—-—<•'. - M "7 *^

               United States          Office of Water        EFA ^fl/E-ffl 044
               Environmental Protection     Regulations and Standards   October 19f!0
               Agency            Criteria and Standards Division    —  •
                              Washington DC 20460       C' • |
vvEPA        Ambient
               Water  Quality
               Criteria for
               2,4-dimethylphenol

-------
      AMBIENT WATER QUALITY CRITERIA FOR

            2,4-DIMETHYLPHENOL
                 Prepared By
    U.S. ENVIRONMENTAL PROTECTION AGENCY

  Office of Water Regulations and Standards
       Criteria and Standards Division
              Washington, D.C.

    Office of Research and Development
Environmental Criteria and Assessment Office
              Cincinnati, Ohio

        Carcinogen Assessment Group
             Washington, D.C.

    Environmental Research Laboratories
             Corvalis, Oregon
             Duluth, Minnesota
           Gulf Breeze, Florida
        Narragansett, Rhode Island


         Jr'v      -  --^;ucn Agency
         *-'•-'   '•','  -'. ''

-------
                              DISCLAIMER
      This  report  has  been reviewed by  the  Environmental  Criteria and
Assessment Office, U.S.  Environmental  Protection  Agency,  and approved
for publication.   Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
                         AVAILABILITY NOTICE
      This  document  is available to  the public through  the  National
Technical Information Service, (NTIS), Springfield,  Virginia  22161.
                                   11

-------
                                FOREWORD

     Section  304 (a)(l) of  the  Clean  Water Act of  1977  (P.L.  95-217),
 requires  the Administrator of  the  Environmental  Protection Agency  to
 publish  criteria for  water quality  accurately  reflecting the  latest
 scientific knowledge on the kind and extent of all  identifiable effects
 on  health  and welfare  which  may  be  expected  from  the  presence  of
 pollutants in any body of  water,  including ground water.  Proposed water
 quality  criteria  for  the  65 toxic pollutants listed under  section  307
 (a)(l)  of the  Clean  Water Act  were  developed  and a  notice  of  their
 availability was  published for  public  comment on March 15,  1979  (44  FR
 15926), July 25, 1979 (44 FR 43660), and October  1,  1979  (44 FR 56628).
 This  document   is a revision  of those  proposed  criteria based  upon  a
 consideration  of  comments received  from other Federal  Agencies,  State
 agencies,  special  interest  groups,  and  individual scientists.    The
 criteria contained in  this document replace any previously published  EPA
 criteria  for  the  65  pollutants.    This  criterion document  is also
 published in satisifaction  of paragraph  11 of the Settlement Agreement
 in  Natural  Resources  Defense  Council,  et. al.  vs.  Train,  8  ERC 2120
 (O.D.C. 1975),  modified,  12 ERC  1833  (D.D.C. 1979).

    The term "water quality criteria"  is  used  in  two  sections  of the
 Clean Water Act, section 304 (a)(l)  and section 303 (c)(2).  The  term has
 a different  program impact in  each  section.   In section 304,  the term
 represents a non-regulatory,  scientific assessment  of ecological ef-
 fects. The criteria presented  in this publication  are  such scientific
 assessments.    Such water quality  criteria  associated  with   specific
 stream uses  when adopted as State water quality standards under section
 303  become  enforceable maximum  acceptable levels  of  a pollutant   in
 ambient waters.  The water quality criteria adopted in the State water
 quality standards could have the same numerical limits  as the criteria
 developed under section  304.  However,  in many situations States  may want
 to adjust water quality criteria developed  under section 304 to reflect
 local  environmental  conditions  and  human  exposure   patterns  before
 incorporation  into  water   quality  standards.    It  is   not  until  their
 adoption as  part of  the  State water  quality standards that the criteria
 become regulatory.

    Guidelines  to  assist   the States  in the modification  of  criteria
presented in this  document,  in  the  development  of water  quality
standards, and  in other water-related programs of  this Agency, are being
developed by EPA.
                                    STEVEN SCHATZOW
                                    Deputy Assistant Administrator
                                    Office of Water Regulations and Standards
                                  111

-------
                                   ACKNOWLEDGEMENTS
Aquatic Life Toxicology:

    William A. Brungs, ERL-Narragansett
    U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:

    Martha Radike (author)
    University of Cincinnati

    John F. Risher (doc. mgr.) ECAO-Cin
    U.S. Environmental Protection Agency

    Jerry F. Stara (doc. mgr.) ECAO-Cin
    U.S. Environmental Protection Agency

    A. Wallace Hayes
    University of Mississippi

    Steven D. Lutkenhoff, ECAO-Cin
    U.S. Environmental Protection Agency

    Gary Osweiler
    University of Missouri

    Geraldine L. Krueger
    University of Cincinnati
Herbert Cornish
University of Michigan

Patrick Durkin
Syracuse Research Corporation

Alfred Garvin
University of Cincinnati

Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency

David McKee, ECAO-RTP
U.S. Environmental Protection Agency

Rudy Richardson
University of Michigan

Philip J. Wirdzek, OWPS
U.S. Environmental Protection Agency
Technical Support Services Staff:  D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C,A. Cooper,
M.M. Denessen.

Clerical Staff:  C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, P. Gray, R. Rubinstein.
                                           iv

-------
                           TABLE OF CONTENTS

                                                      Page


Criteria Summary

Introduction                                           A-1

Aquatic Life Toxicology                                B-1
     Introduction                                      B-1
     Effects                                           B-2
          Acute Toxicity                               B-2
          Chronic Toxicity                             B-3
          Plant Effects                                B-3
          Residues                                     B-4
          Miscellaneous                                B-4
          Summary                                      B-5
     Criterion                                         B-5
     References                                        B-7

Mammalian Toxicology and Human Health Effects          C-l
     Introduction                                      C-l
     Exposure                                          C-4
          Ingestion from Water                         C-4
          Ingestion from Food                          C-9
          Inhalation                                   C-ll
          Dermal                                        C-12
     Pharmacokinetics                                  C-12
          Absorption                                   C-12
          Distribution                                 C-13
          Metabolism                                   C-13
          Excretion                                    C-16
     Effects                                           C-16
          Acute,  Subacute and Chronic  Toxicity         C-16
          Synergism and/or Antagonism                   C-27
          Teratogenicity and  Mutagenicity              C-27
          Carcinogenicity                              C-28
     Criterion  Formulation                             C-33
          Existing  Guidelines and  Standards             C-33
          Current  Levels of Exposure                    C-33
          Special  Groups at Risk                        C-33
          Basis and Derivation  of  Criterion             C-33
     References                                         C-35

-------
                        CRITERIA DOCUMENT



                        2,4-DIMETHYLPHENOL



Criteria



                           Aquatic  Life



     The available data for 2,4-dimethylphenol indicate that acute



toxicity to freshwater aquatic  life occurs at concentrations as low



as 2,120 yg/1 and would occur at  lower concentrations among species



that are more sensitive than those  tested.   No data are available



concerning  the  chronic  toxicity of  dimethylphenol  to sensitive



freshwater aquatic life.



     No  saltwater  organisms have  been  tested  with 2,4-dimethyl-



phenol  and  no  statement can be  made  concerning  acute  or  chronic



toxicity.



                           Human  Health



     Sufficient data  are  not  available  for  2,4-dimethylphenol to



derive a level which  would  protect  against  the potential toxicity



of this compound.  Using available organoleptic data, for control-



ling undesirable taste and  odor quality of ambient water, the esti-



mated level is 400 ug/1.   It should be recognized  that organoleptic



data as  a  basis for  establishing  a  water quality  criterion have



limitations  and  have  no   demonstrated  relationship  to potential



adverse human health effects.
                                VI

-------
                           INTRODUCTION
     2,4-Dimethylphenol  (2,4-DMP)  is  a  naturally occurring,  sub-
stituted  phenol  derived  from the cresol  fraction of petroleum  or
coal tars by fractional distillation  and extraction with  aqueous
alkaline  solutions (U.S.  EPA, 1976;  Lowry, 1963;  Gruse and Stevens,
1942; Rudolfs, 1953).  2,4-DMP  is also known  as  m-xylenol,  2,4-xy-
lenol or  m-4-xylenol, and has the empirical formula CgH,QO  (Weast,
1972).  2,4-DMP is used commercially as an important  chemical feed-
stock or constituent for  the manufacture  of a  wide range of  commer-
cial products for  industry and agriculture.   It is used  in the
manufacture  of  phenolic antioxidants,   disinfectants,  solvents,
Pharmaceuticals,  insecticides,   fungicides,   plasticizers,   rubber
chemicals, polyphenylene oxide, wetting agents,  and dyestuffs, and
is an additive  or constituent of lubricants,  gasolines,  and cre-
sylic acid.   No  direct commercial application for 2,4-DMP  appears
to exist presently.
     Five  other  positional  isomers  of dimethylphenol  or   xylenol
exist and  include 2,3-,  2,5-, 2,6-,  3,4-, and 3,5-dimethylphenol.
Since these  isomers  result   from the  different positioning  of the
two methyl groups on the  phenol  ring,  they are  referred to as posi-
tional  isomers.   As  would be expected, variations in their physi-
cal,  chemical, and biological properties exist.
     2,4-DMP  has  a  molecular weight  of  122.17  and  in  its  normal
state exists as a colorless, crystalline  solid (Weast,  1972; Ben-
net,  1974).  It has a melting point of 27 to 28°C, a boiling point
of 210  C  (760 mm Hg), a vapor pressure of 1 mm Hg at 52.8°C, and a
density of 0.9650  at 20°C  (Weast,   1972;  Bennet,  1974;  Jordan,
1954) .
                               A-l

-------
     2,4-DMP  is  slightly  soluble  in water  and  as  a  weak acid
 (pka-10.6) it is also soluble in alkaline solutions (Sober,  1970).
2,4-DMP readily  dissolves  in organic solvents such as alcohol and
ether  (Weast, 1972).
     2,4-DMP can  be  oxidized to form  pseudoquinone  (Rodd,  1952).
However,  the conditions  required for  this  reaction  generally are
not found in the environment.  2,4-DMP reacts  with  aqueous alkaline
solutions to form  the corresponding  salt.   Such salts are readily
soluble in water, provided that an alkaline pH is maintained.  The
free position on the  aromatic ring, ortho to the hyroxyl group, may
be alkylated (Kirk  and Othmer,  1964)  or  halogenated (Rodd,  1952).
However, such reactions under normal environmental conditions have
not been reported.
     Information  regarding  the  concentration,  persistence, fate
and effects of  2,4-DMP in  the environment is limited.  However, its
presence  in  petroleum fractions and coal  tars,  together with its
use as a chemical  feedstock  or  constituent  for  the manufacture of
numerous products, clearly  indicates  the potential for both point
and non-point source  water contamination.  The complete biodegrada-
tion of  2,4-DMP has  been  reported  to occur  in  approximately two
months although the conditions were not stated (Rodd,  1952).
     A large number  of products  utilize  2,4-DMP as a  feedstock or
constituent.  Hence,  disposal of chemical  and  industrial process
wastes and distribution from normal product applications represent
feasible modes  of entry of 2,4-DMP into the environment.  Examples
of  the latter   mode  include  pesticide applications,   asphalt and
roadway runoff,  and the washing of dyed materials (U.S.  EPA,  1975).
                               A-2

-------
                            REFERENCES







Bennet, H.  1974.  Concise Chemical and Technical Dictionary.  3rd



ed.  Chemical Publishing Co., Inc., New York.







Gruse, W.A.  and  D.R.  Stevens.   1942.   The  Chemical Technology of



Petroleum.  McGraw-Hill Book Co., Inc., New York.







Jordan, T.E.  1954.   Vapor  Pressure of Organic Compounds.  Inter-



science Publishers, Inc., New York.







Kirk, R.E. and D.F. Othmer  (eds.)   1964.  Kirk-Othmer Encyclopedia



of Chemical  Technology.   2nd ed.   John Wiley  and Sons,  Inc., New



York.







Lowry, H.H.  1963.  Chemistry of Coal Utilization.  John Wiley and



Sons, Inc., New York.







Rodd, E.H.   1952.  Chemistry of Carbon Compounds.   Elsevier Pub-



lishing Co., New York.







Rudolfs,  W.   1953.   Industrial  Wastes, Their  Disposal and Treat-



ment.  Reinhold Publishing Corporation, New York.







Sober, H.A.   1970.  Handbook of Biochemistry.   Selected Data for



microbiology.  2nd ed.  CRC Press,  Cleveland, Ohio.
                               A-3

-------
U.S. EPA.  1975.  Identification of organic compounds in effluents



from industrial sources.  Prepared for U.S. Environ. Prot. Agency.



Versar, Inc., Springfield, Virginia.







U.S. EPA.  1976.  The  industrial  organic chemicals industry, Part



I.   Prepared for  U.S. Environ. Prot.  Agency,  Res. Triangle Inst.



Monsanto Research Corp., Dayton, Ohio.







Weast, R.C.  1972.  Handbook of Chemistry and Physics.  CRC Press,



Cleveland, Ohio.
                               A-4

-------
 Aquatic  Life  Toxicology*

                                  INTRODUCTION

    A  variety of data are  available  for  freshwater aauatic life and 2,4-di-

 methylphenol  with  no observed adverse effects  at  concentrations  below 2,120

 ug/1.

    No  data on  the  effects  of  2,4-dimethylphenol  on  any  saltwater species

 are available.

                                    EFFECTS

 Acute Toxicity

    The  48-hour EC5Q  value for  Daphnia  magna is  2,120  ug/1   (Table  1)  and

 the  96-hour  LCcn  value,  obtained  using  flow-through conditions  and  meas-

 ured concentrations,  is  16,750 ug/1 for juvenile  fathead minnows  (Table  1).

 The  192-hour LCcn  obtained from  this  same  exposure  (Phipps, et  al.  Manu-

 script)  is  13,650  ug/1 (Table 5) which  indicates  little  additional mortali-

 ty.  The 96-hour LCrn  value for the bluegill is 7,750 ug/1.

 Chronic Toxicity

    An  early-life-stage  test  (U.S.  EPA,  1978) with  the  fathead minnow  has

 been conducted,  and  the chronic  value  derived from  those  results  is  2,191

 ug/1  (Table 2).  An  additional  embryo-larval  test  (Holcombe, et  al.  Manu-

 script)  with  the  fathead  minnow duplicated  that  result  well.  The  acute-

 chronic ratio for  the  fathead  minnow  is  6.8 (Table 2).  No  chronic  test with

 an invertebrate  species  has been performed.  Since Daphnia magna appears  to

 be more  acutely sensitive  than  the  fathead minnow  or bluegill,   a  chronic

 test for this invertebrate species would  be desirable.
*The  reader  is referred  to  the Guidelines  for Deriving Water  Quality  Cri-
teria for  the  Protection of  Aauatic  Life and  Its Uses  in  order to  better
understand  the  following  discussion  and  recommendation.    The  following
tables contain the  appropriate  data that were  found  in the  literature,  and
at the  bottom  of each table  are  calculations for deriving  various  measures
of toxicity as  described  in  the  Guidelines.
                                     B-l

-------
 Plant Effects
     Huang  and  Gloyna (1967)  exposed the freshwater  alga,  Chlorella pyrenoi-
 dosa> to 2,4-dimethylphenol and observed complete destruction  of chlorophyll
 after  48  hours  at  a concentration  of 500,000  wg/l  (Table  3).   Duckweed
 demonstrated chlorosis at  a concentration  of 292,800 wg/l  (Blackman,  et  al.
 1955).
 Residues
     The  bluegill  was  exposed  for  28  days  to  14C-2,4-dimethylphenol  (U.S.
 EPA, 1978)  and the bioconcentration factor for whole  body is 150  (Table  4).
 The half-life in the  bluegill  is  less  than 1 day, which  indicates  that 2,4-
 dimethylphenol  residues are probably not a  potential  hazard for aquatic  or-
 ganisms.
 Miscellaneous
     As  stated earlier,  the 192-hour  LC5Q  value  is  13,650  ug/l  (Table  5).
 Since  the  96-hour  LC5Q value  obtained by  the  same  investigators  (Phipps,
 et  al. manuscript)  is 16,750  ug/l,  there appears to  be  no appreciable cumu-
 lative mortality.
 Summary
    The  acute  toxicity levels  for  2,4-dimethylphenol  and  Daphnia  magna and
two  warmwater  fish species range  from  2,120  to  16,750  wg/l.    The 96- and
192-hour  LC5Q  values   for  the  fathead  minnow  using  flow-through tests with
measured  concentrations  were  16,750  and 13,650  wg/1, respectively.   These
results  indicate  little cumulative mortality.  Two embryo-larval tests with
the  fathead minnow have   been  conducted by  different  investigators.  The
chronic values were 2,191  and 2,475 wg/l.  The resultant  acute-chronic ratio
is  6.8.   An  alga  and  duckweed  were much more  resistant  with effects  occur-
                                     8-2

-------
ring  at  292,800 ug/1 and higher.   The  bluegill  accumulated 2,4-dimethylphe-
nol to  a bioconcentration factor  of  150.  The  half-life  was less  than  one
day, which indicates little likelihood of residue problems.
    No data are available for 2,4-dimethylphenol and saltwater organisms.
                                   CRITERIA
    The  available  data  for 2,4-dimethylphenol  indicate that  acute  toxicity
to freshwater aquatic life occurs  at  concentrations as low as 2,120 ug/1  and
would occur  at lower concentrations  among species  that are  more  sensitive
than those tested.   No data are  available concerning the chronic toxicity of
2,3-dimethylphenol to sensitive freshwater aquatic life.
    No saltwater  organisms  have been  tested  with  2,4-dimethylphenol  and  no
statement can be made concerning acute or chronic toxicity.
                                     B-3

-------
                                                    Table t.  Acute values for 2,4-dlnethy(phenol
                             SpecIes
                                        LC50/EC50     Species Acute
                           Method*       (pg/U        Value (ug/l)
Reference
FRESHWATER SPECIES
Cladoceran, S, U 2,120
Daphnla magna
Fathead minnow (juvenile), FT, M 16,750
Pimephales promelas
Bluegl II, S, U 7,750
Lepomls macrochlrus

2,120 U.S. EPA, 1978
16,750 Phlpps, et al.
Manuscript
7,750 U.S. EPA, 1978
CO
 I
* S = static, FT = f low-through,  U = unmeasured,  M = measured


  No Final Acute Values are calculable since the  minimum data base requirements are not met.

-------
                                                   Table 2.  Chronic values  for 2,4-dlmethyIphenol
co
 I
I/I
Spec 1 as
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
* E-L = embryo- larval
Chronic
Limits Value
Method* ((ig/l) (yg/l) Reference
FRESHWATER SPECIES
E-L 1,500-3,200 2,191 U.S. EPA, 1978
£-L 1,970-3,110 2,475 Holcombe, et al.
Manuscript
Acute-Chronic Ratio
Chronic Acute
Value Value
Species (ug/1) (ug/l) Ratio
Fathead minnow, 2,475* 16,750** 6.8
Plmephales promelas
                                  **These two values were selected to calculate  the acute-chronic ratio because

                                    both tests were conducted  in the same  dilution  water (Lake Superior).
                                    Geometric mean acute-chronic ratio = 6.8

-------
                                                     Table 3.  Plant values for 2,4-dlmethy(phenol


                                                                                     Result
                                   Species                            Effect          (ug/l)      Reference

                                                                  FRESHWATER SPECIES
                                   Alga,                        Complete             500,000      Huang 4 G loyna,  1967
                                   Chi ore I la  pyrenoldosa        destruction of
                                                               chlorophyll after
                                                               48 hrs

                                   Duckweed,                    Chlorosis            292,800      Blackman, et al.  1955
                                   Lemna  minor                  (LC50)
to
 I

-------
                                              Table 4.  Residues for 2,4-dI methylphenol (U.S. EPA, 1978)

                                                                                   BIoconcentratIon     Duration
                                       Species                        TI ssue       	Factor	      (days)
                                                                   FRESHWATER SPECIES
                                       Blueglll,                    whole body            150              28
                                       Lepomls macrochirus
W
 I

-------
                                         Table  5.  Other data for 2,4-dlmethyIphenol  (Phipps,  et al.  Manuscript)


                                                                                                        Result
                                         Species                      Duration           Effect          dig/I)


                                                                  FRESHWATER SPECIES
                                         Fathead minnow  (juvenile),    192  hrs             LC50           13,650
                                         Pimephales promelas
W
 I
oo

-------
                                  REFERENCES







Blackman,  G.E.,  et  al.   1955.   The  physiological  activity  of  substituted



phenols.   I.  Relationships  between  chemical   structure   and  physiological



activity.  Arch. Biochem. Biophys.  54: 45.







Holcombe,  G.L.,  et al.   Effects of phenol, 2,4-dimethylphenol, 2,4-dichloro-



phenol,  and  pentachlorophenol  on embryo,  larval  and early  juvenile fathead



minnows  (Pimephales promelas).  (Manuscript)







Huang, J.  and E. Gloyna.  1967.   Effects  of toxic organics on photosynthetic



reoxygenation.  Environ. Health Engin. Res. Lab.  PB 216-749.







Phipps,  G.L., et al.   The acute  toxicity of phenol and  substituted phenols



to the fathead minnows.  (Manuscript)







U.S.  EPA.   1978.   In-depth  studies  on health  and environmental   impacts  of



selected  water  pollutants.   U.S.   Environ.   Prot.  Agency,   Contract   No.



68-01-4646.
                                     B-9

-------
Mammalian Toxicology and Human Health  Effects



                           INTRODUCTION



The  compound  2,4-dimethylphenol  is  one  of  a  group  of  substi-



tuted phenols  which  are  derived  from petroleum or coal tar  acids.



The compound also occurs naturally  in  plants and  has  been detected



in tea, tobacco, and cigarette smoke.



     A common  name  of  the  dimethylphenols is xylenol, a  name  fre-



quently  used  in the  literature.   Throughout  this  document,   di-



methylphenol rather than xylenol, and methylphenol rather  than  cre-



sol will  be used.    Cresol  and  cresylic  acids will  designate  the



complex mixtures produced commercially.



     This document  is  intended  to  deal  specifically with  2,4-di-



methylphenol;  however, three methylphenol isomers  and six  dimethyl-



phenol isomers generally occur  together  in nature,  as  well as  in



several  industrial  processes,  commercial products,  and   phenolic



wastes.   It is unlikely that any  large  segment of the population



would be exposed to 2,4-dimethylphenol alone.   Because quantitative



and  qualitative  data  are  not   available for  human  exposure  to



2,4-dimethylphenol, it is difficult to establish a direct  relation-



ship between this compound and health effects  in humans.



     The six dimethylphenol isomers of [(CH,)2CgH3OH| are substituted



derivatives of phenol;  when  the hydroxyl  group  is  assigned the  num-



ber one position,  they  are designated  as  follows:  2,3-, 2,4-, 2,5-,



2,6-,  3,4-,  and 3,5-dimethylphenol.   The  isomers  can occur alone



but are usually derived from fossil fuels as complex mixtures  con-



taining phenol,  the  three  cresol  isomers (2-, 3-,  and   4-methyl-
                               C-l

-------
phenol),and other  substituted phenols.  Commercial  cresol  and  ere-
sylic  acids  usually contain phenol,  the  three methylphenols,  and
the dimethylphenols.  Some chemical and physical properties  of the
dimethylphenols are listed in Table 1.
     Dimethylphenols are derived from petroleum or  coal  tar  acids.
The initial fractionation of petroleum  or  coal tar acids yields  a
complex mixture composed primarily of phenol and methylated deriva-
tives.   In  1976,  Klapproth,  in  reviewing  cresols  and cresylic
acids,  stated  that dimethylphenols,  methylphenols, and  phenol  are
removed  from  petroleum  in  the  naphtha-cracking  process  and   are
present in the spent caustic liquor used to wash petroleum distil-
late.   Coal tar acids  are obtained  from coke oven by-products,  gas-
retort  oven tars,  and distilled  tar  by-products.   It is estimated
that 151 million pounds of cresol and cresylic acids were produced
in the United States in  1975, down  21  percent  from  1974.  Cresol is
used as a  disinfectant,  commercial degreasing agent,  and  in many
manufacturing processes.  The National  Institute for Occupational
Safety and Health  (NIOSH, 1978) estimated that  11,000 people  in  the
United  States   are occupationally  exposed  to cresol   containing
2,4-dimethylphenol.
     Considerable amounts of dimethylphenols are discharged  in  tar
water  from shale distillation along with oxybenzene, methylphenols,
and other  phenolic compounds  (Maazik, 1968).   The dimethylphenol
content of  the  waste material was reported to reach 22.1  percent of
the total  monohydric  phenols in  tar waters.   According  to data
reported by the Tallin Polytechnical  Institute (Maazik,  1968),  the
                               C-2

-------
                                               TABLE 1
                       Some Physical and Chemical Properties of Dimethylphenol
                                   Molecular Formula (CH3)2CgH



o
1
Ul




Isomer, methyl
Molecular Weight
Boiling Point (°C)
Melting Point (°C)
Crystalline Form
Solubility in:
Water
Ethyl Alcohol
Density3
2,3-
122.17
218
75
Needles

Slightly
Soluble
-
2,4-
122.17
210
27-28
Crystals

Slightly
Soluble
0.9650 20°/4
2,5-
122.17
211 5 ^ 62mm
75
Needles

Soluble
Soluble
-
2,6-
122.17
212
49
Leaflets

Soluble
Soluble
0
3,4-
122.17
225
66-68
Needles

Slightly
Soluble
.9830 20°/4
3,5-
122.17
219 (Subliming)
68
Crystals

Soluble
Soluble
0.9680 20°/4
*Source: Weast, 1976.
 Values, e.g., 20°/4 means 20°C,  referred to water at 4°C.

-------
 River  Purtse  discharges  about  800  kg  of  dimethylphenols  daily into
 the  Gulf  of Finland.
     Methyl and  dimethylphenols  were  found  in  relatively high con-
 centrations in the water-soluble fraction from four  fuel  oils (Win-
 ters,  et  al.  1976).  The  fuel oils were  refined  in  four different
 locations  (Baytown,  Texas; Baton Rouge,  Louisiana;  Billings,  Mon-
 tana;  and  Linden,  New Jersey).   All six  isomers of  dimethylphenol
 were present  in  the water-soluble  fraction.
 Ingestion  from Water
     In  1975, Versar, Inc., prepared  for  the  U.S.  EPA  an  initial
 assessment of the  possible sources of 154 organic compounds  which
 have been identified in drinking water  supplies  (Versar,  1975).
 The manufacturing point  source  of 2,4-dimethylphenol  was  designated
 as coal tar fractionation and coal processing.  Commercial utiliza-
 tion of 2,4-dimethylphenol included:   use  as an intermediate  in the
manufacture of phenolic  antioxidants,  use as  a cresylic  acid  con-
 stituent, and use  in  the manufacture of Pharmaceuticals,  plastics,
resins,   disinfectants   (microbicides)   solvents,   insecticides,
 fungicides, rubber chemicals, polyphenylene oxide, wetting agents,
and dyestuffs.  The gross estimate  of  the  United States annual  dis-
charge  was 100 tons.
     Small quantities of  2,4-dimethylphenol  were reported  to be
formed  during  sewage treatment  (biological  step) and   biological
degradation of municipal,  biological,  and industrial wastes  (Ver-
sar,  1975).   There  was  no  evidence  that 2,4-dimethylphenol was
formed  during water purification,  although  the report  states  that
the compound  is  probably formed in small  quantities.
                               C-4

-------
      Leachates  from municipal and  industrial  wastes  contained the
 2,4-DMP  compound,  which  was  also formed by the degradation of high
 molecular weight tars and polymers.  Anthropogenic nonpoint sources
 of  2,4-dimethylphenol were reported to be  from asphalt and roadway
 runoff;  the general use  of  Pharmaceuticals,  fuels,  plastics,  and
 pesticides; washing of dyed materials; and  domestic sewage (Versar,
 1975).
      Biological  treatment of wastes  containing  2,4-dimethylphenol
 was  reported  to be 95 to 100  percent effective,  activated  carbon
 filtration  95  to 100 percent effective, and  incineration approxi-
 mately 95  percent  effective.  The  persistence of the compound  in
 the  environment was considered to be low, with complete degradation
 accomplished in approximately  two months  (Versar,  1975).
      Fitter and  Kucharova-Rosolova  (1974)  determined  the  biologi-
 cal  degradability  of  123  organic compounds and found  that  2,4-di-
 methylphenol  was  94.5  percent  removed  based on  chemical  oxygen
 demand (COD).   The  rate  of degradation was  28.2 mg  of  2,4-dimethyl-
 phenol removed per hour by a gram of the initial  dry matter  of  bio-
 logical  inoculum.  The percent of dimethylphenols  removed  based  on
 COD  ranged from 89.3 percent  (for the  3,5-dimethyl  isomer)  to  97.5
 percent  (for the 3,4-dimethyl isomer).  The  rates of degradation
 ranged  from 9.0 mg/g  inoculum  (2,6-dimethyl  isomer)  to 35  mg/g
 inoculum (2,3-dimethyl isomer).
     Bad taste or odor in drinking water is often  reported and has
 been ascribed to constituents  of industrial  wastes or microscopic
organisms and decaying vegetation.   Phenolic compounds are widely
 blamed for causing  medicinal odors  and  tastes  in  water supplies.
                               C-5

-------
 In  1957, Hoak reported the odor threshold of phenol and 19 phenolic
 compounds.   In  a  study conducted  at  the  Mellon Institute in Pitts-
 burgh,  Pennsylvania,  a  panel of 2 or 4  persons  sniffed  samples of
 pure  phenolic  compounds  in odor-free water, which had been heated
 to  30°C.   A flask of plain  odor-free water was provided  for  com-
 parison.   The  various samples were  placed  in random order  before
 the  test  persons, and the  flask  with the lowest perceptible  odor
 was  noted  by each  individual sniffer.   The lowest  concentration
 detected was considered  to be the threshold.  Chlorinated  phenols
 were  the compounds most easily detected;  at  30°C, the odor  thresh-
 old   for   2,4-dimethylphenol  was   determined  to   be   55.5  ug/1
 (Table 2) .
      Dietz and  Traud  (1978)  used  a  panel composed of 9  to  12  per-
 sons  of both sexes and various age groups to  test the organoleptic
 detection thresholds for 126 phenolic compounds.  To  test  for  odor
 thresholds,  200 ml samples  of  the  different  test concentrations
 were  placed  in  stoppered  odor-free  glass  bottles, shaken   for
 approximately five minutes,  and sniffed  at  room temperature (20  -
 22°C).  For each test, water  without  the  phenolic additive  was  used
 as a background sample.   The  odor  tests took  place in  several indi-
 vidual rooms in which phenols  and  other substances  with  intense
 odors had  not  been used previously.   Geometric  mean values  were
 used  to determine threshold levels.
     To determine taste  threshold  concentrations  of selected pheno-
 lic compounds,   a panel of  four  test  individuals  tasted water  sam-
ples containing various  amounts of phenolic additives.  As  a point
of comparison,   water without phenolic  additives  was  tasted first.
                               C-6

-------
                          TABLE 2

      Odor Thresholds of Selected Phenolic Compounds*
Compound
Phenol
2-methylphenol
3-methylphenol
4-methylphenol
2 , 4-dimethylphenol
2 , 5-dimethylphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol
2 , 4-dichlorophenol
2, 5-dichlorophenol
Threshold
60°C
5,000
25
100
200
100
11
5,000
714
6.5
0.45
Cone., ppb**
30°C
10,000
71
333
45.5
55.5
33
5,000
333
0.65
3.3
 *Source:  Hoak,  1957.
**Lowest concentration perceptible by a panel of two or four
  individuals.
                          C-7

-------
Samples with  increasing  phenolic concentrations were then  tested.
Between samples, the mouth was rinsed  with  the comparison  water  and
the  test  person ate several  bites of  dry  white bread to "neutra-
lize" the taste.
     Geometric mean detection level values for  both tests provided
threshold levels of  500  yg/1  for taste and  400 yg/1  for  odor  for
the chemical 2,4-dimethylphenol.
     Neither the Hoak  nor Dietz and  Traud studies., however,  indi-
cated whether the determined  threshold levels made the water  unde-
sirable or unfit for consumption.
     Difficulty in developing  analytical techniques for the  separa-
tion of phenolic substances in water supplies had  in the past been
a  factor  in attributing  odors and bad  taste   in  water  to phenol
alone.  The  distilled 4-aminoantipyrine method measured  all sub-
stances which react with the reagent  to form  a dye.  Even  though it
was recognized  that the  technique was  nonspecific, it became cus-
tomary to report  results as  phenol.   As late  as  1967,  Faust  and
Mikulewicz  presented  data  which showed  the  limitations  of  the
analytical application of 4-aminoantipyrine  for the determination
of phenols in water and  waste water.   Literature published before
1965 does not  contain quantitative or  qualitative information  on
2,4-dimethylphenol in water.
     Analytical techniques  have since been  developed  to separate
and identify methylphenol and  dimethylphenol isomers in known mix-
tures (Freedman and Charlier,  1964;  Dietz, et al.  1976; Husain,  et
al.  1977; Buryan,  et  al.  1978),  although many procedures could  not
separate 2,4-dimethylphenol from at  least  one  other  isomer.    An
                               C-8

-------
analytical method based on solvent extraction of complex mixtures,
concentration of the extract,  and  analysis  by GC/MS has been used
by the EPA and industry to detect 2,4-dimethylphenol at concentra-
tions as  low  as 0.2 yg/1; however,  analytical  interferences were
also  encountered in  these  studies.    The  applicability  of this
method  to real-world  waters must  be  verified  to  guard  against
interferences which are likely to be present.
     As mentioned  previously, Maazik   (1968)  reported  that  large
amounts (800 kg daily)  of dimethylphenols were discharged  into the
Purtse River in Finland.  However, the  presence of dimethylphenols
in public water supplies was not reported.
     Phenol,  2-  and 3-methylphenol,  and  2,4-dimethylphenol have
been  identified  in  samples of raw and  treated water (Goren-Strul,
et al. 1966).   The sources of raw surface water and treated waters
from two unspecified plants were not named  in this study conducted
in the Netherlands.
     The amount  of  2,4-dimethylphenol  in drinking water will vary
according to the concentration of  the  compound  in untreated water
and the efficiency of water treatment systems in removing  phenolic
compounds.  No  data were found  which  estimated  the  ingestion  by
humans of 2,4-dimethylphenol via drinking water.
Ingestion from Food
     Dimethylphenols have  been  identified  as naturally-occurring
constituents of some plants:   tea (Kaiser,  1967), tobacco  (Baggett
and Morie, 1973; Spears, 1963), marijuana (Hoffmann, et al. 1975),
and a conifer  (Gornostaeva,  et  al.  1977).    Although  evidence  is
lacking that the compound occurs in  a  great number  of  plants used
                               C-9

-------
 for  food,  it  may  reasonably  be  assumed  that  small  amounts  are



 ingested.



     A bloconcentration factor  (BCF) relates the concentration of a



 chemical  in aquatic animals to the concentration  in the water  in



 which  they live.    The  steady-state BCFs for a  lipid-soluble  com-



 pound in the tissues of various aquatic animals  seems to  be  propor-



 tional to  the  percent  lipids  in the tissue.   Thus,,  the  per  capita



 ingestion of a lipid-soluble chemical  can be  estimated  from  the per



 capita consumption of fish and shellfish, the weighted  average  per-



 cent lipids of consumed fish and shellfish,  and  a  steady-state BCF



 for the chemical.



     Data from a recent survey of  fish and  shellfish  consumption in



 the United States  was anlyzed  by SRI  International  (U.S.  EPA,



 1980).  These  data  were used  to estimate that the per capita  con-



 sumption  of freshwater and  estuarine fish  and shellfish  in  the



United States  is  6.5  g/day  (Stephan, 1980).   In  addition, these



data were used  with  data on the fat content of the edible  portion  of



the same  species  to estimate  that  the weighted  average percent



lipids for consumed freshwater and estuarine fish and shellfish  is



3.0 percent.



     A measured  steady-state  bloconcentration  factor  of  150 was



obtained for 2,4-dimethylphenol using  bluegills (U.S.  EPA,   1978).



Similar bluegills contained an average of 4.8 percent lipids  (John-



son,  1980).  An adjustment factor of 3.0/4.8  = 0.625  can  be used  to



adjust the measured BCF from the 4.8 percent  lipids of the bluegill



to the 3.0 percent lipids  that  is the weighted average for consumed



fish and  shellfish.   Thus, the weighted average bioconcentration
                              C-10

-------
factor  for  2,4-dimethylphenol  and  the  edible  portion  of  all fresh-
water and estuarine aquatic organisms consumed by Americans is cal-
culated  to  be  150  x  0.625  =  93.8.
Inhalation
     No  literature  was  found which  indicated  that  humans  are
exposed  to  2,4-dimethylphenol  other  than  as a component  of complex
mixtures.   Even though adverse  health effects have  been  reported
due  to  the  exposure  of  workers  to  complex  mixtures  containing
dimethylphenols, the compounds were present  in  low concentrations
relative  to  other  hydrocarbons,  and the  adverse effects  were  not
attributed  to  dimethylphenols  (NIOSH,   1978).    Health   effects
observed  following inhalation  exposures  to cresol vapors  (Corcos,
1939) are similar to those observed in  the chronic exposure of rats
to orally administered 2,6- or 3,4-dimethylphenol  (Maazik,  1968).
     Many workers are  exposed  by inhalation to commercial  degreas-
ing  agents  which contain methylphenols and  dimethylphenols;  how-
ever, no adverse health effects have been reported to date (NIOSH,
1978) .
     The compound  2,4-dimethylphenol has  been identified  in  ciga-
rette  smoke condensate  (Smith and  Sullivan, 1964;   Hoffmann  and
Wynder,  1963;  Baggett and Morie,  1973).   Concentrations  in  smoke
condensates from six  different  brands of American cigarettes ranged
from 12.7 to 20.8 mg  per cigarette  with filters removed,  and 4.4 to
9.1 mg per  cigarette with filters  in  place  (Hoffmann and  Wynder,
1963).   The compound  has also been  identified  in  the smoke  of mari-
juana cigarettes (Hoffmann, et  al.  1975) .
                              C-ll

-------
      Combustion  and  pyrolysis  of  building  materials  containing
 phenolic  resin  produce  phenol,  2-  and  3-methylphenol,  2,4-  and
 2,6-dimethylphenol   and   2,4,6-trimethylphenol   in   approximate
 descending  order of  quantity  (Tsuchiya and Sumi, 1975).   Phenolic
 resins  are  used in  the  building  industry  as foam  insulation  and
 adhesives in  laminates.   Combustion of  such  materials may  expose
 humans  to 2,4-dimethylphenol.
      Due to the  paucity of mammalian toxicity data,  a  quantitative
 estimate of the  amounts of  2,4-dimethylphenol inhaled by the gen-
 eral  population  cannot currently  be made.
 Dermal
      The ability of  cresols  to be absorbed  through the skin  and
 produce local and systemic effects has been demonstrated  in  humans
 (Berwick and Treweek, 1933;  Cason, 1959;  Green,  1975).   The  skin is
 considered to be  the  primary route of occupational exposure  to com-
 plex  mixtures  containing  2,4-dimethylphenol.    In  addition   to
 workers  exposed  in   petroleum,   coal  and  coke  processing,   and
 degreasing  operations,  the  general public  uses many commercial
 products containing  complex mixtures  of phenol  and  the mono-  and
 dimethylphenols.
                        PHARMACOKINETICS
Absorption
     Uzhdovini, et al. (1974)  determined that all of the dimethyl-
phenol isomers produced necrosis when applied in a molten state  to
 rat skin.   Only 2,4-dimethylphenol was lethal in the molten  state,
with an LD^Q of 1040 mg/kg.  In only one case was an isomer reported
 to be applied  in a solvent, namely 2,6-dimethylphenol in ethanol.
                              C-12

-------
In this instance,  the solubilized compound was lethal,  with  an LE>5Q
of 920 mg/kg.
     In mouse skin bioassays, Boutwell and Bosch (1959)  tested five
of  the six  dimethylphenol  isomers  (2,3-dimethylphenol was  not
tested) and  observed  that  irritation and hair loss paralleled the
ability of each compound to promote a carcinogenic  response to  a
single subcarcinogenic dose of dimethylbenzathracene  (DMBA).  A  20
percent solution  of  the  2,4-dimethyl isomer  in  benzene applied  2
times a week was the most active  promoting agent among  the isomers.
In these bioassays, phenol  was more damaging to the skin and more
active in initiating and promoting skin carcinomas than was  2,4-di-
methylphenol  when the two  were  applied  in  equal concentrations.
These  results from  animal  studies  suggest  that the  2,4-dimethyl
isomer is readily absorbed  through  the skin.
Distribution
     No literature  was found showing  the distribution of  2,4-di-
methylphenol  in humans or animals.   In an 8-month chronic study  of
rats  orally  administered 2,6-dimethylphenol  (0.06  or  6 mg/kg)   or
3,4-dimethylphenol  (0.14 or  14   mg/kg),  pathological  damage  was
observed in  the liver, spleen, kidneys, and  heart; distribution  of
2,6- or 3,4-dimethylphenol  (and/or their  metabolites)  through these
organs may be postulated  (Maazik,  1968).
Metabolism
     In 2 to  3 kg female rabbits,  the pattern of metabolism of the
six isomers of dimethylphenol was shown to be quite  similar  for the
various isomers (Bray, et al. 1950).  In  a single oral dose of 850
mg of  2,4-dimethylphenol,  8 to  16 percent was excreted  conjugated
                               C-13

-------
 with  sulfuric  acid and 50 to  72  percent  with glucuronic acid.   A
 small  proportion  was  also  hydroxylated,  but  was  not  identified.
 Observations  obtained from  identification  of  the  metabolites  of
 2,4-dimethylphenol in  urine are reported  in Table 3.
      In 1967, Gilbert, et al. demonstrated induction of microsomal
 enzyme activity in the liver by pretreatment of weanling rats with
 2,4-dimethylphenol (6  daily  oral  doses  of 1.5 raillimoles per kg).
 The activities  of  hexobarbitone oxidase and aminopyrine demethylase
 were measured  in  microsomal  fractions derived  from  the livers of
 treated and untreated  animals.  It was  observed  that  the inducing
 capacity of a compound was stimulated by  the  presence  of an alkyl
 substituent in  position 4.
      The metabolism  of 2,4-dimethylphenol has  been studied  in  a
 Pseudomonas species  isolated  from  river mud   (Chapman  and  Hopper,
 1968).   Metabolism was initiated by  the  oxidation of  the  methyl
 group  in position  4 relative to the hydroxyl group.  Three  inter-
 mediates  identified  were  4-hydroxy-3-methylbenzoic  acid,   4-hy-
 droxyisophthalic acid,  and protocatechuic  acid.
     That 2,4-dimethylphenol can be produced in the body by metabo-
 lism of  1,3-dimethylbenzene  has  been  demonstrated in at  least  two
 studies.   In whole animal  studies of rats  that received 1,3-di-
 methylbenzene  orally,  2,4-dimethylphenol  was  the  only phenolic
 metabolite  reported  in  the  urine  (Bakke and  Scheline,   1970).
 Approximately 2 percent of the  dose was  excreted as 2,4-dimethyl-
 phenol.   The  2,6  and 3,5-dimethyl  isomers  were  not detected.
 Jerina, et  al.  (1971)  and Kaubisch,  et  al.  (1972)  presented data
which  showed  that 2,4-dimethylphenol  was  the  major  metabolite
                              C-14

-------
                          TABLE 3

            Urinary Excretion of Metabolites of

            2,4-Dimethylphenol* in the Rabbit**
Percent of Dose Administered
Metabolic Product
Free nonacidic phenol
Ethereal sulphate
Ester glucuronide
Ether glucuronide
Ether-soluble acid
Range
0-5
12-14
0-4
35-56
49-75
Average
2
13
1
46
64
 *A dose of 850 mg administered by stomach tube.
**Source: Bray, et al.  1950.
                          C-15

-------
 produced  in  the  metabolism  of  1,3-dimethylbenzene  by rat  liver
 microsomes.   The  2,6-dimethyl isomer  was  also a metabolic  product,
 but  production of  the 2,4-isomer  was  10 times  that of  the  2,6-
 isomer.  These studies suggest that metabolic pathways exist in the
 liver  for the production of dimethylphenols from phenolic compounds
 which  find  their  way  into  the blood stream.
 Excretion
     The excretion of metabolites of 2,4-dimethylphenol was studied
 in rabbits  by Bray,  et al. in 1950.  The pattern of  metabolism  of
 the  six  isomers  was  quite similar, and  only the results   for  the
 2,4-isomer  are  reported in  Table 3.   These  data  indicate  rapid
 metabolism and excretion.  Analytical techniques of  the 1950's made
 the quantitation  of metabolites difficult.
                              EFFECTS
Acute, Subacute,  and Chronic  Toxicity
     The germicidal activity  of phenol and substituted phenols was
 recognized  more   than  50  years ago  (Schaffer  and  Tilley, 1927) .
Data  were  presented  which  compared  the  germicidal  activity  of
 2,4-dimethylphenol and other substituted phenols to  the activity  of
phenol.  It was observed that 5.8  times  as much phenol as  2,4-di-
methylphenol  was  required  to  kill the  test  organism  (Bacillus
 typhosus)  in the  same period of time.
     Woodward, et al.  (1934) reported data from testing 37  deriva-
tives of phenol for their  fungicidal  activity.   Dialkyl compounds
were more  powerful fungicides than  the corresponding monoalkyl com-
pounds.  In comparison to phenol (1.0),  the fungicidal activity  of
                              C-16

-------
2,4-dimethylphenol was  6.3  times greater  in  experiments with  the
yeast, Monilia tropicalis.
     In 1975, Leifertova,  et  al. studied the relationship between
the  biological  activity of phenolic  compounds  as  antifungal  and
antibacterial agents  and  the  chemical structure of the  compounds.
The  dialkyl-  and  trialkylphenols were the  most  active.   Activity
was  increased when alkyl groups  were  in  the 2- and 4-positions, as
in 2,4-dimethylphenol.
     Dimethylphenols and methylphenols were among compounds tested
as a chemotherapeutic treatment  to  selectively destroy plant neo-
plasms without  injuring normal  plant  tissues  (Schroth and Hilde-
brand, 1968) .   Solutions were applied  with a swab  to tumors  and
surrounding  areas.   The most  selective  of the methylated phenols
tested were  3-methylphenol  and 2,4-dimethylphenol.   At  concentra-
tions of 1.5 percent (v/v),  60 to 80 percent of tumor  tissues  (2 to
2.5  cm  in  diameter)  on  tomato plants were destroyed with little
injury  to  adjacent  stem tissues.   The compounds  that   indicated
selectivity in destroying plant  neoplasms were further studied  for
their activity in killing the  bacterium,  Agrobacterium tumefaciens,
responsible for  producing neoplastic growth in  plants.  At 0.6 per-
cent, 2,4-dimethylphenol was bacteriocidal  to this organism.
     Ascites  sarcoma  BP8  cells,  cultured  in  suspension  in vitro,
were used  to study the  toxicity of more than  250  compounds which
have been identified in tobacco  and tobacco smoke (Pilotti, et  al.
1975).   Phenol,  methylphenols,  and dimethylphenols  all   inhibited
the growth of cells; among these compounds, 2,4-dimethylphenol was
the most active  (Table 4).   The moderate toxicity of phenol to BP8
                               C-17

-------
                       TABLE 4
Inhibition of Ascites Sarcoma BP8 Cell Culture Growth
       Rate  by Phenol and Methylated  Phenols*
Compound
Phenol
2-methylphenol
3 -me thy Iphenol
4 -me thy Iphenol
2 , 3-dimethy Iphenol
2 , 4-dimethylphenol
2 , 5-dimethylphenol
2 , 6-dimethy Iphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol
*Source: Pilotti, et al.
Percent
1 mM
25
56
31
93
78
99
74
79
75
44
1975.
Inhibition
0.1 mM
5
7
5
13
2
11
0
5
5
7

                      C-18

-------
cells was  increased  by the introduction of electron-donating  sub-
stituents such as alkyl groups.
     The acute  toxicities  of  phenol, methylphenols, and dimethyl-
phenols in  422  mice  and 289 rats were  reported  in 1974 by Uzhdo-
vini, et al.  The  number of animals used for each  experiment was not
reported.   Compounds  were  administered  by inhalation,  intubation,
intraperitoneal injection, or by application to  the skin.
     Uzhdovini, et al. (1974) reported that  inhalation of dimethyl-
phenol vapors  at  "levels  of  hundreds of milligrams per liter" did
not cause death in the animals.   A mixture of vapors and  aerosols
condensed  in  the  chamber  and  deposited on  the  chamber walls and
skin of the animals.    Toxic effects were attributed to  penetration
of compounds  through the skin.   Signs  observed  during inhalation
included irritation of mucous membranes, enlargement of blood  ves-
sels  of  the  ears  and extremities,  and  excitation  followed by
lethargy.
     Ten percent  solutions  of  phenol,  methylphenols, or dimethyl-
phenols in oil were intubated into the stomachs  of animals  to  test
the  acute   toxicities of  ingested  compounds  (Uzhdovini,   et  al.
1974).  As  shown  in  Table  5,  LDcQ data  indicated that dimethyl-
phenols were less toxic than phenol and methylphenols in mice.  In
rats, 2,4-dimethylphenol was the least toxic.
     Solutions of  2,6-dimethylphenol were injected intraperitone-
ally into mice (Uzhdovini,  et al.  1974).   In  these  experiments  each
group consisted of 10 mice.  When the same concentration (0.5  per-
cent) of 2,6-dimethylphenol was administered  in  oil  or  water,  the
toxicity of the water solution  was  greater than  the oil solution.
                               C-19

-------
                              TABLE  5

         Acute Toxicity of Phenol and Methylated Phenols*
     Compound
                                           (mg/kg)
     Mice
                                                       Rats
phenol

2-methylphenol

3-methylphenol

4-methylphenol

2,4-dimethylphenol

2, 5-dimethylphenol

2,6-dimethylphenol

3,4-dimethylphenol

3, 5-dimethylphenol
436  (311-610)

344  (270-436)

828  (695-985)

344  (266-433)

809  (724-914)

1140 (797-1530)

980  (823-1166)

948  (658-1365)

836  (733-906)
                                                  1470   (1170-1830)

                                                  2010   (1240-3200)

                                                  1460   (1260-1670)

                                                  3200   (2780-3680)

                                                  1270°

                                                  1750   (1420-2150)

                                                  1620

                                                  1915C
*Source: Uzhdovini, et al. 1974.

alntubated into the stomach 10% in oil.
 LD50 calculated  according  to the method  of Prozorovskii,  1962;
 figures in parentheses interpreted as extreme values observed.

 LD50 according to Deichmann and LeBlanc, 1943.
                            C-20

-------
Following a dose of 300 mg/kg, 60 percent (+ 15.4)  of  the mice  that
received  the  aqueous  solution  died,  as  compared to  20  percent
( + 12.6) fatalities among the mice  injected  with the  oil solution.
Apparently more than one group of mice was  dosed per treatment;  the
number of groups was not reported.
     The application of molten or crystalline compounds to  the  skin
of  rats  produced  necrosis  on contact  (Uzhdovini, et  al. 1974).
Molten methylphenols and 2,4-dimethylphenol  were lethal  (Table  6).
Solid dimethylphenols  (2,5-;  2,6-;  3,4-;  3,5-)  and molten 2,6-di-
methylphenol did  not  produce fatal  toxicity in  rats; however, an
ethanol solution of 2,6-dimethylphenol was  lethal  to  mice, with an
LD5Q of 920 mg/kg.  From these experiments,  Uzhdovini, et  al.  con-
cluded that the greatest danger  of  poisoning to  man  is by absorp-
tion through the skin.
     Maazik (1968)  presented  data on the short-term  toxic effects
of  four  dimethylphenol  isomers  (2,5-; 2,6-;  3,4-;   3,5-).   Even
though 2,4-dimethylphenol was not used as a test compound,  Maazik's
observations will be summarized  because of  the limited data on  the
toxicity  of  dimethylphenols  in  mammals.    Compounds  were admin-
istered in a single dose by  mouth in the form of  finely dispersed
aqueous suspensions,  and the  animals were  observed  for  15  days.
LD5Q values  for  white mice  and albino  rats were determined by
probit  analysis  as modified  by  Prozorovskii  (1962);  in  rabbits,
LDcgS were determined  by the method  of Deichmann and LeBlanc (1943)
(Table 7) .   The clinical  signs  of  acute  poisoning  were  dyspnea,
                              C-21

-------
                    TABLE 6

  Acute  Toxicity  of  Methylated  Phenols Applied
              to  the Skin of  Rats*
Compound3
2-methylphenol
3-methylphenol
4-methylphenol
2 , 4-dimethylphenol
LD50
620
110
750
1040
(mg/kg)b
(370-1110)
(800-1400)
(510-1100)
(630-1716)
*Source: Uzhdovini, et al. 1974.

 Compounds were described as "molten".
 Values in parentheses interpreted as extreme values
 observed.
                     C-22

-------
                                                 TABLE 7



                         Toxicity of Dimethylphenol Isomers in Animals Following

                                     A  Single  Peroral  Dose  (mg/kg)*
o
i
Isomer
2 , 5-dimethylphenol
2 , 6-dimethylphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol

LD50
White Mice
383 +
479 +
400 +
477 +
36
47
43
49
+ SE

Albino Rats
444 +
296 +
727 +
608 +
26
36
70
44
LD50
Rabbits
938
700
800
1,313
            *Source: Maazik, 1968

-------
disturbance of motor  coordination,  rapid onset  of  clonic spasms,
and asymmetrical  body position.  Most of  the animals died within 24
hours.
     Guinea pigs  were relatively insensitive to the dimethylphenols
(Maazik, 1968).  Administration of 2,115 mg 2,6-dimethylphenol per
kg caused  signs  of  poisoning,  but these  disappeared after 10 min-
utes.  Administration of 1,200 mg  3,4-dimethylphenol per kg caused
only mild poisoning.
     In longer-term experiments 30 male albino  rats, divided  into 3
groups of 10,  received perorally for 10 weeks 29.5 mg 2,6-dimethyl-
phenol per  kg, 72.5  mg 3,4-dimethylphenol  per  kg,  or  no treatment
(Maazik, 1968).  Since the  doses were described as being 10 percent
of the LDcn for albino rats,  the reporting of doses  in the publica-
tion as yg  amounts  is concluded to be an error.   Animals treated
with 2,6-dimethylphenol exhibited  a  depressed  weight  gain in com-
parison to controls and increased weight coefficients of the liver
and  spleen.   Rats  treated  with  3,4-dimethylphenol  exhibited  a
statistically  significant  lag  in  weight gain  and  a statistically
significant  increase of  the weight  coefficients  of  the spleen,
heart, and lungs. Histological  examination revealed marked atrophy
and  parenchymatous  dystrophy of the  hepatic  cells in both experi-
mental groups.   No  differences  were  observed  in the morphological
picture of the blood, prothrombin  time, ratios  of the serum protein
fractions, or  the concentration of phenol in the urine.
     A long-term experiment was performed with  53 male  albino rats,
using  6  or 0.06 mg  2,6-dimethylphenol  per  kg  and 14  or  0.14 mg
3,4-dimethylphenol  per  kg;   the   doses  represent  2  x  10    and
                               C-24

-------
2 x 10~4 r  respectively,  of  the  LE>cQ for rats (Maazik, 1968).  The



compounds  were  administered  perorally for eight  months.   No  sig-



nificant  differences were  noted  in  animals receiving  the  lower



doses.   Some of  the  effects  of  the higher doses are  summarized  in



Table 8.   Pathological changes  observed  in  animals  receiving the



high doses of dimethylphenols included  fatty dystrophy and  atrophy



of  the  hepatic  cells,  hyaline-droplet dystrophy  in the kidneys,



proliferation of myeloid  and  reticular  cells,  atrophy of the  lym-



phoid  follicles of  the  spleen,  and parenchymatous  dystrophy  of



heart cells.



     The  2,4-isomer  is known to be an ATP  blocking agent  and  as



such has  been used as  an experimental tool.   Hauge,  et al.   (1966)



observed  the  development of  vasoconstriction  in  isolated  blood-



perfused  rabbit lung  preparations  as  a  function  of  time  after



arterially injecting ATP  (50 yg).  Vasoconstriction  resulting  from



physiological causes or  added ATP  was "surprisingly" inhibited  by



the addition of a commercial preparation  of tri-cresol which was



found to contain phenol, methylphenols, and dimethylphenols.



     In 1968,  Lunde,  et al.  reported  the effects of  the individual



compounds  found  in tri-cresol on vasoconstriction in the isolated



perfused  lung.   The effectiveness of  the substituted  phenols  in



inhibiting  vasoconstriction  was  related  to  the  position  of the



methyl groups relative  to the hydroxy group.  Among  the dimethyl-



phenol isomers,  2,4- and 2,6-were  the most effective  in inhibiting



vasoconstriction; 2,3-,  2,5-,   and 3,4- were less  effective, and



3,5-had no effect.  Inhibition of  vasoconstriction can be reversed



by additional ATP.   The mechanism of ATP-induced vasoconstriction



and 2,4-dimethylphenol  inhibition  of vasoconstriction is unknown.





                              C-25

-------
                                            TABLE  8

                          Toxic Effects of Dimethylphenol Administered
                                    Perorally  for  8 Months*
         Compound
  Dose
       Observation
      2,6-dimethylphenol
 6 mg/kg
o
      3,4-dimethylphenol
14 mg/kg
Significant decrease in blood serum SH.
Decrease in blood pressure.
Increase in concentration of SH groups
  in liver, spleen, and brain.
Pathological changes in liver, spleen,
  kidneys, and heart.

Decrease in blood serum SH.
Decrease in erythrocytes and hemoglobin.
Increase in concentration of SH groups
  in liver, spleen, and brain.
Pathological changes in liver, spleen,
  kidneys, and heart.
      *Source:  Maazik,  1968,

-------
 Lunde,  et al.  (1968)  suggested that the most likely explanation is
 that  the 2,4-dimethylphenol directly inhibits the effect of ATP on
 smooth  muscle  at a receptor level.
      In a  study of  the role  of histamine  in  hypoxic  pulmonary
 hypertension  in  the rat, Hauge (1968)  showed that semicarbazide, a
 histaminase  inhibitor,  potentiated  the  induced hypoxic  vasocon-
 strictor response  in  isolated  and  ventilated  lungs  perfused  with
 homologous  blood.   This  response  was blocked by 2,4-dimethylphenol
 through the dose range of 1 to 10 mg (administered  through a 35 ml
 blood  reservoir).   This demonstration  of physiological  activity
 indicates  that  the  compound  may cause  adverse health effects  in
 humans  as a result  of  chronic  exposure.
 Synergism and/or Antagonism
     Apart  from  the tumor-promoting  activity of 2,4-dimethylphenol
 (Boutwell  and  Bosch,  1959) ,  data were  not  found concerning  com-
 pounds  which  compete  with  or  enhance  the  biological activity  of
 2,4-dimethylphenol.
 Teratogenicity and  Mutagenicity
     No  investigations of the teratogenic or mutagenic potential of
 2,4-dimethylphenol  were  found  in  the literature.
     Phenol was  found to be  mutagenic  to E.  coli  strain  B/Sd-4
 (Demerec, et al.  1951).   Phenol was also shown  to be mutagenic  in
Drosophila  in  a  study in  which  isolated gonads  were  exposed  in
vitro and  then  implanted  into  host  larvae   (Hadorn  and Niggli,
1946).  Levan  and Tjio (1948a,b)  observed C-mitosis  in root tips  of
Allium cepa exposed to phenol or methylphenol  isomers, but chromo-
some fragmentation was rare.
                               C-27

-------
Carcinogenicity



     Boutwell and Bosch  (1959) reported that 2,4-dimethylphenol  in



high concentrations produced papillomas and carcinomas on the  skin



of tumor-susceptible female mice of the Sutter strain.  Five mg  in



benzene  (25  yl  of  10  percent  2,4-dimethylphenol)  applied twice



weekly  produced  carcinomas in 12  percent  of 26 mice  at  28 weeks



(Table 9).  It should be noted,  however, that the mice were housed



in wood  cages  treated  with creosote,  which may have initiated the



carcinogenic response.   In  this experiment,  benzene alone was not



evaluated; the only data related to benzene itself  refer to a  test



of its promoting  activity following a  subcarcinogenic dose of DMBA.



Benzene was applied twice weekly  to the  skin of mice after a single



application of 75 ug  DMBA  in  benzene; observation  at  24  weeks  of



the 27 surviving mice showed no carcinomas and an 11 percent inci-



dence of papillomas.



     In  the  1959 study  by  Boutwell  and Bosch,  over  50 different



compounds related to phenol were tested  for their ability to initi-



ate or promote the appearance of tumors.   (Only those results  with



compounds closely related to 2,4-dimethylphenol are  reported here.)



In these  experiments,  2,4-dimethylphenol  was  shown to promote the



appearance of papillomas and carcinomas after a single subcarcino-



genic application of DMBA.   Animals were selected at random from a



common pool of 2-  to 3-month old female Sutter  mice.  The fur was



shaved  from  the  test area  of the mid-dorsal  region of mice about



one week  prior   to  the  first application  of  the  test substance.



Because of the possibility of mechanical  irritation and damage  to



papillomas, the mice were not  shaved again  after  the experiment was
                               C-28

-------
                                                       TABLE 9

                          Carcinogenic Effects of Dimethylphenol and Phenol on Mouse Skin*
Amount (mg)
Administered Twice
Agent in Weekly in 25 *}! Duration

2,

2,
2,
^ 3,
O
N> 3'
Benzene
4-dimethylphenol

5-dimethylphenol
6-dimethylphenol
4-dimethylphenol

5-diraethylphenol
phenol






Applications
5.
2.
2.
2.
2.

2.
5.
2.
2.
1.
0
5
5
5
5

5
0
5
5
25
(weeks)
24
20
20
20
20

20
24
24
20
24
No. of
Survivors
Original
19/24
26/29
25/30
26/30
28/29

22/30
20/33
19/33
24/30
25/33
Average
Pa/
Survivor
1.42
0.66
0.40
0.15
0.71

0.91
2.25
2.68
0.62
1.16
Percent
Survivors
with Pa
63
31
24
8
50

55
90
95
33
56
Percent
Survivors
with Ca
5
0
0
0
4

5
15
37
33
4


(42
(12
(8

(14

(14
(65
(68
(29
(12


at
at
at

at

at
at
at
at
at


39 wk)
28 wk)
28 wk)

28 wk)

28 wk)
40 wk)
39 wk)
28 wk)
40 wk)
*Source:  Boutwell and Bosch,  1959.
 Pa = Papilloma
 Ca = Carcinoma

-------
 started.   A single application of 75 ug DMBA (25 yl of 0.3 percent
 in benzene)  was given;  after  one week,  the promoting agent in ben-
 zene was  applied twice weekly for the  duration  of  the experiment.
 The gross  identifications  of  benign  and malignant tumors were con-
 firmed  periodically  by microscopic examination.  Five mg of 2,4-di-
 methylphenol in benzene  (25 yl of 20 percent) ,  applied twice a week
 after  a single application of 75 yg DMBA,  elicited  a carcinogenic
 response in  18 percent of the  mice at 23 weeks (Table 10) .  All four
 of  the  dimethylphenol isomers promoted the appearance of  papillomas
 and  carcinomas; 2,4-dimethylphenol was the most  active in promoting
 carcinomas.   Results reported with  phenol as  the promoting  agent
 suggest that the  solvent used for the  initiator and promoter  may
 alter the biological response.
     The Boutwell and Bosch (1959) data were inconclusive regarding
 the  possible carcinogenic effect  of 2,4-dimethylphenol.   The  study
 did  indicate that  2,4-dimethylphenol was  a promoting agent.   Al-
 though  promoters  have  a potential  carcinogenic risk  to  humans,
 there was no dose-response data with  which to formulate a quantita-
 tive risk extrapolation.
     The cresol isomers  (2-,  3-, and  4-methylphenol)  tested by
Boutwell and Bosch  (1959) did  not  promote carcinogenesis  in  animals
at  12 weeks.   Five mg  of  a cresol  isomer  in  acetone was  applied
 twice weekly to the backs of mice initiated with a subcarcinogenic
dose of DMBA  (75 yg) in  acetone.  At  12 weeks  the  incidence of
papillomas  observed in the survivors ranged from 35 to 59 percent.
     Phenolic  fractions  of cigarette  smoke condensate  have been
shown to promote carcinogenesis in mouse skin bioassays  (Lazar, et
                              C-30

-------
                                                       TABLE 10

                      Carcinogenic Promoting Effects of Dimethylplienol and  Phenol  on  Mouse Skin
                                   Following the Single Application of 75 bg  DMBA*
Amount (mcj)
Promoting Administered Twice
Agent in Weekly in 25 *sl
Benzene Applications
None (Benzene
2 , 4-dimethylphenol
2, 6 -dimethyl phenol
3 , 4-dimethylphenol
3, 5-dimethylphenol
^j phenol
h-1

phenol**
phenol***
5
5
5
5
5
2
1
5
5
control)
.0
.0
.0
.0
.0
.5
.75
.0
.0
Duration
(weeks)
24
15
15
15
15
24
24
24
12
12
No. of Average
Survivors/ Pa/
Original Survivor
27/32
28/30
27/30
21/30
20/30
10/33
15/33
27/33
22/27
21/24
0
1
0
2
0
3
3
1
1

.15
.21
.44
.66
.90
.20
.94
.67
.50

Percent "Percent
Survivors Survivors
with Pa with Ca
11
50
30
95
40
100
100
74
64
58
0
11
4
0
0
20
33
4
0
5

(18
(11
(14
(5
(70
(93
(26



at 23 wk)
at 23 wk)
at 23 wk)
at 23 wk)
at 38 wk)
at 39 wk)
at 40 wk)


*  Source: Boutwell and Bosch, 1959.

** Initiator, 75 ijg DMBA in acetone.

***Initiator and promotor in acetone.
  'Pa = Papilloma
   Ca = Carcinoma

-------
 al.  1966; Bock, et al. 1971; Roe, et al.  1959).   Phenol and methyl-
 phenols were contained in the fraction in yg amounts  per cigarette;
 therefore  the  carcinogenic promoting  action cannot  be  directly
 ascribed to 2,4-dimethylphenol alone.
     No  reports of  epidemiologic  studies  of workers  exposed  to
 2,4-dimethylphenol were  found  in the  literature.   It  is  unlikely
 that  any  segment of  the population  is  exposed  to  this  compound
 alone.   Large  segments  of  the  population  are  exposed  to  small
 amounts of 2,4-dimethylphenol in complex mixtures in petroleum and
 coke oven industries,  commercial  cresol,  cigarettes,  and commercial
 products using fractions obtained from coal  tar acids and petroleum
 distillates.
     No data were found relating the exposure of humans to  2,4-di-
methylphenol to the incidence of  cancer.  In general,  the  complex
mixtures in which 2,4-dimethylphenol is often present are so  toxic
 that contact is avoided when the toxicity of the mixture is known.
                              C-32

-------
                      CRITERION FORMULATION



Existing Guidelines and Standards



     Standards have not been promulgated for  2,4-dimethylphenol  for



any sector of the environment or workplace.



Current Levels of Exposure



     Data are not  available for estimating the exposure of  humans



to 2,4-dimethylphenol.



Special Groups at Risk



     Workers  involved  in  the  fractionation and  distillation of



petroleum or coal and coal tar products comprise one  group  at risk.



Workers  who  are  intermittently  exposed  to   certain  commercial



degreasing agents containing cresol may also  be  at  risk.  Cigarette



and marijuana smoking groups and those exposed to cigarette smoke



inhale ug quantities  of 2,4-dimethylphenol.



Basis and Derivation  of Criterion



     The data are insufficient to  indicate that 2,4-dimethylphenol



is a carcinogenic agent.  The only  study found  (Boutwell and  Bosch,



1959) was designed  to detect promoting activity and the effect of



2,4-dimethylphenol  as a primary carcinogen  was  not  well  defined.



In addition, the dermal route of administration in this study ren-



ders the data inappropriate  for  extrapolation  of  the carcinogenic



risk of ingesting small amounts in drinking water.  The Carcinogen



Assessment  Group of  the U.S.  EPA  and  the  National Academy  of



Sciences  (1977)  concur  in the judgement  that  the  role of 2,4-di-



methylphenol as a primary cancer-producing agent is uncertain.



     The recommended  criterion  for 2,4-dimethylphenol is  based on



organoleptic properties.  The data of Dietz and  Traud  (1978)  and
                               C-33

-------
 Hoak  (1957)  indicated  that  microgram  concentrations  of  2,4-di-
 methylphenol  in  water are capable  of  causing a discernable  odor.
 Dietz  and Traud further  observed  a distinct flavor alteration  of
 water also  at microgram levels of  2,4-dimethylphenol.
     The  odor  threshold determined  by  Dietz and Traud  (1978)  for
 the detection of  2,4-dimethylphenol in water is used to arrive  at
 the criterion level of 400 yg/1.   The  study  of  Dietz and Traud  was
 chosen as the basis for the criterion for a number  of reasons.   The
 authors present  a  recent  study involving a  reasonably  substantial
 number of individuals and with  a number  of documented controls.
 This study utilized "fresh" water from the base  outlet  of the Verse
 Dam  (Germany)  for all  experiments.    The water was  described  as
 "cool and clear" and "neutral with respect to both  odoc  and  taste."
 These conditions  are  considered  to  more  closely  approximate  the
 conditions  of  ambient water  found in lakes, rivers,  and   streams
 than would those of the Hoak study, which utilized carbon-filtered
 laboratory  distilled  water at 30°C.   This  level  is  closely sup-
 ported by  the  taste  threshold  for  2,4-dimethylphenol in water
 (500 yg/1) reported by Dietz and Traud in the same paper.
     Therefore,  based  on the prevention of undesirable organoleptic
qualities, the criterion  level  for 2,4-dimethylphenol in water  is
 400 ug/1.   This criterion is based on aesthetic rather than health
effects.   Data on mammalian health effects need to be developed  as
a more  substantial  basis for setting  a criterion for the protection
of human  health.
                               C-34

-------
                            REFERENCES

Baggett, M.S. and G.P. Morie.  1973.  Quantitative determination of
phenol  and alkylphenols  in  cigarette smoke  and  their removal  by
various  filters.  Tob. Sci.   17:  30.

Bakke, O.M.  and R.R. Scheline.   1970.   Hydroxylation of  aromatic
hydrocarbons  in  the  rat.  Toxicol.  Appl.  Pharmacol.   16:  691.

Bock, F.G.,  et  al.   1971.  Composition studies on tobacco.   XLIV.
Tumor-promoting  activity  of  subfractions  of  the weak  acid  fraction
of cigarette  smoke condensate.  Jour. Natl.  Cancer Inst.   47:  427.

Boutwell,  R.K.  and  O.K.  Bosch.  1959.  The  tumor-producing  action
of  phenol and  related  compounds  for  mouse  skin.    Cancer  Res.
19: 413.

Bray, H.G., et al.   1950.  Metabolism of derivatives of toluene.  5.
The fate of  the  xylenols  in  the  rabbit,  with further observations
on the metabolism of the  xylenes.   Biochem.  Jour.  47: 395.

Buryan,  P.,  et  al.    1978.    Investigation  of the  composition  of
coal-tar phenols and  xylenols by capillary chromatography.  Jour.
Chromatogr.  148: 203.

Cason, J.S.   1959.   Report  on three extensive industrial chemical
burns.  Br. Med. Jour.  1: 827.
                               C-35

-------
Chapman,  P.J.  and D.J.  Hopper.    1968.   Bacterial  metabolism of
2,4-xylenol.  Biochem. Jour.  110: 491.

Corcos, A.   1939.  Contribution  to the study of occupational poi-
soning by cresols.  Dissertation.  Vigot Freres Editeurs.   (Fre)

Deichmann,  W.B.  and  T.J.  LeBlanc.   1943.   Determination  of  the
approximate  lethal dose  with  about six animals.   Jour.  Ind. Hyg.
Toxicol.  25: 415.

Demerec, et al.  1951.  A survey of chemicals for mutagenic activ-
ity in E. coli.  Am.  Nat.  85: 119.

Dietz, F. and J.  Traud.   1978.  Geruchs- und Geschmacks- Schwellen-
Konzentrationen von PhenolKorpern.  Gas-Wasserfack.  Wasser-Abwas-
ser.  119: 318.

Dietz, F., et al.  1976.   Systems for the identification of pheno-
lic  compounds  by thin-layer  chromatography.    Chromatographia.
9: 380.

Faust, S.D.  and  E.W.  Mikulewicz.  1967.  Factors influencing  the
condensation of  4-aminoantipyrine  with  derivatives of hydroxyben-
zene.  II.  Influence  of  hydronium ion concentration on absorptiv-
ity.  Water Res.  1:  509.
                               C-36

-------
Freedman, R.W. and G.O. Charlier.  1964.  Quantitative analysis of



low-boiling phenols  by capillary column  separation of trimethyl-



silyl ethers.  Analy. Chem.  36: 1880.







Gilbert, D., et al.  1967.  Induction of  liver microsomal process-



ing enzymes by substituted phenols.  Biochem. Jour.  103: IIP.







Goren-Strul, S.,  et al.   1966.   Identification and determination of



phenols and chlorophenols in very dilute  aqueous solutions by gas-



liquid chromatography, paper chromatography and spectrophotometry.



Anal. Chem. Acta.  34: 322.







Gornostaeva,  L.I.,  et  al.    1977.    Phenols  from  abies  sibirica



essential oil.  Khim. Pirir. Soedin; ISS  3, 417-418.







Green, M.A.  1975.  A household remedy misused - fatal cresol poi-



soning following cutaneous absorption  (A  case  report).   Med. Sci.



Law.  15: 65.







Hadorn, E.  and H. Niggli.   1946.   Mutations  in  Drosophila after



chemical treatment of gonads j.n vitro.  Nature.  157: 162.







Hauge,  A.,  et al.    1966.   Vasoconstriction  in  isolated  blood-



perfused rabbit  lungs  and  its  inhibition by cresols.   Acta.  Phy-



siol. Scand.  66: 226.
                               C-37

-------
Hauge, A.  1968.  Role of histamine in hypoxic pulmonary hyperten-



sion in the rat.   I.  Blockage or potentiation of endogenous amines,



kinins, and ATP.  Circ. Res.  33: 371.







Berwick, R.P. and D.N. Treweek.  1933.  Burns from anesthesia mask



sterilized in compound solution  of  cresol.   Jour.  Am. Med. Assoc.



100: 407.







Hoak, R.D.  1957.  The causes of tastes and odors in drinking water.



Proc. llth Ind.  Waste Conf.  Purdue Univ.  Eng. Bull.  41: 229.







Hoffmann, D.  and  E.L.  Wynder.   1963.  Filtration  of phenols from



cigarette smoke.  Jour. Natl.  Cancer Inst.  30: 67.







Hoffmann, D., et  al.  1975.  On  the  carcinogenicity of marijuana



smoke.  Recent Adv.  Phytochem.   9: 63.







Husain, S.,  et al.   1977.   Separation of isomeric alkylphenols by



high  performance  liquid  chromatographic and  gas-liquid  chroma-



tographic techniques.  Jour. Chromatogr.   137:  53.







Jerina, D.M., et  al.   1971.  Arene  oxides as intermediates in the



metabolism of  aromatic substrates.   Alkyl   and oxygen migrations



during isomerization of alkylated arene oxides.  Proc. Natl. Acad.



Sci.  68: 2545.
                               C-38

-------
Johnson, K.  1980.  Memorandum to D. Kuehl.  U.S. EPA.  March 10.








Kaiser, H.E.   1967.   Cancer-promoting effects  of  phenols in tea.




Cancer.  20: 614.







Kaubisch, N.,  et  al.   1972.   Arene  oxides as intermediates in the



oxidative  metabolism  of  aromatic  compounds.    Isomerization  of



methyl-substituted arene oxides.  Biochemistry.  11: 3080.








Klapproth, E.M.   1976.   Cresols and Cresylic  Acid.   In;  Chemical



Economics Handbook.  Stanford Res. Inst.  Menlo Park, California.








Lazar, P., et  al.   1966.   Benzo(a)pyrene content and carcinogeni-



city  of  cigarette  smoke  condensate -  results of  short-term and



long-term tests.  Jour. Natl. Cancer Inst.  37: 573.








Leifertova, I., et al.   1975.  Antifungal and antibacterial effects



of phenolic substances.  A  study  of  the relation between the bio-



logical  activity and  the  constitution  of the  investigated  com-



pounds.  Acta. Univ. Palacki. Olomuc., Fac. Med.  74: 83.








Levan, A.  and J.H. Tjio.   1948a.    Induction  of  chromosome frag-



mentation by phenols.  Hereditas.   34: 453.








Levan, A.  and  J.H.  Tjio.    1948b.    Chromosome  fragmentation  by



phenols.   Hereditas.  34:  250.
                               C-39

-------
Lunde,  P.K.,  et  al.   1968.   The  inhibitory  effect  of  various


phenols on ATP-induced vasoconstriction in  isolated perfused rabbit


lungs.  Acta.  Physiol. Scand.  72: 331.




Maazik,  I.K.   1968.   Dimethylphenol  (xylenol)  isomers and  their


standard contents in water bodies.  Gig. Sanit.  9: 18.




National Academy  of  Sciences.   1977.   Drinking  Water and  Health.


Washington, D.C.




National Institute of Occupational Safety and Health.   1978.  Occu-


pational exposure to cresol.  DHEW (NIOSH)  Publ. No.  78-133.  U.S.
                                   i

Dept. Hlth. Edu.  Welfare,  Pub.  Hlth.  Serv., Center for Disease Con-


trol.




Pilotti, A., et  al.   1975.   Effects of  tobacco  and   tobacco  smoke


constituents on cell multiplication j.n vitro.  Toxicology.   5: 49.




Fitter, P.  and P. Kucharova-Rosolova.  1974.   Relation between the


structure  and  the  biodegradability  of  organic  compounds.   III.


Biodegradability  of  aromatic hydroxy  derivatives.    Sb.  Vys. Sk.


Chem.-Technol.   Praze Technol.  Vody,  F19, 43.




Prozorovskii, V.B.  1962.  Use of  the smallest square  method in the


test analysis of lethality curves.  Farmakol. Toxicol.  25:  115.
                              C-40

-------
Roe,  F.J.C.,  et al.   1959.   Incomplete  c<^
                                                ^ens in cigarette

smoke condensate:   tumor-production by a  phenolic
                                                      -tion.  Br*

Jour. Cancer.  13: 623.
Schaffer, J.M.  and F.W. Tilley.   1927.   Further investigation of


the relation between  the chemical  constitution and the germicidal


activity of alcohols and phenols.  Jour. Bacteriol.  14:  259.




Schroth,  M.N.  and  D.C.  Hildebrand.    1968.    A chemotherapeutic


treatment  for  selectively  eradicating  crown gall  and  olive knot


neoplasms.  Phytophatol.  58: 848.




Smith, G.A. and P.J. Sullivan.  1964.  Determination of the  steam-


volatile phenols present in cigarette-smoke condensate.  Analyst.


89: 312.




Spears, A.W.  1963.  Quantitative determination of phenol in ciga-


rette smoke.  Anal. Chem.   35: 320.




Stephan, C.E.  1980.  Memorandum to J. Stara.  U.S. EPA.  July 3.




Tsuchiya, Y. and K. Sumi.   1975.   Toxicity of decomposition prod-


ucts -  phenolic  resin.   Build. Res.  Note-^Natl.  Res.  Counc. Can.,


Div. Build. Res. 106.
                               C-41

-------
                           ,a  studies on  health and  environmental
 V'S-  EPA.    1978>    T
 ;                  u water  pollutants.    Contract  No.  68-01-4646.
 impacts of  se1
          ^i. Prot. Agency.  Washington,  D.C.
 U.S.  Er>-


U.S.  EPA.   1980.   Seafood  consumption data  analysis.   Stanford

Research Institute  International, Menlo  Park,  California.   Final

rep., Task II.  Contract No. 68-01-3887.
Uzhdovini, E.R.,  et al.  1974.   Acute toxicity of  lower  phenols.

Gig. Tr.  Prof. Zabol.  2: 58.



Versar, Inc.  1975.  Identification of organic  compounds in efflu-

ents  from  industrial sources.   EPA-560/3-75-002.   U.S.  Environ.

Prot. Agency.



Weast, R.C.  (ed.)   1976.  Handbook of  Chemistry and  Physics.   57th

ed.  Chemical Rubber Co. Press, Cleveland,  Ohio.



Winters, K.,  et  al.  1976.   Water-soluble  components  of four fuel

oils: Chemical  characterizations and  effects  in growth  of micro-

algae.  Marine Biol.  36: 269.



Woodward, G.J., et  al.  1934.  The fungicidal power of phenol deri-

vatives.   I.  Effect of  introducing  alkyl groups  and  halogens.

Jour. Lab. Clin. Med.   19: 1216.
                               C-42
                                         o U. S. GOVERNMENT PRINTING OFFICE 1980 720-0,6/4379

-------