No.  71
        1,l-Sichlorethylene


  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.

-------
                             1,1-DICHLOROETHYLENE
                                   Summary  .
     Ambient levels  of 1,1-dichloroethylene have  not been determined.   The
primary effect  of  acute and chronic  occupational  exposure to  1,1-dichloro-
ethylene is depression  of  the  central nervous system.  In  experimental  ani-
mals, both  liver and kidney damage have  been  noted after  exposure,  regard-
less of the route of administration.   1,1-Oichloroethylene  has  been  shown to
be a  mutagen  in bacterial  systems and  a carcinogen in  mice.   Both  kidney
adenocarcinomas and  mammary adenocarcinomas were 'produced  after exposure to
1,1-dichloroethylene  by  inhalation.    No  teratogenic effects  have been  ob-
served.
     For  freshwater  fish,   the   reported  96-hour  LC5Q  values  range  from
73,900  to  108,000  ug/1  1,1-dichloroethylene.   Reported 48-hour EC5Q  values
for  Daphnia magna  range  from 11,600  to 79,GOO ug/1.   96-Hour LC,-n  values
       —•        - -                                                  >u
of over 22^,000 ug/1 have  been  observed  for  saltwater  fish  and  inverte-
brates.  An embryo-level test with  freshwater  fish  resulted  in  an  adverse
effect occurring at  2,800 ug/1.   Algae,  both  fresh  and  saltwater,  apparently
are  not  affected   by  concentrations  of  1,1-dichloroethylene  as  high  as
716,000 ug/1.
                                 7/-3

-------
                             1,1-OICHLOROETHYUENE
I.   INTRODUCTION
     This  profile  is based  on the  Ambient  Water Quality  Criteria Document
for Dichloroethylenes (U.S. EPA, 1979a).
     1,1-Dichloroethylene  (C2H2C12;  molecular  weight  96.95)  is  a  clear
colorless liquid used as a chemical  intermediate  in  the synthesis of methyl-
chloroform  and  in  the production  of  polyvinylidene chloride  copolymers
(PVCDs).   Prior  to 1976, annual  production  of 1,1-dichloroethylene  was ap-
proximately  120,000 metric  tons  (Arthur 0.  Little,  Inc.t  1976).   1,1-Qi-
chloroethylene has  the  following physical/chemical  properties:   water solu-
bility  of 2,500 ug/ml,  vapor  pressure  591  mm Hg,  and  a melting  point of
-122.1°C.   For  more  general  information  regarding  the  dichloroethyienes,
the  reader  is referred to the EPA/ECAO  Hazard Profile  on Dichioroethyler.es
(U.S. EPA, 1979b).
II.  EXPOSURE
     A.  Water
         The  National  Organic Monitoring Survey  (U.-S. EPA,  1978a)  reported
detecting 1,1-dichloroethylene in  finished drinking  waters;  however,  neither
the amount nor the occurrence was quantified.
     8.  Food
         Pertinent data could  not be located  in  the available literature on
the  ingestion of  1,1-dichloroethylene  in  foods.  The  U.S.  EPA  (1979a)  has
estimated  the weighted, bioconcentration  factor  for 1,1-dichloroethylene- to
be 6.9  for the edible portions of fish and  shellfish  consumed by Americans.
                                                    *•
This estimate was  based on  the  octanol/water partition coefficient  of 1,1-
dichloroethylene.                                                     '

-------
     C.  Inhalation
         The population  at  risk due to vinylidene  chloride  exposure is com-
posed  primarily  of workers in  industrial  or commercial  operations manufac-
turing or using  it.  Airborne  emissions  of vinylidene chloride are not like-
ly to  pose  a significant risk  to  the general  population.   Emissions during
production,  storage,  and transport can  be controlled by methods  similar to
those planned for control of vinyl chloride (Hushon and Kornreich,  1978).
III.  PHARMACOKINETICS
     A.  Absorption
         Specific  data  en  the  absorption  of dichloroethylenes  are unavail-
able.  However,  a  recent study by McKenna,  et  al.  (1978b)  suggests  that in
rats  most,  if not  all,  of the orally administered dcss is  absorbed  at two
dose levels:  1 and 50 mg/kg.
     3.  Distribution
         Distribution of 1,1-dichlorcethylene v;ss  studied  in rats follcv;ir.g
inhalation  (Jaeger, et  al.  1977).   The largest  concentrations  were found in
kidney,  followed by  liver, spleen,  heart,  and  brain,  and  fasting  made no
difference  in  the  distribution  pattern.   At  the  subcellular  level 1,1-di-
chloroethylene or  its metabolites  appear  to bind  to rnacromolecules  of the
iTiicrosomes and mitochondria  (Jaeger, et al.  1977).   There is also  some asso-
ciation with the lipid fraction.
     C.  Metabolism
         In  the  intact  animal,  a large portion  of  the systemically absorbed
1,1-dichloroethylene  is  metabolically converted, with 36  percent appearing
in the  urine of rats within 26 hours (Jaeger,   et  ai.  1977).  The essential

-------
feature of 1,1-dichloroethylene metabolism  is  the  presence  of epoxide inter-
mediates, which are  reactive  and  may form covalent bonds with  tissue macro-
molecules (Henschler, 1977).  In  rats  and mice,  covalently  bound metabolites
ars found in  the  kidney and liver  (McXenna,  et  al. 1978b).   Interaction  of
1,1-  dichloroethylene  with the microsomal  mixed function oxidase  system  is
not clear, since both inhibitors  (dithiocarbamate)  and  inducers (phenobarbi-
tal)  decreased the  toxic effects  of  the  compound  (Anderson and- Jenkins,
1977;  Reynolds, et  al.  1975; Jenkins,  et  al. 1972).   However,  Carlson  and
Fuller (1972)  reported  increased  mortality  from  1,1-dichloroethylene in rats
following phenobarbital pretreatment.   There  is  evidence  that  the  1,1-di-
chloroethylene metabolites are conjugated with glutathione,  which presumably
represents a detoxification step  (McXenna,  et al. 197Sa).
     0.  Excretion
         It  is speculated  that  1,1-dichloroethylene  has  a  rapid  rate  of
elimination,  sir.ce a substantial  fraction of the total absorbed  oose may  be
recovered in  the  urine  within 26 to 72 hours  (Jaeger,  et al.  1977; McKanna,
et al. 1978a).  Also, disappearance  of  covalently  bonded metabolites of 1,1-
dichloroethylene  (measured  as TCA-insoluble fractions) appears  to  be fairly
rapid, with a reported half-life  of 2 to 3 hours  (Jaeger,  et al. 1977).
IV.  EFFECTS
     A.  Carcinogenicity
         1,1-Oichloroethylene has  been shown  to produce kidney  adenocarci-
nomas in male  mice  and mammary adenocarcinomas  in female mice  upon inhala-
tion  of  100  mg/m3  (Maltoni,  1977;  Maltoni,  et  al. 1977).   In  similar  ex-
periments with  Sprague-Oawley rats exposed  up to  800 mg/m  ,  no  significant
increase in tumor incidence  was  noted.  Also, hamsters  exposed  to  t'he  same
                                    71-6

-------
conditions as  the  mice failed to exhibit  an  increased tumor incidence (Mai-


toni, et al. 1977).   In  rats  exposed  to 1,1-dichloroethylene in their drink-


ing  water  (200 mg/1), there  was  no evidence of  increased  tumors (Rampy, et


al.  1977).'  There  was an increased incidence of  mammary tumors  in  rats  re-


ceiving 20  mg  of  1,1-dichloroethylene  by  gavage 4  to 5 days  a  week for 52


weeks.  The  incidence was 42 percent in the  treated animals and  34 percent


in the  controls;  however,  the data was  not  analyzed statistically (Maltoni,


et al. 1977).

     B.  Mutagenicity


         1,1-Dichloroethylene has  been  shown to  be  mutagenic  in  S^ typhimu-


rium  (Bartsch,  et  al. 1975) and E^ coli K12  (Greim, et al. 1975).   In both


systems,  mutagenic activity  required  microsomal activation.   In mammalian


systems,  1,1-dichloroethylene was  negative  in  the  dominant  lethal  assay


(Short, et al.  1977b; Andersen,  et al. 1977).


     C.  Teratcgenicity


         A  study  by  Murrary, et  al.  (1979)  failed to  shcv/ tsratogenic  af-


fects  in  rats  or  rabbits  inhaling  concentrations cf  up to 160  ppm 1,1-di-


chloroethylene  for 7  hours per  day or  in  rats  given drinking  water contain-


ing 200 ppm  1,1-dichloroethylene.

     0.  Other Reproductive Effects


         Pertinent data could not be located in the available literaure.


     E.  Chronic Toxicity


         In  animal studies,  liver  damage is  associated with exposure, either

in  the air  or water, to  1,1-dichloroethylene  (6 jdg/m   or 0.79  pg/1)  with


transitory damage  appearing as vacuolization  in liver  cells.  In  both guinea
                                                                      »
pigs  and  monkeys,  continuous exposure  to 1,1-dichloroethylene produced  in-

creased mortality,  while intermittent exposure  to the same  concentration in

-------
air produced no  increase  in mortality (U.S..EPA, 1979a).  Less attention has
been  paid  to the  renal  toxicity of  1,1-dichloroethylene  despite the occur-
rence  of histologically  demonstrated damage at  exposures equal  to or less
than  those  required for  hepatotoxicity  (Predergast,  et al.  1967; Short,  at
al. 1977a).
     F.  Other Relevant Information
         Alterations in  tissue glutathione concentrations affect  the hepato-
toxicity of '1,1-dichloroethylene,  with  decreased  tissue  glutathione   asso-
ciated  with greater  toxicity and  elevated glutathione associated  with de-
creased toxicity (Jaeger, et al. 1973,1977).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Dill, et  al.  calculated, for  the fathead  minnow, Pimephales prome-
las,  96-hour  1C--,  values  of  169,000  jug/1   using   static   tachnicues and
1CS,CCO ug/1 using flow-through  tasts with measured concentrations.   The re-
ported  96-hour LC--, value  for the bluegill, Leoomis  mactochirjs, is 73,900
ug/1  in a  static  test (U.S.  EPA,  1978b).  Two  48-hour  tests  with Daphnia
maona  resulted  in  ECcg values of  11,600  and  79,000  jjg/1,   respectively
(Dill,  et  al.;   U.S.  EPA, 1978b).  The  96-hour LC5Q  values  for  the sheeps-
heao  minnow,  Cyorinodon  varieoatus,  and  the   tidewater  silversioe, Menidia
beryllina,  are 249,000 and  250,000 ug/1,  respectively (U.S. EPA,   1978b; Daw-
son,  et  al.  1977).   The  96-hour  LC^,,   for   the  mysid  shrimp,  Mysidoosis
bahia, is reported to be  224,000 ug/1 (U.S. EPA, 1978b).
     B.  Chronic Toxicity
         An  embryo-larval test  with  the  fathead minnow resulted in  no ad-
                                                                      •
verse effects occurring  at 2,800 /jg/1, the highest test concentration  (U.S.
EPA, 1978b).

-------
     C.  Plant Effects

         The  96-hour  EC--  value based  on  cell  numbers  of  the  freshwater

alga, Selenastrum capricornutum, is reported to be  greater than  798,000 ug/1

(U.S.  EPA,-1978b).   The  effective  concentration of  1,1-dichloroethylene  on

the  saltwater  alga,  Skeletonema costatum,  was observed  to be  712,CGO  ug/1

(U.S. EPA, 1978b).

     D.  Residues

         Pertinent data could not be located in the available  literature.

VI.  EXISTING GUIDELINES AND STANDARDS

     A.  Human

         The  American  Conference  of   Governmental   Industrial  Hygienists

(ACGIH,  1977)  threshold  limit  value (TLV)  for  1,1-dichloroethylene  is  40

mg/m ,  with  calculated daily exposure  limits  of 286  mg/day.   1,1-Oichloro-

ethylene is  suspected  of  being  a human  carcinogen;  and using the  "one-hit"

model,  the U.S.  EPA  (1979a) has estimated levels of  l,l-dichlcrcethyler:e  in

ambient water which will result  in soecified risk levels of human cancer:

Exposure Assumptions         Risk Levels with Corresponding Draft Criteria
     (per day)
                                      10-7           ig-6           ig-5

2 liters of drinking water         0.013 ug/1      0.13-.ug/1      1.3 jjg/1
and consumption of 18.7
grams fish and shellfish.

Consumption of fish and            0.21  ug/1       2.1 ug/1       21 jug/1
shellfish only.


     8.  Aquatic

         For  1,1-dichloroethylene,  the   drafted  criterion to protect  fresh-

water  aquatic  life  is  530  ug/1 as a 24-hour average,  not to  exceed  1,200
                                                                     »
/jg/1 at  any  time.  No  saltwater  criterion has been proposed because of in-

sufficient data.
                                   7'-?

-------
                             1,1-OICHLOROETHYLENE

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

Anderson, 0.,  et al.   1977.   Dominant  lethal studies with  the  halogenated
olefins  vinyl  chloride and vinylidene  dichloride in male CD-I mice.   Envi-
ron. Health Perspect.  21: 71.

Anderson, M.E.  and  L.J.  Jenkins,  Jr.   1977.  Enhancement  of  1,1-dichloro-
ethylene hepatotoxicity by  pretreatment with  low  molecular  weight epoxides.
Proc. Soc. Toxicol.  41.

Arthur D. Little,  Inc.  April, 1976.   Vinylidene Chloride monomer emissions
from the monomer, polymer,  and  polymer  processing industries, Arthur 0. Lit-
tle, Inc., for the U.S. Environ. Prot. Agency, Research Triangle Park, N.C.

Bartsch,  H.,   et  al.   1975.   Tissue-mediated  mutagenicity  of  vinyiidene
chloride and 2-chlorobutadiene in Salmonella tyohirnurium.  Nature.  255: 641.

Carlson, G.P.  and  G.C. Fuller.   1972.   Interactions  of  modifiers of hepatic
microscmal drug  metabolism  and  the inhalation toxicity of 1,1-dichloroethyl-
ene.  Res. Comm. Chem. Pathol. Pharmacoi.  4:  553.

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

Oiil,  O.C.,  at al.   Toxicity of  1,1-dicnlcroethylene  (vinylidene chloride)
to aquatic organisms.  Dow Chemical Co.   (Manuscript)

Greim, H.,  et  al.    1975.   Mutagenicity  in vitro  and potential carcinogeni-
city of  chlorinated  ethylenes as  a function  of  metabolic oxirane formation.
Siochem. Pharmacoi.  24: 2013.

Henschlar, D.   1977.   Metabolism  and  mutagenicity of halogenated  olefins - A
comparison of structure and activity.  Environ'. Health Perspect.   21: 61.

Hushon,  J. and  M.  Kornreich.   1978.  Air  pollution  assessment of vinylidene
chloride.  EPA-450/3-78-015.  U.S. Environ. Prot. Agency, Washington, O.C.

Jaeger,  R.J.,  et al.  1973.  Diurnal variation of hepatic  glutathione con-
centration and its correlation  with  1,1-dichloroethylene  inhalation toxicity
in rats.  Res.  Comm. Chem. Pathol. Pharmacoi.  6: 465..

Jaeger,  R.L.,  et al.   1977.   1,1-Oichloroethylene hepatotoxicity:  Proposed
mechanism of  action  of  distribution and  binding of ^C-radioactivity^ f0j__
lowing inhalation exposure in rats.  Environ. Health  Perspect.  21: 113!

Jenkins, L.I., et al.  1972.   Biochemical  effects of 1,1-dichlorpethylene in
rats: Comparison with carbon tetrachloride and  1,2-dichloroethylene.   Toxi-
col. Appl. Pharmacoi.  23: 501.

-------
Maltoni,  C.   1977.   Recent  findings  on  the. carcinogenicity  of chlorinated
olefins.  Environ. Health Perspect.  21: 1.

Maltoni,  C.,  et  al.   1977.   Carcinogenicity bioassays  of  vinylidene chlor-
ide.  Research plan and early results.  Med. Lav.  68: 241.
McKenna,  M.J.,   et  al.   1978a.    The  pharmacokinetics  of  (14C)  vinylidene
chloride  in  rats following  inhalation  exposure.  Toxicol.  Appi.  Pharmacol.
45: 599.

McKenna,  M.J.,  et  al.   1978b.  Metabolism  and pharmacokinetics  profile of
vinylidene chloride  in rats  following  oral administration.   Toxicol.  Appl.
Pharmacol.  45: 821.

Murray, F.J.,  et al.  1979.   Embryotoxicity and fetotoxicity  of  inhaled or
ingested  vinylidene  chloride  in  rats  and  rabbits.   Toxicol:  Appl.  Pharma-
col.  49: 189.

Prendergast,   J.A.,  et al.   1967.   Effects  on experimental  animals  of long-
term inhalation of  trichloroethylene,  carbon tetrachloride, 1,1,1-trichloro-
ethane,  dichlbrodifluoromethane,   and  1,1-dichloroethylene.   Toxicol.  Appl.
Pharmacol.  10: 270.

Rampy,  L.W.,  et  al.  1977.   Interim  results  of  a two-year toxicological
study in  rats of vinylidene  chloride  incorporated  in the  drinking  water or
administered by repeated inhalation.  Environ. Health Perspect.  21~: 33.

Reynolds, E.S.,  et al.   1975.  Hepatoxicity  of vinyl  chloride  and  1.1-di-
chioroethylene.  Am. Jour. Pathol.  81: 219.

Short,  R.D.,  et al.   1977a.  Toxicity of   vinylidene  cnloride in mice  and
rats  and its alteration  by  various  treatments.   Jour.  Toxicoi.  Environ.
Health.  3:  913.

Short,  R.D.,  et  al.   1977b.  A dominant  lethal  study in  male rats after re-
peated  exposures  to vinyl  chloride  or  vinylidene chloride.   Jour.  Toxicol.
Environ, health.  3: 965.

U.S.  EPA.   1973a.   Statement of basis and  purpose  for  an  amendment  to cne
National interim primary  drinking  water regulations  on  a  treatment technique
for  synthetic organics.   Off. Drinking  Water.  U.S. Environ.  Prot.  Agency,
Washington,  D.C.

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

U.S.  EPA.   1979a.   Dichloroethylenes:  Ambient Water Quality  Criteria Docu-
ment. (Draft)

U.S. EPA.   1979b.   Environmental  Criteria and Assessment Office.   Dichloro-
ethylenes: Hazard Profile.   (Draft)

-------
                                      No.  72
     trana-l,2-Oichloroethylene


  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 accuracv.

-------
                  TRANS-1,2-DICHLQRETHYLENE




                           SUMMARY




     There is little specific information available on trans-



1,2-dichloroethylene.   This  compound is  quantitatively  less



toxic  than  the   1,1-dichloroethylene  isomer;  however,   the



toxicity  appears  qualitatively  the  same  with  depression



of  the  central nervous  system  as well  as liver  and kidney



damage.    Trans-l,2-dichloroethylene  has  been   shown  to  be



a  mutagen in  bacterial  systems.   The  teratogenicity  and



carcinogenicity of this compound have not been evaluated.



     In  the  only aquatic  study  reported,  the   observed  96-



hour LCeg value for  the bluegill  is  135,000 pg/1 in  a static



bioassay.
                             7*-}

-------
                  TRANS-1,2-DICHLORETHYLENE


I.   INTRODUCTION


     This  profile  is  based  on  the  Ambient  Water  Quality


Criteria Document for Dichloroethylenes  (U.S. EPA, 1979).


     Trans-1,2-dichloroethylene   (traans  1,2-DCE;  C-tUCl-;


molecular weight  96.95)  is  a clear  colorless liquid.   Since


the early  1960's trans-l,2-dichloroethylene  has  had  no wide



industrial usage  (Patty, 1963).   Trans-l,2-dichloroethylene


has  the  following  physical/chemical  properties:     water


solubility of  6,300 ug/ml,  a  vapor  pressure of  324  mm Hg,


and a melting point of -50°C (Patty,  1963).



II.  EXPOSURE


     A.   Water


          Trans-l,2-dicnloroethylene  was found at a  concen-


tration of 1 ug/1 in Miami  drinking water  (U.S.  EPA,  1975,


1978) .


     B.   Food


          Pertinent data could  not be  located  in the avail-


able literature on the ingestion of trans-1,2-dichloroethylene


in  foods.   The U.S. EPA (1979)  has  not  estimated a  biocon-


centration factor for trans-1,2-dichloroethylene.


     C.   Inhalation


          Pertinent  information  could  not  be   located  in



the available literature.
                          7 a.-4/
                         - V/J*
                          "^5^7

-------
III. PHARMACOKINETICS
     A.   Absorption
          Animal  or human  studies  do  not  appear  to exist
which  specifically  document the  degree of  systemic  absorp-
tion of trans-l,2-dichloroethylene by any route.
     B,   Distribution
          Pertinent data  could  not be  located  in the avail-
able literature.
     C.   Metabolism
          Trans-l,2-dichloroethylene  is metabolized  through
an  epoxide  intermediate   to  either  a  dichloroacetaldehyde
or  monochloroacetic acid   (Liebman  and Ortiz,  1977).   The
epoxide  intermediate  which  is  reactive,  may  form covalent
bonds  with  tissue  macromolecules  (Henschler,  1977).   Meta-
bolism  of  the  cis-isomer  relative  to  the  amount  tak'en up
by the liver was much greater than the trans-isomer  (McKenr.a,
et al. 1977).
     D.   Excretion
          Pertinent data  could  not be  located  in the avail-
able literature.
IV.  EFFECTS
     A.   Carcinogenicity
          Pertinent data  could  not be  located  in the avail-
                                            *
able literature.
     B.   Mutagenicity
                                                           »
          Trans-l,2-dichloroethylene  has  been  shown to be
negative  in  the  E^  coli  K12  and  Salmonella  mutagenicity
assays  (Greim, et al.  1975; Cerna and Kypenova, 1977).

-------
     C.   Teratogenicity and Other Reproductive Effects
          Pertinent  information  could  not  be  located  in
the available literature.
     D.   Chronic Toxicity
          Although  little  data  is  available  specifically
on trans-1,2-dichloroethylene,  it appears  that chronic expo-
sure  results in  kidney  and  liver  damage  similar   to  that
noted with  1,1-dichloroethylene (U.S.  EPA,  1979).   Jenkins,
et al. (J.972) found  trans-l,2-dichloroethylene  to be consider-
ably less potent than 1,1-dichloroethylene.
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          The reported  96-hour  LC^Q value  for  the bluegill,
Lepomis  macrochirus,   exposed   to   1,2-dichloroethylene  is
135,000 ug/1 (U.S. EPA, 1979)  in a static test procedure.
     B.   Chronic Toxicity, Plant Effects and Residues
          Pertinent  information  could  not  be  located  in
the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          The American  Conference of Governmental Industrial
Hygienists  (ACGIH,   1977)  threshold  limit  value  (TLV)  for
1,2-dichloroethylene  is  790  mg/m  ,  with  calculated  daily
exposure limits of  5,643  mg/day.   The U.S.  EPA  (1979)  draft
Water Quality  Criteria Document for  Dichloroethylene stat.es
that  human  health  criterion could not  be  derived  due  to
the lack of sufficient data on which to base a criterion.
                          74-6

-------
     B.   Aquatic
          Guidelines  do not  exist  for  salt  water  species
because of  insufficient data.    The  draft criterion  to pro-
tect freshwater  aquatic  life  is 530 ^g/1 as a  24-hour  aver-
age and not to exceed 1200  pq/1 at any time (U.S. EPA, 1979).

-------
                 TRANS 1,2-DICHLOROETHYLENE

                         REFERENCES

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

Cerna, M. , and H. Kypenova.  1977.  Mutagenic activity of.
chloroethylenes analyzed by screening system tests.  Mutat.
Res.  46: 214.

Greim, H., et al.  1975.  Mutagenicity in vitro and potential
carcinogenicity of chlorinated ethylenes as a function of
metabolic oxirana formation.  Biochem. Pharmacol. 24: 2013.

Henschler, D.  1977.  Metabolism and mutagenicity of halo-
genated olefins - A comparison of structure and activity.
Environ. Health Perspect.' 21: 61.

Jenkins, L.J., et al.  1972.  Biochemical effects of 1,1-di-
chloroethylene in rats: Comparisons with carbon tetrachloride
and 1,2-dichloroethylene.  Toxicol. Appl. Pharmacol. 23: 501.
Leibman, K.C., and E. Ortiz.  1977.  Metabolism of halogen-
ated ethylenes.  Environ. Health Perspect. 21: 91.

McKenna, M.J., et al.  1977.  The pharmacokinetiLcs of  i^c]
vinylidene chloride  in rats following inhalation exposure.
Toxicol. Appl. Pharmacol. 45: 599.

Patty. F.A.  1963.  Aliphatic halogenated hydrocarbons.  Ind.
Hyg. Tox. 2: 1307.

U.S. EPA.  1975.  Preliminary assessment of suspected  carcin-
ogens in drinking water.  Rep. to Congress.  Off. Toxic
Subst.  U.S. Environ. Prot. Agency, Washington, D.C.

U.S. EPA.  1978.  List of organic compounds identified in
U.S. drinking water.  Health Effects Res. Lab.  U.S. Environ.
Prot. Agency, Cincinnati, Ohio.

U.S. EPA.  1979.  Dichloroethylenes: Ambient Water Quality
Criteria. (Draft).

-------
                                  No. 73
         Dlchloroethylanes


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

          APRIL 30, 1980
       73-1

-------
                          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.
                        73-3-

-------
                            DICHLOROETHYLENES




                                 Summary




     Of the three dichloroethylene  isomers,  cis 1,2-dichloroethylene,




trans 1,2-dichloroethylene,  and 1,1-dichloroethylene,  only the 1,1-dichloro-




ethylene isomer is produced in large quantities.   Most of the health




effects information available is related to  the 1,1-dichloroethylene




isomers; however, qualitatively the toxicity of the  1,2-dichloroethylene




isomers appears to be similar, with depression of the  central nervous




system and liver and kidney damage.   Of the  three isomers, 1,1-dichloro-




ethylene is the most toxic.   Both 1,1-dichloroethylene and trans  1,2-




dichloroethyler.e are autagenic in bacterial  systems.   Only 1,1-dichloro-




ethylene has been shown to be a carcinogen.




     All of the available aquatic data, with one  exception,  are for 1,1-




dichlcroethyiene. Reported 96-hour  [,€50 values for the bluegill are 73,900




and 135,500 ug/1, respectively, for 1 , 1-dicnlorcehtylene and  1,2-di-



chloroethylene. Two observed 46-hcur ^€50 values for  Daphnia exposed to



1,1-dichloroethylene range were 11,600  and 79,000 ug/1.   All  saltwater



fish and invertebrates tasted with  1,1-dichioroethylene showed 96-hour



LC5Q values over 224,000 ug/1, and  all  algae tested  both in fresh  and



saltwater, had 96-hour EC^g values  (based on cell numbers) of 716,000




and over.  In the only reported chronic study,  no adverse effects  were



observed at the highest test concentration of 2,800  ug/1 for  fathead




minnows exposed to 1,1-dichloroethylene.
                               73-3

-------
                            DICHLOROETHYLENES




I.   INTRODUCTION




     This profile is based on the draft Ambient Water Quality Criteria




Document for Dichloroethylenes (U.S.  EPA,  1979).




     The dichloroethylenes (^2^2^2'i  molecular weight 96.95)  consist of




the three isomers:  1,1-dichloroethylene,  cis- 1,2-dichloroethylene, and




trans-l,2-dichloroethylene.  Dichloroethylenes are clear colorless liquids




with water solubilities between 2,500 and  6,300 ug/1, vapor pressures

                                                v

between 591 and 208 mm Hg, and melting points between -50°C and -122°C




(U.S. EPA, 1979).  The 1,1-dichloroethylene isomer is the most extensively




used in industry, with annual production prior to  1976  of approximately




120,000 metric tons (Arthur D. Little, Inc.,  1976).   The 1,1-dichloroethylene




isomer is used as a chemical intermediate  in the synthesis of methylchloroform




ana in the production of pclyvinylidene chloride copciymers (FVDCs).



II.  EXPOSURE



     I.
     A.   water



          The National Organic Monitoring  Survey (U.S. EPA, 1973a) reported




detecting 1,1-dichloroethylene in finished drinking waters; however,




neither the amount nor the occurrence was  quantified.  Both cis and trans-




1,2-dichlcroethylene were found at concentrations  of 16 and 1 ug/1,




respectively, in Miami drinking water (U.S.  EPA, 1975, 1978b).




     B.   Food




          Pertinent data could not be located on the ingestion of dichloro-




ethylene in foods.  The U.S.  EPA (1979) has estimated the weighted bioconcen-




tration factor for 1,1-dichloroethylene to be 6.9  for the edible portions of
                               73-/

-------
fish and shellfish consumed by Americans.  This estimate is based on the



octanol/water partition coefficients of  1,1-dichloroethylene.  There is no



estimate for a bioconcentration factor for the other iscrners.



     C.   Inhalation



          The population at risk due to vinylidene chloride exposure is composed



primarily of workers in industrial or commercial operations manufacturing or



using it.  Airborne emissions of vinylidene chloride are not likely to pose a



significant risk to the general population.  Emissions during production,



storage, and transport can be controlled by methods similar to those planned



for control of vinyl chloride (Hushon and Kornreich, 1978)
     •


III. PHARMACOKINETICS



     A.   Absorption



          Specific data on the absorption of dichloroethylenes are unavailable.



However, a recent study by McXenna, et al. (1973b) suggests that in rats most,



if not all, of the orally administered dose is absorbed at two dose levels: 1



and 50 35/kg.



     B.   Distribution



          Distribution of 1,1-dichloroethylene was studied in rats following



inhalation (Jaeger, et al. 1977).  The largest concentrations were found in



kidney, followed by livsr, spleen, heart, ar.d brain; and fasting made no



difference in the distribution pattern.  At the subcellular level 1,1-dichloro-



ethylene or its metabolites appear to bind to macromolecules of the microsomes



and mitochondria (Jaeger, et al. 1977).  There is also some association with



the lipid fraction.  Distl,2-dichloroethylene isomers, are not available.



     C.   Metabolism



          The essential feature of all dichloroethylene metabolism is the



presence of epoxide intermediates which are reactive and may form covalent

-------
bonds with tissue raacromolecules (Henschler, 1977).  In rats and mice,

covalently bound metabolites of 1,1-dichloroethylene are found in the

kjdney and liver (McKenna, et al. 1978b).  Interaction of dichloroethylenes

with the microsomal mixed function oxidase system is not clear,' since

both inhibitors (dithiocar'oamate) and inducers (phenobarbital) decreased

the toxic effects of 1,1-dichloroethylene (Anderson and Jenkins, 1977;

Reynolds, et al. 1975; Jenkins, et al. 1972).  Carlson and Fuller (1972),

however, reported increased mortality from 1,1-dichloroethylene in rats

following phenobarbital pretreatment.  There is evidence that the 1,1-

dichloroethylene metabolites are conjugated with gluthathione, which

presumably represents a detoxification step  (McKenna, et al. 1978b).

     B.   Excretion

          The only information available on elimination pertains to the

1,1-dichlorcethylene isc~er.  It is postulated that the 1,1-dichloro-

ethylane isorner has a rapid rate of elimination since a substantial

fraction of the total absorbed dose may be recovered in urine within 26

to 72 hours (Jaeger, et al. 1977; McKenna, et al. 1978a).  Also, dis-

appearance of covalently bonded metabolites of 1,1-dichloroethylene

(measured as TCA-insoluble fractions) appears to be fairly rapid, with a

reported half-life of 2 to 3 hours (Jaeger, et al. 1977).

IV.  EFFECTS

     A.   Carcinogenicity

          There is only data on the carcinogenicity of the 1,1-dichloro-

ethylene isomer.  This isomer has been shown to produce kidney adeno-

carcinomas in male mice and mammary- adenocarcinomas in female mice upon
                                                                    «
inhalation of 100 mg/m3 (Maltoni, et al. 1977; Maltoni, 1977).  In

-------
similar experiments with Sprague-Dawley rats exposed as high as 800 mg/m^ f



no significant increase in tumor incidence was noted.  Hamsters exposed



to the same conditions as the mice failed to exhibit an increased tumor



incidence-(Maltoni, et al. 1977).  In rats exposed to 1,1-dichloroethylene



in their drinking water (200 mg/1) there was no evidence of increased



tumors (Rampy, et al. 1977).  There was an increased incidence of mammary



tumors in rats receiving 20 mg of 1,T-dichloroethylene by gavage U to 5



days a week for 52 weeks.  The incidence was 42 percent in the treated



animals and 31* percent in the controls; however, the data was not analyzed



statistically (Maltoni, et al. 1977).



     B.   Mutagenicity



          1,1 -Dichloroethylene has been shown to be mutagenic in S_._ typhimuriuj



(Bartsch, et al. 1975) and Z^ coli K12 (Greim, et al. 1975); however,



both the cis and trans iscaers of 1,2-dichioroethylene were non-mucagenic



when assayed with £_._ coli K"2.  In order to demonstrate mutagenic activity,



1,1-dichloroethylene needed microsomal activation.  In addition, cis



1,2-dichloroethylene was tnutagenic in Salmonella tester strains, and



promoted chromosomal aberrations in cytogenic analysis of bone marrow



cells (Cerna and Kypenova, 1977).  In mammalian systems,  1,1-dichloroethylene



was negative in the dominant lethal assay (Short, et ai.  1977b; Anderson,



et al. 1977).



     C.   Teratogenicity



          A study by Murray, et al. (1979) failed to show teratogenic

                                                  ,-
effects in rats or rabbits inhaling concentrations of up to 160 ppm 1,1-di-



chloroethylene for 7 hr/day or in rats given drinking water containing
                                                                    »


200 ppm 1,1-dichloroethylene.
                                 ? 1-

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



          Pertinent data could not be located in the available literature.



     E.   Chronic Toxicity



          In- animal studies, liver damage is associated with exposure



either in the air or water, to dichloroethylenes (6 mg/m3 or 0.79  mg/1)



with transitory damage appearing as vacuolization in liver cells  (U.S.



EPA, 1979).  Jenkins,  et al. (1972) found both cis and trans 1,2-dichloro-



ethylene to be considerably less potent than 1,1-dichloroethylene  as  a


hepatotoxin.  Less attention has been paid to the renal toxicity of the



dichloroethylenes despite the occurrence of histologically demonstrated



damage at 1,1-dichloroethylene exposures equal to or less than those



required for hepatoxicity (Prendergast, et al. 1967; Short,  et al.  1977a).



     F.   Other Relevant Information



          Alterations in tissue glutathione concentrations affect  the



hepatotoxicity of 1,1-dichloroethylene, with decreased tissue slutathicr.e



associated with greater toxicity and elevated gluthachione associated



with decreased toxicity (Jaeger, et al. 1973, 1977).



V.   AQUATIC TOXICITY



     A.   Acute Toxicity



          All of the available data for dichloroethyiene,  with one exception,


are for 1,1-dichloroethylene.  The data on acute static tests with bluegill,



Lepomis macrochirus,  under similar conditions show a correlation between


the degree of chlorination and toxicity.  The 96-hour LC5Q values  for the



bluegill are 73,900 and 135,000 ug/1 for 1,1- and 1,2-dichloroethylene,


respectively.  Additional data for other ethylene chlorides are as follows:  44,700
                                                                      »

ug/1 for trichloroethylene, and 12,900 ug/1 for tetrachloroethylene (U.S.



EPA, 1978c).  These results indicate an increase in the lethal effect on


bluegills with an increase in chlorine content.
                                73-?

-------
     The 96-hour LC5Q value for the sheepshead minnow, Cypuimocen variegatus,


tidewater silverside, Menidia beryllina, and mysid shrimp, Mysidepsis


behia, following exposure to 1,1-dichloroethylenes are all over 224,000


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


     B.   Chronic Toxicity


          In the only reported chronic study, an embryo-larval test  in


fathead minnows, no adverse effects were observed at the highest test


concentration of 1,1-dichloroethylene, 2800 _ug/l (U.S. EPA,  1979).


     C.   Plant Effects


          The 96-hour £050 values based on cell numbers of the freshwater


algae, Salenestr-un: capriecrr.utur. and the saltwater algae,  Sksletcns-a


costatum, are 798,000 and 712,000 ug/1, respectively, for exposure to


1,1-dichloroethylsne (U.S. EPA,  1978c).


     D.   Residues


          Pertinent information could not be located in the  available


literature.


VI.  EXISTING GUIDELINES AND STANDARDS


     A.   Human


          The American Conference of Governmental Industrial Hygienists


(ACGIH, 1977) threshold limit values (TLV) are 40 mg/m3 (1,1-dichloro-


ethylene) and 790 mg/ni3 (1,2-dichloroethylene).  These values allow daily


exposures of 286 ag 1,1-dichloroethylene per day and 5,643 eg 1,2-di-


chloroethylene per day.  The U.S.  EPA (1979) draft water criteria document
                                                 f

for dichloroethylene states that no human health criterion could be derived


for cis- and trans-l,2-dichloroethylene due  to the lack of sufficient


data on which to base a criterion.  1,1-dichloroethylene is  suspected of

-------
being a human carcinogen, and using the "one-hit" model, the U.S. EPA

(1979) has estimated levels of 1,1-dichloroethylene in ambient water

which will result in specified risk levels of human cancer:
Exposure Assumptions
    (per day)

2 liters of drinking water
 and .consumption of 18.7
 grams fish and shellfish

Consumption of fish and
 shellfish only.
 Risk levels and Corresoondine Draft Criteria
      10'
10
                  -6
    0.013 ug/1  0.13 ug/1


    0.11  ug/1  2.1  ug/1
  IP"3

•1.3 ug/1


21   ug/1
     B.   Aquatic

          The -proposed draft criterion to protect freshwater species

from dichlcroethylene toxicity are as follows (U.S. EPA._ 1979):
Compound


1,1-dichloroethylene
1,2-dichloroethylene

For saltwater species:

1,1-dichioroethylene
1,2-dichloroethylene
2*4-hr.  Average

   530  us/I
   620  ug/1
 1,700 ug/1
Not available
      Concentration not to be
      exceeded at anytime

             1,200 us/1
             1,400 ug/1
             3,900 ug/1
            Not available

-------
                               DICHLOROETHYLENES

                                  References

American  Conference  of  Governmental  Industrial  Hygenists.   1977.   Docu-
mentation of.the threshold limit values.  3rd ed.

Anderson, p.,  et al.   1977.   Dominant  lethal  studies with  the  halogenatea
olefins  vinyl  chloride  and   vinylidene   dichloride  in  male  CO-i  mice.
Environ. Health Perspect.  21: 71.

Anderson, M.E.  and  L.J.  Jenkins,  Jr.   1977.   Enhancement  of 1,1-dichloro-
ethylene hepatotoxicity  by  pretreatment with low molecular  weight epoxides.
Proc. Soc. Toxicol.  41.

Arthur  D.  Little,   Inc.  April,  1976.   Vinylidene chloride  monomer emissions
from  the monomer,  polymer,   and  polymer  processing  industries,  Arthus  D.
Little,  Inc.,  for  the  U.S.  Environ.  Prot.  Agency,  Research  Triangle Park,
N.C.

Bartsch,  H.,  'et al.,   1975.   Tissue-mediated  mutagenicity   of  vinylidene
chloride and 2-chiorobutadiene in Salmonella tv^himurii:". . Mature 255: 641.

Carlson, G.P. and  G.C.  Fuller.  1972.   Interactions  of modifiers  of hepatic
microsomal  drug metabolism  and  the   inhalation toxicity  of  1,1-dichloro-
ethylene.  Res. Comm. Chem.  Pathol. Pharmacol.   4:  553.

Carna,  M.,  and  H.  Xypenova.    1977.   The  acute toxicity  of  47  industrial
chemicals to fresn and saltwater fishes.  Jour. Hazsrc. Mater,  i: 3C3.

Dill, O.C., et  al.  Toxicity  of  1,1-dichlcroethylene  (vinylidene chloride)
to aquatic organisms.  Dow Chemical Co.  (Manuscript).

Greim,  H.,  et  al.   1975.    Mutagenicity  in  vitro  and potential  carcino-
genicity of chlorinated  ethylenes as  a  function  of metabolic  oxirane forma-
tion.  Biochem. Pharmacal.  24: 2013.

Henschler, D.   1977.  Metabolism  and  mutagenicity of halogenated  ol'efins - a
comparison of structure ana activity.   Environ. Health Fersoect.  21: 6i.

Hushon,  J.  and  M.  Kornreich.   1978.  Air pollution assessment of vinylidene
chloride.  EPA-480/3-78-015.  U.S. Environ.  Prot. Agency, Washington, D.C.  "

Jaeger,  R.J.   1973.   Diurnal  variation  of  hepatic  glutathions concentration
and  its  correlation with 1,1-dichloroethylene  inhalation toxicity  in rats.
Res. Comm. Chem. Pathol. Pharmacol.  6:  465.

Jaeger,  R.L., et  al.  1977.   1,1-Dichloroethylene  hepatotoxicity:   Proposed
mechanism of  action of  distribution  and binding of ^C  radioactivity  fol-
lowing inhalation exposure in  rats.  Environ. Health Perspect.   21: 113,

-------
Jenkins, L.J., et  al.   1972.   Biochemical effects of 1,1-dichloroethylene in
rats:   Comparison  with  carbon  tetrachloride   and  1,2-dichloroethylene.
Toxicol. Appl. Fharmacol.  23: 501.

Maltoni, C.   1977.   Recent  findings  on the carcinogenicity  of chlorinated
olefins.  Environ. Health Perspect.  21: 1.

Maltoni,  C.,   et  al.   1977.    Carcinogenicity  bioassays  of  vinylidene
chloride.   Research plan and early results.  Med. Law.  63: 241.

McKenna,  M.J..  et  al.   1978a.   The  pharmokinetics  of  [14C]  vinylidene
chloride in  rats  following  inhalation, exposure.  Toxicol.  Appl.  Pharmacol.
45: 599.

McKenna,  M.J.,  et  al.   1978b.   Metabolism  and  pharmokinetic profile  of
vinylidene chloride  in rats  following oral administration.   Toxicol. Appl.
Pharmacol.  45: 821.

Murray, F.J.,  et al.   1979.   Embryotoxicity and fetotoxicity  of  inhaled or
ingested   vinylidene  chloride   in    rats   and   rabbits.    Toxicol.   Appl.
Pharmacol.  49: 139.

Prendergast,   J.A.,  et al.   1967.  Effects on experimental  animals  of long-
term inhalation of trichloroethylane,  carbon tetrachloride, 1,1,1-trichioro-
ethans, dichlorodifluorcmethane,   and  1,1-dichloroethylene.   Toxicol. Appl.
Pharmacol.  10: 270.

Rsmpy,   L.W.,   et  =1.   1977.   Interim  results  of  a tv/o-yesr   toxicologies!
study  in rats of vir,yiidene chloride  incorporated  in the  drinking  water or
administered by repeated inhalation.    Environ. Health Psrspect.  21: 33.

Reynolds.    E.S.,   et   al.    1975.    Hepatoxicity  of  vinyl   chloride  and
1,1-dichloroethylene.  Am. Jour. Pathol.  81: 219.

Short,   R.D.,  et al.   1977a.   Toxicity  of vinylidene chloride in  mice  and
rats  and   its alteration  by  various  treatments.   Jour,  Toxicol.  Environ.
Health  3: 913.

Short,   R.O.,  et  al.   1977b.   A  dominant  lethal study  in male  rats after
repeated exposure  to  vinyl  chloride  or  vinylidene chloride.   Jour.  Toxicoi.
Environ. Health  3: 965.

U.S.   EPA.    1975.    Preliminary   assessment  of  suspected  carcinogens  in
drinking water,  Rep.  to  Congress.  Off.  Toxic  Subst.  U.S.  Environ. Prot.
Agency, Washington, D.C.

U.S. EPA.   1978a.  Statement  of  basis  and  purpose  'for  an  amendment  to  the
National interim primary drinking  water  regulations  on a  treatment technique
for  synthetic organics.  Off.  Drinking  Water.   U.S. Environ.  Prot.   Agency,
Washington, O.C.

U.S. EPA.   1978b.   List  of  organic  compounds  identified in  U.S.  drinking
water.   Health Effects  Res.  Lab. U.S.  Environ.  Prot.   Aoency,  Cincinnati,
Ohio.

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

U.S.   EPA.    1979.   Dichloroethylenes:   Ambient  Water  Quality  Criteria.
(Draft).
                              73-'?

-------
                                         SJ-46-04
                                         DRAFT
                                         10-21-80
                                       No.  74
          Dichloromethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY

      WASHINGTON, B.C.  20460


          October 30, 1980

-------
                            DISCLAIMER
     This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical.  The
information contained in the report is drawn chiefly from secondary
sources and available reference documents.  Because of the limi-
tations 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.
                               74-2

-------
                      DICHLOROMETHANE (DCM)




                             SUMMARY






     In humans, DCM is a central nervous system depressant




resulting in narcosis at high concentrations, and impaired task




performance.  Dichloromethane is metabolized to carbon monoxide




and causes an increase in carboxyhemoblogin, placing persons with




cardiovascular disease, and perhaps those-who are pregnant, at




increased risk of disease.  On the basis of present evidence, DCM




cannot be firmly identified as an animal or human carcinogen.




DCM has been shown to be mutagenic to Salmonella, but not to




S.  cerevisia and Drosophi'la, and causes cell transformation.




     Aquatic organisms are fairly resistant to dichloro-




methane, with acute toxicity values ranging from 193,000 to 331,000




ug/1.
                               74-?

-------
                          DICHLOROMETHANE









 I.<   INTRODUCTION




      This  profile  is  based  on  the  Ambient Water  Quality  Criteria




 Document for  Ha'lomethanes (U.S.  EPA,  1979a).




      Dichloromethane  (CH2C12,  methylene chl'oride, methylene




 dichloride, and methylene bichloride; molecular  weight 84.93)  is




 a  colorless liquid with  a melting  point of -95.18C,  a boiling




 point of 40°C, a. specific gravity  of  1.327 g/ml  at 20°C, a vapor
                                             e



 pressure of 362.4 mm  Hg  at  20*C, and  a solubility in water of




 13.2  g/1 at 25°C.  Dichloromethane is a common industrial solvent




 found in insecticides, metal cleaners, -paints, and paint and




 varnish removers (Balmer, et al.,  1976).  In 1976, 244,129 metric




 tons  were  imported (U.S.  EPA,  1977).  For additional information




 regarding  the halomethanes  as  a  class, the reader is referred  to




 the Hazard Profile on Halomethanes (U.S. EPA, 1979b).




 II.   EXPOSURE




      A.   Water




          The U.S. EPA (1975)  has  identified dichloromethane in




 finished drinking waters  in the U.S.  in R of 83  sites, with a




maximum level of 0.007 mg/1 and a median of less than 0.001




mg/1.  The dichloromethane  in  drinking water is  not  a product  of




water chlorination (U.S. EPA,  1975; Morris and McKay, 1975).   In




the national organics monitoring survey, dichloromethane was




detected in 15 of 109 sites, with a mean concentration (positive




results only)  of 0.0061 mg/1 (U.S.  EPA,  1978).






                               74-4

-------
      B.    Food


           Pertinent  information  could not be  located  in the


available  literature.


      C.    Inhalation


           Reported background  concentrations  of dichloromethane


in both continental  and  saltwater atmospheres were about 0,0001?.


mg/m^, and urban  air concentrations ranged from less  than 0.00007


to 0.00005 mg/m^.  Local indoor  concentrations can be high due to


the use of aerosol sprays or solvents (Natl.  Acad. Sci., 1978).


III.  PHARMACOKINETICS


      A.    Absorption


           Efficiences of absorption of dichloromethane by the


lungs are  between 30 to  75 percent, depending on length of


exposure,  concentration, and activity level (Natl. Acad. Sci.,

                                                             I
1978; Natl. Inst. Occup. Safety  a.nd Health, 1976).


      B.    Distribution


          Upon inhalation and  absorption, dichloromethane levels


increase rapidly in  the blood  to equilibrium  levels that depend


primarily upon atmosphere concentration (Natl. Acad.  Sci.,  1978).


Carlsson and Hultengren (1975) reported that  dichloromethane


and its metabolites  were in highest concentrations in white


adipose tissue, followed in descending order by levels in brain


and liver.


     C.   Metabolism


          Dichloromethane is metabolized to carbon monoxide.


Some of this carbon monoxide is  exhaled, but a significant  amount



                               74-5

-------
 is  involved  in  the  formation  of  carboxyhemoglobin  (Natl.  Inst.




 Occup. .Safety and' Health,  1976).   Cardiorespiratory  stress  from




 elevated  carboxyhemoglobin may be  greater  as  a  result  of




 dichloromethane exposure  than from exposure  to  carbon  monoxide




 alone due to the continued formation  of  carbon  monoxide  following




 cessation'of dichloromethane  exposure (Stewart  and Hake,  1976).




 As  shown  by  animal  experiments,  other possible  human metabolites




 of  dichloromethane  include carbon  dioxide, formaldehyde,  and




 formic acid  (Natl.  Acad.  Sci., 1978).



     D.    Excretion




           A  large proportion  of  absorbed dichloromethane  is ex-




 creted unchanged, primarily via  the lungs, with some in  the urine.




 DiVincenzo,  et  al.  (1972)  have reported  that  about 40  percent of




 absorbed  dichloromethane  undergoes  some  reaction and decomposition




 process in the  body.



 IV.  EFFECTS




     A.    Carcinogenicity




          Friedlander et  al.  (1978) analyzed  the mortality of



 Eastman-Kodak male employees  exposed  to  low levels of  methylene




 chloride.  No significant  neoplastic  risk  factors were identified.




     Theiss and  coworkers  (1977) examined  the tumorigenic activity




 of dichloromethane in strain A mice.  Dichloromethane  at  the low




 dose (1:5 dilution of the maximum  tolerated dose) produced




marginally significant increases in tumor  response.  Shimkin and



 Stoner (1975) did not report a positive carcinogenic response for




 the strain A mouse bioassay system.






                               74-6

-------
        Although the data base is inadequate, there is a basis to




   suspect' the potential carcinogenicity of DCM based on the (marginally




   positive) pulmonary adenoma response in strain A mice, on positive




   responses for mutagenicity in the Ames test, and on the ability




   to transform rat embryo cells (see below).




        B.    Mutagenicity




             Simmon, et al.  (1977)  reported that dichloromethane




   tfas mutagenic to Salmonella typhimurium strain TA1QO when assayed




   in a dessicator whose atmosphere contained the test compound.




   Metabolic activation was  not required, and the number of revertants




   per plate was directly dose-related.  A linear dose response curve




   was observed.  Dichloromethane did not increase mitoti.c recombination




   in S_.  cerevisia D3 (Simmon, et al.,  1977), and it was reported




   negative  on testing for mutagenicity in Drosophila (Filippova, et




   al.,  1967).  Positive results for dichloromethane in the Ames




   assay  were recently confirmed by Jongen,  et al. (1978) with vapor




   phase  exposures (5,700 ppm) of strains TA98 and TA100.




        C.    Teratogenicity
4



             Schwetz et al.,  (1975)  showed that DCM can affect




   embryonal and fetal development  in rats and mice as evidenced by




   the increased incidence of  extra  sternebrae.   DCM also affects the




   development of  chick embryos,  causing  a 2  to 3-fold increase in mal-




   formation frequencies (Elsavaara  et  al.,  1979).




       D.    Other Reproductive Effects




             Gynecologic problems in femal workers exposed for
                                  74-7

-------
 long  period  to  gasoline  and  dichloromethane  vapors  were  reported




 by Vozovaya  (1974).   Also, inhalation  exposures  of  rats  and mice




 to vapor  levels  of  4,342 mg/m^  for  seven  hours daily  on  gestation




 days  6  to  15  produced evidence  of feto- or embryotoxicity  (Schwetz,




 et al., r975; Natl. Inst. Occup. Safety and  Health, 1976).




      E.    Chronic Toxicity




           Acute  exposures to  dichloromethane produce  central




 nervous system disfunction,  are irritating to mucous  membranes,




 and increase  the level of carboxyhemoglobin  (Natl.  Acad. Sci.,




 1978).  Price, et al.  (1978)  reported  that Fischer  rat embryo




 cells (F1706) were  transformed  by dichloromethane at  high




 concentrations (1.6 x 10"^M)  in the growth medium.  However,




 Sivak (1978)  indicated the presence of carcinogenic contaminants




 in the  dichloromethane and could not demonstrate transformation



 in the  BALB/C-3T3 assay system  with highly purified food grade




 dichloromethane.




 V.    AQUATIC TOXICITY




      A.    Acute Toxicity




           Acute toxicity values have been obtained  for two species




 of freshwater fish and one species of  freshwater invertebrates.




 LC5Q values for the fathead minnow (Pimephales promelas) ranged




 from 193,000 ug/1 in  a flowthrough assay to  310,000 ug/1 in a




 static assay.  An LC^Q value  of 224,000 ug/1 was obtained  for the




bluegill (Lepomis Macrochirus)  in a static assay.  Daphnia magna




were reported as having an "LC^Q value of 224,0^0 ug/1 (U.S. EPA,

-------
 1979a).   For  the  marine fish,  the  sheepshead  minnow  (Cyprinodon




 variegatus) ,  an 1650  of 331,000  ug/1  was  obtained.   The  marine




 mysid  shrimp  was  reported  as having an  LC5Q value  of 256,000




 ug/1.




     B.    Chronic Toxicity




           Chronic tests for freshwater  or marine species  could




 not  he located  in the available  literature.




     C .    Plant Effects




           Both  species of  freshwater  algae, Selenastrum  capricor-




 nortum  and marine  algae,  Skeletonema cornutum, were equally




 resistant  to  dichloromethane, with l>C$r\ values in  excess  of




 662,000 ug/1.




 VI.  EXISTING GUIDELINES AND STANDARDS




     Neither  the  human health nor the aquatic criteria derived by




 the 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 be changed.




     A.    Human




           OSHA  (1976)  has  established an eight-hour, time-weighted




 average for dichloromethane of 1,737 mg/m^; however, NIOSH (1976)




 has recommended a ten-hour, time-weighted average exposure limit




 of 261 mg/m^.   The U.S. EPA (1979a) draft water quality criterion




 for dichloromethane is  2 ug/1.    The reader is referred to the




Halomethanes Hazard Profile for  discussion of criteria derivation




 (U.S. EPA, 1979b).
                               74-9

-------
     B.«   Aquatic



          The criterion for protecting freshwater aquatic life has




been drafted as 4,000 ug/1, not to exceed 9,000 ug/1, while the




marine criterion has been drafted as 1,900 ug/1, not to exceed




4,400 ug/1.
                              74-10

-------
                          DICHLOROMETHANE
                             References
 Balmer, M.  F . •,  et  al.   1976.   Effects  in  the  liver  of
 methylene  chloride inhaled  alone  and with  ethyl  alcohol.
 Am.  Ind. Hyg. Assoc.  Jour.   37:345.

 Carlsson,.A., and  M.  Hultengren.   1975.   Exposure to
 methylene  chloride,  III.  Metabolism of 14C-labeled
 methylene  dichloride _in rat.  Scand. Jour.  Work Environ.
 Health  1:104.

 DiVincenzo, G.  D.,  et  al.   1972.  ^Hutnan and canine  exposures
 to methylene  chloride  vapor.   Am.  Ind. Hyg. Assoc.  Jour.
 33:125.

 Elovaara,  E., K. Hemminki,  and H.  Vaimio.  1979.  Effects of
 methylene  chloride,  trichloroethane, trichloroethylene and
 tolerance  on  the development  of chick  embryos.   Toxicology
 2:111-119.

 Filippova, L. M.,  et  al. 1967.  Chemical mutagens.  IV.
 Mutagenic  activity  of  geminal  system.  Genetika  8:134.

 Friedlander,  B. R., T. Hearne  and  S. Hall.  1978.  Epedemi-
 ologic investigation  of employees  chronically exposed to
 methylene  chloride.   J. Occup. Med.  20:657-666.

 Jongen, W.  M. F.,  et  al.  1978.  Mutagenic effect of di-
 chloromethane on Salmonella typhimurium.   Mutat. Res.  56:245.

 Morris, J.  C.,  and  G.  McKay.   1975.  Formation of halogenated
 organics by chlorination of water  supplies.  EPA 600/1-75-002.
 PB 241-511.  Natl.  Tech. Inf.  Serv., Springfield, Va.

 National Academy of Sciences.  1978.   Nonfluorinated halometh-
 anes in the environment.  Washington,  B.C.

 National Institute  of  Occupational Safety  and Health.  1976a.
 Criteria for a  recommended standard:   Occupational exposure
 to methylene chloride.  HEW Pub. NO. 76-138.   U.S. Dep. Health
Educ. Welfare,  Cincinnati, Ohio.

 Occupational Safety and Health Administration.   1976.  General
 industry standards.  OSHA 2206, revised January  1976.  U.S.
Dep.  Labor.  Washington, D.C.
                              74-11

-------
 Price,  P.  J.,  et  al.   1978.   Transforming  activities  of  tri-
 chloroethylene and  proposed  industrial  alternatives.   In Vitro
 14:290*.

 Schwetz, B.  A., et  al.   1975.   The  effect  of maternally  in-
 haled trichloroethylene,  perchloroethylene, methyl  chloro-
 form, and  methylene chloride  on embryonal  and  fetal develop-
 ment in mice and  rats.   Toxicol. Appl.  Pharmacol.   32:84-96.

 Shimkin, M.  B., and G. D.  Stoner.   1975.   Lung  tumors  in mice:
 application  to carcinogenesis bioassay.  A'dv.  Cancer  Res.  21:1

 Simmon, V. F.  et  al.   1977.   Mutagenic  activity  of  chemicals
 identified in  drinking water.   In;  S. Scott, et  al.,  eds.
 Progress in  Genetic Toxicology.

 Sivak, A.  1978.  BALB/C-3T3  neoplastic transformation
 assay with methylene chloride (food grade  test  specification).
 Rep. Natl. Coffee Assoc.,  Inc.

 Stewart, R.  D., and C. L.  Hake.  1976.  Paint  remover  hazard.
 Jour. Am. Med.  Assoc.  235:398.

 Theiss, J. C.,  et al.  1977.  Test  for  carcinogenicity of
 organic contaminants of United  States drinking waters  by
 pulmonary  tumor response  in strain  A mice.  Cancer  Res.
 37:2717.

 U.S. EPA.  1975.  Preliminary assessment of suspected  carcino-
 gens in drinking water, and appendices.  A report to  Congress,
 Washington,  D.C.

 U.S. EPA.  1977.  Area 1.  Task 2.  Determination of  sources
 of selected  chemicals in waters and amounts from these sources.
 Draft final  rep.  Contract No.  68-01-3852. Washington, D.C.

 U.S. EPA.  1978.  The National  Organic Monitoring Survey.
 Rep. (unpubl.).  Tech. Support  Div., Off. Water  Supple.
Washington,  D.C.

U.S. EPA.  1979a.    Halomethanes:  Ambient Water  Quality,
 (Draft).

U.S. EPA.  1979b.    Evironmental Criteria and Assessment
Office.   Halomethanes:   Hazard  Profile.  (Draft).

Vozovaya, M.  A.  1974.   Gynecological illnesses  in workers
of major industrial rubber products plants occupations.  Gig.
Tr. Sostoyanie Spetsificheskikh Funkts.  Tab.  Neftekhim.  Khim.
Prom-sti.  (Russian).56  (Abstract)
                              74-12

-------
                                   LB-45-01
                                   No.  75
       2,4 - Dichlorophenol

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

          October 1, 1980

-------
                            DISCLAIMER

     This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical.  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 reflect all
available information impacts presented by the subject chemical.
This document has undergone scrutiny to ecsure its technical accuracy
                               75-2

-------
                         2, 4-DICHLOROPHENOL




                              Summary






      Insufficient data exist to indicate that 2,4-dichlorophenol




 is a carcinogenic agent.  2 ,4-Dichlorophenol appears to act as a




 nonspecific irritant in promoting tumors in skin painting studies.




 No information on mutagenicity, teratogenicity, or chronic toxicity




 is available.  In a subacute study, the only adverse effect noted




 in mice was microscopic nonspecific liver changes.  2,  4-




 Dichlorophenol app.ears to be a weak uncoupler of oxidative




 phosphorylation.




      Acute and chronic toxic effects of 2,4-dichlorophenol have




 been observed at  a concentrations as low as 2,200 and 365 ug/1




 respectively.  Mortality to early life stages of one species of




 fish occurs at 70 ug/1.  Flavor impairment  studies indicate'




 that the highest  concentrations of 2,4-dichlorophenol in water




 which would not cause tainting of the  edible portions of fish




 range from 0.4 to 14 ug/1 depending on the  species of fish




• consumed.
                                75-3

-------
                   2,4-DICHLOROHENOL (2,4 DCP)

I.  INTRODUCTION
    «
     This profile is in large part based on  the Ambient Water

Quality Criteria Document for 2,4-dichlorophenol (U.S. EPA,1980).

     2,4-Dichlorophenol is a colorless, crystalline solid having

the empirical formula CgH^^O and a molecular weight of 163.0

(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 ethanol and
                                           benzene

     2,4-DCP is a commercially produced, substituted phenol used

entirely as an intermediate in the manufacture of industrial and

agricultural products such as the herbicide 2,4-dichlorophenoxyacetic

acid (2,4-D), germicides, and miticides.

     Little data exists regarding the persistence of 2,4-

dichlorophenol in the environment.  It is a product resulting

from degradation of many commercial products by plants, micro-

organisms, and sunlight.  Its low vapor pressure cause it to be

only slowly removed from surface water via volatilization (U.S.

EPA, 1980).  Studies have indicated low absorption of 2,4-DCP

from natural surface waters by various clays (Aly and Faust,

1964).   2,4-DCP is photolabile in aqueous solutions (Aly and Faust,

1964;  Crosby and Tutass, 1966) and can be degraded to succinic
                               75-4

-------
 acid  by  microorganisms  in  soil  and water  (Alexander  and Aleera,




 1961;  Ingols,  et .al., 1966; Loos, et  al.,  1967).   In lake water,




 under  laboratory conditions,  the half  life  of  2,4-DCP  is 8-9




 days  in  aerated waters  and  17 days under  anaerobic conditions




 (U.S.  EPA  1980).




 II.  EXPOSURE




     A.  Water




     Sources of 2,4-DCP in  water are  agricultural  run-off (as a




 contaminant' and metabolic breakdown product of biocides) and




 manufacturing waste discharges  (U.S. EPA,  1980).   Recent




 experiments under conditions  simulating the natural environment




 have not demonstrated that  2,4-dichlorophenol  is a significant




 product  resulting from  chlorination of phenol-containing wastes




 (Glaze,  et  al. 1978; Jolley,  et al. 1978).  The worst-case exposure




 to 2,4 DCP  from drinking water, as calculated  from 2,4-DCP level




 in water downstreams from a 2,4-DCP manufacturing,  facility,




 has been estimated as 36 ug/kg body weight/day.




     B.  Food




     Contamination of food with 2,4-DCP could  be an indirect




 result from use of the herbicide 2,4-D (U.S. EPA,  1980).  The




worst use estimate for the degree of human exposure to 2,4-DCP from




consumption of contaminated meat is about 4 ug 2,4-DCP/kg body




weight.




     The U.S.  SPA (1980) has estimated the weighted average




bioconcentration factor for 2,4-dichlorophenol to be 41 for the




edible portions of fish and shellfish consumed by Americans.




This estimate is based on the octanol/water partition coefficient.






                               75-5

-------
      C.   Inhalation


      Pertinent  information  regarding  direct  evidence  indicating
       *

 that  humans  are  exposed  to  significant amounts of  2,4-dichlorohenol


 through  inhalation has not  been  found in  the  available  literature.



 III.   Absorption


      Pertinent  information  regarding  the  Absorption of  2,4-


 dichlorophenol  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).


 B.  Distribution


     Pertinent information  dealing directly with tissue distribution


 after  2,4-dichlorophenol exposure was not found in the  available


 literature.  Feeding of 2,4-D (300 - 2000 ug/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


administered 2,4-dichlorophenol was not  found in the available


literature.  In mice, urinary metabolites of ^C-labelled gamma
                               75-6

-------
 or beta benzene  hexachloride  (hexachlorocylohexane) included 2,4-

 dichorophenol  and  its  glucuronide and  sulfate conjugates (as 4-6

 percent of  total metabolites) (Kurihara,'1975) .

 D.  Excretion

     Pertinent information dealing with  excretion of administered

 2,4-dichlorophenol was not found in the  available literature.

 After oral  administration 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

         Existing  data are not sufficient to indicate whether

 2,4-dichlorophenol is  a carcinogen.  The only study performed

 (Boutwell and  Bosch, 1959) indicate that 2 ,4-dichlorophenol may

 promote skin cancer in mice after initiation with dimethylbenz-

 anthracene.  An analysis of the data of Boutwell and Bosch using

 the Fisher Exact Test  indicated that the incidence of papillomas.

 in 2,4-DCP-treated groups was significantly elevated over controls,

while the incidence of carcinomas was not (U.S.  EPA, 1980) .

     B.  Mutagenicity, Teratogenicity and Other Reproductive
         Effects

         No studies addressing the mutagenicity, teratogenicity

or other reproductive effects of 2,4-DCP in mammaliam systems

were found in the available literature.  However, genotoxic

effects of 2,4-DCP have been reported in plants.  Exposure of


                               75-7

-------
flower buds or root cells of vetch (Vicla fabia) to solutions of




2,4-DCP, 01M and 62.5 mg/1, respectively, caused meiotic and




mitotic changes including alterations of chromosome stickiness,




lagging chromosome anaphase bridges and fragmentation (Amer and




Ali, 1968, 1969, 1974).  The relationship of such changes in




plant cells .to potential changes in mammalian cells has not been




established (U.S. EPA, 1980).




     C,  Chronic Toxicity




         One report (Bleiberg, et al. 1964) suggested that 2,4-




dichlorophenol was involved in the induction of chloracne and




porphyria cutanea tarda in workers manufacturing 2 ,4-dichlorophenol




and 2 , 4 , 5-trichlorophenol.  Since various chlorinated dioxins




(powerful chloracnegens) have been implicated as contaminants of




2,4,5-trichlorophenol, the specific 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 nonspecific- 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-DCP is a weak uncoupler of oxidative phosphorylation




(Farquharson,  et al.  1958;  Mitsuda, et al.  1963).   Values on odor
                               75-8

-------
 threshold, for  2,4-DCP  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  (U.S.  EPA,  1980)




          Two 96-hour assays have been  performed  examining the




 acute  effects  of  2,4-dichlorophenol in freshwater  fish.  An LC^O




 value  of  2,020 ug/1  for the bluegill,  Lepomis macrochirus, and an




 LC5Q  value of  3,230 ug/1  for  the juvenile  fathead  minnow,




 Pimpephales promelas, have been  reported.  Two  studies on the




 freshwater cladoceran, Daphnia magna,  have produced 48-hour static




 LC5Q  values of 2,610 and  2,600 ug/1.




          Only one marine  fish or invertebrate species has been




 tested for the acute effects  of 2,4-DCP: the mountain bass, a




 species endemic to Hawaii is  poisoned  at 20 mg 2,4-DCP/l.




     B.   Chronic Toxicity




          Data for the chronic effects  of 2,4-DCP for either




 freshwater or marine organisms were not located  in the available




 literature .




     C.   Plant Effects




          Concentrations of 2,4-DCP causing a 56  percent reduction




 in photosynthetic oxygen production or a complete  destruction of




 chlorophyll were 50 or 100 mg/1, respectively, in  algal assays




with Chlorella pyrenoidosa.   An earlier study reported that 58.3




mg 2,4-D/l caused a 50 percent reduction in Chlorophyll in the




duckweed, Lemna minor.   No marine plant species have been examined.
                               75-9

-------
     D.  Residues




         A bioconcentration factor of 130 has been estimated from
     *



the octanol-water partition coefficient of 2,4-dichlorophenol for




aquatic organisms having a lipid content of  eight percent.  The




estimated weighted average bioconcentraion factor for the edible




portion 'of aquatic organisms is 41.




     E.  Miscellaneous




         Flavor impairment studies indicated that the highest




concentration of 2,4-DCP in the exposure water which would not




cause tainting of the edible portion of fish ranged from 0.4 ug/1




for the largemouth bass (Microbterus salmoides), to 14 ug/1 for




the bluegill (Lepomis marcrochirus).  The value for the rainbow




trout (Salmo gairdneri) was 1 ug/1.




     A.  Human



         Based upon the prevention of adverse organoleptic




effected,  the criterior for 2,4-DCP in water recommended by the




U.S. EPA (1980) is 0.3 ug/1.  This level is  far below minimal no-



effect concentrations determined in laboratory animals (U.S. EPA,




19RO).  3.09 mg/1 is the criterion based on toxicity' data (U.S.




EPA, 1980).




     B.  Aquatic



         The criterion for protecting freshwater organisms is




2020 ug/1  (acute)  and 365 ug/1 as a chronic exposure value.   No



criterion  was derived for marine organisms (U.S.  EPA,  1980).
                              75-10

-------
                         2,4-DICHLOROPHENOL

                             REFERENCES
 Alexander,  M.  and  M.I.H.  Aleera.   1961.   Effect  of  Chemical
 structure  on microbial  decomposition  of  aromatic herbicides.
 Jour.  Agric.' Food  Chera.  9;44.

 Aly, O.M.  and  S.D.  Faust.   1963.   Studies  on  the fate  of 2,4-D
 and ester  derivatives in  natural  surface waters.   Jour. Agric.
 Food Chem.   12:541.

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

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

 Amer,  S.M.  and E.M.  Ali.   1^74.   Cytological  effects of pesticides.
 V. Effect  of some  herbicides on Specia f aba.  Cytologia 33:633.

 Bleiberg,  J.M., et  al..   1964.  Industrially acquired prophyria.
 Arch.  Dermatol.  89:793.

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

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

Deichmann, W.B. 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.  13:2D.

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.

Hoak, R.D. 1957.  The causes of tastes and odors in drinking
water.  Water and Sew. Works.  104:243.
                              75-11

-------
 Huff,  J.E.  and  J.S.  Wassom.   1974.   Health  hazards  from  chemical
 impurities:   chlorinated  debenzodioxins  and  chlorinated  dibenzofurans
 Int. Jour.  Environ.  Studies  6:13.
     »
 Ingols,  R.S., et  al.   1966.   Biological  activity  of  halophenols.
 Jour.  Water  Pollut.  Control.  Fed.  38:629.

 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-Othmer  encyclopedia of
 chemical  technology.   2nd ed.  Interscience Publishers,  New York.

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

 Kurihara, N. 1975.   Urinary metabolites  fromjfand £-BHC in the
 mouse:   chlorophenolic  conjugates.   Environ.  Qual.  Saf.  4:56.

 Loos,  M.H.,  et  al.   1967b.  Phenoxyacetate herbicide detoxication
 by bacterial enzymes.   Jour.  Agrlc.  Food Chem.  15:858.

 Mitsuda, W., et al.   1963.  Effect of  chlorophenol  analogues on
 the oxidative phosphorylation  in rat liver mitochondria.  Agric.
 Biol.  Chem.  27:366.

 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 halo and
 nitrophenols.  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 Nemacide  [o-(2,4-dichlorophenol)-o,o-diethylphosphoro-
 thioate] to  laying hens.  Jour.  Agric. Food Chem.   20:617.

 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.

U.S. EPA.  1980.  Ambient Water Quality Criteria for 2,4-dichloro-
 pehnol:  EPA 440/5-80-042.

Weast,  R.C., ed.  1975.  Handbook of chemistry and physics.  55th
ed.  CRC Press, Cleveland, Ohio.
                              75-12

-------
                                             No.  76
         2,6-Dichlorophenol

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

          OCTOBER 30, 1980

                76-1

-------
                          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 so.urces , 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.
                             76-2

-------
                      2,6-DICHLOROPHENOL




                           SUMMARY








     There is 'no available information on the possible




carcinogenic, teratogenic, or adverse reproductive effects




of 2,6-dichlorophenol.




     The compound did not show mutagenic activity in the Ames




assay.   A single report has indicated that 2,6-dichlorophenol



produced chromosome aberrations in rat bone marrow cells;




details of this study were not available for evaluation.




     Prolonged administration fo 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 metachlorophenol,




2,4,5-trichlorophenol,  and 2,3,4,6-tetrachlorophenol.
                             76-3

-------
I.     INTRODUCTION

       2, 6-Dichlorophenol  (2,6-DCP), CAS registry number 87-65-0,

exists' as white needles and has a strong penetrating odor

resembling o-chlorophenol .  It has the following physical and

chemical constants (Weast, 1972; Hawley, 1971):
         Formula:
         •Molecular Weight:             163
         Melting Point:                68AC - 69°C
         Boiling Point:                219°C - 220°C (74n torr)
         Vapor Pressure:               1 torr @ 59.5°C
         pH:             .              6.79
         Production:                   unknown
2,6-DCP is produced as a by-product from the direct chlorination

of phenol.  It is used primarily as a starting material for

the manufacture of trichlorophenols , tetrachlorophenols , and

pentachlorophenols (Doldens, 1964).

II.   EXPOSURE

      A.  Water

          Phenols occur naturally in the environment and

chlorophenols are associated with bad taste and odor in tap

water (Hoak, 1957).  2,6-DCP has a taste and odor threshold
 •
of 0.002 mg/1 and 0.003 mg/1, respectively (McKee and Wolf,

1963).  Piet and DeGrunt (1975) found unspecified dichlorophenols

in Dutch surface waters at 0.01 to 1.5 ug/1, and Burttschell,

et al. (1959) demonstrated that chlorination of phenol-

containing water produced, among other products, 2,6-DCP in a

25-percent yield after 18 hours of reaction.
                             76-4

-------
       B.  -Food




          Pertinent  data  could  not  be  located  in  the  available




literature.




       C.  Inhalation




          Olie, et al.  (1977) reported  finding dichlorophenols




in flue gas•condensates from municipal  incinerators.  The




levels were not quantified.




       D.  Dermal




          Pertinent  data  could  not  be  located  in  the  available




literature; however, it is known  that  dichlorophenols are




less toxic by skin contact than mono-chlorophenols and less




likely to be absorbed through the skin  (Doldens,  1964).




III.   PHARMACOKINETICS




     .  A.  Absorption




          Pertinent  data  could  not  be  located  in  the  available




literature.   By comparison with other  chlorophenols,  it is




expected that 2,6-DCP is  absorbed through the  skin and from




the gastrointestinal tract, and rapidly eliminated (U.S. EPA,




1980).




       B.  Distribution




          Pertinent  data  could not  be  located in  the  available




literature.   The high lipid solubility of the compound would




suggest that the unexcreted and unmetabolized compound distributes




to adipose tissues.




      C.  Metabolism and Excretion




          Pertinent data  could not  be located in  the  available




literature.   By comparison with other chlorophenols,  it is






                             76-5

-------
 expected  that  2,6-DCP  is  rapidly  eliminated  from  the  body,


 primarily as urirvary sulfate and  glucuronide  conjugates  (U.S.
       •

 EPA,  1980).


 IV.    EFFECTS-


       A.  Carcinogencity


          • Pertinent data  could not be  located  in  the  available


 literature.


       B.  Mutagenicity


          2,6-DCP did not show mutagenic activity in  the Ames


 assay  (Rasanen, et al. 1977).  Chromosome aberrations in rat


 bone marrow cells 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 Tcxicity


          Administration  of 2,6-DCP 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-DCP  inhibits


 liver mitochondrial respiration (level not specified) (Chung,


 1978).  At relatively high concentrations 2,6-DCP affects the


nervous system  (U.S. EPA, 1980).
                             76-6

-------
V.    AQUATIC TOXICITY


      A.  Acute
      *
          McLeese., et al. (1979) reported a 52-hour lethal


threshold limit of 19,100 ug/1 for marine shrimp (Crangon


septemspinosa) exposed to 2,6-DCP.

      B.  Chronic Toxicity, Plant Effects and Residues


          Pertinent data could not be located in the available


literature.

VI.   EXISTING GUIDELINES AND STANDARDS


      A.  Human

          Based on the organoleptic properties of 2,6-DCP, a

water quality criterion of 0.2 ug/1 has been recommended by


the U.S. EPA (1980).


      B.  Aquatic

          No existing criteria to protect fresh and saltwater


organisms were found in the available literature.
                             76-7

-------
                           REFERENCES
 Burttschell,  R.H.,  et  al.  1959.   Chlorine  derivatives  of
 phenol  causin'g  taste and  odor.   Jour.  Amer.  Water  Works Assoc.
 51:205.

 Chung,  Y.  1978.   Studies  on  cytochemical toxicities  of
 chlorophenols to  rat.  Yakhak Hoe  Chi  22:175.

 Doldens, J.D. 1964.  Chlorophenols.  In; Kirk-Othmer Encyclopedia
 of  Chemical Technology.   John Wiley and Sons,  Inc.,  New York.
 p.  325.

 Hawley, G.G.  (ed.)  1971.   The Condensed Chemical Dictionary,
 8th ed.  Van Nostrand  Reinhold Co., New York.

 Hoak, R.D. 1957.  The  causes of  tastes and odors in  drinking
 water.  Purdue  Eng. Exten. Service.  41:229.

 McKee,  J.E. and H.W. Wolf.   1963.  Water quality criteria.
 The Resources Agency of California, State Water Quality
 Control Board.

 McLeese, D.W.,  V. Zitko and M.R. Peterson.   1979.  Structure-
 lethality  relationships for phenols, anilines, and other
 aromatic compounds  in  shrimp and clams.  Chemosphere 8:53.

 Olie, K.,  et al.  1977.   Chlorodibenzo-p-dioxins and
 chlorodibenzofurans are trace components of  fly ash  and flue
 gas of  some municipal  incinerators in  the Netherlands.
 Chemosphere  8:445.

 Pfet, G.J. and  F. DeGrunt.  1975.  Organic chloro  compounds
 in surface and drinking water of the Netherlands in -problems
 raised by  the contamination of nan and his environment.
 Comm. Eur. Communities, Luxembourg, p.81.

 Rasanen, L., M.L. Hattula and A. Arstila.  1977.   The
 mutagenicity of MCPA and its soil metabolites, chlorinated
 phenols, catechols and some widely used slimicides in Finland.
 Bull.  Environ. Contam. Toxiciol.  18:565.

 U.S. EPA,  1980.  Ambient Water Quality Criteria for Chlorinated
 Phenols, EPA 440/5080-032.

Weast, R.C. 1972.  Handbook of Chemistry and Physics, 53rd
 ed.  Chemical Rubber Co., Cleveland, Ohio.
                             76-8

-------
                                      No. 77
2,4-Dlchlorophenoxy3cetic Acid (2,4-D}


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

           APRIL 30, 1980
             77-/

-------
                          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.
                           77-2.

-------
                        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  2,4-0 has been  reported to  produce reticu-


lum cell sarccmas 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,   Drosoohila,  Saccharomyces ,  or  the  dominant


lethal assay with mice.


     2,4-0 and  several of  its  esters  failed  to shew  teratcgsnic  effects in


mice; the propylene glycol butyl ether  ester  of the  compound  produced an in-


crease in  cleft  palates  in  this st'jdy.   Studies  in  hamsters  orally adminis-


tered 2,4-0 and derivatives showed teratogenic  effects.   Oral administration


of 2,4-0 to rats failed to  indicate teratogenicity  in one study;  another 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 (PGSE) ester  at  con-
                                                       s

centrations of  900  to  2,000 ug/1.   Daphnids  and  freshwater seed  shrimp  were


sensitive to the PGBE  ester at concentrations of 100 to 300 ug/1.   Chronic


exposure of several species of  fish to  concentrations  up  to 310 jug/1  has not


demonstrated any toxic effect.
                                 77-3

-------
                        2,4-QICHLOROPHENOXYACETIC ACID
I.   INTRODUCTION
     2,4-Oichlorophenoxyacetic acid,  CAS Registry  number 94-75-7,  commonly
known as 2,4-0, is a whits  or slightly yellow crystalline compound  which  is
odorless when  pure.   2,4-0  has the  following physical and chemical proper-
ties (Herbicide Handbook, 1979}:
                Density:
                Vsc-or Pressure:
                Solubility:
                Formula:                  C^
                Molecular Weight:         221.0
                Msltina Point:            135°C-133°C (technical);
                                          140°C-141°C (purs)
                                          160  C S 0.4 torr
                                          1.56530
                                          0.4  torr 1 lc'GcC
                                          Acetone  alcohol, oioxane ether,
                                          isopropyl alcohol;  slightly
                                          soluble in benzene,  solubility  in
                                          water 0.09c/100g, H20
                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
                                    /v »  i
                                  ' J W
                                 77-

-------
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).
     B.   Food
          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-dichlorophenol.  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 pcnd was  treated
with a  2.4_o  ester.   The highest tissue concentration  reached  was 0.24 ppm
sight days sftsr application.  Subssc'jently, ths  herbicide  cr its ^etacclite
•"as eliminated  raoidlv.  Clams  and  ovsters  acc'.jrr"jiste  more  2,4-Q  than dc
fish and crabs.  Residue peaks occur from  1 to 9 days  after  application and
then rapidly decline (Gangst, 1979).
     C.    Inhalation
          Pertinent  data  were not  found in  the  available literature;  how-
ever,  some  2,4-0  esters which are  much more volatile  than the  parent  com-
pound have  been monitored  in  air  up  to 0.13 pg/nv5 (Farwell,  et  al.  1976;
Stanley,  et  al. 1971).
     0.    Dermal
          Pertinent data were not found in the available literature.
                                  77-J-

-------
III. PHARMACQKINETICS
     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  indicated 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).
     3.   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 show  levels  lower  than those determined
in  the  bleed  (NRCC, 1973).  withdrawal of dietary  compound  produced  almost
complete tissue loss of residues in seven cays (Clark,  at al.  1975).
          Small  amounts  of phenoxy  herbicides  are  passed   to  the  young
through the mother's milk  (Blerke.  e^  al.  ^972).   Transolacsntal transfer  of
2.4-0 has been renorted in mice (Lindquist and Ullberg,  1971).
     C.   Metabolism
          Sauerhoff, et al.  (1976)  determined  that following  oral adminis-
tration of 2,4-0 to human volunteers,  the  major amount  excreted in the urine
was free  compound: a  smaller  amount  was excreted  as  a 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).
     D.   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

-------
of  an  oral dose of  labelled 2,4-0 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).
IV.  EFFECTS
     A .   Carcinogenicity
          Innes, et  al.  (1969)  reported no significant increase  in  tumors
following  feeding  of mice  with  2,4-0  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  tolerated doses of  2,4-0 and  its
butyl,  isoprcoyl, and isooctyl  esters  in a long-terrr,  carcir.ogenicity  study.
Carcinogenic effects were seen  after subcutaneous acministraticr,  of the  iso-
octyl ester (reticulum cell  sarcomas)  (NiCI,  1963).
     3.    Mutansnicity
          No  mutagenic   effects   of   2,4-0   in   tests  with   Salmonella,
Saccharomvces,  or  Orosophila  were observed  (Fahrig,  1974).    Siebert   and
Lemperle  (1974)  have  reported  m.'jtaaenic  effects  following   tr3=t~ert  of
Saccharomvces  csrevisiae 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) .
                                                       t
     C.    Teratogenicity
          Testing of  2,4-0  and  its n-butyl, isopropyl,  and  isooctyl  esters
in pregnant mice produced no significant teratogenic  effects.   There was a
                                77-7

-------
significant  increase  in  cleft palate deformities after administration of  the
propylene 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  (Caujells,  et  al.  1967),  although  the DMSC  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-D  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 butoxy ethanol and dimethylamine salts,  produced teratogenic  ef-
fects  (Khera and  McKinlay,  1972).  However, Sclr.vetz,  et  al. (1971)  were  un-
able to  show teratogenic effects in rats following  the  oral administration
of 2,4_o or its isoocytoi or  propylene giycol butyl ether esters.
     0.   Other Ssorccuctivs  Effects
          Embryctoxic effects following  subcutaneous administration of 2,4-0
to pregnant  mice 'nave  been   reported  (Caujolle,  et al.  1967;  Sage, et  al.
1973).
          Fetotoxic effects of the compound  and its  esters have been report-
ed after  oral  aciTiiniSursLiGn  or  rnaxii7iaij.y  L0i=rauec doses  vjcruvcuz,  ec  5^.
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  (1965)  reported  no
adverse reproductive effects  in rats fed 1,000 mg/1 2,4-0 in drinking water.

-------
     E.   Chronic Toxicity
          Animal  studies with prolonged oral  administration of 2,4-0 or  its
amine  salt  have  indicated renal  and hepatic  effects  (Bjorklund  ana  Erne,
1971; Sjorn and Northen,  1948);  the chemical purity of  the  material  adminis-
tered is not  known.   A feeding study  in  rats  has reported  histcpatholcgical
liver changes at  dietary  levels  of 2,4-0 equivalent  to 50 mg/kg (Oow  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  blusgill   sunfish   (Lescmis
macrcchirus),  2,4-0  acid and  2,4-0 dimethyl amine produced toxic affects at
concentrations greater than 100,000 ug/1.  At  2,4-0  concentrations of 50,000
ug/1 or  less,  no  increased mortalities were reported  except in pink salmon.
The  isoprcpyi,  butyl,  ethyl,  butoxy etnanoi,  and  FG5E  esters  produced
48-hour  LC5Q  values of  900,  1,300,  1,400.  2,100,  and  from 1,000  to  2,100
ug/1, respectively.
          For other  fish species,  the  results  follow  a similar trend in that
the esters  tend  to  be more  toxic than other  formulations.  Meehan,  st  al.
(1974)  ccnductac  tssts of various  formulations  of  2,4-0  en echo salmon  fry
and fingerlings (Oncorhycus Kitutch),  chum salmon fry  (0_.  keta),  pink salmon
fry  (0_.  gorbuscha),   sockeye  salmon  smolts  (0_.   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  were
reported to have  shown  a  48-hour LC5Q vaiue  Of 1,100  /ug/i on  exposure  to

-------
the  PG8E ester  of 2,4-0.   Harlequin  fish  (Rasbora  heteromorpha)  showed  a
48-hour  LC5Q 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-hour  LC50  values   of  26,700;  40,000;  70,100;  70,700;
94,600;  96,500;  and  300,600 ug/1 for  banded  killifish (Fundulus diaphanus),
white  perch (Roccus  americanus),  stripped bass  (Morone sazatilis), guppies
(Libistes   reticulatus),   bumpkinseed   sunfish   (Lepomis   gibbosus),   carp
(Cyprinus  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  formulations  of  2,4-0 for  six species  of  freshwater  crustaceans.
The PG8E ester was  generally  most  toxic,  while  the  dimethylamine  salt was
least toxic.  The  crayfish  (Orconectes  nails)  was the most resistant species
tested,  with  46-hour static 1C    values  areater than 100.COO uo/1  for all
                                ^u          -                     ••  -
formulations  tested.   The  water flea  (Dap'nnia  ~.acna)   and   seed  shrimp
(Cypridopsis  vidua)  were  most sensitive  to  the FGBE  ester,  with  43-hour
LC=g   values   of   100  and   320  jug/1,   respectively.    Scuds   (Gammarus
fasciatus),   scwbugs   (Ascellus brevicaucus),  and  freshwater  grass  shrimp
(Palaemonetes  kadiakensis)  were also  moderately sensitive,  with  48-hour
LC5Q  values  ranging  from  2,200 to  2,700 ,ug/l.   Sanders  and Cope (1968)
reported  a   96-hour  LC5Q  value   of  1,600   ug/1   for   stonefly   naiads
(Pteronarcv californica) exposed to  the butoxyethanol ester of 2,4-0.  Tech-
nical grade 2,4-0  produced a  96-hour  LC5Q vaiue  of  14,000 ug/1.   Robertson
                                                       .•
and  Bunting  (1976)   reported  96-hcur  LC5Q  values  ranging  from  5,320  to
11,570 /jg/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.

-------
          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 PGEE ester of  2,4-0.   The 2,4-0 acia
had  no  detectable effect  at exposures  of 2,000 jug/1  for 96-hours.  Butler
(1963)  observed  paralysis  of brown shrimp (Penaeus aztecus) exposed to 2,4-0
acid  at a  concentration of 2,000 (ug/l for 48-hours.   Sudak and Claff (1960)
found   a  96-hour  LC5Q  vaiue  of  5,000,000  jug/1  for  fiddler  crabs  (yea
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 lev; as 1,000  ug/I  produced  -3. 40
percent mortality for  fingerling  bluegills 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.
     E.   Chronic Tcxicity
          Rehwoldt!,  et al.  (1970)  exposed several  species  of fish  to  100
jug/1  2,4-0  for  ten  months  and  observed  no   overt  effects  to  any  tasted
species.  The  percent  reduction of brain  acetylcolinestarase  ranged from 16
percent in white  perch  to  35 oercent in  American eels.  In breeding exoeri-
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  ccnc-i-
tions.   Cope,  et al.  (1970)  examined the  chronic effects of  FGEE  ester  of
2,4-0 to bluegill sunfish.  Fish  were exposed to  the herbicide in one-eighth
                                                       .-
acre pcr.ds containing  initial concentrations  of up to  10,CCO  pg/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
                                  -*»•

-------
days.   Mount and Stsphan  (1967)  exposed  1-inch  fathead minnows  (Pimeohales
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 ug/1 1,4-0 (acid  equivalent  in  Wesdone
LV-4 formulation).
                                                     ».
     C.   Plant Effects
          The  genera  Microcystis,  Scanedesmus,   Chlorella,   and   Nitzschia
shewed  no tcxic response  when  exposed to 2,OCO jug/1  2,4-0 Lawrence  (1952).
Poorman  (1973)  treated cultures  of Euglena  gracilis  with concentrations  of
50,OCO  .ug/1  2,4-0  for  24   hours  and   observed   cecressed   growth   rates.
Valentine and Einc°?.m  (1974)  cemonstrateo that  at 100,000  ug/1,  2,4-D  re-
duced  the  ceil  nurnoers of  Scenecesmus  to  one  percent of  control  levels,
Chlai7iydo~.or.3s  to  43 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  muscor.ji~1  displayed s.  68-percent  reduc-
•^-.cpi — n  grew ^i .  n)icr< cxposec ^c  -LWW  ug/j. *_,-T— ^  ^w^.-w-^  o.iv- wav'ci«.j — •>— ,  — ^«^/.
Singh (1974)  exposed Cylindrosoermum to  2,4-0  sodium salt at  concentrations
ranging  from  100,000  to  1,200,000  jjg/1 and  reported  that  concentrations
above 800,000 ug/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 jug/1  have
been effective in controlling a number of species.
                                   • ? 7 ?~
                                  ^^^^^^^^7

-------
     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 ug/1 applications  of  the  chemical.   A
 gradual depeletion of the  herbicide  to insignificant levels was•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  ug/1  level
 realized in the water two weeks after application.
          The National Research  Council of Canada (NRCC)  (1978) has reviewed
 the bioconcsntraticn  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  found for fish  and oyster.   At water  concentrations of  100  to 2CQ
 ug/1, the bicconcentration  of  2,4-0  various  aquatic invertebrates v/as one to
 two orders  of magnitude greater  than  lin  the  water.   Oysters   (Crassostica
 viroinica)  were  reported to have  a  bioconcentration  factor  of  150 when ex-
oosed to  the butoxyethanol  ester of  2,4-0.   The freshwater oluegill and mos-
quito fish (Garnbusia  affinls)  had  bioccncsntration  factors ranging from 7 to
55,  respective  to water concentrations.'  fish  fee;  a diet  containing  2,4-G
bicconcentrated the 2,4-0 acid by less than 0.2.
VI.   EXISTING GUIDELINES
     A.   Human
          The acceptable daily intake  of  2,4-0  for  humans has  been  estab-
 lished at 0.3 mg/kg (FAO, 1969).
     B.   Aquatic
          Pertinent data were not found in the available literature.

-------
                         2,4-OICHLOROPHENOXYACETIC ACID

                                   References
 Bage,  at al.   1973.  Teratogenic and embryotoxic effects of herbicides  diand
 trichlorophenoxyacetic  acids (2,4-0 and  2,4,5-T).   Acta Pharmacol.  Toxicol.
 32:  408.

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

 Bjorklund,  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.

 Bjorn,  M.  and H. Northen.   1948.   Effects  of 2,4-dichlorophenoxyacetic acid
 on chicks.  Science  108: 479.

 Butler,  P.A.  1963   Commercial  Flshary  Investigations.   U.S.   Oept.  Interior
U.S. Fish anc Wildlife Service Circ.  167: 11.

Butler,  P.A.    1965.   Effects   of herbicides   on  estusrir.e  fauna.   Prcc.
Southern Weed Conference  18: 576.

Caujoile, F.,  et al.   1967.   Limits cf  toxic and tsratcgsnic  tolerance  of
ci~3thyl sulfc:
-------
 Dow  Chemical Company.  1962.  Results  of  90-day dietary feeding of  the  pro-
 pylene  glycol isobutyl ether  ester of  silvex  (Dowco 171)  to rats.   Unpub-
 lished  Report.  Oow Chemical Co., Midland, MI.

 Epstein,  S.,  et al.  1972.  Detection  of chemical  mutagens  by the  dominant
 lethal  assay  in the mouse.  Toxicol. Appl. Fharmacol.  23: 283.

 Food  and  Agriculture  Organization  of the United Nations (FAO).  1969.  Work-
 ing  party of experts on  pesticide residues.   Evaluations  at some pesticide
 residues  in  food, the monographs.   FAQ/WHO PL 1968/m/9/l.

 Fahrig, R.   1974.  Comparative mutagenicity  studies with pesticides.  Chem-
 ical  Carcinogenesis Assays.  IARC Scientific Publication  10:  161.  Lyoh.

 Farwell,  S.O.  et al.   1976.   Survey   of  airborne  2,4-0  in  south  central
 Washington.   Jour. Air Pollut.  Control Assoc.   26: 224.

 Gangst, E.O.   1979.   Herbicide Residue  of 2,4-0,  Office of Chief of Engine-
 ers,  Washington, O.C.  NTIS AD-67160.

 Hansen, w. et al.   1971.   Chronic  toxicity of 2,4-dichlorophenoxyacetic acid
 in rats and dogs.  Toxicoi. Api. Fharmacoi.  20: 122.

 Herbicide  Handbook.   1979.   4th   ed.   Weed   Science   Society  of  America,
 Champaign, IL.  p. 129.

 Innes,  J. ,  et ai.   1969.   Bicassay of pesticides  and  industrial  chemicals
 for tumorigencity in  mice:   A  preliminary note.   Jour.  Nstl.  Cancer Instit.
 42: 1101.

 p'nera,  K.  ana w.  McKiniey.  1572.   Pre and postnatal  srjci^s en 2,4,5-tri-
 chlorophenoxyacetic acid,  2,4-dichiorophenoxyacetic  acid  and  their  deriva-
 tives in rats.  lexical.  Appl. Fharmacol.   22:  14.

 Konli,  J., et al.  1974.   Absorption  and  excretion  of  2,4-dichlorophenoxy-
 acetic acid in man.   Xenobiotica,  4: 97.

 Lawrence,  J.M.   1962.   Aquatic Herbicide  Data.   U.S. Dept.  of Agriculture,
                                  p.
Lindquist, N. and S. Ullberg.   1971.   Distribution  of the herbicides 2,4,5-T
and  2,4-0  in  pregnant  mice.   Accumulation  in the yolk  sac  epithelium.
Experientia, 27:  1439.

McKee,  J.E.  and H.w.  Wolf.   1963.   Water Quality  Criteria.   Calif.  State
water Quality Board Publication 3-A.

Meehan, W.R.,  et al.   1974.   Toxicity of  various  formulations of  2,4-0  to
saimcnids in southeast Alaska.  Jour. Fish Red. 3d.  Canada  31: 480.

Mount,  O.I.  and  C.E. Stephen.  1967.   A  method  for  establishing  acceptable
toxicant limits for  fish -  malathion and  the butoxy  ethanol ester of 2,4-0.
Trans. Am. Fish Soc.  96:  185.

-------
National  Research Council Canada  (NRCC).   1978.   Phenoxy Herbicides -  Their
Effects   on   Environmental  Quality.    Associate   Committee  on  Scientific
Criteria  for Environmental  Quality  NRCC No.  16075,  ISSN 0316-0114.  Avail-
able:  Publications NRCC/CNRC Ottawa K1A OR6.

National  Cancer  Institute.  1968.  Evaluation of carcinogenic, teratogenic,
and  mutaaenic. activities  of selected  pesticides and  industrial chemicals.
National Cancer Institute, PB-223 159.

Poorman,  A.E.   1973.   Effects  of  pesticides on  Euglena gracilis  I growth
studies.  Bull. Environ. Contain. Toxicol.  10: 25.

Rehwoldt, R.E.,  et al.   1977.   Investigations  into  the acute  toxicity and
some chronic  effedts  of selected  herbicides and pesticides  on  several fish
species.  Bull. Environ. Contam. Toxicol.  18: 361.

Robertson, E.B. and D.L.  Bunting.   1976.  The acute,  toxicity of four herbi-
cides  to 0-4 hour  Nauplli  of  Cyclops  vernalis fishes.   Bull.  Environ.
Contam. Toxicol.   16: 682.

Sanders, H.O.  1970.  Toxicities of  some herbicides  to six species of fresh-
v/ater crustaceans.  Int. Jcur. Water Pcllut. Ccntrcl Fed.  42: 1544.

Sanders, H.O. and O.B.  Cope.  1963.   The relative toxicities of several pes-
ticides  to  naiads  of  three  species  of stoneflies.   Limnol and  Oceanogr.
13: 112.

Sauerhcff, M..,  et  ai.    1976.   The  fate  of  2,i-dichicrcpr,er,oxyacetic  acia
(2,4-C)  fallawina oral  administration  to  rr,an.   Toxicoi.  Apcl.  Fhsr~iacci.
37: 136.

Scnwetz,  3.,  et  al.    1571.   The effect  of  2,4-tiichlorcphenoxyacetic  acid
(2,4-0) and  esters  of 2,4-0  on rat srcbrycnal,  foetal,  sr.d  necnatal growth
and development.   Food Cosmet. Toxicol.  9: 301.

Schultz, D.P. and E.O. Gangstad.   1976.  Dissipation  of  residues of  2,4-0 in
water,  hydrosoil,  and fish.  Jour.  Aquat. Plant Managa.  14: 43

Sisoer^". 0.   and P.  Lsn^c^rle,  1974.   Genetic  effects  of herbicides:  inc'jc—
ticn of  mitotic  gene  conversion  in  Saccharcrnyres  cerevisiae.  Mut.  Res.
22: 111.

Sigmon, C.F.   1979.   Influence  of  2,4-0 and  2,4,5-T  on  life history charac-
teristics  of  Chironomus  (Diptera  Chironomidae).   Bull  Environ.   Contam.
Toxicol.  21: 596.

Singh,   P.K.   1974.   Algicidal  effect of  2,4-dichlorophenoxyacetic   acid  on
blue-green algae.   Cylindrosperum sp. Arch. Microbiol. ' 97:  69.

Stanley,  C.W., et al.   1971.   Measurement  of atmospheric  levels of pesti-
cides.   Environ.  Sci.  Technol.  5:  430.

-------
Sudak, F.N.  and C.L. Claff.   1960.   Survival of Uca  pugnax  in sand, watsr,
and  vegetation  contaminated  with  2,4-dichlorophenoxyacetic  acid.   Proc.
Northeast Weed Cont. Conf.  14: 5Q8.

Valentine,  J.P.  and  S.'.v. Bingham.   1974.   Influence of  several  algae  on
2,4-0 residues in water.  Weed Sci.  22: 358.

-------
                                      No.  78
        l,2-Dichloropco,pane


  Health and Environmental Effects
U.S. ENVKOT.ENTAL 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.
                             - ?~J cr~

-------
                              1,2-DICHLOROPROPANE
                                    Summary

     The major  environmental  source of dichloropropane  is  from the use of a
mixture  of dichlorcpropanes  and dichloropropenes  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  LC--,  values  for  the  bluegill  are
230,000  and  320,000 jjg/1  and  the  43-hour  LC50  value  for Osphnia magna is
52,500  jug/1.   A  saltwater  fish  has  a   reported  96-hour   LC5Q   value  of
240,000 Jjg/i.

-------
                               1.2-OICHLOROPRQPANE
' 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-rDC,  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, dichloropropane refers  to  the  1,2-dichlorcpropane  iscmer.   When
 heated to decomposition  temperatures,  l,2-dichioropropane  emits highly toxic
 fumes of phosgene (Sax,  1975).
 II.  EXPOSURE
      A.   ',','3 tar
          Oichlorooropane  can enter the  aquatic  environment   as  discharges
 from  industrial  and manufacturing processes,   as  run-off  frcm agricultural
 land, and  from municipal  effluents.   This  compound  was identified  but  not
 quantified in New Orleans drinking water (Oowty, et al. 1975).
      8.   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  dichloropropane to be  20.   This
 estimate  is  based on the octanol/water partition coefficients of  dichloro-
                                                                       9
 propane.  The weighted average  BCF  for edible portions  of  all aquatic organ-
 isms consumed by Americans is calculated to be 5.3.

-------
     C.  Inhalation
         Atmospheric  levels  of  aichloropropane  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 (Thc~as
and McXeury, 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  dichloropropane.  in the  rat,  approximately
50 percent  of  an  orally administered dose of  dichloropropane was eliminated
in the urina in 24 hours (Hutson, et ai.  1971).
     A.  Carcinogenicity
         Only  one  study  is  reported  on  the  carcinogenicicy of  dichloro-
propane.   Heppel,  et  al.   (1948)  repeatedly  exposed  mice  (37  exposure
periods) to  1.76  mg dichloropropane per liter  of air.   Of  the 80 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)   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

-------
(Bignami, et  al.  (1977),  and to cause  chromosomal aberrations  in  rat bone
marrow (Dragusanu and Goldstein, 1975).
     C.  Teratogenicity
         Pertinent information  ccuid 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 tcxicity  studies  of dichloroprooane  exposure in
humans.  In  one study by  Heppel,  et al. (1948) rats,  guinea  pigs,  and dogs
were exposed  to 400  ppm of dichloropropane  for 128 to 140  daily seven hour
•period (given  five aays  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,   Lepcmis
macrochirus,  upon  exposure to  1,2-dichloropropane  were 280,000-and 320,000
ug/1 (Oawscn,  et al.  1977; U.S.  EPA, 1978).   In the only freshwater inverte-
brate  study  reported,  the 48-hour  LCjQ for Daphnia  macna is  52,500 ug/1
(U.S.  EPA,   1979).   Tidewater  silverside,   (Menidia bewllina),   has  an
observed 96- hour LC^ of 240,000/jg/l (Oawson, et al.  1977).
     8.  Chronic Toxicity
         Chronic  data  are not  available  for any  saltwater or freshwater
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  dichloropropane  is  75 pom (350 mg/m  )  (Am. Conf.  Gcv.
Ind. Hyg.,  1977).  The draft  water  criteria  for  dichloropropane is  203  ug/i
(U.S. EPA,  1979).
         ;-cr  i.2-dichlorcprcpane,  the  proposed  draft  criteria  to  protect
                                                                        i
frsshv/ater aquatic life are 92C ug/1 a 24-hour average-and the concentration
should not  exceed 2,ICO ug/1  at  any  time.   Criteria are not  available  for
saltwater species (U.S.  EPA,  1979).
                               ni'i
                               7 ' i *S4f
                              71-7

-------
                     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: 3.   ~*"~~~~~~~~~

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

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

Dragusanu, S., and I. Goldstein.  1975.  Structural and nu-
merical changes of chromosomes in experimental intoxication
with dichloropropane.  Rev. Ig. Bacteriol. virusol.  Parazi-
tol. Epidemiol. Pr.euir.cf itziol. Ig 24: 37.

Heppel, L.A., =t al.  1943-.  Toxicology of 1,2-d ichloroprc-
pane (propylene dichloride) IV. Effect of repeated exposures
to a lev; concentration of the vapor.  Jcur. Ind. Hyg.  Tex i-
col. 30: 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. Toxicol. 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.
                              7F-?

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

U.S. EPA.   1979b.   Dichloropropenes/Dichloropropanes:  Hazard
Profile.
                          7*-?
                          '

-------
                                    No. 79
                «•
  Dichloropropane/Dichloropropenes



  Health and Rnvlrotnaental Effects
u.s.  ENvmoNMEmL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980
            77-t

-------
                          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.

-------
                DICELGROPROPANES/DICHLOROPROPENES
                             SUMMARY
      The major environmental source of dichloropropanes  and
dichloropropenes is from the use of these compounds  as  soil fumi-
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
of the dichloropropanes decreases as the distance  between the
chlorine atoms increases.  As an example, the reported  96-hour
LCen values for the bluegill, Lepomis macrochirus, for  1,1-,
1,2-, and 1,3-dichloropropane are 97,900, 280,000, and  greater
than 520,000 ug/1, respectively.  For Daphnia itiagna,  the  corres-
ponding reported 48-i-iour LC-fl values are 23,000, 52,000,  and
282,000 ug/1, respectively.  Similar results have  been  obtained
with marine organisms.
      The dichloropropenes ara 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 pg/1 compared
to 520,000 ug/1 for 1,3-dichloropropane.  For Daphnia magna,
the corresponding values are 6,150 and 282,000 pg/1,  respectively.
The ECSQ, based on chlorophyll a for a freshwater  alga, is 4,950
ug/1 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).

      Dichloropropanes (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 degreasing processes (Windholz,

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

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

pane gives off toxic fumes of chlorides  (Sax, 1975).  Production

of mixtures of dichloropropanes/dichioropropenes approached 50

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

II.   EXPOSURE

      A.   Water

           Dichlorcpropanes 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. EPA
                               7T-Y

-------
(1979) has estimated the weighted average bioconcentration  fac-
tors  (BCFs) of dichloropropanes and dichioropropenes 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 octanol/
water partition coefficients of these compounds.
      C.   Inhalation
           Atmospheric levels of dichloropropanes and dichioro-
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).
Ill.  PHARMACOKINETICS
      A.   Absorption, Distribution and Metabolism
           ?3rtinent information regarding tha absorption,  dis-
tribution, and metabolism of the dichloroprcpanes and dichioropro-
penes could not be located in the available information.
      B.   Excretion
           No human data are available on the excretion of  dichlor-
cpropanes or dichloroprcpenes.  In the rat, 30 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 dichioropropenes could not be located
                           79-f

-------
in the available literature.  However, cis-l,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

capable of being produced by the individual compounds.

      C.   Teratogenicity and Other Reproductive Effects

           Pertinent information could not be located  in the

available literature.

      D.   Chronic Toxicity

           Inhalation exposure of rats, guinea pigs, and decs

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 to 130 days pro-

duced cloudy swelling in renal tubular epithelium which disap-

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

1977) .

V.    AQUATIC TOXICITY

      A.   Acute Toxicity
                                                           »
           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 LC-Q for 1,3-dichloropropene is
5,060 ug/1 for the bluegill, approximately two orders of magni-
tude lower than for 1,3-dichloropropane (U.S. EPA, 1979).  Under
static test conditions, reported 48-hour LC5Q values for 1,1-,
1,2-, and 1,3-dichloropropanes are 23,000, 52,500 and 282,000
ug/1, respectively, (U.S. SPA, 1978)  for the only freshwater
invertebrate species tested, Daphnia magna.  The 48-hour LC-Q
value for 1,3-dichloropropene and Daphnia magna under static
conditions is 6,150 ug/1 (U.S. SPA, 1978).
           The 96-hour -Ceg values for the saltwater sheepshead
minnow, Cyprinodon variegatus, exposed to 1,3-dichloropropane
and 1,3-cichioroprcpane ware 36,700 jjg/'l and 1,770 ug/1, respec-
tively (U.S. SPA, 1973).  Dawson, et al. -(1977)  obtained a 96-
hour LCSO of 240,000 ug/1 for the tidewater silvsrsida, Manidia
beryllina, for exposure to 1,2-dichloropropane.
           For Mysidopsis sahia, the 96-hour LC^Q for 1,3-dichlcro-
propene was one-thirteenth thac for 1,3-dichloropropane, i.e.,
790 ug/1 and 10,300 ug/1, 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, Pimephales promelas,  exposed to 1,3-
dichloropropene was 122 ug/1 (U.S. EPA, 1978).   The  chronic value
                                                           »
for mysid shrimp, Mysidopsis bahia, was 3,040 ug/1 for 1,3-di-
chloropropane in a life cycle study (U.S.  EPA,  1978)
                             77-7

-------
      C.   Plant Effects


           For 1,3-dichloropropene, the 96-hour EC5Q values,


based on chlorophyll a concentrations and cell numbers of  the


freshwater alga, Selenastrum capricornutum, were  4,950 ug/1 and


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


1,3-dichloropropane were 48,000 and 72,200 ug/1.  Thus,  the pro-


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


is true for the bluegill and Daphnia magna.


      0.   Residues


           Measured steady-state bioconcentration factors  (BCF)


are not available for any dichloropropane or dichloropropene


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


ficients of dichloropropanes and dichloropropenes, the U.S. EPA;


(1979) 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 1,2-dichloro-


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-l,3-dichlorobenzene  is


chemically hydrolyzed in moist soils to the corresponding  cis-

-------
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 ppra (350 rag/m )

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

(U.S. EPA, 1979) for dichloropropane is 203 ug/I.  The draft

water criterion for dichloropropenes is 0.53 pg/1  (U.S.  EPA,

1979) .

      3.   Aquatic

           The dr'aft criteria for the dichioroprcpanes and gi-

chloropropsr.as to prctact frashwatar aquatic life  are as  follows

(U.S. EPA, 1979):


                                               Concentration not
                                                 to be exceeded
Compound                  24-Hour Average          at any  time

1,1-dichloropropane           410 pg/1                930 ug/1

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

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

1,3-dichloropropene            L8 pg/1                250 ug/1


The draft criteria to protect saltwater species  are  as follows
                                                           #
(U.S. EPA, 1979):

-------
                                               Concentration  not
                                                to be exceeded
Compound                  24-Hour Average         at any time

1,1-dichloropropane         not derived          not derived

1,2-dichloropropane          400 jig/1              910 ug/1

1,3-dichloropropane           79 pg/1              180 pg/1

1,3-dichloropropene          5.5 ng/1               14 pg/1

-------
                       DICHLOROPROPANES/DICHLOROPROPENE5

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

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

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

Oowty, 8.,  et al.   1975.   Halogenated  hydrocarbons  in  New  Orleans drinking
water and blood plasma.  Science  37: 75.

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

Hutson, D.H.,  et al.  1971.  Excretion and  ratantion  of comocnents  of the
soil  fumigant  0-OAR) and their metabolites  in the  rat.   Food Cosrnet. Toxi-
col.  9: 677.

Leistra,  M.   1970.  Distribution of 1,3-dichloropropene  over the pnase in
soil.  Jour. Agric. Food Chem.  13: 1124.

Roberts,  R.T.   and  G.   Stoydin.    1975.   The   degradation  of  (2)- arc
(E)-l,3-di-  chioropropenes  and  l,2-dichioroproper.5s  in soil.  Psstic.  Sci.
7: 325.

Sax,  N.I.   1975.  Dangerous properties of  industrial  materials.   Reinhoid
Book Corp.,  New York.

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.
Assoc.  38:  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  Oijk,  J.    1974.   Degradation  of 1,3-dichloropropenes   in   the  soil.
Agro-Ecosystems.  1: 193.

Van Ouuren,  8.L., et al.   1979.   Carcinogenicity of halogenated olefinic and
alipahtic hydrocarbons.  (In press).                                    •

Windholz,  M.,  ed.  1976.   The  Merck Index.   9th  ed.  Merck  and  Co.,  Inc.,
Rahway, N.J.
                                 77-//

-------
                                      No. 80
          Dichloropropanol


  Health and Envirorraental 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.

-------
                               DICHLOROPROPANOL


                                    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.

-------
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 iscmers  with the  mole-
cular  formula  C-3H6OC12.   The  physical  properties  of   each   isomer  are
given below.
                        Boiling Point Density     Solubility (Weast.  1976)
                                                 Water      Alcohol    Ether
2,3-Oichloro-l-propanol    182QC      1.368    slight      miscible   miscible
l,3-Oichloro-2-propanol    1740c      1.367    very        very      miscible
3 , 3-Oichloro-l-pfooanol   32-33°C     1.316    not listed
1 , l-Oichioro-2-prcpanol  146-1 AO^C     1.3334   slight      very      very
     Additional physical data  and synonyms of  the  above isomers are  avail-
able in Heilbron  (1965), Fairchild (1979)-,  Sax (1979), Windholz  (1976),  ana
Verscnueren (1977).
     Oichioropropanol is prepared from glycerol,  acetic acicj, and  hydrogen
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 (Windholz, 1976).   The compound  is
considered to ba a moderate  firs  hazard when  exposed  to  neat,  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  Selyakov,  1975).  Unreacted  dichloropro-
panol was  also  found in  the  wastewater effluent of a  halohydrin  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.
     8.   Mutagenicity
          2,3-OichloropropanoI  and  1,3-dichloroprcpanol were evaluated  for
mutagenicity by  a modified  Ames assay using  S_._ typhimurium  strains.   Some
evidence of  rnutagenic  activity was  seen,  but  the authors fait  that  further
evidence and clarification  of the metabolic activation pathway to  mutagens
             I
via halcalkanols were r.ecessary (Nskamura,  et al. 1579).
     C.   Teratogenicity, Other Reproductive Effects and Chronic Toxicity
          Pertinent data could not be located in the available literature.
     0.   Acute Toxicity
          2,3-Dichlcropropanol was  found to  have  an  oral LD^  j_n the  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-Dichloropropanol 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 LD50  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  rsnal 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 fou.nd in the available literature.
  VI.  EXISTING GUIDELINES AND STANDARDS
       A.   Human
            The  maximum  allowable  concentration  of  dichloropropanol in  the
  working  environment  air  in  the U.S.S.R.  is 5  mg/m3 (lipina and  Belyakov,
  1975).
            The maximum allowable ccncar.tration in Class  I  waters  for  the  pro-
  duction of drinking water is 1 mg/1 (verschueren, 1577).
       B.   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 haiohydrin
manufacture.  Chem. Abs.  CA/083/15875D.

Fairchild,   E.  (ed.)   1979.    Registry  of  Toxic  Effects  of  Chemical  Sub-
stances.  U.S.  Department 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.

Nakamura. A.,  et al.  1979.   The mutagenicity  of halogenated  alkanols and
their  phosphoric  acid  esters  for  Salmonella   tyohimurium.   Mutat.   Res.
66: 373.

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

Verschueren, !<.   1977.  Handtcc-k of Environmental Data on Organic Chemicals.
Van Ncstrand Reinhold Co., New York, p. 659.
                                  i
V/east,  R.C.  (ed-.)   1976.  Handbook  of  Chemistry  and Physics.   CRC Press,
Cleveland,  Ohio,  p. c-^54.

Windholz, M. (ed.)  1976.  The  Merck Index.  9th ed.  Merck and Co., Rahway,
New Jersey.
                                       Sro-7

-------
                                      No. 81
        1,3-Dichloropropene


  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.

-------
                              1.3-OICHLOROPROPENE
                                    SUMMARY

     The major environmental  source  of dichlorcpropenes is from the use of  a
mixture  of dichloropropenes  and dichloropropanes  as  a soil  funigant.   On
chronic exposure of  rats  to  dichloropropene mild kidney damage was observed.
Dichloropropene 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.
                                                      o
     The bluegill  (Leoomis  macrochirus)  has  a reported 96-hr  LC5Q value of
oCoG uc/1;  Saohnia magna has a reported  43-hr  LC5Q of 5130 ug/i.   ^or the
saltwater  invertebrate,   Mysidoosis  bahia,  a reported  96-hr LC--  value is
790 /jg/1.   In the  only   long-term  study  available,  the  value  obtained for
1,3-dichloropropene  toxicity  to fathead  minnows  (Pimeohales oromeles) in an
embryo-larval  test  is 122 jug/1.   Based en chlorophyll  a  concentrations and
cell  numbers,  the  96-hr EC-- values  for  the  frsshwazar  alga  Selsnastrun
caorieornutum  are  4,950  and  4,960 ug/1,  respectively:  for  the' marine alga
Skeletonema costatum, the respective values are- 1,000 and  1,040 ;jg/l.

-------
                              1,3-DICHLOROPROPENE

I.   INTRODUCTION

     This  profile  is based  on the  Ambient  Water Quality  Criteria Document

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

     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- 1,3-dichloropropene and

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

dichloropropene will refer to either cis- or trans-1,3-dichloropropene.  For

more  information  regarding the dic'nloroprcoanss,  tha reader is  rsfsrrsd to

the EPA/ECAC  Hazard  Profile  on  Dichlorcpropanes/Dichloropropenes  (U.S. EFA,

1979b).

II.  EXPOSURE

     A.  Water

         Dichloropropene  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).

     B.  Food

         Information was   found  in  the  available  literature  concerning the

concentration of dichloropropene in  commercial  foodstuffs.   Thus,  the amount
                                                                       »
of this  compound  ingested by humans  is  not  known.   The U.S.  EPA (1979a) has

estimated  the weighted  average  bioconcentration factor (BCF)  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  dichlcrcprcpene 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. PHARMACOKINETICS
                                                    ^.
     A.  Absorption
         Data  on  the absorption,  distribution and metabolism of dichloropro-
pene could not be located in the available  literature.
         Data  on  the  excretion of  dichloropropene by  humans could  not be
located in  the available literature.  In the  rat,  however, approximately 80
percent of  an  orally  aoninistered dose of  dicnioropropene  was eliminated in
the urine within 24 hcurs (Hutson, et al. 1971).
IV.  EFrECTS
     A.  Carcinogenicity
         Van Ouuren, et al. (1979)  investigated  the ability of dichloropro-
pene  to  act as a tumor  initiator  or promoter  in mouse  skin,  or to cause
tumors  after  subcutaneous  injection.   Dichloropropene  showed  no  initiation
or  promotion activity, and  only  local  sarcomas developed  in mice  following
subcutaneous administration.   In  none of the  studies were treatment-related
remote tumors  observed.
                                                       ^
     8.  Mutagenicity
         DeLorenzo, et al.  (1977) and Neudecker,  et al. (1977) reported tjhat
dichloropropene was mutagenic in  S.  typhimurium strains TA1535 and  TA100 but
not  in  TA1978, TA1537, or TA98.  Results did  not differ with or without the

-------
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


         No  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  (Torkelson  and Oyen,  1977),  or


rats, guinea pigs, and  rabbits  to  1  or 3 ppm of dichloropropene, 7 hours per


day for 125-130 days over a  180-day period,  only rats exposed 4 hours/day  at


3.0 ppm  showed  an effect (U.S. EPA,  1979a).   The only effect observed was a


cloudy  swelling  of  the  renal  tubular  epithelium  which  disappeared  by  3


months after exposures ended.


V.   AQUATIC TOXICITY


     A.  Acute Toxicity


         Tests  on the  bluegill,  Legcmis .Tiacrochirus, yielded  a  96-hr LC5Q


value of 6060 )jg/l for  1,3-dichloroprcpene  exposure.  For Daphnia maona, the


48-hr  LC5Q  value  is  6,150 jug/1  (U.S.  EPA,  1978).   The  observed  96-hr


LC5Q  for the  saltwater my rid  shrimp,  Mysidopsis  bania,  is  790  jjg/1 (U.S.


EPA, 1973).


     B.  Chronic Toxicity


         An  embryo-larval test  has  been conducted  with  the  fathead minnow


(Pimephales  promeles)  and 1,3-dichloropropene.   The.  observed  chronic value


was 122 jjg/1 (U.S. EPA, 1979a).


     C.  Plant Effects
                                                                         »

         Based  on chlorophyll  a  concentrations and cell  numbers,  the 96-hr


EC5Q  values  for  the freshwater alga,  Selenestrum  caoricornutum,  are 4,950

-------
and  4,960  pg/1, respectively  (U.S.  EPA,  1978).   The  respective  values for
the saltwater alga Skeletonema ccstatum  were  1,000 and 1,040 jug/1 (U.S. EPA,
1978).
     0.  Residues
         Measured steady-state bioconcentration  factors (8CF) 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).
     E.  Other Relevant Information
         Following  field  application,   movementsof 1,3-dichloropropene  in
soil results  in vapor-phase diffusion (Leistra, 1970).   The distribution of
1,3-dichloropropene within  soils depends  on  soil  conditions.   For example,
cis-l,3-dichlcroprcpane is  chemically hydroiyzed in moist soils  to  the cor-
responding cis-3-chloroalkyl  alcohol,  which  can be  microbially degraded to
carbon dioxide and water by Pseudomonas so.  (Van Dijk  1974).
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human health nor the  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  will  be
changed.
     A.  Human
         The  draft water   criterion  for  1,3-dichloropropene  is 0.63  /jg/1
(U.S. EPA,  1979a).
     B.  Aquatic
         The  draft criterion  to protect freshwater'species is  18 /jg/1  as a
24-hr average not  to  exceed 250 jug/1 at any  time.   For  marine  species, the
                                                                      »
value is 5.5-jug/l as  a 24-hr  average not to exceed 14 ;jg/l at any time  (U.S.
EPA, 1979).

-------
                              1,3-DICHLOROPROPENE

                                  REFERENCES
OeLorenzo, p.,  et al.  1977.  Mutagenicity of  pesticides containing 1,3-di-
chloropropene.  Cancer Res. 37: 6

Dowty, 8.,  et al.  1975.   Halogenated  hydrocarbons in  New  Orleans drinking
water and blood plasma.  Science 87: 75.

Hutson,  O.H.,  et al.   1971.   Excretion  and  retention of components  of the
soil, fumigant  QrQ^>  and  their   metabolites   in   the   rat.   Food  Cosmet.
Toxicol.  9: 677.

Lsistra,  M.  .197,0.   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-dichloropropene.  Experientia 33: 8.

Sax,  M.I.   1975.   Dangerous  Properties  of  Industrial  Materials.   Reinhold
Book Corp., New York.

Torkelson, R.R. and F. Oyen.   1977.   The toxicity of 1,3—dichloroprcpene as
determined by  repeated  exposure  of laboratory animals.   Hour.  Am.  Ind. Hyg.
Asscc.. 38: 217.     .

U.S.  EPA.   1978.   In-depth  studies on  health,  and  environmental  impacts of
selected water pollutants.  Contract No. 63-01-4646.

U.S.  EPA.   1979a.  Oichloropropanes/Oichloropropenes: Ambient  Water Quality
Criteria (Draft)

U.S.  EPA.   1979b.   Dichloropropanes/Dichloropropenes:  EPA/ECAO  Hazard Pro-
file.

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

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

-------
                                       No. 82
              Dieldrin


  Health and EirrLroTaaental  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 (CAG) has evaluated



dieldrin and has found sufficient evidence to indicate that



this compound is carcinogenic.

-------
                           DIELDRIN
                           SUMMARY
      Dieldrin is a compound belonging  to  the  group  of  cyclodiene
insecticides.  The chronic toxicity of  low doses  of  dieldrin
includes shortened life span, liver changes  ana  teratogenic effects.
The induction of hepatocellular carcinoma  in mice by dieldrin
leaas to the conclusion that it Is lively  to" be  a human carcinogen.
Dieldrin has been found to be non-mutagenic  in several  test sys-
tems.  The WHO'S acceptable daily  intake for dieldrin is 0.0001
mg/kg/day.
      The toxicity of disidrin to  aquatic organisms  has been
investigated in numerous studies.  The  96-hour i->Ccn  values for
the common freshwater fish range from 1.1  to 360  ug/1.   The acute
toxicity is considerably more varied for ft.esnwacer  invertebrates,
with 96-hcur I^Q values ranging frcrr, 0.5 ug/1 for  the  stonefiy
to- 7^0 ,ug/l for the crayfish.  Acute i-Ccn values  for eight salt-
water fish species range from 0.66 to 24.0 ug/1  in  flow-through
tests; LC,-Q values for estuarine invertebrates range from 0.70
to *:40 ug/1.  The only reported chronic values are  0.11 jug/I
for steel head trout  (Salmo guirdnes) in an  emoryolarval study
ana 0.4 ug/1 for the guppy (Poecilia reticulata)  in  a life-cycle
test.  Both fresh and salt water algae  are less  sensitive to
dieldrin toxicity than the corresponding fish  ana inverteorates.
Bioconcentration factors were 128  for a freshwater  alga,  1395
for Daphnia magna, 2993 for the channel catfish,  ana 8000 for
        — -       	                                            #
the edible tissues of the Eastern  oyster.

-------
                             DI2LDRIN

I.     INTRODUCTION

      This  profile  is  based on  the draft Ambient  Water Quality

Criteria  Document  for  Aldrin  and  Dieldrin   (U.S.  EPA,  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-1,4,4a,5,6,7,8,8a-octohydro-endo, exo-1,4:5,3-dimethanonaph-

thalene.                                    v

      Dieldrin  is extremely  stable and persistant in the  environ-

ment.   Its  pe'rsistance is  due  to  its extremely low  volatility

(1.78  x   10"7  mm  Hg  at 20°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.  (1972)  reported that  dieldrin 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,  ana 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  dieldrin

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).

-------
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  (Karris,  et  al.  1977).   The

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

mated to be 723 days  (i-iacKay and Wolkoff, 1373).

      B.   Food

           Dieldrin  is  one  of  the  most  stable  and persistant

organcchiorine  pesticides  (Nash and  Woolson,  1957} ,  and  because

it  is  lipophilic,  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  particulates.    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 2.8  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  used  in  the United
States,  there  is  still  the possibility of airborne  contamination
from ocher parts of the world.
      D.   Cerraai
           Dermal .exposure to dieldrin is  limited  to  those  in-
volved  in  its manufacture  or  application as  a  pesticide.   Wolfe,
et al.  (1972)  rapcrtad 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
cis'< of e:-:pc:s_re.
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,  1954).  These authors also demonstrated
that absorption takes place via  the portal vein, and  that dieldrin

-------
could 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   times

the blood concentration.

           Additional animal  studies on  the distribution of  diel-

drin  have  shown that concentrations in   tissues  are  dose related

and  IT.ay  vary with the  sex cf the  animal  ("yalk-=r:;  et al.   136^).

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 predomir.atly as  diel-

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

trans-hydro-aidrin and a polar metabolite, were  detected.

           The  concentrations  of dieldrin  in  human  body  fat were

found to be  0.15  + 0.02 ^ag/g for the  general population and 0.36

ug/g  in  one   individual  exposed  to   aldrin  (aldrin is metabolized

to  dieldrin)  (Dale and  Quinby,  1963).   The  tnean 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,

1963).   Correlations  between, the   dose  and  length  of  exposure

to  dieldrin  and  the  concentration   of dieldrin  in  the  blood  and

-------
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  mice,  rats,  rabbits,  and  sheep.     Dieldrin
metabolites  have  been  identified  in  the  urine  and  faces in  the
form  of several  compounds  more  polar  than  the  parent   compound
(u.S. E?A,  1979).   Bedford  and  Hutscr. (1975) summarized  the  four
.
-------
as in  the  feces.   Robinson,  et  al.  (1969)  found  that 99 percent



of the  dieldrin  fed  to rats  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).   Tha half-life



for  dieidrin in  the  blood  of  humans ranges  from  141-592  days



with  a  mean of 369  days  (Hunter,  et al.  1969).    Jager   (1970)



reported the half-iifa tc  be 265   days.  Because there is a rela-



tionship between  the  concentration of  dieidrin in  che  blood   and



that  in adipose and  other  tissues, it seems  likely that che half-



life  in  the blood  may  reflect  the  over-all half-life  in  other



tissues (U.S. EPA, 1979).



IV    EFFECTS



      .-..    Care i nog en ic i 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



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  (1972) .   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  activation system  was added  (Fahrig,  1S73; Bidwell,  et  al.



1575; Marshall,  et  al. 1976) .   A host-mediated assay and a domi-



nant  lethal  test,  also  yielded  negative  results   (Bidwell,   et



ai.  1975).    L-iajumdar,  et  al.   (1977),  however,   fcund  dial-rin



to  be  mutagenic in  S.  typ.h iph imur i urn,  although  these  positive



results  wera  questioned  because  several differences existed  be-



tween their procedures  and those recommended  (U.S. EPA,  1979).



           A  decrease  in the  mitotic index  was  observed in  vivo



v;itli  .T.CUSS  bone  marrow  cells  and _in y i erg  wicn  human  iung cells



treated with 1 mg/kg and  1 ^ig/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  teracogenic  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  were found

in mice  administered dieldrin  for  day 5  through 14  of gestation

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

1374).

      E.   Chronic  Toxicity

           The other effects  produced  by  chronic administr -sticr.

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.   Gch=r Relevanc  Information

           Since  aldrin  and  dieldrin are  metabolized  by  way of

the  mixed function  oxidase  (MFC)  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 dose9-^i£_ior
                                                               »
to  an  acute dose  of dieldrin alters  its  metabolism  (Baldwin,

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

-------
1979) and  induce a. greater number of  tumors in mice when  admini-
stered with DDT as compared to DDT alone  (Walker, at  al.  1372).
V.    AQUATIC TOXICITY
      A.   Acute Toxicity
           The  acute  toxicity of  dieldrin  has  been investigated
in numerous studies.  Reported 96-hour LC5Q 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 macrochirus
(Henderson, et al.  1959; Macek, et al. 1969; Tarzwell and  Henderson,
1957) .   Freshwater invertebrates  appear  to be more  variable  in
their sensitivity  to  acute dieldrin  toxicity.   The 96-hour  LC
values  range  from  0.5  ug/1 for  the  stone  fly  (Sanders  and Cope,
i:>66) to 740 ug/1 for the crayfish (Sanders, 1372) .
           The acute LCr« values for  eight saltwater fish  species
                       -* u
range from  0..55  to  24.0  ug/1  in  flow-through tests  (Butler, 1963;
Earnest  and  Benville,  1972;  Korn  and  Earnest,   1974; Parrish,
et al.  1973;  Schoettcer, 1970;  and  Lowe,  undated).   LC5Q  values
ranging from  0.7 to 240.0  ug/1  have  oeen  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  (Salmo
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 pg/1  (Roelofs,  1971).

      C.   Plant Effects


           Freshwater  plants  are less  sensitive to dieldrin  than


freshwater fish  or invertebrates.   For  example,  a concentration


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


alga  Scenedlesmus  quadricaudata  (Stadnyk  and  Campbell,   1971) ,

and  12,800 ug/1  reduced  growth by 50 percent in  the diatom,  Navi-

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

saltwater plant  species  growth rate was reduced  at concentrations

of approximately 950 ug/1  (Batterton, et al.  1971).

      D.   Residues


           Bioconcentration  factors  (BCF)  have been determined


for  9  freshwater  species  (U.S.  EPA,  1976).   Representative  BCF


values  are 128  for the alga,  Sc_ence=_smus_ gbl^guus  (Reinert,  1972,

1395 for p_a£hn_i_a mag_na (Reinert,  1972) ,  2385-2993 for  the  channel

catfish,  Ictjilurus pu_nctatus_  (Shannon,  1977a;  i»77b)  and  63,268


for  the yearling  lake  trout,  Salvelinus  namaycush   (Reinert,  et


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

vjLrgj^nica, 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 1959, 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 rag/kg/day  (Mrak, 1969).
           The  carcinogenicity  data  of   Walker,  et   al.   (1972)
were  used  to calculate the draft  ambient water quality criterion
for dieldrin of 4.4  x 10~2  ng/1  (U.S.  EPA,  1979).   This level
keeps the lifetime cancer risk for  humans  below iO'3.
      B.    Aquatic
           The  draft  criterion  to  protect  freshwater   life   L=
0.0019 ug/1  as a  24-hcur average;  the concentration  should  noc
exceed 1.2  ug  at  any time.   To protect  saltwater  acu?.cic life..
she  draft  criterion  is   0.0069  ^ug/1  as   a  24-hour   average;  the
concentration should not exceed 0.16 ug/1  at any  time.

-------
                          DIELDRIN

                         REFERENCES

Baldwin, M..K. , et al.  1972.  A comparison  of  the  metabolism
of HEOD (dieldrin)  in the CFT mouse with  that  in  the  CFE  rat.
Food Cosmet. Toxicol.  10: 333.

Batterton, J.C., et al.  1971.  Growth  response of  bluegreen
algae to aldrin, dieldrin, endrin and  their metabolites.
Bull. Environ. Contam. Toxicol.  6: 589.

Bedford, C.T., and  D.H. Hutson.  1976.  The comparative me-
tabolism in rodents of the isomeric insecticides dieldrin and
endrin.  Chem. Ind.  10: 440.

Bidwell, K., et al.  1975.  Comprehensive evaluation  for  mu-
tagenic activity of dieldrin.  Mutat.  Res';   31: 314.

Butler, P.A.  1963.  Commercial fisheries investigations. I_n
Pesticide and wildlife studies: A review of Fish and  Wildlife
Service investigations during 1961 and  1962.   U.S.  Fish
V;ilcl. Serv. Ci~c.  167: ''I.

Cairns, J., et al.  1968.  Ths effects  of dieldrin  on dia-
toms.  Mosquito News  28: 177.

Chadwick, G.G., and D.L. Shumway.  1969.  Effects  of  dieldrin
on the growth and development of steelhead  trout.   Page 9.0 _in
The Biological impact of pesticides in  the  environment.   En-
viron. Health Sci.  Ser. No. 1  Oregon  State University.

Chernoff, N., et al.  1975.  Prenatal  effects  of dieldrin and
photodieldrin in mice and rats.  Toxicol. Appl. Pharmacol.
31: 302.

Cleveland, F.P.  1966.  A summary of work on aldrin and diel-
drin toxicity at the Kettering Laboratory.   Arch.  Environ.
Health  13: 195.

Cole, J.F., et al.  1970.  Endrin and  dieldrin: A  comparison
of hepatic excretion in the rats.  Toxicol.  Appl.  Pharmacol.
16: 547.

Cueto, C., Jr., and F.J. Biros.  1967.  Chlorinated insecti-
cides and related materials in human urine.  Toxicol.  Appl.
Pjharmacol.  10: 261.

Dale, W.E., and G.E. Quinby.  1963.  Chlorinated  insecticides
in the body fat of  peoole in the United States,  Science  142:
593.

-------
Davis, K.J.  1965.  Pathology report on  mice  for  aldrin,
dieldrin, heptachlor, or heptachlor epoxide for two  years.
Int. Food and Drug Admin.

Davis, K.J., and O.G. Fitzhugh.   1962.   Tumorigenic  potential
of aldrin and dieldrin for mice.  Toxicol. Appl.  Pharmacol.
4: 187.

Deichmann, W.B.  1972.  Toxicology of DDT and  related  chlor-
inated hydrocarbon pesticides.  Jour. Occup. Med.  14:  285.

Deichmann, W.B., et al.  1967.  Synergism among oral carcino-
ge-ns in the simultaneous feeding  of four tumorigens  to  rats.
Toxicol. Appl. Pharmacol.  11: 88.

Deichmann, W.B., et al.  1968.  Retention of dieldrin  in
blood, liver, and fat of rats fed dieldrin for six months.
Ind. Med. Surg.  37: 837.

Deichmann, W.B., et al.  1970.  Tumor igenicity of aldrin,
dieldrin and endrin in the albino rat.   Ind. Med. Surg.   39:
Dix, K.H., et al.  1977.  Toxicity studies with dieldrin:
Teratoiog ical studies in mice dosed orally with HEOD.   Tera-
tology .  16 : 57 .

Earnest, R.D., and P.E. Benviile, Jr.  1972.  Acute  toxicity
of four qrganochior ine  insecticides to two species or  surf
perch.  Calif. Fish Game.  58:

Edwards, C.A.  1966.  Insecticide residues  in soils.   Residue
Epstein, S.S.  1976.  Case study 5: Aldrin and dieldrin  sus-
pension based on experimental evidence and evaluation  and  so
cietal need.  Ann. N.Y. Acad. Sci.  271: 187.
,
            1972.  Comparative -utagenicity studies with pes-
ticides.  Chera. Carcinogenesis Essays  10: 161.

Fitzhugh, O.G., et al.  1964.  Chronic oral toxicity of al-
drin and dieldrin in rats and dogs.  Food Cosmet. Toxicol.
2: 551.

Harris, R.H., et al.  1977.  Carcinogenic hazards of organic
chemicals in drinking water.  Page 309 in H.H. Hiath,  et al .
eds.  Origins of human cancer.  Cold Sp"rTngs Harbor Lab. Mew
York .

Hathaway, D.E., et al.  1967.  Transport of dieldrin from
mother to blastocyst and from mother to foetus in pregnant
rabbits.  Eur. Jour. Pharmacol.  1: 167.

-------
Hayes, W.J.,  and A.  Curley.   1968.  Storage and excretion  of
dieldrin and  related  compounds:  Effect oif occupational  expo-
sure.  Arch.  Environ.  Health  16:  155.

Heath, D.F.,  and M.  Vandekar.   1964.  Toxicity and metabolism
of dieldrin  in  rats.   Br.  Jour.  Ind. Med.   21: 269.

Henderson, C.,  at  al.   1959.  Relative toxicity of ten chlor-
inated hydrocarbon insecticides  to four species of fish.
Trans. Am. Fish. Soc.   88:  23.

Hunter, C.G., et al.   1969.   Pharmacodynamics of dieldrin
(HEOD).  Arch.  Environ.  Health   18:  12.

Jager, K.W.   1970.   Aldrin,  dieldrin, endrin and telodrin:  An
epidemiological and  toxicological  study of long-term occupa-
tional exposure.   Elsevier Publishing Co., Amsterdam.

Katz, M.  1961.  Acute toxicity  of some organic insecticides
to three species of  salmonids  and  to the threespine sticle-
back.  Trans. Am.  Fish.  Soc.  90:  264.

Korn, 5., and R. Earnest.   1974.   Acute toxicity of twenty
insecticides  to striped  bass,  Morone saxatilis.  Calif.  Fish
Game.  60: 128.

Lowe, J.I.   Results  of toxicity  tes-ts with fishes and macro
i^*r3v*tebrcit':ic.  D^ts  sbeets  —T?.~ "' ^ s'c 13 frcrr. 'T. S. E^v^^cr.
O *~o i~  LI rj a rvo * 7  ^r> TT i y-/^n   Oac  ^".^•^    ("I'iT^ O >- p o -7 a  ^ 1 a

Macek, K.J.,  et al.   1969.   The  effects of temperature on  the
encr*o»^***^^ 1 i*-t»  r\£  V-.1 «•• o *"• ^ T 1 ^  ^r\ A  v- -3 i ^ l-> *•>». T *-•*-.-> i •»*- *-<•> r^o^i'^1-^^
— UOw^.j—'— — -^—-i.~s_)-  ^_ -^  *-/j_— ^-^— — — J  C* * . \_*  i. w — - . *- ^-^ •' w.v^v. w — O— -.^.^.w — ^*
pesticides.   Bull.  Environ.  Contam.  Toxicol.   4: 174.

HacKay, D.,  and A.W.  Wolkoff.   1973.  Rate of evaporation  of
low-solubility  contaminants  from water bodies to atmosphere.
Environ. Sci. Technol.  7:  611.

Majuir.dar, S.K., et al.  1976.   Dieldrir,- induced chromosome
damage in mouse bone-marrow  and  WI-38 human lung cells.
Jour. Hered.  67:  303.

Majumdar, S.K., et al.  1977.   Mutagenicity of dieldrin  in
the Salmonella-microsome test.   Jour. Herd.  68: 194.

Marshall, T.C., et al.  1976.   Screening of pesticides for
mutagenic potential  using  Salmonella typhimurium mutants.
Jour. Agric.  Food  Chem.   24: 560.

Matsumura, F.,  and G.M.  Bousch.   1967.  Dieldrin: Degradation
by soil microorganisms.   Science  156: 959.                •
                               _ A ft —

-------
Matthews, H.B., et al.   1971.   Dieldrin  metabolism,  excre-
tion, and storage in male  and  female  rats.   Jour.  Agric.
Food Chem.  19: 1244.

Mick, D.L., et al.  1971.  Aldrin  and  dieldrin  in  human  blood
components.  Arch. Environ. Health   23:  177.

Mrak, E.M.  1969.  Chairman 1969 report  on  the  secretary's
commission on pesticides and their  relationship to environ-
ment health.  U.S. Dept. Health Edu.  Welfare, Washington,
D.C.

Nash, R.G., and E.A. Woolson.   1967.   Persistence  of chlori-
nated hydrocarbon insecticides  in  soils.  Science   157:   924.

Ottolenghi, A.D., et al.   1974.  Teratogenic effects of  al-
drin, dieldrin and endrin  in hamsters  and mice.  Teratology
9: 11.

Parrish, P.R.  1974.  Arochlor  1254,  DDT and DDD,  and diel-
drin: accumulation and loss by  American  oysters, Crassostrea
virginica exposed continuously  for  56  weeks.  ?roc.  Naci.
Shellfish Assoc.  64.

Parrish, P.R., et al.  1973.   Dieldrin:  Effects  en several
estaurine organisms.  Pages 427-434  in Proc. 27th  Annu.  Conf.
S.E. Assoc. Game Fish Comn.

Patil, K.C., et al.  1972. -Metabolic  trar.sfsrnaticn of  DITT,
dieldrin, aldrin, ar.d endrin by -.r.arine microorganisms.   Envi-
ron. Sc'i. Technol.  5: 631.

Reinert, R.E.  1972.  Accumulation  of  dieldrin  in  an alga
Scenedesrnus obi iqus, Daphnia magna  and the  guppy,  Poecilia
reticulata.  Jour. Fish  Res. Board  Can.  29: 1413.

Reinert, R.E., et al.  1974.  Dieldrin and  DDT:  Accumulation
from water and food by lake trout,  Salvelinus namaycush,  in
the laboratory.  Proc. 17th Conf. Gr^=t  Lakes Res.  52.

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.

-------
Sanders, H.O., and O.B. Cope.   1968.   The  relative  toxicities
of several pesticides  to naiads of  three species  of  stone-
flies.  Limnol. 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.
Contam. 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 irs  a freshv;ater alga.   Bull.
Environ. Contam. Toxicol.   6: 1.

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

Thorpe, E., and A.I.T. Walker.  1973.  The  toxicology  of
dieicrin (HECD).  Part II.  Comparative long-term  oral  toxic-
icy studies in mice with dieidrin,  DDT, phenobarbitone,  beta-
3HC and garrjr.a-BHC.  Food Cosrr.at. 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, ai'Jrin 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.
                                -W-
                                y

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

-------
                                      No. 83
 o,o-Dlethyl Dithiophosphoric Acid


  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.
                              £3-3-

-------
                       0,0-DIETHYL 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,  E.  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 /jg/1 has  been  reported for rainbow  trout  exposed



to  a diethyl   dithiophosphoric  acid  analogue,   dioxathion.   A  synergistic



toxic effect with the latter chemical and  malathicn is suaaested.

-------
 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:  azinphcsmethyl,  carbcphenothion, dialifor,  dioxathion,  disulfoton,
 ethion, phorate, phosalone and terbufos.  It  is  made from phosphorus penta-
 sulfide (SRI,  1976).
 II.  EXPOSURE
     A.   Water                                     v
          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 phorate  or disulfoton (Daughton,  et al. 1575),  or as a contaminant
 of any of the above pesticides  for which it is a starting compound.
     8.   Food
          Pertinent  data were  net found in  t.u;2 available  literature;  how-
 ever,  if  present  in food,  the compound would  probably  originate  from  the
 same  sources discussed above.   Organcphosphorus  pesticide  residues have been
 found in feed  (Vettorazzi,  1975).
     C.   Inhalation
          Pertinent  data  were  not 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.

-------
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, 1553).
     C.   Metabolism
          Pertinent data were net  found in the available literature.  Metab-
olism  studies  with disulfoton (3ull,  1965)  and phorate  (Sc.vman  and Casida,
1958}  indicate  that  both compounds  are converted  to  diethyl phosphorodithic-
ate, diethyl phorphorcthicate, and diethyl phosphate.
     0.   Excretion
          Pertinent data were  net  round in the available  literature,   c^sed
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

-------
long-term  feeding.  No  carcinogenic effects  were  noted in  either  species
(NCI,  1978).
     Q.   Mutagenicity
          Diethyl  phosphorothioate,  a possible metabolite of the parent com-
pound,  did  not show mutagenic  activity in  Orosophila,  £.  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 feeding study conducted in mice with  pnorate (0.6 to 3.0 ppm) indicated
that the  hicrest  level  of  compound  did  produce sc^e  adverse rsprcd'jctive
effects (American  Cyanaaiid,  1966}.  Chronic  feeding of mics  with technical
dicxatnion  at  levels of 430 to  6CG ppm  produced  seme  testiscular atrophy
(NCI, 1978).
     E.   Chronic Toxicity
          Chronic  feeding  of  technical  dioxathicn  produced  hyperplastic
nodules "'^  ^iv°rs  of  ^s1?  mice,   o c-Oisthyl  dit~iocncsrhc!ric scid   like
other  organophosphates,  is  expected  to  produce cholinesterase  inhibition
(MAS, 1977).
V.   AQUATIC TOXICITY
     A.   Acute
          Marking  (1977)  reports  on  LC5Q  value of 47>2 jug/i f0r  rainbow
trout   (Salmo   gairdneri)   exposed   to   the   dithiodioxane   analogue •  of
bis(o,o-diethyl  dithiophosphoric  acid),  dioxathion,  and  an  LC5Q  value  of

-------
3.44 pg/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.

-------
                                  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   1958.   Further studies on the metabolism of Thimet
by plants, insects,  and mammals.  J. Econ. Entomol.  51: 338.

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

Daughton, C.G.,  A.M.  Cook, M.  Alexander  1979.   Phosphate and  soil binding
factors   limiting  bacterial   degradation  of   ionic   phosphorus-containing
pesticide metabolites.  App. Environ. Micrcbio.  37: 605.
                                                  «.
Fahrig,  R.    1974.    Comparative  mutagenicity  studies   with   pesticides.
Chemical Carcinogsnesis Assays,  IARC Scientific Publication #10,  p. 161.

Gaines, T.   1969.   Acute  toxicity of pesticides.  Toxicol. A.ppl. Pharmacol.
14: 515.

Marking,  L.I.   1977.   Method for asssessing  additive toxicity  of  chemical
mixtures.   In:    Aquatic  Toxicology and Hazard  Evaluation.   STP 634  ASTM
Special Technical Publication.  p. 99.

Matsumura, F.   1975.   Toxicolocy of Insecticides.  Mew  York:  Plenum Press,
o. 223.      '                  "                                     •   •

National  Academy  of  Sciences  1977.  Drinking  Water and  Health.   National
Sesearcn Council, wasnington,  p. 615.

National  Cancer  Institute   1973.    3icassay  of  Oioxathion  for  Possible
Carcinogenicity.  U.S.  OHEW,   NCI  Carcinogenesis  Technical  Report  Series
0125, 44 pp.

Richert, E.  and '<.  Prahlad  1972.  Effect of the organophcsohate o,o-diethvl
s-t(ecnylthio)metnyij pnospnoroaitnioate on tne cnick.   Pouit.  Sci.  51: 513.

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

vettorazzi,  G.    1975.   State  of  the  art  on  the  tcxicolcgical  evaluation
carried  out  by  the joint   FAO/WHO  meeting  on  pesticide  residues.   II.
Carbamate  and  organophosphorus  pesticides  used in  agriculture and  public
health.  Res. Rev.  63:  1.
                                     PT(9—
                                  -  /  /  v

-------
                                        No. 84
            3
o,o-Diethy1-4-methyl Phosphorodithioate
    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  documen-ts.
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.

-------
                    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,o-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  (phorate).   The possible metabolite
of  this  compound,   o,o-diethyl phosphorothioate,  did  not  show  mutagenic
activity  in Drosophila,  E.  coli,  or Saccharomyces.   o,o-Oiethyl-S-methyl
phosphorodithioate,  like other organophosphate  compounds,   is  expected  to
produce chclinesterase inhibition in humans.
     There is no available data on the aquatic toxicity of this compound.

-------
                    0,0-0IETHYL-S-METHYL  PHOSPHORODITHIOATE
 I.   INTRODUCTION
      o,o-Oiethyl-S-methyl .phosphorodithioate (CAS  registry number 3288-58-2)
 is described in  German  patents 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
                    Boiling Point:         ICCOQ  to 102°C  (4 torr)
                    (CA  55:8335h)
                    Density:               1.192420
                    (CA  55:S335n)
      Pertinent  data were not  found in  the available literature with  respect
 tc production, consumption  or the current  use of this ccmcound.
 II.   EXPOSURE
      Pertinent data were not  found in the  available  literature.
 III.  PHARMACGKINETICS
      A.   Absorption
          Information  relating  specifically to the  absorption  of c,o-di-
ethyl-S-methyl  phosphcrcdithioats  was  not  found  in  the available  liter-
ature.  Oral  administration of the S-ethylthio  derivative of  this ccmpcund,
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  22p  radiolabelled phorate in the  cow  indicated  that following
oral  administration,   residues  were   found  in   the  liver,   kidney,   lung,

-------
 alimentary   tract,   and   glandular   tissues;   fat   samples   showed   very   low
 residues  (Bowman  and Casida,  1958).
      C.   Metabolism
          Pertinent  data were not found  in the available literature.  Based
 on  metabolism  studies with various  crganophosphatss in mammals,  o,o-diethyl-
 S-methyl  phosphorodithioate may  be  expected to undergo hydrolysis to diethyl
 phosphorodithioic acid,  diethyl  phosphorothioic acid,  and diethyl phosphoric
 acid  (Matsumura,  1975).
      0.   Excretion
          Pertinent   data  were   not  found  in  the  available  literature.
 Related  metabolites   (o,o-diethyl  phosphorodithioic,  phosphorothioic,  and
 phosphoric  acids) have  been  identified  in  the urine  of   rats  fed phcrate
 (Bowman and Casida,  1958).
 IV.   EFFECTS
      A.   Carci.noqenicity
          Pertinent  data were not  found in  the available  literature.   The
dioxane-S-S-diester  with  o,o-diethyl  phosphorodithioate,   dioxathion,  has
been  tested  for carcinogenicity in  mice  and rats  by  long-term feeding.   No
carcinogenic effects wers noted in either species (NCI, 1978).
     3.   Mutagenicity
          Pertinent  data   were  not   found  in  the  available  literature.
Diethyl phosphorothioate, a  possible  metabolite of the parent  compound,  did
not show mutagenic activity  in Orosphila, E_.  coli,  or  Saccharomyces  (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  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, 1978).
     E.   Chronic Toxicity
          Pertinent  data   were   not  found  in  the  available   literature.
Chronic feeding of technical dioxathion  produced hyperplastic  nodules in  the
livers  of   ,7,aie  mice.    o,o-Oietnyi-S-methyI onospnoroaichioats,  like  other
organophosphates,  is expected  to  produce  choiinesterase  inhibition  (NAS,
1977).
V.   AOJATIC TOXICITY
     Pertinent data were not found in the available literature.
VI.  EXISTING GUIDELINES AND STANCAF.CS
     Existing  guidelines  and  standards  were  not  found  in  the available
literature.

-------
                    0,0-OIETHYL-S-METHYL PHOSPHORODITHIOATE

                                  References
American Cyanamid.  1966.   Toxicity  data  on 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. Econ. Entom.  51: 838.

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
Research Council, Washington, DC.  p. 615.

National Cancer  Institute.   1578.   3ioassay of Dioxathion  for Possible Car-
cinogenicity.    QHEW.   National  Cancer Institute.   Carcinogenesis  Tecnnical
Report Series No. 125: 44.

Richert,  E.P.  and  K.V.   Prahlad.    1972.   Effect  cf  the  crganophcspnate
o,o-dirthyl-5-C(sthyithio)methyi]  phospnorocithiste on  the  chick.   Fault.
Sci. 31: 513.

-------
                                      No. 85
         Dlethyl Phchalate


  Health and Eavironnental Effaces
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  ana  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.
                          _ L^^"r .
                          ') I/ U ) ""

-------
                      DIET3YL PHTHALATE
                           SUMMARY"
     Diethyl  phthalate  has  been shown  to produce  rautagenic
effects in the Ames Salmonella assay.
     Teratogenic  effects  were  reported foJ .owing  i.p.  admin-
istration of  diethyl  phthalate  to pregnan  rats.   This  same
study has also indicated  fetal toxicity aa  increased  resorp-
tions after i.p. administration of DEP.
     Evidence  that diethyl  phthalate  prc .uces carcinogenic
effects has not been found.
     A single clinical  report  indicates t. at the  development
of hepatitis  in  several  hemodialysis  pati nts  may have  been
related  to  leaching  of  diethyl  phthalate  from  the  plastic
tubings utilized.
     Diethyl  phthalate  appears  to  be mor   toxic  for  marine
species acutely  tested,  with a  concentra  :on  of  7,590  ug./l
being  reported  as  the  LC-n  in  marine i  vertebrates.    The
data base  for  the  toxic  effects of  die  lyl  phthalates  to
aquatic  organisms  is   insufficient  to  d  ift  criterion   for
their protection.
                                 * "/!?l/ Cr"

-------
                      DIETHYL PHTHALATE

I.   INTRODUCTION

     This  profile  is based  on  the  Ambient  Water  Quality

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

     Diethyl 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  diethyi phthalate  was:

3.75 x 10  tons/year  (U.S.  EPA, 1979a).

     Phthalates 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

bacterial  flora  may  be   capable  of  metabolizing phthalates

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

II.  EXPOSURE

     Phthalate  esters  appear  in  all  areas  of  the  environ-

ment.   Environmental  release of  the  phthalates may  occur

through leaching  of plasticizers  from  plastics, volatiliza-

tion of  phthalates  from  plastics,  and  the  incineration of

plastic items.   Human exposure to phthalates 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).

-------
     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,

ec  al.  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. PKARMACOKINETICS

     Specific  information is  not  available  on  the   absorp-

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

reader is  referred to a general coverage of onthalate  metabo-

lism in the phthalate ester hazard  profile  {"J.5.  SPA,  137Sb) .

IV.  EFFECTS

     A.    Carcinocenicity

          Pertinent  information  could  not  be  located   in.

the available literature.

     3.    Mutagenici*:y

          Diethyl 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).
A
                                    -i /> / * -
                                     u i J

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



          Fetal   toxicity   and  increased  resorptions   were



produced  following  i.p.  injection  of  pregnant   rats   with



DEP  (Singh, et al. 1972).



     E.   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.   Acute Toxicity



          Among  aquatic  organisms,  the  bluegill sunfish,  ;



Lepomis macroc'nirus,  has beer, shown  to be acutely sensitive



to  diethyl  phthalate;  a 96-hour static  LCCQ of  98,200  pg/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  variegatus,   showing



a 96-hour static LC5Q of 29,600  jjg/1, while the mysid  shrimp,



Mysidopsis  bahia,  showed  an  96-hour  static  LC   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-

-------
strum  capcicornutum,  ranged  from  35,600  to  90,300  ug/1,
while the marine  alga,  Skeletonema costatum, was more  sensi-
tive,  with  effective  concentrations  ranging   from   65,500
to 35,000 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 possibility that  these criteria  will be changed.
     A.   Human
          Based  on  "no  effect"  levels  observed  in chror.ic
feeding studies  with rats or  dogs,  the U.S.  E?A has  calcu-
lated an  acceotable daily  intake  (ADI)  level of 438  me/day
for DEP.
          The  recommended  water   quality  criterion   level
for  protection  of  human health   is 50  mg/1  for  DE?   (U.S.
EPA, 1979a).
     B.   Aquatic
          Data are insufficient  to  draft criterion  for  the
protection of  either  freshwater  or  marine  organisms   (U.S.
EPA, 1979a).

-------
                      DIETHYL PHTHALATES

                          REFERENCES

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

Milkov, L.E.,  et al.   1975.  Health status of  workers  ex-
posed to phthalate 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  phthalate esters
in rats.  Jour. Pharm. Sin. Gl, 51.

U.S. EPA.    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.   Phthalate Esters:   Ambient  Water Quality
Criteria (Draft).

U.S.  EPA.    I979b.   Environmental Criteria and  Assessment
Office.  Hazard Profile:  Phthalate Esters (Draft).

-------
                                      No. 36
        DimethyInitrosamine


  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.
                            ¥<-

-------
                     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 fig dimethylnitrosamine in
their diet.
                                  -j &/ 3 "

-------
                      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


          Dimethylnitrosamine has beer, detected at a concen-


 tration cf 2  to  4  ug/1  ir. wastawatar 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.    Feed


           Dimethyinitrosamine was found to oe present in


Na variety of foods (including smoked, dried or salted fish,
   ^

 chees£v<3alaiai,  frankfurters, and cured meats)  in the 1


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


 (Montesano anc>Bartsch, 1976).


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


 average bioconce.ntrati°r;  factor for dimethylnitrosamine


 for  the edible pc?rtions of  fish and shellfish  consumed  by

-------
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. JHA3MACCKINETICS
     A.   Absorption
          Pertinent data could  not  be  located in  the  avail-
able literature.
     3.   Distribution
          Following intravenous  injection  into rats, dimetnyi-
nitrosamine is rapidly  and rather uniformly distributed
throughout the body (Mages,  1972).
     C.   i-ietaboiism and Excretion
          In vitro studies have demonstrated that  the  organs
in the rat with the major capacity  for metabolism  ct dimethyl-
nitrosamine are the liver and kidney  (Montesanc and  Magee,
1974).  After administration of  14C-labeled-- "imethylnitro-
samine to rats oc mice, about 60  percent o: fc^e  isotope
appears as I4C02 within 12 hours, while 4  tarcent  is axcretaa"
                                  .„ / a ^*"

-------
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

          Dimethylnitrosamine and diethylnitrosamine have

been reported to induce forward and reverse mutations in

3_. typhimurium, E. coli, iMeurospora crassa and other organisms;

gene recombination and conversion in Saccharomyces cerevisiae;

"recessive lethal mutation" in Drosophila; and chromosome

aoerracions in mammalian cells (Montesano and Bartsch, 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.   Teratogenicity and Other Reproductive Effects
                                                           *
          Pertinent information could not be located in

the available literature on the teratogenicity and other

reproductive effects of dimethylnitrosamine.

-------
     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 dimechyl-

nitro-samine (Stenback, et al., 1973; Magee,  et al.,  1976).

V.   AQUATIC TOXICITY

     Pertinent information about acute and chronic aquatic

toxicity was not found in the available literature.   Addition-

ally, -c mention was made in any reports ariout plane  effects

or residues.

     One study reported that Shasta strain rainbow trout

(Salmo gaircneri), 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. EPA (1979a) has estimated that the water
concentrations of dimethylnitrosamine corresponding to 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.  CoTd 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.  Inr  W.  Nakahara,  et al., eds.
Topics  in chemical carcinogenesTs.  University  of Tokyo
Press, Tokyo.

Magee, P.N., and J.M. Barnes.  t956.   The producrion  of ma-
lignant primary hepatic tumors in  the  rat by feeding  dimethyl-
nitrosamine.  Br. Jour. Cancer   10: 114.

Magee, P.N., and J.M. Barnes.  1959.   The experimental pro-
duction of tumors in  the  rat  by  dirnechylnitrosamine  (N-nitro-
sodimethyiamine).  Acta.  CJn.  Int.  Cancer  15: 137.

Magee, P.N1., ac al.   1976.  N-Nitroso  compounds and  related
carcinogens.  In; C.S. Searie, ed.  Chemical Carcir.ccens.
ACS Monograph No. 173.  Am. Chem.  Soc.,  Washington,  D.C.

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

Montesano, R., and P.N. Magee.   1974.  Comparative metacoiism
_in vitro of nitrosamines  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-
ethylnitrosamine in  the rat.  Science  152c  83.

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

-------
Stenback,, P., 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.f 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.  Nitrosamines: Hazard Profile.
                                 -SO

-------
                                    No. 37
       2,4-Dlmethylphenol


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

          APRIL 30, 1980
            -103.1-

-------
                          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
niay 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-OIMETtiYLPhENOL
                                    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  LC-j-,  value  for  fathead  minnows  is  16,750 jug/1;
chronic value using embryo-larval  stages of the  same  species  is 1,100 ug/1.
Oacnnia  magna  has  an   observed  48-hour  LC-Q  value  of 2,120 ,ug/l.    In
limited  testing,  one  aquatic  alga  ana  auckweed are over  100  times less
                                                                              •«
sensitive  than  the  Caonnia in acute  exposures.   The  bioconcsntration  factor
for  2,4-  diiTietnyiphehoi is  150 for  the  bluegili.   rrom  half-life  stuoies,
residues of the chemical are noc a potential hazard for aquatic species.

-------
I.   INTRODUCTION


     This profile  is based primarily  on the Ambient  Water Quality Criteria


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


     2,4-Oimethylphenol  (2,MM5)  is  derived from coal and petroleum sources


and  occurs  naturally  in  some  plants.   2,4-DMP  (C-H,gO)  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°Cr  and a dens-


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


     2,4-QMP  is a  weak  acid   (pk_-10.6)  and is  soluble in  alkaline  solu-


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


water (Weast, 1976).                                                          •


     2,4-OM?  is  a chemical  intermediate in  the manufacture of  a number of


industrial  and  agricultural  products, including  phenolic antioxidants,  dis-


infectants,   solvents,   Pharmaceuticals,  insecticides,   fungicides,  plasti-


cizers,  rubber chemicals,  polyphenylene  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

-------
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.   Leachates  from  municipal  and  industrial
wastes also contain  the compound  (U.S. EPA, 1979).
         Hoak  (1957) determined  that, at 30°C, the  odor threshold  for  2,4-
OMP was 55.5>jg/l.
     8.  Food
         DMP's  occur naturally  in  tea (Kaiser,  1967)T  tobacco (Baggett and
Marie, 1973; Spears,  1963),  marijuana (Hoffmann, et al. 1975), and a conifer
(Gcrncstasva,   et   al.   1977).   There   is   no  evidence  to  suggest   that
dimethylphenols  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  (1979)  has   estimated  the  weighted  average   biocon-
centraticn  factor  for 2,4-QMP to be  340  for  tna edible portions of  fish ana
shellfish  consumed  by Americans.  This  estimate is  based on  the  measured
steady-state bioconcentration studies in  the  bluegill.
     C.  Inhalation
         2,4-Oimethylphenol  has  been  found  in  commercial  degreasing agents
(NIQSH,  1978),   cresol  vapors  (Corcos,   1935),  cigarette  smoke  condensatss
(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 20.3 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-DMP 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;  however,  the  effects  were  not  attributed  to
dimethylphencl 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-DMP  is  readily  absorbed  through the skin (U.S.  E?A, 1979).  The
dermal  LD^g for  molten 2,4-OMP  is  1,040  mg/kg in  the rat  (Uzhdovini,  et
al. 1974).
     8.  Distribution
         U.S. EPA  (1979)  found  no  pertinent data 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  350  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.  Carcinogenicity
         Epidemiologic  studies  of workers exposed  to  2,4-OMP were not  loca-
ted in the available literature.
         In a  Carcinogenicity 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  Ooutwell  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  acclication  of a  sub-carcinogenic dose (75
ug) of CMBA.   Papillomas  or carcinomas developed in 18 percent  of the mice,
indicating that 2,4-OMP may be a promoting agent for carcinogenesis.
         Fractions of  cigarette smoke condensate containing  phenol,  methyl-
phenols  and 2,4-OMP  have  been snown  to promote  carcinogenesis in mouse skin
bioassays  (Lazar, et al. 1566; Sock, et al. 1971; Roe, et al. 1559).
     B.  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- OMP
was not  located  in the available  literatureHU.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-dircethylphencl
for eight  months  revealed fatty dystrophy and atrophy  of the hepatic  ceJ^ls,

-------
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 cculd net  be  located  in the available literature re-



garding any saltwater species.



     A.  Acute Toxicity



         A  reported  96-hour LC-g value  for  juvenile  fathead  minnows  is



16,750  ,ug/l  (U.S.  EPA,  1979).    For the  freshwater  invertebrate  Dacnnia



maqna, the observed 48-hour LC5Q is 2,120 jjg/1 (U.S. EPA,  1579).



     3.  Chronic Toxicity



         3ased on an  embryo-larval test  with  the fathead minnow,  Pimeohales



oromelas,   the  derived chronic  value  is  1,100 pg/1  (U.S. .EPA,  1978).   NO



chronic values are available for  invertebrate  species.



     C.  Plant Effects



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



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



1955).



     D.  Residues
                                                                          »


         A  bioconcentration  factor  of 150 was obtained  for the  bluegill.



The biological half-life  in  the  bluegill  is   less  than one  day,  indicating
                                           -j^r\ iLr



                                           17'?

-------
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-CMP  for  any sector of  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-dimethylphenol,  the draft  criterion  to  protect  freshwater
aquatic life  is  38  ug/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, 1575).

-------
                              2.4-OIMETHYLPHENOL

                                  Referencss
Baggett,  M.S.,  and G.P. Morie.   1973.   Quantitative determination of phenol
and  alkylpnenols  in cioarette  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  xylenois  in the rabbit  with further observations on the metab-
olism of  the xyienes.  Biochem. Jour. _ 47: 395.

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

Gornostaeva,  L.I.,  et  al.   1977.   Phenols from  abies  sibirica sssentaial
oil.  Khim. Pirir.  Soedin:  ISS 3, 417-413.

Hcak, R.D.   1957.  The  causes  of tastes and odors  in  drinking water.  Proc.
llth Ind. Waste Conf.  Purdue Univ. Eng. Bull.    41:  229.

Hoffmann,  0.,   et  al.   1975.   On  the  carcinogenicity of  marijuana smoke.
Recent Adv. Phytochem.  9:  63.

Hoffmann, 0.,  and E.L. Wyncer.   1963.   Filtration of phenols from cigarette
smoke.  Jour. Natl. Cancer Inst.  30: 67.

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

Lazar,  P.,  et  al.   1966.   8enzo(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
ATF-induced  vasoconstricticn  in  isolated  perfused  rabbit  lungs.   Acta.
Physiol. Scand.  72: 331.
                                                                      »
Maazik,  I.K.  1963.   Oimethylphenol  (xylenoi)  isomers  and  their  standard
contents in water bodies.   Gig. Sanit. 9: 18.

-------
National  Institute of Occupational  Safety and  Health.   1978.  Occupational
exposure  to  cresol.   OHEW (NIOSH) Publ.  No.  78-133.  U.S.  Dep. Health Edu.
Welfare, Pub. Health Ser., Center for Dis. Control.
Roe, r.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.2. Sullivan.   1964.  Determination of the steam-volatile
phenols present in cigarette-smoke condensate.  Analyst  89: 312.
Spears,  A.W.   1963.    Quantitative   determination  of  phenol  in  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-Oimethylphenol:    Ambient  Water  Quality  Criteris
(Draft).
Uzhdovini, E.R.,  et  al.   1974.  Acute  toxicity of  lower  phenols.   Gig.  fr.
Prof. Zaboi.   (2): 58.
Versar,  Inc.   1975.   Identification  of organic compounds in  effluents frcm
industrial sources.  EPA-560/3-75-002.  U.S. Environ. Prat. Agency.
Weast,  R.C.   1576.  Handbook  of chemistry and physics.   57th  ed.  CRC Press,
Cleveland, Ohio.

-------
                                      No. 88
         Dimethyl Phthalate


  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 acc-uracv.

-------
                      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  phthalate included  impaired implantation



and parturition in rats following  i.p.  administration.



     Chronic  feeding  studies  in  female  rats  have  indicated



an  effect  of  dimethyl  phthalace   on  the  kidneys.    There is



no evidence to indicate that dimethyl phthalate has carcino-



genic effects.



     Among  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 daca



concerning the toxic effects  of dimethyl phthalates to aquatic



organisms.
                                 **/$ 3 7

-------
                      DIMETHYL PHTHALATE

I.   INTRODUCTION

     This  profile  is  based  on  the  Ambient  Water  Quality

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

     Dimethyl  phthalate  (DM?)   is  a  diester  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  282°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.

     Current  Production:  4.9 x _10"  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  vegeta-

tion.   Evidence  from  _in_ vitro studies indicates  that  certain
                                             i
bacterial  flora  may  be  capable of  metabolizing  DMP  to  the

monoester form  (Englehardt, et al. 1975).

     For  additional   information   regarding  the   phthaiate

escers  in  general,  the reader  is  referred  to  the EPA/SCAO

Hazard Profile on Phthalate Esters (U.S. EPA, 1979b).

II.  EXPOSURE

     Phthalate  esters appear  in  all  areas of  the environ-

ment.   Environmental  release of  phalates 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,  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. SPA  (1979a)  has estimated the weighted average
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-
tra^ion studies in bluegills.
III.  PHARMACGKINETICS
     Specific  information   is  not   available  on  the  absorp-
tion, distribution,  metabolism, 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  ai.
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

DMP  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).

7.  . AQUATIC TOXICITY

     A.   Acute Toxicity

          Two  freshwater  species   were  examined   for  acute

toxicity  from  dimethyl phthalate  exposure.    The   48-hour

static  "C_Q  for  the Cladcceran,  Daphnia rnagna,  was   33,000

ug/1  (U.S.  EPA,  1978).   The 96-hour  static LC-Q  value  for

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

marine  species,  96-hour static  kC^Q  values for  the   sheeps-

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

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

     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  algae  Selena-

.strum  capricornutum and  the marine algae  Skeletonema costa-

tum  ranged from  39,800  to 42,700  pg/1  and 26,100  to 29,800

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  gone

through the process  of  public review;  therefore,   there  is

a possibility that  these  criteria  will be changed.

     A.    Human

           Based  on  "no   effect"  levels  ooserved in  chronic

^do^ * -~ e*-i-J-a=   i— >- = -c  3->r* [•'r«e=   h h P  fl ^  ^T^A  MQ7Qa\  U-^
^.c^C^xii^ OUM^*^.G>^  ^.^. j.
-------
                     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  raicrobial  metabolism
of  di-n-butyl  phthalate  and  related  dialkyl  phthalates.
Bull. Environ. Contain.  Toxicol. 13: 342.

Milkov, L.2., 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 Perspect.
Jan.  91.

Rubin, R.J., et al.  1979.   Ames rautagenic assay of a series
of phthalic acid  esters:   positive response  of  the dimethyl
and diethyl esters  in TA  100.   Abstract. Sec. Toxicoi. Annu.
Meet. Naw'orleans, March 11.

Singh, A.,  at  al.-  1972.   Terat:cgenicity of phthalate esters
in ra^s.   Jour. Pharin.  Sci. 61: 51.

U.S.   EPA.   1978.   In-depth studies  on  health  and environ-
mental impacts of selected water  pollutants.   "J.5. Environ.
Prot.  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).

-------
                          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.

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

           APRIL 30, 1980

-------
                                DINITROBENZENE5
                                    Summary

     Due to  ths lack of  available  information  no sssessmsnt  of ths °ctsn—
tial of dinitrobenzenes  to  produce  carcinogenic effects,  mutagenic  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.
                                                  x
     Fish have been  acutely affected  by  exposure to non-specified isomers of
dinitrobenzene at concentrations ranging from 2,000 to 12,000 ug/1.

-------
                                OINITR08ENZENE-
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 118°C,  and a specific  gravity of
1.57.   Meta-dinitrobenzene  (1,3-dinitrobenzene)  is  a  yellow,  crystalline
solid  that  melts  at  89-90°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 coiling  point of  299°C,  a melting  point of  173-174°C,  and a
density  of  1.63  (windholz,  1976).   The  dinitrobenzenes  have low  aqueous
sclubiiitv =nd z~°  soluble in  alcohol.
     The dinitrcbenzanes are  used in  organic  synthesis-,   the  orccuc'ion of
ayes, and as a camphor substitute  in celluloid prediction.
     The  ccmestic  production  volume  of meta-dinitrcbenzsne   in  1572  was
aporoximately 6 x Id^ tons (U.S. EPA, 1976).
     Oinitrobenzenes are  generally stable in  neutral aqueous  solutions; as
tne medium oecomes  more  alkaline  they may 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).
                                                                         »
     Based on  the  octanol/water partition coefficient,  Neely  et  al. (1974)
have estimated a low bioconcentration potential  for the dinitrobenzenes.

-------
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
          Metherccglobin  formation  in  workers exposed to dinitrobenzene indi-
cates  that  absorption  of the  compound  by  inhalation/dermal  routes  occurs.
Animal  studies demonstrate  that .dinitrobenzene is  absorbed  following  oral
„ ,j_ .• _ .• _ j— i. .• - „
awl—i lj.iv-.Lac-i.ui i.
     3.  Distribution
          Pertinent  information on districution  of  dinicrcbenzenes \vas  not
found  in the available  literature.
     C.  Metabolism
          Dinitrobenzene  undergoes both  metabolic  reduction  and  cxidaticn.
.-.nri2_  s^ucies  indicate ... .sti •„.
-------
     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 feces (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  possible dinitrobenzene metabolite,
dinitropnenoi  (U.S. EPA,  1979),  has  been reported to induce chromatid breaks
in bone ."arrow cells of injected mice (Micra ana Manna, 1971).
     C.  Teratogenicity
          Information on  the  ceratogenicity  of the  oinitrobenzenes  was not
fc-jrd in  the available  literature.  The  possible dinitrcbenzene metacoiite,
dinitropnenoi  (U.S.  EPA,  1979), has produced  developmental  abnormalities  in
the sea urchin (Hagstrom  and  Lonning,  1966).   No  effects were seen follcv.-i.-g
injection cr era! administration of dinitropnenol to mice (Gioson, 1973).
     0.  Other Reproductive Effects
          Pertinent information was not found in the available literature.
     E.  Chronic Toxicity
          Oinitrobenzene  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).

-------
V.   AQUATIC TOXICITY



          A.  Acute Toxicity



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



toxic effects of dinitrobenzenes to aquatic  life.   A  study by LeClsrc  (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 ug/1  in  hard  water.   Meinck et al. (1956)  reported  lethal



concentration of 2,000 pg/1 for  unspecified dinitrobenzenes  for  an unspeci-



fied fish species.



     8.  Chronic Toxicity



          Pertinent  data could  not  be  found  in  the 2vail3ble  litsrsturs



regarding aquatic toxicity.



     C.  Plant Effects



          Howard et al.  (1975) rsport that  the  algae  Chlorella sp.  dispiayec



inhibited  photosynthetic activity  upon  exposure  to  n-dinitrobenzene at  a



concentration of 10~4 M.



VI.  EXISTING GUIDELINES



     The 8-hour  time-weighted-averace  (TWA) occupational  exoosure  limit for



dinitrobenzenes is 0.15 ppm(ACGIH, 1974).

-------
                                DINITR08ENZENES

                                  References
ACGIH.   1974.   Committee  on threshold  limit values:  Documentation  of the
threshold limit values for substances in the  workroom air.  Cincinnati, Ohio.

3ringmann, 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.£.   1973.   Teratology  studies  in mice with 2-sec-Butyl-4,- 6-dini-
trophenol (Dinoseb).  Fd. Cosmet. Toxicol.  11: 31.,.

Hagstrom, 8.E.  and S. Lcnning.  1966.  Analysis  of the effect of  -Qinitro-
phenol on  cleavage and  development  of the sea urchin  embryo.  Protoplasms.
42(2-3): 246.  •

Hashimoto, 5.  and K.  Xano.   1572.  Fhotocnsmical  reduction  of nitrobenzene
and  reduction  intermediates.    X.   Photochemical   reduction  of  the  mono-
substitutsc1 nitrcbenzanes in 2-propanol.  Bull. Chem. Soc. Jap.  45(2): 549.

Howard,  P.M.,  et  al.   1975.  Investigation  of selected  potential  environ-
mental  contaminants:  Nicrcaromatico.   Syracuse,  N.Y.:    Syracuse  Research
Corccration,  T° 76-573.

LeClerc, E.   1960.   Self  purification .of  streams  and the  relationship  ce-
tv/een  chemical arc1  biological  tests.   2nd  Symposium on  the  Treatment  of
Waste Waters.  Pergamon Press, p. 282.

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, ,-.,  et al.   1956.   Industrial waste water.  2nd  ed.  Gustav Fisher
Verlag Stutosrt, o. 536.

Micra,  A.3.  and  G.K. Manna.   1971.   Effect of  some phenolic compounds  on
chromosomes of bone marrow cells on mice.  Indian J. Med.  Res.  59(9): 1442.

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.
                                                      s
Neely,  W.B.,   et   al.   1974.   Partition  coefficient  to  measure  bicconcan-
tration  potential of organic  chemicals  in  fish.    Environ.  Sci.  Technoi.
3: 1113.
                                                                        «

Parke,  O.W.    1961.   Detoxication.   LXXXV.   The  metabolism  of  m-dinitro-
benzene-C^ 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-Dini-
trophenol:  Hazard Profile (Draft).

Windholz, M.  (ed.)   1975.  The  Merck  Index.   9th ed.   Merck  and  Co.,  Inc.,
Rahway, N.J. p. 3269.

-------
                                     No. 90
        4,6-Dinitro-o-cresol
  Health and  Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCt
       WASHINGTON, D.C.  20460

           APRIL 30, 1980
                 Jo-/

-------
                          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-aracy.

-------
                    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  Proteus



mirabilis but failed to show mutagenic  effects in the Ames



assay or in E. 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.

-------
                     4 ,6-DINITRO-O-CRESOL



I.   INTRODUCTION



     This profile  is based  on  the Ambient  Water  Quality Cri-



teria Document for Nitrophenols  (U.S.  EPA,  1979a).



     Dinitrocresols  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 85.8°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 miticide on the  fruit trees  during the dormant  season.



There is no record of current  domestic manufacture  of  DNOC



(U.S. EPA, 1979a).   For  additional  information regarding the



nitrophenols in general, the reader  is referred  to  the  Hazard



Profile on Nitrophenols  (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 mg/1  in effluents from  chemical plants  (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



bioconcentration 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.
                             X

-------
III. PHARMACOKINETICS



     A.   Absorption



          WOC  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.   Metabolism



          Animal studies on  the metabolism  of  DNOC indicate



that like the nitrophenois,  both  conjugation of  the  compound



and reduction of the nitro groups to  amino  groups  occurs.



The metabolism  of  DNOC to  4-amino-4-nitro-c-crescl  is a de-



toxification mechanism that  is effective  only  when  toxic



doses of DNOC are  administered (U.S.  EPA, 19T9a).   The



metabolism of DNOC Ls 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.

-------
IV.  EFFECTS



     A.   Carcinogenicity



          Pertinent data could not  located  in  the  available



1iterature.



     B.   Mutagenicity



          Adler, et al.  (1976) have  reported  that  DNOC  shows



some evidence of producing DNA damage  in Proteus mirabilis.



Testing of this compound in  the Ames Salmonella system



(Anderson, et al., 1972) or  in JB. coli  (Nagy,  et al., 1975)



failed to show any mutagenic effects.



     C.   Teratogenicity and Other Reproductive Effects



          Pertinent data could n.ot be  located  in the



available literature regarding teratogenicity  and  other



reproductive effects.



     D.   Chronic Tcxicity



          Human use of DNOC as a dieting aid has produced



poisoning cases at accepted thereputic dose levels, as well



as some cases of cataract development  resulting from



overdoses (HIOSH, 1978).



     E.   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 12.8 ug/1 by the  U.S. EPA  (1979a).   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



tcxicoiogical evidence (U.S. SPA, 1979a) .

-------
VI.  EXISTING GUIDELINES AND STANDARDS



     A.   An eight-hour TLV exposure  limit  of  0.2  mg/m-3  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. SPA  (197Sa).   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



toxlcological evidence (U.S. EPA, 1979a).

-------
                                       No. 91
         2,4-Dlnitrophenol
  Health and Environmental Effects
CJ.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980
                _^^*^--A.
                 ) U U ^

-------
                          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 ONA 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  taratocenic  effacts.


At the levels of compound used  in these mammalian studies, embryo-
                                                                 *

toxic effecrs were observed.


     Human  use of  2,4-dinitrophenol  as  a 'dieting aid  has produced


seme cases  cf  agranulccytosis,  neuritis,  functional  heart da.~age,


and cataract development.


     For aquatic  organisms  LC^g  values  ranged from  620 ug/1  for


the biuegill tc 15,700 j:g/l  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-Dinitrophenol 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, photochemicais,  pest  control agents,  wood

preservatives,  and  explosives  (U.S. EPA,  1979a).   The 1963  pro-

duction of  2,4-dinitroohenol was 4.3  x 10^  tons/yr.    (U.S.  EPA^
                       *"                                           *

1979a).

     For  additional  ir.fcrniaticn  regarding  the  nitrochenols as

a class,  the' reader  is referred  to  the Hazard  Profile on Nitro-

phenols (1979b).

II.  EXPOSURE

     The  lack of  monitoring data  for  the nitrophenols makes it

difficult co  assess  exposure  from  water,   inhalation,  and foods.

Nitrophenols  have  been detected in  effluents  from chemical plants

(U.S. SPA,  1979a) .    Dermal  absorption of  the  dinitrcphenols  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  en  the. cctanol/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 nitro-grcups to  amino—groups,  or oxidation to

dihydric-nitropher.Qls (U.S. EPA,  1979a) .

     D.   Excretion

          Experiments .with several  animal  species  indicate  that

urinary clearance of dinitrophenols is  rapid  (Harvey, 1959).

"TT   r~--n r^T">/-*fT*r^
>/l.  ixriCTS                                             •**

     A.   Carcinogenicity-

          2,4-Dinitrophenol  has  been  found  not to  promote  skin

tumor  formation  in mice following  DMBA initiation (Bautwell  and

Sosch, 1959) „

     B.   Mutagenicity

          Testing  of  2,4-dinitrophenol  has  indicated   mutagenic
                                                             »
effects  in  E. coli  (Demerec,  et al.. 1951) .   In  vitro  assays  of

unscheduled  DNA  synthesis  (Friedman  and  Staub,  1976)  and  DNA

-------
damage  induced  during  cell culture (Swenberg, et al. 1976)  failed

to show the potential for mutagenic activity  of  this compound.

     C.   Teratogenicity

          2,4-Dinitrophenol has been shown  to produce development-

al abnormalities  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 or. maternal health may have contributed to these effects.

     S.   Chronic Toxicity

          Use of 2,4— dir.itroohenol as a human distinc aid has pro-

duced  some  cases of  agranulocytosis,  neuritis,  functional heart

damage, and  a  large number  of patients  suffering  from cataracts

(Horner, 1342).

     ?.   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/1 in  a  static,


96-hour assay  (U.S.  EPA,  1978).   Juvenile fathead minnows  (Pime-


phales promelas)  were more  resistant in  flow through tests, with


an I*CCQ of  16,720 pg/1  (Phipps, et  al.   manuscript).  The  fresh-


water  cladoceran  (Daphnia  magna)  displayed  a range  of  observed


LC5Q  values of  4,090   to  4,710  pg/1  (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 (Rosenthal


and  Stelzer,  1970).   The marine mysid  shrimp (Mysidopsis  bahia)


had an LC5Q of 4,350 ug/1 (U.S. EPA, 1978).                       j.


     3.   Chronic Toxicity


          Pertinent  data  could  not  be  located  in  the   available


literature.


     C.   Plant Effects


          Effective  concentrations  for  freshwater  plants   ranged


from  1,472  pg/1  for duckweed  (Lemna minor)  to  50,000  /ag/1  for


the  alga  (Chlorella  pyranoidosa)  (U.S.  EPA,  1979a).   The  marine


alga  (Skeletonema costatum)  was more  resistant  with  a  reported


96-hour SC-Q 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.
                                  ?f-7

-------
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  not to exceed



180  ug/1.    The marine  criterion has  been  proposed as  37  ug/1



as  a  24-hour average not  to  exceed  84  ug/1  at  any  time  (U.S.



EPA, 1979aj .



          To protect  saltwater  life,  the  draft criterion  is  37



ug/1 as a 24-hour average  not  to  exceed  84  ug/1 at any time (U.S.



EPA, 1979a).

-------
                         2,4-DINITROPHENOL

                            REFERENCES
Bautwell,  R.,  and  D.  Bosch.   1959.   The tumor-promoting  action
of  phenol  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 rautagenic 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.   Mutat.  Res.   37: 67.

Gibson, J.E. 1973.  Teratology  studies  in mice with 2-secbutyl-4,
5-dinitrcphenol (dinoseb).  Food  Cosmet.  Toxicol.  11:  31.

Harvey, D.G. 1959.  On  the  metabolism of some  aromatic  nitro  com-
pounds by 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.   II:  462.

Homer, W.D. 1942.  Dinitroohenol  and ics  relation to formation of
cataracts.  Arch. Ophthal.  27: 1097.

Landauer, W., and  E.  Clark.  1964.   uncoupiers  of oxidative phos-
phorylation and teratogenic activity  of insulin.  Nature 204:  235.

Miyamoto, K., ec al. 1975.  Deficient myelination by 2,  4-dinicro-
phencl administration  in early stage of  development.    Teratology
12: 204.
                      .-nu,A -. *^ . . ^ — <_—.,,,_,;_.. ,— —  -> « — — -s '  -. „ -i  — ,-*.— i. : »«
                      J. ** ^ AW M <_ w wOA.iO.fcwy <*J A.  ^llCliw^  dli**J  d U«^ M *- X W
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. Commun.  72:  732.

U.S. EPA.   1979a.   Nitrophenols:   Ambient water quality criteria.
(Draft).

U.S. EPA.   I979b.   Nitrophenols:   Hazard  Profile.   Environmental
Criteria and Assessment Office (Draft).
                                *    LJ.  '&-
                                   * i D i) ^

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

Wulff,  L.M.B., et al. 1935.   Some effects of alpha-  dinitrophenol
on pregnancy  in the white rat.  Proc. Soc.  Exp. Biol. Med.  32:  678.
                               9/-/0

-------
                                       No.  92
           Dinitrotoluene
  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.
                              ,„{,{} ^7 /
                            *  I V ) ''"

                              7

-------
                        DINITROTOLUENE



                           SUMMARY



     Most of the information on the effects of dinitrotoluene



deals with 2,4-dinitrotoluene.  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, raethemo-



globinemia and anemia in humans and animals.



     Acute studies in freshwater fish and invertebrates



suggest that 2,3-dinitrotoiuene is much more  toxic  than



2,4-dinitrotoluene.

-------
                        DINITROTOLUENE



I.   INTRODUCTION



     This profile is based on the Ambient Water Quality



Criteria Document for Dinitrotoluene  (U.S. EPA, 1979).



     There are six isomers of dinitrotoluene  (CH-,CgH3  (N02)2;



molecular weight 182.14), with the 2,4-isomer being  the



most important commercially.  2,4-Dinitrotoluene has a melt-



ing point of 71°C, a boiling point of 300°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-Dinitrotoluene has a melting point



of 66°C and is soluble in alcohol.  Production in 1975 was



273 x 10  tons per year for the 2,4- and 2,6- isomers com-



bined (U.S. S?A, 1979) .



     Dinitrotcluene is an ingredient of explosives for commer-



cial anc military use,  a chemical stabilizer  in the manufac-



ture of smokeless powder, an intermediate in  the manufacture



of toluene diisocyanates used in the production of urethane



polymers, and a raw material for the manufacture of dyestuffs.



Dinitrotoluenes are relatively stable at ambient tempera-



tures (U.S. EPA, 1979).



II.  EXPOSURE



     A.    Water



          Data on concentration levels for dinitrotoluene



were not available.  Dinitrotoluene waste products are dumped



into surface water or sewage by industries that manufacture



dyes, isocyanates, polyurethanes and munitions (U.S. SPA,



1979) .

-------
     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 on  the octanol/water



partition coefficient.



     C.   Inhalation



          Exposure to dinitrotoluene by inhalation  is most



likely to occur occupationally  (U.S. EPA, 1979).  However,



pertinent data could not  be located  in  the available litera-



ture en atmospheric concentrations of dinitrctcius-2 and,



thus, ocssible human •=.v<'oosure canr.ct be sstimatac.
     A.   Absorption


                            14
          The absorption of   "C-labeled  iscmers of  dinitrctol



uene after oral administration to rats was essentially com-



plete 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 2,5-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 characterizing the metabolism of dinitro-



toluene in mammals are available.  However, on the basis



of a comparison of the metabolism of 2,4-dinitrotoluene



and 2,4,5-trinitrotoluene in microbial sys-ems, and the



known metabolism of 2,4,5-trinitrotoluene in mammals, the



U.S. Z?A (1379) speculated that tiie metabolites of 2,4-di-



nitrotoluene in mammals would be either tcxic  and/or car-



cinogenic .



     D.   Excretion

                                                      T  |

          In studies involving oral administration of ~"C-



dinitrotoluene or  H-2,4-dinitrotoluene to rats (Hodgson,



et al., 1977; Mori, et al., 1977), elimination of radioactiv-



ity occurred mainly in urine and feces.  No radioactivity

                                           .•

was recovered in the expired air.  About 46 percent of the



administered dose in the latter study was excreted in the



feces and urine during the seven days following administration.

-------
IV.  EFFECTS



     A.   Carcinogenicity



          2,4-Dinitrotoluene fed to rats and mice  for  two



years produced dose-related increases  in fibromas  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 hepatccailuiar carcinomas and



neoplastic nodules in the livers.of females, a significant



increase of mammary gland tumors in females, and a suspicious



ir.craase of hepaeocellular carcincrr.as of che liver in  males.



Male mice had a highly signi'f icar.c ir.craase of kidney  tumors



(Lee, et ai., 1975; .



     2.   Mutagenicicy



          2,4-Dinitrotoluene was mutagenic in the  dominant



lethal assay and in Salmonella typhimurium strain  TA1535



(Hodgson,  et al. 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 chroraatid breaks  (Hodgson, et al.,



1976).



          The mutagenic effects of products from ozonation
                                                          »


or chlorination of 2,4-dinitrotoluene and other dinitrotoluenes
                               7*1-7

-------
were negative in one study  (Simmon, et al.,  1977),  and,


for products of 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 avail-


able literature.


     D.    Chronic Toxicity


          Chronic exposure  to 2,4-dinitrotoluene may produce


liver damage, jaundice, methemoglobineraia  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                 N


          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  Baumann,  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 LCen  value of  330  ug/1 for
2,3-dinitrotoluene  (U.S. EPA, 1978),  while the same assay
with the fathead minnow (Pimephales promelas)  produced a
96-hour LC5Q value of 31,000 pg/1  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 I*CCQ values of 660 jjg/l(U.S. EPA,  1978)
and 35,000 ug/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 LC5Q- value of 2,280 ug/1
was reported (U.S. EPA, 1978).  For marine invertebrates
a 96-hour static LC5Q value of 590 jig/1 was obtained for
the mysid shrimp (Mysidopsis bahia) with  2,3-dinitrotoluene.
     3.   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 ug/1 based  on reduced
survival of these stages.  No marine chronic data  were pre-
sented  (U.S. EPA, 1979).
     C.    Plant Effects
           Concentrations of 2,3-dinitrotoluene that caused
50  percent  adverse effects in cell numbers or  chlorophyll

                              ^^^^^2OL-_
                                lu ) i!!"*

-------
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.  ECco values were 370 or  400 ug/1,

respectively.

     D.   Residues

          A bioconcentration factor of 19 was obtained for

aquatic organisms having a lipid 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 Criteric
      (Per day)                     £    ^7      ^-6^o         '

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
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 mg/m .
     3.   Aquatic
          A criterion to protect freshwater life has been
drafted as 620 ug/1 for a 24-hour average not to exceed
1,400 pg/1 for 2.4-dinitrotoluene and 12 ug/1 not to exceed
27 pg/1 for 2,3-dinitrotoluene.  For marine environments
a criterion has been drafted for 2,3-dinitrotoluene as a
4.4 pg/1 as a 24-hour average not to exceed 10 pg/1.  Data
was insufficient to draft a criterion for 2,4-dinitrotoluene
for marine environments.
                              ft    ' ~ r> *
                               '  I U v **
                           72-11

-------
                                DINITROTOLUENE
                                  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. Dept.  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.  Dev.  Command.   Contract No.  OAMO-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.

McGee, L.C.,  et al.   1942.    Metabolic  distrubances in  workers  exposed  to
dinitrotoluene.  Am. Jour.  Dig. Ois.   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 (^H^^-ONT) in the rat.  Radioisotopes   26: 780.

-------
National Cancer Institute. '  1978.   Bioassay of 2,4-dinitrotoluene for possi-
ble  carcinogenicity.   Carcinogenesis Tech.  Rep.  Ser. No.  54.   USOHEW  (NIH)
Publ. No. 78-1360.  U.S. Government Printing Office, Washington, O.C.

Proctor, N.H.  and J.P.  Hughes.   1978.   Chemical hazards  of the workplace.
J.8. Lippincott Co., Philadelphia/Toronto.

Shils, M.S. 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 DAM017-75-
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.  Oinitrotoluene: Ambient Water Quality Criteria.  (Draft) ^

-------
                                      No. 93
         2,4-Dinitrotoluene


  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.
                            93-2-

-------
                       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 jug/I.  No marine data are available.
                                   •*f D 
-------
                              2,4-OINITROTOLUENE
I.   INTRODUCTION
     This  profile  is  based  on the  Ambient Water  Quality Criteria  Document
for Dinitrotoluene (U.S. EPA, I979a).
     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 of  tol-
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,  I979a).   For  additional infor-
mation  regarding the dinitrotoluenes in  general,  the  reader is referred to
the EPA/ECAO Hazard Profile on Oinitrotoluenes (U.S. EPA, 1979b).
II.  EXPOSURE
     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).
     8.  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.
                                    ,n/ ~f
-------
         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. PHARMPCOKINETICS
     A.  Absorption
         The  absorption  of    u-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, I979a).
     B.  Distribution
         Tissue/plasma  ratios  of  radioactivity  after  administration   of
  C-labeled   dinitrotoluene   (DNT)  to  rats   indicated   retention  of    C
2,4-QNT in  both  liver and  kidneys  but  not in other  tissues  (Hodgson,  et al.
1977).    A   similar  experiment   with   tritium-labeled   2,4-dinitrotoluene
(rl-2,4-QNT)  in  the  rat  showed  relatively  high  amounts  of  radioactivity
remaining  in adipose  tissue,  skin,  and  liver seven days after administration
(Mori,  et  al.  1977).
                                    17* 3 0"u "

-------
     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
 H-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.  Carcinogenic!ty
         2,4-Dinitrotoluene  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 suspicipus in-
crease  of  hepatocellular  carcinomas  of the  liver  in  males.    Mice  had a
highly significant increase of kidney tumors  in males  (Lee,  et al.   1978).
                                     93-7

-------
     8.  Mutagenicity
         2,4-Oinitrotoluene  was mutagenic  in  the dominant  lethal assay and
in  Salmonella  typhimurium strain TA  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
         Chronic exposure  to  2,4-dinitrotoluene may  produce  liver  damage,
jaundice, methemoglobinemia  and reversible  anemia  with  reticulocytosis  in
humans and animals (Linen, 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).
                                73 -8

-------
     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  LCcn value  for  the  fat-
                                                       j\j


head minnow (Pimephales promelas) was  reported as 31,000 pg/1 and  a 48-hour



static  LC5Q  value  for  the  cladoceran,  Daohnia  magna,  was  reported  as



35,000 ;jg/l.



     8.  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

                                                    s

(1979a) has  estimated  levels  of 2,4-dinitrotoluene   in ambient  water which



will result in specified risk levels  of human  cancer:
                                    , ~| O> -
                                   fV ) l




                                     73-?

-------
Exposure Assumptions                 Risk Levels  and  Corresponding Criteria
     (per day)
                                      0       1C.-7        10-*         10-5
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 jjg/1   1.56 jjg/1    15.6/jg/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  .
     8.  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 jug/1, • not to  exceed  1,400 ;jg/l,  has  been proposed.   Data are insuffi-
cient for drafting a marine criterion.

-------
                      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--fa-fe-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
(TNT) and isomers of dinitrotoluene (DNT)  in rats.  Fed.
Proc.  36: 996.

Key, M.M., et al. (eds.)  1977.  Pages 278-279  Ijn:
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.

-------
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  tox ic-
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. DHEW (NIH) Pufal. 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.

Q.S. EPA.  1979a.  Dinitrotoluene: Ambient Water Quality  Cri-
teria. (Draft).

U.S. EPA.  1979b.  Dinitrotoluene: Hazard Profile.   Environ-
mental Criteria and Assessment Offica.

-------
                                      No.  94
         2,6-Dinitrotoluene


  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.
                        9Y-.

-------
                                                             Ill
                        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
                                                            »

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.


—/ 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

-------
     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)



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).
                               W-5

-------
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^cu-



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 LDSO'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 microbial degradation of substituted benzenes.   J. Aor.  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_ jal^.  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 j|t_ ^1^.  Subacute toxicity of 2,4-dinitrotoluene
and 2,6-dinitrotoluene.  Toxicol. Appl. Pharm.  37," 116, -1976.

Hodgson, J.R. et 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. 3.  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.

-------
Vernot, E.H. et_ _al^.  Acute toxicity  and' skin  corrosion data for
some organic and inorganic compounds  and  aqueous  solutions.
Toxicoi. 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
                             -11 * 3-
                             *f r o J

-------
                                     No.  95
        Di-n-octyl Phthalate




  Health and Environmental  Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY

       WASHINGTON,  D.C,   20460



           APRIL 30,  1980
         ^^^-j±M-
          -yyw

-------
                          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-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.
                                 . / /> z.—
                                ) )w v

-------
                           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 (OOP) 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 103  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,  et 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,  I979a).
                                   / / fl s
                                 ^7 
-------
      Monitoring studies have indicated that most water  phthalate  concentrations



are in the ppm range, or 1-2 jug/liter  (U.S. EPA, I979a).   Industrial



air monitoring studies have measured air levels of  phthalates  from 1.7



to 66 mg/m3-(Milkov, at al. 1973).



      Information on levels of OOP in  foods is not  available.   Bio-



concentration factor is not available  for OOP.



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.

-------
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 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 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.

-------
                             DI-N-OCTYL PHTHALATE
Engelhardtj • G., at  al.   1975,   The microbial rnetabolism of di-n-butyl  phtha-
late.  and  related  dialkyl  phthalates.   Bull.  Environ.  Contam.  Toxicol.
13: 342.

Milkov, L.E.,  at  al.   1973.   Health status of  workers exposed to phthalata
plasticizers in the manufacture  of artificial  leather and films based  on  PVC
resins.  Environ.  Health Perspect.   (Jan.): 175.

Singh,  A.R.,  st  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)

-------
                                      No. 96
       1,2-Dlphenylhydrazine


  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. EPA's Carcinogen Assessment Group (CAG)  has evaluated
1,2-diphenylhydrazine and has found sufficient evidence to
indicate that  this compound is carcinogenic.
                            16-3

-------
                      1, 2-DIPHENYLHYDRAZINE
                             Summary
     The adverse  effects  of exposure to 1,2-diphenylhydrazine  in-
clude damage to both the kidney and liver.  Acute  LD5Q  values have
ranged from 300 to 960  rag/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/3,'
were reported  for  bluegill and Daphnia magna, respectively, and  a
single chronic value of 251 jag/1 was reported  for  Daphnia magna.

-------
                      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  ia 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  lively an  underestimation  of  the


total amount of diphenylhydrazine available.   Diphenylhydrazine  is


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.   Food


          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.

-------
     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 mg/kg), intraperitoneally
(200 mg/kg),  intratracheally (5r10  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 18.3 ug/kg/day in both sexes of rats; Zymbal's gland squamous-
cell  tumors  in  male  rats   at  13.8  ug/kg/day; neoplastic  liver
nodules  in  female   rates  at  7.5 ug/kg/day;   and  hepatocellular
carcinomas in female mice  at 3.75  ug/kg/day (NCI, 1978).  Diphenyl-
hydrazine was not carcinogenic in male mice.
     B.   Mutagenicity
          No microbial mutagenetic assays witir'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  (  H)-thymidine into testicular  DNA  of  experimental mice
(Sieler, 1977).
                             76-7

-------
     C.   Teratogenicity
          Pertinent information could not be located  in the avail-
able literature.
     D.   Toxicity
          One study reported an LDcg 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  LD5Q  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  LCen  values   for freshwater  organisms
have been  reported as 270 pg/1  for the bluegill,  Lepomis macro-
chirus,  and  the 48-hour LCcg  for  the  cladoceran,  Daphnia magna,
is  4,100 ug/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  ^ag/1  has  been obtained  for the
freshwater cladoceran, Daphnia Magna  (U.S. EPA,  1978).  No chronic
                                                              »
tests of diphenylhydrazine ace available for marine organisms.

-------
     C.   Plants
          Pertinent  data could  not be  located  in the  available
literature.
     0.   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; the'refore,  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  10f7         lOf6         10_~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     0  .019  ug/1   0/19  ug     1.9
shellfish only.
                           ~*} / t V "

-------
     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 ug/1  at  any


time.
                               ./ / ft
                             *i) I • /*"

-------
                        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  rautagens  and  carcinogens..   Preliminary results  in  the
validation of a novel short term test.  Mutat. Res.  46: 305.

U.S. EPA.    1375.    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.

-------
                                      No. 97
             Disulfoton
  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.

-------
                          Disclaimer  Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

-------
                                  DISULFOTON
                                   Summary

     Oisulfotcn is a highly toxic organophosphorous insecticide used on many
agricultural  crops,   the  human  oral LDLQ  is  estimated  at  5 'mg/kg  body
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/m5.  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.
                                   I I  *] //
                                 ') I  A. * •
                                  77-y

-------
 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,  Misr
 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).   Disulfoton  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
                                    tjn  IT t
                                 * It X -!»'

-------
           TABLE 1.  PHYSICAL AND CHEMICAL PROPERTIES OF OISULFQTON
Synonyms:  0,0-Qiethyl S-(2-(ethylthio)ethyl) phosphorodithioate;
           0,0-Oiethyl S-(2-(ethylthio)ethyl) dithiophosphate;   Thiodemeton;
           Frumin;  Glebofos;  Ethylthiometon  B;   VUAgT  1964;  Di-Syston  G;
           Disipton; ENT-23437;  Ethyl  thiometon;  VUAgT 1-4; Bay 19639;  M 74
           [pesticide]; Ekatin  TO;  CAS Reg. No. 298-Q4-4;  M  74 (VAN); Bayer
           19639;  Oi-Syston; Dithiodemeton;  Oithiosystox; 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

                                   2Q
Specific Gravity and/or Density:, d,   = 1.144

Melting and/or Boiling Points:  bp 620Q 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 2QQC

Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient (Kow): •  KQW =  1.91
                                            BCF =1.0
Source:  Martin and Worthing,  1974;  Fairchild,  1977;  Windholz,  1976;
         U.S. EPA, 1980; Berg, et al.  1977.
                                    ,' |  ~\ f
                                    T^&*^

-------
km) in a  river  environment.   Decomposition  in  a lake environment is estimat-
ed to be  near 90 percent in one year (U.S. EPA 1980).     —-  ""•  -" ~~r -'  -
     B.   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-
                                  ? 7-7

-------
 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
                                                    •
           Oisulfoton 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
           Oisulfoton is highly toxic to all  terrestrial and aquatic fauna.
 Human  oral  LD^  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  LD^Q concentrations  for other  species  are summarized  below (Fair-
 child, 1977).
                                   -*f) Si 2 "•

-------
        Species            Exposure Route              LD5Q (mg/kg)
          rat                   oral                        5
          rat                   dermal                      6
          rat              intraperitoneal                  5.4
          rat              intravenous                      5.5
         mouse                  oral                        5.5
         mouse             intraperitoneal                  7
          bird        .          oral                        3.2
Rats survived  for  60 days at 0.5 mg/kg/day (Martin and Worthing 1974).  The
no-effect level  in the diet was  2 ppm for rats  and  1 ppm  for  dogs  (Fair-
child, 1977).
          In rats, single injections of 1.2 mg disulfoton per kg body weight
caused 14 percent  reductions of hippocampal norepinephrine within 3 hours of
exposure.  Norepinephrine returned to control levels within 5 days (Holt and
Hawkins, 1978).  In  female chicks  administered  with disulfoton  intraperito-
neally  (single dose  8.6 mg/kg),  the total  lipid content of  the  sciatic
nerve,  kidney and  skeletal muscles  increased  whereas  that  of the  brain and
spinal cord remained  the  same  or  decreased.   When female chicks were orally
administered with disulfoton  (0.29 mg/kg  daily for 71  days), the total lipid
content in  all the  organs  except  the  liver and  sciatic  nerves  decreased.
Although degenerative changes  were indicated in  both exposure  studies,  no
adverse, effect on the growth  of chicks was noted (Gopel and Ahuja,  1979).
          Disulfoton applied at 1  to 1.5 kg/ha very  markedly decreased the
populations of soil bacteria  (Tiwari, et al. 1977). "
V.   AQUATIC TOXICITY
          The  96-hour  Tl_m   (equivalent  to  a  96-hour  1X50)   for  fathead
minnows was found  to  be  2.6  mg/1  in hard water and 3.7 mg/1 in  soft water.
                                   77-?

-------
Both  tests were conducted  at 25°C.   The corresponding  value for bluegilis
is estimated to be Q.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 Ajg/m'.   Established residue  tolerance  for  crops  range  from
0.3 to 12.0 ppm; 0.75 ppm for most (Fairchild, 1977).
     B.   Aquatic
          Pertinent data could not be located in the available literature.

-------
                                  REFERENCES
Belanger, A. and H.A. Hamilton.   1979.   Determination of disulfpton and per-
methrin  residues  in an  organic soil and  their translocation  into lettuce,
onion and carrot.  Jour. Environ. Sci. Health.  814: 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.  LLpid  and  growth changes  in organs of
chicks Gallus domesticus during  acute and  chronic toxicity with disyston and
folithion.

Holt, T.M.  and  R.K. Hawkins.   1978.  Rat hippocompel norepinephrine response
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.  of the
Interior Special Scientific Report  — Wildlife No. 184, Washington, D.C.

Stanford Research  Institute.   1977.  Directory  of Chemical Producers.   Menlo
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 600/
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.

-------
                                      No.  98
             Endosulfan


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, B.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.
                            L^^^^^,
                          • 4) J->

-------
                                  ENOOSULFAN
                                    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 humansr 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 resorptions.  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  s
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  ug/1  for  five
freshwater fish; from 0.09 to 0.6 ug/1  for five saltwater fish in 48- or  96-
hour  tests;  from 0.04  to  380  ug/1  (EC50  and  t-C5Q)  for  seven  saltwater
invertebrate species;  and from  62  to  166 pg/1  for Daphnia  maqna  (48-hour
LC3Q).  In  the  only chronic aquatic  study involving  endosulfan,  no  adverse
effects on fathead minnows were observed at 0.20 jug/1.

-------
I.   INTRODUCTION
     Endosulfan        (6,7,8,9,10,10-hexachloro-l,5,5a,6,9,9a-hexahydro-6,9-
methano-2,4,3-benzodioxathiepin-3-oxide;         CgClgHgO,S;         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 pg/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-  4
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
(Cassil and Drummond, 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

-------
 and Mahfouz,  1977; Gorbach, et al. 1968; Miles  and  May,  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 jug/1,,  which was  found  in  Ontario- municipal
 water  samples but 68 jjg/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 Comeliussen, 1972).  The  U.S. EPA
 (1979) has estimated the  weighted average  bioconcentration factor for  sndo-
 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 (Comeliussen,  1970).
                                      7

-------
     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  mg/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
jug/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 ug/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 Dobo.s,  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-Bode,  1968).  Inhalation is  not  considered to be an impor-
tant route of  absorption for endosulfan  except in spray operators (U.S.  EPA,
1979).

-------
     8.  Distribution
         After  ingestion by  experimental animals,  sndosulfan 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  Oobos,  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).
     C.  Metabolism
         Endosulfan sulfate  is the metabolite most commonly present  in  tis-
sues, feces,  and  milk  of  mammals  after  administration of endosulfan  (Whit-
acre, 1970;  Oemma,  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,  andosulfan hy-
droxyether,  and endosulfan ether (Knowles, 1974; Menzie, 1974).  These meta-
bolites have also been found  in microorganisms and plants (U.S. EPA, 1979).

-------
     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 (GorbachT  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).
     B.  Mutagenicity
         Data from  assays with Salmonella typhimurium (with and without mi-
crosomal activation)  (Dorough, et al. 1978), Sacchaxomyces. cerevisiae, Esch-
ericia coli, and  Serratia marcescens  (Fahrig,  1974) indicate that endosulfan
is not mutagenic.

-------
     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 (Ounachie  and
Fletcher,  1969).  Alterations  in  the  gonads  of the  embryos  within  sprayed
hens' _eggs were  noted  and the progeny  of  hens and quails, Cotumix  Cotumix
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 LD50 for technical  endosulfan in  rats  is *— 22 to  &6
mg/kg and  6.9 to 7.5 mg/kg in mice  (Gupta,  1976).  Reagent grade  a- and  £-
endosulfan are less  toxic to rats (76  and 240 mg/kg,  respectively; Hoechst,

                                      .  I . I A_
                                   -  I I 7<>
                                      /,

-------
 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-
 cies 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 LC5g  values,  using  technical  grade  endosulfan,
 for five  species of  freshwater fish range  from  0.3  jjg/1  for  the  rainbow
 trout,  Salmo qairdneri,  (Macek,  et  al.  1969)  to  11.0  ;jg/l for  carp  finger-

                                   - I [ >/..{—
                                  ' j ) I >
                                      f

-------
lings, Cyprinus  caraio (Macek,  et  al. 1969;  Schoettger,  1970; Ludemann  acid-
Neumann,  1960;  Pickering  and Henderson,  1966).  Among  freshwater  inverte-
brates, Oaohnia  magna is  reported  to have  48-hour  LC5Q values ranging, from-
62 to 166 ug/r (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
Gvmonocorymbus  ternetzi.   The  96-hour LCep value was  1.6 ug/L- (Amminikutty—
and Rege, 1977,1978).
         Of  the  five saltwater fish species  tested,  the reported 48- or  96-
hour  LCeg values  ranged  from  0.09  (Schimmel,  et  al.  1977) to  0.6" ^g/1
(Butler,  1963,1964;  Korn  and Earnest,  1974; Schimmel,  et  al.  1977).    The
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 LC5Q  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).
     3.  Chronic Toxicity
         Macek,  et  al. (1976)  provided  the  only aquatic  chronic  study  in-
volving endosulfan.  No adverse  effects on fathead minnow, Pimephales orome-
las,  parents or offspring were  observed  at 0.20 jug/1.   Gvmonocorvmbus 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/macrophytes.   Growth  of  Chlorella  vuloaris   was  inhibited
 >2000ug/l (Knauf and Schulze, 1973).
                                      4
                                       ?*•//

-------
     0.  Residues
         Schimmel, et  al.  (1977)  studied the uptake, depuration, and metabo-
lism of endosulfan by  the striped mullet, Mugil  cephalus.   When the-eoncen--
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 B-endosulfan  and 70 pg/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 jug/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.
                                                          j
     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 mg/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.
                                     • ••it
                                 ^}) I  J

-------
         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 .
         The  ADI for  endosulfan established by  the Food  and Agricultural
Organization and the World Health Organization is 7.5 ug/kg (FAO, 1975).
     B.  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 ug/1 at any
time.  Saltwater criteria cannot be developed because  of insufficient data
(U.S. EPA, 1979).

-------
                                  ENDOSULFAN
                                  REFERENCES
ACGIH.   1977.   'Threshold limit  values "for chemical  substances and physical
agents in the workroom environment  with intended changes for 1977.  1977 TLV
Ariborne  Contaminants Committee,  American Conference  of  Government  Indus-
trial Hygienists, Cincinnati, Ohio.

Agarwal, O.K.,  et  al.  1978.  Effect  of  endosulfan  on  drug metabolizing en-
zymes and lipid peroxidation in rat.   Jour. Environ. Sci. Health  C13: 49.

Aleksandrowicz,  O.R.  1979.   Endosulfan  poisoning  and  chronic  brain  syn-
drome.  Arch. Toxicol.  43: 65.

Amminikutty, C.K.  and M.S.  Rege.   1977.  Effects  of acute  and  chronic ex-
posure to pesticides, Thioden-35 E.C.  and Aoallol "3" on the liver of widow
tetra (Gymonocorymbus ternetzi).  Boulenger-Indiana Jour. Exp. Biol.  15: 97.

Amminikutty, C.K. and M.S. Rege.  1978.   Acute and chronic  effect of Thioden
35 E.C.  and Aoallol "3"  on kidney, stomach and intestine of the widow- tetra
(Gymonocorymbus temetzi).  Boulenger-IndiaRa Jour.  Exp. Biol.  16: 202.

Berg,  H.    1976.    Farm   chemicals   handbook.   Meister   Publishing  Co.,
Willoughby, Ohio.

Boyd, E.M.  and  I. Dobos.   1969.  Protein deficiency  and tolerated oral doses
of endosulfan.  Arch. Int. Pharmacodyn.  178: 152.

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
studies.  A review  of Fish  and  Wildlife Service Investigations  during 1961
and 1962.  U.S. Oept. Inter. Fish Wildl. Circ.  167:  11.

Butler, P.A.  1964.   Pesticide-wildlife  studies,  1963.   A review  of Fish and
Wildlife Service Investigations during the calendar  year.   U.S. Oept.  Inter.
Fish Wildl. Circ.  199: 5.

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  eridosulfa'h  I,  endosulfan
II, and endosulfan sulfate in tobacco leaf.  Jour. Agric^ Food Chem.  25: 32.

Comeliussen, 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  i4C-endo-
sulfan  in the mouse.   Jour. Econ.  Entomol.   59:  546.

Oemeter,  3.  and A.  Heyndrickx.   1978.  Two  lethal endosulfan  poisonings  in
man.  Jour. Anal. Toxicol.  2: 68.

Oemeter,  J.,  et al.   1977.   Toxicological analysis  in a case  of endosulfan
suicide.  Bull. Environ.  Contain. Toxicol.   18:  110.

Ocmanski,  J.J., et  al.  1973.   Insecticide  residues on  1971  U.S.  tobacco
products.  Tobacco Sci.   17: 80.

Oomanski,  J.J., et  al.  1974.   Insecticide  residues on  1973  U.S.  tobacco
products.  Tobacco Sci.   13: 111.

Oorough,  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.   Comeliussen.   1972.   Dietary intake  of  pesticide
chemicals  in. the  United States  (III),  Jutfe 1968 to April  1970.   Pestic.
Monit.  Jour.  5: 331.

Ounachie, 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. Qccup. Med.  9: 36..

Estesen,  B.J.,  et  al.   1979.   Oislodgable  insecticide residues on  cotton
foliage: Permethrin, Curocron, Fenvalarate, Sulprotos, Oecis and  Endosulfan-
Bull. Environ. Contain. Toxicol.  22: 245.

Fahrig, R.   1974.   comparative mutagenicity studies  with  pesticides.  Int.
Agency Res. Cancer Sci. Publ.  10: 161.

FAQ.  1975.  Pesticide  residues in food: report of the 1974 Joint Meeting  of
the FAQ 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: Maie"r-8ode,'' 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:  Nati.
Res. Council, Canada, 1975.

Gorbach, S.G., et al.   1968.  Metabolism of endosulfan in milk  sheep.   Jour.
Agric. Food Chem.  16: 950.

-------
Gupta,  P.K.   1976.   Endosulfan-induced  neurotoxicity  in  rats  and mice.
Bull. Environ. Contain. 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,
Virginia.  In: ACGIH, 1971.

Hoechst.   1966.   Unpublished  report of  Farbwerke Hoechst  A.G., Frankfurt,
West Germany.  In: Maier-Bode, 1968.

Hoechst.   1967.   Oral  1050 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  C^-markierten Thiodan.
Unpublished.  In: Maier-8ode, 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.  Bederka, 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,  D.  and H.  Neumann.   1960.   Versuche   uber   die  akute  toxische
Wirkung  neuzeitlicher Kontaktinsektizide  auf  einsommerige Karfen  (Cyprinum
carpio L.)  Z. Angew. Zool.   47: 11.

-------
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.

Macsk, K.J.,  et 'al.   1976.   Toxicity of  four  pesticides to water  fleas and
fathead minnows.  EPA-600/3-76-G99.  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-
organisms.  Appl. Environ. Microbiol.  31: 853.

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-
olites by a mixed" culture of  soil microorganisms.  Bull~ Environ. Contam..
Toxicol.  23: 13.

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. Sac. Test. Mat.

Schoettger,  R.A.  1970.   Fish-pesticide  research  laboratory,  progress  in
sport  fishery  research.  U.S.  Dept.   Inter.  Bur.  sport  Fish Wildl. Resour.
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,  O.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.

-------
                                       No. 99
               Endrin
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980
           	,-i ./ r>~
             11  ) 7 -*

-------
                          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.

-------
                           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 LC^Q value of 0.73 ug/1,  than



freshwater fish with an arithmetic mean LC^Q value  of



4.42 ug/1.  Invertebrate species tend to be more  resistant



than fish with arithmetic mean LC^Q values of 3.80  and



58.91 ug/1 for marine and freshwater invertebrates,  respec-



tively.


-------
                           ENDRIN



I.   INTRODUCTION



     Endrin (molecular weight 374) is a broad  spectrum  insec-



ticide of- the group of polycyclic chlorinated  cyclodiene  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 ingred'ient.  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 400,000 ..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 ug/1 decreased from ten percent in 1964-
                           99-f

-------
1965 to zero Ln 1966-1967  (Schafer,  et  al.,  1969)..  The  high-


est concentration of endrin  in drinking water  in New Orleans,


Louisiana measured by the U.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 ug/kg 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/ra3 in


1971 to a maximum level of 0.5 ug/m3 in 1975 (U.S.  EPA,


1979).


          Tobacco products are contaminated  with endrin  cesir-


dues.  Average endrin residues for  various types of  tobacco


products have been reported  in the  range of'0.05 ug/g to 0.2


ug/<3 (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

-------
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 tox ic  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-tMendel



rats, endrin was neither tumorigenic nor carcinogenic  (Deich-



mann, et al., 1970; Deichmann and MacDonald, 1971;  Deichmann,



1972).  A recent MCI bioassay concluded that endrin was  not



carcinogenic for Qsborne-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 mgAg) administered intratesticularly



caused chromosomal aberrations in germinal tissues of  rats,



including stickiness, bizarre configurations, and abnormal



disjunction (Dikshith and Datta, 1972, 19731) .



     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 LD^g



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 retardation (Ottolenghi, et al.,



1974).



     E-   Chronic Toxicity



          Mammals 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, 1968).  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-



ling of the liver, and slight enlargement, discoloration or



congestion of the kidneys (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  (Kevin, 1968).
     P.   Other Relevant Information
          Endrin is more toxic, in both acute and chronic
studies, than other cyclediene 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 LD5Q values, sug-
gestive of antagonism.  Endrin given in equitoxic doses with
aldrin (a closely related compound) or chlordarie gave higher
than expected LD50 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.  LCgQ values for static
bioassays ranged from 0.046 ug/1 £or carp fry (Cyprinus
carpio) fry to 140.00 ug/1 for adult carp (lyatomi, et  al.,

                              y
                            Co-//)

-------
1958).  Excluding the results of age factor differences  for


this species, adjusted static LCjQ 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  LC5Q 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, LCgQ 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 LC50 value of  0.037


ug/1, while the blue crab (Callinectes sapidus) was  the most


resistant, with an LC50 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 flagf ish.. (Jordanella


floridae) Hermanutz, 1978), respectively, in life cycle


toxicity tests.  No freshwater  invertebrate species  have been
                                                           •

chronically examined.  The marine fish, the sheepshead minnow


(Cyprinodon variegatus) has provided a chronic  value of 0.19


ug/1 from embryolarval tests (Hansen, et al., 1977).   The

-------
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 appeared.  more_ sensi-


tive with effective concentration ranging  from  0.2 ug/1  for


the algae, Agmenellum quadruplicaturn (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, Gambusia-.affinjls  (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 NOAEL of  0.1 mg/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/m3 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 addition,  d iseharge.. 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. Contam. 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.  Tumorigenfcity of aldrin,
dieldrin, and endrin in the albino rat.  Indt 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.

-------
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 estuarirve  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. Contain. 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: TZT~.

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  Ii: 69-7-.

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.  Toxicity to  fathead
minnows of endrin in food and water.  Arch. Environ. Contain.
Toxicol. 7: 409.

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. Appl. Pharmacol.
10: 586.

Martin, H.  1971.  Pesticide manual, 2nd ed.  Brit.  Crop
Prot. Council.

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. . Carcinogenicity of endrin.  Sci.  Tot.
Environ. 12: 101.

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.

-------
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
                100"/

-------
                          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 (CAG) has evaluated
epichlorohydrin and has found sufficient evidence to in-
dicate that this compound is carcinogenic.

-------
                          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.
                                100-V

-------
 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  (OLOCHOLCl;   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


-------
 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
 respiratory and gastointestinal  tracts,  and by  percutaneous absorption (U.S.
EPA,   1979).  Blood  samples  obtained  from rats  after  6  hours  exposure"  to
 (1Z;C)epichlorohydrin at  doses of 1 and 100 ppm  in air  revealed  0.46+0.19
 and 27.8+4.7 ;jg epichlorohydrin  per ml  of plasma, respectively.   The rates


-------
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
(1ZlC)-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 of  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  14C02  in expired air  sug-
gests a rapid and extensive metabolism of (^C)-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.
     0.  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

-------
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 Ouuren, 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  turbinatss 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.

-------
     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
        i
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/m3)  (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.
     D.  Other Reproductive Effects
         The antifertility 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.


-------
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-
          i
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  LDjg values  in  experimental animals  have  ranged frcm
155 to 238 mg/kg for the mouse and from  90 to 260 mg/kg in the rat.   Inhala-
tion LC5Q  values range from  360  to  635 ppm  in rats,  to- 800  ppm  in mice
(SRC, 1979).   Single subcutaneous injections of epich-lorohydrin in  rats  at
doses  of  150  or 180 mg/kg have  resulted  in  severe  injury to  the kidney
                                                                         •
(Rotara and Pallade,  1966).
                                     -  ) /....>•» / ^
                                    ^^^^7

-------
         Accidental human  exposures  have been .reviewed  (NIOSH,  1976; Santo-
donato,  et  al.  1979).  Direct  exposure to epichlorohydrin  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/m3  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/m-5).
                                 I oo-

-------
         l-CHLORO-2,3-EPOXYPROPANE(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. Pert.   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 workers 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 al.  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 alpha- and epichlorohydrin  in  the  rat.  Nature
24: 83.

Lawrence, W.H., et al.   1972.   Toxicity profile  of epichloro-
hydrin.  Jour. Pharm. 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  epickloroh-ydrin.  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.
                             ^T-U^^J^^^—
                              }) / &

-------
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
histopathological features in acute epichlorohydrin
(l-chloro-2,3-epoxypropane) toxicity.  Mortal Norm. Patol.
11: 155.

SantodonatOj 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 (-^c)-epichlorohydrin in male and female rats.     *
Res. Comm. Chem. Pathol. Pharmacol.  20: 275.
                            /06-/J

-------
Weil,  C.S.  1964.  Experimental carcinogenicity and acute
toxicity of representative epoxides.  Amer.  Ind. Hyg. Jour.
24: 305.
                            too-ff

-------
                                      No. 101
         Ethyl Methacrylate

  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.

-------
                              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.

-------
                              ETHYL METHACRVLATE
I.   INTRODUCTION
     Ethyl  methacrylate  (molecular  weight  114.15)  is the  ethyl  ester of
methacrylic '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

-------
     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.   Carcinogenicity 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 mg/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  LD5g 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
irregular, 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, Qeichmann  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 (Qeichmann, 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).
                                         f
                                  -V7 $$-.
                                  ltt-6

-------
          The  findings  of Deichmann  (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 LO^Q  values were  found for  only rab-
bit and  rat;  these were  established  by Deichmanrr 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 LD5Q  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.
                                    11 r>7-
                                 * ff u i
                                        -7

-------
                              ETHYL METHACRYLATE
                                  References
Austian,  J.   1975.   Structure-toxicity  relationships  of  acrylic monomers.
Environ. Health Perspect.  19: 141.
Oeichmann, w.   1941.  Toxicity  of methyl, ethyl,  and  n-outyl 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.

-------
                                      No. 102
           Ferric Cyanide

  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.

-------
                                 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,   [Fe(CN)6]4-,  and  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]}  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,
'^[^(CN)^]},   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 Qthmer, 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

-------
   available  literature.   Prussian  blue,  potassium  ferric  hexacyanoferrata
   (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.
        8.   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.


-------
VI.  EXISTING GUIDELINES AND STANDARDS


     Pertinent data could not be located  in the available literature.
                                   i >n ~> -
                                 "lit'-'

-------
                                  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-Othmer  Encyclopedia of  Chemical
Technology,  II edition,  Vol.  12.   Intersciencs 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.
                                           ,
                                  /OSL.-6

-------
                                      No. 103
         Fluoranthene
  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.
                          — ) / o s—
                           ! I I *

-------
                         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 mutagenicr  teratogenic or ..


adverse reproductive effects.


     Daphnia magna appears to have low sensitivity to fluoran—


thene with  a  reported  48-hour  EC5Q of  325,000  ug/1.   The '•
                                                               »

bluegill, however,  is  considerably  more  sensitive  with an


observed  9-6-hour   LC5Q  value  of 3,980.    The  96-hour  LC5Q


for  mysid  shrimp  is 16  ug/1,. and  a  reported  chronic value


is  16  ;ug/l.   Observed  96-hour   EC^Q values  based on  cell


numbers for  fresh and saltwater algae are over 45,000 ug/1.
                         ^^^^^_^^^^^^^^
                         -Hi) -

-------
                         FLDORANTHENE
I.   INTRODUCTION
     This  profile  is  based  on  the  Ambient  Water Quality
Criteria Document for Fluoranthene  (U.S. EPA, 1979).
     Pluoranthene  (1,2-benzacenapthene,  M.W.  202)  is a  poly-
nuclear  aromatic  hydrocarbon  of  molecular  formula C]_gH^Q.
Its physical  properties include:  melting point, 111°C;  boil-
ing  point,  375°C;  water  solubility,  265 pg/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

-------
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

               Water          0.017 ug/day

               Food           1.6 - 16 ug/day

               Air            0.040 - 0.080 ug/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. PHARMACOKINETICS

     A.   Absorption

          Based  on  animal  toxici.ty  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).

-------
     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  available  literature.   Experiments  with  PAH compounds
indicate  excretion  through the hepatobiliary  system and  the -1
feces; urinary excretion  varies with  the degree of formation
of conjugated metabolites  (U.S. EPA,  1979).
                                                               i
IV.  EFFECTS
     A.   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  Duuran

-------
and Goldschmidt, 1976).  The combination of  fluoranthene


and  benzo(a)pyrene produced  an  increased  number  of papil-


lomas  and  carcinomas,  with  shortened  latency  period   (Van


Duuren and Goldschmidt, 1976).


     B.   Mutagenicity


          Fluoranthene  failed  to  show  mutagenic   activity


in the Ames Salmonella assay in the  presence  of  enzyme activa-


tion mix  (Tokiwa, et al.  1977; La Voie, et  al.   1979).


     C.   Teratogenicity


          Pertinent  information  could  not be  located   in


the  available  literature.   Certain PAH  compounds  (7,12-di-


methylbenz(a)anthracene  and  derivatives)   have  been  shown


to produce  teratogenic effects  in  the rat  (Currie,  et al.


1970; Bird, et al.  1970).


     D.   Other Reproductive Effects


          Pertinent  information  could  not be  located   in


the available literature.


     E.   Chronic Toxicity


          Pertinent  information  could  not be  located   in


the available literature.


V.   AQUATIC TOXICITY


     A.   Acute Toxicity


          The  96-hour  LC5Q  value  for the. bluegill, Lepomis


macrochiruss is  reported  to be 3,980 ^ug/1 '(U.S.  EPA, 1978).

The  sheepshead  minnow?  Cyprinodon  variegatus^  was exposed
                                                           •

to concentrations  of  fluoranthene  as high  as  560,000  ug/1


with  no  observed LC5Q  value  (U.S.  EPA,  1978)  .   The fresh-

-------
water  invertebrate   Daphnia  magna  appears   to  have  a  low
sensitivity  to  fluoranthene  with  a  reported  48-hour  EC-g
value of 325,000  ug/1.   The 96-hour LC5Q value for  the salt-
water raysi'd shrimp, Mysidopsis bahia } is  16 ug/1.
     B.   Chronic. Toxicity
          There  are  no  chronic  toxicity data  presented  on
exposure of  fluoranthene to  freshwater  species.   A  chronic
value foe the mysid shrimp  is  16 pg/L.
     C.   Plant Effects
          The  freshwater   alga,  Selenastrum  capricornutum,
when  exposed  to  fluoranthene resulted  in  a  96-hour  ECeQ
value for cell number of 54,400 jag/1.   On the  same criterion,
the  96-hour   ECSO  value  for  the  marine  alga,  Skeletonema
costatum, is 45,600 ug/1 (U.S. SPA, 1979).
     D.   Residues
                         »
          No  measured  steady-state  bioconcentration  factor
(BCF)  is  available  for  fluoranthene.    A  3CF of  3,100  can
be  estimated  using  the  octanol/water  partition coefficient
of 79,000.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          The World Health Organization (1970)  has established
a  recommended standard  of   0.2  jug/1  for all--2AH  compounds
in drinking water.
          Based on the no-effect level  determined in  a  single
                                                           »
animal  study  (Hoffman,  et  al.  1972),  the U.S.  EPA  (1979)
has  estimated a  draft  ambient water criterion of  200 ;ag/l
for  fluoranthene.    However,  the  lower  level  derived  for
                             A

-------
total PAH compounds is expected to have precedence for  fluor-
anthene.
     B.   Aquatic
         'For  fluoranthene,  the  draft criterion  to protect
freshwater  aquatic  life  is  250 pg/1  as  a  24-hour  average,
not  to  exceed  560  ug/1  at  any  time.   For  saltwater  life,
the  criterion  is  0.30  ug/1  as  a  24-hour  average, not to
exceed 0.69 ug/1 at any time.

-------
                        FLUOROANTHENE

                         REFERENCES

Barry, G., et al.  1935.  The production of cancer  by  pure
hydrocarbons-Part III.  Proc. Royal Soc., London.   117:  318.

3asu, O.K., et al.  1978.  Analysis of water samples for
polynuclear aromatic hydrocarbons.  U.S. Environ. Prot.
Agency, P.O. Ca-8-2275B, Exposure Evaluation Branch, HERL,
Cincinnati, Ohio.

Bird, C.C., et al.  1970.  Protection from the embryopathic
effects of 7-hydroxymethyl-12-methylbenz(a)anthracene  by
2-methyl-I, 2-bis-{3 pyridyl)-l-propanone(metopirone ciba)
and£ -diethylaminoethyldiphenyl-n-propyl acetate  (SKR  525-A).
Br. Jour. Cancer^ 24: 348.

Borneff, J.  1977.  Fate of carcinogens in aquatic  environ-
ment.  Pre-publication copy received from author.

Currie, A.R., et al.  1970.  Embryopathic effects of 7,12-
dimethylbenz(a)anthracene and its hydroxymethyl derivatives
in the Sprague-Dawley rat.  Nature  226: 911.

Hoffmann, D., and E.L. Wynder.  1963.  Studies on gasoline
engine exhaust.  Jour. Air Pollut. Control Assoc.   13: 322.

Hoffmann, D., et al.  1972.  Fluoranthenes: Quantitative de-
termination in cigarette smoke, formation by pyrolysis,  and
tumor initiating activity.  Jour. Natl. Cancer Inst.   49:
1165.

La Voie, E., et al.  1979.  A comparison of the mutagenicity,
tumor initiating activity and complete carcinogenicity of
polynuclear aromatic hydrocarbons,  ^n:Polynuclear Aromatic
Hydrocarbons.  P.W. Jones and C. Leber (eds.).  Ann Arbor
Science Publishers, Inc.

Smythe, H.F., et al.  1962.  Range-finding toxicity data:
List VI. Am. Ind. Hyg. Assoc. Jour.  23: 95.

Tokiwa, H., et al.  1977.  Detection of mutagenic activity in
particullate air pollutants..  Mutat. Res.   48: 237.

U.S. EPA.  1978.  In-depth studies on health '&nd environmen-
tal impacts of selected water pollutants.  -U.S. Environ.
Prot. Agency.  Contract No. 68-01-4646.

U.S. EPA.  1979.  Fluoranthene: Ambient Water Quality Cri7
teria. (Draft).

-------
Vainio, H., et al.  1976.  The fate of  intratracheally  in-
stalled benzo(a)pyrene in the isolated  perfused  rat  lung  of
both control and 20-methylcholanthrene  pretreated  rats.   Res,
Commun. Chem. Path. Pharmacol.  13: 259.

Van Duuren, B.L., and B.M. Goldschmidt.  1976.   Cocarcino-
genic and tumor-promoting agents  in tobacco carcinogenesis.
Jour. Natl. Cancer Inst.  51: 1237.

World Health Organization.  1970.  European standards for
drinking water, 2nd ed., Revised^ Geneva.

-------
                                 No. 104
           Formaldehyde

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

          APRIL 30, 1980
        soy-/

-------
                          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.

-------
                           FORMALDEHYDE




SUMMARY


     The ma.jor source of  formaldehyde  contamination in the envi-


ronment is combustion processes,  especially  automobile emissions.


Formaldehyde is a recognized  component of  photochemical smog.   A


recent source of concern  is the release of formaldehyde from


resins used in home construction  and insulation.


     Bioaccumulation of formaldehyde is considered  unlikely due


to its high chemical reactivity.  Formaldehyde  rapidly degrades


in the atmosphere by photochemical processes? however,  it can


also be formed by the photochemical oxidation of  atmospheric


hydrocarbons.


     Formaldehyde is rapidly  absorbed  via  the lungs or gut? fol-


lowing- absorption into the blood, however, formaldehyde dis-


appears rapidly due to reactions  with  tissue components and


because of its metabolism.


     The U.S. EPA1s Carcinogen Assessment  Group recently con-


cluded that "there is substantial evidence that formaldehyde is


likely to be a human carcinogen." This finding was based on pre-


liminary results from a chronic inhalation study  of formaldehyde


which reported carcinomas of  the  nasal cavity in  3  rats after  16


months of exposure.  This type of tumor is extremely rare is


unexposed rats of the strain  used in the study.


     There is an extensive data base showing that formaldehyde is


rautagenic in microorganisms,  plants, insects, cultured mammalian


cells, and mice.  It was  negative in a teratogenicity assay.


Formaldehyde is known to  be a mucous membrane irritant in humans?
                              -' ^ * &
                              / & * ^

-------
it is also known to be an allergen  in  sensitive  individuals.



I.   INTRODUCTION

     This profile  is based on  a U.S. EPA  report  entitled  "Inves-

tigation of Selected Potential Environmental  Contaminants:

Formaldehyde"  (1976) and other selected references.

     Formaldehyde  (HCHO; molecular  weight 30.03)  is  a  colorless
        •
gas having a pungent odor and  an  irritating effect on  mucous  mem-

branes.  It has the following  physical/chemical  properties  (U.S.

EPA, 1976; Windholz, 1976):

          Boiling  Point:          -19.2°C

          Melting  Point:          -92°C

          Density  in Air:         1.067

          Solubility:             soluble in  water and many

                                  organic solvents.

     A  review  of the production range  (includes  importation)

statistics for formaldehyde  (CAS  No. 50-00-0) which  is listed in

the initial TSCA Inventory (1979a)  has shown  that between 2 bil-

lion and 7 billion pounds of this chemical were  produced/imported

in 1977 JL/

     Formaldehyde  is usually sold as an aqueous  solution  contain-

ing 37% formaldehyde by weight; it  is  also available as a linear
—/ 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
   Regulations (40  CFR  710).

-------
polymer known as parafonnaldehyde and a cyclic  trimer  known  as


trioxane.  Formaldehyde is used in the production  of urea-formal-


dehyde resins, phenol-formaldehyde resins, polyacetal  resins,


various other resins, and as an intermediate in the production  of


a variety of chemicals.  Manufacture of resins  consumes  over 50%


of annual domestic formaldehyde production.  Urea-formaldehyde


and phenol-formaldehyde resins are used as adhesives for particle


board and plywood, and in making foam insulation.  Polyacetal


resins are used to mold a large variety of plastic parts for


automobiles, appliances, hardware, and so on (U.S. EPA,  1976).




II.  EXPOSURE


     HIOSH (1976) estimates that 1,750,000 workers are poten-


tially exposed to formaldehyde in the workplace.


     A.   Environmental Fate

     Formaldehyde and nascent forms of formaldehyde can  undergo


several types of reactions in the environment including  depoly-


merization, oxidation-reduction, and reactions  with other


atmospheric and aquatic pollutants.  Formaldehyde  can  react


photochemically in the atmosphere to form H and HCO radicals;

once formed, these radicals can undergo a wide  variety of


atmospheric reactions (U.S. EPA, 1976).  Hyj3rogen  peroxide can


also be formed during photodecomposition of formaldehyde (Purcell


and Cohen, 1967; Bufalini jt_ al., 1972).  The atmospheric half-
                                                             »
life of formaldehyde is less than one hour in sunlight (Bufalini


et al., 1972).

-------
     Even though formaldehyde is often used as a bacteriocide,



there are some microorganisms which can degrade the chemical



(U.S. EPA, 1976).  Kamata (1966) studied biological degradation



of formaldehyde in lake water.  Under aerobic conditions in the



laboratory, known quantities of formaldehyde were decomposed  in



about 30 hours at 20"C; anaerobic decomposition took about 48



hours.  No decomposition was noted in sterilized lake water.



     Paraformaldehyde slowly hydrolyzes and depolymerizes as  it



dissolves in water to yield aqueous formaldehyde.  Trioxane has



more chemical and thermal stability? it is inert under aqueous



neutral or alkaline conditions.  In dilute acid solutions, it



slowly depolymerizes (U.S. EPA, 1976).



     B.   Bioconcentration



     Formaldehyde is a natural metabolic product and does not



bioconcentrate (U.S. EPA, 1976).



     C.   Environmental Occurrence



     Environmental contamination from formaldehyde manufacture



and industrial use is small and localized compared with other



sources.  Combustion and incineration processes comprise the



major sources of formaldehyde emissions.  Stationary sources of



formaldehyde emissions include power plants, manufacturing facil-



ities, home consumption of fuels, incinerators, and petroleum



refineries.  Mobile sources of formaldehyde emissions include



automobiles, diesels, and aircraft.  The automobile, however,, is



the largest source of formaldehyde pollution.  It is estimated



that over 800 million pounds of formaldehyde were released to the



air in the United States in 1975; of this amount, over 600
                              -ifTtf •—
                              I Wl

-------
million pounds are estimated to result  from  the  use of automo-


biles.  In addition to formaldehyde, automobile  exhaust also
             ,                                        .-•-*•
contains large quantities of hydrocarbons.   Through photochemical

processes in the atmosphere, these hydrocarbons  are oxidized to

formaldehyde, among other things, further  adding to the environ-

mental load of formaldehyde (U.S. EPA,  1976).

     Urea-formaldehyde foam insulation  has been  implicated as a


source of formaldehyde fumes in homes insulated  with this

material.  Wood laminates (plywood, chip board,'  and particle

board) commonly used in the construction of  mobile  homes are also

known to release formaldehyde vapors into  the home  atmosphere

(U.S. EPA, 1979b).




III. PHARMACOKINETICS

     A.   Absorption

     Under normal conditions formaldehyde  can enter the "body

through dermal and occular contact, inhalation and  ingestion.   On

dermal contact, formaldehyde reacts with proteins of the skin

resulting in crosslinking and precipitation  of the  proteins.

Inhalation of formaldehyde vapors produces irritation and

inflammation of the bronchi and lungs;  once  in the  lungs,

formaldehyde can be absorbed into the bloodi  Ingestion of

formaldehyde is followed immediately by inflammation of the

mucosa of the mouth, throat, and gastrointestinal tract (U.S.
                                                              •
EPA, 1976).  Absorption appears to occur in  the  intestines

(Malorny _et_ _al_., 1965).

-------
     B.   Distribution


     Following absorption into the blood  stream,  formaldehyde


disappears rapidly due to condensation reactions  with  tissue


components and oxidation to formic acid  (U.S.  EPA,  1976).


     C.   Metabolism


     The main metabolic pathway for  formaldehyde  appears  to


involve initial oxidation to formic  acid,  followed  by  further


oxidation to CO2 and I^O.  In rats fed radiolabeled formaldehyde,


40% of the radiolabel was recovered  as respiratory  COj  (Buss et


al., 1964).  Liver and red blood cells appear  to  be the major


sites for the oxidation of formaldehyde to  formic acid  (U.S.  EPA,


1976; Malorny et_ _al_., 1965).


     D.   Excretion


     Some of the formic acid metabolite is  excreted in  the  urine


as the sodium salt; most, however, is oxidized to CO- and


eliminated via the lungs (U.S. EPA,  1976).




IV.  HEALTH EFFECTS


     A.   Carcinogenicity


     Watanabe et^ al. (1954) observed sarcomas  at  the site of


injection in 4 of 10 rats given weekly subcutaneous  injections of


formaldehyde over 15 months (total dose 260 mg per  rat).  Tumors


of the liver and omentum were reported in two "'other  rats.   The


authors do not mention any controls.
                                                             »

     Groups of mice were exposed to  formaldehyde  by  inhalation at


41 ppm and 81 ppm for one hour a day thrice weekly  for  35 weeks.


After the initial 35-week exposure to 41 ppm, the mice  were

-------
exposed for an additional 29 weeks at  122 ppm.   No  tumors  or


metaplasias, were found, although numerous changes were  observed


in respiratory tissues  (Horton et_ ^1^.,  1963).   The  study is


considered flawed for several reasons:  mice were not observed


for a lifetime; survival was poor; many tissues were not examined


histologically (U.S. EPA, 1976; U.S. EPA, 1979b).


     In a lifetime inhalation study of the  combination  of  hydro-


chloric acid (10.6 ppm) and formaldehyde  (14.6  ppm) vapors in


rats, 25/100 animals developed squamous cell carcinomas of the


nasal cavity (Nelson, 1979).  Nelson also reported  that bis-


chloromethyl ether, a known carcinogen, was detected in the


exposure atmosphere; however, concentrations were not reported.


     In a report of interim results (after  16 months of a  2-year


study) from a chronic inhalation study of formaldehyde  in  rats


and mice, the Chemical  industry Institute of Toxicology (1979)


reported that squamous  cell carcinomas  of the nasal cavity were


observed in three male  rats exposed to IS ppm of formaldehyde


(highest dose tested).  This type of tumor  is extremely rare in


unexposed rat of the strain used in this  study.


     Following receipt  of the CUT (1979) study, the U.S.  EPA's


Carcinogen Assessment Group (1979c) concluded that  "there  is


substantial evidence that formaldehyde  is likely to be  a human


carcinogen."  The unit  risk calculation (the lifetime cancer risk


associated with continuous exposure to 1 ug/m   of formaldehyde)


based on the preliminary results from  CUT  is estimated to be 3.4

   — 5
xJ-°  .  This estimate may change when  the final results of "the

CUT study become available.

-------
     B.   Mutagenicity


     There is an extensive data base showing that  formaldehyde  is


mutagenic in several species including mice, Drosophila, plants,


Saccharomyces cerevisiae, Neurospora Crassa, and several species


of bacteria.  Formaldehyde also produced unscheduled DNA syn-


thesis in a human cell line.  These and other early reports  of


mutagenic activity have been reviewed by Auerbach  et al. (1977)


and U.S. EPA (1976).


     Reports in the recent literature have  supported the finding


that formaldehyde is a mutagen:  Magana-Schwencke £t_ ^1_. (1978)


in a study with S. cerevisiae; Wilkens and  MacLeod  (1976)  in


E. coli; Martin ^t^ _al_. (1978) in an unscheduled DNA synthesis


test in human HeLa cells? Obe and Beek (1979) in sister chromatid


exchange assays in a Chinese hamster ovary  (CHO) cell line and  in


cultured human lymphocytes.


     C.   Teratogenicity

     Formaldehyde has been found negative in teratogenicity

assays in beagle dogs (Hurni and Ohden, 1973) and  rats  (Gofmekler


and Bonashevskaya, 1969).


     D.   Other Reproductive Effects


     No changes were observed in the testes of male rats exposed


to air concentrations of 1 mg/m  of formaldehyde.for 10 days


(Gofmekler and Bonashevskaya, 1969).

     E.   Other Chronic Toxicity
                                                             •
     Groups of rats, guinea pigs, rabbits, monkeys, and dogs were

continuously exposed to approximately 4.6 mg/m3 of formaldehyde


for 90 days.  Hematologic values were normal, however, some

-------
interstitial inflammation occurred  in  the  lungs  of all species



(Coon _et_ ai^., 1970).



     P.   Other Relevant Information



     Formaldehyde vapor is quite irritating  and  is a  major cause



of the mucous membrane irritation experienced  by people exposed



to smog.  Dermatitis from exposure  to  formaldehyde is a common



problem in workers and consumers who contact the chemical



regularly.  Formaldehyde is also known to  be an .allergen in



sensitive individuals (U.S. EPA, 1976).







V.   AQUATIC EFFECTS



     The use of formalin (aqueous formaldehyde)  as a  chemothera-



peutant for control of fungus on fish  eggs and ectoparasites  on



fish is a widely accepted and successful technique.   However,



unless certain criteria are met formalin may cause acute toxic



effects in fish (U.S. EPA, 1976).   The acute toxicity of formalin



to fish has been reviewed by the U.S.  Department of Interior



(1973).  Analysis of toxicity levels indicates that a wide range



of tolerances exist for different species; striped bass appear to



be the most sensitive with an LCg0  of  15 to  35 ppm.



     The LCjQ of formaldehyde for Daphnia  magna  is reported to



range between 100 to 1000 ppm (Dowden  and  Bennett,  1965).   The



48-hour median threshold limit  (TLm) for Daphnia"was  about 2  ppm



(McKee and Wolf, 1971).



     No effects were observed in crayfish  (Procambarus blandingi)



exposed to 100 ul/1 of formalin (concentration unspecified) for



12 to 72 hours (Helm, 1964).

-------
VI.  EXISTING GUIDELINES



     The OSHA standard for formaldehyde in workplace air is a



time weighted average (TWA) of 3 ppm with a ceiling concentration



of 5 ppm (39 CFR 23540).  The NIOSH recommended standard is a



ceiling concentration of 1.2 mg/m  (about 0.8 ppm) (NIOSH, 1976).



The ACGIH (1977) recommends a ceiling value of 2 ppm (3 mg/m3).

-------
                            REFERENCES

American Conference of Governmental  Industrial Hygenists (ACGIH).
1977.  TLVs:  Threshold  limit values for  chemical substances in
workroom air adopted.  Cinninnati, Ohio.

Auerbach, C./ M. Moutschen-Dahen,  and J.  Moutschen.   1977.
Genetic and cytogenetical effects  of formaldehyde and relative
compound.  Mutat. Res. 39:317-361  (as cited in U.S.  EPA, 1979c).

Bufalini, J.J., Gay, Jr., B.W. and Brubaker,  K.L.  1972.  Hydro-
gen Peroxide Formation from Formaldehyde  Photoxidation and Its
Presence in Urban Atmospheres.  Environ.  Sci.  Technol. ^(9), 816
(as cited in U-.S. EPA 1976).

Buss, J., Kuschinsky, K., Kewitz,  H.  and  Koransky,  W.  1964.
Enterale Resorption von  Formaldehyde.   Arch.  Exp. Path. Pharmak.,
247, 380 (as cited in U.S. EPA, 1976).

Chemical Industry Institute of Toxicology.   Statement Concerning
Research Findings, October, 1979.

Coon, R.S., Jones, R.A., Jenkins,  L.J.  and  Siegel,  J.  1970.
Animal Inhalation Studies on Ammonia, Ethylene Glycol, Formalde-
hyde, Dimethylamine, and Ethanol.  Tox. Appl.  Pharmacol, 16, 646
(as cited in U.S. EPA, 1976).

Dowden, B.F. and Bennett, H.J.  1965.   Toxicity of Selected Chem-
icals to Certain Animals.  J. Water  Pollut.  Cont. Fed., 37(9),
1308 (as cited in U.S. EPA, 1976).

Gofmekler, V.A. and Bonashevskaya, T.I.   1969.   Experimental
Studies of Teratogenic Properties  of Formaldehyde,  Based on
Pathological Investigations.  Gig. Sanit.,  _3_4J5), 266 (as cited
in U.S. EPA, 1976).

Helms, D.R.  1964.  The  Use of Formalin to  Control Tadpoles in
Hatchery Ponds.  M.S. Thesis, Southern  Illinois University,
Carbondale, 111. (as cited in U.S. EPA, 1976).

Horton, A.W., Tye, R. and Stemmer, K.L.   1963.   Experimental
Carcinogenesis of the Lung.  Inhalation of'Gaseous Formaldehyde
on an Aerosol Tar by C3H Mice.  J. Nat. Cancer Inst., .3_p_(l), 30
(as cited in U.S. EPA, 1976 and U.S.  EPA, 1979c).

Hurni, H. and Ohder, H.  1973.  Reproduction Study with
Formaldehyde and Hexamethylenetetramine in  Beagle Dogs.  Food
Cosmet. Toxicol., _11_(3), 459 (as cited  in U.S.  EPA,  1976).

Kamata, E.  1966.  Aldehyde in Lake  and Sea Water.   Bull. Chem.
Soc. Japan, _3JL(6)' I227  
-------
Induction of single strand breaks in DNA and their  repair.
Mutat. Res. 50; 181-193 (as cited by U.S. EPA in 1979a).

Malorny, G./ Rietbrock, N. and Schneider, M.  1965.  Die Oxyda-
tion des Forraaldeshyds zu Ameiscansaure im Blat. ein Beitrag  Zum
Stoffwechsel des Formaldehyds.  Arch. Exp. Path. Pharmak.,  250>
419 (as cited in U.S. EPA, 1976).

Martin, C.N., A.C. McDermid, and R.A. Garner.   1978.  Testing of
known carcinogens and non-carcinogens for their ability to  induce
unscheduled DNA synthesis in HeLa cells.  Cancer Res. 38; 2621-
2627 (as cited on U.S. EPA, 1979c).

McKee, J.E. and Wolfe, H.W.  1971.  Water Quality Criteria, 2nd
Ed., California State Water Resources Control Board, Sacramento,
Publication 3-8 (as cited in U.S. EPA, 1976)

National Institute of Occupational Safety and Health (NIOSH).
1976.  Criteria for a recommend standard.  Occupational Exposure
to Formaldehyde.  NIOSH Publication No. 77-126.

Nelson, N. (New York University) Oct. 19, 1979.  Letter to
Federal Agencies.  A status report on formaldehyde  and HC1
inhalation study in rats.

Obe, G. and B. Seek.  1979.  Mutagenic Activity of  Aldehydes.
Drug Alcohol Depend., 4(1-2), 91-4 (abstract).

Purcell, T.C. and Cohen, I.R.  1967.  Photooxidation of Formal-
dehyde at Low Partial Pressure of Aldehyde.  Environ. Sci.
Technol., 1(10), 845 (as cited in U.S. EPA, 1976).

U.S. Department of the Interior.  1973.  Formalin as a Thera-
peutant in Fish Culture, Bureau of Sport Fisheries  and Wildlife,
PB-237 198 (as cited in U.S. EPA, 1976).

U.S. EPA.  1976.  Investigation of selected potential environ-
mental contaminants:  Formaldehyde.  EPA-560/2-76-009.

U.S. EPA. 1979a. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-Confi-
dential Initial TSCA Inventory.

U.S. EPA.  1979b.  Chemical Hazard Information Profile on
Formaldehyde.  Office of Pesticides and Toxics Substances.

U.S. EPA.  1979c.  The Carcinogen Assessment Group's Preliminary
Risk Assessment on Formaldehyde.  Type I - Air Programs.  Office
of Research and Development.

Watanabe, F., Matsunaga, T., Soejima, T. and Iwata, Y.  1954.
Study on the carcinogenicity of aldehyde, 1st report.  Experi-
mentally produced rat sarcomas by repeated injections of aqueous
solution of formaldehyde.  Gann, 45, 451.  (as cited in U.S.  EPA,
1976 and U.S. EPA, 1979c)

-------
Wilkins, R.J., and H.D. MacLeod.  1976.  Formaldehyde induced DNA
protein crosslinks in E. coli.  Mutat. Res.  36:11-16.

Windholz, M,, ed. 1976.  The Merck  Index,  9th  ed.,  Merck and
Company, Inc.

-------
                                 No. 105
          Formic Acid

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

         APRIL 30, 1980
        /OS"/

-------
                          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.

-------
                                 FORMIC ACID
                                   Summary

     There is  no information available on  the  possible  carcinogenic,  muta-
genic, teratogenic,  or adverse reproductive  effects of formic acid.
     Formic acid has  been  reported to produce  albuminuria  and hematuria  in
humans following chronic exposure.  Exposure to high  levels of the  compound
may  produce  circulatory  collapse, renal  failure,  and  secondary  ischemic
lesions in the liver and heart.
     Formic acid is toxic  to freshwater organisms  at  concentrations  ranging
from 120,000  to 2,500,000  ug/1.   Daphnia magna was  the most  sensitive fresh-
water species  tested.   Marine  crustaceans were  adversely affected by  expo-
sure to formic  acid  at concentrations from 80,000 to 90,000 ug/1.
                                     /f
                                /of-3

-------
                                  FORMIC ACID
I.   INTRODUCTION
     Formic acid (CAS registry number  64-18-6)  is a colorless, clear, fuming
liquid with a pungent.odor  (Hawley,  1571;  Windholz,  1576; Walker, 1566).  It
is  a naturally  formed product, produced by bees, wasps,  and ants (Casarett
and Ooull, 1575).  Formic  acid has widespread occurrence  in  a large variety
of  plants,  including pine  needles,  stinging nettles,  and foods  (Furia and
Bellanca, 1971;  Walker,  1966).  Industrially,  it is made by  heating carbon
monoxide with sodium  hydroxide under heat and pressure,  or  it may be formed
as  a coproduct  from  butane oxidation  (Walker,  1966).   It has  the following
physical and chemical constants (Windholz, 1976; Walker, 1966):
    Property
    Formula:
    Molecular Weight:
    Melting Point:
    Boiling Point:
    Density:
    Vapor Pressure:
    Solubility:

    Demand (1979):
Pure
90%
8535
 46.02
  8.4°C
100. 5°C
  1.220?°
       4
-4°C
1.202^
-12°C
1.154;
25
'25
      33.1 torr ® 20°C
      Miscible in water, alcohol,
      and ether; soluble  in
      acetone,benzene, and toluene
      67.5 million lias.   (CMR,  1579)


-------
Formic  acid  is marketed  industrially  in 85,  90,  and 98 percent aqueous solu-
tions.   It  is  also  available  at 99+  percent purity  on  a semicommercial
scale.   Formic acid is  used  primarily  as  a volatile acidulating  agent;  in
textile  dyeing'  and  finishing,  including carpet  printing; in chemical syn-
thesis  and Pharmaceuticals; and  in tanning  and leather treatment (CMR, 1579;
Walker,  1966).
II.  EXPOSURE
     A.   Water
          Formic  acid has  been  detected in xaw sewage,  in effluents  from
sewage treatment plants,  and  in  river water (Mueller, et  al.  1958).   It has
also been identified  in  effluents  from chemical plants and paper mills (U.S.
EPA, 1576).
     B.   Food
          A  large  variety of plants  contain  free formic  acid;  it has  been
detected in  pine needles,  stinging nettle, and  fruits  (Walker,  1966).   It
has  been identified  in  a  number  of essential  oils, including  petitgrain
lemon and bitter orange  (Furia and  Bellanca, 1571).   Formic  acid  is  also re-
ported to be a constitutent of strawberry aroma  (Furia  and  Bellanca,  1971).
In the U.S.  this chemical may be used  as  a food  additive;  allowable  limits
in  food range  from  1  ppm in  non-alcoholic beverages  to 18 ppm in  candy
(Furia and Bellanca, 1571).   It may also occur in  food as  a result of  migra-
tion from packaging materials  (Sax, 1975).
     C.    Inhalation
          Ambient air concentrations  of formic acid  range from  4 to 72 ppb
(Graedel, 1578).   Emission sources include forest  fires,  plants,  tobacco
smoke,  lacquer manufacture, and  combustion  of  plastics (Graedel,  1978). '  It

-------
has  also been  identified in  the liquid  condensate from  the pyrolysis  of
solid municipal waste (Orphey and Jerman, 1970).
     0.   Dermal
          Pertinent data were not found in the available literature.
III. PHARMACOKINETICS
     A.   Absorption
          Acute toxicity  studies in  animals  and poisoning incidents  in  man
indicate  that  formic acid is  absorbed from the  respiratory  tract  and  from
the gastrointestinal tract (Patty, 1563; NIQSH, 1977)'.
     B.   Distribution
          Pertinent data were not found in the available literature.
     C.   Metabolism
          Formate may be  oxidized to produce carbon dioxide by the activity
of  a catalase-peroxide complex,  or  it  may enter  the  folate-dependent  one
carbon  pool following  activation and proceed  to carbon  dioxide via these
reactions (Palese  and Tephly,  1975).  Species differences in the  relative
balance of these two pathways for the metabolism  of  formate have  been  postu-
lated in  order  to  explain the greater accumulation  of  formate in the blood
of monkeys administered methanol, compared  to rats similarly treated (Palese
and Tephly,  1975).
     D.   Excretion
          Following intraperitoneal  administration  of  ^C  formate to rats,
significant  amounts  of  14CCL were  detected  in  these  samples  (Palese   and
                                                   - *     • •.
Tephly, J975).
IV.  EFFECTS
     A.   Pertinent data could not be located  in the  available  literature.'

-------
      8.    Chronic Toxicity
           Chronic human exposure to formic acid has been reported to  produce
 albuminuria and hematuria (Windholz,  1976).
      C.    Other Pertinent Information
           Formic acid is severely  irritating  to  th skin,  eyes, and respira-
 tory tract  (NIOSH,  1977).   Gleason  (1969) has  indicated  that  exposure  to
 high levels of compound may produce circulatory collapse, renal failure,  and
 secondary  ischemic lesions  in the liver  and heart.
 V.    AQUATIC TOXICITY
      A.    Acute Toxicity
           Dowden  and  Bennett  (1965)  demonstrated  a  24-hour LC_0  value  of
 175,000  ^ig/1  for bluegill sunfish (Lepomis  macrochirus)  exposed  to formic
 acid.  Bringmann  and  Kuhn (1959)  observed  a 48-hour LC5Q  vaiue  of  120,000
/jg/1 for waterfleas  (Daphnia  maqna) exposed to formic acid.-
           Verschueren  (1979)   reported  that a formic  acid  concentration  of
 2,500,000 >jg/l was lethal to  freshwater scuds (Gammarus pulex) and 1,000,000
jug/1 was a perturbation threshold value  for the fish Trutta  iridea.
           Portmann and Wilson (1971) determined  48-hour  LC5Q  values rang-
 ing  from 80,000 to 90,000 xig/1 for the marine shore crab  (Carcinus maenas)
 exposed  to formic acid in static  renewal bioassays.
      B.    Chronic Toxicity
           Pertinent data  were not found  in the available literature.
      C.    Plant Effects
           McKee and Wolf  (1963) reported that  formic acid at a concentration
 of  100,000xig/l was toxic to  the  freshwater algae, Scenedesmus sp.
      0.    Residue
           Pertinent data  were not found  in the available literature.
                                 -  \S\ 1 "7^
                                 *V oL*"^'

-------
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Humsn
          The  eight-hour,  TWA  exposure  limit  for  occupational exposure  to
formic acid is 5 pprn (ACGIH, 1977).
     B.   Aquatic
          Hahn  and Jensen (1977)  have suggested  an aquatic toxicity  rating
range  of  100,000  to  1,000,000 /jg/1 based on 96-hour LC_Q  values for  aqua-
tic organisms exposed to formic acid.

-------
                                  FORMIC ACID

                                  References
 American Conference  of  Government Industrial  Hygienists.   1977.   Threshold
 limit 'values  for chemical  substances  and physical  agents in  the workroom
 environment with intended changes  for  1977.   American Conference of Govern-
 mental Industrial Hygienists, Cincinnati,  OH.

 Bringmann,  G.  and R. Kuhn.   1959.  The toxic effects of wastewater on aqua-
 tic bacteria,  algae  and  small crustaceans.  Gesundheits-Ing 80:  115.

 Casarett,  L.J.  and  I.  Doull.   1975.    Toxicology:   The  Basic Science -of
 Poisons.  Macmillian Publishing Co., New  York.

 CMR.   1979.  Chemical Profile.   Formic  acid.   Chemical Marketing  Reporter,
 December  17, p. 9.

 Dowden,  B.F.  and  H.J.   Bennett.   1965.  Tgxicity  of selected  chemicals  to
 certain  animals.  Jour.  Water Poll. Contr. Fed.  37:  1308.

 Furia, T.E.  and N.  Bellanca (eds.)   1971.  Fenaroli's Handbook of Flavor In-
 gredients.   The Chemical Rubber Company, Cleveland, 0.

 Gleason,  M.   1569.   Clinical  Toxicology  of  Commercial  Products,  3rd  ed.
 Williams  and Wilkins, Baltimore, MO.

 Graedel,  T.E.   1978. Chemical  Compounds  in the Atmopshere.   Academic  Press,
 New York.

 Hahn, R.W.  and P.A.  Jensen.   1977.  Water Quality  Characteristics of Hazard-
 ous Materials.  Texas A  &  M  University.  Prepared  for National Oceanographic
 and Atmospheric Administration Special Sea Grant Report.   NTIS PB-285 946.

 Hawley, G.G.  (ed.)   1971.   The Condensed Chemical Dictionary, 8th ed.   Van
 Nostrand Reinhold Co, New York.

 McKee, J.E.  and H.W. Wolf.   1963.  Water Quality  Criteria Resources  Board,
 California Water Quality Agency, Publication No. 3-A.

 Mueller,  H.F.,  et al.   1958.  Chromatographic  identification  and determina-
 tion of organic acids in water.   Anal.  Chem.  30: 41.

 National  Institute  for  Occupational Safety and  Health.   1977.   Occupational
 Diseases:  A Guide to Their  Recognition.   Washington",  DC:  U.S.  DHEW,  Publi-
 cation No. 77-181.

Orphey, R.D. and R.I. Jerman.   1960.  Gas  chrpmatographic  analysis of  liquid
condensates  from  the pyrolysis of  solid municipal waste.   Jour. Chroma,to-
 graphic Science.  8: 672.

Palese, M.  and  T.  Tephly.    1975.   Metabolism of formate in the rat.  Jour.
Toxicol. Environ.  Health.  1: 13.
                                        - f

-------
Patty,  F.    1563.   Industrial Hygiene  and  Toxicology,  Vol.  II.   2nd  ed.
Intersciencs, New York.

Portmsnn, J.E.  and K.W. Wilson.   1971.   The toxicity of  140 substances to
the brown shrimp arid other marine animals.  Ministry of Agriculture, Fisher-
ies and  Food, Fisheries Laboratory, Burnham-on-Crouch, Essex, Eng. Shellfish
Leaflet No.  22,  AMIC-7701.

Sax,  N.I.    1975.   Dangerous  Properties  of  Industrial Materials.   4th  ed.
Van Nostrand Reinhold, Co,  New  York.

U.S. EPA.   1976.   Frequency of organic  compounds  identified in water.   U.S.
Environ. Prot. Agency, EPA-600/4-76-062.

Verschueren,  K.    1979.    Handbook of  Environmental Data  on  Organic  Chem-
icals.  Van  Nostrand Reinhold,  Co, New York.

Walker, J.F.  1966.  Formic acid and derivatives.  In:  Kirk-Othmer Encyclo-
pedia  of Chemical Technologyt  2nd ed.   A. Standen,  (ed).   John  Wiley  and
Sons,  New York.   Vol. 10,  p. 99.

Windholz, M. (ed.)  1976.   The Merck Index.  9th ed.  Merck and Co., Rahway,
NJ.
                               IOS-16

-------
                                      No.  106
           Futnaronitrile

  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  a-11 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.

-------
                                 FUMARONITRILE
                                    Summary

     Information  on the  carinogenic,  mutagenic,  or teratogenic  effects  of
fumaronitrile was not found  in the available  literature.  LD5Q  values  for
injected mice and orally dosed  rats were  38  and 50 mg/kg,  respectively.  Re-
ports of chronic toxicity studies were not found in the available literature.

-------
                                 RJMARONITRILE

 I.    INTRODUCTION
          This'profile is based  upon relevant literature identified  through
 mechanized   bibliographic  searches   such  as   TOXLINE,   BIOSIS,  Chemical
 Abstracts,  AGRICOLA  and  MEDLARS,  as  well  as  manual  searches.    Despite
 approximately  70 citations  for  fumaronitrile,  approximately  95  percent  of
 these  concerned  the chemistry  of fumaronitrile or  its  reactions with  other
 chemicals.  Apparently,  the chief use of  fumaronitrile  is as a chemical  in-
 termediate  in  the manufacture  of other  chemicals,  rather than  end .uses  as
 fumaronitrile per se.  Undoubtedly,  this  accounts for its low profile in  the
 toxicological literature.
          Fumaronitrile   or   trans-l,2-dicyanoethylene   (molecular  weight
 78.07)  is  a solid  that  melts at  96.8°c  (Weast,  1975), has  a boiling  point
 of  186°c,   and  a  specific gravity  of 0.9416 at  25°C.  It is  soluble  in
water,  alcohol,  ether,  acetone,  chloroform,  and benzene.   Fumarcnitrile  is
used  as a bactericide  (Law,  1968),  and  as an antiseptic  for metal cutting
 fluids  (Wantanabe, et al., 1975).   It is used  to make polymers with styrene
numerous other  compounds.  This  compound is  easily isomerized to  the  cis-
 form, maleonitrile, which is  a  bactericide and fungicide (Ono, 1979).    It  is
conveniently  synthesized  from  primary amides under  mild conditions  (Cam-
pagna, et al., 1977).
 II.  EXPOSURE
          Human exposure  to fumaronitrile  from foods cannot  be assessed, due
to a lack of monitoring data.
          3ioaccumulation data on  fumaronitrile were not found in the avail-
able literature.

-------
 III. PHARMACOKINETICS
          Specific  information  on the metabolism,  distribution,  absorption,
or elimination of fumaronitrile was not found in the available literature.
IV.  EFFECTS  •
     A.   Carcinogenicity,  Mutagenicity,  Teratogenicity,  Reproductive
          Effects, and Chronic Toxicity
          Pertinent data could not be located in the available literature.
     8.   Acute Toxicity
          LD50 values  for  injected  mice  and orally  dosed  rats were 38 and
5Q mg/kg, respectively (Zeller,  et al., 1969).
V.   AQUATIC TOXICITY
          Data concerning the effects of fumaronitrile to  aquatic  organisms
were not found in the available  literature.
VI.  EXISTING GUIDELINES AND STANDARDS
          Data concerning  existing  guidelines  and  standards for  fumaroni-
trile were not found in the  available literature.
                                /0%'S

-------
                                  REFERENCES
Campagna,  F.,  et  al.    1977.   A  convenient  synthesis  of  nitriles   from
primary amides under mild conditions.  Tetrahendron Letters.   21: 1313.

Law, A.  1968.  Fumaronitrile as a bactericide.  Chen, Abst.   68: 1135.

Ono,  T.    1979.   Maleonitrile,  a  bactericide and  fungicide.   Chem.   Abst.
32: 126.

Wantanabe, M.,  et al.  1975.   Antiseptic for a metal cutting fluid.   Chem.
Abst.  .82: 208.

Weast, R.  1975.   Handbook of Chemistry  and  Physics^  56th ed.  Chem. Rubber
Publ. Co.  p. 2294.
                                                  •.

Zeller,  H.,  et  al    1969.    Toxicity   of  nitriles:   Results  of  animal
experiments  and  industrial  experiences  during   15  years.   Chem.   Abst.
71: 326.
                                     0

-------
                                      No. 107
            Halomethanes

  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.
                          107-

-------
                                 HALOMETHANES'
                                    Summary
     The halomethanes  are a subcategory  of halogenated hydrocarbons.  There
is little  known concerning the  chronic toxicity of  these compounds.  Acute
toxicity results in central nervous system depression and liver damage.  The
fluorohalomethanes are  the  least toxic.  None of  the halomethanes have been
demonstrated to  be carcinogenic; however, chloro-, bromo-, dichloro-, bromo-
dichloro-, and  tribromomethane  have been  shown  to be mutagenic  in the Ames
assay.   There  are  no  available  data on  the  teratogenicity  of  the halo-
methanes,  although  both  dichloromethane  and bromodichloromethane  have been
shown to affect the fetus.
     Brominated methanes  appear  to be  more toxic to aquatic life than chlor-
inated methanes.   Acute toxicity  data  is  rather  limited in scope,  but re-
veals toxic concentrations in the  range of  11,000 to 550,000 jug/1.

-------
I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water  Quality  Criteria Document
for Halomethanes (U.S. EPA, 1979).
     The  halomethanes  are a  sub-category  of halogenated hydrocarbons.  This
document   summarizes  the   following  halomethanes:   chloromethane   (methyl
chloride);  bromomethane  (methyl  bromide,  monobromomethane,  embafume);  di-
chloromethane  (methylene  chloride,  methylene dichloride,  methylene bichlor-
ide);  tribromomethane  (bromoform);  trichlorofluoromethane   (trichloromono-
fluoromethane,  fluorotrichloromethane,  Frigen 11,  freon-11,  Arcton  9);  and
dichlbrodifluoromethane  (difluorodichloromethane,  Freon 12,  Frigen 12, Arc-
ton 6, Genetron' 12,  Halon,  Isotron  2) and bromodichloromethane.  These  halo-
methanes  are  either  colorless gases or liquids at environmental  temperatures
and  are   soluble  in  water  at  concentrations from 13  x   10   to  2.5  x  10°
jug/1, except  for tribromomethane  which is only slightly soluble  and bromodi-
chloromethane  which  is insoluble.  Halomethanes are  used  as  fumigants, sol-
vents, refrigerants,  and in  fire extinguishers.   Additional  information  on
the  physical/chemical properties of chloromethane,  dichloromethane,  bromo-
methane,  and  bromodichloromethane,  can be  found in the ECAO/EPA (Dec.  1979)
hazard profile on these chemicals.
II.  EXPOSURE
     A.   water
          The  U.S. EPA (1975)  has  identified chloromethane, bromomethane,  di-
chloromethane,  tribromomethane,  and bromodichloromethane -in  finished drink-
ing waters in the United  States.  Halogenated hydrocarbons  have been  found
in finished waters at greater concentrations than  in  raw  waters (Symons,  et
                                                                         »
al. 1975), with  the  concentrations  related to the  organic content  of the  raw •
water.   The  concentrations of  halomethanes detected  in one  survey  of U.S.
drinking  waters are:

-------
                     Halomethanes in the U.S.  EPA Region V
                          Organics Survey (83 Sites)
Compound
Bromodichloromethane
Tribromome thane
Oichloromethane
Percent of
Locations with
Positive Results
78
14
8
Concentrations (mq/1)
Median
0.006
0.001
0.001
Maximum
0.031
0.007
0.007
Source:  U.S. EPA, 1975
Symons, et  al.  (1975) concluded that  trihalomethanes  resulting from chlori-
nation are  widespread in  chlorinated  drinking  waters.   An  unexplained in-
crease in the  halomethane concentration  of water  samples occurred  in the
distribution system water as compared to the treatment plant water.
     B.  Food
         Bromomethane  residues from  fumigation  decrease  rapidly  from both
atmospheric  transfer  and  reaction  with proteins  to form  inorganic bromide
residues.    With  proper  aeration  and  product  processing,  most  residual
bromomethane  will  disappear  rapidly   due   to  methylation  reactions  and
volatilization  (Natl.  Acad.  Sci.,   1978; Davis,  et al.  1977).   The U.S. EPA
(1979) has  estimated  the weighted   average  bioconcentration  factors  for
dichloromethane and tribromomethane to be 1.5 and  14,  respectively, for the
edible portions of  fish and shellfish consumed  by  Americans.   This estimate
is based  on  the octanol/water partition coefficient of  these two compounds.
Bioconcentration factors for the other halomethanes have not been determined.
     C.  Inhalation
         Saltwater  atmospheric background  concentrations  of  chloromethane
and  bromomethane,  averaging  about 0.0025 mg/m   and  0.00036  mg/m   respec-
tively, have been  reported  (Grimsrud  and  Rasmussen,   1975;  Singh, et  al.
1977).  These values  are higher than  reported average  continental background

-------
and urban  levels  suggesting that the oceans may  be  a major source of global
chloromethane and bromomethane.  Outdoor bromomethane concentrations as high
as O.QOQ85 mg/m  may occur  near light traffic.  This  results  from the com-
bustion of ethylene dibromide, a component  of leaded  gasoline  (Natl.  Acad.
Sci.,  1978).   Reported  background concentrations of dichloromethane in both
continental  and saltwater atmospheres  are  about 0.00012 mg/m  ,  while  urban
air  concentrations  ranged  from  less  than  0.00007  to 0.0005  mg/m .   Local
high  indoor concentrations can  be  caused by  the use  of  aerosol  sprays  or
solvents  (Natl.  Acad.  Sci., 1978).   Concentrations  of dichlorodifluorometh-
ane and  trichlorofluoromethane in the  atmosphere over urban areas are sev-
eral  times those  over  rural or oceanic areas.   This probably indicates that
the primary  modes of entry into the  environment, i.e., use  of refrigerants
and aerosols,  are greater in industrialized and  populated  areas  (Howard,  et
al.  1974).  Average concentrations  of  trichlorofluoromethane reported  for
urban  atmospheres  have  ranged  from  nil  to  3  x   IQ'^ mg/m5,  and concen-
                                                           -3               2
trations  for dichlorofluoromethane  ranged   from  3.5  x 10    to  2.9 x  10
mg/m  .
III. PHARMACOKINETICS
     A.  Absorption
         Absorption  via  inhalation  is of primary  importance and  is  fairly
efficient  for the halomethanes.  Absorption  can also occur via the skin and
gastrointestinal tract,  although this is generally  more significant for the
nonfluorinated  halomethanes  than for the fluortJCarbons- (Natl. Acad.  Sci.,
1978; Oavis, et al.  1977; U.S. EPA,  1976;  Howard, et al. 1974).
                                 107-6

-------
     8.  Distribution
         Halomethanes are  distributed rapidly to  various tissues  after  ab-
sorption  into  the  blood.   Preferential  distribution  usually  occurs   to
tissues witlVhigh lipid content (U.S.  EPA, 1979).
     C.  Metabolism
         Chloromethane  and bromomethane  undergo  reactions  with  sulfhydryl
groups  in  intracellular enzymes  and  proteins,  while bromochloromethane  in
the body  is hydrolyzed  in significant amounts  to yield  inorganic bromide.
Dichloromethane is  metabolized to carbon  monoxide which  increases carboxy-
hemoglobin  in  the  blood and  interferes with  oxygen transport  (Natl.  Acad.
Sci.,   1978).   Tribromomethane  is apparently  metabolized to carbon monoxide
by the cytochrome  P-450-dependent mixed  function  oxidase system  (Ahmed,  et
al. 1977).  The fluorinated halomethanes  form  metabolites  which  bind to cell
constituents,   particularly when  exposures are long-term  (Blake  and Mergner,
1974).  Metabolic data  for bromodichloromethane  could not be  located  in  the
available literature.
     D.  Excretion
         Elimination of  the halomethanes  and  their metabolites occurs mainly
through expired breath and urine (U.S. EPA, 1979).
IV.  EFFECTS
     A.  Carcinogenicity
         None  of  the halomethanes summarized  in  this document  are considered
to be  carcinogenic.  Theiss and  coworkers (1977). examined  the  tumorigenic
activity  of tribromomethane,  bromodichloromethane, --and dichloromethane  in
strain A mice.  Although increased  tumor  responses were noted with each,  in
                                                                        »
no case were  all  the requirements met  for a  positive carcinogenic response,
as defined  by  Shimkin and  Stoner  (1975).   Several  epidemiologic  studies have
                                /07-7

-------
 established an association between trihalomethane levels  in  municipal  drink-
 ing water supplies in the United States and certain cancer death  rates (var-
 ious sites) (Natl.  Acad.  Sci.,  1978; Cantor  and McCabe, 1977).  Cantor,  et
 al. (1978) cautioned that these  studies  have  not  been  controlled for  all
 confounding variables,  and  the limited monitoring  data that were  available
 may not have been an accurate reflection of past exposures*
     •B.  Mutagenicity
          Simmon,   et  al.  (1977)  reported  that chloromethane,  bromomethane,
_and dichloromethane  were  all mutagenic  to  Salmonella  typhimurium  strain
 TA1QQ  when assayed in a dessicator whose  atmosphere contained  the  test com-
 pound.   Metabolic activation  was  not required.  Only  marginal positive  re-
 sults  were obtained with  bromoform  and  bromodichloromethane.   Andrews,  et
 al. (1976) and  Jongen,  et al. (1978)  have confirmed  the- positive  Ames  re-
 sults  for  chloromethane and dichloromethane,   respectively.   Oichloronethane
 was negative in  tnitotic recombination in  S^  cerevisiae  03  (Simmon,  et  al.
 1977)  and  in mutagenicity  tests  in Drosophila  (~ilippova, et  al.  1967K
 Trichlorofluorcmethane and dichlorofluoromethane  were negative in  the  Ames
 assay  (Uehleke,   at  al.  1977), and dichlorodifluoromethane  in a rat feeding
 study  (Sherman,  1974) caused no increase in mutation rates over controls.
     C.   Teratogenicity
          Pertinent information could not be located in the available litera-
 ture.
     0.  Other'Reproductive Effects
          Gynecologic problems have  been  reported in  female workers exposed
 to dichloromethane and  gasoline vapors (Vozovaya,  1974).   Evidence  of  fete-
                                                                      »
 embryotoxicity has  been noted in  rats  and mice  exposed to  dichlorcmethane
                                  (07-?

-------
vapor on  gestation  days 6 to  15  (Schwetz,  et al. 1975).   Some  fetal  anoma-
lies were  reported  in  experiments  in which  mice were  exposed  to vapor  of
bromodichloromethane at  8375  mg/m ,  7 hours/day  during gestation days  6  to
15 (Schwetz, et al.  1975).
     E.  Chronic Toxicity
         Schuller, et al. (1978) have observed a. suppression  of  cellular and
humoral immune response  indices in female  ICR mice exposed by gavage  for  90
days to bromodichloromethane at 125  mg/kg  daily.   Tribromomethane suppressed
reticuloendothelial system function  (liver and  spleen phagocytic uptake  of
Listeria monocytoqenes)  in mice exposed  90 days at daily  doses  of 125 mg/kg
or less  (Munson,  et al. 1977,1978).  Information pertinent  to  the  chronic
toxicity  of the  other  halomethanes  could  not be located in the  available
literature.
     F.  Other Relevant Information
         In general,  acute  intoxication by  halomethanes  appears  to  involve
the central nervous system and liver  function (U.S. EPA, 1979).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Acute toxicity  studies  for halomethanes have  obtained acute  LC5Q
values for the bluegill sunfish  (Lepomis  machrochirus) of 11,000 ug/1  for
methylbromide, 29,300 ug/1  for bromoform,  224,000 ug/1  for methylene  chlor-
ide and 550,000 for methyl  chloride.  A static  bioassay  produced a  96-hour
LC5Q  value  of 310,000 ug/1  methylene  chloride  for. the  fathead  minnow
(Pimephales promelas) while  a flow-through assay  produced an LC5Q value  of
193,000 /jg/1.   In  freshwater  invertebrates  two  acute  studies  with  Daphnia
                                /07-J

-------
maqna  resulted in  LC^ values  of  46,500  .ug/1  for  bromoform,  and  224,000
pg/1  for  methylene chloride.   In  marine fish,  LC_Q  values for the  sheeps-
head  minnow  (Cyorinodon  varieqatus)  were  17,900 pg/1  for  bromoform  and
180,958 ug/1  for methylene chloride.   For  the tidewater silversides (Menidia
bervllina)  LC5Q values of  12,000 pg/1  for  methylbromide  and 147,610  ug/1
for methylene chloride were obtained.   Adjusted LC^ values  for  the  marine
mysid  shrimp  (Mysidopsis  bahia) were  24,400  ug/1 for bromoform and  256,000
pg/1 for methylene chloride (U.S. EPA, 1979).
     8.  Chronic Toxicity
         The  only  chronic value  for an aquatic species  was  9,165 jug/1 for
the sheepshead minnow.
     C.  Plant Effects
         Effective  concentrations  for  chlorophyll  a  and  cell  numbers  in
freshwater  algae  Selenastrum  capricomutum  ranged from  112,000 to  116,000
ug/1  for  bromoform  and 662,000 pg/1 for methylene chloride, while effective
concentrations  for  the marine  algae (Sketonema  costatum)  were  reported  as
11,500 to  12,300 pg/1 for bromoform and   662,000 ug/1  for methylene  chlor-
ide (U.S. EPA, 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
         Positive associations between human  cancer mortality  rates and  tri-
halomethanes  (chloroform, bromodichloromethane,  tribromomethane) in drinking
                                 107-10

-------
water have been reported.  There have also been  positive  results  for tribro-
momethane using  strain A/St. male  mice in  the  pulmonary adenoma  bioassay.
Bromomethane, chloromethane,  dichloromethane,  bromodichloromethane and  tri-'
bromomethane have been reported as  mutagenic in  the Ames test without meta-
bolic activation.   Dichlorodifluoromethane caused a significant  increase  in
mutant frequency in Neurospora  crassa  (mold), but  was  negative  in the  Ames
test.  No  data  implicating  trichlorofluoromethane  as  a  possible  carcinogen
have been published.
         Because positive  results  for  the mutagenic endpoint correlate  with
positive results  in in  vivo bioassays  for  oncogenicity, mutagenicity  data
for  the  halomethanes suggests  that several  of  the compounds might also  be
carcinogenic.  Since carcinogenicity data currently available for  the halo-
methanes were  not  adequate  for the development of water  quality  criteria
levels,  the  draft  criteria recommended  for  chloromethane, bromomethane, di-
chloromethane,  tribromomethane and  bromodichloromethane are the same  as  that
for chloroform,  2 /jg/1.
         Chloromethane:  OSHA (1976) has  established the maximum acceptable
time-weighted average air  concentration for  daily  8-hour occupational expo-
sure at 219 mg/m .
         Bromomethane:   OSHA  (1976)  has  a threshold  limit  value  of  80
mg/m  for  bromomethane,  and  the American  Conference of  Governmental  Indus-
trial Hygienists (ACGIH,  1971) has  a threshold limit value of  78 mg/m3. .
         Dichloromethane:  OSHA  (1976a,b)  has  established  an  8-hour time-
weighted average  for dichloromethane of 1,737  mg/m ,  however,  NIOSH  (1976)
has  recommended  a  10-hour   time-weighted   average  exposure   limit  of  261
mg/m  of dichloromethane  in the presence of no more  carbon monoxide  than
9.9 mg/m3.
                                  txrr
                                    7-//

-------
         Tribromomethane:   QSHA  (1976a,b)  has  established an  3-hour time-
weighted average for tribromomethane of 5 mg/m .
         Bromodichloromethane:   There is  no  currently  established  occupa-
tional exposure standard for bromodichloromethane.
         Trichlorofluoromethane  and  dichlorodifluoromethane:   The  current
OSHA  (1976)  8-hour  time-weighted  average occupational  standards  for tri-
chlorofluoromethane  and dichlorodifluoromethane  are 5,600  and  4,950 mg/m  ,
respectively.   The U.S.  EPA (1979)  draft'water  quality  criteria  for tri-
chlorofluoromethane  and dichlorodifluoromethane -are 32,000 and  3,000 /jg/1,
respectively.
     8.  Aquatic
         Draft  criteria  for the  protection  of  freshwater life  have been
derived  as 24-hour  average concentrations  for the  following halomethanes:
methylbromide - 140 ug/1 not to exceed  320 ug/1; bromoform - 840 jjg/1 not to
exceed 1,900 ug/1; methylene chloride -  4,000 ug/1 not to exceed 9,000 ug/1;
and methyl chloride - 7,000 jug/1 not to exceed 16,000 ug/1.
         Draft criteria  for the protection of marine  life have been derived
as 24-  hour average concentrations for  the  following halomethanes:  methyl-
bromide 170 ug/1 not  to exceed  380 ug/1;  bromoform  -  180 pg/1 not to exceed
420  ug/1;   methylene  chloride - 1,900 jug/1  not  to exceed 4,400  pg/1;  and
methyl chloride -  3,700 ug/1 not to exceed 3,400 ug/1.


-------
                        HALOMETHANES

                         REFERENCES

Ahmed, A.E., et al.  1977.  Metabolism of haloforms  to carbon
monoxide, I. Ijn vitro studies.  Drug. Metab. Dispos.  5: 198.
(Abstract).

American Conference of Governmental and Industrial Hygienists
1971.  Documentation of the threshold limit value for sub-
stances in workroom air.  Cincinnati, Ohio.

Andrews, A.W., et al.  1976.  A comparison of the mutagenic
properties of vinyl chloride and methyl chloride.  Mutat.
Res.  40: 273.

Blake, D.A., and G.W. Mergner.  1974.  Inhalation studies on
the biotransf ormation and elimination of '(^C)-trichloro-
fluoromethane and (14C)-diphlorodifluoromethane  in beagles.
Toxicol. Appl.  Pharmacol.  30: 396.

Cantor, K.P., and L.J. McCabe.  1977.  The epidemiologic
approach to the evaluation of organics in drinking water.
Proc. Conf. Water Chlorination: Environ. Impact  and  Health
Effects.  Gatlinburg, Tenn.  Oct. 31-Nov. 4.

Cantor, K.P. et al.  1978.  Associations of halomethanes in
drinking water with cancer mortality.  Jour. Natl. Cancer
Inst. (In press).

Davis, L.N., et al.  1977.  Investigation of selected poten-
tial environmental contaminants: monohalomethanes.   EPA 560/
2-77-007; TR 77-535.  Final rep. June, 1977, on  Contract No.
68-01-4315.  Off. Toxic Subst. U.S.' Environ. Prot. Agency,
Washington, D.C.

Filippova, L.M., et al.  1967.  Chemical mutagens.   IV.
Mutagenic activity of geminal system.  Genetika   8:  134.

Grimsrud, E.P., and R.A. Rasmussen.  1975.  Survey and analy-
sis of halocarbons in the atmosphere by gas chromatography-
mass spectrometry.  Atmos. Environ.  9: 1014.

Howard, P.H., et al.  1974.  Environmental hazard assessment
of one and two carbon fluorocarbons.  EPA 560/2-75-003.  TR-
74-572-1.  Off. Toxic Subst.  U.S. Environ. Prot. Agency,
Washington, D.C.

Jongen, W.M.F., et al.  1978.  Mutagenic effect  of dichloro-
methane on Salmonella typhimurium. Mutat. Res. 56: 246.
                             -Tj? V—-
                             jf IA. I ^

-------
Munson, A.E.,.et al.  1977.  Functional  activity  of  the  re-
ticuloendothelial system  in mice exposed  to  haloalkanes  for
ninety days.  Abstract.   14th Natl. Reticuloendothelial  Soc.
Meet. Tucson, Ariz.  Dec. 6-9.

Munson, A.E., et al.  1978.  Reticuloendothelial  system  func-
tion in mice exposed to four haloalkanes:  Drinking water con-
taminants.-  Submitted: Soc. Toxicol.  (Abstract).

National Academy of Sciences.  1978.  Nonfluorinated  halo-
methanes in the environment.  Washington,  D.C.

National Institute for Occupational Safety and  Health.   1976.
Criteria for a recommended standard:  Occupational exposure to
methylene chloride.  HEW  Pub. No.  76-138.  U.S. Dep.  Health
Edu. Welfare, Cincinnati, Ohio.

Occupational Safety and Health Administration.  1976.  Gener-
al industry standards.  OSHA 2206, revised January,  1976.
U.S. Dept. Labor, Washington, D.C.

Schuller, G.B., et al.  1978.  Effect of  four haloalkanes on
humoral and cell mediated immunity in mice.  Presented Soc.
Toxicol. Meet.

Schwetz, B.A., et al.  1975.  The  effect  of  maternally in-
haled trichloroethylene,  perchloroethylene,  methyl chloro-
form, and methylene chloride on embryonal  and fetal  develop-
ment in-mice and rats.  Toxicol. Appl. Pharmacol.  32:   84.

Sherman, H.  1974.  Long-term feeding studies in  rats and
dogs with dichlorodifluoromethane  (Freon  12  Food  Freezant).
Unpubl. rep. Haskell Lab.

Shimkin, M.B., and G.D. Stoner.  1975.   Lung tumors  in mice:
application to carcinogenesis bioassay.   Adv. Cancer Res.
21: 1.

Simmon, V.F., et al.  1977.  Mutagenic activity of chemicals
identified in drinking water.  S.  Scott,  et  al.,  eds.  In
Progress in genetic toxicology.

Singh, H.B., et al.  1977.  Urban-non-urban  relationships of
halocarbons, SFg, N20 and other atmospheric  constituents.
Atmos. Environ.  11: 819.

Symons, J.M., et al.  1975.  National organics "reconnaissance
survey for halogenated organics.   Jour.  Am.-• Water Works
Assoc.  67: 634.

Theiss, J.C., et al.  1977.  Test  for carcinogenicity of or,-
ganic contaminants of United States drinking waters  by pul-
monarv tumor response in  strain A  mice.   Cancer Res.  37:
2717."

-------
Uehleke, H., et al.  1977.  Metabolic activation of haloal-
kanes and tests _in vitro for mutagenicity.  Xenobiotica  7:
393.

U.S. EPA.  1975.  Preliminary assessment of suspected carcin-
ogens in drinking water, and appendices.  A report to Con-
gress, Washington, D.C.

U.S. EPA.  1976.  Environmental hazard assessment report,
major one- and two- carbon saturated fluorocarbons, review of
data.  EPA  560/8-76-003.  Off. Toxic Subst. Washington,
D.C.

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

U.S. EPA.  1979b.  Environmental Criteria and Assessment Of-
fice.  Halomethanes: Hazard Profile (Draft).

Vozovaya, M.A.  1974.  Gynecological illnesses in workers of
major industrial rubber products plants occupations.  Gig.
Tr.  Sostoyanie Spetsificheskikh Funkts.  Rab. Neftekhim.
Khim. Prom-sti. (Russian) 56. (Abstract).

Wilkness, P.E., et al.  1975.  Trichlorofluoromethane in the
troposphere, distribution and increase, 1971 to 1974.
Science  187: 832.

-------
                                       No.  108
             Heptachlor

  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  (CAG) has  evaluated

heptachlor and has found sufficient evidence to indicate

that  this compound is carcinogenic.
                          -IAS*-
                          /Of" 3

-------
                                  HEPTACHLOR
                                    Summary
     Heptachlor  is  an organochlorinated cyclodiene insecticide, and has been
used mostly  in its technical, and  hence,  impure form, in  most bioassays up
to  the present.   Nevertheless,  it  has been  found that heptachlor  and its
metabolite,  heptachlor epoxide,  induce liver cancer in mice and rats.  Hep-
tachlor was  mutagenic in two mammalian assays  but not in the Ames test.  In
long-term  reproductive studies  in rats, heptachlor caused  reduction  in lit-
ter size,  decreased lifespan  in  suckling  rats,  and cataracts in both parents
and offspring.  Little  is  known about other  chronic effects  of heptachlor
except that  it induces  alterations  in glucose homeostasis.   It causes con-
vulsions  in  humans.   Heptachlor  epoxid_e,  its major  metabolite, accumulates
in adipose tissue and  is more acutely toxic than the parent compound.       ,
     Numerous  studies  indicate that  heptachlor  is  highly  toxic, both acutely
and chronically,  to  aquatic  life.   Ninety-six  hour  LC-Q  values  for fresh-
water  fish range from 7.0 ug/1  to  320 pg/1 and  24 to  96-hour LC5Q values
for invertebrates  from 0.9 ug/1  to 80 pg/1.   The 96-hour values  for salt-
water  fish range from 0.8  to 194 ug/1.   In  a 40-week life  cycle  test with
fathead  minnows, the determined  no-adverse-effect concentration  was  0.86
pg/1.   All fish  exposed at 1.84 ug/1  to heptachlor were  dead after 60 days.
The fathead  minnow bioconcentrated  heptachlor  and its  biodegradation  pro-
duct,   heptachlor  epoxide,   20,000-fold over  ambient  water  concentrations
after 276  days exposure.  The saltwater sheepshead minnow  accumulated these
two compounds  37,000-fold after  126 days  exposure."  Heptachlor  epoxide has
approximately the same toxicity values as  heptachlor.
                               /6 8"',

-------
I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water  Quality Criteria  Document
for Heptachlor (U.S. EPA, 1979).
     Heptachlor  is  a broad  spectrum insecticide of  the group of  polycyclic
chlorinated hydrocarbons  called cyclodiene insecticides.   From 1971 to  1975
the  most important  use  of  heptachlor  was to  control agricultural  soil  in-
sects (U.S. EPA, 1979).
     Pure, heptachlor   (dnemical  name  l,4,5,6,7,8,8-heptachloro-3a,4,7,7a-
tetrahydro-4,7-fnethanoindene;   C,J-lcCl7;   molecular   weight  373.35)  is   a
white crystalline  solid  with a camphor-like  odor.    It  has a vapor  pressure
of  3 x  10~4  mm Hg  at  25°C, a solubility in  water  of 0.056  mg/1 at 25  to
29°C,  and is  readily soluble  in  relatively  nonpolar solvents  (U.S.  EPA,
1979).                                                                        i
     Technical  grade heptachlor  (approximately  73  percent  heptachlor;  21
percent  trans  chlordane,  5  percent  heptachlor epoxide  and 2 percent  chlor-
dene  isomers)  is  a tan,  soft, waxy  solid with  a  melting  range of  46  to
74°C and a vapor pressure of 4 x 10"4 mm Hg at  25°C (U.S.  EPA,  1979).
     Since 1975,  insecticidal uses  and  production  volume  have declined  ex-
tensively because of the  sole producer's  voluntary restriction and  the  sub-
sequent issuance of  a registration suspension  notice  by the U.S. EPA,  August
2, 1976,  for all  food crop  and  home  use of heptachlor.  However, significant
commercial use of  heptachlor for termite control and non-food  crop pests
continues.                                         -       \-
     Heptachlor  persists  for prolonged  periods  in  the environment.   It  is
converted  to  the  more  toxic  metabolite,  heptachlor  epoxide,  in  the  soil
                                                                        »
(Lichtenstein,  1960; Lichtenstein,  et  al.  1970,   1971;   Nash and  Harris,
1972),  in plants  (Gannon and  Decker,  1958),   and  in  mammals  (Oavidow  and

-------
Radomski, 1953a).  Heptachlor,  in  solution or thin films, undergoes photode-
composition  to photoheptachlor  (Benson,   et  al.  1971)  which  is  more  toxic
than  the  parent compound to  insects (Khan,  et al.  1969),  aquatic inverte-
brates  (Georgacakis  and Khan,  1971; Khan,  et al. 1973)  and rats, bluegill
(Lepomis  machrochirus) and  goldfish (Carassius  auratus)  (Podowski,  et  al.
1979).  Photoheptachlor. epoxide  is also  formed in sunlight., and is  more  toxic
than the parent compound (Ivie, et al. 1972).
     Heptachlor and  its epoxide will bioconcentrate  in numerous species  and
will accumulate in the food chain  (U.S. EPA, 1979).
II.  EXPOSURE
     A.  Water
         Various  investigators  have detected heptachlor  and/or  heptachlor
epoxide in  the major  river  basins of the U.S. at a  mean concentration  for
both of 0.0063 pg/1  (U.S.  EPA,  1976).  Levels of  heptachlor  ranged from .001
jjg/1  to 0.035  ug/L and heptachlor/heptachlor  apoxide were  found  in  25 per-
cent  of all  river samples  (Breidenbach,  et  al.  1967).   Average  levels  in
cotton sediments are around 0.8 ug/kg (U.S. EPA, 1979).
     B.  Food
         In  their  market basket  study  (1974-1975) for  20 different cities,
the FDA  showed that 3 of  12 food  classes contained  residues  of  heptachlor
epoxide ranging from 0.0006  to  0.003 ppm (Johnson and Manske, 1977).  Hepta-
chlor epoxide  residues greater than 0.03  mg/kg have  been found in 14 to  19
percent  of   red  meat,   poultry,  and  dairy products "sampled  from  1964-1974
(Nisbet, 1977).  Heptachlor  and/or heptachlor epoxide were  found  in  32 per-
cent of 590  fish  samples obtained nationally,  with  whole fish residues from
                                                                           »
0.01 to 8.33 mg/kg (Henderson, et al. 1969).


-------
         The  U.S.  EPA  (1979)  has estimated the  weighted average bioconcen-
tration  factor  for heptachlor in the  edible portions of  fish and shellfish
consumed  by  Americans  to  be  5,200.   This  estimate is  based  on  measured
steady-state  bioconcentration factors- for  sheepshead minnows,  fathead min-
nows, and spot  (Leiostomus xanthuru).
         Human  milk can be contaminated with  heptachlor epoxide.  A nation-
wide  survey indicated that  63.1 percent of  1,936 mothers'  milk samples con-
tained heptachlor  epoxide residues  ranging  from 1 to 2,050 ug/1  (fat adjust-
ed)  (Savage,  1976).  Levels of 5 ug/1 of  the epoxide have  been reported in
evaporated milk (Ritcey, et al. *1972).
      C.  Inhalation
         Heptachlor  volatilizes  from  treated  surfaces,   plants,  and  soil
(Nisbet, 1977).  Heptachlor,  and to a  lesser  extent heptachlor epoxide,. are
widespread  in ambient  air  with typical mean  concentratons of approximately
0.5  ng/m .   On the basis of  this  data, typical human exposure  was  calcu-
lated to be 0.01 ug/person/day (Nisbet, 1977).   Thus, it  appears that inha-
lation is not a major route for  human exposure to heptachlor.  Air downward
from  treated  fields may contain  concentrations as high  as  600 ng/m  .   Even
after three weeks, the  air from  these fields may contain up  to 15.4  ng/m3.
Thus, sprayers,  farmers and nearby  residents  of sprayed  fields  may  receive
significant exposures (Nisbet, 1977).
     0.   Dermal
         Gaines (1960)  found  rat  dermal LD^g "values • af  195  and 250  mg/kg
for males  and females,  respectively,  compared with  oral l-Dc0's of 100  and
162 mg/kg,  respectively,  for  technical  heptachlor.   Thus, dermal  exposures
                                                                      »
roay be important in humans under the right  exposure conditions.
                                   (07-7

-------
III. PHARMACOKINETICS
     A.  Absorption
         Heptachlor  is  readily  absorbed  from  the  gastrointestinal  tract
(Radomski  and  Davidow, 1953;  Mizyukova and  Kurchatov, 1970;  Matsumura  and
Nelson, 1971).  The  degree- to  which heptachlor is absorbed by  inhalation  has	
not been reported  (Nisbet,  1977).   Percutaneous absorption is  less  efficient
than through  the  gastrointestinal  tract,  as indicated  by  comparison of  the
acute toxicity resulting from dermal vs. oral exposures  (Gaines,  1960).
     8.  Distribution and Metabolism
         Heptachlor  reaches all  tissues of the rat within one  hour  of a sin-
gle oral dose and  is metabolized to heptachlor epoxide.  Heptachlor  has been
found to bind to hepatic  cytochrome P-450, an enzyme of the liver hydroxyla-
tion system (Donovan,  et  al.  1978).  By the end of  one month  traces  of heq-
tachlor epoxide were detectable only in fat  and liver.  Levels of  the  epox-
ide in fatty tissues stabilized  3 to 6 months after  a single  dose of hepta-
chlor  (Mizyukova and Kurchatov,  1970).   Human fat  samples  may also  contain
nonachlor  residues  derived from  technical heptachlor  or  chlordane  exposure
(Sovocool  and  Lewis,  1975).   When experimental animals were   fed heptachlor
for two months, the  highest levels of heptachlor  epoxide  were found  in fat,
with lower levels  in  liver,  kidney and  muscle and  none  in brain  (Radomski
and Davidow, 1953).   There is evidence to show that  the  efficiency  of con-
version to the epoxide  in  humans is less than in the rat (Tashiro and Matsu-
mura, 1978).  Various  researchers  have  found that heptachlor epoxide  is more
toxic to mammals than  the  parent compound (U.S. EPA', 1979).  There  is an  ap-
proximate  ten to fifteen-fold  increase in heptachlor residues found  in body
fat, milk  butterfat,  and  in the  fat of poultry,  eggs, and livestock  as com-
pared to residue levels found  in  their  normal food rations (U.S. EPA, 1976).

-------
Heptachlor  and its  epoxide  pass readily  through  the placenta  (U.S.  EPA,
1979).  The  epoxide can be  found in over 90  percent of the U.S. population
at approximate mean levels of 0.08 to 0.09 mg/kg  (Kutz,  at  al.  1977).
     C.  Excretion
         Elimination  of  non-stored  heptachlor   and  its  metabolites  occurs
within the  first  five days, chiefly in  the  feces and  to  a lesser extent  in
the urine (Mizyukova  and  Kurchatov,  1970).   In addition, a primary route for
excretion in females  is  through lactation,  mostly as  the epoxide.   Levels
can be as high as 2.05 mg/1  (Jonsson, et al. 1977).'
IV.  EFFECTS
     A.  Carcinogenicity
         The studies  on rats have generated, much controversy,  especially for
doses around 10 mg/kg/day.   However,  heptachlor and/or heptachlor epoxide  (1
to 18  mg/kg/day  of unspecified  purities) have induced hepatocellular  carci-
nomas  in  mice  during  three chronic  feeding  studies.   Heptachlor  epoxide
(also of  unspecified purity) has produced  the same  response  in rats  in one
study (Epstein,  1976; U.S.  EPA,  1977).   Clearly,  studies  with chemicals  of
specified purity  still need to be performed  to  establish if contaminants  or
species differences are responsible for the observed effects.
     8.  Mutagenicity
         Heptachlor  has  been  reported  to be  mutagenic in mammalian  assays
but  not  in  bacterial assays.   Heptachlor  (1  to  5  mg/kg)  caused  dominant
lethal changes in male rats  as  demonstrated  by the number 'of resorbed  fetus-
es in intact pregnant rats  (Carey, et al. 1973).  Bone marrow cells of  the
treated animals showed increases  in  the  incidence of abnormal  mitoses, chro-
                                                                          »
matid abnormalities,  pulverization,  and translocation.  9oth  heptachlor and
heptachlor  epoxide  induced  unscheduled  DNA  synthesis in  SV-AO transformed

                                   tlt^j /n -
                                  * I ai V "

-------
human  cells  (VA-4)  in  culture  with metabolic  activation  (Ahmed,  et al.
1977).  Neither  heptachlor nor  heptachlor epoxide was  mutagenic for Salmo-
nella tvphimurium in the Ames test (Marshall, et al. 1976).
     C.  Teratogenicity
         In  long-term feeding  studies with  heptachlor, cataracts  developed
in  the parent  rats and  in the  offspring shortly  after  their  eyes opened
(Mestitzova,  1967).
     D.  Other Reproductive Effects
         In  long-term feeding  studies  in rats, heptachlor  caused a marked
decrease in litter size and  a  decreased  lifespan  in  suckling rats (Mestit-
zova,  1967).   However,  newborn  rats were less susceptible  to  heptachlor than
adults  (Harbison, 1975).
     E.  Chronic Toxicity
         Little  information on  chronic effects is  available.   When  admini-
stered  to  rats  in  small daily doses  over  a  prolonged  period of  time, hepta-
chlor  induced alterations  in  glucose  homeostasis  which were  thought  to  be
related to an initial stimulation of the cyclic AMP-adenylate  cyclase system
in  liver  and kidney  cortex  (Kacew  and  Singhal,  1973,   1974;  Singhal  and
Kacew, 1976).
     F.  Other Relevant Information
         Heptachlor  is  a convulsant  (St.  Omer,  1971).   Rats fed protein-de-
ficient diets are  less susceptible  to heptachlor and  have lower heptachlor
epoxidase  activities  than pair-fed controls  (Webb  and  Miranda, 1973; Miran-
da,  et al.  1973;  Miranda  and  Webb,  1974).   Pnenobarbital  potentiates the
toxicity of heptachlor  in newborn  rats  (Harbison,  1975).  Many  liver and
brain enzymes are affected  by heptachlor down to 2 mg/kg doses in pigs  (U.S.
EPA, 1979).

-------
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
        •Numerous  studies on the acute  toxicity of heptachlor  to  freshwater
fish and invertebrate  species  have  been conducted.  Many of these  studies on
heptachlor  have  used technical grade  material.   Available data  suggest  that
toxicity of the  technical material  is attributable to the heptachlor  and its
degradation product,  heptachlor  epoxide,  and that  toxicities of  these  com-
pounds  are  similar (Schimmel,  at  al.  1976).   In  addition,  during  toxicity
testing with  heptachlor, there is  apparently an  appreciable  loss of hepta-
chlor by volatilization  due  to aeration or mixing, leading to variability of
static  and flow-through results  (Schimmel,  et al.  1976;  Goodman,  at  al.
1978).
         Fish  are less  sensitive  to  heptachlor than  are invertebrate  spe.-
cies.   Ninety-six hour  l_C50 values  for  fish  range  from  7.0  ug/1   for  the
rainbow trout,  Salmo  qairdneri,  (Macek,  et  al. 1969)  to 320  ug/1   for  the
.goldfish  (Carassius auratus).   Ten  days  after a dose  of 0.863  ug/g    C-
heptachlor  to  goldfish,  91.2  percent  was  unchanged,  5.4 percent  was hepta-
chlor  epoxide,   1  percent was  hydroxychlordene, 1.1  percent  was  1-hydroxy-
2,3-epoxychlordene and 1.2 percent was  a  conjugate  (Feroz  and Khan,  1979).
Reported values  for  invertebrate  species  range  from  0.9 pg/1 for  the stone-
fly, Pteronarcella badia,  (Sanders  and Cope,  1968)  to 80 ug/1 for  the clado-
ceran  (Simoceohalus serrulatis).   These  data  indicate  that  heptachlor  is
generally highly toxic in acute exposures.
         The relative  toxicity of heptachlor to its'  common degradation  pro-
duct, heptachlor epoxide,  is 52 ug/1  to 120 ug/1-as  determined  in a  26-hour
                                                                       »
LCs  Oaohnia maona bioassay (Frear and Soyd, 1967).

-------
         Heptachlor  has  been shown to be  acutely toxic to a number  of salt-
water  fish  and invertebrate  species.   The 96-hour  LC5Q values derived  from
flow-through tests on  four  fish species  range from 0.85 to 10.5 jjg/1 (Hansen
and Parrish,  1977;  Korn and.Earnest,  1974;  Schimmel, et al. 1976).   Results
of static exposures  of eight fish species are  from  0.8 to 194 ug/1  (Eisler,
1970;  Kutz,  1961).   The commercially valuable pink  shrimp  (Penaeus  duorarum)
is especially  sensitive, with  reported  96-hour  values  as low  as 0.03  jjg/1
(Schimmel,  et  al. 1976).   Other species  such  as the blue crab,  Callinectes
sapidus, and American  oyster, Crassostrea virginica, are 2,100 and  950 times
less sensitive, respectively, than the pink shrimp  (Butler, 1963).
     B.  Chronic  Toxicity
         In a  40-week  life  cycle test with fathead minnows (Pimephales prom-
elas),  the  determined  no-adverse-effect  concentration  was 0.86  jjg/1.   All
•••IBM**                                                                        ^
fish  exposed  to  1.84 ug/1  were dead  after 60  days (Macek,  et  al.  1976).
Valid  chronic  test  data are not available for  any aquatic invertebrate  spe-
cies.
         In a  28-day exposure starting with sheepshead minnow embryo (Cypri-
nodon  varieqatus) growth of fry was significantly  reduced  at  2.04 jug/l,  the
safe dose being  at  1.22 jug/1 (Goodman,  et al.  1978).  In an 18-week partial
life cycle exposure  with this same  species,  egg production was significantly
decreased at 0.71 jug/1 (Hansen and Parrish, 1977).
     C.  Plant Effects
         In the only study  available,  a  concentration of 1,000 jug/1  caused a
94.4 percent  decrease  in productivity of a natural- saltwater  phytoplankton
community after a 4-hour exposure to heptachlor (Butler, 1963).
     0.  Residues
         The amount  of  total residues,   heptachlor  and heptachlor   epoxide,
accumulated by fathead minnows after  276 days  of exposure  was found to be

-------
20,000 times  the concentration  in water  (Macek,  et  al.  1976).  Heptachlor
epoxide constituted  10-24 percent  of the  total residue.   Adult sheepshead
minnows exposed  to  technical grade material  for 126 days accumulated  hepta-
chlor and  heptachlor epoxide 37,000 times  over  the concentration of ambient
water  (Hansen and  Parrish,  1977).   Juvenile sheepshead  minnows exposed  in
two  separate  experiments  for  28 days  bioconcentrated heptachlor  5,700  and
7,513 times the  concentration in the water (Hansen and Parrish, 1977;  Good-
man, et al. 1976).
VI.  EXISTING GUIDELINES AND STANDARDS
     The issue  of the carcinogenicity  of heptachlor  in  humans is being  re-
viewed; thus, it is possible that the human health criterion will be changed.
     A.  Human
         Based on the data for the carcinogenicity  of heptachlor epoxide  in
mice (Davis,  1965),  and using the  "one-hit"  model,  the U.S.  EPA (1979)  has
estimated  levels of heptachlor/heptachlor  epoxide  in ambient  water  which
will result in risk levels of human cancer as specified in the  table below. ,
Exposure Assumptions            Risk Levels and  Corresponding Draft Criteria
     (per day)
                                0         10-7           10-6        iQ-5
2 liters of drinking water      0       0.0023 ng/1     0.023 ng/1  0.23 ng/1
and consumption of 13.7
grams fish and shellfish.
Consumption of fish and         0       0.0023 ng/1     0.023 ng/1  0.23 ng/1
shellfish only.
                       Existing Guidelines and Standard? ._
Agency                     Published Standard       '     Reference
Occup.  Safety           500 ug/m^* on skin from  air    Natl. Inst. Occyp.
  Health Admin.                                          Safety Health,  1977
Am. Conf. Gov.          500 ug/rn-^ inhaled              Am. Conf. Gov. Ind.
  Ind.  Hyg. (TLV)                                        Hyg.,  1971
world Health Org.       0.5 ug/kg/day acceptable       Natl. Acad. Sci., 1977
                          daily intake in diet
                                    / o r-LL
                                  *T LA f I   .

-------
U.S. Publ. Health       Recommended drinking water     Natl. Acad.  Sci.,  1977
  Serv. Adv. Comm.        standard (1968) 18 jjg/1 of
                          heptachlor and 18 )jg/l of
                          heptachlor epoxide

*Time-weighted average


     B.  Aquatic

         For  heptachlor the.  draft criterion  to protect  freshwater aquatic

life is  0.0015 jjg/1 as  a  24-hour average,-  not to  exceed 0.45  ug/1 at  any

time.  To protect  saltwater aquatic  life,  the draft criterion is 0.0036  ug/1

as a 24-hour average, not to exceed 0.05 ug/1 at any time  (U.S. EPA,  1979).

-------
                          HEPTACHLOR
                          REFERENCES

Ahmed, F.E-., at al.  1977.  Pesticide-induced DNA  damage
and its repair in cultured human cells.  Mutat.  Res.  42:
161.

American Conference of Governmental Industrial Hygienists
1971.  Documentation of the threshold limit values for
stances in.workroom air.  3rd. ad-

Benson, W.R., at al.  1971.  Photolysis of solid and  dis- '
solved dieldrin.  Jour. Agric. Food Chem. 19: 66.

Breidenbach, A.W., et-al.  1967.  Chlorinated hydrocaroon
pesticides in major ri-ver basins, 1957-65.  Pub. Health
Rep. 32: 139.

Butler, P.A.  1963.  Commercial Fisheries Investigations,
Pesticide-Wildlife Studies, a Review of Fish and Wildlife
Service Investigations During 1961-1962.  U.S. Dept.  Inter.
Fish and Wildl/Circ. 167: 11.

Cerey, K.r at al.  1973.  Effect of heptachlor on  dominant
lethality and bone marrow in rats.  Mutat. Res.  21: 26.

Davidow, B. and J.L. Radomsici.  1953.  Isolation of an epox-
ide metabolite from fat tissues of dogs fed heptachlor.
Jour.  Pharmacol. Exp. Ther. 107: 259.

Davis, K.J.  1965.  Pathology report on mice fed aldrin,
dieldrin, heptachlor, or heptachior epoxide for  two years.
Internal Memorandum to Dr. A.J. Lehman.  U.S. Fcod Drug
Admin.

Donovan, M.P., at al.  1978.  Effects of pesticides on metabo-
lism of steroid hormone by rodent liver microsomes.   Jour.
Environ. Pathol. Toxicol.. 2: 447.

Sisler, R.  1970.  Factors affecting pesticide-induced
toxicity in an estuarine fish.  Bur. Sport Fish. Wildl.
Tech. Paper 45.  U.S. Dept. Inter, p. 20_.
                                         *    * ..
Epstein, S.S.  1976.  Carcinogenic!ty of heptachlor and
chlordane.  Sci. Total Environ. 6: 103.
                                                   14
Feroz, M., and M.A.Q. Khan.  1979.  Metabolism of   C-hepta-
chlor in goldfish (Carassius auratus) .  Arch Environ.  Contain.
Toxicol. 3: 519.

-------
Frear, D.E.H., and J.E. Boyd.  1967.  Use of Daphnia magna
for the microbioassay of pesticides.  I.  Development ot
standardized techniques for rearing Daphnia and preparation
of dosage-mortality curves for pesticides.  Jour. Econ.
Entomol. 60: 1228.

Gaines, T.B.  1960.  The acute toxicity of pesticides to
rats.  Toxicol. Appl. Pharinacol. 2: 88.

Gannon, N., and G.C. Decker.  1958.  The conversion of aldrin
to dieldrin on plants.  Jour. Econ. Entomol. 51: 8.

Georgackakis, E., and M.A.Q.- Khan.  1971.  Toxicity of the
photoisomers of cyclodiene insecticides to freshwater animals.
Nature 233: 120.

Goodman, L.R.-, et al.  1978.  Effects of heptachlor and
toxaphene on Laboratory-reared embryos and fry of the sheeps-
head minnow.  Proc. 30th Annu. Conf. S.E. Assoc. Game Fish
Comm.  p. 192.

Hansen, D.J., and P.R. Parrish.  1977.  Suitability of sheeps-
head minnows (Cyprinodon variegatus) for life-cycle toxicity
tests.  Pages 117-126 In; F.L. Mayer and J.L. Hamelink,
eds.  Toxicology and hazard evaluation.  ASTM STP 634, Am.
Soc.  Test. Mater.

Harbison, R.D.  1975.  Comparative toxicity of selected
pesticides in neonatal and adult rats.  Toxicol. Appl.
Pharmacol. 32: 443.

Henderson, C., et al.  1969.  Organochlorine insecticide
residues in fish (National Pesticide Monitoring Program).
Pestic. Monitor. Jour. 3: 145.

Ivie, G.W., et al.  1972.  Novel photoproducts of hepta-
chlor expoxide, trans-chlordane and trans-nonachlor.  Bull.
Environ. Contam. Toxicol. 7: 376.

Johnson, R.D., and D.D. Manske.  1977.  Pesticide and other
chemical residues in total diet samples (XI).  Pestic. Monitor.
Jour. 11: 116.

Jonsson, V., et al.  1977.  Chlorohydrocarbon pesticide
residues in human milk in greater St. Louis, Missouri, 1977.
Am. Jour. Clin. Nutr. 30: 1106.

Kacew, S., and R.L. Singhal.  1973.  The influence of p,p -
DDT, and chlordane, heptachlor and endrin on hepatic and
renal carbohydrate metabolism and cyclic AMP-adenyl cyclas«e
system.  Life Sci. 13: 1363.

-------
Kacew, S-., and R.L. Singhal.  1974.  Effect  of  certain,halo-
genated hydrocarbon insecticides on cyclic adenosine  3  ,5i-
monophosphate- H formation by rat kidney cortex.   Jour.
Pharmacol. Exp.  Ther. 183: 265.

Khan, M.H., et al.  1969.  Insect metabolism of photoaldrin
and photodieldrin.  Science 164:  318.

Khan, M.A.Q., et al.  1973.  Toxicity-metabolism  relation-
ship of the photoisomers of certain chlorinated cyclodien
insecticide chemicals.  Arch. Environ. Contain.  Toxicol.
1: 159.

Korn, S., and R. Earnest.  1974.  Acute toxicity  of twenty
insecticides to the striped bass, Morone saxtilis.  Calif.
Fish Game 60: 128.

Kutz, F.W., et al.  1977.  Survey of pesticide  residues
and their metabolites in humans.  In: Pesticide management
and insecticide resistance.  Academic. Press, New  York.

Kutz, M.  1961.  Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine stickle-
back.  Trans. Am. Fish. Soc. 90:"264.

Lichtenstein, E.P.  1960.  Insecticidal residues  in various
crops grown in soils treated with abnormal rates  of aldrin
and heptachlor.  Agric. Food Chera. 8: 448.

Lichtenstein, E.P., et al.  1970.  Degradation  of aldrin
and heptachlor in field soils.  Agric. Food  Chem.  18:   100.

Lichtenstein, E.P., et al.  1971.  Effects of a cover crop
versus soil cultivation on the fate of vertical distribution
of insecticide residues in soil 7 to 11 years after soil
treatment.  Pestic. Monitor. Jour. 5: 218.

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.  U.S. Environ. Prot.
Agency, EPA 600/3-76-099.

Marshall, T.C., et al.  1976.  Screening" *of  pesticides for
tnutagenic potential using Salmonella typhimurium  mutants.
Jour. Agric. Food Chem. 241 TSTT      '"

Matsumura, F., and J.O. Nelson.  1971.  Identification of
the major metabolite product of heptachlor epoxide in rat '
feces.  Bull. Environ. Contam. Toxicol. 5: 489.
                           I

-------
Mestitzova, M.  1967.  On reproduction studies on the occur-
rence of cataracts in rats after long-term feeding of the
insecticide heptachlor.  Experientia 23: 42.

Miranda, C.L., and R.E. Webb.  1974.  Effect of diet and
chemicals on pesticide toxicity in rats.  Philipp. Jour.
Nutr. 27: '30.

Miranda, C.L., et al.  1973.  Effect of dietary protein
quality, phenobarbital, and SKF 525-A on heptachlor metabo-
lism in the rat.  Pestic. Biochem. Physiol. 3: 456.

Mizyukova, I.G., and G.V. Kurchatav.  1970.  Metabolism
of heptachlor.  Russian Pharmacol. Toxicol. 33: 212.

Nash, R.G., and W.G. Harris.  1972.  Chlorinated hydrocarbon
insecticide residues in crops and soil.  Jour. Environ.
Qual.

National Academy of Sciences.  1977.  Drinking water and
health.  Washington, D.C.

National Institute for Occupational Safety and Health.
1977.  Agricultural chemicals and pesticides:  a subfile
of the registry of toxic effects of chemical substances.

Nisbet, I.C.T.  1977.  Human exposure to chlordane, hepta-
chlor and their metabolites.  Unpubl. rev. prepared for
Cancer Assessment Group, U.S. Environ. Prot. Agency, Wash-
ington, D.C.

Podowski, A.A., et al.  1979.  Photolysis of heptachlor
and cis-chlordane and toxicity of their photoisomers to
animals.  Arch. Enviorn. Con tarn. Tox.icol. 8: 509.

Radomski, J.L., and B. Davidow.  1953.  The metabolite of
heptachlor, its estimation, storage, and toxicity.  Jour.
Pharmacol. Exp. Ther. 107: 266.

Ritcey, W.R., et al.  1972.  Organochlorine pesticide resi-
dues in human milk, evaporated milk, and some milk substi-
tutes in Canada.  Can. Jour. Publ. Health 63: 125.

St. Omer, V..  1971.  Investigations into mechanisms respon-
sible for seizures induced by chlorinated_ hydrocarbon insecti-
cides:  The role of brain ammonia and glutamine in convul-
sions in the rat and cockerel.  Jour. Neurochem. 18: 365.

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

-------
Savage, E.P.  1976.  National study  to determine  levels
of chlorinated hydrocarbon insecticides  in  human  milk.
Unpubl. rep, submitted to U.S. Environ.  Prot. Agency.

Schimmel, S.C., et al.  1976.  Heptachlor:  Toxicity  to
and uptake by several estuarine organisms.  Jour.  Toxicol.
Environ. Health 1: 955.

Singhal, R.L., and S. Kacew.  1976.  The role of  cyclic
AMP in chlorinated hydrocarbon-induced toxicity.   Federation
Proc. 35: 2618..

Sovocool, G.W., and R.G.. Lewis.  1975.   The identification
of trace levels of organic pollutants in humans:  compounds
related to chlordane heptachlor exposure.  Trace  Subst.
Environ. Health 9: 265.

Tashiro, S., and P. Matsumura.  1978.  Metabolism of  trans-
monachlor and related chlordane components  in rats and man.
Arch. Environ. Contain. Toxicol. 7: 113.

U.S. EPA.  1976.  Chlordane and heptachlor  in relation to
man and the environment.  EPA 540/476005.

U.S. EPA.  1977.  Risk assessment of chlordane and hepta-
chlor.  Carcinogen Assessment Group.  U.S. Environ. Prot.
Agency, Washington, D.C.  Unpubl. rep.

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

Webb, R.E.., and C.L. Miranda.  1973.  Effect of the quality
of dietary protein on heptachlor toxicity.  Food  Cosmet.
Toxicol. 11: 63.
                              i 1 >-*x
                             / c* / (/ -

-------
                                      No. 109
         Heptachlor Epoxide

  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.

-------
                      HEPTACHLOR  EPOXIDE
                           SUMMARY
     Heptachlor epoxide is the principal metabolite of hepta-
chlor in microorganisms,  soil, plants,  animals,  and probably
man,  and  is  more acutely  toxic  than  the parent  compound.
Its  intrinsic  effects  are  difficult  to gauge  since  most
of  the  relevant  data in the  literature  is  a side  product
of  the  effects  of technical heptachlor.   Heptachlor  epoxide
(mostly  of  unspecified  purity)   has  induced  liver  cancer
in  mice and  rats and  was  mutagenic  in  a  mammalian  assay
system, but. not in a bacterial system.   Pertinent information
on  teratogenicity  and chronic toxicity could not  be  located
in  the  available  literature.   Heptachlor epoxide  accumulates
in adipose tissue..
     The chronic  value  for  the  compound derived from  a  26-
hour exposure of  Daphnia  magna  is  reported  to be  120  ug/1,
approximately the same value obtained for heptachlor.
     Fathead  minnows  bioconcentrated   heptachlor  and  its
biodegradation  product,   heptachlor  expoxide,  20,000  times
after 276 days  of exposure.   Heptachlor  epoxide  constituted
between 10 and 24 percent of the  total residue.
                         /09-J

-------
                      HEPTACHLOR EPOXIDE
I.   INTRODUCTION
     This  profile  is  based  on  the  Ambient  Water  Quality
Criteria Document for Heptachlor  (U.S. EPA,  1979a).
     Heptachlor epoxide is the principal metabolite  of hepta-
chlor in microorganisms,  soil,  plants, and mammals,  although
the  conversion in  man may  be  less  efficient  (Tashiro  and
Matsumura, 1978) .   Since  much of the  data has been  obtained
as  a side-product  of  the effects  of  technical heptachlor
and  the  purity of  the epoxide  is  often  unspecified,  there
is  a paucity  of  reliable literature  on  its  biological  ef-
fects (U.S. EPA, 1979a).
     Heptachlor  epoxide  is  relatively   persistent   in   the
environment  but has  been shown  to undergo photodecomposi-
tion  to  photoheptachlor  epoxide  (Graham,  et  al.   1973).
Photoheptachlor epoxide has been  reported  to exhibit  greater
toxicity than heptachlor epoxide  (Ivie, et al. 1972).   Hepta-
chlor epoxide  will  bioconcentrate   in numerous  species  and
will accumulate in the food chain (U.S. EPA, 1979a).
II.  EXPOSURE
     A.    Water
          Heptachlor  epoxide  has  been  detected  by  various
investigators in the major river  basins  of the United  States
(U.S. EPA,   1979a)  at  levels ranging from  0.001  to 0.020
ug/1 (Breidenbach, et al.  1967).
     B.    Food
          The PDA showed in their market basket survey  (1974-
1975) of  20  different  cities  that 3 of  12 food  classes con-

-------
tained  residues of  heptachlor  epoxide ranging  from  0.0006
to 0.003 ppm  (Johnson  and  Manske,  1977).  Heptachlor  epoxide
residues  greater  than 0.03  mg/kg were found  in 14  to  19
percent  of  red meat,  poultry,  and  dairy  products  during
the  period 1964-1974.   Average  daily  intake  was estimated
to be between  0.3  to 3 ug  from  1965  to 1974 (Nisbet,  1977).
Heptachlor  and/or  heptachlor  epoxide  were  found  in  32  per-
cent  of 590  fish  samples obtained  nationally,  with whole
fish  residues  containing  0.01  to  8.33  mg/kg   (Henderson,
et al.  1969) .    Human  milk  can  be contaminated  with  hepta-
chlor epoxi.de;  63  percent of  samples  in 1975-1976 contained
1  to 2,050 ug/1  (fat  adjusted)  (Savage,  1976).   Levels  of
5  ng/1  have been  reported in evaporated milk.   Cooking did
not  reduce the residue  level in  poultry  meat  by more  than
one-half (Ritcey, et al. 1972).
          The  U.S.  EPA  (1979a)   has  estimated  the  weighted
average  bioconcentration  factor  for  heptachlor to  be 5,200
for  the edible  portions  of  fish  and  shellfish  consumed  by
Americans..   This estimate  is based on  the  measured  steady-
state  bioconcentration  studies   in  three  species of fish.
Since heptachlor epoxide is  the  primary metabolite of  hepta-
chlor and  shows greater persistence  in body fat  (U.S.  EPA,
1976) , it may be assumed that  heptachlor  epoxide  is bioconcen-
trated to at least the same extent as heptachlor.
     C.    Inhalation
          Heptachlor  epoxide  is  present  in ambient  air ,to
a  lesser  extent than heptachlor  and  is not  thought  to  con-

-------
tribute  substantially  to  human  exposure  except   in  areas
near sprayed fields, where  concentrations  of up to 9.3 pg/ra
may be encountered  (Nisbet, 1977).
     0.   Dermal
          Gaines  (1960)   found  rat  dermal  LDen  values  of
195 and  200  mg/kg  for  males and  females,  respectively, com-
pared  with  oral LDcQ' s of  100 and  162  mg/kg,  respectively,
for technical  heptachlor.   Thus,   it  is likely  that  dermal
exposure in humans can be important under certain conditions.
III. PHAEMACOKINETICS
     A.   Absorption
          Heptachlor epoxide  is  readily  absorbed   from  the
gastrointestinal tract (U.S. EPA, 1979a).
     B.   Distribution
          Studies dealing directly  with exposure to  hepta-
chlor  epoxide could  not  be located  in the  available litera-
ture.    After oral  administration  of  heptachlor to experi-
mental  animals,  high  concentrations  of heptachlor  epoxide
have been  found in  fat,  with much  lower  levels in  liver,
kidney, and muscle, and none in  brain  (Radomski and  Davidow,
1953).    Another study  (Mizyukova  and Kurchatav,  1970)  also
demonstrated the  persistence  of  heptachlor epoxide in  fat.
Levels in  fatty  tissues  stabilize  after three  to  six  months
after   a  single  dose.   The  U.S.   EPA  (1979a)  states  that
there   is approximately 10-  to  15-fold increase  in heptachlor
                                                          »
residues found  in  body  fat, milk  butter fat,  and in the  fat
of poultry eggs  and livestock  as  compared  to residue  levels
found   in  their  normal  food  rations.   "Heptachlor  residues"
                          /of-/

-------
probably  refers  primarily to heptachlor epoxide.   Heptachlor
epoxide passes readily through  the placenta  (U.S.  EPA,  1979a)
and could  be  found  in over 90 percent of the U.S.  population
at average levels of  around  90  ng/kg  (Kutz,  et  al.  1977).
     C.   Metabolism  and  Elimination
          Heptachlor  epoxide accumulates  in adipose  tissue,
as  discussed  in  the  "Distribution"  section.    The  primary
route for excretion is fecal  (Mizyukova and  Kurchatav,  1970).
When  heptachlor  epoxide  was fed  to  rats  over a  period of
30  days,  approximately  20  percent of  the  administered  dose
(approximately 5  mg  heptachlor epoxide/rat/30 day)  was ex-
creted  in the feces,  primarily  as  1-exo-hydroxyheptachlor
epoxide   and   1,2-dihydroxydihydrochlordene  (Matsumura  and
Nelson,  1971; Tashiro  and  Matsuraura,  1978).    In  females,
a  primary route for excretion  is  via   lactation,   usually
as the  epoxide.   Levels can be as  high  as 2.05 mg/1  (Jonas-
son, et al. 1977).
IV.  EFFECTS
     A.   Carcinogenicity
          Heptachlor  epoxide of  unspecified  purity  induced
hepatocellular carcinoma  in a  chronic  feeding   study  with
mice  and  in   one  study with  rats  (Epstein,  1976;  U.S.  EPA,
1977) .
     B.   Mutagenicity
          Heptachlor  epoxide  induced  unscheduled  DNA  syn-
thesis  in SV-40   transformed human cells   (VA-4)   in culture
when  metabolically  activated  (Ahmed,  et  al.  1977),  but was

-------
not  mutagenic for  Salmonella typhimurium  in the  Ames test
(Marshall, et al. 1976) .
     C.   Teratogenicity,  Other   Reproductive  Effects  and
          Chronic Toxicity
          Pertinent data  could not be  located in the avail-
able literature.
     0.   Other Relevant Information
          Heptachlor  epoxide  is  more  acutely  toxic  than
heptachlor  (U.S.  EPA,  1979a) .  It  inhibits synaptic calcium
magnesium dependent ATPases in rats (Yamaguchi, et al. 1979).
V .   AQUATIC TOXICITY
     A.   Acute Toxicity
          Acute  toxicity  data could  not  be  located  in the
available literature  relative to  the effects of heptachlor
epoxide on fish or invertebrates.
     3.   Chronic Toxicity
          In  the only  reported  chronic  study,   the 26-hour
LCcn for • heptachlor epoxide  in  Daphnia magna was  120  ug/1
(Frear and Boyd,  1967) .   In  the  same  test, the corresponding
value for heptachlor was 52 ug/1.
     C.   Plant Effects
          Data  on  the  toxicity  of  heptachlor  epoxide  to
plants could not be located in the available literature.
     D.   Residues          *
          Macek,  et al.  (1976) determined 'the bioconcentra-
tion factor of  20,000  for heptachlor and  heptachlor epoxide
                                                          »
in  fathead  minnows  after 276 days'   exposure.    Heptachlor
epoxide  residues were  reported  as  constituting  10  to  24
percent of the  total residue.  The  geometric mean bioconcen-
                          /or-3

-------
    tration  factor  for heptachloc  in  all species of  fish  tested

    is 11,400  (U.S.  EPA, 1979a).   As explained  in the  "Distri-

    bution"  section of  this  text, the  bioconcentration  factor

    for  heptachlor  epoxide would  be as  least as  great as  that

    for heptachlor.

    VI.  EXISTING GUIDELINES AND STANDARDS

         A.   Human

              The  existing  guidelines  and standards  for  hepta-

    chlor and heptachlor epoxide are:
 AGENCY/ORG.

Occup. Safety
 Health Admin.

Am. Conf. Gov.
 Ind. Hyg. (TLV)

Fed. Republic
 Germany

Soviet Union
World Health
 Organ.**

U.S. Pub. Health
 Serv. Adv. Comm.
          STANDARD
500 ug/m * on skin from air
500 ug/m  inhaled


500 ug/ra3 inhaled
10 ug/m  ceiling value
 inhaled

0.5 ug/kg/day acceptable
 daily intake in diet

Recommended drinking water
 standard (1968) 18 pg/1 of
 heptachlor and 18 ug/1
 heptachlor epoxide
    REFERENCE

Natl. Inst. Occup.
 Safety Health, 1977

Am. Conf. Gov. Ind.
 Hyg., 1971

Winell, 1975
Winell, 1975
Natl. Acad. Sci.,
 1977

Natl. Acad. Sci.,
 1977
*   Time weighted average

** Maximum residue limits in certain foods can be found in Food Agric,
   Organ./World Health Organ. 1977, 1978


              The U.S. EPA (1979a)  is in the  process of establish-

    ing ambient water quality criteria  for  heptachlor and hepta-

    chlor epoxide.   Based on potential carcinogenicity of hepta-

    chlor epoxide, the draft criterion  is calculated on the esti-

-------
mate that 0.47  ng/raan/day would result in an increased addi-
tional  lifetime cancer  risk  of  no  more  than  1/100,000.
Based  on  this  lifetime  carcinogenicity  study  of heptachlor
epoxide at  10  ppm in  the diet  of C3Heb/Pe/J  strain mice,
the  recommended draft  criterion  is  calculated  to  be 0.233
ng/1.
     B.   AQUATIC
          No  existing guidelines  are  available  for  hepta-
chlor epoxide.  However, since heptachlor epoxide  is a biode-
gradation product of heptachlor, the hazard profile on hepta-
chlor should be consulted  *U.S. EPA, 1979b).
                             *

-------
                              HEPTACHLOR EPOXIDE

                                  REFERENCES
Ahmed, F.E.,  et al.  1977.   Pesticide-induced  DNA damage and  its repair in
cultured human cells.  Mutat. Res.  42: 1612.

American Conference  of  Governmental Industrial  Hygienists.   1971.  Documen-
tation of  the threshold limit values  for substances in workroom  air.   3rd.
«U

Breidenbach,  A.W.,  et   al.   1967.   Chlorinated  hydrocarbon  pesticides  in
major river basins, 1957-65.  Pub. Health Rep.  82: 139.

Epstein,  S.S.   1976.   Carcinogenicity  of heptachlor  and chlordane.   Sci.
Total Environ.  6: 103.

Frear, D.E.H.  and  J.E.  Boyd.  1967.  Use  of  Daphnia magna for the microbio-
assay and  pesticides.   I. Development  of standardized techniques for rearing
Daohnia  and preparation  of dosage-mortality curves for  pesticides.   Jour.
Econ. Entomol.  60: 1228.

Gaines,  T.B.   1960.  The acute  toxicity of pesticides  to  rats.   Toxicol..
Appl. Pharmacol.  2:88.                                                     i

Graham, R.E.,  et al.  1973.   Photochemical decomposition of heptachlor epox-
ide.  Jour. Agric. Food Chem.  21: 284.

Henderson,  C., et  al.   1969.  Organochlorine  insecticide residues  in  fish
(National Pesticide Monitoring Program).  Pestic. Monitor.  Jour.  3: 145.

Ivie, G.W., et al.   1972.   Novel  photoproducts  of heptachlor  epoxide,  trans-
chlordane, and trans-nonachlor.   Bull.  Environ.  Contain. Toxicol.  7: 376.

Johnson, R.D.  and D.D.  Manske.  1977.   Pesticide and other chemical residues
in total diet samples (XI).   Pestic. Monitor. Jour.  11: 116.

Jonasson,  V.,  et al.   1977.  Chlorohydrocarbon pesticide  residues  in  human
milk in greater St. Louis, Missouri, 1977.  Am.  Jour. Clin. Nutr.  30: 1106.

Kutz, F.w.,  et al.   1977.   Survey of  pesticide residues  and  their metabo-
lites  in  humans.   In:    Pesticide management   and  insecticide  resistance.
Academic Press, New York.

Macek, K.J.,  et  al.  1976.    Toxicity  of four pesticides to  water  fleas  and
fathead minnows.  U.S. Environ.  Prot. Agency,  EPA-600/3-76-099.

Marshall,  T.C., et  al.   1976.  Screening of pesticides for mutagenic  poten-
tial using Salmonella typhimurium  mutants.  Jour. Agric. Food  Chem.   24:  560.

Matsumura, F.  and J.O.  Nelson.  1971.   Identification of the  major metabolic
product of heptachlor epoxide in  rat feces.   Bull. Environ. Contam.  Toxicol.
5: 489.
                                /&?•//

-------
 Mizyukova,  I.G.  and  G.V.  Kurchatav.   1970.   Metabolism  of  heptachlor.
 Russian Pharmacol.  Toxicol.  33: 212.

 National   Academy  of   Sciences.    1977.    Drinking   water   and  health.
 Washington, O.C.

 National  Institute  for  Occupational Safety and  Health.   1977.   Agricultural
 chemicals  and  pesticides: a  subfield of the  registry  of toxic  effects of
 chemical substances.

 Nisbet,  I.C.T.   1977.   Human exposure  to chlordane,  heptachlor  and  their
 metabolites.   Unpubl.  rev.  prepared,  for  Cancer  Assessment  Group,  U.S.
 Environ. Prat.  Agency, Washington, O.C.

 Radmoski,  J.L.  and 8.  Oavidow.    1953.   The metabolite of  heptachlor,  its
 estimation, storage, and toxicity.  Jour. Phaimacol. Exp. Ther.   107: 266.

 Ritcey,  W.R.,  et al.   1972.  Organochlorine  insecticide residues  in  human
 milk, evaporated milk and some milk substitutes  in  Canada.  Can. Jour. Publ.
 Health.  63: 125.

 Savage,  E.P.    1976.   National  study  to  determine  levels  of  chlorinated
 hydrocarbon insecticides  in  human milk.   Unpubl.  rep.  submitted to  U.S.
 Environ. Prat.  Agency.
                                                                             4
 Tashiro, S. and  F.  Matsumura.  1978.   Metabolism of  trans-nonachlor and  re-
 lated chlortane  components  in rat and man.  Arch.  Environ.  Contain. Toxicol.
 7: 113

 U.S. EPA.   1977.  Risk assessment  of chlordane and  heptachlor.   Carcinogen
 Assessment Group.  U.S.  Environ.  Prat. Agency,  Washington, O.C.   Unpubl.  rep.

"U.S. EPA.  1979a.  Heptachlor:  Ambient Water Quality Criteria (Draft).

 U.S. EPA.  1979b.  Environmental Criteria and Assessment Office.   Heptachlor
 Epoxide: Hazard Profile.  (Draft)

 Winell, M.A.   1975.   An international comparison  of hygienic standards  for
 chemicals in the work  environment.   Ambio.   4:  34.

 Yamaguchi, I.,  et al.   1979.  Inhibition of  synaptic atpases by  heptachlor
 epoxide in rat  brain.  Pest. Biochem.  Physiol.   11:  285.
                                J

-------
                                   No. HO
        Hexachlorobenzene

  Health and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON,  D.C.  20A60

          APRIL 30, 1980
        /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.

-------
                      SPECIAL NOTATION
U.S.  EPA13  Carcinogen Assessment Group  (CAG) has evaluated




hexachlorobenzene and has found sufficient  evidence to




indicate  that  this compound is carcinogenic.
                             //0-3

-------
                               HEXACHLOROBENZENE
                                    Summary

     Hexachlorobenzene is ubiquitous  in the environment and has an extremely
slow  rate of  degradation.   Ingested  hexachlorobenzene is  absorbed  readily
when  associated  with lipid material  and,  once absorbed,  is stored for  long
periods  of time  in the  body  fat.   Chronic exposures  can cause  liver  and
spleen damage and can induce the hepatic microsomal mixed functional  oxidase
enzyme.  Hexachlorobenzene can pass the placenta! barrier and produce toxic
or lethal  effects on the  fetus.  Hexachlorobenzene appears  to be neither a
teratogen nor a  mutagen;  however, this compound has produced tumors in  both
rats and mice.
     In  the  only  steady-state  study  with  hexachlorobenzene,  the  pinfish,
Laqodon.  rhoimboides, bioconcentrated  this compound  23,000 times in  42  days
of exposure.  The concentration  of  HC8 in muscle of pinfish was reduced  only
16 percent  after 28 days of depuration,  a  rate  similar to that  for  DOT in
fish.

-------
                               HEXACHLOROBENZENE
I.   INTRODUCTION
     This  profile  is based  on the Ambient  Water Quality Criteria  Document
for Chlorinated Benzenes (U.S. EPA, 1979).
     Hexachlorobenzene  (HCB;  CgCl^;  molecular weight  284.79)  is  a  color-
less solid with  a  pleasant aroma.   Hexachlorobenzene has a melting point  of
230°C,  a  boiling  point  of 322°C,  a density  of 2.044- g/ml,  and  is  vir-
tually  insoluble  in  water.   Hexachlorobenzene  is  used  in  the control  of
fungal  diseases  in cereal seeds intended  solely  for planting,  as a  plasti-
cizer for polyvinyl chloride, and as a flame retardant (U.S.  EPA, 1979).
     Commercial production  of  hexachlorobenzene in the  U.S.  was  discontinued
in 1976 (Chem. Econ.  Hdbk.,  1977).   However,  even prior to 1976, most, hexa-
chlorobenzene was  produced as a waste by-product during the  manufacture 4'of
perchloroethylene, carbon tetrachloride,  trichloroethylene, and  other  chlor-
inated  hydrocarbons.  This is  still the major  source of hexachlorobenzene  in
the  U.S.,  with  2,200 kg  being produced  by  these   industries  during  1972
(Mumma  and Lawless, 1975).
II.  EXPOSURE
     A.  Water
         Very little  is known regarding  potential  exposure  to  hexachloro-
benzene  as a result of ingestion  of  contaminated water.  Hexachlorobenzene
has been detected  in specific bodies of  water,  particularly near points  of
industrial discharge  (U.S.  EPA,  1979).  Hexachlorobenzene  has been detected
in the  polluted  waters  of the Mississippi River  (usually below  2 ng/kg) and
in  the   clean waters of  Lake  Superior  (concentrations  not  quantitatively
measured).    Hexachlorobenzene  was  detected  in drinking water  supdlies  at
                                 \io-s

-------
three  locations,  with  concentrations  ranging  from  6 to  10  ng/kg,  and  in
finished drinking water at two locations, with concentrations  ranging  from 4
to 6 ng/kg (U.S. EPA, 1975).
     B.  Food
         Ingestion of excessive amounts of hexachlorobenzene has been  a con-
sequence  of  carelessness,  usually  from  feeding  seed grains  to  livestock.
Foods high in  animal  fat (e.g., meat, eggs, butter,  and  milk)  have the high-
est concentrations of hexachlorobenzene.   The daily intake of  hexachloroben-
zene by  infants from human breast  milk in part of Australia was 39.5 jjg per
day per 4 kg baby.  This exceeded the acceptable daily intake  recommended by
the FAO/WHO of 2.4 jjg/kg/day  (1974).  The dietary intake by young  adults (15
to 18-year old  males.) was estimated to be 35 jug hexachlorobenzene  per  person
per  day (Miller  and Fox,  1973).   The  U.S.  EPA  (1979) has  estimated  the
weighted average bioconcentration factor for hexachlorobenzene to be  12,000
for the  edible portions  of  fish and  shellfish  consumed by Americans.   This
estimate is based  on the octanol/water partition  coefficient  of hexachloro-
benzene.
     C-  Inhalation
         Hexachlorobenzene  enters  the air  by   various  mechanisms,  such  as
release  from   stacks  and  vents  of industrial  plants,   volatilization  from
waste dumps and impoundments,  intentional spraying and dusting, and uninten-
tional dispersion  of hexachlorobenzene-laden  dust from  manufacturing  sites
(U.S. EPA  1979).   No  data  is  given on  the concentrations  of hexachloro-
benzene  in  ambient air.   Significant occupational"  exposure  can  occur  par-
ticularly to pest control operators  (Simpson and Chandar, 1972).

-------
     0.  Dermal
         Hexachlorobenzene may  enter the body by absorption through the  skin
as a result of skin contamination (U.S. EPA,  1979).
III. PHARMACOKINETICS
     A.  Absorption
         To date, only  absorption of hexachlorobenzene from the gut has  been
examined  in detail.   Hexachlorobenzene in  aqueous suspensions  is absorbed
poorly in  the  intestines of rats (Koss and  Koransky,  1975); however, cotton
seed oil  (Albro and  Thomas,  1974)  or olive  oil  (Koss and  Koransky, 1975)
facilitated  the  absorption.   Between  70  and 80  percent  of doses of hexa-
chlorobenzene ranging from 12  mg/kg to 180 mg/kg were absorbed.  Hexachloro-
benzene in  food  products will selectively partition  into  the lipid portion,
and hexachlorobenzene in  lipids  will be absorbed  far  better  than  that in an
aqueous milieu (U.S. EPA, 1979).
     8.  Distribution
         The highest  concentrations  of hexachlorobenzene  are  found  in  fat
tissue (Lu  and Metcalf,  1975).   In rats receiving a  single intraperitoneal
(i.p.)  injection or  oral dose  of  hexachlorobenzene  in olive  oil,  adipose
tissue contained  about 120-fold more hexachlorobenzene than muscle tissue;
liver,  4-fold;  brain,  2.5-fold; and kidney,  1.5-fold  (Koss  and  Koransky,
1975).   Adipose  tissue  serves  as a reservoir for  hexachlorobenzene,  and de-
pletion of  fat deposits  results  in  mobilization and redistribution of stored
hexachlorobenzene.  However, excretion is  not increased, and the  total body
                                                    s
burden is not lowered (Villeneuve,  1975).

-------
     C.  Metabolism
         Hexachlorobenzene  is metabolized  after i.p.  administration in  the
rat  to pentachlorophenol,  tetrachlorohydroquinone  and  pentachlorothicphenol
(Koss,  et al.  1976).   In  another study using  rats in which the  metabolic
products were  slightly  different,  only a small percentage of  the  metabolites
were present as glucuronide conjugates (Engst, et al.  1976).   Hexachloroben-
zene  appears  to  be  an inducer  of the  hepatic  microsomal  enzyme system  in
rats (Carlson,  1978).   It has been proposed that both  the phenobarbital type
and  the 3-methylcholanthrene type  microsomal enzymes  are  induced  (Stonard,
1975; Stonard and Greig,  1976).
     0.  Excretion
         Hexachlorobenzene  is excreted' mainly in the  feces  and,  to some  ex-
tent,  in  the  urine in the  form  of several metabolites  which  are more  polar
than • the  parent compound  (U.S.  EPA,  1979).   In  the rat, 34  percent of  the
administered hexachlorobenzene was excreted in the feces, mostly as unalter-
ed  hexachlorobenzene.    Fecal excretion  of  unaltered  hexachlorofaenzene  is
presumed to be due to biliary  secretion.   Five percent, of the administered
HCB was excreted in the urine (Koss and Koransky, 1975).
IV.  EFFECTS
     A..  Carcinogenic!ty
         Carcinogenic activity of  hexachlorobenzene was assessed in hamsters
fed 4.3 or 16  mg/kg/day  for life (Cabral,  et  al.  1977).  Whereas 10 percent
of the  unexposed hamsters  developed  tumors,  92 percent of  the hamsters  fed
16 mg/kg/day,  75 percent  fed 8 mg/kg/day,  and 56  percent  fed  4 mg/kg/day
developed  tumors.   The   tumors  were  hepatomas,  haemangioendotheliomas  and
thyroid adenomas.  In a study on mice fed  6.5, 13 or  26 mg/kg/day for  life,
£he only  increase in  tumors was  in  hepatomas (Cabral, et  al.  1978).   How-

-------
ever,  the incidence of  lung tumors in  strain A mice  treated three times  a
week  for  a total  of 24  injections of  40  mg/kg each  was not  significantly
greater than the incidence in control mice (Theiss, et al.  1977).   Also,  ICR
mice  fed  hexachlorobenzene at  1.5  or 7.0  mg/kg/day  for  24  weeks showed no
induced hepatocellular carcinomas (Shirai,  et  al.. 1978).
     B.  Mutageriicity
         Hexachlorobenzene  was assayed  for mutagenic activity  in the  domi-
nant  lethal assay.   Rats were  administered  60  mg/kg/day  hexachlorobenzene
orally for  ten  days;  there was no significant difference  in  the incidence of
pregnancies (Khera, 1974).
     C.  Teratogenicity
         Hexachlorobenzene  does  not  appear  to be  teratogenic  for  the  rat
(Khera, 1974).   CO-1 mice  receiving  100 mg/kg/day  hexachlorobenzene oraily
on gestational  days 7 to 11  showed a  small increase  in the incidence of  ab-
normal fetuses  per litter (Courtney,  et al. 1976).   However,  the  statistical
significance was  not mentioned,  and  the abnormalities appeared in both  the
exposed and unexposed groups.
     D.  Other Reproductive Effects
         Hexachlorobenzene  can  pass  through  the placenta  and  cause   fetal
toxicity  in rats  (Grant,  et al.  1977).   The  distribution  of hexachloro-
benzene  in the  fetus appears to  be the  same  as  in  the  adult,  with  the
highest concentration in  fatty tissue.
     E.  Chronic Toxicity
         In one long-term study  where  rats were given  50 mg/kg hexachloro-
benzene every  other  day for  53 weeks,  an equilibrium  between  intake  and
elimination was achieved after nine weeks.  Changes in  the  histology of  the

-------
liver and  spleen were noted  (Koss,  et al. 1578).  On  human exposure  for  an
undefined  time  period,  porphyrinuria  has  been shown  to  occur  (Cam  and
Nigogosyan, 1963).
     F.  Other Relevant Information
         At  doses far  below  those  causing mortality,  hexachlorobenzene  en-
hances  the capability  of animals to  metabolize  foreign  organic  compounds.
This type  of interaction may be  of  importance in determining the  effects  of
other concurrently encountered xenobiotics (U.S.  EPA, 1979).
V.   AQUATIC TOXICITY
     A.  NO  pertinent  information is available on acute and chronic  toxicity
or plant effects.
     B-  Residues
         Hexachlorobenzene  (HCS)  is bioconcentrated  from  water into  tissues
of  saltwater  fish  and  invertebrates.   Bioconcentration  factors  (BCF)   in
short 96-hour exposures are as  follow (Parrish, et al. 1974):  grass  shrimp,
Palaeomonetes  puqio,  - 4,116 jjg/1;  pink  shrimp, Penaeus  duorarum,   - 1,964
ug/1; sheepshead minnow,  Cyprinodon variegatus,  - 2,254 yg/1.   In a  42-day
exposure,  the pinfish,  Lagodon  rhomboides,   BCF was  23,000.   The   concen-
tration of HCS in pinfish  muscle was reduced only 16  percent after  28 days
of depuration; this slow  rate is similar to that  for DOT in  fish.
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 will   be
changed.


-------
     A.  Human
         The  value  of 0.6  pg/kg/day  hexachlorobenzene  was  suggested  by
FAO/WHO as a reasonable upper limit for  residues  in  food for human consump-
tion (FAO/WHO, 1974).  The Louisiana State Department of Agriculture has set
the tolerated level of hexachlorobenzene  in meat fat  at 0.3 mg/kg (U.S. EPA,
1976).  The FAO/WHO recommendations for residues in foodstuffs are 0.5 mg/kg
in fat for milk and eggs, and 1 mg/kg in  fat  for  meat and poultry (FAO/WHO,
1974).   Based on  bioassay data,  and using  the  "one-hit"  model,  the  EPA
(1979) has estimated levels of hexachlorobenzene in ambient water which will
result in specified risk levels of  human cancer:

Exposure Assumption           Risk Levels  and Corresponding Draft Criteria
   (per day)
                              0       " .  10-7          10-6       io-5
2 liters of drinking water    0       0.0125 ng/1   0.125 ng/1  1.25 ng/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and       0       0.0126 ng/1   0.126 ng/1  1.26 ng/1
shellfish only..

     B.  Aquatic
         Pertinent  information  concerning  aquatic  criteria could  not  be
located in the available literature.
                                +f A r 3'
                                  11*6-11

-------
                      HEXACHLOROBENZENE

                         REFERENCES

Albro, P.W., and R. Thomas.   1974.  Intestinal  absorption of
hexachlorobenzene and hexachlorocyclohexane  isomers in  rats.
Bull. Environ. Contam. Toxicol.   12:  289.

Cabral, J.R.P., et al.  1977.  Carcinogenic  activity of hexa-
chlorobenzene  in hamsters.  Nature  (London).  269:  510.

Cabral, J.R.P., et al.  1978.  Carcinogenesis study in  mice
with hexachlorobenzene.  Toxicol. Appl.  Pharmacol.   45: 323.

Cam, C., and G. Nigogosyan.   1963.  Acquired toxic  porphyria
cutanea tarda  due to hexachlorobenzene.  Jour.  Am.  Med.
Assoc.  183; 88.

Carlson, G.-P.  1978.  Induction of cytochrome P-450 by  halo-
genated benzenes.  Biochem. Pharmacol.   27:  361.

Chemical Economic Handbook.   1977.  Chlorobenzenes-Salient
statistics.  In: Chemical Economic Handbook, Stanford Res..
Inst. Int., Menlo Parkr Calif.. .

Courtney, K.D., et al.  1976.  The effects of pentachloro-
nitrobenzene,  hexachlorobenzene,  and  related compounds  on
fetal development.  Toxicol.  Appl. Pharmacol.   35:  239.

Engst, R., et  al.  1976.  The metabolism of hexachlorobenzene
(HCB) in rats.  Bull. Environ. Contam. Toxicol.  16:  248.

Pood and Agriculture Organization.  1974.  1973 evaluations
of some pesticide residues in food.   FAO/AGP/1973/M/9/1; WHO
Pestle- Residue Ser. 3.  World Health Org., Rome, Italy p.
291.

Grant, D.L., et al.  1977.  Effect of hexachlorobenzene  on
reproduction in the rat.  Arch. Environ. Contam. Toxicol.   5:
207.

Khera, K.S.  1974.  Teratogenicity and dominant lethal
studies on hexachlorobenzene  in rats.  Food Cosmet.  Toxicol.
12: 471.

Koss, R., and W. Koransky.  1975.  Studies on the toxicology
of hexachlorobenzene.  I*  Pharraacokinetics.  Arch  Toxicol.
34: 203.

Koss, G., et al.  1976.  Studies on the toxicology  of hexa-
chlorobenzene.  II. Identification and determination of
metabolites.  Arch. Toxicol.  35: 107.

-------
Koss, G., et al.  1978.  Studies on  the  toxicology  of  hexa-
chlorobenzene.  III. Observations  in a long-term  experiment.
Arch. Toxicol.  40: 285.

Lu, P.Y., and R.L. Metcalf.  1975.   Environmental fate  and
biodegradability of benzene derivatives  as studied  in a model
aquatic  ecosystem.  Environ. Health  Perspect.   10:  269.

Miller,  G.J., and J.A. Fox.  1973.   Chlorinated hydrocarbon
pesticide residues in Queensland human milks.   Med. Jour.
Australia  2: 261.

Mumma, C.E., and E.W. Lawless.  1975.  "Task I  -  Hexachloro-
benzene  and hexachlorobutadiene pollution from  chlorocarbon
processes".  EPA 530-3-75-003, U.S.  Environ. Prot.  Agency,
Washington, D.C.

Parrish, P.R., et al.  1974.  Hexachlorobenzene:  effects on
several  estuarine animals.  Pages  179-187 in Proc.  28th Annu.
Conf. S.E. Assoc. Game Fish Comm.

Shirai,  T., et al.  1978.  Hepatocarcinogenicity  of poly-
chlorinated terphenyl (PCT) in ICR mice  and its enhancement
by hexachlorobenzene (HCB).  Cancer  Lett.  4: 271.

Simpson, G.R., and A. Shandar.  1972.  Exposure to  chlori-    .
nated hydrocarbon pesticides by pest control operators.  Med..
Jour. Australia.  2: 1060.

Stonard, M.D.  1975.  Mixed type hepatic microsomal enzyme
induction by hexachlorobenzene.  Biochem. Pharmacol.  24:
1959.

Stonard, M.D., and J.B. Greig.  1976.  Different  patterns of
hepatic microsomal enzyme activity produced by  administration
of pure  hexachlorobiphenyl isomers and hexachlorobenzene.
Chem.-Biol. Interact.  15: 365.

Theiss, J.C., et al.  1977.  Test  for carcinogenicity of or-
ganic contaminants of United States drinking waters by pul-
monary tumor response in strain A mice.  Cancer Res.  37:
2717.

U.S. EPA.  1975.  Preliminary assessment of suspected carcin-
ogens in drinking water.  Report to Congress.  EPA 560/4-75-
003.  Environ. Prot.. Agency, Washington,  D.C.

U.S. EPA.  1976.  Environmental contamination from hexachloro-
benzene.  EPA 560/6-76-014.  Off. Tox.  Subst.  1-27.

U.S. EPA.  1979.  Chlorinated Benzenes: Ambient Water Quality
Criteria. (Draft).

-------
villeneuve, D.C.  1975.  The effect  of  food  restriction on
the redistribution of hexachlorofaenzene  in  the  rat.   Toxicol.
Appl. Pharmacol.  31: 313.

-------
                                      No. Ill
        Hexachlorobutadiene




  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY

       WASHINGTON, D.C.  20A60


           APRIL 30, 1980
             - / "i n *»
              / <*. >  >


             111-1

-------
                          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. EPA's Carcinogen Assessment Group (GAG) has evaluated



hexachlorobutadiene and has found sufficient evidence to




indicate that this compound is carcinogenic.

-------
                     HEXACHLOROBUTADI EH E



                           SUMMARY



     Hexachlorobutadiene (HCBD) is a significant by-product



of the manufacture of chlorinated hydrocarbons.  HCBD has



been found to induce renal neoplasms in rats (Kociba, et al.,



1971).  The mutagenicity of HCBD has not been proven conclu-



sively, but a bacterial assay by Taylor (1978)  suggests a



positive result.  Two studies on the possible teratogenic



effects of HCBD produced conflicting results.



     Ninety-six hour LC50 values for the goldfish, snail,



and sowbug varied between 90 and 210 ug/1 in static renewal



tests.  Measured bioconcentration factors after varying per-



iods of exposure are as follows: crayfish, 60;  goldfish, 920-



2,300; Scuyemouth bass, 29; and an alga, 160.
                         ///-y

-------
                     HEXACHLOROBUTADIEN E
I.   INTRODUCTION
     Hexachlorobutadiene (HCBD) is produced in the United
States as a significant by-product in the manufacture of
chlorinated hydrocarbons such as tetrachloroethylene, tri-
chloroethylene, and carbon tetrachloride..  This secondary
production in the U.S. ranges from 7.3 to 14.5 million pounds
per year, with an additional 0.5 million pounds being import-
ed (U.S. EPA, 1975).
     HCBD is used as an organic solvent, the major domestic
users being- chlorine producers.  Other applications include
its use as an intermediate in the production of rubber com-
pounds and lubricants.  HCBD is a colorless liquid with a
faint turpentine-like odor.  Its physical properties include:
boiling point, 210-220°C vapor pressure, 0.15 mm Hg; and
water solubility of .5 ug/1 at 20°C (U.S. EPA, 1979).
     Environmental contamination by HCBD results primarily
during the disposal of wastes containing HCBD from chlori-
nated hydrocarbon industries (U.S. EPA, 1976).  It has been
detected in a limited number of water samples.  HBCD appears
to be rapidly adsorbed to soil and sediment from contaminated
water, and concentrates in sediment from water by a factor of
100 (Leeuwangh, et al., 1975).
II.  EXPOSURE
                                           v
     A.   Water
          HCBD contamination of U.S. finished drinking water
supplies does not appear to be widespread.  The problem is
localized in areas with raw water sources near industrial
                          111-5'

-------
plants discharging HBCD.  From  its physical  and  chemical  pro-
perties, HBCD removal from water by adsorption  into  sediment
should be rapid (Laseter, et al., 1976).  Effluents  from
various industrial plants were  found  to contain  HCBD levels
ranging from 0.04 to 240 ug/1 (Li, et al., 1976).  An EPA
study of the drinking water supply of ten U.S. cities re-
vealed that HCBD was detected in one  of the  water  supplies,
but the concentration was less  than 0.01 ug/1  (U.S.  EPA,
1975).
     B.   Food
          Since the air, soil and water surrounding  certain
chlorohydrocarbon plants have been shown to  be contaminated
with HCBD (Li, et al., 1976), food produced  in the vicinity
of these plants might contain residual levels of HCBD.  A
survey of foodstuffs produced within  25 miles of tetrachloro-
ethylene and trichloroethylene  plants did not detect measur-
able levels of HCBD.  Freshwater fish caught  in  the  lower
Mississippi contained HBCD residues in a range from  0.01  to
1.2 mgAg«  Studies on HCBD contamination of  food  in several
European countries have measured levels as high  as 42 ug/kg
in certain foodstuffs (Kotzias,'et al., 1975).
          The U.S. EPA (1979) has estimated  a HCBD bioconcen-
tration factor of 870 for the edible  portions of fish and
shellfish consumed by Americans.  This estimate  is based  on
measured steady-state bioconcentration studies  in  goldfish.
     C.   Inhalation
          The levels of HCBD detected in the  air surrounding
chlorohydrocarbon plants are generally less  than 5 uc

-------
although values as high as 460 ug/ni  have been measured

(Li, et al.  1976).

III. PHARMACOKINETICS

     A.   Absorption

          Pertinent data were not found on the absorption of

HCBD in the available literature.

     B.   Distribution

          HCBD did not have a strong tendency to accumulate

in fatty tissue when administered orally with other chlori-

nated hydrocarbons.  Some of the chlorinated hydrocarbons

were aromatic compounds and accumulated significantly  in fat

(Jacobs, et al.  1.974) .

     C.   Metabolism

          Pertinent data were not found in the available

literature.

     D.   Excretion                    .-;

          Pertinent data were not found in the available

literature.

IV.  EFFECTS ON MAMMALS

     A.   Carcinogenicity

          Kociba, et al. (1977) administered dietary levels

of HCBD ranging from 0.2 mg/kg/day to 20.0 mg/kg/day for two

years to rats.  In males receiving 20 mg/kg/day, 18 percent

(7/39) had renal tubular neoplasms which were classified as

adenocarcinomas; 7.5 percent (3/40) of the females on  the
                                                          »
high dose developed renal carcinomas.  Metastasis to the lung

was observed in one case each for both male and female rats.
                              *
                          1/1-7

-------
No carcinomas were observed  in  controls,  however,  a nephro-
blastoma developed in one male  and one  female.
          A significant  increase  in  the  frequency  of lung
tumors was observed  in mice  receiving  intraperitoneal injec-
tions of 4 mgAg or  8 mgAg  of  HCBD, three  times per week un-
til totals of 52 mg  and  96 mg,  respectively,  were  admin-
istered (Theiss, et  al... 1977).
     B.   Mutagenicity
          Taylor (1978)  tested  the mutagehicity of HCBD on _S.
typhimurium TA100.   A dose dependent increase in reversion
rate was noted, but  the  usual criterion  for mutagenicity of
double the background rate was  not reached.
     C.   Teratogenicity
          Poteryaeva (1966)  administered  HCBD to nonpregnant
rats by a single subcutaneous injection of  20 mg/kg.   After
mating, the pregnancy rate for  the dosed  rats was  the same as
that of controls.  The weights  of the young rats from the
dosed mothers were markedly  lower than  the  controls.   Autop-
sies at 2-1/2 months revealed gross pathological changes in
internal organs including g-lomerulonephritis  of the  kidneys.
Degenerative changes were also  observed  in  the red  blood
cells.
     D.   Other Reproductive Effects
          Schwetz, et al. (1977) studied  the  effects  of  di-
etary doses of HCBD  on reproduction,  in  rats.   Males  and  fe-
                                                           »
males were fed dose  levels of 0.2 to 20 mg/kg/day  HCBD start-
ing 90 days prior to mating  and continuing  through  lactation.
At the two highest doses, adult rats suffered  weight  loss,
                                  ,
                             > *lAlS-
                            i J  I "-
                           III-7

-------
decreased food consumption and alterations  of  the  kidney cor-



tex, while the only effect on weanlings consisted  of  a  slight



increase in body weight at 21 days of age at the 20 mg/kg



dose level.  Effect on survival of the young was not  effected.



     E.   Chronic Toxicity



          The kidney appears to be the organ most  sensitive



to HCBD.  Possible chronic effects are observed at doses  as



low as 2 to 3 mg/kg/day (Kociba, et al., 1971, 1977;  Schwetz,



et al., 1977).  Single oral doses as low as 8.4 mg/kg have
                                         \


been observed to have  deleterious effects  on  the  kidney



(Schroit, et al. 1972).  Neurotoxic effects in rats have  been



reported at a dose of 7 mg/kg and effects may  occur at  even



lower dose levels (Poteryaeva, 1973? Murzakaev, 1967).   HCBD



at 0.004 mg/kg gave no indication of neurotoxicity.   Acute



HCBD intoxication affects acid-base equilibrium in blood  and



urine (Popovich, 1975; Poteryaeva, 1971).   Some investigators



report a cumulative effect for HCBD during  chronic dosing by



dermal (Chernokan, 1970) or oral Poteryaeva, 1973) routes.



An increase in urinary coproporphyrin was observed in rats



receiving 2 mg/kg/day and 20 mk/kg/day HCBD for up to 24



months (Kociba, 1977).



     F.   Other Relevant Information



          The possible antagonistic effect of  compounds  con-



taining mercapto (-SH) groups on HCBD have  been suggested by

                                            *•

two studies.  Murzokaev (1967) demonstrated a  reduction  in



free -SH groups in cerebral cortex homogenate  and  blood  serum



following HCBD injection in rats.  Mizyukova,  et al.  (1973)



found thiols (-SH compounds) and amines to  be  effective  anti-

-------
dotes against the toxic effects of HCBD when  administered
prior to or after HCBD exposure.
V.   AQUATIC TOXICITY
     A.   Acute Toxic ity
          Goldfish,  (Carassius auratus), had  an  observed 96-
hour LC50 of 90 ug/1 in a static renewal test  (Leeuwangh,  et
al. 1975).  A snail, (Lymnaea stagnalis), and  a  sowbug,
(Asellus aquaicus), were both exposed for 96-hours  to HCBD
resulting in EC5Q values of 210 and 130 v.g/1,  respective-
ly (Leeuwangh, et al., 1975).  No acute studies  with marine
species have been conducted.
     B.   Chronic Toxic ity
          Pertinent  information was not found  in the avail-
able literature.
     C.   Plant'Effects
          Pertinent data was not found in the  available
literature.
     D.   Residues
          Measured bioconcentration factors are  as  follows:
crayfish, Procambaeus clarhi, 60 times after 10 days expo-
sure; goldfish, Caressius auretus, 920-2,300 times  after 49
days exposure; large mouth bass, Microptorus salmoides, 29
times after 10 days exposure; and a freshwater alga, Oedogon-
ium cardiacum, .160 times after 7 days exposure (Laseter, et
al., 1976).  Residue data on saltwater organisms are not
available.

-------
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.   Human



          Standards or guidelines for exposure  to HCBD  are



not available.



          The draft ambient water quality, criteria for  HCBD



have been calculated to reduce the human carcinogenic risk



levels to ID"5, 10-6, and lO"7 (U.S. EPA, 1979).



The corresponding criteria are 0.77 ug/1, 0.077 ug/lf 0.0077



u.g/1, respectively.



     B.   Aquatic



          Draft freshwater or saltwater criterion for hexa-



chlorobutadiene have not been developed because of insuffi-



cient data (U.S. EPA, 1979).
                           ll-Ht

-------
                              HEXACHLOROBUTAOIENE

                                  REFERENCES
Chernokan,  V.F.   1970.  Some  data of the  toxicology  of hexachlorobutadiene
when ingested into  the organism through the skin. •  Vop.  Gig. Toksikol. Pes-
tits.  Tr.  Nauch.  Tr.  Sess. Akad. med.  Nauk.  SSSR.   (no vol.): 169.  CA:74:
97218r. (Translation)

Jacobs, A.,  et  al.    1974.  Accumulation  of noxious  chlorinated substances
from Rhine River water in the fatty tissue of rats.  Vom. Wasser  43: 259.

Kociba, R.J.,  et al.  1971.   Toxicologic  study of  female  rats administered
hexachlorobutadiene  or hexachlorobenzene  for  30  days.   Dow  Chemical  Co.,
Midland, Mich.
                                                   •.
Kociba, R.J.,  et al.   1977.   Results of  a two-year  chronic toxicity study
with hexachlorobutadiene in rats.  Am. Ind. Hyg. Assoc.  38:  589.

Kotzias, 0., et  al.  1975.  Ecological chemistry.   CIV.  Residue analysis of
hexachlorobutadiene in food and poultry  feed.  Chemosphere  4:  247.

Laseter,  J.L.,   et  al»  1976.   An  ecological  study  of hexachlorobutadiene
(HCSD).  U.S. Environ.  Prot. Agency, EPA-560/6-76-010.

Leeuwangh, P., et al.   1975.   Toxicity of  hexachlorobutadiene in aquatic or-
ganisms.   In:  Sublethal  effects  of  toxic  chemicals  on  aquatic  animals.
Proc.  Swedish-Netherlands  Symp.,  Sept.  2-5.  Elsevier Scientific Publ. Co.,
Inc., New York.

Li,  R.T.,  et  al.   1976.   Sampling  and  analysis  of  selected toxic  sub-
stances.  Task  IB - hexachlorobutadiene.   EPA-560/6-76-015.   U.S.. Environ.
Prot. Agency, Washington, O.C.

Mizyukova, I.G., et al.  1973.  Relation between  the structure and detoxify-
ing  action  of  several  thiols  and  amines during  hexachlorobutadiene poison-
ing.  Fiziol.  Aktive.  Veshchestva.  5: 22.  CA:81:22018M. (Translation)

Murzakaev,  F.G.   1967.   Effect of  small  doses  of  hexachlorobutadiene  on
activity  of the  central nervous  system  and morphological  changes  in  the
organisms of animals  intoxicated  with it.  Gig.  Tr.   Prog.  Zabol.   11: 23.
CA:67:31040a. (Translation)

Popovich,  M.I.   1975.   Acid-base equilibrium and  mineral metabolism follow-
ing  acute  hexachlorobutadiene  poisoning.    Issled.  Abl.  Farm.  Khim.   (no
vol.): 120.  CA:86:26706K.  (Translation)
                                                     ••

Poteryaeva,  G.E.   1966.   Effect of  hexachlorobutadiene on the  offspring  of
albino rats.  Gig Sanit.  31:  33.   ETIC:76:8965. (Translation)
                                                                        »
Poteryaeva, G.E.  1971.  Sanitary  and  toxicological  characteristics  of hexa-
chlorobutadiene.  Vrach. Oelo.   4:  130.  HAPAB:72:820.   (Translation)
                                  III'II

-------
Poteryaeva, G.E.   1973.   Toxicity  of hexachlorobutadiene during  entry into
the organisms through  the gastorintestinal tract.  Gig. Tr.   9:  98.   CA:85:
29271E. (Translation)

Schroit, I.G.,  et al.   1972.  Kidney  lesions  under experimental  hexachloro-
butadiene  poisoning.   Aktual.  Vop. gig.  Epidemiol.  (no  vol.):  73.   CA:81:
73128E. (Translation)

Schwetz, 8.A.,  et al.   1977.   Results of  a  reproduction study in  rats fed
diets containing hexachlorobutadiene.   Toxicol. Appl. Pharmacol.  42: 387.

Taylor, G.   1978.  Personal communication.  Natl. Inst.  Occup. Safety Health.

Theiss, J.C., et. al.   1977.  Test for carcinogenicity of  organic  contami-
nants of United States drinking  waters by pulmonary tumor response in strain
A mice.  Cancer Res.  37: 2717.

U.S. EPA.   1975.   Preliminary assessment of suspected  carcinogens  in drink-
ing water.   Rep. to Congress.  U.S. Environ. Prot. Agency.

U.S. EPA.  1976.   Sampling  and analysis of selected  toxic substances.   Task
IB  - Hexachlorobutadiene.  EPA-560/6-76-015.   Off.  Tox.  Subst.  U.S.  Envi-
ron. Prot.  Agency, Washington, D.C.

U.S. EPA.  1978.   Contract No. 6803-2624.   U.S.  Environ.  Prot.  Agency,  Wash-
ington, D.C.

U.S.  EPA.   1979.   Hexachlorobutadiene:   Ambient  Water  Quality  Criteria
(Draft).
                                //  /'-

-------
                                   No. 112
         ichlorocyclohexane


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

          APRIL 30, 1980
            //a-/

-------
                          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. EPA13 Carcinogen. Assessment Group (GAG) has evaluated



hexachlorocyclohexane and has found sufficient evidence to



indicate that this compound is carcinogenic.

-------
                             HEXACHLOROCYCLOHEXANE
                                    Summary

     Hexachlorocyclohexane (HCH),  a broad spectrum insecticide, is a mixture
of  five configurational  isomers.   HCH  is no  longer  used  in  the  United
States; however,  its gamma-isomer,  commonly known as  lindane, continues to
have  significant  commercial  use.   Technical  HCH,  alpha-HCH,  _beta-HCH,  and
lindane  (gamma-HCH)  have  all  been shown  to  induce  liver tumors  in mice.
Most of the  studies  on hexachlorocyclohexanes deal only with  lindane.  Evi-
dence for mutagenicity of  lindane  is equivocal.   Lindane was not  teratogenic
for  rats,  although it reduced  reproductive capacity in rats   in  a  study of
four generations.   Chronic exposure of  animals  to lindane  caused liver en-
largement  and,  at  higher  doses,  some liver  damage  and  nephritic  changes.
Humans chronically exposed to HCH  suffered  liver damage. Chronic  exposure of
humans  to  lindane: produced  irritation of  the central  nervous system.   HCH
and  lindane  are  convulsants.  The U.S. EPA (1979)  has estimated  the ambient
water  concentrations  of hexachlorocyclohexanes  corresponding  to  a  lifetime
cancer  risk  for humans of  10   as  follows:   21 ng/1  for  technical  HCH, 16
ng/1 for alpha-HCH, 28 ng/1  for beta-HCH, and  54 ng/1 for lindane  (gammaHCH).
     Lindane has  been  studied in a  fairly  extensive  series of acute studies
for both freshwater and marine  organisms.   Acute toxic levels as  low as 0.17
ng/1 have been reported for marine invertebrate species.

-------
                             HEXACHLOROCYCLOHEXANE
I.   INTRODUCTION
     This profile  is based  on the  Ambient  Water Quality  Criteria Document
for   Hexachlorocyclohexane   (U.S.    EPA,   1979).    1,2,3,4,5,6-Hexachloro-
cyclohexane   (CJ-LClj   molecular  weight  290.0)   is   a  brownish-to-white
crystalline  solid with  a  melting point  of 65°C  and a solubility  in water
of 10  to  32 mg/1.   It  is  a mixture  of five configurational  isomers and is
commonly referred  to as BHC or benzene hexachloride.   Lindane is the common
name  for  the  gamma isomer  of 1,2,3,4,5,6-hexachlorocyclohexane  (U.S.  EPA,
1979).
     Technical •  grade   hexachlorobenzene   (HCH)   contains  the  hexachloro-
cyclohexane  isomers in  the  following ranges:   alpha-isomer,  55 to  70 per-
cent;  beta-isomer,  6 to  8 percent;  gamma-isomer ,  10 to  18 percent; delta-
isomer, 3 to 4 percent; epsilon-isomer, trace  amounts.   Technical  grade HCH
may  also  contain 3  to  5 percent of  other  chlorinated  derivatives  of cyclo-
hexane,  primarily  heptachlorocyclohexane  and  octachlorocyclohexane  (U.S.
EPA,  1979).
     Hexachlorocyclohexane  (HCH)  is   a  broad  spectrum  insecticide  of  the
group of cyclic  chlorinated  hydrocarbons  called organochlorine insecticides.
Since  the  gamma-isomer  (lindane)  has  been shown  to be  the  insecticidally
active  ingredient  in   technical  grade  HCH,  technical  grade HCH   has  had
limited commercial use  except as  the raw material  for  production  of lin-
dane.  Use  of technical HCH has been banned in  the U.S., but  significant
commercial  use of  lindane  continues.  Lindane  is used in a  wide  range  of
applications including  treatment  of  animals,  buildings,  man  (for  ectopara-
sites), clothes, water  (for  mosquitoes), plants,  seeds,  and soils (U.S. 'EPA,
1979).

-------
     NO  technical grade  HCH  or  lindane  is currently  manufactured  in the
U.S.; all lindane used in the U.S. is imported (U.S. EPA, 1979).
     Lindane  has  a  low  residence  time in  the  aquatic environment.   It is
removed  by  sedimentation,  metabolism,  and volatilization.   Lindane contri-
butes less to  aquatic  pollution than the other hexachlorocyclohexane isomers
(Henderson, et al. 1971).
     Lindane  is  slowly  degraded by soil  microorganisms  (Mathur  and  Saha,
1975; Tu,  1975,  1-976)  and is  reported  to  be isomerized to  the alpha and/or
delta isomers  in  microorganisms and plants  (U.S.  EPA,  1979), though this is
controversial  (Tu,  1975, 1976;  Copeland and Chadwick,  1979;  Engst,  et al.
1977).   It  is-not isomerized  in  adipose tissues  of rats,  however  (Copeland
and Chadwick, 1979).
II.  EXPOSURE
     A.  Water
         The  contamination  of water  has  occurred  principally  from direct
application of technical hexachlorocyclohexane  (HCH) or lindane to water for
control of mosquitoes, from  the use of HCH in agriculture and  forestry, and,
to a  lesser  extent,  from  occasional contamination  of  wastewater from manu-
                                                 *
facturing plants  (U.S.  EPA, 1979).
         In the  finished- water of.  Streator,  Illinois,  lindane  has  been de-
tected at a concentration of 4 pg/1  (U.S. EPA, 1975).
     B.  Food
         The daily  intake  of  lindane  has  been reported to  be  1 to 5 ug/kg
body weight and the daily intake of  all other HCH  isoraers to  be 1 to 3 ug/kg
body weight (Duggan and Ouggan, 1973).   The  chief  sources  of HCH residues in
the human  diet are milk, eggs,  and other dairy  products  (U.S.  EPA,  1979),
and carrots  and  potatoes (Lichtenstein, 1959).   Seafood is  usually a minor

-------
source of  HCH,  probably because  of the relatively  high rate of dissipation
of HCH in the aquatic environment (U.S. EPA, 1979).
         The  U.S.   EPA  (1979)  has  estimated   the  weighted  average biocon-
centration factor  for lindane  to  be 780 for the  edible  portions of fish and
shellfish consumed  by Americans.   This estimate is based on measured steady-
state bioconcentration in bluegills.
     C.  Inhalation
         Traces of  HCH have  been  detected  in the air of central and suburban
London (U.S. EPA,  1979).  No further pertinent information could be found  in
the available literature.
     0.  Dermal
         Lindane has been  used to eradicate human  ectoparasites and few ad-
verse reactions have been reported (U.S. EPA, 1979).
III. PHARMACOKINETICS
     A.  Absorption
         The  rapidity  of  lindane absorption  is  enhanced  by  lipid mediated
carriers.  Compared to  other  organochlorine  insecticides, HCH  and lindane
are unusually  soluble  in  water,  which  contributes to  rapid  absorption and
excretion  (Herbst  and Bodenstein,  1972;  U.S.  EPA,  1979).  Intraperitoneal
injection  of lindane resulted in  35 percent  absorption   (Koransky,  et al.
1963).  Lindane is absorbed after oral.and dermal exposure  (U.S. EPA, 1979).
     8.  Distribution
         After administration  to  experimental  animals,  lindane  was detected
in  the  brain at  higher concentrations  than  in  other  organs  (Laug,  1948;
                                                     ^
Davidow and  Frawley,  1951;  Koransky,  et  al.  1963; Huntingdon  Res.  Center,

-------
1972).  At  least 75 percent  of an intraperitonial  dose of 14C-labeled lin-
dane was consistently found in  the skin,  muscle,  and fatty tissue (Koransky,
et al.  1963).   Lindane enters  the human fetus through the placenta; higher
concentrations were  found  in  the skin than  in the  brain  and  never exceeded
the  corresponding   values  for  adult  organs  (Poradovsky,   et  al.  1977;
Nishimura, et al. 1977).
     C.  Metabolism
         Lindane  is metabolized  to  gamma-3,4,5,6-tetrachlorocyclohexene  in
rat  adipose tissue,  but  is  not  isomerized  (Copeiand  and Chadwick,  1979);
other  metabolites are  2,3,4,5,6-pentachloro-2-cyclohexene-l-ol,  two  tetra-
chlorophenols, and  three  trichlorophenols (Chadwick, et al. 1975;  Engst,  et
al.  1977).   These are. commonly  found  in the urine as conjugates (Chadwick
and Freal,  1972).  Lindane metabolic  pathways are still matters of some con-
troversy  (Engst, et al.   1977;  Copeiand  and Chadwick,  1979).   Hexachloro-
cyclohexane  isomers  other than lindane  are  metabolized to trichlorophenols
and  mercapturic  acid conjugates  (Kurihara,  1979).   Both free  and conjugated
chlorophenols  are far  less  toxic than  the  parent compounds  (Natl.  Acad.
Sci., 1977).                                      ;
     D.  Excretion
         HCH and  lindane  appear to be eliminated  primarily as conjugates  in
the  urine.   Elimination of lindane appears  to be  rapid after  administration
ceases.  Elimination of beta-HCH is  much slower  (U.S. EPA,   1979).   In  fe-
males, HCH is excreted in the milk  as well as in  the urine.   The beta-isomer
usually  accounts for  above  90 percent  of   the  HCH -present  in human  milk
(Herbst and Bodenstein, 1972).

-------
IV.  EFFECTS
     A.  Carcinogenicity
         An increased  incidence  of liver tumors was  reported  in male and/or
female mice of various  strains  fed technical hexachlorocyclohexane (Goto, et
al. 1972;  Hanada,  et al.  1973;  Nagasaki, et al.  1972),  alpha-HCH (Goto, et
al. 1972;  Hanada,  et al. 1973;  Ito,  et  al.  1973,  1975),  beta-HCH (Goto, et
al.  1972;  Thorpe  and Walker,  1973)  and  lindane  (gamma-HCH)  (Goto,  et al.
1972:  Hanada,  et  al.  1973;  Natl.  Cancer Inst.,  1977a;  Thorpe  and Walker,
1973).   Male  rats  fed alpha-HCH  also  developed  liver tumors  (Ito,  et al.
1975).   A  mixture containing  68.7 percent  alpha-HCH,  6.5  percent beta-HCH
and 13.5 percent lindane  in  addition to other  impurities (hepta- and octa-
chlorocyclohexanes),  administered  orally (100 ppm  in the diet,  or 10 mg/kg
body  weight  by  intubation),  caused tumors  in  liver and  in lymph-reticular
tissues  in male  and  female mice after 45 weeks.   Application  by skin paint-
ing  had  no  effect   (Kashyap,  et  al.   1979).   A  review  by   Reuber  (1979)
suggests that lindane is carcinogenic on uncertain evidence.
     B.  Mutagenicity
         Evidence  for  the  mutagenicity of lindane  is equivocal.  Some alter-
ations in  mitotic  activity and  the karyotype of  human lymphocytes cultured
with  lindane at  0.1 to  10 ug/ml have been  reported  (Tsoneva-Maneva,  et al.
1971).   Lindane  was  not  mutagenic in  a dominant-lethal  assay  (U.S.  EPA,
1973) or a host-mediated assay (Buselmair, et al. 1973).
     Gamma-HCH  was   found  to   be  mutagenic  in  microbial   assays   using
Salmonella typhimurium with metabolic  activation,  the host-mediated  assay,
and the  dominant lethal test in rats.   Other  reports indicate that it  does
not have significant mutagenic activity (U.S. EPA,  1979).
                                 II-9

-------
     C.  Teratogenicity
         Lindane given  in the  diet during pregnancy "at levels of  12 or 25
mg/kg  body   weight/day  did  not   produce   teratogenic  effects   in  rats
(Mametkuliev, 1978; Khera, et al. 1979).
     0.  Other Reproductive Effects
         Chronic lindane  feeding in a study of  four  generations of rats in-
creased  the  average duration of pregnancy,  decreased the number  of  births,
increased  the proportion  of stillbirths, and  delayed  sexual  maturation in
F7  and  F,  females.    In  addition,  some of  the  F.  and   F_ animals  ex-
hibited  spastic paraplegia (Petrescu, et al. 1974).
         In  rats and  rabbits, lindane given  in  the diet during pregnancy in-
creased  postimplanation death of embryos  (Mametkuliev,  1978;  Palmer,  et al.
1978).   Testicular atrophy  has  been observed  for lindane in  rats  and mice
(National Cancer Institute, 1977b; Nigam,  et al. 1979).
     E.  .Chronic Toxicity
         Irritation of  the central  nervous system, with other toxic side ef-
fects  (nausea,  vomiting,  spasms,  weak respiration with cyanosis  and blood
dyscrasia),  was  reported  after  prolonged  or improper  use  of Hexicid  (1 per-
cent  lindane) for  the  treatment of  scabies  on humans  (Lee, et  al.  1976).
Production  workers exposed  to  technical HCH  exhibited  symptoms  including
headache,  vertigo,  irritation  of the  skin,  eyes,  and  respiratory  tract mu-
cosa.  In  some  instances,  there were apparent disturbances  of carbohydrate
and  lipid  metabolism  and dysfunction  of the  hypothalamo-pituitary-adrenal
system (Kazahevich, 1974;  Besuglyi,  et al. 1973).  A' study  of persons occu-
pationally exposed  to HCH for 11 to 23 years  revealed  biochemical manifes-
                                                                        »
tations  of toxic hepatitis (Sasinovich, et al. 1974).

-------
         In  chronic  studies with  rats  given  lindane  in  oil,  liver  cell;
hypertrophy,(fat degeneration and necrosis)  and nephritic changes were  noted
at higher  doses (Fitzhugh,  et  al. 1950; Lehman,  1952).  Rats  inhaling lin-
dane  (0.78  mg/m-3)  for seven  hours,   five  days a  week  for  180 days  showed
liver cell enlargement,  but showed no toxic symptoms or other  abnormalities
(Heyroth,  1952).   The addition  of 10 ppm lindane to  the diet  of rats for one
or  two  years   decreased  body  weight  after  five  months  of  treatment  and
altered  ascorbic  acid levels in  urine,  blood, and tissues (Petrescu,  et al.
1974).   Dogs  chronically  exposed  to  lindane  in  the  diet  had   slightly
enlarged livers (Rivett, et  al. 1978).
     F.  Other-Relevant Information
         Hexachlorocyclohexane  is a convulsant.
         Lindane is  the most acutely  toxic isomer of HCH.  The  toxic effects
of lindane are antagonized  by  pretreatment  with phenobarbital  (Litterst  and
Miller,  1975)  and by treatment  with  silymarin (Szpunar,  et al.  1976)  and
various tranquilizers  (Ulmann,  1972).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Among  16 species  of  freshwater  fish, LC_Q values   from  one  flow-
through  and  24  static  bioassays  for  the  gamma  isomer   of hexachloro-
cyclohexane  ranged from 2 jug/1  for the- brown trout (Salmo trutta) (Macek  and
McAllister,  1970)   to  152  jjg/1  for  the  goldfish   (Carassius   auratus)
(Henderson,  et  al.  1959).    In  general,, the salmon tended  to  be more sensi-
tive  to the action  of lindane  than did  warm  water  species.   Zebra fish
(Brachydanio rerio)  showed  a  lindane  LC5Q  value  of 120 ng/1,  but rainbow
trout (Salmo qairdnerl)  evidenced respiratory  distress at 40 ng/1   (Slooff,
1979).   Technical  grade HCH was much  less toxic than pure  lindane;  LC50

-------
values obtained  for  lindane  in 96-hour  studies of  the freshwater  goldfish
(Carassius  auratus)  ranged from 152 jjg/1  for  100 percent  lindane to  8,200
jjg/1  for  BCH (15.5  percent  gamma  isomer)  (Henderson,  et al.  1959).   Static
tests  on  freshwater  invertebrates revealed  a  range of LC5Q values of from
4.5  jug/1   (96-hour  test)   (Sanders   and   Cope,   1968)  for   the  stonefly
(Pteronarcys  californica)  to • 880 jug/1  (48-hour  test)  (Sanders  and  Cope,
1968)  for the clado- ceran  (Simocephalus  serralatus)  for  lindane.   Canton
and  Slooff  (1977)   re-  ported  an LC5(,  value  for  the  pond snail  (Lymnaea
staqnalis)  of l,200;jg/l  for  alpha-HCH in a 48-hour  static test.
         Among  seven species of marine fish tested for  the  acute  effects of
lindane,  static  test  LC5Q   values  ranged  from 9.0 ^g/1  for the  Atlantic
silversides (Menidia  menidia)  to  66.0 ug/1  for  the  striped  mullet  (Mugil
cephalus)  (Eisler,   1970).   The results  of six flow-through assays on five
species  of marine  fish produced  LC5Q values from  7.3 jjg/l for the  striped
bass  (Morone saxatilis)  (Korn  and Earnest,  1974)  to  240 jug/1 for the long  .
nose  killifish  (Fundulus similis)  (Butler,  1963).    A single species,  the
pinfish  (Laqodon rhomboides),  tested  with  technical  grade  hexachlorocyclo-
hexane, produced a  96-hour  flow-through LC_Q value  of  86.4 jjg/1  (Schimmel,
et al. 1977).   Acute tests on  marine  invertebrates  showed six  species  to be
quite  sensitive  to  lindane,  with  LC5Q values from  both  static  and  flow-
through assays ranging from  0.17 jug/1-for the pink shrimp  (Panaeus duorarum)
(Schimmel,  et al.   1977)  to 10.0 /jg/1  for the grass  shrimp  (Palaemonetas
vulqaris)  (U.S.  EPA,  1979).    An  LC5Q value of 0.34  jug/1  was obtained  for
technical grade  hexachlorocyclohexane  for the pink  shrimp (Schimmel, et  al.
1977).  The American  oyster  had an EC5Q  of 450 jjg/1  based on shell 'decom-
position (Butler, 1963).

-------
     8.  Chronic
         A chronic  value of  14.6 jjg/1 for  lindane  was obtained in  a  life-
cycle  assay  of  the  freshwater  fathead  minnow  (Pimephales promelas).   For
three  species  of  freshwater  invertebrates  tested  with  lindane,  chronic
values  of 3.3,  6.1,  and 14.5 pg/l  were  obtained  for Chironomus  tentans,
Gammarus  fasciatus,  and  Daphnia magna  (Macek,  et  al.  1976)..   No- chronic
marine data for any of the hexachlorobenzenes were available.
     C.  Plant Effects
         Concentrations  causing growth  inhibition of  the  freshwater  alga,
Scenedesmus acutus were reported to be 500,  1,000, 1,000,  and  5,000 jug/1 for
alpha-HCH,   technical   grade   HCH,   lindane,   and   beta-HCH,   respectively
(Krishnakumari,  1977).   In  marine  phytoplankton  communities,  an  effective
concentration  value  of 1,000 fig/1 (resulting  in  decreased productivity) was
reported  for  lindane;  and for the alga, Acetabularia mediterranea  an effec-
tive  concentration  of  10,000 jug/1 was  obtained for lindane-induced  growth
inhibition.  No effect  in 48 hours  was observed  for  the  algae  Chlamydomonas
so. exposed  to lindane  at the maximum solubility  limit.   Irreparable damage
to Chlorella  sp.  occurred at  lindane concentrations of  more  than  300  ;jg/l
(Hansen, 1979).
     0.  Residues
         Bioconcentration factors  for- lindane  ranging  from 35  to  938  were
reported  for  six species of  freshwater  organisms (U.S. EPA, 1979;  Sugiura,
et  al. 1979a). . In marine  organisms,  bioconcentration  factors  (after  28
days)  for  39 percent  lindane of 130,  218,  and  617..were  obtained for  the
edible  portion of  the  pinfish (Lagodon  rhomboides),  the American oyster
                                  111-13

-------
(Crassostrea virqinica),  and offal tissue  of the pinfish  (Schimmel,  et al.
1977). Sugiura, et al.  (1979a)  found alpha-, beta-, and  gamma-HCH had accu-
mulation  factors  of  1,216,  973  and   765  in  golden  orfe  (Leuciscusidus
melanotus); 330,  273,  and 281 in carp  (Cyprinus  carpio); 605, 658,  and 442
in  brown  trout   (Salmo  trutta  fario);  and  588,  1,485,  and  938 in  guppy
(Poecila reticula),  respectively.   Further, these accumulation  factors were
proportional to the  lipid content  of the fish.   Accumulation occurred in the
adipose tissues and  the gall bladder, with  the  alpha and  beta-HCH being more
persistent (Sugiura, et al.  1979b).
         Equilibrium  accumulation  factors  of  429  to  602  were  observed  at
days 2 to  6 after exposure of Chlorella sp. to 10 to 400 ;jg/l of lindane in
aqueous solution  (Hansen,  1979).
VI.  EXISTING STANDARDS AND  GUIDELINES
     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
                                                 i
         Based on the  induction  of liver tumors in  male  mice, and using the
"one-hit" model,  the U.S. EPA (1979) has  estimated  the  following  levels  of
technical  hexachlorocyclohexane  and its isomers in ambient  water which will
result in specified risk  levels of human cancer.
         The water  concentrations of technical HCH corresponding to  a  life-
        icer risk   for  I"
Nagasaki,  et al. (1972).
time  cancer risk  for  humans of  10~   is  21  ng/1, "'based  on  the  data  of
                                  ^^^^.^u.
                                  1 / JeL J

-------
         The water  concentrations of  alpha-HCH corresponding  to a lifetime
cancer  risk  for humans  of 10    is  16 ng/1,  based on  the data  of Ito, et
al. (1975).
         The water  concentrations of beta-HCH  corresponding  to  a lifetime
cancer  risk  for humans  of 10    is  28 ng/1, based  on the data  of Goto, et
al. (1972).
         The water  concentrations of  lindane  (gamma-HCH)  corresponding to a
lifetime cancer risk  for humans of  10    is 54 ng/1, based on  the data of
Thorpe and Walker (1973).
         Data  for  the  delta  and  epsilon isomers  are insufficient  for the
estimation of cancer risk levels  (U.S. EPA, 1979).
         An ADI of  1 jjg/kg  for HCH has been set by the Food and Agricultural
Organization and the World Health Organization (U.S. EPA, 1979).
         Tolerance  levels set by  the  EPA are as follows:  7 ppm for animal
fat, 0.3 ppm  for milk,  1 ppm for most  fruits  and vegetables, 0.004  pm for
finished drinking water, and 0.5 ug/m3 (skin) for air  (U.S. EPA, 1979).
     8.  Aquatic
         For  lindane,  freshwater criteria  have been  drafted  as  0.21 ug/1
with 24-hour average concentration not to  exceed 2.9 ug/1.  For marine or-
ganisms, criteria  for  lindane have  not  been drafted.  No  criteria for mix-
tures of isomers of hexachlorocyclohexane (benzene  hexachloride)  were draft-
ed for freshwater or marine organisms because of the lack of data.

-------
                    HEXACHLOROCYCLOHEXANE

                          REFERENCES

Besuglyi, V.P.,  et al.   1973.   State of  health  of persons
having prolonged  occupational contact  with hexachlorocyclo-
hexane.  Idrabookhr Beloruss.  19: 49.

Buselmair,  W.,   et al.    1973.    Comparative  investigation
on the mutagenicity of  pesticides in mammalian test systems.
Mutat. Res.  21: 25.

Butler,  P.A.    1963.    Commercial  fisheries investigations,
pesticide-wildlife  studies,  a  review  of  fish and  wildlife
service  investigations  during 1961-1962.   U.S.  Dept.  Inter.
Fish Wildl. Circ. 167: 11.
                                          ».
Canton, J.H., and W. Sloof.  1977.  The usefulness of Lymnaea
stagnalis  L.  as  a   biological   indicator   in  toxicological
bioassays (model substance cA-HCH).  Water Res. 11: 117.

Chadwick, R.W.,  and J.J.  Freal.   1972.   The identification
of  five  unreported  lindane  metabolites  recovered  from rat
urine.  Bull. Environ. Contam. Toxicol.  7:  137.

Chadwick, R.W.,  et al.   1975.  Dehydrogenation, a previously
unreported pathway of lindane metabolism in  mammals.  Pestic.
Biochem.  Physiol.  6:  575.

Copeland, M.F.,  and  R.W. Chadwick.   1979.   Bioisomerization
of  lindane  in  rats.     Jour.  Environ.  Pathol.  Toxicol.  2:
737.

Davidow,  B.  and J.P.  Frawley.    1951.    Tissue distribution
accumulation and elimination  of  the  isomers of benzene  hexa-
chloride (18631).  Proc. Soc. Exp. Biol.  Med.  76: 780.

Duggan,  R.E.,  and M.B.  Duggan.    1973.   Residues  of  pesti-
cides  in milk,  meat 'and foods.   Page  334  In:   L.A.  Edwards,
ed.  Environ. Pollut.  Pestic. London.

Eisler,  R.    1970.    Acute  toxicities  of  organochlorine and
organophosphorus  insecticides  to  estuarine  fishes.    Bur.
Sport Fish Wildl. Pap. No. 46.

Engst, R., et al.  1977.  Recent  state of lindane metabolism.
Residue Rev. 68: 59.

Fitzhugh, O.G.,  et al.   1950.  Chronic toxicities of benzene
hexachloride, and  its alpha,  beta,  and gamma isomers.    Jour.
Pharmacol. Exp. Therap.  100: 59.

Goto,  M.,  et al.   1972.   Ecological  chemistry.   Toxizitat
von a-KCH in mausen. Chemosphere  1: 153.

-------
Hanada,  M.,  et  al.    1973.    Induction  of  hepatoma  in mice
by benzene hexachloride.  Gann. 64: 511.

Hansen,  P.D.    1979.    Experiments  on  the  accumulation  of
lindane  (gamma BHC)  by  the  primary producers Chlorella spec.
and Chlorella pyrenoidosa.   Arch.  Environ.  Contam. Toxicol.
8: 721.

Henderson, C.,  et al.  1959.   Relative  toxicity  of  ten chlori-
nated  hydrocarbon- insecticides  to  four   species of  fish.
Trans. Am. Fish Soc. 88: 23.

Henderson, C., et  al.   1971.  Organochlorine pesticide resi-
dues in fish-fall 1969: Natl. Pestic. Monitor.  Progr. Pestic.
Monitor. Jour.   5: A.

Herbst,  M.,  and G.  Bodenstein.   1972.   tToxicology  of lin-
dane.  Page 23 In; E. Ulmann,  (ed.) Lindane. Verlag K. Schil-
linger Publishers, Freiburg.

Heyroth,  F.F.   1952.   In;  Leland, S.J.,  Chem. Spec. Manuf.
Ass. Proc. 6:110.

Huntingdon Research  Center.   1972.    In;  Lindane: Monograph
of  an  insecticide E.  Illmon  (ed.).    Lube  Verlag K.  Schil-
linger p. 97.

Itp, N.,  et  al.    1973.  Histologic' and  ultrastructur.al stu-
dies  on  the  hepatocarcinogenicity  of  benzene hexachloride
in mice.  Jour. Natl. Cancer Inst.  51: 817.

Ito, N. ,  et  al.    1975.   Development  of  hepatocellular car-
cinomas  in  rats  treated with  benzene hexachloride.   Jour.
Natl.  Cancer Inst.  54: 801.

Kashyap,  S.K., et  al.   1979.  Carcinogenicity of  hexachloro-
cyclohexane (BHC)  in pure inbred  Swiss mice.  Jour. Environ.
Sci. Health B14: 305.

Kazahevich,  R.L.    1974.   'State  of  the  nervous  system  in
persons with a prolonged professional contact with hexachlor-
ocyclohexane and  products  of  its synthesis.    Vrach.  Delo.
2: 129.

Khera, K.S., et al.   1979.   Teratogenicity studies on pesti-
cidal  formulations  of  dimethoate,  diuron and   lindane  in
rats.  Bull. Environ. Contam. Toxicol.  22:  5.22.

Kocansky, w.,  et al.   1963.   Absorption,  distribution,  and
elimination of alpha-  and  beta- benzene  hexachloride.  Arch.
Exp. Pathol. Pharmacol.  244: 564.

Korn,  S.,  and  R.  Earnest.   1974.   Acute  toxicity of twenty
insecticides  to  striped bass, Marone  saxatilis.    Calif.
Fish Game 60:  128.
                           -/ ^ ~i /^
                            I ^) *.u

-------
Krishnakumari, M.K.   1977.   Sensitivity of  the alga Scene-
desmus acutus to some pesticides.  Life Sci.  20: 1525.

Kurihara,  H.,  et  al.    1979.    Mercapturic acid  formation
from lindane in rats.  Pest. Biochem. Physiol.   10: 137.

Laug, E.P.  1948.   Tissue distribution of a toxicant follow-
ing oral  ingestion of the  gamma-isomer  of  benzene hexachlo-
ride by rats.   Jour. Pharmacol. Exp. Therap.  93: 277.

Lee, B., et al.   1976.   Suspected reactions to gamma benzene
hexachloride.   Jour. Am. Med. Assoc.  236: 2846:

Lehman, A.J.   1952a.   Chemicals in  food:   A  report  to the
Assoc.  of  Food  and  Drug  officials.    Assoc.  Food  and  Drug
Off., U.S. Quart. Bull.  16:  85.
                                          ".
Lehman, A.J.   1952b.     Chemicals  in foods:   A  report  to
the Association of Food  and Drug officials on current develop-
ments.   Part  II.   Pesticides Section  V.    Pathology.   U.S.
Assoc. Food Drug Off., Quart.  Bull.  16: 126.

Lichtenstein,  E.P..   1959.    Absorption of  some chlorinated
hydrocarbon  insecticides   from  soils  into  various  crops.
Jour. Agric. Food Chem. 7:  430.

Litterst, C.L.,  and  E.  Miller.   1975.   Distribution of lin-
dane  in brains of control  and phenobarbital pretreated dogs
at the  onset of  lindane induced  convulsions.  Bull. Environ.
Contam. Toxicol.   13: 619.

Macek,  K.J.,  and W.A. McAllister.   1970.   Insecticide  sus-
ceptibility  of  some  common  fish  family  representatives.
Trans. Am. Fish Soc. 99: 20.

Macek,  K.J.,  et  al.   1976.   Chronic  toxicity of  lindane
to  selected  aquatic  invertebrates  and  fishes.   EPA-600/3-
76-046.  U.S.  Environ. Prot. Agency.

Mametkuliev, C.H.   1978.   Study of  embryotoxic and terato-
genic properties  of  the gamma  isomer of HCH  in experiments
with rats.  Zdravookhr.  Turkm.  20: 28.

Mathur, S.P.,  and J.G. Saha.   1975.   Microbial degradation
of  lindane-C-14  in  a flooded sandy  loam  soil.    Soil  sci.
120: 301.
                                            .-
Nagasaki,  H. ,  et  al.   1972.    Carcinogenicity of  benzene
hexachloride (BHC).  Top. Chem.  Carcinog.,  Proc. Int.  Symp.,
2nd. 343.

National  Academy of  Sciences -  National  Research  Council.
1977.   Safe Drinking  Water Committee.   Drinking  Water  and
Health,  p. 939.

-------
National  Cancer  Institute.   1977a.   A bioassay  for  possible
carcinogenicity of  lindane.   Fed.  Reg^  Vol.  42  No.  218.

National  Cancer  Institute.    1977b.    Bioassay  of  lindane
for  possible carcinogenicity.   NCI Carcinogenesis  Technical
Report, Series No.  14.

Nigam,  S.K.,  et al.   1979.   Effect of hexachlorocyclohexane
feeding  on  testicular  tissue  on pure  inbred  Swiss  mice.
Bull. Environ. Contain. Toxicol.  23: 431.

Nishiraura,  H.,  et  al.    1977.   Levels  of polychlorinated
biphenyls  and organochlorine insecticides  in  human  embryos
and  fetuses.  Pediatrician 5:  45.

Palmer, A.K.,  et al.  1978.   Effect  of lindane  on  pregnancy
in the  rabbit and rat.   Toxicology  9: 239.

Petrescu, S.,  et  al.   1974.  Studies on the effects  of  long-
terra administration of  chlorinated organic pesticides  (lin-
dane,  DDT)   on laboratory white  rats.    Rev.  Med.  -  Chir.
78:  831.

PoradovsJcy,  R.,  et al.    1977.   Transplacental  permeation
of pesticides during  normal  pregnancy.  Cesk  Gynekol.    42:
405.

Reuber, M.D.   1979.   Carcinogenicity  of  lindane.    Environ.
Res.  19:  460.

Rivett,  K.P.,  et  al.    1978.    Effects  of  feeding  lindane
to dogs for periods of up  to  2  years.   Toxicology 9:  237.

Sanders,  H.O., and  O.B.  Cope.   1963.  The relative  toxicities
of serveral  pesticides to naiads  of  three  species of stone-
.flies.  Limnol. Oceanogr.  13:  112.

Sasinovich,  L.M.,  et  al.    1974.   Toxic  hepatitis  due  to
prolonged exposure  to  BHC.  Vrach. Delo.  10: 133.

Schimmel, S.E., et  al.   1977.  Toxicity and bioconcentration
of  BHC and  lindane  in  selected  estuarine animals.    Arch.
Environ.  Contain. Toxicol.   5:  355.

Sloof,  W.   1979.    Detection  limits  of a biological  monitor-
ing  system based on fish respiration.   Bull. Environ.  Contam.
Toxicol.  23:  517.

Sugiura,  K.,  et al.   1979a.   Accumulation of  organochlorine
compounds  in  fishes.    Difference  of accumulation  factors
of fishes.  Chemosphere  5:  359,

-------
Sugiura, K.,  et  al.   19795.   Accumulation of organochlorine
compounds  in  fishes.   Distribution  of 2,4,5-T, 
-------
                                    No.  113
    ganma-flexachlorocyclohexane


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

          APRIL 30,  1980
            1/3-1

-------
                          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.
                      7

-------
                          Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

-------
                     GAMMA-HEXACHLOROCYCLOHEXANE (Lindane)
                                    Summary

     Gamma-l,2,3,4,5,6-hexachlorocyclohexane, commonly  known as lindane, can
induce liver tumors  in  mice.   Evidence for mutagenicity  of lindane is equi-
vocal.  Lindane  was  not teratogenic for rats,  although it reduced reproduc-
tive capacity over four generations.   Chronic exposure of animals to lindane
caused liver enlargement and,  at  higher doses,  some liver damage and nephri-
tic  changes.   Humans   chronically  exposed  to  HCH  suffered  liver  damage.
Chronic exposure of humans to  lindane produced  irritation of  the  central
nervous system.  Lindane is a convulsant.
     Lindane  has been  extensively studied  in  a  number  of  freshwater  and
marine acute studies.  Levels as  low as 0.17 jjg/1 are toxic to marine inver-
tebrate species.

-------
                     GAMMA-HEXACHLOROCYCLOHEXANE (Lindane)
I.   INTRODUCTION
     This  profile is based  on the  Ambient Water  Quality Criteria  Document
for Hexachlorocyclohexane  (U.S. EPA, 1979).
     Gamma-l,2,3,4,5,6-hexachlorocyclohexane     or     lindane     (C^H^Cl^;
molecular  weight  290.0)  is  a crystalline  solid  with  a melting  point  of
112.8°C,  a  vapor pressure  of  0.003  mm Hg  at  20°C  (U.S.   EPA,  1979),  a
solubility  in water  at 25°C  of  7.8 rag/1  (Hansen, 1979),  and a  solubility
in ether of 20.8  g/100 g at  20°C  (U.S.  EPA,  1979).   Other trade names  in-
clude  Jacutin,  Lindfor 90,  Lindamul 20, Nexit-Staub, Prodactin,  gamma-HCH,
gamma-SHC,  and purified BHC  (U.S. EPA,  1979).  Technical  grade hexachlorocy-
clohexane contains 10 to 18 percent lindane.
     Lindane  is  a broad spectrum insecticide,  and  is a member  of  the  cyclic
                                                                             *
organo-chlorinated hydrocarbons.  It  is used  in a wide range of applications
including  treatment  of animals,  buildings, man  (for ectoparasites),  cloth-
ing, water  (for  mosquitoes),  plants, seeds,  and soil.   Lindane is not cur-
rently  manufactured  in the  U.S.; all  lindane  used in  the  U.S. is  imported
(U.S. EPA, 1979).
     Lindane has a low  residence  time in the  aquatic  environment.  It  is  re-
moved by sedimentation, metabolism, and volatilization.  Lindane contributes
less to  aquatic  pollution  than the  other hexachlorocyclohexane  isomers (Hen-
derson, et al. 1971).
     Lindane  is  slowly  degraded by  soil  microorganisms (Mathur  and  Saha,
1975; Tu, 1975,  1976) and  is  reported to be  isomerized to the  alpha- and/or
delta- isomers in  microorganisms and  plants  (U.S.  EPA,  1979), but not  in
rats (Copeland and Chadwick, 1979).   The  metabolic  pathway in microorganisms  '
is still controversial (Tu, 1975,  1976;  Copeland and Chadwick, 1979).

-------
II.  EXPOSURE
     A.  Water
         The  contamination of  water  has  occurred  principally  from  direct
application of technical hexachlorocyclohexane  (HCH) or  lindane  to  water for
control  of  mosquitoes or  from  the use of  HCH in agriculture and  forestry;
and  to  a  lesser  extent  from  occasional  contamination  of wastewater  from
manufacturing plants (U.S. EPA,  1979).
         Lindane has been  detected in the finished water of  Streator,  Illi-
nois, at a concentration of 4 ug/1 (U.S. EPA, 1975).
     B.  Food
         The daily  intake  of  lindane has been  reported  at  1  to  5 ug/kg body
weight and  the  daily  intake of all  other  HCH isomers at 1 to 3 ug/kg  body
weight (Duggan and  Duggan,  1973).   The chief sources of HCH  residues  in the
human  diet  are milk,  eggs,  and other  dairy products (U.S.  EPA,  1979)  and
carrots  and  potatoes   (Lichtenstein,  1959).   Seafood   is  usually  a  minor
source of HCH,  probably because of  the  relatively  high  rate of dissipation
of HCH in the aquatic environment (U.S. EPA, 1979).
         The U.S.  EPA  (1979)  has  estimated  the weighted average bioconcen-
tration  factor  for lindane to  be 780  for  the edible portions  of fish  and
shellfish consumed by Americans.   This estimate is based on measured steady-
state bioconcentration studies in bluegills.
     C.  Inhalation
         Traces of HCH have been detected in the air of  central  and suburban
London (Abbott, et al.  1966).   Uptake of lindane by , inhalation is estimated
at 0.002 jug/kg/day (Barney,  1969).
     0.  Dermal                                                       '
         Lindane has been  used  to eradicate human ectoparasites, -a few  ad-
verse reactions have been  reported  (U.S. EPA, 1979).
                                113-6

-------
III. PHARMACOKINETICS
     A.  Absorption
         The  rapidity  of  lindane absorption  is enhanced  by lipid-mediated
carriers.  Compared  to  other organochlorine insecticides,  lindane is unusu-
ally soluble  in water which  contributes to its  rapid  absorption and excre-
tion (Herbst  and  Bodenstein,  1972; U.S. EPA,  1979).   Intraperitoneal injec-
tions of  lindane  resulted in 35  percent absorption  (Koransky,  et al. 1963).
Lindane is also absorbed after oral and dermal exposure (U.S. EPA, 1979).
     B.  Distribution
         After  administration  to experimental animals,  lindane  was detected
in  the  brain  at  higher  concentrations than  in other  organs  (Laug,  1948;
Davidow and  Frawley, 1951; Koransky,_ et al. 1963; Huntingdon Research Cen-
ter, 1971).   At least 75  percent of an intraperitoneal  dose of   C-labeJ,ed
lindane was consistently found in the  skin,  muscle,  and fatty tissue (Koran-
sky, et  al.  1963).   Lindane  enters  the human  fetus through the placenta;
higher concentrations were found  in the skin than in  the brain,  but  never
exceeded the corresponding values for  adult  organs  (Poradovsky,  et al.  1977;
Nishimura, et al.  1977).
     C.  Metabolism
         Copeland and  Chadwick  (1979)  found that lindane  did not isomerize
in  adipose  tissues   in  rats,  but  noted dechlorination to  T*-3,4,5,6-tetra-
chlorocyclohexene.   Some other metabolites  reported  have  been 2,3,4,5,6-pen-
tachloro-2-cyclohexene-l-ol,    pentachlorophenol,   tetrachlorophenols,    and
three trichlorophenols  (Chadwick, et al. 1975;  Engst,  et  al. 1977),  all  of
which were  found in the  urine  as conjugates  (Chadwick  and Freal,  1972).
                                                                     »
Lindane metabolic pathways are  still  matters of some controversy  (Engst,  et
                                 . isii / -
                                ' I JJU
                                 1/3-7

-------
al. 1977; Copeland and  Chadwick,  1979).   Both free and conjugated chlorophe-
nols with  the possible exception' of pentachlorophenol (Engst,  et al. 1977)
are far less toxic than lindane (Natl. Acad. Sci., 1977).
     0.  Excretion
         Metabolites of lindane appear to be  eliminated  primarily as conju-
gates in the urine.  Very  little  unaltered lindane is excreted  (Laug, 1948).
Elimination of lindane  appears  to be rapid after administration ceases (U.S.
EPA, 1979).
IV.  EFFECTS
     A.  Carcinogenicity
         Nagasaki, et al.  (1972b) fed *{,/&, T~,  and 0 isomers separately
in the diet  to  mice at levels  of 100,  250,  and  500  ppm.   At termination of
the experiment  after 24 weeks, multiple  liver tumors, some  as  large as 2.0
centimeters in diameter were observed in  all  animals  given ^-HCH at the 500
ppm level.   The  250 ppmV -HCH level resulted in  smaller nodules,  while no
lesions were  found  at  levels of  100 ppm.   The various dosages  did  not pro-
duce any  tumors  with respect to  the other isomers.   Pathomorphological in-
vestigations by  Didenko,  et al.  (1973)  established  that the  IT isomer did
not induce  tumors in mice  given  intragastric administration  at doses of 25
mg/kg twice a week for five weeks.
         Hanada,   et  al. (1973)  fed  six-week-old mice a  basal  diet  of 100,
300, and 600 ppm  t-HCH  and  the^(, $,• IT isomers for a  period  of 32 weeks.
After  38  weeks,   liver  tumors  were  found  in   76.5  percent of the males and
43.5 percent  of  the  females fed  t-HCH,  indicating  males were  more highly
susceptible to HCH-induced  tumors than  females.   Multiple nodules were found
in  the  liver, although no  peritoneal  invasion  or  distinct  metastasis  was
found.   Thep -isomer-treated animals had no tumors.

-------
            Goto,  et al. (1972) essentially confirmed  the  findings of the above
   study using diets containing 600 ppm levels over a  26 week period.  The com-
   bination of/?-, T-,  or 0 -HCH  with  the highly carcinogenic  action  of °(-
   HCH  revealed  no  synergistic  or  antagonistic effect on  the  production of
   tumors by °( -HCH for dd strains of mice  (Ito,  et al. 1973).  Kashyap,  et al.
   (1979) found that 2T-HCH (14 percent lindane)  at 100 ppm  levels  in the diet
   or at  10 mg/kg/day  caused  liver and  lymphoreticular tissue tumors in both
   male and  female  mice after 45  weeks.   Application by  skin painting  had no
   effect.
            The National Cancer Institute conducted a  bioassay for the possible
   carcinogencity  of 0  -HCH  to Osbome-Mendel rats and 86C3F1  mice.   Adminis-
   tration continued  for  80 weeks  at  two  dose  levels:   time-weighted  average
   dose for male rats  was  236 and 472  ppm; for  female  rats, 135 and 275 ppm;
   and for all mice, 80 and 160 ppm.  NO  statistically significant incidence of
   tumor occurrence was noted  in any of  the experimental  rats as  compared to
   the controls.  At  the  lower dose concentration  in male mice,  the incidence
•'  of hepatocellular carcinoma was significant when compared to  the  controls,
   but not significant in the higher dose males.  "Thus, the  incidence of hepa-
   tocellular carcinoma in male mice cannot clearly be  related  to treatment."
   The incidence of hepatocellular carcinoma among female mice  was not signifi-
   cant.   Consequently, the  carcinogenic  activity  of  T'-HCH  in mice is  ques-
   tionable (Natl. Cancer Inst.,  1977).
        B.   Mutagenicity
            Some alterations  in mitqtic  activity and the karyotype of  human  ly-
   phocytes cultured with lindane  at 0.1 to 10 mg/ml have been  reported (Tsone-
   va-Maneva,  et al.  1971).  %" -HCH was  mutagenic  in  assays using  Salmonella
   typhimurium with  metabolic activation,  the  host-mediated  assay, and  the

-------
dominant lethal assay in rats.  Other reports  indicate  that  it  does  not  have
significant mutagenic activity (U.S.  EPA,  1979; Buselmair,  et al.  1973).
     C.  Teratogenicity
         Lindane given  in  the diet  during pregnancy at levels of 12 or 25
mg/kg body weight/day did  not produce teratogenic effects in rats (Mametku-
liev, 1978; Khera,  1979).
     0.  Other Reproductive Effects
         Chronic lindane feeding  in  a study of four generations  of  rats in-
creased the  average  duration of  pregnancy,  decreased  the  number of births,
increased the proportion of  stillbirths, and delayed sexual  maturation in F2
and F3 females.  In  addition, some of the  Fl and F2 animals  exhibited spas-
tic paraplegia (Petrescu,  et al.  1974 )_.
         In rats and rabbits, lindane given  in  the diet during  pregnancy in-
creased postimplantatlon death of embryos  (Mametkuliev, 1978; Palmer, et al.
1978).  Testicular atrophy has been observed in rats and mice (National Can-
cer Institute, 1977;  Nigam, et al. 1979).
     E.  Chronic Toxicity
         Irritation of the central nervous system with other toxic side ef-
fects  (nausea,  vomiting,  spasms,  weak  respiration  with .cyanosis and blood
dyscrasia) have been reported after  prolonged  or improper  use  of Hexicid (1
percent lindane) for the treatment of scabies on humans  (Lee,  et al.  1976).
         In chronic  studies  with  rats given lindane in oil, liver cell hy-
pertrophy  (fat  degeneration  and  necrosis)  and  nephritic changes  were noted
at  higher  doses (Fitzhugh,  et  al.  1950;  Lehman," 1952a,b).  Rats  inhaling
lindane (0.78 mg/m )  for  7  hours, 5  days  a week  for  180  days  showed liver
                                                                    »
cell  enlargement  but showed no  clinical   symptoms  or  other  abnormalities
(Heyroth,  1952).  The addition of 10 ppm lindane  to the diet  of rats for one
                               in-/*

-------
or  two  years decreased  body weight  after five months  of treatment and  al-
tered ascorbic  acid levels  in  urine, blood,  and tissues  (Petrescu,  et  al.
1974).   Dogs chronically  exposed  to lindane  in the  diet  had  friable  and
slightly enlarged livers (Rivett, et  al. 1978).
     F.  Other Relevant Information
         Lindane  is a  convulsant and  is the  most acutely  toxic isomer  of
hexachlorocyclohexane.  The  toxic effects of lindane are antagonized by  pre->.
treatment  with phenobarbitol  (LLtterst and  Miller, 1975)  and by  treatment
with  silymarin (Szpunar,  et al. 1976),  and various  tranouilizers  (Ulmann,
1972).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The  range  of adjusted LC5Q  values  for one  flow-through  and'24
static  bioassays  for lindane in  freshwater  fish ranged from  1 pg/l for  the
brown  trout Salmo  trutta  (Macek,- et al.  1970)  to 83 jug/1 for the goldfish
(Carassius  auratus),  and  represents  the  results  of tests  on 16  freshwater
fish  species  (U.S. EPA,  1979).   Zebrafish  (Brachydanio rerio)  showed  an
LC5Q  value of  120  ;jg/l  but rainbow  trout  (Salmo qairdneri)  exhibited  re-
spiratory distress  at 40 jug/1  (Slooff,  1979).   Among eight species of  fresh-
water invertebrates studied  with lindane,  stone flies (Pteronarcys  califomi-
ca) and three species of crustaceans: scuds  (Gammarus lacustris and G^ faci-
atus) and  sowbugs (Ascellus brevicaudus)  were most  sensitive, with adjusted
LC5Q  values  ranging  from  4  to  41 jug/1.    Three  species  of  cladocerans
(Daohnia pulex,  D^ maqna  and  Simocephalus  serralatus)  were  most resistant
with  LC5Q  values of  390  to 745 jjg/1.  The  midge (Chironomus  tentans)  was
intermediate in sensitivity with LC5Q values of 175 pg/1 (U.S. EPA, 1979).

-------
         Among eight  species  of marine fish  tested  in static bioassays  with
lindane, the Atlantic  silversides  (Menidia menidia)  was most sensitive,  with
an  acute  LC5Q  of 9  jjg/1 (Eisler,  1970), while  the  striped  mullet  (Muqil
cephalus)  was  reported  as having  an  acute  static  LC5Q of  66.0 ug/1  (U.S.
EPA,  1979).   The  results of six  flow-through  assays on  five  species  of
marine  fish  revealed  that the striped  bass (Morone  saxatilis) was most  sen-
sitive  with  an  acute LC_0  of 7.3  jug/1  (Korn  and  Earnest,  1974);  and  the
longnose  killifish (Fundulus  similis)  was  most  resistant  with  a  reported
LC-.,  of 240 jjg/1.   Acute studies  with six  species of marine  invertebrates
showed  these organisms   to  be  extremely  sensitive to  lindane,  with  LC5Q
values  ranging from 0.17 jjg/1 for the  pink shrimp,  Panaeus duorarum  (Schim-
mel, et al. 1977), to 8.5 ug/1 for the grass shrimp (Palaemonetes  vulqaris).
     B.  Chronic
         A chronic value  of  14.6 ug/1 was obtained for lindane in  a life-
cycle assay of the freshwater fathead  minnow (Pimephales promelas).  Chronic
values  of  3.3,  6.1,  and  14.5 ug/1  were obtained for three freshwater  inver-
tebrates, Chironomus  tentans,  Gammarus fasciatus, and  Daphnia maqna  (Macek,
et al.  1976).  No marine chronic studies were available.
     C.  Plant Effects
         For freshwater  algae,  Scenedesmus acutus,  the effective concentra-
tion  for  growth  inhibition  was  1,000 ug/1.   Effective concentrations   for
marine  phytoplankton  communities and  the  algae,  Acetabularia mediterranea,
were  1,000  and  10,000 pg/1, respectively.   Irreparable damage  to Chlorella
spec, occurred at concentrations greater than 300 ug/1  (Hansen, 1979).
     0.  Residues
                                                                     »
         Bioconcentration  factors  for  lindane  ranging  from  35  to  938 have
been obtained for  six  species of  freshwater fish and invertebrates.  No bio-
concentration factors  for lindane have been  determined for  marine organisms
                                  / -7 {('
                                X /'  ->' >" '^

-------
(U.S. EPA,  1979;  Sugiura,  et al. 1979).  Equilibrium accumulation  factors  of
429 to 602 were observed at  days 2  to 6 after exposure of Chlorella  spec,  to
10 to 400 ug/1 -of lindane  in aqueous  solution  (Hansen,  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
         Using  the  "one-hit" model,  the  U.S.  EPA  (1979)  has estimated  that
the water  concentration of  lindane (gamma-HCH) corresponding  to a  lifetime
cancer risk for humans of 10    is  54 ng/1, based on the  data of Thorpe and
Walker (1973) for the induction  of  liver tumors  in male mice.
         Tolerance  levels set  by the  U.S.  EPA are  as follows:   7 ppm for
animal fat;  0.3 ppm for  milk;  1 ppm for most  fruits  and vegetables; 0.004
ppm  for  finished  drinking water;  and  0.5 mg/m  (skin)  for  air (U.S. EPA,
1979).  It  is not clear  whether these levels are for hexachlorocyclohexane
or for lindane.
     3,  Aquatic
         The criterion has been  drafted to  protect freshwater organisms as a
0.21 ug/1  24-hour average concentration  not  to exceed 2.9 ug/1.   Data are
insufficient to draft  criterion for  the protection of  marine life from gam-
ma-hexachlorocyclohexane (lindane).
                                I > 3

-------
           .  GAMMA-HEXACHLOROCYCLOHEXANE(LINDANE)


                          REFERENCES

Abbott, D.C., et al.  1966.  Nature 211: 259.

Barney, J.E.  1969.  Ghent. Eng. News, Vol. 42.

Buselmair,  W.,   et al.    1973.    Comparative  investigation
on the mutagenicity of pesticides  in  mammalian test systems.
Mutat. Res. 21: 25.

Chadwick, R.W.,  and  J.J. Freal.   1972.   The indentification
of  five  unreported  lindane metabolites  recovered  from rat
urine.  Bull. Environ. Contam. Toxicol. 7: 137.

Chadwick, R.W., et al.   1975.   Dehydrogenation, a previously
unreported pathway of lindane metabolism in mammals.  Pestic.
Biochem. Physiol. 6: 575.

Copeland, M.F.,  and  R.W. Chadwick.   1979.   Bioisoraerization
of lindane in rats.  Jour. Environ. Pathol. Toxicol.  2: 737.

Davidow, B.,  and J.P. Frawley.   1951.   Proc.  Soc. Exp. Biol.,
Med. 76: 780.

Didenko, G.G.,  et  al.    1973.   Investigation-of the possible
carcinogenic  action of  the gamma  isomer  of  hexachlorocyclo-
hexane.  Gig. Sanit. 38:  98.

Duggan,  R.E.,  and M.B.  Duggan.   1973.   Residues  of  pesti-
cides  in milk,  meat and  foods.   Page 334 In;  L.A.  Edwards,
(ed.) Environ. Pollut. Pestic. London.

Eisler,  R.    1970.   Acute  toxicities  of organochlorine and
organophosphorus  insecticides  to   estuarine  fishes.    Bur.
Sport Fish Wilfl. Pap. No. 46.

Engst, R.,  et al.  1977.   Recent state of lindane metabolism.
Residue Rev. 68: 59.

Fitzhugh, O.G., et al.   1950.   Chronic toxicities of benzene
hexachloride, and its alpha, beta,  and  gamma  isomers.   Jour.
Pharmacol.  Exp.  Therap..  100: 59.

Goto,'  M.,  et al.   1972.   Ecological chemistry.   Toxizitat
von a-HCH in mausen.   Chemosphere 1: 153.

Hanada,  M.,  et  al.   1973.   Induction  of  hepatoma in  m'ice
by benzene hexachloride.   Gann. 64: 511.

-------
Hansen,  P.O.   1979   Experiments  on the accumulation of  lin-
dane  (  -BHC)  by  the primary  producers  Chlorella  spec.
and  Chorella pyrenoidosa.   Arch.  Environ,  contam. Toxicol.
8: 72TT

Henderson, C.,  et al.  1971.  Organochlorine pesticide  resi-
dues in fish-fall 1969:  Natl.  Pestic. Monitor.  Progr. Pestic.
Monitor. Jour. 5: A.

Herbst, M., and G. Bodenstein.  1972.  Toxicology of lindane.
Page 23  in;  E.  Ulmann, (ed.)  Lindane.   Verlag K. Schillinger
Publ., Freiburg.

Heyroth, F.P.  1952.   In; Leland,  S.J.,  Chem. Spec. Manuf.
Assoc. Proc.  61  110.

Huntingdon Research  Center.    1971.   In;  Lindane:  Monograph
of an  insecticide.   E. Ullman (ed.),  Verlag K. Schellenger,
(Pub.), p. 97, 1972.

Ito, N-, et al.   1973.  Histologic and ultrastructural studies
on  the  hepato  carcinogenicity  of  benzene  hexachloride in
mice.  Jour. Natl. Cancer  Inst. 51:  817.

Kashyap, S.K., et al.   1979.   Carcinogenicity of hexachloro-
cyclohexane  (BHC).  Jour.  Environ. Sci. Health B14: 305.

Khera, K.S.,  et al.   1979.  Teratogenicity studies on pesti-
cides  formulations  of  dimethoate,  diuron  and lindane in
rats.  Bull. Environ.  Contam.  Toxicol. 22: 522.

Koransky,  W.,  et al.   1963.  Absorption,  distribution, and
elimination of alpha-  and  beta-  benzene  hexachloride.   Arch.
Exp. Pathol. Pharmacol. 244: 564.

Korn,  S.,  and  R. Earnest.    1974.   The  acute  toxicity of
twenty  insecticides   to  striped  bass,  Marone  saxatilis.
Calif. Fish Game  60: 128.

Laug, E.P.    1948.   Tissue  distribution  of  a  toxicant  fol-
lowing oral  ingestion of  the  gamma-isomer of  benzene  hexa-
chloride by rats.  Jour. Pharmacol. Exp. Therap. 93: 277.

Lee, B., et al.   1976.  Suspected reactions to gamma benzene
hexachloride.  Jour. Am. Med. Assoc. 236:  2846.

Lehman, A.J.   1952a.   Chemicals in food:''  A  report  to the
Assoc. of  Food  and  Drug  officials.  Assoc.  Food  and   Drug
Office, U.S. Quant. Bull.  16:  85.
                                                          »
Lehman,  A.J.    1952b.   U.S.  Assoc. Food  Drug Off.  Quant.
Bull. 16: 126.

-------
Hansen,  P.D.   1979  Experiments  on  the accumulation of  lin-
dane  (  -BHC)   by  the • primary  producers  Chlorella  spec.
and  Chorella pyrenoidosa.   Arch. Environ.  Contain. Toxicol.
8: ITT.

Henderson, C.,  et al.   1971.  Organochlorine pesticide resi-
dues in fish-fall 1969:  Natl.  Pestle. Monitor. Progr. Pestic.
Monitor. Jour.  5: A.

Herbst, M., and G. Bodenstein.  1972.  Toxicology of lindane.
Page 23  in;  E.  Ulmann,  (ed.)  Lindane.   Verlag K. Schillinger
Publ., Freiburg.

Heyroth, F.F.   1952.   In; Leland,  S.J.,  Chera.  Spec.  Manuf.
Assoc. Proc.  6:  110.

Huntingdon Research  Center.    1971.   In;  Lindane:  Monograph
of an  insecticide.   E.  Ullman  (ed.), Verlag K.  Schellenger,
(Pub.), p. 97,  1972.

Ito, N., et al.   1973.  Histologic and ultrastructural studies
on  the  hepato  carcinogenicity  of  benzene  hexachloride in
mice.  Jour. Natl. Cancer  Inst. 51:  817.

Kashyap, S.K.,  et al.  1979-.   Carcinogenicity of hexachloro-
cyclohexane  (BHC).  Jour.  Environ. Sci.  Health B14: 305.

Khera, K.S., et al.  1979.  Teratogenicity studies on pesti-
cides  formulations  of   dimethoate,   diuron  and lindane in
rats.  Bull. Environ. Contam. Toxicol. 22: 522.

Koransky, W.,  et al.   1963.   Absorption,  distribution,  and
elimination of  alpha- and  beta-  benzene hexachloride.   Arch.
Exp. Pathol. Pharmacol.  244: 564.

Korn,  S.,  and  R. Earnest.    1974.   The  acute   toxicity of
twenty  insecticides  to  striped  bass,  Marone  saxatilis>
Calif. Fish Game  60: 128.

Laug,  E.P.   1948.   Tissue  distribution  of  a  toxicant  fol-
lowing oral  ingestion  of  the  gamma-isomer  of benzene  hexa-
chloride by rats.  Jour.  Pharmacol. Exp. Therap.  93: 277.

Lee, B., et  al.   1976.   Suspected reactions to gamma benzene
hexachloride.  Jour. Am.  Med. Assoc.  236: 2846.

Lehman,  A.J.    1952a.  Chemicals in food:   A report  to the
Assoc.  of  Food  and  Drug  officials.    Assoc.  Food  and   Drug
Office, U.S. Quant. Bull.  16: 85.
                                                          »

Lehman,  A.J.   1952b.    U.S.  Assoc. Food  Drug   Off.  Quant.
Bull. 16: 126.

-------
Lichtenstein,  E.P.   195r.   Absorption  of  some chlotinted
hydrocarbon  insecticides  from  soils  into  various  crops.
Jour. Agric. Pood Chem. 7: 430.

Litterst, C.L.,  and E. Miller.  1975.   Distribution of lin-
dane  in  brains of  control and  phenobarbital  pretreated dogs
at the onset of lindane induced convulsions.   Bull. Environ.
Contarn. Toxicol. 13: 619.

Macek, K.J.,  and W.A^  McAllister.   1970.   Insecticide sus-
ceptibility  of  some   ccsnon  fish  family  representatives.
Trans. Am.  Fish. Soc.  99: 20.

Macek,  K.J.,  et al.   Ir76.   Chronic  toxicity  of lindane
to  selected aquatic  invertebrates  and  fishes.    EPA  600/3-
76-046.  U.S. Environ.  Prct. Agency.

Mametkuliev, C.H.   1978..   Study of embryotoxic  and terato-
genic  properties of the gamma  isomer  of HCH  in experiments
with rats.  Zdravookhr. T~ckm. 20:  28.

Mather,  S.P.,  and  J.G. Saba.   1975.   Microbial degradation
of  lindane-C-14 in a  flsoded  sand loam soil.   Soil  Sci.
120: 301.

Nagasaki,  H.,   et   al.   1972.   Carcinogenicity of benzene
hexachloride (BHC) .  Top. Chem. Carcinog., Proc. Int.  Syrup.,
2nd.  343.

National  Academy of  Sciences -  National Research  Council.
1977.   Safe Drinking  Wa.ar  Committee.   Drinking Water  and
Health p. 939.

National Cancer  Institute.    1977.   A bioassay  for  possible
carcinogenicity of  lindans*  Fed. Reg.  Vol.  42. No.  218.

Nigam, S.K.,  et al.  1979.   Effect of hexachlorocyclohexane
feeding  on  testicular  -issue  on  pure  inbred  Swiss  mice.
Bull. Environ. Contain.  Tczicol. 23:  431.-

Nishimura,  H.,   et  al.   1977.   Levels  of  polychlorinated
biophenyls  and  organochlzrine insecticides in  human embryos
and fetuses.  Pediatrician 6: 45.

Palmer, A.K.,  et al.    1S73.   Effect of  lindane  on pregnancy
in the rabbit and rat.  Toxicology 9: 239. ,

Petrescu, S., et al.   19~4.   Studies on  the  effects  of long-
term administration of chlorinated  organic pesticides  (lin-
dane,  DDT)  on  laboratory white  rats.   Rev.  Med.  -  Cttir.
78: 331.

Poradovsky,  R.,  et al.   1977.   Transplacental  permeation
of pesticides  during  ncraal  pregnancy.    Cesk Gynekol.  42:
405.
                        IIZ-I7

-------
Lichtenstein,  E.P.   1959.    Absorption  of  some chlorinted
hydrocarbon  insecticides  from  soils  into  various  crops.
Jour. Agric. Food Chem. 7: 430.

Litterst, C.L.,  and E.  Miller.   1975.   Distribution of  lin-
dane  in  brains of control and phenobarbital pretreated  dogs
at the onset  of lindane induced convulsions.  Bull. Environ.
Contain. Toxicol. 13: 619.

Macek, K.J.,  and W.A.  McAllister.   1970.   Insecticide  sus-
ceptibility  of  some  common  fish  family  representatives.
Trans. Am.  Fish. Soc. 99: 20.

Macek,  K.J.,   et al.   1976.    Chronic  toxicity  of lindane
to  selected aquatic  invertebrates  and  fishes.    EPA 600/3-
76-046.  U.S. Environ. Prot. Agency.

Mametkuliev, C.H.   1978.   Study of embryotoxic  and terato-
genic properties of the  gamma isomer  of HCH  in experiments
with rats.  Zdravookhr. Turkm. 20: 28.

Mather,  S.P.,  and J.G. Sana.    1975.   Microbial degradation
of  lindane-C-14  in  a  flooded  sand  loam soil.    Soil   Sci.
120: 301.

Nagasaki,  H.,   et  al.    1972.    Carcinogenicity  of benzene
hexachloride (BHC).  Top. Chem.  Carcinog., Proc. Int.  Symp.,
2nd.  343.

National  Academy of  Sciences - National Research Council.
1977.   Safe Drinking  Water  Committee.   Drinking  Water  and
Health p. 939.

National  Cancer  Institute.    1977.   A bioassay  for possible
carcinogenicity of lindane.  Fed. Reg. Vol. 42. No.  2l8.

Nigam, S.K.,  et al.  1979.   Effect of hexachlorocyclohexane
feeding  on  testicular  tissue   on  pure  inbred  Swiss  mice.
Bull. Environ.. Contam. Toxicol.  23:  431.

Nishimura,  H.,  et  al.   1977.   Levels  of  polychlorinated
biophenyls  and  organochlorine insecticides  in  human embryos
and fetuses.  Pediatrician 6: 45.

Palmer, A.K.,  et al.   1978.   Effect of  lindane  on pregnancy
in the rabbit and rat.  Toxicology 9: 239.

Petrescu, S., et al.  1974.   Studies  on  the  effects of long-
term administration  of  chlorinated organic  pesticides  (lin-
dane,  DDT)  on  laboratory white rats.   Rev.  Med.  -  Ch»ir.
78: 831.

Poradovsky,  R.,   et  al.   1977.    Transplacental  permeation
of pesticides  during normal pregnancy.    Cesk Gynekol.  42:
405.

-------
Reuber,  M.D.    1979.   Carcinogenic!ty  of Lindane.   Environ.
Res. 19: 460.

Rivett,  K.F.,  et al.    1978.    Effects of  feeding  lindane
to dogs  for periods of up to  2  years.   Toxicology 9:  237.

Schimmel,  S.E.,  et al.    1977.  Toxicity  and  bioconcentration
of  BHC  and  lindane  in   selected  estuarine  animals.    Arch.
Environ. Contain.  Toxicol. 6:  355.

Sloof, W.   1979.  Detection  limits  of a biological  monitor-
ing system based  on fish  respiration.   Bull.  Environ.  Contarn.
Toxicol. 23:  517.

Sugiura,  R.,  et  al.   1979.   Accumulation of  organochlorine
compounds  in  fishes.    Difference  of  accumulation  factors
by fishes.  Chemosphere 6:  359.

Szpunar, K.,  et al.   1976.  Effect of  silymarin  on  hepatoxic
action of  lindane.  Herba.  Pol. 22:  167.

Thorpe,  E., and A.I.  Walker.   1973.  The toxicology  of  diel-
drin (HEOD) .  II.  In  mice with dieldrin,  DDT/ phenobarbitone,
beta-BCH,  and gamma-BCH.   Food  Cosmet.  Toxicol. 11:  433.

Tsoneva-Maneva,  M.T., et  al.   1971.   Influence  of  Diazinon
and  lindane  on  the  mitotic  activity  and the  karyotype  of
human  lymphocytes  cultivated  in  vitro.    Bibl.   Haematol.
38: 344.

Tu,  C.M.   1975.   Interaction between  lindane and  microbes
'in soil.   Arch. Microbiol.  105: 131.

Tu,  C.M.   1976.   Utilization and  degradation  of  lindane
by soil  microorganisms.   Arch.  Microbiol. 108:  259.

Ulmann,  E.   1972.    Lindane:   Monograph  of  an  insecticide.
Verlag K.  Schillinger Publishers,  Freiburg, West  Germany.

U.S SPA.   1979.  Hexachlorocyclohexane:  Ambient Water Quality
Critera  (Draft).

-------
                                      No.  114
     Hexachlorocyclopentadiene

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

           APRIL 30,  1980
           /  '^^  f  I

          111-I

-------
                          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.

-------
                           HEXACHLOROCYCLOPENTADIENE
                                    Summary

     Hexachlorocyclopentadiene  (HEX) is  used as a  chemical intermediate  in
the  manufacture of  chlorinated pesticides.  Evidence  is  not  sufficient  to
categorize  this compound  as  a carcinogen or  non-carcinogen;  HEX  was  not
mutagenic  in either short-term  in  vitro  assays  or a  mouse dominant  lethal
study.   Teratogenic effects were not  observed in rats receiving oral  doses
of HEX during gestation.
     The  reported   96-hour  LC5Q value  for the  fathead minnow  under  static
and  flow-through conditions  using larval and  adult fish ranges from 7.0 pg/1
to  104 jug/1.   The  chronic  value for  fish in  an embryo-larval  test is  2.6
pg/1.

-------
                           HEXACHLOROCYCLOPENTADIENE
I.   INTRODUCTION
     Hexachlorocyclopentadiene  (HEX;   C5Clg)  is  a  pale  to  greenish-yellow
liquid.  Other physical properties include:  molecular  weight,  272.77;  solu-
bility  in  water,  0.805 mg/1;  and  vapor pressure, 1 mm Hg at  78-79°C.   HEX
is a highly reactive compound  and  is  used as a chemical  intermediate  in the
manufacture of  chlorinated pesticides (Kirk-Othmer, 1964).  Recent  govern-
ment bans  on  the use  of  chlorinated  pesticides  have  restricted the use  of
HEX  as  an   intermediate   to   the endosulfan  and   decachlorobi-2,4-cyclo-
pentadiene-1-yl industries.  Currently, the major use of  HEX  is as an inter-
mediate  in the  synthesis  of  flame retardants (Sanders, 1978;  Kirk-Othmer,
1964).   Production  levels  of HEX  approximate 50  million, pounds per  year
(Bell, et al.  1978).
   .  Environmental  monitoring  data for  HEX are  lacking, except  for  levels
measured in  the  vicinity  of  industrial  sites.   The  most likely route  of
entry of HEX  into the environment  arises from its  manufacture  or  the  manu-
facture  of HEX-containing  products.   Small amounts of  HEX  are present  as
impurities in pesticides made  from it; some HEX  has undoubtedly entered the
environment via this route.
     HEX appears  to be  strongly adsorbed  to soil  or  soil  components,  al-
though  others have  reported   its  volatilization  from  soil  (Rieck,   1977a,
1977b).    HEX  degrades   rapidly  by   photolysis,   giving   water-soluble
degradation products  (Natl. Cancer  Inst.,  1977).   Tests  on its  stability
towards hydrolysis at  ambient  temperature indicated  ''a half-life of about  11
days at pH3-6, which was  reduced to 6  days at pH  9.
                                  lit-

-------
II.  EXPOSURE
     A.  Water
         HEX has  been  detected in water near  points  of industrial discharge
at levels ranging  from 0.156  to  18 mg/1 (U.S. EPA, 1979).   Other than this,
there  is little   information  concerning  HEX concentrations  in  surface  or
drinking waters.   Due  to its low  solubility,  photolability,  and tendency to
volatize, one would not expect HEX to remain in flowing water.
     8.  Food
         HEX has  been  identified in a  few  samples-- of fish taken from waters
near  the Hooker   Chemical  Plant  in Michigan . (Spehar,  et  al.  1977).   No
reports concerning HEX contamination of other foods could be located.
         The U.S.  EPA. (1979) has  estimated the weighted  average bioconcen-
tration factor of  HEX  for  the edible portions of fish and shellfish consumed
by Americans  to be  3.2.   This  estimate is  based  on  measured  steady-state
bioconcentration studies in fathead minnows.
     C.  Inhalation
         The most  significant chronic  exposure  to HEX occurs  among persons
engaged directly in  its  manufacture  and among production  workers fabricating
HEX-containing products.   Inhalation is the primary mode  of  exposure  to HEX
in the event of accidental  spills, illegal discharges,  or occupational situ-
ations.
III.  PHARMACOKINETICS
     A.  Absorption
         Kommineni  (1978)  found  in  rats  that HEX is  absorbed  through  the
squamous  epithelium  of  the  nonglandular  part  of  the  stomach,  causing
                                                                       »
necrotic changes,  and  that the major route  of elimination of HEX is through
the  lungs.   This  information  is based on  morphological  changes in  rats


-------
administered HEX  by  gayage.   Further study-with  guinea pigs showed that HEX
was  absorbed  through the  skin;  but,  unlike the  rat  stomach,  the squamous
epithelium of these animals did not undergo necrotic changes.
     B.  Distribution
         The tissues  of four rats administered single  oral doses of HEX re-
tained only  trace amounts of  the compound  after 7 days  (Mehendale,  1977).
For example, approximately 0.5 percent of the total dose was retained in the
kidney and less  than 0.5 percent in  the liver.   Other organs  and tissues -
fat,  lung,  muscle, blood,  etc.  - contained even less HEX.   Tissue homoge-
nates  from  rats  receiving  injections of    C-HEX showed that  93 percent of
the radioactivity  in  the kidney  and  68 percent in  the  liver were associated
with the cytosol  fraction (Mehendale, 1977).
     C.  Metabolism
         At least  four  metabolites were  present  in the urine of rats admini-
stered HEX  (Mehendale,  1977).  Approximately  70  percent of  the metabolites
were extractable using a hexane:isopropanol mixture.
     0.  Excretion
         Mehendale (1977)  found that  approximately 33 percent  of the total
dose  of  HEX administered  to rats via oral intubation was excreted  in  the
urine  after  7 days.   About  87 percent  of  that  (28.7 percent  of the total
dose)  was eliminated during the  first 24 hours.   Fecal  excretion accounted
for  10 percent  of the  total  dose;   nearly 60 percent of  the 7  day  fecal
excretion occurred during  the  first  day.  These  findings  suggest that elim-
ination of  HEX may occur  by routes  other  than  urine  and  feces,  and  it  has
been postulated that a major route of excretion may be  the respiratory.tract.

-------
         Whitacre  (1978)  did not agree  with-the study  by  Mehendale (1977).
This recent study  of HEX  excretion  from mice and  rats  showed that excretion
was mainly by the fecal route with no more than 15 percent in the urine.
         Approximately nine  percent  of an injected dose  of  HEX was excreted
in the  bile in one hour  (Mehendale, 1977).  Because this  quantity is equi-
valent to that  excreted  in  the  feces  over seven days,  enterohepatic circu-
lation of this compound is probable.
IV.  EFFECTS
     A.  Carcinogenicity
         Only .one  in  vitro  test of HEX for  carcinogenic activity could be
located.  Litton Bionetics  (1977)  reported the  results of a test  to deter-
mine whether  HEX  could  induce  malignant  transformation in  BALB/3T3 cells.
HEX was  found  to  be relatively  toxic  to cells,  but no significant carcino-
genic activity was reported with this assay.
         The National  Cancer Institute  (1977)  concluded  that  toxicological
studies conducted  thus far have  not been adequate for evaluation of the car-
cinogenicity of HEX.  Because of this  paucity of information and HEX's high
potential for  exposure,  HEX has been  selected for the NCI's carcinogenesis
testing program.
     B.  Mutagenicity
         HEX has  been reported  to  be non-mutagenic  in  short-term in vitro
mutagenic  assays   (Natl.  Cancer Inst.,   1977;   Industrial  Bio-Test  Labora-
tories,  1977; Litton  Bionetics,  1978a) and in a  mouse  dominant lethal assay
                                                     .-
(Litton Bionetics, 1978b).

-------
     C.  Teratogenicity
         International  Research and  Development Corporation  (1978)  studied
the effect of oral  doses  of up to 300 mg/kg/day of  HEX administered to rats
on days 6 through 15 of gestation.   Teratogenic effects were not reported at
doses up  to  100 mg/kg/day;  the highest  dosage (300 mgAg/day)  resulted in
the death of all rats  by day ten of'gestation.   In this study, elimination
via the respiratory tract did not appear to be  significant.
     0.  Other Reproductive Effects
         Pertinent  information  could not be located in the available liter-
ature.
     E.  Chronic Toxicity
         There are  very few  studies  concerning the chronic  toxicity  of HEX
in laboratory  animals.   Naishstein  and Lisovskaya  (1965)  found  that  daily
administration of  1/30  the median  lethal dose (20  mg/kg)  for  6 months res-
ulted in the death of two of  ten  animals.   The investigators judged the cum-
ulative effects  of  HEX  to be weak;  no  neoplasms or ether abnormalities were
reported.  Naishstein and Lisovskaya  (1965) applied  0.5 to  0.6  ml of a solu-
tion  of  20  pom  HEX daily to the  skin  of rabbits  for  10 days  and  found no
significant   adverse effects  from exposure.   Treon, et  al. (1955)  applied
430-6130  mg/kg   HEX  to the  skin of rabbits.   Degenerative changes of the
brain, liver, kidneys,  and adrenal  glands of  these animals were  noted,  in
addition to  chronic skin  inflammation,  acanthosis,  hyperkeratosis,  and epil-
ation.  Further  study by Treon,  et al. (1955)  revealed  slight degenerative
changes in the liver  and  kidney of  guinea pigs, rabbits, and rats exposed to
0.15  ppm  HEX for daily seven-hour  periods over approximately  seven  months.
Four of five mice receiving the same dosage died within this period.

-------
         There  is  virtually  no information,  regarding the human  health ef-



fects  of  chronic  exposure  to  HEX.   According  to Hooker's  material safety



data sheet for  HEX,  (1972)  acute exposure to the compound results in irrita-



tion of  the eyes  and mucous membranes,  causing  lacrimation,  sneezing, and



salivation.  Repeated contact with the skin  can  cause blistering  and burns,



and inhalation  can cause pulmonary edema.  Ingestion  can  cause nausea, vom-



iting,  diarrhea, lethargy, and retarded respiration.



V.   AQUATIC TOXICITY



     A.  Acute Toxicity



         The .  reported   96-hour  LC5Q   values   for   the   fathead  minnow



(Pimephales promelas)  under static and  flow-through  conditions with larval



and adult  fish range from  7.0  fjg/1 to 104 jjg/1.  The effect of water hard-



ness is minimal (Henderson  1956; U.S. EPA,  1978).   There are  no  reports of



studies of the acute toxicity of HEX on saltwater organisms.



     B.  Chronic Toxicity



         In the only chronic  study  reported,  the lowest chronic  value for



the fat- head minnow  (embryo-larval) is 2.6 jjg/1 (U.S. EPA, 1978).



     C.  Plant Effects



         Pertinent  information  could  not be  located  in the available liter-



ature.



VI.  EXISTING GUIDELINES AND STANDARDS



     Neither the human health nor the 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  will  be



changed.                                                               »


-------
     A.  Human
         The  Occupational Safety  and  Health Administration  has not  set a
standard  for  occupational  exposure  to  HEX.   The  American  Conference  of
Governmental  Industrial Hygienists  has  adopted a threshold limit value (TLV)
of 0.01  ppm (0.11 mg/m ) and  a  short term exposure  limit  of  0.03 ppm (0.33
mg/m3) (ACGIH, 1977).
         The draft ambient water quality  criterion for HEX is 1.0 ug/1 (U.S.
EPA, 1979).
     8.  Aquatic
         For HEX, the  draft  criterion to protect  freshwater  aquatic life is
0.39 ;jg/l  as a 24-hour average,  not to  exceed 7.0  jug/1  at any  time (U.S.
EPA, 1979).   Criteria., have not  been  proposed for  saltwater  species because
of insufficient data.
                                \ I if-in

-------
                           HEXACHLOROCYCLOPENTADIENE

                                  REFERENCES
American  Conference  of Governmental  Industrial  Hygienists.    1977,  TLV's:
threshold  limit  values for  chemical substances  and  physical agents  in the
workroom environment with intended changes for 1977.  Cincinnati, Ohio.

Bell, M.A., et al.   1978.  Review  of the environmental effects of pollutants
XI.   Hexachlorocyclopentadiene.   Report by  Battelle  Columbus Lab.  for U.S.
EPA Health Res. Lab., Cincinnati, Ohio.

Henderson, D.   1956.   Bioassay  investigations for International  Joint Com-
mission.   Hooker Electrochemical  Co.,  Niagara   Falls,  N.Y.   U.S.  Dep.  of
Health  Educ.  Welfare,  Robert  A.  Taft  Sanitary  Eng.   Center,  Cincinnati,
Ohio.  12 p.

Hooker  Industrial Chemicals  Division.   1972.   Material safety data  sheet:
Hexachlorocyclopentadiene.-  Unpublished internal memo dated April, 1972.

Industrial  Bio-Test  Laboratories,  Inc.   1977.   Mutagenicity  of  PCL-HEX
incorporated  in  the  test  medium tested against  five strains  of  Salmonella
typhimurium  and  as  a volatilate against tester  strain  TA-100.   Unpublished
report submitted to Velsicol Chemical Corp.

International  Research  and Development Corp.  1978.   Pilot teratology study
in rats.  Unpublished report submitted to Velsicol Chemical Corp.

Kirk-Othmer  Encyclopedia  of  chemical  technology.   2nd  ed.   1964.   Intersci-
ence Publishers, New  York.

Kommineni,  C.   1978.  Internal memo  dated  February  14, 1978,  entitled:
Pathology  report  on  rats  exposed to hexachlorocyclopentadiene.   U.S.  Dep. of
Health  Ed.  Welfare,   Pub.  Health  Serv.  Center for  Dis.  Control, Natl. Inst.
for Occup. Safety and Health.-

Litton  Bionetics, Inc.   1977.    Evaluation  of  hexachlorocyclopentadiene in
vitro malignant  transformation  in  BALB/3T3  cells:  Final  rep.   Unpublished
report submitted  to Velsicol Chemical Corp.

Litton  Bionetics,  Inc.   1978a.   Mutagenicity  evaluation of hexachlorocyclo-
pentadiene  in the mouse  lymphoma forward mutation assay.   Unpublished rep.
submitted  to Velsicol Chemical Corp.

Litton  Bionetics,  Inc.   1978b.   Mutagenicity  evaluation of hexachloropenta-
diene in  the mouse  dominant  lethal assay:  Final  report.   Unpublished rep.
submitted  to Velsicol Chemical Corp.

Mehendale,  H.M.    1977.  The chemical reactivity  - absorption,  retention,
metabolism,  and  elimination  of  hexachlorocyclopentadiene.   Environ.  Health,
Perspect.  21: 275.
                                     11

-------
Naishstein,  S.Y.,  and E.V.  Lisovskaya.   1965.   Maximum permissible concen-
tration of  hexachlorocyclopentadiene  in  water bodies.   Gigiena i Sanitariya
(Translation) Hyg. Sanit.  30: 177.

National  Cancer  Institute.  1977.  Summary of data  for chemical selection.
Unpublished  internal  working paper,  Chemical  Selection Working  Group, U.S.
Dep. of Health Edu. Welfare, Pub. Health Serv., Washington, O.C.

Rieck,  C.E.  1977a.   Effect of hexachlorocyclopentadiene  on soil  microbe
populations.   Unpublished  report  submitted  to  Velsicol  Chemical  Corp.,
Chicago, 111.

Rieck,  C.E.   1977b.    Soil  metabolism  of  14C-hexachlorocyclopentadiene.
Unpublished report submitted to Velsicol Chemical Corp., Chicago,  111.

Sanders,  H.J.   1978.   Flame  retardants.   Chem.  Eng.  News:   April  24,
1978: 22.

Spehar,  R.L.,  et  al.   1977.  A  rapid assessment of the toxicity  of three
chlorinated  cyclodiene  insecticide intermediates  to  fathead  minnows.   Off.
Res. Oev. Environ. Res. Lab., Ouluth,  Minn.  U.S. Environ. Prot. Agency.

Treon,  J.F.,  et  al.  '1955.    The   toxicity  of  hexachlorocyclopentadiene.
Arch. Ind. Health.  11: 459.

Whitacre,  O.M.   1978.   Letter  to  R. A.  Ewing,  Battelle Columbus  Labora-
tories,  dated  August  9,  1978.   Comments  on  documpnt  entitled:   Review  of
Environmental Effects of Pollutants  XI.   Hexachlorocyclopentadiene.

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, 0.C.

U.S. EPA.   1979.   Hexachlorocyclopentadiene:   Ambient Water Quality  Criteria
(Draft).

-------
                                      No. 115
          Hexachloroethane

  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.

-------
                               HEXACHLOROETHANE

                                   SUMMARY

     Results of  a National  Cancer Institute  (NCI)  carcinogenesis  bioassay
showed  that hexachloroethane  produced an  increase  in  hepatocellular car-
cinoma incidence in mice.
     Testing of  hexachloroethane  in  the  Ames  Salmonella assay  showed no
mutagenic effects.   No  teratogenic effects were observed  following oral or
inhalation  exposure  of  rats to hexachloroethane, but  some toxic effects on
fetal development were observed.
     Toxic  symptoms  produced in  humans  following  hexachloroethane  exposure
include  central  nervous  system  depression and  liver,  kidney,  and  heart
degeneration.
     Hexachloroethane is  one of  the  more  toxic of  the chlorinated  ethanes
reviewed for aquatic organisms with marine invertebrates appearing  to  be the
most  sensitive organisms  studied.   This  chlorinated  ethane also  had the
greatest bioconcentration factor,  139  for bluegill sunfish, observed in this
class of compounds.
                                   //S--3

-------
                               HEXACHLOROETHANE
I.  INTRODUCTION
     This  profile  is based  on the  Ambient Water  Quality  Criteria Document
for Chlorinated Ethanes (U.S. EPA, 1979a).
     The chloroethanes are hydrocarbons  in which one or more of the hydrogen
atoms are  replaced by chlorine  atoms.   Water solubility  and vapor pressure
decrease with  increasing chlorination,  while density and  melting point  in-
crease.  Hexachloroethane  (Perchloroethane; M.w. 236.7)  is a  solid  at  room
temperature  with  a boiling  point of 186°C,  specific gravity  of 2.091;  and
is insoluble in water (U.S. EPA, 1979a).
     The chloroethanes are used  as solvents,  cleaning and degreasing agents,
and  in  the  chemical  synthesis of  a number  of  compounds.   Hexachloroethane
does not appear to  be commercially produced in the U.S., but 730,000 kg  were
imported in 1976.   (U.S. EPA, 1979a).
     The chlorinated  ethanes  form azeotropes with water  (Kirk  and Othmer,
1963).  All  are very soluble  in organic  solvents  (Lange,  1956).  Microbial
degradation  of  the  chlorinated -ethanes has not  been, demonstrated (U.S.  EPA,
1979a).
     The reader is  referred  to the Chlorinated  Ethanes  Hazard Profile for a
more general discussion of chlorinated ethanes (U.S. EPA, 1979b).
II.  EXPOSURE
     The chloroethanes are present in raw  and finished  waters due primarily
to industrial discharges.  Small amounts of  the  chloroethanes  may be formed
by chlorination  of drinking  water or treatment of sewage.   Air  levels  are
produced by evaporation of volatile chloroethanes.
                                                                        »
     Sources of  human  exposure to chloroethanes  include  water, air,  contam-
inated foods and fish, and dermal  absorption.  Fish and  shellfish have shown

-------
levels of  chloroethanes  in  the  nanogram range  (Dickson and  Riley,  1976).
Information on the levels of hexachloroethane in foods is not available.
     U.S.  EPA (1979a)  has  estimated  the weighted  average  bioconcentration
factor for hexachloroethane to  be 320  for  the edible  portion of  fish and
shellfish  consumed  by  Americans.  This  estimate  is  based  on  the octanol/
water partition coefficient.
III. PHARMOKINETICS
     Pertinent  data could  not  be located  in the  available  literature on
hexachloroethane  for absorption,  distribution, metabolism,  and  excretion.
However,  the  reader  is  referred  to a more general treatment of chloroethanes
(U.S. EPA,  1979b) which indicates rapid  absorption  of chloroethanes follow-
ing  oral  or  inhalation  exposure;  widespread distribution  of the chloro-
ethanes  through the  body;   enzymatic dechlorination  and oxidation to the
alcohol and ester forms;  and excretion of the chloroethanes  primarily in the
urine and in expired air.
IV.  EFFECTS
     A.  Carcinogencitiy
         Results  of  an  NCI  carcinogenensis  bioassay  for  hexachloroethane
showed that oral administration  of the compound produced an  increase  in the
incidence  of  hepatocellular  carcinoma in mice.  No statistically significant
tumor increase was seen in rats.
     8.  Mutagenicity
         The  testing of hexachloroethane in the Ames  Salmonella assay  or in
a yeast mutagenesis  system  failed to show any mutagenic activity  (Weeks, et
al. 1979).

-------
     C.  Teratogenicity
         Teratogenic  effects  were not  observed in pregnant  rats exposed  to
hexachloroethane by inhalation or intubation (Weeks, et al. 1979).
     0.  Other Reproductive Effects
         Hexachloroethane administered  orally  to pregnant rats decreased the
number of  live fetuses per  litter and  increased  the fetal  resorption rate
(Weeks, et al. 1979).
     E.  Chronic Toxicity
         Toxic symptoms  produced in humans  following hexachloroethane expo-
sure  include liver,  kidney,   and heart  degeneration,  and  central nervous
system depression (U.S. EPA, 1979a).
         Animal studies  have  shown that chronic exposure to hexachloroethane
produces both hepatotoxicity and nephrotoxicity  (U.S. EPA, 1979a).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Among   freshwater   organisms,   the    bluegill   sunfish   (Lepomis
macrochirus)  was  reported  to  have  the  lowest  sensitivity   to  hexachloro-
ethane, with a 96-hour  static LC5Q value  of  980 pg/1.   The 48-hour static
LC5Q  value  of  the  freshwater Cladoceran  (Daphnia maqna)  was  reported  as
8,070 ug/1 (U.S.  EPA,  1978).   For  the marine  fish,  the  sheepshead  minnow
(Cyprinodon  varieqatus).  a 96-hour  LC-0  value of  2,400 /jg/1 was  reported
from  a  static assay.   The  marine mysid shrimp  (Mysidopsis  bahia) was  the
most  sensitive aquatic  organism tested,  with a  96-hour static LC5Q  value
of 940pg/l  (U.S.  EPA, 1978).
     B.  Chronic Toxicity
                                                                        »
         Pertinent data could not be located in the available literature.
                                          //«

-------
     C.  Plant Effects

         For  the  freshwater  algae,  Selenastrum capricornutum,  the 96-hour

ECcn  effective  concentrations  based  on  chlorophyll and  cell  number were
  j\j

87,000  and  93,200  ug/1  for  chlorophyll  a  production  and  cell  growth,

respectively.    The   marine  algae,  Skeletonema  costatum,   was  much  more

sensitive,  with effective  concentrations  from  7,750  to  8,570  ug/1  being

reported.

     0.  Residues

         A  bioconcentration  factor  of 139  was dbtained for  the freshwater

bluegill sunfish (U.S. EPA, 1979a).

VI.  EXISTING GUIDELINES AND  STANDARDS

     Neither  the human health  nor  the 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  will  be

changed.

     A.  Human

         By applying  a linear,  non-threshold model to the  data from the NCI

bioassay for carcinogenesis,  the U.S.  EPA (1979a) has estimated the level of

hexachloroethane in  ambient water  that will  result in an  additional risk of

10"5 to be 5.9 ug/1.

     The  eight-hour  TWA exposure  standard  established  by  OSHA  for  hexa-

chloroethane is 1 ppm.

     8.  Aquatic Toxicity
                                                    »•
         The  proposed criterion  to  protect freshwater aquatic  life  is  62

ug/1 as  a  24-hour average and  should  not exceed 140 /jg/1 at any  time.   The

drafted  criterion  for saltwater aquatic  life  is a  24-hour  average concen-

tration of 7 ug/1 not to exceed 16 pg/1 at any time.

-------
                       HEXACHLOROETHANE

                          REFERENCES

Dickson, A.G., and J.P. Riley.  1976.  The distribution
of short-chain halogenated aliphatic hydrocarbons in some
marine organisms.  Mar. Follut. Bull. 79: 167.

Kirk, R., and D. Othxner.  1963.  Encyclopedia of Chemical
Technology.  2nd ed.  John Wiley and Sons, Inc. New York.

Lange, N.  (ed.)  1956.  Handbook of Chemistry.  9th ed.
Handbook Publishers, Inc. Sandusky, Ohio.

National Cancer Institute.  1978.  Bioassay of hexachloro-
ethane for possible carcinogenicity.  Natl. Inst. Health,
Natl.  Cancer Inst. DHEW Publ. No. (NIH)  78-1318.  Pub.
Health Serv. U.S. Oept. Health Edu. Welfare.

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

a.S. EPA.  1979a.  Chlorinated Ethanes:   Ambient Water Qual-
ity Criteria (Draft).

U.S. EPA.  1979b.  Environmental Criteria and Assessment
Office.  Chlorinated Ethanes:  Hazard Profile (Draft).

Van Dyke, R.A., and C.G. Wineman.  1971.   Enzymatic dechlori-
nation:  Dechlorination of chloroethane  and propanes in-
vitro.  Biochem.  Pharmacol. 20: 463.

Weeks, M.H.,•et al.  1979.  The toxicity of hexachloroethane
in laboratory animals.  Am. Ind. Hyg. Assoc. Jour. 40: 137.
                         //r-r

-------
                                      No. 116
          Hexachlorophene

  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.

-------
                                HEXACHLOROPHENE
                                    Summary

     Oral,  dermal,  and  subcutaneous  administration  of  hexachlorophene  in
animal studies has failed to show significant carcinogenic effects.
     Mutagenic effects  of hexachlorophene  exposure have been reported in one
study which  indicated increased chromosome aberrations in rats.   Testing  of
hexachlorophene in the  host mediated assay or  the dominant  lethal assay did
not produce positive effects.
     Several  reports have  indicated that hexachlorophene  may produce  some
teratogenic  and  embryotoxic effects.  A three generation  feeding study  in
rats  failed  to  show any  teratogenic activity.   Hexachlorophene has  shown
some adverse effects on male reproductive performance.
     Chronic administration  of hexachlorophene has produced  central  nervous
system effects and muscular paralysis.

-------
 I.   INTRODUCTION
     Hexachlorophene   (C13H6a2CL6,   molecular  weight   406.9)   is  a  white
 powder  which melts  between 166°c  and 167°C.   The compound  is practically
 insoluble in water but is soluble in ethanol,  ether,  and other organic sol-
 vents.  Under alkaline conditions,  hexachlorophene forms water-soluble salts
 (IARC,- 1979).
     The principle uses of hexachlorophene have been  for the  manufacture of
 germicidal  soaps,  as a  topical  anti-infective agent  for humans, as  a vet-
 erinary anti-helminthic, for  disinfection of  hospital  equipment,  and  as a
 broad-spectrum  soil  fungicide (IARC,  1979).   Limitation  of drugs and cos-
 metics containing hexachlorophene was instituted by the FDA in 1972.
     Commercial hexachlorophene  produced  from 2,4,5-trichlorophenol contains
 less than 15 ug/kg of 2,3,7,8-tetrachlorodibenzo-para-dioxin (IARC,  1979).
 II.  EXPOSURE
     There are  no  available estimates on daily exposure  levels  of  humans to
hexachlorophene from air, water,  or food.   .
     Water monitoring  studies  have detected  hexachlorophene in  two finished
drinking water  samples  (Shackelford  and  Keith,  1976) and  in  effluents  of
sewage treatment  plants at  levels  of 3.2 to 44.3 ug/1  (Sims.and  Pfaender,
1975),  as  well as in creek sediments (9.3 to 377 jjg/kg).
     Data on  hexachlorophene levels  in aquatic organisms indicate that  the
compound is bioaccumulated (Sims and Pfaender, 1975).
     Hexachlorophene has been  detected  in human milk at  levels  up  to  9 ;jg/l
 (West,  et al.  1975).   Blood  levels of the  compound  in  users  of soap  con-
                                                                         »
taining  hexachlorophene  have  been  reported  (0.02   to  0.14  mg/1   blood)
 (Butcher,  et al. 1973); blood levels fall  after use is discontinued.
     A 1974  survey  by NIOSH indicated  that  exposure  to  hexachlorophene  was
primarily  in hospitals, sanitariums, and convalescent  homes (IARC, 1979).

-------
III. PHARMACOKINETICS
     A.   Absorption
          Systemic  toxicity  following dermal  application  or  ingestion  of
hexachlorophene indicates that  the  compound  is  absorbed through the skin and
the gastrointestinal tract (AMA Drug Evaluations, 1977).
     B.   Distribution
          Whole-body autoradioigraphs  of the murine fetus  during  late ges-
tation following administration of  labelled  hexachlorophene  indicate an even
distribution pattern of the compound  .   The compound  crosses  the  placenta;
fetal  retention  increases during  the course  of pregnancy  (Brandt,  et  al.
                                                     \
1979).  Hexachlorophene has been detected in human  adipose samples  at levels
of 0.80 jug/kg (Shafik,  1973).
     C.   Metabolism
          Hexachlorophene is  metabolized by the liver,  producing   a  glucu-
ronide conjugate.   The clearance of blood  hexachlorophene  is  dependent  on
this hepatic activity (Klaassen, 1979).
     0.   Excretion
          Within three  hours of hexachlorophene  administration to  rats,  50
percent of the initial dose was excreted in  the bile (Klaassen,  1979).  Oral
administration of  the  compound to  a cow  resulted in excretion  of  63.8 per-
cent of  the  initial dose in  the  feces and  0.24 percent  in the urine (St.
John and Lisk,  1972).
IV.  EFFECTS
     A.   Carcinogenicity
          The lifetime  dermal application of  25-percept and 50-percent  so-
lutions  of  hexachlorophene   to mice  failed  to  produce  significant  car-
cinogenic effects  (Stenback,  1975);  the  levels  of compound  used caused nigh
toxicity.   Rudali   and   Assa   (1978)  were  unable  to  produce  carcinogenic
effects  in  mice  by  lifetime  feeding or  subcutaneous injection at  birth  of
hexachlorophene.    Oral  lifetime feeding of  hexachlorophene  to  rats  (17  to
150   ppm)   also   failed   to  show  carcinogenic   effects  (NCI,   1978).

-------
     B.   Mutagenicity
          Single    intraperitoneal    injections    of   2.5    or    5.0   mg/kg
hexachlorophene  failed  to induce dominant  lethal  mutations in mice (Arnold,
et al. 1975).
          Desi,  et  al.  (1975)   have reported  that  hexachlorophene   admin-
istered  to  rats   produced   chromosome   aberrations  (dose  and  route  not
specified).
     C.   Teratogenicity
          Kennedy, et al.  (1975a)  reported  that  the fetuses of pregnant rats
                                                     «.
exposed to hexachlorophene at 30 mg/kg on  days  6 to 15 of gestation  show a
low  frequency  of  eye defects and  skeletal abnormalities  (angulated   ribs).
Fetuses of rabbits exposed to this compound  at  6 mg/kg on days  6  to 18 of
gestation showed a  low incidence  of skeletal  irregularities,  but no soft
tissue anomalies  (Kennedy,  et al. 1975a).  A  three-generation feeding study
of hexachlorophene  to rats at levels of 12.5 to  50 ppm did not show tera-
togenic effects (Kennedy, et al.  1975b).
          A  single retrospective  Swedish  study  on  infants born  to  nurses
regularly exposed  to antiseptic  soaps containing hexachlorophene  has sug-
gested that  the  incidence of malformations in this  infant  population  is in-
creased (Hailing, 1979).
     D.   Other Reporductive Effects
          Gellert,  et  al.  (1978)  have  reported  that male neonatal  rats
washed for eight days with three  percent  hexachlorophene solutions showed as
adults a decreased fertility due  to inhibited reflex ejaculation.
          Oral administration of  hexachlorophene  to  rats  has been  reported
to.produce  degeneration  of  spermatogenic  cells  (Casaret  and Doull,  1975).
Subcutaneous  injection of hexachlorophene to mice  at  various periods of ges-
tation produced increased fetal resorptions  (Majundar, et al. 1975).

-------
     E.   Chronic Toxicity
          Administration  of hexachlorophene  by" gavage  (40  mg/kg)  produced
hind leg  paralysis  and growth impairment  after two to  three weeks (Kennedy
and  Gordon,  1976).   Histological  examination  showed  generalized edema  or
status spongiosus of  the  white matter of  the  entire  central nervous  system.
These  gross effects and  histopathological lesions  have been  reported  to  be
reversible  (Kennedy, et al. 1976).
          Central  nervous  system effects  in  humans  following chronic  ex-
posure to hexachlorophene include diplopia, irritability, weakness of  lower
extremities, and convulsions (Sax, 1975).
V.   AQUATIC TOXICITY
     A.   Acute and Chronic Toxicity and Plant Effects
          Pertinent data were not found in the available literature.
     8.   Residues
          Sims  and  Pfaender  (1975)   found levels  of  hexachlorophenol  in
aquatic organisms  ranging  from  335  ppb  in sludge  worms to  27,800  ppb  in
water boatman (Sigara spp.).
VI.  EXISTING GUIDELINES
     A.   Human
          Hexachlorophene  is  permitted as a  preservative  in drug and  cos-
metic products at levels up to 0.1 percent (USFDA, 1972).
     B.   Aquatic
          Pertinent data were not found in the available literature.

-------
American Medical Association.  1977.  AMA Council on Drugs, Chicago.

Arnold,  0.,   et  al.   1975.   Mutagenic   evaluation  of  hexachlorophene.
Toxicol. Appl. Phaimacol.  33: 185.

Brandt,  I.,  et  al.   1979.   Transplacental  passage  and  embryonic-fetal
accumulation of hexachlorophene in mice.  Toxicol. Appl. Pharmacol.  49: 393.

Butcher,  H./  et al.   1973.   Hexachlorophene  concentrations  in blood  of
operating room personnel.  Arch. Surg.  107: 70.

Casaret,  L.  and  J.  Doull.   1975.   Toxicology:   The  Basic  Science  of
Poisons.  MacMillan, New York.
                                                  \
Oesi,   I.,   et   al.    1975.   Animal   experiments   on  the   toxicity   of
hexachlorophene. Egeszsegtudomany  19: 340.

Gellert,   R.J.,  et  al.    1978.    Topical   exposure   of   neonates   to
hexachlorophene:  Long-standing effects  on  mating behavior and  prostatic
development in rats.  Toxicol. Appl. Pharmacol.  43: 339.

Hailing, H.   1979.   Suspected link  between exposure to  hexachlorophene  and
malformed infants.  Ann.  NY. Acad.  Sci.   320: 426.

International Agency  for Research  on Cancer.  1979.   IARC  monographs  on  the
evaluation of  the carcinogenic risk  of chemicals to  humans.  Vol.  20,  Some
Halogenated Hydrocarbons, p. 241.   IARC, Lyon.

Kennedy, G.L.,  Jr.  and D.E.  Gordon.   1976.   Histopathologic changes produced
by hexachlorophene in the rat as a function of both magnitude and number of
doses.  Bull. Environ. Contain. Toxicol.   16: 464.

Kennedy,  G.L.,   Jr.,  et  al.   1975a.   Evaluation  of  the  teratological
potential of hexachlorophene in rabbits and rats.  Teratology.  12: 83.

Kennedy, G.L. Jr., et al.  1975b.   Effect of hexachlorophene on  reproduction
in rats.  J. Agric.  Food Chem. 23:  866.

Kennedy, G.L. Jr.,  et al.   1976.   Effects  of  hexachlorophene in the rat  and
their reversibility.  Toxicol. Appl. Pharmacol.  35: 137.

Klaassen,  C.D.   1979.   Importance  of  hepatic  function  on   the  plasma
disappearance  and  biliary   excretion of   hexachloroghene.   Toxicol.   Appl.
Pharmacol.  49: 113.
                                  It 6'

-------
Majundar,  S.,  et  al.   1975.  Teratologic  evaluation of hexachlorophene  in
mice.  Proc. Pennsylvania Acad. Sci.  49: 110.
National Cancer  Institute.   1978.   Bioassay of Hexachlorophene  for Possible
Carcinogenicity  (Tech.  Rep.  Ser.  #40).   DHEW,   Publication  No.  78-840,
Washington.
Rudali,  G.  and  R.   Assa.    1978.   Lifespan  carcinogenicity  studies  with
hexachlorophene in mice and rats.  Cancer Lett.  5: 325.
Sax, N.   1975.   Dangerous Properties of Industrial Materials..  4th  ed.  Van
Nostrand Reinhold, New York.
Shafik,    T.     1973.     The   determination   of   pentachlorophenol    and
hexachlorophene in human  adipose tissue.  Bull.  Environ. Contamin.  Toxicol.
10: 57.
                                                  v
Shackelford,  W.  and  L.  Keith.   1976.   Frequency  of  organic  compounds
identified in water.   U.S. EPA, 600/4-76-062, p.  142.
Sims,  J.  and  F.  Pfaender.    1975.  Distribution  and  biomagnification  of
hexachlorophene in urban  drainage  areas.  Bull.  Environ. Contamin.  Toxicol.
14: 214.
St.  John,  L. and  0.  Lisk.   1972.  The  excretion  of hexachlorophene in  the
dairy cow.  J.  Agr. Food Chem.  20: 389.
Stenback,  F.   1975.    Hexachlorophene.   in   mice.   Effects  after  long-term
percutaneous applications.  Arch. Environ. Health,   30:  32.
West,  R.,   et  al.   1975.   Hexachlorophene concentrations  in  human  milk.
Bull. Environ.  Contamin. Toxicol.  13:  167.
                                    ±4 *7 7
                                    ) J r }
                                    \\t~1

-------
                                       No.  117
          Hydrofluoric Acid

  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.

-------
                             , HYDROFLUORIC ACID
                                   Summary

     Hydrofluoric acid (HF) has  produced mutagenic  effects in plants and
Drosophila, and lymphocyte chromosome aberrations in  rats. _Chromosome ef-
fects were not observed in mice  following sub-chronic inhalation exposure to
the compound.
     No data are avilable on the possible carcinogenic or teratogenic ef-
fects of HF.
     Chronic exposure to the compound has produced skeletal, fluorosis,  den-
tal mottling and pulmonary function impairment.
     One short-term bioassay test demonstrated that a concentration of
50,000 ug/1 HF was lethal to bluegill sunfish in one hour.
                                  It 7-J

-------
                              • HYDROFLUORIC ACID

 I.    INTRODUCTION
      Hydrofluoric acid (CAS registry number  7664-39-3)  (HF)  is a colorless,
 clear,  fuming  corrosive liquid made  by  treating  fluorspar fGaF-x)-Kith  sul-
 furic acid.  An unusual property  of  HF  is  that it will  dissolve glass  or  any
 other silica-containing material.  It has  the following physical and chem-
 ical  properties (Windholz,  1976;  Hawley, 1971; Weast, 1972):
                                   Pure                   Constant Boiling
      Formula:                     HF                          HF/H^
      Molecular Weight:           20.01                          —
      Melting Point:              -83.55QC                        —
      Boiling Point:              19.51QC                        —
      Density:                     0.987                    1.15 - 1.18
      Vapor Pressure:             1 atm i 19.5loc
      Solubility:                 Very soluble in water;
                                  soluble in many organic
                                  solvents, e.g., benzene,
                                 toluene, xylene, etc.
     HF is used in the aluminum industry, for the production of  fluoro-
carbons, for uranium processing,   for petroleum alkylation, for the produc-
tion of fluoride salts, and as a pickling agent for stainless steel.  It has
many other minor uses (CMR, 1978).
II.  EXPOSURE
     A.   Water
          Other than occasional leaks and spills, very small amounts of HF
are released into water from manufacturing and production facilities (Union
Carbide, 1977;  U.S. EPA, 1977a).   HF is released into the air from coal

-------
 fires  (U.S.  EPA,  1977b)  and from manufacturing and production facilities
 (Union Carbide, 1977).   HF released into the air has a high affinity for
 water,  and it is  expected  that  it will  rain out (Fisher,  1976).   The amounts
 of HF  in water and  the extent of its presence could not be determined from
 the  available literature.   Under alkaline conditions,  HF  will form aqueous
 salts.
     8.   Food  •
          Pertinent data were not found  in the available  literature.
     C.   Inhalation
          HF  occurs in the atmosphere from coal fires  and  from manufacturing
 and production facilities  (see above), as  well as  from the photochemical re-
 action of &Lf2 with NO and humid air (Saburo,  et al.  (1977).  It  is
 present in the stratosphere (Zander, et al. 1977; Orayson,  et al. 1977;
 Farmer and Paper, 1977).  The extent and amounts of HF in  the atmosphere
 could not be  determined from the available  literature.
     D.   Dermal
          Pertinent data were not found in the available literature.
 III. PHARMACOKINETICS
     A.   Absorption
          The major route of HF absorption is by the respiratory system;
penetration of liquefied anhydrous HF through the skin has been reported
 (Burke, et al. 1973).   Fatal inhalation of HF fumes resulted in a blood
 fluoride level of 0.4 mg/100 ml (Greendyke and Hodge, 1964),. while skin
penetration of anhydrous HF produced a maximum blood fluoride concentration
of 0.3 mg/100 ml (Burke,  et al.  1973).   These levels are 100-fold higher

-------
 than normal serum fluoride levels (Hall et al. 1972).  Forty-five percent of
 fluoride present in the air in gaseous or particulate form is absorbed on
 inhalation (Dinman,  et al.  1976).
      B.    Distribution
           Absorbed fluoride is deposited mainly in the skeleton and teeth;
 it  is also found in  soft tissues  and body fluids (NAS,  1971;  NIOSH,  1975;
 NIOSH, 1976)>  Fluoride reaches fetal circulation via the placenta and is
 deposited in the fetal skeleton (NAS,  1971).
           Fluoride deposition  in  bone is not  irreversible (NAS,  1971).   How-
 ever,  laboratory animals chronically exposed  to HF gas  retained abnormally
 high  levels of fluoride in  the skeleton  for up to 14  months after  exposure
 (Machle  and Scott, 1935).
      C.    Metabolism
           The physiological or biochemical basis of fluoride  toxicity  has
 not been  established,  although it appears that enzymes  involved  in vital
 functions are inhibited by  fluoride  (NAS, 1971).   Examination of the data of
 Collins,  et al.  (1951)  indicates  that metabolism of absorbed  fluoride  is the
 same whether it  is inhaled  as  a particulate inorganic or  gas  (as HF) (NIOSH,
 1976).
     0.    Excretion
           Fluoride is excreted in the urine,  feces  and  sweat, and  in trace
 amounts in milk, saliva, hair  and probably tears.   Data are lacking regard-
 ing loss of fluoride by expired breath (NAS,  1971).
                                                     *•
          The primary route of  fluoride elimination is  through the urine.
The urinary fluroide concentration is influenced by factors such as total
absorption, the  form of  fluoride absorbed, frequency of exposure and general

-------
 health (MAS,  1971).   It is recognized that urinary fluoride levels are di-
 rectly related to the concetration of absorbed fluoride (NAS, 1571).
           In  a relatively unexposed person,  about one-half of an acute dose
 of fluoride is excreted within 24 hours in the urine,  and about one-half is
 deposited in  the skeleton (NAS,  1571).
 IV.   EFFECTS
      A.    Carcinogenic!ty
           Pertinent  data were  not found in the available literature.
      B.    Mutagenicity
           Mohamed (1563)  has reported various  aberrations in  second  genera-
 tion  tomato plants following parenteral treatment with HF at  3 ^g/m^.
 These results  could  not be duplicated by Temple and Weinstein (1576).
           Rats inhaling 0.1 mg HF/m5  chronically  for two months were re-
 ported to  develop lymphocyte chromosomal aberrations;  aberrations could not
 be.detected in sperm cells of  mice administered the same levels of HF-
 (Voroshilin, et al.  1573).
           Weak mutagenic  effects  in the  offspring of Drosophila exposed to
 air bubbled through  2.5 percent HF have  been reported  (Mohamed, 1571).
      C.    Teratogenicity
           Pertinent  data  were  not found  in the  available literature.
     0.    Other Reproductive Effects
           Reduced  fertility in Drosophila and decreased  egg hatch have been
 reported following exposure to 2.5 ppm HF  (Gerdes, et al. 1571).
     E.    Chronic Toxicity
          Among the adverse physiologic effects of long-term exposure to HF
are skeletal fluorosis, dental mottling and pulmonary impairment (NAS,  1571;
NIOSH, 1575; NIOSH, 1576).  Skeletal fluorosis is characterized by increased

-------
bone  density,  especially  in  the  pelvis  and  spinal  column,  restricted spinal
motion,  and ossification  of  ligaments.   Nasal irritation,  asthma  or  short-
ness  of  breath, and in some  cases pulmonary fibrosis  are associated  with
HF-induced pulmonary distress  (NIOSH, 1976).   Digestive disturbances have
also  been noted (NIOSH, 1976}.   Fluoride-induced renal pathology  has not
been  firmly established in man (Adler,  et al.  1970).  Causal relationships
in industrial  exposures are  difficult to determine because exposure  often
involves other compounds  in  addition to  fluorides  (NIOSH, 1976).
          Laboratory animals chronically exposed to 15.2 mg HF/m3 devel-
oped  pulmonaryr kidney and hepatic pathology  (Machle  and Kitzmiller,  1935;
Machle, et al. 1934), while  animals exposed to 24.5 mg HF/m3 developed
lung  edema (Stokinger, 1949).  Testicular pathology was also observed in
dogs  at 24.5 mg HF/m3 (Stokinger, 1949).  Several animal studies have
demonstrated that inhalation of HF increased fluoride deposition in the
bones (NIOSH,.  1976).
      F.   Other Relevant  Information
          Fluoride has anticholinesterase character which,  in conjunction
with  the reduction in plasma calcium observed in fluoride intoxication, may
be responsible for acute nervous system effects (NAS, 1971).  The severe
pain  accompanying skin injury from contact with 10 percent HF has been at-
tributed to immobilization of calcium,  resulting in potassium nerve stimula-
tion  (Klauder, et al 1955).
          Inhibition of enolase,  oxygen uptake, and tetrazolium reductase
                                                      .•
activity has been demonstrated in vitro from application of HF to excised
guinea pig ear skin (Carney,  et al.  1974).

-------
 V.    AQUATIC TOXICITY
      A.    Acute  Toxicity
           McKee  and Wolf  (1963) reported that HF was toxic to. fish
 (unspecified at  concentrations ranging from 40,000 to 60,000 ;jg/l.  Bonner
 and Morgan (1576) observed that 50,000 ^ig/1 HF was lethal to bluegill sun-
 fish  (Lepomis macrochirus) in one hour.
      B.    Chronic Toxicity, Plant Effects, and Residue
           Pertinent data were not found in the available literature.
      C.    Other Relevant Information
           Bonner and Morgan (1976) observed a marked increase in the oper-
cular "breathing" rate of bluegill sunfish exposed to a concentration of
25,000 ug/1  for four hours.  The fish recovered within three days.
VI.  EXISTING GUIDELINES AND STANDARDS
      A.    Human
           In 1976, NIOSH proposed a workplace environmental  limit for HF of
2.5 mg/nh5  (3 pom) as a time-weighted average to provide protection  from
the effects of HF over a working lifetime  (NIOSH,  1976).  A  ceiling limit of
5 mg HF/nv5 based on 15-minute exposures was also recommended to  prevent
acute irritation from HS (NIOSH,  1976).
     B.   Aquatic
          Pertinent data were not found in  the  available  literature.
                                    . ^JS^
                                 •*; j J u
                                  117-f

-------
                               HYDROFLUORIC ACID

                                   References
 Adler,  P., et al.  1970.   Fluorides  and Human Health.  World Health Organi-
 zation,  Monograph 59,  Geneva.

 Sonner,  W.P.  and E.L.  Morgan.   1976.  On-line surveillance of industrial ef-
 fluents  employing chemical-physical methods  of  fish as sensorsa.   Dept. of
 Civil    Engineering,    Tennessee   Technological   University,   Cookeviller-
 Tennessee.   Prepared  for  the  Offica  of  Water  Research  and  Technology.
 Available  from NTIS:   PB261-253.

 Burke,  W.J.,  et  al.   1973.   Systemic  fluoride poisoning resulting  from  a
 fluoride skin burn.  Jour. Occup. Med.   15: 39.

 Carney,  S.A., et  al.   1974.  Rationale of the treatment of hydrofluoric acid
 burns.   Br. Jour.  Ind. Med.  31: 317.

 Chemical  Marketing Reporter.   1978.   Chemical Profile  -  Hydrofluoric acid.
 Chem. Market. Rep.  August 21.

 Collins,  G.H.,   Jr..,   et  al.   1951.   Absorption  and  excretion  of  inhaled
 fluorides.  Arch.  Ind. Hyg. Occup. Med.  4: 585.

 Dinman,  D.B.,  et  al.   1976.   Absorption  and excretion of  fluoride  immedi-
 ately after exposure.  Pt. 1.  Jour. Occup. Med.   18: 7.

 Drayson,  S.R.,  et al.   1977.   Satellite  sensing  of  stratospheric  halogen
 compounds  by  solar  occulation.   Part  1.   Low  resolution  spectroscopy.
 Radiat. Atmos. Pap. Int. Symp.   p. 248.

 Farmer,  C.B.  and  O.F.  Raper.    1977.   The hydrofluoric acid:   Hydrochloric
 acid ratio in the 14-38 km region of the  stratosphere.  Geophys. Res.  Lett.
 4: 527.

 Fisher, R.W.  1976.  An air pollution  assessment of  hydrogen fluoride.   U.S.
 NTIS.  AD Rep. AS-AS027458, 37 pp.

 Gerdes, R., et al.  1971.  The  effects of atmospheric hydrogen fluoride upon
 Drosophila  melanogaster.    I.    Differential  genotypic   response.    Atmos.
 Environ.  5: 113.

Greendyke, R.M.  and H.C. Hodge.  1964.   Accidental death due  to hydrofluoric
 acid.  Jour. Forensic Sci.  9:  383.

Hall, L.L., et al.  1972.  Direct potentiometric deterination  of total  ionic
 fluoride in biological fluids.   Clin.  Chem.  18:  1455.
                                                                       »
Hawley,  G.G.    1971.   The Condensed  Chemical  Dictionary.    8th   ed.    Van
Nostrand Reinhold Co.,  New York.
                                   / / /-/O

-------
 Klauder, J.V., et  al.   1955.  Industrial  uses of compounds  of fluorine and
 oxalic acid.   Arch. Ind.  Health.   12: 412  •

 Machle,  W. and K.  Kitzmiller.  1935.   The effects of the  inhalation of hy-
 drogen fluoride  — II.  The  response following  exposure to  low  concentra-
 tion.   Jour.  Ind. Hyg.  Toxicol.   17:  223.

 Machle,  W. and  E.W. Scott.   1935.   The  effects of  inhalation of  hydrogen
 fluoride —  III.   Fluorine  storage  following exposure to sub-lethal concen-
 trations.   Jour.  Ind. Hyg. Toxicol.   17:  230.

 Machle,  W., et al.  1934.   The  effects of the inhalation of  hydrogen fluor-
 ide  —  I.  The   response  following  exposure to  high concentrations.   Jour.
 Ind. Hyg.   16: 129.

 McKee,  J.E. and H.W. Wolf.  1963.  Water Quality  Criteria.  California State
 Water  Quality Control Board  Resources Agency  Publication  No. 3-A.

 Mohamed,  A.   1968.   Cytogenetic  effects of hydrogen  fluoride treatment  in
 tomato plants.  Jour. Air Pollut.  Cant. Assoc.  18: 395.

 Mohamed,  A.   1971.   Induced recessive  lethals in  second  chromosomes  of
 Drosoghila  melanogaster. by hydrogen  fluoride.  In:   Englung,  H.,  Berry, W.,
 eos. Proc.  2nd internet. Clean Air Cong.- New YorT<:  Academic  Press.

 National  Academy  of Sciences.  1971.  Fluorides.  U.S.  National  Academy  of
 Sciences, Washington, DC.

 National  Institute  for Occupational  Safety and Health.   1975.  Criteria for
 a recommended standard  -  occupational exposure to inorganic fluorides.  U.S.
 OHEW,  National Institute for Occupational Safety and Health.

 National  Institute  for  Occupational  Safety and Health.   1976.  Criteria for
 a  recommended standard  - occupational  exposure  to hydrogen  fluoride, U.S.
 OHEW  National Institute  for  Occupational  Safety and  Health, March  1976.
 Pub. No. 76-43.

 Saburo, K., et al.   1977.  Studies on  the  photochemistry of aliphatic  halo-
 genated  hydrocarbons.    I.    Formation of  hydrogen   fluoride  and  hydrogen
 chloride  by the   photochemical reaction of dichlorodifluoromethane  with ni-
 trogen oxides in  air.  Chemosphere p. 503.

 Stokinger,  H.E.   1949.  Toxicity  following  inhalation of fluorine and hydro-
gen fluoride.   In:   Voegtlin, Hodge,  H.C.,  eds.   Pharmacology  and Toxicology
of Uranium Compounds.  McGraw-Hill Book Co., Inc., New York.  p. 1021.

Temple,  P.  and L.   Weinstein.   1976.   Personal   communication.  Cited in:
Drinking Water and  Health.   Washington,  DC:   National Research Council,  p.
486.
                                                                        »
Union Carbide.  1977.   Environmental  monitoring report,  United States Energy
Research  and  Development  Administration,  Paducah  gaseous diffusion  plant.
NTIS Y/UB-7.

-------
U.S.  EPA.   1977a.   Industrial  process  profiles  for  environmental  use:
chapter  16.   The fluorocarbon-hydrogen  fluoride  industry.   U.S.  Environ.
Prot. Agency.  U.S. DHEW PB281-483.

U.S. EPA.   1977b.  A survey  of sulfate,  nitrate  and  acid aerosol emissions
and their control.  U.S. Environ. Prot. Agency.  U.S. DHEW PB276-558.

Voroshilin,  S.I.,  et al.   1973.   Cytological effect  of  inorganic compounds
of fluorine on human and animal cells in vivo and in vitro.  Genetika 9: 115.

Weast, R.C..  1972.  Handbook  of Chemistry  and Physics.  53rd ed.  Cleveland,
OH:  Chemical Rubber Co.

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

Zander, R.,  et  al.  1977.  Confirming  the presence of hydrofluoric acid in
the upper stratosphere.   Geophys. Res.  Lett.  4: 117.

-------
                                       No.  118
          Hydrogen Sulfide

  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.
                            11 *-3L

-------
                       Hydrogen Sulfide



                           Summary
     Pertinent information could not be located on the



carcinogenicity,  mutagenicity,  or teratogenicity of H£S.



     Hydrogen, sulfide is very toxic to humans via inhalation



and has been reported to cause death at concentrations of



800 to 1000 ppm.



     Hydrogen sulfide is reported to be very toxic to fish




with toxic effects resulting from 1 to 100 ppm.

-------
I.   INTRODUCTION

     Hydrogen sulfide (^S; CAS No. 7783064) is a colorless

flammable gas with a rotten egg odor.  It has the following

physical properties:

          Formula                  t^S

          Molecular Weight         34.08

          Melting Point            -85.5°C

          Boiling Point            -60.4°C

          Density                  1.539 gram per liter at 0°C

          Vapor Pressure           20 atm. at 25.5°C



     Hydrogen sulfide is soluble in water, alcohol, and

glycerol (ITII, 1976).   Hydrogen sulfide is a flammable gas

and the vapor may travel considerable distance to a source of

ignition and flash back.

     Hydrogen sulfide and other sulfur compounds occur to some

extent in most petroleum and natural-gas deposits.  Very

substantial quantities  of this gas are liberated in coking

operations or in the production of manufactured gases from

coal (Standen, 1969).  Hydrogen sulfide is used to produce

substantial tonnages of elemental sulfur, sulfuric acid, and

a variety of other chemicals.  Completely dry hydrogen sulfide,

whether gaseous or liquid, has no acidic properties.  Aqueous

solutions, however, are weakly acidic (Standen, 1969).  In

1965,  some 5.2 million  metric tons of H2S was recovered from
                                                            »
fossil fuels (Standen,  1969).

-------
II.  EXPOSURE



     A.   Water



          Bacterial reduction of sulfates accounts for the



occurrence of I^S in numerous bodies of water, such as the



lakes near El Agheila, Libya.  Hydrogen sulfide is familiarly



formed as a bacterial decomposition product of protein



matter, particularly of animal origin (Standen, 1969) and this



gas can be found in most sewage treatment plant and their



piping systems.



     B.   Food



          H2S may be formed within the gastrointestinal tract



after the ingestlon of inorganic sulfide salts or elemental



sulfur due to the actions of gastric acid and of colonic



bacteria. (Division of Industrial Hygiene, 1941).



     C.   Inhalation



          Wherever sulfur is deposited, pockets of hydrogen



sulfide may be encountered, thus it is found at coal, lead,



gypsum, and sulfur mines.  Crude oil from Texas and Mexico



contain toxic quantities of H2S (Yont and Fowler, 1926).   The



decay of organic matter gives rise to the production of I^S



in sewers and waste from industrial plants where animals



products are handled.  Thus, there has been accidental poisoning



from H2§ in tanneries, glue factories, fur-dressing and



felt-making plants, abattoirs, and beet-sugar factories;  for



example, in Lowell, Massachusetts five men were poisoned
                                                            »


(three died)  when sent to repair a street sewer which drained



waste from a tannery (Hamilton and Hardy, 1974).

-------
     Hydrogen sulfide is formed in certain industrial processes




such as the production of sulfur dyes, the heating of rubber




containing sulfur compounds, the making of artificial silk or




rayon by viscose process (Hamilton and Hardy, 1974).




     D.   Dermal




          Pertinent information could not be found in the




available literature.




III. PHARMACOKINENTICS




     A.   Absorption




          By far the greatest danger presented by hydrogen




sulfide is through inhalation, although absorption through




Ithe skin has been reported (Patty, 1967).




     B.   Distribution




          Pertinent information could not be. found in the




available literature.




     C.   Metabolism and Excretion




          Evidence has been obtained for the presence of a




sulfide oxidase in mammalian liver (Baxter and Van Reen,




1958; Sorbo, 1960), but important nonenxymatic mechanisms for




sulfide detoxication are also recognized.  Sulfide tends to




undergo spontaneous oxidation to non-toxic products such as




polysulfides, thiosulfates or sulfates (Gosselin, 1976).




     When free sulfide exists in the circulating blood a




certain amount of hydrogen sulfide is excreted in the exhaled




breath, this is sufficient to be detected by odor, but the




greater portion, however, is excreted in the urine, chiefly as




sulfate, but some as sulfide (Patty, 1967).
                             11    -

-------
IV.  EFFECTS



     A..   Carcinogenic! ty



          Pertinent information could noc be found in the



available literature.



     B.   Mutagenicity



          Pertinent information could not be found in the



available literature.



     C.   Teratogenicity



          Pertinent information could not be found in the



available literature.



     D.   Other Reproductive Efforts



          Pertinent information could not be found in the



available literature.



     E.   Chronic Toxicity



          At low concentrations of hydrogen sulfide (e.g., 50



to 200 ppm) the toxic symptoms are due to local tissue



irritation rather than to systemic actions.  The most



characteristic effect is on the eye, where superficial injury



to the conjunctiva and cornea is known to workers in tunnels,



caissons, and sewers as "gas eye" (Grant, 1972).  More



prolonged or intensive exposures may lead to involvement of



the respiratory tract with cough, dyspnea and perhaps pulmonary



edema.  Evidence of severe pulmonary edema has been found at



autopsy and in survivors of massive respiratory exposures
                                                            »


(Gosselin, 1976).  The irritating action has been explained



on the basis that I^S combines with alkali present in moist



tissues to form sodium sulfide, a caustic (Sax, 1979).  Chronic

-------
poisoning results in headache, inflammation of the conjunctivas



and eyelids, digestive disturbances, loss of weight, and



general debility (Sax, 1979).



     F.   Other Relevant Information



          Hydrogen sulfide is reported with a maximum safe



concentration of 13 ppm (Standen, 1969), although at first



this concentration can be readily recognized by its odor, H2S



may partially paralyze the olfactory nerve to the point at



which the presence of the gas is no longer sensed.  Hamilton



and Hardy (1974) report that at a concentration of 150 ppm,



the olfactory nerve is paralyzed.



     Exposures of 800-1000 ppm may be fatal in 30 minutes,



and high concentrations are instantly fatal (Sax, 1979).



There are reports of exceptional cases of lasting injury,



after recovery from acute poisoning, which point to an



irreversible damage to certain cells of the body resulting



from prolonged oxygen starvation (Hamilton and Hardy, 1974).



Hydrogen sulfide has killed at concentrations as low as



800 ppm (Verschueren, 1974).



V.   AQUATIC TOXICITY



     A.   Acute Toxicity



          Verschueren (1974) has reviewed the effects of H2S



on several aquatic organisms.  Goldfish have been reported to



die at a concentration of 1 ppm after long time exposure in
                                                            »


hard water.   Verschueren (1974) reports a 96-hour LC50 value of



10 ppm for goldfish.  Verschueren also reports on a large number



of fresh water fish with toxic effects resulting from exposure

-------
Co H2§ at concentrations ranging from 1 to 100 ppm.

     Verschueren (1974) reports median threshold limit values

for Arthropoda: Asellus, 96-hour at 0.111 mg/1;  Crangonyx,

96 hour at 1.07 mg/1;  and Gammarus, 96-hour at 0.84 mg/1.

     B.   Chronic Toxicity, Plant Effects and Residues

          Pertinent information could not be located in the

available literature.

     C.   Other Relevant Information

          Verschueren (1974) reports that sludge digestion is

inhibited at 70-200 mg/1 of ^S in wastewater treatment plants

VI.  EXISTING GUIDELINES AND STANDARDS

     A.   Human

          The 8-hour,  time-weighted average occupational

exposure limit for H£S has been set in a number  of countries

and are tabled below (Verschueren, 1974):


           T.L.V.:  Russia            7 ppm
                    U.S.A.            20 ppm "peak"
                    Federal German    10 ppm
                      Republic


     #2$ is a Department of Transportation flammable and

poisonous gas and must be labelled prior to shipment.

     B.   Aquatic

          Maximum allowable concentration of .0.1 mg/1 for

Class I and Class II waters has been established in Romania

and Bulgaria for I^S (Verschueren, 1974).
                             11 Co
                            ) -J/ U

-------
                          References
Baxter, C. F. and R. Van Reen.  19S8a.  Some Aspects of
Sulfide Oxidation by Rat Liver Preparations.  Biochem.
Biophys.  Acta 28: 567-572.  The Oxidation of Sulfide
to Thiosulfate by Metalloprotein Complexes and by
Ferritin.  Loc. cit. 573-578.  1958b.

Division of Industrial Hygiene.  1941.  Hydrogen Sulfide,
its Toxicity and Potential Dangers.  National Institute
of Health, U.S. Public Health Service.  Public Health
Rep. (U.S.) 56: 684-692.

Gosselin, R. £., et al.  1976.  Clinical Toxicology of
Commercial Products.  The Williams and Wilkins Company,
Baltimore.

Grant, W. M.  1972.  Toxiciology of the Eye.  2nd ed.
Charles C. Thomas, Springfield, Illinois.

Hamilton, A. and Harriet Hardy.  1974.  Industrial
Toxicology.  Third edition.  Publishing Science Group, Inc.

ITII.  1976.  Toxic and Hazardous Industrial Chemicals
Safety Manual for Handling and Disposal with Toxicity
and Hazard Data.  The International Technical Information
Institute.  Toranomon-Tachikawa Building, 6-5, 1 Chome,
Nishi-Shimbashi, Minato-ku, Tokyo, Japan.

Patty, F.  1967.  Industrial Hygiene and Toxicology.
Interscience Publishers.  New York.

Sax, N. Irving.  1979.  Dangerous Properties of Industrial
Materials.  Van Nostrand Reinhold Company, New York.

Sorbo, B.  On the Mechanism of Sulfide Oxidation in Bio-
logical Systems.  Biochem.  Biophys.  Acta 38: 349-351.

Standen, A. et. al. (editors).  1969.  Kirk-Othmer
Encyclopedia of Chemical Technology.  Interscience
Publishers.  New York.

Verschueren, K.  1977.  Handbook of Environmental Data
on Organic Chemicals.  Van Nostrand Reinhold Company,  New
York.

Yant, W. P. and H. C. Fowler.  1926.  Hydrogen Sulfide
Poisoning in the Texas Panhandle.  Rep. Invest. U.S. Bureau
of Mines.  Number 2776.

-------
                                     No. 119
      Indeno (1,2,3-aOpyTene

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

           APRIL  30, 1980
          n  j-l

-------
                          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 (CAG) has evaluated
indeno(l,2,3-c,d)pyrene and has found sufficient evidence to
indicate that this compound is carcinogenic.

-------
                          INDENO[1,2,3-cd]PYRENE




                                 Summary






     IndenoC1,2,3-cd]pyrene (IP) is a member of the polycyclic aromatic




hydrocarbon (PAH) class.  Several compounds in the PAH class are well




known to be potent animal carcinogens.  However, IP is generally regarded




as only a weak carcinogen to animals or man.  There are no reports




available concerning the chronic toxicity of IP.  Exposure to IP in the




environment occurs in conjunction with exposure to other PAH; it is not




known how these compounds may interact in human systems.




     There are no reports available concerning standard acute or chronic




toxicity tests of this chemical in aquatic organisms..

-------
I.   INTRODUCTION



     This profile is based primarily on  the  Ambient Water  Quality Criteria



Document for Polynuclear Aromatic Hydrocarbons  (U.S. EPA,  1979a)  and  the




Multimedia Health Assessment Document for Polycyclic Organic  Matter (U.S.




EPA, 1979b).




     IndenoCl,2,3-cd]pyrene (IP; 022^12) is  one of fcne  family of  polycyclic



aromatic hydrocarbons (PAH) formed as a  result of incomplete  combustion



of organic material.  Its physical and chemical properties have not been



well-characterized.



     PAH, including IP, are ubiquitous in the environment.  They  have



been identified in ambient air, food, water, soils, and sediments  (U.S.



EPA, 1979b).  The PAH class contains several potent carcinogens (e.g.,



benzCblfluoranthene), weak carcinogens (benzCa]anthracene), and cocarcinogens



(e.g.,  fluoranthene), as well as numerous non-carcinogens  (U.S. EPA,



1979b).



     PAH  which contain more than three  rings (such as IP) are relatively



stable in the environment,  and may be transported in air and  water  by



adsorption to particulate matter.  However,  biodegradation and chemical



treatment are effective in eliminating most  PAH in the environment.  The



reader is referred to the PAH Hazard Profile for a more general discussion




of PAH (U.S. EPA, 1979o).



II.  EXPOSURE



     A.   Water



          Basu and Saxena (1977, 1978) have conducted monitoring  surveys



of U.S. drinking water for the presence of six representative PAH,  including
                                                                           »


IP.  They found the average total level of the six PAH (fluoranthene,



benzolk]fluoranthene,  benzoCjlfluoranthene,   benzoCajpyrene, benzoCg,h,i]-



perylene, and indenoC1,2,3-cd]pyrene) to be  13.5 ng/1.

-------
     B.   Food




          Levels of  IP are not  routinely  monitored  in food,  but it has




been detected in foods such as  butter  and smoked  fish (U.S.  EPA,  1979a).




However, the total intake of  all  types of PAH  through the  diet has been




estimated at 1.6 to  16 ug/day (U.S.  EPA,  1979b).  The U.S. EPA (1979a)




has estimated the bioconcentration  factor of IP to  be 15,000 for  the




edible portion of fish and shellfish consumed  by  Americans.   This estimate




is based upon the octanol/water partition coefficient for  IP.



     C.   Inhalation




          There are  several studies  in which IP has been detected in




ambient air (U.S. EPA, 1979a).  Measured  concentrations ranged from 0.03




to L.34 ng/m^ (Gordon, 1976;  Gordon  and Bryan, 1973).  Thus,  the  human



daily intake of IP   by inhalation of ambient air  may be in the range  of




0.57 to 25.5 ng, assuming that  a human breathes 19  m3 of air per  day.




III. PHARMACOKINETICS




     There are no data available concerning the pharmacokinetics  of IP,




or other PAH, in humans.  Nevertheless, some experimental animal  results




were published on several other PAH, particularly benzo[a]pyrene.



     A.    Absorption




          The absorption rate of IP  in humans  or  other animals has  not



been studied.  However, it is known  (U.S.  EPA, 1979a)  that,  as a  class,




PAH are well-absorbed across  the respiratory and  gastrointestinal  epithelia




membranes.   The high lipid solubility  of  compounds  in  the PAH  class supports



this observation.

-------
     B.   Distribution



          Based on an extensive literature review, data on the distribution




of IP in mammals were not found.  However, it is known (U.S. EPA, 1979a)




that other PAH are widely distributed throughout the body following their-



absorption in experimental rodents.  Relative to other tissues, PAH tend



to localize in body fat and fatty tissues (e.g., breast).



     C.   Metabolism



          The metabolism of IP in animals or man has not been directly




studied.  However, IP, like other PAH, is most likely metabolized by the



microsomal mixed-function oxidase enzyme system in mammals (U.S.  EPA,



1979b).  Metabolic attack on one or more of the aromatic rings leads to




the formation of phenols and isomeric dihydrodiols by the intermediate



formation of reactive epoxides.  Dihydrodiols are further metabolized  by



microsomal mixed-function oxidases to yield diol epoxides, compounds



which are known to be biologically reactive intermediates for certain



PAH.   Removal of activated intermediates by conjugation with glutathione



or glucuronic acid, or by further metabolism to tetrahydrotetrols,  is  a



key step in protecting the organism from toxic interaction with cell



macromolecules.



     D.   Excretion



          The excretion of IP by mammals has not been studied.   However,



the excretion of closely related PAH is rapid, and occurs mainly  via the



feces (U.S.  EPA, 1979a).  Elimination in the bile may account for a



significant percentage of administered PAH.   It is unlikely that  PAH will



accumulate in the body as a result of chronic low-level exposures.
                                 119-7

-------
IV.  EFFECTS




     A.   Carcinogenicity




          IP is regarded as only a weak carcinogen  (U.S.  EPA,  1979b).   LaVoie




and coworkers  (1979) reported that IP had  slight activity as a tumor  initiator




and no activity as a complete carcinogen on the skin of mice which  is  known




to be highly sensitive to the effects of carcinogenic  PAH.




     B.   Mutagenicity




          LaVoie and coworkers  (1979) reported that IP gave positive results



in the Ames Salmonella assay.




     C.   Teratogenicity and Other Reproductive Effects



          There are no data available concerning the possible  teratogenicity




or other reproductive effects as a result  of exposure  to  IP.   Other related



PAH are apparently not significantly teratogenic in mammals (U.S. EPA,  l979aX.




V.   AQUATIC TOXICITY




     Pertinent information could not be located in the available literature.




VI.  EXISTING GUIDELINES AND STANDARDS




     Neither the human health nor aquatic  criteria derived by  U.S. EPA  (1979a),




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




          There are no established exposure criteria for  IP.   However,  PAH,



as a class, are regulated by several authorities.  The World Health Organization




(1970) has recommended that the concentration of PAH in drinking



water (measured as the total of fluoranthene, benz[g,h,i]perylene, benzCb]-



fluoranthene, benz[h]fluoranthene,  indeno[1,2,3-cd]pyrene, and benz[a]p,yrene)



not exceed 0.2 ug/1.  Occupational exposure criteria have been established
                                     X

-------
for coke oven emissions, coal tar products, and coal tar pitch volatiles,



all of which contain large amounts of PAH, including IP (U.S. EPA, 1979a).



     The U.S. EPA O979a) draft recommended criteria for PAH in water are



based upon the extrapolation of animal carcinogenicity data for benzCa]-



pyrene and dibenz[a,h]anthracene.



     B..   Aquatic



          There are no standards or guidelines concerning allowable concen-



trations of IP in aquatic environments.
                               //

-------
                           INDENO[1,2,3-cd]PYRENE

                                 REFERENCES
 Basu,  O.K.,  and J.  Saxena.   1977.  Analysis of raw and drinking water
 samples for  polynuclear aromatic hydrocarbons.  EPA P.O. No. CA-7-2999-A,
 and CA-8-2275-B.   Exposure  Evaluation Branch, HERL, Cincinnati, Ohio.

 Basu,  O.K. and J.  Saxena.   1978.  Polynuclear aromatic hydrocarbons in
 selected U.S.  drinking waters and their raw water sources.  Environ.  Sci.
 Technol., 12:   795.

 LaVoie, et al. 1979.   A comparison of the mutagenicity,  tumor initiating
 activity, and  complete carcinogenicity of polynuclear aromatic hydrocarbons
 In: "Polynuclear Aromatic  Hydrocarbons".   P.W. Jones and P.  Leber (eds.).
 Ann Arbor Science Publishers, Inc.
 Gordon,  R.J.   1976.   Distribution of airborne polycyclic aromatic hydro-
 carbons  throughout Los Angeles,  Environ.  Sci. Technol.  10:  370.

 Gordon,  R.J.  and R.J.  Bryan.   1973.   Patterns of airborne polynuclear
 hydrocarbon concentrations at four Los Angeles sites.   Environ.  Sci.  7:
 T050.

 U.S.  EPA.   1979a.   Polynuclear aromatic hydrocarbons.   Ambient water
 quality  criteria.   (Draft).

.U.S.  EPA.   1979.   Multimedia health assessment document for polycylic
 organic  matter.   Prepared under  contract  by J. Santodonato, et al., Syracuse
 Research Corp.

 U.S.  EPA.   1979.   Environmental  Criteria  and Assessment Office.   Poly-
 chlorinated Aromatic Hydrocarbon:  Hazard Profile.  (Draft).

 World  Health Organization.  1970.  European standards  for drinking water,
 Ind ed.   Revised,  Geneva.

-------
                                      No.  120
          Isobutyl Alcohol

  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.
                           -777V

-------
                                                                      If 7


                            Isobutyl Alcohol



I.   Introduction

     Isobutyl alcohol (2-methyl-l-propanol, C,ILQ0; molecular weight

74.12) is a flaaanabla, colorless, refractive liquid with an odor  like  of

amyl alcohol,, but weaker.  Isobutyl alcohol is used in  Che manufacture of

esters for fruit flavoring essences, and as a solvent in paint and varnish

removers.  This compound is soluble in approximately 20 parts water, and is

miscible with alcohol and ether.

II.  Exposure-

     No data were readily available.

III. Pharmacokinetics

     A.   Absorption

          Isobutyl alcohol is absorbed through che intestinal cract and

the lungs.

     B.   Distribution

          No data were readily available.

     C.   Metabolism

          Isobutyl alcohol is oxidized Co isobutyraldehyde and isofaucyric

acid in che rabbit, with further metabolism proceeding  Co acetone and  carbon

dioxide.  Some conjugation with glucuronic acid occurs  in che rabbic and dog.

     D.   E
          Approximately 141 of isobutyl alcohol is excreted as urinary

conjugates in che rabbic.

IV.  Effects

     A.   Carcinogenic!£7

          Rats receiving isobutyl alcohol, either orally or subcucaneously,

one co cvo times a week for 495 co 643 days showed liver carcinomas and
                                ' // "->
                               / /'-c.

                              /ifl-  ?

-------
sarcomas, spleen sarcomas and myeloid leukemia  (Gibel, £C_ al_.,  Z.  Exp.

Chir. Chir. Forsch. 7: 235  (1974).

     B.   Teratogenicity

          No data were readily available.

     C.   Other Reproductive Effects

          No data were readily available.

     D.   Chronic Toxicity

          Ingestion of one molar solution of isobutyl alcohol in water by

rats for 4 months did not produce any inflammatory reaction of  the liver.

On ingestion of two molar solution for two months rats developed Mallory's

alcoholic hyaline bodies in the liver, and were observed  to have decreases

in fat, glycogen, and RNA in the liver.

     E.   Other Relevent Information

          Acute exposure to isobutyl alcohol causes narcotic effects, and

irritation to the eyes and throat in humans exposed to 100 ppm  for repeated

8 hour periods.  Formation of facuoles in the superficial layers of  the

cornea, and loss of appetite and weight were reported among workers  subjected,

to an. undetermined, but apparently high concentration of  isobutyl alcohol and

butyl acetate.  The oral LD_Q of isofautyl alcohol for rates if  2.46  g/kg

(Smith et. al., Arch.. Ind. Hyg. Occup. Med. 10_: 61, 1954).

V.   Aquatic Toxicity

     A.   Acute Toxicity

          The LC_- of isobutyl alcohol for 24-hour-old Daphnia  magna is

between 10-1000 mg/1.

VI.  Existing Guidelines and Standards

     OSHA   -  100 ppm
     NIOSH  -  None
     ACGIH  -   50 ppm

-------
711. Information Sources

     1.   NQi Toxicology Data Bank.
     2.   March. Index, 9th ad.
     3.   NIOSH Registry of Toxic Effects of Chemical Substances, 1978.
     4.   NCM Toxline.
     3.   Sax, I. "Dangerous Properties of Industrial Materials."
     6.   Proctor, N. and Hughes, J. " Chemical Hazards of ehe Workplace"
          Lippincott Co., 1978.
     7.   Occupational Diseases.  A Guide to Their Recognition, NIOSH
          publication Ho. 77-181, 1977.
     3.   Hunter, D.  "The Diseases of Occupations" 5th ad., Hodder and
          Stoughton, 1975.
                                 ,- >'((('
                                 ''   i r '/**

-------
                                     No.  121
               Lead


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


           APRIL 30, 1980
                       ,
            JU-I

-------
                          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.

-------
                             LEAD
                           SUiMMARY
     The hazards of human exposure to lead have been well-
recognized for centuries.  The hematopoietic system is  the
most sensitive target organ for  lead in humans, although
subtle neurobehavioral effects are suspected in children
at similar levels of exposure.   The more serious health
effects of chronic lead exposure, however,, involve neuro-
logical damage, irreversible renal damage, and adverse  repro-
ductive effects observed only at higher levels of lead  expo-
sures.  Although certain inorganic lead compounds are car-
cinogenic to some species of experimental animals, a clear
association between lead exposure and cancer development
has not been shown in human populations.
     The effects of lead on aquatic organisms have been
extensively studied, particularly in freshwater species.
As with other heavy metals, the  toxicity is strongly depen-
dent on the water hardness.  Unadjusted 96-hour LC^Q values
with the common fathead minnow,  Pimephales promelas, ranged
from 2,400-7,480 pg/l in. soft water to 487,000 pg/1 in  hard
water.  Toxicity is also dependent on the life stage of
the organism being tested.  Chronic values ranged from  32
jug/1 to 87 /jg/1 for six species  of freshwater fish.  Lead
at 500 jug/1 can reduce the rate  of photosynthesis by 50
percent in freshwater algae.  Lead is bioconcentrated by   •
all species tested - both marine and freshwater - including

-------
fish, invertebrates, and algae.  The mussel, Mytilus edulis,
concentrated lead 2,568 times that found in ambient water.
Two species of algae concentrated lead 900-1000-fold.

-------
                             LEAD
I.    INTRODUCTION
     This hazard profile is based primarily upon  the Ambient
Water Quality Criteria Document  for Lead  (U.S. EPA, 1979).
A number of excellent comprehensive reviews on the health
hazards of lead have also been recently published.  These
include the U.S. EPA Ambient Air Quality Criteria Document
for Lead and the lead criteria document of the National
Institute for Occupational Safety and Hearth  (1978).
     Lead (Pb, At. No. 82)  is a  soft gray acid-soluble metal
used in electroplating, metallurgy, and the manufacture
of construction materials, radiation protection devices,
plastics, electronics equipment, storage batteries, gasoline
antiknock additives, and pigments  (NIOSH, 1978).  The solu-
bility of lead compounds in water depends heavily on pH
and ranges from about 10  pg/1 at pH 5.5 to 1 /ag/1 at pH
9.0 (U.S.  EPA, 1979).  Inorganic lead compounds are most
stable in the +2 valence state,  while organolead compounds
are more stable in the -t-4 valence state (Standen, 1967) .
     Lead consumption in the United States has been fairly
stable from year to year at about 1.3 x 10  metric tons
annually.  Consumption of lead as an antiknock additive
to gasoline (20 percent annual production) is expected to
decrease steadily.  Since lead is an element, it will remain
indefinitely once released to the environment (U.S. EPA,
1979).

-------
II.  EXPOSURE
     A.   Water
          Lead is ubiquitous in nature, being a natural
constituent of the earth's crust.  Most natural groundwaters
have concentrations ranging from 1 to 10 ug/1.
          Lead does not move readily through stream beds
because it easily forms insoluble lead sulfate and carbonate.
Moreover, it binds tightly to organic ligands of  the dead
and living flora and fauna of stream beds.-- However, lead
has been found at high concentrations in drinking water
(i.e., as high as 1000 ug/1), due primarily to conditions
of water softness, storage, and transport  (Beattie, et al.
1972).
          The magnitude of"the problem of  excessive lead
in drinking water is not adequately known.  In one recent
survey of 969 water systems, 1.4 percent of all tap water
samples exceeded the 50 pg/1 standard (McCabe, 1970).  The
U.S. EPA (1979) has not estimated a bioconcentration factor
for lead in aquatic organisms.
     B.   Food
          It is generally believed that food constitutes
the major source of lead absorption in humans.  The daily
dietary intake of lead has been estimated  by numerous investi-
gators, and the results are generally consistent  with one
another.  This dietary intake is approximately 241 jig/day
for adults  (Nordman, 1975; Kehoe, 1961).   For children  (ages'
3 months to 3.5 years) the dietary intake  is 40 to 210 ug
of  lead per day  (Alexander, et al. 1973).

-------
     C.   Inhalation
          A great deal of controversy has been generated
regarding the contribution of air to total daily  lead  absorp-
tion.  Unlike the situation with food and water,  ambient
air lead concentrations vary greatly.   In metropolitan areas,
average air lead concentrations of 2 jjg/m , with  excursions
of 10 ug/m  in areas of heavy traffic or industrial point
sources, are not uncommon (U.S. EPA, 1979).   In non-urban
areas average air lead concentrations are ..usually on the
order of 0.1 pg/m2  (U.S. EPA, 1979).
III. PHARMACOKINETICS.
     A.   Absorption
          The classic studies of Kehoe  (1961) on  lead  metabo-
lism in man indicate that on the average and  with consider-
able day-to-day excursions, approximately eight percent
of the normal dietary lead  (including beverages)  is absorbed.
More recent studies have confirmed this conclusion  (Rabino-
witz, et al. 1974).  The gastrointestinal absorption of
lead is considerably greater in children than in  adults
(Alexander, et al.  1973; Ziegler, et al. 1978).
          It has not been possible to accurately  estimate
the extent of absorption of inhaled lead aerosols.  To vary-
ing degrees,, depending on their solubility and particle
size, lead aerosols will be absorbed across the respiratory
epithelium or cleared from the lung by mucociliary action
and subsequently swallowed.
          Very few  studies concerning dermal  absorption
of lead in man or experimental animals  are available.  A
                             I ! ! ""I j —
                          <* '/ V1 BL I

-------
recent study by Rastogi and Clausen  (1976)  indicates  that
lead is absorbed through intact skin when applied  at  high
concentrations in the form of lead acetate  or  naphthenate.
     B.   Distribution
          The general features of lead distribution  in  the
body are well known/ both from animal studies  and  from  human
autopsy data.  Under circumstances of long-term  exposure,
approximately 95 percent of the total amount of  lead  in
the body (body burden) is localized  in the  skeleton  after
attainment of maturity (U.S. EPA, 1979).  By contrast,  in
children only 72 percent is in bone  (Barry, 1975).  The
amount in bone increases with age but the amount in  soft
tissues, including blood, attains a  steady  state early  in
adulthood (Barry, 1975; Horiuchi and Takada, 1954).
          The distribution of lead at the organ  and cellular
level has been studied extensively.  In blood, lead  is  pri-
marily localized in the erythrocytes (U.S.  EPA,  1979).
The ratio of the concentration of lead in the  cell to lead
in the plasma is approximately 16:1.  Lead  crosses the  pla-
centa readily, and its concentration in the blood  of  the
newborn is quite similar to maternal blood  concentration.
     C.   Excretion
          There are wide interspecies differences  concerning
routes of excretion for lead.  In most speci.es biliary  ex-
cretion predominates in comparison to urinary  excretion,
except  in the baboon  (Eisenbud and Wrenn, 1970).   It  also
appears that urinary excretion predominates in man (Rabino-
                              x
                          - j ,Y i o ^
                          ^^^F^^^C^

-------
witz, et al. 1973).  This conclusion, however, is based
on very limited data.
IV.  EFFECTS
     A.   Carcinogenicity
          At least three studies have been published which
report dose-response data for lead-induced malignancies
in experimental animals  (Roe, et al. 1965; Van Esch, et
al. 1962; Zollinger, 1953; Azar, et al. 1973).  These studies
established that lead caused renal tumors in rats.
          Several epidemiologic studies have been conducted
on persons occupationally exposed to leaa (Dingwall-Fordyce
and Lane, 1963; Nelson, et al. 1973; Cooper and Gaffey,
1975; Cooper, 1978).  These reports do not provide a con-
sistent relationship between lead exposure and cancer develop-
ment.
     B.   Mutagenicity
          Pertinent information could not be located in
the available literature concerning mutagenicity of lead.
However, there have been conflicting reports concerning
the occurrence of chromosomal aberrations in lymphocytes
of lead-exposed workers  (O'Rioraan and Evans, ly74; Forni,
et al. 1976).
     C.   Teratogenicity
          In human populations exposed to high concentra-
tions of lead, there is evidence of embryotoxic effects
                                                             »
although no reports of teratogenesis have oeen published
(U.S. £PA, 197y).  In experimental animals,  on the other
hana, leaa has repeatedly produced teratogenic effects  (Cat-

-------
zione ana Gray, 1941; Karnofsky ana Ridgway, 195
-------
(Kline, 1960), electrocardiographic abnormalities  (Kosmider
and Pentelenz, 1962), impaired liver  function  (Dodic,  et
al. 1971), impaired thyroid function  (Sandstead, et  al.
1969) , and intestinal colic (Beritic, 1971).
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          The available data base on  the  toxic  effects of
lead to freshwater organisms is quite large and clearly
demonstrates the relative sensitivity of  freshwater  orga-
nisms to lead.  The data base shows that  the different lead
salts have similar LC^Q values, and that  LCcQ values for
lead are greatly different in hard and soft water.   Between
soft and hard water; the LC   values  varied by  a factor
of 433 times for rainbow trout, 64 times  for fathead min-
nows,  and 19 times for bluegills  (Davies, et al. 1976; Picker-
ing and Henderson, 1966).
          Some 96-hour LC^Q values for freshwater  fish are
2,400 to 7,480 pg/1 for fathead minnows in  soft water  (Tarz-
well and Henderson, 1960; Pickering and Henderson, 1966),
482,000 for  fathead minnows in hard water  (Pickering and
Henderson, 1966), 23,800 ug/1 for bluegills in  soft  water
(Pickering and Henderson, 1966), and  442,000 ug/1  for  blue-
gills in hard water  (Pickering and Henderson, 1966).
          For invertebrate species, Whitely  (1968) reported
24-hour LC5Q values of 49,000 and 27,500  ug/1 for  sludge
worms  (Tubifex sp.) obtained from tests conducted  at pH


                             /r
                             hi* «£-
                           *•/ 7 9-J

-------
levels of 6.5 and 8.5, respectively.  The effects of water
hardness on toxicity of lead to invertebrates could not
be located in the available literature.
          The acute toxicity data base for saltwater orga-
nisms is limited to static tests with invertebrate species.
The LC5Q values ranged from 2,200 to 3,600 ug/1 for oyster
larvae in a 48-hour test  (Calabrese, et al. 1973) to 27,000
ug/1 for adult soft shell clams (Eisler, 1977) in a 96-hour
test.
     B.   Chronic Toxicity
          Chronic tests in soft water have been conducted
with lead on six species of fish.  The chronic values ranged
from 32 ug/1 for la'ke trout (Sauter, et al. 1976) to 87
ug/1 for the white sucker (Sauter, et al. 1976), both being
embryo-larval tests.
          Only one invertebrate chronic test result was
found in the literature.  This test was with Daphnia magna
in soft water, and the resulting chronic value was 55 jug/1,
about one-eighth the acute value of 450 ug/1  (Biesinger
and Christensen, 1972).
          Life cycle or embryo-larval tests conducted with
lead on saltwater organisms could not be located in the
available literature.
     C.   Plant Effects
          Fifteen tests on eight different species of aqua-
tic algae are found in the literature.  Most studies mea-
                                           14
sured the lead concentration which reduced   CO- fixation
by 50 percent.  These values range from 500 ug/1 for Chlorella

-------
sp. (Monahan, 1976) to 28,000 for a diatom, Navicula  (Malan-
chuk and Gruendling, 1973).
          Pertinent data could not be located  in  the  avail-
able literature on the effects of lead on marine  algae.
     D.   Residue
          The mayfly (Ephemerella grandis) and  the  stonefly.
(Pteronarcys californica)  have been studied for their ability
to bioconcentrate lead (Nehring, 1976).  The bioconcentra-
tion factor for lead in the mayfly is 2,366 and in  the stone-
fly 86, both after 14 days of exposure.
          Schulz-Baldes  (1972) reported that mussels  (Mytilus
edulis) could bioconcentrate lead 2,568-fold.   Two  species
of algae bioconcentrate lead 933 and 1,050-fold  (Schulz-
Baldes, 1976).
VI   EXISTING GUIDELINES AND STANDARDS
     A.   Human
          As of February 1979, the U.S. Occupational  Safety
and Health Administration  has set the permissible occupa-
tional exposure limit for  lead and inorganic lead compounds
at 0.05 mg/m  of air as an 8-hour time-weighted average.
The U.S. EPA  (1979) has also established an ambient airborne
lead standard of 1.5 pg/m  .
          The U.S. EPA (1979) has derived a draft criterion
for lead of 50 jug/1 for ambient water.  This draft  criterion
is based on empirical observation of blood lead in  human
population groups consuming their normal amount of  food     ,
and water daily.
                             A

-------
     B.   Aquatic
          For lead, the draft criterion  to protect  fresh-
water aquatic life is:
               e(1.51 In  (hardness) - 3.37
as a 24-hour average, where e is the natural logarithm;
the concentration should not exceed:
               e(1.51 In  (hardness) - 1.39)
at any time  (U.S. EPA, 1979).
          For saltwater aquatic life, no draft criterion
for lead was derived.

-------
                             LEAD

                          REFERENCES
Alexander, F.W., et al. 1973.  The uptake and excretion
by children of lead and other contaminants.  Page  319  in
Proc. Int.  Symp. Environ. Health.  Aspects of Lead.   ATnster-
dam, 2-6 Oct., 1972.  Comm. Eur. Commun.  Luxembourg.

Azar, A., et al. 1973.  Review of lead studies in  animals
carried out at Haskell Laboratory - two-year feeding study
and  response to hemorrhage study.  Page 199 iji Proc. int.
Symp. Environ. Health, Aspects of Lead.  Amsterdam, 2-6
Oct., 1972.  Comm.  Eur. Commun. Luxembourg.

Barry, P.S.I. 1975.  A comparison of concentrations of lead
in human tissues.  Br.  Jour. Ind. Med. 32: 119.

Beattie, A.D., et al. 1972.  Environmental lead pollution
in an urban soft-water area. Br. Med. Jour. 2: 4901.

Beritic, T. 1971.  Lead concentration found in human blood
in association with lead colic. Arch. Environ. Health. 23:
289.

Biesinger, K.E., and G.M. Christensen.  1972.  Effect  of
various metals on survival, growth, reproduction and metabo-
lism of Daphnia magna.  Jour. Fish. Res. Board Can.  29:
1691.

Calabrese, A., et. al.  1973.  The toxicity of heavy metals
to embryos of the American oyster Crassostrea virginica.
Mar. Biol. 18: 162.

Carpenter, S.J., and V.H.. Ferm. 1977.  Embryopathic effects
of lead in the hamster.  Lab. Invest. 37: 369.

Catzione, 0., and P. Gray..1941.  Experiments on chemical
interference with the early morphogenesis of the chick.
II.  The effects of lead on the central nervous system. Jour.
Exp. Zool.  87: 71.

Chisolm, J.J. 1968.  The use of chelating agents in the
treatment of acute and chronic lead, intoxication in child-
hood.  Jour. Pediatr. 73: 1.

Chisolm, J.J., et. al. 1975.  Dose-effect and dose-response
relationships for lead in children.  Jour. Pediatr. 87:
1152.
                                                          »
Clarkson, T.W., and J.E. Kench.  1956.  Urinary excretion
of amino acids by men absorbing heavy metals. Biochem. Jour.
62:  361.

-------
Cooper, W.C. 1978.  Mortality in workers  in  lead  production
facilities and lead battery plants during  the  period  1971-
1975.  A report to International Lead  Zinc Research Organiza-
tion, Inc.

Cooper, W.C., and W.R. Gaffey. 1975.   Mortality of lead
workers. Jour. Occup. Med.  17: 100.

Cramer, K., et al. 1974.  Renal ujtrastructure renal  func-
tion and parameters of lead toxicity in workers with  dif-
ferent periods of lead exposure.  Br.  Jour.  Ind.  Med 31:.
113.

Davies, P.H., et al.  1976.  Acute and chronic toxicity
of lead to rainbow trout  (Salmo gairdneri) in  hard and soft
water.  Water Res. 10: 199.

Dingwall-Fordyce, J., and R.E. Lane. 1963.   A  follow-up
study of lead workers.  Br. Jour. Ind. Mech. 30:  313.

Dodic, S., et al. 1971.  Stanjc jetre  w pojedinih profesion-
alnih intosksikaiija In:  III Jugoslavanski  Kongres Medicine
Dela, Ljubljana, 1971.

Eisenbud, M., and M.E. Wrenn. 1970.  Radioactivity studies.
Annual Rep. NYO-30896-10. Natl. Tech.  Inf.  Serv. 1:  235.
Springfield, Va.

Eisler, R.  1977.  Acute toxicities of selected heavy metals
to the softshell clam, Mya arenaria.   Bull.  Environ.   Contain.
Toxicol.  17: 137.

Forni, A., et al.  1976.  Initial occupational exposure
to lead.  Arch. Environ. Health 31: 73.

Horiuchi, K., and I. Takada.  1954.  Studies on the indus-
trial lead poisoning.  I.  Absorption, transportation, deposi-
tion and excretion of lead.  1.  Normal limits of lead in
the blood, urine and feces among healthy Japanese urban
inhabitants.  Osaka City Med. Jour. 1: 117.

Jacquet, P., et al.  1975.  Progress report  on studies into
the  toxic action of lead in biochemistry of  the developing
brain and on cytogenetics of post-meiotic germ cells.  Eco-
nomic Community of Europe, Contract No. 080-74-7, Brussels,
Belgium.

Jacquet,  P., et al.  1977.  Cytogenetic investigations on
mice  treated with lead.  Jour. Toxicol. Environ.  Health
2:  619.

Karnofsky,  D.A.,  and L.P. Ridgway. 1952.  Production  of
 injury  to the  central  nervous system of the  chick embryo
by  lead salts.  Jour.  Pharmacol. Exp.  Therap.  104: 176.

-------
  Kehoe,  R.A.  1961.   The metabolism of lead in man in health
  and  disease.   The  Harben Lectures,  1960.   Jour.  R.  Inst.
  Publ.  Health  Hyg.   34: 1.

.  Kimmel,  C.A.,  et al.  1976.   Chronic lead  exposure:   Assess-
  ment of  developmental toxicity.   Teratology 13:  27  A (ab-
  stract) .

  Kline,  T.S.  1960.   Myocardial changes in  lead poisoning.
  AMA  Jour.  Dis.  Child. 99:  48.

  Kosmider,  S.,  and  T.  Pentelenz.  1962.  Zmiany elektro kardio-
•  grayficzne u.  starszychosol, 2.  prezwleklym zauo-dowym zatru-
  ciem olowiem.   Pol. Arch.  Med.  Wein 32:  437.

•  Lancranjan,  I., et al.  1975.  Reproductive ability of work-
  men  occupationally exposed to lead.  Arc'h.  Environ.  Health
  30:  396.

•  Lane,  R.E. 1949.  The care of the lead worker.   Br. Jour.
  Ind. Med.  6:  1243.

  Malanchuk, J.L., and  G.K.  Gruendling.  1973.   Toxicity of
  lead nitrate  to algae.  Water Air and Soil. Pollut.   2: 181.

.  McCabe,  L.J.  1970. Metal levels found in distribution sam-
  ples.   AWWA Seminar on Corrosion by Soft  Water.  Washing-
  ton, D.C.

  McClain,  R.M.,  and B.A. Becker. 1975.  Teratogenicity,
  fetal  toxicity and placental transfer of  lead nitrate in
  rats.   Toxicol. Appl. Pharmacol. 31: 72.

•  Monahan,  T.J.   1976.   Lead inhibition of  chlorophycean micro-
  algae.   Jour.  Psycol.  12:  358.

  Morgan,  B.B.,  and  J.D. Repko- 1974.  In  C. Xintaras, et
  al.  eds.  Behavioral  toxicology.  Early detection of occu-
  pational hazards.   U.S.Dep- Health Edu.  Welfare.  Washington,
  D.C.

  Nehring,  R.B.   1976.   Aquatic insects as  biological monitors
  of heavy metal pollution.   Bull. Environ. Contain. Toxicol.
  15:  147.

  Nelson,  W.C. ,  et al.  1973..  Mortality among orchard workers
  exposed  to lead arsenate spray:   a cohort study.  Jour.
  Chron.   Dis.  26: 105.

  NIOSH.   1978.   Criteria for a recommended standard.  Occupa-
  tional exposure to inorganic lead.   Revised criteria 1978.
  National Institute for Occupational Safety and  Health.
  DHEW (NIOSH)  Publication No. 78-158.

-------
Nogaki, K. 1958.  On action of lead on body of lead  refinery
workers:  Particularly conception, pregnancy and parturition
in case of females and their newborn.  Excerp.  Med. XVII.
4: 2176.

Nordman, C.N. 1975.  Environment lead exposure in Finland.
A study on selected population groups.  Ph.D. thesis.  Univer-
sity of Helsinki.

O'Riordan, M.L., and H.J. Evans.  1974.  Absence of  signifi-
cant chromosome damage in males occupationally exposed to-
lead.  Nature (Lond.) 247: 50.

Pickering, Q.H., and C. Henderson.  1966.  The acute toxicity
of some heavy metals to different species of freshwater
fishes.  Air. Water Pollut. Int. Jour. 10: 453.
                                        >.

Rabinowitz, M.B., et al. 1974.  Studies of human lead metabo-
lism by use of stable isotope tracers.  Environ. Health
Perspect. Exp. Issue 7: 145.

Rastogi, S.C., and J. Clausen.  1976.  Absorption of lead
through the skin.-  Toxicol. 6: 371.

Roe, F.J.C., et al. 1965.  Failure of testosterone or xanthop-
terin to influence the induction of renal neoplasms  by lead
in rats.  Br. Jour. Cancer 19: 860.

Sandstead, H.H., et al. 1969.  Lead intoxication and the
thyroid.  Arch. Int. Med.  123: 632.

Sauter, S., et al.  1976.  Effects of exposure to heavy
metals on selected freshwater fish.  Ecol. Res. Ser. EPA
600/3-76-105.

Schulz-Baldes, M.  1972.  Toxizitat und anreicherung von
Blei bei der Miesmuschel Mytilis edulis im Laborexperiment.
Mar. Biol.  16: 266.

Schulz-Baldes, M.  1976.  Lead uptake in two marine  phyto-
plankton organisms.  Biol. Bull.  150: 118.

Standen, A., ed.  1967.  Kirk-Othmer encyclopedia of chemi-
cal technology.  Interscience Publishers, New York.

Stowe, H.D., and R.A. Goyer. 1971.  The reproductive ability
and progeny of F, lead-toxic rats.  Fertil. Steril.  22:
755.            i

Tarzwell, C.M., and C. Henderson.  1960.  Toxicity of less
common metals to fishes.  Ind. Wastes  5: 12.
                            \n^ o _
                           ) i J<^-

-------
U.S. EPA.  1979.  Lead:  Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.

Van Esch, G.J., et al. 1962.  The induction of renal tumors
by feeding basic lead acetate to rats.  Br. Jour. Cancer
16: 289.

Wedeen, R.P., et al. 1975.  Occupational lead nephropathy,
Am. Jour. Hed.  59: 630.

Whitley, L.S.  1968.  The resistance of tubificid worms
to three common pollutants.  Hydrobiologia  32: 193.

Ziegler, E.E., et al. 1978.  Absorption and retension of
lead by infants.  Pediatr. Res.  12: 29.

Zollinger, H.U. 1953.  Durch Chronische Bleivergiftung Er-
zeugte Nierenadenome und Carcinoma bei Ratten und Ihre Bezie-
hungen zu Den Entsprechenden Neubildung des Menschen.  (Kid-
ney adenomas and carcinomas in rats caused by chronic lead
poisoning and their relationship to corresponding human
neoplasma).  Virchow Arch. Pathol. Anat.  323: 694.
                               -IT

-------
                                      No. 122
          Maleic Anhydride

  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..
                             )/li£-
                          <^ I } JJ

-------
                                                       151
                         MALEIC  ANHYDRIDE
SUMMARY



     Maleic anhydride is readily soluble in water where it



hydrolyzes to form maleic acid.   It is readily biodegraded by



microorganisms and is not expected to bioconcentrate.



     Maleic anhydride induced local tumors in rats following



repeated subcutaneous injections.   Maleic anhydride is an acute



irritant and can be an allergen in sensitive individuals.







I.   INTRODUCTION



     A.   Chemical Characteristics



     Maleic anhydride (C4H203; 2,5-furandione; CAS No.  108-31-6)



is a white, crystalline solid with an acrid odor.   The chemical



has the following physical/chemical properties (Windholz,  1976):







              Molecular Weight:    98.06



              Boiling Point:       202. O'C



              Melting Point:       52. 80°C



              Solubility:         Soluble in water and many



                                  organic solvents







     A review of the production range (includes importation)



statistics for maleic anhydride (CAS No.  108-31-6) which is



listed in the initial TSCA Inventory (1979a) has  shown thai
                         VJUJt-3

-------
between 200 million and 300 million pounds  of  this  chemical  were

produced/imported in 1977. _V

     Maleic anhydride is used as a chemical intermediate  in  the

production of unsaturated polyester resins,  fumaric  acid,

pesticides, and alkyd resins (Hawley, 1977).



II.  EXPOSURE

     A.   Environmental Fate

     Maleic anhydride is readily soluble  in water where it

hydrolyzes to form maleic acid  (Hawley, 1977;  Windholz, 1976).

Matsui e t_ al. (1975) reported that maleic anhydride  in wastewater

is easily biodegraded by activated sludge.

     B.   Bioconcentration

     Maleic anhydride is not expected to bioaccumulate  (U.S.  EPA,

1979b).

     C.   Environmental Occurrence

     The major source of maleic anhydride emissions  is associated

with release of the chemical as a byproduct of phthalic anhydride

manufacture.  Emissions can also occur during  the production  and

handling of maleic anhydride and its derivatives (U.S. EPA,

1976).
*/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 Regulations  (40
CFR 710).

-------
III. PHABMACOKINETICS



     No data were found.  Nonetheless,  it  is  expected  that any



maleic anhydride that is absorbed would be hydrolyzed  to  maleic



acid and then neutralized to a maleate  salt.  Maleate  should be



readily metabolized to COj and HjO.








IV.  HEALTH EFFECTS



     A. Carcinogenicity



     Dickens (1963) reported that local fibrosarcomas  developed



in rats after repeated subcutaneous injections of maleic



anhydride suspended in arachis oil.  Multiple injections  of



arachis oil alone or a hydrolysis product derived from maleic



anhydride (sodium maleate) did not produce any tumors  at  the



injection site.



     A long term dietary study of maleic anhydride  in  rats  for



possible carcinogenicity is now in progress.  Terminal necropsies



are schedules for January, 1980 (CUT,  1979).



     B.   Other Toxicity



     Maleic anhydride vapors and dusts  are acute irritants  of the



eyes,  skin,  and upper respiratory tract (ACGIH, 1971).  Repeated



exposures to maleic anhydride concentrations above  1.25 ppm in



air have caused asthmatic responses in workers.  Allergies  have



developed in which workers have become  sensitive to even  lower



concentrations of the compound.  An increased incidence of  bron-



chitis and dermatitis has also been noted among workers with*



long-term exposure to maleic anhydride.  One case of pulmonary



edema in a worker has been reported (U.S. EPA, 1976).

-------
V.    AQUATIC EFFECTS




     The 24 to 96-hr median threshold limit  (TLm) for maleic




anhydride in mosquito fish is 230-240 mg/1.  The 24-hr TLm  for




bluegill sunfish is 150 mg/1  (Verschueren, 1977).








VI.   EXISTING GUIDELINES




     The existing OSHA standard for maleic anydride is an 8-hour



time weighted average (TWA) of 0.25 ppm in air  (39CFR23540).

-------
                            REFERENCES
American Conference of Governmental  Industrial Hygienist (1971).
Documentation of Threshold Limit  Values  for Substances in Work-
room Air, 3rd ed. , 263.

Chemical Industry  Institute  of  Toxicology (1979).   Research
Triangle Park, N. C. , Monthly Activities  Report (Nov-Dec 1979).

Dickens, F.  (1963).  Further Studies on  the Carcinogenic and
Growth-Inhibiting  Activity of Lactones and Related Substances.
3r. J. Cancer. 17(1);100.

Hawley, G. G.  (1977).  Condensed Chemical Dictionary,  9th ed.  Van
Nostrand Reinhold  Co.

Matsui, S. _et_ _al_.  (1975).  Activated sludge degradability of
organic substances in the waste water of the Kashima  petroleum
and petro chemical industrial complex in Japan.  Prog.  Water
Technol. 2:645-659

U.S. EPA  (1976).   Assessment of Maleic Anhydride as a Potential
Air Pollution Problem Vol. XI.  PB 258 363.

U.S. EPA  (1979a).  Toxic Substances  Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals Listed on
the Non-Confidential Initial TSCA Inventory.

U.S. EPA  (1979b).  Oil and Hazardous Materials.  Technical
•Assistance Data System  (OHMTADS DATA BASE).

Verschueren,  K (1978).  Handbook  of  Environmental Data on Organic
Chemicals.   Van Nostrand Reinhold Co.

Windholz, M.  (1976).  The Merck Index, 9th Edition.   Merck and
Company,  Inc.

-------
                                      No. 123
           Malononitrlle

  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.

-------
                                  DISCLAIMER
     This  report  represents a brief  assessment of the  potential health and
environmental  hazards  from exposure  to the subject  chemical.   The informa-
tion 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  on the subject
chemical.  This document  has  undergone scrutiny to ensure  its technical ac-
curacy .

-------
                                 MALONONITRILE
                                    Summary

     Nitriles, as a group, are sources of the cyanide ion, which interferes
with basic cellular oxidative mechanisms.  Malononitrile has effects on the
cardiovascular, renal, hepatic and central nervous systems.  This compound
can take effect after inhalation, dermal contact or ingestion.  No carcino-
genic, mutagenic or teratogenic effects have been reported.
     Malononitrile has been used in the treatment of various forms of mental
illness.  A thorough documentation of the side effects of this compound
exists.  The only human toxicity data on malononitrile found in the avail-
able literature are those reported during clinical psychiatric use.

-------
                                 MALONONITRILE

 I.   INTRODUCTION
      Malononitrile (NCCH2CH),  CAS  registry number 109-77-3, is an odor-
 less, yellow crystalline chemical  with a molecular weight of 66.06 and a
 specific gravity  of 1.049.   Its melting point, is between 30°c and 31°C.
 Malononitrile is  soluble in  water, acetone, alcohol and ether, but is insol-
 uble in ethanol (Weast,  1974).  When heated to decomposition, nitriles emit
 toxic fumes  containing cyanides (Sax, 1968).
      Malononitrile is used in  the  following applications:  as a lubricating
 oil  additive,  for thiamine synthesis, for pteridine-type anti-cancer agent
 synthesis, and in the synthesis of photosensitizers, acrylic fibres,  and
 dyestuffs  (Eur. Chem. News,  1975; Lonza Inc., 1978).
      Imports of malononitrile, which currently is not manufactured in the
 United  States,  were 60,000 pounds for 1976 (NIOSH, 1978).
.II.   EXPOSURE
      A.  Water and Food
          Pertinent data were not found in the available literature.
      8.   Inhalation
          Research by Panov  (1969)  indicates that malononitrile was readily
 absorbed by  the lungs of animals.   As test chamber temperatures increased,
 the  mortality  rate also increased,  presumably due to higher  absorption.
          The major occupational exposure to nitriles occurs principally  by
 inhalation of  vapor or aerosols and by skin absorption.   The likelihood of
 such  exposure  increases during the handling,  transferring and quality con-
                                                                       »
 trol  sampling of these compounds.
                                 IJL3-5

-------
      C.   Dermal
           Panov (1969) reported that malononitrile was readily absorbed
 through the eyes of rabbits.   He also reported that mice and rabbits absorb
 the compound through the skin.  Extreme irritation resulted from both modes
 of application.
 III.  PHARMACOKINEJICS
      A.   Absorption
           Animal studies indicated that malononitrile is absorbed through
 the lungs  and by the skin (Panov,  1969).
      8.   Distribution
           Hicks (1950)  determined  that,  to  some extent,  malononitrile exerts
 tissue  specificity  (brain,  liver,  kidney, lung and thyroid)  in  its action.
           The formation of  thiocyanate  in vitro from  malononitrile and thio-
 sulfate was .highest in  the  presence of  liver tissue,  lowest  with brain, and
 intermediate with kidney  (Stem et al.,  1952).
      C-   Metabolism
           The dinitrile compounds  (such as malononitrile) presumably can ex-
 ert a greater toxic effect  than the mononitriles due  to  the  more rapid re-
 lease of cyanide from the parent compound.  Malononitrile released cyanide
j£ vivo and was ultimately excreted as thiocyanate after oxidation
 (Ghiringhelli, 1955).
          The CSN group may be converted to a carboxylic acid derivative and
ammonia, or may be  incorporated into cyanocobalamine.  Ionic cyanide also
reacts with carboxyl groups and with disulfides (McKee et al., 1962).
                                      Jt
                                   < n,ii
                                  I ) > 9*

-------
           Stern et al.  (1952)  found that in vitro respiration of brain,  kid-
 ney,  and liver slices was inhibited by  0.01 M  malononitrile.   The same in-
 vestigators  also demonstrated  the  formation of thiocyanate  from  malononi-
 trile and thiosulfate in  liver and kidney tissues in  vitro.   The release of
 cyanide  from dinitriles suggests that their mechanism of acute toxicity  may
 be similar to  that of the mononitriles.
           The  enzyme  rhodanase,. which catalyzed the formation  of thiocyanate
 from  cyanide and thiosulfate,  was  ineffective  in  the  catalysis of thiocya-
 nate  from malononitrile.  In vivo  thiocyanate  formation apparently came  from
 an intermediate  metabolite and not the malononitrile  molecule.
      D.    Excretion
           After  absorption, malononitrile may be metaboilized  to an organic
cyanide, which is  oxidized to  thiocyanate and excreted in the urine (McKee
et al, 1962).  No  evidence of  respiratory excretion was found in the avail-
able  literature.
IV.   EFFECTS
      A.    Carcinogenic!ty, Mutagenicity, Teratogenicity and Reproductive
           Effects
           Pertinent data were not  found in the available literature.
      B.    Chronic  Toxicity
           The only available human toxicity data on malononitrile are those
reported during  the clinical use of the compound in the treatment of mental
illness.
           Hyden and Hartelius  (1948) reported on the clinical use of malo-
nonitrile during psychiatric treatment.   Its intended purpose was to stimu-
late  the production of proteins and nucleic acids in the pyramidal cells, of
the frontal cortices of psychiatric patients, particularly  those who were
depressed or schizophrenic.   All patients experienced tachycardia 10 to 20

-------
 minutes after the infusion of malononitrile (1-6 mg/kg).  Facial redness,
 headache, nausea, vomiting, shivering, cold hands and feet, muscle spasms
 and numbness were also reported with varying frequency.  Similar results
 were also submitted by MacKinnon et al.  (1949),  Hartelius (1950), and Meyers
 et al.  (1950) in the treatment of mental patients.
           Hicks (1950) reported that malononitrile  poisoning induced brain
 lesions in rats.  The compound produced  demyelinating lesions of the optic
 tract and nerve, the cerebral cortex,  the olfactory bulb and the substantia
 nigra.
           Panov (1969)  found  the repeated exposure  to malononitrile (36
 mg/m5 for 2 hours per day  for 35 days) was slightly toxic to rats-   The
 exposure  caused slight anaplasia of bone.marrow,  i.e.  a  lower hemoglobin
 level and elevated reticulocyte  count.
      F.    Acute Toxicity
           Panov (1969)  subjected mice to  a single,  2-hour inhalation expo-
 sure  to malononitrile.  The mice showed signs of restlessness  and increased
 respiration  rate in the early post-treatment period  followed by Lassitude,
decreased  respiration rate, cyanosis, noncoordination of movement, tremb-
ling, convulsions and eventual death of some animals.  The exposure concen-
tration was not  noted.
          Panov  (1969) reported that liquified malononitrile applied to the
eyes of rabbits caused tearing, blepharospasm. hyperemia of the conjunctiva,
and swelling of  the eyelids.  Panov also applied malononitrile solution
(concentration not stated) to the tails of mice.   The -animals showed signs
of restlessness, rapid respiration and slight cyanosis of the extremities
                                                                        »
and the mucosa of the lips.  He also observed trembling and skin irritation
following dermal application of malononitrile to  a rabbit.

-------
          Nuclear changes in neurons and  satellite  spiral  ganglia were  seen
in rats administered single doses  (6-8 mg/kg) of malononitrile  (Van Breeman
and Hiraoka, 1961).
V.   AQUATIC TOXICITY
     Pertinent data were not found in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          Because malononitrile is about three times as toxic as  isobutyro-
nitrile, NIOSH recommends that employee exposure to malononitrile not exceed
3 ppm (8 mg/nv5) as a TWA limit for up to 10-hour workshift in a 40-hour
work week (NIOSH, 1978).
     B,   Aquatic
          Pertinent data were not found in the available literature.

-------
                                 MALONONITRILE

                                   References


Eur.  Chem.  News.  1975.   Lonza develops malononitrile  process  for wide  ap-
plication.  March 15, 1975.

Ghiringhelli,  L.  1955.   Toxicity of  adipic nitrile—Clinical  picture  and
mechanism of poisoning.  Med. Lav.  46: 221.

Hartelius, H.   1950.  Further experiences in  the use of malononitrile in  the
treatment of mental illnesses.  Am. Jour. Psychiatry.  107: 95.

Hicks,  S.P.   1950.   Brain metabolism  in vivo—II.  The  distribution of  le-
sions  caused  by azide  malononitrile,  plasmocid and  dinitrophenol poisoning
in rats.  Arch. Pathol.  50: 545.

Hyden,   H.,   and   H.   Hartelius.    1948.    Stimulation  of   the  nucleo-
protein-production in the nerve  cells  by  malononitrile  and its  effect  on
psychic  functions in mental  disorders.   Acta.   Psychiatr.  Neurol.  Suppl.
48: 1-

Lanza, Inc.  1978.  Malononitrile—Production Information.  Fairlawn, NJ.

MacKinnon, I.H., et al_  1949.  The use  of malononitrile in the treatment of
mental illness.  Am.  Jour. Psychiatry.  105: 686.

McKee, H.C., et  al.   1962.  Acetonitrile in body  fluids  related to smoking.
Public Health Rep.  77: 553.

Meyers,  0.,  et  al.   1950.  Effect of  malononitrile on  physical  and mental
status of schizophrenic patients.   Arch. Neurol. Psychiatry.  63: 586.

National Institute for  Occupational  Safety and Health.   1978.   Criteria for
a  recommended  standard...occupational  exposure  to  nitriles.    U.S.  DHEW
(NIOSH) Report No. 78-212.

Panov,  I.K.    1969.   Study  of  acute  dicyanomethane toxicity  in  animals.
Jour. Eur. Toxicol.   2:  292.

Sax, N.I.  1968.  Dangerous Properties of Industrial  Materials,  3rd ed.   Van
Nostrand Reinhold Co., New York.

Stem, J., et  al.  1952.   The effects and the  fate  of malononitrile and re-
lated compounds in animal tissues.  Biochem.  Jour.   52:  114.

Van Breeman, V.L. and J. Hiraoka.  1961(abst.)  Ultra structure  of nerve and
satellite cells  in spinal ganglia of  rats  treated with  malononitrile.   Am.
Zool.  1: 473.

Weast, R.C.  (ed.)  1974.   CRC Handbook  of  Chemistry and Physics  —  A Ready
Reference    Book   of     Chemical    and    Physical    Data,    54th    ed.
                                           -I H

-------
                                       No.  124
              Mercury

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

-------
                             MERCURY



                             SUMMARY





      Short chain alkyl mercurials represent a toxic species



that distributes widely and accumulates in the liver, kidneys



and other organs.  These compounds are eliminated from the body



at a slow rate.  In humans, mercurials have been associated with



neurological disorders, sensory impairment and tremors.  Prenatal



exposure has produced psychomotor disorders.v  Brain development



is impaired by accumulation of mercurials, and lesions in the



cerebral and cerebellar areas have been observed.



      Methylmercury crosses the placental barrier and is secreted



in milk.  Methylmercury and mercuric chloride have been shown



to produce teratogenic effects in animals.  Reproductive effects



in animals of alkyl mercury compounds involve reversible inhibi-



tion of spermatogonia and damage to unfertilized gametes.  A



high infant mortality rate has been reported in a study of mothers



exposed to high levels of mercurials.



      Mercurials have induced chromosome breakage in plant cells



and point mutations in Drosophila.  Mercurials have not been



shown to produce carcinogenic effects other than non-specific



injection site sarcomas.  The U.S. EPA (1979)  has calculated



an Acceptable Daily Intake (ADI)  for mercury of 200 pg/day.



      Mercury can be bioconcentrated many-fold in fish and other



aquatic organisms because of rapid uptake and the excretion of

-------
mercury from their tissues.  In general, the methylmercury com-
pounds are more toxic than the inorganic forms of mercury.  Toxi-
city varies widely among species.  Concentrations as low as 0.1
ug/1 have been shown to be toxic to freshwater crayfish.

-------
                             MERCURY
I.     INTRODUCTION
      This profile is based on the Ambient Water Quality Criteria
Document for Mercury  (U.S. EPA, 1979).
      Mercury  (Hg; atomic weight 200.59) is a silver-white metal,
which is a liquid at room temperature.  It has the following
physical properties:  melting point, -38.87°C; boiling point, •
356-358°C; specific gravity, 13.546; and vapor pressure at 20°C,
0.0012 mm Hg (Stecher, 1968).
      Mercury exists in three oxidation states:  elemental (0),
mercurous (+1)  , and mercuric (+2).  The solubilities of some
common mercuric salts are as follows: HgCl2 (1 g/13.5 ml water),
Hg(N03)2 (soluble in a "small amount" of water), Hg(CH3COO)2
(1 g/2.5 ml water) (Stecher, 1968).  Mercurous salts are much
less soluble in water; Hg2Cl2 is practically insoluble in water
(Stecher, 1968).
      Major usage of mercury include the following:  as a cathode
in the electrolytic preparation of chlorine and caustic soda,
in electrical apparatus, in industrial and control instruments,
in general laboratory applications, in dental amalgams, in anti-
fouling and mildew-proofing paints, and as a fungicide in treat-
ing seeds, bulbs, and plants.  However, mercury is no longer
registered by the U.S.. EPA for this last application.
      Elemental mercury can be oxidized to the mercuric form
in water in the presence of oxygen (Stock and Cucuel, 1934);
this transformation in water is facilitated by the presence of
organic substances (Jensen and Jernelov, 1972).  The mercuric

-------
ion is a substrate for biomethylation reactions; both dimethyl
and monomethyl mercury may be formed by bacteria present  in sedi-
ments (Wood, 1976 and Cotton and Wilkinson, 1966).  Considerable
bacterial demethylation of methylmercury occurs in the environ-
ment, limiting the buildup of methylmercury (Tonomura and Konzaki,
1969).  The degree of oxygenation, pH, and the presence of inor-
ganic and organic ligands are determining factors regulating
which state of mercury is present in water.  On thermodynamic
grounds, one would expect inorganic mercury to be present mainly
as mercuric compounds in well-oxygenated water and, in an increas-
ing fraction of total mercury, as the elemental form or the sul-
fide form under reducing conditions (NAS, 1978).
II.   EXPOSURE
      Mercury undergoes a global cycle of emission and deposi-
tion.  Total entry of mercury into the atmosphere is approximately
40,000 to 50,000 metric tons per year, mainly from natural sources
(NAS, 1978 and Korringa and Hagel, 1974).  Deposition from the
atmosphere into the ocean is estimated at about 11,000 tons per
year (NAS, 1978).  These waters represent a relatively large
mercury pool that maintains a stable concentration (U.S. EPA,
1979).
      Industrial release of mercury involves both organic and
inorganic forms.  These emissions are from the burning of fossil
fuels, discharges of waste from the chloralkali industries, dis-
charges of methylmercury from chemical manufacturers, and runoff
from the use of ethyl and methylmercury fungicides (U.S. EPA, •
1979) .

-------
      Based on available monitoring data, the U.S. EPA  (1979)

has estimated the uptake of mercury by adult humans  from air,

water, and food:
                       Adult - ug/day
Source
Air
Water
Food
Minimum
0.3
0.1
3.0
Maximum
0.8
0.4
5.0
                        Predominant form
                                                  elemental
                                                  mercuric
                                               methylmercury
          Total
3.4
6.2
      Fish and shellfish represent a source of high methylmercury

intake.  The U.S. EPA  (1979) has estimated average bioconcen-

tration factors of 1,700 for mercuric chloride and 6,200 for

methylmercury in the edible portions of fish and shellfish con-

sumed by Americans.  This estimate is based on bioconcentration

studies in several species, and on other factors.

III.  PHARMACOKINETICS

      A.   Absorption

           Inorganic mercury salts are absorbed poorly by the

human gastrointestinal tract; less than 15 percent absorption

was reported (Rahola, et al., 1971).  Inhalation of mercuric

oxide has been shown to produce pulmonary deposition and absorp-

tion of the compound, with 45 percent of the administered dose

cleared within 24 hours (Morrow, et al., 1964).  Dermal absorp-

tion of mercuric chloride has been reported in studies with guinea

pigs (Friberg,  et al., 1961; Skog and Vahlberg", 1964).

           Metallic mercury is not absorbed significantly from

the gastrointestinal tract.  Friberg and Nordberg  (1973)  calculate

that less than 0.01 percent of an orally administered- dose is

absorbed.  Studies with human subjects reveal approximately 80


                                X

-------
percent of inhaled mercury vapor is retained  (Hursh, et  al.,
1976}, with alveolar regions indicated as the probable site of
absorption into the bloodstream  (Berlin, et al., 1969).  Animal
studies indicate dermal absorption of metallic mercury can occur
(Juliusberg,  1901; Schamberg, et al., 1918).
           Methylraercury shows virtually complete absorption
from the gastrointestinal tract  (Aberg, et al., 1969; Miet-
tinen, 1973).  Inhalation of alkyl mercurials leads to high
retention, perhaps as high as 80 percent (Task Group on
Metal Accumulation, 1973).  Severe poisoning of humans follow-
ing topical methylmercury applications indicates some dermal
absorption of the compound (U.S. EPA, 1979).
      B.   Distribution
           Methylmercury, after absorption from the gastrointes-
tinal tract,  distributes readily to all tissues in the body (WHO
Expert Committee, 1976), with the highest concentrations being
found in the kidney cortex and red blood cells.  Approximately
five percent of an ingested dose is found in the blood compart-
ment following tissue distribution.  Human studies with  a radio-
actively labeled compound have indicated that approximately ten
percent of the body burden may be transferred to the head region
following complete tissue distribution (Aberg, et al., 1969).
The ratio of methylmercury in the brain to levels in the blood
may be as high as 10:1 (U.S.  EPA, 1979).   In muscle tissue, an-
alysis of the mercury present indicates that it is almost entirely
methylmercury, while liver and kidney contain a substantial amount
of demethylated, inorganic forms (Magos,  et al., 1976).

-------
           Determination of methylmercury  in cord  blood  and  fetal
red cells indicates that the compound  is transported  across  pla-
cental membranes  (Tejing, 1970; Suzuki, et al.,  1971).   Methyl-
mercury is secreted in mother's milk and may average  as  much
as five percent of the maternal blood  level  (Bakir, et al.,  1973).
           Mercury in the mercuric form concentrates  in  the  kid-
neys following inhalation of mercury vapor.  Animal studies  show
that up to 90 percent of an administered dose  may  localize at
this site (Rothstein and Hayes, 1964).  Experiments using  radio-
labeled mercury in human volunteers have shown approximately
seven percent accumulation of the inhaled compound in the  head
region (Hursch, et al., 1976).  Oxidation of absorbed elemental
mercury to the mercuric form takes place _iri vivo,  probably largely
through the enzymatic activities of red blood  cells (Clarkson,
et al., 1978).
           Mer.cury has been shown to be transferred into the
fetus after maternal exposure.  The rate of transfer  of  elemental
mercury appears to be greater than ionic forms of  mercury  (Clark-
son, et al., 1972).
           Animal studies with inorganic mercury salts indicate
the distribution pattern is similar to the pattern observed  after
exposure to mercury vapors (Friberg and Vostal,  1972); however,
the ratio of mercuric ion in red cells to plasma levels  is lower
(Rahola, et al., 1971)..  The major site of mercuric ion  accumula-
tion is the kidney (U.S. EPA, 1979).
      C.   Metabolism
                                                              »
           Methylmercury undergoes cleavage of the carbon mercury
bond, resulting in the production of inorganic mercury in vivo.

-------
Plasma, liver, and kidney all contain substantial  amounts  of
inorganic mercury following administration of  the  organic  form
of the compound  (Bakir, et al.,  1973).  Norseth and Clarkson
(1971) have suggested that gut microflora may  aid  in this  bio-
transformation.  Bakir, et al.  (1973) have determined  a mean
half-life value of 65 days for 16 hospital cases.  However, a
wide range of blood half-lives have been determined in human
studies (U.S. EPA, 1979).  Whole body half-life values for methyl-
mercury appear to be in the same range  (-<-52^93 days)  as blood
clearance half-lives (Miettinen, 1973).
           Elemental mercury can undergo oxidation in  the  body
to the mercuric form, which is then capable of interacting with
many tissue ligands  CClarkson, et al.,  1978).  Limited experi-
ments with subjects exposed to mercury  vapor indicate  a two com-
ponent loss of mercury from the bloodstream.  Clarkson (1978)
has estimated half-lives of 2.4 days for the fast component and
14.9 days for the slow component following a brief exposure to
mercury vapor.  Hursh,  et al. (1976) have estimated that the
whole body half-life of elemental mercury is comparable with
that of methyl mercury.
      D.   Excretion
           The excretion of methylmercury occurs predominantly
by the fecal route in humans.  Less than ten percent of excretion
occurs in the urine  (U.S. EPA, 1979).   Norseth and Clarkson (1971)
have determined significant biliary secretion of methylmercury
in animals, raising the possibility that biotransforraation to»
the inorganic form might be affected by microflora in  the gut.

-------
           Elemental mercury exposure has been shown  to  lead
to mercury excretion predominantly through the feces  and  urine
(Lovejoy, et al., 1974).  As kidney levels of mercury  increase,
a greater urinary excretion of the compound occurs  (Rothstein
and Hayes, 1964).  Urinary excretion values from 13 percent to
58 percent have been determined.  Elimination of inhaled  mercury
has been observed in expired air  (7 percent)  (Cherian, et al.,
1978)  and in sweat (Lovejoy, et al., 1974).
           Human studies with small ingested*, doses of mercuric
salts have indicated that following excretion of the  unabsorbed
compound, urinary and fecal excretion of inorganic mercury were
approximately equal (Rahola, et al., 1971).
IV.   EFFECTS
      A..   Carcinogenicity
           Intraperitoneal injection of metallic mercury  into
rats produced injection site sarcomas (Druckrey, et al.,  1957).
           Pertinent data could not be located in the available
literature indicating that mercury is carcinogenic.
      B.   Mutagenicity
           Methylmercury has been shown to block mitosis  in plant
cells and in human leukocytes treated in vivo, and human  cells
in vitro, as well as to induce chromosome breakage in plant cells
and point mutations in Drosophila (Swedish Expert Group,  1971;
Ramel, 1972).
           No evidence for the mutagenic effects of elemental
or inorganic mercury could be located in the available literature.

-------
      C.   Teratogenicity
           Oharazawa  (1968) reported increased frequency of cleft
palate in mice treated with an alkyl mercury compound.  Embryo-
toxic effects without gross teratological effects were reported
by Fujita (1969)  in mice.  Prenatal exposure to methylmercury
has produced histological evidence of brain damage in several
species (Matsumoto, et al., 1967; Nonaka, 1969; Morikawa, 1961).
Spyker and Smithburg  (1972) and Olson and Massaro (1977) have
also reported anatomical malformations in animals exposed pre-
natally to methylmercury.
           Teratological effects of mercuric chloride have been
reported in animals (Gale and Perm, 1971).  However, data are
not available on the  teratogenicity of inorganic mercury in human
populations.
          • Exposure of rats prenatally to mercury vapor produced
fetal toxicity without evidence of teratological effects (Baranski
and Szymczyk, 1973).
      D.   Other Reproductive Effects
           A high mortality rate in infants born to women suffer-
ing mercury poisoning has been reported  (Baranski and Szymczyk,
1973) .
           Methylmercury has been reported to interfere with
reproductive capability in adult animals treated with this com-
pound (Ramel, 1972; Suter, 1975).  Khera (1973) has observed
that administration of alkyl mercury compounds to rats may damage
gametes prior to fertilization.  Reversible inhibition of spesma-
togonial cells in mice treated with mercuric chloride has been
reported (Lee and Dixon, 1975).

-------
      E.   Chronic Toxicity



           Chronic exposure to methylmercury has produced several



outbreaks of poisoning, characterized by neurological symptoms



following central nervous system damage (Nordberg, 1976; NAS,



1978).   Adult exposure to methylmercury has produced symptoms



of paresthesia of the extremities, impaired peripheral vision,



slurred speech, and unsteadiness of gait and of limbs (U.S.  EPA,



1979).   Neuropathological investigation showed cerebellar atrophy



and focal atrophy of the calcarine cortex (Hunter and Russell,



1954) .



           Prenatal exposure to methylmercury produced psycho-



motor brain abnormalities (Engleson and Herner, 1952; Harada,



1968) .   Brain development was shown to be disturbed, and both



cerebral and cerebellar lesions were observed (U.S. EPA, 1979).



An epidemiological study on school children in the Minamata  Bay



area has reported a higher incidence of neurological deficits,



learning difficulties, neurological symptoms, and poor performance



on intelligence tests for these residents of a high methylmercury



exposure region (Med.  Tribune, 1978).



           An ethylmercury poisoning outbreak indicated renal



and cardiac damage following this exposure (Jalili and Abbasi,



1961).



           Mercury vapor poisoning may produce signs of mental .



disturbances, tremors, and gingivitis (U.S.  EPA,  1979).   Exposure



to extremely high concentrations can damage lung  tissue causing



acute mercurial pneumonitis.  Kidney dysfunction  (proteinuria)
                                                             »


in workers exposed to mercury vapor has also been reported  (Kazantzis,



et al., 1962; Joselow and Goldwater, 1967).
                             ^ . >i / 4 -
                            **) } v -> *

                            /a/-/3

-------
V..    AQUATIC TOXICITY
      A.   Acute Toxicity
           Observed LC^Q values for three  flow-through  and  two
static-renewal assays for mercuric chloride with  the  rainbow
trout as the test species ranged from 155  to 903  ug/1.   The re-
sults of two flow-through and three static-renewal  assays on
rainbow and brook trout provide an LC50 range  for methylmercuric
compounds from 24 to 84 ug/1, with the rainbow trout  being  from
three to five times as sensitive as the brook  trout.  For five
other mercury compounds, LC5Q values ranged from  5.1  for phenyl-
mercuric acetate to 39,910 ug/1 for merthiolate.  Ethyl- and
phenylmercury compounds generally were more toxic while merthio-
late and pyridylmercuric acetate were less toxic.   A  total  of
14 freshwater invertebrate species have been tested in  static
and static-renewal bioassays for acute toxicity to  mercuric chloride
and mercuric nitrate.  LCCQ values ranged  from 0.02 to  2,100
ug/1 (U.S. EPA, 1979).  Heit and Pingerman (1977) and Beisinger
and Christensen (1972) reported the more sensitive  species  to
be the crayfish Faxonella clypeata and the daphnid, Daphnia magna,
respectively.  Warnick and Bell (1969) reported that  the mayfly
(Ephemerella subvaria), the stonefly  (Acroneuria  lycorius),  and
the caddisfly (Hydropsyche betteni) were among the  most resistant
freshwater invertebrates to mercuric chloride.  Two static  tests
have produced 96-hour LC5Q values of 800 and 2,000  ug/1 for  mer-
curic chloride to the marine fish, the mummichog  (Fundulus  heter-
clitus).  Among marine invertebrates exposed to mercuric chloride,
LCgg values ranged from 3.6 to 32,000 pg/1 for 21 species.   Embryo
                                itf

-------
stages of the oyster (Crassostrea virginica),  the hard-shell
clam (Mercenaria mercenaria),  and the mysid shrimp (Mysidopsis
bahia),  the latter in the only acute flow-through test reported,
were the more sensitive species reported.  Lockwood and Inman
(1975)  provide the only acute  study for methylmercuric chloride
with a adjusted 96-hour LC5Q value of 150 ug/1.
      B.   Chronic Toxicity
           McKim, et al. (1976)  offered the single source reported
for chronic effects to freshwater fish.  Examining the long-term
effects of methylmercury chloride on three generations of the
brook trout (Salvelinus fontinalis), adverse effects  were reported
at 0.93 ug/1,.but not at 0.29  pg/1.   Brook trout were from three
to four times more resistant than rainbow trout (Salmo gairderi).
Sosnowski, et al. (1979) have  examined the effects of mercuric
chloride by a flow-through, life-cycle bioassay on the mysid
shrimp,  Mysidppsis bahia.  The highest concentration  producing
no-observed-effect was 0.82 ug/1.
      C.   Plant Effects
           A number of different parameters have been used to
determine the toxic effects of mercury compounds on freshwater
plants.   Effective concentrations .of mercuric  chloride ranged
from 60 to 2,590 pg/1.  Blinn, et al.  (1977)  demonstrated altered
photosynthetic activity in a summer assemblage of algal species
at 60 pg/1.  Two of these studies on the effects of methylmercury
chloride to freshwater algae revealed enzyme inhibition at 1,598
pg/1 in Anklstrodesmus braunii' and 50 percent  growth  inhibition
to Coelastrum microporum at concentrations of  2.4 to  4.8 pg/1.
For other organomercury compounds, effective concentrations ranged

                                if
                             ^tii tS-
                            ^^^^^^^^^
                            /ay-AT

-------
 from  less  than  0.6  to  200.6  ug/1.   Using 18  marine species,  Ber-


 land, et al.  (1976) measured growth inhibition at mercuric chloride

 concentrations  from 5  to  15  pg/1 and lethalities from 10 to 50

 ug/1.  Effective  concentrations  for the alga Isochrysis galbana

 ranged up  to  2,000,000 jig/1, at  which no growth was observed

 (Davies, 1976).   For other organomercury compounds, effective

 concentrations  ranged  from 0.1  to less than  2,000 ug/1.  Harriss,

 et  al.  (1970) reported reduced  photosynthetic activity to methyl-

 mercury hexachlorophthalimine in the diatom,. Nitzchia delictissima,
       .                              ,   *
 at  the level  of 0.1 ug/1.  Methylmercury chloride was reported

 by  Overnell  (1975)  to  reduce photosynthetic  activity at concen-

 trations of less  than  2,000  ug/1.

      D.   Residues

           Bioconcentratlon  data for freshwater species for  various

 mercury compounds can  be  summarized by the following.bioconcen-

 tration factors':   33,800  for the algae Synedra ulna (Fujita  and

 Hashizuma, 1972)  exposed  to  mercuric chloride; 4,532 to 8,049

 for juvenile  rainbow trout exposed to methylmercury chloride

 (Reinert,  et  al.,  1974);  12,000  to 20,000 for brook trout exposed

 to  methylmercury  chloride  (McKin,  et al., 1976); and 62,898  for

 the fathead minnow exposed to methylmercury  chloride (Olson,

 et  al., 1975).  It should be noted that for  the high bioconcen-

 tration value for the  fathead minnow, the fish were allowed  to .

 forage on  aquatic organisms  growing within the mercury enriched

 exposure chambers;  therefore, this measurement may more closely

 reflect actual  field data.   The  trout were fed a pelleted diet.

 A variety  of  marine organisms have been used to demonstrate  the

'rapid accumulation of  inorganic  and organic  mercury compounds.

-------
Bioconcentration values for marine algae ranged from 853 to 7,400,

with exposure periods of two to eight days for mercuric chloride.

A 30-day bioconcentration factor of 129 for the lobster, Homarus

americanus, has been reported by Thurberg, et al.  (1977), and

a range of 2,800 to 10,000 reported for adult oysters, Crassostrea

virginica, (both species for mercuric chloride).  Kopfler  (1974)

reports a biomagnification value of 40,000 for the oyster C.

virginica to methylmercury and phenyl-mercury chloride.  The

biological half-lives of rapidly accumulated., mercuric compounds

indicate that clearance is not rapid even after several months.

VI.   EXISTING GUIDELINES

      A.   Human

           The U.S. EPA has recommended a drinking water standard

of 2 ug Hg/1 to protect human health (U.S. EPA, 1973).

           Calculation of an acceptable daily intake (ADI) of

mercury by the U.S. EPA (1979)  has produced a tentative criterion

of 0.2 pg/1 (with an uncertainty factor applied) for ambient

water.

      B.   Aquatic

           The criteria for mercury are divided into tentative

recommendations for inorganic and organic mercury.  Freshwater

criteria have been drafted as follows:  for inorganic mercury,

the draft criterion is 0.064 pg/1 for a 24-hour average exposure,

not to exceed 3.2 pg/1 at any time.  For methylmercury, the draft

criterion is 0.016 pg/1 for a 24-hour average, not to exceed
                                                             •
8.8 pg/1 at any time.  To protect marine life from inorganic

mercury, the draft criterion is 0.19 pg/1 for a 24-hour average,

not to exceed 1.0 pg/1 at any time.  For methylmercury, the tenta-

-------
tive criterion is 0.025 ug/1 as a 24-hour average not  to  exceed



2.6 pg/1 at any time (U.S. EPA, 1979).



           The above criteria have not yet gone through the  pro-



cess of public review;  therefore, there is a possibility  that '



the criteria may be changed.

-------
                           MERCURY

                          REFERENCES

Aberg, B., Qt al. 1969. Metabolism of methyl mercury  (Hg-
203) compounds in man.  Arch. Environ. Health 19: 478.

Bakir, F., et al. 1973.  Methyl mercury poisoning in  Iraq.
Science 181: 234.

Baranski, B., and I. Szymczyk.  1973,  Effects of mercury
vapor upon reproductive functions of female white rat.
Medycyna. Pracy.  24: 248.

Beisinger, K.E., and G.M. Christensen.  1972.  Effects of
various metals on survival, growth, reproduction, and metabo-
lism of Daphnia magna.  Jour. Fish. Rev. Board Can. 29:
1691.

Berland, 3.R., et al.  1976.  Action toxique de quarte metaux
lourds sur la croissance d'algues unicellulaires marines.
C.R. Acad. Sci. Paris, t. 282, Ser. D: 633.

Berlin, M.H. , et al.  1969..  On the site and mechanism of
mercury vapor resorption in the lung.  Arch. Environ. Health
18: 42.

Blinn, D.W., et al.  1977.  Mercury inhibition on primary
productivity using large volume plastic chambers _in situ.
Jour. Phycol.  13: 58.

Cherian, M.G., et al. 1978.  Radioactive mercury distribu-
tion in biological fluids and excretion in human subjects
after inhalation of mercury vapor.  Arch. Environ. Health
33: 109.

Clarkson, T.W.  1978.  Unpublished data.  Environ. Health
Sci. Center.  University of Rochester.

Clarkson, T.W., et al. 1972.  The transport of elemental
mercury into fetal tissues.  Biol. Neonate.  (Basel) 21:
239.

Clarkson, T.W., et al. 1978.  The metabolism of inhaled
mercury vapor in animals and man.  Jour. Am. Chem. Soc.
(In press.)

Cotton, F.A., and G. Wilkinson.  1966.  Advanced inorganic
chemistry—a comprehensive text.  Wiley-Interscience, N.Y.

Davies, A.G.  1976.  An assessment of the basis of mercury
tolerance in Dunaliella tertiolecta.  Jour. Mar. Biol.
Assn. U.K. 56": J9.

-------
Druckrey, H./ et al. 1957.  Carcinogenic action of metallic
mercury after intraperitoneal administration  in rats.   Z.
Krebsforsch.  61: 511.

Engleson, G., and T. Herner.  1952.  Alkyl mercury poison-
ing.  Acta. Pediat. Scan. 41: 289.

Friberg, L.', and F. Nordberg.  1973.  Inorganic mercury-
A toxicological and epidemiological appraisal.  Pages  5-
19 _in M.W. Miller, and T.W. Clarkson, eds.  Mercury, mercu-
rials and mercaptans* Charles C. Thomas, Springfield,  111.

Friberg, L., and J. Vostal, eds.  1972.  Mercury  in  the
environment. Chemical Rubber Co., Cleveland,  Ohio.

Friberg, L., et al. 1961.  Resorption of mercuric chloride
and methyl mercury dicyand.iamide in guinea-pigs through
normal skin and through skin pre-tested with  acetone,  alkyl-
arylsulphonate and soap.  Acta. Derm. Venerol.  41:  40.

Fujita, E.  1969.  Experimental studies on organic mercury
poisoning:  the behavior of Minamata disease  causal  agent
in maternal bodies and its transfer to their  infants via
either placenta or breast milk.  Jour.  Kumamoro Med.  Soc.
43:  47.

Fujita, M., and K. Hashizuma.  1972.  The accumulation of
mercury by freshwater planktonic diatom.  Chemosohere  5:
203.

Gale, T., and V. Ferm. 1971. Embryopathic effects of mer-
curic salts.  Life Sci. 10: 1341,"

Harada, 7..C. 1968.  Clinical investigations on Minamata
disease. C. Congenital (or fetal) Minamata disease.  Page
93. i£ M. Kutsuna, ed. Minamata disease. Study group of
Minamata disease. Kumomoto University, Japan.

Harriss, R.C., et al.  1970.  Mercury compounds reduce photo-
synthesis by plankton.  Science  170: 736.

Heit, M., and M. Fingerman.  1977.  The influence of size,
sex and temperature on the toxicity of mercury to two  species
of crayfishes.  Bull. Environ. Contain. Toxicol.  13: 572.

Hunter, D., and D.S. Russell. 1954. Focal cerebral and cere-
bellar atrophy in a human subject due to organic mercury
compounds. Jour. Neurol. Neurosurg. Psychiatry  17:  253.

Hursh, J.3., et al.  1976.  Clearance of mercury  (197Hg,
203rtg) vapor inhaled by human subjects.  Arch. Environ.
Health  4: 302.
                              16

-------
Jalili, M.A., and A.H. Abbasi.  1961.  Poisoning  by  ethyl
mercury toluene sulphonanilide.  Br. Jour.  Ind. Med.   18:
303.

Jensen, S., and A. Jernelov.  1972.  Behavior of  mercury
in the environment. Page 43.  iri Mercury contamination  in
man and his environment. Vienna Int. Atomic Energy Agency.
Tech. Rep. Ser. 137.

Joselow, M.M., and L.J. Goldwater.  1967.   Absorption  and
excretion of mercury"  in man.  XII.  Relationship  between
urinary mercury and proteinuria.  Arch. Environ.  Health
15: 155.

Juliusberg, F.  1901.  Experimentelle untersuchungem uber
quicksilber-resorption bei der schmierkur.  Arch. Derm.
Syph.  56: 5.

Kazantzis, G., et al.  1962.  Albuminuria and the nephrotic
syndrome following exposure to mercury and  its compound.
Q. Jour. Med. 31: 403.

Khera, K.S. 1973. Reproductive capability of male rats and
mice treated with methyl mercury.  Toxicol. Appl. Pharmacol.
24: 167.

Kopfler, F.C.  1974.  The accumulation of organic and  inor-
ganic mercury compounds by the eastern oyster  (Crassgstrea
virginica) .  Bull. Environ. Contain. Toxicol.  111 275.

Korringa, P., and P.  Hagel.   1974.  Ln.  Proc.  International
symposium on problems of contamination of man and his  environ-
ment by mercury and cadmium.  Comm. Eur.  Commun., Luxembourg
July 3-5, 1973.

Lee, I.D., and R.L. Dixon.  1975.  Effects  of mercury  on
spermatogenesis studied by velocity sedimentation, cell
separation and serial mating. Jour. Pharmacol Exp. Ther.
194: 171.

Lockwood, A.P.M., and C.B.E.  Inman.  1975.  Diuresis in
the amphipod, Gammarus duebeni induced by methylmercury,
D.D.T., lindane and fenithcothien.  Comp. Biochem. Physiol.
52C: 75.

Lovejoy, H.B. , et al.  1974.  Mercury expos.ure evaluations
and their correlation with urine mercury excretion.  Jour.
Occup. Med.  15: 590.

Magos, L., et al. 1976. Tissue levels of mercury  in  autopsy
specimens of liver and kidney. Page 93. in  WHO Conf.  on   '
intoxication due to alkyl mercury treatea~seed.   Baghdad
Nov. 9-13, 1974. Geneva, WHO  11  (Suppl. to  Bull.  WHO 53).
                            - i(Ml -
                            I }  /I1'1*

-------
Matsumoto, H., et al. 1967.  Preventative effect of penicil-
lamine on the brain defect of fetal rat poisoned transpla-
centally with methyl mercury.  Life Sci.  6:  2221.

McKim, J.M., et al.  1976.  Long-term effects of merthylmer-
curic chloride on three generations of brook trout  (Salv-e-
linus fontinalis):  Toxicity, accumulation, distribution,
and elimination.  Jour. Fish. Res. Board Can.  33:  2726.

Medical Tribune. 1978. Methyl mercury affects Japanese school-
children.  13 September, 1978.

Miettinen, J.K. 1973.  Absorption and elimination of dietary
(Hg "*") and methyl mercury in man.  Page 233. in  M.W.  Miller,
and T.W., Clarkson, eds. Mercury, mercurials and mercaptans.
Charles C. Thomas, Springfield, 111.

Morikawa, N. 1961.'  Pathological studies in organic mercury
poisoning.  Kumamota Med. Jour.  14:  71.

Morrow, P.2., et al. 1964.  Clearance of insoluble dust
from the lower respiratory tract.  Health Phys. 10: 543.

NAS.  1978. An assessment of mercury in the environment.
Panel on Mercury. Washington, D.C.

Nonaka, I. 1969. An electron microscopic study of the experi-
mental congenital Minamata Disease in rat.  Kumamoto Med.
Jour.  22:  27.

Nordberg, G.F., ed. 1976.  Effects and dose-response of
toxic metals.  Elsevier-Amsterdam.

Norseth, T. and T.W. Clarkson.  1971. Intestinal transport
of    Hg-labelled methyl mercury chloride; role of biotrans-
formation in rats.  Arch. Environ. Health 22: 258.

Oharazawa.  1968.  Chromosomal abnormalities and teratogenesis
induced by ethyl mercuric phosphate in pregnant mice.  Nippon
Sanka-Fujinka Gakka:  Zasshi  20: 1479.

Olson, F.C., and E.J. Massaro.  1977.  Pharmacodynamics
of methyl mercury in the marine maternal/embryo fetal unit.
Toxicol. Appl. Pharmacol.  39:  263.

Olson, G.F., et al.  1975.  Mercury residue's in fathead
minnows, Pimephales promelas Rafinesque, chronically exposed
to merthyimercury in water.  Bull. Environ. Contain.  Toxicol.
14: 129.
                                                            •
Overnell, J.  1975.  The effect of heavy metals on photo-
synthesis and loss of cell potassium in two species of marine
algae, Dunaliella tertiolecta and Phaeodactvlum tricornutum.
Mar .  BToTT"29 : 957

-------
Rahola, T., et-al- 1971.  The biological half-time of inorgan-
ic mercury (Hg  )  in man.  Scand. Jour. Clin. Invest. Abst.
27: 77 (Suppl. 116).

Ramel, C. 1972.  Genetic effects. Page 9 jji  L. Friberg,
and J. Vostal, eds.   Mercury in the environment -a toxico-
logical and epidemiological appraisal.  Chemical Rubber
Co.,  Cleveland.

Reinert,  R.E. et al.;  1974.  Effect of temperature on accu-
mulation of methylmercuric chloride and p,p'DDT by rainbow
trout  (Salmo gairdneri).  Jour. 'Fish. Res. Board Can.  31:
649.

Rothstein, A., and A.D.  Hayes.  1964.  The turnover of mer-
cury in rats exposed repeatedly to inhalation of vapor.
Health Phys.  10: 1099.

Schamberg, J., et al. 1918.  Experimental studies of the
mode of absorption of mercury when applied by inunction.
Jour. Am. Med. Assoc. 70: 142.

Skog, E.  and J.E. Wahlberg.  1964.  A comparative investi-
gation of the percutaneous absorption of metal compounds,
in the,guinearpig by,means of,the radioactive isotopes   Cr,
5SCo, 63Zn, llSAq, ll3mCd, 2()3Hg.  Jour. Invest. Derm. 43:
187.

Sosnowski, S.L., et al.   1979.  The effects of chronic mer-
cury exposure on the mysid shrimp.  Mysidopsis bahia Abst.
N.E.  Fish & Wildlife Conf.  April 1-4.  Providence R.I.

Spyker, J.M., and M.  Smithberg.  1972.  Effects of methyl
mercury on prenatal development in mice.  Teratology  5: 181.

Stecher,  P.  ed.  1968.  The Merck Index, 8th. ed., Merck
and Co.,  Rahway, N.J.

Stock, A., and F. Cucuel.  1934.  Die Verbreitung des Quick-
silbers.   Naturwissenschaften  22: 390.

Suter, K.E.  1975.  Studies on the dominant lethal and fertil-
ity effects of the heavy metal compounds methyl mercuric
hydroxide, mercuric chloride, and cadmium chloride in male
and female mice.  Mutat. Res.  30:  365.

Suzuki, T., et al. 1971.  Comparison of mercury contents
in maternal blood, umbilical cord blood and placental tissue.
Bull. Environ. Contam. Toxicol. 5.

Swedish Expert Group.   1971.  Methyl mercury in fish - toxi-
cological-epidemiological evaluation of risks.  Report from
an expert group.  Nordisk. Hyg. Tidsknift. Suppl. 4.

-------
Task Group on Metal Accumulation.  1973.  Accumulation of
toxic metals, excretion and biological half-times.  Environ.
Phys. Biochem.  3: 65.

Tejning, S. 1970. Mercury contents in blood corpuscles and
in blood plasma in non-fisheaters. Dep. Occup. Med., Univer-
sity Hospital, Lund. Rep. No. 700406.

Thurberg, F.P., et al.  1977.  Response of the lobster,
Homarus americanus,- to sublethal levels of cadmium and mer-
cury.  InPhysiological Responses of Marine Biota to Pollut-
ants.  Academic Press, New York.

Tonomura, K., and F. Kanzani.  1969.  The reductive decom-
position of organic mercurials by cell-free extracts of
a mercury-resistant Pseudomonas.  Biochem. Biophys. Acta.
184: 227.         '

U.S. EPA.  1973.  Water, quality criteria, 1972.  Ecol. Res.
Ser. Rep. Comm. of Water Quality Criteria.  Natl. Acad.
Sci.  EPA/R3/73/033.  U.S. Government Printing Office.
Washington, D.C.

U.S. EPA.  1979.  Mercury:  Ambient Water Quality Criteria
(Draft).

Warnick, S.L., and ELL. Bell.  1969.  The acute toxicity
of some heavy metals to different species of aquatic insects.
Jour. Water Pollut.  Control Fed.  41: 280.

Wood, J.M.  1976.  Les mataux toxiques dans I1environment.
La Recherche 7: 711.

World Health Organization.  1976.  Environmental health
criteria,  Mercury.  Geneva.

-------
                                      No.  125
              Me thorny 1

  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.
                               i If "T Ctr
                            •* /"J1 ) O

-------
                         Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

-------
                                    METHOMYL
                                    Summary
     Methomyl  is  a  toxic  carbamate  insecticide  used on  field  crops and
 fruit.   It  is  readily absorbed through inhalation  or dermal exposure ana  is
 almost  completely eliminated  from  the body  within 24 hours.   Chronic tox-
 icity studies  in rats  and  dogs show  that no  effects occur below  100 ppm.
 The  threshold  limit  value  for methomyl in  air is 2.5 fig/m^.   Methomyl in-
 hibits the  activity  of cholinesterase  in the boay.   Studies have shown that
 methomyl is  not  carcinogenic  in rats and dogs  or mutagenic  in the Ames oio-
 assay.  However,  a different type of bioassay showed  mutagenic activity at a
 methomyl concentration  of 50  ppm.   A potential  product  of the  reaction  of
methomyl with certain nitrogen compounds  in the  environment or in mammalian
 systems is nitrosomethomyl,  which is a potent mutagen, carcinogen,  ana tera-
togen.
     Methomyl is  toxic to many  aquatic organisms  with 96-hour  LC5Q  levels
 ranging from 0.1 to 3.4 ppm.

-------
                                   METHOMYL
 I.    INTRODUCTION
      Methomyl  is a broad-spectrum insecticide used on many vegetables, field
crops, certain fruit  crops,  and ornamentals  (3erg, et al. 1977).  Introduced
by  DuPont  in   1966  as  an  experimental  insecticide-nematacide  (Martin  and
Worthing  1974),  methomyl -is now  manufactured by  DuPont  and  Shell (Stanford
Research  Institute 197A)  and used commercially as a foliar treatment to con-
trol  aphids, army  worms,  cabbage looper, tobacco_budworm,  tomato fruitworm,
cotton  leaf perforator,  and  ballworm  (Martin and  Worthing  1974).   About
three million  pounds  (1360 "tonnes) of  methomyl were produced" in'the united
States in 1974 under the  trade name Lannate® (Pest  Control,  1975).   Wastes
                                           *
associated with methomyl  production  may contain  methylene  chloride.   Metho-
myl  formulations  may contain  pyridine  as  a  contaminant  (Sittig,  1977).
Methomyl  is  highly soluble  in  water.   Its  bioconcentration  factor  is  1.0;
octanol/water coefficient, 2.0 (see Table 1).
II.  EXPOSURE
     A.   Water
          Methomyl is considered  stable in  ground water  ana  decomposes at  a
rate of less than  10 percent in  5 days in  a river environment.  In  a  lake
environment, methomyl decomposes  at  a rate  of  less than  85 percent  per  year
(U.S. EPA 1980).
     B.   Food
          After the application of methomyl  from 0.25 to 0.50  kilograms  per
hectare (kg/ha) on tomatoes, plant residues  were  below 0.2  ppm..  Application
of 1 kg/ha left residues of  0.3,  0.13,  and 0.06 ppm at 1, 2,  and 3 days,  re-
spectively, after  spraying  (Love and Steven,  1974).  Methomyl applied at  a
rate of 3 oz/acre (0.2 kg/ha) left a  17 ppm residue on rape  plants immediate-

-------
            TABLE 1.  PHYSICAL AND CHEMICAL PROPERTIES OF METHOMYL
    Synonyms:  S-methyl N-(methylcarbamoyl)oxy)thioac3tamidate;
           l-(methylthio)ethylideneamino methylcarbamate;
           l-(methylthio)acetaldehyde 0-methylcarbamoyloxime;
           methyl N-(((methylamino)carbonyl)oxy)ethanimidothioate;
           CAS Registry No. (16752-77-5); OuPont 1179; Lannate;
           Mesomile; Nudrin
    Chemical Formula:  (CH3S)(CH3)C=N-0(C=0)NHCH3

    Molecular Weight:  162.2

    Description:  White crystal solid
             Slight sulfurous odor
             Soluble in organic solvents

                                   24
    Specific Gravity and/or DensityJ  d   = 1.2946

    Melting and/or Boiling Points:  nip 78 to 79QC  -

    Stability: Stable in aqueous solution .
               Subject to decomposition in moist soil
               Overall degradation rate constant (0.01/day)

               Half-life approximately 50 days

Solubility (water):  5.3 g/ioo'ml at 25Qc

                   sediment .  .5
                     H20    '   1
    Vapor Pressure:  5 x 10-5 mm Hg at 25°C

    Bioconcentration Factor (BCF) and/or
    Octanol/water partition coefficient (Kow):   KQW =2.0
                                            BCF = 1.0
    Source:   Martin and worthing,  1974;  Fairchild,  1977;
    Windholz,  1976, U.S. EPA,  1980.
                                      X

                                   - >U.^^
                                  S*) I u u

-------
 ly  after application.   This concentration declined rapidly to 1.5, 1.0, 0.4,
 and 0.2  ppm,  1,  2,  5,  and 9  days later,  respectively.   Methomyl resioues
 were  not detected  (less than  0.02  ppm)  in  seed harvested  22  days  after
 application.   Rape  plant leaves collected after  the  application of methomyl
 at  3  to 4 oz/acre  (0.2-0.3  kg/ha)  had 2.5  to  16 ppm residues  (Lee,  et al.
 1972).
          Methomyl  has  a half-life in plants of  3 to 7 days.   Harvey (1975)
 detected  methomyl  residue,   its  oxime, and  small polar fractions  one  month
 after  application.   Methomyl residue  standards for  crops  are noted in the
 Existing  Guidelines and Standards Section of this report.
     C.   Inhalation and Dermal
          Data are  not  available indicating  the number  of  people  exposed  to
methomyl  by  inhalation  or dermal contact.  Most  human exposure  would appear
to  occur during  production and  application.  The  U.S. EPA  (1976)  listed the
 frequency of illness among  occupational  groups  exposed to pesticides.   In
1157  reported  cases,  most illnesses occurred among ground  applicators  (229)
and mixer/  loaders  (142).  The  lack  of or  refusal to  use safety  equipment
was a  major factor of  this  contamination,   other groups affected  were  gar-
deners  (101), field workers  exposed to pesticide  residues  (117), nursery and
greenhouse  workers   (75),  soil  fumigators  in  agriculture  (29),   equipment
cleaners  and mechanics  (28), tractor  drivers  and  irrigators  (23),  workers
exposed  to  pesticide drift  (22),  pilots (crop dusters) (17), and  flaggers
for aerial application  (6).  Most illnesses  resulted  from 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 condi-
tions  also  tended  generally  to increase  pesticide levels and  dust on the
                                                                         »
workers.

-------
 III.  PHARMACOKINETICS
      A.   Absorption and Distribution
          Methomyl  is  a highly water-soluble carbamate insecticide which can
 be absorbed  readily by moist mucous membranes or through the skin  (Guerzoni,
 et al.  1976).   Methomyl applied to  the  skin is less toxic than methomyl ao-
 ministered  orally  (Kaplan" and Sherman,  1977).   Kaplan  and  Sherman  (1977)
 noted that  there was  no  buildup  of methomyl in  fish after a 30-day  feeding
 study,  indicating that methomyl was not distributed or  retained  in any one
 specific  organ  of the body.   In another study, there was ho cumulative oral
 toxicity  in  rats  (Harvey,  et al.  1975).   The  investigators measured a total
 clearance rate  of  less than 24 hours after  oral administration of methomyl
                                            %
 to rats.
      B.   Metabolism
          Harvey,   et   al.   (1973)  administered  l4C-labeled  methomyl  to
 rats.   The  radioactive methomyl  was eliminated  in  the  form of  carbon ai-?
 oxide,  acetonitrile,   and  urinary  metabolites.   They  noted the  absence  of
 methomyl, S-methyl  N-hydroxythioacetimioate,  methyl  S,S-aioxide,.  and conju-
 gates  of the  former   two  compounds.   Radiolabeled methomyl  administereo  in
 the rat by Huhtanen and Oorough (1976) also was metabolized to carbon dioxide
 and  acetonitrile.  Carbon dioxide  was  also   found  in  soils treated  with
methomyl  (Heywood 1975), without the presence  of sulfoxide  or sulfone (Baron
 1978).
          Han  (1975)   investigated  the   formation of  nitrosomechomyl  from
cured meats  containing methomyl  and  residual  sodium  nitrite.  The  samples
were  incubated  under  simulated   stomach  conditions  (pH^)  for  1  and   3
hours.   Nitrosomethyl  was  not founo  in  the  test  material;  the  detection
limit was less than 1 ppb.

-------
      C.    Excretion
           Methomyl   is   eliminated  primarily  through  the  urinary  system
 (Harvey, et al. 1975).
 IV.   EFFECTS
      A.    Carcinogenicity
           No  evidence of methomyl carcinogenicity  was observed in tests with
 rats  and dogs  (Kaplan and Sherman,  1977).   LLjinsky  and Schmaehl (1978) con-
 cluded that if nitrosomethyl  carbamates  (nitrosomethomyl)  were formed by the
 reaction of  the parent  insecticide  (methomyl)  with nitrite in  the environ-
 ment  or  in the stomach,  the  carcinogenic risk of the parent  compound could
 increase.
           In  pesticide  workers,  two cases  of embryonal cell  carcinoma have
 been  associated  with  exposure,  to  methomyl  and-  three  other  pesticides
 (carbaryl, paration,  and dimethoate).   One  of the pesticide  workers under-
 went  surgery for a testicular mass; the  second  worker died of  metastatic em-
 bryonal cell  carcinoma.   These  cases led the authors  to  suggest that testi-
 cular cancer may be  related to  agricultural  chemical  exposure  (Prabhakar and
 Fraumeni, 1978).
      B.   Mutagenicity
          Blevins, et  al. (1977)  screened  methomyl  and its nitroso  deriva-
 tive  for mutagenic  activity.   Using histidine  auxotrophs  of  S^_ typhimurium
 derived by  Ames,  they  noted  that methomyl,  unlike  its nitroso  derivative,
 did not cause  a significant increase  in  the number of  revertant  colonies  in
 any of the strains used.  Thus,  while nitrosomethomyl appeared to oe  a po-
 tent mutagen,  they considered methomyl to be non-mutagenic.
          Guerzoni,  et  al.  (1976) tested methomyl for mutagenic  activity  on
Saccharomyces  cerevisiae.  Methomyl was  considered  mutagenic at  50 ppm.  The

-------
 authors  noted,  however,  that  the  mutagenic  effect  depended  on  the  S^
 cerevisiae  strain.
      C.   Teratogenicity and Other Reproductive  Effects
          Methomyl  was fed to pregnant  New Zealand White  raobits on days  3
 to  16 of gestation.  Teratogenic effects were not found at any  of three  die-
 tary  levels,  0,  50,  and  100  ppm  (Kaplan  and Sherman,  1977).   The  same
 authors  also  reported on  a  3-generation,  6-litter  reproduction study  with
 rats  with the  same  dietary levels.   Methomyl did not have adverse  effects  on
 reproduction and lactation  performance;  in addition,  pathological changes
 were  not observed in the third-generation weanling pups,  using a  model  eco-
 system,  Howe (1978) did not see effects  on quail egg production or egg  fer-
 tility from  a  diet  of  10,  40, and 30 ppm methomyl.
          Blevins,  et al.  (1977)  treated  normal  human  skin cells with six
 insecticidal  esters  of N-
-------
     0.   Chronic Toxicity
          Rats  of  both sexes  were  fed nutritionally  complete diets  con-
taining  0,  10,-50,  125, and  250 ppm of methomyl in a  90-day  feeding study
and  0,  50,  100, 200.,  and  400 ppm  of methomyl in a  22-month feeding study.
The weight gain for the high-dose males  was  significantly  lower than that of
controls.   No clinical, hematological,  biochemical,  urinary,  or  pathologic
evidence  of toxicity  was  observed  at  90 days.   However,  in  the  22-month
study,  decreased  Hb  values  were noted  in  the  two higher-dose female  test
groups.   A  higher  testis/body  weight ratio was observed  in  the  high-dose
males.   Histopathologic alterations  were observed  in  kidneys of male  and
female  rats  receiving 400 ppm and  in spleens of  the female rats  receiving
200  and  400 ppm of methomyl.   Beagles  of both sexes  fed  nutritionally  com- •
plete diets  containing 0,  50,  100, and  400 ppm of  methomyi in 90-day  and
2-year  feeding  studies  showed  no  nutritional,  clinical,  urinary,  or  bio-
chemical  evidence of  toxicity.   In  the  2-year study, an  additional  dietary
level of 1000  ppm  caused  some clinical  signs of  toxicity and  mortality.
Similar  to  findings in the 22-month feeding study in rats,  histopathologic
changes were  observed after  2 years in the  kidney, spleen,  and liver  at the
two higher feeding levels.  Dogs receiving the high-level  diet  showed  a  com-
pound-related anemia.   Results  of  the long-term studies indicated that  the
no-effect level for rats and dogs was 100 ppm (Kaplan and Sherman,  1977).
     E.   Other Relevant Information
          Several incidents  of  acute occupational  exposure have  been  re-
ported  in the  literature.    In  the  first  incident,  four  crews  of fiela
workers  harvesting  vegetables and  fruits  treated with  pesticides  including
methomyl were studied.  One crew had  depressed blood  cholinesterase  activity

-------
  after harvesting corn treated with methomyl.   Forty-eight percent of another
  crew  had  significant  cholinesterase  depression  after  harvesting  treated
  citrus, tomatoes, and gladiolas (Owens, et al. 1978).
            A second  incident involved  120  grape pickers where  IQb displayed
  symptoms  suggesting  pesticide   poisoning.    Methomyl  and  other   cnolin-
  esterase-inhibiting pesticides, such as dimethorate  and torak,  were  named in
  a legal complaint against the grower.   The major symptoms  claimed by the ex-
  posed workers were  headache,  dermatitis,  vomiting, nausea, fatigue,  and eye
'  pain (McClure,  1976).
            Kumagaya,  et  al.  (1978) reported  on two  cases  of poisoning  from
  swallowing methomyl.  The general symptoms were loss  of consciousness,  re-
  spiratory failure,  miosis,  myofibrillary  twitching,  increase in airway  se-
  cretions, and reduced serum cholinesterase  activity.  Complications  of  pul-
  monary edema, hepatitis, and polyneuritis were also observed.
            The  oral  LD^ values for  rats,  mice, ducks, and wild biros  have
  been reported as  17,  10, 15,  and 10  mg  methomyl per  kilogram body weight
  (mg/kg),   respectively.   The  oral  LD5Q values for  dogs, monkeys, guinea
  pigs,  and chickens  are  reportedly 30,  40,  15, and  15 mg/kg,  respectively.
  Inhalation i_C5Q values  for  rats, quails,  and ducks are  77,  3680,  and  Ib90
  ppm,  respectively.   The  dermal LD5Q  for rabbits is  5000  mg/kg.  NO  adverse
  effects were noted  when bootail  quail  and  aloino  rabbits  were sprayed  six
  times  (at  5-day  intervals)  with  1.1 kg/ha of a 90 percent  formulation of
  methomyl. Methomyl  is  relatively  non-toxic to bees, once the spray has dried
  (Fairchild,  1977; Martin and worthing,  1974).
            Carbamate  pesticides,  such  as methomyl,  have  cholinergic   proper-
  ties similar to  those  of the  organic phosphates,  out  of shorter duration.
  Methomyl  inhibits both  RBC  and  plasma cnolinesterase  activity.   The period

-------
 of inhibition  of the  cholinesterases  is  approximately  1-2  hours,  and  re-
covery  usually  occurs between 24  and  48 hours after  contact.  Atropine  ad-
ministration is the treatment of choice  (Simpson and Bermingham, 1977).
V.   AQUATIC TOXICITY
     A.   Acute and Chronic Toxicity
          Methomyl  24-hour   TLm  (median  toxic   limit)   values  for  carp
(Cyprinus carpio) and tilapia  fish range from 1.054 to  3.16 mg/1 (El-Refai,
et  al.  1976).   The  LC5Q  (96-hour  exposure)  for  rainbow  trout  (Salmo
gainneri) was 3.4 ppm;  for bluegill  (Lepomis  macrochirus),  0.87 ppm; and for
goldfish  (Carrasius  auratus),  greater  than  0.1 ppm  (Martin  and  Worthing,
1974).   Following exposure  (4-48  hours) of  marine or  estuarine fishes  to
carbamate pesticide,  the acetylcholinesterase activity in  the brain was in-
hibited by 77 to 89 percent (Coppage, 1977).
     B.   Plant Effects and Residues
          Pertinent data could not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          The  threshold limit  value  for  air  is  established at  2.5 mg/m-3
(Fairchild, 1977).  The  Office of  Water  and Waste Management  is  in  the pro-
cess  of  conducting  preregulatory  assessment  of  methomyl under  the  Safe
Drinking Water  Act.   The Office of Toxic Substances has  promulgated regula-
tions for methomyl under Section 3 of the Federal  Insecticide, Fungicide and
Rodenticide Act.
          Methomyl  residue   concentrations  in  crops   are   regulated   as
follows:  0.1  ppm  for  lentils and  pecans;  1  ppm  for  forage, hay,  barley
                                                                         »
(grain), and  oats (grain); 2  ppm  for strawberries and  avocados; 5  ppm  for
Chinese cabbage;  6  ppm  for  blueberries, beets,  collard,   danoelions,  kale,

-------
mustard greens,  parsley,  swiss chard, turnip greens, and  watercress;  10 ppm
for wheat,  rye,  barley,  and oats used as  hay,  straw, or  forage;  and  40 ppm
for bermuda grass  hay (Federal. Register [43(98):  21700,  1978;  43 and (112):
25120, 1978;  44(63):  18972; 44(83):  24846;  44(129): 38844;  44(160):  47934,
and 44(227): 67117, 1979]);
     B.  Aquatic  -
          Guidelines  or  standards  to protect aquatic life coulo  not  be lo-
cated in the available literature.

-------
                                   REFERENCES
 Baron,  R.L.  1978.  Terminal residues of carbamate  insecticides.   Pure Appl.
 Chem.   50:  503.

 Berg,  Gil., et al., (ed)   1977.   Farm Chemicals Handbook Meister  Publishing
 Company,  Willoughby, Ohio.

 Blevins,  R.O., et al.   1977.   Mutagenicity  screening of  five methyl  car-
 bamate   insecticides  and.  their   nitroso  derivatives   using  mutants   of
 Salmonella  typhimurium LT2.   Mutat.  Res.  56:  1.

 Coppage,  O.L.   1977. - Anticholinesterase  action of pesticide carbamates  in
 the  central nervous system  of  poisoned fishes.  Physiological  Response  Mar.
 Biota.  Pollut. Proc. Symp.   pg.  93.

 El-Refai,  A.,  et  al.  1976.  Toxicity of  three  insecticides to two  species
 of fish.  Int.-Pest  Control,  18: 4.

 Fairchild,  E.J.  (ed.)   1977.  Agricultural Chemicals and Pesticides:   A  sub-
 file  of the NIOSH Registry  of  toxic effects of chemical  substances,  U.S.
 Dept. of  HEW,  July.

 Guerzoni, M.E.,  et al.   1976.   Mutagenic activity-of  pesticides.  Riv.  Sci.
 Tecnol. Alimenti.  Nutr. Urn.,  6:  161.

 Han,  J. C-Y,  1975.   Absence of  nitroso  formation  from  (14-C)  methomyl and
 sodium  nitrite under simulated  stomach  conditions.  Jour. Agric.  Food Chem.
 23: 892.

 Harvey, J.J.,  et  al.  1973.  Metabolism of methomyl in the rat.   Jour.  Agr.
 Food Chem., 21: 769.

 Harvey,  J.J.  1975.   Metabolism  of  aldicarb and  methomyl.   Environmental
 Quality Saf., Suppl.  Vol. 3, ISS Pesticides,  389.

 Heywood,  O.L.    1975.    Degradation  of  carbamate  insecticides  in  soil.
 Environ. Qual.  Saf., 4: 128.

 Howe, G.J.   1978.   The effects of various  insecticides applied to a terres-
 trial model  ecosystem  or  fed in the  diet  on  the serum cholinesterase level
 and  reproductive  potential of coturnix   quail.    Oiss.   Abstr.   Int.  3.
 38: 4785.

 Huhtanen,  K.  and   H.W. Dorough   1976.  Isomerization.ana  Beckman rearrange-
ment  reactions in  the  metabolism  of  methomyl  in.rats.   Pest.  Biochem.
 Ftiysiol.  6: 571.

Kaplan,    A.M.   and  H.   Sherman   1977.    Toxicity   studies   with   methyl
N-(((methylamino)carbonyl)oxy)ethanimidothioate.  Toxicol.  Appl.  Pharmacol.
40: 1.
                                     XL

-------
 Kumagaya,  S.,  et  al.   1978.   Pesticide  Intoxication.   Yamaguchi  Igaku
 27:  211.

 Lee,  Y.M.,  et  al.   1972.   Residues  of  methomyl in  rape  plant ana  seed
 following  its  application  for  the  control of  bertha  army  worm,  Mamestra
 configurata  Lepidoptera Noctuidae.

 Lijinsky,  w.  and 0.  Schmaehl  1978.  Carcinogenicity  of N-nitroso  deriva-
 tives of N-methylcarbamate insecticides in rats.   Ecotoxicol.  Environ.  Saf.,
 2: 413.

 Love,  J.L.  and  0.  Steven   1974.   Methomyl residues on  tomatoes.  N ana  J.
 Exp. Agric.,  2:  201.  ••••-•

 Martin and worthing  (ed.), 1974.  Pesticide Manual, 4th edition.

 McClure,  C.O.   1976.   Public  health concerns  in  the  exposure  of  grape
 pickers to high  pesticide residues  in  Madera County, Calif. Public Health
 Report-.93:  421,  September.

 Owens,  C.O.,  et  al.   1978.   The  extent of exposure of  migrant workers  to
 pesticide  and  pesticide  residues.   Int. Jour. Chronobiol.   5:  428.

 Pest Control  1975.   pg. 314.

 Prabhakar,  J.M.  and J.F. Fraumeni   1978.   Possible relationship of insecti-
 cide exposure  to  embryonal cell carcinoma.   Jour. Am. Med.  Assoc.   240: 288.

 Simpson, G.R.  and S.  Birmingham  1977.  Poisoning by  carbamate pesticides.   .
Med. Jour.  Aust.  2: 148.

 Sittig,   M.   1977.    Pesticides  Process  Encyclopedia,  Chemical   Technology
Review no.  81.  Noyes Data Corporation, Park Ridge, N.J.

 Stanford Research Institute.  1977.   Directory of  Chemical Producers. Menio
Park, California.

 U.S. Environmental  Protection Agency.  1976.   Organophosphate Exposure from
 Agricultural Usage,  EPA 600/1-76-025.

U.S. Environmental  Protection Agency.   1980.   Aquatic  Fate  and Transport
Estimates   for  Hazardous   Chemical   Exposure   Assessments.    Environmental
Research Laboratory,. Athens,  Georgia.

windholz,   M.   1976.   The  Merck Index, Ninth  Edition,  Merck  and  Co., Inc.,
Rahvvay,  N.J., USA.

-------
                                     No.  126
          Methyl Alcohol

 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 tha 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  inpacts  presented by  the
subject chemical.   This document  has undergone  scrutiny to
ensure its technical accuracy.

-------
                          BIOLOGIC EFFECTS OF EXPOSURE





Extent of Exposure


      Methyl alcohol, CH30H, also called methanol, is the first member of a


homologous series of monohydric aliphatic alcohols.  At  room  temperature,
                                            -'  .
methyl alcohol is a colorless, neutral liquid possessing a mild distinctive


odor. [1]  Additional chemical and physical properties  of  methyl  alcohol

are presented in Table XIII-1. [2,3,4]

      The greater part of methyl alcohol manufactured in the US is produced

synthetically. [5]  One  widely  used  synthetic  process  is  the  "medium

pressure   process"   which  involves  the  reduction  of  carbon  monoxide

(containing small amounts of carbon dioxide) with hydrogen.  The  reduction

step  is carried out at 250-400 C and at 100-600 atmospheres pressure using

a catalyst. [1]

;  "   During  the years 1968-»73, synthetic methyl alcohol production in  the


US increased at an average  annual  rate  of  over   13.2%.   In   1973,   the

production  of  synthetic  methyl  alcohol  amounted to slightly over seven

billion pounds, around one billion gallons.  In addition, an   estimated   10

million   pounds    (1.5  million  gallons)  of  "natural"   (eg,  from  wood

distillation) methyl alcohol were produced.  [5]

      Methyl  alcohol  is  used  in a variety of industrial processes.   The

major use is in 'the production of formaldehyde which amounted  to  39% of  the
                            •  r                    •      '
methyl  'alcohol  consumed in the US in  1973..   [5] "Other commercial uses of

methyl alcohol are  in the  production  of  chemical  derivatives,  such   as

dimethyl  terephthalate,  methyl halides, methyl methacrylate, acetic a'cid,

and  methylamines, and because of its solvent properties, methyl alcohol   is

-------
 also  used  in  paints,  varnishes, cements, and  other  formulations such as

 inks and dyes. [1,5]  Table XIII-2 lists the consumption  of methyl  alcohol

 by product and quantity produced in the US for the year 1973.  [5]

       A. number of occupations with potential exposure to  methyl alcohol are

 listed in Table SLII-3. [6]

       NIOSE  estimates, .that  approximately  175,000  workers  in the US.,ara
 ipotentially  exposed to methyl alcohol:

                              EFFECTS  ON HUMANS
              Burk  [26]  attributed  the toxic effects of  methyl alcohol to

 formaldehyde and formic acid, indicating that both compounds were oxidation

 products of  methyl alcohol.  The author stated that the diagnosis of methyl

 alcohol poisoning is sometimes very difficult,  and  would   be  more  easily

 verified  by  quantitative  determinations  of  formic acid in the urine of

 persons suspected of being poisoned with methyl alcohol.

                         ^rcutaneous absorption of methyl alcohol can lead

to serious consequences, including death..  In  1968,  Gimenez   et  al [27]

reported  an  analysis  of  19  cases  of children, ranging in  age from  1.5

months to 4 years, who were poisoned as a result of having cloths soaked in

methyl  alcohol  applied  to  their,  abdomens  to  relieve gastrointestinal

troubles or other unspecified complaints.  There were  2   additional cases

reviewed  in which both methyl and ethyl alcohols  had been employed  in this

way, making a total of  21 cases.  Although absorption of methyl alcohol  via

 the resoiratory tract was possible in  these cases, the fact  that the cloths

 were held in place by  rubber baby pants would favor percutaneous absorption

 of  the  alcohol  as  the significant route of exposure.  The length of time

 between  application   and onset of symptoms of intoxication was 1-13 hours

 (7  1/4  hours average) .  The  aarly signs of  intoxication  were  described* 'oy

 the authors  as central nervous  system  depression with   13  children  having

-------
exhibited severe respiratory depression and U. of these having convulsions.

Slood pH in the 21 patients ranged from 6.4  to  7.38  (normal:   7.36-7.41

[23])>  indicating  acidosis in most cases.  Twelve of the 21 children died

of cardiac or respiratory arrest 2-10 days after hospital  admission.   The

survivors  recovered  without  apparent  permanent damage.  Papilledema and
                                           .  >  .
ocular fundus bleeding were observed in 2 of the infants  who  subsequently

died.   Abdominal  skin  lesions  were  present  in  5  patients,  3 of the

erythematous type and '2 of the scaling type.^  The  authors  [27]  commented

that while there was no relationship between methyl alcohol blood levels as

tested  in  11  children   (57-1,130  mg%)  and  prognosis,  there   was   a

relationship  between the initial blood pH and the subsequent course of the

illness.   In  general,  treatment  consisted   of   administering   sodium

bicarbonate, glucose, ethyl alcohol, fluids, and electrolytes.  Other forms

of treatment included peritoneal dialysis, exchange transfusion, mechanical

raspiration,.  and  the  administration of anticonvulsant drugs.  It must be

pointed out that the absorptive properties  of  the  skin  of  infants  are

probably   different   from   those   of  adults  and  consequently  infant

susceptibility to, and manifestations of, methyl alcohol  intoxication  may

not  parallel those seen, in adults.                                          :

      In 1952, Leaf and Zatman [30] reported on experiments in which 5 male

voluntaers ingested 2.5-7.0 ml of methyl alcohol diluted  to  100  ml  with

water.   These  amounts  of  methyl  alcohol corresponded to doses of 29-84

ing/kg.  Two blood samples were taken from 3 subjects, 2-5 hours  after  the

ingestion.  Urine was collected frequently for 11-16 hours following methyl

alcohol administration.  Both the blood and urine samples were analyzed for

methyl  alcohol  by  a colorimetric method based on the oxidation of methyl

alcohol to formaldehyde and formation of a colored complex with a  modified
                                                                       »
Schiff's  reagent.   The  results  of  this experiment indicated that under

these  conditions  methyl   alcohol   was   rapidly   absorbed   from   the

gastrointestinal  tract.    The  maximum methyl alcohol concentration in the

urine  was  achieved  approximately  one  hour  after  ingestion  and  then

decreased  exponentially. .. The  ratio  of  blood  to  urine methyl alcohol

-------
concentrations remained almost constant for the 3 subjects in which it  was


determined,  and  the  authors  [20]  concluded  that  che  change  in  the


concentration of methyl alcohol in the urine was an accurate  .indicator  of


the change in aethyl alcohol concentration in the body.  At the levels used


in this experiment, the  concentration  of  methyl  alcohol  in  the  urine


declined  to  control  values within 13-16 hours after ingestion.  Leaf and


Zatmaa [30] also stated'that only 0.4-1.2Z of the ingested  methyl  alcohol

                                     I        >  •
was eliminated unchanged in the urine.


       In  another  experiment  in  the  same  study, [30]  2 male volunteers


 ingested 15  ml of ethyl alcohol and 4 ml of methyl alcohol  simultaneously.


 They  then ingested 10 ml of ethyl alcohol every hour for the next 7 hours.

                                                 j  .
 The  same individuals served as their own controls in a previous  experiment


 in  which  they  ingested only 4 ml of methyl alcohol.  Urine was collected


 hourly and analyzed for methyl alcohol.  The maximum urinary methyl alcohol


 concentrations  for  those individuals who ingested both methyl alcohol and


 ethyl alcohol were 8.82 and 9.20 mg/100 ml, compared to values of 6.05  and


 5.50 mg/100 ml when methyl alcohol alone was ingested.  Moreover, the total


 amount of methyl alcohol excreted unchanged in the urine  in  the  first  7


 hours  after  ingestion  was  107.1  tag  and 125.5 mg (3.7 and 3.96% of the


 administered dose respectively) when both methyl alcohol and ethyl  alcohol


 were  ingested,  whereas  only  from  18.2  to  30.8  mg (0.57-0.97% of the


 administered dose) was excreted unchanged in a similar  time  period  after


 ingestion of 4 ml methyl alcohol alone.  The authors  [30] concluded that  in


 humans ethyl  alcohol  interfered,  with  the  normal  oxidation  of  methyl


 alcohol,  causing  more  of  it  to  be  excreted 'unchanged  in the urine.


 Moreover, according to the authors' conclusion,  higher  concentrations   of


 methyl alcohol in the blood are maintained in the presence of ethyl alcohol


 at any given time after absorption, as compared to concentrations  achieved


 In  che absence of ethvl alcohol.

-------
                                 Ethyl alcohol may inhibit the oxidation of


methyl alcohol in  vivo  by  competing  (competitive  inhibition)  for  the


alcohol  dehydrogenase  system.  It is conceivable, therefore, that chronic


alcoholics might exhibit measurable concentrations of methyl alcohol in the


blood or urine even though they have not been exposed to methyl alcohol. L.3?J


      In  summary,  an  integration of in vitro  [33-35] and in vivo studies


[29-31,37]-  indicates that in humans methyl alcohol is  oxidized  primarily


by  alcohol  dehydrogenase.  The results discussed in the section on Animal


Toxicity, however, suggest that in nonprimates methyl alcohol  is  oxidized


primarily by the catalase-peroxidase system.



                          . ANIMAL TOXICITY



         Gilger   and   Potts  [42]  concluded  from their studies  that the results.


   of  oral administration   of  methyl  alcohol  to*  rats,   rabbits,   and  dogs


   differed  from  those reported on  humans  in 4 important areas,  namely, lethal


   dose,  time course  of development and  signs of intoxication,   eye  effects,


   and acidosis.  The  authors also  concluded that, following intoxication with


   methyl alcohol,  the responses  of  primates more closely   approximated  human


   responses  than, did  those   of   nonprimates.    An  extensive review of the


   literature dealing  with the  oral  toxicity of methyl alcohol in  humans  and


   nonprimates was  supportive of  their  conclusion.  The authors  concluded that


   the approximate  lethal  oral  dose  of  methyl  alcohol in humans   (0.85-1.4


   g/kg) was  1/3  the equivalent dose in monkeys and 1/9  the equivalent dose in


   rats.  Moreover,  nonprimates  exhibited   severe  early  intoxication  with


   narcosis   lasting   until   death   whereas   primates  showed  much  less early


   intoxication followed by a symptomless  latent  period, then  by sickness  and


   death.    The  only   eye changes observed  with  certainty in  nonprimatea were


   early pupillary  changes and  corneal  opacities  following exposure  keratitis.


   Some  monkeys,   however,   and  many  humans  developed   partial or  complete
                                      i >'n->
                                   .-• ) i  > 7 "

-------
    blindness accompanied by eyeground changes such as hyperemia of   the  optic



    discs  and venous engorgement.  Finally, humans and monkeys often developed



    severe acidosis (COZ-combining capacity  less  than  20  volumes  7,}  after



    methyl  alcohol  ingestion;  this  condition  was  rare  in nonprimates and



    occurred only at near lethal or lethal doses.
Correlation of Exposure and Effect




      Well-documented studies that correlate environmental, levels of methyl




alcohol with observed toxic effects have not been found in the  literature,




nor   have   any  long-term  epidemiologic  studies  of  chronic  low-level




occupational exposure been found.



      Effects  seen from either of the 2 most common routes of  occupational




exposure  (inhalation  and  percutaneous  absorption)  include:    headache




[14,16,17,39];   dizziness   [13,19];  nausea   [16,17,26];  vomiting   [17];




weakness  (unspecified) [16]; vertigo  [17,26]; chills  [13];  shooting   pains




in   the   lower  extremities  [13];  unsteady  gait   [17];  dermatitis  [U];



multiple  neuritis characterized by paresthesia,  numbness,  prickling,  and




shooting  pain  in  the back of  the hands and forearms, as well as  edema of




the  arms  [15]; nervousness  [19];  gastric pain  [19];  insomnia  [19];  acidosis




[19];  and  formic  acid  in   the urine.  [26]   Eye  effects,'such  as blurred




vision,  [16,17] constricted visual fields,   [17,19,25]  blindness,   [13,25]




changes   in   color  perception,  [17]  double vision,  [19]  and  general  visual

-------
disturbances [17] have been reported.  Eye examinations have shown sluggish


pupils,  [13,17] pallid optic discs,  [13] retinal edema,   [17]  papilledema,


[26] ' hyperemia  of  the  optic discs with blurred edges  and dilated veins.


[17]


      The  study  by  Bennett  et al  [40] showed similar  symptoms resulting
                                              >  •
from  ingestion.   These  are  acidosis,  headache,  visual   disturbances,


dizziness,  nausea  and  vomiting, severe upper abdominal pain, dilated  and


nonreactive pupils.  Eyeground examinations showed hyperemia of   the  optic


discs and retinal edema.  The eyeground changes were almost always found in


acidotic patients.  This finding is  suggestive  of  a  correlation  between


acidosis  and visual disturbances.   However,  a number of  patients, with  and


without  acidosis, complained of visual disturbances.   Additionally,  blood


tests  showed  elevated  serum  amylase  levels in 14 of  21 patients.  This


finding  in  conjunction  with  complaints  of  upper  abdominal  pain   and


pancreatic  necrosis  seen at autopsy led the authors  [40] to conclude that


hemorrhagic pancreatitis resulted from acute  methyl  alcohol  intoxication.


However,  reports  of  acute  hemorrhagic pancreatitis by parenteral routes


have-not been found.


      Direct  skin  contact  with  methyl  alcohol  has   been said to cause


dermatitis,  [14] erythema, and scaling.   [27] The reported variability   in


susceptibility   [14]  is  probably largely becaus.e of variations  in  tine of


contact  with methyl alcohol; it is evident that sufficient  -dermal  contact


.,with  any lip id solvent such as methyl alcohol has  the potential  for causing


skin  irritation.


 Basis for the Recommended Environmental Standard


       Epidemiologic   studies   incorporating  comprehensive   environmental


 surveys, well-planned surveillance,   a  sufficient  study  population,   and


 statistical  analysis  have  not  been  found  in  the  literature.    It is


 therefore  difficult  to  recommend  an  environmental  limit  based    upon


 unequivocal scientific data... .

                                      r '/rffl—
                                  **?)//

-------
                                TABLES AND FIGURE
                               TABLE XIII-1

            PHYSICAL AND CHEMICAL PROPERTIES OF METHYL ALCOHOL
Molecular formula
j
Formula weight
Apparent specific gravity at 20 C
Boiling point at 760 mmHg
Vapor pressure at 20 C
Melting point
Solubility in water
Solubility in alcohols, ketones, esters,
and halogenated hydrocarbons
Flash point, Tag open cup
Flash point, Tag closed cup
Flammable limits
(% in air)
Vaoor density
CH30H
32.04
0.7910
64.5 C
96 nmHg
-97.6 C
Miscible
Miscible
16 C
12 C
6.72-36.50
1.11
(air-1)

Corrosivity
Conversion factors
(760 tnmHg and 25 C)
Noncorrosive at
normal atmospheric
temperatures.
Exceptions: lead and
aluminum

1 ppm-"l.310 mg/cu m
1 mg/cu o».763 ppm
Adapted from ANSI 237  [2],  Che Manufacturing  Chemists  Association [3],
and the Handbook of Chemistry and Physics  [4]
                            ISL

-------
 f
i."
 I
*
                                             TABLE XIII-2

                                  US METHYL ALCOHOL CONSUMPTION, 1973
-
Formaldehyde
Dimethyl terephthalate
Solvent usage
Methyl halides
Methylamines
Methyl methacrylate
Inhibitor for formaldehyde
Exports
Glycol methyl ethers
Acetic acid
Miscellaneous
Total
Million Pounds
2,778
435
565
435
232
265
66
824
81
240
1,207
7,128
Million Gallons
420
66
85
66
35
40
10
124
12
36
181
1,075
               From Blackford  [5]
                                             I-It

-------
                              TABLE XIXI-3
           POTENTIAL OCCUPATIONAL EXPOSURES TO METHYL ALCOHOL
Acetic acid makers
Adhesive workers
Alcohol distillery workers
Alcohol lamp users
Aldehyde pumpmen
Antifreeze workers
Art glass workers
Automobile painters
Aviation fuel handlers
Bookbinders
Bronzers
Brushmakers
Denatured alcohol workers
Dimethyl sulfate makers
Drug makers
Drycleaners
Dye makers
Dyers
Ester makers
Explosives workers
Feather workers
Felt-hat makers
Flower makers, artificial
Formaldehyde makers
Foundry workers
Furniture polishers
Gilders
Glassmakers, safety
Hectograph operators
Incandescent lamp makers
Inkmakers
Japan makers
Japanners
Jet fuel workers
Lacquerers
Lacquer makers
Lasters
Leather workers
Linoleum makers
Lithographers
Metal polishers
Methyl acrylate makers
                                Methyl alcohol workers
                                Methyl amine makers
                                Methylation workers
                                Methyl bromide makers
                                Methyl chloride makers
                                Methyl methacrylate makers
                                Millinery workers
                                Motor fuel blenders
                                Organic  chemical synthesizers
                                Painters
                                Paintmakers
                                Paint remover workers
                                Patent leather makers
                                Perfume  makers
                                Photoengravers
                                Photographic film makers
                                Polish makers
                                Printers
                                Rayon makers
                                Resin makers
                                Rocket fuel handlers
                                Rocket fuel makers
                                Rubber shoe cementers
                                Rubber workers
                                Shellackers
                                Shellac  makers
                                Shea factory workers
                                Shoe finishers
                                Shoe heel  coverers, wood
                                Shoe stitchers
                                Soapmakers
                                Straw-hat  makers
                                Sugar  refiners
                                Textile  printers
                                Type cleaners
                                Vacuum tube makers
                                Varnish  workers
                                Vulcanizers
                                Wood alcohol distillers
                                Wood stainers
                                Wood stain makers
From Gafafer [6]

-------
                               TABLE XIII-4

                      ANIMAL EXPERIMENTATION RESULTS
                        OF METHYL ALCOHOL EXPOSURE
Species
 Route of
 Exposure
  Dose
         Effect
 Ref-. .
erence
Monkeys
Inhalation
5,000 ppm
duration
unknown
The monkey survived for
an unstated period of time.
  47
                           1,000 ppm
                           duration
                           unknown
                              The monkey died promptly      47
                              upon exposure at this level.
Dogs
               450-500 ppm
               8 hr/day
               7 days/week
               for 379 days
               Blood levels of methyl
               alcohol were found to range
               from 10 to 15 mg/100 ml
               of blood and on occassion
               went as high as 52 rag/100 ml.
               No abnormal eye findings
               were reported.
                              41
            Oral
               2.5 to 9.0     Of the 9 treated dogs, 2
                  g/kg        died at doses of 4 and
               body weight    9 g/kg.  C02 combining
                              capacities dropped below
                              normal in 2 dogs, and no
                              ophthalmoscopic changes
                              were noted.
                                             42

-------
                         TABLE XIII-4 (CONTINUED)

                      ANIMAL EXPERIMENTATION RESULTS
                        OF METHH. ALCOHOL EXPOSURE
Species
 Route of
 Exposure
  Dose
Effect
 Ref-
erence
Monkeys
Oral
1.0 to 3.0     Acidosis developed in
   g/kg        monkeys receiving doses
               ranging from 3.0 to 6.0
               g/kg.  The animal receiving
               1.0 g/kg did not develop
               acidosis.  Definite eye-
               ground change occurred to
               2 of the acidotic monkeys.
                     42
Rats
               4.75 g/kg      70% mortality                  42


               4.5 g/kg       None of  the 9  tested rats      42
                              developed acidosis.
Rabbits
               3.5 g/kg       One animal receiving  this
                              dose died in  less  than  24
                              hours.  No eye  fundus
                              changes were  reported.
                                             42
Rabbits
               2.1 g/kg       Of  the  3 animals  tested  at     42
                              this dose, all died between
                              24  hours, and  3 days after
                              dosing.
             Intra-          10  ing  and       At 10  nig,  there was  no skin   49
             cutaneous       35  mg           reaction, .whereas  at 35
                                           mg,  a  9-sq  mm skin reaction
                                           occurred.

-------
                         TABLE XIII-4 (CONTINUED)

                      ANIMAL EXPERIMENTATION RESULTS
                        OF METHYL ALCOHOL EXPOSURE
Species
 Route of
 Exposure
  Dose
         Effect
 Ref-
erence
Monkeys
i.p.  inj
0.5 g/kg of
14 C-methyl
alcohol with
an equimolar
amount of
ethyl al-
cohol
The ethyl alcohol reduced
the oxidation of methyl
alcohol 90%.
  52
                           1.0 g/kg       The methyl alcohol was
                           14 C-methyl    oxidized at a rate of
                           alcohol and    37 mg/kg/hour between the
                           6.0 g/kg       first and fourth hour.  The
                           14C-raethyl     C02 formation was linear at
                           alcohol        the high dose; the oxidation
                                          rate was 47 mg/kg/hour which
                                          is a significant difference.
                                                            52
Rats
               1.0/kg 14C-    The oxidation rate of the     51
               methyl         methyl alcohol was 24 mg/kg/hr
               alcohol        for the first 28 hours.  At
                              the end of 36 hours 77% of
                              the methyl alcohol had been
                              oxidized to 14C-labled C02
                              and 24% was excreted unchanged
                              in approximately equal amounts
                              by the pulmonary' and combined
                              urinary and fecal routes.

-------
                                  REFERENCES
 1.   Woodward  HF  Jr:   Methanol,  in Kirk-Othmer  Encyclopedia of  Chemical
     Technology, ed 2 rev.  New York, John Wiley and  Sons,  1967,   vol   13,
     pp 370-98

 2.   American  National Standards Institute:   Acceptable  Concentrations  of
     Methanol, ANSI 2 37.14-1971.   New York,  ANSI, 1971,  8  pp

 3.   Chemical   Safety   Data   Sheet    SD-22—Properties   and  essential
     information for safe handling  and use of tnethanol.   Washington,   DC,
     Manufacturing Chemists' Association Ir.c, 1970,  17 pp

 4.   Weast  RC (ed):  Handbook of Chemistry and Physics—A  Ready-Reference
     Book of Chemical and Physical  Data, ed   55.    Cleveland,  CRC  Press,
     1974, p D-85

 5.   Blackford  JL:   Methanol (methyl   alcohol),  in  Chemical Economics
     Handbook.  Menlo Park, Cal, Stanford Research   Institute,  1974,   pp
     674.50213-674.5021G

 6.   Gafafer  WM:   Occupational  .Diseases—A Guide  co Their Recognition,
     publication No.  1097.    US  Department   of   Health,  Education,   and
     Welfare, Public Health Service,  1964, pp 176-78

 7.   Taylor P:  On pyroligneous aether.   Philos Mag J 60:315-17, 1822

 8.   Dumas J, Peligot E:  {Organic  chemistry—I.   On  a. new  alcohol and  its
     compounds-extract  from an article.]  J   Prakd  Chem  3:369-77, 1834
      (Gar)

 9.   MacFarlan  JF:   On methylated spirits,  and  scr.e of  its preparations.
     Pharm J  Trans  15:310-15,  1855

10.   Wood  CA:  Death and blindness as  a result of poisoning by methyl, or
     wood  alcohol  and its various  preperations.   Int  Clin 16:68-78, 1906

11.   Wood  CA,  Buller   F:    Cases   of   death and  blindness from Columbian
      spirits  and   other methylated  preparations.   JAMA  43:972-77,1058-
      62,1117-23,  1904

 12.    Saskerville   C:    Wood  alcohol—A report of  the chemistry,  technology
      and pharmacology  of and che  legislation  pertaining  to  methyl  alcohol.
      New  York  State  Factory Investigation  Commission,  Appendix 6, vol 2,
      pp 917-1042,  1913

 13.    De Schweinitz GE:   A case of methyl-alcohol  amaurosis, che pathway of
      entrance of  che poison  being  che lungs   and   che  cutaneous   surface.
      Ophthalmic Rec 10:289-96, L901

-------
14.    Dangers  in  the  manufacture   and   industrial  uses of wood alcohol,
      special bulletin No.  86,   Albany, State of  New  York  Department  of
      Labor,  Division of Industrial  Hygiene, 1917, pp 1-17

15.    Jelliffe  SE:   Multiple neuritis  in  wood alcohol poisoning.  Med News
      86:387-90,  1905

16.    Hawes  AT:   Amblyopia from the fumes of wood alcohol.  Boston Med Sur
      J 153:525,  190-5
                                         *  .
17.    Tyson  HH:    Amblyopia from  inhalation  of  methyl  alcohol.   Arch
      Ophthalmol 16:459-71, 1912

18.    Wood  CA:   Death and blindness from methyl or wood-alcohol poisoning
      with means of prevention.  JAMA 59:1962-66, 1912

19.    Ziegler  SL:   The  ocular  mena'ce   of  wood alcohol poisoning.  JAMA
      77:1160-66, 1921

20.    Scherberger  RF, Happ GP,  Miller  FA, Fassett DW:  A dynamic apparatus
      for preparing air-vapor mixtures  of  known concentrations.  Am Ind Hyg
      Assoc j'19:494-98, 1958

21.    May  J:  [Odor thresholds  of solvents for evaluating solvent odors in
      air.] Staub-Reinhalt Luft  26:385-89, 1966 (Ger)

22.    Chao  Chen-Tsi:  [Materials on  the  hygienic standardization of the
      maximally  permissible concentration of  methanol  vapors  in   the
      atmosphere.] Gig Sanit 24:7-12, 1959 (Rus)

23.    Ubaydullayev  R:   A  study of hygienic properties of methanol as an
      atmospheric air pollutant, in  Levine BS  (transl):  USSR Literature on
      Air  Pollution  and Related Occupational Diseases—A Survey 17:39-45,
      1963

24.    Thies  0:  [Eye damage in  chemical  industries.]  Zentralbl Gewerbehyg
      Unfallverhut 15:303-08, 1923 (Ger)

25.    Humperdinck K:  [On the problem of  chronic intoxication with methanol
      vapors.]  Arch Gewerbepathol Gewerbehyg  10:569-74, 1941  (Ger)

26.    Burlc M:  [On chronic occupational methyl alcohol intoxication.]  Klin
      Monatsbl Augenheilkd 130:845-50,  1957 (Ger)

27.    Gimenez  ER, Vallejo ME, Roy E, Lis  M, Izurieta EM, Rossi S, Capuccio
      M:  Percutaneous alcohol  intoxication. Clin Toxicol 1:39-48, 1968

28.    Table  of  normal  values,  in Davidsohn  I,  Henry JB  (eds):, Todd-
      Sanfords  Clinical  Diagnosis   by    Laboratory   Methods,   ed   15.
      Philadelphia, WB Siiuruiers  Company,  1974, Appendix 3
                         ll-t-17

-------
T
              29.   Agner  K,  Hook  0, von Forat B:  The  treatment of methanol poisoning
                    with ethanol—With report of two cases.   J  Stud  Alcohol  9:515-22,
                    1949

              30.   Leaf. G,  Zatman  LJ:  A study of the  conditions under which methanol
                    may exert a toxic hazard in industry.  Br J Ind Med 9:19-31, 1952

              31'.   Kendal  LP,  Ramanathan  AN:   Excretion  of  formate  after methanol
                    ingeation in man.  Biochem J 54:424-26, 1953

              32.   Bastrup  J:   Method  for  the determination of formic acid in urine.
                    Acta Pharmacol 3:303-11, 1947

              33.-  Von  Wartburg  IP,  Bethune  JL,  Vallee  BL:   Human  liver  alcohol
                    dehydrogenase—Kinetic and physiochemical  properties.   Biochemistry
                    3:1775-:82, 1964

              34.   Blair  AH,  Vallee  BL:   Some  catalytic  properties  of human liver
                    alcohol dehydrogenase.  Biochemistry 5:2026-34, 1966

              35.   Goodman  JI,  Tephly TR:  Peroxidative oxidation of methanol in human
                    liver—The role of  hepatic  microbody and  soluble  oxidases.   Res
                    Conmun Chem Pathol Pharmacol 1:441-50, 1970

              36.   Ritchie  JM:   The aliphatic alcohols, in Goodman LS, Oilman A (eds):
                    The Pharmacological Basis of  Therapeutics,  ed  4.   New  York,  The
                    MacMillan Co, 1970, p,141

              37.   Majchrowics  E,  Mendelson  JH:  Blood methanol concentrations during
                    experimentally  induced  methanol  intoxication  in  alcoholics.     J
                    Pharmacol Exp Ther 179:293-300, 1971

              38.   Greenburg  L,  Mayers  MR, Goldwater LJ, Burke WJ:  Health hazards in
                    the  manufacture  of  "fused  collars"—II.   Exposure  to   acetone-
                    methanol.  J Ind Hyg Toxicol 20:148-54, 1938

              39.   Kingsley WH, Hirsch FG:  Toxicologic considerations in direct process
                    spirit duplicating machines.  Compen Med 40:7-8, 1954-1955

              40.   Bennett  IL  Jr,  Gary  FH,  Mitchell  GL Jr, Cooper MN:  Acute methyl
                    alcohol poisoning—A review based on experiences in  an  outbreak  of
                    323 cases.  Medicine 32:431-63, 1953

              41.   Sayers RR, Yant WP, Schrenk HH, Chomyak J, Pearce SJ, Patty FA, Linn
                    JG:  Methanol poisoning—I.  Exposure  of dogs to' 450-500 ppm methanol
                    vapor  in  air—Report  of  Investigations  'RI  3617.     US  Dept of
                    Interior, Bureau of Mines, 1942, pp 1-10

              42.   Gilger  AP, Potts AM:  Studies on the  visual toxicity of methanol—V.
                    The role of  acidosis  in  experimental  methanol  poisoning.   Am   J
                    Ophthalmol 39:63-86, 1955

-------
43.   Roe  0:   The  metabolism  and  toxicity  of methanol.  Pharmacol Rev
      7:399-412, 1955

44.   Cooper  JA,  Kini  MM:   Editorial—Biochemical  aspects  of methanol
      poisoning.  Biochem Pharmacol 11:405-16, 1962

45.   Tephly  TF,  Watkins  WD,  Goodman JI:  The biochemical toxicology of
      methanol, in Essays'in Toxicology.  New York, Academic  Press,  1974,
      chap 6

46.   Von   Oettingen  WF:   The  aliphatic  alcohols—Their  toxicity  and
      potential dangers in relation  to  their  chemical  constitution  and
      their  fate  in  metabolism,  bulletin  No.  281.  US Dept of Health,
      Education, and Welfare, Public Health Service, 1943

47.   McCord  CP:   Toxicity  of  methyl  alcohol (methanol) following skin
      absorption and inhalation—A progress report.  Ind Eng  Chem  23:931-
      36, 1931

48.   Cooper  JR,  Felig  P:   The  biochemistry of methanol poisoning—II.
      Metabolic acidosis in the monkey.  Toxicol Appl  Pharmacol  3:202-09,
      1961.

49.   Renkonen  KO,  Teir H:  Studies on the local reactions of the skin to
      chemical compounds.  Ann Med Exp Biol Fenn 35:67-69, 1957

50.   Carpenter  CP, Smyth HF Jr:  Chemical burns of the rabbit cornea.  Am
      J Ophthalmol 29:1363-72, 1946

51.   Tephly  TR,  Parks  RE  Jr, Mannering GJ:  Methanol metabolism in the
      rat. J Pharmacol Exp Ther 143:292-300, 1964

52.   Makar  AB,  Tephly  TR,  Mannering  GJ:   Methanol  metabolism in the
      monkey.  Mol Pharmacol 4:471-83, 1968

53.   Clay  KL,  Murphy  RC, Watkins WD:  Experimental raethanol toxicity in
      the primate—Analysis of metabolite acidosis.  Toxicol Appl Pharmacol
      34:49-61, 1975

54.   Saha  AK,  Khudabaksh AR:  Chromosome aberrations induced by methanol
      in germinal cells of grasshopper, Oxya velox Fabricius.  J  Exp  Biol
      12:72-75, 1974

55.   Technology  Committee  (GA  Hedgecock, chtnn), Working Party (SJ Silk,
      chmn):  Chemical indicator tubes for measurement of the concentration
      of  toxic  substances  in air—First report Of a working party of the
      Technology Committee of  the  Britisn  Occupational  Hygiene  Society.
      Ann Occup Hyg 16:51-62,  1973
                                                                     »
56.   Smith  BS,  Pierce  JO:   The  use of plastic bags for industrial air
      sampling.  Am Ind Hyg Assoc J 31:343-48, 1970

-------
57.   Rogers GW:  Sampling and determination of methanol in air.  J Ind Hyg
      Toxicol 27:224-30, 1945

58.   Documentation  of  NIOSH Validation Tests, NIOSH contract No. CDC 99-
      74-45. .US Qapt of Health,  Education,  and  Welfare,  Public  Health
      Service',-'   Center   for   Disease  Control,  National  Institute  for
      Occupational Safety and Health, 1975, pp S59-1 to S59-9

59.   Feldstein  M,  Balestrieri  S,  Levaggi DA:  The use of silica gel in
      source testing.  Am Ind Hyg Assoc J 28:381-85, 1967

60.   Methyl alcohol Class 3, NIOSH Sampling Data Sheet #36.01.  US Dept of
      Health, Education, and Welfare, Public  Health  Service,  Canter  for
      Disease  Control,  National.  Institute  for  Occupational  Safety and
      Health, December 15, 1975, December 16, 1975, January 26, 1976

61.   Skoog  DA, West DM:  Fundamentals of Analytical Chemistry.  New York,
      Hblt, Rinehart and Winston, 1963, pp 667-69

62.   Deniges MG:  [Analytical chemistry-Study of methyl alcohol in general
      and especially in the presence  of  ethyl  alcohol.]  C  R  Acad  Sci
      (Paris) 150:832-34, 1910 (Fr)

63.   Ellvove  E:'  A note on the detection and estimation of small amounts
      of methyl alcohol.  J Ind Eng Chem 9:295-97, 1917

64.   Wright  LO:  Comparison of sensitivity of various tests for methanol.
   •   In'd Eng Chem 19:750-52, 1927

65.   Chapin RM:  Improved Deniges test for the detection and determination
      of methanol in Che presence of ethyl alcohol.  J Ind Eng Chem 13:543-
      45, 1921

66.   Jephcott  CH:   Determination  of methyl alcohol in the air.  Analyst
      60": 588-92,  1935

67.   Jansson BO, Larson BT:  Analysis of organic compounds in human breath
      by gas chromatography-mass spectrometry.  J Lab Clin  Med  74:961-66,
      1969

68.   Matsumura   Y:   The  adsorption  properties  of  active  carbon—II.
      Preliminary study on adsorption of various organic vapors  on  active
      carbon by gas chromatography.  Ind Health 3:121-25, 1965

69.   Baker RN, Alenty LA, Zack JF Jr:  Simultaneous determination of lower
      alcohols, acetone and acetaldehyde in blood by gas chromacography.  J
      Chromatogr  Sci 7:312-14,  1969

70.   Hurst  RE:   A  method  of  collecting  and  concentrating head space
      volatiles for gas-chromatographic analysis.  Analyst 99:302-05, 1974

-------
                 71.    Occupational  Health   Hazards   in Massachusetts  Industries—IV.  Wood
                       heel covering,  WPA  No.  65-14-6060.   Boston, Massachusetts  Department
                       of Labor and Industries,  Division of Occupational Hygiene, 1937

                 72.    Goss  AE, Vance GH:  Methanol vapors from duplicating machines may be
                       health hazard.   Ind Hyg Newsletter  8:15, 1948

                 73.    McAllister   RG:    Exposure  to  methanol  from spirit  duplicating
                       machines.  Am Ind Hyg  Assoc Q 15:26-28,  1954

                 74.    Dutkiewicz  T,   Blockowicz A:   [Evaluation of exposure  to methanol in
                       view of field studies.] Med Pr  18:132-41, 1967  (Pol)

                 75.    Methyl  alcohol  (methanol), AIHA Hygienic Guide Series.  Southfield,
                       Michigan, American  Industrial Hygiene Association,  1957

                 76.    Methanol,  Data  Sheet 407,  Revision   A.   Chicago, National Safety
                       Council, 1967,  pp 1-5

                 77.    American  Conference of Governmental Industrial  Hygienists, Committee
                       on  Industrial  Ventilation:    Industrial  Ventilation—A  Manual  of
                       Recommended Practice,  ed  13.  Lansing, Michigan, ACGIH, 1974

                 78.    American  National  Standards   Institute:  Fundamentals Governing the
                       Design and Operation of Local Exhaust Systems,  Z9.2-1971.  Mew  York,
                       American National Standards Institute Inc, 1971

                 79.    Bowditch  M, Drinker CK,  Drinker P,  Haggard HH,  Hamilton A:  Code for
                       safe concentrations of  certain  common toxic  substances  used  in
                       industry.  J Ind Hyg Toxicol 22:251, 1940

                 80.    Cook  WA:  Maximum  allowable concentrations of  industrial atmospheric
                       contaminants.  Ind  Med 14:936-46, 1945

                 81.    Methyl  alcohol  (methanol), AIHA Hygienic Guide Series.  Southfield,
                       Michigan, American  Industrial Hygiene Association,  1964

                 82.    American  Conference of Governmental Industrial  Hygienists, Committee
                       on Threshold Limit  Values:  Documentation of Threshold  Limit  Values
                       for  Substances  in Workroom   Air,  ed 3. Cincinnati, ACGIH, 1971, pp
                       155-56

                 83.    American  Conference   of  Governmental Industrial Hygienists:  .TLVs—
J Ji                     Threshold Limit Values for Chemical Substances  and  Physical Agents in
                       the Workroom Environment  with Intended Changes  for  1974.  Cincinnati,
                       ACGIH, 1974
                 84.   Winell  MA:    An  international  comparison  of  hygienic  standards  for
                       chemicals in the work environment.   Ambio  4:34-36,  1975,  p  2J
                                          /3.6-3-f

-------
85.   Smelyanskiy ZB, Ulanova IP:  [New standards for peraissible levels of
     coxic gases, fumes, dust in che air of  work  areas.]  Gig  Tru  Prof
     Zabol 5:7-15, 1959 (Rus)

86.   Czechoslovakia  Committee  of HAG (J Teisinger, chmn):  Documentation
     of MAC in Czechoslovakia.  Prague, June 1969, pp 114-15

87.   Elkins, HB, in Patty FA (ed):  Industrial Hygiene and Toxicology, rev
     ed 2; Toxicology (Fassett DW, Irish DD, eds).  New York, Interscience
     Publishers, 1963, vol 2, pp 1409-22,

88.   Methyl  alcohol  (methanol), AIHA Hygienic Guide Series.  Southfield,
     Michigan, American Industrial Hygiene Association, 1964
                                          •
89.   Methanol—Storage  and  Handling.   Wilmington,  Delaware, du Pont de
     Nemours Ca, W74, 10 pp

90.   National   Electric   Code   1975,   NFPA   No.   70-1975.    Boston,
     Massachusetts, National Fire Protection Association, 1975

91.   American  National  Standards—Occupational  and  Educational Eye and
     Face  Protection,  Z87.1.   New  York,  American  National  Standards
     Institute Inc, 1968
                               ' ~s ' ^
                           *•"'/_!)  /<*.

-------
                                                No. 127
S,S'-Methylene - 0,0,0',o'-Tetraethyl Phosphorodithioate

            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 accuracv.
                           i i~
                        *«*Tj /  /'

-------
                            PHOSPHORODITHOIC ACID,
              S,S'-METHYLENE,0,0,0',0'-TETRAETHYL ESTER  (ETHIQN)
                                   Summary

     The S,S'-methylene,0,0,0',0'-tetraethyl ester  of phosphorodithoic acid,
ethion, has  not shown mutagenic  effects  in mice or  teratogenic  effects  in
fowl.  Subcutaneous injection of the  compound into  atropinized chickens pro-
duced neurotoxic effects.  There is no available information on the possible
carcinogenic effects of ethion.
     Ethion has  shown  acute toxicity in  stonefly  naiads  at  a  96-hour LC5Q
range from 1.8 to 4.2 jjg/1.
                              J3.7-J

-------
 I.   INTROOUCTON
      0,0,0',0'-Tetraethyl-S,S'-methylene bisphosphorodithioate (CAS registry
 number 563-12-2),  also called  ethion,  is an  insecticide and  miticide made
 from phosphorus pentasulfide (SRI, 1976).  Ethion  has the following physical
 and chemical properties -(Windholz, 1576; FAQ, 1569):
               Formula:                       C9H22°4P2S4
               Molecular Weight:              384.48
               Melting Point:                 -12°C to -13°C
               Density:.                      1.22020
               Vapor Pressure:                Practically non-volatile at
                                             ordinary temperatures
               Solubility:                    Insoluble in water, soluble in
                                             organic solvents
               Consumption:                   0.7 million Ibs/year (SRI,  1576)
      Ethion is a  pre-harvest topical insecticide  used  primarily on  citrus
 fruits, deciduous  fruits,  nuts and cotton (SRI, 1976).   It  is  also used as a
 cattle  dip for ticks and  'as a  back-line treatment  for  buffalo  flies  (FAO,
 1969):
'll.   EXPOSURE
      A.    Water
           Pertinent data  could  not be  located  in  the available  literature.
 Water contamination from ethion  manufacturing may be minimal due  to  the com-
 mon use of industrial wastewater treatment plants (U.S. EPA, 1977).
     3.    Food
           Residues  on a variety of foods have  been reported (FAO,  1969).  A
 sampling shows the  residues on  fruits and vegetables .range from 10.4 ppm for
 raisins to less than 0.1 ppm for almonds.  The majority  are less  than  1 ppm.
 Treated cotton  showed no  residue  in  the seed.   Tea  at harvest showed 'resi-
 dues  of up to 7 ppm; since tea  is blended  prior to sale, residues are  lower


-------
when  consumed.   Lactating  cows  fed up to 20 ppm radioactive ethion  showed  no
residues  in  their  milk.   In  meat,  the  highest  radioactivity was  in the
liver;  however,  chemical analysis showed these  residues were not ethion but
metabolites.  , When  animals were  dipped,  residues  from' skin  absorption  of
ethion  were found  in the body fat.
      C.   Inhalation and Dermal
          Pertinent  data could not be  located in the available literature.
III.  PHARMACOKINETICS
      A.   Absorption
          Results  of acute toxicity studies in  animals indicate that ethion
is absorbed following oral  and dermal  exposure (Gaines,  1969).
      3.   Distribution
          Following  feeding of  dairy cattle with  ethion,  small  amounts of
the  unchanged compound  were  found  in milk and fatty  tissues  (Vettorazzi,
1976) .           '
      C.   Metabolism
          Rao and  McKinley (1969)  have reported that _in_ vitro  metabolism of
ethion  occurs through  oxidative desulfuration  of  the  compound by chicken
liver homogenates.
     D.   Excretion
          Pertinent  data could  not  be located  in the  available literature.
Based on studies  of  other organophosphorous insecticides, it may  be antici-
pated that  ethion metabolites  would  be  eliminated primarily  in the  urine
(Matsumura,  1975).
IV .   EFFECTS
     A.    Carcinogenicity
          Pertinent data could not be located in  the available literature.


-------
      8.   Mutagenicity
          Vettorazzi  (1976)  has  cited an  unpublished study which  found no
dominant lethal effects in mice administered ethion.
      C.   Teratogenicity
          Oral administration  of ethion (100 ppm)  to  chickens,  chukars,  and
quail failed  to  produce teratogenic or adverse reproductive  effects (Abbott
and Walker, 1972).
      0.   Other Reproductive Effects
          Oral feeding  of ethion  to  chickens,  chukar,  and quail  failed to
affect egg hatch (Abbott and Walker, 1972).
      E.   Chronic Toxicity
          Subcutaneous injection of atropinized chickens with 400  mg/kg eth-
ion produced  neurotoxic effects '(flaccid  paralysis) (Gaines, 1969).   Ethion
will produce anti-cholinesterase effects in  mammals (Vettorazzi,  1976),
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Sanders  and  Cope  (1968)  observed  96-hour  LCCQ  values  ranging
from  1.3 to  4.2  ug/1 for stonefly naiads  (Pteronarcys califomica)  exposed
to ethion.
     3.   Chronic Toxicity,  Plant Effects and Residues
          Pertinent data could  not be  located in the available literature.
VI.  EXISTING GUIDELINES AND  STANDARDS
     A.   Human
          The World  Health  Organization (FAO, 1969) 'has established an  ADI
level of 0.005 mg/kg for ethion based  on cholinesterase inhibition  studies.
  '   9.   Aquatic
          Pertinent data could  not be  located in the available literature.
                                     / S\a
                                    / _> I Q  *
                                     7
                                 I2.T-B

-------
                                   REFERENCES
 Abbott,  U. and  N.  Walker.   1972.   Effects of  pesticides  and  related  com-
 pounds  on  several  avian  species,  chemistry and  toxicology of agricultural
 chemicals.   Summary  Report 1971.   Food Protection  and  Toxicology Center.,..
 University  of California at Davis,  p. 9.

 Food  and  Agriculture  Organization/World  Health Organization.  1969.  Evalua-
 tions of  some pesticide residues  in  food.   The monographs  FAO/WHO/Pl:1968/-
 M/9/1.

 Gaines, T.   1969.  Acute  toxicity  of  pesticides.   Toxicol. Appl. Pharmacol.
 14: 515.

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

 Rao,  S. and w.  McKinley.   1969.   Metabolism of organophosphorus insecticides
 by liver homogenates  from  different species.  Can. Jour. Biochem.  47: 1155.

 Sanders, H.O. and 0.8. Cope.   1968.   The relative toxicities of several pes-
 ticides  to  naiads   of  three  species  of  stoneflies.   Limnol.  Oceanogr.
 13: 112.

 Stanford  Research Institute.  1976.   Chemical Economics  Handbook,  Insecti-
 cides..

 U.S.  EPA.   1977.  Industrial  process  profile for  environmental use:  chapter
 8, pesticides industry.  U.S. Environ. Prot. Agency, U.S. NTIS PB 266 225.

 Vettorazzi, G.  1976.  State  of the art  of  the toxicological evaluation car-
 ried out by the joint FAO/WHO  meeting  on pesticides residues.   II.  Carbamate<
 and  organophosphorus  pesticides   used  in   agriculture  and public  health.'
Residue Reviews.  63:  1.

Windholz,  M.  (ed.)    1976.  The Merck Index, 9th  ed.   Merck and Co.,  Inc.,
Rahway, New Jersey.

-------
                                     No. 128
        Methyl Ethyl Ketone

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

           APRIL 30, 1980
              -J *s* A -
               J  y ^^
          /a ?-

-------
                         . 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.
                              > r*>'i.it--
                             y j ^i

-------
                                                    SJ-27-10








                     Methyl Ethyl Ketone






I.   INTRODUCTION




     Methyl 'ethyl ketone or (MEK) as it is commonly referred




to i3 a clear, colorless, volatile liquid (VP of 100 mm at 25°C)




with a molecular weight of 72.12.  It has a melting point of




-86.35°C and a boiling point of 76.6°C.  It is very soluble




in water (25.5 g/loo at 2 percent) and soluble in all




proportions in alcohol, ether, acetone and benzene.2  it is




also highly flammable (22"? - open cup).3




     MEK is produced and used as a solvent in nitrocellulose




coatings and vinyl films; in the synthesis of colorless




resins; in the manufacture of smokeless powder;  in paint




removers, cements, adhesives, and cleaning fluids; in printing




industry; as a catalyst carrier; in lube oil dewaxing and in



acrylic coatings.^




II.  ROUTES OP EXPOSURE




     MEK is rapidly absorbed through Che skin by inhalation.




III. PHA&MACOKINETICS




     MEK occurs in trace amounts in normal human urine and




may have a dietary origin.^  Most probable precursor is




  - methylacetoacetic acid.^-




     Urine of rabbits exposed to MEK reported to contain




glucuronide of 2-butanol.3-




IV .  EFFECTS ON MAMMALS



     The chief effect of MEK is narcosis but is  also a strong*



irritant of the mucous membranes of the eyes and nose.  The




oral LD50 for rats is 3.3 g/kg and the inhalation LC50 is
                            /2.S--.3

-------
around 700 ppm.l




     Repeated exposure of guinea pigs for 12 weeks to 235 ppm




caused no symptoms.^




     Lethal doses in animals caused marked congestion of




internal organs and slight congestion of brain.  Lungs showed




emphysema (see Table 1) .




     Slight throat irritation in humans occured at 100 ppm




and in eyes at 200 ppm.




     Dermatoses among workers having direct contact and



exposed to vapors are not uncommon.  Some workers complained




of numbness of fingers and arms.-'-

-------
                           Table 1

          Effects of Methyl Ethyl Ketone on Animals
           Concentration/
              Duration
                              Animal
Methyl
 Ethyl
  Ketone
33,000-100,000 ppm/200 tain.   Guinea Pigs
           3,300 ppm/810 min.

           1,125 ppm/24 hr/3,55d
           1,126 or 2,618 ppm/7 hr/d
             on d 6-15 of gestation
                              Guinea Pigs

                              Rats
                              Pregnant
                                Rats
Effects
Gasping, death,
emphysema, slight
congestion of the
brain, marked
congestion of the
systemic organs
especially the
lungs and corneal
opacities

No abnormal signs

No evidence of
peripheral neuro-
pathy

Embryo toxicicy,
facotoxicity and
possible terato-
genicity

-------
                          References
1.   Toxicity and Metabolism of Industrial Solvents.

2.   Ketonic Solvents, Open File Report, Working Draft prepared
     by Clement Associates, Inc., September 19, 1978.

3.   Sax, N. Irving, Dangerous Properties of Industrial Materials,
     Fourth Edition, '1975, Van Nostrand Reinhold, New York,
     New York  10001

4.   Patty, F. A., Schrenk, H. H., Yant W. P.: Acute Respone of
     guinea Pigs to Vapors of Some New Commercial Organic
     Compounds—VIII.  Butanone.  U.S. Public Health  Pep 50:
     1217-28, 1935.

5.   Spencer, P. S., Schaumburg, H. H. : Feline Nervous System
     Response to Chronic Intoxication With Commercial Grades
     of Methyl n-Butyl Ketone, Methyl Isobutyl Ketone, and
     Methyl Ethyl Ketone.  Toxicol. Appl. Pharmacol. 37:301-11,
     1976.

6.   Griggs, J. H. , Waller, E. M. , Palmisano, P. A., Niedermeier,
     W.: The Effect of Noxious Vapors on Embryonic Chick Develop-
     ment, Ala. J Med. Sci.  8:342-45, 1971.

-------
                                      No. 130
       Methyl Methacrylate

  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.

-------
                             METHYL METHACRYLATE
                                   Summary

     Oral or skin  painting studies in  rats  have failed to show carcinogenic
effects of administration of methyl methacrylate.  Implantation of  the  com-
pound in mice also failed to produce tumors.
     Exposure of  rats  to a mixture  of chloroprene and methyl  methacrylate
produced an increase in lymphocyte chromosome aberrations.   Increased  chrom-
atid breaks and chromosome breaks have been reported in workers exposed to
this same chemical mixture.
     Teratogenic effects  (hemangiomas)  have been reported  following  intra-
peritoneal administration of methyl methacrylate to pregnant rats.  Inhala-
tion exposure of pregnant rats  to an  acrylic cement containing  methyl  metha-
crylate failed  to  produce  significant teratogenic effects.
     Ninety-six hour LC5Q values for  four  species of  fish range  from 159
to 368 ppm.   Inhibition of cell multiplication of an alga begins at 120 ppm.
                                      s
                               730-3

-------
 I.    INTRODUCTION
      Methyl methacrylate,  CAS  registry  number  80-62-6,  is  a  colorless,
 clear,  volatile  liquid.   It is made from acetone cyanohydrin which  is  hydro-
 lyzed in  sulfuric acid to yield methacrylamide sulfate, which is  then  treat-
 ed with methanol to yield methyl methacrylate.   It has the following  physi-
 cal  and  chemical  properties  (Windholz,  1976;  Hawley,  1971;  Weast,   1972;
 Verschueren, 1977):
              Formula:                  C5H802
              Molecular Weight:         100.12
              Melting Point:.            -48.2°C
              Boiling Point:            101°c
              Density:                  0.944020
              Vapor Pressure:           28 torr 1 20°C
              Solubilityr               Sparingly soluble in water, miscible
                                        in alcohol, benzene, ether, etc.
              Production:               706 million Ibs (1973) (Gruber,  1975)

     virtually all  the methyl  methacrylate produced in this  country is used
 for  polymers,  e.g.,  surface  coating  resins and  plastics (plexiglass, lu-
 cite), ion exchange resins, dentures, etc.
 II.  EXPOSURE
     A.   Water
          According to Gruber  (1975),  about  1.8  g of methyl methacrylate per
kilogram final product  (methyl methacrylate) is present in wastewater.  The
amount  of  methyl methacrylate entering  domestic, water supplies  is probably
small.
     B.   Food
          Polymethyl methacrylate  is  used  for  food  storage.   A  very  .small
amount of  residual monomer may  migrate into food from the  polymer.
                                      If

-------
     C.    Inhalation
           Fugitive  emissions  from  production,  storage,  and  transportation
probably  constitute the  only major  sources  of methyl  methacrylate in  the
air.   The concentration would most  likely  be highest in production facili-
ties.  Production was estimated  to be 7.9 million pounds in 1974  (U.S.  EPA,
1976).   A 550-million  pound-per-year production facility  with 0.5  percent
loss emits 39.6 grams of  methyl  methacrylate  per second.   If this  is consi-
dered  to be a  virtual  point  source,  the downwind concentration 500 meters
avray would be 1.5 ppm one-hour average (U.S. EPA,  1976).
     0.    Dermal
           Pertinent data could not be located in the available literature.
III. PHARMACQKINETICS
     A.    Absorption and Distribution
          Pertinent data could not be located  in the available literature.
     3.   Metabolism
          Bratt and Hathway  (1977)  found that  up to 88  percent of a single
methyl(^C) methacrylate  dose  of  5.7  mg/kg  body weight  was expired  as C07
within 10  days.  Neither- the route of administration nor the specific label-
ling of  the propylene residue changed this  value.   Small amounts of several
metabolites  were  excreted   in  the  urine,   including  i4C-methylmalonate,
^•4C-succinate,  2-formylpropionate,  and possibly ^C-/-hydroxybutyrate.
          Corkill,  et  al.  (1976)  found  that  the  disappearance of methyl
methacrylate in  human  blood  _!£ vitro  showed  a  first order dependence on
methyl methacrylate concentration.   The calculated  half-life was  20 to 40
minutes,   irrespective of  the  sex or  age  of the blood donor.   More than 40
percent of the initial  dose  of methyl methacrylate  was converted  to metha-
crylic acid within  90  minutes.
                                no-s

-------
      C.    Excretion
           Pertinent data could not be located in the available literature.
 IV.   EFFECTS
      A.    Carcinogenicity
           The  International Agency  for Research on Cancer (IARC, 1979) has
 evaluated  the  available data and concluded that there is not  enough  informa-
 tion  to determine  the  potential  carcinogenicity of  methyl methacrylate  to
 humans.  Borzelleca, et  al.  (1964)  observed no  treatment-related tumors  in
 male  and female Wistar rats administered  6,  60, or 2,000 mg/1 methyl metha-
 crylate  in their drinking water  for two years.  Oppenheimer,  et al.. (1955)
 found  no  local  tumors  in ten  Wistar rats painted  with methyl methacrylate
 three  times  per week for  four months and"observed for their entire life span.
           Another  study,  by Spealman,  et  al.  (1945),  in  which male  and
 female mice  received implants consisting of  0.075  gm of methyl methacrylate
 in a gelatin capsule also yielded negative results.
     8.    Mutagenicity                                                   '
           The  only  data available on the mutagenic  effects of methyl metha-
 crylate  are  two studies involving exposure  to  a mixture of  chloroprene  and
 methyl methacrylate (Bagramjan, et  al.  1976; Bagramjan and  Babajan, 1974).
 In  both  studies,  an increased frequency  of  chromosomal  aberrations  were
 found  in rats   exposed  to the mixture.  Bagramjan,  et al.   (1976)  also  mea-
 sured  a  significant increase  in  chromatid breaks  and chromosome breaks  in
 the lymphocytes of  workers  exposed  to  a  mixture of chloroprene  and methyl
methacrylate.
     C.   Teratogenicity
          Singh, et al.  (1972a,b)  and  Autian  (1975) injected  intraperito-
neally three groups  of  pregnant Sprague-Oawley  rats  with methyl methacrylate
at doses of  0.1, 0.2, or 0.4 g/kg body weight on days 5, 10,  and  15  of ges-

-------
 cation.   In  animals  administered  the  two  higher  doses,  a significantly
 greater  number  of hemangiomas were seen at various  sites.   All three groups
 exhibited  reduced  fetal, weights,  but no  significant increase  in skeletal
 defects  was observed in any group.
          McLaughlin, et'al.  (1978)  exposed pregnant mice to a vapor concen-
 tration  of 1,330  ppm  methyl methacrylate (as acrylic  cement,  Simplex  p) for
 two  hours  two times per  day  for days 6  through 15 of  gestation.   No feto-
 toxic'or teratogenic effects  were noted  other than a  slight  decrease  in the
 average  fetal weight.
     0.   Other Reproductive Effects
          Pertinent data could not be located in the available literature.  .
     E.   Chronic Toxicity
          Spealman,  et   al.   (1945)  conducted  a   series   of   sub-chronic
 inhalation  ex-  periments  involving guinea  pigs, and  dogs.   Guinea  pigs
 exposed  to  39.0 mg/1  methyl  methacrylate  for  two hours per day  for  three
 days exhibited  significant liver  degeneration,  while dogs  exposed to  46.3
 mg/1 methyl  methacrylate  for two  hours  per day for  8 to 15  days  exhibited
 liver degeneration and tubular degeneration of the kidneys.
          Sorzelleca,  et  al.  (1964)  administered 6,  60,  and  2,000 ppm of
 methyl methacrylate in drinking  water to male and  female  rats for  a  period
 of two years.   Weight  gain was decreased for the first  few weeks in animals
 given the highest dose.  No changes  in hematological values or urine concen-
 trations of  protein and  reducing agents were  noted..  Females  receiving the
 highest dose level exhibited an increase  in kidney to 'body weight  ratios.
          Blagodatin,  et  al.  (1970) reported symptoms of  headache, pain in
 the- extremities,  fatigue,  sleep  disturbance,  loss of  memory, and  irritabi-
 lity in  152 workers exposed to concentrations of 0.5 to  50  ppm methyl metha-
crylate.   Most of the  workers  had been employee  for  longer than 10 years.
                                    ]^^£r
                                  "f J J U "'
                                 S30-7

-------
      F.    Acute Toxicity
           No  detectable  acute  effects were  noted  in workers  employed  in
 manufacturing  polymethyl methacrylate  sheets  (Cromer and Kronoveter,  1976).
 The  airborne concentrations of methyl methacrylate  varied  from  4  to  49  ppm.
 V.    AQUATIC TOXICITY   .
      A.    Acute Toxicity
           Pickering  and  Henderson  (1966)  observed  the  fallowing 96-hour
 ^50 va^ues  f°r  fish  exposed  to  methyl  methacrylate:   fathead   minnow
 (Pimephales. promelas)  - 159  ppm  in  soft water  (20  mg/1);  fathead  minnow -
 311  ppm  in hard water (360  mg/1); bluegill  (Lepomis macrochirus) - 357 ppm
 in  soft water  (20  mg/1);  goldfish  (Carassius auratus)  - 277 ppm  in soft
 water (20  mg/1);  guppies (Lebistes retieulatus) - 368  ppm in soft water (20
 mg/1).
     B.   Chronic Toxicity
          Pertinent data could not be located in the  available  literature.
     C.   Plant Effects
          Inhibition of  cell multiplication  of the  alga, Microcystis aerugi-
 nosa, by methyl methacrylate begins at 120 ppm (Bringmann and Kuhn 1976).
 D.   Residues
          Pertinent data could not be located in the available literature.
 VI.  EXISTING GUIDELINES AND STANDARDS
     A.    Human
          Guidelines have been  established for exposure to methyl methacry-
 late by  the American  Conference  of Governmental  Industrial  Hygienists  and
QSHA.  Both the TLV and the  federal standard have  been set  at  100 ppm (or
410 mg/rn3)  (ACGIH,  1977; 29 CFR  1910).

-------
     B.   Aquatic
          No guidelines  have been established for the  protection  of aquatic
organisms from acute  or  chronic methyl methacrylate toxicity because  of the
lack of pertinent data.

-------
                                   REFERENCES
 American Conference of Governmental  Industrial  Hygienists.   1977.  Threshold
 limit  values  for  chemical  substances  and physical  agents in  the workroom
 environment.  Cincinnati, Ohio.

 Autian,  J.'   1975.   Structure-toxicity  relationships  of  acrylic  monomers.
 Environ. Health Perspect.  11: 141.

 Bagramjan, S.B.. and E'.A. Babajan.   1974.   Cytogenetic study of the mutagenic
 activity of chemical  substances  isolated  from Nairit  latexes  MKH and LNT-1.
 (Russ.) Biol.  Zh. Arm.  17: 102.

"Bagramjan, S.B., et al.   1976.  Mutagenic effect  of  small  concentrations'of
 volatile substances emitted from polychloroprene  latexes LNT-1 and MKH,  dur-
 ing their combined uptake by the animal.   (Russ.) Biol. Zh.  Arm.  19: 98.

 Blagodatin, V.M.,  et  al.   1970.   Issues  of  industrial hygiene  and occupa-
 tional  pathology  in  the manufacture  of  organic glass.   (Russ.)  Gig.  Tr.
 Prof. Zabol.  14: 11.

 Borzelleca, J.F.,  et al.   1964.    Studies on the chronic oral  toxicity  of
 monomeric ethyl aerylate and methyl  methacrylate.   Toxicol. Appl. Pharmacol.
 6: 29.

 Bratt,  H.  and  O.E.  Hathway.   1977.   Fate of  methyl methacrylate  in  rats.
 Br. Jour. Cancer.  36: 114.

 Bringmann,  G.  and R.  Kuhn.   1976.   Vergleichende Befunde  der Schadwirkung
 wassergefahrdender Stoffe genen Bakterien  (Speudomonas putida) und Blaualgen
 (Microcystis aeruginosa).  Nwf-Wasser/Abwasser,  (117)  H.9.

 Corkill, J.A., et al.   1976.   Toxicology of methyl methacrylate:  The rate of
 disappearance of methyl methacrylate in  human blood i.n vitro.   Clinica Chim-
 ica Acta.  68: 141.

 Cromer, J.  and  K.  Kronoveter.  1976,   A study of methyl methacrylate  expo-
 sures and  employee health.   National  Institute  for Occupational  Safety and
 Health, Cincinnati, Ohio.  DHEW 77-119.

 Gruber,  G.I.    1975.   Assessment   of industrial  hazardous  waste  practices,
 organic chemicals,  pesticides, and explosive industries.  TRW  Systems Group,
 NTIS PB-251 307.

 Hawley, G.G.  (ed.)  1971.   The Condensed Chemical Dictionary.   8th ed., Van
 Nostrand Reinhold Co.,  New York.

 International  Agency for Research  on Cancer.   1979.   IARC  monographs on the
 evaluation of  the carcinogenic risk of chemicals  to humans.   Vol.  19,.Methyl
 methacrylate:  187.

 McLaughlin, R.E., et al.  1978.  Methyl  methacrylate:  a study  of teratogeni-
 city and  fetal  toxicity  of  the vapor in the mouse.   Jour.  Bone  Jt.  Surgery
 Am.  Vol. 60A: 355.

-------
Oppenheimer,  3.S.,  at al.   1955.   Further  studies  of polymers  as carcino-
genic agents in animals.  Cancer Res.  15: 333.

Pickering,  Q.H.  and C. Henderson.   1966.   Acute toxicity  of some important
petrochemicals to fish.  Jour. Water Poll. Con. Fed.  38: 1419.

Singh,  A.R.',  et  al.   1972a.  Embryonic-fetal toxicity and  teratogenic ef-
fects of a group of methacrylate esters in rats.  Jour. Dent. Res.  51: 1532.

Singh,  A.R.,  et al.   1972b.  Embryo-fetal toxicity  and  teratogenic effects
of  a group of  methacrylate  esters  in  rats  (Abstract  No.  106).   Toxicol.
Appl. Pharmacol.  22: 314.  .

Spealman,  C.R.,  et  al.    1945.   Monomeric  methyl  methacrylate:  Studies • on
toxicity.  Ind.  Med.  14: 292.

U.S. EPA.   1976.   Assessment of methyl methacrylate  as  a  potential air pol-
lution problem.   U.S. Environ. Prat.  Agency, NTIS P8-258 361.

verschueren, K.   1977.   Handbook of Environmenal Data, on  Organic Chemicals.
Van Nostrand Reinhold Co., New York.

Weast,  R.C.   1972.   Handbook of Chemistry  and Physics.   53rd  ed., Chemical
Rubber Company,  Cleveland, Ohio.

Windholz, M.  (ed.)   1976.   Merck Index.  9th  ed.,  Merck  and Co., Inc., Rah-
way, New Jersey.
                             I  3 o-lt

-------
                                      No. 131
            Naphthalene

  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.

-------
                               NAPHTHALENE
                                 Summary


     Naphthalene is present in ambient water as well  as  drinking water.
Naphthalene can be absorbed by any route, although  the efficiency of
absorption has not been determined.  The  toxicological properties are due
to the formation of highly reactive metabolites.  Chronic  exposure produces
cataracts, hemolytic anemia, and kidney disease.  Naphthalene  can cross
the placenta and produce these effects on newborns.   Naphthalene has been
found to be nonmutagenic in several microsomal/bacterial assay systems.
Chronic toxicity  studies of naphthalene  have shown it to  be noncarcinogenic.
     Naphthalene has been shown to be acutely toxic in freshwater fish
                                                                          *
with LC5Q values of 150,000 ug/1 being reported in  one static  bioassay.
Freshwater invertebrates were more sensitive with LC5Q values  of 8,570
jig/1,  as were marine fish with LC5Q values ranging from 2,350 to 2,600  .

-------
INTRODUCTION



     This profile is based on the Ambient Water Quality Criteria Document



for Naphthalene (U.S. EPA, 1979).



     Maphthalene (CigHs; molecular weight 128.16) is a bicyclic, aromatic



hydrocarbon which in a pure grade, forms a white crystalline solid at



room temperature  (Windholz, 1976). Pure naphthalene has a melting point



of 80.2°C, a boiling point of 217.96°C (Manufacturing Chemists Assoc.,



1956) and a  vapor pressure of 0.0492 mm Hg at 19.8°C (Gil'denblat, et



al. 1960).  Naphthalene is water soluble, with solubility ranging from



30,000 ug/1 (Mitchell, 1926) to 40,000 ug/1 (Josephy and Radt, 1948).



Naphthalene vapor and dust can form explosive mixtures with air (Windholz,



1976).  Naphthalene is used as an intermediary in the production of dye



compounds, in the formulation of solvents, lubricants and motor fuels,



and as a feedstock in the synthesis of phthalic anhydride.   Naphthalene



is also used directly as a moth repellant, insecticide,  antihelminthic ,



vermicide, and an intestinal antiseptic (U.S. SPA, 1979).   In. 1974,



production of naphthalene was approximately 2.9 x 10^ metric tons (U.S.



SPA, 1976).








II.  EXPOSURE



     A.   Water



          The two major sources of naphthalene in the aquatic environment



are from industrial effluents and from oil spills.  The  final effluents



of sewage treatment plants receiving discharges from these  industrial



facilities have been noted to have up to 22 ug/1 naphthalene, while. natural



waters have up to 2.0 ug/1, and drinking water supplies  have up to 1.4



     naphthalene (U.S. EFA, Region IV, unpublished data).
                                            131-1

-------
     B.    Food




          The U.S. EPA (1979) has estimated the weighted average  bio-




concentration factor for naphthalene to be 60 for the edible  portions of



fish and shellfish consumed by Americans.  This estimate was  based on



octanol/water partition coefficients.



     C.    Inhalation




          In the ambient air, inhalation of naphthalene is negligible



with vapor concentrations ranging from 0.00005 to 0.0001 ug/m3 and




particulate concentrations ranging from 0.000003 to 0.00025 ug/m^



(Krstulovic, et al. 1977).  Industrial exposure can range from 0.72 yig/m^



to 1.1 x 10^ ug/m3  in the vapor phase (Bjrseth, et al., 1978b; Robbins,



1951) and from 0.09 ug/m3 to 4.40 pg/m^ in particulates (Bjrseth, 1978a,



1978b).   Naphthalene has also been found in cigarette smoke condensate



(Akin, et al. 1976).



III.  PHARMACOKINETICS



     A.    Absorption



          Little detailed information is available on the absorption of



naphthalene in man or animals. Adequate amounts of naphthalene can be



absorbed when ingested as a solid, or by inhalation, to cause significant



toxicity (U.S. EPA, 1979).  Absorption seems to be facilitated if naphthalene



is dissolved in oil (Solomon, 1957), and hindered if naphthalene, is bound




to protein (Sanborn and Malins, 1977).



     B.    Distribution



          Naphthalene distributes widely after absorption.  In mallards,



the relative distribution of naphthalene was as follows:  greatest* in



skin, followed by liver,  brain, blood, muscle, and heart (Lawler, et al.



1978).

-------
     C.   Metabolism



          Naphthalene is first metabolised by hepatic mixed-function




oxidases to an epoxide, which is an obligatory step  in  the metabolism  of




naphthalene.  Further metabolism can occur leading to the formation of a




variety of compounds.  Most of these compounds are enzymatically conjugated




with glucuronic acid or sulfate.  During metabolism  a number of highly




reactive compounds are formed such as  1,2-dihydroxynaphthalene and 1,2-




naphthoquinone (U.S. EPA, 1979).



     Naphthalene metabolites undergo further conversions in the eye.




This multi-step pathway can lead to the formation of 1,2-naphthaquinone




which can irreversibly bind to lens protein and amino acids (Van Heyningen



and Pirie, 1966).




     D.   Excretion




          Naphthalene has not been identified in urine  after absorption. •




With sufficient absorption of naphthalene to result  in  toxicity to an  18




month old infant, Mackell, et al. (1951) noted metabolites of naphthalene




in the urine that were still identifiable two weeks  after exposure but




which had disappeared 18 days after exposure.



     1-Napthol is the predominant spontaneous decomposition product of



the epoxide of napohthalene.  1-Napthol is excreted  unchanged as well  as



congugated with glucuronic acid or sulfate prior to  excretion.  The finding



of 1,4-nathoquinone in the urine of a child poisoned with naphthalene



(Mackell, at al. 1951) suggests that 1-napthol can also be further oxidized



in mammals (Cerniglia and Gibson, 1977).



IV.  EFFECTS



     A. Carcinogenicity




          In attempts to demonstrate its carcinogenicity, naphthalene  has



Seen given orally, subcutaneously, implanted in the  bladder, and painted

-------
on the backs of a number of animal species  (U.S.  EPA,  1979).   In  these




experiments naphthalene caused no increase  in tumor  formation.  Two




experiments have produced increases in lymphosarcoma and  lymphatic




leukemia after treatment with coal tar derived naphthalene.  The  first of




these studies (Knake, 1956) was complicated by the presence of  10 percent




impurities in the naphthalene and the painting of the  injection site with




carbolfuchsin, a known experimental carcinogen, prior  to  injection.  In




the second study (Knake, 1956) where excess leukemia was  noted, naphthalene




was dissolved ,in benzene, a known human leukemogenic agent,  and painted on




the backs of mice. Benzene treatment resulted in  no  leukemia.  Skin




papillomas have been produced on mice following painting  with 1,4— naththa-




quinone, a metabolite of naphthalene (Takizawa, 19^0).  Also, Pirie (1968)




noted abnormal mitotic figures in metaphase and cell overgrowth in the
                                                                        *



epithelial cells of the lens of rabbits given 1 g/kg/day  of naphthalene




by gavage.




     8.   Mutagenicity




          Naphthalene has been found to be nonmutagenic in several microsomal/




bacterial assay systems (McCann, et al. 1975; Kraemer, et al. 1974).




     C.   Teratogenicity




          Pertinent data could not be located in  the available literature.




     D.   Other Reproductive Effects




          Naphthalene or its metabolites can cross the placenta in sufficient




amounts to cause fetal toxicity (Zinkham and Childs, 1958; Anziulewicz,




et al.  1959)-   When a metabolite of naphthalene," 2-naphthol, was admin-




istered to pregnant rabbits, their offspring were born with cataracts and




evidence of retinal damage (Van der Hoeve, 1913).

-------
     E.   Toxicity

          Oral administration of two percent naphthalene or 2-napthol  to

rats for at Least 60 days resulted in the development of cataracts

(Fitzhugh adn Busckke, 19^9).  Van Heyningen and Pirie  (1976) dosed  rabbits

daily by gavage with 1000 mg/lcg of naphthalene  for a maximum of 28 days.

Lens changes developed after the first dose, and retinal changes developed

after the second dose.  Rabbits fed 1000 mg/kg/day developed cataracts

between day 3 and 46.  Topical application of a 10 percent solution  in oil

to the eyes of rabbits did not produce cataracts after  a period of 50  days.

Intraperitoneal injection of 500 mg/kg of naphthalene in an oily solution

produced weight loss over a period of 50 days (Ghetti and Mariani, 1956).

Hemolytic anemia- with associated jaundice and occasionally renal disease

from precipitated hemoglobin has been described in newborn infants,     4

children and adults after exposure to naphthalene by ingestion, inhalation,

or possibly by skin contact (U.S. EPA, 1979).   The extent or duration  of

exposure was not given.  Mahvi, et al. (1977) noted a dose related damage

to bronchiolar epithelial cells in mice given intraperintoneal injections

of naphthalene in corn oil.  Bronchiolar epithelial changes were not

noted in two control groups.  The authors noted minor bronchiolar epithelial

changes in the treated group receiving 67.4. mg/kg of naphthalene.

Those mice receiving higher doses (128 and 256  mg/kg of naphthalene)

developed reversible necrosis of bronchiolar cells.

     F.   Other Relevent Information

          Alexandrov and Frayssinet (1973) demonstrated that naphthalene

administered intraperitoneally to rats could inhibit the mixed-function
                                                                  »
tnicrosomal oxidase enzyme system, and could also inhibit the induction of

these enzymes by 3-
-------
V.   AQUATIC TOXICITY




     A.   Acute




          For the freshwater mosquitofish  (Gambusia affinis)  a  96-hour




ststic bioas'say provided an LCcg value of  150,000 ug/1  (Wallen,  et  al.




1957), while the freshwater cladoceran (Daphnia magna)  was  shown to have




an US-hour LC5Q value of 8,570 ug/1 (U.S.  EPA, 1978).   Marine organisms




tended, to be somewhat more sensitive to naphthalene with an 24-hour static




^050 value of 2,400 ug/1 for the sheepshead minnow (Cyprinodon  variegatus).




Two 24-hour static LC5Q values of 2,500,' 2,600 were obtained  for two




species of marine shrimp, (Penaeus aztecus) and (Palaemonetes pugio),




respectively (Anderson, et al. 1974).  A 96-hour LC5Q value of  2,350 ug/1




was obtained for grass shrimp (Palaemonetes pugio) (Tatem,  1976).




     B.   Chronic Toxicity




          A single embryo-larval test on the fathead minnow (Piaephales




promelas) stated that no effects were observed at concentrations as high




as 440 ug/1 (U.S. EPA, 1978).




          Data pertaining to the chronic toxicity of naphthalene for any




marine species could not be located in the available literature.




     C.   Plant Effects




          A 48-hour EC5Q value of 33,000 ug/1 for reduced cell  numbers




has been reported for the freshwater algae (Chlorella vulgaris)  exposed




to naphthalene.  Data pertaining to the effects of naphthalene  to marine




plants could not be located in the available literature.




     D.   Residues




          Using the octanol/water partition coefficient of  2,300  for




naphthalene, a bioconcentration factor for aquatic organisms  with an 8




percent lipid content has been estimated as 210.   Bioconcentration

-------
factors determined for niarine invertebrates ranged from 50 to 60 in the



marine copepod Calanus helgolandicus after one day (Harris, et al. I977a,



I977b) .to 5,000 in the copepod Eurytemcra affinis, after nine days,



(Harris, et al. I977b) indicating that equilibrium may not occur rapidly.



Bioconcentration factors of 32 to 77 after 1 to 24 hours were reported



for these 3 species of marine fish and one species of mussel (Lee, at al.



1972a; 1972b).




VI.  EXISTING GUIDELINES AND STANDARDS



          Neither the human health nor aquatic criteria derived by U.S.



SPA (1979'), which are summarized below, have gone through the process of



public review; therefore, there is a possibiliity that these criteria



will be changed.




     A.   Human



          The Occupational Safety and Health Administration standard for



exposure to vapor for a time-weighted industrial exposure is 50 tng/m3.



The American Conference of Governmental Industrial Hygienists (ACGIH,



1971) threshold limit value is 75 tng/m3, while at present the ACGIH also



suggests a maximum 15 minute exposure value of 75 mg/m3 (ACGIH, 1978).



The acceptable daily intake for naphthalene is 448 ^ug/day for a 70 kg



person.  The U.S.  EPA (1979) draft ambient water criterion  for



naphthalene is 143 ug/1.



     B.   Aquatic



          Criterion can not be derived for naphthalene for either fresh-



water or marine organisms, because of the lack of sufficient toxicological



data.
                               l-3/r/O

-------
                                  NAPHTHALENE

                                  REFERENCES
Akin,  F.J.,   at  al.   1976.   Identification  of polynuclear  aromatic hydro-
carbons in- cigarrette  smoke  and their importance as tumorigens.  Jour. Natl.
Cancer Inst.  57: 191.

Alexandrov,   K.   and-  C.  Frayssinet.   1973.   In   vitro  effect  of  some
naphthalene-related  compounds  on  aryl hyrocarbcn  (benzo(a)pyrene) hydroxy-
lase.  Jour.  Natl. Cancer Inst.  51: 1067.

American  Conference of Governmental  Industrial -Hygienists.    1971.   Docu-
mentation  of  the  threshold  limit values for substances in workroom air.  3rd
ed.  Cincinnati, Ohio.

American Conference  of Governmental Industrial Hygienists.  1978.  Threshold
limit  values  for  chemical  substances  and physical  agents in  the workroom
environment with intended changes for 1978.  Cincinnati, Ohio.

Anderson,  J.w.  et  al.   1974.   The  effects  of  oil  on  estuarine animals:
Toxicity uptake  and depuration,  respiration.   In;  pollution  and physiology
of marine  orgasnisms.  Adademic Press.' New York
                                                                           •<«
Anziulewicz,  J.A.,  et  al.   1959.  Transplacental naphthalene poisoning.  Am.
Jour. Obstet. Gynecol.   78: 519.

Bjorseth,  A.  et al.   1978a.    Polycyclic  aromatic  hydrocarbons  in  the work
atmosphere. II.  Determination  in  a coke  plant. Scand. Jour.  Work. Environ.
Health.  4: 212.

Bjorseth,  A.  et al.   1978b.    Polycyclic  aromatic  hydrocarbons  in  the work
atmosphere. I.  Determination in an aluminum  reduction  plant.   Scand. Jour.
Work Environ. Health.  4: 212.

Cerniglia,   C.E.  and  D.T.  Gibson.   1977.   Metabolism  of  napthalene  by
Cunninqhamella eleoans.  Appl. Environ. Microbiol.   34: 363.

Fitzhugh,  O.G.  and  W.H. Buschke.   1949.   Production of cataract in  rats by
beta-tetralol and other derivatives of naphthalene.   Arch.  Ophthal.  41: 572.

Ghetti, G. and L.  Mariani.  1956.   Eye  changes  due to  naphthalene.  Med.
Lavoro.  47:  524.

Gil'denblat,  I.A.,  et  al.   1960.   Vapor  pressure over  crystalline naphtha-
lene.  Jour. Appl. Chem. USSR.  33: 245.

Harris, R.P.  et al.   1977a.  Factors  affecting the  retention  of a petroleum
hydrocarbon   by  marine  planktonic  copepods.   In:   Fate  and  Effetts   of
petroleum hydrocarbons in marine ecosystems and organisms.   Proc. Symp.  286.

Harris, R.P.  et  al.   1977b.   Accumulation of carbon-14-l-napthalene by  an
oceanic and an estuarine copepod during long-term exposure to  low-level con-
centrations.   Mar.  Biol.  42: 187.
                                   /3/-V

-------
Josephy,  E.  and F.  Radt,  (eds.)  1948.   Encyclopedia of organic  chemistry:
Series  III.  Elsevier Publishing Co.,  Inc.,  New  York.

Xnake,  E.   1956.  Uber  schwache geschwulsterzengende Wirkung  von  Naphthalin
und Benzol.  Virchows Archiv.  Pathol.  Anat.  Physiol.   329:  141.

Kraemer,  M.,' et al.   1974.   S^ typhimurium and §_._  coli to detect  chemical
mutagens.  Arch. Pnarmacol.  284: B46.

Xrstulovic,  A.M.,   et al.   1977.   Distribution  of  some  atmospheric  poly-
nuclear aromatic hydrocarbons.   Am. Lab.   9(7):  11.

Lawier,  G.C.,  et  al.   1978.   Accumulation  of  aromatic  hydrocarbons  in
tissues of petroleum-exposed  mallard  ducks  (Anas  olatyrhynchos).   Environ.
Sci. Technol.   12: 51.

Lee,. R.F..  et al.  1972a.   Uptake, metabolism and discharge of polycyclic aro-
matic hydrocarbons by marine fish.  Mar. Biol.   17:  201.

Lee, R.F.  et al.  1972b.   Petroleum hydrocarbons:   uptake  and discharge  by
the marine mussel Mytilus edulis.  Science.   177: 344.

Mackell,  J.V.,  et  al.   1951.   Acute hemolytic anemia  due  to ingestion  of
napthalene moth balls.   Pediatrics.  7: 722.
                                                                              A
Mahvi,  D.,  et  al.   1977.   Morphology of  a naphthalene-induced bronchiolar
lesion.  Am. Jour. Pathol.  86:  559.
                                                                      •.
Manufacturing  Chemists  Assoc.   1956.   Chemical  safety  data  sheets  SD-58:
Napthalene.  Washington, O.C.

McCann,  J.,   et al.   1975.   Detection  of  carcinogens  as  mutagen  in the
Salmonella/microsome test.   Assay of 300 chemicals.   Proc.  Natl.  Acad.  Sci.
72: 5135.

Mitchell,  S.  1926.   A  method  for  determining  the  solubility of sparingly
soluble substances.  Jour. Chem. Soc.  129:  1333.

Pirie,   A.  1968.   Pathology in  the eye of the naphthalene-fed rabbit.   Exp.
Eye Tes.  7: 354.

Robbins, M.C.   1951.  Determination of Napthalene in air.   Arch.  Ind.  Hyg.
Occuo.   Med.  4: 85.

Sanborn, H.R.  and  D.C.  Malins.   1977.   Toxicity and  metaoolism  of  naphtha-
lene: a study with marine  larval invertebrates.  Proc- Soc.  Exp.  3iol.  Med.
154: 151.

Solomon, T.   1957.   A  manual of pharmacology  and  its applications to  th^ra-
peutics and toxicology.  3th ed.  W.3. Saunders Co., Philadelphia.

Takizawa,  N.    1940.   Carcinogenic  action  of certain quinones.   Proc.  Imp.
Acad. (Tokyo)  16:  309.
                                    13 l-

-------
Tatem, H.E.   1976.   Toxicity and physiological affects  of oil and petroleum
hydrocarbons  on  astuarine  grass shrimp, Palaeminetes  pugio.   Holthuis Ph.D.
dissertation.  Texas A and M University.  133 pp.

U.S. EPA..  1971-1977.  Unpublished data from Region IV, Atlanta, Ga.

U.S.  EPA.   1976.  Organic  chemical producer's data  base program.  Chemical
No. 2701.  Radian Corporation.

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.

U.S. EPA.  1979.  Naphthalene: Ambient Water Quality Criteria.  (Draft)

Van Heyningen,  R. and  A.  Pirie.   1966.   Naphthalene cataract.  In:  M.U.S.
Dardenne,  ed.   Symposium  on  the  biochemistry  of the  eye.    Karger,  Asel,
Switzerland.

Van Heyningen,  R. and  A.  Pirie.   1976.   Naphthalene cataract  in pigmented
and albino rabbits.  Exp. Eye Res.  22: 393.

Van der  Hoeve,  J.   1913.   Wirkung  von napbthol auf  die  augen von menschen,
tieren, und auf fatale augen.  Graele Arch. Ophthal.  85: 305.

Wallen,  I.E.,  et al.   1957.   Toxicity of  Gambusia affinis  of  certain pure
chemicals in turbid waters.  Sewage Ind. Wastes.  29: 695.

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

Zinkham,  W.J. and 8. Childs.  1958.   A defect  of  glutathione metabolism in
erythrocytes  from patients  with   a   naphthalene-induced hemolytic  anemia".
Pediatrics  22: 461.
                                          I 3  H3

-------
                                       No.  132
         1,4-Naphthoquinone

  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENC7
       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.

-------
                                                                                itA
I                                      1,4-NAPHTHOQUTNONE                      '

|             SUMMARY.

                   1,4-Naphthoquinone is used as a polymerization regulator and an
              intermediate.  Some data are available which indicate that 1,4-naphtho-
              quinona is biodegradable.
                   The most consistent findings reported in the literature for health
              effects of 1,4-naphthoquinone involve hematological changes, irritant and
              allergenic activity, and inhibition of biochemical oxidation processes.
              One study found 1,4-naphthoquinone to be oncogenic.  Some evidence of
              inhibition of in vitro endocrine function and of nerve activity was re-
              ported.

              I.  INTRODUCTION.

                   1,4-Naphthoquinone (1,4-aaphthalenedione; CiQH,0 • molecular weight 158.15)
              is a solid at room temperature.  It occurs as a greenish yellow powder or
              as yellow triclinlc needles.  It has a melting point of 123-126 C and begins
              to sublime at 100 C; its density is 1.422.  1,4-Naphthoquinone is only
              slightly soluble in water; it is soluble in a variety of organic solvents
              (Windholz 1976; Hawley 1971).
                   Current production (including importation) statistics for 1,4-naphtho-
              quinone (CAS Mo. 130-15-4) listed in the initial TSCA Inventory (U.S. EPA 1979)
              show that between 1,000,000 and 9,000,000 pounds of this chemical were
                                         *
              produced/imported in 1977.
                   1,4-Naphthoquinone is used as a polymerization regulator for rubber
              and polyester resins, in the synthesis o'f dyes and Pharmaceuticals, and as
              a fungicide and algicide (Hawley 1971).

              II.  EXPOSURE
                   A.  Environmental Fate
                   No specific information on the biological, chemical or photochemical
              transformation of 1,4-aaphthoquinone under environmental conditions was
              identified in the literature.  Napthoquinones undergo few substitution
              * This production range information does not include any production/importation
1             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 Regulations (40 CFR 710).

-------
reactions (Thirtle 1965).  Like other quinones, 1,4-naphthoquinone can
interconvert with its corresponding hydroquinone iny an oxidation-reduction
                                                   X-
system.
     Talakin (1964) reported that 1,4-naphthoquinone in river water apparently
undergoes slow biochemical oxidation, based on an observed increase in
BOD.  Verschueren (1977) reports that the BOD- is 0.81, using the standard
dilution technique with normal sewage as seed material,'and that the theoretical
oxidation demand is 2.1.                               .'..

     B.  Bioconcentration

     No information was found on the bioconcentration potential of 1,4-naph-
thoquinone.  Based on its low water solubility and its solubility in organic
solvents, 1,4-naphthoquinone could be expected to bioconcentrate to some
extent.

     C.  Environmental Occurrence
     No information was found on the presence of 1,4-naphthoquinone in
environmental media.
     In addition to its potential entry into the environment from its
manufacture, processing and uses, 1,4-naphthoquinone may also enter the.
environment as a degradation product of certain naphthalene derivatives.
For example, the U.S. EPA (1975) reported studies showing that the pesticide
carbaryl (1-naphthyl-n-methyl-carbamate) undergoes hydrolysis to 1-naphthol,
which is then converted by bacteria to 1,4-naphthoquinone and other products.

III.  PHAKMACOKINETICS

     No information was obtained.

IV.  HEALTH EFFECTS

     A.  Carcinogenicity

     1,4-Naphthoquinone was found to induce neoplasm when applied dermally
to mice for 28 weeks.  The total dose applied was 2000 mg/kg.  (Proceedings
of the Imperial Academy of Tokyo 16:309, 1940, as cited in NIOSH 1975).

-------
     3.  Reproductive Effects

     I,4-Naphthoquinone completely  inhibited  the  gametokinetic  effect
of human chorionic gonadotropin in  toads  (Pakrashi  1963) .

     C.  Other Toxicity
     The oral LD5Q for rats was reported  as 190 mg/kg  (NIOSH, 1975) .  The
LD.QQ of 1,4-naphthoquinone in rats was 0.5 g/kg, 0.25 g/kg, and 0.5 g/kg
for intraventricular, subcutaneous, and intraperitoneal' administrations,
respectively.  The LC.nn in air was 0.45  mg/L for a one-hour exposure.
Acute (0.5 g/kg) and subchronic (0.3 g/kg for 4 days) exposure  of rats re-
sulted in the formation of 39 and 13% methemoglobin, respectively,  followed
by the appearance of Heinz bodies and development of hemolytic  anemia.
A decrease in total respiration and hypothermia due to disturbances in
oxidation-reduction processes was also observed.  According to  the authors,
"threshold concentrations of 1,4-oaphthoquinone detected for rats and rabbits
in single-exposure and chronic experiments were 0.0004 and 0.0007 mg/L with
respect to their irritant and toxic, effects"  (Slyusar  et al. 1964).   !

     D.  Other Relevant Information
     1,4-Naphthoquinone exerted an allergenic effect in guinea  pigs
(Kryzhanovskaya et al. 1966).  A possible role for  1,4-naphthaquinone
in drug-induced thrombocytopenia was suggested by Niewig et al.  (1973)
as 1,4-naphthoquinone was found to be involved in the destruction of normal
blood platelets by serum antibodies in vitro.  1,4-Naphthoquinone blocks
the biosynthesis of adrenal steroids by bovine adrenal cortex in vitro
(Kahnt and Neher 1966), and has an inhibitory effect on mixtures of cytochrome
_c and dehydrated succinate oxidase from beef heart  (Heymann and Falser 1966) .
1,4-Naphthoquinone inhibited ATPase and nerve activity in the (American)
             •j
cockroach.   (Baker and Norris 1971, Baker 1972).

V.  AQUATIC  TOXICITY
     Very little information was available.  For  1,4-naphthoquiaone, a
median threshold limit value (TLM:24-28 hr) of 0.3-0.6 mg/L was  listed for
an unspecified species of fish (Verschueren 1977).

VI.  GUIDELINES
     No guidelines for exposure to  1,4-naphthoquinone were located.

-------
                               References


Baker JE. 1972.  Effects of feeding-inhibitory quiripnes on the nervous
system of Periplaneta.  Experientia.  28(l):31-32.

Baker JE, Norris DM.  1971.  Neurophysiological and biochemical effects
of naphthoquinones on the central nervous system, of Periplaneta.
J. Insect Physiol. 17:2383-2394.

Hawley GG.  1971.  Condensed Chemical Dictionary, 8th edition.  Van Nostrand
Reinhold Co.

Heymaan H, Feiser LF. 1948.  Naphthoquinone antimalarials.  XXI.  Anti-
succinate oxidase activity.  Jour. Biol. Chem. 176(3):1359-1369.

Kahnt FW, Neher R. 1966.  Biosynthesis of adrenal steroids in vitro.  II.
Importance of steroids as inhibitors.  Helv. Chim. Acta 49(1):123-133. (Ger.)

Kotsifopoulos PN.  1975.  In vitro effect of oxidizing and analgesic agents
on the erythrocyte membrane protein electrophoretic pattern.  Nouv. Rev.
Fr. Hematol. 15(1) -.141-146.  (Abstract in Chemical Abstracts, 83,72709Z).

Kryzhanovskaya MV, et al. 1966.  Allergenic activity of some atmospheric
pollutants of a chemical nature.  Gig. Sanit. 31(3):8-11.

National Institute of Occupational Safety and Health.  Registry of Toxic
Effects of Chemical Substances. 1975.                     .     -

Nieweg HO, et al. 1973.  Drugs and thrombocytes.  Proc. Eur. Soc. Study
Drug Toxic.  14:101-109.

Pakrashi A.  1963.  Endocrinological studies of plant products.  IV.  Effect
of certain coumarins upon the biological potency of human chorionic gonado-
tropin.  Ann. Biochem. Exptl. Med. (Calcutta) 23:357-370.

Slyusar MP, et al. 1964.  Data on the toxicology of alpha-naphthoquinones:
and its permissible concentration in a working area.  Gigiena 95-100.
(Abstract in Zh. Farmakol. Toksikol.  11.54.373, 1965).

Talakin YN.  1965.  The experimental determination of the maximum permissible
concentration of alpha-naphthoquinone in water resources.  Hyg. and Sanit.
30:184.

Thirtle JR.  1965.  Quinones.  In: Kirk-Othmer Encyclopedia of Chemical
Technology.  2nd Edition.  John Wiley and Sons, -Inc., New York.

U.S. EPA 1975.  Microbial degradation and accumulation of pesticides in
aquatic systems.  EPA 660/3-75-007, PB 241 293.
                                                                     »
U.S. EPA 1979.  Toxic Substances Control Act Chemical Substance Inventory,
Production. Statistics for Chemicals on the Non-Confidential TSCA Inventory.

-------
Verschueren, K.  1977.  Handbook of Environmental Data on Organic Chemicals, -
Van Nostrand Reinhold Co.
        , M. .1. 1976.  The Merc, Index, Here. . Co., lac.,  Rahway, «e» Jersey.
                                   m-7

-------
                                  No.  133
             Nickel

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

          APRIL 30,  1980
           /33-/

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



nickel and has found sufficient evidence to indicate that



this compound is carcinogenic.

-------
                                    NICKEL
                                    Summary

     Nickel  is  a  ubiquitous  multi-media  environmental  contaminant.   Al-
though nickel  is toxic and  appears to be a carcinogen to  man,  there  is an
increasingly  strong  indication that  nickel  is  an  essential element.   The
route of  exposure to nickel is  very  important, since  oral intake of nickel
metal is  comparatively nontoxic.   However,  exposure to nickel by  inhalation
or parenteral  administration as well as  cutaneous contact can produce toxic
         •                                           •
affects.   In  terms of human health effects,  probably the most acutely toxic
nickel compound is  nickel  carbonyl.   Nickel  in  several  chemical forms  has
been  associated  with  lung cancer in_ man  and  experimental  animals  upon
inhalation;  carcinogenic effects,  however, are  not  indicated by  the  oral
route.  The  acceptable daily intake (ADI)  of  nickel is 254 ug per day  for a
70 kg man.
     The  toxicity  of nickel to  aquatic life  is  affected by water hardness.
In the aquatic environment nickel  is  acutely toxic to freshwater fishes at a
concentration of 2,480 jug/1 (26 mg/1 hardness).   Chronic toxicity to fishes
has  been   reported  at  527  jug/1  (210 mg/1 hardness).   Nickel  toxicity  is
affected  by  water hardness.   Algae appears  to be  more  sensitive to nickel
than  fish.   Based on  the  limited  number  of studies  performed,  the  biocon-
centration  factor for  fish is 61,  for   algae  the  factor  is 9.8,  and  the
weighted average bioconcentration  factor is 11 for  fish and shellfish.

-------
                                    NICKEL
I.   INTRODUCTION
         This  profile  is based on  the Ambient Water  Quality Criteria Docu-
ment for Nickel (U.S. EPA, 1979).
     Nickel  (Ni;  atomic weight 58.71),  a bright,  silver  metal of the iron-
cobalt-nickel  triad, is  a  hard  and  malleable  metal with  a  high  tensile
strength used  in  virtually  all areas of metallurgy.  Nickel does not  readily
form chloro-complexes  under environmental  conditions and  would not  be  ex-
pected to form significant amounts of  sulfate complexes (U.S. EPA,  1979).
     In 1972,  U.S.  consumption of nickel,  exclusive  of  scrap,  was estimated
to total about 160,000 tons (Reno,  1974).   The estimate consisted mainly of
commercially  pure nickel  (about  110,000  tons)  which  is used  in stainless
steel, electroplating, and various other alloys.                            *
II.  EXPOSURE
     The route by which  most  people  in the general  population receive  the
largest portion  of daily nickel  intake is  through foods.   Total  daily  di-
etary intake  values may  range up  to 900 ;jg nickel,  depending  on the nature
of the diet,  with average  values  of 300 to  500  ug daily  (NAS,  1975).    The
U.S. EPA (1979) has  estimated  a weighted average  bioconcentration  factor  for
nickel to  be 11  for  the edible portions of  fish and shellfish  consumed by
Americans.   This  estimate is based on measured steady-state bioconcentration
studies in  fathead minnow larvae  (Pimephales  promelas)  (Lind,  et  al. Manu-
script).   The  values for  nickel levels in 969 U.S., public water supplies  for
1969-1970 was 4.8 pg/1, with only 11  systems  of this" total exceeding 25 pg/1
(NAS, 1975).   The  levels of  nickel  in the  air  are  also  low, with  a  1974
                                                                       »
arithmetic  mean level for urban air of 9 ng/m3 (U.S. EPA,  1976).

-------
III. PHARMACOKINETICS
     A.  Absorption
         The major  routes of nickel absorption  are inhalation and  ingestion
via  the diet.   Percutaneous  absorption is  a  less significant  factor  for
nickel's systemic effects but  important in the allergenic responses to  nick-
el.  Collectively the data  of  Tedeschi and Sunderman (1957), Perry  and  Perry
(1959), Nomoto  and  Sunderman (1970), Nodiya  (1972),  and Horak and  Sunderman
(1973)  indicate that 1 to  10  percent  of  dietary nickel  is absorbed.   Skin
penetration of  nickel has  been- demonstrated with, nickel  entering at sweat-
duct °and hair-follicle ostia (Wells, 1956).  The  extent to which nickel en-
ters the bloodstream  by way of the skin cannot be  stated  at the present time
(U.S. EPA, 1979).
         Respiratory  absorption of  various forms of nickel is probably  the
                                                                            «
major route of  nickel entry into man  under conditions  of occupational  expo-
sure.   Pulmonary absorption into the  bloodstream is  probably greatest  for
nickel  carbonyl vapor, with animal  studies suggesting  that  as much as  half
of  the  inhaled .amount  is  absorbed  (Sunderman  and  Selin,  1963).   Nickel  in
particulate matter  is absorbed from the pulmonary tract  to a lesser degree
than nickel carbonyl  (Leslie,  et  al. 1976).  Based on  animal studies, nickel
appears to have a half-life cf  several  days in  the body, yet there  is little
evidence for tissue accumulation.
     B.  Distribution
         Blood  is  the main vehicle  for  transport of  absorbed nickel,   with
serum albumin being the main carrier protein, although  a  specific nickelrich
metalloprotein  has  been  identified in  man  (NAS,  1975).  Tissue distribution
                                                                       »
of absorbed nickel appears  to  be dependent on the  route of intake.   Inhaled
nickel  carbonyl leads to highest  levels in  the  lung,  brain, kidney,  liver,

-------
and adrenals (Armit,  1908;  Sunderman  and Selin, 1968; Mikheyev, 1971).   Par--
enteral administration  of  nickel salts usually  results  in highest levels  in
the kidney,  with  significant uptake  shown by  endocrine glands,  liver and
lung (Wase, -et al. 1954; Smith and Hackley, 1968).
     C.  Metabolism
         A  number of disease  states and  other physiological  stresses are
reported to  alter the movement and tissue  distribution of  nickel in man  as
well as experimental  animals.  In man,  increased  levels of serum nickel are
seen in cases  of acute myocardial infarction  (D'Alonzo  and Pell,  1963;  Sun-
derman, et al.  1972),  acute stroke  and extensive burn injury (McNeely,  et
al. 1971).   Reduction is  seen in hepatic cirrhosis or uremia, possibly  sec-
ondary to hypoalbuminemia.
         Nickel  appears to  be an essential  element,  at  least  in experimental
animals.   Nickel deficient  diets  have produced  decreased  growth  rates and
impaired  reproduction in  swine (Anke,  et  al.  1974) and  rats  (Schnegg and
Kirchgessner, 1975).                               •
     D.  Excretion
         The routes  of elimination for  nickel in man  and animals depend  in
part on the chemical  forms  of nickel  and the mode of nickel intake.  Dietary
nickel, due  to the  low  extent of gastrointestinal absorption, is simply  lost
in the feces (U.S. EPA, 1979).   Urinary  excretion  in  man and animals is usu-
ally the major clearance route for absorbed nickel.   In some  instances sweat
can constitute a major  route of nickel elimination (Hohnadel, et  al. 1973).
Nodiya  (1972)  reported a fecal  excretion average of 258  jjg in Russian stu-
dents.  Horak  and Sunderman  (1973) determined fecal  excretion  of nickel  in
                                                                       *
10 healthy  subjects and arrived  at a value  identical  to that  found in the
Russian study.

-------
IV.  EFFECTS
     A.  Carcinogenicity
         A  carcinogenic  response to"'various nickel compounds upon  injection
has deen observed in a number  of animal studies (Lau,  et al. 1972;  Stoner,
et  al.  1976;  IARC,  1976).   In nickel  refinery  workers, an  excess risk  of
nasal and lung cancer  has been demonstrated (IARC, 1976).  However,  there  is
no  evidence at present  to indicate  that orally  ingested nickel is  tumori-
genic.
     The qualitative and ..quantitative  character  of the carcinogenic  effects
of nickel as  seen in experimental animal models has  been shown to vary  with
the chemical  form of the  nickel, the route of exposure,  the animal model em-
ployed, and the amounts of the  substance administered (U.S. EPA,  1979).
3.   Mutagenicity
         Pertinent information  could  not be located in the available  litera-
ture.
     C.  Teratogenicity
         While Ferm  (1972) has  claimed unspecified malformations in  surviv-
ing hamster embryos  when mothers were  exposed to  parenteral  nickel (0.7  to
10.0 mg/kg),  Sunderman, et al.  (1978) found no teratogenic effects  from  oral
administration of either  nickel chloride (16 mg/kg) or nickel subsulfide (80
mg/kg) in rats.   Exposure of pregnant  rats  by inhalation to nickel carbonyl
on days 7 or  8 of gestation  frequently  caused the  progeny to develop ocular
anomalies,   including anophthalmia and  microphthaimia.   The  incidence of ex-
traocular anomalies  is very low.  The specificity  of nickel carbonyl for in-
duction of ocular anomalies in  rats  appears to be unique among known terato-
genic agents (Sunderman,  et al. 1979).

-------
     D.  Other Reproductive Effects
         Schroeder and  Mitchner (1971) have  demonstrated adverse affects in
a three generation  study with rats  at a level of  5 mg/1  (5  ppm) nickel in
drinking water.   In  each of the generations,  increased numbers of runts and
enhanced neonatal mortality were  seen.  A  significant  reduction in  litter
size  and  a .reduced  proportion of  males in  the  third  generation were also
observed.  Nickel sulfate  (25  mg/kg) has been demonstrated to be  gametotoxic
in  rats,  with  complete obliteration  of spermatozoa  following  exposure for
120 days (Hoey, 1966; Waltschewa, et al. 1972).
     E.  Chronic  Toxicity
         Chronic  exposure  to nickel  has resulted  in injury to both the upper
and lower  respiratory tract in  man  (Tolot, et al.  1956;  McConnell,  et al.
1973).  Inhalation of nickel particulate matter  is  likely to play a role in
chronic, respiratory  infections by  effects on  alveolar macrophages.  Contact
dermatitis  in man with nickel  sulfate has  been observed  (Fregert,  et al.
1969;   Brun,  1975).    Also,  dietary nickel  can elicit  a dermatitic response
(Kaaber, et al. 1978).
     F.  Other Relevant Information
         There are experimental data that  demonstrate that nickel has a syn-
ergistic effect  on  the  carcinogenicities  of  polycyclic hydrocarbons  (Toda,
1962;   Maenza,  et al.  1971;  Kasprzak,  et  al.  1973).   Nickel  and  other ele-
ments  are known  to  be  present in  asbestos and may  possibly be  a factor in
asbestos carcinogenicity   (Cralley,  1971).   Also,., a synergistic  action be-
tween nickel and  viruses has been suggested (Treagon'and Furst, 1970).
V.   AQUATIC TOXICITY
                                                                       »
     A.  Acute Toxicity
         Water hardness  significantly  influences  the acute toxicity of nick-
el  to freshwater fish.   For  fish,   observed  LC5Q  values range  from  2,480


-------
/jg/1  for  the  rock  bass  (Ambloohites  ruoestris)  (hardness  =  26  mg/1)  to
110,385  jug/1 for  the  bluegill  (Lsoomis macrochirus)  (hardness  = 42  mg/1).
At  a hardness  of 20-29  mg/1,  six  freshwater  species .have  LC_Q values  of
between  2,916 and 5,360 ug/1 (Pickering  and  Henderson,   1966;  Lind et  al.,
manuscript).  At  a hardness of  360  ug/1,  values range from 39,600  to  44,500
/jg/1.  In  comparison,  acute tests with  freshwater invertebrate  species  have
a  greater  range  of  LC--  values at a  fixed hardness.   The  stonefly  (Aero-
neuria  lycorias)   exhibited the  highest  LC5Q  of  33,500 jug/1  (Warnick  and
Bell, 1969)  and Daphnia maqna gave  the  lowest value  of  510  ug/1 (Biesinger
and Christensen,  1972).   LLnd, et al.  (1979)  provide the only data obtained
under  relatively  high hardness  conditions  (244  mg/1),  an  LC5Q  value  of
2409 jug/1  for Daphnia  pulicaria.
         Data on  the acute toxicity of  nickel  to saltwater fishes is  limit-
ed.   The  LC.Q  values  range  from  29,000 jug/1  for  the  Atlantic Silverside
(Menidia menidia)  to 350,000 ug/1 for the mummichog (Fundulus heteroclitus)
(Eisler and  Hennekey,  1977).   The invertebrate acute toxicity data base  con-
sists of  14 results,  with a range  of LC-- values from- 310 ug/1 for  larvae
                                          >u
of  the  hard  clam (Mercenaria  mercenaria)  (Calabrese  and Nelson,  1974)  to
500,000 ug/1 for adults of  the cockle Cardium edule (Portmann, 1963).
     B.  Chronic Toxicity
         A  life  cycle test  (Pickering,   1974)  and  an  embryo-larval  test
(Lind,  at   al.,  manuscript)  have been  conducted  with  the  fathead   minnow
(Pimeohales  oromelas).  The chronic  values are 527 ug/L (210 mg/1 hardness)
and  109  jug/1 (44 mg/1 hardness) respectively,   aiesinger and  Christensen
(1972) conducted a life cycle  test with  Daohnia manna resulting  in a chronic
                                                                       »
value of 53  ug/1  at  a hardness  of 45  mg/1.  There are no chronic saltwater
data available (U.S.  SPA,  1979).

-------
     C.  Plant Effects
         Hutchinson  (1973)  and Hutchinson and Stokes (1975) observed  reduced
growth of  several algae  species  at concentrations  ranging from  100  to  700
jjg/1.  A decrease  in diatom diversity was observed by Patrick, et  al.  (1975)
to occur at concentrations as  low as 2 ug/1.
     D.  Residues
         Bioconcentration  data is limited  to the fathead minnow,  Pimephales
promelas,  (Lind,  et  al., manuscript)  and  the  alga,  Scenedesmes acuminata
(Hutchinson  and Stokes,  1975).  The  bioconcentration factor  for  the whole
body of the fathead minnow is  61 and for  the  alga the factor is 9.8.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human health  nor  the_ 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 will be
changed.'
     A.  Human
         The  American   Conference   of  Governmental  Industrial   Hygienists
(ACGIH, 1971) has  adopted a threshold limit  value  (TLV)  for a workday expo-
sure of 1  ppb.  The  acceptable daily intake (ADI) for man has been determin-
ed to be 294 jjg/day  (U.S.  EPA,  1979).  The U.S.  EPA (1979) draft water qual-
ity criterion for nickel is 133 ug/1.
     B.  Aquatic
         For  nickel,  the draft criterion  (U.S. EPA,  1979)  to protect  fresh-
water aquatic life is:
                (1.01  . In  (hardness) - 1.02)
              e
                                                                       »<
as a 24-hour average, and the concentration should not exceed at any time:
                (0.47  . In  (hardness) + 4.19)
              Q                             *
         The  draft criterion to protect  saltwater  aquatic life  is 220 ug/1
as a 24-hour average, not to exceed 510 ug/1 at any time (U.S. EPA, 1979).

-------
                           NICKEL

                         REFERENCES

American Conference of Governmental  Industrial  Hygienists.
Threshold- limit values for chemical  substances  and  physical
agents  in the workroom environment with  intended changes for
1978.   94 pp.

Anke, M. , et al.  1974.  Low  nickel  rations  for growth and
reproduction in pigs.  In; Trace Element  Metabolism in Ani-
mals- 2.  W.G. Hoekstra, J.W.  Suttie,  H.S.  Ganther and W.
Mertz (eds.).  University Park Press,  Baltimore,  MD.,  pp.
715.'

Armit,  H.W_  1908.  The toxicology of  nickel carbonyl.   Part
II.  Jour. Hygiene  8: 565.
                                                        0
Biesinger, K.E., and G.M. Christensen.   1972.   Effects of
various metals on survival, growth,  reproduction,  and  metabo-
lism of Daphnia magna.  Jour. Fish.  Res.  Board  Can..  29:
1691.

Brun, R.  1975.  Epidemiology of contact  dermatitis in Geneva-
(1,000  cases).  Dermatol.  150: 193.  (French)

Calabrese, A., and D.A. Nelson.  1974.   Inhibition  of  embry-
onic development of the hard  shell clam,  Mercenaria mercen-
aria, bv heavy metals.  Bull. Environ. Contain.  Toxicol.  2:
Cralley, L.J.  1971.  Electromotive phenomenon  in  metal  and
mineral particulate exposures.  Relevance  to  exposure  to as-
bestos and occurrence of cancer.  Am. Ind.  Hyg.  Assoc. Jour.
32: 653.

D'Alonzo, C.A., and S. Pell.  1963.  A  study  of  trace  metals
in myocardial  infarction.  Arch. Environ.  Health  6:  381.

Sisler, R, , and R.J. Hennekey.  1977.   Acute  toxicities  of
Cd2"*", Cr2*, Ni2"*". amd Zn2* to estaurine macro fauna.
Arch. Environ. Contam. Toxicol.  6: 315.

Perm, v.H.  1972.  The teratogenic effects  of metals  on  mam-
malian embryos.  In: Advances in Teratology,  Vol.  5.   D.H.M.
Wollam (ed. )   Academic Press, New York.  pp.  51-75.

Fregert, S.,  et al.  1969.  Epidemiology of contact dermati-
tis.  Trans.  St. Johns Hosp. Derm. Soc. 55: 71.

Hoey, M.J.  1966.  The effects of metallic  salts on the  his-
tologv and functioning of the rat testes.   Jour. Reprod.
Fertil.  12:  461.

-------
Hohnadel, D.C., et al.   1973.  Atomic  absorption  spectrometry
of nickel, copper, zinc, and  lead  in sweat  collected  from
health subjects during sauna  bathing.   Clin.  Chem.   19:
1288.

Horak, E., and F.W. Sunderman.   1973.   Fecal  nickel  excretion
by healthy adults.  Clin. Chem.  29: 429.

Hutchinson, T.C.  1973.  Comparative studies  of the  toxicity
of heavy metals to phytoplankton and their  synergistic  inter-
actions.  Water .Pollut.  Res.  (Canada)  8:  68.

Hutchinson, T.C., and P.M. Stokes.  1975.   Heavy  metal  toxi-
city and algal bioassays.  ASTM  STP 573,  Am.  Soc. Test.
Mater.  pp. 320-343.

International Agency for Research  on Cancer.   1976.   Nickel
and nickel compounds.  In; Evaluation  of  Carcinogenic Risk of
Chemicals to Man  (International Agency for  Research  on  Cancer
Monographs, 11) IARC, Lyon, p. 111.

Kaaber, K., et al.  1978.  Low nickel  diet  in the treatment
of patients with chronic nickel-dermatitis.   Brit.. Jour.
Derm..  98: 197.

Kasprzak, K.S., et al.   1973.  Pathological reactions in  rat
lungs following intratracheal injection of  nickel subsulfide
and 3,4-benzpyrene.  Res. Comm. Chem.  Pathol.  Pharmacol.  6:
237.

Lau, T.J., et al.  1972.  The carcinogenicity of  intravenous
nickel carbonyl in rats.  Cancer Res.   32:  2253.

Leslie, A.C.D., et al.   1976.  Prediction of  health  effect of
pollution aerosols.  In; Trace Substances in  Environmental
Health - X.  D.D. Hemphill (ed.),  University  of Missouri,
Columbia, Mo.  pp. 497-504.

Lind, D., et al.  Regional copper-nickel  study, Aquatic Tox-
icology Study, Minnesota Environmental Quality Board, State
of Minnesota (Manuscript).

Maenza, R.M. et al.  1971.  Rapid  induction of sarcomas in
cats by combination of nickel sulfide  and 3,4-benzypyrene.
Cancer Res.  31: 2067.

M.cConnell, L.H., et al.  1973.  Asthma caused  by  nickel sen-
sitivity.  Ann. Ind. Med.  78: 888.

McNeely, M.D., et al.  1971.  Abnormal concentrations of
nickel in serum in cases of myocardial  infarction, stroke,
burns, hepatic cirrhosis, and uremia.  Clin.  Chem.   17:
1123.
                          J

-------
Mikheyev, M.I.   1971.   Distribution  and  excretion of nickel
carbonyl.  Gig.  Tr.  Prof.  Zabol.   15:  35.

National Academy of  Sciences.   1975.   Nickel.   National Acad-
emy of Sciences  Committee  of Medical  and Biological Effects
of Environmental Pollutants.  Washington,  DC.

Nodiya, P.I.  1972.  Cobalt and  nickel balance  in students of
an occupational  technical  school.  Gig.  Sanit.   37:  108.

Nomoto, S., and  F.W. Sunderman,  Jr.   1970.   Atomic absorption
spectrometry of  nickel  in  serum,  urine,  and  other biological
materials.  Clim. Chem.  16: 477.

Patrick, R., st  al.  1975.  The  role  of  trace elements  in
management of nuisance  growths.   U.S.  Environ.  Prot.  Agency,
EPA 660/2-75-008, 250 p.

Perry, H.M., Jr.,. and E.P. Perry.  1959.  Normal concentra-
tions of some trace  metals in human urine:   Changes  produced
by ethylenediametetracetate.  Jour. Clin.  Invest.   38:  1452.

Pickering, Q.H.  1974.  Chronic  toxicity of-  nickel to the
fathead minnow.  Jour.  Water Pollut.  Control Fed.   46:  760.

Pickering, Q.H., and C. Henderson.  1966.  The  acute  toxicity
of some heavy metals to different  species  of warmwater
fishes.  Air Water Pollut. Int.  Jour.  10: 453.

Portmann, J.E.   1968.   Progress  report on  a  program  of
insecticide analysis and toxicity  testing  in relation to the
marine environment.  Helgolander wiss. Meeresunters   17:
247.

Reno, H.T.  1974.  Nickel.  In:  Minerals Yearbook 1972,  Vol.
I.  Metals, Minerals and Fuels.  Washington, DC,  U.S.   Gov-
ernment Printing Office, pp. 871.

Schnegg, A.,  and M.  Kirchgessner.  1975.  The essentiality of
nickel for the growth of animals.  Z.  Tierphysiol.,  Tierer
naehr.  Futtermittelkd.  36: 63.

Schroeder, H.A., and M. Mitchner.  1971.  Toxic  effects  of
trace elements on the reproduction of  mice and  rats.  Arch.
Environ. Health  23: 102.

Smith, J.C. ,  and 3.  Hackley.  1968.   Distribution  and excre-
tion of nickel-63 administered intravenously to  rats.   Jour.
Nutr.  95: 541.
                                                          »
Stoner, G.D., at al.  1976.  Test  for  carcinogenicity of me-
tallic compounds by  the pulmonary  tumor  response  in  strain A
mice.  Cancer Res.   36: 1744.

-------
Sunderraan, F.W., et  al.   1978.   Embryotoxicity and  fetal
toxicity of nickel  in  rats.  Toxicol.  Appl.  Pharmacol.  43:
381.

Sunderman, F.W., Jr.   1978.  Carcinogenic  effects of metals.
Fed. Proc.  37: 40.

Sunderman, F.W., Jr.,  and C.E.  Selin.   1968.   The metabolism
of nickel-63 carbonyl  Toxicol.  Appl. Pharmacol.   12:  207.

Sunderraan, F.W., Jr.,  et  al.   1972.  Nickel  metabolism  in
health and disease.  Ann. N ,.Y.  Acad. Sci.  199:  300.

Sunderman, F.W.,- Jr., -et  al. -  1979.  Eye. malformation in
rats:  Induction by  prenatal exposure  to nickel  carbonyl.
Science  203: 550.
                             s
Tedeschi, R.E., and  F.W.  Sunderman.  1957.  Nickel  poisoning.
V.  The metabolism of  nickel under normal  conditions  and
after exposure  to nickel  carbonyl.  Arch.  Ind.   Health   16:
486.

Toda, M.  1962.  Experimental  studies  of occupational lung
cancer.  Bull. Tokoya  Med.. Dentr Univ.   9: 441.

Tolot, F. , et al..  1956..  Asthmatic forms  of  lung disease  in
workers exposed to chromium, nickel and  aniline  inhalation.
Arch. Mol. Prof. Med..  Tran.. Secur. Soc.  18:  288.

Treagon, L., and A.  Furst.  1970.  Inhibition  of  interferon
synthesis in mammalian cell cultures after nickel treatment.
Res. Comm.- Chem. Pathol.  Pharmacol.  1:  395.

U.S. EPA.  1976 (August).  Air  quality data  for  metals  1970
through 1974 from the  national  air surveillance  network.
EPA-600/4-76-041, U.S. Environ.  Prot.  Agency,  Research
Triangle Park, NC.

U.S. EPA,  1979.  Nickel:  Ambient Water Quality Criteria.

Waltschewa, V.W. et  al.   1972.   Hodenveranderungen  bei
weissen Ratten durch chronische  Verabreichung  von Nickel sul-
fate.  (Testicular changes due  to long-term administration of
nickel sulphate in rats.)  Exp..  Pathol.  6: 116.  In German
with Engl. abstr.

Warnick, S.L., and H.L. Bell.   1969.   The  acute  toxicity of
some heavy metals to different  species of aquatic insects.
Jour. Water Pollut.  Control Fed.  40:  280.
                                                          »
Wase, A.W., et al.   1954.  The metabolism of nickel.  I.
Spatial and temporal distribution of Ni^3  ^n the mouse.
Arch. Biochem. Biophys.   51: 1.

-------
Wells, G.C.  1956.  Effects of nickel on the skin.  Brit.
Jour. Dernatol.  68: 237.

-------
                                      No. 134
            Nitrobenzene

  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»

-------
                                 NITROB5NZENE
                                    Summary

     Nitrobenzene  is a.  pale yellow  oily liquid  with an  almond-like odor.
There is little or no  information  available  on its teratogenic, mutagenic or
carcinogenic  effects.    Nitrobenzene  yielded  negative results  in  the Ames
assay for  mutagenicity.   Gross abnormalities  were observed  in  4 fetuses of
30 rats administered nitrobenzene.
     Chronic  exposure  to nitrobenzene produces cyanosis, methemoglobinemia,
jaundice, anemia, and sulfhemoglobinemia in man.
     Static  tests  with  the  bluegill,  sunfish,  Daphnia maqna,  and  an alga,
Selenestrum  capricomutum,  indicates little  difference in  sensitivity with
no  50  percent effective  concentration  lower  than 27,000 ug/1.   An embryo-
                                                                            ^
larval test  with  the fathead minnow demonstrated  no  adverse chronic effects
at the highest  concentration tested (32,000 ug/1).   Static  tests with salt-
water  fish,   shrimp,  and  alga gave  repeated  96-hour LC_Q  or  EC5Q  values
of 58,538 jjg/1, 6,676 ug/1  and 9,600 jug/1, respectively.

-------
I.  INTRODUCTION
     This  profile is based  on the  Ambient Water  Quality Criteria  Document
for Nitrobenzene  (U.S.  EPA,  1979).   The principal  uses  of nitrobenzene  are
for reduction  to aniline (97  percent),  solvent for Friedel-Crafts  reaction,
metal polishes,  shoe black,  perfume,  dye  intermediates,  crystallizing  sol-
vent  for  some substances,  and  as a  combustible  propellant  (Dorigan  and
Hushon, 1976).
     Nitrobenzene   (CJHJOJ   is   a  pale   yellow  oily   liquid  with   an
almond-like  odor.   Its  physical  properties  include:   melting  point,  6°C;
vapor pressure,  0.340 mm Hg  at 25°C; and  solubility in  water  of 1000  mg/1
at 20°C  (U.S.  EPA,  1979).   Nitrobenzene is miscible  with most organic  sol-
vents, a  fairly  strong  oxidizing agent,  and undergoes  photoreduction  when
irradiated with  ultraviolet light in organic  solvents that contain  abstraci-
table hydrogen atoms.
II.  EXPOSURE
                                                     i
     A.  Water
         Levels of nitrobenzene in  wastewater are  monitored  by plants  pro-
ducing and using  the  chemical, but nitrobenzene levels in city water  systems
are usually too low to measure (Pierce, 1979).
     3.  Food
         Nitrobenzene is  not an approved food  additive  (Oorigan and  Hushon,
1976).  There have been  reports of nitrobenzene poisoning resulting  from  its
contamination of alcoholic drinks and food (Nabarfo, 1948).
     The U.S. EPA  (1979) has  estimated  the  weighted average bioconcentration
factor for nitrobenzene to be  4.3  for  the edible portions of fish and.shell-
fish consumed  by  Americans.   This  estimate  was based on  octanol/water par-
tition coefficients.

-------
     C.  Inhalation
         Atmospheric  nitrobenzene levels  outside a  plant  are not  monitored
by industry.   Since  inner plant  levels  are below  the Threshold Limit  Value
(TLV)  of  5 mg/m   and  nitrobenzene vapors  accumulate at the floor  level  due
to their  high density, the  external  concentrations  are  expected to be  very
low (Dorigan and Hushon, 1976).
III. PHARMACOKINETICS
     A.  -Absorption
       •  Nitrobenzene  absorption can  occur by  all  possible  routes,  but  it
takes  place mainly through the respiratory tract and skin.  On  the average,
80 percent  of the nitrobenzene vapors are retained in the human respiratory
tract  (Piotrowski, 1977).
         Nitrobenzene,  as  liquid  and  vapor,  will  pass  directly through  the
skin.  The  rate  of vapor absorption depends on  the air concentration,  rang-
ing  from  1 mg/hr  at  5  mg/m  concentration to  9 mg/hr  at 20 mg/m .   Maxi-
                                                                     2
mal cutaneous  absorption  of liquid nitrobenzene is 0.2 to  3 mg/cm /hr  de-
pending on skin temperature.
     3.  Distribution
         Upon'  entry   into   the body,  nitrobenzene  enters  the  bloodstream.
Nitrobenzene  is  a very  lipid soluble with an  oil  to water  coefficient  of
800.   In a  rat study,  the ratio  of  concentration of nitrobenzene in adipose
tissue versus blood in internal organs and muscle was approximately 10:1  one
hour after  an intravenous injection (Piotrowski, -1977).   Oorigan and HusHon
(1976)   found  that 50  percent of the nitrobenzene  administered to rabbits
accumulated unchanged  in tissues within two days  after intubation.

-------
     C.  Metabolism
         There are two  main  pathways for the metabolism of  nitrobenzene:   1)
reduction  to  aniline   followed  by  hydroxylation  to  aminophenols,  and  2)
direct  hydroxylation  of nitrobenzene  to form  nitrophenols.  Further  reduc-
tion of nitrophenols to- aminophenols may also occur (Piotrowski,  1977).   The
first  pathway proceeds  via  the  unstable intermediates,  nitrosobenzene  and
phenylhydroxylamine, both  of which  are  toxic  and have  pronounced  methemo-
globinemic  capacity.   These  reactions occur  in the  cytoplasmic and  micro-
somal  fractions  of liver cells  by the nitro-reductase  enzyme system  (Fouts
and Brodie,  1957).  The  aniline  is then excreted as an acetyl derivative,  or
hydroxylated  and excreted as  an aminophenol.   The second  pathway  does  not
occur  in the microsomal fraction.  This .reaction  proceeds via peroxidase  in
the presence of oxygen (Piotrowski, 1977).                                    ;
         Robinson, at al. (1951)  found p-aminophenol  to be the main  metabol-
ic product  of nitrobenzene metabolism in rabbits.  Little  unchanged  nitro-
benzene was  excreted  in the urine and only 1  percent was expired as  carbon
dioxide.  Together  with nitrophenols  and nitrocatechol,  p-aminophenol con-
stituted 55  percent of  the  urinary metabolites.   Metabolites were  detected
in the urine up to one week after dosing.
     D.  Excretion
         In  man,  the primary  known  excretion  products of  nitrobenzene  are
p-aminophenol  and  p-nitrophenol  which  appear  in the  urine  after chronic  or
acute  exposure.   In   experimental   inhalation  exposure -to  nitrobenzene,
p-nitrophenol  was formed  with  the  efficiency of  6  to  21  percent.    The
efficiency  of  p-aminophenol  formation  is  estimated  from  acute poisorjing

-------
cases  where  the molar  ratio of  excreted p-nitrophenol  to  p-aminophenol  is'
two to one, since p-aminophenol is  not formed at a detectable level  in  short
subacute exposure (Piotrowski, 1977).
         Ikeda  and  Kita' (1964)  found the  rate of  excretion of  these  two
metabolites to parallel the level of methemoglobin in the blood.
         Nitrobenzene  remains in the  human  body  for a  prolonged  period  of
time.   The excretion  coefficient  of  urinary  p-nitrophenol  (followed  for
three  weeks)  in man is  about 0.008 per  hour.   The  extended systemic reten-
tion and slow excretion of metabolites in man is determined by the low  rates
of metabolic  transformation "(reduction and  hydroxylation)  of the nitroben-
zene itself.  The conjugation and excretion  of  the  metabolites,  p.-nitrophe-
nol and p-aminophenol,  is  rapid (Piotrowski,  1977).   The urinary metabolites
in man account  for  only  20 to 30 percent of  the nitrobenzene dose; the  fate
of the rest of the metabolites is not  known (Piotrowski, 1977).
IV.  EFFECTS
     A.  Carcinogenicity
         The  available  literature  does not  demonstrate  the Carcinogenicity
of nitrobenzene, although it is suspect (Dorigan and Hushon,  1976).
         Some nitrobenzene  derivatives have  demonstrated carcinogenic  capa-
cities.  Pentachloronitrobenzene  (PCN8)'induced hepatomas and papillomas  in
mice (Courtney,  et al. 1976).
         l-Fluoro-2,4-dinitrobenzene  (ONFB)  was  found  to be a  promoter  of
skin tumors  in  mice,  although  it  does  not  induce  them when  administered
alone (Bock,  et al 1969).
     B.  Teratogenicity
                                                                      »
         There  is  a paucity  of  information  on  the  teratogenic effects  of
nitrobenzene.    In  one  study,  125  mg/kg  was  administered  to  pregnant   rats
                                      J*

-------
during preimplantation  and placentation periods  (Kazanina,  1963).  Delay  of
embryogensis,  alteration  of  normal placentation,  and  abnormalities  in  the
fetuses  were  observed.   Gross  morphogenic defects  were  seen  in  4  of  30
fetuses examined.
     C,  Mutagenicity .
         Nitrobenzene was  not found to  be mutagenic  in the Ames Salmonella
assay  (Chiu,  et al.,  1978).  Trinitrobenzene  and 'other nitrobenzene  deriva-
tives  have  demonstrated mutagenicity  in  the  Ames Salmonella microsome  assay
and  the  mitotic  recombination  assay  in  yeast (Simmon,  et  al.  1977),  thus
raising questions concerning the mutagenicity  of  nitrobenzene.
     0.  Other Reproductive Effects
         Changes  in the tissues  of  the  chorion  and placenta  of pregnant
women  who  worked in  the  production of  a  rubber catalyst  that  used  nitro-
benzene were  observed.   No mention was made of the effects  on  fetal develop-
ment or  viability (Dorigan and Hushon, 1976).  Menstrual disturbances  after
chronic nitrobenzene exposure have been reported.
         Garg,  at-al. (1976)  tested substituted nitrobenzene derivatives  for
their  ability  to  inhibit  pregnancy in  albino rats.   Two  of  the compounds
tested (p-methoxy and p-ethoxy derivatives)  inhibited implantation and  preg-
nancy 100 percent when administered on days 1  through  7 after impregnation.
     E.  Chronic Toxicity
         Symptoms of chronic occupational nitrobenzene  absorption are  cyan-
osis,  methemoglobinemia, jaundice,  anemia,  sulfhemoglobinemia,  presence  of
Heinz  bodies  in  the erythrocytes,  dark  colored  urine,  and the  presence  of
nitrobenzene  metabolites  (e.g.,   nitrophenol) in  the  urine  (Pacseri and
                                                                      9
Magos,  1958;  Hamilton,   1919;  Wuertz,  et  al.  1964; Browning,  1950;  Maiden,
1907; Piotrowski, 1967).


-------
         Chronic exposure of  laboratory  animals to nitrobenzene (via  inhala-


tion,  ingestion  or  subcutaneous   injection)  produced  symptoms  similar  to


those  mentioned above  for humans as  well as  tissue  degeneration  of  the


heart,  liver,  and  kidney,  and  reductions in  erythrocytes  and   hemoglobin


levels in the blood (U.S. EPA, 1979).


     F.  Other Relevant Information


         Alcohol ingestion  has been found to act synergistically with  nitro-


benzene in man and animals  (Dorigan and Hushon, 1976; Smyth, et al., 1969).


         Kaplan, et al.  (1974) showed that caffeine, an inducer of microsom-


al enzymes,  increases the  rate  of metabolism and' excretion of nitrobenzene


thus causing a rapid decline in nitrobenzene induced methemoglobin  levels-


         Metabolism and  excretion  of nitrobenzene in humans is slower by  an


order of magnitude than in  rats or rabbits  (Piotrowski, 1977).              .


V.   AQUATIC TOXICITY


     A. • Acute Toxicity


         The  96-hour  LC5Q  reported  value  for the  bluegill (Lepomis  macro-


chirus)  is  42,600 ug/1  and the observed  48-hour LC^n for  Daohnia magna  is
—•«-^•  ^           '                                  J\J      —•••••••••••_ i^HHMBMBM-


27,000 ug/1.  Saltwater  species  tested  are the sheepshead minnow,   Cyprinodon


varieqatus, which  has a reported  96-hour LC5Q of  58,539 jug/1 and the mysid


shrimp, Mysidopsis  bahia,  with a  reported 96-hour  LC5_.  of  6',676  jug/1  (U.S.


EPA, 1979).


     8.  Chronic Toxicity


         In  the  only  chronic  data  available, .,no  adverse  effects  were


observed during  an embryo-larval  test  with the  fathead minnow  (Pimephales


promelas) at  nitrobenzene  test concentrations  as  high as 32,000  pg/1  (U.S.
                                                                       »

EPA, 1978).


-------
     C.  Plant Effect
         Based  on  cell numbers  and  chlorophyll  a  concentration,  reported
EC5Q  values for  the  freshwater alga,  Selenastrum capricornutum.  are  42,000
and  44,100 ug/1; and  for  the marine  alga, Skeletonema  costatum,  there  are
reported £C.Q values of-9,600 and  10,300 ug/1  (U.S. EPA,  1979).
     0.  Residues
        _A  bioconcentration  factor of 15 was estimated for  aquatic organisms
that contain 8 percent lipids.
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  TLV  for  nitrobenzene  is 5  mg/m .   This  is  the  OSHA Federal
standard, the value set by  the  ILO/WHO committee on Occupational  Health,  and
the TLV suggested  by  the American  Conference  of Governmental and  Industrial
Hygienists  (Goldstein, 1975, ACGIH, 1977).
         The draft  water  quality  criteria  for nitrobenzene  is 30 ug/1  (U.S.
EPA, 1979).  This  value is  based  on the TLV  and organoleptic level  (minimum
detectable odor limit in water) of  nitrobenzene.
     S.  Aquatic
         For nitrobenzene the drafted criterion to.-protect  freshwater  aquat-
ic life is  480  ug/1 as a 24-hour  average  concentration  not to  exceed  1,100
ug/1 at any time.   To  protect  saltwater aquatic life, the 24-hour average is
                                                                         •
53 ug/1 and this concentration should not  exceed 120 ug/1 at any time  (U.S.
EPA, 1979).

-------
                                 NITROBENZENE

                                  REFERENCES
American  Conference  of  Governmental  Industrial Hygiensts.   1977.   Docu-
mentation  of  the  threshold  limit  value  for  substances  in  workroom  air.
Cincinnati, Ohio.

Bock, A.G.,  et al.  1969.  Tumor  promotion  by  1-fluoro-2, 4-dinitrobenzene,
a potent skin sensitizer.  Cancer-Res.  29: 179.

Browning,  E.    1950.    Occupational  jaundice   and   anemia.   Practitioner
164: 397.

Chiu, C.W., et al.   1978.  Mutagenicity of some commercially available nitro
compounds for Salmonella typhinurium.  Mut. Res.  58: 11.

Courtney, K.D.,  et al.   1976.   The effects of pentachloronitrobenzene, hexa-
chlorobenzene, and  related compounds on  fetal  development.   Toxicol.  Appl.
Pharmacol.  35: 239-

Dorigan,  J.,   and  J.  Hushon.    1976.   Air  pollution  assessment  of  nitro-
benzene.  U.S. Environ. Prot. Agency.

Fouts,  J.R.,  and  B.B.  Brodie,   1957.   The  enzymatic  reduction of  cloram-
phenicol,  p-nitrobenzoic  acid  and  other  aromatic   nitro  compounds   in
mamma]*.  Jour. Pharaiacol. Exp. Ther.  119: 197.

Garg, S.X., et al.   1976.  Potent  female  antifertility  agents.  Indian Jour.
Med. Res.  64: 244.

Goldstein, I.   1975.   Studies   on  MAC  values of  nitro  and amino-derivatives
of  aromatic  hydrocarbons.   Adverse  Effects  Environ.  Chem.  Psychotropic
Drugs  1: 153.

Hamilton,  A.    1919.   Industrial  poisoning  by  compounds  of the  aromatic
series.  Jour. Industr. Hyg.   1: 200.

Ikeda, M., and A. Kita.   1964.   Excretion  of p-nitrophenol and p-aminophenol
in  the  urine  of a  patient  exposed  to nitrobenzene.   Br.  Jour.  Ind.  Med.
21: 210.

Kaplan, A.M.,  et al.   1974.   Methemoglobinemia  and metabolism of  nitro  com-
pounds.  Toxicol. Appl. Pharmacol.  29:  113-

Kazanina, S.S.   1968.   Morphology and  histochemistry -of hemochorial  placen-
tas  of white  rats during  poisoning of  the maternal   organisms  by  nitro-
benzene.  Bull. Exp. Biol. Med.  (U.S.S.R.)  65: 93-
                                                                        *
Maiden, W.   1907.   Some observations on  the condition  of  the blood  in  men
engaged  in aniline  dyeing and  the manufacture  of nitrobenzene and  its  com-
pounds.  Jour. Hyg. 7:  672.
                                     _/  ^£a
                                     1J U >

-------
Nabarro,  J.D.N.   1948.   A  case  of  acute mononitrobenzene  poisoning.   3r.
Med. Jour.  1: 929.

Pacseri, I.,  and  L.  Magos.  1953.  Determination  of the measure of exposure
to  aromatic  nitro and  amino  compounds.   Jour.  Hyg.  Epidemiol.  Microbiol.
Lnmunol.  2: 92.

Pierce,   M.     1979.    Personal   communication.    Quality  Control   Dep.,
Philadelphia Water Treatment Div., Philadelphia, ?a.

Piotrowski, J.   1967.   Further investigations on  the  evaluation of exposure
to nitrobenzene.  3r. Jour. Ind. Med.  24: 60.

Piotrowksi, J.   1977.   Exposure  tests for  organic compounds  in industrial
toxicology.  NIOSH 77-144.  U.S. Dep. Health, Edu. Welfare.

Robinson, D.,  et  al.   1951.   Studies in detoxication.   40.   The metabolism
of  nitrobenzene  in  the rabbit,   o-,  o-, and p-aitrophenols,  o-,  m-,  and
p-aminophenols   and   4-nitrocatechol  as   metabolites  of   nitrobenzene.
Biochem.  Jour.  50:  228.

Simmon, V.F.r  et  al.   1977.  Munitions wastewater treatments:   Does chlori-
nation  or ozonation  of  individual  components  produce  microbial  mutagens?
Toxicol. Appl. Pharmacol.   41: 197.

Smyth,  H.F.,   Jr.,  et  al.   1969.   An exploration of  joint  toxic  action:
Twenty-seven  industrial chemicals intubated  in  rats in  all  possible  pairs.
Toxicol. Appl. Phannacol.   14: 340.

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

U.S. SPA.  1979.  Mitrobenzenes.  Ambient Water Quality Criteria   (Draft).

Wuertz,   R.L.,  et al.  1964.   Chemical  cyanosis  - anemia  syndrome.   Diag-
nosis, treatment,  and recovery.  Arch. Environ. Health  9: 478.

-------
                                      No.  135
           •4-Nitrophenol

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

           APRIL 30,  1980
    / -3 ff-

-------
                          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.

-------
                          4-NITROPHSNOL



                             SUMMARY



     There is-no evidence to indicate that 4-nitrophenol  is carcin-



ogenic.



     Weak mutagenic  effects in Saccharomyces  and  in Proteus have



been  observed.  Results  from  the  Ames  assay, the  E.   coli,  and



the dominant  lethal assay  failed  to show  mutagenic effects from



4-nitrophenol.



     No  information on  the  teratogenic  or  adverse reproductive



effects of 4-nitrophenol is available.



     A single animal study  indicates cumulative chronic .toxicity;



the methodology of this study was not available for  review.



     For freshwater  organisms,  acute values for the toxic effects



of  4-nitrophenol  ranged  from  8,280  to  60,500  pg/1,   and  7,170



to  27,100  ug/1  for marine  organisms.    Effective  concentrations



for aquatic plants fall within these ranges of concentrations.

-------
                          4-NITROPHENOL
I.    INTRODUCTION
     This profile  is  based on the  Ambient Water Quality Criteria
Document for Nitrophenols (U.S. EPA, 1979).
     The  raononitrophenols  are  a  family  of  compounds  composed
of  the  isomers  resulting  from  nitro group  substitution  at the
2,3, and 4 position of  phenol (the  ortho, meta,  and para isomers,
respectively).   The -para  isomer,  4-nitrophenol, has  a molecular
weight of  139.11,  a  boiling point of  279°C,  a' melting  point of
113-114°C,  a  density  of 1.479 g/ml; it  is  soluble  in  water  (U.S.
EPA, 1979).
     Uses of  the mononitrophenols  include  the  following: produc-
tion of dyes, pigments,  Pharmaceuticals, rubber  chemicals,  lumber
preservatives, photographic chemicals, and pesticidal and fungici-
dal  agents  (U.S. EPA,  1979).  'Production  was 17.5   x  10  tons
per year in 1975 (Chem.  Market.  Reporter, 1976).
     The nitrophenols  may  be  formed  via microbial   degradation
or  photodegradation   of pesticides  (e.g., parathion)  containing
the  nitrophenol  moiety.   4-Nitrophenol  may  be produced  in the
atmosphere  through  the photochemical   reaction between  benzene
and nitrogen monoxide  (U.S. EPA,  1979).   Partial  microbial degrada-
tion  of  certain nitrophenols  has  been  shown, particularly • by
acclimated microorganisms.    Mononitrophenols  appear to  be  effi-
ciently degraded by unacclimated microorganisms  (Haller, 1978).
II.  EXPOSURE
                                                              »
     The lack of  monitoring data  on the  mononitrophenols  makes
it difficult to assess  exposure from water, inhalation, and foods.

-------
Mononitrophenols  in  water  have  been  detected  in  the  effluents
of  chemical plants  (U.S.  EPA,  1976,  1979).    4-Nitrophenol  has
been shown  to  penetrate the skin and  to  produce damage  at  thres-
hold concentrations of  0.8  and  0.9 percent  (w/v) ,  respectively
(U.S.  EPA, 1979) .
     Exposure  to  nitrophenols appears, to  be  primarily through
occupational contact  (chemical  plants, pesticide  applications) .
Contaminated water may result  in isolated poisoning incidents.
     The U.S.  EPA  (1979)  has  estimated the  weighted  average bio-
concentration  factor  for 4-nitrophenol to  be 4.9  for  the  edible
portions of fish and  shellfish consumed by  Americans.  This  esti-
mate is based on the octanol/water partition coefficient.
III. PHARMACOKINETICS
     A.   Absorption and Distribution
          Pertinent  data could  not  be located  in  the  available
literature regarding absorption or distribution.
     B.   Metabolism
          Metabolism  of  the  mononitrophenols  occurs   primarily
by conjugation.  Other  possible  routes  are  reduction  of  the  nitro
group  to  an  amino  group or  oxidation  to  dihydric-nitrophenols
(U.S.   EPA, 1979).    These  reactions  are  mediated  primarily  by
liver enzyme systems, although other tissues show lower metaboliz-
ing activity (U.S. EPA, 1979).
     3.   Excretion
          An animal study has indicated  that- oral  or intraperi-
                                                              •
toneal administration of  4-nitrophenol  leads to rapid  elimination
in  all  species  tested,  and  that   the  total elimination  period
is not likely to exceed one week  (Lawford, et al.  1954) .


-------
IV.  EFFECTS
     A.   Carcinogenicity
          There is no evidence available regarding the carcinogeni-
city of raononitrophenols.
     B.   Mutagenicity_
          A  weak  rautagenic  effect was  detected  in  Saccharomyces
cerevisiae by  4-nitrophenol  (Fahrig,  1974);  this  was also  indi-
cated .by  testing  4-nitrophenol  for  growth  inhibition  in  a  DNA
repair  deficient  strain of  Proteus  mirabilis  (Adler,  et  al. ,
1976).  This compound has also induced chromosome breaks  in  plants
(U.S.   EPA,  1979).   4-Nitrophenol has  failed to  show  mutagenic
effects in the  Ames  assay,  in E.  coli,  or  in the dominant  lethal
assay (U.S. EPA, 1979).
     C.   Teratogenicity and Other Reproductive Effects
          Pertinent  data could  not  be  located  in  the  available
literature regarding teratogenicity and other  reproductive effects.
     D-.   Chronic Toxicity
          A  single Russian  study (Makhinya,  1969)  reported  that
chronic  administration  of   mononitrophenol  to  mammals  produced
hepatitis, splenic hyperplasia, and neurological symptoms. Method-
ology of this study was not available  for review.
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          L<~50 va^-ues have been obtained for  two  species  of  fresh-
water  fish:  8,280  ug/1  for  bluegills,  Lepomis  macrochirus,  in
                                                              »
a  96-hour static  assay  (U.S.  SPA,  1973),  and  60,510  ug/1  for
the fathead minnow, Pimephales oromelas, in a 96-hour  flow-through
assay  (Phipps,  et  al.  unpublished manuscript).    For the  fresh-

-------
water  invertebrate,  Daphnia magna,  determined LCen  values  range



from  8,396  to 21,900  ug/1 (U.S.  EPA,  1979).   The  marine  fish,



sheepshead  minnow,  Cyprinodon  variegatus,   has  produced  deter-



mined  LCjQ  va'lue of 27,100  816  ug/1 in  a 96-hour  static  assay,



while  the  marine mysid shrimp,  Mysidopis bahia,  was  more  sensi-



tive^ with a reported LCen value of 7,170 pg/1.



     B.   Chronic Toxicity



          No chronic studies on freshwater  organisms are available.



In an  embryo-larval test  of  the marine  fish,  sheepshead  minnow,



a chronic  value  of  6,325  ug/1 was obtained.    No  chronic  testing



for marine invertebrates was available.



     C.   Plant Effects



          Four  species  of  freshwater   plants have  been  tested



with  4-nitrophenol.    The  algae,   Selenastrum capricornutum  and



Chlorella  vulgar is,  and   the  duckweed,  Lemna minor ,  were  most



sensitive  with  effective  concentrations  of  4,190,  6,950,  and



9,452  pg/1,  respectively; while the  alga,  Chlorella pyrenoidosa,



was much more resistant, with an effective concentration of 25,000



ug/1.   The  marine alga,  Skeletonema  costatum,  provided effective



concentrations of 7,370 to 7,570 pg/1 (U.S. EPA, 1979).



     D.   Residues



          No  bioconcentration  factors  for either   freshwater • or



marine species were available.



VI.  EXISTING GUIDELINES AND STANDARDS



     Neither the  human health  nor  aquatic  criteria  derived  by
                                                             9


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



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



these criteria will be changed.
                             /3S-7

-------
     A.   Human



          Available data  pertaining to  4-nitrophenol is  insuffi-



cient for deriving a criterion to protect human health.



     B.   Aquatic



          A  criterion  for  protecting  freshwater   organisms  has



been drafted  as  240  ug/1, for  a 24-hour  average   concentration,



not  to  exceed 550 ug/1.   For marine  life, a  criterion has been



drafted as  53  ug/1 for a  24-hour average,  not  to exceed 120 ug/1
                                        •


(U.S. EPA, 1979).

-------
                        4-NITROPHENOL
                          REFERENCES

Adler, Bi", et al.  1976.  Repair-defective mutants of Pro-
teus mirab'ilis as a prescreening system for the detection
of potential carcinogens.  Biol. Zbl. 95: 463.

Chemical Marketing Reporter.  1976.  Chemical profile:
p-nitrophenol.  Chem. Market. Reporter p. 9.

Fahrig, R.  1974.  Comparative mutagenicity studies with
Pesticides.  Pages 161-181 In: R. Montesano and L. Tomatis
eds.  Chemical carcinogenesls" essays.  Proc. workshop on
approaches to assess the significance of experimental chemi-
cal carcinogenesis data for man organized by IARC and the
Catholic University of Louvain, Brussels, Belgium.  IARC
Sci. Publ.  No. 10.  Int. Agency Res. Cancer, World Health
Organization.

Haller, H.D.  1978.  Degradation of mono-substituted ben-
zoates and phenols by wastewater.  Jour. Water Pollut. Con-
trol Fed; 50: 2771.

Lawford, D.J., et al.  1954..  On the metabolism of some
aromatic nitro-compounds by different species of animals.
Jour. Pharm. Pharmacol. 6: 619.

Makhinya, A.P.  1969.  Comparative hygienic and sanitary-
toxicological studies of nitrophenol isomers in relation
to their normalization in reservoir waters.  Prom Zagryazneniya
Vodoemov. 9: 84.

Phipps, G.L., et al.  The acute toxicity of phenol and sub-
stituted phenols to the fathead minnow.  (Manuscript).

U.S. EPA.  1976.  Frequency of organic compounds identified
in water.  U.S. Environ. Prot. Agency.  Contract No. EPA
600/4-76-062.

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

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

-------
                                  No.  136
           Nitrophenols

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

          APRIL 30,  1980
       J36'l

-------
                          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.
                          .. ( f f\L
                         " f ]} V I

-------
                         NITROPHENOLS
                           SUMMARY
     None of the nitrophenols have shown carcinogenic  activity.
     Mutagenicity testing has indicated positive  effects
of:  2,4-dinitrophenol in mouse bone marrow cells and  E.
coli; 2,4,6-trinitrophenol in E. coli and Salmonella;  and
4,6-dinitro-ortho-cresol in Proteus.  Weak mutagenic effects
of 4-nitrophenol have been reported  in Saccharomyces and
in Proteus.  Other mutagenic test assays have shown negative
results for these compounds.
     Teratogenic effects have been reported in the develop-
ing chick embryo following administration of 2,4-dinitro-
phenol.  This compound did" not produce teratogenic effects
in mammalian studies.  Adverse reproductive effects (embryo
toxicity)  were seen- in rats exposed  to 2,4-dinitrophenol.
     {The chronic effects of 2,4-dinitrophenol ingestion
have included cases of agranulocytosis, neuritis, functional
heart damage, and cataract formation.  Ingestion  of 4,6-
dinitro-ortho-cresol has also produced cataracts  in humans.
     One Russian study has reported cumulative toxic effects
in animals produced by the mononitrophenols; methodology
of this study was not available for review.
     Freshwater fish appeared to be the most sensitive or- •
ganism to the action of nitrophenols, wi'th acute  values
ranging from 230 to 167,000 ug/1.  The reactivities of vari-
ous nitrophenols in order of decreasing toxicity  are,  in  .
general:  2,4-dinitro-6-methylphenol, 2,4-dinitrophenol,
2-nitrophenol, 4-nitrophenol, and 2,4,6-trinitrophenol.

-------
                         NITROPHENOLS



I.   INTRODUCTION



     This profile is based on the Ambient Water Quality



Criteria Document for Nitrophenols  (U.S. EPA, 1979).



     The nitrophenols are a family of compounds which, de-



pending on the extent and position of nitro group substituents,



include the mononitrophenols, dinitrophenols, and trinitro-



phenols.  Dinitrocresols are related compounds bearing an



additional 2-position methyl group.  The mononitrophenols



(molecular weight 139.11) show boiling points from 194-279°C



(depending on the isoraeric form) and melting points of 44—



114°C.  They have a density of 1.485 and are soluble in



water.  The dinitrophenols (molecular weight 184.11) have



melting points from 63.5-144°C and show a density of 1.67



to 1.70.  Water solubility is from 0.42 to 2.3 g/1.  Tri-



nitrophenols (molecular weight 229.11) have melting points



from 96-123°C; they are slightly soluble in water.  2,4,6-



Trinitrophenol, the most widely used isomer, has a density



of 1.763 g/ml and a solubility of 1.28 g/1.  Of the six



isomers of dinitrocresol, 4,6-dinitro-o-cresol is the only



one of any commercial importance.  The physical properties



of 4,6-dinitro-o-cresol, hereafter referred to as dinitro-



ortho-cresol, include a molecular weight of 198.13, a melt-



ing point of 85.8°C and a solubility of 100,mg/l in water



(U.S.  EPA, 1979).



     Uses of the mononitrophenols include the following:



production of dyes,  pigments, Pharmaceuticals, rubber chemi-

-------
cals, lumber preservatives, photographic chemicals, and
pesticidal and fungicidal agents.  The dinitrophenols are •
used as chemical intermediates for sulfur dyes, azo dyes,
photochemicals, pest control agents, wood preservatives,
and explosives.  2,4,6-Trinitrophenol  (picric, acid) is used
for dye intermediates, germicides, tanning agents, fungi-
cides, tissue fixative, photochemicals, Pharmaceuticals,
and for the etching of metal surfaces.  Dinitro-ortho-cresol
is used primarily as a blossom-thinning agent on fruit trees
and as a fungicide, insecticide, and miticide on fruit trees
during the dormant season (U.S. EPA, 1979).

Current Production:   2-nitrophehol      5-. 7.5x10  tons/year  .(1976)
                      4-nitrophenol        17.5x10  tons/year  (1976)
                                                  2
                      2,4-dinitrophenol     4.3x10  tons/year  (1968)

     The nitrophenols may be formed via microbial degrada-
tion or photodegradation of pesticides (e.g., parathion)
containing the nitrophenol moiety  (U.S. EPA,   1979).  Partial
microbial degradation of certain nitrophenols has been shown,
particularly by acclimated microorganisms.  Mononitrophenols
appear to be efficiently degraded by unacclimated microorgan-
isms (Haller, 1978).
II.  EXPOSURE
     The lack of monitoring data on the nitrophenols makes
it difficult to assess exposure from water, inhalation,
and foods.  Nitrophenols in water have been detected in

                              •a-
                           -V 6 W "

-------
effluents from chemical plants  (U.S. EPA,  1976;  1979) or


following dumping of explosives  (Harris, et al.  1946).


Dermal absorption of mononitrophenols, dinitrophenols,  tri-


nitrophenols  (picric acid), and dinitro-ortho-cresol  (DNOC)


has been detected .(U.S. EPA, 1979).


     Exposure to nitrophenols appears to be primarily through


occupational contact (chemical plants, pesticide applica-


tion) .  Contaminated water may result in isolated poisoning


incidents.
                                                    •

     The U.S. EPA (1979) has estimated weighted  average


bioconcentration factors for the following nitrophenols:


2-nitrophenol, 4.0; 4-nitrophenoJL, 4.9; 2,4-dinitrophenol,


2.4; 2,4,6-trinitrophenol, 6.0; and 4 ,6-dinitrocresol,  7.5


for fish and shellfish consumed by Americans.  This estimate


is based on octanol/water partition coefficients.


III. PHARMACOKINETICS


     A.   Absorption


          Specific data on the absorption  of the mononitro-


phenols is not available.  The dinitrophenols are readily


absorbed following oral, inhalation, or dermal administra-


tion.  Data on the absorption of trinitrophenols is not


available.  Animal studies with oral administration of  2,4,6-


trinitrophenol indicate that it is readil-y absorbed from


the gastrointestinal tract.  Dinitro-ortho-cresol is readily


absorbed through the skin, the respiratory tract, and the
                                                          »

gastrointestinal tract in humans (NIOSH, 1978).

-------
     B.   Distribution
          No information on the distribution of the raono-
nitrophenols is available.  Dinitrophenol blood levels rise
rapidly af-ter absorption, with little subsequent distribu-
tion or storage at tissue sites (U.S. 2PA, 1979) .  2,4,6-
Trinitrophenol and dinitro-ortho-cresol have been found
to stain several body tissues; however, the compounds may
be bound to serum proteins, thus producing non-specific
organ distribution (U.S. SPA, 1979).
     C.   Metabolism
          Metabolism of the nitrophenols occurs through
conjugation, reduction of nitro groups to amino groups,
or oxidation to dihydric-nitrophenols (U.S. EPA, 1979) .
These reactions are mediated primarily by liver enzyme systems,
although other tissues show lower metabolizing activity
(U.S. EPA, 1979) .   The metabolism of dinitro-ortho-cresol
is very slow in man as compared to that observed in animal
studies (King and Harvey, 1953) .
     Q.   Excretion
          Evidence from human poisoning with parathion indi-
cates that excretion of 4-nitrophenol in the urine is quite
rapid (Arteberry,  at al. 1961).   Experiments with urinary
clearance of dinitrophenols in several animal species indi-
cate rapid elimination of these compounds (Harvey,  1959) .
2,4,6-Trinitrophenol has been detected in the urine of ex-
posed human subjects indicating at least partial urinary
elimination (Harris,  et al. 1946).  The experiments of Parker
                           136-7

-------
and coworkers  (1951) in several animal species  indicate



that dinitro-ortho-cresol is rapidly excreted following



injection; however, Harvey, et al.  (1951) have  shown  slow



excretion 'of dinitro-ortho-cresol in human volunteers given



the compound orally.



IV..  EFFECTS



     A.   Carcinogenicity



          There are no available data to indicate that the



mononitrophenols are carcinogenic.  Both 2- and 4-nitrophenol



failed to show promoting activity for mouse skin tumors



(Boutwell and Bosch, 1959); this same study failed to show



promoting activity for 2,4-dinitrophenol.  No evidence is



available to indicate that dinitrophenols, trinitrophenols,



or dinitro-ortho-cresol produce any carcinogenic effects



(U.S. EPA, 1979).



     B.   Mutagenicity



          A weak mutagenic effect was detected  in Saccharo-



myces cerevisiae for 4-nitrophenol  (Fahrig, 1974); this



was also indicated by testing 4-nitrophenol for growth in-



hibition in a DNA repair deficient strain of Proteus mirabilis



(Adler, et al. 1976).  This compound has also induced chromo-



some breaks in plants (U.S. EPA, 1979).  4-Nitrophenol has



failed to show mutagenic effects in the Ames assay, in E.



coli, or in the dominant lethal assay (U.S.,EPA, 1979).



          Testing of 2,4-dinitrophenol has indicated muta-



genic effects in E. coli  (Demerec, et al. 1951)  and damage'



in murine bone marrow cells (chromatid breaks)  (Mitra and



iManna, 1971) .  Tn vitro assays of unscheduled DNA synthesis

-------
(Friedman and Staub, 1976) and DNA damage  induced  during
call culture (Swenberg, et ai. 1976)  failed  to  show  positive
results with this compound.
          '2,4,6-Trinitrophenol has produced  mutations  in
E. coli and Salmonella assays  (Demerec, et al.  1951; Yoshikawa,
et al. 1976) .  Testing in Drosop'nila  has failed to indicate
mutagenic activity.
          Adler, et al. (1976) have reported that  dinitro-
ortho-cresol shows some evidence of producing DNA  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.   Teratogenicity
          No information is available to indicate  that mono-
nitrophenols, 2,4,6-trinitrophenol, or dinitro-ortho-cresol
produce teratogenic effects.
          2,4-Dinitrophenol has produced developmental abnor-
malities in the chick embryo  (Bowman, 1967;  Miyamoto,  et
al. 1975).  No teratogenic effects were observed following
intragastric administration to rats (Wulff,  et  al. 1935)
or intraperitoneal administration to mice  (Gibson, 1973).
     D.   Other Reproductive Effects
          Feeding of 2,4-dinitrophenol to. pregnant rats
produced an increased mortality in offspring  (Wulff, et
al. 1935); similarly, intraperitoneal administration of
the compound to mice induced embryotoxicity  (Gibson, 1973) '

-------
Influence of the compound on maternal health may have contri-
buted to these effects  (U.S. EPA, 1979).
     E.   Chronic Toxicity
         • Chronic administration of mononitrophenols to
mammals has been reported to produce hepatitis, splenic
hyperplasia, and neurological symptoms  in a single Russian
study (Makhinya, 1969).  Methodology of this study was not
available for review.
          Use of 2,4-dinitrophenol as a human dieting aid
has produced some cases of agranulocytosis, neuritis, func-
tional heart damage, and a large number of cases of cataracts
(Homer, 1942).  Cataracts have also been reported in patients
poisoned with dinitro-ortho-cresol (NIOSH, 1978).
          Human effects resulting from  2,4,6-trinitrophenol
exposure have been reported as temporary impairment of speech,
memory, walking, and reflexes (Dennie, et al. 1929).
     F.   Other Relevant Information
          A synergistic action in producing teratogenic
effects in the developing chick embryo has been reported
with a combination of 2,4-dinitrophenol and insulin (Landauer
and Clark, 1964).
          The combination of 2,4,6-trinitrophenol and opioids
or minor analgesics produced an increase in analgesia (Huidobro,
1971).
          2,4-Dinitrophenol is a classical uncoupler of
oxidative phosphorylation, which accounts for its marked
acute toxicity.  Dinitro-ortho-cresol is also well known
for its activity as an uncoupler.

-------
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Freshwater fish LC   values reported  for  the  blue-
gill (Lepomis macrochinus) ranged from 230 to 167,000 ug/1
and for the juvenile fathead minnow  (Pimephales promelas),
from 2,040 to 60,510 ug/1.  The order of decreasing toxicity
for five nitrophenols examined was:  2,4-dinitro-6-methyl
phenol, 2,4-dinitrophenol, 2-nitrophenol, 4-nitrophenol,
    •
2,4,5-trinitrophenol (U.S. EPA, 1979).  For three of the
phenols tested with both the bluegill and fathead minnow,
                                              »
the bluegill appeared more sensitive.  In static bioassays
with the freshwater invertebrate, Daphnia magna, 48-hour
LC5Q values of 4,090 to 4,710; 8,396 to 21,900; and 84,700
ug/1 were reported for 2,4-dinitrophenol, 4-nitrophenol
and 2,4,6-trinitrophenol, respectively (U.S. ,SPA, 1979).
The marine fish, sheepshead minnow (Cyprinodon variegatus),
was the only fish species acutely tested for three nitro-
phenols, with reported LC5Q values of 29,400; 27,100 and
134,000 ug/1 being obtained for 2,4-dinitrophenol, 4-nitro-
phenol, and 2,4,6-trinitrophenol.  Observed LC.-Q values
of 4,350; 7,170 and 19,700 ug/1 were reported for the mysid
shrimp  (Mysidopsis bahia) for the same three formulations,
respectively.
     3.   Chronic Toxicity
          Pertinent information on the chronic effects  on
freshwater species could not be located in the available
literature searches.  The only chronic test on a marine

-------
species was an embryo-larval assay of the sheepshead minnow
that produced a chronic value of 6,325 ug/1  (U.S. EPA, 1978).
Pertinent information relative to chronic effects on marine
invertebrates could not be located in the available literature.
     C.   Plant Effects
          The effects of various nitrophenols vary widely
among species of freshwater plants and according to the
formulation of nitrophenol tested.  The duckweed, Lemna
minor, was the most sensitive plant tested with 2,4-dinitro-
phenol and was the most resistant with 2-nitrophenol, hav-
ing effective concentrations (50 percent growth reduction,
time unspecified)ranging from 1,472 to 62,550 ug/1 for the
two respective formulations.  The marine alga, Skeletonema
costatum, appeared to be slightly more resistant than fresh-
water species tested, with effective concentrations ranging
from 7,370 to 141,000 ug/1 for 4-nitrophenol and 2,4,6-tri-
nitrophenol, respectively.
     D.   Residues
          Bioconcentration factors were not determined for
any freshwater or marine species.  However, based on octanol/
water partition coefficients, bioconcentration factors were
estimated as 8.1, 21, and 26 for 2,4-dinitrophenol, 2,4,5-
trinitrophenol, and 2,4-dinitro-6-dimethylphenol, respectively.
VI.  EXISTING GUIDELINES AND STANDARDS
     The human health and aquatic criteria derived by U.S.
EPA (1979), which are summarized below, have not yet gone
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
                          / 3 6-

-------
     A.   Human
          Eight-hour TWA exposures for 2,4,6-trinitrophenol
(0.1 mg/m )  and 4,6-dinitro-ortho-cresol  (0.2 rag/m ) have
been established by the ACGIH (1971).
          Draft, water quality criteria for the following
nitrophenols have been estimated, by U.S. SPA  (1979) based
on adverse effects data:  dinitrophenols - 63.6 pg/1; tri-
nitrophenols - 10 /ig/1; and dinitrocresols - 12.3 }ig/l.
     B.   Aquatic
          Criteria drafted to protect freshwater life from
nitrophenols follow:  57 ^g/1 as a 24-hour average concen-
tration, not to exceed 130 ug/1, for 2,4-dinitro-6-methyl-
phenol; 79 jug/1, not to exceed 180 ug/1, for 2,4-dinitro-
phenol; 240 ug/1, not to exceed 550 ug/1, for 4-nitrophenol;
2,700 pg/1, not to exceed 6,200 pg/1, for 2-nitrophenol;
and 1,508 ug/1, not to exceed 3,400 ug/1, for 2,4,6-trinitro-
phenol.  For marine life the following criteria have been
drafted as 24-hour average concentrations:  37 ug/1, not
to exceed 84 ug/1, for 2,4-dinitrophenol; 53 pg/1, not to
exceed 120 pg/1, for 4-nitrophenol; and 150 ug/1, not to
exceed 340  g/1, for 2,4,6-trinitrophenol.
                             if (11
                            J U I B^
                         I36-/3

-------
                        NITROPHENOLS

                         REFERENCES

Adler, B., et al.  1976.  Repair-defective mutants  of  Proteus
mirabilis as a prescreening system for  the detection of  po-
tential carcinogens.  Biol. Zbl.  95: 463.

American Conference of Governmental Industrial Hygienists.
1971.  Documentation of the threshold limit  values  for sub-
stances in workroom air.  Vol. 1. 3rd ed.  Cincinnati, Ohio.

Anderson, K.J., et al.  1972.  Evaluation of  herbicides  for
possible mutagenic properties.  Jour. Agric.  Food Chem.   20:
649.

Arterberry, J.D., et al.  1961.  Exposure to  parathion:   Mea-
surement by blood cholinesterase level  and urinary  p-nitro-
phenol excretion.  Arch. Environ. Health  3:  476.

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

Bowman, P.  1967.  The effect of 2,4-dinitrophenol  on  the
development of early chick embryos.  Jour. Embryol. Exp..
Morphol.  17: 425.

Demerec, M., et al.  1951.  A survey of chemicals for  muta-
genic action on E_. coli.  Am. Natur.  85: 119.

Dennie, C.C., et al.  1929.  Toxic reactions  produced  by  the
application of trinitrophenol (picric acid).  Arch. Dermatol.
Sypnilol.  20: 698.

Fahrig, R.  1974.  Comparative mutagenicity  studies with Pes-
ticides.  Pages 161-181 In; R. Montesano and  L. Tomatis.
(eds.)  Chemical carcinogenesis essays.  Proc. workshop on
approaches to assess the significance of experimental  chemi-
cal carcinogenesis data for man.  Organized by IARC and the
Catholic University of Louvain, Brussels, Belgium.  IARC Sci.
Publ. No.  10.  Int. Agency Res. Cancer, World Health  Organi-
zation.

Friedman, M.A., and J. Staub.  1976.  Inhibition of mouse
testicular DMA synthesis by mutagens and carcinogens as a po-
tential simple mammalian assay for mutagenesis.  Mutat. Res.
37: 67.

Gibson, J.E.  1973.  Teratology studies in mice with 2-sac-
butyl-4, 6-dinitrophenol (dinoseb).  Food Cosmet. Toxicol.'
11: 31.

-------
Haller, H.D,   1978.   Degradation of mono-substituted benzo-
ates and ohenols  by wastewater.   Jour.  Water Pollut. Control
Fed.   50:  2771.

Harris, A.H.,  et  al.   1946.   Hematuria  due to picric acid
poisoning  at a naval  anchorage  in Japan.   Am. Jour.  Pub.
Health  3.6: 727.

Harvey, D.G.   1959.   On  the  metabolism  of some aromatic nitro
compounds  by different species of animal.   Part III.  The
toxicity of the dinitrophenols,  with a  note on the effects of
high environmental temperatures.   Jour.  Pharm. Pharmacol.
11: 462.                                       »•

Harvey, D.G.,  et  al.   1951.   Poisoning  by dinitro-ortho-cre-
sol.  Some observations  on the effects  of  dinitro-ortho-cre-
sol administration by mouth  to human vplunteers.   3r.  Med.
Jour.  2:  13.

Horner, W.D.   1942.   Dinitrophenol and  its relation  to forma-
tion to cataracts.  Arch. Ophthal.   27:  1097.

Huidobro,  F.   1971.   Action  of picric acid on the  effects of
some drugs acting on  the  central  nervous  system, with  special
reference  to opiods.   Arch.  Int.  Pharmacodyn Ther.   192:.
362.

Xing, E.,  and  D.G. Harvey.   1353.   Some  observations on the
absorption and excretion  of  4,6-dinitro-o-creosol  .(DNOC). I.
Blood dinitro-o-cresol levels in  the cat  and rabbit  following
different methods of  absorption.   Biochem.  Jour.   53:  185.

Landauer, W. ,  and E.  Clark.   1964.   Uncouplers of  oxidative
ohosphorylation and teratogenic  activity  of  insulin.   Nature
204: 285.

Makhinya, A.P.  1969.  Comparative hygienic  and  sanitary
toxicological  studies  of  nitrophenol isomers in  relation to
their normalization in reservoir  waters.   Prom.  Zagryazneniya
Vodoemov.  9:  84. (Translation).

Mitra, A.B., and G.K.  Manna.  1971.   Effect  of some  phenolic
compounds on chromosomes  of  bone  marrow cells of mice.   In-
dian Jour. Med. Res.   59: 1442.

Miyamoto, K.,   et al.   1975.  Deficient myelination by  2,4-
dinitrophenol  administration  in  early stage  of development.
Teratology  12: 204.

Nagy, A., et al.  1975.   The correct mutagenic affect  of pes-
ticides on Escherichia coli WP2  strain.  Acta. Microbiol. '
Acad.  Sci. Hung.22: 309.

-------
National Institute for Occupational Safety and Health.   1978.
Criteria for a recommended standard: Occupational exposure  to
dinitro-ortho-creosol.  Dep.. Health Edu. Welfare, Washing-
ton, D.C.

Parker, V.H., et al.  1951.  Some observations on the  toxic
properties of 3,5-dinitro-ortho-cresol.  Br. Jour. Ind. .Med.
9: 226.

Swenberg,' J.A., et al.  1976.  In vitro DNA damage/akaline
elution assay for predicting carcinogenic potential.
Biochem. Biophys. Res. Cbiranun.  72: 732.

U.S. EPA.  1976.  Frequency of organic compounds identified
in water.  U.S. Environ. Prot. Agency.  Contract No. EPA
600/4-76-062.

U.S. EPA.  1978.  In-depth studies on health and environmen-
tal impacts of selected water pollutants.  Contract No.
6801-4646.

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

Wulff, L.M.B., et al.  1935.  Some effects of alpha-dinitro-
phenol on pregnancy in the white rat.  Proc. Soc. Exp.  Biol.
Med.  32: 678.

Yoshikawa, K., et al.  1976.  Studies on the mutagenicity of
hair-dye.  Kokurltsu Eisei Shikenjo  94: 28.

-------
                                       No.  137
            NItrosamines

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



nitrosamines and has found sufficient evidence to indicate



that this compound is carcinogenic.

-------
                                 NITROSAMINE5
                                    Summary

     Nitrosamines and nitrosamides  are  widespread in the environment and can
also be  produced end.ogenously by  nitrosation  of constituents  of food.  Ni-
trosamines  and  nitrosamides are  considered to  be  among the  most potent of
all carcinogenic,  mutagenic, and  teratogenic  agents  known.   The  livers of
rats chronically exposed to nitrosamines exhibit pathological changes.
     Toxicity data  examining the effects  of nitrosamines on  aquatic organ-
isms is  scant.   For  freshwater  life forms, acute toxicity levels of 5,850 to
7,760 ug/1  were reported,  while for marine fish an  acute  value  of nearly
3,300,000 ug/1  was  reported (both values for N-nitrosodiphenylamine).  N-ni-
trosodimethylamine  has  been shown  to   induce  hepatocellular carcinoma .in
rainbow trout.
                                    i / i &
                                *~) v> I

-------
                                 NITROSAMINES
I.   INTRODUCTION
     This  profile is  based on  the  Ambient  Water  Quality Criteria  Document
for Nitrosamines  (U.S. EPA,  1979).
     The  nitrosamines _(and  nitrosamides)  belong to a  large group of  chemi-
cals generally  called N-nitroso compounds.   Because they  frequently coexist
with N-nitrosamines  in the  environment and  are  structurally related  to  ni-
trosamines,  nitrosamides  .are also  included in the  U.S.  EPA (1979)  document
and in .this profile.
     The nitrosamines  vary  widely  in their physical properties and may exist
as solids, liquids or gases.  Nitrosamines of low molecular  weight are vola-
tile at room