Agency
                                           500ECAOCING013

                                                             >  1987
>EPA       Research and
              Development
              HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
              FOR  CHLORINATED PHENOLS
              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


  U.S. Environmental Protection Agen^pj. QO NOT CITE OR QUOTE
  Region V, Library
  230 South Dearborn Street^,
  Chicago, Illinois  60604        „*$     NOTICE
           This document Is a preliminary draft. It has not been formally released
        by the U.S. Environmental Protection  Agency and should not at this stage be
        construed to represent  Agency policy. It is  being circulated for comments
        on its technical accuracy and policy Implications.

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                                  DISCLAIMER







    This report  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.
                                      11

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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  from Agency Program Office  files  are  evaluated as they
pertain to  potential  human health,  aquatic  life and environmental effects of
hazardous  waste  constituents.  The literature  searched  for  In this document
and  the  dates  searched  are  Included  1n "Appendix:  Literature  Searched."
Literature  search  material  1s current  up to 8 months  previous  to  the final
draft  date  listed  on the  front  cover.  Final  draft  document  dates  (front
cover) reflect the date the document 1s sent to the Program  Officer (OSWER).

    Several  quantitative  estimates  are  presented provided  sufficient  data
are available.   For systemic  toxicants,  these  Include Reference doses (RfOs)
for  chronic  and  subchronlc  exposures   for  both  the  inhalation  and  oral
exposures.   The  subchronlc  or  partial  lifetime   RfD,  is  an  estimate  of  an
exposure  level   that  would  not  be  expected to  cause adverse  effects  when
exposure occurs  during  a  limited  time  Interval,  for  example,  one  that does
not constitute a significant  portion of  the  lifespan.  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.   A
carcinogenic  potency   factor,   or  q-f*  (U.S.   EPA,   1980a),  Is   provided
Instead.  These  potency  estimates  are  derived  for both oral  and Inhalation
exposures  where  possible.   In  addition,  unit  risk  estimates  for air  and
drinking water are presented based on Inhalation and oral data, respectively.

    Reportable quantities  (RQs)  based  on both  chronic  toxiclty  and carclno-
genldty are  derived.   The  RQ 1s used  to determine  the quantity  of a hazar-
dous substance for  which  notification  is required  in  the  event  of  a release
as specified  under  the CERCLA.  These  two RQs  (chronic toxiclty and carclno-
genlcity) represent two of  six  scores  developed  (the  remaining  four reflect
1gn1tabil1ty, reactivity,  aquatic toxiclty,  and  acute  mammalian toxiclty).
Chemical-specific RQs  reflect the  lowest  of  these six primary criteria.   The
methodology  for  chronic   toxldty  and  cancer-based RQs  are  defined  in  U.S.
EPA, 1983a and 1986a,  respectively.
                                      111

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                              EXECUTIVE SUMMARY

    All the chlorophenols discussed with the exception  of  2-chlorophenol  are
crystalline solids  at  room temperature.   The monochlorophenols  are  slightly
soluble in water,  but  as  the number of chlorine  substitution  Increases,  the
higher substituted phenols become less and less soluble  in  water.   Thus,  the
di-,  tr1- and  tetra-substltuted  chlorophenols   are  sparingly  soluble   In
water.  These compounds are,  in  general,  soluble  in ethanol,  ethyl  ether or
benzene  (Verschueren,  1983;  Weast, 1980).   The  presence  of  chlorophenols
Imparts  unpleasant  taste  and   odor   In  water.   The  taste  threshold  for
2,3-d1chlorophenol  1s  0.00004  mg/8.  (Verschueren,   1983).   Currently,  five
companies  1n  as  many  locations manufacture   chlorophenols  in the  United
States.   The  current  annual  U.S.   production volumes  for  the  chlorophenols
are not available.   The  estimated  annual  world  production  volume of  chloro-
phenols is 150 kllotons (Hutzinger  et  al., 1985).   Chlorophenols are  commer-
cially produced  either by direct chloMnatlon  of phenol or by  the  alkaline
hydrolysis of  polychlorobenzenes  (Kozak  et  al.,  1979).   Trace amounts  of
highly toxic  polychlorlnated dibenzo-p-dloxlns  and dlbenzofurans have  been
found  as  contaminants  In  some   commercial chlorophenols (Hutzinger  et  al.,
1985).  The monochlorophenols are  primarily  used  1n the  synthesis  of higher
chlorinated phenols.   The  higher chlorinated phenols are used  as  germicides
and  as  Intermediates   In  the   manufacture  of  pesticides  (Krljgsheld  and
Vandergen, 1986;  Kozak et al., 1979).
    The  two  Important  processes that  may  have a significant  effect  on  the
fate of chlorophenols  in water are  photolysis and blodegradatlon.  The photo-
lytic  half-lives  of 4-chloro-,  2,4-d1chloro- and  2,4,5-trichlorophenols  at
the  top  surface  of  distilled water under midday  sunlight  irradiation  were
                                      iv

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estimated  to  be  2.6  days,  0.8  and  0.5  hours,  respectively (Hwang  et  al.,
1986).  From an outdoor  pond  experiment,  Suglura  et  al.  (1984)  estimated the
photolytlc  half-life  of 2,4,6-trlchlorophenol  at  a  depth  of  10 cm  to  be  4
days.  The photolysis  of chlorophenols will  be  Important  1n  clear  shallow
bodies  of water,  but  as  the  depth  and  turbidity  of  water  Increase,  the
Importance  of  photolysis will  decrease  because  of  light  attenuation.   The
blodegradatlon  half-lives   of  chlorophenols  In  natural waters  range  from
>1-17 days.  The  half-life  values  Increase  as  the number of chlorine substi-
tutions Increases and  the temperature  of  the  water decreases.  The half-lives
of the compounds  also  decrease  In  sediments  of  surface waters because of the
presence  of a greater  number  of  microorganisms  (Lee  and  Ryan, 1979; Banerjee
et  al.,   1984;  Hwang  et al.,  1986).   Hydrolysis and  evaporation  are  not
Hkely to be  Important processes for chlorophenols  In water  (Krljgsheld and
Vandergen,  1986).  Oxidation  may  be   a  significant  process  In  water  but
experimental data on  such  reactions  could not  be located  In  the  available
literature.   The  removal   of  chlorophenols  from water  by  sorptlon  onto
suspended solids  and  sediments may be  Important  and  will depend on  the pH of
water  and the  organic  content  of the  sorbents.   Sorptlon will  Increase at
lower pH  and higher organic content of  the  sorbents,  and will also  be higher
for higher  chlorinated than lower chlorinated phenols (Schellenberg  et  al.,
1984;  Isaacson  and  Fink,   1984;  Krljgsheld and  Vandergen, 1986).   Experi-
mental data  Indicate  that  mono- and dlchlorophenols will  not  bloconcentrate
but that  the  higher  chlorinated phenols  may bloconcentrate  significantly In
aquatic organisms  (Velth et  al.,  1980;  Kobayashl et  al.,  1979; Hattula  et
al.,  1981a; Vlrtanen  and Hattula, 1982).

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    In  the  atmosphere,  the chlorophenols  are  likely to undergo  significant
photolysis  (Korte  and  Klein,  1982).   Based  on  the  rate  constant of  phenol
reaction  with  OH  radicals  1n the  atmosphere  (Atkinson,  1985),  it  1s  con-
cluded  that  such  reactions  may  be significant  for the  lower  chlorinated
phenols.  The  detection  of  these compounds  in  rainwater and  snow  indicate
that they will be  removed from the  atmosphere by  wet deposition  (leuenberger
et a!., 1985b; PaasWirta  et al., 1985a).
    Based on  data  regarding  chlorophenols  In  water, photolysis,  hydrolysis
and evaporation will not  be significant  processes In soils.  The  two  Impor-
tant processes  in  soil  are   sorption  and  blodegradation.   While  2-chloro-,
4-chloro-, 2,4-dichloro- and  2,4,6-tMchlorophenols  were  found  to be  easily
biodegradable 1n a natural  soil, 3-chloro-, 2,5-dichloro-,  2,4,5-trichloro-
and 2,3,4,6-tetrachlorophenols were persistent 1n soil  (Alexander  and  Aleem,
1961).   The sorption of chlorophenols  in  soils  Increases  with a  decrease  1n
soil pH and Increase in chlorine  substitution.   Chlorophenols are  especially
susceptible to  leaching from  sandy soils  and  soils  with pH >10  (Schwarzen-
bach and Westall,  1985;  Sutton and  Barker, 1985;  Boyd,  1982;  Johnson et  al.,
1985).
    Although  chlorophenols  have   been  detected  in municipal  and  industrial
effluents (X1e  et  al.,  1986;  Kringstad  and Lindstrom,  1984;  Ellis et  al.,
1982;  Callahan et  al., 1979),  in  urban runoff water  (Cole et  al.,  1984), and
in surface and  groundwater near  effluent  discharge  and waste disposal  sites
(Valo   et  al.,  1984; Bedient  et   al.,  1984;  Salkinoja-Salonen  et  al.,  1984;
Watanabe et al., 1985; Xie et al.,  1986),  these  compounds have  been  detected
Infrequently  in  drinking  waters.  According to  Callahan  et al.  (1979), the
frequency of detection of  chlorophenols  In U.S.  tap waters was  0%.   Kopfler
et  al.  (1977),  however,  qualitatively   detected   2,4-di-,  2,4,5-tri- and
                                      vi

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2,4,6-trlchlorophenol   1n   U.S.   drinking  waters.    2-Chloro-,   4-chloro-,
2,4-d1chloro- and 2,4,6-trlchlorophenol at  respective  maximum concentrations
of  39,  34, 17  and  60  ng/2.  have been  detected  1n Canadian  drinking  waters
(Slthole et al., 1986).  A  few of  these compounds  have also been detected In
waters  from  England, the  Netherlands  and  Germany  (Crathorne et  al.,  1984;
KMjgsheld and Vandergen, 1986).  The  available  data  are  Inadequate to esti-
mate the dally exposure  of  a  U.S.  Individual  to  these compounds  by Ingestlon
of drinking water.
    2,4,5-TMchlorophenol  was  detected  1n  air  samples  In  Love  Canal,  NY,
(Hauser  and   Bromberg,   1982)   and   2-chloro-,   4-chloro-,   2,6-dlchloro-,
2,4,5-tMchloro- and  2,4,6-trlchlorophenol  were  Identified  In  the  exhaust
gases  from an experimental  Industrial  Incineration facility  (James et  al.,
1984).   Quantitative air  monitoring  data  on  chlorophenols  In  the  United
States  or  elsewhere, however, are  not available.   Occupational exposure  to
chlorophenols  1n  a  Finnish  sawmill  was  reported  by  Kaupplnen  and  Llndroos
(1985).  The  mean  concentration  of 2,4,6-trlchlorophenol  1n one work  area
was  58  ng/m3.  but  the  concentrations  of  chlorophenols  In the air  were
usually well below the Finnish occupational  limit value of 500 yg/m3.
    Chlorophenols have   been  detected  In  a   few   edible  aquatic  organisms
collected  from  contaminated  surface  waters   In  Finland.    The  muscles  of
salmon,  Salmo  salar. and  trout,  Salmo trutta.  collected  from  these  waters
contained  maximum  average  concentrations  of  5.9,  2.5  and   29.3 yg/kg  of
2,4,6-trlchloro-,   2,4,5-trlchloro-  and   2,3,4,6-tetrachlorophenol,   respec-
tively  (Paaslvlrta  et  al.,  19855;  VuoMnen  et  al.,  1985).   Although  the
available  data  are   Insufficient  to estimate  the  average exposures  through
air, food  or  drinking water,  the data  Indicate  that  exposure  of  the  general
public to the various chlorinated phenols  Is low  and sporadic.

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    In  general,  the  tox1c1ty  of  chlorinated   phenols   to   aquatic   biota
Increases with  Increasing  chlorlnatlon  (U.S.  EPA, 1979a, 1980b,c).  This  Is
probably due  to higher  uptake of  the  more chlorinated compounds  (Kobayash!
et al., 1979).  The  toxldty of chlorophenols also  Increases  with  decreasing
pH  (Konemann  and  Musch,   1981;   Saar1kosk1  and  Vlluksela,  1981,   1982).
Structure-activity   studies  with   aquatic  organisms  Indicated   that   the
presence of  chloro  substHuents  1n the  ortho  position decreased  toxldty,
while  substHuents  In the  para  position  Increased  toxldty   (Devlllers  and
Chambon, 1986; R1bo and  Kaiser, 1983).
    There Is  a  large volume of data concerning toxldty of chlorophenols  to
freshwater  species.  The most  sensitive  species  for which there was a large
amount  of  data  were salmonlds  (rainbow  trout,  Salmo qalrdnerl  and  brown
trout,  Salmo  trutta)  and  bluegllls   (Lepomls   macrochlrus).  The   lowest
reported acutely  toxic  concentration  for freshwater  fishes  was 0.085  mg/J.
2,3,4,6-tetrachlorophenol,   a  96-hour  LC5Q  for  rainbow  trout  (Mayer  and
Ellersleck,   1986).    The  lowest  reported  acutely   toxic  concentration  for
freshwater    Invertebrates   was   0.29    mg/8.   2,3,4,6-tetrachlorophenol,   a
48-hour  LC5Q for  Daphnla  magna   (U.S.  EPA,  1978a).   Data   for  freshwater
plants,  fungi  and bacteria  Indicated  toxic  concentrations  similar to those
for freshwater  fishes and  Invertebrates.  The lowest  reported toxic  concen-
tration  for  freshwater   plants  was  0.603  mg/i  2,3,4,6-tetrachlorophenol,
the 48-hour  EC5Q  for  chlorosis  1n  duckweed  (Blackman et  al., 1955).   For
bacteria and  fungi,  the  lowest reported  toxic  concentration   was 0.176  mg/J.
2,3,4,5-tetrachlorophenol,   a  30-mlnute  EC™  for  Inhibition  of  luminescence
of PhotobacteMum phosphoreum (R1bo and Kaiser,  1983).

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    Relatively  IHtle  Information was  available concerning  marine  species.
The lowest  reported  acutely toxic concentration  for marine  species  was  1.1
mg/l  2,3,4,6-tetrachlorophenol,   a   96-hour  LC,._   for   the  cypMnodontld
fish,  RWulus  marmoratus  (Koenig  and McLean,  1980).  The  lowest  reported
toxic    concentration    for   marine   plants   was   0.44   mg/J.   2,3,5,6-
tetrachlorophenol,  a  96-hour  EC™  for  Skeletonema  costatum  (U.S.  EPA,
1978a).
    Few  studies  concerning chronic  toxlclty  of  chlorophenols  to  aquatic
organisms  were  available.   The  only  study  Involving  a  full  Hfecycle
exposure was  that of  Koenig and  McLean  (1980)  who  found that  fin  erosion
occurred   In   all   fish   (Rlvulus   marmoratus)   exposed   to   0.055   mg/J.
2,3,4,6-tetrachlorophenol, the lowest concentration tested.
    Chlorinated phenols  have been shown  to  Impair  the flavor  of freshwater
fish flesh  at  concentrations much lower  than those  that  are toxic  (Shumway
and Palensky, 1973;  U.S.  EPA,  1980b,c,d).   The  lowest reported concentration
for flavor  Impairment was  0.0004 mg/Z  2,4-d1chlorophenol,  a  threshold  for
largemouth  bass  (Mlcropterus  salmoldes)  (Shumway  and  Palensky,* 1973).   As
discussed by  U.S.  EPA (1980b,c,d), threshold concentrations  for  tainting of
fish flesh  may  be more  Important  than  toxic concentrations  1n establishing
water  quality criteria for aquatic biota.
    The chlorophenols  seem to  be readily absorbed  from  the  gastrointestinal
tract  and from parenteral  sites of Injection  (Delchmann  and  Kepllnger, 1981;
Carpenter et  al.,  1985).   Rats  dosed orally with  l4C-2,4,6-tr1chlorophenol
absorbed at  least 82.3%  of the  dose  based  on  urinary  excretion of  radio-
activity  (Korte  et  al.,   1978).   Roberts et  al.  (1977)  found  that  .2- and
4-chlorophenol,  2,4-d1chlorophenol  and  2,4,6-trlchlorophenol  can  penetrate

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human  epidermis  .In.  vitro.   Acutely  toxic levels  of 2,4,5- and  2,4,6-trl-
chlorophenol were not  absorbed  through  the Intact skin of  rabbits  or  guinea
pigs, while  toxic  levels of 2,3,4,6-tetrachlorophenol were  absorbed  through
the skin (Gosselln et al.. 1976).
    Pharmacoklnetic   studies  of  the  chlorophenols   In   laboratory  animals
Indicate that  the  compounds are distributed  rapidly,  but do not  accumulate
In any  tissue (Exon  and Koller,  1982; Somanl  and  Khallque, 1982; Korte  et
al.,  1978;  PekaM et  al., 1986; Hattula et al.,  1981b).   Metabolism  studies
Indicate that  the chlorophenols are  conjugated  to glucuronldes  and  sulfates,
with  glucuronldes predominating In  rats  (Karpow,  1893, Koster  et al.,  1981;
Somanl  and  Khallque,  1982;  Bahlg  et al.,  1981). Other metabolites  that have
been  Identified  are  dlchloromethoxyphenols Identified 1n an Uj_ vitro  study
of the  metabolism  of 2,4-d1chlorophenol  (Somanl et al.,  1984), tetrachloro-
hydroqulnone  as  a  metabolite  of   2,3,5,6-tetrachlorophenol  and  tMchloro-
hydroqulnone as a minor  metabolite  of  2,3,4,5-  and  2,3,4,6-tetrachlorophenol
(Ahlborg and  Larsson, 1978).   In  addition,  Bahlg et al. (1981) found that
other  trlchlorophenol  Isomers  are   excreted  when 2,4,6-trlchlorophenol  was
administered orally to rats.
    Studies  using  laboratory  animals   (Karpow,  1893;  Korte et  al.,  1978;
Bahlg  et   al.,   1981;  Ahlborg  and   Larsson,   1978)   Indicate   that  the
chlorophenols  are  excreted  predominantly  In  the  urine  as glucuronlc  and
sulfurlc  acid  conjugates,   and as  the  unchanged  compounds.    Kalman  and
Horstman    (1983)    found   that    the    half-time    of    elimination   of
2,3,4,6-tetrachlorophenols In occupatlonally exposed  humans was  ~63±34 hours.
    In a  subchronlc  Inhalation  study of 4-chlorophenol  (Gurova,  1964), rats
exposed  to 2  mg/m3,  6  hours/day  for  4  months  showed  neuromuscular  excit-
ability, a reduction of  endurance.  Increased myoneural  excitability,  slight

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congestion of  organs  and minor  flbrotlc  changes  In alveolar  septa.   Gurova
(1964) also  reported  symptoms  of  nervous  exhaustion,  Insomnia, Irritability,
frequent mood changes and rapid  fatlgabUHy  In workers  exposed to 4-chloro-
phenol  1n  an  aniline  dye  plant.   The   lack  of  detail  1n   these  studies
precludes adequate assessment of their reliability.
    Kleu and Goeltz  (1971)  reported symptoms of  chloracne,  decreased sexual
activity, easy  fatlgablllty,  Irritability, muscular weakness,  loss  of  appe-
tite and memory, discouragement, alcohol  Intolerance and  loss  of  Interest In
workers occupatlonally exposed to  a  tMchlorophenol  formulation for  up  to 15
years.   A  causal  relationship  was  not  established.    Alexandersson  and
Hedenstlerna (1982) found pulmonary  effects  1n workers exposed to  low levels
of trlchlorophenols 1n gas masks for up to 10 years.
    Exon and Keller  (1985)  found 1mmunolog1cal  effects 1n  rats exposed sub-
chronically to 2,4-d1chlorophenol  at 30 and  300 ppm In  their drinking water.
Similar  effects  were  not noted  1n rats  exposed  to  up  to 500  ppm 2-chloro-
phenol,  or  up to  300 ppm  2,4,6-trlchlorophenol.  Kobayashl  et   al.  (1972)
reported minor, hlstologlcal  changes  1n the livers  of mice  fed 2,4-d1chloro-
phenol  at  230   mg/kg/day  for  6  months.   No  effects   were   noted  at  100
mg/kg/day.
    A subchronlc drinking water study  of  2,4-d1chlorophenol  In mice  found no
consistent  effects that  could  be  related  to   treatment  at  up  to  2  ppm
(Borzelleca  et  al.,   1985a).   The  study  was confounded  by  the addition  of
Emulphor to the dosing solution.
    McColllster  et al. (1961)  studied  the  toxlclty  of  2,4,5-tMchlorophenol.
In a  28-day  gavage study,  microscopic changes  were noted  1n  the liver  and
kidneys of rabbits dosed  with  0.1  and 0.5 mg/kg  but not  0.01  mg/kg  20  times
                                      x1

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over the  study  period.   No  changes were noted  1n  rats  dosed  with  2,4,5-tr1-
chlorophenol at  up  to 1.0 g/kg  18 times over  24  days.  In  a  98-day  study,
pathologic changes 1n the livers and kidney were noted  In  rats  provided with
diets containing 2,4,5-trlchlorophenol  at 0.03 and  1.0% but  not  at  <0.01%.
    In a 70-day dietary  study, Vlzethum  and Goerz  (1979)  reported  that 0.05%
2,4,5-trlchlorophenol was  not porphyrogenlc  In rats.  The  NCI (1979)  sub-
chronic  study  noted an Increase  1n   splenic  hematopolesis  and  mldzonal
vacuolatlon of  hepatocytes In  rats  fed 2,4,5-trlchlorophenol  In the diet  at
46,000 ppm  for  7 weeks.  Survival  of  rats fed >21,500 ppm  but not <14,700
ppm was also affected.   In mice, survival was  affected  at  31,500 ppm but not
at  <21,500  ppm  (NCI, 1979);  no  hlstopathologlcal  data were   reported.   A
dose-dependent decrease  1n body weight was observed  1n  both rats and mice In
the NCI (1979) study.
    Kawano et al.  (1979)  observed  changes  1n  growth, organ weights,  several
biochemical parameters and liver drug metabolizing enzymes  In rats  fed diets
containing  2,3,5-tMchlorophenol  or   2,3,4,5-,  2,3,5,6- or   2,3,4,6-tetra-
chlorophenol at  0.2% for 3  weeks.   Dose-related  hlstopathologlc  changes  In
the  Hver  were  noted 1n rats  treated  by  gavage  with  2,3,4,5-tetrachloro-
phenol for 55 days at >50 mg/kg/day but  not at 10  mg/kg/day (Hattula et al.,
1981b).
    In a  chronic  study,  numbers  of RBC  and hemoglobin  levels were Increased
1n  rats  provided with  drinking  water  containing  500 ppm  2-chlorophenol  or
300  ppm  2,4-dlchlorophenol,   but  not  at  10-fold  lower concentrations  (Exon
and  Koller,  1985).   The NCI  (1979)   found  a  dose-related  Increase  1n  the
Incidences of  bone  marrow hyperplasla and  leukocytosis in rats at  5000 and
10,000 ppm.   In  mice,  dose-related hyperplasia  of   the  liver  was  noted  1n
males at 5000 and 10,000 ppm (NCI,  1979).
                                      xii

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    In  studies  of  the  Induction  of  enzymes  by  the  chlorinated  phenols,
Carlson  (1978)  found  that 2,4,5-trlchlorophenol  reduced mlcrosomal  NADPH-
cytochrome  c  reductase activity  and cytochrome  P-450  content.   Denomme  et
al. (1983)  reported  that  4-d1methylam1noant1pyrlne  N-demethylase  was  Induced
by  3,4,5-trlchlorophenol.  The other   tr1-  and  tetrachlorophenols  had  no
effects  on  enzyme   Induction.   The  mutagenldty  of  2-am1noanthracene  and
benzo[a]pyrene were  enhanced  In an  Ames assay by S-9 from  rats  treated  with
2,3,4,5-tetrachlorophenol  (Sussmuth  et al.,  1980).
    MHsuda  et  al.   (1963)  observed  that  chlorophenols  Inhibit  oxldatlve
phosphorylatlon  jm   vitro, with  the   Inhibiting  activity  Increasing  with
Increasing chlorlnatlon.
    The  acute toxldty  of the  chlorinated  phenols  has  been  studied by  a
number of  Investigators (Delchmann,   1944; Bubnov  et al.,  1969;  Borzelleca  et
al.,  1985a,b; Farquharson  et   al.,  1958;   Chrlstensen  and  Luglnbyhl,  1975;
Delchmann  and  Mergard,   1948;  Angel   and  Roberts,   1972;   Gurova,   1964;
Schrotter  et  al.,   1977;   Kobayashl  et  al.,  1972;  Vernot  et  al.,   1977;
HcColllster  et  al.,  1961;  Ahlborg  and Larrsson,  1978;  Hattula  et  al.,
1981b); In general,  the toxldty Increases as  the chlorlnatlon  Increases.
    Ep1dem1olog1cal   studies that are confounded by some  small  study  popula-
tions and  multiple exposures  Indicate  that  a mixture of  compounds  Including
chlorophenol  are  associated   with   soft  tissue  sarcomas   and   malignant
lymphomas  (Lynge, 1985; Cook,  1981;  Honchar  and HalpeMn,  1981;  Pearce  et
al.,  1986).   The  Influence of  the   chlorophenols alone,  however,  cannot  be
determined.
    Increased tumor  Incidences  were not  observed In rats  exposed to up  to
500 ppm 2-chlorophenol  or  up to 300  ppm 2,4-d1chlorophenol  1n  their drinking
water for  2 years (Exon and Keller,  1985).   Innes  et  al.  (1969)  found  Incon-
clusive results In a  carclnogenldty study  of 2,4,6-tMchlorophenol  In mice.

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In the  NCI  (1979)  study of 2,4,6-trlchlorophenol, an  Increased  Incidence  of
leukemia was  observed   In  male  rats,  while an  Increase  1n the  Incidence  of
Hver carcinoma and adenoma was  observed 1n male and  female mice.
    Exon and  Keller  (1985) found  that  2-chlorophenol  Increased  tumor  Inci-
dence and decreased tumor  latency  of  transplacental  tumors  In  rats  Initiated
by END.  This  effect  was  not observed  with 2,4-d1chlorophenol  although  the
rats were exposed to a  lower level  of  ENU.
    In  a  study  by  Boutwell and  Bosch   (1959),  2-,  3-chlorophenol,  2,4-d1-
chlorophenol and 2,4,5-tMchlorophenol  acted  as promoters of  skin  tumors  In
mice treated with a single  dose of  DMBA.   2,4,6-TMchlorophenol  was negative
1n the  skin tumor  promoting study.   2,4,6-Trlchlorophenol was also negative
1n a lung adenoma  bloassay 1n  which  strain A/J mice were  dosed  by  gavage  or
Intraperltoneal  Injection  (Stoner  et  a!.,  1986).  Tumor  Incidences  were  not
Increased 1n  mice  observed for- 18  months following  a   single  subcutaneous
Injection   of  2,4,5-,   2,4,6-trlchlorophenol   or   2,3,4,6-tetrachlorophenol
(BRL, 1968a).
    2-,  3-,  4-Chlorophenol,  2,3-,   2,4-,   2,5-, * 2,6-,  3,4-,  3,5-d1chloro-
phenol, 2,3,5-,  2,4,5-, 2,4,6-trlchlorophenol  and  2,3,4,6-tetrachlorophenol
have  tested negative   In  at  least   one assay  for  reverse  mutation  In  £.
tvphlmuMum (Haworth et a!., 1983;  Probst  et  al.,  1981;  Simmon et a!.,  1977;
Rasanen and Hattula,  1977).  Haworth et al.  (1983)  found  equivocal  results
for 2,4- and 3,5-d1chlorophenol.
    In  Chinese hamster  V79 cells,  2,4-, 2,6-d1chlorophenol,  2,4,6-trlchloro-
phenol  and  2,3,4,6-tetrachlorophenol  did  not  cause  an  Increase  1n mutation
(Jansson  and  Jansson,   1986;  Hattula  and Knuutlnen,.  1985).   In  contrast,
weakly  positive  results   were   noted  1n   Chinese  hamster  V79  cells  with
2,4,6-trlchlorophenol    and . 2,3,4,6-tetrachlorophenol   In  the   absence   of
                                      x1v

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but not In  the  presence  of  S-9  (Hattula  and Knuutlnen, 1985).  2,4-D1chloro-
phenol did  not  cause an  Increase  1n  unscheduled  ONA synthesis In primary rat
hepatocytes (Probst et a!., 1981).
    An  Increase  In  chromatld  deletions  was  noted  1n  rats  dosed  with
2-chlorophenol  (Chung,  1978).   2,4,6-TMchlorophenol was weakly  positive In
a spot test using mice (Fahrlg et a!., 1978).
    Teratogenlc  studies  of  the  chlorinated phenols  Indicate that  the  com-
pounds are  not  potent  teratogens although  they  are fetotoxlc.   Fetotoxldty
as  evidenced  by Increased  embryonic  death was  found  for 2,4-d1chlorophenol
at  oral doses of 750 mg/kg/day  (Rodwell  et al.,  1984)  and 2,4,5-tMchloro-
phenol  at  >9 mg/kg/day  (Neubert and  Dlllmann,  1972;  Hood  et  al.,  1979;
Chernoff  and  Kavlock, 1982).   Schwetz et al.  (1974)  reported an  Increase of
subcutaneous  edema   1n  rats  treated  through  gestation  with  2,3,4,6-tetra-
chlorophenol  at 10 mg/kg/day.  This effect  was not observed at 30 mg/kg/day,
although  at the higher dose  an  Increase  1n delayed ossification of the skull
bones  was  observed.   The  only   study  1n  which an  Increase'd  Incidence  of
anomalies  was observed was  In a  study by  BRL (1968b) 1n  which an Increase In
anomalies  1n  AKR mice given  subcutaneous  Injections of 2,4-d1chlorophenol at
74  mg/kg/day  during gestation was  noted.   This  effect  was  not  observed In
C57B16 mice  or  1n   either  strain of mice  when they were  treated with  85
mg/kg/day  2,4,5-trlchlorophenol.
    Research  Triangle   Institute  (1987)   In  a   teratology  study  observed
maternal   toxldty  In pregnant  CD rats  exposed  by  gavage  to  200  mg/kg/day
tetrachlorophenol  (TCP).   Embryo/fetal  growth  and  prenatal  viability  were
not  adversely  affected   by TCP  exposure,  nor  was  there  any  definitive
evidence of an effect of TCP upon fetal morphological development.
                                      xv

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     Reproductive   studies   of   2-chlorophenol,    2,4-d1chlorophenol    and
 2,4,6-tMchlorophenol  also resulted  In  reduced  Utter sizes of  rats  treated
 from  3  weeks  of  age  with >300  ppm 1n  drinking  water  through mating  and
 lactation  (Exon  and  Koller,  1982).   Blackburn  et  al.   (1986)  reported  no
 significant effects  on reproduction  In rats  treated by gavage with up  to
 1000 mg/kg 2,4,6-trlchlorophenol 5  days/week.   In  an jun vitro  study,  Seyler
 et  al.   (1984)  found   that  2,5-,  3,4-  and  3,5-d1chlorophenol   significantly
 depressed sperm penetration of  ova from mice.
     Data were  Insufficient  to  derive Inhalation RfOs  for monochlorophenols.
 An RfO  of  0.005 mg/kg/day or  0.4 mg/day for a  70 kg human was  derived  for
 both  subchronlc and  chronic oral exposure  to 2-chlorophenol,  based on  the
 NOAEL for  reproductive effects In  rats exposed  to  50  ppm  (5  mg/kg/day)  In
 their drinking water (Exon and Koller,  1982).  An  uncertainty  factor  of  1000
•(10 for  Interspecles  extrapolation,  10 to protect sensitive Individuals  and
 10  for  using a  subchronlc study)  was  used.   At  the LOAEL of  500 ppm  (50
 mg/kg/day), there were decreased  IHter size  and an  Increased  percentage  of
'stillborn  pups.   An  RQ   of  1000 was  derived   from  the LOAEL.   Data  were
 Insufficient   to  derive   values  for   3- and  4-chlorophenol.    Since   data
 regarding  the  carclnogenlclty  of  the  monochlorophenols  were  limited or  not
 available,  these chemicals were placed In EPA  Group D "not classified".
     Data were Insufficient to  derive Inhalation  RfDs  for  the dlchlorophenols.
 An RfD of 0.003 mg/kg/day  or  0.2 mg/day for  a  70  kg human for  both subchronlc
 and chronic oral exposure  to 2,4-d1chlorophenol was derived, based on a  NOAEL
 for Immunologlcal effects  of  30 ppm  (3 mg/kg/day) 1n the  drinking  water  of
 rats .(Exon  and  Koller,   1985).    An   uncertainty  factor  of  100  (10  for
 Interspecles  extrapolation and 10 to  protect  the most sensitive Individuals)
 was used.  At  the LOAEL  of 300 ppm  (30  mg/kg/day),  rats  had  Increased  serum
 antibody levels and  a decrease In  delayed  type hypersensHWIty  response.
                                       xv1

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An  RQ  of 1000  was  derived  based  on the  LOAEL.   Data were  Insufficient  to
derive  values  for   the  other  dlchlorophenols.   Since  data  regarding  the
carclnogenlclty  of  dlchlorophenols were  Inadequate  or not  available,  these
chemicals were placed In EPA Group 0, "not classified".
    Data  were  Insufficient  to  derive   Inhalation  RfDs  for  the  trlchloro-
phenols.  RfDs  of 1  mg/kg/day  or 70 mg/day and  0.1  mg/kg/day or  7  mg/day
were  derived  for subchronlc and  chronic  oral  exposure  to  2,4,5-tMchloro-
phenol based  on  a NOAEl  of  0.1% In the  diet (100 mg/kg/day)  for pathological
changes  In   the  liver  and  kidney  of   rats   In  the  subchronlc  study  by
McColllster et  al.  (1961).   Uncertainty  factors of 100  (10  for  Interspedes
extrapolation and 10 for the protection  of the most  sensitive  Individuals)
for the subchronlc RfD and  1000 (an  additional  factor  of  10  for the use of a
subchronlc NOAEL). for  the  chronic RfD  were  used.  At  the LOAEL  of  0.3% (300
mg/kg/day),  rats had mild hlstopathologlcal  lesions  1n  the liver and kidney.
An  RQ   of   1000   was  derived   from    the   LOAEL.    Data    regarding  the
cardnogenlc'Hy  of 2,4,5-trlcnlorophenol  were  not  available; therefore, this
chemical 1s  placed In EPA Group  D, "not  classified".
    The data  for the carclnogenlclty of  2,4,6-trlchlorophenol were considered
sufficient  to classify It  as a EPA Group  82  chemical,  that  1s, a  probable
human   carcinogen.    A  q,*   of  1.94x10~a   (mg/kg/day)'1   for  oral   exposure
was derived  for 2,4,6-trlchlorophenol  using  the data   for  hepatocellular
carcinoma/adenoma In  male  mice  In the NCI (1979)  bloassay.    The  concentra-
tions  In drinking water associated with an Increased  lifetime  risk  of  cancer
at  levels    of   10~5,   10~*   and  10~7  are   1.8xlO~2,    1.8xlO~3   and
1.8x10"*  mg/i,   respectively.    An   F    factor  of   1.4xlO"2   (mg/kg/day)'1
was derived  for  2,4,6-trlchlorophenol  based on  the  bloassay  data  for  liver
tumors In mice  (NCI, 1979); therefore,  this chemical  was placed 1n Potency
                                     xv11

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Group 3.  Chemicals 1n EPA Group B2  and  In  Potency  Group 3 are ranked LOW in
the  Hazard  Ranking  Scheme.   A LOW  ranking  Indicates an  RQ  of 100  based  on
cardnogenldty.
    Data  were  Insufficient   to  derive  RfOs,  q *s  or   RQs  for  the  other
trlchlorophenols,  and  these   chemicals  are  placed  in  EPA  Group D,  "not
classified".
    Data  were  insufficient  to  derive Inhalation RfDs  for  the  tetrachloro-
phenols.  RfDs of 0.1 mg/kg/day or 7  mg/day and  0.01  mg/kg/day or  0.7 mg/day
for  subchronic and  chronic  oral  exposure  to 2,3,4,6-tetrachlorophenol  were
derived based  on NOAELs  of  10 mg/kg/day  In the subchronic  study  by Hattula
et al.  (1981b) and  1n  the  teratology  study  by Schwetz  et  al. (1974).   An
uncertainty factor of 100 (10 for  Interspedes  extrapolation and  10 for the
protection of  sensitive  Individuals)  for  the  subchronic  RfD and of  1000 (an
additional  factor of  10  for  the use  of  a  subchronic NOAEL) for the chronic
RfD were used.   At the LOAEL  of 30 mg/kg/day, there was  delayed ossification
of  the  skull  bones  In  the  offspring of   rats   treated  during   gestation
(Schwetz  et  al.,  1974).   An RQ   of  1000  was  derived  based  on  hlsto-
pathologlcal liver lesions  in  rats  treated  at 50 mg/kg/day  (Hattula et al.,
1981b).     Data   were    insufficient   to   derive   values   for   other
tetrachlorophenols.    Since data  regarding  the carcinogenlclty  of  the tetra-
phenols were not  available,  these  chemicals are placed  1n  EPA  Group D, "not
classified".
                                     XV111

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                              TABLE  OF  CONTENTS
1.  INTRODUCTION	1-1

    1.1.   STRUCTURE AND CAS NUMBER	1-1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	  1-1
    1.3.   PRODUCTION DATA	1-5
    1.4.   USE DATA	1-6
    1.5.   SUMMARY	1-6

2.  ENVIRONMENTAL FATE AND TRANSPORT	2-1

    2.1.   WATER	2-1

           2.1.1.   Photodegradatlon	2-1
           2.1.2.   Hydrolysis	2-2
           2.1.3.   Oxidation 	  2-3
           2.1.4.   Blodegradatlon	2-3
           2.1.5.   Evaporation 	  2-5
           2.1.6.   Sorptlon	2-6
           2.1.7.   B1oconcentrat1on	2-6

    2.2.   AIR. . .'	2-9
    2.3.   SOIL	2-10
    2.4.   SUMMARY	2-11

3.  EXPOSURE	3-1

    3.1.   WATER	3-1
    3.2.   AIR	3-2
    3.3.   FOOD	3-3
    3.4.   SUMMARY	3-4

4.  AQUATIC TOXICITY	4-1

    4.1.   ACUTE TOXICITY	4-1
    4.2.   CHRONIC EFFECTS	4-7
    4.3.   PLANT EFFECTS	4-13
    4.4.   OTHER RELEVANT INFORMATION 	  4-16
    4.5.   SUMMARY	4-21

5.  PHARMACOKINETCS	5-1

    5.1.   ABSORPTION	5-1
    5.2.   DISTRIBUTION	5-3
    5.3.   METABOLISM	5-4
    5.4.   EXCRETION	5-5
    5.5.   SUMMARY	5-7
                                    x1x

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                           TABLE  OF  CONTENTS  (cont.)

                                                                        Page

 6.  EFFECTS	   6-1

     6.1.   SYSTEMIC TOXICITY	   6-1

            6.1.1.   Inhalation Exposures	   6-1
            6.1.2.   Oral  Exposures	   6-3
            6.1.3.   Other Relevant  Information	   6-10

     6.2.   CARCINOGENICITY	   6-11

            6.2.1.   Inhalation	   6-11
            6.2.2.   Oral	   6-15
            6.2.3.   Other Relevant  Information	   6-17

     6.3.   MUTAGENICITY	   6-22
     6.4.   TERATOGENICITY	   6-26
     6.5.   OTHER REPRODUCTIVE  EFFECTS 	   6-31
     6.6.   SUMMARY	   6-35

 7.  EXISTING GUIDELINES AND STANDARDS 	   7-1

     7.1.   HUMAN	   7-1
     7.2.   AQUATIC	   7-1

 8.  RISK ASSESSMENT	   8-1

     8.1.   CARCINOGENICITY	'.	   8-1

            8.1.1.   Inhalation	   8-1
            8.1.2.   Oral	   8-1
            8.1.3.   Other Relevant  Information	   8-2
            8.1.4.   Weight of  Evidence	   8-3
            8.1.5.   Quantitative Risk Estimates  	   8-4

     8.2.   SYSTEMIC TOXICITY	   8-6

            8.2.1.   Inhalation Exposure 	   8-6
            8.2.2.   Oral  Exposure	   8-7

 9.  REPORTABLE QUANTITIES 	   9-1

     9.1.   BASED ON SYSTEMIC TOXICITY 	   9-1
     9.2.   BASED ON CARCINOGENICITY	   9-19

10.  REFERENCES	10-1

APPENDIX A: LITERATURE SEARCHED	A-l
APPENDIX B: CANCER DATA SHEETS  FOR DERIVATION OF  q-j*s	B-l
APPENDIX C: SUMMARY TABLES FOR  CHLORINATED PHENOLS 	  .  C-l
                                      xx

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                               LIST OF  TABLES

No.                               TUIe                                Page

1-1     Symonyms, Empirical Formulas,  Molecular  Weights,  Structure
        and CAS Numbers of the Selected Chlorophenols	1-2

1-2     Selected Physical Properties of Chlorophenols  	   1-4

2-1     BCFs of Chlorophenols In Aquatic Organisms	2-7

4-1     Acute Toxldty of Chlorinated  Phenols to Freshwater
        Fishes	4-2

4-2     Acute Toxldty of Chlorinated  Phenols to Freshwater
        Invertebrates 	   4-8

4-3     Acute Toxldty of Chlorinated  Phenols to Marine Fishes.  .  .  .   4-11

4-4     Acute Toxldty of Chlorinated  Phenols to Marine
        Invertebrates 	   4-12

4-5     Toxldty of Chlorinated Phenols to Freshwater  Plants	4-14

4-6     Toxldty of Chlorinated Phenols to Aquatic  Bacteria
        and Fungi	4-17

4-7     Toxldty of Chlorinated Phenols to Marine Plants	4-19

4-3     Concentrations of Chlorinated  Phenols that  Impair
        the Flavor of Fish	,	4-20

5-1     Permeability Coefficients and  Threshold  Concentrations
        for Damage 1n Human Epidermis  for  Chlorophenols 	   5-2

6-1     Acute Toxldty Data for Chlorophenols	6-12

6-2     Incidence of Neoplasms In F344  Rats and  B6C3F1  Mice
        Treated with 2,4,6-TMchlorophenol (96-97%  pure)  In
        the Diet for 105-107 Weeks	6-18

6-3     Mutagenldty Testing of Chlorophenols	6-23

6-4     Teratogenldty Studies of 2,4-D1chlorophenol,
        2,4,5-TMchlorophenol and 2,3,4,6-Tetrachlorophenol  	   6-32

7-1     Guidelines and Standards for Chlorophenols	7-2

9-1     Oral Toxldty Summary for Chlorophenols	9-2

9-2     Oral Composite Scores for 2-Chlorophenol  Using  the Rat.  .  .  .   9-4

9-3     2-Chlorophenol:  Minimum Effective  Dose (MED) and
        Reportable Quantity (RQ)	9-5
                                    xx1

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                           LIST OF TABLES (cont.)

No.                               Title                                Page

9-4     3-Chlorophenol and 4-Chlorophenol:  Minimum Effective
        Dose (MED) and Reportable Quantity  (RQ)	9-6

9-5     Oral Composite Scores for 2,4-01chlorophenol	9-7

9-6     2,4-D1chlorophenol: Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	9-9

9-7     2,3-, 2,5-, 2,6-, 3,4- and 3,5-D1chlorophenol:  Minimum
        Effective Dose (MED) and Reportable Quantity (RQ) 	  9-10

9-8     Oral Composite Scores for 2,4,5-Trlchlorophenol 	  9-11

9-9     2,4,5-Trlchlorophenol: Minimum Effective Dose  (MED)- and
        Reportable Quantity (RQ)	9-13

9-10    2,3,4-, 2,3,5-, 2,3,6-, 3,4,5-Trlchlorophenol:  Minimum
        Effective Dose (MED) and Reportable Quantity (RQ) 	  9-14

9-11    Oral Composite Scores for 2,3,4,6-Tetrachlorophenol
        Using the Rat	9-15

9-12    2,3,4,6-Tetrachlorophenol: Minimum Effective Dose (MED)
        and Reportable Quantity (RQ)	9-17

9-13    2,3,4,5- and 2,3,5,6-Tetrachlorophenol:  Minimum Effective
        Dose (MED) and Reportable Quantity  (RQ)	9-18

9-14    Derivation of Potency Factor (F) for 2,4,6-Trlchlorophenol.  .  9-20
                                     xxll

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                             LIST  OF  ABBREVIATIONS

AWQC                    Ambient water quality criterion
BCF                     B1oconcentrat1on factor
bw                      Body weight
CAS                     Chemical Abstract Service
CS                      Composite score
CV                      Closing volume
DMBA                    Dimethyl benzanthracene
DMSO                    Dimethyl sulfoxlde
DNA                     DeoxyMbonuclelc add
DWEL                    Drinking water effect level
ECso                    Concentration effective to 50% of recipients
EMU                     EthylnHrosurea
ETC                     Estimated highest concentration that will not
                        Impair the flavor of exposed fish
FEV-)                    Forced expired volume In 1  second
FEVC                    Forced expired vital capacity
159                     Inhibition concentration to 50% of recipients
Koc                     Soil sorptlon coefficient standardized with
                        respect to soil organic matter
Kow                     Octanol/water partition coefficient
LC5Q                    Concentration lethal to 50% of recipients
HATC                    Maximum acceptable threshold concentration
MED                     Minimum effective dose
MEF                     Maximum expiratory flow rate
NADPH                   N1cot1nam1de adenlne dlnucleotlde phosphate
NOAEL                   No-observed-adverse-effect  level
NOEC                    No-observed-effect concentration
                                     XX111

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                         LIST  OF  ABBREVIATIONS  (cont.)





NOEL                    No-observed-effect level



ppm                     Parts  per million



RBC                     Red blood cell



RfD                     Reference dose



RfD$                    Subchronlc reference dose



RPAR                    Rebuttable Presumption Against Registration



RQ                      Reportable quantity



RV(j                     Dose-rating value



RVe                     Effect-rating value



SGPT                    Serum glutamlc pyruvlc transamlnase



TCDD                    Tetrachlorod1benzo-p-d1ox1n



TWA                     Time-weighted average



UV                      Ultraviolet



WBC                     White blood cell



w/v                     Weight per volume
                                     xxlv

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                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    The 18  chlorophenols  selected for  examination  In this  document  are 2-,
3- and 4-chlorophenol;  2,3-,  2,4-, 2,5-,  2,6-,  3,4- and 3,5-d1chlorophenol;
2,3,4-,   2,3,5-,   2,3,6-,   2,4,5-,   2,4,6- and   3,4,5-tMchlorophenol;   and
2,3,4,5-,  2,3,4,6- and  2,3,5,6-tetrachlorophenol.   The  synonyms,  structures,
empirical   formulas,  molecular  weights  and  CAS  Registry  numbers  for  these
chlorophenols are given 1n Table 1-1.
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    At room  temperature, all  the chlorophenols  are  crystalline solids except
2-chlorophenol,  which  Is   a  colorless  liquid.  The monochlorophenols  are
slightly  soluble  In  water,  but  as   the  number  of  chlorine  substitution
Increases   the  higher  substituted  phenols  become less   and  less   soluble  1n
water.    Thus,   the  dl-,   tr1- and    tetra-substltuted   chlorophenols   are
sparingly soluble In water.  These compounds  are, In general,  either  soluble
In ethanol,  ethyl ether or benzene,  although several of these compounds are
soluble 1n  all  three  solvents  (Weast,  1980; Verschueren,  1983).   Selected
physical  properties of  the chlorophenols are given  1n Table 1-2.   Consider-
able  variability  exists for  these  parameters and  the   best possible values
are given  In Table  1-2.   The  water  solubility  of  the  various chlorophenols
1s  Influenced  greatly  by  the  pH of  the  water,  and the addition  of  chloro-
phenols to distilled water affects  the pH.   Because  the chlorinated  phenols
are weak acids they are expected to form salts  with strong bases.   The water
solubilities of  the  sodium and  potassium  salts  that are formed  are higher
than the parent compounds.  The  formation  of  1on1c  salt  becomes Important  at
pH of  water  above the  pK   of  the Individual chlorophenols  (Schellenberg  et
                         a
a!., 1984).
0015d                               1-1                               06/17/87

-------
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0015d
1-4
05/07/87

-------
    The  presence  of   chlorophenols  Imparts  unpleasant  taste  and  odor  In
water.   The  odor  thresholds   for   2-chloro-,  4-chloro-,  2,4-d1chloro- and
2,6-d1chlorophenol  are  0.0002,  0.0005,  0.00065  and  0.0075  mg/8.,  respec-
tively.  The  taste thresholds  for  these  compounds are even  lower  and their
respective   values   are    0.0001,   0.0001,   0.008   and   0.0002   rng/l,
respectively.  2,3-D1chlorophenol has  the  lowest  reported taste threshold of
any chlorophenol, 0.00004 mg/8. (Verschueren, 1983).
1.3.   PRODUCTION DATA
    According  to  the  TSCA  production  data base  (U.S.  EPA, 1977),  one U.S.
company  at  one  location  either produced  or  had  the capability to produce
2,3-d1chloro-,  2,5-d1chloro-,   2,6-d1chloro-,  2,3,6-trlchloro- and  2,3,4,6-
tetrachlorophenol  1n  1977.   4-Chloro-,  2,4,5-trlchloro- and 2,4,6-tMchloro-
phenol  were  produced by  three  companies  1n  the  United  States   In  1977,
although one  company  reported  no production of 4-chlorophenol  1n 1977 (U.S.
EPA,  1977).   3-Chlorophenol  was  produced  by two or  possibly  three  companies
In  1977  In  the United States  at as many  locations.   2,4-Dlchlorophenol  was
produced In  the  United  States  by five companies  at five  locations  In 1977
(U.S. EPA.  1977).
    As  of  January   1986   1n   the   United  States,   Aldrlch   Chemical  Co.,
Milwaukee,   HI,  manufactured  3-chlorophenol,  2,6-,  3,4- and  3,5-dlchloro-
phenol;  Specialty  Organlcs,  Inc.,  Irwlndale,  CA,  manufactured  3-chloro-
phenol,  2,3-,  2,6-  and   3,5-d1chlorophenol;  Dow  Chemical,   Midland,  MI,
manufactured  2,4-d1chlorophenol;  and   Farley  Northwest  Industries,   Inc.,
Beaumont, TX, produced 2,6-d1chlorophenol  (SRI,  1986).
    In  addition   to  the  companies   listed  above,  USITC  (1986)  also  lists
Vertac  Chemical   Corp.,   Jacksonville,  AR,  as  a  current  manufacturer  of
0015d                               1-5                              06/17/87

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2,4-d1ch1orophenol.    Chlorophenols   not   Included   among   those   listed   are
presumably not manufactured  1n  the  United States In  significant  quantities.
The  current   U.S.   production   volumes   for  the  Chlorophenols  were   not
available.   The   estimated  annual   production   volumes   for   2-chloro-,
4-chloro- and  2,4-d1chlorophenol  In  Europe  were  5,  5  and  20 kHotons,
respectively (KMJgsheld  and Vandergen,  1986).  The  estimated  annual world
production  of  Chlorophenols  was  150  kllotons   (Hutzlnger  et  a!.,  1985).
Chlorophenols  are commercially  produced  either  by  direct  chloMnatlon  of
phenol   or by  the alkaline  hydrolysis  of   polychlorobenzenes  in methanol,
ethylene  glycol   or   a  mixture  of  similar  solvents.   Higher   chlorinated
phenols are  also  manufactured by chloMnatlon of lower Chlorophenols  (Kozak
et   a!.,   1979).    Trace   amounts    of   highly    toxic    polychlorlnated
d1benzo-p-d1ox1ns   and  dlbenzofurans  have  been  found  as  contaminants  In
commercial Chlorophenols (Hutzlnger  et  al.,  1985).
1.4.   USE DATA
    The  monochlorophenols   are   used  as  Intermediates In  the  synthesis  of
higher   Chlorophenols  and  phenolic  resins;   In  the  synthesis  of  dyes   and
drugs;  and as  selective solvents 1n refining  of  mineral oils.   2,4-D1chloro-
and 2,4,5-trlchlorophenol  are principally used as Intermediates  1n the manu-
facture  of   pesticides  and  herbicides.   2,4.5-Trlchloro-,  2,4,6-tMchloro-
and 2,3,4,6-tetrachlorophenol and their salts are used as germicides  for the
preservation of   wood,  glue, latex,  leather  and  textiles  (KMjgsheld  and
Vandergen, 1986;  Kozak et  al., 1979).
1.5.   SUMMARY
    All the  Chlorophenols discussed with  the  exception of  2-chlorophenol are
crystalline  solids at room  temperature.  The monochlorophenols are  slightly
soluble  1n water, but as  the number of chlorine  substitution  Increases, the
higher   substituted phenols  become  less  and  less soluble  In water.   Thus,

0015d                               1-6                              06/17/87

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the  d1-,  tr1- and tetra-substltuted  chlorophenols  are sparingly  soluble  In
water.  These  compounds  are,  1n general, soluble In  ethanol,  ethyl  ether  or
benzene  (Verschueren,  1983;  Weast,  1980).   The  presence of  chlorophenols
Imparts  unpleasant  taste  and  odor   In  water.   The  taste  threshold  for
2,3-d1chlorophenol  Is   0.00004  mg/i   (Verschueren,   1983).  Currently,  five
companies  1n  as  many  locations  manufacture   chlorophenols  In  the  United
States.   The current  annual  U.S.  production-  volumes for  the  chlorophenols
are  not available.   The  estimated annual world production  volume  of chloro-
phenols 1s 150 kllotons  (Hutzlnger  et  al.,  1985).   Chlorophenols are commer-
cially produced  either by direct  chlorlnatlon  of  phenol  or by  the  alkaline
hydrolysis  of  polychlorobenzenes  (Kozak et  al.,  1979).   Trace  amounts  of
highly toxic polychloMnated  d1benzo-p-d1ox1ns  and  dlbenzofurans have  been
found  as  contaminants  1n  some  commercial  chlorophenols  (Hutzlnger et  al.,
1985).  The  monochlorophenols  are  primarily used In  the  synthesis  of  higher
chlorinated  phenols.   The  higher chlorinated phenols are  used  as  germicides
and  as  Intermediates   1n   the  manufacture  of  pesticides  (KMjgsheld  and
Vandergen, 1986;  Kozak  et al., 1979).
0015d                               1-7                              05/07/87

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                     2.  ENVIRONMENTAL FATE AND TRANSPORT
2.1.   WATER
    An   Important   factor   that   determines   the   environmental   fate   of
chlorophenols  1n water  and soil  1s  the degree of  1on1zat1on  as  dictated by
the  pH   of   the   medium.    At  an   environmental   pH   range   of  6-9,   the
monochlorophenols  with  pka  values  of  8.5-9.2  will exist  primarily  1n  the
undlssodated   form.     Therefore,    acidification   of   surface   by   add
precipitation  1s   expected  to  have  little  effect  on  their   fate;  however,
higher chlorinated phenols  with pka  values as  low  as  5.4 may  transform from
dissociated  to  undlssodated  forms  as  the  pH  of  the surface  water  1s
decreased  because  of  add  precipitation.   This may alter  the environmental
fate and transport  of the chlorophenols.
2.1.1.   Photodegradatlon.  The light absorption capability  of  the  chloro-
phenols will  depend  on the  state  of  1on1zat1on of  the  specific  compound In
water  (see Table   1-2).   The  dissociated forms  will absorb light  at  higher
wavelengths.   Therefore,  the absorption of  light  by the higher  chlorinated
phenols  Is expected  to  Increase  as   the  pH  of water  1s Increased  (Aly  and
Faust,  1964; .  Boule  et  al.,  1984a).    Photolysis  of the molecular form  of
2-chlorophenol  produces  pyrocatechol  as  the primary  product.   The  anlonlc
form,  on   the  other  hand,  produces cyclopentadlenolc  add, which  dlmerlzes
during  Isolation.   Photolysis  of  3-chlorophenol  both  1n the  molecular  and
anlonlc  form  leads to  the  formation  of resordnol.   The  main  Irradiation
products of 4-chlorophenol  1n  both  the 1on1c and molecular  state are  hydro-
qulnone, benzoqulnone, trlhydroxybenzenes and  d1hydroxyb1phenyls  (KMjgsheld
and Vandergen, 1986;  Tlssot et  al., 1985).   The photolysis  of  3,5-, 3,4- and
2,4-d1chlorophenols was  reported  by  Boule  et al.  (1984b).    With  3,5- and
3,4-d1chlorophenols,  hydroxylatlon  occurred  at  the meta position.   In  the
case   of   2,4-d1chlorophenol,   chlorocyclopentadlene  carboxyllc   was   also

0016d                               2-1                               06/17/87

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formed.  The photolysis occurred preferentially at  the meta  position  and  was
easier with  the anlonlc  than with  the molecular  form.   The photolysis  of
2,4,6-tMchlorophenol  formed  polyhydroxylated  products  and  qulnones  (Tlssot
et  al.,  1985).  Irradiation  of  2,3,4,5-, 2,3,4,6- and  2,3,5,6-tetrachloro-
phenol with  light  of wavelength  >287 nm produced  the dechloMnated  products
and several  hydroxylated and  blphenyl-substltuted  products  (Choudhry  et  al.,
1985).   In  acetonltrlie/water  solution,  >69%  of  the  parent compound  dis-
appeared  1n   24  hours  (Choudhry  et al.,  1985).  The  photolytlc  fate  of
chlorophenols  1n  natural  waters under  field  conditions  Is  uncertain.   From
the experimental  measurement  of quantum  yield  1n aqueous  solution,  Lemalre
et al.  (1985)  estimated  that  the photolytlc half-life of  2,4-d1chlorophenol
1n  the  top  few mm  of  natural water  1n midsummer,  midday sunlight at  40-50
degrees  North  Is  ~3  minutes.    The photolytlc   half-lives  for  4-chloro-,
2,4-d1chloro- and  2,4,5-trlchlorophenols  at  the  top  surface  of  distilled
water under  midday sunlight  Irradiation were  estimated  to be 2.6  days,  0.8
and 0.5  hours,  respectively.   The  half-lives  were longer during winter  artd
shorter  1n   estuary  water.   The more  rapid  photodegradatlon  In  estuarlne
water may have been  due to  photosensltlzatlon  by  humlc  substances  present 1n
the water (Hwang et  al., 1986).  From an  outdoor  pond  experiment,  Suglura et
al. (1984) estimated the photolytlc  half-life  for  2,4,6-trlchlorophenol  at a
depth of  10  cm to be 4 days.   It can be  concluded  from  the above  discussion
that  photolysis  of chlorophenols will  be  Important 1n  clear shallow  bodies
of  water.   As   the  depth  and   turbidity  of  water Increase,  however,  the
Importance of photolysis  will  decrease because of light  attenuation.
2.1.2.   Hydrolysis.   Although  no  experimental  data  were  available,  these
compounds are  not likely  to  hydrolyze  significantly  because aryl  chlorides
0016d                               2-2                              06/17/87

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have  a  low  tendency for  dech 1 or 1 nation and  the presence  of the  hydroxyl
group further  hinders nucleophlllc  substitution  (KMjgsheld  and  Vandergen,
1986).
2.1.3.   Oxidation.   Chlorophenols   are  likely  to  be   oxidized   by   free
radicals  present   1n  most  natural  waters with  the  formation of  qulnones.
This  reaction  may  be further  accelerated  by  silica, clay and  various  metal
Ions  present  1n water (Krljgsheld  and  Vandergen, 1986);  however,  pertinent
data  regarding the  occurrence of  such  reactions  under  environmental  con-
ditions   could  not  be  located   1n  the  available,  literature  as  cited  In
Appendix A.
2.1.4.   B1odegradat1on.    The  blodegradatlon  of  Chlorophenols  has   been
studied  with   pure  cultures,   mixed  microorganisms  and  natural waters.  The
bacteria  NCIB  8250  (Beverldge and Tall,  1969)  and  KC3  (Chu and  Klrsch,
1973),  Candida alblcans  and  TMchophyton gypseum  and  Trlchophyton  qypseum
var.  Kaufman-Wolf  (Polster  et a!.,   1986),  a  gram negative  nonmotlle  coccus
(Banerjee  et   al.,   1984),    Pseudomonas  sp.,   and  Alcallgenes   eotrophus
(Knackmuss and  Hellwlg,  1978) are  a  few microorganisms known  to  blodegrade
these Chlorophenols.   Mixed  microorganisms  obtained  from  activated  sludge
(Beltrame  et  al.,  1982;  Patterson  and   Kodukala, 1981;  PHter, 1976),  from
aerated   lagoons  (Patterson   and  Kodukala,  1981),   from  petroleum  refinery
lagoons  (Tabak  et  al.,  1964),  from settled  domestic  wastewaters (Tabak  et
al.,  1981)  and from  catalytic plant waste  lagoons  (Chambers  et al.,  1963)
have  been  shown to  degrade  mono-,  d1-  and  trlchlorophenols.   Thorn and  Agg
(1975)  also   reported   that  o-,  m-,   p- and  2,4-d1chlorophenol  should  be
biodegradable  by biological  sewage  treatment, provided  suitable  acclimation
can be  achieved.   Based  on  a blodegradatlon  study  under the  Japanese  MITI
test  conditions  (Sasaki,  1978),  which   consist  of  a  5-day   Incubation  with
activated   sludge,  Kawasaki  (1980)  concluded  that the  monochlorophenols  and

0016d                               2-3                               06/17/87

-------
2,4,5-tMchlorophenol  would  be  resistant to  degradation  In natural  waters.
It  Is  concluded  from the  studies  described that significant  blodegradatlon
of chlorophenols requires  adaptation  of  microorganisms to phenol or  chloro-
phenols.    In  addition,  the  degradation  rate  will  depend  on  pH,  substrate
concentration, oxygen  availability,   nature  and  concentration of  nutrient,
and the water  temperature.   At high  concentrations,  failure to  degrade  may
be due to  tox1c1ty  to  microorganisms  (Section  4.3.).
    The blodegradabUHy  of  chlorophenols  under  anaerobic  conditions  was
studied by  several  authors.   Although   a  few  Investigators  (Johnson  and
Young,  1983;  Horowitz  et   al.,  1982)  failed  to  observe  anaerobic   bio-
degradation of chlorophenols and Inhibition of the anaerobic process  by some
chlorophenols, others  (Sahm et al., 1986; Boyd and Shelton,  1984; Salklnoja-
Salonen et al., 1984) found  that the  three  monochlorophenols,  2,3-d1chloro-,
2,4-d1chloro-,  3,4-d1chloro-,  3,5-d1chloro-,  2,4,6-trlchloro- and  2,3,4,6-
tetrachlorophenol   were  susceptible  to  anaerobic  blodegradatlon  by micro-
organisms   from lake sediments  and  sewage sludge.  Although  3,4-  and  3,5-d1-
chlorophenols  were more  resistant,   specific  cross-acclimation  with  mono-
chlorophenols degraded these compounds (Boyd and  Shelton,  1984).
    The  blodegradatlon  of  chlorophenols  with  natural  waters  was   also
reported by several authors.  WHh Skldaway River water In  Savannah,  6A,  the
blodegradatlon  half-lives   of  2-chlorophenol  and  2,4,5-tMchlorophenol  at
21°C were  20 and 690 days,  respectively.  At  9°C,  the  half-life  of  2-chloro-
phenol Increased to  490 days.  The  half-lives  for  both  compounds  decreased
1n the presence of river sediments.   For  example,  the  half-life  of  2-chloro-
phenol at  22°C  was 3 days  and  that  of 2,4,5-trlchlorophenol at  21°C was  23
days  (Lee  and  Ryan,  1979).   WHh  the mean of  the experimental values of  the
blodegradatlon   rate    constants    1n   five    surface   waters    (T.lxlO"11
l/organlsm-hour)   given  by   Paris   et  al.   (1983)   and  a   value  of  108
0016d                               2-4                              06/17/87

-------
organlsms/i  as   the   concentration  of  microorganisms,  the  half-life  of
4-chlorophenol   In   natural  water   1s  estimated   to   be  4   days.    The
blodegradatlon  half-life  of  2,4,6-trlchlorophenol  with  suspended  sediment
was   reported   to   be  7   days    (Blades-Flllmore   et   al.,   1982).    The
blodegradatlon  half-lives  of 2-chloro-,  2,4-dlchloro-,  2,4,5-trlchloro- and
2,3,4,5-tetrachlorophenols  In  natural  waters  can  be   estimated   from  the
experimentally  determined  rate  constant  values  given  by  Banerjee et  al.
(1984) and  range  from 14 hours to  17  days.   The half-lives Increased as the
number  of chlorine  substitutions   Increased.   In  the summer,  the  half-life
for microblal  transformation  of  4-chlorophenol  1n an  estuarlne  water  was 28
hours  (Hwang et  al.,  1986).  It 1s  concluded  from the above discussion that
blodegradatlon  of  chlorophenols   1n  natural  waters  will  be  an  Important
process.
2.1.5.   Evaporation.   The evaporation  half-lives of 2-  and  4-chlorophenol
from a water  depth  of 0.38 cm 1n  stirred solution was experimentally deter-
mined  to  be -1.5 and 13 hours, respectively  (Chlou et al.,   1980).   Since
the  evaporation  rate  1s   Inversely  proportional  to the  water  depth,  an
Increase  of  water depth  from 0.38  cm  to 1  m will  Increase the evaporation
half-life  of  2-chlorophenol  to  -15 days  (Krljgsheld and  Vandergen,  1986).
Therefore,  1n  most  natural  waters  evaporation  may  not  be  Important  unless
the  body  of  water   Is  extremely  shallow.    The  evaporation  half-life  of
2,4,6-trlchlorophenol from  a  pond at a depth of 10.2 cm, a water temperature
of 20.7°C  and  a  wind speed of 1.7  m/sec  was estimated to  be 4  days  (Suglura
et  al.,   1984).   Klncannon  et  al.  (1983)  and Leuenberger  et  al.  (1985a)
showed  that  evaporation  was Insignificant  for  2,4-dlchloro-,  2,4,6-tr1-
chloro- and 2,3,4,6-tetrachlorophenol  during  treatment of  waste-waters.  The
evaporation half-life  should also  be  strongly  Influenced  by  the pH of  the
water.

0016d                               2-5                              06/17/87

-------
2.1.6.   Sorptlon.   The  sorptlon  of  chlorophenols  depends  on  the  organic
matter in  sediment  and  suspended solids and the pH of  the  water.   If  the pH
of the water  is such that  the  compound remains undlssoclated,  the sorption
can be related  to the K   value of  the compound and hence with  the  organic
carbon content   of   the  sorbent.  For  tetrachlorophenols   that  are  usually
present  predominantly  1n the  Ionized  form  at  pH  >7,  the  sorption  by  the
phenolate  form  cannot  be neglected.  The  sorption  of  the  phenolate  species
may depend on the partitioning process  between  the  aqueous  and  organic  phase
present  in a  natural  sorbent  and the sorptlon may  be dependent  on  the  1on1c
strength   of  the  aqueous  phase.   The  prediction about  the  distribution  of
such  sorblng  species  based  on  simple  partitioning of  the  nondlssociated
species  will  be  erroneous   (Schellenberg  et  al.,   1984).    Isaacson  (1985)
concluded  that  hydrogen-bonding  was  the main mechanism of  sorptlon and  that
increasing the  degree of  cnlorinatlon  of  phenol  would Increase  adsorption
(Krijgsheld and  Vandergen,  1986;   Isaacson  and  Fink,   1984).   The  average
values   for   the   KQC   of   2,3-d1-,   2,4-di-,   2,4,6-trl-,   2,4.5-tM-,
3,4,5-tri-, 2,3,4,6-tetra- and  2,3,4,5-tetrachlorophenols  in sediments  from
three  lakes  and  rivers  were  426,   545,  1070,  2330,  3680,  6640 and  13,200,
respectively  (Schellenberg  et al.,  1984).   Thus,   it can  be concluded  that
sorptlon  will  be an  Important process in the removal  of these compounds  from
most aquatic media (Leuenberger  et  al.,  1985a).
2.1.7.   B1oconcentrat1on.   The  experimentally  determined  BCFs for  several
aquatic  species  are shown in Table  2-1.   The BCFs  given  by Hattula  et  al.
(1981a)  and  Kobayashl  et al.  (1979) were  obtained by administering  lethal
concentrations  of  the compounds and  by measuring  the  tissue concentrations
1n dead  fish.   Based on  the equation,  log  BCF  = 0.76  log  KQW  -  0.23  (Velth
et al.,  1980),  the  BCF  is  expected  to  increase as the K    values  increase.


0016d                               2-6                              05/08/87

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As can be  seen  from  Table  1-2,  the BCF should also Increase as the number of
chlorine  substitutions  Increases.  The  experimental  values  given  In  Table
2-1, however, differ  considerably from the estimated  values  and  do not show
the Increasing  trend  as predicted.  The  difference between  the estimated and
the  experimental   values  may  be  due  to  several  factors  Including use  of
nonstatlonary state  conditions,  high  concentrations  of  test  compounds  and
the determination  of BCF  values  1n whole  tissue  rather  than  In  I1p1d.   In
addition,  at  physiological   pH,   higher   chlorinated  phenols  should  exist
significantly  1n   the  dissociated  form  with  a  lower K   ,  which  makes  the
experimental BCFs lower than predicted by the equation.
2.2.   AIR
    The  fate  and  transport of  chlorophenols  In  the atmosphere has not been
studied  comprehensively.   When  2,4,6-trlchlorophenol was sorbed  onto silica
gel and  Irradiated with mercury  lamps  at wavelengths >290 nm, 65.8% of the
compound photom1neral1zed  Into  carbon dioxide In  17 hours (Freltag  et al.,
1985;  Korte and Klein,  1982).   Although  the available  data  cannot be used In
estimating  the  half-life  of  the  compound  under  natural  sunlight  conditions,
1t can be  concluded  from these Investigations that  the  chlorophenols may be
susceptible  to  significant photolysis  In  the atmosphere.  Kanno  and Nojlma
(1979) also showed that the monochlorophenols  can  react  with  nitrogen oxides
1n air  to  form chloronltrophenols.   The  reaction  of  chlorophenols  with  OH
radicals 1n  the atmosphere may also  be Important.  The  half-life of phenol
reaction with  OH  radicals at  an  atmospheric  concentration of 10* radicals
cm3 Is  estimated  to  be -7  hours  based on  a  rate constant for  the reaction
of   28.3xlO"12    cmVmolecule-sec    (Atkinson,    1985).     Increasing    the
chlorine substitution 1s expected  to  Increase  the  half-life of the reaction.
Therefore,  this   reaction   may  be   significant   for  mono- and  dlchloro-
substHuted phenols.

0016d                                2-9                              06/17/87

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    The detection  of  d1-,  tr1- and tetrachlorophenols 1n  rainwater  and  snow
obtained  from  Portland,  OR,  and   Finland   (Leuenberger   et   al.,  1985b;
Paas1v1rta et  al., 1985a) Indicates  that these  compounds  are  removed  from
the atmosphere by  wet  deposition.   From their study  of  chlorophenol concen-
trations  1n   snow  collected   In   southern,  central  and  northern  Finland,
PaasWIrta et  al.  (1985a) concluded  that  these compounds,  which  originated
from anthropogenic  sources,  precipitate before  being transported by  air  to
northern parts of Finland.
2.3.   SOIL
    The fate  and  transport  of chlorophenols  In soil  1s  less  well  studied
than 1n water.   An examination of  the fate of these  compounds  In  water  (see
Section 2.1.) reveals  that photodegradatlon and  blotransformatlon  are Hkely
to  be   Important  1n   determining  the  fate   of   these  compounds  In  soils.
Although photodegradatlon  may  be  significant  on the  surface  of  soil,  this
process Is unlikely  to have  much significance beyond  the  surface  because  of
reduced light  Intensity,  which  1s  due to attenuation  and  scattering.   The
blodegradatlon  of   chlorophenols   with   pure   cultures   of  microorganisms
Isolated from  soil was reported by  Bollag et al.  (1968)  and Haider  et  al.
(1974);  Arthrobacter   sp.   and   both  Pseudomonas   sp.  and   Nocardla   sp.
precultlvated  on   benzene  degraded   chlorophenols.   The   Incubation   of
2-chloro-, 4-chloro-,  dlchloro- and trlchlorophenols  1n  a  natural  soil for 1
week degraded 13,  22.2, 31.4 and 35%  of  the  respective original  compounds  to
complete  mineralization (Haider  et  al.,  1974).   On  the  other  hand,  the
complete disappearance  of  the  parent  chlorophenols  In two  natural  soils  took
the following  time periods:  2-chlorophenol,  14-47  days;  3-chlorophenol,  >47
to  >72  days;   4-chlorophenol,  3-9   days;   2,4-d1chlorophenol,  5-9  days;
2,5-d1chlorophenol,  >72   days;  2,4,5-trlchlorophenol,   >47  to  >72  days;

0016d                               2-10                             06/17/87

-------
2,4,6-tMchlorophenol ,    5-13  days;   2,3,4,6-tetrachlorophenol ,   >72   days
(Alexander  and   Aleem,   1961).    It  can  be  concluded   that   while   some
chlorophenols are easily biodegradable 1n soils, others are more resistant.
    Schwarzenbach and  Westall  (1985)  studied  the dependence  of  the K    on
the pH  of  soils.   At neutral soil  pH,  higher  chlorinated  phenols with  lower
pka values will  exist  primarily  1n  the  1on1c  state  and  will  not  be signifi-
cantly  sorbed onto  soils, although  sorptlon  to soil, particularly clay  soil,
may be  due to  1on1c  attraction.   The sorptlon  of  chlorophenols on soils  will
also  Increase with  an  Increase  of  organic carbon  content  of  soil.   Thus,  In
a  sandy aquifer,  Sutton and Barker (1985)  observed  very  little  sorptlon  of
chlorophenol.  Boyd  (1982)  measured  the following  K    values In  a  natural
soil  at  a  neutral   pH:   2-chloro-,   51;   3-chloro-,   66;  4-chloro-,   70;
2,4-d1chloro-,  126;  2,4,5-trlchloro-,  363.   In another  natural  soil of  pH
10,   the   following   K     values   were   reported:   2,4-d1chloro-,    0;
2,6-dlchloro-,  0;  2,4,6-tMchloro-, 0;  2,3,4,6-tetrachloro-,  75  (Johnson  et
al.,  1985).  It  1s  concluded that  chlorophenols are  susceptible  to leaching
from  soils to  groundwater  particularly from sandy soils and  soils  with  a  pH
2.4.   SUMMARY
    The  two  Important processes  that  may have  a  significant effect  on  the
fate of chlorophenols In water are  photolysis  and  blodegradatlon.  The photo-
lytlc  half-lives  of  4-chloro-,  2,4-dlchloro- and  2,4,5-tMchlorophenols  at
the  top  surface of  distilled  water under midday  sunlight  Irradiation  were
estimated  to  be 2.6  days,  0.8  and 0.5  hours,  respectively (Hwang  et  al.,
1986).   From an outdoor pond experiment,  Suglura et  al.  (1984)  estimated the
photolytlc half-life  of  2,4,6-trlchlorophenol at  a  depth of  10  cm  to  be  4
days.  The  photolysis of chlorophenols  will  be  Important  In clear  shallow
bodies  of  water,  but as  the  depth  and  turbidity  of  water Increase,  Us

0016d                               2-11                              06/17/87

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importance  will   decrease   with   light  attenuation.   The   blodegradatlon
half-lives of  chlorophenols  In  natural waters  range  from   >1-17 days.   The
half-life values  Increase  as  the  number of chlorine  substitutions  increases
and the  temperature of  the  water  decreases.  The half-lives of  the  compounds
also decrease  in  sediments  of  surface waters  with the presence  of  a  greater
number of microorganisms  (Lee  and Ryan,  1979;  Banerjee  et a!.,  1984;  Hwang
et  a!.,  1986).  Hydrolysis and  evaporation  are not  likely to  be  Important
processes  for  chlorophenols   1n  water   (KMjgsheld  and  Vandergen,   1986).
Oxidation may  be  a  significant  process  1n  water but  experimental data  on
such reactions could  not  be located  In the available literature  as cited in
Appendix A.    The  removal   of  chlorophenols  from  water  by  sorptlon  onto
suspended sol Ids and  sediments may be  Important and will depend  on  the pH of
water and  the organic  content  of  the  sorbents.   Sorption will  Increase at
lower pH and  higher organic content  of the sorbents; 1t will  also  be  higher
for higher chlorinated  than lower  chlorinated phenols (Schellenberg et  al.,
1984;   Isaacson    and  F1nk,   1984;   KMjgsheld   and   Vandergen,   1986).
Experimental    data   Indicate   that   mono- and   dlchlorophenols  will   not
bloconcentrate but that  the  higher  chlorinated  phenols  may  bloconcentrate
significantly  In  aquatic  organisms  (Velth  et al., 1980;  Kobayashl et  al.,
1979; Hattula et al.,  1981a; Vlrtanen and  Hattula,  1982).
    In  the  atmosphere,  the chlorophenols  are likely  to undergo  significant
photolysis (Korte  and Klein, 1982).   Based  on the  rate constant  of  phenol
reaction with  OH  radicals  In  the  atmosphere  (Atkinson,  1985),  It 1s  con-
cluded  that  such  reactions may  be   significant  for  the   lower  chlorinated
phenols.  The  detection of  these  compounds   1n rainwater  and snow  Indicate
that they will be  removed  from  the atmosphere by  wet  deposition  (Leuenberger
et al., 1985b; Paaslvirta et al.,  1985a).


0016d                               2-12                             06/17/87

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    Based  on  data regarding  chlorophenols  in  water,  photolysis,  hydrolysis



and evaporation  will  not be significant processes  In  soils.   The two Impor-



tant  processes   1n  soil  are  sorptlon  and  blodegradatlon.   While  2-chloro-,



4-chloro-,  2,4-d1chloro- and  2,4,6-trIchlorophenols were  found  to  be easily



biodegradable In a natural soil,  3-chloro-,  2,5-d1chloro-, 2,4,5-trlchloro-



and 2,3,4,6-tetrachlorophenols were  persistent  1n  soil  (Alexander  and Aleem,



1961).  The  sorptlon  of  chlorophenols  In soils  Increases  with a decrease 1n



soil  pH and  Increase  1n  chlorine substitution.   Chlorophenols  are especially



susceptible  to  leaching  from sandy  soils  and  soils with  pH  >10 (Schwarzen-



bach  and Westall,  1985;  Sutton and Barker,  1985; Boyd,  1982; Johnson et al.,



1985).
0016d                               2-13                             05/08/87

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                                 3.  EXPOSURE
3.1.   WATER
    Sources  of  chlorophenols   in  the  environment  are  effluents  from  the
manufacturing  industry,  effluents  from wastewater  treatment,  degradation of
the pesticide  2,4-D  in  the environment, effluents  from  kraft  pulp  mills  and
sawmills,  waste  disposal   sites  and   Incineration   of  Industrial   wastes
(Krijgsheld and Vandergen, 1986; James et al., 1984).
    In   kraft   bleaching   process   wastewaters,   up   to    7.5   yg/i   of
2,3,4,6-tetra-,   8.3  wg/i   of   2,4,5-tri-,   0.75   vg/i  of   2,4,6-tr1-,
0.093   pg/i   of   2,6-dl- and    0.27    ug/8.   of   2,4-d1chlorophenol   were
detected  (Xie et al.,  1986; Krlngstad  and  Llndstrom,  1984;  Paaslvlrta  et
al.,  1985b).   Chlorophenols have  also   been  reported   In  effluents  from
municipal  and  Industrial  treated wastewaters  (Ellis  et al.,  1982; Young et
al.,  1983;  Bulsson   et  al.,  1984; Callahan  et al.,  1979).  In  a  Nationwide
Urban Runoff  Program,  Cole  et  al.  (1984)  detected 2-chlorophenol  In  1% of
the  samples  at   a   concentration  of  2 yg/l;  2,4-d1- and  2,4,6-trlchloro-
phenol were not detected 1n any  of the samples.
    Chlorophenols  were  detected  In  groundwater  and  surface   water  near
contaminated sites (Valo  et  al.,  1984;  Mauser  and Bromberg,  1982;  Bedlent et
al.,  1984).    The   concentrations   of  2,4-d1-,  2,4,6-tr1-,   2,4,5-tr1-,
2,3,4,6-tetra- and   2,3,4,5-tetrachlorophenols  In  ditch  waters   within  a
sawmill   were  390, 957,  47,  14,300  and  6  vg/1,  respectively  (Valo  et  al.,
1984).   These  authors  also  detected  chlorophenols  In  groundwaters and  lake
waters collected around the  saw  mills.   In  the groundwater near  an  abandoned
creosote  facility In Conroe, TX,  Bedlent  et  al.  (1984)  detected  concentra-
tions as  high  as  80  and  135   wg/i of  2,4-d1chloro- and  2,4,6-trlchloro-
phenol,   respectively.    2,4-01chorophenol   was  reported  1n  17.2%  of  the
sampled  groundwater   supplies  In  the  United States  (Dyksen and Hess,  1982).

0017d                               3-1                               05/08/87

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Chlorophenols  were  also   found   1n  several  surface  waters  and  In  their
sediments  (Salklnoja-Salonen  et  al.,  1984;  Hegman  and  Vandenbroek,  1983;
Watanabe  et  al.,  1985;  X1e,  1983).   Concentrations  of  2,4-d1-,  2,6-dl-,
2,4,6-tr1- and  2,3,4,6-tetrachlorophenol  as  high  as  10,  1.2,  1.2  and  0.1
vg/l,  respectively,  were  found  In  a  lake  water   that  received bleaching
effluents from  kraft  pulping  (Salklnoja-Salonen et  al.,  1984).   X1e et  al.
(1986)  detected  chlorophenols  In  seawater  receiving  effluents  from a  pulp
mill.
    According  to   Callahan  et   al.   (1979),  the  frequency  of  detection  of
chlorophenols  In  U.S.  tap water  was 0%. Morgade et al.  (1980)  detected  no
chlorophenols  other  than  pentachlorophenol  1n  several drinking  waters  from
Dade  County,  FL;  however,  Kopfler  et   al.  (1977)  qualitatively  detected
2,4-d1-,  2,4,5-tr1-  and  2,4,6-trlchlorophenol  In  U.S.  drinking waters.   A
survey  of six  unspecified  cities  In Canada showed concentrations  as  high  as
39  ng/j,  of   2-chloro-,  34  ng/l  of  4-chloro-,  17  ng/l  of  2,4-dlchloro-
and  60   ng/i   of  2,4,6-trlchlorophenol  1ri  the   treated   drinking   waters
(SHhole  et  al.,   1986).   In  British drinking  waters,  2,4,6-trlchlorophenol
has  been  detected (Crathorne  et  al., 1984).   Both  2-chloro- and 4-chloro-
phenol  were  reported  In  the   tap  water  In  the  Netherlands  at a  maximum
concentration  of   2.2  vg/l.   2,4-01chlorophenol  was  detected  at a  concen-
tration  range   of  0.003-0.006   yg/l  1n  German   drinking  waters  (KMjgsheld
and Vandergen, 1986).
3.2.   AIR
    None  of  the chlorophenols  have  been  detected  In ambient air  other  than
air  from contaminated  sites;  however,  the  detection  of 2,4-d1-,  2,6-d1-,
2,4,5-trl-,  2,4,6-tr1- and  2,3,4,6-tetrachlorophenols 1n rainwater and  snow
In  the  United  States and  elsewhere  (Leuenberger  et  al.,  1985a;  Paas1v1rta et


0017d                               3-2                              06/18/87

-------
al.,  1985a)  Indicates that  these  compounds  are also  present  in the ambient
air.   Mauser  and  Bromberg  (1982)  qualitatively   detected  2,4,5-trlchloro-
phenol  1n  air  samples 1n Love Canal,  NY.   Incineration of Industrial wastes
at   four   different   test   facilities  produced   2-chloro-,   4-chloro-,
2,6-d1chloro-,  2,4,5-trlchloro- and  2,4,6-trlchlorophenol  In  the  exhaust
gases  from  one facility;  produced  2-chloro-,  4-chloro- and  2,6-d1chloro-
phenol  from  the second facility; and produced  no  chlorophenols  from the two
other facilities (James et al., 1984).
    Kaupplnen  and  Undroos  (1985)  studied occupational  exposure  to chloro-
phenols  1n  10  Finnish sawmills where a  chlorophenolate formulation  was used
as  a  wood  preservative.   The machine  stacking area,  on the average,  con-
tained  the maximum  atmospheric  concentration  of   chlorophenols.   The  mean
concentration  of the sum of tr1-, tetra-  and pentachlorophenol  1n  this area
was  75   yg/m3.   The  mean  concentration  of  2,4,6-trlchlorophenol   alone  In
this  area  was  58  yg/m3.  Thus,  the  concentrations of chlorophenols  In the
air  were  usually  well  below  the  Finnish  occupational  limit  value  of
500 yg/m3.
                                                                          *
3.3.   FOOD
    Chlorophenols have been detected  In  urine  of  humans;  this  Is  possibly
due to  the  metabolism of various pesticides by  the body  (Kutz  et al.,  1978;
Fat1ad1, 1984)  or  to  direct exposure to  these  compounds  through Inhalation
(Kaupplnen and  Undroos,  1985) or  to  the 1ngest1on  of water  and foods.   Data
on  the   exposure  to  these  compounds  through   foods   are  limited.   Fishes
collected  from coastal  Finnish  water  and from lake  waters receiving  pulp
mill  effluents  were  found    to   contain   chlorophenols.    The   average
concentrations  of   2,3,4,6-tetrachloro- and  2,4,6-trlchlorophenol   In  the
muscle  of  pike,  Esox   ludus.  were   34  and   13.6  yg/kg,   respectively.
Similarly,   the muscles  of  salmon,  Salmo salar,   and  trout.  Salmo  trutta,
                                           •
0017d                               3-3                              06/18/87

-------
collected from these waters contained maximum average concentrations of  5.9,
2.5    and    29.3   ug/kg    of    2,4,6-tMchloro-,     2,4,5-trlchloro- and
2,3,4,6-tetrachlorophenol,   respec-   tlvely   (Paas1v1rta   et   al.,   1985b;
VuoMnen  et  al.,  1985).   Ho et  al.  (1983)  Identified 4-chlorophenol  In  the
volatile flavor constituents of  fried  bacon.
3.4.   SUMMARY
    Although  chlorophenols  have been  detected  1n  municipal  and  Industrial
effluents {Xle  et al., 1986; KMngstad  and Llndstrom,  1984;  Ellis et  al.,
1982; Callahan et al., 1979), In urban runoff water  (Cole  et al.,  1984),  and
1n surface and groundwater  near  effluent  discharge and waste disposal  sites
(Valo et  al., 1984; Bedlent  et al.,  1984;  Salklnoja-Salonen  et al.,  1984;
Watanabe et al.,  1985; Xle  et al., 1986), these compounds  have  been detected
Infrequently  In  drinking waters.   According to Callahan  et al. (1979),  the
frequency of  detection of  chlorophenols  1n  U.S.  tap waters was  0%.  Kopfler
et  al.   (1977),   however,   qualitatively  detected  2,4-d1-,  2,4,5-trl- and
2,4,6-trlchlorophenol  In   U.S.   drinking  waters.   2-Chloro-,   4-chloro-,
2,4-d1chloro- and 2,4,6-trlchlorophenol at respective maximum concentrations
of  39,  34,  17 and  60 ng/l  have  been detected  In Canadian drinking  waters
(SUhole et al.,  1986).  A  few  of  these compounds  have  also been detected In
waters  from  England, the  Netherlands  and Germany  (Crathorne  et al.,  1984;
KMJgsheld  and  Vandergen,  1986).   The  available . data  are  Inadequate  to
estimate  the  dally  exposure of  a  U.S.  Individual  to  these  compounds  by
Ingestlon of drinking water.
    2,4,5-Trlchlorophenol   was  detected  In   air  samples  1n Love  Canal,  NY
(Hauser   and   Bromberg,   1982)   and  2-chloro-,   4-chloro-,  2,6-d1chloro-,
2,4,5-trlchloro- and  2,4,6-trlchlorophenol  were  Identified In  the exhaust
gases from  an experimental  Industrial  Incineration  facility  (James et  al.,


0017d                               3-4                              06/18/87

-------
1984).   Quantitative  air  monitoring  data  on  chlorophenols  In  the  United
States  or  elsewhere,  however,  are  not available.   Occupational  exposure to
chlorophenols  1n  a  Finnish  sawmill  was  reported  by Kaupplnen  and  Undroos
(1985).   The mean  concentration  of  2,4,6-trlchlorophenol  1n one work  area
was  58  yg/m3,  but  the  concentrations  of  chlorophenols  In  the air  were
usually well below the Finnish occupational limit value of 500 yg/m3.
    Chlorophenols  have  been  detected  1n  a  few  edible aquatic  organisms
collected  from  contaminated  surface  waters  in- Finland.    The muscles  of
salmon,  Sal mo  salar.  and  trout,  Salmo trutta,  collected from  these  waters
contained  maximum  average   concentrations  of   5.9,  2.5  and  29.3 yg/kg  of
2,4,6-tMchloro-,   2,4,5-tMchloro-  and   2,3,4,6-tetrachlorophenol,   respec-
tively  (Paasivirta  et  al.,   1985b;  Vuorlnen  et  al.,  1985).   Although  the
available  data  are  Insufficient  to  estimate  the average exposures  through
air,  food  or  drinking  water, the data  Indicate  that exposure of the  general
public to the various chlorinated phenols  1s low and sporadic.
0017d                               3-5                              05/08/87

-------

-------
                             4.  AQUATIC TOXICITY
4.1.   ACUTE TOXICITY
    Toxldty of  chlorophenols  to aquatic organisms  generally  Increases  with
Increasing  degree  of chlorlnatlon  (U.S.  EPA,  1979a, 1980b,c).  Kobayashl  et
al.  (1979)  proposed that  this  Increased toxlclty  was  related  to  Increased
uptake  of  the more chlorinated  compounds.   The most  toxic of  the  chloro-
phenols  Is  pentachlorophenol  (U.S.  EPA,  1979a), which  Is not  a  subject  of
this document.
    Data concerning acute  toxlclty  of  chlorophenols  to  freshwater fishes are
presented In Table  4-1.  The most  sensitive  species  for  which  a large amount
of  data  was available  were  salmonlds  (rainbow  trout,  Salmo  qalrdnerl.  and
brown  trout. Salmo  trutta) and bluegllls (Lepomls macrochlrus).   The lowest
reported acutely  toxic  concentration  for freshwater  fishes was 0.085  mg/a,
2,3,4,6-tetrachlorophenol,   a   96-hour  IC™  for  rainbow  trout  (Mayer  and
Ellersleck, 1986).
    Table  4-1  also  contains  data  concerning  pH-1nduced  variation  In  acute
toxlclty  of  chlorophenols to   gupples,  PoeclHa  retlculata.  Chlorophenol
toxlclty  Increased  with  decreasing  pH  (see  Table  4-1).  Holcombe  et  al.
(1980)   reported   Increasing   toxlclty  of  2,4-d1chlorophenol   to  fathead
minnows, Plmephales promelas with  decreasing pH.  At lower  pH,  the undlsso-
dated form of the  chlorophenols 1s more prevalent.  The  undlssoclated  form
Is  more  toxic  than  the dissociated form because of Us greater ability  to
penetrate biological membranes  (Holcombe  et  aT., 1980).   Water  hardness  had
little effect  on toxlclty of  chlorophenols  to  freshwater fishes  (B1rge  et
al., 1979;  Pickering and Henderson, 1966).
0018d                               4-1                               06/18/87

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05/08/87

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    Information  about  acute  toxlclty of chlorophenols to freshwater  Inverte-
brates  Is  summarized  In Table 4-2.  Toxlclty  again  appears to Increase with
Increasing  chlorlnatlon.   The lowest  reported toxic  concentration  was 0.29
mg/J.  2,3,4,6-tetrachlorophenol,   a  48-hour  LC5Q  for  Daphnla  magna   (U.S.
EPA, 1978a).
    Devlllers  and  Chambon   (1986)  studied  structure-activity relationships
for chlorophenol toxlclty to  Daphnla  magna  (see Table 4-2)  and  found that
the presence of  chloro substltuents  1n  the ortho  (2-  or  6-) or  para (4-)
positions  of  the phenol ring affected  toxlclty.   Chloro substltuents In the
ortho   position   decreased   toxlclty,   while  para  substltuents  apparently
Increased  toxlclty.
    Relatively   Uttle   Information   1s  available  concerning  toxlclty  of
chlorophenols to  marine species.-  The  only marine fishes for which there are
data are the sheepshead minnow, CypMnodon varlegatus, and  the cyprlnodontld
Rlvulus marmoratus  (Table 4-3).   Data  for  marine  Invertebrates are presented
In Table 4-4.  The  lowest reported toxic  concentration for marine fishes was
1.1  mg/5,  2,3,4,6-tetrachlorophenol,  a  96-hour  LC-n  for  Rlvulus  marmo-
ratus   (Koenlg  and McLean, 1980),  and  for  marine  Invertebrates  was  1.5 mg/Z.
3,5-d1chlorophenol,  a  96-hour   lethal  threshold  for  sand  shrimp,  Crangon
septemsplnosa (McLeese et al., 1979).
4.2.   CHRONIC EFFECTS
    Holcombe et  al.  (1982)  conducted a 32-day  continuous  flow embryo-larval
test with  fathead minnows exposed  to various concentrations of 2,4-d1chloro-
phenol.   They  found  that  survival  was  decreased  by  concentrations  >0.46
mg/a,   and  growth  was  depressed  at concentrations  >1.24  mg/1.   A  MATC  of
0.29-0.46  mg/l  2,4-d1chlorophenol  was  estimated  based  on  these  results.
U.S.  EPA   (1978a,  1980b)  reported a chronic  value  of  0.72  mg/l  2,4,6-trl-
chlorophenol determined  1n  an early life  stage test  with  fathead minnows.

0018d                                4-7                              06/18/87

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0018d
4-12
05/08/87

-------
No  adverse   effects   occurred   at   3.9   mg/8.  2-chlorophenol,  the  highest
concentration used (U.S. EPA, 1978a, 1980c).
    Koenig and McLean  (1980)  conducted  full  Hfecycle (8-month) exposures of
the brackish  water cyprlnodontld fish,  Rlvulus marmoratus. to 2,3,4,6-tetra-
chlorophenol  concentrations  of   0,  0.055,  0.110  and  0.220 mg/i.   Fish were
held  singly,  and  all  solutions  were  changed weekly.   Gill  erosion occurred
In  all  of  the  exposed  fish  and none  of  the  controls.  Exposed  fish also
experienced fin erosion  that  was dose-related  In  Incidence.   There was also
a  dose-related  trend  1n percent survival  of  the F. 'generation.   Parental
mortality,  percent   hatching  and   embryo   mortality   were   unaffected  by
2,3,4,6-tetrachlorophenol.
    Trabalka  and   Burch  (1978)   reported  that   10   mg/i   3-chlorophenol
decreased  hatching  of  carp  (Cyprlnus  carplo)  eggs  In a   static  renewal
exposure,  but 3 mg/i  had no effect.  Llndstrom  and Llndstrom  (1980)  found
that  exposure to  0.1  mg/1  4-chlorophenol  for  10  days  decreased swimming
activity of the amphlpod, Pontoporela aff1n1s.
4.3.   PLANT EFFECTS
    Table  4-5 summarizes  the available  Information  on  toxldty  of  chloro-
phenols  to freshwater  plant species.   The  more chlorinated chlorophenols
again  seem to  be  more  toxic.    This  variation  1n  toxldty  was  especially
large  1n  the  studies by  Blackman et  al. (1955)  with  duckweed,  Lemna minor.
where a  500-fold  difference  In   toxldty was  observed  between 4-chlorophenol
and  2,3,4,6-tetrachlorophenol  as  measured  by  the  48-hour  EC5Q  causing
chlorosis.  The  lowest  reported toxic  concentration  for freshwater  plants
was  0.603 mg/z,  2,3,4,6-tetrachlorophenol,  the  48-hour  EC5_  for  chlorosis
1n this study.
0018d                               4-13                             06/18/87

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0018d
4-14
05/08/87

-------
airways  and chest  X-rays  were taken.   Results  were compared  with standard



lung   function   values   form  various  sources.    HEF75«  was  significantly



reduced  In  6/7  subjects  and  all  7  showed  Increased  CV.,,  the  Increases
                                                            7»


being  greater  In  the smokers.   Changes In  other  lung  function  parameters



were  not  noted.   Results  of  the  questionnaire showed  that  complaints  of



upper  airway symptoms were  -60%  1n  the 7 subjects  compared with 10% In a



control  group  of  126 office  employees of similar  age and  smoking  habits.



Chest  X-rays of two  subjects  showed  Increased  Interstitial densities.   This



change  disappeared 1n one  subject after  1  month of no  exposure.   Although



the effects  could  have been  caused by exposure  to tMchlorophenols, they may



also  have  been  due  to  long-term  and  repeated use  of  gas  masks,  which



Involves Us own occupational stresses.



6.1.2.   Oral Exposure.



    6.1.2.1.    SUBCHRONIC — Immunologlc  competence  was  assessed  1n  groups



of  8-10  Sprague-Oawley  rats  exposed  to 2-chlorophenol   (Exon  and  Keller,



1983a,  1985), 2,4-d1chlorophenol  (Exon et al.,   1984; Exon  and  Keller.  1985)



or  2,4,6-tMchlorophenol  .In.  utero and  continued on chlorophenol  treatment



for an  additional  12-15  weeks (Exon  and  Koller,  1985).  Both dams  and their



progeny were provided with chlorophenols  In  their drinking water at 0, 5, 50



or  500 ppm  2-chlorophenol   or  0,  3,  30  or  300 ppm  2,4-dlchlorophenol  or



2,4,6-trIchlorophenol.   The  1mmunolog1ca1   parameters   examined   were  as



follows: humoral  Immunity,  measurement  of  the  ratio  of serum IgG antibody



levels  to  bovine  serum albumin  or keyhole limpet  hemocyanln;  cell-mediated



Immunity,   measurement   of   delayed-type  hypersens1t1v1ty   response;  and



macrophage  function,  assessed by the  ability  of peritoneal  cavity  derived



cells  to  phagocytlze sheep  red  blood cells In  vitro.  In  addition,  body,



liver, spleen and thymus  weights of these rats were recorded.









0020d                               6-3                              06/18/87

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    Exposure  of  rats  to 2-chlorophenol did  not  significantly affect any  of
 the  Immune  functions  examined.   The  ratios  of  serum antibody  levels  to
 bovine  serum albumin were  consistently decreased  In  2-chlorophenol-treated
 rats  but  these  decreases  were  not  statistically  significant.   In  2,4-d1-
 chlorophenol-exposed  rats,  the  ratios  of serum  antibody  levels to  keyhole
 limpet  hemocyanln  were  consistently greater than controls.   These  Increases
 appeared  to  be  dose-related  and reached statistical significance  (p<0.05  by
 analysis  of  variance  and least  square  means)  In the 300 ppm exposed group.
 Delayed-type  hypersens1t1v1ty  responses  showed  a  dose-related  suppression
 that was  significant  (p<0.05)  1n  the  30  and 300  ppm  groups.  No effect  on
macrophage  function  was noted  In  the rats  treated with  2,4-d1chlorophenol.
 In  the  2,4,6-tMchlorophenol-exposed  rats,  antibody  levels,  delayed-type
 hypersensHlvlty reactions and  macrophage numbers were  consistently  greater
 than controls, but the Increases were not  statistically significant.
    No  significant changes  In  body weights were noted  In any of  the  chloro-
phenol-exposed rats.  The only  significant  (p<0.04)  organ weight differences
were Increased  liver  and spleen weights   In  the 300  ppm  2,4-d1chlorophenol
and 2,4,6-trlchlorophenol groups and Increased  liver  weights 1n the  30 ppm
2,4,6-tMchlorophenol group.
    Kobayashl et  al.  (1972) fed male  strain  dd mice  2,4-d1chlorophenol   1n
 the diet  at levels of  0.02-0.2% for 6 months.   The  number  of  mice  used  In
 the experiment  was not  stated  and 1t was not  clear  If controls  were  used.
By measuring  body  weights  and  food  consumption, the authors  estimated that
 the mice  consumed 45,  100  and  230  mg/kg bw/day.   No effects  on  behavior,
growth   rate or hematology were  observed.   The  only  changes  noted were hyper-
plasla   of  hepatic  cells 1n  one high-dose  mouse and  slightly  reduced  liver
weights and  SGPT  levels  1n  the  high-dose  group.   The  authors concluded that
 the maximum no effect level  of  2,4-d1chlorophenol In feed was 100 mg/kg/day.

0020d                               6-4                              06/18/87

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     In  a  study  by  Borzelleca et al.  (1985a), groups of 20 male and 20 female
 CD-I mice  were  provided  with 2,4-d1chlorophenol  (99% pure)  In their drinking
 water  at  0.2,  0.6  or 2.0  mg/9. for 90  days.   The  drinking  water solutions
 also  contained  Emulphor,  a polyoxyethylated vegetable oil,  which was added
 to  Improve  solubility  and  to Increase  palatabllUy.   Control  mice  were
 provided with delonlzed  water or  a 10% Emulphor  solution.  The 2,4-d1chloro-
 phenol  doses  calculated  by the authors were  50,  143  and  491  mg/kg/day for
 females and  40, 114  and  383  mg/kg/day  for males  In  the  low-,  middle- and
 high-dose  groups,   respectively.    The   results  of  the  study  Indicated  no
 consistent compound-related differences  1n  terminal  body weight or absolute
 or  relative  organ  weights,  hematology  or  clinical  chemistry  when compared
 with  Emulphor-treated mice.   There  were major  differences  In hematologlcal
 and  clinical  chemistry   values,  mixed-function  oxldase  activity  and organ
 weights,   between   control   mice   receiving  Emulphor  and  those  receiving
 delonlzed  water.    The  authors concluded   that  Emulphor  was  "not  without
 effect"  and   that   2,4-dlchlorophenol  elicited  no  consistent  treatment- or
 dose-related effects.
    McColHster et  al. (1961)  studied  the  toxldty of 2,4,5-tMchlorophenol
 In  rabbits and rats.   Groups of  1-3  rabbits   were  dosed  by  gavage  with
 2,4,5-trlchlorophenol  1n  5X  gum  acacia  solution  at 0,  0.001,  0.01,  0.1  or
 0.5  g/kg  20  times  over   28  days.   The  only  changes noted were  very slight
microscopic kidney  changes  at the 0.1  g/kg  level  and very slight kidney and
 liver changes at the  0.5  g/kg level.  In the rat study,  groups of five males
were dosed by  gavage with  2,4,5-trlchlorophenol   1n  olive oil  at  0, 0.03,
0.1, 0.3 or 1.0 g/kg 18  times  over  24  days.  No evidence of adverse  effects
was  noted.   The  parameters  examined  were  growth,  mortality,   hematologlc
parameters, blood  urea  nitrogen   levels,  body and  organ weight  ratios and


0020d                               6-5                              06/18/87

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microscopic  examinations  of  lung,  heart,  liver,  kidney,  spleen,  adrenal,
pancreas and testes.
    In  a  98-day study of the toxldty of  2,4,5-tMchlorophenol  (McColllster
et  al.,  1961),  groups of 10  male  and  10 female 50-day-old Hlstar  rats  were
fed diets  containing  the test compound  at  0,  0.01, 0.03,  0.1, 0.3  or  1.0%.
No  effects  1n  gross appearance,   behavior,  mortality,  food  consumption,
growth,  terminal  hematologlc  values,  final  average body  and organ  weight
ratios  or  gross or microscopic  examinations  of  tissues  were noted  In  rats
fed  0.01,   0.03 or   0.1%  (0.01,  0.03   or  0.1  g/kg/day  calculated  by  the
authors).   Wetness  of the abdominal  area  Indicating a  diuretic  effect  was
noted In rats  treated at  0.3 or 1.0%.   Body weights of both  male  and female
rats were  reduced  at  1.0% but  the average final body weights were signifi-
cantly  (p=0.03)  decreased   only  1n  females.   Microscopic  examination  of
tissues revealed slight pathologic  changes  In the  liver and  kidneys of rats
treated  at  0.03 and  1.0%.    These  changes, which  were  milder  In  the  0.3%
group,  Involved moderate degenerative  changes  1n  the  epithelial  lining  of
the convoluted  tubules and early proliferation  of  the  Interstitial tissue In
the kidneys,  and mild  centMlobular degenerative  changes  characterized  by
cloudy  swelling  and  an occasional  area  of  focal necrosis  1n  the  liver.   In
addition, slight proliferation of  the  bile ducts and early portal cirrhosis
were noted  at 1.0%.   The authors concluded  that the liver  and kidney changes
observed at both 0.3 and 1.0%  "were of  a mild  and  reversible  nature  and
probably of minor significance.*
    Vlzethum and Goerz  (1979) fed  rats  2,4,5-trlchlorophenol  In  their diets
at 0.05% for >70 days and concluded that the  compound  was not porphyrogenlc.
No other parameters  were examined.
    To determine doses of  2,4,6-tMchlorophenol to be used 1n a cardnogen-
1c1ty study, NCI (1979) conducted  a subchronlc  feeding  study using F344 rats

0020d                               6-6                              06/18/87

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 and  B6C3F1  mice.   Groups  of five male and five female rats and mice were fed
 2,4,6-tMchlorophenol  In  the  diet  for 7 weeks followed by 1 week of observa-
 tion.   The  rats  were  fed  dietary  concentrations  of   0,  10,000,  14,700,
 21,500,  31,500  or  46,000  ppm,  while  the mice  were  fed  0,  6800,  10,000,
 14,700, 21,500  or  31,500  ppm.  In  rats, survival  was not affected at <14,700
 ppm,  but  at the 21,500 ppm level  one male died,  at  31,500  ppm one male and
 two  females  died,  while  at  46,000  ppm two males and  three females died.  The
 only  hlstopathologlc  lesions  noted  1n  rats  were In  the  46,000 ppm group 1n
 which  moderate to marked  Increases  1n  splenic  hematopo1es1s  was  noted and
 mldzonal  vacuolatlon  of  hepatocytes  was  observed 1n  two males.   Except for
 one  control  female that died,  survival of mice  was  not  affected at <21,500
 ppm,  but  at  31,500  ppm  two  males  and  two  females  died.   Tissues  of mice
 dosed  at  21,500  ppm  were  essentially  normal.    Whether  hlstopathologlcal
 effects were observed  1n mice fed  31,500 ppm was  not  stated.   A dose-related
 decrease  In body weight  was  observed  In both rats  and  mice.   The decrease
 was >10X  In rats treated at  >14,700  ppm,  1n  male mice at >14,700 ppm and In
 female mice at  >21,500 ppm.  This  decrease In body weight was  used to  select
 the doses for the chronic study.
    Kawano  et  al.  (1979)  described an  experiment  1n  which  female Wlstar JCL
 rats   were   fed  diets   containing   2,3,5-trlchlorophenol   or   2,3,4,5-,
 2,3,5,6- or  2,3,4,6-tetrachlorophenol at  0.2% for  3 weeks.   The  purity of
 the compounds  was  not stated.   At the  level  provided,  the compounds  caused
 considerable changes  1n  growth,  organ  weights,  serai biochemical  data and
 liver   drug  metabolizing  enzymes.    2,3,4,6-Tetrachlorophenol   caused   a
 relatively  strong  growth  Inhibition.   Further  details concerning this  study
were not available.
    Hattula  et  al.  (1981b)  dosed 2-month-old male Wlstar  rats  (322±27 g)
with  2,3,4,6-tetrachlorophenol  1n  olive  oil  by gavage at  0,  10,  50 and 100

0020d                               6-7                              06/18/87

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mg/kg/day  for  55  days.   The number of  rats  per  dose  group  was  not provided.
After  55 days  the  rats were  sacrificed  and  samples  of the "liver,  kidney,
spleen,  stomach,  small  and large  Intestine,  muscle and brain  were examined
h1stolog1cally.   There  were   no  changes   1n  the  brain,  muscle  or  large
Intestine.   In the  stomach,  mild dilation  of  the veins of  the  mucosa  was
observed,  but  the dose level  at which this effect occurred was  not  stated.
Necrosis of  tie small  Intestines was noted  In the  high-dose  rats.  The most
significantly  affected  organ  was  the liver.   The  authors  provided  three
levels  of  hlstopathologlcal  changes of the  liver:  level I, mild prolifera-
tion  of  the  bile canallcull,  swelling  of  the endothellal  cells  of the bile
tract  and  occasional necrosis  of  the  endothellal cells  of canallcull  and
some  hepatocytes;  level  II, focal  areas  of necrosis  of  several  hepatocytes
and  prominent  proliferation of  the  bile  canallcull  and  Inflammatory Infil-
trates around  the  bile  duct;  level III, large necroses  (which  Included most
of  the liver  parenchyma).   At  10  mg/kg,   no  changes were observed  1n  the
liver  parenchyma  (whether  other changes were  noted  Is  not  clear), while at
50  mg/kg  one  rat  showed  level  III  changes and at  100  mg/kg  two rats "had
changes  In  the liver corresponding  to  the levels  (II)  and (III).'  Further
details concerning this study were not reported.
    6.1.2.2.   CHRONIC -- As  part  of  a   carc1nogen1c1ty-cocarc1nogen1c1ty
study  (Sections 6.2.2. and  6.2.3.),  Exon and Koller (1985)  provided drinking
water  containing  0,  5,  50  or 500  ppm  2-chlorophenol  or  0,  3,  30 or  300 ppm
2,4-d1chlorophenol  to  groups  of  24-32 Sprague-Oawley rats/sex from weaning
to  -2  years  of age.  These rats  were  offspring  of dams exposed  to the same
treatments from 3 weeks of  age  through weaning of  their  progeny.  In rats
treated with  500 ppm 2-chlorophenol  or 300  ppm 2,4-d1chlorophenol,  numbers
of  RBC  and  hemoglobin  levels  were  Increased  compared with  controls.   Packed
cell  volume  was  also  Increased  1n  500   ppm  2-chlorophenol  rats.   These

0020d                               6-8                               06/18/87

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effects  were significant  (p<0.05)  at  H months  of  exposure.   Hematologlcal
parameters at lower doses and other signs of toxlclty were not discussed.
    To  examine  the ' cardnogenldty  of  2,4,6-tMchlorophenol,  NCI  (1979)
conducted  a  2-year feeding  study using  F344  rats and  B6C3F1  mice (Section
6.2.2.).   In this  study,  groups  of  50 male  and 50  female  rats  were fed
2,4,6-trlchlorophenol  1n  the  diet  at  5000  or  10,000 ppm  for  106  weeks.
Groups  of  50 male mice  were  fed  5000  or 10,000 ppm  for 105 weeks,  while
groups  of  50 female mice were fed  at  TWA doses of 5214 or  10,428  ppm.   The
actual  dietary  levels  the female  mice  were fed were  10,000 or 20,000 ppm for
38 weeks,  followed by 2500 and 5000 ppm for  an additional 67 weeks.  Groups
of 20  male and  20 female rats and  20  male and female mice maintained on the
basal diet for 105-107 weeks served as controls.
    Throughout  the study, rats and  mice were  checked  twice  dally  for  sick,
and  moribund animals  or  animals  with  tumors.   The  animals were weighed,
examined clinically and  were palpated for  tumors  monthly.  Moribund animals
and those  that  survived  the  study were sacrificed and necropsled.  Gross and
microscopic  examinations  of major  tissues,  organs  and all  gross lesions were
conducted.    In addition,  peripheral  blood smears  were made for rats and mice
whenever possible.
    In  addition   to   the  carcinogenic   effects   of  2,4,6-tMchlorophenol
observed In  this  study   (Section  6.2.2.),  a  dose-related decrease  In  body
weight was observed throughout  the study  1n  both  rats  and mice.   Results of
hlstopathologlc  examinations  1n  rats  revealed  that  the only noncardnogenlc
effects Increased  above  controls  were  bone marrow hyperplasla and  leukocyto-
sls.    Bone marrow hyperplasla was noted  In  0/20, 26/50  and  15/50 control,
low-dose and high-dose male  rats, respectively, and  1n 0/20,  16/50 and 2/50
control, low-dose  and  high-dose  female rats,  respectively.  Leukocytosls was


0020d                               6-9                              06/18/87

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observed  in  0/20,  13/50  and 11/50 control, low-dose and  high-dose  male  rats
and  in 0/20,  6/50 and  3/50 control,  low-dose and  high-dose female  rats,
respectively.   In  mice,  except  for  hyperplasla   of   the  liver  in  males,
similar nonneoplastlc  lesions  were  found  In  both  control and  treated  mice.
The  incidences of  hyperplasla of  the  liver  in  male  mice were  2/20,  12/49 and
6/47 1n control, low- and high-dose  groups.
6.1.3.   Other  Relevant   Information.   Carlson  (1978)  found  that  2,3,5-,
2,3,6-,  2,4,5- and  2,4,6-trlchlorophenol   administered  orally  to  rats  at
doses as high as  400 mg/kg/day  for  14 days did not  Induce xenoblotlc metabo-
lism.   2,4,5-TMchlorophenol  at  400 mg/kg   did   reduce  mlcrosomal  NADPH-
cytochrome c reductase activity and  levels  of  cytochrome P-450.
    Oenomme  et al.  (1983)  examined  the ability of  the  trl- and tetrachloro-
phenols  to  Induce rat  hepatic  drug-metabolizing  enzymes.   The  compounds
examined,   3,4,5-,  2,4,6-,   2,4,5-,   2,3,6-,  2,3,5-,   2,3,4-trlchlorophenol,
2,3,5,6- and  2,3,4,5-tetrachlorophenols, were Injected  1ntraper1toneally In
corn oil  Into 1-month-old male Wlstar  rats.   The  enzyme  activities assayed
were  4-d1methylam1noant1pyr1ne  N-demethylase,  benzo[a]pyrene  hydroxylase,
aldrln epoxldase  and mlcrosomal EROO.   The Induction  of 4-d1methylam1noant1-
pyrlne  N-demethylase  by  600   ymol/kg  3,4,5-trlchlorophenol  was   the  only
significant  (p<0.01) finding.
    Sussmuth et al. (1980) found that S-9 from rats  treated Intraperltoneally
with 2,3,4,5-tetrachlorophenol at 0.43 or  1.3  mmol  enhanced  the mutagenlcHy
of  2-am1noanthracene  and benzo[a]pyrene  in an  Ames  assay using  Salmonella
typh1mur1um  strain TA1538 compared with results with unlnduced S-9.
    MHsuda  et al.  (1963)  studied the effects of chlorophenols  on  oxldatlve
phosphorylatlon  In rat liver mitochondria in vitro.    The  compounds studied
0020d                               6-10                             06/18/87

-------
were  2-,  3-,  4-chlorophenol,  2,4-,  2,6-d1chlorophenol,  2,4,5-,  2,4,6-tM-
chlorophenol  and  2,3,4,6-tetrachlorophenol.   At  low  concentrations,  all
compounds   studied   uncoupled  oxldatlve   phosphorylatlon   and  accelerated
respiration.  The  most active  compound  was  2,3,4,6-tetrachlorophenol  with a
I50   concentration   of   2xlO~* H.   As  the   number   of   chlorine   atoms
decreased,  the  Inhibiting activity of  the  compound also  decreased,  so that
the  Igfl values  for  trlchlorophenols, dlchlorophenols  and monochlorophenols
were 3-18xlO~*. 42-400xlO~» and 150-520xlO~« M, respectively.
    Acute  toxldty  values for  the chlorinated  phenols  are  listed  In Table
6-1.   In general,  the  acute toxldty  of  the chlorinated  phenols  Increases
with  Increasing  chloMnatlon  (Exon,  1984).   The  mode  of  action   of  the
chlorinated  phenols  changes  from  convulsant-llke  effects  In the monochloro-
phenols  to  an Increase  In the uncoupling of oxldatlve phosphorylatlon 1n the
higher chlorinated phenols.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.    Ep1dem1olog1cal  studies  of  workers  provide  evidence
that  chlorophenol  exposure   Is associated  with  soft  tissue  sarcomas  and
malignant  lymphomas.   In a  follow-up study, Lynge  (1985)  reported signifi-
cant  Increases  In  relative  risk   ratios  for  lung cancer,  rectal  cancer and
soft  tissue sarcomas  In  men exposed  to 2,4-dlchlorophenol  and 4-chloro-o-
cresol  based phenoxy  herbicides.   In   female  workers,  an   Increase  In  the
relative risk of cervical cancer was  observed.   Lynge (1985) considered only
the  soft  tissue  sarcoma  Incidence  to  be  of  significance.   Several other
ep1dem1olog1cal   studies  (Cook,   1981;  Honchar  and  Halperln,  1981)  also
reported  elevated  Incidences   of  soft   tissue   sarcoma.   In  a case-control
study, Pearce et al. (1986)  found  an  Increased risk of non-Hodgk1ns lymphoma
(ICO code  202)   1n New Zealand meat  workers who  were exposed to chemicals
0020d                               6-11                             08/11/87

-------





















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6-14
                                                                     05/11/87

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 Including  2,4,6-trlchlorophenol, but not  In  farmers, who  were  more  likely  to
 be  exposed to  phenoxyherblcldes.   All  the ep1dem1olog1cal studies are  con-
 founded  by multiple exposures and some have  small  study  populations;  never-
 theless,  the  Influence of  the chlorophenols cannot  be determined from  the
 available  data.   The  studies  Involve  exposures  to  multiple chemicals  Includ-
 ing  phenoxyacetate  herbicide  compounds   with   dloxln  (TCOO)  contaminants.
 According  to  the  U.S.  EPA  (1986c)  Carcinogen  Risk  Assessment  Guidelines,  the
 evidence 1s limited; that 1s, Group 81 for this mixture of exposures.
 6.2.2.   Oral.   2,4-Olchlorophenol  has been  tested  for  cardnogenldty  by
 the  NTP  1n a dietary  study  using rats and  mice,  but  the  report  1s  not  yet
 available  (NTP, 1986).
     In  an  examination of  the cardnogenldty of  2-chlorophenol  and  2,4-d1-
 chlorophenol  In  Sprague-Dawley rats,  24-32  offspring/sex of  chlorophenol
 exposed  dams  (Section  6.5.)  were provided with  drinking  water containing 0,
 5,  50  or  500 ppm 2-chlorophenol  or 0, 3,  30 or  300  ppm 2,4-d1chlorophenol
 from weaning until death or 24 months (Exon and Koller, 1985).
    Microscopic  examination  of  major  organs  of 2-chlorophenol  and  2,4-dl-
 chlorophenol  exposed  rats   did   not   reveal  Increased  tumor  Incidences,
 decreased  latency to  tumor formation  or  variations 1n  tumor  types compared
with controls.
    Innes  et  al.  (1969)  examined the  cardnogenldty  of 2,4,6-tMchloro-
phenol 1n  B6C3F1  and  B6AKF1  mice.  Details  of  this study were also reported
 In BRL (1968a) and  evaluated  by IARC  (1979).  Groups of at least 18 male  and
18  female  mice  were   dosed  by  stomach  tube  with 100  mg/kg/day  2,4,6-trl-
chlorophenol  (maximum  tolerated dose) In  5X gelatin beginning  at  7  days of
age.  Control mice  were treated  with  gelatin.  After  the mice were weaned,
2,4,6-trlchlorophenol   was  added  to  the diet  at 260  ppm and  the  mice were


0020d                               6-15                             08/11/87

-------
 maintained  until  they  reached  78  weeks of age.   Since  Innes  et al.  (1969)
 examined  a  total  120 compounds  (Including  2,4,6-trIchlorophenol), the  actual
 time  of onset and  termination  were  staggered  to effectively conduct  hlsto-
 pathologlcal  evaluations.   Several  groups  of  both  positive  and   negative
 controls  were  Included  1n  this  study to account  for  the  staggering  schedule.
 Appropriate  statistical  evaluations were conducted  to examine heterogenldty
 among  different control  groups  with respect to  tumor  types.  Since  this  test
 was  not  significant  at  the  5% level  with any  of the  four  categories  of
 tumors,  the  respective  control  groups  were  lumped  together  to  give  an
 approximate  figure  with which  the  tumor1gen1c1ty of experimental  compounds
 could  be  compared.   Total tumor Incidences were 10/18  and 8/18 In  male and
 female  B6C3F1  mice,  respectively,  and 4/18  and  2/18  In  male and  female
 86AKF1  mice,  respectively  (BRL,  1968a).   Pooled control  Incidences  were
 22/79  and 8/87 In male  and female  B6C3F1 mice and 16/90  and 7/82 In male and
 female  B6AKF1  mice  (BRL,  1968a).   When matched with  pooled  control  Inci-
 dences  the  combined   Incidences  of  hepatomas  (5/36)   and  retlculum-cell
 sarcomas  (6/36)  In  male and female B6C3F1 mice  were  Increased  significantly
 (p<0.05).  In  their  evaluations,  IARC   (1979)  observed that  the  results  were
 no  longer  significant  when  the data  for  males and  females were  considered
 separately or  when  matched controls  are considered.  Thus,  the  IARC Working
 Group  considered  the studies  to be Inadequate  to  support  cardnogenlclty of
 2,4,6-tMchlorophenol.   Innes  et  al.  (1969) concluded that  the results  were
 Inconclusive and  that  the cardnogenlclty  of  2,4,6-tMchlorophenol  should be
 evaluated further.
    The  NCI  (1979)  conducted  an  oral  cardnogenlclty  study  of  2,4,6-trl-
 chlorophenol  In  F344 rats  and B6C3F1   mice.   Male and   female  rats  and  male
mice were  fed  2,4.6-trlchlorophenol  at dietary levels   of  0,  5000  or 10,000


 0020d                               6-16                             08/11/87

-------
 ppm for up to  106  weeks.   Female  mice were fed 2,4,6-tMchlorophenol at TWA
 doses  of  0,  5214  or 10,428  ppm  for  105 weeks (see Section 6.1.2.2.}-
     In male rats,  a  dose-related  significantly  Increased  Incidence of mono-
 cytlc  leukemia and malignant lymphoma or  leukemia  (Table  6-2)  was observed.
 The  Incidence of  leukemia  was  also   Increased  In  female rats,   but  not
 significantly.   That 2,4,6-trlchlorophenol affects  the hematopoletlc system
 1s  supported  by the finding of  bone marrow hyperplasla and  leukocytosls (see
 Section   6.1.2.2.).   In  mice,   the  Increased  Incidence   of  hepatocellular
 adenoma  and hepatocellular carcinoma was  significant  (see  Table 6-2).  From
 their  results, NCI (1979) concluded  that  under  the  conditions  of the study,
 2,4,6-trlchlorophenol was  carcinogenic In male F344 rats,   Inducing lymphomas
 or   leukemlas   and  was  carcinogenic  In  male  and   female mice.   Inducing
 hepatocellular  carcinomas and adenomas.
 6.2.3.    Other  Relevant  Information.   Exon and Roller  (1983b,  1985)   studied
 the  ability of 2-chlorophenol  and 2,4-d1chlorophenol  to  promote the trans-
 placental  carcinogen  ENU In  Sprague-Oawley  rats.   Control   and  chlorophenol-
 exposed  dams  (5,  50  or  500 ppm 2-chlorophenol  or  3.  30 or 300 ppm  2,4-d1-
 chlorophenol  In drinking water) were  also treated with ENU  on gestation days
 14-21.   ENU  was provided as precursors:  ethylurea  1n the diet at 0.316X  for
 2-chlorophenol  rats  and at  0.15% for  2,4-dlchlorophenol   rats,  and sodium
 nitrite  1n the drinking water   at  1  ppm  NO.  for both  groups.   At  weaning,
 groups  of  24-32   progeny   of   these  dams were  maintained  on  the  parental
 chlorophenol treatment for  up to 2  years.
    Increased  tumor Incidences  and decreased  time-to-tumor latency  occurred
 In  all groups  of  male  rats  from  ENU  treated  dams  exposed  pre- and  post-
 natal 1y  to 2-chlorophenol,  compared  with those  from  dams exposed to  ENU
alone.  These  effects were not   observed  In  female rats treated  with ENU  and
0020d                               6-17                              08/11/87

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08/11/87

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 2-chlorophenol  or  In  either sex  of  the rats  treated  with ENU  and 2,4-d1-
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 or most  tumors  that developed may  have been spontaneous.
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 2,4-d1chlorophenol,  2,4,5- and  2,4,6-tMchlorophenol  to  promote tumors   In
 mouse  skin treated with  a  single application  of  DMBA.   The Initiator, DMBA
 In benzene,  was  applied  to  the  shaved  skin  of  2- to  3-month-old   female
 Sutter  mice,  followed with  biweekly  applications  of  1   drop  of  a   20-21%
 chlorophenol  solution  In  benzene  for  12-24  weeks.   Tumors were Identified  by
 gross  examination  with  periodic  confirmation  by microscopic  examination.
 All  the   chlorophenols  examined,  except  2,4,6-tMchlorophenol,   exhibited
 tumor  promoting activity.   In  addition,  an  experiment with 2-chlorophenol  In
 dloxane  also  resulted In  papllloma  formation without  application  of the
 Initiator.  A  dloxane  control  was not  tested  so It  Is uncertain whether the
 tumors were a  result  of  2-chlorophenol  or  dloxane treatment.   The  U.S. EPA
 (1980c)  criticized  these studies  on  the  basis   of  the  severe Irritation
 caused  by  the  high chlorophenol  concentrations used  and  the  reporting  of
 only gross  pathological results.   U.S.  EPA  (1986c) also stated that the mice
 were housed In  wood  cages   treated with creosote, which  may have  Increased
 the promoting activity.
    Stoner  et  al.  (1986)  reported  negative   results  when  2,4,6-trlchloro-
 phenol  was  tested In  a lung adenoma  bloassay  In strain A/J mice.   Groups  of
 16  male  and  16  female 8-week-old mice  were  treated  with  2,4,6-trlchloro-
 phenol  In  trlcaprylln  by  1ntraper1toneal Injection or by gavage  3 times/week
 for 8  weeks.   The total dose each mouse received  was 1200 mg/kg  In the oral
 experiment  and  1200,   600  or 240  mg/kg In  the Intraperltoneal  experiment.
                                                                             •

0020d                               6-21                             08/11/87

-------
 Controls  were  treated wHh trlcapryHn.   After the 8-week  treatment  period,
 the  mice  were  observed for 16 weeks, when  they were  sacrificed  and  examined
 for  tumors.
     BRL  (1968a)  studied  the  carclnogenldty  of 2,4,5- and  2,4,6-trlchloro-
 phenol and  2,3,4,6-tetrachlorophenol  1n mice  following a  single  subcutaneous
 Injection.   Groups  of 18  male  and  18  female B6C3F1  mice  and  groups of  18
 male  and  18 female B6AKF1 mice  were Injected at  28  days of age.   All  mice
 were  observed  for  -18 months.   The exposure  levels used  were 1000 mg/kg
 2,4,5-trlchlorophenol  In  corn oil,  464  mg/kg 2,4,6-trlchlorophenol  1n  corn
 oil  and   100  mg/kg   2,3,4,6-tetrachlorophenol  1n   DMSO.   The  Incidence  of
 tumors  In  all  three  groups was   not  Increased  compared  with  untreated
 controls, or controls treated with corn  oil  or DMSO.
 6.3.   HUTAGENICITY
    Hutagenlclty studies  of  the  chlorinated phenols  are  summarized  1n  Table
 6-3.   In  Ames  type assays,  Haworth  et  al.  (1983)  observed  negative results
 for  2-,  3-, 4-chlorophenol,   2,3-,  2,5-,  2,6-,   3,4-d1chlorophenol,  2,4,5-
 and  2,4,6-trlchlorophenol  and equivocal  results   for  2,4-  and  3,5-d1chloro-
 phenol.   In  similar   assays,  Probst  et  al.  (1981)  and Simmon et  al.  (1977)
 reported negative  results  for 2,4-d1chlorophenol;  Rasanen and Hattula (1977)
 reported  negative  results for  2,3-, 2,4-,  2,5-,   2,6-,  3,4-,  3,5-d1chloro-
 phenol, 2,3,5-, 2,4,5-, 2,4,6-trlchlorophenol  and 2,3,4,6-tetrachlorophenol.
    Nestmann and Lee  (1983)  observed negative results for 2.6-d1chlorophenol
and  2,4,5-trlchlorophenol  In Saccharomyces  cerevlslae.   In  contrast, 2,4,6-
 trlchlorophenol  caused weak  but  significant  results  In  a mutation   study
 using  S.  cerevlslae   (FahMg  et  al.,  1978).   In  DrosophUa  melanogaster.
 2,4,6-trlchlorophenol  was   negative  for  sex-linked   recessive   mutations
 (Valencia et al., 1985).


0020d                                6-22                              08/11/87

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     In  Chinese  hamster  V79 cells, Jansson and  Jansson  (1986)  found  negative
 results   for  2,4-,  2,6-d1chlorophenol,   2,4,6-trlchlorophenol  and  2,3,4,6-
 tetrachlorophenol  without  metabolic  activation.   In  a  study by  Hattula  and
 Knuutlnen  (1985),  2,6-d1chlorophenol  tested  negative In Chinese  hamster  V79
 cells,  while  2,4,6-trlchlorophenol and  2,3,4,6-tetrachlorophenol  were weakly
 positive  In  the absence of  S-9,  but  negative when S-9  metabolic activation
 was  present.  Probst  et  al.  (1981) found  negative  results  when 2,4-d1chloro-
 phenol was tested  for unscheduled DNA synthesis 1n primary rat hepatocytes.
     Rats  dosed  orally with  130  mg/kg 2-chlorophenol  every other day  for 1
 week  showed  a  5-fold  Increase In chromatld  deletions  In  their  bone marrow
 (Chung, 1978).   Complete Inhibition  of  mitosis was noted  In the bone marrow
 of rats exposed  to 2-chlorophenol for 2-3 weeks.
     FahMg et  al.  (1978)  found  weak  positive  results  when 2,4,6-trlchloro-
 phenol was  tested  In a  spot  test  In  mice Injected with  the compound on  day
 10 of gestation.
 6.4.   TERATOGEHICITY
     Rodwell et  al. (1984) examined the  teratogenlclty  of 2,4-dlchlorophenol
 1n Fischer 344  rats.  Pregnant rats were  dosed with the compound  In  corn  oil
 by  gavage at  0, 200,  375  or 750  mg/kg  on gestation days 6-15.  Throughout
 the  study,  females   were  observed   for   toxIcUy and  weighed   at  regular
 Intervals.  On  gestation  day  20, the dams  were  sacrificed and the fetuses
were weighed,  sexed  and examined  for  gross  anomalies.   Half of  the fetuses
were examined  for  skeletal  anomalies while  the remaining were examined  for
visceral  anomalies.   A  dose-related  statistically significant  (p value'  not
 stated) Inhibition In maternal body  weight occurred 1n all  dose  groups.   The
only  effects  on  the offspring  were  a   slight  Increase  In early  embryonic
death and reduced  fetal  weights  In the high-dose group.


0020d                               6-26                              08/11/87

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     BRL  (19685)  conducted  teratogenldty studies  of  2,4-d1ch1orophenol  and
 2,4,5-trlchlorophenol  In AKR and  C57B16  mice.   The compounds  were  given by
 subcutaneous  Injection  In  OMSO on  gestation days  6-14  for C57B16  mice or
 days 6-15  for  AKR  mice.    The  mice  were  sacrificed  and  the  fetuses  were
 weighed  and examined  for  anomalies  on gestation day  18  (C57B16  mice)  or 19
 (AKR mice).   Additional  parameters  examined   were  maternal  body  weight,
 maternal  liver  weight,  amnlotlc  fluid per  fetus,  placenta! weight  and  the
 number  of  live   fetuses  and Implantations  per   litter.   Control mice  were
 treated with DMSO.
     In  the  2,4-dlchlorophenol study,  six C57B16 dams  and  six  AKR dams were
 treated  as  stated  above  at a  dose  of  74  mg/kg.   The  results showed an
 Increase  In anomalies  1n  the  AKR mice  (18%)  when compared  with controls.
 Half  of  the anomalies  were  extended  legs.   The fetal weights and  maternal
 liver weights of  the  AKR mice were also  decreased  and  the amount  of amnlotlc
 fluid per  fetus was  Increased  compared  with controls.   In  contrast, C57B16
 mice  did  not  show  an  Increase In  the  number  of  anomalies noted  (3%)  and
 fetal weights  were  comparable  with  controls.   Changes  In  other parameters
 were not noted.
     In the  2,4,5-trlchlorophenol study,  seven C57B16 dams and  eight AKR  dams
 were  treated  by  the  previously  stated protocol  at a  dose  of  85 mg/kg.   No
 changes 1n maternal or fetal  parameters were  noted  1n  either  strain.
     In a  study  by Neubert  and  DUlmann  (1972),  pregnant  mice  were dosed by
 gavage with 2,4,5-trlchlorophenol  at 0,  0.9 or  9.0  mg/kg  bw on  gestation
 days  6-15.   No teratogenlc  effects  (ascertained  by  the  Incidence  of cleft
 palate  1n   the  offspring)  were noted  at either   dose  level.    At  9  mg/kg,
 slightly higher  embryo  mortality  was  noted.  This  Increase  was marginally
 statistically significant.


0020d                               6-27                              08/11/87

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     Hood  et  al. (1979) conducted  teratogenldty  studies  of  2,4,5-trlchloro-
 phenol  In  CD-I  mice.   Groups  of  at least  eight  pregnant mice were treated by
 gavage  with  2,4,5-trlchlorophenol  1n  honey and  water  (1:1)  at  800-900  mg/kg
 on  1 of gestation  days 8-15  or  at 250-300 mg/kg on  3 consecutive  gestation
 days  (7-9,  10-12  or 13-15).  Groups of control mice  were  treated with  honey
 and  water  or  were  left  untreated.   The  dams  were  sacrificed  on  gestation day
 18  and  the numbers of live, dead  and  resorbed  fetuses were  determined.   All
 live  fetuses  were  examined for gross  malformations, while  several  fetuses
 from  each  Utter   were  examined  h1stopatholog1cally or  were  examined  for
 visceral  or   skeletal  malformations.    The  only  significant  finding was  an
 Increase  In prenatal  mortality  when dams were  treated on  day 14  as compared
 with  solvent   treated  controls  (p<0.05);  however,  this   Increase was  not
 significant when  compared  with  untreated controls.   The authors  concluded
 that   under   the   study    conditions,   2,4,5-trlchlorophenol  produced  no
 significant effects on development.
    Chernoff  and   Kavlock   (1982)  found that  2,4,5-trlchlorophenol  In  corn
 oil, administered by  gavage to  CD-I mice  at  800 mg/kg on gestation days 8-12
 resulted  1n  a  significant  reduction  (p<0.05)  In litter  size  compared with
 controls.  No  effects were noted  on  maternal weight  gain,  survival  of pups
at  day  3 postpartum  and  pup  weights  on  postpartum days  1  and 3.   Gray and
Kavlock  (1984)  observed the growth and viability  of  the  F. generation  from
 the  Chernoff  and  Kavlock  (1982) study for  250 days,  and  noted  that 2,4,5-
 trlchlorophenol treatment  had no  effects  on postnatal  growth, viability  or
morphology.   Ratings  of   the  F,  generation  resulted  In  smaller  Utters.
The  reduction  was  significant  by  the  t-test  (p<0.05) but  not by  MANOVA  or
                                                   •
ANOVA, although the comparison was made to an unusually  high  control  value.
0020d                               6-28                              08/11/87

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     Schwetz  et al.  (1974)  examined the  effect  of 2,3,4,6-tetrachlorophenol
 on  the fetal  development  of  rats.   Groups of  20-40  pregnant Sprague-Dawley
 rats  were dosed  by  gavage with  purified (99.6%) or  commercial  grade (73%)
 2,3,4,6-tetrachlorophenol   1n  corn  oil  at  doses  of  10  or  30  mg/kg  on
 gestation  days 6-15.   Control rats were  dosed  with  corn oil.  The dams were
 sacrificed on  gestation  day 21  and the number and position of live, dead and
 resorbed  fetuses  were  recorded.   The  fetuses   were  weighed, examined  for
 gross  anomalies  and  the  crown-rump length was measured.  Part of each Utter
 was  examined  for  visceral  defects,  while the remaining fetuses were examined
 for  skeletal   abnormalities.   No changes  In  maternal  weight gain  or other
 signs  of  maternal toxIcHy occurred 1n  dams  treated  with either purified or
 commercial  grade  2,3,4,6-tetrachlorophenol.   The  treatments  also  had  no
 effect  on  resorptlons,  fetal body  weight, fetal  crown-rump  length or gross
 anomalies.   A significant  Incidence of  subcutaneous  edema  was  observed In
 the  10  mg/kg  groups,  but  not  1n  the  30  mgAg   groups.   Significantly
 Increased  Incidences  of  delayed ossification of  the  skull  bones  occurred In
 fetuses  (23/88,  p<0.05)  and  litters  (8/16,  p<0.05) of  the 30 mg/kg  commer-
 cial  grade  tetrachlorophenol group  compared with  controls  (14/143 fetuses,
 6/31  Utters).   In  the  30  mg/kg  purified  tetrachlorophenol   group,  the
 Incidence  of  delayed ossification  of  the  skull  In  fetuses  (18/104)  was
 significantly  Increased, but net the Incidences  1n  Utters  (7/20).
    In  order  to  clarify  and  extend   the work  of Schwetz   et  al.  (1974),
 Research Triangle  Institute (1987) (sponsored  by the  Office of Solid  Waste,
U.S. EPA) conducted  a teratology study  with  rats gavaged  at  different  doses
of  purified   grade  of  2,3,4,6-tetrachrlorophenol.   The  study  was  conducted
using a  two-repl1cate design; the  second replicate was  Initiated  (gestation
day  0)  21  days   after   Initiation  of   the first  replicate.    Sperm-positive


0020d                               6-29                              08/11/87

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 females  (14-20 animals/group  1n  each  replicate) were  exposed  by gavage  to
 TCP  suspended  In  olive oil  at  doses  of  0, 25,  100 and  200  mg/kg/day  on
 gestation  days 6-15.   Dams  were  weighed on gestation  days  0,  6  through  15
 (prior  to  dally dosing), and  on  gestation  day  20 (prior to  sacrifice),  and
 were  observed dally during  the  treatment period  and prior to sacrifice  on
 gestation  day  20  for clinical  signs  of toxldty.   On  gestation  20, dams  were
 anesthetized   with  CO.  and  sacrificed   by   cervical  dislocation.    At
 sacrifice,  dams  were  weighed  and  examined  for  gross   signs  of  toxlclty.
 Liver  weight, gravid  uterine weight,  and  status of  uterine  contents  were
 determined.   Live  fetuses  were  dissected  from  the  uterus and  Immediately
 anesthetized  by  hypothermia.  Individual live  fetuses  were  weighed,  sexed,
 and  examined  for  external   morphological  abnormalities.   All  live  fetuses
 were  examined  for  visceral  malformations  using  a  fresh  tissue  dissection
 method.  Half of  the  fetal heads were  removed, fixed  in  Bouln's solution,
 and  examined by  free  hand   sectioning of  the whole  fetal  head.   All  fetal
 carcasses  were double-stained w1h Aldan Blue/Alizarin Red S and  examined
 for   skeletal   malformations.    Results   of   this    study   Indicated   no
 statistically  significant  adverse maternal  effects  at  25  or  100 mg/kg/day.
 However, dams  1n the  100 mg/kg/day  group exhibited  a  corrected  gestatlonal
weight  gain  that was  only  87% of the  control  group,   so  that the mid-dose
 appeared  to  approach   the  low effect   level  for  this   endpolnt.   Maternal
 toxldty  was  Indicated at  200  mg/kg/day  by   a  significant  reduction   In
corrected  gestatlonal  weight gain to  74% of the  control value.   During  the
 posttreatment  period,   all   TCP-exposed  groups   consumed significantly  more
 food  than  the  control  group.   Embryo/fetal growth  and prenatal viability
were not adversely  affected by TCP exposure, nor was any definitive evidence
 obtained for  an effect  of  TCP upon fetal  morphological development.   Thus,


QQ20d                                6-30                            08/11/87

-------
 TCP  did not appear  to  be a selective developmental  toxicant  with  regard  to
 Jhn utero development of the postlmplantatlon conceptus.
     These  teratogenlclty  studies are summarized In Table 6-4.
 6.5.    OTHER REPRODUCTIVE EFFECTS
     Exon   and   Roller   (1982,  1985)  studied  the  reproductive  effects  of
 2-chlorophenol,  2,4-dlchlorophenol  and  2,4,6-trlchlorophenol  In  Sprague-
 Dawley  rats.   Groups of  12-20  female  rats were  treated  with  a chlorophenol
 In their  drinking  water from 3 weeks of  age through breeding and lactation.
 The  females were mated  at 90  days  of age with untreated males.  The drinking
 water  contained 0, 5,  50  or  500 ppm 2-chlorophenol  or 0,  3,  30  or 300 ppm
 2,4-d1chlorophenol  or   2,4,6-tMchlorophenol.   Statistical  methods  Included
 analysis  of  variance  and  chl-square  tests.   The  Investigators  considered
 results to be statistically significant If p<0.10.
     Significantly   (plO.10)  smaller  IHter  sizes   compared  with  controls
 occurred  In  rats  treated  with 500  ppm  2-chlorophenol, 300 ppm 2,4-dlchloro-
 phenol  or  300  ppm  2,4,6-tMchlorophenol.   The percent of  stillborn pups was
 significantly (p<0.10)  Increased 1n the 500 ppm 2-chlorophenol  treated group.
 In the  2,4-d1chlorophenol and  2,4,6-trlchlorophenol  groups,  the  percent of
 stillborn  pups  tended  to  be  Increased over  controls, but  the Increase was
 not  statistically   significant.   In  the  group  of  rats  given 2,4-dlchloro-
 phenol, survival  to weaning  was  significantly  (p<0.10)  less  than  controls.
 Treatment with  any  of  the chlorophenols  examined did  not  have  any  effects on
 the birth weight of pups.   No data  concerning effects  on dams  were  reported.
    Blackburn et al. (1986) examined  reproductive effects In male  Long  Evans
 hooded  rats  treated  by  gavage  with  2,4,6-trlchlorophenol.   Groups  of >15
male  rats  were  treated  with 2,4,6-trlchlorophenol  (99X pure)  In corn oil at
0, 100, 500 or  1000  mg/kg,  5  days/week  for 11 weeks.   Before  treatment  began


0020d                               6-31                              08/11/87

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     0020d
6-33
                                                                                          08/11/87

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 and  after  10  weeks  of  treatment,  copulatory  behavior  and  semen  profiles
 (sperm  count,  motlllty  and morphology)  were examined.   At 11  weeks,  the
 males  were mated  with  untreated  females.   The  females  were  sacrificed  on
 gestation  day  18 .and the  sex,  weight  and  viability  of  the  fetuses  were
 determined.  No  effect  on  male  reproduction  was  noted.   The  only  effects
 observed  were  In  the  high-dose group  1n  which  a reduction  In weight  gain
 occurred and eight rats died during the flrs.t 4 weeks of treatment.
    Blackburn  et al.  (1986)  also  studied  the  effects  of  2,4,6-tMchloro-
 phenol on  female reproduction In  groups  of  >30 rats  treated with  0, 100, 500
 or 1000  mg/kg.   The rats were  dosed  5  days/week for 2 weeks and  then mated
 with  untreated  controls.   Dally  dosing  continued   from  the  beginning  of
 mating through  gestation day  21.  The  females  were  allowed to deliver, and
 the sex  ratio  of the litter and  body weight of  the pups  were  recorded.  On
 day 4  postpartum the Utters were reduced  to eight  pups  and at  weaning the
 Utters  were   further  reduced  to four  pups  (two  males  and  two  females).
 These remaining pups were sacrificed  on day 42 postpartum.
    Body weights weVe significantly   depressed In  high-dose females (p<0.05)
 during  the 2  weeks  of  dosing  before  mating and  on  days 1,  7  and  14 of
 gestation.  The  only  other  effect  noted  was a decrease In body weight of the
 fetuses  from the 500 and 1000  mg/kg  treated groups  on  postpartum day 1.  By
 postpartum  day  4 these  differences  were  no longer  detected.  Blackburn et
al.  (1986)  stated  that  this decrease  may  have been  a  result of  a  slight
 Increase  1n Utter  size  In  the  500 and  1000  mg/kg  groups.   The  authors
concluded  that  at  maximally  tolerated  doses, 2,4,6-trlchlorophenol did  not
affect male or  female reproduction.
OQ20d                               6-34                              08/11/87

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     Seyler   et  al.   (1984)  found  that  2,5-,  3,4- and  3,5-d1chlorophenol
 significantly  (p<0.05)  depressed  sperm  penetration  of  ova  from mice  In vitro
 at  a concentration  of 1 mM.   This effect was not observed with 2,4-dlchloro-
 phenol.   In  addition,  no  effects  on  sperm penetration  of  ova were  noted
 using  sperm from mice  given drinking water  containing 2,4-dlchlorophenol  at
 0,  0.2, 0.6  or 2.0 mg/mt  for 90 days.
 6.6.   SUMMARY
     In a  subchronlc  Inhalation study of  4-chlorophenol  (Gurova,  1964),  rats
 exposed  to  2  mg/m3,  6  hours/day for  4 months showed  neuromuscular  excit-
 ability,  a  reduction  of  endurance.  Increased  myoneural  excitability,  slight
 congestion  of  organs  and minor  flbrotlc changes In alveolar  septa.  Gurova
 (1964) also  reported  symptoms  of  nervous exhaustion,  Insomnia, Irritability,
 frequent  mood  changes and rapid  fat1gab1!1ty In workers  exposed to 4-chloro-
 phenol  In  an aniline   dye  plant.   The  lack  of  detail  In   these studies
 precludes adequate assessment of  their reliability.
    Kleu  and Goltz (1971)  reported  symptoms of chloracne,  decreased  sexual
 activity,  easy   fatlgabllHy,   Irritability,   muscular   weakness,  loss  of
 appetite  and  memory,  discouragement,  alcohol  Intolerance,  and  loss  of
 Interest  In  workers  occupatlonally exposed  to a tMchlorophenol formulation
 for up to 15 years.   A  causal  relationship was not established.  Alexanders-
 son  and  Hedenstlerna  (1982)  found  pulmonary  effects  In  workers  exposed to
 low levels of trlchlorophenols In gas masks  for  up  to  10 years.
    Exon  and Keller  (1985)  found 1mmunolog1cal  effects  In rats exposed  sub-
chronically  to 2,4-d1chlorophenol at  30 and  300 ppm In  their  drinking water.
Similar effects  were  not noted  In  rats  exposed to up  to 500 ppm  2-chloro-
phenol, or   up to 300  ppm  2,4,6-trlchlorophenol.   Kobayashl   et  al.   (1972)
reported  minor hlstologlcal  changes  In  the  livers  of  mice fed 230  mg/kg/day
2,4-d1chlorophenol for 6 months.  No effects were noted  at 100 mg/kg/day.

0020d                               6-35                             08/11/87

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    A  subchronlc drinking water study of  2,4-d1ch1orophenol  In mice  found  no
 consistent  effects  that  could  be  related  to  treatment  at up  to  2  ppm
 (Borzelleca  et a"L,  1985a).   The  study  was confounded  by  the  addition  of
 Emulphor  to the dosing solution.
    McColllster et  al.  (1961)  studied  the toxlclty  of  2,4,5-trlchlorophenol.
 In  a  28-day gavage  study,  microscopic  changes were noted  In the liver  and
 kidneys of  rabbits  dosed  with 0.1 and 0.5 mg/kg but not  0.01 mg/kg  20  times
 over the  study period.   No  changes were  noted 1n rats  dosed with  2,4,5-trl-
 chlorophenol at  up to 1.0  g/kg  18 times over 24  days.  In  a 98-day  study,
 pathologic changes  In the livers  and  kidney  were  noted  1n rats  provided with
 diets containing 2,4,5-trlchlorophenol at 0.03 and 1.0% but not  at  <0.01%.
    In a  70-day dietary study, Vlzethum  and  Goerz  (1979)  reported  that 0.05%
 2,4,5-trlchlorophenol was  not porphyrogenlc  In  rats.   The NCI {1979}  sub-
 chronic  study  noted an   Increase  In   splenic  hematopolesls  and  mldzonal
 vacuolatlon of  hepatocytes  1n rats fed 2,4,5-trlchlorophenol In the diet at
 46,000 ppm  for 7 weeks.  Survival of rats  fed  >21,500 ppm  but not <14,700
 ppm was also affected.  In  mice,  survival was affected  at 31,500 ppm but not
 at  <21,500  ppm  (NCI, 1979);  no  h1stopatholog1cal  data  were   reported.   A
 dose-dependent decrease In  body weight was  observed  In  both rats and mice In
 the NCI (1979) study.
    Kawano et  al.  (1979)  observed changes  In  growth,  organ weights, several
 biochemical parameters and  liver  drug metabolizing  enzymes 1n rats  fed diets
containing  2,3,5-trlchlorophenol  or  2,3,4,5-,   2,3,5,6- or  2,3,4,6-tetra-
chlorophenol at  0.2% for 3 weeks.  Dose-related hlstopathologlc  changes  In
 the liver were  noted In rats treated  by  gavage  with  2,3,4,5-tetrachloro-
phenol  for 55  days  at >50 mg/kg/day but  not at 10 mg/kg/day  (Hattula et  al.,
 1981b).


 0020d                               6-36                              08/11/87

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     In  a chronic study, numbers of  R8C  and  hemoglobin  levels  were Increased
 In  rats provided  with  drinking water  containing  500 ppm  2-chlorophenol  or
 300  ppm 2,4-dlchlorophenol,  but not  at 10-fold lower  concentrations  (Exon
 and  Koller,  1985).   The  NCI   (1979)  found  a  dose-related  Increase In  the
 Incidences  of bone marrow  hyperplasla  and  leukocytosls  in rats  at  5000  and
 10,000  ppm.   In  mice,  dose-related  hyperplasla of  the  liver was  noted  In
 males at 5000  and  10,000 ppm (NCI, 1979).
     In  studies  of the  Induction  of  enzymes  by  the  chlorinated  phenols,
 Carlson  (1978)  found  that  2,4,5-trlchlorophenol  reduced  mlcrosomal  NADPH-
 cytochrome  c  reductase  activity  and cytochrome  P-450  content.   Oenomme  et
 al.  (1983)  reported  that  4-d1methylam1noant1pyr1ne  N-demethylase was Induced
 by   3,4,5-trlchlorophenol.   The  other  tr1- and tetrachlorophenols  had  no
 effects  on  enzyme  Induction.   The  mutagenlclty  of 2-aralnoanthracene  and
 benzo[a]pyrene were  enhanced  in an Ames assay  by  S-9 from rats treated with
 2,3,4,5-tetrachlorophenol  (Sussmuth et al., 1980).
    HHsuda  et al. (1963) observed  that the  chlorophenols Inhibit oxldative
 phosphorylatlon  ^n  vitro,  with  the  Inhibiting   activity increasing  with
 Increasing  chlorlnatlon.
    The  acute toxlclty  of  the chlorinated  phenols  has  been studied  by  a
 number of Investigators (Delchmann,  1944;  Bubnov et al., 1969; Borzelleca et
al.,  1985a,b; Farquharson  et  al.,   1958;  ChMstensen  and  Luglnbyhl,  1975;
 Oelchmann   and   Mergard,   1948;  Angel   and  Roberts,  1972;  Gurova,  1964;
Schrotter  et  al.,  1977;   Kobayashl  et al.,  1972;   Vernot  et   al.,  1977;
McColllster  et  al.,  1961;  Ahlborg  and  Larrsson,  1978;  Hattula   et  al.,
1981b);  In general, the toxlclty Increases as the chlorlnatlon  Increases.
0020d                               6-37                              08/11/87

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     Ep1dem1olog1cal  studies   that   are   confounded   by   multiple   exposures
 Indicate  that  chlorophenol  exposure  1s associated with soft  tissue  sarcomas
 and  malignant  lymphomas  (Lynge,  1985;   Cook,  1981;  Honchar  and  HalpeMn,
 1981; Pearce et aT.. 1986).
     Increased  tumor  Incidences were not  observed In  rats  exposed to up  to
 500  ppm 2-chlorophenol or up  to  300  ppm  2,4-d1chlorophenol  In  their  drinking
 water  for  2  years  (Exon  and  Keller,  1985).    Innes  et  al.  (1969)  found
 Inconclusive results  In  a carclnogenlcHy study  of  2,4,6-trlchlorophenol  In
 mice.   In  the  NCI   (1979)   study   of  2,4,6-trlchlorophenol,  an  Increased
 Incidence  of  leukemia  was  observed  1n male rats, while  an Increase  In  the
 Incidence  of  liver  carcinoma  and adenoma  was  observed  In male  and  female
 mice.
    Exon   and   Koller  (1985)   found  that   2-chlorophenol   Increased  tumor
 Incidence  and  decreased  tumor  latency  of  transplacental  tumors   In  rats
 Initiated  by   ENU.   This effect was  not  observed  with  2,4-dlchlorophenol
 although the rats were exposed to a lower level  of ENU.
    In a   study  by  Boutwell  and  Bosch  (1959),  2-,   3-chlorophenol,  2,4-dl-
 chlorophenol and  2,4,5-tMchlorophenol  acted as promoters  of  skin tumors In
mice treated with a  single  dose  of  DMBA.   2,4,6-TMchlorophenol  was negative
 In the  skin tumor promoting study.  2,4,6-Trlchlorophenol  was  also negative
 In a lung  adenoma bloassay  In which strain  A/J mice were dosed  by gavage or
 1ntraper1toneal  Injection (Stoner  et al., 1986).  Tumor  Incidences were not
 Increased  In  mice observed for  18  months  following a  single  subcutaneous
 Injection   of   2,4,5-,   2,4,6-trlchlorophenol   or   2,3,4,6-tetrachlorophenol
 (BRL, 1968a).
0020d                               6-38                              08/11/87

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     2-,  3-,  4-Chlorophenol, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-d1chlorophenol,
 2,3,5-,   2,4,5-,  2,4,6-trlchlorophenol  and  2,3,4,6-tetrachlorophenol   have
 tested  negative  In  at  least  one assay for  reverse mutation 1n !5.  typhlmuMum
 (Haworth  et  al.,  1-983;  Probst  et  al., 1981;  Simmon et al., 1977;  Rasanen and
 Hattula  1977).   Haworth et al.  (1983)  found equivocal  results for  2,4- and
 3,5-d1chloropheno1.
     In  Chinese  hamster  V79 cells, 2,4-,  2,6-d1chlorophenol,  2,4,6-trlchloro-
 phenol  and  2,3,4,6-tetrachlorophenol did  not  cause an  Increase  1n  mutation
 (Jansson  and  Jansson,. 1986;  Hattula and  Knuutlnen,  1985).  In  contrast,
 weakly  positive  results   were   noted  1n  Chinese  hamster   V79  cells  with
 2,4,6-trlchlorophenol  and 2,3,4,6-tetrachlorophenol  In  the  absence of  S-9
 but  not  1n  the  presence of S-9 (Hattula  and Knuutlnen, 1985);  2,4-01chloro-
 phenol  did  not  cause an Increase  1n unscheduled DMA synthesis In primary rat
 hepatocytes  (Probst et  al., 1981).
     An   Increase  In  chro:nat1d   deletions  was  noted   1n  rats  dosed  with
 2-chlorophenol  (Chung,  1978).   2,4,6-TMchlorophenol was  weakly  positive 1n
 a spot  test  In mice (FahMg et al., 1978).
     Teratogenlc  studies of  the  chlorinated phenols  Indicate that  the com-
 pounds  are  not  potent   teratogens although  they are fetotoxlc.  Fetotoxlclty
 as  evidenced by  Increased  embryonic death was  found for 2,4-dlchlorophenol
 at  oral  doses of 750  rag/kg/day  (Roduell   et al.,  1984) and  2,4,5-tMchloro-
 phenol  at  >9 ng/kg/day  (Neubert  and  OHlmann,  1972;  Hood et  al.,  1979;
 Chernoff  and  Kavlock,  1982).   Schwetz et  al.  (1974)  reported an Increase of
 subcutaneous  edema   In  rats  treated  through  gestation  with 2,3,4,6-tetra-
 chlorophenol  at 10 mg/kg/day.   This  effect was not observed  at 30 mg/kg/day,
although at  the higher  dose  an Increase  In delayed ossification of the  skull
bones was observed.  In a similar  study  (Research Triangle  Institute,  1987)
0020d                               6-39                              08/11/87

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where  CD  mice  were  gavaged  with  0,   25,  100  and  200 mg/kg/day  TCP  on
gestation  days  6-15,   there  were  no  adverse  effects  of  TCP  exposure  on
embryo/fetal  growth and  prenatal   viability,  nor was  there any  definitive
evidence  of  an effect  of  TCP  upon fetal morphological  development.   At  the
200  mg/kg/day  TCP  dosage,  corrected  maternal  weight gain was  significantly
depressed below controls.   The only  study  In which  an Increased  Incidence of
anomalies was  observed  was  In  a  study by BRL  (1969b) In which an Increase In
anomalies  In AKR  mice given subcutaneous Injections  of  2,4-d1chlorophenol at
74  mg/kg/day  during gestation was noted.  This  effect was  not  observed In
C57B16  mice  or  In either  strain  of mice when  they  were  treated  with 85
mg/kg/day 2,4,5-tMchlorophenol.
    Reproductive    studies   of    2-chlorophenol,    2,4-d1chlorophenol   and
2,4,6-tMchlorophenol  also  resulted In reduced Utter  sizes  of  rats treated
from  3 weeks  of  age  with >300  ppm  1n drinking water through  mating  and
lactation  (Exon  and  Keller,   1982).   Blackburn  et   al.  (1986)   reported no
significant effects on  reproduction  In  rats  treated  by gavage  with  up to
1000 mg/kg 2,4,6-trlchlorophenol  5 days/week.   In an hj. vitro  study, Seyler
et  al.  (1986)  found  that 2.5-,  3,4- and 3,5-dlchlorophenol  significantly
depressed sperm penetration of ova from mice.
0020d                               6-40                              08/11/87

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                     7.  EXISTING GUIDELINES AND STANDARDS
 7.1.    HUMAN
     Existing  guidelines  and standards for  the  chlorophenols  covered  1n  this
 document  are  given  In Table 7-1.   No  guidelines or  standards  were  located
 for  3,5-d1chlorophenol,  2,3,4-,  2,3,5-,  2,3,6- or  3,4,5-trlchlorophenol  or
 2,3,4,5- or 2,3,5,6-tetrachlorophenol.
    The  U.S.   EPA  (1978b)  Issued  an RPAR  for  2,4,5-tMchlorophenol.   The
 concern  was  based  solely  on  oncogenlclty and  fetotoxlclty  data  for  TCOD,  a
 common  contaminant  1n  2,4,5-tMchlorophenol.   U.S.  EPA   (1979b)  requested
 that additional  Information be submitted  regarding 2,4,5-trlchlorophenol/TCOD
 exposure  and  estimated  safety.   U.S.  EPA   (1986d)  stated  that all  uses  of
 2,4,5-trlchlorophenol  have been voluntarily  cancelled or suspended.
 7.2.   AQUATIC
    U.S. EPA  (1980b)  noted that  the derivation of a single criterion for all
 chlorophenols was  Inappropriate  because  of 'the wide variability In toxlclty
 of  these compounds;  therefore,  criteria  for  Individual  chlorophenols  were
 not calculated.   U.S.  EPA  (1980b)  did,  however. Identify the lowest reported
 toxic concentrations  for freshwater  and  saltwater  organisms. For freshwater
 species,  acute   toxlclty  occurred  at  concentrations  as  low  as  0.03  mg/i
 4-chloro-3-methylphenol,  a  methylated   derivative  of  4-chlorophenol,  and
 chronic  toxlclty  occurred  at concentrations as low as  0.97 mg/i 2,4,6-tr1-
 chlorophenol.    Among  saltwater  species,  acute  toxlclty occurred  at concen-
 trations as  low  as 0.44  mg/i  2,3,5,6-tetrachlorophenol.    No  data concern-
 Ing chronic toxlclty to  saltwater species were  available.
    U.S. EPA  (1980c)  summarized  aquatic  toxlclty data for 2-chlorophenol and
concluded  that  acute  toxldty  to  freshwater  species  occurred  at concentra-
 tions as  low  as 4.38  mg/i,  and  that flavor  Impairment  had been reported  In
one fish species at 2 mg/l.  No other conclusions were made.

0021d                               7-1                               06/18/87

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                                  TABLE 7-1

                  Guidelines and Standards  for  Chlorophenols
   Chlorophenol
                                Guideline/Standard
                                    Reference
2-Chlorophenol



3-Chlorophenol

4-Chlorophenol

2,3-D1chlorophenol

2,4-01chlorophenol
2,5-Olchlorophenol

2,6-01chlorophenol

3,4-01chlorophenol

2,4,5-TM Chlorophenol
2.4,6-TMchlorophenol
2.3,4,6-Tetrachlorophenol
DWEL, 0.175 mg/l
RfO, 0.005 mg/kg/day
organoleptlc AWQC,  0.1  ug/i

organoleptlc AWQC,  0.1  yg/l

organoleptlc AWQC,  0.1  yg/i

organoleptlc AWQC,  0.04 »g/l

DWEL, 0.105 mg/l
RfO, 0.003 mg/kg/day
RfO, 0.003 mg/kg/day
health AWQC, 3.09 mg/l
organoleptlc AWQC,  0.3 vg/l

organoleptlc AWQC,  0.5 yg/l
                            organoleptlc AWQC, 0.2
organoleptlc AWQC, 0.3 wg/l

oral RfO, 0.1 mg/kg/day
RfO$g, 70 mg/day
RfOQ, 7.0 mg/day
health AWQC, 2.6 mg/l
organoleptlc AWQC, 1.0 yg/l

qi*. 0.0114  (mg/kg/day)"1
10~s risk level, 3.07xlO"2 mg/l
q-j*. 0.01984 (mg/kg/day)"1
10~» risk level, 36 Mg/l*
organoleptlc AWQC, 2.0 wg/l
q-|*, 0.0198  (mg/kg/day)"1

organoleptlc AWQC. 1.0 wg/l
oral RfO, 0.01 mg/kg/day
                                                              U.S.  EPA,  1986b
                                                              U.S.  EPA,  1986b
                                                              U.S.  EPA,  1980c
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
EPA,
EPA,
EPA,
EPA,
EPA,
ERA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA.
EPA,
EPA,
EPA,
EPA.
1980b
1980b
1980b
1986b
19865
1986c
19804
1980d
1980b
1980b
1980b
1985a
1984a
1984a
1980b
1980b
1986b
1986b
198Qb
1980b
1980b
                                                              U.S. EPA, 1984b

                                                              U.S. EPA. 1980b
                                                              U.S. EPA, 1985b
*Assum1ng  consumption  of  2 I/day  drinking  water  and  6.5  g/day  fish and
 shellfish.
0021d
                                    7-2
                                          06/18/87

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     U.S.  EPA (1980d) summarized aquatic  toxlclty  data  for  2,4-d1chlorophenol
 and concluded that acute and chronic toxlclty  to  freshwater  species  occurred
 at concentrations  as  low as  2.02 and  0.365  mg/l, respectively.   Mortality
 to early life  stages  of one  fish  species  occurred at concentrations  as  low
 as 0.07 mg/i.   No data  concerning  2,4-d1chlorophenol  toxlclty  to  saltwater
 species  were available.
     U.S.  EPA  (1980b,c,d)  did  not  recommend  criteria  for  the  chlorinated
 phenols  for  the protection of aquatic  life, but stated  that  lower concentra-
 tions  might  be  toxic  to  species  more  sensitive than those that  were tested.
0021d                                7-3                              06/18/87

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                              8.  RISK ASSESSMENT
 8.1.    CARCIN06ENICITY
 8.1.1.    Inhalation.   Ep1dem1o1og1cal  studies  provide limited evidence  that
 occupational  exposure to  chlorophenols  may be  associated with  soft  tissue
 sarcomas  and  malignant  lymphomas  although the  Influence of  chlorophenols
 alone  cannot  be determined.   Lynge  (1985)  found an  Increase  1n  soft  tissue
 sarcoma  \n  male workers exposed  to  2,4-d1chlorophenol  and 4-chloro-o-cresol
 based  phenoxy  herbicides.   In a  case-control  study, Pearce  et al.  (1986)
 reported  an  Increased  risk  of non-Hodgklns  lymphoma   In  New Zealand  meat
 workers exposed to chemicals Including 2,4,6-tMchlorophenol.   These studies
 are confounded  by  some small study populations and multiple exposures.
    Other data  concerning  the cardnogenlcHy  of the chlorophenols  following
 Inhalation  exposure  could  not  be located  In   the  available literature  as
 cited In Appendix  A.
 8.1.2.   Oral.   Exon  and   Koller  (1985)   reported  negative  results   In   a
 cardnogenlcHy  study  of   2-chlorophenol   and   2,4-dlchlorophenol   1n  rats.
 Rats  exposed  to  the compounds  J_n utero were  provided with  drinking  water
 containing  2-chlorophenol  at 0, 5,  50 or   500 ppra,  or  2,4-d1chlorophenol  at
 0, 3, 30 or 300 ppm for up to 24 months.
    Results of  a  cardnogenlcHy  study of 2,4,6-tMchlorophenol  (Innes  et
 al., 1969;  BRL, 1968a; IARC.  1979)  were Inconclusive.  Two  strains (B6C3F1
 and B6AKF1) of  male and female mice  were  treated with  2,4,6-trlchlorophenol
 at  100  mg/kg/day  by  gavage  starting at 7  days  of age.   After  weaning, the
mice were  provided  with  diets  containing  2,4,6-trlchlorophenol at  200 ppm
 for  -18  months.   IARC  (1979)   stated  that   the  combined  Incidences  of
 hepatomas  and  retlculum-cell  sarcomas  In   male  and  female B6C3F1  mice were
 Increased  significantly (p<0.05),  but that  the significance disappeared when
 the data for males and females were considered separately.

0022d                               8-1                              08/11/87

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     The  NCI   (1979)  oral  carclnogenldty  study  of  2,4,6-trlchlorophenol
 reported  dose-related statistically  significant  Increases  In the  Incidence
 of   leukemia  In  male  F344  rats  and  the  Incidence  of  liver carcinoma  and
 adenoma  1n  male  and female B6C3F1 mice.  Male and female rats and  male  mice
 were fed diets containing  2,4,6-trlchlorophenol at 0,  5000  or 10,000  ppm for
 up  to 106  weeks,  while female mice were  fed  TWA  doses of 0,  5214  or  10,428
 ppm  for 105 weeks.
 8.1.3.   Other  Relevant  Information.    Exon  and  Koller   (1985)   observed
 Increased   tumor . Incidence  and  decreased  time-to-tumor  latency  1n  male
 offspring of  rat  dams exposed  orally to 2-chlorophenol both  pre-  and post-
 natally  and  treated  orally with  ENU  during gestation  compared  with  rats
 given  ENU  alone.   This effect  was  not observed  In  rats  exposed to  ENU and
 2,4-d1chlorophenol.
     Boutwell  and  Bosch (1959)  found  that  2-,  3-chlorophenol, 2,4-dlchloro-
 phenol and  2,4,5-tMchlorophenol  applied to  the  skin  promoted the formation
 of skin  tumors  In mice following a single  application of DHBA.   This effect
 was  not observed  with  2,4,6-trlchlorophenol.   This  study  has been  criticized
 on  the basis  of  severe   Irritation  caused  by   the  high  concentrations  of
 chlorophenols  used  and  the  reporting  of  only  gross pathological   results
 (U.S. EPA,   1980c).
     2,4,6-Trlchlorophenol   tested  negative  In  a  mouse  lung adenoma bloassay
 by both  oral  and  Intraperltoneal  routes  of  exposure  (Stoner et al., 1986).
The  mice were treated over an 8-week period  with a  total dose of  1200  mg/kg
 In  the oral  experiment  and 1200,  600  or  240 mg/kg  1n  the  Intraperltoneal
experiment.   After  dosing,  the mice  were maintained  for  16 weeks when  they
were examined for tumors.
0022d                               8-2                               06/18/87

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     BRL  (1968a)  found  no  Increased  tumor  Incidences  In  mice  given  single
 s.c.   Injections  of  2,4,5-,  2,4,6-tMchlorophenol  or  2,3,4,6-tetrachloro-
 phenol  and  observed  for  -18 months.   The exposure  levels  used were  1000
 mgAg  2,4,5-tMchlorophenol, 464  mg/kg  2,4,6-tMchlorophenol  and 100  mg/kg
 2,3,4,6-tetrachlorophenol.
 8.1.4.   Height  of  Evidence.  The only available carclnogenlclty  study  of  a
 monochlorophenol  1s  a- negative  drinking  water  study of  2-chlorophenol  In
 mice  (Exon and  Keller,  1985).   Studies by  both  Exon and  Keller  (1985)  and
 Boutwell  and Bosch  (1959)  Indicate that  2-chlorophenol  may be  a promoter.
 The  study  by  Boutwell  and  Bosch  (1959)  also  Indicated  that  3-chlorophenol
 may  be  a  promoter.   No  human  data  concerning  the  carclnogenlclty of  the
 monochlorophenols were  available.  The  limited data concerning the  carclno-
 genlclty  of  the  monochlorophenols Indicate  that 2-,  3-  and  4-chlorophenol
 should be  classified  as CAG Group  0  chemicals  (U.S. EPA,  1986e), Inadequate
 human and animal evidence of carclnogenlclty.
    2,4-01chlorophenol  tested negative  1n  an oral  carclnogenlclty  study In
 mice   (Exon  and  Koller,  1985).   In  addition  2,4-d1chlorophenol  tested
 negative  In  a  promotion  study using  EMU  (Exon  and  Koller,  1985),  although
 Boutwell  and  Bosch  (1959)  found  positive  results  for   the   promotion  of
 DMBA-lnduced skin tumors  In mice.   The ep1dem1olog1cal study by Lynge (1985)
 Indicates  that   there  may  be  an  association  between  the  chlorophenols and
 soft  tissue  sarcomas.   Because  of exposures  to other  chemicals,  however,
 this study -Is  considered Inadequate evidence  of  human carclnogenlclty.  The
remaining dlchlorophenol  Isomers  (2,3-, 2,5-,  2,6-,  3,4-  and  3,5-)  have not
been*   tested   for  carclnogenlclty.    The  lack  of   data  concerning  the
carclnogenlclty  of  the  dlchlorophenols  Indicate that  they should  also be
classified as CAG  Group D  chemicals  (U.S.  EPA,  1986e), Inadequate human and
animal  evidence of carclnogenlclty.

0022d                               8-3                              08/11/87

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     Pearce  et  al.  (1986)  reported  an Increase  In  the risk of  non-Hodgk1ns
 lymphoma  In New  Zealand  meat workers exposed  to 2,4,6-trlchlorophenol and
 other  chemicals.   This  study provides Inadequate evidence of human  cardno-
 genldty  of  2,4,6-trlchlorophenol.  The  Increased Incidence of hepatomas and
 retlculum-cell  sarcoma  In  B6C3F1  mice (BRL, 1968a)  suggests that  2,4,6-trl-
 chlorophenol  may  be  a  carcinogen.    Further  evidence that  2,4,6-trlchloro-
 phenol  Is a  carcinogen  Is  provided  by  the  NCI  (1979)  study.  In which  an
 Increased  Incidence  of  leukemia was  observed In male  rats, and  an  Increased
 Incidence of hepatomas was observed 1n male  and  female mice.  The  NCI  (1979)
 study  provides  sufficient  animal  evidence  of cardnogenlclty of  2,4,6-trl-
 chlorophenol.   Therefore,  according   to  the  CAG classification  scheme  (U.S.
 EPA,  1986e)  2,4,6-trlchlorophenol  can be classified  as  an EPA  82  chemical,
 probable human carcinogen.
    The   remaining   tMchlorophenols   (2,3,4-,   2,3,5-,   2,3,6-,  2,4,5- and
 3,4,5-)  and the  tetrachlorophenols   (2,3,4,5-,  2,3,4,6- and 2,3,5,6-)  have
 not  been  adequately studied  1n cardnogenlclty bloassays.   Therefore,  these
 compounds are  placed In EPA Group  0  (U.S.   EPA,  1986e),  Inadequate evidence
of human and animal cardnogenlclty or no data available.
8.1.5.   Quantitative Risk Estimates.
    8.1.5.1.   INHALATION — There  were   no  Inhalation  studies  concerning
 the  cardnogenlcUy  of   2,4,6-trlchlorophenol   located  In  the  available
 literature cited  In  Appendix A.   The  NCI (1979)  oral  bloassay Indicates that
2,4,6-trlchlorophenol 1s an animal carcinogen by 1ngest1on.
    8.1.5.2.   ORAL — The   NCI    (1979)   oral   bloassay   Indicates   that
2,4,6-trlchlorophenol Is a carcinogen 1n rats and mice.   Male  rats and mice
were  provided   with  diets  containing 2,4,6-trlchlorophenol  at 0,  5000  or
10,000  ppm  for  up  to  107  weeks.   In  male  rats, the  Incidences of leukemia
                                                    e

0022d                               8-4                              08/11/87

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 were  4/20 controls, 25/50  low  dose  and 28/50 high dose.   In  male  mice,  the
 incidences  of  liver carcinoma or adenoma were 4/20  controls,  32/49 low dose
 and  39/47 high  dose.   Both  tumor Incidences  are  statistically  significant by
 the  Cochran-ArmUage test  for  linear  trend  and  the Incidences  of the treated
 groups  are  statistically   significant  by  the  Fisher  Exact  test.   Further
 details of  this study were  presented 1n Section 6.2.2.
    Values  for q  * can  be calculated  using the  data  for  Increased  Inci-
 dences  of leukemia, leukemia or  malignant  lymphoma  In  male rats  or hepato-
 cellular  adenoma  or  carcinoma  1n  male  mice  In  the  NCI  (1979)  studies
 (Appendices  B-l,  B-2 and  B-3).   Dietary concentrations were  transformed to
 mg/kg/day  by multiplying by a factor of  0.05 for  rats  and 0.13 for mice (It
 Is assumed  that  rats and mice consume  a  dally amount of food  equal to 5 and
 13%,  respectively,  of  their body  weight).   The unadjusted  q,*s were calcu-
 lated  using the computerized  multistage model  developed  by  Howe  and Crump
 (1982).   The  human  q *s   were  calculated   by  multiplying  the   unadjusted
 q,*s  by  the cube   roots  of the  ratios of  the  reference  human body weight
 (70 kg)  to the animal  body weights (0.36  kg for  male  rats and 0.04 kg for
 male  mice,  as  estimated  from  growth  curves   1n   the  study).    The   most
 conservative   q *   of    1.94xlO~a   (mg/kg/day)"1  was   obtained  using  the
 data  for  hepatocellular  adenoma/carcinoma  In male mice.   Using the q^ and
 assuming  that  a 70 kg  man consumes  2 l  water/day, the  concentrations  In
 drinking  water  corresponding to  Increased lifetime  risk  of  cancer at  risk
 levels    of    10"5,   10"»   and   10"7   are    1.8xlO"a,   1.8xlO~»   and
 1.8x10"* mg/l.
    In  deriving   a q,*  of  1.4xlO~a  (mg/kg/day)"1   for  2,4,6-trlchloro-
phenol, U.S. EPA  (1986b) used  the leukemia  Incidence  levels  In male  rats.
0022d                               8-5                               08/11/87

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 The  reason  that  the  leukemia  Incidences,  rather  than  the  Incidences  of  liver
 tumors  1n male  mice  were used was  not  discussed.   U.S.  EPA  (1980b, 1984b)
 derived  a  q,*  of  1.98xlO~2   (mg/kg/day)'1  using  the  liver  tumor  data  In
 male  mice.   The reason  for the  small  difference In q,* derived  In  Appendix
 B-3 and  that  derived  by  U.S.  EPA  (1980b,  1984b)  1s  not  apparent;  however.  It
 may  be  due to differences  In  the multistage model  program  (GLOBAL  79)  used
 by U.S. EPA (1980b) and GLOBAL 82, used In Appendix  B.
 8.2.   SYSTEMIC TOXICITY
 8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME  EXPOSURES  (SUBCHRONIC) -- The  lack  of
 data  concerning subchronlc  Inhalation  toxldty  of  the  chlorophenols  pre-
 cludes the  derivation of Inhalation RfOs  for all  18 chlorophenol  congeners
 discussed In this document.
    The  only  subchronlc Inhalation  study  available  was   a  Russian  study
 concerning  the  toxldty  of  4-chlorophenol   In  rats  (Gurova, 1964).  .This
 study  (see  Section 6.1.1.1.)  examined  the Inhalation  toxlclty of  4-chloro-
                                  *
 phenol at  one  dose  In  an  unstated number  of white  rats.   No  Information
 concerning control rats  was provided.   In rats exposed to  4-chlorophenol  at
 2 mg/m3,  6  hours/day for  4  months, changes  In weight  gain, neuromuscular
 excitability,  reduction  In  endurance.  Increased  myoneural  excitability,
 slight congestion of  organs and minor  flbrotlc changes  1n the alveolar septa
 of  some   rats  were  noted.    Because  the  significance  of  these   effects  Is
uncertain,  and  because   there  are  no  supporting  data,  this  study  Is   not
appropriate for risk assessment.
    8.2.1.2.   CHRONIC   EXPOSURES -- Data   concerning   chronic   Inhalation
exposure to the  chlorophenols  were  not  available;  therefore,  chronic Inhala-
 tion RfOs cannot be derived.


0022d                               8-6                               08/11/87

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 8.2.2.    Oral  Exposures.   The lack  of  data  concerning the oral  tox1c1ty  of
 3-,  4-chlorophenol,  2,3-,  2,5-,  3,4-,  3,5-d1chlorophenol,   2,3,4-,  2,3,5-.
 2,3,6-,   3,4,5-tMchlorophenol,  2,3,4,5- and  2,3,5,6-tetrachlorophenol  pre-
 cludes  the  derivation of  subchronlc  and  chronic  oral  RfDs.  U.S.  EPA (1986g)
 proposed  an RfD of  0.003  mg/kg/day  for 2,6-dlchlorophenol based  on analogy
 to  2,4-d1chlorophenol  (Section  8.2.2.2.),  but  this  RfD  has  not  yet  been
 verified.   While  It  may be possible  to derive RfOs for 3- and 4-chlorophenol
 by  analogy  to  2-chlorophenol;  for  2,3-,  2,5-, 3,4- and 3,5-d1chlorophenol  by
 analogy   to  2,4-d1chlorophenol;  for  2,3,4-,  2,3,5-,   2,3,6- and  3,4,5-trl-
 chlorophenol  by  analogy  to  2,4,5-trlchlorophenol;  and  for  2,3,4,5- and
 2,3,5,6-tetrachlorophenol  by  analogy  to  2,3,4,6-tetrachlorophenol,  because
 of  the  lack of  data regarding  toxlclty and  cardnogenlcHy of  the chlori-
 nated phenols  specified above,  H would  not  be prudent  to  base  their risk
 assessments  on  analogy to a  single  Isomer within  the  groups  of  mono-, d1-,
 tr1- and  tetrachlorophenols.   2,4,6-Tetrachlorophenol  was   carcinogenic  to
 rats  and  mice  (NCI,.  1979}  and   results  of  a   cardnogenlcHy   study  of
 2,4-d1chlorophenol are  forthcoming (NTP, 1986).
    8.2.2.1.   LESS  THAN  LIFETIME  EXPOSURES  (SUBCHRONIC)  — Subchronlc oral
 toxlclty  studies  of 2-chlorophenol  1n which  adequate  parameters  of toxldty
were  examined  are  not  available.    Exon  and  Koller  (1983a, 1985)  found no
 limunologlcal effects  1n  rats  exposed  both pre- and postnatally to  2-chloro-
phenol  In  their  drinking water at levels  up to  500 ppm for 12-15 weeks.  In
a reproductive  study, Exon and Koller  (1982)  found reduced Utter  sizes  and
an Increase  In  the  number  of stillborn pups from dams  provided with drinking
water containing 2-chlorophenol   at  500  pom from 3  weeks  of  age  through
breeding and lactation.  No effects were noted at  50 ppm.
0022d                               8-7                               08/11/87

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     U.S.  EPA (19865) used  the  reproductive NOAEL of  50  ppm  to calculate a
 chronic  RfD of  0.005 mg/kg/day  or 0.4  mg/day  for a  70  kg human.  Because
 little  confidence can  be  placed  In  the  subchronlc  toxldty  data  base of
 2-chlorophenol,  the  chronic oral  RfD (Section  8.2.2.2.)  will  be adopted as
 the  subchronlc oral RfO.
     In  a  subchronlc  dietary  study  of  2,4-dlchlorophenol  In mice, Kobayashl
 et al.  ("1972)  found  a  NOAEL for hlstologlcal liver effects at  2000  ppm  (100
 mg/kg/day).   Exon and   Keller  (1985)   reported  a NOAEL  for  Immunologlcal
 effects In  rats  of 30  ppm  2,4-dlchlorophenol In  the drinking water.   At  300
 ppm.  Increased  serum antibody levels and  a decrease In delayed  type  hyper-
 sensHWHy  response was  observed.  The   rats  were  exposed  both  pre- and
 postnatally.
    Using  the  Exon  and  Keller  (1985)  study,  U.S.  EPA  (1986b,c) derived  a
 chronic RfO for 2,4-dlchlorophenol.  Assuming  a  rat  dally  water Intake  of
 10%  the  rat  body weight,  an  experimental  dose of  0.3 mg/kg bw/day  was
 estimated.   Applying an uncertainty  factor  of  100  (10  for  1nterspec1es
 extrapolation and  10 to protect sensitive  Individuals)  a human  chronic  RfO
of 0.003  mg/kg/day or 0.2 mg/day  for a 70  kg human  Is derived.   This  RfO Is
adopted for subchronlc   oral  exposures  as   well.   Confidence  In  this  RfO Is
 low;  the  endpolnts examined In  the study are not commonly  used In the deri-
vation of human  health risk,  and the other  toxldty  studies  of 2,4-dlchloro-
phenol did  not examine a variety of parameters.
    The only subchronlc  oral  study of  2,4,5-tMchlorophenol  Is  the  study by
McColUster et  al. (1961)  In  which young  rats  were  fed  diets containing the
compound  at 0,  0.01, 0.03, 0.1,  0.3 or 1.0%  for 98  days.   No effects were
noted 1n  the 0.1X  group,  while  at  higher levels mild pathological changes  1n
the  kidneys and  liver  were  observed.   Using  this  study,  U.S.  EPA  (1984a)


0022d                               8-8                              08/11/87

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 calculated  a subchronlc RfD.  An  animal  Intake of  100  mg/kg/day  was  calcu-
 lated  from  the  0.1% group  assuming that  young,  growing rats  consume  food
 equivalent  to  10X of their  body  weight/day. Dividing this value by an  uncer-
 tainty  factor  of  TOO  (10 for  Interspecles extrapolation and  10  to protect
 sensitive  Individuals),  a subchronlc  oral  RfO of  1 mg/kg/day  or  70  mg/day
 for  a  70 kg human 1s derived.   Confidence  1n  this  RfO  Is medium because the
 study was  well-conducted.  The only other studies concerning  the toxlclty of
 2,4,5-trlchlorophenol  are teratogenlcHy  studies   (BRL,  1968b; Neubert  and
 DUlmann,  1972;   Hood  et  al.t   1979;  Chernoff and  Kavlock,  1982)  In  which
 fetotoxlc  effects were  noted In mice  at  doses similar  or  higher  than  the
 NOAEL found  In the McColllster et al. (1961) study.
     Data  concerning  the  toxldty  of 2,4,6-tMchlorophenol  Indicate that It
 Is a carcinogen  (NCI,  1979); therefore,  a  risk  assessment based on carclno-
 genlclty 1s  presented 1n Section 8.1.5.
     Hattula  et  al.  (1981b)  found  hlstopathologlc  changes In  the  livers of
 rats  treated  by gavage  with   2,3,4,6-tetrachlorophenol  at  50  and  100
 mg/kg/day  for  55  days.   No  changes  In  the  liver  parenchyma  were  noted In
 rats treated at  10 mg/kg/day.  Whether  other changes In  the liver were noted
 was  not stated.
     In a teratogenlcHy  study, Schwetz  et al.  (1974) observed an Increase In
 the  Incidence  of  delayed ossification  of   the  skull  bones  In fetuses  from
 dams treated by  gavage  with 2,3,4,6-tetrachlorophenol at 30 mg/kg on  gesta-
 tion days  6-15.   At  10  mg/kg,  a significant  Increase  In subcutaneous edema
was noted. This change was not noted In the  30 mg/kg rats.
    Based on these two  studies of  2,3,4,6-tetrachlorophenol, 10 mg/kg may be
a NOAEL  In rats.   Dividing  the NOAEL by an  uncertainty  factor  of 100,  10 for
 Interspedes  extrapolation  and  10  to  protect  sensitive  Individuals,   the
 subchronlc  oral   RfD  of  0.1  mg/kg/day  or   7  mg/day  for a  70 kg  human  Is

0022d                               8-9                              08/11/87

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             UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                      OFFICE OF RESEARCH AND DEVELOPMENT
                   ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
                                CINCINNATI. OHIO 45268

                               August  20,  1987
SUBJECT: Health and Environmental Effects Document
[V
FROM:    Chris DeRosa
         Chief
         Chemical Mixtures Assessment Branch,  ECAO-CIn
TO:      Matthew Straus
         Chief, Waste Characterization Branch
         Office of Solid Waste (WH-562B)

THRU:    Steven 0. Lutkenhoff ^"      /       /   '
         Acting Director    '--TTT. - <   'A  /  //
         Environmental Criteria and Assessment  Offlce-CIn
                                  ^
         Peter W. Preuss    \ u ,  \ r^^    S£p   8 I98T
         Director
         Office of Health and Environmental Assessment (RD-689)
    Attached please find two unbound copies of the Health and Environmental
Effects Document (HEED) for:

    Chlorinated Phenols (ECAO-Cln-6013)

    This document represents scientific summaries of the pertinent available
data on the environmental fate and mammalian and aquatic toxlclty of each
chemical at an extramural effort of about 10K.  This document received
Internal OHEA, OPP and OTS reviews as well as review by two external
scientists.  Any part of this document's files (e.g., drafts, references,
reviews) 1s available to you upon request.

Attachments

cc: M. Callahan (RD-689)
    P. Durkln, Syracuse Research Corporation (w/enclosures)
    W. Farland (RD-689)
    R. Hardesty (RD-689)
    J. Kooyoomjlan (WH-548B) (w/enclosures)
    E. HeNamara (PH-211A) (w/enclosures)
    D. McK1e (WH-562) (w/enclosures) .
    J. Moore (RD-689)
    M. Lee (WH-562) (w/enclosures)
    M. Pfaff (RO-689) (w/enclosures)
    R. Rubensteln (WH-562B)
    R. Scarberry (WH-562B)
    0. Vlllarl (WH-562B) (w/enclosures)
    C. Zamuda (WH-548D)

-------

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                                                          FINAL DRAFT
              United States                                     ECAO-C1N-G013
              Environmental Protection                               »,.nnc+  TOUT
              Agency                                        August, 1987
vEPA       Research  and
              Development
              HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
              FOR CHLORINATED PHENOLS
              Prepared for
              OFFICE OF  SOLID WASTE AND
              EMERGENCY  RESPONSE
             Prepared  by
             Environmental Criteria and Assessment Office
             Office of Health and  Environmental  Assessment
             U.S. Environmental  Protection Agency
             Cincinnati,  OH  45268
                          DRAFT: DO NOT CITE OR QUOTE
                                  NOTICE

           This document Is a preliminary  draft. It has  not been formally released
        by the U.S. Environmental Protection Agency  and should  not at this stage be
        construed to represent Agency policy.  It Is being circulated  for comments
        on Its technical accuracy and policy Implications.

-------
                                  DISCLAIMER

    This report  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.
                                       11

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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
 Is  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 from Agency Program Office  files  are evaluated as they
 pertain  to potential human health,  aquatic  life and environmental effects of
 hazardous  waste constituents.  The literature  searched  for In this document
 and  the  dates searched  are Included  1n "Appendix:  Literature  Searched."
 Literature search  material  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,  for  example, one  that does
 not  constitute a significant portion  of the Hfespan.  This type of exposure
 estimate  has   not been extensively used,  or rigorously  defined  as previous
 risk   assessment   efforts   have   focused  primarily   on   lifetime  exposure
 scenarios.   Animal  data  used   for  subchronlc  estimates  generally reflect
 exposure  durations   of  30-90 days.   The  general  methodology   for  estimating
 subchronlc RfOs  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.    A
 carcinogenic   potency  factor,   or  q-j*   (U.S.   EPA,   1980a),   Is  provided
 Instead.  These potency estimates  are derived  for both  oral   and  Inhalation
 exposures  where possible.   In  addition, unit  rlsic   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 hazar-
 dous substance for  which  notification  Is required In the  event of a release
 as specified under  the CERCLA.   These two RQs (chronic  toxlclty  and cardno-
 genlclty)  represent  two  of six  scores  developed (the remaining  four reflect
 1gn1tab1l1ty,  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 1n  U.S.
 EPA, 1983a and 1986a,  respectively.
                                       11

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                               EXECUTIVE SUMMARY

    All  the  chlorophenols discussed with  the  exception of  2-chlorophenol  are
crystalline  solids  at  room temperature.   The monochlorophenols are  slightly
soluble  1n water,  but  as the number of chlorine  substitution  Increases,  the
higher substituted phenols become less and  less soluble  In  water.   Thus,  the
d1-,  trl- and  tetra-substltuted  chlorophenols   are -sparingly   soluble   1n
water.   These  compounds  are,  In general,  soluble 1n ethanol,  ethyl  ether or
benzene  {Verschueren,  1983;  Weast, 1980).   The presence  of  chlorophenols
Imparts  unpleasant  taste  and   odor   In  water.   The  taste  threshold  for
2,3-d1chlorophenol  1s  0.00004  mg/i  (Verschueren,   1983).   Currently,  five
companies  1n  as  many  locations manufacture   chlorophenols  In  the  United
States.  The current  annual  U.S.   production  volumes  for  the  chlorophenols
are not  available.   The  estimated  annual  world production  volume  of chloro-
phenols  1s 150 kllotons  (Hutzlnger  et  al.t  1985).   Chlorophenols  are commer-
cially produced  either by direct chloMnatlon  of phenol or  by  the alkaline
                              *
hydrolysis of  polychlorobenzenes  (Kozak  et  al.,  1979).   Trace amounts of
highly toxic polychloMnated d1benzo-p-d1ox1ns  and dlbenzofurans  have been
found as contaminants In  some  commercial  chlorophenols (Hutzlnger  et al.,
1985).   The  monochlorophenols  are  primarily used 1n the  synthesis  of higher
chlorinated  phenols.   The  higher chlorinated phenols are  used as germicides
and  as  Intermediates   1n   the   manufacture  of   pesticides   (KMJgsheld  and
Vandergen,  1986; Kozak-et al., 1979).
    The  two  Important  processes  that  may  have  a significant  effect on the
fate of  chlorophenols  In water  are  photolysis and blodegradatlon. The  photo-
lytlc half-lives  of 4-chloro-,  2,4-d1chloro- and  2,4,5-trlchlorophenols at
the top  surface of  distilled water under  midday  sunlight  Irradiation  were
                                      1v

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 estimated  to  be  2.6 days,  0.8  and 0.5  hours,  respectively (Hwang et  al.,
 1986).   From an  outdoor  pond experiment,  Suglura  et  al.  (1984)  estimated the
 photolytlc  half-life of  2,4,6-tMchlorophenol  at  a  depth of  10  cm to  be  4
 days.  The photolysis  of chlorophenols will  be  Important  In clear  shallow
 bodies  of water,  but  as the  depth and  turbidity  of  water Increase,  the
 Importance  of photolysis  will  decrease  because  of  light attenuation.   The
 blodegradatlon  half-lives  of  chlorophenols  In  natural waters  range  from
 >1-17 days.   The  half-life  values  Increase  as  the number of  chlorine substi-
 tutions  Increases and  the temperature  of  the  water decreases.  The half-lives
 of  the  compounds  also  decrease  In  sediments of  surface waters because of the
 presence of  a  greater  number of  microorganisms  (Lee  and  Ryan,  1979; Banerjee
 et  al.,  1984;  Hwang  et  al.,  1986).   Hydrolysis and  evaporation are  not
 likely  to  be Important processes for chlorophenols  In water (Krljgsheld and
 Vandergen,  1986).   Oxidation may  be  a  significant  process  In  water  but
 experimental  data on  such  reactions could not  be located  In  the  available
 literature.   The .removal  of  chlorophenols  from water  by  sorptlon  onto
 suspended sol Ids  and sediments may  be  Important and  will depend on the pH of
water and  the organic  content  of  the  sorbents.   Sorptlon  will  Increase at
 lower pH and  higher  organic  content of the  sorbents,  and will also be higher
 for higher chlorinated than  lower  chlorinated  phenols  (Schellenberg et al.,
 1984;  Isaacson and  Fink, 1984;  KMjgsheld  and  Vandergen.  1986).  Experi-
mental  data  Indicate that mono- and dlchlorophenols  will  not bloconcentrate
but that  the higher chlorinated phenols  may  bloconcentrate  significantly  In
aquatic  organisms  (VeUh et  al.,   1980;  Kobayashl  et al.,  1979;  Hattula  et
al., 1981a; Vlrtanen and Hattula, 1982).

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     In  the atmosphere,  the  chlorophenols  are  likely to undergo  significant
 photolysis  (Korte  and Klein,  1982).   Based on  the  rate  constant of  phenol
 reaction  with OH  radicals  In  the  atmosphere  (Atkinson,  1985),  1t  1s  con-
 cluded  that  such  reactions  may  be  significant  for the  lower  chlorinated
 phenols.  The  detection of  these compounds  1n rainwater and  snow  Indicate
 that  they  will be  removed  from the  atmosphere  by  wet deposition  (Leuenberger
 et al:, 1985b; Paas1v1rta  et  al., 1985a).
    Based  on  data  regarding  chlorophenols  In  water, photolysis,  hydrolysis
 and  evaporation will  not  be  significant processes In soils.   The two  Impor-
 tant  processes  In  soil  are  sorptlon  and  blodegradatlon.   While 2-chloro-,
 4-chloro-,  2,4-dlchloro- and  2,4,6-trlchlorophenols  were  found  to be  easily
 biodegradable 1n a natural soil, 3-chloro-, 2,5-d1chloro-,  2,4,5-trlchloro-
 and  2,3,4,6-tetrachlorophenols were persistent  In  soil  (Alexander and  Aleem,
 1961).  The sorptlon  of chlorophenols In soils Increases with a decrease 1n
 soil  pH and Increase  In chlorine substitution.   Chlorophenols  are especially
 susceptible to  leaching  from  sandy soils  and  soils with pH  >10 (Schwarzen-
 bach  and Hestall,  1985; Sutton and  Barker,  1985;  Boyd,  1982;  Johnson et al.,
 1985).
    Although  chlorophenols  have  been detected  In  municipal   and Industrial
effluents  (Xle  et  al., 1986;  Krlngstad and Llndstrom, 1984;  Ellis  et al.,
1982; Callahan et  al., 1979),  1n urban runoff  water  (Cole  et al., 1984), and
 1n surface  and groundwater  near effluent discharge  and waste  disposal  sites
 (Valo  et  al., 1984;  Bedlent  et  al.,  1984; Salklnoja-Salonen  et al.,  1984;
Hatanabe et al., 1985; X1e et  al.,  1986),  these compounds  have  been detected
 Infrequently  1n  drinking  waters.  According to  Callahan et  al. (1979), the
 frequency  of  detection  of  chlorophenols 1n U.S.  tap waters was  0%.   Kopfler
et  al.  (1977),   however,  qualitatively  detected  2,4-dl-,   2,4,5-tr1- and
                                      v1

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 2,4,6-trlchlorophenol   In  U.S.  drinking   waters.    2-Chloro-,   4-chloro-,
 2,4-d1chloro- and  2,4,6-trlchlorophenol  at  respective  maximum concentrations
 of  39, 34,  17  and 60  ng/i have been  detected  1n Canadian  drinking  waters
 (S)thole  et  al.,  1986).   A few of these compounds  have also been detected In
 waters  from England,  the Netherlands  and  Germany  (Crathorne et  al.,  1984;
 Krljgsheld and  Vandergen,  1986).  The  available  data  are Inadequate to esti-
 mate  the  dally  exposure  of a  U.S. Individual to these compounds by Ingestlon
 of drinking  water.
    2,4,5-TMchlorophenol  was  detected  In  air  samples  In  Love  Canal,  NY,
 (Mauser   and  Bromberg,    1982)   and   2-chloro-,   4-chloro.-,   2,6-
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     In  general,  the  toxlclty  of  chlorinated  phenols   to   aquatic   biota
 Increases  with  Increasing chloMnatlon  (U.S.  EPA, 1979a, 1980b,c).  This  Is
 probably  due to higher uptake  of  the more chlorinated compounds  (Kobayashl
 et  al., 1979).   The  toxlclty  of  chlorophenols also  Increases with  decreasing
 pH   (Konemann  and  Musch,  1981;  Saarlkoskl   and  Vlluksela,   1981,   1982).
 Structure-activity   studies   with   aquatic  organisms  Indicated   that   the
 presence  of  chloro  substHuents  1n  the  ortho  position decreased  toxlclty,
 while  substHuents  In  the  para position  Increased  toxlclty  (Oevlllers  and
 Chambon, 1986; Rlbo and Kaiser, 1983).
    There  Is  a  large volume of data  concerning  toxlclty of  chlorophenols to
 freshwater species.  The  most sensitive species for which there was  a large
amount  of  data  were  salmonlds  (rainbow  trout.  Salmo  qalrdnerl  and  brown
 trout,  Salmo  trutta)  and  bluegllls  (Lepomls  macrochlrus).   The  lowest
 reported  acutely toxic concentration for  freshwater  fishes  was  0.085  mg/l
 2,3,4,6-tetrachlorophenol,  a  96-hour  LC5Q  for  rainbow  trout   (Mayer  and
 Ellersleck,  1986).    The  lowest  reported  acutely   toxic  concentration  for
 freshwater   Invertebrates  was   0.29   mg/l    2,3,4,6-tetrachlorophenol,   a
48-hour LC5Q for  Daphnla  maqna  (U.S.  EPA,  1978a).   Oata   for  freshwater
plants, fungi  and bacteria  Indicated toxic concentrations similar  to those
for  freshwater  fishes  and Invertebrates.  The  lowest  reported toxic concen-
tration  for   freshwater  plants was  0.603  mg/l  2,3,4,6-tetrachlorophenol,
the  48-hour  EC5Q for  chlorosis 1n duckweed  (Blackman  et al..  1955).   For
bacteria and  fungi,  the lowest  reported  toxic concentration  was  0.176 mg/l
2,3,4,5-tetrachlorophenol,  a  30-mlnute ECrQ  for  Inhibition  of luminescence
of Photobacterlum phosphoreura (Rlbo and Kaiser, 1983).

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     Relatively  little  Information  was  available concerning  marine  species.
 The  lowest reported acutely  toxic  concentration  for marine  species  was  1.1
 mg/i  2,3,4,6-tetrachlorophenol,   a  96-hour  LC-.   for   the  cyprlnodontld
 fish,  Rlvulus marmoratus  (Koenlg and  McLean,  1980).  The  lowest  reported
 toxic   concentration    for   marine   plants   was   0.44   mg/i   2,3,5,6-
 tetrachlorophenol,  a  96-hour  EC™  for  Skeletonema  costatum  (U.S.  EPA,
 1978a).
     Few  studies  concerning  chronic  toxldty  of  chlorophenols  to  aquatic
 organisms  were  available.   The  only  study  Involving  a  full  Hfecycle
 exposure  was  that  of  Koenlg and  McLean (1980)  who found  that  fin  erosion
 occurred   In   all   fish   (Rlvulus   marmoratus)   exposed  to   0.055  mg/l
 2,3',4,6-tetrachlorophenol, the lowest concentration  tested.
     Chlorinated  phenols  have been  shown  to  Impair  the  flavor  of freshwater
 fish  flesh at concentrations much  lower than those  that  are toxic  (Shumway
 and  Palensky, 1973; U.S.  EPA, 1980b,c,d).   The lowest reported concentration
 for  flavor Impairment  was  0.0004  mg/l 2,4-d1chlorophenol,  a  threshold  for
 largemouth  bass  (Mlcropterus  salmoldes) (Shumway  and Palensky,  1973).   As
 discussed  by  U.S.  EPA (1980b,c,d), threshold  concentrations for  tainting of
 fish  flesh may  be more  Important than  toxic  concentrations 1n  establishing
water quality criteria for aquatic biota.
    The chlorophenols  seen to be readily absorbed  from the gastrointestinal
 tract and  from parenteral  sites  of  Injection (Oelchmann and KepHnger, 1981;
Carpenter  et  al.,  1985).   Rats  dosed  orally  with  l4C-2,4,6-tr1chlorophenol
absorbed  at  least 82.3%  of  the  dose  based  on  urinary excretion  of  radio-
activity  (Korte  et  al.,   1978).   Roberts  et  al.  (1977)   found  that  2- and
4-chlorophenol,   2,4-d1chlorophenol  and 2,4,6-trlchlorophenol  can penetrate
                                       1x

-------
 human  epidermis in  vitro.   Acutely  toxic levels  of  2,4,5- and  2,4,6-tM-
 chlorophenol were  not  absorbed  through  the Intact skin of rabbits or guinea
 pigs,  while  toxic  levels of 2,3,4,6-tetrachlorophenol  were absorbed  through
 the  skin  (Gosselln et a!., 1976).
     Pharmacok1net1c  studies  of  the  chlorophenols   In   laboratory   animals
 Indicate  that  the  compounds are distributed  rapidly,  but do not  accumulate
 In  any tissue  (Exon  and Koller,  1982;  Somanl  and  Khallque,  1982; Korte  et
 al., 1978; PekaM  et  al., 1986; Hattula et al.,  1981b).   Metabolism  studies
 Indicate  that  the  chlorophenols are  conjugated  to glucuronldes  and sulfates,
 with glucuronldes  predominating In  rats  (Karpow,  1893, Koster  et  al.,  1981;
 Somanl and Khallque,  1982;  Bahlg  et al.,   1981).  Other metabolites that  have
 been  Identified are dlchloromethoxyphenols Identified In an in vitro  study
 of  the metabolism  of  2,4-d1chlorophenol  (Somanl et al.,  1984), tetrachloro-
 hydroqulnone  as a metabolite  of   2,3,5,6-tetrachlorophenol  and  trlchloro-
 hydroqulnone as a  minor  metabolite  of  2,3,4,5-  and  2,3,4,6-tetrachlorophenol
 (Ahlborg  and  Larsson,  1978).   In  addition,  Bahlg  et  al. (1981)  found  that
 other  trlchlorophenol  Isomers  are   excreted  when 2,4,6-tMchlorophenol  was
 administered orally to rats.
    Studies  using   laboratory  animals  (Karpow,  1893;  Korte  et  al.,  1978;
 Bahlg  et  al.,  1981;   Ahlborg  and   Larsson,  1978)   Indicate   that   the
chlorophenols  are   excreted  predominantly  In  the  urine  as glucuronlc  and
 sulfuMc   add  conjugates,   and as   the   unchanged  compounds.    Kalman  and
Horstman    (1983)    found   that    the    half-time   of   elimination   of
2,3,4,6-tetrachlorophenols 1n occupatlonally exposed humans was -63^34 hours.
    In a  subchronlc Inhalation  study of 4-chlorophenol  (Gurova, 1964), rats
exposed  to  2  mg/ra",  6  hours/day  for 4  months  showed  neuromuscular excit-
ability,   a reduction  of  endurance,  Increased myoneural  excitability, slight

-------
 congestion  of  organs and minor  flbrotlc  changes  In alveolar  septa.   Gurova
 (1964)  also reported symptoms  of nervous  exhaustion,  Insomnia, Irritability,
 frequent mood  changes and  rapid  fatlgabllHy  In workers  exposed  to 4-chloro-
 phenol  1n  an  aniline   dye  plant.   The   lack  of  detail   1n  these  studies
 precludes adequate assessment of their reliability.
    Kleu and  Goeltz  (1971) reported  symptoms of  chloracne,  decreased  sexual
 activity, easy fatlgabllHy,  Irritability, muscular weakness, loss  of appe-
 tite and memory,  discouragement, alcohol  Intolerance and  loss  of  Interest In
 workers occupatlonally exposed  to  a  trlchlorophenol  formulation  for  up to 15
 years.   A  causal   relationship  was  not  established.    Alexandersson  and
 Hedenstlerna (1982)  found pulmonary  effects  In  workers  exposed to low levels
 of tMchlorophenols  1n gas masks for up to 10 years.
    Exon and  Keller  (1985)  found  Immunologlcal effects  In  rats  exposed sub-
 chronlcal'ly to  2,4-d1chlorophenol  at  30 and  300 ppm 1n their drinking water.
 Similar effects were net noted  In rats  exposed  to up to  500 ppm 2-chloro-
 phenol, or  up  to 300 ppm 2,4,6-tMchlorophenol.   Kobayashl  et  al.  (1972)
 reported minor  hlstologlcal  changes  1n the livers  of  mice  fed 2,4-d1chloro-
 phenol  at  230  mg/kg/day  for   6  months.   No  effects  were noted   at  100
 mg/kg/day.
    A subchronlc  drinking water  study of  2,4-d1chlorophenol 1n mice found no
 consistent  effects  that  could  be  related  to  treatment   at  up  to  2  ppm
 (Borzelleca et al.,   1985a).   The  study  was  confounded  by  the  addition of
 Emulphor to the dosing solution.
    McColllster et al. (1961)  studied the toxldty of 2,4,5-tMchlorophenol.
 In a  28-day gavage  study,  microscopic changes were noted  1n  the liver and
kidneys of  rabbits dosed with 0.1 and 0.5 mg/kg  but not 0.01 mg/kg 20 times
                                      xl

-------
over  the  study  period.   No changes were noted In  rats dosed with  2,4,5-trl-
chlorophenol  at  up to 1.0  g/kg  18 times over 24  days.   In a 98-day  study,
pathologic changes  1n the  livers and  kidney were noted 1n  rats provided with
diets containing 2,4,5-trlchlorophenol at 0.03 and  1.0% but  not at  <0.01%.
    In a  70-day  dietary  study, Vlzethum  and Goerz  (1979) reported  that 0.05%
2,4,5-tMchlorophenol was  not porphyrogenlc  1n  rats.  The  NCI  (1979) sub-
chronic  study  noted  an  Increase 1n   splenic  hematopolesis   and  mldzonal
vacuolatlon of hepatocytes  In  rats fed 2,4,5-tMchlorophenol  1n the diet  at
46,000 ppm for  7  weeks.   Survival  of rats fed >21,500  ppm but not <14,700
ppm was also  affected.   In  mice, survival was  affected at  31,500 ppm but  not
at  <21,500 ppm  (NCI,  1979);  no  hlstopathologlcal  data  were  reported.    A
dose-dependent decrease  In  body weight was observed  In both rats and mice In
the NCI (1979) study.
    Kawano et al.  (1979) observed  changes 1n growth, organ weights,  several
biochemical parameters and  liver drug  metabolizing enzymes  In  rats fed diets
containing  2,3,5-trlchlorophenol  or   2,3,4,5-,   2,3,5,6-  or   2,3,4,6-tetra-
chlorophenol  at  0.2% for  3 weeks.  Dose-related  hlstopathoToglc  changes  In
the  liver  were  noted  In  rats  treated  by  gavage with  2,3,4,5-tetrachloro-
phenol for 55 days  at >50  mg/kg/day but  not  at 10 mg/kg/day (Hattula et al.,
1981b).
    In a  chronic  study,  numbers  of R8C  and hemoglobin  levels  were Increased
In  rats  provided with drinking  water containing  500 ppm  2-chlorophenol  or
300  ppm  2,4-d1chlorophenol,  but  not   at 10-fold   lower  concentrations (Exon
and  Koller,   1985).   The  NCI  (1979)   found  a dose-related Increase  1n   the
Incidences of bone marrow  hyperplasla  and  leukocytosls  1n  rats at 5000  and
10,000 ppm.   In  mice,   dose-related  hyperplasla   of  the  liver  was  noted  In
males at 5000 and 10.000 ppm (NCI,   1979).
                                      xll

-------
     In  studies  of  the  Induction  of  enzymes  by  the  chlorinated  phenols,
 Carlson  (1978)  found  that  2,4,5-trlchlorophenol  reduced mlcrosomal  NADPH-
 cytochrome  c  reductase  activity and  cytochrome  P-450  content.   Denomme  et
 al.  (1983)  reported that 4-dlmethylamlnoantlpyrlne N-demethylase  was  Induced
 by   3,4,5-trlchlorophenol.   The  other  trl-  and   tetrachlorophenols  had  no
 effects  on  enzyme  Induction.    The  mutagenldty  of  2-am1noanthracene  and
 benzo[a]pyrene  were enhanced In an Ames assay by  S-9  from rats treated with
 2,3,4,5-tetrachlorophenol (Sussmuth et al., 1980).
     MUsuda  et  al.  (1963)  observed  that chlorophenols  Inhibit  oxldatlve
 phosphorylatlon  In  vitro,   with  the   Inhibiting   activity  Increasing  with
 Increasing chlorlnatlon.
     The  acute  toxlclty  of  the chlorinated  phenols  has  been  studied  by  a
 number of Investigators  (Delchmann,  1944;  Bubnov  et al.,  1969;  Borzelleca et
 al.,  1985a,b;   Farquharson  et   al.,  1958;  Chrlstensen  and  luglnbyhl,  1975;
 Oekhmann  and   Mergard,  1948;   Angel  and  Roberts,   1972;  Gurova,  1964;
 Schrotter  et  al.,  1977;  Kobayashl   et  al.,  1972;  Vernot et   al.,  1977;
 McColHster  et  al.,  1961;  Ahlborg   and  Larrsson,  1978;  Hattula   et  al.,
 1981b); In general,  the toxlclty  Increases as the chlorlnatlon  Increases.
     Ep1dem1olog1cal  studies  that are  confounded by  some  small  study popula-
 tions and multiple exposures Indicate that a mixture  of  compounds Including
 chlorophenol   are   associated   with   soft  tissue  sarcomas  and  malignant
 lymphomas (Lynge,  1985; Cook,  1981;   Honchar and  Halperln,  1981;  Pearce et
al.,  1986).   The  Influence  of   the  chlorophenols  alone,  however,  cannot be
determined.
     Increased  tumor Incidences   were  not observed  In  rats  exposed  to up to
500  ppm 2-chlorophenol or up to 300 ppm 2,4-dlchlorophenol  In  their  drinking
water for 2 years  (Exon  and  Koller, 1985).  Innes et al.  (1969)  found  Incon-
clusive results  1n  a carclnogenldty  study of 2,4,6-trlchlorophenol  In  mice.

-------
                                  TABLE 9-14
          Derivation of Potency Factor (F)  for  2,4,6-TMchlorophenol
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment: 105 weeks
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:

Experimental doses/exposures (ppm):
Transformed doses (mg/kg/day):

Tumor Incidence:
Unadjusted 1/EO]Q:
Adjusted 1/EOio (F Factor):
        NCI,  1979
        oral
        mouse
        B6C3F1
        male
        diet
        0.04  kg

        1-05 weeks
        105 weeks
        liver
        hepatocellular  adenoma  and
        carcinoma
        0
        0
5000
 650
10,000
 1,300
        4/20         32/49          39/47
        1.16158xlO~* (mg/kg/day)'1
        1.39978xlO~i (mg/kg/day)"1
0023d
9-20
            05/11/87

-------
                                10.   REFERENCES

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0024d                               10-1                              06/19/87

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0024d                               10-2                             06/19/87

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0024d                               10-3                              06/19/87

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0024d                               10-4                              06/19/87

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0024d                               10-5                             06/19/87

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0024d                               10-6                              06/19/87

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0024d                               10-7                              06/19/87

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Q024d                               10-8                              06/19/87

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0024d                               10-9                              06/19/87

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0024d                               10-10                            06/19/87

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0024d                               10-11                             06/19/87

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0024d                               10-12                            06/19/87

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0024d                               10-13                            06/19/87

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0024d                               10-15                            06/19/87

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0024
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0024d                               10-17                             06/19/87

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0024d                               10-19                             06/19/87

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0024d                                10-20                             06/19/87

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 assessing  the phototransformatlon of  chemicals  In  water.   Chemosphere.   14:
 53-77.

 Leuenberger,  C.,  H.  G1ger,  R.  Coney,  J.W.  Graydon  and  E.  Molnar-Kublca.
 1985a.   Persistent  chemicals  In  pulp mill   effluents.   Water  Res.   19:
 885-894.

 Leuenberger,  C.,  M.P.  L1gock1   and  J.F.   Pankow.    1985b.   Trace  organic
 compounds  In  rain.  4.  Identities,  concentrations  and scavenging mechanisms
 for  phenols In urban air and rain.  Environ. Sc1. Technol.  19: 1053-1058.

 Linden, E., B.E.  Bengtsson, 0. Svanberg and G.  Sundstrom.   1979.  The acute
 toxlclty  of  78  chemicals  and pesticide  formulations against  two  brackish
 water  organisms,  the  bleak  (Alburnus  alburnus)  and  the...   Chemosphere.
 8(11-12): 843-851.

 Undstrom, H. and  A.  Llndstrom.   1980.  Changes  In  the swimming activity of
 pontoporela  afflnls  (Crustacea.  Amphlpoda)  after   exposure  to  sublethal
 concentrations of  phenol.  4-chlorophenol,   and  styrene.   Ann.  Zool.  Fennlcl.
 17: 221-231.  (Cited 1n KMJgsheld and Vandergen, 1986)

 Lynge,  E.   1985.  A  follow-up  study  of  cancer Incidence among  workers In
manufacture  of  phenoxy  herbicides  In Denmark.   Br.   3.  Cancer.   52(2):
259-270.
0024d                               10-21                             06/19/87

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 Mayer,  F.L.,   Jr.  and M.R.  Ellersleck.   1986.   Manual  of  acute  toxUHy:
 Interpretation and  data  base  for  410 chemicals and 66 species of freshwater
 animals.   U.S.  Dept.  of  Interior, F1sh and  Wildlife  Service Resource Publ.
 160.

 Hayes,  M.A.,  H.C.  Alexander  and  O.C. 0111.   1983.   A study  to  assess  the
 Influence of age  on the  response  of  fathead  minnows In static  acute toxldty
 tests.  Bull.  Environ. Contam. Toxlcol.  31(2):  139-147.

 McColllster, O.D.,  O.T.  Lockwood  and  V.K.  Rowe.   1961.  Toxlcologlc Informa-
 tion on 2,4,5-trlchlorophenol.  Toxlcol. Appl.  Pharmacol.   3:  63-70.

 McLeese,  D.H.,  V.  Zltko  and  M.R.  Peterson.   1979.   Structure-lethality
 relationships   for  phenols,  anilines  and  other  aromatic  compounds In  shrimp
 and clams.  Chemosphere.   8(2):  53-57.

MHsuda,  H.,   K.   Murakami  and   F.   Kaw1.   1963.   Effect  of  chlorophenol
analogues  on   the  oxldatlve  phosphorylatlon   In  rat   liver  mitochondria.
AgMc. B1ol. Chera.  27(5):  366-372.

Morgade,  C.,  A.  Barquet and  C.O.   Pfaffenberger.   1980.    Determination  of
polyhalogenated phenolic compounds  1n drinking water, human  blood  serum and
adipose tissue.  Bull. Environ.  Contam.  Toxlcol.  24:  257-264.

NCI  (National  Cancer   Institute).   1979.   Bloassay of  2,4,6-tMchlorophenol
 for  possible  cardnogen1c1ty.   NCI  Cardnogenesls  Tech   Rep.   Ser.   No.
NCI-C6-TR-155.
0024d                               10-22                            06/19/87

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 U.S.   EPA.   1983d.   Reportable  Quantity  Document   for  2,6-01ch1orophenol.
 Prepared  by the Office of Health and Environmental Assessment, Environmental
 Criteria  and Assessment  Office,  Cincinnati,  OH for  the  Office  of Emergency
 and  Remedial Response, Washington, DC.

 U.S.  EPA.   1983e.   Reportable Quantity  Document  for 2,4,5-Trlchlorophenol.
 Prepared  by the Office of Health and Environmental Assessment, Environmental
 Criteria  and Assessment  Office,  Cincinnati,  OH for  the  Office  of Emergency
 and  Remedial Response, Washington, DC.

 U.S.  EPA.   1983f.   Reportable Quantity  Document  for 2,4,6-Trlchlorophenol.
 Prepared  by the Office of Health and Environmental Assessment, Environmental
 Criteria  and Assessment  Office,  Cincinnati,  OH for  the  Office  of Emergency
 and Remedial Response, Washington, DC.

 U.S.  EPA.   1983g.    Reportable   Quantity  Document  for   2,3,4,6-Tetrachloro-
 phenol.   Prepared  by the  Office  of  Health  and  Environmental   Assessment,
 Environmental  Criteria  and Assessment  Office,  Cincinnati,  OH for the  Office
 of Emergency and Remedial Response, Washington,  DC.

 U.S.  EPA.   1984a.    Health  Effects  Assessment  for 2,4,5-Trlchlorophenol.
 Prepared  by the Office of Health and Environmental Assessment, Environmental
 Criteria  and Assessment  Office,  Cincinnati,  OH for  the  Office  of Emergency
 and Remedial Response, Washington, DC.  EPA 540/1-86-034.
0024d                               10-33                             06/19/87

-------
 U.S.  EPA.   1984b.   Health  Effects  Assessment  for  2,4,6-TMchlorophenol.
 Prepared  by  the  Office  of  Health  and  Environmental  Assessment,  Environmental
 Criteria  and Assessment Office, Cincinnati, OH  for  the Office of  Emergency
 and Remedial Response, Washington, DC.  EPA 540/1-86-042.

 U.S.  EPA.  1985a.    Integrated  Risk  Information System  (IRIS).    Reference
 Doses  (RfDs) for  Oral  Exposure  to  2,4,5-TMchlorophenol.   Prepared by  the
 Office  of Health  and  Environmental  Assessment,  Environmental  Criteria  and
 Assessment Office, Cincinnati, OH.  Verification Date 5/20/85.

 U.S.  EPA.   1985b.   Integrated Risk  Information  System  (IRIS).   Reference
 Doses  (RfDs)  for  Oral  Exposure  to  2,3,4,6-Tetrachlorophenol.   On-line.
 Prepared  by  the  Office  of  Health  and  Environmental  Assessment,  Environmental
 Criteria and Assessment Office, Cincinnati, OH.  Verification Date 7/8/85.

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

U.S.  EPA.   1986b.   Drinking  Water  Criteria  Document  for  Chlorophenols.
Prepared  by  the  Office  of  Health  and  Environmental  Assessment, Environmental
Criteria  and Assessment Office,  Cincinnati,  OH  for  the Office  of Drinking
Water, Washington, DC.
0024d                               10-34                             06/19/87

-------
 U.S.   EPA.   1986c.   Integrated  R1.sk  Information  System  (IRIS).   Reference
 Dose  (RfD) for Oral Exposure for 2,4-D1chlorophenol.  On-line.  Verification
 Date  01/22/86.  Office of Health and Environmental Assessment, Environmental
 Criteria and  Assessment  Office,  Cincinnati, OH.

 U.S.  EPA.  1986d.   Report  on  the Status of  Chemicals  In  the Special Review
 Program,  Registration  Standards  Program and Data call-In Program.   Office of
 Pesticide Programs,  U.S.  EPA, Washington, DC.

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

 U.S.  EPA.  1986f.   Reference  Values for  Risk Assessment.   Prepared by the
 Office  of  Health  and Environmental  Assessment,  Environmental  Criteria and
 Assessment  Office,  Cincinnati,  OH  for the Office of Solid Waste, Washington,
 DC.

 U.S.  EPA.   1986g.   Integrated  Risk  Information  System  (IRIS).   Reference
 Dose  (RfD)  for  Oral  Exposure  for  2,6-D1chlorophenol.    On-Hne.    (Final
 approval   pending).   Office   of   Health    and   Environmental  Assessment,
 Environmental  Criteria and Assessment Office,  Cincinnati,  OH.

 USITC  (U.S.   International  Trade   Commission).    1986.   Synthetic  Organic
 Chemicals.  U.S.  Production and Sales,  1985.   USITC Publ.  1892, Washington,
 DC.  p. 38.
0024d                               10-35                             06/19/87

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 Valencia,  R.,  J.M.  Mason, R.C. Woodruff  and  S.  ZlmmeMng.   1985.  Chemical
 mutagensls  testing  1n Drosophlla.  III. Results of 48 coded compounds  tested
 for  the National Toxicology Program.   Environ.  Hutagen.   7(3):  325-348.

 Valo,  R.,  V.  KUunen,  M.  Salklnoja-Salonen  and S. Ralsanen.   1984.  Chlori-
 nated  phenols  as  contaminants of  soil   and  water  1n  the  vicinity  of  two
 Finnish sawmills.  Chemosphere.  13:  835-844.

 Velth, G.O., O.L.  Delore  and  8.V.  Bergstedt.   1979.   Measuring and estimat-
 ing  the  bloconcentratlon  factor  of chemicals  In  fish.   J.  F1sh.  Res.  Board
 Can.  36: 1040-1048.

 Velth, G.O., K.J.  Macek,  S.R.  PetrocelH  and J. Carroll.   1980.   An evalua-
 tion of using partition coefficient and water  solubility  to estimate blocon-
 centratlon  factors  for  organic chemicals  1n  fish.  ASTM STP 707.  Aquatic
 Toxicology, J.G. Easton et al., Ed.  Am.  Soc.  Test. Mater,  p.  116-129.

 Vernot,  E.H.,   J.O.  MacEwen,  C.C.  Haun and  E.E.  Klnkead.   1977.    Acute
 toxlclty and  skin  corrosion data  for some  organic  and  Inorganic compounds
and aqueous solutions.   Toxlcol.  Appl. Pharmacol.   42:  417-423.

Verschueren, K.  1983.  Handbook of  Environmental  Data  on Organic Chemicals,
 2nd ed.  Van Nostrand Relnhold Co., New York.   p.  375-379. 492-495.

Vlrtanen, M.T.  and M.L.  Hattula.   1982.   The fate  of  2,4,6-tMchlorophenol
 In an aquatic continuous flow system.  Chemosphere.  11: 641-649.
0024d                               10-36                            06/19/87

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 Vlzethum,  W. and  G.  Goerz.   1979.   Is  2,4,5-trlchlorophenol  a  porphyrogen?
 Dermatosen  Beruf  Umuelt.   27(3): 78.   (Taken from PESTAB/79/3028)

 von  Oettlngen,  ii.F.   1949.   The  halogenated  phenols.   .In.:  Phenol and  Us
 Derivatives.   The  relation  between  their chemical  constitution  and  their
 effect  on  the  organism.   National  Institutes  of  Health Bulletin  No.  190.
 U.S. Public  Health Service, Washington, DC.  p. 193-220.

 Vuorlnen,  P.J.,   J.  Paas1v1rta,  T.  P11lola,  K.  Surma-Aho  and  J.  Tarhanen.
 1985.   Organochlorlne  compounds  In baltlc  salmon  and  trout.   I. Chlorinated
 hydrocarbons and  chlorophenols 1982.   Chemosphere.  14: 1729-1740.

 Hatanabe, I., T.  Kashlmoto and R. Tatsukawa.   1985.   Bromlnated phenols and
 anlsoles  In river  and marine  sediments   In  Japan.  Bull.  Environ.  Contain.
 Toxlcol.  35: 272-278.

 Weast,  R.C., Ed.   1980.   CRC  Handbook  for Chemistry  and  Physics, 61st ed.
 CRC Press, Boca Raton, FL.  p. C-474-476,  C-481.

 Hegman, R.C.C. and H.H. Vandenbroek.   1983.  Chlorophenols 1n river sediment
 1n the Netherlands.  Water Res.  17:  227-230.

Wellens,  H.   1982.   Comparison of  the sensitivity of  Brachydanlo rerlo and
Leuclscus 1dus  by testing  the fish  toxldty  of  chemicals  and  wastewaters.
Z. Hasser Abwasser Forsch. (Ger).  15: 49.  (Cited  In Pickering  et  a!.,  1983)

X1e,   T.M.   1983.   Determination  of  trace   amounts   of  chlorophenols and
chlorogualacols  1n sediment.  Chemosphere.  12: 1183-1191.

0024d                               10-37                            06/19/87

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Xle, T.M.,  K.  Abrahamsson,  E.  Fogelqvlst  and.B.  Josefsson.   1986.   Distribu-
tion  of  chlorophenollcs  In a  marine  environment.   Environ.  Sc1.  Technol.
20: 457-463.

Yoshloka,  Y.,  Y.  Ose and  T.   Sato.   1986.   Correlation  of  the   five  test
methods  to assess  chemical toxldty  and  relation  to physical  properties.
Ecotoxlcol. Environ. Saf.  12(1): 15-21.

Young,  D.R.,   R.W.  Gossett, R.B.  Balrd,   O.A.  Brown, P.A.  Taylor  and  M.J.
M1lle.   1983.    Hastewater   Inputs  and  marine  bloaccumulatlon  of  priority
pollutant   organlcs   off  southern  California.    In.:   Water   Chlorlnatlon:
Environmental  Impact and Health Effects.  4(Book 2): 871-884.
QQ24d                                10-38                             06/19/87

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                                  APPENDIX A

                              LITERATURE SEARCHED



     This   HEED   1s  based  on  data  Identified  by  computerized  literature

 searches  of  following:


          TSCATS
          CASR online  (U.S. EPA Chemical Activities Status Report)
          TOXLINE
          TOXBACK 76
          TOXBACK 65
          RTECS
          OHM TADS
          STORET
          SRC Environmental Fate Data Bases
          SANSS
          AQUIRE
          TSCAPP
          NTIS
          Federal Register


These  searches  were  conducted In January, 1987.   In  addition,  hand searches

were made of Chemical Abstracts (Collective Indices  5-9),  and  the following

secondary  sources should be reviewed:


    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1986.   Documentation  of  the  Threshold Unit  Values  and Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1986-1987.  TLVs: Threshold  Limit  Values  for Chemical Substances In
    the  Work Environment  adopted  by  ACGIH with Intended  Changes for
    1986-1987.  Cincinnati, OH.  Ill p.

    Clayton,  G.O.   and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed.,  Vol. 2A.   John Wiley and
    Sons, NY.  2878 p.

    Clayton,  G.O.   and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed.,  Vol. 28.   John Wiley and
    Sons, NY.  p. 2879-3816.

    Clayton,  G.D.   and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
    Hygiene  and Toxicology,  3rd rev.  ed.,  Vol. 2C.   John WHey and
    Sons, NY.  p. 3817-5112.
0025d                               A-l                              06/18/87

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    Grayson,  M.  and D.  Eckroth,  Ed.  1978-1984.   Klrk-Othmer  Encyclo-
    pedia of  Chemical Technology, 3rd ed.   John  Wiley  and  Sons,. NY.   23
    Volumes.

    Hamilton, A. and H.L.  Hardy.  1974.   Industrial  Toxicology,  3rd  ed.
    Publishing Sciences Group, Inc., MA.   575 p.

    IARC  (International  Agency  for  Research  on  Cancer).   IARC  Mono-
    graphs  on  the  Evaluation  of  Carcinogenic   Risk  of  Chemicals   to
    Humans.  WHO,  IARC, Lyons, France.

    Jaber,  H.M.,  W.R.  Mabey,  A.T.   L1eu,  T.W.   Chou  and H.L.  Johnson.
    1984.   Data   acquisition   for   environmental   transport   and   fate
    screening for  compounds  of Interest  to  the  Office of Solid  Waste.
    SRI   International,  Menlo   Park,  CA.   EPA   600/6-84-010.    NTIS
    PB84-243906.

    NTP  (National  Toxicology  Program).   1986.   Toxicology Research  and
    Testing   Program.    Chemicals   on  Standard   Protocol.    Management
    Status.

    Ouellette,  R.P. and  J.A.  King.   1977.  Chemical  Week  Pesticide
    Register.   McGraw-Hill  Book Co., NY.

    Sax,  I.N.   1984.   Dangerous Properties  of  Industrial  Materials,  6th
    ed.  Van Nostrand Relnhold Co.,  NY.

    SRI  (Stanford   Research  Institute).   1986.   Directory of  Chemical
    Producers.  Menlo Park, CA.

    U.S.  EPA.   1986.  Report  on Status  Report   In  the  Special  Review
    Program,  Registration   Standards  Program  and  the  Data  Call   In
    Programs.    Registration  Standards and  the  Data  Call In  Programs.
    Office of Pesticide Programs,  Washington, DC.

    U.S.  EPA.   1985.   CSB  Existing  Chemical Assessment Tracking System.
    Name  and  CAS  Number Ordered  Indexes.  Office  of  Toxic  Substances,
    Washington,  DC.

    USITC  (U.S.  International  Trade  Commission).   1985.    Synthetic
    Organic Chemicals.   U.S.  Production  and  Sales.  1984, USITC  Publ.
    1422, Washington. DC.

    Verschueren, K.   1983.  Handbook of  Environmental  Data  on Organic
    Chemicals, 2nd ed.   Van Nostrand Relnhold Co., NY.

    Wlndholz,  H.,  Ed.  1983.   The Merck  Index,  10th ed.  Merck and  Co.,
    Inc., Rahway, NJ.

    Worthing,  C.R.  and  S.B.  Walker, Ed.    1983.   The  Pesticide Manual.
    British Crop Protection Council.  695 p.
0025d                               A-2                               05/12/87

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     In addition,  approximately  30  compendia  of aquatic  toxldty  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
     Toxldty  Tests  Conducted  at  Columbia  National  Fisheries Research
     Laboratory.    1965-1978.   U.S.  Dept.   Interior,  Fish  and Wildlife
     Serv.  Res. Publ. 137,  Washington,  DC.

     McKee,  J.E.  and  H.W.  Wolf.   1963.   Water  Quality Criteria, 2nd ed.
     Prepared  for  the   Resources   Agency   of   California,   State  Water
     Quality Control  Board.  Publ.  No.  3-A.

     Plmental, 0.   1971.   Ecological Effects of  Pesticides  on  Non-Target
     Species.  Prepared for the U.S.  EPA, Washington,  DC.   PB-269605.

     Schneider, 8.A.   1979.  Toxicology Handbook.  Mammalian and Aquatic
     Data.   Book  1: Toxicology  Data.  Office of  Pesticide  Programs, U.S.
     EPA, Washington, OC.   EPA  540/9-79-003.  NTIS PB  80-196876.
0025d                               A-3                               05/12/87

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                                 APPENDIX B-l
                   Cancer  Data  Sheets  for Derivation of a q-j*
 Compound:   2,4,6-tMchlorophenol
 Reference:   NCI,  1979
 Specles/straln/sex:  rat/F344/H
 Body weight  = 0.36 kg  (measured)
 Length  of exposure (le) «  107 weeks
 Length  of experiment (Le)  =  107 weeks
 Llfespan of  animal (L) * 107 weeks
 Tumor site and  type:   hematopoletlc  system/leukemia or malignant  lymphoma
 Route/vehicle:  oral/diet
Experimental Doses
or Exposure (ppm)
0
5,000
10,000
Transformed Dose
(mg/kg/day)
0
250
500
Incidence
No. Responding/No. Tested
4/20
25/50
29/50
Unadjusted q-j* - 2.0675297x10"'  (mg/kg/day)"1
Hunan q-)* » 1.197798x10"'  (mg/kg/day)"1
0026d
8-1
05/12/87

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 Nestmann,  E.R.  and E.G.H. Lee.  1983.  Mutagen1c1ty of  constituents  of  pulp
 and   paper  mill  effluent  In  growing  cells  of  Saccharomyces  cerevlslae.
 Mutat.  Res.   119:  273-280.

 Neubert,  0.   and  I.  DUlmann.   1972.   Embryotoxlc  effects  In mice  treated
 with  2,4,5-trlchlorophenoxy  acetic  add and 2,3,7,8-tetrachlord1benzod1ox1n.
 Naunyn-Schmledeberg's  Arch.  Pharmacol.    272:  243-264.   (Cited  In Kozak  et
 al.,  1979)

 NTP (National Toxicology  Program).  1986.   Management Status Report.

 Oksama, M. and  R.  KMstoffersson.   1979.   The  tox1c1ty of phenol  to Phoxlnus
 phoxlnus.  Gammarus duebenl  and Hesldotea  entomon  1n brackish  water.   Ann
 Zool. Fenn.   16(3): 209-216.

 Paas1v1rta.  J., N.  Knuutlla,  R.   Paukku and  S.  Herve.   198Sa.  Study  of
 organochlorlne  pollutants In snow  at North  Pole and  comparison  to the snow
 at North, Central and South Finland.  Chemosphere.  14: 1741-1748.

 Paas1v1rta,  J., K.  Helnola,  T.  Humppl,  et  al.   1985b.   Polychlorlnated
 phenols,  gualacols and  catechols  1n  the  environment.    Chemosphere.   14:
 469-491.

 Paris,  O.F.,  N.L.  Wolfe. H.C.  Steen  and  G.L.  Baughman.   1983.   Effect of
phenol  molecular   structure  on  bacterial transformation  rate constants  In
pond and river samples.   Appl. Environ.  Mlcroblol.  45: 1153-1155.
0024d                               10-23                            06/19/87

-------
 Patterson,  J.W.  and  P.S.   Kodukala.   1981.   B1odegradat1on   of  hazardous
 organic pollutants.  Chem. Eng.  Prog.   77:  48-55.

 Pearce  N., A.H.  Smith,  J.K.  Howard,  R.A.  Sheppard,  H.J.  Giles  and  C.A.
 league.   1986.   Non-Hodgk1n's  lymphoma  and  exposure  to phenoxyherblddes,
 chlorophenols,  fencing work and meat works employment: A case-control study.
 Br. J. Ind. Med.  43(2): 75-83.

 Pekarl, K.,  C.  Boudene  and  A.  A1t1o.  1986.   Kinetics of  2,4,6-trlchloro-
 phenol In different organs of the rat.   Arch.  Toxlcol.   59(1):  41-44.

 Perry. R.H. and 0.  Green.   1984.   Perry's  Chemical  Handbook.   Physical  and
 Chemical Data, 6th ed.  HcGraw H111. New York.

 Phlpps,  G.L.,  G.W.  Hoi combe and   J.T.  Flandt.   1981.   Acute  toxldty. of
 phenol  and  substituted  phenols   to   the  fathead  minnow.    Bull.  Environ.
 Contam. Toxlcol.  25(5): 585-593.

 Pickering, Q.H. and  C. Henderson.   1966.   Acute  toxldty of  some Important
 petrochemicals to fish.  J.  Water Pollut.  Control  Fed.   38(9):  1419-1429.

 Pickering, Q.H., E.O.  Hunt, G.L. Phlpps, et  al.   1983.   Effects of pollution
on  freshwater  fish  and  amphibians.   3. Water  Pollut.  Control Fed.   55(6):
840-863.

 PHter,  P.   1976.    Determination  of  biological degradabHUy   of  organic
 substances.  Water Res.  10:  231-235.
0024d                               10-24                            06/19/87

-------
 Roister,  M.t  B.  Rlttlch  and  R.  Zaludova.   1986.   Relationships  between
 biological   activity   of  phenols  and  their  physico-chemical   parameters.
 Collect.  Czech.  Chem.  Commun.  51: 241-248.

 Probst,  G.S.,  R.E.  McMahon,  I.E.  H111,  et al.   1981.   Chemically-Induced
 unscheduled  DMA synthesis  1n  primary rat hepatocyte cultures:  A comparison
 with  bacterial  mutagenldty  using   218  compounds.  Environ.  Mutagen.   3:
 11-32.

 Randall,  T.L.  and  P.V.  Knopp.   1980.   Detoxification  of  specific  organic
 substances   by   wet   oxidation.    J.   Water   Pollut.   Control  Fed.   52(8):
 2117-2130.

 Rasanen,  L.  and M.L.  Hattula.  1977.  The mutagenldty  of MCPA  and Us soil
 metabolites,  chlorinated phenols, catechols  and  some widely used  sllmlcldes
 In Finland.   Bull. Environ. Contam. Toxlcol.  18: 565-571.

 Research    Triangle    Institute.     1987.     Teratologlc    evaluation   of
 2,3,4,6-tetrachlorophenol  administered  to CO rats  on gestatlonal days 6-15.
 Final Report  submitted to  the Office  of Solid Waste, Washington,  DC.

 Rlbo, J.H.  and  K.L.  Kaiser.  1983.   Effects  of  selected chemicals to  photo-
 luminescent  bacteria  and their  correlations  with acute  and  sublethal  effects
on other organisms.  Chemosphere.  12(11-12): 1421-1442.

Roberts, M.S., R.A. Anderson  and  J.  Swarbrlclc.   1977.   Permeability of human
epidermis to phenolic compounds.  J.  Pharm.  Pharmacol.  29:  677-683.
0024d                               10-25                             06/19/87

-------
 Rodwell,  O.E.,  R.D.  Wilson, M.D.  Nemlc  and M.O.  Meroleca.   1984.   A tera-
 tology  study  In  Fischer  344  rats with  2,4-d1chlorophenol.  Toxlcologlst.  4:
 167.

 Rowe, E.L.,  R.J.  Zlobro, C.J.K. Wang and C.W.  Dence.   1982.   The use of an
 alga Chlorella pyrenoldosa and a duckweek Lemna perpusllla as  test organisms
 for  tox1c1ty bloassays  of  spent  bleaching  liquors  and  their  components.
 Environ. Pollut.  Ser.  27(4): 289-296.

 SaaMkoskl, J. and M.  Vlluksela.   1981.   Influence of pH on  the  toxIcHy of
 substituted  phenols   to  fish.    Arch.   Environ.   Contam.  Toxlcol.    10(6):
 747-753.

 SaaMkoskl,  J.  and  M.  Vlluksela.   1982.   Relation between  phys1cochem1cal
 properties  of   phenols   and  their   toxldty  and  accumulation   In   fish.
 Ecotoxlcol. Environ.  Saf.  6: 501-512.

 Sahm, H.,  H.  Brunner  and  S.M.  Schoberth.   1986.   Anaerobic  degradation  of
 halogenated aromatic  compounds.   Hlcrob.  Ecol.   12: 147-153.

 SalklnoJa-Salonen, M.S.,  R.  Valo,  J.  Apajalahtl,  R. Hakullnen,  L.  Sllakoskl
 and  T.   Jaakkola.   1984.    B1odegradat1on   of  chlorophenollc  compounds  In
wastes  from wood-processing  Industry.   ITK Current  Perspectives  1n  Micro-
 biology, H.a. Klug and C.A. Reddy, Ed.   Natl. Acad. Sc1.  p.  668-675.
0024d                               10-26                             06/19/87

-------
 Sasaki,  S.   1978.   The scientific aspects of the chemical substances control
 law In Japan.  .In: Aquatic Pollutants: Transformation and Biological Effect,
 0.  Hutzlnger,  L.H.  Von  Letyveld and  B.C.   Zoeteman,  Ed.   Pergamon  Press,
 Oxford,   p.  283-Z98.

 Schellenberg,  K.,  C.  Leuenberger and R.P. Schwarzenbach.  1984.  Sorptlon of
 chlorinated  phenols by  natural   sediments  and  aquifer  materials.   Environ.
 Sc1.  Techno!.   18:  652-657.

 Schrotter,  E.,  et  al.    1977.   Organlsche  synthetlca  undlhre  vermlzatlon
 elgenschaften.  Parmozlc.  32: 171.   (Cited  1n U.S. EPA,  1980b)

 Schwarzenbach,  R.P. and  J.  Westall.   1985.  Sorptlon  of hydrophoblc trace
 organic compounds  1n groundwater  systems.  Hat. Sc1.  Technol.   17: 39-55.

 Schwetz,  B.A.,  P.A.  Keeler and  P.J.  Gehrlng.   1974.   Effect of purified and
 commercial  grade  tetrachlorophenol  on rat  embryonal  and fetal development.
 Toxlcol. Appl.  Pharmacol.  28(1): 146-150.

 Scow,  K., H.  Goyer,  3. Perwak,  C. Woodruff  and K. Saterson.  1982.  Exposure
 and  Risk  Assessment  for  Chlorinated  Phenols  (2-Chlorophenol,  2,4-01chloro-
 phenol, 2.4,6-Tr1chlorophenol).   EPA  440/4-85-007.  NTIS  P885-211951/xAB.

 Seyler, D.E., J.M.  East,  L.U.  Condle and J.F. Borzelleca.   1984.  The use  of
In  vitro  methods  for  assessing   reproductive   toxldty:   Dlchlorophenols.
 Toxlcol Lett. (AMST).  20(3): 309-315.
0024d                               10-27                             06/19/87

-------
 Shumway, D.L. and J.R. Palensky.  1973.  Impairment of the flavor of fish by
 water pollutants.  EPA-R3-73-010.   (Cited  In  U.S. EPA, 1980b,c,d)

 S1kka,  H.C.  and  G.L.  Butler.   1977.   Effects of selected wastewater chloM-
 natlon  products  and  captan on marine  algae.  U.S.  EPA,  Off.  Res.  Dev.  EPA
 600/3-77-029.  p. 38.

 Simmon,  V.F.,  K. Kauhanen and  R.G.  Tardlff.   1977.  Mutagenlc  activity of
 chemicals  Identified  In  drinking  water.    Dev.  Toxlcol. Environ.  Sc1.   2:
 249-258.

 SHhole, B.B., O.T.  Williams, C. LastoMa and J.I.  Robertson.  1986.   Deter-
mination of halogenated phenols In raw and potable  water by  selected  1on gas
chromatography-mass  spectrometry.   J.  Assoc.  Off. Anal. Chem.   69: 466-473.

Sletten, 0.  and M.C.  Burbank.   1972.  A  resplrometMc screening  test for
 toxic  substances.   Eng.  Bull.  Purdue Univ.  Eng.  Ext.  Ser.   141:   24-32.
 (Cited 1n Krljgsheld  and Vandergen,  1986)

Somanl,  S.H.  and A.   Khallque.   1982.   Distribution  and  metabolism of  2,4-
dlchlorophenol In rats.   J. Toxlcol.  Environ. Health.  9(5-6):  889-897.

Somanl,  S.H., T. Smart  and A. Khallque.   1984.  Metabolism  of 2,4-d1chloro-
phenol  by  Isolated   perfused  rat   liver.    J.  Toxlcol.   Environ.  Health.
13(4-6): 787-798.

Spencer, B.  and  R.T.  Williams.  1950.  No  title  provided.   Blochem.  J.  47:
279.  (Cited in Scow et  al.,  1982)

OQ24d                               10-28                             06/19/87

-------
 SRI   (Stanford   Research   Institute).   1986.   1986  Directory  of  Chemical
 Producers.   United  States  of America.  SRI, Menlo Park, CA.  p. 554, 587.

 Stoner,  G.D., P-B.  Conran,  E.A.  Grelslger,  J. Stober,  M.  Morgan and  M.A.
 Perelra.   1986.   Comparison  of two routes of chemical  administration  on  the
 lung  adenoma response  In  strain  A/J  mice.   Toxlcol.  Appl. Pharmacol.   82(1):
 19-31.

 Suglura,  K., M.  Aok1. S.  Kaneko, et al.   1984.   Fate  of  2,4,6-tMchloro-
 phenol,  pentachlorophenol,  p-chlorob1phenyl  and  hexachlorobenzene  In  an
 outdoor  experimental  pond:  Comparison  between  observation  and  predictions
 based on laboratory  data.  Arch. Environ. Contain. Toxlcol.  13: 745-758.

 Sussmuth,  R., B.  Ackermann-Schmldt  and  F.  Llngens.   1980.   Activation  of
 liver mlcrosomes by  2,3,4,5-tetrachlorophenol.  Mutat. Res.  77(3): 279-282.

 Sutton, P.A.  and J.F.  Barker.   1985.  Migration and  attenuation  of selected
 organlcs  1n  a sandy aquifer.   A  natural  gradient  experiment.  Groundwater.
 23: 10-16.

 Tabak, H.H..  C.W.  Chambers and P.W.  Kabler.  1964.   Mlcroblal metabolism of
 aromatic  compounds.   I.   Decomposition  of phenolic  compounds and aromatic
 hydrocarbons by phenol-adapted bacteria.   J. BacteMol.   87: 910-919.

Tabak, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth.  1981.  BlodegradabllHy
 studies with  organic priority  pollutant  compounds.   J. Hater  Pollut.  Control
Fed.   53:  1503-1518.
0024d                               10-29                             06/19/87

-------
 Telford,  M.  1974.   Blood  glucose  In  crayfish II.   Variations  Induced  by
 artificial  stress.  Comp. Blochem. Physical.  48A:  555.   (CUed 1n  U.S.  EPA,
 1980d)

 Thorn,  N.S.  and  A.R.  Agg.   1975.   The breakdown  of  synthetic organic  com-
 pounds  In biological processes.  Proc.  R.  Soc.  Lond. B.   189:  347-357.

 Thursby, G.B., R.L. Steel and  M.E. Kane.   1985.   Effect  of  organic  chemicals
 on growth and reproduction  1n  the  marine  red alga  Champla parvula.   Environ.
 Toxlcol. Chem.  4(6):  797-805.

 Tlssot. A., P.  Boule,  J.  Lemalre,  S. Lambert and  J.C.  Palla.   1985.   Photo-
 chemistry and the  environment.   X. Evaluation  of  the  toxlclty  of  the photo-
 transformation products of  hydroqulnone and chlorophenols  In  aqueous media.
 Chemosphere.  14: 1221-1230.

 Trabalka, J.R. and H.B. Burch.   1978.   Investigation  of  the effects of halo-
 genated organic  compounds produced In cooling  systems  and  process  effluents
 on aquatic  organisms.   R.L. Jolley, H.  Gorchev and  D.R.  Hamilton, Jr., Ed.
Hater Chlorlnatlon: Environmental Impact and Health Effects,  p. 163-173.

 U.S. EPA.  1972a.  The effects of Chlorlnatlon on  selected organic  chemicals.
Water Pollut.  Control  Res. Service.  12020.  (Cited In U.S. EPA, 1980b)

U.S. EPA.   1972b.   Water  Quality  Criteria 1872.   A  report of the committee
 on water quality criteria.  NTIS PB-236199.
0024d                               10-30                             06/19/87

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

 U.S.  EPA.   1978a.   In-depth  studies  on  health and environmental  effects  of
 selected water  pollutants.  E.G. and  G.  Blonetlcs,  War hem,  HA.   Contract  No.
 68-01-4646.

 U.S.  EPA.   19785.   Rebuttable presumption against registration  and continued
 registration  of pesticide products containing  2,4,5-trlchlorophenol  and  Us
 salts.  Federal Register.  43(149): 34026-34054.

 U.S.  EPA.   1979a.   Reviews of the Environmental  Effects  of  Pollutants.   XI.
 Chlorophenols.   Prepared by  the Health  Effects  Research  Lab.,  Cincinnati,
 OH.   EPA 600/1-79-012.

 U.S.  EPA.   1979b.   2,4,5-Trlchlorophenol  and Us  sodium and potassium salts:
 Position document.  Report, Iss.   p.  70.   EPA/SPRD-80/79.  NTIS PB 81-10311.
 (CA 094:15562U)

 U.S.  EPA.   1980a.   Guidelines  and  Methodology Used  In  the  Preparation of
 Health  Effect  Assessment  Chapters   of   the  Consent  Decree Water  Criteria
 Documents.  Federal Register.   45(231): 49347-49357.

U.S.  EPA.   1980D.   Ambient Water  Quality Criteria  for  Chlorinated Phenols.
Prepared by the Office  of Health and Environmental Assessment, Environmental
Criteria  and  Assessment Office,  Cincinnati,  OH  for  the  Office  of Water
Regulations   and   Standards,   Washington,   DC.    EPA   440/5-80-032.    NTIS
PB81-117434.

0024d                               10-31                             06/19/87

-------
 U.S.   EPA.   1980c.   Ambient  Water  Quality  Criteria  for   2-Chlorophenol.
 Prepared  by  the  Office  of  Health  and Environmental  Assessment,  Environmental
 Criteria  and  Assessment  Office,  Cincinnati,  OH  for  the Office  of  Water
 Regulations   and   Standards,   Washington,   DC.    EPA/440-5-80-034.    NTIS
 PB81-117459.

 U.S.  EPA.   1980d.   Ambient  Water  Quality  Criteria  for  2,4-D1chlorophenol.
 Prepared  by  the  Office  of  Health  and Environmental  Assessment,  Environmental
 Criteria  and  Assessment  Office,  Cincinnati,  OH  for  the Office  of  Water
 Regulations   and  Standards,  Washington,   DC.    EPA   440-5-80-042.    NTIS
 PB81-117533.

 U.S.  EPA.   1983a.   Mehtodology  and  Guidelines  for  Reportable  Quantity
 Determinations Based  on Chronic  Toxlclty  Data.   Prepared  by the  Office of
 Health  and  Environmental Assessment,  Environmental  Criteria and Assessment
 Office, Cincinnati, OH  for the Office  of  Solid Waste and Emergency Response,
Washington, DC.

U.S.   EPA.    1983b.    Reportable   Quantity   Document   for   2-Chlorophenol.
Prepared   by   the   Office   of   Health   and  Environmental    Assessment,
Environmental Criteria  and  Assessment Office, Cincinnati, OH for the  Office
of Emergency and Remedial Response, Washington, DC.

U.S.  EPA.   1983c.   Reportable   Quantity   Document  for   2,4-01chlorophenol.
Prepared by the  Office  of  Health  and Environmental Assessment, Environmental
Criteria and  Assessment Office,  Cincinnati,  OH  for  the  Office  of  Emergency
and Remedial Response, Washington,  DC.


0024d                                10-32                             06/19/87

-------
                                 APPENDIX B-2
                   Cancer  Data Sheets for Derivation of a q-j*
 Compound:   2,4,6-tMchlorophenol
 Reference:  NCI. 1979
 Specles/straln/sex:  rat/F344/M
 Body weight = 0.36 kg  (measured)
 Length of exposure (le) - 107 weeks
 Length of experiment (Le) » 107 weeks
 Llfespan of animal (L) - 107 weeks
 Tumor site and type:   hematopoletU system/leukemia
 Route/vehicle:  oral/diet
Experimental Ooses
or Exposure (ppm)
0
5,000
10,000
Transformed Dose
(mg/kg/day)
0
250
500
Incidence
No. Responding/No.
3/20
23/50
28/50
Tested



Unadjusted q-j* . 2.0347122xlO~»  (mg/kg/day)"1
Human qi* » 1.1787856xlO"a (mg/kg/day)"1
0026d
B-2
05/12/87

-------
                                 APPENDIX B-3
                  Cancer Data Sheets for Derivation of a q-|*
Compound:  2,4,6-trlchlorophenol
Reference:  NCI, 1979
Spec1es/strain/sex:  mouse/B6C3Fl/male
Body weight = 0.04 kg (measured)
Length of exposure (le) - 105 weeks
Length of experiment (Le) » 105 weeks
Llfespan of animal (L) - 105 weeks
Tumor site and type:  11ver/hepatoce11u1ar adenoma and carcinoma
Route/vehicle:  oral/diet
Experimental Doses
or Exposure (ppm)
0
5,000
10.000
Transformed Dose
(mg/kg/day)
0
650
1300
Incidence
No. Responding/No. Tested
4/20
32/49
39/47
Unadjusted q-j* « 1.6119958x10"' (mg/kg/day)'1
Human q-j* « 1.9425697x10"' (mg/kg/day)'1
0026d
8-3
05/12/87

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                                                  4-15
                                                                                          05/08/87

-------
     Data  concerning toxldty of chlorophenols  to  aquatic  bacteria  and fungi
 are presented  1n  Table  4-6.   The lowest  reported  toxic  concentration  was
 0.176  mg/1  2,3,4,5-tetrachlorophenol,  a  30-m1nute  EC5Q  for  Inhibition  of
 luminescence  of  Photobacterlum phosphoreuro  (R1bo and Kaiser, 1983).
     R1bo   and  Kaiser   (1983)  studied  structure-toxldty  relationships  of
 chlorophenols 1n the  Mlcrotox assay  using Photobacterlum  phosphoreum.  and
 found  that chlorine substitution  1n  the ortho (2- or 6-) positions  decreased
 toxldty   of  the  chlorophenols.   This  effect  was   attributed to  hydrogen
 bonding and the  shielding of the OH group by chloro substUuents.
     Information  concerning  toxlclty  of  chlorophenols to marine plant species
 are summarized  In  Table  4-7.   The  lowest  reported toxic  concentration was
 0.44  mg/i   2,3,5,6-tetrachlorophenol,   a   96-hour  EC-,   for  Skeletonema
 costatum  (U.S. EPA, 1978a).
     Kulper  and  Hanstvelt  (1984)  conducted  experiments with  natural  marine
 plankton   communities  exposed  to  4-chlorophenol or   2,4-d1chlorophenol  In
 plastic enclosures.  They  found  that  0.3  mg/l of  either  compound slightly
 Inhibited  phytoplankton  growth.   Exposure  to 1  mg/l  of  either  compound
 Inhibited  phytoplankton  growth,   changed  the  species  composition  of  the
 phytoplankton   community   and   affected  development   of  some  zooplankton
 species.   Concentrations  of  0.1   mg/t  4-chlorophenol  or  2,4-d1chlorophenol
 did.not affect phytoplankton or zooplankton growth.
 4.4.   OTHER  RELEVANT INFORMATION
     Chlorinated  phenols  Impair  the  flavor  of  freshwater  fish   flesh  at
concentrations much lower than those  that  are  toxic  (Shumway and  Palensky,
1973; U.S. EPA,  1980b,c,d).  Data  concerning flavor Impairment are  presented
 In  Table  4-8.   In  the studies by  Shumway and Palensky  (1973), rainbow  trout
and  other  fishes were exposed  to  various  chlorophenol  concentrations for 48
0013d                               4-16                              06/18/87

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 hours.   A panel  of  15  judges  then  scored  the flavor  of  cooked fish,  and
 results  were  plotted  against  exposure concentration  to  determine  graphically
 an  estimate  of the highest concentration  that  would not Impair  flavor.  The
 lowest  such  concentration  was  0.0004 mg/l  2,4-dlchlorophenol,  the  ETC  for
 largemouth bass  (Mlcropterus  salmoldes).   In another  study,  Henderson  et  al.
 (1960)  reported  that  people  experienced mild  to  severe nausea after  eating
 flesh of bluegllls exposed to 2 mg/l 2-chlorophenol  for  1-4  weeks.
 4.5.   SUMMARY
    In  general,  the  toxlclty  of  chlorinated  phenols  to  aquatic   biota
 Increases with  Increasing chlorlnatlon (U.S. EPA, 1979a, 1980b,c).  This Is
 probably  due  to higher uptake  of  the more  chlorinated  compounds (Kobayashl
 et al.,  1979).  The toxlclty  of  chlorophenols  also  Increases with decreasing
 pH  (Konemann  and  Musch,  1981;  SaaMkoskl  and  Vlluksela,  1981.  1982).
 Structure-activity  studies   with   aquatic  organisms   Indicated  that  the
 presence  of  chloro substHuents  In  the  ortho position  decreased  toxlclty,
while  substltuents  In  the  para position  Increased   toxlclty  (Devlllers  and
Chambon, 1986; R1bo and Kaiser, 1983).
    A large volume of  data  1s available  concerning  toxlclty of chlorophenols
 to  freshwater  species;  the  most  sensitive  species   were salmonlds  (rainbow
trout.  Salmo  qalrdnerl.  and  brown  trout,  Salmo  trutta)  and  bluegllls
 (Lepomls macrochlrus).   The lowest reported acutely  toxic  concentration for
freshwater  fishes  was   0.085   mg/l  2,3,4,6-tetrachlorophenol,   a  96-hour
LC,.Q  for  rainbow trout  (Mayer  and  Ellersleck,  1986).   The lowest  reported
acutely  toxic  concentration   for   freshwater   Invertebrates  was 0.29  mg/l
2,3,4,6-tetrachlorophenol,  a  48-hour  LC5Q  for   Daphnla  magna   (U.S.  EPA,
1978a).   Data  for  freshwater  plants,  fungi  and  bacteria  Indicated  toxic
concentrations  similar to  those for  freshwater  fishes  and  Invertebrates.
0018d                               4-21                              06/18/87

-------
 The  lowest  reported  toxic  concentration  for  freshwater  plants  was  0.603
 mg/l   2,3,4,6-tetrachlorophenol,   the   48-hour   EC5_   for   chlorosis   \n
 duckweed   (Blackman  et  al.,   1955).    For  bacteria  and  fungi,   the  lowest
 reported   toxic  concentration  was  0.176  mg/l  2,3,4,5-tetrachlorophenol,  a
 30-m1nute    EC™    for    Inhibition    of    luminescence   of    Photobacterlum
 phosphoreum  (Rlbo and Kaiser,  1983).
     Relatively  little  Information  was available  concerning  marine species.
 The lowest reported acutely  toxic  concentration  for marine  species  was 1.1
 mg/l  2,3,4,6-tetrachlorophenol,  a  96-hour  LC5Q  for   the  cyprlno-  dontld
 fish,  Rlvulus  marmoratus (Koenlg  and McLean,  1980).   The  lowest reported
 toxic   concentration    for    marine   plants   was   0.44   mg/l   2,3,5,6-
 tetrachlorophenol,   a   96-hour   EC-0   for   Skeletpnema   costatum   (U.S.  EPA,
 1978a).
     Few studies  were available  concerning  chronic toxlclty of chlorophenols
 to  aquatic organisms.   The  only study Involving a  full  Hfecycle exposure
 was  that  of  Koenlg and  McLean  (1986)  who found that fin erosion  occurred  In
 all     fish     (Rlvulus    marmoratus)     exposed     to     0.055     mg/l
 2,3,4,6-tetrachlorophenol, the  lowest  concentration  tested.
     Chlorinated phenols have been  shown  to Impair  the  flavor of  freshwater
 fish  flesh at concentrations  much  lower  than  those  that  are  toxic  (Shumway
 and  Palensky, 1973;  U.S. EPA,  1980b,c,d).  The lowest reported concentration
 for  flavor Impairment  was 0.0004  mg/l 2,4-d1chloropheno1,  a threshold  for
 largemouth  bass  (Hlcropterus  salmoldes)  (Shumway and  Palensky,   1973).   As
 discussed  by  U.S.  EPA  (1980b,c,d),  threshold  concentrations  for  tainting  of
 flsn  flesh may  be more Important than toxic  concentrations  In  establishing
water quality criteria  for aquatic biota.
0018d                                4-22                              06/18/87

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                             5.  PHARHACOKINETICS
 5.1.   ABSORPTION
    Delchmann and Kepllnger  (1981)  stated  that  the  chlorophenols  are  readily
 absorbed  from the gastrointestinal  tract and  from parenteral sites  of  Injec-
 tion.   Carpenter  et  al.   (1985)  reported  that  peak   plasma   levels   of
 radioactivity were reached 2 hours  after male rats  were  dosed  by  gavage with
 14C-labeled 2- and 4-chlorophenol (levels not provided).
    Korte  et  al.  (1978)  administered  l4C-2,4,6-tr1chlorophenol  to male
 rats at  three dally  doses equivalent  to 1 ppm  1n the diet.  Of  the adminis-
 tered radioactivity, 82.3% was  detected In the urine and  22.2%  1n the feces
 collected over 5 days.   Thus, at least 82.3% was absorbed.
    Roberts et al. (1977) examined  the  permeability of  human  epidermis to 2-
 and 4-chlorophenol, 2,4-d1chlorophenol  and 2,4,6-tMchlorophenol  In vitro. A
 2.5  cm2  area  of  epidermal  membrane,  obtained  from  abdominal  skin   at
 autopsy,  was  supported  between  two  halves  of   a  cell   for  exposure  to  the
 compounds  that  were  dissolved  In  water.    Results Indicated  that all  the
 chlorophenols studied were absorbed by  the epidermal  membrane.  Permeability
 coefficients  and  threshold  concentrations  for  tissue  damage are  shown In
 Table 5-1.
    Gosselln et al. (1976) reported that acutely toxic  amounts of 2.4,5- and
 2,4,6-tMchlorophenol  were  not  absorbed  through Intact  skin, of  rabbits or
guinea pigs.  In  contrast,  toxic levels of  2,3,4,6-tetrachlorophenol  can be
absorbed through the skin.
    Additional quantitative  data concerning the absorption   of  the  chloro-
phenols  could  not  be   located   1n   the  available   literature  as  dted  In
Appendix A.
0019d                               5-1                               06/18/87

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                                   TABLE 5-1
           Permeability  Coefficients  and  Threshold  Concentrations  for
                  Damage 1n  Human  Epidermis  for  Chlorophenolsa
       Compound
Permeability Coefficient
     (cm/mln x 104)
Threshold Concentration
      for Damage
        (% w/v)
 2-Chlorophenol
 4-Chlorophenol
 2,4-01chlorophenol
 2,4,6-Trlchlorophenol
          5.51
          6.05
         10.01
          9.90
0.8
0.75
no damage'1
no damage*3
aSource: Roberts et al.,  1977
bAt any concentration of  chlorophenol  up  to  saturation
0019d
           5-2
                05/08/87

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 5.2.   DISTRIBUTION
    Exon  and  Keller  (1982)  examined  the 2-chlorophenol  content of the  liver
 and  kidneys  of  five  female Sprague-Oawley  rats  that  were  provided  with
 drinking  water  containing  2-chlorophenol  at 5, 50  or  500 ppm for 10 weeks.
 The 2-chlorophenol  levels  1n the liver were 2.20, 3.20 and 0.08 ppm for  the
 5, 50 and  500 ppm  groups,  respectively.   In  the kidney,  the  levels were 2.6,
 2.4 and 2.0 ppm  for  the  5,  50 and  500 ppm groups, respectively.  No  explana-
 tion  was  given   for  the  decrease 1n  tissue  concentrations  1n the high-dose
 group.
    Somanl  and   Khalique  (1982) studied  the  distribution  of  2,4-dlchloro-
 phenol 1n  rats following Intravenous  administration of a  10  mg/kg  dose.  The
 highest  concentration  of   2,4-d1chlorophenol  was  found   In   the  kidney,
 followed by the  liver,  fat and  brain.  The  plasma  volume of  distribution of
 2,4-d1chlorophenol was 3.7  t/kg.
    Korte  et al.  (1978)  did not detect any  radioactivity In  the  liver, lung
 or fatty  tissue  of  three  rats,  5  days after  the rats received three  dally
doses   of  14C-labeled  2,4,6-tMchlorophenol   by  stomach tube.   The  doses
were equivalent  to 1 ppm 1n the  diet..
    PekaM  et  al.  (1986)  administered 2,4,6-tMchlorophenol  at 25  mg/kg In
propylene glycol Intraperltoneally to  male Ulstar rats.   At  0.5,  1,  2,  4, 6,
8  and 10  hours  after  administration, blood  samples  and  samples  from  the
 liver, kidney, muscle, fat  and  brain  were examined  for 2,4,6-tMchlorophenol
and conjugates.   The highest concentrations of 2,4,6-tMchlorophenol  1n  all
tissues were  noted 30 minutes  after  the  dose was  administered.  The kidney,
with 329^117 nmol/g,  contained  the  highest concentration of 2,4,6-tMchloro-
phenol, followed by  the  blood,  liver,  fat,  muscle  and  brain.   At 30 minutes
0019d                               5-3                              06/18/87

-------
 after  dosing,  70% of the 2,4,6-trlchlorophenol  In  the  blood  was  In the con-
 jugated  form.   At 10 hours  after dosing, only  minute  amounts  of 2,4,6-trl-
 chlorophenol were  found  In the blood and  tissues.
     In  a 55-day  gavage  study of  the  toxldty  of 2,3,4,6-tetrachlorophenol,
 Hattula  et  al.  (1981b)  determined tissue concentrations In male Wlstar rats.
 In  rats  dosed  at  10  mg/kg/day,  no residues of 2,3,4,6-tetrachlorophenol were
 found  1n muscle or brain and concentrations  In  the spleen, kidney and liver
 were  very  low.   At  dose  levels of   50  and  100  mg/kg/day,   the  highest
 2,3,4,6-tetrachlorophenol  concentrations were found  In the  spleen (1.4 and
 3.2  ppm) and  kidney  (1.0 and 5.1  ppm)  the smallest levels were found 1n the
 muscle and  brain.
 5.3.   METABOLISM
    Karpow  (1893)  found  that   2- and   4-chlorophenol  administered  to  dogs
 (route not  stated) resulted  In  the excretion of  sulfurlc and glucuronlc add
 conjugates.   In rabbits, 82% of a 150-300 mg/kg  dose  of  2-chlorophenol was
 conjugated  with  glucuronlc  acid,  while  -19%  was  conjugated with  sulfate
 (Spencer and Williams. 1950).
    Koster  et  al.  (1981)  examined   the  metabolism  of   4-chlorophenol   In
 anesthetized male  Hlstar rats.   The rats  were  Injected Intravenously 1n the
 femoral  vein  with 4-chlorophenol  at  doses of 14-135  ymol/kg dissolved 1n  1
mt  aqueous  0.9%  (w/v)   NaCl.   81 le  and  urine were  analyzed for  conjugates
 for  4  hours   postexposure.    The  results  showed  that  4-chlorophenol  was
predominantly  glucuronldated (61-72%  of the dose),  while  the remainder was
sulfated  (39-21%  of  the dose).   As  the  Injected  dose  Increased,  the  amount
excreted as the glucuronlde  Increased,  and  the  amount  of  sulfate  decreased,
although  these  changes  were  not large.  Throughout  the experiment,  100%  of
the administered dose was  recovered.   Koster et  al.  (1981) also  examined  the


0019d                               5-4                              06/18/87

-------
metabolism  of  4-chlorophenol  In  Isolated  rat  hepatocytes.   At  concentrations
of  25  and  800  nM,  glucuronldatlon  of  4-chlorophenol   predominated,  and  a
concentration-dependent shift  In  the ratio between sulfatlon  and  glucuronl-
datlon was  not observed.
    Somanl  and  Khallque  (1982)  found  that  2,4-d1chlorophenol  administered
Intravenously  to rats  was metabolized  to glucuronlde and  other  conjugates.
In an In  vitro study using  Isolated  perfused  rat  liver,  Somanl et  al.  (1984)
Identified  two dlchloromethoxyphenols as metabolites  of  2,4-d1chlorophenol.
    After  orally  dosing  Wlstar  and  Sprague-Oawley  rats  with  14C-labeled
2,4,6-trlchlorophenol  for  15 days,  Bahlg  et  al.  (1981)  Identified  glucuro-
nlde  conjugates  and trlchlorophenol  Isomers  (2,4,6-, 2,3,6-  and  2,4,5-)  1n
the urine.
    Ahlborg  and  Larsson  (1978)  examined  the  metabolism of purified  tetra-
chlorophenols  In Sprague-Oawley rats.   After being  dosed  Intraperltoneally
with  10  mg/kg  of a  tetrachlorophenol  Isomer  In propylene  glycol,  rats  were
placed  1n metabolism  cages,  two per  cage,  and the  urine  was  collected  at
24-hour  Intervals  for   up  to 72 hours.   Before the  urine  was  analyzed for
metabolites,  1t  was  boiled  with   concentrated  hydrochloric  add  to  split
possible  conjugates.   Analysis  of  the  urine  revealed that  tetrachlorohydro-
qulnone  was a  major  metabolite of  2,3,5,6-tetrachlorophenol.   Except for
Insignificant  amounts   of  tr1chlorohydroqu1none   Identified   In   the  urine,
2,3,4,5- and  2,3,4,6-tetrachlorophenol  were  excreted  In  the  urine  essen-
tially unchanged or as  conjugates.
5.4.   EXCRETION
    In the  study by  Karpow  (1893),  87% of 2- and 4-chlorophenol administered
to dogs was excreted 1n the urine as sulfuMc and glucuronlc add  conjugates.
0019d                               5-5                               05/08/87

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     Somanl  and  Khallque  (1982)  found  that  the half-lives  of  2,4-d1chloro-
 phenol  and  Us  conjugates  varied  from 4-30  minutes  In  the  plasma,  fat,
 brain,  liver and  kidneys of rats treated with 10 mg/kg Intravenously.
     Korte  et  al.  (1978)  found  that  over 5 days, rats excreted 82.3%  of  the
 radioactivity   from  14C-labeled  2,4,6-tMchlorophenol  1n  the  urine,  while
 22.2% was  eliminated 1n  the  feces.   The products  excreted  were  not Identi-
 fied.   The  compound  was  administered In three dally doses to three male rats
 by  stomach  tube  at a level equivalent to 1 ppm 1n the diet.
     Bahlg  et  al. (1981) examined  the excretion  of  2,4,6-trlchlorophenol  and
 metabolites after six Wlstar  and  Sprague-Oawley rats  were dosed  by  gavage
 with  25  vg  14C-labeled 2,4,6-tMchlorophenol  for  15  days.   The  results
 showed  that 28% of  the  applied  radioactivity was found In the urine In water
 soluble  form  (conjugates plus water  soluble metabolites),  63% was  found In
 the  urine  1n  chloroform-soluble  form and 6.4%  was  found  1n the feces.  At 3
 days  after  cessation of  the  15-day  dosing  period,  urinary  and fecal excre-
 tion  of  radioactivity decreased  sharply to  4.3  and  1.9% of  the dose, respec-
 tively.  The  high recovery and  rapid  decline  In excretion  of  radioactivity
 Indicate that 2,4,6-tMchlorophenol  Is  not accumulated In  rats.
    PekaM  et   al.   (1986)  found  that   90%  of  a   single 25  mg/kg  dose of
 2,4,6-trlchlorophenol  Injected   1ntraper1toneally Into  male Wlstar  rats  was
 excreted  1n  4-6  hours.   The  half-life  of  2,4,6-trlchlorophenol  ranged  from
 1.4-1.8 hours  1n  the blood, liver, kidney, muscle,  fat and brain.
    After  administration   of  an   Intraperltoneal   dose  of   10  mg/kg  of
 2,3,5,6-tetrachloropnenol  1n   rats,  Ahlborg  and Larsson (1978)  found  that
98.7% of  the  dose was  excreted  1n  the  urine after 24 hours.  Approximately
0019d                               5-6                               05/08/87

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 66.5X  of  the dose was  unchanged,  while -33.5X was excreted  as  tetrachloro-
 hydroqulnone.   When  2,3,4,6-tetrachlorophenol  was  given  to  rats  Intraperl-
 toneally,  95.9% of  the  dose  was  recovered  unchanged  In  the  urine at  72
 hours, while only  58.8% of  a  dose  of  2,3,4,5-tetrachlorophenol was  recovered
 In the urine 72 hours after dosing.
    Kalman  and  Horstman  (1983)  examined  the excretion  of  2,3,4,6-tetra-
 chlorophenol  In humans  occupational!;/ exposed  to Permatox.100 (3%  penta-
 chlorophenol,  21%  2,3,4,6-tetrachlorophenol).   Exposures were considered  to
 be primarily by the  dermal route rather  than  through  Inhalation.   The urine
 of  two workers was  examined  for  2,3,4,6-tetrachlorophenol  every  other  day
 during a  16-day vacation.   Both workers showed an  Initial  period  of between
 2  and  3  days  during   which   the  urinary  level  was  >100  ppb  before  an
 exponential  decay  In urinary  2,3,4,6-tetrachlorophenol  was  observed.   This
 delay  Is   consistent   with  an  Initial  distribution  phase   followed  by
 first-order elimination.   In  addition, the urine of 24  workers  was examined
 before and  after a 16-day vacation.   Adjusting the data from the  24 workers
 for  the   distribution   phase  observed  In  the  2 more  frequently  examined
workers,   the  average half-time of elimination  of 2,3,4,6-tetrachlorophenol
was estimated at 63+34 hours.
 5.5.   SUMMARY
    The chlorophenols  seem to be readily  absorbed from the gastrointestinal
 tract and from  parenteral  sites  of  Injection  (Delchmann and KepHnger, 1981;
Carpenter  et  al.,  1985).   Rats dosed  orally  with l4C-2,4,6-tr1chlorophenol
absorbed  at least 82.3% of  the  dose based on  urinary excretion  of radio-
activity  (Korte et  al.,  1978).   Roberts  et  al.  (1977)  found  that 2-  and
4-chlorophenol,  2,4-
-------
 human  epidermis  j_n  vitro.   Acutely  toxic  levels  of  2,4,5- and  2,4,6-tr1-
 chlorophenol  were not  absorbed through the  Intact  skin  of  rabbits  or  guinea
 pigs,  while toxic levels  of  2,3,4,6-tetrachlorophenol  were  absorbed through
 the  skin  (Gosselln et al., 1976).
     Pharmacoklnetlc  studies  of  the  chlorophenols  In  laboratory  animals
 Indicate  that the compounds  are  distributed rapidly, but do not  accumulate
 In  any tissue  (Exon  and Koller, 1982;  Somanl  and Khallque, 1982;  Korte  et
 al.,  1978;  PekaM et  al., 1986;  Hattula  et  al.,  1981b).  Metabolism studies
 Indicate  that  the chlorophenols  are conjugated  to glucuronldes  and sulfates,
 with  glucuronldes predominating  In  rats  (Karpow, 1893,  Koster  et  al.,  1981;
 Somanl and  Khallque,  1982; Bahlg et al.,  1981).  Other  metabolites that have
 been  Identified are dlchloromethoxyphenols  Identified  1n an _h)  vitro  study
 of  the metabolism of 2,4-d1chlorophenol  (Somanl  et al., 1984), tetrachloro-
 hydroqulnone  as  a metabolite  of  2,3,5,6-tetrachlorophenol and  tMchloro-
 hydroqulnone  as  a minor metabolite  of 2,3,4,5- and 2,3,4,6-tetrachlorophenol
 (Ahlborg  and  Larsson,   1978).   In addition,  Sahlg  et al.  (1981)  found that
 other  trlchlorophenol   Isomers  are   excreted when  2,4,6-trlchloropnenol  was
 administered orally to  rats.
    Studies In  laboratory animals  (Karpow,  1893; Korte  et  al..  1978;  Bahlg
 et al., 1981; Ahlborg and Larsson,  1978)  Indicate  that  the  chlorophenols are
 excreted  predominantly  1n the urine  as  glucuronlc and  sulfuMc  add  conju-
 gates, and  as  the unchanged  compounds.   Kalman  and Horstman  (1983)  found
 that  the  half-time of  elimination  of  2,3,4,6-tetrachlorophenols  In occupa-
 tional ly exposed  humans was -63+34 hours.
0019d                               5-8                               05/08/87

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                                  6.   EFFECTS
 6J.    SYSTEMIC TOXICITY
 6.1.1.    Inhalation Exposure.
    6.1.1.1.   SUBCHRONIC -- In  a Russian  study  (Gurova,  1964),  rats  and
 mice  were exposed  to supraHmlnal concentrations  (levels  not provided)  of
 4-chlorophenol 4  hours/day  for  28 days.  Pathological changes  1n  the  organs
 Included  congestion  and  focal  hemorrhages 1n  the brain,  lungs,  Hver  and
 myocardium,  thickening  of  the  alveolar   septa  and  some  atelectases  and
 emphysema  1n the  lungs.
    In  another experiment by Gurova (1964), white  rats  were exposed  to 0.002
 mg/a  (2  mg/m3)  4-chlorophenol  6  hours/day  for  4  months.   During  the
 first 30  days of  exposure,  the  exposed rats  showed  a weight  loss  compared
 with controls.  By the end  of  the study,  the  exposed  rats gained more weight
 than  controls.    Throughout   the  study,  neuronuiscular   excitability  was
 Increased  and  a  reduction  of  general  endurance  compared with  controls  was
 observed.  The exposed rats also  showed an Increased  myoneural excitability.
 Hemoglobin,  RBC,  WBC, sedimentation  rate  and body temperature were similar
 to  controls.   Microscopic examination  of  organs  revealed  slight  congestion
 and minor  flbrotlc  changes 1n  the alveolar septa of  some  rats.   This study
 lacked  sufficient detail to adequately assess the reliability of the results.
    6.1.1.2.   CHRONIC — Gurova   (1964)   studied    workers   exposed    to
 4-chlorophenol at an  aniline  dye plant In  the  Soviet Union.   Exposures were
 by  both Inhalation  and  dermal  routes.   The authors  stated  that  the total
 quantity  of  4-chlorophenol absorbed  did  "not  exceed  10-15  mg/sh1ft."   The
 highest  ambient  air   concentration   was  reported  to  be  0.021   mg/i.   The
workers  experienced   a  higher  Incidence  of  neurologic  disorders.    Effects
 noted   Included  nervous   exhaustion,  Insomnia,  Irritability,  frequent  mood


 0020d                               6-1                               05/11/87

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 changes  and  rapid  fatlgabUHy.   A  two-point   touch  discrimination  test
 showed  that  the workers  suffered  a lessening of touch sensation.   Peripheral
 nerve  stimulation examinations  Indicated Increased  myoneural  excitability.
 Again,  the lack of  detail  precludes  adequate assessment of  the  reliability
 of  the  results.
     Kleu   and   Goltz  (1971)  reported  the   case   histories  of  10  patients
 suffering  from  chloracne, who were occupatlonally  exposed  to  an  unspecified
 tMchlorophenol  formulation  for   15  years.   In  addition   to  chloracne,  a
 psychopathologlcal  syndrome  was   described.   Symptoms,  which  Increased  In
 Intensity  over  the  period  of exposure,  Included  decreased  sexual  activity,
 easy fatlgabllUy,  Irritability, muscular  weakness,  loss  of appetite  and
 memory,  discouragement,  alcohol   Intolerance and  loss  of  Interest.   When the
 report  was written, a  permanent   defect, described as reduced  vital  physic
 and  Intellectual  capacities  combined with  neurasthenia  and  mental  depres-
 sion, was  becoming evident.  However,  there was  no  detailed  Information on
 the  exposure history  of these patients and  the  study  made  no  attempt to
 establish  a causal relationship.
     Alexandersson  and  Hedenstlerna (1982) studied the pulmonary  function of
 two  men and  five  women  who were  occupatlonally exposed  to  an  unspecified
 trlchlorophenol  Isomer  for  up   to   10  years.   The  subjects  studied  were
 exposed during  the  testing  of gas masks, a  process that uses trlchlorophenol
 as  a tracer  gas.    Exposure levels  were probably  variable,  but  levels of
 <0.003 mg/i  were measured,  with  each Individual  testing up  to  25 gas masks
 per  day.   The subjects  studied  Included three smokers  (15-20 cigarettes/day)
and  four  nonsmokers.  The  parameters examined  Included  FEVC, FEV,,  HEF at
75,  50  and 25X of FEVC  and CV%  In percent  of  vital  capacity.  In addition,
 the  subjects  were  given  a  questionnaire  regarding  symptoms  of  the  upper


0020d                               6-2                               06/18/87

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 derived.   Confidence  1n this RfD  Is  medium.   Although the study  by  Hattula
 et  al.  (19815) uses only  a  few animals,  dosing was 7 days/week and  several
 parameters  were examined;  and  the study by  Schwetz  et  al.  (1974)  supports
 the NOAEL.
    8.2.2.2.    CHRONIC  EXPOSURE -- In a  chronic  toxlclty  study  (Exon  and
 Keller, 1985),  hematologlc effects were noted  In  rats  provided  with  drinking
 water containing 2-chlorophenol at 500 ppm.   These  effects  were not  observed
 at 50 ppm.  No  other parameters of toxldty were examined  1n this study.
    Exon and Koller (1982) found  reproductive  effects  In  female rats  exposed
 to  2-chlorophenol  In  their  drinking water  at  500  ppm but  not at  50 ppm.
 U.S.  EPA  (1986b)  used  the reproductive  NOAEL to derive a  chronic  RfD.  The
 RfD was derived from a  NOAEL  dose of  5  mg/kg/day, estimated by assuming that
 the dally  Intake of  water  by rats Is 10% of  their  body weight.  Application
 of an  uncertainty  factor of  TOOO (10 for  1nterspec1es extrapolation,  10 to
 protect  sensitive  Individuals  and 10  for extrapolation  from  a  subchronlc
 study), results In  a  chronic RfD of  0.005 mg/kg/day,  or  0.4  rag/day  for a 70
 kg  human.   Confidence  In  this  RfD  1s  low;  adequate  parameters  of  the
 toxlclty of 2-chlorophenol  were not examined.
    U.S.  EPA   (1986b,c) derived  an  RfD  for   2,4-dlchlorophenol  from  the
subchronlc  study  by Exon  and Koller (1985).   This RfD,  0.003 mg/kg/day or
0.2 rag/day  for a  70 kg  human,  which  was presented as the  subchronlc RfO 1n
Section 8.2.2.1., 1s  also  adopted as the  chronic RfD.  An additional  uncer-
 tainty  factor  of  10 to  extrapolate  from subchronlc  data  was not considered
necessary because the rats were exposed  .In. utero and  through the milk  before
the  15-week  exposure  period  (U.S.  EPA,  1986c).    As  stated  1n  Section
8.2.2.1., confidence  In the  RfD  Is low  because of the limited  parameters of
 toxlclty that  have been examined  In  studies of the toxlclty  of  2,4-dlchloro-
phenol .

QQ22d                               8-10                              08/11/87

-------
     No chronic oral studies concerning the  toxlclty  of  2,4,5-tMchlorophenol
 are available.  A  chronic  oral  RfD of 0.1  mg/kg/day  or  7.0  mg/day for a 70
 kg human was  derived  by U.S. EPA  (1985a)  from  the  study  by McColllster et
 al.  (1961)   by  applying an  uncertainty  factor of  1000  (10 for  Interspedes
 extrapolation,  10  for  the  protection of  sensitive  Individuals and  10 to
 approximate  chronic exposures)  to  the  NOEL  of  100  mg/kg/day  (see Section
 8.2.2.1.).   Because   the  subchronlc  study  was  well-conducted  but because
 supporting  data are  not available,  confidence  In  the chronic  oral  RfO Is
 medium to low.
    Chronic  studies of  the  oral  toxlclty of  the tetrachlorophenols are  not
 available.   A  chronic   oral  RfD  of  0.01  mg/kg/day or  0.7  mg/day for a 70 kg
 human   for  2,3,4,6-tetrachlorophenol  was derived   by U.S.  EPA  (1985b) by
 applying  an  uncertainty factor  of  1000   to  the  subchronlc oral  NOEL  of 10
 mg/kg/day  In  the  study by  Hattula  et  al.  (1981b)  (see Section  8.2.2.1.).
 The uncertainty  factor reflects  an additional factor  of 10 for  subchronlc to
 chronic  extrapolation.  For  reasons stated  In  Section 8.2.2.1.,  confidence
 In the  RfD Is medium.
0022d                                8-11                              08/11/87

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                           9.   REPORTABLE  QUANTITIES
 9.1.    BASED ON SYSTEMIC TQXICITY
     Toxlclty  data  concerning  the chlorophenols were discussed  In  Chapter  6.
 Data   suitable  for  deriving   RQs  are  summarized  In  Table  9-1.   No  data
 concerning  the  toxlclty  of   3-,  4-chlorophenol,  2,3-,   2,5-,  2,6-,  3,4-,
 3,5-d1chlorophenol,  2,3,4-,  2,3,5-,   3,4,5-tMchlorophenol  or  2,3,4,5- and
 2,3,5,6-tetrachlorophenol  were available;  therefore, RQs  for  these compounds
 cannot  be derived.
    U.S.  EPA  (1983b)  examined the data concerning the toxlclty of 2-chloro-
 phenol  and concluded  that there  were  Insufficient  data  to  derive  an  RQ;
 however,  since  that time,  Exon  and  Koller  (1982)  completed  a reproductive
 study  that  1s appropriate for RQ derivation.   In  this   study,  Utter sizes
 were  significantly reduced 1n  rat  dams  exposed  to  2-chlorophenol  1n their
 drinking  water at  500  ppm from 3 weeks  of age through lactation.  Multiply-
 ing  the  transformed  human dose  (12  mg/kg/day)  by  70   kg (the  human  body
 weight)  a human  MED of  840 rug/day 1s  derived,  which  corresponds  to  an RV.
 of  1.1.  The  fetotoxldty observed  In  the study corresponds  to  an  RV  of
 8.   Multiplying  the  RVg  by  the  RVd,  a  CS  of  9  Is  derived.  This  CS
 corresponds  to  an  RQ  of  1000.   The  data   used  to   derive  the   RQ  for
 2-chlorophenol are shown In Tables 9-2 and  9-3.   As  Indicated In  Table 9-4,
 there were Insufficient data to derive RQs for both 3- and  4-chlorophenol.
    Three  studies  are   available   for   the  derivation  of   an  RQ  for
 2,4-d1chlorophenol  (Table 9-5).   In  the study  by  Rodwell  et  al.   (1984),
 signs  of  maternal   toxlclty and fetotoxldty  were  noted  1n  rats  treated by
 gavage  with  2,4-d1chlorophenol  at  750 mg/kg  on gestation  days  6-15.  In
 calculating the human  MED, the transformed  human  dose,  128.2 mg/kg/day, was
multiplied by  the  human body  weight  of  70 kg.   The  human  MED  of  8960 mg/day


 0023d                               9-1                               06/18/87

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9-3
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-------
                                   TABLE 9-2

             Oral  Composite  Score  for  2-Chlorophenol Using the Rat*
 Animal  Dose
 (mg/kg/day)
 Chronic
Human MEO
(mg/day)
RVd
Effect
RV0     CS
RQ
     70
   840
1.1      Decreased Utter
        size; Increase 1n
        stillbirths
                               1000
*Source: Exon and Koller,  1985
0023d
                     9-4
                                        05/11/87

-------
                                   TABLE  9-3
                                2-Chlorophenol
           Minimum Effective  Dose  (MED) and Reportable Quantity  (RQ)

Route:                  oral
Dose*:                  840 mg/day
Effect:                 decrease 1n Utter size and a slight Increase 1n
                        stillbirths
Reference:              Exon and Koller,  1982
RVd:                    1.1
RVe:                    8
Composite Score:        9
RQ:                     1000
'Equivalent human dose
0023d                               9-5                               05/11/87

-------
                                   TABLE 9-4

                       3-Chlorophenol  and 4-Chlorophenol

           Minimum Effective Dose (MED) and Reportable Quantity (RQ)




Route:

Oose:

Effect:

Reference:

RVd:

RVe:

Composite Score:

RQ:                     Data are Insufficient for deriving an  RQ for either
                        3- or 4-chlorophenol.
0023d                               9-6                               05/11/87

-------




















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-------
 corresponds  to  an  RV,  of  1.    In  the  study by  Exon  and  Koller  (1985),
 fetotoxlclty  was also noted  In  rats  exposed  to  2,4-d1chlorophenol  In  their
 drinking  water  at  300 ppm  from 3 weeks  of  age through parturition.   The
 human  MED of 504 mg/day was  calculated  by  multiplying  the human transformed
 dose,  7.2 mg/kg/day, by  the  70  kg human body weight.   This  MED corresponds
 to  an  RVd  of 1.4.   The  RVQs of both  the Rodwell et  al.  (1984)  and  Exon
 and  Holler  (1985)  studies  correspond   to  8,  so  that   the  Exon  and  Keller
 (1985)  study  with  a CS of 11.2  would  be more  appropriate for  the derivation
 of an  RQ  than the Rodwell et al.  (1984) study with a  CS  of  8.8.  Despite a
 lower  RV  ,  the  highest  CS  for  2,4-d1chlorophenol.  1s  calculated  from  the
 study  by  Kobayashl  et al.-(1972)  In  which hlstopathologlcal  changes  were
 observed  In  the  livers of rats  provided with  diets containing 2,4-d1chloro-
 phenol  at 0.2%  for  6  months.  The human MED, 121  mg/day, was  calculated by
 multiplying  the  human  transformed dose, 17.3  mg/kg/day,  by  70  kg human body
 weight  and  by dividing by  10 to account for  subchronlc  exposure.  This  MED
 corresponds  to  a  RV.  of  2.4.   The  liver   changes  correspond  to an  RV   of
 5.   Multiplying  the  RVd  by  the  RVg,  a  CS of  12  Is  derived.  This  CS
 corresponds to an RQ of 10QQ (Table 9-6).
    An  evaluation  of the data concerning the  toxlclty  of 2,6-d1chlorophenol
 (U.S.  EPA,  1983d)  found that  there were Insufficient  data  to  derive  an RQ.
 Table  9-7 Indicates  that  there were  Insufficient data  to derive RQs  for
 2,3-, 2,5-, 2,6-, 3,4- and 3,5-dlchlorophenols.
    Two  studies  are  available   for   the   derivation  of  an  RQ  for  2,4,5-
 tMchlorophenol  (Table 9-8).  In the  study  by Chernoff  and Kavlock  (1982), a
 reduction   1n  IHter  size  was observed  In   mice  treated by  gavage  with  the
compound   on   gestation   days    6-15.     The   chronic   human   MED,    4221
0023d                               9-8                               06/18/87

-------
                                  TABLE 9-6
                              2,4-01chlorophenol
           Minimum  Effective Dose  (MED) and Reportable Quantity (RQ)

Route:                  oral
Dose*:                  121  mg/day
Effect:                 reversible hepatic changes
Reference:              Kobayashl  et al.t  1972;  U.S.  EPA,  1983c
RVd:                    2.4
RVe:                    5
Composite Score:        12
RQ:                     1000
'Equivalent human dose
0023d                               9-9                               06/18/87

-------
                                   TABLE 9-7
                 2,3-, 2,5-, 2,6-, 3,4- and 3,5-01chlorophenol
           Minimum Effective Dose (MED) and Reportable Quantity (RQ)


 Route:
 Dose:
 Effect:
 Reference:
 RVd:
 RVe:
 Composite Score:
 RQ:                     Data are  Insufficient  for deriving an  RQ  for any of
                        the dlchlorophenol  Isomers  listed above.
0023d                               9-10                              05/11/87

-------



















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-------
 rog/day,  was  calculated  by  multiplying  the  transformed  human  dose,  60.3
 mg/kg/day,  by the 70  kg  human  body  weight.   This MED corresponds to an  RV.
 of  1.   FetotoxIcHy   corresponds  to  an  RV   of  8,  so by  multiplying  the
 RV.  by  the  RV ,  a  CS of 8  1s derived.  A  higher CS  Is  derived from  the
 study  by  McColHster  et  al.   (1961)  In  which  degenerative  changes  In  the
 liver  and  kidney  were  noted  1n  rats  fed 2,4,5-tMchlorophenol  In  the  diet at
 0.3X for 98 days.  U.S. EPA (1983e, 1984a) derived an RQ from the  McColllster
 et al.  (1961)  study  using a  5%  food  factor  and a rat body  weight  of  0.35  kg.
 Because  young  rats  were used In this  subchronlc  study,  a  food  factor of  10X
 and  the body weight of  0.191  kg,  provided by  the authors,  are  more appro-
 priate  values  for use  1n  calculating  the  transformed animal  dose.  Using  the
 more  appropriate  transforming   values,  the   human  MED  (293.3  mg/kg)  was
 derived  by  multiplying the transformed human dose  (41.9 mg/kg/day)  by  70 kg
 (the human  body weight).,  and by dividing  by  a factor of 10.   This MED corre-
 sponds   to  an  RV.   of  1.8.    The  liver  and  kidney  degenerative  changes
 correspond  to  an RVg of  6.   Multiplying   the   RVd  by  the  RVg, a  CS  of
 10.8  1s  derived.   This  CS corresponds to  an RQ  of  1000.   This  RQ  and  the
 data used to derive It are presented 1n Table 9-9.
    U.S. EPA  (1983f)  concluded  that  the data were Insufficient to derive an
 RQ  for   2,4,6-trlchlorophenol   based  on  chronic   tox1c1ty.    An   RQ  for
 2,4,6-tMchlorophenol  based  on  carclnogenlclty  will  be derived  In  Section
 9.2.    Table  9-10  Indicates  the  lack of  toxldty data  available  for  the
derivation of RQs for 2,3,4-, 2,3,5-,  2,3,6- and 3,4,5-trlchlorophenol.
    Two   studies   are   available    for  the   derivation    of   an   RQ   for
2,3,4,6-tetrachlorophenol  (Table 9-11).   U.S.  EPA (1983f)  derived an RQ  from
 the teratogenldty  study  conducted by Schwetz  et al.  (1974)  In  which  feto-
 toxlclty (subcutaneous  edema)  was  observed  In  offspring of  rats treated by
0023d                               9-12                             06/18/87

-------
                                  TABLE 9-9
                            2,4,5-Trlchlorophenol
           Minimum  Effective Dose (MED) and Reportable Quantity (RQ)

Route:                  oral
Dose*:                  293 mg/day
Effect:                 slight degenerative  changes  1n  the  liver  and kidney
Reference:              HcColHster  et al.,  1961
RVd:                    1.8
RVe:                    6
Composite Score:        10.8
RQ:                     1000
'Equivalent human dose
0023d                               9-13                             05/11/87

-------
                                  TABLE 9-10

               2,3,4-, 2,3,5-, 2,3,6- and 3,4,5-Trlchlorophenol

           Minimum Effective Dose (MED)  and  Reportable  Quantity  (RQ)




 Route:

 Oose:

 Effect:

 Reference:

 RVd:

 RVe:

 Composite Score:

 RQ:                     Data are Insufficient for deriving an RQ for any of
                        the tMchlorophenol Isoraers listed above.
0023d                               9-14                             05/11/87

-------
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 gavage  with the  compound  on gestation  days  6-15.  In  the  derivation,  U.S.
 EPA (1983f) applied a factor of  10  to  the  dose;  this  Is not appropriate for
 a  teratogenlclty study because exposure  1s chronic to  the  fetus.   Further-
 more,   the  subcutaneous  edema  was  not  seen  at   the  higher  dose  and  was
 considered  nontreatment-related.   Using  the  dose  of  30 mg/kg/day  from the
 Schwetz et  al.  (1974)  study that  caused delayed ossification, a human MED of
 322 mg/day  Is  derived  by  multiplying  the  transformed   human  dose,  4.6
 mg/kg/day,  by  the 70  kg  human  body weight.  This  MED  corresponds  to  an RV.
 of  1.7, and the fetotoxlclty corresponds  to  an  RV  of  8.   Multiplying the
 RV.  by  the  RV ,   a  CS   of   13.1   1s  derived.   The  Research  Triangle
 Institute (1987)  study reported maternal  toxldty  and  no fetotoxlclty at 200
 mg/kg/day tetrachlororphenol.   A human MED of 239.8 mg/day  Is derived from
 the  animal  dose by  using  the cube  root  of animal/human body  weight  and an
 uncertainty  factor  of 10  to account for chronic  toxldty  to the dam.  This
 MEO  corresponds  to  an RV.  of  1.9,  loss of  maternal  body  weight  to  an RV
 of  3 and a  CS  of  6.   A  higher  CS value  can  be  derived from the  study by
 Hattula  et  al.  (1981b) In which  hlstopathologlcal  changes  In  the liver were
 observed  In rats  treated  with  2,3,4,6-tetrachlorophenol   by  gavage  at  50
 mg/kg/day   for   55   days.    The   human   MED,   61.6  mg/day,  1s  derived  by
 multiplying  the  transformed  human  dose, 8.8  mg/kg/day, by  the  70  kg  human
 body weight and by  dividing by  10  to  extrapolate  from a  subchronlc  study.
 This MED corresponds  to an  RV.  of  2.8,  while the hlstopathologlcal  changes
 1n  the  liver  correspond   to  an  RV   of  6.  Multiplying   the  RV.  by  the
 RVe, a  CS of 16.8  1s  derived.    This CS corresponds to an  RQ of 1000.   The
 RQ and  the  data  used to derive  It are presented In  Table 9-12.   As  Indicated
 In Table 9-13, no toxldty data  were available for  the  derivation of  RQs  for
 2,3,4,5- and 2,3,5,6-tetrachlorophenol.
0023d                               9-16                              06/18/87

-------
                                  TABLE  9-12

                           2,3,4,6-Tetrachlorophenol

           Minimum  Effective Dose  (MED)  and  Reportable Quantity (RQ)



Route:                  oral

Dose*:                  61.6  mg/day

Effect:                 histopathologlcal  changes 1n the liver;  one rat
                        most  of the parenchyma Involved

Reference:              Hattula et al.,  1981b

RVd:                    2.8

RVe:                    6

Composite Score:        16.8

RQ:                     1000
'Equivalent human dose
0023d                               9-17                              05/11/87

-------
                                  TABLE 9-13
                     2,3,4,5- and  2,3,5,6-Tetrachlorophenol
           Minimum Effective Dose (MED) and Reportable Quantity (RQ)


 Route:
 Dose:
 Effect:
 Reference:
 RVd:
 RVe:
 Composite Score:
 RQ:                     Data are  Insufficient  for deriving  an  RQ  for  either
                        2,3,4,5-  or 2,3,5,6-tetrachlorophenol.
0023d                               9-18                              05/11/87

-------
9.2.   BASED ON CARCINOGENICITY
    2,4,6-TMchlorophenol has been shown to be a carcinogen  1n rats  and mice
(NCI, 1979).  In male  rats,  the  compound caused  an  Increase  In the  Incidence
of  leukemia, while  In  mice,  an Increase 1n the  Incidence of  Hver  carcinoma
and adenoma were observed  (see Section 6.2.2. and Table 6-2).  Based  on  the
NCI  (1979)  study and  the  lack of  human  data,  2,4,6-tMchlorophenol  can  be
classified as an EPA Group B2 chemical, probable  human carcinogen.
    The data for the derivation of  the F factor  Is  shown  In  Table 9-14.   The
F  factor  of  1.4xlO~x  (mg/kg/day)"1   for  2,4,6-tMchlorophenol,  was  calcu-
lated   by  multiplying   the  1/ED1(],   1.16xlO~2    (mg/kg/day)'1,   obtained
from  the  multistage model,  by the cube root  of  the ratio of the human  body
weight,  70 kg,  to  the  animal body weight, 0.04  kg.   This F  factor  Indicates
that  2,4,6-tMchlorophenol  should be  placed  1n  Potency Group 3.   Compounds
In EPA Group B2 and 1n Potency Group  3 are ranked  LOW 1n the Hazard Ranking
Scheme.    The low hazard ranking  for 2,4,6-trlchlorophenol Indicates  that It
should be assigned an RQ of 100.
0023d                               9-19                              08/11/87

-------