-ERA
        United States
        Environmental Protection
        Agency
                                                          FINAL DRAFT
                                                          ECAO-CIN-G082
                                                          March, 1991
        Research  and
        Development
         HEALTH AND  ENVIRONMENTAL  EFFECTS  DOCUMENT
         FOR 4-METHYLPHENOL
        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                    DRAFT:  DO NOT CITE OR QUOTE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 1s 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  1s being circulated for comments
g?on Us technical accuracy and policy Implications.
CO
                         .  j:.;.'RTtRS LIBRARY
                        . ..'•-•li.'jIJMLNTAL PROTECTION AGENCY
                        WASHINGTON, D.C. 20460

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                                                DISCLAIMER

                  This  report 1s  an  external draft  for  review purposes only and  does  not
              constitute  Agency  policy.   Mention  of  trade names  or  commercial  products
              does not  constitute endorsement or recommendation for  use.
1
                                                    1.1

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                                    PREFACE
    Health and  Environmental  Effects  Documents (HEEOs) are prepared  for  the
Office of Solid  Waste  and Emergency Response  (OSWER).  This  document  series
1s Intended to support listings under  the  Resource  Conservation  and Recovery
Act  (RCRA) 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  for  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 In  "Appendix: Literature  Searched."
Literature search  material  Is  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 Is sent to the  Program Officer  (OSWER).

    Several quantitative  estimates are  presented  provided  sufficient  data
are available.   For systemic toxicants,  these  Include Reference  doses  (RfDs)
for  chronic  and  subchronlc  exposures  for  both  the  Inhalation  and  oral
exposures.  The  subchronlc  or  partial  lifetime RfD  Is  an  estimate of  an
exposure  level   that  would  not  be expected  to  cause  adverse  effects  when
exposure occurs  during a  limited  time  Interval  I.e.,  for an Interval  that
does  not  constitute a  significant portion  of the  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  Is  the same as  traditionally employed for  chronic  estimates,
except that subchronlc data are utilized  when available.

    In the case  of suspected carcinogens,  RfDs are  not estimated.   Instead,
a  carcinogenic  potency   factor,  or   q^*   (U.S.  EPA,  1980),  Is  provided.
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 toxlclty  and carclno-
genldty are derived.  The RQ Is  used  to determine  the quantity  of a hazard-
ous  substance  for  which   notification  1s  required In the event  of  a  release
as  specified  under  the   Comprehensive  Environmental Response,  Compensation
and  Liability  Act  (CERCLA).   These  two  RQs  (chronic toxUHy  and cardno-
genUlty) represent two of six  scores  developed  (the  remaining  four  reflect
IgnltabllUy,   reactivity, aquatic toxlclty,  and acute mammalian  toxlclty).
Chemical-specific  RQs reflect the lowest of  these six primary criteria.   The
methodology for  chronic   toxlclty and  cancer  based  RQs  are  defined  In  U.S.
EPA, 1984 and  1986a, respectively.
                                      111

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                               EXECUTIVE  SUMKARY

    4-Methylphenol  Is  a  solid  at room temperature.  It has  a  phenolic  odor,
and  1s  soluble  In  water and common  organic  solvents  (Sax and  Lewis,  1987;
Wlndholz  et  al.,   1983).   It   Is  produced  commercially   by  the  fractional
distillation  of  the mixture  of  methylphenols  obtained  from coal  tar.   It can
also  be  produced using  p-cymene as  a starting material.   Production  volume
In  1977  was   between  30  and   90  million  pounds  (TSCAPP,  1989).   Current
production volumes  could not be located;  however,  combined production  volume
for  all  methyl  phenols, excluding  that  produced  from  coke and  gas-retort
ovens, was >73 million pounds In 1987 (USITC, 1988).
    4-Methylphenol  1s  used  In  a  wide  variety  of applications,  Including
disinfectants,  resins,  ore  flotation,  textiles,  food  flavors,  and  as  an
Intermediate  In  the manufacture of  other  organic compounds (Sax  and  Lewis,
1987).
    In  the  atmosphere,  4-methylphenol Is  expected to exist almost  entirely
In the vapor  phase  (Elsenrelch  et  al., 1981;  Cautreels and Van Cauwenberghe,
1978).    The   gas-phase   reaction   with   photochemlcally-produced  hydroxyl
radicals  1s expected  to  be  rapid,  with  an estimated  half-life  of 10  hours.
The  nighttime degradation  of   4-methylphenol  In  the  atmosphere  over  urban
areas  Is also expected  to be rapid (Atkinson,  1985).   Rain  washout  and
photolysis may occur,  but they are  not  expected  to be competitive processes
(Gaffney  et al.,  1987; Cupltt,  1980).  If released  to water,  blodegradatlon
Is expected   to  occur  under  both aerobic  and  anaerobic  conditions.   This
process  may   be  rapid  under  certain  conditions.   Acclimation  periods  vary
widely  (Lewis  et al.,  1986).   Hydrolysis  and oxidation are not expected to
be  significant.    Available  data  on  the  adsorption   of  4-methylphenol  to
                                      1v

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 sediment  and suspended matter,  as  well as  data  on the photolytlc breakdown
 of  this compound  In water,  suggest  that  the  Importance  of these processes
 varies  with the local conditions.  Under certain conditions, these processes
 may  be  significant.  If released to  soil,  4-methylphenol  can be expected to
 undergo blodegradatlon.   Adsorption  to  soil  may  be  significant,  but  the
 process 1s  not well  understood  and  1t  appears  to  depend  on  the unique
 properties  of  each  soil.    Volatilization   from  the  soil  surface   to  the
 atmosphere  1s not expected  to be  significant.
     4-Methylphenol   has  been  detected  1n  surface  water, groundwater  and
 rainwater.   Hater  concentrations can vary widely;  however,  high  levels  are
 usually associated   with   Industrial  activity.    4-Methylphenol   has  been
 detected  In surface water  near  the  site  of  the  Mount St.  Helens eruption
 (Mcknight et al.,  1982).   It can enter  the  atmosphere  as  a result of Indus-
 trial activity,  and by the burning of  vegetable  and plant matter  (Hawthorne
 et al., 1988; Ubertl  et al.,  1983;  McKnlght et al., 1982).  Also, 4-Methyl-
 phenol  occurs naturally  In coal  tar  (Sax  and Lewis, 1987).  It Is a product
 of  the  chemical and biological  breakdown  of  benzenold  compounds  (Fatladl,
 1984).
     Occupational  exposure   to  4-methylphenol   may  occur  by Inhalation  and
 dermal  contact  during  Us  manufacture  and  formulation  Into  commercial
 products.    The  general population may be  exposed  by  Ingesting contaminated
water,  or   by  Inhalation and  dermal  contact during the  use  of  commercial
 products  containing  4-methylphenol.   Also,   exposure  to  4-methylphenol  may
 occur by  Inhaling  smoke  from wood  fires  or  from  the  smoke resulting  from
 burning other vegetable matter.
     Data are available  on  the acute  toxlclty  of 4-methylphenol  to salmonld,
warmwater  fish  and  several  Invertebrates.   Acute  toxlclty values  shown  In
Table 4-1  Indicate  that rainbow  trout,  S.  galrdnerl. are more sensitive than

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are  fathead minnows,  P.  promelas.  with  LC5g  values  of 7.9  mg/t and  28.6
mg/t,  respectively (DeGraeve et  al.,  1980).   Fertilized  eggs of  cod  fish,
G.  morhua. and  sea  urchins,  S.  droebachjensls,  are  equally sensitive  to
96-hour  exposure  to  4-methylphenol  (Falk-Petersen  et  al.,   1985).   Damsel
flies,  JL  vert1cal1s.  were not  adversely  affected by  40 mg/i  (Cooper  and
Stout,  1985),  but the  water  flea,  D.  maqna.  showed  50X  lethality  to  a
concentration  of 1.4 mg/i.   Variation  In  sensitivity  between D.  maqna  and
D.  pullcarla,  with  48-hour LC5Qs  of  1.4  and  22.7 mg/i,  respectively,  may
be  explained  by  the  age  difference at  time of  testing (0.   magna were  <24
hours  old  and 0.  pull car la  were <72  hours  old)  (Parkhurst  et  al.,  1979;
DeGraeve et al.,  1980).
    The chronic  toxlclty  of 4-methylphenol  In  the planarlan,  D.  tlgrlna.  was
assessed  by  Solskl   and  Plontek  (1987).   A   240-hour  LC5Q   of   11.08  mg/l
was Identified.  Follow-up  testing  for  four generations  (test  animals cut In
half  and  retested) showed  successively  Increased mortality  at   the  LOEC of
2.0 mg/t, but the LOEC value did not change.
    Chlorophyll  content  and   photosynthesis   are  adversely   affected  (as
evidenced  by  decreased dissolved oxygen  concentrations)  In freshwater  algae
by  4-methylphenol  concentrations  >0.9  mg/t  (Stout  and  Kllham,  1983).   A
72-hour  LCcn  of  50  mg/t  was  Identified  for  chlorophyll content  with  C.
           t>u
pyrenoldosa.  This effect was dose-dependent  (Huang,  1967;  Huang and  Gloyna,
1968).   A  concentration  of  100  yg/cc   (100   mg/t)   severely  Inhibited
growth of  the  unicellular green alga, A. falcatus.  and  totally  Inhibited It
at 500 tig/cc (500 mg/t) (Robinson et al., 1976).
    B1oaccumulat1on/b1oconcentrat1on   studies   were  not   located   1n   the
available  literature,  but  evidence  suggests   that  4-methylphenol will  not
accumulate appreciably In aquatic biota.

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    Bacterial  luminescence  was   reduced  50%  by  5-mlnute  exposure  to  >1.3
mg/i  4-methylphenol  (Lebsack  et  al.,  1981).   An 8-hour  Incubation of  £.
phosphoreum  with 206 mg/l  4-methylphenol  reduced the  number  of fluorescent
cells  by 50%  (Delesmont and  Delattre,  1983).   Growth of the  trlchal  blue
alga,  Phormldlum.  was  totally  Inhibited  by 100  yg/test  spot  of  4-methyl-
phenol  (Benecke and  Zullel,  1977).   Concentrations  of  >500  ppm  4-methyl-
phenol  totally  Inhibited mycellal growth  In the  fungus, A.  flavus (Dube  et
al.,  1988).    A 24-hour EC5Q  of  160  mg/s. 4-methylphenol  was   Identified
with the protozoan, T. pyMformls  {Yoshloka et al., 1985).
    The  effects of  4-methylphenol  on  terrestrial  fauna  were assessed  In
Insects,  birds  and  small  mammals.    An   LD™  for   topical   exposure  to
4-methylphenol   of   80   >ig/an1mal  for  the  housefly,  N.   domestlea,   was
reported  by  Marcus  and  Llchtensteln  (1979).   Oral  L05Qs  Of   96  mg/kg/day
for  the redwing blackbird,  A.  phoenlceus  (Schafer et  al.,  1983) and  1238
mg/kg/day  for  deer  mice, £.  manlculatus   (Schafer  and Bowles, 1985)  were
reported.
    Assessments  of  toxldty  of 4-methylphenol to  terrestrial  plants  Identi-
fied ECcns  of 100,  40-60 and  150 ppm  for  germination, tube production and
tube growth,  respectively,  with  1.  sultanll (Bllderback,  1981).    An  EC5Q
of  122.2 ppm  was   reported  for   fruit  germination In  U  satlva  (Reynolds,
1978) and reduced germination of  sclerotla  was noted  1n S.  ceplvorum  exposed
to 10 ppm 4-methylphenol (A11 et  al.,  1987).
    The  pharmacoklnetlcs  of  4-methylphenol   Involves documented   dermal
(Green, 1975; Anderson  et  al.,  1976;  Roberts et  al.,  1977)  and gastrointes-
tinal (Bray et  al.,  1950) absorption  of the  test  chemical  with distribution
to the  brain,  liver,  blood  and  possibly all organs (Green.  1975).  Metabo-
lism Includes  oxidation  of the  -CK   group of  the  4-methylphenol  to  the

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Intermediates  -CH2OH  and -CHO and  finally  to -COOH, as determined  In. vitro
(Sato  et  al.,  1956).  The  sulfate  conjugates corresponding to  these  Inter-
mediates  and  the final  product  are p-hydroxybenzyl  alcohol,  p-hydroxybenz-
aldehyde  and  p-hydroxybenzolc  add, respectively.  Small amounts  of 3,4-d1-
hydroxybenzolc  add  were also  formed  by  this pathway.  The  |ri  vitro  data
support Jhi  vl.yo  observations.  Excretion data  from  Bray et  al.  (1950)  and
Neuberg  and  Kretchmer  (1911)  Indicate  that  4-methylphenol  1s  excreted
primarily In  the urine  as  sulfate  and glucuronlde conjugates.  Bray  et  al.
(1950) reported  that  an average oral  dose  of 65% was excreted  In the urine
(as total  cresols) within 24 hours.
    Because of  Insufficient evidence  for carclnogenlclty  1n animals  and  no
data  regarding  carclnogenlclty In  humans,  4-methylphenol  Is placed  In  U.S.
EPA welght-of-evidence  Group  D:  not  classifiable  as to carclnogenlclty  to
humans.  Cancer  potency  factors  were not estimated and  the  compound was  not
assigned a cancer-based RQ.
    An RfD of  0.05  mg/kg/day was derived for  subchronlc oral  exposure based
on the NOEL of  5  mg/kg/day  for maternal toxlclty  In a developmental toxldty
study  1n  rabbits (CMA,   1988a).  The NOEL of 5 mg/kg/day also  served  as  the
basis  for an  RfO of  0.005  mg/kg/day for chronic oral exposure  to 4-methyl-
phenol.   The  LOAEL of  175  mg/kg/day  associated with  labored  breathing  1n
rats  In a 13-week  subchronlc  gavage  study  (U.S.  EPA,  1967a)  served  as  the
basis for  an RQ of 1000 for  chronic  (noncancer) toxldty.

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                              TABLE OF  CONTENTS
                                                                       Page
1.  INTRODUCTION	    1

    1.1.   STRUCTURE AND CAS NUMBER	    1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	    1
    1.3.   PRODUCTION DATA	    2
    1.4.   USE DATA	    2
    1.5.   SUMMARY	    2

2.  ENVIRONMENTAL FATE AND TRANSPORT	    4

    2.1.   AIR	    4

           2.1.1.   Reaction with Hydroxyl Radicals 	    4
           2.1.2.   Reaction with Ozone 	    4
           2.1.3.   Photolysis	    5
           2.1.4.   Physical Removal Processes	    5

    2.2.   WATER	    5

           2.2.1.   Hydrolysis	    5
           2.2.2.   Oxidation 	    5
           2.2.3.   Photolysis	    5
           2.2.4.   M1crob1al Degradation 	    6
           2.2.5.   B1oconcentrat1on	    7
           2.2.6.   Adsorption	    7
           2.2.7.   Volatilization	    8

    2.3.   SOIL	    8

           2.3.1.   M1crob1al Degradation 	    8
           2.3.2.   Adsorption/Leaching 	    8
           2.3.3.   Volatilization	    9

    2.4.   SUMMARY	    9

3.  EXPOSURE	   10

    3.1.   WATER	   10
    3.2.   FOOD	   12
    3.3.   INHALATION	   12
    3.4.   DERMAL	   12
    3.5.   OTHER	   12
    3.6.   SUMMARY	   13
                                     1x

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                          TABLE  OF  CONTENTS (cent.)

                                                                       Page
4.  ENVIRONMENTAL TOXICOLOGY	   14

    4.1.   AQUATIC TOXICOLOGY 	   14

           4.1.1.   Acute Toxic Effects on Fauna	   14
           4.1.2.   Chronic Effects on Fauna	   17
           4.1.3.   Effects on Flora	   17
           4.1.4.   Effects on Bacteria and Other Aquatic
                    Microorganisms	   19

    4.2.   TERRESTRIAL TOXICOLOGY 	   20

           4.2.1.   Effects on Fauna	   20
           4.2.2.   Effects on Flora	   20

    4.3.   FIELD STUDIES	   21
    4.4.   AQUATIC RISK ASSESSMENT	   21
    4.5.   SUMMARY	   23

5.  PHARMACOKINETICS	"   26

    5.1.   ABSORPTION	   26
    5.2.   DISTRIBUTION	   27
    5.3.   METABOLISM	   27
    5.4.   EXCRETION	   28
    5.5.   SUMMARY	   30

6.  EFFECTS	   31

    6.1.   SYSTEMIC TOXICITY	   31

           6.1.1.   Inhalation Exposure 	   31
           6.1.2.   Oral Exposure	   31
           6.1.3.   Other Relevant Information	   33

    6.2.   CARCINOGENICITY	   36

           6.2.1.   Inhalation	   36
           6.2.2.   Oral	   36
           6.2.3.   Other Relevant Information	   37

    6.3.   GENOTOXICITY	   37
    6.4.   DEVELOPMENTAL TOXICITY 	   39
    6.5.   OTHER REPRODUCTIVE EFFECTS 	   41
    6.6.   SUMMARY	   41

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                           TABLE OF CONTENTS (cont.)

                                                                        Page

 7.  EXISTING GUIDELINES AND STANDARDS 	   42

     7.1.   HUMAN	   42
     7.2.   AQUATIC	   42

 8.  RISK ASSESSMENT	   43

     8.1.   CARCINOGENICITY	   43

            8.1.1.   Inhalation	   43
            8.1.2.   Oral	   43
            8.1.3.   Other Routes	   43
            8.1.4.   Weight of  Evidence	   43
            8.1.5.   Quantitative Risk Estimates 	   43

     8.2.   SYSTEMIC TOXICITY	   43

            8.2.1.   Inhalation Exposure 	   44
            8.2.2.   Oral Exposure	   44

 9.  REPORTABLE QUANTITIES 	   47

     9.1.   BASED ON SYSTEMIC TOXICITY 	   47
     9.2.   BASED ON CARCINOGENICITY	   51

10.  REFERENCES	   52

APPENDIX A: LITERATURE  SEARCHED	   75
APPENDIX B: SUMMARY TABLE FOR 4-METHYLPHENOL 	   78
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
            4-METHYLPHENOL 	   79
                                      X1

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                               LIST OF  TABLES
No.                               Title                               Page
4-1     Acute Effects of 4-Methylphenol on Aquatic  Fauna	   15
6-1     Acute Effects of 4-Methylphenol 	   34
6-2     Mutagenldty and GenotoxUHy of 4-Hethylphenol	   38
9-1     Tox1c1ty Summary for 4-Methylphenol 	   48
9-2     Composite Scores for Orally Administered 4-Methylphenol  ...   49
9-3     4-Methylphenol:  Minimum Effective Dose (MED)  and
        Reportable Quantity (RQ)	   50

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                             LIST OF ABBREVIATIONS
AEL
BCF
BOD
CAS
CNS
cs
D/h2

DM8A
DNA
"50
PEL
FR
Km
LC50

LD50

LDfr
LOAEL
LOEC
Adverse effect level
Bloconcentratlon factor
Biological oxygen demand
Chemical Abstract Service
Central nervous system
Composite score
Ratio of the diffusion coefficient to the square
of the membrane thickness
Dimethyl benzanthracene
Deoxyrlbonuclelc acid
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Frank effect level
Treated food refused as a percentage of food
offered over a 3-day period
Median mobilization concentration
Membrane: vehicle partition coefficient
Soil sorptlon coefficient
Octanol/water partition coefficient
Permeability coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
(and all other subscripted dose levels)
Amount of chemical Ingested during FR test that
killed 50% of test animals
Lowest dose lethal to recipients
Lowest-observed-adverse-effect level
Lowest observed effects concentration

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                         LIST OF  ABBREVIATIONS  (cont.)

NEO                     Minimum effective dose
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
NOEL                    No-observed-effect level
PLAN                    Plasma leuclne amlnonaphthylamldase
ppb                     Parts per billion
ppm                     Parts per million
ppt                     Parts per trillion
RfD                     Reference dose
RQ                      Reportable quantity
RV
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                               1.  INTRODUCTION
 1.1.   STRUCTURE AND CAS NUMBER
    4-Methylphenol   1s   also  known   by  the  synonyms  p-cresol,  4-cresol,
 p-cresyllc  acid,  p-hydroxytoluene, p-methylhydroxybenzene,  p-tolyl  alcohol,
 4-toluol  and  others  (Chemllne,  1989;  SANSS,  1989).   The structure,  CAS
 Registry number, empirical formula and molecular weight are given below:
                                    OH
CAS Registry number:  106-44-5
Empirical formula:  C,HQ0
                      / o
Molecular weight:  108.13
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    4-Methylphenol  1s  a  solid at  room temperature and has  a  phenolic  odor.
It  Is  soluble  1n polar organic solvents  (for  example,  chloroform,  ether  and
alcohol)  and  In  water   (Sax  and  Lewis,  1987;  VMndholz  et  al.t  1983}.
Selected physical properties for 4-methylphenol are given below:
    Melting point:
    Boiling point:
    Density (20°C):
    Vapor pressure (25DC):
    Water solubility (25°C):
    Log Kou:
    Flash point:
    Conversion factor:
34.8°C
201.9°C
1.0178 g/ma
0.11 mm Hg
21,520 mg/i
1.94
86'C
1 ppm =4.42 mg/m3;
1 mg/m3 = 0.226 ppm
Weast et al., 1988
Weast et al., 1988
Weast et al., 1988
Chao et al., 1983
Yalkowsky et al., 1987
Hansch and Leo, 1985
Wlndholz et al., 1983
0219d
     -1-
                03/21/90

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1.3.   PRODUCTION DATA
    4-Methylphenol  1s  manufactured  by   the  fractional  distillation  of  a
mixture  of  Isomerlc  cresols  (methylphenols),  which  are  components of  coal
tar.   It can  also  be  obtained  by  the  cumene  process using  p-cymene as  a
starting material  (Sax  and Lewis,  1987).   Data  from the  U.S. EPA  TSCA  pro-
duction  file (TSCAPP, 1989) Indicate  that during  1977,  27  U.S.  manufacturing
plants  produced  between  30.1  and  90.1  million  pounds  of  4-methylphenol.
Primary  production   sites  were   located   In   Chicago,   IL;   Dublin,   OH;
Follansbee,  WV; Venango,  PA;  and Elizabeth, NJ  (TSCAPP, 1989).   More  recent
production  data could  not  be located;  however,  combined production  volume
for all  methyl phenols,  excluding  that  produced from coke and  gas-retort
ovens, was >73 million pounds  In 1987 (USITC,  1988).
1.4.   USE DATA
    4-Methylphenol Is used as a  disinfectant, In  phenolic  resins,  ore  flota-
tion and synthetic food flavors,  as  a textile scouring  agent,  surfactant and
organic  Intermediate,  and  In  the  manufacture  of saHcylaldehyde,  coumarln
and herbicides  (Sax and Lewis, 1987).
1.5.   SUMMARY
    4-Methylphenol 1s a solid  at room temperature.   It has  a  phenolic odor,
and Is  soluble In water  and  common  organic  solvents (Sax and  Lewis,  1987;
Hlndholz  et al.,  1983).    It Is  produced  commercially  by  the  fractional
distillation of the mixture of methylphenols obtained from coal  tar.   It can
also be  produced  using p-cymene  as  a starting  material.   Production  volume
In  1977 was   between  30  and 90  million  pounds (TSCAPP,  1989).   Current
production volumes could  not  be  located;  however,  combined production  volume
for all  methyl phenols,  excluding  that  produced from coke and  gas-retort
ovens, was >73 million pounds  In 1987 (USITC,  1988).

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     4-Methylphenol  Is  used  1n  a  wide  variety  of  applications,  Including
 disinfectants,  resins,   ore  flotation,  textiles,  food  flavors,  and as  an
 Intermediate  In  the manufacture of  other  organic compounds  {Sax  and Lewis,
 1987).
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                     2.  ENVIRONMENTAL FATE  AND  TRANSPORT
2.1.   AIR
    Based  on  a vapor  pressure  of 0.11 mm  Hg at  25°C  (Chao  et al., 1983),
4-methylphenol  Is  expected to  exist  almost entirely 1n  the  vapor phase In
the  ambient  atmosphere  (ElsenreUh   et  al., 1981).   Participate 4-methyl-
phenol  was   not  found  In  urban  air   samples   containing   this   compound
(Cautreels and Van Cauwenberghe, 1978).
2.1.1.   Reaction with Hydroxyl  Radicals.    An  experimental  rate  constant
for  the   gas  phase  reaction  of  photochemically-produced  hydroxyl  radicals
with  4-methylphenol   was   determined  to  be  3.8xlO~11   cmVmolecule-sec  at
26°C  (Atkinson,  1985).   If the average atmospheric hydroxyl  radical  concen-
tration  Is 5xl05  molecules/cm3  (Atkinson,  1985),  then   the  half-life  for
this  reaction  1s  10  hours.  Thus, the  atmospheric destruction of 4-methyl-
phenol by hydroxyl radicals Is  expected  to be a  dominant fate  process.
    The experimental  rate  constant for the reaction  of 4-methylphenol with
nitrate  radicals  was  determined  to  be  13xlO"12 cmVmolecule-sec  at 27°C
(Atkinson  et  al.,  1984;   Carter  et  al.,  1981).   Using   a  nitrate   radical
concentration  of  2.4x10"  molecule/cm3  (Atkinson,  1985),   the  half-life
for this reaction would be 3.7  minutes.   This value suggests  that  the night-
time  degradation  of  4-methylphenol   1n   urban  areas  will be  an Important
atmospheric fate process.
2.1.2.   Reaction with Ozone.   Experimental  rate  constants for the  reaction
of  4-methylphenol  near   room  temperature  were  reported   to  range  from
1.4xlO"18   to  4.71xlO~"  cmVmolecule-sec   (Atkinson  and   Carter,  1984).
If  an  average  atmospheric   ozone  concentration  Is   IxlO12  molecule/cm3,
then the half-life for this reaction  can  be  calculated to  be  5.7-13.4 days.
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 2.1.3.    Photolysis.   Since  4-methylphenol  can absorb  light  In  the environ-
 mentally  significant  range >290  nm,  It Is a candidate for direct photochemi-
 cal  degradation.   This  process  Is not expected  to be able  to  compete with
 the  blmolecular  pathways discussed previously, however, and  H  may not be a
 significant fate process  (Smith et al., 1978).
 2.1.4.    Physical  Removal Processes.   The  relatively high  water  solubility
 of  4-methylphenol,  21,520 mg/i  at 25°C  (Yalkowsky et al.,  1987),  suggests
 that  atmospheric  removal  by  wet  deposition  may  be  a  significant  process
 (Gaffney  et  al..  1987).  However,  CupHt (1980)  suggested  that  this  removal
 process  would be  unlikely  for this  compound  because of  Us  expected  rapid
 rate of chemical degradation.
 2.2.   WATER
 2.2.1.    Hydrolysis.   Since   4-methylphenol  contains  no  hydrolyzable  func-
 tional groups, hydrolysis at  environmentally  significant  pHs 1s  not expected
 to be an  Important fate process (Harris, 1982; Kolllg et al., 1987).
 2.2.2.    Oxidation.   A  rate  constant  for  the   reaction  of  4-methylphenol
 with  peroxy  radicals  was  estimated   to  be   20   i/molecule-sec  In  aquatic
 media  (Smith  et  al., 1978).   If  the  average peroxy  radical  concentration
 equals  1x10-9  mol/8.  (Hill   et al.,   1980),  then  the  half-life  for  the
 oxidation  of  4-methylphenol   In  aquatic media would  be 1 year.  Humlc  acid
 accelerated  this  process  slightly   (Smith  et   al.,  1978).   Oxidation  of
 4-methylphenol In water  Is,  therefore,  not  expected to be a significant fate
 process.
 2.2.3.    Photolysis.   4-Methylphenol   1n  distilled  water had  an  estimated
 half-life  of  70  days  when 1t was  exposed to 8 hours  of natural  sunlight per
 day  (Smith et  al.,   1978).   When  humlc  add was present  In  solution  (10
 wg/l),  the rate  of   photodegradatlon   Increased   by a  factor  of 12.   Based
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on  literature quantum  yield  values,  the  authors  estimated  that  the half-life
for  photodegradatlon  was between  200  and 400  days  using a  hand  calculator
and  a computer  model, respectively.  No  rationale  was  given  for the  dis-
crepancy.  Different results  were  obtained when  4-methylphenol  was subjected
to  sunlight  photolysis  In  water   from  Lake  Grelfensee,  Switzerland.   The
half-life In the  top meter of water  was  determined to be 4.4 days  (Faust and
Holgne,  1987).    Therefore,   photochemical degradation  1n  water  may  be  an
Important fate  process  1n clear  surfaclal  water  where the  attenuation  and
scattering of sunlight are minimal.
2.2.4.   H1crob1al  Degradation.    4-Methylphenol   blodegraded  rapidly   In
environmental waters Including eutrophlc  lakes and ponds,  rivers,  creeks and
bays  (Smith  et  a!.,  1978;  Rogers  et  al.,  1964;  Van  Veld and  Spain.  1983;
Spain and Van  Veld, 1983).    Complete  degradation  of  4-methylphenol  occurred
within 6  days  In water  obtained from  Lake  Tahoe,  NV.   In a  eutrophlc  pond,
degradation was  complete within 8.5 hours,  after  an  Initial  5.5- to  6-hour
lag  period.   In  two   fish  ponds,   the half-life  for  the blodegradatlon  of
4-methylphenol   was  2-7  hours  after  a  30- to  56-hour acclimation  period
(Smith et al., 1978).  In three rivers located  1n  the Pacific Northwest, the
half-life for blodegradatlon  ranged  from 1-10 hours after a  2-day Induction
period (Rogers et al., 1984).  The  lag time  for  acclimation  of the mlcroblal
population  to  4-methylphenol  was  found to  vary widely  as  a function  of
nutrients present 1n the media (Lewis et al., 1986).
    Blodegradatlon  of  4-methylphenol  was  slow  In ollgotrophlc lake  water,
with an estimated half-life  MOO  days  (Smith et al.,  1978).   4-Methylphenol
blodegraded rapidly 1n screening  studies using  sewage,  activated  sludge and
freshwater Inocula  (Alexander  and  Lustlgman,  1966; Babeu and Valshnav,  1987;
Balrd  et  al.,  1974;   Heukeleklan  and Rand,  1955;  KHano,  1978; Lund  and


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Rodriguez,  1984;  Fitter,  1976; Thorn  and  Agg, 1975).   Phenol  was Identified
as an Intermediate 1n these blodegradatlons (Young and Rivera, 1985).
    Under  anaerobic  conditions,   the  mineralization  of 4-methylphenol  was
complete  In  3 and 8  weeks  In different studies that  used  a  digester sludge
seed  (Boyd  et  al.,  1983;   Shelton  and  Tledje,  1984).   No   degradation  of
4-methylphenol  was observed   In  a study  that  used a  lake   sediment  seed;
however,  using  two different  sewage sludge seeds, degradation occurred  at  a
rate  equal  to 51% removal  after  4 weeks,  and  complete loss  after  3 weeks,
respectively  (Horowitz   et   al.,   1982).    4-Hethylphenol,  at  an  Initial
concentration of  100  and 400  ppb,  underwent  mineralization after  a 15- and
39-day  acclimation  period,  respectively,  using an anaerobic  sludge Inoculum
(Fedorak  and  Hrudey,  1984).   4-Methylphenol degraded completely In  8 days 1n
groundwater  under anaerobic  conditions  (Delflno  and  Miles,   1985).   Using
lake  water   and   swamp   water  Inocula,   4-methylphenol  underwent  aerobic
degradation (Hwang et al.. 1989).
2.2.5.    Bloconcentratlon.   The BCF  for  4-methylphenol,   as  determined  by
the  regression  equation  log  BCF = 0.76 log  K    -   0.23 (Bysshe, 1982),  can
be  determined to  be  17.6,  based  on  the  log K   of  1.94  (Hansch  and  Leo,
1985).   This  value suggests  that  the bloconcentratlon  of  4-methylphenol  In
fish and aquatic organisms may not be an Important fate process.
2.2.6.   Adsorption.  Adsorption to  sediment  was determined  to be  -0.3X of
the  total  4-methylphenol  concentration  In ponds, 0.0554  1n  lakes  and 0.1% 1n
rivers  (Smith et al., 1978).   These data  suggest  that adsorption to sediment
and suspended organic matter  may not  be an  Important fate  process.   However,
the adsorption  characteristics  of  phenols are Influenced by a wide range of
factors  (Section  2.3.2.), and under  certain  conditions, adsorption  can  be  a
significant fate process.
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2.2.7.   Volatilization.   Based  on  the  water   solubility,  21,520  mg/l  at
25°C  (Yalkowsky  et a!.,  1987),  and  the vapor pressure,  0.11  mm Hg at  25°C
(Chao  et al.,  1983),  a  Henry's  Law  constant  of 7.95xlO~7  atm-m3/molecule
can  be  calculated  (Thomas,  1982).   Using  the  group  method  of  H1ne  and
Mookerjee  (1975),  a  value  of  7.05xlO~7  atm  mVmolecule  at  25°C  can  be
obtained.  Based  on these  values,  a  volatilization  half-life from a  model
river  1 m deep,  flowing at 1 m/sec, with  a wind velocity of  3  m/sec can be
estimated to be -50 days (Thomas, 1982).
2.3.   SOIL
2.3.1.   Mlcroblal  Degradation.   A  concentration decrease as  a  function  of
depth  for  4-methy!phenol   In  well  samples  taken   near  a  wood  preserving
facility could  not  be accounted for  by  dilution,  and the  discrepancy  was
attributed to the  blodegradatlon  of  this compound In  soil  (Goer 1 Hz  et al.,
1985).   4-Hethylphenol degraded  completely  In  soil  after  7 days  with  an
application rate of 500 mg/kg (Huddleston et al., 1986).
2.3.2.   Adsorption.   Experimental   K    values  for  4-methylphenol   ranged
from  19-49   (Boyd,  1982;  Roy  and  Griffin,  1985),  suggesting  a  very  high
mobility In  soil   (Swann  et  al.,  1983).   The pH, mineral or  metal  content,
and  organic   make-up  of  the  soil  appear   to  be  Important  factors   that
Influence the ability  of  4-methylphenol  to leach  through  soil; under  certain
conditions,   Its mobility may decrease,  and H  can be  strongly  held  to soil
(Artlola-Fortuny and Fuller, 1982).
    The  potential  for  4-methylphenol  to leach  Into groundwater  varies.   If
rapid  blodegradatlon or  strong  adsorption  to soil  occurs,  then contamination
of  groundwater  would  not   be   expected.    Since   high   concentrations  of
4-methylphenol  can  be  toxic  to the  mUroblal  population,  however,  the
compound may  leach Into groundwater.   This  phenomenon has been  observed 1n


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 leachate  from land fills or dump  sites,  and near underground coal gasifica-
 tion  sites  (Sawhney  and Kozloskl,  1984; Dunlap  et  al.,  1976;  Stuermer et
 al..  1982; McCreary et al., 1983).
 2.3.3.    Volatilization.  The  vapor pressure of  4-methylphenol,  0.11 mm Hg
 at  25°C  (Chao et al., 1983),  suggests  that  volatilization from dry soil may
 occur,  but  It  Is  not expected  to  be a  rapid  fate  process.  Volatilization
 from  moist soil  1s not expected  to  be significant.
 2.4.   SUMMARY
    In  the atmosphere,  4-methylphenol  Is expected to  exist almost entirely
 In  the vapor phase (Elsenrelch et  al.,  1981; Cautreels and  Van Cauwenberghe,
 1978).    The  gas-phase  reaction   with   photochemically-produced  hydroxyl
 radicals  Is  expected to  be  rapid,  with  an  estimated  half-life  of 10 hours.
 The  nighttime  degradation  of  4-methylphenol  1n  the  atmosphere  over  urban
 areas  Is  also   expected  to  be rapid  (Atkinson, 1985).   Rain  washout  and
 photolysis may  occur,  but they  are  not expected  to  be competitive processes
 (Gaffney  et  al., 1987;  CupHt,  1980).  If released  to water, blodegradatlon
 Is  expected   to  occur under  both  aerobic   and  anaerobic  conditions.   This
 process  may   be  rapid under  certain conditions.   Acclimation  periods  vary
 widely (Lewis  et al., 1986).   Hydrolysis and oxidation  are not  expected to
 be  significant.   Available  data   on  the  adsorption   of  4-methylphenol  to
 sediment  and suspended  matter,  as  well  as   data  on  the photolytlc breakdown
 of  this  compound  In  water,  suggest  that the Importance  of these processes
 varies with  the  local conditions.   Under  certain  conditions, these processes
 may be significant.   If  released to soil, 4-methylphenol  can be expected to
 undergo  blodegradatlon.   Adsorption to  soil  may be  significant, but  the
 process  Is  not  well  understood  and  It  appears to  depend  on  the  unique
 properties  of  each   soil.   Volatilization  from  the   soil  surface  to  the
 atmosphere 1s not expected to be significant.
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                                 3.  EXPOSURE

    4-Methylphenol  can  enter  the  environment  In  wastewater  from a  broad
range  of  Industrial classifications.   It  has also  been found  In  emissions
from  automobile and dlesel  engines,  wood  pulping  and  brewing  glass  fiber
manufacture,  as well  as In tobacco  smoke  (Graedel,  1978).   4-Methylphenol
occurs  naturally and  can be  formed  by  the  high  temperature  breakdown  of
other  naturally-occurring materials  (Hawthorne et al.,  1988).   It  can enter
the environment through the chemical  and  biological  breakdown  of  benzenold
compounds  (Fatladl, 1984).   4-Methylphenol   can  be  produced  by the  photo-
oxidation  of  toluene   (Shepson  et  al.,   1985),  and  as a  metabolite  from
exposure to toluene and other aromatic solvents (Fatladl, 1984).
    The National  Occupational  Exposure  Survey,  conducted  between  1981  and
1983,  estimated that  3269  workers are  occupatlonally  exposed  to  4-methyl-
phenol  (NIOSH,  1984).    Occupational  exposure may result from  Inhalation  or
dermal  contact  with  the compound  during Its  manufacture and  formulation.
The  general  population  may  be  exposed  by  the  Ingestlon  of  contaminated
waters obtained  from either  surface or ground sources.   Inhalation of smoke
from wood fires  may also be a route  of exposure.   Also, the  general popula-
tion  can  be  exposed   during  the  use  of   commercial  products  containing
4-methylphenol.
3.1.   HATER
    4-Methylphenol,  analyzed as  a  mixture with  3-methylphenol,  was detected
In  groundwater  samples  near an  abandoned  pine-tar  manufacturer  In  Galns-
vllle, FL, at concentrations ranging  from  2300-11,100 ppb,  3100-6200 ppb and
<0.3-95 ppb at  wells  on the  original site, at downgradlent  sites  and  at
upgradlent  sites,  respectively  (McCreary  et  al., 1983).  4-Methylphenol was


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4»
           found  as a  mixture with  3-methylphenol at  the Hoe  Creek  underground coal
           gasslflcatlon  site,  HY,  at 9.6-16,000 ppb,  15 months after gasslfIcatlon had
           ceased  (Stuermar  et a!.,  1982).   4-Methylphenol  was found  In groundwater
           samples  obtained near municipal landfill sites  1n  Oklahoma and Connecticut,
           (14.6  and  15 ppb, respectively) (Dunlap  et  al., 1976; Sawhney and Kozloskl,
           1984),  and  In Barcelona,  Spain  (Albalges et al.,  1986).   It  was  also found
           In  a  sand aquifer at a wood preserving facility In Pensacola, FL, at concen-
           trations  up  to  6.17  ppm (Goerlltz et al.,  1985).   It was not  found  In the
           leachate of  Industrial landfills (Brown and Donnelly, 1988).
              4-Methylphenol  was  detected In  the  lower Tennessee  River  below Calvert
           City, KY, at  a concentration  of  200 ppb  (water/sediment sample) (Goodley and
           Gordon, 1976).   It  was  Identified  near the  site of a leather Industry on the
           Hayashlda River, Japan,  at  204 ppb  (Yasuhara  et  al., 1981), and  1n  Spirit
           Lake,  HA,  shortly  after  the Mount  St.  Helens  eruption (McKnlght et  al.,
           1982).   4-Methylphenol   was  detected  In  rain  water  1n  seven  out  of  seven
           rainfalls  In  Portland,  OR (Leuenberger   et  al., 1985).   4-Methylphenol  was
           detected qualitatively 1n drinking water   (Lucas, 1984).
              In  a  comprehensive  survey of  the wastewater  from 4000  Industrial  and
           publicly-owned  treatment works,  4-methylphenol   was  Identified  In  discharges
           from  the  following  Industries   (Including   percent   occurrence  and  median
           concentration):  timber products  (15%, 166.5 ppb),  leather  tanning  (7X,  31.9
           ppb).  Iron and steel manufacturing  (8X,  33.2 ppb), petroleum  refining  (IX,
           10298 ppb),  nonferrous  metals (3X.  18.4  ppb),   paving  and  roofing  (IX,  18.5
           ppb), organlcs and  plastics  (24X,  477.2  ppb),  Inorganic  chemicals  (3X,  37.7
          ppb), textile  mills (9X,  50.9 ppb),  pulp and  paper  (5X, 36.7  ppb),  rubber
          processing (2X,  17659.4  ppb),  soaps and  detergents (2X,  94.2  ppb),  auto and
          other laundries  (2X, 31.6  ppb), photographic  Industries (3X,  327.7), gum and
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wood  Industries  (3%.  3.6  ppb), Pharmaceuticals  (4%,  89.2 ppb),  explosives
(IX,  3.7 ppb),  foundries   (16X.  47 ppb),  aluminum (13X,  95.7  ppb),  elec-
tronics  (7%,  66.6  ppb), oil  and  gas  extraction  (10%,  6.4  ppb).,  organic
chemicals (13X,  95.7 ppb),  mechanical  products (8X, 398.5  ppb),  transporta-
tion  equipment   (IX,  0.3  ppb), synfuels  (15X,  181.1  ppb),  publicly-owned
treatment  works   (44.7X,  134   ppb)  and  the  rum  Industry  (3X,  87.5  ppb)
(Shackelford et al., 1983).
3.2.   FOOD
    4-Methylphenol  was Identified as a volatile component  of  fried bacon (Ho
et al.,  1983)  and  roasted  filberts  (Klnlln  et al., 1972).   Also, 4-methyl-
phenol 1s used as a synthetic flavor additive for  food  (Sax and Lewis, 1987).
3.3.   INHALATION
    4-Methylphenol  was not  detected In  urban  or  rural air samples  obtained
In Utah and Western  Colorado (Hawthorne  and  Slevers, 1984).   It  was detected
1n  seven  of seven  samples  taken  In  Portland, OR,  at  19-52  ppt  (avg.=29.4
ppt), and was analyzed as a mixture with 3-methylphenol  (Leuenburger  et al.,
1985).   It   was  detected   In   urban  air  over Belgium  (Cautreels  and  Van
Cauwenberghe, 1978).
3.4.   DERMAL
    Pertinent  data  rergardlng  dermal  exposure  to  4-methylphenol were  not
located In the available literature cited In Appendix A.
3.5.   OTHER
    4-Methylphenol  was Identified  as  a component  of tobacco  smoke and as an
emission of automobile and  dlesel  engines (Graedel, 1978).   It  was  detected
In the  emission  from burning vegetable  matter that Is likely to  be  present
In  urban  waste  (Llbertl et al.,  1983),  and  In  the smoke from residential
0219d                               -12-                             08/04/89

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 wood   stoves   (Hawthorne  et  al.,  1986).   4-Hethylphenol  is   a  naturally-
 occurring  component  of  coal tar  (Sax and  Lewis,  1987).   It  1s  a volatile
 component  of  poultry  manure  (Yasuhara,  1987).
    4-Hethylphenol  has   been   detected   1n   the  urine  of  varnish  workers
 (Angerer  and  Wulf,  1985) and others  exposed to benzenold solvents (Fat1ad1,
 1984).   It Is believed  to  be a metabolite  resulting  from exposure to these
 solvents  (Fat1ad1,  1984).
 3.6.    SUMMARY
    4-Hethylphenol  has  been  detected  1n  surface water,  groundwater  and
 rainwater.   Water concentrations  can vary widely; however,  high  levels  are
 usually   associated  with  Industrial  activity.   4-Methylphenol   has  been
 detected  In  surface  water  near  the  site of  the  Hount St.  Helens  eruption
 (Mcknight  et  al., 1982).  It can  enter  the  atmosphere as  a result of Indus-
 trial  activity,  and by the burning of  vegetable and  plant matter  (Hawthorne
 et al..  1988;  Ubertl  et al.,  1983;  HcKnlght et al.,  1982).  Also, 4-Methyl-
 phenol  occurs  naturally  In  coal tar  (Sax  and Lewis, 1987).   It 1s a product
 of  the chemical  and  biological  breakdown of  benzenold  compounds (Fatladl,
 1984).
    Occupational  exposure  to  4-methylphenol   may  occur  by  Inhalation  and
 dermal  contact   during   Its  manufacture  and  formulation  Into  commercial
 products.   The general  population may be exposed  by  Ingesting contaminated
 water,  or   by  Inhalation and  dermal  contact during  the  use  of  commercial
 products  containing  4-methylphenol.   Also,   exposure  to  4-methylphenol  may
 occur  by  Inhaling  smoke from wood  fires or  from  the smoke resulting  from
 burning other  vegetable matter.
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                         4.  ENVIRONMENTAL TOXICOLOGY
4.1.   AQUATIC TOXICOLOGY
4.1.1.   Acute  Toxic  Effects  on  Fauna.   Acute  toxlclty  data  on  4-methyl-
phenol for freshwater fish,  Invertebrates,  cod  fish  and sea urchin eggs (the
only saltwater species data  located)  are  summarized  In Table 4-1.  Addition-
ally,  Hattson et  al.  (1976)  reported 24-,  48-, 72- and 96-hour  LC5_s  of
26,  21,  21   and  19  mg/i,  respectively,  for  Juvenile  fathead  minnows,
Plmephales promelas.   Dissolved  oxygen  concentration was  low  (<4.0  mg/i)
during  these  tests and  may have  enhanced the  toxlclty  of  4-methylphenol,
thus  rendering  these  data  questionable.   Total  lethality was  noted  at  a
concentration of  20 mg/i  from a 96-hour  dynamic  acute study by Cooper  and
Stout  (1985).   No effect  on  survival  or  growth   of £.  promelas  larvae
occurred with exposures  to  5  nig/a, 4-methylphenol  for 96  hours  (Barron  and
Adelman, 1984).   Fertilized  eggs  of codfish,  Gadus  morhua.  and  sea urchins.
Strongylocentrotus  droefaachlensls.  showed  equal  sensitivity,  with 96-hour
EC5Qs  of  5   mg/8.  (Falk-Petersen  et  al., 1985).    Damsel  flies,  Ischnura
vertlcalls. showed  no  effects  from a  48-hour exposure  to 40  mg/t, 4-methyl-
phenol (Cooper and  Stout,  1985) and  thus  appear  to be the least  sensitive of
the  Invertebrates tested.    The water  flea,  Daphnla magna. may  be  the most
sensitive  Invertebrate.   One-hundred  percent mortality was noted  when this
species  was   exposed  to  10 mg/8.  4-methylphenol  for 48  hours  (Cooper  and
Stout,  1985).   A  24-hour  IC5Q  of  12.44 mg/t  (Devlllers,  1988) for  D.
maqnla  and a 48-hour  LC5Q of  22.7  mg/i for  Daphnla pullcarla   (OeGraeve
et al.,  1980) were for  older animals  (<72  hours  old at the start of tests).
A  48-hour  LC5Q  of 1.4  mg/l  for  animals  <24  hours  old  was  determined  by
Parkhurst et  al.  (1979).   Survival  of the  amphlpod, Hyallela  azteca. from a
96-hour acute dose of 8 ppm was estimated at -50% (Cooper and Stout, 1985).
0219d                               -14-                             08/04/89

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    Hodson  et al.  (1984)  reported  a  96-hour  Intraperltoneal  LD,-n of  0.73
                                                                  t)U
mmol/kg  (78.94 mg/kg) and  a  static acute 96-hour  LC5Q  of 0.069 mmol  (7.45
ppm)  for 4-methylphenol  1n  rainbow trout,   Salmo  galrdnerl.   Bols  et  al.
(1985) compared  these data with  that  for  cytotoxlclty and found a signifi-
cant  correlation  between effect  levels.   Cell  cultures  from  gonadal  tissue
of  $.  galrdnerl  were treated with  10  concentrations of 4-methylphenol,  and
viability  was determined  by  the  number  of  cells able  to  attach  to  the
surface  of   the   Petrl   dish.   A 30-mlnute   EC5Q  of  26.4   mmol/i  was
determined.
    The  acute sublethal   toxldty of  4-methylphenol  administered  by  Intra-
perltoneal  Injection  or  In a water medium  to  rainbow trout,  S.  galrdnerl.
was examined  by  D1xon et  al.  (1984,  1985,  1987).   Injections  of  4-methyl-
phenol  dissolved   In  ethanol  were   administered  to 10  fish  at five  doses
ranging  from  10-75X  of  the   Intraperltoneal  96-hour  LD5Q   of  74.94  rag/kg
(experimental) and 0%  (controls).   Blood  samples were taken  96 hours  after
Injection and analyzed  for SSDH  and PLAN  activity as Indicators of  hepato-
toxlclty.  An  Increase In PLAN  activity  was  noted at  an  Intraperltoneal dose
of  1.0 mH/kg. and  SSDH  activity  Increased  at  0.275  mM/kg.   Exposure  to  a
waterborne concentration of 0.028 mM 4-methylphenol for 48,  96 and  192 hours
led to a statistically  significant  dose-dependent  Increase  1n these  enzymes
(doses  ranged  from  0.25-4.0  mmol/kg)  (Dlxon   et  al.,  1984).   Doses  of
0.075-0.75  of  the  96-hour   LD5Q  Induced   elevations  of  27-63*  of  PLAN.
Biochemical  lesions  preceded  evidence of  hlstopathology,  detected by  light
microscope.   SSDH  responded  at  lower  doses  of  toxicant   than  PLAN  and,
therefore, may be  a  more sensitive  indicator of  toxic stress (Dlxon  et al.,
1985,  1987).   These data suggest that  rainbow  trout,  S. qalrdnerl. are more
0219d                               -16-                             08/04/89

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 sensitive  than  fathead minnows,  P.  promelas.   to  4-methylphenol  and  that
 variability  of several  magnitudes  exists with respect  to sensitivity among
 crustaceans.
 4.1.2.   Chronic  Effects on Fauna.
     4.1.2.1.   TOXICITY  — Solskl  and  Plontek  (1987) assessed  the  chronic
 toxUHy  of  4-methylphenol  with  the  planaMan,  Dugesla  tigrlna.    Thirty
 animals  were  exposed  to five  concentrations  for  240 hours.   The  240-hour
 LC5Q  was  11.08  mg/dm3  (11.08  mg/i).   Surviving  animals  were  then  cut,
 exposed  to  the same concentrations  of 4-methylphenol for  another  240 hours
 and  counted  for mortality.  This  procedure  was  repeated  for four generations
 (animals  regenerated  from  cuttings  of  four  successive  groups  of  exposed
 planaMans).   The LOEC  (mortality  of  2.5X) occurred  at  a  concentration  of
 2.0  mg/i 4-methylphenol In  the  second  generation,  a   concentration  about
 one-fourth  that  of  the  LC      Successive  generations   showed  Increasingly
 higher  mortality  rates  with  exposures >1  rag/i,  but  no  effects  were noted
 at lesser concentrations.
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION — Pertinent  data  regarding
 the  b1oaccumulat1on/b1oconcentrat1on  potential  of 4-methylphenol  In aquatic
 fauna  were   not  located  In  the available  literature cited  In Appendix  A.
 Mackay et al.  (1985) concluded  that  reaction  (blodegradatlon and photolysis)
 In water  1s  the  dominant  removal  process, with only a  small  concentration
 enhancement  1n biota.
 4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY — Stout and   Kllham  (1983)  conducted   a  series  of
 Investigations on physiological effects of  4-methylphenol  1n the filamentous
 green  alga,   Splrogyra   spp.    The  algae  were  exposed In  a system  closely
 approximating  natural systems.  Two closed-cycle  streams  were used,  each 3.4
0219d
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03/21/90

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km  long  and 4 m  wide,  with alternating  pools  and riffles ranging  In  depth
from 0.5-1.0 m.   The  channels  were continuously monitored for 4-methylphenol
concentrations, dissolved  oxygen,  pH,  temperature,  velocity,  depth  and  solar
radiation.   Clumps of  Spyrogyra  were  maintained  1n  six concentrations  of
4-methylphenol.   After   3  hours  of exposure,  samples  from each  treatment
level  were  placed  In   BOD  bottles  directly  In  the  channel   for  1  hour.
Dissolved  oxygen  levels decreased  from a control  value  of  7.0 ppm  to 6.2,
6.8, 5.4,  5.2  and 5.6 ppm at  4-methylphenol  concentrations  of  0.9,  4.6,  14,
34 and 71  ppm, respectively.   These results  Indicate  that low concentrations
of  4-methylphenol  Inhibit  photosynthesis   and  Increase  algal  respiration
rates.    The data  agree  with  findings  by Cooper  and  Stout   (1985)  In  which
48-hour  exposure   to   concentrations   of  8  ppm  4-methylphenol   Inhibited
respiration 1n filamentous green algae (species not reported).
    Huang  (1967)   and   Huang   and  Gloyna  (1968)  grew the  alga,  Chlorella
pyrenoldosa. for  72  hours  In  test  tubes  under  constant  temperature,  Illumi-
nation and  nutrient conditions  and  assessed  the effects  of 4-methylphenol on
chlorophyll  content.    Destruction   of   chlorophyll  was   dose-dependent.
Concentrations  of  50   mg/8.  4-methylphenol  reduced  chlorophyll  content  to
5054  of  Its  pretreatment  value at  72  hours,  whereas  1000 mg/l  4-methyl-
phenol  reduced chlorophyll content to ~OX within 24 hours of exposure.
    Robinson et  al.  (1976)  tested  the  effects  on  axenlc  cultures of  the
unicellular green  alga,  Anklstrodesmus  falcatus.   Experimental  cultures were
prepared by  Inoculating  40 cc  of nutrient medium  with 500 cells/cc  of  algae
In the  log phase of growth.   Concentrations  of 1, 10, 25, 50.  100,  500  and
1000 yg  4-methylphenol/cc  of  culture medium  yielded  10-day   growth  rates
(measured as optical  densities at 660 nm) of  0.38, 0.34, 0.29, 0.26. -0.03,
0219d                               -18-                             08/04/89

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           0.07  and  0.01,   respectively.    These  data   Indicate  that   4-methylphenol
           severely  Inhibits  growth   at   100  yg/cc,  and  no  growth  occurs  at   >500
           yg/cc.
               4.1.3.2.    BIOCONCENTRATION  — Pertinent  data  regarding  the   bloconcen-
           tratlon potential of 4-methylphenol In aquatic flora were not  located In the
           available literature cited  1n  Appendix A.   Mackay  et al.  (1985) concluded
           that  reaction  (blodegradatlon  and  photolysis)   1n  water  Is  the  dominant
           removal process,  with only  a small concentration  enhancement  In biota.
           4.1.4.   Effects  on  Bacteria and  Other Aquatic  Microorganisms.   Lebsack et
           al.  (1981) measured  luminescence  Inhibition  to assess  toxlclty of 4-methyl-
           phenol to  the  marine  bacterium,  PhotobacteMum  MscheM  {now known as £.
           phosphoreum).   Blolumlnescence  was measured by a Mlcrotox toxlclty meter.  A
           decrease  1n  bacterial  light output  was  noted  after  5  minutes exposure of
           bacterial  suspension to  four toxicant  concentrations  {4-methylphenol  In 2%
           sodium  chloride)   and  a  control.   The  5-mlnute  EC™  was   1.3 mg/i   for
           luminescence  Inhibition.
               Bullch  and   Isenberg  (1980)  and  Btillch  et  al.   (1981)   Identified  a
           5-mlnute   EC     of   1.5   mg/s.   for   exposure   of   P.   phosphoreum   to
           4-methylphenol.   The  authors concluded   that  this  value,  obtained by   the
           Mlcrotox Assay, generally agreed with those found  In  fish bloassays.
               Delesmont and Delattre  (1983)  measured the toxlclty of 4-methylphenol to
           P.   phosphoreum   and  Identified   an  8-hour  Incubation  IC5Q   of  206   mg/t
           (concentration that reduced  the  number  of  fluorescent cells by  50%).
               The spreading of  trlchal blue  alga, Phormldlum. cultured 1n petrl dishes
           was  completely  Inhibited by  100  vg/test spot  of  4-methylphenol  (Benecke
           and  Zullel, 1977).
0
          0219d
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03/21/90

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    Dube  et  al.   (1988)  assessed  the  toxlclty  of  4-methylphenol  to  the
fungus,  Asperglllus  flavus.  Test  concentrations  of  0,  500,  700,  1000  and
2000  ppm  were  added  to   presteMUzed  petrl  plates  containing  9  ml of
Czapek's  agar  medium.  Plates  were Inoculated  with mycellal  discs 5 mm In
diameter  and  Incubated for  6  days.  Percent mycellal  Inhibition calculated
on day 7 was 82% for 500 ppm 4-methylphenol and  100% for higher doses.
    Yoshloka et al.  (1985)  assessed  the  acute toxldty  of 4-methylphenol  to
the  protozoan,  Tetrahymena pyMformls.  and Identified  a  24-hour EC,- of
160 mg/a at 30°C.
4.2.   TERRESTRIAL TOXICOLOGY
4.2.1.   Effects  on  Fauna.   Marcus  and  Hchtensteln  (1979)   tested  the
toxlclty of extracts of anise plants,  Plmplnella an Is urn,  a widely used spice
and   flavoring   agent.   Topical   exposure  (duration   not  reported)  of
houseflles,  Husca  domestlea,   to  4-methylphenol   yielded  an  LDcn  of 80
             	                                                au
ijg/anlmal.   Schafer  et  al. (1983)  administered   4-methylphenol  to  trapped
wild  birds  2-6  weeks  from  preconditioning  to  captivity  to  assess   the  com-
pound's  acute  oral toxlclty.   An  oral  L05Q of 96 mg/kg/day  was Identified
for the redwing blackbird, Agelalus phoenlceus.
    The  acute oral toxlclty and repellency  of  4-methylphenol  to deer  mice,
Peromyscus  manlculatus.  was   assessed   by Schafer   and  Bowles  (1985).
Repellency tests yielded an  FR  value of 1% and an  LD,   of  1238  mg/kg/day.
4.2.2.   Effects  on  Flora.    Bllderback   (1981)   assessed  the  Inhibitory
effects  of  4-methylphenol  In a basal  growth medium on germination and  tube
elongation  of  Impatlens  sultan11  pollen.   The EC^s  for germination,  tube
production  and  tube  growth were   100,  40-60  and  150  ppm 4-methylphenol,
respectively.
0219d                               -20-                             03/21/90

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     Reynolds  (1978)  tested  4-methylphenol  for  Inhibitory effects  on fruit
germination  In  lettuce,  Lactuca  satlva.   The EC5Q  for  percent germination
after  3  days  exposure to 4-methylphenol In aqueous solution was 1.13i0.19 mH
(122.2±20.5 ppm).
     All  et al.  (1987)  tested  the  Inhibitory  effects of  4-methylphenol  on
sclerotla  of  the  fungus,  Sclerotlum  ceplvorum.  a  pathogen  of  onions  and
other  All 1 urn  species.  After 44 hours  growth on  potato-dextrose agar medium
at   20°C,  10  ppm  4-methylphenol  caused  reduced  germination  and  germtube
elongation and totally  Inhibited both at concentrations >50 ppm.
4.3.   FIELD STUDIES
     Cooper  and Stout  (1985)  conducted  multlspedes  toxlclty  tests  1n eight
channels,   500 m  In   length,   with   alternating   pools  and  riffles.   The
biologically diverse  nature  of  these facilities closely approximated natural
streams  and, therefore,  their  findings  may be viewed as either  laboratory or
field data.  See Section 4.1.1. for data pertinent to this document.
4.4.   AQUATIC RISK ASSESSMENT
     The  lack of  pertinent data regarding  the effects  of  exposure of aquatic
fauna and  flora  to 4-methylphenol  prevented  the  development  of  a freshwater
criterion  (U.S.  EPA/OHRS, 1986) (Figure 4-1).  Available  data Indicate that
acute  toxic  effects   can  occur  at  concentrations  >1.4  mg/i.   Additional
data  required  to  develop a  freshwater  criterion  Includes  the  results  of
acute  assays  with  an  additional  fish  species  or  an  amphibian,  a  benthlc
crustacean, an Insect,  a nonarthropod and nonchordate  species  and an Insect
or  species  from  a phylum  not  previously  represented.  The  development  of  a
freshwater criterion  also  requires data from chronic toxldty tests with two
species  of fauna and  one species of  algae or vascular plant and at least one
bloconcentratlon study.
0219d
-21-
08/04/89

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TEST TYPE
Family
#1
Chordate (Salmonid-f ish)
12
Chordate (warmwater fish)
#3
Chordate (fish or amphibian)
#4
Crustacean (planktonic)
#5
Crustacean (benthic)
#6
Insectan
17
non-Arthropod/ -Chordate
#8
New Insectan or phylum
repr esenta t i ve
#9
algae
#10
Vascular plant
GMAVa
(mg/1)
7.9b
21.79C
NA
1.4*
NA
NA
NA
NA
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
GMCVa
(mg/1)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
BCFa
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
•NA-Not available
*96-hour LCso for rainbow trout. S.  galrdnerl
cMean 96-hour LCSO for fathead minnows, P.  promelas
"48-hour LCso for water fleas, D. magna.
                                  FIGURE 4-1

    Organization Chart of GHAVs,  GMCVs  and  BCFs  Required to Derive Numerical
Hater Quality  Criteria to Protect  Freshwater  Aquatic Life  from Exposure to
4-Hethylphenol, according to U.S. EPA/OHRS (1986)
0219d
-22,
                                                                     08/04/89

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     Lack  of  pertinent data  regarding  the  effects  of exposure  of  aquatic
 fauna  and flora  to  4-methylphenol  precluded the  development  of a  saltwater
 criterion (U.S.  EPA/OWRS,  1986).   Additional  data  required   to  develop a
 saltwater criterion  Includes  the  results  of acute  assays  with two  chordate
 species,   a   nonarthropod  and  nonchordate  species,  a  mysld  or   panaeld
 crustacean,  two  additional  nonchordate species  and  one  other  species of
 marine  fauna.   The development  of  a saltwater  criterion  also  requires  data
 from chronic  toxlclty tests with  two  species   of  fauna and one  species of
 algae or  vascular plant and  at least one bloconcentratlon study.
 4.5.    SUMMARY
     Data  are available on the acute  toxlclty of 4-methylphenol to  salmonld,
 warmwater  fish and  several  Invertebrates.   Acute toxlclty values  shown 1n
 Table 4-1  Indicate that  rainbow  trout,  S.  galrdnerl. are more  sensitive  than
 are  fathead  minnows,  P.   promelas.  with LC5_  values  of  7.9   mg/a  and  28.6
 mg/a,  respectively  (DeGraeve  et  al.,  1980).   Fertilized  eggs   of  cod fish,
 G.  morhua.  and  sea   urchins, S.  droebachlensls.  are  equally   sensitive to
 96-hour  exposure  to   4-methylphenol  (Falk-Petersen  et al., 1985).  Damsel
 files,  I., vertical Is.  were  not  adversely  affected  by 40 mg/a  (Cooper  and
 Stout,  1985),  but  the  water  flea,  D.  magna.  showed 50%  lethality to a
 concentration  of  1.4  mg/a.   Variation  1n  sensitivity  between   D.  magna  and
 D.  pullcarla.  with  48-hour   LC5Qs  of  1.4 and  22.7  mg/a,  respectively,  may
 be  explained by  the  age  difference at  time of  testing (J). magna  were  <24
 hours  old and  0.  pullcarla  were <72  hours  old)  (Parkhurst   et  al., 1979;
 DeGraeve et al., 1980).
    The chronic toxlclty  of  4-methylphenol  In the  planarlan,  D. tlgrlna.  was
assessed  by   Solskl   and   Plontek  (1987).    A   240-hour  LC5(J of 11.08  mg/a
was  Identified.  Follow-up testing  for  four  generations (test animals cut In
0219d
-23-
03/21/90

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half  and retested)  showed  successively  Increased mortality  at  the  LOEC  of
2.0 mg/l, but the LOEC value did not change.
    Chlorophyll  content  and   photosynthesis   are  adversely  affected  (as
evidenced by  decreased dissolved oxygen concentrations)  1n  freshwater  algae
by  4-methylphenol   concentrations  >0.9  mg/l  (Stout  and  KHham,  1983).   A
72-hour  LC5Q of  50  mg/l was  Identified  for  chlorophyll  content   with  C_.
pyrenoldosa.  This  effect was  dose-dependent  (Huang,  1967;  Huang and Gloyna,
1968).   A   concentration  of  100  yg/cc   (100   mg/l)   severely  Inhibited
growth of the  unicellular green alga, A.  fa_l.cjLt.us.  and  totally Inhibited H
at 500 yg/cc (500 mg/l) (Robinson et al., 1976).
    B1oaccumulat1on/b1oconcentrat1on   studies   were  not   located   In   the
available  literature, but  evidence  suggests   that  4-methylphenol will  not
accumulate appreciably In aquatic biota.
    Bacterial  luminescence  was  reduced  50%  by  5-m1nute  exposure   to  >1.3
mg/l  4-methylphenol  (Lebsack  et  al, 1981).   An  8-hour  Incubation of  £.
phosphoreum with  206 mg/l 4-methylphenol  reduced the number  of fluorescent
cells  by 50%  (Delesmont  and  Delattre,  1983).   Growth  of  the  trUhal  blue
alga,  Phorm1d1um.  was totally  Inhibited  by  100  yg/test  spot  of  4-methyl-
phenol  (Benecke and  Zullel,   1977).   Concentrations of  >500  ppm 4-methyl-
phenol totally  Inhibited  mycellal  growth  1n  the fungus, A.  flavus  (Dube et
al.,  1988).  A 24-hour  EC5Q  of  160  mg/l  4-methylphenol  was  Identified
with the protozoan, T. pyrlformls (Yoshloka et al., 1985).
    The  effects of  4-methylphenol  on  terrestrial  fauna  were assessed  In
Insects,  birds  and   small  mammals.    An  LDgQ   for   topical  exposure  to
4-methylphenol  of   80  yg/an1mal   for  the  housefly,   M.   domestlca.   was
reported by Marcus  and   Llchtensteln  (1979).   Oral  LD50$  of  9&  mg/kg/day
0219d                               -24-                             03/21/90

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 for  the  redwing  blackbird,  A.  phoenlceus  (Schafer et  al.,  1983) and  1238
 mg/kg/day for  deer  mice,  P.  manlculatus  (Schafer  and  Bowles,  1985)  were
 reported.
    Assessments  of  toxIcHy of  4-methylphenol  to  terrestrial  plants  Identi-
 fied  EC^s of  100,  40-60 and 150  ppm for  germination, tube  production  and
 tube  growth,   respectively,  with  I..  sultan11  (Bllderback,  1981).   An  EC5Q
 of  122.2  ppm was  reported  for  fruit germination  In  L.   satlva  (Reynolds,
 1978)  and  reduced   germination   of  sclerotla  was  noted   1n   S.  cepIvor urn
 exposed  to 10  ppm 4-methylphenol  (AH et al., 1987).
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                             5.  PHARMACOKINETICS
5.1.   ABSORPTION
    Delchmann and  Kepllnger  (1961)  report that cresol (a mixture  of  Isomers
Including  paracresol)  can be  absorbed  through skin,  wounds  and  the  mucous
membranes  of  the  respiratory  and  gastrointestinal  tracts.   The absorption of
4-methylphenol  (paracresol)  following  dermal and  oral exposure  was  studied.
Anderson et al. (1976) measured the  desorptlon  of  the test  article and other
phenolic  compounds In  vitro  from  human stratum  corneum  to estimate  the
stratum  corneum-water  partition  coefficient  and  the   relative  diffusion
coefficient of  phenolic  compounds  1n  human  stratum  corneum.   The D/h2  was
11.0+?.8  sec"1  x   10* and  the Km  was  determined  to  be  10.6+0.8  using  four
samples of  hydrated  stratum corneum equilibrated  with a  nondamaglng  aqueous
solution  of  4-methylphenol  (concentration  not  reported).  Likewise,  Roberts
et  al.  (1977)  determined  the k   of 4-methylphenol  In  vitro  through  human
                                P
abdominal  epidermal  membranes. The  k   was  estimated from  the  steady-state
slope  of  the  ratio  between  the  cumulative  amount of   the  test  article
penetrating  through  a  unit  area  of  membrane  with  time.    The  k   for
4-methylphenol at  concentrations that did not damage  the  stratum corneum was
2.92x10*  cm/minute.   The  k   Increased  after   the   threshold  concentration
                             P
was  reached,  Indicating  that  damage   to the  membrane  had  occurred.   The
threshold concentration resulting 1n damage was 8.85% w/v.
    Green  (1975)   reported  mortality   1n  a  12-month-old  Infant  dermally
exposed  to   coal   tar   fluid  (90%  cresols   In  water),   Indicating  that
substantial  dermal  absorption  had  occurred.   Cresols  are  a  mixture  of
ortho-,  meta- and paracresol  (4-methylphenol).   There  was  no evidence  of
Inhalation or oral Ingestlon.  Clinical  and  hlstologlcal  observations taken
>4.25  hours  after exposure  Included "burns" on  the  face, scalp,  hands  and
0219d                               -26-                             03/21/90

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           forearms  and  destruction  of the epidermis with  loss  of  the stratum corneum.
           Cresols were  Identified  In  the blood,  urine,  liver and brain.  The mother of
           the  Infant reportedly  washed  the head  and  scalp  of  the Infant  -5  minutes
           after  exposure.   At that time,  the  Infant was unconscious and  "blue  In  the
           face."
              Oral  absorption  was  studied  where  2-3  kg  rabbits  were  administered
           4-methylphenol  (250-500  mg/rabblt)  1n a  NaHCOg  solution by gavage {Bray  et
           al.,  1950).   Within 24  hours  of dosing,  -65%  of the administered dose  was
           recovered  In  the  urine  as total  cresol  metabolites,  Indicating  that >65%  was
           absorbed  through  the gastrointestinal tract.
           5.2.   DISTRIBUTION
              Pertinent data  regarding actual  concentrations  of  4-methylphenol  In body
           tissues  following  exposure were  not   located  In  the available  literature
           cited  In  Appendix A; however,  Green  (1975)  detected  cresols (Section  5.1.)
           In  the  brain, liver, blood and  urine  of an  Infant dermally exposed  to coal
           tar fluid.  All of the organs  had a strong cresol  odor.
           5.3.   METABOLISM
              According to  OeUhmann  and WHherup  (1944), Embody et  al. (1940),  Hunakl
           (1940) and  KUnger  and Norton (1945),   the metabolism of 4-methylphenol   Is
           similar to  that  of  phenol.   These  Isomers  are oxidized and conjugated with
           sulfurlc  and   glucuronlc  acids  (DeUhmann and   KepHnger,  1981; Williams,
           1938).  Bray  et  al.  (1950) concluded  that 4-methylphenol  and  other   cresol
           Isomers form  conjugates  primarily  at  the hydroxyl  group.  Williams   (1938)
           recovered  16% of a gavage dose of  290 mg 4-methylphenol/kg administered to  2
          kg  female rabbits as an  ethereal sulfate conjugate   In  the  urine within  2
          days  following   dosing.    Likewise,   the  urine  of  rabbits   administered
          4-methylphenol by gavage   at  a  level   of  250-500  mg/rabblt  contained  an
          average 15%  of the  dose  as ethereal  sulfate  and  61% as ether  glucuronlde
O
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of  the  parent compound within 24 hours of  dosing  {Bray  et  al.,  1950).   Free
and conjugated hydroxybenzolc acid were also  detected  In the  urine.   Neuberg
and   Kretchmer   (1911)   also  detected  sulfate  and   glucuronlde   forms   of
4-methylphenol In the  urine following oral  administration of  the test chemi-
cal  to  dogs.  These  forms  were double  barium salts  of p-cresylg!ucuron1de
and p-cresylsulfurlc acid.
    These in  vivo results are supported by  the in  vitro  metabolic  experiment
by  Sato  et  al.  (1956)  In  which the Intermediates, which had  not  previously
been  Isolated,  were  Identified.   4-Methylphenol  was  Incubated  for 1  hour
with  S35-sulfate  and  supernatant  or liver  slices  prepared from  livers  from
white  rats.   The supernatant  mixture  yielded  p-cresylsulfate,  Indicating
that  oxidation had  not occurred.   However,  Incubation with the  liver slices
produced the  sulfate  conjugate  of  p-hydroxybenzo1c  add, which Investigators
hypothesized  arose  from  formation  of  the  Intermediate  p-hydroxybenzaldehyde,
Indicating  that   oxidation  of  the  methyl   group  had  occurred.   "Meager"
amounts  of  3,4-d1hydroxybenzo1c add were  formed   from  the p-hydroxybenzo1c
add.  The  Intermediate  between the test chemical  and p-hydroxybenzaldehyde
was tentatively  Identified as p-hydroxybenzyl alcohol. The  authors concluded
that  sulfate  conjugation 1s  preceded by  the  oxidation of  the -CH~  group  of
4-methylphenol through  the  probable  Intermediates of  -CH-OH  and   -CHO  to
-COOH (Figure 5-1).
5.4.   EXCRETION
    The  major route of  4-methylphenol  excretion  In rabbits  Is through  the
urine.   Within  24  hours of  administration  of  a  250-500  mg  oral   dose  of
4-methylphenol, an average of  65% of the dose was  recovered  In  the  urine  of
rabbits  In  the form of various  metabolites.   Williams  (1938)  detected 16% of
a  290 mg/kg  dose  of 4-methylphenol  administered orally  to  rabbits  as  a


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      CH,
           sup
      OH
CHgOH        CHO
                         COOH
                                                       COOH
                       •up
OH

OH
                            •»  pup
                              CHO
                        OH
     OH
OH
 COOH*
                                             COOH
                                     OH
                                   \
                                   OH \A
                              OH
                                                 OH
                                            OH
                               FIGURE 5-1
                    Metabolic  Pathway of 4-Methylphenol
                        Source: Sato et al.» 1956
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sulfate conjugate  (ethereal  sulfate)  In  the  urine.   This  urine  was  collected
on  the day  of  the  dosing  through   the  day after  dosing.   Data  regarding
excretion  following  dermal  or  Inhalation  exposure were  not  located In  the
available  literature;  however,  cresols  were  detected In  the  urine  of  an
Infant  dermally  exposed  to  coal  tar  fluid (90%  cresols In water)  (Green,
1975}.  Wandel (1907) also reported  that  cresols  can be excreted In bile and
exhaled air, but further details were not available.
5.5.   SUMMARY
    The  pharmacok1net1cs  of   4-methylphenol   Involves   documented   dermal
(Green, 1975;  Anderson  et al., 1976; Roberts et al.,  1977)  and gastrointes-
tinal  (Bray  et al.,  1950) absorption of  the test  chemical with distribution
to  the  brain,  liver, blood  and  possibly all organs  (Green,  1975).   Metabo-
lism  Includes  oxidation  of  the  -CH«  group of  the  4-methylphenol  to  the
Intermediates  -CH_OH and  -CHO and finally  to  -COOH, as  determined  In  vitro
                 i                                                           ^
(Sato et al.,  1956).  The sulfate conjugates  corresponding   to  these  Inter-
mediates and  the final product  are  p-hydroxybenzyl  alcohol,  p-hydroxybenz-
aldehyde   and   p-hydroxybenzolc   add,   respectively.    Small  amounts   of
3,4-d1hydroxybenzo1c add  were also  formed  by this  pathway.   The !n  yHro
data  support  In  v1vo observations.  Excretion  data  from  Bray et al.  (1950)
and  Neuberg  and Kretchmer   (1911) Indicate  that  4-methylphenol 1s  excreted
primarily  1n  the urine  as sulfate and  glucuronlde  conjugates.  Bray et  al.
(1950) reported  that an average  oral dose  of  65% was excreted  1n  the  urine
(as total cresols)  within 24 hours.
0219d                               -30-                             03/21/90

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                                  6.  EFFECTS
 6.1.    SYSTEMIC  TOXICITY
 6.1.1.    Inhalation  Exposure.
    6.1.1.1.   SUBCHRONIC  — Pertinent    data    regarding   the   subchronlc
 Inhalation  toxlclty  of 4-methylphenol  were  not  located  1n  the available
 literature  dted 1n  Appendix A.
    6.1.1.2.   CHRONIC  —  Pertinent  data  regarding  the chronic  Inhalation
 toxlclty  of  4-methylphenol  were  not  located  In  the  available  literature
 cited  In  Appendix A.
 6.1.2.    Oral  Exposure.
    6.1.2.1.   SUBCHRONIC  — The   oral   toxlclty   of   4-methylphenol   was
 evaluated In  groups of  30  male  and  30  female Sprague-Dawley  rats  admin-
 istered  the compound (99.9% pure) by gavage  In  corn oil at levels of 0, 50,
 175 and  600 mg/kg/day,  7  days/week  for  13 weeks (Dletz and Mulligan, 1988).
 Mortality was  observed  1n  three  high-dose females during the first 3 days of
 the  study.    Two of  these  animals  experienced  tremors  and  were  comatose
 before  death.   Clinical  observations  Included  signs  of  CNS  Impairment
 (lethargy,  tremors  and  occasional  convulsions  and  comas)  and  reduction 1n
 body weight  gain In  high-dose animals of  both sexes.   Decreased body weight
 and  decreased body  weight gain  were  also observed  In mid-dose  males,  but
 only during  the  first 3 weeks of  the  study.   Terminal body weights  were not
 significantly  different   from  controls.   Complete  gross  and  microscopic
 examination  of  29 organs  and tissues  revealed  hepatotoxlc  and nephrotoxlc
 effects.   Statistically significant  (p<0.05)  Increases  In  relative  organ
weights were observed 1n the  livers  and  kidneys  of mid- and high-dose males;
 the  heart,  testes  and  brain  of  high-dose  males;  the spleens of  low-dose
 females;  and   the   kidneys   of   high-dose   females.    Chronic  nephropathy
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was  observed  at a statistically  significant  (p<0.05)  Increased  Incidence  1n
low- and  high-dose  male  rats.   Epithelial   metaplasia  of  the  trachea was
observed  at  a significantly (p<0.05) greater  Incidence  In  high-dose  animals
of   both   sexes.    Comprehensive  hematologlcal,  urlnalysls  and   clinical
chemistry  observations  revealed  mild anemia  In mid- and  high-dose  females.
Dose-related  reductions  In  red  blood  cell  count,  hemoglobin  concentration
and  hematocrlt were observed  In mid- and  high-dose  females.   Significant
elevations 1n  SGPT  and  SGOT levels were observed  1n four  high-dose  females,
two of which  also had chronic  hepatic  Inflammation.   Total  serum protein was
significantly  Increased  In  mid- and high-dose males.  The  authors  concluded
that no toxic effects occurred at 50 mg/kg/day.
    A  subchronU  gavage  study was  performed on  groups  of  10  male and  10
female CO  rats administered  4-methylphenol In corn oil at  a level of 50, 175
or 600 mg/kg/day  for 13 weeks  (U.S. EPA,  1987a).   Mortality was observed  In
4 males'and 4  females at  the high-dose  level; however,  the deaths of 2 males
and 2  females  were  caused by  aspiration or  Inhalation of  the test  compound.
Clinical   observations  Included  salivation,  tremors,   urine-wet  abdomens,
hypoactlvUy. rapid  respiration,  myoclonus and low body  posture  1n males and
females  of all  treatment  groups;   however,  these  clinical signs  occurred
primarily  during  the first  hour  after  dosing and during  the first  week  of
dosing.  The  signs were low  In Incidence and  sporadic  thereafter,  suggesting
that  they were a  response  to the  rapid  bolus administration  of  the  test
article.   Myotonus was  observed in  only high-dose group animals  and  labored
respiration was observed 1n mid- and high-dose males and  females.
    Neurobehavloral   toxldty (clinical  observations and several  performance
and  reflex tests)  was  evaluated once during  pretreatment, 1  and   6  hours
after the  first dose, and before dosing on days  2,  7,  14,  30,  60,  and  90.


0219d                               -32-                             03/21/90

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           Slightly  Increased  urination  and decreased  locomoter  activity  were observed
           1n high-dose males  and  females.   The urination  Increase  occurred  at  the end
           of the  study for  both  sexes; however,  the locomotor activity  decrease was
           observed  at  the end for  males  only.   Females had  statistically significant
           (p<0.05)  decreases  In   activity   24  hours   after   the   first   dose  only.
           Increases 1n palpebral  closure,  rales and  labored  respiration were observed
           In both  sexes  at the high dose  level  during the Initial  part of  the study.
           Food  consumption was  decreased  (p<0.01)   1n  male and  female  rats  In  the
           high-dose group during  the  first  week  of  the  study.   Decreased  mean  body
           weights  (p<0.05)  were  reported  1n  high-dose  males  during the first  week  of
           the  study.   A   slight  but nonsignificant  reduction  In mean relative  brain
           weight was reported In  high-dose females.
               HlstopathologUal examination,  limited  to  selected  rats  of both  sexes
           from  the  control and  the high-dose  groups and  rats that  died during  the
           study, consisted  of hematoxylln  and  eosln-stalned sections  of  the  central
           and  peripheral  nervous  systems,  esophagus, stomach,   lungs  and  trachea  and
           sections   of  selected   gross   lesions.    No  compound-related   lesions   were
           reported  1n  the test animals.
           6.1.3.   Other   Relevant  Information.   Mortality,  convulsions  and  decreases
           1n weight  gain,  apparent  In   rats   during  subchronlc   oral   exposure  to
           4-methylphenol,  were also observed  In rabbits,  rats,  mice,  guinea pigs  and
           cats   following  acute   exposure  to  the   test  article  by  oral,   dermal,
           Intraperltoneal,  Intravenous  or   subcutaneous   routes  (Table   6-1).    Skin
           corrosion was also a result of  dermal exposure to 4-methylphenol  (Vernot  et
           al.,   1977)   (see  Table  6-1).   Clinton   (1948)  reported  severe  eye  burns
           following cresol  exposure with  subsequent  necrosis of  the cornea, scarring
           and blindness.   Further  Information  was not reported.
O
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-33-
03/21/90

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0219d
                                               -35-
                                                                       08/04/89

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    The  LQ50  values  reported for oral  exposure  1n  rats  are 207 mg/kg  (Sax,
1984}  and  1800  mg/kg  (Delchmann  and  WHherup,  1944).   Mortality  was not
observed  until  600  mg/kg/day In the subchronlc studies described previously
(Dletz  and  Mulligan,  1988;  U.S. EPA,  1986b).   The  oral  LD .  for  mice 1s
344 mg/kg (Sax,  1984} and the  LD.-  for rabbits  Is  620 mg/kg  (Delchmann and
WHherup. 1944}.  The dermal LD5Q for  rabbits  Is  300 mg/kg (Vernot et  al.,
1977); therefore, 4-methylphenol appears to be more toxic through the dermal
route  for  rabbits.    The apparently  rapid dermal  absorption  and  resulting
mortality  (see   Section  5.1.)  reported by  Green  (1975)  corroborate  these
acute  data.  Subcutaneous  exposures  resulted  In  LD  s  that  were  similar
for rats, mice,  rabbits and  guinea  pigs  (Sax,  1984;  Gordon and  McCandless,
1959).
    Subchronlc dermal  (Shelley,  1974)  and  Intravenous (Yehuda et al.t  1977)
studies  with  4-methylphenol  were also  performed  on  mice  and rats,  respec-
tively.   An unoccluded  dose  of  0.5X 4-methylphenol  1n acetone  (total amount
not reported)  was sprayed  on  the  clipped or  epllated  caudal  half  of the
backs  of CBA/J  agouti  and  black  mice 3  times/week  for 6 weeks  (Shelley,
1974).   By  6  months  following exposure, deplgmentatlon of  the  hair and  skin
was observed.    Intravenous  administration of  4-methylphenol  to rats  as  a
dally 0.1 mg/kg  Injection for 7  weeks  at room  temperatures  of  4,  20 and  37°C
resulted  In convulsions, with minimum seizures  at  20°C (Yehuda  et  al., 1977).
6.2.   CARCINOGENICITY
6.2.1.    Inhalation.    Pertinent  data   regarding   the  cardnogenHHy  of
4-methylphenol   following  Inhalation   exposure  were  not   located   1n  the
available literature cited in Appendix A.
6.2.2.   Oral.   Pertinent  data   regarding  the  cardnogenldty  of  4-methyl-
phenol following oral  exposure  were  not located In the available literature
cited In Appendix A.
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6.2.3.   Other  Relevant  Information.   The  only  relevant  cancer  data  on
4-methylphenol  In  the literature was an  experiment  promoting  skin tumors 1n
young  adult albino  mice  of several  strains  (Boutwell and  Bosch,  1959).  A
single  Initiating  dose  of  75  vq  DMBA as  a 0.3%  solution In  acetone was
applied  to  shaved  back  skin  of  groups  of  28 animals.   One  week  later,
4-methylphenol,  as a  20%  solution  1n  benzene,  was applied twice  each  week
for  12 weeks.   A  control  group  of 12  animals  was  exposed only to benzene
following  DMBA  Initiation.   Clinical observations  Included eight mortalities
In  the 4-methylphenol  group.  Examination  of the  test  group  revealed  0.55
paplllomas  per  survivor  and 35%  of  the  survivors  bearing paplllomas,  but no
carcinomas  were  observed.   No  paplllomas or  carcinomas were observed  In the
control group.   A  20-week  experiment with  DMBA  Initiation  (Identical  to the
12-week  experiment)  and   4-methylphenol  promotion  as  a  5.7%  solution  In
benzene  revealed  mortality  1n  2/20  control animals  and  In   6/20  treated
animals.   Evaluation revealed 0.36  paplllomas  per  treated  survivor and 29%
of  the  survivors had  paplllomas;  no paplllomas or  carcinomas  were observed
1n  control animals.   Further  experimental protocol  was  not  reported.   The
Investigators  concluded that  4-methylphenol  was  a  tumor  promoter In  this
test.
6.3.   GENOTOXICITY
    Available data  regarding the mutagenlclty and  genotox1c1ty of 4-methyl-
phenol are  summarized  1n Table  6-2.   4-Methylphenol  has  not been found to be
mutagenlc  when  tested up  to levels  of  toxUlty In  reverse mutation  assays
with  Salmonella  typhlmurlum strains TA1535,  TA1537,  TA1538.  TA98  or  TA100
(Florin et a!.,  1980;  Douglas  et al.,  1980; Haworth et al.,  1983;  Crowley
and Margard, 1978; Case Western Reserve, 1980; Pool  and Lin, 1982).
0219d
-37-
03/21/90

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0219d
-38-
07/19/90

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     ID. vivo and itt vUro SCE assays with human dlplold flbroblasts and DBA/2
 mice  (CUT,   1983;  Cheng  and  KUngerman,  1984)   revealed   no  significant
 Increases  1n SCE.  A  cell  transformation assay with  C3H10T1/2 mouse flbro-
 blasts  was  negative  (Crowley and Hargard, 1978).
     Crowley and Margard (1978),  however, found 4-methylphenol to be positive
 In  an unscheduled DNA  synthesis  assay  using  human  lung  flbroblasts  (HI-28)
 and  biological  activation (further  protocol not provided).
 6.4.    DEVELOPMENTAL TOXICITY
     A range finding  developmental   toxlclty study with  groups of  eight mated
 female  New  Zealand White rabbits administered  4-methylphenol  1n  corn  oil by
 gavage  at  levels of 50,  150,  300  and 500 mg/kg/day for  days 6-18  of gesta-
 tion  was  performed  for  CMA  (1987).    Dose-related  maternal  mortality  was
 observed  In the three highest dose levels  (2/8,  4/8 and 7/8, respectively).
 There were  no  mortalities  1n  controls.   Gasping and labored respiration were
 observed  at all  dose   levels,  but  only  In a  few  rabbits at  50 mg/kg/day.
 More  Intense CNS and  cardlopulmonary  effects  (hypoactlvlty,  ataxla,  twitch-
 Ing  and breathing problems)  were  observed  In the  dams  at  the  two  highest
 levels.   Significant  maternal weight  loss  was observed  at  the  150  and  300
 mg/kg levels;   excessive  (7/8)  mortality  at  the   highest  level  precluded
 statistical  analysis.    External  malformations  possibly  attributed  to  the
 test  chemical  were restricted to forellmb and  pectoral  girdle variations at
 300  mg/kg/day.  There  was  no  mention  of examination  for Internal  malfor-
 mations.
    In  the  final  study,  groups  of 14  mated  New  Zealand white rabbits  were
 treated by  gavage with 4-methylphenol  1n corn oil  at doses  of 5.0,  50.0 or
 100.0  mg/kg/day  on  gestation  days 6-16 (CMA,  1988a).   The  day  on  which
mating  was   observed  was designated  gestation day  0.   A negative  control
group of  28 rabbits  was  treated on the same schedule with corn  oil  alone.
0219d
-39-
03/13/91

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The  dams  were observed  for  clinical signs, and  body weights and  food  con-
sumption were  measured  until  sacrifice  on gestation day  29.   Upon  necropsy,
the  dams  were evaluated  for  body,  liver and  gravid uterine weight and  the
number  and  condition of  Implantation  sites.   Live  fetus  were weighed  and
examined  for  external.  Internal   and   skeletal  variations.   Approximately
one-half of  the  fetuses from  each Utter were examined  for  soft  tissue and
cranlofaclal  malformations.   Maternal  mortality  claimed  5/14  (p<0.01)  and
2/14  (p>0.10)  rabbits  treated  with 100.0 and  50.0  mg/kg/day,  respectively,
(Fisher exact  test  performed  at  SRC).   The  Investigators  attributed  these
deaths  to  4-methylphenol.   Respiratory  distress,  cyanosis,  ocular  discharge
and  hypoactlvlty were observed In  dams  treated with  >50.0  mg/kg/day.   There
were  no effects  on food consumption or body weight  at  any  dose level  and no
maternal effects  of  any  kind at  5.0  mg/kg/day.   There  were no effects  on
gestatlonal  parameters,  fetal  body   weight/litter   or   the  frequency  of
Internal,  external or skeletal variation.
    CMA  (1988b)   used  a  similar   protocol  to evaluate  the  developmental
toxldty of 4-methylphenol  In  rats.  Groups of 25 mated  Sprague-Dawley  rats
were  treated with  30.0,  175.0 or  450.0 mg/kg/day on  days 6-15 of gestation.
Fifty  rats  were  maintained as negative  (vehicle)  controls.  The  dams  were
sacrificed on  gestation  day  21.  Approximately one-half  the fetuses  1n  each
litter  were   examined   for   visceral   and   cranlofaclal   malformations   and
one-half were  examined  for skeletal variations.   Maternal  effects,  limited
to the high dose group.  Included clinical signs (CNS signs, labored respira-
tion), reduced food  consumption, body weight and  body weight gain during the
treatment  period,  and  reduced body weight  at termination.   There were  no
effects on  gestatlonal  parameters  or  on  the Incidence  of  external,  soft
tissue  or  skeletal  variations.  Fetal  body weight/Utter  was significantly
decreased  at 450.0 mg/kg/day.
0219d                                -40-                             03/13/91

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 6.5.    OTHER  REPRODUCTIVE  EFFECTS
     Pertinent  data  regarding  other  reproductive  effects  of 4-methylphenol
 were not  located  In  the available  literature cited 1n Appendix A.
 6.6.    SUMMARY
     Data  are  lacking on  the  chronic toxlclty and carcinogenic  potential  of
 4-methylphenol   following  oral   or   Inhalation   exposure.   4-Hethylphenol
 appeared  to be a  tumor  promoter  In  the  two-stage skin tumor assay  In mice
 following  Initiation by  DMBA  (Boutwell  and Bosch,  1959).   Mutagenlclty and
 genotoxlcty   studies  resulted  In  negative  responses   In  reverse  mutation
 assays, In vitro and in  vivo  SCE tests and  cell  transformation assays (see
 Table  6-2); however,  Crowley and Margard  (1978)  reported positive results  In
 an  unscheduled DNA  synthesis  assay.  Subchronlc  and acute  Inhalation data
 are  lacking.    Oral, IntraperHoneal,  Intravenous,   dermal  or  subcutaneous
 acute,  subchronlc  and  developmental toxldty  studies  resulted In  common
 toxlcologlcal  effects.  Mortality,  CNS effects  and decreases  In  body weights
 were  observed In each of  these  types of studies  {Dletz  and  Mulligan,  1988;
 U.S.  EPA,  1987a;  Yehuda et al.,  1977; CMA,  1987,  1988a,b).   Labored respira-
 tion  was   also observed  following  subchronlc  oral   (U.S.   EPA,  1987a)  and
 developmental  toxldty (CMA, 1987)  studies  using rats  and rabbits treated  by
 gavage  at  50  mg/kg/day,  the lowest dose tested.   Subchronlc  dermal  exposure
 1n mice resulted In deplgmentatlon of the skin and  hair (Shelley, 1974).
0219d
-41-
03/15/91

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                     7.  EXISTING GUIDELINES AND  STANDARDS
7.1.   HUMAN
    ACGIH  (1988)  and OSHA  (1989)  adopted  a TLV-TWA of 22 mg/m3  (5  ppm)  for
cresols  (all  Isomers).  NIOSH  (1978),  however,  recommended  a TLV-THA  of  10
mg/m3  for  cresol.   The cresol  TLV recommended by ACGIH 1s  based on analogy
to the toxlclty of phenol (ACGIH,  1986).
    U.S.  EPA  (1987b)  reported  a  verified  oral  RfD  of  5E-2 mg/kg/day  for
4-methylphenol.  The derivation of this RfD 1s explained In Chapter 8.
7.2.   AQUATIC
    Cresol (p-) 1s listed as  a  hazardous  substance (U.S.  EPA, 1982) and 1s a
substance designated for ground-water monitoring (U.S. EPA, 1988).
0219d                               -42-                             03/13/91

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                              8.  RISK ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.    Inhalation.   Pertinent  data  regarding  the  Inhalation  cardnogen-
Iclty  of 4-methylphenol were  not  located 1n the  available  literature dted
1n Appendix A.
8.1.2.    Oral.    Pertinent   data   regarding  the  oral  carclnogenlclty   of
4-methylphenol  were  not   located  In  the  available  literature  dted  In
Appendix  A.
8.1.3.    Other  Routes.   4-methylphenol  appeared  to  be  a promoter   1n  the
two-stage  mouse  skin  assay In mice Initiated with  DMBA (Boutwell and Bosch,
1959).
8.1.4.    Height of  Evidence.   There  Is  Insufficient  evidence regarding  the
carclnogenlclty of  4-methylphenol  1n  animals.   There are no  data  regarding
the  carclnogenlclty  In humans;  therefore,  4-methylphenol   1s  most  appro-
priately  placed  In Group  0,  not classifiable  as to  human  carclnogenlclty,
according  to U.S. EPA (1986b) classification schene.
8.1.5.    Quantitative Risk Assessment.
    8.1.5.1.   INHALATION — No    pertinent    Inhalation    carclnogenlclty
studies  with  4-methylphenol   are  available,  precluding  the  derivation  of
• v-
    8.1.5.2.   ORAL — No   pertinent   oral   carclnogenlclty   studies   with
4-methylphenol are available, precluding the derivation of a  q *.
8.2.   SYSTEMIC TOXICITY
    In  this  section,  "Rec. #"  refers to  the  data  records  for the  dose/
duration-response graphs In Appendix C.
0219d
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03/15/91

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8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME   EXPOSURE  (SUBCHRONIC) — Pertinent  data
regarding the  Inhalation  toxldty of 4-methylphenol were not  located  In  the
available literature cited 1n Appendix A.
    8.2.1.2.   CHRONIC  EXPOSURE  —  Pertinent  data  regarding  the  Inhalation
toxldty  of 4-methylphenol  were  not  located  In  the available  literature
cited In Appendix A.
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS  THAN  LIFETIME  EXPOSURE ~ The  subchronH oral  toxlclty
of 4-methylphenol  1s  discussed  In Section 6.1.2.1.  Results  from  both D1etz
and  Mulligan  (1988)  and U.S.   EPA  (1987a)   Indicate  that  the  NOAEL  for
decreased body  weights,  hepatic  and kidney  effects  and  CNS Impairment  1n
rats Is 50 mg/kg/day  (Recs.  #7,  10)  for a 90-day exposure to 4-methylphenol.
The LOAEL In each  study was  175  mg/kg/day (Recs.  18, 11).  Clinical signs of
CNS  stimulation  were  observed  at the  50 mg/kg/day level  (Rec.  #7)  1n  the
U.S. EPA  (1987a)  study;  however, these effects were observed principally In
the  first  hour after  dosing during  the  first  week of  exposure,  suggesting
that they occurred  1n  response  to the rapid  bolus administration  of the test
chemical and that some degree of tolerance may have developed.
    This also  suggests  that  the 50 mg/kg/day dose  Is  near  the threshold for
adverse CNS effects In rats.
    Recent development  toxlclty gavage  studies  Identify the  rabbit  as  more
sensitive than the  rat  to the maternal  toxlclty  of 4-methylphenol.  A range-
finding  study  using  groups  of  eight rabbits reported  gasping and  labored
respiration 1n "a  few  rabbits"  treated  with  50  mg/kg/day (Rec. #3); maternal
mortality  occurred  1n rabbits   treated  with 150   (Rec.  #3), 300 and  500
mg/kg/day (2/8, 4/8 and 7/8, respectively)  (CMA,  1987).   In the final study,


0219d                               -44-                             03/15/91

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 groups  of  14 rabbits  were treated with 5, 50 or 100 mg/kg/day during 13 days
 of  gestation  (CHA,  1988a).   There were  no signs  of maternal  toxlclty  In
 rabbits  treated with 5  mg/kg/day (Rec.  #1), which 1s a  NOEL  1n this study.
 Respiratory   distress,   cyanosis,   ocular  discharge  and  hypoactlvlty  were
 observed   In   rabbits  treated  with  50  (Rec.   #2)  or   100  mg/kg/day.   In
 addition,  deaths  of  two  dams treated with 50 mg/kg/day and five dams treated
 with  100  mg/kg/day  were  attributed  to  4-methylphenol.   The  50  mg/kg/day
 dose, therefore,  1s a PEL  (Rec. #2) associated with maternal mortality.
    U.S. EPA (1978b)  derived a chronic  oral  RfD from  the NOAEL  of 50 mg/kg/
 day  (Rec.  #7,  10)  1n the two subchronlc  studies  1n  rats  described above.
 The  Identification  of   50  mg/kg/day  as  a   FEL  (Rec.  #2)  associated  with
 maternal mortality  In  rabbits 1n a more  recent  study  (CMA,  1988a), however,
 compels a  reevaluatlon of  the data.
    The most defensible  basis for  a  subchronlc oral  RfD for  4-methylphenol
 Is the  NOEL  of 5 mg/kg/day  (Rec.  #1)  In the developmental toxlclty study In
 rabbits (CHA,  1988a).   Although  the developmental toxlclty  study  was not  of
 sufficient  duration  to   be   considered  subchronlc,   the  rabbit NOEL  of  5
 mg/kg/day  1s  less than  the  NOAEL of 50  mg/kg/day  (Rec.  #7, 10)  1n  the two
 rat subchronlc  studies.   Furthermore,  the  rat data  (U.S.  EPA,  1987a)  suggest
 that tolerance may  develop  with  continued exposure.   The application  of  an
 uncertainty  factor   of   100   (10  for  Interspedes   sensitivity  and  10  for
 Intraspecles  sensitivity)  to the  NOEL  of  5  mg/kg/day  (Rec.  #1)  results 1n a
 subchronlc oral RfD of 0.05  mg/kg/day.   Confidence  1n  the key study 1s high,
 because an appropriate  protocol  applied  to  a suitable animal model  Identi-
 fied a  NOEL  and  FEL for maternal  toxlclty.   Confidence  1n  the  data  base  Is
 low;   the  subchronlc  toxlclty   of  4-methylphenol   In   rabbits,   the  more
 sensitive  species,  has  not been adequately  Investigated.  Confidence 1n the
 subchronlc oral RfD 1s medium.

0219d                               -45-                             03/15/91

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    8.2.2.2.   CHRONIC  EXPOSURE — Chronic  oral  exposure  data  were  not
located  In the  available  literature cited  In Appendix  A.   A chronic  oral
RfD,  however,  can  be  derived  from  the data  chosen as  the  basis  of  the
subchronlc RfO.  As discussed In Section  8.2.2.1.,  the most  defensible  basis
for  the  subchronlc  oral  RfD  1s  the  NOEL  of  5  mg/kg/day  (Rec.  #1)  for
maternal  toxlclty  1n  rabbits.   Application of  an uncertainty  factor  of 1000
(10 for  Interspedes  variability,  10 for Intraspedes variability and  10 to
extrapolate from subchronlc  to chronic  exposure)  results 1n  a  chronic oral
RfD of  0.005 mg/kg/day.   Confidence  In the key  study 1s  high, confidence In
the data base 1s low,  and confidence In the RfD Is  medium.
0219d
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                                                                     03/15/91

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                           9.  REPORTABLE QUANTITIES
 9.1.    BASED ON  SYSTEMIC  TOXICITY
     A previous  RQ  of  100  was  derived  for  cresols  based on  an  Inhalation
 study by  Uzhdav1n1  et al.  (1972) with  rats exposed  to  ortho-cresol  (U.S.
 EPA,  1983a,  1985).
     Data  pertaining  specifically  to  4-methylphenol  Inhalation  exposure are
 not  available.   The  most  severe   effects  occurring at  each dosage  In the
 subchronlc  oral  exposure  studies are  summarized 1n Table 9-1.  These  studies
 are  described more fully  1n Section  6.1.2.  Mortality  occurring within the
 first  3  days In  female  rats  at   600  mg/kg/day  1n  the D1etz  and Mulligan
 (1988)  study was not  Included  1n  Table 9-1  because  1t  was  an acute effect.
 For  this  reason,  maternal  mortality In rabbits  1n the developmental toxlclty
 study  by  CMA  (1988a)  Is   not  Included  In Table  9-1.   The  forellmb and
 pectoral  girdle  malformations   reported  1n  rabbits  at 300  mg/kg/day  (CMA,
 1987)  were not  Included  In  Table  9-1 because of  maternal  mortality at that
 dosage.   Oral exposure 1n  rats  resulted  In mortality  and  CNS  Impairment
 (D1etz  and  Mulligan,   1988;  U.S.   EPA,  1987a).    M1ld  anemia,  organ  weight
 changes  (D1etz and  Mulligan,  1988) and labored  respiration (U.S. EPA, 1987a)
 were  also observed.   The CSs  and corresponding  RQs  for  these  effects are
 summarized  1n Table 9-2.   All  of  the resulting RQs  were  1000.   The labored
 respiration  observed  In  male and  female  rats  at 175 mg/kg/day  (U.S.  EPA,
 1987a)  resulted   1n  the highest  CS,  which  Is  selected as most stringently
 representative   of   the  chronic   (noncancer)   toxlclty  of   4-methylphenol
 (Table 9-3).
0219d
-47-
03/15/91

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                                   TABLE  9-3
                                4-METHYLPHENOL
                              (CAS No. 106-44-5)
           Minimum Effective  Dose  (MED) and Reportable  Quantity  (RQ)
Route:                  oral
Species/sex:            rats/male and female
Dose*:                  209.47 mg/day
Duration:               13 weeks
Effect:                 labored breathing
RVd:                    2.0
RVe:                    B
CS:                     16.2
RQ:                     1000
Reference:              U.S. EPA. 1987a

^Equivalent human dose
0219d                               -50-                             03/13/91

-------
 9.2.    BASED ON CARCINOGENICITY
    Pertinent  data  regarding  the  carclnogenldty  1n  humans  or animals  of
 4-methylphenol were  not  located  In the available literature and the compound
 was  assigned  to   EPA  Group  D:  not  classifiable as  to carclnogenldty  to
 humans.   Hazard  ranking 1s  not  performed for EPA Group  D  compounds;  there-
 fore an  RQ based on  carclnogenldty cannot be assigned to 4-methylphenol.
0219d
-51-
03/15/91

-------
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0219d                               -55-                             03/15/91

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0219d                               -67-                              03/15/91

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0219d                               -71-                             03/15/91

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 convulsion.  Int. J.  Neurosd.  7: 223-226.

 Yoshloka, Y., Y. Ose  and  T.  Sato.   1985.   Testing  for the toxldty of chemi-
 cals with Tetrahymena pyrlformls.  Scl. Total Environ.  43(1-2): 149-157.

 Young,  L.Y.  and  M.D.   Rivera.    1985.    Nethanogenlc   degradation  of  four
 phenolic compounds.  Hater Res.  19: 1325-1332.
0219 d
-74-
03/15/91

-------
                                  APPENDIX A

                              LITERATURE SEARCHED



    This  HEED   Is  based  on  data  Identified  by  computerized  literature

 searches of  the  following:

              CHEHLINE
              TSCATS
              CASR online  (U.S. EPA Chemical Activities Status Report)
              TOXLINE
              TOXLIT
              TOXLIT 65
              RTECS
              OHM TADS
              STORET
              SRC Environmental Fate Data Bases
              SANSS
              AQUIRE
              TSCAPP
              NTIS
              Federal Register
              CAS ONLINE (Chemistry and Aquatic)
              HSDB
              SCISEARCK
              Federal Research In Progress


 These  searches   were  conducted  1n  May,  1988,   and  the  following  secondary

 sources were 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).
    1987.   TLVs:  Threshold Limit Values  for  Chemical  Substances  1n the
    Work   Environment   adopted   by   ACGIH  with  Intended  Changes  for
    1987-1988.  Cincinnati, OH.  114 p.

    Clayton,  G.D.  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.  2B.   John Wiley  and
    Sons, NY.  p. 2879-3816.
0219d                               -75-                             03/15/91

-------
     Clayton,  G.O.  and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
     Hygiene  and  Toxicology,  3rd  rev.  ed.,  Vol.  2C,   John WHey  and
     Sons, NY.  p. 3817-5112.

     Grayson,  M.  and  D.  Eckroth, Ed.   1978-1984.   K1rk-0thmer  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.   IARC, WHO, Lyons, France.

     Jaber,  H.M.,  W.R.  Mabey,  A.T.  Lieu,  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.
     EPA  600/6-84-010.   NTIS  PB84-243906.   SRI  International,   Menlo
     Park, CA.

     NTP  (National Toxicology  Program).  1987.   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).   1987.   Directory  of  Chemical
     Producers.  Menlo Park, CA.

     U.S. EPA.  1966.   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.

     USITC  (U.S.  International  Trade  Commission).    1986.   Synthetic
     Organic  Chemicals.   U.S.   Production  and  Sales,  1985,  USITC  Publ.
     1892, 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.8. Walker,  Ed.   1983.  The  Pesticide Manual.
    British Crop Protection Council.  695 p.
0219d
-76-
03/15/91

-------
     In  addition, approximately  30  compendia  of aquatic  toxklty  data were

 reviewed,  Including  the  following:


     Battelle's  Columbus  Laboratories.    1971.   Water  Quality 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.W. and M.T.  Flnley.  1980.  Handbook  of  Acute Toxlclty
     of  Chemicals  to  F1sh  and  Aquatic   Invertebrates.    Summaries  of
     Toxlclty  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, 0.   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.
0219d                               -77-                             03/15/91

-------



















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0219d
-78-
03/15/91

-------
                                  APPENDIX C
          DOSE/DURATION  RESPONSE GRAPHS FOR EXPOSURE TO 4-METHYLPHENOL
 C.I.    DISCUSSION
     Dose/duration-response   graphs   for  oral   exposure  to  4-methylphenol
 generated by the method  of  Crockett et al.  (1985)  using the computer soft-
 ware  by Durkln  and  Meylan (1989)  developed under contract to ECAO-C1nc1nnat1
 are  presented  In Figures C-1 and  C-2.   Data used to  generate  these graphs
 are  presented  In   Section  C.2.   In the  generation  of  these  figures,  all
 responses are classified as adverse (PEL, AEL  or  LOAEL) or nonadverse (NOEL
 or  NOAEL) for  plotting.  For  oral  exposure, the  ordlnate  expresses dose as
 human  equivalent dose.   The  animal dose  In mg/kg/day  1s multiplied by the
 cube  root of the ratio of the animal:human body weight to adjust for species
 differences  In   basal  metabolic rate  (Mantel  and Schnelderman,  1975).   The
 result  1s then  multiplied  by  70   kg,  the  reference  human  body weight,  to
 express  the  human equivalent dose as mg/day for a 70 kg human.
    The  boundary for adverse  effects  (solid  line)  1s drawn  by Identifying
 the  lowest adverse  effect dose or  concentration at  the shortest duration of
 exposure  at  which  an adverse effect occurred.   From  this point, an Infinite
 line  1s  extended upward, parallel  to  the dose axis.  The  starting point Is
 then  connected   to  the  lowest  adverse  effect  dose  or  concentration  at  the
 next  longer  duration of exposure that has an  adverse  effect dose or concen-
 tration  equal to or lower than the  previous  one.   This  process  Is  continued
 to the  lowest adverse  effect  dose  or concentration.   From this point, a line
 1s  extended  to  the right,   parallel  to  the duration axis.   The  region  of
adverse effects  lies above the adverse effects boundary.
0219d                               -79-                             03/15/91

-------
T
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fi
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9

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     10000 -r
      1000 -r
       100
          0.0001
                                                                     rn
                                                                     LIB
                                                   	Hi
                                                   4-
             0.001              0.01               0.1

              HUMAN EQUIU DURATION (fraction  lifespan)

                                 METHOC
    KEY:
F - PEL

L » LOAEL

n - NOAEL
Solid Line » Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
                                        FIGURE  C-1


            Dose/Duration-Response Graph for Oral Exposure to 4-Methy1phenol,
                                     Envelope Method
      0219d
                           -80-
                                                                          03/15/91

-------
    100000 p
fr
73
-=-   ioooo-t-
UJ
d
o
o
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      1000--
       100-
        0.0001
                 4 methylphenol
                               F14
                J	I
                         I I I I
                                  I	I
                                        N1
                                                L6
                                                N5
                                                                 F92
                                                                 L81
                                                                            i i 1
                          0.001             0.01              0.1

                       HUMAN EQUIVALENT DURATION (fraction lifespan)

                                CENSORED MTfl fOHOD - (Oral Exposure)
  KEY:   F - FEL
         L - LOAEL
         N - NOEL
         n * NOAEL

  Solid Line « Adverse Effects  Boundary
  Dotted Line - No Adverse  Effects Boundary
                                    FIGURE  C-2

         Dose/Duration-Response Graph for Oral Exposure to 4-Methy!phenol,
                               Censored  Data  Method
  02194
                                      -81-
03/15/91

-------
     Using  the envelope method,  the  boundary for no  adverse  effects  (dashed
 line)  1s drawn  by Identifying the highest no adverse effects  dose or  concen-
 tration.   From  this point, a  line parallel  to  the  duration axis Is extended
 to  the dose or  concentration  axis.  The  starting point  Is then connected to
 the  next  lower  or equal no adverse  effect  dose or  concentration at a longer
 duration of exposure.   When this process can no longer  be continued, a line
 Is  dropped  parallel to the dose  or  concentration axis  to the duration axis.
 The  no adverse effects  region lies below  the   no  adverse effects  boundary.
 At  either   ends  of  the graph  between the  adverse  effects  and no  adverse
 effects  boundaries  are regions  of ambiguity.   The area  (If  any}  resulting
 from  Intersection of the  adverse effects and  no adverse effects boundaries
 Is defined  as the region of contradiction.
    In  the  censored  data method,  all no adverse effect  points located In the
 region  of  contradiction are  dropped from  consideration  and  the no  adverse
 effect  boundary Is  redrawn so that 1t  does  not   Intersect  the adverse effects
 boundary and  no region of contradiction  Is generated.    This  method  results
 In the most conservative definition of  the no adverse effects region.
    In  Figures  C-l  and C-2,   the adverse effects  boundary 1s defined  by  a
 dose  associated  with   mortality   In  rabbits (Rec.  #13),  an  L0cn  1n  mice
                                                                  t»u
 (Rec. #16)  and, 1t  Us  lowest Inflection, a dose of 50  mg/kg/day In develop-
mental  studies  1n rabbits  (Recs. #2 and  4),  which  was  a  LOAEL  In  one study
 (CMA,  1987} and a  PEL  1n  the other (CMA,  1988a).   These  points are super-
 Imposed  and  difficult to read.   In   Figure   C-l,   the  no adverse  effects
boundary Is defined  by  a NOEL for maternal  and  developmental  effects  In rats
 (Rec. #5) and a NOAEL  of 50 mg/kg/day  1n  two, 13-week studies 1n rats (Recs.
#7  and  10,  superimposed and  difficult  to read).   Record #1,  the  NOEL  of  5
mg/kg/day 1n  the  developmental study  1n  rabbits chosen as the  basis of the
0219d
-82-
03/15/91

-------
 RfD   (CMA,   1988a)   1s   well   below  the  adverse  effects  boundary,  which
 strengthens  confidence  1n  the choice of  these data as the basis for the RfD.
     In  Figure C-2,  generated by  the  censored  data  method,  the  no adverse
 effects  boundary Is  defined  only by  the NOEL  of  50 mg/kg/day  1n  the two,
 13-week  studies  1n rats  (Recs. #7 and 10, superimposed).
 C.2.   DATA  USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
 C.2.1.   Oral Exposure.
 Chemical Name:    4-methylphenol
 CAS  Number:       06-44-5
 Document Title:   Health and Environmental Effects Document on 4-Methylphenol
 Document Number:  pending
 Document Date:    pending
 Document Type:    HEED
RECORD #1:






Species
Sex:
Effect:
Route:

Number
Number
: Rabbits
F ema 1 e
NOEL
Gavage

Exposed:
Responses:
Body weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
14
0
3.825 kg
5 mg/kg/day
5 mg/kg/day
13 days
24 days


               Type of Effect:
               SHe of Effect:
               Severity Effect:         4
Comment:       Doses  of  5,  50 or  100 mg/kg/day were  given  on days  6-18 of
               gestation In a developmental toxlclty study (see next record).
Citation:      CMA, 1988a
0219d
-83-
03/15/91

-------
 RECORD #2:
Comment:
Citation:
Comment:
Citation:
Comment:


Citation:
Species;
Sex:
Effect:
Route:
Rabbits
Female
PEL
Gavage
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:

14
2
DEATH
BODY
10
3.825 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
See previous record; distressed  respiration,  cyanosis,  ocular
dlschage,  hypoactlvlty  were  also  observed  at  this  dose.
Mortality claimed 5/14 at 100 mg/gk/day.

CMA, 1988a
RECORD #3:




Species:
Sex:
Effect:
Route:

Rabbits
Female
FEL
Gavage

Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
150 mg/kg/day
150 mg/kg/day
13 days
24 days
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
                         8
                         2
                         DEATH
                         BODY
                         10
Doses used were  50,  150,  300 and 500  mg/kg/day;  dose-related
maternal  mortality occurred.   Forellmb  and pectoral  girdle
malformations were observed at 300 mg/kg/day.

CHA, 1987
RECORD #4:




Species:
Sex:
Effect:
Route:

Rabbits
Female
LOAEL
Gavage

Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
                         8
                         NR
                         FUND
                         LUNG
                         8
See  previous  record  for  other  doses.
respiration were observed at all doses,

CHA, 1987
                              Gasping  and  labored
0219d
                     -84-
                                           03/15/91

-------
RECORD #5:
Comment:


Citation:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

25
0
0.29 kg
175 mg/kg/day
175 mg/kg/day
10 days
16 days
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
Doses of 30, 175 and 450 mg/kg/day were given on days 6-15 of
gestation (see next record).

CMA, 1988b
RECORD #6:


Comment:
Citation:
RECORD #7:


Species: Rats
Sex: Female
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
See previous record.
CMA. 1988b
Species: Rats
Sex: Both
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
25 25
NR NR
FUND WGTDC
CNS FETUS
8 8


Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
20
NR
FUNS
CNS
7
0.29 kg
450 mg/kg/day
450 mg/kg/day
10 days
16 days




0.35 kg
50 mg/kg/day
13 weeks
13 weeks


Citation:
Doses administered  were  50,  175 or  600 mg/kg/day.  Some  CNS
signs were observed for 1  hour  after  dosing  during first week
of study,  probably as result  of bolus administration  of  the
compound,  (see next record).

U.S.  EPA, 1987a
0219d
                     -85-
                                           03/15/91

-------
 RECORD #8:
Comment:
Citation:
Comment:
Citation:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

20
NR
FUNDH
LUNG
8
0.35 kg

175 mg/kg/day
13 weeks
13 weeks
Labored respiration, tremors, hypoactWHy,  rapid respiration,
myoclonus and low body posture were observed  In  both  sexes  at
this level (see previous  record for further  protocol).

U.S. EPA, 1987a
RECORD #9:




Species:
Sex:
Effect:
Route:

Rats
Both
PEL
Gavage

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg

600 mg/kg/day
13 weeks
13 weeks
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
                         20
                         8
                         DEATH
                         BODY
                         10
Nyotonus,   labored   respiration   and   decreased   locomotor
activity were also  observed  (see  previous  records  for  further
protocol).

U.S. EPA, 1987a
RECORD #10:




Species:
Sex:
Effect:
Route:

Rats
Both
LOAEL
Gavage

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period
Duration Observation:
0.35 kg

50 mg/kg/day
13 weeks
13 weeks
Number Exposed:          60
Number Responses:        0
Type of Effect:
SHe of Effect:
Severity Effect:         2

Doses administered were  50,  175 and  600  mg/kg/day (see  next
record)

D1etz and Mulligan, 1988
0219d
                     -86-
                                           03/15/91

-------
RECORD
Comment:
Citation:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

30
NR
WGTDC
BODY
4
0.35 kg

175 mg/kg/day
13 weeks
13 weeks
Females had  anemia, males  had Increased  relative  weight  of
liver  and  kidneys  (and  other  organs   at   higher   doses);
Increased total serum protein.   Also see previous  record.

D1etz and Mulligan, 1988
RECORD #12:




Species:
Sex:
Effect:
Route:

Rats
Both
PEL
Gavage

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg

600 mg/kg/day
13 weeks
13 weeks
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
30
3
DEATH
BODY
10
30
NR
WGTDC
BODY
4
Comment :
Citation:
RECORD #13:


See previous records; other effects Included liver and kidney
lesions, organ weight changes, tracheal epithelial metaplasia.
D1etz and
Species:
Sex:
Effect:
Route:

Mulligan, 1988
Rabbits
NR
PEL
Oral (NOS)


Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

3.8 kg
620 mg/kg/day
1 day
1 day
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
                         1
                         1
                         DEATH
                         BODY
                         10
Doses administered  were 180,  280,  420,
2100 mg/kg as a 20% emulsion  In water.

Dlechmann and WHherup,  1944
                               620,  940,  1400  and
0219d
                     -87-
                                           03/15/91

-------
RECORD #14:

Comment:
Citation:
RECORD #15:

Comment:
Citation:
RECORD |16:

Comment :
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1800 mg/kg was the LOso
Dlechmann and Wltherup,
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
The LDgQ was 207 mg/kg;
Sax, 1984
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
The LDso was 344 mg/kg;
Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
10
5
DEATH
BODY
10
0.35 kg
1800 mg/kg/day
1 day
: 1 day

; other doses not specified
1944; Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10
other doses not sped

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10

0.35 kg
207 mg/kg/day
1 day
: 1 day

fled

0.03 kg
344 mg/kg/day
1 day
: 1 day

other doses not specified


NR = Not reported
0219d
-88-
03/15/91

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