FINAL DRAFT
       United States
       Env^onmenta, Protect-on               5QOECAOCING01 5
       Research  and
       Development
      HEA1TH AND ENVIRONMENTS EFFECTS DOCUMENT
      FOR P-HYDRQQUINQNE
      Prepared for
       OFFICE OF SOLID WASTE AND
       EMERGENCY RESPONSE
      Prepared  by

      Environmental Criteria and Assessment Office
      Office of Health and  Environmental Assessment
      U.S. Environmental Protection Agency
      Cincinnati, OH  45268 U.S. Environmental Protection
                               Region V, Library
                               230 south Dearborn Street &r
                               Chicago, Illinois  60604 x^

                   DRAFT: DO NOT CITE OR QUOTE


                          NOTICE

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

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                                  DISCLAIMER

    This report  1s  an external draft  for  review purposes only  and  does not
constitute  Agency  policy.   Mention  of  trade names  or  commercial  products
does not constitute endorsement or recommendation for use.
                                      11

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                                    PREFACE
    Health and  Environmental  Effects Documents (HEEDs) are  prepared  for the
Office of  Solid  Haste and Emergency Response  (OSWER).  This document series
Is  Intended to support  listings  under  the  Resource Conservation and Recovery
Act  (RCRA)  as  well as  to provide health-related  limits  and goals  for emer-
gency  and  remedial actions  under the  Comprehensive  Environmental  Response,
Compensation  and  Liability  Act  (CERCLA).   Both  published literature  and
Information obtained  from Agency Program Office files are  evaluated  as they
pertain to potential  human health, aquatic  life and environmental  effects of
hazardous  waste  constituents.   The  literature  searched for  In  this document
and  the  dates  searched  are  Included  In  "Appendix:  Literature  Searched."
Literature search  material  1s  current  up  to 8 months previous  to  the final
draft  date listed  on the front  cover.  Final  draft document  dates  (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).

    Several quantitative  estimates  are presented provided  sufficient  data
are available.  For systemic toxicants,  these  Include Reference doses {RfDs)
for  chronic  and  subchronlc  exposures  for  both  the Inhalation  and  oral
exposures.  The  subchronlc  or  partial  lifetime  RfD, Is  an estimate  of  an
exposure  level  that  would  not  be  expected to  cause adverse  effects  when
exposure occurs  during a limited time  Interval,   for  example,  one  that does
not constitute a significant portion of  the  Hfespan. This type of exposure
estimate has  not  been  extensively  used, or  rigorously  defined as  previous
risk   assessment   efforts  have  focused  primarily   on   lifetime  exposure
scenarios.  Animal data  used  for  subchronlc  estimates  generally  reflect
exposure durations of  30-90  days.   The  general  methodology  for  estimating
subchronlc RfDs Is  the  same  as  traditionally employed for chronic  estimates,
except that subchronlc data are utilized when available.

    In  the cas°  of   suspected   carcinogens,   RfDs   are  not  estimated.   A
carcinogenic potency  factor,  or  q-|* (U.S.  EPA, 1980), Is  provided  Instead.
These  potency  estimates  are  derived for  both  oral and  Inhalation  exposures
where possible.  In addition, unit risk  estimates  for air and drinking water
are presented  based on Inhalation and oral  data, respectively.

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

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                               EXECUTIVE  SUMMARY

    p-Hydroqu1none  Is  a  white crystalline solid  at  room temperature;  It  Is
soluble  In water  and  a variety of organic solvents  (Hawley,  1981;  Varagnat,
13,81).   It  Is currently  produced  by two  U.S.  manufacturers  (Eastman  Kodak
and  Goodyear),  with  a combined  annual   production  capacity  of 34  million
pounds   (SRI,  1986),   p-Hydroqulnone   and   Its   derivatives   are   used  as
developers 1n black-and-wh1te photography and 1n  other  applications  such  as
lithography and x-ray  films  (Varagnat,  1381).  It Is also  used as  an Inter-
mediate  to produce  antloxldants for  rubber and  food.  p-Hydroqulnone 1s  added
to  a  number  of   Industrial  monomers   to   Inhibit   polymerization  during
shipping, storage and processing (Varagnat, 1981).
    p-Hydroqulnone  Is  not  a  persistent  compound  1n the  environment.   In the
atmosphere,  p-hydroqu1none  will   react   In   the   vapor-phase  with  hydroxyl
radicals  at  an  estimated  half-life  of   -14' hours.  In  the  aquatic environ-
ment, photooxldatlon of p-hydroquinone can be expected  to  be a major removal
process  1n  sunlit  natural  waters.   The  half-lives  for   the  oxidation  of
p-hydroqu1none by hydroxyl radicals  and  by peroxy radicals  are 20  hours and
12 minutes,  respectively,  1n typical natural water  (Mill  and  Mabey,  1985).
p-Hydroqu1none has  been found  to be  biodegradable In  aquatic media  (Harbison
and  Kelly,  1982).  Hydrolysis,  volatilization,  adsorption  to  sediment  and
bloconcentratlon are  not  expected  to be  Important.   In  soil,  p-hydroqu1none
may  be   susceptible to free   radical  oxidation   (Dragun  and Helling,  1985).
Estimated  K    values  (10-50)  Indicate  that   leaching   1n   soil  may  be
significant.    Leaching  through   soil  to  groundwater   is  possible  in  the
absence   of   significant    degradation  processes.     In   a   laboratory
                                      1v

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experiment, the  persistence  of  p-hydroqu1none 1n a  chernozem  soil  was found
to be  only 1  day  at  a  concentration  of 500  lag/leg (Medvedev  and Oavldov,
1981a,b).
    A  National  Occupational   Hazard  Survey conducted  between  1972  and  1976
estimated  that   378,028  U.S.  workers   In  132  occupational  categories  were
possibly exposed  to p-hydroqulnone  annually  (NIOSH, 1984).   More  recently,
NIOSH estimated that -470,000 U.S. workers  In 137  occupations  may be exposed
to  p-hydroqu1none  annually  (U.S.  EPA,  1984).   p-Hydroqulnone  has  been
detected  In  wastewater   effluents  frora chemical   plants  (Shackelford  and
Keith,    1976),   coal-tar   chemical   production  (IARC,   T977)   and   coal
gasification processes  (Mohr  and King,   1985).   p-Hydroqu1none has  also  been
detected  1n cigarette  smoke  and 1n  dlesel  engine exhausts   (IARC,  1977;
Graedel, 1978).   Adequate data  were not available  to  permit estimation  of
the average dally human exposure to this compound.
    The lowest reported toxic concentrations  for freshwater  fishes. Inverte-
brates   and  bacteria  are all   -0.04  mg/8.   p-hydroqulnone.   The  data  for
freshwater   plant  species  are  highly  variable  but  seem  to  Indicate  that
plants  are  somewhat less  sensitive,  with  the lowest reported toxic concen-
trations close  to  1 mg/i.   There Is  too Uttle  Information  about p-hydro-
qulnone effects on marine species to  draw any conclusions.
    Pharmacoklnetlc  studies   Indicate   that   following  oral  administration,
p-hydroqulnone  Is   absorbed  rapidly, conjugated with  sulfate  and  glucuro-
nlde,  and  excreted   In  the  urine.  These results  have  been found  In  humans
(Fassett and Roudabush, 1952),  rabbits   (Garton and  Williams,  1949)  and  rats
(D1v1ncenzo  et   al.,  1984).   Cats  metabolize  p-hydroqu1none   primarily  to
p-hydroqu1none sulfate  (Miller et al.,  1976).

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    Davis (1979) did not  find  p-hydroqu1none  In  the  blood of rats 15 minutes
to 6  hours  after they were  given oral doses of  p-hydroqu1none.   In distri-
bution  studies  of  radlolabeled  p-hydroqu1none  Injected  Into  rats,  Greenlee
et  al.   (1981a,b)   found   that   residual   radioactivity   associated   with
A4C-laJbeled  p-hydroqu1none   was   concentrated   1n   the  bone   marrow  and
lymphoid organs.
    At  physiologic  ptt, p-hydroqulnoas  autoxldl^es  to  qu1no*i€  {Greenlee  et
al.,  1981b).  However,  this reaction has not been shown to occur In vivo.
    Women who used cosmetic  p-hydroqu1none ointments excreted  higher concen-
trations of  urinary  volatile  phenols  than women  who  did, not yse the  oint-
ments (Kahambwe et al., 1986).
    Eye lesions have been  reported  In  workers exposed  to p-hydroqu1none dust
and qulnone vapor (Sterner et  al.,  1947;  Anderson, 1947; Miller, 1954).  The
severity  of eye  lesions  Increased with  the length  of  exposure,  and  the
lesions can progress even  after exposure  has  ended.   Concentrations  found 1n
a plant  where  eye Injuries  were  observed were 0.044-14.1 mg/m3 qulnone and
20-36  mg/m3  p-hydroqu1none  (Oglesby  et  al., 1947).   At  these  levels,  no
signs  of  systemic Intoxication  were  noted   In workers  with or  without  eye
lesions (Sterner et  al.,  1947).
    In  a  subchronlc  toxldty  study,  Carlson and Brewer  (1953)  found that
rats   fed  a diet  containing  5%  p-hydroqu1none  for  9 weeks  ate  less,  lost
weight and  developed aplastlc  anemia.   Atrophy of the  bone  marrow and  other
tissues,  and   superficial  ulceratlon  and  hemorrhage  of the   stomach  were
noted.  No  changes  were  observed  In dogs  fed p-hydroqu1none at  up  to  a TWA
dose   of  25.1  mg/kg/day for  80 weeks  or 100  mg/kg/day  for 26  weeks  (Carlson
and  Brewer,  1953).    Blood   analyses   and urlnalyses   revealed  no  effects
                                      v1

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In humans  fed  p-hydroqulnone at  300-500  mg/day for  3-5  months  (Carlson and
Brewer, 1953).  No  effects  were noted  In Syrian hamsters fed p-hydroqu1none
In the diet at 0.5% for 20 weeks (Hlrose et al., 1986).
    Mozhayev et  al. (1966)  found  that rats  treated with  p-hydroqulnone' In
the  drinking  water  at 100  rag/kg/day  gained  weight  slower  than  controls.
Rats treated at  50 mg/kg/day or more exhibited a  decrease  In  the  number of
erythrocytes,  and  an  Increase  In  the  number  of  leukocytes  and  dystrophlc
changes  1n  the  small  Intestines,  liver,  kidneys  and  myocardium.   Nakamura
(1982) found lowered heraatocrlt and a  decrease In  the  number of bone marrow
cells  In  »1c*  provided with p-toydroqo1none In the  drinking water at  4 g/J,
(4000 ppm) for  4 weeks.
    Delcambre et al. (1962)  observed  blood  effects  1n rats treated by gavage
with p-hydroqu1none at 15  mg/kg,  6  days/week for  40 days.   These  effects
were not  observed  1n rats treated  at  7.5  mg/kg/day for  40  days,  or  In rats
treated at 5 and  10 mg/kg,   6 days/week for  4  months.  •Mortality was  high In
the  10  mg/kg  group.   Rats   treated orally  at  156  mg/kg  for  30  days  showed
Increased  liver  weights,  decreased  hepatic glycogen  and vitamin  C  content
and decreased blood serum protein levels (Anlkeeva,  1974).
    In an 8-week study  (Christian  et  al.,  1980), a  depression In body weight
was  observed  1n  rats  treated  with p-hydroqu1none  In the drinking water at
>470 mg/kg/day.   Changes  1n relative  organ  weights were  observed  1n  rats
treated at >390  mg/kg/day.   There  were no effects  at <270  mg/kg/day.   In a
15-week study  (Christian  et al.,  1980),  the only  significant  change  was an
Increase In relative liver and  kidney weights  In rats provided with p-hydro-
qulnone 1n the  drinking water at >110 mg/kg/day.

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    The NTP sponsored a 13-week gavage  study  (Keller,  1982;  Bloassay Systems
Corp., 1981a)  1n which  rats  died  at >200 mg/kg/day.   Survivors  were lethar-
gic,  and  toxic nephropathy  and  squaraous hyperplasla  and  acanthosls  of  the
stomach were  observed.   There were  no  effects  at  <100 mg/kg/day.   The  NTP
13-week  gavage  study  using  alee  (Keller,   1982;  Bloassay  Systems  Corp.,
198113) resulted  In  death  at  >200 mg/kg/day.   Males   treated  dally  at  >25
mg/kg  and  females  at  >H3Q  mg/kg wer-e  lethargic,  and  hunched  posture  was
observed at  >200 mg/kg.  The  only significant hlstopathologlc  effects  were
forestomach lesions at >200 mg/kg/day.
    In a oral  toxlclty study [Vtoodard,  1951),  no  changes  In  body weight gain
or  blood  counts were  observed 1n  dogs treated  with  p-hydroqu1none  In  TWA
doses  of  21.5 and  42.9 mg/kg/day  for  810  days.  Hyperplasla  of  the  bone
marrow and  excessive pigment  deposits  In  the  spleens were observed  In  all
dogs.  No  changes  In hematologlcal  parameters or hlstopathology  were noted
In  rats  fed  p-hydroqu1none  In the  diet at concentrations  up  to  1% for  103
weeks (Carlson and Brewer,  1953).
    Gastrointestinal disease attributed  to  p-hydroqu1none  was  reported  In
crewmen aboard a navy vessel (Hooper et  al.,  1978).   Other  symptoms noted In
humans Ingesting p-hydroqulnone at  relatively  large  doses,  Include acldosls,
anemia, erosion  of  the  gastric  mucosa,  edema of  Internal  organs,  convul-
sions, coma and death (NIOSH, 1978).
    A  review  of  all   the   p-hydroqu1none  toxldty   data  by  the  Cosmetic
Toiletry and  Fragrance  Assoc.  (1986) concluded that p-hydroqu1none Is "safe
for  cosmetic  use at  concentrations of  <1.0/4  1n  formulations  designed  for
discontinuous, brief use followed  by rinsing from the skin and  hair."

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    In a  14-day  gavage study  sponsored  by NTP (Davis,  1979),  doses  of 1000
and 500 rag/kg were  lethal  to  rats,  while 500 and  250 mg/kg doses were lethal
to mice.   Rats  at  all  doses  (>63  mg/kg/day)  lost weight.   Gross  pathology
revealed no consistent changes In either rats or mice.
    The  acute  oral  LD5Q  ranged  from  -200-1200  mg/kg  In  rats, dogs,  mice
and guinea pigs  depending  on the solvent  of p-hydroquinone  (Anlkeeva,  1974;
Carlson and Brewer,  1953;  Lehman et a!.,  1951).   The compound  Is more toxic
to cats, with an oral L05Q of 42-86 rog/kg (Carlson and Brewer, 1953).
    No  studies  concerning  the  carclnogenlclty of  p-hydroqu1none by  either
the Initiation or  oral routes of  exposure were located.  A  gavage study of
the carclnogenlclty  of p-hydroqu1none  has been completed  but  the data  are
not yet available (NTP, 1987).
    An  Increased  tumor  Incidence was  observed  1n  mice  In  which  cholesterol
pellets containing  20% p-hydroqu1none  were Implanted  1n  the bladder  (Boyland
et al., 1964).  In  an  18-week  study,  no Increased  skin tumor Incidences were
observed In mice  treated  weekly  with p-hydroqulnone  and  croton  oil  (Roe and
Salaman, 1955).  Boutwell  and  Bosch  (1959)  concluded  that p-hydroqu1none was
Inactive as a promoter In mouse skin following a single application  of DHBA.
    Holmberg et al.  (1986)  found  that  after  an  1ntraper1toneal  dose  of DENA,
p-hydroqulnone  administered  orally   to  rats  at   100 mg/kg  resulted  In  a
significant  elevation  of   y-glutamyl-transpeptldase   positive  foci  1n  the
liver.  p-Hydroqu1none  Injected  Into laboratory animals  results  In  arrested
metaphase  (Parmentler  and  Dustln,  1948;  Parmentler,   1953;  Rosin  and
Doljanske,  1953).
    p-Hydroqu1none  Injected subcutaneously  Into mice  with melanoma  Increased
survival (Chavln et al.,  1980).
                                      1x

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    p-Hydroqu1none tested positive for  reverse mutation  1n  £.  typhlmuMum on
ZLM medium  but  was  negative on VB medium  {Gocke  et  al.,  1981).   The remain-
ing Ames  type assays  have been  negative (Goodyear Tire and  Rubber Co., 1982;
Sakal et  al., 1985).   DNA damage  was  observed  when p-hydroqu1none was tested
E.. coll (Goodyear Tire and Rubber Co., 1982).
    Negative  results   have  been  found  1n  studies  of sex-1Inked  recessive
lethal mutations  In  J). melanoqaster  (Gocke  et al., 1981;  Goodyear  Tire and
Rubber  Co., 1982)  ami  1n  a test  for  DNA  damage  In  mouse  lymphoma  cells
(Pel lack-Walker  and   Sluraer,   1986).   p-Hydroqu1none   did   not  transform
BaW3T3  wous*  cells  (Goodyear "Hre  and Rubber  Co., 1982).   Post «t  al.
(1984), Penney  et  al. (1984) and  Painter  and Howard  (1982) have shown that
p-hydroqu1none  Inhibits   DNA  and  RNA  synthesis.   p-Hydroqu1none  has  been
shown shown to  Increase the rate  of  SCE 1n human  lymphocytes  (MoMmoto and
Wolff, 1980; Knadle, 1985; Erexson et al.,  1985).
  •  p-Hydroqu1none  tested  positive  In 'a mouse mlcronucleus  test  (Gocke  et
al., 1981).  A  spot  test  In mice  was  negative  (Gocke et al.,  1983).  Jowa et
al.  (1986)  found that _^n_ vitro.  p-hydroqu1none  reacts  with  deoxyguanoslne
and DNA to  form two adducts.
    An  Increase  In  the resorptlon rate  was  observed In  rats  fed a  total  of
0.5 g  of  p-hydroqu1none  throughout  gestation (Telford  et  al.,  1962).   The
only effects noted  In rats  dosed by  gavage  with  p-hydroqulnone on gestation
days  6-15  at doses  of 300 mg/kg,  were decreased  maternal weight  gain  and
decreased  female  fetal weights  (Krasavage, 1985).   No  effects  were observed
at <100 mg/kg.
    The  number   of  young  produced  In  two  successive Utters  by male  and
female rats fed  p-hydroqulnone  1n  their  diet  for  6 months at levels up to 1%
were  similar   to controls  (Carlson  and  Brewer,  1953).  Female  rats  fed

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p-hydroqulnone  In  the diet at  concentrations  up to 0.3%  for  10 days before
mating and  throughout  gestation showed  no changes In reproductive parameters
(Ames et al., 1956).
    Racz et  al.  (1959) found  that  oral administration  of  p-hydroqulnone at
200  mg/kg/day  and  possibly  at  50  and  100 mg/kg/day  for  2  weeks  prolonged
estrus In  female rats.  In a  study by Skalka  (1964),  reduced fertility was
observed  1n male  rats subcutaneously  Injected  with  p-hydroqu1none  at 100
mg/kg/day  for  51  days before  mating.   Other  effects  noted  were  decreased
testes, ep1d1dym1des, seminal  vesicle and suprarenal gland weights.
    Data regarding  ttw carcinogenItIty of p-foydroqtJltvone  were Inatteqnate to
perform  quantitative  risk  assessments  based  on carclnogenlcHy.   p-Hydro-
qulnone, therefore, was classified as an EPA Group D chemical.
    An RfD  of  0.4 mg/kg/day or 30 mg/day for  a 70 kg  human for subchronlc
oral  exposure  and of  0.04 mg/kg/day or  3  mg/day for  chronic oral  exposure
were  derived based on a NOAEL  of 300 mg/day (4.3 mg/kg/day)  for 3-5 months
1n humans  In the study by Carlson  and  Brewer  (1953).   An  uncertainty factor
of 10  for  the  protection  of the  most sensitive Individuals  was used for the
subchronlc  oral  RfD.   An  uncertainty factor of  100  (an additional  factor of
10  for  the use  of a  subchronlc  NOAEL) was  used for  the chronic  oral  RfD.
Confidence  1n  the chronic oral  RfD Is  medium  to low because  the  study was
subchronlc  1n   humans  and  examined  urine  and  blood   parameters,  also  an
assessment  of  the potential  cardnogenldty  of the chemical  1s  pending the
results of the  NTP bloassay.
                                      x1

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                              TABLE OF CONTENTS
                                                                        Page

1.  INTRODUCTION	     1

    1.1.   STRUCTURE AND CAS REGISTRY NUMBER.	     1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES  	     1
    1.3.   PRODUCTION DATA	     2
    1.4.   USE DATA	     2
    1.5.   SUMMARY	     4

2.  ENVIRONMENTAL FATE AND TRANSPORT	,	     5

    2.1.   AIR	     5
    2,2.   UATJ-B	     5

           2.2.1.   Hydrolysis	     5
           2.2.2.   Photoox1dat1on	     5
           2.2.3.   Mlcroblal Degradation  	     6
           2.2.4.   Volatilization	     6
           2.2.5.   Adsorption	     6
           2.2.6.   81oconcentrat1on	     6

    2.3.   SOIL	     9

           2.3.1.   Chemical Degradation	     9
           2.3.2.   Mlcroblal Degradation  	     9
           2.3.3.   Adsorption	     9
           2.3.4.   Persistence	-.  .  .    10

    2.4.   SUMMARY	    10

3.  EXPOSURE	    11

    3.1.   WATER	    11
    3.2.   FOOD	    11
    3.3.   INHALATION	    11
    3.4.   DERMAL	    12
    3.5.   SUMMARY	    12

4.  AQUATIC TOXICITY	    13

    4.1.   ACUTE TOXICITY	    13
    4.2.   CHRONIC EFFECTS	    13
    4.3.   PLANT EFFECTS	    16
    4.4.   SUMMARY	    16

5.  PHARMACOKINETCS	    19

    5.1.   ABSORPTION	    19
    5.2.   DISTRIBUTION	    19

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                           TABLE  OF  CONTENTS (cont.)

                                                                        Page

     5.3.   METABOLISM .	   20
     5.4.   EXCRETION	   22
     5.5.   SUMMARY	   22

 6,  EFFECTS	   24

     6.1.   SYSTEMIC TOXICITY	   24

            6,1.1.   Inhalation Exposures	   24
            6.1.2.   Oral Exposures	   26
            6.1.3.   Other Relevant Information	   33

     6.2.   CARCINQGENICITY	. . . .   39

            fc.2.1.   Inhalation.	 	   39
            6.2.2.   Oral	   39
            6.2.3.   Other Relevant Information	   40

     6.3.   MUTAGENICITY	   41
     6.4.   TERATOGENICITY	   45
     6.5.   OTHER REPRODUCTIVE EFFECTS 	   46
     6.6.   SUMMARY	   48

 7.  EXISTING GUIDELINES AND STANDARDS 	   53

     7.1.   HUMAN	   53
     7.2.   AQUATIC	   53

 8.  RISK ASSESSMENT	   54

     8.1.   CARCINOGENICITY	   54

            8.1.1.   Inhalation	   54
            8.1.2.   Oral	   54
            8.1.3.   Other Routes	   54
            8.1.4.   Weight of Evidence	   55
            8.1.5.   Quantitative Risk Estimates 	   55

     8.2.   SYSTEMIC TOXICITY	   55

            8.2.1.   Inhalation Exposure 	   55
            8.2.2.   Oral Exposure	   57

 9.  REPORTA8LE QUANTITIES 	   61

     9.1.   BASED ON SYSTEMIC TOXICITY 	   61
     9.2.   BASED ON CARCINOGENICITY	   65

10.  REFERENCES	   67

APPENDIX A: LITERATURE SEARCHED	   87
APPENDIX B: SUMMARY TABLE FOR p-HYDRIQUINONE 	   90

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                               LIST OF TABLES
No.                               TUIe                                Page
1-1     p-Hydraqu1none Production Data for 1977	     3
2-1     81odegradat1on Test Results for p-Hydroqu1none	     7
4-1     Acute Toxldty of p-Hydroqu1none to Freshwater F1sh	    14
4-2     Acute Toxldty of p-Hydroqu1none to Aquatic
        Invertebrates 	    15
4-3     Acute ToxIcHy of p-Hy
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                             LIST OF  ABBREVIATIONS

BCf                     B1oconcentrat1on factor
BHA                     Butylated hydroxyanlsole
bw                      Body weight
CAS                     Chemical Abstract Service
CNS                     Central nervous system
COO                     Chemical oxygen demand
CS                      Composite score
0£MA                    N,N~d1ethyln1trosaralne
OHBA                    Dlmethylbenzanthracene
DNA                     Deoxyrlbonuclelc acid
DOC                     Dissolved organic carbon
ECso                    Concentration effective to 50/4 of recipients
                        (and all other subscripted concentration levels)
Koc                     Soil sorptlon coefficient standardized
                        with respect to organic carbon
Kow                     Octanol/water partition coefficient
                        Concentration lethal to 50% of recipients
                        (and all other subscripted dose levels)
                        Dose lethal to 50% of recipients
LOAEL                   Lowest-observed-adverse-effect level
MED                     Minimum effective dose
NMR                     Nuclear magnetic resonance
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
PEL                     Permissible exposure limit
ppm                     Parts per million
RBC                     Red blood cell
                                      xv

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                         LIST OF  ABBREVIATIONS (cont.)
RfD                     Reference dose
RNA                     Rlbonucleic add
RQ                      Reportable quantity
RVjj                     Dose-rating value
RVe                     Effect-rating value
SCE                     Slster-chromaild exchange
ThOO                    Theoretical oxygen demand
TLV                     Threshold limit value
TWA                     Time-weighted average
UV                      Ultraviolet
W8C                     White blood cell
                                      xv1

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                               1.  INTRODUCTION
1,1.   STRUCTURE AND CAS REGISTRY NUMBER
    p-Hydroqu1none  Is  the common  chemical  name, but  this compound  Is  also
known  as  1,4-benzened1ol,   1,4-d1hydroxybenzene,  hydroqulnol,  p-d1hydroxy-
benzene  and  p-hydroxyphenol  (U.S.  EPA,  19865). The structure,  molecular
weight, empirical  formula and CAS Registry number for  p-hydroqu1none are as
follows:
                                   H
                                   H
Molecular weight:  110.06
Empirical formula:  C^H^O-
CAS Registry number:  123-31-9
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    p-Hydroqu1none  1s  a  white  crystalline  solid  (Hawley,  1981)  that  Is
soluble  1n water, alcohol,  ether,  acetone  and  carbon tetrachlorlde,  but only
slightly  soluble  1n  benzene (Varagnat,  1981).   Selected  physical  properties
are listed below:
Melting point:
Boiling point:
Specific gravity:
  g/cm3 (15/4°C)
Water solubility:
  at 15'C
  at 25°C
  at 60°C
Vapor pressure:
  at 25°C
  at 132°C
172°C
287°C

1.332
59,000 ppm
70,000 ppm
260,000 ppm
0.000019 mm Kg
1.0 mm Hg
Varagnat, 1981
Varagnat, 1981
Varagnat, 1981
Verschueren, 1983
Verschueren, 1983
Varagnat, 1981
Jones, 1960
Perry and Green, 1984
0049d
        -1-
                 07/14/87

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Log Kow:,                   0.59                    Hansch and Leo,  1981
pKa at 30*C:                9.914                   Varagnat,  1981
Flash point:                165*C (closed cup)       Varagnat,  1981
A1r conversion
factor at 25°C:             1  ppm = 4.50 mg/m3       Verschueren,  1983

    Chemically,  p-hydroqu1none  undergoes  the  typical  reactions of  phenols
(Varagnat, 1981).  It undergoes  the  normal  esierlfIcatlon and etherlfIcatlon
reactions, giving rise to mono- and  dlesters and ethers.   It  1s  autooxldlzed
tn aqueous  solutions  by reacting with  oxygen  and 1s easily  tialogenated  and
sulfonated.   Oxidation,  which  becomes  rapid  In the  presence of  alkali,
causes solutions of p-hydroqulnone to turn brown  In air  (Wlndholz,  1983).
1.3.    PRODUCTION DATA
    Production data available  from the  public portion  of the U.S.  EPA  TSCA
Production  File  for  1977  1s  presented  In Table 1-1.   p-Hydroqu1none  1s
currently manufactured  by Eastman  Kodak  (Tennessee  Eastman) In  Klngsport,
TN, and  by  Goodyear  T1re 1n  Bayport,  TX (SRI, 1986);  their  combined annual
production capacity Is  34 million pounds.  In 1983,  0.433 million  pounds of
p-hydroqu1none was Imported through  principal  U.S. customs districts (USITC,
1984).
    p-Hydroqu1none  Is  manufactured   1n   the   United  States  by  either  the
oxidation  of  aniline  or  by  the  hydroperoxldatlon  of  d11sopropylbenzene
(Varagnat,  1981).   Eastman Kodak uses  the aniline  process  while  Goodyear
uses  the d11sopropylbenzene  process (SRI, 1986).
1.4.    USE DATA
    The  estimated  domestic  use  pattern  of   p-hydroqu1none   Is as  follows
(Varagnat, 1981):  photographic  developers, 45%; antloxldants and  polymeri-
zation  Inhibitors,  50%;  other,  5%.   p-Hydroqulnone  and  Us  derivatives  are
0049d                               -2-                              07/14/87

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                                  TABLE  1-1
                   p-Hydroqu1none Production Data for 1977*
       Company
Manufacturer/Importer
Production Range
    (pounds)
Tennessee Eastman
fioody«ar T1re & Rubber
Haven Chem.
Carcus Chem.
EM Laboratories
Fallek Chem.
Agfa-Gevaett.Inc.
SPS Technologies
Sakal Trading NY
MHsul & Co.
Phlllpp Br1s. Chem.
Holtrachem. Inc.
Rhone-Poulenc, Inc.
Confidential
    manufacturer
    manufacturer
    manufacturer
    manufacturer
    Importer
    Importer
    Importer
    Importer
    Importer
    Importer
    Importer
    Importer
    confidential
    confidential
10-50 million
1-10 «mion
1-10 thousand
confidential
confidential
1-10 thousand
10-100 thousand
<1000
none
10-100 thousand
confidential
none
1-10 thousand
0.1-1.0 million
*Source: U.S. EPA, 1977
0049d
     -3-
        06/02/87

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used as  developers  In  black-and-white  photography and  In a  variety of other
applications such as lithography and x-ray  films  {Varagnat,  1981).   p-Hydro-
qulTKjne  1s  used as  an  Intermediate to  produce  antloxldants for rubber  and
food (Varagnat, 1981);  the  main  food antioxldant Is  BHA.   p-Hydroqu1none Is
added  to a number  of  industrial  monomers  to  Inhibit  polymerization  during
shipping, storage and processing and Is  also used as  a  chemical  Intermediate
{Varagnat, 1981).
1.5.   SUMMARY
    p-Hydroqulnone  Is a  white crystalline  solid  at  room temperature;  It 1s
soluble  1n water  and a  variety of organic  solvents  (Hawley,  1981;  Varagnat,
1981).    It  1s  currently  produced  by two  U.S.  manufacturers  (Eastman Kodak
and  Goodyear),  with  a  combined  annual  production  capacity  of  34  million
pounds    (SRI,  1986).   p-Hydroqu1none   and  Us  derivatives  are   used   as
developers 1n  black-and-white  photography  and  In other applications  such as
lithography and x-ray films  (Varagnat,  1981).   It Is also  used as  an Inter-
mediate  to produce  antloxldants for rubber  and food.  p-Hydroqulnone 1s added
to  a  number  of   Industrial  monomers   to Inhibit   polymerization  during
shipping, storage and processing  (Varagnat,  1981).
0049d                               -4-                              07/14/87

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                     2.  ENVIRONMENTAL FATE AND TRANSPORT
2.1.   AIR
    The  vapor  pressure  of  p-hydroqu1none  (0.0130013  nro  Hg  at  25*t,  see
Section 1.2.)  suggests  that  It may exist  In  both  the vapor- and participate
adsorbed-phases 1n the ambient atmosphere  (Elsenrelch et  al.,  1981).  In the
vapor-phase,  p-hydroqu1none  win  degrade quite rapidly.   The  estimated rate
constant for  the  vapor-phase reaction of p-hydroquinone with photochemical!y
produced  hydroxyl radicals   In  the  atmosphere  1s   1.7xlO~ai  cm3/molecule-
sec at 258C  (U.S. EPA, 1987).  Giving a  typical atmospheric hydroxyl radical
concentration  of  S.OxlQ3  molecules/cm*,   the estimated   half-life Is  ~14
hours for this reaction (U.S. EPA, 1987).
    p-Hydroqulnone  absorbs   light   significantly   at  wavelengths  >290  nm
(Sadtler, 1966) and has been shown  to photomlnerallze to  carbon dioxide when
adsorbed to  silica gel  and exposed to light  (Kotzlas et  al.,  1979).  There-
fore, p-hydroqu1none adsorbed  to  partlculates 1n the  atmosphere, may be 'sus-
ceptible to  photolysis;  however,  this 1s  likely  to  depend  on  the nature of
the  adsorbing substrate.   Partlculates  1n  the atmosphere  may  be  physically
removed by wet and dry deposition.
2.2.   WATER
2.2.1.   Hydrolysis.    Since  p-hydroqu1none   does   not   contain   functional
chemical groups  that are susceptible  to  environmental hydrolysis,  hydrolysis
Is not expected to be Important.
2.2.2.   Photoox1dat1on.    Photoox1dat1on of  p-hydroqu1none 1s  expected  to
be a major removal process In  sunlit  natural  waters.  The half-lives for the
oxidation  of p-hydroqu1none  by  photochemlcally  produced  hydroxyl  radicals
and by peroxy radicals are 20  hours  and  12 minutes,  respectively,  1n typical
natural  water (Mill  and Mabey, 1985).


0049d                               -5-                              06/02/87

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2.2.3.   M1crob1al Degradation.   The  b1odegradabH1ty of p-hydroqu1none  has
been  studied  by a number  of  Investigators.   Table 2-1  presents  the results
of  selected  blodegradatlon tests, which demonstrate  that p-hydroqulnone  may
be biodegradable in natural waters.
    Harbison  and   Kelly  (1982)  reviewed  literature, pertaining   to  the
blodegradatlon  of  p-hydroqu1none.   In general, Warburg  resplrometer studies
have  shown  that p-hydroquinone  requires  an  acclimation period  when exposed
to activated sludges.  In  addition, Inhibitory effects  can  occur  1n  unaccll-
mated  sludge systems  exposed to  concentrations  >50~100  ppm.  The authors
experimentally  tJenonstrated  ttiat  p-tiydroqu1none  present   1n  a  synthetic
photographic waste stream  at  a concentration of 100  ppm was readily degraded
by an acclimated activated sludge.
    p-Hydroqu1none has  also  been  shown  to be biodegradable  under  anaerobic
conditions (Young  and  Rivera, 1985;  Szewzyk  et al,  1985; Speece,  1983; Chou
et al.t 1979).
2.2.4.   Volatilization.   Based  on a  water  solubility  of  70,000 ppm  and  a
vapor pressure  of  0.000019 mm Hg at 25°C  (see  Section 1.2.), the Henry's  Law
constant  for   p-hydroqulnone is   estimated   to   be   3.9xlO~10  atm-m3/mol.
This  value of Henry's  Law constant Indicates that volatilization  from water
1s not environmentally Important  (Lyman et al.,  1982).
2.2.5.   Adsorption.   Based  on  a  relatively high  water solubility (70,000
ppm  at  25°C)  and  low   log  K    (0.59),  adsorption  to   sediments  in  the
aquatic environment 1s not likely to be important.
2.2.6.   B1oconcentrat1on.   The   8CF   for  p-hydroqulnone   in  goldfish  was
experimentally  determined  to  be  40  in  a  3-day  static  system test (Freltag et
al.,  1984).   In a 1-day  static  system test, a  BCF  of  40-65  was  determined
for p-hydroqu1none 1n algae (Freltag et al.,  1984; Geyer et  al., 1981).


0049d                               -6-                              06/02/87

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    The  BCF  of  an  organic  chemical  can  be estimated  from  the  following
regression equations (Lyman et a"!., 1982):
                         log BCF  = 0.76 log KQW - 0.23                  (2-1)
                     log BCF = 2.791-0.564 log WS (In ppra)               (2-2)
For p-hydroqulnone,  the BCf  values  calculated from Equations 2-1 and 2-2 are
-2 and  1,  respectively, based on a Tog  K   of  0.59 and  a water solubility
of 70,000  ppffl.  These  BCF  values  and the experimental BCF  values Indicate
that  p-hydroqu1none  Is  not  expected  to bloconcentrate   significantly  In
aquatic organisms.
2.3.    SOIL
2.3.1.   Chemical  Degradation.   Dragun  and Helling  (1985) listed  p-hydro-
qulnone  as  an  organic  compound  that  can  be  oxidized  at  soil  and  clay
surfaces by  free radical  mechanisms.  Oxidation  causes  aqueous solutions of
p-hydroqu1none to  turn  brown In  air;  the process becomes  very rapid  In the
presence of  alkali  (Wlndholz, 1983).   It Ys   therefore  likely  that p-hydro-
qulnone will undergo oxidation 1n soils, particularly at higher  soil pHs.
2.3.2.   M1crob1al   Degradation.   p-Hydroqulnone  Is  biodegradable  under  both
aerobic  and  anaerobic  conditions  (see   Section  2.2.3.).    The quantitative
significance  of  blodegradatlon   In  soil  Is   not  clear,  however,  from  the
available data.
2.3.3.   Adsorption.   The  K    of  an  organic  chemical  can  be  estimated
from the following regression equations (Lyman et al., 1982):
                      log  KQC =  3.64-0.55 Log  WS  (In  ppm)                (2-3)
                        Log  KQC  = 0.544 Log KQW * 1.377                  (2-4)
For  p-hydroqu1none,  the  K    values  calculated  from  Equations 2-3 and  2-4
are -10  and  50,  respectively, based on  a water  solubility  of 70,000 ppm and
a  log  KQw  of  0.59.   These K    values  Indicate  very  high  to  high  soil
0049d                               -9-                              07/14/87

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mobility  (Swann  et  a"!.,  1983).  Therefore, p-hydroqu1none  Is  susceptible to
significant leaching  from  soil  to groundwater In the  absence  of significant
degradation processes.
2.3.4.   Persistence.  Hedvedev  and  Davidov  (1981a,b)  examined  the rate  of
degradation of .p-hydroquInane  in chernozem soil  (.554 humus content)  at 19°C
1n laboratory tests.  p-Hydroqu1none 1n  the soil  at  an Initial concentration
of 500 rag/kg persisted for only 1 day,
2.4.   SUMMARY
    p-Hydroqu1none  1s not  a  persistent compound In  the  environment.   In the
atmosphere,  p-hytfroqu1none  will  react   In   the  vapor-phase  with  hydroxyl
radicals  at  an  estimated  half-life  of  -14 hours.   In  the aquatic environ-
ment, photooxldatlon of p-hydroqu1none can be expected  to be  a major removal
process  1n sunlit  natural  waters.    The  half-lives  for  the  oxidation  of
p-hydroqu1none by hydroxyl radicals  and  by peroxy radicals are  20 hours and
12 minutes,  respectively,  1n typical  natural  water  (Mill and Mabey,  1985).
p-Hydroqu1none has  been  found  to  be  biodegradable 1n  aquatic media  (see
Table 2-1)  (Harbison  and Kelly,  1982).   Hydrolysis, volatilization,  adsorp-
tion to  sediment  and  bloconcentratlon  are not expected  to  be  Important.  In
soil, p-hydroqu1none  may  be susceptible  to  free radical  oxidation  (Dragun
and  Helling,  1985).   Estimated  K    values  (10-50)  Indicate  that leaching
1n  soil  may be  significant.    Leaching  through   soil  to   groundwater  1s
possible  1n the  absence  of significant  degradation  processes.   In  a  labora-
tory experiment,  the  persistence of p-hydroqu1none  1n a chernozem soil was
found  to  be  only  1  day  at  a  concentration of  500  mg/kg   (Hedvedev and
Oavldov, 1981a,b).
0049d                               -10-                             06/02/87

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                                 3.  EXPOSURE

    A  National  Occupational  Hazard  Survey  conducted  between 1972  and  1976
estimated  that  378,028  U.S.  workers  in  132  occupational  categories  might
have  been  exposed  to p-hydroqu1none  (NIOSH,   1984).   More  recently,  NIOSH
estimated that potentially -470,000 U.S. workers  in  137  occupations  might be
exposed to p-hydroqu1none annually (U.S.  EPA, 1984).
3.1.   WATER
    p-Hydroqu1none  was  detected  In  a  wastewater effluent  from a  chemical
plant  1n  Ra1*1gh,  Nt,  1n  1974  (SJwclcelford  and  Keith,   1976).   It  was
detected in effluents from  the  production  of coal-tar  chemicals  (IARC,  1977)
and  1n effluents from  coal  gasification  processes   (Mohr  and  King,  1985).
The U.S. EPA STORET Data Base contained no data on p-hydroqu1none.
    p-Hydroquinone  might be  released  to  the  aquatic   environment from  a
variety  of  wastewater   effluents  resulting  from   industrial  applications.
Disposal of used  photographic developing  solutions  containing p-hydroquinone
is one possible source (Dynamac Corp.,  1982).
3.2.   FOOD
    Pertinent  food  monitoring  data  could  not  be located  in the  available
literature as cited in Appendix A.
3.3.   INHALATION
    p-Hydroquinone has been detected 1n cigarette smoke  and  in diesel  engine
exhausts  (IARC,   1977;  Graedel, 1978).   No ambient  atmospheric  monitoring
data  were  located,  although  this  compound  is  known  to  be   released to  the
atmosphere during methyl methacrylate manufacture and  production of  coal  tar
chemicals (Dynamac Corp., 1982).
0049d                               -11-                             06/02/87

-------
3.4.   DERMAL
  -  Pertinent  data  regarding dermal  exposure could  not be  located  1n  the
available  literature  as  cited In Appendix A; however,  dermal  exposure would
seem to be possible during  use  of  photographic  developing solutions contain-
ing p-hydroqulnone.
3.5.   SUMMARY
    A  National  Occupational  Hazard  Survey conducted  between  1972  and  1976
estimated  that  378,028  U.S. workers   In  132  occupational  categories  were
possibly  exposed to p-hydroqu1none  annually  (NIOSR*  1984).   More  recently,
HIOSH estimated  that -470.000 U.S. workers  In 137  occupations  way be exposed
to p-hydroqu1none annually  (U.S. EPA,  1984).  p-Hydroqulnone was detected 1n
wastewater  effluents   from  chemical  plants  (Shackelford  and  Keith,  1976),
coal-tar  chemical  production (IARC,  1977) and  coal  gasification  processes
(Mohr  and  King,  1985).  p-Hydroqu1none was  detected  In  cigarette  smoke  and
1n dlesel  engine* exhausts '(IARC,  1977;  Graedel,  1978).  Adequate  data  were
not  available  to permit  estimation  of the  average dally human  exposure to
this compound.
0049d                               -12-                             07/14/87

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                             4.  AQUATIC TOXICITY
4.1.   ACUTE
    The available data  concerning  acute  toxIcHy of p-hydroquinone to fresh-
water fishes  are  presented  in Table 4-1.   The  lowest  reported toxic concen-
tration  was  0.044  mg/l,  a  96-hour  LCrQ  for  fathead  minnows,  Pimephales
promelas   (Degraeve  et  al.,   1980).    Additional   data  were  provided  by
Applegate  et  al.   (1957),  who  reported  that  5  mg/s,  was  lethal  to  rainbow
trout,  Salmo  qairdnerl.  bluegllls,  Leporols  macrochirus,  and   larval  sea
lampreys,  Petroaiyzon  marinus.   Bandt  (1955)  reported that 0.2  rog/a was  a
toxic threshold for carp,  Cvorlnus  carpio, perch,  Perta sp.,  and  stickle-
back, Gasterosteus sp.   No data on marine fish species were found.
    Acute  toxicity  data for  Invertebrates  are presented in Table 4-2.   The
lowest  reported  toxic   concentration  was  0.05  mg/d,  a   96-hour LC50  for
Daphnia magna (NAPM, 1974).   Among the  freshwater  species  tested, the clado-
cerans  Daphnia  magna and  Daphnia  pullcaria  appeared  to  be  more sensitive
than  the  other   freshwater   Invertebrates  tested,  i.e.,   three   species  of
protozoa  and  one  rotifer  (see Table  4-2).  The  only  data   available  for
marine  invertebrates  was  a  lethal  threshold of  0.83  for shrimp,  Cranqon
septemspinosa (McLeese et al., 1979).
4.2.   CHRONIC
    Pertinent data  regarding chronic toxicity of  p-hydroquinone to aquatic
organisms  could  not  be  located  in  the  available literature  as  cited  in
Appendix A.
0049d                               -13-                             06/02/87

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4.3.   PLANT EFFECTS
    Information concerning  effects  of  p-hydroqu1none  on aquatic  plants and
bacteria  1s  presented  In  Table  4-3.   The data  for aquatic  plants  show  a
great  deal  of  variability,  with  the  lowest  reported  toxic  concentration
being  0.93 mg/l,  a  threshold for  Inhibition  of  cell  multiplication  In the
green  alga,   Scenedesmus  quadrlcauda   (Brlngmann  and  Kuehn,  1980).   Among
bacteria,  the  lowest  reported  toxic  concentration  was   0.0382  mg/i,  a
30-m1nute   EC5Q   for   Inhibition   of   luminescence   In   Photobacterlum
phosphoreum.
4.4.   SUHNAJTC
    The  lowest  reported toxic concentrations  for  freshwater fishes, Inverte-
brates  and  bacteria  are   all   -0.04   mg/l  p-hydroqulnone.   The  data  for
freshwater  plant  species  are  highly   variable  but  seem  to  Indicate  that
plants are somewhat  less  sensitive, with  the lowest reported  toxic concen-
trations  close  to 1  mg/i.   There  Is  too Uttle  Information  about p-hydro-
qulnone effects on marine species to draw any conclusions.
0049d                               -16-                             07/14/87

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                             5.  PHARMACOKINETICS
5.1.   ABSORPTION
    Recovery  of  p-hydroqulnone  and  Its  conjugates  1n  the  urine  following
oral exposure Indicate that  It  Is  readily  absorbed  from the gastrointestinal
tract.  Fassett and  Roudabush  (1952)  recovered 40-45% of  a  250 or  500 mg/kg
oral dose  of  p-hydroqu1none In  the  urine  of a human  subject  collected over
22 hours.  About 73% of  a  100-230  mg/kg oral dose of p-hydroqu1none given to
rabbits  was   recovered   In  the  urine  collected  over  24  hours  (Garton  and
Williams, 1943), while 92-100%  of  oral  doses of p-nydroqulnone {5-200 mg/kg)
were  recovered  In  the  urine  of  rats  collected  over  48  or  96  hours
(Dlvlncenzo et al., 1984).
5.2.   DISTRIBUTION
    No  p-hydroqu1none  was  found  In   the  blood  of  rats  at  periods  of  15
minutes  to  6  hours after the  rats  were treated by gavage with  doses of 250
or 500 mg/lcg (Davis, 1979).
    Dlvlncenzo et  al.  (1984)  examined  the distribution of  radioactivity In
tissues  of rats  48  and  96  hours  after   they were  dosed  by  gavage  with
[14C]-labeled p-hydroqu1none  at 200  mg/kg.  The  results  showed concentra-
tions  of  radioactivity  of  <0.2%   of   the  dose  In the  liver  and  kidneys.
Radioactivity concentrations were  lower In  the lung,  heart,  brain  and fat.
At 96 hours after  dosing,  concentrations of  radioactivity  were lower than at
48 hours.  Radioactivity 1n the bone marrow was not determined.
    Greenlee  et  al.  (1981a)  studied the  distribution of  p-hydroqulnone In
rats.  Control or  Aroclor  1254  pretreated  male  F344 rats  were given a single
Injection  of   14C-labeled   p-hydroqu1none   (100 yd,  1.3   mg/kg)   In  the
lateral  tall  vein.   The rats  were  sacrificed 2 hours later  and the distri-
bution of  radioactivity was determined by whole body  autoradlography.   The


0049d                               -19-                             07/14/87

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results  showed  that  radioactivity  associated  with  14C-labeled  p-hydro-
qulnone was concentrated In the bone marrow  and lymphold  organs.   A decrease
\n  total  circulating  radioactivity  and  1n  the  uptake  of radioactivity  by
bone marrow and lymphold organs was noted in  the Aroclor pretreated rats.
    In  a  similar   study  by  Greenlee   et  al.  (1981b),  control  or  Aroclor
pretreated  rats were  given  a  single  Injection of   14  mg/kg  1*C-labeled
p-hydroquinone  (100 jaC1)  in  the  lateral tall  vein.    The  rats were  sacri-
ficed 2 or 24 hours  later,  and  soluble and tovalently bound radioactivity 1n
the liver, spleen,   thymus and bone marrow were  determined using a scintilla-
tion counter.   Tne  results showed that  {i*C3p-hydroquJno«e»der1ved  soluble
radioactivity was retained  1n the  bone  marrow for at  least 24 hours,  but was
not retained  1n the liver  or  thymus.   In contrast,  covalently bound  radio-
activity  was  Increased  at  24  hours  in all   tissues,  with  the  greatest
Increase  noted   in   bone  marrow.    Aroclor   pretreatment  depressed  covalent
bonding of radioactivity in the liver,  white  blood cells and bone marrow.
5.3.   METABOLISM
    About 10-15% of  a  250 ur  500 mg/kg dose  ingested  by a human was found in
the urine  collected over  22  hours  as  unchanged  p-hydroquinone  (Fassett and
Roudabush, 1952).   Approximately 38-42% of  the  dose was  found  as  conjugates
in the urine.
    Garton and  Williams  (1949) dosed  rabbits  by gavage  with  p-hydroquinone
at  100-230  mg/kg and  collected the  urine   for  24 hours.   Analysis  of the
urine  revealed  a  recovery  of  30% of  the   dose  as   p-hydroquinone  ethereal
monosulfate, 43% p-hydroquinone monoglucuronlde and a  trace (0.065%)  of free
p-hydroquinone.
    Divincenzo  et  al.  (1984)  dosed groups of  four male  Sprague-Oawley rats
by  gavage  with  either  a single  dose  of 200  mg/kg  [14C]p-hydroquinone,  or


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with  four  dally doses  of  200 mg/kg  unlabeled  p-hydroquinone followed  by  a
single  200 rag/kg  dose  of Jl4C]p-hydroqu1none.   Most  of  the  administered
radioactivity was  recovered  In  the  urine.   In  the  single dose  experiment,
56.4%  of  the radioactivity  in  the  urine was  a glucuronlc  acid  conjugate,
42.3%  a  sulfurlc  add conjugate and  1.1% was  unchanged  p-hydroquinone.   In
the  multiple  dose  experiment,   72.2,  23.2  and  1.3% of  the  urinary  radio-
activity  was   glucuronic   add   conjugate,  sulfuric   add  conjugate   and
unchanged p-hydroqulnone, respectively.
    Miller et al.  (1976) dosed  one  male and  one female  domestic  cat  intra-
venously  with  2,3.5«6-1*t  labeled  p-tiydroqulnone  at 20 ng/kg.   Six  tours
after  the  compound was administered,  -87%  of  the dose was recovered  1n the
urine  as  p-hydroqu1none  sulfate, 10% as  unmetabollzed p-hydroqulnone  and  3%
as a  glucuronlc add  conjugate.  The  Investigators noted that sulfate  conju-
gation 1s the only detoxification mechanism available  to the  cat,  presumably
because cats are deficient In glucuronlc add  conjugating pathways.
    Greenlee et al.  (1981b)  found  that at physiologic pH  (7.4),  p-hydroqul-
none  autoxldlzes  to  a product with  a  UV absorption  maximum  of 248  nm.   The
product  was  most  likely  qulnone,  and  the  authors  proposed the  following
oxidatlve pathway:
                  p-hydroqu1none  + 20- -> qulnone * 201 *  2H*
                            20~  * 2H*  -»  H202 + 02
The  latter  reaction  was  catalyzed  by  superoxlde  dlsmutase.  The  rate  of
autoxldatlon of  p-hydroqulnone  was   enhanced  5-fold  by  250 units of  super-
oxide  dismutase.   Metabolism  studies  do  not   clearly   indicate  that  this
reaction occurs  in vivo.
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5.4.   EXCRETION
    Approximately 40-45'/.  of a  250  or 500  rag/kg dose of  p-hydroqu1none was
excreted  1n  the  urine  22  hours  after  It  was  Ingested  by a  human  subject
(Fassett and Roudabush,  1952).
    Xaharabwe et al. (1986)  found  that  women  who  used cosmetic p-hydroqu1none
ointments  excreted  urinary  volatile  phenols  at  a  level  of  71.5  mg/i
compared with  39  mg/i in  Individuals  who  did not use ike  ointments.   It 1s
not clear 1f the phenols  are metabolites  of p-hydroqu1none.
    Olvlncenzo  et  al. (1984) examined the excretion of  radioactivity after
groups   of   2-4  male  Spr ague-Daw! ey   rats   were  dosed   by   gavatje  with
[l4C]p-hydroqu1none  at  a   single  dose  of  5-200  mg/kg,  or  four  doses  of
unlabeled  p-hydroqulnone   (200  mg/kg/day)   followed by   a  single  dose  of
[l4C]p-hydroqu1none  (200   mg/kg).    The  results   showed   that  -87%  of  the
administered  radioactivity was  excreted In  the  urine during  the first  24
hours,  while  almost  all   of the  radioactivity was excreted  In the  urine
within 96  hours.   Radioactivity eliminated  In  expired  air  and  feces  ranged
from 0.1-5.8%  of  the dose,  while <1.3%  of the dose  remained  In  the  carcass
and  excised  tissue.   Throughout   the  experiment,   total   recovery  reached
92-102% at 48-96 hours after dosing.
5.5.   SUMMARY
    Pharmacok1net1c  studies  Indicate that   following  oral  administration,
p-hydroqu1none  Is  absorbed rapidly,  conjugated  with   sulfate  or  glucuro-
nlde, and  excreted  In the urine.   These  results  have  been  found  1n  humans
(Fassett and  Roudabush, 1952),  rabbits  (Garton and  Williams,  1949)  and rats
(Olvlncenzo  et al.f  1984).   Cats  metabolize  p-hydroqu1none  primarily  to
p-hydroqu1none sulfate (Miller  et  al., 1976).
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    Davis (1979) did not  find  p-hydroqu1none  1n  the blood of rats 15 minutes
to 6  hours  after they were  given oral doses of  p-hydroqu1none.   In distri-
bution  studies  of  radlolabeled  p-hydroqu1none  Injected  Into  rats,  Greenlee
et  al.   (1981a,b)   found   that  residual   radioactivity   associated  with
14C-labeled  p-hydroqu1none   was  concentrated   in  the   bone   marrow  and
lymphold organs.
    At  physiologic  pH,  p-hydroquinone autoxldlzes  to  quinone  (Greenlee  et
al., 1981b).  This  reaction has not been shown to occur 14 vivo.
    Women who used cosmetic  p-hydroqu1none ointments excreted  higher concen-
trations of  urinary  volatile  phenols  tnan women who  did not use  the oint-
ments (Kahambwe et  al., 1986).
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                                  6.   EFFECTS
6.1.   SYSTEMIC TOXICITY
6.1.1.   Inhalation Exposures.
    6.1.1.1.   SUBCHRONIC — Pertinent   data   regarding   the   toxldty   of
p-hydroqulnone following subchronlc  Inhalation exposure  could  not  be located
In the available literature as cited 1n Appendix  A.
    6.1.1,2.   CHRONIC — Occupational  exposure  to  p-hydroqulmwie  dust  and
qulnone vapor has resulted  In eye  lesions.  Sterner  et  al.  (1947)  found that
94/201  workers  Involved  In  the  manufacture  of  p-hydroqulnone  had  eye
Injuries, which varied from mild  Irritation and  staining of  conjunctlvae and
cornea,  to  changes  In  the thickness  and  curvature of  the  cornea,  loss  of
corneal  luster  and  Impaired vision.   The  severity  of the eye  Injury tended
to Increase with length of exposure.
    Oglesby  et  al.  (1947)  reported  exposure  concentrations  In   the  plant
where  eye  Injuries'  were  observed.   The  qulnone vapor  concentration ranged
from  0.01-3.2  ppm   (0.045-14.4  mg/m3)  and  the concentration  of  p-hydro-
qulnone dust ranged from 20-35 mg/m3.
    Anderson  (1947)  and Miller  (1954)  reported that  ocular  lesions developed
1n Individuals  Involved  In  the  manufacture  of  p-hydroqulnone.   These studies
agree  that  prolonged  exposure  (>5 years) Is required  for  the  development  of
severe ocular effects.
    In  1955  and  1956,  Anderson   and  Oglesby (1958)  examined  the  eyes  of
workers  who  had  not  been exposed   for  3-5   years.   Although  conjunctiva!
staining had disappeared, corneal  effects progressed 1n some  Individuals.
    Naumann  (1966)  examined microscopic  changes  1n  corneal  specimens  from
three  workers  exposed  to p-hydroqu1none  for  9,  9 and 11 years.   The speci-
mens  were   obtained  when  corneal  transplant  operations were performed  to
Improve  vision  7-20  years after  qu1none/p-hydroqu1none  exposure  had ended.

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Microscopic  examinations  of  the  specimens  revealed  two  types  of  abnormal
pigment.  The first,  a  diffuse brown pigment, found  1n  the epithelial layer
tested  Iron-positive.   The  second  pigment,  a  fine  granular  material,  was
located  In  the  most damaged  part  of the corneal  stroma and  stained similar
to melanin.   Nauman  (1966}   stated  that  the  loss  of vision  was  likely  a
result of lost keratocytes and marked  stromal  damage,  which was demonstrated
by the  loss of  birefringence of  the  collagen fibers with  polarized  light.
In addition. Bowman's membrane was Irregularly thickened or absent In places.
    All  studies  describing  eye  lesions  Involve  exposure  to both  qulnone
vapor and  p-hydroqu1none  dust.  The relative  contributions of the  two  com-
pounds  In causing  eye Injury 1s uncertain.  Oglesby  et  al. (1947) suggested
that  p-hydroqulnone may have  a greater  role.   Qulnone vapor 1s only slightly
soluble  1n  aqueous  solvents  so  that  compared with  qulnone,  p-hydroqu1none
dust   may stay  1n   contact  with  the eye  for  longer  periods  of  time.   The
authors-  also suggested  that  the more  Irritating  qulnone vapor  may be  a
greater  stimulant   of lacrlmatlon   so  that  qulnone   1s  more  likely  to  be
diluted and washed  away.
    Sterner  et  al.  (1947)  examined p-hydroqu1none  workers with  eye  Injury
for evidence of  systemic absorption  and  Intoxication.   Physical examinations
and laboratory tests  Including hemoglobin, RBC,  WBC  and differential counts,
hematocrlt,  sedimentation  rate,  Icteric  Index  and  the  ratio of  Inorganic
sulfate  to  total  sulfate  1n  the urine,  were  performed.   During  1943  and
1945, three  groups  of workers were  examined.   The  first  group consisted  of
47 p-hydroqu1none workers with  some  degree of eye  Injury.   The second group
of 100   Individuals,  Included all  workers  Involved   1n  the manufacture  of
p-hydroqu1none.   The  control  group  consisted  of  1018 workers  from  the  same
0049d                               -25-                             07/14/87

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plant with  no exposure  to  harmful  materials.  Exposure  concentrations  were
0.045-14.4  rag/ra3   quinone   vapor  and   20-35  mg/m3   p-hydroqu1none   dust
(Oglesby et al.,  1947).
    The  results  of  the  study Indicated  no  significant  differences  between
the controls  and  workers  with eye Injury or  workers  engaged  In the manufac-
ture of p-hydroqulnone.  According to NIOSH  (1978),  the  most  nearly signifi-
cant differences  from  control  values  were the percent of  lymphocytes  1n the
blood for all  exposed  employees  and those with eye  Injuries  In 1943,  1n the
Icterus Index of the employees with eye  Injuries  1n  1945,  and 1n the percent
of  basophlls   1n  the  blood  of  exposed  workers  1n 1943.   Ho  significant
differences were  noted  between  workers  with eye  Injuries  and the  entire
exposed  population  of workers.   Sterner et  al.  (1947)  concluded  that  the
exposure  to  qu1none/p-hydroqu1none of  the  order  sufficient  to  produce  eye
Injuries  Is   not  sufficient  to  produce systemic   effects  as  measured  by
physical examinations and laboratory tests.
6.1.2.   Oral  Exposures.
    6.1.2.1.    SUBCHRONIC -- Carlson  and  Brewer  (1953)  fed  a  group  of  14
adult Sprague-Oawley rats diets containing 5% p-hydroqu1none  for 9  weeks.   A
similar  group, fed  the basal diet, was  maintained as controls.   During the
9-week  study,  the  treated  rats   experienced a  46%   loss  1n  weight  and
developed  aplastlc  anemia.   Microscopic  examination   of  the  bone  marrow
showed  a  decrease  1n  cellularlty  with marked  atrophy   of  the  hematopoletlc
elements.  Atrophy  of  the  liver cord  cells,  lymphold tissue  of the spleen,
adipose  tissue  and  striated  muscle,  and superficial ulceratlon  and  hemor-
rhage of  the  stomach  mucosa  were also  noted.   The  authors  stated  that  the
adverse findings  were due In part to reduced  food Intake.
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    Carlson and  Brewer  (1953) also  fed  4-month-old male  and  female mongrel
pups p-hydroqu1none  In  sugar-coated  tablets mixed  1n  the  diet for 80 weeks.
One pup  was  fed 16 mg/kg/day  for  80 weeks, two pups  were-fed 1.6 mg/kg/day
for 31  weeks  and  then  40 mg/kg/day  for  49 weeks  (TWA=25.1  mg/kg/day), and
two pups  were maintained  as  controls.   In a second  experiment,  five adult
male dogs  were  fed diets  containing p-hydroqu1none at  100  mg/kg/day for 26
weeks.    Ur1nalys1s,   hematologlcal  analyses  and  hlstopathologlcal  examina-
tions of major organs and tissues revealed  no changes compared with controls.
    In  a  study  of  p-hydroqulnone toxlclty In  humans   (Carlson and  Brewer,
1953),  2 wen  ^twjestetJ 500 ing/day for  5 months and 17  men  and women Ingested
300 mg/day  for  3-5  months.   The  total  dally doses  were  Ingested  In three
doses  with  meals.   Results   of  blood  analyses  and  urlnalyses conducted  1
month before  the study and during  the study revealed  no  abnormal findings.
The blood analysis Included % hemoglobin,  hematocrlt  or RBC  count, differen-
tial WBC  count,  sedimentation*'rate,  platelet  count,  coagulation  time and
Icteric Index.   The  urine  parameters examined  were albumin,  reducing sugars,
white and red cell counts, casts and  urobHlnogen.
    Hlrose et al. (1986)  found  that  p-hydroqulnone In  the  diets of 15 Syrian
Golden  hamsters  at  0.5% for  20  weeks did  not result  In significant changes
in body weight or Hver weight  when  compared with controls.   In addition, no
hlstopathologlc  changes   In   the  liver,   kidneys,  cheek  pouch,  stomach,
esophagus, lung, pancreas or  bladder  were observed.
    Mozhayev  et  al.   (1966)  treated   rats   for 6 months with  p-hydroqu1none
added to the  drinking water.   The  compound was  added to the water at concen-
trations designed  to  provide  doses  of  0.025,  0.05, 0.25,  0.5,  5,  50 or 100
mg/kg/day.  The  number,  age  and sex  of  the rats used  in  the  study  were not
0049d                               -27-                             07/14/87

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reported.   The  parameters examined  were  body weight,  hemoglobin  concentra-
tion,  and  RBC  and  WBC  counts.   At  sacrifice,  the "liver,  spleen,  kidneys,
small  Intestine and brain were examined microscopically.
    Rats treated with  p-hydroqulnone  at  TOO  mg/kg/day  showed a significantly
(p<0.05)  slower weight  gain  than  controls.   Weight  gain  changes  were  not
observed  1n the  other  treatment  groups.   Treatment  of  rats  at >50  mg/kg
resulted  1n a  slight  decrease  1n  hemoglobin  (p<0.1),  a  decrease 1n  the
number of  erythrocytes  (p
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abnormalities,  but  one 15 mg/kg  rat  developed slight  anemia  with decreased
neutrophlls,  anlsocytosls,  severe  polychromatophma  and  numerous  erythro-
blasts.  On day  40,  one  control  rat showed anlsocytosls and erythroblastosls
and  one  7.5  mg/kg  rat also  had erythroblastosls.  In  the 15  mg/kg group,
four  rats  had  anlsocytosls,  five  had  definite polychromatophllla  and  four
had erythroblasts In the peripheral blood.
    In another  study by  Delcarobre et al.  (1962),  two  groups  of 15 rats  were
dosed with  a  solution  of p-hydroqu1none  1n water  by stomach  tube at 5 or 10
mg/kg, 6 days/week  for   4  months.   Fifteen   rats  dose
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of  treatment  revealed no  abnormalities.   Kidney and liver  weights  relative
to  body  weights  were  Increased  1n   rats  at  the  5000  and  10,000  mg/i
levels.  Microscopic  examinations of the  heart,  aorta,  lungs,  liver,  spleen,
kidney,  stomach,  duodenum,  pylorus, Heum, colon,  urtnary  bladder,  prostate
and testes, ovary and uterus,  pancreas,  thyroids,  adrenal,  pituitary,  brain,
spinal  cord,   eye,  skeletal  muscle and  skin  revealed no  compound-related
pathological changes.
    Christian  et  al.   (1980)  also conducted a  15-week  study  using  Carworth
Farm weanling rats.   Groups of 15 rats/sex  were  provided  with  drinking water
containing  p-hydroquVnone  at 0,  1000, 2000  or 4000 mg/i.   Based on  water
consumption data  provided  by  the authors,  the  male rats consumed  p-hydro-
qulnone  at  -110,  200  and 360 mg/kg/day and  the females at  140,  240  and 430
mg/kg/da.y.   Water  Intake   In this study  also  decreased  with  Increasing
p-hydroqulnone concentration.  Terminal body weights  were slightly depressed
1n hrgh  dose males but were  similar or higher  than controls  1n other  groups.
Hemoglobin  levels  were slightly  reduced  In males  at 200 and  360 mg/kg/day
after  5  and 10 weeks  of treatment  but were normal after 14 weeks  of  treat-
ment.  No change  1n the  total  number of  leukocytes or 1n the distribution of
leukocytes  was noted.  A statistically significant  Increase  (p<0.001)  In the
ratio of I1ver-to-body weight was noted  In  all  dose groups.   Relative kidney
weights  were also  Increased  (p<0.01)  1n all groups  except  the 140 mg/kg/day
females.  Microscopic examination of the  same organs  and  tissues as  examined
in  the  8-week  study  revealed  no  compound-related  changes.    In  addition,
measurement  of  spontaneous  locomotor  activity  with   running  wheels  and
activity platforms showed no discernible effects on the  CNS.
    An abstract of a  Russian  study  (Anlkeeva, 1974) reported that dally oral
administration of  p-hydroqu1none at 156  mg/kg  to   rats  for  30 days  resulted
In  Increased  Hver  weights,  decreased  hepatic   glycogen  and  vitamin  C

0049d                               -30-                             07/14/87

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content, and  decreased  blood  serum protein levels.  p-Hydroqu1none treatment
also  Inhibited pseudochollnesterase  activity.   Additional  details  of  this
study were not available.
    In  preparation  for  an  NTP  2-year  cardnogenlcHy study of p-hydroqulnone
using  F344  rats  and   B6C3F1  mice,  a  13-week  gavage  study was  conducted
(Keller,,  1982;  Bloassay Systems  Corporation,  1981a,b).  Groups  of  10 males
and 10  females of  each species were treated by  gavage  with p-hydroqulnone
(>97% pure)  suspended  1n corn oil, 5 days/week for 13 weeks at  doses of 0,
25, 50,  100,  200 or  400  mg/kg/day.   Major  organs  of  rats and mice In the
control, 400 and 200 tng/kg/day group.; «er« examined microscopically.
    All rats  treated at  400 mg/kg/day died.   Except for three females at 200
mg/kg/day, all other rats  survived  the  13-week study period.  Clinical signs
of toxldty  Included tremors and convulsions  1n rats that died,  and  lethargy
In survivors  at 200 mg/kg/day.  At  100  mg/kg/day, weight gain was 14 and 10%
below controls  In males and  females,  respectively.  Hlstopathologlc  examina-
tions  revealed  toxic  nephropathy  In  7/10 males  and 6/10  females  and focal
squamous hyperplasla and acanthosls of  the stomach 1n two males  dosed at 200
mg/kg/day (Bloassay Systems Corporation, 1981a).
    In  mice   (Bloassay  Systems Corporation,  1981b),  eight  males  and eight
females  died at  dally  doses  of  400 mg/kg/day,  and  two  males  died  at  200
mg/kg/day.  Clinical signs In  mice  that  died  were similar to those described
for rats.  Lethargy was observed  1n  the  25,  50,  100,  200  and  400 mg/kg/day
males  and  the 100,  200  and 400 mg/kg/day  females. Hunched posture was noted
in the  400 mg/kg males  and  females  and  the  200 mg/kg/day  males.   Males at
400 and 200  mg/kg/day   showed  a   decrease 1n  body  weight  gain.  The  only
significant hlstopathologlc effects noted  were forestomach lesions Including
mucosal  ulceratlon, Inflammation and  squamous hyperplasla  In three males and
two females at 400 mg/kg/day and one female at 200 mg/kg/day.

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    Two  male  and  two  female young  mongrel  dogs  (6.1-8.4  kg)  were  given
single  doses  of  p-hydroqulnone  by  stomach  tube  at  100  mg/kg  (Woodard,
1951).   After  this  Initial  dose,  the dogs  were  divided  Into two  groups  of
one male  and  one  female and  treated  with  p-hydroqulnone  in  gelatin capsules
at  25  or 50  mg/kg/day,  6  days/week  for  809  days  (TWA doses 21.5  and 42.9
lag/kg/day).    Two  untreated dogs served  as controls.    Throughout  the  study,
body weights were monitored and blood counts were performed,   p-Hydroqu1none
treatment was  suspended on days 20-73 for  one 25  mg/kg dog because of  weight
loss and  on days  238-309  for all dogs  to  study effects on body  weight.   At
ttte  end  of   the  experiment,  the   dogs   were  sacrificed   for   gross  and
microscopic examinations of Internal  organs.
    The  results  of  the  experiment  showed   no  significant  changes  In  weight
gain or  blood counts.   Microscopic  examinations  revealed  hyperplasla  of  the
bone marrow and  excessive pigment deposits  1n the spleens of all  dogs.   It
Is not clear 1f these lesions were also observed In controls.
    6.1.2.2.   CHRONIC -- Carlson  and  Brewer   (1953)   examined  the  chronic
toxldty of p-hydroqulnone  in groups  of  10 male and 10 female Sprague-Oawley
rats  fed diets containing p-hydroqu1none   at  0,  0.1,  0.5 or  1.0% for  103
weeks.   In  a  second  103-week experiment,  groups of  16-23 rats  of  each  sex
were fed  diets containing p-hydroqulnone  that  had  been heated with  lard  at
190°C for 30 minutes before  being Incorporated  into the diet  at  0, 0.1, 0.25
or 0.5%.  Throughout  the  study,  body weights of  the  rats  were  recorded,  and
hematologlcal  parameters   Including   RBC,  %  hemoglobin  and differential  WBC
were determined.  At the  end  of the  study, hlstopathologlcal  examinations  of
major organs and tissues were completed.
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    The results  of  the study  showed  a significant decrease  (p<0.05)  in the
growth rate  of  rats fed  0.5  and 1.0% p-hydroqu1none during  the first month
of the study.  The  final  body  weights  of  treated rats were not significantly
different from controls.   This effect  was not observed  In rats treated with
p-hydroqu1none  Incorporated  Into  lard.   No  changes were noted  In  hemato-
loglcal parameters  or  In  hlstopathologlcal  examinations of  rats from either
study.
6.1.3.   Other Relevant Information*   Hooper et  al.  {1978)  studied  an out-
break  of  gastrointestinal  disease 1n   544  crewmen  who  were  exposed  to
p-tiydroquTnon* In the  water  supply aboard a  navy vessel.   Symptoms  of the
Illness  Included nausea, vomiting,  abdominal  cramps   and  diarrhea,  which
usually ended  1n 12-36 hours.  Levels of  p-hydroqulnone 1n  the  water were
not  determined,   but  p-hydroqu1none   was  Identified   (>0.1   pg/ma)   In  the
serum of  3/6 111  patients, and  1t  was not  found  1n  the  serum of 6/6 healthy
controls.
    NIOSH  (1978)  reported  a  number  of  cases   1n  which   people  Ingested
p-hydroqu1none   or    photographic   developer   containing   p-hydroqulnone.
p-Hydroqu1none caused  mild to severe systemic effects  1n  humans.   Depending
on  the  dose,  symptoms   noted   Included  addosls, anemia,   erosion  of  the
gastric mucosa,  edema of  Internal organs,  convulsions, coma and death.
    p-Hydroqu1none  1s  used 1n  cosmetic  formulations  designed to lighten skin
and In oxldatlve hair  dyes.   Because of  these uses,  the toxldty of p-hydro-
qulnone  following  skin  application  has  been  examined.   These  studies,
reviewed by  the  Cosmetic  Toiletry  and  Fragrance Assoc.  (1986),  revealed  no
systemic effects  following the  skin application  of  p-hydroqu1none, although
at concentrations >3X, the  studies Indicate that  p-hydroqu1none   1s  a skin
Irritant.   The Cosmetic Toiletry and Fragrance  Assoc.  (1986) concluded that


0049d                               -33-                             07/14/87

-------
p-hydroqulnone  Is  "safe  for  cosmetic use at concentrations  of  1.0% and less
1n  formulations designed  for  discontinuous, brief  use followed  by rinsing
from the skin and hair."
    Sterner et  al.  (1947)  tried  repeatedly  to  develop eye  lesions in rabbits
similar  to  those  observed  In humans.  Rabbits were  exposed  to  qulnone vapor
up  to  concentrations  where corneal  edema  and  ulceratlon were  observed.   In
addition,  subconjunctlval   Injections  of   qulnone   did  not  result  1n  ttve
development  of  the  characteristic  lesions.   Ferraris des  Gaspare  (1949)
exposed  rabbits   to   finely  powdered  p-hydroqti1none   (concentration  not
provided) for 2 aontlis.  The rabbits developed eye  lesions  similar to ttiose
observed 1n  humans; a brown  pigmentation  first  on  the  conjunctiva and then
on  the  cornea  was  observed.    These  effects  occurred earlier   1n  colored
rabbits  than  1n albinos,  and  1n rabbits exposed  to light opposed  to those
kept 1n darkness.
    In an early study,  Vollmer  (1932) demonstrated  an  Increased  toxlclty In
mice with  repeated subcutaneous  Injections  of p-hydroqulnone at  doses below
the single  lethal  dose.    In  this  experiment,  12 white  mice  (sex not speci-
fied)  were  Injected 6 times  at  5-day Intervals with  p-hydroquinone at 0.05
mg/g  bw.   Five  control  mice,  which were  handled  1n  a  manner  similar  to
treated mice,  showed  signs of restlessness  throughout  the  study.   After the
first  Injection of  p-hydroqulnone,  the  mice were restless.   After the third
Injection,  all  treated mice  displayed signs of trembling,  and  clonlc spasms
were noted  1n  9/12 mice after  the  fourth  Injection.   Four  deaths occurred
after  both  the  fifth and sixth Injections.  This  experiment was  repeated
with  a group  of  29  mice,  except  p-hydroqulnone  doses of  0.12  mg/g  (0.12
vg/kg)  bw  were used.   As  In  the  first   experiment,  deaths  were  observed
after  repeated  doses  of  p-hydroquinone.  The author Interpreted  the results


0049d                               -34-                             07/14/87

-------
to  mean  that  small  nonlethal doses  of p-hydroqulnone  stimulated  metabolic
oxldatlve processes so that  subsequent  small  doses  were rapidly converted to
more toxic substances.
    Vollmer (1932) also reported  that  the  toxldty  of  p-hydroqulnone In mice
Increased  following  repeated subcutaneous  Injections  of  ethyl  alcohol.  Six
days  after seven  alcohol  Injections   at  4.73  mg/g   (4.73  vg/kg)   given  at
5- to  6-day  Intervals, p-hydroqu1none  Injected  subcutaneously at  0.2 mg/g
was lethal to  21/32 mice.  The surviving mice exhibited paralysis and clonlc
spasms.  This  1n  contrast  to deaths of 6/32  mice receiving  a single dose of
0.2 mg/g  \Q.2  jig/fcg) without alcohol  pro-treatment.  Of  the  surviving  mice,
19 suffered from clonlc spasms,  2 paralysis and 2 trembling.
    In  a  cumulative  toxlclty  study,   Carlson  and  Brewer  (1953)   found  no
cumulative toxlclty  when  p-hydroqu1none was  given  to  rats by  stomach  tube.
Groups of  20-48 rats  were  given nine  doses  of  p-hydroqulnone at  500, 750,
1000,  1250, 1500  or  1750  mg/kg  In  12 days.   Deaths were  observed 1n rats In
the  500-1750  mg/kg  groups,  with 71%  of  the mortality  occurring  within  24
hours  after the first  dose.   During the remaining days of the study, mortal-
ity averaged <5% per day.
    To determine  an  appropriate   route  of  exposure  for a chronic study,  NTP
sponsored  14-day  skin painting  and gavage  studies of  p-hydroqulnone  using
F344 rats  and  B6C3F1  mice  (Davis,  1979).   Treatment  groups  1n both studies
consisted  of  five rats and mice of  each  sex.  In  the  skin-painting study,
p-hydroqu1none  In  95/4 ethanol was  applied to the  shaved scapular  region  of
the animals.   No  dose-related systemic or local effects  were  noted In rats
or mice  that  were given  12  applications  of  p-hydroqulnone.   The  rats were
treated at 0,  240, 480, 960,  1920 or  3840  mg/kg, while the mice were treated
at 0, 300, 600, 1200, 2400 or 4800 mg/kg.


0049d                               -35-                             07/14/87

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    In the  gavage  study,  rats  and mice were  dosed  12  times  with p-hydroqul-
none In corn oil.  Rats were dosed  at  0,  63,  125, 250, 500 or 1000 ing/kg and
mice were dosed at 0,  31,  63,  125,  250 or 500 mg/kg.  All rats at 1000 mg/kg
died while  1/5  male  and 4/5 females at  500 mg/kg died within  2 hours after
the  first  or   second  dose;   death  was  preceded   by   body  tremors  and
convulsions.   All  rats  at  lower  doses  survived,  and  by  the  end  of  the
experiment exhibited a weight  loss  relative to  controls.   Gross pathology at
necropsy  revealed  no  consistent dose-related  changes.   In  mice,  only  one
male mouse  survived at  500 mg/kg,  while  at  250 fflg/kg,  2/5 males  and  5/5
females survived.  Except for one malt at 31  mg/kg and one female In each of
the 63 and  31 mg/kg  groups,  the  remaining mice  survived.   Signs before death
were similar to  that described for rats.   In mice,  p-hydroqulnone treatment
did not significantly  affect weight gain, and gross  pathology did not reveal
a target organ.
    Dlvlncetvzo et  al.  (1984) found no  significant Increases  In  absolute or
relative  liver  weights,  hepatic  mlcrosomal  protein,  cytochrome  b-5 concen-
trations  or cytochrome  c-reductase  activity  1n male  Sprague-Oawley  rats
treated by  gavage  with four dally  doses  of p-hydroqu1none at  200 mg/kg.  A
slight  but  significant  decrease  In  cytochrome  P-450 values  was  noted  In
p-hydroqu1none treated rats compared with controls.
    Acute LD,_  data  for  p-hydroqu1none  are  summarized   In  Table  6-1.   As
Indicated 1n the  table,  p-hydroqu1none  1s  more toxic   to  cats,  a species In
which  detoxification  of  p-hydroqulnone  1s   limited   to  conjugation  with
sulfate  (Miller  et  al.,  1976).   The  acute  toxidty  of p-hydroqu1none  Is
restricted  to a  fairly narrow  range.   Woodard  (1951)  found  that fasted rats
could  tolerate an  oral dose of 200 mg/kg with  no mortality  while the lowest
dose resulting In 100% mortality was 420 mg/kg.
0049d                               -36-                             07/14/87

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                                   TABLE 6-1
                     Acute 1050 Values  for  p-Hydroqu1none
Species/Strain
Rat/NS
Rat/Priestly
Rat/Sprague-
Dawley
Rat /Spr ague -
Dawley
Rat/Sprague-
Dawley
Rat/Sprague-
Oawley (fasted)
Rat./WUtar
Rat/W1star
(fasted)
Oog/NS
Cat/NS
Mouse/NS
Rat/NS
Guinea pig/NS
P1geon/NS
Solvent
NS
glycerin
glycerin
distilled
water
propylene
glycol
propylene
glycol
propylene
glycol
propylene
glycol
tablets
tablets
NS
NS
NS
NS
Route
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
(mg/kg)
781.3
1005-1295
1081
1182
1090
323
731
298
299
42-86
400
320
550
300
Reference
Anlkeeva, 1974
Carlson and
Brewer, 1953
Carlson and
Brewer, 1353
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Carlson and
Brewer, 1953
Lehman et al . ,
1951
Lehman et al . ,
1951
Lehman et al . ,
1951
Lehman et al . ,
1951
0049d
-37-
06/02/87

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                              TABLE 6-1  (cont.)
Species/Strain Solvent Route
1059 Reference-
(mg/kg)
Dog/NS
Cat/NS
Rat/NS
NS
NS
NS
oral
oral
Intravenous
200
 70
115
Lehman et al.,
1951

Lehman et al.,
19S1

Lehman et al.,
1951
NS = Not stated
0049d
                 -38-
                                    06/02/87

-------
    An  abstract  of  a  Russian  study  (Dzhokhadza  and  Papel1shv1li,  1973)
stated that when p-hydroqulnone was Incubated with  Isolated  rat  liver nucle'1
at 10-50 yg/ms, the activity of nuclear RNA polymerase  was Inhibited.
    In  an  |n_  vitro  study,  Usaml et  al.  (1980)  found that  p-hydroqu1none
reduced  the  activity of  tyroslnase  Isolated from  tissue  cultures of  human
melanoma cells  when  both  dopa and  tyroslne were  used  as  substrates.   The
reduction was  dose-related and reached  significance  (p<0,001) at a  concen-
tration of 0.1 H.
    In  a  study by Galdo  and  Wlerda  (1984), exposure  of  mouse bone marrow
stromal  cells  to p-hydroqulmme resulted  1n  a  significant  dose-related
decrease 1n  adherent colony  formation.   At a  concentration  of  1.5x10~4M,
a  29-37% decrease In  colony  formation  was observed,  while at 50xlO~6  and
IQOxlO"6 M complete  Inhibition was noted.   In  a  second study described  by
Galdo and Wlerda  (1984),  p-hydroqulnone  exposure of mouse bone marrow cells
also  resulted  1n  a significant decrease  In  the number  of  granulocyte/mono-
cyte colonies formed.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.    Pertinent   data   regarding   the  cardnogenldty   of
p-hydroqulnone  following   Inhalation  exposure  could  not be  located   1n  the
available literature as  cited  1n Appendix A.   p-Hydroqulnone, however,  has
been  shown  to  be a metabolite  of benzene (Galdo and  Wlerda,  1984),  a human
carcinogen;   the role  of   p-hydroqu1none  In benzene  carclnogenlclty   is  not
known.
6.2.2.   Oral.   The  103-week  oral toxldty  study of   p-hydroqu1none  using
rats (Carlson and Brewer,   1953) (see  Section 6.1.2.2.)  did  not discuss tumor
Incidences.
0049d                               -39-                             07/14/87

-------
    The NTP has sponsored a  2-year  gavage  study  of p-hydroqu1none using rats
and mice,  but  the  report  Is  not  yet  available, as  tfte quality  assurance
phase 1s In progress (NTP, 1987).
6.2.3.   Other  Relevant  Information.   In a  study  by Boyland et  al.  (1964),
mice  1n  which  cholesterol  pellets  containing p-hydroqu1none were  Implanted
1n  the  bladder  developed significantly  (p=0.03) more  bladder  tumors  than
mice  Implanted  with  just  cholesterol.   The results  are  from 19 treated mice
and 77 control  mice  that  survived 25 weeks.  Although not  stated 1n  Boyland
et al.  (1964),  IARC  (1977)  stated that 10  mg cholesterol  pellets containing
20% p-hydrt>qulTK>ne were used.
    In a study  by  Roe and Salaman  (1955),  an Increased  skin tumor  Incidence
was not  observed In  mice treated  with  weekly  skin  applications of  0.3  ma
of a  6.7%  p-hydroqu1none  solution 1n acetone.  These mice  were also  treated
with  18 skin  applications  of croton oil starting  3  weeks  after the p-hydro-
qulnone treatment began.   Mice treated with  croton  oil  served  as  controls.
The mice were observed for 18 weeks.
    Boutwell  and  Bosch (1959)  found  that  p-hydroqulnone  was   Inactive  as  a
promoter 1n mouse  skin following a  single application  of DHBA.   Details  of
this study were not  provided.
    In a  tumor  promotion study,  Holmberg  et al.   (1986)  found  that after  an
Intraperltoneal dose of DENA,  p-hydroqulnone, administered  orally to  rats  at
100  mg/kg,  caused   a  significant   elevation  of  y-glutamyl-transpeptldase
positive foci  1n  the  liver.   p-Hydroqulnone  at  20 mg/kg did not cause this
effect when administered  to  male Sprague-Dawley  rats that were treated with
DENA  at  30  mg/kg  24 hours  after  a   partial  hepatectomy.   p-Hydroqu1none
treatment began 7 days after  the  hepatectomy  and  was given 5 days/week for 7
weeks.   The  rats  were  sacrificed   10  days  after  the  last  p-hydroqulnone
treatment.

0049d                               -40-                             07/14/87

-------
    Parmentler  and  Oustln  (1948)  found  that single  doses  of p-hydroqu1none
at 0.15 or 0.175  mg/g  Injected  1ntraper1toneally or subcutaneous!y Into mice
resulted  in  arrested metaphase  in  cells  of intestinal  tissues.   The Intes-
tinal  tissue  was  examined during the  first  2  hours after the p-hydroquinone
injection.   In  cells   that were  in  arrested  metaphase,   small  groups  of
chromosomes were  found  near the poles in  addition  to those collected in the
equatorial plate  (three-group  metaphase).   Signs of  chromosomal stickiness,
as  evidenced  by  clumping  of  the  central  mass  of chromosomes  and  bridges
between central and  polar chromosomes, were also observed  from 1 hour after
p-hydroquinone  injection.   Similar  mltotic  effects  have been noted following
p-hydroquinone  exposure  in the  bone  marrow of  golden  hamsters (Parmentler,
1953)  and in  the bone  marrow,  liver cells and cornea of  rats  (Rosin and
Doljanske, 1953).
    Chavin et al. (1980)  found  that  p-hydroquinone  Injected subcutaneously
into mice with melanoma  at 80  mg/kg/day-increased survival  over  a  140-day
observation  period.    The  mice  were  treated  on  days  1-9  after  they  had
received  melanoma  transplants.   The  Incidence  of successful transplantation
was  91.7%  in  untreated  mice,  and  55.6  and   23.7%  in  mice  treated  with
p-hydroquinone at 16 and 80 mg/kg, respectively.
6.3.   MUTAGENICITY
    p-Hydroquinone mutagenlcity  data  are  summarized  in  Table 6-2.   Gocke et
al. (1981) found  that p-hydroquinone  was  positive for reverse mutation in j>.
typhimurium on  ZLM  medium  without  S-9 metabolic activation  but  negative on
VB medium.  Other  reverse mutation assays of p-hydroquinone using  £. typhi-
murium have been  negative  (Goodyear Tire  and Rubber Co., 1982; Sakai  et al.,
1985).
0049d                               -41-                             07/14/87

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    p-Hydroqu1none  tested  positive  for  DNA  damage  In  the  Pol1", Pol  A" E_.
col 1  assay (Goodyear T1re  and Rubber Co.,  1982).  The  study  was conducted
without metabolic activation.
    In  two studies  of  sex-linked  recessive  lethal  mutations  In Drosophlla
melanoqaster.  p-hydroqulnone  tested negative  (Gocke et  al.,  1981;  Goodyear
Tire and Rubber Co., 1S82).
    p-Hydroqulnone  did  not  Increase  the  percent of  single  strand  DNA In
mouse  lymphoma  cells  (Pellack-Walker and Blumer,  1986).   In  a  study of  cell
transformation,   p-hydroqu1none   was  negative   in   8alb/3T3   mouse   cells
tGoodyear T1re and Rubber Co., 1982).
    In_  vitro  studies have  shown  that p-hydroqu1none  Inhibits   DNA and  RNA
synthesis.  Post  et  al.  (1984) found  that p-hydroqu1none at  a concentration
of 6xlO~6  M  Inhibited  mRNA synthesis  In rabbit bone marrow  nuclei.  Penney
et al.  (1984)  studied  the effect of p-hydroqulnone  on  DNA and RNA synthesis
In  two  melanotlc  and   three nonmelanotlc   cell  lines.   They   found   that
p-hydroqulnone  has  a dose-dependent  Inhibitory effect  on both  RNA and  DNA
synthesis.   This  effect  was  much  greater  1n  the melanotlc   cell  lines;
Inhibition  to  50%  of  control  values  occurred  at  1   yg/ma,   1n melanotlc
cells  but  at  100-500   yg/mi  In   nonmelanotlc  cells.    p-Hydroqulnone  has
also  been  shown to Inhibit DNA synthesis  In  Hela  cells (Painter  and Howard,
1982).
    Three  In  vitro  studies  Indicate that p-hydroqu1none  Increases  the  rate
of SCE  1n  human lymphocytes  (Morlmoto  and Wolff, 1980;  Knadle, 1985; Erexson
et al., 1985).
    Gocke  et  al.  (1981) found positive  results In  a  mlcronucleus test  when
mice  were  Injected  1ntraper1toneally with 110 mg/kg p-hydroqu1none  at 0 and
24 hours.   The test was  negative  at lower doses.   In  a spot test, negative


0049d                                -44-                             07/14/87

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results were  observed  when mice were  given an  1ntraper1toneal  Injection of
p-hydroqu1none at 110 mg/kg on gestation day 10 (Goclce et a!.. 1983).  •
    Jowa  et   al.   (1986)   found   that   two   adducts   were   formed  when
[14C]p-hydroquinone   was   Incubated   with   [3H]deoxyguanos1ne.     Similar
adducts were  found  when  p-hydroqu1none was Incubated with  DNA Isolated from
Clostrldlum perfrinqens.  Hlcrococcus  lysodeiktlcus. human  placenta  and calf
thymus.  Based on  NHR  and mass spectral  results,  the  authors suggested that
one adduct  was  (3'OH)benzepheno(l,fl-2)deoxyguanosine.  The other  adduct  was
not Identified.
6.4.   TEKATOSEflltm
    Telford et  al.  (1962)  found   that  p-hydroqu1none  fed  to a  group of 10
pregnant Walter  Reed-Carworth  rats  1n  the diet throughout gestation resulted
in an  Increase  in the  resorptlon  rate  compared  with  controls. The rats were
fed a  total  of  0.5  g  of the  compound  and  were sacrificed on gestation  day
22.  Additional daia, Including maternal effects, were not reported.
    In a study by  Krasavage  (1985),  groups  of  30 pregnant Crl:COBS*CD*(SD)BR
rats were dosed  by  gavage with  p-hydroqulnone in distilled  water  at  0,  30,
100 or  300  mg/kg  on gestation days 6-15.   The dose levels  were determined
using  body  weights  of  dams  measured  on  gestation  day  0.    Maternal  body
weight and  food  consumption  were  measured  throughout  the  study.   On  gesta-
tion day  20,  the dams were  sacrificed and the  number  of  live  and resorbed
fetuses was determined.  All  fetuses were  examined  for  gross anomalies, while
half were  examined  for  visceral   anomalies  and  the  remaining  fetuses  were
examined for skeletal defects.
    A slight but  significant  reduction  in  maternal  body  weight gain and food
consumption  was  observed in  dams  treated at  300 mg/kg.   Results  of  histo-
pathologic examinations  of the liver  and kidneys of the  high dose dams were


0049d                               -45-                             06/02/87

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normal.   Tissues  of  other groups  were  not  examined.  Pregnancy  rate,  the
number of litters with resorptlons,  the number  of  Implantation sites, viable
fetuses and  resorpt1ons/dam,  mean  gravid  uterus weights and  fetal  sex ratio
did  not  differ  among treated  and  control groups.   Combined  male and female
mean  fetal  body weight was significantly (p<0.05)  reduced 1n  the  300 mg/kg
group  compared  with controls.  When body weights  were  analyzed separately,
however,  only  fewale  fetal   body   weights  were  significantly  lower  than
controls.   There were  no  treatment-related  effects  on   the   Incidence  of
gross, visceral or skeletal malformations.
6.5.   OTHER REPRODUCTIVE EFFECTS
    The number  of offspring produced  In  two  successive Utters  by male and
female rats  treated with p-hydroqu1none  In  the diet for 6 months  at levels
up  to  1%  was similar to controls  (Carlson and  Brewer,  1953).  Normal growth
rate  was  observed  In  these offspring, reared  on  diets containing p-hydro-
qulnone 1n lard at  0, 0.1,  0.25  or  0.5%.   This  study was part of the chronic
oral study described In Section 6.1.2.2.
    Groups of 10  female rats  were  fed  p-hydroqu1none  1n the diet at 0, 0.003
or  0.3% for  10  days before  ir.at1ng and  throughout  gestation  (Ames  et  a!.,
1956).  Fertility  Index,  Utter  efficiency,  mortality  Index,  mean  length of
gestation,  mean  Utter   size,  viability Index  and   lactation  Index  were
similar 1n the treated and control  rats.
    In  a  study  by  Racz  et al.  (1959),  10  mature  female rats  were orally
dosed  with  p-hydroqulnone in   saline  solution  at  200 mg/kg/day for 2 weeks.
Ten  rats  treated  with   saline  solution  served  as  controls.   During  the
experiment,  three treated  rats  died and were  replaced with  an unspecified
number  of rats  dosed with p-hydroqulnone at  50  or  100  mg/kg/day.   Dally
0049d                               -46-                             08/26/87

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cytologlcal examinations  of  vaginal smears revealed  prolonged  estrus In all
rats dosed  at  200 mg/kg/day and  some  rats at the lower  doses.   In the dead
rats, the fallopian tubes contained an excess amount of blood.
    In  a  study  of  the effects  of p-hydroqulnone on  the  fertility  of male
rats,  16  males   were   Injected  subcutaneously  with  p-hydroqulnone  at  100
rag/kg/day  for   51  days  (Skalka^   1964).   Seventeen  male  rats   served  as
controls.  At  the end  of the dosing period,  seven treated and seven  control
rats were  sacrificed and  the  weights  of  the testes,  ep1d1dym1des,   seminal
vesicles and  suprarenal  glands  were  determined.  H1stolog1cal  examinations
of  these  tissues were  also  performed.  The  remaining rats  were  each mated
for 5 days  to  two female rats at  some unspecified time  during the study, as
soon as the Injections stopped  or at  17 days  after  the  Injections.   The
females  were   sacrificed  7  days  later  and  their uteri  were  examined  for
fetuses.
    The average  weights  of  the  testes,  epldldymldes,  seminal  vesicles  and
suprarenal   glands were decreased  In   the  treated  group  by  26.1,  21.4, 41.2
and  21.2%,  respectively.   H1stolog1cal  examination  of  testes  from  the
treated group  revealed  that  spermlogenesls  had been  disrupted.   Untreated
females mated  with  treated males  had  an  average  of  10.4 fetuses/2 females;
39% were  not  pregnant.   Untreated females mated  with control  males  had an
average of  15.4  fetuses/2  females; 20% were not pregnant.   Compared with
controls,  male fertility was decreased by  32.5%  and  the pregnancies In mated
females were reduced by nearly 24% 1n  the  experimental  group.  At  the end of
the Injection period, females mated with  treated males  had an average of 7.3
fetuses/2 females; 58% were not  pregnant.   Mating  of  6 treated males  17 days
after the  Injections resulted  In  an  average  of 6.3  fetuses/2  females;  58%
were not pregnant.


0049d                               -47-                             08/26/87

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6.6.   SUMMARY
    Eye lesions have been reported  1n workers  exposed  to  p-hydroqu1none dust
and qulnone vapor (Sterner et al.,  1947;  Anderson,  1947-,  Miller,  1954).  The
severity  of  eye  lesions  Increased with  the  length  of  exposure,  and  the
lesions can progress even after exposure  has  ended.   Concentrations  found In
a plant where eye Injuries were  observed were 0.044-14.1 mg/m3  qulnone  and
20-36  mg/ffl3 p-hydroqu1none  (Oglesby et  al.,  1947).   At  these  levels,  no
signs  of  systemic  Intoxication  were noted  In workers with  or  without  eye
lesions (Sterner et  al., 1947).
    In a  sufechrotrtc toxltlty study, Carlson  and Brewer  (1953)  found that
rats  fed  a diet  containing 5/4  p-hydroqu1none for  9 weeks  ate  less,  lost
weight and  developed aplastlc anemia.   Atrophy of the bone marrow  and other
tissues,  and   superficial  ulceratlon  and  hemorrhage of the  stomach  were
noted.  No  changes  were observed In dogs  fed p-hydroqu1none  at  up  to a  TWA
dose  of 25.1  mg/kg/day for 80 weeks  or  100 mg/kg/day for 26  weeks  (Carlson
and  Brewer,  1953).   Blood  analyses and  uMnalyses revealed  no  effects  In
humans  fed  p-hydroqu1none  at  300-500  mg/day  for  3-5 months  (Carlson  and
Brewer, 1953).  No  effects  were  noted In Syrian  hamsters  fed  p-hydroqulnone
1n the diet at 0.5% for 20 weeks  (Hlrose et al., 1986).
    Mozhayev  et  al.  (1966) found  that  rats  treated  with p-hydroqu1none  In
the  drinking  water  at 100  mg/kg/day  gained  weight  slower  than  controls.
Rats  treated  at  50  mg/kg/day or more exhibited a decrease In  the  number  of
erythrocytes,   and  an  Increase  In  the  number  of  leukocytes  and dystrophic
changes In  the  small  Intestines,   liver,  kidneys and myocardium.   Nakamura
(1982) found  lowered hematocrlt  and a decrease In  the number  of  bone marrow
cells  In  mice provided with  p-hydroqu1none 1n the  drinking  water  at  4  g/2.
(4000 ppm) for 4 weeks.


0049d                               -48-                             07/14/87

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    Delcambre et al.  (1962)  observed  blood  effects  In rats treated by gavage
with  p-hydroqu1none  at  15  mg/ktj,  6  days/week  for  40 days.   These effects
were  not  observed  In rats treated  at  7.5 mgAg/day for 40  days,  or In rats
treated at  5  and  10 mg/kg,  6 days/week  for  4  months.   Mortality was high In
10  mg/kg  group.   Rats   treated  orally  at 156 mg/kg  for  30 days  showed
Increased  liver  weights, decreased hepatic glycogen  and  vitamin  C content
and decreased blood serum protein levels  {Anlkeeva, 1974).
    In an 8-week study  (Christian  et  al., 1980), a depression  1n body weight
was observed  1n rats  treated  with p-hydroqu1none  1n the drinking  water at
>470  mg/kg/day.   Changes  in relative  organ weights  were observed  In  rats
treated at  >390  mg/kg/day.   There  were no effects at <270  mg/kg/day.   In a
15-week study  (Christian et al.,  1980),  the only  significant  change was an
Increase  in relative  liver and  kidney  weights  In rats provided with p-hydro-
qulnone 1n the drinking water at >110 mg/kg/day.
    The NTP sponsored a  13-week  gavage study (Keller,  1982;  Bloassay Systems
Corp., 1981a)  In which  rats  died at >200 mg/kg/day.   Survivors were lethar-
gic,  and  toxic nephropathy  and squamous  hyperplasla  and  acanthosls  of  the
stomach were  observed.   There  were no  effects  at <100 mg/kg/day.   The  NTP
13-week  gavage mice  study  (Keller,   1982;  Bloassay  Systems  Corp.,  1981b)
resulted  1n  death  at >200 mg/kg/day.   Males treated  dally  at  >25  mg/kg  and
females at  >100 mg/kg  were  lethargic,  and  hunched posture  was  observed at
>200  mg/kg.   The  only  significant  hlstopathologlc effects  were forestomach
lesions at >200 mg/kg/day.
    In a oral toxiclty  study (Woodard,  1951),  no changes  In body weight gain
or blood  counts  were observed  In  dogs treated  with p-hydroqu1-  none in  TWA
doses   of  21.5 and  42.9  mg/kg/day  for  810  days.  Hyperplasla of  the  bone
marrow  and   excessive   pigment  deposits   1n   the   spleens  were  observed


0049d                                -49-                             07/14/87

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In all  dogs.   No  changes  In hematologlcal parameters or  hlstopathology  were
noted  in rats  fed  p-hydroqu1none  1n the diet at concentrations up  to  1% for
103 weeks (Carlson and Brewer,  1953).
    Gastrointestinal  disease  attributed  to  p-hydroqu1none  was  reported  In
crewmen aboard a navy vessel  (Hooper  et al.,1978).  Other  symptoms  noted In
humans  Ingesting p-hydroqulnone at  relatively large doses  Include  acldosls,
anemia,  erosion  of  the  gastric  mucosa,  edema  of  Internal  organs,  convul-
sions, coma and death (NIOSH,  1978).
    A  review  of   all the  p-hydroqu1none  toxldty  data  by  the   Cosmetic
Toiletry and fragrance Assoc.  (1986)  concluded  that p-hydn>qu1nowe  Is  "safe
for  cosmetic  use  at  concentrations of  <1.0/4 In  formulations  designed  for
discontinuous,  brief use  followed  by rinsing  from the skin and hair."
    In  a  14-day  gavage study sponsored  by  NTP  (Davis,  1979), doses  of  1000
and 500 mg/kg were  lethal to rats,  while  500  and  250 mg/kg doses  were lethal
to mice.   Rats at  all  doses  (>63  mg/kg/day)  lost weight.   Gross  pathology
revealed no consistent changes  In  either rats  or  mice.
    The  acute  oral  LD5Q  ranged  from -200-1200  mg/kg  In  rats,  dogs,  mice
and guinea  pigs depending  on  the  solvent of  p-hydroqulnone  (Anlkeeva,  1974;
Carlson and Brewer,  1953;  Lehman  et a!., 1951).   The compound  Is more toxic
to cats, with an oral LD5Q of  42-86  mg/kg (Carlson and Brewer, 1953).
    No  studies  concerning  the  cardnogenldty  of  p-hydroqu1none by  either
the  Inhalation  or  oral  routes of exposure  were located.   A  gavage  study of
the  cardnogenldty of  p-hydroqu1none  has  been completed  but  the  data  are
not yet available (NTP,  1987).
    An  Increased tumor  Incidence  was observed  In  mice  In  which  cholesterol
pellets containing  20% p-hydroqu1none were Implanted  in the bladder  (Boyland
et al.,  1964).  In  an  18-week  study,  Increased  skin tumor  Incidences  were
0049d                               -50-                             07/14/87

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not observed  In  mice  treated weekly with p-hydroqu1none and  croton  oil  (Roe
and Salaraan,  1955).   Boutwell and  Bosch  (1959)  concluded  that p-hydfoqutnone
was Inactive  as  a promoter  1n  mouse skin following a  single application  of
DMBA.
    Holmberg et al. (1986)  found that  after  an  Intraperltoneal  dose  of DENA,
p~hydrot|u1none  administered  orally  to  rats  at  100   mg/kg  resulted  1n  a
significant  elevation  of  f-glutamyl-transpeptldase   positive  foci  1n  the
Hver.  p-Hydroqulnone  Injected  Into laboratory animals results  In  arrested
raetaphase   (Parroentler   and  Oustln,  1948;  Parroentler,   1953;   Rosin   and
Doljanske, 1953).
    p-Hydroqulnone Injected  subcutaneously  Into  mice with  melanoma Increased
survival (Chavln et al., 1980).
    p-Hydroqu1none tested positive for reverse mutation In £. typhlmuMum on
ZLM medium  but  was  negative on  VB medium  (Gocke et al.,  1981).   The remain-
Ing Ames type assays  have been  negative  {Goodyear  T1re and Rubber Co.,  1982;
Sakal  et al., 1985).  DNA damage was observed  when p-hydroqu1none was tested
E_. coll {Goodyear T1re and Rubber Co.,  1982).
    Negative  results  have  been  found  In   studies of sex-1Inked  recessive
lethal mutations  In  0.  melanogaster (Gocke  et  al., 1981;  Goodyear  Tire  and
Rubber  Co.,  1982)  and   In  a test  for  DNA  damage 1n  mouse lymphoma  cells
(Pellack-Walker  and  Blumer,   1986).    p-Hydroqu1none  did   not  transform
Balb/3T3 mouse  cells  (Goodyear  T1re  and Rubber  Co., 1982).   Post et  al.
(1984), Penney  et  al. (1984) and  Painter  and  Howard   (1982)  have shown  that
p-hydroqu1none  Inhibits   ONA and  RNA  synthesis.   p-Hydroqulnone  has  been
shown  to Increase  the rate  of SCE 1n  human  lymphocytes (MoMmoto and Wolff,
1980;  Knadle, 1985; Erexson  et al., 1985).
0049d                               -51-                             07/14/87

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    p-Hydroqu1none  tested  positive  1n  a mouse  mlcronucleus  test  (Gocke  et
al., 1981).  A spot  test using  mice  was  negative (Gocke et al., 1983).  Jowa
et al.  (1986) found  that jn.  vitro,  p-hydroqulnone  reacts  with deoxyguanoslne
and DNA to form two adducts.
    An  Increase  In the resorptlon rate  was  observed 1n rats fed  a total  of
0.5 g  of  p-hydroqu1none throughout  gestation (Telford  et al.,  1962).   The
only effects noted In  rats dosed by gavage with p-hydroqu1none on gestation
days 6-15  at doses  of 300  mg/kg were  decreased maternal  weight gain  and
decreased  female  fetal  weights  (Krasavage,  1985).   No  effects  were observed
at <1DO tag/kg.
    The  number  of young  produced  In  two   successive  Utters  by male  and
female  rats  treated with   p-hydroqu1none  1n  the  diet for  6 months at levels
up to  1% were  similar  to  controls (Carlson and Brewer,  1953).   Female rats
fed  p-hydroqu1none 1n  the diet  at  concentrations  up  to 0.3/4 for  10  days
before  mating  and  throughout  gestation  showed  no  changes   In  reproductive
parameters (Ames et al., 1956).
    Racz et  al.  (1959) found that  oral  administration of p-hydroqu1none  at
200  mg/kg/day  and  possibly  at  50 and  100  mg/kg/day  for 2  weeks prolonged
dlestrus In  female  rats.   In  a  study by  Skalka (1964),  reduced fertility was
observed  1n  male  rats subcutaneously  Injected  with  p-hydroqu1none  at  100
mg/kg/day  for  51   days  before  mating.   Other effects  noted were decreased
testes, ep1d1dym1des, seminal vesicle and suprarenal gland weights.
0049d                               -52-                             07/14/87

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                     7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUMAN
    The  OSHA  (1985)  PEL and  the ACGIH (1986a,b)  TLV-TWA for p-hydroquinone
are  2 mg/m3.   NIOSH'  (1978)  has  also recommended  2 mg/m3  as  a  !5-m1nute
celling.   The  level  of  2  mg/m3  1s  based  on human  exposure  which  Indicated
that  at  2 mg/m3  eye lesions do not occur  or  that  1f  they do  occur,  they
are mild and reversible (ACGIH,  1986a; NIOSH, 1978).
    Additional  guidelines   and   standards   for  p-hydroqu1none  could  not  be
located  in the available literature as cited in Appendix A.
7.2.   AQUATIC
    Guidelines  and  standards for the  protection  of aquatic  organisms  from
the effects of  p-hydroquinone could not be  located  in  the available litera-
ture as cited In Appendix A.
0049d                               -53-                             06/02/87

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                              8.  RISK ASSESSMENT
 8.1.    CARCINQGENICITY
 8.1.1.   Inhalation,    Pertinent   data  regarding   the   carc1nogen1c1ty  of
 p-hydroqu1none  following  Inhalation  exposure  could not  be located  1n  the
 available  literature as cited  1n  Appendix  A.   p-Hydroqulnone has been  shown
 to  be a metabolite  of  benzene, a human  carcinogen.  Whether p-hydroqu1none
 plays a role  in benzene  care1nogen1city Is  not clear.
 8.1.2.   Oral,   Pertinent  data regarding  the  cardnogenldty   of  p-hydro-
 qulnone following  oral  exposure  could  not  be  located  In the  available
 literature  as cited 1n  Appendix A.   The  103-week toxlclty  study usltvtj rats
 (Carlson and  Brewer, 1953)  did not  discuss  tumor  Incidences.   The  NTP  has
 sponsored  a 2-year gavage study of p-hydroqulnone,  but  the data are not  yet
 available  (NTP, 1987).
 8.1.3.   Other   Routes.    Cholesterol   pellets   containing  p-hydroqulnone
'Implanted  In  the  bladder of mice  Induced  significantly (p=0.03)  more bladder
 tumors  than In mice  Implanted with just cholesterol  (Boyland  et a!., 1964).
    p-Hydroqu1none  did   not  Increase   tumor  Incidences  1n  the  skin  of mice
 when  It  was   applied   with  croton  oil  (Roe and   Salaman,  1955)  and when
 p-hydroqulnone  was  applied following  DMBA  treatment  (Boutwell  and   Bosch,
 1959).   p-Hydroqulnone  treatment  did,  however,  result  In a  significant
 elevation  of  y-glutamyl-transpept1dase positive  foci  In  the Hvers  of rats
 following a single DENA  treatment.
    p-Hydroqu1none  treatment of rats  (Parmentler and Dustln, 1948; Rosin  and
 Doljanskl,  1953)  and hamsters  (Parmentler,  1953)  has  been  shown  to  affect
 mitosis.   A mitosis  state called  three-group metaphase  has  been observed  In
 bone  marrow,  liver and  cornea!  cells  of treated animals.
 0049d                                -54-                              07/14/87

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    Chavln et al.  (1980)  found that p-hydroqu1none  Improved  the  survival  of
mice receiving melanoma transplants.
8.1.4.   Weight  of  Evidence.   Although p-hydroqu1none  Is  a metabolite  of
the human  carcinogen,  benzene,  and p-hydroqu1none  has  been shown  to  cause
mltotlc effects, there are no  laboratory animal  studies  of p-hydroqu1none  by
relevant routes  of  exposure  that Indicate  that p-hydroqu1none  Is  a carcino-
gen.  In addition,  no human  data  are  available.   This  lack of data Indicates
that p-hydroqu1none can be placed  1n  U.S.  EPA  Group D  (U.S. EPA,  1986c), not
classifiable as to human carclnogenldiy.
    IARC 0977)  reviewed all the  available  data  concerning the carclnogenlc-
1ty of p-hydroqu1none and concluded that "the  available  data do not allow an
evaluation of carclnogenldty."
8.1.5.   Quantitative  Risk  Estimates.  There  are  no  data  Indicating  that
p-hydroqu1none  Is  a carcinogen  by  either   the  Inhalation  or oral  routes  of
exposure; therefore, q * values cannot be  derived.
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME  EXPOSURES  (SUBCHRONIC) -- No  subchronlc
Inhalation toxldty  studies  of p-hydroqu1none are  available.   Therefore,  an
Inhalation RfD for subchronlc exposure cannot be derived.
    8.2.1.2.   CHRONIC  EXPOSURES — Studies   1n   which   laboratory  animals
were chronically exposed to p-hydroqu1none  by Inhalation  are not available.
    Occupational exposure to p-hydroqu1none dust and qulnone  vapor  has  been
shown to result  1n  eye lesions.  The eye  lesions  described varied from  mild
Irritation  and   staining  of  the  conjunctiva  and  cornea  to  changes 1n  the
thickness and  curvature  of  the  cornea, loss of cornea! luster and Impaired
vision.   The  severe  eye  Injuries tended to  occur  only after  exposures of  >5
years (Anderson, 1947;  Miller,  1954).

0049d                               -55-                             07/14/87

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    Concentrations that resulted In eye  Injuries were  reported by Oglesby et
al.   (1947)   as   0.044-14.1   mq/m*    qulnone   vapor   and   20-36   mg/m3
p-hydroqu1none  dust.   At  these concentrations.  Sterner  et al.  (1947)  found
no evidence of  systemic effects In  Individuals with  eye  Injuries as measured
by physical examinations and laboratory tests.
    The  Inhalation  toxlclty  of  p-hydroqulnone  has  not  been  studied  1n
laboratory animals.   p-Hydroqulnone In  the  air  oxidizes to  qu1non«^   NIQSH
(1978)  stated  tnat   to  Improve  the  basis   for  their  recommendation,  the
equilibrium between p-hydroqu1none  and qulnone 1n air  should  be Investigated
further.   Further, the  role  of  p-hydroqulnone  In  the careInogenlcity  of
benzene should  be  Investigated, so  that  H can be  stated with some certainty
that p-hydroqulnone 1s not  a carcinogen  by  Inhalation.   A chronic Inhalation
RfO for p-hydroqulnone cannot be derived from the available data.
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS THAN  LIFETIME  EXPOSURE  — The  subchronlc  oral  toxldty
of  p-hydroqulnone  has  been studied 1n  a number  of  species.   In  a  9-week
study  using  rats,   Carlson  and   Brewer  (1953)  found  that  rats  fed  5/4
p-hydroqulnone  In  the diet  ate  less,  experienced a  46% loss  1n  weight  and
developed  anemia.   Microscopic  examinations revealed  atrophy  of  the  bone
marrow, liver  cord cells,  lymphold  tissue of the spleen,  adipose tissue and
striated  muscle.   Superficial ulceratlon   and  hemorrhage   of  the  stomach
mucosa were also noted.  These effects were  attributed In part to Inadequate
nutrition.
    Dogs  fed  p-hydroqu1none at doses  of 16  mg/kg/day,  TWA of  23.5,  or  100
mg/kg/day  for  up  to  80  weeks  showed  no significant  changes  In urlnalysls,
hematologlcal  analysis or  hlstopathologlcal examinations  as  compared  with
controls  (Carlson  and  Brewer,  1953).   No changes  In  blood analysis and urine


0049d                               -56-                             07/14/87

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parameters  were  noted  In  humans fed  three  doses of  p-hydroqu1none  per day
for a  total dose of  300  or 500 rag/day  for  3-5 months  {Carlson  and Brewer,
1953).
    Christian et al.  (1980)  treated  rats  with  p-hydroqu1none In the drinking
water  for  8 weeks  at 230, 390 and 700 mg/kg/day  for  males,  and 270, 470 and
810 mg/1cg/day  for  females.   Decreased water  Intake, decreased  body  weight
and Increased  relative  liver and kidney  weights  were noted  In males  at 700
mg/kg/day  and  females at 470 and  810 mg/kg/day.   Relative  liver  and  kidney
weights were  also  Increased In  males  at 390  mg/kg/day.   Increased relative
Hver and  kidney weights were also noted  In  rats  treated with p-hydroq«1none
1n drinking water  at 110,  200 and 360 mg/kg/day  for  males,  and 140, 240 and
430 mg/kg/day for females.
    Delcambre  et  al.  (1962)  found  blood  effects   (polychromatophlUa  and
erythroblastosls)  1n  rats   treated   by   gavage  with  p-hydroqulnone  at  15
mg/kg/day, G days/week  for  40  days.   These  effects were not observed  at 7.5
mg/kg/day  for  40  days,  nor were  they  observed  when rats  were  treated  by
gavage with  p-hydroqu1none  at  5 or  10 mg/kg/day, 6  days/week  for 4 months.
There was  a high rate of mortality, however,  at  10 mg/kg/day.   The cause of
death was  not  reported,  but three of  the  seven high-dose rats  died during a
scabies  epidemic.   However,  no  rats  or  mice treated  by  gavage  with  <100
mg/kg/day  for 13 weeks in a NTP study died (Keller, 1982).
    Rats treated with p-hydroqu1none 1n  the  drinking  water  for  6  months at a
dose  of  >50 mg/kg/day  showed  a decrease  1n  hemoglobin,  a  decrease  in the
number  of  erythrocytes,  an  Increase   In   the  number   of  leukocytes,  and
dystrophlc  changes   In  the   small  intestine,  Hver,  kidneys and  myocardium
(Hozhayev  et al.,  1966).   Anlkeeva  (1974) reported that oral  administration
0049d                               -57-                             07/14/87

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of p-hydroqu1none to rats at  156  mg/kg/day  for  30 days resulted 1n Increased
liver weights,  decreased hepatic glycogen  and  vitamin C  content,  decreased
blood serum protein levels and an Inhibition of  pseudochollnesterase.
    In  mice,  p-hydroqu1none  1n  the  drinking water at  4000 ppm for  4 weeks
markedly  lowered  the hematocrH  and  slightly decreased  the number  of  bone
marrow  cells  (Nakamura,  1982).   p-Hydroqulnone  In the  diet of hamsters  at
0.5X  for  20  weeks  did  not  result 1n  significant changes  1n body  weight,
Hver weight or hlstopathologlc changes (Hlrose  et a!., 1986).
    In  the  13-week  study  sponsored  by NTP  (Keller, 1982),  mice and  rats
treated  by  gavage  with  p-hytiroqnlnone at  400  mg/Vg/ttay  died.   Signs  of
toxlclty  that  occurred after  dosing  were tremors  and convulsions.   At  200
mg/kg,  three  female rats and  two  male  mice  died.   No  deaths occurred at <100
mg/kg/day.  Toxic  nephropathy was observed  In  rats  and  forestomach lesions
were  observed  In  mice at  200 mg/kg/day.  H1stopatholog1cal examinations  of
animals at lower doses were not completed.
    No  significant  changes  1n weight  gain  or  blood  counts  were  observed  in
four dogs treated with p-hydroqu1none  In gelatin  capsules  at TWA doses up to
42.9  mg/kg  for 810  days  (Woodard,  1951).   Microscopic  examination revealed
hyperplasla of  the  bone  marrow and excessive deposits  In  the  spleens of all
dogs.   It was not clear  1f  these lesions  also occurred  In control animals.
Because of  the  small  number of dogs studied, and  the lack of  study details,
this study 1s not  sufficient for risk assessment.
    The LOAEL  for the  subchronlc effects  was  reported  1n  the  Oelcambre  et
al.  (1962)  study   1n  which  blood  effects  were  observed  In rats  treated  by
gavage  at  15  mg/kg/day,  6  days/week  for  40 days.  A  dose  of  12.9 mg/kg/day
for  the  LOAEL  was  derived  by  multiplying by  6  days/7  days.   The  most
appropriate NOAEL  below the  LOAEL  1s  the NOAEL  1n humans  found  by Carlson


0049d                               -58-                             07/14/87

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and  Brewer  (1953).    In   this   study,  a  group  of  17  men  and  women  fed
p-hydroqulnone, 3 limes/day  (with  meals)  for a total  dose  of  300  rag/day for
3-5 months,  did  not  develop abnormalities  1n blood and urlnalyses.   A dose
of  500 mg/day  was  also  a  NOAEL, but  this was  administered  to only  two
subjects.   Because the body weights of  the  subjects  In this  study were not
provided,   a  human  body weight of  70 kg  (U.S. EPA, 1985) will  be  assumed  to
estimate a NOAEL of  4.29  mg/kg/day for the  300 mg/day dosage.   Dividing the
NOAEL  of  300  mg/day  by  10  to  protect  sensitive  Individuals,  a  subchronlc
oral HfD of 30 mg/day for  a 70 kg human or 0,4 mg/kg/day 1s  derived.
    Confidence In  the subchronlc  RfO  1s  medium.   The human  study  (Carlson
and Brewer,  1953)  Is adequate  1n  that blood analyses and  urlnalyses  of the
subjects  were done  1  month before  the  start  of  the  study  so that  the
subjects served as their  own controls.  Confidence  In  the  RfD 1s  not  higher
because p-hydroqulnone,  a  metabolite  of  benzene,  has  not been  adequately
studied for  cardnogenldty. -When  the  results of the NTP  cardnogenlclty
study are  available,  this  RfD should be reviewed.
    8.2.2.2.    CHRONIC  EXPOSURES —   Carlson and  Brewer  (1953)   found no
hematologlc  effects  or hlstopathologlc  changes  In  organs  of  rats  provided
with p-hydroqulnone  1n the  diet at levels  up  to  1%  for   103  weeks.   Tumor
Incidences were not discussed.
    The highest NOAEL  1n  the chronic rat  study  (Carlson  and Brewer,  1953)  Is
derived by multiplying the 10,000  ppm  dose level by the 0.05 rat food  factor
(U.S.   EPA, 1985)  to  obtain  a  dose of 500 mg/kg/day.   Because  this dose  Is
much  higher   than   the  subchronlc  rat  LOAEL,   12.9  mg/kg/day,   found  by
Delcambre   et  al.  (1962),   It  cannot be used  for  risk assessment.  The most
appropriate  basis  for  the  chronic  RfD  1s   the  subchronlc  human study  by
Carlson and   Brewer   (1953).   The  chronic  RfD  will  be   derived  from  the


0049d                               -59-                             07/14/87

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subchronlc NOAEL  of  4.29 mg/kg/day.  The  subchronic  NOAEL Is divided by  an
additional uncertainty factor of  10 to  extrapolate from subchronlc data,  to
derive a chronic oral RfD of 3 mg/day for  a 70 kg human,  or 0.04  mg/kg/day.
    Confidence  In  the  chronic  RfD 1s medium to  low.  The  study  used  for  the
derivation of the  RfD examined blood and  urine parameters  In  humans,  but  was
subchronlc.  Furthermore, p-hydroquinone  has not  been adequately studied  for
cardnogenlcity.   When  the results  from   the NTP cardnogenldty study  are
available, this fifO should be reviewed.
0049d                               -60-                             07/14/87

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                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The  toxlclty  of p-hydroqu1none  was  discussed  1n  Chapter  6.   The  data
suitable  for  deriving  RQs  are summarized  in  Table  9-1.   The  dog  study  by
Woodard  (1951) is not  Included  because  only two dogs/dose group were studied
and  U  Is not clear If  bone  marrow hyperplasla and  pigment  deposits  1n the
spleen were also observed In control dogs.
    The  derivation   of  RQs  1s summarized  In  Table  9-2.   The most  severe
effect was  found  In the 13-week  study sponsored  by  the NTP  (Keller,  1982;
Bloassay  Systems  Corporation,  1981a,t>).   In  this   study,  several  deaths,
lethargy  and  some   hlstopathologlc  effects  were  noted  1n  rats   and  mice
treated  by gavage  with  p-hydroqu1none  at  200  mg/kg,  5  days/week for  13
weeks.   The  RV  for both  rats and  mice  corresponds  to 10.   The  human MED
values of 75.6 mg/day  from the mouse  study and  150.5 mg/day from the rat
study  were  calculated  by  multiplying  the  equivalent  human  dose by 70 and
dividing  by  10  to   approximate  chronic  exposure.   The  MED  from  the  mouse
study  corresponds   to  an  RV.  of  2.7,  while  the  MED  from  the  rat  study
corresponds  to an   RV.  of  2.2.    Multiplying  the   RV  s  by the RV.s,  CSs
of 27 and 22 are obtained.   These CSs correspond to RQs of 100.
    In  two  other  studies,  effects  occurred  at a lower  human  MED  than ob-
served 1n the 13-week  gavage  study.   In the study by  Mozhayev et  al. (1966),
rats treated with p-hydroqu1none 1n  the drinking water  at 50 mg/kg/day  for 6
months  showed  decreased  numbers   of  erythrocytes,   Increased  numbers  of
leukocytes and dystrophlc changes In  the  small  Intestines,  liver, kidney and
myocardium.   The MED,  59.5  mg/day,  calculated  by multiplying the human  dose
by  70  kg  and by  dividing by  an   uncertainty  factor  of  10 to  approximate
chronic  exposure, corresponds  to  an  RV.  of 2.8.  The  effect  corresponds  to


0049d                               -61-                             07/14/87

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-64-
                                                                     07/14/87

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an  RVg  of  6.   Multiplying  the  RVrf  by  the  RVg  results  1n  a  CS  of  17,
corresponding to  an  RQ of  1000.   In the  study  by  Delcambre et al.  (1962),
blood  effects were  observed  1n rats  dosed by gavage with  p~hydroqu1none  at
15  mg/kg,  6  days/week  for  40  days.  The  MED,  15.4  rag/day,  calculated  as
described above,  corresponds to  an  RV.  of 3.7. The  effect corresponds  to
an  RVg  of  5.   Multiplying  the  RVrf  by  the  RVg  results  In  a  CS  of  19,
corresponding to an ftQ of 1000.
    The  remaining studies available  for  RQ  derivation  (Telford et  al.,  1962;
Krasavage, 1985; Carlson and  Brewer,  1953;  Nakaraura, 1982;  Christian  et  al.,
1980)  show effects less  severe  at doses higher  than observed In  the  13-week
gavage study; therefore,  CSs need  not be calculated.
    The  highest  CS,  27,  calculated  from  the  13-week  gavage  mice  study
(Keller  et al., 1981; Bloassay  Systems Corporation,  1981b)  Is recommended  as
the basis for the RQ (Table 9-3).
9.2.   BASED ON CARCINOGENICITY
    The  data  on  the  cardnogenlcity  of  p-hydroqu1none  were  Inadequate  to
calculate  a   q^*  (see  Section  8.1.).   Therefore,  an  F   factor  cannot  be
calculated and an RQ based on cardnogenldty cannot  be derived.
0049d                               -65-                             07/14/87

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                                  TABLE 9-3

                                p-Hydroqu1none

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




Route:                  oral

Dose*:                  74.9  mg/day

Effect:                 deaths of  2  males,  lethargy,  hunched position and
                        decreased  weight  gain 1n males,  forestomach lesions

Reference:              Keller,  1982

RVd:                    2.7

RVe:                    10

Composite Score:        27

RQ:                     100


*Equ1valent  human dose
0049d                               -66-                             07/14/87

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Pub!., Ann Arbor,  MI.   p. 245-254.
0049d                               -77-                             07/14/87

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Mill, T.  and  W.  Mabey.  1985.  Photochemical transformations.   IJK  Environ-
mental Exposure from Chemicals, Volume I, VI.B. Neely  and  G.E.  Blau,  Ed.   CRC
Press, Inc., Boca Raton, FL.  p.  209.

Miller. S.J.H.   1954.   Ocular ochronosls.   Trans. Ophthalmol. Soc.  UK.   74:
349-366.  (Cited In NIOSH,  1978)

Killer, J.J., G.W. Powell,  A.H. Olavesen and C.8.  Curtis.   1976.   The toxlc-
Uy  of  dimethoxyphenol and  related compounds  1n the  cat.   Toxlcol.  Appl.
Pharmacol.  38: 47-57.

Mohr, D.H.  and C.J.  King.   1985.   Identification of  polar  organic compounds
In  coal-gaslf1cat1on  condensate  water by  gas chromatography-mass  spectrom-
etry  analysis  of  high  pressure  liquid  chromatography fractions.   Environ.
Sc1. Techno!.  19: 929-935.

Morlmoto,  K.  and S. Wolff.   1980.   Increase  in  sister chromatld  exchanges
and  perturbations  of cell  division  kinetics  In human  lymphocytes  by benzene
metabolites.  Cancer Res.   40: 1189-1193.

Mozhayev,  Y.A.,  V.P.  Oslntseva  and Y.V.  Arzamastsev.  1966.   Hydroqulnone
toxldty  1n chronic poisoning.  Farmakol.  Tokslsol.   29:  238-240.   (Rus.)
(Cited In NIOSH,  1978)

Nakamura,  S.  1982.  The effects of oral administration of  resorclne, hydro-
qulnone or  phenol  on  hemopoletlc  system  In mice.  Osaka-furltsu  Koshu  E1se1
Kenkyusho Kenkyu Hokoku, Rodo Elsel  Hen.   20:  45-49.   (CA  99:48611w)


0049d                               -78-                              07/14/87

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NAPM  (National  Association  of   Photographic  Manufacturers,  Inc.)-   1974.
TSCA  Submission.   Environmental   effects  of pnotoprocesslng  chemicals.  Vol.
1.  U.S. EPA, OTS, Washington, DC.  F1che OTS 050 7473, Doc. No.  40-8469216.

Nauraann, 6.   1966.   Cornea!  damage  1n hydroqulnone workers.  A  cllnlpatho-
loglc study.  Arch.  Ophthalmol.  76(2): 189-194,

NIOSH  (National  Institute  for   Occupational   Safety  and  Health),   1378.
Criteria for a  Recommended  Standard...Occupational  Exposure to Hydroqulnone.
NIOSH, Cincinnati OH.   NTIS PB81-226508.

NIOSH  (National  Institute  for   Occupational   Safety  and  Health).   1984.
Current  Awareness  File.    RTECS  (Registry of  Toxic  Effects  of  Chemical
Substances).

NTP (National Toxicology Program).  1987.  Management Status Report.

Oglesby, F.L., J.H.  Sterner and  B. Anderson.   1947.   Qulnone vapor and their
harmful effects - II. Plant exposures  associated with  eye Injuries.  3.  Ind.
Hyg. Toxlcol.  29: 74-84.

OSHA  (Occupational  Safety  and  Health  Administration).   1985.    Safety  and
Health Standards.   29 CFR  1910.1000.

Painter, R.B. and R.  Howard.   1982.   The HeLa DNA-synthesIs  Inhibition  test
as a rapid  screen for mutagenlc carcinogens.  Mutat. Res.   92(1-2): 427-437.
0049d                               -79-                             07/14/87

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Parmentler,  R.   1953.  Production  of "three-group metaphases"  1n the  bone
marrow  of  the golden  hamster.   Nature.   171:  1029-1030.   (Cited 1n  NIOSH,
1978)

Paraeniler,  R. and  P. Dustln, Jr.   1948.   Early effects of hydroqulnone  on
mitosis.  Nature.   161: 527-528.   (Cited  In  NIOSH,  1978)

Pellac*-Walker,  P.  and J.L.  Blumer.  1986.   ONA  damage  in  L5178YS  cells
following exposure to benzene wetabrlUes,   flol.  Pharmacol,  30(1)4 42-47.

Penney,  K.B.,  C.J.  Smith  and  J.C.   Allen.   1984.  Deplgmentlng  action  of
hydroqulnone  depends  on   disruption  of  fundamental  cell  processes.    J.
Invest. Dermatol.   82(4):  308-310.

Perry, R.H.  and  0.  Sreen.   1984.  Perry's  Chemical  Handbook.   Physical and
Chemical Data, 6th ed.  McGraw H111  Book  Co.,  New York.

PHter,  P.   1976.    Determination  of biological  degradablllty  of   organic
substances.  Water Res. 10:  231-235.

Post, G.B.,  R. Snyder  and G.F. Kalf.   1984.   Inhibition  of  mRNA  synthesis  In
rabbit  bone  marrow  nuclei  j£  vitro by   qulnone  metabolites  of benzene.
Chem-Blol.  Interact.  50(2):  203-211.

Racz, G.,  J. Fuz1,  G.  Kemeny  and Z.  Klsgyorgy.   1959.  Effect  of  hydroqulnon
and phlorlzln on  the  ouarlan  cycle  of rats.  Rev. Med.  (Tirgu-Mures,  Rom.).
5: 67-69.  (Cited  1n Oynamac  Corp.,  1982)


0049d                               -80-                             07/14/87

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R1bo,  J.M.   and  K.L.E.  Kaiser.    1983.   Effects  of  selected  chemicals  to
photoluralnescent bacteria  and their  correlations with  acute and  sublethal
effects on otner organisms.  Chemosphere.  12(11-12): 1421-1442.

Roe, F.J.C.  and M.H. Salaman.  1955.   Further  studies  on Incomplete carclno-
genesls  —   trlethylene melamlne  (TEM),  1,2-benzanthracene  and  beta-proplo-
lactone, as  Initiators of  skin tumor  formation  In the  mouse.  Br. 3.. Cancer.
9; 177-203.  (Cited 1n NIOSH, 1978")

Rosin,  A.  and  F.   Ooljanskl.   1953.   Effect  of hydroqulnone   on  mitosis.
Nature.  172: 1151.  (Cited In NIOSH, 1978)

Rott, 8., R. Vlswanathan,  D. Freltag  and  F.  Korte.   1982.   Comparison of the
applicability of  various   tests for  screening  the degradabUHy  of environ-
mental chemicals.   Chemosphere.   11:  531-538.

Sadtler.   1966.   Sadtler   Standard  Spectra.   60  UV.  Sadtler Research  Lab,
Philadelphia, PA.

Sakal,  M.,  D.  Yoshlda and S.  M1zusak1.   1985.   Mutagenlclty of polycycllc
aromatic hydrocarbons  and  qulnones  on  Salmonella typhlmurlum TA97.   Mutat.,.
Res.  156(1-2):  61-67.

Sasaki, S.   1978.   The  scientific  aspects of the Chemical  Substance Control
Law  1n  Japan.    ln_:  Aquatic  Pollutants:  Transformation  and   Biological
Effects, 0.  Hutzlnger, L.H.  von  Letyoeld and 8.C.J. Zoeteman, Ed.   Pergamon
Press, Oxford,   p.  283-298.


0049d                               -81-                             07/14/87

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Shackelford,  W.M.  and  L.H.  Keith.   1976.   Frequency  of organic  compounds-
Identified In water.   U.S. EPA,  Athens.  GA.   p.  146,   EPA 600/4-76-062.

Skalka,  P.   1964.   The  Influence  of hydroqulnone on  the fertility  of  male
rats.   Sb.  Vys. Sk  Zeraed. Brne  Rada B.   12:  491-494.   (Cze.)    (CHed  In
NIOSH, 1978)

Sollraan, T.   1949.  Correlation of  the  aquarium goldfish toxlcltles  of  some
phenols,  qulnones  and  other  beniene  derivatives  with  their  Inhibition  of
autooxldatlve reactions.   J.  Gen.  Physio!.   32:  671-679.   (CHed 1n WcKee
and Wolf, 1963)

Speece,  R.E.   1983.    Anaerobic   biotechnology  for   Industrial   wastewater
treatment.  Environ.  Sd. Technol.   17:  416A-427A.

SRI  (Stanford  Research  Institute).   1986.    1986   Directory  of  Chemical
Producers:  United  States  of  America.   SRI  International,  Menlo  Park,  CA.
p. 722-723.

Sterner,  J.H.,  F.L.   Oglesby  and  B. Anderson.   1947.   Qulnone  vapors  and
their harmful effects.   I.  Corneal  and  conjunctiva!  Injury.   J.  Indus.  Hyg.
Toxlcol.  29: 60-73.

Stom,  D.I.  and  R.  Roth.  1981.   Some  effects  of poly  phenols  on  aquatic
plants.   1.  Toxlclty  of phenols In  aquatic  plants.   Bull.  Environ.  Contam.
Toxlcol.  27(3): 332-337.
0049d                               -82-                             07/14/87

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

Szevzyk,  U., R.  Szewzyk  and B.  Schlnk.   1985.  Methanogenlc  degradation  of
hydroqulnone and  catechol  via  reductive  denydroxylatlon  to phenol.   FEMS
M1crob1ol.  Ecol.   31: 79-87.

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

Telford,  I.R., C.S.  Woodruff and R.H.  Llnford.   1962.  Fetal  resorptlon  1n
the rat as  Influenced by  certain antloxldants.  Am. J. Anat.  110: 29-36.

Usaml, Y.,   A.B.  Landau,  K.  Fukuyama  and G.A. GelUn.   1980.   Inhibition  of
tyroslnase   activity  by  4-tert-butylcatecol  and  other  deplgmentlng agents.
J. Toxlcol.  Environ.  Health.  6:  559-567.

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

U.S.  EPA.   1980.  Guidelines  and  Methodology Used In  the  Preparation  of
Health Effect  Assessment   Chapters  of  the  Consent  Decree Water  Criteria
Documents.   Federal  Register.  45(231):  49347-49357.
0049d                               -83-                             07/14/87

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

U.S. EPA.   1984.   HydnMUJifwwe;  Proposed lest Rule,  federal Register.   49:
438-448.

U.S. €PA.   1985.   Reference  Values for  Risk Assessment.   Prepared by  the
Office  of  Health   and  Environmental Assessment,  Environmental  Criteria  and
Assessment Office, Cincinnati, OH  for  the Office of  Solid  Waste,  Washington,
DC.

U.S. EPA.   1986a.  Methodology  for  Evaluating Potential  Carc1nogen1c1ty  In
Support of  Reportable Quantity Adjustments  Pursuant to CERCLA Section  102.
Prepared by  the  Office  of  Health  and Environmental Assessment,  Carcinogen
Assessment  Group   for  the  Office   of  Solid  Waste   and  Emergency  Response,
Washington, DC.

U.S.  EPA.    1986b.    SANSS   (Structure  and  Nomenclature  Search   System)
Database.   On-Hne.

U.S.  EPA.    1986c.   Guidelines  for   Carcinogen  Risk  Assessment.   Federal
Register.   51(185): 33992-34003.
0049d                               -84-                             07/14/87

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U.S.  EPA.   1987.    Graphical   Exposure  Modeling  System  (GEMS).   Fate  of
Atmospheric  Pollutants   (FAP)   computer  data  systems,   U.S.  EPA.  Research
Triangle Park, NC.

USITC  (U.S.  International Trade  Commission).   1984.   Imports  of  Benzenold
Chemicals and Products 1983.   USITC Publ.  1548, Washington,  DC,   p.  19.

Varagnat, 3.  1981.   Hydroqulnone,  resorclnol  and  catechol.   In:  Klrk-Othroer
Encyclopedia  of  Chemical Technology  Vol.  13, 3rd ed.  Wiley-Interscience.
Hew York.  p. 39-69.

Verschueren, K.  1983.   Handbook of  Environmental  Data  on  Organic Chemicals,
2nd ed.  Van Nostrand Relnhold Co., New York.  p.  746.

Vollmer, H.   1932.   Studies  on  oxldatlve  Intoxication and detoxlcatlon  as  a
function  of  habltuation.   Arch.   Exp.  Pathol.  PharmakH.   166:  405-431.
(Ger.)  (CHed In NIOSH,  1978)

Wellens, H.   1982.   Comparison  of  the  sensitivity  of Brachydanlo  rerlo  and
Leudscus 1dus  1n  the study  of the toxldty  to  fish of chemical  compounds
and wastewaters.   Z. Wasser  Abwasser Forsch.   15(2):  49-52.   (Ger.)

Wlndholz, M., Ed.   1983.  The Merck Index,  10th ed.  Merck  and  Co.,  Rahway,
NJ.  p. 699.

Woodard, G.D.L.  1951.   The  Toxldty,  Mechanism of Action and Metabolism of
hydroqulnone.   Dissertation,   George   Washington   Univ.,    Washington,   DC.
(Cited in NIOSH,  1978; Dynamac Corp., 1982)

0049d                               -85-                             07/14/87

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Young,  L.Y.   and  M.D.  Rivera.   1985.   Methanogenle  degradation   of  four
phenolic compounds.   Water  Res.   19:  1325-1332.

Young, R.H.F., D.H.  Ryckman  and 3.C.  Buzzell,  Jr.   1968.   An Improved tool
for measuring blodegradabnUy.   J. Water  Pollut. Control Fed.  40: 354-36EU
0049d                               -86-                              07/14/87

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                                  APPENDIX A

                             LITERATURE  SEARCHED



    This  HEED  Is  based  on  data  Identified  by  computerized  literature

searches of the following:
         TSCATS
         CASR online (U.S. EPA Chemical Activities Status Report)
         TOXLINE
         TOXBACK 76
         TOXBACK 65
         RTECS
         OHM TADS
         STORET
         SRC Environmental Fate Data Bases
         SANSS
         AQUIRE
         TSCAPP
         NTIS
         Federal Register
These' searches were  conducted  In January, 1987.  Tn  addition,  hand  searches

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

secondary sources should be reviewed:


    AC6IH (American  Conference of Governmental  Industrial  Hyglenlsts).
    1986.   Documentation  of the  Threshold  Limit Values  and  Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

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

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

    Clayton,  G.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.

    Clayton,  G.O.  and  F.E.  Clayton,  Ed.   1982.    Patty's  Industrial _
    Hygiene  and  Toxicology,  3rd rev.  ed., Vol.  2C.   John  WHey  and
    Sons, NY.   p. 3817-5112.
0049d
-87-
07/14/87

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    Grayson, M.  and  0. Eckroth,  Ed.   1978-1984.  K1rk-0thmer  Encyclo-
    pedia of Chemical Technology, 3rd ed.  John Wiley and  Sons,  NY.   23
    Volumes.

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

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

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

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

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

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

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

    U.S.  EPA.   1986.   Report  on  Status  Report  1n  the  Special  Review
    Program,  Registration   Standards   Program   and   the   Data  Call   in
    Programs.    Registration  Standards  and  the Data  Call  in  Programs.
    Office of  Pesticide Programs,  Washington, DC.

    U.S. EPA.    1985.   CS8 Existing Chemical  Assessment Tracking System.
    Name  and  CAS Number Ordered  Indexes.   Office of Toxic  Substances,
    Washington,  DC.

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

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

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

    Worthing,  C.R.  and S.8. Walker, Ed.   1983.  The Pesticide  Manual.
    British  Crop Protection  Council.  695  p.
0049d                               -88-                             07/14/87
          U.S. Environmental  Protection Agency,
          Region V, Library
          230 South Dearborn Street
          Chicago,  Illinois  60604

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    In  addition,  approximately  30  compendia of  aquatic  toxldty  data  were

reviewed. Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality  Criteria
    Data  Book.   Volume  3.  Effects  of  Chemicals  on  Aquatic  Life.
    Selected  Data  from the  Literature  through  1968.  Prepared  for the
    U.S. EPA under Contract No. 68-01-0007.  Washington,  DC.

    Johnson,  W.W.  and M.T.  Flnley.   T980.  Handbook of  Acute  Toxldty
    of  Chemicals  to  Fish  and   Aquatic   Invertebrates.   Summaries  of
    Toxldty  Tests  Conducted  at Columbia  National Fisheries  Research
    Laboratory.   1965-1978.   U.S.  Dept.  Interior, F1sh  and  Wildlife
    Serv. Res. Publ. 137,  Washington, DC.

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

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

    Schneider, B.A.   1979.   Toxicology  Handbook.   Mammalian and Aquatic
    Data.   Book  1: Toxicology  Data.   Office  of  Pesticide  Programs, U.S.
    EPA, Washington, DC.   EPA 540/9-79-003.  NTIS PB 80-196876.
0049d                               -89-                             07/14/87

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