United States 500ECAOCING006
Environmental Protection
Agency
EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR METHYL STYRENES
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It is being circulated for comments
on its technical accuracy and policy Implications.
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DISCLAIMER
This report Is a* -external draft for review purpose* only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation For use.
11
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PREFACE
ftealth and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSUER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RORA) as well as to provide health-related limits and -goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSyER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. A
carcinogenic potency factor, or q-|* (U.S. EPA, 1980), 1s provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required In the event of a release
as specified under the CERCLA. These two RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
IgnltabllHy, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined In U.S.
EPA, 1984 and 1986b, respectively.
111
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EXECUTIVE SUMMARY
The methyl slyrenes are colorless liquids that are soluble In many
organic solvents but are almost Insoluble In water (Hawley, 1981; Lewis et
al., 1983). Currently, methyl styrenes are manufactured by three companies
1n the United States, Estimated annual production of methyl styrene (Isomer
mixtures) 1s -30-50 million pounds/year {Hoff, 1983). The methyl styrenes
(the mixture and the para-lsomer) are commercially used as monomers In the
production of polymers and resins for paints, coatings, varnishes and
high-Impact polyesters (Lewis et al., 1983; Hoff, 1983).
Data regarding the environmental fate of the methyl styrenes (o-, m- and
p-1somers) were limited. Therefore, the predictions of their environmental
fate are based primarily on physical properties and chemical structure. In
the atmosphere, the methyl styrenes will exist almost entirely In the vapor
phase. The dominant fate mechanism In the atmosphere 1s the vapor phase
reaction with hydroxyl radicals and ozone, which has an estimated half-life
of only 2.4 hours 1n typical air (U.S. EPA, 1987). In water, volatiliza-
tion 1s expected to be a major fate process. The volatilization half-life
of methyl styrene from a river 1 m deep flowing at a speed of 1 m/sec with a
wind velocity of 3 m/sec 1s estimated to be 3.6 hours. Oxidation by
hydroxyl radicals and singlet oxygen In natural water may also contribute to
the removal of some methyl styrenes. Hydrolysis, adsorption to sediment and
bloconcentratlon are not expected to be Important. In soil, methyl styrenes
may be expected to leach moderately based on an estimated K of 370.
Evaporation from dry and moist soil 1s expected to be Important.
1v
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Only limited ambient monitoring data are available. The methyl styrenes
have been detected In engine exhaust (Fleming. 1970a,b), In wood smoke
(Kle1nd1enst et al., 1986). and In emissions froa polyethylene and poly-
styrene Incineration {Hawley-Fedder et al., • 1984a,b). The compounds have
also been detected In Indoor air, where certain building materials may be
the source {3arke et a!., 1981; Klselev et al.t 1983). Unspecified Isomers
of methyl styrene were tentatively Identified 1n Philadelphia drinking water
(Suffet et a!., 1980), 1n treated wastewater effluents from California
{Lucas. 1984) and In river water from Great Britain {Waggott, 1981).
Adequate monitoring data are not available to estimate the htiman exposure to
this compound from Inhalation of air and Ingestlon of drinking water and
food.
Pertinent data regarding toxldty of methyl styrenes to aquatic organ-
Isms could not be located In the available literature as cited 1n Appendix A.
Data regarding the extent or rate of absorption of o-, m- or p-methyl
styrene or a mixture of these Isomers were not located. Methyl styrene was
detected In the fat and brain of rats repeatedly exposed by Inhalation to a
mixture of 70% m- and 30% p-methyl styrene; concentrations In fat were much
higher than those 1n the brain and showed a slight tendency toward accumula-
tion by the end of the second week, but concentrations remained fairly
constant through 15 weeks (Savolalnen and PfaffU, 1981; Seppalalnen and
Savolalnen, 1982b). The metabolism of o-, m- and p-methyl styrene Involves
epoxldatlon of the vinyl side-chain, followed by conjugation with gluta-
thlone or hydratlon to dlols; the dlols form glucuronlde conjugates or,
after further oxidation, glyclne conjugates (Bergemalm-Rynell and Steen,
1982; Helnonen, 1984). No studies on the extent or rate of excretion of the
methyl styrenes following oral or Inhalation exposure were found. In 1ntra-
perltoneal studies using rats, 30-55% of the administered dose (40-500
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rag/kg) was excreted In the urine as metabolites, primarily In the first 24
hours after dosing (Bergemalm-Rynell and Steen. 1982; Helnonen, 1984). No
attempt was made to account for the remainder of the dose.
An Industrial mixture of methyl styrenes (70% m- and 30% p-) was nega-
tive for carcinogenlclty In ,103-week Inhalation studies using rats (MRI,
1984b) and mice (HRI, 1984a). Data were not available regarding the
cardnogenldty of methyl styrenes to animals by oral exposure or to humans
by any route of exposure. Mixtures of methyl styrenes (probably 60% m- and
40% p-) were negative for reverse mutations 1n assays with S. typhlinurluiB
and negative for sex-linked recessive lethal mutations In D. melanoqaster
(Norppa et al., 1981; Knaap et al., 1984). All Isomers of methyl styrene
gave positive results 1n the sister chromatld exchange test In human
lymphocytes (Norppa and Va1n1o, 1983a). The above described mixture was
positive 1n the SCE and chromatld aberration tests In human lymphocytes
(Norppa, 1981a; Norppa et al., 1981) and In the mlcronucleus test In mouse
erythrocytes (Norppa, 1981b).
IntraperHoneal administration of 250 mg/kg/day of an unspecified
mixture or Isomer to pregnant rats resulted In Increased resorptlon and a
decrease In the proportion of female fetuses, but yielded no teratogenlc
effects or maternal toxldty (Hardln et al., 1981). Krynskaya et al. (1969)
reported fetal loss 1n guinea pigs exposed by Inhalation to a mixture of
o- and p-1somers of >29 mg/m3, 4 hours/day for 4 months and reduced birth
weights In rats exposed to the same mixture at 50 mg/m3 (exposure protocol
not specified).
Subchronlc Inhalation studies have been performed with a mixture of
methyl styrene composed of 55-70% m- and 30-45% p-lsomers (Wolf et al.,
1956). Several species were exposed to 580, 1130 or 1350 ppm (2800, 5430 or
6520 mg/m3), 7-8 hours/day, 5 days/week for 92-100 exposures In 139 days.
v1
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No effects were observed 1n aionkeys at any level or 1n any species at 580
ppa. Adverse effects on the liver and kidney were reported at >1130 ppm 1n
rats, rabbits and guinea p160 ppm (290 mg/m3) of a mixture of 70% m- and 30%
p-lsomers 1n mice exposed 6 hours/day, 5 days/week for 90 days. Depressed
body weight gain and liver weights were also reported, but the exposure
level at which these effects occurred was not specified. Male rats exposed
to >160 ppm (773 mg/ra3) by the same protocol had reduced body weight gain
and kidney lesions (MRI, 1984b). Increased liver weights were also reported
but the exposure level at which it occurred was not.
In a series of Investigations of the potential neurotoxlclty of a
mixture of the same composition, Seppalalnen and Savolalnen (1982a,b) and
Seppalalnen (1985) reported Inactivity and altered cerebral enzyme activi-
ties at 50 ppm (242 mg/m3), and reversible alterations In nerve conduction
velocities and altered gel electrophoretlc patterns 1n proteins from spinal
cord axons at >100 ppm (483 mg/m3) In rats exposed 6 hours/day, 5 days/
week for up to 15 weeks. In a 21-week study using the same mixture with
rats, however, altered nerve conductions were reported at 332 ppm (1600
mg/m3), but not at 102 ppm (493 mg/m3), 6 hours/day, 5 days/week
(Gagnalre et a!., 1986).
Helnonen et al. (1982) Investigated the effects of 50, 100 or 300 ppm
(242, 483 or 1450 mg/m3) of the same mixture with exposures of 6 hours/
day, 5 days/week for up to 15 weeks on liver cell size, electron microscopic
appearance and drug metabolizing enzyme activity of the liver and kidney of
male rats. Decreased hepatocyte size and slightly altered ultrastructural
appearance were observed at 300 ppm. Some liver and kidney enzyme activi-
ties were significantly altered at 300 ppm.
vll
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Chronic Inhalation studies consist of the 103-week NTP sponsored studies
using mice and rats with a mixture of 70% m~ and 30% p-roethylstyrene. Mice
were exposed to 10 or 25 ppn (48.3 or 121 ag/ffl*). 6 hours/day, 5 days/week
for 103 weeks (MRI, 1384a). Reduced mean body weights and lesions of the
nasal passages were reported In both treated groups, but the lesions were
less severe In the low group. In rats exposed to 100 or 300 ppm by the same
schedule, depressed mean body weights and nasal lesions occurred (MRI,
1984b). Increased mortality was reported In nigh-dose females.
Data were not located regarding the oral toxldty of the Individual
methyl styrene 1 sowers ar their mixtures.
Data were not sufficient to estimate carcinogenic potencies for any of
the Isomers or for the Industrial mixture of methyl styrene. An RfD for
subchronlc and chronic Inhalation exposure to the Industrial mixture of 0.04
mg/m3 or 0.8 mg/day was based on a LOAEL 1n mice exposed to 10 ppm (48.3
mg/m3), 6 hours/day, 5 days/week for 103 weeks (MRI, 1984a). The same
data were used to derive an RfD of 0.006 mg/kg/day or 0.4 mg/day for
subchronlc and chronic oral exposure to the Industrial mixture. Data were
not sufficient to derive either Inhalation or oral RfDs for Individual
Isomers of methyl styrene. A toxldty-based RQ of 1000 for the Industrial
mixture was also based on the LOAEL 1n the 103-week mouse study. Data were
not sufficient to determine chronic toxlclty RQs for the Individual
Isomers. Cancer-based RQs were not derived.
The Industrial mixture was assigned to EPA Group D, since 2-year
Inhalation studies In mice and rats, while negative, did not fully meet the
EPA guideline criteria for a Group E we1ght-of-ev1dence. The Individual
Isomers of methyl styrene were also assigned to EPA Group D, nonclasslflable
as to human cardnogenlclty.
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TABLE OF CONTENTS
Page
1. INTRODUCTION. . 1
1.1. STRUCTURE AW) CAS REGISTRY NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 1
1.4. USE DATA . ., 5
1.5. SUMMARY 5
2. ENVIRONMENTAL FATE AND TRANSPORT 6
2.1. AIR 6
2.1.1. Reaction w1tti Hydroxyl Radicals 6
2.1.2. Photolysis 6
2.2. WATER 6
2.2.1. Hydrolysis 6
2.2.2. Photolysls-Photooxldatlon 7
2.2.3. Mlcroblal Degradation 7
2.2.4. Volatilization 7
2.2.5. Adsorption 8
2.2.6. B1oconcentrat1on 8
2.3. SOIL 8
2.3.1. Adsorption 8
2.3.2. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 10
3.3. INHALATION 10
3.4. DERMAL 11
3.5. SUMMARY 11
4. AQUATIC TOXICITY 12
5. PHARMACOKINETCS 13
5.1. ABSORPTION 13
5.2. DISTRIBUTION 13
5.3. METABOLISM 14
5.4. EXCRETION 17
5.5. SUMMARY 18
1x
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TABLE Of CONTENTS (cont.)
Page
6. EFFECTS , . 20
6.1. SYSTEMIC TOXICITY 20
6.1.1. Inhalation Exposures 20
6.1.2. Oral Exposures 28
6.1.3. Other Relevant Information 28
6-2- CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. Oral 30
6,2-3- Other Relevant Information. . . . , . 30
6.3. WUTAfiEtilCITY 30
6.4. TERATOGENICITY 31
6.5. OTHER REPRODUCTIVE EFFECTS 33
6.6. SUMMARY 33
7. EXISTING GUIDELINES AND STANDARDS 37
7.1. HUMAN 37
7.2. AQUATIC 37
8. RISK ASSESSMENT 38
8.1. CARCINOGENICITY 38
8.1.1. Inhalation 38
8.1.2. Oral 38
8.1.3. Other Routes 38
8.1.4. Weight of Evidence 38
8.1.5. Quantitative Risk Estimates 39
8.2. SYSTEMIC TOXICITY 39
8.2.1. Inhalation Exposure 39
8.2.2. Oral Exposure 42
9. REPORTABLE QUANTITIES 44
9.1. BASED ON SYSTEMIC TOXICITY 44
9.2. BASED ON CARCINOGENICITY 49
10. REFERENCES 51
APPENDIX A: LITERATURE SEARCHED 61
APPENDIX B: SUMMARY TABLE FOR INDUSTIRAL MIXTURE OF METHYL
STYRENES (70% m- and 30% p-lsomers) 64
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LIST OF TABLES
No. Title Page
1-1 Methyl Siyrene Synonyms, CAS Numbers and Structures 2
1-2 Physical Properties of the Methyl Styrenes 3
1-3 1977 Production Data for Methyl Styrenes 4
6-1 Mutagenldty Testing of Methyl Styrenes 32
9-1 Inhalation Tox1c1ty Summary for Methyl Styrene 45
9-2 Inhalation Composite Scores for Industrial Mixture
(70X m- and 30% p-) Methyl Styrene 48
9-3 Industrial Mixture of Methyl Styrenes (70% ra~ and
30% p-Isorners: Minimum Effective Dos* (M£0) and
Reportable Quantity (RQ) 50
x1
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The synonyms, CAS Registry numbers and structures of the methyl styrenes
are presented 1n Table 1-1. The empirical formula and molecular weight of
all the methyl styrenes are C H and 118.18, respectively. In this
document, methyl styrenes does not refer to a- or B-methyl styrene 1 sowers.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The methyl styrenes are colorless liquids (Hawley, 1981) that are
Infinitely soluble In acetone, carbon tetrachlorlde, benzene, dlethyl ether,
n-h«ptane ethanol (lewis et al., 1963). Selected physical properties of the
methyl styrenes are presented In Table 1-2.
Methyl styrene Is combustible and considered a moderate fire hazard
(Hawley, 1981).
1.3. PRODUCTION DATA
Production data for 1977 are presented In Table 1-3. U.S. EPA (1977)
reported no data for o-methyl styrene.
Currently, methyl styrene (mixed Isomers) Is manufactured by Dow
Chemical 1n Midland, MI (SRI, 1986). In 1985, 1n addition to Dow, BTL of
Illinois, Inc. manufactured mixed Isomers of methyl styrene (USITC, 1986).
p-Methyl styrene 1s manufactured by Mobil 011 Corp. In Baton Rouge, LA (SRI,
1985). Dow Chemical has produced methyl styrene (-33% para- and 67% meta-)
commercially since the late 1940s; Cosden 011 began producing a similar
mixture 1n the late 1970s (Lewis et al., 1983). Apparently, Cosden 011 no
longer manufactures this chemical. The estimated annual production of
methyl styrene (mixtures) 1s -30-50 million pounds/year (Hoff, 1083).
0032d -1- 06/12/87
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TABLE 1-1
Methyl Styrene Synonyms^ CAS Numbers and Structures
Synonym
CAS Number
Structure
o-Mettiyl styrene
1-E thenyl-2-methy1 benzene
(2-methylphenylJethylene
o-Tolylethylene
o-V1nyltoluene
2-Methylstyrene
2-Vlnyltoluene
l-Methyl~2-v1nyll)enzene
611-15-4
H=CH,
m-flethyl styrene
l-Ethenyl-3-methylbenzene
<3-methylphenyl)ethylene
m-Tolyletnylene
m-Vlnyltoluene
3-Methylstyrene
3-V1.nyl toluene
l-Methyl-3-v1nylbenzene
100-80-1
H=CH,
p-Methyl styrene
l-Ethenyl-4-methylbenzene
(4-methylphenylJethylene
p-Tolylethylene
p-V1nyltoluene
4-Methylstyrene
4-V1nyltoluene
1-Methyl-4-vlnylbenzene
622-97-9
= CH,
Methyl styrene
(mixed Isomers)
Ethenylmethylbenzene
ar-methylstyrene
Vinyl toluene (mixed Isomers)
25013-15-4
H=CH,
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05/22/87
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TABLE 1-3
1977 Production Data for Methyl Styrenes*
Producer
Production Range
(pounds)
Mixed Isomers:
Dow Chem. (Midland, MI)
Cosden 011 (B1g Spring, TX)
m-Methyl styrene:
DuPont (Wilmington, DE)
p-Methyl styrene:
Mobil Chem. (Edison, NJ)
confidential
0.1-1.0 million
confidential
NA
'Source: U.S. EPA, 1977
NA: Not available
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06/12/87
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The methyl styrenes are manufactured by alkylatlng toluene with ethylene
and dehydrogenating the resulting ethyUoluene to methyl siyr«n« (Hoff,
1983).
1.4. USE DATA
The methyl styrenes (the mixture and the para-1somer) are commercially
used as monomers Vn the production of polymers and resins for paints,
coatings, varnishes and high-Impact polyesters (Lewis et a!., 1983; Hoff,
1983).
1,5. SUMMARY
The methyl styrenes are colorless liquids that are soluble In many
organic solvents but are almost Insoluble In water (Hawley, 1981; Lewis et
al., 1983). Currently, methyl styrenes are manufactured by three companies
1n the United States. The estimated annual production of methyl styrene
(Isomer mixtures) 1s ~30-50 million pounds/year (Hoff, 1983). The methyl
styrenes (the mixture and the para-lsomer) are commercially used as monomers
1n the production of polymer* and resins for paints, coatings, varnishes and
high-Impact polyesters (Lewis et al., 1983; Hoff, 1983).
0032d -5- 06/12/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
Data regarding the environmental fate of the methyl styrenes {«-. w- and
p-1s.Df»ers) were limited. Therefore, predictions of their environmental fate
are based primarily on physical properties and chemical structure.
2.1. AIR
The vapor pressures of the methyl styrenes (see Table 1-2) Indicate that
they will exist almost entirely 1n the vapor phase In the atmosphere
(€1senre1ch et al.. 1981).
2.1.1. Reaction with Hydroxyl Radicals. The rate constants for the
vapor-phase reactions of methyl styrene (o-, m- or p-1somer) with photo-
chemlcally produced hydroxyl radicals and with ozone In the atmosphere at
25°C are estimated to be 9.0xlO~1:l and 1.3xlO~17 cm3/molecule-sec,
respectively (U.S. EPA, 1987). Given typical atmospheric hydroxyl radical
and ozone concentrations of 8xl05 and and SxlO11 molecules/cm3, a
combined atmospheric half-life of 2.4 hours 1s estimated (U.S. EPA, 1987).
These reactions will therefore be the dominant environmental fate mechanisms
1n air.
2.1.2. Photolysis. m-Methyl styrene and p-methyl styrene absorb light of
wavelengths >290 nm (Sadtler, 1960, 1965); therefore, direct photolysis 1s
possible. Although kinetic rate data were not available, 1t 1s unlikely
that photolysis will be competitive with hydroxyl radical/ozone reactions In
air.
2.2. WATER
2.2.1. Hydrolysis. Since methyl styrene does not contain functional
groups that are significantly susceptible to hydrolysis, environmental
hydrolysis Is not expected to occur.
0032d -6- 05/22/87
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Mil. Phetelyill-Photooxtdatlon, m-Methyl styrene and p-methyl styrene
absorb light of wavelengths >290 nra In a methane! solution (Sadtler, 1360,
1965); therefore, direct photolysis In water may be possible. Kinetic data
were not found for estlmatlmg the half-life of the compound In natural
waters because of direct photolysis.
The general olefln structure 1s susceptible to reaction with photo-
oxldant species, such as hydroxyl radicals or singlet oxygen, In sunlit
natural water (Mill and Habey, 1985). The general olefln class has a
half-life of -13-14 days for the reaction with hydroxyl radicals and 8 days
for the reaction with singlet oxygen (Mill and Mabey, 1985). Therefore, the
vinyl group of the methyl styrenes may be susceptible to oxldatlve reactions
1n sunlit natural waters.
2.2.3. M1crob1al Degradation. Pertinent data regarding mlcroblal
degradation of the methyl styrenes could not be located In the available
literature as cited 1n Appendix A.
2.2.4. Volatilization. Based on * water solubility of 89 ppm and a vapor
pressure of 1.13 mm Hg at 20-25°C (see Table 1-2), the Henry's Law constant
for methyl styrene Is ~2.0xlO~3 atm-m3/mol. This value of Henry's Law
constant Indicates that volatilization from water may be rapid. Using the
method outlined 1n Lyman et al. (1982), the volatilization half-life of
methyl styrene from a river 1 m deep flowing at a speed of 1 m/sec with a
wind velocity of 3 m/sec Is estimated to be -3.6 hours. The volatilization
rate from deeper bodies of water or less rapidly moving bodies of water will
be slower; however, the estimated half-life Indicates that volatilization
will be a major fate process 1n water.
0032d -7- 06/12/87
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2.2.5. Adsorption. Given the estimated K for methyl styrene of 370
(Section 2.3.1.), moderate adsorption of this compound 1s expected; however,
H Is unlikely that the adsorption process can compete with the rapid
volatilisation process.
2.2.6. B1oconcentrat1on. Ogata et al. (1984) measured BCF values of 31.6
and 35.5 for p- and m-methylstyrene, respectively, 1n goldfish.
The BCF of an organic chemical can be estimated from the following
regression equation (Lyman et al., 1982):
log BCF » 2.791 - 0.564 log WS (1n ppm) (2-1)
for methyl styrene, the BCF calculated from Equations 2-1 1? -49 based on a
water solubility of 89 ppm. This compares favorably with the measured BCF
values above. These BCF values Indicate that the methyl styrenes are not
expected to bloconcentrate significantly In aquatic organisms.
2.3. SOIL
2.3.1. Adsorption. The K of an organic chemical can be estimated
from the following regression equation (Lyman et al., 1982):
log KQC = 3.64 - 0.55 log WS (In ppm) (2-2)
For methyl styrene, the K value calculated from Equation 2-2 Is 370
based on a water solubility of 89 ppm. This K value Indicates a medium
degree of soil mobility (Swann et al., 1983). Therefore, methyl styrene can
be expected to leach moderately 1n soil and may eventually reach groundwater
1n the absence of reasonable blotransformatlon.
2.3.2. Volatilization. Given the vapor pressures of the methyl styrenes
(see Table 1-2) evaporation from dry surfaces Is expected to be Important.
In addition, evaporation from moist soils may also be Important since methyl
styrene volatilizes rapidly from water.
0032d -8- 05/22/87
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2.4. SUMMARY
Data regarding the environmental fate of the methyl styrenes ^o~, tt» and
p-lsomers) were limited. Therefore, the predictions of their environmental
fate are based primarily on physical properties and chemical structure. In
the atmosphere, the methyl styrenes will exist almost entirely 1n the vapor
phase. The dominant fate mechanism 1n the atmosphere 1s the vapor phase
reaction with hydroxyl radicals and ozone, which has an estimated half-life
of only 2.4 hours 1n typical air (U.S. EPA, 1987). In water, volatilization
Is expected to be a major fate process. The volatilization half-life of
methyl styrene from a river 1 m deep flowing at a speed of 1 m/sec with a
wind velocity of 3 m/sec Is estimated to be 3.6 hours. Oxidation by
hydroxyl radicals and singlet oxygen 1n natural water may also contribute to
the removal of some methyl styrenes. Hydrolysis, adsorption to sediment and
bloconcentratlon are not expected to be Important. In soil, methyl styrenes
may be expected to leach moderately based on an estimated K of 370.
Evaporation from dry and moist soil 1s expected to be Important.
0032d -9- 06/12/87
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3. EXPOSURE
o-ftethy] styrene Mas detected In tne essential oil of Mississippi salt
marsh plants (Wody et.al., 1975), but it 1s not clear whether the compound
occurs naturally 1n the plants or 1s an environmental contaminant.
3.1. WATER
Unspecified Isoraers of methyl styrene were tentatively Identified 1n
drinking water collected 1n Philadelphia, PA, between 1975 and 1977 (Suffet
et al., 1980). Kool et al. (1982) detected methyl styrene (mixed Isomers)
1n drilling *ater, but the location of the sample(s) and the concentration
were not reported. o-Methyl styrene was tentatively Identified 1n treated
wastewater effluents collected from Lake Tahoe, CA, and Pomona, CA, 1n 1974
and 1975 (Lucas, 1984). Unspecified methyl styrene Isomers were also tenta-
tively Identified 1n water collected from the Lee River 1n Great Britain
(Waggott, 1981).
Industrial effluents from commercial production and use facilities may
be the major sources of release of the methyl styrenes to water. Kappeler
and Wuhrmann (1978) detected o-methylstyrene as a microblal metabolite of
o-ethyltoluene.
3.2. FOOD
Pertinent food monitoring data could not be located 1n the available
literature as cited In Appendix A.
3.3. INHALATION
The methyl styrenes have been detected 1n exhaust emissions from spark-
Ignition engines (Fleming, 1970a,b) and 1n wood smoke (Kle1nd1enst et al.,
1986). They have also been detected 1n emissions from the Incineration of
polyethylene and polystyrene polymers (Hawley-Fedder et al., 1984a,b).
0032d -10- 05/22/87
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o-Methyl styrene was Identified 1n Indoor air of homes 1n Washington, DC
ami Chicago, II (Jarke et al., 1981J; the specific source of the compound
was not determined. Kiselev et al. {1983} Identified o-methyl styrene In
the volatile emissions from polychloroprene-based mastic building materials.
3.4. DERMAL
Pertinent dermal monitoring data could not be located In the available
literature as cited In Appendix A.
3.5. SUMMARY
Only Halted ambient wonltorlng data are available. The methyl styrenes
have been detected 1n engine exhaust {Fleming, 1970a,b), In wood smoke
(Kle1nd1enst et al., 1986), and In emissions from polyethylene and poly-
styrene Incineration (Hawley-Fedder et al., 1984a,b). The compounds have
also been detected 1n Indoor air, where certain building materials may be
the source (Jarke et al., 1981; Klselev et al., 1983). Unspecified Isomers
of methyl styrene were tentatively Identified 1n Philadelphia drinking water
(Suffet et al., 1980), In treated wastewater effluents from California
(Lucas, 1984) and 1n river water from Great Britain (Waggott, 1981).
Adequate monitoring data are not available to estimate the human exposure to
this compound from Inhalation of air and Ingestlon of drinking water and
food.
0032d -11- OS/22/81
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4. AQUATIC TOXICITY
Perilneni data regarding toxIcUy of methyl styrenes to aquatic
organisms could not be 'located 1n the available literature as cited In
Appendix A.
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5. PHARMACOKINETICS
5.1. ABSORPTION
Perttneni data regarding the extent and rate of absorption of o-, »- or
p-methyl styrene or a mixture of these Isomers could not be located In the
available literature as cited In Appendix A.
5.2. DISTRIBUTION
Savolalnen and PfaffH (1981) studied brain and perlrenal fat concentra-
tions of methyl styrene In male Wlstar rats exposed to 0, 50, 100 or 300 ppm
(0, 242, 483 or 1450 mg/ra3} of "vinyltoluene" Iprobably a mixture of 70%
m~ and 30% p-methyl styrene (Seppalalnen and Savolalnen, 1982a)] by Inhala-
tion 6 hours/day, 5 days/week for 1 or 2 weeks, and killed Immediately after
the last exposure. Concentrations of methyl styrene 1n both tissues were
directly proportional to exposure level, but were much higher 1n the fat
than 1n the brain. The concentrations 1n the fat, but not the brain, were
higher after the second week than after the first week of exposure.
In an experiment on the potential neurotoxldty of methyl styrene
(Section 6.1.1.), Seppalalnen and Savolalnen (1982a,b) exposed male Wlstar
rats to 0, 50, 100 or 300 ppm (0, 242, 483 or 1450 mg/m3) of methyl
styrene (mixture of 70% m- and 30% p-methyl styrene) by Inhalation for 6
hours/day, 5 days/week. At the end of 4, 8, 12 or 15 weeks of exposure,
five rats/group were killed and samples of perlrenal fat were analyzed for
methyl styrene content (Seppalalnen and Savolalnen, 1982b). The concentra-
tions of methyl styrene In the perlrenal fat were slightly lower than In the
experiment by Savolalnen and PfaffH (1981); these concentrations were
proportional to exposure level and remained fairly constant throughout the
experiment.
0032d -13- 06/12/87
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5.3. METABOLISM
Bergemalm-Rynell and Steen (1982) and ttelntmen 11984) Investigated ttie
metabolism of methyl styrwne Isomers by analyzing urinary metabolites fol-
lowing Intraperltoneal administration of the compounds to rats. Bergemalm-
Rynell and Steen (1982) administered single doses of 10-40 mg of o-, m- or
p-methyl styrene to 200-300 g male Wlstar rats (40-160 mg/kg for a 250 g
rat) and collected urine for up to 96 hours thereafter; Helnonen (1984)
administered single doses (1.p. Injection) of 50-500 mg/kg of p-roetnyl
styrene to 350-400 g male Wlstar rats and collected the urine for 23 hours
thereafter. At the dose of 50 mg/kg, 55% of the dose was detected as
urinary metabolites within 23 hours, mainly within the first 6 hours. The
amounts of the excreted metabolites expressed as percent of the Injected
dose (250 or 500 mg/kg) were lower than at the dose of 50 mg/kg and
noticeable amounts were excreted within 11-23 hours suggesting that the
excretion was still continued with the doses of 250 and 500 mg/kg 23 hours
after the Injection. Urinary metabolites were Identified using gas
chromatography with mass spectrometry. Since the metabolic schemes proposed
by the authors of these studies are similar, they have been combined Into
the single scheme shown In Figure 5-1. Metabolism of the o-, m- and
p-1somers appeared to be similar, except that the metabolites
hydroxymethylphenylethylene glycol and hydroxymethylphenylglyoxyllc acid
were found only after administration of m-methyl styrene. The primary
metabolic pathway for all three Isomers appeared to Involve the epoxldatlon
of the vinyl side-chain to form v1nyltoluene-7,8-ox1de, which was conjugated
with glutathlone and excreted as thloethers, or hydrated to dlols, followed
by glucuronlde conjugation or further oxidation and glydne conjugation.
0032d -14- 08/21/87
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CHgCNHCHjCOOH
CH=CH,
••
n
C-COOH
• «thylph»nylglyo«y1 1C «Cld
(11.97 for p->
HOCH,
II
C-COOH
(for •- on 1 y >
COOH
(9.31 for p-)
Metabolism of o-, m- and p-Methyl Styrene
.Hm^n^r1!-^ c°mpounds were Uentlfled in urine after intraperi toneal
!|L£^^
on p-n
4098H
15
9/01/87
-------
Additional evidence for the metabolism of methyl styrenes to epoxldes
that conjugate with glutathlone 1s presented in studies of depletion of
hepatic gluiatlilone levels and enhancement of urinary thloether excretion
following administration of methyl styrene (mixture) to rats and mice.
Exposure of rats to 0, 50, 100 or 300 ppm (0, 242, 483 or 1450 mg/m3) of
methyl styrene (60% m- and 40% p-), 6 hours/day for 1 or 2 weeks decreased
the concentrations of nonproteln thlols In the liver In a dose-related
manner 1n rats billed 0.5 hours after the last exposure (Helnonen and
Va1n1o. 1981). Slnllar results were obtained In rats 1n another experiment
using the same exposure concentrations, but exposed for 6 hours/day, 5
days/week for 8, 12 and 15 weeks (Helnonen et a!., 1982). In addition, the
urinary excretion of thloethers, measured In urine collected for one night/
week (Thursday-Friday) during exposure weeks 6-10 and 12, was Increased In a
dose-related manner, and showed no evidence of saturation (Helnonen and
Valnlo, 1981). Single 1ntraper1toneal Injections of 100 or 500 mg/kg of
methyl styrene (mixture) 1n corn oil Into rats and mice produced dose-
related decreases 1n hepatic nonproteln thlol concentrations, which were
more marked In mice than In rats; some of the mice that received the higher
dose died (Helnonen and Valnlo, 1980). Single Intraperltoneal Injections of
50, 250, 500 or 1000 mg/kg In olive oil In rats decreased hepatic
glutathlone concentrations and Increased urinary thloether concentrations
(measured at 12 hours after Injection) In a dose-related manner, but with
evidence of saturation at >250 mg/kg (Helnonen, 1984).
Additional evidence for the metabolism of methyl styrenes to epoxldes
followed by hydratlon to dlols was obtained by Hanzllk et al. (1978) In Ui
vitro studies with mlcrosomal preparations from the livers of noninduced
male Holtzman rats. Incubation of p-methyl (8-3H)styrene with the micro-
somes and a NADPH generating system under oxygen for 30 minutes, followed by
0032d -16- 08/21/87
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ether extraction, yielded significant radioactivity only In the dlol band
and the olefin (parent compound} band of thin-layer chromatograras.
p-Methyl styrene and the mixture {60% tn-, 40% p-) gave a type I -differ-
ence binding spectrum with mlcrosomes 1n the studies by Hanzlik et al.
(1978) and Helnonen and Valnlo (1980), which the Investigators state Is
Indicative of substrate-type binding to cytochrome P-450. Pretreatraent with
an Inhibitor of cytochrome P-450, 1-phenyllmldazole,, greatly decreased the
urinary excretion of thloethers and p-methylmandel1c add, p-methylglyoxyllc
acid, p-methylphenylbenzoyl glyclne and p-methylphenylacetyl glyclne 1n rats
given a single intrapernoneal Injection of 500 rag/kg of p-acthyl styrene
(Helnonen, 1984).
5.4. EXCRETION
No quantitative studies of the excretion of the methyl styrenes and
metabolites following oral or Inhalation exposure were found. The urinary
excretion of thloethers Increased 1n a dose-related manner In male Wlstar
rats exposed to 0, 50, 100 and 300 ppm (0, 242, 483 and 1450 mg/m3) of
methyl styrene (60% m-, 40% p-) by Inhalation for 6 hours/day, 5 days/week
(Helnonen et al., 1982). Urine was collected for 1 night/week (Thursday-
Friday) during exposure weeks 6-10 and 12; results were reported as mol
thloethers/mol creatlne with no Indication of total thloether excretion or
time course of excretion.
Following the Intraperltoneal administration of 10-40 mg of o-, m- or
p-methyl styrene to 200-300 g male Wlstar rats (40-160 mg/kg for a 250 g
rat), Bergemalm-Rynell and Steen (1982) found that for the m- and p-1somers,
94-98% of the total recovered metabolites were excreted within the first 24
hours, and for the o-lsomer, 90% of the total recovered metabolites were
excreted within the first 24 hours of the 96-hour collection period. The
0032d -17- 08/21/87
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total amount (mg) of urinary metabolites excreted was directly proportional
to the dose and accounted for 30-40X of the dose. No attempt was made to
account for the retraining W-70% of ttie dose.
Following Intraperltoneal administration of single doses of 50-500 mg/kg
In olive oil to male Wlstar rats, Helnonen (1984) found that excretion of
metabolites In the urine occurred primarily within the first 6 hours at 50
and 250 mg/kg, but was not complete within 23 hours at 500 mg/kg. Total
urinary metabolites accounted for 55% of the dose at 50 mg/kg, 50% of the
dose at 250 mg/kg and 40% of the dose at 500 mg/kg. The decrease In the
percent of dose excreted as urinary metabolites was dye mainly to a decrease
In the percent of dose excreted as thloethers, which Indicated saturation of
the pathway Involving glutathlone conjugation and was 1n agreement with
ottrer evidence presented 1n Section 5.3.
5.5. SUMMARY
Data regarding the extent or rate of absorption of o-, m- or p-methyl
styrene or a mixture of these Isomers were not located. Methyl styrene was
detected In the fat and brain of rats repeatedly exposed by Inhalation to a
mixture of 70% m- and 30% p-methyl styrene; concentrations In fat were much
higher than those In the brain and showed a slight tendency toward accumula-
tion by the end of the second week, but concentrations remained fairly
constant through 15 weeks (Savolalnen and PfaffH, 1981; Seppalalnen and
Savolalnen, 1982b). The metabolism of o-, m- and p-methyl styrene Involves
epoxldatlon of the vinyl side-chain, followed by conjugation with gluta-
thlone or hydratlon to dlols; the dlols form glucuronlde conjugates or,
after further oxidation, glydne conjugates (Bergemalm-Rynell and Steen,
1982; Helnonen, 1984). No studies of the extent or rate of excretion of the
methyl styrenes following oral or Inhalation exposure were found. In Intra-
perltoneal studies using rats, 30-55% of the administered dose (40-500
0032d -18- 08/21/87
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mg/kg) was excreted 1n the urine as metabolites, primarily In the first 24
hours after dosing (Bergemalw-Rynell and Steen, 1982; HelT»on«i, 1984). No
attempt was made to account for the remainder of the dose.
0032d -19- 08/21/87
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6. EFFECTS
6.1. SYSTfMIC TOXICITY
6.1.1. Inhalation Exposures.
'6.1.1*1. SU8CHROHIC --As part of ^a study cm alkylated benzenes and
benzene, Wolf et al. (1956) studied the Inhalation toxlclty of methyl
styrene to four species of laboratory animals. The chemical was >98% pure,
and was composed of 55-70% m- and 30-45% p-roethyl styrene. Groups of 10-25
male and female Wlstar rats, 5-10 male and female albino guinea pigs, 1 male
and 1 female albino rabbit, and 1-2 female monkeys were exposed to 0, 580,
1130 or 1350 ppm (0, 2800, 5430 or 6520 iaq/m») meUiy3. styrene, 7-8
hours/day, 5 days/week, for a total of 92-100 exposures In 139 days.
Concentrations In mg/m3 were derived from the mg/i values provided by
the authors. Controls were air-exposed or unexposed (the authors did not
specify which type was used for methyl styrene). General appearance and
behavior, growth, food consumption, mortality, hematologlcal parameters,
bone marrow counts and terminal blood urea nitrogen concentrations were
observed. In addition, the Hver, kidneys, lungs, heart, spleen and testes
were weighed and subjected to gross and hlstopathologlc examination.
Portions of the adrenal, pancreas and femoral bone marrow were also taken
for hlstopathologlc examination. Monkeys had no effects at the exposure
levels tested. At 580 ppm, no effects were seen In any of the other three
species tested. At 1130 ppm, rats had a moderate depression of body weight
gain, an equivocal effect on liver weight and slight fatty degeneration In
the liver; guinea pigs had a slight depression of body weight gain, an
equivocal effect on liver and kidney weights, and slight fatty degeneration
1n the liver; rabbits had equivocal effects on kidney weight and slight
fatty degeneration In the liver. At 1350 ppm, mortality was moderate 1n
rats, depression of body weight gain was moderate, effects on liver weight
0032d -20- 08/21/87
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was moderate and rats experienced slight fatty degeneration 1n the liver;
guinea pigs had a slight depression of body weight gain, equivocal effects
on liver and kidney weights, and fatty degeneration 1n the liver; rabbits
had an equivocal effect on kidney weight and slight fatty degeneration In
the liver. Whether the effects on organ weights were Increases or decreases
was not specified, and cause of death 1n the rats exposed to 1350 ppm was
not discussed.
Preliminary reports of a chronic Inhalation toxlclty and cardnogenlclty
study of methyl styrene (70% m-, 30% p-) using rats and mice, which were
performed for the NTP by MRI 0984a,t>), Included brief summaries of the
results of the subchronlc tests. Groups of 10 male and 10 female B6C3F1
mice were exposed to 0, 10, 25, 60 or 160 ppm (0, 48.3, 121, 290 or 773
mg/ma) of methyl styrene, 6 hours/day, 5 days/week for 90 days (MRI,
1984a). Mortality occurred among the male mice exposed to >60 ppm. Mean
liver weights and body weight gains were depressed 1n both sexes of mice
(exposure levels not specified). Treatment-related lesions (not further
described) were observed In the lungs and nasal turblnates of males and
females at 60 and 160 ppm.
Groups of 10 male and 10 female F344/N rats were exposed to 0, 25, 60,
160, 400 or 1000 ppm (0, 121, 290, 773, 1930 or 4830 mg/m3), 6 hours/day,
5 days/week for 90 days (MRI, 1984b). None of the rats died. Body weight
gains were depressed 1n both sexes of rats at >160 ppm. Mean absolute and
relative liver weights were Increased (sex and exposure levels not
specified). M1ld glomerulonephropathy was observed In male rats exposed to
>160 ppm.
Seppalalnen and Savolainen (1982a,b) and Seppalalnen (1985) Investigated
the potential neurotoxlclty of Inhaled methyl styrene (70% m- and 30%
p-methyl styrene) to rats by measuring the MCV of the tall nerve, enzyme
0032d -21- 08/21/87
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activity of cerebral homogenates, and electrophoretlc profiles of proteins
from spinal axons. Groups of 20 male Wlstar rats with average body weights
of 330 g (age 3 months) were exposed to 0, 50, 100 or 300 pen (0, 242, 463
or T450 imj/m*) of methyl slyrene, B hoars/day, 5 days/week for up to 15
weeks (Seppalalnen and Savolalnen, 1982a,b). The rats were maintained on a
reversed light/dark schedule; the rats were exposed during the dark cycle.
Control rats were sham-exposed. MCVs were measured In the same 10 rats/
group at 4, 8 and 12 weeks of exposure and 1n the remaining same 5 rats/
group at 15 weeks of exposure. The MCV of the tall nerve was measured by
stimulating the nerve at the base of the tall and recording the evoked
action potential from the Ipsllateral tan muscle. This procedure measures
the average latency through the axon, neuromuscular junction and muscle
fibers (Fox et a!., 1982). Five rats/group were killed at 4, 8 and 15 weeks
of exposure for analysis of brain and spinal cord.
Although rats are nocturnal and would normally be active during the dark
cycle, the rats exposed to methyl styrene were "quite Inactive" during
exposure. The activity level of controls was not mentioned by the authors.
Body weight of the 300 ppm group was slightly depressed relative to the
control group (p<0.05). At 0-8 weeks of exposure, the MCVs of all groups
were similar. The MCVs of the 50 ppm group remained similar to those of
controls throughout the experiment. At 12 weeks of exposure, the MCVs of
the 100 and 300 ppm groups were slightly, but significantly, decreased
relative to controls (p<0.01 at 100 ppm and p<0.001 at 300 ppm). At 15
weeks, a slight further decrease was noted 1n the 100 ppm group, while the
300 ppm group remained at the same level of depression as at 12 weeks. In
addition, the amplitude of the evoked muscle action potential of the rats
exposed to 100 or 300 ppm was -50% of that of controls or rats exposed to
50 ppm.
0032d -22- 08/21/87
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Cerebral lysosomal add protelnase activity was Increased In the 100
pp» group at 15 weeks and In the 300 pptn group at 8 and 15 weeks; mitochon-
dria! sucdnate o>hydrogenase yas significantly lower Its all treated groups
than In controls at-all times studied. PolyacryTamlde geT electrophoresls
of proteins from spinal cord axons of rats at the end of 15 weeks revealed
two small protein fractions In the samples from ttie 100 and 300 ppm groups
that were not seen 1n samples from controls or the 50 ppm group.
A similar depression of MCVs was obtained In a second series of five
rats/group, started on the same exposure levels after the first series had
been on the test for 4 weeks, and studied at 0, 4, 8 and 11 weeks of
exposure and at 4 weeks after cessation of 11 weeks of exposure (Seppalalnen
and Savolalnen, 1982b). MCVs were depressed relative to control values at
11 weeks of exposure In the 100 and 300 ppm groups (p<0.01), but not the 50
ppm group. No significant differences In MCVs were seen among groups after
the 4-week recovery period.
Gagnalre et al. (1986) assessed the potential neurotoxldty of Inhaled
methyl styrene (70% m- and 30% p-) to rats through MCV and SCV measurements
of tall nerves and hlstopathologlcal examination of the sciatic nerves.
Groups of 10 male Sprague-Dawley rats (6 weeks old) were exposed to 0 (sham
exposure), 102 or 332 ppm (0, 493 or 1600 mg/m3) of methyl styrene, 6
hours/day, 5 days/week for 21 weeks. Positive controls consisted of addi-
tional groups of rats treated by gavage with 2,5-hexaned1one at 200 or 400
mg/kg/day, 5 days/week; this treatment 1s known to produce peripheral neuro-
pathy. Nerve conduction velocities were measured every 1-2 weeks during the
experiment. MCVs were calculated by relating the distance between two
different stimulating sites to the difference In the arrival times of the
resulting action potentials In the muscle, which according to the authors
0032d -23- 08/21/87
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allows measurement of MCV Independently of latency In the myoneural junc-
tion. SCVs were calculated by a similar method, using a single stimulus
site and two different recording sites.
No signs of neurotoxlclty or other systemic toxlclty were observed In
the methyl styrene-exposed rats, other than a slight depression of body
weight gain 1n the 332 ppm group as compared with controls; this depression
was not statistically significant. Significant decreases In MCV and SCVs,
relative to controls, occurred at weeks 15, 20 and 21 1n the 332 ppm group,
but not in the 102 ppm group. No histopathologlcal changes were seen 1n the
sciatic nerves of the methyl styrene-treated rats. In comparison, the
2,5-hexaned1one-treated rats developed dose-related weakness In the hind
limbs, culminating In paralysis for the high-dose group, and statistically
significant, dose-related decreases 1n MCVs and SCVs, relative to controls,
starting at week 2 In the high-dose and week 4 In the low-dose group, and
becoming more pronounced with Increasing duration of treatment. Histopatho-
loglcal examination revealed structural damage to the sciatic nerve axons In
rats of both 2,5-hexanedlone-treated groups.
In a study primarily designed to provide evidence regarding the metabo-
lism of methyl styrene, Helnonen et al. (1982) Investigated the effects of
subchronlc Inhalation exposure to methyl styrene (60% m- and 40% p-) on
hepatic cell size, electron microscopic appearance and drug metabolizing
enzymes In rats. Groups of -20 male Wlstar rats (330 g bw) were exposed to
0, 50, 100 or 300 ppm (0, 242, 483 or 1450 mg/m3) methyl styrene, 6
hours/day, 5 days/week for up to 15 weeks. The rats were maintained on a
reversed light/dark schedule; exposures were conducted during the dark
cycle. Controls were sham-exposed. Monitoring for potential body weight
0032d -24- 08/21/87
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effects or signs of toxldty was not mentioned. The livers of two rats/
group/exposure duration were examined for hepatocyte s\ze and electron
microscopic appearance and livers and kidneys of five rats/group/exposure
duration were used for determination of drug metabolizing enzymes. Liver
and kidney weights were not reported. Slight but significant decreases In
hepatocyte size occurred in the 300 ppm group at 8 weeks (p100 ppm. Renal 7-ethoxycoumar1n 0-deethylase activity Increased signifi-
cantly In a dose- and duration-related manner. Renal UDP glururonosyltrans-
ferase activity was significantly Increased at >100 ppm at most of the
exposure durations, but the Increases were not dose-related.
In a study from the Russian literature, Krynskaya et al. (1969) reported
the Inhalation toxlclty of a different mixture of methyl styrene (72% p- and
28% o-) to rats and mice In a 1-month experiment and to rats, mice and
guinea pigs In a 4-month experiment. The Investigators did not report
pertinent details such as number, sex and strain of experimental animals,
exposure schedule (4-month experiment), toxlcologlcal endpolnts evaluated In
each species, or the nature and severity of effects observed at each
exposure level In a manner that would permit evaluation of their results.
0032d -25- 08/21/87
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Krynskaya et al. (1969) exposed rats and mice by Inhalation to 100-150 or
550 mg/ma of methyl styrene 4 hours/day, 6 days/week for 1 month. In
comparisons of treated and control animals, no significant differences were
observed 1n body weight, relative organ weights, clinical analyses of blood
and urine from the rats, duration of floating of mice, and the time of
summation of subthreshold pulses 1n rats. The only "morphological change"
seen In either species was productive Inflammation with papillary growths In
the wall of the trachea of rats exposed to 550 mg/ma. Some differences In
the establishment of conditioned reflexes were seen In treated animals at
both exposure levels compared with controls. In tne experiment of longer
duration, rats, mice and guinea pigs were exposed to 29 or 300 mg/m3 of
methyl styrene, 4 hours/day (days/week not specified) for 4 months. In
rats, there were no significant differences between treated and control
groups In body weights, relative organ weights, amount of fat 1n the liver,
"morphological changes" of the Internal organs hematologlca'l parameters,
serum choHnesterase activity and the duration of hexenal sleep. In mice,
body weight gain was depressed, relative to controls, at both exposure
levels. Some of the treated mice had focal pneumonia with leukocytlc
exudate; none of the control mice had this condition. Some differences 1n
the establishment of conditioned reflexes were seen In both groups of
treated mice, as compared with controls. Treated mice did not differ from
control mice In relative organ weights, amount of fat 1n the liver or
duration of floating. The only results mentioned for guinea pigs were that
premature, dead or nonvlable fetuses were born to most of the treated guinea
pigs.
6.1.1.2. CHRONIC — Pertinent data regarding the chronic toxldty of
Inhalation exposure to the Individual o-, m- or p-lsomers of methyl styrene
could not be located In the available literature as cited In Appendix A.
0032d -26- 08/21/87
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The NTP (1987) sponsored a study of the toxicology and carclnogenldty of
methyl styrene (mixture; listed as vinyl toluene) administered by Inhalation
to rats and mice; prellalnary reports and evaluation of these data are
available (WRI, 1984a,b). The chemical tested was an Industrial mixture
consisting of 70% m- and 30% p-methyl styrene. In the chronic study using
nice, groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 10, or
25 ppm (0, 48.3, or 121 mg/m3) of methyl styrene for 6 hours/day, 5
days/week for 103 weeks (MRI, 1984a). Survival was not affected adversely;
survival of the high-dose mice was better than that of controls. The only
treatment-related clinical signs of toxicHy were detention of the urinary
bladder 1n 7/48 high-dose mice and enlargement of the preputlal gland In
11/47 high-dose and 1/48 low-dose male mice. These signs did not occur In
controls. Mean body weights were significantly depressed 1n both sexes of
mice at both exposure levels 1n a dose-related manner throughout the study.
Comprehensive hlstopathologlcal examinations were performed on control and
high-dose mice. Only the nasal tissues and lungs of low-dose mice were
examined h1stopatholog1cally. Lesions of the nasal passages were seen In
all but one of the high-dose mice of both sexes. The only high-dose mouse
that did not have these lesions died the first week of exposure. The nasal
lesions consisted of chronic active Inflammation of the mucosa and
hyperplasla of the respiratory epithelium. These nasal lesions also
occurred 1n the low-dose mice, but were less severe; Incidences were not
reported. Lung lesions were observed in most of the low- and high-dose mice
of both sexes. These lesions primarily consisted of multlfocal chronic
active Inflammation with hyperplasla of the bronchioles and alveoli.
Incidences and severities were reported only for the high-dose mice. No
other treatment-related lesions were observed.
0032d -27- 08/21/87
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In the chronic study using rats, groups of 50 male and 50 female F344/N
rats were exposed to 0, 100 or 300 ppm (0, 483 or 1450 mo/a3) of methyl
styrene 6 hours/day, 5 days/week for 103 weeks {HRI, 1984b). Survival was
unaffected 1n male rats. A sllgtit deer-ease In survival occurred 1n the
high-dose female group toward the end of the study. No treatment-related
clinical signs of toxldty were observed 1n any group. Mean body weights
were depressed In all treated groups relative to controls. Comprehensive
histopathologlcal examinations were performed on rats 1n the control and
high-dose groups. Only the nasal tissues and lungs of low-dose rats were
examined histopathologlcally. The only treatment-related lesions found In
the rats were minimal to mild Inflammation of the nasal mucosa with an
Increase In mucosal glands. No lesions were seen 1n the lungs.
6.1.2. Oral Exposures. Pertinent data regarding the subchronlc or
chronic toxldty of oral exposure to o-, m- or p-methyl styrene or to a
mixture of these Isomers could not be located In the available literature as
cited In Appendix A.
6.1.3. Other Relevant Information. Wolf et al. (1956) Investigated the
acute toxldty, 1rr1tancy and odor properties of a methyl styrene mixture
(55-70% m-, 30-45% p-). The approximate oral LD5Q was 4.0 g/kg for rats.
Necropsy showed slight, unspecified liver changes; 1t 1s unclear whether
these changes were seen 1n rats that died or 1n survivors. Repeated
application of an unspecified amount to the shaved skin of rabbits produced
blistering, but no signs of systemic toxldty. The chemical produced slight
conjunctiva! Irritation, but no corneal damage, when two drops were Intro-
duced Into the eyes of rabbits. Human subjects exposed to the vapor for
very short periods detected the odor but experienced no Irritation at 50 ppm
(242 mg/m3); found the odor to be strong but tolerated the exposure
0032d -28- 08/21/87
-------
without excessive discomfort at 200 ppm (967 mg/m3); found the odor
objectionably strong at 300 ppm (1450 rog/tn3); and experienced a very
strong odor, and strong eye and nasal Irritation at 400 ppm {1930 mg/ro").
Krynskaya et al. (19B9) tested tne acute toxlclty and Irrltancy of a
different methyl styrene mixture (72% p-, 28% o-). They determined an oral
ID,.- of 5.7 g/kg for rats and 3.16 g/kg for mice and a 4-hour Inhalation
LC5n of 3020 mg/m3 for mice. No rats or guinea pigs died when exposed
to 1600 mg/m3 for 4 hours; the authors stated that a higher concentration
could not be achieved In the larger chamber In which these species were
exposed. In rabbits and guinea pigs, the chemical was Irritating to the
eyes and when applied repeatedly, severely Irritating to the skin.
Krynskaya et al. (1969) reported that experiments with rats and mice showed
that dermal administration of large amounts (>4.5 g/kg) of the chemical can
be lethal.
Savolalnen and PfaffH (1981) studied the neurochemlcal effects on male
Wlstar rats (15/exposure level) of Inhalation exposure to 0, 50, 100 or 300
ppm (0, 242, 483 or 1450 mg/m3) of methyl styrene (mixture), 6 hours/day,
5 days/week for 1 or 2 weeks. The rats were exposed during the dark cycle
of a reversed light/dark schedule. The treated rats had no apparent signs
of toxldty, except Inactivity.
Slight changes occurred In some biochemical paramenters (Increase In
brain lysosomal acid protelnase at the highest exposure level, dose-related
decreases In brain glutathlone peroxldase and 2',3'-cycl1c nucleotlde
3'-phosphohydrolase, and Increase In gllal azoreductase) In the first week.
A man with contact allergy to styrene cross-reacted to methyl styrene
(mixture of m- and p-1somers)(Sjoborg et al., 1982). The same sample of
methyl styrene was tested for sens1t1zat1on In guinea pigs with negative
results (Sjoborg et al., 1982).
0032d -29- 08/21/87
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6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
Intwlatlon exposure to the Individual o-, m- or p-lsoreers of methyl styrene
could not be located 1n the available literature as cited In Appendix A.
The NTP (1987) has conducted studies of the toxicology and cardnogenldty
of inhaled methyl styrene (mixture; listed as vinyl toluene) 1n rats and
mice. Preliminary reports (MRI, 1984a,b) of these studies were available.
86C3F1 mice (MRI, 1984a) were exposed to 0, 10 or 25 ppm (D, 48.3 or 121
mg/m3) and F344/N rats {MRI, 19845) were exposed to 0, TOO or 300 ppm (0,
483 or 1450 mg/m3) of an Industrial mixture consisting of 70% is- and 30%
p-methyl styrene 6 hours/day, 5 days/week for 103 weeks. Groups consisted
of 50 an1mals/sex/spec1es/exposure level. No Increased Incidences of
neoplastlc lesions were found In treated groups of either species, relative
to controls.
6.2.2. Oral. Pertinent data regarding the cardnogenlcHy of Ingested
o-, m- or p-methyl styrene or a mixture of these Isomers could not be
located in the available literature as cited 1n Appendix A.
6.2.3. Other Relevant Information. In a study from the Russian
literature, rats exposed by Inhalation to 550 mg/m3 of methyl styrene (70%
m- and 30% p-lsomer), 4 hours/day, 6 days/week for 1 month had productive
Inflammation with papillary growths 1n the wall of the trachea (Krynskaya et
al., 1969). No pertinent details that would aid 1n the Interpretation of
this result were provided. Papillary growths were not observed In the
103-week rat study at 1450 mg/m3 by MRI (1984b).
6.3. MUTAGENICITY
The mixture (60% m-, 40 % p-) and the Individual Isomers of methyl
styrene have been tested for mutagenldty and clastogenlclty In a limited
0032d -30- 08/21/87
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number of assays (Table 6-1). The mixture did not produce reverse mutations
In five strains of ftalropnella typ.h.1inur1.mB in the presence or absence of an
exogenous metabolic activating system or recessive lethal nutations In
OrosophUa melanoqaster (Norppa et al., 1981; Knaap et al., 1984) and did
not produce gene mutations In mouse lymphoma cells (Knaap et al., 1984).
The mixture and all three Individual Isomers Induced sister chromatld
exchanges 1n human lymphocytes j_n vitro (Norppa, 1981a; Norppa et al.,
1981). The mixture also gave positive results for chromatld aberrations In
human lymphocytes jn. vitro {Norppa, 1981a; Norppa et al., 1981) and 1n the
flrtcroftttcleas test 1n mice tNorppa, 1981b). The methyl styrenes tested
negative 1n Salmonella with or without S9. However, mlcroblal testing of
the parent compound styrene yielded contradictory results due to a narrow
mutagenlc concentration range and problems with the S9 activation system
(Norppa and Valnio, 1983b). Similar difficulties probably exist with
mlcroblal testing of the methyl styrenes (Norppa and Valnio, 1983b). In
addition, a potential reactive metabolite of p-methyl styrene, p-methyl
styrene-7,8-ox1de, 1s mutagenlc In Salmonella and Escherlchla coll without
activation (Suglura and Goto, 1981) and 1n Chinese hamster V-79 cells
(Suglura et al., 1979). In studies using endogenous metabolic activation
(e.g., chromosomal effects 1n human lymphocytes and mice), the methyl
styrenes tested positive. The evidence therefore suggests that the methyl
styrenes are clastogens and possibly mutagens.
6.4. TERATOGENICITY
The only Investigation of the teratogenlclty of the subject methyl
styrenes was an Intraperltoneal study performed for NIOSH by Hardln et al.
(1981), 1n which the authors did not specify the Isomer or mixture of
Isomers used. NIOSH (1987), however, lists this study as evidence of the
effects of methyl styrene, CAS No. 25013-15-4, mixed Isomers. Hardln et al.
0032d -31- 08/21/87
-------
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(1981) Injected 0 or 250 mg/kg/day of methyl styrene In corn oil
IntraperHoneally to groups of 10-15 inseminated fenale Sprague-Qawley rats
on days 1-15- of gestation. The dosage of methyl styrene was the NTD
determined In preliminary studies with nonpregnant female rats. The only
effects seen In the methyl styrene-treated group were fetotoxic effects: an
Increased Incidence of resorptlons (p
-------
by any rout* of exposure. Mixtures of methyl styrenes (probably 60% m- and
40% p-) were negative for reverse mutations 1n assays with jS. typhjipur 1 urn
and negative for sex-linked recessive lethal nutations In £. melanoqaster
(Norppa et al., 1981; Knaap et al., 1984). All Isomers of methyl styrene
gave positive results In the sister chromatld exchange test 1n human lympho-
cytes (Norppa and Va1n1o, 1983a). The above described mixture was positive
In the SCE and chromatld aberration tests In human lymphocytes (Norppa,
1981a; Norppa et al., 1981) and 1n the mlcronucleus test In mouse erythro-
cjtes (Norppa, 1981b).
Ititraperltoneal adnltilstratlon of 250 mo/kg/day of an unspstlfled
mixture or Isomer to pregnant rats resulted In Increased absorption and a
decrease 1n the proportion of female fetuses, but yielded no teratogenlc
effects or maternal toxlclty (Hardln et al., 1981). Krynskaya et al. (1969)
reported fetal loss In guinea pigs exposed by Inhalation to a mixture of
o- and p-1somers of >29 mg/m3, 4 hours/day for 4 months and reduced birth
weights In rats exposed to the same mixture at 50 mg/m3 (exposure protocol
not specified).
Subchronlc Inhalation studies have been performed with a mixture of
methyl styrene composed of 55-70% m- and 30-45% p-1somers (Wolf et al.,
1956). Several species were exposed to 580, 1130 or 1350 ppm (2800, 5430 or
6520 mg/m3), 7-8 hours/day, 5 days/week for 92-100 exposures In 139 days.
No effects were observed 1n monkeys at any level or 1n any species at 580
ppm. Adverse effects In the liver and kidney were reported at >1130 ppm 1n
rats, rabbits and guinea pigs. MRI (1984a) reported mortality and nasal and
lung lesions at >60 ppm (290 mg/m3) of a mixture of 70% m- and 30%
p-lsomers In mice exposed 6 hours/day, 5 days/week for 90 days. Depressed
body weight gain and liver weights were also reported, but the exposure
level at which these effects occurred was not specified. Rats exposed to
0032d -34- 08/21/87
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>160 ppm (773 mg/m3) by the same protocol had reduced body weight gain and
kidney lesions In the males (MRI, 1984i>), Increased liver weights were also
reported but the exposure level at which 1t occurred was not.
In a series of Investigations of the potential neurotoxldty of a
mixture of the same composition, Seppalalnen and Savolainen (1982a,b) and
Seppalalnen (1985) reported Inactivity and altered cerebral enzyme activi-
ties at 50 ppm (242 mg/m3), and reversible alterations In nerve conduction
velocities and altered gel electrophoretlc patterns 1n proteins from spinal
cord axons at >100 ppm (483 mg/m3) in rats exposed 6 hours/day, 5 days/
week for up to 15 weeks. In a 21-week study asing rats with the same
mixture, however, altered nerve conductions were reported at 332 ppm (1600
mg/m3), but not at 102 ppm (493 mg/m3), 6 hours/day, 5 days/week
(Gagnalre et a!., 1986).
Helnonen et al. (1982) Investigated the effects of 50, 100 or 300 ppm
(242, 483 or 1450 mg/m3) of the same mixture with exposures of 6" hours/
day, 5 days/week for up to 15 weeks on Hver cell size, electron microscopic
appearance and drug metabolizing enzyme activity of the liver and kidney of
male rats. Decreased hepatocyte size and slightly altered ultrastructural
appearance were observed at 300 ppm. Some liver and kidney enzyme
activities were significantly altered at 300 ppm.
Chronic inhalation studies consisted of the 103-week NTP sponsored
studies using mice and rats with a mixture of 70% m- and 30%
p-methylstyrene. Mice were exposed to 10 or 25 ppm (48.3 or 121 mg/m3), 6
hours/day, 5 days/week for 103 weeks (MRI, 1984a). Reduced mean body
weights and lesions of the nasal passages were reported in both treated
groups, but the lesions were less severe 1n the low group. In rats exposed
0032d -35- 08/21/87
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to 100 or 300 ppm by the same schedule, depressed mean body weights and
nasal lesions occurred (MRI, 1984b). Increased mortality was reported In
high-dose females.
;Baia were not located regarding the oral toxlclty of the Individual
methyl styrene Isomers or their mixtures.
0032d -36- 08/21/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUHAH
The ACGIH (1986a) adopted a TIV-TUA of 50 ppn (-240 mg/m*J and a
TiV-STEL of TOO pptn (-485 mg/ma) for methyl styrene (vinyl toluene, CAS
number 25013-15-4). These TLVs were based on the data of Wolf et al. (1956)
regarding the toxlclty of Inhaled methyl styrene (mixture of m- and
p-lsomers) to several species of laboratory animals and odor and Irritation
thresholds 1n humans (see Sections 6.1.1.1. and 6.1.3.), and on chemical and
toxlcologlcal similarities between this chemical and styrene (ACGIH, 1986b).
The OSHA {1985) standard {PEL) far methyl styrene (vinyl toluene) Is 100 ppm
(-480 mg/m3).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of methyl styrenes could not be located 1n the available
literature as cited In Appendix A.
0032d -37- 08/21/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. An Industrial mixture of methyl styrenes (70% m- and
30% ) and mice (MRI, 1984a). Exposures were to 10 or 25
ppm (48.3 or 121 mg/m3), 6 hours/day, 5 days/week for mice and to 100 or
300 ppra (483 or 1450 mg/m3) by the same schedule to rats. Data were not
located regarding the cardnogenlcHy of oethyl styrenes to humans exposed
by Inhalation.
8.1*2. Oral. Pertinent data regarding tiie carctnogenltlty of tnetnyl
styrenes to animals or humans by oral exposure could not be located 1n the
available literature as cited In Appendix A.
8.1.3. Other Routes. Pertinent data regarding the carclnogenldty of
methyl styrenes by other routes of exposure or other data regarding the
4 *
cardnogenlcHy of methyl styrenes could not be located In the available
literature as cited 1n Appendix A.
8.1.4. Weight of Evidence. No data were located regarding the cardno-
genlcHy of the Individual methyl styrene Isomers or their mixtures to
humans. WHh the possible exception of female F344 rats In which a
decreased survival ratio was suggested In the high dose groups, the rat
study (MRI, 1984b) showed no evidence of dose-related toxldty. It Is
uncertain, therefore, whether the dosing levels were adequate In this study
for detecting cardnogenlcHy. Although a dose-related decrease 1n weight
gain was observed In males and females 1n the B6C3F1 mouse study, suggesting
that toxic levels were achieved for this strain, the guideline criteria of
no evidence for cardnogenldty 1n at least two adequate animal tests In two
species has not been met. The data must, therefore, be considered
0032d -38- 08/21/87
-------
Inadequate. Applying guidelines for carcinogenic risk assessment adopted by
the U.S. EPA (19B6b)>, the 1ndusi~1a3 Mixture of 70% m- and 30% p-rcethyl
styrene Is assigned to EPA Group D. not classifiable as to human carclno-
genlclty. There were no data regarding1 the cardnogenlclty of individual
methyl styrene Isomers 1n animals and the o-, m- and p-lsomers are assigned
to EPA Group D, not classifiable as to human careInogenlcity.
8.1.5. Quantitative Risk Assessment.
8.1.5.1. INHALATION — The only cardnogenldty data located regard-
Ing the methyl styrenes were the negative frnnalatlon studies using rats and
alee with the Industrial mixture of 7t)% m- and 30% p-methyl styrene by MRI
(1984a,b). Quantitative estimation of carcinogenic potency cannot be
performed for any of the Isomers or for the Industrial mixture of Isomers of
methyl styrene by Inhalation exposure.
8.1.5.2. ORAL — A complete lack of data precludes estimation of
carcinogenic potency for any Isomer or mixture of Isomers of methyl styrene
for oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Subchronlc
Inhalation studies have been performed with a mixture of methyl styrene
composed of 55-70% m- and 30-45% p-1somers (Wolf et a!., 1956). Several
species were exposed to 580, 1130 or 1350 ppm (2800, 5430 or 6520 mg/m3)
7-8 hours/day, 5 days/week for 92-100 exposures In 139 days. No effects
were observed In monkeys at any level or 1n any species at 580 ppm. Adverse
effects In the liver and kidney were reported at >1130 ppm In rats, rabbits
and guinea pigs. MRI (1984a) reported mortality and nasal and lung lesions
at >60 ppm (290 mg/m3) of a mixture of 70% m- and 30% p-lsomers In mice
exposed 6 hours/day, 5 days/week for 90 days. The concentrations tested 1n
0032d -39- 08/21/87
-------
this experiment were 10, 25, 60 and 160 ppm (48.3, 121, 290 and 773
rag/ma). Depressed body weight gain and liver weights were also reported,
but. the exposure level at which these effects occurred was not specified.
Rats exposed to >150 .ppn (773 mg/m3) by the same protocol had reduced body
weight gain and kidney lesions In the males (MRI, 1984b). The concentra-
tions tested 1n rats were 25, 60, 160, 400 and 1000 ppm (121, 290, 773, 1930
and 4830 mg/ra3}. Increased Hver weights were also reported but the
exposure level at which It occurred was not.
In a series of Investigations of the potential neurotoxldty of a
mixture of the same composition, Seppalalnen and Savolalnen (1982a,b) and
Seppalalnen (1985) reported Inactivity and altered cerebral enzyme activi-
ties at 50 ppm (242 mg/m3), and reversible alterations 1n nerve conduction
velocities and altered gel electrophoretlc patterns In proteins from spinal
cord axons at >100 ppm (483 mg/m3) 1n rats exposed 6 hours/day, 5 days/
week for up to 15 weeks. In a 21-week study with the same mixture of methyl
styrene Isomers, however, altered nerve conductions were reported at 332 ppm
(1600 mg/m3), but not at 102 ppm (493 mg/m3), 6 hours/day, 5 days/week
(Gagnalre et al., 1986).
Helnonen et al. (1982) Investigated the effects of 50, 100 or 300 ppm
(242, 483 or 1450 mg/m3), 6 hours/day, 5 days/week for up to 15 weeks on
liver cell size, electron microscopic appearance and drug metabolizing
enzyme activity of the liver and kidney of male rats. Decreased hepatocyte
size and slightly altered ultrastructural appearance were observed at 300
ppm. Some liver and kidney enzyme activities were significantly altered at
300 ppm.
Subchronlc Inhalation data are Insufficient for derivation of an RfD for
subchronlc Inhalation exposure to the Individual Isomers or mixtures of
0032d -40- 08/21/87
-------
Isomers of methyl styrene. The NTP-sponsored studies using mice and rats
(MRI, 1984a,b) suggest that mice are the more sensitive species to the
effects of methyl styrene. It Is likely that this study nay have Identified
a NOAEL and a LOAEL for the Industrial mixture In mice, but the brief manner
In which the results were presented 1n the preliminary report of the chronic
study precludes recognition of a NOAEL or LOAEL. The study by Wolf et al.
(1956) Identifies a NOEL and a LOAEL In several species, but the lowest
concentration tested, 580 ppm (2800 mg/ra3}, was above a concentration (60
ppm, 290 mg/m3) associated with mortality 1n male mice (MRI, 1984a). In
the absence of suitable subchronlc inhalation data, the chronic inhalation
RfD of 0.04 mg/m3 or 0.8 mg/day for the Industrial mixture Is adopted as
the RfD for subchronlc Inhalation exposure to the Industrial mixture of
methyl styrenes (Section 8.2.1.2.). Confidence 1n this RfD Is medium, as
explained 1n Section 8.2.1.2. Tox1colog1c data are Insufficient for deriva-
tion of subchronlc Inhalation RfDs for the Individual Isomers by" analogy to
the Industrial mixture.
8.2.1.2. CHRONIC EXPOSURES -- Chronic Inhalation studies consist of
the 103-week NTP-sponsored studies using mice and rats with a mixture of 70%
m- and 30% p-methylstyrene. Mice were exposed to 10 or 25 ppm (48.3 or 121
mg/m3), 6 hours/day, 5 days/week for 103 weeks (MRI, 1984a). Reduced mean
body weights and lesions of the respiratory tract were reported 1n both
treated groups, but both the reduction In mean body weight and the lesions
were less severe In the low group. In rats exposed to 100 or 300 ppm by the
same schedule, depressed mean body weights and nasal lesions occurred In all
treated groups (MRI, 1984b). Increased mortality was reported In high-dose
females.
0032d -41- 08/21/87
-------
An RfD for chronic Inhalation exposure to the Industrial mixture of
methyl styrenes can be derived from the low concentration. 10 ppra (48.3
mg/!B»}, 1n the flRI {1964a) mouse study, 1f H Is agreed that the effects
observed at this concentration define a LOAEL. The LOAEL 1n the mouse study
based on actual toxlclty data appears to be a more reasonable basis for an
RfD than the ACGIH (1986a,b) TWA-TLV of 50 ppm (-240 mg/m3). Uptake of
methyl styrene 1n mice corresponding to Inhalation of 10 ppm for 6
hours/day, 5 days/week Is 11.2 mg/kg/day. Application of an uncertainty
factor of 1000,, 10 to estimate a NQAEL from a IQA£L, 10 for animal to human
extrapolation and 10 to protect unusually sensitive Individuals results In
an RfD of 0.01 mg/kg/day or 0.8 mg/day for a 70 kg human. This corresponds
to a continuous Inhalation exposure of 0.04 mg/m3. Confidence In this RfD
Is considered to be medium, because the key study and data base do not
Identify a NOAEL and because virtually nothing Is known of the developmental
and reproductive toxldty of the Industrial mixture.
Data were not located regarding Inhalation exposure to Individual
Isomers of methyl styrene. Tox1colog1c data are not sufficient for deriva-
tion of RfDs for the Individual Isomers by analogy to the Industrial mixture
of 70% m- and 30% p-methyl styrene.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Data were not
located regarding the subchronlc oral toxlclty of the methyl styrene Isomers
or their mixtures. Lacking sufficient subchronlc oral data for derivation
of an RfD for subchronlc oral exposure, the RfD of 0.006 mg/kg/day or 0.4
mg/day for a 70 kg human for chronic oral exposure to the Industrial mixture
Is adopted as the RfD for subchronlc oral exposure to the Industrial mixture
assuming an Inhalation absorbtlon factor of 0.5 (Section 8.2.2.2.).
0032d -42- 08/21/87
-------
Confidence 1n this RfD 1s considered low, because toxlcologlc data are
Insufficient for derivation of RfOs for subchronlc oral exposure to the
Individual Isomers of methyl styrene by analogy to the mixture.
8.2.2.2. CHRONIC EPXOSURES -- Data were not located regarding the
chronic oral toxlcity of the Isomers of methyl styrene or their mixtures.
The chronic Inhalation study In which ralce were exposed to the Industrial
mixture of methyl styrenes at 10 or 25 ppm (48.3 or 121 mg/m3), 6 hours/
day, 5 days/week for 103 weeks (MRI, 1984a) may serve as the basis for an
RfD for chronic oral exposure to the Industrial mixture. An equivalent
absorbed dose is estimated by expanding the concentration of 48.3 mg/m3 to
continuous exposure, multiplying the result by the reference Inhalation rate
for mice of 0.039 mg/day (U.S. EPA, 1980) and dividing by the mouse body
weight of 0.03 kg estimated from graphic data provided by the Investigators,
and multiplying by an assumed absorption factor of 0.5. The estimated
equivalent absorbed dose of 5.6 mg/kg/day 1s divided by an uncertainty
factor of 1000, 10 to account for a use of a LOAEL, 10 to extrapolate from
animals to humans and 10 to protect unusually sensitive Individuals. An RfO
of 0.006 mg/kg/day or 0.4 mg/day for a 70 kg man Is estimated for chronic
oral exposure to the Industrial mixture of methyl styrenes. Confidence In
this RfD 1s considered low because of the uncertainties of route-to-route
extrapolation as well as the fact that virtually nothing 1s known of the
developmental or reproductive toxldty of this mixture of methyl styrene
Isomers.
Data were not located regarding the chronic toxldty of the Individual
Isomers of methyl styrene and toxlcologlc data are Insufficient for deriva-
tion of RfDs for chronic oral exposure to Individual Isomers by analogy to
the mixture.
0032d -43- 08/21/87
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
TJie sysieaic toxiclty studies of the methyl styrenes discussed In
Chapter 6 are largely restricted to subchronlc and chronic Inhalation
studies with mixtures of m- and p-methyl styrene. Effects and their asso-
ciated exposure levels that may be useful for computation of CSs are summa-
rized In Table 9-1. Effects noted In subchronlc exposure studies Include
depression of body weight gain and slight liver lesions 1n rats and guinea
pigs (Wolf et al.t 1956); mortality in rats {Wolf et a!., 1956); Inactivity
and altered nerve conduction velocities 1n rats {Seppala1n*n and Savolalnen,
1982a,b; Gagnalre et al., 1986); altered drug metabolizing enzyme activities
and altered ultrastructural appearence of hepatocytes In rats (Helnonen et
al., 1982); depressed body weight gain and glomerulonephropathy In rats
(MRI, 1984b); and mortality and respiratory lesions 1n mice (MRI, 1984a).
Available chronic data consist of' Inhalation studies using mice (MRI,
1984a) and rats (MRI, 1984b) exposed to an Industrial mixture of 70% m- and
30% p-methyl styrene. The rats had a slight decrease In survival, depressed
body weight gain and mild lesions 1n the nasal mucosa. At concentrations
~10% of those to which rats were exposed, mice had depressed body weight
gain and respiratory lesions.
Adequate chronic exposure data are available for the derivation of CSs
for exposure to the Industrial mixture of methyl styrene (70% m- and 30%
p-lsomers). CSs are calculated from the chronic data according to the
methodology for chronic toxldty RQs (U.S. EPA, 1984) and are presented In
Table 9-2. CSs are not calculated from the subchronlc data because of the
uncertainties In expanding from subchronlc to chronic exposure. The highest
CS, 11.2, was calculated for decreased rate of body weight gain and chronic
0032d -44- 08/21/87
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respiratory Inflammation and hyperplasla In mice exposed to 48.3 rag/m3, 6
hours/day, 5 days/week for 103 weeks {M8I. 1984a). The CSs derived 1n Table
9-2 support the observation presented 1n Chapter 8, that nice are more
sensitive than rats to the toxlclty of methyl styrene. The CS of 11.2
corresponding to an RQ of 1000 1s chosen to represent the chronic toxldty
of the Industrial mixture of methyl styrene (Table 9-3).
Data are not sufficient for derivation of CSs for Individual Isoraers of
methyl styrene by analogy to the Industrial mixture.
9.2. BASED ON CARCINOGENICITY
As reviewed In Chapter 6, cardnogenlcity data for the methyl styrenes
are limited to the negative Inhalation studies with the Industrial mixture
1n rats and mice sponsored by the NTP (MRI, 1984a,b). The Industrial
mixture was assigned to EPA Group D, since a 2-year study showed Inadequate
evidence of cardnogenlcHy 1n mice or rats. The Individual Isomers of
methyl styrene were also assigned to EPA Group D; nonclasslf1able as to
human carclnogenlcHy. Potency factors cannot be derived for the Individual
Isomers or for the mixture, and hazard ranking based on cardnogenldty Is
not possible for the Individual Isomers or for the Industrial mixture.
0032d -49- 08/21/87
-------
TABLE 9-3
Industrial Mixture of Methyl Styrenes (70% m- and 30% p-1somers;
Minimum Effective Dose (MED) and Reportable Quantity IRQ)
Route: Inhalation
Dose*: 58.8 mg/day
Effect: depressed body weight gain, Inflammation and
hyperplasla of respiratory tract
Reference: MRI, 1984a
RVd: 2.8
« *
RVe: 4
Composite Score: 11.2
RQ: 1000
*Equ1valent human dose
0032d -50- 08/21/87
-------
10. REFERENCES
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0032d -51- 08/21/87
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0032d -53- 08/21/87
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Kappeler, T. and K. Wuhrmann. 1978. Mlcroblal degradation of the water-
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-------
Lucas, S,V. 1984. GC/MS analysis of organlcs In drinking water concen-
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0032d -55- 08/21/87
-------
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0032d -57- 08/21/87
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0032d -58- 08/21/87
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U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity
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0032d -59- 08/21/87
-------
Va1n1o, H., M.D. Waters and H. Norppa. 1985. MutagenlcHy of selected
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0032d -60- 08/21/87
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APPENDIX A
LJTfRATURE SEARCHEJ)
This HEED 1s based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORE!
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In January, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0032d -61- 08/21/87
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. Kirk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc.* Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Henlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program)- 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park-, CA.
U.S. EPA. 1986. Report on Status Report in the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call in Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
U.S. Environmental Protection Agency
Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604 ,#
0032d -62- 08/21/87
-------
In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Colunbus Laboratories. 1971. Water !)ua"l1ty Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.VJ. and fl.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, including the following:
BatteHe's Columbus Laboratories. 1971. Water tjuallty Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Jotinson, W.W. arid H.I. Flnley, 1980, Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J,E. and H.W. Wolf. 1963, Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of 'California, State Water
Quality Control Board. Publ, No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0032d -63- 08/21/87
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