United States                                   FINAL DRAFT
               Environmental Protection                              ECAO-CIN-P188
               A8encv                                      September. 1987
&EPA       Research  and
               Development
               HEALTH AND ENVIRONMENTAL EFFECTS PROFILE FOR
               PHTHALIC ACID ALKYL.  ARYL AND ALKYL/ARYL ESTERS
               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                           DRAFT: DO NOT CITE OR QUOTE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

               document  Is a preliminary draft.  It has not been formally released
               .S. Environmental  Protection  Agency and should not at this stage be
               d to represent Agency policy.  It  Is being  circulated  for comments
               schnlcal accuracy and policy Implications.

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                                  DISCLAIMER

    This report  Is 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.
ECAO-CIN-P188

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                                   PREFACE
    Health and  Environmental  Effects Profiles  (HEEPs)  are prepared  for  the
Office of  Solid Waste  and  Emergency Response  by the  Office  of Health  and
Environmental Assessment.   The  HEEPs  are  Intended  to  support  listings  of
hazardous constituents  of  a  wide range  of  waste streams  under  Section  3001
of the Resource Conservation  and Recovery Act  (RCRA),  as  well as  to  provide
health-related limits for emergency actions under Section  101  of  the  Compre-
hensive  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  and  the  dates of   the  searches  are  Included  1n  the
section  titled   "Appendix:   Literature   Searched."    The   literature   search
material  Is  current through November,  1985.

    Quantitative  estimates  are  presented   provided   sufficient   data   are
available.  For  systemic toxicants, these Include Reference  doses  (RfOs)  for
chronic exposures.   An  RfO  (formerly  known  as  the  ADI)   is  defined  as  the
amount of a chemical to which  humans can  be  exposed on  a  dally basis  over an
extended  period  of time (usually  a  lifetime)  without  suffering a  deleterious
effect.   In  the case  of  suspected  carcinogens, RfDs  are not estimated  in
this  document  series.    Instead,  a  carcinogenic potency  factor  of  q-|*  is
provided.   These potency estimates  are  derived  for  both oral  and  Inhalation
exposures where  possible.    In addition,  unit   risk  estimates  for  air  and
drinking  water are presented  based on Inhalation and oral  data, respectively.

    Reportable quantities  (RQs)  based  on both  chronic  toxldty and carclno-
genlclty  are derived.  The RQ  1s  used to  determine  the  quantity  of  a  hazard-
ous substance for  which notification Is  required  in  the   event of  a  release
as specified under CERCLA.   These two  RQs (chronic toxkUy and  carclnogen-
IcHy) represent  two of  six  scores  developed   (the  remaining four  reflect
1gn1tab1l1ty, reactivity,  aquatic toxldty and acute mammalian  toxldty).

    The  first  draft  of  this  document  was  prepared   by  Syracuse Research
Corporation  under  EPA  Contract  No.  68-03-3228.   The document  was   subse-
quently  revised  after  reviews  by  staff  within the  Office  of  Health  and
Environmental Assessment:  Carcinogen  Assessment Group, Reproductive  Effects
Assessment Group,  Exposure  Assessment  Group, and the  Environmental Criteria
and Assessment Office In Cincinnati.

    The HEEPs will become part of the EPA RCRA and CERCLA  dockets.
                                      111

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                              EXECUTIVE SUMMARY

    The literature was  broadly  searched for Information pertaining  to  alkyl
and  aryl   phthalate   esters.    The  only   compounds   for   which  appropriate
toxlcologlcal  data  were located  Include  d1(2-ethylhexylJphthalate,  dlethyl
phthalate, d1-n-butyl  phthalate,   dimethyl  phthalate,  d1-n-octyl  phthalate,
n-butylbenzyl phthalate and d11sononyl  phthalate.
    Alkyl  and  aryl phthalates are  generally  colorless  and  odorless  compounds
(CEH, 1975).   Most alkyl phthalates  are liquids at ambient  temperature.   In
general,  the phthalate esters  are poorly  soluble In water  but soluble  In
most organic  solvents,  Including  acetone,  benzene and ether  (Hawley,  1981).
Phthalate  plastldzers  can   undergo   oxidation  during  plastic  processing;
antloxldants are added to resins to Inhibit this reaction.
    The alkyl  and aryl  phthalates are produced  by  reacting  phthallc  anhy-
dride with an  excess  amount  of  the corresponding  alcohol(s)  1n the presence
of  an   esterlfIcatlon  catalyst.    The  commercial   products  are  usually  >99%
pure {U.S.  EPA,  1978b).  Sixteen  U.S.  manufacturers  produce  one or  more  of
the 17  selected phthallc acid esters.   Reported production  figures  and  esti-
mated production  volumes were  available  for each  of  the alkyl  phthalates.
Total  U.S.   production  volume  of  phthallc  add  esters  amounted  to  1179
million pounds  1n 1984  (USITC,  1985).  Alkyl  and aryl  phthalates  are  used
predominantly  as   plastldzers   for  polyvlnyl  chloride  resins  (U.S.   EPA,
1978a,b).   To  a lesser  extent,  they are used as plastldzers  for other  vinyl
resins, cellulose  ester plastics,  synthetic elastomers  and  other  polymers.
End-uses  Include  construction,  home  furnishing,  consumer goods,  packaging,
electrical  uses,   transportation,  medical   products  and   others  (U.S.  EPA,
1978a,b).    Some  alkyl  esters  have  minor   applications  as dielectric  fluid
                                      1v

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[d1(2-ethylhexyl)phthalate],   active   Ingredients    1n   pesticides,   resin
solvents,  perfume  fixatives,  solvents  and  other  uses  (Hawley,  1981;  U.S.
EPA, 1979).
    Hydrolysis  Is  not  expected  to  be  a  significant  removal   mechanism  of
phthalate esters (Suffet  et  al.,  1981).  Mabey et  al.  (1981)  estimated that
phthalate  esters   will   not   undergo  significant   oxidation  In  water.   UV
absorption  spectra  for   some  phthalates Indicate  that  potential  exists  for
direct  photolysis  1n  the environment.  The  photolysis  half-life  of  n-butyl
benzyl  phthalate has  been  observed  to be  >100  days  (Gledhlll  et al.,  1980).
Phthalate esters are  reported to be  metabolized  1n  the aquatic environment
by a variety of pure  microorganisms  and degraded  by mixed  mlcroblal  systems.
The  mlcroblal   degradation  rates vary  widely  depending  upon  environmental
conditions such as temperature,  pH,  amount of  oxygen present  and  the  phtha-
late  structure  (HattoM  et  al., 1975).   BlodegradablHty  of phthalates  In
freshwater  decreases  with  Increasing  size and  complexity  of the  phthalate
ester chains (Hattorl  et al., 1975;  Johnson et al.,  1984).
    Results from river  die-away  tests and activated  sludge  studies  Indicate
that phthalates, as a class,  undergo rapid degradation by  bacteria  commonly
found In the environment  (Saeger and  Tucker,  1973a,b,  1976;  Gledhlll  et al.,
1980).   For  example,  1n  a  simulated lake microcosm Gledhlll  et  al.  (1980)
observed >95X primary degradation of  the complex  ester  n-butyl  benzyl  phtha-
late  1n 7  days.   Under  anaerobic  conditions,  blodegradatlon  of short-chain
alkyl esters  has  been  shown  to  be possible,  but slower  than under  aerobic
conditions, while  degradation  of  the long-chain esters has  been shown  to  be
very slight or  undetectable  (Johnson  et al.,  1984;  Johnson  and  Lulves,  1975;
Horowitz et  al.,  1982;   Shelton  et  al.,  1984).  From the  estimated  Henry's
Law  Constants   for  n-butyl  benzyl,   d1-n-butyl,  d1(2-ethylhexyl),  dlethyl,
dimethyl and  d1-n-octyl  phthalates,  phthalate esters  are  predicted to  not

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significantly volatilize from water  (Lyman et  al.,  1982).   D1-n-octyl  phtha-
late may  significantly  volatilize from shallow  rivers,  although  volatiliza-
tion from  deeper  waters  should  not be significant  (Lyman  et  al.,  1982).   In
sea water, adsorption onto clay minerals and calclte  appears  to  be a revers-
ible process, whereas adsorption  onto  sediments  Is  Irreversible  (Sullivan  et
al., 1982).  This  suggests  that  marine sediments may act  as  a  final  reposi-
tory of phthallc  acid  esters  (Sullivan et al.,  1982).   Calculated sediment-
water partitioning coefficients Indicate adsorption Is  likely  for  all  phtha-
late esters, with  adsorption  tendency  Increasing with the  size and  complex-
ity of  the ester  chain  (Mabey et al., 1981).   Complexatlon with  the  widely
occurring  humlc  and  fulvlc   substances  causes  solubH1zat1on  of  phthalate
esters  In  water,  thus  modifying  their  mobility  (Hatsuda  and  Schnltzer,
1971).  Phthalates have been  Identified In living matter,  and  data collected
from field and laboratory studies  Indicate that  these compounds can  bloaccu-
mulate 1n aquatic  organisms  (Callahan et  al.,  1979a).
    In air,  the  phthalate esters,  as  a  class,  are  predicted to  react with
hydroxyl  radicals,  with  a  t      of  <1 day  (U.S.  EPA,  1986a).    The  actual
atmospheric  t, ?,  however,  may  be longer  than the  estimated  values  because
of  adsorption  onto  airborne  partlculate matter.   Removal  of  atmospheric
phthalate  by wet   and  dry deposition  has  also  been  observed (Kawamura and
Kaplan,  1983; Atlas and G1am,  1981; Karasek et  al.,  1978; Weschler, 1984).
    Significant hydrolysis  of  phthalate  esters  1n  wet  soils  Is  unlikely
(Wolfe et al., 1980; Gledhlll et  al.,  1980).   Shanker et al.  (1985)  observed
mlcroblal   degradation  of d1-n-butyl,  d1(2-ethylhexyl)   and dimethyl  phtha-
lates 1n  garden  soil.   Results  Indicate  that  soil  mlcroflora  significantly
degrade  phthalates  under  aerobic  conditions,  and  short-chain   phthalates
degrade at  a faster  rate  than the  longer  chain phthalates.  The anaerobic
degradation  of phthates was very  slow  compared with aerobic blodegradatlon.

                                      v1

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The  water  solubilities  and  K    values   of   the   phthalates  suggest  that
adsorption  to  soils  1s dependent  on  the  size and complexity  of phthalate
ester  chains.    Dimethyl  phthalate  should  be  reasonably  mobile  In  soils,
whereas  large  or  branched  chain esters,  Including dlphenyl  phthalate,  should
remain  strongly  adsorbed  to soils.   The mobility of phthalate  esters  1n the
presence  of  fulvlc add  should Increase.    Since  dimethyl  phthalate  1s  not
likely  to adsorb  to  soils, volatilization  from  dry soil surfaces may  be  a
potential  removal  mechanism.   Volatilization  should  be Insignificant  for
other phthalates.
    Phthalate  esters  are   ubiquitous  In  the   environment,   they  have  been
Identified  In  surface  waters  In  the  United  States  and  elsewhere   1n  the
world.   The  maximum reported concentration  of  d1(2-ethylhexyl)  phthalate  1n
any  surface  water  was  600 ug/l,  which  was detected  In Mississippi  River
water  (Corcoran,  1973).  The  average  concentration of  Individual  phthalate
esters  1n  surface water   1s  <1  vq/i   (Michael  et  al.,  1984).   Phthalate
esters  have  also been  Identified 1n  groundwater  from contaminated sites;  a
maximum   of   100   yg/l   of  d1(2-ethylhexyl)   phthalate  was   detected   \n
groundwater  from  a landfill  site   In  New  Castle   County,  DE   (DeWalle  and
Chlan,  1981).   Several  phthalate  esters  have been Identified  In  drinking
water  abstracted  both  from surface  water  and  groundwater.   The  maximum
concentrations   of  dlethyl, d1-n-butyl,  d1(2-ethylhexyl) and  butyl   benzyl
phthalates 1n  39 public water  wells  were   reported  to  4.6,  470,  170  and  38
vig/1,   respectively  (CEQ,   1980;  1981;   Burmaster,   1982).    The  Science
Advisory  Board  of  the  U.S.  EPA   reviewed  selected  organic  chemicals  and
estimated  that  the  distribution  of  the  phthalate  esters  1s  -50% In  U.S.
drinking  waters,   with  an overall  phthalate  concentration   of  ~1   yg/5.
(U.S.  EPA,  1978c).  On the basis  of these data  and an  average  consumption
                                      vll

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rate  of  2  I/day,   dally  phthalate   exposure   to  a  U.S.  Individual  from
Ingesting drinking water 1s estimated to be 2 pg.
    Phthalate esters have  been  detected  In ambient  atmosphere.   Probably the
biggest contributor  to  atmospheric  phthalate  1s  the Incineration of plastics
that  contain  the esters  (Peakall,  1975).   The  concentrations  of  d1-n-butyl
and  d1(2-ethylhexyl) phthalate  1n  New York  City's  ambient   air  were  4.2
mg/m3  and  13.7  ng/m3,  respectively  (Bove  et  al..  1978).    In  College
Station,  TX,   the  corresponding  values  were reported  to  be   3.8 and  2.4
ng/m3  (Atlas   and  Glam,   1981).    Until   more   air  monitoring  data  become
available, 1t  Is  not possible  to  provide  an average  urban  and rural  levels
of phthalate  esters.   Consequently, Inhalation  exposure of  phthalate  esters
to the U.S. population  residing  In  urban,  suburban  and rural areas cannot be
estimated.  Maximum  exposure to phthalate esters  1s  likely to occur  under
occupational   conditions.    Concentrations  of  phthalate esters ranged  from
1.7-40 mg/m3  1n a  mixing  area  and from  10-66  mg/m3  In  another  area  of  a
company manufacturing artificial leather and  films  of  PVC  (U.S. EPA,  1980b).
NIOSH  (1985)   estimates  that  -2,406,700  workers  are annually exposed  to
dlethyl, d1-n-butyl  and d1(2-ethylhexyl) phthalate  In the  United States.
    Several authors  have  Identified phthalate esters  In  foods.  D1(2-ethyl-
hexyl) phthalate was  detected at a  concentration of  6.50 mg/kg 1n mackerel
fillets (Muslal et al., 1981).   The  concentration of  dl-n-butyl phthalate In
rainbow trout  from  the Great Lakes  was reported  to  be 8.1  mg/kg  (Glass  et
al.,  1977).   In butter samples obtained  from  Japan,  the  concentration  of
d1-n-butylphthalate was 4-11  mg/kg  (Horlta et  al.,  1973).   Instant vegetable
cream  soup  obtained   from  a   Japanese   market  contained   6.35   mg/kg  of
d1-n-butyl phthalate (Tomlta  et al.,  1977).  No  estimate  of phthalate ester
exposure  from food  composites  typically  consumed  by  an  Individual  In  the
United States 1s known.

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    Phthalate esters can be absorbed  through  the  skin  during  the  use of  many
cosmeUc products,  Insect  repellants and  the water from  PVC-Hned  swimming
pools (U.S.  EPA,  1980a).   A  special segment  of the  population  1s  exposed  to
phthalate  esters  during medical/surgical  procedures,  such as  hemodlalysls
and  Intravenous  applications.    No  estimates  on   the  dermal  exposure  of
phthalate  esters  to  Individuals  can be  made  from the data available  In  the
literature.
    It  Is  difficult  to draw conclusions  about   the  relative  toxkHy  of
phthallc add  esters  to aquatic  biota  because of  the larqe variability  In
toxldty of  each  ester  to  different  species.  It Is also  difficult  to  pick
out those  species most  sensitive  to  phthalates; however,  Table  6-10  contains
the most and least  sensitive species and  toxic concentrations reported  for
each ester.  All  of  the esters  listed 1n Table 6-10 caused toxic  effects  at
<3.2  mg/a,.   The  lowest  concentration reported  to  cause  toxic  effects  was
0.003  mg/1  dl(2-ethylhexyl)  phthalate,   which  caused  decreased  production
of offspring by Daphnla  magna (Mayer and  Sanders,  1973).
    Although there were large differences  In  species  sensitivity among ma'jor
taxonomlc  groups, none  of  these  groups  except bacteria were especially  more
or  less  sensitive than  other groups.  Bacteria  were clearly less  sensitive
than other organisms to d1-n-butyl,  dlallyl,  dlethyl and  dimethyl  phthalates
(Sugatt  and  Foote,  1981).    The  available Information concerning  freshwater
and  saltwater  species   Indicated  no difference 1n  phthalate  ester  toxldty
between freshwater and  saltwater  environments.
    Many Investigators  have  reported toxic effects  of phthalates  at  concen-
trations greater  than   their  aqueous  solubility;  however,  the data  Indicate
that  all  of  the  phthalates  except  dlhexyl,  dlnonyl,  d1-n-decyl  and  dllso-
decyl phthlates were toxic to at  least one  species  at  concentrations near  or
below their  solubility  (Sugatt and Foote, 1981).

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    Information concerning residues of phthallc add esters In aquatic biota
suggests that  accumulation  Is determined  primarily  by the degree  to which
species can  metabolize  and eliminate  them (Soedergren,  1982).   F1sh gener-
ally  have  a well-developed  mechanism In  this  regard and  therefore  do  not
accumulate phthalates to a great  extent.
    Oral studies show that d1(2-ethylhexyl) phthalate, d1-n-butyl phthalate,
and  d11sooctyl  phthalate are  absorbed   from   the   gastrointestinal  tract
(Williams  and Blanchfleld, 1974,  1975; Daniel  and Bratt, 1974; Ikeda  et  al.,
1978.  1980;  Tanaka  et  al.,  1978;  Pollack et al.,  1985a;  Olshl  and  Hlraga,
1982; Telrlynck and Belpalre, 1985; Schmld and Schlatter,  1985).  Pollack  et
al.  (1985a)  demonstrated  that uptake  of  IntraperHoneally  administered d1(2-
ethylhexyl)  phthalate Into the  blood  1s  poor  In rats.  Orally  administered
phthallc add esters  are  primarily  and largely  converted  to  their  monoester
derivatives  by  enzymes  1n   the  gastrointestinal  tract  before absorption
(Albro  and  Thomas,  1973;  Rowland,  1974;  Rowland  et  al.,  1977;  Lake  et  al.,
1977b;  Carter  et  al.,  1974;  White  et  al.,  1980;  Pollack  et  al..  1985a;
Telrlynck  and  Belpalre,  1985; Olshl  and  HUoga,  1982).   Other   tissues  such
as  the  liver  have  also  been  shown to  hydrolyze  phthallc add esters  (Carter
et  al., 1974).   In  contrast,  Intraperltoneally  administered d1(2-ethylhexyl)
phthalate 1s  taken  up primarily  as d1(2-ethylhexyl) phthalate,  with  only  1%
hydrolyzed to monoethylhexyl  phthalate (Pollack  et al., 1985a).
    Oral  and Intravenous  studies  Indicate that  d1(2-ethylhexyl) phthalate,
d1-n-butyl  phthalate  and  d11sooctyl  phthalate are  not retained  for  long  1n
the  body  (Tanaka et  al.,  1975,  1978; Williams and Blanchfleld,  1974,  1975;
Daniel  and  Bratt,  1974;  01sh1  and  Hlraga,  1982;  Telrlynck  and  Belpalre,
1985;  Ikeda  et  al.,  1978,   1980).    In  general,  phthallc add  esters  and
metabolites  distribute  primarily  to  liver,  kidneys,  fat and  the  gastro-
intestinal  tract.   Metabolites have  been found  In almost every tissue;  1n

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particular a  high  concentration  of monoethylhexyl phthalate,  the  hydrolytlc
derivative of d1(2-ethylhexy1)  phthalate, has been observed  In  the  testes  of
rats (01sh1  and  Hlraga,  1982).   The distribution of  d1(2-ethylhexyl)  phtha-
late and  metabolites  In  various  tissues,  particularly  liver,  kidneys  and
fat, has  been observed to vary  with  route  of administration  (diet,  gavage,
parenteral),   vehicle  and  dose   (Thomas  and Thomas,  1984;  Pollack  et  al.,
1985a;  Albro  et  al.,  1982).   In  a dietary  study  on  rats,  radioactivity  from
i«C-d1(2-ethy1hexy1)  phthalate   In  the  liver  and  fat  declined  with  half-
lives of  1-2  and 3-5  days, respectively  (Daniel and  Bratt,  1974).   In  gavage
studies  (Olshl   and  Hlraga,  1982),  the disappearance  of  d1(2-ethylhexyl)
phthalate  from  tissues It.,,-  ranging from 1.49-156 hours)  was  more  rapid
than  for  that  of  monoethylhexyl  phthalate   (t, ._  ranging  from  22.6-68
hours).
    Although  short-chain  phthallc  acid  dlesters  such as  dimethyl  phthalate
can  be  excreted  unchanged   1n  the urine,  most   phthallc  add  dlesters  are
further metabolized  before  excretion.   The  first step of  metabolism  entails
hydrolysis of  the  parent  compound  to  a  monoester derivative.  Once  formed,
the monoester derivative can then  be  further hydrolyzed  to  phthallc add and
excreted,  conjugated  with  glucuronlde  then  excreted,   or   oxidized   and
excreted.  The  first  alternative occurs primarily with  short-chain phthallc
add esters  (Albro and Thomas,  1973;  Albro and  Moore,  1974; Albro et  al.,
1973).    The   second  alternative   Is  the primary route  of  metabolism  for
d1(2-ethylhexyl) phthalate and  occurs  1n all  spedes except the  rat  (Albro
et  al.,  1973, 1981,  1982; Kluwe,  1982a,b;  Peck  et al.,  1978;  Teirlynck  and
Belpalre,  1985;  Schmld and Schlatter, 1985; Williams  and  Blanchfleld,  1975;
Daniel   and Bratt.  1974; Chu et  al.,  1981;  Tanaka  et al.,  1975;  Thomas  and
Thomas,  1984);  however,  glucuronlde conjugates of d1-n-butyl  phthalate  have
                                      x1

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been observed  1n  rats  (Tanaka et  a!.,  1978;  Foster et al.,  1982;  Kaneshlma
et  al.,  1978).  The  third  route  of  metabolism has been  observed  In  rats,
guinea pigs  and hamsters (Williams  and Blanchfleld,  1974,  1975; Tanaka  et
al.,  1978;  Daniel  and  Bratt,  1974;  Chu  et  al.,  1981;  Shuguenot  et  al.,
1975).  The metabolism of phthallc add esters  Is  not  qualitatively  affected
by route of exposure (Kluwe,  1982).
    Excretion  of  d11sooctyl  phthalate,  d1-n-butyl  phthalate  and  d1(2-ethyl-
hexyl) phthalates  has  been  studied   (Ikeda et  al., 1978,  1980;  Schmld  and
Schlatter,  1985;  Telrlynck  and  Belpalre,  1985;   Williams  and  Blanchfleld,
1974, 1975;  Daniel  and  Bratt, 1974;   Kaneshlma  et  al., 1978; Tanaka et  al.,
19-75, 1978).   These  compounds and their metabolites  are excreted 1n  urine,
bile and  feces; the relative  Importance  of  the  route of excretion depends
upon  the  compound and  species,  while  the  rate of  excretion  appears  to  be
rapid.  Half-lives  of  7.9 and 12  hours were  reported for urinary  excretion
of  d1(2-ethylhexyl)  phthalate 1n  humans and  rats, respectively  (Schmld  and
Shlatter,  1985"; Telrlynck and Belpalre, 1985).  PharmacoklneMc data on  aryl
or aryl/alkyl  pthalates could  not  be located  1n the available  literature  as
cited 1n the Appendix.
    D1(2-ethylhexyl) and  n-butyl  benzyl  phthalates  have  been  tested  for
carcinogenic potential  1n feeding studies  with F344  rats  and B6C3F1   mice.
D1(2-ethylhexyl) phthalate was  found  to cause  Increased Incidences  of  liver
neoplasms   1n  both rats and  mice (NTP,  1982b;  Kluwe  et  al., 1982b).   Using
EPA's we1ght-of-ev1dence  classification  system, this  Is  a group  B2  chemical
meaning there  1s  sufficient  evidence In  animals  and  thus DEHP  1s  probably
carcinogenic  1n  humans.   n-Butyl  benzyl  phthalate  caused   an   Increase  1n
myelomonocytlc  leukemia  In  female  F344 rats  (NTP,  1982a).   Because of  high
background  Incidence  of  myelomonocytlc leukemia  In F344  rats   and because

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dose-related and  significant  decreases  1n malignant  lymphoma,  all  lymphoma,
and  leukemia  or  lymphoma  were  observed  In male  B6C3F1  mice  (NTP,  1982a),
there  Is  only  limited  evidence to conclude that n-butyl  benzyl  phthalate  Is
carcinogenic.   The EPA weight  of evidence category Is group  C,  meaning  that
the compound Is considered a possible human carcinogen.
    The  mutagenldty  and  genotoxIcHy  of  phthaUc  acid  esters  have  been
reviewed  by Thomas  and Thomas  (1984)  and Hopkins  (1983).   D1(2-ethylhexyl)
phthalate and  metabolites have yielded mostly negative results  In  Ames  tests
with ^.  typhlmur 1um.  and mixed  results with  J_n v1 tro and  J_n y1 vo tests  of
genotoxIcHy.   Dlethyl phthalate,  dimethyl  phthalate, and  dl-n-butyl  phtha-
late were found  to  be  mutagenlc  1n J_n vitro mlcroblal assays with S.  typhl-
mur 1 urn (Kozumbo et al.,  1982;  Rubin et  al.,  1979;  Seed, 1982).
    Oral  studies  have   shown  that  d1(2-ethylhexyl)   phthalate,  dl-n-butyl
phthalate,  and  d1-n-heptyl  phthalate  can produce  adverse  effects upon  the
developing fetus when mice and rats are exposed during gestation  (Wolkowskl-
Tyl, 1984a,b;   Bell  et  al.,  1979;  Bell,  1980;  Shlota  and Mima,  1985;  Shlota
and  Nlshlmura,  1982;  Shlota  et  al., 1980;  Nakamura  et   al.,  1979;  Yagl  et
al., 1978,  1980; TomHa  et al.,  1982b;  Onda  et   al.,  1974).   Whether  the
observed  effects  (reduced fetal  weight,  fetal  mortality, gross  external  and
skeletal  malformations)   represent a  primary  effect  of  the  compound  In
question  or whether  they occur as a result  of  maternal  toxkKy has yet  to
be  demonstrated  unequivocally.   Studies   conducted  by NTP  (Wolkowskl-Tyl  et
al., 1984a,b)  Indicate  that  mice  are  more  sensitive than  rats.
    NTP  has  recently  conducted   reproduction  and   fertility  assessments  on
CD-I mice for  dlethyl phthalate  (Reel et  al., 1984) and  dl-n-octyl phthalate
(Gulatl  et  al.,  1985).   Dietary d1-n-octyl  phthalate   had  no  effects  on

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reproduction  and  fertility  among  parental  or   F-j  mice.   Dietary  dlethyl
phthalate had no effects on reproduction and  fertility  In  parental  mice,  but
dlethyl  phthalate-exposed  F   mice had  fewer  pups/Utter  than  did  controls,
as well  as  Increased liver weights  (males  and females).  Increased  prostate
weights,  Increased  pituitary  weights  (females   only)   and  decreased  sperm
concentrations.   Booth  et  al.   (1983)  and  Plasterer et  al. (1985)  reported
that  dimethyl  phthalate   had   no  effects  on  reproduction  In  CD-I   mice.
Dimethyl  phthalate  was  administered  by gavage  on days  7-15   of  gestation.
The fertility of Sherman  rats  was  not affected by  dietary administration of
dl(2-ethylhexyl) phthalate  (up to  0.4%)  for  1-2 years  (Carpenter  et  al.,
1953).
    Orally   administered   dl (2-ethylhexyl),   d1-n-butyl,   n-butyl   benzyl,
d1-n-pentyl,  dllsobutyl and dl-n-heptyl  phthalates have been shown  to  cause
testlcular atrophy In rats to mice  (Gray et al.,  1977,  1982;  Shaffer et al.,
1945;  Gangolll,  1982;  Olshl  and Hlraga, 1980a,  1983;  Gray and Butterworth,
1980;  Mangham et al.,  1981;  Olshl,  1985;  Agarwal et  al.,  1985; Foster  et
al.,  1980).   D1-n-octyl,  dimethyl,  dlethyl, dlpropyl and  dl-n-heptyl  phtha-
lates  did not cause  testlcular  atrophy In  rats (Gray and  Butterworth,  1980;
Foster  et  al.,   1980).  Species  differences  In phthalTc add  ester-promoted
testlcular atrophy have been observed.  Gray et al.  (1982) failed to observe
testlcular  atrophy   1n  hamsters gavaged with d1-n-butyl,  d1-(2-ethylhexyl)
and dl-n-pentyl  phthalates  at  doses  equlmolar to those that caused atrophy
In  rats.    In   the   same  study,  mice  gavaged   with   equlmolar  doses   of
dl-n-butyl,  d1(2-ethylhexyl)   and   dl-n-pentyl  phthalates  had  only  slight
focal  atrophy.
    Chronic  or  subchronlc  oral  studies have been  conducted with d1(2-ethyl-
hexyl),  d1-n-butyl,   dimethyl,   dUsononyl,   n-butyl  benzyl  and  d1-n-octyl
phthalates  (Carpenter  et  al.,   1953;  Harris et al., 1955;  Nlkonorow et al.,

                                      xlv

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1973; Gray  et  al.,  1977; Gangolll, 1982;  NTP,  1982a,b;  Kluwe et al., 1982b;



Shaffer et  al.,  1945;  Popp  et  al.,  1985; Canning et  al.,  1985;  Nagasaki  et



al., 1974;  Ota  et  al.,  1974; Lake et  al.,  1976,  1977a;  Haslenko,  1968;  Food



Research Laboratories, 1955;  Brown et  al., 1978;  Smith,  1953;  Lefaux,  1968;



Plekacz, 1971; LeBreton,  n.d.;  Bornmann et al.,  1956;  Lehman,  1955;  Living-



ston,  1971;  Monsanto,   1972;  Plekacz,  1971).   Liver,   kidneys  and  testes



appear  to  be  target organs.  Occupational  exposure  to phthalate  esters  has



been  associated  w1h polyneuropathy  (Mllkov  et  al.,  1973;  GlUoll   et  al.,



1978).



    Acute  oral   LO   s  have  been  reported for  d1(2-ethylhexyl),   dimethyl,



d1-n-butyl,  dlethyl,  n-butyl   benzyl,   d1-n-octyl,   dlhexyl,   dlnonyl   and



dldecyl phthalates.   These values are summarized In Table  5-11.



    An   Interim   q *    of   8.36xlO"3   (mg/kg/day)~1   was    derived    for



d1(2-ethylhexyl)   phthalate   based  on   the   Incidence  of   hepatocellular



carcinoma or  adenoma  In  male mice  In  the NTP (1982b) study.  This value  Is



considered  Interim  pending  additional  analysis   of  potential  1nterspec1es



differences In metabolism.   The  concentrations  1n  water associated with  risk



levels   of   10"s,   10~*   and   10"7    are   4.19xlO"2,    4.19xlO~3    and



4.19x10"*   mg/i,   assuming   that   a   70  kg   human  consumes   2  l/day.



Additional   metabolic   factors   need  to   be   considered  before  a   value   1s



proposed.



    The  RfD  of   0.75   mg/kg/day  (52.5  mg/day)   was   derived   for   dlethyl



phthalate,  based on a subchronlc oral  rat  NOEL  of  159  mg/kg/day  In  the study



by Brown et al.  (1978)  and  using  an uncertainty  factor  of  1000.  An RfD  of



0.13 mg/kg/day (8.75 mg/day)  for  d1-n-butyl  phthalate 1s derived based on  a



52-week oral  rat NOAEL  of  125  mg/kg/day  In  the  study  by  Smith (1953)  and



using an uncertainty factor of  1000.   The U.S. EPA (1980b) derived  an  RfD  of
                                      xv

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10 mg/kg/day  (700  mg/day)  for  dimethyl  phthalate  based on  a  chronic  rat
NOAEL of  1000  mg/kg/day In the  study  by  Lehman (1955) using  an  uncertainty
factor of 100.   A  revaluation  of  the Lehman  (1955)  study suggests  that  the
data, as presented In this  paper  are  Inadequate for  development of  an RfD.
    An  RfD  was  not derived  for d1-n-octyl  phthalate based  on  Inadequate
data.  An RfD  of 0.16 mg/kg/day (11.1  mg/day) could be  derived for  n-butyl
benzyl phthalate based  on  a  subchronlc  rat NOEL of  159 mg/kg/day  In  the  NTP
(1985)  study.    However,  this RfD  would  not  be  protective  for   potential
carcinogenic effects of butyl  benzyl  phthalate.
    CSs were  calculated for  dl(2-ethylhexyl)  phthalate,  dlethyl  phthalate,
dl-n-butyl  phthalate,   dimethyl  phthalate,   d1-n-octyl   phthalate,   n-butyl
benzyl phthalate  and d11sononyl  phthalate  (Table  9-7).  In  each  case,  the
data   that resulted  1n  the  highest  CS,  are  recommended as the basis  for  the
RQs  (Tables 9-8  to 9-14).   The  RQ  for each  of  the phthalate esters  listed
are  >1000.   Data  were  not   sufficient  for  deriving an  RQ  for  the  other
phthalate esters  discussed  1n  this document.
    An  F   factor  of   5.14xlO~2  (mg/kg/day)"1  was   calculated   for   d1(2-
ethylhexyl)  phthalate,  placing   this  chemical  In Potency Group  3.   Because
the evidence for cardnogenldty 1n animals was  sufficient,  d1 (2-ethylhexyl)
phthalate 1s placed  1n EPA Group B2.   An EPA  Group B2 chemical  In  Potency
Group  3  has  a   low   hazard  ranking  under   CERCLA.   The  evidence   for
cardnogenldty  of  n-butyl  benzyl   phthalate   1n  the NTP  (1982a)  study  was
limited,  Implying  an  EPA Group  C classification, possible human carcinogen,
while no  data  regarding the  cardnogenldty  of  other phthalate esters were
available; therefore, these chemicals  are  placed In  EPA Group  D.
                                      xv1

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                              TABLE  OF  CONTENTS

                                                                       Page

1.  INTRODUCTION	1-1

    1.1.    STRUCTURE AND CAS NUMBER	1-1
    1.2.    CHEMICAL AND PHYSICAL PROPERTIES 	  1-1
    1.3.    PRODUCTION DATA	1-1
    1.4.    USE DATA	1-8
    1.5.    SUMMARY	1-13

2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES	2-1

    2.1.    WATER	2-1

           2.1.1.    Hydrolysis	2-1
           2.1.2.    Oxidation 	  2-1
           2.1.3.    Photolysis	2-2
           2.1.4.    Mlcroblal Degradation 	  2-2
           2.1.5.    Volatilization	2-6
           2.1.6.    Adsorption	2-6
           2.1.7.    B1oaccumulat1on 	  2-8

    2.2.    AIR	2-8

           2.2.1.    Chemical Degradation	2-8
           2.2.2.    Physical Removal	2-8

    2.3.    SOIL	2-9

           2.3.1.    Chemical Degradation. '	2-9
           2.3.2.    Mlcroblal Degradation 	  2-9
           2.3.3.    Volatilization	2-11
           2.3.4.    Adsorption	2-11

    2.4.    SUMMARY	2-12

3.  EXPOSURE	3-1

    3.1.    WATER	3-1
    3.2.    AIR	3-11
    3.3.    FOOD	3-15
    3.4.    DERMAL	3-15
    3.5.    SUMMARY	3-18

4.  PHARMACOKINETCS	4-1

    4.1.    ABSORPTION	4-1
    4.2.    DISTRIBUTION	4-4
    4.3.    METABOLISM	4-7
    4.4.    EXCRETION	4-8
    4.5.    SUMMARY	4-11
                                    xv11

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                          TABLE  OF  CONTENTS (cont.)



5.  EFFECTS	5-1

    5.1.   CARCINOGEN1CITY	5-1

           5.1.1.   n-Butyl  Benzyl  Phthalate	5-1
           5.1.2.   D1-2(ethylhexyl) Phthalates 	  5-5

    5.2.   MUTAGENICITY	5-9
    5.3.   TERATOGENICITY	5-12
    5.4.   OTHER REPRODUCTIVE EFFECTS 	  5-18
    5.5.   CHRONIC AND SUBCHRONIC TOXICITY	5-24

           5.5.1.   D1-2(ethylhexyl) Phthalates 	  5-24
           5.5.2.   Olethyl  Phthalate 	  5-29
           5.5.3.   Dl-n-butyl Phthalate	5-32
           5.5.4.   Dimethyl Phthalate	5-32
           5.5.5.   Dllsononyl Phthalate	5-36
           5.5.6.   n-8utyl  Benzyl  Phthalate	5-36
           5.5.7.   D1-n-octyl Phthalate	5-^
           5.5.8.   Human Studies 	  5-3^

    5.6.   OTHER RELEVANT INFORMATION	5-"3S
    5.7.   SUMMARY	5-40

6.  AQUATIC TOXICITY	6-1

    6.1.   ACUTE	  6-1
    6.2.   CHRONIC	6-12
    6.3.   PLANTS	6-15
    6.4.   RESIDUES	6-15
    6.5.   SUMMARY	6-24

7.  EXISTING GUIDELINES AND STANDARDS 	  7-1

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

8.  RISK ASSESSMENT	8-1

    8.1.   DI(2-ETHYLHEXYL)  PHTHALATE 	  8-1
    8.2.   DIETHYL PHTHALATE	8-7
    8.3.   DI-n-BUTYL PHTHALATE  	  8-7
    8.4.   DIMETHYL PHTHALATE 	  8-9
    8.5.   DI-n-OCTYL PHTHALATE  	  8-9
    8.6.   n-BUTYL BENZYL PHTHALATE  	  8-10
    8.7.   DIISONONYL PHTHALATE  	  8-11
    8.8.   SUMMARY	8-12
                                    XV111

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                          TABLE OF CONTENTS  (cont.
 9.   REPORTABLE QUANTITIES 	    9-1

     9.1.   REPORTABLE QUANTITY (RQ)  RANKING BASED ON CHRONIC
            TOXICITY	    9-1

            9.1.1.    D1(2-ethylhexyl)  Phthalate	    9-1
            9.1.2.    Dlethyl  Phthalate 	    9-2
            9.1.3.    01-n-butyl Phthalate	    9-3
            9.1.4.    Dimethyl  Phthalate	    9-5
            9.1.5.    Dl-n-octyl Phthalate	    9-5
            9.1.6.    n-Butyl  Benzyl  Phthalate	    9-6
            9.1.7.    Dllsononyl Phthalate	    9-6
            9.1.8.    01-n-heptyl  Phthalate  	    9-7
            9.1.9.    Summary  	    9-7

     9.2.   HEIGHT  OF  EVIDENCE  AND POTENCY  FACTOR (F=1/E010)
            FOR CARCINOGENICITY	    9-16

            9.2.1.    DM2-ethylhexyl)  Phthalate	    9-16
            9.2.2.    n-Butyl  Benzyl  Phthalate	    9-t*
            9.2.3.    Other Phthalate  Esters	    9-19

10.   REFERENCES	10-1

APPENDIX: LITERATURE SEARCHED	    A-l
                                     x1x

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                               LIST OF TABLES

No.                               Title                                Page

1-1     General  Information on Selected Dlalkyl  Phthalates	1-2

1-2     Chemical  and Physical Properties	1-6

1-3     Manufacturers of Alky! and Aryl Pthtalates 1n the
        United States	1-9

1-4     Annual United States Production Volume of  Alkyl  and
        Aryl Phthalates	1-11

2-1     Blodegradatlon Screening of Some Alkyl and Aryl
        Phthalates	2-4

2-2     Blodegradatlon of Phthalates In Garden Soil	2-10

3-1     Concentrations of n-Butyl Benzyl Phthalate 1n United
        States Haters Near Industrial Sites 	   3-5

3-2     Median Concentration of Phthalate Esters  1n Industrial
        Effluents and Ambient Water 1n the United  States
        Compiled  from STORET Stations 	   3-8

3-3     Concentrations of Commonly Reported Phthalate Esters
        Detected  In Drinking Waters 1n the United  States	3-9

3-4     Percentage Occurrence of Phthalates by Water  Source  	   3-10

3-5     Atmospheric Levels of a Few Phthalate Esters  Measured
        Throughout the World	3-13

3-6     Concentrations of Phthalate Esters 1n Some Foods	3-16

4-1     Biological Half-Lives of 01{2-ethylhexyl)  Phthalate  and
        Monoethylhexyl Phthalate In Rats After a  Single  Oral
        Dose of  01 (2-ethylhexyl) Phthalate	4-6

4-2     Excretion of Phthallc Add Esters	4-10

5-1     Inadequate Cancer Studies 	   5-2

5-2     Hematopoletlc Neoplasms In F344/N Rats and B6C3F1 Mice
        Fed n-Butyl Benzyl Phthalate In the Diet  for  103 Weeks.  ...   5-4

5-3     Liver Neoplasms 1n F344/N Rats and B6C3F1  Mice Fed
        D1(2-ethy1hexyl) Phthalate 1n the Diet for 103 Weeks	5-6

5-4     Summary of Oral TeratogenlcHy Studies with D1(2-ethyl-
        hexyl) Phthalate	5-14
                                     xx

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                           LIST OF  TABLES  (cont.)

No.                                Title                                Page

5-5     Summary of  Oral  Teratogenld ty  Studies  for  Phthallc
        Add Esters Other  than  D1 (2-ethylhexyl)  Phthalate	5-17

5-6     Orally Administered Phthalate  Esters  Causing  Testlcular
        Atrophy \n  Rats	5-21

5-7     Oral ToxkHy Summary for  D1(2-ethylhexyl)  Phthalate	  5-25

5-8     Oral ToxkHy Summary for  Dlethyl  Phthalate	5-30

5-9     Oral ToxkHy Summary for  D1-n-butyl  Phthalate	5-33

5-10    Oral ToxkHy Summary for  Miscellaneous  Phthalate  Esters.  .  .  5-34

5-11    Acute Oral  ToxkUy of  Phthalate Esters	5-33'

6-1      Acute ToxkHy of  Phthallc  Acid  Esters  to Aquatic
        Vertebrates	6-2

6-2     Acute ToxkHy of  Phthalk  Add  Esters  to Aquatic
        Invertebrates 	  6-7

6-3     Range of Acute LC50 and EC50  Values  for  Phthalate  Esters.  .  .  6-11

6-4     Chronic ToxkHy of Phthalk  Add  Esters  to Aquatic
        Vertebrates	6-13

6-5     Chronk ToxkHy of Phthalk  Add  Esters  to Aquatk
        Invertebrates 	  6-14

6-6     Acute ToxkHy of  Phthalate Esters  to Aquatic  Plants
        and Bacteria	6-16

6-7     Data from Uptake and Elimination Studies  with  Phthalk
        Add Esters In Aquatk  Biota	6-19

6-8     Data from Model  Ecosystem  Studies  Concerning  Phthalate
        Residues	6-22

6-9     MonHoMng  Data  for Phthalk  Add  Esters  In Aquatk
        Organisms	6-23

6-10    Range of Spedes Sensitivity  for Algae,  Invertebrates
        and Vertebrates  to Phthalate  Esters  	  6-26

7-1     Existing AOIs/RfOs for  Phthalk  Add  Esters	7-2

8-1     Cancer Data Sheet  for Derivation of  q-|*	8-3

8-2     Cancer Data Sheet  for Derivation of  q^*	8-4
                                    xxl

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                           LIST OF  TABLES (cont.)

No.                               Title                                Page

8-3     Cancer Data Sheet for  Derivation of q-j*	8-5

8-4     Cancer Data Sheet for  Derivation of q-]*	8-6

9-1     Summary of RQs Derived for  Phthallc Add Esters	9-8

9-2     D1(2-ethylhexyl)  Phthalate:  Minimum Effective Dose (MED)
        and Reportable Quantity (RQ)	9-9

9-3     Dlethyl Phthalate:  Minimum Effective Dose  (MED) and
        Reportable Quantity (RQ)	9-10

9.4     D1-n-butyl Phthalate:  Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	9-11

9-5     Dimethyl Phthalate: Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	9-12

9_6     Dl-n-octyl Phthalate:  Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	9-13

9-7     n-Butyl Benzyl Phthalate:  Minimum Effective Dose (MED)
        and Reportable Quantity (RQ)	9-14

9-8     Dllsononyl Phthalate:  Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	   9-15

9-9     Derivation of Potency  Factor  (F).  Agent:  D1(2-ethyl-
        hexyl) Phthalate	9-18
                                    xx11

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                             LIST  OF  ABBREVIATIONS





ADI                     Acceptable dally Intake



AP                      Add phosphatase



ADC                     Area under curve



B8P                     n-Butyl benzyl phthalate



BCF                     B1oconcentrat1on factor



BOD                     Biological oxygen demand



bw                      Body weight



CAS                     Chemical Abstract Service



CHO                     Chinese hamster ovary



CS                      Composite score



DAP                     Olallyl phthalate



DBP                     01-n-butyl phthalate



DEHP                    D1(2-ethylhexyl) phthalate



DEP                     Olethyl phthalate



DHP                     Olhexyl phthalate



DHeP                    Dlheptyl phthalate



OIBP                    Dllsobutyl phthalate



DIDP (D1DP)             Dllsodecyl phthalate



DINP                    Dllsononyl phthalate



DIOP (D10P)             D11sooctyl phthalate



DMP                     Dimethyl phthalate



DMSO                    Dimethyl sulfoxlde



DNA                     Deoxyr1bonucle1c acid



DNP                     Dlnonyl phthalate



OOP                     D1-n-octyl phthalate



DPep                    D1-n-pentyl  phthalate







                                     XX111

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                         LIST OF  ABBREVIATIONS  (cont.)

OUP                     Dlundecyl phthalate
ECso                    Concentration effective to 50% of recipients
PEL                     Frank-effect level
Koc                     Soil sorptlon coefficient
Kow                     Octanol/water partition coefficient
LCso                    Concentration lethal to 50% of recipients
1050                    Dose lethal to 50% of recipients
LOAEL                   Lowest-observed-adverse-effect level
MED                     Minimum effective dose
MEHP                    Monoethylhexyl phthalate
HTO                     Maximum tolerated dose
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
NOEL                    No-observed-effect level
ppm                     Parts per mil Hon
ppt                     Parts per thousand
PVC                     Polyvlnyl chloride
RQ                      Reportable quantity
RV(j                     Dose-rating value
RVe                     Effect-rating value
SCE                     Sister chromatld exchange
SGOT                    Serum glutamlc oxaloacetlc transamlnase
SGPT                    Serum glutamlc pyruvlc  transamlnase
SS                      Saturated solution
TWA                     Time-weighted average
UV                      Ultraviolet
HS                      Hater solubility

                                     xxlv

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                               1.  INTRODUCTION



1.1.   STRUCTURE AND CAS NUMBER



    The  synonyms,   CAS  number,  structure,  empirical  formula  and  molecular



weight for each  of  the  phthallc  add alkyl  and aryl esters discussed  In this



report are presented In Table 1-1.



1.2.   CHEMICAL AND PHYSICAL PROPERTIES



    Alkyl  and  aryl  phthalates   are  generally  colorless   and  substantially



odorless  compounds  (CEH,   1975).   Most alkyl   phthalates   are  liquids  at



ambient  temperature.  In general,  the  phthalate  esters  are poorly soluble 1n



water  but  soluble  1n  most organic  solvents  Including acetone,  benzene and



ether  (Hawley, 1981).



    Alkyl  phthalates  undergo  the typical reactions  of  carboxyllc  esters, for



example,  saponlf1cat1on  by  strong  bases,  hydrolysis  In  the  presence  of



strong aqueous  adds,  reduction  to alcohols  by the  action  of hydrogen, ester



Interchange  and  conversion  to amides by  reaction with ammonia.



    Commercially,   phthalate   plastldzers   can  undergo   oxidation   during



plastics  processing,  forming  peroxides  which  later decompose  with  develop-



ment  of  colored  and odorous compounds.   Ant1ox1dants  such  as blsphenol A are



added to the resin  to Inhibit this reaction (U.S. EPA,  1978b).



    Selected physical  properties  of a  few  phthalate  esters  are listed  In



Table 1-2.   The data  on  the  physical properties of phthalate  esters  varies



to  a   great  extent  from one source  to  another.   The  most  recent and  appar-



ently reasonable values for these parameters are given.



1.3.    PRODUCTION  DATA



    Alkyl  and aryl  phthalates  are formed by  reacting  phthallc anhydride with



an  excess  amount   of   the  corresponding alcohol(s)  1n  the  presence   of  an



esterlfkatlon   catalyst  (for  example,  sulfurlc add  or  p-toluenesulfonlc










0779p                               1-1                              06/05/86

-------
                                                                            TABIF  1-1

                                                       General Information on Selected Dlalkyl  Phthalates
<£>
•o
 i
 oj
CAS Number
85-68-7




85-69-8






84-74-2

Chemical Name
n-Butyl benzyl
phthalate



n-Butyl ?-ethyl-
hexyl phthalate





Ot-n-butyl
phthalate
Synonyms*
1.2-benzenedlcarboxyllc
acid, butyl phenylmethyl
ester; BBP; benzyl n-
butyl phthalate


1 .2-benzenedlcarboxyl Ic
acid, butyl 2-ethyl-
hexyl ester




1 ,2-benzenedtcarboxyllc
acid, dlbutyl ester;
Chemical Molecular Structure
Formula Uelqht
C19H?00« 312.37 9,
II
^J:-0-C,N,
(oT /-^
^^^c-o-CMj-^N
0
C20H30°4 334.50 0
II
^v^^C-O-C^Ht
COJL
^^^ C-0-CH,CM(CjH, )C4Mt
II
0
Cl6H22°4 278.35 g
II
84-77-5
        117-81-7
 o
 tn
 oo
                                                        DBP;  n-butyl  phthalate
                            01 -n-decylphthalate
1,2-benrenedlcarboxy 1Ic
acid, dldecyl ester; OOP;
decyl phthalate
C28H46°4
                                                                                                      "8.6?
                    Dl(2-ethylhexyl)
                    phthalate
1,?-benzenedlcarboxy lie
acid. bls(?-ethyl
hexyl) ester;  OfHP;
OOP; dloctyl  phthalate;
octyl phthalate
                                                                                                               390.57
                                                                                                                         C-0 CH,CH(C,M,)C4Ht


                                                                                                                         C-0-CM,CH(C,H$)C«H,

                                                                                                                         0

-------
                                                                      TABU 1-1 (cont.)
CAS Number Chemkal Name
0
-o
vD
"° 84-66-2 Dtethyl phthalate
Synonyms*
1 ,2-ben7ened1carboxyl1c
actd, dlethyl ester;
DfP; dlethyl-o-
phenylene-dt acetates
Chemical Molecular Structure
Formula Weight
^^^ C-Q-CjH4
II
0
i
CJ
       3648-?! -3
       84-75-3
Dlheptyl phthalate
Dlhexyl phthalate
1 ,?-ben?ened\carboxyUc
actd. dlheptyl ester;
heptyl phthaUte;  OHeP
1 ,?-benienedtcarboxyl Ic
actd. dlhexyl ester;  DHP
C?3H34°4
36?. Sb
                                                                                                                                    C-0-C,H,s

                                                                                                                                    0
                                                                                                                                   C-O-CtH,,

                                                                                                                                   0
o
tn
PO
^H
CO
        26761-40-0
        285S3-12-3
Dllsodecyl phthalate
Dltsononyl phthalate
1,?-beniened1car boxy 1 tc
actd, dttsodecylester;
D10P
1 ,?-ben?enedlcarboxyl )c
acH. dl Isonony Jester ;
OINP
                                                                                                             446.68
                                                                                                             418 68
                                         C 0-CH(CM,)CiM,,


                                         C-0-CH(CH,)C»H|7

                                         0

                                        0
                                        II
                                        C-0-CH(CH,)CfM,s


                                        C-0-CH(CH,)C,Hlf

                                        0

-------
                                                                      TABlf 1-1 (cont.)
       CAS Number
  Chemical Name
                                    Synonyms'
                                                                                         Chemical
                                                                                         Formula
                                                     Molecular
                                                      Weight
                                            Structure
o
in
       27554-26-3
       131-11-3
       84-76-4
       117-84-0
       84-62-8
Dtlsooctyl phthalate
Dimethyl phthalate
Dlnonyl phthalate
Dl-n-octyl phthalate
Olphenyl phthalate
1,2-benzenedtcarboxyllc
acid; DIOP
1,2-benienedlcarboxyllc
acid, dimethyl ester; DNP
1,2-benienedlcarboxylIc
acid, dlnonyl ester; DMP
1 ,?-ben7enedtearboxy 1tc
acid, dl-n-octyl ester;
OOP; DNOP; n-octyl
phthalate
1, 2-benzenedlcarboxylIc
acid, dlphenyl  ester;
DPP; phenylphthalate
C?4«38°4
ClOH10°4
C?0HH04
390.62
194.19
                    418.68
                    390.6?
318.33
  C-0-CM(CM,)C,M|,


  C-0-CH(CH,)C,H,,

  0

  0
  II
  C-O-CH,

  C-O-CH,

  0

  0
  II
  C-0 C,H,,
                                                                                                                                 C-0-C,M,,

                                                                                                                                 0
 C-O-CiM,,


 C-O-C.M,,

 0

0

i'-o -
CO
cr>

-------
                                                                        TABLE 1-1 (cont.)
o
—j
CAS Number
                               Chemical Name
Synonyms*
                                                                                  Chemical
                                                                                  Formula
                                                     Molecular
                                                      Height
                                           Struc lure
2119-06-2
                             OUrldecyl phthalate
1,2-benzenedlcarboKyUc
acid, dltrldecylester;
OIDP
C34"S9°4
                                               S30.9?
3648-20-2
                             Olundecyl phthalate
1 ,?-benzenedtcarboxyl Ic            C30H50°4
acid, dlundecyl ester;  DUP
                                               474.80
                                                                                                                                       0

                                                                                                                                       0
                                                                                                                                       C 0-C..H,,

                                                                                                                                       0
         *SANSS. 1985
 O
 tn
 03
 CT-

-------
                                                                            TABLE  1-2



                                                                Chemical  and Physical Properties3
— 1
•o
CAS Number
85-68-7
85-69-8
84-74-2
84-77-5
117-81-7
84-66-2
3648-21-3
84-75-3
26761-40-0
28553-12-3
27554-26-3
131-11-3
84-76-3
§> 117-84-0
O
en
Chemical Name
n-Butyl benzyl
phthalate
n-Butyl 2-ethyl-
hexyl phthalate
Dl-n-butyl
phthalate
Dl-n-decyl
phthalate
01(2-ethyl-
hexyl) phthalate
Dlethyl phthalate
Otheptyl phthalate
01-n-hexyl
phthalate
Dllsodecyl
phthalate
Dl Isononyl
phthalate
Ollsooctyl
phthalate
Dimethyl phthalate
Dlnonyl phthalate
Dl -n-octyl
phthalate
Melting
Point
CC)
-35
-37b
-40
-37C
-46b
-40.5
NA
-33b
-50b
<-50
-46b
0
NA
-25
Bol ling
Point
CC)
370
224
(5 mm Hg)
335
261
(5 mm Hg)
236
(5 ram Hg)
296
NA
210
(5 mm Hg)
250-257
(4 mm Hg)
222-230
(5 mm Hg)
370
283
413
220-240°
(4 mm Hg)
Vapor Pressure
8.6x10"* mm Hg
(20')
NA
1.06x10-* mm Hg
(25-C)
NA
0.62x10'' mm Hg
(25-C)
3.45xlO"« mm Hg
(20-C)
NA
NA
0.3 mm
(200'C)
NA
NA
4.19xlO-'d mm Hg
(20°C)
NA
1.44xlO~-
(25»)
Water Solubility
2.9 mg/l
NA
13 mg/l
(25-C)
0.33 »g/lc
(24-C)
0.29 mg/l (20*C)
0.40 mg/l (25*C)
129 mg/l (20*C)
896 mg/l (25*C)
NA
NA
0.28 n»q/ic
(24-C)
NA
NA
4.32x10* mg/l
(25-C)
3 n>g/i
(25°C)
3.0 mg/l
(25-C)
Log KOH
4.91
7.61
4.72
NA
9.64
2.47
NA
7.74
11.80
10.50
9.64
1.56
10.98
5.22
Specific
Gravity
1.113-1.121
(25/25-C)
0.9941
(25-C)
1.047
(20/4-C)
0.9675
(20/20-C)
0.986
(20/20-C)
1.123
(25/4-C)
NA
1.008
(20°C)
0.966
(20/20'C)
0.982
(25-C)
0.986
(20°C)
1.189
(25/25-C)
0.972
(25-C)
0.978
(20°C)
Refractive
Index
1.535-1.540
(25')
1.4868
(25-C)
1.4915
(25-C)
NA
1.4830-1.4859
(20-C)
1.5002
(25-C)
NA
1.491
(20"C)
1.484
(20°C)
NA
1.484
(20-)
1 . 5 1 38
(25«)
1.4871
(20°C)
1.482
(25°C)
CD

-------
                                                                       TABLE 1-2 (cont.)

CAS Number

84-62-8

119-06-2

3648-20-2


Chemical Name

Olphenyl phthalate

Dltrldecyl
phthalate
Dtundecyl
phthalate
Melting Boiling
Point Point Vapor Pressure
(•C) CC)
68-70 405*C NA

-37b 240 NA
(2 on Hg)
2e NA NA


Water Solubility

0.082 ng/l
(25'C)
0.34 ng/tc
(24-C)
NA

Specific
Log Kow Gravity

NA 1.28
(20*C)
15.10 0.951
(20/20'C)
13.14 0.954
(25'C)
Refractive
Index

1.572
(74-C)
1.484
(20-C)
1.481
(25-C)
        aSources:  Agranoff. 1985;  Dobbs  and Cull. 1982;  Claw  et  al..  1980;  Grayson  and Fosbraey. 1982;  Hansch  and Leo.  1985;  Hawley.  1981;  1ARC.
         1982; Holllfleld. 1979; Leyder and  Boulanger.  1983;  Habey et al.. 1981; Scala and  Banerjee.  1982;  Schwarz.  1980;  U.S.  EPA.  1978c.   1980a,b;
         Verschueren. 1983; Wolfe et al..  1980

        bPour point

        cMultIcomponent nlxture

        dCalculated

        eFreeztng point

        NA ^ Not available
OS

-------
acid).   Many  of  these  products are  Isomerlc mixtures  of alcohols  derived
from  the  oxo  reaction of  olef1ns--a  reaction that results 1n  the  formation
of alcohols with  varying  amounts  of branching.   In addition,  some  producers
offer  an ester  made from a mixture  of  two  or  more  alcohols.   Thus,  d1-
(heptylnonyl)  phthalate may  consist of  dlheptyl  phthalate,  dlnonyl  phthalate
and  heptylnonyl  phthalate.  The commercially available  products  are  usually
>99%  pure with  a residual  maximum  acidity  of  0.01X  (presumably  monoalkyl
phthalates  containing one carboxyllc  add group).  The  remaining Impurities
could  be  dlesters   of   1so-phthal1c   acid,   terephthallc  acid   or   malelc
anhydride (U.S. EPA, 1978b).
    Table 1-3  lists  the  primary manufacturers and production  sites of  alkyl
and  aryl  phthalate  esters.   Reported  production  data  and  estimates  of
production  for these phthalates  are presented In Table 1-4.
1.4.   USE  DATA
    Alkyl and  aryl  phthalates  are used  as  plastldzers  primarily  for  PVC
resins  and  less  often  for  other  vinyl   resins,  cellulose ester  plastics,
synthetic  elastomers and other  polymers.   Plastldzer  end  uses  are  wide
ranging  and Include construction, home  furnishings,  consumer  goods,  packag-
ing, electrical uses, transportation and medical products (U.S. EPA,  1978b).
    n-Butyl benzyl  phthalate Is used exclusively  as  a  plastldzer,  predomi-
nantly  1n  vinyl   flooring.   The  second  most  common  use 1s  In  polyvlnyl
acetate  emulsions used  as adheslves  (I.e.,  1n the packaging  Industry).   It
has  also been  used  as   a plastldzer  1n  acrylic resins, ethyl  cellulose,
polyvlnyl forma!  and polyvlnyl butyral resins (IARC,  1982).
    D1-n-butyl  phthalate  Is  used mostly  as   a  plastldzer  In  polyvlnyl
acetate  emulsions  for  surface  coatings,  adheslves,  and  paper  and  textile
treating  (U.S. EPA,  19785).   This  compound 1s a registered active Ingredient
0779p                               1-8                              06/05/86

-------
                                  TABLE  1-3

       Manufacturers of Alkyl  and Aryl  Phthalates  In the United  States3
     Phthalate
             Manufacturer/Location
n-Butyl benzyl

Butyl(2-ethy1hexyl)

D1-n-butyl
D1-n-decylb
D1(2-ethylhexyl)
Dlethyl



01heptylc

01hexylb


DUsodecyl
D11sononyl
Monsanto Co.,  NJ

Hatco Chemical Corp., Fords, NJ

Badlsche Corp., Kearny, NJ
Eastman-Kodak, TN
Hatco Chemical Corp., Fords, NJ
Nuodex Chemical Inc., Chestertown, MD
Union Camp Corp., Dover, OH
U.S. Steel Corp., Neville Island, PA

Continental 011 Co., Aberdeen, NJ
Eastman-Kodak, NY
Tenneco Chemical Inc., Chestertown, MD

Badlsche Corp.; Kearny, NJ
B.F. Goodrich Co., Avon Lake, OH
Eastman-Kodak, TN
Hatco Chemical Corp., Fords, NJ
Monsanto Co.,  TX
Nuodex Chemical Inc., Chestertown, MD
Teknor Apex Co., Hebronvllle, MA
U.S. Steel Corp., Neville Island, PA

DynamH Nobel  of America, Stony Point, NJ
Eastman-Kodak, TN
Morfex Chemical Co., Greensboro, NC

Monsanto Co.,  TX

Continental 011 Co., Aberdeen, NJ
U.S. Steel Corp., Neville Island, PA

Badlsche Corp., Kearny, NJ
Exxon Corp.,  Baton Rouge, LA
Hatco Chemical Corp., Fords, NJ
Nuodex Chemical Inc., Chestertown, MD
ReUhold Chemicals,  Inc., Carteret, NJ
Teknor Apex Co., Hebronvllle, MA
U.S. Steel Corp., Neville Island, PA

Exxon Corp.,  Baton Rouge, LA
U.S. Steel Corp., Neville Island, PA.
0779p
       1-9
06/05/86

-------
                              TABLE 1-3  (cont.)
     Phthalate
             Manufacturer/Locate on
Dllsooctyl


Dimethyl




Dlnonyl



D1-n-octylb


Dlphenyl13

DUrldecyl
D1undecyld
Relchold Chemicals, Inc., Carteret,  NJ
Teknor Apex Co., Hebronvllle, MA

DynamH Nobel of America, Inc., Stony Point, NJ
Eastman-Kodak, TN
Morfex Chemical Co., Greensboro, NC
Sybron Corp., Lyndhurst, NJ

Monsanto Co., TX
Relchold Chemicals, Inc., Carteret,  NJ
Tenneco Chemical Inc., Chestertown,  MD

Eastman-Kodak, NY
Tenneco Chemical Inc., Chestertown,  MD

Monsanto Co., MO

Exxon Corp., Baton Rouge, LA
Nuodex Chemical Inc., Chestertown, MD
Relchold Chemicals, Inc., Carteret,  NJ
Teknor Apex  Co., Hebronville, MA
U.S. Steel Corp., Neville Island, PA

Monsanto Co., TX
aSRI. 1985

bU.S. EPA, 1985b

cManufactured as the mixture d1(heptyl, nonyl, undecyl)  phthalate

^Manufactured  as  the  mixture d1(heptyl,  nonyl,  undecyl)  phthalate and  as
 dlundecyl phthalate alone
 0779p
       1-10
08/31/87

-------
                                   TABLE  1-4



      Annual  United States  Production Volume of Alky!  and Aryl  Phthalates
Chemical
n-Butyl benzyl phthalate
Total butyloctyl phthalates
[Include butyl(2-ethylhexyl )
phthalate]
CMbutyl phthalates
(Include d1-n-butyl phthalate)
Dldecyl phthalate
D1(2-ethylhexyl) phthalate
Dlethyl phthalate
Dlheptyl phthalate
Dlhexyl phthalate
Dllsodecyl phthalate
Dllsononyl phthalate
Dllsooctyl phthalate
Dimethyl phthalate
Dloctyl phthalates
[Include 01-n-octyl phthalate,
exclude D1 (2-ethylhexyl )
phthalate]
Dlphenyl phthalate
DHrldecyl phthalate
Dlundecyl phthalate
Volume Produced Year
(ml H1on pounds)
101-510
12.28
22.21
1-10
251.1
17.75
10-50
0.2-2.0
145.82
<0.001
1-10
8.64
301.12
0.1-1.0
21.79
10-50
1977
1982
1984
1977
1982
1984
1977
1977
1984
1977
1977
1984
1984
1977
1984
1977
Reference
U.S. EPA, 1985b
USITC, 1983
USITC, 1985
U.S. EPA, 1985b
USITC, 1983
USITC, 1985
U.S. EPA, 1985b
U.S. EPA, 1985b
USITC, 1985
U.S. EPA, 1985b
U.S. EPA, 1985b
USITC, 1985
USITC, 1985
U.S. EPA, 1985b
USITC, 1985
U.S. EPA, 1985b
0779p
1-11
08/31/87

-------
1n  pesticides  and 1s  used  as an  Insect  repellant  for  textiles  (U.S.  EPA,
1979).   Other  uses  are  as  a perfume  solvent  and  fixative,  and as a  resin
solvent (Hawley, 1981).
    D1(2-ethylhexyl)phthalate Is  used  1n  wire  Insulation,  cloth  coatings,
elastomerlc  molded  materials,  extruded and  calendered  compositions,   food
packaging and  1n  blomedkal  applications.   The only significant  non-PVC  use
Is as a dielectric fluid 1n  capacitors (IARC,  1982).
    Olethyl phthalate  Is used almost  entirely as  a  plastldzer  for  cellulose
ester  plastic   films  and sheets  (photographic,   blister  packaging and  tape
applications)  and  molded and extruded articles  (consumer  articles such  as
toothbrushes, automotive components,  tool  handles and toys).   This compound
Is  also  used  as a  solvent  for  nitrocellulose  and  cellulose acetate,  In
Insecticide sprays and mosquito  repellants, as a  camphor  substitute and  as  a
perfume fixative and solvent  (U.S.  EPA, 1978a,b;  Hawley,  1981).
    Dlhexyl  phthalate  Is used  In  plastlsols  for  carpetback   coating  (U.S.
EPA, 1978a,b).
    D1-1sodecyl phthalate 1s used In  automotive  upholstery,  PVC and urethane
foams and 1n wire cable  Insulation with dllsononyl,  dltrldecyl  and  dl-noctyl
phthalates  (U.S. EPA,  1978a,b).
    Dllsononyl   phthalate 1s  used  mainly as a  plastldzer and  has minor  use
as a dielectric fluid In capacitors  (U.S. EPA,  1978a,b).
    Dimethyl  phthalate  1s   used   1n   solid   rocket   propellants,   lacquers,
plastics,  safety  glasses,   rubber  coating  agents,  molding powders  and  In
Insect repellants  {Hawley,  1981)  and  1s  a registered  active   Ingredient  In
pesticides  (U.S. EPA,  1979).
    Olnonyl phthalate  1s used mainly  as a  plastldzer and  the  pure grade  Is
used as stationary liquid phase  1n  chromatography (Hawley,  1981).


0779p                               1-12                            10/15/87

-------
    D1-n-octyl  phthalate  1s  used In plastlsols  for  carpetback  coating (U.S.



EPA,  1978b)  and Is also  a  registered  active  Ingredient  In  pesticides (U.S.



EPA,  1979).



    Dlphenyl  phthalate  Is used  primarily  as  a plastlclzer,  but  1s  also  a



registered active  Ingredient  1n pesticides (U.S. EPA, 1979).



    Phthalates  based  on  C^-C,,   alcohols  are  used  heavily  1n  PVC  resins



for automotive  applications and  to  a lesser  extent  1n plastlsols,  dispersion



coatings,  and  In  other  film,  sheeting, coated  fabric  and  extrusion  applica-



tions (U.S. EPA, 1978b).



1.5.   SUMMARY



    Alkyl  and aryl  phthalates are generally  colorless  and  odorless  compounds



(CEH,  1975).   Most  alkyl   phthalates  are  colorless  liquids   at   ambient



temperature.  In  general,  the  phthalate  esters  are  poorly  soluble  1n  water



but soluble  In  most organic  solvents,  Including  acetone,  benzene and  ether



(Hawley, 1981).   Phthalate plastldzers can  undergo  oxidation  during plastic



processing; antloxldants are  added to resins to Inhibit this  reaction.



    The  alkyl  and aryl  phthalates  are produced  by  reacting phthallc  anhy-



dride with  an  excess  amount  of  the corresponding alcohol(s)  In  the  presence



of  an esterlfIcatlon  catalyst.   The  commercial  products  are  usually  >99%



pure  (U.S.  EPA, 1978b).  Sixteen U.S.  manufacturers  produce one or more of



the 17 selected phthallc add esters.   Reported  production figures and  esti-



mated production  volumes  were available  for each of  the alkyl  phthalates.



Total  U.S.  production  volume  of  phthallc  add  esters  amounted  to  1179



million  pounds  1n 1984  (USITC,  1985).   Alkyl  and  aryl  phthalates  are  used



predominantly  as   plastldzers   for  polyvlnyl  chloride  resins  (U.S.  EPA,



1978a,b).  To a lesser  extent, they are used as plastldzers for  other  vinyl



resins,   cellulose  ester plastics,  synthetic elastomers and  other  polymers.










0779p                               1-13                             10/15/87

-------
End-uses  Include  construction,  home  furnishing,  consumer  goods,  packaging,



electrical  uses,  transportation and  medical products  (U.S.  EPA,  1978a,b).



Some alkyl  esters have minor applications  as dielectric  fluid  [d1(2-ethyl-



hexyl)phthalate],  active  Ingredients  in pesticides, resin  sqlvents,  perfume



fixatives, solvents and other uses  (Hawley,  1981;  U.S.  EPA, 1979).
0779p                               1-14                             10/15/87

-------
                2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES



2.1.   WATER



2.1.1.   Hydrolysis.  Limited  data  regarding  the hydrolysis of  the  phthallc



acid  esters  were  located   In the  available  literature  as  cited  In  the



Appendix.   Gledhlll  et  al.  (1980)  observed  <5X  hydrolysis   of  1   mg/l



n-butyl benzyl  phthalate  1n  28 days.  Wolfe  et  al.  (1980)  estimated second-



order  rate  constants  for alkaline  hydrolysis  of phthalates at  pH  10-12 and



30°C.



    Rate constants  varied with the  size  and  complexity  of the  phthalates and



ranged   from   l.lxlO"4   M"1   sec"1   fo.r   dl (2-ethyhexyl)   phthalate   to



6.9xlO~2   M"1   sec'1   for    dimethyl   phthalate.     Thus,    corresponding



estimated half-lives  at  pH  7  range  from 3.2-2000 years, respectively.   The



hydrolysis half-lives of dlphenyl and  d1-t-butyl  phthalates at a pH  of  7 are



estimated  to  be  35  days  and 12,000  years,  respectively  (Suffet  et  al.,



1981).  Hydrolysis  may  not  result 1n  significant degradation of most  phtha-



late esters compared with other mechanisms such as mlcroblal degradation.



2.1.2.   Oxidation.    No  experimental  data pertaining  to  the   oxidation  of



alkyl and aryl  phthalates  In water  were  located  In  the available literature



as  cited  In  the  Appendix.    Mabey  et  al.  (1981)   calculated  R0?  radical



reaction  rate  constants  for  phthalate  esters,  which  become  larger  with



Increasing size and  complexity of the phthalate  ester  chains.   Values  range



from  0.05   M"1   sec"1   for   dimethyl   phthalate  to  7.2  M'1  sec'1   for



d1(2-ethylhexyl)  phthalate   and   280  M"1  sec"1  for  n-butyl  benzyl  phtha-



late.   Assuming  an  ambient  RO   radical  concentration  of  10~9  M,   (Mill  et



al.,  1980),   oxidation  half-lives  were  calculated to  be  >3  years  for  the



alkyl phthalates.   A  significantly  shorter half-life  of  -29 days was  calcu-



lated  for  n-butyl  benzyl  phthalate  using  data  from Mabey et   al.  (1981).










0780p                               2-1                              08/26/86

-------
Habey  et  al.  (1981)  predicted  that  reaction  of   phthalates  with  singlet
oxygen would not be environmentally Important.
    The Interaction  of  alkyl  phthalates with  OH radicals present  In  normal
ambient water  1s  considered  to  be  too slow to be of  Importance  (Callahan  et
al., 1979a).
2.1.3.   Photolysis.   GledhUl  et  al.  (1980)  studied   the   photolysis   of
aqueous n-butyl  benzyl  phthalate  In  sealed tubes.   The  photolysis  half-life
was >100  days.   Experimental  data  regarding the photolysis  of alkyl  phtha-
lates  1n  water  were not located  In the available literature as  dted  1n  the
Appendix;   however,   the  UV absorption  spectra  for  d1-n-butyl,  d1(2-ethyl-
hexyl),  dlethyl,  dimethyl  and  d1-n-octyl  phthalates   In  organic  solvents
Indicates slight absorption at wavelengths of  290nm.  The absorption  becomes
even  less  significant  at longer  wavelengths and no absorption occurs  above
310 nm (Sadtler, n.d.).  This Information  Indicates  that  although  the  poten-
tial  for  direct  photolysis exists, the photolysis  of phthalates  In  ambient
waters may not be significant.
2.1.4.   M1crob1al  Degradation.   Phthalate  esters  have  been reported  to  be
metabolized  In  water by pure cultures  of  microorganisms, mixed  microorgan-
isms  and  1n natural water.  The rates  of  degradation vary widely  depending
upon  environmental  conditions, such  as temperature, pH,  amount  of  dissolved
oxygen and  the  structure of  phthalate (HattoM  et al.,  1975).   The degrada-
tion  of phthalate  esters by  pure  culture  Isolated  from  natural  water,  acti-
vated  sludge  and  soil  have been  studied by several  Investigators  (Taylor  et
al.,  1981;  Kurane et al.,  1979a,b; Engelhardt  et al., 1975,  1977;  Engelhardt
and Wallnofer,  1978; Klausmeler  and  Jones,  1960;  Perez  et  al.,  1977;  Ohta
and  Nakamoto, 1979).   Several  authors  have  studied  the blodegradatlon  of
phthalate esters  by mixed  microorganisms.   Thus, activated sludge,  domestic


0780p                               2-2                              08/26/86

-------
wastewater  and  natural  river water  have  been used  as  mlcroblal  Inoculum to
study  the  blodegradatlon  of  phthalate  esters  (O'Grady et  a!.,  1985;  Saeger
and  Tucker,  1973b, 1976;  Sasaki,  1978;  Sugatt et al., 1984).   Tabak  et al.
(1981)  observed  100X degradation of dimethyl, dlethyl, dl-n-butyl  and butyl
benzylphthalate  In  7  days  with unaccllmated  microorganisms from  domestic
wastewater.   On  the other hand,  b1s-(2-ethylhexyl)  phthalate and d1-n-octyl
phthalate  needed  21  days  of acclimatization before  a  blodegradatlon  of  >90%
In 7 days  were observed (Tabak  et al.,  1981).   Similarly,  the mineralization
of  >85X occurred  with  various  phthalates  In  28 days  with  both  activated
sludge  and  river  water  (Saeger  and Tucker,  1976;  Sugatt et  al.,  1984).   The
metabolic   pathway   data   Indicate  that   phthalate   esters   first   undergo
enzymatic  hydrolysis  to   form the  monoester, followed by  further  hydrolysis
to phthallc  acid.   The  phthallc  add  1s  further  degraded  to carbon  dioxide
and water  (U.S.  EPA, 1978b;  Saeger and Tucker,  1976).
    Results  of various  river die-away  studies  using a few  phthalate  esters
are presented In  Table  2-1.   Saeger and Tucker  (1973a,b,  1976)  and  Gledhlll
et  al.   (1980)  concluded   from   their  river  die-away and  activated  sludge
studies  that phthalate   plastldzers,  as  a  class,   undergo rapid  primary
degradation  and  mineralization   by  bacteria commonly  found   In the  environ-
ment.   In  a simulated  lake  microcosm,  Gledhlll  et al. (1980) observed  >95%
primary  degradation of  n-butyl  benzyl  phthalate  In  7   days  (Cn=l   mg/i).
The  blodegradatlon  half-life for  n-butyl   benzyl  phthalate   In this  natural
water system was  <4 days.   The  length  and configuration  of  the  alkyl ester
chains   significantly  influences  the blodegradatlon  rate   of phthalates  1n
freshwater   ecosystems,  whereas   acclimation of  microbes  appears  to  have
IHtle  effect (HattoM  et al.,   1975; Johnson  et al., 1984).  In  freshwater
systems, phthalates  such  as  dimethyl and  dlethyl  phthalate  are expected  to


0780p                               2-3                              08/26/86

-------
o
en
00
                                                     TABLE  2-1


                             Blodegradatlon  Screening of  Some Alkyl and Aryl Phthalates3
03
•o
Phthalate
n-Butyl benzyl
D1(2-ethylhexyl)
D1(hexyl, nonyl,
undecyl)
i. D1(hexyl, octyl,
nonyl, decyl, undecyl)
Dlundecyl


River Die-Away.
X Primary
Degradation1*
100
40
55
NA
20


Unaccl
(weeks
1.3
5.0
5.0
NA
5.0


Imated System
tl/2c
) (weeks)
0.2
2.5
NA
3.0
2.5


River Dte-Away.
% Primary
Degradation
100
NA
NA
NA
NA


Unaccl Imated
t
(days)
9
NA
NA
NA
NA


Systemd
M/2
(days)
2
NA
NA
NA
NA
    aln1t1al concentrations = 1 mg/i


    DSaeger and Tucker, 1973a


    cSaeger and Tucker, 1973b


    dGledh111 et al., 1980


    NA = Not available

-------
degrade  faster  than  the  larger  and  more complex phthalate esters (Johnson et



al.,  1984;  HattoM  et  al.,  1975).   Hattorl  et  al.  (1975)  observed  100%



decomposition  of  dlethyl phthalate  after  6  days  and  100%  decomposition  of



dimethyl  phthalate  after 8-11  days  In  river water  Initially spiked with  25



mg/i  of  the ester.   D1 (2-ethylhexyl)  phthalate degraded  only -40%  after  2



weeks  In  river  water.   In relatively clean  ocean  water,  -14-20% degradation



of  dlethyl  and  dimethyl phthalate  was measured  after  14  days,  while  the



larger phthalates were decomposed >30%  during the  same period.  The degrada-



tion  of  all  the phthalate esters  were  much higher  with polluted ocean water.



For  example, while  33%  of  dlbutyl  phthalate  and  14% of dlethyl  phthalate



degraded  1n  clean ocean  water  1n  14  days,  the degradation was 100% 1n 5 days



for dlbutyl  phthalate and 68%  1n  14  days  for dlethyl phthalate with polluted



ocean water.  The higher degradation  1n polluted water was  attributed to the



presence  of  higher  concentrations and  nutrients  In  polluted  water.   Longer



chain phthalate esters decomposed  faster  than dimethyl and  dlethylphthalates



1n clean ocean water, a finding not further explained (Hattorl et al., 1975).



    In aquatic  sediments under  anaerobic  conditions, blodegradatlon of short



chain  alkyl  esters  appears  to  be slow and  degradation of   the  longer  chain



esters has been observed to be very slight  or  undetectable  (Johnson et  al.,



1984;  Johnson   and  Lulves,   1975;  Horowitz  et al., 1982;   Shelton  et  al.,



1984).   Johnson and  Lulves  (1975)  observed 61  and 98% anaerobic  mineraliza-



tion  of  dl-n-butyl   phthalate   In 14  and   30  days,   respectively.   Under  the



same  conditions, no  detectable  degradation of dl(2-ethylhexyl) phthalate was



measured  after  30   days.    Johnson  et al.   (1984)   measured  10%  anaerobic



mineralization  of radlolabeled  d1 (2-ethylhexyl) phthalate after  28 days  and



<1% mineralization  of  dllsononyl  and dllsooctyl phthalates.   Optimal degra-



dation of  long  chain phthalates occurred at  high concentrations  In  nutrient-



rich  aquatic sediments  with  temperatures above  22°C.  Such  environmental






0780p                               2-5                              08/26/86

-------
conditions are  typical  of  sewage treatment ponds, wetlands, eutrophlc  lakes

and  enriched  streams  during  summer.   Winter  conditions,  particularly  at

northern  latitudes   and  environmentally  realistic  (low,  <1  yg/l)   concen-

trations would adversely affect blodegradatlon  (Johnson  et  al.,  1984).

2.1.5.   Volatilization.   No significant  volatility  losses (O.5X/24 hours)

were  observed   for   n-butyl   benzyl,  d1(2-ethylhexyl),  d1(hexylt  nonyl,

undecyl)  and   dlundecyl   phthalates   during  blodegradatlon   studies   with

activated sludge  (Saeger  and  Tucker,  1976).   Atlas et  al.  (1982)  measured

the mass-transfer coefficient of dl-n-butyl phthalate to be 0.104  cm/hour  In

stirred  (200-300  rpm)  seawater  free  of  Interfering  organic  contaminants  at

23°C.   At  a  depth   of  4.5 cm,  the  volatilization  half-life  of  d1-n-butyl

phthalate has been calculated to be 30 hours following  the method  of  DHUng

(1977).

    Henry's   Law  constants  for  some phthalate  add esters, calculated  using

vapor pressure and water  solubility  data  from Table 1-2  are as  follows:


           dl-methyl  phthalate                  2.5xlO~7  atm.mVmol
           dl-ethyl  phthalate                  7.8xlO"7  atm-rnVmol
           dl-n-butyl phthalate                2.2x10"*  atm-rnVmol
           dl-n-octyl phthalate                2.4xlO"s  atm«m3/mol
           d1-(2-ethylhexyl)phthalate           l.lxlO"7  atm-rnVmol
           n-butyl benzyl  phthalate             1.2x10"'  atm-mVmol


    This  Information  also  suggests   that  volatilization  would  not  be   a

significant   removal  process  for  these phthalate  esters,  except  dl-n-octyl

phthalate, which  could volatilize significantly  from  shallow  rivers (Lyman

et al.,  1982).  The  evaporation  half-life  of d1(2-ethylhexyl)  phthalate  from

bodies of water has been estimated to  be  15 years  (Callahan et  al., 1979a).

2.1.6.   Adsorption.    Sullivan  et  al.  (1982)  studied  the   adsorption  of

d1-n-butyl and  d1(2-ethylhexyl)  phthalates onto  clay  minerals, caldte and

sediment samples  from  seawater.   Results  Indicate that adsorption Increases



0780p                               2-6                              08/26/86

-------
with  Increased  salinity or  decreased solubility  of  phthalates.   Adsorption



onto  the clay  minerals and  calclte  appeared  to  be  a  reversible  process,



whereas  adsorption  onto  sediments   was  Irreversible.   This   suggests  that



marine  sediments   may  act  as  a  final  repository of  phthallc  acid  esters



(Sullivan  et a!.,  1982).   Mabey  et al.  (1981)  calculated  sediment-water



partition coefficients  for phthalates,  Indicating adsorption  1s  likely for



all  phthalate  esters   with  adsorption  tendency  Increasing  with  size  and



branching of  the   ester  chain.   Sediment adsorption coefficients  range  from



98  for  dimethyl   phthalate  to >150,000 for  d1-n-butyl   phthalate  and  the



larger phthalate esters  Including n-butyl  benzyl  phthalate.   Gledhlll  et al.



(1980)  observed  significant   partitioning  of  n-butyl benzyl  phthalate  to



sediments In a  simulated lake  microcosm.   The  average  ratio  of this  compound



measured In sediments versus water was 571:1.



    The  contention  that  phthalates  will  be  adsorbed significantly onto sedi-



ments  In aquatic  ecosystems  Is supported by the  observation that phthalates



are commonly  found In  bottom sediments  from both  streams  and  seas  (Callahan



et al.,  1979a).



    Evidence suggests  that complexatlon  of phthalates  In  natural  water  with



organic  substances  may  be one  mode  of  transport  of phthalates  (Khan,  1980;



Ogner  and  Schnltzer,  1970; Matsuda  and  Schnltzer, 1971).   Phthalate  esters



have been observed readily Interacting with fulvlc acid,  a  widely  occurring



humlc  substance found  1n soils and  waters.  The  phthalates  appear  to  adsorb



to  the  surface  of  the  fulvlc  add  molecule rather than react  with  It.   The



fulvlc acld-phthalate  complex  Is very soluble  1n  water;  thus,  mobility  of



otherwise Insoluble  phthalate  esters  Is modified.   Extent  of  solub1llzat1on



appears  to  vary with phthalate size.  Equivalent quantities of  fulvlc  add



will solublUze 4  times  as many equivalents of  d1(2-ethylhexyl) phthalate as



of d1-n-butyl phthalate  (Matsuda and  Schnltzer, 1971).





0780p                               2-7                              08/26/86

-------
2.1.7.   B1oaccumulat1on.   Phthalate  esters have  been  Identified  In  living
matter, and  data  collected from  field  and laboratory  studies  Indicate  that
these  compounds  can be  taken  up and  bloaccumulated  In a  variety  of  organ-
Isms.   The  majority of  data  1s  on  d1(2-ethylhexyl)  phthalate  (Callahan  et
al..  1979a).   Host  phthalates   have   relatively  high  KW  values  (>250),
suggesting   I1poph1llc1ty   and   potential  for   bloconcentratlon.    Studies
pertaining to  the  uptake  and  bloaccumulatlon of phthalate  esters  In aquatic
organisms are discussed In Chapter 6.
2.2.   AIR
2.2.1.   Chemical   Degradation.   Limited  data  regarding  the  degradation  of
the  phthalate  esters  1n  the  atmosphere  are  available  In  the  literature  as
dted  In  the   Appendix.    The   HO  radical  reaction  half-life  of  gaseous
dimethyl, d1-n-butyl, d1(2-ethylhexyl)  and  n-butyl benzyl  phthalates at  25°C
have been estimated to be  23.80,  18.44,  11.86  and  14.29 hours,  respectively,
by the GEMS programming method  (U.S.  EPA, 1986a).
    The  same  GEMS  programming  method   predicts  that  reaction  of  phthalates
with atmospheric ozone Is not  a  significant process (U.S.  EPA, 1986a).
    The  UV  absorption  spectra  for  dl-n-butyl,  dl(2-ethylhexyl),  dlethyl,
dllsodecyl and  d1-n-octyl  phthalate  reveal  slight absorption of UV  light  at
wavelengths  >290  nm although  no absorption  occurs  at  wavelengths >310  nm
(Sadtler, n.d.).   These  data  suggest  that although there  Is  a  potential  for
photodegradatlon  In  the  atmosphere,  the  process  1s  probably not  a  signifi-
cant one.
2.2.2.   Physical   Removal.   Monitoring  data  reveal  that  phthalate  esters
can  be  removed from the  atmosphere  by wet and  dry deposition  (Kawamura  and
Kaplan, 1983;  Atlas and  G1am,  1981;  Karasek et  al.,  1978;  Weschler, 1984).
0780p                               2-8                              08/31/87

-------
Average  measured  ratios  of  the  concentration  In  precipitation  to  air  are
3.56x10*   and   3.93x10*   for   d1-n-butyl  phthalate   and   d1(2-ethylhexyl}
phthalate,  respectively  (Atlas  and Glam,  1981).   This  Indicates  significant
removal  of  atmospheric  phthalates  through precipitation.   The probability of
removal  of  an  atmospheric  pollutant   through  adsorption  on  atmospheric
aerosols  and  subsequent  precipitation   1s   reasonable   for  chemicals  with
saturation  vapor  pressures  of  <10~T mm  Hg (CupHt, 1980).   Since  the vapor
pressures of all  the  phthalates,  listed   1n Table  1-2,  with the exception of
d1(2-ethyl  hexyl)  phthalate, are  <10~7   mm  Hg,  they  are  not  likely  to  be
removed  significantly by  this mechanism.   01(2-ethylhexyl)  phthalate, on  the
other hand, may be significantly removed.
2.3.   SOIL
2.3.1.   Chemical  Degradation.    Pertinent   data  regarding   the   chemical
degradation  of  phthalate esters In soil  could  not be  located  In  the avail-
able  literature  as cited  In the  Appendix.   Considering data presented  In
Section  2.1.,  hydrolysis  In wet  soils   (excluding  dlphenyl  phthalate)  and
photolysis at soil surfaces would not  be   Important degradation mechanisms.
2.3.2.   M1crob1a1 Degradation.   Shanker  et  al.   (1985)  observed  mlcroblal
degradation  of  d1-n-butyl,  dl(2-ethylhexyl)  and  dimethyl  phthalates   In
garden soil.   Results of  this  study are  listed In  Table  2-2.   This Investi-
gation  Indicates   soil  mlcroflora  significantly   degraded  phthalates  under
aerobic  conditions, and  shorter chain phthalates  degraded  at a  faster  rate
than  the  compounds with  longer  chains.   The anaerobic  degradation  of phtha-
lates  was  much   slower  than  the  aerobic degradation.    In  various  other
studies, a  considerable  number  of  widely occurring microorganisms  capable of
degrading phthalate esters,  such as Nocardla.  Arthrobacter.  Pseudomonas  and
the  fungus  Penlcllllum  Illadntum. have  been  Isolated  from soils  and other


0780p                               2-9                              05/13/86

-------
GO
0
•o
TABLE 2-2
Blodegradatlon of Phthalates In Garden Solla'b
Dimethyl Phthalate
Incubation
Tine
(days)

0
5
10
15
1, 20
o
30
Autoclaved
control
Aerobic

DHP
468 O 6
18001
43*9
0
0

0
465*6


PA
0
9*0.5
8i0.5
0
0

0
traces

Anaerobic

OMP
47102
410*8
376^6
302OO
245.6

178^2
467*8


PA
0
8*1.1
lOiO.5
240. 7
90.1

3*1.0
0

Dl-n-butyl
Aerobic

DNBP
47204
11003
40*6
0
0

0
465*10


PA
0
8i0.6
6±0.6
0
0

0
traces

Phthalate
D1(2-ethylhexyl)phthalate
Anaerobic

DNBP
470O7
402*9
348^8
30 U 9
239*9

159*4
463*9


PA
0
12O.1
14*2.9
29^3.5
22*2.3

15O.7
0

Aerobic

DEHP
480*9
430.8
320 Ol
NA
120*4

40^8
471.4


PA
0
8*1.1
7*1.1
NA
11*0.6

5±0.6
0

Anaerobic

DEHP
478^9
460^8
439*6
NA
389*5

318*7
478*7


PA
0
traces
2*0
NA
8*1.1

Ill0.6
0

aSource:  Shanker et al., 1985
''Each value Is the meatuSE of triplicate samples In
PA = Phthallc acid
NA = Not available
                                                              compound  recovered/g  soil
o
tn
CD

-------
natural  sources  (Kurane et  al.,  1977; Ohta  and Nakamoto,  1979;  Englehardt



and Wallnofer, 1978; Englehardt et  al., 1977;  Williams  and Dale,  1983; Lewis



et al.,  1984;  Klausmeler and  Jones,  1960).   In view of  this  Information as



well   as  the  aquatic  blodegradatlon data  (see Section  2.1.4.),  significant



removal  of  phthalate   esters   may   be  possible  under  aerobic  conditions;



however, anaerobic degradation may be a very slow removal mechanism.



2.3.3.   Volatilization.   Pertinent data  regarding  the  volatilization  of



alkyl and  aryl  phthallc  acid esters from  soil  surfaces  could  not  be located



1n  the  available  literature  as  cited  In  the Appendix.   Considering  the



tendency  of  the  larger  phthalates   to  adsorb  to  soils  (Section  3.2.4.)  as



well   as  their relatively  low  vapor pressures,  volatilization  will  probably



not  be  an  Important  removal  mechanism.    Since  dimethyl  phthalate  Is  not



likely  to  adsorb to soils,  volatilization from dry  soil  surfaces  may  be  a



potential removal mechanism for this compound.



2.3.4.   Adsorption.  Pertinent data  regarding the adsorption  of  alkyl  and



aryl  phthalates  to  soils could  not  be  located In the  available literature as



cited  In  the  Appendix.   Wide ranging  water  solubilities and  K    values



suggest  that  adsorption to  soils by  the  phthalate esters  Is  dependent  upon



the  size and  complexity of  the phthalate  ester chains.   Mobility  of  phtha-



lates  1n soil  has  been categorized  using adsorption  coefficients  obtained



from  the following equation (Kenaga,   1980):   log K    =  3.64-0.55 log  WS.



From  this  equation, dimethyl  phthalate  should predictably  be  highly  mobile



1n  soils  (K  =44).   n-Butyl   benzyl,  d1-n-butyl,  d1-n-octyl  and  dlnonyl



phthalates  should  be  low  to  slightly  mobile  (K    890-2400), while  larger



or  branch-chained  compounds,   Including  dlphenyl   phthalate,   should  remain



strorgly  adsorbed  to   soils   (K  >5000).   Data  presented  In  Section  2.1.



Indicate  that   the  mobility  of  phthalates  Is  affected,  and  expectably



enhanced, by the presence of fulvlc  add In soils.





0780p                               2-11                             06/06/86

-------
2.4.   SUMMARY
    Hydrolysis  Is  not  expected  to  be  a  significant  removal  mechanism  of
phthalate esters (Suffet  et  al.,  1981).  Mabey et  al.  (1981)  estimated that
phthalate  esters  will   not   undergo   significant   oxidation  In  water.   UV
absorption spectra  for  some  phthalates  In nonaqueous  solvents  Indicate that
potential exists  for direct  photolysis  In  the environment.  The  photolysis
half-life of  n-butyl  benzyl  phthalate  has   been  observed  to  be >100  days
(Gledhlll et al., 1980).  Phthalate esters are  reported  to be  metabolized  In
the aquatic environment  by  a  variety of pure microorganisms and  degraded  by
mixed  mlcroblal  systems.   The  mlcroblal   degradation  rates   vary  widely
depending upon  environmental  conditions such  as  temperature,  pH, amount  of
oxygen present  and  the  phthalate  structure  (Thomas et al.,  1984;  Hattorl  et
al.,  1975).   Blodegradablllty  of phthalates   In  freshwater  decreases  with
Increasing size and complexity  of the  phthalate  ester  chains  (Hattorl  et
al., 1980; Johnson  et al., 1984).
    Results  from river  die-away tests and activated  sludge  studies  Indicate
that phthalates, as  a  class,  undergo rapid degradation  by bacteria  commonly
found 1n  the environment  (Saeger  and  Tucker,  1973a,b,  1976;  Gledhlll et al.,
1980).   For  example, In  a  simulated  lake microcosm  Gledhlll  et  al.  (1980)
observed >95X primary degradation  of  the complex  ester  n-butyl  benzyl  phtha-
late  In  7 days.  Under  anaerobic conditions,  btodegradatlon of  short-chain
alkyl esters  has been  shown  to be possible,  but  slower  than under aerobic
conditions,  while degradation of  the  long-chain esters  has  been  shown  to  be
very slight or  undetectable (Johnson  et  al.,  1984;  Johnson and  Lulves,  1975;
Horowitz  et  al., 1982;  Shelton  et al.,  1984).  From the  estimated Henry's
Law  Constants  for   n-butyl  benzyl,   ch-n-butylt  d1(2-ethylhexyl),  dlethyl,
dimethyl  and  d1-n-octyl  phthalates,  phthalate esters  are predicted to  not


0780p                               2-12                             08/26/86

-------
significantly volatilize  from  water  (Lyman  et al.,  1982).   Dl-n-octyl phtha-
late may  significantly volatilize from  shallow  rivers,  although volatiliza-
tion from  deeper  waters  should not be  significant  (Lyman  et  al.,  1982).  In
seawater,  adsorption  onto  clay minerals and  calclte appears  to  be a revers-
ible process, whereas  adsorption  onto  sediments  1s  Irreversible  (Sullivan et
al., 1982).   This  suggests  that marine  sediments may  act  as  a  final reposi-
tory of  phthallc  acid esters   (Sullivan  et  al.,  1982).   Calculated sediment-
water partitioning coefficients  Indicate adsorption  1s  likely for  all phtha-
late esters,  with  adsorption  tendency  Increasing with  the  size  and  complex-
ity of  the ester chain  (Habey et al.,  1981).   Complexatlon  with  the widely
occurring  humlc  and  fulvlc  substances  causes  solub1!1zat1on   of  phthalate
esters  In  water,  thus  modifying  their  mobility   (Matsuda  and  SchnHzer,
1971).   Phthalates have been  Identified  1n  living matter,  and data collected
from field and laboratory studies  Indicate  that  these  compounds  can  bloaccu-
mulate 1n aquatic organisms (Callahan et al.. 1979a).
    In air,  the  phthalate  esters,  as  a  class,  are  predicted to  react  with
hydroxyl   radicals,  with  a  t,/2  of  <1  day   (U.S.  EPA,  1986a).    The  actual
atmospheric  t, ._,  however,  may be longer  than  the  estimated values  because
of  adsorption onto   airborne  partlculate  matter.   Removal  of  atmospheric
phthalate  by wet and dry  deposition  has  also  been observed (Kawamura  and
Kaplan,  1983; Atlas and Glam,  1981; Karasek et al.,  1978; Weschler, 1984).
    Significant  hydrolysis  of  phthalate  esters In  wet  soils  1s  unlikely
(Wolfe et  al., 1980;  Gledhlll  et  al.,  1980).   Shanker  et al.  (1985)  observed
mlcroblal  degradation of  dl-n-butyl,  d1(2-ethylhexyl)  and  dimethyl  phtha-
lates 1n  garden  soil.  Results  Indicate that soil  mlcroflora  significantly
degrade  phthalates   under  aerobic   conditions,  and  short-chain  phthalates
degrade  at a faster  rate than  the  longer  chain phthalates.  The anaerobic


0780p                               2-13                             08/31/87

-------
degradation of  phthalates was  very slow  compared  with aerobic  blodegrada-
tlon.   The water  solubilities  and K    values  of  the  phthalates  suggest
that adsorption  to  soils  Is dependent  on  the size and complexity  of  phtha-
late ester chains.  Dimethyl phthalate  should  be  reasonably  mobile  1n  soils,
whereas large or  branched chain  esters,  Including dlphenyl  phthalate,  should
remain  strongly adsorbed  to  soils.   The mobility of  phthalate  esters  1n  the
presence  of  fulvlc  add  should  Increase.   Since  dimethyl  phthalate  Is  not
likely  to  adsorb to  soils,  volatilization from  dry  soil  surfaces  may be  a
potential   removal mechanism.   Volatilization  will  be  Insignificant  for other
phthalates.
0780p                               2-14                             06/06/86

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                                 3.  EXPOSURE







    Phthalate  esters  are  ub1qu1t1ous   1n  the  environment.   They have  been



found  In  underground  and drinking waters,  surface waters, soil, oil,  food,



plants,  fish,  animals and  humans  (Callahan  et  a!.,  1979a).   There  Is  some



evidence  that  phthalate  esters  occur  naturally In certain plants and  organ-



Isms  {Callahan  et al.,  1979a;  Peakall, 1975;  Mathur,  1974).   The  environ-



mental contribution of phthalate  esters  from anthropogenic sources,  however,



far exceeds  Us  contribution from natural  sources.   The  disposal of  plastic



materials  containing   phthalate  esters  In  disposal  sHes  constitutes  the



major  reservoir  of  these  compounds   In   the  environment   (Mathur,   1974;



Peakall,  1975).   All  these  environmental  media containing phthalate  esters



may  directly  or  Indirectly cause human  exposure to  these  compounds.   The



leaching  of  phthalate esters from the  hemodlalysls  tubing and  the  PVC  bags



containing  Intravenous  solutions  can  be  sources   of  exposure  to  these



compounds  for  a special  segment  of  the population.   A considerable  body of



research  has been done  In   this  area (Ono  et  al.,  1975; Corley  et al.,  1977;



Pollack  et al.,  1985b; Fayz et  al.,  1977).  The levels  of these compounds In



water,  air  and  food  and  possible  human  exposure  to phthalate esters  from



these  sources are discussed 1n the following sections.



3.1.   WATER



    Phthalate  esters  have   been  detected  In  Industrial  effluents by  several



Investigators.    Jungclaus   et  al.  (1976)  reported the  presence of  dlethyl



phthalate  at  a  concentration  of  60  yg/l  (60 ppb)   1n  the  wastewater  from



a  tire manufacturing  plant.   In  a  survey  of effluents   from  the  petroleum



refining  Industry,  Snider  and  Manning   (1982)  reported the   detection  of
0781p                               3-1                              05/13/86

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dimethyl,  dlethyl,  dl-n-butyl,  d1(2-ethylhexyl)  and  n-butyl  benzyl  phtha-
lates 1n both  the  blotreatment  effluents  and final effluents of  the  treated
wastewaters.   The  concentrations  of  dimethyl,  dlethyl  and  n-butyl  benzyl
phthalates  In  the  final  effluents were  always  <20  ^g/j,  (ppb),  but  final
effluents  from  one type  of  refinery  wastewater  had  a d1-n-butyl  phthalate
concentration  In  the  range  of  2-32  yg/8..   In  another  class  of  refinery,
the concentration range of d1{2-ethylhexyl)  phthalate  In  the  final  effluents
was  reported  to be  <0.1-2000  wg/s.  (Snider  and  Manning,  1982).   HHes  and
Lopez-Avlla  (1980)  reported  the presence  (concentration  not quantified)  of
dloctyl  and  d1(2-ethylhexyl)  phthalates  In  wastewaters from an  unspecified
specialty  chemical  manufacturing   plant.    The   average   concentrations   of
dlethyl, d1(2-ethylhexyl), dl-n-octyl,  d1-n-butyl  and  n-butyl benzyl  phtha-
lates  In  76  sources  of  pollution  Into   the  Influent of  sewage  treatment
plants  of  two  cH1es were reported to  range from 16.2-22.0, 19-46,  33-62.5
and  16-17  vg/4,   respectively   (Callahan  et  al.,  1979b).   Other  authors
have  detected  dimethyl,  dlethyl, dlbutyl, dllsobutyl and  dloctyl  phthalates
In  the   treated  effluents from  pulp  and  paper   manufacturers  (Voss,  1984;
Brownlce  and  Strachan,  1977;  Fox,  1977).  The  concentrations  of  dlethyl,
dlbutyl  and  dloctyl  phthalates   In  the  effluents  were reported  to be  50,  70
and 15 yg/l, respectively (Brownlee and  Strachan,  1977;  Voss,  1984).
    Phthalate esters were also  Identified  In the  Influents and effluents  of
sewage  treatment  plants  (Thomson et al.,  1981;  McCarty and  Relnhard,  1980;
Ellis  et al.,  1982; HHes,  1979;   Callahan  et  al.,  1979b).  The  concentra-
tions  of  dimethyl,  dlethyl,  d1-n-butyl,  dllsobutyl,  d1(2-ethylhexyl)  and
n-butyl  benzyl phthalates  In  sewage Influent were reported to be  as  high  as
6.0,  17,  50,  3.0,  200 and  40  yg/l,  respectively  (Callahan  et  al.,  1979b;
McCarty  and Relnhard,  1980;  HHes,  1979).   The  removal  of  the  phthalate


0781p                               3-2                              05/13/86

-------
esters  as  a  result  of  treatment  of  wastewater  evidently  depends  on  the



nature of  treatment.   For example,  Callahan  et  al.   (1979a)  reported  almost



complete removal  of  dlethyl,  d1 (2-ethylhexyl),  n-octyl  and n-butyl  benzyl



phthalates  in  the effluent  from a  sewage  treatment  plant.  Other  Investi-



gators  have  observed  partial  removal  or,  In some  cases,  Increases   In  the



concentrations  of phthalate  esters   In  the  effluent  from sewage  treatment



plants  (Young  et  al.,  1983;  HHes,  1979;  McCarty  and  Relnhardt,   1980).



Thus, although  the concentration of  d1 (2-ethylhexyl)  phthalate  1n  the  Influ-



ent  water  of  the Los  Angeles  County  sewage  treatment plant  was 42  yg/8.,



the  treated  effluent  had  a reported   concentration  of 420  ^g/l  (Young  et



al.,  1983).   Other  Investigators  have  Identified the  presence of dlethyl,



d1-n-butyl  and  d1(2-ethylhexyl)  phthalates  In the wastewater from  a  poultry



plant,  which had  undergone  wastewater  treatment  and  reclamation,  and  In



wastewater   from  a   dining  hall,  laboratory and  dormitory  of  a  Japanese



university (Shlbuya, 1979; Andelman et al.,  1984).



    Phthalate esters  have been  Identified  In surface waters throughout  the



United States.  The  presence  of  dimethyl phthalate In  surface  waters  around



the  contaminated  area  1n Love  Canal,  Niagara  Falls,  NY,  was reported  by



Hauser and Bromberg  (1982).  The concentrations  of dlbutyl,  dl(2-ethylhexyl)



and  n-butyl  benzyl  phthalates  1n  Delaware  River  water  2 miles  downstream



from  a  Philadelphia  wastewater  treatment plant  were   reported to  be 0.6,  1.0



and  0.6  vg/l,  respectively  (HHes,   1979).   Oewalle  and  Chlan (1978)  also



Identified dlbutyl,  dlethyl  and hexyl  esters and an  unidentified  phthalate



In  Delaware  River water  and  Us  major tributaries; dlethylhexyl  phthalate



occurred 1n  these waters  with  a  90X  frequency.   The  concentrations  of  phtha-



late  esters  1n Delaware  River  water  between Marcus  Hook, PA, and Trenton,



NJ,  was  reported  to be higher  In  winter than 1n summer (Sheldon  and  HHes,










0781p                               3-3                             06/06/86

-------
1978).   The  reported  concentration   ranges  for  dlbutyl,  dloctyl and  butyl
benzyl  phthalates  In  this  Mverwater  during  the winter  of 1976-1977  were
0.2-0.6,  3.0-5.0  and  0.4-1.0  vg/l,   respectively.    Goodley   and  Gordon
(1976)  reported  the  presence  of dlethyl,  dl-n-butyl  and  d1-n-octyl  phtha-
lates In lower Tennessee River water  near  Calvert CHy,  KY.  Corcoran (1973)
reported  the  concentration   of  d1(2-ethylhexyl )  phthalate  In  Mississippi
River water  to  be  (tentatively)  as high  as  600  wg/l.   The  concentration
further   downstream In  the  water of  Escambla  Bay,  FL,  was  much less  (not
quantified),  and  the  concentration  was even  less  (not  quantified)  1n  the
water of the Gulf  Stream.   Murray  et al.  (1981)  Identified d1(2-ethylhexyl )
phthalate In  the water from  Galveston  Bay,  TX,  at  a mean  concentration  of
0.6   yg/l.   Other   Investigators   have   Identified   dlbutyl,   dlethyl   and
dloctyl   phthalates   1n  water   from   lower  Fox  River,  WI  (Peterman  et  al.,
1980).   Results  of  an extensive survey designed to determine the  levels  of
butyl benzyl  phthalate In surface  waters   near  various  Industrial  sites  In
the United States are reported 1n Table 3-1.
    Phthalate  esters  also  have  been   Identified  1n  river  waters   In  other
countries, Including  the Rhine,  Ijssel,  Mense  and Waal  rivers 1n the Nether-
lands (Schouten  et  al.,'  1979;  Meljers and  VanderLeer,  1976),   in  the  Kiel
Bright  In  Germany  (Ehrhardt   and  Derenbach,  1980),  In  the Caronl  River,
Trinidad  (Moore  and  Karasek,  1984),  and   1n  the  River  Glatt,  Switzerland
(Zuercher  and   G1ger,   1976).   The   maximum  reported  concentrations   of
d1-n-butyl phthalate  and  dl (2-ethylhexyl )  phthalate 1n  these foreign  waters
were  2.8  yg/J.   (Ijssel   River)  and   4.1   ^g/l   (Mense   River),   respec-
tively  (Schouten et al., 1979).
    Rainwater  collected from  West   Los Angeles,  CA,  during 1981-1982  con-
tained  a  maximum  of  9.0  »q/i  of  total  phthalate  esters (Kawamura  and
0781p                               3-4                              06/06/86

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                                   TABLE  3-1

          Concentrations  of  n-8utyl  Benzyl  Phthalate  In  United  States
                         Haters  Near  Industrial  Sites*
                                              Concentration In Hater	
            Sampling Site
                                             1980        1981           1982
Alabama River, Mobile, AL
Baltimore Harbor, Sparrow1 s. Point, MO
Charles River, Boston, MA
Chesapeake Bay, Fisherman IS, MA
Delaware Bay, Lewes, DE
Delaware River, Port Penn, DE
Delaware River, Wilmington, DE
Detroit River, Gllwater, MI
Illinois River, 3ol1et, IL
Kanawha River, NHro, HV
Kanawha River, Hlnfleld Dam, HV
Lake Erie, Erie, PA
Lake Huron, Saglnaw Bay, MI
Lake Michigan, Charlevolx, MI
Lake Michigan, Calumet, IL
Lake Onelda, Verona Beach, NY
Lake Ontario, Four Mile Creek, NY
Lake Superior, Sault St. Marie, MI
Mississippi River, St. Paul, MN
Mississippi River, above St. Lonls, MO
Mississippi River, below St. Louis, HO
Mississippi River, Memphis, TN
Missouri River, St. Louis, MO
Mobile Bay, Ft. Morgan, AL
Niagara River, Sandy Beach, NY
Ohio River, GalUpolls Ferry, OH
Ohio River, Plttsburg, PA
Potamac River, Popes Creek, MD
Saglnaw River, Bay City, MI
San Francisco Bay, Brooks Island, CA
NO
NS
NS
NO
NO
ND
NO
NS
NS
NS
NS
ND
ND
ND
ND
NS
NS
ND
ND
ND
NS
ND
ND
ND
NS
NS
NS
ND
NS
ND
NS
NS
ND
ND
ND
ND
NS
NS
0.6-0.9
NS
NS
ND
ND
ND
ND
ND
NS
ND
ND
ND
NS
ND
ND
NS
NS
NS
NS
ND
NS
NS
ND
ND
NS
ND
ND
ND
ND
ND-0.35
NS
ND-0.3
ND
NS
ND
ND
ND
NS
ND
ND-0.45
NS
ND
ND-0.85
ND
ND
NS
NO
ND
ND-0.3
NS
ND
ND-0.3
*Source: Michael et al., 1984

NS = Not sampled

ND = Not detected with the detection limits being 0.5,  0.5  and  0.3
     In 1980, 1981 and 1982, respectively.
0781p                               3-5                              05/13/86

-------
Kaplan, 1983).   Dimethyl,  dlethyl, dl-n-butyl,  d1-n-octyl,  d1(2-ethylhexyl)
and  n-butyl  benzyl  phthalate  esters  have  been  Identified  In  urban  runoff
waters  at  concentration  ranges  of   2-10,  0.5-11.0,  0.4-1,  7-39  and  10.0
vg/l,  respectively (Cole et  al., 1984).   From  their  survey of  contamina-
tion of Japanese rivers, Takana et al.  (1978)  concluded  that  only 10% of the
phthalate ester load In river waters  Is  attributable to  atmospheric  precipi-
tation and 90X to wash off  following  periods of rain.
    Phthalate  esters have  also  been   Identified  In  groundwater  from  contami-
nated sites.    In a  system developed to  study  the trace organic  removal  effi-
ciency by an  Infiltration site  In  Phoenix,  AZ,  Tomson et al.  (1981)  reported
complete  removal  of  dimethyl   phthalate  from  sewage   water   (0.023  pg/9.
Initial  cone.)  passed  through   a  60-foot  deep   Infiltration  basin.   The
removal of  dlethylphthalate was  -93%,   but  dlbutyl  phthalate  concentration
was observed  to  Increase as a result  of  Infiltration.  Francis  et al. (1980)
specified dlbutyl,  dlethyl  and  several  unidentified  phthalates  In  leachates
from  radioactive  waste  disposal  sites  at Maxey   Flats,  KY,  and  at  West
Valley, NY.   Dunlap et  al.  (1976a,b) detected  several  phthalate esters  In
groundwater   from  a  landfill   site   near  Norman,   OK;    concentrations  of
dlethyl,  dllsobutyl and  dloctyl   phthalates   were   4.1,   0.1  and  2.4  yg/a,
respectively  (Dunlap  et  al.,  1976a,b).   Groundwater samples  from a  well  at
General  ElectMc's  capacitor   manufacturing   facility   1n  Ft.  Edward,  NY,
contained d1(2-ethylhexyl)  phthalate  (Welch,  1982).  Hutchlns  et  al.  (1983)
Identified  dimethyl,  dlethyl,  dlbutyl  and d1(2-ethylhexyl)  phthalates  In
groundwaters  at  Infiltration sites of secondary  effluents  at  Ft.  Devens, MA;
Boulder, CO;  Lubbock,  TX;  and  Phoenix,  AZ.  The maximum reported concentra-
tions  of dimethyl,  dlethyl, dlbutyl and  dl(2-ethylhexyl) phthalates  In these
groundwaters  were  0.19,  0.87,  2.38  and  1.40  yg/i,  respectively.   DeHalle


0781p                               3-6                              06/06/86

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and Chlan  (1981)  reported  cMbutyl  and  d1(2-ethylhexyl)  phthalates  at concen-



trations  up  to  1  and  100  yg/t  In  groundwaters  from a  landfill  site  In



New Castle  County,  DE.   Leachate from a  landfill  site  In  Broome County,  NY,



contained  various  phthalate  esters,   Including  dlethyl   phthalate  at   15



pg/l   (Russell   and  McDuffle,   1983).    Dlethyl  phthalate  at   0.3   Mg/i



concentration was  Identified  In  groundwater  from a contaminated site  In  the



Netherlands (Zoeteman et al., 1981).



    The concentrations  of  several  phthalate esters In  effluents and ambient



waters are given In Table 3-2.



    Several   phthalate   esters   have  been  Identified   In   drinking   water



abstracted  from  groundwater  and  surface water  In  the  United  States  and



elsewhere.  The  concentrations  of  four  most frequently occurring  phthalate



esters detected  In the U.S.  drinking  waters are given  In Table 3-3.   It  Is



evident  from  Table  3-3  that even  the most  frequently occurring  phthalate



esters  do not  occur  In all  U.S.  drinking waters.   In a National  Organlcs



Reconnaissance  Survey  of  drinking waters  from  10 U.S.  cities  (Seattle,  HA;



New York,  NY; Miami, PL;  Tuscon,  AZ;  Ottumwa,   IA; Grand  ForKe, ND; Cincin-



nati,   OH;  Lawrence,  MA; Philadelphia,  PA;  and  Terrebonne Parish,  LA),  both



dl-n-butyl and  dlethyl phthalate occurred  In 60% of  those  waters (Bedding et



al.,  1982).   The  Science  Advisory  Board  of   U.S.  EPA  reviewed  selected



organic  chemicals  and  estimated  that  the distribution  of  the  phthalate



esters 1s -50%  In  U.S.  drinking  waters, with an overall phthalate  concentra-



tion of -0.1  Mg/l  (U.S. EPA, 1975).



    Levins et  al.  (1979)  reported In a survey  of water from Cincinnati,  St.



Louis, Atlanta  and Hartford  that  the  following percentages  of  samples  from



each category contained the designated  phthalates (Table 3-4).
0781p                               3-7                              08/26/86

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                                  TABLE  3-2

            Median Concentration of  Phthalate Esters 1n Industrial
               Effluents and Ambient Hater In the United States
                       Compiled from STORE! Stat1onsa«b
Phthalate

Dimethyl phthalate
Dlethyl phthalate
D1(2-ethylhexyl) phthalate
n-Butyl benzyl phthalate

Dimethyl phthalate
Dlethyl phthalate
D1(2-ethy1hexyl) phthalate
n-Butyl benzyl phthalate
Median
Concentration
(ng/l)
EFFLUENTS
<10.0
<10.0
10.0
<6.0
AMBIENT WATERS
<10.0
<10.0
10.0
<10.0
Number
of
Samples

1255
1286
1385
1337

836
862
901
1220
Frequency of
Occurrence
(X)

2.8
9.9
38.9
7.2

0.6
3.0
24.0
3.0
aSource: Staples et al., 1985

bThe  authors  used U.S.  EPA  STORET data  only  from the  1980s  because  better
 quality control practices were used to develop the data at that time.
0781p
3-8
06/06/86

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o
—J
CO
 o
 OD
 ISi
 CD
                                                                              1ABLE 3-3


                                Concentrations of Commonly Reported Phthalate Esters Detected In Drinking Haters In the United States
•a
Location
Thirty-nine public water wells In
New York State
Maters from Torresdale Treatment
Plant In Philadelphia, PA
District of Columbia drinking water
CarrolUon Water Plant In New
Orleans. LAC
Jefferson fl Mater Plant In New
Orleans. LAC
Jefferson f? Mater Plant In New

-------
o
oo
TABLE 3-4
Percentage Occurrence of Phthalates by Hater Source
Residential Commercial Industrial Tap Water
to Total number of samples 47 42 21 12
i
0 Dlethyl phthalate 49 36 8
Dl-n-butyl phthalate 34 43 57 25
DEHP/d1-n-octyl phthalate 23 38 24 17




Influent
18
50
67
22
o
CD
en

-------
    Levins et  al.  (1979)  also  reported tap  water  concentrations of  phtha-
lates for  each  of  the  four  cH1es.   Dlethyl  phthalate was detected  only  In
Cincinnati  at  a  concentration  of   3.3  vg/l.    D1-n-butyl   phthalate  was
detected  In  Cincinnati  at  14.3 an  In  Hartford  at  3.8  wg/i.  Butyl  benzyl
phthalate  was  not  detected  In  tap water  for any of  the four cH1es  while
DEHP was found In Cincinnati only,  at a concentration of  16.5  ng/l.
    Phthalate esters are reportedly present In drinking water  1n  other  parts
of  the  world.   Dl-n-butyl  phthalate  at  concentrations   up  to  1  jjg/l  has
been detected In drinking  water  In Shlzuoka,  Japan  (Shlbuya,  1979).   Several
esters  Including  d1-n-butyl and  dlethyl phthalate  have  been  Identified  In
several  water supplies  In  England* (Fielding et al.,  1981; Crathorne  et al.,
1984; Packham et al.,  1981).  Morlta  et al.  (1974)  Identified d1-n-butyl  and
d1(2-ethylhexyl)  phthalate  In Tokyo  tap water at mean concentrations of  2.3
and   1.3   yg/i,   respectively.    Shlralsh!    et    al.    (1985)   Identified
dl(2-ethylhexyl)  phthalate  In tap water  from  Tsukuba,  Japan.   Tap water from
Kltakyushu,   Japan,   was   reported   to  contain  dlethyl,   d1-n-butyl   and
d1(ethylhexyl) phthalates  at  maximum concentrations  of 0.021,  0.24 and 0.24
vg/l, respectively (Aklyama et al., 1980; Shlnohara et al., 1981).
    On'  the  basis  of  an  overall  average phthalate drinking water  concentra-
tion  of 1  pg/l  (U.S.  EPA,  1975)  and  a consumption  rate of  2  l/day,  the
dally exposure to  phthalate ester by an Individual  In the United States  Is
-2 Mg.
3.2.   AIR
    It  Is  difficult  to  estimate  the  magnitude  of  different  sources  In
contributing  to  the  atmospheric  level of phthalate  esters.  Phthalate esters
used  for   nonplastlclzer purposes,  such as  pesticide carriers,  cosmetics,
fragrances and  Insect  repellant, are  subject to direct  evaporation  and  may


0781p                               3-11                             08/26/86

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contribute  substantially  to  the  atmospheric  burden  of  these  compounds
(Peakall, 1975).  The release of  phthalates  Into  the atmosphere from various
plastics  used  In  weather stripping, furniture, auto  upholstery,  wall  cover-
Ings and  other  household materials  will  add  to this.   Reportedly, a new room
with  PVC  flooring  may  contain  0.15-0.26  mg/m3  of  phthalates  (Peakall,
1975).  Klselev et al. (1983) have  shown  that  the use of certain plastics as
household Items can  result  In  the release of  dlethyl,  dimethyl,  dlbutyl  and
dloctyl  phthalates   Into  the atmosphere.    Probably  the  largest amount  of
atmospheric phthalate esters originate  from  the  Incineration  of the plastics
containing  phthalate esters.   Peakall   (1975)  estimated  that  -2% of  total
phthalate-contalnlng plastics used  In  the  United States  vaporizes  Into  the
atmosphere  during   Incineration.   Several   Investigators  have  Identified
phthalate esters  In  fly  ash  from  municipal  Incinerators,  Including dimethyl,
dlethyl,  dlbutyl, dloctyl, dllsooctyl and n-butyl  benzyl  phthalates  (long et
al.,  1984;  Vlau et  al.,  1984;  Elceman  et al., 1979,  1981).   The concentra-
tions  of  dimethyl,  dlbutyl  and  dloctyl  phthalates  In the  fly ash from an
electrostatic  predpltater  of  a  coal-fired  power station In  Frultland,  NH,
were  reported   to be  46  ppb   (371  vg/m3},   140  ppb  (1620   yg/m3)  and  45
ppb  (731  pg/m3),  respectively  (Harrison  et  al.,  1985).  Esters  Including
dlethyl,  dllsobutyl, dlbutyl and  d! (2-ethylhexyl)  phthalates  were Identified
In  the  emissions from  combination  coal/refuse   combustion   (Vlck  et  al.,
1978).  Similarly,  phthalate esters were  Identified  In  the  emissions of  a
wire-reclamation  Incinerator (Hryhorczuk et  al.,  1981).
    The  presence  of atmospheric  phthalate   esters  were reported  by  several
Investigators  (Wauters et al.,  1979; Karasek et al.,  1978; Meyers and  HHes,
1982;  Weschler,  1980) and   quantitative  worldwide  levels are presented  In
Table  3-5.   These data  for  different urban  and   rural  locations  are  greatly


0781p                               3-12                             08/26/86

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O

CO

•o
OJ
 i
O
CO
cr
•^
CO
                                                      TABLE 3-5


                     Atmospheric Levels of a Few Phthalate Esters Measured  Throughout  the  World
Concentrations of
Phthalate Esters (mq/m3)
Location
Chacaltaya, Bolivia (background level)
Antwerp, Belgium
Atmosphere of Gulf of Mexico
Atmosphere of Gulf of Mexico
Atmosphere of North Atlantic
Barrow, AK
Atmosphere of Enewetak Atoll,
North Pacific Ocean (background)
College Station. TX
Pigeon Key, FL
New York City. NY
Sterling Forest. NY
Indoor air, Wichita, KS
Outdoor air, Wichita, KS
Indoor air, Lubbock, TX
Outdoor air, Lubbock, TX
Hamilton, Ontario, Canada
DEP
0.66
4.4
NR
NR
NR
0.2
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
DBP
28
50
1.30
0.3
1.0
1.0
0.87
3.8
18.5
14.2
1.1
NR
NR
0.2
0.2
700*
DEHP
19
70
1.16
0.4
2.9
-20
1.4
2.4
16.6
13.7
2.8
55
2.2
20
2.0
300*
Reference
Cautreels et a)., 1977
Cautreels et al.. 1977
Glam et al. , 1980
Glam et al., 1978
Glam et al.. 1978
Weschler. 1981
Atlas and Glam. 1981
Atlas and Glam, 1981
Atlas and G1am. 1981
Bove et al.. 1978
Bove et al.. 1978
Weschler, 1984
Weschler, 1984
Weschler. 1984
Weschler, 1984
Thomas. 1973
    *These values are much higher because the sampling  site was  adjacent  to  a  municipal  Incinerator.


    NR = Not reported

-------
varied.   For  example, the  sum  of d1-n-butyl  and  d1(2-ethylhexyl)  phthalate


concentrations  In  New York  CUy was  <20 ng/m3  (Bove  et al.,  1978),  while


the  value  for  the  sum  of  the  same  two  compounds   was  -120  ng/m3  for


Antwerp,  Belgium  (Cautreels,  et al.,  1977).   There Is  also a  large  differ-


ence 1n the reported  levels of  phthalate  esters for remote areas and  1n some


cases  the phthalate  concentrations  In remote  areas  reported  by one  author


exceeds  the  urban  phthalate  level  reported  by another  author.   Obviously,


unless more air monitoring data are developed  In  the  United  States,  1t will


not be possible to  provide an average urban  and  rural  levels  for  the  phtha-


late esters.   The Great  Lakes Science  Advisory Board  (1980)  estimates  that a


total of  -95  metric  tons of airborne  d1-n-buty1  and  d1(2-ethylhexyl)  phtha-
                                0

lates are deposited Into the Great Lakes  every year.


    Maximum exposure  to  phthalate  esters  1s  likely to  be under  occupational


conditions.  The National  Occupational Hazard Survey  (NIOSH,  1985)  estimates


that  -2,406,700  workers  are annually exposed  to  dlethyl,  d1-n-butyl  and


d1(2-ethylhexyl)  phthalates 1n  the United  States.   U.S.  EPA  (1980a)  reported


that the  concentration  of  phthalate esters  ranged from  1.7-40  mg/m3  1n  one


area and  from 10-66  mg/m3 In  another  area  of  a company that  manufactured


artificial  leather  and  PVC  films.    The  level  of  dlethyl   phalate  1n  the


vulcanization area of a  shoe-sole  factory  was reported  to vary  between  0  and


120  ng/m3  (Cocheo  et  al.,  1983).    Concentrations  of  d1-n-butyl,   dllso-


butyl  and d1(2-ethylhexyl) phthalate  In   the vulcanization  area  of  a  tire


retreading  factory   were   10-2500,   5-500   and  0-2   yg/m3,   respectively


(Cocheo et al., 1983).


    American published reports  on  the  levels of phthalate esters  1n  occupa-


tional atmosphere  are rare.  The  exposure of  phthalate esters to the  U.S.


population residing  In  urban,  suburban and  rural  areas  cannot  be  estimated


because of the lack of reliable  monitoring data.



0781p                               3-14                             08/26/86

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3.3.   FOOD



    Many  of  the packaging  materials  and  tubings  used to  produce  foods  and



beverages  are  plastics  that  contain  phthalate  esters.   These esters  may



migrate  from  the  plastics  to the food  during  contact.  Two 1  m PVC tubings,



one  containing  47.2%  dlnonyl  phthalate  and  the  other  containing  5.5X



d1(2-ethylhexyl)  phthalate,  when  kept   In  contact with  100 ml  milk for  a



period of  24  hours  at a temperature  of  38°C,  leached  out  46 and 20  mg/l  of



the  two  respective  compounds  Into  the  milk  (HUdbrett,  1973).  It  Is  also



reported  that cheese  and lard  kept  In contact  with plastic films for  1 month



at  ?5°C  were  contaminated  with  phthalate esters,  at  concentrations   <2  ppm



(U.S.  EPA, 1980a).   Since  commercial  vegetable  oils   are  often  sold  In



plastic  containers, Williams  (1973b)  analyzed one  corn  oil and  several  soy



oil samples for d1(2-ethylhexyl)  phthalate,  but  did not  detect  It  In  any  of



these  oils.   Several  authors  have  Identified  phthalate  esters   In  foods,



particularly  aquatic  foods;  levels  and  their  food  sources   are  given  In



Table 3-6.



    It Is  evident  that  phthalate  esters are  present  In  a variety of  foods



consumed  by  humans.    Estimates,  however,  of  human  consumption  of  these



compounds  from  foods  requires  the  foreknowledge  of phthalate  levels  In  such



foods.   In the absence  of  such  data,   It  Is  not  possible to  estimate  the



phthalate exposure from food sources.



3.4.   DERMAL



    Phthalate esters  can be  absorbed  through the  skin  during  the use  of  many



cosmetic   products,  Insect  repellants and  the  water from  PVC-Hned  swimming



pools.    Hemod1alys1s  tubing and  PVC bags containing  Intravenous  solutions



also can  be sources  of  exposure to these  compounds  for a  special  segment  of



the  population.   U.S.  EPA  (1980a) describes  phthalate  ester  exposure  from










0781p                               3-15                            08/26/86

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o
«J
oo
                                                                              TABlt  3-6


                                                          Concentrations of Phthalate  Esters  tn  Some  foods
CO
i
o
oo
CO
cr
                                                                                       Concentration  of  Phthalate  (mq/kq)
Food
Perch (Perca f luvlatllls) muscle
Pike (Esox hlclus) muscle
Clams
Herring (fillets)
Mackerel (fillets)
Plaice (fillets)
Redflsh (fillets)
Spade fish (muscle)
Croaker (muscle)
Trout (muscle)
Shark (muscle)
Catfish (muscle)
Shrimp (whole)
Sting ray (muscle)
Eel (whole)
Blue crab (muscle)
Rainbow trout (whole)
Whole milk
Skim milk
Butter
Bourbon whiskey
Unprocessed eel
Unprocessed catfish
Unprocessed pickerel
Unprocessed pickerel
a
Canned tuna
Canned salmon
Canned shrimp
Source
South Coast of Finland
South Coast of Finland
Portland. ME
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Tokoyo. Japan
Tokoyo. Japan
Tokoyo, Japan
Tokoyo. Japan
Imported to Japan
Canada
Lake St. Pierre
Lake Huron
Lake Ontario

Canada
Canada
Canada
DBP
NR
NR
0.07
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
0.6
O.OS
0.2
4-11
0.06
ND
ND
ND
NQ

0.078
0.037
NO
01 HP
0-0.1
0
0.14
4.71
6.50
<0.010
<0.010
0.011
0.003
0.004
0.00?
ND
0.008
0.012
0.002
0.003
NR
NR
NR
NR
NR
0.104
NO
NO
NO

0.160
0.089
ND
Reference
Persson et al, . 1978
Persson et al. . 1978
Ray et al.. 1983
Muslal et al.. 1981
Muslal et al., 1981
Muslal et al.. 1981
Muslal et al.. 1981
Gtam et a).. 19/5
Glam et al.. 1975
Glam et al.. 1975
Glam et al.. 1975
Gtam et al.. 1975
Glam et al. , 1975
Glam et a).. 1975
Glam et al. . 1975
Gtam et al.. 1975
Mortta et al.. 19/3
Morlta et al.. 1973
Horlta et al.. 1973
Morlta et al.. 1973
Salto et al. . 1980
Williams. 1973a
Williams. 1973a
Williams. 1973a
Williams. 1973d

Williams. 1973d
Williams. 1973a
Williams, 1973d

-------
                                                                         TABLE  3-6 (cont. )
— 1
CO
•o Food
Frozen rainbow trout
Frozen ocean perch
Frozen mackerel
Hatchery-reared Juvenile
Atlantic salmon (commercial)
Egg white
Salad oil3
Lard
Soft margarine3
Mayonnaise3
Instant vegetable cream soup
Instant corn cream soup
OS
j_, Fried cake
•^ Wheat flour3
Bread crumbs3
Rice powder
Hashed potatoes
Sugar
Table salt3
Soy sauce
Worcestershire sauce
Honey
Pickles
Rainbow trout
Long-nose sucker
Whlteflsh (fillet)
o
	
Source
Canada
Canada
Canada
Atlantic Ocean
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Great Lakes
Great Lakes
Great Lakes
Concentrat Ion of
OBP
ND
ND
ND
NR
0.098
0.11
0.09
3.1?
1.25
6.35
0.17
0.64
?.47
0.77
0.03
0.09
0.16
1.41
0.03
0.17
0.11
0. 16
5.4
8.1
NR
Phthalate (mq/kq)
DC HP
NO
NQ
NQ
)3-)6b
0.18?
0.15
0.10
O.b5
ND
ND
0.49
1 .57
0.03
0.33
0.05
0.01
0.04
o.o;
0.08
0.17
0.37
NK
NR
7-1
Reference
Williams. 1973a
Williams. I9?3a
Williams. 1973d
Zltko. 1973
Ishlda et al.. 1981
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al. . 1977
Tomlta et al. . 1977
Tomlta et al. . 1977
Tomlta et al.. 1977
Tomlta et al.. 197?
Tomlta et al.. 1977
Tomlta et al.. 197?
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al. . 1977
Tomlta et al., 1977
Tomlta et al., 1977
Tomlta et al. , 1977
lomlta et al. . 197/
Glass et al.. 1977
Glass et al. , 1977
Glass et a). . 1977
ro       aThese are the highest reported values



CD       bTh1s represents concentration range In the llptd



         NR = Not reported; NQ = compound Identified but not quantified; NO -- not detected

-------
other medical  sources.   Several authors  have  measured the  levels  of phtha-
late  esters  In  serum from  surgical  patients  (Chlng  et  al.,  1981)  and  in
human adipose  tissues (Mes and  Campbell,  1976; Mes et  al.,  1974), although
the  latter  concentrations  probably  represent  exposure  from  Inhalation,
Ingestlon and dermal exposure sources.
3.5.   SUMMARY
    Phthalate  esters are  ubiquitous  In  the   environment.   They  have  been
Identified  1n   surface  waters  In   the  United  States  and  elsewhere  In  the
world.   The  maximum reported concentration of  dl(2-ethylhexyl)  phthalate  1n
any  surface  water  was  600  yg/a,   which  was   detected  In  Mississippi  River
water (Corcoran,  1973).   The average concentration of  Individual  phthalate
esters  in  surface   water  Is <1   vq/l  (Michael  et al.,   1984).   Phthalate
esters have  also  been Identified  In  groundwater from contaminated  sites;  a
maximum   of   100   ug/l  of   d1(2-ethylhexyl)   phthalate   was   detected   In
groundwater  from  a  landfill  site  In  New Castle  County,  DE   (DeWalle  and
Chlan,  1981).   Several  phthalate   esters  have  been  Identified  In  drinking
water abstracted  both  from  surface  water  and groundwater.    The  maximum
concentrations   of  dlethyl,  d1-n-butyl,  d1(2-ethylhexyl)   and  butyl  benzyl
phthalates In  39  public  water  wells  were reported to  4.6, 470, 170  and  38
wg/t,  respectively   (CEQ,   1980,   1981;   Burmaster,   1982).    The  Science
Advisory  Board  of   the  U.S.  EPA   reviewed  selected   organic  chemicals  and
estimated  that  the  distribution   of  the  phthalate  esters  Is  -50%  In  U.S.
drinking  waters,  with  an   overall  phthalate  concentration   of   ~1   yg/l
(U.S. EPA,  1978c).   On  the  basis  of these data and  an average  consumption
rate  of  2  l/day,   dally  phthalate  exposure   to  a  U.S.  Individual  from
Ingesting drinking water  Is estimated to be 2  vg.
0781p                               3-18                             08/26/86

-------
    Phthalate esters have been  detected  In  ambient atmosphere.   Probably the
biggest contributor  to atmospheric  phthalate  Is  the Incineration of plastics
that contained the  esters  (Peakall,  1975).   The  concentrations  of dl-n-butyl
and  dl (2-ethylhexyl) phthalate  -In  New   York  City's  ambient  air  were  4.2
mg/m3  and  13.7  ng/m3,   respectively  (Bove  et  al.,  1978).    In  College
Station,  TX,   the   corresponding  values   were  reported  to  be   3.8 and  2.4
ng/rn3  (Atlas   and   G1am,   1981).    Until  more  air  monitoring  data  become
available.  It  Is  not possible  to  provide average urban and  rural  levels  of
phthalate esters.   Consequently,  Inhalation exposure  of phthalate  esters  to
the U.S.  population residing  In  urban,   suburban  and  rural  areas  cannot  be
estimated.  Maximum exposure to phthalate  esters  Is  likely  to  occur  under
occupational  conditions.   Concentrations  of  phthalate  esters  ranged  from
1.7-40  mg/m3  1n a  mixing area  and from 10-66  mg/m3  In  another  area  of  a
company manufacturing artificial leather   and films  of  PVC  (U.S.  EPA,  1980b).
NIOSH  (1985)   estimates   that  -2,406,700  workers  are  annually exposed  to
dlethyl, d1-n-butyl and  d1(2-ethylhexyl)  phthalate 1n the United States.
    Several  authors  have  Identified phthalate esters  In  foods.   D1(2-ethyl-
hexyl)  phthalate was detected at a  concentration of  6.50  mg/kg In mackerel
fillets (Huslal et  al., 1981).  The  concentration  of d1-n-butyl  phthalate  In
rainbow trout  from the  Great  Lakes  was  reported  to be  8.1  mg/kg  (Glass  et
al.,  1977).   In butter  samples obtained  from Japan,  the concentration  of
d1-n-butyl  phthalate  was   4-11  mg/kg   (Morlta   et   al.,   1973).    Instant
vegetable cream soup obtained  from  a  Japanese  market contained  6.35 mg/kg  of
dl-n-butyl phthalate (TomHa et al.,  1977).  No  estimates  of  phthalate  ester
exposure  from  food  composites  typically consumed  by  an  Individual  In  the
United States  are available.
0781p                               3-19                             08/26/86

-------
    Phthalate esters can  be  absorbed through the skin during the use of many
cosmetic  products,  Insect repellants  and the water  from PVC-Hned swimming
pools  (U.S.  EPA,  1980a).   A special  segment  of  the population 1s exposed to
phthalate  esters  during  medical/surgical  procedures,  such  as  hemodlalysl's
and  Intravenous  applications.   No  estimates   on   the   dermal  exposure  of
phthalate  esters  to Individuals can  be made from  the data  available  1n the
literature as dted In the Appendix.
0781 p                               3-20                             08/26/86

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                             4.   PHARMACOKINETICS

    The  pharmacoklnetlcs  of  phthalate  esters   has  been  reviewed  by  Kluwe
(1982), Albro et  al.  (1982),  Thomas and Thomas  (1984),  and  U.S.  EPA  (1978b,
1980b,  1985a).   The  majority  of  studies  have  focused on  d1(2-ethylhexyl)
phthalate.  Information on the pharmacoklnetlcs  of  aryl  or  aryl/alkyl  esters
of phthallc add  could not be  located 1n  the available literature as  cited
1n the Appendix.
4.1.    ABSORPTION
    In  general,  excretion  profiles  Indicate that alkyl  phthallc  acid  esters
and their  degradation  products  are probably  well  absorbed  from  the  gastro-
intestinal tract.
    When  d1(2-ethylhexyl)  phthalate  (10 or  2000  ppm)  was administered  to
rats   In  the diet,  >90% of the administered dose was  excreted  as  metabolites
In the  urine;  the remainder  was excreted In  the feces  (Williams  and  Blanch-
field.  1974).   When d1(2-ethylhexyl)  phthalate  was administered to  rats  by
gavage  (3 or  1000  mg/kg,  vehicle  =  corn  oil),  42-54% of  the  administered
dose  was  excreted  as  metabolites  1n the urine,  while  24-57% was  excreted  as
metabolites In  the feces within  1-4  days  (Williams  and  BlanchHeld,  1974;
Daniel  and Bratt,  1974).   In  humans,  10-15%  of  a  single  oral  dose  of
d1(2-ethylhexyl)  phthalate  was  excreted In  the urine  within  24  hours  of
administration  (Schmld  and  Schlatter,  1985).   Absorption of d1(2-ethylhexyl)
phthalate  and  degradation  products  may be  greater  than  urinary levels  of
metabolites would  Indicate,  since  substantial  biliary  excretion  has  been
observed  1n rats,  dogs and miniature  pigs  (Daniel  and  Bratt,  1974;  Ikeda  et
al.,   1980).
0782p                               4-1                              06/06/86

-------
    Gastrointestinal absorption of d1-n-butyl  phthalate  can  be  Inferred  from
observations that >90% of a single dose  of  d1-n-butyl  phthalate administered
to  rats  by gavage  (60,  270 or  2310 mg/kg, vehicles  =  corn oil,  DMSO)  was
excreted  as metabolites  In  the  urine  within  2  days;  the  remainder   was
excreted In the  feces  (Tanaka et  al..  1978;  Williams  and BlanchMeld,  1975).
Substantial biliary excretion of  d1-n-butyl  phthalate  metabolites  (30-60% of
60 mg/kg dose within 2 days) was also observed  (Tanaka et al.,  1978).
    Ikeda  et  al.  (1978)  observed that  metabolites  of  d11sooctyl  phthalate
were excreted  In  the  urine, feces and bile  of dogs,  rats  and  miniature  pigs
exposed  orally  to  dllsooctyl   phthalate  (21-28  days  In  feed,  then  single
gavage   dose   of  l4C-d1 Isooctyl   phthalate   In   corn  oil),   qualitatively
Indicating  that  gastrointestinal  absorption of  dllsooctyl  phthalate  or  Its
degradation products occurs  In each of these species.
    Apparent   hydrolytlc  activity  toward  d1 (2-ethylhexyl )   phthalate   1n
pancreatic  homogenates led  Albro  and Thomas (1973) to hypothesize  that  very
little,  1f  any.  Intact phthalate  dlester  Is absorbed from  the gastrointes-
tinal  tract.   Further studies  have  shown  that phthalate  esters  d1(2-ethyl-
hexyl)   phthalate,  dimethyl   phthalate,   d1-n-butyl   phthalate,   d1-n-octyl
phthalate)  are readily hydrollzed to  their  monoester  derivatives  by  enzymes
In  Intestinal  mucosal cells  (Rowland, 1974;  White  et al., 1980)  and other
tissues  (Carter  et al.,  1974), and  by extracellular  enzymes  present  In  the
Intestinal  contents of rats,  ferrets and baboons  (Rowland,  1974;  Rowland et
al., 1977;  Lake  et al., 1977b).
    Recent  gavage  studies  on   rats   demonstrated   that  d1 (2-ethylhexyl )
phthalate  was  hydrolyzed  to monoethylhexyl  phthalate,  which was subsequently
absorbed  (TeUlynck  and  Belpalre, 1985; Olshl and Hlraga, 1982).   Telrlynck
and  Belpalre  (1985)  reported  that  plasma  concentrations of  8.8^1.7
 0782p                               4-2                              06/06/86

-------
d1(2-ethylhexyl)  phthalate  and   63.2^8.7   pg/mi  monoethylhexyl   phthalate
were  reached  within  3  hours after  a  single  oral  dose  of  d1(2-ethylhexyl)
phthalate  {2.8  g/kg  1n  corn  oil).  These  observations  raise concern  about
the validity of using route-to-route  extrapolation  In  either  quantitative  or
qualitative assessment  of  risk associated  with  1ngest1on,  since  It  appears
that  the  d'alkyl  esters  are   largely  hydrolyzed  to  monoester  derivatives
before  absorption  from  the  gastrointestinal  tract.   In  a   recent  study  on
rats,  Pollack et al.  (1985a) found  that 80% of a single  oral  (gavage  In corn
oil)  dose  of  d1(2-ethylhexyl)  phthalate  was  hydrolyzed  to Us  monoester
derivative  (monoethylhexyl phthalate)  and  subsequently absorbed;  13%  of  the
dose was  absorbed  as  d1(2-ethylhexyl)  phthalate.  The ratio  of  the AUCs  for
monoethylhexyl  phthalate  to  dl(2-ethylhexyl)  phthalate  was  -1.   Repetitive
oral dosing did not affect the  extent  of  absorption.   In  contrast,  uptake  of
d1(2-ethylhexyl) phthalate and  Us derlvatlve(s)  Into the  bloodstream from
the peritoneal  cavity was poor.   Only IX  of  an equivalent  Intraperltoneal
dose  was  hydrolyzed  to  monoethylhexyl  phthalate;  5.2% was  taken  up  as
d1(2-ethylhexyl) phthalate.  The  ratio of  the AUC  for monoethylhexyl  phtha-
late  to d1(2-ethylhexyl)  phthalate  after  either  Intraperltoneal  or  Intra-
arterlal  administration  was  <0.4.   Furthermore, repetitive  Intraperltoneal
administration of  d1(2-ethylhexyl)  phthalate led to an apparent  decrease  1n
the rate  and  extent  of  uptake.   Poor   Intraperltoneal uptake  Into  the  blood
was attributed to  the fact that  d1(2-ethylhexyl)  phthalate  1s UpophlUc  and
distributed Into the  peritoneal fat.   U.S.  EPA (1980b) and  Thomas  and Thomas
(1984)  state  that  phthallc  add esters  may not be  readily  taken Into  the
bloodstream  from  the peritoneal  cavity, and  both  sources  question  whether
Intraperltoneal studies are useful 1n oral  risk assessment.
0782p                               4-3                              06/06/86

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4.2.   DISTRIBUTION
    Several  studies  have  shown  that  d1(2-ethylhexyl)  phthalate and  d1-n-
butyl  phthalate,  administered  either  orally  or  Intravenously,  are  cleared
rapidly  from  the  body,  largely within  24 hours of exposure  (Tanaka  et  al.,
1975, 1978; Williams and Blanchfleld,  1974,  1975;  Ikeda  et  al., 1980; Daniel
and Bratt, 1974; Olshl and Hlraga,  1982;  Telrlynck  and Belpalre,  1985).   The
same  observation   holds  true  for  orally  administered  d11sooctyl  phthalate
(Ikeda,  et al., 1978).   The  parent compound and metabolites  are  distributed
primarily  to plasma,  liver,  kidney,  the  gastrointestinal  tract  and  fat.
Metabolites have also been  found  In almost every other  tissue.  In  particu-
lar,  a  high  concentration  of  monoethylhexyl  phthalate,  the   hydrolytlc
derivative of  d1(2-ethylhexyl)  phthalate,  has  been found  1n  the testes  of
rats  (Olshl  and Hlraga,  1982).  Concentrations  of  d1(2-ethylhexyl)  phthalate
and metabolites In various tissues, particularly liver,  kidney  and  fat,  vary
with  route of  administration  (diet,  gavage,  parenteral),  vehicle and  dose
(Thomas and Thomas, 1984; Polla.ck  et al.,  1985a; Albro et al., 1982).
    In  a  dietary  study  on  rats,  Daniel  and  Bratt   (1974)   reported  that
steady-state  tissue   concentrations of   radioactivity   from  l4C-d1(2-ethyl-
hexyl }  phthalate   were  proportional to  dietary concentrations  and  reached
maximum  values  1n  liver  and fat within  1  and 2 weeks of  treatment,  respec-
tively.  When dietary  d1(2-ethylhexyl)  phthalate was  removed,  radioactivity
1n  the  liver and  fat  declined, with  half-lives  of 1-2 days  and 3-5  days,
respectively.
    The  distribution  and  retention of  d1(2-ethylhexyl)  phthalate  and  Us
monoester  derivative,  monoethylhexyl   phthalate,   were  examined  1n  gavage
studies  on  rats.   Telrlynck   and  Belpalre   (1985)  reported  that  maximum
concentrations  of  monoethylhexyl  phthalate  and  d1(2-ethylhexyl)  phthalate


0782p                               4-4                              05/13/86

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were  reached  In the plasma  within  3 hours  of  a single  dose  of d1(2-ethyl-
hexyl)  phthalate  (2.8  g/kg  In  corn  oil).  The  ratio  of the  AUCs  for  mono-
ethylhexyl phthalate to  d1(2-ethylhexyl)  phthalate  was 16.1^6.1.  Monoethyl-
hexyl  phthalate  disappeared from  the  plasma with  a  t.  .  of  5.2+.0.5 hours.
The concentration of dl (2-ethylhexyl) phthalate  1n  the plasma  was considered
too   low   for  accurate   estimation  of   t,/7-   Repetitive   dosing   with
d1(2-ethylhexyl) phthalate  (2.8 g/kg/day  In  corn oil  for 7  days) produced no
accumulation  of  either monoethylhexyl  phthalate or  d1(2-ethylhexyl)  phtha-
late  In the plasma.
    Olshl   and   Hlraga   (1982)   reported   that   maximum  concentrations  of
d1(2-ethylhexyl) phthalate  and  monoethylhexyl  phthalate  were observed In the
blood  and tissues  of  rats  within  6-24  hours  after  a  single  oral  dose  of
d1(2-ethylhexyl)  phthalate  of   25   mmol/kg  (9.8  g/kg)  In  corn  oil.   In
general,  the  disappearance  of  monoethylhexyl phthalate  from  the tissues was
slower  than  that of  d\(2-ethylhexy1)  phthalate;  half-lives  for  monoethyl-
hexyl  phthalate  ranged  from 22.6-68 hours, while half-lives  for d1(2-ethyl-
hexyl)  phthalate  In  several  tissues  ranged from  1.49-156 hours  (Table  4-1).
The ratio  of  monoethylhexyl  phthalate/d1(2-ethylhexyl) phthalate,  measured 6
hours  after dosing,  was  113+23, 79*.!?,  210i4.8,  46*.0.57  and  87*24 In blood,
liver,  testes,  heart  and   epldldymal  fat,  respectively.    In  this  study,
concentrations of d1(2-ethylhexyl)  phthalate  and monoethylhexyl  phthalate In
the kidneys were very low.
    Little Is  known about  the  ability  of phthallc  acid  esters  to  cross the
placenta  (Kluwe,  1982).   Using  perfuslon  techniques,  Klhlstrom  (1983) showed
that  Intravenously   administered  dl(2-ethylhexyl)  phthalate  Is transported
across  the placenta of  guinea  pigs and  appears In  the  fetal  circulation.
0782p                               4-5                              05/13/86

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                                  TABLE 4-1

    Biological  Half-Lives  of  01(2-ethylhexyl)  Phthalate and Honoethylhexyl
        Phthalate 1n Rats  After  a Single Oral  Dose of D1(2-ethylhexyl)
                     Phthalate  (25 imnol/kg In  Corn  01l)a
Tissue
Blood
Liver
Testes
Heart
Spleen
Lung
Ep1d1dymal fat
M/2
MEHP
23.8
31.9
49.9 (6 < t < 48)
28.8
22.6
NO
67.6 (24 < t < 96)
(hours)b
DEHP
18.6
28.4
8.28 (24 < t < 96)
15.2
NO
1.49 (1 < t < 6)
25.3 (6 < t < 96)
156 (48 < t < 96)
aSource:  01sh1 and Hlraga, 1982

bB1olog1cal  t]/2  calculated   from  least-squares  fit  of  data  during  6-96
 hours except for tlmeframes Indicated for testes, lung and fat.

NO = No data
0782p                               4-6                              05/13/86

-------
Singh  et  al.   (1975)   demonstrated   that   radioactivity   from   l4C-d1ethyl
phthalate  and   14C-d1(2-ethylhexyl)   phthalate   (position   of   label   not
reported) administered  IntrapeM toneal ly  to rats  on  either  day  5  or 10  of
gestation  was   found   In  the  placentas,   amnlotlc  fluid  and  fetal   tissue
throughout gestation.   The   relevance  of  these  findings  to orally  Ingested
phthallc add esters Is unclear.
4.3.   METABOLISM
    Kluwe et  al.  (1982a) states  that,  In  general,  the metabolism of alkyl
phthallc add esters  1s not qualitatively  affected  by  route of  administra-
tion.   The   first   step  of   metabolism entails  hydrolysis  to  a  monoester
derivative (Kluwe,  1982);  the location  and extent to  which this occurs  Is
route-dependent  (Pollack et  al.,  1985a).   Ingested phthallc add esters  are
converted to  their  monoester derivatives  by enzymes  1n  the  gastrointestinal
tract  before absorption  (see  Section  4.1.).   Since other  tissues  contain
enzymes  capable  of  hydrolyzlng phthallc add  esters  (Carter et   al.,  1974),
parenterally administered phthallc add esters  can  also  be  hydrolyzed.
    Once formed, the monoester derivative  can  then be  further hydrolyzed  to
phthallc  add   and  excreted;  conjugated  to  glucuronlde  and  excreted;   or
oxidized and excreted (Kluwe, 1982).
    Short-chain   phthallc add  esters,  such  as  d1-n-butyl  phthalate   and
dimethyl  phthalate   can be  excreted  as   parent  compound,  their  monoester
derivatives  and  pthallc add.   In rats, only  small  quantities of  monoester
derivatives  from longer-chain  phthallc add  esters, such as  d1 (2-ethylhexyl)
phthalate  or dllsooctyl  phthalate  are  converted  to  phthallc  add  before
excretion  (Albro  and  Thomas,  1973;  Albro  and  Moore,  1974;  Albro  et al.,
1973).
0782p                               4-7                              06/06/86

-------
    In all  mammalian  species tested  but  the rat, glucuronlde  conjugates  of
monoethylhexyl  phthalate  are the  major  urinary  metabolites of  d1(2-ethyl-
hexyl)  phthalate  (Albro  et  al.,   1982;  Kluwe,  1982).   Species  that  form
glucuronlde conjugates of monoethylhexyl  phthalate  Include  humans,  hamsters,
green monkeys,  guinea  pigs  and  mice  (Albro  et  al.,  1981, 1982;  Peck  et  al.,
1978;  Telrlynck  and   Belpalre,  1985;  Schmld  and  Schlatter,  1985).   The
absence  of conjugates  of  dM2-ethylhexyl)  phthalate metabolites  has  been
confirmed  In  3  strains  of  rat   (Williams  and  Blanchfleld,   1975; Daniel  and
Bratt, 1974;  Chu et al., 1981;  Tanaka  et al.,  1975; Albro  and  Moore,  1974;
Albro  et  al.,  1973;  Albro  et  al.,  1982;  Kluwe, 1982;  Thomas and  Thomas,
1984).   In contrast,  a   glucuronlde  conjugate  of  the dl-n-butyl  phthalate
monoester  derivative  (mono-butyl phthalate) has  been  Identified as  a  major
urinary  metabolite In  rats, In  hamsters  and  guinea  pigs  (Tanaka  et  al.,
1978; Foster et al., 1982; Kaneshlma et al., 1978).
    Oxidation  of monoester   derivatives of  dlalkyl  phthallc acid esters  has
been  observed  1n rats, guinea  pigs  and hamsters (Williams  and Blanchfleld,
1974,  1975;  Tanaka et al.,  1978;  Daniel  and Bratt,  1974; Chu  et al.,  1981;
Lhuguenot  et  al.,  1985).   In general, the  terminal or  next-to-last  carbon
atom  1n   the  monoester  derivative  1s  oxidized  to  an alcohol.   Aldehydes,
ketones and carboxyllc adds are formed by successive  oxidations.   Compounds
with  alkyl  chains  containing  six  or  more  linear   carbons  may  undergo
B-ox1dat1on (Kluwe, 1982; Albro and Moore, 1974; Albro et  al.,  1973).
4.4.   EXCRETION
    Excretion  of dllsooctyl phthalate, d1-n-butyl phthalate and d1(2-ethyl-
hexyl) phthalate and  their  metabolites  has been studied.   Routes  of excre-
tion  for  these compounds Include urine,  feces  and  bile;  the relative Impor-
tance  of  route of excretion depends upon  the compound  and species,  while the


0782p                               4-8                              06/06/86

-------
rate  of  excretion  appears  to  be  rapid  despite  those  considerations.   The
available studies are summarized In Table 4-2.
    Half-lives  of  7.9  and  12  hours  have  been  reported  for  excretion  of
d1 (2-ethylhexyl)  phthalate  and metabolites  1n  rats  (Telrlynck  and Belpalre,
1985)  and  humans  (Schmld  and  Schlaffer,  1985),  respectively.   Excretion
half-lives of  1.2 and  5.4 hours have  been  reported  for dllsooctyl phthalate
and  metabolites   In  dogs  and  miniature  pigs,  respectively  (Ikeda et  al.,
1978).
    Comparative  studies with   14C-dnsooctyl  phthalate  (Ikeda et  al..  1978)
have  shown   that  urinary  excretion   prevails   In  mlnlplgs,   fecal  excretion
prevails  In  dogs,  and  rats  excrete approximately equal  quantities  of  radio-
activity  1n  urine  and feces.   Early  biliary  excretion  (4-24  hours  after
dosing) was  shown to be substantial 1n dogs, but low 1n rats  and  mlnlplgs.
    In rats, d1-n-butyl phthalate  1s  primarily  excreted In  the  urine (-90X),
with  the  balance excreted  In  the feces  (Tanaka  et  al., 1978; Williams  and
Blanchfleld,  1975).   Substantial biliary  excretion  has been shown  to  occur
from  within   a  few  hours  to  5  days  after dosing  {Tanaka et   al.,  1978;
Kaneshlma et al., 1978).
    It Is difficult  to  generalize  about  patterns  of  excretion of  d1(2-ethyl-
hexyl) phthalate  In rats,  althrough  the reasons for  apparent  discrepancies
are  unclear.   In a  recent  comparative  study  where  rats, dogs and mlnlplgs
were  fed a  diet  containing   d1(2-ethylhexyl)  phthalate  (equivalent  to  50
mg/kg/day)  for    21-28  days  then  treated by  gavage  with a  single dose  of
14C-d1(2-ethy'lhexyl) phthalate (50 mg/kg),  urinary  excretion was  the  major
route  In  mlnlplgs only.  Rats  and dogs,  1n  particular, excreted  radioactiv-
ity  primarily  In the feces.   Biliary excretion was shown to be  substantial
In dogs and minimal  1n mlnlplgs and rats  (Ikeda et al., 1980).


0782p                               4-9                              05/13/86

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                                                                   TABLE 4-?



                                                       Excretion of Phthallc Acid Esters
0
-J
CD
•o







_^
1
0








98/90/90


Compound Species tj/?
(hours)
DEHP human
human
rat
rat
rat
rat
rat
rat
dog
mlnlplg
DBP rat
rat
rat
rat
OIOP rat
dog
dog
mlnlplg
mlnlplg
aVeh1cle = corn oil for
bD1etary administration
12
NR
7.9
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR.
1.2
1.2
5.4
5.4
gavage
for 21

Route3
oral (single dose)
oral (4 doses)
gavage
gavage
diet or gavage
d1et/gavageb
diet
l.v.
dlet/gavageb
d1et/gavageb
gavage or l.v.
gavage
gavage
l.v.
d1et/gavageb
dlet/gavageb
d1et/gavageb
dlet/gavageb
d1et/gavageb
studies
-28 days, fasted overnight








X Dose
Time
2 days
2 days
72 hours
48-192 hours
48 hours
4 days
NR
7 days
4 days
4 days
48 hours
48 hours
5 hours
5 hours
4 days
4-21 days
4-24 hours
4-21 days
4-24 hours
. then by gavage
Urine
10-15
10-25
19.3
-60
42-57
27-37
91-98
49
1?-21
79
>90
80-90
NR
NR
41-57
23-28
9
65-86
15-49
with
Feces
NR
NR
balance
-40
38-57
53-56
2-8
28
5S-75
26
-8
balance
NR
NR
38-45
69-80
41
13-32
0-0.13
14C-Ester
Bile
NR
NR
NR
NR
9-14
<1
NR
NR
7-10
0.01-1.2
32-57 (gavage only)
NR
4.5
10
<1
trace-0.29
6-13
trace-0.01
0.25-0.73
In corn ol 1 .
Reference
Schmld and Schlatter, 1985
Schmld and Schlatter. 1985
Telrlynck and
Williams
and
Bel pa Ire,
Blanchf leld
1985
. 1974
Daniel and Bratt. 1974
Ikeda et
Williams
Tanaka et
Ikeda et
Ikeda et
Tanaka et
Williams
al..
and
al.
al..
al..
al.
and
Kaneshlma et
Kaneshtma et
Ikeda et
Ikeda et
Ikeda et
Ikeda et
Ikeda et

al..
al..
a)..
al..
al..

1980
Blanchf leld
. 1975
1980
1980
. 1978
Blanchf leld
al.. 1978
al.. 1978
1978
1978
19/8
1978
1978


. 1974




. 1975








HR = Not reported

-------
    Daniel and  Bratt  (1974) observed  substantial  biliary  excretion  (9-1454)



In rats  when  d1(2-ethylhexyl)  phthalate was  administered  1n the diet  for  7



days  or  as a  single  dose by gavage.   The  dose  of  d! (2-ethylhexyl)  phthalate



(2.6  mg/kg bw)  was  considerably  lower  than the dose applied by  Ikeda  et  al.



(1980) (50 mg/kg bw).   The reason for the discrepancy  remains unclear.



    Other oral  studies  (gavage and  diet) on rats  Indicate  that  either  fecal



and  urinary   excretion  are approximately  equal  (Williams  and  BlanchMeld,



1974;  Daniel  and Bratt,  1974)  or  that  fecal  excretion prevails  (Telrlynck



and  Belpalre,  1985).   In a dietary  study  on rats, Williams and  BlanchMeld



(1974) showed  that  regardless  of concentration  [10  or 2000 ppm  d1(2-ethyl-



hexyl)  phthalate],   urinary  excretion  prevailed   (91-98%  of   administered



dose).   In humans, only  10-1554 of a  single oral  dose  or 10-2554 of  four  dally



oral   doses  of  d1(2-ethylhexyl)  phthalate were  recovered  as metabolites  1n



the urine within 48 hours of administration (Schmld and Schlatter,  1985).



4.5.    SUMMARY



    Oral   studies  show  that  d!(2-ethylhexyl)  phthalate, d1-n-butyl  phthalate,



and  dllsooctyl  phthalate  are  absorbed  from  the   gastrointestinal   tract



(Williams and  Blanchfleld,  1974,  1975;  Daniel and  Bratt,  1974;  Ikeda  et al.,



1978,  1980;  Tanaka  et  al.,  1978; Pollack et  al., 1985a;   01shl and  Hlraga,



1982;  Telrlynck  and Belpalre,  1985;  Schmld  and  Schlatter,  1985).   Pollack et



al.  (1985a)   demonstrated  that   uptake  of  1ntraper1toneally  administered



d1(2-ethylhexyl)  phthalate  Into  the blood Is poor 1n  rats.   Orally adminis-



tered  phthallc  add  esters are  primarily  and  largely  converted  to  their



monoester  derivatives  by  enzymes   In  the  gastrointestinal   tract   before



absorption  (Albro and  Thomas,  1973;  Rowland,  1974;   Rowland  et al.,  1977;



Lake et  al.,  1977;  Carter et al.,  1974; White  et  al., 1980;  Pollack  et al.,



1985;  Telrlynck  and  Belpalre,  1985; 01sh1 and Hlroga,  1982).   Other  tissues










0782p                               4-11                             06/06/86

-------
such  as  the Hver  have  also been  shown to  hydrolyze  phthallc acid  esters
(Carter  et   al.,  1974).    In   contrast,    IntrapeMtoneally   administered
d1(2-ethylhexyl)  phthalate  Is  taken up  primarily as  d1(2-ethylhexyl)  phtha-
late, with  only 1% hydrolyzed to  monoethylhexyl  phthalate (Pollack et  al.,
1985a).
    Oral and  Intravenous studies  Indicate  that d1(2-ethylhexyl)  phthalate,
dl-n-butyl  phthalate  and  dllsooctyl phthalate are  not  retained for long  1n
the  body (Tanaka  et al.. 1975,  1978;  Williams and Blanchfleld, 1974,  1975;
Daniel  and  Bratt,  1974;  OUhl  and Hlraga,  1982;  Telrlynck  and  BelpaUe,
1985;  Ikeda  et  al.,   1978,  1980).   In general,  phthallc acid  esters  and
metabolites  distribute  primarily  to  liver,   kidneys,  fat and  the  gastro-
intestinal  tract.   Metabolites  have been  found In almost  every tissue;  1n
particular  a high concentration  of monoethylhexyl  phthalate,  the  hydrolytlc
derivative  of d1(2-ethylhexyl) phthalate, has  been  observed In  the  testes  of
rats  (OIsM  and Hlraga,   1982).  The distribution of  d1(2-ethylhexyl)  phtha-
late  and  metabolites  1n  various  .tissues,  particularly  liver,  kidneys  and
fat,  has been  observed  to vary  wHh  route  of  administration  (diet,  gavage,
parenteral), vehicle  and  dose   (Thomas  and  Thomas,  1984; Pollack  et  al.,
1985a; Albro et  al.,  1982).   In  a  dietary  study on rats,  radioactivity from
l4C-d1(2-ethylhexyl)  phthalate   In  the  liver and  fat  declined  with  half-
lives of 1-2 and  3-5  days,  respectively (Daniel  and Bratt,  1974).   In  gavage
studies  (Olshl   and  Hlraga,  1982).  the disappearance  of  d1(2-ethylhexyl)
phthalate  from  tissues  (t,,~  ranging  from 1.49-156  hours)  was  more  rapid
than  for  that  of  monoethylhexyl  phthalate  (t,/?   ranging  from  22.6-68
hours).
 0782p                               4-12                             05/13/86

-------
    Although short-chain  phthallc  acid cHesters  such  as dimethyl  phthalate
can  be  excreted  unchanged   In  the urine,  most  phthallc add  dlesters  are
further metabolized  before  excretion.   The first step of metabolism  entails
hydrolysis  of  the  parent  compound to  a  monoester  derivative.  Once  formed,
the monoester derivative can then be further hydrolyzed  to  phthallc add  and
excreted,    conjugated  with  glucuronlde   then   excreted,   or  oxidized   and
excreted.    The  first  alternative occurs primarily with  short-chain phthallc
add esters  (Albro and Thomas,  1973;  Albro and Moore,  1974;  Albro et al.,
1973).   The second  alternative  Is   the   primary  route  of  metabolism  for
d1 (2-ethylhexyl J phthalate  and  occurs  In  all  spedes  except  the  rat  (Albro
et  al.,   1973,   1981,   1982;  Kluwe  et  al.,   1982a,b;  Peck  et   al.,   1978;
Telrlynck   and   Belpalre,  1985;  Schmld  and Schlatter,  1985; Williams  and
BlanchMeld, 1975; Daniel and  Bratt,  1974; Chu et al., 1978; Tanaka et al.,
1975;  Thomas   and  Thomas,   1984);   however,   glucuronlde  conjugates  of
dl-n-butyl phthalate have been observed In  rats  (Tanaka et  al., 1978;  Foster
et al., 1982;  Kaneshlma et  al.,  1978).   The  third  route  of metabolism  has
been observed  In  rats,  guinea pigs and  hamsters (Williams  and BlanchHeld,
1974, 1975;  Tanaka et  al.,   1978; Daniel and  Bratt,  1974;  Chu et  al.,  1981;
Shuguenot   et al.,  1975).    The  metabolism of  phthallc  add esters  Is  not
qualitatively affected  by  route of  exposure (Kluwe,  1982).
    Excretion of  dllsooctyl  phthalate,  dl-n-butyl  phthalate and  d1(2-ethyl-
hexyl)  phthalates  has  been  studied  (Ikeda  et  al., 1978,  1980;  Schmld  and
Schlatter,  1985;   Telrlynck  and  Belpalre,  1985; Williams  and  BlanchMeld,
1974, 1975;  Daniel  and  Bratt, 1974; Kaneshlma  et  al.,  1978; Tanaka et al.,
1975, 1978).   These  compounds  and their metabolites are  excreted In  urine,
bile and  feces;  the relative  Importance   of the route  of  excretion depends
upon the  compound and  species,  while  the rate  of excretion appears  to  be
0782p                               4-13                            06/06/86

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rapid.  Half-lives  of  7.9 and  12  hours  were reported  for  urinary  excretion
of d1(2-ethylhexyl)  phthalate  In  humans  and rats, respectively  (Schmld  and
Shlatter, 1985; Telrlynck and  Belpalre,  1985).   Pharmacoklnetlc  data  on  aryl
or aryl/alkyl  pthalates  could  not  be located In  the  available  literature as
cited In the Appendix.
0782p                               4-14                             05/13/86

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                                  5.   EFFECTS
5.1.   CARCINOGENICITY
    D1(2-ethylriexyl)  and  n-butyl  benzyl  phthalates  have  been  tested  for
oncogenlcity  In  NTP-dlrected  feeding studies  on  rats and  mice.   Wllbourn
and  Montesano  (1982)  reviewed  other studies  on  dl(2-ethylhexyl),  n-butyl
benzyl and  d1-n-butyl  phthalates, which  were conducted before  the  NIP bio-
assays, and concluded  that  they  were  Insufficient  to assess  the carcinogenic
potential of  phthalate esters because  of design  and  reporting limitations;
U.S.  EPA  (1985a)  concurred with  this assessment.   These  studies  are listed
In  Table  5-1.   The  NTP  studies,   though   not  flawless,  provide  the  only
reasonable tests of oncogenlclty, and are reported as follows.
5.1.1.   n-Butyl  Benzyl   Phthlate.    n-Butyl  benzyl  phthalate   (0,  6000  or
12,000 ppm)  was  fed to  groups  of 50 male  and 50  female  F344/N  rats  and  50
male  and  50 female B6C3F1  mice  for   28  weeks (male rats  only)  or 103 weeks
(mice  and  female  rats)   (NTP,  1982a).    Control  mice  and female  rats  were
killed after  106  weeks on  test.   Because of  high mortality,  high-dose male
rats  and  male  controls were killed after 29 weeks on  test.   Male and female
mice  and  female  rats exposed  to n-butyl benzyl  phthalate were killed after
104-106  weeks.   Endpolnts monitored  Include body  weight,  food consumption,
mortality,  clinical  signs of toxlclty,   and  gross  and  microscopic pathology.
When  treated animals  were  compared  with  controls,  a  number   of  compound-
related  effects  were  observed.   Increased   mortality  associated  with "unex-
plained  Internal   hemorrhaglng"  was  observed  In  n-butyl  benzyl  phthalate-
exposed male  rats  beginning  at  the  14th  week of exposure.   Consequently, the
study on male rats was terminated after week  28 of exposure.
0783p                               5-1                              06/06/86

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                                  TABLE 5-1



                          Inadequate Cancer Studies
Species
Rats, dogs,
guinea pigs
Rats
Mice
Mice
Rats
Mice
Compound
DEHP
DEHP
DEHP
BBP
BBP
DBP
Route
oral (diet)
oral (diet)
1ntraper1toneal
IntraperHoneal
NR
1ntraper1toneal
Reference
Carpenter et al
Harris et al . ,
OmoM, 1976
Thelss et al.,
Anonymous, 1968
Omorl, 1976

., 1953
1955

1977


NR = Not reported
0783p
5-2
05/14/86

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    Survival curves were  comparable for treated and  control  mice  and female
rats.   Reduced  body  weights were  observed  1n all rats  and  mice  fed n-butyl
benzyl  phthalate.  The  reduction was  slight  In female  rats  but  substantial
in  male and  female  mice.   Food  consumption was  reduced 70-80%  In treated
female  rats,  but  data  on  food  consumption  were  not  reported for  mice  and
male  rats.    A   statistically  significant  Increase  (p=0.011.  Fisher  Exact
test)  In  mononuclear cell  leukemia  was  observed  In  high-dose female  rats
(Table  5-2) and  was  frequently  accompanied  by splenomegaly and hepatomegaly.
A  statistically  significant  Increase  In   leukemia   or   lymphoma  was  also
observed  In  high-dose female  rats  (p=0.007, Fisher  Exact test).    No  other
compound-related   Increases  In  neoplastlc  or  nonneoplastlc  lesions   were
observed  1n  female'rats.    The  study  on male  rats  was too brief  to provide
meaningful  analysis   of   the  data.   No  compound-related  Increases  1n  the
Incidences of  neoplastlc  or nonneoplastlc  lesions  were observed  in  mice  of
either  sex.    Dose-related and   significant  decreases   In   mammary  gland
adenomas  (female  rats),  alveolar/bronchlolar  adenomas  or carcinomas  (male
mice),  lymphomas  (male  mice),  and lymphomas  or  leukemia  (male mice)  were
observed (see Table 5-2).
    NTP  (1982a)  concluded  that  n-butyl  benzyl  phthalate  was   "probably
carcinogenic  for female  F344/N  rats.    In a  separate report, Kluwe et  al.
(1982a),  however,  concluded that  since  the  background  Incidence  of  myelo-
monocytlc  leukemia  1s  normally  high  In  F344/N  rats (8-15X  and   9-24%  In
females and  males, respectively),  results  presented   In  NTP  (1982a)  provide
only  equivocal  evidence of  n-butyl  benzyl  phthalate-lnduced  cancer  In female
rats.   Furthermore,  the  fact that  significant  and  dose-related  decreases  In
Incidences  of  malignant  lymphoma,  all  lymphoma, and lymphoma or  leukemia
were  observed  In  male  mice  contributes  to  the  uncertainty  that  n-butyl


0783p                               5-3                              05/14/86

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CO
TO
                                     TABLE 5-2

Hematopoletlc Neoplasms In F344/N Rats and B6C3F1 Mice Fed n-Butyl Benzyl Phthalate
                             In  the  Diet  for  103  Weeks3
LTI
1
Incidence (p-value)^
Species Sex
Tumor Type
Rat F mononuclear cell
leukemia
House H mal
all
Ignant
leukemia
or lymphoma
1 ymphoma
lymphoma s
lymphoma s
F mal
all
Ignant
or leukemia
lymphoma
lymphoma s
lymphoma
or leukemia.
Control
7/49
7/49
12/50
13/50
14/50
15/50
17/50
17/50
(0
(0
(0
(0
(0
.006)
.004)
.024N)C
.015N)C
.008N)C
(NS)
(NS)
(NS)
Low Dose
(6000 ppm)
7/49
7/49
10/49
11/49
11/49
14/50
16/50
16/50
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
High Dose
(12,000 ppm)
18/50
19/50
4/50
4/50
4/50
15/50
17/50
18/50
(0.011)
(0.007)


(0.027N)C
(0.016N)C
(0.009N
(NS)
(NS)
(NS)
)c



CD
    aSource:  NTP, 1982a

    bp-Values next  to the control  Incidences  Indicate the  probability  level  for  the  Cochran-Armltage test; p-
     values next to dosed-group Incidences Indicate the probability level for the Fisher Exact Test.

    CN Indicates a negative trend, that Is, the Incidence for dosed groups Is lower than for controls.

    NS = Not significant; p-value >0.05

-------
benzyl phthalate  may  cause leukemia  1n  humans.   IARC  (1982)  concluded  that
the NTP  (1982a)  studies  were  Insufficient  to  assess  the carcinogenic  poten-
tial  of  n-butyl  benzyl phthalate.   U.S.  EPA  (1985a)  Is  currently reviewing
this  Issue.
5.1.2.   01(2-ethylhexyl)   Phthalates.   01(2-ethylhexyl)  phthalate  was  fed
to groups  of  50  male  and  50 female F344  rats  at  levels  of  0,  6000 or  12,000
ppm,  and to groups  of  50  male  and 50 female 86C3F1  mice at  levels of 0,  3000
or 6000  ppm  for  103 weeks  (NTP,  1982b;  Kluwe  et  al.,  1982b).   Average doses
calculated from  data   on  food  consumption  and body  weight  were  322 and  674
mg/kg/day  for  low-  and high-dose male rats,  394  and  774 mg/kg/day  for  low-
and high-dose  female  rats,  672  and  1325  mg/kg/day  for low- and  high-dose
male  mice,  and 799 and  1821  mg/kg/day  for low- and  high-dose  female mice,
respectively.  Throughout  the  study, food  consumption,  body  weight,  mortal-
ity and  clinical  signs of  toxldty  were monitored.   Animals  surviving  103
weeks on  test  were maintained  for  an additional 1-2  weeks  after treatment,
then  evaluated by necropsy  and  hlstopathology.  Animals  that  died before  103
weeks were evaluated similarly.
    There  were  no  compound-related  effects  on  survival.    A  number   of
compound-related  effects  were  observed  when  treated  animals were  compared
with  controls.   A  moderate   decrease   In  body weight   was   observed   1n
d1(2-ethylhexyl) phthalate-treated  female mice, but was  not  accompanied by  a
reduction  In  food consumption.    Body weight  was  also reduced moderately  In
low-  and high-dose  male and high-dose female  rats,  but  food  consumption  was
also  slightly  reduced.  A  significantly  higher Incidence (Fisher Exact test)
of  hepatocellular  carcinoma was  observed 1n high-dose  female  rats,  mlddle-
and high-dose  female  mice and  high-dose  male mice  (Table  5-3).   A  signifi-
cantly greater  Incidence  (Fisher Exact  test)  of  hepatocellular  carcinoma  or


0783p                               5-5                               06/06/86

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                                                     TABLE 5-3


                   Liver Neoplasms In F344/N Rats and B6C3F1 Hlce Fed 01(2-ethylhexyl) Phthalate
CO
GO
XJ
In the Diet for 103 Weeks3
Incidence
Species Sex Tumor Type
Rat H hepatocellular
hepatocellular
or neoplastlc
F hepatocellular
en
^ hepatocellular
or neoplastlc
House H hepatocellular
hepatocellular
or adenoma
F hepatocellular
hepatocellular
or adenoma
care
Inoma
carcinoma
nodule
care
Inoma
carcinoma
nodule
care
care
care
care
Inoma
Inoma
Inoma
Inoma
Control
1/50
3/50
0/50
0/50
9/50
14/50
0/50
1/50
(0.
(0.
(0.
(
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                                                 TABLE 5-3 (cont.)
CD
CO
•o
o

\
o
CO
cr>
                                                QUALITY OF EVIDENCE


    Strengths  of  Study:   Lifetime  study of both  sexes  of two  species;  adequate number of  animals  tested at
                         MTD;  relevant  route  of  exposure;  appropriate  statistical  analysis;  comprehensive
                         hlstologlcal  examination.


    Overall  adequacy:     Adequate



    aSource:   NTP.  1982b
         p-value  next  to  the  control  Incidence  Indicates  the  probability  level  for  the Cochran-Armltage  lest;
     the  p-value  next  to  the  dosed  group  Incidence  Indicates  the  probability  level  for the  Fisher Exact  lest.


    cRats  were  given dietary  concentrations  of  6000 and  12,000  ppm; mice  were given  3000 and  6000 ppm.


    NS  =  Not  significant;  p-value >0.05

-------
neoplastlc  nodules  was  observed  In  high-dose  male rats,  middle-  and  high-
dose  female rats  and a  significantly  greater  Incidence  of  hepatocellular
carcinoma or  adenoma  was observed  In middle- and high-dose male and  female
mice  [see Table  5-3).   Significantly  decreased  Incidences of  Interstitial
cell  tumors of  the  testes,  pituitary  carcinoma  or adenoma and  thyroid C-cell
carcinoma or adenoma  were also  observed 1n high-dose male rats.   Significant
compound-related  Increases   In  seminiferous  tubule  degeneration   (rats  and
mice)  and hypertrophy of cells In the anterior  pHultary  (male rats)  were
also observed.
    NTP  (1982b),  Kluwe  et   al.  (1982b),  U.S.  EPA  (1985a)  and  IARC  (1982)
concluded that  these  results provide  sufficient  evidence of d1(2-ethylhexyl)
phthalate-lnduced  cardnogenlclty  1n   rats   and  mice.   This   conclusion,
however,  Is  disputed.   Northrup  et  al.   (1982)  claim  that the  NTP  (1982b)
results  are  equivocal since  the MTO  was  exceeded  In  some  treatment  groups,
Incidences  of   liver  tumors varied within different  control  groups  of  the
same  species  and  sex,  and  treated  animals  may   have been  malnourished.
Northrup  et  al. (1982) also  claimed  that the rodent data  cannot be  used to
predict  carcinogenic  risk  In humans  because d1(2-ethylhexyl)  phthalate 1s
metabolized differently  1n  rats than 1n humans.    In  response,  Kluwe  et  al.
(1983)  noted  that  MTD  was  not  technically  exceeded  since  there were no
compound-related  effects on survival,  the  Incidence   of  liver tumors  was
Increased  1n  d1(2-ethylhexyl)  phthalate-treated animals  regardless  of  the
control  data  used  and  the differences  1n  metabolism  between   rodents  and
humans   would   not   affect   the  carcinogenic  response  1n  rodents.   More
recently, Turnbull  and Rodrlcks  (1985)  concluded  that using NTP (1982b) data
to  estimate d1(2-ethylhexyl)  phthalate-lnduced  carcinogenic  risk  to humans
will  probably  overestimate  actual  risk.  This conclusion  was  based on  the


0783p                              5-8                              06/06/86

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differences  between  rodents and  primates  In  the metabolism  of  dl(2-ethyl-
hexyl) phthalate,  a  nonlinear  relationship between the  administered  dose  of
d1(2-ethylhexyl)  phthalate  to  the  dose  of  the  "proximate  carcinogenic
species"   in  rodents,  the  fact  that  the  "proximate  carcinogenic  species,"
which  Is  hypothesized  to Induce cancer,  Is produced  to a greater  extent  In
rodents  than  In  primates  and that  there  are  differences   1n  target-site
sensH1v1ty between humans and  rodents for liver tumors  1n  general.
    In conclusion,  results  of   NTP  bloassays  Indicate  that  d1(2-ethylhexyl)
phthalate  1s  carcinogenic  for   B6C3F1  mice and F344  rats  of  both  sexes  but
are  only  limited  to assess  the  carcinogenic  potential  of   n-butyl  benzyl
phthalate.  The relevance of these  studies to  the carcinogenic  potential  of
pthalate   esters  tn  humans  .1s  questionable.   Pertinent data  regarding  the
carclnogenldty of phthalates  In  humans  could  not be  located  In  the  avail-
able  literature  as dted  In  the  Appendix.   Adequate  cancer  bloassays  have
not been  conducted for  other pthalate esters.
5.2.   MUTAGENICITY
    Thomas and  Thomas   (1984)  and  Hopkins  (1983) reviewed  the  mutagenlclty
and  genotoxldty  of  d1 (2-ethylhexyl)  phthalate,   Us  metabolites  and  other
phthallc   add  esters.    D1-2(ethylhexyl)  phthalate   and   Us  metabolites,
monoethylhexyl phthalate  and 2-ethylhexanol,  have been  tested  extensively  In
Ames  assays  with  Salmonella typhlmurlum  with and without  metabolic  activa-
tion.  Negative results have been reported  by  Zelger  et  al.  (1982),  K1rby  et
al.  1983,  Kozumbo  et  al.  (1982),   Ruddlck  et al.  (1981),   Simmon  et  al.,
(1977), Warren et al. (1982),  and Yoshlkawa  et  al. (1983).   D1{2-ethylhexyl)
phthalate was  also  found not  to cause reverse mutation In  EscheMchla  coll
with and  without S9  (Toralta et  al.,  1982a;  Yoshlkawa  et al.,  1983).   Kozumbo
et  al.  (1982) and  Rubin et al.  (1979)  reported  that  dimethyl and  dlethyl


0783p                               5-9                              08/31/87

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phthalates were mutagenlc  In  strain  TA100 of S.  typhlmurlum  but  only  1n  the
absence  of  59.   Seed  (1982)  reported  that   dimethyl,  dlethyl  (with  and
without S9)  and  d1-n-butyl phthalates  (without,  but  not with, S9), but  not
d1(2-ethylhexyl),   d1-n-octyl,  dllsodecyl  and  dllsobutyl  phthalates, were
found  to  cause mutation  to  8-azaguan1ne  resistance 1n  bacterial  suspension
assays  with  S.   typhlmurlum;  the  d1(2-ethylhexyl)   phthalate  metabolite,
2-ethylhexanol, was found  to  be mutagenlc without  S9.   TomHa et  al.  (1982a)
reported  that  monoethylhexyl,  but not  d1(2-ethylhexyl),  phthalate yielded
positive results  1n rec assays with Bacillus  subtllls.
    With  two  exceptions,  jjn  v1tro genotoxlclty assays  have  yielded  negative
results.   01-2(ethylhexyl) phthalate  failed  to cause an  Increase  In chromo-
somal  aberrations  In  human  lymphocytes  (Turner  et al.,  1974),   1n Chinese
hamster Mbroblasts (Abe and  Sasaki,  1977; Ishldate and Odashlma,  1977),  and
In  CHO cells  (Phillips  et al.,  1982).   D1-2(ethylhexyl)  phthalate did  not
cause  aneuploldy   In   human   fetal  lung  cells   (Stenchever   et  al.,   1976).
D1(2-ethylhexyl)  phthalate and Us metabolites  (monoethylhexyl  and  2-ethyl-
hexanol)  failed to  Induce unscheduled  DNA synthesis  1n primary  rat hepato-
cytes  (Hodgson et  al.,  1982).    Monoethylhexyl  phthalate  was reported  to
cause  an  Increase  In  chromosomal  aberrations and SCE  1n  Chinese  hamster  V79
embryonic cells (TomHa et al., 1982a) and CHO cells (Phillips et  al.,  1982).
    Chromosomal aberrations  were  observed 1n embryonic  cells 1n a study  1n
which   Syrian  golden  hamsters  were  treated  orally  with  3.75-15 g/kg
d1(2-ethylhexyl)  phthalate on day 11  of gestation  (TomHa   et al.,  1982a).
Putman  et  al.  (1983)  failed   to observe significant Increases In  clastogenlc
changes  In bone marrow cells taken  from  male F344  rats  treated by  gavage
with  d1(2-ethylhexyl)  phthalate  (0.5-5  g/kg/day)  or monoethylhexyl phthalate
 0783p                               5-10                             06/06/86

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(0.01-0.14 g/kg/day)  for  5  days.   PosHWe results were observed  1n  a  domi-
nant/lethal study on  ICR  mice, where  d1(2-ethylhexyl)  phthalate  was  adminis-
tered as a single 1ntraper1tonea1  dose (2/3 LD5Q)  (Singh et al.,  1974).
    Agarwal et al.  (1985b)  evaluated  the  ant1fert1lHy  and mutagenlc  effects
of DEHP  In  ICR  mice.   In the first phase  of  the  study, eight male mice  per
group were  given DEHP  by s.c.  Injection  at  doses of  0.99,  1.97, 4.93  and
9.86  gAg  on  days  1,  5  and 10 of  the  experiment.  Sixteen  control  animals
were gWen saline by  s.c.  Injection.  On  day  21,  each  male was  housed with  a
female for 7 days.
    In  phase  two,  five  groups  of 10 male mice  each  were Injected  with 0,
0.99, 1.93, 4.93 and 9.86  mg/kg  DEHP on  days  15 and  10  of  the  experiment.
One  untreated  female  mouse  was  housed  with  each  male  at  each  treatment
Interval.  After  the  last dose, females were  replaced  at  5-day  Intervals  for
the first 21 days and  at  7-day  Intervals  through  a total  of 8 weeks  from  the
start of the experiment.
    The  females  were  sacrificed  13  days from the  middle  of their  respective
periods  of  cohabitation.    The  uterine  horns  and  ovaries  were examined  for
total number of  corpora  lutea,  Implantations, early fetal  deaths  and viable
fetuses.  The difference  between  the  number of corpora lutea and  the number
of  Implantations  was calculated  to  reflect prelmplantatlon  loss.  The data
for all  endpolnts were evaluated  In three  time  frames:   the first  3  weeks of
the study, the final 5 weeks and the totals for  the 8 weeks.
    HutagenlcHy  was  evaluated  utilizing  two   Indices:   prelmplantatlon
loss/Implants per pregnancy and early  fetal deaths/Implants per  pregnancy.
    In  the  phase I  study there was  a  reduction   In the   Incidence of  preg-
nancies.   Although  prelmplantatlon  loss  appeared to  be somewhat  greater  In
the  treated  groups,  none of these differences were  significant  (p<0.05).


0783p                               5-11                             08/29/86

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In contrast,  early fetal  death  was  significantly  Increased In  all  treated
groups.   The  numbers  of  viable  fetuses  were  significantly reduced  1n  the
lowest and  highest  dose  groups  only.  Both of  the  mutagenlclty Indices  were
Increased In all of the treated groups (statistics not reported).
    In the  phase  II study, there was  no  effect of DEHP on  the Incidence  of
pregnancies.  The  number  of  Implantations were reduced  In  the  1.93 and  9.86
g/kg  groups  In  the  day  2  to  21   Interval,  but  not   1n  the   4-  to  8-week
Interval.   Combining  across  weeks  (1-8)  there  was  a reduction 1n  Implanta-
tions  for  the high  dose  alone.   Prelmplantatlon  loss  was  Increased  In  all
dose  groups  for the  early study Interval  and  for  the  total  8-week  period.
Early  deaths  were  Increased  for   all  dose  groups  for  all  three  time
Intervals.  The number of viable fetuses was  significantly decreased  during
the first study segment and  for  the total 8 weeks.   The prelmplantatlon  loss
mutagenldty  Index  was  significantly   Increased  during   the  early  study
segment  In  the  0.99,  1.97 and  0.86 mg/kg  groups  and for  the  overall  study
(weeks 1-8)  In  the 1.97,  4.93  and  0.86 mg/kg  dose groups.   The early death
Index was significantly Increased for all  doses at all study segments.
    In experiments  with  F344  rats, Albro  et  al.  (1982)  showed that  radio-
labeled  d1(2-ethylhexyl)   phthalate and  monoethylhexyl  phthalate  (but  not
ethylhexanol) associated  strongly with DNA.  Covalent  binding, however,  was
not demonstrated.
5.3.   TERATOGENICITY
    A  number  of oral  studies  have  shown  that  exposure  to  d1(2-ethylhexyl),
d1-n-butyl  and  dl-n-heptyl   phthalates   during  gestation  can   have  adverse
effects  upon  the  developing fetus.   Whether  the observed  effects (reduced
fetal  weight,  fetal  mortality,  gross  external  and  skeletal  malformations)
0783p                               5-12                             08/26/86

-------
represent a primary effect  of  the  compound  1n  question  or  whether they occur
as  a  result  of maternal  toxlclty  has yet  to  be  demonstrated  unequivocally.
Oral   studies   concerning  d1 (2-ethylhexyl)  phthalate  are   summarized   In
Table 5-4.
    D1-2(ethylhexyl)  phthalate-lnduced  fetotoxlc  and   teratogenlc   effects
have been reported  1n  rats and mice  (Wolkowsk1-Tyl  et  al.,  1984a,b;  Bell  et
al., 1979;  Bell,  1980;  Shlota  and Mima,  1985;  Shlota  and  Nlshlmura,  1982;
SMota et al.,  1980;  Nakamura  et al., 1979; Yag1  et  al.,  1978,  1980;  ToraUa
et  al.,  1982b; Onda  et al.,  1974;  Nlkonorow  et  al.,  1973).   Studies  con-
ducted by  NTP   (Wolkowsk1-Tyl  et  al., 1984a,b)  Indicate  that  mice are more
sensitive to  d1(2-ethylhexyl)  phthalate  than  rats.  The  studies that  show
effects  at  the  lowest   level  of  exposure  and  In the  absence  of maternal
toxlclty  report a  significantly  Increased Incidence of percent of malformed
fetuses/lHter   In  CD-I  mice whose  dams were  fed  91  mg/kg/day  throughout
gestation (Ho1kowsk1-Tyl  et al., 1984b); significantly decreased  fetal  body
weight  In ddY-SlcXCBA  mice whose dams  were  gavaged  with 0.05  ml/kg  (49
mg/kg) on  day  7 of gestation  (TomUa et al.,  1982b);  and the formation  of
renal  cysts  In the  F   and  F    generations  of  mice  exposed  orally  (not
specified) to 10 or 100  mg/kg/day  for  3  generations  (Onda  et al.,  1974);  (no
other  details   provided).    The  decreased  fetal  body  weights  observed  by
TomHa  et al.   (1982b)   were  not  observed  In  ICR  or  CD-I  mice  treated  at
somewhat higher (0.05X  diet or  -65 mg/kg/day)  or  lower  (44  mg/kg/day)  doses
throughout  gestation   (Wolkowskl-Tyl  et  al.,  1984b;  Shlota  et  al.,  1980;
Shlota and  Nlshlmura,  1982).  The  study conducted  by  Holkowsk1-Tyl  et  al.
(1984b)  Is  thorough  and well-reported,  and  provides  a  NOEL of 44 mg/kg/day
and a  LOAEL  of 91  mg/kg/day for d1(2-ethylhexyl)  phthalate-promoted  terato-
genlc effects.


0783p                               5-13                            08/26/86

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                                                                              TABLE 54

                                                Summary of Oral  Teratogenlclty  Studies  with  01(2-ethylhexyl)  Phthalate
"     Species/
03      Strain
co
•o   	
                      Dose. Vehicle and
                     Duration of Treatment
                          Endpolnts Monitored
                             Maternal  Response
                                                                                             Fetal  Response
                                                                                                        Reference
    Rat/F344
    Rat/NR
    Rat/Sprague-
    Oawley
    Rat/Sprague-
    Dawley
    Rat/Sprague-
    Dawley

    Rat/Wlstar
    Mouse/CD-I
o
CO
CO
0. 0.5. 1.0. 1.5 or
2% diet (0. 356.7.
666.4. 856.5 or
1054.8 ng/kg/day) on
days 0-20 of gesta-
tion
2.5 or 5.0 ml/kg on
days 7-13 of gesta-
tion (vehicle NR)

0. 0.5 or IX diet on
last 16 days of ges-
tation and throughout
lactation

0. 0.5 or IX diet for
5-10 days after mating
0. 0.5X diet on days
5-18 of gestation

0. 0.34 or 1.7 g/kg/
day In olive oil for
3 months before
mating or 0. 0.34 or
1.7 g/kg/day In olive
oil on days 0-21 of
gestation
0. 0.025. 0.05. 0.1
or 0.15X diet (0.
44. 91. 191 or 292
mg/kg/day) on days
0-18 of gestation
standard NTP
teratology study
                                              NR
                         sterologenesls In
                         livers of pups 8 days
                         after birth
sterologenesls In
brain and liver of
18-day fetuses

sterologenesls In livers
of fetuses and dams

day 21 of gestation:
number live fetuses;
number dead fetuses;
number resorptlons;
fetal body weight.
placental body weight.
skeletal examination of
fetuses; placental weight

standard NTP
teratology study
                                                    dose-related decrease
                                                    In bw.  significant  at
                                                    >1X;  significant  dose-
                                                    related Increase  In
                                                    absolute and relative
                                                    liver weight, signifi-
                                                    cant  at all  doses;
                                                    significant  dose-
                                                    related decrease  In
                                                    gravid uterine weight,
                                                    significant  at 2%

                                                    NR
                                                                         NR
                                                                         NR
                           reduced sterologenesls
                           NR
                           Dose-related decrease
                           In body  weight,  signi-
                           ficant at  0.1 and  O.I5X;
                           dose-related Increase In
                           related  liver weight,
                           significant  at 0.1  and
                           0.1 SX
                                                      Dose-related Increase In X resorptIons/          Wolkowskl-Tyl
                                                      litter.  X nonlive/litter (dead and  resorbed).    et  al..  1984a
                                                      and number of affected fetuses/litter  (non-
                                                      live and malformed),significant at  ?X; dust--
                                                      related decrease In bw. significant at all
                                                      doses; significant dose-related Increase In
                                                      X malformed fetuses/litter but no statisti-
                                                      cally significant palrwtse differences
                                                                               No teratogenlc  effects;  50X resorptIon  of        Nakayama,
                                                                               Implants at  ?.5 ml/kg;  no other  details         1968
                                                      (Both doses)  significant  reduced  sterolo-        Bell  et  a).,
                                                      genesis;  significant  reduced  body weight;        1979
                                                      significant Increased related liver weight
                                                                               (Both doses) significant  reduced  sterolo-        Bell  et  al.,
                                                                               genesis In brain and liver                       1919
                                                                               Reduced sterologenesls  (not  statistically        Bell,  1980
                                                                               significant)

                                                                               No effects  when administered before  ges-         Nlkonorow
                                                                               tatlon;  significantly reduced fetal  body         et al..  1973
                                                                               weight  when administered  during  gestation
                                                                               (high dose);  significantly reduced placental
                                                                               weight  (both  doses);  Increased number  of
                                                                               resorptlons (high  dose);  no  skeletal effects
                                                                               dose-related  Increase  In X resorptlons/         Wolkowskl-lyl
                                                                               litter,  dead/litter, nonl1ve/11tter  (dead       et  al..  1984b
                                                                               nd  resorbed).  and  affected fetuses/Utter
                                                                               (dead  and  malformed),  significant  at  0.1
                                                                               and 0.1SX;  significant  decrease  In fetal
                                                                               body weight at  0.15X;  significant  Increases
                                                                               In  X malformed  fetuses/litter  at O.OS. 0.1
                                                                               and 0.15X  (external, visceral  and  skeletal
                                                                               defects)

-------
                                                                            TABLE 5-4 (cont.)
oo
CO
•o
        Species/        Dose,  Vehicle and
         Strain        Duration of  Treatment
                          Endpolnts Honltored
                                                                            Maternal  Response
              Fetal Response
                                                                                                        Reference
      Wouse/S/C-ICR
      Mouse/ICR
 tn
 i
      House/random
      strain ddY-
      Slc x CBA
      House/ddY-
      Slc x CBA
0. 250. 500. 1000 or
2000 mg/kg In olive
oil on days 7-9 of
gestation
0. 0.05. 0.1. 0.?.
0.4 or IX diet on
days 0-18 of gesta-
tion
0, 0.05. 0.1 or 1
til/kg on day 7 of
gestation (no vehicle)
various doses on day
6, 7. 8. 9 or 10 of
gestation (gestation
day 6) 2.5 mt/kg
(7) 1. 2.5 or 5 mt/kg
(8) 7.5 or 10 nt/kg
(9) 7.5, 10 or 30
mt/kg (10) 10 or 30
mt/kg (no vehicle)
day 18 of gestation:
number of abortions,
maternal mortality.
resorptlons. Implants,
dead fetuses, fetal
body weight, gross
external anomalies

day 18 of gestation:
maternal body weight;
number resorptlons;
number Implants; number
dead fetuses; fetal
body weight; gross
external, skeletal and
visceral anomalies

day 18 of gestation:
maternal body weight,
number Implants, early
and late resorptlons,
number live, gross
external and skeletal
malformations

day 18 of gestation:
maternal body weight,
number Implants,
number early and late
resorptlons, number
live fetuses wMh gross
external or skeletal
anomalles
                                                                          3/11  aborted and 1/11
                                                                          died  at ?000 mg/kg;
                                                                          abortions and mortality
                                                                          were  not  observed at
                                                                          any other level
                                                                          significant decreased
                                                                          body weight at 0.?,
                                                                          0.4 and  IX
                                                                          (1 ml/kg) slight
                                                                          decrease In body weight
                                                                          on day 14 of gestation
                                                                          decreased body weight
                                                                          at all  doses given on
                                                                          days 6,  7 or 8 of
                                                                          gestation
(1000 and 2000 mg/kg) significant Increases     Shlota and
In X resorptlons and dead fetuses, and X        Mima.  1985
malformed fetuses (exencephaly/anencephaly;
tall anomalies); decreased fetal body weight
100X early resorptlon (all Implants) at 0.4     Shlota and
and IX; significant Increased X resorptlons     Nlshlraura.
at 0.1 and 0.?X; significant Increased X        198?;  Shlota
fetuses with gross external malformations       et al..  1980
(neural tube defects) at 0.2, 0.4 and IX
(1 mt/kg) increased Incidence of gross and      Nakamura
skeletal anomalies (elongated and fused ribs,   et al., 1979
absence of tall and leg bones) (0.1  and 1
mt/kg) significant Increased fetal mortality
Significant reduced fetal body weight at all    Yagl el al.,
doses on all days; Increased fetal mortallly    1978. 1980;
and resorptlons al all doses on days 7 and 8    Tomlla
of gestation; dose-related Increase In Incl-    et a)., 1982a
dences of gross external and skeletal anom-
alies on days 7 and 8 of gestation (all
doses); some external anomalies but no
skeletal anomalies on days 9 or 10 of gesta-
tion (10 and 30 mt/kg on day 9. 30 mt/kg on
day 10); no resorptlons. dead fetuses, or
gross or skeletal anomalies were observed
In controls
oo
\
ro

^v
CO
      House/ddy-
      Slc x CBA
      Mouse/ddy-
      JCL and ICR
0. 0.05, 0.1 or 1
ml/kg on day 7 of
gestation (no vehicle)
0. 10 or 100 mg/kg/
day for 3 generatIons
(vehicle NR)
                                                same as  above
                                                NR
                                                                          decreased body weight
                                                                          at  1  mt/kg
Significant reduced fetal body weight at all    1 omit a
doses; significant Increase In Incidences of    el al., 1982b
gross and skeletal anomalies at IX; decreased
X live fetuses at 0.1 and IX

Formation of renal cysts In t\ and f?           Onda et al.,
(both doses)                                    1974
      NR = Not reported

-------
    Studies  concerning  phthallc   add   esters  other  than  d1 (2-ethylhexyl)
phthalate  are  summarized  In Table  5-5.   In  separate reports  of the  same
study,  Booth  et  al.  (1983)  and  Plasterer  et al.  (1985)  reported that  di-
methyl  phthalate  had  no effects  on reproduction  In  CD-I mice.   Groups  of  50
female mice were  gavaged with 0 or  the  MTD  of dimethyl phthalate (3500  mg/kg
In  corn oil)  on  days 7-15 of gestation, and allowed to  deliver  naturally.
There were  no  significant  effects on survival, body weight,  birth weight  of
pups, or  average  number live/Utter, average number dead/Utter,  or  average
weight  of  pups  on days 1  and 3  postpartum.   The  pups were  not  examined  for
malformations.
    Shlota  et  al. (1980)  and  SMota and Nlshlmura  (1982)  reported  terato-
genlc and fetotoxlc effects  In mice  caused  by d1-n-butyl  phthalate, but only
at  a  dietary concentration (1%)  that also produced  a  significant  depression
of  maternal weight gain.   No effects  on  the fetuses  or dams were observed  In
mice  fed <0.4X dl-n-butyl  phthalate  throughout  gestation.   In a  3-generat1on
study,  Onda  et  al.  (1974) observed  renal  cyst  formation  In the  F. and  F
generations of  mice  exposed  orally  (not specified)  to 10  or  100 mg  dl-n-
butyl phthalate/kg/day;  however,  no other details were given.   An Increased
number  of   resorpUons  and  significantly  reduced  fetal   body  weights  were
observed 1n  rats  gavaged with 600 mg d1-n-butyl  phthalate/kg/day  throughout
gestation  (Nlkonorow  et al., 1973); reduced  placental weights were observed
In  mice gavaged  with  120  or 600  mg d1-n-butyl  phthalate/kg/day.   Unfortu-
nately,  this study  did not randomly select  test  animals and did not  examine
gross or visceral malformations.
    It  Is  difficult  to  define  a  dose-response relationship  for  d1-n-heptyl
phthalate.  The  only  study,  Nakashlma  et  al.  (1977), Is  poorly  reported.
0783p                               5-16                             08/26/86

-------
                                  Summary of Oral Teratogentclty Studies  for  Phthallc  Acid Esters  Other  Than Dl (?-e thylhexyl)  Phthalate
OD
CO
       Species/            Dose. Vehicle and
        Strain           Duration of  Treatment
                                                     Endpolnts Monitored
                                     Maternal
                                     Response
             fetal Response
                                                                                                   Reference
                                                                           DIMETHYL PHTHALATE
      Mouse/CD-I       0  or  3SOO mg/kg/day on
                      days  7-15 of gestation
en
I
      Rat/Wlstar       0,  0.12  or 0.60 g/kg/day
                      In  olive oil  for  3 months
                      prior  to mating or 0. 0.12
                      or  0.60  g/kg/day  In olive
                      oil  on days 0-21  of gesta-
                      tion
House/lCR       0. 0.05. 0.1. 0.2. 0.4 or
                IX diet on days 0-18 of
                gestation (0. 80. 180. 370.
                660 or 2100 mg/kg/day)
dams were allowed to deliver;       no effect
dams observed for survival and
body weight, pups observed for
birth weight, number of live/
Utter. dead/Utter, average
weight on day 1 or 3 post par turn

                      DI-n-BUTYL PHTHALATE

day 21 of gestation: number live    NR
fetuses; number resorptlons;
fetal body weight, placental
body weight; skeletal examina-
tion of fetuses; placental
weight
day 18 of gestation:  maternal       significant
body weight, number resorpttons.    decreased
number Implants, number dead        body weight
fetuses,  fetal body weight.         at IX
gross external, skeletal and
visceral  anomalies
                                                                                                   No effects;  pups  were not  examined  for
                                                                                                   ma 1 format tons
                                                                                                 Booth et  al..
                                                                                                 1983;
                                                                                                 Plasterer
                                                                                                 et  al..  1985
No effects when D8P was administered         Nlkonorow
prior to gestation; significantly reduced    et al.. 1973
fetal body weight when administered
during gestation (0.6 g/kg/day); In-
creased number resorpttons (0.6 g/kg/day);
significant reduced placental weight
(both doses); no skeletal effects

Significant Increase In number of resorp-    Shlota
tlons and dead fetuses at IX; significant    et al.. 1980;
Increase In Incidence of gross external      Shlota and
Malformations at IX; significant decreased   Nlshlmura.
number of ossified coccygla at all  levels    1982
of treatment
      Mouse/ddY/JCL
      and 1CR
                0. 10 or 100 mg/kg/day for
                3 generations (vehicle NR)
                                                    NR
                                    NR
                                                                          Dl-n-HEPTYL PHTHALATE
                                                    Formation of renal  cysts
                                                    (no other details)
                                                                                                                                 In
                               and fp
                                                                                                 Onda  et  al.
                                                                                                 1974
      Mouse/ICR:JCL    administered  various  doses
                      on  either  day 7.  8. 9.  10
                      or  11  of gestation  (day 7)
                      0.94.  1.88 or 3.75 ml/kg
                      (8) 1.50.  2.50 or 7.50  ml/kg
                      (10)  7.50. 11.3 ml/kg
                      (11)  7.50. 11.3 ml/kg
O
co
CD
                                               embryo/fetotoxlclty (NOS)  gross      NR
                                               external  and skeletal  anomalies
                                                    Dose-response relationships  not  clearly
                                                    presented;  high Incidence of gross
                                                    external  anomalies  on days 7 and 8  of
                                                    gestation at  ?.S and 7.5 ml/kg;  embryo/
                                                    fetotoxtclty  highest on days 7  and  8;
                                                    100% resorptlons at 7.5 mt/kg (no other
                                                    Information); high  Incidence of  skeletal
                                                    anomalies on  day 8, 100X with fused ribs
                                                    at 2.5 mt/kg  (no other Information);
                                                    gross anomalies Included open eyelid.
                                                    cleft palate  and olIgodactyl la  on day  9.
                                                    exencephaly on day  8. and tall  anomaly,
                                                    ollgodactyl la and hematoma on days  10  and 11
                                             Nakashlma
                                             et  al..  1977
      NOS =  Not  otherwise specified;  NR  =  not  reported

-------
Fetotoxlc  and  teratogenlc  effects  were observed,  but  the  study seemed  to
focus on  which  days of gestation  the  mice were more  likely  to  be  sensitive
to  exposure,  and  there  was  no consistent  effort  to  report which  effects
occurred  at  each  particular  dose.  Furthermore,  maternal  effects  were  not
reported.
    A  recent  study  Indicates  that phthallc  acid esters  may cause  adverse
effects when transported  to the developing organism by  milk.   Parmar  et  al.
(1985)  observed  a  decrease  In weight  gain  and  changes  In enzyme  "levels
Indicative of  liver damage  in  21-day-old  rat  pups  whose dams  were  gavaged
with 2000 mg dl(2-ethylhexyl) phthalate/kg  throughout lactation.
    A  number  of  IntraperHoneal  studies  have  been  conducted with  phthallc
add esters on rats  (Singh  et al.,  1972).   Given  the route-dependent  differ-
ences In absorption, distribution and  excretion of phthallc  add esters,  the
relevance  of  IntraperHoneal studies  to oral  risk  assessment  1s  uncertain.
Singh  et  al.   (1972)  reported   that  parenterally  administered   dimethyl
phthalate   (0.38-1,125   ml/kg),  dlethyl   phthalate  (0.506-1.686   ml/kg),
dl-n-octyl   phthalate   (5,   10  ma/kg),   d1(2-ethylhexyl)   phthalate   (10
ml/kg)  and  d1-n-buty1  phthalate   (0.3-1.017   mi/kg)   caused  fetotoxlc   or
teratogenlc  effects when  administered  to  rats  on  days  5,  10 and  15  of
gestation.
5.4.   OTHER REPRODUCTIVE  EFFECTS
    NTP  recently  conducted  reproduction  and  fertility  assessments  on  CD-I
mice  for  dlethyl  phthalate  (Reel  et   al.,  1984)  and  dl-n-octyl  phthalate
(Gulat!  et  al.,  1985), using a  new protocol,   "fertility assessment  by  con-
tinuous breeding."  The protocol consists  of four  tasks:  1) a  range-fIndlng
study  to determine  maximum tolerated   dose;  2) a continuous breeding study
entailing  exposure  during  7  days before mating,  followed by  98  days  of
cohabHat^on and  21 days  of segregation;  3}  a  crossover  breeding study  to

0783p                               5-18                             08/26/86

-------
determine  the  affected sex; and 4)  a  reproductive  performance assessment of
control  and high-dose  Utters  from  Task 2.   Task 3  Is performed  only If
adverse  effects  are detected In Task  2.   If  no adverse effects are detected
In Task  2,  then Task 4 1s performed.
    Based  on  the  range-finding  studies,  dietary concentrations  of  0,  0.25,
1.25 and  2.5% dlethyl  phthalate  and  0, 1.25,  2.5 and 5% dl-n-octyl phthalate
were  chosen for  Task 2.   No  adverse compound-related  effects  (number  of
pairs  able  to  produce at  least  one litter,  number  of  litters/pair,  propor-
tion  of  pups  born  alive,  sex  of  pups  born alive,  live  pup  weight)  were
observed  for  either dlethyl  phthalate or dl-n-octyl  phthalate; Task  4  was
therefore  performed  for  bojih  compounds.   Endpolnts  monitored  for  Task  4
Include  body  weight  at  weaning  and  at  74  days  of  age,  mating  behavior,
reproductive  performance  as  measured  In  Task  2 (beginning  at  74  days  of
age),  sperm assessment  and  selected  organ  weights.   F,  male and  female
pups born to  dams  fed 2.5X dlethy]  phthalate had  significantly  lower  body
weights  than   controls at  weaning  and  at   74   days  of age.   The  dlethyl
phthalate-exposed  F.  had  significantly fewer  live  pups per  litter  than  did
controls.   Males  had  significantly  reduced  sperm concentrations and signifi-
cantly  Increased  prostate  weights  In  comparison with  controls.   Both  males
and  females  exposed to dlethyl  phthalate had significantly  Increased  liver
weights;  females   also  had  significantly Increased  pituitary weights.   In
contrast,  there  were  no  significant, adverse  compound-related effects  on
fertility,  reproduction  or  organ   weights   In  F,  mice   exposed   to   5%
d1-n-octyl phthalate.
    The  fertility of Sherman rats  was not  affected by  dietary  exposure  to
d1{2-ethylhexyl)  phthalate  (up  to  0.4%).  Significantly Increased  relative
kidney  and  liver  weights,  however, were  observed   In  F,  males  and  females
(Carpenter et  a!., 1953)  (Section 5.5.1.).

0783p                               5-19                             08/26/86

-------
    The testlcular effects of  phthallc  acid esters have been  studied  exten-
sively  In  rats.   Orally administered d1(2-ethylhexyl)  phthalate,  d1-n-butyl
phthalate,  n-butyl  benzyl  phthalate,   dl-n-pentyl   phthalate,   d1-1sobutyl
phthalate,  and  dl-n-hexyl  phthalate  cause  testlcular  atrophy  characterized
In general  by  reduced testlcular weight, hlstologlcal  evidence  of  degenera-
tion,  reduced   testlcular  zinc  concentration  and  either  an  Increase  or
decrease  1n  testlcular  testosterone  concentration (Gray et al.,  1977,  1982;
Gangolll,   1982;  Olshl  and  Hlraga,  1980a, 1983;  Gray and  Butteruorth,  1980;
Mangham et al.,  1981; Olshl,  1985; Agarwal  et al..  1985;  Cater  et  al.,  1976,
1977; NTP,  1982b;  Kluwe  et al.,  1982b;  Foster et  al.,  1980).   These  studies
are  summarized  In  Table  5-6.    Cater  et  al.   (1977)   demonstrated   that
co-administration  of  zinc  could  counteract  the  degenerative  effects  of
dl-n-butyl  phthalate,  while  Olshl   and  Hlraga   (1983).  demonstrated   that
co-administration  of  zinc  had  no   effect  on  d1(2-ethylhexyl)  phthalate-
promoted  atrophy.    Furthermore,  Gray  and  Butterworth  (1980)  demonstrated
that  when  rats  were  removed  from  d1 (2-ethylhexyl)   phthalate  exposure,
testlcular weight  and  morphology were  restored within  12-20 weeks of  expo-
sure; Olshl  (1985)  observed  only  slight  recovery after 45  days.   Equlmolar
concentrations   (compare with  effective  phthallc  add  esters)  of  dimethyl
phthalate, dlethyl phthalate,  dlpropyl  phthalate, d1-n-heptyl  phthalate  and
d1-n-octyl phthalate did not cause testlcular  atrophy  In  rats  when  adminis-
tered orally for 4-10 days  (Gray and  Butterworth,  1980;  Foster et al.,  1980).
    Sjoberg  et  al.  (1985) Investigated  the kinetics of orally  administered
DEHP  In 25-, 40- and  60-day-old male  Sprague-Dawley  rats 1n an  attempt  to
elucidate  the   greater   testlcular  sensitivity  to  this   compound  In  young
animals.   For  the  toxldty study,  groups of 7-8  rats/group  from each  of  the
three  age designations  were treated by  gavage with  either  1 g  OEHP/kg  1n


0783p                               5-20                             08/26/86

-------
                                                                            TABLf  5-6


                                             Orally Administered Phthalate Esters  Causing  Testlcular  Atrophy  In  Rats
CO
CO
•o
Compound
                      Vehicle
                                Effective Dose(s)
                                             Duration
                                                                              Reference
          DEHP
en
 i
ro
          BBP


          DBP
 O
 00
 CD
          OPeP
  DIBP


  DHP
diet


diet


diet


diet


diet


diet


corn oil


corn oil


corn oil


none; gavage


none; gavage


diet


corn oil


corn oil


corn oil


corn oil


Corn oil


corn oil


corn oil


diet


corn oil


corn oil
1.0. 2.OX (7SO. 1500 mg/kg/day)


12,000 pp« (674 mg/kg/day)


1.0. 2.OX


2X


2X (1200 •g/kg/day)


1.5 or 3X


2800 mg/tcg/day


2800 mg/kg/day


2500 mg/kg/day


2000 mg/kg/day


2000 Mg/kg/day


2.5 or 5.OX


2000 mg/kg/day


equlmolar to 2800 mg DEHP/kg


2000 mg/kg


500. 1000. 2000 mg/kg/day


2200 mg/kg/day


2100 mg/kg/day


equlmolar to 2800 rag DEHP/kg/day


2X


equlmolar to 2800 mg DEHP/kg/day


2400 rog/kg/day
 90 days


104 weeks


 17 weeks


  7 days


 10 days


 90 days


 10 days


  9 days


 21 days


 10 days


 14 days


 14 days


4-9 days


 10 days


  9 days


  6 days


  4 days


  4 days


 10 days


  7 days


 10 days


  4 days
Gangolll. 1982*


NTP. 1982b; Kluwe et al.. 1982b


Gray et al.. 1977*


Olshl and Hlraga. 1980<)


Gray and Butterworth. 1980


Shaffer et al.. 194S


Gray and Butterworth. 1980


Gray et al.. 1982


Mangham et al.. 1981


Olshl and Hlraga. 1983


Olshl. 1985


Agarwal et al., 1985


Cater et al.. 1976


Gray and Butterworth. 1980


Gray et al.. 1982


Cater et al.. 1977


Gray et al.. 1982


foster et al..  1980


Gray and Butterworth. 1980


Otshl and Hlraga, 1980a


Gray and Butterworth, 1980


foster el al..  1980
         *These are probably  the same study

-------
corn oil  or with  corn  oil alone  dally for  14  days.   Body weights  and  the
following  organ  weights   were  recorded:   liver,  testes,  ventral  prostate
seminal  vesicles.   In addition,  testes  were fixed, sectioned  and  evaluated
using light microscopy.
    For  the kinetic  study, groups  of  9-10 rats  from  each  of  the  three  age
designations were  utilized.   DEHP  at a dose  of  1  g/kg  was  administered  as  a
single gavage  dose.   Blood samples  were  drawn  from a  Jugular  cannula at  1,
3,  5,  7,  9, 12,  15,  24 and  30  hours postdoslng  (0.25  ml/sample).   DEHP  and
MEHP analysis was conducted on hexane extracts by gas chromatography.
    For  the excretion studies,   two  groups of  six rats each  were  utilized.
One  group  consisted  of   25-day-old  animals and  the  other  of  60-day-old
animals.    Each  animal  received  1 g  14C-DEHP/kg  1n   corn  oil  by  gavage.
Urine  was  collected  each  day   for  3  days.   Excretion  was  quantified  by
scintillation  counting.    In  addition,  allquots  of urine  were  extracted,
evaporated, dissolved 1n  dlethyl  ether  and streaked on thin  layer  plates  of
silica gel.   Standards  of  DEHP  and MEHP  were  utilized.   Radioactive  zones
were located utilizing a radio scanner.
    For  the Jjrc  vitro metabolism  evaluations, four  groups  of  six  rats  each
were utilized.   Groups  consisted of two  groups  of  25-day -old  animals,  one
pretreated  with  phenobarbHal   and  the   other   not  pretreated.   The  same
procedure  was   followed  with  the  60-day-old  animals.    DEHP   was  given  by
gavage 1n  corn oil at a  dose of  1  g/kg/day for  14  days.   PhenobarbHal  was
given by  1.p.  Injection of  three dally  doses  of  100 mg/kg.   Liver mlcrosomal
preparations were  utilized  to evaluate  the rate  of conversion  of MEHP to  Us
hydroxylated product,  mono-(2-ethyl-5-hydroxyhexylJphthalate.
    Protein  binding  of  MEHP  to blood  plasma from  25-,  40-  and  60-day-old
rats  was  also  evaluated.   This  was   accomplished  using  14C-MEHP  and  an
equilibrium dialysis technique.

0783p                               5-22                             08/29/86

-------
    The  25-day-old  rats  were  the  only  age group  exhibiting significantly
reduced  testlcular  weights.   Liver  weights were  Increased  In  all  treated
groups  In  the toxlclty study.   The testes  of  the  25-day-old animals showed
severely affected  seminiferous  tubules.   The cell  type most affected was the
primary  spermatocyte.   Some  spermatogonlal   Involvement  was also  seen.   No
abnormalities were seen In animals  from the  other age groups.
    No  age-related differences were  seen 1n maximum  MEHP  plasma concentra-
tion  or  MEHP plasma  elimination  half-lives.   The  mean area  under  the  MEHP
plasma concentration curve was  significantly greater  In 25-day-old rats  than
In  40- or  60-day-old  rats.    Cumulative  excretion  of  14C-DEHP  was  44  and
26%  of  the  administered  dose  for 25-  and  60-day-old  rats,  respectively.
Significant  differences  were  not   seen   In conversion  of  MEHP  to  mono-
(2-ethyl-5-hydroxyhexyl)phthalate   using   liver   mlcrosomes   from   25- and
60-day-old rats.   Significant differences  among the  age groups In binding of
MEHP to plasma proteins were not seen.
    The  authors  concluded   that  their  data  suggested  that   the  Increased
susceptibility of  young rats to  the  testlcular effects of  DEHP  may  In  part
be explained  by  greater absorption  of  DEHP   from the  gastrointestinal  tract
of the young animals based on  he  larger  amount  of  excreted radioactivity and
the  Increased  area  under  the  plasma  MEHP  concentration  time curve  In  the
young  animals.   The  possibility of differential tissue sensitivity  was  also
suggested.
    Species  differences In  phthallc  acid ester-promoted  testlcular  atrophy
have  also  been  observed.  Gray et  al.  (1982)  failed  to  observe testlcular
atrophy  In  hamsters  gavaged  with  dl-n-butyl, d1(2-ethylhexyl)  and  d1-n-
pentyl phthalates  at equlmolar  doses  equivalent to  those  that caused  atrophy
0783p                               5-23                             08/26/86

-------
In rats.   In  the  same study,  mice gavaged  with equlmolar  doses  of  dl-n-
butyl,  d1(2-ethylhexyl)  and  dl-n-pentyl  phthalates  had  only  slight  focal
atrophy  (Gray  et  al.,  1982).   B6C3F1  mice  fed 6000  ppm  (1325 mg/kg/day)
d1(2-ethylhexyl) phthalate  In  the diet for  103  weeks had a  slight but  sig-
nificantly higher  Incidence of  seminiferous  tubule atrophy than  did controls
(NTP, 1982b;  Kluwe et al.,  1982b).
5.5.    CHRONIC AND SUBCHRONIC  TOXICITY
    Chronic or  subchronlc  oral  studies  have been conducted  with  d1(2-ethyl-
hexyl),  dl-n-butyl,   dimethyl,   dllsononyl,  n-butyl  benzyl  and  d1-n-octyl
phthalates.  The  Hver,  kidney  and  testes  appear  to be  the  organs affected
most  by phthallc add esters.
5.5.1.   D1-2(ethylhexyl)   Phthalates.   Oral  studies  with  d1(2-ethylhexyl)
phthalate  have  been   conducted  on  rats  (Carpenter  et  al.,  1953; Harris  et
al.,   1955; Nlkonorow et al.,  1973; Gray et al., 1977;  Popp et al.,  1985;
Gannlng  et  al., 1985;  Nagasaki  et  al.,  1974;  Maslenko,  1968;   NTP,  1982b;
Kluwe  et  al.,  1982b;  Shaffer  et  al.,  1945),  mice  (NTP,  1982a; Gannlng  et
al.,   1985; Nagasaki  et al., 1974;  Ota  et  al.,  1974),  ferrets (Lake  et  al.,
1976,  1977a),  guinea  pigs  (Carpenter et al.,  1953), and  dogs (Carpenter  et
al.,  1953, Harris  et  al.,  1955).   These studies  are  summarized  1n Table  5-7.
The  studies  that  show adverse  effects  at  the  lowest levels  of  exposure  are
those  of  Carpenter et  al.  (1953), Gray et  al.   (1977)  and Nagasaki   et  al.
(1974).
    Carpenter  et  al.  (1953) fed  d1(2-ethylhexyl)  phthalate  to  rats,  guinea
pigs  and dogs.  Groups of  Sherman  rats  (32/sex/group) were fed 0, 0.04,  0.13
or 0.4X  d1(2-ethylhexyl)  phthalate In  the  diet  (0,  20, 60  or 200 mg/kg/day
doses  provided  by  the Investigators)  for  2  years, and  were  allowed to breed
within  the  first  year.   After  1  year,   groups of  eight  males and  eight


0783p                               5-24                             08/26/86

-------
                                                                                TABLE 5-7

                                                           Oral Toxlclty Summary for 01(2-ethylhexy1)  Phthalate
co
CO
•o
Species/Strain    Number  and Sex
    Dose. Vehicle and
  Duration of Treatment
                                                                              Endpolnts Monitored
                                                                                                                           Effects
                                          Reference
      Rat/Sherman
      Rat/F344
 en
 I
 ro
 en
      Rat/NR
      Rat/Wlstar
      Rat/Ulstar
0   Rat/Wlstar
oo
 co
                  2 generations:
                  P| = 32H and
                  32F/group
                  (reduced to 8M
                  and BF/group
                  after 1  year);
                  F! . 3?H and
                  32F/group

                  SOH and  SOf/
                  group
                  NR/NR
                  43H and 43F/
                  group
                  ION and 10F/
                  group

                  20H and 20F
                         ?OM and 20F/
                         group
Pi: 0. 0.04. 0.13 or 0.4X
diet (0. 20. 60. or 200
mg/kg/day) for 2 years;
(Fj) 0. 0.4X diet (0. 190
mg/kg/day) for 1 year
0. 6000. 12.000 ppm diet
(0. 322. 674 mg/kg/day for
•ales; 0. 394. 774 mg/kg/
day for females) for 105
weeks
0. 0.375. 0.75. 1.5 or 3X
(0. 0.2. 0.4. 0.9. 1.9 g/
rat) for 90 days

0. 0.1. 0.5X diet for up
to 24 months (Interim
Mils at 3. 6. 12 months)
0.34 or 3.40 g/kg/day for
3 months (gavage: vehicle*
olive oil)
0 g/kg/day for 3 months
(olive oil)

0. 0.35X diet for 12
months
                                                                        body weight, mortality,  food
                                                                        consumption, hematology,  ferti-
                                                                        lity, liver and kidney weights,
                                                                        hlstopathology (major organs)
                                                                        body weight, mortality, food
                                                                        consumption, clinical signs
                                                                        of toxlclty. gross and micro-
                                                                        scopic pathology
                                                                        growth,  mortality, hematology.
                                                                        pathology (extent not reported)
                                                                        mortality,  body weight, food
                                                                        consumption, organ weights.
                                                                        hlstopathology
                                                                        behavior; body weight; hemato-
                                                                        logy; serum proteins; gross
                                                                        and microscopic examination of
                                                                        kidneys, liver and spleen
                                                                   behavior;  body weight;  food
                                                                   consumption;  hematology;  serum
                                                                   proteins;  gross and microscopic
                                                                   examination of liver,  kidneys
                                                                   and spleen
                                        Carpenter
                                        et  a!..  1953
(0.4X): significantly increased
relative liver and kidney weights
In P| males (1 year only) and Fj
males and females; no hlstopatho-
loglcal changes
Moderate reductions In body weight      NIP.  I962b;
In low- and high-dose males and In      Kluwe et a)..
high-dose females: slight reductions    198?b
In food consumption (all treated
rats); Increased Incidence of hyper-
trophy of cells In the anterior
pituitary (males only; 1/46. 0/43
and 2P/49 for 0. low- and high-dose
rats, respectively); seminiferous
tubule degeneration (1/49. 2/44.
43/48 for 0, low- and high-dose
rats, respectively

(0.75-3X) slight decrease In growth     Shaffer
(1.5. 3X) tubular atrophy and           et al., 1945
degeneration In testes

Reduced body weight and food con-       Harris et al.,
sumption In rats fed 0.5X DfHP;         1955
significant Increases In absolute
and relative liver and kidney
weights In rats fed 5X DEHP (3 and
6 months; but not at 12 or 24 months)

Increased mortality In high-dose        Nlkonorow
group (75X); statistically slgnlfl      et al.. 1973
cant  Increase In relative liver
weight In low dose group (changes
In high dose group NR)

Increased mortality (30X vs. 10X.       Nlkonorow
controls); significantly decreased      et al., 1973
body weight; significantly Increased
relative liver weight; no hlsto-
loylcal changes

-------
                                                                            TABLE  5-7 (cont.)
o
—J
CD
      Species/Strain    Number  and  Sex
                       Dose. Vehicle and
                     Duration of Treatment
                                    Endpolnts Monitored
                                                  Effects
                                          Reference
Rat/Sprague-
Dawley
derived-CD
                        15M and  15F/
                        group
      Rat/CF-344/
      Cr/BR

      Rat/NR
Rat/NR




Rat/NR


Mouse/B6C3fl
1 Of/group


NR/male




NR/NR




NR/NR


SON and 50F/
group
Mouse/NR


Mouse
                        NR/NR


                        NR/NR
                   0. 0.2. 1.0 or 2.OX diet
                   (0. 150. 750. 1500 mg/kg/
                   day) for 17 weeks
1.2X diet for 3 or 6
months

0.02. 0.2. 2% diet for
-2 years
                                           500.  1000 ppn diet  for 48
                                           weeks
                                          0.5 mg/kg/day  (vehicle not
                                          reported)  for  6 months

                                          0. 3000. 6000  ppm diet
                                          (0. 672. 13?5  mg/kg/day.
                                          males; 0.  799. 1821 mg/kg/
                                          day,  females)  for 103 weeks
                              body weight, food consumption,
                              clinical signs of toxlctty.
                              serum biochemistry, hematology.
                              urlnalysls. gross and micro-
                              scopic pathology (major organs)
preneoplastl'c foci In liver
Induction of hepatic and
Mitochondria! peroxlsomes
                              NR
                              NR
                              body weight. Mortality, food
                              consumption, clinical signs of
                              toxlclty.  gross and microscopic
                              pathology
o
oo
                   500. 1000 ppm diet for 48     NR
                   weeks

                   0.5. 5 g/kg/day diet  for       NR
                   1-3 months
Reduced body weight gain and food
consumption (1. 2X); significantly
reduced packed cell volume (1.  2X);
significantly reduced hemoglobin
concentrations (1, 2X; males only);
significantly Increased relative and
absolute liver weight (0.?.  1.  ?X);
dose-related Increase In Incidence of
testlcular  damage (significant  at 1.
2X) and castration cells In  pituitary;
significantly reduced relative  and
absolute lestes weight (1. 2%)

None
Dose-related Induction of palmltoyl
CO-A dehydrogenase. carnttlne acetyl-
transferase; Induction of cytochrome
P-4SO {significant at ?X only)

Interstitial nephritis (more severe
at 1000 ppm than at 500 ppm);
Increased SGPT; decreased blood
glucose (500.  1000 ppm)

None; recommend 2.5 mg/t HjO based
on odor and taste

Moderately decreased body weight
gain In low- and high-dose females;
no effects on  food consumption;
Increased Incidence of seminiferous
tubule degeneration (1/49. 2/48.
7/49 for  0. low and high dose,
respectIvely)

No changes In  SGPT or blood glucose
                                                                  Degenerative  changes  In  kidneys  and
                                                                  liver
                                                                            Gray et al..
                                                                            1977;
                                                                            Gangolll, 1982
                                                                                                                                               Popp  et  al..
                                                                                                                                               1985

                                                                                                                                               Canning
                                                                                                                                               et al..  1985
                                                                                                          Nagasaki
                                                                                                          et  al..  1974
                                                                                                          Maslenko,  1968
                                                                            NIP. 198?b;
                                                                            Kluwe et al..
                                                                            1982b
                                                                            Nagasaki
                                                                            et al.. 1974

                                                                            Ota et al.,
                                                                            1974
CO
cr*

-------
                                                                           TABLE  5-/ (cont.)
     Species/Strain     Number  and  Sex
o
—I
CO
                       Dose.  Vehicle and
                     Duration of  Treatment
                                    Endpolnts Monitored
                                                  Effects
                                                                              Reference
     Ferret/aTblno
     Ferret/albino
     (1150-1850 g)
     Guinea  pigs/
     hybrid,  NOS
     Dog/Cocker
     Spaniel;
     Ulre-Halred
     Terrier
     Dog/mongrel
     Dog/NR
 o
 oo
 00
6-7/group
(sex NR)
6-7 males/
group
24M and 23F

23K and 23F

24H and 22F

4/group.
'randomly
separated by
breed and sex*
1 (sex NR)
1 (sex NR)
no concurrent
control

If; no con-
current control
0. IX diet for T4 months
0, IX (average - 1200 mg/
kg/day) diet for 14 months
0.13X diet for 1 year
(64 mg/kg/day)
0.04X diet for 1 year
(19 mg/kg/day)
OX diet for 1 year

gelatin capsules; 0.03
ml/kg 5 times/week for 19
doses, then 0.06 mi/kg/day
for 240 doses TWA .54.7
mg/kg/day; controls given
gelatin capsules only

0.06 mi/kg/day for 77
doses then 0.09 roi/kg/day
for 169 doses (gavage with
gelatin capsules) TWA --
79.3 mg/kg/day

5 g/kg/day (gavage) for
14 weeks
                                          0.1  g/kg  diet  for  14 weeks
biochemistry and ultrastructure
of the liver
enzyme activities. DMA content.
and protein In liver homogenate
and mlcrosomal fractions; llpld
peroxldatlon In mlcrosomal
fractions; microscopic (light
and EH) examination of liver
tissue; liver hlstochemlslry;
microscopic examination of
major tissues; body weight

body weight, mortality, food
consumption, hematology. liver
and kidney weights, hlstopatho-
logy (major organs)
body weight, liver and kidney
weight, sulfobromophthaleln
test, plasma prothrombln time,
plasma cholInesterase, gross and
microscopic pathology (major
organs)

same as above
body weight, hematology. gross
and microscopic pathology
(major organs)

body weight, hematology. gross
and microscopic pathology
                                                                                     Marked  enlargement  of  liver;  slgnlf-
                                                                                     Icantly decreased activities  of
                                                                                     succenate  dehydrogenase.  aniline
                                                                                     4 -hydroxylase.  and  mlcrosomal
                                                                                     glucose 6-phosphatase;  deci eased
                                                                                     AP activity In  centr I lobular  region;
                                                                                     Increased  AP In mtdzonal  region;
                                                                                     Increased  smooth endoplasmlc  retlc-
                                                                                     ulura and numbers of lysosomes  and
                                                                                     autophaglc  vacuoles

                                                                                     Significantly reduced  body  weight;
                                                                                     significantly Increased absolute
                                                                                     liver weight; morphological and
                                                                                     biochemical changes In  liver;
                                                                                     testlcular  damage
Significantly Increased relative
liver weight In females fed both
doses; no other effects
                                                                                     None
Fatty vdcuolatlon and congestion In
liver; cloudy swelling and conges-
tion In kidney
chronic cholecystitis; some hemosl-
derosls of spleen
                                                                  None
                                        lake et al..
                                        19/7a
                                        take et al.,
                                        1976
                                                                                                                             Carpenter
                                                                                                                             et  al.,  1953
                                                                                                                             Carpenter
                                                                                                                             et  al..  1953
                                                                            Carpenter
                                                                            et al.. 1953
                                                                                                                             Harris  et  a).
                                                                                                                             1955
                                                                                                          Harris  et  al.
                                                                                                          1955
     NR = Not reported;  NOS =  not  otherwise specified

-------
females were  continued  on test for  1  year more.   Groups  of 32 male  and  32
female progeny were  chosen  from the control and  high-dose  groups  and  placed
on the appropriate control or  high-dose  diet  for  1  year.   Hybrid guinea pigs
(~22-24/sex/group') were  fed  either  0,  0.04 or  0.13X  d! (2-ethylhexyl)  phtha-
late  In  the  diet (0, 19  or  64 mgAg/day)  for  1  year.  Groups  of  four  dogs
(wire-haired  terrier  and cocker  spaniel,  "randomly  separated  by  breed  and
sex") were  kept  as  controls or fed  gelatin capsules  equivalent to a  TWA  of
54.7  mg/kg/day  for  a total  of  259  dally doses (0.03 ma/kg  5  times/week  for
a  total  of  19 doses, then  0.06 ml/kg/day  for  240  doses).   One mongrel  dog
(sex  not  specified)  was given  gelatin  capsules equivalent  to a TWA of  79.3
mg/kg/day for  a  total  of 246  dally doses  (0.06 ml/kg  for  77 doses,  then
0.09  mi/kg   for   169 doses).   Body  weight,   mortality,  food  consumption,
fertility,  hematology,   liver   weights,   kidney  weights  and  hlstopathology
{major  organs)  were  monitored for  the  parental rats.   All  endpolnts  but
fertility were  assayed   for  the F   rats,  guinea pigs and  dogs.   In  addi-
tion, measurements of plasma prothrombln  time  and plasma  chollnesterase,  and
the  sulfobromophthalln  test  for  liver  function, were  performed   for  dogs.
Parental  male  rats   and  F.  males   and  females  fed  0.4X  d1(2-ethylhexyl)
phthalate  (200  mg/kg/day)   had significantly   Increased   liver  and  kidney
weights,  but  no  hlstopathologlcal  changes.    No  other   compound-related
effects  were  observed   In   rats.   Significantly  Increased  relative  liver
weight  without  accompanying  hlstologlcal change  was  observed   In  female
guinea  pigs  fed  0.04 or  0.13X d1(2-ethylhexyl)  phthalate  (19  or  64  mg/kg/
day,  respectively).   Fatty  vacuolatlon  and   congestion  In  the  liver,  and
cloudy swelling and  congestion  In the kidneys  were  observed 1n the dog given
a  TWA  dose  equivalent  to  79.3  mg  d!(2-ethylhexyl) phthalate/kg/day.   No
other effects were observed 1n dogs.
0783p                               5-28                             08/26/86

-------
    Gray  et  al.  (1977)  fed  either  0,  0.2,  1.0  or  2.0%  dl(2-ethylhexyl)
phthalate  to  groups  of  "15 male and  15  female  Sprague-Dawley derived CO rats
for  17  weeks.   Dietary  concentrations  were  equivalent  to  0,  150,  750  and
1500  mg/kg/day  as reported  In a  subsequent  review  (Gangolll,  1982).   Body
weight,  food  consumption,  clinical  signs  of  toxldty,  serum  biochemistry,
urlnalysls  and  hematology  were  monitored  (Gray  et  al.,  1977).    Gross  and
microscopic pathology were  performed on  all animals  at  the end of the study.
Effects  were  observed   at   all   levels  of   exposure   to  d1(2-ethylhexyl)
phthalate.  Significantly  Increased  absolute and  relative liver  weights were
observed  In all  dl(2-ethylhexyl)  phthalate-exposed  groups.  Food  consumption
and  growth  were  reduced  In  rats  fed  either  1  or  2%  d1(2-ethylhexyl)
phthalate.   In . comparison  with  controls,  significantly  reduced  testkular
weights,  significantly  Increased  testlcular  damage  (dose-related)  and  a
significant decrease  In  hemoglobin concentration were  observed  In  male rats
fed either  1  or   2%  d1{2-ethylhexyl} phthalate.   Both  males and  females  fed
either 1 or 2% dl(2-ethylhexyl)  phthalate  had  a  significantly  reduced packed
cell  volume  In  comparison  with  controls.  Nagasaki  et al. (1974)  reported
that  Interstitial nephritis.  Increased  SGPT and  decreased blood  glucose were
observed  In  rats fed  either  500  or 1000 ppm d\(2-ethylhexyl) phthalate  In
the  diet   for  48 weeks.   The  dietary  levels  are  equivalent  to  25 or  50
mg/kg/day, respectively, assuming  that  a rat consumes a dally  amount of food
equal to 5% of Its body weight.  No other details were available.
5.5.2.   Dlethyl   Phthalate.   Toxldty  studies   of  dlethyl  phthalate  are
summarized  In Table 5-8.   U.S.  EPA   (1980a)  summarized  a  study  by  Food
Research Laboratories  (1955)  1n  which  groups  of  30  rats  (strain  and sex  not
reported) were fed  dlethyl phthalate  at concentrations of  0.5,  2.5  or  5.0%
for  104 weeks.   The dietary  levels  are  equivalent  to  250,  1250  or  2500
mg/kg/day, assuming a dally food  consumption equal  to 5% of  the body weight.

0783p                               5-29                             08/26/86

-------
                                                      TABLE 5-8

                                     Oral Toxlclty Summary for Dlethyl Phthalate
co
CO
•o

Species/ Number and
Strain Sex

Rat/NR 30/group
(sex NR)

Dose.
Vehicle and
Duration of
Treatment
0.5, 2.5 or
554 diet for
104 weeks


Endpolnts Monitored Effects

NR Small but significant
reduction In body
weight gain for rats
fed 5X DEP; food con-
sumption was not affected

Reference

Food Research
Laboratories ,
1955

     Rat/CD
CO
o
o
CD
15 H and
15F/group
0, 0.2, 1.0
or 5% diet
for 16 weeks
body weight, food
consumption, water
Intake, hematology.
urInalysls, serum
biochemistries,
gross and mUro-
scoplc pathology
Significantly reduced
body weight (males and
females, 5X; females,
IX)
Brown et al.,
1978
Oog/NR







3

1

1

3

(sex

(sex

(sex

( sex

NR)

NR)

NR)

NR)

0.5X diet NR
for 1 year
1.5X diet
for 1 year
2. OX diet
for 1 year
2.5X diet
for 1 year
None Food Research
Laborator
1955





ies,






     NR = Not reported
CD

-------
The  only  effect  observed  was  a  small  but  significant reduction  In  growth
rate among  rats  fed 5% dlethyl phthalate.   Food  consumption  was not affect-
ed.  U.S.  EPA (1980a) did  not  report which endpolnts  were monitored  1n the
study.
    Food Research  Laboratories  (1955) also fed dlethyl phthalate  to dogs  at
concentrations of  0.5% (three dogs),  1.5% (one dog),  2.0% (one dog) and 2.5%
(three  dogs)  for  1  year.   Food  consumption  varied  throughout  the  study;
average doses as  provided  1n  the  study were  114,  343, 500 and 629 mg/kg/day.
No  effects  were  observed  at any  level  of  exposure.  Again,  the  endpolnts
which were monitored 1n the study were not reported.
    Brown et  al.  (1978)  fed groups of  15 male and 15  female  CD rats  either
0,  0.2,  1.0  or   5.0%  dl(2-ethylhexyl)   phthalate  (0,  150,  770  or  3160
mg/kg/day, males;   0,  150,  750 or  3710 mg/kg/day,  females)  1n  the diet  for  16
weeks.  Variables  that were monitored 1n  the  study Include  body weight, food
consumption, water  Intake,  hematology,  urlnalysls, serum  biochemistries, and
gross and microscopic  pathology.   Terminal  body  weights  of male  and  female
rats fed 5%  dlethyl phthalate and female  rats  fed 1% dlethyl  phthalate were
reduced significantly  In comparison  with controls.  Paired  feeding studies
Indicated that  these  reductions  were  not  due  to  decreased  food consumption.
In comparison with controls,  statistically significant  decreases 1n absolute
organ  weights  (brain,  heart,  spleen,  kidneys)   and  Increases  In  relative
organ weights (brain,  liver,  stomach,  small  Intestine,  full calcium, testes,
kidneys) were observed 1n  males  and  females  fed  5.0%  dlethyl  phthalate for
16 weeks.   These  changes were  attributed to the  compound-related  effect  on
growth  rate  since  dose-related  changes   1n gross or  microscopic  pathology
were observed.  No other  effects were observed.
0783p                               5-31                             08/26/86

-------
5.5.3.   01-n-butyl  Phthalate.   The  oral  toxldty of  d1-n-butyl  phthalate
has  been  tested  1n  rats  (Smith,  1953;  Nlkonorow et  al.,  1973;  Maslenko,
1968;  Lefaux,  1968;  Plekacz,  1971;  LeBreton, n.d.;  Bornmann et al.,  1956)
and  mice  (Ota  et  al.,  1974).   These studies are  summarized In Table  5-9.
The  only  Investigators who  reported  effects  are Smith  (1953),  Ota et  al.
(1974) and Nlkonorow et al. (1973).
    Smith  (1953)  fed  either   0,   0.01,  0.05,  0.25,  or  1.25%  d1-n-butyl
phthalate 1n  the diet  to  groups  of  10 male Sprague-Dawley rats  for  1  year.
Equivalent doses  using  a   factor  of  5% are 0,  5,  25, 125  or  625 mg/kg/day.
Endpolnts monitored  Include body  weight,   food  consumption,   hematology  and
gross  and microscopic pathology.   The  only  effect  observed  was 50% mortality
during the first week of the study among rats  fed 1.25% d1-n-butyl phthalate.
    Increased  relative liver  weight  1n  the absence  of  hlstopathologlcal
liver  lesions were  observed  In  rats  treated with 120  or  1200  mg/kg/day  for  3
months  (Nlkonorow  et al.,  1973),   Degenerative changes  1n the  kidneys  and
liver  were  reported  to occur  1n  mice fed  500  or  5000 mg  d1-n-butyl  phtha-
late/kg/day In  the  diet for  1-3  months  (Ota  et  al.,  1974).   No other details
were given.
5.5.4.   Dimethyl Phthalate.  Lehman  (1955)  fed  groups of  rats  (number,  sex
and  strain  not  reported)  dimethyl phthalate at  levels  of 2,  4 or  8%  1n  the
diet  (1000, 2000 or  4000 mg/kg/day  using a  food  factory  of  0.05)  for 2  years
(Table 5-10).   U.S.  EPA (1980a) Incorrectly attributed this  study  to  Oralze
et  al.  (1948).   No  effects   were   observed  among  rats  fed  2%  dimethyl
phthalate.  A  minor  effect  on  growth was  observed  at 8%, while "nephritic
Involvement" (U.S. EPA, 1980a)  was observed at 4 and  8%.
0783p                               5-32                             10/09/87

-------
                                                                             TA. . 5-9

                                                           Oral  loxtclty Sumnary for  Dl-n-butyl  Phlhaldte
CD
CO
•o
Species/
Strain
Rat/Sprague-
Oawley
Number and
Sex
10 M/group
Dose, Vehicle and
Duration of Treatment
0. 0.01. 0.05. 0.?5
or 1.25X diet for 1
year
Endpolnts fkmltored
body weight, food consumption.
heoatology. gross and micro-
scopic pathology (Major organs)
Effects
50% mortality In first week In
1 . ?SX group
Reference
Smith. 1953
          Rat/Wlstar
          Rat/Ulstar
          Rat/Wlstar
 tn
 i
 CO
 CO
Rat/NR
                 10 M and       0.  0.1? or  1.20 g/kg/
                 10 f/group     day for 3 Months
                 ?0 H and       0 or 0.125X diet  for
                 20 F/group     1 year
40 H and       0 or 1250 ppn for
40 F/group     7-12 Months (30 rats/
               group killed after  7
               Months; the renalntng
               rats were killed after
               12 Months)

NR/NR          0, 100. 300 ppn diet
               for 21 Months
body weight, behavior, hemato-
logy. serum proteins, gross and
Microscopic exaMlnatton of liver,
kidney and spleen

body weight, behavior, hemato-
logy, serun proteins, gross and
Microscopic examination of liver,
kidney and spleen

body weight; kidney, liver and
spleen weights; SCOT and SGP1
activities
                                                          NR
                                                                Increased relative liver  weight
                                                                (0.12 and 1.20 g/kg/day); no
                                                                changes  In pathology of liver
                                                                or other  tissues

                                                                No compound-related hematologl-
                                                                cal or hlstologlcal changes;
                                                                4/40 and  6/40 controls and
                                                                treated  rats  died, respectively

                                                                None
                                                                                                None
                                                                                                                  Nlkonorow
                                                                                                                  et  al.,  1973
                                                                                                                  Nlkonorow
                                                                                                                  et  al.,  1973
                                                                                                                                   Plekac*.
                                                                                                                                   1971
                                                                         LeBreton.
                                                                         n.d.
          Rat/NR
          Rat/NR
          Rat/NR
                 NR/NR
                 NR/NR
                 NR/NR
 CO
          Mouse/NR
                 NR/NR
500 ppn diet for 15       NR
months; 500 or 1000
mg/kg (2 times/week)
by gavage (vehicle NR)
for 1 year

2.5 mg/kg/day for 6       NR
months (vehicle NR)

100 mg/kg/day for 21      NR
months or 5 genera-
tions; 300 mg/kg/day
for 21 months or 3
generations; 500 mg/
kg/day for 15 months
or 3 generations

0.5. 5 g/kg/day diet      NR
for 1-3 months
                                                                                                          None
                                                                                                          None
                                                                               'No carcinogenic  or  poisonous
                                                                               effects'
                                                                               Degenerative changes In kidney
                                                                               and liver
                                                                                                                  Bornmann
                                                                                                                  et  al..  1956
                                                                         Maslenko.
                                                                         1968

                                                                         Lefaux. 1968
                                                                         Ota et al.,
                                                                         1974
          NR = Not reported

-------
                                                                           TABU 5-10

                                                     Oral  Toxlclty  Summary  for Miscellaneous Phthalate Esters
CD
CO
•o
Ester
Dimethyl
phthalate
Species/
Strain
rat/NR
Number and
Sex
NR/NR
Dose. Vehicle and Endpotnts Honltored
Duration of Treatment
2. 4 or 8% diet for 2 NR
years
Effects
•Minor' effect on growth at
4 and 8%; 'some Indication of
nephritic Involvement* at 8%
Reference
Lehman,
1955*
         Dllsononyl
         phthalate
              rat/NR
                       dog/NR
 I
 CO
n-Butyl
benzyl
phthalate
                       rat/NR
                       rat/F344
 o
 CO
n-Butyl
benzyl
phthalate
                       mouse/
                       B6C3F1
                       dog/NR
h and F
(numbers NR)
4 N and F
(not clear
whether 4
dogs/group or
4 dogs total;
appears to be
4 dogs total)

NR. NR
                          50 H.  50 F/
                          group
                          50 H. 50 F/
                          group
                                   NR/NR
0. 50. 150. 500 ing/leg/
day for 13 weeks
(vehicle NR)
                                           0.  0.125.  0.500% for
                                           13  weeks;  2% for 8
                                           weeks  then Increased
                                           to  4%  for  remaining  5
                                           weeks  (TWA . 2.8%)
0. 0.25. O.S. 1.0. 1.5
or 2.OX diet for 90 days
                 0. 6000 or 12.000 ppm
                 diet for 103 weeks
                 (females) or 28 weeks
                 (males)
                 0. 3000 or 6000 ppn
                 diet for 103 weeks
                 0. 1. 2 or 5% diet In
                 capsule form for 90
                 days
                                                                              NR
                                                                              NR
growth, heutology.
urlnalysls. gross and
Microscopic pathology
                          body weight,  food con-
                          sumption, mortality.
                          clinical signs of toxlc-
                          Ity. gross and micro-
                          scopic pathology
                          body weight, mortality.
                          clinical signs of tox-
                          Iclty. gross and micro-
                          scopic pathology

                          weight gain, mortality.
                          food consumption, hema-
                          tology. urlnalysls.
                          liver and kidney function
(50. 150 mg/kg/day) no effects    Livingston,
(500 mg/kg/day) slight reduc-     1971
tlon In growth rate. Increased
liver weight (NOS)

(0.125X) no effect; (O.SX)        Livingston.
questionable Increased liver      1971
weight (NOS); (2.8X) decreased
body weight; Increased liver
weight, hlstologlcal changes
In liver, gall bladder, spleen
and kidney

0.25-0.5%; no effects; (1.50%)    Honsanto.
slightly reduced growth rate;     1972
(2.OX) slightly reduced growth
rate;  Increased liver weight
(1-2.OX) but no hlstopatho-
loglcal changes were observed

Increased mortality associated    NIP.  1982a
with 'unexplained Internal
heroorrhaglng' In treated male
rats only; slightly reduced
body weight  In treated females
accompanied by reduction  In
food consumption

Reduced body weight In treated    NTP.  1982a
males and females; no data on
food consumption
                             Initial reduction In body         Monsanto,
                             weight due to refusal to eat      1972
                             (5X group only)
 co

-------
                                                                      TABLE 5-10 (conl.)
00
CO
•o
          Ester
              Species/
               Strain
 Number and
    Sex
  Dose.  Vehicle and
Duration of Treatment
   Endpolnts Monitored
           Effects
                                                                                                                                    Reference
        Ot-n-octyl
        phthalate
              rat/
              Ulstar
                      mouse/
40 H and
40 f/group
                          pairs of 20
                          M and f/group
0 or 3SOO pp* diet for
7-12 months (30 rats
killed after 7 months;
remainder killed after
12 months)
                 1.25.  2.5 or  5X In
                 diet for  2 generations
body weight; kidney,
liver and spleen weights;
S&OT and SGP1 activities
                          number  of 1Itters/patr.
                          X pups  born alive,  live
                          pup weight, weight  at
                          weaning,  mating behavior.
                          reproductive performance.
                          sperm counts
Elevated relative liver weight
(females at 7 and 12 months);
elevated relative kidney weight
(females at 12 months); signi-
ficantly elevated SCOT and SGPT
(males and females at 12 months)

None
Plekdc;,
19/1
                                                               Gulall  et
                                                               al.,  1985
tn
i
tn
•U.S. EPA (1980b) Incorrectly attributed these  data  to  OraWe  et al.  (1948)

NR * Mot reported; NOS ~ not otherwise specified
O
vD
co

-------
5.5.5.   D11sononyl  Phthalate.    Livingston   (1971)  exposed  rats  and  dogs
orally  (method  not  specified)  to  dllsononyl  phthalate  for  13 weeks  (see
Table 5-10).  Male and  female rats  (strain,  numbers  not  reported) were given
0,  50,   150  or  500  mg/kg/day.    No  effects  were  observed  among  low- and
middle-dose  rats.   Increased  liver weight and  a slight reduction  In  growth
rate  were  observed among high-dose rats.   Dogs were given 0,  0.125  or  0.5%
dimethyl  phthalate for  13  weeks,  or  2% for  8 weeks followed  by  4% for  5
weeks (TWA  2.8%).  Dogs  given a TWA concentration  of 2.8% dimethyl  phthalate
had   decreased  body  weights,  Increased  liver  weights,   and  hlstologlcal
changes  in  the  liver,  gall  bladder,  spleen  and kidneys.   Assuming a  dog
consumes  a  dally amount of  food  equal  to 2.5% of  Us body  weight  (Durkln,
1985),  the TWA  concentration  Is   equivalent  to 700 mg/kg/day.  No  effects
were  observed among  low-dose  dogs (31.25  mg/kg/day),  but middle-dose  (125
mg/kg/day) dogs had Increased liver weights.
5.5.6.   n-Butyl   Benzyl  Phthalate.    NTP   (1982a)   fed   n-butyl   benzyl
phthalate  to  female F344 rats at  concentrations of 0,  6000 or 12,000 ppm and
B6C3F1  mice  of  both  sexes  at  concentrations  of  0, 3000  or 6000  ppm  (see
Section  5.1. for  doses) for 103 weeks.   The  only  noncardnogenlc  effects
observed  In  female rats and  male and female mice were  reductions  In growth
rate  (see  Table  5-10).   Growth rate reduction In female rats  was accompanied
by reduced  food  consumption.  Data  on food  consumption  were not reported for
mice.   Male F344  rats  were  also  fed 0,  6000  or  12,000 ppm n-butyl  benzyl
phthalate,  but  the  study  was  terminated  after  28 weeks  because of  high
mortality  among   treated  rats.    Mortality   was  attributed  to  unexplained
hemorrhaglng.
 0783p                               5-36                             08/26/86

-------
    Krauskopf  (1973)  reported  90-day  feeding  studies  on  rats  and  dogs
(strains,  sex,  numbers  not  reported)  conducted  by  Monsanto  (1972).   Rats
were fed  0,  0.25,  0.5,  1.0, 1.5 or 2%  (0,  125,  250,  500, 750 or  1000 mg/kg/
day, assuming  a food  Factor  of 0.05)  n-butyl  benzyl  phthalate,  while  dogs
were fed 0,  1,  2  or  5%  (0,  250, 500 or  1250  mg/kg/day,  assuming  a  food
factor  of 0.025) n-butyl benzyl  phthalate.   No  adverse  effects  were observed
among dogs  fed n-butyl benzyl  phthalate at  any  level, or  among rats fed  0.25
or  0.5%  n-butyl benzyl  phthalate.   Increased  liver  weights without  accom-
panying  hlstopathologlcal  changes  were observed among  rats  fed  1-2% n-butyl
benzyl   phthalate.    Slightly  reduced   growth  rate  was  observed  at  the  two
highest  doses.   In  a  draft   report.  NTP  (1985)  conducted  a  toxldty  and
mating  trial study  In F344  rats  concomltantly.   The toxldty portion of  this
report  was  conducted  to  determine  the  no toxic  effect  level  and  to evaluate
the dose response  of BBP.  Rats  were  administered concentrations  of  either
0, 0.03, 0.09, 0.28, 0.83  or  2.50% BBP 1n the diet for  26 weeks.   There  were
15 male  animals  1n  each  dose  group,  starting at  6 weeks  of  age.   Throughout
the  study,   body  weight  gain  was   significantly  depressed   at  the  2.5%  BBP
level when  compared with the  controls.   There  were  no deaths  attributed  to
BBP  toxIcHy.   All  the  rats  given  2.5% BBP  had small  testes   upon gross
necropsy at  the 26-week  termination.   Five of  11  had  soft  testes  and  only
1/11 had a  small  prostate  and seminal  vesicle.   In  the 0.03, 0.09,  0.28  and
0.83%  BBP   dose  groups  there were  no  grossly observable   effects  on  male
reproductive organs.  The kidneys  of  six  animals  1n the 2.5% group contained
focal  cortical  areas   of   1nfarct-l1ke  atrophy.   In  addition,   testlcular
lesions  were   also  observed  at  the  2.5%  dose  level.    Lesions   were
characterized  by  atrophy  of  seminiferous  tubules  and  aspermla.    The other
treatment  groups  showed  no  evidence  of  abnormal morphology  1n any other
organs.

0783p                               5-37                             08/31/87

-------
    H1stopatholog1cal changes were  also  seen at the  2.5%  BBP  level  after 10
weeks of  exposure  In the maUng  trial portion of  this  study.   After  hlsto-
pathologlcal  examination,  testlcular  lesions  were characterized  by  atrophy
of seminiferous tubules and a near  total  absence  of mature sperm production.
When 10/30  females  successfully mated with  the 2.5%  treatment  level  males,
none were  pregnant  at necropsy.  The  Investigators concluded that  the  data
suggest a  depression In  male reproductive  organ  weights  by either  a  direct
or Indirect toxic effect after  2.5% BBP  administration.   BBP  at  0.83% In the
diet did  not  result In  any  treatment-related effects  as evaluated  by  the
authors.  The  Investigators concluded  from the results  of  both  studies  that
a threshold for toxlclty  would be between 0.83 and 2.5% BBP.
    In contrast to the author's conclusions,  some  alterations  1n animals fed
0.83%  BBP  were  noted which  may have been  compound related  1n that  they
occurred In  the  2.5% group also,  but  not In  lower  exposure  groups.   Liver-
to-body weight ratios were significantly  Increased  In both the  0.83  and  2.5%
diet groups,  while   llver-to-braln  weight  ratio was  Increased  In the  0.83%
group alone.   Absolute  liver  weight was  also Increased In the  0.83%  group.
Hematologlcal  evaluations  showed small  but  significant  elevations  In  mean
corpuscular hemoglobin 1n  the 0.83% group  at  60,  90, 120 and 150 days,  but
not at  30  or  180 days,  while mean  corpuscular hemoglobin concentration was
Increased  at  60  and  120  days.    Interestingly,   no alterations  In  these
parameters  was seen  1n  the  lower   dose  groups.    The  2.5%  group showed  a
consistent  pattern  of Increased  retlculocytes, decreased red   blood  cells,
Increased mean corpuscular volume,  Increased mean  corpuscular  hemoglobin and
hemoglobin  concentration  1n  addition  to  reduced  cellularlty  of  the  bone
marrow.
0783p                               5-38                             08/31/87

-------
5.5.7.   01-n-octyl  Phthalate.   A  Polish  abstract  (Plekacz,  1971)  reports
that groups of 40  male  and  female  rats  (strain not reported) were fed either
0 or  3500  ppm (0  or  175  mg/kg/day,  using  a food  factor  of  0.05)  d1-n-octyl
phthalate  In  the diet  for  7-12  months.   Elevated relative  liver  weight  was
observed  among  d1-n-octyl  phthalate-treated  females  at  7  and   12  months.
SGOT and  SGPT were  significantly  Increased  1n both males and  females  at  12
months.   Increased kidney weight  was  reported among  females  at   12  months.
Effects on  spleen  weight  or body weight were  not  observed.   Hlstopathologl-
cal  examination was apparently not performed.
5.5.8.   Human  Studies.  The  health  status  of   147  workers  who   handled
phthalate plastldzers  was  evaluated  by  Mllkov et al. (1973).  Workers were
exposed to  a  mixture of  compounds Including  d1-n-butyl  phthalate,  OAP-789,
d1-n-octyl  phthalate,   dllsooctyl  phthalate,  n-butyl   benzyl   phthalate,
seladnates,  adlplnates,  vinyl  chloride, carbon  monoxide amd  mixed  ethers.
Phthalate exposure was  estimated  to  be  1-40  mg/m3.   Effects  attributed  to
phthalate exposure  Included polyneurUls (frequency and  Intensity Increased
with duration of employment), decline  1n vestlbular  and  olfactory  excitabil-
ity  and  reductions In thrombocytes, leukocytes, hemoglobin  and "blood  color
Index."
    GIHoll et al. (1978) performed clinical  neurological  electromyographlc
and   electroneurologlc  tests  on  38  workers  In   the  phthalate  plastldzer
Industry.    Of  the  38 workers, 23  had  been  exposed only  to  phthalate esters
(not  otherwise  specified)  for  an  average  of   4.5  years;  the  remainder  had
been  exposed   only  to  alcohols  or  only   to   phthallc  anhydride.   Ambient
concentrations of  phthalate esters were  
-------
motor types.  The  frequency  and  severity Increased wHh  length  of  exposure;
no cases were found 1n workers exposed for <2 years.
    Aldyreva et  al.   (1974)  reported an  Increase  In  the Incidence  of  mis-
carriages and menstrual disorders among women  exposed  to  phthalate  esters  In
the  synthetic  leather  Industry.   Details concerning the  exposed  and  control
populations were  not  given.   Thless  et  al.  (1978) examined  morbidity  among
101 workers employed  In  the  production  of d1(2-ethylhexyl) phthalate  for  an
average  of  12  years   (range=4  months to  35  years).   Exposure  ranged  from
0.0006-0.01  ppm  (0.01-0.16  mg/m3).   There  was  no   evidence  of  a  higher
Incidence of miscarriages  or deformities  of offspring among  female  workers
or  the   wives  of  male  workers.    No other   compound-related  effects  were
observed, though dl(2-ethylhexyl) phthalate was  found  1n  the  blood  and  urine
of both exposed and control  groups.
5.6.   OTHER RELEVANT  INFORMATION
    Acute oral  toxlcltles for phthalate  esters are summarized  1n Table 5-11.
5.7.   SUMMARY
    D1(2-ethylhexyl)   and n-butyl   benzyl  phthalates  have been  tested  for
carcinogenic potential  In  feeding  studies  with  F344  rats and  B6C3F1  mice.
D1(2-ethy1hexyl) phthalate was  found to cause  Increased  Incidences  of  liver
neoplasms 1n both  rats  and  mice (NTP, 1982b;  Kluwe et al.,  1982b).   n-Butyl
benzyl  phthalate  caused an   Increase  1n myelomonocytlc  leukemia  In  female
F344  rats  (NTP,  1982a).  Because of high background  Incidence  of myelomono-
cytlc  leukemia  1n  F344  rats   and  because  dose-related  and  significant
decreases 1n malignant lymphoma, all  lymphoma,  and leukemia or  lymphoma were
observed 1n male B6C3F1 mice  (NTP,  1982a),  there 1s only  limited evidence  to
conclude that n-butyl  benzyl  phthalate 1s carcinogenic.
0783p                               5-40                             08/31/87

-------
                                  TABLE 5-11



                    Acute  Oral  Toxlclty of  Phthalate Esters
Phthalate Ester
D1(2-ethylhexy1)
Dimethyl
Dlethyl
Dlbutyl







n-Butyl benzyl
D1-n-octyl
Dlhexyl
Dlnonyl
Oldecyl
Species
rat
rabbit
guinea pig
mouse
rat
mouse
rabbit
guinea pig
rat
rabbit
rat




mouse
mouse (H)
mouse (M)
rat (MiF)
mouse (M)
mouse (F)
rat
rat
rat
rat
LD50
26 g/kg
33.9 g/kg
26.3 g/kg
33.5 g/kg
6.9 ma/kg
7.2 mi/kg
4.4 mi/kg
2.4 mi/kg
8.2 ml/kg
1.0 g/kg
23.0 g/kg
12.5 g/kg
14.95 g/kg
-8 g/kg
>20 ml/kg
9 g/kg
14.8-17.0
9.77 g/kg
2.33 g/kg
6.16 g/kg
4.17 g/kg
>13 g/kg
29.6 g/kg
>2 g/kg
>64 g/kg
Reference
Krauskopf, 1973
Shaffer et al., 1945
Krauskopf, 1973
Krauskopf, 1973
Dralze et al., 1948
Dralze et al. , 1948
Dralze et al., 1948
Dralze et al., 1948
Krauskopf, 1973
Sandermeyer and Klrwln, 1981
Radeva and Dlnoeva, 1966;
Gesler, 1973
Homrowskl and Nlkonorow, 1959;
Nlkonorow et al., 1973
Komarova, 1979
Smith, 1953
Lehman, 1955
Komarova, 1979
Oraorl, 1976;
Yamada et al., 1975
Mlyahara et al., 1973;
Omorl, 1976
NTP, 1982a
NTP, 1982a
NTP, 1982a
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
0783p
5-41
08/31/87

-------
    The  mutagenklty  and  genotoxklty  of  phthalk  acid  esters  have  been
reviewed by  Thomas  and Thomas  (1984) and  Hopkins  (1983).   D1-2(ethylhexyl}
phthalate and metabolites have yielded mostly negative results In Ames tests
with S.  typhlmurlum,  and mixed results  with j_n  vitro and  hi  vivo  tests  of
genotoxklty.  Dlethyl phthalate, dimethyl  phthalate,  and  d1-n-butyl  phtha-
late were found to  be  mutagenk  1n  in vitro mkroblal assays  with S.  typhl-
murlum (Kozumbo et  al.,  1982;  Rubin  et al.,  1979; Seed, 1982).
    Oral  studies   have   shown  that  d1(2-ethylhexyl)   phthalate,  dl-n-butyl
phthalate,  and  dl-n-heptyl  phthalate can  produce  adverse  effects  upon  the
developing  fetus when  mice and rats are  exposed during gestation  (Wolkowskl-
Tyl, 1984a,b;  Bell  et  al.,  1979; Bell,  1980;  Shlota  and M1ma, 1985;  Shkta
and N1sh1mura,  1982;  Shlota  et  al.,  1980;  Nakamura  et  al.,   1979; Yag1  et
al., 1978,  1980;  Tomlta  et  al.,  1982b;  Onda  et  al., 1974).   Whether  the
observed effects (reduced fetal  weight, fetal  mortality, gross external  and
skeletal malformations)   represent  a  primary   effect of  the  compound  )n
question or  whether they occur as a result  of maternal  toxklty has  yet  to
be  demonstrated unequivocally.   Studies  conducted  by  NTP  (Wolkowsk1-Tyl  et
al., 1984a,b) Indicate that mice  are more sensitive than rats.
    NTP  has  recently  conducted  reproduction  and  fertility   assessments  on
CD-I mke for dlethyl  phthalate (Reel et al., 1984) and d1-n-octyl phthalate
(Gulatl  et   al.,  1985).   Dietary  d1-n-octyl  phthalate  had  no  effects  on
reproduction  and   fertility  among  parental  or  F,  mke.   Dietary  dlethyl
phthalate had no effects on reproduction and fertility 1n parental mke,  but
dlethyl  phthalate-exposed F,  mke had fewer pups/litter than did controls,
as  well  as  Increased  liver  weights  (males  and  females),  Increased prostate
weights,  Increased pituitary  weights  (females  only)  and decreased  sperm
concentrations.  Booth  et  al. (1983) and  Plasterer  et al.  (1985)  reported
that  dimethyl   phthalate  had  no  effects  on  reproduction 1n  CD-I  mke.

0783p                               5-42                             08/31/87

-------
Dimethyl  phthalate  was  administered  by  gavage  on  days  7-15 of  gestation.
The fertility  of  Sherman rats was not  affected  by dietary administration  of
dl(2-ethylhexyl)  phthalate  (up  to  0.4%)  for  1-2  years  (Carpenter et  al.,
1953).
    Orally   administered  d1(2-ethylhexyl),   d1-n-butyl,   n-butyl   benzyl,
dl-n-pentyl, d11sobutyl  and  d1-n-heptyl phthalates have been  shown  to  cause
testlcular atrophy  In  rats to  mice  (Gray et  al.,  1977,  1982;  Shaffer et al.,
1945;  Gangolll,  1982;  01shl  and  Hlraga,  1980a,  1983; Gray and  Butterworth,
1980;  Mangham  et al.,  1981;  Olshl,  1985;  Agarwal et  al.,  1985;   Foster  et
al.,  1980).  01-n-octyl, dimethyl,  dlethyl, dlpropyl and  d1-n-heptyl  phtha-
lates  did  not  cause testlcular atrophy  In rats  (Gray and  Butterworth,  1980;
Foster  et  al., 1980).   Species  differences  In phthallc add  ester-promoted
testlcular atrophy  have  been  observed.   Gray et  al.  (1982)  failed  to observe
testlcular atrophy  in  hamsters gavaged  with  dl-n-butyl,  d1(2-ethylhexyl) and
d1-n-pentyl  phthalates  at  doses  equlmolar  to  those  that  caused atrophy  In
rats.    In  the  same  study,  mice  gavaged with equlmolar doses  of d1-n-butyl,
d1(2-ethylhexyl) and dl-n-pentyl  phthalates had only slight focal atrophy.
    Chronic  or  subchronlc  oral studies have been  conducted with d1(2-ethyl-
hexyl),   d1-n-butyl,  dimethyl,  dllsononyl,  n-butyl  benzyl  and  dl-n-octyl
phthalates  (Carpenter  et al., 1953;  Harris  et  al., 1955;  Nlkonorow et  al.,
1973;  Gray  et  al.,  1977; Gangolll,  1982; NTP, 1982a,b; Kluwe  et al.,  1982b;
Shaffer  et  al.,  1945;  Popp et al.,  1985;  Canning et al.,  1985; Nagasaki  et
al.,  1974;  Ota  et al., 1974;  Lake et al., 1976,  1977a; Maslenko,  1968;  Food
Research Laboratories, 1955;  Brown  et al., 1978;  Smith, 1953; Lefaux,  1968;
Plekacz,  1971;  LeBreton,   n.d.;  Bornmann  et   al.,   1956;   Lehman,   1955;
Livingston,  1971; Monsanto,  1972).   Liver, kidneys  and  testes appear  to  be
target  organs.   Occupational   exposure   to  phthalate esters  has  been  asso-
ciated wlh polyneuropathy (Mllkov et al., 1973;  G1l1ol1  et  al., 1978).

0783p                                5-43                             08/31/87

-------
    Acute  oral   LD5Qs  have  been  reported  for  d1(2-ethylhexyl),  dimethyl,
d1-n-butyl,  dlethyl,  n-butyl   benzyl,   d1-n-octyl,   dlhexyl,   dlnonyl   and
dldecyl phthalates.   These values are summarized 1n Table 5-11.
0783p                               5-44                             08/31/87

-------
                             6.   AQUATIC TOXICITY

    Many aquatic  toxIcHy tests wHh  phthalate esters have  used  concentra-
tions  greater  than  the  aqueous  solubility  of these  compounds.   In  these
cases, H 1s necessary  to determine  1f  toxic  effects  occur  at concentrations
that  are  environmentally plausible.   Some  Investigators  have  used  carriers
or solvents  to dispense or  emulsify phthalate  esters  In  water,  and  thus  may
have  Influenced toxlclty  by  Increasing phthalate availability.   Furthermore,
the  carriers  or  solvents may  have  toxic  effects  of  their  own (Sugatt  and
Foote. 1981 ).
    Another  concern In  Interpreting  the  results  of aquatic  toxlclty  tests  Is
that  some  phthalate  esters  (such  as  n-butyl  benzyl  and d1-n-butyl  phtha-
lates)  are   rapidly   blodegraded  1n  natural   waters   (t     <2  days);  such
exposure  conditions  could   change   significantly  during  a  96-hour  static
bloassay.  Of  32  acute  toxlclty  studies with  phthalate  esters reviewed  by
Sugatt  and  Foote  (1981), 28  were  static  exposures,  and  all   results  were
based  on  nominal  rather than measured concentrations.  This  Illustrates  the
need for caution  1n applying these  results to environmental  situations.
6.1.   ACUTE
    Data concerning the  acute toxlclty of phthalate  esters  to aquatic  verte-
brates and  Invertebrates  are presented 1n Tables 6-1  and 6-2,  respectively.
The  ranges  of acute  LC,Q or  EC,-  values  1n  the  various  phthalate  esters
are  presented  In  Table  6-3.  Four  of  the  esters had LC5Q values  for  only
one  species.   The  other  esters  had  a fairly  wide  range  of values.   Ten  of
the  esters   had  LC_n  or EC,n  values  <10  mg/i. In  at  least   one  species.
Six  of  the esters  were  acutely   toxic  at  concentrations  of  <1.0  mg/n..
0784p                               6-1                              06/06/86

-------
                          TABLE 6-1



Acute Toxlclty of Phthallc Acid Esters to Aquatic Vertebrates
o
GO

T3












CT
1
ro














O
LT>
^
en
>^
CD



Species Chemical


Fathead minnow BBP
Plmephales promelas


DBP



OOP
DUP

S-7903
Golden orfe DAP
Leuclscus Idus melanotus
DEP
Goldfish BBP
Carasslus auratus
DBP
DEHP
OOP
Rainbow trout BBP
Salmo qalrdnerl
OBP


DEHP




Toxic
Concentration
<»g/i)

2.1
2.25
2.32
5.3
1.0-1.8

1.30
2.02
10
>}QQO

1000
0.4

61
200

1-12
NR
200b
3.3

1.2-1.8
2.6
6.47
>100
540




note
(«g/t)
FRESHWATER
1.0
<1.06
NR
2.2
0.56

NR
NR
3.2
NR

NR
0.3

11
100

0.5
200
NR
<0.36

>0.5. <2.0
NR
NR
NR
230




Effect Measured

SPECIES
96-hour LCso hardwater
14-day LCcg. flowthrough exposure
96-hour LCso. flowthrough exposure
96-hour LCso softwater
reduced egg hatchablllty and larval
survival
96-hour LCso
LCso. newly hatched larvae
reduced egg hatchablllty
96-hour LCso

0-10* mortality. 96-hour
48-hour LCso

48-hour LCso. 1ab '
heart rate depression

dose-related depression of heart rate
heart rate depression
LCso. embryo-larval stages
96-hour LCso

96-hour LCso
96-hour LCso
96-hour LCso
96-hour LCso
96-hour LCso




Reference


Gledhtll et al.. 1980
Gledhlll et al.. 1980
Gledhtll et al.. 1980
Gledhlll et al., 1980
McCarthy et al.. 1985

Mayer and Sanders. 1973
McCarthy and Uhttmore. 1985
McCarthy et al.. 1985
ABC. 1979a

ABC. 1979b
Juhnke and Luedemann, 1978

Juhnke and Luedemann. 1978
Pfuderer and Francis. 1975

Pfuderer and Francis. 1975
Pfuderer and Francis. 1975
Blrge et al.. 1979
Gledhlll et al. . 1980

Hrudey et al.. 1976
Johnson and Flnley. 1980
Mayer and Sanders. 1973
Johnson and Flnley. 1980
Hrudey et al. . 1976


-------
                     TABLE
                               (cont.)


o
-J
00
•£




Species




Rainbow trout
Sal mo galrdnerl

Toxic
Chemical Concentration NOEC
(mg/l) (mg/l)


FRESHWATER
OOP NR 1000

139.1 >71.87. <148

Effect Measured



SPECIES (cont.)
48-hour survival

.2 22-day LCjg at water hardness of

Reference




Sllvo. 1974

Blrge et al.. 1978
139.5
149.2
1S4.0
                  SO mg/l CaC03. embryos exposed
                  from fertilization through hatching.
                  flowthrough

>55.3. <7K87     26-day LC50 at water hardness of
                  50 mq/l CaC03. embryos exposed
                  front fertilization through 4 days after
                  hatching, flowthrough

>0.5. <48.9       26-day LC^g at water hardness of
                  200 mg/i CaCOj, embryos exposed
                  from fetlUzatlon through 4 days after
                  hatching, flowthrough

>0.5, <48.9       22-day LCtn. at water hardness of
                  200 mg/t caCOj, embryos exposed
                  From fetlllzatton through hatching.
                  flowthrough


Coho salmon
Oncorhynchus klsutch
Channel catfish
Ictalurus punctatus


o
tn
~»^
tn
\
03
OUP
S-790a
DEHP

OBP
OEHP
DINP

OOP

>1000
>1000
>100

2.91
>100
0.42
0.87
0.69
1.21
NR 96-hour Uso
1000 96-hour LCSO
NR 96-hour IC^n,

NR 96-hour LC$o
NR 96-hour LC50
>0.01. <0.10 7-day LCjQ of embryos exposed from
fertilization through 4 days after
hatching
>0.1. <1.0 3-day LCjp of embryos exposed from
fertilization to hatching
>0.01, <0.1 7-day LC^p, of embryos exposed from
fertilization through 4 days after
hatching
>0.01, <0.1 3-day LCjQ of embryos exposed from
fertilization to hatching
Blrge et al.. 1978
Blrge et al.
                                                                          Blrge et al.
                                                                                        1978
              1978
                                                                          ABC. 1979c

                                                                          ABC. 1979d

                                                                          Johnson and Flnley,  1980
                                                                          Mayer  and Sanders.  1973
                                                                          Johnson and Flnley.  1980

                                                                          Blrge  et al..  1978
                                                                          Blrge et  al..  1978
                                                                          Blrge et  al..  1978
                                                                          Blrge et  al..  1978

-------
                                                                      TABLE  6-1  (cont.)
o Toxic
2J Species Chemical Concentration
4^ (mg/t)
•o

Blueglll sunflsh BBP 1.7
Lepomls macrochlrus 43.3
DBP 0.73
1.22
DEHP >100
>770
DEP 98.2
110
DMP 49.5
Redear sunflsh DINP 4.67
Lepomls mlcrolophus
cr
i
* 71.9

OOP 6.18


77.2

Largemouth bass OOP 32.9
NOEC Effect Measured
FRESHWATER SPECIES (cont.)
0.36 96 -hour 1C 50
22 96 -hour LC50
NR 96-hour LC^g
NR 96-hour LCso
NR 96 -hour LCSO
770 96-hour LC$o
<6.8 96-hour LC^o
NR 96 -hour LCio
<13 96-hour LC<,0
>0.1-<1.0 7- to 8-day LCcg of embryos exposed
froa fertilization through 4 days after
hatching

>0.1-<1.0 3- to 4-day LCjQ of embryos exposed
from fertilization to hatching
>0.1-<1.0 7- to 8-day LCtn of embryos exposed
from fertilization through 4 days after
hatching
>0.1-<1.0 3- to 4-day LCjQ of embryos exposed
fro* fertilization to hatching
>0.3. <35.5 7- to 8-day LCtQ of embryos from
Reference



Gledhlll et al.. 1980
U.S. EPA. 1978c
Mayer and Sanders.
Buccafusco et al . .
Johnson and F Inley,
U.S. EPA. 1978c
U.S. EPA, 1978c
Buccafusco et al . .
U.S. EPA. 1978c
Blrge et al.. 1978



Blrge et al.. 1978

Blrge et al.. 1978


Blrge et al.. 1978

Blrge et al.. 1978

1973
1981
1980


1981













      Hlcropterus  salmoldes
fertilization through 4 days after
hatching, hardwater
                                                42.1



                                                63.9


                                                66.1
>0.3. <46.3



>0.3. <46.3


>0.3, <35.5
7- to 8-day LCso of embryos from
fertilization through 4 days after
hatching, softwaler

3- to 4-day LCjn of embryos from
fertilization to hatching, softwater
                                                                                 3- to 4-day LCsg of embryos from
                                                                                 fertilization to hatching, hard water
Blrge et al.. 1978



Blrge et al.. 1978


Blrge et al.. 1978
CD
cr>

-------
                                                                      TABLE 6-1 (cont.)
Toxic
2 Species Chemical Concentration NOEC Effect Measured
00 (mg/l) (ntg/l)
FRESHWATER SPECIES (cont.)
Perch OOP NR Maturation 3- to 4-day survival
Perca fluvlatllls
Roach OOP NR saturation 3- to 4-day survival
Rutllus rutllus
Leopard frog DINP 3.63 >0.1. <1.0 7- to 8-day \.C$$ of embryos exposed
Rana plplens fro* fertilization through 4 days
after hatching
4.94 >0.1. <1.0 3- to 4-day LCcn of embryos exposed
fro* fertilization to hatching
OOP 4.44 >0.1. <1.0 7- to 8-day LC50 of embryos exposed
from fertilization through 4 days
after hatching
<^ 5.52 >0.1. <1.0 3- to 4-day LCcg of embryos exposed
^ fro* fertilization to hatching
Fowler's toad DINP 2.95 >0.1, <1.0 7- to 8-day LC50 of embryos exposed
Bufo fowler 1 from fertilization through 4 days
after hatching
23.51 >0.1. <1.0 3- to 4-day LCjn of embryos exposed
fro* fertilization to hatching
OOP 3.88 >0.1, <1.0 7- to 8-day LCcn of embryos exposed
Reference
Nehrlng, 1966
Nehrlng. 1966
Blrge et al. ,
Blrge et al.,
Blrge et al . .
Blrge et al. ,
Blrge et al. ,
Blrge et al . ,
Blrge et al . ,
1978
1978
1978
1978
1978
1978
1978
                                                 44.14
                            >0.1.  <1.0
from fertilization through 4 days
after hatching

3- to 4-day LC$n, of embryos exposed
from fertilization to hatching
                                                                                                                           Blrge  et  al..  1978
O
en
       Bleak
       Alburnus  alburnus
DMP
                                                 100-115
                                                                      SALTWATER SPECIES
                            NR
96-hour LCjQ. brackish water
(7 ppth salinity)
                                                                                       Linden et al., 1979
en
•»v
CD

-------
                                                                      TABLE 6-1 (cont.)
o
— 1
oo
•o






cr<
i
o»


Species

Sheepshead minnow
Cvpr Inodon varlegatus




Hullett
Huqll cephalus
Shiner perch
Cymatogaster aqqregata
English sole
Parophrys vetulus


Toxic
Chemical Concentration
(»»q/i)

BBP 3.0
378
440
DEHP >550
>770
DEP 29.6
DNP S8.0
S-711b NR
OEP 26
BBP 0.08
0.24
0.51
BBP 0.1
0.30-0.45
O.SS-0.66
NOEC
(nxj/l)
SALTWATER
1.0
355
360
550
7/0
22.2
?1.5
1000
10-15
NR
NR
NR
NR
NR
NR
Effect Heasured
SPECIES (cont.)
96-hour ICjn
96 -hour LC^g
96-hour LC-50
96-hour LC5Q
96-hour LC$0
96-hour LC^o
96-hour Lf-so
no Mortality
86-hour LCjQ
effect on coloration
effect on schooling behavior
96-hour LCt,Q
sublethal effects on equilibrium and
activity
lethal threshold
96-hour LCjQ
Reference

Gledhlll et al.. 19BO
U.S. EPA. 1978C
Heltmuller et al.. 1981
Heltrouller et al., 1981
U.S. EPA. 1978c
U.S. EPA. 197Bc
U.S. EPA. 1978c
EG&G Bionomics. 1980
Shlmada et al.. 1983
Oiretlch et al.. 1983
Ozretlch et al.. 1983
Ozrettch et al.. 1983
Randall et al.. 1983
Randall et al.. 1983
Randall et al.. 1983
      aS-790 . dl(heptyl. nonyl) phthalate  (Monsanto.  1983a)


      bS-711 - dlfheptyl. nonyl. undecyl) phthalate  (Nonsanto.  1983b)
03
er>

-------
                                                                           TABU  6-2


                                                Acute Toxlclty of Phthallc Acid Esters  to Aquatic  Invertebrates
--J
tn
\
CD
Species

Protozoa
Uronema par due* 1

tntoslphon sulcatum

Tetrahymena pyrlformls

Cladoceran
Daphnla magna




Cladoceran
Daphnla magna



Toxic
Chemical Concentration NOEC Effect Measured
(rog/l) (mg/l)

DAP
DEP
DAP
DEP
DBP
DIBP
BBP




BBP and
DEHP (1:1
w/w mixture)
DAP
DBP


22
48
13
19
0.05
0.05
1.0
1.6-2.2
3.7
2.43
1.91
92
0.97
22
1.8
5.2
FRESHWATER SPECIES
<22 20-hour toxic threshold (5X Inhibition
of cell multiplication)
<48 20-hour toxic threshold |5X Inhibition
of cell multiplication)
<13 72-hour toxic threshold (5X Inhibition
of cell multiplication)
<19 72-hour toxic threshold (5X Inhibition
of cell multiplication)
NR complete growth Inhibition
NR complete growth Inhibition
NH 48-hour ECjQ. no solvent carrier
0.62 48-hour EC^Q. various solvent carriers
<1.0, <2.5 48-hour ECjQ. lake water
<2.5 48-hour LCi,0. river water containing
natural humlc acid
<1.0 48-hour LC5Q. lake water with 250 ppffl
fulvlc acid added
<3b 48-hour LC«,o
<0.15 48-hour LC$O. duplicate tests
NR 24-hour £CS0. Immobilization
0.56 decreased fecundity
NR 48-hour LCSO
Reference

Brlngmann and Kuhn, 1980a
Brlngnwnn and Kuhn, 19BOa
Brlngmann and Kuhn. 1980b
Brlngmann and Kuhn. 1980b
Yoshlzawa et a). . 1977
Yoshlzawa et al., 197;
Barer a and Adams, 1983
Barera and Adams, 1983
Gledhlll et al.. 1980;
landvatter. n.d.
landvatter, n.d.
landvatter, n.d.
UBlanc, 1980
landvatter, n.d.;
Monsanto, 1983d
Brlngmann and Kuehn,
1982
McCarthy et al.. 1985
McCarthy and Whltmore.
                                                                                                                            1985

-------
                                                                       TABLE  6-2  (cont.)
Toxic
Species Chemical Concentration NOEC
(mg/l) (mg/t)
o
~j
CO
Effect Measured





Reference


•£ FRESHWATER SPECIES (cont.)
Cladoceran DEHP 1.59 <1.0
Daphnta magna
2.0 NR
2.30 <1.0
48-hour
<96 hour
48-hour
48-hour
LCso.
-old
LC50
LC50.
lake

water.

daphnlds

Landvatter, n

.d.

Monsanto. 1983d
lake
water.
daphnlds
Landvatter. n
.d.
<72 hours old
3.85 <1 .0
48-hour
LCSO.
of unspecified
5.29 <1.0

8.90 <1.0

11 1.1
 13.9 <1.0
48-hour
<6 days
48-hour
48 hours
48-hour
48-hour
LC50.
old
LC$0.
old
LCso.
LCSO.
lake
age
lake

lake

water.

water.

water.

daphnlds <24
lake
daphnlds

daphtds

daphnlds

hours old
water with 250 ppm
Landvatter. n

Landvatter. n

Landvatter. n

LeBlanc. 1980
Landvatter. n
.d.

.d.

.d.


.d.
i
oo
                                    OEP
                                                 41
NR
fulvlc acid added, daphnlds of  unspeci-
fied age

24-hour ECso. Immobilization
Cladoceran
Daphnla magna

0 Midge larvae
tn Chlronomus plumosus
\ — —
tn
^
CO
52
DMP 33
DOP 1.0
DUP 15
16
S-711* >10
S-790 0
DBP 0
4
5

DEHP >'
.12
.76
.0
.46

18
10
0.32
10
<3.2
10
<2.5
<0.056
NR
NR
NR

NR
48-hour LCso
48-hour LCso
decreased fecundity
48-hour LCso
48-hour LCso
48-hour ECso. Inmobl 1 Izat Ion
48-hour LCso
48-hour
48-hour
48-hour
48-hour

48-hour
LCso
£C50
LCso
LCSO

ECSO

. 3rd-4th Instar

larvae
. 2nd Instar larvae
. 3rd-4th Instar

and 48-hour ICy
larvae

)
Brlngmann and Kuehn,
1982

LeBlanc. 1980

LeBlanc. 1980

McCarthy et al.. 1985
McCarthy and Whltmore. 1985

ABC. 1979e
Monsanto. 1983c

Landvatter, n.d.

ABC. I979f

Streufert. 1977
Streufert. 1977
Streufert, 1977

Streufert. 1977

-------
                                                                         TABLE  6-2 (cont.)
o
-J
CD
 I
10
Species
Chemical
Toxic
Concentration
(i*g/t)
NOEC
Effect Measured
Reference
FRESHWATER SPECIES (cont.)
Midge larvae
Paratanytarsus parthero-
genetlca
Blackfly larvae
Slroullum sp.
Scud
Ganroarus pseudollnmaeus

Scud
Gammarus pulex
Crayfish
Orconcctes nals
Nematode
Panaqrellus redlvlvus



Mysld shrimp
Mysldopsls bahla



Grass shrimp
Palaemonetes puqlo


S-711*


DMP

DBP

DEHP
DEHP

DBP

OBP




BBP

DfP
OMP
S-711*
DBP

DEHP
DMP
>10


0.7-1.0

2.10

>32
NR

>10.00

NR
0.028



0.9
9.63
7.59
73.7
NR
10 ppm

NR
100 ppm
NR


NR

NR

NR
0.4

NR

0.28
O.OOP8


SALTWATER
0.4
3.S5
3.94
47.8
1000
1 ppm

1 ppm
10 ppm
48-hour LC5Q


9-24X Mortality. 24-hour

96-hour LCjg

96-hour LC$o
no Mortality

96-hour LCjo

96-hour survival rate
96-hour change In distribution of
larval stages during development
relative to control distribution
SPECIES
96-hour LC$g
96-hour LC5Q
96-hour I €50
96-hour LC5Q
non-toxic
larval mortality during 6-day exposure

larval mortality during 6-day exposure
larval mortality during 6-day exposure
Monsanto, 1983e


Gjullln et al.. 1949

Mayer and Sanders, 1973;
Sanders et al., 1973
Sanders et al. , 1973
Shell Oil Co.. 198?

Mayer and Sanders, 1973;
Sanders et al.. 1973
Samolloff et al. . 1980
Samolloff et al.. 1980



Gledhlll et al.. 1980
U.S. EPA. 1978c
U.S. EPA. 1978c
U.S. EPA. 1978c
EG&G Btoneralcs, n.d.
Laughlln et al., 1977

Laughlln et al. , 1977
Laughlln et al., 1977
 oo

-------
TABLE  6-2 (cent.)
o
•-J
oo
4^
•o





1
0





o
in
CD
Species

Brine shrimp
Arteala sallna





Copepod
Nltocra splnlpes


Copepod
Nltocra splnlpes
Mud crab
Rhl thropanopeus harrlsM

•S-711 = d1(heptyl. nonyl.
NR = Not reported
Toxic
Chemical Concentration
(«g/O

DBP
OOP
DEP
OEHP
DHP
DMP
DBP
DEHP
DEP
DIBP
DMP
DNP
DBP
DMP
undecyl)


S.6
8.0
8.2
10.3
10 ppn
saturation
NR
61.5
SO ppn
saturation
SO
NR
NR
1.7
>300
74
3.0
62
>300
NR
NR
phthalate (Monsanto.

NOEC
(flKj/1)
SALTWATER
NR
NR
NR
NR
NR
NR
123
1?.2
10 ppn
NR
NR
SO ppn
120
NR
NR
NR
NR
NR
NR
1 .0 ppn
1 .0 ppra
1983b)

Effect Measured
SPECIES (cont.)
24-hour LC<,o. Larvae
24 -hour LCjg
24-hour survival of larvae
24-hour hatching success of eggs
72-hour hatching success of eggs
24-hour LC50. larvae
24-hour survival of larvae
24-hour hatching success of eggs
72-hour hatching success of eggs
24-hour LC$o. larvae
slight reduction In hatching success.
40-hour
72-hour hatching success of eggs
24-hour survival of larvae
96-hour LCso
96-hour LCjo
96-hour LC«,g
96-hour LC5Q
96-hour LCso
96-hour LCi,o
survival, development time and
abnormalities of larvae
survival, development time and
abnormalities of larvae


Reference

Hudson et al.. 1978
Hudson et al., 1981
Sugawara. 1974b
Sugawara. 1974b
Sugawara. 1974a
Price et al.. 1974
Sugawara. 1974b
Sugawara. 1974b
Sugawara. 1974a
Price et al.. 1974
Sugawara. 1974a
Sugawara. 1974a
Sugawara. 1974b
Linden et al.. 1979
Linden et al.. 1979
Bengtsson and larkpea. 1983
Linden et al., 1979
Linden et al.. 1979
Linden et al.. 1979
Laughlln et al.. 1977
Laughlln et al.. 1977



-------
                                                      TABLE  6-3
0
—J
co
Phthalate
Ester
DMP
DEP
DAP
DPP
o> DBP
- DIBP
BBP
OOP
DEHP
DNP
DINP
DDP
DUP
Range of Acute LC5Q and EC5Q Values for Phthalate Esters
Solubility3
Limit
(mg/i)
1744-5000
210-1000
100
56
6.2
0.71-2.9
3
0.285-1.3
NR
NR
0.33
NR
Range
Algae
26.1-185 (3)b
3-90.3 (3)
NR
0.9-65 (1)
0.0034-0.6 (1)
NR
0.11-1.0 (5)C
NR
31.000 (1)
NR
NR
NR
<360->1000 (1)
of Acute LC5Q or
Invertebrates
7-73.4 (4)
7.6-74 (3)
22 (1)
NR
1.7->10.0 (4)
3.0 (1)
0.9-92 (2)
1.0->10 (2)
1.6->300 (4)
>300 (1)
NR
>saturat1on (1)
15-16 (1)
EC5Q Values (mg/i or
Fish
49.5-115 (3)
29.6-110.0 (3)
0.4 (1)
NR
0.73-6.47 (4)
NR
0.51 440.0 (4)
0.69-200.0 (7)d
540->770 (5)
NR
0.42-71.85 (4)d
NR
>1000 (2)
ppm)
All Organisms
7-185 (10)
3-110.0 (9)
0.4-22.0 (2)
0.9-6.5 (1)
0.0034->10 (9)
3.0 (1)
0.11 -440 (11)C
0.69-200.0 (9)d
1.6-31,000 (10)
>300 (1 )
0.42-71.85 (4)d
>saturat1on (1)
15->1000 (4)
     Source:  Sugatt and Foote, 1981
o    Number  In parentheses Is the number of species tested.
^   C0ne species of algae had a clearly exceptional LC,0 of 1000 mg/i.
oo    Includes two amphibian species
    NR = Not reported

-------
    Data  concerning  chronic  toxlcity  of  phthallc  add  esters  to  aquatic
vertebrates  are presented  In  Table  6-4.   D1(2-ethylhexyl) phthalate was  the
ester  for  which there was  the most data.   Toxic effects  were reported at
concentrations  as low  as  0.0037  mg/8.  In  brook  trout,  Salvellnus  fontlnal Is
(Mayer  et a!.,  1977).   In  embryo-larval  tests  with  fathead minnows,  Plme-
phales promelas. the order  of  decreasing  toxldty for  four  esters  was  d1{2-
ethylhexyl)  phthalate,  n-butyl benzyl  phthalate, d1-n-butyl  phthalate  and
dl-n-octyl phthalate.  01(2-ethylhexyl)  phthalate caused  decreased  collagen
content of  the backbones  of  fry exposed  to concentrations of  0.011-0.100
mg/i  for  127  days  (Mayer  et  al.,  1977).  n-butyl  benzyl  phthalate  caused
reduced growth  at  0.360   mg/i  (Gledhlll  et  al.,  1980),  while  d1-n-butyl
phthalate  and d1-n-octyl phthalate affected survival  and/or  egg  hatchabUHy
at 1.0 and 10.0 mg/l,  respectively (McCarthy and WhHmore, 1985).
    Data concerning chronic  toxIcHy  of  phthalates to  aquatic  Invertebrates
are presented In Table 6-5.  Once again,  d1(2-ethylhexyl) phthalate appeared
to  be  more  toxic  than the  other  esters, having  Inhibited reproduction of
Daphnla magna  at concentrations as  low  as  0.003 mg/i  (Mayer and  Sanders,
1973).   N-butyl  benzyl   phthalate,   d1-n-octyl   phthalate   and   d1-n-butyl
phthalate  were about equal  In  toxldty to Daphnla  magna,  adversely affecting
reproduction  at 0.76,  1.0  and  1.8  mg/l,  respectively  (GledhUl  et  al.,
1980; McCarthy and Whltmore, 1985).
0784p                               6-12                             05/15/86

-------
                           TABLE  6-4



Chronic Toxlclty of Phthallc Acid Esters to Aquatic Vertebrates
— J
oo
T5
1
CO
o
tn
tn
CO
Toxic
Species Chemical Concentration NOEL Effect Measured
(mg/l) (mg/l)
FRESHWATER SPECIES
Rainbow trout DEHP 0.014-0.054 0.005 Decreased collagen content of backbone. 90-day
Sal mo qalrdnerl exposure, eggs and fry
0.054 0.005-0.014 Mortality of sac fry. decreased protein content
exposure was 12-day eggs and 90-day post-hatch
NR 0.1 No effect on growth or survival of adults, 60-day
exposure
Brook trout DEHP 0.0037-0.052 NR Decreased collagen content of backbone. 150-day
Salve! Inus fontlnalls exposure, adults
Fathead minnow DEHP 0.011-0.100 NR Decreased collagen content of backbone, no effects
Plmephales proroelas growth, 127-day exposure, fry
NR 0.062 No effects on growth or survival, 56-day exposure,
embryo-larval stages
BBP 0.36 0.14 Reduced growth, normal hatching and survival
0.22 NR Embryo-larval stages, exposure for 30-day post-
hatch mean chronic value
DBP 1.0 0.56 Effects on survival, hatching rate 20-day embryo-
larval test
OOP 10 3.2 65X decreased hatchabl 1 1 ty. no effect survival
S-711 NR 0.001-0.265 34-Day embryo-larval test, no effects on egg
hatchabll tty, fry survival, growth 30-day exposure
Frog DEHP 2.0 NR Retarded development, reduced pigmentation, 8- to
Xenopus laevls 30-week exposure, tadpoles

Reference
Mayer et al . .
197?
Mehrle and
Mayer. 1976
McCarthy and
Mhltmore. 1985
Mayer et al . .
197?
Mayer et al. .
1977
Mehrle and
Mayer. 1976
Gledhlll et al..
1980
U.S. EPA. 1980a;
Pickering. 1983
McCarthy and
WhHmore. 1985
McCarthy and
WhHmore. 1985
Monsanto. 1983f
Dumper t and
Zlet/. 1984


-------
                                                                              TABLE 6-5


                                                  Chronic Toxlctty of Phthallc Acid Esters to Aquatic Invertebrates
o
— 1
CO
"° Species Chemical

Cladoceran DEHP
Oaphnla magna
DEHP
DBP
DOP
BBP
D1DP

-------
6.3.   PLANTS
    Data concerning  effects  of  phthallc  acid esters  on aquatic  plants  and
bacteria  are presented  In  Table 6-6.   There  are  four  species  for  which
sufficient data  are  available to compare  t.he toxldty  of  different  esters.
For the  freshwater alga, Selenastrum  caprlcornutum.  n-butyl benzyl phthalate
was 2-3  orders  of  magnitude  more toxic than  dimethyl  and dlethyl  phthalates
(U.S.  EPA, 1978c).   Dlallyl  phthalate was -20 times more toxic  than  dlethyl
phthalate, which was  -50 times  more  toxic than n-butyl  benzyl  phthalate to
the  blue-green   alga,  Hlcrocystls  aeruqlnosa  (BMngmann  and  Kuehn.  1978;
Gledhlll  et  al.,  1980).  Among  saltwater algae,  the  order  of  decreasing
toxldty  of  phthalates   to   the  dlnof lagellate,   Gymnod1n1um   breve,   was
d1-n-butyl,  dlphenyl,  dlethyl,  dimethyl  and  d1(2-ethylhexyl)  phthalates
(Wilson  et  al., 1978).  The  range of  toxic  concentrations 1n  this  species
was -107 (Table  6-7).  In  the  green  alga,   Skeletonema  costatum.  n-butyl
benzyl phthalate was  -100  times more toxic than dimethyl and  dlethyl phtha-
lates (U.S.  EPA, 1978c).  The  difficulty  Tn making  generalizations about  the
relative  toxldty  of  phthalates  1s  Illustrated by  the  fact   that  n-butyl
benzyl  phthalate  was  the  most  toxic  of  three esters  to Selenastrum  and
Skeletonema. but was the least toxic of three  esters to Hlcrocystls.
6.4.   RESIDUES
    Pharmacoklnetlc  Information  for   phthalates and   aquatic  organisms  1s
summarized  In  Table  6-7.   Data  from  model  ecosystem  studies  concerning
phthalate  ester residues are  presented 1n Table  6-8.    Monitoring data  for
phthalate residues 1n  various fish species are presented  1n Table 6-9.
0784p                               6-15                             06/06/86

-------
                                                                          TABLE 6-6



                                              Acute Toxtctty of Phthalate Esters to Aquatic Plants and Bacteria
o
CD
T3
Species Chemical
Toxic
Concentration
(mg/l)
NOEC
(mq/1)
Effect Neasured
Reference
FRESHWATER SPECIES
BACTERIA
Nixed bacteria D8P
OEHP
Nixed microorganisms
Pseudoroonas put Ida DAP
DEP
&• Pseudomonas aeruglnosa ONP
PLANTS
Selenastrum BBP
capr Icornutum
DMP
Selenastrum DEP
capr Icornu turn
DUP
S-790
S-711
NR
NR
NR
NR
NR
1500 ppm

0.11
0.13
0.4
42.7
39.8
90.3
85.6
>1000
>1000
>1000
1000
1000
100
100
400
1000 ppm

<0.07
NR
0.1
NR
<22.2
NR
<360
<360
NR
growth Inhibition of cultures Isolated from
pond hydrosoll
growth Inhibition of cultures Isolated from
pond hydrosoll
growth Inhibition and physiological activity
In flow-through hydrosoll microcosm
16-hour toxic threshold (3X Inhibition of cell
Multiplication)
16-hour toxic threshold (3X Inhibition of cell
multiplication)
temporary and slight growth Inhibition

96-hour ECjg. chlorophyll a
96-hour ECjQ, cell number
96-hour LC«,o. cell number
96-hour EC<,Q. chlorophyll a
96-hour ECso. ce'l number
96-hour EC5Q. chlorophyll a
96-hour EC^Q. cell number
96-hour EC^Q. chlorophyll a and cell number
96-hour EC^g. chlorophyll a and cell number
96-hour ECjg. chlorophyll a and cell number
Johnson. 1975
Johnson. 1975
Nut? and Jones. 1977
Brlngmann and Kuehn,
1980b
Brlngmann and Kuehn.
1980b
Perez et al. . 1976

U.S. EPA. 1978c
U.S. EPA. 1978c
Gledhlll et al.. 1980
U.S. EPA. 1978c
U.S. EPA. 1978c
U.S. EPA. 19/8c
U.S. EPA. 1978C
EG&G Bionomics. I979a
EG&G Bionomics, 1979b
EG&G Bionomics, 1978
o
o
er
00

-------
TABLE  6-6 (cont.)
06/06/86
Species

Hlcrocystls aeruqlnosa





Navlcula pelllculosa

Scenedesmus
quadrlcauda


Gvmnodlnlum breve









Skeletonema costatum




Chemical

DAP

DEP

BBP
S-711
BBP
S-711
DAP

DEP

DBP

DPP

DEP

DHP

DEHP

BBP


DHP

Toxic
Concentration
(ntg/t)

0.65

15

1000
>1000
0.6 (0.2-2)
>1000
2.9

10

0.0034-0.2 ppm
0.02-0.6 ppm
0.9-2.4 ppm
1 .3-6.5 ppm
3-6.1 ppm
33 ppm
54-96 ppm
125-185 ppm
31.000 ppm
NR
0.17 (0.08-0.36)
0.19 (0.09-0.38)
0.6 (0.3-2.0)
26.1 (15.9-39.3)
29.8 (22.2-40.8)
NOEC
(reg/l)
FRESHWATER
<0.65

<15

560
NR
0.3
NR
<2.9

<10

NR
NR
NR
NR
NR
NR
NR
NR
NR
100.000 ppra
<0.03
NR
0.1
<11.9
NR
Effect Measured
SPECIES (cont.)
8-day toxic threshold (3% Inhibition of cell
multiplication)
8-day toxic threshold (3X Inhibition of cell
multiplication)
96-hour l-C^o- cell number
96-hour ECjQ. chlorophyll a and cell number
96-hour EC$o. c«'l number
96-hour EC«,o. chlorophyll a and cell number
B-day toxic threshold (3X Inhibition of cell
multiplication)
6-day toxic threshold (3% Inhibition of cell
mult Ipl (cat ton)
96-hour EC5Q. growth rate, duplicate tests
96-hour LC<,0. cell population, duplicate tests
96-hour ECi,0. growth rate, duplicate tests
96-hour LC^Q, cell population, duplicate tests
96-hour fCt,o. growth rate, duplicate tests
96-hour tCijQ. cell population
96-hour EC^Q. growth rate, duplicate tests
96-hour LCi,Q. cell population, duplicate tests
96-hour ECi,o. growth rate
96-hour LC<,O. cell population
96-hour ICjo. chlorophyll a
96-hour fC^Q. cell number
96-hour LCt,Q. cell number
96-hour EC<,o. chlorophyll a
96-hour ECi,0. cell number
Reference

Brlnqmann and Kuehn,
1978
Brlngmann and Kuehn,
1978
Gledhlll et al.. 19BO
EG&G Bionomics. 1978
Gledhlll et al. . 1980
EG&G Bionomics. 19/8
Brlngmann and Kuehn,
1980b
Brlmjmann and Kuehn,
1980b
Wilson et al.. 19/8
Wl Ison et al. , 19/8
Wilson et al., 19/8
Wilson et al.. 19/8
Wilson et a)., 19/8
Wl Ison et a 1 . . 19/8
Wilson et al. . 19/8
Wilson et al. , 19/8
Wilson et al. , 1978
Wl Ison et a 1 . . 19/8
U.S. EPA. 19/8c
U.S. tPA. 19)0c
Gledhlll et al.. 1900
U.S. EPA. 19/8c
U.S. EPA, 19/8c

-------
                                                                         TABLE  b-b (cont.)
O
-~j
oo
->
•o
Toxtc
Species Chemical Concentration
(i»9/t)

Skeletonema costatun DIP 65.6 (22. 3-193)
BS.O (Sb. 9-124)
D8P SOX ss
SOX ss
NR
NR
S-711 >1000
Dunallella tertlolecta BBP 1.0(0.2-5)
S-711 >1000
NOEC
(iog/i)
FRESHWATER
<39.4
NR
20X ss
20% ss
50* ss
NR
NR
0.3
NR
Effect Measured
SPECIES (cont.)
96-hour EC^rj. chlorophyll a
96-hour fC<,0. cell number
96-hour growth rate, 14 ppth salinity
96-hour growth rate. 22 ppth salinity
96-hour growth rate. 27 ppth salinity
96-hour growth rate. 36 ppt salinity
96-hour £C$o. chlorophyll a and cell number
96-hour LC^g. cell number
96-hour EC <,rj. chlorophyll a and cell number
Reference

U.S. EPA. 19/Bc
U.S. EPA. 1978c
Medlln, 1980
Medlln. 1900
Nedlln. 1980
Medlln. 1980
EG&G Bionomics.
Gledhtll et al.
EG&G Bionomics.




1978
. 1980
1978
cr>
 i
00
       NR  «  Not  reported
o
cr

-------
                                                                                 TABLE  6.7


                                            Data  from Uptake  and  Elimination  Studies  with Phthallc Acid Esters In Aquatic Biota
 o
 •—J
 00
 4*
T3
 O


 O

 \
 CO
Species
Chemical
Water
Concentration
(rag/l)
Tissue
Tissue
Concentration
(pq/9)
BCF
Ourat Ion
(days)
Depuration
Half-time
(days)
Reference
FRESHWATER SPECIES
FISH
Fathead minnow
Plmephales prpmelas

Rainbow trout
Sal mo qalrdnerl




Mosqultof Ish
Gambusla afflnls
BlueglTl
Lepomls macrochlrus




INVERTEBRATES
Water flea
Oaphnla magna









Damsel fly

DEHP


DEHP





DEHP

BBP

OEHP

DEP
DMP

DBP



DEHP





DIDP
DBP

0.001-0.062

0.0019
NR
0.07



0.5
0.1
10.0
0.00973

0.0057
0.00582
0.00942
O.OOB74

0.00008
0.0001
0.0001
0.00008
0.0054
0.0003
0.1
10.0
0.0003
NR
NR
0.0001

whole body

whole body
whole body
muscle
blood
bile
liver
btle
whole body
whole body
whole body

whole body
whole body
whole body
whole body

whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body

NR

NR
NR
0.0?1
0.142
51.4
0.86
NR
?6.5
469
NR

0.64
NR
NR
NR

NR
0.4
0.6
NR
2.8
NR
18.26
1551
NR
NR
NR
NR

886-155

458
42-113
NR
NR
NR
NR
247
NR
NR
663

112
114
117
57

5000
NR
6000
400
518
420
NR
NR
5000
209
116
?700

56

14
36
1
1
1
1
1
2
2
21

35
42
?1
21

14
7
10
14
1
7
2
2
7
21
21
7

12.2

NR
NR
NR
NR
NR
NR
NR
NR
NR
>1. <2

NR
3
>1. <2
>1. <2

NR
3
3
NR
NR
NR
NR
NR
NR
NR
NR
NR

Mayer. 1976;
Mehrle and Mayer . 1976
Mayer and Sanders. 1973
Mehrle and Mayer. 1976
Melancon et al . . 1977
Nelancon et al. . 1977
Melancon et al. , 1977
Melancon et al., 1977
Statham et al.. 1976
Metcalf et al.. 1973
Metcalf et al.. 1973
Barrows et al . . 1980

Macek et al.. 1979
Barrows et al . , 1980
Barrows et al. . 1980
Barrows et al.. 1980

Sanders et al. . 1973
Sanders et a). , 1973
U.S. EPA. 1972
Mayer and Sanders. 1973
Macek el al.. 1979
Mayer and Sanders. 1973
Metcalf et al., 1973
Mi-tcalf et al. . 1973
Sanders et al. , 1973
Brown and Thompson. 19B2a
Brown and Thompson. 1982a
Sanders et aJ., 1973
      Ischnura vertical);

-------
TABLE  6-7 (cont.)
o
-J
CD
•o












0>
1
o













0
v^
o
CO
cr«
Species

Sowbug
Asellus brevlcaudus
Midge
Chlronomus plumosus



Mayfly
Hexagenla blllneata


Scud
Gamroarus pseudollmnaeus




Mosquito larvae
Culex sp.
Mosquito pupae
Culex sp.
Snail
Physa sp.
Glass shrimp
Palaeroonetes kakladensls
PLANTS

Alga
Selenastrum caprlcornutum
Plant
Elodea sp.
Chemical

DEHP

DBP

DEHP


DBP

DEHP

DBP

DEHP



DEHP

DEHP

OEHP

OBP



DBP

OEHP

Water
Concentration
(mg/l)

0.0019
0.062
0.00018
0.00018
0.000?
0.0003
0.0003
0.00008
0.0001
0.0001
0.0001
0.0001
0.0001
0.063
0.0001
0.0001
0.0001
0.1
10.0
0.1
10.0
0.1
10.0
0.00008



NR

0.1
10.0
Tissue
Tissue Concentration
(wg/g)
FRESHWATER
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body



whole body

whole body
whole body
SPECIES (cont.
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
5.4
16.37
3657
2.03
4346
85.7
487
NR



NR

23.24
290
BCF

70
250
720
6600
29?
350
3100
430
1900
575
2300
6700
1400
260
3600
13.400
NR
NR
NR
NR
NR
NR
NR
5000



22.700

NR
NR
Duration
(days)

21
21
7
7
2
7
7
7
7
7
7
NR
14
21
14
14
3
2
2
2
2
2
2
3



NR

2
?
Depuration
Half-time
(days)

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
<4
NR
NR
NR
NR
NR
NR
NR



NR

NR
NR
Reference

Sanders et al.. 1973
Sanders et al. . 1973
Mayer and Sanders. 1973
Sanders et al.. 1973
Streufert et al.. 1980
Mayer <\nd Sanders. 1973
Sanders et al.. 1973
Mayer and Sanders. 1973
Sanders el al.. 1973
Mayer and Sanders, 1973
Sanders et al. . 1973
Sanders et al.. 1973
Mayer and Sanders, 1973
Sanders et al.. 1973
Mayer and Sanders. 1973
Sanders et al.. 1973
Sanders et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al., 1973
Metcalf et al.. 1973
Sanders et al. . 1973



Casserly et al.. 1983

Metcalf el al. . 1973
Motcalf el al.. 1973

-------
                                                                            TABL[ 6-7 (cont.)
o
— 1
co
T3




i
Species

FISH
Sheepshead minnow
Cypr Inodon varlegatus
Hullet
Hug 11 cephalus
INVERTEBRATES
Brine shrimp
Artemla sallna
Hussel
Mvtllus edum
Water Tissue
Chemical Concentration Tissue Concentration BCF

-------
o
—4
CD
                                                                            TABLE  6-6


                                                Data  from Model  Ecosystem Studies Concerning Phthalate Residues
i
IV)
Species
Alga
Water flea (Daphnla sp.)
Mosquito (Culex plplens)
Snail (Physa sp. )
Fish (Ganbusla afflnls)
Alga
Water flea (Oaphnla sp.)
Mosquito (Culex plplensl
Snail (Physa sp.)
Fish (Gambusla afflnls)
Alga IQedogoMua sp.)
Snail (Physa sp.)
Mosquito (Culex sp.)
Fish (Gambusla afflnls)
Plant (Menthu aquatlca)
Plant (Chara chara)
Planarian (Dendrocoelun lacteum)
Leech (Helobdella sp.)
Snail (Planorbls corneus)
Scud (Gammarus pulex)
Midge (Chlronorous sp.) and
Ollgochaete (Tublfex sp.)
Caddlsfly (Llmnephllus sp.)
Alderfly (Slalls sp.)
River lamprey (Lampetra planer 11
Minnow (Phoxlnus phoxlnus)
Stickleback (Pungltlus punqltlus)
Chemical
DOP
DOP
DOP
DOP
DOP
DOP
DOP
DOP
OOP
DOP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
OEHP
DEHP
DEHP

OEHP
DEHP
DEHP
DEHP
DEHP
Water
Concentration
0.000064
0.000064
0.000064
O.OOOOf 4
O.OOOUH
0.00345
0.00345
0.00345
0.00345
0.00345
0.0078
0.0078
0.0078
0.0078
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013

0.001013
0.001013
0.001013
0.001013
0.001013
Tissue
Concentration
(v-g/9)
1.8
0.16
0.59
0.65
0.59
2.28
32.5
18.3
1.51
0.004
19.1
20.3
36.6
0.20b
18.53
18.50
4.15
2.00
17.70
25.19
1.23

19.46
2.30
10.70
0.18
0.31
BCF
28.500
2.600
9.400
13.600
9.400
660
9.426
5.300
438
1.16
NR
NR
NR
NR
18.292
18.263
4.097
1.974
17.473
24.456
1.214

19.210
2.271
10.563
178
306
Duration
(days)
33
33
33
33
33
3
3
3
3
3
33
33
33
33
27
27
27
27
27
27
27

27
27
27
27
27
Reference
Sanborn et al. , 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al.. 1975
Sanborn et al. , 1975
Sanborn et al. . 1975
Sanborn et al.. 1975
Sanborn et al. . 1975
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al. , 1973
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982

Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Socdergrcn. 1982
o
en
CO

-------
                          TABLE 6-9



Monitoring Data For Phthallc Acid Esters In Aquatic Organisms
o
co
•o






1
ro
CO




O
cn
CD
cr>

Species

Lake trout
Salvellnus namavcush

Whlteflsh
Coregonus

Fish (general)


Herring fillets
Clupea harengus
Mackerel fillets
Scomber scombrls
Cod liver
Gadus morhua
Plaice fillets
Hlppoglossoldes platessoldes
Redflsh fillets
Sebastes marlnus




Chemical

DBP
DEP
DEHP
DBP
DEP
DEHP
DBP
DEHP

DEHP
OHP
DEHP
DHP
DEHP
DHP
DEHP
DHP
DEHP
OHP




Tissue
Concentration
(ng/q)
FRESHWATER
0-3.2
0-2.0
0-1.3
0.04-0.07
1.3-2.2
0.4-0.7
0-0.5
0-3.2
SALTWATER
4.71
17
6.5
27.2
5.19
<0.01
<0.01
<0.01
<0.01
<0.01




Location
SPECIES
Lake Superior
Lake Superior
Lake Superior
Lake Superior
Lake Superior
Lake Superior
North America
North America
SPECIES
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - GulF of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence




Reference

Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Johnson et al.
Johnson et al.

Muslal el al..
Muslal et al. .
Muslal et al . .
Mus la 1 et a 1 . .
Muslal et al..
Muslal et al. .
Muslal et al . .
Muslal et al..
Muslal et al . ,
Muslal et al..










. 1977
. 1977

1981
1981
1981
1981
1981
1981
1981
1981
1981
1981




-------
    The  Information   1n  these  three  tables  Indicates  that  phthalates  1n
general are  not strongly  bloaccumulated by  fishes,  even  though  phthalates
are  fairly  I1poph1l1c.   This  1s  because fishes  are  able  to metabolize  and
eliminate phthalates, especially  d1(2-ethylhexyl) phthalate, rather  quickly
(Soedergren,  1982).   In both  fish  and  Invertebrates,  d1(2-ethylhexyl)  phtha-
late was  degraded  to the  monoester  (monoethylhexyl  phthalate)  and then  to
free phthallc add,  phthallc anhydride  and  a  variety of conjugates  (Mehrle
and Mayer, 1976; Sodergren,  1982).  In  studies  with several  benthlc  Inverte-
brate  species exposed to  radlolabeled  d1(2-ethylhexyl)  phthalate,  Sodergren
(1982)  concluded  that the capacity  to  metabolize and  eliminate  d1(2-ethyl-
hexyl)  phthalate was  the primary  determinant  of accumulation.   Those  species
that accumulated  radioactivity to the  greatest extent  were those that  had
almost  all of the  radioactivity still  1n the form of  d1(2-ethylhexyl)  phtha-
late, while  lower  total amounts  of radioactivity were  found  1n  species  that
had metabolized  the compound  to other  forms.
    In  a  35-day study with bluegllls,  Lepomls  macrochlrus.  and  radlolabeled
d1(2-ethylhexyl) phthalate   (Macek et   al.,  1979),  food  and water  did  not
accumulate radioactivity  to  a greater  extent  than  fish  exposed  to  d1(2-
ethylhexyl)   phthalate In  water  alone.   Steady-state  whole-body  concentra-
tions  In  bluegllls exposed  to d1(2-ethylhexyl) phthalate only  In the  diet
were -1/3 of those 1n fish  exposed  to  d1(2-ethylhexyl) phthalate  In  water.
These  results  suggest that  d1(2-ethylhexyl)  phthalate uptake from water  Is
more Important  than d1(2-ethylhexyl)  phthalate uptake  from  food.
6.5.   SUMMARY
    It  1s difficult  to  draw conclusions  about  the  relative  toxldty  of
phthallc  acid  esters  to aquatic  biota  because of  the  large variability  1n
toxkHy  of  each ester  to different  species.   It Is  also difficult  to  pick


0784p                               6-24                             05/15/86

-------
out those species most sensitive  to  phthalates;  however.  Table  6-10 contains
the most  and  least  sensitive  species  and toxic concentrations  reported  for
each ester.  All  of  the  esters listed  In  Table  6-10  caused  toxic  effects  at
<3.2 mg/i.   The  lowest  concentration  reported  to cause  toxic effects  was
0.003  mg/8. dl{2-ethylhexyl)  phthalate,  which  caused  decreased  production
of offspring by Daphnla magna (Mayer  and Sanders, 1973).
    Although there were  large  differences  In  species  sensitivity among major
taxonomlc groups, none of  these groups except bacteria were  especially more
or  less  sensitive than other  groups.   Bacteria  were clearly less  sensitive
than other  organisms  to  d1-n-butyl,  dlallyl,  dlethyl  and  dimethyl  phthalates
(Sugatt  and  Foote,  1981).   The available  Information concerning  freshwater
and  saltwater  species Indicated  no  difference  1n phthalate ester  toxldty
between freshwater and saltwater environments.
    Many  Investigators have reported toxic effects of phthalates  at  concen-
trations  greater  than their aqueous  solubility; however, the  data  Indicate
that all  of the  phthalates except  dlhexyl,  dlnonyl, d1-n-decyl  and  dllso-
decyl phthlates were  toxic  to  at  least  one species at concentrations  near  or
below their solubility (Sugatt and Foote, 1981).
    Information concerning  residues  of  phthallc  acid  esters  In  aquatic biota
suggests  that  accumulation  Is  determined primarily  by  the  degree to which
species  can metabolize and  eliminate  them (Soedergren,   1982).   Fish  gener-
ally have a well-developed mechanism  1n this  regard and therefore  do  not
accumulate phthalates to a great extent.
0784p                               6-25                             06/06/86

-------
                                       TABLE 6-10



Range of Species Sensitivity for  Algae.  Invertebrates and Vertebrates  to  Phthalate  Esters
-J
00
•o
Compound3
BBP
DAP
DBP
DEHP
DEP
01BP
i
ro
°* DINP
DHP
OOP
DUP

aComparlsons
parlsons for
No. of
Species
Compared
15
6
IB
16
16
2
4C
13
12
4

Host Sensitive Species
Least Sensitive Species
Toxic Nontoxlc Toxic Nontoxlc
Species Concentration Concentration Species Concentration Concentration
algae 0.03 NR
(S. costatum)
Ide (L. jjus) 0.4 0.3
neraatode 0.028 0.0028
(P. redlvlvus)
water flea 0.003 NR
algae (G. breve) 3.0 NR
protozoa O.OS NR
(T. pyrlformls)
catfish 1.0 0.10
(i. punctatus)
water flea 1.7 NR
(D. magna)
catfish 0.1 0.01
(I_. punctatus)
water flea IS <3.2
(D. magna)

for DHP. DPP. DNP and OOP could not be made because comparable
DIDP could not be made because no toxic affects occurred at any
° bBacterla were even less
^^
^x
jjj clncludes two
^^
oo
amphibian

sensitive to these phthalate esters.
species.

algae 1.000 S60
(H. aeruglnosa)
protozoab 22 <22
(U. parductl)
algae (S. costatunp NR SOX saturated
solution
algae (G. breve) 31.000 NR
brine shrlmpb NR 123
1.000 NR
(P. promelas)
rainbow trout >1.000 NR
(S. qalrdnerl)
results were available for only 1 species for each ester. Corn-
concentration tested.




-------
                     7.   EXISTING GUIDELINES AND  STANDARDS
7.1.   HUMAN
    RfDs have been  derived  for  d1(2-ethylhexyl)  phthalate, dimethyl phtha-
late, dlethyl phthalate,  d1-n-butyl  phthalate, ethylphthalyl  ethylglycoate,
and butylphthalyl butylglycoate (U.S. EPA, 1980b).   These  are  summarized  In
Table 7-1.   A cancer-based water  qualHy criterion  for  d1 (2-ethylhexyl)
phthalate was derived (U.S. EPA, 1980b).  A drinking water document for this
class of compounds 1s currently In  preparation.
7.2.   AQUATIC
    U.S. EPA  (1980b)  did  not  derive  an  ambient water quality criterion for
the protection of aquatic  life  for  phthalates, but did, however, note that
acute and chronic toxldty  to freshwater aquatic life occurred at concentra-
tions as low  as  0.940 arid 0.003 mg/1,  respectively.   For  saltwater  biota,
U.S. EPA (1980a) noted that acute toxldty occurred at  concentrations as low
as  2.944 mg/l,  and  that  toxklty  to one  algal  species  occurred  at 0.0034
mg/l.   More  recent   data  (see  Chapter  6) gave  no Indication of  toxic
effects  occurring at concentrations <0.003 mg/l 1n either  freshwater  or
saltwater.
    Earlier U.S. EPA  (1972, 1976) documents recommended criteria for  phtha-
lates for  the protection of aquatic life.  U.S.  EPA (1972)  recommended a
level of 0.003 mg/l  to protect  fish  and their food supply.  This was based
on  the  0.003 mg/l  concentration  reported to  Inhibit   growth  of  Daphnla
maqna (Mayer  and  Sanders,  1973) and  contained a  safety factor of 10.  U.S.
EPA  (1976)  recommended  a  criteria  of  0.003  mg/l  for   freshwater aquatic
life, recognizing that this concentration caused adverse effects In Daphnla.
This  level was  considered acceptable because   other  species appeared  to  be
much more resistant.
0785p                               7-1                              09/02/86

-------
o
~J
CD
                                                      TABLE 7-1


                          Existing ADIs/RfOs for Phthallc Acid Esters from U.S. EPA, 1980ba
Ester
Dlethyl
Dlbutyl
r!o Butylphthalyl
Ethylphthalyl
Dimethyl


butylglycoate
ethylglycoate

ADI
(mg/kg/day)
13
1.3
10
2.5
10
Dose
(mg/kg/day)
NOEL
NOAEL
NOEL
NOEL
NOEL
= 1250
= 125
= 1000
= 250
= 1000
Species
rat
rat
rat
rat
rat
Reference
Food Research Lab. , 1955
Smith, 1953
Solver et al. , 1950;
Hazelton Labs. , 1950
Hodge et al.. 1953
Lehman, 1955b
    aThese values are all currently under review and a drinking water document  Is currently under development.


    blncorrectly attributed to Dralze et al. (1948) In U.S. EPA (1980b)
o

\
o

>•»
CD

-------
                              8.   RISK  ASSESSMENT







    Risk assessment for phthalate esters must  be  performed  on  a compound-by-



compound basis, since not all phthallc acid  esters  produce  the same effects.



For example,  dl (2-ethylhexyl)  phthalate  causes testlcular  atrophy,  but  when



administered  In  equlmolar  doses,  d1-n-octyl  phthalate does  not  (Gray  and



Butterworth,  1980;  Foster   et   al.,   1980);  both   compounds   are  8-carbon



dlesters.



    The   following   section  contains   assessments  for   dl(2-ethylhexyl),



dlethyl,  d1-n-butyl,  dimethyl,  dl-n-octyl,   n-butyl  benzyl  and  dllsononyl



phthalate.  There were either Insufficient or  no  available  published data  on



chronic  toxlclty with which  to  assess  the other  phthalate  esters  covered  by



this document.



8.1.   DI(2-ETHYLHEXYL)  PHTHALATE



    In  lifetime  feeding  studies  conducted  by NTP  (1982b),  d1(2-ethylhexyl)



phthalate was  shown  to  cause statistically  significant  Increased  Incidences



of  hepatocellular   carcinoma  and  hepatocellular  carcinoma   or   neoplastk



nodules  In  F344 rats  dietary  concentrations >6000  ppm and  hepatocellular



carcinoma and  hepatocellular  carcinoma or  adenoma In B6C3F1 mice  at dietary



levels >3000 ppm.  Based on  these results, IARC  (1982b)  concluded  that  there



1s  sufficient  evidence  that  d1(2-ethylhexyl)  phthalate 1s carcinogenic  for



rats  and mice.  The U.S.  EPA came to an  equivalent conclusion.   Using  the



EPA classification system for we1ght-of-ev1dence  OEHP 1s a  Group  B2 carcino-



gen, meaning  there  1s  sufficient animal  evidence and thus  probably carcino-



genic  1n  humans.   Other  effects observed  at low levels of exposure In  oral



teratogenlcHy  and  chronic   studies   Include   the  following:    Increased



relative  liver  weight  In  female guinea  pigs (19  mg/kg/day)   (Carpenter  et










0786p                               8-1                              08/26/86

-------
al., 1953); liver and kidney congestion  In  a  dog (79.9 mg/kg/day) (Carpenter
et  al.,  1953);  teratogenlc  effects  1n  the  absence of maternal  toxldty  In
CD-I  mice  (91  mg/kg/day  on days  0-18  gestation)  (Wolkowskl-Tyl  et.  al.,
1984b);  and  Interstitial  nephritis,  Increased  SGOT, and  Increased  blood
glucose  In  rats  500 ppm)  (Nagasaki  et al.,  1974).   Testlcular  effects  were
also observed In  a  number  of studies  on  rats,  but  these  effects occurred  at
higher  levels  of exposure  (Gray et  al.,  1977,  1982; Gangolll,  1982;  NTP,
1982b; Kluwe et  al.,  1982b;  Olshl and Hlraga,  1980a,  1983;  Gray and Butter-
worth,  1980; Hangham  et al., 1981;  01sh1,  1985).  Doses  <19  mg/kg/day  have
not been tested.
    Using  data  from  NTP  (1982b),  q *s   were derived  for combined  hepato-
cellular carcinoma and  neoplastlc nodules  1n  rats,  and combined  hepatocellu-
lar carcinoma and adenoma  In mice (Tables  8-1  to 8-4),   As  seen from Tables
8-1  to 8-4, the  experimental   doses  were  multiplied  by   le/Le  In  order  to
expand  the  dose over  the entire experimental  period.   Because  the weights  of
the  rats  and mice  In the  different  treatment  groups varied,  each  dose  was
transformed  to  the  corresponding human  dose before  the  calculation  of  q *
by  multiplying  the  animal  dose by the cube root of the  ratio of  the animal
body weight  to  the  reference human  (70  kg)  body weight.  From  these doses,
human  q *  values  were  calculated   directly  using  the  computerized  multi-
stage  model  developed  by Howe  and Crump  (1982);  no further  adjustments  were
necessary.   The  highest   value,   an  adjusted  human   q *  of   8.36xlO"3
{mg/kg/day)"1 (Interim  value as discussed  later) was obtained  from  data  on
male mice.  This  value  differs  slightly  from the value estimated by U.S.  EPA
(1980b).   The  1980  value  was   calculated  before  the availability  of  NTP
(1982)   that   provided  estimates   of  doses  and   utilized  default  food
consumption  values.   The concentrations  1n drinking  water  corresponding  to
risk   levels   of  10"5,   10'6   and   10~7   are  4.19x10'2,   4.19xlO~3   and

0786p                               8-2                              08/31/86

-------
                                  TABLE  8-1

                    Cancer  Data  Sheet  for  Derivation  of  q-|*



Compound:  d1(2-ethylhexyl) phthalate

Reference:  NTP, 1982b

Species, strain, sex:  rat, F344/N,  male

Body weight:  0.4 kg (control);  0.36 kg (low dose);  0.32 kg (high dose]

Length of exposure (le) (weeks)  = 103

Length of experiment (Le)  (weeks) =  105 (0,  low dose);  104 (high dose)

Llfespan of animal (L) (weeks) =  105 (0, low dose);  104 (high dose)

Tumor site and type:  hepatocellular carcinoma or neoplastlc  nodules

Route, vehicle:  oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
322
674
Transformed Dose
(mg/kg/day)b
0
54.52
110.79
Incidence
No. Responding/No.
3/50
6/49
12/49
Examined

aThe  dietary  concentrations   were  0,  6000  or  12,000  ppm;  the  doses  1n
 mg/kg/day were provided by NTP (1982b).
bDose  x  le/Le  x  (WA/70)1/3  x   (Le/L)3
 WA = rat body weight
          transformed  dose  where  L=Le;
Unadjusted q-]* from study = not calculated (see text)
Human q-|* = 2.95xlO"3 (mg/kg/day)'1
0786p
8-3
05/15/86

-------
                                  TABLE  8-2
                    Cancer  Data  Sheet  for  Derivation  of  q-|*

Compound:  d1(2-ethylhexyl) phthalate
Reference:  NTP, 1982b
Species, strain, sex:  rat, F344/N,  female
Body weight:  0.27 kg (control); 0.26 (low dose); 0.23 kg (high dose)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105 weeks
Llfespan of animal (L) =  105 weeks
Tumor site and type:  hepatocellular carcinoma or neoplastlc nodules
Route, vehicle:  oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
394
774

Transformed Dose
(mg/kg/day)b
0
59.93
112.88

Incidence
No. Responding/No.
0/50
6/49
13/50

Examined



aThe rats were given 6000 or 12,000 ppm 1n the diet; the doses In mg/kg/day
 were provided by NTP (1982b).
bDose  x  le/Le  x  (WA/70)1/3  x  (Le/L)3 =   transformed  dose  where  L=Le;
 WA = rat body weight
Unadjusted q-j* from study = not calculated (see text)
Human q-|* = 3.52xlO"3 (mg/kg/day)'1
0786p                               8-4                              05/15/86

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                                   TABLE  8-3

                    Cancer  Data  Sheet  for  Derivation  of  q-|*



Compound:  dl(2-ethylhexyl) phthalate

Reference:  NTP, 1982b

Species, strain, sex:  mouse, B6C3F1,  male

Body weight:  0.04 kg (measured)

Length of exposure (le)  = 103 weeks

Length of experiment (Le) = 105 weeks  (0, low dose);  104 weeks (high dose)

Llfespan of animal (L) =  105 weeks (0,  low dose); 104 weeks (high dose)

Tumor site and type:  hepatocellular carcinoma or adenoma

Route, vehicle:  oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
672
1325
Transformed Dose
(mg/kg/day)b
0
54.70
108.89
Incidence
No. Responding/No.
14/50
25/48
29/50
Examined



aThe mice  were  given 3000  or  6000 ppm  1n  the  diet; the  doses  In  mg/kg/day
 were provided by NTP (1982b).

bDose  x  le/Le   x  (WA/70)1/3   x   (Le/L)3   =  transformed  dose  where  L=Le;
 HA = mouse body weight

Unadjusted q-|* from study = not calculated (see text)
Human q-j* = 8.36xlO~3 (mg/kg/day)'1
0786p                               8-5                              05/15/86

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                                  TABLE  8-4
                   Cancer  Data  Sheet  for  Derivation  of  q-|*

Compound:  d1(2-ethylhexyl) phthalate
Reference:  NTP, 1982b
Species, strain, sex:  mouse, B6C3F1, female
Body weight:  0.039 kg (control); 0.034 (low dose); 0.030 (high dose)
Length of exposure (le) = 103 weeks
Length of experiment  (Le) = 105 weeks
Llfespan of animal (L) =  105 weeks
Tumor site and type:   hepatocellular carcinoma or adenoma
Route, vehicle:  oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
799
1821
Transformed Dose
(mg/kg/day)b
0
61.61
134.68
Incidence
No. Responding/No.
1/50
12/50
18/50
Examl ned



aThe mice  were given 3000  or  6000 ppm  1n  the diet;  the  doses In mg/kg/day
 were provided by NTP (1982b).
bDose  x  le/Le  x  (WA/70)1/3  x  (Le/L)3  =   transformed   dose  where  L=Le;
 HA = mouse body weight
Unadjusted q-|* from study = not calculated  (see text)
Human q-|* = 4.73xlO~3 (mg/kg/day)'1
0786p                               8-6                              05/15/86

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4.19x10 *  mg/i,   assuming  a  70  kg  human  consumes  2  I/day.   Turnbull  and
RodMcks  (1985)   have  cautioned  that  using  rodent  data  to  estimate  d1(-
2-ethylhexyl)  phthalate-promoted   carcinogenic   risk  to   humans   may  ov-
erestimate  the  actual  risk.   This  caution  was  based  on  several  factors
Including  differences  between  rodents  and  primates   In  the  metabolism  of
d1(2-ethylhexyl)   phthalate,   a  nonlinear   relationship  between   the  ad-
ministered  dose  of  dl (2-ethylhexyl)  phthalate  and  the  dose  of  the  hypot-
hesized "proximate carcinogenic species"  In rodents,  the  fact  that  the  hypo-
thesized "proximate  carcinogenic  species"  1s  produced  to  a  greater  extent  In
rodents than  In  primates  and  differences  In  target site  sensitivities  bet-
ween humans and  rodents for  liver  tumors  In general.   These  factors have not
been evaluated as yet by EPA  to see 1f an alternate risk assessment approach
Is  warranted.   Until such  an  analysis Is  conducted  the  q * should be  con-
sidered to be an Interim value.
8,2.   DIETHYL PHTHALATE
    U.S. EPA  (1980b) derived an  RfD  of 13 mg/kg/day  for  (Methyl  phthalate.
This  value  was  based  on  a  chronic  oral  rat NOEL  of 1250 mg/kg/day  (2.5%
diet) defined by Food Research  Laboratories (1955)  and an uncertainty  factor
of  100.   Higher  doses  (5% diet)  caused a reduction 1n body weight.  A  rep-
roduction  study  by  Reel   et  al.  (1984)  demonstrated  that   F,   but  not
parental  mice exposed  to  2.5%  dlethyl   phthalate  In  the  diet  had  fewer
pups/litter,  Increased liver weights  (males and  females),  Increased prostate
weights,  decreased  sperm   concentration   and   Increased  pituitary  weight
(females only) 1n  comparison  with controls.  Assuming  that  mice  consume 13/4
of  their  weight  In  food/day,  2.5% Is equivalent to 3250 mg/kg/day, a  value
well above the NOEL  used to  derive the RfD.  Dlethyl  phthalate  did  not  cause
testlcular atrophy 1n rats  (Gray and Butterworth, 1980; Foster  et  al.,  1980).


0786p                               8-7                              08/31/86

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    Although In  general  H Is  preferable  to utilize chronic  data  over  sub-
chronic  data  for  RfD development,  deficiencies  1n  reporting  of  the  Food
Research  study   reduce  confidence  In  the  data.   Therefore,   based  upon  a
revaluation of  the two studies,  the  subchronlc  study of Brown et al.  (1978)
1s  chosen  as  the basis  of  the  RfD.   This study  defined a  NOAEL  of  750
mg/kg/day with decreased  body weight  and Increased liver  weight  seen  at  the
next highest exposure level.  Applying  an uncertainty factor  of 1000  (10  for
subchronlc  to  chronic,   10   for  Interspecles  variability and  10  for  1n-
terlndlvldual  variability)  results  In   an  RfD  of  0.75  mg/kg/day,  or  52.5
mg/day for a 70  kg human.
8.3.   DI-n-BUTYL PHTHALATE
    U.S. EPA (1980b) derived  an RfD of  1.3  mg/kg/day  based on a 52-week  oral
rat NOAEL  of  125 mg/kg/day (Smith, 1953)  and an uncertainty  factor of  100.
A  higher  dose  (1.25% diet  or 625 mg/kg/day)  caused  50% mortality within  1
week of  the  Initial  exposure  (Smith,  1953)..   A re-evaluation  of this  study
suggests  that  the  duration  was  not  truly  chronic  and  suffered from  def-
iciencies  of  limited  numbers of  animals  of  a single  sex.    These  factors
suggest  the  application  of  an  additional   uncertainty  factor  of  10.   The
resulting RfD estimate 1s  0.12 mg/kg/day (8.6 mg/day for  a 70  kg human).
    Onda et al.  (1974)  observed  the  formation  of  renal  cysts  1n the  FI  and
Fp  generations   of  3CL  and   ICR  mice  exposed  orally to  either  10  or  100
mg/kg/day  for  three  generations.   These doses  are below the  NOAEL used  by
U.S.  EPA  (1980a)  to  derive  the  RfD  for  d1-n-butyl phthalate.  Since  no
details  of the  Onda  et  al.   (1974)  study  were  reported, 1t  was  not  con-
sidered In risk  assessment.
    When  d1-n-butyl  phthalate  (0.12  or  0.6 g/kg/day)  was administered  to
rats  by gavage  during  gestation,  an  Increased  number   of resorptlons  and


0786p                               8-8                              10/09/87

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reduced fetal  body  weight were observed  at the 0.6 g/kg  dose  (Nlkonorow  et



al., 1973).  No gross skeletal effects  were observed.   Maternal  toxldty was



not reported,  but  significantly reduced  placental  weights were  observed  at



both doses.  Since  there  were no  effects on  reproductive  or  fetal  endpolnts



1n  rats  exposed  to 0.12  g/kg/day,  the  reduced  placental  weight  probably



represents  a NOAEL.   The  LOAEL for  this  study (0.6 g/kg/day)  Is well  above



the NOAEL  used  to derive the RfD.



    Shlota  et  al.  (1980)  and  Shlota  and  Nlshlmura  (1982) observed  maternal



toxldty,   fetotoxlclty  and  gross  external  malformations  1n  ICR mice  fed  1%



dl-n-butyl  phthalate  In  the  diet   (2100  mg/kg/day, as  provided  by  the  In-



vestigators)  on  days 0-18  of gestation.   Significantly reduced numbers  of



ossified coccygla were  observed at  all levels  of  treatment  (80,  180,  370  or



660 mg/kg/day),  but there were no  significant differences  between  controls



and  treated   mice  In  Incidences   of  skeletal  malformations,   lumbar  rib



variations  or   delayed  sternal  ossification.   Doses   <660  mg/kg/day  would



therefore   represent  NOAELs  for this  study  and 2100 mg/kg/day  represents  an



PEL.   01-n-butyl  phthalate  has  been  shown to cause  testlcular  atrophy  1n



rats,   but  only  at   doses  greater   than the  NOAEL   (125  mg/kg/day)   used  to



derWe  the  RfD  (Cater  et  al.,  1976, 1977;  Gray  et  al.,   1982;  Gray  and



Butterworth,  1980).  The  RfD of 0.1  mg/kg/day 1s  therefore  recommended  for



Ingestlon  of  d1-n-butyl  phthalate.



8.4.   DIMETHYL PHTHALATE



    U.S. EPA (1980b)  derived an RfD  of 10 mg/kg/day  for  dimethyl  phthalate



based  on a chronic  rat NOEL  of 1000 mg/kg/day and  an  uncertainty  factor  of



100.   Higher  doses  caused   chronic   nephritis and  decreased  growth  rate



(Lehman,  1955).   There  are  no  other  chronic  oral   studies  for   dimethyl



phthalate.    No adverse  effects  upon  reproduction,  growth  or  survival  of










0786p                               8-9                              10/09/87

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offspring were observed In mice gavaged with  dimethyl  phthalate  (3500 mg/kg)
on days 7-15 of gestation  (Booth et  a!.,  1983;  Plasterer  et al.,  1985).   The
pups were  not  examined  for  malformations.    Furthermore,  testlcular  effects
were not observed In rats  gavaged with  dimethyl  phthalate at doses equlmolar
to  those  at which  d1(2-ethylhexyl)  phthalate  caused  testlcular   atrophy  In
rats (Gray  and  Butterworth,  1980;  Foster et  al.,  1980).   A  Devaluation  of
the Lehman  (1959)  study suggests that  the  data as reported,  are  Inadequate
for RfD development.
8.5.   OI-n-OCTYL PHTHALATE
    The only available chronic study on d1-n-octyl phthalate  was  reported  In
an abstract  by  Plekacz (1971), In which  Wlstar  rats  were  given either  0  or
3500 ppm dl-n-octyl  phthalate  In  the diet for 7-12 months.  Assuming that a
rat consumes 5%  of  Us weight In food/day,  3500 ppm  Is equivalent to a  dose
of  175  mg/kg/day.   Females had elevated  kidney  and  liver  weights,  and  both
males and females had  Increased SGOT and  SGPT.   D1-n-octyl phthalate did not
cause  testlcular  atrophy  In  rats when  given orally  at  a  dose equlmolar  to
that at  which  dl(2-ethylhexyl} phthalate caused testlcular atrophy  In  rats
(Gray  and   Butterworth,  1980;  Foster  et  al.,  1980).   Furthermore,  adverse
effects on  reproduction  and  fertility  were  not  observed  In 2 generations  of
CD-I mice  fed  1.25,  2.5  or  5X  (12,500-50,000  ppm)  d1-n-octyl phthalate  In
the diet (Gulat! et al.. 1985).
    The data base  for  d1-n-octyl  phthalate  Is limited and does not  define a
NOAEL,   but  the  LOAEL of 3500  ppm (175  mg/kg/day)  could  be used to  derive a
provisional  RfO.  However, because  of  lack  of details of  data reporting,  an
RfD Is  not derived at this time.
0786p                               8-10                             08/31/86

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8.6.   n-BUTYL BENZYL PHTHALATE
    n-Butyl  benzyl  phthalate  has  been  tested  for  oncogenlclty  In  feeding
studies   on   F344   rats   and   B6C3F1   mice   conducted   by   NTP   (1982a).
Statistically  significant  Increases   In  the  Incidences  of mononuclear  cell
leukemia and  leukemia  or  lymphoma  were observed  In  female  rats.   Because of
the  normally  high  background  Incidence of  myelomonocytlc  leukemia  In  F344
rats,  and  because  dose-related  and  significant  decreases  In  malignant
lymphoma, all  lymphoma,  and  leukemia  or lymphoma were  observed  In  male  mice
In  the  same  study,  there  Is  Insufficient  evidence  to  conclude  that  n-butyl
benzyl  phthalate  Is   carcinogenic.   IARC  (1982a)  concluded  that  the  NTP
(1982a)  studies  are  Insufficient  to  assess  the  carcinogenic potential  of
                                                                         9
n-butyl   benzyl    phthalate.    The    equivalent   EPA   we1ght-of-ev1dence
classification for  this  compound  Is  Group C  meaning  that  there  Is  limited
animal   data   and   that   the  compound   Is  considered  a   possible   human
carcinogen.   It  Is  therefore  not  appropriate to derive  a q *  for  n-butyl
benzyl phthalate until further testing Is performed.
    Increased  mortality  caused by unexplained hemorrhaglng was  observed  In
male  F344  rats fed 6000 or  12,000 ppm  (300  or 600 mg/kg/day, us'lng  a  food
factor  of 0.05)  n-butyl  benzyl  phthalate  (NTP,   1982a).    The  study  was
terminated after  28 weeks.   In  90-day  feeding studies on  rats  conducted  by
Monsanto  (1972),  rats  were fed  0, 0.25,  0.5,  1.0,  1.5 or 2%  (0,  125,  250,
500,  750  or  1000 mg/kg/day)  n-butyl  benzyl phthalate, and dogs  were  fed  0,
1,  2  or 5X  (0,  250,  500  or  1250 mg/kg/day)  n-butyl   benzyl  phthalate.   No
adverse effects were observed  among dogs  fed  n-butyl benzyl phthalate  at any
level,  or  among  rats fed  125  or  250 mg/kg/day  n-butyl   benzyl  phthalate.
Increased  liver  weights  without  accompanying  hlstopathologkal  changes  were
observed  among  rats  fed  500-1000   mg/kg/day  n-butyl  benzyl  phthalate.


0786p                               8-11                             09/01/87

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Dietary  concentrations  of  2.5  or  5% have  been  shown  to  cause  testlcular
atrophy 1n a 14-day study on rats  (Agarwal et al., 1985).
    In the NTP  (1985)  study,  rats were fed  dietary  levels  of  0,  0.03,  0.09,
0.28 and  0.83%  butyl  benzyl phthalate.  Using data  presented  1n  the report,
these  dietary  levels  correspond  to  ~0r  17, 51,  159 and 470  mg/kg/day.   At
2.5%,  weight  gain  was  significantly depressed  and  testlcular  and  kidney
lesions  were  apparent.    In  addition,   I1ver-to-body  weight  ratios   were
Increased  and   hematologlcal  evaluations   suggested  a  pattern of  Increased
erythrocyte  turnover.    At  0.83%,  the  only  effects   noted were  Increased
absolute  liver   weight,  Increased  I1ver-to-body  weight  and  I1ver-to-braln
weight ratios and Increases In mean corpuscular hemoglobin.
    Using  the   NOEL  of  159  mg/kg/day  (0.28%)  and  applying  an  uncertainty
factor  of  1000, an  RfD  of  11.1   mg/day  could  be  developed;  however,  this
value  would  not be  protective for  potential  carcinogenic  effects of  this
compound.
8.7.   DIISONONYL PHTHALATE
    The  database  for  d11sononyl  phthalate  Is   restricted   to  unpublished
studies  conducted  by  Livingston   (1971)  and  reported  1n  Krauskopf  (1973).
Dogs were  dosed orally (method  not specified) to 0, 0.125,  0.5%  or  a  TWA of
2.8%   (0,  31.25,  125  or   700  mg/kg/day   using  a  food  factor  of  0.025)
d11sononyl  phthalate  for  13  weeks,   with  apparently  only  one dog/level  of
treatment.  Rats were  exposed orally  to  0,  50,  150 or 500  mg/kg/day  for  13
weeks.  A  slight  reduction  In  growth  rate  and  Increased   liver  weight
(absolute  or  relative  not  specified) were  observed  In high-dose  rats.   No
effects  were  reported  for   rats treated with 50  or  150  mg/kg/day dllsononyl
phthalate.  The dog treated  with  a   TWA  of 2.8%  (700  mg/kg/day)  dllsononyl
0786p                               8-12                             10/09/87

-------
phthalate had decreased  body  weight,  Increased  liver  weight and histologlcal



changes  In  the  liver,  gall  bladder  and  spleen.   The  dog  given  0.5%  (125



mg/kg/day}  dllsononyl  phthalate  had Increased liver  weight;  no effects  were



observed  at  0.125% (31.25 mg/kg/day).   This  report  1s  considered Inadequate



for RfD development.



8.8.   SUMMARY



    An  Interim  q  *   of   8.36xlO"3   (mg/kg/day)"1   was   derived  for   d1(2-



ethylhexyl)  phthalate  based on the Incidence of  hepatocellular  carcinoma  or



adenoma In  male  mice  In  the NTP  (1982b)  study.   The  concentrations  In  water



associated  with   risk   levels  of  10"5,  10"6  and   10"7   are  4.19xlO~2,



4.19xlO"3  and  4.19xlO~4  mg/s.,   assuming  that  a  70  kg  human  consumes   2



l/day.



    An  RfD   of   0.75  mg/kg/day  (52.5  mg/day)   for   dlethyl  phthalate,  was



derived based  on a chronic oral  rat  NOEL of  750 mg/kg/day  1n  the  study  by



Brown  et  al.  (1978}  and  using  an uncertainty  factor  of  1000.  An RfD  of



0.125  mg/kg/day  (8.8  mg/day)  for d1-n-butyl  phthalate  was  derived.   The



value  Is  lower by  a factor  of  10  than  that derived by U.S. EPA (1980b)  based



on a  52-week  oral  rat  'NOAEL of 125 mg/kg/ day In  the study  by Smith (1953).



The difference Is  In the  uncertainty  factor with  1000.   The U.S. EPA (1980b)



derived an  RfD of  10  mg/kg/day (700 mg/day)  for  dimethyl  phthalate based  on



a chronic rat NOAEL of 1000 mg/kg/day  1n  the  study by Lehman (1955) using  an



uncertainty  factor of  100.   A   revaluation  suggested  that  this report



provides an Inadequate basis for  RfD development.



    The only  data  available for  d1-n-octyl  phthalate based  on  a  subchronlc



rat  LOAEL  of 175  mg/kg/day In the study  by  Plekacz  (1971)  were  considered



Inadequate  for risk assessment.   An RfD of 0.16  mg/kg/day (11.1 mg/day) was



derived for  n-butyl  benzyl phthalate  based  on  a subchronlc  rat  NOEL of  159










0786p                               8-13                             10/09/87

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mg/kg/day  In  the  NTP  (1985) study.  An uncertainty  factor  of  1000 was_used.
It should  be  noted  that  butyl  benzyl  phthalate  has been classified as an EPA
Group  C  carcinogen.  The  proposed RfD would  not necessarily  be  protective
for potential carcinogenic  effects.  An RfO  was  not  developed  for  dllsononyl
phthalate because of limited data.
0786p                               8-14                              08/31/86

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                           9.   REPORTABLE QUANTITIES



9.1.   REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY



    Oral  studies  have  shown  that  d1(2-ethylhexyl),   d1-n-butyl  and  d1-n-



heptyl phthalates can produce adverse effects  upon  the  developing  fetus  when



mice and  rats  are  exposed during gestation  (Wolkowsk1-Tyl,  1984a,b;  Bell  et



al.,  1979;  Bell, 1980; Shlota  and Mima,  1985;  Shlota  and  Nlshlmura,  1982;



Shlota et al.,  1980;  Nakamura  et al., 1979; Yag1 et al.,  1978,  1980;  Tomlta



et  al.,  1982b;  Onda et al.,  1974).   These studies  are summarized  In  Tables



5-4  and   5-5.   Whether  the  observed effects  (reduced  fetal  weight,  fetal



mortality,  gross  external and  skeletal  malformations)  represent  a  primary



effect  of the  compound  1n question  or  whether  they  occur as  a  result  of



maternal  toxlclty  has   yet   to   be   demonstrated   unequivocally.    Studies



conducted by NTP (Holkowskl-Tyl et al.,  1984a,b)  Indicate  that mice  are  more



sensitive than rats.



    Chronic or  subchronlc  oral  studies  have been conducted  with d1(2-ethyl-



hexyl),  d1-n-butyl,  dimethyl,   d11sononyl,  n-butyl  benzyl  and  dl-n-octyl



phthalates  (Carpenter  et  al.,  1953;  Harris  et al.,  1956; Nlkonorow  et  al.,



1973;  Gray  et  al.,  1977;  Gangolll, 1982;  NTP,  1982a,b; Kluwe  et al.,  1982b;



Shaffer  et  al.,  1945; Popp et al.,  1985;  Canning et al., 1985; Nagasaki  et



al., 1974;  Ota  et  al.,  1974;  Lake et al.,  1976,  1977a; Haslenko,  1968;  Food



Research  Laboratories, 1955;  Brown  et al., 1978; Smith,  1953; Lefaux,  1968;



Plekacz,  1971;  LeBreton,  n.d.;  Bornmann  et al.,  1956;  Lehman, 1955;  Living-



ston,  1971; Monsanto,  1972).   Liver,  kidneys and testes  appear  to  be target



organs.   Relevant  Inhalation  studies could  not  be  located  1n the  published



literature as dted 1n the Appendix.



9.1.1.    D1(2-ethylhexyl)   Phthalate.   Relevant  chronic  and subchronlc  data



for d1(2-ethylhexyl) phthalate are  summarized  1n Table  5-7.  The most severe










0787p                               9-1                               06/06/86

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effects  occurring  at  the  lowest dose  were the  teratogenlc  effects In  the
offspring of  mouse  dams  treated by  gavage  wHh  91,  191 or 292 mg/kg/day  on
days 0-18 of  gestation 1n  the Wolkowsk1-Tyl et  al.  (1984b) study  (see  Table
5-4).   These  effects   (external  and   visceral  malformations  and  skeletal
defects)  occurred  1n   the  absence  of  signs  of  maternal  toxlclty  at   91
mg/kg/day, warranting  an  RV  of 10.   The  dose of 91 mg/kg/day (measured  by
Investigators) was multiplied by  the cube  root of the  ratio  of mouse weight
(0.029 kg; measured) to  the reference human weight  (70 kg) and by  the  human
weight (70 kg)  to  obtain  a  human MED of 475 mg/day, which  corresponds  to  an
RV   of  1.5.   Multiplying   the  RVg   by  the  RVd  yields  a  CS  of  15,  corre-
sponding  to  an RQ of  1000.  Equivalent or  less  severe effects occurred  at
higher doses;  therefore, calculation of a CS for  these  effects  1s  not  neces-
sary.  The only doses  lower than 91  mg/kg/day  at  which  effects  occurred were
19  and 64 mg/kg/day, at which  guinea  pigs  treated for  1 year  had  Increased
relative  liver  weights.   The RV&  1s 4.  Multiplying the  dose of  19  mg/kg/
day by the cube root of  the ratio of the  reference guinea  pig weight of 0.83
kg  (Durkln,  1985)  to  the reference  human  body weight  (70  kg)  and  by  70  kg
results  1n  an MED of  304 mg/day,  which corresponds  to an  RV  of  1.8.   The
CS  1s  7.2, which corresponds to an RQ of 1000.
9.1.2.   Dlethyl Phthalate.   Toxldty  data  for dlethyl  phthalate  are  summa-
rized  In  Table 5-8.  The  most severe effect 1s  the  reduced sperm  concentra-
tion and  reduced  numbers  of pups/Utter  1n F, mice exposed  to 2.5% dlethyl
phthalate In  the  diet  (Reel  et  al., 1984).  Assuming  that a mouse consumes
13X of Us  weight 1n  food/day,  2.5X 1s  equivalent to a dose of 3250  mg/kg/
day.   Multiplying 3250 mg/kg/day by  the cube root  of the  ratio  of  the  refer-
ence mouse weight  (0.03 kg) to  human weight (70  kg), and  by the human  weight
(70 kg)  yields a  human  MED of  17,152 mg/day,  which  corresponds   to an  RV.
0787p                               9-2                              06/06/86

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of  1.   An  RV   of  8  1s  assigned   on  the  basis  of  reduced  reproductive
capacity.   Multiplying  the RVg  by  the RVd  yields a CS  of 8, which  corre-
sponds  to  an RQ of  1000.   U.S.  EPA  (1983b)  derived  an RQ of  5000  based  on
the  2-year study  by  Food  Research  Laboratories  (1955),  In  which  rats  had
significantly  reduced  body  weight  gain  (RV =4)  at  a  dietary  level  of  5%
(2500  mg/kg/day;  MED=29,925 mg/day;  RVd=l).  The  CS  1s  4.    The  reproduc-
tion  study  of Reel et al.  (1984) was  not  available during the  preparation  of
the previous RQ document by U.S.  EPA (1983b).
9.1.3.   D1-n-Butyl  Phthalate.   Toxldty  data  are  summarized  In Table  5-9
and  teratogenldty  data   are  summarized  In  Table   5-5.   The  most  severe
effects  were  the  fetotoxldty,  teratogenldty  and maternal toxldty  In  ICR
mice  exposed  orally  to   2100  mg   d1-n-butyl  phthalate/kg/day   (Shlota  and
Nlshlmura,  1982;  Shlota  et al., 1980).   These  effects  warrant an RV   of  9.
Multiplying  2100  mg/kg/day by  the product of  the  cube  root of the  ratio  of
mouse  weight  (0.03 kg;  measured) to  human weight  (70 kg), and by  the  human
weight  (70  kg)  yields  a human  MED of  11,083 mg/day,  which  corresponds  to  an
RVrf  of  1.  Multiplying   the  RVg   by  the   RV   yields   a  CS   of  9,  corre-
sponding to an RQ of 1000.
    Onda  et al.  (1974)  apparently  observed  renal cysts  1n   the  F,  and  F_
generatlons  of  rats  treated orally with  10  or  100 mg  d1-n-butyl  phthalate/
kg/day  for three  generations.    Since no  details  were  provided,   this  study
could not be considered 1n the  derivation  of  an RQ.
    Smith  (1953)  observed 50%  mortality  (5/10)  within   1  week  of   dally
exposure  to  1.25X (625  mg/kg/day)  
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exhibit pathologic  or  hematologlc effects  after  1  year  of treatment  (U.S.
EPA, 1983a).  Furthermore, using  these  data to derive a  CS would  not  result
1n an RQ >1000 .
    Shlota  et al.  (1980) and  Shlota  and  Nlshlmura  (1982)  fed  d1-n-butyl
phthalate  to  ICR  mice  on  days  0-18  of  gestation.   In  addition  to  the
maternal toxldty,  fetotoxldty and  gross  external  malformations  observed  at
2100  mg/kg/day,   there   were   significantly   reduced  numbers   of  ossified
coccygla at  all  levels  of  treatment (80,  180,  370  or  660 mg/kg/day),  but
there were  no significant differences  between  controls  and treated mice  1n
Incidences  of  skeletal  .malformations,  lumbar  Mb  variations  or  delayed
sternal ossification.  In a previous  RQ determination, U.S. EPA  (1983a)  used
delayed ossification  at  80 mg/kg/day as  the  basis  for  the  RQ of  1000.   An
MED  of  420 mg/day,  an  RV, of  1.6 and an  RV  of  8 were calculated  yield-
Ing  a  CS  of  12.8  and  an RQ of  1000.  Nlkonorow et al.  (1973)  treated  rats
wHh  600  mg/kg/day on days  0-21 of  gestation  and  found reduced  fetal  body
weight  and   Increased  numbers  of  resorptlons  (RV =8).   Multiplying  600
mg/kg/day  by  the cube root of  the rat weight  (0.165 kg with study)  to the
human weight  (70 kg) and  by  70 kg  results  1n an MED of 5590 mg/day,  which
corresponds to an RV. of  1.  The CS of 8 corresponds to an RQ  of  1000.
     In  subchronlc  studies,  Nlkonorow  et  al.  (1973)  found Increased  liver
weight  without  hlstologlcal   evidence  of  liver  damage  (RV =4)  1n  rats
treated  with >120 mg/kg/day  for 3  months;  however,  no  treatment-related
effects were  observed  1n rats given  0.125% 1n  the  diet  (62.5  mg/kg/day) for
1  year.   Therefore,  H 1s not necessary  to divide  the  subchronlc  dose by an
uncertainty  factor of 10,  because  the resulting  dose  would  be  well  below
62.5  mg/kg/day.  Multiplying  120  mg/kg/day  by the  cube  root of the reference
 0787p                               9-4                              06/06/86

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rat  weight  (0.35  kg)  to  70  kg, and  by 70  kg,  results  In  an  MED  of  1436
mg/day, corresponding  to  an RV   of  1.   The  CS  of  4 would  correspond  to  an
RQ of 5000.
    Ota et  al.  (1974)  observed  marked degenerative changes  In  the  liver  and
kidneys of  mice  given  500 or  5000 mg/kg/day  for  3  months.   This  Information
was  taken  from an  abstract,  which  provided  little detail;  therefore,  this
study was not considered for RQ  derivation.
9.1.4.   Dimethyl  Phthalate.   ToxUUy  data  are summarized  In  Table  5-10.
Lehman  (1955)  observed chronic  nephritis   (RV =7)  1n rats  fed  8%  dimethyl
phthalate and  decreased  body  weight  (RV =4)  1n  rats fed  4%  dimethyl  phtha-
late  for 2  years.   Assuming that  a  rat  consumes  5%  of Its weight  In  food  per
day,  8X  Is  equivalent  to  a dose of 4000 mg/kg/day and  4X  1s equivalent  to
2000  mg/kg/day.   Multiplying  2000 and 4000  mg/kg/day by the product  of  the
cube  root of  the  ratio of rat weight  (0.35  kg;  assumed)  to  human weight  (70
kg;  assumed),  and  human  weight  (70   kg)  yields human  HEDs  of  23,940  and
47,879 mg/day,  respectively.   Both  MEDs correspond  to   RV s  of  1.   Multi-
plying  the  RV   by the  RV s  of  4  and  7  yields  CSs  of 4  and  7,  respec-
tively, corresponding to RQs of  5000 and 1000, respectively.
9.1.5.   D1-n-0ctyl  Phthalate.    Only  two   chronic  toxldty  studies  were
available for  the assessment  of  d1-n-octyl  phthalate (see Table 5-10);  the
2-generat1on  reproduction  and fertility  assessment  conducted  by  Gulat!   et
al.  (1985)  on  CD-I mice,  and  the 12-month  toxldty  study by  Plekacz  (1971)
conducted on Wlstar rats.  No effects were  observed by Gulatl  et al.  (1985).
A CS  of  6  can be derived from Plekacz (1971) on  the  basis  of  elevated  liver
and  kidney  weights  (female  rats)  and  Increased  SGOT  and  SGPT  (male  and
female)  1n  rats  fed   3500  ppm   d1-n-octyl  phthalate.  Assuming that  a  rat
consumes 5X of  Us  body  weight  1n food per day,  3500 ppm  1s  equivalent to  a
0787p                               9-5                              06/06/86

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dose of  175 mg/kg/day.  Multiplying  175 mg/kg/day by  the cube root  of  the
ratio of rat  weight  (0.35  kg; assumed)  to human weight  (70  kg;  assumed)  and
human weight  yields a  human MED  of   2095  mg/day.  The  MED 1s assigned  an
RV.  of  1.   The  RV  of  6  Is  assigned  on  the basis  of  the above  effects.
Multiplying the  RV  by  the  RV   yields  a CS  of   6.   The RQ for  dl-n-octyl
phthalate Is therefore 1000.
9.1.6.    n-Butyl  Benzyl  Phthalate.   The toxlclty  data  for  n-butyl  benzyl
phthalate are  summarized  on Table  5-10.   In  a chronic dietary  study,  there
was  a  dose-related and significant early  mortality from  unexplained  hemor-
rhaglng  1n  male  F-344 rats  fed  6000  or  12,000 ppm n-butyl  benzyl  phthalate
In  the  diet for  28 weeks  (NTP,  1982a).   In  a subchronlc study by  Monsanto
(1972),  the only  effect  \n  rats  treated for  90 days  was   Increased  liver
weight  at   >10,000  ppm.   Since  the discrepancy cannot  be  resolved,  a  CS  for
the  mortality  1s calculated.  Assuming  that  a rat consumes  554 of  Us  body
weight  In food  per  day,  6000 ppm  1s  equivalent to 300 mg/kg/day.   Multiply-
ing  300  mg/kg/day  by  the  cube root of the  ratio  of rat weight  (0.375  kg  In
the  study)  to  human weight  (70 kg) and  by the human weight  (70  kg)  yields  a
human  dose  of  3674 mg/day.   Because the  mortality  occurred  during  15-28
weeks,   the  dose  should  be  divided  by  an  uncertainty  factor  of  10.   The
resultant MED  of 367  mg/day  corresponds  to  an RV. of  1.7.   Multiplying  the
RV   by  the RV   of 10  for   mortality  results In  a CS  of 17,  which  corre-
sponds  to an RQ of 1000.
9.1.7.    D11sononyl Phthalate.   The only studies   available  for  the assess-
ment  of dllsononyl  phthalate  are  unpublished   studies   on  dogs  and  rats
conducted by  Livingston  (1971)  and reported  by  Krauskopf (1973)  (see  Table
5-6).  The  RQ Is based on  slightly reduced growth rate  and  Increased  liver
weight In rats  treated with  500  mg dllsononyl  phthalate/kg/day  for 13  weeks.
0787p                               9-6                              06/06/86

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Dividing 500  mg/kg/day  by 10 and multiplying  by the cube root of  the  ratio
of reference  rat  weight  (0.35  kg)  to the  reference  human  weight  (70  kg)  and
human weight  (70  kg)  yields a  human MED  of  598 mg/day.   The MED  Is  corre-
sponds  to  an  RV   of  1.3.   An  RV   of   4  Is  assigned  on the  basis  of  the
above effects.   Multiplying the  RV  by  the  RV   yields   a  CS  of  5.2.   The
dog(s) given  a TWA concentration of  2.8% had hlstologlcaal changes  In liver,
gall   bladder, spleen  and  kidney.   Assuming  that  a  dog  consumes  a  dally
amount of  food equal  to  2.5% of  Us body weight, the  2.8%  concentration  1s
equivalent   to 700 mg/kg/day.   Dividing  by  an  uncertainty factor of 10  and
multiplying by the cube root of the  reference  dog weight  of  12.7  kg (Ourkln,
1985) to the  human weight,  and  by 70 kg,  results In an MED of 2774  mg/day.
The  RVrf  Is  1,  the  RVg  Is  6 and  the  CS  1s  6,  which  corresponds  to an  RQ
of 1000.
9.1.8.   D1-n-Heptyl   Phthalate.   The  only  available   study  of  dl-n-heptyl
phthalate  1s  the  teratogenlcHy study by  Nakashlma  et al.  (1977),  reported
as an abstract (see Table 5-5).  It  1s  not appropriate to calculate a CS  for
this   study,  because,  In  the  absence of   other  toxlclty  data,  1t Is  not  known
1f fetotoxldty and teratogenlclty are the most  sensitive  endpolnts  for  this
chemical.  Furthermore,  the  data were not clearly presented.
9.1.9.   Summary.    CSs  were  calculated  for   d1(2-ethylhexyl)  phthalate,
dlethyl   phthalate,   d1-n-butyl   phthalate,  dimethyl  phthalate,   d1-n-octyl
phthalate,   n-butyl  benzyl phthalate and  dllsononyl  phthalate  (Table  9-1).
In each  case, the data  that  resulted  1n  the  highest  CS  are recommended  as
the bases  for  the RQs  (Tables 9-2  to 9-8).  The RQ for each of  the  phthalate
esters  listed above  1s  1000.   Data were  not  sufficient  for deriving an  RQ
for the other phthalate esters  discussed 1n this document.
0787p                               9-7                              06/06/86

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                                                                   lABlf 9-1



                                                Summary of RQs Derived for Phthallc Acid Esters
0
—J
GO
-0
o





i
co





o
o»
•*>,
o
0>
^^
00
cr
Compound Species
(bw/kg)
Olethylhexyl phthalate guinea pig
mouse
Dlethyl phthalate rat
mouse
Dlbutyl phthalate rat
rat
mouse
mouse
Dimethyl phthalate rat
rat
Dloctyl phthalate rat
n-Butyl benzyl male rat
phthalate
Dltsononyl phthalate rat
dog
Animal Dose
(mg/kg/day)
19
91
?500
3250
600
1?0
2100
80
4000
2000
175
300
500
700
Chronic
Human MED
(rag/day)
305
475
29.925
17.152
5.590
1.436
11.083
420
47.879
23.940
2.095
367'
598*
2.774'
RVd
1.8
1.5
1.0
1.0
1.0
1.0
1.0
1.6
1.0
1.0
1.0
1.7
1.0
1.0
Effect
Increased relative
liver weight
leratogenlctty without
maternal toxlclty
Reduced body weight
Decreased sperm concen-
tration; reduced number
of pups/Utter In F )
Increased fetal resorp-
tlons; decreased fetal
body weight
Increased liver weight
Fetotoxlclty; terato-
genlclty; maternal
toxlclty
Eetotoxlclty
Chronic nephritis
Decreased body weight
E levated liver and
kidney weights (f ):
Increased SCOT and
SGPT (male and female)
Mortality due to unex-
plained hemorrhagtng
Slightly reduced growth
rate; Increased liver
weight
Hlstologlc changes In
1 Iver , gallbladder ,
spleen and kidney
RVe CS RQ Reference
4 7.2 1000 Carpenter
et al.. 1953
10 15 1000 Molkowskl-lyl
et al.. I984b
4 4 5000 Food Research
Lab.. 1955
8 8 1000 Reel et al. .
1984
8 8 1000 Nlkonorow
et al.. 1973
4 4 5000 Nlkonorow
et al.. 1973
9 9 1000 Shlota and
Nlshlmura.
1982; Shlota
et al.. 1980
8 12.8 1000 Shlota
et al.. 1980
7 7 1000 Lehman. 1955
4 4 SOOO Lehman. 1955
6 6 1000 Plekacz. 1971
10 17 1000 NTP. 1982a
4 4 5000 Livingston.
197)
6 6 1000 Livingston,
19M
"The    e was divided by 10 to approximate chronic  exposure

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                                  TABLE 9-2



                          D1(2-ethylhexyl)  Phthalate



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







Route:                   oral



Dose*:                   305 mg/day



Effect:                  teratogenk!ty  without maternal toxldty



Reference:               Wolkowskl-Tyl  et al., 1984b



RVd:                     1.5



RVe:                     10



Composite Score:         15



RQ:                     1000
'Equivalent human dose
0787p                               9-9                             05/15/86

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                                  TABLE 9-3

                              Olethyl Phthalate

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



Route:                   oral

Dose*:                   17,152 rug/day

Effect:                  reduced  number  of  pups/Utter; decreased  sperm
                        concentrations

Reference:               Reel  et  a!.,  1984

RVd:                    1

RVe:                    8

Composite Score:         8

RQ:                     1000
*Equ1valent human dose
0787p                               9-10                             05/15/86

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                                  TABLE 9-4



                             D1-n-butyl  Phthalate



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







Route:                   oral



Dose*:                   420 mg/day



Effect:                 fetotoxUHy



Reference:               Shlota  et al.,  1980



RVd:                    1.6



RVe:                    8



Composite Score:         12.8



RQ:                     1000
*Equ1valent human dose
0787p                               9-11                             06/06/86

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                                  TABU 9-5



                              Dimethyl  Phthalate



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







Route:                  oral



Dose*:                  47,879 mg/day



Effect:                 chronic nephritis



Reference:              Lehman, 1955



RVd:                    1



RVe:                    7



Composite Score:        7



RQ:                     1000
'Equivalent human dose
0787p                               9-12                             05/15/86

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                                  TABLE 9-6

                             D1-n-octyl  Phthalate

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



Route:                  oral

Dose*:                  2095  mg/day

Effect:                 elevated liver  and kidney  weights;  Increased  SGOT  and
                        SGPT

Reference:              Plekacz, 1971

RVd:                    1

RVe:                    6

Composite Score:         6

RQ:                      1000
'Equivalent human dose
0787p                               9-13                             05/15/86

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                                  TABLE 9-7



                           n-Butyl  Benzyl  Phthalate



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







Route:                  oral



Dose*:                  367 mg/day



Effect:                 mortality



Reference:              NTP.  1982a



RVd:                    1.7



RVe:                    10



Composite Score:         17



RQ:                     1000
*Equ1valent human dose
0787p                               9-14                             05/15/86

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                                   TABLE 9-8

                             Dllsononyl Phthalate

          Minimum Effective Dose (MED) and Reportable  Quantity  (RQ)
Route:                   oral

Dose*:                   2774

Effect:                  hlstologlc changes  1n liver, gall bladder, spleen and
                         kidney

Reference:                Livingston,  1971

RVd:                     1

RVe:                     6

Composite Score:          6

RQ:                      1000
*Equ1valent human  dose
0787p                                9-15                             05/15/86

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9.2.   WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED1Q) FOR CARCINOGENICITY
9.2.1.   D1(2-Ethylhexyl) Phthalate.   In lifetime feeding  studies  conducted
by  NIP  (1982b),  dl(2-ethylhexyl}  phthalate  was  shown  to cause  Increased
Incidences  of  liver   neoplasms   In  F344/N  rats   (hepatocellular  carcinoma,
hepatocellular  carcinoma  or  neoplastlc nodules) and  1n  B6C3F1  mice (hepato-
cellular  carcinoma,  hepatocellular  carcinoma  or  adenoma).   This  study  was
discussed  In  detail  In Section  5.1.  and Is summarized  1n  Table  5-3.   Based
on  these  results,  IARC (1982b)  concluded  that there  1s  sufficient evidence
that d1 (2-ethylhexyl)  phthalate  Is carcinogenic  for  rats  and mice.   No  human
studies  were  available  for   evaluation.   IARC  has   ranked  d1(2-ethylhexyl)
phthalate as  a  group  28  compound.   Using  the EPA scheme,  this  compound  can
be classified as a 82 chemical (U.S.  EPA, 1986b).
    Since d1{2-ethylhexyl) phthalate  Is  probably  carcinogenic  for  humans,  H
1s appropriate  to derive  a   potency factor.   As  discussed  1n  Chapter 8,  the
highest  q^,   a  value  of   8.36xlO~3  (mg/kg/day)'1  (Interim  value),   was
calculated  from  the  data  on   Increased Incidence  of  hepatocellular  carcinoma
or  adenoma  In  male  mice;   therefore,   the  same  data  are   used  In   the
calculation of  F.   The   doses  used  In  the multistage  model  were  adjusted
before the calculation of the q * as  follows:
                      dose x  le/L£  x  (WA/70)1/3 x  UE/L)3
where  le = length of treatment study
       U = length of study
       W. = animal body weight
       L  = Hfespan of the animal; In this  case L=L..
0?87p                               9-16                             08/28/87

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In  order   to  obtain  a  human  1/ED,Q(F),  adjustments  for  body  weight  and
less-than-Hfetlme  exposure are  normally  applied  to the  unadjusted  animal
l/EQ,n  obtained   from  the  computerized  multistage  model.   However,  since
body  weight  varied  1n  some  of  the  dose  groups  In  the NTP  (1982b)  study,
these  adjustments  were  applied   to   the  doses  before   the  calculation  of
l/ED,n.   The  resulting  l/ED,n   1s  thus  adjusted  (human)  F  values  (Table
9-9).   Because   the   F   factor   of   5.14xlO~2  (mg/kg/day)"1  Is   <1,   d1(2-
ethylhexyl)  phthalate   Is  placed  In  Potency  Group  4.    An  EPA  Group  B2
chemical  In  Potency  Group  4  has a  low  hazard  ranking  under CERCLA.   The
potency value  1s  considered  Interim  because  there  Is   evidence  suggesting
that  metabolites   may  be  responsible  for   the  effects.   EPA has  not  yet
evaluated   the  possibility  of  utilizing  metabolized dose as  a  means  of
accomplishing the  Interspedes  conversion  for  the  quantitative  estimate.
Until EPA  evaluates  the cancer data  In the context of  potential  differences
1n metabolized  dose  the  q,*  should be  viewed as an  Interim estimate.
    Some  dispute  exists,  however,   concerning  whether   rodent  studies  on
d1(2-ethylhexyl)   phthalate  can  be  used   to quantify  potential  effects  In
humans  (Northrup  et  al.,  1982;  Kluwe  et al.,  1983; Turnbull and  Rodrlcks,
1985).   These   doubts  are  based  primarily   on  differences   In   the   way
d!(2-ethylhexyl)    phthalate  Is  metabolized  In   rodents  and   humans,   and
hypotheses that  the  proximate carcinogenic   species Is produced to a  greater
extent  In  rodents  than  1n  humans  (Turnbull  and Rodrlcks,  1985)  (see Section
5.1.).  Turnbull  and Rodrlcks  (1985)  suggest that  human  potency  factors  for
d1(2-ethylhexyl)   phthalate  that   are  based on  rodent  data  probably  over-
estimate the carcinogenic  risk of  d1(2-ethylhexyl) phthalate for  humans.
0787p                               9-17                             08/28/87

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                                  TABLE  9-9
                       Derivation of Potency Factor (F)
                       Agent:  D1(2-ethylhexyl)  Phthalate
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or
physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/
exposure (ml/kg):

Transformed doses*
(mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
1/ED10 (F factor):
NTP. 1982b
Oral
Mouse
B6C3F1
Male

Diet
0.04 kg
103 weeks
105 weeks (low dose); 104 weeks (high dose)
105 weeks (low dose); 104 weeks (high dose)
Liver
Hepatocellular carcinoma or adenoma
0
0
3000
 672
6000 ppm
1325 mg/kg/day (measured)
0           54.7        108.89
14/50       25/48       29/50
Not calculated (see text)
5.14xlO~2 (mg/kg/day)"1
*For all data  from NTP  (1982b),  doses were  transformed  prior  to  calculation
 of  1/EO-)Q due  to  differences  between  treatment  groups  1n  body  weight:
 dose x le/Le x (0.04/70)1/3 x (Le/L)3 = transformed dose,  where Le/L = 1
0787p
        9-18
                             05/15/86

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9.2.2.   n-Butyl  Benzyl  Phthalate.   n-Butyl benzyl  phthalate  has also  been
tested  for  oncogenldty  In  feeding studies on  F344/N rats and  B6C3F1  mice
conducted by  NTP  (1982a).   These data are  discussed  In Section 5.1.  and are
summarized  In  Table 5-2.  Based  on the observation  of  increased Incidences
of  mononuclear  cell leukemia  and  leukemia  or  lymphoma In  female  rats,  NTP
(1982a)  concluded that  n-butyl  benzyl  phthalate was  "probably carcinogenic
for  female   F344/N  rats."   In  a  separate report,  however,   Kluwe  et  al.
(1982a)  concluded  that   since  the  background  Incidence  of  myelomonocytIc
leukemia  Is  normally high In  F344/N  rats,  results presented  In  NTP  (1982a)
provide  only  equivocal  evidence  of n-butyl benzyl  phthalate-lnduced  cancer
In  female  rats.   Furthermore,   the fact  that  dose-related and  significant
decreases In  malignant  lymphoma,  all  lymphoma  and  leukemia  or  lymphoma  were
observed  In male  mice  (NTP,  1982a)  adds  to  the  uncertainty that  n-butyl
benzyl  phthalate  may cause  cancer  1n humans.   IARC   (1982a)  concluded  that
the  NTP  (1982a)   studies   are   Insufficient  to  assess   the  carcinogenic
potential of n-butyl benzyl phthalate.
    Based on  the   normally high  background  Incidence  of  leukemia  In  F344/N
rats,  on  the compound-related decreases  In leukemia  and  lymphomas  In  male
B6C3F1  mice,  and  on Interspecles  differences  In  the metabolism of  phtha-
lates,  the   NTP   (1982a)  study  provides  only  limited evidence  of  n-butyl
benzyl   phthalate-lnduced   carclnogenlclty.    Therefore,   n-butyl   benzyl
phthalate Is  best  classified  as an  EPA Group  C  chemical,  albeit  with  no
potency factor derived.
9.2.3.   Other  Phthalate  Esters.   Other   phthalate  esters  have  not  been
tested for oncogenldty.   These compounds are best classified In EPA Group D.
0787p                               9-19                             08/28/87

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Wolfe, N.L., W.C.  Steen and  L.A. Burns.  1980.   Phthalate  ester  hydrolysis:



Linear  free energy  relationships.    Chemosphere.   9:   403-408.   EPA  600/J-



80-016.







Wolkowsk1-Tyl,  R., C.  Jones-Price and H.C.  Harr.   1984a.   Teratologlc  evalu-



ation  of dlethylhexyl   phthalate (CAS  No.   117-81-7)  In  Fischer  344  rats.



Gov. Rep. Announce. Index.   85(2):  70.







Wolkowsk1-Tyl,   R.,  C.  Jones-Price,   M.C.   Marr   and   C.A.  Klmmel.    1984.



Teratologlc evaluation  of  dlethylhexyl  phthalate   (CAS No.  117-81-7)  In  CO-1



mice.  Gov. Rep.  Announce.  Index.  85(2): 70.







Yag1,  Y.,   et  al.   1978.   Poster  presentations.   In.:  Proc.  of  the  First



International  Congress  of  Toxicology:  Toxicology as  a Predictive  Science,



P.L. Plaa and W.A.M. Duncan,  Ed.   Academic  Press,  New York.  p.  590-591.







Yag1,  Y.,   Y.  Nakamura,  I.   Tomlta,  K.  Tsuchlkawa  and   N.  Shlmol.    1980.



Teratogenlc  potential  of d1-  and mono-(2-ethylhexyl)phthalate  In mice.   J.



Environ. Pathol.  Toxlcol.  4(2-3):  533-544.
0788p                               10-55                            08/31/87

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Yamada, A.,  et al.   1975.   ToxlcHy studies  on  plastldzers.   1.  Subacute
toxldty of  d1 (2-ethylhexyl)  phthalate.  Trans.  Food  Hyg.  Soc.  Japan,  29th
Meeting,  p. 36.  (Cited In Anonymous,  1985)

Yoshlkawa,   K.,  A.  Tanaka,  T.  Yamaha   and  H.  Kurata.   1983.   Mutagenlclty
study  of 9  mono alkyl  phthalates  and  a d!  alkyl phthalate using  Salmonella
typhlmurlum and EscherIchla coll.   Food  Chem.  Toxlcol.   21(2):  221-223.

Yoshlzawa,   T., M.  Teraura  and  N.  Morooka.    1977.    Inhibitory  effect  of
phthallc add  esters on multiplication  of Tetrahymena pyrIformls (strain H).
Kagawa  Oalgaku  Nogakubu Gakujutsu  Hokuku.   28:  149-155.   (Cited  In  Sugatt
and Foote,  1981)

Young,  D.R.,  R.W.  Gossett,  R.B.  Balrd,  O.A.  Brown,  P.A.  Taylor  and  H.3.
M1lle.   1983.   Wastewater  Inputs  and marine bloaccumulatlon  of  priority
pollutant   organlcs   off   Southern  California.   In:  Hater  Chlorlnatlon.
Environ. Impact Health Eff.   4(2):  871-874.

Zelger, E., S.  Haworth, W.  Speck  and K. Mortelmans.  1982.   Phthalate  ester
testing In  the national toxicology program's  environmental  mutagenesls  test
development program.  Environ.  Health Perspect.  45:  99-101.

ZHko,  V.   1973.   Determination of  phthalates In biological  samples.   Int.
J. Environ. Anal.  Chem.   2:  241-252.

Zoeteman,   B.C.J.,  E.  Degreef  and  F.J.J.  Brlnkman.   1981.   Persistence  of
organic contaminants  In ground  water,  lessons  from soil pollution  Incidents
In the Netherlands.  Scl.  Total  Environ.  21:  187-202.

0788p                               10-56                             08/31/87

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Zuercher, F. and W.  Glger.   1976.   Volatile organic  trace  components  In the



Glatt River.  Vom Wasser.   47:  37-55.
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                                   APPENDIX

                             LITERATURE SEARCHED



    This  profile  1s  based  on  data  Identified  by  computerized  literature

searches  of  the  following:


         CASR  online (U.S. EPA  Chemical  Activities Status  Report)
         CAS online  STN  International
         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  October,  1985.  In addition,  hand  searches

were  made   of  Chemical   Abstracts  (Collective  Indices  6  and  7),  and  the

following secondary  sources  were reviewed:


    ACGIH (American Conference  of Governmental Industrial  Hyglenlsts).
    1980.   Documentation of  the Threshold  Limit  Values,  4th ed.   (In-
    cludes   Supplemental   Documentation,  1981,  1982,  1983).   Cincinnati,
    OH.   486 p.

    ACGIH (American Conference  of Governmental Industrial  Hyglenlsts).
    1985.   TLVs:  Threshold   Limit Values  for  Chemical  Substances  and
    Physical Agents  In  the  Workroom  Environment  wUh  Intended  Changes
    for  1985-1986.   Cincinnati,  OH.   114 p.

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

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

   Grayson,  M. and  D.  Eckroth, Ed.   1978-1983.   K1rk-0thmer  Encyclo-
   pedia  of  Chemical  Technology,  3rd ed.   John Wiley and Sons, NY.  23
   Volumes.

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

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

   ITII  (International  Technical  Information  Institute).  1982.  Toxic
   and  Hazardous Industrial  Chemicals Safety Manual  for Handling and
   Disposal  with  Toxlclty  and  Hazard Data.   ITII,  Tokyo,  Japan.  700 p.

   NTP  (National  Toxicology Program).  1984.   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,  N.I.  1979.   Dangerous Properties of  Industrial  Materials, 5th
   ed.   Van  Nostrand  Relnhold  Co.. NY.

   SRI  (Stanford  Research Institute).   1984.  Directory  of  Chemical
   Producers.  Menlo  Park,  CA.

   U.S.  EPA.  1985.   Status  Report on  Rebuttable Presumption Against
   Registration  (RPAR) or  Special  Review Process.  Registration Stan-
   dards  and the Data Call 1n 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).    1983.    Synthetic
   Organic  Chemicals.  U.S.  Production  and Sales, 1982,  USITC  Publ.
   1422,  Washington,  DC.

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

   Worthing,  C.R. and  S.B. Walker, Ed.   1983.   The Pesticide Manual.
   British  Crop  Protection Council.   695  p.

   Wlndholz, M.,  Ed.  1983.  The Merck Index, 10th ed.   Merck  and Co.,
   Inc.,  Rahway,  NJ.
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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.
    Sele'cted  Data  from the Literature  through  1968.   Prepared for  the
    U.S.  EPA under Contract No.  68-01-0007.  Washington,  DC.

    Johnson,  W.W.  and  H.T. Flnley.   1980.   Handbook  of  Acute  Toxldty
    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, B.A.  1979.  Toxicology  Handbook.   Mammalian and Aquatic
    Data.   Book  1: Toxicology Data.   Office of  Pesticide  Programs, U.S.
    EPA,  Washington,  DC.   EPA 540/9-79-003.   NTIS  PB  80-196876.
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