylenes that is permitted in food adhesives,
the regulations do provide guidelines to limit the amount of xylenes. These guidelines state that
the adhesive should be separated from the food by a functional barrier, or that in dry foods, the
quantity of adhesive that contacts the food shall not exceed the limits of good manufacturing
practice, and that in fatty and aqueous foods, the quantity of adhesive that contacts foods shall
not exceed the trace amount at seams and at the edge exposure between packaging laminates
that may occur within the limits of good manufacturing practice. See 21 C.F.R. ?175.105.
Similar guidance, with no specified limit, is provided for the use of xylenes in the food-contact
surfaces of packaging for processing, transporting, or holding certain foods. See, 21 C.F.R.
Ё 176.180. Xylenes are not approved for use in food packaging cellophane. See 21 C.F.R.
?177.1200.
FDA also limits the permissible amount of xylenes in bottled water. The permissible level of
xylenes in bottled water products is 10.0 mg/L. See 21 C.F.R. ?165.110(b)(4)(iii)(B).
FDA provides guidance on the amount of residual solvents that are considered safe in
pharmaceuticals. According to FDA, use of xylenes should be limited in pharmaceutical
products because of their inherent toxicity. If xylenes are used, they should be limited to a
permitted daily exposure of 21.7 mg/day or a concentration of 2,170 ppm. FDA, Guidance for
Industry, Q3C--Tables and List.
4.4 Workplace Regulations and Standards
The Occupational Safety and Health Administration (OSHA) is the primary federal agency
responsible for establishing and enforcing workplace standards, including exposure limits for
many substances. The National Institute for Occupational Safety and Health ("NIOSH") and the
American Conference of Governmental Industrial Hygienists ("ACGIH") also develop and
recommend exposure limits for worker protection, though these limits are not enforceable.
OSHA sets both permissible exposure limits ("PELs") and short-term exposure limits ("STELs").
A PEL is the maximum average concentration to which workers may be exposed in any 8-hour
work shift of a 40-hour work week, and a STEL is the maximum 15-minute concentration to
which workers may be exposed during any 15-minute period of the workday. For xylenes,
Xylenes VCCEP Submission 19
OSHA has set the PEL at 100 ppm (435 mg/m 3) as an 8-hour time-weighted average ("TWA")
concentration and 150 ppm (655 mg/m 3) as a 15-minute STEL. See 29 C.F.R. ?1910.1000,
Table Z-1.
The NIOSH recommended exposure limits ("RELs") for xylenes are 100 ppm (435 mg/m 3) as a
TWA for up to a 10-hour workshift and a 40-hour workweek and 150 ppm (655 mg/m 3) for 15
minutes as a short-term limit. See NIOSH Pocket Guide to Chemical Hazards.
Workplace Air Standards ?Table 4.2 is a summary of the various xylenes occupational
exposure limits.
Table 4.2: Summary of Occupational Exposure Limits
Organization OEL Description
OSHA 100 ppm 8-hr TWA, PEL (29 CFR 1910.1000)
150 ppm 15-min STEL (29 CFR 1910.1000)
NIOSH 100 ppm 10-hr TWA, REL
150 ppm 15-min STEL
900 ppm IDLH
ACGIH 100 ppm 8-hr TWA-TLV (2003)
150 ppm 15-min STEL (2003)
IDLH = Immediately dangerous to life and health
PEL = Permissible exposure limit
REL = Recommended Exposure Limit
STEL = Short Term Exposure Limit
TWA = Time weighted average
TLV = Threshold Limit Value
These exposure limits apply to the individual isomers of xylenes, mixed xylenes, or any
combination thereof. OSHA has set workplace air standards for general industry and
construction. Only the OSHA PEL is a legally enforceable exposure limit. The permissible
exposure limit (PEL) for xylenes is an 8-hour time-weighted average of 100 ppm (435 mg/m 3).
4.5 HUD Regulation
The Department of Housing and Urban Development attempts to minimize exposure to xylenes
through regulations relating to the location of HUD-assisted projects. These regulations help
calculate the acceptable separation distance between HUD-assisted projects and hazardous
operations that store, handle, or process hazardous substances and provide guidance for
identifying and assessing these hazardous operations. Xylenes are hazardous substances
addressed by these regulations. See 24 C.F.R. Part 51, Subpart C, App. I.
4.6 State Regulation
In addition to the Federal regulatory programs briefly described above, xylenes are subject to a
wide variety of state regulations. A description of such programs is well beyond the scope of
this regulatory overview, but in many instances, these regulatory programs are more stringent
Xylenes VCCEP Submission 20
than Federal requirements. Many Federal statutes, such as the Clean Air Act and the
Occupational Safety and Health Act, permit or, in some instances, require states to apply
additional regulatory measures. For example, California has extensive air toxics and VOC
regulations that go well beyond Federal requirements. These include specific air toxics
programs, broad regulation of xylenes as VOCs in consumer and commercial products, and
stringent mobile source (both fuels and vehicle) controls. Similar regulations have been
adopted by other states in recent years particularly those in the northeastern U.S that are part of
the Ozone Transport Commission. More recently, several localities have enacted local air
toxics programs that provide further controls on releases of xylenes to the environment.
Xylenes VCCEP Submission 21
5 CHEMICAL OVERVIEW
This section presents a summary of data on the commercial extraction, production, and uses of
xylenes (chain of commerce). The section also presents information on the release to the
environment from these processes, and other commercial p rocesses (formation during the
process of incomplete combustion) and from sources outside of the chain of commerce
(biomass burning). A detailed description of the various chain of commerce sources of xylenes
can be found in Chemical Economic Handbook ?Xylenes (CEH, 2005). Detailed sector
notebooks are also available for several industries that use xylenes (e.g., the organic chemical
industry, petroleum refining industry, or printing industry) from the EPA Office of Compliance
(EPA, 1995a, 1995b, 2002a).
For the facilities that reported year 2003 Toxic Release Inventory (TRI) data, on-site air
emissions accounted for 97% of total facility emissions of o-, m- and p-xylene isomers. Since
the vast majority of xylenes released to the environment partition to the air (ATSDR, 1995a), this
section focuses primarily on air releases of xylenes to the air. Releases to water and soil are
discussed briefly at the end of this section.
5.1 Commercial Xylenes Production and Demand
Mixed xylenes are produced by the petroleum industry and to an appreciably lesser degree, by
the steel industry as a byproduct of coke production (Table 5.1). The major chemical processes
used in xylene production include catalytic reforming (dehydrogenation of straight-run light
naphtha in presence of hydrogen), toluene disproportionation (catalytic conversion of toluene to
equal volumes of benzene and xylenes), hydrotreating (subjecting liquid hydrocarbon stream to
hydrogen with a catalyst at an elevated temperature and pressure), distillation (chemical
separation from crude or light oils based on boiling points), and destructive distillation
(separation at high temperature in the absence of oxygen).
Table 5.1: Industrial Sources of Commercial Mixed Xylenes
Percentage of 2003 U.S.
Xylenes production
Industry Process Inputs (CEH, 2005)
Petrochemical Catalytic reforming Hydrotreated light naphthas 82%
(e.g., methylcyclohexane)
Petrochemical Toluene Toluene 17%
disproportionation
Petrochemical Hydrotreating / Pyrolysis gasoline (unsaturated <1
distillation aliphatic hydrocarbons
produced by steam cracking of
gas oil or heavy naphtha)
Steel Destructive distillation Coal <1
Xylenes VCCEP Submission 22
Some limited data on historical xylenes production or demand levels are available from trade
publications or the EPA. Aggregate production volume data is available under the EPA's
inventory update rule (IUR) every four years ( http://www.epa.gov/oppt/iur/ ). However, to
protect confidential business information (CBI), the production volumes are reported in broad
ranges. The IUR database provides 2002 production volumes for mixed xylenes (> 1 billion
pounds), m-xylene (>100 million ?500 million) o-xylene (> 500 million ?1 billion pounds), and p-
xylene (> 1 billion pounds).
CEH (2005) reports both consumption and production capacity data for xylenes. The demand
for mixed xylenes has increased steadily from 2 million metric tons in 1970 to 6.5 million tons in
2004. During this time period, demand for o-xylene has remained fairly constant ranging from
300,000 to 500,000 metric tons per year. Demand for m-xylene has steadily increased from
approximately 30,000 to 225,000 metric tons and p-xylene demand has risen from 865,000
metric tons to more than 5 million metric tons. These demand data include exports, which are
significant for the xylene isomers particularly p-xylene which in 2003 had total U.S. exports of
almost 2 million metric tons.
When consumption rates are compared to facility air releases, it can be seen that even as
consumption of all xylenes has increased, the releases show a steady decline. Table 5.2 shows
the total TRI air releases for mixed xylene and the three isomers from reporting year 1988 to
2003. During this time period, reported air releases of mixed xylene and individual isomers
decreased by more than 70%.
Table 5.2: Annual U.S. Consumption versus Total TRI Air Emissions
for Commercial Xylenes
Consumption Total TRI Air Emissions
b c
(thousand metric tons) (million lbs)
Year
mixed o- m- p- mixed o- m- p-
xylenes xylene xylene xylene xylenes Xylene xylene xylene
1988 4,048 508 NA 2,248 166 2.5 2.2 6.0
1989 3,894 435 NA 2,116 165 1.5 2.0 5.1
2,041
1990 3,763 377 NA 146 1.6 2.2 4.7
1991 3,897 360 NA 2,190 126 1.5 1.8 5.3
1992 4,144 365 NA 2,245 117 1.5 2.2 4.1
1993 4,170 318 NA 2,236 116 1.9 2.0 4.4
1994 4,308 354 NA 2,424 113 1.2 1.4 3.4
1995 4,433 444 NA 2,487 99 1.2 1.4 2.9
1996 4,311 416 NA 2,514 86 1.3 1.3 2.8
1997 5,272 461 NA 2,866 78 1.2 1.5 2.5
1998 5,204 469 NA 2,881 73 1.2 1.3 1.8
1999 5,838 500 93 2,937 71 0.98 0.90 1.7
2000 5,769 457 107 2,843 61 0.62 0.74 1.3
2001 5,197 415 100 2,683 49 0.54 0.77 1.3
2002 5,741 424 93 2,833 44 0.46 0.74 1.2
2003 6,316 423 91 2,810 40 0.56 0.66 1.3
2004 6,562 432 94 2,909 NA NA NA NA
a
NA indicates that data was not available.
b
Data from CEH, 2005.
c
Original TRI industries (primarily SIC Codes 20-39).
Xylenes VCCEP Submission 23
In addition to total industry capacity and production rates, CEH (2005) provides information on
xylenes production capacity by petroleum producer parent company (Table 5.3). In general, the
production rate is about 60-80% of the total capacity. Most of the xylene production capacity is
found in Texas (12 facilities) and Louisiana (2 facilities). In 2004, there were 21 facilities that
produced mixed xylenes, 4 facilities that produced o-xylene, 2 facilities that produced m-xylene,
and 9 facilities that produced p-xylene.
Table 5.3: U.S. Xylenes Production Capacity (2004)
2004 Capacity
(thousand metric tons)
a
Company and Plant Location
o- m- p-
Mixed xylenes xylene xylene xylene
Total Petrochemicals USA, Inc.
Port Arthur, TX 388 -- -- --
BP
Decatur, AL -- -- -- 1,098
Texas City, TX 1,005 -- 218 1,222
Whiting, IN 787 -- -- --
Chevron Phillips
Guayama, PR -- -- -- 330
Pascagoula, MS 410 -- -- 454
Citgo Petroleum
Corpus Christi, TX 246 -- -- --
ConocoPhillips
Alliance, LA 196 -- -- --
Sweeny, TX 476 -- -- --
ExxonMobil Chemical
Baytown, TX 776 127 -- 597
Beaumont, TX 320 -- -- 275
Chalmette, LA 229 68 -- 190
Flint Hills Resources
Corpus Christi, TX 961 185 50 600
Hovensa
St. Croix, VI 378 -- -- --
Lyondell-Citgo Refining
Houston, TX 347 123 -- 181
Marathon Ashland
Catlettsburgh, KY 83 -- -- --
Texas City, TX 33 -- -- --
Shell
Deer Park, TX 161 -- -- --
Sunoco
Marcus Hook, PA 85 -- -- --
Toledo, OH 171 -- -- --
Westville, NJ 200 -- -- --
Valero Energy
Corpus Christi, TX 523 -- -- --
Three Rivers, TX 164 -- -- --
Total Capacity (2004) 7,939 503 268 4,947
Total Export (2004) 854 117 139 1,500
a
Idle plant locations are not included.
Xylenes VCCEP Submission 24
5.2 Commercial Xylenes Uses
The majority of commercial mixed xylenes are used in the production of the o-, m-, and p-xylene
isomers which account for most of the consumption. The U.S. consumption of mixed xylenes is
shown graphically in Figure 5.1. The isomers are used as an intermediate feedstock in the
production of fibers, plastics, coatings, and inks. Some of the mixed xylenes produced are
added to products such as paints and coatings formulations as a solvent. A smaller portion of
the mixed xylenes produced annually are added to gasoline to improve octane ratings.
Figure 5.1
2004 U.S. Consumption of Mixed Xylenes
Gasoline/Inventory
2%
o-Xylene
Solvents/Other 8%
m-Xylene
4%
3%
p-Xylene
83%
Source: Chemical Economics Handbook, 2005
The chemicals and derived products for which xylene is a building block are summarized in
Table 5.4 (ATSDR, 1995a; CMR, 2002; EPA, 1994; Flint Hill Resources, 2003, CEH, 2005).
Xylenes VCCEP Submission 25
Table 5.4: Major Uses of Xylenes Isolated from Petroleum Products and Coal
End Use or
Chemical
Description of End Use or Typical Use for Derived Chemical
Produced from
Mixed Xylene
Intermediate for dimethyl terephthalate and terephthalic acid
(DMT/TPA), which are used in the production of polyethylene
p-xylene
terephthalate (PET). PET is used to manufacture polyester fibers,
molded plastic, films and beverage bottles.
Used in manufacture of phthalic anhydride, that is used as
o-xylene
plasticizer in PVC pipes or coatings, or in the manufacture of resins.
Intermediate for isophthalic acid, which is used in manufacture of
m-xylene
polyesters for coatings, inks or reinforced plastics.
Used as a solvent in some consumer and commercial products
Solvent uses such as adhesives, spray paints, carburetor cleaner or engine
cleaner.
Gasoline blending
Added to gasoline to improve octane ratings.
or other uses
5.3 Production and Uses of Refined Petroleum Products
Xylenes are frequently constituents in petroleum products, particularly gasoline. Unleaded
automobile gasoline generally has a total xylenes content of about 6.6% by weight (ATSDR,
1995b). Xylenes are also found in the aromatic fraction of commercial and military jet fuel and
distillate fuel oil (e.g. diesel fuel) (ATSDR, 1995c, 1998). In addition to the xylenes that are
naturally present in petroleum streams, a small portion of mixed xylenes may also blended into
automobile gasoline to increase the octane rating (See Table 5.4). Aromatic hydrocarbons such
as xylenes contribute to the anti-knock properties (prevention of engine pinging or rattling due to
secondary detonations) of unleaded automobile gasoline. Table 5.5 summarizes petroleum
based fuel production and consumption volumes (DOE, 2000).
Xylenes VCCEP Submission 26
Table 5.5: U.S. Petroleum-Based Fuel Production and Consumption
U.S. Production or Consumption Rate, 1999
(million gallons per day) a
Economic Activity
Motor Distillate
Jet Fuel Kerosene
Gasoline fuel oil
Consumption
354 70 3.1 143
(demand)
Production (supply) 341 66 2.8 150
Net import to U.S.
13 5 0.3 7.3
to meet demand
a
Consumption and production volumes based on assumption of 42 gallons per barrel.
5.4 Releases of Xylenes to Ambient Air
Xylenes are released to the air during a number of processes including xylenes production,
xylenes use, combustion of fuel, biomass combustion (mobile and non-mobile sources), and
miscellaneous processes such as disposal of municipal solid waste. Each of the various
sources of xylenes emissions to air is described in detail by the EPA (1994). Table 5.6 lists
various emission sources of xylenes and the section number where more information can be
found in this EPA reference. The emissions from most of these identified sources are regulated
and limited by the federal government. Environmental regulations governing the xylenes
production industry are further discussed in Section 4.
Xylenes VCCEP Submission 27
Table 5.6: Summary of Sources of Xylenes to Ambient Air
Type of Activity Process or Source Section of EPA (1994)
Releases from
Hydrotreating (pyrolysis or straight run Section 4.1.1: Hydrotreating
mixed xylenes
gasoline)
production
Catalytic reforming (straight run Section 4.1.2: Catalytic reforming
gasoline)
Section 4.1.3: Secondary hydrogenation (for
Secondary hydrogenation (pyrolysis
pyrolysis gasoline)
gasoline)
Section 4.1.4: Xylenes production from
Toluene disproportionation toluene disproportionation or transalkylation
Section 4.1.5: Coal-derived mixed xylenes
Destructive distillation (coke oven)
Releases from
para-xylene Section 4.2.1: Para-xylene production
xylene isomer
production
Releases from
xylene isomer ortho-xylene Section 4.2.2: ortho-xylene production
production
(continued)
meta-xylene Section 4.2.3: meta-xylene production
ethylbenzene (byproduct of isomer
Section 4.2.4: ethylbenzene production
production from mixed xylene)
Releases from
Phthalic anhydride (PA) production Section 5.1: Phthalic anhydride production
xylenes use
Terephthalic acid (TPA) production Section 5.2: Terephthalic acid production
Maleic anhydride (MA) production Section 5.3: Maleic anhydride production
Paint and ink manufacturing Section 5.4: Paint and ink manufacturing
Releases from
use of xylene-
Application of surface coatings (e.g.
containing Section 6.1: Surface coating operations
paint, varnish, lacquer or primer)
products or
materials
Operation of printing presses (e.g.
Section 6.2: Printing and publishing
gravure printing)
Releases from Section 6.3 Gasoline and automotive
On-road and off-road sources
mobile sources emissions
Releases from Section 7.2: Hazardous and solid waste
Waste incineration
combustion incineration
sources
Coal combustion Section 7.1: Coal combustion
Storage and distribution of gasoline
Other activities Section 6.4: Gasoline marketing
(marine vessel loading, bulk gasoline
plants, terminals and service stations)
Section 7.3: Wastewater treatment
Wastewater treatment
processes
The EPA Office of Air Quality Planning and Standards (OAQPS) collects emissions inventory
data for hazardous air pollutants (HAP) pursuant to the 1990 amendments to the Clean Air Act.
The most recent emissions inventory available in final form is the September 21, 2001 revision
Xylenes VCCEP Submission 28
to the 1996 National Toxics Inventory (NTI). The NTI emissions estimates are based on the
following sources of data:
? State and local air pollution control agency HAP inventories;
? OAQPS Maximum Achievable Control Technology (MACT) databases;
? Toxic Release Inventory (TRI) data;
? Mobile source estimates from the EPA's Office of Mobile Sources; and
? Area source emission estimates using emissions factors and activity data.
Emission quantities for four general source categories are provided for the chemicals in the NTI
database, including:
? Major sources (stationary facilities with potential to emit 10 tons of any one toxic air
pollutant or 25 tons of more than one pollutant);
? Area and other sources (such as biomass burning including wildfires and agricultural
burning, as well as small facilities such as dry cleaners with emissions less than that of
major sources);
? On-road mobile sources (vehicles that travel on roads and highways such as cars,
trucks, and buses); and
? Non-road mobile sources (mobile sources that are not found on roads such as lawn
mowers, snowmobiles, and heavy construction vehicles).
Figure 5.2 shows the relative contribution of the various sources to the total xylenes emissions
on a nationwide basis based on the NTI 1996 database (EPA, 2000a). It should be noted that
the contribution from biomass and other area sources is greater in rural areas, as there is less
of a contribution from motor vehicles and more likely to be biomass burning.
Figure 5.2:
Relative Contribution of Various Total o-, m-, p-Xylene
Emission Sources to Xylenes Emissions
Major
source
emissions
Non-road 9%
emissions Biomass &
22%
other area
emissions
17%
On-road
emissions
52%
Xylenes VCCEP Submission 29
5.5 Releases of Xylenes to Soil and Water
Xylenes can be released to surface water by discharges of industrial or municipal wastewater
that contain xylenes o accidental spills during transfer of petroleum or chemical products
r
(ATSDR, 1995a). Sources of xylenes in groundwater include leaks of gasoline underground
storage tanks, accidental spills and leachate from landfills (ATSDR, 1995a). Xylenes are also
disposed in on-site industrial underground injection wells as part of the EPA Underground
Injection Control (UIC) Program, which is regulated under the Safe Drinking Water Act. Under
this program, liquids are pumped into deep, confined, and isolated formations that are located
beneath potable water supplies. EPA's Underground Injection Control Program regulates the
location, construction, operation, and enclosure of injection wells to insure that underground
drinking water supplies are protected. Xylenes can be released to soils as a result of land
disposal of xylenes-containing wastes or from gasoline as a result of a leaking underground
storage tank (ATSDR, 1995a). The amount of xylenes released to soil is negligible (less than
0.3% of total environmental releases) (ATSDR, 1995a).
The 2001 TRI estimates for xylenes releases are summarized below in Table 5.7. Facilities that
are subject to TRI reporting are those with ten or more full-time employees (or the equivalent in
man-hours), those that exceed any one threshold for manufacturing (including importing),
processing, or otherwise using a toxic chemical listed in 40 CFR Section 372.65, and that fall
under the covered SIC codes below:
? Manufacturing (SIC codes 20 through 39);
? Metal mining (SIC code 10, except for SIC codes 1011, 1081, and 1094);
? Coal mining (SIC code 12, except for 1241 and extraction activities);
? Electrical utilities that combust coal and/or oil for the purpose of generating electricity for
distribution into commerce (SIC codes 4911, 4931, and 4939);
? Resource Conservation and Recovery Act (RCRA) Subtitle C hazardous waste
treatment and disposal facilities (SIC code 4953);
? Chemicals and allied products wholesale distributors (SIC code 5169);
? Petroleum bulk plants and terminals (SIC code 5171);
? Solvent recovery services (SIC code 7389 limited to facilities primarily engaged in
solvent recovery services on a contract basis); and
? Federal facilities that meet the thresholds also must report by Executive Order.
Emissions from facilities that are not required to submit reports (i.e., those with few employees
or chemical usage/production rates below regulatory threshold) are not expected to have a
major impact on the overall evaluation because they would represent minor xylenes sources.
Xylenes VCCEP Submission 30
Table 5.7
Xylenes Releases for All Industries Reporting TRI data for 2003
Release Amount Percent of Total Release
(million pounds/year)
o-,m-
o-,m- and p-
o-xylene m-xylene o-xylene m-xylene p-xylene
and p-
Type of Release p- xylene xylene
only only xylene only only only
mixture only
mixture
Total air emissions 37.7 0.66 0.56 1.3 95% 97% 97% 98%
Surface water discharges 0.014 0.000064 0.000036 0.0035 0.04% 0.01% 0.01% 0.3%
Underground injections 0.11 0.012 0.014 0.014 0.3% 1.8% 2.4% 1.1%
Releases to land 1.1 0.000036 0.000008 0.00032 2.8% 0.01% 0.01% 0.2%
Transfer to disposal 0.75 0.0033 0.0043 0.0033 1.9% 0.5% 0.7% 0.3%
Total 39.7 0.68 0.58 1.32 100% 100% 100% 100%
Xylenes VCCEP Submission 31
6 Hazard Assessment
6.1 Xylenes Hazard Assessment Summary
This hazard assessment addresses the available xylenes mammalian toxicology data on the
VCCEP endpoints and includes a review of the human health studies on xylenes. Studies are
presented for mixed xylenes [CAS #1330-20-7] and for the three xylene isomers: meta-(m-
xylene, CAS #108-38-3), ortho- (o-xylene, CAS #95-47-6) and para- (p-xylene, CAS #106-42-3).
Results used for hazard assessment from animal studies and from human experience are
summarized below in Sections 6.1.1 and 6.1.2. Table 6.1 lists key toxicology data by endpoint
for the VCCEP tiers. Sections 6.2 through 6.12 address the mammalian toxicology and Section
6.13 reviews the human studies.
6.1.1 Summary of Animal Studies
Acute Toxicity (Tier 1): Mixed xylenes and xylene isomers induce minimal oral (rats and mice),
dermal (rabbits), intraperitoneal (rats and mice), or inhalation (rat and mice) acute toxicity.
Mixed xylenes, m- and p-xylene are moderate to marked dermal irritants and induce mild to
moderate eye irritation in rabbits.
Repeat Dose Studies (Tier 1 and 2): The predominant effects of repeat exposures to xylenes
administered by inhalation or orally were mild hepatic alterations that were considered adaptive
responses to hydrocarbon exposure. NOAELs and LOAELs were determined primarily on
decreases in body weight and increased liver weight and liver enzyme changes. Inhalation
studies performed by different investigators and single dose levels over durations of exposure of
6 weeks to 6 months demonstrated NOAELs in the range of 800-1000 ppm. Oral administration
of mixed xylenes for 13 weeks (5 days/week) to rats or mice resulted in LOAELs of 1000
mg/kg/day for rats and 2000 for mice (NTP, 1986). Treatment of rats for 90 consecutive days
with mixed xylenes (Condie et al., 1988), m- or p-xylene (Wolfe, 1988) demonstrated decreased
body weights at doses of 750-800 mg/kg/day.
Meta-, para- or ortho-isomers produced similar activity for general toxicity in rats at comparable
doses (Condie et al., 1988), required similar alveolar concentrations to induce anesthesia (Fang
et al., 1996), and demonstrated similar minimal dose to induce narcosis (Moln醨 et al., 1986),
although lower doses showed somewhat different effects on motor activity between isomers.
Moser et al. (1985) showed operant response and motor performance in mice was similar for all
three isomers while Korsak et al. (1990) reported that o-xylene altered motor performance by
rats on the rotarod more severely than m- or p-xylene.
Genetic Toxicity (Tier 1 and 2): Xylenes do not induce gene mutation or DNA damage in
bacteria, or gene mutation or cytogenetic damage to mammalian cells in culture. No
chromosome aberrations or increased incidence of sister chromatid exchanges were seen in
animal or human subjects. Xylenes are not genotoxic.
Reproductive and Developmental Toxicity (Tiers 1 and 2): Reproduction parameters in rats
were not adversely affected by exposure to mixed xylenes in a 1-generation study at
concentrations up to 500 ppm (API, 1983) nor in two dominant lethal studies in which male rats
and mice were treated by injection and mated with untreated females, weekly throughout the
spermatogenic cycle (API 1973). Nyl閚 et al. (1989) did not observe effects on testes,
Xylenes VCCEP Submission 32
accessory sex glands, or circulating male hormones of rats exposed to 1000 ppm mixed xylenes
for 61 days. Extremely high anesthetizing doses of xylene, administered daily for 7 days did
affect testes weight, testosterone levels, and spermatozoa counts in Wistar rats (Yamada,
1993).
A number of studies have examined standard developmental toxicity endpoints in offspring of
animals exposed to xylenes. Developmental effects in offspring of pregnant animals exposed to
xylenes have been observed although generally at dose levels high enough to induce maternal
stress and toxicity. Saillenfait et al. (2003) conducted the most comprehensive developmental
studies of xylenes in rats, evaluating o-, m-, p-xylene, and mixed xylenes under the same
laboratory conditions at concentrations of 0, 100, 500, 1000, or 2000 ppm, 6 hr/day during GD
6-20, in accordance with OECD protocol 414 (2001) and EPA OPPTS 870.3700 (1998) testing
guideline. All materials caused maternal toxicity (reduction in maternal body weight gain) at
1000 and 2000 ppm. Decreased corrected weight gain (without gravid uterus) and food
consumption were observed at 1000 and 2000 ppm o-, m-, and p-xylene and at 2000 ppm of
mixed xylenes. No fetal malformations were induced by any test material. Decreased fetal
body weight occurred at the maternally toxic doses of 1000 and 2000 ppm for all materials, and
also at 500 ppm and greater for o-xylene and mixed xylenes. Significant increase in mean
percent fetuses with skeletal variations of all types/litter was seen at 2000 ppm concentrations
of o- and p-xylene. No single skeletal variation occurred at an incidence significantly higher
than that in controls.
Immunotoxicity (Tier 2): Xylenes do not appear to affect the immune system in animals and
limited human data does not demonstrate diminished immunological reactivity. Mice exposed
by inhalation to para-xylene at concentrations up to 1200 ppm did not exhibit adverse effects on
natural killer (NK) cells (Selgrade et al., 1993). Repeated oral exposure to meta-, para-, or
ortho-isomers for 10 days at oral doses up to 2000 mg/kg/day increased liver weight but slight
decreases in thymus or spleen weight were only seen with p-xylene exposure (Condie et al.,
1988). Mixed xylenes did not induce any organ weight changes.
Metabolism (Tier 2): Xylenes are rapidly absorbed by the respiratory tract with uptake
increased by physical exercise. Absorption is also positively correlated with the amount of body
fat. Liquid m-xylene is well absorbed through the skin, but m-xylene vapor (up to 600 ppm)
does not appear to be appreciably dermally absorbed. Xylenes are highly soluble in blood and
are taken up primarily in lipid-rich tissues (e.g., fat, brain) and in organs highly perfused with
blood (e.g., liver, kidney). Small amounts of p-xylene and o-xylene have been reported to cross
the placenta and distribute in amnionic fluid and fetal tissue (Ghantous and Danielsson, 1986;
Ungv醨y et al., 1980b). Xylenes undergo extensive metabolism, primarily side-chain oxidation
and conjugation with glycine and glucuronic acid for m- and p-xylenes (Sugihara and Ogata,
1978; Ogata et al., 1980; Elovaara et al., 1984) and by glucuronide formation with a small
amount of sulfate conjugates for o-xylene (Ogata et al., 1980).
Metabolites are primarily excreted in urine with small amounts of xylenes released unchanged in
expired air. About 90% of the absorbed dose is excreted in the urine as methylhippuric acid, the
glycine conjugate of methylbenzoic acid, following inhalation or dermal (liquid) exposure.
Adult Neurotoxicity and Auditory Effects (Tier 3): Exposure to mixed xylenes and its isomers by
the oral or inhalation routes can result in nervous system effects such as tremors,
incoordination, muscle spasms, respiratory distress, hearing loss or elevated auditory
Xylenes VCCEP Submission 33
thresholds, lethargy, hyperactivity, and changes in brain enzyme activity and levels of brain
protein.
Korsak et al. (1994) demonstrated that exposure to m-xylene for 3 months decreased rotarod
performance at 100 ppm in trained male rats beginning after 1 month of exposure and
continuing at the same level throughout the exposure period without altering body weight, organ
weight or clinical chemistry parameters; no effect was observed at 50 ppm m-xylene. Korsak et
al. (1992) previously reported the same decreased rotarod performance at 100 ppm in trained
male rats following 6 months of exposure.
Auditory impairment in rats induced by xylenes exposure at high inhalation concentrations (800-
1800 ppm) over durations of 5 days to 6 weeks have been reported (Pryor et al., 1987; Nyl閚
and Hagman, 1994; Crofton et al., 1994). Pryor et al. (1987) also noted that some hearing loss
measured by the conditioned avoidance test occurred in rats exposed to 1450 ppm xylenes for
8 hours but exposure of 1700 ppm for 4 hours did not induce ototoxic effects, indicating that the
duration of exposure as well as xylenes concentration is important in assessing auditory
impairment.
Neurobehavioral effects are considered critical endpoints to assess xylenes toxicity and assays
for these effects are used by regulatory agencies to set acceptable levels for human exposure.
The work of Korsak et al. (1994) with m-xylene was used to establish the EPA, 2003A RfC and
to derive the chronic inhalation health benchmark of 0.66 mg/m 3 in the VCCEP Risk
Assessment (see Section 8.1).
Developmental Neurotoxicity (Tier 3): There are several studies that have assessed
developmental neurotoxicity in xylenes. The available studies have some limitations, including
the absence of dose response data, lack of definitive NOAEL levels, and variability of the results
of the various test batteries. However, the study by Hass et. al. (1995, 1997), while only a single
dose level of 500 ppm, was a well-conducted sophisticated evaluation of the postnatal
development and behavior of rats exposed prenatally to mixed xylenes. There were some slight
effects of on learning and memory performance based on Morris water maze in female offspring
that were not seen significantly in males or in females with various toys in their cages. In a study
on p-xylene in rats, there were no neurobehavioral effects in the offspring of dams exposed to
800 and 1600 ppm prenatally (Rosen 1986). EPA concluded in the xylenes IRIS database that
the LOAEL for developmental neurobehavioral effects is 500 ppm, based primarily on the Hass
1995 study, and that the developing organism is not more sensitive than the adult to xylenes
exposure (EPA 2003a).
Chronic Toxicity and Carcinogenesis (Tier 3): Chronic oral toxicity/carcinogenicity studies have
been performed in rats and mice. Studies of 103 weeks duration completed by National
Toxicology Program (NTP 1986) did not result in significant toxicological changes beyond
increased levels of hyperactivity after dosing in high dose rats and mice and slightly lower body
weight in high dose male rats exposed to 500 mg/kg mixed xylenes (top dose). Increased
mortality in rats at the 500 mg/kg dose was attributed to dosing errors but still was used as the
basis for the establishing a tentative LOAEL of 500 mg/kg and a NOAEL of 250 mg/kg. In mice,
the LOAEL was set at the maximum dose of 1000 mg/kg and the NOAEL was 500 mg/kg.
Xylenes VCCEP Submission 34
6.1.2 Human Experience Summary
Effects of xylenes in humans have been noted in a variety of studies, including controlled
experiments with volunteers for acute or limited duration exposures, very high accidental or
abusive exposures, and from occupational studies in which exposures frequently have been to
mixtures of compounds rather than to just xylenes. Occupational studies have confounders in
addition to co-exposure with other materials, such as smoking, alcohol use, and other lifestyle
factors.
Acute poisoning and mortality in humans have occurred after very high exposure to xylenes.
Loss of consciousness occurs at approximately 10,000 ppm (Morely et al., 1970). Individuals
recovering from severe overexposure exhibit EEG alterations, confusion, coma, nystagmus,
gastrointestinal effects, and impaired renal and hepatic function (Ghislandi and Fabiani, 1957;
Recchia et al., 1985). Respiratory irritation and eye and throat irritation are induced by
exposure to concentrations of 400-600 ppm xylene for 15-30 minutes (Hastings 1986).
Controlled human studies demonstrate that 4-hour exposure to xylenes at approximately 200
ppm can cause impairment of sensory motor and information processing in the CNS
(Savolainen 1979, 1981, 1982, 1985 and Sepp鋖鋓nen 1991), though these effects were
reversible upon termination of exposure. Some evidence of effects on reaction times in humans
was also observed above 100 ppm, though the results were varied. A study at 103.5 ppm for 4
hours showed prolonged reaction time (Dudek, 1990) while similar studies at higher levels ?138
ppm for 4 hours ?showed no effect on reaction time (Savolainen 1980, 1981). No effects were
observed were below 100 ppm.
High-level exposure to xylenes or solvents containing xylenes can induce a variety of
neurological symptoms in humans ranging from dizziness, headache, nausea, difficulty in
concentrating, to slurred speech, ataxia, tremors at higher acute exposures, and in isolated
instances, unconsciousness, amnesia, and epileptic seizures (ATSDR, 1995).
Xylenes do not appear to induce genetic toxicity in humans exposed occupationally or under
controlled laboratory conditions. No differences in frequency of sister chromatid exchange
(SCE), micronuclei, or chromosome aberrations were reported in worker monitoring studies
(Haglund et al., 1980; Zhong et al., 1980; Pap and Varga, 1987), or in a study of service station
attendants exposed to mixed solvents (Pitarque et al., 1997a, b). Richer et al. (1993) performed
a controlled study with male volunteers exposed to xylenes daily for 3 days, repeated 3 times at
2 week intervals and did not identify any significant effects on sister chromatid exchange (SCE),
cell cycle delay, or cell mortality.
No occupational or environmental studies are available to address developmental or teratogenic
effects of xylenes, in the absence of other chemical agents, and limited data are available to
address fecundity and reproductive effects. Effects on pregnancy outcome vary from no
increase in miscarriage rate (Axelsson et al., 1984) to increased spontaneous abortions among
laboratory workers also exposed to formalin and other solvents (Taskinen et al., 1994). Two
case reports suggest that congenital defects observed in the CNS of children were associated
with maternal occupational exposures to mixed xylene vapors (Holmberg and Nurminen, 1980;
Kucera, 1968). These studies had many limitations and no conclusions can be drawn about
causation.
Limited human data are available to evaluate the immunological effects of xylenes in humans.
Decreased lymphocyte counts have been reported in workers exposed to xylenes in the
Xylenes VCCEP Submission 35
presence of other solvents without systemic changes or diminished immunological reactivity
(Moszczynsky and Lisiewicz, 1983, 1984).
Metabolic profiles for xylenes are similar for humans and animals. Absorption and metabolism
have been studied in human volunteers by both inhalation and dermal routes of exposure.
Inhalation absorption occurs in 2 phases, a short phase (0-15 minutes) and a longer phase of
approximately one hour that represents a steady state between blood and inhaled xylene.
Retention does not appear to differ with gender. Dermal absorption was found to be directly
proportional to vapor concentration. After systemic absorption, xylene is largely distributed to
adipose tissue. Metabolism in humans, like animals, proceeds primarily via side-chain oxidation
to methyl benzoic acid, which is conjugated mainly with glycine to form methylhippuric acid and
excreted in the urine with small amounts released as unchanged xylene in expired air. Half-lives
for excretion of xylenes metabolites in humans are in the range a few hours to 10-20 hours.
Conclusion
From the animal and human toxicology data, xylenes can be characterized as neurotoxic
chemicals at moderate to high doses inducing symptoms in humans of dizziness, headache,
nausea, and neuromuscular effects, speech impairment, and amnesia at high doses.
Ototoxicity has been reported in animals but not in humans. Other effects of inhaled xylenes in
rodents were mild hepatic alterations consistent with adaptive response to hydrocarbon
exposure. Effects of mixed xylenes compared with effects of individual isomers indicate
similarities in type and severity of response. Absorbed xylenes are rapidly metabolized and
excreted in humans and animals with only a small percentage retained in adipose tissue.
Xylenes have not demonstrated genotoxic activity in animals or humans and do not appear to
be immunotoxic. No adverse effects on reproductive performance were seen in laboratory
studies and developmental toxicity (fetal weight decrements) occurred at doses that were
typically also produced maternal toxic. Several developmental neurotoxicity studies have
shown learning deficits in offspring of treated animals which resolved as offspring matured. No
conclusive reproductive or developmental effects have been reported in human exposure
studies. Current data indicate that xylenes are not likely to be carcinogenic to humans.
Neurobehavioral effects are considered the critical endpoint to assess xylene toxicity and
assays for these effects are used by regulatory agencies to set acceptable levels for human
exposure. The work of Korsak et al. (1994) with m-xylene was used to establish the EPA,
2003A RfC and to derive the chronic inhalation health benchmark in the Risk Assessment (see
Section 8.1).
Xylenes VCCEP Submission 36
Table 6.1. Xylenes Hazard Assessment: Key Studies for VCCEP Endpoints
Endpoint Study Result Reference
TIER 1
Acute Toxicity
Inhalation Hine and Zuidema,
Rat-4hr (mixed LC50 = 6350 ppm
1970
xylenes)
Carpenter et al.,
Rat-4hr (mixed 1975
LC50 = 6700 ppm
xylenes)
Mice- female- 6hr
Bonnet et al., 1979
m-xylene 5267 ppm
o-xylene 4595 ppm
p-xylene 3907 ppm
Rat- male- 6hr
Bonnet et al., 1979
m-xylene 5984 ppm
o-xylene 4330 ppm
p-xylene 4591 ppm
Oral
Hine and Zuidema,
Rat (mixed xylenes) LD50 = 8640 mg/kg
1970
Smyth et al., 1962
Rat (m- xylenes) LD50 = 6661 mg/kg
Rat
Ungv醨y et al.,
m-xylene 5010 mg/kg
1979
o-xylene 3580 mg/kg
p-xylene 4020 mg/kg
mixed xylenes 5830 mg/kg
Dermal
Hine and Zuidema,
Rabbit (mixed >4.3g/kg
1970
xylenes)
Smyth et al., 1962
Rabbit (m-xylene) 12.1g/kg
Repeat Dose Screening Studies: Superceded by definitive subchronic, reproductive and
developmental studies
Genetic Toxicity
Bacterial Reverse Ames Assay Negative +/- S9 Bos et al., 1981
Mutation m-xylene
o-xylene
p-xylene
Negative
Human lymphocytes Richer et al., 1993
In Vitro cytogenetics
TIER 2
Subchronic Toxicity Rat/ Oral: 13 weeks Wolfe, 1988
m-xylene NOAEL[M] = 100 mg/kg
NOAEL[F] = 200 mg/kg
p-xylene NOAEL [M&F] = 200
mg/kg
Rat/Mouse ?Oral 13 NOAEL rats = 500 mg/kg NTP, 1986
wks; mixed xylenes NOAEL mice = 1000
mg/kg
Xylenes VCCEP Submission 37
Endpoint Study Result Reference
TIER 2 (CONT .)
Developmental toxicity Rat/ Inhalation Saillenfait et al.,
2003
m-xylene NOAEL = 500 ppm
o-xylene NOAEL = 500 ppm
p-xylene NOAEL = 100 ppm
NOAEL = 100 ppm
Mixed xylenes
Reproductive and Fertility Rat: 1generation, NOAEL F1 = 500 ppm API, 1983
Inhalation
Immunotoxicity Rat/Oral Condie et al., 1988
m-xylene NOAEL = 1000 mg/kg
o-xylene NOAEL = 1000 mg/kg
p-xylene NOAEL = 1000 mg/kg
NOAEL = 1500 mg/kg
Mixed xylenes
Micronucleus 璏ice
In vivo Cytogenetics Mohtashamipur et
Intraparitoneal Negative al., 1985
m-xylene NOAEL = 650 mg/kg
o-xylene NOAEL = 440 mg/kg
p-xylene NOAEL = 650 mg/kg
Richer et al., 1993
SCE - humans Negative
Mixed xylenes [3day NOAEL =40 ppm
inhalation, 3 times
over 2 wk intervals]
Metabolism/ Multiple studies EPA 2003a,
Pharmacokinetics Toxicokinetics Tardiff 1995
Ogata et al., 1980
Engstr鰉 et al.,
1984
Riihim鋕i et al.,
1979a, b
TIER 3
Rat-male: Inhalation NOAEL = 50 ppm Korsak et al., 1994
Neurotoxicity
m-xylene LOAEL = 100 ppm
NOAEL tumors Rats =
Chronic/Carcinogenesis Rat/mouse 2 year NTP, 1986
500 mg/kg
Oral (mixed xylenes)
NOAEL tumors mice =
1000 mg/kg
Developmental Rat Inhalation LOAEL = 500 ppm Hass et al. (1995,
Neurotoxicity (single dose tested) 1997)
(mixed xylenes)
Xylenes VCCEP Submission 38
6.2 Acute Toxicity (see Table 6.2)
Inhalation: Inhalation toxicity in rodents ranged from approximately 3900 ppm (p-xylene in mice, 6-
hour exposure) to 6700 ppm (mixed xylene in rats, 4-hour exposure). In an early acute study by
Cameron et al. (1938) with 24-hour exposure, Wistar rats and mice (strain unknown) were exposed
to 1531, 3062 and 6125 ppm. Although an LC50 was not calculated, results indicated no deaths at
1531 ppm, 1/10 rat and 4/10 mice died at 3062 ppm, and 8/10 rats and 9/10 mice died at 6125
ppm. In the same study, 2010 ppm m-xylene caused deaths in 6/10 mice after 24-hour exposure.
In more recent studies the inhalation LC50 for mixed xylenes in rats ranged from 5267-6700 ppm
with 6-hour exposure (Bonnet et al., 1979) or 4-hour exposure (Carpenter et al., 1975; Hine and
Zuidema, 1970). Meta-xylene LC50 in rats was 5984 ppm, and in mice 5267 ppm with 6-hour
exposure; o-xylene LC50 in rats was 4330 ppm, and in mice 4595 ppm with 6-hour exposure; and
p-xylene LC50 with 6-hour exposure in rats was 4591 ppm, in mice, 3907 ppm (Bonnet et al., 1982
[rats], 1979 [mice] respectively), or with 4-hour exposure in rats, LC50=4740 ppm (Harper et al.,
1975).
Oral: A single gavage dose of undiluted mixed xylenes to rats at graded dose up to 25 ml/kg
[21.4g/kg] resulted in an LD50 of 8640 mg/kg (Hine and Zuidema, 1970). In the 1986 NTP series
of studies on toxicity and carcinogenicity, the LD50 for mixed xylenes in oil for rats was 3523 mg/kg
and for mice, LD50 for males was 5627 mg/kg; LD50 for females was 5251 mg/kg. Meta-xylene
(undiluted) administered orally by gavage induced LD50 of 6661 mg/kg in male rats (Smyth et al.,
1962). Similar results had b een reported by Gerarde (1959) when treatment of rats with 4400
mg/kg o-xylene in oil caused death in 7 of 10 rats and treatment with p-xylene in oil at 4305 mg/kg
caused death in 6 of 10 rats. Oral administration of neat mixed xylenes or each isomer to rats
ranked acute LD50 toxicity as o-xylene (3580 mg/kg) > p-xylene [4029 mg/kg] > m-xylene (5010
mg/kg) > mixed xylenes (5830 mg/kg) (Ungv醨y et al., 1979). Intraperitoneal administration of p-
xylene to rats produced an LD50 range of 2880-3680 mg/kg in female Sprague Dawley rats (Drew
and Fouls, 1974).
Dermal: Dermal toxicity in rabbits from treatment with m-xylene produced an LC50 of 12.1 g/kg
(Smyth et al., 1962). Hines and Zuidema (1970) also reported high dermal toxicity concentrations
for m-xylene with a dermal LC50 greater than 4.3 g/kg, the highest dose tested, at which only 1/3
rabbits died.
Irritation: Mixed xylenes and the m- and p- isomers are demonstrated to be moderate to marked
dermal irritants in rabbits (Hine and Zuidema, 1970; Smyth et al., 1962; Jacobs, 1992). Hine and
Zuidema (1970) reported mixed xylenes as a moderate conjunctival irritant. Para-xylene was a
slight to mild eye irritant (Kennah et al., 1989) and m-xylene was a slight irritant in rabbit eyes
(Smyth et al., 1962). No skin or eye irritation tests on o-xylene were found.
Xylenes VCCEP Submission 39
Table 6.2: Representative Hazard Studies for Xylenes Toxicity: Acute (Tier 1)
Study Type LD50/LC50 Comments Reference
Test Article Species
Acute: Mixed Rat-male 6700 ppm 4 hr exposure Carpenter et al., 1975
Inhalation xylenes (Harlan-Wistar)
Rat-male 6350 ppm 4 hr exposure Hine and Zuidema, 1970
(Long Evans)
Mouse 5267 ppm 6 hr exposure, observed 14d Bonnet et al., 1979
Meta-xylene Rat 5984 ppm 6 hr exposure, observed 14d Bonnet et al., 1982
Mouse-female 5267 ppm 6 hr exposure, observed 14d Bonnet et al, 1979
(SPF-Of1)
Ortho-xylene Rat 4330 ppm 6 hr exposure, observed 14d Bonnet et al, 1982
Mouse 4595 ppm 6 hr exposure, observed 14d Bonnet et al, 1979
Para-xylene Rat 4591 ppm 6 hr exposure, observed 14d Bonnet et al., 1982
6 hr exposure, observed 14d
Mouse 3907 ppm Bonnet et al., 1979
Rat 4740 ppm 4 hr exposure Harper et al., 1975
Acute: Oral Mixed Rat-male 8640 mg/kg Graded single undiluted doses/group to Hine and Zuidema, 1970
xylenes (Long Evans) 25ml/kg
Rat-male 3523 mg/kg Single gavage dose in oil NTP, 1986
(F344/N)
Mouse Male 5627 mg/kg Single gavage dose in oil NTP, 1986
(B6C3F1) 5251 mg/kg
Female
Meta-xylene Rat-male 6661 mg/kg Single gavage dose Smyth et al., 1962
Ortho-xylene Rat 3580 mg/kg Single dose Ungv醨y et al, 1979
Para-xylene 4029 mg/kg
Meta-xylene 5010 mg/kg
Mixed 5830 mg/kg
xylenes
Acute: Para-xylene Rat- female 2880-3680 mg/kg Single doses Drew and Fouls, 1974
Intraperitoneal Meta-xylene Mouse (NMRI) 2.003ml/kg Single dose Mohtashamipur et al, 1985
(1.73g/kg)
Ortho-xylene (micronucleus paper)
1.550ml/kg
Para-xylene
(1.36g/kg)
2.450ml/kg
(2.11g/kg)
Xylenes VCCEP Submission 40
Table 6.2: Representative Hazard Studies for Xylenes Toxicity: Acute (Tier 1) continued
Study Type LD50/LC50 Comments Reference
Test Article Species
Acute: Dermal Meta-xylene Rabbit-Male 12.1g/kg (14ml/kg) - Smyth et al., 1962
(NZW)
Rabbit-Male >4.3g/kg (>5ml/kg) - Hine and Zuidema, 1970
Irritation: Mixed Human 15 min exposure Carpenter et al., 1975
LOAEL = 460 ppm
Inhalation xylenes (eye)
LOAEL =690 ppm
(throat)
Human NOAEL = 396 ppm 30 min exposure Hastings et al., 1984
(eye and respiratory)
Skin Irritation Mixed Rabbit-male Moderate irritant PII = 2.21; intact and Hine and Zuidema, 1970
xylenes (NZW) abraded skin; Draize
scoring
Meta-xylene Rabbit-male Irritant - Smyth et al., 1962
(NZW)
Para-xylene Rabbit ?male Mild Irritant OECD 404 (1981) Jacobs, 1992
(NZW)
Avg. score = 5.33 at
Eye Irritation Mixed Rabbit-male Moderate Irritant Hine and Zuidema, 1970
24hr;
Xylenes (NZW) conjunctiva effect
6.33 at 48 hr; 6.67 at
72hr
Meta-xylene Rabbit-male Slight Irritant - Smyth et al, 1962
(NZW)
Para-xylene Rabbit (NZW) 0.1ml instilled in one Kennah et al., 1989
Mild Irritant
eye; other eye control
Xylenes VCCEP Submission 41
6.3 Repeated Dose Toxicity - Subchronic Toxicity (See Table 6.3)
Inhalation:
Several inhalation studies have investigated the subchronic systemic effects of xylenes and no
specific target organ effects have been consistently observed. The most predominant effects were
body weight and weight gain changes and mild hepatic alterations, which may be indicative of
adaptive response to hydrocarbon exposure rather than toxic effects. The studies are summarized
below.
Jenkins et al. (1970) exposed rats (12-14/group), guinea pigs (15/group), beagle dogs (2/group),
and squirrel monkeys (2-3/group) to 0 or 780 ppm o-xylene (3358 mg/m3), 8 hours/day, 5
days/week for 6 weeks or 78 ppm (337 mg/m 3) 24 hours/day, 7 days/week for 90 days. Guinea
pigs showed a marked decrease in body weight but no other clinical, neurological, or pathological
effects. One of 2 dogs experienced tremors throughout the exposure period, and one monkey died
on day 7 of exposure. No other signs of toxicity were reported. Carpenter et al. (1975) exposed
groups of 25 male rats and four male beagle dogs to concentrations of 180, 460, and 810 ppm of
mixed xylenes for 6 hours/day, 5 days/week for 65-66 days. No treatment related effects were
observed in either species. Ungv醨y et al. (1980) evaluated biochemical effects in rats exposed to
4500 ppm o-xylene, 8 hours/day for 6 weeks. At the end of the first week of exposure, relative liver
weight was increased, hexobarbitol sleeping time was shortened, the concentration of cytochrome
P450 increased, and the activities of analine dehydroxylase (AH) and aminopyrine N-demethylase
(ApN-D) were decreased. By six weeks exposure, similar effects in liver, sleep time, and P450
were seen but AH and ApN-D activities had increased. These changes in liver weight and the
mixed function oxidase (MPO) system activity were considered adaptive responses to exposure to
a xenobiotic agent. In a study by T醫rai and Ungv醨y (1980), groups of 30 male, CFY rats were
exposed to 0 or 3500 ppm o-xylene, 8hr/day for 6 weeks. Body weight gain was reduced by
xylenes exposure. Exposed rats had hepatic changes including: increased absolute and relative
liver weights, hepatocellular hypertrophy, increased proportion of smooth endoplasmic and rough
endoplasmic reticulum, decreased glycogen, and increased peroxisomes. It was concluded that
the liver effects were adaptive and probably reflected induction of enzymes. In a follow-up study to
evaluate the potential for xylenes to cause hepatotoxicity, T醫rai et al. (1981) exposed male CFY
rats to concentrations of 0 and 1090 ppm o-xylene for 8hr/day, 7days/week, for 6 or 12 months.
Ortho-xylene caused reduced body weight gain, increased absolute and relative liver weight, and
induction of mixed function oxidase (MFO) enzymes. However, microscopic evaluation of the liver
did not reveal any abnormalities, but there was proliferation of endoplasmic reticulum. In 1990,
Ungv醨y exposed male CFY rats to mixed xylenes (10% o-; 50% m-; 20% p-xylene, and 20%
ethylbenzene) at levels of 0, 140, 350, and 920 ppm for 8 hr/day, 7 days/week for 6 weeks, then 5
days/week for 6 months. Exposure related hepatic effects included increased relative liver weight,
hypertrophy of the centrilobular zone, increased hepatocyte volume, proliferation of smooth
endoplasmic reticulum; increased concentration of CYP-450 and b5; and increased activities of
NADPH:cytochrome c-reductase, alanine p-hydroxylase, succinate dehydrogenase and
aminopyrine N-demethylase; decreased barbiturate sleeping time, and transient increase in
glycogen. Additional exposure studies in mice, rats, and rabbits produced similar liver changes.
The authors considered these effects adaptive rather than adverse.
Rydzynski et al. (1992) exposed Wistar rats to 1000 ppm m-xylene for 6 hr/day, 5 days/week for 3
months and to 100 ppm for 6 months. Slight ultrastructural changes, including proliferation of
smooth endoplasmic reticulum, were found in hepatocytes. Bowers et al. (1982) examined
ultrastructural changes in livers of young rats exposed to o-xylene at dose of 73 mg/kg/day for 3
days intraperitoneal [IP] injection, or in livers of aging rats exposed to 200 mg/kg diet daily for 6
months. IP treatment of o-xylene to young rats did not cause ultrastructurally observable
Xylenes VCCEP Submission 42
abnormalities in hepatocytes but chronic oral ingestion did cause formation of vacuolar structures
in hepatocytes of older rats.
Several studies have specifically investigated the effects of xylenes on induction of enzymes of
xenobiotic metabolism in liver (Toftgard and Nilsen, 1982; Toftgard et al., 1981; 1983a,b; Elovaara
et al., 1982). The basic conclusion of these studies was that xylenes, and especially m-xylene, are
phenobarbitol-like inducers of xenobiotic metabolism in liver. The findings indicate that the hepatic
effects of xylene exposure are adaptive pharmacologic responses related to xylene elimination and
should not be considered toxic effects in determining adverse effects levels.
Oral: Subchronic oral studies do not consistently show effects on a single organ system. Effects
in different studies have included increased mortality (possibly related to test article inspiration),
reduced body weight gain, salivation, nephrotoxicity, and hepatic changes observed by electron
microscopy.
In an NTP oral study (1986), 10 male and 10 female rats received doses of 0, 62.5, 125, 250, 500,
and 1000 mg/kg/day mixed xylenes (60% m-, 13.6% p-, 9.1% o-xylene, 17% ethylbenzene), 5
days/week for 13 weeks. At termination necropsy was performed on all rats and comprehensive
histological examinations were performed on rats from control and high dose groups. High dose
males and females gained 15% and 8% less body weight than controls after 13 weeks of
exposure. No sign of toxicity or gross and microscopic pathologies were noted. In the same study,
groups of 10 male and 10 female mice received 0, 125, 250, 500, 1000, and 2000 mg/kg/day of
mixed xylenes in corn oil 5 days/week, for 13 weeks. As with rats, necropsy was performed on all
mice and comprehensive histologic examinations were performed on mice in the high dose and
control groups. High dose mice exhibited transient CNS effects 5-10 minutes after dosing that
lasted 15-60 minutes.
A subchronic oral gavage study of mixed xylenes was conducted by Condie et al. (1988). Groups
of 10 male and 10 female rats received 0, 150, 750, or 1500 mg/kg/day xylene in corn oil for 90
consecutive days. Effects included decreased body weight in high-dose males, dose-related
increased liver weight and relative liver weight in mid- and high-dose males and females.
Increased kidney weight and relative kidney weight were seen in mid- and high-dose males and
high-dose females. It was suggested that the liver findings were adaptive rather t an toxic.
h
Microscopic examination revealed a dose-related increase of kidney hyaline droplet formation in
males and the appearance of minimal chronic nephropathy in females.
In studies conducted by Wolfe (1988 a, b) m- and p-xylene were separately evaluated in the rat.
Groups of 20 male and 20 female rats received gavage doses of 0, 100, 200, and 800 mg/kg/day,
in corn oil for 90 consecutive days. With m-xylene, high levels of salivation were observed in high-
dose males and females. Body weight gains were reduced in males at the 200 and 800 mg/kg
doses (75-89% of controls) and in females at 800 mg/kg (85% of controls); this was associated
with decreased food consumption. There were no other treatment related toxic effects and no
abnormal gross or microscopic pathological findings. With p-xylene, treatment related clinical
effects were limited to increased salivation in high dose males and females. Body weight gain was
slightly reduced in both sexes at the high dose. No other treatment related toxic effects were
observed and there were no gross or microscopic pathologic findings.
The LOAELs and NOAELs for all subchronic studies are shown in Table 6.3
Comparison of Toxicity of Individual Xylene Isomers
Several studies have compared o-, m-, and p-isomers for their toxicological effects and differences
have been reported for some endpoints. Condie et al. (1988) found no significant differences
Xylenes VCCEP Submission 43
between the three isomers in a 10-day subacute oral gavage study in the rat. In a 4 -hour
inhalation study in the rat, Moln醨 et al. (1986) found that the minimal narcotic dose was similar for
the three isomers (o- xylene, 2180 ppm; m-xylene, 2100 ppm; p-xylene, 1940 ppm). However, at
lower doses, o-xylene (150-1800 ppm) caused a slight depression in motor activity, m-xylene (130-
1500 ppm) caused a slight increase in activity, and p-xylene (130-1500 ppm) caused a marked
increase in activity. Fang et al. (1996) showed that the alveolar concentrations of the three
isomers needed to produce anesthesia in the rat were similar. Moser et al. (1985) showed that
operant response and motor performance in mice were similar for the three isomers. However,
Korsak et al. (1990) found that o-xylene was the more potent than m- or p-isomers in altering motor
performance in the rat as indicated by the number of failures in the rotarod test. Potency was
decreased in the following order: o-xylene > m-xylene > p-xylene (see Section 6.8 Adult
Neurotoxicity).
Xylenes VCCEP Submission 44
Table 6.3: Representative Hazard Studies for Xylenes Toxicity: Repeat Dose (Tier 1 and 2)
Study Type Test Article Species NOAEL LOAEL Duration of Exposure Reference
Repeat Dose Ortho-xylene Rat-male None-one dose 3500 ppm ?decr. 6 weeks ?8hr/d, 7 Tatr醝 and Ungv醨y,
Toxicity level only body weight, inc. liver d/wk 1980
Inhalation weight
Rat-male None ?one dose 1090 ppm ?decr. 6-12 months, 8hr/d, 7 Tatr醝 et al, 1981
level only body weight, inc. liver d/wk
weight, induced MFO
enzymes
Meta-xylene Rat ?male & 1000 ppm None 6 months, 6hr/d, 5d/wk Rydzynski et al.,
female 1992
Mixed Rat ?male 920 ppm None; changes in liver 6 wks, 8hr/day, 7d/wk, Ungv醨y et al.,
xylenes weight and enzymes then 5d/wk for 6 mon 1990
not considered 0, 140-920 ppm
adverse.
Mixed Rat-male; 810 ppm Not determined 65-66 days 6hr/d, Carpenter et al.,
xylenes Dog-male 5d/wk; 1975
0, 180-810 ppm,
Oral gavage Mixed Rat ?male & 500 mg/kg 1000 mg/kg: decr. 90 days, 5d/wk by NTP, 1986
xylenes female body weight in both gavage in corn oil
sexes 0, 62.5-1000 mg/kg
Mouse ?male 1000 mg/kg 0, 125-2000 mg/kg
& female 2000 mg/kg- decr.
body wt., neurotoxicity
(lethargy, tremors 5-60
min after dosing)
Rat ?male & 150 mg/kg 750 mg/kg ?inc. liver 90 consecutive days; Condie et al., 1988
female & kidney weight in mid 0, 150 to 1500 mg/kg
& high dose males in corn oil
and high dose females
Rat ?male & 100 mg/kg [M] 800 mg/kg 璪ody 90 consecutive days; Wolfe, 1988a
Meta-xylene
female 200 mg/kg [F] weight decrease once a day
in corn oil 0, 100, 200,
Rat ?male & 200 mg/kg [M&F] 800 mg/kg ?slight
Para-xylene
800 mg/kg/day
female body weight decrease
Xylenes VCCEP Submission 45
6.4 Genetic Toxicity - (See Table 6.4)
Mixed xylenes and the xylene isomers have been tested in both in vitro and in vivo assays and are
substantially non-genotoxic. In vitro studies of mixed xylenes and xylene isomers in bacterial cells,
including Salmonella typhimurium, Escherichia coli, and Bacillus subtilis, for mutation or DNA
damage with and without metabolic activation were negative, as was a mitotic gene conversion
study in yeast, Saccharomyces cerevisiae, D4. Although most Salmonella studies were performed
using plate incorporation, the API Litton Bionetics study (1978a) employed a suspension assay as
well in order to optimize interaction between bacteria and mixed xylenes; no increase in gene
mutation was observed by either method.
When mouse lymphoma cells were exposed to mixed xylenes at doses of 0, 5.6-87.0 礸/ml with or
without metabolic activation, no mutational events were induced (API, 1978a). Cytogenetic
damage, expressed as sister chromatid exchange ( SCE) or chromosome aberrations were not
observed in Chinese hamster ovary cells with or without activation (Anderson et al., 1990), or in
cultured human lymphocytes that retain endogenous metabolic activity (Gerner-Schmidt and
Friedrich, 1978; Richer et al., 1993).
Exposure to mixed xylenes (18.3% ethylbenzene) caused recessive lethal mutations in Drosophila
melanogaster, but exposure to m-xylene or o-xylene alone did not cause this effect (Donner et al.,
1980). The same report stated that exposure of rats to 300 ppm mixed xylenes, 6 hours/day, 5
days/week for 9, 14, or 18 weeks did not induce chromosome aberrations in bone marrow cells.
Results of other studies in laboratory animals were also negative for xylenes-induced cytogenetic
effects. The American Petroleum Institute (1978a) sponsored chromosome aberration studies in
rats using mixed xylenes (11.4% o-xylene, 0.3% p-xylene, 36.1% ethylbenzene, and 52% m-
xylene). Sprague Dawley rats were treated intraperitoneally with 0, 0.044, 0.147, and 0.441 ml/kg
(approximately 0, 38, 127, and 381 mg/kg) xylenes in a single dose or daily for 5 days.
Chromosome aberrations were not induced in femoral bone marrow of treated rats under either
regime. Mohtashamipur et al. (1995) administered each xylene isomer to male NMRI rats
intraperitoneally in 2 similar doses, 24 hours apart over a range of concentrations from 0, 0.12-
0.75ml/kg (105-650 mg/kg) and evaluated femoral bone marrow 30 hours after the first injection.
No increase in micronucleated polychromatic erythrocytes was observed for any xylene isomer (or
for ethylbenzene which was also tested) at any dose level.
Two dominant lethal assays in rat and mouse have been performed (API, 1973). Male animals
were treated with a single 1 ml/kg (865 mg/kg) of mixed xylenes and mated with untreated females
at intervals throughout the spermatogenic cycle. Rats were treated intraperitoneally and mice were
treated subcutaneously. Females were euthanized during the later part of gestation and uteri were
examined for living and dead implantations and total number of implantation sites. Xylenes did not
increase pre- or post-implantation loss from matings at any stage of the spermatogenic cycle and
was not considered mutagenic to sperm in this assay. Ortho-xylene was examined for its potential
to induce abnormal sperm by injecting Sprague Dawley rats with 0.5 or 1.5 ml/kg (440 or 1320
mg/kg) o-xylene in corn oil (Washington et al., 1983). Animals were euthanized 5 weeks after
treatment and the sperm examined for abnormalities. Rats housed at room temperature of 20-
240C showed no significant increase in abnormal sperm, while those housed at a higher
temperature of 24-300C showed a significant increase in abnormal sperm at the low dose only.
The authors suggested a synergistic effect between o-xylene and temperature, but since no
increase in abnormal sperm or other adverse effects were observed at the high dose, the
significance of this result is questionable.
Xylenes VCCEP Submission 46
There is sufficient evidence of overall negative results in a variety of in vitro and in vivo tests,
including occupational exposure in humans, to conclude that mixed xylenes, m-xylene, o-xylene,
and p-xylene are not genotoxic (ATSDR, 1995; EPA 2003a).
Xylenes VCCEP Submission 47
Table 6.4: Representative Hazard Studies for Xylenes Toxicity: Genetic Toxicity (Tier 1 and 2)
Study Type Test Article Species Result Reference
Genetic Mixed xylenes Sal. Typhimurium Negative +/-S9 NTP, 1986;
Toxicology: TA98, 97, 100, 1535: plate incorp. Zeiger et al., 1987
Bacterial- reverse
Meta-xylene Sal. typhimurium Negative +/-S9 Haworth et al., 1983
mutation +/-S9
TA98, 100, 1535, 1537: plate incorp.
Para-xylene
Ortho-xylene
Meta-xylene Sal. typhimurium Negative +/-S9 Conner et al., 1985
TA98, 100, UTH8414, UTH8413: plate
Para-xylene
incorp.
Ortho-xylene
Meta-xylene Sal. typhimurium Negative+/-S9 Bos et al., 1981
TA98, 100, 1535, 1537, 1538: plate
Para-xylene
incorp.
Ortho-xylene
Meta-xylene Sal. typhimurium Negative+/-S9 Florin et al., 1980
TA98, 100, 1535, 1537: plate incorp. and
Para-xylene
spot test
Mixed xylenes Sal. typhimurium Negative +/-S9 API 1978a
TA98, 100, 1535, 1537, 1538:
Saccharomyces cerevisiae:
plate incorp. and suspension
Para-xylene Sal. typhimurium Negative+/- S9 Shimizu et al., 1985
TA98, 100, 1535, 1537, 1538:
Escherichia coli WP2uvrA Negative +/- S9
plate incorporation.
E.coli prophage Mixed xylenes E. coli WP2 (?)(Ionii, sulA1, trpE65, Negative +/- S9 DeMarini et al., 1991
induction assay ? uvrAa55, IamB+),
S9
E coli DNA repair Technical grade E. coli WP2, WP2uvrA, WP67, CM611, Negative +/- S9 McCarroll et al., 1981a
suspension assay xylene WP100, WP3110polA+, p3478pol a-
+/-S9 [DNA damage]
Bacillis subtilis Technical grade B. subtilis H17, M45 [DNA damage] Negative +/-S9 McCarroll et al., 1981a
Modified rec assay xylene
Xylenes VCCEP Submission 48
Table 6.4: Representative Hazard Studies for Xylenes Toxicity: Genetic Toxicity (Tier 1 and 2) continued
Study Type Test Article Species Result Reference
Genetic Toxicology: Negative +/-S9 API, [Litton Bionetics],
Mammalian cells in 1978
Mixed xylenes Mouse lymphoma cells (L5178Y,
culture TK+/-) forward mutation.
Negative for SCE and chromosome Gerner-Schmidt and
Xylene
aberrations Friedrich, 1978
Cultured human lymphocytes
undefined
endogenous metabolism: SCE &
Chromosome aberrations
Negative for SCE Richer et al., 1993
Mixed xylenes
Cultured human lymphocytes
endogenous metabolism: SCE
Negative+/-S9 for SCE and Anderson et al., 1990
Mixed xylenes
Chinese hamster ovary cells (CHO) chromosome aberrations
+/-S9; SCE and chromosome
aberrations
Genetic Toxicology In Mouse-male/ Intraperitoneal injection. NOAEL=650 mg/kg [max.dose], for Mohtashamipur et al.,
Meta-, para-,
vivo Animals Micronucleus assay meta-& para-xylenes 1995
ortho-xylene
Cytogenetics (0,105-650 mg/kg, 2 doses 24hr NOAEL=440 mg/kg for ortho
apart) No increased micronuclei/PCE
NOAEL= 381 mg/kg
Mixed xylene Rat/intraperitoneal injection. API, 1978a
Chromosome aberrations assay (0, No chrom aberration in bone
38, 127, 381 mg/kg in a single dose marrow cells under either regime.
or daily for 5 days)
NOAEL=40 ppm
Mixed xylene Male/Inhalation: 40 ppm only dose (3 Richer et al., 1993
days exposure, repeated 3 times at 2
Cytogenetics No increase in SCE, cell cycle
Human wk intervals) delay or cell death
Mixed xylene 23 workers; Sister chromatid NOAEL=11 ppm (47.3 mg/m3) and Pap and Varga, 1987
13 ppm (55.9 mg/m3)
exchange assay (SCE) exposed to 11
and 13 ppm (duration of exposure No increase in SCE
between 4 mon ?3 yrs)
NOAEL=865 mg/kg
Commercial Mouse-male; singe subcutaneous API, 1973
xylene injection of 865 mg/kg; Rat-male
Dominant Lethal No affect on mating, reproductive
single intraperitoneal injection of 865
assay No increase in pre- or post-
mg/kg [1ml/kg] mated with untreated implantation loss from any week of
females through spermatogenic cycle mating; not mutagenic to sperm.
Xylenes VCCEP Submission 49
6.5 Reproductive Toxicity (see Table 6.5)
Reproductive data on xylenes include a single one-generation inhalation study in rats and two
dominant lethal studies (rat, mouse), as well as evaluation of male and female reproductive organs
in repeated dose studies, all of which indicate that xylenes do not affect reproductive performance.
In the one generation reproduction study, no adverse reproductive effects were found following
inhalation exposure of male and female CD rats to mixed xylenes concentrations as high as 500
ppm during premating, mating, pregnancy, and lactation (API 1983). Groups of male and female
CD rats were exposed to 0, 60, 250, or 500 ppm mixed xylenes (20.3% p-xylene, 44.2% m-xylene,
and 20.4% o-xylene, 12.8% ethylbenzene and 2.4% toluene) by inhalation, 6 hours/day, 5
days/week for 131 days prior to mating, and during 20 days of mating. Mated females were
exposed during gestatation days (GD) 1-20 and days 5-20 of lactation; pups were exposed only
through the milk. Additional animals exposed to 500 ppm were mated to unexposed partners to
identify any sex-specific effects. One half of all parental (F0) males were euthanized after mating
for post-mortem examination; the remaining males were sacrificed and examined 21 days later.
One half of 500 ppm and control females were euthanized on GD21 for developmental toxicity
evaluation and the remaining parental females delivered litters and were maintained through
lactation to weaning. Litters were culled, if possible, to 8 pups (4M, 4F) on lactation day (LD) 4.
Pups were weighed, sexed, and given gross external examinations on LD1, 4, and 21. Randomly
selected pups from each group (1/sex/litter) and all F0 dams with litters were euthanized on LD21.
Remaining pups were maintained for a post-weaning interval of 28-49 days and weighed and
sacrificed on day 49. No adverse effects were observed in parental rats. No differences were
seen in testes weight or histological examination of reproductive tissue in xylene-exposed males.
Male mating index and fertility index were comparable among exposed and control rats. Although
the female mating index was significantly below the 100% in controls, 85% in the 250 ppm (both
sexes treated), and 85% in the 500 ppm (females only treated) groups; a significant decrease in
mating did not occur at the 500 ppm (both sexes treated) and 500 ppm (males only treated)
groups. The authors did not consider these decreases to be xylenes-induced because the effect
was not seen in the highest dose when both sexes were treated and the controls had an unusually
high mating performance. There were no treatment-related effects in mean duration of pregnancy,
mean litter size, or pup survival. Mean pup weight in the 500 ppm (both sexes treated) group was
slightly but significantly lower than controls on lactation day 14 and 21, and at sacrifice on day 49.
Despite these marginal decreases in pup weight in the 500 ppm (both sexes treated) group, no
decrease in pup body weight was observed in the 500 ppm (females only treated) group. Thus,
these decreases were not considered adverse effects of treatment. Female pups sacrificed at
weaning in the 250 and 500 ppm groups had statistically significant decreases in absolute and
relative ovary weight at 21 days of age, but the decreases were not concentration-related and were
not observed at 49 days of age. Among the females evaluated for teratogenesis, there were no
significant effects on litter size, implantations, or malformations. Mean fetal weight in the 500 ppm
group was lower than controls but the difference was significant only in female fetuses. Parental
systemic and developmental NOAEL was 500 ppm.
The dominant lethal studies (API 1973) involved a single injection of 1 ml/kg (864 mg/kg) mixed
xylenes to male rats intraperitoneally and to male mice, subcutaneously, followed by sequential
mating to untreated females throughout the spermatogenic cycle. No xylenes-induced effects were
seen on the incidence of pre- or post-implantation loss in either species.
The absence of xylenes-induced toxicity in male reproductive organs and performance correlates
with the negative results from a study by Nyl閚 et al. (1989) in which male SD rats were exposed to
1000 ppm mixed xylenes, 18 hours/day, 7 days/week for 61 days. No alterations in testes,
Xylenes VCCEP Submission 50
accessory glands, or circulating male hormone levels were observed. When Yamada (1993)
exposed Wistar rats for 7 days to xylenes (not characterized), twice a day until disappearance of
righting reflex, anesthesia was produced within 10 min (actual doses not reported). Animals were
sacrificed on day 8. Decreases in body weight, testes weight, and weight of accessory
reproductive organs, reduced acid phosphate activity in prostate, and reduced plasma testosterone
levels, and decrease in spermatozoa count in the epididymides were observed in rats exposed to
extremely high, anesthetic doses of mixed xylenes.
There were no reported oral animal reproductive studies available for mixed xylenes or individual
isomers. However, histological examination of rodents administered mixed xylenes at doses as
high as 1000 mg/kg/day in rats and 2000 mg/kg/day in mice for 13 weeks, and up to 500
mg/kg/day in rats and 1000 mg/kg/day in mice for 103 weeks, revealed no adverse effects on
prostate/testes, ovary/uterus, or mammary glands (NTP, 1986). Similarly, no adverse
histopathological changes were observed in reproductive organs of rats given m- or p-xylene at
doses as high as 800 mg/kg/day for 13 weeks (Wolfe, 1988a,b).
All studies indicate that xylenes do not substantially affect reproductive performance or induce
histologically observable structural damage to reproductive organs of laboratory animals at non-
anesthetic doses. The comprehensive one-generation animal inhalation reproductive study (API,
Biodynamics, 1983) demonstrated that xylenes are not a reproductive toxicant. Although this study
may not meet current test guidelines that generally call for a two-generation study, the lack of
reproductive effects at exposure up to 500 ppm suggests that xylenes do not present a
reproductive hazard. It is unlikely that xylenes exposure would induce adverse effects in a second
generation in the absence of damage to parental or the F1 generation. This is further supported by
evaluating data for similar chemicals with multigeneration studies. The NOAELs from the second
generation of the studies are similar to the NOAEL for the first generation. For toluene, the NOAEL
and LOAEL for parents and offspring of both generations are 500 ppm and 2000 ppm, respectively
(Roberts et al. 2003). For C9 aromatic naphtha, the NOAEL and LOAEL are 500 ppm and 1500
ppm, respectively, for both parent and offspring from the first and second generation (McKee et al.,
1990). The International Life Sciences Institute's (ILSI) Health and Environmental Sciences
Institute (HESI) also recently concluded that the second generation of a multigeneration study has
little impact on the chronic RfD based on an evaluation of 200 pesticides representing very
different classes of chemistry. ILSI-HESI concluded that a multigeneration study need not be
conducted unless triggered by results in the first generation such as (1) an adverse effect on
fertility or fecundity of the parental generation, (2) indications of abnormal sexual development of
the F1 pups, or (3) deaths or evidence of toxicity to the F1 pups pre-weaning
(http://www.ilsi.org/file/LifeStagesDraftPaperJan05.pdf). Xylenes did not cause effects that would
trigger a multigeneration study.
Of even greater importance is the availability of developmental neurotoxicity studies that provide
focused and sophisticated neurobehavioral evaluation on pups following developmental exposures
to mixed xylenes and p -xylene. Neurobehavioral endpoints are the critical effects of concern
based on both the human and animal literature on xylenes and related solvents. They are likely to
be more sensitive than the standard endpoints required on a multigeneration study. Gestational
exposure of animals to xylenes resulted in slight neurodevelopmental effects (Hass et al, 1995;
1997) at 500 ppm. Though this study is limited because it was conducted at only one dose level, it
evaluated multiple neurobehavioral endpoints including developmental landmarks, auditory startle,
air righting, rotarod, 3-minute open field activity, brain weight, and Morris water maze. In a
separate study, other neurological endpoints such as acoustic startle response and figure-8 maze
activity were not affected in male or female offspring of rats exposed to up to 1600 ppm p-xylene 6
hours per day on GDs 6-15 (Rosen et al., 1986). It would be unlikely for a multigeneration study to
be more sensitive to xylenes exposure compared to these developmental neurobehavioral studies.
Xylenes VCCEP Submission 51
6.6 Developmental Toxicity (see Table 6.5)
Developmental studies in pregnant animals indicate that xylenes are fetotoxic at dose levels that
are high enough to induce maternal stress and often maternal toxicity, making it difficult to
determine whether effects are from direct action of xylene or secondary to maternal toxicity.
ATSDR (1995) observed that large variations in concentrations of xylenes producing
developmental effects, and of those producing no developmental effects, were influenced by strain
and species of animal, purity of xylene, method of exposure, exposure pattern, and duration.
Oral exposure-Mice: Marks et al. (1982) administered mixed xylenes (60.2% m-, 9.1% o-, 13.6%
p-xylene, 17% ethylbenzene) by gavage in cottonseed oil to pregnant CD-1 mice, 3 times/day at
doses of 0, 520, 1030, 2060, 2580, 3100, or 4130 mg/kg/day (0.6, 1.2, 2.4, 3.0, 3.6, and
4.8ml/kg/day) from GD6-15; sacrifice was on GD 18. Maternal lethality of 100% and 32% occurred
at 4130 and 3100 mg/kg, respectively, with a 40% decrease in body weight gain in remaining 3100
mg/kg maternal mice over GD1-18 compared to controls. Fetal resorptions increased at the
maternally toxic dose of 3100 mg/kg, and significantly reduced fetal body weights and increased
incidence of cleft palate were observed at 2060 mg/kg and above. Maternal toxicity LOAEL was
3100 mg/kg/day and the NOAEL was 2580 mg/kg/day. Fetal toxicity LOAEL was 2060 mg/kg/day
and the NOAEL was 1030 mg/kg/day. It should be recognized that mice under stress are
predisposed to produce offspring with cleft palate and that maternal stress induced at high levels of
xylenes could impact both fetal weight and malformations (Brown et al., 1972; 1974; Khera 1984).
These investigators found that cleft palate in mice is associated with maternal stress and may be
due to elevated levels of corticosterol.
Nawrot and Staples (1980) gave pregnant CD-1 mice m-, p- or o-xylene by gavage at approximate
total daily doses of 0, 780, 1960, or 2610 mg/kg (0, 0.30, 0.75, 05, and 1.0ml/kg/dose, 3 times a
day) on GD 6 -15, or 2610 mg/kg/day on GD12-15. Overt maternal toxicity and significantly
increased incidences of resorptions and cleft palate occurred at 1960, 2610 mg/kg doses of o- or
p-xylene and maternal toxicity and resorptions only at 2610 mg/kg m-xylene, given from GD6-15.
Targeted exposures to 2610 mg/kg/day on GD12-15 resulted in significant increases in maternal
lethality and increased incidence in fetal malformations particularly cleft palate in p- and m-xylene
groups. Subsequent exposure to m-xylene at 1960 and 2610 mg/kg/day on GD12-15 induced
maternal toxicity and cleft palate at 2610 mg/kg, and a small but statistically significant increase in
cleft palate at 1960 mg/kg/day in the absence of maternal toxicity (4.4% vs 0% in controls).
Authors considered the increase to be low and characterized m-xylene as a weak teratogen.
However, in a separate screening teratology study in mice, 2000 mg/kg/day m-xylene administered
from GD8-12 did not induce fetal toxicity or malformations (Seidenberg et al., 1986).
Inhalation: A number of developmental inhalation studies from xylenes are available. The quality
and interpretability of these studies vary considerably and a complete assessment of the results
was sometimes hampered due to the absence of key data and reporting, particularly in early
studies. The Saillenfait et al. (2003) was selected as the key study for this endpoint because it is
the most modern and comprehensive study, concurrently evaluating mixed xylenes, the individual
xylene isomers and ethylbenzene, and providing key data and statistics.
Saillenfait (2003) exposed Sprague Dawley rats to o-, m-, and p-xylene, mixed xylenes, and
ethylbenzene at concentrations of 0, 100, 500, 1000, or 2000 ppm, 6 hours/day during gestation
days (GD) 6-20, in accordance with OECD protocol 414 (2001) and EPA OPPTS 870.3700 (1998)
testing guideline. All materials caused maternal toxicity (reduction in maternal body weight gain) at
1000 and 2000 ppm. Decreased corrected weight gain (without gravid uterus) and food
consumption were observed at 1000 and 2000 ppm o-, m-, and p-xylene, and ethylbenzene, and at
2000 ppm mixed xylenes. No fetal malformations were induced by any test material. Decreased
Xylenes VCCEP Submission 52
fetal body weight occurred at the maternally toxic doses of 1000 and 2000 ppm for all materials,
and also at 500 ppm and greater for o-xylene and mixed xylenes. Significant increase in mean
percent fetuses with skeletal variations of all types/litter was seen at 2000 ppm concentrations of o-
and p-xylene, and ethylbenzene. No single skeletal variation occurred at an incidence significantly
higher than that in controls.
In a 1978 teratology study from American Petroleum Institute (API 1978), no maternal or
developmental effects were observed following exposure of pregnant CD rats to 0, 100, or 400
ppm mixed xylenes (52% m-, 11% o-, 0.31% p-xylene, and 36% ethylbenzene), 6 hours/day,
during GD6-15. The NOAEL for maternal and developmental effects was 400 ppm. In the
teratogenic portion of the 1-generation reproduction study (API 1983) one-half of the control and
500 ppm high dose pregnant females were euthanized on GD21 for developmental toxicity
evaluation. Animals had been exposed to mixed xylenes for 151 days prior to and during mating,
and GD1-20. No effects were observed on maternal body weight, food consumption or utilization,
or postmortem examination. No statistically significant differences were reported for mean number
of corpora lutea, implantations, live fetuses, live fetus/implantation, or fetal sex ratios. A slight
increase in mean number of resorption sites (1.6 vs. 1.2 in controls) was not statistically significant.
Fetuses from exposed dams had slightly higher incidence of unossified sternebrae and
incompletely ossified cervical vertebral processes, reported by fetal incidence. Mean body weight
of female fetuses on GD21 was marginally but statistically decreased (93% of control values), but
male fetuses were comparable to controls. This marginal decrease occurring in only one sex was
difficult to assess due to small sample size (12 litters compared to 20 litters in controls). Maternal
toxicity NOAEL was 500 ppm and the developmental LOAEL was 500 ppm (decreased female fetal
weight) with a NOAEL of 250 ppm. In the animals allowed to deliver litters, mean pup weights
were statistically significantly decreased in treated litters on lactation day (LD) 4 probably as a
consequence of elevated mean pup weights in the control group where the mean litter size was
smaller that all treated litters in any group (9.6 live pups/litter in controls vs. 10.8-12.5 pups/litter in
treated groups). Marginally decreased mean pup weight in 500 ppm (both sexes treated) litters
was observed on LD21 and at 49 days of age (92% males, 93% females of control values), but no
decrease in pup weights was observed in offspring of litters in which only the dam or the male
parent was exposed to 500 ppm, suggesting these marginal weight decreases were not an effect
of xylenes exposure. Offspring NOAEL was 500 ppm.
Ungv醨y et al. regularly employed 24-hour exposure periods when treating rats with solvents
compared to the 6-8 hour exposures used by other investigators. Hud醟 and Ungv醨y (1978)
treated pregnant CFY rats with 0, or 230 ppm (1000 mg/m3) mixed xylenes ([10% o-, 50% m-, 20%
p-xylene, 20% ethylbenzene), 24 hours/day, GD9-14; study was terminated on GD 21. No effects
were observed for any parameter (maternal body weight, fetal deaths, fetal or placental weights, or
malformations) other than an increased frequency of fused sternebrae and extra ribs. However,
frequency was based on number of fetuses, rather than affected litters. Subsequently, Ungv醨y
and T醫rai (1985) exposed pregnant CFY rats (19-23/group) to a wider range of doses - 0, 60, 440,
and 780 ppm (0, 250, 1900, and 3400 mg/m 3) xylenes again for 24hours/day, GD 7-15; animals
were euthanized on GD 21. Pregnant CFLP mice (17-18/group) and pregnant New Zealand white
rabbits (10) were exposed to 0, 115, or 230 ppm (0, 500 or 1000 mg/m3) mixed xylene 3 times for
4 hours/day intermittently or to 115 ppm o-, p-, or m-xylene on GD6-15 or 7 -20, respectively;
animals were sacrificed on GD 18 or 30, respectively. Although an increase in percentage of
skeletal retardation (no specifics given) was reported in mouse and rat fetuses, the increases were
not concentration-related, the occurrence/litter was not reported, and incidences were not
statistically significant compared to controls. Rats exposed to 780 ppm had an increased
percentage of dead or resorbed fetuses (13% vs. 5% in controls). Maternal toxicities in rats were
reported as moderate and concentration-related. Rats exposed at all doses had approximately
30% incidence of fetal skeletal abnormalities and an average 13% weight reduction at 780 ppm.
Xylenes VCCEP Submission 53
Mice had a slight increase in skeletal abnormalities and fetal weight reduction at 115 ppm for each
isomer and for mixed xylenes at 230 ppm but not at 115 ppm. In rabbits, exposure to 230 ppm
resulted in 3 maternal deaths, increased relative liver weight in dams, and an increased number of
abortions. Exposure of pregnant rabbits to 115 ppm o-, m-, p-xylene or mixed xylenes, produced
only slight decrements in fetal weight of female offspring. The authors considered xylenes to be, at
most, only slightly developmentally toxic. ATSDR (1995) concluded that effect levels could not be
determined from this study.
Ungv醨y et al. (1980) also explored differences in maternal and developmental effects induced by
the 3 isomers in CFY pregnant rats exposed to 0, 35, 350, or 700 ppm o-, m- or p-xylene
continuously from GD7-14; study termination was on GD 21. Signs of maternal toxicity at 700 ppm
included decreased maternal weight gain, decreased food consumption, and increased liver to
body weight ratio. Exposure to m-xylene was the only isom er that resulted in lasting maternal
growth inhibition or maternal mortality (4 dams died). Meta-xylene at 700 ppm caused decreased
number of mean implantations/dam; and 700 ppm p-xylene had increased postimplantation loss
with corresponding decreased litter size. Fetal body weight was statistically decreased in the 350
and 700 ppm o-xylene groups, and at 700 ppm in p- and m-xylene groups with corresponding
increases in weight-retarded fetuses. Histochemical analysis of 700 ppm fetuses in the o- and p-
xylene groups showed decreased staining of alkaline phosphatase, succinic hydrogenase, acid
phosphatase, and glucose-6-phosphatase in the kidney; succinic dehydrogenase and glucose-6-
phosphatase also showed decreased activity in the liver and thymus cells of 700 ppm groups of all
3 isomers. No structural effects were observed histopathologically. Enzyme changes, especially in
the liver, are likely adaptive responses to exposure and are not considered adverse (see repeated
dose section - subchronic toxicity). The authors reported statistically significant increases in extra
ribs in fetuses of 700 ppm o-xylene, and all p-xylenes groups on a per fetus basis; litter incidence
data was not reported.
To study effects of xylenes on sex steroids during pregnancy, Ungv醨y et al. (1981) exposed CFY
rats to 0 or 681 ppm p-xylene for 24 hours on GD 10 and continuously on GD9-10; sacrifice was on
GD11. No data on maternal toxicity were provided. The sex hormones, progesterone and 17?
oestradiol, in uterine and femoral veins were decreased in the exposed group. The authors
suggested that this reduction in hormones may play a role in embryotoxicity. Balogh et al. (1982)
observed an increase in placental weight in CFY rats exposed continuously to mixed xylenes at
concentrations of 438 and 775 ppm on GD7-14. These data suggested that relatively high
concentrations of xylenes could limit oxygen delivery to the placenta that, in turn, can lead to
increased placental weights, increased postimplantation loss and delayed ossification that
occurred at 775 ppm.
K黭ner et al. (1997,1998) examined the effects of inhaled xylenes on the liver of non-pregnant and
pregnant Wistar rats and pups of exposed litters, at concentrations of 0 or 2600 ppm mixed
xylenes (composition not specified), 8 hours/day, GD6-21 or equivalent days for non-pregnant rats.
Controls were pregnant unexposed rats. Xylenes induced minimal increases in asparate
aminotransferase (18%), alanine aminotransferase (19%), alkaline phosphatase (17%), and
arginase (63%) in pregnant rats. Electron microscopic evaluation of liver tissue from pregnant and
non-pregnant rats showed mitochondria that concentrated near the periphery of hepatocytes and
nuclei, increased number of lysosomes, and expanded smooth endoplasmic reticulum (ER). In
fetal livers, expanded smooth ER and granular ER and structurally deformed mitochondria were
observed. No structural defects were seen in kidney or pancreas of any exposed animal.
A study by Mirkova et al. (1983) in which pregnant Wistar rats were exposed to 0, 3, 12, or 110
ppm mixed xylenes, 6 hours/day on GD 1-21 resulted in effects not reported by other investigators
at higher doses or longer exposures. Effects included low pregnancy rate, increased
Xylenes VCCEP Submission 54
postimplantation losses, reduced fetal weights, and statistically significant increases in visceral
abnormalities (e.g. hydrocephalus, micropthalmia, hematomas) and ossification defects in sternum
and skull at concentrations of 12 ppm and above. Maternal toxicity was not addressed. Incidence
rates for anomalies were not presented. A statistically significant decrease in pup weight on
postnatal days 7 and 21 was reported in the 12 and 100 ppm groups, but no data were supplied. A
significant increase in percentage of hemorrhages in fetuses was also reported. ATSDR (1995)
speculated that these results may have been influenced by poor animal health as indicated by low
pregnancy rates (81, 61, 67, and 73% in control, 3, 12, and 110 ppm, respectively) and the high
incidence of fetal hemorrhage in control and treated rats. Further, incomplete reporting of methods
and results, and inadequate litter sizes for proper evaluation prohibit establishment of a maternal or
developmental effect level. Hass and Jakobsen (1993) attempted to replicate s ome of these
results by exposing 36 pregnant Wistar rats to clean air or 200 ppm mixed xylenes, 6 hours/day on
GD4 ?0. No maternal toxicity, no decrease in fetal weight, or increases in soft tissue or skeletal
malformation were seen. However, a large increase in the incidence of delayed ossification in the
os maxillare of the skull was observed (53% of exposed fetuses vs. 2% in control). Rotarod
performance was impaired in 2-day old pups and later in female pups on post-natal days 22 and
23, and in male pups on postnatal day 23. However, the authors of this paper questioned the
rotarod results from this study because experimental bias could have been introduced because
evaluators were aware of animals' exposure status. In a subsequent study, this effect could not be
repeated at the higher dose of 500 ppm (Hass 1995). See Section 6.10 Developmental
Neurotoxicity for more discussion on these studies.
Rosen et al (1986) conducted an inhalation study in rats to assess the postnatal effects of prenatal
exposure to p-xylene. The study design was a Chernoff/Kavlock "teratology screen" and did not
include all of the procedures and assessments normally incorporated into a conventional
developmental toxicity study, though postnatal neurobehavioral tests were included in this study
(see Section 6.10 Developmental Neurotoxicity). Maternal toxicity (significantly decreased body
weight gain) was reported at the highest exposure level. No adverse effects were observed in the
offspring. Based on these findings, the developmental NOAEL is 1600 ppm.
In vitro exposures of 9.5-day old Sprague Dawley postimplantation embryos to 0.1, 0.5, or 1.0 ml/l
medium of mixed xylenes (60% p-xylene, 22% o-xylene, 0% m-xylene, 18% ethylbenzene) did not
induce teratogenic effects after 48hr growth (Brown-Woodman et al., 1991). Dose-dependent
growth retardation and development was observed. In a similar study, Brown-Woodman et al.
(1994) incubated rat embryos in vitro with up to 2.7 祄ol xylene/ml for 40 hours. Concentrations =
1.89 祄ol/ml retarded embryo growth and development; no gross morphological malformations
were observed.
These studies indicate that xylenes can produce fetotoxic effects, although most effects occur in
the presence of maternal toxicity, making it difficult to determine whether xylenes are selectively
toxic to the fetus or the observed developmental toxicity was secondary to maternal toxicity and
stress (ATSDR, 1995). In addition maternal effects were not always addressed in all studies. EPA
concluded that adverse developmental effects occur only at doses higher than doses producing the
critical neurobehavioral effects observed in adult rats, suggesting that the developing fetus is not at
special risk from low-level xylenes exposure (EPA 2003a).
Xylenes VCCEP Submission 55
Table 6.5: Representative Hazard Studies for Xylenes Toxicity: Reproductive and Developmental Toxicity (Tier 2)
Study Type Test Article Species/Route of NOAEL LOAEL Duration of Reference
Exposure Exposure
Reproductive Mixed Rats- male & 500 ppm ?max. None 151d, 5d/wk API (1983)
Toxicity xylenes females/ inhalation dose 35d, 7d/wk, 6hr/d 1-generation
parents & F1 gest. (1-20); lact.
offspring (5-20)
Mixed Rats ?males/ None 61 days; 18h/day, Nyl閚 et al, (1989)
1000 ppm ?only
xylenes inhalation 7d/wk
dose: no effect on
testes or accessory
organs
Developmental Meta-xylene Rats ?female/ m-, p- =500 ppm 1000 ppm- decr. dam & fetal GD 6-20, 6hr/day, Saillenfait et al., 2003
Toxicity Para-xylene inhalation (dams/fetal) wt (m-, p-xylene). 7d/wk
Ortho-xylene o-, mixed xylenes = 1000 ppm dam; 500 ppm 100-2000 ppm
Technical 500 ppm (dam) fetal
xylene 100 ppm (fetal) 2000 ppm ortho- & para-
xylene - inc % fetuses with
skeletal variations/litter
Mixed Rats-female/ None GD 6-15, 6 hr/d API, 1978
400 ppm (dam/fetal)
xylenes inhalation 0, 100, 400 ppm
Meta-xylene Rats ?female/ 350 ppm 700 ppm ?maternal and fetal
inhalation wt decr. reduced implants GD7-14, Ungv醨y et al. (1980)
Ortho-xylene 35 ppm 24hr/d for 8 days
350 ppm ?% decr. in fetal
Para-xylene not determined wt
35 ppm ?inc in fetal ribs
Mixed Mice-female/Oral 1030 mg/kg (fetal) 2060 mg/kg- (fetal) decr. GD6-15, sacrificed Marks et al., 1982
xylenes body wt, cleft palate on GD18
2580 mg/kg (dam) 3100 mg/kg (dam)-
decreased body wt, inc
resorptions
Meta-xylene Mice-female/Oral 780 mg/kg for para-, 1960 mg/kg: maternal GD6-15, Newrot and Staples,
Para-xylene ortho-xylenes toxicity, inc. resorptions, cleft 0, 780, 1960, 1980
Ortho-xylene 1960 mg/kg for palate 2610 mg/kg
ortho- 2610 mg/kg: maternal
toxicity, increased
resorptions
Meta-xylene Mice-female/Oral 2000 mg/kg (only None GD8-12 Seidenberg et al., 1986
dose)
Xylenes VCCEP Submission 56
6.7 Immunotoxicity (see Table 6.6)
Mice exposed to p-xylene at concentrations of 0, 600, or 1200 ppm, 6 hours/day for 4 days, did not
exhibit adverse effects on splenic natural killer (NK) cell activity by exposure to concentrations as
high as 1200 ppm (Selgrade et al., 1993). Significant synergistic effects between cytomegalovirus
administered concurrently and 1200 ppm p-xylene were seen at four but not at seven days post-
infection, including serum SGPT, SGOT, and LDH activities indicative of liver damage. Significant
increases in SGTP and LDH due to virus alone and in cholinesterase due to p-xylene were still
apparent seven days post-infection. No synergistic effect was seen in serum enzymes following
exposure to 600 ppm p-xylene. Para-xylene significantly enhanced and virus significantly
suppressed P-450 levels measured four days post-infection. Increased mortality appeared to be
due to synergistic effects of virus and p-xylene in the liver, and not to immunosuppression.
Repeated oral exposure of male and female rats to m-, o-, or p-xylene at dose levels of 0, 250,
1000, or 2000 mg/kg/day for 10 consecutive days resulted in increased liver weight in both sexes
for all 3 isomers at 2000 mg/kg/day. Decreases in thymus and spleen weight were seen less
frequently, primarily for p-xylene (2000 mg/kg/day), and no corroborative histopathological changes
were seen in spleen or thymus (Condie et al., 1988). Weight decrements in spleen and thymus
may be indicative of slight immunological impairment or may be in response to systemic stress
induced by ingestion of high doses of xylenes over several days. Exposure of rats to 0, 150, 750,
or 1500 mg/kg/day mixed xylenes for 90 days did not cause decreases in thymus or spleen
weights (Condie et al., 1988). Intermittent exposure of rats and dogs to mixed xylenes for 10 to 13
weeks showed no effect on spleen weight (Carpenter et al., 1975).
6.8 Adult Neurotoxicity (see Table 6.7)
Exposure to xylenes by the oral or inhalation routes can result in nervous system effects such as
tremors, incoordination, muscle spasms, respiratory distress, hearing loss or elevated auditory
thresholds, lethargy, hyperactivity, and changes in brain enzyme activity and levels of brain protein.
Oral: CNS effects were reported in the NTP (1986) oral studies. In an acute oral study, rats and
mice (5/sex/group) were given a single dose of 0, 500, 1000, 2000, 4000, or 6000 mg/kg mixed
xylenes in corn oil (NTP 1986). Significant mortality was observed at 4000 (30% rats died) and
6000 mg/kg (100% rats, 70% mice). Clinical signs at 4000 and 6000 mg/kg included tremors,
prostration, and/or slowed breathing in mice; and lack of coordination, loss of hind limb movement,
prostration, and hunched posture in rats within 48 h ours. Surviving animals did not exhibit any
clinical signs by the end of the first week of observation.
B6C3F1 mice were administered mixed xylenes in corn oil at concentrations ranging from 125-
2000 mg/kg/day, 5 days/week for 13 weeks (NTP, 1986). Death of 2 female mice occurred at the
2000 mg/kg dose. Clinical signs included lethargy, short and shallow breathing, unsteadiness,
tremors, and paresis which began 5-10 min post-dosing and lasted 15-60 min in both sexes.
Decreased body weight gain was observed in males (7% below control) and females (17% below
control). No treatment related gross or microscopic changes were observed. For neurological
effects LOAEL was 2000 mg/kg/day; NOAEL was 1000 mg/kg/day.
Xylenes VCCEP Submission 57
Table 6.6: Representative Hazard Studies for Xylene Toxicity: Immunotoxicity (Tier 2)
Study Type Test Article Species/Route NOAEL LOAEL Duration of Reference
of Exposure Exposure
Immunotoxicity Para-xylene Mouse/Inhalation 1200 ppm, no effect on None 4 days, 6hr/d 0, 600, Selgrade et al.,
natural killer cells 1200 ppm 1993
Para xylene Mouse/Inhalation 600 ppm 1200 ppm: liver damage Mortality due to liver
at 4 d post- damage, not to
infection with immunotox.
cytomegalovirus
Meta-xylene Rat/Oral 1000 mg/kg 2000 mg/kg: inc. liver 10 days, o, 250, Condie et al.,
Para-xylene with for all isomers; decr. 1000, 2000 mg/kg/d 1988
Ortho-xylene relative thymus wt for
para-xylene
Mixed xylenes Rat/Oral 1500 mg/kg None: no effect on 90 days, 0, 150,
thymus or spleen wt 750, 1500 mg/kg/d
Xylenes VCCEP Submission 58
Inhalation: Neurological effects of acute exposures to xylenes in rats and mice vary in the dose
range of 114 ppm mixed xylenes effects on operant conditioning or self-stimulation behavior
(Ghosh et al., 1987; Wimolwattanapun et al, 1987) to 1000 ppm, o-xylene induction of immobility in
a behavioral despair swimming test (DeCeaurriz et al., 1983), cited in ATSDR, 1995. Bushnell
(1989) reported hyperactivity in rats at 1600 ppm p-xylene and Carpenter et al. (1975) observed
incoordination in rats given 1300 ppm mixed xylenes which did not persist after exposure ended;
no overt toxicity was observed at 580 ppm. At 2000 ppm, all three xylene isomers can induce
narcosis in rats after 1-4 hours of exposure (Molnar et al., 1986).
In the Korsak et al. (1992) study, 12 male Wistar rats were exposed to toluene, m-xylene, or a 1:1
mixture, 6hr/day, 5 days/week at a concentration of 100 ppm for 6 months or 1000 ppm for 3
months. Rats were trained on the rotarod (2 min evaluation period) prior to exposure. Meta-
Xylene alone induced significantly decreased rotarod performance and decreased spontaneous
activity 24 hrs after termination of exposure. Failure rate was 60% after 1000 ppm for 3 months
and 35% after 100 ppm for 6 months (values taken from graph). No exposure related changes in
body weight, absolute or relative organ weight, clinical chemistry or hematology were reported.
The LOAEL was 100 ppm; NOAEL was not determined. In a subsequent study at exposure
concentrations of 50 or 100 ppm, m-xylene for 3 months, decreased rotorod performance was
observed at both concentrations beginning at 1 month of exposure and remaining at the same level
until the end of 3 months (Korsak 1994). This study does not specify the timing of the neurologic
examinations, but an assumption is made by EPA that it was the same as the earlier study by the
same investigators; namely, 24 hours after termination of exposure (EPA 2003a). Failure rate was
8% at 50 ppm (not statistically significant) and 33% (p<0.05) at 100 ppm. Thus, the effect on
rotarod did not change following 1, 2, 3 or 6 months of exposure. LOAEL was 100 ppm and the
NOAEL was 50 ppm. A limitation of these studies is that the methods section did not provide
sufficient detail to determine whether experimental bias was controlled for (e.g. observer blind to
treatment level; time of testing balanced across dose groups; animals tested alone or adjacent to
other animals). This can make an important difference in the study as discussed by Hass et al.
(1995) who questioned the significance of their own rotarod effects following developmental
exposure to xylenes because of lack of control of experimental bias. In addition Hass et al. (1995)
reported that pilot studies showed that the noise when the first animal fell off the rotarod often
made the other animals fall off. The lack of methodological detail in the Korsak et al. studies raises
some uncertainty about the reliability of these results. Nevertheless, this effect on rotarod was
repeated in two separate studies (Korsak 1992, 1994) with a clearly defined NOAEL of 50 ppm.
Gralewicz et al. (1995) investigated whether xylenes exposure resulted in accelerated aging of the
CNS by exposing 8 month old male LOD-Wistar rats (total of 20 male rats divided into 3 groups of
unspecified numbers of animals) to 0, 100 or 1000 ppm m-xylene, 6 hours/day, 5 days/week for 3
months. Brain aging was evaluated by EEG, and spatial learning abilities in an 8-arm radial maze.
Exposed rats demonstrated some differences in radial maze performance and EEG spike and
wave discharge activities compared to controls 70-83 days after exposure, but effects were
inconsistent with the authors' hypothesis that xylenes causes accelerated brain aging. There were
no significant group or group by consecutive recordings interaction in any of the EEG
measurements. After multiple a posteriori analysis were conducted, a single difference on day 84
after exposure between controls and treated, but there was no difference between 100 and 1000
ppm group. No effects were noted on days 14, 28 and 56 days after exposure. The overall pattern
is not consistent with a treatment-related effect, and the effect that was noted is of uncertain
biological significance. There was a statistically significant group difference in trial duration on the
radial arm maze. The trial duration in the control group was significantly shorter than in both the
exposed groups, but there were no dose-related differences between the 100 and 1000 ppm
group. There were no statistically significant effects in total number of entries, omission errors or
Xylenes VCCEP Submission 59
perseveration errors with respect to group effect, group by days interaction or effect of days. The
1000 ppm group had fewer omission errors initially, but both the 100 and 1000 ppm group had
higher omission errors compared to controls by the last (5th) trial. The sample sizes of 7 or 6 make
it difficult to interpret the significance of these findings on radial arm maze without repeating the
study and evaluating the laboratory's historical control data. This effect on radial arm maze was not
reproduced in a later study (Gralewicz and Wiaderna., 2001), although differences in duration of
exposure and time of testing after exposure between the two experiments could have been a
factor.
This same group of investigators found no treatment-related effects of m-xylene (100 ppm; 4
weeks of exposure) on open field activity and active avoidance, but did find significantly shorter
step-down time (trial 6 only; no difference in trials 1-5) in the passive avoidance test and
significantly greater paw-lick latency in the hot plate - shock behavior test (Gralewicz and
Wiaderna, 2001). The results of the passive avoidance test are difficult to interpret because there
was no shock applied for trials 4, 5, and 6. This means there was no negative consequence of
stepping down more quickly. The hot plate test involved shocking the animal every 2 seconds for 2
minutes after the 1st of 3 hot plate trials but not after trials 2 (several seconds after shocking) or 3
(24 hours after trial 2). Meta-xylene exposed animals had a longer paw-lick latency for the 3rd trial
but not the 1st or 2nd trial. This indicates that m-xylene had no effects on hot plate paw-lick latency
per se, but did have an effect following repeated shocking of the animals immediately after the first
hot plate trial. The biological significance of this finding to humans is uncertain. This result was not
repeated by these investigators. In summary the same group of investigators (Gralewicz and
Wiaderna, 2001; Gralewicz et al., 1995) evaluated several behavioral endpoints and performed
multiple statistical comparisons that resulted in selected effects depending on statistical analysis
conducted as well as many negative results. The statistically significant effects are difficult to
interpret because these investigators usually did not repeat these findings using the same
behavioral endpoints under the same exposure conditions. In addition, the methods sections did
not indicate whether the behavioral experiments were conducted with appropriate control of
experimental bias (e.g. observers should be unaware of treatment level; time of testing should be
balanced across dose groups). Based on these results, the LOAEL was 100 ppm and the NOAEL
was not determined.
In studies measuring xylenes induced changes in brain enzymes and activity, Savolainen et al.
(1979) observed transient, decreased preening frequency and an increase in microsomal
superoxide dismutase activity in the brain of 20 male Wistar rats exposed to 300 ppm mixed
xylenes (85% m-, 15% o- and p- xylenes) 6hr/day, 5 days/week for 5-18weeks with or without
concomitant exposure to ethanol in drinking water. Anderson et al. (1981) reported decreased
acetylcholine and norepinephrine in the hypothalamus of Sprague Dawley rats exposed to 2000
ppm of one of the three isomers, 6 hours/day for 3 days. These results were suggestive of effects
on motor control, sleep, and memory maintenance. Rosengren et al. (1986) measured increased
regional brain concentrations of glial fibrillary acetic protein (GFAP), S-100 protein, and DNA in
brains of Mongolian gerbils (4 male and 4 female/group) exposed to xylenes (uncharacterized) at
concentrations of 0, 160, or 320 ppm for 3 months, followed by a 4-month post-exposure period.
These increases in GFAP, S-100 protein, and DNA were considered compatible with the presence
of astrogliosis. Padilla and Lyerly (1989) observed decreased axonal transport after acute
exposure to 800 ppm p-xylene, but the decrease was not apparent 3 days post-exposure. At 1600
ppm, decreased axonal transport persisted for 13 days after exposure ceased.
In summary, the weight of evidence indicates that slight effects on rotarod are noted at the LOAEL
of 100 ppm that do not change in severity with increasing duration of exposure. The NOAEL for
this endpoint is 50 ppm, based on the same study (Korsak 1994), and this is used as the critical
effect and point of departure in the Risk Assessment (see Section 8.1).
Xylenes VCCEP Submission 60
6.9 Auditory Toxicity (see Table 6.7)
Pryor et al. (1987) demonstrated ototoxicity in male weaning F344 rats exposed to 0, 800, 1000, or
1200 ppm mixed xylenes (10% p-, 80% m-, 10% o-xylene) 14 hours/day for 6 weeks. All exposed
rats had concentration dependent increases in behavioral auditory thresholds and measured
brainstem auditory evoked response (BAER) relative to controls at some frequency (4, 8, 12, or 20
kHz). LOAEL was 800 ppm; a NOAEL not d etermined. Pryor et al. (1987) also reported that
hearing loss occurred in rats exposed to 1450 ppm mixed xylenes for 8 hours, but exposure to
1700 ppm for 4 hours did not affect hearing, indicating that duration of exposure is important for the
observation of ototoxic effects in the conditioned avoidance test. Male Sprague Dawley rats
exposed to air containing 1000 ppm mixed xylenes (1.5% o-, 65% m-, 32% p-xylene, 2.5%
ethylbenzene) 18 hours/day. 7 days/week for 61 days demonstrated statistically significant
decreased body weight and slight loss of auditory sensitivity by BAER compared to controls 2 days
after exposure ended (Nyl閚 and Hagman, 1994). No adverse effects were observed on flash
evoked potentials or nerve and muscle action potentials measured in the tail. Adult male Long-
Evans rats were exposed by inhalation to 1800 ppm mixed xylenes, 8 hours/day for 5 days.
Testing of auditory function was conducted five to eight weeks after exposure using reflex
modification audiometry (RMA). RMA thresholds were determined for frequencies from 0.5 to 40
kHz. The RMA thresholds were increased for the mid-frequency tones (e.g., 8 to 16 kHz), and at
24 kHz for the xylene-exposed animals (Crofton et al., 1994). Gagnaire et al. (2001) exposed male
rats to o-, m- or p-xylene by inhalation at concentrations of 450, 900, or 1800 ppm, 6hours/day, 6
days/week for 13 weeks and sacrificed the rats 8 weeks after end of exposure. Brainstem auditory
evoked responses were used to determine auditory thresholds at different frequencies. Only p-
xylene produced moderate to severe ototoxicity in 900 and 1800 ppm exposed rats and thresholds
did not reverse after 8 weeks recovery. Moderate to severe losses of outer hair cells in the organ
of Corti were seen in the p-xylene exposed rats. The NOAEL for p-xylene was 450 ppm and the
NOAEL for m- and o-xylene was 1800 ppm.
Xylenes VCCEP Submission 61
Table 6.7: Representative Hazard Studies for Xylene Toxicity: Adult Neurotoxicity and Auditory Toxicity (Tier 3)
Study Type Test Article Species/Route NOAEL LOAEL Duration of Reference
of Exposure Exposure
Adult Meta-xylene Rat-male/ 50 ppm 100 ppm ?decr. motor 3 months, 6hr/d, Korsak et al.,
Neurotoxicity Inhalation 5 d/wk 1994
activity; decr. rotorod activity
beginning at 1 mon
exposure to end of study at
same level
Mixed xylenes Mouse/Oral 2000 mg/kg 4000 mg/kg: CNS effects Single dose, 0, NTP, 1986
Rat/Oral 500, 1000, 2000,
within 48hr of exposure
4000, 6000
mg/kg: mortality
at 4000 & 6000
mg/kg
Mixed xylenes Rat/Oral 500 mg/kg None 103 weeks, NTP, 1986
5 d/wk- 0, 250,
[per ATSDR, 1995]
500 mg/kg/d
[see Sect. 6.10
Chronic)
Astrogliosis Xylene Gerbils/ None 160 ppm: incr. GFAP 3 months, 0, Rosengren et al.,
[GFAP] uncharacterized Inhalation 160, 320 ppm; 1986
conc., S-100protein and
DNA in brains sacrificed 4
months post-
exposure.
Auditory Mixed xylenes Rat-weanling None 800 ppm; incr. auditory 6 wks, 14hr/d Pryor et al., 1987
Toxicity male/ Inhalation threshold, inc. BAER 0, 800, 1000,
Hearing loss also at 1450
1200 ppm
ppm for 8 hr. No effect at
1700 ppm for 4 hr.]
Mixed xylenes Rat-male/ None 1000 ppm (only dose): 61 days, 14hr/d, Nyl閚 and
Inhalation 7d/wk
decr. body wt, inc. BAER at Hageman, 1994
2 days post-exposure
Meta-xylene Rat-male/ 1800 ppm None 13 wks, 6hr/d, Gagnaire et al.,
Para-xylene Inhalation 450 ppm 900 ppm 6d/wk 2001
Ortho-xylene 1800 ppm None 0, 450, 900,
1800 ppm
Xylenes VCCEP Submission 62
6.10 Developmental Neurotoxicity (see Table 6.8)
Several investigators have evaluated effects of prenatal exposure to xylenes on neurobehavioral
development. The currently available developmental neurotoxicity studies are limited by the
absence of dose response data and a definitive NOAEL level. However, they provide very
comprehensive evaluation of the critical endpoint of concern during a period of in utero
development when the brain is rapidly developing. Hass et al. (Hass and Jakobsen, 1993, Hass
1995, Hass 1997) has done the majority of this research, conducting two separate developmental
neurotoxicity of mixed xylenes in rats. The first study conducted at 200 ppm (Haas and Jakobsen,
1993) was not considered by the authors to be as reliable as the second study (Haas et al., 1995)
which was conducted at 500 ppm. Some animals from the second study were maintained for up to
a year for additional follow 璾p examination (Haas et al., 1997).
The Hass and Jakobsen (1993) study is discussed in Section 6.6. The only developmental
neurotoxicity evaluation from this study was a decrease in rotarod performance in rats exposed in
utero to 200 ppm mixed xylenes. In a later publication, these researchers noted methodology
concerns with the rotarod evaluation of the 1993 study. These effects were not considered
treatment related because there were no effects at 500 ppm mixed xylenes when experimental
conditions to reduce bias were better controlled (Hass 1995).
Hass et al (1995) exposed pregnant Wistar rats to 0 or 500 ppm mixed xylenes (19% o-, 45% m- ,
20% p-xylene, 15% ethylbenzene) 6 hours/day on GD7-20. From each litter, 2 of each sex were
selected for behavioral testing: one/sex/litter were kept in standard housing [2 same sex, same
dose rats/cage], left undisturbed except for feeding and weighing until 3 months of age when they
were tested in the Morris water maze; one/sex//litter were kept in an enriched environment (4-5
same sex, same dose rats/cage; cages contained toys) and tested for rotarod, open field and
Morris water maze performance at 3 months. Mixed xylenes exposure did not adversely affect
maternal clinical signs, body weight gain or food consumption. Both control and exposed groups
had similar gestation periods, number of pups/litter and sex distribution/litter. Litters from exposed
dams had a slight decrease in mean birth weight (5%) and a trend toward lower body weight during
the postnatal period (not statistically significant). At necropsy on postnatal day 28, absolute brain
weights were statistically significantly decreased for males and females combined but not when
sexes were analyzed separately for absolute weight or for relative brain/body weight ratios
separately or sexes combined.
There were no statistically significant effects on rotarod performance at 500 ppm indicating that the
investigators were unable to repeat effects on rotarod performance at 200 ppm in their earlier study
(Haas and Jacobson, 1993). The mean time on the rotarod was shorter and a higher percentage
of animals in the exposed group failed to stay on the rod for 30 seconds compared to controls with
females more affected than males. The air-righting reflex was delayed by one day in exposed
litters due to the ability of only 4 pups from 4 litters to right themselves. All animals were able to
right themselves on postnatal day 17. No differences were observed in open field activity.
Offspring from xylene-exposed rats raised in cages with various toys showed no difference in the
Morris water maze compared to controls. Offspring raised in standard housing showed impaired
performance at 12 weeks when a non-significant trend for increased latency in finding the platform
in the beginning of the learning test was evident. The effect was attributed to a slight increase in
latency during the first 2 trials of a 5-trial learning phase with no difference in learning during the
last 3 trials. At 16 weeks, females also used significantly more time to find a hidden platform in the
center of the pool and showed an increase in swimming length, while speed was not affected.
Although these effects are statistically significant, the latency for treated females was less than 6-
13 seconds which is comparable to male control values and also similar to the latency during the
5th day of the initial learning phase for all control offspring. Male offspring of exposed dams
Xylenes VCCEP Submission 63
performed comparably to controls. The overall effects on developmental neurotoxicity from this
study, especially noting the lack of effects in a separate group of treated females that had various
toys in their cages, appear to be relatively slight effects.
In a follow-up study to assess persistence of the decreased water maze performance, these same
female offspring raised in standard housing were maintained and evaluated at 28 and 52 weeks.
(Hass et al, 1997). At 28 and 55 weeks, an increased latency in finding the platform in the center
was not repeated. There was an effect in finding the platform when placed in a new position not
earlier used on the rim (original starting point) and animals were placed in a new starting point.
Increased latency again corresponded to increased swimming length was measured on the first
trial but resolved itself by the second and third of 3 trials. No other significant differences were
observed for other testing situations in the water maze and no statistically significant differences of
any kind were observed at 55 weeks. Xylene exposure during development may cause subtle
deficits in some learning and memory tasks of offspring, which eventually resolve in the absence of
additional exposure as the animal matures. These data were limited because no dose-response
can be determined and no clear effect in other neurological tests was observed (EPA, 2003a). The
learning and memory test involved 10 component phases each with four to five trials. While this
extended evaluation may increase the possibility of detecting very subtle effects, there is also
increased opportunity for statistically significant effects that may not be treatment related.
An additional developmental neurotoxicity study was conducted, by a separate laboratory, on p-
xylene in rats (Rosen et al., 1986). In this study, the Chernoff/ Kavlock screen was used on
exposed pregnant Sprague Dawley rats (25/group) to 0, 800 or 1600 ppm para-xylene (99% pure)
on GD7-16. No adverse effects were observed on litter size or pup weight at birth or on postnatal
day 3. No effects were seen on central nervous system (CNS) development measured by acoustic
startle response on postnatal day 13, 17, 21 and 63, or the figure 8 maze activity on days 22 and
65; or on pup growth rate. The only effect of exposure was a significant decrease in maternal body
weight in 1600 ppm dams (74% of control values). The maternal LOAEL was 1600 ppm; the
developmental neurotoxicity NOAEL was 1600 ppm.
Previous shorter term studies did not indicate a consistent difference in effects of p-xylene or m-
xylene on neurobehavioral endpoints (Moser et al., 1985; Gagnaire et al., 2001; Korsak et al.,
1990).
In summary, developmental neurotoxicity data have been developed on mixed xylenes, by Hass et
al. (1993, 1995, 1997), in which exposure of pregnant rats at 500 ppm during most of gestation
resulted in some learning and memory effects in offspring tested from 2 days to 16 weeks
postnatally. These investigators questioned the significance of their own results at 200 ppm
conducted in the earlier study (Hass 1993) because of lack of control of experimental bias and
because these decreases in rotarod performance could not be replicated at the higher exposure
levels of 500 ppm with improved methods (Hass 1995). A different group of investigators from EPA
Health Effects Research Laboratory demonstrated that p-xylene did not affect neurobehavior in
offspring of dams exposed to 800 and 1600 ppm prenatally (Rosen 1986). Taken together, these
studies provide comprehensive sophisticated evaluation of many neurobehavioral endpoints at
multiple time points following exposure during the vulnerable period of rapid brain development.
Although each study is limited in the number of dose levels, they collectively provide sufficient
evaluation to conclude that there are slight effects in offspring at exposure levels of 500 ppm.
These slight effects were measured primarily in female offspring and were not measured in males
or in females with various toys in their cages. These studies support a LOAEL of 500 ppm for
developmental neurobehavioral effects and support EPA's conclusion that the developing
organism is not more sensitive than the adult to xylene exposure (EPA 2003a).
Xylenes VCCEP Submission 64
Table 6.8: Representative Hazard Studies for Xylene Toxicity: Developmental Neurotoxicity (Tier 3)
Study Type Test Article Species/Route NOAEL LOAEL Duration of Reference
of Exposure Exposure
Developmental Mixed-xylene Rat-female/ None 200 ppm ?(only dose) GD 6-20, 6hr/d, Hass and Jakobsen,
Neurotoxicity Inhalation decr. rotorod activity by 7d/wk 1993
pups at postnatal days 22,
23; delayed skull
ossification; no other
reproductive effects.
Mixed xylenes Rat-female/ None 500 ppm ?(only dose) GD7-20, 6hr/d, Hass et al., 1995,
Inhalation slight decreased pup wt; air 7d/wk 1997
righting reflex delayed 1
day; decr. water maze
performance in female pups
(std. housing) at 12, 16
wks, resolved by 55 wks
Para- xylene Rat-female/ 1600 ppm None: no effect on offspring GD 7-16, 0, 800, Rosen et al., 1986
Inhalation developmental parameters, 1600 ppm
acoustical startle response [Chernoff-Kavlock
or figure 8 maze screen]
performance
Maternal LOAEL=1600 ppm
Xylenes VCCEP Submission 65
6.11 Chronic Toxicity and Carcinogenicity (see Table 6.9)
Chronic Toxicity:
The NTP (1986) conducted studies in rat and mouse with mixed xylenes (60% m-, 13.6% p-, 9.1%
o-xylene, 17% ethylbenzene) dissolved in corn oil and administered by gavage, 5 days/week for
103 weeks. Clinical signs and effects on tissues and organs were evaluated. Gross necropsies
were performed on all animals, and comprehensive histologic examinations were conducted.
Groups of 50 male and 50 female rats received doses of 0, 250, or 500 mg/kg/day. Effects of
exposure were limited to high dose males, which weighed 4% less than controls at termination and
showed increased mortality that was likely related to gavage errors; however, definitive evidence
that gavaging errors were responsible for increased mortality was not obtained. Groups of 50 male
and 50 female mice received doses of 0, 250, 500, or 1000 mg/kg/day. Hyperactivity was
observed 5-30 minutes after dosing in all high dose mice from week 4 until termination. No other
effects were noted.
In the mouse, NOAEL and LOAEL were 500 mg/kg/day and 1000 mg/kg/day, respectively, based
on hyperactivity. In the rat, based on increased mortality, a tentative NOAEL of 250 mg/kg/day and
a LOAEL of 500 mg/kg/day were assigned. However, these values should be taken in the context
of possible gavaging errors.
Carcinogenicity:
Cancer studies have been performed by the oral route. These studies include the NTP (1986)
chronic study in rat and mouse described above and a rat study conducted by Maltoni et al. (1983,
1985) with mixed xylenes. In the NTP (1986) studies there were no treatment related tumors in
mice or rats ascribed to treatment with mixed xylenes and indicate no potential for caricongenic
activity up to the highest doses tested in rats (500 mg/kg/day) and mice (1000 mg/kg/day). In the
Maltoni study, groups of 40 male and 40 female rats were dosed by gavage with a mixture of o-, m-
, and p-xylenes (in unknown proportions), dissolved in olive oil, at doses of 0 or 500 mg, 4 -5
days/week for 104 weeks, after which dosing was discontinued and the rats were observed until
natural death. An increase in total number of tumors was induced by xylene treatment. However,
tumor types were not specified, the aged rats died at different times, and the work was
incompletely reported. Thus, there is no acceptable basis for assessing the validity of the results.
Xylenes VCCEP Submission 66
Table 6.9: Representative Hazard Studies for Xylene Toxicity: Chronic Toxicity and Carcinogenesis (Tier 3)
Study Type Test Article Species/Route NOAEL LOAEL Duration of Reference
of Exposure Exposure
Chronic Toxicity Mixed-xylene Rats/oral: male 250 mg/kg 500 mg/kg ?mortality 103 wk, 5d/wk NTP (1986)
female 500 mg/kg > 500 mg/kg
Carcinogenesis Mixed xylenes Rats/oral (M&F) 500 mg/kg >500 mg/kg 103 wk, 5d/wk NTP (1986)
Mice/oral (M&F) 1000 mg/kg >1000 mg/kg
Xylenes VCCEP Submission 67
6.12 Toxicokinetics and Metabolism
The absorption, distribution, metabolism, and elimination of xylenes have been extensively studied
and are well characterized. Xylenes are rapidly absorbed by the respiratory tract with uptake
increased by physical exercise. Absorption is also positively correlated with the amount of body
fat. Liquid m-xylene is well absorbed through the skin, but dermal absorption of m-xylene vapor
(up to 600 ppm) does not appear to be appreciably absorbed. Xylenes are highly soluble in blood
and fat, and are distributed widely in the body. Xylenes undergo extensive metabolism and are
primarily excreted as metabolites in the urine with small amounts released unchanged in expired
air. About 90% of the absorbed dose is excreted in the urine as methylhippuric acid, the glycine
conjugate of methylbenzoic acid, following inhalation or dermal (liquid) exposure.
Absorption
Animals: Whole body exposure of mice to 14C-m-xylene vapor for 10 minutes showed that
absorption was mainly via respiration (Bergman, 1979, 1983). In pregnant mice, approximately
30% of inhaled p-xylene (600 ppm) was absorbed after 10 minutes of exposure (Ghantous and
Danielsson, 1986).
Almost complete absorption of 1.8 g m-xylene, or 1.7 g p- or o-xylene was observed in orally dosed
rodents (Bray et al., 1949). Absorption after oral administration was rapid and peak levels of m-
xylene were seen 20 minutes after a dose of 0.27 mg/kg (Turkall et al., 1992). After oral
administration, absorption rate was faster in females.
Dermal absorption has been studied by in vivo exposure of rat skin to liquid or vapor (Skowronski
et al., 1990; McDougal et al., 1990). Permeability constants were determined and were higher
than those for humans. In excised rat skin preparations, duration of exposure correlated with level
of skin penetration (Tsuruta, 1982); rate was 0.967 nmole/ cm2/min. Skin:air partition coefficient for
m-xylene was 50.4?.7 (Mattie et al., 1994) and this correlated with the permeability constant
(McDougal et al., 1990).
Distribution
Animals: In rats and mice (Ghantous and Danielsson, 1986; Carlsson, 1981), m- and p-xylene are
distributed primarily to lipid-rich tissues, such as fat, blood, and brain and also in organs highly
perfused with blood such as kidney and liver. Small amounts of p-xylene and o-xylene cross the
placenta and distribute to amnionic fluid and fetal tissue (Ghantous and Danielsson, 1986; Ungv醨y
et al., 1980b).
Oral administration of m-xylene to rats led to distribution of 14C-m-xylene in adipose tissue,
approximately 0.3% of dose in female and 0.1% in males (Turkall et al., 1992). There were no
available studies in which systemic distribution of xylene was determined after dermal
administration.
Metabolism
Animals: The principal pathway in the rat for m- and p-xylene is the same as that in humans, side-
chain oxidation and conjugation with glycine and glucuronic acid (Sugihara and Ogata, 1978;
Ogata et al., 1980; Elovaara et al., 1984). For o-xylene, the glucuronide formation predominates
(Ogata et al., 1980) and a small amount of sulfate conjugate also is produced. Hydroxylation of the
aromatic ring of xylenes is also a minor pathway in the rat (Bakke and Scheline, 1970; Elovaara et
al., 1984).
Xylenes VCCEP Submission 68
Generally in animals, the metabolism of xylenes is similar to that of humans but there are some
qualitative differences (Figure 1). The major difference is in the metabolism of methylbenzoic acid
as noted above for o-xylene. Metabolism of xylenes may be influenced by prior exposure
(Elovaara et al., 1987). Rats pretreated with m-xylene showed an approximately 10% increase in
the percentages of methylhippuric acid and thio ethers in urine. Gastric intubation of rats with 1.1-
1.4 ml/kg of m-xylene for 3 consecutive days was found to induce CYP2B and CYP2E1 in liver
microsomes (Raunio et al., 1990). In the Wistar rat, 4 days of inhalation of xylene at 4 g/m 3, 20
hours/day, induced CYP2B1 but reduced CYP2E1 (Gut et al., 1993).
Elimination
Animals: After an oral dose of radiolabeled m-xylene, rats excreted most of the radioactivity [50-
59%] in urine within 12 hours of dosing, with expired air secondary [8-22%] (Turkall et al., 1992).
m-Methylhippuric acid conjugates were 67-75% of the label with xylenol , 2-18%, and unchanged
m-xylene approx. 1%. Excretion in expired air was less in males (8%) t an in females (22%),
h
suggesting a higher metabolic capacity in males.
After dermal administration, the primary route of excretion of m-xylene was in expired air (62% of
dose) with 43% in urine (Skowronski et al., 1990). Most of the air excretion was in the first 24
hours. Less than 0.5% was excreted in feces. The urinary metabolites of xylenes are similar when
dosing is by different routes but the quantities of the different metabolites vary more with degree of
absorption than with dose or duration of exposure (ATSDR, 1995).
The neurotoxic effects of xylenes are commonly attributed to the distribution and accumulation of
the xylenes in neuronal membranes. However, metabolites have also been mentioned as possible
sources of toxicity. Savolainen and Pf鋐fli (1980) suggested that brain cell microsomal enzymes
might oxidize xylenes to toxic intermediates such as methylbenzaldehyde and arene oxides.
Inhibition of pulmonary enzymes has also been attributed to the formation of reactive intermediates
(Patel et al., 1978; Smith et al., 1982) that bind to microsomal protein and inactivate the enzymes.
6.13 Human Experience
This section summarizes the available human data, but does not analyze the studies in depth as
human studies are not used in the quantitative development of the RfD and RfC. In general, these
human studies are not well reported and have few numbers of observations, with no systematic
review of confounding exposures from smoking or other occupational and environmental sources.
They frequently include exposures to a variety of solvents and chemicals in addition to than
xylenes. Moreover, many of the studies report subjective symptoms common in the general
population, such as headache and dizziness.
6.13.1 Acute Toxicity
Acute poisoning and mortality have occurred after very high exposures, such as that resulting from
oral ingestion. Loss of consciousness occurs at approximately 10,000 ppm (Morely et al., 1970).
Individuals recovering from severe overexposure exhibit EEG alterations, confusion, coma,
nystagmus, gastrointestinal effects, and impaired renal and hepatic function (Ghislandi and
Fabiani, 1957; Recchia et al., 1985). Recchia et al. (1985) reported that recovery was generally
complete.
Xylenes VCCEP Submission 69
TABLE 6.10. Single inhalation exposure to xylene in humans
Exposure Concentration Time Effect Reference
(mg/m3)
3,000 (690 ppm) 1 hr Dizziness, irritation Klaucke et al. (1982)
3,000 (690 ppm) 15 min Dizziness Carpenter et al. (1975)
1300 during exercise (299 ppm) 2 hr Performance decrement Gamberale, et al. (1978)
900: peak values of 1800 mg/m3 4 hr Prolonged reaction times Laine et al. (1993)
900 (207 ppm) 4 hr Impairment of vestibular and visual Savolainen et al. (1979,
function and prolonged reaction 1981, 1982, 1985)
time
900 (207 ppm) 4 hr Minor effect on EEG Sepp鋖鋓nen et al. (1991)
600 (138 ppm) 4 hr No effect on reaction time Savolainen et al. (1980,
1981)
450 (103.5 ppm) 4 hr Prolonged reaction time Dudek et al. (1990)
300 (69 ppm) 4 hr No effects in psychophysiological Anselm-Olsen et al. (1985)
test
From IPCS, 1997
Xylenes VCCEP Submission 70
Information on controlled acute toxicity studies in humans is summarized in Table 6.10
(IPCS, 1997). These studies demonstrate that 4-hour exposure to xylenes at
approximately 200 ppm can cause impairment of sensory motor and information
processing in the CNS, though these effects were reversible upon termination of exposure.
Some evidence of effects on reaction times in humans was also observed above 100 ppm,
though the results were varied. A study at 103.5 ppm for 4 hours showed prolonged
reaction time (Dudek, 1990) while similar studies at higher levels ?138 ppm for 4 hours ?br>
showed no effect on reaction time (Savolainen 1980, 1981). No effects were observed
were below 100 ppm.
Carpenter et al. (1975) reported that 15-minute inhalation exposure to mixed xylenes
induced eye irritation at a LOAEL of 460 ppm and throat irritation at a LOAEL of 690 ppm.
Hastings et al. (1986) showed similar results with 30-minute inhalation exposure, reporting
NOAEL of 400 ppm for respiratory and eye irritation. The Hastings et al. (1986) study was
the basis for the AEGL-1 values (see Section 3.2).
6.13.2 Repeat Dose Toxicity
Case reports and occupational studies are often difficult to evaluate because exposure
conditions are either not well characterized or subjects may have been exposed to other
chemicals in addition to xylenes. High-level exposure to xylenes or solvents containing
xylenes can induce a variety of neurological symptoms in humans ranging from dizziness,
headache, nausea, difficulty in concentrating, to slurred speech, ataxia, tremors at higher
acute exposures, and in isolated instances, unconsciousness, amnesia, and epileptic
seizures (ATSDR, 1995).
Seizures following exposure to products that contain xylenes and other chemicals have
been reported in case reports by several investigators. Goldie (1960) reported that 8
painters exposed to paint containing 80% xylenes and 20% methylglycolate complained of
headache, vertigo, gastric discomfort, and slight drunkenness after 30 minutes. After 2
months exposure, an 18-year old worker exhibited symptoms of convulsive seizure
including weakness, dizziness, inability to speak, and unconsciousness but recovered 20
minutes later. Arthur and Curnock (1982) reported major and minor seizures in an
adolescent worker using a glue containing xylenes and other chemicals for building model
airplanes. Exposure concentrations were not reported in either case report.
Exposure to up to 700 ppm xylenes in the workplace for at least 1 hour resulted in
vomiting, vertigo, nausea, headache, eye and nasal irritation, and dizziness in a group of
15 employees (Klaucke et al., 1982). Hipolito (1980) reported severe symptoms (e.g.,
leukopenia, chest pain, ECG abnormalities, dyspnea, impaired lung function, mental
confusion, and complete disability) in 5 female workers after 1.5-1.8 years exposure to
xylene.
Long term exposure (10-44 years) of 83 spray painters to mixed solvents at levels
predominantly below historical TLVs was associated with an increase (p<0.05) in
depression and "loss of interest" but no significant effects on psychological performance
tests or CAT-scan measures of brain atrophy were found (Triebig et al., 1992 a,b).
Chinese factory workers reported a variety of subjective symptoms after being exposed for
an average of 7 years to xylenes levels of 21 ppm TWA arithmetic mean (14 ppm TWA
geometric mean), measured with a diffusion sampler (Uchida et al., 1993). Peak
exposures were not reported or considered. Xylenes were reported to comprise the
Xylenes VCCEP Submission 71
majority of the total workplace solvent exposure that also included 1 ppm toluene and 3
ppm ethylbenzene. No information on other chemicals in the workplace was reported. The
symptoms included increased prevalence of anxiety, forgetfulness, inability to concentrate,
and dizziness.
6.13.3 Genetic Toxicity
Limited human data are available regarding genotoxic effects of mixed xylenes following
inhalation or oral exposure and no studies have been reported on genotoxic effects from
m- o- or p-isomers individually. Haglund et al. (1980) examined workers in the Swedish
paint industry exposed to mixtures of organic solvents, mainly toluene and xylene. The
threshold limit value was 436 mg/m 3. No differences in the frequency of sister chromatid
exchanges or chromosome aberrations were found in peripheral blood lymphocytes from
16 exposed workers and a matched unexposed reference group (0.192 or 0.193
SCE/chromosome, respectively). No correlation was found between xylene or toluene
exposure and SCE frequency. The frequency of chromosome aberrations was also
investigated in the 5 most exposed workers and a matched reference group and no
differences were found. Sister chromatid exchange in peripheral lymphocytes were also
studied in two groups of 23 workers each with exposures of 11 and 13 ppm (47.3 and 55.9
mg/m 3) mixed xylenes (containing ethylbenzene) for between 4 months and 23 years (Pap
and Varga, 1987). No differences in SCE frequency were seen. A worker study by Zhong
et al. (1980) gave similar negative results. Studies of filling station attendants exposed to
xylene among other petroleum derivatives (chemical exposure levels were not provided)
did not demonstrate increases in sister chromatid exchanges (SCE) or micronucleus
frequencies (Pitarque et al., 1997a,b). Although Funes-Cravioto et al. (1977) described
increased incidences of chromosome aberrations or effects on SCE in laboratory and
rotogravure printing workers, results are difficult to assess because exposure levels of
xylene were not defined or xylene was accompanied by exposure to other solvents
including benzene. Richer et al. (1993) performed a controlled study with 5 adult, white
male volunteers to examine cytogenetic effects of xylene (40 ppm) or toluene (50 ppm)
alone or in combination, administered 7 hours/day over 3 consecutive days. Exposures
were repeated 3 times at 2-week intervals with blood samples taken before and after each
exposure cycle. No significant effects on SCE, cell cycle delay, or cell mortality were
induced by xylene or toluene, or the mixture. In vitro exposure of human blood
lymphocytes to xylene (0-2 mM) for 72 hours did not cause significant cytogenetic effects
at lower concentrations and only increased cell d eath at high concentration. These
studies indicate that mixed xylenes do not induce genetic toxicity in humans exposed
occupationally or under controlled conditions (ATSDR, 1995).
6.13.4 Reproductive and Developmental Toxicity
No studies have been located which address fecundity and reproductive effects in humans
following oral exposure to mixed xylenes or individual isomers and very limited data is
available by the inhalation route. Effects on pregnancy outcome were studied among
university laboratory workers exposed to xylenes primarily by inhalation (exposure levels
not identified) during the first trimester of pregnancy. There were no differences in
miscarriage rate compared to controls not exposed to solvents (Axelsson et al., 1984). A
similar case control study by Taskinen et al. (1994) reported an increase in spontaneous
abortion among 37 workers exposed to xylene and formalin as well as other solvents used
Xylenes VCCEP Submission 72
in histology and pathology laboratories, three or more days per week during the first
trimester of pregnancy. Exposures also appeared to be associated with an increase in
birth weight. Occupational exposure of men to solvents in the same study were reported
to increase the potential of their wives to experience spontaneous abortion. Because of
exposure to multiple solvents, the exact role of xylenes could not be determined.
There are no occupational or environmental studies available that address the
developmental or teratogenic effects of xylenes in the absence of other chemical agents in
humans. There are limited studies that involve concurrent exposure to chemical agents in
addition to xylenes, but they cannot be used to assess the relationship between xylenes
exposure and developmental effects. Two case reports suggest that congenital defects
observed in the CNS of children were associated with maternal occupational exposures to
mixed xylene vapors (Holmberg and Nurminen, 1980; Kucera, 1968). These studies had
many limitations and no conclusions can be drawn about causation.
6.13.5 Immunotoxicity
Little human data are available to evaluate the immunological or lymphoreticular effects of
xylenes. Decreased serum complement (Smolik et al., 1973) and decreased lymphocyte
counts (Moszczynski and Lisiewicz, 1983, 1984) were reported in workers exposed to 0.13
ppm xylenes and other chemicals, including benzene and toluene for 0.25-18 years.
Moszczynski and Lisiewicz (1984) reported that workers, after service of 4 -10 years,
showed decreased T-lymphocyte count without alteration in function. No clinical signs of
diminished immunological reactivity were noted in the subjects. Palmer and Rycroft
(1993) reported immunological contact uticaria in one worker exposed to xylenes vapor.
6.13.6 Adult Neurotoxicity
Neurological effects in humans following oral or dermal exposure to xylene have not been
studied, but there are some experimental studies, case reports, and occupational studies
by the inhalation route. Results of experimental studies with human volunteers indicate
that acute inhalation exposure to mixed xylenes or m-xylene caused impairment of short-
term memory, reaction time, performance decrements in numerical ability, and alteration in
equilibrium and body balance. These effects are reversible upon termination or removal
from exposure. Effects appear to occur in the range of 100 to 200 ppm with a NOAEL of
70 ppm (Olson 1985).
In controlled experimental studies, Carpenter et al. (1975a) stated that dizziness was
reported by four of six subjects exposed to 690 ppm p-xylene for 15 minutes but only 1 in
6 subjects exposed to 460 ppm. No impairment in performance test results were observed
in 10 male sedentary subjects exposed to 400 ppm xylenes for 30 minutes (Hastings et al.,
1986). No impairment was observed in 15 male subjects exposed to 300 ppm mixed
xylenes (40% ethylbenzene) for 70 minutes, but exposure to 300 ppm for 70 minutes with
exercise resulted in impaired short-term memory and reaction time (Gamberale et al.,
1978). The increased CNS response may have resulted from increased xylenes
respiratory uptake during exercise. Dudek et al. (1990) determined that exposure to 100
ppm mixed xylenes for 4 hours induced prolonged reaction time. Exposure to 70 ppm p-
xylene for 4 hours did not adversely affect heart rate, subjective symptoms, simple
reaction time, choice reaction time, or short-term memory (Olson 1985). When
Xylenes VCCEP Submission 73
Sepp鋖鋓nen et al. (1991) exposed 9 male volunteers to 200 ppm (TWA) m-xylene for 4 hr
with short-term peak exposures up to 400 ppm, effects on electroencephalography (EEG)
were minor and no deleterious effects were observed. Under comparable exposure
conditions, Laine et al. (1993) saw no clear effects on visual reaction time or auditive
choice reaction time in 9 male volunteers exposed to levels of m-xylene fluctuating
between 135-400 ppm (TWA 200 ppm), although Sepp鋖鋓nen et al. (1989) had reported a
slight decrease in the latency of visual evoked potentials. Exposure of subjects to p-
xylene for 4 hours, or up to 7 hours/day for 5 days at concentrations ranging from 69-150
ppm did not affect objective measures of neurological function, including EEG, motor
activity or cognitive performance (Hake et al., 1981; Olsen et al., 1985). Hake et al. (1981)
did observe some sex differences in subjective reports of CNS effects. Women exposed
to 100 ppm p-xylene for 1 to 7.5 hours/day for 5 days reported headache and dizziness as
a result of exposure although no effects were seen on EEG, evoked potentials, or
cognitive performance. Men exposed at concentrations up to 150 ppm under a similar
regimen reported no increase in headaches or dizziness. Overall, experimental human
studies suggest that exposure to 100 to 200 ppm (435-870 mg/m 3) xylenes over 4 hours
may have caused a slight impairment in reaction time performance and vestibular function.
Adaptation at 200 ppm m-xylene to the impairment occurred over 5 successive days.
6.13.7 Metabolism
Absorption: Absorption of xylenes has been studied via inhalation and dermal
routes of administration. After 5 to 10 minutes of inhalation exposure to 100 ppm (430
mg/m 3), pulmonary retention of m-xylene was relatively constant at approximately 60%
(Riihim鋕i et al., 1979a). Pulmonary retention of o-, m-, and p-xylene at 45-90 ppm (196?br>
391 mg/m 3) was reported by Sedivec and Flek (1976) to be 62-64% for exposure up to 7
hours. During rest and intermittent exercise, m-xylene retention was 59% at exposures of
70-220 ppm (304-957 mg/m 3). Exercise induced increased rates of breathing associated
with increased retention (Riihim鋕i et al., 1979b; 舠trand et al., 1978). Similar rates of
pulmonary absorption of ethylbenzene and xylenes were observed by Engstr鰉 and
Bjurstr鰉 (1978). Retention does not appear to differ with gender (Senczuk and Orlowski,
1978). Absorption occurred in two phases, a short phase (0-15 minutes exposure) and a
longer phase of approximately 1 hour that represented a steady state between blood and
inhaled xylenes.
Dermal absorption of m-xylene vapor has been studied in volunteers exposed at
300 ppm (1305 mg/m 3) and 600 ppm (2610 mg/m 3) for 3.5 hours (free of respiratory
exposure). Dermal absorption was found to be directly proportional to the vapor
concentration. At 1305 mg/m 3, absorption was approximately 0.01 礸/cm2 skin/min
(Riihim鋕i and Pf鋐fli, 1978). Dermal absorption of liquid xylenes has been studied via
determination of uptake after a 15-20 minute hand immersion in neat m-xylene. Uptake
was estimated by measuring the level of m-methylhippuric acid (m-xylene metabolite) in
urine of 8 volunteers. Mean absorption was approx. 2 礸/cm2 skin/min (Engstr鰉 et al.,
1977) with total amount of absorption through two hands approx. 35 mg. This amount of
absorption was about the same as that of 15-20 minutes of inhalation exposure to 100
ppm (435 mg/m 3). Lauwerys et al. (1978) obtained similar values for dermal absorption.
Permeability coefficient data for xylenes (i.e., the rate at which a chemical penetrates the
outer layer of epidermis normalized by concentration) is shown in Table 6.11. The
permeability constants vary by orders of magnitude depending on the xylenes solution or
vehicle tested.
Xylenes VCCEP Submission 74
Table 6.11: Xylenes Permeability Coefficients
Permeability
Study Constant
(cm/h)
Chemical Vehicle Type Skin Reference
Mixed Neat Human
in vivo 3.41E-04 Kezic et al., 2001
Liquid forearm skin
Xylenes
Mixed Predictive
Water -- 9.50E-02 EPA, 1992
Equation
Xylenes
Mixed Xylene Human
in vivo 1.20E-01 Kezic et al., 2000
Vapor forearm skin
Xylenes
Absorption factors for volatile chemicals are available from EPA Region III for dermal
contact with soil. These values are also appropriate estimates for products such as
lacquer adhering to the skin because their magnitude is based on the chemical's volatility
and the permeability of human skin to volatile organic chemicals. Recommended
absorption factors are also available from EPA Region IV. However, Region IV's
absorption factors do not take into account the volatility of the chemical. Absorption
factors proposed by the EPA are summarized below in Table 6.12.
Table 6.12: EPA Absorption Factors
Chemical Type (EPA 1995a) (EPA 1995b)
Region III Region IV
Semivolatile Chemicals 10% 1%
Volatile Chemicals (moderate vapor pressure
3% 1%
chemicals including toluene and o-, m- and p-xylene
isomers)
Volatile Chemicals (high vapor pressure chemicals
0.05% 1%
including benzene)
Distribution: About 90% of xylene in blood is bound to serum proteins and
approximately 10-15% is in protein-free serum. After systemic absorption, xylene is
largely distributed to adipose tissue. After inhalation exposure, adipose tissue
accumulates 5-10% of the absorbed dose (舠trand, 1978; Engstr鰉 and Bjurstr鰉, 1978)
and this is increased by exercise (Riihim鋕i et al., 1979a,b).
Metabolism: The metabolism of xylenes in humans proceeds primarily via side-
chain oxidation to methyl benzoic acid (Fig. 1), which is conjugated mainly with glycine to
form methylhippuric acid, which is excreted in urine. Small amounts of methyl benzoic
acid are excreted as the glucuronide. In addition, trace amounts of methylbenzyl alcohol
are also found in urine as well as small amounts of dimethylphenol isomers, formed by
hydroxylation of the aromatic ring, and their conjugates (Sedivec and Flak, 1976; Riihim鋕i
et al., 1979a,b; Ogata et al., 1980; Engstr鰉 et al., 1984).
Xylenes VCCEP Submission 75
Elimination: Xylenes are primarily excreted as metabolites in urine with small
amounts released unchanged in expired air. Excretion in feces is unimportant. Clearance
of p-xylene from blood was calculated to be 2.6L/kg/hr at exposure of 20 ppm [87 mg/m 3]
and 1.6L/kg/hr at 70 ppm (304 mg/m 3) (Wall閚 et al., 1985). In human volunteers exposed
to o-, m-, or p-xylene, 95-97% was excreted as m-methyl benzoic acid conjugates
(primarily hippuric acid) and 0.1-2% of the metabolites were 2,4-dimethylphenol
conjugates (Riihim鋕i et al., 1979a,b; Sedivec and Flek, 1976). A linear relationship has
been observed between intensity of exposure to xylenes and the concentration of
methylhippuric acid in urine (Kawai et al., 1991a; Huang et al., 1994). Urinary
methylhippuric acid excretion of xylene-exposed workers occurred in two phases: 3.6
hours for the first 10 hours and 30.1 hours for the following 24 hours (Engstr鰉 et al.,
1978). After m-xylene exposure, excretion of m-methylbenzoic acid conjugates was
triphasic with half times of 1-2, 10 and 20 hours (Riihim鋕i et al., 1979a).
Xylenes VCCEP Submission 76
Xylenes VCCEP Submission 77
7.0 Exposure Assessment
This section summarizes the methodology, results, and conclusions of the exposure
assessment for the xylenes category under VCCEP. As part of this pilot program, EPA
has requested that exposure information be submitted to determine the extent of children's
and prospective parents' exposure to xylenes. The types of exposure information needed
for the assessment includes the identification and characterization of the population
groups exposed, sources of the exposure, as well as frequencies, levels, and routes of
exposure. The methodology employed in this assessment provides a comprehensive
analysis of potential childhood exposures to xylenes and uses the available data to focus
on those sources of exposure that are likely to have the most significant impact on
children's total xylenes exposures. As discussed in previous section, mixed xylenes may
contain ethylbenzene. Ethylbenzene exposure from mixed xylenes was not considered in
this assessment as ethylbenzene is being assessed separately in VCCEP.
7.1 Methodology/Scope of Assessment
As suggested by EPA, exposure assessments for both children and prospective parents
were conducted. Sources of exposure to xylenes in the ambient environment can come
from both chain-of-commerce and non-chain-of-commerce sources, and in many
environments, it is impossible to quantify the exposure contribution from each type of
source. In accordance with the notice of the program published in the Federal Register
(2000), exposures for xylenes chain-of-commerce sources were assessed and quantified.
In addition, exposure to xylenes from petroleum chain-of-commerce sources (e.g.,
gasoline) were also assessed and quantified. Contribution to xylenes exposure from non-
chain of commerce sources such as automobile exhaust, cigarettes, and other sources of
combustion are frequently captured in the exposure data presented (e.g., indoor air
monitoring data, in-vehicle monitoring data). Additionally, the exposure assessment does
not include exposures from accidents or intentional misuse of products containing xylenes.
A child-centered approach was used to define realistic exposure scenarios for children's
interaction with sources of xylenes including environmental (ambient) sources, and use of
consumer products. Figure 7.1 shows the relevant sources of xylenes exposure for
children and prospective parents. For most people, exposure to xylenes is a daily
occurrence. Xylenes exposures to children and prospective parents have been quantified
by evaluating the ambient or background xylenes levels in a child's/parent's air (indoor and
outdoor), diet, and water, as well as specific sources and microenvironments to which
subpopulations of children may be exposed. Available data indicate that all children are
exposed to background levels of xylenes in the ambient air, water, and food supply as a
result of releases from natural sources, mobile sources, and the chain of commerce
sources described in Section 5. In addition to these ubiquitous sources, certain
subpopulations of children may be exposed to xylenes in microenvironments depending
on specific activities such as transportation via gasoline powered vehicles, use of xylenes-
containing consumer products, or living in a home where tobacco smoking occurs (either
used by parents or teenage children).
Xylenes VCCEP Submission 78
Figure 7.1
Xylenes Exposure
Assessment
Parental Child
Occupational Personal Parental Personal
Production/Processing Background sources Breast Milk Background Sources
Manufacturing Ambient Air Ambient Air
Miscellaneous Food/Water Food/Water
Source Specific Source Specific
Fuels Fuels
Consumer Products Consumer Products
Tobacco Smoke Tobacco Smoke
Xylenes VCCEP Submission 79
In evaluating prospective parents, only prospective mothers have been included in the
exposure assessment because xylenes are not associated with male reproductive health
effects. Thus, a prospective father's exposure to xylenes does not impact his children.
Consideration of prospective mothers' exposures provides a picture of potential fetal
exposures as well as consideration of the human milk pathway. As discussed in Section
6, xylenes are not mutagenic or teratogenic, and are only toxic to the fetus at levels
associated with maternal toxicity. Therefore, fetal exposures have not been quantified
separately. Table 7.1 is a summary of the age groups considered in the exposure
assessment.
Table 7.1: Age Groups for the Xylenes Exposure Assessment
Age Group Category Subcategory
< 1 year old Children Infant
1-5 year old Toddler
6-13 year old Child
14-18 year old Teenager
Female 19-35 * Adult Prospective
year old Mother
*It is acknowledged that some women conceive children later in life, however,
the largest percentage of pregnancies occur in women between the ages of 19 and 35.
Exposures from each source of xylenes are characterized using exposure scenarios. The
exposure scenarios define the population, source of exposure, the routes of exposure, and
the values for the exposure factors that determine the dose and dose rate received from
the source. A summary of ambient and the source-specific exposure scenarios for specific
age groups is provided in Table 7.2.
Xylenes VCCEP Submission 80
Table 7.2: Summary of Xylenes Exposure Scenarios
Age Group
Female
Exposure Scenarios <1 1-5 6-13 14-18
19-35
year old year old year old year old
year old
Ambient Exposures
Outdoor Air
? ? ? ? ?br>
Urban
? ? ? ? ?br>
Rural
Indoor Air
? ? ? ? ?br>
In-home
? ? ?br>
In-School
? ? ? ? ?br>
Food
? ? ? ? ?br>
Water
Source-Specific Exposures
Tobacco Smoke
? ? ? ? ?br>
ETS
? ?br>
Mainstream
Consumer Products
? ?br>
Users
? ? ?br>
Non-users
Gasoline Sources
? ? ? ? ?br>
In-Vehicle
?(16 ?18
?br>
Refueling years old)
Occupational
?br>
Production/Processing
?br>
Non-Production
?= Included in evaluation.
A child's exposure to xylenes depends upon a number of variables, or exposure factors.
These exposure factors include the activities of the child that bring the child into contact
with the source of exposure and which determine the dose resulting from the interaction
and the physiology of the child. The relevant exposure parameters associated with each
exposure scenario are presented in Appendix A-1.
For the various types of exposure, efforts were made to characterize both typical
exposures and high-end exposures. In general, typical exposures were calculated using
central tendency descriptors such as the average or median exposure concentrations in a
given dataset and the average or median exposure parameters (e.g., exposure frequency,
body weight, inhalation rate, etc.). High-end exposures for sources of xylenes other than
consumer products were calculated using exposure concentrations representative of a 90
- 95th percentile of the range of values in a dataset (where data were sufficient to allow the
determination of a range). In defining high-end exposure scenarios for the consumer
Xylenes VCCEP Submission 81
product scenarios, 90th percentile product usage amounts were used to estimate airborne
concentrations. It should be noted that the high-end scenario is meant to represent a
reasonable, higher than average exposure, but not the absolute "worst case" estimate for
exposure.
Defining the high-end scenarios raises a number of challenges in the assessment of
xylenes exposure from consumer products. In this assessment the following decisions
were made on the characterization of consumer exposure. First, the assessment does not
consider exposures that occur from the intentional misuse of the products (solvent abuse).
Second, the product uses that are considered in this assessment are those that are
consistent with label directions. Thus, xylenes containing products with label directions
instructing the user to avoid skin contact and use with adequate ventilation will not be
assessed in a manner that contradicts these instructions (extensive dermal contact or use
in small unventilated spaces). Third, exposures from use of consumer products occur in a
wide range of situations where various amounts are used, under varying conditions
(frequencies of use, room sizes, and ventilation rates), and in the presence or exclusion of
children. Scenarios based on conservative (exposure enhancing) values for all possible
exposure factors will result in situations that contradict label directions (i.e., use with
adequate ventilation). Therefore, the high-end consumer product exposure scenarios
considered in this assessment are based on above average but not the theoretical
maximum values of all exposure-related factors.
7.2 Sources of Xylenes Exposure
This section provides a summary of the sources of potential exposure to xylenes for
children and prospective parents. Xylenes exposure has been quantified based on
information provided in the scientific peer-reviewed literature or through exposure
modeling using various EPA exposure models. The sources of xylenes are defined in
terms of two general source categories: ambient sources of exposures and exposures
resulting from the use of consumer products.
7.2.1 Ambient Environmental Exposures
Ambient childhood exposures to xylenes could occur from four general sources: 1)
ambient air, 2) food, 3) drinking water, and 4) human milk. Potential exposures to each
source are described further below.
7.2.1.1 Ambient Air
During the 1980s and early 1990s the EPA funded and provided oversight for human
exposure research with the objective of directly measuring exposure using personal air
samplers. The conclusion of this extensive research project, known as the EPA Total
Exposure Assessment Methodology (TEAM) Studies, was that the most important sources
of exposure are small and originate close to the person (Wallace, 2001). The presence of
major point sources, such as refineries, was not correlated with increased personal
exposure to organic chemicals. For many chemicals, including xylenes, distant sources of
air release, such as refineries and chemical facilities play a smaller part in the
determination of total dose than localized sources such as consumer products, use of
petroleum products, time spent in vehicles, and use of tobacco products.
Xylenes VCCEP Submission 82
The Clean Air Act Amendments of 1990 provided for creation of the National Urban Air
Toxics Research Center (NUATRC). The goal of this organization is to promote, develop
and support research related to human health risks from air toxics. As part of the
NUATRC mission, several studies have been conducted where VOC exposures to
children have been evaluated. The Health Effects Institute (HEI) and the Mickey Leland
National Urban Air Toxics Research Center (NUATRC) are jointly funding a project called
the Relationship between Indoor, Outdoor and Personal Air (RIOPA); a large urban air
toxics project that is comprised of three studies. The RIOPA project tests the hypothesis
that personal exposure to air toxics is influenced by outdoor sources of these air toxics. It
involves 3 cities with different air pollution source profiles: Los Angeles, California is
dominated by mobile sources; Houston, Texas is dominated by industrial point sources;
and Elizabeth, New Jersey includes a mixture of mobile and point sources. In each city,
100 homes were monitored for 48 hours in each of the 2 seasons. The homes were
monitored indoors and outdoors for PM2.5 VOCs, and aldehydes. In addition, personal
exposure to PM2.5, VOCs, and aldehydes, and in-vehicle exposure to aldehydes were
measured for residents of these homes. At the time of this assessment, the data for the
VOCs had not been formally published, although summary data was made available for
preliminary review by HEI. In general it was found that indoor air xylene concentrations
were higher than outdoor air, but lower than the personal xylene concentrations.
A community based study conducted by Buckley et al.,(2005) in Baltimore evaluated the
impact of industry on community air quality and individual resident exposure to 15 VOCs.
The study was designed to examine the potential industry effect by comparing indoor,
outdoor, and personal air concentrations in South Baltimore to those in Hampden, an
urban Baltimore community with a less intense industrial presence. Buckely et al.
concluded that except for ethylbenzene and m,p-xylene, the VOC concentrations at all
three levels of monitoring (outdoor, indoor, and personal) were comparable in the two
communities, suggesting no industrial impact or an impact smaller than that detectable
with the sample size of the study. For the m/p-xylene, where there appeared to be a
possible impact, the indoor and outdoor differences did not translate into significant
differences in personal exposure levels between the two communities.
Inhalation of xylenes in outdoor and indoor air was evaluated for each childhood age
grouping and the prospective mother. For ambient outdoor air, both u rban and rural
settings were considered, as xylenes concentrations are highly dependent on mobile
source emissions. For indoor air, exposures from both in-home and in-school
environments were considered.
Ambient Outdoor Air
Urban and rural ambient air concentrations of xylenes were obtained from EPA's AirData
database (http://www.epa.gov/aqspubl1/annual_summary.html; accessed 8/20/03). This
database contains annual summaries from air monitoring stations, pulling data from three
EPA databases: 1) Air Quality System, 2) National Emissions Trends, and 3) National
Toxics Inventory. Collectively, these databases represent measured data from air
monitoring stations, as well as estimated air data from point, area and mobile source
emission measurements.
The most recent year for which data was available was 2004. The 2004 data for two
geographical setting categories, rural and urban were evaluated. The AirData database
presents xylenes data for m/p-xylenes and o-xylenes. Therefore, these two isomer
Xylenes VCCEP Submission 83
concentrations were summed together to calculate the concentration of total o-, m-, and p-
xylene isomers. A summary of the geographical diversity of the AirData for xylenes is
provided in Table 7.3 below.
Table 7.3: Summary Description of the AirData Database for Xylenes
Number of
Number of Monitoring
Setting States Counties Stations
Rural AZ, CA, CT, DE, FL, 42 49
GA, LA, ME, MI, MN,
MO, MS, NH, NJ, NY,
NC, ND, OH, PA, SC,
TX, VT, VA, WI
Urban AZ, CA, CO, CT, DE, 73 123
D.C., FL, IL, IN, IA, LA,
MD, MA, MI, MN,MS,
MO, NH, NY, NC, OH,
PA, RI, SD, TN, TX,
VT, VA, WI
The 2004 AirData data for total xylenes are presented in Table 7.4. It should be noted that
this data was collected from photochemical assessment monitoring stations (PAMS).
PAMS stations are located in areas of ozone non-attainment, and are used to measure
ozone precursors such as xylenes. Therefore, they are likely to be located in areas where
xylenes concentrations are higher than in other areas. However the HAPs data from
AirData only provided m-xylene and p-xylene from California. Therefore it was determined
that the PAMS data had broader geographic coverage and therefore, more representative
of total xylenes concentrations.
Table 7.4: 2004 Ambient Air Xylenes Concentrations from EPA' s AirData Database
95th Percentile Total
Mean Total Xylenes
Air Concentration Xylenes Air
(礸/m 3) Concentration (礸/m 3)
Setting
Rural 1 2.4
Urban 2.5 5.9
Ambient outdoor air concentrations have been steadily declining over time. The average
total xylenes ambient air concentrations across the US, as measured at the PAMS stations
since 1985 are shown on Figure 7.2.
Xylenes VCCEP Submission 84
Figure 7.2 Trend in Total Xylenes Ambient Air Concentrations
in the U.S. (1985 ?2005)
25.0
Concentration (ug/m3)
Average Total Xylenes
20.0
15.0
10.0
5.0
0.0
97
99
01
03
85
89
91
93
95
19
19
20
20
19
19
19
19
19 Year
* Note the data in Figure 7.2 were converted from the units of ppbC in the AirData database
As shown on this graph, significant decreases in total xylenes concentrations have
occurred since the mid 1980s. Therefore, use of the most recent air monitoring data (as
shown on Table 7.4) to characterize typical and high-end exposure concentrations is
appropriate. As such, the mean rural concentration of 1.0 礸/m 3 and the mean urban
concentration of 2.5 礸/m 3 have been selected as representative of typical exposure
concentrations for the child and prospective mothers in the rural and urban settings,
respectively. The 95th percentile concentrations of 2.4 礸/m 3 and 5.9 礸/m 3 have been
selected as representative of high-end exposure concentrations for rural and urban
settings, respectively.
Average daily doses were calculated for residents living in urban and rural settings.
Exposure was quantified according to the following equation:
C ?ED ?EF ?ET ?IR ?ABSi ?CF
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
concentration of xylene in ambient air (礸/m 3)
C =
ED = exposure duration (years)
EF = exposure frequency (days/year)
ET = exposure time (hours/day)
inhalation rate (m3/hour)
IR =
ABSi = xylene inhalation absorption factor; 0.6 (unitless)
CF = conversion factor (0.001 mg/礸)
BW = body weight (kg)
AT = averaging time (days)
Xylenes VCCEP Submission 85
Age-specific doses are presented below in Tables 7.5 and 7.6. In this exposure
assessment, ambient doses were calculated so as to appropriately represent the exposure
frequencies and exposure times for school days and non-school days. For children,
ambient outdoor exposures for school and non-school days were summed to derive
average daily doses representing a full year of exposure. For the infant and prospective
mother, it was assumed that all days are non-school days. Table 7.7 presents the total
doses from outside ambient air exposures.
Table 7.5: ADDs for School Day Exposure to o-, m-, and p-Xylene Isomers in
Ambient Air
1-5 6-13 14-18 1-5 6-13 14-18
Exposure year year year year year year
Parameter Units old old old old old old
Rural - Typical Rural ?High-End
3
C 礸/m 1.0 1.0 1.0 2.4 2.4 2.4
ET hours/day 2.1 2.0 1.9 2.1 2.0 1.9
EF days/year 180 180 180 180 180 180
ED Years 5 8 5 5 8 5
3
IR m /h 0.31 0.51 0.60 0.31 0.51 0.60
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 1825 2920 1825 1825 2920 1825
BW Kg 15.4 35 61 15.4 35 61
0.6 0.6 0.6 0.6 0.6 0.6
ABSi Unitless
Dose mg/kg/d 1.3E-05 8.6E-06 5.5E-06 3.0E-05 2.1E-05 1.3E-05
Urban - Typical Urban ?High-End
3
C 礸/m 2.5 2.5 2.5 5.9 5.9 5.9
ET hours/day 2.1 2.0 1.9 2.1 2.0 1.9
EF days/year 180 180 180 180 180 180
ED Years 5 8 5 5 8 5
3
IR m /h 0.31 0.51 0.60 0.31 0.51 0.60
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 1825 2920 1825 1825 2920 1825
BW Kg 15.4 35 61 15.4 35 61
0.6 0.6 0.6 0.6 0.6 0.6
ABSi Unitless
Dose mg/kg/d 3.1E-05 2.2E-05 1.4E-05 7.4E-05 5.1E-05 3.3E-05
Xylenes VCCEP Submission 86
Table 7.6: ADDs for Non-School Day Exposure to
o-, m-, and p-Xylene Isomers in Ambient Air
Female Female
<1 1-5 6-13 14-18 19-35 <1 1-5 6-13 14-18 19-35
year year year year year year year year year year
Exposure
old old old old old old old old
Parameter Units old old
Rural - Typical Rural- High-End
3
C 礸/m 1.0 1.0 1.0 1.0 1.0 2.4 2.4 2.4 2.4 2.4
ET h/d 1.4 3.1 2.2 2.3 1.5 1.4 3.1 2.2 2.3 1.5
EF d/y 365 185 185 185 365 365 185 185 185 365
ED years 1 5 8 5 17 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.60 0.47 0.19 0.31 0.51 0.60 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
AT days 365 1825 2920 1825 6205 365 1825 2920 1825 6205
BW kg 7.2 15.4 35 61 62.4 7.2 15.4 35 61 62.4
ABSi unitless 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
mg/kg/d 2.2E-05 1.9E-05 9.7E-06 6.9E-06 6.8E-06 5.3E-05 4.6E-05 2.3E-05 1.7E-05 1.6E-05
Dose
Urban - Typical Urban ?High-End
3
C 礸/m 2.5 2.5 2.5 2.5 2.5 5.9 5.9 5.9 5.9 5.9
ET h/d 1.4 3.1 2.2 2.3 1.5 1.4 3.1 2.2 2.3 1.5
EF d/yr 365 185 185 185 365 365 185 185 185 365
ED Years 1 5 8 5 17 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.60 0.47 0.19 0.31 0.51 0.60 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 365 1825 2920 1825 6205 365 1825 2920 1825 6205
BW Kg 7.2 15.4 35 61 62.4 7.2 15.4 35 61 62.4
ABSi Unitless 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
mg/kg/d 5.5E-05 4.7E-05 2.4E-05 1.7E-05 1.7E-05 1.3E-04 1.1E-04 5.8E-05 4.1E-05 4.0E-05
Dose
Table 7.7: Total ADDs for Exposure to o-, m-, and p-Xylene Isomers in Ambient Air
(mg/kg/d)
Female
<1 1-5 6-13 14-18 19-35
year old
Setting year old year old year old year old
Rural Typical 2.2E-05 3.1E-05 1.8E-05 1.2E-05 6.8E-06
Rural High-End 5.3E-05 7.6E-05 4.4E-05 3.0E-05 1.6E-05
Urban Typical 5.5E-05 7.9E-05 4.6E-05 3.1E-05 1.7E-05
Urban High-End 1.3E-04 1.9E-04 1.1E-04 7.3E-05 4.0E-05
Xylenes VCCEP Submission 87
Analysis of Ambient Xylenes Concentrations in Industrial Source Areas
A common misconception regarding individuals' exposures to xylenes and other volatile
compounds is that those living near industrial air emitters (stationary sources) have higher
exposures than those who live elsewhere. For many chemicals this has been shown not
to be true (Buckley et al., 2005; Ott and Roberts, 1998; Wallace, 1996; Wallace, 1989). In
this assessment, an analysis of exposure from stationary sources was conducted to
determine the contribution from this source.
The approach used was to develop a reasonable high-end estimate of the long-term
average concentration for an individual living near a facility. This value is then compared
to the levels that typically occur in urban and rural environments. At the time of this
assessment, the most recent TRI release data was that for reporting year 2003. In 2003,
2,875 facilities reported total o-,m- and p-xylene isomer emissions. The top 5 urban and
rural facilities based on total pounds released to the air are listed on Table 7.8.
Table 7.8: Top Five Sources of Xylenes Isomers in Rural and Urban Settings
Total Air Total Air
Releases Releases
(pounds) (pounds)
Urban Rural
1. GM Pontiac Assembly 975,000 1. Honda of America Mfg., Union 492,450
Center, Oakland County, MI County, OH
2. McChord Air Force Base, 586,171 2. Sanderson Plumbing 472,122
Pierce County, WA Products, Lowndes County, MS
3. Ford Motor Company, Clay 552,900 3. American Woodmark Corp., 168,642
County, MO Hardy County, WV
4. Nissan Smyrna 515,646 4. Roll-Offs of America, Bryan 145,764
Manufacturing Plant, County, OK
Rutherford County, TN
5. BP Chemical Texas City 496,000 5. Wood-Mode Inc., Snyder 141,388
Plant B, Galveston Co., TX County, PA
Of the 2,875 facilities, no facilities reported emissions exceeding 1 million pounds, with the
top emitting facility located in an urban county of Michigan. Only 4 facilities, or
approximately 0.1%, reported emissions exceeding 500,000 pounds.
To determine a reasonable high-end for exposure, the air concentrations surrounding the
top TRI facility, the GM Pontiac Assembly Center located in Pontiac, MI, were estimated
using EPA's SCREEN3 air dispersion model. Details of the modeling are presented in
Appendix A -2. Results of this model run predicted long-term xylenes concentration at the
hypothetical fenceline would be 64 礸/m 3.
The SCREEN3 model prediction for the top TRI emitting facility is about 8 times greater
than the high-end air concentration of 7.7 礸/m 3 selected for urban settings. However, it is
believed that the vast majority of individuals living near facilities would not experience air
concentrations that differ from the range of background concentrations in the rural or
urban environments (Table 7.4). The reason for this is that the total xylenes concentration
Xylenes VCCEP Submission 88
of 64 礸/m 3 is predicted to only occur for a home located 500 meters (576 yds) from the
highest TRI emitter. Given that >99% of the TRI reporting facilities emit far less xylenes
than the GM Pontiac, MI facility did in 2003, the high-end for the majority of the U.S
population is believed to be reasonably characterized by the measured xylenes data
presented on Table 7.4. Despite the conservative nature of this modeling, the predicted
air concentration is less than the IRIS RfC of 0.1 mg/m 3.
Ambient Indoor Air
The indoor environment in which children and prospective mothers spend most of their
time is the home. Indoor air concentrations of o-, m-, and p-xylene isomers were obtained
from the summary of the residential indoor air data presented in the ATSDR Toxicological
Profiles for xylenes (ATSDR, 1995a), various residential indoor air studies, and indoor air
quality studies of schools. The available data indicate that indoor air generally has higher
concentrations of xylenes than the outdoor ambient air.
Xylenes in the indoor air environment occur as a result of a variety of indoor sources,
including the use of common household products, smoking tobacco products, wood
stoves, cooking, and infiltration from attached garages. Xylene levels in the home may
also be influenced by outdoor air levels and the whole house air exchange rates, which
vary with the season and are lower in cold weather (Murray and Burmaster, 1995). Within
the home, the two most common sources of xylenes are household products and cigarette
smoke (ATSDR, 1995a). Source specific exposures to xylenes from use of consumer
products and exposure to tobacco smoke and are addressed separately in Sections 7.6
and 7.9, respectively.
The ATSDR review of xylenes p resents measurement data from two indoor air studies
published in the 1980s, which measured levels of m- and p-xylenes (combined) that
ranged from 10 - 47 礸/m 3, and weighted median indoor o-xylene and combined m- and p-
xylenes of 4.9 礸/m 3 and 14 礸/m 3, respectively (ATSDR, 1995a). A review of the recent
peer-reviewed literature of indoor air studies was conducted and focused on residential
studies. Several studies from the mid-1990s to the present were identified, although those
conducted in the US are limited (Adgate et al., 2004a,b; Buckley, et al., 2005; Bozzelli et
al., 1995; Hodgson et al., 2000; Kinney et al., 2002; Phillips et al., 2004; and Van Winkle
and Scheff, 2001). Table 7.9 summarizes the data from these studies.
Xylenes VCCEP Submission 89
Table 7.9
Summary of Current Published Indoor Air Studies of Xylenes
Indoor
concentration:
Study Location Notes
Total Xylenes
(礸/m 3)
Adgate et al., Minneapolis, MN, Evaluated 101 private residences in
10.8 (mean)
2004a St. Paul, MN, 1997 for indoor air, outdoor air and
th
5.2 (25
Rice County MN, personal air concentrations of VOCs.
percentile)
and Goodhue Examined both urban and nonurban
th
6.7 (50
County MN households and included smoking and
percentile) non-smoking households and those
th
28.4 (95 with and without attached garages.
percentile)
4.7 (avg of winter
and spring Evaluated 113 different households
medians) measuring indoor home air, outdoor air
concentrations of VOCs in an urban
2.5 (avg of winter
Adgate et al., th
Minneapolis, MN and spring 10 area. Both single family homes 43%)
2004b
percentiles) and apartments (55%) were surveyed,
and included both smoking and non-
15.5 (avg of
winter and spring smoking households.
th
90 percentiles)
Evaluated indoor air impacts during use
Bozzelli, et al,
Elizabeth, NJ 12.5 ?13.6 of kerosene heaters. Data on this table
1995
is without the heaters in use.
Evaluated 36 non-smoking homes in South
Baltimore and 21 non-smoking homes in
9.7 (mean)
Hampden, MD for outdoor, indoor and
th
3.3 (10
South Baltimore
Buckley et al., personal air VOC exposures. Children were
percentile)
and Hampden included in the personal monitoring
2005 th
MD 21 (90 program. Questionnaires were provided to
percentile) each household to document indoor
activities and home characteristics.
2.2 ?50
4.34 ?16.9 Measured values in newly constructed
Hodgson et al., East and homes prior to occupancy. Both
(range of
2000 Southeast US geometric manufactured and site-built homes
means) included.
Study of 8 homes to characterize
Kinney et al, New York City, 11 (mean, range
personal exposures to urban air toxics
2002 NY not reported)
in inner city neighborhoods.
Phillips et al., Oklahoma City, Study conducted of 37 U.S. homes in
2.6 (median day)
2004 OK; Tulsa, OK; 2000 ?2001 in urban and rural
3.9 (median
Ponca City, OK; Oklahoma to characterize indoor,
night)
Stillwater, OK outdoor and personal air concentrations
th
70 (95 of various VOCs. Presence of refinery
percentile day by was a primary factor investigated.
rank)
th
49 (95
percentile night
by rank)
Van Winkle and 6.85 ?604
Chicago, IL Study of 10 homes in 1994 -1995
Scheff, 2001 17 (median)
Xylenes VCCEP Submission 90
None of the recent studies are necessarily representative of the current overall U.S.
demographic because of differences in home construction, presence of an attached
garage, and outdoor ambient air concentrations. Phillips et al. (2004) found that for
xylenes, there was no significant correlation between the indoor and outdoor air
concentrations. Also, recent studies in Germany have shown that for xylenes, outdoor air
is not the predominant source of xylenes in the indoor air, with perhaps the exception in
high traffic density areas (Ilgen et al., 2001a,b). Therefore, it was determined that the
difference (i.e., I-O delta) between the indoor and outdoor values could be used to
estimate indoor air concentrations, as it represents the incremental total xylenes
concentration attributable to indoor sources.
Of the studies listed on Table 7.9, only Adgate et al. (2004b) had paired indoor and
outdoor data for individual homes. Therefore, this study was used to derive typical and
high-end I-O deltas. These are presented on Table 7.10. It should be noted that this data
was not published. However, the Minnesota Department of Health provided the raw air
sampling data (personal communication with J. Panko, 2004).
Table 7.10
I-O Deltas from Adgate et al. (2004b)
Study Typical I-O High-End I-O Delta
Delta (礸/m3) (礸/m3)
Adgate et al., 2004b 6.6 30
As such, because of the limited data from recent representative studies of xylenes in the
indoor air, typical and high-end indoor air concentrations have been estimated by applying
the I-O delta as follows:
Cindoor = Coutdoor + Cindoor source
The results are summarized on Tables 7.11 and 7.12 below.
Table 7.11: Typical Representative Ambient Air o-, m-, and p-Xylene Concentrations
in Rural and Urban Areas
Typical Outside
Typical Indoor Exposure
Exposure
Setting Concentration (礸/m 3)
3
Concentration (礸/m )
Rural 1.0 7.6
Urban 2.5 9.1
Xylenes VCCEP Submission 91
Table 7.12: High-End Representative Ambient Air o-, m-, and p-Xylene
Concentrations in Rural and Urban Areas
High-End Outside
High-End Indoor Exposure
Setting Exposure
Concentration (礸/m 3)
Concentration (礸/m 3)
Rural 2.4 32.4
Urban 5.9 35.7
The estimated typical and high-end indoor air exposure concentrations are consistent with
the mean or median and high-end values presented in the recent literature.
In-Home Dose Calculations
Age-specific average daily doses were calculated for in-home exposures with the
representative indoor concentrations provided in Tables 7.11 and 7.12 for typical and high-
end exposures, respectively. Urban and rural exposure was quantified according to the
following equation:
C ?ED ?EF ?ET ?IR ?ABSi ?CF
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
concentration total xylenes in home air (礸/m 3)
C =
ED = exposure duration (years)
EF = exposure frequency (days/year)
ET = exposure time (hours/day)
inhalation rate (m3/hour)
IR =
ABSi = xylenes inhalation absorption factor; 0.6 (unitless)
CF = conversion factor (0.001 mg/礸)
BW = body weight (kg)
AT = averaging time (days)
The age-specific doses from in-home xylenes exposures are presented in Tables 7.13-
7.15.
Xylenes VCCEP Submission 92
Table 7.13: ADDS for School Day In-Home o-, m-, and p- Xylene Isomers Exposures
1-5 6-13 14-18 1-5 6-13 14-18
Exposure year year year year year year
Parameter old old old old old old
Units
Rural - Typical Rural ?High-End
3
C 礸/m 7.6 7.6 7.6 32.4 32.4 32.4
ET hours/day 17.8 15.0 14.2 17.8 15.0 14.2
EF days/year 180 180 180 180 180 180
ED years 5 8 5 5 8 5
3
IR m /h 0.31 0.51 0.60 0.31 0.51 0.60
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001
AT days 1825 2920 1825 1825 2920 1825
BW Kg 15.4 35 61 15.4 35 61
0.6 0.6 0.6 0.6 0.6
ABSi unitless 0.6
Dose mg/kg/d 8.1E-04 4.9E-04 3.1E-04 3.4E-03 2.1E-03 1.3E-03
Urban - Typical Urban ?High-End
3
C 礸/m 9.1 9.1 9.1 35.7 35.7 35.7
ET Hours/day 17.8 15.0 14.2 17.8 15.0 14.2
EF days/year 180 180 180 180 180 180
ED Years 5 8 5 5 8 5
3
IR m /h 0.31 0.51 0.60 0.31 0.51 0.60
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 1825 2920 1825 1825 2920 1825
BW Kg 15.4 35 61 15.4 35 61
0.6 0.6 0.6 0.6 0.6
ABSi unitless 0.6
Dose mg/kg/d 9.6E-04 5.9E-04 3.8E-04 3.8E-03 2.3E-03 1.5E-03
Xylenes VCCEP Submission 93
Table 7.14 ADDS for Non-School Day In-Home o-, m-, and p- Xylene Isomers Exposures
Female
<1 1-5 6-13 14-18 19-35 <1 1-5 6-13 14-18 Female
year year year year year year year year year 19-35
Exposure
old old old old old old old old year old
Parameter Units old
Rural ?Typical Rural- High-End
3
C 礸/m 7.6 7.6 7.6 7.6 7.6 32.4 32.4 32.4 32.4 32.4
ET h/d 21.4 19.7 20.8 20.3 21.2 21.4 19.7 20.8 20.3 21.2
EF d/y 365 185 185 185 365 365 185 185 185 365
ED Years 1 5 8 5 17 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.60 0.47 0.19 0.31 0.51 0.60 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 365 1825 2920 1825 6205 365 1825 2920 1825 6205
BW Kg 7.2 15.4 35 61 62.4 7.2 15.4 35 61 62.4
ABSi unitless 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
mg/kg/d 2.6E-03 9.2E-04 7.0E-04 4.6E-04 7.3E-04 1.1E-02 3.9E-03 3.0E-03 2.0E-03 3.1E-03
Dose
Urban ?Typical Urban ?High-End
3
C 礸/m 9.1 9.1 9.1 9.1 9.1 35.7 35.7 35.7 35.7 35.7
ET h/d 21.4 19.7 20.8 20.3 21.2 21.4 19.7 20.8 20.3 21.2
EF d/yr 365 185 185 185 365 365 185 185 185 365
ED Years 1 5 8 5 17 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.60 0.47 0.19 0.31 0.51 0.60 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
AT Days 365 1825 2920 1825 6205 365 1825 2920 1825 6205
BW Kg 7.2 15.4 35 61 62.4 7.2 15.4 35 61 62.4
ABSi unitless 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
mg/kg/d 3.1E-03 1.1E-03 8.4E-04 5.5E-04 8.7E-04 1.2E-02 4.3E-03 3.3E-03 2.2E-03 3.4E-03
Dose
Table 7.15: Total ADDS for Exposure to o-, m-, and p- Xylene Isomers in In-Home
Air (mg/kg/d)
Female
<1 1-5 6-13 14-18 19-35
Setting year old year old year old year old year old
Rural Typical 2.6E-03 1.7E-03 1.2E-03 7.8E-04 7.3E-04
Rural High-End 1.1E-02 7.3E-03 5.1E-03 3.3E-03 3.1E-03
Urban Typical 3.1E-03 2.1E-03 1.4E-03 9.3E-04 8.7E-04
Urban High-End 1.2E-02 8.1E-03 5.6E-03 3.6E-03 3.4E-03
Xylenes VCCEP Submission 94
In-School Air
There is no systematic program in the United States requiring the collection of indoor air
samples for VOC analyses in schools. In cases where data are collected, the data are
usually collected by a private consultant in response to an indoor air quality complaint.
Results from these studies are not usually published; rather, they are typically presented
as a private report to the school administration. Thus, database searches of the scientific
published literature did not identify a large number of studies of schools and indoor
concentrations of xylenes that would be representative of schools nationwide.
EPA conducted 10 indoor air studies (n =39) of schools from 1995-1998 (EH&E, 2000).
The purpose of these studies was to determine whether intervention actions could improve
indoor air quality and other endpoints. For o-xylene, the in-school detection frequency
was 85%, and the mean and high-end (95th percentile) concentrations were 2.3 礸/m 3 and
4.9 礸/m 3, respectively. For m- and p-xylenes, the in-school detection frequency was
97%, and the mean and high-end concentrations were 7.9 礸/m 3 and 19 礸/m 3,
respectively. The summed o-, m-, and p-xylene mean and high-end concentrations were
9.6 礸/m 3 and 23.9 礸/m 3, respectively. These values are consistent with those estimated
for in-home air concentrations described in Section 7.2.
This study did not include information regarding the setting of the schools (e.g., urban,
suburban, or rural). The representativeness of the data is questionable for schools
nationwide, because the schools that were studied were those for which complaints about
the air quality had been made and the air samples were collected prior to implementation
of any interventions in any given building. Additionally, no data regarding the outdoor
xylenes concentrations were presented.
Two other studies of indoor air at public schools indicate that the in-school levels of
xylenes are likely more comparable to concentrations found in the outside ambient air than
concentrations typically found in homes. This was most evident in a nine-school study
conducted in the Saugus Union School District in Santa Clarita, California (Spielman,
2000). In-school summed o-, m-, and p-xylene concentrations ranged from 2.7 to 8.1
礸/m 3 and had an average of 4.5 礸/m 3, and outdoor concentrations ranged from 2.7 to
8.22 礸/m 3 and had an average of 4.8 礸/m 3. The study was initiated under the EPA's
Tools for Schools Program, which was developed to evaluate and ensure healthy indoor
air quality for students and staff at U.S. schools. Indoor levels of total VOCs were
measured concurrently with outdoor levels in each of the schools, and the researchers
found that the indoor school concentrations were similar to the outdoor ambient
concentrations. An additional study for a portable school building in the Saugus District
(Spielman, 1999) indicated similar results, with in-school concentrations ranging from 1.4
to 5.1 礸/m 3 with an average of 2.39 礸/m 3, and outdoor concentrations ranging from 0.96
to 1.5 礸/m 3 with an average of 1.2 礸/m 3.
In addition to the Spielman studies, an investigation by Brown et al. (1994) provides
summary indoor air concentration data from numerous U.S. and overseas sources. The
total VOC concentrations measured in this study indicated that the concentrations in-
school were on average 6 times lower than those measured in homes.
Because none of the published studies are necessarily representative of i -school air
n
quality nationwide, exposures have been estimated using both the findings of the
Spielman and the EPA studies. The typical exposure is represented by the urban outdoor
Xylenes VCCEP Submission 95
ambient concentration and the high-end exposure is represented by the high-end
concentration from EPA's 10-school study (EH&E, 2000). These values are presented in
Table 7.16.
Table 7.16: Typical and High-End In-School Xylenes Exposures
Exposure o-, m- and p- Xylene
Concentration (礸/m 3)
Typical 2.6
High-end 23.9
In-School Dose Calculation
Both typical and high-end total xylenes doses from in-school exposures were calculated
using the following equation:
C ?ED ?EF ?ET ?IR ?ABSi ?CF
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
concentration of total xylenes in school air (礸/m 3)
C =
ED = exposure duration (years)
EF = exposure frequency (days/year)
ET = exposure time (hours/day)
inhalation rate (m3/hour)
IR =
ABSi = xylenes inhalation absorption factor; 0.6 (unitless)
CF = conversion factor (0.001 mg/礸)
BW = body weight (kg)
AT = averaging time (days)
The in-school total xylenes doses were calculated and are presented on Table 7.17.
Xylenes VCCEP Submission 96
Table 7.17: Summary of Age-Specific Doses from In-School Xylenes Exposure
Exposure 1-5 6-13 14-18 1-5 6-13 14-18
Parameter year old year old year old year old year old year old
Units
Typical High-End
3
C 礸/m 2.6 2.6 2.6 23.9 23.9 23.9
ET h/d 2.9 6.0 6.5 2.9 6.0 6.5
EF d/y 180 180 180 180 180 180
ED years 5 8 5 5 8 5
3
IR m /h 0.31 0.51 0.60 0.31 0.51 0.60
CF mg/礸 0.001 0.001 0.001 0.001 0.001 0.001
AT d 1825 2920 1825 1825 2920 1825
BW kg 15.4 35 61 15.4 35 61
ABSi unitless 0.6 0.6 0.6 0.6 0.6 0.6
Dose mg/kg/d 4.5E-05 6.7E-05 4.9E-05 4.1E-04 6.2E-04 4.5E-04
Xylenes VCCEP Submission 97
7.2.1.2 Food and Tap Water
The o-, m-, and p-xylene isomers occur in both food and water; therefore, exposure to
xylenes can occur as a result of diet and tap water consumption. Xylenes in tap water
also cause exposure by inhalation and dermal routes during showering. Xylenes
exposures from these sources and routes are evaluated using LifeLineTM Version 2.0, a
publicly available software program for the simulation of aggregate exposures to
chemicals (The Lifeline Group, 2002). This software allows the determination of the total
concurrent dose from the oral exposures, ingestion of food and tap water, from dermal
exposure to xylenes in shower water, and inhalation exposures to xylenes that are
released from shower water. Infant exposures to xylenes in human milk were determined
separately as described in Section 7.2.1.3.
Exposure concentrations for food were derived from FDA's Total Diet Survey (FDA, 2003).
In the Total Diet Survey, FDA personnel purchased foods from supermarkets or grocery
stores four times per year from each of the four U.S. geographic regions. Each collection,
referred to as a Market Basket, is a composite of similar foods purchased in three cities in
each of the four regions (12 cities). Foods are prepared for consumption (i.e., as they will
be eaten) and analyzed.
One Market Basket per quarter from the third quarter of 1995 through the fourth quarter of
2001 was available for analysis (totaling 24 applicable Market Baskets). The analytical
results for o-xylene and m/p-xylene in the various foods range from non-detect up to 76
ppb and 291 ppb, respectively. The FDA only presents in summary form the number of
times o- or m/p-xylene was detected in a food item (N) and the mean concentration for that
food item for those times it was detected (detect mean) and the maximum and minimum
measured values. Appendix A-3 provides details of the Market Basket analysis.
The sources of the xylenes residues are unclear, but are not likely to be a function of the
commercial use of the chemical. Xylenes are not used in food processing and are not
approved as a direct or indirect food additive (See Section 4.2). One source of exposure
could be the concentration of xylenes in fatty foods by absorption from air. This may
explain the levels reported in fatty materials such as cheese or butter. Second, detectable
levels of xylenes have been found in the polystyrene packaging for products such as eggs
(ATSDR, 1995). Finally, xylenes were consistently found in a variety of cooked meats.
Because of its volatility and solubility and the ability of mammals to metabolize xylenes,
the compound is not anticipated to bioaccumulate in animals. This suggests that the
xylenes would not be present in uncontaminated raw meat but may have been formed
during the cooking processes.
The total xylenes food concentrations were entered into the Lifeline program and doses
were calculated for the various age ranges. A detailed description of the food
consumption modeling process is provided in Appendix A-4.
Exposure concentrations for the determination of xylenes exposure from drinking water
were obtained from EPA's National Drinking Water Contaminant Occurrence Database
(NCOD) for water from public water supplies and the U.S. Geological Survey (USGS)
National Water Quality Assessment (NAWQA) program for a representation of private well
Xylenes VCCEP Submission 98
users. The typical and high-end concentrations were characterized by mean and 95th
percentile values as shown on Table 7.18 and 7.19 below.
Table 7.18: Public Water Supply Summary Statistics (January 1993 through
November 2000)a
Statistic Public Water Supply
Concentration
(N= 25,302)
(礸/L)
172b
Maximum Detect
Mean 0.55
Median 0.25
95th Percentile (by rank) 0.25
a
The mean, median, and 95th percentile values were calculated using half the
detection limit for non-detects.
A sample value of <10,000 礸/L was also identified.
b
Table 7.19: Summary Statistics for Total o-, m-, and p- Xylene Isomer Analyses from
Ambient Groundwater and Surface Water
(May 1993 through March 1996)a
Groundwater Surface Water All
Statistic (N = 1,620) (N = 20) (N = 1,640)
(礸/L) (礸/L) (礸/L)
Maximum Detect 36 5.2 36
Mean 0.13 0.37 0.13
Median 0.10 0.10 0.10
95th Percentile (by rank) 0.10 0.45 0.10
a
The mean, median, and 95th percentile values were calculated using half the detection limit for non-detects.
Details of the determination of exposure concentrations for drinking water and the input
into the Lifeline model are contained in Appendix A-5. The results of the food and drinking
water exposure analysis are presented on Tables 7.20 through 7.24 below and are based
on model results for specific ages (`actual age') rather then the general age ranges.
These actual ages are the median age of each of the age ranges. Both the typical dose
and high-end doses are presented. The typical dose is estimated based on the median
dose of a simulated population of 1,000 individuals. The high-end is based on the 95th
percentile of the 1,000 simulated individuals. For food, the percentile results for o-xylene
and m/p-xylene were summed to obtain the total xylene isomer dose.
For oral ingestion, the highest high-end total annual average dose that occurs to total o-,
m-, and p- xylene isomers is 0.00037 mg/kg/day for children ages 1 to 5. The majority of
this dose is from oral exposure from diet (0.00033 mg/kg/day). For inhalation exposures
during showering, the highest high-end annual average dose is 0.00026 mg/kg/day for
infants. The highest dermal dose from showering is 0.0000066 mg/kg/day for children
ages 1 to 5.
Xylenes VCCEP Submission 99
The total xylenes doses from food presented in this exposure assessment can be
compared with other estimates made recently. For instance, the UK Ministry of Agriculture,
Fisheries and Food (MAFF; now known as the Department for Environment, Food and
Rural Affairs) determined in a Total Diet Study that the average UK intake of xylenes
varied from 0.9 to 4.6 礸/day for o-xylene and 1.2 to 4.9 礸/day for m/p-xylene (MAFF,
1995). The lower bound estimate of the average was determined by assigning a
concentration of zero to food group samples where the result was below the detection
limit. The high-end estimate of the average was determined by using a concentration of ?br>
the detection limit when the result was below the detection limit. The survey consisted of
twenty food groups collected at 10 UK locations and included retail food products in
amounts representative of UK consumption patterns. The method detection limit of 2 ppb
was higher than the FDA's TDS detection limit of 1 ppb.
The median dietary intakes (excluding tap water) derived from the Lifeline dose estimates
are presented in Table 7.25. For m/p-xylene, the average median intake among the age
groups of 2.0 礸/day is within the range of the UK estimates of 1.2 to 4.9 礸/day. The
average median intake from Lifeline for o-xylene of 0.24 礸/day is below the UK range for
average intake of 0.9 to 4.6 礸/day. One reason for the difference may be the higher
detection limit in the UK study.
Table 7.20: Oral Exposures to Total o-, m-, and p- Xylene Isomers from Tap Water
Annual Average Daily Dose (mg/kg/day)
th
Age Range Actual Age Median 95
<1 1 2.94E-05 3.84E-05
1 to 5 3 2.59E-05 3.40E-05
6 to 13 9 1.15E-05 1.72E-05
14 to 18 16 7.01E-06 1.32E-05
Female
19 to 35 27 8.12E-06 1.46E-05
Table 7.21: Oral Exposures to Xylenes from Diet
Annual Average Daily Dose (mg/kg/day)
o-xylene m,p-xylene o,m,p-xylene (sum)
Actual
Age Range th th th
Age Median 95 Median 95 Median 95
<1 1 1.03E-05 1.81E-05 1.35E-04 2.82E-04 1.45E-04 3.00E-04
1 to 5 3 1.46E-05 2.26E-05 1.64E-04 3.03E-04 1.78E-04 3.25E-04
6 to 13 9 8.58E-06 1.46E-05 6.95E-05 1.20E-04 7.81E-05 1.34E-04
14 to 18 16 5.10E-06 1.05E-05 3.57E-05 7.18E-05 4.08E-05 8.22E-05
Female
27 5.04E-06 9.40E-06 3.25E-05 6.47E-05 3.76E-05 7.41E-05
19 to 35
Xylenes VCCEP Submission 100
Table 7.22: Total Oral Exposures to Total o-, m-, and p-Xylene Isomers
from Tap Water and Diet
Annual Average Daily Dose (mg/kg/day)
Age Range Actual Age th
Median 95
<1 1 1.8E-04 3.6E-04
1 to 5 3 2.1E-04 3.7E-04
6 to 13 9 9.0E-05 1.6E-04
14 to 18 16 4.8E-05 9.5E-05
Female
27 4.6E-05 8.8E-05
19 to 35
Table 7.23: Inhalation Exposure to Total Xylenes in Tap Water While Showering
Annual Average Daily Dose (mg/kg/day)
th
Age Range Actual Age Median 95
<1 1 5.1E-05 2.6E-04
1 to 5 3 2.3E-05 9.1E-05
6 to 13 9 3.3E-06 1.3E-05
14 to 18 16 2.3E-06 1.0E-05
Female
19 to 35 27 1.7E-06 9.7E-06
Table 7.24: Dermal Exposure to Total Xylenes in Tap Water While Showering
Annual Average Daily Dose (mg/kg/day)
th
Age Range Actual Age Median 95
<1 1 2.8E-06 6.1E-06
1 to 5 3 3.4E-06 6.6E-06
6 to 13 9 2.3E-06 4.6E-06
14 to 18 16 1.8E-06 3.6E-06
Female
19 to 35 27 1.8E-06 4.3E-06
Xylenes VCCEP Submission 101
Table 7.25: Oral Intake Based on Lifeline Dietary Doses
Annual Average Intake (礸/day)
Body
o-xylene m,p-xylene o-,m-,p-xylene (sum)
Weight
Age Actual
Range Age (kg) th th th
Median 95 Median 95 Median 95
<1 1 7.2 0.07 0.13 1.0 2.0 1.0 2.2
1 to 5 3 15.4 0.22 0.35 2.5 4.7 2.7 5.0
6 to 13 9 35 0.30 0.51 2.4 4.2 2.7 4.7
14 to 18 16 61 0.31 0.64 2.2 4.4 2.5 5.0
Female
19 to 35 27 62.4 0.31 0.59 2.0 4.0 2.3 4.6
Average 0.24 0.44 2.0 3.9 2.3 4.3
Xylenes VCCEP Submission 102
7.2.1.3 Human Milk
Xylenes have been detected in the milk of nursing mothers, although it has not been
quantified. Therefore, transfer of xylenes to nursing infants from human breast milk is
possible. Lactational transfer of xylenes to nursing infants whose mothers return to the
workplace following birth was assessed by Fisher et al. (1997). Fisher et al. developed a
physiologically based pharmacokinetic (PBPK) model for lactating women to estimate the
amount of volatile organic chemical that a nursing infant ingests for a given nursing
schedule and maternal occupational exposure. The results of this modeling predict that a
nursing infant would ingest approximately 6.5 mg of xylenes per day if its mother were
exposed at the ACGIH TLV of 100 ppm.
Because it is believed that the majority of occupational exposures are well below the TLV
(See Section 7.2.3), and non-occupationally exposed mothers have much lower ambient
air exposures, the estimation of xylenes concentrations in breast milk and lactational
transfer of xylenes were recalculated. In doing so, the maternal exposure levels estimated
in this assessment were used in conjunction with the conservative schedule described by
Fisher et al. (1997). Accordingly, during the workday, the mother was assumed to be
exposed at the respective workplace TWA concentrations for 8 hours and background
concentrations of xylene for the remainder of the day. Eight nursing events were assumed
to occur each day, lasting 12 minutes each, with 115 mL of milk ingested per nursing
event, yielding a daily milk consumption of 0.92 L. Three individual nursing events were
assumed to occur during working hours and the remainder five nursing events were
assumed to occur after working hours. The nursing events that occurred during working
hours all occurred after the xylene blood concentrations had reached steady-state with the
workplace exposures and occurred at 2.1, 4.1 and 7.1 hours into the workday. The
remaining five nursing events occurred at 2, 5, 10, 13 and 15 hours post-work-shift. If the
working day were assumed to begin at 8:00 a.m., this would amount to nursing events
occurring at 2:00 a.m., 5:00 a.m., 7:00 a.m., 10:00 a.m., 12:00 p.m., 3:00 p.m., 6:00 p.m.,
and 9:00 p.m.
All parameters for the PBPK model of xylenes were obtained from Fisher et al. (1997),
except the metabolic rate constants for xylenes which were obtained from Tardif et al.
(1995). The Fisher et al. (1997) model was reproduced successfully before using it to
simulate the lactational transfer of xylenes according to the defined exposure scenarios.
The human milk concentrations for both the non-occupationally exposed mother (urban,
typical and high-end) and the occupationally exposed mother were calculated.
The parameters of the model and the simulations of lactational transfer are included in
Appendix C. The results of the model are summarized in Table 7.26 below.
Table 7.26
Summary of Mass of Total Xylenes Ingested
Scenario Mass Ingested (mg/day)
Urban, typical 0.00013
Urban, high-end 0.000513
Occupational, typical 0.0027
Occupational, high-end 0.1896
Xylenes VCCEP Submission 103
Average daily doses of total xylenes in terms of mass per body weight for an infant were
calculated and are presented on Table 7.27 below.
Table 7.27
Average Daily Doses of Total Xylenes to Nursing Infant of Occupationally Exposed
Mothers
Scenario Average Daily Dose
(mg/kg/day)
Urban, typical 1.8E-05
Urban, high-end 7.1E-05
Occupational, typical 3.8E-04
Occupational, high-end 2.6E-02
7.2.1.4 Summary of Ambient Background Xylenes Exposures
Of the ambient background sources described in Section 7.2.1, inhalation of indoor air is
the predominant pathway of exposure for children and prospective parents (See Figure
7.2). It should be noted that for nursing infants of occupationally exposed mothers, the
contribution of xylenes exposure from human milk ingestion, results in a higher percentage
of the background dose (i.e.15%) (See Figure 7.3). Section 7.5 provides further
discussion of estimated total xylenes doses from exposure to various sources.
Figure 7.2 Predominant Pathways of Xylene Exposure for
Children and Prospective Parents from Ambient Sources
Ingestion Dermal
0%
5%
Inhalation
Ingestion
Dermal
Inhalation
95%
Xylenes VCCEP Submission 104
Figure 7.3 Predominant Pathways of Xylene Exposure for
Nursing Infants of Occupationally Exposed Mothers*
Ingestion Dermal
0%
15%
Inhalation
Ingestion
Dermal
Inhalation
85%
* Typical occupational exposure levels (See Section 7.2.3)
7.2.2 Source Specific Exposures
In addition to the ambient sources of xylenes exposure, certain subpopulations of children
and prospective mothers may be exposed to xylenes in specific microenvironments related
to automotive transportation, use of xylene-containing consumer products, or living in a
home with tobacco smokers. Exposures to each of these specific sources have been
quantified and are discussed below.
7.2.2.1 Gasoline Sources of Exposure
Xylenes are common constituents in gasoline. Exact levels in gasoline will vary, but
previous assessments indicate that the typical range is 5-10% by weight (See Section 3).
While xylenes in gasoline contribute to the overall concentration of xylenes in the ambient
air, exposures to gasoline may also occur while riding in a vehicle and during refueling of a
vehicle. As such, xylenes exposures from these specific activities have been assessed. It
is recognized that there are other sources of gasoline exposure beyond those associated
with in-vehicle travel and refueling (e.g., use of small engine equipment such as lawn
mowers, chain saws, leaf blowers, edge trimmers, snow blowers, ATVs, and
snowmobiles). However, monitoring data for xylenes are not available for characterizing
these exposures. Additionally, while data for small engine emissions are available,
adequate models are not available for predicting personal exposures from these sources.
As such, xylenes exposures from small engine equipment have not been quantified.
Xylenes VCCEP Submission 105
In-Vehicle Xylenes Exposure
Vehicle emissions of xylenes contribute to xylenes concentrations measured inside
vehicles during driving. In-vehicle exposure to VOCs and xylenes are due to the
penetration of xylenes in roadway air (e.g., tailpipe emissions) and from engine running
loss into the vehicle cabin while driving (Fedoruk and Kerger, 2003; Batterman et al.,
2002; Weisel et al., 1992). In-vehicle VOC exposure levels can be affected by various
conditions including mode of transportation, driving route, time of day (rush vs. non-rush),
type of fuel distributions system, season of the year, meteorological conditions, and
vehicle ventilation conditions (Chan et al., 1991a,b; Dor et al., 1995; Lawryk and Weisel,
1996; Batterman et al., 2002; Fedoruk and Kerger, 2003). In many cases, the findings of
the various studies can be conflicting, and in-vehicle VOC concentrations can vary
considerably with sampling day and time (Lawryk et al.,1995; Batterman et al., 2002).
Of all modes of transportation involving potential non-occupational exposure to gasoline
constituents (e.g., automobile, bus, subway, walking, biking), in-vehicle exposures while
driving in an automobile are the highest (Chan et al., 1991a). Although many children
commute in school buses, studies show that, because of variables including vehicle
height, location of engine, ventilation conditions, and fuel type, exposure in a car is greater
(Chan et al., 1991a; Jo and Choi, 1996; Jo and Park, 1999a,b; Jo and Yu, 2000) or similar
(Batterman et al., 2002) as that of a bus. The transportation route and traffic density (e.g.,
urban or rural, following closely or far behind a lead car, rush or non-rush) have been
determined to be the most important in-vehicle exposure variables (Batterman et al.,
2002). It is expected that in-vehicle exposures in suburban areas, rural areas, and in
general, areas with lower automobile densities will have lower in-vehicle concentrations.
Numerous studies have been conducted in the U.S., which have evaluated in-vehicle
xylenes exposures (Batterman et al., 2002; CARB, 1998; Chan et al., 1991a,b; Chang et
al., 2000; Fedoruk and Kerger, 2003; Lawryk et al., 1995; SCAQMD et al., 1989; Weisel et
al., 1992). Due to the emission reduction initiatives discussed in Section 5, only the most
recent U.S. data were included in this analysis. Although the CARB (1998) study is
relatively recent, it was excluded because the study design required evaluation of highly
unusual and unrealistic conditions (i.e., travel behind a high emitting vehicle for 2 hours).
It is unlikely that a driver would closely tail a high-polluting vehicle for the entirety of his or
her driving time. It is more likely that the driver would move from behind such a vehicle,
either intentionally or as the result of the general movement of vehicles in traffic, and
therefore would be behind a variety of vehicles while driving during any given time period.
The studies used to derive representative exposure concentrations are summarized in
Table 7.28 below. Each of the automobile studies evaluated specifically excluded
smokers and/or the influence of smoking on VOC in-vehicle concentrations.
Xylenes VCCEP Submission 106
Table 7.28: Summary of Key In-Vehicle Studies
Type of
Vehicle Used
Study Comments
Chang et al., 2000 Minivan, Baltimore, MD, Summer 1998 - Winter 1999. This
occasionally a bus study was designed to simulate activities performed
by older adults. Samples were obtained in 1-hour
increments. The data used in this study was not
published with the paper, but obtained separately.
Reformulated gasoline (RFG) was in regular use in
Baltimore at the time of the study.
Batterman et al., 2002 Car Detroit, MI, Fall 1999.
This study was conducted during 2- 3 hour urban
rush hour commutes. Information on the car used
was not provided. Use of RFG was not required in
Detroit.
Fedoruk and Kerger, 2003 Car Los Angeles, CA, 1997.
This study was conducted during urban commutes.
90 minute TWAs were obtained. A 1993 Toyota, in
good condition, was used. The time of day that
measurements were obtained was not reported.
RFG was in regular use in Baltimore at the time of
the study.
In-vehicle exposure scenario concentrations were derived from means presented in the
three studies above and are representative of a person of any age. Table 7.29 presents
the means from the various studies and an average of the means for all of the studies.
Table 7.29: Average of Mean In-Vehicle Concentrations
3
Mean In-Vehicle Concentration (礸/m )
total o-, m- and p-
Study Description m,p-xylene o-xylene
xylene
Chang et al. a b
Urban 18.9 7.4 26.3
(2000)
Batterman et al.
Urban 6.8 2.2 9.0
(2002)
Fedoruk and
LA Freeway 2.4 11.8 14.2
Kerger (2003)
Average of study means: 4.5 5.9 13.5
a 3
Mean of m-/ p-xylene summer and winter averages of 4.0 and 4.7 礸/m , respectively.
b 3
Mean of o-xylene summer and winter averages of 5.6 and 1.8 礸/m ,respectively.
Due to various driving conditions under which a person may be exposed to in-vehicle
concentrations of xylenes, mean concentrations best portray long-term exposure
concentrations. An average total o-, m-, and p-xylene isomer concentration was derived
using the means of each of the three key studies above. This average is used as the
Xylenes VCCEP Submission 107
typical representative in-vehicle exposure concentration and is considered to be an
average of a high-end scenario, as it is representative of urban exposures where traffic
densities are highest.
As noted in Section 5, VOC emissions from motor vehicles, including xylenes, are on the
decline as a result of the 1990 Clean Air Act Amendments, which called for lower tailpipe
standards, more stringent emissions testing, expanded inspection and maintenance
programs, new vehicle technologies and clean fuels programs. Therefore, as these
programs are matured, the exposure estimates described above are likely to overestimate
in-vehicle exposures in the future.
In-Vehicle Dose Calculations
Age-specific in-vehicle xylenes exposures were quantified according to the following
equation:
C ?ED ?EF ?ET ?IR ?ABSi ?CF
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
concentration of total xylenes in vehicle air (礸/m 3)
C =
ED = exposure duration (years)
EF = exposure frequency (days/year)
ET = exposure time (hours/day)
inhalation rate (m3/hour)
IR =
ABSi = xylenes inhalation absorption factor; 0.6 (unitless)
CF = conversion factor (0.001 mg/礸)
BW = body weight (kg)
AT = averaging time (days)
The average of the mean study concentrations presented in Table 7.29 was utilized with
exposure factors presented in Section 6 to quantify ambient exposures. The in-vehicle
ADDs are presented below in Table 7.30.
Xylenes VCCEP Submission 108
Table 7.30: Summary of ADDs From In-Vehicle Total Xylenes Exposure
Female
19-35
Exposure <1 1-5 6-13 14-18
year old
Parameter Units year old year old year old year old
Typical
3
C 礸/m 13.5 13.5 13.5 13.5 13.5
ET h/d 1.2 1.2 1.0 1.4 1.3
EF d/y 365 365 365 365 365
ED years 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.6 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001
AT d 365 1825 2920 1825 6205
BW kg 7.2 15.4 35 61 62.4
ABSi unitless 0.6 0.6 0.6 0.6 0.6
Dose mg/kg/d 2.6E-04 2.0E-04 1.2E-04 1.1E-04 7.9E-05
Refueling Exposures
A variety of researchers have reported that self-serve automobile refueling generates the
greatest and most common source of gasoline exposure to the general population (Backer
et al., 1997; Pope and Rall, 1995; Wixtrom & Brown, 1992). As such, xylenes exposures
while refueling an automobile have been assessed. Exposure occurs primarily via
inhalation of vapors during refueling. There are many potential sources of exposure to
gasoline vapors at service stations, including breathing and working losses from
underground storage tanks, displacement air losses from filler pipes during refueling, fill
spillage during refueling, and evaporative and exhaust emissions from motor vehicles in
the station. The displacement of fuel vapors from the gas tank while refueling, however,
generates the majority of exposure to gasoline vapors ( Backer et al., 1997; Guldberg,
1992).
The Northeast States for Coordinated Air Use Management (NESCAUM) reviewed nine
pre-1989 refueling studies and determined mean and high-end exposure concentrations
for xylenes and other VOCs (NESCAUM, 1989). Data were reviewed and weighted,
yielding mean and high-end total o-, m-, and p-xylene exposure estimates of 0.87 and 4.8
mg/m 3. Two more recent studies, API (1993) and Backer et al. (1997), however, were
selected as having the best representative data for this exposure assessment. This is
because data collected before 1990 are not reflective of exposures associated with current
gasoline formulations, which have reduced VOC emissions and the implementation of
vapor recovery systems at the pump and on the cars.
The API study was conducted in 3 cities across the U.S and the Backer et al. study was
conducted in Fairbanks, AK. These key studies focus on the exposure of a self-service
customer while refueling; occupational exposure concentrations were excluded. The
xylenes content of gasoline in each study is similar (3.9 to 9%), and the presence or
absence of VRS controls at the pump was also documented in the studies. The selected
data are representative of potential refueling exposures in different U.S. regions, using
Xylenes VCCEP Submission 109
different blends, grades, and types of gasoline, and using a variety of controls at the
pump. A summary of the key studies is provided in Table 7.31.
Table 7.31: Summary of Key Refueling Studies
Date/location data
Study collected Controls at the Pump Type of Gasoline
October - November Only LA had Stage II Three grades of
Cincinnati, OH VRSs and extensively gasoline were
API, 1993
Phoenix, AZ used pump safety evaluated: regular
Los Angeles, CA latches unleaded, mid-grade
Backer, et al., January - March, 1995 Regular gasoline and
No Stage II VRS
1997 Fairbanks, AK E10 gasoline
An individual will refuel under a variety of conditions, which are collectively represented by
the two key studies. For example, they will spend varied amounts of time, under varied
meteorological conditions, at different gasoline stations, filling their tanks.
Personal breathing zone exposure measurements have been used as representative
exposure point concentrations. Thus, although displacement of vapors from the gas tank
is the dominant exposure source, the measurements in the studies will capture the
contributions from any other sources of xylenes that are present at the gas stations.
Exposure data from the key studies are presented in Table 7.32.
Table 7.32: Total o-, m-, and p-Xylene Air Concentrations During Refueling (mg/m3)
Study Mean Maximum
0.55 1.5
API, 1993 0.75 2.2
0.54 1.2
0.81 1.8
Backer, et. al., 1997
0.53 2.9
Average 0.64 1.9
Averaging the mean exposure concentrations in each of the key studies resulted in a
mean exposure concentration of 0.64 mg/m 3; this value is used to describe a typical
exposure. Obtaining an average of the maximum concentrations from each study resulted
in a maximum exposure concentration of 1.9 mg/m 3; this value is used to describe a high-
end exposure.
A comparison of the NESCAUM mean of 0.87 mg/m 3 and high-end estimate of 4.8 mg/m 3
to the exposure concentrations shown on Table 7.32 demonstrates that the refueling
exposure concentrations of xylenes have decreased by approximately 30 to 60% over the
years. This decrease can be attributed to the changes in gasoline formulations, pump
controls, and on-board emission controls of newer vehicles. Thus, xylenes exposure
concentrations during refueling are likely lower than those represented in the key studies
Xylenes VCCEP Submission 110
due to RFG phase-in across the country and fleet vehicle changeovers since the mid-
1990s. For these reasons, it is expected that exposures during refueling will continue to
decline in the future.
Refueling Dose Calculations
Age-specific dose calculations were made for a typical and high-end exposed individual
while refueling. Doses were estimated for a woman of child-bearing age and a teenager
16 to 18 years old. It was assumed for the purposes of this assessment that children
younger than 16 would not pump gasoline on a regular basis. The exposure estimates are
limited to refueling only (i.e., the time spent pumping gasoline into the vehicle); the total
amount of time spent at the service station is not evaluated. It is also assumed that the
refueler remains at the pump the entire time that he or she is refueling.
Exposure was quantified according to the following equation:
C ?ED ?EF ?IR ?ABSi ?CF
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
concentration of total xylenes in refueling air (mg/m 3)
C =
ED = exposure duration (years)
EF = exposure frequency (days/year)
CF = conversion factor (0.001 mg/礸)
ABSi = xylenes inhalation absorption factor; 0.6 (unitless)
inhalation rate (m3/day)
IR =
BW = body weight (kg)
AT = averaging time (days)
Age-specific refueling ADDs are presented in Table 7.33 below.
Xylenes VCCEP Submission 111
Table 7.33: Summary of ADDs from Refueling o-, m-, and p-Xylene Exposure
Female Female
16-18 19-35 16-18 19-35
year old year old year old year old
Exposure
Parameter Units Typical High-end
mg/m 3
C 0.64 0.64 1.9 1.9
ET h/d 0.027 0.027 0.062 0.062
EF d/y 70 70 104 104
ED years 3 17 3 17
M3 /h
IR 0.5 0.5 0.5 0.5
AT D 1095 6205 1095 6205
BW Kg 62.9 62.4 62.9 62.4
ABSi unitless 0.6 0.6 0.6 0.6
Dose mg/kg/d 1.6E-05 1.6E-05 1.6E-04 1.6E-04
It should be noted that in-vehicle-while-refueling xylenes concentrations appear to be
lower than ambient concentrations at gasoline service stations and in-vehicle
concentrations while commuting (Vayghani and Weisel, 1999; API, 1993). Thus, a child
who remains in the car while it is being refueled was not evaluated, as it was determined
that the xylenes exposure concentrations were much lower (i.e., about 1 order of
magnitude) than measured refueling exposures.
7.2.2.2 Consumer Products
A number of specialty consumer products contain at least a trace amount of xylene
isomers. As part of an EPA study, 1,159 consumer products from 65 product categories
were analyzed for VOC content by GC/MS with a detection limit of 0.1% by weight (Sack
et al., 1992). The Sack et al. study was reviewed to determine which product categories
had products that contained greater than 0.1% by weight o-, m-, and/or p-xylene isomers.
Appendix A contains tables which summarize the products that contain xylenes. Based
-6
on this review, 13 product categories were identified for which at least one product
contained one or more of the xylene isomers.
Because the Sack et al. (1992) study is somewhat dated (i.e., from 1987), steps were
taken to verify the xylenes composition information by obtaining current material safety
data sheets (MSDS) for the various products. From each of the Sack et al. product
categories, five products were randomly selected a the total xylene isomer content
nd
verified using the product MSDSs. This analysis is presented in Appendix A -7. The
sources of consumer product MSDS information included the product manufacturer when
possible, as well as:
? Vermont Safety Information Resources, Inc. ?180,000 MSDS archived at
http://www.hazard.com
? Cornell University Planning Design and Construction ?250,000 MSDS archived at
http://msds.pdc.cornell.edu/msdssrch.asp; and
? Seton Compliance Resource Center ?350,000 MSDS archived at
http://www.setonresourcecenter.com/MSDS/index.htm.
Xylenes VCCEP Submission 112
The EPA's Source Ranking Database (SRD) (EPA, 2000) was also reviewed to determine
products that contain xylene isomers. The SRD is a compilation of product composition
information from a variety of sources. While the SRD has the same limitation that Sack et
al. does in that the information is dated, it contains information from a variety of sources
and is not limited to just those products that may have contained chlorinated VOCs. The
SRD was developed to rank consumer products for screening a large number of indoor air
pollution sources and prioritizing them for future evaluation. Because the Sack et al. study
is one of the major sources of data in the SRD, much of the same information from Sack et
al. is included in the SRD. When comparing the two consumer product data sources, it
was found that the same product categories that contained xylene isomers were identified
in Sack et al. and SRD and that the percent xylenes composition was similar with the
exception of commercial mixed xylenes. Mixed xylenes as a neat solvent were identified
in the SRD as miscellaneous use aromatics. Mixed xylenes (70-95% o-, m-, and p- xylene
isomers and 5-25% ethylbenzene) is sold in gallon-sized or smaller containers at various
hardware/home improvement stores for use as a paint thinner or degreaser, and therefore
it was also included in the exposure assessment.
As presented in Appendix A it can be seen that a variety of consumer products contain
-7,
xylene isomers; however, the majority of those products contain the isomers at less than
1% by weight and therefore are unlikely to be important sources of exposure. Thus, this
assessment has focused on those consumer products that have the greatest potential for
resulting in significant exposures to children. Those consumer products, which contain
xylene isomers greater than 1% by weight are listed on Table 7.34. Each of these
products was then considered in the context of how they would be used and the likelihood
of children being exposed during their use.
Table 7.34: Typical and High-End Xylenes Content of Consumer Products
Typical High-End
a
Usage Scenario Product Category b c
Content (%) Content (%)
Surface preparation / Metal
Commercial mixed xylene 81 95
parts degreasing
Spray primer 11 20
Spray Painting
Spray paint 9.5 16
Carburetor and choke cleaner 29 60
Automobile maintenance
Ignition wire dryer 6.1 50
a
Based on MSDS records for product categories identified by Sack et al and Source Ranking Database
b
Average of four lowest weight contents listed on five representative MSDS records.
Where the MSDS provided a range, the highest weight content was used.
c
Maximim weight content listed on five representative MSDS records.
It is believed that all of the products listed on Table 7.34 could be used in the home.
However, the number of homes where some of these products (e.g., automotive products
such as carburetor and choke cleaner and ignition wire dryer) are used is small and the
uses would be restricted to areas of the home (garages) and times when children are less
likely to be present.
Evidence of this can be seen in an EPA sponsored consumer product survey (WESTAT,
1987). This survey found that the fraction of the surveyed individuals ever using
Xylenes VCCEP Submission 113
carburetor cleaners or ignition wire dryers were 4.8 and 22%, respectively. Of those that
have used these products, the majority (86 to 88%) reported that the products were used
outdoors. Less than 1.5% of the product users used these products in the home, with the
remainder reporting that they were used in a garage.
For these reasons, the paint-related products and commercial mixed xylenes were
selected for a quantitative exposure assessment. Based on the likelihood of use by or in
the presence of children in the home, the paint products and commercial mixed xylenes
were evaluated for exposure in two scenarios. These scenarios include:
? residential metal parts degreasing scenario (mixed xylene solvent); and
? residential spray painting scenario (spray primer and spray paint).
Generic Scenario Assumptions
In the consumer scenarios the residence was assumed to be divided into two
microenvironments: 1) room of use and 2) other rooms in house. Current consumer
product exposure models are not sufficiently sophisticated to accurately characterize the
difference between product users and non-users in the same room (i.e., near field
exposures are difficult to accurately predict). Thus, in this situation both the user and non-
user would be assumed to have the same exposures. In order to best approximate
exposure to the product user, a small room size (20 m 3) was selected in accordance with
default values for the various E-Fast scenarios. Typical and high-end exposure estimates
were made based on the amount of product used. In addition, typical and high-end short-
term one-hour average exposure estimates were calculated for both scenarios.
One-hour, eight-hour, and 24-hour time-weighted average exposure concentrations were
calculated using the EPA Multi-Chamber Concentration and Exposure Model Version 1.2
(MCCEM) and the conceptual framework (i.e., base exposure scenario including activity
pattern, emissions models, and interzonal airflow equation) of the EPA Exposure, Fate
Assessment Screening Tool Version 1.1 (EFAST) Consumer Exposure Module (CEM).
Exposure concentrations were calculated using MCCEM rather than EFAST to take
advantage of the more detailed output of MCCEM (e.g., concentration versus time) and
the ability to save input files for future review. MCCEM and EFAST use the same
computational engine for indoor air quality modeling.
For products formulated with xylenes, manufacturers recommend that if using the product
indoors, it should be done in a well-ventilated area. Excerpts from a typical xylenes-
containing consumer product are provided in Table 7.35.
Xylenes VCCEP Submission 114
Table 7.35: Excerpts from Typical Consumer Product Label Instructions and
Warnings
Label Section Text Example Source
Directions "Use in a well ventilated area."
"Use only with adequate ventilation. Do not All Pro Cover Shield Stain Killer
breathe dust, vapors or spray mist. Open windows Instructions dated March 2002.
and doors or use other means to ensure fresh air (http://www.allprocorp.com/
entry during application and drying. If you techbuls/SeymourTB/
Caution
experience eye watering, headaches or dizziness, 7000TB11069CoverShield.cfm
increase fresh air or wear respiratory equipment accessed 8/12/2003.)
protection (NIOSH/MSHA approved) or leave the
area. Close container after each use."
Recently, the EPA conducted a residential ventilation study of carbon monoxide in which
whole house air exchange rates were determined under various ventilation conditions of
windows and doors open (Johnson et al., 1998, 1999). This study indicated that median
air exchange rate for a house with at least one window open was 1.34 air changes per
hour (ACH) and a high-end air exchange rate was 3.0. Higher air exchange rates are
achievable by using a window fan or whole house fan. The Air King TM brand window box
fan has a reported airflow ranging from 2100 cfm at low speed to 4300 cfm at high speed.
Assuming the fan is 50% efficient (to account for losses due to presence of a screen or an
incomplete seal at the window), whole house air exchange rates of 5 to 10 air changes per
hour are achievable in a 369 m 3 home. The importance of using exhaust fans to achieve
air exchange rates in the range of 10 to 15 air changes per hour during large solvent-
based projects is discussed as part of a recent exposure modeling study of home paint-
stripper users (Riley et al., 2000).
When products containing xylenes are used in the home in accordance with consumer
product labeling, it is expected that the user will open windows or doors for small to
moderate sized projects. For large projects, it can be assumed that user will conduct the
activity outside or will introduce additional fresh air into the home by using a window fan or
whole house fan. For a typical usage amount, the windows are assumed to be open for a
24-hour period to induce cross-ventilation as specified on product labels found on products
containing xylenes. Therefore, an air exchange rate of 1.3 ACH was used during the
modeling of the typical scenario. For the high-end usage amount, the user is assumed to
operate a window fan at the highest speed for the duration of the product use and for one-
half hour after use. It is also assumed that the user leaves the windows open for the
remainder of the 24-hour period after use began. Therefore, an air exchange rate of 5
ACH was applied during the modeling of the high-end scenario.
It should be noted that the modeled air concentration is relatively linear with the whole
house air exchange rates used in this assessment. If one were to assume that no
additional ventilation measures were taken when using the product, the default air
exchange rate would be 0.45 ACH. This value is approximately 3 times less than the air
exchange rate used for the typical scenario, and approximately 11 times less than the air
exchange rate used for the high-end scenarios. Thus, the under a "no additional
ventilation" scenario, the predicted air concentrations would be 3 and 11 times higher for
the typical and high-end scenarios modeled in this assessment, respectively. It should be
Xylenes VCCEP Submission 115
noted that the "no additional ventilation" scenario was not considered in this assessment
as it is contrary to the manufacturer instructions for product use (See Table 7.35).
Modeled indoor air concentrations available in one-minute increments were averaged to
calculate short-term one-hour average concentrations. The short-term one-hour average
concentration is the maximum one-hour average that occurs during the scenario or
individual product use.
Residential Metal Parts Degreasing Scenario
There are no published data on xylene isomer exposures from the use of solvents for
metal parts degreasing in the home. Paint thinners or pure solvents are commonly used
as metal parts degreasers in hobbies such as firearms restoration or classic automobile
restoration. While it is expected that common solvents such as mineral spirits or acetone
are most frequently used in metal parts degreasing, from time to time a hobbyist may
choose to use mixed xylenes (consisting of 81-95% o-, m-, and p-xylene isomers) which
is commercially available in hardware stores in quart or half-gallon sized containers. In
this scenario, the typical and high-end uses are distinguished by the xylene isomer weight
content in mixed xylenes, usage time, and usage amount.
EPA sponsored survey data (Westat, 1987) indicate that among the U.S. population ages
18 years and older, approximately 28% of the population have used a solvent type
cleaning fluid or degreaser in their lifetime. Of those that have used a degreaser, 59%
used the product in the home. Survey data also indicate that u sers generally read the
directions (68%) and open a door or window during indoor use (57%). With respect to a
conservative estimate of children's exposures, the population of interest is those limited
number of households where mixed xylenes is used indoors.
Because degreasers are usually applied to a surface using a cloth, the EFAST product
applied to surface scenario was selected as the baseline scenario. The parameter values
used in the models were taken from the Exposure Factors Handbook (EPA, 1997a), the
Toxicological Profile for Xylenes (ATSDR, 1995), and professional judgment. These
values are presented on Tables A -8-1 and A-8-2 in Appendix A -8. Likewise, the activity
patterns for users and observers in the room of use and non-users in the other room,
which are based on the default EFAST activity pattern, are presented in Table A -8-3 in
Appendix A-8.
The Westat (1987) survey of solvent product usage provides a distribution of the volume of
solvent used per degreasing event for the United States population (Table D-18). Detailed
information regarding specific uses of mixed xylenes were not found in the peer-reviewed
or gray literature. However, websites for do-it-yourself/hobbyists indicate that mixed
xylenes may be used as a degreaser for automobile repair, firearm restoration, metal
surface preparation, etc. However, the usage data reported by Westat is likely much
greater than that which would be used for because it is representative of a wide variety of
products including Easy-OffTM oven cleaner, Fuller BrushTM cleaners, WooliteTM and
DawnTM, none of which contain xylenes. In addition, despite the likelihood that larger
projects involving volatile solvents would be performed outdoors, the Westat usage survey
also does not provide separate usage amount distributions for indoor and outdoor uses.
As such professional judgment was used in combination with a `bench scale' simulation
Xylenes VCCEP Submission 116
using water to estimate the amount of degreaser that might be used for a typical indoor
project (i.e., small object with a surface area of 1 ft2) and a high-end usage amount for a
larger project (i.e., object with a surface area 10 ft2). The estimated usage amounts are
provided in Table 7.36.
Table 7.36: Degreaser Usage Amount
Usage ounces/use cups/use grams /use
Typical 0.4 0.05 10
High-End 4 0.5 102
For this scenario, a typical use is characterized by typical usage amounts and usage times
along with the typical weight content provided in Table 7.34. The high-end use is
characterized by high-end usage amount and time, along with the high-end weight content
given in Table 7.34.
The model was run to estimate exposure concentrations for users and non-users of a
degreaser according to the usage distributions provided above. Only inhalation exposures
have been assessed in this scenario. While there could be dermal contact during use,
there is likely to be significant volatilization from the skin surface, as it is not expected to
be submersed in the product. The predicted total o-, m-, and p-xylene isomer air
concentrations are shown on Table 7.37. The typical use corresponds to the use of a
moderate amount of a product containing a typical level of o-, m-, and p-xylene isomers as
a metal parts degreaser under well-ventilated conditions (e.g., open windows). The high-
end use represents an above average usage amount of degreaser containing a high-end
weight content of xylenes under well-ventilated conditions (e.g., with an exhaust fan at low
speed).
Table 7.37: Predicted Total o-, m-, and p-Xylene Isomer Concentrations for
Residential Metal Parts Degreasing Scenario
TWA (1-Hour) Exposure TWA (8-Hour) Exposure TWA (24 Hour) Exposure
Concentration (ppm) Concentration (ppm) Concentration (ppm)
Usage
Child Non- Child and Child Non- Child and Child Non- Child and
User Adult User User Adult User User Adult User
Typical usage
amount with
2.3 9.5 0.42 1.4 0.14 0.45
open windows
a
(ACH =1.34)
High-end
usage amount
8.9 30 1.5 4.3 0.49 1.4
with exhaust
b
fan (ACH = 5)
a
ACH = air changes per hour.
b
Exhaust fan is assumed to be turned off one-half hour after end of product use and the windows are assumed to be left
open, resulting in a post-usage air exchange rate of 1.34 hr -1.
Xylenes VCCEP Submission 117
Residential Spray Painting Scenario
There are no published data on xylenes exposures from the use of aerosol painting
products or paint removers in the home. Spray paints are commonly used to coat metal
surfaces, such as lawn furniture or automobile parts. A typical project where metal
surfaces are being repainted consists of two steps :
? surface priming with an aerosol spray can product; and
? surface painting with an aerosol spray can product.
The Westat (1987) survey data indicate that among the U.S. population ages 18 years and
older, approximately 35.4% of the population have used spray paint in their lifetime. Of
those that have used spray paint, only 17.8% painted indoors the last time they used spray
paint. Survey data also indicate that spray paint users generally read the directions
(73.2%) and open a door or window during indoor spray paint use (62.9%). With respect
to a conservative estimate of children's exposures, the population of interest is those
limited number of households where spray painting is performed indoors.
The EFAST product sprayed on a surface baseline scenario was used for spray primer
and spray paint. The parameter values used in the models were taken from the Exposure
Factors Handbook (EPA, 1997a), the Toxicological Profile for Xylenes (ATSDR, 1995a),
and professional judgment. These values are presented on Tables A -9-1 and A-9-2 of
Appendix A -9. Likewise, the activity patterns for users and observers in the room of use
and non-users in the other room, which are based on the default EFAST activity patterns,
are presented in Table A-9-3 of Appendix A-9. The Westat (1987) survey of solvent
product usage provides a distribution of the volume of spray paint used per painting event
for the United States population (Table Q-18).
The usage amount of both products used in this scenario (spray primer and spray paint) is
correlated because each of these three products is used on the same surface area. It was
assumed that equal amounts of spray primer and spray paint were used based on an
assumption of one coat of primer and paint, and similar wet film thickness for each
product.
Despite the likelihood that larger projects involving spray paints would be performed
outdoors, the Westat usage survey does not provide separate usage amount distributions
for indoor and outdoor uses. Therefore, it was assumed the 90th percentile of the Westat
distribution (slightly less than 2 cans of spray paint) represents the high-end usage
quantity for spray paint. Table 7.40 summarizes the usage amounts used in the
assessment.
Xylenes VCCEP Submission 118
Table 7.40: Spray Paint Scenario Usage Amount
ounces/ ml/ cans/ grams
Product Usage Percentile a b c
use use use product/use
th
Typical 50 8 237 0.6 204
Spray Primer th
High-End 90 26 769 1.9 661
th
Typical 50 8 237 0.6 187
Spray Paint th
High-End 90 26 769 1.8 607
a
The volume of spray paint and spray primer is based on the distribution for spray paint from Westat (1987)
Table Q-18.
b
Cans of spray paint or spray primer calculated using standard can size in Table 14.14
c
grams/use= ( ounces/use ) * ( 29.57 ml/ounce ) * ( density g/ml )
The model was run to estimate exposure concentrations for users and non-users of the
paint products according to the usage distributions provided above. Only inhalation
exposures have been assessed in this scenario. While there could be dermal contact with
these products during use, there is likely to be significant volatilization from the skin
surface as it is not expected to be submersed in the product. The predicted total o-, m-,
and p- xylene isomer air concentrations are shown on Table 7.41. The typical use
corresponds to the use of moderate amounts of spray primer and spray paint containing
typical amounts of xylenes under well-ventilated conditions (e.g., open windows). The
high-end use represents an above average usage amount and weight content of xylenes
under well-ventilated conditions (e.g., with an exhaust fan at low speed).
Xylenes VCCEP Submission 119
Table 7.41: Predicted Total o-, m-, and p-Xylene Isomer Concentrations for
Residential Spray Paint Scenario
TWA (1-Hour) TWA (8-Hour) TWA (24-Hour)
Exposure Exposure Exposure
Concentration Concentration Concentration
(ppm) (ppm) (ppm)
Usage
Child Child Child
Child
and Child and Child and
Non-
Non-User Non-User
Adult Adult Adult
User
User User User
Spray Primer (1-hour usage time)
Typical usage amount
with open windows (ACH 6.2 26 1.2 3.8 0.39 1.3
a
=1.34)
High-end usage amount
with exhaust fan (ACH = 12 43 1.8 6.1 0.61 2.1
b
5)
Spray Paint (1-hour usage time)
Typical usage amount
with open windows (ACH 4.9 21 0.91 3.0 0.31 0.99
a
=1.34)
High-end usage amount
with exhaust fan (ACH = 8.9 30 1.5 4.2 0.49 1.4
b
5)
Cumulative Scenario (2-hour total usage time)
Typical usage amount
with open windows (ACH 7.2 27 2.1 6.7 0.69 2.2
a
=1.34)
High-end usage amount
with exhaust fan (ACH = 13 46 3.3 10 1.1 3.5
b
5)
a
ACH = air changes per hour.
b
Exhaust fan is assumed to be turned off one-half hour after end of last product use and the windows are assumed to be left
open, resulting in a post-usage air exchange rate of 1.34 hr -1.
7.2.2.3 Tobacco Smoke
While not a chain-of-commerce source, xylenes are present in both the mainstream
tobacco smoke inhaled by the smoker directly from the cigarette and sidestream smoke
released to the environment from the smoldering end of a cigarette. Because cigarette
smoke is a significant source of exposure for smokers, and a contributor to indoor xylenes
concentrations, cigarettes as a source of exposure have been evaluated (ATSDR, 1995a;
Wallace, 1987).
Environmental tobacco smoke (ETS) is comprised of both sidestream smoke and exhaled
mainstream smoke (Daisey et al., 1994; NAP, 1986). Children may be exposed to xylenes
from tobacco smoke directly as smokers (mainstream smoke) or indirectly as non-smokers
(ETS). Numerous studies have been conducted to identify and quantify the individual
chemical constituents from tobacco smoke. Researchers have identified over 4,800
Xylenes VCCEP Submission 120
individual constituents, including xylenes, in both mainstream smoke and ETS. Due to
physical and chemical differences in burning conditions, xylenes have a higher rate of
release per cigarette into sidestream smoke than into mainstream smoke (Wallace and
O'Neill, 1987; Daisey et al., 1994; Fowles et al., 2000; NAP, 1986; Darrall et al., 1998).
Smoking occurs almost anywhere there are people; however, on a daily basis, children
spend most of their time inside at home and therefore their greatest potential for xylenes
exposure from ETS would be if they lived with a smoker. Also, although significant
decreases in teenage smoking have been demonstrated in recent years, many teenagers
are cigarette smokers. Thus, exposures to xylenes via tobacco smoke were quantified for
children from mainstream smoke and ETS. Since smoking is not permitted on school
properties and is now banned in most indoor public places, xylenes exposure from ETS
has been assumed to occur primarily in the home.
In order to calculate exposure to xylenes from tobacco smoke exposure, the xylenes
cigarette mainstream and sidestream emission rates were determined. Numerous studies
have been conducted to evaluate the chemical emission rates. These are summarized in
Table A-10-1 in Appendix A-10. In order to evaluate the exposure to xylenes from tobacco
smoke, the general school year weekday microenvironment activity patterns for children
as presented in Table A-10-2 of Appendix A-10 were considered. Exposure to ETS was
assumed to occur in the home, as ETS exposure in outdoor environments was assumed
to be negligible. Because most studies evaluate the m- and p-xylene isomers together,
the emission rates and exposure concentrations were calculated for total xylenes (e.g.,
sum of o-, m-, and p-xylene isomers).
Environmental Tobacco Smoke (ETS) Exposures
The total time spent with smokers was obtained for children and adults from the Exposure
Factors Handbook (EFH), and is presented in Table A-10-3 in Appendix A-10. In
accordance with the information provided in Table A-10-2, it was assumed that a smoker
was actively smoking inside the home for up to 6 hours per day in the presence of a child
or female adult.
It was assumed that an adult female smokes one pack of cigarettes per day (20 cigarettes)
and that half of the pack is smoked indoors at home, which is equivalent to 10 cigarettes
smoked at home indoors per day. This assumption is consistent with EPA estimates
(EPA, 1997b). The total mass of xylenes released in cigarette smoke was calculated
based on the sum of the m/p- and o-xylene emission factors presented in Daisey et al.,
(1994). The total mass was divided by the 6 hours that the adult is awake and at home to
account for smoking "off and on" during this time. Table 7.44 lists the emission factor and
resulting emission rate.
Xylenes VCCEP Submission 121
Table 7.44: Emission Factor and the Calculated Emission Rate
Emission Usage Time Emission rate
Isomer(s)
factor (礸/cig) (cig) (hours) (mg/hr)
m/p-xylene 299 10 6 0.50
o-xylene 67 10 6 0.11
total o-, m-
366 10 6 0.61
and p- xylene
Air concentrations were modeled using the Multi-Chamber Concentration and Exposure
Model (MCCEM). This model accounts for the emission of xylenes over discrete time
periods and exposure of the individual based on their activity patterns (see Appendix A -
10). A hypothetical house was created where all the living space was on one floor such
that all exposures were modeled to occur in one zone. This scenario was developed
because it was assumed that the smoker would move throughout the house and that all
areas of the house would have similar xylenes air concentrations as it is known that the
various rooms of the house come into equilibrium in a short period of time (Johnson et al.,
1999). Default values of 0.45 ACH for the air exchange (which assumes no open doors or
windows) and 369 m3 for the volume of the residence were used (EPA, 1997). The
following equation was used to calculate the average daily d ose of xylene from ETS
exposure:
C ?ET ?EF ?ED ?IR ?ABSi
ADD =
BW ?AT
where:
ADD = average daily dose (mg/kg/day)
exposure concentration of total xylenes (mg/m 3)
C =
ET = exposure time (hr/day)
EF = exposure frequency (days/yr)
ED = exposure duration (years)
inhalation rate (m3/hr)
IR =
ABSi = xylenes inhalation absorption factor (0.6)
BW = body weight (kg)
AT = averaging time (days)
Age-specific xylenes concentrations and doses resulting from ETS exposure in the home
were calculated and are presented on Tables 7.45 and 7.46.
Xylenes VCCEP Submission 122
Table 7.45: Summary of Average Daily [Xylenes] Concentrations (ADCs) from ETS
Exposure (礸/m3)
Female
19-35
< 1 year 1-5 years 6-13 years 14-18
old old old years old years old
Isomer(s)
m/p-xylene 0.66 0.65 0.57 0.50 0.66
o-xylene 0.15 0.14 0.13 0.11 0.15
total o-, m- and
p- xylene 0.81 0.79 0.69 0.61 0.81
Table 7.46: Summary of ADDs from ETS Xylenes Exposure (mg/kg/day) (total
isomers)
Female
19-35
<1 1-5 6-13 14-18
year old
year old year old year old year old
Exposure
Parameter Units Typical
3
C 礸/m 0.81 0.79 0.69 0.61 0.81
ET h/d 24 24 24 24 24
EF d/y 365 365 365 365 365
ED years 1 5 8 5 17
3
IR m /h 0.19 0.31 0.51 0.6 0.47
CF mg/礸 0.001 0.001 0.001 0.001 0.001
6205
AT d 365 1825 2920 1825
BW kg 7.2 15.4 35 61 62.4
0.6 0.6 0.6 0.6
ABSi unitless 0.6
Dose mg/kg/d 3.1E-04 2.3E-04 1.5E-04 8.7E-05 8.8E-05
As Table 7.45 indicates, the personal exposure concentration increases by 0.61 to 0.81
礸/m 3 as a result of having one smoker in the home. The personal exposure
concentration for a particular age range is a function of the time spent in the home and the
number of hours in the home while active smoking is occurring. Additional exposure
would be expected if there were more than one smoker residing at the house. Due to the
activity patterns, the personal exposure concentrations in Table 7.46 are less than the
average concentration of xylenes in the home (attributable to ETS) of 0.89 礸/m 3.
Mainstream Tobacco Smoke Exposures
Exposure to xylenes from mainstream smoke was evaluated for adults (19-35 years) and
teenagers (14-18 years). Breathing patterns for the inhalation of mainstream smoke (MS)
and ETS differ considerably; active smokers inhale intensely and intermittently and usually
hold their breath for some time at the end of inspiration. This increases the amount of
Xylenes VCCEP Submission 123
smoke components that are deposited and absorbed (EPA, 1992). Thus, an absorption
factor was not used.
C ?SF ?CF
ADD =
BW
where:
ADD = average daily dose (mg/kg/day)
C = concentration of xylenes in mainstream smoke (礸/cigarette)
SF = smoking frequency (cigarettes/day)
CF = conversion factor (0.001 mg/礸)
BW = body weight (kg)
The dose was calculated using the sum of the m/p-xylene mainstream smoke emission
rate (9.2 礸/cig) and o-xylene emission rate (2.0 礸/cig) average emission factors from
Darrall et al. (1998), or 11 礸/cig. A teenager smokes an average of about 7 cigarettes
per day, whereas, a adult female smokes an average of 14 cigarettes per day (EFH
n
Table 15-146), which results in a daily intake of xylenes from mainstream smoke of 0.08
mg/day for the teenage smoker and 0.2 mg/day for the adult smoker. The annual average
daily doses were calculated and are presented in Table 7.47.
Table 7.47: Summary of ADDs from Exposure to Xylenes in Mainstream Smoke
(mg/kg/day)
(total isomers)
Female
Exposure 14 ?18 19 ?35
Parameter Units years old years old
C 礸/cigarette 11 11
SF cigarette/day 7 14
CF mg/礸 0.001 0.001
BW kg 61 62.4
Dose mg/kg/day 1.3E-03 2.5E-03
Wallace (1989) assumed a smoking frequency of 32 cigarettes/day. However, of the
smoking data reported in EFH, only 14% of smokers indicated that they smoke more than
24 cigarettes in a day and of those who reported s moking at home, only 6% reported
smoking more than 24 cigarettes. Thus, the uncertainty surrounding chemical dose from
mainstream cigarette smoke is primarily associated with the smoking frequency.
Therefore, the smoking frequency used by Wallace is a high-end estimate.
Xylenes VCCEP Submission 124
7.2.3 Occupational Exposure
Occupational exposure to o-, m-, and p- xylene isomers occurs primarily in one of three
types of occupations: (1) production/processing of xylene, (2) use of xylenes as feedstock
for the manufacturing of other chemicals, and (3) use of chemical products containing
xylene isomers in a commercial or skilled trade occupation (e.g., solvents, paints, or
lacquers). Exposure data relevant to these general occupational settings were obtained
from industry trade organizations, the recent peer-reviewed literature, and the
"Occupational Exposure Database ?Solvents End-Use" prepared by the American
Chemistry Council and European Chemical Industry Council (Caldwell et al., 2000).
Inhalation Exposures
Production/Processing and Manufacturing Exposure Concentrations
In order to assess recent xylenes exposure to workers in the chemical manufacturing and
distribution industries, industrial hygiene monitoring records from January 1995 through
December 2001 were collected from members of the BTX VCCEP Consortium. As this
survey was originally conducted to develop information on actual exposure, only data from
employees who were not wearing respirators have been summarized. The analysis of
these industrial hygiene data is summarized in Table 7.48. The exposure concentrations
were converted to the units of mg/m 3 for use in subsequent dose calculations by
multiplying the units in ppm by 4.34.
Table 7.48: ACC BTX VCCEP Consortium Members' Occupational Xylene Exposure
Survey
Total o-, m-, and p-Xylene Isomer Exposure
Concentrations for Normal Full-Shift Operations
Number of
95th Percentile
Operation Mean
Samples
(mg/m 3) (mg/m 3)
(ppm) (ppm)
Manufacturing 1,450 0.11 0.48 0.27 1.2
Distribution 42 0.11 0.48 0.16 0.69
Solvent End Use Exposure Concentrations
To improve the state of knowledge of occupational exposure concentrations to VOCs
found in common solvents, a database was prepared for the American Chemistry Council
and European Chemical Industry Council (Caldwell et al., 2000). Summary statistics and
the database structure were published in the American Industrial Hygiene Association
Journal. The database consists of air concentration exposure data from about 100 journal
articles from 1961-1988, which were selected from an initial list of 22,000 papers. For the
VCCEP occupational exposure assessment, this database was accessed and queried for
records that met the following criteria:
Xylenes VCCEP Submission 125
? The exposure occurred in the United States;
? At least one discrete sample or an average concentration and sample number was
available for xylenes;
? The sample was collected in the breathing zone; and
? For TWA exposures, the exposure time was greater than 15 minutes.
The xylenes query of the database resulted in identification of numerous publications of
occupational exposure studies. Based on the above criteria, occupational exposures data
for xylenes are available to characterize exposures in the following industries:
? Automobile (adhesive, painting);
? Electronics (general use);
? Rubber (curing, mixing, extruding);
? Furniture (painting); and
? Plastics (polyurethane molding).
From the database, a typical (average of all samples) and high-end (95th percentile of all
job task averages) TWA exposure concentration have been estimated and are presented
in Table 7.49 below.
Table 7.49: Xylenes Solvent End-Use Occupational Exposure Concentrations
Exposure Exposure
Parameter Concentration Concentration
(mg/m 3)
(ppm)
TWA ?Mean 3.5 15
(N = 892)
TWA ?95th Percentile 7.8 34
(N = 892)
A search of recent occupational literature published since 1997 was also conducted to
supplement the Caldwell et al. database. The primary database searched was the
National Library of Medicine's PubMed/Medline citation database, which indexes major
occupational hygiene journals and medical journals. In addition to this database, the
NIOSH Health Hazard Evaluations and OSHA publications printed since 1997 were
reviewed. An emphasis was placed on exposures occurring in the United States. This
search resulted in identification of xylene exposure data for the following occupational
categories:
? Exposure to solvents used in graffiti removal;
? Exposure to jet fuel during military aircraft maintenance;
? Exposure to lacquers, stains, or construction adhesive during residential
construction activities; and
? Exposure to smoke during structural firefighting activities, especially during
overhaul (i.e., the post-suppression inspection for hidden fires).
Xylenes VCCEP Submission 126
The recently published (1997-2001) literature is summarized on Table 7.50.
Table 7.50: Recently Published Data on Occupational Exposure to Xylene Isomers
Average 8-hour
TWA
Occupation Reference
Concentration
(ppm)
Graffiti Removal 0.07 Anundi, 2000
Lemasters, 1999; Smith,
Aircraft Maintenance Personnel ?Military 0.006 - 0.3
1997
Municipal Firefighter 1.7 Austin 2001a,b;
Painter Applying Stains and Laquers
8.3 Methner, 2000
Used in New Home Construction
Upon review of Tables 7.48-7.50, it is apparent that the occupational exposures to xylenes
in the production/processing and manufacturing industry and the end-use industries are
significantly lower than the OSHA PEL and the ACGIH TLV of 100 ppm as an 8-hr TWA.
The recently published data are consistent with that of the production/processing industry,
with the exception of the painter applying lacquer or stain during new home construction,
where the TWA exposure concentrations are consistent with the high-end exposure
concentrations obtained using the extensive database of Caldwell et al. (2000). As such,
the typical occupational exposure concentration is represented by the mean concentration
on Table 7.48 and the high-end concentration is represented by the 95th percentile
concentration on Table 7.49.
Dermal Exposures
Occupational chemical exposure studies typically do not report dermal dose due to the
difficulty of properly estimating the contribution of the dermal route, and very few in vivo
human studies of dermal exposure to solvents have been published (Kezic et al., 2001). It
is important to note that because inhalation and dermal exposure could co-occur in an
occupational environment, interpretation of occupational in vivo studies can be difficult.
Controlled in vivo studies are relatively rare (Kezic et al., 2000).
Of the limited number of studies investigating dermal exposure to xylenes, one study that
investigated exposure to xylenes in the autobody painting (Daniell et al. 1992) industry
found a correlation between a biological exposure index (i.e., methylhippuric acid in urine)
and dermal exposure to xylenes. However, the researchers concluded that the amount of
xylenes absorbed was of little clinical importance because the level of methylhippuric acid
in the urine was well below the ACGIH biological exposure index (BEI) for xylenes. The
post-shift level of methylhippuric acid in the urine of painters was 4.9% of the BEI.
In an occupational setting such as the petroleum processing or chemical manufacturing
industries, xylenes or products containing xylenes are generally handled in closed systems
in order to minimize volatile emissions, avoid product loss, and to minimize the risk of fire.
As such, dermal exposure to the product is not common except under "upset" conditions,
Xylenes VCCEP Submission 127
where personal protective clothing including gloves and suits would be worn. However, it
is recognized that occasional dermal occupational exposure to xylenes could occur during
the use of products containing xylenes.
There are few screening level exposure models available for occupational dermal
exposure to chemicals. As of this time, the best screening level model is EASE (United
Kingdom Health and Safety Executive, 1997), which is a knowledge-based system that
can be used when exposure data are limited or not available. This model provides
estimates of product adherence to the skin during the work shift based on use pattern and
contact level. Estimates are provided in units of mg of product per area of skin per day.
In using EASE to evaluate occupational dermal exposures, assumptions have been made
regarding the quantity of the chemical product that is in contact with the skin and the
percent weight content of the xylenes in the product. As such, it has been assumed that
the adult female of average body weight and skin surface area occasionally exposes her
hands to xylenes during application of a stain or varnish. During the work shift, the coating
covers about ?of each hand during application. Exposures are assumed to occur under
non-occluded skin conditions. The coating contains about 10% xylenes. Typical
exposures are characterized by the intermittent, non-dispersive use of the xylenes-
containing product in contact with the skin and high-end dermal exposures are
characterized by extensive wide dispersive use of the xylenes-containing product (United
Kingdom Health and Safety Executive, 1997) and a xylene weight content of 20%.
Typical and high-end doses of total o-, m-, and p-xylene isomers from occupational dermal
exposures have been quantified using the following equation:
Qdermal ?Fxylene ?ABS xylene ?Askin ?EF
ADdermal =
day
BW ?365
year
where,
ADdermal Absorbed dose (mg/kg/day)
Qdermal Quantity of commercial product (paint, solvent, etc.) adhering to skin
(mg/cm 2-day) from EASE model
Fxylene Fraction of applied product that contains xylenes by weight (unitless)
ABSxylene Absorption factor for xylenes, equal to 0.03
Area of skin exposed to commercial product (cm 2)
Askin
EF Exposure frequency (days/year)
BW Body weight (kg)
The dermal dose results are presented in Table 7.51.
Xylenes VCCEP Submission 128
Table 7.51: Dose of o-, m-, and p-Xylene Isomers from Typical and High-End
Occupational Dermal Exposures
Typical High-End
Female Female
19-35 19-35
Exposure Parameter Units year old year old
mg/cm 2-day
Qdermal 0.55 10
cm 2
Askin 373 373
EF day/year 12 12
Fxylene % weight 0.1 0.2
ABSxylene Unitless 0.03 0.03
BW kg 62.4 62.4
Dose mg/kg/day 3.24E-04 1.18E-02
7.3 Discussion of Biomonitoring Data
In addition to the NHANES III blood concentration data for xylenes (See Section 2.1), a
focused study on children's blood levels of xylenes is reported by Sexton et al. (2005). In
this study, blood concentrations of 11 VOCs were measured up to four times over two
years in a probability sample of more than 150 children from Minneapolis, MN. The blood
concentrations for xylenes reported by Sexton et al. are presented on Table 7.52.
Table 7.52: Blood Concentrations of Xylenes in Children from Sexton et al. (2005)
Number Detection Percentile (ug/L)
Chemical
Date of Frequency th
50th 75th
Name 10 95th
Samples (%)
m-/p-Xylene Feb. 2000 113 98 0.10 0.13 0.17 0.22
May 2000 115 98 0.09 0.11 0.13 0.17
Feb. 2001 63 66 0.15 0.19 0.23 0.31
May 2001 88 99 0.23 0.37 0.47 0.60
o-Xylene Feb. 2000 113 73 0.02 0.03 0.05 0.08
May 2000 114 44 0.02 0.02 0.03 0.05
Feb. 2001 63 32 0.03 0.03 0.04 0.06
May 2001 88 66 0.03 0.07 0.11 0.14
Sum of m-/p- Feb. 2000 -- -- 0.12 0.16 0.22 0.30
Xylene and o- May 2000 -- -- 0.11 0.13 0.16 0.22
Xylene Feb. 2001 -- -- 0.18 0.22 0.27 0.37
May 2001 -- -- 0.26 0.44 0.58 0.74
The median levels of m-/p-xylenes are comparable to those measured in the NHANES III,
whereas the median levels of o-xylene are nearly 3 times lower than the NHANES III
concentrations.
Xylenes VCCEP Submission 129
Sexton et al. (2005) also collected matched personal air samples for each child and
oncentration was 10.8 ug/m 3.
analyzed them for xylenes. The mean total xylenes c
Although the authors found that the personal air samples were primarily influenced by time
spent in the home, they also found only moderate statistical correlation (i.e., R2 ~0.2)
between matched personal air concentrations of xylenes and blood concentrations of
xylenes.
Human physiologically-based pharmacokinetic (PBPK) models can be used to estimate
internal doses of a chemical from external exposures. A human PBPK model for xylene
was used to estimate blood concentrations that would be predicted in children of various
ages given the inhalation exposure concentrations for background exposures used in this
assessment (see Appendix C for additional information). The results are provided on
Table 7.53.
Table 7.53: Predicted Average Blood Concentrations in Children Based on VCCEP
Exposure Estimates
Mixed xylenes 24-hour TWA Mixed xylenes blood
(ug/m 3)
Age concentration (ug/L)
Typical High-End Typical High-End
9 months 8.9 35 0.047 0.19
3 years 8.4 33 0.040 0.16
10 years 8.6 34 0.037 0.15
16 years 8.6 34 0.032 0.12
Adult females 8.8 35 0.032 0.13
The blood levels were predicted using the inhalation exposure information based on the
typical 24-hr time weighted average air concentrations to which children may be exposed.
Consequently, the predicted blood values do not account for the small amounts of xylene
that may be ingested via food or water or dermally absorbed. As shown on Table 7.55,
the predicted mixed xylenes blood concentration ranges from 0.032, for typical exposures
to both 16-year olds and adult females, to 0.19 for high-end exposures of infants. Across
age groups, the predicted mixed xylenes blood concentration is reasonably consistent.
The typical predicted blood values (range, 0.032-0.047 ug/L) are about five to ten times
lower than the median concentrations reported by Sexton et al. (2005) (range, 0.16-0.44
ug/L). Similarly, the predicted high-end blood concentrations (range, 0.12-0.19 ug/L) are
about two to four times lower than the Sexton et al. (2005) 95th percentile mixed xylenes
blood concentrations (range, 0.22-0.74 ug/L). Because the PBPK model of Tardiff et al.
(1995) (see Appendix C for additional information on the PBPK model) was calibrated for
occupational exposures to xylene (i.e., 80 ppm), it would not necessarily be expected to
accurately predict mixed xylenes blood concentrations from background exposures.
Xylenes VCCEP Submission 130
7.4 Uncertainties in the Exposure Assessment
Uncertainties are associated with any exposure assessment, and for this Tier I
asses sment, they are primarily associated with the use of published monitoring data to
represent exposures for the U.S. population, and in the absence of monitoring data, the
use of mathematical models to estimate human exposures. Each of these is described
further below.
7.4.1 Monitoring Data
Published monitoring data were used to characterize children's and prospective mothers'
exposures to xylenes from ambient air, in-vehicle exposures, vehicle refueling activities,
occupational environments, and drinking water. Each of these is discussed further below.
Outdoor Ambient Air
The outdoor ambient air monitoring data for xylenes were obtained from EPA databases,
which included data from 18 rural counties and 32 urban counties nationwide. This
monitoring data may not be representative of the entire U.S. outdoor ambient air because
the monitoring stations are sparsely distributed geographically. However, ambient air
concentrations vary by geographical area and the monitoring data that are available
include that for both rural and urban settings. The urban settings include those city
locations which have the greatest population densities (e.g., Los Angeles, Chicago, New
York, and Philadelphia), and thus the highest potential for xylenes loading to the ambient
air from mobile and non-mobile sources. While there may be significant variation around
the typical exposures estimated from use of the monitoring data, the high-end exposure
concentrations used in this assessment were the 95th percentile values of the datasets and
thus are reasonable high-end estimates.
Indoor Ambient Air
There are few monitoring data that are representative of current indoor xylenes
concentrations throughout the U.S. Although earlier data are available, use of monitoring
data from the 1980s would have introduced uncertainty into the exposure assessment
because of the dramatic decrease in outdoor air concentrations, and improved emissions
controls on automobiles and gasoline reformulations which can impact in-home xylenes
concentrations from attached garages and infiltration from ambient air. Additionally, in
most of the studies reviewed, insufficient information is provided to understand the
potential indoor sources of xylenes, which results in a wide range of reported
concentrations. Therefore, efforts were made to determine more realistic exposures that
might capture some of the differences between current indoor air levels of xylenes and
those from the 1980s. To do so, a delta value representing the incremental increase in
xylenes concentrations due to indoor sources was applied to the outdoor ambient air
values. The typical delta used was 6.3 礸/m 3 and the high-end delta was 47 礸/m 3, both
of which were derived from studies done in New York City in 1999, Chicago in 1994-1995,
a series of studies done in the eastern and southeastern U.S. in 1997 and 1998, a series
Xylenes VCCEP Submission 131
of studies done in Minnesota, and a series of studies conducted in Oklahoma in 2000 and
2001. These deltas, therefore, may be higher or lower than in individual homes across the
country. Insufficient data are currently available to determine the range of indoor to
outdoor deltas, which would account for all variations in housing characteristics, whole
house air exchange rates, and personal characteristics of the residents of individual
houses. However, it is unlikely that the indoor to outdoor deltas would vary by more than
an order of magnitude on a long term basis, and therefore the uncertainty associated with
the use of the delta is likely to be inconsequential in terms of estimating chronic
background exposure from the indoor air. It is recognized that over short durations, the
I/O delta may be more than an order of magnitude higher than that used in this exposure
assessment; however, that condition would likely result from introduction of a source of
xylenes into the home. This has been demonstrated by Bozzelli et al. (1995) in their study
of kerosene heater use, and by Ilgen et al. (2001b) during redecoration activities using of
certain paint products. Since these types of source specific exposure concentrations have
been estimated in Section 7.2.2.2 aggregate exposures from background indoor air and
temporary excursions of xylenes concentrations due to consumer product use can be
determined.
In-Vehicle Exposures
In-vehicle xylenes exposure levels can be affected by various conditions including mode of
transportation, driving route, time of day (rush vs. non-rush), type of fuel distribution
system, season of the year, meteorological conditions, and vehicle ventilation conditions.
The data used in this exposure assessment to characterize in-vehicle xylenes exposures
come from three studies, all of which were conducted in urban areas. Because in-vehicle
exposures are influenced by the ambient air immediately outside of the vehicle, xylenes
data collected in vehicles during an urban commute are likely to be higher than those
which would occur in-vehicle during a typical rural commute. Thus, the data used in this
exposure assessment likely overestimate in-vehicle exposures in rural areas.
In addition to ambient environmental conditions surrounding the vehicle, on-board
emission controls also affect the in-vehicle xylenes levels. Only one of the three in-vehicle
studies provided information on the model year of the vehicle in which the xylenes
measurements were made (i.e., Fedourek and Kerger, 2003). Because the study dates
for the other investigations were 1998 and 1999, it is likely that the vehicles were of the
early 1990s fleet. Given that present day vehicles have better on-board emission controls
that will continue to improve with future models, it is likely that use of data from older
model years overestimate current and future in-vehicle xylenes exposures.
It is recognized that a high-end in-vehicle exposure estimate has not been quantified. This
is because the studies used in this assessment only provided mean xylenes
concentrations, and the data do not support use of professional judgment to estimate a
high-end exposure concentration. A high-end exposure, however, could be defined by
increasing the exposure time (i.e., time spent in the vehicle each day). In doing so, the in-
vehicle exposure time would be increased which would result in a decreased exposure
time at the indoor air concentration estimate. However, because the indoor air
concentrations are similar to the mean in-vehicle concentrations, the net result would be
no significant change in the overall aggregate xylenes exposure.
Xylenes VCCEP Submission 132
Vehicle Refueling
The data used to represent xylenes exposures during refueling were collected in 3 cities
across the continental U.S. and in Fairbanks, AK. Additionally, a variety of refueling
scenarios were evaluated and use of various grades of gasoline was considered. Thus, it
is believed that while the data are generally representative of typical and high-end
refueling exposures, some uncertainty exists and is related to on-board emission controls,
use of vapor recover systems (VRS) at the pump, and continued reduction in aromatic
content in gasoline blends. The three studies used to quantify refueling exposures were
conducted in 1993 through 1997. As such, the vehicle fleet represented would have
included vehicles without significant on-board vapor controls. Additionally, only one of the
cities where xylenes measurements were made had Stage II VRS at the pump. Thus,
based on the technology available for later fleet years and the requirement for use of
Stage II VRS in some ozone non-attainment areas, the data used in this assessment may
overestimate current and future xylenes exposures during refueling.
Occupational Exposure Estimates
The monitoring data used to derive typical and high-end occupational exposure estimates
come from recent data collected from xylenes production/processing and chemical
manufacturing industry and an extensive database of end-use occupational solvent
exposures including 100 studies where xylenes were specifically evaluated (Caldwell et
al., 2000). The exposure data for end-use occupational exposures derived from the more
current (1997 ?present) peer-reviewed literature is consistent with the relatively low
exposures observed in the production/processing and manufacturing industries. Thus,
there is high confidence that the typical occupational xylenes exposures have been well
characterized by use of the mean exposure levels observed in the production/processing
and chemical manufacturing industries. The high-end exposures were characterized using
the data from Caldwell et al. (2000). While not a worst-case estimate, the high-end
estimate is believed to be reasonable, based on a limited comparison of high exposure
scenarios available in the current peer-reviewed literature.
Tap Water
The monitoring data used to characterize exposures to xylenes from tap water were
obtained from 25,302 recent measurements of public water systems from 32 states
throughout the U.S. and 1,640 measurements from non-public water systems including
groundwater and surface water sources. As such, a robust dataset was available for
evaluation. Because xylenes in drinking water are regulated, public water supplies are
unlikely to serve a source of elevated xylenes levels on a chronic basis and therefore it is
believed that the children's and prospective mother's exposure estimates made in this
assessment adequately characterize the typical and high-end exposures from tap water.
Contamination of groundwater in source specific areas is, however, uncertain. While
contamination of groundwater from various sources has occurred, potential childhood
exposures for these conditions have not been quantified in this VCCEP exposure
assessment, as regulatory programs are in place whereby site-specific risk assessments
are performed for clean-up purposes.
Xylenes VCCEP Submission 133
7.4.2 Exposure Modeling
The uncertainties associated with any modeling exercise are typically those associated
with the various model parameters. In this exposure assessment most of the uncertainty
errs on the conservative side (i.e., exposure enhancing). To address the uncertainties
with the consumer product exposure modeling, a sensitivity analysis was conducted to
determine which of the parameters had the greatest effect on predicted air concentrations.
The parameters most sensitive were: 1) amount of product used, 2) whole house air
exchange rate, and 3) total home volume. A complete discussion of the sensitivity
analysis is presented in Appendix A-11.
In addition to modeling parameter uncertainties, there are also scenario specific
uncertainties. Each is briefly described below.
Residential Metal Parts Degreasing Scenario: The primary uncertainty with this scenario
is the intended use of mixed xylenes sold in quart size containers. Searches of the peer
reviewed and other literature alluded to its use as a degreaser, but provided no information
regarding the amount of product to be used or whether it would be used indoors. The
Westat survey data regarding product usage amounts for solvent-based cleaners is likely
much greater than for a paint thinner containing xylenes or for mixed xylenes because it is
representative of a wide variety of products including Easy Off oven cleaner, Fuller Brush
cleaners, Woolite and Dawn, none of which contain xylenes. As such, a `bench scale'
degreasing simulation was done using water to estimate the amount of degreaser that
might be used indoor for small (i.e., 1 ft2) and larger (i.e., 10 ft2) projects.
An additional uncertainty is that regarding human behavior when using the solvent;
specifically whether the product is used under adequate ventilation conditions. Because
the Westat survey indicated that most people read the product directions and some
opened windows or doors, the xylenes exposures were modeled assuming adequate
ventilation. Although, it is recognized that some people will not follow the directions or
heed the warnings, reasonable exposure bounds have been evaluated in this assessment
given the conservative nature of the other assumptions including: 1) indoor use of the
solvent and 2) small room of use (i.e., 20 m 3). If it were assumed that adequate ventilation
is not provided, the whole house air exchange rate would be assumed to be 0.45 ACH,
which is approximately one-third of the ventilation rate under open windows/door
conditions. Thus, because the air exchange rate and the predicted air concentrations are
linearly related over this range, the predicted xylenes concentrations would increase 3-
fold.
Residential Spray Painting Scenario: The uncertainties associated with this scenario are
the amount of products used, the correlation of amount of product used to location of use
(inside versus outside), the steps taken to ventilate space (opening windows or exhaust
fans) and the compounding effect in the high-end scenario regarding the use of two paint
products, both with high-end xylenes weight content. The Westat survey provides some
useful information on these points. Some of the relevant details of the survey results are
discussed below.
Xylenes VCCEP Submission 134
Over 80% of the survey respondents indicated that the last time they used spray paint, it
was used outside or in a garage. In the residential spray paint scenario presented in
Section 7.2.2.2, the assumption was made that the activity would take place within a room
integral to the house. However, according to the Westat survey, this is not a common
practice for most spray paint users. Thus, the assumption of indoor use may overestimate
the xylenes exposure during spray painting, particularly for high-end usage amounts (i.e.,
2 cans of spray paint), which are unlikely to be used indoors.
For those survey respondents that used products inside, 63% opened a window, 10%
used an exhaust fan, and 61% left the inside door of the room open. In the sensitivity
analysis, the whole house air exchange rate was determined to be a sensitive parameter,
thus using a default value for the air exchange rate would not be representative of typical
use conditions. Of the survey respondents, 73% indicated that they read the directions on
the label. Most spray paint labels contain a warning to use the product outdoors or in a
well-ventilated space. Thus, it is reasonable to assume that a majority of the product
users will heed the warnings and that the additional ventilation will minimize typical
exposures during spray painting. As indicated in the degreaser uncertainty discussion,
failure to use adequate ventilation would result in estimates of exposure approximately 3-
fold higher.
The use of two paint products both containing high-end weight content of xylenes on the
same day within a 2 hour window of time is uncertain. Although, consumer product data
regarding the correlation between the uses of related paint products was not identified, this
scenario was evaluated in an effort to capture a reasonable high-end for a single day use.
Although it is often preferable to use actual air monitoring data to characterize exposures,
no studies of residential use of spray paint were identified. It is believed however,
because of the wide variation in consumers' use of various products, the modeled
exposure assessment likely provides a broader picture of potential exposures. For
instance, in using the consumer product models, various scenario conditions can be
evaluated (e.g., usage amounts, various ventilation conditions, rates of application, etc.).
These types of variables are not likely to be documented or accounted for in a monitoring
study, thus limiting the usefulness of the monitoring data. To assess reasonableness of
the xylenes exposure estimates for the spray paint scenario, comparisons can be made to
the limited occupational spray paint studies that have been conducted. For instance, in
the Methner (2000) occupational study of residential construction activities, a total xylenes
concentration of 8 ppm was measured during an application of spray lacquer indoors over
a 1.7-hour period. The commercial use of spray lacquer in a residential construction
project is representative of a high-end indoor use of a product containing xylenes. Thus,
comparing the high-end 1-hr time weighted average of 30 ppm from the modeled
residential spray paint scenario, it can be seen that the high-end exposure estimate used
in this assessment is adequate to capture the potential high-end exposures.
7.5 Summary of Exposures
Childhood exposures to xylenes have been quantified in terms of background exposures
(e.g., ambient air, food, and water) and specific source exposures, some of which are
associated with xylene chain of commerce (e.g., consumer products) and some that are
non-chain of commerce sources ( e.g., gasoline, and tobacco smoke). Table 7.54 is a
Xylenes VCCEP Submission 135
summary of annual average daily doses calculated for each exposure due to background
sources. From Table 7.54, it can be seen that the inhalation pathway is the primary
pathway of exposure with doses at least one order of magnitude higher than those
received from ingestion or dermal contact. The exception to this is that of the nursing
infant with a high-end occupationally exposed mother, where the dietary ingestion pathway
dominates as a source of exposure. Of the inhalation sources of exposures, indoor air
contributes the most to overall inhalation doses. These findings are graphically presented
on Figures 7.4 and 7.5, which show doses from background exposures to xylenes from
typical and high-end urban exposures.
Age-specific doses for chronic exposures to xylenes from specific sources are presented
on Table 7.55. From this table, it can be seen that for children (<1 to 13 yrs old) exposure
to ETS is the only chronic source specific exposure that was identified, and exposures are
approximately 10-fold lower than that from typical urban background. For the teenagers
and adults, ETS adds insignificantly to background doses, as does exposure to xylenes
from refueling. Exposure to total xylenes from mainstream smoke are nearly equal to that
of typical total background exposures, but approximately three to five times lower than
high-end total background exposures. These findings are graphically presented on
Figures 7.6 and 7.7, which show the comparison of the total high-end urban background
dose for children to that received from other chronic-type exposures to tobacco smoke,
and fuel-related sources.
Xylenes VCCEP Submission 136
Table 7.54: Summary of Age-Specific Background Total Xylenes Doses (mg/kg/day)
Age Group
<1 1-5 year old 6-13 year old 14-18 Female 19-35
Scenario year old year old year old year old year old
BACKGROUND DOSES - OUTDOOR AIR
Ambient Outdoor Air - School Day
Rural - Typical -- 1.3E-05 8.6E-06 5.5E-06 --
Rural - High-end -- 3.0E-05 2.1E-05 1.3E-05 --
Urban - Typical -- 3.1E-05 2.2E-05 1.4E-05 --
Urban - High-end -- 7.4E-05 5.1E-05 3.3E-05 --
Ambient Outdoor Air - Non-School Day
Rural - Typical 2.2E-05 1.9E-05 9.7E-06 6.9E-06 6.8E-06
Rural - High-end 5.3E-05 4.6E-05 2.3E-05 1.7E-05 1.6E-05
Urban - Typical 5.5E-05 4.7E-05 2.4E-05 1.7E-05 1.7E-05
Urban - High-end 1.3E-04 1.1E-04 5.8E-05 4.1E-05 4.0E-05
Ambient Outdoor Air - Total
Rural - Typical 2.2E-05 3.1E-05 1.8E-05 1.2E-05 6.8E-06
Rural - High-end 5.3E-05 7.6E-05 4.4E-05 3.0E-05 1.6E-05
Urban - Typical 5.5E-05 7.9E-05 4.6E-05 3.1E-05 1.7E-05
Urban - High-end 1.3E-04 1.9E-04 1.1E-04 7.3E-05 4.0E-05
BACKGROUND DOSES - INDOOR AIR
In Home - School
Day
Rural - Typical -- 8.1E-04 4.9E-04 3.1E-04 --
Rural - High-end -- 3.4E-03 2.1E-03 1.3E-03 --
Urban - Typical -- 9.6E-04 5.9E-04 3.8E-04 --
Urban - High-end -- 3.8E-03 2.3E-03 1.5E-03 --
In Home - Non-School Day
Rural - Typical 2.6E-03 9.2E-04 7.0E-04 4.6E-04 7.3E-04
Rural - High-end 1.1E-02 3.9E-03 3.0E-03 2.0E-03 3.1E-03
Urban - Typical 3.1E-03 1.1E-03 8.4E-04 5.5E-04 8.7E-04
Urban - High-end 1.2E-02 4.3E-03 3.3E-03 2.2E-03 3.4E-03
In Home - Total
Rural - Typical 2.6E-03 1.7E-03 1.2E-03 7.8E-04 7.3E-04
Rural - High-end 1.1E-02 7.3E-03 5.1E-03 3.3E-03 3.1E-03
Urban - Typical 3.1E-03 2.1E-03 1.4E-03 9.3E-04 8.7E-04
Urban - High-end 1.2E-02 8.1E-03 5.6E-03 3.6E-03 3.4E-03
In School
Typical -- 4.50E-05 6.70E-05 4.90E-05 --
High-end -- 4.10E-04 6.20E-04 4.50E-04 --
In-Vehicle
Typical 2.60E-04 2.00E-04 1.20E-04 1.10E-04 7.90E-05
BACKGROUND DOSES - FOOD & WATER
Food & Tap Water Ingestion
Typical 1.80E-04 2.10E-04 9.00E-05 4.80E-05 4.60E-05
High-end 3.60E-04 3.70E-04 1.60E-04 9.50E-05 8.80E-05
Human Milk
Urban, typical 1.81E-05 -- -- -- --
Urban, high-end 7.13E-05 -- -- -- --
Occupational, typical 3.75E-04 -- -- -- --
Occupational, high-
end 2.63E-02 -- -- -- --
Showering - Dermal
Typical 2.80E-06 3.40E-06 2.30E-06 1.80E-06 1.80E-06
High-end 6.10E-06 6.60E-06 4.60E-06 3.60E-06 4.30E-06
Showering -
Inhalation
Typical 5.10E-05 2.30E-05 3.30E-06 2.30E-06 1.70E-06
High-end 2.60E-04 9.10E-05 1.30E-05 1.00E-05 9.70E-06
Xylenes VCCEP Submission 137
Table 7.54: Summary of Age-Specific Background Total Xylenes Doses (mg/kg/day)
(continued)
BACKGROUND DOSES - SUM OF AMBIENT AIR, INDOOR AIR, FOOD & WATER
Age Group
<1 1-5 year old 6-13 year old 14-18 Female 19-35
Scenario year old year old year old year old year old
Inhalation Pathway
Rural - Typical 2.91E-03 2.02E-03 1.40E-03 9.49E-04 8.16E-04
Rural - High-end 1.16E-02 8.12E-03 5.88E-03 3.91E-03 3.21E-03
Urban - Typical 3.45E-03 2.41E-03 1.66E-03 1.12E-03 9.69E-04
Urban - High-end 1.27E-02 8.98E-03 6.46E-03 4.29E-03 3.55E-03
Ingestion Pathway
Typical 1.98E-04 2.10E-04 9.00E-05 4.80E-05 4.60E-05
High-end 4.31E-04 3.70E-04 1.60E-04 9.50E-05 8.80E-05
Dermal Pathway
Typical 2.80E-06 3.40E-06 2.30E-06 1.80E-06 1.80E-06
High-end 6.10E-06 6.60E-06 4.60E-06 3.60E-06 4.30E-06
Xylenes VCCEP Submission 138
Figure 7.4: Contribution of Various Ambient Sources to Typical Total Chronic
Background Dose
Indoor
(Urban)
19-35
Outdoor
14-18
(Urban)
Age Ranges
6-13 Vehicle
1-5
School
<1
Dietary
Ingestion
0.0E+00 5.0E-04 1.0E-03 1.5E-03 2.0E-03 2.5E-03 3.0E-03 3.5E-03 4.0E-03
o-, m-, p- Xylene Isomer Dose (mg/kg-day)
Figure 7.5: Contribution of Various Ambient Sources to High-end Total Chronic
Background Dose
Indoor
(Urban)
19-35
Outdoor
14-18
(Urban)
Age Ranges
Vehicle
6-13
1-5
School
<1
Dietary
Ingestion
0.0E+00 5.0E-03 1.0E-02 1.5E-02 2.0E-02 2.5E-02 3.0E-02 3.5E-02 4.0E-02 4.5E-02
o-, m-, p- Xylene Isomer Dose (mg/kg-day)
*The dose for the <1yr old includes exposure from human milk of a high-end occupationally exposed mother.
Xylenes VCCEP Submission 139
Table 7.55: Summary of Source-Specific Total Xylenes Doses (mg/kg/day)
Age Group
Female
<1 1-5 6-13 14-18 16-18 19-35
Scenario year old year old year old year old year old year old
SOURCE SPECIFIC DOSES
Tobacco Smoke
ETS (nonsmoker's dose) 3.1E-04 2.3E-04 1.5E-04 8.7E-05 -- 8.8E-05
Mainstream (smoker's dose) -- -- -- 1.3E-03 -- 2.5E-03
Refueling
Typical -- -- -- -- 1.6E-05 1.6E-05
High-end -- -- -- -- 1.6E-04 1.6E-04
Xylenes VCCEP Submission 140
Figure 7.6: Summary of Various Source Specific Doses at Typical Exposures
1.00E+01
Typical Urban
Background
1.00E+00
Xylene Dose (mg/kg-day)
1.00E-01
Refueling
1.00E-02
1.00E-03
ETS
1.00E-04
Mainstream
1.00E-05
Smoke
<1 1-5 6-13 14-18 19-35
Age Category
Figure 7.7: Summary of Various Source Specific Doses at High-end Exposures
High End
1.00E+01
Urban
Background
1.00E+00
Xylene Dose (mg/kg-day)
Refueling
1.00E-01
1.00E-02
1.00E-03 ETS
1.00E-04
1.00E-05
Mainstream
<1 1-5 6-13 14-18 19-35 Smoke
Age Category
Xylenes VCCEP Submission 141
8.0 Risk Assessment
Risk assessment is the integration of the findings of the Hazard Assessment and the
Exposure Assessment to provide numerical characterizations of risk. As discussed in the
Hazard Assessment (Section 6), xylenes may cause both short-term acute and chronic
health effects. The primary health effects are irritation, impairment of neurobehavioral
function, and CNS depression. This risk assessment presents an evaluation of the
potential for the occurrence of these effects in the exposed populations following acute
and chronic exposures.
The general EPA guidance for assessing short-term, infrequent events (for most
chemicals, an exposure of less than 24 hours that occurs no more frequently than
monthly) is to treat such events as independent, acute exposures rather than as chronic
exposure (EPA, 1998b). Therefore, the short-term episodic exposures such as those
associated with the consumer products, were evaluated in terms of the potential risks from
the acute effects of xylenes using the peak 1-hour and 8- hour exposure concentrations.
This approach is appropriate for acute exposures for volatile solvents because
concentration plays a stronger role in determining the strength of the effects than does
time (Bushnell, 1997; Boyes 2005). Acute effects appear to be more closely related to
momentary and maximum exposures rather than cumulative exposure. Therefore, acute
exposures were compared against the AEGL-1 value to protect against threshold effects
resulting from acute exposures. Chronic exposures were compared against a chronic
health benchmark that is based on the same point of departure used by EPA to derive the
IRIS inhalation RfC (EPA 2003a). In this assessment, the potential for the occurrence of
chronic adverse health effects is evaluated based on the background xylenes exposure
concentrations and annual average doses developed in Section 7.
This section consists of the following sections: (1) a brief overview of the hazard
assessment information and regulatory health benchmarks; (2) derivation of a health
benchmark for chronic inhalation exposure (3) the evaluation of the risk of the chronic
hazards of xylenes; and (4) an evaluation of the risk of the acute hazards from the use of
selected consumer products. Uncertainties are also discussed. Finally, overall
conclusions are presented concerning the potential for xylenes exposure to pose health
risks to children.
8.1 Benchmarks Used to Characterize Chronic and Acute Adverse Health Effects
of Xylenes
8.1.1 Benchmarks Used to Evaluate the Chronic Effects of Xylenes
As discussed in Section 7, chronic exposures to xylenes can occur via inhalation,
ingestion and dermal contact. Therefore, in evaluating the potential health risks
associated from these exposures, route-specific health benchmarks were required. Oral
and dermal exposures were evaluated using EPA's oral reference dose (RfD) of 0.2
mg/kg/day. Inhalation exposures were evaluated using an inhalation reference
concentration of 0.66 mg/m 3 as discussed in greater detail below. The values for these
health benchmarks are presented in Table 8.1.
Xylenes VCCEP Submission 142
Table 8.1: Xylenes Chronic Health Benchmarks for the VCCEP Risk Assessment
Route Health Benchmark
Oral 0.2 mg/kg/d
0.66 mg/m 3
Inhalation
The chronic inhalation health benchmark of 0.66 mg/m 3 (VCCEP chronic inhalation health
benchmark) is based on many of the same assumptions and adjustments that were made
by EPA in deriving the RfC, including selection of the point of departure. The derivation of
this health benchmark and an alternative health benchmark based on PBPK modeling are
presented in Table 8.2 and discussed in the next section.
8.1.1.1 Derivation of the IRIS RfC and Alternative Chronic Inhalation Health
Benchmarks
This section discusses the basis for EPA's derivation of the inhalation RfC, the derivation
of the chronic inhalation health benchmark used in this risk assessment (VCCEP Chronic
Inhalation Health Benchmark) and another alternative chronic inhalation health benchmark
using PBPK models.
Table 8.2: Analysis of the Adjustment and Uncertainty Factors for the Xylenes EPA
IRIS RfC, the Xylenes VCCEP Chronic Inhalation Health Benchmark and
an Alternative PBPK Inhalation Health Benchmark
Adjustment IRIS VCCEP PBPK Comment
Factors
Point of Departure 217 217 217 Based on rotarod effects
(mg/m 3 ) from study with limited
description of methods.
PBPK value of 217 mg/m 3 is
EPA model estimate for
continuous human exposure
level needed to achieve
same internal peak blood
concentration as that
estimated for rat at NOAEL
for rotarod effects.
Duration Divide by Divide by Divide by This factor may have been
adjustment (5 5.56 5.56 5.56 accounted for in PBPK model
days/week, 6 estimate of human equivalent
hours/day to 7 continuous exposure level.
days/week, 24
hours/day.
Adjustment for Multiply by 1 Multiply by Multiply by 1 Rats have higher blood:gas
human equivalent 1.7 partition coefficient. Data
concentration should be used instead of
default policy assumption.
PBPK model already
accounts for rat-human
differences.
Xylenes VCCEP Submission 143
Adjustment IRIS VCCEP PBPK Comment
Factors
Interspecies pK 1 1 1 Adjustment for pK factor is
uncertainty factor already accounted for when
adjusting for human
equivalent concentration
101/2 101/2 101/2
Interspecies
pharmacodynamic
uncertainty factor
101/2
Intraspecies 10 10 PBPK modeling by Pelekis et
pharmacokinetic al. (2001) suggests no adult-
and children pharmacokinetic
pharmacodynamic differences. In assessing
uncertainty factor children's risk, the
intraspecies uncertainty
factor could then be lowered
to 101/2 accounting for human
for pharmacodynamic
uncertainty only.
101/2 101/2 101/2
Subchronic to Rotarod performance did not
chronic duration increase with time following
uncertainty factor 1, 3 and 6 months of
exposure.
Database 3 1 1 It is unlikely for multi-gen
uncertainty factor repro study to result in
for lack of NOAEL lower than the point
multigeneration of departure of 50 ppm
study. based on 1-gen NOAEL of
500 ppm; DNT LOAEL of 500
ppm.
The NOAEL of 217 mg/m 3
(TOTAL UF) x 300 x 5.56 100 x 3.27 27 x 5.56
(other dose (50 ppm) should be DIVIDED
adjustment factors) by these total factors
RfC (mg/m 3) 0.1 0.66 1.44
Each of the adjustment and uncertainty factors in deriving these chronic inhalation health
benchmarks are discussed below. The adjustment and uncertainty factors for the EPA
IRIS RfC are further discussed in Section 5.2.3 of the IRIS Toxicology Review (EPA
2003a):
1. The point of departure is based on a NOAEL of 50 ppm (217 mg/m 3) for
neurobehavioral effects in rats following 3 months of exposure.
2. A standard adjustment was made by multiplying the point of departure by 5 days/ 7
days and by 6 hrs/day/24 hours /day. Thus, the NOAEL of 217 mg/m 3 was divided by
5.6 to derive a duration adjusted NOAEL for continuous exposure of 39 mg/m 3. EPA
refers to this adjustment as a duration adjustment.
Xylenes VCCEP Submission 144
3. The EPA's duration adjusted NOAEL of 39 mg/m 3 was expressed as a human
equivalent concentration by using the default assumption of 1. This value does not
take into consideration the ratio of 1.7 for blood:gas partition coefficient for the
laboratory animal species to the human value. The VCCEP health benchmark
considers this factor in adjust the HEC to 66.3 mg/m 3 ?39 mg/m 3 x 1.7 = 66.3 mg/m3.
4. A UF of 3.16 (10?) was applied to account for toxicodynamic interspecies differences
between laboratory animals and humans. The toxicokinetic portion of the UF is 1
because human equivalent concentration dosimetric adjustments were already
accounted for. This is supported by the data and should be applied after using data
derived adjustments based on pharmacokinetic data.
5. A UF of 10 was applied to the RfC for intraspecies uncertainty to account for human
variability and sensitive populations. Briefly, this intraspecies uncertainty factor is
based on a combination of uncertainty factors for pharmacokinetic (10?) and
pharmacodynamic (10?) differences - 10?x 10?= 10. There is pharmacokinetic data
to suggest that the pharmacokinetic portion of the intraspecies uncertainty factor can
be reduced to 1. Specifically, Pelekis et al. (2001) compared adult-to-child
pharmacokinetic intraspecies difference using conventional physiological-based
pharmacokinetic models and physiological parameters from the literature for an
average 10-kg child, 1 year of age, and a range of physiological parameters for adults.
The results of this comparison of pharmacokinetic differences between children and
adults ranged between 0.033-0.88 for xylenes suggesting no adult-children differences
in the internal concentrations of xylenes that are likely to be observed during inhalation
exposures. In fact, values less than "1" indicate that children may have lower internal
concentration than adults for same inhalation exposure levels. As discussed below,
the UF for intraspecies uncertainty factor was not adjusted for the VCCEP health
benchmark (i.e. total intraspecies UF remained 10). However, the intraspecies factor
was reduced to 10?for the alternative PBPK chronic inhalation health benchmark
which makes use of the available pK data. This analysis does not address potential
pharmacodynamic differences and that factor (10?) is retained for all of the health
benchmarks. However, there are data to indicate that offspring exposed during
gestation are not more vulnerable to effects on neurobehavioral endpoints which is the
critical effect of xylenes.
6. A UF of 3.16 (10?) was applied for extrapolation from subchronic to chronic duration.
EPA used this UF because the changes in rotarod performance did not increase with
time from 1 to 3 months, and they were similar to those described in a separate study
of 6 months duration. The same uncertainty factor was used in the derivation of the
alternative inhalation health benchmarks.
7. A UF of 3 was applied for database uncertainty primarily due to the lack of a two-
generation reproduction study. This UF was reduced to 1 for both of the alternative
health benchmarks because a one-generation reproductive study, two dominant lethal
studies, and comprehensive developmental neurotoxicology studies have been
conducted. Neurobehavioral endpoints are the most sensitive endpoint for xylenes and
other solvents in animals and humans. Therefore, these developmental neurotoxicity
studies provide much more comprehensive evaluation of the sensitive endpoint of
concern in offspring than would be obtained from a guideline multi-generation
reproduction study. Database uncertainty factors should not be applied if there is good
reason to conclude that the missing study is unlikely to impact the RfC.
Xylenes VCCEP Submission 145
Xylenes VCCEP Chronic Inhalation Health Benchmark:
The above comparison of chronic inhalation health benchmarks indicates a possible range
of 0.1 to 1.44 mg/m 3. The Consortium has selected the VCCEP chronic inhalation health
benchmark of 0.66 mg/m 3 because it is in the middle of this range and because the
Consortium believes that the adjustments for blood:gas partition coefficient and database
uncertainty factor are well supported.
Blood:Gas partition coefficient:
Typically the duration adjusted NOAEL is multiplied by the ratio of the blood:gas partition
coefficient for the laboratory animal species to the human value. However, since this ratio
is 1.7, EPA used the value of 1 for policy reasons. Recently, EPA has suggested that this
practice should be reconsidered for category 3 gases (i.e., a gas that is relatively water-
insoluble and unreactive in the respiratory tract and for which the site of toxicity is
generally remote to the site of absorption in the pulmonary region). EPA encouraged the
use of data-derived values even when the ratio is much greater than 1 (EPA, 1998; page
4-33). Therefore, the human equivalent concentration should be 39 * 1.7 = 66.3 mg/m3.
Data-base uncertainty factor:
The data-base uncertainty factor of 3 should be removed because there are
comprehensive developmental neurotoxicity studies, a one generation reproductive toxicity
study, and two dominant lethal studies. Exposure in the one-generation reproductive
toxicity study was via inhalation. In addition to the required groups of male and female CD
rats exposed to 0, 60, 250 and 500 ppm mixed xylenes, there were two additional 500-
ppm groups similarly exposed, except that only the F0 males were exposed in one group
and only the F0 females were exposed in the other group. There were no effects on F0 or
F1 generation at 500 ppm. Two dominant lethal studies in male rats and mice were
treated by injection and mated with untreated females, weekly throughout the
spermatogenic cycle. Xylenes did not cause treatment-related effects on reproduction or
toxicity to offspring in any of these studies. In addition, several developmental
neurotoxicity studies have been conducted. This is of relevance because neurobehavioral
endpoints are the most sensitive endpoints of concern based on both the human and
animal literature on xylenes and related solvents. A LOAEL of 500 ppm is estimated for
developmental neurotoxicity based on exposure during one of the most critical periods of
rapid brain development. Thus, it is unlikely that xylene exposure would induce adverse
effects in the second generation of a guideline 2 -generation study that would be more
sensitive than the reproductive data from the 1-generation study, dominant lethal studies,
and the extensive neurobehavioral endpoints measured on F1 generation. It is even more
unlikely for effects in the 2nd generation of a guideline 2-generation study would occur at
doses below the NOAEL of 50 ppm for adult toxicity.
This conclusion is further supported by evaluating data for similar solvents with
multigeneration studies. For toluene, the NOAEL and LOAEL for parents and offspring of
both generations are 500 ppm and 2000 ppm, respectively (Roberts et al. 2003). For C9
aromatic naphtha, the NOAEL and LOAEL are 500 ppm and 1500 ppm, respectively, for
both parent and offspring from the first and second generation (McKee et al., 1990. In
addition, The International Life Sciences Institute's (ILSI) Health and Environmental
Sciences Institute (HESI) recently concluded that the second generation of a
multigeneration study has little impact on the chronic RfD based on an evaluation of 200
Xylenes VCCEP Submission 146
pesticides representing very different classes of chemistry (ILSI, 2005 publication is in
peer review).
In conclusion, the overall weight of evidence indicates that the comprehensive evaluation
of neurotoxic effects in adults and offspring provide the most sensitive data for risk
assessment. These studies indicate a LOAEL of 500 ppm. This together with the lack of
effects in the 1-generation study at 60, 250 and 500 ppm indicate that it is unlikely that
conducting a multi-generation study would yield results that are not already protected by
the NOAEL of 50 ppm based on motor coordination in adult rats which is currently used as
the point of departure for the chronic RfC.
8.1.1.2 Discussion of use of PBPK data from Xylenes IRIS in Deriving Chronic
Inhalation Health Benchmarks
Rat and human PBPK models for xylenes have been developed (Tardiff et al., 1993, 1995;
see also Appendix C) and were used in the xylene IRIS assessment to support the
derivation of the RfC (EPA 2003a). Rat PBPK models for xylene inhalation can be applied
to the rat NOAEL of 50 ppm (217 mg/m3) and the actual exposure protocol used in the
Korsak et al. (1994 rat study (6 hours per day, 5 days per week, for 3 months) to predict
arterial blood concentration in rats as a function of time up to 13 weeks. The results show
a daily rise and fall of xylene concentrations consistent w rapid elimination from the
ith
blood
Figure 8.1: PBPK predicted arterial blood levels in rats exposed to 50 ppm xylene 6
hours/day, 5 days/week for 13 weeks from Xylene IRIS Appendix B
Xylenes VCCEP Submission 147
Blood levels rapidly approach maximum levels during exposure, and then rapidly approach
0 mg/L immediately after exposure as is illustrated in the figure below (Tardiff et al., 1993).
Figure 8.2 PBPK Model Prediction Comparisons from Xylenes IRIS
EPA calculated three following dose surrogates for internal animal dose (EPA 2003a):
? An overall TWA blood concentration (0.198 mg/L, averaged over 1-hour
intervals across 13 weeks),
? The maximum (MAX) blood concentration attained on any given day during
exposure (1.09 mg/L, essentially a constant over 13 weeks), and
? The mid-point (MID) concentration between the maximum (1.09 mg/L) and the
minimum (0 mg/L) concentration on any given day during exposure (0.55 mg/L)
The TWA blood concentration ignores the contribution of the maximum peak effects that
are considered to play an important role in both acute and repeated exposure to solvents
(Lammers 2005). There is no scientific rationale to use the mid-point (MID) concentration
between maximum and minimum concentration because the model predicts exposures
Xylenes VCCEP Submission 148
rapidly approach mid-concentration within the first hour of exposure. It is more reasonable
to assume that the rotarod effects in the animal study are related to repeated exposure to
the maximum blood levels during the 6 hours of exposure rather than a time weighted
average blood concentration that is averaged over 1-hour intervals across all 24 hours and
13 weeks including the long periods when blood levels are at 0 mg/L. This analysis is
further supported by the lack of decrease in rotarod performance after 1, 2, 3 or 6 months
of exposure (Korsak 1994, 1992). These data suggest that the effect is unlikely to be due
to cumulative exposures and most likely due to peak exposures.
The use of peak levels is biologically plausible even if it is assumed that rotarod testing
occurred 24 hours after exposure when blood and fat concentrations are estimated to
approach zero following repeated daily exposures. Preliminary in vitro data indicate that
solvents can block NMDA receptors, alter function of voltage sensitive calcium channels
and augment function of GABA and glycine receptors (see review by Bushnell et al. 2005).
With repeated exposures there are opportunities for receptor up or down regulation and
other compensation which have not been well described as yet for the solvents, but which
may account for effects seen after repeated exposures and clearance of tissue levels of
the compound. For example, the acute effects following exposure to toluene by van
Lammers et al. (2005) were not easily explained by brain tissue concentration, but the
intermittent exposure paradigm left room for receptor modifications or other physiological
changes. Thus, the maximum rat blood concentration of 1.09 mg/L should be used as the
point of departure for derivation of an RfC based on PBPK modeling.
Alternative PBPK Inhalation Health Benchmark
Based on human PBPK modeling, EPA estimates that the external air concentrations
predicted to attain steady state blood concentrations of 1.09 mg/L in humans with
continuous exposure is 50 ppm (217 mg/m 3). In other words, the continuous human
exposure level (24 hours/day, 7 days/week) that will result in the maximum daily rat blood
levels that were rapidly attained each exposure day for 13 weeks (3 months) is 217
mg/m 3. The duration exposure adjustment factors (5.56 and 3) were applied. However, it
is debatable if the duration adjustment of 5.56 to account for continuous exposure (24
hours/day, 7 days/week) is needed because the human PBPK modeling adjusts for
continuous exposure. Based on PBPK modeling by Pelekis et al (2001), the intraspecies
uncertainty factor was reduced from the default 10 to 101/2. Overall, PBPK modeling of
adult and child pharmacokinetic intraspecies uncertainty factors for xylene and other
volatile organic compounds suggests that there are no adult-children differences in the
parent chemical concentrations that are likely to be observed during inhalation exposures.
In addition, the database (reproduction, developmental, developmental neurotoxicity
studies) indicates that the developing fetus and offspring are not more sensitive than
adults to the effects of xylene. Taken together, these data support a reduction of the
intraspecies uncertainty factor to 3.
The PBPK chronic inhalation health benchmark is derived by using the human equivalent
exposure level of 217 mg/m 3 and dividing by 5.56 (duration adjustment for continuous
exposure), 3 (interspecies factor), 3 (intraspecies) and 3 (subchronic to chronic
extrapolation) resulting in a health benchmark of 1.44 mg/m 3. This PBPK health
benchmark was not used in the risk assessment calculations as a decision was made to
use the VCCEP health benchmark of 0.66 mg/m 3 which is approximately the mid-point of
the range between the RfC of 0.1 mg/m 3 and this health benchmark of 1.44 mg/m 3. The
Xylenes VCCEP Submission 149
decision not to use this chronic inhalation health benchmark was based on practical
considerations to simplify the presentation of the quantitative results and is not a reflection
on its appropriateness. As Section 8.6 (Uncertainty) discusses, the choice of chronic
inhalation health benchmarks would have little impact on the overall results of the risk
assessment as all chronic inhalation exposures are below all three health benchmarks.
8.1.2 Benchmark Used to Evaluate the Acute Effects of Xylenes
The acute effects are associated with short-term high-level exposures. In the case of
xylenes, the short-term acute exposures are dominated by inhalation exposures. For this
reason, an inhalation-based criterion was used to evaluate acute effects. The EPA has
begun a process for deriving acute RfCs, however, one is not currently available for
xylenes (Strickland and Fourman, 2002; EPA, 1998, 2004). Therefore, the criteria that
were used to evaluate potential acute health risks are the 1 and 8-hr Interim A
-hr cute
Exposure Guideline Levels (AEGL-1) of 130 ppm (EPA, 2005). AEGLs represent
threshold exposure limits that the EPA believes are applicable to the general population
(including children and susceptible subpopulations) for emergency periods ranging from
10 minutes to 8-hours. Three AEGL levels are developed for the various time periods and
are differentiated by varying degrees of severity of toxic effects. The AEGL-1 is the
airborne concentration of a substance above which it is predicted that the general
population could experience notable discomfort, irritation or certain asymptomatic, non-
sensory effects. However, the effects are not disabling and are transient and reversible
upon cessation of exposure.
The AEGL-1 for xylenes was derived from a h uman exposure study where volunteers
were exposed to mixed xylenes at a concentration of 400 ppm for 30 minutes (Hastings et
al., 1986). The sensitive endpoint for this study was eye irritation. An interspecies
uncertainty factor was not applied because the key study used human data. However, an
intraspecies uncertainty factor of 3 was applied because eye slight irritation is caused by a
direct effect of the chemical and the response is not expected to vary greatly among
individuals.
8.2 Risk Assessment Methodology
The risk characterization methodology used for xylenes employs a Hazard Quotient (HQ)
approach where, calculated chronic doses and compared to the chronic RfC or RfD.
Hazard quotients represent the potential occurrence of adverse effects from single
exposure scenarios, or single route exposures. HQs were determined for both chronic
and acute exposures to xylenes. For chronic effects, the HQ was determined based on
the following equation:
Exposure
HQ =
Health Benchmark
where:
HQ = Hazard quotient (unitless)
Exposure = Annual average daily dose (mg/kg/d) or
exposure concentration
Health Benchmark = Reference Dose (RfD) or Reference Concentration (RfC)
Xylenes VCCEP Submission 150
When a person receives concurrent exposure (i.e., has exposures from more than one
scenario or exposure pathway), the HQs associated with each dose are summed to give a
Hazard Index (HI).
HI = HQ 1 + HQ 2 + ... HQ i
where:
HI = Cumulative hazard index (unitless)
Hazard quotient (unitless) for the ith exposure route and
HQ =
source
A complete description of this approach is given in Risk Assessment Guidance for
Superfund Sites (EPA, 1989). Under this approach, HQs are determined for each
exposure scenario (both ambient and source specific) in the assessment. Findings of
values less than 1 indicate that adverse effects are unlikely to occur in even sensitive
members of the exposed population. Where exposures to multiple sources occur to the
same individual at the same time, the values of the relevant HQs are added to produce the
HI values. If the total HI is less than 1, risks from all routes of exposure are considered
negligible. It is important to note that an HI >1 is not a bright line dividing actual health
hazard from non-hazard. Given that the xylenes RfC is based on a NOAEL and
incorporates a total uncertainty factor of 300, an HI of 10 for example, still leaves a factor
of 30 between the estimated exposure and the NOAEL. This line of reasoning is the basis
for the recommended risk-based prioritization scheme within the1990 Am endments to the
Clean Air Act for determining and managing residual risk after MACT implementation
(Presidential/Congressional Commission on Risk Assessment and Risk Management,
1997). In this guidance, it has been recommended that if after a screening level risk
assessment of an air toxic, the HI is less than 10, further action is not deemed necessary
in terms of a more detailed assessment or risk control options.
8.3 Evaluation of the Risk of Chronic Effects
8.3.1 Evaluation of the Risk of Chronic Effects from Background Sources of
Exposure
The HQs associated with the oral, dermal and inhalation exposure to background sources
(ambient air, food and tap water, and in-vehicle exposures) were summed to generate a
total background hazard index (HI). For the background evaluation, ambient air
incorporates outdoor and indoor air, as well as in-vehicle exposures. In-vehicle exposures
have been considered as part of a person's background exposure because, while they
may be thought of as source-specific, in the general population they occur on a daily
basis. The age-specific HIs for typical and high-end exposures are well below 1 and are
presented in Table 8.2.
Xylenes VCCEP Submission 151
Table 8.2
Chronic Risk Evaluation for Children's Background Exposures to Xylenes
Typical Exposure Hazard Quotients High End Exposure Hazard Quotients
<1 1-5 6-13 <1 1-5 6-13
14-18 19-35 14-18 19-35
year old year
Source year old year old year old year old year old year old year old year old
* old *
Air
Rural 0.01 0.01 0.01 0.01 0.01 0.05 0.04 0.04 0.04 0.04
Urban 0.01 0.01 0.01 0.01 0.01 0.05 0.05 0.05 0.05 0.05
Food &
Tapwater
Ingestion 0.001 0.001 0.0005 0.0002 0.0002 0.002 0.002 0.0008 0.0005 0.0004
Breast Milk-
Occupational 0.003 -- -- -- -- 0.133 -- -- -- --
Showering - 0.000
dermal 0.0001 0.0002 0.0001 0.00009 0.00009 3 0.0003 0.0002 0.0002 0.0002
Showering ?br>
inhalation 0.0002 0.0001 0.00002 0.00002 0.00002 0.001 0.0005 0.0001 0.0001 0.0001
Ambient HIs
Rural 0.02 0.01 0.01 0.01 0.01 0.2 0.04 0.04 0.04 0.05
Urban 0.02 0.01 0.01 0.01 0.01 0.2 0.05 0.05 0.05 0.05
*The total HI for the <1 yr old includes ingestion of breast milk from an occupationally exposed
mother. The hazard index for the nursing infant of a non-occupationally exposed mother would be
less.
The background sources of exposure either individually or in aggregate result in HIs
ranging from 0.01-0.1. Thus, the health risks from background exposures to xylenes are
negligible.
The largest HI is calculated for the infant where the high-end exposure to food and
tapwater results in an HI of 0.1. For all age groups except the infant, the inhalation hazard
quotients contribute the most to the total hazard index.
8.3.2 Evaluation of the Risk of Chronic Effects from Source-Specific Exposures
Source specific exposures may occur on a frequent or infrequent basis. The source-
specific exposures that are frequent or continuous in nature, such as from refueling and
smoking are more important in a chronic evaluation than those where exposures are more
sporadic (e.g., spray paint, degreasing, etc.). Tables 8.3 and 8.4 present the HIs for
source-specific xylenes exposures and the aggregate result when high-end background is
considered as well.
Frequent Source-Specific Exposures
The HI resulting from refueling exposures range from 0.00022 to 0.0025, and the total HIs,
including background xylenes exposures, range from 0.01 to 0.1. Thus, as shown on
Table 8.3, the addition of xylenes exposures from refueling, do not appreciably change the
potential health risk beyond that of typical and high-end background exposures.
Table 8.3
Xylenes VCCEP Submission 152
Chronic Hazard Evaluation of Children's Exposure to Xylenes from Refueling
Typical Exposure Hazard High-end Exposure
Quotients Hazard Quotients
Scenario
16-18 year 19-35 year 16-18 year 19-35 year
old old old old
Refueling 0.00025 0.00022 0.0025 0.0022
Background HI (urban) 0.01 0.01 0.05 0.1
Typical Refueling Hazard High-end Refueling
Indices Hazard Indices
Total HI 0.01 0.01 0.05 0.1
The HIs from tobacco smoke exposures range from 0.0009 for ETS to 0.03 for mainstream
smoke. The total HIs incorporating background exposures and tobacco smoke therefore
range from 0.01 to 0.05. As shown on Table 8.4, the contribution of xylenes from ETS to
background health risks is not significant. However, for mainstream smoking, the total HI
increases by a factor of 3, although the total HI is still less than 1 when aggregated with
background exposures.
Table 8.4
Chronic Hazard Evaluation of Children's Exposure to Xylenes
from Tobacco Smoke
Tobacco Smoke Exposure Hazard Quotients
Scenario
<1 1-5 6-13 19-35
14-18
year old
year old year old year old year old
ETS 0.0012 0.0012 0.0010 0.00092 0.0012
Mainstream Smoke -- -- -- 0.014 0.034
Background HI (urban) 0.04 0.01 0.01 0.01 0.01
Typical Tobacco Smoke Hazard Indices
Total HI 0.04 0.01 0.01 0.03 0.05
8.4 Evaluation of the Risk of Acute Effects from Short-Term Infrequent Sources
of Exposure
The risks from the acute effects of xylenes were evaluated using the short-term exposure
concentrations that result during consumer product use. The estimates of concentration
used in this analysis were the time weighted air concentrations for 1 -hour and 8-hour
exposure durations previously presented in Section 7.2.2.2 of the Exposure Assessment.
Xylenes VCCEP Submission 153
The HI values for the degreasing and spray painting scenarios are presented on Tables
8.5 and 8.6.
Table 8.5
Hazard Evaluation for Children's Short Term Exposure to Xylenes from
Residential Metal Parts Degreasing
Typical High End
Exposure Exposure
Exposure Scenario
HI HI
User 0.073 0.23
1-hr TWA Non-
User 0.018 0.068
User 0.011 0.033
8-hr TWA Non-
User 0.0032 0.012
Table 8.6
Hazard Evaluation for Children's Short Term Exposure to Xylenes from
Residential Spray Painting
Typical High End
Exposure Exposure
Exposure Scenario
HI HI
User 0.21 0.35
1-hr TWA Non-
User 0.055 0.10
User 0.052 0.077
8-hr TWA Non-
User 0.016 0.025
The HIs for both the consumer product users and non-users range from 0.01 to 0.3. Thus,
the short-term exposure concentrations associated with the indoor use of xylenes as a
degreaser or a component of spray paint in accordance with manufacturer instructions are
unlikely to produce noticeable discomfort or irritation to the general public and susceptible
individuals.
8.5 Occupational Exposures
A HI for the maternal dose received from occupational exposure has not been calculated
because occupational risk is not evaluated using the hazard index ?reference dose
approach. Occupational exposure levels are established primarily on human data and the
100 ppm TLV for xylenes was established using human studies of workers exposed via
inhalation (ACGIH, 2005). Exposures below the TLV are considered safe for nearly all
workers exposed daily. Current data from the xylenes production industry and from the
general literature indicate that typical occupational exposures (
0.11 ppm) and high-end
Xylenes VCCEP Submission 154
exposures (8 ppm) are well below the TLV of 100 ppm. As explained in Section 6.0
(Hazard Assessment), xylene data do not suggest a developmental or reproductive
hazard. Therefore, information on maternal occupational exposures has been used only
to estimate an infant's exposure to xylenes through human milk when the mother is
occupationally exposed.
8.6 Discussion of Uncertainties
Uncertainties in the exposure estimates are described in the Exposure Assessment
(Section 7). The strengths and weakness of the underlying hazard data used in the
development of the health benchmarks are discussed in the Hazard Assessment (Section
6). A comparison of the uncertainty and adjustment factors that went into the chronic
inhalation health benchmark are discussed in Section 8.1. Neither hazard assessment nor
exposure assessment is an exact science, but conservative (i.e., health protective)
assumptions have been employed in each area, such that margins of safety are more
likely to be overprotective than underprotective.
Figure 8.3: Comparison of Hazard Indices from IRIS RfC and
VCCEP Chronic Inhalation Health Benchmark
1
0.9
0.8
0.7
Hazard Index
0.6 High End Urban Inhalation
Benchmark = 0.66
0.5
High End Urban RfC = 0.1
0.4
0.3
0.2
0.1
0
<1 1-5 6-13 14-18 19-35
Age Group
Xylenes VCCEP Submission 155
To understand any potential uncertainty in the characterization of risk from the use of an
alternative chronic inhalation health benchmark, a comparison of the hazard indices
calculated for the chronic background exposures using both the value used in the Risk
Assessment and the EPA RfC value was made. Figure 8.3 presents a comparison of the
urban chronic background high-end scenario HIs calculated using both inhalation
benchmarks.
As shown on Figure 8.3, the HIs calculated using the EPA RfC of 0.1 ug/m 3 are still below
1. Therefore, use of the more conservative inhalation benchmark does not change in any
significant fashion the characterization of risk to children from chronic xylenes exposure.
8.7 Conclusions
The information in this risk assessment and the underlying hazard assessment and
exposure assessment demonstrates the following:
? Very low xylenes exposures are received from everyday background sources of
exposure such as ambient air, water, food and in-vehicle exposures. Aggregated
background doses result in HIs that are less than 0.05 at the high-end for all age
groups, except the nursing infant of an occupationally exposed mother;
? Total xylenes doses to the nursing infant of an occupationally exposed mother
range from a typical dose of 0.004 mg/kg-day to a high end dose of 0.03 mg/kg-
day, which results in HQs ranging from 0.02 to 0.2.
? Chronic, source-specific, inhalation exposures to xylenes from tobacco smoking
and vehicle refueling scenarios do not result in exceedances of the health
benchmark, even when aggregated with background ambient doses. Tobacco
smoke HIs range from 0.0009 for a child exposed only to ETS to 0.034 for an adult
exposed to ETS and mainstream smoke. Refueling HIs do not exceed 0.003 for a
high-end exposure; and
? Short term air concentrations of xylenes to which children may be exposed during
use of various consumer products are not expected to exceed the interim AEGL-1
value of 130 ppm under typical or high-end exposure conditions. HIs for the
product users ranged from 0.01 to 0.3.
The quantitative risk characterization indicates that reasonably anticipated children's
exposures to xylenes from the ambient background environment and specific sources
such as gasoline during refueling and consumer product use are unlikely to pose
significant health risks.
Xylenes VCCEP Submission 156
9.0 VCCEP Data Needs Assessment
9.1 Hazard
Toxicity data on xylenes are available for all the Tier 1 VCCEP endpoints and most of the
higher tiered endpoints, including subchronic and chronic repeated-dose,
reproductive/developmental toxicity, neurotoxicity, developmental neurotoxicity,
immunotoxicity, and metabolism. These data are reviewed in Section 6 (Hazard
Assessment). While the available data for some endpoints are not the exact study
indicated in the VCCEP Federal Register notice, the available toxicity data adequately
address the endpoints of interest. On the reproductive and developmental toxicity
endpoints, a one-generation reproductive study, two dominant lethal studies, and several
comprehensive developmental and developmental neurotoxicology studies are available.
As neurobehavioral effects appear to be the most sensitive endpoint for xylenes and there
are no indications of reproductive performance effects in the available data, there appears
to be little to gain from conducting a two-generation reproductive toxicity study (see
Section 6.5 for addition discussion). The existing developmental neurotoxicity studies
provide much more comprehensive evaluation of the sensitive endpoint of concern in
offspring than would be obtained from a guideline multi-generation reproduction study. A
LOAEL of 500 ppm can be identified based on subtle behavioral effects in rats following in
utero exposure to xylene. The NOAEL for the 1-generation study is also 500 ppm. Based
on these results and that of related chemicals, it would be unlikely that a new
multigeneration study will result in a NOAEL that is lower than the NOAEL of 50 ppm that
is used as the point of departure. Furthermore, the large significant margins between the
HIs and estimated exposures make it unlikely for a new multigeneration study to have
significant impact on the risk assessment.
9.2 Exposure
For compounds, like xylenes, that are used in consumer products and occur in many
environments, additional exposure assessment work is always possible. The VCCEP
sponsors believe, however, that the information presented in this document is fully
adequate to demonstrate that reasonably anticipated exposures to the compound from
environmental sources are not likely to present significant health risks to children. The
hazard indices from the Risk Assessment are very small, indicating low potential for
chronic risk, and there are considerable margins of safety for short-term acute exposures.
Equally important, xylenes exposures have been declining for the last few decades due to
regulatory and other factors. As described in Section 4, extensive regulatory controls are
already in place and additional anticipated controls will further reduce exposures in the
years to come.
Xylenes VCCEP Submission 157
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