United States Prevention, Pesticides
Environmental Protection and Toxic Substances September 26, 2005
Agency (7508C)
Reregistration
Eligibility Decision for
Xylene
ListC
Case No. 3020
Approved by: Date:
Debra Edwards, Ph. D. September 26,2005
Director
Special Review and Reregistration Division
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Reregistration Eligibility Decision
Xylene
Special Review and Reregistration Division
Office of Pesticide Programs
U.S. Environmental Protection Agency
1801 South Bell Street
Arlington, VA 22202
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Table of Contents
Background: 1
I. Executive Summary 1
n. Use Information 2
HI. Physical/Chemical Properties 3
IV. Hazard Characterization 4
V. Exposure Assessment: 5
VL Risk Characterization 7
\T1. Dietary (Food) Exposure: 7
VIQ. Drinking Water Exposure: 8
IX. Environmental Fate and Ecotoxicity Considerations 8
X. Labeling for End-Use Products 11
XL Tolerance Reassessment: 11
XII. References: 11
Appendix A - Xylene Label Table 13
Appendix B - Data Supporting Guidelines for the Reregistration of Xylene 16
Appendix C - Occupational Handler Calculations 21
Appendix D - Toxicological Data Summary from review of IRIS (EPA, 2003) 23
in
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Background:
EPA has completed its Registration Eligibility Decision (RED) document for xylene. In this document, EPA presents the
results of its review of the potential human health effects of dietary, drinking water, and occupational exposure to xylene,
as well as ecological risks. Currently, there are no homeowner products, so there are no use patterns that are likely to
result in residential handler or postapplication exposures. The only use is as an aquatic herbicide in programs of the
Bureau of Reclamation, U.S. Department of Interior, and for its cooperating water user organizations. There are also inert
ingredient uses for xylene which the Agency will be assessing, but these uses are considerably different from these
aquatic herbicide uses of the active ingredient, so another document is being written by the Agency's Lower Risk
Pesticide Chemical Focus Group to reassess the exemption from the requirement for tolerances for the inert ingredient
uses of xylene.
I. Executive Summary:
Xylene is used as an aquatic herbicide. There is only one registered pesticide product containing xylene as the active
ingredient. The current label for this end use product clearly indicates that it is only for use in programs of the Bureau of
Reclamation, U.S. Department of Interior, and for its cooperating water user organizations. For this assessment of
xylene, occupational handler inhalation and dermal exposures were examined. An oral NOAEL of 150 mg/kg/day was
used to assess short-term risks from dermal exposures. The oral dose was converted to an equivalent dermal dose using a
100% dermal absorption factor (a conservative assumption). An inhalation NOAEL of 57.6 mg/kg/day was used to
assess short-term risks from inhalation exposures. This endpoint was based on behavioral effects, and is more health
protective than some other studies which could have been selected such as those showing reduced body weight gain,
developmental effects, or mortality, all of which were seen at higher exposure doses. Available data indicate that xylene
is not a carcinogen.
Due principally to its high vapor pressure, no residues of xylene are expected to occur on harvested crops as a result of
irrigation with xylene-treated waters. Thus, the Agency plans to propose revocation of the tolerance exemption for this
use at 40CFR 180.1025. Further, based on current and future label restrictions, residues in drinking water are expected to
be well below the Maximum Contaminant Level (MCL) established by the Agency under the Safe Drinking Water Act.
For occupational applications of liquid formulations to water, the current label indicates that xylene is directly metered
into the suction side of a pump, and injected below the surface of the water to treat aquatic plants. This technique is the
only method of application to flowing waters, but is also used for applications to quiescent waters. It has been
determined that there is a potential for exposure to xylene in occupational scenarios from handling the xylene product
during the mixing/loading and the application process (i.e., mixers/loaders/applicators) and a potential for postapplication
worker exposure. Postapplication occupational exposures following application to aquatic areas is likely limited to
persons who contact the treated water to perform tests, such as testing the levels of xylene, or persons such as agricultural
workers or irrigation water suppliers who contact treated water in irrigation canals. The exposure scenarios and
application rates chosen for this risk assessment were based on the anticipated use patterns and the current label for the
xylene product.
For the handler assessment, combined dermal plus inhalation risks for all of the handler scenarios (which included only
engineering controls for a closed system) are below EPA's level of concern. The dermal margin of exposure (MOE) was
calculated to be 840, and the inhalation MOE was calculated to be 39,000. The combined dermal plus inhalation MOE
was calculated to be 820. The target MOE is 100. Thus, these occupational exposures do not pose a risk of concern to
the Agency.
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The most important environmental fate property for xylenes applied to a drainage ditch is volatilization. Xylenes are also
susceptible to biodegradation under aerobic conditions, but the rate of volatilization (with a vapor pressure between 5 and
9 mm Hg) is significantly greater than the rate of degradation (half-life on the order of 20 days). Abiotic degradation
mechanisms, such as hydrolysis and photolysis, are not important. Although xylenes have high to moderate mobility in
soils when applied directly to water, leaching to groundwater is considered unlikely. The Agency evaluated risks to both
aquatic and terrestrial organisms. The assessment does show risk to certain aquatic species, however a reduction in
allowable discharge concentrations of xylene-treated water and a restriction on the states in which xylene may be used
addresses this risk concern.
II. Use Information:
Xylene (dimethyl-benzene) is composed of three isomers: o-, m-, and p-xylene. The CAS Number of the mixed isomers
is 1330-20-7, and the CAS Nos. of the individual isomers are 95-47-6 for o-, 108-38-3 for m-, and 106-42-3 for p-xylene.
This active ingredient is used in an end-use product which is an aquatic herbicide; there is only one registered pesticide
product containing xylene as the active ingredient (EPA Reg. No: 9768-18).
According to information in the Agency REFS database, there had been as many as 1391 products registered with Xylene
(OPP Chemical Code 086802) as the active ingredient, and 982 products registered with Xylene Range Aromatic
Solvents (OPP Chemical Code 086803); however, except for the one registered product all these other products have
been cancelled, the registrants have modified the formulation or, conversely, have not modified the formulation, but have
made requests to the Registration Division that the "xylene" or "xylene range aromatic solvent" be considered an inert
ingredient (for example, listed on the CSF as an inert ingredient, with declared use as a solvent).
The current label for the one remaining active product lists "Xylene Range Aromatic Solvents" as the active ingredient.
According to the Confidential Statement of Formulation on file from the Registrant, the current active ingredient is
xylene (mixed isomers). Thus, the revised label, required to be submitted as part of the Product Reregistration process,
will correct this active ingredient name, and the product will now be placed into OPP Chemical Code 086802, rather than
OPP Chemical Code 086803.
The product is an aquatic weed ready-to-use herbicide produced by the Thatcher Company, containing 98% xylene. This
product was first registered in February, 1968, so its original registration was with the U.S. Department of Agriculture,
and predates the Environmental Protection Agency.
The tolerance exemption being reassessed in this document, the respective citation in the Code of Federal Regulations
(CFR), and the use pattern as an active ingredient are listed in Table 1.
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Table 1, Tolerance Exemptions Being Reassessed for Xylene, for both Inert Ingredient and Active
Ingredient Uses Listed 1,
Tolerance Exemption
Expression .
Xylene
• CAS No, '.
1330-20-7
40 CFR
180.910 2'3
180.920 4
180.930 5
180.1025
PCCode
Inert:
886802 '
Active:
086802 6
Use Pattern (& Limits)
Solvent or co-solvent
(in pesticide formulations for
grain storage only)
solvent, co-solvent
solvent, co-solvent
aquatic herbicide applied to
irrigation conveyance systems
1. Xylene used as an inert ingredient has various use patterns, all very different from the use patterns of the aquatic herbicide which is
the subject of this RED; therefore, another document is being written to address the inert ingredient tolerances.
2. Expressed in 40 CRF 180.910 as "Xylene meeting the specifications listed in 21 CFR 172.884(b)(4)."
3. Residues listed in 40 CFR §180.910 [formerly 40 CFR§ 180.1001(c)] are exempted from the requirement of a tolerance when used
as inert ingredients in pesticide formulations when applied to growing crops or to raw agricultural commodities after harvest.
4. Residues listed in 40 CFR §180.920 [formerly 40 CFR§ 180.1001(d)] are exempted from the requirement of a tolerance when used
as inert ingredients in pesticide formulations when applied to growing crops only.
5. Residues listed in 40 CFR §180.930 [formerly 40 CFR§ 180.1001(e)] are exempted from the requirement of a tolerance when used
as inert ingredients in pesticide formulations when applied to animals only.
6. The active ingredient PC Code for this end-use product had formerly been considered to be 086803, Xylenes Range Aromatic
Solvents; however, the registrant has provided clarification regarding the actual chemical composition of the active ingredient which is
being utilized; therefore, 086802, Xylene, is now deemed to be the correct PC Code for this end-use product.
III. Physical/Chemical Properties:
The key physical/chemical properties for xylene are listed in Table 2.
Table 2, Physical/Chemical Properties of the Mixed Isomers of Xylene (CAS No. 1330-20-7)
Molecular formula
Molecular weight
Boiling Point
Vapor Pressure
Density
Water Solubility
Henry's Law Constant
Soil sorption (Koc)
LogKow
Odor Threshold
QH10
106.16
138.5°C
5-9mmHgat25°C
0.864 gm/cm3
130 - 190 mg/L
6.4 x 10"3 atm/m3 • mole
2.2
3.12-3.20
Air: 0.2 - 3.7 ppm (0.0045 - 0.016 mg/L)
Water: 0.5 - 2 mg/1
Reference: ATSDR ToxProfile (1995) and HSDB (2005)
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IV. Hazard Characterization:
The acute data in Table 3 are from ATSDR (1995), WHO (1991), and ChemlDplus (TOXNET).
Table 3. Acute Toxicity Profile - Mixed Isomers of Xylene and Each Individual Isomer,
Study Type
(endpoint)
Acute oral
(LD50)
Acute dermal
(LD50)
Acute inhalation (LC50)
Eye irritation
Dermal irritation
Skin sensitization
Species
Rat
Rabbit
Rat
Rabbit
Rabbit
Guinea Pig
Isomer
mixed
0-
m-
P-
mixed
0-
m-
P-
mixed
0-
m-
P-
Results
3523 - 8700 mg/kg
3608 - 4400 mg/kg
4320 -6661 mg/kg
4029 - 5000 mg/kg
1700 mg/kg
no data found
3228 -14, 100 mg/kg
no data found
5000 - 10950 ppm ( mg/L)
4330 - 4595 ppm
5267 - 5984 ppm
4550 - 4740 ppm ( mg/1)
moderate
mild to severe
no data
Toxicity Category
m-rv
m
m-rv
m-rv
m
m-rv
IV
m
II -IV
The toxicity endpoint data in Table 4 were chosen based on a review of toxicological data provided in the IRIS and
ATSDR assessments, with a full summary of these data provided in Appendix B.
Table 4, Subchronic, Chronic and Other Toxicity Profile - Xylene
Study Type .
Oral: 90-day study:
male and female Sprague-
Dawley rats
(Condie 1988, as cited in
IRIS (EPA 2003))
Classification/Doses
0, 150, 750, or 1500 mg/kg-day
mixed xylenes (17.6% o-xylene,
62.3% m-xylene and p-xylene
[which coeluted], and 20% ethyl
benzene)
Results
NOAEL: 150 mg/kg-day
LOAEL: 750 mg/kg-day
(based on increased kidney weights and early
appearance of mild nephropathy in female
rats)
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Table 4. Subchronic, Chronic and Other Toxicity Profile - Xylene
Inhalation: 3-month
study:
male Wistar rats
(Korsak et al. 1994, as
cited in IRIS (EPA
2003))
0, 50, or 100 ppm
m-xylene
Behavioral NOAEL: 50 ppm
(217 mg/m3 or 57.6 mg/kg/day)a
Behavioral LOAEL: 100 ppm
(based on decreased rotarod performance and
decreased latency in the paw-lick response in
the hot-plate test)
Carcinogenicity: gavage
study in male and female
rats and mice, 5 days per
week for 103 weeks
rats: 0, 250, or 500 mg/kg/day
mice: 0, 500, or 1000 mg/kg/day
mixed xylenes (60% m-xylene,
13.6%p-xylene, 9.1%o-xylene,
and 17.0%ethylbenzene)
not carcinogenic to either rats or mice at
highest doses administered
(NTP 1986); Evaluations of genotoxic effects
have consistently given negative results
(IRIS, 2005)
mg/m3 value provided in IRIS documents. Conversion to mg/kg/day = NOAEL (217 mg/m3) * default respiratory volume for Wistar rat
(0.0096 mVhr) * exposure time (6 hr/day, from IRIS website) /default body weight for Wistar rat (0.217kg) = 57.6 mg/kg/day.
Toxicological Endpoint Selection:
For this assessment of xylene, occupational handler inhalation and dermal exposures were examined. An oral NOAEL
was used to assess short-term risks from dermal exposures. The dermal dose was converted to an equivalent oral dose
using a default/conservative 100% dermal absorption factor. The oral toxicological endpoint of 150 mg/kg-day was used.
This NOAEL was based on an increase in kidney weights and an early appearance of mild nephropathy observed in
female rats from a 90-day oral toxicity study (Condie, 1988).
An inhalation NOAEL was used to assess short-term risks from inhalation exposures. The inhalation toxicological
endpoint of 57.6 mg/kg/day was used. This NOAEL was based on decreased rotarod performance and decreased latency
in the paw-lick response in the hot-plate test from a 3-month inhalation study on rats. This endpoint is somewhat
"conservative" (i.e., health protective), since it is based on a neurologic or behavioral effect; if another endpoint had been
selected based on a frank toxicological effect (i.e., reduced body weight and/or developmental effects), the NOAEL
would probably have been 3 to 5 times higher than that in Table 4.
V. Exposure Assessment:
Xylene is formulated as a liquid concentrate for use as an aquatic weed herbicide. For occupational applications of liquid
formulations to water, xylene may be directly metered into the suction side of a pump and injected below the surface of
the water. This technique is the only method of application to flowing waters, but is also used for applications to
quiescent waters. Table 5 provides the maximum application rates. The daily areas treated were defined for each handler
scenario (in appropriate units) by determining the amount that can be reasonably treated in a single day. It was assumed
that the average occupational workday is 8 hours. It was also assumed that dermal absorption was 100%. The target
MOE for this assessment is 100, considering a lOx uncertainty factor for intraspecies variation and a lOx uncertainty
factor for interspecies extrapolation.
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Table 5; Summary of Maximum Application Rates for Xylene
Crop Type/ Use Site
aquatic weeds
Maximum
Application
Rate
2.61 Ib ai/min
Application
Equipment
Direct metering
Amount Treated Per
Day
30 minute treatments over
an 8-hour workday (480
minutes/day)
It has been determined that there is a potential for exposure to xylene in occupational scenarios from handling xylene
products during the mixing, loading and application process (i.e., mixers/loaders/ applicators) and a potential for
postapplication worker exposure. Postapplication occupational exposures following application to aquatic areas is likely
limited to persons who contact the treated water to perform tests, such as testing the levels of xylene, or persons such as
agricultural workers or irrigation water suppliers who contact treated water in irrigation canals.
The exposure scenarios and application rates chosen for this risk assessment were based on the anticipated use patterns
and the current label for the xylene product (see Table 5). The quantitative exposure/risk assessment developed for
occupational handlers is based on the following scenario:
Mixer/Loader/Applicators Applying to Water:
(1) Liquid: Direct Metering (using data for mixing/loading liquid formulations in a closed system)
Exposure and Risk Summary
Handler Assessment
A summary of the occupational handler risks for each exposure scenario is presented in Table 6. For the handler
assessment, the dermal risk for the handler scenario (which included only engineering controls for a closed system) is
well below EPA's level of concern. The target MOE is 100, and the dermal MOE was calculated to be 840. For
inhalation exposures, the MOE was calculated to be 39,000, based on the behavioral effects endpoint of 50 ppm (57.6
mg/kg/day) identified in Table 4 (there would be much higher MOEs were this assessment have utilized frank
toxicological effects, such as reduced body weight and/or developmental effects, endpoints only observed at much higher
inhalation exposures). The combined dermal and inhalation MOE was calculated to be 820. Thus, the Agency does not
have worker risk concerns.
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Table 6. Summary of Occupational Handler Exposures and Risks from Xylenes
Exposure
Scenario
Crop or
• Target .
AppRate"
Time
Handled
Daily
Engineering Control
• UnitExposures , •
Dermal
(mg/lb ai)
Inhalation
(ug/lbai),.
Engineering Controls
Dermal"
Dose
(mg%/ ,
day)
MOEC
Engineering Controls
Inhalation d
Dose
(ing/kg/-
day)
MOEe
Mixer/Loader/Applicator
Mixing/Loading/
Applying
Emulsifiable
Concentrate with
Direct Metering f
aquatic
weed
2.61 Ib
ai/min
480
min/day
0.0086
0.083
0.18
840
0.0015
39,000
a Application rates are the maximum application rates determined from the EPA registered label for xylenes
b Eng Controls Dermal: Closed mixing/loading system, enclosed cab, or enclosed cockpit.
c Dermal MOE = NOAEL (150mg/kg/day) / dermal daily dose (mg/kg/day), where dermal dose = daily unit exposure (mg/lb ai) x application rate x amount
handled per day / body weight (60 kg adult).
d Eng Controls Inhalation: Closed mixing/loading system, enclosed cab, or enclosed cockpit.
e Inhalation MOE = NOAEL (57.6 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily unit exposure (mg/lb ai) x application rate
x amount handled per day / body weight (70 kg adult).
f Using PHED: mixing/loading liquid - closed system (engineering controls)
Postapplication Assessment
Postapplication exposure would be limited to persons testing the water in canals/irrigation ditches and also to persons
exposed to irrigation water that is applied to crops. At this time there is no known method to assess these type of
exposures. However, the Agency assumes that the level of exposure from these scenarios would not exceed that obtained
from handling and applying the product. In addition, xylenes are highly volatile and would not be expected to remain in
solution for very long, decreasing the potential for postapplication exposure.
VI. Risk Characterization:
Occupational exposure to xylenes through the application of an aquatic herbicide was evaluated in this assessment.
Anticipated occupational exposures (dermal and inhalation) were not found to pose a risk (i.e., the calculated MOE was
above the target MOE).
VII. Dietary (Food) Exposure:
At present, xylene is exempt from requirement for a tolerance (40CFR 180.1025) based on its use in irrigation water. The
Agency expects that when xylene-treated waters are used as irrigation waters applied to fields or sprayed onto plants by
overhead irrigation, the xylene will readily volatilize; the xylene isomers have vapor pressures of 5-9 mm Hg at 25° C,
and Henry's Law Constants of about 6.4 x 10"3 atm/m3 • mole, suggesting that xylene will readily partition into the
atmosphere from water, soil, and the exposed surfaces of plants. Moreover, the mobility of xylene in soils is predicted to
be moderate to high, based on the Koc values ranging from 39-365, suggesting that sorption to soil will also not be likely
to add to any amounts of xylene available for incorporation into plant tissues. Therefore, on the basis of this information,
it is expected that crops will not bear residues of xylene as a result of their receiving any applications of xylene-treated
irrigation waters. Thus, the Agency has no risk concerns for dietary exposure from use of xylene in irrigation water. As a
follow-up action to this RED, the Agency intends to propose revocation of the existing tolerance exemption at 40CFR
180.1025.
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VIII. Drinking Water Exposure:
To minimize the risks of effects to human health, the current label indicates that water discharged from the treated
drainage ditch should not flow into receiving waters if the concentration of xylene exceeds 10 ppm, and also states "Do
not allow the treated water to enter any domestic system." The Agency does not have any human health risk concerns,
based on the current label because 10 ppm is equivalent to the Maximum Contaminant Level (MCL) established by EPA
under the Safe Drinking Water Act. However, additional label refinement will be implemented on the revised label to
further clarify the description of "any domestic system," and a lower discharge level (1 ppm) will be specified for
discharges of treated water into receiving rivers, streams, or lakes to accommodate the Agency concerns regarding
ecological risks to aquatic organisms.
IX. Environmental Fate and Ecotoxicitv Considerations:
Environmental Fate and Transport:
Xylene isomers are highly volatile and have been found to disappear rapidly from solution (WHO, 1997); for example,
the half-life of o-xylene has been estimated to be 39 minutes in agitated water, 1 meter deep and with aim2 surface for
evaporation. Both m-xylene and p-xylene are readily biodegradable; however, in soil and water, o-xylene has been
observed to be more persistent. Bioaccumulation of all three xylene isomers has been reported to be low. Based on
experimental Koc values, xylene is expected to have moderate to high mobility in soils, and based on measured Koc values,
xylene is expected to adsorb somewhat to sediment or particulate matter in water (HSBD, 2005).
The EFED Science Chapter reports the following: "The most important fate property for xylenes applied to a drainage
ditch is volatilization. Xylenes are also susceptible to biodegradation under aerobic conditions, but the rate of
volatilization (half-life of about 2 days in a shallow water body; 1.2 days in typical river and 6.0 days in a pond
http://www.epa.gov/OGWDW/dwh/t-voc/xylenes.html) is significantly greater than the rate of degradation (half-life on
the order of 20 days) (API 1994). Abiotic degradation mechanisms, such as hydrolysis and photolysis, are not important
for aromatic petroleum solvents. Although xylenes have high to moderate mobility in soils when applied directly to
water, leaching to groundwater is considered unlikely." In addition, additional information is presented indicating that
photolysis and hydrolysis are not important environmental fate pathways because the xylene isomers do not absorb
photons of light with a wavelength greater than 290 nm, nor do they possess functional groups that are susceptible to
hydrolysis under environmental conditions.
Mean background levels of the xylene isomers are around 1 pg/m3 and 0.1 pg/L in ambient air and in surface waters,
respectively (WHO, 1997). Higher values have been measured in industrial areas, particularly around oil industries
associated with discharge pipes. High levels of xylenes have been reported in groundwater associated with underground
tanks and pipes.
Estimated Environmental Concentrations:
There is some uncertainty regarding the maximum exposure concentrations for aquatic organisms in both the irrigation
canals and receiving waters. The solubility limits for xylene isomers are approximately 160-180 mg/L; however, within
the irrigation canals, the xylene product is applied with an emulsifier which results in a greater apparent solubility,
approaching the initial 740 ppm concentration level. It is known that turbulent mixing with the irrigation waters will
immediately result in a lowering of this concentration, probably rapidly approaching the solubility limits of the isomers;
in addition, it is known that xylene will readily dissipate from water (by degradation, volatilization, and sorption), further
reducing the water concentrations as the treated water moves down-gradient in the irrigation systems.
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In addition, there is also uncertainty in assuming the xylene concentrations in water bodies receiving effluents (i.e.,
unused irrigation water) from those irrigation districts which are discharging xylene-treated waters. The current label
permits up to 10 ppm; however, it is assumed that typically very little water would be released, that the concentrations
actually present in the discharge water are going to be significantly lower, and that dilution will occur in the receiving
waters, as well as continued volatilization, sorption, and degradation, further reducing the actual water concentrations to
which aquatic organisms would be exposed downstream in the receiving waters. In summary, the xylene dissipation from
the return flows into the receiving water body depends on the amount, rate, and length of the irrigation system, the
amount and rate of xylene used to treat the irrigation canals, the length of time it takes for the treated water to reach the
receiving body, the volume of any irrigation water which finally enters the receiving body, the degree of turbulent mixing
within the receiving water body, and the rate of flow and volume within receiving water body. Some irrigation districts
discharge their released water into lakes, while some discharge into small streams, but it is not uncommon for discharges
to be into large rivers, such as the Snake River or the Columbia River. Discussions with stakeholders have indicated that
of these various types of receiving waters, essentially none are estuarine or marine waters.
Ecotoxicity:
WHO (1997) has described xylene as having moderate to low acute toxicity for aquatic organisms. The variation
between each isomer with regard to aquatic toxicity is small. The lowest LC50 value, 1 mg/L, is based on a 24-hour
exposure with Daphnia magna. This value is much higher (close to 10,000 times higher) than the mean background
concentrations in surface water, as reported in the WHO (0.1 pg/L). In the WHO (1997) review, the lowest 96-hour LC50
value for any fish species was 1.7 mg/L, to the striped bass, a marine species, and the lowest 96-hour LC50 value to a
freshwater species was 2.6 mg/L to the rainbow trout. Studies on terrestrial organisms (e.g., Japanese quail) have
reported no overt toxicity at concentrations as high as 5000 mg/kg and LC50's of greater than 20,000 mg/kg. No studies
on terrestrial plants invertebrates or field effects have been reported. Limited information is available on the chronic
exposure of aquatic organisms and none of the effect levels were lower than those observed in the acute studies. The
overall risk to the aquatic environment has been determined to be low, considering the rapid volatilization and
degradation of xylenes and their low to moderate toxicity to organisms (WHO, 1997).
The EFED Science Chapter characterizes the ecotoxicity data as follows: "In general, results of acute toxicity studies
indicate that mixed xylenes and xylene isomers are moderately to highly toxic to aquatic species. The acute toxicity
values used to estimate risks to aquatic organisms are as follows:
• freshwater fish: 96-hour LC50 value of 2.6 mg/L for p-xylene in rainbow trout (Salmo gairdneri);
• freshwater invertebrates: 24-hour LC50 value of 1.0 mg/L for m-xylene in water flea (Daphnia magna);
estuarine/marine fish: 24-hour LC50 value of 2.0 mg/L for p-xylene in striped bass (Morone saxatilis);
estuarine/marine invertebrates: 96-hour LC50 value of 1.3 mg/L for o-xylene in bay shrimp (Crago
francisocrum);
• algae: 72-hour LC50 value of 3.2 mg/L for p-xylene in green algae (Selenastntm capricomutum)"
In addition, due to the rapid volatilization of xylenes from water (half-lives range from less than 2 days in a shallow
flowing water body to 6 days in a pond), chronic exposure of aquatic and terrestrial ecosystems is not expected. Thus,
chronic toxicity studies were not assessed, and there are no requirements for additional chronic toxicity testing.
Environmental Risk Assessment:
Xylene is used as an aquatic weed control herbicide in irrigation ditches in the Western United States. This use pattern
means xylene will be present in irrigation waters after treatment, and sets up several ecological risk exposure scenarios.
The Agency is evaluating risks to both terrestrial and aquatic organisms. For terrestrial organisms, risk scenarios include
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both drinking treated water and inhalation resulting from off-gassing from treated irrigation ditches. Risk to aquatic
organisms is possible both in the irrigation canals and in the receiving waters.
Terrestrial Organisms
Considering risk to terrestrial animals, birds and mammals were assessed for oral ingestion of xylene-treated water in
irrigation canals. In addition, mammals were assessed for potential inhalation risk and for combined inhalation/ingestion
risk from xylene-treated irrigation canal water. Due to lack of inhalation toxicity data in birds, acute risks of exposure to
birds via inhalation of volatilized xylene and combined exposure via contaminated water and inhalation could not be
assessed.
The oral ingestion assessment shows that all acute RQs for mammals and birds for exposure from drinking contaminated
water are below acute endangered species LOCs (LOG = 0.1). For birds, acute RQs range from <0.01 (for all three
weight classes for water concentrations of 10 and 178 mg/L) to <0.027 (20 g birds for a water concentration of 740
mg/L). For mammals, acute RQs range from 0.0003 (1000 g mammals consuming water at a concentration of 10 mg/L)
to 0.032 (15 g mammals consuming water at a concentration of 740 mg/L). Additionally, mammals do not appear to be
at acute risk from inhalation exposure or from combined exposure via ingestion of contaminated water and inhalation.
Acute RQs for mammals exposed to xylene via inhalation are below the acute endangered species LOCs (LOC = 0.1).
The acute inhalation RQ based on the maximum inhalation EEC for the exposure scenario is 0.019 and the acute
inhalation RQ based on the minimum inhalation EEC for the exposure scenario is several orders of magnitude below all
acute LOCs. Oral ingestion/inhalation acute composite RQs for mammals range from 0.040 (1000 g mammals) to 0.051
(15 g mammals). As a result of this terrestrial risk assessment, risk management is not warranted at this time for
terrestrial organism risk.
Aquatic Organisms
Aquatic organisms can be potentially exposed to xylene from both the irrigation canal where the product is used, as well
as any naturally occurring water body where treated water is discharged. The Agency's ecological risk assessment does
show potential risks to aquatic organisms in the treated canals. However, since these canals are part of highly managed
agricultural systems, and are dry much of the year, the agency has decided that risk management is not warranted at this
time for aquatic organisms in canals.
The Agency also evaluated potential exposure to aquatic organisms resulting from the discharge of xylene treated
irrigation water into natural water bodies and has established a "safe" concentration of 0.04 ppm in receiving water based
on the freshwater invertebrate 24-hour LC50 value of 1.0 mg/L, and the target RQ for endangered species of 0.05. The
current label has the following statement: "Do not allow return flows of treated irrigation water into receiving rivers,
streams, or lakes if xylene residues are in excess of 10 parts per million (ppm)." Using 10 ppm as a concentration starting
point, the Agency's ecological risk assessment shows potential risks to aquatic organisms. Several scenarios were
developed using a steady-state plug flow model. It is not possible to evaluate every discharge location and their varying
flow conditions; however the model results consistently showed potential concerns when using a discharge concentration
of 10 ppm. At a 1.0 ppm discharge concentration however, only a 1:25 dilution is needed to reach the 0.04 ppm level.
When considering that the RQ estimates are based on aquatic toxicity tests of 24-hours or 96-hours duration (for some
groups, concentrations are continuously renewed by use of a continuous-flow dilutor), and that once in receiving waters
xylene is constantly dissipating due to volatilization and mixing, a 1.0 ppm discharge concentration is considered
appropriate. Therefore, the Agency is requiring the following label adjustments:
• Treated irrigation water must be used to irrigate fields. Since xylene is highly volatile (vapor pressure 5-9 mm
HG at 25 C) this common cultural practice will greatly reduce the amount of xylene in the canal outflows that
10
-------
ultimately may discharge into natural water bodies.
• If treating the fields is not feasible, the treated water must be held until measurable levels are 1 ppm or less.
• The use of xylene will be restricted to the following four States: Idaho, Montana, Oregon, and Washington.
X. Labeling for End-Use Products:
The following label changes are intended to address the potential ecological risk concerns by minimizing the amount of
xylene which reaches natural receiving waters. Table 7 describes how language on the labels should be revised.
Treated water must be either: (1)
used to irrigate fields; or, (2) held in
an irrigation ditch/canal until the
xylene concentration has dropped to
1 ppm or below, as determined by
an EPA approved method, before
released from the irrigation
network.
Xylene is highly volatile (vapor pressure of 5-9 mm Hg at 25C). By ensuring the treated water gets used
to irrigate fields, or held until xylene has had enough time to volatilize to a target concentration of 1 ppm
prior to release from the irrigation network.
Restricting the use to four States.
Currently xylene is only used in four Western States, Washington, Oregon, Idaho, and Montana. By
modifying the label to reflect the actual use pattern, the Agency will have a better understanding of the
possible impact of xylene on endangered species.
XL Tolerance Reassessment:
Based on this scientific assessment, the Agency concludes that crops irrigated with xylene will bear no residues as a result of treatment of irrigation
waters. Thus the tolerance exemption is not needed. As a follow-up action to this decision, the Agency will propose revocation of the exemption at
40CFR 180.1025.
XH References:
Agency for Toxic Substances and Disease Registry (ATSDR). 1995. Toxicological Profile for Xylenes. (Available on-line as
http://www.atsdr.cdc.gov/toxprofiles/tp71.html, which is also available in an adobe acrobat file as http://www.atsdr.cdc.gov/toxprofiles/tp71 .pdf).
Condie, LW; Hill, JR; Borzelleca, JF. 1988. Oral toxicology studies with xylene isomers and mixed xylene. Drug Chem Toxicol 11:329-354. (As
cited in IRIS)
EPA. 2003. Integrated Risk Information System (IRIS): Xylenes. Full IRIS Summary
(available on-line as http://www.epa.gov/iris/subst/0270.htm ), with another fuller, 133 page, acrobat file, Toxicological Review also available, as
follows: Toxicological Review of Xylenes (CAS No. 1330-20-7) hi Support of Summary Information on the Integrated Risk Information System
(IRIS); January 2003 (available on-line as http://www.epa.gov/IRIS/toxreviews/0270-tr.pdf).
Hazardous Substances Data Bank (HSDB). 2005. Xylene. (Available on-line as
http://www.toxnet.nlm.nih.gOV/cgi-bin/sis/search/i7./temp/~dfOZsb:l ).
Korsak, Z; Wisniewska-Knypl, J; Swiercz, R. 1994. Toxic effects of subchronic combined exposure to n-butyl alcohol and m-xylene in rats. Int J
Occup Med Environ Health 7:155-166.
NTP (National Toxicology Program). 1986. NTP Technical Report on the Toxicology and Carcinogenesis of Xylenes (mixed) (60% m-xylene,
14% p-xylene, 9% o-xylene, and 17% ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Research
Triangle Park,
NC. NTP TR 327, NIH Publ. No. 87-2583.
11
-------
Nawrot, PS; Staples, RE. 1980. Embryotoxicity and teratogenicity of isomers of xylene in the mouse. Soc Toxicol Abst PAP 19th: A22, 65.
Ungvary, G; Tatrai, E. 1985. On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits. Arch Toxicol., Suppl.
8:425^130.
Ungvary, G; Tatrai, E; Hudak, A; Barcza, G; Lorincz, M. 1980. Studies on the embryotoxic effects of ortho-, meta- and para-xylene. Toxicology.
18:61-74.
Ungvary, G; Varga, B; Horvath, E; Tatrai, E; Folly, G. 1981. Study on the role of maternal sex steroid production and metabolism in the
embryotoxicity of para-xylene. Toxicology. 19:263-268.
Washington State Water Resources Association (WSWRA). 2004. Engineering Report to Support General Permit for Aquatic Weed Control in
Irrigation Systems. Prepared for Washington State Water Resources Association, Olympia, WA. Prepared by Parametrix, Sumner, WA. Project
No. 215-4222-001 (02/08). 259pp.
World Health Organization. 1997. United Nations Environment Programme, International Labour Organization, World Health Organization.
International Programme on Chemical Safety. Environmental Health Criteria 190: Xylenes.
(Available on-line as http://www.inchem.org/documents/ehc/ehc/ehc 190.htm)
12
-------
Appendix A - Xylene Label Table
13
-------
Summary of Labeling Changes for Xylene
Depription
ded La%eh>g Language
Placement on Label
/ #- //// • ,-'
Environmental Hazards
Statements Required by
the RED and Agency
Label Policies
"This pesticide is toxic to fish and aquatic invertebrates. Do not discharge
effluent containing this product into lakes, streams, ponds, estuaries, oceans or
other waters unless in accordance with the requirements of a National Pollutant
Discharge Elimination System (NPDES) permit and the permitting authority has
been notified in writing prior to discharge. Do not discharge effluent containing
this product to sewer systems without previously notifying the local sewage
treatment plant authority. For guidance contact your State Water Board or
Regional Office of the EPA. Do not contaminate water when disposing of
equipment washwaters."
Immediately following/below
Precautionary Statements: Hazards to
Humans and Domestic Animals
Ijnd
PPE Requirements
Established by the RED
for Liquid Formulations1
"Personal Protective Equipment (PPE)"
"Some materials that are chemical-resistant to this product are" (registrant
inserts correct chemical-resistant material). "If you want more options, follow
the instructions for category" [registrant inserts A,B,C,D,E,F,G, orH] "on an
EPA chemical-resistant category selection chart."
"All handlers and application and other handlers must wear long sleeved shirt,
long pants, shoes and socks, and chemical resistant gloves."
Immediately following/below
Precautionary Statements: Hazards to
Humans and Domestic Animals
14
-------
User Safety
Recommendations
"User Safety Recommendations
Users should wash hands before eating, drinking, chewing gum, using tobacco,
or using the toilet.
Users should remove clothing/PPE immediately if pesticide gets inside. Then
wash thoroughly and put on clean clothing.
Users should remove PPE immediately after handling this product. Wash the
outside of gloves before removing. As soon as possible, wash thoroughly and
change into clean clothing."
Precautionary Statements under:
Hazards to Humans and Domestic
Animals immediately following
Engineering Controls
(Must be placed in a box.)
Environmental Hazards
"Irrigated water treated with this product may be hazardous to aquatic
organisms."
"Runoff may be hazardous to aquatic organisms in water adjacent to
treated areas."
Precautionary Statements immediately
following the User Safety
Recommendations
General Application
Restrictions
"Do not apply this product in a way that will contact workers or other persons,
either directly or through drift. Only protected handlers may be in the area
during application."
Place in the Direction for Use directly
above the Agricultural Use Box.
Other Application
Restrictions (Risk
Mitigation)
"For use only in Washington, Oregon, Idaho, and Montana."
"Treated water must be either held on the irrigated field until absorbed by
the soil or held in an irrigation ditch/canal until the xylene concentration
has dropped to 1 ppm or below, as determined by an EPA approved
method, before being released from the irrigation network."
Directions for Use
1 PPE that is established on the basis of Acute Toxicity of the end-use product must be compared to the active ingredient PPE in this document. The more protective PPE must be placed in the product
labeling. For guidance on which PPE is considered more protective, see PR Notice 93-7.
15
-------
Appendix B - Data Supporting Guidelines for the Reregistration of Xylene
16
-------
Appendix B. Data Supporting Guideline Requirements* for the Reregistration
of Xylene (086802)
REQUIREMENT
CITATION(S)
PRODUCT CHEMISTRY
New
Guideline
Number
830.6304
830. 7050
830.7220
830.7300
830.7550
830.7560
830.7570
830.7840
830.7860
830.7950
Old
Guideline
Number
63-4
none
63-6
63-7
63-11
63-8
63-9
* Guidelines in bold and italicized are those listed as required in GDCI dated January 2004.
Odor
UV/Visible Absorption
Boiling Point
Density
Octanol/Water Partition
Coefficient
Solubility
Vapor Pressure
ATSDR ToxProfile 1995; HSDB 2005
Gabetal, 1977
ATSDR ToxProfile 1995; HSDB 2005
ATSDR ToxProfile 1995; HSDB 2005
ATSDR ToxProfile 1995; HSDB 2005
ATSDR ToxProfile 1995; HSDB 2005
ATSDR ToxProfile 1995; HSDB 2005
ECOLOGICAL EFFECTS (Terrestrial and Aquatic Nontarget Organisms)
850. 1 010
850.1025
850.1035
850.1045
850.1055
850.1075
850.1075
850.1300
850.1350
850.1400
850.1950
72-2B
72-3B
72-3C
72-3
72-1C
72-3A
72-4B
72-4
72-7
Aquatic invertebrate acute toxicity,
test, freshwater daphnid
Oyster acute toxicity test (shell
deposition)
Mysid acute toxicity test
Penaeid acute toxicity test
Bivalve acute toxicity test,
estuarine/marine
Fish acute toxicity, freshwater
Fish acute toxicity,
estuarine/marine
Daphnid chronic toxicity test
Mysid chronic toxicity test
Fish- Early Life Stage
Field Testing for aquatic organisms
Abernathy et al. 1986 (supplemental);
Galassi et al, 1988 (supplemental);
Holcombe et al. 1987 (supplemental)
Reserved; exposure to estuarine/marine
invertebrates not expected, based on
current use pattern.
Abernathy et al. 1986 (supplemental);
Tatem et al (supplemental) 1978
Reserved; exposure to estuarine/marine
invertebrates not expected, based on
current use pattern.
Folmar 1976; Galassi et al, 1988
(supplemental); Holcombe et al. 1987
(supplemental)
Reserved; exposure to estuarine/marine
fish not expected, based on current use
pattern.
Reserved; chronic exposures to
freshwater and estuarine/marine
invertebrates not expected, based on
current use pattern.
Galassi etal, 1988
Ogata and Miyaka 1978; Ogata et al.
1984
17
-------
Appendix B. Data Supporting Guideline Requirements* for the Reregistration
of Xylene (086802)
REQUIREMENT
850.2100
850.2200
850.2300
850.2300
71-1
71-2A
71-4A
71-4B
Avian Acute Oral Toxicity
Avian Dietary Toxicity - Quail
Avian Reproduction - Quail
Avian Reproduction - Duck
CITATION(S)
Hill and Carmardese, 1986
(supplemental, adjusted values based on
data in this study)
Hill and Carmardese, 1986
(supplemental)
Reserved; repeated-dose exposure to
birds during breeding is not expected,
based on current use pattern.
Nontarset Plant Protection
850. 4025
850.4100
850.4150
850.4200
850.4225
850.4250
850.4300
850.4400
850.4450
121-1
122-1
122-1
122-1
123-1A
123-1B
124-1
123-2
124-2
Target area phytotoxicity
Terrestrial Plant Toxicity, Tier 1
(seedling emergence)
Terrestrial Plant Toxicity, Tier 1
(vegetative vigor)
Seedling Germination/Root
Elongation
Seedling Emergence, Tier 2
Vegetative Vigor, Tier 2
Terrestrial plants field study, Tier 3
Aquatic plant toxicity test using
Lemna spp. Tiers I and II
Aquatic plants field study, Tier 3
Reserved; exposure is not expected,
based on current use pattern.
Reserved; no additional data is needed
beyond Tier 1 screening levels, based on
current use pattern.
TOXICOLOGY
870.1100
870.1200
870.1300
870.2400
870.2500
870.2600
870.3100
870.3150
870.3200
870.3465
81-1
81-2
81-3
81-4
81-5
81-6
82-1A
82-1B
82-2
82-4
Acute Oral Toxicity
Acute Dermal Toxicity
Acute Inhalation Toxicity
Acute Eye Irritation
Acute Dermal Irritation
Skin Sensitization
90-Day Oral Toxicity - Rodent
90-Day Oral Toxicity - Non-rodent
21/28-Day Dermal Toxicity
90-Day Inhalation-Rat
Wolf et al. 1956; Smyth et al. 1962; Hine
and Zuidema 1970; NTP 1986
Smyth etal. 1962
Bonnet et al. 1979; Bonnet et al. 1982;
Carpenter et al. 1975
Smyth etal. 1962
Smyth etal. 1962
Data gap, will be required in PDCI
Condie et al. 1988; NTP 1986; Wolfe et
al. 1988
Reserved; long-term oral exposure is not
expected, based on current use pattern.
Reserved; long-term dermal exposure not
expected, based on current use pattern.
Korsak et al. 1994; Korsak et al. 1992;
Gralewicz et al. 1995; Gralewicz and
Wiaderma2001
18
-------
Appendix B. Data Supporting Guideline Requirements* for the Reregistration
of Xylene (086802)
REQUIREMENT
870. 3 700
870.3700
870.3800
870.4100
870.4200
870.4300
870.5100
870. 5300
870.5375
870.6200
870. 7485
83-3A
83-3B
83-4
83-1A
83-2 A, B
83-5
84-2A
84-2A
84-2B
81-8
85-1
Prenatal Developmental Toxicity -
Rat
Prenatal Developmental Toxicity -
Rabbit
Reproduction and Fertility Effects
Chronic Toxicity
Carcinogenicity
Combined Chronic Toxicity/
Carcinogenicity
Bacterial Reverse Mutation Test
(Ames Test)
In vitro Mammalian Cell Gene
Mutation Test
In vitro Mammalian Chromosomal
Aberration Test
Acute Neurotoxicity Screen
Metabolism and Pharmacokinetics
CITATION(S)
Ungvary et al. 1980; Ungvary et all 981;
Ungvary and Trarai 1985
Ungvary and Trarai 1985
Reserved; data not needed at this time,
because chronic exposures are not
expected, based on current use pattern.
NTP 1986
NTP 1986
NTP 1986
Lebowitz et al. 1979; Bos et al. 1981;
Haworth et al. 1983; Connor et al. 1985;
Shimizu et al. 1985; Zeiger et al. 1987
Lebowitz et al. 1979
Gerner-Smidt and Freidrich 1978;
Anderson et al. 1990
NTP 1986
Dutkiewicz and Tyras 1968; Engstrom et
al. 1977; Riihimaki et al. 1979a, b; Ogata
et al. 1980; Wallen et al. 1985; Kawai et
al. 1 99 1; Huang et al. 1994
ENVIRONMENTAL FATE
835.1230
835.1240
835.2120
835.2240
835.2370
835.2410
835.4100
835.4200
835.4300
835.4400
835.6100
835.6200
835.8100
163-1
163-1
161-1
161-2
161-4
161-3
162-1
162-2
162-4
162-3
164-1
164-2
163-3
Sediment and soil
absorption/desorption for parent
and degradates
Leaching/ Adsorption/Desorption
Hydrolysis
Photodegradation - Water
Photodegradation - Air
Photodegradation - Soil
Aerobic Soil Metabolism
Anaerobic Soil Metabolism
Aerobic Aquatic Metabolism
Anaerobic Aquatic Metabolism
Terrestrial Field Dissipation
Aquatic Field Dissipation
Field Volatility
API, 1994
Pavlostathis and Mathavan 1992; Vowles
and Mantoura 1987; Lindhart et al. 1994
HSDB 2005; ATSDR 1995
HSDB 2005; ATSDR 1995
HSDB 2005; ATSDR 1995
HSDB 2005; ATSDR 1995
Tsaoetal. 1998
API, 1994
API, 1994
API, 1994
Aurelius and Brown 1987
Walsh etal., 1977
Smith and Harper 1980
19
-------
Appendix B. Data Supporting Guideline Requirements* for the Reregistration
of Xylene (086802)
REQUIREMENT
850.1730
165-4
Accumulation in Fish
CITATION(S)
Ogata and Miyaka 1978; Ogata et al.
1984
RESIDUE CHEMISTRY
860. 1300
860.1300
860.1340
860.1340
860.1380
860.1400
860.1480
860.1520
171-4A
171-4B
171-4C
171-4D
171-4E
171-4F,
171-4G,
171-4H,
165-5
171-4 J
171-4L
Nature of Residue - Plants
Nature of Residue - Livestock
Residue Analytical Method -
Plants
Residue Analytical Method -
Animals
Storage Stability
Water, fish and irrigated crops
Magnitude of Residues -
Meat/Milk/Poultry/Egg
Processed food/feed (ABIU)
Not applicable
OTHER
850.3020
141-1
Honey Bee Acute Contact
Reserved; exposure to nontarget
terrestrial insects is not expected, based
on current use pattern.
20
-------
Appendix C - Occupational Handler Calculations
21
-------
Handler Calculations:
(1) Daily Exposure:
Where:
E
UE
AR
AT
E = UE * AR * AT
amount (mg or ug ai/day) deposited on the surface of the skin that is available for dermal absorption or amount
inhaled that is available for inhalation absorption;
unit exposure value (mg or ug ai/lb ai) derived from August 1998 PHED data, from ORETF data, from CMA data,
and from Proprietary data;
normalized application rate based on a logical unit treatment, such as acres, square feet, gallons, or cubic feet.
Maximum values are generally used (Ib ai/A, Ib ai/sq ft, Ib ai/gal, Ib ai/cu ft); and
normalized application area based on a logical unit treatment such as acres (A/day), square feet (sq ft/day), gallons
per day (gal/day), or cubic feet (cu ft/day).
(2) Daily Dose:
ADD = E*(ABS/BW)
Where:
ADD
E
ABS
BW
(3) Margins of Exposure:
absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg
body weight/day);
amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount
inhaled that is available for inhalation absorption;
a measure of the amount of chemical that crosses a biological boundary such as the skin or lungs (% of
the total available absorbed); and
body weight determined to represent the population of interest in a risk assessment (kg).
MOE = (NOAEL or LOAEL) / ADD
Where:
MOE
NOAEL or LOAEL =
ADD
= margin of Exposure, value used to represent risk or how close a chemical exposure is to being a
concern (unitless);
dose level in a toxicity study, where no observed adverse effects (NOAEL) or where the lowest observed
adverse effects (LOAEL) occurred in the study; and
= average Daily Dose or the absorbed dose received from exposure to a pesticide in a given
scenario (mg pesticide active ingredient/kg body weight/day).
22
-------
Appendix D - Toxicological Data Summary from review of IRIS (EPA, 2003)
23
-------
Route:
Study
NTP Chronic 2-year
study (1986)
NTP Chronic 2-year
study (1986)
NTP 13-week study
(1986)
NTP 13-week study
(1986)
Wolfe (1988a) 90-day
study
Wolfe (1988b) 90-day
study
Condie (1988) 90-day
study
Oral (gavage)
Organism
Rats
Mice
Rats
Mice
Rats
Rats
Rats
Doses
0, 250, or 500
mg/kg-day
0, 500, or 1000
mg/kg-day
0,62.5,125,250,
500, or 1000
mg/kg-day
0, 125, 250, 500,
1000, and 2000
mg/kg-day
0, 100, 200, or
800 mg/kg-day
0, 100, 200, or
800 mg/kg-day
0,150, 750, or
1500 mg/kg-day
Chemical
Mixed xylenes (60% m-
xylene, 13.6%p-xylene,
9.1%o-xylene, 17.0%
ethylbenzene)
Mixed xylenes (60% m-
xylene, 13.6%p-xylene,
17.0% ethylbenzene, 9.1%
o-xylene)
m-xylene (99% purity)
p-xylene (99% purity)
Mixed xylenes (17.6% o-
xylene, 62.3% m-xylene and
p-xylene [which coeluted],
20% ethyl benzene)
Results
NOAEL: 250 mg/kg-day
LOAEL: 500 mg/kg-day
(based on decreased body weight and
decreased survival)
NOAEL: 500 mg/kg-day
LOAEL: 1000 mg/kg-day
(based on hyperactivity)
NOAEL: 500 mg/kg-day
LOAEL: 1000 mg/kg-day
(based on decreased body weight in
male rats without tissue lesions)
NOAEL: 1000 mg/kg-day
LOAEL: 2000 mg/kg-day
(based on transient signs of nervous
system depression in mice without
tissue lesions)
NOAEL: 200 mg/kg-day
LOAEL: 800 mg/kg-day
(based on decreased body weight)
NOAEL: 200 mg/kg-day
LOAEL: 800 mg/kg-day
(based on early mortality in male rats
that showed signs of test material
aspiration into the lungs)
NOAEL: 150 mg/kg-day
LOAEL: 750 mg/kg-day
(based on increased kidney weights
and early appearance of mild
nephropathy in female rats)
NTP (1986) study:
Chronic 2-year study
> Target organisms:
50 male and 50 female Fischer 344 rats
• 50 male and 50 female B6C3F1 mice
> Doses/Length of study:
• Mixed xylenes (60% m-xylene, 13.6% p-xylene, 9.1%o-xylene, 17.0% ethylbenzene)
Administered by gavage in com oil
Rats: 0,250, or 500 mg/kg-day
Mice: 0, 500, or 1000 mg/kg-day
• 5 days/week for 103 weeks
Results:
Rats: LOAEL is 500 mg/kg-day and the NOAEL is 250 mg/kg-day for decreased body weight and decreased survival
Mice: The LOAEL is 1000 mg/kg-day and the NOAEL is 500 mg/kg-day for hyperactivity
24
-------
Subchronic 13-week study
> Target organisms:
• 10 male and 10 female Fischer 344 rats
10 male and female B6C3F! mice
> Doses/Length of study:
Mixed xylenes (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, 9.1% o-xylene)
• Administered by gavage in com oil
Rats: 0,62.5,125,250, 500, or 1000 mg/kg-day
Mice: 0,125,250, 500,1000, and 2000 mg/kg-day
5 days/week for 13 weeks
> Results:
Rats: The LOAEL is 1000 mg/kg-day and the NOAEL is 500 mg/kg-day based on decreased body weight in male rats without
tissue lesions.
• Mice: The NOAEL is 1000 mg/kg-day and the LOAEL is 2000 mg/kg-day for transient signs of nervous system depression in
mice without tissue lesions.
Wolfe (1988a):
> Target organisms:
• 20 male and 20 female Sprague-Dawley rats
> Doses/Length of study:
• m-xylene (99% purity)
Administered by gavage in com oil
0,100,200, or 800 mg/kg-day
90 consecutive days
> The NOAEL and LOAEL are identified as 200 and 800 mg/kg-day, respectively, based on decreased body weight
Wolfe (1988b):
> Target organisms:
• 20 male and 20 female Sprague-Dawley rats
> Doses/Length of study:
• p-xylene (99% purity)
Administered by gavage in com oil
0,100,200, or 800 mg/kg-day
90 consecutive days
> The NOAEL and LOAEL are identified as 200 and 800 mg/kg-day, respectively, based on early mortality in male rats that showed signs
of test material aspiration into the lungs
Condie(1988):
> Target organisms:
• 10 male and 10 female Sprague-Dawley rats
> Doses/Length of study:
• Mixed xylenes (17.6% o-xylene, 62.3% m-xylene and p-xylene [which coeluted], 20% ethyl benzene)
Administered by gavage in com oil
• 90 consecutive days
0,150,750, or 1500 mg/kg-day
> The LOAEL is 750 mg/kg-day, based on increased kidney weights and early appearance of mild nephropathy in female rats, and the
NOAEL is 150 mg/kg-day.
25
-------
Route:
Study
Korsaketal. (1992)
6-month study
Korsaketal. (1994)
3-month study
Gralewicz et al.
(1995) 3-month
study
Gralewicz and
Wiaderna(2001)4-
week study
Inhalation
Organism
Rats
Rats
Rats
Rats
Doses
0 or 100 ppm for
6 months or
1000 ppm for 3
months
0, 50, or 100
ppm
0, 100, or 1000
ppm
0 or 100 ppm
Chemical
toluene, m-xylene, or a
1:1 mixture
m-xylene or n-butyl
alcohol or a 1 : 1 mixture
"pure" m-xylene (exact
purity not provided)
m-xylene
Results
NOAEL: not identified
LOAEL: 100 ppm
(based on decreased rotarod
performance and decreased
spontaneous motor activity)
NOAEL: 50 ppm
LOAEL: 100 ppm
(based on decreased rotarod
performance and decreased latency
in the paw-lick response in the hot-
plate test)
NOAEL: Not identified
LOAEL: 100 ppm
(based on deficits in radial maze
performance)
NOAEL: Not identified
LOAEL: 100 ppm
(based on neurobehavioral effects)
Korsaketal. (1992):
>• Target organisms:
12 male Wistar rats
>• Doses/Length of study:
• toluene, m-xylene, or a 1:1 mixture
• 6 hours per day, 5 days per week
• Concentration of 0 or 100 ppm for 6 months or 1000 ppm for 3 months
>• Results:
The LOAEL is 100 ppm, based on decreased rotarod performance and decreased spontaneous motor
activity. No NOAEL was identified.
Korsaketal. (1994):
>• Target organisms:
12 male Wistar rats
>• Doses/Length of study:
0,50, or 100 ppm
• m-xylene or n-butyl alcohol or a 1:1 mixture (purity of chemicals not provided)
• 6 hours per day, 5 days per week, for 3 months
>• Results:
The LOAEL is 100 ppm, based on decreased rotarod performance and decreased latency in the paw-lick
response in the hot-plate test, and the NOAEL is 50 ppm.
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Gralewicz et al. (1995):
>• Target organisms:
8-month-old, male LOD-Wistar rats
>• Doses/Length of study:
0, 100, or 1000 ppm
"pure" m-xylene (exact purity not provided)
• 6 hours per day, 5 days per week, for 3 months
>• Results:
• The lowest exposure level in this study, 100 ppm, is designated as a LOAEL for deficits in radial maze
performance.
Gralewicz and Wiaderna (2001):
>• Target organisms:
Male Wistar rats
>• Doses/Length of study:
• 0 or 100 ppm
• m-xylene
• 6 hours per day, 5 days per week for 4 weeks
>• Results:
• Identified 100 ppm as a LOAEL for neurobehavioral effects
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