HEALTH   AND   ENVIRONMENTAL
         E  F P E C
PROFILES
                 APRIL 30,  1980
     U.S.  ENVIRONMENTAL PROTECTION AGENCY
             OFFICE OF  SOLID WASTE

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                              2,4-OICHLOROPHENOL
I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water  Quality  Criteria Document
for 2,4-dichlorophenol (U.S. EPA, 1979).
     2,4-Oichlorcphenol is  a colorless,  crystalline solid having the empiri-
cal  formula  C-H.C^Q  and  a  molecular   weight   of  163.Q   (Weast,  1975).
It  has  the following physical  and chemical  properties  (Sax,  1975;  Aly and
Faust, 1965; Weast, 1975; Kirk and Othmer,  1964):
         Melting Point:              45° C
         Boiling Point:              210° C at 760  mm Hg
         Vapor Pressure:             1.0 mm Hg at 53.0° C
         Solubility:                 slightly soluble in water  at neutral pH;
                                     dissolves readily in ethancl and benzene
     2,4-Oichlorophenol is  a commercially  produced,  substituted phenol used
entirely as an intermediate  in the manufacture of  industrial and agricultur-
al  products  such  as  the  herbicide 2,4-dichlorcphenoxyacetic  acid (2,4-0),
germicides, and miticices.
     Little data  exists  regarding  the persistence  of  2,4-aichlorophenol in
the  environment.   Its  lew  vapor  pressure, and  non-volatility  from aqueous
alkaline  solutions would  cause  it  to be  only  slowly removed from surface
water via  volatilization  (U.S. EPA,  1979).  Studies have  indicated low ab-
sorption of 2,4-dichlorophenol from natural  surface waters  by various clays
(Aly and  Faust,  1964).    2,4-Dichlorpphenoi is  photolabile in  aqueous solu-
tions (Aly and Faust,  1964; Crosby  and Tutass, 1966)  and  can  be degraded
microbially to  succinic  acid  in  soils  and aquatic  environments  (Alexander
and Alesm, 1951;  Ingols, et al.,  1966; Loos, et al., 1967).

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II.  EXPOSURE
     A.  Water
         Sources of 2,4-dichlorophenol in water  are  agricultural run-off (as
a contaminant and metabolic breakdown product of biocides)  and manufacturing
waste discharges (U.S. EPA, 1979).  Recant  experiments  under conditions sim-
ulating the  natural environment  have  not demonstrated  that 2,4-dichlorophe-
nol is  a  significant  product  resulting  from chlorination  of phenol-contain-
ing wastes (Glaze,  et al. 1978;  Jolley,  et al.  1978).
     8.  Food
         Contamination of  food with 2,4-dichlorophenol  would probably result
from use of the herbicide 2,4-0 (U.S.  EPA, 1979).
         The  U.S.  EPA (1979) has  estimated the  weighted  average bioconcen-
tration factor  for 2,4-dichlorophenol to be  37  for  the edible  portions  of
fish  and  shellfish consumed  by Americans.  . This estimate  is based  on the
octancl/water partition coefficient.
     C.  Inhalation
         Pertinent  information  regarding  direct evidence  • indicating  that
humans  are  exposed  to  significant   amounts  of 2,4-dichlorophenol  through
inhalation has not been found in the  available  literature.
III. PHARMACOKINETICS
     A.  Absorption
         Pertinent information  regarding the absorption of 2,4-dichlorophe-
nol in humans or animals was not found in  the available literature, although
data  on toxicity  indicate that  2,4-dichlorophenol -is  absorbed  after  oral
administration  (Deichmann,  1943; Kobayashi, et  al.  1972).   Due  to  its  high
                                                                       »
lipid  solubility and  low ionization at  physiological pH,  2,4-dichlorophenol
is  expected   to  be readily  absorbed  after oral  administration  (U.S.  EPA,
1979).

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     8.  Distribution
         Pertinent  information  dealing  directly  with  tissue  distribution
after  2,4-dichlorophenol  exposure  was not found in the available  literature.
Feeding  of 2,4-0 (300 -  2000 pg/g feed) to cattle  and sheep (Clark, et al.
1975)  and  Nemacide  (50 - 800 ug/g  feed) to  laying  hens  (Sherman,  et al.
1972)  did  not  produce  detectible residues of 2,4-dichlorophenol in muscle or
fat.   Cattle and sheep had high levels of 2,4-dichlorophenol  in kidney and
liver; hens had detectible levels  of  2,4-dichlorophenol in liver and yolk.
     C.  Metabolism
         Pertinent  information  dealing  directly  with  metabolism  of admini-
stered  2,4-dichlorophenol was  not found  in  the  available  literature.   In
mice,  urinary  metabolites of 1AC-labellsd  gamma or beta  benzene hexacnlor-
ide  (hexachlorocylohexane)  included  2,4-dicnlcrcphenol and  its  glucuronide
and  sulfate  conjugates   (as  4-6  percent  of  total metabolites)  (Kurihara,
1575).
     0.  txcretion
               Pertinent  information  dealing with  excretion of  administered  2,4-
      dichlorophenol was  not  found  in the available  literature.   After oral admi-
      nistration  of  1.6 mg  Nemacide  to  rats  over a  3-day  period,  67 percent of
      that compound appeared in urine as  2,4-dichlorophenol  within 3 days.  With a
      dosage of  0.16 mg Nemacide,  70 percent of  the  compound appeared in urine as
      2,4-dichlorophenol within 24 hours  (Shafik, et al. 1973).
      IV.  EFFECTS
           A.  Carcinogenicity
               Insufficient  data  exist  to indicate  that  2,4-dichlorophenor  is a
      carcinogenic  agent.  The only  study  performed  (Boutwell  and  Bosch, 1959)
      suggested  that 2,4-dichlorophenol may  promote skin cancer in mice after  ini-

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tiation with dimethylbenzanthracene and when  repeatedly  applied at a concen-
tration high enough to damage the skin.  An analysis  of  the data of Boutwell
and Bosch using the Fisher Exact Test  indicated  that  'the incidence of papil-
lomas  in  2,4-dichlorophencl-treated groups was  significantly  elevated  over
controls, while the incidence of carcinomas was not (U.S. EPA, 1979).
     8.  Mutagenicity, Teratogenicity and Other Reproductive Effects
         No  studies  addressing  the  mutagenicity, teratogenicity  or  other
reproductive effects  of  2,4-dichlorophenol in mammalian systems- were  found
in the  available  literature.  However,  genotoxic effects of 2,4-dichlorophe-
nol have been  reported in plants.   Exposure of flower buds or  root cells of
vetch,  (Vicia -fabia)'  to solutions of  2,4-dichlorophenol,  0.1M and 62.5 mg/1,
respectively,  caused  meiotic and  mitotic changes including alterations of
chromosome stickiness, lagging  chromosome  anaphase bridges  and fragmentation
(Arcer and -Ali, 1963,  1969, 1974).   The  relationship of such changes in plant
cells  to potential  changes in mammalian cells  has not bean  established (U.S.
EPA, 1979).
     C.. Chronic Toxicity
         One  report  (Blsiberg,  et   al.  1964)  suggested that 2,4-dichlorophe-
noi was  involved  in inducing chloracne and porphyria in workers manufactur-
ing 2,4-dichlorophenol and 2,4,5-trichlorophenol  and  exposed  to acetic acid,
phenol, monochloroacetic acid,  and  sodium hydroxide.   Since  various dioxins
(including one associated with chloracne)  have  been implicated  as contami-
nants  of 2,4,5-trichlorophenol, the  role of  2,4-dichlorophenol  in causing
chloracne and porphyria is not conclusive (Huff and Wassom,  1974).
         In  a  study  (Kobayaski, et al. 1972) in which  male mice  were  fed
2,4-dichlorophenol  at estimated daily  doses  of   45,  100 and 230 mg/kg  body
weight, no adverse  effects were noted except  for  some microscopic nonspeci-

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fie  liver changes,  after the  maximum  dose.   Parameters  evaluated  included
body  and  organ weights  and food  consumption,  as  well as hematological  and
histological changes.
     D.  Other Relevant  Information
         2,4-Qichlorophenol  appears  to  be  a  weak  uncoupler  of  oxidative
phosphorylation (Farquharson,  et  al.  1958;  Mitsuda, et al. 1963).   Values on
odor threshold  for  2,4-dichiorophenol in water  range  from 0.65 to  6.5 ug/1,
depending on the temperature of water  (Hoak,  1957).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Two 96-hour  assays have been  performed  examining the acute  effects
                                                                               \
of  2,4-dichIcrcphanai  in freshwater  fish.   An LC50 value of 2,020 jug/1  fo^ •-'
the  bluegill,  Lepomis macrcchir-js,  (U.S.  EPA,  1978),  and an  LC_n value  of
<3,230 ug/1 for  the  juvenile fathead minnow, Pi^aphalss pro.T.aias,  (Phipps.  at
al.  manuscript),  have  been reported.   Two  studies on  the freshwater clatio-
ceran,  Daohnia maona,  have produced 48-hour  static  LC5Q values  of 2,51---
and 2,600 ug/1 (Kcpperman, et al. 1974; U.S.  EPA, 1978).                      ,  •
         Only  one  marine fish  or invertebrate  species has  been  tested  for
the acute effects of 2,4-dichlorophenol.  Hi-tt,  et al. (1953) observed cniy
a moderate  reaction to  a concentration  of 20,000  pg/1 in mountain bass, a
species endemic to Hawaii.
     B.  Chronic Toxicity
         Data  for  the  chronic  effects  of 2,4-dichlorophenol   for  either
freshwater or marine organisms were not located in the available literature.
     C.  Plant  Effects
         Concentrations  of  2,4-dichlorophenol that  caused a  56  percent  re-
duction in  photosynthetic  oxygen  production or a  complete  destruction   of

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chlorophyll were  50,000  or 100,000 ug/1, respectively,  in algal assays  with
Chlorella pyrenoidosa  (Huang  and Gloyna, 1963).  An  earlier study by Slack-
man,  et  al.  (1955)  reported  a  concentration  of   2,4-dichlorophenol   that
caused  a  50  percent reduction in  chlorophyll  to  be  53,320 jjg/1 in the duck-
weed, Lemna minor.  No marine plant species have been examined.
     D.  Residues
         A bioconcentration  factor of 130 has  been  estimated from the octa-
nol-water partition coefficient  of 2,4-dichlorophenol  for aquatic organisms
having  a lipid  content  of  eight percent.   The  estimated  weighted average
bioconcentration  factor for the edible portion of aquatic organisms is 37.
     E.  Miscellaneous
         Flavor  impairment studies indicated  that the  highest concentration
of  2,4-c'ichiorcphenol  in  the exposure  water  which v/ould  not causa tainting
•of  the  sdible portion of. fish  ranged from 0.4 ug/1  for the iarcemcuth  bass
(Microptarus- saL-oldes),  to  14  ug/1  for the  bluegill (Lepomis iiiacrochirus).
The  value for the  rainbow trout  (Salrno gairdneri)  was 1 pg/1  (Shumway and
Palansky, 1973).
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human health nor the  aquatic criteria derived  oy U.S. EPA
(1979), which are summarized  below,  have gone  through  the  process of public
review;  therefore,   there is  a  possibility  that  these   criteria will be
changed.
     A.  Human
         Based  upon  the  prevention  of  adverse   organoleptic effects,  the
                                                                           *
draft interim criterion  for 2,4-dichlorophenol in water recommended  by the
U.S. EPA  (1979)  is  0.5 ug/1, although  the  recommended  draft interim criter-
ion could be 371 ug/l based on calculations by the U.S.  EPA (1979) from  sub-
acute toxicity data in mice.

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     8.  Aquatic



         The draft criterion for protecting  freshwater  organisms is 0.4 jug/1



as a  24-hour  average  concentration,  not to exceed  110 yg/l.   No criterion



was derived for marine  organisms (U.S. EPA, 1979).
                                    -907-

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                              2.4-OICHLOROPHENOL

                                  REFERENCES
Alexander,  M.  and  M.I.H.  Aleem.   1961.   Effect of  chemical  structure  on
microbial  decomposition of  aromatic  herbicides.   Jour.  Agric.  Food  Chem.
9: 44.

Aly,  O.M.  and S.O.  Faust.   1964.   Studies on the  fate of  2,4-0 and  ester
derivatives in natural surface waters.  Jour. Agric. Food Chem.  12:  541.

Amer,  S.M.  and  E.M.  All.    1968.   Cytological effects of  pesticides.   II.
Meiotic effects of some phenols.  Cytologia  33: 21.

Amer,  S.M.  and  E.M.  Ali.    1969.   Cytological effects of  pesticides.   IV.
Mitotic effects of. some phenols.  Cytologia  34: 533.

Amer,  S.M.  and  E.M.  Ali.   1974.  Cytological  effects  of pesticides.   V.  Ef-
fect of some herbicides on Soecia faba.  Cytologia  33: 633.

Biackfiian,  G.E.,  at  al.  1955.   The  physiological  activity  of  substituted
phenols.   I..  Relationships  between   chemical  structure  and   physiological
activity.  Arch. Bicchem.  Biophys.  54: 45.

Bleiberg, J.M.,  et  al.   1964.   Industrially acquired  porphyria.  Arch.  Oer-
rnatol.  35: 793.

Scutweii, 3.K.  arc  O.K.  Bcsch.  1959.  The  tumor-promoting  sciicn of  phenol
«^f* fo 1 —4- or* f^m^^.1 ir*He f OT rnoi <~O clC* ^   P
ai .U ^.^xawwU U*-t"!_^Ut ,^.O I Ul  >i*Owww brN^-'i.  W
Clark,  D.E.,  et al.   1975.   Residues  of  chlorophenoxy acid  herbicides  and
their  phenolic  metabolites  in  tissues  of sheep  and cattle.   Jour. Agric.
Food Chem.  23: 573.

Crosby. O.G.  and H.O.  Tutass.   1966.   Photodecomposition of ,2,4-dichlorophe-
noxyacetic acid.  Jour. Agric. Food Chem.  14: 596.

Deichrnann, W.3.  1943.   The  toxicity  of chlorophenols  for  rats.  Fed.  Proc.
2: 76.

Farquharson,  M.E.,  et  al.   1958.  The biological action  of chlorophenols.
Br. Jour. Pharmacol.  13: 20.

Glaze,  W.H.,  et al.   1978.   Analysis  of  new chlorinated  organic compounds
formed  by  chlorination of municipal  wastewater.   Page 139  In:  R.L.   Jolley,
(ed.)   Water  chlorination - environmental impact  and health  effects.    Ann
Arbor Science Publishers.

Hiatt,.  R.W.,  et al.  1953.   Effects  of chemicals on schooling fish, -Kuhlia
sandvicensis.   Biol. Bull.  104: 28.                              •

Hoak, R.D.  1957.   The causes of tastes and  odors  in drinking water.   Water
and Sew. Works.  104: 243.

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Huang, J. and  E.F.  Gloyna.   1968.  Effect  of organic compounds on photosyn-
tnetic oxygenation.  I. Chlorophyll destruction  and suppression of photosyn-
thetic oxygen production.   Water Res.   2: 347.

Huff, J.E. and J.S. Wasscm.   1974.  Health hazards from chemical impurities:
chlorinated dibenzodioxins  and chlorinated dibenzofurans.   Int.  Jour. Envi-
ron. Studies  6: 13.

Ingols,  R.5.,  et  al.   1966.   Biological activity  of  haiophenols.   Jour.
Water Pollut. Control. Fed.   33: 629.  "

Jolley, R.L.,  et  al.   1978.  Chlorination  of organics  in cooling waters and
process effluents.  In Jolley,  R.L.,  Water Chlorination environmental impact
and health effects.  1: 105.  Ann Arbor Science Publishers.

Kirk,  R.E.  and.D.F.  Othmer.   1964.   Kirk-Cthmer  encyclopedia  of  chemical
technology.  2nd ed. Interscience Publishers, New York.

Kobayashi,  S., et  al.   1972.   Chronic  toxicity  of  2,4-dichlorophenol  in
mice.  Jour. Md. Soc. Toho,  Japan.  19: 356.

Kopperman, H.L.,  et  al.   1974.  Aqueous Chlorination and ozonaticn studies.
I.  Structure-toxicity  correlations of  phenolic  compounds  to  Daphnia magna.
Chem. 3iol. Interact.  9: 245.

Kurihara,  N.   1975.   Urinary 'metabolites  from     and  B-5HC  in  the  mouse:
chlorcphenolic conjugates.  Environ. Qual.  Saf.  4: 56.

Loos, M.H., et al.   1967b.   Phenoxyacetate herbicide detoxication by bacter-
ial enzymes.  Jour. Agric. Food Chem.   15:  358.

Mitsuda,  W.,  et  al.  1963.   Effect  of chlorophenol  analogues  on the oxida-
tive phosphorylaticn in rat liver mitochondria.  Agric. Siol. Chem.  27: 366.

Phipps, G.L.,  et  al.   The  acute tcxicity  of phenol  and substituted phenols
to the fathead minnow.  (Manuscript)

Sax, N.I.  1975.  Dangerous  properties  of  industrial materials.  4th ed. Van
Nostrand Rheinhold Co., New York.

Shafik,  T.M.,  et  al.   1973.   Multiresidue procedure  for  haloand nitrophe-
nols.   Measurement  of exposure to biodegradable  pesticides  yielding these
compounds as metabolites.   Jour. Agric. Food Chem.  21: 295.

Sherman, M., et al.  1972.   Chronic toxicity  and residues from feeding nema-
cide  [o-(2,4-dichlorophenol)-o,o-diethylphosphorothioate]  to  laying  hens.
Jour. Agric. Food-Chem.  20: 617.

Shumway, D.L.  and J.R. Palensky.   1973.   Impairment of  the flavor of fish by
water pollutants.   EPA-R3-73-010.  U.S. Environ.  Prot. Agency.

U.S.  EPA.   1978.   In-depth  studies  on health  and environmental  impacts  of
selected  water pollutants.    Contract  No.   68-01-4646.   U.S. Environ.  Prot.
Agency.

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U.S.  EPA.    1979.    2,4-Oichlorophenol:   Ambient   Water  Quality  Criteria.
(Draft).

Weast,  R.C.,  ed.   1975.   Handbook  of chemistry  and physics.   55th  ed.  CHC
Press, Cleveland,  Ohio.

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                                      No. 76
         2,6-Dichlorophenol


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the  report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental impacts  presented  by  the
subject chemical.   This  document  has  undergone  scrutiny to
ensure its technical accuracy.

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                              2,6-OICHLOROPHENOL
                                   Summary

     There is no available information en the possible carcinogenic, terato-
genic, or adverse reproductive effects  of 2,6-dichlorophenol.
     The compound did not show mutagenic activity in the Ames assay.  A sin-
gle report has indicated that 2,6-dichlorophenol produced chromosome aberra-
tions in rat bone marrow cells; details  of  this  study were not available for
evaluation.
     Prolonged  administration of  2,6-dichlorophenol may  produce  hepatoxic
effects.   Pertinent  data on  the  toxicity  of 2,6-dichlorophenol to aquatic
organisms  were  not  found  in  the available  literature.   However,  EPA/ECAO
Hazard  Profiles  on  related  compounds  may  be  consulted,   including  meta-
chlorophenol,.2,4.5-trichlorophenol,  and  2,3,4,6-tetrachiorophenol.
                                    -9/3-

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I.   INTRODUCTION
     2,6-Oichlorophenol,  CAS  registry  number 87-65-0,  exists as white  nee-
dles and  has  a  strong  penetrating odor  resembling  o-chlorophenol.   It  has
the following physical and chemical constants (Weast,  1972;  Hawlsy,  1971):

               Formula:                          C6H4C12°
               Molecular Weight:                 163
               Melting Point:                    68°C  - 69°C
               Boiling Point:                    219°C  - 220°C (740 torr)
               Vapor Pressure:                  1 torr 1 59.5°C
               pH:                              6.79
               Production:                      unknown

2,6-Oichlorcphsncl is produced as  a by-product  frcm  ths dirsct  chlcrinaticn
of phenol.  It  is used  primarily as a starting. ->=-eriai for the manufacture
of  trichlorophenols,  tetrachlorophenols,  and  pentachlorophenols  (Ooldens,
1964).
II.  EXPOSURE
     A.   Water
                                                  y
          Phenols occur  naturally  in the  environment and  chlorophenois  are
associated with baa taste and odor  in tap  water \,.isk,  1957)'.   2,6-Oichicro-
phenol has  a  taste  and  odor threshold of  0.002 mg/1  and 0.003 mg/1,  respec-
tively  (McKee  and .Wolf,.  1963).   Piet  and DeGrunt  (1975)   found  unspecified
dichlorophenols  in  Dutch  surface  waters  at 0.01 to 1.5  ug/1,  and  Burtt-
schell, et  al.  (1959)  demonstrated that  chlorination  of  phenol-containing
water  produced,   among  other  products,  2,6-dichlorophenol. in a  25-percent
yield after 18 hours of reaction.
     8.   Food
                                                                      »
          Pertinent data could not  be located in the  available literature.

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     C.   Inhalation
          Qlie, et  al.  (1977)  reported  finding dichlorophenols in  flue  gas
condensates from municipal incinerators.   The levels were not quantified.
     0.   Dermal
          Pertinent data  could not be  located in  the  available  literature;
however,  it  is known that  dichlorophenols  are- less toxic  by skin  contact
than  monc-chlorophenols  and  less  likely  to  be  absorbed  through  the  skin
(Dolcens, 1564).
III. PHARMACOKINETICS
     A.   Absorption
          Pertinent data  cculd not be  located in  the  available  literature.
By comparison with other chlorophenols,  it  is  expected  that 2,6-dichlcrcpna-
nol  will be absorbed through the  skin  and from the gastrointestinal  tract
(U.S. EPA, 1579).
     3.   Distribution
          Pertinent data  could not be  located in  the  available  literature.
The high  lipid solubility of  the  compound  would suggest that unexcreted com-
pound distributes .to adioose"tissues.
     C.   Metabolism and Excretion
          Pertinent data  could not be  located in  the  available  literature.
By comparison with other chlorophenols,  it  is  expected  that 2,6-dichlorophe-
nol  is  rapidly eliminated  from the body,  primarily as urinary sulfate  and
glucuronide conjugates (U.S. EPA,  1979).
IV.  EFFECTS
     A.   Carcinogenicity
          Pertinent data could not be  located in the available literature.-
                                    -7/.T-

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     8.   Mutagenicity
          2,6-Oichlorophenol  did  not  show mutagenic  activity  in the  Ames
assay  (Rasanen,  et  al.  1977).  Chromosome  aberrations in  rat bone  marrow
ceils have been observed following  compound  administration  (route  and dosage
not indicated) (Chung, 1978).
     C.   Teratogenicity and Other Reproductive Effects
          Pertinent data could not be located in the available literature.
     D.   Chronic Toxicity
          Administration of  2,6-dichlorophenol  to rats  (route and  dosage not
specified) has been reported to produce hepatic degeneration (Chung, 1978).
     E.   Other Relevant Information
          In vitro  tests have  indicated  that  2,6-dichlorophenol will inhibit
liver mitochondrial respiration (level not specified)  (Chung,  1978).
V.   AQUATIC TOXICITY
     A.   Acute
          McLeese,  et  al.  (1979)  reported  a 52-hour lethal  threshold  limit
of  15,100 ug/1  for  marine  shrimp  (Cranqon seotemspinosa) exposed  to  2,6-di-
chlorophenol.
     B.   Chronic .Toxicity, Plant  Effects and Residues
          Pertinent data could, not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          Sased  on  the organoleptic  properties  of  2,6-dichlorophenol,  a
water quality  criterion of  3.0 ug/1 has  been  recommended by  the U.S.  EPA
(1979).
     B.   Aquatic
          NO existing criteria to protect  fresh "and saltwater organisms were
found in the available literature.

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                                       No. 77
2,4—Dichloropher.oxyacetic Acid (2,4-Q)
   Health and Environmental Effects
 U.S.  ENVIRONMENTAL PROTECTION AGENCY
        WASHINGTON, D.C.  20460

            APRIL 30, 1980

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                          DISCLAIMER
     This report represents a survey  of  the  potential, health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained  in the report is drawn chiefly
from secondary  sources  and   available  reference  documents.
Because of the limitations of  such sources, this short profile
may not reflect  all  available  information including  all  the
adverse health  and   environmental  impacts presented  by  the
subject chemical.  This  document has  undergone scrutiny  to
ensure its technical  accuracy.
                            -9/9-

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                         2,4-OICHLOROPHENOXYACETIC ACID
                                     Summary

      Oral administration of  2,4-Oichlorophenoxyacetic acid (2,4-0) failed to
 produce carcinogenic  effects  in  mice  or  dogs;  however,   feeding  technical
 grade 2,4-0 did produce  tumors in a study with rats.  Subcutaneous adminis-
 tration of the isooctyl ester  of  2,4-D has been  reported  to  produce reticu-
 lum cell sarcomas  in mice.
      A single study  has  indicated  that  2,4-0 produced mutagenic  effects in
 Saccharomyces.   Other investigations  have  failed  to show  mutagenic  effects
 of  the  compound  Salmonella,  Droscphila,  Saccharomyces,  or  the  dominant
'lethal assay  with  mice.
      2,4-0 and several of  its esters  failed  to snow  teratogenic  effects in
 ~iice;  the prcDylene  glycol  butyl ether ester  of  the  cornpounG  produced  an in-
 crease in cleft palates  in  this  study.  Studies  in  hamsters  orally acrninis-
 i_ered  ^.,4—u aHu  derivatives 5~oweG  i-eratccenic  efrects.  Oral aGiTiiniscrstion
 of 2,4-0 to rats failed to indicate teratcgep.icity  in cr.e  study;  ancther in-
 vestigation using  oral administration of 2,4-0  to rats  found  teratogenic ef-
 fects.   A  three-generation  feeding study  of  2,4-0  to  rats  indicated  feto-
 toxic  effects  at a dosage of  1,500 ppm.
      Toxicity  tests  on a variety  of aquatic  organisms generally  have  demon-
 strated that  various esters  of 2,4-0 are more toxic  than the  2,4-0  acid, di-
 methyl amine, or  sodium  salt.  Freshwater trout and bluegill sunfish  were
 adversely affected by the  propylene glycol butylether. (PGEE) ester at  con-
 centrations of 900 to 2,000  jjg/1.   Daphnids  and  freshwater seed  shrimp  were
 sensitive to the PGBE ester  at concentrations of 100 to  300 yg/1.   Chrcnic
 exposure of several  species of fish to concentrations up to 310 jug/1  has not
 demonstrated  any toxic effect.

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                        2,4-OICHLOROPHENOXYACETIC ACID
I.   INTRODUCTION
     2,4-Oichlorophenoxyacetic acid,  CAS Registry  number  94-75-7,  commonly
known as 2.,4-0, is a white  or slightly yellow crystalline  compound  which is
odorless when  pure.   2,4-0  has  the  following physical and  chemical proper-
ties (Herbicide Handbook, 1979):
                                    9CH2COOH
                                          221.C
                                          135°C-i36cC (technical);
                                          140CC-141°C (pure)
                                          15G0C 9 0.4 torr
                Formula:
                Molecular Weight:
                Melting Point:
                Boiling Point:
                Density:                  i.565'"-J
                Vapor Pressure:           0.4 ton
                Solubility:               Acetone,  aicchci, aicxane ether,
                                          isopropyl alcohol; slightly
                                          soluble in benzene,  solubility in
                                          water 0.09g/100g, H7G
                Production:               unknown
     2,4-0 is used  as  an herbicide along with  its  various salts and esters,
which .vary its  solubility  properties.   It is  used mainly  to  control  broad-
leafed plants  in pastures,  and right-of-ways,  and, and  to  keep  lakes  and
ponds free of unwanted submersed and emersed  weeds.
II.  EXPOSURE
     A.   Water
          No  estimates of  average  daily uptake  of  2,4-0  from  water. are
available;  however,  after  treatment  for water •  milfoil   in  reservoirs  in

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Alabama  and Tennessee, the  Tennessee Valley Authority  found the  concentra-
tion  at  downstream monitoring stations  to  be 2 ppb.  2,4-0 was not found  in
the harvested beans  of red  Mexican bean plants after irrigation with contam-
inated water (Gangst,  1979).
     S.   Focd
          The Food and Drug Administration,  in monitoring  milk  and meat for
residues  of 2,4-0 from  1963 to  1969,   found  no  trace  of  the  herbicide  in
13,000  samples  of  milk  and  12,000 samples of  meat  (Day,  et  al.  1978).
Cattle and  sheep which were  fed 2,000 ppm of 2,4-0  for 28 days had less  than
0.05  ppm 2,4-0  in  the  fat and  muscle tissue and no  detectable  amount  of
2,4-dicnlcrcphenol.  After  seven  days withdrawal from the  2,4-0 diet,  these
tissue levels were drastically reduced  (Clark,  et al.  1975).   Six species  of
fish were monitored  for three weeks after  the water  in a pond was  treated
with a  2,4-D  ester.    The highest tissue concentration  reached  was 0.24 ppm
eight days  after application.  Subsequently,  the  herbicide  or its metabolite
was  eliminated  rapiaiy.  Cisms  and  oysters accumulate  more 2,4-0 than  cc
tish ar.o  crabs.  ~esidue pesKS occur rrc~i  j.  to 9 days  ai u£r  application sr.d
then rapidly decline (Gangst, 1979).
     C.   Inhalation
          Pertinent  data  were net  found in  the  available literature;  ho.v-
ever, some  2,4-D  esters which are  much more volatile  than  the  parent  com-
pound have  been monitored  in  air  up  to 0.13  ug/m3 (Farwell,  et  al.  1976;
Stanley,  et al. 1971).
     D.   Dermal
          Pertinent data were not found in the available literature.

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III. PHARMACOKINETICS
     A.   Absorption
          Human  absorption  of  2,4-0  following  oral  intake  is  extensive;
Kohli  et  al.  (1974) have  determined absorption of  75 to 90  percent of  the
total  dietary  intake  of  the compound.   Animal studies  have  indicatec  that
the  gastrointestinal  absorption of  2,4-0 esters  may  be  less  efficient  than
that of the free acid or salt form of the compound (NRCC, 1978).
     B.   Distribution
          The phenoxy  herbicides are readily distributed throughout the  body
tissues of mammals.  Tissue  levels  of herbicide may be  higher in  the kidney
than in  the  blood;  liver and muscle  shew levels  lower than these .determined
in  the bloco  .(MfiCC, 1978).   withdrawal of dietary  compound•produced almost
complete tissue loss of residues in seven days  (Clark, et ai. 1975).
          -^mal-i.  3fnu!jnk.s  Ci   p. isnoxy  iisroici^ss  srs  passed   LO   uic  young
through the .-ether's milk  (3'jerke,  et al. 1972).   Transplacental transfer, of
2,4—0 has been reported in mice  (Lincjcjuist and  Uu-Ccry, i9/j.;.
     C.   Metabolism
          Sauerhoff, et  al.   (1976)  determined that  following oral adminis-
tration of 2,4-D to human volunteers,  the major amount excreted in the urine
was  free  compound; a  smaller  amount was excreted  as 2  conjugate.   Tissue
analysis of  sheep and  cattle  fed  2 4-0  have  shown unchanged  compound  and
2,4-dichlorophenol to be present (Clark, et al. 1975).
     0.   Excretion
          Elimination  of  orally  administered   2,4-0 by  humans  is  primarily
through the urine  (95.1  percent of the initial dose); the half-life  of the
compound in  the body  has been  estimated as  17.7  hours (Sauerhoff,  et'al.
1976).   Clark,  et al.  (1964)  have reported urinary  elimination of 96 percent

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of  an  oral dose  of  labelled 2,4-Q within-72 hours  by sheep;  approximately
1.4 percent of the administered dose was eliminated  in  the  feces.
          The plasma  half-life  of 2,4-0 has  been estimated  to  be from 11.7
to 33 hours in humans (NRCC, 1978).
TV.  ^FF^CTS
     A.   Carcincgenicity
          Innes,  et  al.  (1969)  reported no  significant increase  in tumors
following  feeding of mice  with  2,4-D for  18 months.   A  two-year  feeding
study in rats did indicate  an  increase in  total tumors in  females and malig-
nant tumors in males  following  feeding  of  technical 2,4-0; a parallel study
with dogs  fed  technical compound did  not show  carcinogenic effects (Hansen,
et al.  1971).
          Mice were  administered  maximum  tolerateo  aoses  of 2,4-0  and  its
butyl,  isooropyl,  and isccctyl  esters in a long-term carcinogenicity study.
Carcinogenic effects were seen  after  subcutaneous administration of cne iso-
octyl ester (reticulum cell sarcomas)   (iCI,  1968).
     B.   Mutagenicity
          No  mutagenic  effects  of   2,4-0   in  tests   with   Salmonella,
Saccharomvces,  or Orosoohila  were observed   (Fahrig,  1974).   Siebert  and
Lemoerle  (1?74)   have  recorted  iryjtacenic  effects   ^ollo'-yinf   ^"^c^T^nt  — ^
Saccharomyces  cerevisiae strain 04 with aqueous 2,4-0 solution (1,000 mg/1).
          Gavage  or  intraperitoneal  administration  of  2,4-0 to mice  failed
to  show  mutagenic effects  in   the  dominant  lethal  assay  (Epstein,  et  al.
1972).
     C.   Teratogenicity
          Testing of  2,4-D  and its n-butyl,  isopropyl, and  isooctyl  esters
in pregnant mice  produced no significant teratogenic effects.   There was  a

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significant  increase  in  cleft palate deformities after  administration of the
prooylene glycol butyl ether  ester of 2,4-0  (Courtney,  1974).
          Subcutaneous  injection of  the two  isopropyl  esters  and the  iso-
octyl ester  of 2,4-0 in  pregnant mice  has  been reported to  produce  terato-
genic effects  (Caujolle,  et  al.  1967),  although  the DMSQ  vehicle used  is,
itself,  a teratogen.  Sage,  et al.  (1973) have  also  reported  teratogenic ef-
fects in mice  following injection of 2,4-0.
          Oral  administration of 2,4-0 to hamsters  resulted  in the  produc-
tion of some terata (Collins  and Williams, 1971).   Studies with  rats  report-
ed that oral administration  of the  parent compound or its isooctyl and butyl
esters,  and buto'xy ethancl and dimethylamir.e salts, produced  teratcgenic  ef-
fects (Khera and  McKinley,  1972).  However ,  Schv/etz,  et al.  (1971) v/ere  un-
able L^ --'show teratogenic effects  in rats following  the oral  administration
                       *   ,-> — -^— -..-., ,-.r~
                       ^J. uj. uo. wu y j-di 1
     D.   Other Reproductive Effects
          Efflbryctcxic effscts  following subcutaneous administration of  2,4-0
to preJKant  mice have been  reported  (Caujolle,  et  al.  1967;  ?sge,  et  al.
1573).  ,; -
      • J
          Fetotoxic effects of the  compound' and its esters have been  repcrt-
— '" =fter  o^si -^"i1' riist~2tion of  :T2'-/i?T'3^1" toisrated clcs~s  !'Sch'v?tz  et  si.
1971; Khera and McKinely, 1972).
          Results  of a  three-generation  study of  rats  fed  2,4-0  indicate
that at dietary levels up  to 500' ppm, no  reproductive effects are  produced;
at levels of 1,500 ppm,  a  decrease  in survival and body weights of  weanlings
was observed (Hansen,  et al. 1971).   Bjorklund and Erne  (1966)  reported  no
adverse reproductive effects in rats fed 1,000 mg/1 2,4-0  in drinking water.

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     E.   Chronic  Toxicity



          Animal  studies with prolonged  oral  administration of 2,4-0 or  its



amine  salt  have  indicated  renal  and  hepatic effects  (Bjorklund and  Erne,



1971; 3jorn and  Northen,  1948);  the chemical  purity of  the  material  adminis-



tered is not  known.   A feeding study  in  rats has reported  histopatholcgical



liver changes at dietary  levels  of 2,4-0  equivalent  to 50 mg/kg (Dow  Chem-



ical, 1962).



V.   AQUATIC  TOXICITY



     A.   Acute Toxicity
                                                    «.


          The National Research  Council  of  Canada  '(1978)  has reviewed  the



toxic  effects  of  2,4-0   to  fish.    For  the  bluegill   sunfish   (Lepcmis



macrochirus), 2,4-0  acid and 2,&-0 dimethyl amine producec ~oxic effects at



concentrations greater than.100,000 ug/1.  At  2,4-0  concentrations of 50,000



pg/1 cr.  13S3, r.c  increased mortalities were  reported  except in pink salr.cr,.



The  iscprcpyi,   butyl,  ethyl,  butcxy ethanci,  and  FGBE  astars  produced




43-hcur  LC5Q  values of  900, 1,300,  1,400, 2,100,  and  from  1,000  to  2,100



uc/1  rescectivelv.



          For other  fish species,  the  results  follow a similar trend in that



the esters  tend  to  be more  toxic  than other  formulations.  Meehan,  et al.



(l?7^)  conducted  tests of various  formulations  of 2,4-D  on echo saLr.cn fry



and fingerlings (Oncorhycus  Kitutch),  chum  salmon fry  (C3.  keta),  pink salmon



fry  (0_.  .gorbuscha),   sockeye   salmon   smolts   (Q_.   nerka),   Dolly  Varden



(Salvelinus malma),  and rainbow  trout (Salmo gairdneri).   The  butyl  ester



was  the  most toxic ester  tested, with  concentrations  of  1,000  ug/1  or



greater producing nearly 100  percent mortalities  in  all  species tested.   The



PGBE ester  was  similar in  toxicity to the butyl ester.   Rainbow trout  «ere



reported  to  have  shown  a  48-hour  LC5Q  vaiue  of  1,100  ug/1 on  exposure  to

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the  PGSE ester  of  2,4-0.   Harlequin  fish (Rasbora  heteromorpha)  showed  a
48-hour  LC    value  of 1,000  ug/1 on  exposure to  the  butoxyethyl ester  of
2,4-0  (National  Research Council  of Canada 1978).   Rehwoldt,  et al.  (1977)
have  observed 96-hcur  LC5Q   values   of   26,700;   40,000;   70,100;   70,700;
94,600;  96,500;  and. 300,600 ug/1  for  banded kiilifish  (Fundulus  diaphanus),
white  perch (Roccus  americanus),  stripped  bass  (Morone sazatilis),  guppies
(Libistes   reticulatus),   pumpkinseed   sunfish   (Lepomis   gibbosus),   carp
(Cvorinus   carpio),   and  American   eel  (Anguilla   rostrata),   respectively,
exposed  to  commercial technical grade 2,4-0.
          Sanders  (1970)  conducted a comparative  study  on the toxicities  of
various  iormulations o>  2,4—0 ior  six species  GI  iresiiwa'-er crustaceans.
The  PGSE ester was  generally most  toxic,  while  the  dimethyiamine salt was
least toxic.   The  crayfish  (Orconectes nails)  was the most resistant  species
tested,  witn 48-nour static  LC^ values  greater than  100,000 /jg/1  for ail
for~jlaticr,s   tested.   The   \vaterflea  (Cacrr.ia  fiiacna)   s~d   seec
-.-, — i r^o
(Cypricopsis  vicua)  '.vere  tr.cst  sensitive tc  the  PGSE  estar,  v/itn  48-hour
LC50   values  of   100   and   320   jug/1,  respectively.    Scuds   (Ganniarus
fasciatus),  sowbugs  (Ascellus  brevicaudus),   and   freshwater  grass   shrimp
(Palaemonetes  kadiakensis)  were  also  moderately   sensitive,  with  43-hour
LC5g  values  ranging  from  2,200  to 2,700 ,ug/l.   Sanders  and  Cope  (1563)
reported   a  96-hour  LC5Q   value  of   1,600  jug/1  for   stonefly   naiads
(Pteronarcy californica) exposed  to  the  butoxyethanol ester of 2,4-0.  Tech-
nical grade 2,4-0  produced a  96-hour  LC5Q vaj.ue of 14,000 jug/1.   Robertson
and  Bunting  (1976)  reported  96-hour  LC5Q  values  ranging  from  5,320   to
11,570 jug/1 for copepods  (Cyclops vernalis) nauplli exposed to 2,4-0  as free
                                                                         »
acid.  The  range  of 96-hour LC5Q values for  nauplli  exposed  to 2,4-0 alko-
nolamine salt was 120,000 to 167,000 Aig/1.

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          Among marine  invertebrates, those  of  commercial significance have
been examined  for toxic effects  on exposure to  2,4-0 formulations.  Butler
(1965) determined  the 96-hour median effective  concentration based on shell
growth for oysters as 140  ug/1 for the FGEE  ester  of  2,4-0.   The 2,4-0 acid
had  no  detectable effect  at exposures  of 2,000 jug/1•for S6-hours.  Sutler
(1963) observed paralysis  of brown shrimp (Penaeus aztecus) exposed to 2,4-0
acid at  a  concentration of 2,000 ;jg/l  for 48-hours.   Sudak and Claff (1960)
found  a  96-hour  LC_0   value  of  5,000,000  ,ug/l  for   fiddler  crabs  (Uca
pugmax) exposed to 2,4-0.
          McKee and Wolf (1963)  have reviewed the  toxic  effects of 2,4-0 to
aquatic organisms.  Toxic  concentrations as low as 1,COC  ug/1  produced a 40
percent mortality for fingeriing  biuegiils exposed  to  2,4-0 butyl ester.   In
general,  esters of 2,4-0 were  reported to  be  more  toxic  than sodium salts of
2,4-0.
     3.   Chronic Toxicity
          Rehv/cict, et  al.  (1970)  exposec several species  of fish  to  ICO
ug/1  2,4-0 for  ten  months  and  observed  no overt  effects  to any  tested
species.   The  percent reduction of brain  acetylcolinesterase  ranged from 16
percent in white perch  to  35 percent in American eels.   In breeding experi-
ments with guppies, a 100  ug/1 concentration  of  2,4-0  had no significant ef-
fect .on  the  reproductive  process of the  species  under  experimental  condi-
tions.   Cope,  et  al. (1970)  examined the  chronic  effects of  PGBE  ester of
2,4-0 to bluegill sunfish.  Fish  were exposed to the  herbicide in one-eighth
acre ponds containing initial concentrations  of up to  10,000 ug/1.   Altera-
tions in  spawning activity,  and  the occurrence  of pathological  lesions  of
the liver, brain, and vascular system were reported for  a period of up to 84

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 days.   Mount  and Stephan  (1967)  exposed 1-inch  fathead  minnows  (Pimephales
 promelas)  to  a continuous  series  of  concentrations  of  the butoxyethanol
 ester of 2,4-0  ranging from 10  to  310  ug/1  for a 10-month period.  No deaths
 of  deleterious  effects,  including  abnormal  spawning  activity  and  reduced
 survival of eggs from exposed fish, were observed.
           In  static-renewal  tests, Sigmon  (1979) reported  that  the  percent
 pupation and  the percent emergence  of Chironomus larvae  were significantly
 reduced by exposure to 1,000  or 3,000  pg/1  1,4-0 (acid equivalent in Weedone
 LV-4 formulation).
      C.   Plant Effects
           The  csnsra  Microcwstis   Scsnedesmus   Chlcrel^s   and  Nitz^chp's
 snowed  no toxic resccnse  when  exposec  to  2.000 ug/1 2,4-0  Lawrence  .(1962).
 Poorman  (1973)  treated cultures of  Euglena gracilis with  concentrations of
 5G,GGG  pg/1  2,4-0  for  24  hours  and  observed  depressed .growth   rates.
 Valentine and  Singhain (1974) demonstrated  that  at  ICC.GCO pg/1, 2,4-0  re-
duced  the  cell  numbers  of Scenedesmus  to  one percent  of control  levels,
 Chlareydsrncnas  to  48 percent  of control levels,  Chlorella to 66  percent of
 control levels,  and--Euglena  to  90 percent  of  control  levels within 4  to 12
 days.   The  bluegreen  algae (Nostoc  muscorum)  displayed a  68-percsnt  reduc-
 tion in growth  when  exposed  to  100 pg/1  2,^-0 (Cerci and  Cavazzini,  1973).
 Singh  (1974)  exposed  Cylindrosoermum to 2,4-0  sodium salt  at  concentrations
 ranging  from  100,000  to  1,200,000  pg/1  and   reported  that  concentrations
 above 800,000 pg/1 caused growth to  cease completely.  McKee and Wolf (1963)
 reviewed the  effectiveness  of  2,4-0• in control. of  emergent  aquatic  plants
 and  reported  that concentrations  ranging  from 6,000 to  100,000 /jg/1  have
 been effective in controlling a  number of species.

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      0.    Residue
           Cope,  et al.  (1970) examined  residues of  the  PG3E ester of  2,4-0
in  the freshwater vascular  plant,  Potamogeten  nodosus,  in a one-eighth  acre
pond  treated with single 100  to  10,000 pg/1 applications of  the chemical.   A
gradual  dspsleticn of the herbicide  to insignificant levels v/as demonstrated
within three months.
           Schultz and Gangstad (1976) reported that  the flesh of fish ex-
posed  to 2,4-0 dimethyl sodium salt  in ponds treated with  from 2.24 to  8.96
kg  (as an acid equivalent) of  the  chemical did not attain the 100 jug/1  level
realized  in  the water two  weeks after application.
           The National Research Council  of Canada (NRCC)  (197S) has reviewed
the bioccncentraticn data and associated  residues  of 2,4-0  in a  number of
studies.   NRCC indicated that  a  relatively short half-life  of less than two
days  is  round for  fish and oyster.   At  water  concentrations of IGO  to 2GG
jug/1,  the  bioccncer.tration of 2,4-0  various  aquatic invertebrates  was one LO
two orders  of magnitude  greater  than  in  the  water.  Oysters  (Crassostica
virjjnica) v/ere  reported  to  have  a  bioconcentraticn factor  of  ISO when ex-
posed  to  the butoxyethanol ester of  2,4-0.   The freshwater bluegill and mos-
quito  fish (Gambusia  affinis)  had  bicconcentration  factors  ranging  from 7 to
CC  	e^^^J.,'.,^ ^^ .,*,!* .-T* ^^,^^^^^-—^4--'«.-.,-.    C"- -'—  ?=,!-*  ~ -I--.-  ^^^J.-;^.,'.-^'-. ^ ' "^
-'-', L w~v^~w ^—. ^ uw -'lav-ij. i-wi i«~c; t c~a u-Lul ib •   i _^>i t  i %*o  a uj-Ci-  «-^i i wd^J 1 -Li i^ *_ , -r— u-
bioconcentrated the 2,4-0 .acid by less than 0.2.
VI.  EXISTING GUIDELINES
     A.    Human
           The acceptable daily intake of  2,4-D  for  humans has been  estab-
lished at  0.3 mg/kg (FAO,  1969).
     3.    Aquatic
           Pertinent data were  not"found in the available literature.
                                   -930-

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                         2.4-OICHLORQPHENOXYA.CETIC ACID

                                   References
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 trichlorcphenoxyacetic  acids (2,4-0 and 2,4,5-T).  Acta  Pharmacol.  Toxicoi.
 32:  408.

 Sjerke,  E.,  et al.  1972.  Residue studies of  phenoxy  herbicides  in  milk and
 cream.   Jour.  Agric.  Food Chem.   20: 963.

 Sjorklund,  N.  and  K. Erne.   1966.  Toxicological studies of phenoxy  acetic
 herbicides in  animals.   Acta Vet.  Scand.  7:  364.

 Bjorklund, M.  and K..Erne.  1971.  Phenoxy-acid-induced renal changes  in the
 chicken.  I. Ultra structure.  Acta Vet. Scand.  12: 243.

 Bjcrn,  M.  and H.  Morthen.   1948.   Effects of  2,4-dichlorcphenoxyacetic  acid
 on chicks.   Science  108:  479.

 Sutler,  P.A.   1963  Commercial Fishery  Investigations.  U.S.  Oept.  Irtsricr
 U.S. Fish arc  Vdiuiife Service Circ.  167.: 11.

 Sutler,  P.A.   1953. •  Effects  of  herbicides  on  estuarine fauna.   Proc.
 Southern Weed  Conference   18: 576.

 Caijjolle, F.,  st  al.   1957.  Limits cf ccxic  and  izeratcgenic  tolerance of
 dimethyl sulfcxide.  Ann.  ,\'.Y. Acad. .Sci.  141:. 110.

 Cenci, P. and  G.  Cavazzini.   1973.   Interaction between environmental micro-
 flora anrj three heriicidal phencxy derivatives.  Ig. Mod.  66: 451.

 Clark,  D.,   et al..  1975.  Residues  of chlorophenoxy acid  herbicides  and
.their  phenolic metabolites  in  tissues  of sheep  and   cattle.   Jour.  Agric.
 Food Chem.  22: 573.

 Clerk,  D.,   et ai. '  1964.   The  fate  of  2,4-dichlorophenoxyacetic  acid in
 sheep.  Jour.  Agric. Food Chem.  12: 43.

 Collins, T.,  and C. Williams.   1971.   Teratogenic studies  with 2,4,5-T and
 2,4-0 in the hamster.  Bull. Environ. Contamin.  Toxicoi.  6: 559.

 Cope,  O.B.,  et  al.   1970.  Some  chronic  effects of  2,4-D .in  the bluegill
 (Lgpamis macrochirus) Trans. Am. Fish Sec.   99:  1.

 Courtney, K.   1974.  in:   The  herbicide 2,4-0.   U.S.  Environmental  Protec-
 tion Agency,  Office of Pesticides Programs, Washington, DC.  2C7 pp.

Day, B.E., et  al.   1978.  The phenoxy herbicides.   Council  for  Agricultural
Science and Technology,  Report 77.

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                                    No. 78
        1,2-Dichloropropane


  Health : ..-d Environnental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

          APRIL 30,  1980
              -93S*-

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                          DISCLAIMER
     This report represents a survey of the potential health
and environmental hazards from  exposure to  the subject chemi-
cal.  The information contained in the report is  drawn chiefly
from secondary  sources   and  available  reference documents.
Because of the limitations of such sources,  this  short profile
may not reflect  all  available  information  including all the
adverse health  and  environmental  impacts,  presented by the
subject chemical. .  This  document, has undergone  .scrutiny  to
ensure its technical  acc-uracy.
                            -936-

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                              1,2-DICHLOROPROPANE



                                    Summary







     The major  environments!  .source of dichloroprcpar.s  is  from the use of a



mixture  of  dichlo'ropropanes  and dichlorcpropenes  as a soil  fumigant.   On



chronic  exposure  of  rats to dichloropropanes  the  only observed effect was a



lack of  normal  weight  gain.   There is no  evidence that dichloropropanes are



carcinogens or  teratogens.   Oichloropropanes have produced mutations in bac-



teria and caused chromosomal aberrations in  rats. ••



     Aquatic  toxicity  tests  of 1,2-dichloropropane are limited to four acute



investigations.   Two  observed  96-hour  LCcp  values  for  the  bluegill  are



280,000  and  320,000 jjg/1  and  the  48-hour  LC,.-  value  for Daohnia  magna is



52,500  jjg/1.   A  saltwater  fish  has  a   reported  96-hour   LCCO   value  of
                                                                 ^r l—'


240,000 jug/1.
                              -937-

-------
                             1,2-DICHLOROPROPANE
I.    INTRODUCTION
     This profile -is based on  the Ambient  Water  Quality Criteria  Document
for Dichloropropanes/Dichloropropenes (U.S.  EPA,  1979).
     1,2-Oichloropropane  (1,2-POC,  molecular weight  112.99)  is a  liquid at
environmental  temperatures.   This  isomer  of dichloropropane  has a  boiling
point of  96.4°C,  a density of  1.156 g/ml,   a vapor pressure of 40 mm Hg at
19.4°C  and   a  water  solubility  of 270  mg/100  at 20°C  (U.S. EPA,  1979).
Mixtures  of  1,2-dichloropropane  and  cis-trans-L,3-dichloropropene are  used
as  soil  fumigants.   For  the  purposes of discussion in this  hazard  profile
document, dichlorcorooane refers  to  the 1,2-dichloroprooane   isomer.   When
heated to decomposition  temperatures,  1,2-aichioropropane  emits highly toxic
fumes of phosgene (Sax,  1975).
II.  EXPOSURE
     A.   Water
frcrr.  industrial  and manufacturing  processes,  as  run-off  from  agricultural
land,   and  from municipal  effluents.   This compound  was identified'but  not
quantified in New Orleans drinking water (uowty,  ec ai.  1975).
     B.  Food
         Information was not  found, concerning  the  concentration of dichloro-
propane in commerical  foodstuffs; therefore, the amount  of  this compound in-
gested by  humans  through food is not  known.   The  U.S.  EPA  (1979)  has esti-
mated  the  bioconcentration  factor  (BCF) of dichlorbpropane to be  20.   This
estimate is  based on  the  octanol/water partition  coefficients  of dichloro-
                                                                      »
propane.  The weighted average BCF  for  edible  portions of all aquatic organ-
isms consumed by Americans is calculated to be  5.8.

-------
     C.  Inhalation.
         Atmospheric  levels  of  dichloropropane  have not  been  positively
determined.  However,  it  is known  that  5-10 percent  of  the dichloropropane
which  is  applied  to the  soil  as a  fumigant  is released to  the  air (Tncmas
and McKeury, 1973).
III. PHARMACOKINETICS
     A.  Absorption, Distribution and Metabolism
         Pertinent  data  could  not  be   located   in  available   literature
searches regarding the absorption of dichloropropane.
     B.  Excretion
         Pertinent  data  cculd   not be   located   in  available-  literature
searches regarding  excretion  of  dichioropropane.  In  the  rat,  approximately
50 percent  of  an  orally administered dose of  dichlorcorooane was eliminated
in the urine in 24 hours (Hutson, et ai.  1971).
IV.  EFFECTS
     A.  Carcinogenicicy
         Only  one  study  is  reported on  the  carcinogenicity of  dichloro-
propane.   Heppel,  et  al.   (1943)  repeatedly  exposed  mice  (37  exposure
periods) to  1.76  mg dichloropropane per liter  of  air.  Of  the 30 mice, only
three  survived  the  exposure and  subsequent observation period; however,  the
three  survivors had  multiple  hepatomas  at the  termination  of the experiment
(13 months of  age).  Due  to the  high mortality, an  evaluation  based on this
study cannot be made.
     B.  Mutagenicity
         DeLorenzo,  et  al.   (1977)  and  Bignami,   et  al.  (1977) f showed
dichloropropane to  be mutagenic  in S.  typhimurium  strains  TA 1535 and  TA
100.   Dichloropropane  has also been shown to  cause  mutations in  A.  nidulans
                                      •2-

-------
(Bignami, et  al.  (1977),  and  to cause  chromosomal  aberrations in  rat  bone
marrow (Oragusanu and Goldstein,  1975).
     C.  Teratogenicity
         Pertinent information could  not be located in  available  literature
searches regarding teratogenicity.
     0.  Other Reproductive Effects
         Pertinent information could  not be  located regarding  other repro-
ductive effects.
     E.  Chronic Toxicity
         Pertinent information could  not be located in  available  literature
searches  regarding chronic toxicity studies of  dichioroprocane exposure  in
humans.   In  one study by  Heppel,  et  al. (1948)  rats,  guinea pigs,  and  dogs
were exposed  to 400  pom of dichioroprooane for 128  to  140 daily  seven  hour
period (given  five oays  per weeK).  The  only effect, observed was a decreased
weight in rats.
V.   AQUATIC TOXICITY
     A.  Acute  Toxicity
         Two   observed   96-hour   LC5Q   values  for  the   bluegill,   LeGomis
macrochirus,  upon  exposure to 1,2-dichloropropane were  280,000 and 320,000
ug/1•(Dawson,  et al.  1977; U.S.  EPA,  1978).   In  the  only freshwater inverte-
brate  study  reported,  the 48-hour . LC5Q for  Daohnia  maona  is 52,500  ug/1
(U.S.  EPA, .1979).  . Tidewater  silverside,   (Menidia   bevyllina),   has  an
observed 96- hour LC5Q of 240,000/jg/1 (Dawson, et al.  1977).
     8.  Chronic Toxicity
         Chronic  data  are not  available  for any  saltwater or  fre.shwater
species.

-------
     C.  Plant Effects
         The phytotoxicity of 1,2-dichloropropane has not been investigated.
     0.  Residues
         No information available.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human health nor  the aquatic criteria  derived by the U.S.
EPA  (1979),  which are  summarized below,  have gone  through the  process of
public review; therefore, there  is  a possibility  that these criteria will be
changed.
     A.  Human
         The  TLV  for dichlorcpropane  is  75 ppm  (350  rng/rr.  ) (Am. Ccnf. Gov.
Ind. Hyg., 1977).  The draft  water  criteria  for  dichioropropane is 203 ug/i
(U.S. EPA, 1979).
     3.  Aquatic
         For  1,2-dichlcroprcpane,  the proposed  drs't  criteria  to  prccsct
freshwater aquatic life are 920  jjg/1 a 24-hcur average and  the  ccr.csntraticn
should not  exceed 2,100  ug/1 at any  time.  Criteria are  not  available for
saltwater species (U.S. EPA, 1979).

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                     1,2-DICHLOROPROPANE

                         REFERENCES

American Conference of Governmental Industrial Hygienists.
1977.  Documentation of the threshold limit values.   3rd.
ed.

Bignami, M., et al.  1977.  Relationship between  chemical
structure and mutagenic activity  in some pesticides:   The  use
of Salmonella typhimurium and Aspergillus nidulans.   Mutag.
Res"! 46: T~.   ~~"

Dawson, G.W., et al.  1977.  The  acute toxicity of  47 indus-
trial chemicals to fresh and saltwater fishes.  Jour.  Hazard.
Mater. 1: 303.

DeLorenzo, P., et al.  1977.  Mutagenicity of pesticides
containing 1,3-dichloropropene.   Cancer Res. 37:  6.

Dcwty, B., et al.  1975.  Halogenated hydrocarbons  in New
Orleans drinking v.'ater and bleed  plasma.  Science  87:  75.

Dragusanu, 3., and I. Goldstein.  1975.  Structural  and  nu-
merical changes of chromosomes  in experimencai intoxication
with dichloropropane.  Rev. Ig. Bacteriol. Virusol.   Parazi-
tol. Epideir.iol. Pneumofitziol.  Ig 24: 37.

Heppel, L.A., ec al.  1943.  Toxicology of 1,2-dicnloropro-
par.e ' Cpropylene d ichloride; IV. Effect of repeated  exposures
tc a low concentration of the vapor.  Jour. Ind.  Hyg.   Toxi-
col. 20: 139

Hutson, D.H., et al.  1971.  Excretion and retention  of  com-
ponents of the soil fumigant D-D^R' and their metabolites
in the rat.  Food Cosmet. Tpxicol. 9: 677.

Leistra, M.  1970.  Distribution  of 1,3-Dichloropropene  over
the phase in soil.  Jour. Agric.  Food Chem.  18:  1124.

Roberts, R.T., and G. Staydin.  1976.  The degradation of  (2)-
and (E)-l,3-dichloropropenes and  1,2-dichloropropanes in
soil.  Pestic. Sci.  7: 325.

Sax, N.I.  1975.  Dangerous properties of industrial  mate-
rials.  Reinhold Book Corp., New  York.

Thomason, I.J., and M.V. McKenry.  1973.  Movement  and fate
as affected  by various conditions in  several soils.   Part  I.
Hallgardia 42: 393.

U.S. EPA.  1978.  In-depth studies on health and  environmen-
tal impacts  of selected water pollutants.  Contract No.   68-
01-4646.

-------
U.S. EPA.  1979a.  Dichloropropenes/Dichloropropanes:  Ambient
Water Quality Criteria. (Draft).

U.S. EPA.  1979b.  Dichloropropenes/Dichloropropanes:  Hazard
Profile.

-------
                                      No.  79
  Cichloropropane/Dichloropropenes


  Health and Knvironaental iffsccs
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to  the subject chemi-
cal.  The information contained in the report is  drawn chiefly
from secondary  sources  and  available  reference  documents...
Because of the limitations of such sources,  this  short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                DICHLOROPROPANES/DICHLOROPROPENES


                             SUMMARY


      The major environmental source of dichloropropanes  and


dichloropropenes is from the use of these compounds  as  soil  fuiai-


gants.  Some mild kidney damage has been observed  in rats chroni-


cally exposed to 1,3-dichlorpropene.  Both dichloropropane and


dichloropropene have been shown to be mutgenic  in  the Ames assay


test.  Data are not available to prove conclusively  that  these


compounds are chemical carcinogens.


      Aquatic toxicity studies suggest that  the  acute toxicity


r~\f ^h^ dic'"lo*"o^^ooa^es decr^sses as ^~he cM stance  bstvs^n t^s


chlorine atoms increases.  As an example, the reported  96-hour


LCsn values for the bluegill, Lepomis macrochirus, for  1,1-,
  ^ ,J                          —V^VMBBH^^^K^B w<^MMMM«nMBB««^Km^«M^«               ,


1,2-, and 1,3-cicnloropropane are 97,300, 280,000, and  greacer


char. 520,000 ug/1, respectively.  For Daphnia magna,  che  corres-


ponding reported 43-hour LCeQ values are 25,000, 52,000,  and


232,000 ug./l, respectively.  Similar results have  been  obtained


with marine organisms.


      The dichloropropenes are considerably more toxic  in acute


exposure than the dichloropropanes.  For 1,3-dichlorpropene,


the 96-hour LC_Q value for the bluegill is 6,060 ^g/1 compared


to 520,000 ug/1 for 1,3-dichloropropane.  For Daphnia magna,


the corresponding values are 6,150 and 282,000 pg/I,  respectively.


The ECCQ,  based on chlorophyll a for a freshwater  alga, is 4,950


pg/l for 1,3-dichloropropene, and 48,000 for 1,3-dichloropropane.
                                                           »

Data on measured residues could not be located  in  the available


literature for any saltwater or freshwater species.

-------
I.     INTRODUCTION



      This profile is based on the Ambient Water Quality Criteria



Document for Dichloropropanes/Dichloropropenes  (U.S. EPA,  1979).



      Dichlorcpropanes  (molecular weight 112.99} and dichloropro-



penes (molecular weight 110.97) are liquids at  environmental



temperatures.  Their boiling points range from  76  to 120.4°C



depending on the compound and the isomer.  They are slightly



denser than water, with densities ranging from  1.11 to 1.22.



The principal uses of dichloropropanes and dichloropropenes are



as soil fumigants for control of nematodes, in  oil and fat sol-



vents, and in dry - cleaning and degraasing prccssses  (Windhclz,



1976).  When heated to decomposition temperatures, 1,2-dichloropro-



pane emits highly toxic fumes of phosgene, while 1,3-dichloropro-r



per.e gives off coxic fumes of chlorides  (Sax, 1975).  Production



of mixtures of dichloropropanes/dichloropropenes approached 60



million pounds per year prior to..1975  (U.S. SPA, 1979).



II.   EXPOSURE



      A.   Water



           Dichloropropanes and dichloropropenes can enter the



aquatic environment in discharges from industrial and manufactur-



ing processes, as run-off from agricultural land, and from munici-



pal effluents.  These compounds have been identified but not


quantified in New Orleans drinking water (Dowty, et al.  1975).



      B.   Food



           Information was not found in the available literature
                                                            *


concerning the concentrations of dichloropropanes and dichloro-



propenes in commercial food stuffs. . Therefore, the amount of



these compounds ingested by humans is not known.  The U.S. SPA

-------
(1979)  has estimated the weighted average bioconcentration  fac-



tors (BCFs)  of dichloropropanes and dichloropropenes to range



between 2.9 and 5.8 for the edible portions of fish and shellfish



consumed by Americans.  This estimate is based on the ocuanol/



water partition coefficients of chese compounds.



      C.   Inhalation



           Atmospheric levels of dichloropropanes and dichloro-



propenes are not known.  However, from information on loss  of



these compounds to the air after land application, it was esti-



mated that, in California alone, about 72 tons  (8 percent of



the pesticide used) were released to the atmosphere in 1971  (Calif.



State Dept. Agric.  1971).



III.  PHARMACOKINETICS



      A.   Absorption, Distrioution-and Metabolism



           Pertinent information regarding the absorption,  dis-



tribution, and metabolism of the dichloropropanes and dichloropco-



penes could not be located in the available information.



      B.   Excretion



           No human data are available on the excretion of  dichlor-



opropanes or dichloropropenes.  In the rat, 80 to 90 percent



of an orally administered dose of dichloropropane or dichloropro-



pene was eliminated by all routes within 24 hours (Hutson,  et



al.  1971).  Approximately 50 percent of the administered dose



was eliminated in the urine within 24 hours.



IV.   EFFECTS



      A.   Carcinogenicity



           Information concerning the carcinogenicity of mixtures



of dichloropropanes and dichloropropenes could not be located

-------
in the available literature.  However,  cis-i,3-dichloropropane


has produced local sarcomas at  the  site of  repeated  subcutaneous


injections  (Van Duuren, et al.,  in  press).   No  remote  treatment-


related tumors were observed.


      B.   Mutagenicity


           Mixtures of 1,2-dichloropropane  and  1,3-dichloropro-


pene are mutagenic to S_._ typhimurium  strains  TA 1535 and TA  100,


as are the  individual compounds.  The mixture,  but not the  in-


dividual compounds, is also mutagenic to TA 1978  (in the presence


of microsomal activation) indicating  a  frame-shift mutation  not


caoable of beina oroduced by the  individual ccm^cur.ds.


      C.   Taratogenicity and Other Reproductive  Effects


           Pertinent information  could  not  be located  in the  ;


available -literature.


      D.   Chronic Toxic icy


           Inhalation exposure  of rats,  guinea  pigs, and -dcgs


to 400 ppm of 1,2-dichloropropane for 128 to  140  daily 7-hour


periods (5 days per week) decreased normal  weight gain in rats


(Keppel, et al., 1948).  Inhalation exposures of  rats  to 3 ppm


of 1,3-dichloropropene, 4 hours a day,  for  125  co 130  days pro-


duced cloudy swelling in renal  tubular  epithelium which disap-


peared by 3 months after exposures  ended (Torkelson and Oven,


1977) .


V.    AQUATIC TOXICITY


      A.   Acute Toxicity
                                                           9

           Exposures of bluegill, Lepomis macrochirus,  to 1,1-,


1,2-, and 1,3-dichloropropane under similar conditions yielded


96-hour LC5Q values of 97,900,  280,000,  and greater than 520,000

-------
rag/1, respectively  (U.S. EPA, 1978). -These data  suggest  that


toxicity decreases as the distance between the chlorine atoms


increases.  A reported 96-hour kC^n for 1,3-dichloropropene is


6,060 pg/i for -the bluegill, approximately two orders  of  magni-


tude lower than for 1,3-dichlorcpropane (U.S. EPA,  1979).   Under


static test conditions, reported 48-hour LCcn values  for  1,1-,


1,2-, and 1,3-dichloropropanes are 23,000, 52,500 and  282,000


p.g/1t respectively, (U.S. EPA, 1978) for the only freshwater


invertebrate species tested, Daphnia magna.  The  48-hour  LC5Q


value for 1,3-dichloropropene and Daphnia magna under  static


conditions is 6,150 yg/1 (U.S. EPA, 1973).


           The 96-hour I>C<-Q values for the saltwater  sheepshead


minnow, Cyprinodon variegatus, exposed to 1,3-dichloropropane


and i, 3-dichloropropene were 36,700 ^ig/i and 1,770  jjg/i,  respec-


tively (I7.3. EPA, 1573).  Dav;son, et ai. (1977) obtained  a  96-


hour LC.-Q of 240,000 jjg/'i for tne tidewacer silver side, rienidig


beryllina, for exposure to 1,2-dichloropropane.
           For Mysidopsis oahia, the 96-hour LC-Q  for  1,3-dichioro-


propene was one-thirteenth that for 1,3-dichloropropane,  i.e.,


790 ug/1 and 10,300 ug/i, respectively  (U.S. SPA,  1978).


      B.   Chronic Toxicity


           Chronic studies are limited  to one freshwater  study



and one saltwater study.  In an embryo-larval test,  the  chronic


value for fathead minnows, Pimeohales promelas, exposed  to  1,3-


dichloropropene was 122 ug/1 (U.S. EPA, 1978).  The  chronic value
                                                           p

for mysid shrimp, Mysidopsis bahia, was 3,040 ug/1 for  1,3-di-



chloropropane in a life cycle study (U.S. EPA, 1978).

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      C.   Plant Effects



           For 1,3-dichloropropene, the 96-hour SC^-Q values,



based on chlorophyll a concentrations and cell numbers of the



freshwater alga, Salanastrum capricornutum, were 4,350 ug/i and



4,960 ug/1, respectively.  The respective values obtained for



1,3-dichloropropane were 43,000 and 72,200 jig/1.  Thus, the pro-



pene compound is much more toxic than the propane compound, as



is true for the bluegill and Daphnia magna.



      D.   Residues



           Measured steady-state bioconcentration factors (BCF)



are not available for any dichioropropane or dichioropropene



in any fresh or saltwater species.  Based on octanol/water coef-



ficients of dichloropropanes and dichloropropenes, the U.S. SPA.



(1973) has estimated the bioconcentration factors for these com-



pounds to range between 10 and 35.



VI.   -Other Pertinent Information



      In the non-aquatic environment,  movement of i,2-cichloro-



propane in the soil results from diffusion in the vapor phase,



as these compounds tend to establish an equilibrium between the



vapor phase, water and absorbing phases (Leistra, 1970).  1,2-



dichloropropane appears to undergo minimal degradation in soil



with the major route of dissipation appearing to be volatiliza-



tion  (Roberts and Staydin, 1976).



      Following field application, movement of 1,3-dichloropro-



pene in soil results in vapor-phase diffusion (Leistra, 1970).



The distribution of 1,3-dichloropropene within soils depends



on soil conditions.  For example, cis-1,3-dichlorobenzene is



chemically hydroiyzed in moist soils to the corresponding cis-
                                   -9ft-

-------
3-chloroalkyl alcohol, which can be microbially degraded  to  car-

bon dioxide and water by Pseudomonas sp. (Van Dijk, 1974).

VII.  EXISTING GUIDELINES AND STANDARDS

      Neither the human health nor the aquatic criteria derived

by U.S. EPA (1979), which are summarized below, have gone through

the process of public review; therefore, there is a possibility

that these criteria may be changed.

      A.   Human

           The TLV for dichloropropane is 75 ppm  (350 mg/m )

(Am. Conf. Gov. Ind. Hyg., 1977).  The draft water criterion

(U.S. E?A, 1379) for dichloropropane is 203 uc/I.  The draft

water criterion for dichloropropenes is 0.63 ug/1  (U.S.  EPA,

1979).

      3.   Aquatic

           The draft criteria for the dichloropropanes and di-

chloropropenes to protect freshwater aquatic life are as follows

(U.S. SPA, 1979):


                                               Concentration not
                                                to be exceeded
Compound                  24-Hour Average         at any cime
1,1-dichloropropane           410 ^g/1               930 pg/1

1,2-dichloropropane           920 ug/1             2,100 ug/1

1,3 -dichloropropane         4> 800 pg/1            11,000 ug/1

1/3-dichloropropene            18 ^g/1     ,          250 ug/1
The draft criteria to protect saltwater species are as follows

(U.S. EPA, 1979) :

-------
Compound

1,1-dichloropropane

1,2-dichloropropane

1,3-dichloropropane

1,3-dichloropropene
24-Hour  Average

  not derived

   400 jjg/1

    79 jig/1

   5.5 pg/1
Concentration  not
 to be exceeded
   at any time

  not derived

    910 Fg/l

    180 pg/1

     14
                              -9*3-

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                       DICHLOROPROPANES/DICHLOROPROPENES

                                  REFERENCES
American Conference  of Governmental  Industrial  Hygienists.  1977.  Documen-
tation of the threshold limit values.  3rd. 3d.

California  Stats  Department  of Agriculture.   1971.   State  pesticide  use
report.

Dawson, G.W.,  et al.  1977.   The acute toxicity  of 47 industrial chemicals
to fresh and saltwater fishes.   Jour. Hazard. Mater.  1: 303.

Oowty, B.,.et al.   1975.   Halogenated  hydrocarbons  in  New Orleans drinking
water and blooa plasma.  Science  87: 75.

Heppel, L.A.,  et  al.   1948.   Toxicology  of  1,2-dichloropropane  (propylene
dichloride).  IV. Effect of  repeated  exoosures  to  a low concentration of  the
vapor.  Jour. Ind. Hyg. Toxicol.  30: 189.

Hutson. O.H.,  et al..  1971.   Excretion and  retention  of  ccnncorient3  of  the
soil  fumigsnt  D-0'>RX. and.  their  metabolites in the  rat.   Food Cosmet.  Toxi-
col.  9: 677.       .. )

Leistra,  M.   1970.  Distribution of 1,3-dichloropropene  over  the phase  in
soil.  Jour. Agric. .rooa Cnern.   15: 1124.

Rooerts,   R.T.   2nd  G.   Stcycin.    1976.   The   degradation   of  (2)-  and
(E)-l,3-di-  chlorcpropenes and  1,2-dichloroprcpenes  in soil.   Pestic.  Sci.
~>. ~o<:
/ . st.j.              .^
                    -  f
Sax,  N.I.   1975.   Dangerous properties of industrial  materials.   Reinhc.ld
Bock Corp.,  New York.  .,
                      j
Torkelson,  R.R.  and  F.  Oyen.  1977.  The  toxicity of 1,3-dichloropropene  as
determined by  repeated  exposure of laboratory animals.  Jour.  Am.  Ind. Hyg.
Assee.  33:  217.

U.S.  EPA.   1978.  In-depth  studies -on  health  and environmental  impacts  of
selected water pollutants.  Contract No. 68-101-4646.

U.S.  EPA.   1979.  Dichloropropanes/Dichloropropenes:   Ambient  Water Quality
Criteria.   (Draft).

Van  Dijk,   J.   1974.   Degradation  of 1,3-dichloropropenes   in   the   soil.
Agro-Ecosystems.  1: 193.

Van Duuren,  8.L., et al.   1979.   Carcinogenicity of halogenated olsfinic  and
alipahtic hydrocarbons.  (In press).

Windholz,  M.,  ed.  1976.   The Merck Index.  9th  ed.  Merck and  Co.,   Inc.,
Rahway, N.J.

-------
                                      No. 30
          Dicnlorooronanol
  Health and Environmental Zffects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the  report is drawn chiefly
from secondary  sources  and  available reference' documents.
Because of the limitations of such  sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has  undergone  scrutiny to
ensure its technical acc-uracv.

-------
                              OICHLOROPROPANOL
                                   Summary

     There was  no  evidence found  in  the available  literature  to indicate
that exposure to dichloropropanol produces carcinogenic effects.  Conclusive
evidence of  mutagenic,  teratogenic, or  chronic effects of dichloropropanol
was not found in the available literature.   Acute exposure results in toxi-
city similar to  that  induced by carbon  tetrachloride,  including hepato- and
nephrotoxicity.   Data  concerning the effects  of dichloropropanol to aquatic
organisms was not. found  in the available literature.
                                         -9S7-

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I.    INTRODUCTION

     This profile  is  based on computerized  searches  of Toxline,  Biosis,  and

Chemical Abstracts,  and review of  other appropriate  information sources  as

available.  Oichloropropanol  (molecular weight  128.9),  a colorless,  viscous

liquid with  a chloroform-like odor,  refers to  four  isomers  with the  mole-

cular  formula  C-jHgOCl2.    The   physical  properties  of  each   isomer  are

given below.

                        Soiling Point Density     Solubility  (Weast,  1976)
                                                 Water     Alcohol    Ether

2,3-Dichloro-l-propanol    182Qc      1.368    slight      miscible   miscible
l,3-Oichloro-2-propanol    1740c      1.367    very        very       miscible
3,3-Oichloro-l-oropanol   82-33°C    . 1.316    net listed
1, l-Gicnicrc-2-prcpanoi  146-i45^C    1.3534   siicht      very       very


     Additional physical  data and  synonyms  of the above  isomers are  avail-

able in Heilbrcn  (1965),  Faircnild (1979),  Sax-(1979),  Windhaiz  (1=75),  ana

Vsrschusrsn (1977).

     Pi^^ui—T»,^i~]T"^''*"^»""^'1  -*-»  -,»» = ^,~—a;j  £•.«,-,—  — i . .-. _ — ^ i  Q0_i.*^,  _ _ • ,j  	•  •_. _•	.
     — -.-.^.i-.'.-'-^.rf-wr-.aii*--.  —^  w.k^uG.».du  ij-om  i^.L.j'^c.i.uJ.j  aUc LJ.W  GH-.I.U j 'diiu  ny Ui L/'JCI •

chloride.   It is  used as  a  solvent for  hard resins  and  nitrocellulose,  in

the manufacture  of photographic  and Zapon  lacquer,  as a  cement for  cellu-

loid, and  as  a binder  for water colors  (winoholz,  1976).   The  compouno  is

considered tc be a moderate  fire  hazard when exposed to heat, flame,  or oxi-

dizers, and a disaster  hazard in  that it may  decompose  at-high  temperatures

to phosgene gas (Sax, 1979).

II.  EXPOSURE

     Dichloropropanol was  detectable in the air of  a glycerol manufacturing

plant in  the  U.S.S.R.  (Lipina  and  Belyakov,  1975).   Unreacted  dichloropro-
                                                                          »
panol was also  found in the  wastewater  effluent of  a halchydrin  manufactur-

ing plant  (Aoki and  Katsube, 1975).   No monitoring  data are  available  to

indicate ambient air or water levels of the compound.

-------
     Human exposure  to  dichloropropanol from  foods  cannot be assessed,  due

to a lack of monitoring data.

     Bioaccumulation data on dichloropropanol  was  not  found  in the available

literature.

III. PHARMACOKINETICS

     Pertinent data  could  not  be located in the available literature  on the

metabolism, distribution, absorption, or excretion of dichloropropanol.

IV.  EFFECTS

     A.   Carcinogenicity

          Pertinent data could not be located in the available literature.

     3.   Mutacenicity

          2,3-Dichloropropanol  and  1,3-dichloroprcpancl  were evaluated  for

Tiutagenicity  by  a modified  Ames assay using  S_._ tychi~urium  strains.   Seme

evidence of  mutagenic activity was  seen,  but  the authors felt  that  further

evidence and  clarification  of the metabolic activation pathway to mutagens

via haloalkanois were necessary (Nakamura,  et al.  1979).

     C.   Teratogenicity, Other Reproductive Effects and Chronic Toxicity

          Pertinent data could not be located in the available literature.

     D.   Acute Toxicity

          2,3-Dichloropropanol was  found to  have  an  oral LD-a  i_n tne  rat

of  90  mg/kg.  The  lowest  published lethal  concentration (LCLQ) in rats  is

500 ppm  by inhalation for 4  hours.   A dose of 6,800 ug  in  the eye   of  the

rabbit caused  severe irritation  (Fairchild,  1979).   1,3-Oichloropropanol was
                                                       .-

found  to have an  oral  LD5Q  in the rat  of 490 mg/kg and lowest  published

lethal concentration for inhalation  exposure  in rats of  125  ppm/4  hrs.  .Ten

mg  applied to  the  skin of the rabbit  for 24 hours.produced  mild irritation,


and  800 mg/kg was  the LD5Q  for  the same  route  and  species  (Fairchild,

1979).

-------
          Several references  report the  clinical indications  of acute  di-
chloropropanol intoxication as being similar to carbon  tetrachloride poison-
ing,  i.e.,  central  nervous  depression;  hepatotoxicity,  including hepatic
cell  necrosis  and fatty  infiltration;  and renal toxicity,  including  fatty
degeneration and  necrosis  of the renal tubular epithelium (Sax, 1979;  Gos-
selin, et al.  1976).
V.   AQUATIC TOXICITY
     Data concerning  the effects  of dichloropropanol  to  aquatic  organisms
were not found in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Hunan
          The  maximum allowable  concentration of  dichloroprcpanol  in  the
working  environment  air in  the U.S.S.R.  is  5 mg/m^ .(Lipina  and  Bslyskov,
1975).
          The rnaxiiTium allowable concentration in Class  I Caters  for the  pro-
duction of drinking water is 1 mg/1 (Verschueren,  1977).
     3.   Aquatic.
          The organoleptic limit in  water set  in  the U.S.S.R.   (1970) is  1.0
mg/1 (Verschueren, 1977).

-------
                                  REFERENCES
Aoki, S. and  E.  Katsube.   1975.  Treatment  of waste waters  from  halohydrin
manufacture.  Chem. Abs. CA/083/15875D.

Fairchiid,   E.  (ed.)   1979.   Registry of  Toxic  Effects of  Chemical  Sub-
stances.  U.S. Deoartrnent  of  Health,  Education and Welfare, National  Insti-
tute for Occupational Safety and Health, Cincinnati, Ohio.

Gosselin, et  al.   1976.  Clinical Toxicology  of Commercial Products.   Wil-
liam and Wilkins  Publishing Co., Baltimore,  Maryland.

Heilbron, I.  (ed.)  1965.  Dictionary of Organic  Compounds.   4th  edition.
University Press, Oxford.

Lipina,  T.G.  and  A. A.  Belyakov.  1975.  Determination of allyl alcohol,  al-
lyl chloride, epichlorohydrin and dichlorohydrin in the  air.   Gig.  Tr.  Prof.
Zabol.  5:  49.
      r?., A.,  et al.   1979.   The mutagenicity  cf halcgensted alkancls  and
their  phosphoric  acid  asters  for  SalrnG.-.ella  tychimuriurn.   Mutat.   Res.
66: 373.

Sax, N.I.   1979.  Dangerous  Properties of  Industrial  Materials.   Van  Ncs-
trand Reinhold Co.,  New York.

Verschueren, K.  1577.  Handbook of Environmental  Data  en  Organic  Chemicals.
Van Ncstrand Reinhold Co., New York,  p.  659.

Weast,   R.C.  (ed.)    1976.   Hancbook of  Chemistry and  Physics.   CRC Press,
Cleveland, Ohio, p.  c-454.

Windholz, M. (ed.)   1976.  The Merck Index.   9th ed.  Merck and Co.,  Railway,
New Jersey.
                                        •961-

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                                     No. 81
        1,3-Dichloropropene
  Health and  Environmental Effects
U.S. ENVIRONMENTAL  PROTECTION AGENCY
       WASHINGTON,  D.C.  20460

           APRIL  30, 1980.
                -9 £3.-

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                              1 , 3-DICHLOROPROFENE



                                    SUMMARY








     The major  environmental source of  dichlorcoropenes is from  the  use of a



mixture  of dichloropropenes and  dichloropropanes  as  a  soil  fumigant.   On



chronic exposure  of rats to dichloropropene  mild kidney damage was  observed.



Oichloropropene  has produced  subcutaneous tumors  at the  site of  injection,



and has  been  shown to  be mutagenic in  bacteria.  However, not enough infor-



mation is  available to  classify  this compound as a carcinogen.



     The  bluegill  (Leoomis  macrochirus) has  a  reported  96-hr LC_.^  value of



6C6G ug/1; Sasnnia  ir.agna nas a ' reporzec 48-hr  LC^n of  615C jug/i.   For  the
            ^ ^~—   '                             ^U


 -l '-•t--  •   >T--~—-     "^°   ne -T'e  Ssh-'s   3  — annrfaH  C
                                ^O^-O  LjCi* i— a ,   d  ^.^(^wx^^^  ^
790  UQ/1.   In  the only  lonn— term  st'jdv  available   the  v^lue nb^-insp  fo^



1, 3-dichloroprcp3ne  toxicity  to  fa^r.aad minr.-'/s  (Pi.r.eohales prc~3l3s)  in an



•cTnbr'/c-i3''~va "'  '"sst is ' ^'~>r> ''—/!.'  B-seG' on cnlor^^hv'' ''•  3. c~r^'=r''f"rs''""'cns  -r'~



cell  numbers,  the 96-hr  EC_n  values  for the  freshwater  alga  Selenastrum



capricornutum are 4,950  and. 4, 960  jug/1,   respectively;  'fcr .the



Skeletonema costatum,  the  respective values are 1,000  and  1,040 pg/1.

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                              1,3-OICHLOROPROP£.V€



I.   INTRODUCTION



     This profile  is based  on the  Ambient  Water Quality  Criteria Document



for DichlGrcprcpsnss/Oichloropropenes (U.S. EPA, 1579a).



     1,3-dichloropropene  (molecular  weight 110.97)  is a  liquid  at environ-



mental temperatures.• The  isomers  of 1,3-dichloropropene  have boiling points



of  104.3°C  for the trans-isomer  and  112°C  for  the  cis-isomer, and  the



densities are  1.217 and 1.224 g/ml,  respectively.   The water solubility for



the   two  isomers   is   approximately   0.275   percent.    When   heated   to



decomposition  temperatures,   1,3-dichloropropene gives  off  toxic  fumes  of



chlorides  (Sax.  1975).   Mixtures  of cis-  and trans- l,3-dichioropropep,e and



1,2-dichioropropane  are   used  as   soil   fumigants.    In   this  document,



dichloroprcoene will refer to either cis- or trans-l,3-dichloropropene.  For



more  information  regarding the dichioropropenes,  the reader is  referred  to



tha EPA/ECAO  Hazard Profile  on  Dichloropropanes/Dichioropropenes (U.S. EPA,



1979c).



II.  EXPOSURE



     A.  Water



         Oichloropropene  can  enter the  aquatic environment in the discharges



from  industrial and manufacturing processes,  in  run-off  from  agricultural



land,  or from  municipal  effluents.   This compound  has  been  identified  but



not quantified in New Orleans drinking water  (Dowty, et al. 1975).



     8.  Food



         Information was   found  in the  available  literature  concerning  the



concentration of dichloropropene in  commercial  foodstuffs.   Thus,  thefamount



of  this  compound  ingested by humans  is  not known.   The U.S.  EPA (1979a) has



estimated the weighted  average bioconcentration factor (8CF)  of dichloropro-



pene  to  be 2.9 for the  edible  portions  of  fish  and  shellfish  consumed  by

-------
Americans.   This  estimate  is  based  on  the dctanol/water  partition coeffi-
cient of dichloropropene.
     C.  Inhalation
         Atmospheric levels  of  dichloropropene  have not been measured.  How-
ever, it  is  estimated  that about 8  percent of the  dichloropropene which  is
applied to  the soil as  a  fumigant  is released to  the  atmosphere  (U.S. EPA,
1979a).
III. PHARMACCKINETICS
     A.  Absorption
         Data  on  the absorption,  distribution  and metabolism of dichloropro-

         Data  on the  excretion of  dichicrcproper.e  by  humans could  not be
located in  the available literature.  In the  rat,  hcv/ever,  approximately £G
percent of  an  orally administered dose of  dichicrcprcper.e  v/as eliminated in
the urine within 2
-------
addition of  liver  microsomal fraction.   Neudecker,  et al.  (1977)  found the
cis-isomer to be twice as reactive as the trans-isomer.
     C.  Teratogenicity  and Other Reproductive Effects
         Me  pertinent  information  regarding  the  teratogenicity  and  other
reproductive effects could not be located in the available literature.
     D.  Chronic Toxicity
         On  exposure  of rats to 3 ppm  dichloropropene for period of 0.5, 1,
2 or 4  hours/day,  5  days a  week for 6 months  (Torkeison' and Oyen,  1977), or
rats, guinea pigs, and  rabbits  to  1 or 3 ppm of dfchloropropene, 7 hours per
day for 125-130 days over a  180-day period,  only  rats exposed 4 hours/day at
3.0 ppm  shewed  an  effect (U.S. EFA,  1979a).   The  only effect observed was a
cloudy  swelling . of  the  renal  tubular  epithelium  which  disaooesred  by  3
months after exposures ended.
V.   AQUATIC TCXICITY
     A.  Acute Toxicity
         Tests  or,  the  bluegiii,  Lepomis macrochirus,  yielded  a  96-hr LC=n
value of 6060 }jg/l for  1,3-dichlorcprcpene  exposure.   For Daphnia maqna, the
48-hr  LC-0  value   is  6,150 jug/1  (U.S.  EPA,  1973).   The observed  96-hr
LC5Q  for the  saltwater rnyrid  shrimp,  Mysidopsis  bahia,  is 790 jug/1 (U.S.
SPA, 1978).
     8.  Chronic Toxicity
         An  embryo-larval  test  has  been conducted  with  the  fathead minnow
(Pimeohales  promeles)  and 1,3-dichloropropene.   The  observed  chronic value
was 122.jjg/l (U.S.  EPA, 1979a).
     C.  Plant Effects
         Based  on  chlorophyll a concentrations  and cell  numbers,  the 96-hr
EC50  values  for the  freshwater alga,  Selenestrum caoricornutum,  are 4,950
                                           -$67-

-------
and 4,960  jug/1,  respectively  (U.S.  EPA,  1978).   The respective  values  for
the saltwater alga Skeletonema costatum  were  1,000 and  1,040 jug/1 (U.S. EPA,
1973).
     0.  Residues
         Measured steady-state bioconcentration  factors  (3CF) are not avail-
able  for .1,3-dichloropropene.  A  BCF of 19 has  been estimated based  on  the
octonol/water coefficient for 1,3-dichloropropene (U.S.  EPA, 1979a).
     £.  Other Relevant Information
         Following  field  application,   movement •• of 1,3-dichloropropene  in
soil  results  in  vapor-phase  diffusion (Leistra,  1970).   The  distribution of
1,3-uiohlcrcprcpsne within  soils  depends  en  sell  conditions.   Fcr exarcoie.
cis-l,3-dichioropropane is chemically hydroiyzed in moist soils to  the cor-
responding cis-3-chloroalkyl  alcohol,  which  can be microbially  degraded to
carbon dioxide ana water oy .-seuoornonas  sp.  (Van Oijk 1574).
VI.  EXISTING GUIDELINES AND STANDARDS
     ^either  the  human health nor cr.e  aquatic  criteria cerivec  by  U.S. EPA
(1979a), which are summarized below, have  gone through  the  process of public
review:  therefore,   there  is  a  possibility  that  these  criteria  will  cs
changed.
     A.  Human
         The  draft, water  criterion  for  1,3-dichloropropene  is  0.63  /jg/1
(U.S.  EPA, 1979a).
     8.  Aquatic
         The  draft,criterion  to  protect  freshwater species is 18 jug/1  as a
24-hr average not  to  exceed  250/jg/1 at  any  time.  For marine  species, the
value is 5.5 -jug/1 as  a 24-hr  average not to exceed 14 jug/1  at any time  (U.S.
EPA, 1979).

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                              1.3-OICHLOROPROPENE
                                  REFERENCES
DeLorenzo, F.,  gt  al.   1977.  Mutagenicity of  pesticides  containing  1,3-di-
chloropropene.  Cancer Res. 57: 5

Oowty, 3., et al.   1975.   Halogenated  hydrocarbons  in New Orleans  drinking
water and blood plasma.  Science 87T75.

Hu-tson,  O.H.,'et al.   1971.   Excretion and  retention of components of  the
soil  fumigant  D-0>R)   and  their  metabolites  in  the  rat.    Food   Cosmet.
Toxicol.   9:  677.

Leistra,   M.   1970.  Distribution  of 1,3-dichloropropene  over  the phase  in
soil.  Jour.  Agric. Food Chem.  18: 1124.

Neudecker, T.,  et  al.   1977.  _In  vitro  mutagenicity  of the soil  nematocide,
1,3-dichlorcpropene.  Experientia 33: 8.

Sax,  N.I.   1975.   Dangerous. Drrcarti3S of  Industrial Materials.   Reir.hold
Book Corp., New York.          ')

Torkelscn, R.R, and F. Oven.   1977.   The toxicity  of  1,3—dichlorcpropene  as
determined by  repeated  exposure  of laboratory animsls.  Hour. Am. Ind. Hvo.
Assoc. 38: 217.

U.S.  EPA.   1973.    In-depth  studies  on  health  and  environmental impacts  of
selected water pollutants.  Contract  No. 68-01-4646.

U.S.  EPA..   1979a.   Cicnloroprdpanes/Dichloropropenes:  Ambient Water  Quality
Criteria (Draft)               .
                             .  ) '
U.S.  EPA.   1979b.   Dichloropropanes/Dichloropropenes:  EPA/ECAO  Hazard Pro-
file.

Van Oijk, J.   1574.  Degradation of  i,3-dicnloropropenes in the  soil.   Agro-
Ecosystems.  1: 193.

Van  Duuren,   et al.   1979.   Carcinogenicity  at  halogenated  olefinic  and
aliphatic hydrocarbons.  (In press).
                                   -96?-

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                                    No. 82
             Dleldrin
U.S.  ENVIRONIiENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

          APRIL 30,  1980
                  -970-

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                          DISCLAIMER
     This report represents a  survey  of  the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the  report is drawn chiefly
from secondary  sources  and   available reference  documents.
Because of the limitations of  such sources, this short profile
may not reflect  all available  information  including  all  the
adverse health  and   environmental  impacts  presented  by  the
subject chemical.   This  document  has  undergone scrutiny  to
ensure its technical accuracv.
                              -9-71'

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                      SPECIAL NOTATION










U.S.  EPA's Carcinogen Assessment Group (CAG)  has  evaluated



dieldrin  and has found sufficient evidence to indicate  that



this  compound is carcinogenic.
                          -973.-

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                           DIELDRIN



                           SUMMARY



      Dieldrin is a compound belonging to the group of cyciodier.e



insecticides.  The chronic toxicity-of low dcses of dieidrin



includes shortened life span, liver changes ana teratogenic effects,



The induction of hepatocellular carcinoma in mice by dieidrin



leaas to the conclusion that it is likely to be a human carcinogen.



Dieidrin has been found to be non-mutagenic in several test sys-



tems.  The WHO's acceptable daily  intake for dieidrin is 0.0001



mg/kg/day.



      The toxicity of dieidrin to  aquatic organisms has been



investigated in numerous studies.  The 96-hour LC,-g values for



the common freshwater fish range from 1.i.to 3oO ug/1.  Tha acute



tcxicity is considerably more varied for f reshv/ater inver titrates,



witn 96-hour ^C-~ values ranging from 0.5 ug/i for the stonefiy



to 7
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                             DIELDRIN



I.     INTRODUCTION



      This  profile  is  based on  the  draft Ambient  Water Quality



Criteria  Document  for  Aldrin  and  Dieldrin  (u.S.  SPA,  1979).



Dieldrin  is a -white  crystalline substance  with a  melting point



of 176-177°C and  is soluble  in  organic  solvents (U.S.  EPA, 1979).



The  chemical name  for  dieldrin is  1, 2 , 3 ,.4 ,10 ,10-hexachlor-6 , 7-



epoxy-i, 4,4a,5,6,7,8 ,8a-octohydro-endo/ exo-1, 4 : 5 , 8-dimethanor.aph-



thalene.



      Dieldrin is extremely  stable  and  persistant in the envircn-



men.t.   Its  persistance is  due to  its extremely  low   volatility



(1.78  x 10~7 mm Hg  at 2Q°C)  and  low  solubility  in  water   (186



ug/1 at 25-29°C).  The time required  for 95 percent of the dieldrin



to disappear  from soil  has  been estimated  to  vary from  5  to 25



years  depending   on  the  microbial  flora  of  the  soil  (Edwards,



1966;.'  Patil,  et  al.  (1372;  reported that dieidrin was not  de-



graded or metabolized in sea water or polluted water.



      Dieldrin was .primarily used as  a broad spectrum  insecticide



until  1974,  when  the  U.S.  EPA  restricted  its use  to termite  con-



trol by direct soil injection,  and  non-food  seed and plant treat-



ment (U.S.  EPA,  1979).   From 1966 to  1970, the  amount of dieldrin



used  in 'the  United  States  decreased  from  500  to approximately



335,000  tons '(U.S.  EPA,  1979).  This  decrease  in use  has   been



attributed  primarily  to  increased  insect  resistance  to dieidrin



and  to  development  of  substitute materials.   Although the produc-



tion of dieldrin. is  restricted in: the' United  States,   formulated



products  containing  dieldrin  are  imported  from  Europe  (U.S.



EPA, 1979).

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II.   EXPOSURE



      A.   Water



           Dieldrin  has been  applied  to  vast areas  of agricul-



tural  land  and aquatic  areas  in the  united States,  and  in most



parts  of  the  world.    As  a  result,   this  pesticide  is  found  in



most  fresh  and  marine  waters.    Dieldrin  has  been  measured   in



many  freshwaters  of  the United States,  with mean  concentrations



ranging from 5  to  395 ng/1 in surface  water  and  from  1 to 7 ng/1



in  drinking water  (Epstein,  1976) .    Levels  as  high  as  50 ng/1



have  been  found  in  drinking water  (Harris, et  al.  1977) .   The



half-life of  dieldrin in water, 1  meter  in. depth,  has been  esti-



mated  to be 723 days  (MacKay and Wolkoff,  1973).



       B.   Food



           Dieldrin   is  one  of  the  most  scable  and persistant



orcancchiorine  pesticides  (Mash and  Woolson, 1967),  ar.d  because



it  is  iipophilic,  it  accumulates  in the  food  chain  (Wurster,



1971).   Its persistence in soil  varies   with  the .type  of  soil.



(Matsumura and Boush, 1967).



           The  U.S.   EPA  (1971)  estimated  that  99.5  percent  of



all  human  beings  have'dieldrin  residues  in  their  tissue.    These



residues  are  primarily  due  to  contamination of  foods of animal



origin.   The  overall concentration  of dieldrin  in  the  diet  in



the  United States  has  been  calculated   to  be  approximately  43



ng/g of food consumed (Epstein,  1976).  The  U.S. EPA has estimated



the  weighted  average  bioconcentration  factor   for  dieldrin   to



be  4,50.0  in  the  edible  portion of  fish  and  shellfish consumed



by Americans  (U.S. EPA,  1979).   This  estimate  is based  on measured

-------
steady-state bioconcentration  studies in several  species of  fish



and shellfish.



      C.   Inhalation



           Dieldrin  enters   the  air  through various  mechanisms,



such  as spraying,  wind  action,  water  evaporation,  and adhesion



to  par ticulates.    The  U.S. EPA  detected  dieldrin in  more  than



85  percent  of  the  air  samples  tested  between  1970-1972,   with



the -mean  levels  ranging from. 1  to 2.3  ng/m   (Epstein,   1976).



From  these levels,  the average  daily intake of  dieldrin by  respi-



ration was calculated to be 0.035 to 0.098 ug.



           Although  dieldrin  is  no  longer  'jssd  in   the  United



States, there  is  still  the possibility, of  air-borne contamination



from other parts of the  world.



      D.   Dermal



           Dermal  exposure  to  dieldrin  is  limited to  those in-



volved  in its  manufacture or  application as a  pescicids..  vvcifa,



et al.  (1972)  reported that exposure in workers was mainly through



dermal absorption rather than inhalation.  The ban on the manufac-



ture  of dieldrin  in  the United  States  has greatly  reduced the



risk of exposure.



III. PHARMACOKINETICS



      A.   Absorption



           The  absorption  of dieldrin  by  the  upper  gastrointes-



tinal  tract- begins almost  immediately  after oral administration



in  rats and has  been found to vary with  the  amount  of solvent
                                                               »


used  (Heath and Vandekar, 1964).  These  authors also demonstrated



that absorption takes place via the portal vein, and that dieldrin

-------
couid be recovered from the stomach, small intestine, large intes-

tine and feces one hour after oral administration.

      B.   Distribution

           The distribution of dieldrin has been studied in numer-

ous feeding  experiments.   Dieldrin  has  an affinity  for  fat,  but

high  concentrations  are  also reported  in  the liver  and  kidney,

with moderate concentrations  in  the  brain one and two hours after

administration  in rats   (Heath  and Vandekar,  1964). .  Deichman,

et  al.  (1968)  fed  dieldrin  to  rats  for a'- period of  183  days.

The mean concentration in the fat was 474 times that  in the blood,

while the  concentration  in  the  liver  was approximately  29  tiT.es

the blood concentration.

           Additional animal  studies on  the  distribution of diel-

drin  have  shown that concentrations in   tissues  are  dose  related

and rr.ay vary with the  sex  of the  animal (Walker,  et  al.  1963).

Matthews, et  al.  (1971)  found that  female rats administered oral

doses of  dieldrin had  higher  tissue levels  of  the compound than

male rats.  The  females  stored the  compound  predominatly as diel-

drin.   In males,  other metabolites,  identified  as keto-dieldrin

trans-hydro-aldrin and'a polar metabolite, were detected.

           The concentrations of dieldrin in  human  body  fat were

found to be  0.15  + 0.02 pg/g for the  general population and 0.3S

ug/g  in one   individual  exposed  to   aldrin (aldrin  is metabolized
                                               *•
to  dieldrin)  (Dale and  Quinby,  1953).   The  mean  concentrations

of  dieldrin  in  the  fat,  urine,   and plasma   of  pesticide  workers

were 5.67, 0.242 and 0.0185  mg/g, respectively (Hayes and Curley,

1968).   Correlations  between  the   dose  and  length of  exposure

to  dieldrin  and  the  concentration   of dieldrin in  the  blood and
                                    -97
7-

-------
other  tissues have  been  reported  (Hunter,  et  al.   1969).   Dieldrin



residues  in the  blood  plasma  of  workers averaged  approximately



four  times higher  than  that  in  the  erythrocytes  (Mick,  et  al.



1971) .



       C.    Metabolism



            The  epoxidation  of aldrin to  dieldrin  has  been reported



in  many  organisms,  including man  (U.S.  EPA,  1979).   The reaction



is. NADPH-dependent, and  the enzymes  have .been  found  to  be  heat



labile (Wong and Terriere,  1965).



            The  metabolism of dieldrin has been studied  in  several



species,   including  mica,  rats,,  rabbits,  and  sheep.     Dieldrin



metabolites have been  identified  in  the  urine  and  feces in  the



form  of  several  compounds  more  polar  than   the  parent  compound



'{U.S.. EPA, 1379).    Bedford and  Hutson .(1976) summarized the  four



.
-------
as in  the  feces.   Robinson,  et al.  (1969)  found that 99 percent
of the  dieldrin  fed  to  cats  for   8  weeks was  excreted  during  a
subsequent 90-day  observation period.   The  half-life of dieldrin
in the liver and blood was 1.3 days  for  the period of  rapid  elimi-
nation and  10.2 days  for  a  later,  slower period.   The  half-life
of dieldrin  in adipose tissue  and brain were  10.3  and 3.0 days,
respectively.
           The  concentration  of  dieldrin in  the  urine  of   the
general  human  population  is  0.3  mg/1  for man  and  1.3  mg/1  for
women  as  compared to  5.3,  13.8,  or  51.4  mg/1  for  men with  low,
medium, or high exposure  (Ceuto and Biros,  1967).   The  half-life
ifor  dieldrin  in  the  blood  of  humans  ranges  from  141-592  day '-• \
with  a mean of 369  days (Hunter,  et  al.  1969).    Jager   (1970)
reported -the half-life  tc be .265  days.  Because there is a rela-
tionship between  the concentration  of  dieldrin  in  the ciood  and
that  ir. adipose and  ether  tissues, it seems  likely  that  the hai£-\._
                                                                   ) "
life  in  the blood may  reflect the  over-all  half-life  in other
tissues (U.S. EPA, 1979).                                         ' - -{
IV    EFFECTS
      A.    Carcinogenic!ty
           Dieldrin'has  produced  liver  tumors  in several strains
of mice according  to  six  reports of chronic  feeding studies  (NCI,
1976  (43  FR 2450);  Davis and  Fitzhugh, 1962;  Davis,  1965;  Song
and Harville, 1964; Walker, et al.   1972; Thorpe''and  Walker,  1973).
In rats,  dieldrin has failed to  induce a statistically  significant
                                                               f
excess of tumors  at  any site in three  strains  during six chronic
feeding  studies  (Treon  and  Cleveland,  1965;   Cleveland,  1966;

-------
Fitzhugh,  et al.  1964;  Deichman,  et  al.  1967;  Walker,  et  al.



1969; Deichmann, et al. 1970).



           The only information concerning the carcinogenic  poten-



tial  of  dieldrin  in  man  is  an  occupational  study  by Versteeg



and Jager  (1973) .   The workers had been  employed  in a plant  pro-



ducing aldrin and dieldrin with a mean exposure time of  6.6  years.



An  average  of  7.4  years had  elapsed  since the  end of  exposure.



No permanent adverse effects,  including cancer, were observed.



      B.  Mutagenicity



           Microbial assays  concerning  the mutagenicity  of  aldrin



and  dieldrin have  yielded  negative results  even when  some  type



of  accivacicn  system  was  added  (Fahrig,  1973;  Bidweii •- et  al.



1975; Marshall,  et  al. 1976).  A host-mediated  assay  and a  domi-



nant  lethal  test,   also  yielded  negative  resuics   (oidweil,  et



al.  1975).    Majumdar,  et  al.   (1577), .however,  found dieldrin



tc  be rr.utagenic in  5.  cyph iph iaur i urn ,  although  these --positive

                      ~~                                   '• j'

results  were .questioned  because  several  differences  existed- be-



tween their  procedures  and those recommended  (U.S. EPA,  ii .}}.



           A  decrease  in the  mitotic  index was  observed in  vivo



•filth  mouse  bone marrow  ceils and _iri vitro  wicn  human lung  cells



treated with 1 mg/kg and 1 jjg/ml dieldrin, respectively  (Majumdar,



et al. 1976).



      D.    Teratogenicity


                                                          14
           In  1967, Hathaway,  et  al.  established  that   C-diel-



drin could cross the placenta in rabbits.   Dieldrin caused signifi-



cant  increases   in  fetal death  in  hamsters, and  increased  fetal



anomalies  (i.e.. open eye, webbed  foot,  cleft palate,  and others)

-------
in hamsters  and  mice when administered, in  single oral doses dur-



ing  gestation  (hamsters  50,  30,  5  mg/kg  and mice  25,  15,  2.5



mg/kg) {Ottolenghi, et al. 1974).



           However,  in  subsequent  studies  no evidence  has been



found  that  dieldrin causes  teratogenic effects  in mice  and rats



(Chernoff, et al.  1975)  or mice  (Dix, et al. 1977).



      D.   Other Reproductive Effects



           Deichmann  (1972)   reported  that aldrin  and  dieldrin



(25  mg/kg/diet)  fed to mice  for six generations affected  ferti-



lity, gestation,  viability,  lactation,  and survival of the  young.



However,  no  changes in  weight  or  survival of  fetuses  v:ere fcund



in mice  administered dieldrin  for  day  6  through 14  of gestation



at doses  already  mentioned  in  this report   (Ottoler.ghi,  et  al.



1974) .



      E.   Chronic Toxicity



           The other  effects  produced  by  chronic administration



of dieldrin  to mice,  rats,  and dogs  include  shortened  life span,



increased  liver  to  body  weight ratio,  various  changes  in liver



histology, and the  induction of hepatic enzymes (U.S. EPA, 1979).



      F.   Other Relevant Information



           Since  aldrin  and. dieldrin are  metabolized  by  way  of



the  mixed function  oxidase  (MFO)   system  and dieldrin  has been



found  to  induce   the production of  these  enzymes,  any  inducer



or  inhibitor of   the MFO enzymes  should  affect  the  metabolism



of dieldrin  (U.S.  EPA,  1979).   Dieldrin  fed   in  low  doses pjrior



to  an acute dose  of  dieldrin  alters  its metabolism  (Baldwin,



et al. 1972).   Dieldrin  can effect the  storage of DDT (U.S. EPA,
                                *   -9*1-

-------
1979) and  induce  a greater number  of  tumors  in mice when  admini-



stered with DDT as compared to DDT  alone  (Walker, et al.  1972).



V.    AQUATIC TOXICITY



      A.   Acute Toxicity



           The  acute  toxicity of  dieldrin has  been investigated



in numerous studies.  Reported 96-hour LC^Q values for  freshwater



fish are 1.1 to 9.9 ug/1 for rainbow trout, Salmo gairdneri  (Katz,



1961; Macek,  et al.  1969); 16  to 36  ug/1 for  fathead  minnows,



Pimephales promelas (Henderson, et al. 1959; Tarzwell and  Henderson,



1957);  and 8  to  32  pg/1   for  the bluegill,  Lepomis  macrochir us



(Henderson, et al.  1959;  Macek, et al. 1959; Tar2we11. and  Henderson,



1957) .. .  Freshwater invertebrates  appear  to  be more  variable in



their sensitivity  to  acute dieldrin  toxicity.   The 96-hour  LC-M



values  range  from  0.5 /ig/1 for  the stone  fly  (Sanders  ana Cope,



1963-} to 740 ug/1 for the crayfish  (Sanders, 1972).



           The  acute .'LCcg  values  for  eight saltwater fish  species



range from 0.66 to  24.0  pg/l  in  flow-through tests  (Butler, 1963;



Earnest  and  Benville,   1972;  Korn  and  Earnest,   1974;  Parrish,



et al.  1973;  Schoettger,  1970;  and Lowe,  undated).   LC-^  values



ranging  from  0.7  to  240.0  ug/1  have  been  reported for  estuarian



invertebrates  species,   with   the  'most  sensitive  species  tested



being  the  commercially  important  pink  shrimp,  Penaeus  duorarum



(U..S. EPA> 1978) .



      B.   Chronic Toxicity



           Chronic  toxicity has  been studied  in  two  species of



freshwater  fish.    The  chronic  value  for  steelhead  trout  (S aImp



gairdneri)  from  an  embro-larval   study  is  0.11  ug/1   (Chadwick

-------
and  Shumway,  1969) .   For  the guppy,  Poecilia  reticulata,- in  a



life-cycle test, the chronic value  is 0.4 yg/l  (Roelofs,  1971).



      C.   Plant Effects



           Freshwater  plants  are less  sensitive to dieldrin  than



freshwater fish  or invertebrates.   For  example,  a concentration



of 100  /ag/1  caused a  22  percent reduction  in  the  biomass of  the



alga  Scenedlesmus  quadr icaudata  (Stadnyk  and  Campbell,   1971),



and  12,300 ug/1  reduced  growth by 50 percent in the diatom,  Navi-



cula  seminulum  after  5  days  of  exposure  (Cairns-,  1968).   In  a



saltwater plant  species  growth rate was reduced, at concentrations



of approximately 950 pg/i  (Batterton, et al.  1971).
    ~"                /


      D.   Residues



           Bioconcentration  factors  (3CF)   have been determined



for  9  freshwater  species  (U.S.  EPA,  1973).   Representative  5CF



values  are 123  for ens alga,  See.nee a sinus obliguua  (Reinert,  1972,



1395 for Dap'nnia magr.a  (Reir.ert,  1972), 2335-2993 for  the  channel



catfish, _Ictalurus punc ta tug  (Shannon, 1977a;  1977b)  and  68,258



for  the yearling  lake trout,  Salvelinus namaycusb.  (Reinert,  ec



al.  1974).   The edible  tissue of the Eastern oyster,  Crassostrea



virginica, had  a  3CF  value of  3000 after  392 days  of  exposure



(Parrish, 1974).   Spot,  Leiostomus  xanthurus,  had  a BCF of  2,300



after 35 days exposure to dieldrin  (Parrish,  et  al. 1973).



VI.  EXISTING GUIDELINES AND STANDARDS

                                               .-

      Neither the ' human  health  nor  the  aquatic criteria  derived



by U.S.  EPA  (1979),  which  are summarized below, have gone  through



the  process  of  public review; therefore, there  is a  possibility



that these criteria will be changed.

-------
      A.   Human


           The  current  exposure  level for  dieldrin set  by OSKA


is an air  time-weighted  average of 250 ug/m   for  skin absorption


(37 FR  22139).   In 1953, the  U.S.  Public  Health Service Advisory


Committee  recommended  that  the drinking water  standard for  diel-


drin  be 17  ug/1   (Mrak,  1969) .    The  U.N. Food  and Agricultural


Organization/World Health  Organization's   acceptable daily  intake


for dieldrin is 0.0001 mg/kg/day  (Mrak, 1959).


           The  carcinogenicity  data  of   Walker,   et   al.   (1972)


were  used  to calculate the .draft  ambient  water quality criterion

                          _2
for dieldrin of  4.4  •-: 10    ng/i  (U.S. EPA,  L^l?} .   This  Isvel


keeps the  lifetime cancer risk for  humans  below 10~D.


      B.   Aquatic


           The  draft  criterion  to  protect  freshwater   life   is


0.0019  uc/'i  as a  24-hour average;  the concentration  should  r.c-~


exceed  1.2 ^ug  at  any time.   To protect  saltwater aquatic  life,


the  draft  criterion  is  O.OCS9  jjg/1  as.  a  24-hour  average;  the


concentration should not exceed 0.15 ^5/1  at any tirr.e.

-------
                           DI ELDRIN

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-------
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-------
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-------
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estaurine organisms.  Pages 427-434 in ?roc. 27th Annu. Conf.
S.E. Assoc. Game Fish Comm.

Patil, i'. C . , et al.  1972.  Metabolic transf ormat icr. of DDT,
dieldrin, aldrin, and endrin by-marine microorganisms.  Envi-
ron. Sci. Technol.  6: 631,

Reinert, R.E.  1972.  Accumulation of dieldrin in an alga
Soenedesmus obiiqus, Daphnia maqna and the guppy, Poecilia
reticulata.  Jour. Fish Res. Board Can.  29: 1413.

Reir.ert, R.E., et al.  1974.  Dieldrin and. DDT: Accumulation
from water and food by lake trout, Salvelinus namaycush, in
the laooracory.  Proc. 17th Conf. Great Lakes Res. 52~7~

Robinson, J., et al.  1969.  The pharmacokinetics of HEOD
(dieldrin) in the rat.  Food Cosmet. Toxicol.  7: 317.

Roelofs, T-.-D.  1971.  Effects of dieldrin on the intrinsic
rate of increase of the guppy, Peocilia reticulata Peters.
Thesis.  Oregon State University, Corvallis.

Sanders, H.O.  1972.  Toxicity of some insecticides to  four
species of malacostracan crustaceans.  Bur. Sport Fish. Wild.
Tech. Pap. No. 66.
                               -m-

-------
Sanders,  H.O.,  and  O.B.  Cope.   1968.  The relative toxicities
of several  pesticides  to naiads of three species of stone-
flies.   Linnol.  Oceanogr.   13:  112.

Schoettger,  R.A.  1970.   Progress in sport fishery research.
Fish-Pestic.  Res. Lab.  U.S.  Dep. Inter.  Bur.  Sport Fish Wild.
Resour.  Publ.  106.

Shannon,  L.R.   1977a.   Accumulation  and  elimination of diel-
drin  in  muscle  tissue  of channel catfish.  Bull. Environ.
Contain.  Toxicol.  17:  637.

Shannon,  L.R.   1977b.   Equilibrium between uptake and elimi-
nation of dieldrin  by  channel  catfish, Ictalurus punctatus.
Bull. Environ.  Contam.  Toxicol.  17: 278.

Song, J., and  W.E.  Harville.   1964.   The carcinogenicity of
aldrin and  dieldrin on mouse  and rat liver.  Fed. Proc.  23:
336.

Stadynyk, L.,  and R.S.  Campbell.  1971.   Pesticide effect on
growth and    c  assimilation  in a freshv/ater alga.  Bull.
Environ.  Contam. Toxicoi.   6:  1.

.Tarzwell, C.M.,  and C.  Henderson.  1957.  Toxicity of diel-
drin  to  fish.   Trans.  Am.  Fish. Soc.  86: 245.

Thorpe,  Z.,  and  A.I.T.  v-Jalker.   1973.  The toxicology of
dieldrin (HSOD).  Part II.  Comparative long-term oral coxic-
ifcy studies  in  mice with dieldrin, DDT,  phenobarbitone, bsia-
3HC and  ga-jna-BKC .   Food Ccsmet. Toxicol.  11: 433.

Treon, J.,  and  F.D.  Cleveland.   1955.  Toxicity of certain
chlorinated  hydrocarbon  insecticides for laboratory animals
with  special reference to aldrin and dieldrin.  Agric. Food
Chem. Jour.   3:  402.

U.S.  EPA.   1971.  Reasons underlying the registration deci-
sion  concerning  products containir.g  DDT, 2,4,5-T, aldrin and
dieldrin.

U.S.  EPA.   1979.  Aldrin/Dieldrin: Ambient Water Quality Cri-
teria (Draft).

Versteeg, J.P.J., and  K.W.  Jager.  1973.  Long-term occupa-
tional exposure  to  the insecticides  aldrin and dieldrin, en-
drin, and telodrin.   Br. jour.  Ind.  Med.  30:  201.

Walker,  A.I.T.,  et  al.  . 1969.   The toxicology  and pharmacody-
namics of dieldrin  (HEOD):  Two-year  oral exposures of rats
and dogs.   Toxicol.  Appl.  Pharmacol.  15: 345.
                             iff

-------
Walker, A.I.T., et al.  1972.  The toxicology of dieldrin
(HEOD).  Long-term oral toxicity studies in mice.  Food Cos-
met. Texicol.   11: 415.

Winteringham,  F.P.W., and J.M. Barnes.  1955.  Comparative
response of insects and mammals to certain halogenated hydro-
carbons used as pesticides.  Physiol. Rev.  35: 701.

Wolfe, H.R., et al.  1972.  Exposure of spraymen to pesti-
cides.  Arch.  Environ. Health  25: 29.

Wong, D.T., and L.C. Terriere.  1965.  Epoxidation of aldrin,
isodrin, and heptachlor by rat liver microsomes.  Biochem.
Pharmacol.  14: 375.

Wurster, C.F.   1971.  Aldrin and dieldrin.  Environment 13:
33.
                                   •990-

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                                      No. 83
 o,o-Diethyl Dithiophosphoric Acid


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a survey of  the  potential  health
and environmental hazards from exposure  to  the  subject  chemi-
cal.  The information -contained in the report is drawn chiefly
from secondary  sources   and  available  reference  documents.
Because of the limitations of such sources,  this short profile
may not  reflect  all  available information including all  the
adverse health  and  environmental  impacts  presented  by  the
subject chemical.  This  document has  undergone scrutiny  to
ensure its technical  accuracy.
                              -992-

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                       0,0-OIETHYL DITHIOPHOSPORIC ACID
                                    Summary

     There  is  no available information to  indicate  that o,o-diethyl dithio-
phosphoric  acid  produces  carcinogenic,  mutagenic,  teratogenic,  or  adverse
reproductive effects.
     A  possible metabolite  of  the  compound,  o,o-diethyl  dithiophosphoric
acid, did  not  show  mutagenic  activity in  Drosophila, £.  coli,  or  Saccha-
romyces.
     The pesticide  phorate,  which  may release o,o-diethyl  dithiophosphoric
acid as a metabolite, has shown some  teratogenic  effects  in  developing  chick
embryos and adverse reproductive effects in  mice.
     An acute value of 47.2 pg/1 has  been reported for rainbow  trcut  exposed
to  a diethyl  dithicphosphoric  acid  analogue,   dioxathion.   A  synergistic
toxic effect with the latter chemical and  malathion is succested.

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I.   INTRODUCTION
     o,o-0iethyl hydrogen  dithiophosphate,  CAS registry number 298-06-6, al-
so called o,o-diethyl phosphorodithioic  acid  or o,o-diethyl dithiophosphoric
acid, is used primarily  as an  intermediate  in the synthesis of several pest-
icides:  azinphosmethyl,  carbophenothion, dialifor,  dioxathion,  disulfoton,
ethion, phorate, phosalone and terbufos.  It  is  made  from phosphorus penta-
sulfide (SRI, 1976).
II.  EXPOSURE
     A.   Water
          Pertinent  data were  not  found in  the available  literature;  how-
ever, if found  in water,  its  presence  would most likely be  due  to microbial
action on phorace or disulfoton (Daugnton,  et al. 1375),  or as a contaminant
of any of the above pesticides for which it-is a starting compound.
     8.   P"ood
          Pertinent  data were  net  fc-u.-.d in  the available  literature;  ho•-•,•-
ever,  if  present in feed,  the  cc~pcund would  probably  originate  frc~  the
same sources discussed above.   Organophosphorus pesticide  residues have been
found in food (Vettcrazzi, 1975).
     C.   Inhalation
          Pertinent  data were  net  found in  the available  literature;  how-
ever, major  exposure could  come from   fugitive  emissions in  manufacturing
facilities.
     0.   Dermal
          Pertinent data were'not found in the available literature.

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III. PHARMACOKINETICS
     A.   Absorption
          Information  relating specifically to the  absorption  of o,o-diethyl
dithophosphoic acid  was not found  in  the available literature.   Acute  toxi-
city studies  with the pesticides disulfoton and  phorate indicate  that  these
related organophosophorous  compounds  are absorbed  following  oral or dermal
administration (Gaines, 1969).
     B.   Distribution
          Pertinent  data  were  not  found in  the  available -literature.   Oral
administration of labelled phorate,  the S-(ethyl  thio)methyl  derivative  of
o,o-diethyl  dithiophosphoric  acid, to  cows  accumulated in  liver,   kidney,
lung,  alimentary  tract, and glandular tissues: fat samples  showed very  low
residues (Bowman and Casida, 1956).
     C.   Metabolism
          Pertinent data '.vere  not  found in the available literature.  Metab-
Gj..i3rri  Si-Uoies  wi-.ti uj.suJ.iGi.cn  v,oUj.J.,  i^c^> CLMU pisorsuc  v.ocwfiian and  uss-i—a,
1958)  indicate that  both  compounds  are converted to diethyl phosphcrodithio-
ate, diethyl phcrphorothioate, and  diethyl  phosphate.
     D.   Excretion
          Pertinent d?.ts  were  not  found  in t^e available literature.   5.a.cad
on animal studies  with related organophosphorous compounds,  the parent  com-
pound and its  oxidative metabolites may  be expected to eliminated primarily
in the urine (Matsumura, 1975).
IV.  EFFECTS
     A.   Carcinogenesis
          The  dioxane   s-s  diester  with  o,o-diethyl  dithiophosphoric  acid,
dioxathion,   has  been  tested  for  carcinogenicity  in  mice  and  rats  by

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long-term  feeding.   No  carcinogenic  effects were  noted  in either  species
(NCI, 1978).
     8.   Mutagenicity
          Diethyl phosphorothioate,  a possible metabolite  of the parent com-
pound,  did  not shew mutagenic activity  in  Drosophila,  E_.  coli,  or  Saccha-
romyces (Fahrig, 1974).
     C.   Teratogenicity
          Pertinent  data were  not  found in the  available  literature.   In-
jection  of  phorate  into  developing chick  embryos,  has  been  reported  to
produce malformations (Richert and Prahlad, 1972).
     0.   Other Reproductive Effects
          Pertinent  data were not  found in  the available  literature.   An
oral i ceding study conducted in mice with pnorstc \,G.5 to  .?.u pprn^ indicated
      ^"h°  h^^h0^^"  1 =a\'a ]   Q "P  f^rn^C''Pd  ^^^ Q-rr-^jjpa SCiTlS  ad^'^^S"  •r-o^-r^^''^1--*^^)
effects  (American  Cyanamid, 1566).   Chronic feeding of  mica ,vith  technical
dicxathian  at  levels  of 45G  to 6CG  pprn produced  seme  testiscular  atrophy
(NCI, 1978).
     E.   Chronic Toxicity
          Chronic  feeding  of   technical  dioxathicn   produced   hyperplastic
ncrules  '• n  livers  of fale  mice.   o  c— Die^nvl  cithicn'nosc:~cric  acic   ''ike
other  organophosphates,  is expected  to  produce  cholinesterase  inhibition
(MAS, 1977).
V.   AQUATIC TOXICITY
     A.   Acute
          Marking  (1977) reports on  |_C5Q  value  of 47.2'/jg'/l  for  rainbow
trout   (Salmo   qairdneri)   exposed   to   the   dithiodioxane   analogue •  of
bis(o,o-diethyl  dithiophosphoric  acid),   dioxathion,  and an LC5Q  value  of

-------
3.44 ug/1  when  this  latter  compound is  applied  in  combination  with mal-
athion.   The synergistic action with malathion  suggests  that  the combination
is more  than eight  times as toxic as either of the individual  chemicals.
     B.    Chronic,  Plant Effects, and Residues.
          Pertinent data were not found in the available  literature.
VI.  EXISTING GUIDELINES
     Existing guidelines  or standards were not  found  in the available lit-
erature.
                                            -9?7-

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                                  REFERENCES


American  Cyanamid   1966.   Toxicity  data  on  15  percent   Thimet  granules.
Unpublished  report.    In:   Initial  Scientific  and  Minieconomic  Review of
Phorate (Thimet) Office of Pesticide Programs, Washington.

Bowman, J. and  J. Casida   1553.   Further studies on the metabolism of Thimet
cy plants, insects,  and mammals.  J. Econ. Entomoi.  51: 338.

Bull, 0.  1965.  Metabolism of  di-systox by insects, isolated cotton leaves,
and rats.  J. Econ.  Entomoi.  58: 249.

Oaughton, C.G.,  A.M. Cook, M.  Alexander  1979.   Phosphate  and  soil binding
factors   limiting  bacterial .  degradation  of   ionic  phosphorus-containing
pesticide metabolites.  App. Environ. Microbio.  37: 605.

Fahrig,  R.    1974.    Comparative . mutagenicity   studies  .with  pesticides.
Chemical Carcinogenesis Assays,  IARC Scientific Publication  #10, p. 161.

Gaines, T.   1969.  Acute  toxicity of pesticides.   Toxicol.  Appl. Pharmacol.
Marking,  L.L.   1977.   Method- for  asssessing  additive toxicity  of chemical
mixtures.   In:   Aquatic  Toxicology  and Hazard  Evaluation.   STP  634 ASTM
^O'sn i a 1  Torino -| ^Q 1  P» i^l i njsi" *' ori   n  QQ
^•* w -rf _ — _ • v v^> i> ' J. w w* > ^w-fc-vUtdu^v^'l.  H* • s s •

Matsumura, F.   1975.   Toxicolcay of  Insecticides.   New  Ycrk:  Pler.ur1  °~ess,
p. 223.
Naticr.ai  Academy  of  Sciences   1977.   Drinking  Water ?nd  Health,   national
Researcn Council, Washington, p. 615.

National.  Cancer  Institute   1978.   Sicsssay  of  Dioxathion  for  Possible
Carcinoaenicity. .   U.S.  DHEW,   NCI   Carcinocenesis  Technical  Recort  Series
#125, 44 pp.

Richert, E. and K.  Prahlad   1972.   Effect of the oraancDhosohate c.c-diethvl
s-C (ethyitnio)metnyl] pnospnorcaithioate on tne cnick.  Poult. Sci.  51: 513.

SRI   1976.   Chemical  Economics  Handbook.   Stanford  Research  institute.
Pesticides, July 1976.

vettorazzi,  G.   1976.   State  of  the  art en  the toxicologies!  evaluation
carried  out  by  the  joint FAO/WHO meeting  on  pesticide  residues.   II.
Carbamate  and  organophosphorus pesticides  used in  acriculture  and  public
health.. -Res. Rev.  63: 1.

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                                        No. 84
0,0-Dlethyl-^-methyl Phosphorodithioate


    Health and Environnental Effects
  U.S. ENVIRONMENTAL PROTECTION AGENCY
         WASHINGTON, D.C.  20460

             APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents a survey of the  potential  health
and environmental hazards from exposure to  the subject  chemi-
cal.  The information contained in the report is  drawn chiefly
from secondary  sources,  and  available  reference  documents.
Because of the limitations of such sources,  this  short profile
may not  reflect  all  available information  including all the
adverse health  and  environmental  impacts  presented  by the
subject chemical.  This"  document has undergone  scrutiny  to
ensure its technical  accuracy.
                        -1000

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                   o,o-OIETHYL-S-METHYL PHOSPHORODITHIOATE
                                   Summary

     There is  no available information on  the possible carcinogenic, muta-
genic, teratogenic or adverse reproductive  effects  of o,c-diethyl-S-methyl
phosphorodithioate.    Pesticides   containing   the   o,o-diethyl   phosphoro-
dithioate 'moiety did  not show carcinogenic  effects  in rodents (dioxathion)
or teratogenic  effects  in  chick  embryos (phorats).   The possible metabolite
of  this   compound,  o,o-diethyl  phosphorothioate,   did not  show  mutagenic
activity   in  Drosoohila,  E.  coli,  or  Saccharomyces.   o,o-Oiethyl-S-oiethyl
phosphcrodithioate,  like other  organophosphate compounds,  is expected  to
produce cholinesterase inhibition in  humans.
     There is no available  data on the  aquatic  toxicity of this compound.
                                  -1001-

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                    0,0-OIETHYL-S-METHYL PHOSPHORODItHIOATE

 I.    INTRODUCTION

      0,0-Oiethyl-S-methyl  phosphorodithioate  (CAS  registry number 3288-58-2)

 is  described in German  oatents  1.768,141 (CA 77:151461s)  and 1,233,390  (CA

 66:115324p).   The  latter  states  the  compound  has   "partly insecticidal,

 acaricidal  and fungicidal  activity"  and  is  useful as an  intermediate  for

 organic synthesis.  It has the following physical and chemical properties:


                    Formula:              C5H13

                    Molecular Weight:     200

                    Soiling Point:        lOOoc to 102°C (4 torr)
                    (CA 55:8335h)

                    Density:              1.192420
                    (CA 55:3335h)       "               '-.,3

      Pertinent data were not found in the available literature  with respect

 to production, consLirnption or the current use of this ccmoound.

 II.   EXPOSURE
                                                         •'v
      Pertinent data were not found in the available lite. 'cure.

 III.  PHARMACOKINETICS
                                                        .'-'  "}
      A.   Absorption

          Information  relating  specifically  to  the absorption  of  o,o-di-

sthyl-S-methyl  phosphorodithioate was  not  found  in   the  available  liter-

ature.  Oral  administration  of the S-ethylthio derivative of  this  compound,

the insecticide.phorate, indicates that this, derivative is absorbed  from the

gastrointestinal tract (Bowman and Casida,  1958).

    .3.   Distribution

          Pertinent  data  were   not   found  in  the  available   literature.

Studies with  32p  radiolabelled phorate in the  cow indicated  that  following

oral  administration,   residues  were   found   in  the  liver,   kidney,   lung,
                                   -IQOSL-

-------
 alimentary   tract,   and   glandular   tissues;   fat  samples  showed  very   low
 residues  (Bowman  and Casida,  1953).
     C.   Metabolism
          Pertinent  data were not  found  in the available literature.  Based
 on metabolism  studies with various  orgsncpnosphstas in mammals,  o,c-diethyl-
 S-methyl  phosphorodithioate may  be  expected to undergo hydrolysis to diethyl
 phosphorodithioic acid,  diethyl  phosphorothioic acid,  and diethyl phosphoric
 acid (Matsumura,  1975).
     D.   Excretion
          Pertinent   data  were   not  found  in  the  available   literature.
 Related  metabolites   (0,0-diethyl  .phosphorodithioic,  phosphorothioic,   and
 phosphoric  acids) have  been  identified  in  the urine  of  rats  fed phcrate
 (Bowman and Casida,  1958).
 IV.  EFFECTS
     A.   Carcinoaenicity
        •  Pertinent  data were not   found in  the available  literature.    The
 dioxane-S-3-diester  with. o,o-diethyl  pnosonorodithioate,  dioxathion,   has
 been tested  for csrcinogenicity  in.mice  and rats  by  long-term feeding.   No
 carcinogenic effects were noted in either species (NCI, 1978).
     b.   Mu oagenicii.y
          Pertinent  data   were   not  found  in  the  available  literature.
Diethyl phosphorothioate,  a  possible metabolite of  the parent  compound,  did
not show mutagenic activity  in Drosphila, Ei.  coli,  or  Saccharomyces (Fahrig,
1974).

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     C.   Teratogenicity
          Pertinent  data were  not  found  in  the available  literature.   In-
jection of  phorate  into developing chick  embryos  has been  reported to  pro-
duce malformations (Richert and Prahlad, 1972).
     0.   Other Reproductive Effects
          Pertinent  data were  not found  in  the  available  literature.   An
oral feeding study conducted in mice with  phorate  (0.6 to 3.0 ppm)  indicated
that the highest  level  of compound  did produce some adverse reproductive  ef-
fects  (American Cyanamid,  1966).   Chronic  feeding of  rats  with  technical
dioxathion  at  levels from  450  to  600 ppm produced some testicular atrophy
(NCI, 197S).
     E.   Chronic Toxicity
          Pertinent  oata   were   not   founo   in  the  available   literature.
Chronic feeding of technical dioxathion  procuced nycerpiastic  nodules in  the
livers  of   ,T,aie-mice.    o,o-DiethyI-5-.r1ethyi  phcsohoroaithioace,  iixe  other
organopnosphates,   is expected  to  produce choiinesi:ersse  inhibition   (MAS,
1977).
V.   AQUATIC TQXICITY
     Pertinent data were not found in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     Existing  guidelines, and  standards  were  not  found  in  the available
literature.

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                    0,o-OIETHYL-S-METHYL PHOSPHORODITHIOATE

                                  References
American Cyanamid.   1966.   Toxicity  data en 15 percent Thimet granules.  Un-
published report.  In:  Initial Scientific and Minieconomic Review of
Phorate (Thimet) Washington, DC:  Office of Pesticide Programs.

Bowman,  J.  and  J.  Casida.  1958.   Further  studies  on  the metabolism of
Thimet by plants,  insects,  and mammals.  Jour. Eccn. Entcm.   51: 338.

Fahrig, R.  1974.   Comparative  mutagenicity  studies  with pesticides.  Chem-
ical Carcinogenesis Assays, IARC Scientific. Publication NO. 10.  p. 161.  •

Matsumura, F.   1975.  Toxicology of Insecticides.   Plenum Press,  New York
p. 223.

National  Academy of  Sciences.   1977.   Drinking Water  and Health.  National
Researcn Council,  Washington, DC.  p. 615.

National  Cancer  Institute.  1573.   oioassay  of  Oioxathion for Possible  Car-
cinogenicity.    CHEW.   Nat-'.o-al  Cancer Institute,   Carcinogenesis Technical
Report Series No.  125: 44.. J

Richert,  E.P.  2nd  K.V.   Prshlsd.    1972.    Effect  of  •i'h0  c""3nochccpr;-''"0
o,a-disthyl-5-L(ethyithio)rr.etnyi ]  pnospnorcaitniate  on  the  chick.   Pcuit.
Sci. 51: 513.

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                                    No. 85
         Diethvl Phthalate
   sslC"T,  ^nc Hnvi.ronnsT.£3l Z^^sc^
U.S.  ENVmOciMENTAL PROTECTION AGENCY
      .WASHINGTON, D.C.  20460

          APRIL 30, 1980
           -/006-

-------
                          DISCLAIMER
     This report represents a  survey  of  the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and   available .reference  documents,
Because of the limitations of such sources, this short profile
may not reflect  all  available  information  including  all  the
adverse health  and   environmental  impacts  presented  by  the
subject chemical.  This  document  has  undergone  scrutiny  to
ensure its technical accuracy.
                          '/007-

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                      DISTHYL PHTHALATS



                           SUMMARY



     Diethyl  phthalate  has  been  shown to  produce mutagenic



effects in the Ames Salmonella assay.



     Teratogenic effects were  reported following i.p. admin-



istration of  diethyl  phthalate  to pregnant  rats.   This same



study has also indicated fetal toxicity and  increased resorp-



tions after i.p. administration of DEP.



    • Evidence  that diethyl  phthalate  produces  carcinogenic



effects- has not. been found.



     A single  clinical  report  indicates that the development



of hepatitis  in  several hemodialysis  patients may have been



related  to  leaching  of diethyl  phthalate   from  the  plastic



tubings utilised.



     Diethyl  phthalate  appears to  be more  toxic  foe marine



species acutely  tasted, with a  concentration of  7,590  ug/1



being  reported as  the  LC^Q  in  marine invertebrates.   The



data  base  for  the toxic  effects of  diethyl phthaiates  to



aquatic  organisms   is   insufficient  to  draft criterion  for:



their protection.

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                      DIETHYL PHTHALATE

I.    INTRODUCTION

     This  profile  is  based  on  the  Ambient Water  Quality

Criteria Document for Phthalate Esters  (U.S. EPA, 1979a).

     Diethyi phthalate  (DEP)  is a diester  of the ortho form

of benzene dicarboxylic  acid.   The  compound  has a molecular

weight  of  222.23,  specific  gravity  of  1.123,  boiling point

of 296.1°C', and is  insoluble in water  (U.S. EPA, 1979a) .

     DEP is  used  as a plasticizer  for cellulose ester plas-

tics and as a carrier for perfumes.

     The 1977  current production  of  diethyl  phthalate was:

3.75 x  10  tons/year (U.S.  EPA, I979a).

     Phthaiates have  been detected  in soil,  air,  and water

samples; in animal  and human  tissues;  and  in certain vegeta-

tion.   Evidence  from _in_  vitro  studies indicate  that certain

bactsrisl  flora  mav  be   capable  of  metaboiizinn  phthaiates

to the monoester form (Engelhardt, et  al. 1975).

II.  EXPOSURE

     Phthalate esters  appear  in  all  areas of  the  environ-

ment.   Environmental  release  of  tne  phthaiates may  occur

through leaching  of plasticizers  from plastics, volatiliza-

tion of phthaiates  from plastics,  and the  incineration  of

plastic items.   Human exposure to phthaiates includes contami-

nated  foods  and  fish, dermal  application  -in  cosmetics,  and

parenteral  administration  by  use  of plastic  blood  bags,
                                                          »
tubings, and  infusion devices  (mainly  DEHP  release)   (U.S.

EPA, 1979a).
                                  -/oof-

-------
     Monitoring studies have indicated that most water phthal-

ate concentrations  are  in the ppra  range,  or  1-2  pg/1  (U.S.

EPA,  1979a).    Industrial air monitoring  studies  have mea-

sured air levels of phthalates from  1.7  to  66 mg/m   (Milkov,

et  ai.  1975).   Information  on   levels  of  DEP  in  foods  is

not available. The U.S. EPA (1979a)  has estimated the weighted

average  bioconcentration  factor   for  DEP to  be  270  for the

edible portions of  fish and  shellfish consumed by Americans.

This  estimate is based  on measured  steady-state  bioconcen-

tration studies in bluegills.

III. PHARMACOKINETICS

     Specific  information is  not available  on   the  absorp-

tion, metabolism,  distribution,   or  excretion of  DEP.   The

reader is referred to a general coverage of phthalate metabo-

lism in the phthalate ester hazard profile (U.S.  SPA, IS79b).

IV.  EFFECTS

     A.    Carcinogenicity

          Pertinent  information   could  not  be   located  in

the available literature.

     3.    Mutacenicitv

          Diethyi phthalate  has  been  shown  to produce muta-

genic effects in the  Ames Salmonella assay   (Rubin,  et al.

1979).

     C.    Teratogenicity

          Administration  of   DEP  to  pregnant rats   by  i.p.
                                                          »
injection has been reported  to  produce teratogenic  effects

(Singh,  et al. 1972).
                                   -/oio

-------
     D.   Other Reproductive Effects



          Fetal   toxicity   and  increased  resorptions  were



produced  following  i.p.  injection  of   pregnant   rats  with



DEP (Singh, et al. 1972).



     £.   Chronic Toxicity



          A  single  clinical   report  has  been  cited  by  the



U.S. EPA  (1979a)  which  correlated  leaching of DEP  from  hemo-



dialysis  tubing' in  several  patients with  hepatitis.    Char-



acterization  of  all  compounds  present   in  the hemodialysis



fluids was not done.



V.   AQUATIC TOXICITY



     A.   ACUCS Toxic icy



          Among  aquatic  organisms,  the  bluegiil sunfish,  ;



Lepomis macrochirus,  has been shown  co  be acutaiv sensitive



to  diethyl  chthaiate;  a 36-hour static   LC,--, of  98,200 ^ig/i



is  reported  (U.S. EPA.,  1978) .   For  the freshwater inverte-



brate,  Daphnia  magna,  a 48-hour static   LC^Q of  51,100 pg/1



was obtained.  Marine organisms  proved  to be more  sensitive,



with  the  sheepshead  minnow,  Cyprinodon  var iegacus,  showing



a 96-hour static LC5Q of 29,600 ;jg/l, while the raysid shrimp,



Mysidopsis  bahia,  showed  an  96-hour static  LC^n of   7,590



ug/1 (U.S. EPA, 1978).



     B.   Chronic Toxicity



          Pertinent  information  could'   not  be  located  in



the available literature.



     C.   Plant Effects



          Effective  concentrations  based  on  chlorophyl  a



content  and  cell  number  for  the  freshwater  alga,  Selena-



                              2

-------
strum  capricornutum,  ranged  from  35,600  to  90,300
while the marine alga, Skeletonema  costatum, was more  sensi-
tive,  with  effective  concentrations  ranging   from   65,500
to 85,000 ug/1.
     D.    Residues
          A  bioconcentration  of 117  was  obtained  for  the
freshwater invertebrate, Daphnia magna.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human health  nor  the aquatic  criteria  de-
rived by  U.S.  EPA  (1979a) ,  which  are  summarized below,  have
gone  through  the   process  of  review;  therefore,   there  is
a oossiriJiuV chac  these criteria will be chanced.
          ;j  *                    '
     A.    Human
          Based  on  nno  ^ £ ?- —c ~" lens's  ob s e ^ v°d  '•" chron1'0
feeding  studies  with rats or  dogs,  the  U.S.  EPA has  calcu-
lated an... acceotaole daily  intaks  'ADI*  level of 438  mg/dav
         . r
for DEP.
          ' /
        • _')The  recommended   water   quality  criterion   level
for  protection  of  human health, is  50  nig/I -for  DEP   (U.S.
SPA, 1979a).  -
     B.    Aquatic
          Data are insufficient to  draft criterion  for  the
protection of  either  freshwater or  marine organisms   (U.S.
EPA, 1979a).

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                      DIETHYL PHTHALATES

                          REFERENCES

Engelhardt, G.  at al.   1975.   The  raicroDial  metabolism of
di-n-butyl phthaiate  and  related dialkyl  phthalates.   Bull.
Environ. Contain. Toxicol.   13: 32.

Milkov, L.E.,  et al.   1975.  Health status of  workers  ex-
posed to phthalata plasticizers in  the manufacture of artifi-
cial leather and  films  based on  PVC resins.   Environ. Health
Perspect.  Jan. 1975.

Rubin, R.J., et  al.   1979.   Ames  mutagenic assay of a series
of phthalic acid  esters:   Positive  response  of the dimethyl
and diethyl esters in TA  100.  Abstract. Soc. Toxicol. Annu.
Meet.  March 11, 1979, New Orleans.

Singh. A.  et  al.  1972.   Teratogenicity of  phthaiate esters
in rats.  Jour. Fharm. Sin. Gl, 51.

CJ.S'.  SPA.   1978.   In-depth  studies on  health and environ-
mental  impacts  of selected water pollutants.   U.S. Environ.
Prot.  Agency, Contract No.  68-01-4646.

U.S. EPA.    1979a.   Phthaiate Esters:   Ambient  vvater Quality-
Criteria (Draft).

U.S.  EPA.    IS79b.   Environmental Criteria and  Assessment
Office.  Hazard Profile:  Phthala-e Esters (Draft).

-------
                                     No. 86
        DimethyInitrosaraine


  Health and Environmental Effects
U.S.  ENVIRONMENTAL  PROTECTION AGENCY
       WASHINGTON,  B.C.  20460

           APRIL  30, 1980
                 -10 If-

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny 'to
ensure its technical accuracy.

-------
                     DIMETHYLNITROSAMINE



                           SUMMARY



     Dimethylnitrosamine produces liver and kidney tumors



in rats.  It is mutagenic in several assay systems.  No



information specifically dealing with the teratogenicity,



chronic toxicity or other standard toxicity tests of dimethyl-



nitrosamine was available for review.



     Hepatocellular carcinoma has been induced in rainbow



trout administered 200 to 800 pq dimethylnitrosamine in



their diet.

-------
                     DIMETHYLNITROSAMINE



I.    INTRODUCTION



     This profile is based on the Ambient Water Quality



Criteria Document for Nitrosamines  (U.S. EPA, 1979a).



     Specific information on the properties, production,



and use of dimethylnitrosamine was  not available.  For general



information on dimethylnitrosamine, refer to the ECAO/EPA



Hazard Profile for Nitrosamines  (U.S. EPA, 1979b).



     Dimethylnitrosamine can exist  for extended periods



of time in the aquatic environment  (Tate and Alexander,



1975; .Fine, et al., 1977a).



II.  EXPOSURE



     A.   Water



          Dimethvlnitrcsa~ine has beer, detected at a concen-



tration of 2 to 4 ug/1 in wastewater samples from waste



treatment plants adjacent to. or receiving effluent  from,



industries using nitrosamines or secondary amines in produc-



tion operations (Fine, et al.,  1977b).



     3.   Food



          Dimethyinitrosamine was found to oe present in



a variety of foods (including smoked,  dried or salted fish,



cheese, salami, frankfurters, and cured meats)  in the 1



to 10 u/kg range and occasionally at levels up to 100 ug/kg



(Montesano and Bartsch,  1976).



          The U.S. EPA (1979a)  has estimated the weighted



average bioconcentration factor for dimethylnitrosamine



for the edible portions  of fish and shellfish consumed by
                                 -1017

-------
Americans to be 0.06.  This estimate  is based on  the  n-octanol/



water partition coefficient of dimethylnitrosamine.



     C.   Inhalation



          Dimethylnitrosamine has been detected in  ambient



air samples collected near two chemical plants, one using



the amine as a raw material and the other discharging  it



as an unwanted byproduct  (Fine, et al., 1977a).



          Tobacco smoke contains dimethylnitrosamine.   The



intake of dimethylnitrosamine from smoking 20 cigarettes



per day has been estimated at approximately 2 ug/day  (U.S.



EPA, 1979a) .



III. ?HA?J'!ACGKINETICS



     A.   Absorption



          Pertinent data  could r.ct be  located in  the  avail-



able literature.



     B.   Distribution



          Following intravenous injeccion into, rats,  dimetnyi-



nitrosamine is rapidly and rather uniformly distributed



throughout the body (Magee, 1972) .



     C.   riecaboiism and  ixcrecion



          Ln vitro studies have demonstrated that the  organs



in the rat with the. major capacity f-or metabolism of  dimethyl-



nitrosamine are the liver and kidney  (Montesano and Magee,


                                14
1974).  After administration of   C-labeled--dimethylnitro-



samine to rats or mice, about 60 percent of the isotope



appears as   CO? within 12 hours,  while 4 percent is  excreted


-------
in the urine (Magee, et al., 1976).  Dimethylnitrosamine



is excreted in the milk of female rats  (Schoental, et al.,



1974) .



IV.  EFFECTS



     A.   Carcinogenicity



          Chronic feeding of dimethylnitrosamine at doses



of 50 mg/kg induces liver tumors in rats  (Magee and Barnes,



1956; Rajewski, et al., 1966).  Shorter, more acute expo-



sures to dimethylnitrosamine ranging from 100 to 200 mg/kg



produce kidney tumors in rats and liver tumors in hamsters



(Magee and Barnes, 1959; Tomatis and Cafis, 1967).  A single



unspecified intraperitoneal dose given to newborn mice in-



duced hepatocellular carcinomas (Toth, et al., 1964).



     3.   Mutacenicity



          Di.T.ethylnitrcsamine and diethylnitrosamine have



been reported to induce forward and reverse mutations in



;5. c yphimur ium, S. coli , iVeurospora c r a s s a and other organisms;



gene recombination and conversion in Saccharomyces carevisiae;



"recessive lethal mutation" in Drosophila; and chromosome



aberrations in mammalian ceils (Montesano ana Barcscn, 1976).



Nitrosamines must be metabolically activated to be mutagenic



in microbial assays (U.S. EPA, 1979a).  Negative results



were obtained in the mouse dominant lethal test (U.S. EPA,



1979a).



     C.   Teratogenicicy and Other Reproductive Effects



          Pertinent information could not be located in



the available literature on the teratogenicity and other



reproductive effects of dimethylnitrosamine.
                                   -IOU-

-------
     D.   Chronic Toxicity



          Pertinent information could not be located  in



the available literature on the chronic activity of dimethyl-



nitrosamines.



     E.   Other Relevant Information



          Aminoacetonitrile, which inhibits the metabolism



of dimethylnitrosamine, prevented the toxic and carcinogenic



effects of dimethylnitrosamine in rat livers (Magee,  et



al., 1976).



          Ferric oxide, cigarette smoke, volatile acids,



aldehydes, methyl nitrite, and benzo(a)pyrene have been



suggested .to act in a cocarcinogenic manner with dimethyi-



nitro-samine (Ster.back, et al., 1973; Magee, et al. ,  1975).



".   AQUATIC TOXICITY



     Pertinent information about acute and chronic aquatic



~oxicin^' was not found in the 2v* ?.liable literature.   -edition™



ally, no mention was made in any reports about plant  effects



or residues.



     One study reported that Shasta strain rainbow trout



(Salmo gairdneri),  fed dimethylnitrosamine in their diet



for 52 weeks, developed a dose-response incidence of  hepato-



cellular carcinoma during a range of exposures from 200



to 300 mg dimethylnitrosamine per kg body weight 52 to 78



weeks after dosing (Grieco, 1978).



VI. . EXISTING GUIDELINES AND STANDARDS



     Neither the human health, nor aquatic criteria derived



by U.S. EPA (1979a),  which are summarized below, have gone

-------
through the process of public review; therefore, there is



a possibility that these criteria may be changed.



     A.   Human



          The U.S. SPA (1979a) has estimated that the water



concentrations of dimetnylnitrosamine corresponding co life-



time cancer risks for humans of 10~  , 10~°, or 10~  are



0.026 ug/1, 0.0026 ug/1,  and 0.00026 pg/1, respectively.



     3.   Aquatic



          Data are insufficient to draft freshwater marine



criteria for dimethylnitrosamine.

-------
                     DIMETHYLNITROSAMINE

                         REFERENCES

Fine, D.H., et al.  1977a.  Human  exposure  to N-nitroso com-
pounds in the environment.  In; H.H.  Hiatt,  et  al.,  eds.
Origins of human  cancer.  Cold Spring Harbor Lab.,  Cold
Spring Harbor, New York.

Fine, D.H., et al.  1977b.  Determination of dimethylnitrosa-
mine  in air, water and soil by thermal  energy analysis:  mea-
surements in Baltimore, Md.   Environ. Sci.  Technol.   11:
581.

Grieco, M.P., et  al.  1978.   Carcinogenicity and  acute toxic-
ity of dimethylnitrosamine  in rainbow trout (Salmo  gaird-
neri).  Jour. Natl. Cancer  Inst.   60: 1127.

Magee, P.N;  1972.  Possible  mechanisms of  carcinogenesis and
mutagenesis by nitrosamines.  In:-  W.  Nakahara,  et al., eds.
Topics in chemical carcinogenesTs.   University  of Tokyo
Press, Tokyo.

Magee, P.N., and  J.M. Barnes.  1-956 *  The production of ma-
lignant primary hepatic tumors in  the rat by feeding dimethyl-
nitrcsamine;  Br. Jour. Cancer  10:  114.

Magee, P.M., and  J.M. Barnes.  1959.  The experimental pro-
duction of cumors in che rat  by d iinethylni trosamine  (M-nitro-
3Od ime thyiaiuine ) .  Acta. Un.  Int.  Cancer  13: 187.

Magee, P.:;., et al.  1976.  .l-J-N itroso cc.~pcur.ds and  related
carcinogens.  In: C.S.' Searle, ed.   Chemical Carcinogens.
ACS Monograph Mo. 113..  Am. Chem.  Soc. , Washington,  D.C.

Montesano, R., and H. Bartscn.  1976.   Mutagenic  and carcino-
genic N-nitroso compounds:  possible  environmental hazards.
Mutat. Res.  32:  179.

Montesano, R., and P.N. Magee.  1974.   Comparative  metacolism
jLn v i tro of nitrcsamines in-various  animal  species  including
man.  In: R. Montesano, et.al., eds.  Chemical  carcinogenesis
essays.  IARC Sci. Pub. No. 10.  Int. Agency Res. Cancer,
Lyon, France.

Rajewsky, M.F., et al.  1966.  Liver  carcinogenesis  by-di-
ethyinitrosamine  in the rat.  Science   152:, 83.

Schoental, R., et al.  1974.  Carcinogens in milk:  transfer
of ingested diethylnitrosamine into  milk lactating  rats.   Br.
Jour. Cancer  30:'238.

-------
Stenback,, F., et al.  1973.  Synergistic effect of  ferric
oxide on dimethylnitrosamine carcinogenesis  in  the Syrian
golden hamster.  Z. Krebsforsch.  79: 31.

Tate, R.L., and M. Alexander.  1976.  Resistance of
nitrosamines to microbial attack.  Jour. Environ. Qual.  5:
131.

Tomatis, L., and F. Cefis.  1967.  The effects  of multiple
and single administration of dimethylnitrosamine to  hamsters.
Tumori  53: 447.

Toth, B., et al.  1964.  Carcinogenesis study with dimethyl-
nitrosamine administered orally to adult and subcutaneously
to newborn BALBC mice.  Cancer Res.  24: 2712.

U.S. EPA.  1979a.  Nitrosamines: Ambient Water  Quality Cri-
teria. (Draft).

U.S. EPA.  1979b.  Environmental Criteria and Assessment-Of-
fice. -. Mitrcsamines: Hazard Profile.

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                                      No.  87
        2,4-Dimethylphenol


  Health and Environmental iffacts
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny  to
ensure its technical accuracy.

-------
                              2.4-OIMETHYLPHENOL
                                    Summary
     2,4-Oimethylphenol  (2,4-OMP)  is an  intermediate  in a  number of indus-
trial and  agricultural  products.   The main  route  of exposure  for humans  is
dermal with 2,4-OMP being readily absorbed through the skin.
     Little data is available on the mammalian  effects  of 2,4-OMP.  Tests  on
mice conclude that  the  compound may  be a promoting  agent in carcinogenesis.
2,4-OMP  inhibits  vasoconstriction   in isolated  rat  lungs;  this  ability may
cause adverse health effects in chronically exposed humans.
     A  reported 96-hour LC5Q  value  for fathead  minnows  is   16,750  ,ug/l;
chronic value using embryo-larval  stages  of the same -species  is 1,100 ug/1.
Oaohnia  maqna  has  an  observed  48-hour LC5Q value, of  2,120  ,ug/l.    In
limited  testing,  one  aquatic  alga ana  auckweed  are  over  100  times  less
sensitive  than  the  Dapnnia- in  acute  exposures.  The bicccncentration factor
for  2,4-  dimethyIpnenoi is  150 for  the  oluegill.   From  haif-iife stuoies,
residues of the chemical are not a  potential hazard for aquatic species.

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I.   INTRODUCTION


     This profile  is based primarily  on the Ambient  Water Quality Criteria


Document for 2,4-Oimethylphenol (U.S. EpA, 1979).


     2,4-Oirnethyipnenol (2,4-QMP)  is derived from coal and petroleum sources


and  cccurs  naturally  in  some  plants.   2,4-DMP  (CgH10Q)  is  usually  found


with the five other  dimethylphenol and three methylphenol isomers.  It has a


molecular weight  of 122.17  and normally  exists as a colorless crystalline


solid.   2,4-OMP has a melting point  of  27 to  28°C,  a  boiling  point of


210°C  (at  760 mm  Hg),  a vapor pressure  of 1 mm  Hg at  52.8°C,.  and a dens-


ity of 0.0965 g/ml at 20°C (U.S. EPA, 1979).


     2 &—QMP  is a  \vesk  acid   (pk —10.6)  3nd is  soluble  in  alkaline  solu-


tions.  It readily  dissolves  in organic -solvents  and  is  slightly soluble in


water (Weast, 1976).


     2,4-GMP  is a chemical  intermediate in  the nianufsecure of  a number of


industrial ana  agricultural  products, including  phenolic antioxidants, dis-


infectants,   solvents,  Pharmaceuticals,  insecticides,   fungicides,  plssti-


cizers,  rubber chemicals,  polyphenyiene  oxide,  wetting  agents,   and  dye-


stuffs.  It  is  also found in lubricants,  gasolines,  and  cresylic acid (U.S.


EPA, 1979).


     Very little information exists  on the environmental  persistence of 2,4-


DMP.  Complete  biodegradation  of  2,4-OMP occurs in  approximately two months


(U.S. EPA,  1979); however, no environmental conditions were described.


II.  EXPOSURE


     A.  Water


         U.S. EPA  (1979)  reported  that no  specific data are available on the
                                                                        »

amounts of 2,4-OMP  in drinking  water.  The concentrations of 2,4-OMP present


in  drinking  water  vary depending  on the amounts  present in untreated  water
                                         -1017-
                                      /

-------
and  on  the efficiency of  water treatment  systems  in removing  phenolic com-
pounds.   In the U.S., the gross  annual discharge of 2,4-OMP  into waters was
estimated  to  be  100 tons in  1975 (Versar,  1975).  Manufacturing was the lar-
gest  source  of  the  discharge.    Lsachates   from  municipal  and  industrial
wastes  also contain the  compound  (U.S.  EDA, 1979).
         Hoak (1957) determined  that,  at  30°C, the  odor threshold  for 2,4-
DMP  was 55.5 pg/1.
      B.  Food
         DMP's  occur naturally  in tea  (Kaiser,  1967),  tobacco  (Baggett and
Morie,  1973;  Spears, 1963),  marijuana (Hoffmann, et al.  1975),  and a conifer
(f-orncst3°v3    ^t  3^   ^ 977).    The"**0   is  no  °viderice  to   sur*c°st  tht^t
dimethylpnenols  occur  in many  plants  used   for  food;   however,   it  may  be
assumed that  trace  amounts are  ingested (U.S.  EPA,  1979).
         The  U.S. • E?A  (1575).  has  estimated  the  weightea  average  oiocon-
centration factor for 2.4-OMP  to  be  340 for   the acibis portions  of fish anc
shellfish  consumed  by  Americans.   This estimate  is  basea  on  -ne  measures
steady-state  oicconcentration  studies in the  bluegill.
      C.  Inhalation'
         2,4-Oimethyiphenol  has  been found  in  commercial degreasing  agents
-(.NICSH,  1573),  cresol  vapors  (Corcos,  1939),  cigarette  smoke  condensates
(Baggett and Morie,  1973;  Hoffmann  and Wynder,  1963;  Smith  and  Sullivan,
1964),  marijuana cigarette smoke  (Hoffmann, et al. 1975) and  vapors from the
combustion and  pyrolysis  of building  materials (Tsuchiya  and Sumi,  1975).
Concentrations  in  smoke  condensates from  six different 'brands of  American
cigarettes ranged from 12.7 to 20.8  mg/cigarette  without filters  and  4.4 to
                                                                         *
9.1  mg/cigarette with filters  (Hoffman  and  Wynder,  1963).

-------
         There  is no  evidence in  the  available  literature indicating  that
humans are  exposed to 2,4-OMP other  than as components of  complex  mixtures.
Adverse  health  effects have been  found in workers  exposed  to mixtures  con-
taining  amounts  of  2,4-DMP;  hcwever,   the  effects  were  not  attributed  to
dimethylphenol exposure per  se (NIOSH,  1978).
     0.  Dermal
         Absorption  through the skin  is thought  to  be the primary  route  of
human exposure to  complex mixtures  containing  2,4-OMP (U.S.  EPA,  1979).
III. PHARMACOKINETICS
     A.  Absorption
         2,4-CMP  is  readily  absorbed  through the  skin  (U.S. EPA,  1579).  The
dermal.  LDC(-.  for  molten 2,4-OMP  is 1,040  mg/kg  in  the  rat  (Uzhdovini,  et
al. 1974).
     B.  Distribution
         U.S. EPA  (1979)  found no  pertinent: cats  on  the distribution of  2,4-
OMP in humans or  animals  in the  available literature.  2,6- or 3,4-CMP given
orally to rats  for eight  months  caused damage to  the  liver, spleen,  kidneys,
and heart (Maazik. 1963).
     C.  Metabolism
         Urinary  metabolites,  resulting  from  oral administration  of 850  mg
of 2,4-OMP  to rabbits, were .primarily  ether-soluble  acid  and ether  glucuro-
nide, with  lesser amounts  of ethereal  sulfate,   ester glucuronide  and  free
non-acidic  phenol (Bray,  et  al.   1950).   Similar metabolism  of  the other
dimethylphenol positional isomers was reported.
     0.   Excretion
                                                                        »
         A  study   done  on  rabbits  by  Bray,  et  al.   (1950)  indicates rapid
metabolism and excretion of 2,4-OMP.

-------
IV.  EFFECTS
     A.  Carcinogenic!ty
         Epidemic-logic studies  of workers exposed to  2,4-OMP  were not loca-
ted in the available literature.
         In a  carcinogenic!ty  bioassay,  26 female Sutter  mice were dermally
exposed  to  25 jul  of  20  percent  2,4-OMP in  benzene  twice  weeekly  for 24
weeks.   Twelve percent of  the  exposed  mice developed  carcinomas; however,
benzene  was not  evaluated  by  itself in this  study   (Boutwell  and  Bosch,
1959).   In  a  related  study, Boutwell  and Bosch  (1959)  applied 25  ul of 20
percent  2,4-OMP  in benzene  to  the skin  of female Sutter  mice  twice  a week
for  23  weeks   following a single  application, of a sub-carcinogenic cess (75
ug) of CM8A.   Papillomas  or .carcinomas developed in 18  percent  of the mice,
indicating that 2,4-QMP may  be a promoting agent for carcinogenesis.
         Fractions of  cigarette smoke  condensate containing  pnenol,' methyl-
phenols  and 2,4-OMP  have  been  shewn to promote'carcinogenesis in mouse skin
pioassays (Lazar, et al. 1^66;  Sccx, et ai. 1971; Roe,  et al. 1959).
     3.  Mutagenicity,  Teratogenicity and Other Reproductive Effects
         Pertinent data  could - not be  located  in  the  available  literature
regarding mutagenicity, teratogenicity  and other reproductive effects.
     C.  .Chronic Toxicity
         Pertinent information  concerning the  chronic  effects  of  2,4-  DMP
was not  located  in the available  literatureKU.S. EPA,  1979):  however,  data
was  available  on  other  positional isomers.   Examination  of  rats  treated
orally with 6  mg/kg  of 2,6-dimethylphenol or 14  mg/kg of  3,4-cSimethylphencl
for eight months revealed fatty dystrophy and atrophy of  the  hepatic  cel^s,

-------
hyaline-droplet  dystrophy  in  the  kidneys,  proliferation  of  mycloid  and



reticular cells, atrophy of  the lymphoid follicles of the spleen, and  paren-



chymatous dystrophy of the heart cells  (Maazik,  1968).



     0.  Other Relevant Information



         Tests on isolated rat  lungs indicate that 2,4-OMP may inhibit vaso-



constriction,  most  likely due  to its  ability  to  block ATP  (Lunde,  et  al.



1968).  Because of  2,4-OMP's physiological activity, U.S. EPA  (1979) reports



that  chronic  exposure to the  compound  may  cause adverse  health effects  in



humans.



V.   AQUATIC TOXICITY



         Pertinent  data could net  be located in tha available  literature  re-



garding any saltwater species.



     A.  Acute Toxicity



         A  reported  96-hcur LC-n  value  for   juvenile  fathead  minnows   is
                                 ^-U


16,750  ,ug/l  (U.S.  EPA,  1579).   For  the  freshwater  inverteorate  Oa'phnia



magna, the observed 43-hour -£cQ is  2,120 ;jg/l  (U.S. EPA, 1979).



     3.  Chronic Toxicity



         Based on  an  embryo-larval  test with  the fathead minnow, Pimephales



promelas,  the  derived  chronic  value  is 1,100  ug/1  (U.S.  EPA,  1978).   No



chronic values are available for invertebrate species.



     C.  Plant Effects



         Based on  chlorosis effects,  the  reported LC-g for duckweed,   Lemna



minor,  is  292,800  jjg/1  for  2,4-dimethylphenol  exposure  (Blackman, et  al.



1955).



     0.  Residues
                                                                           »


         A  bioconcentration  factor  of  150  was  obtained for  the bluegill.



The biological  half-life  in the  bluegill  is  less  than one  day, indicating

-------
that  2,4-dimethylphenol residues  are  probably not  a potential  hazard  for
aquatic organisms (U.S. EPA, 1978).
VI.  EXISTING GUIDELINES AND STANDARDS
     Standards have  not been promulgated  for 2,4-DMP  for  any sector cf  the
environment or workplace.
     A.  Human
         The draft  criterion for  2,4-dimethylphenol  in water recommended by
the  U.S.  EPA  (1979)    is  15.5 jug/1  based  upon the  prevention  of adverse
effects attributable to the organoleptic properties of 2,4-OMP.
     8.  Aquatic
         For  2,4-dimethylphenoi,   the  draft  criterion  to  protect  freshwater
aquatic life  is  38  jjg/1 as a  24-hour average; the concentration should  not
exceed 86 jug/1 at any  time.  NO criterion exists for saltwater species  (U.S.
EPA, 1579).

-------
                              2.4-OIMETHYLPHENOL

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

Blackman,  E.G.,   et  al.   1955.   The  physiological  activity  of  substituted
phenols.   I.  Relationships between  chemical  structure  and  physiological
activity.  Arch.  Biochem. Biophys.   54:  45.

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

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

Bray,  H.G..  et al.   1950.   Metabolism  of derivatives of toluene.   5.   The
fate of  the  xylends  in the  rabbit  with further observations on the  metab-
olism of the xylenes.  3iochem. Jour._ 47: 395.

Corccs,  A.  1939.  Contribution  to the study  of  occupational poisoning ;by
cresois.   Dissertation.  Vigot Freres Editeurs.  (Fre).

Gorncstaeva,  !_.!., et  al.   1977.   Phar.cls  frcm  abies  sibirica essentaial
oil.  Khim.  Pirir. Scedin: 1SS'3, 417-413.

Hcak, R.O.   1957.  The  causes  cf tastes and odors  in drinkinc water.   F~c.
llth Ind.  Waste Conf.  Purdue Univ. Eng. Bull.   41:  229.

Hoffmann,  D.,   et  al.   1975.   On  the  carcinogenicity  of marijuana  srncke.
Recent:Adv.  Phytochem.  9: 63.

Hoffmann,  D.,  and E.L. Wynder.   1563.   Filtration of phenols  from cigarette
s,Tioke.   Jcur. Natl. Cancer Inst.  30: 67.

Kaiser,  H.E.  1967.   Cancer-promoting   effects  of  phenols  in tea.   Cancer
20: 614.

Lazar,   P.,  et  al.  1966.   Senzo(a)pyrene,  content and  carcinogenicity of
cigarette  smoke   condensate  -  results   of  short-term  and  long-term  tests.
Jour. Natl. Cancer Inst.  37: 573.

Lunde,   P.K., et  al.    1968.   The  inhibitory  effect  of   various  phenols on
ATP-induced  vasoconstriction  in  isolated  perfused  raobit   lungs.   Acta.
Physiol. Scand.   72: 331.
                                                                      #
Maazik,  I.K.  1968.   Oimethylphenol  (xylenol)  isomers  and  their  standard
contents in water bodies.   Gig.  Sanit. 9: 18.

-------
National  Institute  of Occupational  Safety  and Health.   1973.   Occupational
exposure  to cresol.   OEW  (NIOSH) Publ. No.  78-133.   U.S. Dep.  Health Edu.
Welfare, Pub. Health Ser.,  Center for Ois.  Control.

Roe, F.J.C.,  et  al.  1959.   Incomplete  carcinogens in cigarette  smoke con-
densate:   tumor-production  by  a  phenolic  fraction.   Br.   Jour.  Cancer
13: 623.

Smith,  G.A.,  and P.J. Sullivan.   1964.  Determination of the steam-volatile
phenols present in cigarette-smoke condensate.  Analyse  39: 312.

Spears,  A.W.   1963.   Quantitative   determination  of phenol  in  cigarette
smoke.   Anal. Chem.   35:  320.

Tsuchiya,  Y.,  and  K. Sumi.   1975.    Toxicity  of  decomposition products  -
phenolic  resin.   Build.  Res. Note-Natl. Res.'Counc.  Can., Oiv.  Build. Res.
106.

U.S. EPA.   1978.   In-depth  studies  on health  and environmental  impacts  of
selected  water  pollutants.   Contract  NO.   68-01-4646.   U.S.  Environ.  Prot.
Agency, Washington,  O.C.

U.S.  EPA.    1979.    2,4-Dimethylphenol:    Ambient  Water  Quality  Criteris
(Draft).

Uzhdovini, E.R.,  et  al.   1974.   Acute  toxicity  of lower  phenols.   Gig.  fr.
Prof.. Zaboi.  (2): 56.

Versar,  Inc.   1975.   Identification, of • organic  ccmccuncs in effluents from
industrial sources.   EPA-560/3-73-Q02.   U.S. Environ.  Prot. Agency.

'iVeast,  R.C.   1976.  Handbook of chemistry  and physics.   57th ed.  CRC Press,
Cleveland, Ohio.

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                                       No.  88
         Dlmethvl Phthalate
  Health and Environnsr.-iai Effaces
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a survey of the  potential  health
and environmental hazards from exposure  to  the  subject  chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources   and   available  reference  documents.
Because of the limitations of such sources,  this short profile
may not reflect  all  available information  including all  the
adverse health  and  environmental  impacts  presented  by  the
subject chemical.  This  document has undergone  scrutiny  to
ensure its technical  accuracv.
                         1036-

-------
                      DIMETHYL PHTHALATE



                           SUMMARY



     Dimethyl phthalate  has been  shown to produce mutagenic



effects in the Ames Salmonella assay.



     Administration  of  dimethyl  phthalate to  pregnant  rats



by  i.p.  injection has been  reported to  produce teratogenic



effects in  a  single study.   Other reproductive effects  pro-



duced  by  dimethyl  ph.thalate included  impaired implantation



and parturition in rats following  i.p.  administration.



     Chronic  feeding  studies  in  female  rats  have  indicated



an  effect  of dimethyl  phthalate   on  the  kidneys.    There  is



no evidence to indicate  that dimethyl phthalate has carcino-



genic effaces.



     Amcnc  the   four  aquatic species  examined,  freshwater



fish  and  invertebrates  appeared   to  be more  sensitive  than



their marine  counterparts.   Acute toxicity values  at concen-



trations .of  49,500  pg/1 were  obtained  for  freshwater  fish.



Criterion could  not  be  drafted because of insufficient  data



concerning the toxic effects  of dimethyl phthalates to aquatic



organisms.
                             /   '/D37-

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                      DIMETHYL PHTHALATE

I.    INTRODUCTION

     This  profile  is  based  on  the  Ambient  Water  Quality

Criteria Document for Phthalate Esters  (U.S.  EPA,  1979a).

     Dimethyl 'phthalate  (DMP)   is  a  diescer  of  the  ortho

form of benzene dicarboxylic  acid.   The compound has  a  mole-

cular  weight  of  194.18,  specific gravity  of 1.189,  boiling

point  of  232°C,  and  a solubility  of 0.5  gms  in  100 ml  of

water  (U.S. EPA, 1979a).

     DMP is  used  as  a  plasticizer  for cellulose ester  plas-

tics and as an insect repellant.
                                   •3
     Currant  Production:  4.9  x .10w  tons/year. ":--'^ 1977  (U.S.

SPA, 1979a).

     Phthalates have  been  detected  in soil,  air,  and  water

samples; in' animal  and  .human  tissues;  and in certain  ve^eca-

tion.   Evidence  from  in vitro studies indie?.t
-------
by use  of plastic  blood  bags, tubing,  and  infusion devices



(mainly  DEHP  release).   Relevant  factors  in  the migration



of phthalate  esters  from  packaging  materials  to  food and



beverages are:   temperature,  surface area contact, lipoidial



nature of the food, and length of contact  (U.S. EPA, 1979a).



     Monitoring studies have  indicated that  most water phtha-



late  concentrations are  in  the  ppm range,  or  1-2 pg/liter



(U.S.   EPA, 1979a).  Industrial  air monitoring  studies have



measured  air  levels of  phthalates from 1.7 to 66 mg/m   (Mil-



kov,   et al.  1973).   Information on levels  of DMP  in  foods



is not  available.



     The  U.S. EPA  (1979s)  has estimated the wei9hted avsrace



bioconcentration  factor for  BMP to be  130 for  the  edible



portions  of fish and  shellfish consumed, by  Americans.   This



estimate  is  based  on  the  measured  steady-state  bioconcen-



tration studies in  biuegills.



III.  PEARMACOKINETICS



     Specific  information  is not  available on  the  absorp-



tion,  distribution, metabolis:?.,  or excretion of  DMP.   The



reader  is referred  to a general coverage of phthalate metabo-



lism in the phthalate ester hazard  profile (U.S.  EPA, 1979b).



IV.  EFFECTS



     A.   Carcinogenicity



          Pertinent data  could not  be located in  the avail-



able  literature.



     B.   Mutagenicity



          Dimethyl  phthalate  has  been  shown  to produce muta-



genic  effects  in the  Ames  Salmonella  assay (Rubin,  et al.



1979) .

-------
     C.   Teratogenicity

          Administration  of  DMP  to  pregnant  rats  by  i.p.

injection  has  been reported  to produce  teratogenic effects

(Singh,  et  al.  1972).    Intraperitoneal administration  of

DM?  to pregnant  rats  in  another  study  did  not  result  in

teratogenic effects (Peters and Cook, 1973).

     D.   D.   Other Reproductive Effects

          Adverse effects by DMP on implantation and parturi-

tion were  reported  by Peters and Cook  (1973)  following i.p.

administration of the compound to rats.

     E.   Chronic Toxicity

          Two-year  feeding  studies with  dietary  DMP  have

produced some kidney  effects  in female  rats  and minor growth

effects (Draize, et al.  1943).

'/.   AQUATIC TOXICITY

     A.   Acute Toxicity

          Two  freshwater  species  were  examined   for  acute

toxicity  from  dimethyl  phthalate   exposure.    The  48-hour

static  LC    for  the  Cladoceran,  Daphnia  magna, was  33,000

ug/i  (u.3.  EPA,  1978). .  The 96-hour static LC-~  value  for

the  bluegill,  Lepomis  macrochirus, was  49,500  pg/1.    For

marine  species,  96-hour static LC5Q values  for  the sheeps-

head minnow, Cyprinodon  variegatus, .and  mysid shrimp, Mysid-

opsis bahia, were 58,000 and 73,700 ^ig/1,  respectively.

     B.   Chronic Toxicity
                                                          »
          Pertinent  information  could   not   be  located  in

the available literature.
                                  -sow

-------
     C.   Plant Effects

          Effective  concentration's  based  on   chlorophyl   a

content  and  cell  number  for  the  freshwater  algae  Selena-

strum  capr icornutum  and the marine  algae Skeletonema  costa-

tum ranged from 39/300 to  42,700  ug/1  and  25,100 to  29,300

ug/1,  respectively.

     D.   Residues

          A  bioconcentration factor of 57 was  obtained for

the freshwater bluegill, Lepomis macrochirus.

VI.  EXISTING GUIDELINES AND STANDARDS

     Neither  the human health nor the aquatic  criteria  derived

by U.S.  SPA  ( 1979a)  . -..which are  summarized below, have cone

through  the  process  of puolic  review;  therefore,  there  is

a possibility that these criteria will  be changed.

     A.   Human

          3ased  on  "no  effect'1  levels observed  in  chronic
                      \ '
feeding  studies  in rats and dogs,  the  U.S.  EPA  (1979a) has

calculated an   accep. l>le   daily  intake  (ADI)   level  of 700

mg/day for DMP.
                                 .
protection  of  human  health  is  160 mg/liter  for  DMP  (U.S.

EPA, 1979a) .

     B.   Aquatic

          The  data  base  for  toxicity of  dimethyl phthalate

was  insufficient  for  drafting criterion  for  either  fresh-

water or marine organisms  (U.S. EPA, 1979a) .


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                     DIMETHYL PHTHALATES
                          REFERENCES

Draize, J.K.,  et  al.    1948.    Toxicological  investigations
of compounds  proposed  for use  as  insect  repellents.   Jour.
Pharmacol. Exp.  Ther. 93: 26.

Engelhardt,  G.,  et  al.   1975.    The  microbial  metabolism
of  di-n-butyl  phthalate  and  related   dialkyl  phthalates.
Bull. Environ. Contam.  Toxicol. 13: 342.

Milkov, L.S., et al.  1973.  Health status of workers exposed
to phthalate  plasticizers in  the  manufacture  of  artificial
leather  and  films  based  on  PVC  resins.   Environ.  Health
Perspect. Jan. 175.

Peters, J.W.,  and  R.M.  Cook.    1973.   Effects  of phthalate
esters on  reproduction of rats.   Environ.  Health Pecspect.
Jan.  91.

Rubin, R.J.,  et al.  1979.   Ar.as niutagenic assay of a series
of phthalic acid esters:   positive response of  the dimethyl
and  diethyl esters  in  TA 100,   Abstract:.  Sec.  Texicol. Anna.
Meet. New Orleans,  March 11.

Singh, A.,  et ai.   1972.   Teratccenicity  cf phthalate escers
in rats.   jour.  Pharis.  Sci. 61: 31.

U.S.   EPA.   1978.   In-depth  studies  on  health  and environ-
mental impacts  cf  selected water  pollutants.   U.S. Environ..
?rot.  Agency, Contract No. 68-01-4646.

U.S.  SPA.   1979a.   Phthalate Esters:    Ambient  Water Quality
Criteria  (Draft).

U.S.   EPA.   1979b.    Environmental  Criteria and  Assessment
Office. .Hazard'Profile:  Phthalate Esters  (Draft).
                               -JO ¥2-

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                                      No. 89
          Dinitrobenzenes
  Haaith and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                           DISCLAIMER
      This  report  represents a survey of  the  potential  health
 and  environmental  hazards  from exposure  to  the  subject  chemi-
 cal .   The  information- contained in the report is drawn chiefly
 from  secondary  sources  and  available  reference  documents.
 Because  of the limitations of such sources,  this short profile
 may  not  reflect all  available information including all  the
 adverse  health  and  environmental  impacts  presented  by  the
 subject  chemical.   This document has undergone scrutiny  to
•ensure its technical  accuracy.

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                                DINITROBENZENES

                                    Summary




     Du6 to  th8 lack of . availsole  infoTT'sticr'  no  assessment  of the octsn—

tial of dinitrobenzenes  to  producs carcinogenic effects,  mutsgenic effects,

teratogenic effects, or adverse reproductive effects can be made.

     Oinitrobenzene  is  the  most  potent  methemoglobin-forming  agent  of the

nitroaromatics and rapidly produces cyanosis in exposed populations.
                                                   •.
     Fish have been  acutely  affected  by  exposure to non-specified isomers of

dinitrobenzene at concentrations ranging  from 2,000 to 12,000 ug/1.
                                      /  -j

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                             •   DINITROBENZENE-


I.  INTRODUCTION


     This  profile  is  based  on  the   Investigation  of  Selected  Potential


Environmental Contaminants:  Nitroaromatics (U.S. EPA, 1976).


     The dinitrobenzenes exist as the ortho, meta, or  para isomers, depend-


ing on  the  position of the  nitro  group  substitutents.   Ortho-dinitrobenzene


(1,2-dinitrobenzene, M.W.  168.1)  is a white, crystalline solid  with a boil-


ing point  of  319°C,  a  melting point  of 11S°C,  and  a specific  gravity of


1.57.    Meta-dinitrobenzene  (1,3-dinitrobenzene)  is  a  yellow,  crystalline


solid  that  melts at  39-90°C,  boils  at  300-303°C,  . and  has  a  density of


1.55.    Para-dinitrobenzene  (1,4-dinitrobenzene)  is  a  white,  crystalline


solid with  a  boiling  point of  29S"C,  a melting  point of  173-174UC,  and a


density  of  1.63  (Windholz, 1976).   The  dinitrobenzenes  have low  aqueous


solubility and are soluble  in alcohci.


     The dinitrobenzenes. are-  used in  organic  synthesis,  the  pr:cuccion of


dyes,  and as a camphor substitute in.celluloid production.


     The  domestic  production   volume   of meta-dinitrobenzene   in  1572  was


approximately 6 x 103 tons  (U.S. EPA,  1976).


     Oinitrcbsnzanas are  generally stable in  neutral aqueous  solutions; as


the medium  becomes  more, alkaline they ~ay undergo  hydrolysis  (Murto,  1966).


Para-dinitrobenzene  will  undergo  photochemical  reduction  in  isoproparol


under  nitrogen,, but this  reaction is quenched  when  the solvent  is aerated


(Hashimoto and Kano, 1972).


     Biodegradation . of  dinitrobenzenes  .has been  reported  for  acclimated


microorganisms (Chambers, et al. 1963;  Bringmann and Kuehn,  1959).
                                                                         9

     Based  on  the octanol/water  partition coefficient,  Neely et  al.  (1974)


have estimated a low bioconcentration  potential  for the dinitrobenzenes.

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II .   EXPOSURE
     Industrial  dinitrobenzene  poisoning  reports  have- shown  that  workers
will develop  intense cyanosis  with only  slight exposure  (U.S.  EPA, 1976).
Exposure  to  sunlight  or  ingestion  of  alcohol  may  exacerbate  the  toxic
effects of dinitrobenzene exposure  (U.S. EPA,  1976).
     Monitoring- data on  levels of  dinitrobenzenes  in  water, air,  or  food
were  not  found  in   the  available  literature;  human  exposure  from  these
sources cannot be evaluated.
III. PHARMACOKINETICS
     A.  Absorption
          Methe.T.oglcbin  formation  in v/crksrs exposed to dinitrobenzene indi-
cates  that  absorption  of the  compound  by  inhalation/dermal  routes  occurs.
Animal  stuoies  demonstrate  tnat oinitrooenzene  is  absorbed  following  oral
     B.  Distribution
          Pertinent  information on  Distribution of  dinitrcbenzenss  was not
found in the available literature.
     C.  Metabolism
          Dinitrocsnzene  undergoes both  metabolic reduction  ard oxidation .
.-•-linal  studies  indicate  that the major  reduction  productions fallowing oral
dinitrobenzene  administration were  nitroaniline and  phenylene  diamine (35%
of the  administered  dose)  (Parke,  1961).   The major oxidative metabolites of
meta-dinitrobenzene   were   2,4-diaminophenol  (31%   of   initial  dose)  and
2-amino-A-nitrophenol  (1455 of initial dose).   The phenols  are  further con-
jugated as giucuronides or etheral sul fates  (Parke, 1961).

-------
     0.  Excretion
          Oral   administration  of   radiolabelled   meta-dinitrobenzene   to
rabbits was  followed  by elimination of 65-93%  of the -dose  within two  days.
Excretion was  almost  entirely via the urine;  1-5% of the administered  label
was determined in the fecss (Parks, 1961).
IV.  EFFECTS
     A.  Carcinogenicity
          Information on  the Carcinogenicity of  the dinitrobenzenes was not
found in the available literature.
     B.  Mutagenicity
          Information  on  the mutagenicity . of the  dinitrobenzenes  was not
found  in  the available  literature.  The  oossible dinitrobenzene rnetsco'its
dinitropnenoi ~\u'.S. EPA,  1979),  has  been  reported to induce chromatid breaks
ir, bone marrow ceils of injected'mice (Micra anc-Manna. 1971).
     C.  TeratoGsnicicy
          Information on  tne  teratogenicity  of the  dinitrobenzenes was not
found  in  the .available  literature.  The  oossible dinitrobenzene rnetaoolite,
dinitropnenoi  ";>S.  EPA,  1979), has produced  developmental abnormalities  in
the sea urchin (Hagstrom  and  Lonning,  1966).   No  effects were sesr,  foilov/ing
i~jecti-n cr crai sc.T.ir.istraticn cf ciinitrophenoi  to mice (Gibson, 1973).
     0.  Other Reproductive Effects
          Pertinent information was not found in the available literature.
     E.  Chronic Toxicity
          Dinitrobenzene  is  the most  potent methemoglobin-forming  agent  of
the  nitroaromatics.   Poisoning  symptoms   in  humans  may  be potentiated  by
exposure to sunlight or ingestion of alcohol (U.S. EPA. 1976).
                                       ,/

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V.   AQUATIC TOXICITY


          A.  Acute Toxicity

               McKee and Wolf  (1963)  have presented a  brief  synopsis of the

toxic effects of dinitrcbenzer.es to aquatic  life.   A study by LeClerc (1960)

reported lethal  doses  of non-specific isomers  of  dinitrobenzene for minnows

(unspecified) at concentrations  of 10,000 to 12,000 ug/1  in  distilled water

or 8,000 to  10,000 pg/1  in  hard  water.   Meinck et al.  (1956) reported lethal

concentration of•2,000 jug/1 for unspecified dinitrobenzenes  for an unspeci-
                                                   ».
fied fish species.

     8.  Chronic Toxicity

          Pertinent  data could  not  be  found  in  ths  available  iitp^stu^s

regarding aquatic toxicity.

     C.  Plant Effects

          Howard et ai.  (i^7o) report  that  the  sigae Chlorella sp. aisplayec

inhibited  phciosynthetic activity  upon  exposure  to  m-dinitrocenzers at  s

concentration of 1C"  M.

VI.  EXISTING GUIDELINES

     The 8-hour  time-weighted-average  (TWA) occupational  exposure limit for

dinitrobenzenes is 0.15 pprn(ACGIH, 1974).
                                      A

-------
                                DINITROBENZENES

                                  References
ACGIH.   1974.   Committee  on  threshold - limit  values:  Documentation  of the
threshold limit values for substances in the workroom air._ Cincinnati, Ohio.

Bringmann, G.  and R. Kuehn.   1959.   Water toxicity  studies  with protozoans
as test organisms.  Gesundh.-Ing.  80: 239.

Chambers, C.W.,  et al.  1963.   Degradation of aromatic  compounds-by pheno-
ladopted bacteria.  Jour. Water Pollut. Contr. Fedr. 35: 1517.

Gibson,  J.E.   1973.   Teratology  studies  in mice with 2-sec-Sutyl-4,- 6-dini-
trophenol (Dinoseb).  Fd. Cosmet. Toxicol.  11: 31...

Hagstrom, 8.E.  and S. Lonning.  1966.  Analysis  of the effect of  -Dinitro-
phenol on  cleavage and development  of the sea urchin  embryo.  Protoplasma.
42(2-3): 246.

Hashimctc, S.  and K.  Xano.   1972.   Photochemical  reduction  of nitrobenzene
and  reduction  intermediates.    X.    Photochemical   reduction  of  the  mono-
substit'Jtsd nitre-benzenes in 2-propanol.  Bull. Chem. Soc. Jap.  45(2): 549.

Howard,  P.M.,  et  al.  .1976.   Investigation  cf selected  potential  environ-
mental  contaminants:  Nitrcsrcmatics.   Syracuse-,  N.Y.:   Syracuse  Research
Corporation,  TR 75-57'3.

LeClerc,   E.   I960.   Self  purification of  streams  and the  relationship be-
tween  chemical and  biological  tests.   2nd  Symposium' on  the  Treatment  of
Waste Waters.  Peraamon Press, p. 232.

McKee, J.E.  and  H.W. Wolf.   1963.   Water  quality criteria.   The  Resource
Agency of California  State Water Quality Control Board Publication No. 3-A.

Meinck.,  F.,  et al.   1956.   Industrial waste water.  2nd ed.  Gustav Fisher
Verlsg Stutgsrt, o. 536.

Micra, A.B.  and  G.K. Manna.   1971.   Effect  of  some  phenolic compounds  on
chromosomes of bone marrow, cells on mice.  Indian J. Med.  Res.  59(9): 14^2.

Murto, J.  1966.   Nucleophilic  reactivity.   Part 9.  Kinetics .of  the reac-
tions  of  hydroxide  ion  and  water  with  picrylic  compounds.  Acta  Chem.
Scand.  20: 310.

Neely,  W.8.,   et   al.   1974.    Partition coefficient  to   measure  bicconcsn-
tration  potential of •organic  chemicals in  fish.    Environ.  Sci.  Technol.
8: 1113.
                                                                         »

Parke,  D.W.    1961.    Detoxication.   LXXXV.   The  metabolism  of  m-dinitro-
benzene-C14 in the rabbit.  Biochem. Jour.  78: 262.

-------
U.S. EPA.   1976.   Investigation  of selected potential  environmental  contam-
inants:  Nitroaromatics.

U.S. EPA.   1979.   Environmental  Criteria and  Assessment  Office.   2,4-Oini-
trophenol:   Hazard Profile  (Draft).

Windhclz, M.  (ed.)   1975.   The Merck Index.  9th sd.  Merck and  Co.,  Inc.,
Rahway, N.J. p.  3269.
                                     'I OS I-

-------
                                      No.  90
        4,6-Dinitro-o-cresol
  Haaich and Environnantal Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents a survey of  the  potential  health
and environmental hazards from exposure  to the  subject  chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources   and   available  reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all  available information including all  the
adverse health  and  environmental  impacts presented  by  the
subject chemical.  This  document has  undergone scrutiny  to
ensure its technical  acc-uracy.
                           -/QS3-

-------
                    4,6-DINITRO-O-CRESOL



                           SUMMARY



     There is no available evidence to indicate that 4,6-



dinitro-ortho-cresol (DNOC) is carcinogenic.



     This compound has produced some DNA damage in Profceus



mirabilis but failed to show mutagenic effects in the Ames



assay or in Jj. coli.  Available information does not



indicate that DNOC produces teratogenic or adverse



reproductive effects.



     Human exposure incidents have shown that DNOC produces



an increase in cataract formation.
                                  -/05Y-

-------
                     4,6-DINITRO-G-CRESOL




I.   INTRODUCTION



     This profile  is  based  on  the  Ambient Water Quality Cri-



teria Document for Nitrcphenols  (U.S.  EPA, 1979a).



     Dinitrocrescls  are  compounds  closely related  to the di-



nitrophenols; they bear  an  additional  2-position methyl



group.  The physical  properties  of 4,6-dinitro-ortho-cresol



(DNOC, M.W. 198.13)  include a  melting  point of  35.8°C and a



solubility of 100 mg/1  in water  at 20°C  (U.S.  EPA,  1979a).



     Dinitro-ortho-cresol is used  primarily as  a blossom



thinning agent on fruit  trees  and  as  a fungicide,  insecticide



and micicide on  the  fruit trees  during the dormant  season.



There is no record of  current  domestic manufacture  of DNCC



(U.S. EPA, 19792).   For  additional information  regarding the



nitrcphenols in  general,  the reader is referred to  the Hazarc



Profile on Kitrophanols  (U.S.  EPA, 1979b).



II.  EXPOSURE



     The lack of monitoring data makes it difficult to assess



exposure from water,  inhalation, and  foods.  DNOC has been



detected at 13 rr,g/l  in effluents from  chemical  olants (U.S.



EPA, 1979a).



     Exposure to DNOC appears  to be primarily  through occupa-



tional contact (chemical manufacture,  pesticide application).



Contaminated water may result  in isolated poisoning inci-



dents.



     The U.S. EPA (1979a) has  estimated  a weighted  average



biocon.centration factor  for DNOC to be 7.5  for  the  edible



portions of fish and shellfish consumed  by  Americans.   This



estimate is based on the octanol/water partition coefficient.

-------
III. PHARMACOKINETICS



     A.   Absorption



          DNOC is readily absorbed  through  the  skin,  the res-



piratory tract, and the gastrointestinal  tract  (NIOSH,



1978).



     B.   Distribution



          DNOC has been found  in  several  body  tissues;  how-



ever, the compound may be bound to  serum  proteins,  thus pro-



ducing non-specific organ distribution  (U.S. EPA,  1979a).



     C.   tMetabolism



          Animal studies on  the metabolism  of DNOC indicate



that like che nitrophenols,  both  conjugation of  the  compound



and reduction of the nitro groups  to  amino  groups  occurs.



The metabolism of CMOC to 4-amino-4-nitro-o-crasiol  is  a de-



toxification mechanism that  is effective  only when  tcxic



doses of CNOC are administered (I*.3.  EFA, 1979a) .   The



metabolism of DNOC is very slow in  man  as compared  to  that



observed in.animal studies (King  and  Harvey, 1953).



     D.   Excretion



          The experiments of Parker and coworkers  (1951) in



several animal species indicates  that DNOC  is rapidly  ex-



creted following injection;  however,  Harvey, et  al.  (1951)



have shown slow excretion of DNOC  in  volunteers  given  the



compound orally.  As in metabolism, there is a  substantial



difference in excretion patterns  of humans  vs.  experimental



animals.

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IV.  EFFECTS



     A.   Carcinogenicity




          Pertinent data could  not  located  in  the  available




1iterature.



     3.   Mutagenicity



          Adler, et al.  (1976)  have  reported  that  DNOC shows



some evidence of producing  CNA  damage  in  Proteus mirabilis.



Testing of this compound in the Ames Salmonella  system



(Anderson, et al., 1972) or in  E. coli (Nagy,  et al.,  1975)



failed to show any mutagenic effects.



     C.   ^eratocjenicitv and Other  Reproductive  Effects



          Pertinent data could  rjot  be  located  in the



available literature  regarding  teratogenicity  and  other



reproductive effects.



     D.   Chroni'c Tcxicity



          Human use of DNOC as  a dieting  aid  has produced



poisoning cases at accepted  the'reputic  dose levels, as well



as some cases of cataract development  resulting, from



overdoses (NIOSH, 1978).



     £.   Other Relevant Information



          DNOC is an uncoupler  of oxidative phosphorylation,



an effect which accounts for its high  acute toxicity  in



mammals.



V.    AQUATIC TOXICITY



     Pertinent information  could not be located  in the



available literature.

-------
VI.  EXISTING GUIDELINES AND STANDARDS



     A.   An eight-hour TLV exposure limit  of  0.2  mg/m^  has



been recommended for DNOC by the ACGIH  (1971).



          A preliminary draft water criterion  for  DNOC has



been established at 12.3 ug/1 by the U.S. EPA  (iS79a).   This



draft criterion has not gone through the process of ~public



review? therefore, there is a possibility that  the criterion



may be changed.



     B.   Aquatic



          Criteria for the protection of freshwater  and



marine aquatic organisms were not drafted due  to lack,  of



toxicological evidence (U.S. EPA, 1979a) .

-------
VI.  EXISTING GUIDELINES AND  STANDARDS



     A.   An eight-hour TLV exposure  limit  of  0.2 mg/m^  has



been recommended for DNOC by  the ACGIH  (1971).



          A preliminary draft water criterion  for DNOC has



been established at 12.3 ug/1 by the  U.S. EPA  (137Sa).   This



draft criterion has not gone  through  the process of  public



review; therefore, there is a possibility that  the criterion



may be changed.



     B.   Aquatic



          Criteria for the protection of freshwater  and



marine aquatic organisms were not drafted due  to lack of



toxicological evidence (U.S.  SPA, I979a).

-------
                                     No. 91
         2,4-Dinitrophenol
  Health and  Environmental Effects
U.S.  ENVIRONMENTAL  PROTECTION AGENCY
       WASHINGTON,  D.C.  20460

           APRIL  30, 1980
                -ID to -

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This, document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                        2,4-DINITROPHENOL



                             Summary



     There is no  evidence  to indicate that 2,4-dinitrophenol  pos-



sesses carcinogenic activity.



     Genetic toxicity  testing  has  shown positive effects  in mouse



bone marrow  cells and in E_-_ coli.   In vitro  cell culture assays



failed to show the potential for  mutagenic  activity of 2,4-dinitro-



phenol as measured by unscheduled DNA synthesis.



     Teratogenic  effects  have been  observed  in  the  chick embryo



following administration of  2,4-dinitrophenol.  Studies  in mammals



failed to show that the compound produced any  taratcgenic  effects.



At the levels of compound used in these mammalian studies, embryo-



toxic offsets were observed.



     Human, use- of  2,4-dinitrophenol  as  a  dieting aid has  produced



some cases of agranuiocytosis,  neuritis,  functional heart damage,



and cacaract development.



     For  aquatic  organisms  LC^Q values  ranged from  520 jag/1  for



the bluegill to 16,700 ug/1  for the fathead minnow.

-------
                        2,4-DINITROPHENOL


I.    INTRODUCTION


     This profile  is  based on  the  Ambient Water Quality Criteria


Document for Nitrophenols  (U.S. EPA, 1979a).


     The dinitrophenols are  a family of compounds composed of  the


isomers resulting from nitro-group substitution of phenol at vari-


ous positions.  2,4-Dinitropheriol has a molecular weight of 184.11,

a melting point of  114-115°C,  a density of 1.683 g/ml  and is sol-


uble in water at 0.79 g/1  (U.S. EPA, 1979a).


     The dinitrophenols  are  used as  chemical  intermediates   for

sulfur dyes,  azo  dyes,  photochemicals,  pest  control agents, wood

preservatives, and  explosives.  (U.S. EPA,  i979a) .   The. 1963 pro-


duction of  2,4-dinitrophenol was  4.3  x Id44  tons/yr.    (U.S. EPA/

1979a).


     For  additional  information  regarding  the  nitrophenols  as

a class, the  reader is referred  to  the Hazard  Profile on Nitro-


phenois (1979b).


II.  EXPOSURE


     The lack of  monitoring  data  for  the nitrophenols makes  it

difficuic to  assess exposure  from  wacer,   innaiacion,  and roods.

Nitrophenols  have  been detected in effluents from chemical plants


(U.S. SPA,  1979a) .   Dermal  absorption of  the  dinitrophenols   has

been reported (U.S. EPA,  1979a).


     Exposure  to   nitrophenols appears  to  be  primarily  through

occupational  contact  (chemical  plants,   pesticide  application) .
                                                             •
Contaminated water may contribute to isolated poisoning  incidents.

The  U.S. EPA (1979a) has  estimated the weighted  average biocon-


centration  factor  for  2,4-dinitrophenol to be  2.4  for  the edible

-------
portions of  fish and  shellfish  consumed  by Americans.  This esti-

mate  was  based  on the  octanol/water  partition  coefficients  of

2,4-dinitrophenol.

III. PHARMOCOKINETICS

     A.   Absorption

          The dinitrophenols are  readily  absorbed following oral,

inhalation, or dermal administration  (U.S. EPA, 1979a).

     3.   Distribution

          Dinitrophenol  blood  concentrations  rise  rapidly after

absorption, with little subsequent distribution or storage at tis-

sue sites  (U.S. EPA, 1979a).

     C.   Metabolism

         • Metabolism of  the  nitrophenols  occurs  through  conjuga-

tion and reduction  of nitre-groups  to  aminc-groups, or oxidation to

dihydric.-nitrochenols (U.S. EFA, I979a) .

     D.   Excretion

          Experiments with several animal species  indicate that

urinary clearance of dinitrophenols is rapid (Harvey, 1959).

VI.  EFFECTS

     A.   Carcinogenicity

          2,4-Dinitrophenol  has  been  found not  to  promote skin

tumor  formation  in mice following  DMBA  initiation  (Bautwell  and

Bosch, 1959) .

     B.   Mutagenicity

          Testing  of   2,4-dinitrophenol   has   indicated  mutagenic
                                                             »
effects in  E.  coli (Demerec,  et  al.  1951).   ^n  vitro  assays  of

unscheduled  DNA synthesis  (Friedman  and  Staub,   1976)  and  DNA

-------
damage  induced  during  ceil culture (Swenberg, et  al.  1976)  failed

to show the potential  for rnutagenic activity  of  this  compound.

     C.   Teratogenicity

          2,4-Dinitrophenol has been  shown  to produce development-

al aonormalities  in  the  chick embryo (Bowman, 1967;  Miyatmoto,  et

al. 1975).   No teratogenic effects were seen following intragastric

administration  to rats  (Wulff, et  al.  1935) or intraperitoneal  ad-

ministration to mice (Gibson,  1973).

     D.   Other Reproductive  Effects

          Feeding of 2,4-dinitrophenol  to  pregnant  rats  produced

an  increase  mortality  in  offspring  (Wulff,  et  al.,   1935);  simi-

larly ,  intraperitoneal -administration  of  the  compound  to mice

induced  embryotoxicity  (Gibson,   1973).   .The  influence  of this

compound .OP. maternal health niav have  contributed to these  affects.

     E.   Chronic Toxicity

          Use of  2,4—dinitrophenol as  a  hurr.sr. dieting aid  has pro-

duced  some  cases .of agranulocytosis,  neuritis, functional  heart

damage, and  a  large number  of -patients  suffering from cataracts

(Horner, 1342).

     F.   Other Relevant Information

          2,4-Dinitrophenol  is a  classical uncoupler  of oxidative

phosphorylation,  an  effect   which accounts   for   its  high  acute

toxicity in mammals.

          A  synergistic action  in producing ' teratogenic  effects

in  the  developing chick embryo has been  reported with a  combina-
                                                             »
tion of 2,4-dinitrophenol and  insulin  (Landauer  and Clark,  1964).

-------
V.   AQUATIC TOXICITY
     A.   Acute
          The  bluegill  (Lepomis macrochirus)  was  the most  sensi-
tive aquatic organism tested, with an LC^Q of 620 pg/l in  a  static,
96-hour assay  (U.S.  EPA,  1978).   Juvenile fathead minnows  (Piine-
phales promelas) were more  resistant in  flow through tests,  with
an LC5Q of  16,720  ug/1  (Phipps, et  al.   manuscript).  The  fresh-
water  cladoceran  (Daphnia  magna)  displayed  a range  of  observed
LC5Q  values of  4,090   to  4,710  ;ig/l  (U.S.  EPA,  1979a) .   Acute
values  for  the marine  sheepshead minnow  (Cyprinodon variegatus)
are  LC--  values  ranging  from.  5,500   to  29,400   pg/1 (Roser.thal
and  Stelzer,  1970).   The  marine mysid  shrimp (Mysidcpsis  bahia)
had an LC5Q of 4,350 ug/1 (U.S. EPA, 1978).                       i
     B.   Chronic Toxicity
          Pertinent.  data . could • net  be  located, in-  the   available
literature.
          p
          Effective  concentrations  for  freshwater  plants   ranged
from  1,472  ^pg/'l for ducKweed  (Lemna  minor)  to   50,000  ,ug/l   for
the  alga- (Chlorella  oyrenoidosa)  (U.S.  EPA,  1979a)  .   The  marine
alga  (Skeletonema  costatum)  was more  resistant   with  a  reported
96-hour EC5Q value based on cell numbers of 98,700 pg/1.
     D.   Residues
          Based on the octanol/water partition coefficient,  a  bio-
concentration  factor of 8.1  has  been  estimated  for  2,4-dinitro-
phenol for aquatic organisms with a lipid content  of 8 percent.

-------
V.   EXISTING GUIDELINES AND STANDARDS



     Neither the human health nor aquatic criteria derived by U.S.



EPA (1979a)  which are  summarized below have undergone the process of



public review;  therefore,  there  is a .possibility that  these criter-



ia will be changed.



     A.   Human



          The  draft  water  criterion   for  dinitrophenols ,  based



on  data  describing .adverse effects,  has been  estimated by  the



U.S. EPA (1979a) as 68.6 ug/1.



     B.   Aquatic



          For protecting  freshwater  aquatic  life,  the  draft cri-



terion is 79 ug/1 as a 24-hour avetage concentration noc to exceed



130  ug/1.    The  marine  criterion has  been  proposed as  37  pg/I



as  a  24-aour average .not  to  exceed  34  ug/1  at  any  time  (U.S.
          To  protect saltwater  life,  the  draft  criterion  is  37



ug/1 as a 24-hour  average  not  to exceed  84  pg/1 at any time (U.S.



EPA, 197 9 a) .
                                '-1067-

-------
                        2,4-DINITROPHENOL

                            REFERENCES


Bautwell, R. ,  and D.  Bosch.    1959.   The  tumor-promoting action
of  ohenol  and  related compounds  for mouse  skin.    Cancer   Res.
19: "413.

Bowman, P.  1967.   The effect of 2,4-dinitrophenol on  the develop-
ment of early chick embryos.  Jour. Embryol.  Exp.  Morphol.  17:  425.

Demerec,  M.,  et al.  1951.   A survey of chemicals for mutagenic  ac-
tion on E.  coli.  Am. Natur. 85: 119.

Friedman, M.A., and  J.  Staub.  1976.   Inhibition of mouse testicular
DNA  synthesis  by mutagens  and  carcinogens  as a potential simple
mammalian assay for  mutagenesis.  tMutat.  Res.   37: 67.

Gibson, J.E.  1973.  Teratology  studies in mice  with 2-secbutyl-4,
5-dinitrop'nenol  (dincseb) .  Food Cosmet.  Tcxicol.  11: 31.

Harvey, D.G.  1959.  On  the  metabol-ism of  some aromatic nitro com-
pounds oy different species of animal.  Part III.  The toxicity of
the dinitrophenols,  with a note  on  the .effects of high  environment'*-
al temperatures.  Jour. Pharm. Pharmacoi.   11: 452.

Homer,. W.D.  1942.  Dinitrophenol and its  relation co  formation of
cataracts.   Arch. Cphthal.  27:  1097.

Landauer, W.  ,  and E.  Clark. 1964.   iJncoupiers of  oxidative phos-
phorylation  and teratcgenic activity of  insulin.   Nature 204: 285.

Miyamoto, K., et ai. 1975.  Deficient myelination by 2, 4-dinitro-
phenol administration  in  early  stage of development.   Teratology
12: 204.
phenols to the fathead minnow.  (Manuscript).

Rosenthal, H. , and R. Stelzer.  1970.   Wirkungen von 2,4-und 2,5-
dinitrophenol  auf  die   Embryonalentwicklung  des  Herings  Clupea
harengus.  Mar. Biol.  5: 325*.

Swenberg, J.A., et al.  1976.   In  vitro DNA damage/akaline elution
assay  for  predicting carcinogenic  potential.,   Biochem.  Biophys.
Res. Ccmmun.   72:  732.

U.S. EPA.  1979a.   Nitrophenols:   Ambient water quality criteria.
(Draft).

U.S. EPA.   1979b.   Nitrophenols:    Hazard Profile.   Environmental
Criteria and Assessment Office (Draft).

-------
U.S. EPA.   1978.   In-depth studies  on health and  environmental
impacts of selected water pollutants.   Contract No.  68-01-4646.

Wulff,  L.M.3., et al.  1935.  Some  effects  of  alpha-  dinitrophenol
on pregnancy in the white rat.  Proc. Soc. Exp. Biol.  Med.   32: 678.
                                  ~/D £?~

-------
                                      No.  92
           Dinitrotoluene
  Health and Environmental  Effects
U.S. ENVIRONMENTAL  PROTECTION AGENCY
       WASHINGTON,  D.C.   20460

           APRIL 30,  1980
           -/D 70 -

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such  sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny  to
ensure its technical accuracy.

-------
                        DI'NITROTOLUENE



                           SUMMARY



     Most of the information on the affects of dinitrotoluene



deals wich 2,4-dinitrocoiuene.  2,4-Dinitrotoluene induces



liver cancer and mammary tumors in mice and is mutagenic



in some assay systems.  Information on teratogenicity was



not located in- the available literature.   Chronic exposure



to 2,4-dinitrotoluene induces liver damage, jaundice, methemo-



globinemia and anemia in humans and animals.



     Acute studies in freshwater fish and invertebrates



suggest that 2,3-dinitrotoluene is much more toxic than



2,4-dinitrotoluene.
                                -ib 73.

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                        DINITROTOLUENE



I.   INTRODUCTION



     This profile  is  based on the Ambient Water Quality



Criteria Document  for Dinitrotoluene (U.S. SPA, 1979).



     There are  six isomers of dinitrotoluene (CK,C,H3  (N0~)~;



molecular weight 182.14),  with the 2,4-isomer being the



most important  commercially.   2,4-Dinitrotoluene has a melt-



ing point of  7i°C,  a  boiling  point of 3GO°C with decomposi-



tion, and a solubility in  water of 270  mg/1 at 22°C.  It



is readily soluble in ether,  ethanol, and carbon disulfide



(U.S. EPA. 1979).   2,6-Oinitrotoluene has a melting point


     o
of 56 C and is  soluble in  alcohol.  Production in 1975 was



.273 x 1C  tons  per  year  for the 2,4- and 2,6- isomers com-







     Dinitrotoiuene  is an  incr.ecient of explosives fcr conurier-


„;_! ,_^_.:i.•;_.,.,.,  ,,__   - ~l	„.:,,_ i  _ 4. - u ;•!.•-,	:_ i.i	.. s	
	i^. anC -4_ — _ -.ij. _/  ^ —o,  — _..-;.., ^^^-j. o _^_ ^ ^. j. i*a. ±. n -.nc ;.n.\»iu-aw-



iure of smokeless  powder,  an  intermediate in the manufacture



of toluene diisocyanatas used ir.  the production of urethane



polymers, and a raw material  for  che manufacture of dyestuffs.



Dinitrotolusnes are  relatively stable at ambient tempera-



tures (U.S. EPA, 1979) .



II.  EXPOSURE



     A.   Water



          Data  on  concentration levels  for Sinitrotoluene



were not available.   Dinitrotoluene waste products are dumped



into surface water or  sewage  by industries that manufacture



dyes, isocyanates, polyurethanes  and munitions (U.S. EPA,



1979) .
                                -JO 73

-------
     B .   Food

          According  to  the  U.S.  EPA (1979),  the likelihood

of dinitrotoluene  existing  in food is minimal since it is

not used as  a pesticide  or  herbicide.

          The U.S. EPA  (1979)  has estimated  the weighted

average bioconcentration factor  for 2 , 4-dinitrotoluene to

be 5.5 for the  edible portions of fish and shellfish consumed

.by Americans.   This  estimate  is  based en the octanol/water

partition coefficient.

     C.   Inhalation

          Exposure to dinitrotoluene by inhalation is most

likely to occur  occupationaiiy (U.S. EPA,  1979) . ^- 'However ,

pertinent data  could not be located in the available litera-

curs ~n atmospheric  ccnc3~ tra~icr3 cf dini trctc-lusr.a an~,

thus,  oossibls  human exec-sure canncc be 35 tirr.Hisc .
""
     A.   Absorption

          The  absorption  of  ""C-labeled isomers -...  dinitrotol-

uene after oral  adrninistracion to rats  was essentially com-

plete within 24  hours,  with  50 to 90  percent of the dose

being absorbed.   The  2,4- and  3,4-isomers were absorbed

to .a greater extent  than  the 3,5- and 2,5- isomers, which

in turn were absorbed to  a greater extent than the 2,3-

and 2,6-isomers  (Hodgson,  et al.  1977).   2 ,'4-Dinitrotoluene

is known  to be absorbed through the respiratory tract and
                                                           »
skin (U.S.. EPA,  1979).

-------
     B.   Distribution .



          Tissue/plasma ratios of radioactivity  after adminis-


           14
tration of   C-labeled dinitrotoluene  to rats  indicated


             14
retention of   C DMT in both  the liver and  kidneys  but not



in other tissues (Hodgson, et al., 1977).   A similar experi-



ment with tritium-labeled 2,4-dinitrotoluene  ( H-2,4-DNT)



in the rat showed relatively  high amounts of radioactivity



remaining in adipose tissue,  skin, and liver seven  days



after administration (Mori, et al., 1977).



     C.   Metabolism



          No studies characterising the metabolism  of dinitro-



toluene in mammals are available-.  However, on the  basis



of a comparison of the metabolism of 2,4-dinitrotoluene



and 2,4,o-trinitrotoluene in  microbiai syscems,  and the



:
-------
IV.  EFFECTS



     A.   Carcinogenicity



          2,4-Dinitrotoluene fed to rats and mice for two



years produced dose-related increases in fibrc-isas of the



skin in male rats and fibroadenomas of the mammary gland



in female rats.  All of these were benign tumors.  No statis-



tically significant increase in tumor incidence was noted



in mice (Natl. Cancer Inst., 1978).



          In a second bioassay of rats and mice fed 2,4-



dinitrotoluene for two years, the findings in rats included



a significant increase of hepatoceiluiar carcinc-as and



neoplastic nodules in the livers.of females, a significant



increase of mammary gland tumors in females, and a suspicious



ir.craase or hapacoceliular carcinomas of the liv<=r in maj.es.



Male mice had a highly significant increase cf ,\i.cney tumors



{Lee, at al., 1973) .



     3.   Mutagenicity



          2,4-Dihitrotoluene was mutagenic in the dominant



lethal assay and in Salmonella typhimurium strain TA1535



(Hodgson, et ai. 1976).  Cultures of lymphocytes and kidney



cells derived from rats fed 2,4-dinitrotoluene had signifi-



cant increases in the frequency of chromatid gaps but not



in translocations or chromatid breaks (Hodgson, et al.,



1976).



          The.mutagenic effects of products from ozonation
                                                          »


or chlorination of 2,4-dinitrotoluene and other dinitrotoluenes
                                •1676-

-------
were negative in one study  (Simmon,  et al.,  1977),  and,


for products of ozonation alone, were ambiguous  in  another


study (Cotruvd, et al., 1977).


     C.    Teratogenicity and other Reproductive  Effects


          Pertinent data could not be located  in the  avail-


able literature.


     D.    Chronic Toxicity


          Chronic exposure  to 2,4-dinitrotoluene may  produce


liver damage, jaundice, methemoglobinemia  and  reversible


anemia with reticulocytosis in humans and  animals  (Linch,


1974; Key, et al. 1977; Proctor and  Hughes,  1978; Kovalenko,


1973).              •. •


     E.    Other Relevant Information


          Animals were more resistant, to the toxic  effects


of 2,4-dinitrotoluene administered in the  diet when given


diets high in fat or-..protein (Clayton and  Bauraann,  1944,

                    . ;) "
1948; Shils and Goldwater,  1953) or  protein  (Shils  and Gold-


water, 1953) .      •'.")


          Alcohol has a synergistic  effect on  the toxicity


of 2,4-dinitrotoluene  (Friedlander,  1900; McGee,  et al.,


1942).


          In subacute studies (13 weeks),  2,4- and  2,6-dini-


trotoluene caused methemoglobinemia, anemia with  reticulocyto-


sis, gliosis and demyelination in the brain', and  atrophy


with aspermatogenesis of the testes  in several species  (Ellis,
                                                          •

et al.,.1976).

-------
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Static assays with  the freshwater  bluegill  (Lepomis
macrochirus) produced a 96-hour LC5Q value of  330 jag/1  for
2,3-dinitrotoluene  (U.S. EPA, 1978), while the  same assay
with the fathead minnow (Pimephales promelas) produced  a
96-hour LC   value of 31,0.00 }ig/l  for 2,4-dinitrotoluene
(U.S. Army, 1976).  The greater toxicity of  2,3-dinitrotoluene
when compared to that of 2,4-dinitrotoluene, was demonstrated
in 48-hour static assays with the  freshwater cladoceran,
Daphnia magna, with LC5Q values of  660 pg/l(U.S. EPA,. 1978).
and 35,000 pg/1 (U.S. Army, 1976)  being reported.  A single
marine, fish, sheepshead minnow  (Cyprinodon variegatus),
has been tested for adverse acute  effects of 2,3-dinitro-
toluene.  A 96-hour static assay LCeg value of  2,280 pg/1
was reported (U.S. EPA, 1978).  For marine invertebrates
a 96-hour static LC5Q value of  590 pg/1 was obtained for
the mysid shrimp (Mysidopsis bahia) with 2,3-dinitrotoluene.
     B.   Chronic Toxicity
          The sole chronic study examining the  effects  of
2,3-dinitrotoluene in an embryo-larval assay on the fathead
minnow produced a chronic value of  116 pg/1 based, on reduced
survival of these stages.  No marine.chronic data were  pre-
sented (U.S. EPA,  1979).
     C.   Plant Effects
                                       i           •         *
          Concentrations of 2,3-dinitrotoluene  that caused
50 percent adverse effects in cell  numbers or chlorophyll

-------
a in the freshwater algae, Selenastrum capricornutum, were
1,370 or 1,620 ug/1, respectively.  These same effects mea-
sured in the marine algae, Skeletonema costatum,  showed
it to be more sensitive.  EC5Q values were 370 or 400 ug/1,
respectively.
     D.   Residues
          A bioconcentration factor of 19 was obtained for
aquatic organisms having alipid content of 8 percent  (U.S.
EPA, 1979).
VI.  EXISTING STANDARDS AND GUIDELINES
     Neither the human health nor aquatic criteria derived
by U.S. EPA  (1979), which are summarized below, have gone
through the process of public review; therefore,  there is
a possibility that these criteria may be changed.
     A.   Human
          Based on the induction of fibroadenomas of the
mammary gland in female rats  (Lee, et al., 1978), and using
the "one-hit" model, the U.S. EPA  (1979) has estimated levels
of 2,4-dinitrotoluene in ambient water which will result
in specified risk levels of human cancer:

Exposure Assumptions         Risk Levels and Corresponding Draft  Criteri
      (Per day>oi(T7      Iu^   'IJT*
2 liters of drinking water and       7.4 ng/1   74.0 mg/1  740  ng/1
consumption of 18.7 grams fish
and shellfish.
Consumption of fish and shell-      .156 ug/1  1.56 pg/1  15.6  jug/1
fish only.

-------
          The American Conference of Governmental  Industrial
Hygienists (1978) recommends a TLV-time weighted average
for 2,4-dinitrotoluene of 1.5 mg/m  with a short term expo-
sure limit of 5 rag/m .
     B.   Aquatic
          A criterion to protect freshwater life has been
drafted as 620 ug/1 for a 24-hour average not to exceed
1,400 ^ig/1 for 2.4-dinitrotoluene and 12 ug/1 not  to exceed
27 ug/1 for 2,3-dinitrotoluene.  For marine environments
a criterion has been drafted for 2,3-dinitrotoluene as a
4.4 ug/1 as a 24-hour average not to exceed 10 ^ig/1.  Data
was insufficient to draft a criterion for 2,4-dinitrotoluene
for marine environments.

-------
                                OINITROTOLUENE
                                  REFERENCES
American  Conference of  Governmental  Industrial  Hygienists.   1978.   TLV's:
Threshold  limit  values  for  chemical substances  and  physical  agents  in the
workroom environment with intended changes for 1978.

Clayton, C.C.  and  C.A. Baumann.  1944.  Some  effects of diet  on the resis-
tance of mice toward 2,4-dinitrotoluene.  Arch. Biochem.  5: 115.

Clayton, C.C.  and  C.A.  Baumann.   1948.   Effect of fat and calories  on the
resistance of mice to 2,4-dinitrotoluene.  Arch. Biochem.  16:  415.

Cotruvo, J.A., et  al.  1977.   Investigation  of mutagenic effects of products
of ozonation reactions in water.  Ann. N.Y. Acad. Sci.  298: 124.

Ellis, H.V.,-III,  et al.  1976.   Subacute  toxicity of 2,4-dinitrotoluene and
2,6-dinitrotoluene.   Toxicol.  Appl.  Pharmacol.    37:  116.   (Abstract  from
15th Ann. Meet. Soc. Toxicol., March 14-18.)

Friedlander,  A.   1900.  On  the clinical  picture  of poisoning with  benzene
and toluene  derivatives  with  special  reference  to the  so-called anilinism.
Neurol. Centrlbl.  19: 155.

Hodgson,  J.R.,  et  al.    1976.   Mutation  studies  on  2,4-dinitrotoluene.
Mutat. Res.  38: 387.  (Abstract  from the  7th Ann. Meet. Am.  Environ. Muta-
gen. Soc., Atlanta, March 12-15.)

Key, M.M., et  al.  (eds.)  1977.  Pages  278-279  In:  Occupational diseases:  A
guide  to  their recognition.    U.S. Oept. Health Edu. Welfare.   U.S.  Govern-
ment Printing Office,  Washington, O.C.

Kovalenko, I.I.  1973.   Hemotoxicity of nitrotoluenes  in relation to number
and positioning of nitro groups.  Farmakol. Toxicol. (Kiev.)  8: 137.

Lee, C.C., et  al.   1978.  Mammalian toxicity  of munition  compounds.   Phase
III: Effects  of  lifetime exposure.   Part  I: 2,4-dinitrotoluene.   U.S.  Army
Med. Res.  Oev.  Command.   Contract No.  OAMD-17-74-C-4073.   Rep.  NO.  7,  Sep-
tember.

Linch, A.L.   1974.  Biological monitoring  for industrial exposure to cyano-
genic  aromatic  nitro  and  amino  compounds.   Am.  Ind.  Hyg.  Assoc.  Jour.
35: 426.
                                                   s
McGee, L.C.,  et al.   1942.    Metabolic  distrubances  in  workers  exposed  to
dinitrotoluene.  Am. Jour.  Dig. Dis.   9: 329.
                                                                     »
Mori,  M., et  al.   1977.   Studies on the metabolism and toxicity of dinitro-
toluenes — on excretion and  distribution  of  tritium-labeled  2,4-dinitroto-
luene (^-2,4-ONT)  in  the rat.  Radioisotopes  26:  780.
                                      JDZI

-------
National Cancer Institute. ' 1978.  Bioassay of  2,4-dinitrotoluene for possi-
ble carcinogenic!ty.   Carcinogenesis Tech. Rep.  Ser. No.  54.   USDHEW (NIH)
Publ.  No. 78-1360.   U.S. Government Printing Office, Washington, D.C.

Proctor, N.H.  and  J.P.  Hughes.   1978.   Chemical  hazards of  the workplace.
J.B. Lippincott Co., Philadelphia/Toronto.

Shils, M.E. and L.J. Goldwater.   1953.   Effect  of diet on the susceptibility
of the  rat  to  poisoning by 2,4-dinitrotoluene.   Am.  med. Assoc.  Arch.  Ind.
Hyg. Occup. Med.  8: 262.

Simmon, V.F., et al.   1977.   Munitions  wastewater treatments:  does chlorina-
tion  or ozonation   of  individual  components  produce  microbial  mutagens?
Toxicol. Appl. Pharmacol.  41: 197.   (Abstract  from the  16th Ann. Meet.  Soc.
Toxicol., Toronto,  Can., March 27-30.)

U.S. Army  Research  and Development Command.   1976.   Toxicity of  TNT waste-
water  (pink water)  to  aquatic organisms.  Final report,  Contract DAMD17-75-
C-5056.  Washington, D.C.

U.S. EPA.   1978.   In-depth studies  on   health  and environmental  impacts  of
selected water pollutants.  Contract No. 68-01-4646.

U.S. EPA.  1979.  Dinitrotoluene: Ambient Water Quality Criteria.  (Draft) J

-------
                                      No. 93
         2,4-Dlnltrotoluene


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of ts<= ^limitations of such sources, this short profile
may not ref j.. ,-t  all available  information  including all the
adverse health  and  environmental impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                       SPECIAL NOTATION










U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated



2,4-dinitrotoluene and has found sufficient evidence to



indicate that this compound is carcinogenic.

-------
                              2.4-OINITROTOLUENE
                                    Summary

     2,4-Qinitrotoluene induces  liver cancer and mammary  tumors in mice  and
is mutagenic  in some assay  systems.   Information on  teratogenicity was  not
located in  the  available  literature.   Chronic exposure to 2,4-dinitrotoluene
induces liver  damage,  jaundice,  methemoglobinemia  and anemia  in  humans  and
animals.
     Two acute  studies,  one on  freshwater fish and  the  other on  freshwater
invertebrates, provide the only  data  of 2,4-dinitrotoluene's adverse effects
on  aquatic  organisms.    Acute  LC5Q   values  were  reported  as  17,000   and
30,000 jjg/1.  NO marine data are available.

-------
                              2,4-OINITROTOLUENE
I.   INTRODUCTION
     This  profile  is based  on  the  Ambient  Water Quality  Criteria Document
for Oinitrotoluene (U.S. EPA, 1979a).
     2,4-Oinitrotoluene  (2,4-ONT)  has  a  melting point  of 71°C,  a  boiling
point  of 300°C  with  decomposition, and  a solubility  in  water of  270 mg/1
at  22°C.  It  is  readily  soluble  in  ether,  ethanol,  and  carbon  disulfide
(U.S. EPA, 1979a).
     Production   in   1975   was  273  x  10    tons/year  for  the  2,4-  and
2,6-isomers combined  (U.S. EPA,  1979a).   2,4-Oinitrotoluene  is an ingredient
in explosives  for commercial and military use,  a  chemical stabilizer in the
manufacture of  smokeless powder, an intermediate  in  the manufacture .  '  'ol-
uene diisocyanates used in  the production of urethane polymers, and  a raw
material  for the manufacture of dye-stuffs.   Dinitrotoluenes  are relatively
stable  at ambient  temperatures  (U.S.  EPA,  1979a).   For additional  infor-
mation  regarding the  dinitrotoluenes in  general,  the  reader  is  refer- '\d to
the EPA/ECAO Hazard Profile on Dinitrotoluenes (U.S. EPA,  1979b).
II.  EXPOSURE                                                         ''-J
     A.  water
         Data on concentration  levels of 2,4-ONT  in  water  were not  avail-
able.  Dinitrotoluene waste products are dumped  into  surface water  or sewage
by industries  that manufacture dyes,  isocyanates,  polyurethanes and  muni-
tions (U.S. EPA, 1979a).
     B.  Food
         According to  the  U.S.  EPA  (1979a),  the  likelihood  of 2,4-dinitro-
                                                                       »
toluene existing  in food is  minimal since it  is  not  used  as a pesticide or
herbicide.
                                   10*7-

-------
         The  U.S.  EPA  (1979a)  has  estimated  the  weighted  average biocon-
centration  factor  for 2,4-dinitrotoluene  to be  5.5  for  edible  portions  of
fish  and  shellfish consumed  by Americans.  This  estimate was  based on  the
octanol/water partition coefficient.
     C.  Inhalation
         Exposure  to  dinitrotoluene  by  inhalation is  most  likely  to occur
occupationally  (U.S.  EPA,  1979a).   However,  pertinent  data  could  not  be
located in  the available  literature  on atmospheric  concentrations  of dini-
trotoluene; thus, possible human exposure cannot be estimated.
III. PHARMACOKINETICS
     A.  Absorption
         The  absorption  of    C-labeled  isomers  of  dinitrotoluene  after
oral  administration to  rats was  essentially complete within  24 hours,  with
60  to  90  percent of  the  dose being absorbed.  The 2,4-and 3,4-isomers .were
absorbed to  a greater extent  than the 3,5- and  2,5-isomers, which  in  turn
were absorbed to a greater  extent than the 2,3- and 2,6-isomers (Hodgson,  et
al.  1977).   From  toxicity  studies,  2,4-Oinitrotoluene  is known  to  be  ab-
sorbed through the respiratory tract and skin. (U.S.  EPA,  1979a).
     8.  Distribution
         Tissue/plasma . ratios  of radioactivity   after  administration   of
  C-labeled . dinitrotoluene   (DNT)  to  rats  indicated   retention   of   14C
2,4-ONT in both liver and kidneys  but  not  in other tissues (Hodgson,  et  al.
1977).   A   similar  experiment   with  tritium-labeled   2,4-dinitrotoluene
(  H-2,4-ONT)  in the  rat  showed  relatively  high 'amounts of radioactivity
remaining  in adipose tissue, skin, and liver seven  days  after administration
                                                                      »
(Mori, et  al.  1977).

-------
     C.  Metabolism
         No  studies characterizing  the metabolism  of 2,4-dinitrotoluene  in
mammals are  available.   However,  on the basis  of a comparison of  the  metab-
olism  of  2,4-dinitrotoluene and  2,4,6-trinitrotoluene in microbial  systems,
and the metabolism of  2,4,6-trinitrotoluene in mammals, the U.S. EPA (1979a)
speculated  that the  metabolites  of  2,4-dinitrotoluene in  mammals would  be
either toxic and/or carcinogenic.
     D.  Excretion
                                                        14
         In  studies involving  oral administration  of   C-dinitrotoluene  or
3H-2,4-dinitrotoluene  to rats  (Hodgson,  et  al.  1977;  Mori,   et  al,  1977),
elimination  of radioactivity occurred mainly in urine and feces.  NO  radio-
activity was recovered in  the  expired air.  About  46 percent of  the  admin-
istered dose in the  latter  study was excreted  in the feces and urine  during
the seven days  following administration.
IV.  EFFECTS
     A.  Carcinogenicity
         2,4-Oinitrotoluene  fed  to rats  and  mice  for  two  years  produced
dose-related  increases in  fibromas of the  skin  in male  rats and  fibro-
adenomas of  the mammary  gland  in female rats.  These  tumors were benign.   No
statistically  significant  reponse  was noted  in  mice (Natl.  Cancer  Inst.,
1978).
         In  a  second bioassay  of rats  and  mice  fed 2,4-dinitrotoluene  for
two years, the findings  in rats  included a significant  increase of hepato-
cellular carcinomas and  neoplastic nodules in  the livers  of females,  a sig-
nificant increase  of mammary  gland tumors  in females, and  a  suspicious  in-
                                                                      »
crease  of  hepatocellular  carcinomas  of  the  liver  in males.   Mice  had a
highly significant increase of kidney tumors in males  (Lee, et al.  1979).

-------
     B.  Mutagenicity
         2,4-Oinitrotoluene was  mutagenic  in  the dominant  lethal assay  and
in Salmonella  tvphimurium strain T A  1535 (Hodgson,  et  al.  1976).  Cultures
of lymphocytes and kidney cells  derived  from rats fed 2,4-dinitrotoluene  had
significant increases  in  the  frequency of  chromatid gaps but  not in trans-
locations or chromatid breaks (Hodgson, et al. 1976).
         The mutagenic effects of products  from  ozonation or chlorination of
2,4-dinitrotoluene  and  other dinitrotoluenes  were  negative  in  one  study
(Simmon, et al.  1977)  and,  of products from ozonation  alone,  were ambiguous
in another study (Cotruvo, et al. 1977).
     C.  Teratogenicity and Other Reproductive Effects
         Pertinent data could not be located in the available literature.
     0.  Chronic Toxicity                                                  i
         Chronic  exposure to  2,4-dinitrotoluene may  produce  liver  damage,
jaundice,  methemoglobinemia  and  reversible anemia  with  reticulocytosis  in
humans and animals (Linch, 1974; Key,  et  al.  1977;  Proctor and Hughes, 1978;
Kovalenko, 1973).
     E.  Other Relevant Information
         Animals  were  more resistant  to the  toxic  effects of 2,4-dinitro-
toluene administered in  the  diet when given diets  high in  fat  (Clayton and
Baumann,  1944,  1948;  Shils  and  Goldwater,  1953)   or  protein   (Shils  and
Goldwater, 1953).
     Alcohol has  a  synergistic effect on the  toxicity  of 2,4-dinitrotoluene
(Friedlander,  1900;  McGee, et al. 1942).

-------
     In subacute  studies (13 weeks) of several species,  1,2,4-dinitrotoluene
caused methemoglobinemia,  anemia  with reliculocytasis, gliosis, and  demyeli-
nation in  the  brain, and  atrophy  with  aspermatogenesis of the testes  (Ellis
et al., 1976).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The  only toxicity  data  available  for the  effects  of 2,4-dinitro-
toluene in aquatic animals  are  from a  single freshwater  fish and  inverte-
brate  species  (U.S.  Army, 1976).   A 96-hour static  LC-Q value for  the  fat-
head minnow  (Pimephales  promelas)  was reported as  31,000 ug/1 and a 48-hour
static  LC50  value  for  the  cladoceran,  Daphnia maqna,  was reported as
35,000pg/l.
     a.  Chronic Toxicity  and Plant Effects
         Pertinent data could not  be  located in the available  literature.
     C.  Residues
         A bioconcentration  factor of 19 was obtained  for 2,4-dinitrotoluene.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human  health  nor  aquatic criteria derived  by U.S.  EPA
(1979a),  which are summarized below,  have gone through the process of public
review; therefore, there is a possibility that these criteria may be  changed.
     A.  Human
         Based  on the induction  of  fibroadenomas of  the  mammary gland in
female rats  (Lee, et al.  1978),  and using the "one-hit"  model,  the U.S. EPA
(1979a) has  estimated levels  of  2,4-dinitrotoluene'  in ambient water  which
will result in specified risk levels of human cancer:

-------
Exposure Assumptions                 Risk Levels and Corresponding Critgria
     (per day)
                                      0      10~7        10-6         io-5
Consumption of 2 liters of drink-          7.4 ng/1    74.0 ng/1    740 ng/1
ing water and 18.7 grams fish and
shellfish.
Consumption of fish and shellfish            .156 pg/1   1.56 jug/1   15.6yug/l
only .
         The  American  Conference   of   Governmental  Industrial  Hygienists
(1978) recommends  a TLV-time-weighted average  for  2,4-dinitrotoluene of 1.5
mg/m  with a short term exposure limit of 5 mg/m .
     3.  Aquatic
         A criterion  has  been  drafted  for  protecting freshwater  life from
the toxic effects of 2,4-dinitrotoluene.  A  24-hour average concentration of
620 /jg/1,  not to  exceed  1,400 jag/1, has  been proposed.   Data  are insuffi-
cient for drafting a marine criterion.

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                     2,4-DINITROTOLUENE

                         REFERENCES

American Conference of Governmental Industrial  Hygienists.
1978.  TLV'sR: Threshold limit values  for  chemical
substances and physical agents in  the  workroom  environment
with intended changes for 1978.

Clayton, C.C., and C.A. Baumann.   1944.  Some effects of diet
on the resistance of mice toward 2,4-dinitrotoluene.  Arch.
Biochem.  5: 115.

Clayton, C.C., and C.A. Baumann.   1948.  Effect of  fat  and
calories on the resistance of mice to  2,4-dinitrotoluene.
Arch. Biochem.  16: 415.

Cotruvo,, J.A., et al.  1977.  Investigation of mutagenic
effects of products of ozonation reactions  in water.  Ann.
N.Y.  Acad. Sci.  298: 124.

Friedlander, A.  1900.  On the clinical picture of  poisoning
with benzene and toluene derivatives with  special reference
to the so-called anilinism.  Neurol. Centrlbl.   19: 155.

Hodgson, J.R., et al.  1976.  Mutation studies  on 2,4-dini-
trotoluene.  Mutat. Res.  38: 387.  (Abstract from  the  7th
Annu. Meet. Am. Environ. Mutagen Soc., Atlanta,  March 12-15).

Hodgson, J.R.,'et al.  1977.  Comparative  absorption, distri-
bution, excretion, and metabolism of 2,4,6-trinitroluene
(INT) and isomers of dinitrotoluene (DNT)  in rats.  Fed.
Proc.  36: 996.

Key, M.M., et al. (eds.)  1977.  Pages 278-279  In:
Occupational diseases: A guide to  their recognition.  U.S.
Dept. Health, Edu. Welfare.  U.S. Government Printing Office,
Washington, D.C.

Kovalenko, I.I.  1973.  Hemotoxicity of nitrotoluene in rela-
tion to number and positioning of nitro groups.  Farmakol.
Toxicol. (Kiev.) 8: 137.

Lee, C.C., et al.  1978.  Mammalian toxicity of  munition com-
pounds.  Phase III: Effects of life-time exposure.  Part I:
2,4-Dinitrotolune.  U.S. Army Med. Res. Dev. Command.  Con-
tract No. DAMD-17-74-C-4073.  Rep. No. 7, September.
                           '/O 93 ~

-------
Linch, A.L.  1974.  Biological monitoring  for  industrial  ex-
posure to cyanogenic aromatic nitro and amino  compounds.   Am.
Ind. Hyg. Assoc. Jour.  35: 426.

McGee, L.C., et al.  1942.  Metabolic disturbances  in workers
exposed to dinitrotoluene.  Am. Jour. Dig. Dis.   9:  329.

Mori, M., et al.  1977.  Studies on the metabolism  and  toxic-
ity of dinitrotoluenes — on excretion and distribution of
tritium-labelled 2,4-dinitrotoluene (3H-2,4-DNT)  in  the
rat.  Radioisotopes  26: 780.            .  .

National Cancer Institute.  1978.  Bioassay of 2,4-dinitro-
toluene for possible carcinogenicity.  Carcinogenesis Tech.
Rep. Ser. No. 54.  U.S. DREW (NIH) Publ. No. 78-1360.   U.S.
Government Printing Office, Washington, D.C.

Proctor, N.H., and J.P. Hughes.  1978.  Chemical  hazards  of
the workplace.  J.B. Lippincott Co., Philadelphia/Toronto.

Shils, M.E., and L.J. Goldwater.  1953.  Effect of  diet on
the susceptibility of the rat to poisoning by  2,4-dinitro-
toluene.  Am. Med. Assoc. Arch. Ind. Hyg. Occup.  Med. 8:
262.

Simmon, V.F., et al.  1977.  Munitions wastewater treatments:
dose chlorination or ozonation of individual components pro-
duce microbial mutagens?  Toxicol. Appl. Pharmacol.  41:  197.
(Abstract from the 16th Annu. Meet. Soc. Toxicol.,  Toronto,
Can., March 27-30).

U.S. Army Research and Development Command.  1976.   Toxicity
of TNT wastewater (pink water) to aquatic organisms.  Final
Report, Contract DAMD 17-75-C-5056.  Washington,  D.C.

U.S. EPA.  1979a.  Dinitrotoluene: Ambient Water  Quality  Cri-
teria. (Draft).

U.S. EPA.  1979b.  Dinitrotoluene: Hazard Profile.   Environ-
mental Criteria and Assessment Office.

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                                      No. 94
         2,6-Dinltrotoluene


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a survey  of  the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained  in the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all  available  information  including  all  the
adverse health  and  environmental  impacts  presented  by  the
subject chemical.  This  document has  undergone scrutiny  to
ensure its technical  accuracy.
                          -/096-

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                        2,6-Dinitrotoluene




SUMMARY


     2,6-Dinitrotoluene  is known to cause methemoglobinemia  in


cats, dogs, rats, and mice.  When administered orally to  these


animals for a maximum of thirteen weeks, the major  effects seen


in addition to the blood effects were depressed spermatogenesis,


degeneration of the liver, bile duct hyperplasia, incoordination


and rigid paralysis of the hind legs, and kidney degeneration.


     Positive results were obtained with mutagenicity testing in


a number of Salmonella typhimurium strains.


     2,6-DNT has been found in tap water in the United States.


The nitro groups on the aromatic ring retard degeneration so


there is a potential for it to accumulate in the aquatic  environ-


ment .




I.   INTRODUCTION


     This profile is based on the Ambient Water Quality Criteria


Document for Dinitrotoluene (U.S. EPA, 1979b) and a U.S.  EPA


report entitled "Investigation of Selected Potential Environ-


mental Contaminants:  Nitroaromatics" (1976).


     2,6-Dinitrotoluene  (2,6-DNT; CyHgNjO^ molecular weight


182.14) is a solid at room temperature.  It is in the shape  of


rhombic needles and is soluble in ethanol.  Its melting point is
                                                             9

66"C and its density is 1.28 at lll'C (Weast, 1975).


     A review of the production range (includes importation)


statistics for 2,6-dinitrotoluene (CAS. No. 606-20-2) which  is

-------
listed in the initial TSCA Inventory  (1979a) has  shown  that

between 50,000,000 and 100,000,000 pounds of this  chemical  were

produced/imported in 1977.—/

     Mixtures of the dinitrotoluene isomers are intermediates- in

the manufacture of toluene diisocyanates, toluene  diamines  and

trinitrotoluene (Wiseman, 1972).  Dinitrotoluene  (both  2,4- and

2,6-) is an ingredient in explosives  for commercial  and military

use and is also used as  a chemical stabilizer  in  the manufacture

of smokeless powder (U.S. EPA, 1979b).



II.  EXPOSURE

   .  A.   Environmental  Fate

     Based on the photodecomposition  of trinitrotoluene (TNT)

described by Burlinson ^et^ _al_.  (1973), 2,6-dinitrotoluene would be

expected to react photochemically.  Decomposition  of 65% of the

TNT had occurred when the decomposition products were examined.

     2,6-Dinitrotoluene  would  be expected to biodegrade to  a

limited extent.  The nitro groups retard biodegradation and

studies with soil microflora have shown that mono- and  di-

substituted nitrobenzenes persist for more than 64 days

(Alexander and Lustigmann, 1966),  McCormick et al.  (1976)  and

Bringmann and Kuehn (1971) reported microbial  degradation of

2,6-DNT by anaerobic and aerobic bacteria, respectively.


—1 This production range information  does not  include any   .
   production/importation data claimed as confidential  by the
   person(s) reporting for the TSCA inventory, nor does it
   include any information which would compromise  Confidential
   Business Information.  The  data submitted for the TSCA
   Inventory, including  production range information, are subject
   to the limitations contained in the Inventory Reporting

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     B.   Bioconcentration


     In general nitroaromatic compounds do not have high biocon-


centration potential based on calculations using their octanol-


water partition coefficients.  They are not expected to


biomagnify based on their water solubility (U.S. EPA, 1976).


     C.   Environmental Occurrence


     2,6-Dinitrotoluene has been identified in tap water in the


United States (Kopfler and Melton, 1975).  Its environmental con-


tamination would come almost exclusively from the chemical plants


where it is produced.  It was detected in the water effluent from


a TNT plant in Radford, Virginia at concentrations of 3.39 to


56.3 ppm.  It was also found in the raw waste of a DNT plant at


150 ppm.  The raw effluent contained 0.68 ppm and the pond efflu-


ent 0.02 ppm (U.S. EPA, 1976).






III. PHARMACOKINETICS


     2,6-Dinitrotoluene can enter the body through inhalation of


vapors or dust particles, ingestion of contaminated food, and


absorption through the skin (EPA, 1979b) .  Hodgson _et_ _al_. (1977)

                      1 A
traced the pathway of *• C labeled di- and tri-substituted nitro-


toluenes after oral administration of the compounds to rats.  All


of the compounds were well absorbed with 60 to 90% absorption


after 24 hours.  The radiolabel was found in the liver, kidneys


and blood but not in other organs; none was found in the expired


air indicating that the aromatic ring was not broken down through
                                                            »

metabolism of the compounds.  Most of the labeled compounds were




   Regulations (40 CFR 710).



                                2



                             -/or?-

-------
eliminated in the urine as metabolites; biliary excretion  was



also an important elimination pathway.








IV.  HEALTH EFFECTS



     A.   Carcinogenicity



     No carcinogenicity testing of 2,6-DNT has been reported in



the literature.  The National Cancer Institute conducted a bio-



assay to determine the carcinogenicity of 2,4-DNT by administer-



ing it to rats and mice in their diet.  2,4-DNT induced benign



tumors in male and female rats, however, the benign tumors were



not considered a sufficient basis for establishing carcinogen-



icity.  The assay produced no evidence of carcinogenicity  of the



compound in mice (NCI, 1978).



     B.   Mutagenicity



     Simmon et^ al_. (1977) tested 2,6-dinitrotoluene for



mutagenicity in Salmonella typhimurium.  Positive results  were



obtained with strains TA1537, TA1538, TA98, and TA100, but not



TA1535.  These results were obtained without metabolic activa-



tion.



     C.   Other Toxicity



          1.   Chronic



     The subchronic toxicity of 2,6-dinitrotoluene was determined



by oral administration to dogs, rats, and mice for about 13



weeks.  The primary effects were on red blood cells, the nervous



system, and the testes.  Both dogs and rats had decreased mu'scu-



lar coordination primarily in the hind legs, rigidity in exten-



sion of the hind legs, decreased appetite, and weight loss.  The

-------
mice experienced only the decreased  appetite  and weight  loss.



All of the animals had methemoglobinemia,  and  anemia  with  reticu-



locytosis.  The tissue lesions seen  were  extramedullary  hemato-



poeisis in the spleen and liver, gliosis  and  demyelination in  the



brain, and atrophy with aspermatogenesis  in the testes (Ellis  et



al., 1976).  Methemoglobinemia was also found  in cats adminis-



tered 2,6-DNT (U.S. EPA, 1979b).



          2.   Acute



     Oral LD50's have been reported  for rats  and mice.   They are



180 mg/kg and 1,000 mg/kg respectively (Vernot et al., 1977).  A



mixture of 2,4-DNT and 2,6-DNT was applied to  the skin of  rabbits



in a series of 10 doses over a two week period and no cumulative



toxicity was found (U.S. EPA, 1976).








VI.  EXISTING GUIDELINES



     The OSHA standard for 2,6-DNT in air is  a time-weighted



average of 1.5 mg/m3 (39 PR 23540).

-------
                           BIBLIOGRAPHY

Alexander, M. and B.K. Lustigmann.  Effect of chemical  structure
on raicrobial degradation of substituted benzenes.  J. Agr.  Food.
Chem. 14(4), 410-41, 1966.  (As cited in U.S. EPA, 1976).

Bringmann, G. and R. Kuehn.  Biological decomposition of nitro-
toluenes and nitrobenzenes by Azotobacter Agilis.  Gesundh.-Ing.,
92(9), 273-276, 1971.  (As cited in U.S. EPA, 1976).

Burlinson, N.E. et al.  Photochemistry of TNT:  investigation  of
the "pink water" problem.  U.S. NTIS AD 769-670,  1973.   (As  cited
in U.S. EPA, 1976).

Ellis, H.V. , III e_t_ _al_.  Subacute toxicity of 2,4-dinitrotoluene
and 2,6-dinitrotoluene.  Toxicol. Appl. Pharm.  37, 116, 1976.

Hodgson, J.R. _e_t^ _al_.  Comparative absorption, distribution,
excretion, and metabolism of 2,4,6-trinitrotoluene (TNT) and
isomers of dinitrotoluene  (DNT) in rats.  Fed.  Proc. 36, 996,
1977.

Kopfler, F.C. and R.G. Melton.  1977.  Human exposure to water
pollutants.  In Advances in Environmental Science and Technology,
Vol. 8.  Fate of Pollutants in the Air and Water  Environments.
Part 2.  Chemical and Biological Fate of Pollutants in  the
Environment.  Symposium at the 165th National American  Chemical
Society Meeting in the Environmental Chemistry  Division.  Phila-
delphia, PA.  April 1975.  John Wiley and Sons, Inc., New York.

McCormick, N.G. et al.  Microbial transformation  of 2,4,6-trini-
trotoluene and other nitroaromatic compounds.   Appl. Environ.
Microbiol. 31(6), 949-958, 1976.

National Cancer Institute.  Bioassay of 2,4-dinitrotoluene  for
possible carcinogenicity.  PB-280-990, 1978.

National Institute of Occupational Safety and Health.   Registry
of Toxic Effects of Chemical Substances, 1978.

Simmon, V.F. _et_ _al_.  Mutagenic activity of chemicals identified
in drinking water.  Dev. Toxicol. Environ. Sci. 2, 249-258,  1977.

U.S. EPA.  Investigation of Selected Potential  Environmental
Contaminants:  Nitroaromatics.  PB-275-078, 1-976.

U.S. EPA.  Toxic Substances Control Act Chemical  Substance
Inventory, Production Statistics for Chemicals  on the Non-Confi-
dential Initial TSCA Inventory, 1979a.

U.S. EPA.  Ambient Water Quality Criteria:  Dinitrotoluene.
PB-296-794, 1979b. .

-------
Varnot, E.H. £t_ ^1_.  Acute toxicity and' skin  corrosion data  for
some organic and inorganic compounds and aqueous  solutions.
Toxicol. Appl. Pharmacol. 42(2), 417-424,  1977.

Weast, R.C., ed. 1978.  CRC Handbook of  Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.

Wiseman, P.  1972.  An Introduction to Industrial Organic
Chemistry.  Interscience Publishers, John-Wiley and Sons,  Inc.,
New York.
                                y

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                                    No.  95
        Di-n-octyl Phthalate


  Health and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON, D.C.  20460

          APRIL 30,  1980
          -not-

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                          DISCLAIMER
     This report represents a  survey  of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including  all the
adverse health  and   environmental  impacts  presented  by  the
subject chemical.   This  document  has  undergone scrutiny  to
ensure its technical accuracy.
                        •110*-

-------
                         DI-n-OCTYL PHTHALATE




                                Summary








      Di-n-octyl phthalate  has  produced  teratogenic effects following



i.p.  injection, of pregnant  rats.   This same study has also indicated



some increased resorptions  and  fetal toxicity.




      Evidence is not available indicating mutagenic or carcinogenic



effects of di-n-octyl phthalate.




      Data pertaining to  the aquatic toxicity of di-n-octyl phthalate



is not available.
                              -no *-

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                          DI-n-OCTYL PHTHALATE


 I.     INTRODUCTION


       This profile is based on the Ambient Water Quality Criteria Document


 for  Phthalate Esters (U.S.  EPA,  1979a).


       Di-n-octyl phthalate  (DOP)  is a  diester of the ortho form of


 benzene  dicarboxylic acid.   The  compound has a molecular weight of


 391.0, specific  gravity of  0.978,  boiling point of 220°C at 5 mm Hg,


 and  is insoluble in water.


       DOP  is  used as a plasticizer in  the production of certain plastics.


       Current Production:   5.8 x 1fl3 tons/year in 1977 (U.S.  EPA,  1979a).


       Phthalates have been  detected in soil,  air,  and water samples;  in


 animal and human tissues, and in certain vegetation.   Evidence from in


 vitro  studies indicates that certain bacterial flora may be capable of


 metabolizing  DOP to the monoester form (Engelhardt,  st al.  1975).   For


 additional information regarding the phthalate esters in general,  the


 reader is  referred to the EPA/ECAO Hazard Profile  on Phthalate Esters


"(U.S.  EPA  1979b).


 II.    EXPOSURE


       Phthalate  esters appear in all areas of the  environment.  Environmental


 release  of phthalates may occur  through  leaching of  the compound from


 plastics,  volatilization from plastics,  or the incineration of plastic


 items. Sources of human exposure  to phthalates  include contaminated


 foods and  fish,  dermal application,  and  parenteral administration  by


 use  of plastic blood bags,  tubings,  and  infusion devices (mainly DEHP


 release).   Relevant factors in the migration  of phthalate esters from

                                                                       »
 packaging  materials to food and  beverages are:   temperature,  surface


 area contact,  lipoidal nature of the food,  and  length of contact (U.S.


 EPA, 1979a).
                                -1/6 >'

-------
      Monitoring studies have indicated that most water phthalate concentrations

are in the ppm range, or 1-2 jug/liter (U.S. EPA,  1979a).  Industrial

air monitoring studies have measured air levels of phthalates from 1.7

to 56 mg/m3 (Milkov, et al. 1973).

      Information on levels of OOP in foods is not available.  Bio-

concentration factor is not available for DOP.

III.  PHARMACOKINETICS

      Specific information could not be located on the absorption,

distribution, metabolism, or excretion of DOP.  The reader is referred

to 'a general coverage of phthalate metabolism (U.S. EPA, 1979b).

IV.   EFFECTS

      A.     Carcinogenicity

        Pertinent data could not be located in the available literature.    ^

      B.     Mutagenicity

        Pertinent data could not be located in the available literature.



      C.     Teratogenicity

        Administration of DOP to pregnant rats by i.p.  injection  has

been reported to produce some teratogenic effects,  although less  so

than several other phthalates tested (Singh,  et al. 1972).

      D.     Other Reproductive Effects

        An increased incidence of resorption and  fetal  toxicity was

produced following i.p. injection of pregnant rats with DOP (Singh,  et

al. 1972).

      E.     Chronic Toxicity
                                                                      •
        Pertinent data could not be located in the available literature.
                                 -//of-

-------
V.    AQUATIC TOXICITY




      Pertinent data could not be located in the available literature.




VI.   EXISTING GUIDELINES AND STANDARDS




      Neither the human health nor the aquatic criteria derived by O.S.




EPA (1979a), which are summarized below,  have gone through the process




of public review; therefore, there is a possibility that these criteria




will be changed.




      A.     Human




             Pertinent data concerning the acceptable daily intake




(ADI) level in humans of DOP could not be located in the available




literature.




             Recommended water quality criterion level for protection




of human health is not available for DOP.




      B.     Aquatic




             Pertinent data is not available pertaining to the aquatic




toxicity of di-n-octyl phthalate;  therefore,  no criterion could be




drafted.
                            -110?-

-------
                            DI-N-OCTYL PHTHALATE

                                . REFERENCES
Engelhardt,  G.,  et al.   1975.   The  microbial metabolism of di-n-butyl phtha-
late  and  related  dialkyl  phthalates.    Bull.  Environ.  Contam.  Toxicol.
13: 342.

Milkov,  L.E., et  al.   1973.   Health  status  of workers exposed to phthalate
plasticizers in  the manufacture of  artificial leather and films based on PVC
resins.   Environ.  Health Perspect.  (Jan.): 175.

Singh, A.R.,  et  al.   1972.   Teratogenicity  of phthalate  esters in  rats.
Jour. Pharm. Sci.   61:  51.

U.S. EPA.  1979a.   Phthalate Esters: Ambient Water Quality Criteria.  (Draft)

U.S. EPA.   1979b.  Environmental  Criteria  and  Assessment  Office.   Phthalate
Esters:  Hazard Profile.  (Draft)
                             -mo-

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                                      No. 96
       1,2-Diphenylhydrazine


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and available reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                       SPECIAL NOTATION










U.S. EPA1s Carcinogen  Assessment Group (GAG) has evaluated



1,2-diphenylhydrazine  and has found sufficient evidence to



indicate that this  compound  is carcinogenic.
                          -1)13-

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                      1,2-DIPHENYLHYDRAZINE
                             Summary
     The adverse effects  of  exposure to 1,2-diphenylhydrazine  in-
clude damage to both the kidney and liver.  Acute LD,-Q values have
ranged from 300 to  960  mg/kg  in  experimentally  dosed  rats.  No data
concerning the absorption, distribution,  or  excretion of the 1,2-
diphenylhydrazine have been generated.  Benzidine has been identi-
fied  as  a metabolite  in  urine  of  rats  exposed to  the  chemical.
Diphenylhydrazine is carcinogenic in both sexes of rats and  in  fe-
male mice.
     The only  aquatic  toxicity  data for diphenylhydrazine are  for
freshwater organisms.  Acute toxicity levels of 270 and 4,100 ug/1,
were  reported  for  bluegill  and  Daphnia  magna^  respectively,  and a
single chronic value of 251 ^ig/1 was reported for Daphnia magna.

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                      1,2-DIPHENYLHYDRAZINE


I.    INTRODUCTION


     This profile  is  based primarily on the Ambient Water Quality


Criteria Document for Diphenylhydrazine.


     Diphenylhydrazine  (DPH)  has a molecular  weight  of 184.24, a


melting point of 131°C and  a boiling point of 220°C. DPH is slight-


ly  soluble  in  water  and  is  very  soluble in  benzene,  ether  and


alcohol.


     The  symmetrical  isomer  of  diphenylhydrazine,  1,2-diphenyl-


hydrazine is  used  in  the synthesis of  benzidine  for  use in dyes,


and in the synthesis of phenylbutazone, an anti-arthritic drug.


     The  reported  commercial  production of more  than 1000 pounds


annually, as  of 1977,  is  most  Irkely an  underestimation  of  the


total amount of diphenylhydrazine available.   Diphenylhydrazine  i*s


produced  in  several synthetic processes as  an intermediate and a


contaminant, but there  is  no way of  estimating these  substantial


quantities.


II.  EXPOSURE


     A.   Water


          The highest reported concentration of 1,2-diphenylhydra-


zine in drinking water is one ug/1  (U.S. EPA,  1975).


     B.   Pood


          The U.S.  EPA  (1979).has  estimated  the  weighted average


bioconcentration factor  for  diphenylhydrazine to  be  29  for   the
                                             *•

edible portions of  fish and shellfish consumed by Americans.  This


estimate  is  based  on the  octanol/water partition  coefficient of


diphenylhydrazine.

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     C.   Inhalation

          Pertinent data  could  not  be  located  in  the available

literature.

III. PHARMACOKINETICS

     Pertinent information  could not be located  in  the available

literature regarding absorption, distribution and excretion.

     A.   Metabolism

          Various metabolites, including the known carcinogen ben-

zidine, have been identified in  the urine of rats.  1,2-Diphenylhy-

drazine was administered orally  (200,400 rag/kg),  intraperitoneally

(200 mg/kg),  intratracheally (5,10  mg/kg)  and  intravenously (4,8

mg/kg).  The metabolites detected were not dependent upon the base

or route of administration  (Williams, 1959).                       4

IV.  EFFECTS

     A.   Carcinogenicity

          Diphenylhydrazine  has  been   identified   as  producing

significant  increases  in  hepatocellular carcinoma at  5 ug/kg/day

and 18.8 pg/kg/day in both sexes of rats; Zymbal's gland squamous-

cell  tumors  in  male  rats   at  18.8   jjg/kg/day;  neoplastic  liver

nodules  in   female  rates  at  7.5 jag/kg/day;  and  hepatocellular

carcinomas in female mice  at 3.75 pg/kg/day (NCI, 1978).  Diphenyl-

hydrazine was not carcinogenic in male mice.

     B.   Mutagenicity

          No microbial mutagenetic assays with'or without metabolic

activation have been conducted on diphenylhydrazine.  An intraperi-
                                                             »
toneal dose of 100 mg/kg had an  inhibitory effect on the incorpora-

tion of  (JH)-thymidine into testicular  DNA  of  experimental mice

(Sieler, 1977).

-------
      C.    Teratogenicity

           Pertinent  information could not be located in the avail-

 able  literature.

      D.    Toxicity

           One  study  reported an LDcQ  of 959 mg/kg for male rats ad-

 ministered DPH as a five percent  solution.    In  the  Registry  of

 Toxic Effects  of  Chemical  Substances,  the oral LD,-Q  is  listed  as

 301 mg/kg.   Neoplasms  resulted in rats  after 52 weeks with a total

 dose  of  16  g/kg DPH  administered  subcutaneously .   In 2  mice

 studies,  neoplasms resulted after 25 weeks with topical application

 of  5280  mg/kg  and after 38 weeks  with  subcutaneous  injection  of

 8400  mg/kg DPH.   Liver  and  kidney  damage have been  implicated  in

 the  adverse effects  of  diphenylhydrazine chronically administered

 to rats.  No experimental or epidemiological studies have been con-

 ducted  on the  effects  of diphenylhydrazine in humans.

 V.    AQUATIC TOXICITY

      A.    Acute

           Ninety-six-hour LC5Q  values   for  freshwater  organisms

 have  been reported  as  270  jjg/1  for  the  bluegill,   Lepomis  macro-

 chirus,  and the  48-hour kCcn   for  the  cladoceran,   Daphnia  magna,

 is  4,100  pg/1 (U.S.  EPA,  1978).    No  toxicity data for  marine

.animals  could  be  located in  the available literature.

 B.    Chronic

           A chronic  value  of  251 /ig/1  has  be'en obtained  for  the

 freshwater cladoceran,  Daphnia Magna  (U.S. EPA, 1978).  No chronic
                                                              •
 tests of  diphenylhydrazine  are available  for  marine organisms.
                            -I//7

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     C.   Plants
          Pertinent  data could  not be  located  in  the  available
literature.
     D.   Residues
          Based on  the  octanol/water partition coefficient  of  870
for  1,2-diphenylhydrazine,  a  bioconcentration factor  of 100  has
been estimated for aquatic organisms with a lipid content of 8 per-
cent.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human  health  nor aquatic  criteria  derived   by
.U.S.  EPA  (1979),  which  are  summarized  below have  gone  through
the  process  of public  review;  therefore,  there  is  a  possibility
that these criteria may  be changed.
     A.   Humans
          No standards were found for humans exposed.to  diphenylhy-
drazine in occupational  or ambient  settings.
          Recommended draft  criteria for  the  protection. of  human
health are as follows:

Exposure Assumptions        Risk Levels and Corresponding Criteria
                            0  1£~7         ICT6         1£~5
2 liters of drinking water  0  4     ng/1   40    ng/1   400   ng/1
and consumption of 18.7
grams fish and shellfish. (2)
Consumption of fish and     O  .019  pg/1   0;'19  jag     1.9
shellfish only.

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     B.   Aquatic
          Criterion to protect  freshwater  aquatic life from toxic
effects of diphenylhydrazine have  been  drafted  as a 24-hour aver-
age concentration  of 17  ug/1  and  not  to  exceed 38 pg/1  at  any
time.

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                        DIPHENYLHYDRAZINE

                            REFERENCES


NCI Publication NO. (NIH)  78-1342.  1978.  Bioassay of hydrazoben-
zene for possible carcinogenicity.

Sieler, J.P.   1977.   Inhibition  of  testicular DNA  synthesis by
chemical mutagens  and carcinogens.    Preliminary  results  in the
validation of a novel short term test.  Mutat. Res.  46: 305.

U.S. EPA.    1975.    Primary assessment  of suspected  carcinogens
in drinking water.   Report to Congress.

U.S. EPA.   1978.   In-depth studies  on health  and  environmental
impacts of selected water pollutants.   Contract No. 68-01-4646.

U.S. EPA.   1979.   Diphenylhydrazine:   Ambient  Water  Quality Cri-
teria.   (Draft).

Williams,  R.   1959.   Detoxication Mechanisms.   New York:   John
Wiley and Sons. p.  480.

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                                      No. 97
             Disulfoton


  He&   ) and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                          Disclaimer  Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

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                                  DISULFOTQN
                                   Summary

     Oisulfoton is a highly  toxic  organophosphorous  insecticide used on many
agricultural  crops.    The  human  oral  I_DLQ  is  estimated  at  5  mg/kg  boay
weight.   Exposure results  in  central, nervous  system  toxicity.   The  LD5Q
for several animal species ranges  from 3.2 to 6 mg/kg.   Carcinogenic,  muta-
genic, and  teratogenic studies were not  found  in the available  literature.
The occupational  threshold  limit value for  disulfoton  is 10 ug/m^.   Allow-
able residue tolerances  for  agricultural  commodities range from 0.3  to  11.0
ppm.
     Although disulfoton is  considered toxic to aquatic  organisms,  specific
studies on aquatic toxicity were not  located  in  the available  literature.
                                     X

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 I.    INTRODUCTION
      Disulfoton  is  a -highly  toxic  organophosphorous  insecticide used  in
 agriculture  to  control mainly sucking insects  such  as aphids and plantfeed-
 ing mites.   Small  amounts  are used on home plants and. gardens in the form of
 dry granules with  low content of active ingredient (U.S. EPA, 1974).  Disul-
 foton was  introduced in  1956  by Bayer  Leverkusen  (Martin and  Worthing,
 1974), and  today it  is produced by only one  U.S.  manufacturer,  Mobay  Chemi-
 cal Corporation, at  its Chemogro Agricultural  Division  in  Kansas City,  Mis-
 souri (Stanford  Research Institute (SRI),  1977).   An estimated  4500  tonnes
 were  produced  in  1974  (SRI,  1977).   Disulfoton  is  made by  interaction  of
 0,0-diethyl  hydrogen phosphorodithioate   and  2-(2-ethylthio)ethylchloride
 (Martin  and Worthing, 1974).   Oisulfoton  is  slightly soluble in  water  and
 readily  soluble in   most  organics.   Its   overall degradation  constant  is
 0.02/day.   Disulfoton has  a  bioconcentration factor of  1.91  and  an octanol/
 water partition coefficient of 1.0 (see Table 1).
 II.   EXPOSURE
      A.   Water
          Disulfoton  concentrations  are highest during  the  production  pro-
 cess.   Concentrated  liquid wastes  are barged  to  sea (150-200  mi; 240-320
 km),  and sludge wastes are  disposed in landfills.
          Agricultural application  rates  normally range  from 0.25  to  1.0
 Ib/acre  (0.28-1.1  kg/ha);  to a maximum of 5.0 Ib/acre  (5.5  kg/ha)  for  some
uses.   Target crops  include  small  grains,  sorgum,  corn, cotton,  other  field
 crops; some.vegetable, fruit  and nut crops; ornamentals (Fairchild,  1977).
          Disulfoton is considered stable  in groundwater.  Less than 10  per-
 cent  is estimated to  decompose in  five days  (equivalent  to  50-250 mi; 80-400
                                 '// 2 J-

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           TABLE 1.  PHYSICAL AND CHEMICAL PROPERTIES OF OISULFOTON
Synonyms:  0,0-Oiethyl S-(2-(ethylthio)ethyl) phosphorodithioate;
           0,0-Oiethyl S-(2-(ethylthio)ethyl) dithiophosphate;    Thiodemeton;
           Frumin;  Glebofos;  Ethylthiometon  B;  VUAgT  1964;  Di-Syston  G;
           Disipton; ENJ-23437; Ethyl  thiometon;  VUAgT 1-4; Bay 19639;  M 74
           [pesticide]; Ekatin TO;  CAS Reg.  No.  298-04-4; M 74 (VAN);  Bayer
           19639;  Di-Syston;  Dithiodemeton;  Dithiosystox;  Solvirex;  Frumin
           AL; Frumin G

Structural Formula:

Molecular Weight:  274.4

Description:   Colorless  oil;  technical  product is  a  dark  yellowish  oil;
               readily soluble in most organics

Specific Gravity and/or Density:   d^   = 1.144

Melting and/or Boiling Points:  bp 62OQ at 0.01 mm Hg

Stability:   Relatively stable to hydrolysis at pH below  8
             Overall degradation rate constant (0.02/day)

Solubility (water):  25 ppm at room temp.

                   sediment . .5
                     H20    '  1
Vapor Pressure:  1.8 x 10-4 mm Hg at 20°C

Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient .(Kow):   «0w = 1-91
                                            BCF = 1.0
Source:  Martin and Worthing,  1974;  FairchiJrd,  1977;  Windholz,  1976;
         U.S.  EPA, 1980;  Berg, et al.  1977.

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km) in a river  environment.   Decomposition  in a lake environment is estimat-
.ad to be near 90 percent in one year (U.S. EPA 1980).
     8.   Food
          In a  study by  Van  Dyk  and Krause  (1978), disulfoton was applied as
a granular  formulation at 2  g/m length in rows  during cabbage  planting  (5
percent active  ingredients,  rows one meter apart, plants 0.5  meters  apart).
The disulfoton sulphone concentration reached a maximum in 18  to  32 days  and
decreased to between 0.3 and 6.4 mg/kg 52  riays  after application.  The cab-
bage residue of disulfoton at harvest  time was below  the  maximum limit  of
0.5 mg/kg.
          Disulfoton applied  at  about  1.5  kg/10 cm-ha (hectare  slice) per-
sisted for the  first week,  and residue levels declined slowly  the  following
week.  After  one month,  only 20 percent of the  amount  applied was  found.
Disulfoton  was   not  found  to  translocate   into  edible  parts  of lettuce,
onions, and carrots  (less than  5 ppb), but was present  at  about  20  ppb  in
the root system of lettuce (Belanger and Hamilton,  1979).
     C.   Inhalation and Dermal
          Data are not available indicating the number of people subject  to
inhalation or  dermal exposure  to  disulfoton.   The  primary  human exposure
would  appear  to  occur  during  production  and  application.    The  U.S.   EPA
(1976). listed  the frequency  of  illness, by  occupational groups caused  by
exposure  to organophosphorous pesticides.  In 1157 reported cases,  most ill-
nesses  occurred among ground  applicators  (229)  and mixer/loaders (142);  the
lack of or refusal to  use safety equipment, was a major factor of  this con-
tamination.   Other groups  affected  were gardeners  (101),  field workers  ex-
posed to  pesticide residues (117), nursery and greenhouse workers (75), soil
                                                                        »
fumigators in  agriculture (29), equipment cleaners and mechanics  (28), trac-

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tor  drivers and irrigators  (23),  workers  exposed  to pesticide  drift (22),
pilots  (crop  dusters) (17), and  flaggers for aerial  application (6).  Most
illnesses were  a result of carelessness,  lack of knowledge of  the hazards,
and/or  lack of  safety equipment,   under dry,  hot conditions,  workers tended
not  to  wear protective  clothing.   Such  conditions  also tended  to increase
pesticide levels and dust on the crops.
III. PHARMACOKINETICS
     A.   Absorption, Distribution, and Excretion
          Pertinent data could not be located in the available literature.
     B.   Metabolism
          Disulfpton  is  metabolized in plants to  sulfoxide and  sulfone  and
the  corresponding  derivatives  of  the  phosphorothioate and demeton-S.   This
is  also the probable route in  animals  (Martin and Worthing, 1974;  Menzie
1974; Fairchild, 1977).
IV.  EFFECTS
     A.   Carcinogenic!ty, Mutagenicity and Teratogenicity
          Pertinent data could not be located in the available  literature.
     8.   Chronic Toxicity and Other Relevant Information
          Disulfoton  is  highly  toxic to all  terrestrial  and aquatic  fauna.
Human  oral  LDLo is  estimated  to  be 5  mg  disulfoton  per  kilogram body
weight  (5 mg/kg).   The  symptoms  produced by  sublethal doses  are typical  of
central and peripheral  nervous-system  toxicity (Gleason,  et al.  1969).   The
reported LD5Q concentrations  for other species  are summarized below  (Fair-
child,  1977).

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        Species            Exposure Route              LD5Q (mg/}
-------
Both  tests  were conducted at  25°C.   The corresponding value  for  bluegilis
is estimated to be 0.07 mg/1  (McKee and Wolf, 1963).
VI.  EXISTING GUIDELINES AND  STANDARDS
     A.    Human
          The  occupational threshold  limit value  for air  has been  estab-
lished as  100 jug/m3.   Established residue  tolerance  for  crops  range  from
0.3 to 12.0 ppm;  0.75 ppm  for most (Fairchild,  1977).
     8.    Aquatic
          Pertinent data could not be located in the available  literature.
                                  1)30

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                                  REFERENCES
Belanger, A. and H.A.  Hamilton.   1979.   Determination of disulfoton and per-
methrin  residues  in an  organic soil and their  translocation  into lettuce,
onion and carrot.  Jour. Environ. Sci. Health.  B14: 213.

Berg, G.L.,  et  al.  (ed.)  1977.  Farm  Chemicals  Handbook.   Meister Publish-
ing Company, Willoughby, Ohio.

Fairchild,  E.J.,   (ed.)   1977.   Agricultural  chemicals  and pesticides:   A
subfile of  the  NIOSH  registry of toxic  effects of chemical substances, U.S.
Dept. of HEW, July.

Gleason,  M.N.,  et  al.  1969.   Clinical Toxicology of  Commercial Products.
Acute Poisoning, 3rd ed.

Gopal,  P.K.  and S.P.  Ahuja.   1979.  Lipid  and growth changes  in organs of
chicks  Gallus domesticus during  acute and chronic toxicity with disystbn and
folithion.

Holt, T.M.  and  R.K. Hawkins.   1978.  Rat hippocompel norepinephrine re.,  ,,Ase
to cholinesterase inhibition.  Res. Commun. Chem.  Pathol. Pharmacol  20: 239.

Martin  and Worthing, (ed.)  1974.   Pesticide Manual, 4th ed.  p. 225

McKee,  J.E.  and H.W.   Wolf.   1963.   Water Quality Criteria.  2nd  ed.   Cali-
fornia  State Water Quality Control  Board.  Publication 3-A.

Menzie, C.M.  1974.  Metabolism  of  Pesticides:  An Update.   U.S. Dept.  ^ Ythe
Interior Special Scientific Report  — Wildlife No. 184, Washington, D.C."

Stanford Research  Institute.   1977.  Directory  of Chemical Producers.     Jnlo
Park, California.

Tiwari,  J.K.,  et al.    1977.   Effects of  insecticides  on  microbial flora of
groundnut field soil.   Ind. Jour. Micro.   17: 208.

U.S.  EPA.   1974.   Production,  Distribution,  Use, and  Environmental   Impact
Potential of  Selected  Pesticides.   .Report No.  EPA 540/1-74-001.   U.S. Envi-
ronmental Protection Agency,  Office of  Water and Hazardous Materials,  Office
of Pesticide Programs.

U.S.  EPA.   1976.   Organophosphate  Exposure from Agricultural Usage, EPA 6007
1-76-025.

U.S.  EPA.   1980.   Aquatic  Fate and Transport Estimates  for Hazardous Chemi-
cal Exposure  Assessments.   Environmental  Research Laboratory,  Athens', Geor-
gia-

Van Dyk,  L.P.  and M.  Krause   1978.  Persistence  and  efficacy  of disulfoton
on Cabbages.  Phytophylactica  10:  53.

Windholz, M.,  (ed.) 1976.   The Merck  Index,  9th ed.  Merck and  Co., Inc.,
Rahway, New Jersey.
                             7/3 A

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                                      No.  98
             Endosulfan


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not  reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This document  has undergone  scrutiny to
ensure its technical accuracy.

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                                  ENDOSULFAN
                                    Summary
     Endosulfan is an  insecticide  and is a member  of the organochlorocyclo-
diene insecticides.  Endosulfan does  not  appear  to  be carcinogenic,  mutagen-
ic or teratogenic.   In humans,  chronic toxic effects  have  not been observed
when endosulfan has  been properly  handled  occupationally.   Chronic feeding
of endosulfan to rats  and mice  produced  kidney  damage, parathyroid hyperpla-
sia, testicular atrophy, hydropic change  of the  liver, and  lowered survival.
Oral administration of endosulfan to  pregnant  rats  increased fetal mortality
and resorpticns.  Sterility can be  induced  in embryos  in sprayed  bird eggs.
At  very  high levels of acute exposure,  endosulfan  is toxic  to the central
nervous system.  The U.S.  EPA has  calculated  an ADI  of  0.28 mg  based  on a
NOAEL of 0.4 mg/kg for mice in  a  chronic feeding study.  The ADI established
by the Food  and Agricultural  Organization (1975) and  World  Health Organiza-
tion is 0.0075 mg/kg.
     Ninety-six hour  LC5Q  values  ranged from  0.3  to 11.0  jug/1  for  five
freshwater fish; from 0.09 to  0.6 ;jg/l for five  saltwater fish in  48- or 96-
hour  tests;  from  0.04  to  380  jug/1  (EC50 and LC5n)  for  seven  saltwater
invertebrate species;  and  from 62  to 166 pg/1  for  Daphnia  magna  (48-hour
LCcg).  In  the  only  chronic aquatic  study  involving  endosulfan,  no adverse
effects on fathead minnows were observed at  0.20 jug/1.
                                  •1131-

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I.   INTRODUCTION
     Entiosulfan        (6,7,3,9,10,10-hexachloro-l,5,5a,6,9,9a-hexahydro-6,9-
methano-2,4,3-benzodioxathiepin-3-oxide;         C^ClgHgO-jS;        molecular
weight  406.95)  is a light  to  dark brown  crystalline solid  with  a terpene-
like odor. Endosulfan  is a broad  spectrum insecticide of the group of poly-
cyclic  chlorinated hydrocarbons called  cyclodiene insecticides.   It also has
uses as an  acaricite.   It  has  a  vapor pressure  of 9 x  10"  mm Hg  at 80
degrees centigrade.  It exhibits a  solubility  in water of 60 to 150 jug/1 and
is readily soluble in  organic  solvents  (U.S. EPA, 1979).  The trade names of
endosulfan include  Beosit,  Chlorithiepin,  Cyclodan,  Insectophene ,  Kop-Thio-
dan, Malix, Thifor, Thisnuml, Thioden, and  Thionex  (Berg, 1976).
     Technical grade endosulfan has a purity  of 95  percent  and is composed
of a mixture  of two stereoisomers  referred to as alpha-endosulfan and beta-
endosulfan or  I  and II.  These isomers are present  in- a  ratio of 70 parts
alpha-endosulfan  to  30 parts beta-endosulfan.   Impurities  consist  mainly of
the degradation  products  and may  not exceed 2  percent  endosulfandiol  and 1
percent endosulfan ether (U.S.  EPA, 1979).
     Production:  three million pounds, in 1974 (U.S. EPA, 1979).
     Endosulfan  is  presently  on  the Environmental Protection  Agency's  re-
stricted list.   However,  significant commercial use  for  insect control on
vegetables, fruits, and tobacco continues (U.S. EPA, 1979).
     Endosulfan  is  stable to  sunlight  but  is susceptible  to  oxidation  and
the formation  of endosulfan sulfate  in  the presence of growing  vegetation
                                                       s
(Cassil and Drumrcbnd, 1965).  Endosulfan  is readily adsorbed and absorbed by
sediments  (U.S.  EPA,  1979).   It   is  metabolically converted  by microorgan-
isms,  plants, and animals  to endosulfan  sulfate,  endosulfandiol,  endosulfan
ether,   endosulfan hydroxyether and  endosulfan  lactone (Martens,  1976;  Chopra
                                   -1/3

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and Mahfouz, 1977; Gorbach,  et  al.  1968;  Miles and Moy, 1979).  The end-pro-
duct, endosulfan  lactone,  disappears  quickly  once formed.   Accumulation  of
endosulfan sulfate may be favored in acidic soils (Miles and Moy,  1979).
II.  EXPOSURE
     A.  Water
         Endosulfan  has been  detected in  water  samples from  some  of  the
streams, rivers,  and lakes  in  the  United States and  Canada and  in Ontario
municipal water supplies.   The  maximum concentration  of endosulfan monitored
in  municipal water  was 0.083  ^ig/1,  which  was found  in Ontario municipal
water samples but  68 jug/1  has been  measured in irrigation run-off (U.S. EPA,
1979).  Endosulfan contamination  of water results  from agricultural runoff,
industrial  effluents,  and  spills.   One  serious  accidental  industrial dis-
charge  in  Germany in  1969  caused  a  massive  fishkill  in the  Rhine River.
Most  of the  river water  samples contained less  than  500  ng/1  endosulfan.
Residues in  run-off  water  from sprayed  fields can be  as high as  220 jug/1
(U.S. EPA,  1979).
     B.  Food
         An  average  daily  intake (ADI)  less  than  or  equal  to 0.001  mg  of
endosulfan and endosulfan  sulfate was estimated for 1965-1970  from  the mar-
ket basket  study  of the FDA (Duggan and Corneliussen,  1972).   The  U.S. EPA
(1979) has estimated the  weighted average bioconcentration  factor for endo-
sulfan  to  be 28 .for the  edible portions of  fish  and  shellfish consumed  by
Americans.   This estimate is based  on  measured steady-state  bioconcentration
studies with  mussels.   The processing of leafy vegetables causes endosulfan
residues to decline from 11 jug/kg to 6 pg/kg (Corneliussen, 1970).
                                      7

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     C.  Inhalation
         In 1970,  air  samples from 16 states showed an average  level  of 13.0
ng/m   alpha-endosulfan  and  0.2  ng/m   beta-endosulfan.   None  of  the  air
samples collected  in 1971  or 1972 contained detectable levels of either iso-
mer  (Lee,  1976).   Endosulfan residues  (endosulfan and  endosulfan sulfate)
have been  detected in most types of U.S.  tobacco products  in  recent  years
(U.S.  EPA, 1979).   Average  residue levels  range  from  0.12 rag/kg  to  0.83
mg/kg  for  1971-1973 (Domanski, et al.  1973,1974;  Oorough and Gibson,  1972).
The  extent to which  endosulfan  residues  in tobacco products  contribute to
human  exposure  is not  known.   Spray  operators  can  be  exposed  up  to 50
Lig/hour  of endosulfan .from a  usual application  of  a  0.08  percent  spray
(Wolfe,  et al.  1972).   Non-target  deposition  on  untreated   plants  after
spraying may lead  to residues  of  up to 679 ;jg/kg (Keil, 1972).
     0.  Dermal
         Wolfe,  et al. (1972) estimated  that sprayers applying  a  0.08  per-
cent aqueous solution  are  exposed dermally  to 0.6 to 98.3 mg/hour.  Endosul-
fan can persist  on the hands for 1 to 112 days after exposure (Kazen,  et al.
1974).
III. PHARMACOKINETICS
     A.  Absorption
         Undiluted  endosulfan is  slowly  and incompletely absorbed from  the
mammalian  gastointestinal  tract,  whereas endosulfan dissolved  in cottonseed
oil is  readily  though  not completely absorbed  (Boyd and  Oobos,  1969;  Maier-
                                                         -•
Bode, 1968).  The  beta-isomer  is  more readily absorbed  than the alphaisomer.
Alcohols,   oils,  and emulsifiers  accelerate  the absorption of  endosulfan by
the skin (Maier-Sode,  1968).  Inhalation is  not  considered to  be  an  impor-
tant route.of absorption for endosulfan  except  in  spray operators (U.S.  EPA,
1979).

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     8.  Distribution
         After  ingestion  by experimental  animals,  endosulfan  is first dis-
tributed to  the liver and then to  the  other organs of the  body and the-  re-
mainder  of  the  gastrointestinal  tract (Boyd  and  Dobos,  1969; Maier-Sode,
1968).   In cats,  endosulfan levels peaked  in brain,  liver,  spinal  cord  and
plasma,  with the  brain and liver  retaining  the highest concentrations after
administration of a 3 mg/kg dose (Khanna, et al. 1979).
         In  mice,  24  hours  after  oral  administration  of    C-endosulfan,
residues were detected in  fat,  liver,  kidney,  brain,  and  blood (Deema,  et
al. 1966).
         Data  from  autopsies  of three suicides  show levels  of endosulfan in
brain which  were  much lower than  those  in  liver and  kidney,  which  in turn,
were  lower  than levels in  blood  (Coutselinis, et al.  1978).   Data  from  an-
other suicide  indicate  higher levels  of endosulfan  in  liver and kidneys than
in blood (Demeter, et al. 1977).
     Ci  Metabolism
         Endosulfan sulfate  is  the metabolite  most commonly present in tis-
sues,  feces,  and  milk  of  mammals  after administration of  endosulfan (Whit-
acre, 1970;  Demma,  et  al.  1966; FMC,  1963).   The largest  amounts of endosul-
fan sulfate  are found in small intestine and visceral fat  with only traces
in skeletal  muscle  and kidney (Deema, et al.  1966).   Endosulfan sulfate  has
been detected in the brains of  two  humans who committed suicide by ingesting
endosulfan  (Demeter and  Heyndrickx,  1978),  but not  in  the brains  of  mice
given nonfatal doses of endosulfan.   However,  it has been detected in liver,
visceral fat  and  small  intestines  of  mice  (Deema, et  al.  1966).  Other meta-
bolites of endosulfan are endosulfan  lactone,  endosulfandiol,  endosulfan  hy-
droxyether,  and endosulfan ether (Knowles,  1974;  Menzie,  1974).  These meta-
bolites have also been  found in microorganisms and plants  (U.S. EPA,  1979).

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     D.  Excretion
         The principal route  of  excretion for endosulfan and endosulfan sul-
fate is in the  feces  (U.S.  EPA,  1979).   Other  metabolites  are also excreted
in the feces and  to a small extent in the urine, the metabolites in the lat-
ter being  mainly in  the form of  endosulfan alcohol  (U.S. EPA,  1979).   In
studies with sheep  receiving a single oral  dose of radiolabeled endosulfan,
92 percent of the dose was  eliminated in 22 days.  The  organ  with the high-
est concentration of radiolabeled  endosulfan after 40  days was  the  liver.
Major metabolites did not persist in the fat or in the  organs  (Gorbach,  et
al. 1968).  After a single  oral  dose, the half-life of radiolabeled endosul-
fan in  the feces and  urine of sheep was approximately  two days  (Kloss,  et
al. 1966).  Following 14 days of dietary exposure  of  female rats, the half-
life of  endosulfan residues  was approximately  seven  days  (Dorough,  et  al. .-
1978).
IV.  EFFECTS
     A.  Carcinogenicity
         In bioassays  on both mice and  rats,  orally  administered endosulfan
was not carcinogenic  even  though doses were high enough  to produce symptoms
of  toxicity  (Kotin,  et  al.  1968;  Innes,  et al.  1969;  Weisburger,  et  al.
1978).
     8.  Mutagenicity
         Data from  assays with Salmonella typhimurium (with and without  mi-
crosomal activation)  (Oorough, et al. 1978),  Saccharomyces  cerevisiae, Esch-
                                                      *
ericia coli, and  Serratia marcescens  (Fahrig,  1974) indicate that endosulfan
is not  mutagenic.
                                    •11.31-

-------
     C.  Teratogenicity
         Endosulfan  did  not  produce  teratogenic  effects  in  rats  (Gupta,
1978).
     0.  Other Reproductive Effects
         In  rats,  endosulfan  produced dose-related  increases  in  maternal
toxicity  and. caused  increases  in  fetal  mortality and. resorptions  (Gupta,
1978).   Doses of 100  mg/kg  reduce  hatchability  of fertile  white  leghorn
chicken eggs  by  54 percent,  but this was  dependent on carrier  (Dunachie  and
Fletcher,  1969).  Alterations  in  the  gonads  of  the  embryos  within  sprayed
hens'  eggs were  noted  and the progeny  of  hens and quails, Coturnix  Coturnix
japonica, were sterile  (U.S. EPA, 1979).
     E.  Chronic Toxicity
         In the  NCI bioassays (Xotin,  et  al.  1968; Weisberger, et-al.  1978) ^
.endosulfan was  toxic to the kidneys  of rats of both  sexes, and to the kid-
neys  of male mice.   Other signs  of toxicity  were parathyroid hyperplasia,
testicular atrophy in male rats, and high  early death  rates in male mice.
         In  a   two-year  feeding  study  with  rats.  (Hazelton   Laboratories,
1959),  endosulfan at 10 mg/kg diet  reduced testis weight in  males and low-
ered  survival in females; at  100 mg/kg diet,  renal tubular  damage and some
hydropic changes in the liver were induced.
         In humans,  there has been  an absence of toxic effects with proper
handling of endosulfan in the occupational setting (Hoechst, 1966).
     F.  Other Relevant Information
         The  acute  toxicity  of endosulfan  sulfate is  -'about  the same as that
of  endosulfan.    The I_D5Q for technical  endosulfan in  rats  is -— 22  to  46
mg/kg  and 6.9 to 7.5 mg/kg in  mice  (Gupta, 1976).  Reagent grade a- and J3-
endosulfan are  less toxic to rats (76  and 240 mg/kg, respectively; Hoechst,

-------
1967).   The  inhalation  4-hour LC5Q  values for  rats have  been reported as
350  and  80  ug/1  for  males and  females,   respectively  (Ely, et  al. 1967).
Acute  toxicities  of  other metabolites  (endosulfan lactone, endosulfandiol,
endosulfan hydroxyether and  endosulfan ether)  are  less  than  that  of the
parent compound (Dorough, et al. 1978).
         At  very  high levels  of  acute exposure,  endosulfan is  toxic to the
central  nervous  system  (U.S.  EPA,  1979).  Endosulfan  is  a  convulsant and
causes fainting,  tremors,  mental  confusion, irritability, difficulty in uri-
nation,  loss of  memory  and impairment of  visual-motor  coordination.  Acute
intoxification can be  relieved by  diazepam but chronic effects  are manifest-
ed in central nervous system disorders (Aleksandrowicz, 1979).
         There appear to  be  sex  differences  (see previous Chronic  Toxicity
section) and species  differences  in sensitivity to endosulfan.   Of the spe-  ."
pies tested  with  endosulfan, cattle are  the most  sensitive  to the neurotoxic
effects  of endosulfan  and appear  to  be  closer  in  sensitivity  to  humans.
Dermal toxicity of endosulfan-sprayed  cattle is  also high.  Typical  symptoms
are  listlessness,  blind staggers,  restlessness,  hyperexcitability,  muscular
spasms, goose-stepping and convulsions (U.S. EPA,  1979).
         Endosulfan is  a  nonspecific  inducer of   drug metabolizing  enzymes
(Agarwal, et  al.  1978).   Protein  deficient  rats are  somewhat more suscepti-
ble to the toxic  effects of endosulfan than controls  (Boyd and  Oobos, 1969;
Boyd, et al.  1970).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Ninety-six  hour  LC5Q values,  using technical  grade endosulfan,
for  five  species of  freshwater fish  range from  0.3 jjg/1 for  the  rainbow
trout, Salmo  gairdneri,  (Macek, et al.  1969)  to  11.0 ug/1  for  carp  finger-

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lings, Cyprlnus  carpio (Macek, et  al.  1969; Schoettger,  1970;  Ludemann and
Neumann,  1960;  Pickering  and Henderson,  1966).   Among  freshwater inverte-
brates, Daphnia  maqna is  reported  to have 48-hour  LC5Q values ranging from
62 to 166 ug/1 (Macek,  et al. 1976; Schoettger, 1970),  with three other in-
vertebrates  yielding 96-hour  LC5Q  values  of 2.3  (Sanders and  Cope,  1968)
to 107 jjg/1  (Sanders, 1969; Schoettger, 1970).  Levels of  400  and 800 ng/1
of technical endosulfan damaged the kidney,  liver,  stomach and intestine of
Gymonocorymbus ternetzi .   The  96-hour  LC5Q value  was  1.6 ;jg/l (Amminikutty
and Rege, 1977,1978).
         Of the  five saltwater fish species  tested,  the reported 48- or 96-
hour  LC5Q values  ranged  from 0.09  (Schimmel,  et  al.  1977)  to 0.6 jjg/1
(Butler,  1963,1964;  Kom  and Earnest,  1974; Schimmel,  et al.  1977).   The
                    : " j
most sensitive species was the spot (Leiostomus xanthurus ) .
         The seven saltwater  invertebrate  species  tested showed a wide range
of sensitivity  to endosulfan.   The range  of EC5Q  and LC50 values  is from
0.04 (Schimmel,  et al. 1977)  to 380 jug/1 with the  most sensitive species be-
ing the pink shrimp  (Penaeus duorarum) .
     8.  Chronic Toxj "ty
        .Macek,   et  al.  (1976)  provided the  only  aquatic  chronic  study  in-
volving endosulfan.  .No adverse effects on fathead minnow, Pimephales prome-
las,  parents or  offspring were observed  at 0.20 Jug/1.   Gymonocorymbus ter-
netzi chronically exposed  to  400  and  530 ng/1 for 16 weeks evinced necrosis
of intestinal mucosa cells, ruptured hepatic cells and destruction  of pan-
creatic islet cells (Amminikutty and Rege,  1977,1978).
     C.  Plant Effects
                                                                          »
         Little  data is  available  concerning the  effects of  endosulfan  on
aquatic  micro/macrophy tes .   Growth  of  Chlorella  vulqaris  was  inhibited
 >2000jug/l  (Knauf and Schulze, 1973).
                                   -//*-

-------
     D.  Residues
         Schimmel, et  al.  (1977)  studied the uptake, depuration, and metabo-
lism of endosulfan by  the striped mullet,  Mugil  ceohalus.   When the concen-
trations  of endosulfans  I and  II and  endosulfan sulfate  were combined to
determine  the  bioconcentration factor  (BCF), an  average whole-body  BCF of
1,597  was  obtained.   Nearly all  the  endosulfan was in  the  form of the sul-
fate.  Even though the duration  of the study  was  28 days,  this investigator
questioned  whether  a  steady-state condition was  reached.   Complete depura-
tion occurred  in  just two days in an endosulfan-free environment.  Residues
in  pond  sediments may  be  as high as  50 pg/kg 8-endosulfan  and 70 ;jg/kg of
endosulfan  sulfate 280 days after insecticidal endosulfan  application (FMC,
1971).
         Dislodgable  residues  on  cotton foliage  in Arizona declined  to 10
percent and one-third  for the low-melting  and  high-melting  isomers, respec-
tively, 24  hours  after application of 1.1 kg/ha endosulfan.   However, though
residues had declined  to 4 percent and  11 percent respectively, 4 days after
application endosulfan sulfate residues on  the leaves  increased markedly to
0.14 jjg/cm2 (Estesen, 1979).
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human health nor the  aquatic, criteria  derived by U.S.  EPA
(1979), which are summarized below,  have gone through the process of public
review;  therefore,   there is  a  possibility  that  these criteria will  be
changed.
     A.  Human
         The U.S. EPA  (1979) has  recommended a draft criterion for endosul-
fan in ambient  water of 0.1 mg/1  based  on  an ADI of 0.28 ing/day.   This  ADI
was calculated  from a NOAEL  of  0.4 mg/kg obtained for mice  in  a chronic
feeding study (Weisburger, et al.  1978)  and an uncertainty factor of 100.

                                  -///.?-

-------
         The  American  Conference   of   Governmental   Industrial  Hygienists
(ACGIH, 1977)  TLV time weighted  average for  endosulfan is 0.1  mg/m .   The
tentative value  for  the TLV short-term  exposure limit  (15 minutes)  is  0.3
mg/m"5.
         The  ADI for  endosulfan  established  by the  Food and  Agricultural
Organization and the World Health Organization is 7.5  ug/kg (FAQ, 1975).
     8.  Aquatic
         For  endosulfan,  the draft  criterion  to protect  freshwater  aquatic
life is 0.042 ug/1  in. a 24-hour average and  not to exceed 0.49 /jg/1 at  .any
time.  Saltwater criteria cannot be  developed because of  insufficient  data
(U.S. EPA, 1979).
                                  -1111-

-------
                                  ENDOSULFAN

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Agarwal, O.K.,  et  al.  1978.  Effect  of  endosulfan on drug metabolizing en-
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Aleksandrowicz,  O.R.   1979.   Endosulfan  poisoning and  chronic  brain syn-
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Amminikutty,  C.K.  and  M.S.  Rege.   1977.   Effects of  acute  and chronic ex-
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Amminikutty, C.K. and M.S. Rege.   1978.   Acute and chronic effect of Thioden
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Berg,  H.    1976.     Farm   chemicals  handbook.    Meister  Publishing  Co.,
Willoughby, Ohio.

Boyd, E.M.  and  I. Dobos.   1969.  Protein  deficiency and tolerated oral doses
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Boyd, E.M.,  et  al.   1970.   Endosulfan toxicity  and dietary  protein.  Arch.
Environ. Health. 21: 15.

Butler, P.A.  1963.   Commercial fisheries investigations, pesticide-wildlife
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Butler, P.A.  1964.   Pesticide-wildlife studies,  1963.   A review of Fish and
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Cassil, C.C. and P.E. Orummond.  1965. A plant surface oxidation product of
endosulfan.. Jour.  Econ. Entomol.- 58: 356.

Chopra, N.  and A.  Mahfouz.   1977.  Metabolism of endosulfan  I,  endosulfan
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Gorneliussen, P.E.   1970.   Residues in food and  feed:  pesticide residues in
total diet samples (V).   Pestic. Monit. Jour.  4: 89.

Coutselinis, A., et al.  1978.  Concentration  levels  of endosulfan  in bio-
logical material (report of three cases).   Forensic Sci.  11: 75.

-------
Oeema,  P.,  et al.   1966.   Metabolism,  storage,  and excretion  of
sulfan in the mouse.  Jour. Econ. Entomol.  59: 546.

Oemeter,  J.  and  A. Heyndrickx.   1978.   Two lethal endosulfan  poisonings in
man.  Jour. Anal. Toxicol.  2: 68.

Demeter,  J.,  et  al.  1977.   Toxicological  analysis in a case  of endosulfan
suicide.  Bull. Environ. Contain. Toxicol.  18: 110.

Oomanski,  J.J.,  et  al.   1973.   Insecticide  residues on  1971  U.S.  tobacoo
products.  Tobacco Sci.  17: 80.

Oomanski,  J.J.,  et  al.   1974.   Insecticide  residues on  1973  U.S.  tobacco
products.  Tobacco Sci.  18: 111.

Dorough,  H.w.  and J.R.  Givson.   1972.  .Chlorinated insecticide residues in
cigarettes purchases in 1970-72.  Environ. Entomol.  1: 739.

Dorough,  H.W.,  et al.   1978.   Fate  of endosulfan  in  rats and  toxicological
considerations of apolar metabolites.  Pestic. Biochem. Physiol.  8: 241.

Ouggan,  R..E.  and P.E.  Corneliussen.    1972.   Dietary  intake   of  pesticide
chemicals  in the  United States  (III),  June  1968 to April  1970.   Pestic.
Monit. Jour.  5: 331.

Dunachie, J.F. and W.W.  Fletcher.  1966.  Effect  of some  insecticides on the
hatching rate of hens' eggs.  Nature  212: 1062.

Ely,  T.S.,   et  al.   1967.   Convulsions  in Thiodan  workers:  a preliminary
report.  Jour. Occup. Med.  9: 36.

Estesen,  B.J.,  et  al.   1979.   Dislodgable  insecticide  residues  on  cotton
foliage: Permethrin, Curocron, Fenvalarate, Sulprotos, Decis and Endosulfan.
Bull. Environ. Contam. Toxicol.  22:  245.

Fahrig, R.   1974.   comparative mutagenicity  studies  with pesticides.   Int.
Agency Res. Cancer Sci. Publ.  10: 161.

FAO.  1975.  Pesticide residues in food:  report of the 1974  Joint Meeting of
the FAO  Working  Party of Experts  on Pesticide Residues and  the WHO  Expert
Committee  on Pesticide  Residues.   Agricultural   Studies  NO.   97,  Food  and
Agriculture Organization of the United States, Rome.

FMC Corp.   1963.  Unpublished  laboratory  report  of  Niagara Chemical  Divi-
sion,  FMC Corporation, Middleport, New York.  In:  Maier-Bode, 1968.

FMC Corp.  1971.   Project  015:  Determination of endosulfan I,   endosulfan II
and endosulfan sulfate  residues in  soil, pond, mud and water.   Unpublished
report.   Niagara  Chemical  Division, FMC  Corp.,   Richmond, Cal.   In:  Natl.
Res. Council, Canada, 1975.

Gorbach, S.G., et al.  1968.  Metabolism  of endosulfan in milk  sheep.   Jour.
Agric. Food Chem.  16: 950.
                                  -i in-

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Gupta,  P.X.   1976.   Endosulfan-induced  neurotoxicity  in  rats  and mice.
Bull. Environ. Contam. Toxicol.  15: 708.

Gupta, P.K.   1978.   Distribution of endosulfan in plasma and brain after re-
peated oral administration to rats.  Toxicology   9:  371.

Hazleton  Laboratories.   1959.   Unpublished  report,  May 22.   Falls  Church,
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Hoechst.   1966.   Unpublished  report of  Farbwerke  Hoechst  A.G., Frankfurt,
West Germany.  In: Maier-8ode, 1968.                            .   ....

Hoechst.   1967.   Oral  LD5Q values  for white  rats.  Unpublished  report of
Farbwerke  Hoechst A.G.,  Frankfurtr,  West  Germany.   Cited  in  Demeter  and
Heyndrickx, 1978.  Jour. Anal. Toxicol.  2:  68.

Innes,  J.R.M.,  et al.   1969.   bioassay  of pesticides  and  industrial chem-
icals  for tumorigenicity  in  mice:  a  preliminary note.  Jour.  Natl. Cancer
Inst.  42: 1101.

Kazen,  C.,  et  al.   1976.  Persistence of  pesticides  on the  hands  of some
occupationally exposed people.  Arch. Environ, health  29: 315.

Keil,  J.E.,   et  al.   1972.  Decay  of  parathion and endosulfan  residues on
field-treated tobacco, South Carolina,  1971.  Pestic. Monit. Jour.  6: 73.

Khanna, R.N., et  al.  1979.  Distribution of endosulfan in cat brain.  Bull.
Environ. Contam.  Toxicol.  22: 72.

Kloss, G.,  et al.   1966.   Versuche an Schaffen  mit cl^-markierten Thiodan.
Unpublished.  In: Maier-Bode, 1968.

Knaut, W.  and C.F.  Schulze.   1973.  New  findings on the toxicity  of endo-
sulfan and  its  metabolites to aquatic organisms.   Meded.  Fac. Landlouwwey.
Kijksuniv. Gent.  38: 717.

Knowles,  C.O.  1974.  Detoxification  of  acaricides by  animals.   Pages 155-
176  In;  M.A.  Kahn and  J.P.  Sederka, Jr.,  eds.   Survival in  toxic environ-
ments.  Academic Press,  New York.

Korn,  S., and  R.  Earnest.  1974.   Acute  toxicity of  20  insecticides  to
striped bass  Morone saxatilis.   Calif. Fish Game  69: 128.

Kotin, P., et al.  1968.   Evaluation of carcinogenic,  teratogenic  and muta-
genic activites of  selected pesticides and  industrial chemicals.   Pages  64,
69  In:  Vol.   1: carcinogenic  study.  Bionetics  Research  Laboratories report
to Natl. Cancer Inst.  NTIS-PB-223-159.

Lee, R.L., Jr.   1976.   Air pollution  from pesticides and  agricultural pro-
cess.  CRC Press,  Inc.,  Cleveland,  Ohio.

Ludemann,  0.  and H.  Neumann.   1960.   Versuche  uber   die  akute  toxische
Wirkung  neuzeitlicher  Kontaktinsektizide  auf einsommerige Karfen  (Cyprinum
caroio L.)  Z. Angew. Zool.  47:  11.
                                 -If1/7-

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 Macek, K.J., et al.   1969.   The  effects of temperature on the susceptibility
 of  bluegills and  rainbow  trout  to  selected pesticides.   Bull.  Environ.
 Contam. Toxicol.  4: 174.

 Macek, K.J.,  et al.  1976.   Toxicity  of four pesticides  to  water fleas and
 fathead minnows.  EPA-600/3-76-099.  U.S. Environ. Prot. Agency.

 Maier-Sode,  H.   1968.   Properties,  effect,  residues  and analytics  of the
 insecticide endosulfan (review).   Residue Rev.  22: 2.

 Martens,   R.   1976.   Degradation  of (8,9,-C-14)  endosulfan  by  soil  micro-
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 Menzie,  C.M.   1974.  Metabolism of pesticides:  an update.   Special  scien-
 tific  report.   Fish  and  Wildlife Service, Wildlife 184.   U.S.  Department of
 Interior, Washington, D.C.

 Miles, J.R.W. and  P. Moy.   1979.   Degradation of endosulfan  and its  metab-
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 Pickering, Q.H. and  C.  Henderson.   1966.  The acute  toxicity  of some  pesti-
 cides to fish.  Ohio Jour. Sci.  66: 508.

 Sanders,   H.O.   1969.   Toxicity  of pesticides  to  the crustacean  Gammarus
 lacustris.  U.S. Bur. Sport Fish Wildl. Tech. Pap. 25.

 Sanders,  .H.O.   and  O.B.   Cope.   1968.    The  relative  toxicities  of  several
 pesticides  to   naiads  of three  species  of  stoneflies.   Limnol.  Oceanogr.
. 13: 112.

 Schimmel,  S.C.,  et  al.   1977.  Acute  toxicity  to  and bioconcentration of
 endosulfan by estuarine  animals.   Aquatic toxicology and  hazard evaluation.
 ASTM STP 634, AM.  Soc. Test. Mat.

 Schoettger,  R.A.    1970.   Fish-pesticide  research laboratory,   progress  in
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 Publ. 106.

 U.S. EPA.  1979.  Endrin: Ambient Water Quality Criteria.   (Draft)

 Weisburger, J.H.,  et al.   1978.   Bioassay of  endosulfan  for possible  car-
 cinogenicity.   National  Cancer   Institute  Division   of   Cancer  Cause  and
 Prevention,  National Institutes   of  Health,  Public  Health  Service,  U.S.
 Department  of  Health,   Education  and  Welfare,   Bethesda,   Maryland,  Pub.
 78-1312.   Report by Hazleton Laboratories to NCI,  NCI-CG-TR-62.   54 pp.

 Whitacre,  D.M.   1970.  Endosulfan  metabolism in  temperature-stressed rats.
 Diss. Abstr. Int.   30: 44358.

 Wolfe, H.R.,  et  al.   1972.  Exposure  of  spraymen  to  pesticides.   Arch.
 Environ.  Health  25: 29.

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                                      No. 99
               Endrln
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal .  The information contained in  the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

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                           EN DRIM



                           SUMMARY



     Endrin does not appear to be carcinogenic.   Endrin  is



teratogenic and embroytoxic in high doses and produces gross



chromosomal abnormalities when administered  intratesticu-



larly.  Chronic administration of endrin causes damage to  the



liver, lung, kidney, and heart of experimental animals.  No



information about chronic effects in humans  is available.



The ADI established by the Food and Agricultural  Organization



and World Health Organization is 0.002 mg/kg.



     Endrin has proven to be extremely toxic to aquatic  orga-



nisms.  In general, marine fish are more sensitive  to endrin



with an arithmetic mean LCgg value of 0.73 ug/1/'  than



freshwater fish with an arithmetic mean LCgg value  of



4.42 ug/1.  Invertebrate species tend to be more  resistant



than fish with arithmetic mean LCjQ values of 3.80  and



58.91 ug/1 for marine and freshwater invertebrates, respec-



tively .
                          '1151-

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                           ENDRIN

I.    INTRODUCTION

     Endrin (molecular weight 374)  is a  broad  spectrum  insec-

ticide of the group of polycyclic chlorinated  cyclediene  hy- .

drocarbons of which the  insecticides aldrin  and  dieldrin  are

also members.  Endrin is isomeric with dieldrin  and  is  used

as a rodenticide and ovicide.  The  endrin sold  in  the U.S.  is

a technical grade product containing not less  than 95 percent

active ingredient.  The  solubility  of endrin in  water at  25°C

is about 200 ug/1 (U.S.  EPA, 1979).  Its vapor  pressure  is  2

x 10~7 mm Hg at 25°C (Martin, 1971).

     Endrin is used primarily as an insecticide  and also  as  a

rodenticide and avicide.  Over the  past  several  years,  endrin

utilization has been increasingly restricted  (U.S. EPA, 1979.

Endrin production in 1978 was approximately  400,00.0 pounds

(U.S. EPA, 1978).  Endrin persists  in the soil  (U.S. EPA,

1979).

II.  EXPOSURE

     A.   Water

          Occasionally,  groundwater may  contain  more than 0.1

ug/1.  Levels as high as 3 ug/1 have been correlated with

precipitation and run off following endrin applications  (U.S.

EPA, 1978).

          Concentrations of endrin  in finished drinking water

have been decreasing.  In a study of ten municipal water
                                                           »
treatment plants on the  Mississippi or Missouri  Rivers, the

number of finished water samples containing  concentrations of

endrin exceeding 0.1 y.g/1 decreased from ten percent in 1964-

-------
1965 to zero in 1966-1967  (Schafer,  et  al.,  1969).   The  high-

est concentration of endrin  in drinking  water  in New Orleans,

Louisiana measured by the  O.S. EPA  in 1974 was  4 ng/1 (U.S.

EPA, 1974).

     B.   Food

          The general population  is  rarely exposed  to endrin

through the diet.  In the  market  basket  study  by the FDA,  the

total average daily  intake from food  ranged  from approximate-

ly 0.009 ugAg body weight  in 1965  to 0.0005 ugAg  body

weight in 1970 (Duggan and Lipscomb,  1969; Duggan  and Corne-

liussen, 1972).

          The U.S. EPA (1979) has estimated  the weighted  av-

erage bioconcentration factor of  endrin  at 1,900 for the  edi-

ble portions of fish and shellfish  consumed  by  Americans.

This estimate is based on  measured  steady-state bioconcentra-

tion studies in six  species  (both freshwater and saltwater).

     C.   Inhalation

          Exposure of the  general population to endrin via

the air decreased from a maximum  level  of 25.6  ug/^3 in

1971 to a maximum level of 0.5 ug/m3  in  1975 (U.S.  EPA,

1979).

          Tobacco products  are contaminated  with endrin  resi-

dues.  Average endrin. residues for  various types of  tobacco
                                            ,•
products have been reported  in the  range of  0.05 ug/9 to  0.2

ug/g (Bowery, et al., 1959;  Domanski  and Guthrie,  1974).

          Inhalation exposure of  users  and manufacturers  of

endrin sprays may be around  10 ug/hour  (Wolfe,  et  al. 1967)

but use of dusts can produce levels  as  high  as  0.41  mg/hour

(Wolfe, et al. 1963).

-------
     D.   Dermal


          Dermal exposure of spray operators .can  range  up  to


3 mg/body/hour even for operators wearing standard protective


clothing (Wolfe, et al. 1963, 1967).  The spraying of dusts


can lead to exposures of up to 19 mg/hour (Wolfe, et al.


1963).


III. PHARMACOKINETICS


     A.   Absorption


          Endrin is known to be absorbed through  the skin,


lungs,  and gut, but data on the rates of absorption are not


available (U.S.  EPA, 1979).


B.   Distribution


          Endrin is not stored in human tissues  in signifi-


cant quantities.  Residues were not detected in plasma, adi-


pose tissue, or urine of workers exposed to endrin (Hayes  and


Curley, 1968).  Measurable levels of endrin have  not been  de-


tected  in human subcutaneous fat or blood, even  in persons


living  in areas where endrin is used extensively  (U.S.  EPA,


1979).   Endrin residues have been detected in the body  tis-


sues of humans only immediately after an acute exposure (U.S.


EPA, 1979; Coble, et al. 1967).


          In a 128 day study, dogs were fed 0.1 mg/endrin/kg


body weight/day. . Concentrations of endrin in the tissues  at


the end of the experiment were as follows: adipose tissue,


0.3 to  0.8 ug/g; heart, pancreas, and muscle,  0.3 ug/1;
                                                            »

liver,  kidney and lungs, 0.077 to 0.085 ug/g; blood, 0.002 to


0.008 ug/g (Richardson, et al., 1967).  In a six month.feed-


ing study with dogs at endrin levels of 4 to 8 ppm in the
                            -IISV-
                               7

-------
diet, concentrations of endrin were  1  ug/g  in  fat,  1  ug/g  in



liver, and 0.5 ug/g in kidney  (Treon,  et  al. ,_ 1955) .



     C.   Metabolism



          In rats, endrin  is readily metabolized  in  the  liver



and excreted as hydrophilic metabolites  including  hydroxyen-



drins, and 12-ketoendrin  (also known as  9-ketoendrin).   Hy-



droxyendrins and especially 12-ketoendrin have  been  reported



to be more acutely toxic  to mammals  than  the parent  compound



(Bedford, et al., 1975; Hutson,  et al.,  19.75).  The  12-keto-



endrin is also more persistent in  tissues.   Female  rats  me-



tabolize endrin more slowly than males (Jager,  1970).



     D.   Excretion



          Endrin is one of the least persistent chlorinated



hydrocarbon pesticides (U.S. EPA,  1979).  Body  content of  en-



drin declines fairly rapidly after a single  dose  or  when a



continuous feeding experiment  is terminated  (Brooks,  1969).



In rats, endrin and its metabolites  are  primarily  excreted



with the feces (Cole, et  al., 1968;  Jager,  1970).   The major



metabolite in rats is anti-12-hydroxyendrin  which  is  excreted



in bile as the glucuronide.  12-Ketoendrin was  observed  as a



urinary metabolite in male rats; the major  urinary  metabolite



in female rats is anti-12-hydroxyendrin-O-sulfate  (Hutson, et



al. , 1975).



          In rabbits, excretion  is primarily., urinary.  In  fe-



males, endrin excretion also occurs  through  the milk.  Al-



though endrin is rapidly  eliminated  from  the body,  some  of



its metabolites nay persist for  longer periods  of  time  (U.S.



EPA, 1979) .

-------
IV.  EFFECTS

     A.   Carcinogenicity

          In lifetime feeding studies with Osborne-Mendel

rats, endrin was neither tumorigenic nor carcinogenic  (Deich-

mann, et al., 1970; Deichmann and MacDonald, 1971; Deichmann,

1972).  A recent NCI bioassay concluded that endrin was not

carcinogenic for Osborne-Mendel rats or for B6C3F1 mice

(DHEW, 1979).  However, a different conclusion has been

reached by Reuber  (1979) based only on one study  (National

Cancer Institute,  1977), compared with eight other inconclu-

sive or unsatisfactory studies.

     B.   Mutagenicity

          Endrin (1 mg/kg) administered intratesticularly

caused chromosomal aberrations in germinal tissues of  rats,

including stickiness, bizarre configurations, and abnormal

disjunction (Dikshith and Datta, 1972, 1973).

     C.   Teratogenicity

          An increased incidence of club foot was found in

fetuses of mice that had been treated with endrin (0.58 mg/

kg) before becoming pregnant (Nodu, et al., 1972).

          Treatment of pregnant hamsters with endrin (5 mg/

kg) produced the following congenital abnormalities: open

eye, webbed foot,  cleft palate, fused ribs, and meningoen-
                                           *
cephalocele (Ottolenghi, et al.., 1974; Chernoff,  et al.,

1979).  Treatment of pregnant mice with endrin (2-5 mg/kg)

produced open eye  and cleft palate in the offspring (Otto-

lenghi, et al., 1974).  Single doses which produced terato-

-------
genie effects in hamsters and mice were  one-half  the  LDcg

in each species (Ottolenghi, et al.,  1974).

     D.   Other Reproductive Effects

          Endrin given to hamsters during gestation produced

behavioral effects  in both dams and offspring  (Gray,  et  al.,

1979).  In another  study endrin produced a high  incidence  of

fetal death and growth,, retard at ion (Ottolenghi,  et al.,

1974).

     E.   Chronic Toxicity

          Manmals appeared to be  sensitive to  the  toxic  ef-

fects of endrin at  low levels in  their diet.   Significant

mortality occurred  in deer mice fed endrin at  2 mg/kg/day  in

the diet (Morris, 19^>\   The mice exhibited symptoms of CNS

toxicity including  convulsions.   Lifetime feeding  of  endrin

to rats at 12 mg/kg/day in the diet decreased  viability  and

produced moderate increases in congestion and  focal hemor-

rhages of the lung; slight enlargment, congestion  and mott-
                      y
ling of the liver,  and slight enlargement, discoloration or

congestion of the kic. ..eys (Deichmann, et al. ,  1970).   After

19 months on diets  containing 3 mg/kg/day endrin,  dogs had

significantly enlarged kidneys and hearts (Treon,  et  al.,

1955) .

          Chronic administration  of relatively small  doses of

endrin to monkeys produced a characteristic change in the

electroencephalogram  (EEC); at higher doses, electrographic

seizures developed.   EEC and behavior were still abnormal

three weeks after termination of  endrin  administration;  sei-

-------
zures recurred under stress conditions months after  termina-



tion of endrin administration  (Revin, 1968). :



     F.   Other Relevant Information



          Endrin is more toxic, in both acute and chronic



studies, than other cyclodiene  insecticides  (U.S. EPA,



1979).



          Female rats metabolize and eliminate endrin more



slowly than males (Jager, 1970) and are more sensitive  to en-



drin toxicity (U.S. EPA, 1979).  Dogs and ..monkeys are more



susceptible to endrin toxicity  than other species (U.S. EPA,



1979).



          Endrin,•given in equitoxic doses with delnav, DDT,



or parathion gave lower than expected LD$Q values, sug-



gestive of antagonism.  Endrin  given in equitoxic doses with



aldrin (a closely related compound) or chlordane gave higher



than expected LD5Q values suggestive of synergism (Kep-



linger and Deichmann, 1967).   Humans poisoned acutely exhibit



convulsions, vomiting, abdominal pain, nausea, dizziness,



mental confusion, muscle twitching and headache.  Such  symp-



toms have been elicited by doses as low as 0.2 mg/kg body



weight.  Any deaths have usually occurred through respiratory



failure (Brooks, 1974).



V.  . AQUATIC TOXICITY



     A.   Acute



          The toxic effects of  endrin have been extensively



studied in freshwater fish.  LCgg values for static



bioassays ranged from 0.046 ug/1 for carp fry (Cyprinus



carpio) fry to 140.00 ug/1 for  adult carp (lyatomi,  et  al.,

-------
1958).  Excluding the results of age  factor differences  for



this species, adjusted static LC5Q values  ranged  from



0.27 ug/1 for large mouth bass  (Microptecus salmoides)



(Fabacler, 1976) to 8.25 ug/1 for the bluegill  (Lepomis



macrochirus) (Katz and Chadwick, 1961).  The LC50 values



for flow-through assays were 0.27 ug/1 for the  bluntnose



minnow (Pimeplales notatus) to  2.00 ug/1 for the  bluegill



(U.S. EPA, 1979).  Twenty-five  LC50 values for  17 species



of freshwater invertebrates were reported,'' and  ranged  from



0.25 ug/1 for stoneflies (Pteronarcys californica) to  500.0



ug/1 for the snail, (Physa gyrina) (U.S. EPA, 1979).



          For marine fish, LC^Q values ranged from 0.005



ug/1 for the Atlantic silversides (Menidia menidia)  (Eisler,



1970) to 3.1 ug/1 for the northern puffer  (Sphaeroides macu-



latus).  A total of 17 species  were tested in 33  bioassays.



The most sensitive marine invertebrate tested was the  pink



shrimp, (Penaeus duordrum) with an LCgg value of  0.037



ug/1, while the blue crab (Callinectes sapidus) was  the most



resistant, with an LC5Q of 25 ug/1.



     B.   Chronic



          Freshwater fish chronic values of 0.187 ug/1 and



0.257 ug/1 were reported for fathead minnows (Pimephales



promelas) (Jarvinen and Tyo, .1978) and flagfish (Jordanella



floridae) Hermanutz, 1978), respectively,  in life cycle



toxicity tests.  No freshwater  invertebrate species  have been



chronically examined.  The marine fish, the sheepshead minrfow



(Cyprinodon variegatus) has provided a chronic  value of  0.19



ug/1 from embryolarval tests (Hansen, et al., 1977).   The
                            -/AT?

-------
grass shrimp (Palaemonetes pugio) must be exposed  to  less

than a chronic concentration of 0.038 ug/1 for  reproductive

success of this marine invertebrate species  (TylerShroeder,

in press).

     C.   Plants

          Toxic effects were elicited at concentrations  for

freshwater algae ranging from 475 ug/1 for Anacystis  nidu-

laras (Batterton, 1971) to >20,000 ug/1 for  Scenedesmus  quad-

ricauda and Oedogonium sp.  Marine: algae a-ppeared  more sensi-

tive with effective concentration ranging from  0.2 ug/1  for

the algae, Agmenellum quadruplicatum (Batterton, 1978),  to

1,000 ug/1 for the algae Dunaliella tertiotecta  (U.S. EPA,

1979).

     D.   Residues

          Bioconcentration factors ranged from  140 to 222  in

four species of freshwater algae.  Bioconcentration factors

ranging from 1,640 for the channel catfish Ictalurus  puncta-

tus (Argyle, et al. 1973) to 13,000 for the  flagfish  Jordan-

ella floridae (Hermanutz, 1978) have been obtained.   Among

four marine species, bioconcentration factors ranging from

1,000 to 2,780 were observed for invertebrates  and from  1,450

to 6,400 for marine fish.  Residues as high  as  0.5 ppm have

been found in- the mosquito fish, Gambus ia affinis  (Finley, et
                                            -•
al. 1970) and fish frequently have contained levels above  0.3

ppm (Jackson, 1976).

VI.  EXISTING GUIDELINES AND STANDARDS

     Both the human health and aquatic criteria  derived  by

U.S. EPA  (1979), which are summarized below, have  not gone

-------
through the process of public  review;, therefore,  there  is  a



possibility that" these criteria may  be  changed.



A.   Human



          The U.S. EPA (1979)  has  calculated  an  ADI  for en-



drin of 70 ug from a MOAEL of  0.1  rag/kg  for dogs  in  a  128  day



feeding study and an uncertainity  factor of 100.   The  U.S.



EPA (1979) -draft criterion of  1 ug/1  for endrin  in ambient



water is based on the 1  ug/1 maximum  allowable  concentration



for endrin in drinking water proposed  by the  Public  Health



Service in 1965 (Schafer, et al.,  1969)  and on  the calcula-



tions by EPA.  Human exposure  is assumed to come  from  drink-



ing water and fish products only.



          A maximum acceptable level  of  0.002 mg/kg  body



weight/day (ADI) was established by  the  Food  and  Agricultural



Organization (1973) and  the World  Health Organization.



          A time weighted average  TLV for endrin  of  100



ug/m^ has been established by  OSHA (U.S. Code of  Federal



Regulations, 1972) and ACGIH (Yobs,  et  al., 1972).



          The U.S. EPA (40 CFR Part  129.102)  has  promulgated



a toxic pollutant effluent standard  for  endrin  of 1.5  ug/1



per average working day  calculated over  a period  of  one



month, not to exceed 7.5 ug/1  in any  sample representing one



working-day's effluent.  In add ition,. discharge  is not  to  ex-



ceed 0.0006 kg per 1,000 kg of production.

-------
     B.   Aquatic



          The draft criterion for  the protection  of  fresh-



water aquatic life is 0.0020 ug/1  as a  24  hour  average  con-



centration not to exceed 0.10 ug/1.  For marine, organisms,



the draft criterion is 0.0047 ug/1 as a 24 hour average not



to exceed 0.031 ug/1.

-------
                            ENDRIN

                          REFERENCES

Argyle, R.L., et al.  1973.  Endrin uptake and release by
fingerling channel catfish, Ictaluras punctatus.  Jour.
Fish Res. Board Can. 30: 1743"!        "

Batterton, J.C., et al.  1971.  Growth response of bluegreen
algae to aldrin, dieldrin, endrin and their metabolites.
Bull. Environ. Contain. Toxicol. 6: 589.

Bedford, C.T., et al.  1975.  The acute toxicity of endrin
and its metabolites to rats.  Toxicol. Appl. Pharmacol.
33: 115.

Bowery, T.G., et al.  1959.  Insecticide residues on tobacco.
Jour. Agric. Food Chem.  7: 693.

Brooks, G.T.  1969.  The metabolism of diene-organochlorine
(cyclodiene) insecticides.  Residue Rev.  28: 81.

Brooks, G.T.  1974.  Chlorinatedlnsecticides.  Vol. II.
Biological and environmental aspects.  CRC Press, Cleveland,
Ohio.

Chernoff, N., et al.  1979.  Perinatal toxicity of endrin
in rodents. I. Fetotoxic effects of prenatal exposure in
hamsters.  Manuscript submitted to Toxicol. Appl. Pharmacol.
and the U.S. Environ. Prot. Agency.

Colde, Y., et al.  1967.  Acute endrin poisoning.  Jour.
Amer. Med. Assoc. 203.: 489.

Cole, J.F., et al.  1968.  Endrin and dieldrin: A comparison
of hepatic excretion rates in the rat.  (Abstr.) Toxicol.
Appl. Pharmacol.  12: 298.

Deichmann, W.B.  1972.  Toxicology of DDT and related chlorin-
ated hydrocarbon pesticides.  Jour. Occup. Med.  14: 285.

Deichmann, W.B., and W.E. MacDonald.  1971.  Organochlorine
pesticides and human health.  Food Cosmet. Toxicol.  9:
91.

Deichmann, W.B., et al.  1970.  Tumorigenicity of aldrin,
dieldrin, and endrin in the albino rat.  Ind_ Med. Srug.
39: 37.

Dikshith, T.S.S., and K.K. Datta.  1972.  Effect of intra-
testicular injection of lindane and endrine on the testes
of rats.  Acta Pharmacol. Toxicol.  31: 1.
                           -J/63

-------
Dikshith, T.S.S., and K.K. Datta.  1973.  Endrin  induced
cytological changes in albino rats.  Bull. Environ. Cotam.
Toxicol.  9: 65.

Domanski, J.J., and F.E. Guthrie.  1974.  Pesticide residues
in 1972 cigars.  Bull. Environ. Contain. Toxicol.  11:  312.

Duggan, R.E., and G.Q. Lipscomb.  1969.  Dietary  intake
of pesticide chemicals in the United States  (II), June 1966-
April 1968.  Pestic. Monitor. Jour.  2: 153.

Duggan, R.E., and P.E. Corneliussen.  1972.  Dietary  intake
of pesticide chemicals in the United States  (III) , June
1968-April 1970.  Pestic. Monitor. Jour.  5: 331.

Eisler, R.  1970.  Acute toxicities of organochlorine  and
organophosphorous insecticides to estuarine  fishes.  Tech.
Pap. 46.  Bur. Sport Fish. Wildl. U.S. Dep.  Inter.

Fabacher, D.L. 1976.  Toxicity of endrin and an endrinmethyl
parathion formulation to largemouth bass fingerlings.  Bull-
Environ. Contam. Toxicol.  16: 376.

Finley, M.T., et al.  1970.  Possible selective mechanisms
in the development of insecticide resistant  fish.  Pest.
Monit. Jour. 3: 212.

Gray, L..E. , et al.  1979.  The effects of endrin  administra-
tion during gestation on the behavior of the golden hamster.
Abstracts from the 18th Ann. Meet. Soc. of Tox. New Orleans
p. A-200.

Hansen, D.J., et. al.  1977.  Endrin:  Effects on  the  entire
lifecycle .of saltwater fish, Cyprinodon variegatus.  Jour.
Toxicol. Environ. Health  3: T2TT

Hayes, W.J., and A. Curley.  1968.  Storage  and excretion
of dieldrin and related compounds.  Arch. Environ. Health
16: 155.            •

Hermanutz, R.O.  1978.  Endrin and malathion toxicity  to
flagfish  (Jordanella floridae).  Arch. Enviorn. Contam.
Toxicol. 1: 159.

Hutson, D.H., et: al.  1975.  Detoxification  and bioactiva-
tion of endrin in the rat.  Xenobiotica  11: 697.

lyatomi-, K.T., et al.  1958.  Toxicity of endrin  to fish.
Prog. Fish.-Cult.  20: 155.

Jackson, G.A.  1976.  Biologic half-life of  endrin in  chan-'
nel catfish tissues.  Bull. Environ. Contam. Toxicol.  16:
505.

-------
Jager,  K.W.  1970.  Aldrin, dieldrin, endrin, and  telodrin.
Elsevier Publishing Co., Amsterdam.
Jarvinen, A.W., and R.M. Tyo.  1978.
minnows of endrin in food and water.
Toxicol. 7: 409.
                   Toxicity to fathead
                   Arch. Environ. Contam.
Katz, M.,  and G.G. Chadwick.  1961.  Toxicity of endrin
to some Pacific Northwest fishes.  Trans. Am. Fish. Soc.
90: 394.

Keplinger, M.L., and W.B. Deichmann.  1967.  Acute  toxicity
of combinations of pesticides.  Toxicol. Aopl. Pharmacol.
10: 586.
Martin, H.  1971.
Prot. Council.
Pesticide manual, 2nd ed.  Brit.  Crop
Morris, R.D.  1968.  Effects of endrin feeding on survival
and reproduction in the deer mouse, Peromyscus maniculatus,
Can. Jour. Zool.  46: 951.

National Cancer Institute.  1977.  Bioassay of endrin for
possible carcinogenicity.  NCI Technical Report Series,
No. 25.

National Cancer Institute.  1979.  Bioassay of endrin for
possible carcinogenicity.  HEW Pub. No.  (NIH) 79-812.  U.S.
Dept. of Health, Education and Welfare, Bethesda, Md.

Nodu, et. al.  1972.  Influence of pesticides on embryos.
On the influence of organochloric pesticides  (in Japanese)
Oyo Yakuri  6: 673.

Ottolenghi, A.D., et al.  1974.  Teratogenic effects of
aldrin, dieldrin, and endrin in hamsters and mice.  Terato-
logy 9: 11.
Reuber, M.D.  1979.
Environ. 12: 101.
  Carcinogenicity of endrin.  Sci.  Tot.
Revin, A.M.  1968.  Effects of chronic endrin administration
on brain electrical activity in the squirrel monkey.  Fed.
Prac.  27: 597.

Richardson, L.A., et al.  1967.  Relationship of dietary
intake to concentration of dieldrin and endrin  in dogs.
Bull. Environ. Contam. Toxicol.  2: 207.

Schafer, M.L., et al.  1969.  Pesticides  in drinking water
- waters from the Mississippi and Missouri Rivers.  Environ*.
Sci. Technol.  3: 1261.
                            -/I if'

-------
Treon, J.F., et al.  1955.  Toxicity of endrin for labora-
tory animals.  Agric. Food Chem.  3: 842.

Tyler-Schroeder, D.B.  Use of grass shrimp, Palaemonetes
pugio, in a life-cycle toxicity test.  In Proceedings of
Symposium on Aquatic Toxicology and Hazard Evaluation.
L.L. Marking and R.A. Kimerle, eds. Am. Soc. Testing and
Materials (ASTM), October 31-November 1, 1977.   (In press).

U.S. EPA.  1974.  Draft analytical report—New Orleans area
water supply study.  Lower Mississippi River facility, Sur-
veillance and Analysis Division, Revion VI, Dallas. Texas.

U.S. EPA.  1978.  Endrin-Position Document 2/3.  Special
Pesticide Review Division.  Office of Pesticide Programs,
Washington, D.C.
                                          \
U.S. EPA.  1979.  Endrin:  Ambient Water Quality Criteria.
(Draft).

Wolfe, H.R.,- et al.  1963.  Health hazards of the pesticides
endrin and dieldrin.  Arch. Enviorn. Health 6: 458.

Wolfe, H.R., et al.  1967.  Exposure of workers to pesti-
cides.  Arch. Environ. Health 14: 622.

Yobs, A.R., et al.  1972.  Levels of selected pesticides
in ambient air of the United States.  Presented at the National
American Chemical Society—Symposium of Pesticides in Air.
Boston, Maine.

-------
                                          No. 100
Epichlorohydrin (l-chloro-2,3-epoxypropane)

      Health and Environmental Effects
    U.S. ENVIRONMENTAL PROTECTION AGENCY
           WASHINGTON, D.C.  20460

               APRIL 30, 1980

-------
                          DISCLAIMER
     This report represents  a  survey of  the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including ; "' ) the
adverse health  and  environmental  impacts  presented by' the
subject chemical.   This  document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                       SPECIAL NOTATION










U.S. EPA1s Carcinogen Assessment  Group  (CAG) has evaluated



epichlorohydrin and has found  sufficient evidence to in-



dicate that this compound  is carcinogenic.
                            -III?-

-------
                          l-CHLDRO-2,3-EPOXYPROPANE
                              (Epichlorohydrin)
                                   Summary
     The adverse health  effects  associated with exposure to epichlorohydrin
are extreme irritation to the eyes, skin, and respiratory tract.   Inhalation
of  vapor  and  percutaneous  absorption  of  the  liquid  are the  normal  human
routes of  entry.   Exposure  to epichlorohydrin usually  results  from  occupa-
tional contact with the chemical, especially in glycerol and epoxy  resin op-
erations.   Pulmonary effects have been well documented.  Recent studies have
demonstrated epichlorohydrin  to  be a  potent  carcinogen to  nasal tissue  in
experimental animals.   Cytogenic  studies both in vitro and in vivo  in humans
and  experimental  animals  have  indicated  epichlorohydrin to  be  an  active
clastogenic agent.  No data on the concentration of epichlorohydrin  in drink-
ing water or foods have been  reported.  Studies on the  effects of epichloro-
hydrin to aquatic  organisms  could not  be .located in the  available  literature.
                                  -1170-

-------
I.   INTRODUCTION
     This profile  is  based primarily  on  a comprehensive  review  compiled by
Santodonato, et al. (1979).  The  health hazards of epichlorohydrin have also
been reviewed  by  the National  Institute  for Occupational  Safety  and Health
(NIOSH, 1976) and the Syracuse Research Corporation (SRC, 1979).
     Epichlorohydrin  (CHJDCHCHJ]!;  molecular  weight  92.53)  is  a  color-
less liquid at room  temperature  with a  distinctive  chloroform-type  odor.
The boiling point  of epichlorohydrin  is  116.4°C, and  its  vapor  pressure is
20  mm  Hg at 29°C.   These factors  contribute  to  the rapid  evaporation of
the chemical upon release into the environment.
     Epichlorohydrin  is  a  reactive molecule forming covalent bonds with bio-
logical  macromolecules.    It  tends  to  react  more  readily with  polarized
groups, such as sulfhydryl groups.
     The total U.S. production  for epichlorohydrin was estimated  at 345 mil-
lion pounds in 1973 (Oesterhof, 1975), with 160 million pounds used as feed-
stock  for the  manufacture of glycerine   and 180  million  pounds  used in the
production  of  epoxy  resins.   Production levels  for the year  1977  have been
estimated at 400 million pounds.
II.  EXPOSURE
     A.  Water
         No  ambient  monitoring data on epichlorohydrin are  available from
which  reliable conclusions on the potential exposure from drinking water may
be made.  However,  if a major release of  epichlorohydrin were realized, the
chemical is stable enough  to be transported significant distances.   The rate
of evaporative loss would  give  an estimated  half-life of about two days for
epichlorohydrin in  surface waters  (to a  depth of  1m).   The  only reported
contamination of a public water  supply  resulted  from  a  tank car derailment

                                   -//7/-

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 and  subsequent spillage  of 20,000 gallons  (197,000  pounds)  of epichlorohy-
 drin  at Point  Pleasant,  West Virginia  on January 23,  1978.  Wells  at the
 depth  of 25  feet  were heavily  contaminated.   More  specific  information is
 not yet available.
     B.  Food
         Epichlorohydrin  is used as a cross-link  in  molecular sieve resins,
 which  are,  in turn, used  in the treatment  of  foods  (21 CFR  173.40).   Food
 starch  may be  etherified with  epichlorohydrin,  not to  exceed 0
 alone  or  in combination with propylene oxide, acetic anhyd            cc
 anhydride  (21  CFR  172.892).   No  data  concerning  concentrations of epichloro-
 hydrin in foodstuffs has been generated.
     C.  Inhalation
         Numerous  environmental  sources  of .epichlorohydrin have been identi-
 fied  (SRC,  1979).   Epichlorohydrin is released  into  the atmosphere through
 waste  ventilation  processes  from a  number  of industrial  operations  which re-
 sult in, volatilization of  the chemical.  No  quantitative  monitoring informa-
 tion  is  available on  ambient epichlorohydrin concentrations.   High concen-
 trations have been observed  in the  immediate vicinity of  a factory  discharg-
 ing epichlorohydrin  into the atmosphere ,  but  these were quickly  despersed,
with no  detection  of the  chemical  at distances greater  than  600  M (Fomin,
 1966) .
 III. PHARMACOKINETICS
     A.  Absorption
         Absorption  of epichlorohydrin  in man  and  animals  occurs via  the
                                                      s
respiratory and gastointestinal  tracts, and by percutaneous absorption  (U.S.
EPA,  1979).   Blood  samples  obtained  from rats  after  6 hours exposure  to
 (1ZlC) epichlorohydrin at  doses of  1 and  100 ppm  in  air -revealed  0.46^0.19
and 27.8+4.7 jug epichlorohydrin  per ml  of plasma, respectively.   The  rates
                                   -II73--

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epichlorohydrin  per  ml  of plasma,  respectively.   The  rates  of uptake  at
these exposure levels were determined  as  15.48 and 1394  ug per hour,  and the
dose received was 0.37 and 33.0 mg/kg (Smith, et al. 1979).
     B.  Distribution
         The  distribution  of  radioactivity  in various  tissues of rats  fed
(^C)-epichlorohydrin has  been examined  (Weigel,  et al.  1978).   The  chemi-
cal was  rapidly  absorbed with  tissue  saturation  occurring within two  hours
in males  and four hours in females.  The kidney and liver  accumulated  the
greatest amounts  of  radioactivity.  Major  routes af  excretion were in  the
urine  (38  to 40 percent),  expired air  (18 to 20 percent), and the  feces (4
percent).   The appearance  of  large  amounts  of  ^4C02  in expired air  sug-
gests a rapid and extensive metabolism of (^4C)-epichlorohydrin in rats.
     C.  Metabolism
         Limited  data  concerning mammalian  metabolism  of  epichlorohydrin
suggest  in_  vivo  hydrolysis  of  the  compound,  yielding  alpha-chlorohydrin
(Jones, et  al. 1969).   Upon  exposure to radioactively-labeled epichlorohy-
drin  a .small  percentage of the  radioactivity was  expired  as intact  epi-
chlorohydrin, while a large  percentage of the radioactivity  was  excreted as
  C02,  indicating  a  rapid   and  extensive  metabolism  of   the  (^C)epi-
chlorohydrin.  Metabolites  in  the urine  have been  obtained  by  these  re-
searchers,  but the final analysis  as to the  identity of  the compounds  is  not
yet complete.  Van Ouuren  (1977)  has  suggested a metabolite  pathway of  epi-
chlorohydrin to include  glycidol,  glycidaldehyde and epoxy-propionic  acid.
     D.  Excretion
         The  percentages of total radioactivity  recovered in the urine  and
expired air  as  14C02 were 46  percent and  33 percent in  the 1 ppm  group,
and  54 percent  and  25   percent  in the  100  ppm  group,  respectively.   Rats
                                   -// 73 -
                                      3

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orally treated with  100  mg/kg excreted 51  percent  of the  administered  epi-
chlorohydrin in the  urine  and 38 percent in expired air, while  7  to  10  per-
cent remained in  the body 72 hours  after exposure.  Tissue  accumulation  of
radioactivity was highest in kidneys and liver.
IV.  EFFECTS
     A.  Carcinogenicity
         Epichlorohydrin appears to  have  low carcinogenic activity following
dermal application.   In two  studies,  epichlorohydrin applied  topically  to
shaved backs  of rats or  mice did not  induce  any significant occurrence  of
skin tumors  (Weil,  1964;  Van  Duuren,  et al.  1974).   However,  subcutaneous
injection of epichlorohydrin at levels as low as  0.5 mg  have  resulted in the
induction of tumors at the injection site.
         Extensive inhalation  studies  have  recently identified  epichlorohy-
drin as  a  potent  nasal carcinogen  in  rats.'  At  concentrations  of 100  ppm,
significant increases in  the  occurrence of squamous cell  carcinomas  of the
nasal  turbinates  have been  observed.   Such  tumors have  been  reported  in
lifetime exposure  studies at  30 ppm but not  at 10  ppm (Nelson, 1977, 1978).
         Several recent epidemiological studies  have  suggested  the risk  of
cancer as a  result  of occupational epichlorohydrin  exposure.   Both respira-
tory cancers and  leukemia  are in  excess  among some exposed  worker  popula-
tions,, but  this  increase was  not  shown  to  be statistically  significant
(Enterline and Henderson, 1978; Enterline, 1979).   The data suggest a  laten-
cy period of roughly  15  years before the onset of carcinogenic  symptoms.   A
second survey has.failed to substantiate these  findings (Shellenberger,  et
al. 1979).  However,  this  survey used a  younger  study population with  less
exposure to epichlorohydrin.
                                    -I Hi

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     B.  Mutagenicity
         Epichlorohydrin  has  been shown  to cause reverse mutations  in sev-
eral organisms (SRC, 1979).
         Cytogenetic  studies  with  experimental  animals  have  revealed  in-
creased aberrations  in  animals treated with epichlorohydrin.  Both mice  and
rats have  displayed dose-dependent increases  in  abnormal  chromosome  morpho-
logy at  exposure  levels  ranging from 1  to  50  mg/kg  (Santodonato,  et  al.
1979).
         In humans,  the clastogenic properties of  epichlorohydrin  have been
reported in workers occupationally exposed to the chemical and  in  cultured
"normal"  lymphocytes exposed  to epichlorohydrin (SRC, 1979).   Cytogenetic
evaluation of exposed workers  has shown an increase of  somatic  cell  chromo-
some aberrations associated with concentrations ranging from 0.5 to  5.0  ppm
(2.0 to  20 mg/irP)  (SRC,  1979).  Such  chromosomal  damage  appears to be  re-
versible once exposure to the chemical ceases.
     C.  Teratogenicity
         Pregnant rats  and rabbits  exposed to  2.5 to 25 ppm epichlorohydrin
during  days 6 to  15 or days 6  to 18  of 'gestation showed  a  mild  teratogenic
response (John,  et al.  1979).   However  examinations of  all fetal  tissue have
not been completed.   The  incidence of resorbed  fetuses was not altered  by
exposure to epichlorohydrin at the doses employed.
     0.  Other Reproductive Effects
         The antifeftility properties  of epichlorohydrin have been examined
by several investigators.   Administration of 15 mg/kg/day  of epichlorohydrin
for 12 days resulted in reduced fertility of  male rats  (Halen, 1970).  Five
repeated doses of 20 mg/kg were more effective in rendering  male  rats infer-
tile than  was one  100 mg/kg  dose  or  five 50 mg/kg doses  (Cooper,  et  al.

                                   v/zr-

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 1974).  The  suggested mode of action of  epichlorohydrin is via  the in vivo
 hydrolysis of  the compound  which produces  alpha-chlorohydrin.   Altered re-
 productive function  has  been reported for workers occupationally exposed to
 epichlorohydrin at concentrations less than 5 ppm.
      E.  Chronic Effects
          Two species  of rats  and one specie of  mice (both sexes)  were ex-
 posed to 5 to  50 ppm  epichlorohydrin  for six hours  per day,  five  days per
 week for a total of 65 exposures.  All species and  sexes displayed inflamma-
 tory and degenerative changes in  nasal  tissue,   moderate  to severe  tubular
 nephrosis,  and  gross  liver  pathology  at  50 ppm  exposure (Quast,  et  al.
 1979a).   The same  research group  has  also  examined  the effect  of 100  ppm
 exposure for  12 consecutive days.  The toxicity to nasal tissues  was  similar
 (Quast,  et al.  1979b).
         Altered  blood  parameters (e.g.  increased  neutrophilic   megamyelo-
 cytes,  decreased  hemoglobin,  hematocrit,  and erythrocytes)  have  been ob-
 served  in .rats  exposed to 0.00955  to  0.04774 ml  epichlorohydrin per kg  body
 weight  administered  intraperitoneally.(Lawrence,   et  al. 1972).'  Lesions of
 the  lungs and reduced weight gains were also observed.
     Toxicity studies with various  animal  species  have established that epi-
 chlorohydrin  is moderately,  toxic by systemic absorption (Lawrence,  et al.
 1972).   Acute oral  LD5Q values  in experimental  animals  have  ranged  from
 155 to 238 mg/kg for the mouse and from 90 to  260  mg/kg  in  the  rat.  Inhala-
        50  values  range  from  366 to  633  ppm in  rats,  ts  800  ppm  in  mice
 (SRC, 1979).  Single  subcutaneous injections  of epichlorohydrin  in rats at
doses of 150 or  180  mg/kg have resulted in  severe injury  to   the  kidney
 (Rotara and Pallade,  1966).

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         Accidental human exposures  have been reviewed  (NIOSH,  1976;  Santo-
donato, et  al.  1979).  Direct  exposure  to apichlorohydrin vapor  results  in
severe irritation of  the eyes and  respiratory membranes, followed  by nausea,
vomiting,  headache,  dyspnea,  and altered liver function.  A  significant  de-
crease was reported in pulmonary function  among workers  exposed to epichlor-
ohydrin in an epoxy-resin manufacturing  process.   Workers were simultaneous-
ly exposed to dimethyl amino propylamine.
V.   AQUATIC TOXICITY
     Pertinent data could not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     Existing occupational  standards  for exposure  to  epichlorohydrin are  re-
viewed in the  NIOSH  (1976) criteria  document.   The NIOSH recommended  envi-
ronmental exposure  limit is a  2 mg/irP  10-hour  time-weighted average  and  a
19 mg/m3  15-minute ceiling concentration.   The  current  Occupational  Safety
and Health Administration  standard is an  8-hour  time-weighted average con-
centration of 5 ppm (20 mg/nv5).
                                  -1/77-

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         l-CHLORO-2,3-EPOXYPROPAME(EPICHLOROHYDRIN)

                         REFERENCES  "

Cooper, E.R.A., et al.   1974.   Effects  of  alhpa-chlorohydrin
and related compounds on the reproduction  and  fertility of
the male rat.  Jour. Reprod. Fert.   38:  379.

Enterline, P.E.  1979.   Mortality experience of  workers ex-
posed to epichlorohydrin.   In press: Jour.  Occup.  Med.

Enterline, P.E., and V.L. Henderson.  1978.  Communication to
Medical Director of  the  Shell Oil Company:  Preliminary  find-
ing of the updated mortality study  among v/orkers exposed to •
epichlorohydrin.  Letter dated  July  31,  1978.   Distributed to
Document Control Office, Office of  Toxic Substances  (WH-557)
U.S. Environ. Prot.  Agency.

Fomin, A.P.  1966.   Biological  effects  of  epichlorohydrin and
its hygienic significance as an atmospheric pollutant.   Gig.
Sanit.  31: 7.

Halen, J.D.  1970.   Post-testicular  antifertility effects of
epichlorohydrin and  2,3-epoxypropanol.  Nature   226:  87.

John, J.A., et a^.<   1979.   Epichlorohydrin-subchronic
studies. IV.  Interim results of a  study of the  effects of
maternally inhaled epichlorohydrin  on rats' and  rabbits' em-
bryonal and fetal development.  Jan. 12, 1979.   Unpublished
report from Dow Chemical Co.  Freeport,  TX.

Jones, A.R., et al.  1969.  Anti-fertility  effects and  metab-
olism of of alp1"-1.- and epichlorohydrin  in  the  rat.  Nature
24: 83.         •>'

Lawrence, W.H., ^-t/al.   1972.   Toxicity profile  of epichloro-
hydrin.  Jour. Paarm. Sci.  61: 1712.

Nelson, N.  1977.  Communication to  the  regulatory agencies
of preliminary findings of  a carcinogenic  effect in  the nasal
cavity of rats exposed to epichlorohydrin.  New  York  Univer-
sity Medical Center.  Letter dated  March 28, 1977.

Nelson, N.  1978.  Updated  communication to the  regulatory
agencies of preliminary  findings of  a carcinogenic effect in
the nasal cavity of  rats exposed to  epichlorohydrin.  New
York University Medical  Center.  Letter dated  June 23,  1978.

NIOSH.  1976.  NIOSH criteria for a  recommended  standard:
Occupational exposure to epichlorohydrin.   U.S.  DHEW.   Na-
tional Institute for Occupational Safety and Health.

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 Oesterhof,  D.   1975.   Epichlorohydrin-.   Chemical  Economics
 Handbook.   642.302/A-642.3022.   Stanford Research Corp.,
 Menlo Park,  Calif.

 Quast,  J.F.,  et  al.   1979a.   Epichlorohydrin  -  subchronic
 studies.  I.  A 90-day  inhalation  study  in laboratory  rodents.
 Jan.  12,  1979.   Unpublished  report from Dow Chemical  Co.
 (Freeport,  TX).

 Quast,  J.F.,  et  al.   1979b.   Epichlorohydrin  -  subchronic
 studies.   II.  A  12-day study in  laboratory rodents.   Jan. 12,
 1979.  Unpublished  report  from  Dow Chemical Co.   Freeport,
 TX.

 Rotara,  G.,  and  S.  Pallade.   1966.  Experimental  studies of
 histopathblogical  features  in acute epichlorohydrin
 (l-chloro-2,3-epoxypropane)  toxicity.   Mortal Norm.  Patol.
 11:  155.

 Santodonato,  J.,  et al.   1979.   Investigation of  selected
 potential environmental  contaminants:  Epichlorohydrin and
 epibromohydrin.   Syracuse  Research Corp. Prepared for Office
 of Toxic Substances,  U.S.  EPA.

 Shellenberger,  R.J.,  et  al.   1979.  An  evaluation of  the
 mortality experience  of  employees  with  potential  exposure to
 epichlorohydrin.   Departments of Industrial Medicine, Health
 and  Environmental  Research  and  Environmental  Health.   Dow
 Chemical Co.   Freeport,  TX.

 Smith,  F.A.,  et  al.   1979.   Pharmacokinetics  of epichlorohy-
 drin (EPI)  administered  to  rats  by gavage or  inhalation.
 Toxicology Research Laboratory,  Health  and Environmental
.Science.   Dow Chemical Co.,  Midland, MI. Sponsored  by the
 Manufacturing Chemists Association. First Report.

 Syracuse Research  Corporation.   1979.   Review and evaluation
 of recent scientific  literature  relevant to an  occupational
 standard for epichlorohydrin: Report prepared by  Syracuse
 Research Corporation  for NIOSH..

 Van  Duuren,  B.L.   1977.   Chemical  structure,  reactivity, and
 carcinogenicity  of  halohydrocarbons.   Environ.  Health Persp.
 21:  17.

 Van  Duuren,  B.L.,  et  al.   1974.   Carcinogenic action  of alky-
 lating agents.   Jour.  Natl.  Cancer Inst. 53: 695.

 Weigel,  W.W.,  et al.   1978.   Tissue distribution  and  excre-
 tion of (^-4c)-epichlorohydrin in male  and female  rats.
 Res.  Comm.  Chem.  Pathol.  Pharmacol. 20: 275.
                             •mi-

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Weil, C.S.  1964.  Experimental carcinogenicity and acute
toxicity of representative epoxides.  Amer. Ind. Hyg. Jour,
24: 305.

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                                      No. 101
         Ethyl Methacrylate

  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental impacts  presented by  the
subject chemical.   This document  has undergone  scrutiny to
ensure its technical accuracy.

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                              ETHYL METHACRYLATE
                                    Summary

     Information on  the  carcinogenic and mutagenic effects  of ethyl methac-
rylate was  not  found in  the  available literature.  Ethyl  methacrylate  has,
however,  been shown to cause teratogenic effects in rats.
     Chronic occupational  exposure to  ethyl  methacrylate  has not  been  re-
ported in the available literature.
     Data concerning  the effects of ethyl methacrylate  on  aquatic organisms
were not found in the available literature.

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                              ETHYL METHAGRYLATE
I.   INTRODUCTION
     Ethyl  methacrylate  (molecular  weight  114. 15)  is  the  ethyl ester  of
methacry lie acid.   It  is a  crystalline  solid that melts at  less  than 75°C,
has a  boiling  point of 117°C, a  density of 0.9135, and an  index  of refrac-
tion of  1.4147.   It is  insoluble in water  at  25°C and is  infinitely solu-
ble in alcohol and  ether (Weast,  1975).   It possesses a  characteristic un-
pleasant odor (Austian, 1975).
     Widely known as "Plexiglass" (in the polymer- form),  ethyl methacrylate
is used  to  make  polymers, which  in  turn are used  for  building,  automotive,
aerospace,  and furniture  industries.   It is also  used  by  dentists as dental
plates, artificial teeth, and orthopedic cement (Austian,  1975).
II. • EXPOSURE
     Ethyl methacrylate is used in large quantities and therefore  has poten-
tial for  industrial  release  and   environmental contamination.   Ethyl  methac-
rylate in the polymerized form is not  toxic; however,  chemicals used to pro-
duce ethyl  methacrylate  are  extremely  toxic.  No  monitoring  data  are avail-
able to indicate ambient air or water levels of the compound.
     Human exposure  to  ethyl methacrylate from foods cannot  be assessed due
to a lack of monitoring data.
     Bioaccumulation data on ethyl methacrylate were  not  found in  the avail-
able literature.
III. PHARMACOKINETICS
     Specific  information on  the metabolism,  distribution,  absorption,  or
elimination of ethyl methacrylate was not found in the available literature.
                                      y

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     No evidence has been  found  of the presence of ethyl methacrylate in the
human urine.   Therefore,  it is  hypothesized that it  is  rapidly metabolized
and undergoes complete oxidation (Austian, 1975).
IV.  EFFECTS
     A.   Carcinogenic!ty and Mutagenicity
          Information  on   the  carcinogenic  and mutagenic  effects of  ethyl
methacrylate was not found in the available literature.
     B.   Teratogenicity
          Ethyl methacrylate is  teratogenic  in rats.   Female rats were given
intraperitoneal  injections of 0.12 rug/kg,  0.24 mg/kg,  and 0.41 mg/kg,  on
days  5,  10,  and 15 of  gestation.   These doses were 10,  20,  and 33 percent,
respectively,  of the acute  intraperitoneal  LD^Q dose.   Animals were sacri-
ficed one day before parturition (day 20).
     Deleterious effects  were observed  in the developing  embryo  and fetus.
Effects were  compound  and generally  dose-related.   A 0.1223  ml/kg  injected
dose  resulted  in unspecified gross abnormalities  and  skeletal abnormalities
in 6.3 percent  and  5.0  percent  of the test  animals,  respectively,  when com-
pared  to  the untreated controls.   A dose of 0.476 ml/kg  resulted  in gross
abnormalities  in 15.7  percent  of  the treated  animals  and  skeletal abnor-
malities in 11.7 percent of the treated animals (Singh, et al. 1972).
     C.   Other Reproductive Effects and Chronic Toxicity
          Information on  other  reproductive effects and  chronic toxicity of
ethyl methacrylate was not found in the available literature.
     D.   Acute Toxicity
          Lower molecular  weight  acrylic monomers  such as ethyl methacrylate
cause  systemic  toxic effects.   Its administration  results in  an immediate
                                  -//

-------
increase in respiration rate, followed by  a decrease after 15-40 minutes.  A
prompt  fall  in  blood pressure  also occurs,  followed  by  recovery  in  4-5
minutes.   As  the animal  approaches death,  respiration becomes  labored  and
irregularj  lacrimation  may  occur,  defecation  and  urination increase,  and
finally reflex  activity  ceases,  and the  animal  lapses into  a coma and dies
(Austian,  1975).
          Acrylic monomers  are  irritants  to the skin  and  mucous membranes.
When placed in  the eyes of  animals,  they  elicit a very  severe  response and,
if not washed out, can cause permanent damage (Austian, 1975).
          As early  as 1941,  Oeichmann  demonstrated  that  injection  of 0.03
cc/kg  body weight  ethyl methacrylate  caused a prompt and  sudden  fall in
blood pessure,  while  respiration  was stimulated immediately  and  remained at
this level  for  30 minutes.   The  final  lethal dose  (0.90-.12 cc/kg)  brought
about  respiratory failure,  although the hearts  of these animals  were  still
beating (Deichmann,  1941).
          Work  by  Mir,  et  al.  (1974)  demonstrated  that  respiratory system
effects alone  may not kill the animal,  but that cardiac  effects may also
contribute  to  the  cause  of  death  (Austian,   1975).  Twelve  methacrylate
esters  and methacrylic  acid were tested  on isolated  perfused  rabbit heart.
Concentrations  as  low as  1 part in  100,000 (v/v)  produced  significant  ef-
fects.  The effects were  divided into three groups  according to  the rever-
sibility of the  heart response.  Ethyl methacrylate  was placed in "Group 1",
in  which   the. heart  response  is   irreversible  at  all   concentrations
(1:100,000; 1:10,000;  1:1,000).  Five  percent  (v/v-)  caused a  41.2  percent
decrease in the  heart rate  of isolated  rabbit  heart.  The  same concentration
                                                                       »
reduced heart  contraction by 64  percent  and  coronary flow  by  61.5  percent
(Austian,  1975).

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          The  findings  of Oeichmann  (1941) that  ethyl methacrylate affects
blood  pressure  and  respiration  is   substantiated  by  studies  of  Austian
(1975).  Response  following  administration of ethyl methacrylate was charac-
terized by a biphenic response,  an abrupt fall in blood pressure followed by
a more  sustained rise.   Austian (1975) also  found that the respiration rate
is increased,  the duration of  effect being approximately  20  minutes,  after
which time the respiration rate  returned  to normal.
          In the available literature LD5Q  values were  found  for  only rab-
bit and  rat;  these were  established  by  Oeichmanrr- in 1941.  The  oral  value
for the  rat is  15,000  mg/kg,  as  opposed to 3,654-5,481 mg/kg  for the rab-
bit.  Inhalation values for the  rat have  been  reported to be 3,300 ppm for 8
hours  (Patty,  1962).  . Deichmann also established  a  skin  toxicity LD5_ for
rabbit which was greater than  10  ml/kg.   This was substantiated  by another
test  which  showed  that  moderate  skin irritation  (in rabbits)  does result
from ethyl methacrylate exposure (Patty,  1962).
VI.  EXISTING GUIDELINES AND STANDARDS
     Information  on existing guidelines  and  standards was  not  found in the
available literature.

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                              ETHYL METHACRYLATE

                                  References
Austian,  J.   1975.   Structure-toxicity relationships  of  acrylic  monomers.
Environ. Health Perspect.  19: 141.

Deichmann, W.   1941.   Toxicity  of methyl,  ethyl, and  n-butyl methacrylate.
Jour. Ind. Hyg. Toxicol.   23: 343.

Mir, G., et al.  .1974.   Journal  of toxicological and pharmacological actions
of  methacrylate  monomers.  III.   Effects on  respiratory  and  cardiovascular
functions of anesthetized dogs.  Jour. Pharm.  Sci.  63: 376.

Patty,  F.A.   1962.   Industrial  Hygiene  and  Toxicology,  Vol.  II.   Inter-
science Publishers, New York.

Singh, A.R., et  al.   1972.   Embryo-fetal toxicity and teratogenic effects of
a group of methacrylate esters in rats.  Tox.  Appl. Pharm. 22: 314.

Weast,  R. C.    1975.   Handbook  of Chemistry  and Physics.   56th   ed.   CRC
Press, Cleveland, Ohio.

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                                      No. 102
           Ferric Cyanide

  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a  survey  of  the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and   available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including  all the
adverse health  and  environmental  impacts  presented  by  the
subject chemical.   This  document  has  undergone scrutiny  to
ensure its technical accuracy.
                         -fife-

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                                 FERRIC  CYANIDE
I.    INTRODUCTION
      Ferric  cyanide is a  misnomer and is  not listed as a specific  compound
in  the  comprehensive compendia of  inorganic  compounds (Weast, 1978).   There
are,  however,  a class of  compounds known as  "iron cyanide blues"  consisting
of  various  salts  where  the anions  are  the ferricyanide,  [FeCCN)^]3-,  or
the   ferrocyanide,   CFe(CN)6]4-,  ar,d   the  cations   are  either  Fe(III)  or
Fe(II)  and  sometimes  mixtures  of Fe(II)  and  potassium  (Kirk  and Othmer,
1967).   The  empirical  formula of the  misnamed  ferric  cyanide,  Fe(CN),
corresponds  actually to one  of  the ferricyanide compounds,  the ferric ferri-
cyanide  with the  actual   formula  Fe[Fe(CN)6]j also  known  as -Berlin green.
The  acid from  which these  salts   are  derived  is  called  ferricyanic   acid,
H3[Fe(CN)g]   (also  known  as  hexacyanoferric  acid),   molecular  weight
214.98,  exists  as  green-blue deliquescent needles, decomposes upon  heating,
and  is  soluble in water  and alcohol.   .In  this  EPA/ECAO  Hazard Profile only
ferric     ferricyanide,      Fe[Fe(CN)6])      and     ferric     ferrocyanide,
F'e4[Fe(CN)g]j,   are   considered;   other   ferrocyanide  compounds   are   re-
ported in a separate EPA/ECAO Hazard Profile  (U.S. EPA, 1980).
     These compounds are colored pigments,  insoluble  in water or weak acids,
although they  can  form colloidal  dispersions in aqueous media.   These  pig-
ments are  generally used  in  paint, printing  inks, carbon  paper inks,   cray-
ons,  linoleum,  paper pulp, writing inks  and  laundry  blues.   These compounds
are sensitive to alkaline decomposition (Kirk  and Othmer, 1967).
II.  EXPOSURE
     Exposure to  these compounds may occur occupationally  or through inges-
tion of  processed  food or contaminated water.  However,  the  extent  of  food
or water contamination from  these compounds  has  not been described in the

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available  literature.   Prussian  blue,  potassium   ferric  hexacyanoferrate
(II),  has been  reported  as an  antidote  against  thallium  toxicity.   When
administered at  a  dose of 10 g  twice daily by duodenal  intubation,  it pre-
vents the intestinal reabsorption of thallium (Dreisbach, 1977).
III. PHARMACOKINETICS
     A.   Absorption and Distribution
          Pertinent data could not be located in the available literature.
     B.   Metabolism
          There  is  no apparent metabolic alteration,  of these  compounds.  As
for  the  other  ferrocyanide  and  ferricyanide  salts,  these compounds  are not
cyanogenic (Gosselin, et al. 1976).
     C.   Excretion
          No information  is available  for  ferric hexacyanoferrates  (II)  or
(III), but information  is  available for other  related  ferrocyanide and fer-
ricyanide salts  (U.S. EPA,  1980;  Gosselin, et al.  1976) which  seems  to  be
rapidly excreted in urine apparently without metabolic alteration.
IV.  EFFECTS
     A.   Carcinogenicity,   Mutagenicity,  Teratogenicity,  Chronic  Toxicity,
          and Other Reproductive Effects
          Pertinent data could not be located in the available literature.
     B.   Acute Toxicity
          No adequate toxicity  data are  available.    All  ferrocyanide  and
ferricyanide salts  are reported as  possibly moderately  toxic  (from 0.5  to
5.0 mg/kg as a  probable lethal dose in humans)  (Gosselin,  et  al.  1976).
V.   AQUATIC TOXICITY
     Pertinent  data could not be located in the available literature  regard-
ing the aquatic toxicity of ferric cyanide.


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VI.  EXISTING GUIDELINES AND STANDARDS



     Pertinent data could not be located in the available  literature.
                                -// ?3 ~

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                                  REFERENCES
Oreisbach, R.H.   1977.   Handbook  of Poisoning, 9th  edition.   Lange Medical
Publications, Los Altos,  CA.

Gosselin, R.E.,  et  al.  1976.  Clincial  Toxicology  of Commercial Products,
4th edition.   Williams and  Wilkins,  Baltimore,  Maryland.

Kirk,R.E.  and O.F.  Othmer.    1967.  Kirk-dthmer  Encyclopedia  of  Chemical
Technology,  II edition,  Vol.  12.   Interscience Publishers, div.  John  Wiley
and Sons, Inc., New  York.

U.S. EPA.  1980.   Environmental Criteria and  Assessment Office.  Ferrocya-
nide: Hazard  Profile.  (Draft)

Weast,  R.C.   1978.  Handbook of Chemistry and  Physics,  58th ed.  The Chemi-
cal Rubber Company,  Cleveland,  Ohio.
                                  •lilt-

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                                      No. 103
         Fluoranthene
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION A<2NCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents a survey of the potential health
and environmental hazards from exposure to  the subject chemi-
cal.  The information contained in the report is  drawn chiefly
from secondary  sources   and  available  reference documents.
Because of the limitations of such sources,  this  short profile
may not reflect  all  available information  including all the
adverse health  and  environmental  impacts  presented by  the
subject chemical.  This  document has undergone  scrutiny to
ensure its technical  accuracy.
                          -im-

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                         FLUORANTHENE



                           SUMMARY



     No  direct  carcinogenic  effects  have  been  produced  by



fluoranthene  after  administration   to  mice.    The  compound



has  also failed  to  show  activity   as  a  tumor  initiator  or



promoter.    However,  it  has  shown cocarcinogenic  effects



on  the  skin of mice when combined  with  benzo(a)pyrene,  in-



creasing tumor incidence and decreasing tumor latency.



     Fluoranthene  has   not shown mutagenic,   teratogenic  or



adverse reproductive effects.



     Daphnia magna appears to have low  sensitivity to fluoran-



thene  with  a  reported 48-hour  EC5Q of  325,000  pg/1.   The



bluegill,  however,   is  considerably more  sensitive  with  an



observed  96-hour  LC5Q  value  of 3,980.    The 96-hour  LC50



for  mysid  shrimp is  16 ug/1,. and  a  reported  chronic value



is  16  ug/1.   Observed  96-hour   ECcn  values  based  on  cell



numbers for fresh and saltwater algae are over 45,000 ug/1.
                          -II97-

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                         FLUORANTHENE

I.   INTRODUCTION

     This  profile  is  based  on  the  Ambient  Water  Quality

Criteria Document for Fluoranthene  (U.S. EPA, 1979).

     Fluoranthene  (1,2-benzacenapthene, M.W.  202)  is a poly-

nuclear  aromatic  hydrocarbon  of  molecular  formula  c]_5Hig •

Its physical properties,  include:  melting  point, 111°C; boil-

ing  point,  375°C;  water  solubility,  265 ^yg/1  (U.S.  EPA,

1978) .

     Fluoranthene  is  chemically  stable,  but may  be removed

from  water  by  biodegradation  processes   (U.S. EPA,  1979).

The  compound  is  relatively  insoluble  in aqueous  systems.

Fluoranthene may  be adsorbed and concentrated  on  a variety

of particulate matter.   Micelle formation through the action

of  organic  solvents  or  detergents  may   occur.  (U.S.  EPA,

1979).

     Flouranthene  is  produced  from  the pyrolytic  processing

of coal  and petroleum   and  may  result from  natural biosyn-

thesis (U.S.  EPA, 1979).

II.  EXPOSURE

     Fluoranthene  is  ubiquitous  in  the environment;  it  has

been monitored  in food,  water,  air, and   in  cigarette smoke

(U.S. EPA,  1979).   Sources  of contamination  include  indus-

trial  effluents   and  emissions,  sewage,   soil   infiltration,

and  road  runoff  (U.S.  EPA,  1979).   Monitoring of  drinking
                                                          »
water  has   shown  an  average fluoranthene concentration  of

27.5 ng/1  in positive samples  (Basu,  et  al.   1978).   Food

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levels of  the compound  are  in  the ppb  range,  and will  in-



crease in  smoked or  cooked foods  (pyrolysis  of fats)  (U.S.



EPA,  1979).   Borneff  (1977)  has estimated  that dietary  in-



take  of  fluoranthene occurs mainly  from fruits, vegetables,



and bread.



     An  estimated daily  exposure  to fluoranthene  has  been



prepared by EPA  (1979):





               Source         Estimated  Exposure
               ^•^MBM^Vl^MMMI         ^^Ma^H^MB«i^H^MMVB^lMiaM^WWMMBm^^Hn«    f


               Water          0.017 pg/day



               Food           1.6 - 16 pg/day



               Air            0.040 - 0.080 pg/day





     Based  on the  octanol/water partition  coefficient,  the



U.S.  EPA  (1979)  has  estimated  weighted  average  bioconcen-



tration.  factor  of 890  for  fluoranthene  for  the edible  por-



tion of fish and shellfish  consumed by Americans.



III. PHAJRMACOKINETICS



     A.   Absorption



          Based  on  animal   toxicity  data  (Smythe,  et  al.



1962), fluoranthene   seems  well  absorbed following  oral or



dermal  administration.   The  related   polynuclear  aromatic



hydrocarbon (PAH), benzo(a)pyrene,  is readily  absorbed  across



the lungs  (Vainio, et al.   1976).

                                           .*

     B.   Distribution



          Pertinent   information  could   not   be  located  in
                                                           »


the  available literature.   Experiments  with benzo(a)pyrene



indicate  localization  in   a  wide  variety  of  body tissues,



primarily in body fats  (U.S. EPA, 1979).

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     C.   Metabolism
          Pertinent  information  could  not  be   located   in
the  available  literature.   3y analogy  with other  PAH com-
pounds,  fluoranthene  may  be  expected to  undergo metabolism
by.  the  mixed function  oxidase  enzyme complex.    Transforma-
tion products produced  by this action  include  ring hydroxy-
lated  products   (following epoxide   intermediate  formation)
and  conjugated  forms  of  these  hydroxylated products  (U.S.
EPA, 1979).
     D.   Excretion
          Pertinent  information  could  not  be   located   in
the  a   ^)lable  literature.   Experiments  with  PAH compounds
indicate  excretion  through the hepatobiliary system and  the
feces; urinary excretion  varies with  the  degree of formation
of conjugated metabolites  (U.S. EPA, 1979).
IV. . £. "j-ECTS
     A. .t Carcinogenicity
      •' .">
          Testing of fluoranthene  in  a  marine carcinogenesis
bioassay  failed  to  show  tumor  production  following  dermal
or  subcutaneous  administration  of  fluoranthene  (Barry,   et
al., 1935).
          Skin testing  of fluoranthene  as a  tumor  promoter
or  initiator  in mice  has also  failed  to show  activity   of
the  compound  (Hoffman,   et al. ,  1972;  Van Duuren  and Gold-
schmidt,  1976).
          Fluoranthene  has been  demonstrated  to have  car-
cinogenic  activity  (Hoffmann  and  Wynder,  1963;  Van  Duuren
                             X

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