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                       DRAFT: DO NOT CITE OR QUOTE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.

-------
                                  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

-------
                                    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

-------
                               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

-------
    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

-------
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

-------
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

-------
    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.

-------
                             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

-------
                          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

-------
                               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

-------
                               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

-------
                                  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,
0032d
-2-
     05/22/87

-------



















1/1
fl}
c
4?
^
^)
^J
oo
^,
.c
o>
z

CM «J
J. 5

LU '4~
_J ®
CO
< "*
j_ &
«*•
^^
f»
fl;
CL
O
Q_
,—
^
O
***
i/i
>n
.C
Q.


























U
«•*
X
*P»
z
r_
t^
••-
o


o
o
c
O)
t_
>t
«fcj
lOO

1^
^^
^
^.J
£}
^£
1
Q.



S>
C
4)
u
oo

^"
>n
JC
^-»
01
z
1
E



0;
C
0
>>
l^
^^
^0

^™
>lj
^1
^-»

a.
o
a.



^
o
m
CM
in
CM
	
JS O
ja • co
r- r» CO
r- as
1 r- 0
cr
0
«^
\
0

^^

(Q gjj
CO ^D
• ^3 ^^
^* cn QO
CO *«O •
1 •— O



^
5.J
9
.0
CM
Xi^
^^
a
CM
^w*

CO
^J
t& f& CD
o co en
P^ ^O •
1 r- O



^
o
CM
^M»

<£>
0
f^ p"—
i^ C^
^c ^** •
Z r— O






<_) CJ
0 0 >,
-^J
f» * ^«-
C C f^
•**" "^* L*
O O Ci3
a. a-
c c u.
••-> r- u
t— -- O)
^
^J
H— •
£
_P
3
r™
o
00
0)
^^
3



^
J3"
o
O
~
CO
-f^
« .^J




a/
—»»
CJ
O
^D
p~* O'
^-* u^
^»
o un
• ,
i— CO






^3 y^

oj o
9 9
CM in
^ CM C*
•«•* ^^« in
!•••
CM CM in
• • »
m CM co








•o
^•^
f ^
9
CM
CO O»
• — • in
r"»
cn in
• .
CM CO


^^
3^

£
c

•
O)
3
1/1
i/l
 _J


























__^
co
«n
_i ^

C
*•*.
^J
^^
^2

C
0}

,^
o^

u>
0)
O)
E
v_

a.

O)
c

o

c

C
•* —
^^ CO ^
r- CO CTI 91
CO CO CT> r— CL
en 03 r— X
f— en • ^
r- . C
« * 0^ E
\x • ^— g; o
0; • ra t_ l—
OJ i— 03 u_

co ai 73 -o
CP> r— *J CO)
• O •*" rC
i-> «- m r— >> E
fO § *3 3 ti ^
3J ^ O O flj vi
3 t_> _i aa a. LU






















































a>

P^
^o
>

73

"S
3
U

fQ
U

*»»«
1 —
CO
CT>
-_ ^

^^
a.
bu
OO

3
                                                                          4)
0032d
-3-
05/22/87

-------
                                  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
0032d
-4-
06/12/87

-------
    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

-------
                     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

-------
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

-------
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

-------
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

-------
                                 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

-------
    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

-------
                             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.
0032d                               -12-                             05/22/87

-------
                             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

-------
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

-------
           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

-------
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

-------
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

-------
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

-------
                                  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

-------
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

-------
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

-------
    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

-------
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

-------
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

-------
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

-------
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

-------
    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

-------
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

-------
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

-------







































i

>i
,
§^r
i = =
S PO a.



i_ s
o 5
PO e
W PO
— Ol
e o






VI
•<


•

CO P- CO
en PO a
^
01
0.15 <« * evU
k PO CO k.
O — C on O —
* * »**- * «
-
* *• •
PO vi
•w -3  X — PO J,
— c -ox oi oi
•• Ol 01 9 k c_
Su -* x x :
e vi 41 -c
oi e oi e w B
3E w «-— o.—




a i i



It
**
u. Ol
— e
u —
01 «*
Q.T3 e
vi > 4)
en c — —
1 3 X VI
«/) U >> <
*l *(<» vi Z





9 k
Ol CO
X PO bf
Q,2 oa
p- & O C
1 >• p— s
p» p—
of « o i
p— a z b« e»


e
o

PO
o
«£•
— o
PO U k.




PO >i PO
01 P— 41 41
k .0 b. b.
3 PO 3 3
X . O X X
1 z a.'i 1


.5* I
S OP- ~ O 0
HJ 3 O < 3O PO «•

01 3 p— « £p— ft
e g bo co a a <
§«^*nc*} >«. oc
feObnbn •^*eo 1/11
p-aenp-i— en OP-
PQ X < < • < U <
Crt —IP— »— p- tO|p— 0 {



^M
01 4
e e .w a
Ol O 01 0 C -
Ol PO 01 PO >9
> — > — X t,
01 3 41 3 01 9
Of S OX § Mb
..
- - PO PO A

p- p- co eo eo eo
X> X '"" ^ fO ^* ^"
• 11 41 ....
PO PO • PO O PO
a. a. o. a./— a— ex
•o •» w » a. a. p« o. c Q.
 " ™ L« V* ^ VI '
cv a; — » 3 o o a; ii a;
— • C "O E Q.-^» u vt
u L.C i- c a* — z ' o
•» a* oo oo u -^* e a; •* v> a; "o
•*- C — C — ' O £ i^ OJ 4J OJ O O O

J= U. £l_ (.CMC O —

c e c <_juo.i-— L-CO>

,T3 v*u v*u (••'Ob SOCU ^^
 ^ ffl C -~
W •*•• «* ^ O v» 1 ^ O C O
O  O 4)


^ OJO a* o **vtwt»GCi»~ o
-- •* — ^ — — C t, 'TJ «^ 0> •« JZ — CL
e aio a> o o — ^ *— i o «* — *




1 1 Ifr *fr i***t-*



I

Ik. Ol
^ e

01 X
ex PO S
if > 4» ja a
C — X 01 U
s— vi e c
< u >* o o <


« *

o
(M O
cr>
O e B • oi
o .*
p- O «r o -x
.1/1 1 CNl O>
. x « » n s

•e r> -o o o
at at • e o o o
<•» Z Z O <0 1 P— bO


1
pp
•O T3 k.
Soice o o c c «^p—
•J — O O — — O CPOC
e> oi p— >»—p— >,^— no
— u .nuaivifuuvi c —
X —  O — •
W —I OIA3OI OIJC30IP— xu

C CI f>,33£>»33— 11C
^ *"1 J p— u vi J p— u vi v» CX--



>» >. .. X 4l
p— Oi P— li 41- r»Xk. 41-
J3 b. Au ki en en 3 >- = '
PQ3 P09 3SI A Cn O. 3 S CX
• o"x -ox 'xX ... x X X
oe w — CE i_ — <-oo iii — o o
ZO.B zcLg a ws •» o a o. s >o »


b.
41 vi ^^
vi Ol p— 41 01
1 PO vioi vi vi P— x
> O 3 w Ol 01 g >•
ic § PO ">• ">• o
r PO £ u u vo k
> P— 9-O O O x..f
: oi co j= c j= c j= p— oi —•
J 8 ? §• If !§• SSw
1 • bn>i 3 >> 3>> bngoi

V. 0

-o e 41 vi
, 4,41 -o ^e> p— PO -~
§.M > c c — c •- •- u »— »
C^^OPQUO ««^^ 3u^^
<2J2 i oi f PO i— , S 2 0|~ '"tli'c
( 41 3 49 4f 4f 3 ^L ^£ V 3 ^J ^S J3 '_ f ^~ Of 4t
. p- e CAUP-S 3 1— s» a MUPO oo a: — o>
•o
o
o
a
41

O
01

.£
1^

V
^T^
u
*
JC
*^
^^

w

w
^B
***^

"^
^^ ^
v» *^

U ^
0 i
1 5
i ~
PO CO
vi en
at -»

"^ p^
•° —
41 *"

3 "2


5 41
L. ^ C
*> .3 *
5 C >,
O "fl «J
VI
41 ^
£ Ji -0
— * n oi
CO ^^
e en PO
~- >»
vi f

u ll
i o»
v» •*•

' ?
S *3 e
» ||

"c ^ "j

1 "X
e ** u
x - '
g -o u

*. <« o
.a oi PO
PO VI — •

O .C B

a.  e u
- £" t
3 ** O
^ "5 J §
a> ** o **
*• o« o
«- Sec
«^ C ^H
u 5 "
& *- ^ K
v* 3 ^ Z
*rf "™ V» *•
e 1 2 4i
v> °--2 'pi
PO P— U
S e 3 "
c « a.
0 =41 0.
— ?** '
x U >•
•• il u •*
vi A O O
0 3 £ z
fV* !^
= 1 »
u i— i p— «:
PO A z
0032d
-32-
08/21/87

-------
(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

-------
>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

-------
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

-------
                     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

-------
                             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

-------





































01
c
01
k.
Arf
V)
^
£
11
X
u
0
>,
w

u
X
o
c
0
•2
j:
c



































11

c


01

01
Of











B>
VI
C
o
fib
VI
11
Of




— D >,
e «• IB
»^o-5
> e j<
— 3 ^
ill

OJ vi >.
E o -3
o '
kb» 1— O1
£1<
211



3
VI
0
Q.
X




\ t.
r 1
k. VI
3 1-1

01 i-x
u ^ to
> a.
D
O) ^^
>B £ —
k. O> O>
0> — Jt
> 11 —
< 2

O
35

X
OI
V)



VI C
11 —
«~ 
V)



B
,
,^
•B

^
V

**• «A

"~
>•>.!_
•o «* u
S3 — > >
ja IB —

u-
O — ' U
JE .C


•»»" C
VI VI «•-
VI
01 - C
u C 0
a— —
0> IB «""
« O>  O> 01
— — 01
•— 01 01
10 3 -0



co




u
so
Ul
N^
k. Jt VI
O 3 11 >•
CO O 11 "B
•T J= 3 -3
kfl V.
••^un vi en
g r* IB i—
5. -o^
^L • ^3
^3 A I
co 6 •
p- Ol IB O
Alg -0 x-

1 1
E a.
^22?

en wi ei
A ko n

u
o
a.

*

Q

09

e
o

i

V.

•
*
^

1^^
a.

10 0

C *^
— -=
3 t—


m
»
f^

O 0 i
O O 01 *B

u^ in m ^^
e ^ -S ^
Q. - 03
ffl 1

cn v. >» w

•
S a.
^ XX

S J) C3
A m co

u
o
ex
IB


•o

CO

o
CM
1
0

^^

•
z


IB
^*
VI


N^
^^
oe


—
,
i-~
>B

^^
01

». >a

^^

1 U
e >
1^ 3 —
O i—
•o
- c c c
>» o -o

U 11 -^ 11
u u ••
01 01 >» U
•0 -0 -0 11
o o o a.
X S J3 vi



CO
in



u
r*
co
N^
k. ^ VI
3 01 >i
O O 01 IB
CM JS 3 -3
m -v.
*O kfl VI OI
r*» IB r-
t-o ^
• J5
ex — m 01


kfl -s. >> k.
CO O* *B O
i- s -o «-

1 t
S a.
X X
^^ C3 >n

oi m o
A m co











































u
01
>


>»

^^ ^^g
*B •^

e


o> c
— o

"5
•X 01
JZ C
o> u
— o>
3 •=>























































•o
e

c *
u c
c u
— c

*• IB •

CX O «M
& > CO

t» CA-


ll 1—
1 vi -O *B

^ 11 J^ — *
U O C
••"• U > 01
JT i> SI —

— u. Q.
•— • O
vi » C
U 01 0
••X ^ —
>> 3 X
— e -* u

— 01 Q. 01
** vi £ f—
U >B . >i k.
E IB u O
•Q v*»

CO vi k. ^
» k. IB 01
— 3 73 11
0 ^^
ex e vn
CX*A <^ ^^
k. IB
§-» 3 -a
n •«}
f* s ^•^m



E ex

•x X X
OE O O
Z r* CO


o
ex

*

01
o


0
*
L_ r- CM
o


O *- 0 —
CSJ W "*• L.
\ a, at


u.

^

^

^^
^rf
ae













































M
a>
S
m
o

ex
3





































•o
e

c *

e u
— c
IB — ja


&?£
Oi >B en
4/3 «/> —


— • w o
.= > X

— -a oi -o
u > 3
i-- A. —




^ VI — IB

.. ..•< c
>. C —
~* o e
.— — — u
— vi 01 » >» u
 ^
<— k. IB 11
IIII
ex c vi
SL<£ — >>

O n -O



E ex

oe o o
z r- co


0
ex

*

01
o


o
.
o
^ VI VI
01 k. U
0 — 0 —
CM k. u- U
^^ 01 4J
X vi in vi















,












c
0

^^

*B

U

U
VI
3 r—
S IB
01 C
Jf H
0 — i
> O
11 CX












VI
11
U
3
O

a.
3







































^o
co
en

01 *~

*• •

e IB

40 a.
£S
— X

u 11 e

X k-
O 11 vi
— • c c
o o

3 — Kl
11 
c-—<—

kW C O
0 — C

VI 1} •
O> v
1— L. 11
— 3 01
ex vi
CX^3 ^i

S?'



E ex

>. XX
Of O O
Z r- co

u.
0
CX

*

•o
tn
CO

o




o

\
X
01
3
O"

^
CX >»
C/) 11

•— 's
ec o

























0)

k.
u
e


-------
41
U
41
U
41
41
ee







Si
VI
C
0

VI
41
at




•* 4> X

1> O "C>
r- 0 ^.

> C -X

"3 1 01
era t
uj X •—
4> vi X
S O 13
S ea -o
O V.
^ ffl ^rf
C 1 >»
1 — 01
i- e i
~~"





u
3
i/i
S
a.
x



V. u
L. VI
C.

4» *O
f— W 4»
U ••- -»-»
— • vi iq
f X-<->
41 J= tO
» a.
4)
«* J= *^
L. 0> 0>
41 — -*
> 4> —
< 2

O
Z

X
4)
V)

V.
vi c
4> —

U u
4> <-•



CM
CO
^
C
4) -
O r-
is
1 Sil .1
wi ^- O U t/t i/>
O» u* U -~ 4» O>
<*. 3 *-£•*» 3
O w v» V V ^ O O u 
»» E »» »• ja a ^x^ S
^™ ce »»«-'4)i— >cc
«• 4) 4) 4 >_• w
(J O* &*4»W^W O>

e — i— -a c —
t91QM T) 13 O> C TS i^ IX
41 — 4) 4) o At —
ifl — O *« iq O 4> rO — O
0) — ^ 4)41 VI 4< — ' -3
C4I4! CC4>Ce4l4>



«r CM

cn OO
CM


4^
a
LTl J5

^
4)

>» 
•0 u. Jt 00
n v. j< 41 ui .a
CO vi w -X 4) » iq

— ' 3 'O 41 — vi
0 3 tn •«
9.4 — x o a."
i_ T) — g
O — 3 -0 O "V
O n ^ CL ^5*
I I
S a.
•*. X X
ee o a
Z id »


0
a.




^
n

a




a
CM

X
"i

VI

2


ee


^
as

B
MM
£
X

T3 O O
a. a
o c
L. O C
CV vi
4> vi C
c a; —
O 1- TJ
•• a. o>
3 41
u "O —


S v>«—
'Si'^ 3
§01
X 41
— COW
X •" J3 vi



e

un



^^
en
eo

VI
^^
N. us
51 • i- -o
6 x li
« > 0
^ ^3 O cn
r- >»
r*- vi Mi *^
•v u 41 O
O.f >• O
*Q X u
O iq 41

••• n
AlE tn •«
.
v. s cv
en So
I r*« co

u
0
o.




^
o

o
41

X 3
4> VI
*V vi 0
u. \ Q.
•O X
X r— 4>
z

^

^^


ee


^
eo

B
1
VI I/I
*  0
•c o en
O >v
en vi Jt u.
CM U (U O
— 3 41
_ 0 3 -0
S i ^- 0
Q. vi —

"3 41
o — --o a.
tA A
Al E u-> us
.
x s °'
en XX
cn 0 0
1 r- eo


o
ex




CO
0

o'
41

X 3
41 vi
^ vi 0
u_ ^ a.
-o x
X /— 41
O

CO

4)
VI
3
I


^
eo
en
^
at
- -

^~ rQ
1) "O C
3 >—
— 01
O 0 *""

o

O *9 C

C — —
o c -»

v» « «q
41 » (O vi
I. C .— 0




^

at



^_
o
s


 ^
sl^°
a. vi -a
0.^5 x o
* —
o — -o w
O » 41
i— a to a.
t i

Sxx
en o O
t r— co


0
a.




•^
eo

o
4)

X 3
4) i/i
•v vi O
u- v, a.
• o x

z

^

^^


ee







•s 01
1 O O -C

3
vi a. *— u-
= 1
• C «- C
O C O vi
4! — — — 41
VI VI S ** •*-
4Q VI <^ iq
4> 4) • S C
1_ V. C 5 —


T? °O C"*^ 3
C *^
•§.^•§•-5'
Zo"> 3 "i c



CM

eo
CM




!£
'"^


•v.
O
U1 41

i— 3
7"
Ck VI
a. iq

o —
o *
CO g
































0032d
-46-
08/21/87

-------
u
01
k*

Ol
Of











a
VI
C
0
a.
01
ce









«v 41 Ak
C v. -0
Ol O ^
f— ea*x
TO Ol
> C J<
— TO -X
Mi1



•O 01 —
01 VI >»
S 0 V
k. O T3
O X,
U. r— Ol
vi TO •*
c E "x
2 'c i







01
k.
3
i/i
0
C.
X
kU







X. U
— O
k. VI
3 —



Qi TO
r- U Ol
U — "
<^ VI TO
.c >.—
Ol £ to
» a.


Ol
01 —
2 01 01
01 — ^

^g ^




0
z

X
Ol
e/>




VI C
Ol —
*™ TO
U k.
Ol —
 "*



^

*l
"".
I i
V
»» * *»
e k. s u
•—a o TO u-

^Ol»- 1 13 u- C
01 £ o» — — —
3 = a. Q. vi vi
f^ J- 2— <2 —
•o it. i. c a. o
0 C - Ok.—

«• to ^£ o, u
i*. w o vi u >» o
O — U TO & u.
C 3 C > .0
cog S -a
O u «- 3 C >>
<^ ^Z p^ O * * TO k>

vi v< TO 01 e c
01 • 13 — .C 0 O
k. c c v. — — E
Q.— TO — — i—
01 TO fc i— a s 3
o 01 o a. 01 S a.






eo

d







CM

^m
<—



o* •
S ^^ k>
13 O

• v.
00 vi .*
» k. 01
•v 3 0) tfi
o a -if
E J= -x o.
0. VI 01

ea -» ' n
f— A O
Aia ko —






x s" °~

en o o
i r^ n



u
0
a.


Ol
w

01

o

ri.1
j£
^

y

^f^
i

*••
i

e

0)

^^

O

o
H
•a
o

Ol


0>
c

"3
Ol
Ol
u
c
01

01
01
ce
A

^
o
4*.
u
5
e
en

(M
•
o

Ol
™
^

C
o


<

o

"i
^^

^ eo
en
S "~

ws.
e


e •
OS vi

IQ Ol Ol
i "a.
C kT>
Ol m r—
U Ol
c c — -o
o — o c
U 3 CO 13
01 en
Ol --CM
3 O *~

o a. co
a. >> uy
X TO •
u — ^
*x to
Ol n
5s S °
O ~~ -~

C • £
v C5 Ol vi
•— • Ol .S
a— 3 01
•- 0 —
— OD >> Ol
r~ en TS X
• *o
>>« — 0
j>a. 13 ja
0) • 41 O
•*>  0
13 • e oi
r- 3 01 Ol

U 01 k.
13 13 Ol >
u k. at <
u "D 01
ri
*

^
o
*
^
m
E

en
CM
.
O


,QJ

^
^

C
o
^~
*^


'O
£
c

1
e
IB
**
^


v^ ^^
•sr
Ol
r- 3
•x
VI >.

13 0
•D A

Lfl '""

„ S
X ^
VI 13
k. X.
3 i— 1
O -^
t— O
eo
« en
CM "•
x.
VI •

3 a-
O ^^
gp

*^ 1
^3
ja
Ol
« VI
S 3
"oil
E
01
s *
o
c •
0 O
^+ t^
u o
, .
c >>
01 TO
o -o
c ~^
0 «
u E

a, en
u 2

VI '
o *

^( *
01 •£

01
5 "

OlO
= T

ri<0

>- o


i|

*•«
•° S
•o »
Ol «•
" 

3

^
^»
Ol

01


•o
o
J
01
VI
3
i
Ol
u
e
01

Ol
Ol
at








































































VI
01
k.
3
U
JS
1
k.
01

S
o
k.

^
Ol

I

^—
l/>
01
VI
4)

1
Ol



c
I/I
Ol
i

k.
o


e
Ol

^




































































































•o
Ol
•*»

o
Q.
01



O
z

It
ee
z
0032d
08/21/87

-------


























CM
1
O1
I-LJ
_J
oo
H-































01
C
O)

*
CO
^_
.c
0)
i
a.
X
o
e
fO
i
S
X
^^
1 _
"*~*
O)
L_
^~
X
*
/B
*T
_t-
1/1
3
-o
c
>-H
5
^
o
**"
£

0
u
CO
OJ
•£
0
a.
o
CJ
c
£
t—
^•*








91
U
c
0)
La
a>
o>
OS




^^
oe

co


«
>
O£






^^
U
0)
UJ





•a
a-


•M
C2 "^*»
O UJ >»
*^~ 3C 'fl
c -o
o c \
J= I i1
0 =



• — •
a> 13
d) 3 v>
I/I 1/1 O)
o o .*
a a.^
x en
i i . £


(/I
O
.«—
U
a>
a.
CO
CD
OS
*•"
-
S
3u



O
a
o

CM
Ul



1»





>l 1
•o c
0 -»-
J3 C
w r— C
•O fO fO O
un *J C "3
flj JZ E
1- 35 13 =
O.-- r— na
a 3 "i IZ


CO
'-





00






a
in
in






+j
eQ
Q£

CO CO
{^ ^^
r— f—
-
Q£ GC
z z



0 0
o a
o o

TM
0 r-^
i— r—


o •*•
f^

1
U 1
a> i a> •^>
u-i >i S a. a.
O) O «f— £ O) *••
l~ r— J3 C U- 1-0
O ^3 *^m C ^3 ^3
a>> ^ fo "— c u- u
•o ••- a; en >v o •*->
> l/i O
-4-« l_ ufl <-> »- C 03 >i
j= 3 a>^co«-i-
^^ 1/1 u, C^ O •*"" ,
A
•o
V.
Sa/
•V
E

S/1
'O
T3
O)
V/l
i/i
a,
X
4J

Oi
1/1
O
c
I
.c
c
^J
TJ
^
3
CT
O)
5
o>
c

^
a.
-3
3
E
.0*
01 0>
.-a at
(— 3
3
U >»
r— "^
rt3 O
5J Q
•K
0032d
-48-
08/21/87

-------
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

ACfiJH  (American  Conference of  Governmental  Industrial Hyglenlits).   1986a.
TLVs:  Threshold  Limit Values  for  Chemical Substances  in the  Work  Environ-
ment, adopted by ACGIH with Intended  Changes  for  1986-1987.   Cincinnati, OH.
p. 1-109.

ACGIH  (American  Conference of  Governmental  Industrial Hyg1en1sts).   1986b.
TLVs:  Documentation  of  the  Threshold Limit  Values and  Biological  Exposure
Indices, 5th ed.   Cincinnati,  OH.  p. 630.

Bergemalm-Rynell,  K.  and  G.  Steen.   1982.    Urinary  metabolites of  vinyl-
toluene 1n the rat.  Toxlcol.  Appl. Pharmacol.  62(1):  19-31.

Boubllk,  T.,  V.   Fried  and  E.   Hala.   1984.    The vapor  pressures  of  pure
substances:  Selected   values  of  the  temperature  dependence  of  the  vapor
pressures  of  some pure  substances  in  the normal  and low  pressure  region.
Vol. 17.  Elsevler Sc1. Pub!., Amsterdam, Netherlands.

Chemical Week.   1981.  1982  Buyers'  Guide.  McGraw-Hill  Book  Co., New York.
p. 123.

Dean, J.A., Ed.  1985.   Lange's  Handbook  of Chemistry,  13th  ed.  McGraw-Hill
Book Co., New York.  p. 10-48.

Eisenreich, S.J.,  B.B.  Looney  and D.J.  Thornton.   1981.   Airborne  organic
contaminants  In  the  Great Lakes  ecosystem.   Environ.  Sc1.   Techno!.   15:
30-38.

0032d                               -51-                             08/21/87

-------
Fleming* R.D.  197Da.  Effect  of  fuel  composition on exhaust emissions  from
a spark Ignltton engine.   NTIS n  194942.   74 p.   {CA 75;24833y)

Fleming, R.D.  1970b.  Effect  of  fuel  composition on exhaust emissions  from
a spark-Ignition  engine.   Bartlesvllle  Pet.  Res.  Cent.  Bur. Mines,  Bartles-
vllle, OK.   U.S.  Bur. Mines.  Rep.  Invest,   p. 68.   {CA 75:132675g)

fox,  D.A.,  H.E.   Lowndes  and  G.G.  Blerkamper.   1982.   Electrophyslologlcal
techniques  1n neurotoxtcology.  Werv.  Sys.  Toxic,   p. 239-335.

Gagnalre,  F.,  T.  Nlcot,  D.  Zlssu,  P.  Bonnet  and 3.  OeCeaurrlz.   1986.
Assessment   of  tall  nerve function  In  rats  chronically  exposed  to  vinyl-
toluene.  Toxlcol. Lett.  (Amst).  30(1):  27-34.

Hanzllk, R.P., G.O.  Shearer,  A. Hamburg and T. Glllesse.   1978.   Metabolism
In  vitro of para-substituted  styrenes:  Kinetic  observations of  substHuent
effects.  Blochem. Pharmacol.  27(10):  1435-1439.

Hardln,  B.D.,  G.P.  Bond, M.R.  S1kov,  F.D.  Andrew, R.P.  Bellies and  R.W.
N1eme1er.   1981.   Testing of  selected  workplace  chemicals for  teratogenlc
potential.   Scand. J. Work Environ.  Health.  7:  66-75.

Hawley,  G.G.   1981.  The  Condensed  Chemical  Dictionary,  10th  ed.   Van
Nostrand Relnhold Co., New York.

Hawley-Fedder, R.A.,  M.L. Parsons  and  F.W.  Karasek.  1984a.   Products  ob-
tained  during  combustion  of  polymers  under simulated Incinerator  conditions.
2. Polystyrene.  J. Chromatogr.  315:  201-210.

0032d                               -52-                             08/21/87

-------
             .  R.A.,  M.L.  Parsons  and F.W.  Karasek.   1984b.   Products  ob-
tained during combustion  of  polymers  under  simulated Incinerator conditions.
I. Polyethylene.  J. Chromatogr.  314: 263-273.

Helnonen, T.H.H.   1984.   Metabolism of vlnyltoluene  In the  rat.   Effect  of
Induction  and  Inhibition  of   the  cytochroroe  P-450.   Blochem.  Pharmacol.
33(10): 1585-1594.

Helnonen.,  T.   and  H.   Valnlo.    1980.    Vinyl toluene-Induced   changes   In
zenob1ot1c-metdbol1i1ng enzyme  activities  and tissue glutathione  content  In
various rodent species.   Blochem. Pharmacol.  29:  2675-2679.

Helnonen, T.  and H.  Valnlo.   1981.  Dose-dependent effects  of  vlnyltoluene
Inhalation  on  nonproteln  thlols  and  drug  blotransformatlon  1n  liver  and
kidneys of the rat.  Xenoblotlca.  11(4):  285-289.

Helnonen, T., J.  Nickels  and H. Valnlo.  1982.   Subacute  toxldty of vinyl-
toluene vapor:  Effects  on the  hepatic  and  renal  drug  blotransformatlon  and
the urinary excretion of thloether.   Acta  Pharmacol. Toxlcol.   51(1): 69-75.

Hoff,  M.C.    1983.   Toluene.    JJK  Klrk-Othmer   Encyclopedia  of  Chemical
Technology,  3rd ed., Vol. 23, M. Grayson  and  D.  Eckroth,  Ed.   John Wiley  and
Sons, Inc.,  New York.  p.  268-270.

Garke, F.M.,  A.  Dravnleks and  S.M.  Gordon.   1981.   Organic  contaminants  1n
Indoor  air   and  their  relation  to  outdoor  contaminants.   ASHRAE  Trans.
87(1): 153-166.


0032d                               -53-                             08/21/87

-------
Kappeler, T.  and  K. Wuhrmann.   1978.   Mlcroblal  degradation  of the  water-
soluble  fraction of  gas  oil.  IJ. Bloassays  wltn pure strains.  Water  Res.
12(5): 335-342.

Klselev,  A.V.,  V.V.   Hal'tsev,   8.  Saada  and  V.A.  Valovoi.    1983.   Gas
chromatography-mass spectrometry of volatlles released from plastics  used  as
building materials.  Chroraatographla.   17(10):  539-544.

Kle1mJ1enst, I.E., P.B.  Shepson,  £.0.  Edney, L.D.  Claxtou and  L.T.  Cupltt.
1986.  Wood  snake:  Measurement of  the wutagenic  activities  of Us  gas  and
partlculate-phase   photooxldatlon  products,   tnvlron.   Scl.  Techno!.   20:
493-501.

Knaap, A.G.A., C.E.  Voogd  and  P.G.N.  Kramers.  1984.  Hutagenlclty  of vinyl
compounds.  Mutat.  Res.  147(5):  303.

Kool, H.O.,  C.F. Van  Kreljl  and B.C.J. Zoeteman.  1982.   Toxicology assess-
ment  of  organic  compounds  In  drinking  water.   Crlt. Rev. Environ.  Control.
12: 307-357.

Krynskaya,  I.L.,  L.I.  Petrova, Z.G. Gurlcheva,  E.G. Robachevskaya  and  G.M.
Bukevlch.  1969.  Toxlclty of  vlnyltoluene and methods  for Us  determination
1n the air.  G1g.  Sanlt.   34: 40-45.   (In Russian with English translation)

Lewis,  P.J., C.  Hagoplan  and  P. Koch.   1983.    Styrene.  In.:  Klrk-Othmer
Encyclopedia  of  Chemical  Technology,  3rd ed.,  Vol. 21,  M.  Grayson  and  0.
Eckroth, Ed.  John WHey and Sons, Inc., New York.  p. 793-795.


0032d                               -54-                             08/21/87

-------
Lucas,  S,V.   1984.   GC/MS  analysis  of  organlcs  In  drinking  water  concen-
trates  antj  advanced  waste treatment concentrates.  Vol.  1.  Analysis  results
for  17 drinking  water,  16 advanced  waste  treatment  and  3  process  blank
concentrates.  IPA 600/1-84-Q20A.

Lyman,  «.0.,  W.F.  Reehl  and  D.H. Rosenblatt.   T982.   Handbook  of  Chemical
Property Estimation Methods.  McGraw-Hill Book  Co., New York.  p. 4-9;  5-10;
15-16 to 15-29.

Mill, T. and W.  Mabey.  1985.   Photochemical  transformations.   In.:  Environ-
mental  Exposure from  Chemicals,  Volume I, W.B.  Neely  and G.E. Blau,  Ed.  CRC
Press,  Inc., Boca Raton, FL.  p. 208-210.

Mody, N.V., A.A. Delia  Cruz, D.H.  Miles  and P.A. Hedin.  1975.   Constituents
of  marsh  grass.    V.  Essential   oil  of D1st1ch11s  splcata.   Phytochemlstry.
14(2):  599-601.

MRI  (Midwest  Research Institute).  1984a.   Study  of  the Inhalation  carclno-
genlclty (bloassay) of  vinyl  toluene in  B6C3F1  mice.   Final  Chronic  Report.
Performed for the NTP under  Contract No.  N01-ES-38042.

MRI  (Midwest  Research Institute).  1984b.   Study  of  the Inhalation  carclno-
genldty (bloassay) of  vinyl  toluene in  F344/N  rats.   Final  Chronic  Report.
MRI  Project  No.   7801-E-2.   Performed   for  the  NTP  under  Contract  No.
N01-ES-38042.
0032d                               -55-                             08/21/87

-------
NIOSH  (National Institute for Occupational  Safety  and  Health).   1987.   RTECS
(Registry of Toxic Effects of Chemical Substances).  Online:  January,  1987.

Norppa; H.  1S81a.  The In vitro  Induction  of  sister  chromatld  exchanges and
chromosome  aberrations   In   human   lymphocytes   by   styrene   derivatives.
Cardnogenesls.  2: 237-242.

Horppa,  H.   1981b.   Sytrene and  vlnyltoluene 1nduc«  mlcronutlel  1n  mouse
bone fliarrow.  Toxlcol. Lett.   8: 247-251.

Norppa,  H.  and H.  Valnlo.   1983a.   Induction of  slster-chromatld  exchanges
by styrene analogs 1n cultured human lymphocytes.   Mutat. Res.  116: 379-387.

Norppa,  H.  and H. Valnlo.   1983b.   Genetic toxldty of styrene  and  some of
Its "derivatives.  Scand J. Worlc Environ. Health.   9:  108-114.

Norppa,  H., E.  Skyttae,  M.  Conner,  H.  Sorsa  and  H.  Valnlo.   1981.   Mutagen-
1c1ty of vinyl toluene.  Mutat. Res.  85: 294.

NTP  (National  Toxicology Program).   1987.  Management  Status   Report  dated
01/09/87.

Ogata, M.,  K.  Fujlsawa, Y. Oglno  and  E. Mano.   1984.   Partition coefficients
as  a  measure  of  bloconcentratlon potential of  crude oil compounds  In fish
and shellfish.  Bull. Environ. Contam. Toxlcol.  33:  561-567.
0032d                               -56-                             08/21/87

-------
 OSHA  (Occupational Safety  and Health  Administration).   1985.  Occupational
 Standards.  Permissible Exposure Limits.  23 CFR 1910.1000.

•Perry,  R.H.  and D. Green.   1984.   Perry's Chemical  Handbook.  Physical and
 Chemical  Data,  6th ed.  McGraw Hill, New York, NY.  p. 3-58.

 Sadtler.  1960,  4418 UV.  Sadtler Research Laboratories, Philadelphia,  PA.

 Sadtler.  1965.  8303 UV.  Sadtler Research Laboratories, Philadelphia,  PA.

 Savolalnen,  H.  and P.  PfaffH.   1981.  Neurochemlcal  effects of short-term
 Inhalation  exposure  to vlnyltoluene vapor.   Arch.  Environ. Contain. Toxlcol.
 10: 511-517.

 Seppalalnen,  A.M.    1985.    Organic  solvents  and  the  nervous  system.   J.
 Neurochem.  44: 189.

 Seppalalnen,  A.M.  and  H.   Savolalnen.   1982a.   Impaired  nerve  function In
 rats after prolonged exposure to vlnyltoluene.  Arch. Toxlcol.  5: 100-102.

 Seppalalnen,  A.M.  and  H.   Savolalnen.   1982b.   Dose-dependent neurophyslo-
 loglcal  and  biochemical effects  of  prolonged vlnyltoluene vapor Inhalation
 In rat.   Neurotoxlcology.  3: 36-43.

 Sjoborg,  S.,  I.   Dahlqulst,  S.  Fregert  and L.   Trulson.   1982.   Contact
 allergy  to  styrene with cross  reaction to vlnyltoluene.   Contact  Derm.  8:
 207-208.
0032d                               -57-                             08/21/87

-------
SRI  (Stanford  Research  Institute).    1985.    1985  Directory  of  Chemical
Producers:  United  States  of  America.   SRI International,  Menlo Park,  CA.
p. 723.

SRI  (Stanford  Research  Institute).    1986.    1986  Directory  of  Chemical
Producers:  United  States  of  America.   SRI International,  Menlo Park,  CA.
p. 1084.

Suffet,  I.H.,  L.  Brenner  and  P.R.   Cairo.   1980.   Gas  chromatography-mass
spectrometry Identification of  trace  organic*  in  Philadelphia, Pennsylvania,
USA drinking waters during a two year  period.   Water Res.   14: 853-867.

Swann, R.L., D.A.  Laskowskl,  P.J.  McCall, K.  VanderKuy and  H.3.  Dlshburger.
1983.   A rapid  method  for the  estimation of  the environmental  parameters
octanol/water  partition  coefficient,   soil  sorptlon constant,  water  to  air
ratio and water solubility.  Res. Rev.  85: 17-28.

U.S. EPA.   1977.   Computer  print-out  of  nonconf1dent1al  production data from
TSCA Inventory.  OPTS, CIO, U.S. EPA,  Washington,  DC.

U.S.  EPA.  1980.   Guidelines and  Methodology Used  1n  the  Preparation  of
Health  Effect  Assessment   Chapters   of  the  Consent   Decree Water  Criteria
Documents.  Federal Register.   45(231): 49347-49357.
0032d                               -58-                             08/21/87

-------
U.S.  EPA.    1984.    Methodology   and   Guidelines  for  Reportable  Quantity
Determinations  Based  on Chronic  Toxldty  Data.   Prepared  by the  Office of
Health  and  Environmental Assessment,  Environmental Criteria  and  Assessment
Office, Cincinnati, OH  for  the  Office  of Solid Waste and Emergency Response,
Washington, DC.

U.S.  EPA.   T985.   Reference  Values for  Risk  Assessment.   Prepared  by  the
Office  of  Health  and Environmental Assessment,  Environmental  Criteria  and
Assessment Office,  Cincinnati,  OH  for  the  Office  of Solid Waste, Washington,
DC.

U.S.  EPA.   1986a.  Methodology  for Evaluating Potential  Carclnogenlclty In
Support  of  Reportable Quantity Adjustments  Pursuant to  CERCLA  Section 102.
Prepared by  the  Office  of Health  and Environmental  Assessment,  Carcinogen
Assessment Group, Washington, DC  for the Office of Solid Waste and Emergency
Response, Washington,  DC.

U.S.  EPA.    1986b.   Guidelines  for   Carcinogen   Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

U.S.  EPA.  1987.   Graphical Exposure  Modeling  System  (GEMS).   Octanol/Water
Partition  Coefficient (CLOGP)  and/or  Fate  of  Atmospheric  Pollutants  (FAP)
computer data systems.  U.S. EPA,  Research  Triangle Park, NC.

USITC  (U.S.   International  Trade  Commission).   1986.   Synthetic  Organic
Chemicals.    United States  Production  and  Sales,  1985.   USITC Publ.  1892,
Washington, DC.  U.S.  International Trade Commission,  p. 44.


0032d                               -59-                             08/21/87

-------
Va1n1o,  H.,  M.D.  Waters  and  H.  Norppa.   1985.   MutagenlcHy  of  selected
organic solvents.  ScaraL  J.  Work  Environ.  Health.  11:  75-82.

Waggott,  A.    1981.   Trace  organic < substances  In   the  Elver   Lee  (Great
Britain).  Chem. Water Reuse.  2:  55-99.

Weast,  R.C.,  Id.  1985.   CRC  Handbook  of Chemistry and  Physics, 66th  ed.
CfiC Press. Inc.. Boca Raton,  FL.   p. .C-499.

Wolf,  M.A,,  V.K.  Rowe,  0,D. McColHster,  R,C.  HolUngsworth and F.  Oyen.
1956.   lexicological  studies of  certan  alkylated  benzenes and benzene.   Am.
Med. Assoc. Arch. Ind. Health.   14:  387.
0032d                               -60-                             08/21/87

-------
                                  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

-------
tl
0
e
»
i.
Ol
4)
oc
«
C7
^
O
c*
«4
s
1
1
1
IB
»
(
ro (O IO
» w *•
00 00 OB
en en en
. « .
ec oc o «
, >.
t>
4. L. 13 >.
°° >5
• »••>» Ji ~X
E  E
f>» 5""^ E
5j> g 5> »
«
i
i
3
3 •
3 O
s
K .  S
oo

-------
    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

-------


































CO
z
bU
Q.
Q.
*




















































»•»
(/»
1
wi
t
1 Ct
1
^
e
*9
1
E
g

~
VI
Ol
C
01
b.
^^

to
•^
11
„_
o
01
3
X
X
r-
£•
b.
VI
3
C

L.
O


0)
\
3
























0)
' U
c
«i
0)
tk
,ee

*
O"

f_
o
a

at









^
u
0)
v^
bbl














01
b.
3
VI
O
0.
X
bU





I/I
0)

u
01
0.




















t>

00
91
f"
•
CE

O
II >>
E "I
•x -o
ft

O CD
0 0



•• c
.c o

•^ i/i
»4!
><«
•o u

**
T} >»
i o

^3  Ol
u u




01
Ol
*^ I/I
II"

u"1 I/I
co • ,^
• >| 01
Q3 TI 01
I/i CO
E b. o
0. 3 r-
O. O
.C b.
e o

Ol
i/i
3




Ol
u
3
VI
O
Q
X


C U
o «-
— c
•W O

r* £
t) U

C 3
IQ

oo
gn
!"•
•
QC C3
U
O
_ ^^
E ^
•x -0
|f

O 03
O O •-



||

^- i/i
3 i—
>»•<-•
•D u
O i
S 0

^J |fl
O ^
U ^
3 &
u 4) a
L. l_ I— i




4>
1
^ I/I
S < 01
co 'o oi
» -a 3
"™* I/I C"?
EL. 0
3 i—
0. 0
.C b.
o o ea

01

3
i s






^t

^m
U

c
Ol
Ol
U 0
— c
c *~
0 U
b. k.
£ "3
r ^ * *
fQ IT! T)

03 03 CO

F"* *•" ^
.
ac ce iB oe o
* .K *• X •_ -
•S >» -o >•

^/^ ^ \
?^ 2*
o* E
» f
o o o o
• ^ * IM ^S
O O O O <-i



-^ c — c
f O £ O

«• VI ^ l/t
3 .2 3 r^
>»»• >»»*
•O U T3 U
O  -o t)

o — u —
30, 3 O.
"2 £ 01 01 O
l_ b. b. u •— '




Ol 01
01 01
«^ s^
•^ I/I *— » VI
E £ E S"
v. -o -x -o
S? 5*
VI 1^
C") • ^ CO • ^£
• >i 01 • >< 01
O3 tV 01 CO TJ 01
» ^ 3 » ^ 3
VI C*> VI CO
E u O E b. 0
Q. 3 I— O. 3 f—
Q. O O. O O
£ b. £ b. O
o o o o o o o

01 01
VI VI
3 3
i i s
1^ 4^
u ^
W5 — U
bU X —
— i O C
1— 1— 01
h- u O
X Z — C
—• « e —
01 —300
b. O O b. b.
3 •- JB O ^ b. W CU VI VI
b. 3 -C n bu  u u oe 03 co


























































T)

T)
•a

c
01

u

It.
1^,
3
VI
c
1— 1

II

o
no/oi

-------